PL2070538T3

Tamper resistant oral pharmaceutical dosage forms comprising an opioid analgesic

Abstract

This record has no abstract on file.

Term

0.9 yearsto projected expiry

Projected expiry 24 August 2027, counted from filing; an application has no term until it is granted.

28 claims: 19 independent, 9 dependent

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Zastrzeżenia patentowe Stała doustna farmaceutyczna postać dawkowania o przedłużonym uwalnianiu, zawierająca preparat matrycowy o przedłużonym uwalnianiu, preparat matrycowy zawierający kompozycję zawierającą co najmniej jeden środek aktywny oraz co najmniej jeden poli(tlenek etylenu) o przybliżonej masie cząsteczkowej wynoszącej na podstawie pomiarów reologicznych co najmniej 1000000, przy czym preparat matrycowy utwardzony jest w temperaturze co najmniej około 60 o C przez czas wynoszący co najmniej 1 minutę, w formie tabletki lub multicząstek, przy czym tabletka lub poszczególne multicząstki mogą być co najmniej spłaszczone bez rozkruszenia, charakteryzująca się grubością tabletki lub poszczególnych multicząstekpo spłaszczeniu odpowiadającą nie więcej niż około 60% grubości tabletki lub poszczególnych multicząstek przed spłaszczeniem niespłaszczona niespłaszczone w której ta tabletka lub spłaszczona lub spłaszczone lub multicząstki zapewniają szybkość rozpuszczania in-vitro, przy pomiarze w USP Apparatus 1 (basket) przy 100 symulowanego płynu zawierającego 40% obrotach na minutę w 900 ml żołądkowego bez enzymów (SGF) temperaturze 37°C, ilością uwalniania charakteryzującą środka aktywnego odchyla się nie etanolu w się procentową po 0,5 godzinie rozpuszczania, która więcej niż około 20 % punktów od odpowiedniej szybkości rozpuszczenia in-vitro zmierzonej w USP Apparatus 1 (basket) przy 100 obrotach na minutę w 900 ml symulowanego płynu żołądkowego bez enzymów (SGF) w temperaturze 37°C bez etanolu, z zastosowaniem odpowiednio spłaszczonej i nie-spłaszczonej tabletki porównawczej lub spłaszczonych multicząstek porównawczych. Stała doustna farmaceutyczna przedłużonym uwalnianiu według nie-spłaszczonych postać zastrz. tabletka lub poszczególne multicząstki dawkowania o 1, w której mogą być co 287 najmniej spłaszczone bez rozkruszenia, charakteryzująca się grubością tabletki lub poszczególnych multicząstek po spłaszczeniu odpowiadającą nie więcej niż około 60%, lub nie więcej niż około 50%, lub nie więcej niż około 40% lub nie więcej niż około 30% lub nie więcej niż około 20% lub nie więcej niż około 16% grubości tabletki lub poszczególnych multicząstek przed spłaszczeniem i w której ta spłaszczona lub niespłaszczona tabletka lub spłaszczone lub niespłaszczone multicząstki zapewniają szybkość rozpuszczania in-vitro, przy pomiarze w USP Apparatus 1 (basket) przy 100 obrotach na minutę w 900 ml symulowanego płynu żołądkowego bez enzymów (SGF) zawierającego 40% etanolu w temperaturze 37°C, charakteryzującą się procentową ilością uwalniania środka aktywnego po 0,5 godzinie rozpuszczania, która odchyla się nie więcej niż około 20 % punktów lub 15 % punktów od odpowiedniej szybkości rozpuszczenia in-vitro zmierzonej w USP Apparatus 1 (basket) przy 100 obrotach na minutę w 900 ml symulowanego płynu żołądkowego bez enzymów (SGF) w temperaturze 37°C bez etanolu, z zastosowaniem odpowiednio spłaszczonej i niespłaszczonej tabletki porównawczej lub spłaszczonych i niespłaszczonych multicząstek porównawczych. 3. Stała doustna farmaceutyczna postać dawkowania o przedłużonym uwalnianiu według zastrz. 1 lub 2, w której gęstość preparatu matrycowego o przedłużonym uwalnianiu jest równa lub mniejsza niż około 1,20 g/cm 3 , korzystnie równa lub mniejsza niż około 1,19 g/cm 3 . 4. Stała doustna farmaceutyczna postać dawkowania o przedłużonym uwalnianiu według zastrz. 1, w której preparat matrycowy o przedłużonym uwalnianiu po przechowywaniu w 25 o C i 60 % wilgotności względnej (RH) przez co najmniej miesiąc zapewnia szybkość rozpuszczania przy pomiarze w USP Apparatus 1 (basket) przy 100 obrotach na minutę w 900 ml symulowanego płynu żołądkowego bez enzymów (SGF) w temperaturze 37°C, charakteryzującą się procentową ilością uwolnionego środka aktywnego po 1, 4 i 12 godzinach rozpuszczania, która odchyla się nie więcej niż około 15% punktów od odpowiadającej prędkości 288 rozpuszczania in vitro preparatu odniesienia przed przechowywaniem. 5. Stała doustna farmaceutyczna postać dawkowania o przedłużonym uwalnianiu według zastrz. 4 w której preparat matrycowy o przedłużonym uwalnianiu był przechowywany w 40 0 C i 75%wilgotności względnej (RH). 6. Stała doustna farmaceutyczna postać dawkowania o przedłużonym uwalnianiu według zastrz. 1, w której preparat matrycowy o przedłużonym uwalnianiu po przechowywaniu w 25 c C i 60% wilgotności względnej (RH) przez co najmniej miesiąc zawiera ilość co najmniej jednego środka aktywnego w % (wagowo) w odniesieniu do zawartości środka aktywnego w preparacie matrycowym o przedłużonym uwalnianiu zadeklarowanej na etykiecie, która odchyla się nie więcej niż około 10 % punktów od odpowiadającej ilości środka aktywnego w % (wagowo) w odniesieniu do zawartości zadeklarowanej na etykiecie środka aktywnego w preparacie matrycowym o przedłużonym uwalnianiu preparatu odniesienia przed przechowywaniem. 7. Stała doustna farmaceutyczna postać dawkowania o przedłużonym uwalnianiu według zastrz. 6, w której preparat matrycowy o przedłużonym uwalnianiu był przechowywany w 40 0 C i 75% wilgotności względnej (RH). 8. Stała doustna farmaceutyczna postać dawkowania o przedłużonym uwalnianiu według zastrz. 1, w którym dawka zapewnia szybkość rozpuszczania, która przy mierzeniu w USP Apparatus 1 (basket) przy 100 obrotach na minutę w 900 ml symulowanego płynu żołądkowego bez enzymów (SGF) w temperaturze 37°C, zawiera się pomiędzy 12,5 i 55% (wagowo) środka aktywnego uwolnionego po 1 godzinie, pomiędzy 25 i 65 % (wagowo) środka aktywnego uwolnionego po 2 godzinach, pomiędzy 45 i 85 % (wagowo) środka aktywnego uwolnionego po 4 godzinach oraz pomiędzy 55 i 95% (wagowo) środka aktywnego uwolnionego po 6 godzinach. 9. Stała doustna farmaceutyczna postać dawkowania o przedłużonym uwalnianiu według zastrz. 1, w której środkiem aktywnym jest chlorowodorek oksykodonu i w której postać dawkowania gdy badana w porównawczym 289 badaniu klinicznym jest biorównoważna produktowi handlowemu OxyContin TM . 10. Stała doustna farmaceutyczna postać dawkowania o przedłużonym uwalnianiu według zastrz. 1, w której środkiem aktywnym jest chlorowodorek oksykodonu i w której postać dawkowania zawierająca 10 mg chlorowodorku oksykodonu gdy badana w porównawczym badaniu klinicznym jest biorównoważna tabletce odniesienia zawierającej 10 mg chlorowodorku oksykodonu w preparacie matrycowym zawierającym:a) chlorowodorek oksykodonu: 10,0 mg/tabletka b) laktozę (suszoną rozpryskowo): 69,25 mg/tabletka c) Powidon: 5,0 mg/tabletka d) Eudragit ® RS 30D (części stałe) : 10,0 mg/tabletka e) Triacetin ® : 2,0 mg/tabletka f) alkohol stearylowy: 25,0 mg/tabletka g) talk: 2,5 mg/tabletka h) stearynian magnezu: 1,25 mg/tabletka;oraz, przy czym tabletkę porównawczą wytwarza się postępując według następujących etapów: 1. Eudragit ® RS 30D i Triacetin® łączy się podczas przepuszczania przez sito o numerze oczka (mesh) 60, i miesza, stosując małą siłę ścinania przez w przybliżeniu 5 minut lub aż do zaobserwowania jednorodnej dyspersji
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Chlorowodorek oksykodonu, laktozę, i powidon umieszcza się w naczyniu fluidyzacyjnego granulatora/suszarki (FBD), i zawiesinę rozpyla się na proszek w złożu fluidalnym
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Po zakończeniu opryskiwania, granulat, jeśli to konieczne, przepuszcza się przez sito o nr 12, w celu zmniejszenia wielkości grudek
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Suchy granulat umieszcza się w mieszalniku
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Jednocześnie, alkohol stearylowy w wymaganej ilości topi się w temperaturze około 70°C
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Stopiony alkohol stearylowy, mieszając, dodaje się do granulatu
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Woskowany granulat przenosi się do fluidyzacyjnego granulatora/suszarki lub na tacę i pozostawia do ochłodzenia do temperatury pokojowej lub poniżej 290 11. 12. 13. 14.
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Ochłodzony granulat następnie przepuszcza się przez sito o nr 12
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Woskowany granulat umieszcza się w mikserze/mieszalniku i traktuje się talkiem i stearynianem magnezu w wymaganych ilościach przez około 3 minuty.
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Granulat prasuje się na 125 mg tabletki za pomocą odpowiedniego urządzenia do tabletkowania. Postać dawkowania o przedłużonym uwalnianiu według zastrz. 1 do 10, w której kompozycja zawiera co najmniej 80% (wagowo) poli(tlenku etylenu). Postać dawkowania o przedłużonym uwalnianiu według zastrz. 11, w której kompozycja zawiera co najmniej 80% (wagowo) poli(tlenku etylenu) o przybliżonej masie cząsteczkowej wynoszącej na podstawie pomiarów reologicznych co najmniej 1000000. Postać dawkowania o przedłużonym uwalnianiu według któregokolwiek z zastrz. 1-8, w której środkiem aktywnym jest opioidowy środek przeciwbólowy. Postać dawkowania o przedłużonym uwalnianiu według zastrz. 13, w której opioidowy środek przeciwbólowy wybrany jest z grupy obejmującej alfentanyl, alliloprodyna, alfaprodyna, anilerydyna, benzylomorfina, bezytramid, kodeina, diampromid, buprenorfina, dezomorfina, butorfanol, dekstromoramid, klonitazen, dezocyna, diamorfon, dihydrokodeina, dihydromorfina, dimenoksadol, dimefeptanol, dimetylotiambuten, maślan dioksafetylu, dipipanon, eptazocyna, etoheptazyna, etylometylotiambuten, etylomorfina, etonitazen, etorfina, pochodne, izometadon, lofentanyl, metazocyna, metadon, metopon, morfina, narceina, nikomorfina, norleworfanol, nalorfina, nalbufen, normorfina, norpipanon, dihydroetorfina, fentanyl i hydromorfon, hydroksypetydyna, leworfanol, lewofenacylomorfan, meptazinol, myrofyna, normetadon, hydrokodon, ketobemidon, meperydyna, opium, oksykodon, oksymorfon, papaweretum, fenadokson, piminodyna, fenomorfan, pirytramid, fenazocyna, profeptazyna, pentazocyna, fenoperydyna, promedol, properydyna, propoksyfen, sufentanyl, tilidyna, tramadol, 291 ich farmaceutycznie dopuszczalne sole, hydraty i solwaty, mieszaniny dowolnych z powyższych.
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15. Postać dawkowania o przedłużonym uwalnianiu według zastrz. 13, w której opioidowy środek przeciwbólowy jest wybrany z grupy obejmującej kodeinę, morfinę, oksykodon, hydrokodon, hydromorfon lub oksymorfon lub ich farmaceutycznie dopuszczalne sole, hydraty lub solwaty, mieszaniny dowolnych z powyższych.
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16. Postać dawkowania o przedłużonym uwalnianiu według zastrz. 9 lub 14, w której opoidowym środkiem przeciwbólowym jest chlorowodorek oksykodonu oraz postać dawkowania zawiera od około 5 mg do około 500 mg chlorowodorku oksykodonu.
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17. Postać dawkowania o przedłużonym uwalnianiu według zastrz. 16, w której postać dawkowania zawiera 5 mg, 7,5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 60 mg, 80 mg, 90 mg, 120 mg lub 160 mg chlorowodorku oksykodonu.
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18. Postać dawkowania o przedłużonym uwalnianiu według któregokolwiek z zastrz. 9, 10 i 13, w której opioidowym środkiem przeciwbólowym jest chlorowodorek oksykodonu o poziomie 14-hydroksykodeinonu poniżej około 25 ppm, korzystnie poniżej około 15 ppm, poniżej około 10 ppm, lub poniżej około 5 ppm.
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19. Postać dawkowania o przedłużonym uwalnianiu według zastrz. 13, w której opioidowym środkiem przeciwbólowym jest chlorowodorek oksymorfonu oraz postać dawkowania zawiera od około 1 mg do około 500 mg chlorowodorku oksymorfonu.
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20. Postać dawkowania o przedłużonym uwalnianiu według zastrz. 19w której postać dawkowania zawiera 5 mg, 7,5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 60 mg, 80 mg, 90 mg, 120 mg lub 160 mg chlorowodorku oksymorfonu.
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21. Postać dawkowania o przedłużonym uwalnianiu według zastrz. 13 której opioidowym środkiem przeciwbólowym jest chlorowodorek hydromorfonu oraz postać dawkowania zawiera od około 1 mg do około 100 mg chlorowodorku hydromorfonu.
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22. Postać dawkowania o przedłużonym uwalnianiu według zastrz. 21, w której postać dawkowania zawiera 2 mg, 4 292
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23. mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, 48 mg lub 64 mg
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27.
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28. chlorowodorku hydromorfonu. Postać dawkowania o przedłużonym uwalnianiu według któregokolwiek z zastrz. 1 do 22, która jest w formie tabletki utworzonej poprzez bezpośrednie upakowanie kompozycji i utwardzenie poprzez co najmniej poddanie wspomnianej tabletki działaniu temperatury co najmniej około 60 o C lub co najmniej około 62 o C przez czas co najmniej 1 minuty, korzystnie co najmniej około 5 minut lub co najmniej około 15 minut. Postać dawkowania o przedłużonym uwalnianiu według któregokolwiek z zastrz. 1 do 23, w formie tabletki i która jest pokryta warstwą proszku poli(tlenku etylenu) w celu wytworzenia tabletki, która posiada rdzeń tabletki oraz warstwę poli(tlenku etylenu) otaczającą rdzeń tabletki. Postać dawkowania o przedłużonym uwalnianiu według któregokolwiek z zastrz. 1 do 23, która jest w formie piętrowej dwu lub wielowarstwowej tabletki której jedna z warstw zawiera preparat o przedłużonym uwalnianiu i jedna spośród innych warstw zawiera preparat o natychmiastowym uwalnianiu aktywnego środka. Postać dawkowania o przedłużonym uwalnianiu według zastrz. 25, w której preparat o przedłużonym uwalnianiu oraz preparat o natychmiastowym uwalnianiu zawierają takie same lub różne środki aktywne. Postać dawkowania o przedłużonym uwalnianiu według zastrz. 25, w której preparat o przedłużonym uwalnianiu zawiera opioidowy środek przeciwbólowy oraz preparat o natychmiastowym uwalnianiu zawiera nie-opioidowy środek przeciwbólowy. Zastosowanie postaci dawkowania według któregokolwiek z zastrz. 1 do 27 do wytwarzania leku do leczenia bólu, w którym postać dawkowania zawiera opioidowy środek przeciwbólowy. Zastosowanie cząsteczkowej reologicznych poli(tlenku wynoszącej co najmniej etylenu) o dużej masie na podstawie pomiarów 1000000 jako tworzącego matrycę do wytwarzania stałej materiału doustnej
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29. 293 farmaceutycznej postaci dawkowania o przedłużonym uwalnianiu zawierającej środek aktywny wybrany z opioidów w celu nadania stałej doustnej farmaceutycznej postaci dawkowania odporności na ekstrakcję alkoholem.
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30. Tabletka farmaceutyczna według poprzednich zastrzeżeń posiadająca podczas badania metodą wciskania wgłębnika siłę kruszenia co najmniej 110 N, korzystnie 120 N, korzystniej 130 N i i jeszcze korzystniej 140 N,.
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31. Tabletka farmaceutyczna według poprzednich zastrzeżeń posiadająca podczas badania metodą wciskania wgłębnika odległośćgłębokości penetracji do pęknięcia co najmniej 1.0 mm, co najmniej 1,2 mm., korzystniej 1,4 mm, jeszcze korzystniej 1,6 mm
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32. Tabletka farmaceutyczna według poprzednich zastrzeżeń posiadająca odporność na pracę bez rozkruszenia co najmniej 0,06 J. 294 Fig. 1 Fig. 2 295 Fig. 3 Fig. 4 296 Fig. 5 Fig. 6 297 Fig. 7 Fig. 8 298 Fig. 9 299 Utwardzanie według przykładu 13.1 Fig. 10 Temperature - temperatura Time (min) - czas (minuty) Inlet set - ustawiona temperatura powietrza na wlocie Actual - faktyczna temperatura Probe - temperatura zmierzona z zastosowaniem sondy Exhaust - temperatura powietrza na wylocie 300 Utwardzanie według przykładu 13.2 Profil temperaturowy Fig. 11 Temperature - temperatura Time (min) - czas (minuty) Inlet set - ustawiona temperatura powietrza na wlocie Actual - faktyczna temperatura Probe - temperatura zmierzona z zastosowaniem sondy Exhaust - temperatura powietrza na wylocie 301 Utwardzanie według przykładu 13.3 Profil temperaturowy Fig. 12 Temperature - temperatura Time (min) - czas (minuty) Inlet set - ustawiona temperatura powietrza na wlocie Actual - faktyczna temperatura Probe - temperatura zmierzona z zastosowaniem sondy Exhaust - temperatura powietrza na wylocie 302 Utwardzanie według przykładu 13.4 Profil temperaturowy Fig. 13 Temperature - temperatura Time (min) - czas (minuty) Inlet set - ustawiona temperatura powietrza na wlocie Actual -faktyczna temperatura Probe - temperatura zmierzona z zastosowaniem sondy Exhaust - temperatura powietrza na wylocie 303 Utwardzanie według przykładu 13.5 Fig. 14 Temperature - temperatura Time (min) - czas (minuty) Inlet set - ustawiona temperatura powietrza na wlocie Actual - faktyczna temperatura Probe - temperatura zmierzona z zastosowaniem sondy Exhaust - temperatura powietrza na wylocie 304 Utwardzanie według przykładu 14.1 Temperature - temperatura Time (min) - czas (minuty) Inlet -temperatura powietrza na wlocie Exhaust set - ustawiona temp. powietrza na wylocie Exhaust actual - faktyczna temp. powietrza na wylocie 305 Utwardzanie według przykładu 14.2 Time (min) -czas (minuty) Inlet -temperatura powietrza na wlocie Exhaust set - ustawiona temp. powietrza na wylocie Exhaust actual - faktyczna temp. powietrza na wylocie 306 Utwardzanie według przykładu 14.3 Temperature - temperatura Time (min) -czas (minuty) Inlet -temperatura powietrza na wlocie Exhaust set - ustawiona temp. powietrza na wylocie Exhaust actual -faktyczna temp. powietrza na wylocie 307 Utwardzanie według przykładu 14.4 Fig. 18 Temperature - temperatura Time (min) - czas (minuty) Inlet -temperatura powietrza na wlocie IR Gun - temperatura zmierzona z zastosowaniem termometru na podczerwień typu pistoletowego Exhaust set - ustawiona temp. powietrza na wylocie Exhaust actual - faktyczna temp. powietrza na wylocie 308 Utwardzanie według przykładu 14.5 Time (min) - czas (minuty) Inlet -temperatura powietrza na wlocie IR Gun - temperatura zmierzona z zastosowaniem termometru na podczerwień typu pistoletowego Set - ustawiona temp. powietrza na wylocie Actual - faktyczna temp. powietrza na wylocie 309 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 13.1. Distance - odległość 310 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 13.2 Force - siła Distance - odległość 311 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 13.3 Distance -odległość 312 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 13.4 Distance -odległość 313 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 13.5 Distance - odległość 314 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 17.1 Distance - odległość 315 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 18.2 Distance -odległość 316 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 14.1 Distance - odległość 317 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 14.2 Distance -odległość 318 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 14.3 Distance - odległość 319 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 14.4 Distance - odległość 320 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 14.5 Distance - odległość 321 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 16.1 Distance - odległość 322 Przykład 20 Próba twardości metodą wciskania wgłębnika tabletki według przykładu 16.2 Distance -odległość 323 Przykład 21 Próba twardości metodą wciskania wgłębnika Porównanie OxyContinu™ 60 mg i tabletki według przykładu 16.1 Force -siła Distance -odległość Example -przykład 324 Przykład 21 Próba twardości metodą wciskania wgłębnika Porównanie OxyContinu™ 80 mg i tabletki według przykładu 16.2 Force - siła Distance - odległość Example - przykład 325 Time after dosing - czas po podaniu Mean plasma oxycodone concentration versus time profile on linear scale. Population:full analysis (fed state) średnie stężenie oksykodonu w osoczu w zależności od czasu w skali liniowej. Populacja: pełna analiza (stan po posiłku) 326 Skala logarytmiczno-liniowa Fig. 37 Concentration - stężenie Time after dosing - czas po podaniu Mean plasma oxycodone concentration versus time profile on linear scale. Population: full analysis (fed state) średnie stężenie oksykodonu w osoczu w zależności od czasu w skali liniowej. Populacja: pełna analiza (stan po posiłku) 327 Time after dosing - czas po podaniu Mean plasma oxycodone concentration versus time profile on linear scale. Population: full analysis (fed state) średnie stężenie oksykodonu w osoczu w zależności od czasu w skali liniowej. Populacja: pełna analiza (stan na czczo) 328 Mean plasma oxycodone concentration versus time profile 5 on log-linear scale. Population: full analysis (fasted state) - średnie stężenie oksykodonu w osoczu w zależności od czasu w skali logarytmiczno-liniowej. Populacja: pełna analiza (stan na czczo) 329 Przykład 27: Reprezentatywne obrazy rozkruszonej tabletki Rozkruszony OxyContin™ (10 mg)Rozkruszona tabletka według przykładu 7.2 Fig. 40 Przykład 27: Reprezentatywne obrazy zmielonych tabletek według przykładu 7.2 i OxyContinu™ 10 mg przed i po 45 minutach rozpuszczenia Zmielony OxyContin™ (10 mg) Zmielona tabletka według przykładu 7,2 Zmielony OxyContin™ (10 mg) po Zmielona tabletka według 45 minutach rozpuszczenia przykładu 7,2 po 45 minutach rozpuszczenia Fig. 41 330 Przykład 27: Profile rozpuszczania zmielonych tabletek według mg tablet In vitro dissolution - rozpuszczanie In vitro tabletki 10 mg Released - uwolniony Time (min) - czas (minuty) Milled example 7.2 - zmielona tabletka według przykładu 7.2 Crushed Oxycontin - rozkruszony OxyContin Milled OTR - zmielony OTR 331 Przykład 27: Example 7.2 tablet -tabletka według przykładu 7.2 Example 14.5 tablet -tabletka według przykładu 14.5 Percent wt. Retained -% wagowy pozostałych cząstek Sieve # -rozmiar sita

Independent claims28

3,841 paragraphs, as filed

European).

Description

Technical field of the invention

The present invention relates to pharmaceutical dosage forms, e.g., tamper-resistant dosage form containing an opioid analgesic, and methods of making, using and treating it.

State of the art

Pharmaceutical products are sometimes subject to abuse. For example, a particular dose of opioid agonist may be stronger when administered parenterally compared to the same dose administered orally. Certain preparations may be the object of interference in order to obtain the opioid agonist contained therein for illegal use. Controlled release preparations with an opioid agonist are sometimes crushed or solvent extracted (e.g. ethanol) by drug abusers to obtain the opioid contained therein for direct release following oral or parenteral administration.

Controlled release opioid agonist dosage forms that may release part of the opioid upon contact with ethanol may also lead the patient to receive a dose faster than intended if the patient downplays the instructions for use and consumes alcohol simultaneously with the dosage form.

There remains a need in the art for pharmaceutical oral dosage forms containing an opioid agonist without significantly altering the opioid release properties on alcohol contact and / or crushing resistance.

Features and essence of the invention

It is an object of certain embodiments of the invention to provide an oral sustained release dosage form containing an active agent such as an opioid analgesic that is resistant to interference.

It is an object of certain embodiments of the invention to provide an oral sustained release dosage form containing an active agent such as an opioid analgesic that is resistant to crushing.

It is an object of certain embodiments of the invention to provide an oral sustained release dosage form containing an active agent such as an opioid analgesic that is resistant to alcohol extraction and the dose is eliminated when used simultaneously with alcohol or in contact with alcohol.

In certain embodiments, the present invention relates to a solid oral extended release pharmaceutical dosage form comprising a sustained release matrix formulation in the form of a tablet or multi-particles, wherein the tablet or individual multi-particles may be at least flattened without crushing, characterized by the thickness of the tablet or individual multi-particles flattened, corresponding to no more than about 60% of the thickness of the tablet or individual multiparticles before flattening, and in which the flattened tablet or flattened multiparticles provide the in-vitro dissolution rate as measured in USP Apparatus 1 (basket) at 100 rpm in 900 mL simulated gastric fluid without enzymes (SGF) at 37 ° C, characterized by the percentage release of active agent after 0.5 hour dissolution, which deviates no more than about 20% of the points from the appropriate in-vitro dissolution rate of the uncoated comparator tablet or multi-reference particles.

In some embodiments, the invention provides a solid oral extended release pharmaceutical dosage form comprising a sustained release matrix formulation in the form of a tablet or multi-particles, wherein the tablet or individual multi-particles can be at least flattened without crushing. characterized by the thickness of the tablet or individual multiparticles after flattening, corresponding to no more than about 60% of the thickness of the tablet or individual multiparticles before flattening, and in which this flattened or flattened tablet or flattened or uncoated multiparticles provide in-vitro dissolution rate, measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) containing 40% ethanol at 37 ° C, characterized by the percentage release of active agent after 0.5 hour of dissolution, which deviates no more than about 20% of the points from the corresponding in-vitro dissolution rate measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C without ethanol, with using suitably flattened and non-flattened reference tablet or flattened and non-flattened reference multiplicates.

In some embodiments, the invention provides a solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, an extended release matrix formulation comprising a composition comprising at least:

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements; and (2) at least one active agent; and wherein the composition comprises at least about 80% (by wt) polyethylene oxide.

According to some such embodiments, the active agent is oxycodone hydrochloride and the composition contains more than about 5% (by weight) oxycodone hydrochloride.

(1) at least one active agent;

(2) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements; and (3) at least one polyethylene oxide with a molecular weight lower, based on rheological measurements, than 1,000,000.

In certain embodiments, the present invention relates to a method for preparing a solid oral extended release pharmaceutical dosage form comprising at least the steps of:

(a) combining at least (1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements, and (2) at least one active agent to form a composition;

(b) shaping the composition to form an extended release matrix formulation; and (c) curing said extended release matrix formulation comprising at least a curing step in which the extended release matrix formulation is subjected to a temperature that is at least the softening point of the polyethylene oxide used for a period of at least about 1 minute.

In certain embodiments, the present invention relates to a method for preparing a solid oral extended release pharmaceutical dosage form comprising at least the steps of:

In which the tablet or individual multi-particles may be at least flattened without crumbling, characterized by the thickness of the tablet or individual multi-particles after flattening corresponding to no more than about 60% of the thickness of the tablet or individual multi-particles before flattening, and in which the flattened tablet or flattened multi-particles ensure in-vitro dissolution rate, measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C, characterized by the percentage of active agent release after 0.5 hour of dissolution which deviates no more than about 20% of the points from the appropriate in-vitro dissolution rate of the uncoated comparison tablet or multi-particle comparison.

In some embodiments, the invention provides a solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation comprising the active agent in the form of a tablet or multiparticles in which the tablet or individual multiparticles can be at least flattened without crushing. characterized by the thickness of the tablet or individual multi-particles after flattening, corresponding to no more than about 60% of the thickness of the tablet or individual multiparticles before flattening, and in which the flattened tablet or flattened multiparticles and the uncoated comparative tablet or comparative multiparticles provide an in-dissolution rate vitro whose value measured at USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C is between about 5 and about 40% (by weight) of active agent released after 0.5 hours.

In which the tablet or individual multi-particles may be at least flattened without crumbling, characterized by the thickness of the tablet or individual multi-particles after flattening corresponding to no more than about 60% of the thickness of the tablet or individual multi-particles prior to flattening, and in which the flattened or flattened tablet or flattened or uncoated multi-particles ensure in-vitro dissolution rate, measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) containing 40% ethanol at 37 ° C, characterized by the percentage release of active agent after 0.5 hour of dissolution, which deviates no more than about 20% of the points from the corresponding in-vitro dissolution rate measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C without ethanol, with using, respectively, a flattened and non-flattened reference tablet or flattened and non-flattened reference multiparticles.

In some embodiments, the invention provides a solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation comprising the active agent in the form of a tablet or multiparticles in which the tablet or individual multiparticles can be at least flattened without crushing. characterized by the thickness of the tablet or individual multi-particles after flattening, corresponding to no more than about 60% of the thickness of the tablet or individual multiparticles before flattening, and in which this flattened or flattened tablet or flattened or uncoated multiparticles provide in-vitro dissolution rate, whose value measured at USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) containing 40% or 0% ethanol at 37 ° C is between about 5 and about 40% (by weight) active agent released after 0.5 hour.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements; and (2) at least one active agent selected from opioid analgesics; and wherein the composition comprises at least about 80% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements; and (2) 10 mg oxycodone hydrochloride; and

Wherein the composition comprises at least about 85% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements; and (2) 15 mg or 20 mg oxycodone hydrochloride; and wherein the composition comprises at least about 80% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements; and (2) 40 mg oxycodone hydrochloride; and

Wherein the composition comprises at least about 65% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements; and (2) 60 mg or 80 mg oxycodone hydrochloride; and

Wherein the composition comprises at least about 60% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements; and (2) 8 mg hydromorphone hydrochloride; and wherein the composition comprises at least about 94% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements; and (2) 12 mg hydromorphone hydrochloride; and wherein the composition comprises at least about 92% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements; and (2) 32 mg hydromorphone hydrochloride; and wherein the composition comprises at least about 90% (by wt) polyethylene oxide.

(1) at least one active agent selected from opioid analgesics;

(2) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements;

and (3) at least one polyethylene oxide with an approximate molecular weight of less than 1,000,000 based on rheological measurements.

(1) at least one polyethylene oxide with a molecular weight equal to at least 800,000 based on rheological measurements; and (2) at least one active agent selected from such opioid analgesics; and wherein the composition comprises at least about 80% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements; and (2) at least one active agent; and wherein the extended release matrix formulation having a hardness indentation test has a pressure resistance of at least about 110 N.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements; and (2) at least one active agent; and wherein the extended release matrix formulation subjected to a hardness indentation test has a "penetration depth to fracture distance" of at least about 1.0 mm.

In certain embodiments, the invention provides a treatment method in which the dosage form of the invention containing an opioid analgesic is administered to treat pain in a patient in need thereof.

In some embodiments, the invention provides the use of dosage forms of the invention containing an opioid analgesic for the manufacture of medicaments for the treatment of pain.

In some embodiments, the invention relates to the use of high molecular weight polyethylene oxide based on rheological measurements, approximately at least 1,000,000, as a matrix forming material for the preparation of a solid oral sustained release dosage form containing an active ingredient selected from opioids. for giving solid oral extended release dosage form alcohol extraction strength.

In certain embodiments, the present invention relates to a method for preparing a solid oral extended release pharmaceutical dosage form comprising at least the steps of:

(a) combining at least (1) at least one polyethylene oxide having a molecular weight based on rheological measurements of at least 1,000,000, and (2) at least one active agent;

to form a composition;

(b) shaping the composition to form an extended release matrix formulation; and (c) curing said extended release matrix formulation comprising at least a curing step in which the extended release matrix formulation is subjected to a temperature, at least such as the melting point of the polyethylene oxide used, for a period of at least 5 minutes.

In accordance with some embodiments of the invention, the solid extended release pharmaceutical dosage form is for use as a suppository.

The term "sustained release" as defined for the purposes of the present invention refers to products that are formulated to produce a drug that is available for a prolonged period after ingestion, thereby allowing a reduction in the frequency of dosing compared to a drug presented as a typical dosage form (e.g. immediate release solution or dosage form).

The term "immediate release" as defined for the purposes of the invention refers to products that are formulated to allow the drug to dissolve in gastrointestinal content without intending to delay or prolong dissolution or absorption of the drug.

The term "solid oral extended release pharmaceutical dosage form" refers to a dosage form comprising a unit dose of the active agent in sustained release form such as "extended release matrix formulation" and optionally including other adjuvants and additives typical in the art, such as a coating protective or capsule, etc., and optionally any other additional features or ingredients used in the dosage form. Unless otherwise indicated, the term "solid oral extended release pharmaceutical dosage form" refers to this intact dosage form e.g. prior to any interference. The sustained release pharmaceutical dosage form may be, e.g., a tablet containing an extended release matrix formulation or a capsule containing an extended release matrix formulation in the form of multiparticles. A "pharmaceutical sustained release dosage form" may contain a portion of the active agent in a sustained release form and another portion of the active agent in an immediate release form, e.g., as an immediate release layer of active agent surrounding the dosage form or an immediately released component incorporated into the dosage form.

The term "extended release matrix formulation" for the purposes of the present invention is defined as a shaped solid composition containing at least one active agent and at least one prolonged release component such as an extended release matrix material such as e.g. poly (ethylene oxide) high molecular weight. The composition may optionally contain more than these two compounds, namely the next active agent and additional retarding compounds and / or other materials, including but not limited to low molecular weight polyethylene oxides, other adjuvants and additives typical in the art.

The term "bioequivalent / bioequivalent" specified for the purposes of the invention refers to a dosage form for which the geometric mean C valuemax, AUCt, and AUCinf for the active agent, with a 90% confidence interval estimated for the ratio (trial / reference), in the range 80.00% to 125.00%. Preferably, average C valuesmax, AUCt, and AUCinf are in the range of 80.00% to 125.00%, which is determined both during normal food intake and during fasting.

The term "poly (ethylene oxide)" as defined for the purposes of the invention refers to poly (ethylene oxide) having a molecular weight of at least 25,000, measured by techniques conventional in the art, and preferably with a molecular weight of at least 100,000. Lower molecular weight compositions refer to polyethylene glycols.

The term "high molecular weight polyethylene oxide" as defined for the purposes of the present invention refers to polyethylene oxide having an approximate molecular weight of at least 1,000,000. For the purpose of the present invention, the approximate molecular weight is based on rheological measurements. Poly (ethylene oxide) is thought to have an approximate molecular weight of 1,000,000 when a 2% (w / w) aqueous solution of this poly (ethylene oxide) using a Brookfield viscometer Model RVF, spindle No. 1, at 10 rpm, at 25 rpm ° C indicates a viscosity range from 400 to 800 mPa s (cP). Poly (ethylene oxide) is believed to have an approximate molecular weight of 2,000,000 when a 2% (w / w) aqueous solution of this poly (ethylene oxide) using a Brookfield viscometer Model RVF, spindle No. 3, at 10 rpm, at 25 rpm ° C indicates a viscosity range from 2000 to 4000 mPa s (cP). Poly (ethylene oxide) is believed to have an approximate molecular weight of 4,000,000 when a 1% (w / w) aqueous solution of this poly (ethylene oxide) using a Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25 ° C, indicates a viscosity range from 1650 to 5500 mPa s (cP). Poly (ethylene oxide) is thought to have an approximate molecular weight of 5,000,000 when a 1% (w / w) aqueous solution of this poly (ethylene oxide) using a Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25 ° C indicates a viscosity range from 5500 to 7500 mPa s (cP). Poly (ethylene oxide) is thought to have an approximate molecular weight of 7,000,000 when a 1% (w / w) aqueous solution of this poly (ethylene oxide) using a Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25 ° C indicates a viscosity range from 7500 to 10,000 mPa s (cP). Poly (ethylene oxide) is thought to have an approximate molecular weight of 8,000,000 when a 1% (w / w) aqueous solution of this poly (ethylene oxide) using a Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25 ° C indicates a viscosity range from 10,000 to 15,000 mPa s (cP). Considering lower molecular weight polyethylene oxides; it is believed that poly (ethylene oxide) has an approximate molecular weight of 100,000 when a 5% (w / w) aqueous solution of this poly (ethylene oxide) using a Brookfield viscometer Model RVT, spindle No. 1, at 50 rpm, at 25 ° C indicates a viscosity range of 30 to 50 mPa s (cP) and poly (ethylene oxide) is thought to have an approximate molecular weight of 900,000 when a 5% (by weight) aqueous solution of this poly (ethylene oxide) using a Brookfield viscometer Model RVF, spindle No. 2, at 2 rpm, at 25 ° C indicates a viscosity range from 8800 to 17600 mPa s (cP).

The term "low molecular weight polyethylene oxide" as defined for the purposes of the present invention refers to polyethylene oxide having an approximate molecular weight of less than 1,000,000 based on the rheological measurements described above.

The term "direct packing" defined for the purposes of the invention refers to a tableting process in which the tablet or any other packed dosage form is made according to a process comprising the steps of dry mixing the compounds and tableting the dry blend to form the dosage form, e.g. using a diffusion blend and / or convective mixing (e.g. Guidance for Industry, SUPAC-IR / MR: Immediate Release and Modified Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum).

The term "layer of free-flowing tablets" defined for the purposes of the present invention refers to a collection of tablets that are kept in motion relative to others, e.g., in a coating drum at a suitable rotation speed or in a fluidized bed of tablets. The free-flowing tablet layer preferably reduces or prevents the tablets from sticking together.

The term "flattening" and related terms used in the context of flattening tablets or other dosage forms, according to the invention means that the tablet is subjected to a force directed perpendicular to its diameter and substantially in line with the thickness of, e.g., tablet. Unless otherwise stated, the force may be applied using a Carver type bench press to the extent necessary to achieve the target flattening / thickness reduction. According to some embodiments of the invention, the flattening does not cause the tablet to disintegrate into pieces, however, edge recesses and cracks may appear. Flattening refers to the thickness of the flattened tablet compared to the thickness of the uncoated tablet expressed in% of thickness, based on the thickness of the uncoated tablet. In addition to the tablet, flattening can be used for any dosage form, with the force directed in line with the smallest diameter (e.g., thickness) relative to the object when the object has a substantially non-spherical shape and from any direction when the object is about spherical shape. Flattening refers to the thickness / smallest diameter of the flattened object compared to the thickness / smallest diameter of the unflattened object expressed in% of thickness, based on the thickness / smallest diameter of the unflattened object, when the initial object is non-spherical, or% thickness, based on the unflattened diameter of the object, when the initial object has a spherical shape. The thickness is measured using a thickness gauge (e.g. digital thickness gauge or electronic caliper). The tablets shown in Figs. 4 to 6 were flattened using a Carter table press. The initial shape of the tablets is shown in Figs. 1 to 3 on the left side of the photo.

In some embodiments of the invention, a hammer may also be used to flatten the tablet / dosage form in addition to the bench press. In this flattening process, manual hammer blows are used, working with force in line with the thickness of e.g. tablets. Flattening refers to the thickness / smallest diameter of the flattened object compared to the unflattened object expressed in% of thickness, based on the thickness / smallest diameter of the unflattened object when the initial object is non-spherical, or% thickness, based on the unflattened diameter when the initial object is spherical. The thickness is measured using a thickness gauge (e.g. digital thickness gauge or electronic caliper).

Otherwise, when testing the tablet's breaking strength or tablet hardness, as described in Remington's Pharmaceutical Sciences, 18th Edition, 1990, Chapter 89 "Oral Solid Dosage Forms," p. 1633-1665, which are incorporated herein by reference using a Schleuniger device, the tablet / dosage form is placed between a pair of parallel flat plates, and the plates are compressed so that the applied force acts perpendicular to the thickness and in the diameter of the tablet, thereby reducing tablet diameter. The diameter thus reduced is described in% of the diameter, based on the diameter of the tablet before carrying out the crushing strength tests. The tablet's crushing strength or hardness is defined as the force at which the tested tablet / dosage form crumbles. Tablets / dosage forms that do not crumble but which, due to the force used, are deformed, are termed crush resistant using this particular force.

Another test carried out to determine the strength of tablets / dosage forms is the indenter hardness test using a texture analyzer such as the TA-XT2 texture analyzer (Texture Technologies Corp., 18 Fairview Road, Scarsdale, NY 10583). In this method, tablets / dosage forms are placed on a stainless tripod with a slightly concave surface and then penetrated by a descending texture analyzer probe, such as a 1/8 inch diameter stainless steel TA-8A spherical probe. Before starting the measurement, the tablets are placed in line directly below the probe, so that the falling probe penetrates the tablets centrally, e.g. into the center of the tablet, and so that the force with which the probe works is directed perpendicular to the diameter and in the direction consistent with the thickness of the tablet. First, the texture analyzer probe begins to move toward the tablet sample at the initial speed. When the probe reaches the tablet surface and the set trigger force is reached, the probe penetrates the tablet at its test speed. For each depth the probe penetrates, the pressure is measured and these data are recorded for each depth the probe penetrated, later referred to as "distance". When the probe reaches the desired maximum penetration depth, it changes direction and moves in the opposite direction at the final speed. During this time further data is being collected. Crushing force is defined as the force at which the first local maximum occurs in the force / distance diagram and is calculated using e.g. texture analyzer software "Texture Expert Exceed, Version 2.64 English". Without being bound by any particular theory, it is believed that at this point in the tablet / dosage form there is some structural damage in the form of a crack. However, in accordance with some embodiments of the invention, the broken tablets / dosage forms remain cohesive, as demonstrated by continuing strength testing using a falling probe. The appropriate distance at the first local maximum refers to "penetration depth to crack".

For the purposes of certain embodiments of the invention, the term "crush strength" refers to tablet / dosage form hardness, i.e. preferably measured using a Schleuniger device, while the term "crushing strength" reflects the strength of tablet / dosage form, i.e. preferably measured in a hardness test indenter pressing method using a texture analyzer.

Another parameter of the extended release matrix formulation that may be derived from the indenter induction hardness test described above is the work to be performed on the extended release matrix formulation in the indenter indentation test described above. The value of the work corresponds to the total force applied by distance.

The term "crush resistant" is defined for the purposes of certain embodiments of the invention with respect to dosage forms that can be at least flattened using the above-described bench press without crushing to no more than about 60% thickness, preferably no more than about 50% thicknesses, more preferably not more than about 40% thick, more preferred not more than about 30% thick, and most preferably not more than about 20% thick, 10% thick or 5% thick.

For the purposes of certain embodiments of the invention, the dosage forms refer to "alcohol-resistant" when the respective dosage forms provide an in-vitro dissolution rate as measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes ( SGF) containing 40% ethanol at 37 ° C, characterized by the percentage release of active agent after 0.5 hours of dissolution, preferably after 0.5 and 0.75 hours, more preferred after 0.5, 0.75 and 1 hour, even more preferred after 0.5, 0.75, 1 and

1.5 hours and most preferably after 0.75, 1, 1.5 and 2 hours of dissolution, which deviates no more than about 20% of points or preferably no more than about 15% of points at each of said time points from the corresponding dissolution rate in-vitro measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C without ethanol.

The term "tamper-resistant" for the purposes of the present invention refers to dosage forms that at least provide the crushing strength or alcohol extraction resistance as defined above, preferably both, and may have additional tamper-proof features.

For the purposes of the present invention, the term "active agent" is defined as a pharmaceutically active substance which includes, without limitation, opioid analgesics.

For the purposes of the invention, the term "opioid analgesic" includes individual compounds and compound compositions selected from the group of opioids exhibiting analgesic properties, such as one single opioid agonist or combination of opioid agonists, one single opioid agonist-antagonist system or combination of opioid agonist systems , or one single partial opioid agonist or a combination of partial opioid agonists and combinations of opioid agonists, opioid-agonist systems and partial opioid agonists with one or more opioid antagonists, their stereoisomers, ethers or esters, salts, hydrates and solvates, compositions of any of the foregoing, and the like.

The invention disclosed herein particularly includes the use of an opioid analgesic in the form of any pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, aspargate, glutamate and the like, and metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt etc.

The opioids used according to the invention may contain one or more asymmetric centers and may form enantiomers, diastereomers, or other stereoisomeric forms. The invention is intended to include the use of all such possible forms as well as their racemic mixtures and separated forms, and compositions thereof. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, the invention is intended to include both E and Z geometric isomers. All tautomers are also within the scope of the invention.

The term "stereoisomers" as used herein generally refers to all isomers of individual molecules differing only in the orientation of their atoms in space. This also applies to enantiomers and isomers of compounds that have more than one chiral center in their structure and which are not mirror images of other (diastereomers).

The term "chiral center" refers to a carbon atom to which four different substituents are attached.

The term "enantiomer" or "enantiomeric" refers to a molecule that is not superimposed on its mirror image and is therefore optically active, with the enantiomer twisting the plane of polarized light in one direction, and the molecule being its mirror image twisting the plane of polarized light in opposite direction.

The term "racemic" refers to an optically inactive mixture of equal parts of enantiomers.

The term "separation" refers to the separation of a mixture or enrichment or depletion of a mixture into one of two enantiomeric forms of the molecule.

Useful opioid agonists according to the invention include, but are not limited to, alfentanyl, allylprodyna, alphaprodyna, anileridine, benzylmorphine, beestramid, buprenorphine, butorphanol, clonitazene, codeine, deomorphine, dextromoramide, deocin, diampromidine, diamorphine, dimethorphinone, dimethyrene dioxafetyl butyrate, dipipanone, eptazocine, etheheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroethorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypetidine, isometadone, ketobemidone, levorphanol, levofenacylmorphan, lofentanyl, meperidine, meptazinol, metazocin, methadone, methopone, morphine, myrofin, narcein, nicomorphine, norleworfen, naletorphonorphone, normetadone oxymorphone, papaverium, pentazocine, fenadoxone, phenomorphan, fenazocine, phenoperidine, piminodine, pyrithramide, profeptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, their pharmaceutically acceptable salts, hydrates and solvates and mixtures of any of the foregoing and the like.

Opioid antagonists useful in combination with the opioid agonists described above are e.g. naloxone, naltrexone and nalmefene or their pharmaceutically acceptable salts, hydrates and solvates and mixtures of any of the above, etc.

In some embodiments, e.g., a combination of oxycodone hydrochloride and naloxone hydrochloride is used in a 2: 1 ratio.

In some embodiments, the opioid analgesic is selected from codeine, morphine, oxycodone, hydrocodone, hydromorphone or oxymorphone or pharmaceutically acceptable salts, hydrates and solvates thereof, or mixtures of any of the above, etc.

In some embodiments, the opioid analgesic is oxycodone, hydromorphone or oxymorphone or a salt such as, e.g., hydrochloride. The dosage form contains from about 5 mg to about 500 mg of oxycodone hydrochloride, from about 1 mg to about 100 mg of hydromorphone hydrochloride or from about 5 mg to about 500 mg of oxymorphone hydrochloride. If other salts, derivatives or forms are used, equimolar amounts of any other pharmaceutically acceptable salt or derivative or form including, but not limited to, hydrates and solvates or the free base may be used. The dosage form contains e.g. 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 60 mg, or 80 mg, 90 mg, 120 mg or 160 mg oxycodone hydrochloride or equimolar amounts of any other pharmaceutically acceptable salt , derivative or form, including but not limited to hydrates and solvates or the free base. The dosage form contains e.g. 5 mg,

7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 60 mg, or 80 mg, 90 mg, 120 mg or 160 mg oxymorphone hydrochloride or equimolar amounts of any other pharmaceutically acceptable salt, derivative or forms, including but not limited to hydrates and solvates or the free base. The dosage form contains e.g. 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, 48 mg or 64 mg hydromorphone hydrochloride or equimolar amounts of any other pharmaceutically acceptable salt, derivative or form, including but not limited to hydrates and solvates, or free rule.

Applications WO 2005/097801 A1, US 7129248 B2 and US 2006/0173029 A1, all of which are hereby incorporated by reference, describes a process for producing oxycodone hydrochloride with 14-hydroxycodeinone levels below about 25 ppm, preferably below about 15 ppm, below about 10 ppm, or below about 5 ppm, more preferably below about 2 ppm, below about 1 ppm, below about 0.5 ppm or below about 0.25 ppm.

The term "ppm" as used herein means "parts per million". Considering 14-hydroxycodeinone, "ppm" means parts of 14-hydroxycodeinone per million in a particular product sample. The 14-hydroxycodeinone level can be determined by any method known in the art, preferably using HPLC analysis with UV detection.

In certain embodiments of the invention wherein the active agent is oxycodone hydrochloride, oxycodone hydrochloride with a 14-hydroxycodeinone level below about 25 ppm, preferably below about 15 ppm, below about 10 ppm, or below about 5 ppm, more preferably below about 2 ppm is used , below about 1 ppm, below about 0.5 ppm or below about 0.25 ppm.

In certain other embodiments, another therapeutically active agent may be used in conjunction with opioids or instead of opioids in accordance with the invention. Examples of such therapeutically active agents include antihistamines (e.g. dimenhydrate, diphenhydramine, chlorpheniramine and dexschlorfeniramine maleate), nonsteroidal anti-inflammatory agents (e.g. naproxen, diclofenac, indomethacin, ibuprofen, sulindac, Cox-2 inhibitors) and acetaminophen, e.g. metoclopramide, methylnaltrexone), anticonvulsants (e.g. phenytoin, meprobamate and nitrazepam), vasodilators (e.g. nifedipine, papaverine, diltiazem and nicardipine), antitussives and expectorants (e.g. codeine phosphate), anti-thymophilic agents (e.g. , antacids, antispasmodics (e.g. atropine, scopolamine), anti-diabetic drugs (e.g. insulin), diuretics (e.g. ethacrynic acid, bendroflutiazide), antihypertensive agents (e.g. propranolol, clonidine), antihypertensives (e.g. clonidine, methyldopa), bronchodilators (e.g. albuterol), steroids (e.g. hydrocortisone, triamcinolone, prednisone), antibiotics (e.g. tetracycline), antihemorrhoidal agents, hypnotics, psychotropic agents , anti-diarrheal agents, mucus dissolving drugs, sedatives, breathing aid (e.g. pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine) and cannabinoids, as well as pharmaceutically acceptable salts, hydrates, and solvates thereof.

In some embodiments, the invention provides the use of Cox-2 inhibitors as an active agent in combination with opioid analgesics or instead of opioid analgesics, e.g. the use of Cox-2 inhibitors such as meloxicam (4-hydroxy-2- 1,1-dioxide methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide) as disclosed in US Pat. Ser. Nos. 10/056347 and 11/825938, which is hereby incorporated by reference, nabumetone (4- (6-methoxy-2-naphthyl) -2-butanone) as disclosed

10/056348, reference, in U.S. Patent No. Ser. Of US Pat. No. hereby incorporated on a celecoxib (4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide) basis as disclosed in US Pat. Ser. No. 11/698394, which is hereby incorporated herein by reference, nimesulide (N- (4-nitro-2-phenoxyphenyl) methanesulfonamide) as disclosed in US Pat. Ser. No. 10/057630, which is hereby incorporated by reference, and N- [3- (formylamino) -4-oxo-6-phenoxy-4H-1-benzopyran-7-yl] methanesulfonamide (T-614) as disclosed in US Pat. Ser. No. 10/057632, which is hereby incorporated by reference.

The invention is also directed to dosage forms using an active agent such as benzodiazepines, barbiturates or amphetamines. These agents can be combined with appropriate antagonists.

The term "benzodiazepines" refers to benzodiazepines and drugs that are benzodiazepine derivatives that are capable of inhibiting central nervous system function. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quasepam, temazepam, triazolam, and their salts and methylphenidate, and their methylphenidate . Benzodiazepine antagonists that can be used according to the invention include, but are not limited to, flumazenil as well as pharmaceutically acceptable salts, hydrates, and solvates.

The term barbiturates refers to sedative hypnotic drugs derived from barbituric acid (2,4,6, trioxhexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, metohexytal, mefobarbital, metarbital, pentobarbital, phenobarbital, secobarbital and also pharmaceutically acceptable salts, hydrates and solvates and mixtures thereof. Barbiturate antagonists that can be used according to the invention include, but are not limited to, amphetamines as well as pharmaceutically acceptable salts, hydrates and solvates.

The term stimulants refers to drugs that stimulate the central nervous system. Stimulants include, but are not limited to, amphetamines such as amphetamine, dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate as well as pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures thereof. Stimulant antagonists that can be used according to the invention include, but are not limited to, benzodiazepines as well as pharmaceutically acceptable salts, hydrates and solvates thereof.

Short description of the drawings

Figure 1 shows a photo of the tablet according to an example

7.1 from above (view along a line according to the tablet thickness) before (left side) and after (right side) a crushing strength test is carried out using the Schleuniger Model 6D device.

Fig. 2 shows a photo of the tablet according to an example

7.2 from above (view along a line according to the tablet thickness) before (left side) and after (right side) a crushing strength test is carried out using the Schleuniger Model 6D device.

Figure 3 shows a photo of the tablet according to an example

7.3 from above (view along a line according to the tablet thickness) before (left side) and after (right side) a crushing strength test is carried out using the Schleuniger Model 6D device.

Fig. 4 is a photo of the tablet according to Example 7.1 (top view along a line according to the thickness of the tablet) after flattening the tablet using a Carver hand press (hydraulic unit model # 3912).

Fig. 5 is a photo of the tablet according to example 7.2 from above (view along a line according to the thickness of the tablet) after being flattened using a Carver hand table press (hydraulic unit model # 3912).

Fig. 6 is a photo of the tablet according to example 7.3 from above (view along a line according to the thickness of the tablet) after being flattened using a Carver hand table press (hydraulic unit model # 3912).

Fig. 7 is a photo of the tablet according to Example 7.1 (top view along a line according to the thickness of the tablet) after 10 manual hammer blows.

Fig. 8 is a photo of the tablet according to example 7.2 from above (view along a line according to the thickness of the tablet) after 10 manual hammer blows.

Fig. 9 is a photo of the tablet according to example 7.3 from above (view along a line according to the thickness of the tablet) after 10 manual hammer blows.

Fig. 10 is a diagram showing the temperature profile of the curing process according to example 13.1.

Fig. 11 is a diagram showing the temperature profile of the curing process according to example 13.2.

Fig. 12 is a diagram showing the temperature profile of the curing process according to example 13.3.

Fig. 13 is a diagram showing the temperature profile of the curing process according to example 13.4.

Fig. 14 is a diagram showing the temperature profile of the curing process according to Example 13.5.

Fig. 15 is a diagram showing the temperature profile of the curing process according to example 14.1.

Fig. 16 is a diagram showing the temperature profile of the curing process according to example 14.2.

Fig. 17 is a diagram showing the temperature profile of the curing process according to example 14.3.

Fig. 18 is a diagram showing the temperature profile of the curing process according to example 14.4.

Fig. 19 is a diagram showing the temperature profile of the curing process according to example 14.5.

Fig. 20 is a diagram of a hardness test by squeezing an indenter according to example 20 carried out using the tablet according to example 13.1 (cured for 30 minutes, uncoated).

Fig. 21 is a diagram of a hardness test by squeezing an indenter according to example 20 carried out using the tablet according to example 13.2 (cured for 30 minutes, uncoated).

Fig. 22 is a diagram of a hardness test by squeezing an indenter according to example 20 carried out using the tablet according to example 13.3 (cured for minutes, uncoated).

Fig. 23 is a diagram of a hardness test by squeezing an indenter according to example 20 carried out using the tablet according to example 13.4 (cured for 30 minutes, uncoated).

Fig. 24 is a diagram of a hardness test by indenter induction according to example 20 carried out using the tablet according to example 13.5 (cured for 30 minutes, uncoated).

Fig. 25 is a diagram of a hardness test by squeezing an indenter according to example 20 carried out using the tablet according to example 17.1 (cured for 15 minutes at 72 ° C, coated).

Fig. 26 is a diagram of a hardness test by indentering the indenter of Example 20 carried out using the tablet of Example 18.2 (cured for 15 minutes at 72 ° C, coated).

Fig. 27 is a diagram of a hardness test by squeezing the indenter of Example 20 carried out using the tablet of Example 14.1 (cured for 1 hour, coated).

Fig. 28 is a diagram of a hardness test by indenter induction according to example 20 carried out using the tablet according to example 14.2 (cured for 1 hour, coated).

Fig. 29 is a diagram of a hardness test by indenter induction according to example 20 carried out using the tablet according to example 14.3 (cured for 1 hour, coated).

Fig. 30 is a diagram of a hardness test by squeezing an indenter according to example 20 carried out using the tablet according to example 14.4 (cured for 1 hour, coated).

Fig. 31 is a diagram of a hardness test by indenter induction according to example 20 carried out using the tablet according to example 14.5 (cured for 1 hour, coated).

Fig. 32 is a diagram of a hardness test by squeezing an indenter according to example 20 carried out using the tablet according to example 16.1 (cured for minutes, coated).

Fig. 33 is a diagram of a hardness test by squeezing an indenter according to example 20 carried out using the tablet according to example 16.2 (cured for 15 minutes, coated).

Fig. 34 is a diagram of a hardness indentation test of example 21 carried out using the tablet of example 16.1 (cured for 15 minutes, coated) and a commercially available OxyContinu ™ 60 mg tablet.

Fig. 35 is a diagram of a hardness induction test according to example 21 carried out using the tablet according to example 16.2 (cured for 15 minutes, coated) and a commercially available OxyContinu ™ 80 mg tablet.

In Fig. 36 indicates the mean plasma concentration of oxycodone versus time on a linear scale [Population: complete analysis (post meal)] according to example 26.

In Fig. 37 indicates the mean oxycodone plasma concentration versus time on a log-linear scale [Population: complete analysis (post-meal)] according to example 26.

In Fig. 38 indicates the average concentration of oxycodone in plasma versus time on a linear scale [Population: full analysis (fasting)] according to example 26.

In Fig. 39, indicates the average oxycodone plasma concentration versus time on a log-linear scale [Population: full analysis (fasting)] according to example 26.

Fig. 40 is a representative photo of the crushed OxyContinu ™ 10 mg tablet and crushed tablet according to example 7.2, according to example 27.

Fig. 41 is a representative photo of the milled tablet of example 7.2 and the OxyContinu ™ 10 mg tablet before and after dissolution for 45 minutes, according to example 27.

Fig. 42 shows the dissolution profiles of the milled tablet of example 7.2 and crushed tablet

OxyContinu ™ 10 mg, according to example 27.

Fig. 43 is a graph showing the particle size distribution of the milled tablet (OxyContin ™ 10 mg, tablets according to Example 7.2 and Example 14.5), according to Example 27.

Detailed description

In some embodiments, the invention relates to a method for preparing a solid oral extended release pharmaceutical dosage form comprising at least the steps of:

(a) combining at least (1) at least one polyethylene oxide with a molecular weight equal to at least 1,000,000 based on rheological measurements, and (2) at least one active agent to form a composition (b) shaping the composition with producing an extended release matrix formulation; and (c) curing said extended release matrix formulation comprising at least a curing step wherein the extended release matrix formulation is subjected to a temperature, which is at least the softening point of the polyethylene oxide used, for a period of at least about 1 minutes.

Preferably, the curing is carried out at atmospheric pressure.

In some embodiments, the invention relates to a process for preparing a solid oral extended release pharmaceutical dosage form comprising at least the steps of:

(a) combining at least (1) at least one polyethylene oxide with a molecular weight equal to, at the rheological measurement of at least 1,000,000; and (2) at least one active agent to form a composition;

(b) shaping the composition to form an extended release matrix formulation; and (c) curing said extended release matrix formulation comprising at least a curing step wherein the extended release matrix formulation is subjected to a temperature that is at least the softening point of the polyethylene oxide used for a period of at least minutes. Preferably, the curing is carried out at atmospheric pressure.

In some embodiments, the invention relates to a method for preparing a solid oral extended release pharmaceutical dosage form comprising at least the steps of:

(a) combining at least (1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000, based on rheological measurements, and (2) at least one active agent to form a composition;

Preferably, the curing is carried out at atmospheric pressure.

In some embodiments, the composition is shaped according to step b) to form a sustained release matrix formulation in the form of a tablet. When shaping a sustained release matrix formulation into a tablet, the direct compression process can be used. Direct packing is an effective and simple tablet shaping process that avoids steps such as wet granulation. However, any tablet-making process known in the art can be used, such as wet granulation and subsequent compression of the granules to form tablets.

In one embodiment, the curing of the extended release matrix formulation according to step c) comprises at least a curing step in which the high molecular weight polyethylene oxide in the extended release matrix formulation at least partially melts. For example, at least about 20% or at least about 30% high molecular weight polyethylene oxide in the extended release matrix formulation melts. Preferably, at least about 40% or at least about 50%, more preferably at least about 60%, at least about 75% or at least about 90% high molecular weight polyethylene oxide in the extended release matrix formulation melts. In a preferred embodiment, about 100% high molecular weight polyethylene oxide is melted.

In other embodiments, the curing of the extended release matrix formulation according to step c) includes at least a curing step, wherein the extended release matrix formulation is subjected to an elevated temperature for a period of time. In such embodiments, the temperature used according to step c), i.e. the curing temperature, is at least as high as the softening point of the high molecular weight polyethylene oxide. Without wishing to be bound by any particular theory, it is assumed that curing at a temperature that is at least as high as the softening point of high molecular weight polyethylene oxide causes poly (ethylene oxide) particles to at least adhere to each other or even to They merge. According to some embodiments, the curing temperature is at least about 60 ° C or at least about 62 ° C or ranges from about 62 ° C to about 90 ° C or from about 62 ° C to about 85 ° C or from about 62 ° C to about 80 ° C or from about 65 ° C to about 90 ° C or from about 65 ° C to about 85 ° C or from about 65 ° C to about 80 ° C. The curing temperature is preferably in the range of from about 68 ° C to about 90 ° C or from about 68 ° C to about 85 ° C or from about 68 ° C to about 80 ° C, more preferably from about 70 ° C to about 90 ° C or from about 70 ° C to about 85 ° Cor from about 70 ° C to about 80 ° C, most preferably from about 72 ° C to about 90 ° C or from about 72 ° C to about 85 ° C or from about 72 ° C to about 80 ° C. The curing temperature may be at least about 60 ° C or at least about 62 ° C, but lower than about 90 ° C or lower than about 80 ° C. Preferably, the temperature is in the range of from about 62 ° C to about 72 ° C, in particular from about 68 ° C to about 72 ° C. Preferably, the curing temperature is at least as high as the lower limit of the softening temperature range of high molecular weight polyethylene oxide or at least about 62 ° C or at least about 68 ° C. More preferably, the curing temperature is within the softening temperature range of high molecular weight polyethylene oxide or is at least about 70 ° C. Even more preferably, the curing temperature is at least as high as the upper limit of the softening temperature range of the high molecular weight polyethylene oxide or is at least about 72 ° C. In an alternative embodiment, the curing temperature exceeds the upper limit of the softening temperature range of high molecular weight polyethylene oxide, e.g., the curing temperature is at least about 75 ° C or at least about 80 ° C.

In those embodiments where the curing of the extended release matrix formulation according to step c) comprises at least a curing step, wherein the extended release matrix formulation is subjected to an elevated temperature for a period of time, this period is referred to below as the curing time. To measure the curing time, the starting point of the curing step is determined. For the purposes of the invention, the starting point of the curing step is defined as the point in time when the curing temperature is reached.

In some embodiments, the temperature profile during the curing step takes the form of a plateau between the starting point and the end point of the curing process. In such solutions, the end point of the curing step is defined as the point in time when heating is stopped or at least reduced, e.g. by terminating or reducing heating and / or starting the next cooling step, the temperature drops below the curing temperature by more than about 10 ° C and / or below the lower limit of the softening temperature range of high molecular weight polyethylene oxide, e.g. below about 62 ° C. When the curing temperature is reached and the curing step begins, deviations from the curing temperature may occur during the curing step. Such deviations are acceptable until their value exceeds about ± 10 ° C, preferably about ± 6 ° C, and more preferably about ± 3 ° C. For example, if a curing temperature of at least about 75 ° C is to be maintained, the measured temperature may temporarily be up to about 85 ° C, preferably about 81 ° C and more preferably about 78 ° C, and the measured temperature may also temporarily drop to about 65 ° C, preferably about 69 ° C and more preferably about 72 ° C. In cases of greater temperature reduction and / or in cases where the temperature falls below the lower limit of the softening point range of high molecular weight polyethylene oxide, e.g. below about 62 ° C, the curing step is interrupted, i.e. end point is reached. Curing can be resumed by again reaching the curing temperature.

In other embodiments, the temperature profile during the curing step indicates a parabolic or triangular course between the starting point and the end point of the curing process. This means that after the starting point, i.e. the point in time when the curing temperature is reached, the temperature then increases to reach a maximum, and then decreases. In such solutions, the end point of the curing step is defined as the point in time when the temperature falls below the curing temperature.

In this context, it should be noted that depending on the apparatus used in the curing process, which is hereinafter referred to as the curing device, different temperature values may be measured to characterize the curing temperature.

In some embodiments, the curing step may take place in an oven. In such solutions, the temperature inside the oven is measured. On this basis, when the curing step takes place in the oven, the curing temperature is defined as the target temperature reached inside the oven and the starting point of the curing step is defined as the point in time when the curing temperature is reached inside the oven. The end point of the curing step is defined as (1) a point in time when heating is stopped or at least reduced and the temperature inside the oven decreases below the curing temperature by more than about 10 ° C and / or below the lower limit of the softening point range of polyethylene oxide ) with a high molecular weight, e.g. below about 62 ° C when the temperature profile takes the form of a plateau or (2) point in time when the temperature inside the oven decreases below the curing temperature when the temperature profile takes the parabolic or triangular form. Preferably, the curing step begins when the temperature inside the oven reaches a curing temperature of at least about 62 ° C, at least about 68 ° C or at least about 70 ° C, more preferably at least about 72 ° C or at least about 75 ° C . In preferred embodiments, the temperature profile during the curing step takes the form of a plateau, wherein the curing temperature, i.e. the temperature inside the oven, is preferably at least about 68 ° C, e.g. about 70 ° C or about 72 ° C or about 73 ° C, or within a range of about 70 ° C to about 75 ° C, and curing time preferably within a range of about 30 minutes to about 20 hours, more preferably about 30 minutes to about 15 hours, or from about 30 minutes to about 4 hours, or from about 30 minutes to about 2 hours. Most preferably, the curing time ranges from about 30 minutes to about 90 minutes.

In some other embodiments, curing occurs in curing devices that are heated by flowing air, including heated air inlet and outlet, such as a coating drum or fluidized bed. Such curing devices will be referred to as convective curing devices. In such curing devices, it is possible to measure the temperature of the inlet air, i.e. the temperature of the heated air at the entrance to the convection curing device and / or the temperature of the exhaust air, i.e. the temperature of the air leaving the convection curing device. It is also possible to determine or at least estimate the temperature of the formulations inside the convective curing device during the curing step, e.g. using infrared temperature measuring devices, such as a pistol type infrared thermometer, or by measuring the temperature using a temperature probe located inside the curing device close to the extended release matrix formulation. On this basis, when the curing step takes place in a convection curing device, the curing temperature and curing time can be determined.

In one embodiment, in which the curing time is measured according to method 1, the curing temperature is defined as the target inlet air temperature and the starting point of the curing step is defined as the point in time when the inlet air reaches the curing temperature. The end point of the curing step is defined as (1) a point in time when heating is stopped or at least reduced and the inlet air temperature drops below the curing temperature by more than about 10 ° C and / or below the lower limit of the softening range of the poly (oxide) high molecular weight), e.g. below about 62 ° C when the temperature profile takes the form of a plateau or (2) point in time when the inlet air temperature falls below the curing temperature when the temperature profile takes the parabolic or triangular form. Preferably, the curing step begins, according to method 1, when the inlet air temperature reaches a curing temperature of at least about 62 ° C, at least about 68 ° C or at least about 70 ° C, more preferably, at least about 72 ° C or at least about 75 ° C. In a preferred embodiment, the temperature profile during the curing step takes the form of a plateau in which the curing temperature, i.e. the target inlet air temperature is preferably at least about 72 ° C, e.g. about 75 ° C, and the curing time, which is measured according to method 1, is preferably in the range of about 15 minutes to about 2 hours, e.g. 30 minutes or about 1 hour.

In another embodiment, in which the curing time is measured according to method 2, the curing temperature is defined as the target outlet air temperature and the starting point of the curing step is defined as the point in time when the outlet air temperature reaches the curing temperature. The end point of the curing step is defined as (1) a point when the heating is stopped or at least reduced and as a result the outlet air temperature drops below the curing temperature by more than about 10 ° C and / or below the lower limit of the poly softening temperature range ( high molecular weight ethylene oxide, e.g. below about 62 ° C when the temperature profile takes the form of a plateau, or (2) point in time when the outlet air temperature falls below the curing temperature when the temperature profile takes the parabolic or triangular form. Preferably, the curing step begins, according to method 2, when the outlet air temperature reaches a curing temperature of at least about 62 ° C, at least about 68 ° C or at least about 70 ° C, more preferably, at least about 72 ° C or at least about 75 ° C. In preferred embodiments, the temperature profile during the curing step takes the form of a plateau in which the curing temperature, i.e. the target outlet air temperature is preferably at least about 68 ° C or at least about 70 ° C or at least about 72 ° C, e.g., the target outlet air temperature is about 68 ° C, about 70 ° C, about 72 ° C, about 75 ° C or about 78 ° C, and the curing time, which is measured according to method 2, is preferably in the range of from about 1 minute to about 2 hours, preferably from about 5 minutes to about 90 minutes, e.g. curing time is about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 60 minutes, about 70 minutes, about 75 minutes or about 90 minutes. In a more preferred embodiment, the curing time, which is measured according to method 2, ranges from about 15 minutes to about 1 hour.

In a further embodiment, in which the curing time is measured according to method 3, the curing temperature is defined as the target temperature of the extended release matrix formulations and the starting point of the curing step is defined as the point in time when the temperature of the sustained release matrix formulations can be measured e.g. using a pistol type infrared thermometer, it reaches the curing temperature. The end point of the curing step is defined as (1) a point in time when heating is stopped or at least reduced and the temperature of the sustained release matrix formulations falls below the curing temperature by more than about 10 ° C and / or below the lower limit of the poly softening temperature range (ethylene oxide) with a high molecular weight, e.g. below about 62 ° C when the temperature profile takes the form of a plateau or (2) point in time when the temperature of the sustained release matrix formulations falls below the curing temperature when the temperature profile takes the parabolic or triangular form. Preferably, the curing step begins, according to method 3, when the temperature of the sustained release matrix formulations reaches a curing temperature of at least about 62 ° C, at least about 68 ° C or at least about 70 ° C, more preferably, at least about 72 ° C or at least about 75 ° C.

In another embodiment, in which the curing time is measured according to method 4, the curing temperature is defined as the target temperature, measured using a temperature probe, such as a wired thermocouple, which has been placed inside the extended release matrix preparation device close to the release and the starting point of the curing step is defined as a point in time, using a probe inside the device for an extended matrix cure endpoint when the temperature measured temperature placed curing close to the release formulations reaches the temperature of the curing stage is defined as (1) point in time, when heating is stopped or at least reduced and the temperature measured using the temperature probe drops below the curing temperature by more than about 10 ° C and / or below the lower limit of the softening temperature range of high molecular weight polyethylene oxide, e.g. below about 62 ° C when the temperature profile takes the form of a plateau or (2) point in time when the temperature measured using the temperature probe drops below the curing temperature when the temperature profile takes the parabolic or triangular form. Preferably, according to method 4, the curing step begins when the temperature measured with the temperature probe placed inside the curing device close to the sustained release matrix formulations reaches a curing temperature of at least about 62 ° C, at least about 68 ° C or at least about 70 ° C, more preferably, at least about 72 ° C or at least about 75 ° C. In a preferred embodiment, the temperature profile during the curing step takes the form of a plateau in which the curing temperature, i.e. the target temperature measured using a temperature probe placed inside the curing device close to the sustained release matrix formulations, is preferably at least about 68 ° C, e.g. is equal to about 70 ° C, and the curing time, which is measured according to method 4, is preferably in the range of from about 15 minutes to about 2 hours, e.g. the curing time is about 60 minutes or about 90 minutes.

If curing takes place in a convection curing device, the curing time can be measured by any of methods 1, 2, 3 or 4. In a preferred embodiment, the curing time is measured according to method 2.

In some embodiments, the curing temperature is defined as the target temperature range, e.g., the curing temperature is defined as the target inlet air temperature range or the target exhaust air temperature range. In such solutions, the starting point of the curing step is defined as the point in time when the lower limit of the target temperature range is reached, and the end point of the curing step is defined as the point in time when heating is stopped or at least reduced. and then the temperature drops below the lower limit of the target temperature range by more than about 10 ° C and / or below the lower limit of the softening temperature range of high molecular weight polyethylene oxide, e.g. below about 62 ° C.

The curing time, i.e. the period of time during which the extended release matrix formulation is subjected to the curing temperature, which can e.g. be measured according to methods 1, 2, 3 and 4 described above, is at least about 1 minute or at least about 5 minutes . The curing time may vary from about 1 minute to about 24 hours or from about 5 minutes to about 20 hours or from about 10 minutes to about 15 hours or from about 15 minutes to about 10 hours or from about 30 minutes to about 5 hours depending on on the specific composition, preparation and curing temperature. The composition parameters described here, curing time and curing temperature were selected to achieve tamper resistance. According to some embodiments, the curing time varies from about 15 minutes to about 30 minutes. According to further embodiments, wherein the curing temperature is at least about 60 ° C or at least about 62 ° C, preferably at least about 68 ° C, at least about 70 ° C, at least about 72 ° C or at least about 75 ° C or varies from about 62 ° C to about 85 ° C or from about 65 ° C to about 85 ° C, the curing time is preferably at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 75 minutes, at least about 90 minutes or about 120 minutes. In preferred embodiments wherein the curing temperature is e.g. at least about 62 ° C, at least about 68 ° C or at least about 70 ° C, preferably at least about 72 ° C or at least about 75 ° C, or within in the range of from about 62 ° C to about 80 ° C, from about 65 ° C to about 80 ° C, from about 68 ° C to about 80 ° C, from about 70 ° C to about 80 ° C or from about 72 ° C to about 80 ° C, the curing time is preferably at least about 1 minute or at least about 5 minutes. More preferably, the curing time is at least about 10 minutes, at least about 15 minutes, or at least about 30 minutes. In some such solutions, the curing time can be as short as possible while the desired tamper resistance is still maintained. For example, the curing time preferably does not exceed about 5 hours, more preferably does not exceed about 3 hours and most preferably does not exceed about 2 hours. Preferably, the curing time ranges from about 1 minute to about 5 hours, from about 5 minutes to about 3 hours, from about 15 minutes to about 2 hours, or from about 15 minutes to about 1 hour. Any combination of curing temperatures and curing times disclosed herein is within the scope of the invention.

In some embodiments, the composition is subjected to curing temperature only for a time such that the high molecular weight polyethylene oxide in the extended release matrix formulation reaches its softening point and / or at least partially melts. In some such embodiments, the curing time may be less than about 5 minutes, e.g. the curing time may vary from about 0 minutes to about 3 hours or from about a minute to about 2 hours or from about 2 minutes to about 1 hour. Immediate curing is possible if a curing device is selected that allows instant heating of the high molecular weight polyethylene oxide in the extended release matrix formulation to at least a softening point so that the high molecular weight polyethylene oxide has melted at least partially. Such curing devices are e.g. microwave ovens, ultrasound devices, light irradiation such as UV radiation, ultra-high frequency (UHF) fields or any method known to a person skilled in the art.

One skilled in the art is aware that the size of the extended release matrix formulation may determine the required curing time and curing temperature to achieve the desired tamper resistance. Without wishing to be bound by any particular theory, it is assumed that for a large extended release matrix formulation, such as a large tablet, a longer cure time is needed to bring heat into the formulation than for a smaller formulation. The use of a higher temperature increases the rate of thermal conductivity and thus reduces the required curing time.

The curing step c) may take place in an oven. Preferably, the curing step c) takes place in a bed of free flowing extended release matrix formulations such as in a coating drum. The coating drum makes it possible to carry out an effective portion curing step, after which the coating step can be carried out without the need to transfer the dosage form, e.g. tablets. Such a process may include the steps of:

(a) combining at least (1) at least one polyethylene oxide having a molecular weight equal to at least 1,000,000 based on rheological measurements, and (2) at least one active agent to form a composition;

(b) shaping the above composition by direct packaging to form an extended release matrix formulation in the form of tablets;

- subjecting the layer of free-flowing tablets in a coating drum to a temperature in the range of from about 62 ° C to about 90 ° C, preferably from about 70 ° C to about 90 ° C for a period of time of at least about 1 minute or at least about 5 minutes, preferably at least about 30 minutes, and

- then cooling the layer of free-flowing tablets to a temperature below about 50 ° C;

and later (d) coating the dosage form in the above coating drum.

In some embodiments, after coating the dosage form according to step d), an additional curing step may be performed. An additional curing step may be carried out as described for curing step c). In such embodiments, the additional curing step is preferably carried out at a temperature of at least about 70 ° C, at least about 72 ° C or at least about 75 ° C, and the curing time is preferably in the range of from about 15 minutes to about 1 hour, e.g. is about 30 minutes.

In some embodiments, an antioxidant, e.g., BHT (butylated hydroxytoluene) is added to the composition.

In some embodiments, the curing step c) leads to a decrease in the density of the extended release matrix formulation, such that the density of the cured extended release matrix formulation is lower than the density of the extended release matrix formulation prior to performing the curing step c). Preferably, the density of the cured extended release matrix formulation compared to the density of the uncured extended release matrix formulation is reduced by at least about 0.5%. More preferably, the density of the cured extended release matrix formulation compared to the density of the uncured extended release matrix formulation is reduced by at least about 0.7%, at least about 0.8%, at least about 1.0%, at least about 2 , 0% or at least about 2.5%. Without wishing to be bound by any particular theory, it is assumed that the extended release matrix formulation, due to the absence of elevated pressure during curing step c), expands, resulting in a decrease in density.

According to a further aspect of the invention, the density of the extended release matrix formulation in the solid oral extended release pharmaceutical dosage form, preferably in the dosage form containing oxycodone hydrochloride as active agent, is equal to or less than about 1.20 g / cm3. Preferably, it is equal to or less than about 1.19 g / cm33, equal to or less than 1.18 g / cm3, or is equal to or less than about 1.17 g / cm3. For example, the density of the extended release matrix formulation is in the range of about 1.10 g / cm3 up to about 1.20 g / cm3from approx

1.11 g / cm3 up to about 1.20 g / cm3, or from about 1.11 g / cm3 up to about 1.19 g / cm3. Preferably it ranges from about

1.12 g / cm3 up to about 1.19 g / cm3 or from about 1.13 g / cm3 up to about 1.19 g / cm3, more preferably from about 1.13 g / cm3 up to about 1.18 g / cm3.

The density of the extended release matrix formulation is preferably determined by Archimedes' law using a liquid of known density (p0). The extended release matrix formulation is first weighed in air and then immersed and weighed in liquid. The density of the extended release matrix formulation r can be calculated from the equation:

AND r = A - B 'ro where r is the density of the extended release matrix formulation, A is the weight of the extended release matrix formulation in the air, B is the weight of the extended release matrix formulation immersed in the liquid and r0 is the density of the liquid at a given temperature. A suitable liquid with known density0 e.g. is hexane.

Preferably, the density of the extended release matrix formulation is measured using a Mettler Toledo balance, model # AB135-S / FACT, serial number 1127430072 and a density determination kit 33360. Preferably, as a liquid of known density r0, hexane is used.

The density values given in this document correspond to the density values of the extended release matrix formulation at room temperature.

The density of the extended release matrix formulation preferably refers to the density of the uncoated formulation, e.g., the density of the tablet core. In those embodiments where the extended release matrix formulation is coated, e.g. wherein the extended release matrix formulation is subjected to the coating step d) after performing the curing step c), the density of the extended release matrix formulation is preferably measured prior to performing the coating step, or by removing the coating from the coated extended release matrix formulation, and then measuring the density of the uncoated formulation sustained release matrix.

In the above-described solutions, high molecular weight polyethylene oxide can be used, based on rheological measurements, approximately equal to

2000000 up to 150,000 or 2,000,000 to 8,000,000. In particular, polyethylene oxides with an approximate molecular weight equal to 2,000,000, 4,000,000, 7,000,000 or 8,000,000, based on rheological measurements, may be used. In particular, polyethylene oxides with an approximate molecular weight of , based on rheological measurements, 4,000,000.

In embodiments in which the composition comprises at least one low molecular weight polyethylene oxide, polyethylene oxides having an approximate molecular weight equal to, under rheological measurements, less than 1,000,000 are used; polyethylene oxides with an approximate molecular weight of 100,000 to 900,000 based on rheological measurements may be used. Such low molecular weight polyethylene oxides can be added to specifically adjust the release rate, e.g., to increase the release rate of a formulation that is otherwise released too slowly to act specifically. At least one polyethylene oxide with an approximate molecular weight of 100,000 based on rheological measurements may be used in such solutions.

In some such embodiments, the composition comprises at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements, and at least one polyethylene oxide with an approximate molecular weight of less than 1,000,000 based on rheological measurements , the composition comprises at least about 10% (by weight) or at least about 20% (by weight) of polyethylene oxide with an approximate molecular weight of based on rheological measurements, below 1,000,000. In some such embodiments, the curing temperature is below about 80 ° C or even below about 77 ° C.

In some embodiments, the overall polyethylene oxide content of the composition is at least about 80% (by weight). Without wishing to be bound by any particular theory, it is assumed that high levels of poly (ethylene oxide) lead to interference resistance as described herein, such as crushing strength and alcohol extraction strength. According to some such embodiments, the active agent is oxycodone hydrochloride and the composition contains more than about 5% (by weight) oxycodone hydrochloride.

In some such embodiments, the content of the composition of at least one polyethylene oxide with an approximate molecular weight equal to at least 1,000,000 based on rheological measurements of at least about 80% (by weight). In some embodiments, the composition has at least one polyethylene oxide in the composition having an approximate molecular weight of at least 1,000,000 based on rheological measurements of at least about 85% or at least about 90% (by weight). In such embodiments, polyethylene oxide with an approximate molecular weight of at least 4,000,000 or at least 7,000,000 can be used based on rheological measurements. In some such embodiments, the active agent is oxycodone hydrochloride or hydromorphone hydrochloride, although, in this aspect of the invention, also use another active agent, and the composition contains more than about 5% (by weight) oxycodone hydrochloride or hydromorphone hydrochloride.

In some embodiments, where the amount of drug in the composition is at least about 20% (by weight), the polyethylene oxide content may be only about 75% (by weight). In another embodiment, wherein the amount of drug in the composition ranges from about 25% (by weight) to about 35% (by weight), the content of polyethylene oxide can range from about 65% (by weight) to about 75% (by weight). Eg. in embodiments where the amount of drug in the composition is about 32% (by weight), the polyethylene oxide content may be about 67% (by weight).

In some embodiments of the invention, magnesium stearate is added to avoid sticking of the tablets together, during or after the curing / curing step. In some such solutions, magnesium stearate is added at the end of the curing process / curing step, before cooling or while cooling the tablets. Other anti-sticking agents such as talc, silica, fumed silica, colloidal silica, calcium stearate, carnauba wax, long chain fatty alcohols and waxes such as stearic acid and stearyl alcohol, mineral oil, paraffin, microcrystalline cellulose, glycerine , propylene glycol and polyethylene glycol. In addition or alternatively, the coating process can be started at high temperature.

In some embodiments, where the curing step c) is carried out in a coating drum, sticking of the tablets can be avoided, or the agglomerated tablets can be separated by increasing the rotation speed of the drum during the curing step or after the curing step, in the last case e.g. before or during cooling of the tablets. The rotation speed of the drum increases up to the speed when all the tablets are separated or no sticking occurs.

In some embodiments of the invention, prior to carrying out the curing step c), a pre-application or partial application of a coating layer is used. Such an applied coating layer forms a "coating" for extended release matrix formulations or tablets, acting as an anti-sticking agent, ie, preventing the formulations or tablets from sticking together. In some such embodiments, the coating layer used prior to the curing step is the coating layer Opadry. After the curing step c), a coating step can be carried out.

The invention also includes any solid oral extended release pharmaceutical dosage form which can be obtained by following any of the processes described above.

Independently, the invention is also directed to solid oral extended release pharmaceutical dosage forms.

In certain embodiments, the present invention relates to solid oral extended release pharmaceutical dosage forms comprising an extended release matrix formulation comprising the active agent in the form of a tablet or multiparticulates, wherein the tablet or individual multiparticulates can be at least flattened without crushing. characterized by the thickness of the tablet or individual multiparticles after flattening, corresponding to no more than about 60% of the thickness of the tablet or individual multiparticles before flattening, and in which this flattened tablet or flattened multiparticles provide in-vitro dissolution rate, measured in USP Apparatus 1 (basket) at 100 revolutions per minute in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C, characterized by the percentage release of active agent after 0.5 hours of dissolution or after 0.5 and 0.75 hours, or after 0.5, 0.75 and 1 hour, or after 0.5, 0.75, 1 and 1 , 5 hours or after 0.5, 0.75, 1, 1.5 and 2 hours of dissolution, which deviates no more than about 20% of the points from the corresponding in-vitro dissolution rate of the uncoated comparator tablet or reference multiparticles.

In some such embodiments, the tablet or individual multiparticles can be at least flattened without crushing, have a tablet or individual multiparticle thickness after flattening corresponding to no more than about 50%, or no more than about 40%, or no more than about 30%, or no more than about 20% or no more than about 16% of the thickness of the tablet or individual multiparticles before flattening, and in which this flattened tablet or flattened multiparticles provide an in-vitro dissolution rate, measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C, characterized by a percentage release active agent after 0.5 hour of dissolution or after 0.5 and 0.75 hours, or after 0.5, 0.75 and 1 hour, or after 0.5, 0.75, 1 and

1.5 hours or after 0.5, 0.75, 1, 1.5 and 2 hours of dissolution that deviates no more than about 20% of points or no more than about 15% of points from the corresponding in-vitro dissolution rate of uncoated comparison tablet or multi-particle comparison.

In certain embodiments, the present invention relates to a solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation comprising the active agent in the form of a tablet or multi-particles, wherein the tablet or individual multi-particles can be at least flattened without crushing. characterized by the thickness of the tablet or individual multiparticles after flattening, corresponding to no more than about 60% of the thickness of the tablet or individual multiparticles before flattening, and in which the flattened tablet or flattened multiparticles and the uncoated comparative tablet or comparative multiparticles provide in-vitro dissolution rate, whose value measured at USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C is between about 5 and about 40% (by weight) of active agent released after 0.5 hours.

In some such embodiments, a tablet or individual multiparticles, characterized by a thickness of the tablet or individual multiparticles after flattening corresponding to no more than about 50%, or no more than about 40%, or no more than about 30%, or no more than about 20% , or not more than about 16% of the thickness of the tablet or individual multiparticles before flattening, and wherein said flattened tablet or flattened multiparticles and uncoated comparative tablet or comparative multiparticles provide an in-vitro dissolution rate whose value is measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at temperature 37 ° C is between about 5 and about 40% (by weight) of active agent released after 0.5 hour or is between about 5 and about 30% (by weight) of active agent released after 0.5 hour or is between about 5 and about 20% (by weight ) active agent released after 0.5 hour or between about 10 and about 18% (by weight) of active agent released after 0.5 hour, can be at least flattened without crumbling.

In some embodiments, the invention provides a solid oral extended release pharmaceutical dosage form comprising a sustained release matrix formulation comprising the active agent in the form of a tablet or multi-particles, wherein the tablet or individual multi-particles can be at least flattened without crushing. characterized by the thickness of the tablet or individual multiparticles after flattening, corresponding to no more than about 60% of the thickness of the tablet or individual multiparticles before flattening, and in which this flattened or flattened tablet or flattened or uncoated multiparticles provide in-vitro dissolution rate, measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) containing 40% ethanol at 37 ° C, characterized by the percentage release of active agent after 0.5 hours of dissolution or after 0 , 5 and 0.75 hours, or after 0.5, 0.75 and 1 hour, or after 0.5, 0.75, 1 and 1.5 hours, or after 0.5, 0.75, 1, 1 , 5 and 2 hours of dissolution, which deviates no more than about 20% of the points from the corresponding in-vitro dissolution rate measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C without ethanol, with using, respectively, a flattened and non-flattened reference tablet or flattened and non-flattened reference multiparticles.

In some such solutions, the tablet or multiparticles can be at least flattened without crumbling. They are characterized by the thickness of the tablet or individual multiparticles after flattening corresponding to no more than

<td>about</td><td> 60%,</td><td>or</td><td>no</td><td>more</td><td>than</td><td>about</td><td>50%, or</td><td>no more than</td>

<td>about</td><td> 40%,</td><td>or</td><td>no</td><td>more</td><td>than</td><td>about</td><td>30%, or</td><td>no more than</td>

<td>about</td><td> 20%,</td><td>or</td><td>no</td><td>more</td><td>than</td><td>about</td><td colspan="2">16% thick tab-letki</td>

or individual multiparticles prior to flattening, and in which the flattened or uncoated tablet or individual multiparticles provide an invitro dissolution rate, measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) containing 40% ethanol in at 37 ° C, characterized by the percentage release of the active agent after 0.5 hours of dissolution or after 0.5 and 0.75 hours, or after 0.5, 0.75 and 1 hour, or after 0.5, 0.75, 1 and

1.5 hours or after 0.5, 0.75, 1, 1.5 and 2 hours of dissolution which deviates no more than about 20% points or no more than about 15% points from the corresponding in-vitro dissolution rate measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at flattened temperature using a comparative tablet or the subject of the invention is

37 ° C without ethanol, and uncoated comparative multiparticles,

In some embodiments, the solid oral extended release pharmaceutical dosage form containing the extended release matrix formulation containing the active agent in the form of a tablet or multiparticles, wherein the tablet or individual multiparticles can be at least flattened without crushing. they are characterized by the thickness of the tablet or individual multi-particles after flattening, corresponding to no more than about 60% of the thickness of the tablet or individual multi-particles before flattening, and in which this flattened or non-flattened tablet or flattened or non-flattened multi-particles provide an in-vitro dissolution rate whose value measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) containing

40% or 0% ethanol at 37 ° C is between about and about 40% (by weight) of the active agent released after 0.5 hour.

In some such embodiments, the tablet or individual multiparticles can be at least flattened without crushing, characterized by a tablet or individual multiparticle thickness after flattening corresponding to no more than about 50%, or no more than about 40%, or no more than about 30%, or no more than about 20%, or no more than about 16% of the thickness of the tablet or individual multiparticles before flattening, and in which this flattened or flattened tablet or flattened or flattened multiparticles provide an invitro dissolution rate whose value measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) containing 40% or 0% ethanol at 37 ° C, is between about 5 and about 40% (by weight) of active agent released after 0.5 hour or is between about 5 and about 30% (by weight) of active agent released after 0.5 hour or is between about 5 and about 20% (by weight ) active agent released after 0.5 hour or between about 10 and about 18% (by weight) of active agent released after 0.5 hour.

Such dosage forms can be prepared as described above.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000, based on rheological measurements;

and (2) at least one active agent, preferably selected from opioid analgesics; and the composition comprises at least about 80% (by wt) polyethylene oxide. The composition may also contain at least about 85 or 90% (by wt) polyethylene oxide. According to some such embodiments, the composition contains at least about 80% (by wt) polyethylene oxide, the active agent is oxycodone hydrochloride or hydromorphone hydrochloride and the composition contains more than about 5% (by wt) oxycodone hydrochloride or hydromorphone hydrochloride.

In some such embodiments, the composition contains at least about 80% (by wt) polyethylene oxide with an approximate molecular weight of at least 1,000,000 based on rheological measurements.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000, based on rheological measurements; and (2) 10 mg oxycodone hydrochloride; and the composition comprises at least about 85% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000, based on rheological measurements;

and (2) 15 mg or 20 mg oxycodone hydrochloride; and the composition comprises at least about 80% (by wt) polyethylene oxide.

In certain embodiments, the invention relates to a solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, an extended release matrix formulation comprising a composition comprising at least:

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000, based on rheological measurements;

and (2) 40 mg oxycodone hydrochloride; and the composition comprises at least about 65% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000, based on rheological measurements;

and (2) 60 mg or 80 mg oxycodone hydrochloride; and the composition comprises at least about 60% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000, based on rheological measurements;

and (2) 8 mg hydromorphone hydrochloride; and the composition comprises at least about 94% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000, based on rheological measurements;

and (2) 12 mg hydromorphone hydrochloride; and the composition comprises at least about 92% (by wt) polyethylene oxide.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000, based on rheological measurements;

and (2) 32 mg hydromorphone hydrochloride; and the composition comprises at least about 90% (by wt) polyethylene oxide.

(1) at least one active agent, preferably selected from analgesic opioids;

(2) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000, based on rheological measurements;

and (3) at least one polyethylene oxide with an approximate molecular weight of less than 1,000,000 based on rheological measurements. In some such embodiments, the composition comprises at least about 80% (by wt) polyethylene oxide. The composition may also contain at least about 85 or 90% (by wt) polyethylene oxide. According to some such embodiments, the composition contains at least about 80% (by wt) polyethylene oxide, the active agent is oxycodone hydrochloride or hydromorphone hydrochloride and the composition contains more than about 5% (by wt) oxycodone hydrochloride or hydromorphone hydrochloride. The composition may also contain 15 to 30% (by weight) polyethylene oxide with a molecular weight equal to at least 1,000,000 based on rheological measurements; and 65 to 80% (by weight) of polyethylene oxide with a molecular weight lower, based on rheological measurements, than 1,000,000, or the composition may contain at least about 20% (by weight) or at least about 30% (by weight) or at least about 50% (by weight) polyethylene oxide with a molecular weight equal to at least 1,000,000 based on rheological measurements.

(1) at least one polyethylene oxide with a molecular weight equal to, at least 800,000 or at least 900,000, based on rheological measurements; and (2) at least one active agent selected from opioid analgesics; and the composition comprises at least about 80% (by wt) polyethylene oxide.

In certain embodiments of the invention, the density of the extended release matrix formulation is equal to or less than about 1.20 g / cm3.3. In some such embodiments, the density of the extended release matrix formulation is equal to or less than about 1.19 g / cm3.3, preferably equal to or less than about 1.18 g / cm33 or is equal to or less than about 1.17 g / cm3. For example, the density of the extended release matrix formulation is in the range of about 1.10 g / cm3 up to about 1.20 g / cm3, from about 1.11 g / cm3 up to about 1.20 g / cm3, or from about 1.11 g / cm3 up to about 1.19 g / cm3. Preferably it ranges from about

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000, based on rheological measurements;

and (2) at least one active agent;

wherein the extended release matrix formulation subjected to a hardness indenter test exhibits a pressure resistance of at least about 110 N.

In certain embodiments of the invention, the sustained release matrix formulation exhibits a pressure resistance of at least about 110 N, preferably at least about 120 N, at least about 130 N or at least about 140 N, more preferably at least about 150 N, at least about 160 N or at least about 170 N, most preferably at least about 180 N, at least about 190 N or at least about 200 N.

(1) at least one polyethylene oxide with an approximate molecular weight of at least 1,000,000, based on rheological measurements;

and (2) at least one active agent;

wherein the extended release matrix formulation subjected to a hardness indenter test has a "penetration depth to fracture distance" of at least about 1.0 mm.

In certain embodiments of the invention, the extended release matrix formulation has a "penetration depth to crack distance" of at least about 1.0 mm or at least about 1.2 mm, preferably at least about 1.4 mm, at least about 1, 5 mm or at least about 1.6 mm, more preferably at least about

1.8 mm, at least about 1.9 mm, or at least about

2.0 mm, most preferably at least about 2.2 mm, at least about 2.4 mm, or at least about 2.6 mm.

In certain such embodiments of the invention, the sustained release matrix formulation exhibits a pressure resistance of at least about 110 N, preferably at least about 120 N, at least about 130 N or at least about 140 N, more preferably at least about 150 N, at least about 160 N or at least about 170 N, most preferably at least about 180 N, at least about 190N or at least about 200 N, and / or has a "penetration depth to crack" distance of at least about 1.0 mm or at least about 1.2 mm, preferably at least about 1.4 mm, at least about 1.5 mm, or at least about 1 , 6 mm, more preferably at least about 1.8 mm, at least about 1.9 mm or at least about 2.0 mm, most preferably at least about 2.2 mm, at least about 2.4 mm or at least about 2 , 6 mm. The combination of any of the aforementioned value of crushing force and "penetration depth to crack distance" is within the scope of the invention.

In some such embodiments, the extended release matrix formulation subjected to a hardness indentation test without breaking shows a resistance to a force of at least about 0.06 J or at least about 0.08 J, preferably at least about 0.09 J, at least about 0.11 J or at least about 0.13 J, more preferably at least about 0.15 J, at least about 0.17 J or at least about 0.19 J, most preferably at least about 0.21 J, at least about 0.23 J or at least about 0.25 J.

The parameters "crushing force", "penetration depth to fracture distance" and "force operation" were determined in the indenter hardness test described above using a texture analyzer such as the TA-XT2 texture analyzer (Texture Technologies Corp., 18 Fairview Road, Scarsdale, NY 10583). Crushing strength and / or "penetration depth to crack distance" can be determined using an uncoated or coated extended release matrix formulation.

Preferably, the crushing force and / or "penetration depth to crack distance" was determined for the uncoated extended release matrix formulation. Without wishing to be bound by any particular theory, it is assumed that coating, such as the coating used according to step d) of the process for producing a solid oral extended release pharmaceutical dosage form as described above, slightly contributes to the observed crushing force and / or "depth of penetration to crack distance ". So, the crushing force and / or "penetration depth to crack distance" determined for the specifically coated formulation

<td>release</td><td>no</td>

<td>identified</td><td>for</td>

<td>matrix</td><td>about</td>

should be appropriate extended matrix of tablets or matrix extended with significantly different from the value of the uncoated release formulation.

In some embodiments, the sustained release formulation is in the form of multiparticles, the tablet or individual multiparticles can be at least flattened without crumbling, and is characterized by the thickness of the tablet or individual multiparticles after flattening corresponding to no more than about 60% of the thickness of the tablet or individual multiparticles before flattening. Preferably, a tablet or individual multiparticles, characterized by a thickness of the tablet or individual multiparticles after flattening corresponding to no more than about 50%, or no more than about 40%, or no more than about 30%, or no more than about 20%, or not more than about 16% of the thickness of the tablet or individual multiparticles before flattening, can be at least flattened without crushing.

Preferably, the flattening of the tablet or individual multiparticles is carried out using a bench press, such as a Carver table press, or using a hammer, as described above.

In some such solutions, the sustained release matrix formulation is in the form of a tablet or multiparticles, the tablet or individual multiparticles can be at least flattened without crumbling, and is characterized by the thickness of the tablet or individual multiparticles after crushing multiparticles, flattening corresponding to no more than about 60% of the tablet thickness or individual multi-particles before flattening, and in which this flattened tablet or flattened multiparticles provide an in-vitro dissolution rate, measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C, characterized by a percentage of release active agent after 0.5 hour of dissolution or after 0.5 and 0.75 hours, or after 0.5, 0.75 and 1 hour, or after 0.5, 0.75, 1 and 1.5 hours or after 0.5, 0.75, 1, 1.5 and 2 hours of dissolution, which deviates no more than about 20% of the points from the appropriate dissolution rate of the uncoated comparator tablet or multi-particle comparison. Preferably, the tablet or individual may be at least flattened without having a thickness of the tablet or individual multiparticles after flattening corresponding to no

<td>than</td><td>about</td><td> 50%,</td><td>or</td><td>no</td><td>more</td><td>than</td><td>about</td><td>40%, or</td><td>no</td>

<td>than</td><td>about</td><td> 30%,</td><td>or</td><td>no</td><td>more</td><td>than</td><td>about</td><td>20%, or</td><td>no</td>

<td>than</td><td>about</td><td> 16%</td><td colspan="4">tablet thickness</td><td>or</td><td colspan="2">each</td>

more multiparticles before flattening, and in which this flattened tablet or flattened multiparticles provide an in-vitro dissolution rate, measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C, characterizing percentage active release or 0.5

0.75 agent after 0.5 hour of dissolving an hour, or after 0.5, 0.75 and 1 hour, or after 0.5, 0.75, 1 and 1.5 hours, or after 0.5, 0.75 , 1, 1.5 and 2 hours of dissolution, which deviates no more than about 20% points or no more than about 15% points from the corresponding in-vitro dissolution rate of the uncoated comparator tablet or reference multiplier.

In some embodiments, the present invention provides a solid oral pharmaceutical dosage form with extended matrix formulation and the matrix release formulation is in the form of a tablet or multi-particles, and the tablet or individual multi-particles can be at least release, release, wherein the extended prolonged flattened without crushing. characterized by the thickness of the tablet or individual multiparticles after flattening, corresponding to no more than about 60% of the thickness of the tablet or individual multiparticles before flattening, and in which the flattened or uncoated tablet or the flattened or uncoated multiparticles ensure the in-vitro dissolution rate, measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) containing 40% ethanol at 37 ° C, characterized by the percentage release of active agent after 0.5 hours of dissolution or after 0 , 5 and 0.75 hours, or after 0.5, 0.75 and 1 hour, or after 0.5, 0.75, 1 and 1.5 hours, or after 0.5, 0.75, 1, 1 , 5 and 2 hours of dissolution, which deviates no more than about 20% of the points from the corresponding invitro dissolution rate measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C without ethanol, using flattened and non-flattened reference tablet or flattened and non-flattened reference multiparticles. Preferably, the tablet or multiparticles can be at least flattened without crumbling, characterized by the thickness of the tablet or individual multiparticles after flattening which corresponds to no

<td>more</td><td>than</td><td>about</td><td> 60%,</td><td>or</td><td>no</td><td>more</td><td>than</td><td>about</td><td>50%, or</td><td>no</td>

<td>more</td><td>than</td><td>about</td><td> 40%,</td><td>or</td><td>no</td><td>more</td><td>than</td><td>about</td><td>30%, or</td><td>no</td>

<td>more</td><td>than</td><td>about</td><td> 20%,</td><td>or</td><td>no</td><td>more</td><td>than</td><td>about</td><td colspan="2">16% thick</td>

tablets or individual multiparticles before flattening, and in which this flattened or uncoated tablet or individual multiparticles provide an invitro dissolution rate, measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) containing 40% ethanol at 37 ° C, characterized by the percentage release of the active agent after 0.5 hours of dissolution or after 0.5 and 0.75 hours, or after 0.5, 0.75 and 1 hour, or after 0.5, 0.75, 1 and

1.5 hours or after 0.5, 0.75, 1, 1.5 and 2 hours of dissolution which deviates no more than about 20% points or no more than about 15% points from the corresponding in-vitro dissolution rate measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C without ethanol, using appropriately flattened and uncoated comparative tablets can be at least or multiparticles flattened without comparative, crushing.

In some such embodiments, the extended release matrix formulation subjected to a maximum hardness test of about 196 N or about 439 N in a tablet hardness test will not crack.

Preferably, to determine the strength of the extended release matrix formulation against crushing, the tablet hardness test described above is performed in a Schleuniger apparatus. For example, the breaking strength is determined using a Schleuniger 2E / 106 device and applying a force with a maximum value of approximately 196 N, or using a Schleuniger Model 6D device and using a force with a maximum value of approximately 439 N.

It has also been observed that the inventive formulations are stable in storage, with the extended release matrix formulation being stored at 25 ° C and 60% relative humidity or at 40 ° C and 75% relative humidity for at least 1 month, more preferably ensures dissolution rate for at least 2 months, for at least 3 months or for at least 6 months, measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C, characterized by the percentage release of active agent after 1 hour or after 1 and 2 hours, or after 1 and 4 hours, or after 1, 2 and 4 hours, or after 1, 4 and 12 hours, or after 1, 2, 4 and 8 hours, or after 1, 2, 4, 8 and 12 hours of dissolution, which deviates not more than about 15% of points, preferably no more than about 12% points or no more than about 10% points, more preferably no more than about 8% points or no more than about 6% points, most preferably no more than about 5% points from the appropriate in-vitro dissolution rate of the preparation compare 60 what before storage. Preferably, the extended release matrix formulation is stored in bottles (bottles containing the specified number of tablets), such as bottles for 100 tablets. Any combination of the aforementioned storage periods, dissolution times and deviation limits is within the scope of the invention.

According to another aspect regarding storage stability, the extended release matrix formulation after storage at 25 ° C and 60% relative humidity or at 40 ° C and 75% relative humidity for at least 1 month, more preferably for at least 2 months, for at least 3 months or for at least 6 months, it contains at least one active agent in an amount of% (by weight) relative to the labeled active agent content of the extended release matrix formulation which deviates no more than about 10% points, preferably no more than about 8% points or no more than about 6% of points, more preferably no more than about 5% points or no more than about 4% points or no more than about 3% points on the amount of the respective active agent in% (by weight) relative to the content of the active agent of the extended release matrix formulation on the label before storage. Preferably, the extended release matrix formulation is stored in bottles containing a predetermined number of tablets, such as bottles containing 100 tablets. Any combination of storage periods and deviation limits is within the scope of the invention.

According to some such solutions, the active agent is oxycodone hydrochloride.

Preferably, at least one active agent in an amount (% by weight) relative to the labeled active agent content of the extended release matrix formulation is determined by extracting at least one active agent from the extended release matrix formulation followed by analysis using high performance chromatography liquid. In some embodiments, where at least one active agent is oxycodone hydrochloride, preferably the amount of oxycodone hydrochloride in% (by weight) relative to the labeled oxycodone hydrochloride content of the extended release matrix formulation is determined by extracting the oxycodone hydrochloride from the extended release matrix formulation from using a 1: 2 mixture of acetonitrile and simulated gastric fluid without enzyme (SGF), continuously stirring by means of a magnetic stirrer until the extended release matrix formulation is not completely dispersed, or overnight, and then carrying out the analysis by high performance liquid chromatography, preferably high performance reverse phase liquid chromatography. In some embodiments, where the extended release matrix formulation is in the form of tablets, preferably the amount of oxycodone hydrochloride in% (by weight) relative to the labeled oxycodone hydrochloride content on the label is determined by extracting the oxycodone hydrochloride from the tablets in two sets of ten tablets using 900 ml of 1: 2 mixture of acetonitrile and simulated gastric fluid without enzyme (SGF) each time, continuously stirring with a magnetic stirrer until the tablets were not completely dispersed or overnight, and then carrying out high performance liquid chromatography, preferably high performance reverse phase liquid chromatography. Preferably, the test results are mean values of two measurements.

In some embodiments, the invention provides a solid oral extended release pharmaceutical dosage form, the dosage form providing a dissolution rate whose value is measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) in at 37 ° C, is between 12.5 and 55% (by weight) of active agent released after 1 hour, between 25 and 65% (by weight) of active agent released after 2 hours, between 45 and 85% (by weight) active agent released after 4 hours and between 55 and 95% (by weight) active agent released after 6 hours, and optionally between 75 and 100% (by weight) active agent released after 8 hours. Preferably, the dosage form provides a dissolution rate whose value measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C, is between 15 and 45% (by weight) of active agent released after 1 hour, between 30 and 60% (by weight) of active agent released after 2 hours, between 50 and 80% (by weight) active agent released after 4 hours and between 60 and 90% (by weight) active agent released after 6 hours and optionally between 80 and 100% (by weight) active agent released after 8 hours. More preferably, the dosage form provides a dissolution rate whose value measured in USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C is between 17.5 and 35% (by weight ) active agent released after 1 hour, between 35 and 55% (by weight) of active agent released after 2 hours, between 55 and 75% (by weight) of active agent released after 4 hours and between 65 and 85% (by weight) of active agent released after 6 hours and optionally between 85 and 100% (by weight) of active agent released after 8 hours.

In some such embodiments, the active agent is oxycodone hydrochloride or hydromorphone hydrochloride.

Such dosage forms can be prepared by the methods described herein.

In the above-described solutions, a tablet may be formed by directly packing the composition and curing, subjecting the tablet to a temperature of at least about 60 ° C, at least about 62 ° C, at least about 68 ° C, at least about 70 ° C, at least about 72 ° C or at least about 75 ° C for a time period of at least about 1 minute, at least about 5 minutes, or at least about 15 minutes.

In some embodiments of the invention, the above-described tablet may be covered with a polyethylene oxide powder layer. A poly (ethylene oxide) powder layer is applied to the cured or uncured tablet surrounding the core, and then the powder is cured as described above. This outer polyethylene oxide layer coating provides delayed start of release of the active agent and / or reduces the overall release rate.

In some embodiments of the invention, bunk double or multilayer tablets are prepared, wherein at least one of the layers comprises the sustained release formulation described above and at least one of the other layers comprises the immediate release formulation of the active agent contained in the sustained release composition or the other active agent. In some such embodiments, the tablet is a bilayer with an extended release formulation layer as described herein and an immediate release formulation layer. In some such embodiments, in particular for bilayer tablets, opioid analgesics are included in the sustained release layer, while non-opioid analgesics are included in the immediate release layer. Non-opioid analgesics may be non-steroidal anti-inflammatory agents, but also non-opioid analgesics such as acetaminophen. Acetaminophen can e.g. be used in combination with hydrocodone as an analgesic opioid. Such tablets can be made by specific tablet compression techniques that allow compression of at least two compositions to form tablets comprising at least two clearly adjacent layers, each containing one of at least two compositions. Eg. such tablets can be made in tabletting machines by filling the compression mold with the first composition and tableting the first composition, then applying to the surface of the compressed first composition the second composition and then tableting the two compositions to form the final layered tablet. The immediate release composition may be any composition known in the art.

The invention also encompasses the use of high molecular weight polyethylene oxide, based on rheological measurements, approximately equal to at least 1,000,000, as a matrix forming material for producing a solid oral extended release dosage form containing an active ingredient selected from opioids for imparting a solid oral prolonged-release dosage form to alcohol extraction strength. The use can be carried out as described herein in relation to the process or preparations described, or in any other manner conventional in the art.

It is observed that the formulations of the present invention containing high molecular weight polyethylene oxide can be flattened to a thickness of between about 15 and about 18% relative to the thickness of the uncoated formulation and that upon dissolution the flat tablet partially or significantly returns to its initial uncoated shape , apart from the swelling effect that also occurs during dissolution, i.e. during dissolution the tablet thickness increases and the diameter decreases significantly. Without being bound by any particular theory, it is assumed that high molecular weight polyethylene oxide has shape memory and the ability to return to its original shape after deformation, e.g., after flattening, in an environment that allows it, such as the aqueous environment used in dissolution tests. It is believed that this ability contributes to tampering, in particular alcohol resistance to the dosage forms of the invention.

The invention also encompasses a method of treatment wherein the dosage form is administered to treat a disease or certain conditions in a patient in need of treatment, in particular for the treatment of pain, and the use of the dosage form of the invention for the manufacture of medicaments for the treatment of a disease or certain condition in a patient in need treatment, in particular pain treatment.

In one aspect of the invention, the solid oral extended release pharmaceutical dosage form is administered twice daily, which provides an averagemax about 2 to about 6 hours, about 2.5 to about 5.5 hours, or about 2.5 to about 5 hours after administration of a fixed or single dose to human patients. The dosage form may contain oxycodone, a salt thereof, hydromorphone or a salt thereof.

In one aspect of the invention, the solid oral extended release pharmaceutical dosage form is administered once daily, which provides an averagemax about 3 to about 10 hours or about 4 to about 9 hours or about 5 to about 8 hours after administration of a fixed or single dose to human patients. The dosage form may contain oxycodone, a salt thereof, hydromorphone or a salt thereof.

In a further aspect of the invention, the solid oral extended release pharmaceutical dosage form is administered twice daily, wherein the dosage form comprises oxycodone or a salt thereof in an amount from about 10 mg to about 160 mg, and the dosage form provides an average maximum plasma concentration of oxycodone ( Cmax) to about 240 ng / ml or from about 6 ng / ml to about 240 ng / ml after administration of a fixed or single dose to human patients.

In another aspect of the invention, there is provided a solid oral extended release pharmaceutical dosage form, the dosage form comprising oxycodone or a salt thereof from about 10 mg to about 40 mg, and the dosage form provides an average maximum plasma oxycodone concentration (Cmax) from about 6 ng / ml to about 60 ng / ml after administration of a fixed or single dose to human patients.

In another aspect of the invention there is provided a solid oral extended release pharmaceutical dosage form that is bioequivalent to the commercially available OxyContin ™ product.

In a further aspect of the invention there is provided a solid oral extended release pharmaceutical dosage form that is bioequivalent to the commercially available Palladone ™ product marketed in St. Ser. North America in 2005.

In a further aspect of the invention, a solid oral extended release pharmaceutical dosage form is provided,

In which the active agent is oxycodone hydrochloride and

wherein the 10 mg oxycodone hydrochloride dosage form tested in comparative clinical studies is bioequivalent to the comparator tablet containing 10 mg oxycodone hydrochloride in a matrix formulation containing:

a) oxycodone hydrochloride: 10.0 mg / tablet

b) lactose (spray dried): 69.25 mg / tablet

c) Povidone: 5.0 mg / tablet

d) Eudragit® RS 30D (solids): 10.0 mg / tablet

e) Triacetin®: 2.0 mg / tablet

f) stearyl alcohol: 25.0 mg / tablet

g) talc: 2.5 mg / tablet

h) magnesium stearate: 1.25 mg / tablet;

and, wherein the comparative tablet is made by following the steps:

1. Eudragit® RS 30D and Triacetin® are combined while passing through a 60 mesh screen, and mixed using low shear for approximately 5 minutes or until a homogeneous dispersion is observed.

2. Oxycodone hydrochloride, lactose, and povidone are placed in a fluid bed granulator / dryer (FBD) vessel, and the suspension is sprayed into a powder in a fluidized bed.

3. After spraying, the granulate, if necessary, is passed through a No. 12 screen to reduce the size of the lumps.

4. The dry granulate is placed in a mixer.

5. At the same time, stearyl alcohol in the required amount melts at about 70 ° C.

6. The molten stearic alcohol is added to the granulate while mixing.

7. The waxed granulate is transferred to a fluidized bed granulator / dryer or tray and allowed to cool to room temperature or below.

8. The cooled granulate is then passed through a No. 12 screen.

9. The waxed granulate is placed in a mixer / mixer and treated with talc and magnesium stearate in the required amounts for about 3 minutes.

Ten. The granules are compressed into 125 mg tablets using a suitable tabletting machine.

Pharmacokinetic parameters such as Cmax itmax, AUCt, AUCinf, etc. describing the blood plasma curve can be obtained in clinical trials by first administering a single dose of an active agent, e.g. oxycodone, to a number of healthy testers. Then, the values obtained for blood plasma determined for individual persons are averaged by obtaining e.g.

average AUC, C

In the context of the present invention, pharmacokinetic parameters such as AUC, Cmax itmax refer to average values. Then, in the context of the invention, in vivo parameters such as values for AUC, Cmax, volmax, or analgesic efficacy, refers to parameters or values obtained after administration of a fixed or single dose to human patients.

C valuemax indicates the maximum concentration of active agent in the blood plasma. T valuemax indicates a point in time when the C value is reachedmax. In other words, volmax is the max max point over time when plasma is observed.

The AUC (surface area under the proportional to the maximum concentration corresponds to the AUC is under the curve) concentration curve. The value of the amount of active agent absorbed entirely into the blood circulation and is therefore a measure of bioavailability. AUC valuet corresponds to the area under the plasma concentration curve as a function of time elapsed from administration to the last moment when plasma concentration can be measured and calculated by linear up / log down matching using the trapezoidal rule for approximate integration.

AUCinf is the area under the plasma concentration versus time curve extrapolated to infinity and is calculated from the formula:

C AUCinf = AUCt + C "

λ where Ct is the latest measured value of plasma concentration ilFROM is the observed end-rate constant.

lFROM is the observed rate constant in the terminal phase, where lFROM is the magnitude of the slope of the line drawn using linear time regression in the final phase.

t1 / 2Z means observed end-stage is commonly seen lFROM. from the concentration depending on the plasma half-life in termed t1 / 2Z = (ln2) /

Delay time tlag is estimated as the time point immediately before the first measurable plasma concentration.

The term "healthy" human subject refers to a male or female mean of height, weight and physiological parameters such as blood pressure, etc. Healthy human subjects are selected according to the inclusion and exclusion criteria based on and consistent with recommendations of the International Conference for Harmonization of Clinical Trials (ICH).

Thus, the inclusion criteria include men and women aged 18 to 50 inclusive, body weight in the range from up to 100 kg (110 to 220 lbs) and body mass index (BMI) values> 18 and £ 34 (kg / m2) who are healthy and do not have significantly incorrect test results, which is determined by analyzing medical history, physical examination, vital signs and the electrocardiogram, with women who may become pregnant must use an adequate and reliable method of contraception, such as a barrier with an additional foam or jelly with spermicidal effect, intrauterine device, hormonal contraception (consecutive hormonal contraceptives used alone are not acceptable), but women who are postmenopausal must be postmenopausal> 1 year and must have elevated serum alveolar gonadotropin (FSH) levels, and patients must be ready to eat all food provided during the study.

The next inclusion criterion may be that patients refrain from strenuous exercise throughout the study, and that they will not begin a new exercise program or participate in any unusual strenuous physical exertion.

Exclusion criteria include women who are pregnant (positive human chorionic gonadotropin test) or nursing women, patients who have any past history or are currently abusing alcohol or are taking drugs, have a history or are currently able to which may interfere with the absorption, breakdown, metabolism or excretion of the medicine, have taken an opioid containing medicine within the last thirty (30) days, have a history of sensitivity to oxycodone, naltrexone, or related compounds, have any history of frequent nausea or vomiting regardless of etiology, have any history of epileptic seizures or head injuries with current complications, have participated in a clinical trial of the drug in the last thirty (30) days before the initial dose in this study, have suffered from any major illness during the last thirty (30) days prior to the initial dose in this study, have taken any drug including thyroid hormone replacement therapy (hormonal contraception is allowed), vitamins, herbs, and / or mineral supplements 7 days preceding the initial dose, patients who refused to refrain from taking food for 10 hours before and 4 hours after administration or for 4 hours after administration of study drugs and refrain from taking complete caffeine or xanthine during each restriction, patients who took alcoholic beverages within forty-eight (48) hours before the start of the study by giving the medicine (day 1) or at any time after the start of the study by giving the medicine, patients, who have histories of smoking or use of nicotine products within 45 days prior to drug testing or a urine cotinine positive test, received blood or blood products within 30 days prior to administration of study drugs or at any time during the study, except as required by clinical trial protocol, positive results of screening test for urine drug content, alcohol content when reporting in each period, and hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb) (unless the patient has been immunized with this antibody), hepatitis C antibody (anti-HCV), positive test for Naloxone HCl, symptom Gilbert or any other known hepatobiliary abnormalities and such patients who according to the applicant are unsuitable for a reason (s) not specified above.

Patients who meet all inclusion criteria and do not meet any of the exclusion criteria will be randomly selected for the study.

The selected population is the group of patients who provided informed consent.

A randomized population in which safety was assessed is a group of patients who were randomly selected, received study medication, and in whom safety was assessed at least after receiving one dose.

A complete population-based PK analysis will be performed on a randomly selected patient group who received study medication and has at least one normal PK value. Patients who experience vomiting within 12 hours after taking the dose may be included in the test based on visual assessment of the PK profiles before closing the database. Patients and profiles / values excluded from the analyzed system will be documented in the Statistical Analysis Plan.

In the case of a Naloxone HCl challenge test, vital signs and pulse oximetry results (SPO2) is obtained before the Naloxone HCl challenge. The Naloxone HCl challenge test can be performed by intravenous or subcutaneous administration. For intravenous administration, the needle or tube should be left in the arm during administration. 0.2 mg Naloxone HCl (0.5 ml) is administered by intravenous injection. The patient is observed for 30 seconds to obtain evidence of withdrawal of signs or symptoms. 0.6 mg Naloxone HCl (1.5 mL) is then administered by intravenous injection. The patient is observed for 20 minutes to regress the signs and symptoms. For subcutaneous administration, 0.8 mg Naloxone HCl (2.0 mL) is administered and the patient observed for 20 minutes to provide evidence of a reversal of signs or symptoms. After a 20-minute observation, vital signs and SPO results are obtained after a test provoked by Naloxone HCl2.

itself

Vital signs include systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and mouth temperature.

In the case of the question "How do you feel?", Patients will be asked to answer the question not suggesting "How do you feel?" Such as "Have there been any changes in your state of health since the classification / last the answer given? ”at every moment of measuring vital signs. The patient's response will be assessed to determine if any adverse event has been reported. Patients are also encouraged to voluntarily report an adverse event at any other time during the study.

Each patient receiving food as part of the study will consume a standard high-fat meal in accordance with the guidelines of "Guidance for Industry: FoodEffect Bioavailability and Fed Bioequivalence Studies" (US Human Services, Food and Drug Drug Evaluation and Research, will be a topic

Department of Administration, December 2002)

Health

Center and for before

The meal will be delivered 30 minutes in dosing and will be consumed at a constant rate over a 25-minute period so that it is completed 5 minutes before dosing.

Clinical laboratory tests conducted in the course of clinical trials include biochemistry (fasting for at least 10 hours), hematology, serology, urine analysis, drug abuse testing, and other tests.

Biochemical analyzes (fasting for at least 10 hours) include determining the content of albumin, alkaline phosphatase, alanine aminotransferase (alanine transaminase, ALT), aspartate aminotransferase (aspartate transaminase, AST), calcium, chloride, creatinine, glucose, inorganic phosphate, potassium, sodium, total bilirubin, total protein, urea, lactate dehydrogenase (LDH), direct bilirubin and CO2.

Hematological analyzes include determining the content of hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell count, white blood cell percentage (% and absolute): basophils, eosinophils, lymphocytes, monocytes and neutrophils.

Serological analyzes include the determination of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb) and hepatitis C antibody (anti-HCV).

Urinalysis includes determination of color, appearance, pH, glucose, ketone, urobilinogen, nitrite, occult blood, protein, leukocyte esterase, microscopic and macroscopic assessment, specific gravity.

Drug abuse testing includes urine screening for opiates, amphetamines, cannabinoids, benzodiazepines, cocaine, cotinine, barbiturates, phencyclidine, methadone and propoxyphene, and alcohol testing such as blood alcohol analysis and content testing alcohol in the breath.

Other tests for women only include a serum-based pregnancy test, a urine-based pregnancy test and a serum follicular gonadotropin (FSH) test (only for women reporting menopause).

Detailed description of beneficial solutions

The invention is further described below with reference to the accompanying examples. However, it should be understood that the following description is illustrative only and in no way restricts the invention.

Example 1

In Example 1,200 mg, a tablet containing 10 mg oxycodone hydrochloride was prepared using high molecular weight polyethylene oxide in combination with hydroxypropyl cellulose.

Composition:

<td>Ingredient</td><td>mg / unit</td><td>ABOUT. %</td>

<td>Oxycodone hydrochloride</td><td> 10</td><td> 5</td>

<td>Poly (ethylene oxide) (molecular weight: approximately 4,000,000; Polyox ™ WSR-301)</td><td> 160</td><td> 80</td>

<td>Hydroxypropyl cellulose (Klucel ™ HXF)</td><td> 30</td><td> 15</td>

<td>Whole</td><td> 200</td><td> 100</td>

Manufacturing Process:

according to the following stages poly (ethylene oxide) and dry in double high / low strength mode stage 1 compressed to with a single interference crushing station)

The tablets were manufactured processing:

1. Oxycodone hydrochloride, hydroxypropyl cellulose was mixed with a paddle mixer working in abrasion Black & Decker Handy Chopper with a capacity equal to

1.5 cup.

2. The mixture obtained in the target mass, using a tablet press Manesty Type F 3

3. The tablets obtained in step 2 were spread on a tray and to cure the tablets they were placed in a Hotpack model 435304 oven at 70 ° C for about 14.5 hours.

In vitro tests including testing for strength (hammer and strength test and alcohol extraction strength test were carried out as follows.

The tablets were tested in vitro in USP Apparathus 2 (paddle stirrer) at 50 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C using a Perkin Elmer UV-VIS Lambda 20, UV at 230 nm spectrophotometer. The results are shown in Table 1.1.

Uncured, cured and tamper-resistant tablets, i.e. flattened, cured tablets were tested. Cured tablets were flattened with a hammer, using 7 hand strokes to give physical resistance to interference. Tablet dimensions before and after flattening and dissolution profiles were estimated on separate samples. The results are shown in Table 1.1.

In the next tamper test, the cured tablets were subjected to a crushing strength test to assess the fracture strength with a maximum force of 196 N using a Schleuniger 2E / 106 device. The results are also shown in Table 1.1.

In addition, cured tablets were tested in vitro to determine resistance to alcohol extraction using ethanol / simulated gastric fluid (SGF) environment at 0%, 20% and 40% ethanol concentrations. Tests were carried out at USP 2 Apparathus (paddle stirrer) at revolutions per minute in 500 ml medium at 37 ° C, using a Perkin Elmer UV-VIS Lambda 20 spectrophotometer, UV at 220 nm. Tests were carried out for inclusive time points

0.5 and 1 hour. The results are also shown in Table 1.2.

Table 1.1

<td colspan="3"></td><td colspan="2">cured</td>

<td colspan="2"></td><td>Unpaved whole</td><td>All</td><td>Flattened by 7 strokes hammer</td>

<td rowspan="4">dimensions pills</td><td>Thickness (mm)</td><td> 4,521</td><td> 4,391</td><td> 2,232</td>

<td>Diameter (mm)</td><td> -</td><td> 7,561</td><td> 10,272</td>

<td>Strength for crushing (N)</td><td> -</td><td> 196+3</td><td> -</td>

<td>Diameter (mm) after conducting crushing strength test</td><td></td><td> 7,331</td><td></td>

<td rowspan="6">Dissolving (% released) (n = 3 tablets per vessel)</td><td>0.5 hours</td><td> 13</td><td> 34</td><td> 33</td>

<td>2 hours</td><td> 28</td><td> 63</td><td> 62</td>

<td>4 hours</td><td> 43</td><td> 81</td><td> 83</td>

<td>8 hours</td><td> 65</td><td> 86</td><td> 87</td>

<td>17 hours</td><td> 85</td><td> 86</td><td> 87</td>

1 n = median of 3 measurements 2 n = median of 5 measurements 3 196+ means that tablets exposed to a maximum force of 196 N did not break, n = median of 3 measurements

Table 1.2

<td colspan="7">Dissolution (% released) (n = 2 tablets per dish)</td>

<td>Time</td><td colspan="2">0% concentration ethanol in SGF</td><td colspan="2">20% concentration ethanol in SGF</td><td colspan="2">40% concentration ethanol in SGF</td>

<td></td><td>unpaved</td><td>cured</td><td>unpaved</td><td>cured</td><td>unpaved</td><td>cured</td>

Example 2

In Example 2, three different 100 mg tablets containing 10 and 20 mg oxycodone hydrochloride were prepared using high molecular weight polyethylene oxide and optionally hydroxypropyl cellulose.

compositions:

<td></td><td>Example 2.1</td><td>Example 2.2</td><td>Example 2.3</td>

<td>Ingredient</td><td>mg / Unit Barrack</td><td>mg / Unit Barrack</td><td>mg / Unit Barrack</td>

<td>Oxycodone hydrochloride</td><td> 10</td><td> 20</td><td> 10</td>

<td>Poly (ethylene oxide) (mass molecular: approximately 4000000; Polyox ™ WSR301)</td><td> 90</td><td> 80</td><td> 85</td>

<td>hydroxypropyl (Klucel ™ HXF)</td><td> 0</td><td> 0</td><td> 5</td>

<td>Whole</td><td> 100</td><td> 100</td><td> 100</td>

Manufacturing Process:

The tablets were made according to the following processing steps:

1. Oxycodone hydrochloride, polyethylene oxide and hydroxypropyl cellulose were dry-mixed in a double paddle mixer working in high / low abrasion mode Black & Decker Handy Chopper with a capacity equal to

1.5 cup.

2. The mix obtained in stage 1 was compressed to the target mass using a press with a station for a single tablet Manesty Type F 3.

3. The tablets obtained in step 2 were spread on a tray and placed in a Hotpack model 435304 oven at 70-75 ° C for about 6 to hours to cure the tablets.

In vitro tests including interference resistance testing (bench press and crushing strength test) were carried out as follows.

Cured tablets were tested in vitro using USP

Apparatus 2 (paddle stirrer) at 50 rpm in 500 ml simulated gastric fluid without enzymes (SGF) at 37 ° C using a Perkin Elmer UV10 VIS Lambda 20, UV at 220 nm spectrophotometer. Cured and cured flattened tablets were tested. The tablets were flattened under 2,500 psi using a Carver table press to confer physical resistance to interference. The results are shown in Table 2.

Table 2

<td colspan="2" rowspan="2"></td><td colspan="2">Example 2.1</td><td colspan="2">Example 2.2</td><td colspan="2">Example 2.3</td>

<td>All (N = 6)</td><td>Flattened in press table</td><td>All</td><td>Flattened in press table</td><td>All (N = 5)</td><td>Flattened in press tablej</td>

<td rowspan="4">dimensions pills</td><td>Thickness (Mm)</td><td> 3,36</td><td> 0,58</td><td> 3,14</td><td> 0,84</td><td> 3,48</td><td> 0,49</td>

<td>Diameter (Mm)</td><td> 6,48</td><td> 12,80</td><td> 6,58</td><td> 13,44</td><td> 6,46</td><td> 12,86</td>

<td>Thickness (%)</td><td> -</td><td> 17,3</td><td> -</td><td> 26,8</td><td> -</td><td> 14,0</td>

<td>Resistance to crushing (N)</td><td> 196+1</td><td>n / a</td><td> 196+1</td><td>N / A</td><td> 196+1</td><td>n / a</td>

<td rowspan="6">dissolution (% released) (N = 1)</td><td>0.5 hours</td><td> 34</td><td> 46</td><td> 42</td><td> 50</td><td> 40</td><td> 56</td>

<td>2 hours</td><td> 72</td><td> 78</td><td> 78</td><td> 91</td><td> 77</td><td> 89</td>

<td>4 hours</td><td> 81</td><td> 82</td><td> 95</td><td> 93</td><td> 93</td><td> 100</td>

<td>8 hours</td><td> 82</td><td> 82</td><td> 95</td><td> 93</td><td> 94</td><td> 100</td>

<td>12 hours</td><td> 83</td><td> 82</td><td> 96</td><td> 94</td><td> 95</td><td> 101</td>

<td colspan="8">1 196+ means that tablets exposed to a maximum force of 196 N did not break</td>

Example 3

In Example 3, a 200 mg tablet containing was prepared

10mg oxycodone hydrochloride and high molecular weight polyethylene oxide.

Composition:

<td>Ingredient</td><td>mg / unit</td><td>ABOUT. %</td>

<td>Oxycodone hydrochloride</td><td> 10</td><td> 5</td>

<td>Poly (ethylene oxide) (molecular weight: approximately 4,000,000; Polyox ™ WSR301)</td><td> 188</td><td> 94</td>

<td>Magnesium stearate</td><td> 2</td><td> 1</td>

<td>Whole</td><td> 200</td><td> 100</td>

Manufacturing Process:

The tablets were made according to the following processing steps:

1. Oxycodone hydrochloride, polyethylene oxide and magnesium stearate were dry mixed in a double paddle mixer working in high / low abrasion mode Black & Decker Handy Chopper with a capacity of 1.5 cup.

2. The mix obtained in stage 1 was compressed to the target mass using a press with a station for a single tablet Manesty Type F 3.

3. The tablets obtained in step 2 were spread on a tray, and then to cure the tablets, they were placed in a Hotpack model 435304 oven at 70 ° C for 1 to 14 hours.

In vitro tests including an interference test (breaking strength test) were carried out as follows:

The tablets, after curing for 2, 3, 4, 8, and 14 hours, were tested in vitro using USP Apparatus 1 (drum mixer) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C using a Perkin Elmer UVVIS Lambda 20 USP Apparatus spectrophotometer, UV at 220 nm. The dimensions of the uncured and cured tablets and the dissolution results are presented in Table 3.

In the next tamper test, cured and unhardened tablets were subjected to a crush strength test to assess the fracture strength with a maximum force of 196 N using a Schleuniger 2E / 106 device. The results are shown in Table 3.

Table 3

<td colspan="2" rowspan="2"></td><td rowspan="2">unpaved2</td><td colspan="5">Cure Time (hours)</td>

<td rowspan="4">dimensions pills</td><td>Weight (mg)</td><td> 208</td><td> 208</td><td> 209</td><td> 209</td><td> 208</td><td> 210</td>

<td>Thickness (mm)</td><td> 4,74</td><td> 5,17</td><td> 5,25</td><td> 5,17</td><td> 5,17</td><td> 4,85</td>

<td>Diameter (mm)</td><td> 7,93</td><td> 7,85</td><td> 7,80</td><td> 7,75</td><td> 7,69</td><td> 7,64</td>

<td>Strength for crushing (N)</td><td> 176</td><td> 196+3</td><td> 196+3</td><td> 196+3</td><td> 196+3</td><td> 196+3</td>

<td rowspan="6">dissolution (% released) (N = 2)</td><td>0.5 hours</td><td rowspan="6">No studied</td><td rowspan="6">No studied</td><td> 16</td><td> 11</td><td> 15</td><td> 33</td>

<td>2 hours</td><td> 34</td><td> 28</td><td> 36</td><td> 69</td>

<td>4 hours</td><td> 54</td><td> 45</td><td> 58</td><td> 87</td>

<td>8 hours</td><td> 81</td><td> 69</td><td> 83</td><td> 93</td>

<td>12 hours</td><td> 96</td><td> 83</td><td> 92</td><td> 94</td>

1 Tablet dimensions n = 4 2 Tablet dimensions n = 10 3 196+ means that tablets exposed to a maximum force of 196 N did not break.

Example 4

In Example 4, six different 100 mg tablets (Examples 4.1 to 4.6) were prepared containing 10 mg oxycodone hydrochloride and polyethylene oxides in varying amounts and with different molecular weights.

compositions:

<td>Ingredient</td><td>mg / unit MNOs</td><td>mg / jeans nostkę</td><td>Mg / jeans nostkę</td><td>mg / jeans nostkę</td><td>mg / jeans nostkę</td><td>mg / jeans nostkę</td>

<td>hydrochloride oxycodone</td><td> 10</td><td> 10</td><td> 10</td><td> 10</td><td> 10</td><td> 10</td>

<td>Poly (ethylene oxide) (molecular mass: w approximately 4,000,000; Polyox ™ WSR301)</td><td> 89,5</td><td> 79,5</td><td> 69,5</td><td> 89,0</td><td> 0</td><td> 0</td>

<td>Poly (ethylene oxide) (molecular weight; w approximately 100,000; Polyox ™ N10)</td><td> 0</td><td> 10</td><td> 20</td><td> 0</td><td> 0</td><td> 0</td>

<td>Poly (ethylene oxide) (molecular mass: w approximately 2,000,000; Polyox ™ N-60K)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 89,5</td>

<td>Poly (ethylene oxide) molecular weight; in approximately 700,000; Polyox ™ WSR 303)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 89,5</td><td> 0</td>

<td>butylated hydroxytoluene (BHT)</td><td> 0</td><td> 0</td><td> 0</td><td> 0,5</td><td> 0</td><td> 0</td>

<td>Magnesium stearate</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td>

<td>Whole</td><td> 100</td><td> 100</td><td> 100</td><td> 100</td><td> 100</td><td> 100</td>

<td>Mix weight (g)</td><td> 125</td><td> 125</td><td> 125</td><td> 125</td><td> 157,5</td><td> 155,5</td>

<td>Whole batch weight (g) (quantity produced)</td><td> 250</td><td> 250</td><td> 250</td><td> 250</td><td> 157,5</td><td> 155,5</td>

The tablets were made according to the following processing steps:

1. Oxycodone hydrochloride and poly (ethylene oxide) (and BHT 5 if required) were mixed dry for 30 seconds in a double paddle mixer working in high / low abrasion mode Black & Decker Handy Chopper.

2. Magnesium stearate was added to the mix obtained in step 1 and the whole was mixed for another 30 seconds.

3. The mix obtained in step 2 was compressed to the target mass using a Manesty Type F 3 single tablet press station using a standard rounded (0.2656 inch) concave device.

4. The tablets obtained in step 3 were introduced into a 15-inch coating drum deflector (LCDS Vector Laboratory Development Coating System) at 38 rpm. A temperature probe (wired thermocouple) was placed inside the coating drum near the tablet bed to monitor the bed temperature. The tablet bed was heated at a temperature of about 70-80 ° C (the temperature used for each example is detailed in tables 4.1 to 4.6) for a minimum of 30 minutes and a maximum of 2 hours. The tablet bed was then cooled and removed from the drum.

In vitro tests including an interference test (breaking strength and hammer test) were carried out as follows:

Uncured and cured tablets after 0.5, 1, 1.5 and 2 hours of curing were tested in vitro using USP Apparatus 1 (drum mixer) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C, using a Perkin Elmer UVVIS Lambda 20, UV spectrophotometer at 220 nm. Tablet dimensions, appropriate dissolution results, curing times and temperatures used are presented in Tables 4.1 to 4.6.

In addition, the tablets were flattened with a hammer using 10 hand strokes to give physical tamper resistance (hammer test).

Table 4.1

<td colspan="2" rowspan="3"></td><td colspan="5">Example 4.1</td>

<td rowspan="2">unpaved (n = 10)</td><td colspan="4">Cure Time (hours) (n = 5)</td>

<td rowspan="5">Pill dimensions</td><td>Weight (mg)</td><td> 108</td><td> 109</td><td> 108</td><td> 107</td><td> 107</td>

<td>Thickness (mm)</td><td> 3,64</td><td> 3,93</td><td> 3,94</td><td> 3,90</td><td> 3,83</td>

<td>Diameter (mm)</td><td> 6,74</td><td> 6,62</td><td> 6,57</td><td> 6,55</td><td> 6,52</td>

<td>Resistance to crushing (N)</td><td> 94</td><td> 196+2</td><td> 196+2</td><td> 196+2</td><td> 196+2</td>

<td>Diameter (mm) after the test strength for crushing (measured immediately after assay)</td><td>crushed1</td><td> 5,15</td><td> 5,38</td><td> 5,23</td><td> 5,44</td>

<td rowspan="8">Process curing Temperature deposit tablets, ° C (probe temperature in the drum)</td><td>0 min</td><td></td><td> 19,7</td><td> -</td><td> -</td><td> -</td>

<td>30 minutes</td><td></td><td> 73,5</td><td></td><td></td><td></td>

<td rowspan="3">dissolution (% released)</td><td>0.5 hours</td><td> 19</td><td> 21</td><td> 18</td><td> 18</td><td> 19</td>

<td>2 hours</td><td> 47</td><td> 49</td><td> 46</td><td> 46</td><td> 50</td>

<td></td><td>4 hours</td><td> 71</td><td> 76</td><td> 70</td><td> 69</td><td> 75</td>

<td rowspan="2"></td><td>8 hours</td><td> 93</td><td> 96</td><td> 91</td><td> 89</td><td> 93</td>

<td>12 hours</td><td> 99</td><td> 99</td><td> 96</td><td> 93</td><td> 96</td>

<td colspan="2">After the test using a hammer3</td><td>n / a</td><td> 1,70</td><td> 2,18</td><td> 2,37</td><td> 2,09</td>

<td colspan="2">(10 hand strokes)</td><td></td><td></td><td> 2,31</td><td> 2,06</td><td> 2,26</td>

<td>Thickness (mm)</td><td></td><td></td><td></td><td> 2,39</td><td> 2,66</td><td> 2,28</td>

<td>1 Pills</td><td>crushed</td><td colspan="4">and crushed during</td><td>test</td>

<td>strength</td><td>for crushing</td><td></td><td></td><td></td><td></td><td></td>

<td colspan="5">2 196+ means that the tablets are treated</td><td colspan="2">the maximum</td>

<td colspan="4">force equal to 196 N did not break</td><td></td><td></td><td></td>

<td colspan="4">3 10 hammer strokes were used, tablets</td><td colspan="2">flattened</td><td>but</td>

<td>not torn</td><td colspan="5">for parts, a hammer blow resulted</td><td>some</td>

<td colspan="2">edge cracks.</td><td></td><td></td><td></td><td></td><td></td>

Table 4.2

<td colspan="2" rowspan="3"></td><td colspan="5">Example 4.2</td>

<td rowspan="2">Nieutwa rdzone (n = 10)</td><td colspan="4">Cure Time (hours) (n = 5)</td>

<td rowspan="5">dimensions pills</td><td>Weight (mg)</td><td> 108</td><td> 109</td><td> 109</td><td> 109</td><td> 107</td>

<td>Thickness (mm)</td><td> 3,65</td><td> 3,90</td><td> 3,92</td><td> 3,87</td><td> 3,74</td>

<td>Diameter (mm)</td><td> 6,74</td><td> 6,61</td><td> 6,54</td><td> 6,52</td><td> 6,46</td>

<td>Strength for crushing (N)</td><td> 93</td><td> 196+3</td><td> 196+3</td><td> 196+3</td><td> 196+3</td>

<td>Diameter (mm) after the test strength for crushing (measured directly after the test)</td><td>crushed2</td><td> 5,40</td><td> 5,37</td><td> 5,36</td><td> 5,61</td>

<td></td><td>Diameter after relaxation (mm) after conducting test strength for crushing (Period NLT relaxation 15 minutes)</td><td colspan="2"></td><td> 5,60</td><td> 5,52</td><td> 5,48</td><td> 5,73</td>

<td rowspan="8">Process curing Temperature deposits of tablets ° C (probe temperature in the drum)</td><td>0 min</td><td colspan="2"></td><td> 20,2</td><td> -</td><td> -</td><td> -</td>

<td>30 minutes</td><td colspan="2"></td><td> 76,1</td><td></td><td></td><td></td>

<td rowspan="6">dissolution (% released) (N = 3)</td><td colspan="2">0.5 hours</td><td> -</td><td> 20</td><td> 20</td><td> -</td><td> 29</td>

<td colspan="2">2 hours</td><td></td><td> 47</td><td> 47</td><td></td><td> 66</td>

<td colspan="2">4 hours</td><td> -</td><td> 70</td><td> 70</td><td> -</td><td> 90</td>

<td colspan="2">8 hours</td><td> -</td><td> 89</td><td> 91</td><td> -</td><td> 95</td>

<td colspan="2">12 hours</td><td> -</td><td> 92</td><td> 94</td><td> -</td><td> 94</td>

<td colspan="3" rowspan="3">After the test using a hammer (10 manual hammer blows) Thickness (mm)</td><td rowspan="3">n / a</td><td> 1,98</td><td> 2,00</td><td> 1,80</td><td> 1,62</td>

2 Tablets crushed and crushed during a crushing strength test 3 196+ means that tablets exposed to a maximum force of 196 N did not break.

Table 4.3

<td colspan="2" rowspan="3"></td><td colspan="5">Example 4.3</td>

<td rowspan="2">unpaved (n = 10)</td><td colspan="4">Cure Time (hours) (n = 5)</td>

<td rowspan="6">dimensions pills</td><td>Weight (mg)</td><td> 108</td><td> 107</td><td> 108</td><td> 108</td><td> 107</td>

<td>Thickness (mm)</td><td> 3,63</td><td> 3,85</td><td> 3,82</td><td> 3,78</td><td> 3,72</td>

<td>Diameter (mm)</td><td> 6,74</td><td> 6,61</td><td> 6,55</td><td> 6,48</td><td> 6,46</td>

<td>Strength for crushing (N)</td><td> 91</td><td> 196+3</td><td> 196+3</td><td> 196+3</td><td> 196+3</td>

<td>Diameter (mm) after the test strength for crushing (measured directly after the test)</td><td>zmiażdżo AD2</td><td> 5,58</td><td> 5,60</td><td> 5,56</td><td> 5,72</td>

<td>The diameter after relaxation (mm) after conducting test strength for crushing (Period relaxation NLT 15 minutes)</td><td></td><td> 5,77</td><td> 5,75</td><td> 5,68</td><td> 5,82</td>

<td>Process curing</td><td>0 min</td><td></td><td> 20,3</td><td> -</td><td> -</td><td> -</td>

<td>temperature deposit tablets ° C</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="7">(probe temperature in the drum)</td><td>10 min</td><td> -</td><td> 71,0</td><td> -</td><td> -</td><td> -</td>

<td>30 minutes</td><td> -</td><td> 75,9</td><td> -</td><td> -</td><td> -</td>

<td rowspan="6">dissolution (% released)</td><td>0.5 hours</td><td> -</td><td> 22</td><td> 23</td><td> -</td><td> 33</td>

<td>2 hours</td><td> -</td><td> 49</td><td> 54</td><td> -</td><td> 76</td>

<td>4 hours</td><td> -</td><td> 70</td><td> 80</td><td> -</td><td> 93</td>

<td>8 hours</td><td> -</td><td> 94</td><td> 95</td><td> -</td><td> 96</td>

<td>12 hours</td><td> -</td><td> 96</td><td> 96</td><td> -</td><td> 96</td>

<td colspan="2" rowspan="3">After the test using a hammer (10 hand strokes hammer) Thickness (mm)</td><td rowspan="3">n / a</td><td> 2,16</td><td> 1,95</td><td> 1,43</td><td> 1,53</td>

<td colspan="7">2 Tablets crushed and crushed during a crushing strength test3 196+ means that tablets exposed to a maximum force of 196 N did not break.</td>

Table 4.4

<td colspan="2" rowspan="3"></td><td colspan="5">Example 4.4</td>

<td rowspan="2">unpaved (N = 10)</td><td colspan="4">Cure Time (hours) (N = 5)</td>

<td rowspan="3">dimensions pills</td><td>Weight (mg)</td><td> 101</td><td> 101</td><td> 101</td><td> 101</td><td> 101</td>

<td>Thickness (Mm)</td><td> 3,49</td><td> 3,75</td><td> 3,71</td><td> 3,69</td><td> 3,70</td>

<td>Diameter (Mm)</td><td> 6,75</td><td> 6,59</td><td> 6,55</td><td> 6,55</td><td> 6,52</td>

<td rowspan="3"></td><td>Resistance to crushing (N)</td><td> 81</td><td> 196+3</td><td> 196+3</td><td> 196+3</td><td> 196+3</td>

<td>Diameter (mm) after completion test crushing strength (measured immediately after test</td><td>crushed2</td><td> 5,39</td><td> 5,39</td><td> 5,39</td><td> 5,47</td>

<td>Diameter after relaxation (mm) after completion test resistance to crushing (Period relaxation NLT 15 minutes)</td><td></td><td> 5,58</td><td> 5,59</td><td> 5,58</td><td> 5,63</td>

<td rowspan="6">Process curing Temperature deposits of tablets ° C</td><td>0 min</td><td></td><td> 37,3</td><td></td><td></td><td></td>

<td>30 minutes</td><td> -</td><td> 76,2</td><td> -</td><td> -</td><td> -</td>

<td rowspan="3">(probe temperature in pan)</td><td>60 min</td><td></td><td></td><td> 78,7</td><td></td><td></td>

<td rowspan="6">dissolution (% released) (N = 3)</td><td>0.5 hours</td><td> -</td><td> 17</td><td> 16</td><td> -</td><td> -</td>

<td>2 hours</td><td></td><td> 41</td><td> 40</td><td></td><td></td>

<td>4 hours</td><td> -</td><td> 63</td><td> 59</td><td> -</td><td> -</td>

<td>8 hours</td><td> -</td><td> 79</td><td> 75</td><td> -</td><td> -</td>

<td>12 hours</td><td> -</td><td> 82</td><td> 80</td><td> -</td><td> -</td>

<td colspan="2" rowspan="3">After the test using a hammer (10 hand strokes) Thickness (mm)</td><td rowspan="3"></td><td> 2,11</td><td> 2,42</td><td> 2,14</td><td> 2,18</td>

<td colspan="7">2 Tablets crushed and crushed during the test crushing strength.3 196+ means that tablets exposed to a maximum force of 196 N did not break.</td>

Table 4.5

<td colspan="2" rowspan="3"></td><td colspan="5">Example 4.5</td>

<td rowspan="2">unpaved d (n = 10)</td><td colspan="4">Cure Time (hours) (n = 5)</td>

<td rowspan="3">dimensions pills</td><td>Weight (mg)</td><td> 108</td><td> 108</td><td> 107</td><td> 107</td><td> 107</td>

<td>Thickness (Mm)</td><td> 3,61</td><td> 3,87</td><td> 3,84</td><td> 3,84</td><td> 3,84</td>

<td>Diameter (Mm)</td><td> 6,74</td><td> 6,69</td><td> 6,63</td><td> 6,61</td><td> 6,59</td>

<td></td><td>Resistance to crushing (N)</td><td> 116</td><td> 196+3</td><td> 196+3</td><td> 196+3</td><td> 196+3</td>

<td></td><td>Diameter (mm) after completion test resistance to crushing, measured immediately after test</td><td>crushed2</td><td> 5,49</td><td> 5,59</td><td> 5,51</td><td> 5,54</td>

<td></td><td>Diameter (mm) after completion test resistance to crushing (period relaxation NLT 15 minutes)</td><td></td><td> 5,67</td><td> 5,76</td><td> 5,67</td><td> 5,68</td>

<td>Process curing</td><td>5 min</td><td> -</td><td> 56,8</td><td> -</td><td> -</td><td> -</td>

<td>Temperature deposits of tablets ° C</td><td>2 0 min</td><td></td><td> 74,6</td><td></td><td></td><td></td>

<td></td><td>30 minutes</td><td> -</td><td> 76,2</td><td> -</td><td> -</td><td> -</td>

<td rowspan="3">(probe temperature in the drum)</td><td>60 min</td><td></td><td></td><td> 78,2</td><td></td><td></td>

<td rowspan="6">dissolution (% released) (N = 3)</td><td>0.5 hours</td><td></td><td> 21</td><td> 20</td><td></td><td></td>

<td>2 hours</td><td> -</td><td> 51</td><td> 51</td><td> -</td><td> -</td>

<td>4 hours</td><td> -</td><td> 75</td><td> 76</td><td> -</td><td> -</td>

<td>8 hours</td><td> -</td><td> 96</td><td> 96</td><td> -</td><td> -</td>

<td>12 hours</td><td> -</td><td> 100</td><td> 100</td><td> -</td><td> -</td>

<td colspan="2" rowspan="3">After the test using a hammer (10 hand strokes) Thickness (mm)</td><td rowspan="3"></td><td> 2,19</td><td> 2,31</td><td> 2,36</td><td> 2,45</td>

<td colspan="7">2 Tablets crushed and crushed during the test crushing strength3 196+ means that tablets exposed to a maximum force of 196 N did not break.</td>

Table 4.6

<td></td><td></td><td colspan="7">Example 4.6</td>

<td></td><td></td><td>unpaved (N = 6)</td><td>10 min</td><td>twenty min</td><td>0.5 h</td><td>1.0 h</td><td>1.5 h</td><td>2.0 h</td>

<td rowspan="3">dimensions pills</td><td>Weight (mg)</td><td> 110</td><td> 108</td><td> 108</td><td> 109</td><td> 108</td><td> 109</td><td> 109</td>

<td>Thickness (Mm)</td><td> 3,65</td><td> 3,93</td><td> 3,89</td><td> 3,89</td><td> 3,87</td><td> 3,85</td><td> 3,85</td>

<td>Diameter (Mm)</td><td> 6,73</td><td> 6,71</td><td> 6,63</td><td> 6,61</td><td> 6,57</td><td> 6,55</td><td> 6,53</td>

<td></td><td>Resistance to crushing (N)</td><td> 128</td><td colspan="6"> 196+2</td>

<td></td><td>Diameter (mm) after completion test resistance to crushing (the measured about immediately after assay)</td><td>crushed1</td><td> 5,27</td><td> 5,47</td><td> 5,51</td><td> 5,51</td><td> 5,56</td><td> 5,63</td>

<td></td><td>Diameter (mm) after completion test resistance to crushing (period relaxation NLT 15 min)</td><td></td><td> 5,48</td><td> 5,60</td><td> 5,67</td><td> 5,66</td><td> 5,69</td><td> 5,76</td>

<td>Process utwardzarnia</td><td>0 min</td><td></td><td> 30,8</td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="7">Bed temperature tablets ° C (probe temperature in pan)</td><td>10 min</td><td></td><td> 79,5</td><td></td><td></td><td></td><td></td><td></td>

<td>30 minutes</td><td> -</td><td> -</td><td> -</td><td> 79,6</td><td> -</td><td> -</td><td> -</td>

<td rowspan="6">Dissolving (% released) (N = 3)</td><td>0.5 hours</td><td> -</td><td> -</td><td> -</td><td> 19</td><td> 20</td><td> -</td><td> -</td>

<td>2 hours</td><td></td><td></td><td></td><td> 48</td><td> 51</td><td></td><td></td>

<td>4 hours</td><td> -</td><td> -</td><td> -</td><td> 73</td><td> 78</td><td></td><td> -</td>

<td>8 hours</td><td> -</td><td> -</td><td> -</td><td> 99</td><td> 99</td><td> -</td><td> -</td>

<td>12 hours</td><td> -</td><td> -</td><td> -</td><td> 99</td><td> 102</td><td> -</td><td> -</td>

<td colspan="2" rowspan="3">After the test using a hammer3 (10 manual strokes) Thickness (mm)</td><td rowspan="3"></td><td> 1,46</td><td> 2,18</td><td> 2,45</td><td> 2,23</td><td> 2,38</td><td> 2,42</td>

1 Tablets crushed and crushed during a crushing strength test 2 196+ means that tablets exposed to a maximum force of 196 N did not break.

3 Tablets flattened, but not torn into parts, hammering caused some edge cracking.

Example 5

In Example 5, three tablets containing 10% (by weight) oxycodone hydrochloride were prepared.

compositions:

<td></td><td>Example 5.1</td><td>Example 5.2</td><td>Example 5.3</td>

<td>Pill</td><td>mg / Unit portfolio (%)</td><td>mg / Unit portfolio (%)</td><td>mg / Unit portfolio (%)</td>

<td>Oxycodone hydrochloride</td><td> 12 (10)</td><td> 20 (10)</td><td> 12 (10)</td>

<td>Poly (ethylene oxide) (mass molecular: approximately 4000000; Polyox ™ WSR301)</td><td> 106,8 (89)</td><td> 178 (89)</td><td> 82,8 (69)</td>

<td>Poly (ethylene oxide) (1 mass Molecular weight; approximately 100000; Polyox ™ N10)</td><td> 0</td><td> 0</td><td> 24 (20)</td>

<td>Magnesium stearate</td><td> 1,2 (1)</td><td> 2,0 (1)</td><td> 1,2 (1)</td>

<td>Whole</td><td> 120</td><td> 200</td><td> 120</td>

<td>Whole batch weight (kg) (quantity produced)</td><td> 100</td><td> 100</td><td> 100</td>

<td>Coating layer</td><td>mg / Unit tuple</td><td>mg / Unit tuple</td><td>mg / Unit tuple</td>

<td>White coating layer Opadry concentrate, formula Y-518024-A</td><td> 3,6 (3)</td><td> 6,0 (3)</td><td> 3. (3)</td>

The tablets were made according to the following processing steps:

1. The poly (ethylene oxide) was passed through a Sweco screen equipped with a 20 mesh screen in separate suitable containers.

2. The Gemco "V" mixer (equipped with mixer I) with a capacity of 10 cubic feet was placed in succession:

Approximately 1/2 polyethylene oxide WSR 301, oxycodone hydrochloride / polyethylene oxide N10 (only example 5.3), other polyethylene oxide WSR 301.

3. The materials obtained in step 2 were mixed for 10 minutes (example 5.1), 20 minutes (example 5.2) or 15 minutes (example 5.3) using an activated mixer I.

4. Magnesium stearate was placed in the Gemco "V" mixer.

5. The materials obtained in step 4 were mixed for 3 minutes using the switched off stirrer I.

6. The mix obtained in step 5 was placed in clean, tared stainless steel containers.

7. The mix obtained in step 5 was compressed to a target mass using a 40 station tablet press operating at 135,000 tablets per hour, using standard 9/32 rounded concave (simple) instrumentation.

8. The tablets obtained in step 7 were introduced into an Accela-Coat 48-inch coating drum at 7 rpm, with a drum load of 98.6 kg (Example 5.1), 92.2 kg (Example 5.2) and 96.9 kg (Example 5.3) and the tablet bed was heated with air at such an outlet temperature to obtain approximately 80 ° C (Example 5.2 and 5.3) and 75 ° C (Example 5.1) at the inlet and cured for 1 hour at the target inlet temperature.

9. The drum rotation speed was maintained at 7 to 10 rpm and the tablet bed was cooled using the outlet air temperature to obtain an inlet temperature of 25 ° C and a bed temperature of 30-34 ° C.

Ten. The tablet bed was heated using such an outlet air temperature to obtain an inlet temperature of 55 ° C. When the outlet air temperature reached about 39 ° C, the process of applying a single coating layer was started; the process was carried out until the weight of the tablet increased by 3%.

11. After coating, the drum rotation speed was set to 1.5 revolutions per minute, the outlet air temperature was set to 27 ° C, the air flow was kept constant and the system was cooled so that the outlet air temperature was 27-30 ° C.

12. The tablets were removed from the drum.

In vitro tests including interference test (breaking strength and hammer test) and alcohol extraction test were carried out as follows:

Tablets cured for 0.5 hours and tablets cured for 1.0 hours and coated were tested in vitro using USP Apparatus 1 (drum mixer) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C using an Agilent UV-VIS Model HP8453 spectrometer, UV at 220 nm. Tablet dimensions, appropriate dissolution results, curing times and temperatures used are shown in Tables 5.1 to 5.3.

To assess resistance to alcohol extraction, tablets cured for 1.0 hours and coated were tested in vitro using ethanol / simulated gastric fluid (SGF) at a concentration of 40% ethanol. The test was performed using USP Apparatus 1 (drum mixer) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C using an Agilent UV-VIS Model HP8453 spectrometer, UV at 230 nm. The dissolution results of the tablets are presented in Table 5.3.

In the next tamper test, the unhardened and cured tablets were subjected to a crushing strength test, with a maximum force of 439 N using a Schleuniger Model 6D device to assess fracture strength. The results are shown in the tables

5.1 to 5.3.

In addition, the tablets were flattened with a hammer, using 10 hand strokes to confer physical resistance to interference (hammer test).

Table 5.1

<td colspan="2" rowspan="2"></td><td colspan="3">Example 5.1</td>

<td>unpaved</td><td>hardened for 30 minutes (N = 10)</td><td>hardened by 1 hour/ coated (N = 10)</td>

<td rowspan="4">Tablet dimensions</td><td>Weight (mg)</td><td> 119,71</td><td> 120</td><td> 122</td>

<td>Thickness (mm)</td><td> 3,632</td><td> 3,91</td><td> 3,88</td>

<td>Diameter (mm)</td><td> -</td><td> 7,03</td><td> 7,02</td>

<td>Strength for crushing (N)</td><td> 543</td><td> 4394</td><td> 4384</td>

<td></td><td>diameter (mm) after the test strength for crushing</td><td></td><td colspan="2"> 4,18</td><td colspan="2"> 4,26</td>

<td rowspan="6">Process curing Temp ° C at the inlet</td><td>10 min</td><td> -</td><td colspan="2"> 75,8</td><td colspan="2"> 75,8</td>

<td>30 minutes</td><td> -</td><td colspan="2"> 76,0</td><td colspan="2"> 76, 0</td>

<td rowspan="6">Dissolution Switching (% released) (N = 3)</td><td>0.5 hours</td><td> -</td><td colspan="2"> 19</td><td colspan="2"> 19</td>

<td>2 hours</td><td></td><td colspan="2"> 47</td><td colspan="2"> 50</td>

<td>4 hours</td><td> -</td><td colspan="2"> 71</td><td colspan="2"> 76</td>

<td>8 hours</td><td> -</td><td colspan="2"> 93</td><td colspan="2"> 97</td>

<td>12 hours</td><td> -</td><td colspan="2"> 99</td><td colspan="2"> 102</td>

<td colspan="2" rowspan="2">Hammer test (10 hand strokes) Tablet thickness (mm) measured before and after test (N = 3)</td><td rowspan="2"></td><td>in front of</td><td>after</td><td>in front of</td><td>after</td>

1 14 samples (40 tablets for each sample) were tested and results from

<td>every</td><td>samples</td><td>They averaged.</td><td>Value shown</td><td>is</td>

<td colspan="2">average value</td><td>outstretched</td><td>from the average.</td><td></td>

<td>4 n = 10;</td><td>pills</td><td>did not give in</td><td colspan="2">cracking after treatment</td>

maximum force of 438 N / 439 N.

Table 5.2

<td colspan="2" rowspan="2"></td><td colspan="3">Example 5.2</td>

<td>unpaved</td><td>cure for 30 minutes (n = 10)</td><td>hardened by 1 hour/ coated (N = 10)</td>

<td rowspan="5">dimensions pills</td><td>Weight (mg)</td><td> 200,41</td><td> 201</td><td> 206</td>

<td>Thickness (mm)</td><td> 5,502</td><td> 5,92</td><td> 5,86</td>

<td>Diameter (mm)</td><td> -</td><td> 7,03</td><td> 7,01</td>

<td>Strength for crushing (N)</td><td> 853</td><td> 4394</td><td> 4394</td>

<td>Diameter (mm) after the test strength for crushing</td><td></td><td> 5,52</td><td> 5,72</td>

<td rowspan="6">Process curing Temp ° C at the inlet</td><td>10 min</td><td> -</td><td> 79,7</td><td> 79,7</td>

<td>30 minutes</td><td> -</td><td> 79,3</td><td> 79,3</td>

<td rowspan="2"></td><td>0.5 hours</td><td> -</td><td> 14</td><td> 15</td>

<td rowspan="4">Dissolution (% released) (N = 3)</td><td>2 hours</td><td></td><td colspan="2"> 36</td><td colspan="2"> 38</td>

<td>4 hours</td><td> -</td><td colspan="2"> 57</td><td colspan="2"> 60</td>

<td>8 hours</td><td> -</td><td colspan="2"> 83</td><td colspan="2"> 85</td>

<td>12 hours</td><td> -</td><td colspan="2"> 94</td><td colspan="2"> 95</td>

<td colspan="2">Hammer test (10 hand strokes) Tablet thickness (mm) measured before and after the test (N = 3)</td><td></td><td>In front of</td><td>after</td><td>in front of</td><td>after</td>

1 Nine samples (40 tablets for each sample) were tested and the results of each sample were averaged. The value shown is the average value extracted from the average.

2 n = 27 3 n = 90 4 n = 10; the tablets did not break after being subjected to a maximum force of 438 N / 439 N.

Table 5.3

<td colspan="2" rowspan="2"></td><td colspan="3">Example 5.3</td>

<td>unpaved</td><td>hardened by 30 minutes (N = 10)</td><td>hardened by 1 hour/ coated (N = 10)</td>

<td rowspan="5">dimensions pills</td><td>Weight (mg)</td><td> 120,51</td><td> 122</td><td> 125</td>

<td>Thickness (mm)</td><td> 3,642</td><td> 3,85</td><td> 3,77</td>

<td>Diameter (mm)</td><td> -</td><td> 7,03</td><td> 7,01</td>

<td>Strength for crushing (N)</td><td> 563</td><td> 4384</td><td> 4394</td>

<td>Diameter (mm) after the test strength for crushing</td><td></td><td> 3,96</td><td> 4,28</td>

100

<td rowspan="6">Process curing Temp ° C u inlet</td><td>10 min</td><td> -</td><td colspan="2"> 80,0</td><td colspan="2"> 80,0</td>

<td>30 minutes</td><td> -</td><td colspan="2"> 78,9</td><td colspan="2"> 78,9</td>

<td rowspan="6">Dissolution (% released) (N = 3)</td><td>0.5 hours</td><td> -</td><td colspan="2"> 20</td><td> 23</td><td> 21</td>

<td>2 hours</td><td> -</td><td colspan="2"> 50</td><td> 58</td><td> 50</td>

<td>4 hours</td><td> -</td><td colspan="2"> 76</td><td> 86</td><td> 76</td>

<td>8 hours</td><td> -</td><td colspan="2"> 95</td><td> 100</td><td> 99</td>

<td>12 hours</td><td> -</td><td colspan="2"> 98</td><td> 100</td><td> 104</td>

<td colspan="2" rowspan="2">Hammer test (10 hand strokes), tablet thickness (mm) measured before and after the test (N = 3)</td><td rowspan="2"></td><td>In front of</td><td>after</td><td>FOR IN d</td><td>after</td>

<td colspan="7">1 Twelve samples (40 tablets for each sample) were tested and the results of each sample were averaged. The value shown is the average value drawn from the average.2 n = 333 n = 1304 n = 10; the tablets did not break after being subjected to a maximum force of 438 N / 439 N.</td>

Example 6

In Example 6, tablets containing naltrexone hydrochloride were prepared. compositions:

101

<td>Naltrexone Hydrochloride</td><td> 10</td>

<td>Poly (ethylene oxide) (molecular weight: approximately 4,000,000; Polyox ™ WSR 301)</td><td> 89,0</td>

<td>Magnesium stearate</td><td> 1,0</td>

<td>Whole</td><td> 100</td>

<td>Whole batch weight (kg) (quantity produced)</td><td> 20</td>

<td>Coating layer</td><td>mg / unit</td>

<td>Opadry base coat, red layer coating, concentrate, formula Y-5-1-15139</td><td> 3,0</td>

<td>Coating with special effects Opadry FX Silver 3.0, design 62W28547</td><td> 3,0</td>

The tablets were prepared as described in Example 5 using a Gemco "V" mixer (equipped with stirrer I) - 2 cubic feet, 8-station rotary tablet press operating at 24000 tablets per hour, with a standard rounded, concave 9/32 (emphasized on top / flat bottom) tooling and 24 inch Compu-Lab coater. The mixing time according to step 2 was 8 minutes, the drum load was 9.2 kg and the curing time was 2 hours.

Example 7

Further tablets according to three examples were prepared and tested each containing 10 mg oxycodone hydrochloride. compositions:

<td></td><td>Example 7.1</td><td>Example 7.2</td><td>Example 7.3</td>

<td>Oxycodone hydrochloride</td><td> 10 (5)</td><td> 10 (6,67)</td><td> 10 (10)</td>

<td>Poly (ethylene oxide) (molecular weight: approximately 4,000,000; Polyox ™ WSR301)</td><td> 188 (94)</td><td> 138,5 (92,3)</td><td> 69 (69)</td>

102

<td>Poly (ethylene oxide) (molecular weight: approximately 100,000; Polyox ™ N10)</td><td> 0</td><td> 0</td><td> 20 (20)</td>

<td>Magnesium stearate</td><td> 2 (1)</td><td> 1,5 (1)</td><td> 1 (1)</td>

<td>Whole</td><td> 200</td><td> 150</td><td> 100</td>

<td>Whole batch weight (kg) (quantity produced)</td><td> 100</td><td> 100</td><td> 100</td>

<td>Coating layer</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td>

<td>White coating layer Opadry concentrate, formula Y-5-18024-A</td><td> 6</td><td> 4,5</td><td> 3</td>

The tablets were made according to the following processing steps:

1. Magnesium stearate was passed through a Sweco screen fitted with a 20 mesh screen into separate suitable containers.

2. The Gemco "V" mixer (equipped with mixer I) with a capacity of 10 cubic feet was placed in succession:

Approximately 1/2polyethylene oxide WSR 301 Oxycodone hydrochloride

Poly (ethylene oxide) N10 (only Example 7.3)

Other poly (ethylene oxide) WSR 301

3. The materials obtained in step 2 were mixed for 10 minutes using the included stirrer I.

4. Magnesium stearate was placed in the Gemco "V" mixer.

5. The materials obtained in step 4 were mixed for 3 minutes using the switched off stirrer I.

6. The mix obtained in step 5 was placed in clean, tared stainless steel containers.

7. The mix obtained in step 5 was compressed to the target mass using a 40 station tablet press at a speed of 135,000 tablets per hour, using standard 9/32 inch rounded, concave (simple) instrumentation

103 (examples 7.1 and 7.2) and using standard 1/4 inch rounded, concave (straight) instrumentation (example 7.3).

8. The tablets obtained in step 7 were introduced into an Accela-Coat 48-inch coating drum, the cartridge was 97.388 kg (Example 7.1), 91.051 kg (Example 7.2) and 89.527 kg (Example 7.3).

9. The drum rotation speed was set to 7 rpm. The tablet bed was heated to set the outlet air temperature to obtain an inlet temperature of approximately 75 ° C. The tablets were cured at the inlet air temperature for 1 hour (Example 7.1 and 7.2) and for 30 minutes (Example 7.3).

Ten. The drum rotation speed was maintained at 6 to 8 rpm and the tablet bed was cooled using such an outlet air temperature to obtain an inlet temperature of 25 ° C and an outlet air temperature of 30-34 ° C.

11. The bed of tablets was heated with air at the outlet to give an inlet temperature of 55 ° C. When the exhaust air has reached about 39 ° C, the process of applying a single coating layer; the process was carried out until the weight of the tablet increased by 3%.

12. After coating, the drum rotation speed was set to 1.5 revolutions per minute, the outlet air temperature was set to 27 ° C, the air flow was kept constant and the system was cooled so that the outlet air temperature was 27-30 ° C.

13. The tablets were removed from the drum.

In vitro tests including interference resistance tests (breaking strength, hammer test and flattened tablets) and extraction resistance also stability tests equal temperature were started with alcohol as follows:

Cured, tested in vitro, performed and flattened (drum mixer) coated tablets (whole using USP Apparatus 1 at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C. Samples were analyzed by high performance liquid chromatography in

104 reverse phase system (HPLC) on a Waters Atlantis dC 18 column 3, 0 x 150 mm, 3 pm using a mobile phase consisting of a mixture of acetonitrile and non-basic phosphate buffer (pH 3.0), UV detection at 230 nm. Tests were carried out for time points including 0.5, 0.75, 1.0, 1.5 and 2.0 hours. In addition, tests were conducted for time points of 1.0, 4.0 and 12 hours.

Cured, coated tablets (whole and flattened) were tested in vitro using ethanol / simulated gastric fluid (SGF) environment at 0% and 40% concentrations to assess resistance to alcohol extraction. The test was carried out using USP Apparatus 1 (drum mixer) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C. Samples were analyzed by reverse phase high pressure liquid chromatography (HPLC) on a Waters Atlantis dC18 3.0 x 150 mm column, 3 pm using a mobile phase consisting of a mixture of acetonitrile and non-basic phosphate buffer (pH 3.0), UV detection 230 nm. Tests were carried out for time points including 0.5, 0.75, 1.0, 1.5 and 2.0 hours.

To assess the tablet's breaking strength, the cured tablets were subjected to a crushing strength test, with a maximum force of 439 N, using a Schleuniger Model 6D device.

The cured tablets were subjected to high pressure using a Carver hand press (hydraulic unit model # 3912) to impart physical interference resistance by flattening the tablets.

The cured tablets were then subjected to a crushing strength test, manually hammering 10 times to tamper.

The cured, coated tablets were subjected to a stability test by storing them in bottles holding 100 tablets under various conditions (25 ° C / 60% relative humidity or 40 ° C / 75% relative humidity) for a period of time and then testing the tablets in vitro as described above . Storage testing was performed on the initial sample (i.e. before storage), after one month, two months, three months and after six months

105 label percentage. initial storage sample, dissolution tests were carried out for time periods of 1.0, 4.0 and 12.0 hours.

The cured, coated tablets were then subjected to a stability test by storing them in enclosing bottles

100 tablets in various conditions (25 ° C / 60% relative humidity or 40 ° C / 75% relative humidity) for a certain period of time and thereafter, subjecting the tablets to a test to determine the oxycodone hydrochloride content of the tablet, in relation to the content declared for storage was carried out at (i.e. prior to storage), after one month, two months, three months and after six months of storage. Performing the test, oxycodone hydrochloride was extracted from tablets in two sets of ten, each time 900 ml of a 1: 2 mixture of acetonitrile and simulated gastric fluid without enzyme (SGF), continuously stirring with a magnetic stirrer in a 1000 ml volumetric flask until all tablets were completely dispersed or overnight. The solutions were diluted and analyzed by reversed-phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3 column, 0 x 250 mm, 5 pm at 60 ° C, using a mobile phase consisting of acetonitrile and monobasic potassium phosphate buffer pH 3.0, UV detection at 280 nm.

The cured, coated tablets were then subjected to a stability test by storing them in bottles containing 100 tablets under various conditions (25 ° C / 60% relative humidity or 40 ° C / 75% relative humidity) for a period of time and thereafter, subjecting the tablets to tests for Noxide content oxycodone (ONO) to determine the content of the degradation product - oxycodone N-oxide as a percentage of the oxycodone hydrochloride declared on the label. Storage testing was performed on the initial sample (i.e. before storage), after one month, two months, three months and after six months of storage. In the ONO content test, oxycodone hydrochloride and its degradation products were extracted from ten tablets of 900 ml of a 1: 2 mixture

106 acetonitrile and simulated gastric fluid without enzyme (SGF), constantly stirring with a magnetic stirrer in

1000 ml in a volumetric flask until all the tablets have been completely dispersed or overnight. The solutions were diluted and analyzed by reverse phase high pressure liquid chromatography (HPLC) on a Waters Atlantis dC18 3, 0 x 250 mm, 5 gm column at 60 ° C using a mobile phase consisting of acetonitrile and monobasic potassium phosphate buffer at pH 3.0, detection

UV at 206 nm.

The results are shown in Tables 7.1 to 7.3. Table 7.1.1

<td colspan="2" rowspan="2"></td><td colspan="5">Example 7.1</td>

<td colspan="3">Whole (n = 10)</td><td colspan="2">Flattened (n = 3) (15,000 were used lbs (pounds))</td>

<td rowspan="6">dimensions pills</td><td>Weight (mg)</td><td colspan="3"> 205</td><td> 207</td><td> 204</td>

<td>Thickness (mm)</td><td colspan="3"> 5,95</td><td> 1,011</td><td> 0,961</td>

<td>% Thickness</td><td colspan="3"></td><td> 17,0</td><td> 16,1</td>

<td>Diameter (mm)</td><td colspan="3"> 7,02</td><td> 17,132</td><td> 17,352</td>

<td>Strength for crushing (N)</td><td colspan="3"> > 4383</td><td colspan="2"></td>

<td>Diameter (mm) after conducting the test resistance to crushing</td><td colspan="3"> 5,84</td><td colspan="2"></td>

<td colspan="3" rowspan="4">Hammer test, thickness (mm) tablets were measured before and after test</td><td>in front of</td><td>after</td>

107

<td colspan="2" rowspan="2"></td><td>All</td><td>All</td><td>flattened</td><td>flattened</td>

<td rowspan="5">Dissolution (% released) (N = 3)</td><td>0.5 hours</td><td> 11</td><td> 9</td><td> 17</td><td> 13</td>

<td>0.75 hours</td><td> 15</td><td> 12</td><td> 23</td><td> 18</td>

<td>1.0 hours</td><td> 20</td><td> 16</td><td> 28</td><td> 21</td>

<td>1.5 hours</td><td> 27</td><td> 21</td><td> 36</td><td> 29</td>

<td>2.0 hours</td><td> 34</td><td> 27</td><td> 44</td><td> 35</td>

<td rowspan="6">Dissolution (% released) (N = 6)</td><td>0.5 hours</td><td colspan="2"> -</td><td colspan="2" rowspan="6"></td>

<td>2 hours</td><td colspan="2"> -</td>

<td>4 hours</td><td colspan="2"> 57</td>

<td>8 hours</td><td colspan="2"> -</td>

<td>12 hours</td><td colspan="2"> 97</td>

<td colspan="6">1 3 measurements per tablet2 2 measurements per tablet3 the tablets did not break after being subjected to a maximum force of 438 N</td>

108

Table 7.1.2

<td></td><td></td><td colspan="5">Durability tests; Example 7.1</td>

<td></td><td></td><td colspan="5">Storage conditions (° C /% relative humidity) and storage time1</td>

<td></td><td></td><td>Initially</td><td>1 M. 40/75</td><td>2 M. 40/75</td><td>3M 25/60</td><td>3M 40/75</td>

<td rowspan="3">Dissolving (% released) (n = 6) SGF</td><td>1 h.</td><td> 22</td><td> 21</td><td> 21</td><td> 20</td><td> 21</td>

<td rowspan="3">Test (% hydrochloride oxycodone)2</td><td>Test 1</td><td> 96,6</td><td> 96,2</td><td> 97,3</td><td> 97,1</td><td> 95,0</td>

<td>Average</td><td> 96,0</td><td> 96,7</td><td> 96,5</td><td> 97,9</td><td> 95,5</td>

<td colspan="2">ONO test (% oxycodone N-oxide)2</td><td> 0,02</td><td> 0,06</td><td> 0,06</td><td> 0,04</td><td> 0,05</td>

<td colspan="7">1 [M = month (s)];2 in relation to the oxycodone hydrochloride declared on the label</td>

Table 7.2.1

<td colspan="2" rowspan="2"></td><td colspan="3">Example 7.2</td>

<td>Whole (n = 10)</td><td colspan="2">Flattened (n = 3) (used 20,000 lbs (pounds))</td>

<td rowspan="4">Tablet dimensions</td><td>Weight (mg)</td><td> 154</td><td> 154</td><td> 153</td>

<td>Thickness (Mm)</td><td> 4,68</td><td> 0,751</td><td> 0,771</td>

<td>% thick</td><td></td><td> 16,0</td><td> 16,5</td>

<td>Diameter (Mm)</td><td> 7,02</td><td> 17,142</td><td> 16,902</td>

109

<td>Resistance to crushing (N)</td><td> 4383</td><td></td>

<td>Diameter (mm) after completion test resistance to crushing</td><td> 4,93</td><td></td>

<td colspan="2" rowspan="4">Hammer test, tablet thickness (mm) measured before and after the test</td><td>in front of</td><td>after</td><td colspan="2" rowspan="4"></td>

<td colspan="2" rowspan="2"></td><td>All</td><td>All</td><td>flattened</td><td>flattened</td>

<td rowspan="5">Dissolving (% released) (N = 3)</td><td>0.5 hours</td><td> 14</td><td> 10</td><td> 21</td><td> 15</td>

<td>0.75 hours</td><td> 19</td><td> 14</td><td> 27</td><td> 20</td>

<td>1.0 hours</td><td> 24</td><td> 17</td><td> 33</td><td> 26</td>

<td>1.5 hours</td><td> 33</td><td> 23</td><td> 44</td><td> 36</td>

<td>2.0 hours</td><td> 40</td><td> 29</td><td> 53</td><td> 43</td>

<td>Dissolving (% released) (N = 6)</td><td>0.5 hours</td><td colspan="2"></td><td colspan="2"></td>

110

Table 7.2.2

<td colspan="9">Durability tests, Example 7.2</td>

<td></td><td></td><td colspan="7">Storage conditions (° C,% humidity relative) and storage time1</td>

<td></td><td></td><td>Initially</td><td>1 M. 40/75</td><td>2 M. 40/75</td><td>3M 25/60</td><td>3M 40/75</td><td>6 M. 25/60</td><td>6 M. 40/75</td>

<td rowspan="3">Dissolving (% released) (n = 6) SGF</td><td>1 hour</td><td> 26</td><td> 24</td><td> 22</td><td> 23</td><td> 24</td><td> 25</td><td> 25</td>

<td>4 hours</td><td> 67</td><td> 66</td><td> 61</td><td> 65</td><td> 64</td><td> 64</td><td> 69</td>

<td rowspan="3">Test (% hydrochloride oxycodone) 2</td><td>Test 1</td><td> 97,1</td><td> 97,7</td><td> 96,4</td><td> 98,4</td><td> 97,3</td><td> 96,3</td><td> 94,1</td>

<td>Average</td><td> 96,9</td><td> 97,1</td><td> 96,3</td><td> 98,2</td><td> 97,1</td><td> 96,3</td><td> 94,2</td>

<td colspan="2">ONO test (% Oxide oxycodone)2</td><td> 0,02</td><td> 0,08</td><td> 0,04</td><td> 0,03</td><td> 0,04</td><td> 0,06</td><td> 0,26</td>

<td colspan="9">1 [M = month (s)];2 In relation to the oxycodone hydrochloride content declared on the label.</td>

111

Table 7.3.1

<td colspan="2" rowspan="2"></td><td colspan="4">Example 7.3</td>

<td colspan="2">Whole (n = 10)</td><td colspan="2">Flattened (n = 3) (15,000 lbs used (Lbs))</td>

<td rowspan="5">dimensions pills</td><td>Weight (mg)</td><td colspan="2"> 103</td><td> 102</td><td> 104</td>

<td>Thickness (mm)</td><td colspan="2"> 3,92</td><td> 0,611 (15,6)</td><td> 0,661 (16,8)</td>

<td>Diameter (mm)</td><td colspan="2"> 6,25</td><td> 15,362</td><td> 15,242</td>

<td>Strength for crushing (N)</td><td colspan="2"> 4393</td><td colspan="2" rowspan="2"></td>

<td>Diameter (mm) after the test strength for crushing</td><td colspan="2"> 3,80</td>

<td colspan="2" rowspan="4">Hammer test, tablet thickness (mm) measured before and after the test</td><td>in front of</td><td>after</td><td colspan="2" rowspan="4"></td>

<td colspan="2" rowspan="2"></td><td>All</td><td>All</td><td>flattened</td><td>flattened</td>

<td rowspan="5">dissolution (% released) (N = 3)</td><td>0.5 hours</td><td> 19</td><td> 15</td><td> 26</td><td> 19</td>

<td>0.75 hours</td><td> 25</td><td> 20</td><td> 34</td><td> 25</td>

<td>1.0 hours</td><td> 30</td><td> 25</td><td> 40</td><td> 31</td>

<td>1.5 hours</td><td> 41</td><td> 33</td><td> 51</td><td> 41</td>

<td>2.0 hours</td><td> 50</td><td> 41</td><td> 60</td><td> 50</td>

<td rowspan="2"></td><td>0.5 hours</td><td colspan="4"></td>

112

<td rowspan="4">dissolution (% released) (N = 6)</td><td>2 hours</td><td></td>

<td>4 hours</td><td> 83</td>

<td>8 hours</td><td> -</td>

<td>12 hours</td><td> 101</td>

<td colspan="3">1 3 measurements per tablet2 2 measurements per tablet3 The tablets did not break after being subjected to a maximum force of 439 N.</td>

Table 7.3.2

<td colspan="6">Durability tests; Example 7.3</td>

<td></td><td></td><td colspan="4">Storage conditions (° C /% relative humidity) and time storage1</td>

<td></td><td></td><td>Initially</td><td>1 M. 40/75</td><td>2 M. 40/75</td><td>3M 25/60</td>

<td rowspan="3">Dissolving (% released) (n = 6) SGF</td><td>1 hour</td><td> 32</td><td> 29</td><td> 30</td><td> 31</td>

<td>4 hours</td><td> 83</td><td> 76</td><td> 77</td><td> 78</td>

<td>12 hours</td><td> 101</td><td> 103</td><td> 102</td><td> 103</td>

<td rowspan="3">test (% oxycodone hydrochloride) 2</td><td>Test 1</td><td> 99,4</td><td> 99,4</td><td> 97,3</td><td> 101,0</td>

<td>Average</td><td> 99,1</td><td> 99,1</td><td> 98,6</td><td> 101,0</td>

<td colspan="2">ONO test (% oxycodone N-oxide)2</td><td> 0,05</td><td> 0,01</td><td> 0,01</td><td> 0,02</td>

<td colspan="6">1 [M = month (s)];2 in relation to the oxycodone hydrochloride declared on the label</td>

Example 8

Two further tablets containing 160 mg oxycodone hydrochloride were prepared (Examples 8.1 and 8.2).

113

compositions:

<td></td><td>Example 8.</td><td> 1</td><td>Example 8</td><td> .2</td>

<td>Ingredient</td><td>mg / unit</td><td>ABOUT. %</td><td>mg / unit</td><td>ABOUT. %</td>

<td>hydrochloride oxycodone</td><td> 160</td><td> 25</td><td> 160</td><td> 25</td>

<td>Poly (ethylene oxide) (high molecular weight, class 301)</td><td> 476,8</td><td> 74,5</td><td> 284,8</td><td> 44,5</td>

<td>Poly (ethylene oxide) (low weight molecular, class N10)</td><td> 0</td><td> 0</td><td> 192</td><td> 30</td>

<td>Magnesium stearate</td><td> 3,2</td><td> 0,5</td><td> 3,2</td><td> 0,5</td>

<td>Whole</td><td> 640</td><td> 100</td><td> 640</td><td> 100</td>

The tablets were made according to the following processing steps:

1. Oxycodone hydrochloride and poly (ethylene oxide) were dry mixed in a double blade mixer working in high / low abrasion mode Black & Decker Handy Chopper with a capacity of 1.5 cup for 30 seconds.

2. Magnesium stearate was added and mixed with the blend obtained in Step 1 for an additional 30 seconds.

3. The mix obtained in step 2 was compressed to the target mass using a Manesty Type F 3 single tablet press station, using capsule shaping equipment (7.937 x 14.290 mm).

4. The tablets obtained in step 2, for curing, were spread on a tray and placed in a Hotpack oven, model 435304 at 73 ° C for 3 hours.

In vitro tests including an interference test (breaking strength test) were carried out as follows:

The tablets, after curing for 3 hours, were tested in vitro using USP Apparatus 1 (drum mixer) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C, using an Agilent UV-VIS Model HP8453 spectrometer , UV at 280 nm.

114

The dimensions of the uncured and cured tablets as well as the dissolution results are presented in Table 8.

In addition, the tablets were flattened with a hammer, using 10 hand strokes to interfere (hammer test). The results are shown in Table 8.

Table 8

<td colspan="3" rowspan="2"></td><td colspan="5">Example 8.1</td><td colspan="3">Example 8.2</td>

<td colspan="2">unpaved (N = 12)</td><td colspan="3">Cured by 3 hours (N = 5)</td><td colspan="2">unpaved (N = 12)</td><td>hardened by 3 hours (N = 10)</td>

<td rowspan="4">dimensions pills</td><td colspan="2">Weight (mg)</td><td colspan="2"> 648</td><td colspan="3"> 648</td><td colspan="2"> 643</td><td> 643</td>

<td colspan="2">Thickness (mm)</td><td colspan="2"> 7,07</td><td colspan="3"> 7,42</td><td colspan="2"> 7,01</td><td> 7,20</td>

<td colspan="2">Width (mm)</td><td colspan="2"> 7,96</td><td colspan="3"> 7,97</td><td colspan="2"> 7,96</td><td> 7,91</td>

<td colspan="2">Resistance to crushing (N)</td><td colspan="2"> 196+ 1(N = 2)</td><td colspan="3"> 196+ 1(N = 1)</td><td colspan="2"> 196+ 1(N = 2)</td><td> 196+ 1(N = 2)</td>

<td rowspan="6">Dissolving (% released)</td><td>0.5 hours</td><td colspan="2" rowspan="6">no studied</td><td colspan="2"> 9</td><td colspan="3" rowspan="6">no studied</td><td colspan="2"> 13</td>

<td>2 hours</td><td colspan="2"> 23</td><td colspan="2"> 35</td>

<td>4 hours</td><td colspan="2"> 38</td><td colspan="2"> 59</td>

<td>8 hours</td><td colspan="2"> 60</td><td colspan="2"> 89</td>

<td>12 hours</td><td colspan="2"> 76</td><td colspan="2"> 92</td>

<td colspan="2">Thickness (mm) after the test using a hammer (10 hand strokes)</td><td colspan="2">Easily burst</td><td colspan="3"></td><td colspan="2">Easily burst</td><td colspan="2"> 3,80</td>

115 1 The hardness tester could work with a maximum of 20+ Kp equivalent to 196+ Ns (1 Kp = 9,807 Ns), the tablets do not break when subjected to a maximum force of 196 N.

Example 9

Tablets were prepared and tested according to three further examples, each containing 12 mg hydromorphone hydrochloride.

compositions:

<td></td><td>Example 9.1</td><td>Example 9.2</td><td>Example 9.3</td>

<td>hydrochloride hydromorphone</td><td> 12</td><td> 12</td><td> 12</td>

<td>Poly (ethylene oxide) (molecular weight: approximately 7000000; Polyox ™ WSR 303)</td><td> 483</td><td> 681</td><td> 829,5</td>

<td>Magnesium stearate</td><td> 5</td><td> 7</td><td> 8,5</td>

<td>Whole</td><td> 500</td><td> 700</td><td> 850</td>

<td>The weight of the whole batch (kg) (manufactured quantity)</td><td> 100</td><td> 100</td><td> 100</td>

<td>Coating layer</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td>

<td>Magnesium stearate</td><td> 0,100</td><td> 0,142</td><td> 0,170</td>

<td>White layer Opadry coating; concentrate, formula Y-5-18024-A</td><td> 15</td><td> 21</td><td> 25,5</td>

<td>Coated size batch (kg)</td><td> 80</td><td> 79</td><td> 80</td>

The tablets were made according to the following processing steps:

1. Hydromorphone hydrochloride and magnesium stearate were passed through a Sweco screen fitted with a screen

116 20 mesh mesh size into separate appropriate containers.

2. The Gemco "V" mixer (equipped with mixer I) with a capacity of 10 cubic feet was placed in succession:

Approximately 25 kg of polyethylene oxide WSR 303

Hydromorphone Hydrochloride

Approximately 25 kg of polyethylene oxide WSR 303

3. The materials obtained in step 2 were mixed for 10 minutes using the included stirrer I.

4. The remaining polyethylene oxide WSR 303 was placed in a Gemco "V" mixer.

5. The materials obtained in step 4 were mixed for 10 minutes using the included stirrer I.

6. Magnesium stearate was placed in the Gemco "V" mixer.

7. The mixture obtained in step 6 was stirred for minutes using the switched off stirrer I.

8. The mix obtained in step 7 was placed in clean, tared stainless steel containers.

9. The mix obtained in step 8 was compressed to a target mass using a 40 station tablet press operating at 133,000 tablets per hour using standard 1/2 inch rounded concave (simple) tooling.

Ten. The tablets obtained in step 9 were loaded into an Accela-Coat 48-inch coating drum, the drum loading was 80 kg (Example 9.1 and 9.3) and 79 kg (Example 9.2).

11. The drum rotation speed was set at 2 revolutions per minute and the tablet bed was heated by setting the outlet air temperature to achieve an inlet target temperature of approximately 75 ° C. The tablets were cured for 1 hour and 15 minutes at an inlet temperature of 75-87 ° C (Example 9.1), 75-89 ° C (Example 9.2) and 75-86 ° C (Example 9.3).

12. At the beginning of the cooling, the drum rotation speed was increased to 7 rpm and the tablet bed was cooled using such an outlet air temperature to obtain an inlet temperature of 25 ° C and an outlet air temperature of 30-34 ° C. During the process

117 cooling, to reduce tablet sticking, magnesium stearate was added to the tablet bed.

13. The bed of tablets was heated with air at the outlet to give an inlet temperature of 55 ° C. When the outlet air temperature reached about 39 ° C, the process of applying a single coating layer was started; the process was carried out until the weight of the tablet increased by 3%.

14. After coating, the drum rotation speed was set to 1.5 revolutions per minute, the outlet air temperature was set to 27 ° C, the air flow was kept constant and the system was cooled so that the outlet air temperature was 27-30 ° C.

15. The tablets were removed from the drum.

Example 10

A tablet containing 12 mg hydromorphone hydrochloride was prepared.

Composition:

<td></td><td>Example 10</td>

<td>Hydromorphone Hydrochloride</td><td> 12</td>

<td>Poly (ethylene oxide) (molecular weight: approximately 7,000,000; Polyox ™ WSR 303)</td><td> 483</td>

<td>Magnesium stearate</td><td> 5</td>

<td>Whole</td><td> 500</td>

<td>Mass of the whole lot (kg) (manufactured quantity)</td><td> 119,98</td>

The tablets were made according to the following processing steps:

1. Hydromorphone hydrochloride and magnesium stearate were passed through a Sweco screen fitted with a 20 mesh screen in separate suitable containers.

2. The Gemco "V" mixer (equipped with mixer I) with a capacity of 10 cubic feet was placed in succession:

Approximately 60 kg of polyethylene oxide WSR 303

118

Hydromorphone Hydrochloride

3. The materials obtained in step 2 were mixed for 10 minutes using the included stirrer I.

4. The remaining polyethylene oxide WSR 303 was placed in a Gemco "V" mixer.

5. The materials obtained in step 4 were mixed for 10 minutes using the included stirrer I.

6. Magnesium stearate was placed in the Gemco "V" mixer.

7. The mixture obtained in step 6 was stirred for 3 minutes using the switched off stirrer I.

8. The mix obtained in step 7 was placed in clean, tared stainless steel containers.

9. The mix obtained in step 8 was compressed to a target mass using a 40 station tablet press operating at 150,000 tablets per hour, using standard 1/2 inch rounded concave (simple) tooling.

Ten. The tablets obtained in step 9 were introduced into an Accela-Coat 48-inch coating drum, the drum load was 92.887 kg.

11. The drum rotation speed was set at 1.9 revolutions per minute and the tablet bed was heated by setting the outlet air temperature to achieve a target inlet temperature of approximately 80 ° C. The tablets were cured for 2 hours at an inlet temperature of 80-85 ° C.

12. At the end of curing and the onset of cooling, the tablets in the bed began to aggregate (the tablets stuck). The drum rotation speed was increased to 2.8 revolutions per minute, however, the tablet bed was completely concentrated and the tablets could not be separated for coating.

It is believed that tablet agglomeration can be avoided, e.g., by lowering the curing temperature, increasing the drum rotation rate, using magnesium stearate as an anti-sticking agent, or applying a subcoating prior to curing.

However, some tablets, prior to cooling, were taken for in vitro tests, which were carried out as follows:

119

Cured tablets were tested in vitro using USP Apparatus 2 (paddle stirrer) at 75 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C using a Waters Alliance system equipped with a Waters Novapak C column18 3.9 mm x 150 mm using a mobile phase consisting of a mixture of acetonitrile, SDS, and monobasic sodium phosphate buffer (pH 2.9). A PDA detector was used for detection. Tests were carried out for time points of 1, 2, 4, 8, 12, 18, and 22 hours.

Table 10

<td colspan="2"></td><td>USP Apparatus 2</td>

<td rowspan="7">Dissolution (% released) (n = 6)</td><td>1 hour</td><td> 19</td>

<td>2 hours</td><td> 30</td>

<td>4 hours</td><td> 48</td>

<td>8 hours</td><td> 77</td>

<td>12 hours</td><td> 95</td>

<td>18 hours</td><td> 103</td>

<td>22 hours</td><td> 104</td>

Example 11

A tablet containing 12 mg hydromorphone hydrochloride was prepared.

Composition:

<td>Hydromorphone Hydrochloride</td><td> 12</td>

<td>Poly (ethylene oxide) (molecular weight: approximately 7,000,000; Polyox ™ WSR 303)</td><td> 681</td>

<td>Magnesium stearate</td><td> 7</td>

<td>Whole</td><td> 700</td>

<td>Whole batch weight (kg) (quantity produced)</td><td> 122,53</td>

<td>Coating layer</td><td>mg / unit</td>

<td>Opadry white coating layer; concentrate, template Y-5-18024-A</td><td> 21</td>

<td>Weight of coated lot (kg)</td><td> 80</td>

120

The tablets were made according to the following processing steps:

1. Hydromorphone hydrochloride and magnesium stearate were passed through a Sweco screen fitted with a 20 mesh screen in separate suitable containers.

2. The Gemco "V" mixer (equipped with mixer I) with a capacity of 10 cubic feet was placed in succession:

Approximately 60 kg of polyethylene oxide WSR 303

Hydromorphone Hydrochloride

3. The remaining polyethylene oxide WSR 303 was placed in a Gemco "V" mixer.

4. The materials obtained in step 4 were mixed for 10 minutes using the included stirrer I.

5. Magnesium stearate was placed in the Gemco "V" mixer.

6. The mix obtained in step 5 was mixed for 3 minutes using the switched off stirrer I.

7. The mix obtained in step 6 was placed in clean, tared stainless steel containers.

8. The mix obtained in step 7 was compressed to a target mass using a 40 station tablet press operating at 150,000 tablets per hour using standard 1/2 inch rounded concave (simple) tooling.

9. The tablets obtained in step 8 were introduced into an Accela-Coat 48-inch coating drum, the drum load was 80,000 kg.

Ten. The drum rotation speed was set at 1.8 revolutions per minute and the tablet bed was heated by setting the outlet air temperature to achieve a target inlet temperature of approximately 80 ° C. The tablets were cured for 1.25 hours at an inlet temperature of 7585 ° C.

11. At the end of curing and the onset of cooling, the tablets in the bed began to aggregate (the tablets stuck together). The drum rotation speed was increased up to 10 rpm, and the tablets were separated.

121

12. The drum rotation speed was maintained at approximately 10 rpm and the tablet bed was cooled using such an outlet air temperature to obtain an inlet temperature of 25 ° C and an outlet air temperature of 30-34 ° C.

15. The tablets were removed from the drum.

In vitro tests were carried out as follows:

The coated tablets were tested in vitro using USP Apparatus 2 (paddle stirrer) at 75 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C using a Waters Alliance system equipped with a Waters Novapak C column18 3.9 mm x 150 mm using a mobile phase consisting of a mixture of acetonitrile, SDS, and monobasic sodium phosphate buffer (pH 2.9). A PDA detector was used for detection. Tests were carried out for time points including 1, 2, 4, 8, 12, 18, 22, and 24 hours. The results are shown in Table 11.

Table 11

<td colspan="4"></td><td>USP Apparatus 2</td>

<td>dissolution (average n = 6)</td><td> (%</td><td>released)</td><td>1 hour</td><td> 12</td>

<td></td><td></td><td></td><td>2 hours</td><td> 19</td>

<td></td><td></td><td></td><td>4 hours</td><td> 29</td>

<td></td><td></td><td></td><td>8 hours</td><td> 46</td>

<td></td><td></td><td></td><td>12 hours</td><td> 60</td>

<td></td><td></td><td></td><td>18 hours</td><td> 76</td>

<td></td><td></td><td></td><td>22 hours</td><td> 84</td>

<td></td><td></td><td></td><td>24 hours</td><td> 88</td>

122

Example 12

In two further examples, tablets were prepared consisting of cores containing 10 mg oxycodone hydrochloride as per Example 2.3, and polyethylene oxide coating layers that delay the release of the active substance.

Composition: Tablet core composition

<td>Ingredient</td><td>mg / unit</td>

<td>Oxycodone hydrochloride</td><td> 10</td>

<td>Poly (ethylene oxide) (molecular weight: approximately 4,000,000; Polyox ™ WSR301)</td><td> 85</td>

<td>Hydroxypropyl cellulose (Klucel ™ HXF)</td><td> 5</td>

<td>The whole tablet core</td><td> 100</td>

Composition: tablet core compression coating

<td></td><td>Example 12.1</td><td>Example 12.2</td>

<td>Ingredient</td><td>mg / unit</td><td>mg / unit</td>

<td>Poly (ethylene oxide) (mass molecular: approximately 4000000; Polyox ™ WSR301)</td><td> 200</td><td> 100</td>

<td>Tablet core</td><td> 100</td><td> 100</td>

<td>The total weight of the tablet</td><td> 300</td><td> 200</td>

Manufacturing Process:

The tablets were made according to the following processing steps:

1. The tablet of the example was used as the tablet core

2,3.

2. A single-station Manesty Type F 3 tablet press was used, fitted with rounded, standard 0.3125 inch, concave straight tooling.

3. In Example 12.1, about 100mg poly (ethylene oxide) was placed in the die, the tablet core was manually positioned in the center of the die (on the surface of the powder bed), and then an additional 100 mg poly (ethylene oxide) was placed on the tablet surface in the die.

123

4. The materials were manually compressed by turning the press wheel.

5. In Example 12.2, about 50 mg poly (ethylene oxide) was placed in the die, the tablet core was manually positioned in the center of the die (on the powder bed surface), and then an additional 50 mg poly (ethylene oxide) was placed on the tablet surface in the die.

6. The materials were manually compressed by turning the press wheel.

7. The tablets obtained in steps 4 and 6 were spread on a tray and placed in a Hotpack model 435304 oven at 75 ° C for 3 hours to cure the compression coated tablets.

In vitro tests were carried out as follows:

The tablets were tested in vitro using USP Apparatus 1 (drum mixer) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C, using a Perkin Elmer UVVIS Lambda 20 USP Apparatus spectrophotometer, UV at 220 nm. Dimensions of the cured compression-coated tablets and dissolution results are presented in Table 12.

Table 12

<td colspan="2"></td><td colspan="2">Example 12.1</td><td colspan="2">Example 12.2</td>

<td rowspan="3">Tablet dimensions</td><td>Weight (mg)</td><td> 304</td><td> 312</td><td> 209</td><td> 210</td>

<td>Thickness (mm)</td><td> 5,62</td><td> 5,73</td><td> 5,24</td><td> 5,29</td>

<td>Diameter (mm)</td><td> 9,10</td><td> 9,10</td><td> 7,61</td><td> 7,54</td>

<td rowspan="6">dissolution (% released) (n = 2)</td><td>0.5 hours</td><td colspan="2"> 0</td><td colspan="2"> 1</td>

<td>2 hours</td><td colspan="2"> 1</td><td colspan="2"> 47</td>

<td>4 hours</td><td colspan="2"> 9</td><td colspan="2"> 95</td>

<td>8 hours</td><td colspan="2"> 82</td><td colspan="2"> 96</td>

<td>12 hours</td><td colspan="2"> 97</td><td colspan="2"> 96</td>

Example 13

124

In Example 13, using five high molecular weight polyethylene oxide, five different weight tablets were prepared.

156 mg (Examples 13.1 to 13.5) containing 10, 15, 20, 30 and 40 mg oxycodone hydrochloride.

compositions:

<td></td><td>Example 13.1</td><td>Example 13.2</td><td>Example 13.3</td><td>Example 13.4</td><td>Example 13.5</td>

<td>Ingredient</td><td>mg / one TKE</td><td>mg / one TKE</td><td>mg / one TKE</td><td>mg / one TKE</td><td>mg / one TKE</td>

<td>hydrochloride oxycodone</td><td> 10</td><td> 15</td><td> 20</td><td> 30</td><td> 40</td>

<td>Poly (oxide ethylene) (mass Molecular: approximately 4000000; Polyox ™ WSR-301)</td><td> 138,5</td><td> 133,5</td><td> 128,5</td><td> 118,5</td><td> 108,5</td>

<td>Magnesium stearate</td><td> 1,5</td><td> 1,5</td><td> 1,5</td><td> 1,5</td><td> 1,5</td>

<td>Total weight tablet core (Mg)</td><td> 150</td><td> 150</td><td> 150</td><td> 150</td><td> 150</td>

<td>The weight of the whole batch</td><td>10 kg</td><td>10 kg</td><td>10 kg</td><td>10 kg</td><td>10 kg</td>

<td>Coating layer</td><td>mg / one TKE</td><td>mg / one TKE</td><td>mg / one TKE</td><td>mg / one TKE</td><td>mg / one TKE</td>

<td>Coating layer Opadry</td><td> 6</td><td> 6</td><td> 6</td><td> 6</td><td> 6</td>

<td>Total weight tablets (mg)</td><td> 156</td><td> 156</td><td> 156</td><td> 156</td><td> 156</td>

<td>Coated weight batch (kg)</td><td> 8,754</td><td> 9,447</td><td> 9,403</td><td> 8,717</td><td> 8,902</td>

The tablets were made according to the following processing steps:

1. In a Patterson Kelly "V" mixer (equipped with mixer I), with a capacity of 16 quarters, were placed in succession:

Approximately 1/2poly (ethylene oxide) WSR 301

125

Oxycodone hydrochloride

Other poly (ethylene oxide) WSR 301

2. The materials of step 1 were mixed for 5 minutes using the stirrer I on.

3. Magnesium stearate was placed in the "V" mixer.

4. The materials of step 3 were mixed for 1 minute using the switched off stirrer I.

5. The mix obtained in stage 4 was placed in a plastic bag.

6. The mix obtained in step 5 was compressed to the target mass using an 8-station tablet press operating at 35,000 tablets per hour, using standard 9/32 inch rounded, concave (extruded) tooling.

7. The tablets obtained in step 6 were introduced into a Compu-Lab inch coating drum with a drum loading of 8.754 kg (Example 13.1), 9.447 kg (Example 13.2),

9.403 kg (Example 13.3), 8.717 kg (Example 13.4), 8.902 kg (Example 13.5).

8. A temperature probe (wired thermocouple) was placed in the drum directly above the tablet bed so that the end of the probe was close to the moving tablet bed.

9. The drum rotation speed was set to 7 rpm and the tablet bed was heated by setting the inlet air temperature so that the probe indicated 75 ° C. The curing starting point (as described in method 4) was reached when the temperature probe indicated approximately 70 ° C (for example 13.1 - 68.3 ° C, for example 13.2 - 69.9 ° C, for examples 13.3 and 13.4 - 70, 0 ° C, and for example 13.5 71.0 ° C). When the target temperature indicated by the probe was reached, the inlet air temperature was adjusted to maintain this desired temperature. The tablets were cured for 90 minutes. The drum rotation speed was increased to 12 revolutions per minute after about 60 minutes of curing (except for Example 13.5, where the drum rotation speed was maintained at 7 revolutions per minute throughout the curing period). Samples were taken after 30 minutes, 60 minutes and 90 minutes of curing. Temperature profiles of curing processes

126 according to examples 13.1 to 13.5 are presented in the tables

13.1.1 to 13.5.1 and in figures 10 to 14.

Ten. At the end of the curing step, magnesium stearate was added to the moving bed of tablets as an anti-sticking agent. Magnesium stearate was added in the following amounts 8.75 g (Example 13.1), 1.8887 g (Example 13.2), 1.8808 g (Example 13.3), 1.7400 g (Example 13.4), and 1.784 g (Example 13.5). Magnesium stearate was weighed in a weight boat and the powder was manually dosed (dusted) across a moving bed of tablets. The drum rotation speed was kept at 12 rpm (for example

13.5 - 7 rpm) and the tablet bed was cooled by setting the inlet air temperature to 21 ° C. The tablet bed was cooled to an outlet air temperature of less than 41 ° C.

11. The tablet bed was heated to set an inlet air temperature of 55 ° C. The coating process was started when the outlet air temperature reached approximately 43 ° C and continued until the target mass increased by 4%.

12. After the coating process was completed, the drum rotation speed was reduced (3 to 6 rpm) and, in order to cool the system, the inlet air temperature was set at 21 ° to 25 ° C, the air flow was left at the current setting.

13. The tablets were removed from the drum.

In vitro tests including crushing strength tests and density measurement were carried out as follows:

Tablets cured for 30 minutes and 60 minutes, and tablets cured for 90 minutes and coated were tested in vitro using USP Apparatus 1 (tumbler mixer) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C . Samples were analyzed by reversed-phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3.0 x 150 mm column, 3 pm using a mobile phase consisting of a mixture of acetonitrile and a non-basic phosphate buffer (pH 3.0), UV detection 230 nm. Tests were carried out for time points of 1.0, 2.0, 4.0, 8.0 and 12.0 hours.

127

Tablet dimensions, appropriate dissolution results, curing times and temperatures used are shown in the tables

13.1.2 to 13.5.2.

Uncured tablets, cured tablets and cured, coated tablets, in order to assess the tablet's fracture strength, were subjected to a crushing strength test using a maximum force of 439 N using a Schleuniger Model 6D or a crushing strength test using a maximum force equal to 196 N using a Schleuniger 2E / 106 device.

The density of the uncured and cured tablets for various periods of time (30, 60 and 90 minutes) is determined based on the Archimedes principle, using a Mettler Toledo Model # AB 135-S / FACT top loading weight, Serial # 1127430072 and a 33360 density kit. according to the following procedure:

1. A Mettler Toledo balance was set up with a density determination kit.

2. The 200 ml beaker was filled with hexane.

3. The tablet was weighed in air and the mass was designated as A mass.

4. The tablet was transferred to a lower coil inside a hexane filled beaker.

5. The weight of the tablet in hexane was determined and the mass was designated as mass B.

6. Density was calculated according to the equation

AND r = A - B 'ro in which r: Tablet density

A: Weight of the tablet in the air

B: The weight of the tablet immersed in liquid0: Liquid density at a given temperature (density of hexane at 20 ° C = 0.660 g / ml (Merck's index))

7. Density was recorded.

The density values described are average measurement values for 3 tablets and all refer to uncoated tablets.

128

The results are shown in the following tables.

Table 13.1.1: temperature profile of the curing process according to example 13.1

<td>Time</td><td>Time</td><td>Ustawio-</td><td>Fakty-</td><td>Probe</td><td>Distemper-</td><td>Comments</td>

<td>całko-</td><td>curing</td><td>on</td><td>Total</td><td>distemper-</td><td>round</td><td></td>

<td>Temples</td><td>management</td><td>distemper-</td><td>distemper-</td><td>turn-based</td><td>powie-</td><td></td>

<td>(Min.)</td><td>(Min.) 1</td><td>round air on in flight (° C)</td><td>round air on in flight (° C)2</td><td>(° C)3</td><td>on outlet (° C) 4</td><td></td>

<td> 15</td><td> 0</td><td> 85</td><td> 84,8</td><td> 68,3</td><td> 65,5</td><td>Beginning process curing</td>

<td> 45</td><td> 30</td><td> 83</td><td> 83</td><td> 74,8</td><td> 74,7</td><td>30 minutes a sample</td>

<td> 75</td><td> 60</td><td> 81</td><td> 81,1</td><td> 75</td><td> 75,9</td><td>60 minutes a sample</td>

<td> 105</td><td> 90</td><td> 81</td><td> 80,9</td><td> 74,9</td><td> 76</td><td>End process cures u, 90 minutes a sample</td>

129 1 determined according to method 4, 2 inlet temperature measured;

3 temperature measured using a temperature probe (wired thermocouple) 4 outlet temperature measured.

Table 13.1.2

<td></td><td></td><td colspan="4">Example 13.1</td>

<td></td><td></td><td>unpaved (N = 5)</td><td>hardened for 30 minutes (N = 5)</td><td>hardened by 60 minutes (N = 5)</td><td>hardened by 90 minutes, coated (N = 5)</td>

<td rowspan="4">dimensions pills</td><td>Weight (mg)</td><td> 153</td><td> 153</td><td> 152</td><td> 158</td>

<td>Thickness (mm)</td><td> 4,63</td><td> 4,98</td><td> 4,89</td><td> 4,89</td>

<td>Diameter (mm)</td><td> 7,14</td><td> 7,00</td><td> 6,98</td><td> 6,98</td>

<td>Strength for crushing (N)</td><td> 80</td><td> 1961</td><td> 1961</td><td> 4382</td>

<td rowspan="5">dissolves no (% released) SGF</td><td>1 hour</td><td></td><td> 25 (9,5)</td><td> 24 (8,4)</td><td> 27 (7,3)</td>

<td>2 hours</td><td> -</td><td> 39 (7,7)</td><td> 39 (8,7)</td><td> 43 (6,6)</td>

<td>4 hours</td><td> -</td><td> 62 (7,0)</td><td> 62 (5,8)</td><td> 67 (6,8)</td>

<td>8 hours</td><td> -</td><td> 89 (4,7)</td><td> 91 (5,0)</td><td> 92 (2,9)</td>

<td>12 hours</td><td> -</td><td> 100 (3,3)</td><td> 100 (3,6)</td><td> 101 (2,4)</td>

1 maximum strength of the hardness tester, the tablets did not break after being subjected to a maximum force of 196 N.

2 maximum strength of the hardness tester, the tablets did not break after being subjected to a maximum force of 438 N.

130

Table 13.2.1: temperature profile of the curing process according to example 13.2

<td>Time</td><td>Time</td><td>Ustawio-</td><td>Fakty-</td><td>Probe</td><td>Distemper-</td><td>Comments</td>

<td>całko-</td><td>curing</td><td>on</td><td>Total</td><td>distemper-</td><td>round</td><td></td>

<td>Temples</td><td>management</td><td>distemper-</td><td>distemper-</td><td>turn-based</td><td>powie-</td><td></td>

<td> 21</td><td> 0</td><td> 85</td><td> 84,8</td><td> 69,9</td><td> 69,1</td><td>Beginning process curing</td>

<td> 51</td><td> 30</td><td> 82</td><td> 82</td><td> 74,8</td><td> 75,8</td><td>30 minutes a sample</td>

<td> 81</td><td> 60</td><td> 81</td><td> 80,8</td><td> 75</td><td> 75,9</td><td>60 minutes a sample</td>

<td> 111</td><td> 90</td><td> 80,5</td><td> 80,5</td><td> 74,8</td><td> 75,7</td><td>End process curing 90 minutes a sample</td>

131 1 determined according to method 4, 2 inlet temperature measured;

3 temperature measured using a temperature probe (wired thermocouple), 4 outlet temperature measured.

Table 13.2.2

<td></td><td></td><td colspan="4">Example 13.2</td>

<td></td><td></td><td>unpaved (N = 5)</td><td>hardened by 30 minutes (N = 5)</td><td>hardened by 60 minutes (N = 5)</td><td>hardened for 90 minutes, coated (N = 5)</td>

<td rowspan="4">dimensions pills</td><td>Weight (mg)</td><td> 152</td><td> 153</td><td> 152</td><td> 157</td>

<td>Thickness (mm)</td><td> 4,69</td><td> 4,99</td><td> 4,90</td><td> 4,84</td>

<td>Diameter (Mm)</td><td> 7,14</td><td> 6,98</td><td> 6,95</td><td> 6,95</td>

<td>Strength for crushing (N)</td><td> 62</td><td> 1961</td><td> 1961</td><td> 1961</td>

<td rowspan="5">Dissolving (% released) SGF</td><td>1 hour</td><td></td><td> 23(10,6)</td><td> 22 (8,5)</td><td> 25 (5,2)</td>

<td>2 hours</td><td> -</td><td> 38(10,1)</td><td> 37 (7,7)</td><td> 41 (4,6)</td>

<td>4 hours</td><td> -</td><td> 64 (9,5)</td><td> 61 (8,1)</td><td> 65 (3,6)</td>

<td>8 hours</td><td> -</td><td> 92 (6,8)</td><td> 90 (4,6)</td><td> 91 (2,4)</td>

<td>12 hours</td><td> -</td><td> 100(3,4)</td><td> 100(3,2)</td><td> 99 (2,9)</td>

1 maximum strength of the hardness tester, the tablets did not break after being subjected to a maximum force of 196 N.

132

Table 13.3.1: Temperature profile of the curing process according to example 13.3:

<td>Time</td><td>Time</td><td>Ustawio-</td><td>Fakty-</td><td>Probe</td><td>The temperature</td><td>Comments</td>

<td>całko-</td><td>curing</td><td>on</td><td>Total</td><td>distemper-</td><td>rature</td><td></td>

<td>Temples</td><td>management</td><td>distemper-</td><td>distemper-</td><td>turn-based</td><td>powie-</td><td></td>

<td> 13</td><td> 0</td><td> 90</td><td> 90,1</td><td> 70</td><td> 68,3</td><td>Beginning process curing</td>

<td> 43</td><td> 30</td><td> 83</td><td> 83,1</td><td> 75,4</td><td> 76,5</td><td>thirty minutes a sample</td>

<td> 73</td><td> 60</td><td> 81,5</td><td> 81,5</td><td> 74,7</td><td> 76,1</td><td>60 minutes a sample</td>

<td> 103</td><td> 90</td><td> 81,5</td><td> 81,3</td><td> 75</td><td> 76,1</td><td>End process curing 90 minutes a sample</td>

133 1 determined according to method 4, 2 inlet temperature measured;

3 temperature measured using a temperature probe (wired thermocouple), 4 outlet temperature measured.

Table 13.3.2

<td></td><td></td><td colspan="4">Example 13.3</td>

<td></td><td></td><td>unpaved (N = 5)</td><td>hardened by 30 minutes (N = 5)</td><td>hardened by 60 minutes (N = 5)</td><td>hardened by 90 minutes, coated (N = 5)</td>

<td rowspan="4">dimensions pills</td><td>Weight (mg)</td><td> 154</td><td> 154</td><td> 152</td><td> 160</td>

<td>Thickness (Mm)</td><td> 4,56</td><td> 4,85</td><td> 4,79</td><td> 4,77</td>

<td>Diameter (Mm)</td><td> 7,13</td><td> 7,01</td><td> 6,96</td><td> 6,98</td>

<td>Resistance to crushing (N)</td><td> 83</td><td> 1961</td><td> 1961</td><td> 1961</td>

<td rowspan="5">Dissolving (% released) SGF</td><td>1 hour</td><td></td><td> 22 (5,8)</td><td> 26 (9,2)</td><td> 23 (5,7)</td>

<td>2 hours</td><td> -</td><td> 37 (6,4)</td><td> 42 (8,6)</td><td> 39 (4,7)</td>

<td>4 hours</td><td> -</td><td> 61 (6,3)</td><td> 67 (6,3)</td><td> 64 (3,7)</td>

<td>8 hours</td><td> -</td><td> 90 (4,5)</td><td> 93 (3,3)</td><td> 92 (2,7)</td>

<td>12 hours</td><td> -</td><td> 99 (3,1)</td><td> 101 (2,2)</td><td> 101 (1,8)</td>

1 maximum strength of the hardness tester, the tablets did not break after being subjected to a maximum force of 196 N.

Table 13.4.1: Temperature profile of the curing process 5 according to example 13.4:

134

<td>Time</td><td>Time</td><td>Ustawio-</td><td>Fakty-</td><td>Probe</td><td>Distemper-</td><td>Comments</td>

<td>całko-</td><td>curing</td><td>on</td><td>Total</td><td>distemper-</td><td>round</td><td></td>

<td>Temples</td><td>management</td><td>distemper-</td><td>tem-</td><td>turn-based</td><td>powie-</td><td></td>

<td>(Min.)</td><td>(Min.) 1</td><td>round air on in flight (° C)</td><td>rature air on in flight (° C)2</td><td>(° C)3</td><td>on outlet (° C) 4</td><td></td>

<td> 16</td><td> 0</td><td> 90</td><td> 90,1</td><td> 70</td><td> 69,5</td><td>Beginning process curing</td>

<td> 46</td><td> 30</td><td> 84</td><td> 84</td><td> 75,4</td><td> 77,2</td><td>thirty minutes a sample</td>

<td> 76</td><td> 60</td><td> 82</td><td> 81,7</td><td> 74,7</td><td> 76,3</td><td>60 minutes a sample</td>

<td> 106</td><td> 90</td><td> 82</td><td> 82,1</td><td> 75,1</td><td> 76,4</td><td>End process curing 90 minutes a sample</td>

135 1 determined according to method 4, 2 inlet temperature measured;

3 temperature measured using a temperature probe (wired thermocouple), 4 outlet temperature measured.

Table 13.4.2

<td></td><td></td><td colspan="4">Example 13.4</td>

<td></td><td></td><td>unpaved (N = 5)</td><td>hardened by 30 minutes (N = 5)</td><td>hardened by 60 minutes (N = 5)</td><td>hardened by 90 minutes, coated (N = 5)</td>

<td rowspan="4">dimensions pills</td><td>Weight (mg)</td><td> 150</td><td> 151</td><td> 150</td><td> 159</td>

<td>Thickness (Mm)</td><td> 4,43</td><td> 4,73</td><td> 4,67</td><td> 4,68</td>

<td>Diameter (Mm)</td><td> 7,13</td><td> 7,00</td><td> 6,97</td><td> 7,00</td>

<td>Resistance to crushing (N)</td><td> 65</td><td> 1961</td><td> 1961</td><td> 1961</td>

<td rowspan="5">Dissolving (% released) SGF</td><td>1 hour</td><td></td><td> 29 (3,2)</td><td> 25 (7,9)</td><td> 24 (5,5)</td>

<td>2 hours</td><td> -</td><td> 47(3,1)</td><td> 42 (6,7)</td><td> 41 (5,2)</td>

<td>4 hours</td><td> -</td><td> 71 (2,4)</td><td> 67 (5,2)</td><td> 67 (6,2)</td>

<td>8 hours</td><td> -</td><td> 92 (2,5)</td><td> 92 (4,3)</td><td> 94 (3,2)</td>

<td>12 hours</td><td> -</td><td> 99(2,1)</td><td> 100(2,8)</td><td> 101 (2,2)</td>

1 maximum strength of the hardness tester, the tablets did not break after being subjected to a maximum force of 196 N.

136

Table 13.5.1: Temperature profile of the curing process according to example 13.5:

<td>Time</td><td>Time</td><td>Mouth-</td><td>Fakty-</td><td>Probe</td><td>Distemper-</td><td>Comments</td>

<td>całko-</td><td>curing</td><td>Wion</td><td>Total</td><td>tem-</td><td>round</td><td></td>

<td>Temples</td><td>management</td><td>tem-</td><td>tem-</td><td>-temperature</td><td>powie-</td><td></td>

<td>(Min.)</td><td>(Min.) 1</td><td>rature air on in flight (° C)</td><td>rature air on in flight (° C)2</td><td>(° C)3</td><td>on outlet (° C) 4</td><td></td>

<td> 20</td><td> 0</td><td> 90</td><td> 90,2</td><td> 70,9</td><td> 71</td><td>Beginning process curing</td>

<td> 50</td><td> 30</td><td> 85</td><td> 85</td><td> 75,2</td><td> 77,5</td><td>30 minutes a sample</td>

<td> 80</td><td> 60</td><td> 83</td><td> 83,1</td><td> 75,1</td><td> 76,5</td><td>60 minutes a sample</td>

<td> 110</td><td> 90</td><td> 80</td><td> 80,1</td><td> 73,6</td><td> 74,7</td><td>End process cures present, 90 minutes a sample</td>

137 1 determined according to method 4, 2 inlet temperature measured;

3 temperature measured using a temperature probe (wired thermocouple), 4 outlet temperature measured.

Table 13.5.2

<td></td><td></td><td colspan="5">Example 13.5</td>

<td></td><td></td><td>unpaved (N = 5)</td><td>hardened by 30 minutes (N = 5)</td><td>hardened by 60 minutes (N = 5)</td><td>hardened by 90 minutes (N = 5)</td><td>hardened for 90 minutes, coated (N = 5)</td>

<td rowspan="5">dimensions pills</td><td>Weight (mg)</td><td> 156</td><td> 157</td><td> 154</td><td> 153</td><td> 158</td>

<td>Thickness (mm)</td><td> 4,45</td><td> 4,66</td><td> 4,57</td><td> 4,52</td><td> 4,51</td>

<td>Diameter (Mm)</td><td> 7,12</td><td> 7,06</td><td> 7,04</td><td> 7,03</td><td> 7,08</td>

<td>Strength for crushing (N)</td><td> 90</td><td> 4381</td><td> 4381</td><td> 4381</td><td> 4381</td>

<td>The diameter after relaxation (mm) after conducting the test resistance to crushing (Period relaxation NLT 15 minutes)</td><td></td><td> 4,57</td><td> 4,68</td><td> 4,69</td><td> 4,67</td>

138

<td rowspan="4">dissolution (% released) SGF</td><td>2 hours</td><td></td><td> 45 (5,2)</td><td> 45 (5,6)</td><td></td><td> 42 (1,4)</td>

<td>4 hours</td><td> -</td><td> 69 (4,8)</td><td> 70 (4,4)</td><td> -</td><td> 68 (2,0)</td>

<td>8 hours</td><td> -</td><td> 93 (4,2)</td><td> 94 (4,0)</td><td> -</td><td> 94 (4,0)</td>

<td>12 hours</td><td> -</td><td> 98 (3,9)</td><td> 102 (5,2)</td><td> -</td><td> 99(5,1)</td>

<td colspan="7">1 maximum strength of the hardness tester, the tablets did not break after being subjected to the maximum force 438 N.</td>

Table 13.6

<td></td><td colspan="4">Density (g / cm3)1</td><td rowspan="2">Change density after curing (%)2</td>

<td></td><td>unpaved</td><td>hardened by 30 minutes</td><td>hardened by 60 minutes</td><td>hardened by 90 minutes</td>

<td>Example 13.1</td><td> 1,172</td><td> 1,131</td><td> 1,134</td><td> 1,137</td><td> -2,986</td>

<td>Example 13.2</td><td> 1,174</td><td> 1,137</td><td> 1,137</td><td> 1,140</td><td> -2,896</td>

<td>Example 13.3</td><td> 1,179</td><td> 1,151</td><td> 1,152</td><td> 1,152</td><td> -2,290</td>

<td>Example 13.4</td><td> 1,182</td><td> 1,167</td><td> 1,168</td><td> 1,172</td><td> -0,846</td>

<td>Example 13.5</td><td> 1,222</td><td> 1,183</td><td> 1,183</td><td> 1,187</td><td> -2,864</td>

<td colspan="6">1 The density value is the average of the measurements 3 tablets;2 The change in density after curing corresponds to the observed change in density in% of the tablet cured for 90 minutes compared for the uncured tablet.</td>

Example 14

In Example 14, five different 156 mg tablets (Examples 14.1 to 14.5) containing 10, 15, 20, 30 and mg oxycodone hydrochloride were prepared using high molecular weight polyethylene oxide; the batch size was greater compared to example 13.

compositions:

139

<td></td><td>Example 14.1</td><td>Example 14.2</td><td>Example 14.3</td><td>Example 14.4</td><td>Example 14.5</td>

<td>Ingredient</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td>

<td>hydrochloride oxycodone</td><td> 10</td><td> 15</td><td> 20</td><td> 30</td><td> 40</td>

<td>Poly (oxide ethylene) (mass Molecular: approximately 4000000; Polyox ™ WSR-301)</td><td> 138,5</td><td> 133,5</td><td> 128,5</td><td> 118,5</td><td> 108,5</td>

<td>stearate magnesium</td><td> 1,5</td><td> 1,5</td><td> 1,5</td><td> 1,5</td><td> 1,5</td>

<td>Total weight tablet core (Mg)</td><td> 150</td><td> 150</td><td> 150</td><td> 150</td><td> 150</td>

<td>The weight of the whole batch</td><td>100 kg</td><td>100 kg</td><td>100 kg</td><td>100 kg</td><td>100 kg</td>

<td>Layer coating</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td>

<td>Layer coating Opadry</td><td> 6</td><td> 6</td><td> 6</td><td> 6</td><td> 6</td>

<td>Total weight tablets (mg)</td><td> 156</td><td> 156</td><td> 156</td><td> 156</td><td> 156</td>

<td>Coated weight batch (kg)</td><td> 97,480</td><td> 98,808</td><td> 97,864</td><td> 99,511</td><td> 98,788</td>

The tablets were made according to the following processing steps:

1. Magnesium stearate was passed through a Sweco screen fitted with a 20 mesh screen in suitable separate containers.

2. The Gemco "V" mixer (equipped with mixer I) with a capacity of 10 cubic feet was placed in succession:

Approximately 1/2poly (ethylene oxide) WSR 301 Oxycodone hydrochloride Other poly (ethylene oxide) WSR 301

140

3. The materials obtained in step 2 were mixed for 10 minutes using the included stirrer I.

4. Magnesium stearate was placed in the Gemco "V" mixer.

5. The materials obtained in step 4 were mixed for 3 minutes using the switched off stirrer I.

6. The mix obtained in step 5 was placed in clean, tared stainless steel containers.

7. The mix obtained in step 6 was compressed to a target mass using a 40 station tablet press working at a speed of 135,000 tablets per hour, using standard 9/32 inch rounded, concave (extruded) tooling.

8. The tablets obtained in step 7 were loaded into an Accela-Coat 48-inch coating drum, the drum loading was 97.480 kg (Example 14.1), 98.808 kg (Example 14.2), 97.864 kg (Example 14.3), 99.511 kg (Example 14.4) and 98.788 kg (Example 14.5).

9. The drum rotation speed was set to 7 rpm and the tablet bed was heated to set the outlet air temperature so that the inlet air reached a temperature of 75 ° C. The tablets were cured at the target inlet air temperature for 1 hour (examples

14.1 to 14.5). The starting point used to determine the cure time according to method 1 was determined as the point when the inlet air temperature reached the target value of 75 ° C. The temperature profile of the curing processes according to examples 14.1 to 14.5 is presented in tables 14.1.1 to

14.5.1 and in figures 15 to 19.

Ten. The drum rotation speed was maintained at 7 rpm in examples 14.2, 14.4 and 14.5. The drum rotation speed was increased up to 10 rpm in examples 14.1 and up to 8 rpm in the examples

14.3. In examples 14.2 to 14.5, 20 g magnesium stearate was added as an anti-sticking agent. The tablet bed was cooled slowly by lowering the outlet air temperature (Example 14.1) or directly setting the outlet temperature to 25 ° C (Example 14.2) or 30 ° C (examples

141

14.3 to 14.5) so that the outlet air temperature is 30 to 34 ° C.

11. The bed of tablets was heated with air at the outlet to give an inlet temperature of 55 ° C. The coating process was started when the outlet air temperature was around 39 ° C and continued until the target mass increased by 4%.

13. The tablets were removed from the drum.

In vitro tests including crushing strength and durability tests were carried out as follows:

Tablets cured for 1 hour and coated were tested in vitro using USP Apparatus 1 (drum mixer) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C. Samples were analyzed by reversed-phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3.0 x 150 mm column, 3 pm, using a mobile phase consisting of a mixture of acetonitrile and non-basic phosphate buffer (pH 3.0), UV detection 230 nm. Tests were carried out for time points of 1.0, 2.0, 4.0, 6.0, 8.0 and 12.0 hours. Tablet dimensions, respective dissolution results, curing times and temperatures used are shown in Tables 14.1.2 to 14.5.2.

The uncured tablets were subjected to a crushing strength test, with a maximum force of 196 N, using a Schleuniger 2E / 106 device to assess the tablet's breaking strength.

The cured, coated tablets were subjected to a stability test by storing them in bottles containing 100 tablets under various conditions (25aboutC, 60% relative humidity or 40 ° C / 75% relative humidity) for a certain period of time and then testing the tablets in vitro as described above. Storage tests were performed on the initial sample (i.e. before storage), one at a time

142 one month, two months, three months and after six months of storage, dissolution tests were carried out for time periods of 1.0, 2.0, 4.0, 8.0 and 12.0 hours.

The cured, coated tablets were then subjected to a stability test by storing them in bottles holding 100 tablets under various conditions (25 ° C / 60% relative humidity or 40 ° C / 75% relative humidity) for a period of time and thereafter, subjecting the tablets to a test to determine oxycodone hydrochloride content in the tablet. Storage testing was performed on the initial sample (i.e. before storage), after one month, two months, three months and after six months of storage. By conducting the test, oxycodone hydrochloride was extracted from tablets in two sets of ten, each time 900 ml of a 1: 2 mixture of acetonitrile and simulated gastric fluid without enzyme (SGF), continuously stirring with a magnetic stirrer in a 1000 ml volumetric flask until all tablets were completely dispersed or overnight. The solutions were diluted and analyzed by reversed-phase high-performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3 column, 0 x 250 mm, 5 pm at 60 ° C, using a mobile phase consisting of acetonitrile and a monobasic potassium phosphate buffer pH 3.0, UV detection at 280 nm.

The cured, coated tablets were then subjected to a stability test by storing them in bottles containing 100 tablets under various conditions (25 ° C / 60% relative humidity or 40 ° C / 75% relative humidity) for a period of time and thereafter, subjecting the tablets to tests for N content - oxycodone oxide (ONO) to determine the content of - oxycodone N-oxide and unknown in weight percent, relative to the label of the hydrochloride content for storage was carried out on (i.e. before storage), after one three months and six after the ONO content test, and its degradation products, degradation products of degradation products declared for oxycodone. Tests sample initial month, two months, storage months. oxycodone hydrochloride

143 extracted from ten tablets of 900 ml of a 1: 2 mixture of acetonitrile and simulated gastric fluid without enzyme (SGF), stirring continuously with a magnetic stirrer in

1000 ml in a volumetric flask until all the tablets have been completely dispersed or overnight. The solutions were diluted and analyzed by reversed-phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3.0 x 250 mm column, 5 gm at 60 ° C, using a mobile phase consisting of acetonitrile and monobasic potassium phosphate buffer pH 3.0, UV detection at 206 nm.

The density of the uncured, cured and cured / coated tablets was determined as described in the example

13.

The results are shown in the following tables.

Table 14.1.1: Temperature profile of the curing process according to example 14.1

<td>Time total (Min.)</td><td>Time curing (Min.)1</td><td>Temperature air on in flight (° C) 2</td><td>set temperature air on outlet (° C)</td><td>The actual temperature air on outlet (° C) 3</td><td>Speed rotation of the drum (turnover on minute)</td><td>Comments</td>

<td> 0</td><td></td><td></td><td></td><td></td><td> 7</td><td>loading of the drum beginning heating</td>

<td> 36</td><td> 0</td><td> 75,0</td><td> 65</td><td> 65</td><td> 7</td><td>Beginning process curing 0 minutes a sample</td>

144

<td> 51</td><td> 15</td><td> 72,2</td><td></td><td></td><td> 7</td><td>15 minutes a sample</td>

<td> 66</td><td> 30</td><td> 75,0</td><td> 68</td><td> 68</td><td> 8</td><td>30 minutes a sample</td>

<td> 81</td><td> 45</td><td> 74,8</td><td></td><td></td><td> 8</td><td>45 minutes a sample</td>

<td> 96</td><td> 60</td><td> 71,0</td><td> 69</td><td> 69</td><td> 8</td><td>End process curing 60 minutes a sample, not used stearate magnesium beginning cooling stream tablets was sticky</td>

<td> 101</td><td></td><td> 62,0</td><td></td><td></td><td> 8</td><td>Stream tablets begins agglomerated</td>

<td> 104</td><td></td><td> 59,2</td><td></td><td></td><td> 9</td><td>Stream very agglomerated (deposit tablets "Layered")</td>

145

<td> 109</td><td></td><td> 54,9</td><td></td><td></td><td> 9</td><td>Stream tablets still light agglomerated, but better</td>

<td> 110</td><td></td><td> 53,2</td><td></td><td></td><td> 8</td><td>Back to the normal flow tablets</td>

<td colspan="7">1 determined according to method 1,2 inlet temperature measured,3 outlet temperature measured.</td>

Table 14.1.2

<td></td><td></td><td colspan="3">Example 14.1</td>

<td></td><td></td><td>unpaved</td><td>hardened by 60 minutes (N = 5)</td><td>hardened by 60 minutes coated (N = 5)</td>

<td rowspan="3">dimensions pills</td><td>Weight (mg)</td><td>150 (N = 120)</td><td> 150</td><td> 158</td>

<td>Thickness (mm)</td><td>4.42 (n = 5)</td><td> 4,71</td><td> 4,75</td>

<td>Diameter (Mm)</td><td>7.14 (n = 5)</td><td> 7,05</td><td> 7,07</td>

<td></td><td>Strength for crushing (N)</td><td>68 (N = 100)</td><td> 1961</td><td> 1961</td>

<td rowspan="2">dissolution (% released) SGF</td><td>1 hour</td><td></td><td></td><td> 25</td>

<td>2 hours</td><td> -</td><td> -</td><td> 42</td>

146

<td>4 hours</td><td> -</td><td> -</td><td> 67</td>

<td>8 hours</td><td> -</td><td> -</td><td> 94</td>

<td>12 hours</td><td> -</td><td> -</td><td> 101</td>

1 maximum strength of the hardness tester, the tablets did not break after being subjected to a maximum force of 196 N.

Table 14.1.3

Durability tests; Example 14.1, storage at 25 ° C / 60% relative humidity

<td colspan="2" rowspan="2"></td><td colspan="5">Storage time</td>

<td>Initially</td><td>1 month</td><td>2 months</td><td>3 months</td><td>6 months</td>

<td rowspan="5">Dissolving (% released) (n = 6) SGF</td><td>1 hour</td><td> 25</td><td> 24</td><td> 24</td><td> 23</td><td> 23</td>

<td>2 hours</td><td> 42</td><td> 40</td><td> 38</td><td> 38</td><td> 39</td>

<td>4 hours</td><td> 67</td><td> 64</td><td> 61</td><td> 61</td><td> 64</td>

<td>8 hours</td><td> 94</td><td> 90</td><td> 87</td><td> 89</td><td> 90</td>

<td>12 hours</td><td> 101</td><td> 99</td><td> 94</td><td> 100</td><td> 97</td>

<td rowspan="3">Test (mg hydrochloride oxycodone)</td><td>Test 1</td><td> 9,8</td><td> 9,8</td><td> 9,8</td><td> 9,8</td><td> 9,7</td>

<td>Medium</td><td> 9,8</td><td> 9,8</td><td> 9,8</td><td> 9,9</td><td> 9,8</td>

<td rowspan="3">Product Test degradation</td><td>N-oxide oxycodone (%) 1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Each individual unknown (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Whole products degradation (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

147 1 in relation to the oxycodone hydrochloride declared on the label.

Table 14.1.4

<td colspan="7">Durability tests; Example 14/1, storage at 40 ° C / 75% relative humidity</td>

<td colspan="2"></td><td colspan="5">Storage time</td>

<td rowspan="6">Dissolving (% released) (n = 6) SGF</td><td></td><td>Initially</td><td>1 month</td><td>2 months</td><td>3 months</td><td>6 months</td>

<td>2 hours.</td><td> 42</td><td></td><td> 41</td><td> 38</td><td> 39</td>

<td>4 hours</td><td> 67</td><td> 66</td><td> 63</td><td> 62</td><td> 64</td>

<td>8 hours</td><td> 94</td><td> -</td><td> 89</td><td> 88</td><td> 90</td>

<td rowspan="3">Test (mg hydrochloride oxycodone)</td><td>Test 1</td><td> 9,8</td><td> 9,8</td><td> 9,7</td><td> 9,6</td><td> 9,8</td>

<td>Medium</td><td> 9,8</td><td> 9,9</td><td> 9,7</td><td> 9,7</td><td> 9,8</td>

<td rowspan="3"></td><td>N-oxide oksykod one (%) 1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Each individual unknown (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Whole products degradation 0. (%)1</td><td> 1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

148 the oxycodone hydrochloride content declared on the label.

Table 14.2.1: Temperature profile of the curing process according to example 14.2

<td>Time total (Min.)</td><td>Time curing (Min.)1</td><td>Temperature air on in flight (° C)2</td><td>set temperature air on outlet (° C)</td><td>The actual temperature air on outlet (° C) 3</td><td>Speed rotation of the drum (turnover on minute)</td><td>Comments</td>

<td> 0</td><td></td><td> 18</td><td> 50</td><td> 20</td><td> 7</td><td>loading of the drum beginning heating</td>

<td> 8</td><td></td><td> 67,7</td><td> 51,0</td><td> 50,5</td><td> 7</td><td>slow control temp. air on outlet</td>

<td> 14</td><td> 0</td><td> 75,0</td><td> 61,7</td><td> 61,9</td><td> 7</td><td>beginning process curing 0 minutes a sample</td>

<td> 21</td><td> 7</td><td> 77,8</td><td></td><td></td><td> 7</td><td>High temperature air on in flight, then drops to 71 ° C</td>

<td> 29</td><td> 15</td><td> 70,6</td><td> 66,1</td><td> 65,5</td><td> 7</td><td>15 minutes a sample</td>

149

<td> 44</td><td> 30</td><td> 73,3</td><td> 67,0</td><td> 67,4</td><td> 7</td><td>30 minutes a sample</td>

<td> 54</td><td> 40</td><td> 71,7</td><td> 67,5</td><td> 67,3</td><td> 7</td><td>A few tablets stuck to arms supporting the drum no permanent sticking</td>

<td> 59</td><td> 45</td><td> 74,3</td><td> 68,0</td><td> 67,9</td><td> 7</td><td>45 minutes a sample</td>

150

<td> 74</td><td> 60</td><td> 73,0</td><td> 68</td><td> 68</td><td> 7</td><td>End process curing 60 minutes a sample, 20 g added stearate magnesium stream tablets was slightly sticky (based visual assessment flow cascade) flow gradually he was improving after adding stearate magnesium</td>

<td> 75</td><td></td><td> 73</td><td> 25</td><td> 68</td><td> 7</td><td>Normal stream tablets during cooling</td>

1 determined according to method 1, 2 inlet temperature measured, 3 outlet temperature measured.

Table 14.2.2

<td></td><td></td><td>Example 14.2</td>

151

<td></td><td></td><td>unpaved</td><td>hardened by 60 minutes (N = 5)</td><td>hardened by 60 minutes coated (N = 5)</td>

<td rowspan="4">dimensions pills</td><td>Weight (mg)</td><td>150 (n = 120)</td><td> 149</td><td> 156</td>

<td>Thickness (mm)</td><td>4.38 (n = 5)</td><td> 4,68</td><td> 4,70</td>

<td>Diameter (mm)</td><td>7.13 (n = 5)</td><td> 7,07</td><td> 7,09</td>

<td>Strength for crushing (N)</td><td>70 (n = 100)</td><td> 196</td><td> 196</td>

<td rowspan="5">Dissolving (% released) SGF</td><td>1 hour</td><td></td><td></td><td> 23</td>

<td>2 hours</td><td> -</td><td> -</td><td> 39</td>

<td>4 hours</td><td> -</td><td> -</td><td> 64</td>

<td>8 hours</td><td> -</td><td> -</td><td> 93</td>

<td>12 hours</td><td> -</td><td> -</td><td> 100</td>

1 maximum strength of the hardness tester, the tablets did not break after being subjected to a maximum force of 196 N.

152

Table 14.2.3

<td colspan="7">Durability tests; Example 14/2, storage at 25 ° C / 60% relative humidity</td>

<td colspan="2" rowspan="2"></td><td colspan="5">Storage time</td>

<td>Initially</td><td>1 month</td><td>2 months</td><td>3 months</td><td>6 months</td>

<td rowspan="5">dissolution (% released) (n = 6) SGF</td><td>1 hour</td><td> 23</td><td> 24</td><td> 26</td><td> 22</td><td> 24</td>

<td>2 hours.</td><td> 39</td><td> 40</td><td> 41</td><td> 37</td><td> 40</td>

<td>4 hours</td><td> 64</td><td> 65</td><td> 65</td><td> 61</td><td> 65</td>

<td>8 hours</td><td> 93</td><td> 91</td><td> 90</td><td> 90</td><td> 91</td>

<td rowspan="3">Test (mg hydrochloride oxycodone)</td><td>Test 1</td><td> 14,6</td><td> 14,9</td><td> 14,6</td><td> 14,7</td><td> 14,8</td>

<td>Medium</td><td> 14,7</td><td> 14,9</td><td> 14,7</td><td> 14,7</td><td> 14,8</td>

<td rowspan="3">Product Test degradation</td><td>N-oxide oxycodone (%) 1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Each individual unknown (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Whole products degradation (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td colspan="7">1 in relation to the oxycodone hydrochloride declared on the label.</td>

153

154

Table 14.2.4

Durability tests; Example 14.2, storage at 40 ° C / 75% relative humidity

<td colspan="2" rowspan="2"></td><td colspan="5">Storage time</td>

<td>Initially</td><td>1 month</td><td>2 months</td><td>3 months</td><td>6 months</td>

<td rowspan="5">Dissolving (% released) (n = 6) SGF</td><td>1 hour</td><td> 23</td><td> 25</td><td> 26</td><td> 22</td><td> 24</td>

<td>2 hours.</td><td> 39</td><td> 41</td><td> 42</td><td> 36</td><td> 40</td>

<td>4 hours</td><td> 64</td><td> 66</td><td> 66</td><td> 58</td><td> 65</td>

<td>8 hours</td><td> 93</td><td> 94</td><td> 92</td><td> 87</td><td> 91</td>

<td>12 hours</td><td> 100</td><td> 102</td><td> 97</td><td> 97</td><td> 98</td>

<td rowspan="3">Test (mg hydrochloride oxycodone)</td><td>Test 1</td><td> 14,6</td><td> 14,8</td><td> 14,7</td><td> 14,6</td><td> 14,9</td>

<td>Average</td><td> 14,7</td><td> 14,8</td><td> 14,7</td><td> 14,5</td><td> 14,8</td>

<td rowspan="3">Product Test degradation</td><td>N-oxide oxycodo nu (%)1</td><td> £0,1</td><td> £0, 1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Each individual unknown (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Whole products degradation (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

1 in relation to the oxycodone hydrochloride declared on the label.

155

Table 14.3.1: Temperature profile of the curing process according to example 14.3

<td>Time</td><td>Time</td><td>The temperature</td><td>Mouth-</td><td>Fakty-</td><td>Shaft-</td><td>Comments</td>

<td>całko-</td><td>curing</td><td>rature</td><td>Wion</td><td>Total</td><td>bone</td><td></td>

<td>Temples</td><td>management</td><td>powie-</td><td>tem-</td><td>tem-</td><td>swiveled</td><td></td>

<td>(Min.)</td><td>(Min.)1</td><td>on in flight (° C)2</td><td>rature air on outlet (° C)</td><td>rature air on outlet (° C) 3</td><td>present of the drum (turnover on minute)</td><td></td>

<td> 0</td><td></td><td> 17,1</td><td> 50</td><td> 18</td><td> 7</td><td>loading drum, the beginning heating</td>

<td> 15</td><td> 0</td><td> 75,0</td><td> 61,6</td><td> 61,9</td><td> 7</td><td>Beginning of the process curing, 0 sample minutes</td>

<td> 22</td><td> 7</td><td> 79,0</td><td> 62,8</td><td> 66,3</td><td> 7</td><td>High temperature air on in flight</td>

<td> 30</td><td> 15</td><td> 68,4</td><td> 66,0</td><td> 65,3</td><td> 7</td><td>15 minutes sample</td>

<td> 45</td><td> 30</td><td> 76,9</td><td> 68,0</td><td> 67,9</td><td> 7</td><td>30 minutes sample</td>

<td> 60</td><td> 45</td><td> 73,9</td><td> 68,6</td><td> 68,4</td><td> 7</td><td>45 minutes sample</td>

<td> 68</td><td> 53</td><td></td><td></td><td></td><td> 7</td><td>A few tablets (1-4) stuck to arms support drum, good flow tablets</td>

156

<td> 75</td><td> 60</td><td> 77,0</td><td> 70,5</td><td> 70,8</td><td> 8</td><td>End of the process curing, 60 sample minutes, 20 g added stearate magnesium flow tablets he was improving</td>

<td> 76</td><td></td><td> 76</td><td> 30</td><td> 71</td><td> 8</td><td>During cooling observed normal flow</td>

<td> 86</td><td> -</td><td> 30</td><td> 30</td><td> 53</td><td> 8</td><td>No sticking</td>

1 determined according to method 1, 2 inlet temperature measured, 3 outlet temperature measured.

Table 14.3.2

<td></td><td></td><td colspan="3">Example 14.3</td>

<td></td><td></td><td>unpaved</td><td>hardened by 60 minutes (N = 5)</td><td>hardened by 60 minutes coated (N = 5)</td>

<td rowspan="4">dimensions pills</td><td>Weight (mg)</td><td>150 (n = 120)</td><td> 150</td><td> 156</td>

<td>Thickness (mm)</td><td>4.38 (n = 5)</td><td> 4,69</td><td> 4,67</td>

<td>Diameter (mm)</td><td>7.14 (n = 5)</td><td> 7,08</td><td> 7,10</td>

<td>Strength for crushing (N)</td><td>64 (n = 110)</td><td> 1961</td><td> 1961</td>

157

<td rowspan="5">dissolution (% released) SGF</td><td>1 hour</td><td></td><td></td><td> 24</td>

<td>2 hours</td><td> -</td><td> -</td><td> 41</td>

<td>4 hours</td><td> -</td><td> -</td><td> 66</td>

<td>8 hours</td><td> -</td><td> -</td><td> 92</td>

<td>12 hours</td><td> -</td><td> -</td><td> 98</td>

<td colspan="5">1 maximum strength of the hardness tester, the tablets did not break after being subjected to the maximum force 196 N.</td>

Table 14.3.3

Durability tests; Example 14.3, storage at 25 ° C / 60% relative humidity

<td colspan="2" rowspan="2"></td><td colspan="5">Storage time</td>

<td>Initially</td><td>1 month</td><td>2 months</td><td>3 months</td><td>6 months</td>

<td rowspan="5">dissolution (% released) (n = 6) SGF</td><td>1 hour</td><td> 24</td><td> 25</td><td> 22</td><td> 24</td><td> 21</td>

<td>2 hours.</td><td> 41</td><td> 42</td><td> 38</td><td> 40</td><td> 38</td>

<td>4 hours</td><td> 66</td><td> 69</td><td> 61</td><td> 66</td><td> 63</td>

<td>8 hours</td><td> 92</td><td> 96</td><td> 89</td><td> 91</td><td> 88</td>

<td>12 hours</td><td> 98</td><td> 102</td><td> 97</td><td> 99</td><td> 96</td>

<td rowspan="3">Test (mg hydrochloride oxycodone)</td><td>Test 1</td><td> 19,6</td><td> 19,4</td><td> 19,5</td><td> 19,4</td><td> 19,8</td>

<td>Medium</td><td> 19,5</td><td> 19,4</td><td> 19,4</td><td> 19,4</td><td> 19,6</td>

<td rowspan="2">Test products degradation</td><td>N-oxide oxycodo nu (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Each individual unknown (%) 1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

158

<td></td><td>Whole products degradation (%) 1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td colspan="7">1 in relation to the content declared on the label</td>

<td>hydrochloride</td><td colspan="2">oxycodone.</td><td></td><td></td><td></td><td></td>

Table 14.3.4

Durability tests; Example 14.3, storage at 40 ° C / 75% relative humidity

<td colspan="2" rowspan="2"></td><td colspan="5">Storage time</td>

<td>Initially</td><td>1 month</td><td>2 months</td><td>3 months</td><td>6 months</td>

<td rowspan="5">dissolution (% released) (n = 6) SGF</td><td>1 hour</td><td> 24</td><td> 27</td><td> 24</td><td> 23</td><td> 22</td>

<td>2 hours.</td><td> 41</td><td> 44</td><td> 40</td><td> 39</td><td> 40</td>

<td>4 hours</td><td> 66</td><td> 70</td><td> 63</td><td> 63</td><td> 65</td>

<td>8 hours</td><td> 92</td><td> 94</td><td> 90</td><td> 89</td><td> 90</td>

<td>12 hours</td><td> 98</td><td> 102</td><td> 98</td><td> 98</td><td> 98</td>

<td rowspan="3">Test (mg hydrochloride oxycodone)</td><td>Test 1</td><td> 19,6</td><td> 19,3</td><td> 19,6</td><td> 19,3</td><td> 19,7</td>

<td>Medium</td><td> 19,5</td><td> 19,3</td><td> 19,6</td><td> 19,4</td><td> 19,6</td>

<td rowspan="2">Test products degradation</td><td>N-oxide oxycodo nu (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Each individual unknown (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

159

<td></td><td>Whole products degradation (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td colspan="7">1 in relation to the content declared on the label</td>

<td>hydrochloride</td><td colspan="2">oxycodone.</td><td></td><td></td><td></td><td></td>

Table 14.4.1: Temperature profile of the curing process

<td>according</td><td colspan="6">example 14.4</td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>Temperature air on in flight (° C)2</td><td>Temp. deposit (° C)3</td><td>set temperature air on outlet e (° C)</td><td>The actual temperature air on outlet e (° C) 4</td><td>Comments5</td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td>Loading the drum, start of heating</td>

<td> 10</td><td> 0</td><td> 75,0</td><td> 60,5</td><td> 60,0</td><td> 59,0</td><td>Beginning of the process curing, 0 sample minutes</td>

<td> 24</td><td> 15</td><td> 69,2</td><td> 66,7</td><td> 65,7</td><td> 64,9</td><td>15 minutes sample</td>

160

<td> 39</td><td> 30</td><td> 76,5</td><td> 70,2</td><td> 67,7</td><td> 67,7</td><td>30 minutes sample</td>

<td> 47</td><td> 38</td><td> 76,7</td><td> 71,0</td><td> 68,8</td><td> 68,4</td><td>A few tablets stuck to arms support drum, none permanent adherence</td>

<td> 54</td><td> 45</td><td> 79,1</td><td> 72,1</td><td> 70,0</td><td> 69,5</td><td>45 minutes sample</td>

<td> 69</td><td> 60</td><td> 74,0</td><td> 74,5</td><td> 71,7</td><td> 71,3</td><td>End of the process curing, 60 sample minutes, 20 g added stearate magnesium, beginning cooling tablet stream was weakly sticky (on visual basis flow assessment cascading), still a few tablets stuck to arms support, flow improves after adding magnesium stearate</td>

<td> 72</td><td></td><td> 48,9</td><td> 65,3</td><td> 30,0</td><td> 65,3</td><td rowspan="4">Normal flow tablets during cooling</td>

161 1 determined according to method 1, 2 temperature measured at the inlet, temperature of the tablet bed measured at the inlet, i.e. the temperature of the sustained release matrix formulations, measured using a pistol type infrared thermometer, 4 outlet temperature measured, 5 During the curing process, the drum rotation speed was 7 revolutions per minute.

Table 14.4.2

<td></td><td></td><td colspan="3">Example 14.4</td>

<td></td><td></td><td>unpaved</td><td>hardened by 60 minutes (N = 5)</td><td>hardened by 60 minutes coated (N = 5)</td>

<td rowspan="4">dimensions pills</td><td>Weight (mg)</td><td>(150) (N = 120)</td><td> 149</td><td> 157</td>

<td>Thickness (mm)</td><td>4.34 (N = 5)</td><td> 4,60</td><td> 4,63</td>

<td>Diameter (Mm)</td><td>7.14 (N = 5)</td><td> 7,09</td><td> 7,14</td>

<td>Strength for crushing (N)</td><td>61 (N = 100)</td><td> 1961</td><td> 1961</td>

<td rowspan="5">dissolution (% released) SGF</td><td>1 hour</td><td></td><td></td><td> 22</td>

<td>2 hours</td><td> -</td><td> -</td><td> 39</td>

<td>4 hours</td><td> -</td><td> -</td><td> 66</td>

<td>8 hours</td><td> -</td><td> -</td><td> 94</td>

<td>12 hours</td><td> -</td><td> -</td><td> 100</td>

Table 14.4.3

162

Durability tests; Example 14.4, storage at 25 ° C / 60% relative humidity

<td colspan="2" rowspan="2"></td><td colspan="5">Storage time</td>

<td>Initially</td><td>1 month</td><td>2 months</td><td>3 months</td><td>6 months</td>

<td rowspan="5">dissolution (% released) (n = 6) SGF</td><td>1 hour</td><td> 22</td><td> 23</td><td> 24</td><td> 24</td><td> 23</td>

<td>2 hours.</td><td> 39</td><td> 39</td><td> 39</td><td> 41</td><td> 40</td>

<td>4 hours</td><td> 66</td><td> 64</td><td> 63</td><td> 68</td><td> 65</td>

<td>8 hours</td><td> 94</td><td> 91</td><td> 88</td><td> 93</td><td> 91</td>

<td>12 hours</td><td> 100</td><td> 98</td><td> 96</td><td> 99</td><td> 98</td>

<td rowspan="3">Test (mg hydrochloride oxycodone)</td><td>Test 1</td><td> 28,8</td><td> 28,8</td><td> 28,4</td><td> 28,8</td><td> 29,2</td>

<td>Medium</td><td> 29,0</td><td> 28,9</td><td> 28,6</td><td> 28,8</td><td> 29,2</td>

<td rowspan="2">Product Test degradation</td><td>N-oxide oxycodo nu (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Each individual unknown (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td></td><td>Whole products degradation (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

1 in relation to the oxycodone hydrochloride declared on the label.

Table 14.4.4

Durability tests; Example 14.4, storage at 40 ° C / 75% relative humidity

Storage time

163

<td colspan="2"></td><td>Initially</td><td>1 month</td><td>2 months</td><td>3 months</td><td>6 months</td>

<td rowspan="5">dissolution (% released) (n = 6) SGF</td><td>1 hour</td><td> 22</td><td> 26</td><td> 24</td><td> 24</td><td> 24</td>

<td>2 hours.</td><td> 39</td><td> 44</td><td> 41</td><td> 41</td><td> 41</td>

<td>4 hours</td><td> 66</td><td> 70</td><td> 64</td><td> 67</td><td> 67</td>

<td>8 hours</td><td> 94</td><td> 93</td><td> 88</td><td> 92</td><td> 93</td>

<td>12 hours</td><td> 100</td><td> 99</td><td> 96</td><td> 98</td><td> 98</td>

<td rowspan="3">Test (mg hydrochloride oxycodone)</td><td>Test 1</td><td> 28,8</td><td> 29,3</td><td> 28,2</td><td> 29,0</td><td> 28,4</td>

<td>Medium</td><td> 29,0</td><td> 29,3</td><td> 28,1</td><td> 28,9</td><td> 28,5</td>

<td rowspan="3">Test products degradation</td><td>N-oxide oxycodo nu (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Each individual unknown (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Whole products degradation (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

1 in relation to the oxycodone hydrochloride declared on the label.

164

Table 14.5.1: Temperature profile of the curing process according to example 14.5

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>Temperature air on in flight (° C)2</td><td>Temp. deposit (° C)3</td><td>set temperature air on outlet (° C)</td><td>The actual temperature air on outlet (° C) 4</td><td>Comments5</td>

<td> 0</td><td></td><td> 16,6</td><td> 30</td><td> 60,0</td><td> 19,7</td><td>loading drum, the beginning heating</td>

<td> 17</td><td> 0</td><td> 75,0</td><td> 65,3</td><td> 63,0</td><td> 62,5</td><td>Beginning of the process curing, 0 sample minutes</td>

<td> 32</td><td> 15</td><td> 83,1</td><td> 70,8</td><td> 70,0</td><td> 68,7</td><td>15 minutes sample</td>

<td> 42</td><td> 25</td><td> 82,5</td><td> 73,1</td><td> 72,0</td><td> 70,4</td><td>Good flow tablets and flow of cascade</td>

<td> 47</td><td> 30</td><td> 82,7</td><td> 77,6</td><td> 72,2</td><td> 74,1</td><td>30 minutes sample</td>

165

<td> 52</td><td> 35</td><td> 71,2</td><td> 73,8</td><td> 72,2</td><td> 71,4</td><td>Stream tablets was slightly sticky, 1-2 pills stuck to arms support</td>

<td> 62</td><td> 45</td><td> 75,4</td><td> 75,3</td><td> 72,2</td><td> 72,9</td><td>45 minutes sample</td>

<td> 66</td><td> 49</td><td> 73,4</td><td> 74,5</td><td> 72,2</td><td> 71,8</td><td>Stream tablets was slightly sticky, 1-2 pills stuck to arms support (no permanent adherence)</td>

<td> 77</td><td> 60</td><td> 73,9</td><td> 74,9</td><td> 72,2</td><td> 72,2</td><td>End of the process curing, 60 sample minutes, 20 g added stearate magnesium, continuous improvement flow / cascade flow, beginning cooling tablets no stuck to arms support drum,</td>

166

<td> 80</td><td> -</td><td> 46,8</td><td> 64,9</td><td> 30,0</td><td> 64,7</td><td>refrigeration</td>

<td></td><td></td><td></td><td></td><td> 30,0</td><td></td><td>2 tablets stuck to arms support (no permanent adherence)</td>

<td> 82</td><td></td><td> 40,3</td><td> 58,6</td><td> 30,0</td><td> 57,4</td><td>Tablets still in traffic, no stick together</td>

<td> 84</td><td></td><td> 35,8</td><td> 57,4</td><td> 30,0</td><td> 55,6</td><td rowspan="5">Normal flow tablets watched during cooling. Still cooling to temperature air on equal outlet 30-34 ° C in order start coating</td>

<td> 97</td><td></td><td></td><td> -29</td><td> 30,0</td><td></td><td>Surface beds 30.3 ° C, bed bottom 28.5 ° C</td>

1 determined according to method 1, 2 inlet temperature measured, 3 tablet bed temperature, i.e. the temperature of the extended release matrix formulations, measured using a pistol type infrared thermometer, 4 the temperature measured at the outlet, during the curing process, the drum rotation speed was 7 revolutions per minute.

167

Table 14.5.2

<td></td><td></td><td colspan="3">Example 14.5</td>

<td></td><td></td><td>unpaved</td><td>Cured by 60 minutes (N = 5)</td><td>hardened by 60 minutes coated (N = 5)</td>

<td rowspan="4">dimensions pills</td><td>Weight (mg)</td><td>(N = 120)</td><td> 149</td><td> 155</td>

<td>Thickness (mm)</td><td>4.30 (n = 5)</td><td> 4,49</td><td> 4,52</td>

<td>Diameter (mm)</td><td>7.15 (n = 5)</td><td> 7,10</td><td> 7,15</td>

<td>Resistance to crushing (N)</td><td>55 (n = 110)</td><td> 1961</td><td> 1961</td>

<td rowspan="5">dissolution (% released) SGF</td><td>1 hour</td><td></td><td></td><td> 24</td>

<td>2 hours</td><td> -</td><td> -</td><td> 41</td>

<td>4 hours</td><td> -</td><td> -</td><td> 68</td>

<td>8 hours</td><td> -</td><td> -</td><td> 93</td>

<td>12 hours</td><td> -</td><td> -</td><td> 98</td>

1 maximum strength of the hardness tester, the tablets did not break after being subjected to the maximum force

196 N.

Table 14.5.3

<td colspan="7">Durability tests; Example 14.5, storage at 25 ° C / 60% relative humidity</td>

<td colspan="2" rowspan="2"></td><td colspan="5">Storage time</td>

<td>Initially</td><td>1 month</td><td>2 months</td><td>3 months</td><td>6 months</td>

<td rowspan="4">dissolution (% released) (n = 6) SGF</td><td>1 hour</td><td> 24</td><td> 25</td><td> 27</td><td> 23</td><td> 25</td>

<td>2 hours.</td><td> 41</td><td> 43</td><td> 44</td><td> 40</td><td> 43</td>

<td>4 hours</td><td> 68</td><td> 69</td><td> 69</td><td> 66</td><td> 69</td>

<td>8 hours</td><td> 93</td><td> 94</td><td> 93</td><td> 89</td><td> 92</td>

168

<td></td><td>12 hours</td><td> 98</td><td> 98</td><td> 97</td><td> 96</td><td> 96</td>

<td rowspan="3">test (mg hydrochloride oxycodone)</td><td>Test 1</td><td> 37,8</td><td> 38,4</td><td> 36,9</td><td> 37,6</td><td> 39,2</td>

<td>Medium</td><td> 37,8</td><td> 38,0</td><td> 36,7</td><td> 37,9</td><td> 39,2</td>

<td rowspan="3">Test products degradation</td><td>N-oxide oxycodo nu (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Each individual unknown (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Whole products degradation (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0, 1</td>

1 in relation to the oxycodone hydrochloride declared on the label.

Table 14.5.4

Durability tests; Example 14.5, storage at 40 ° C / 75% relative humidity

<td colspan="2" rowspan="2"></td><td colspan="5">Storage time</td>

<td>Initially</td><td>1 month</td><td>2 months</td><td>3 months</td><td>6 months</td>

<td rowspan="5">dissolution (% released) (n = 6) SGF</td><td>1 hour</td><td> 24</td><td> 26</td><td> 27</td><td> 25</td><td> 25</td>

<td>2 hours.</td><td> 41</td><td> -</td><td> 45</td><td> 42</td><td> 43</td>

<td>4 hours</td><td> 68</td><td> 71</td><td> 72</td><td> 68</td><td> 69</td>

<td>8 hours</td><td> 93</td><td> -</td><td> 95</td><td> 93</td><td> 92</td>

<td>12 hours</td><td> 98</td><td> 97</td><td> 98</td><td> 99</td><td> 95</td>

<td>Test (mg hydrochloride oxycodone)</td><td>Test 1</td><td> 37,8</td><td> 38,3</td><td> 37,3</td><td> 37,6</td><td> 37,9</td>

169

<td>Average</td><td> 37,8</td><td> 38,5</td><td> 37,1</td><td> 37,6</td><td> 38,0</td>

<td rowspan="3">Product Test degradation</td><td>N-oxide oxycodo nu (%)1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Each individual unknown</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

<td>Whole products degradation</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td><td> £0,1</td>

1 in relation to the oxycodone hydrochloride declared on the label.

Table 14.6

<td></td><td colspan="3">Density (g / cm3)</td><td>Change density after</td><td>Change density after</td>

<td></td><td>unpaved</td><td>cured</td><td>Hardened and covered</td><td>curing (%)</td><td>curing and coating (%)</td>

<td>Example 14.1</td><td> 1,186</td><td> 1,145</td><td> 1,138</td><td> -3,457</td><td> -4,047</td>

<td>Example 14.2</td><td> 1,184</td><td> 1,152</td><td> 1,129</td><td> -2,703</td><td> -4,645</td>

<td>Example 14.3</td><td> 1,183</td><td> 1,151</td><td> 1,144</td><td> -2,705</td><td> -3,297</td>

<td>Example 14.4</td><td> 1,206</td><td> 1,162</td><td> 1,130</td><td> -3,648</td><td> -6,302</td>

<td>Example 14.5</td><td> 1,208</td><td> 1,174</td><td> 1,172</td><td> -2,815</td><td> -2,980</td>

Example 15

In Example 15, using two high molecular weight polyethylene oxide, two different tablets containing oxycodone hydrochloride were prepared. One 234 mg formulation (Example 15.1) contained 60 mg oxycodone hydrochloride and the other 260 mg formulation (Example 15.2) contained 80 mg oxycodone hydrochloride.

compositions:

<td></td><td>Example 15.1</td><td>Example 15.2</td>

170

<td>Ingredient</td><td>mg / unit</td><td>mg / unit</td>

<td>Oxycodone hydrochloride</td><td> 60</td><td> 80</td>

<td>Poly (ethylene oxide) (mass molecular: approximately 4000000; Polyox ™ WSR- 301)</td><td> 162,75</td><td> 167,5</td>

<td>Magnesium stearate</td><td> 2,25</td><td> 2,50</td>

<td>The total weight of the tablet core (Mg)</td><td> 225</td><td> 250</td>

<td>The weight of the whole batch</td><td>10 kg</td><td>10 kg</td>

<td>Coating layer</td><td>mg / unit</td><td>mg / unit</td>

<td>Opadry coating layer</td><td> 9</td><td> 10</td>

<td>Total tablet weight (mg)</td><td> 234</td><td> 260</td>

<td>Weight of coated lot (kg)</td><td> 8,367</td><td> 8,205</td>

The tablets were made according to the following processing steps:

1. In a Patterson Kelly "V" mixer (equipped with mixer I), with a capacity of 16 quarters, were placed in succession:

Approximately 1/2poly (ethylene oxide) WSR 301

Oxycodone hydrochloride (sieved through a 20 mesh sieve)

Other poly (ethylene oxide) WSR 301

2. The materials of step 1 were mixed for 5 minutes using the stirrer I on.

3. Magnesium stearate (sieved through a 20 mesh screen) was placed in the "V" mixer.

4. The materials of step 3 were mixed for 1 minute using the switched off stirrer I.

5. The blend obtained in step 4 was placed in a plastic bag (note: two 5 kg blend was made to give a 10 kg blend of compression tablets).

6. The blend obtained in step 5 was compressed to the target mass using an 8-station tablet press operating at 35,000 tablets per hour, using standard 3/8 inch rounded concave (extruded) tooling. Tablet core samples were taken.

7. The tablets obtained in step 6 were introduced into a Compu-Lab 24 inch coating drum at loading

171 drum equal to 8,367 kg (Example 15.1) and 8,205 kg (Example

15.2).

8. A temperature probe (wired thermocouple) was placed in the drum directly above the tablet bed so that the probe end was close to the tablet bed.

9. The drum rotation speed was set to 10 rpm and the tablet bed was heated to set the inlet air temperature to reach a target outlet air temperature of 72 ° C. The curing starting point (as described in method 2) was reached when the outlet air temperature reached 72 ° C. The inlet air temperature was adjusted to maintain the desired outlet air temperature. The tablets were cured for 15 minutes. The drum rotation speed was maintained at 10 rpm. The temperature profile of the curing processes according to examples 15.1 and 15.2 is presented in tables 15.1.1 and

15.2.1.

Ten. The drum rotation speed was maintained at 10 rpm. The inlet air temperature was set to 22 ° C and the tablet bed was cooled such that the outlet air temperature was 30.0 ° C. A sample of cured tablets was taken at the end of the cooling process.

11. The tablet bed was heated to set an inlet air temperature of 53 ° C. The coating process was started when the outlet air temperature reached approximately 41 ° C and continued until the target mass increased by 4%. During the coating process, the drum rotation speed was increased to 20 rpm.

12. After coating, the drum rotation speed was reduced and the inlet air temperature was set to 22 ° C, the air flow was kept constant and the system was cooled so that the outlet air temperature was <30 ° C. A sample of cured / coated tablets was taken.

13. The tablets were removed from the drum.

Then, in vitro tests were carried out, including crushing strength tests:

172

The tablet core (uncured), cured tablets for 15 minutes and cured / coated tablets were tested in vitro using USP Apparatus 1 (basket with a blocking spring placed on the surface of the basket to reduce the tendency of the tablets to stick to the base of the stem) at 100 rpm 900 ml simulated gastric fluid without enzymes (SGF) at 37.0 ° C. Samples were analyzed by reversed-phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC 18 3, 0 x 250 mm column, 5 pm using a mobile phase consisting of a mixture of acetonitrile and monobasic potassium phosphate buffer (pH 3.0), UV detection at 230 nm. The tests were carried out for time points covering 1.0, 2.0, 4.0, 6.0,

8.0, 12.0 and 16.0 hours.

The tablet core (uncured), cured tablets for minutes and cured / coated tablets were subjected to a crushing strength test using a maximum force of 196 N using a Schleuniger 2E / 106 device to assess the tablet's breaking strength.

Tablet dimensions and dissolution results are presented in tables 15.1.2 to 15.2.2.

Table 15.1.1: Temperature profile of the curing process according to example 15.1

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>set temp. air at the inlet (° C)</td><td>The actual temp. air at the inlet (° C)2</td><td>Probe (° C)3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td> -</td><td>22 to 85</td><td> 47,4</td><td> -</td><td> 26,4</td><td>Beginning heating</td>

<td> 20</td><td></td><td> 85</td><td> 84,8</td><td> 73,7</td><td> 70,4</td><td>Good flow tablets, lack bonding</td>

173

<td> 25,5</td><td> 0</td><td>85 to 74</td><td> 85,0</td><td> 75,1</td><td> 72,0</td><td>Beginning curing; set temp. 74 ° C inlet for low temp at the outlet fell to 70.9 ° C temp. air on in flight set to 80 ° C</td>

<td> 30,5</td><td> 5</td><td> 80</td><td> 80,0</td><td> 73,6</td><td> 71,9</td><td>Good flow tablets, lack bonding</td>

<td> 35,5</td><td> 10</td><td> 75</td><td> 75,8</td><td> 72,2</td><td> 73,3</td><td>Good flow tablets, lack bonding</td>

<td> 40,5</td><td> 15</td><td>73 to 22</td><td> 72,8</td><td> 70,6</td><td> 71,9</td><td>End process curing good flow tablets, lack gluing, beginning cooling</td>

174

<td> 61</td><td></td><td> 22</td><td> 22,0</td><td> 27,2</td><td> 29,7</td><td>End cooling, during cooling no observed gluing, good flow tablets, downloaded sample hardened tablets</td>

<td colspan="7">1 determined according to method 2,2 inlet temperature measured,3 temperature measured using a probe temperature (wired thermocouple)4 outlet temperature measured.</td>

Table 15.1.2

<td></td><td></td><td colspan="3">Example 15.1</td>

<td></td><td></td><td>unpaved</td><td>hardened for 15 minutes</td><td>Covered</td>

<td rowspan="7">Dissolving (% released) SGF</td><td>1 hour</td><td> 28</td><td> 28</td><td> 24</td>

<td>2 hours</td><td> 44</td><td> 44</td><td> 41</td>

<td>4 hours</td><td> 69</td><td> 69</td><td> 67</td>

<td>6 hours</td><td> 85</td><td> 85</td><td> 84</td>

<td>8 hours</td><td> 95</td><td> 95</td><td> 93</td>

<td>12 hours</td><td> 102</td><td> 102</td><td> 99</td>

<td>16 hours</td><td> 104</td><td> 103</td><td> 102</td>

175

Table 15.2.1: Temperature profile of the curing process according to example 15.2

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>set temp. air at the inlet (° C)</td><td>The actual temp. air at the inlet (° C)2</td><td>Probe (° C) 3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td> -</td><td>22 to 80</td><td> 23,3</td><td> 27,7</td><td> 25,5</td><td>Beginning heating</td>

<td> 20</td><td></td><td> 80</td><td> 80,0</td><td> 70,1</td><td> 68,4</td><td>Good flow tablets, none bonding</td>

<td> 30</td><td></td><td> 80</td><td> 80,1</td><td> 72,5</td><td> 70,6</td><td>Good flow tablets, none bonding</td>

<td> 35</td><td> 0</td><td> 80</td><td> 79,9</td><td> 73,6</td><td> 72,0</td><td>Beginning curing; good flow tablets, none bonding</td>

<td> 38</td><td> 3</td><td></td><td></td><td></td><td> 72,7</td><td>Maximal temperature on outlet</td>

<td> 45</td><td> 10</td><td> 74</td><td> 73,9</td><td> 71,9</td><td> 72,3</td><td>Good flow tablets, none bonding</td>

<td> 50</td><td> 15</td><td>74 to 22</td><td> 74,2</td><td> 72,0</td><td> 72,4</td><td>End of the process curing beginning cooling</td>

176

<td> 71</td><td></td><td> 22</td><td> 21,7</td><td> 28,4</td><td> 30,0</td><td>End cooling, during cooling down no observed gluing, good flow tablets, a sample was taken hardened tablets</td>

<td colspan="7">1 determined according to method 2,2 inlet temperature measured,3 temperature measured using a temperature probe (wired thermocouple)4 outlet temperature measured.</td>

Table 15.2.2

<td></td><td></td><td colspan="3">Example 15.2</td>

<td></td><td></td><td>unpaved (N = 25)</td><td>Cured by 15 minutes (N = 5)</td><td>coated (N = 5)</td>

<td rowspan="3">dimensions pills</td><td>Weight (mg)</td><td> 254</td><td> 250</td><td> 257</td>

<td>Thickness (mm)</td><td> 4,20</td><td> 4,28</td><td> 4,29</td>

<td>Resistance to crushing (N)</td><td> 92</td><td> 1961</td><td> 194 2</td>

<td rowspan="6">dissolution (% released) SGF</td><td>1 hour</td><td> 26</td><td> 28</td><td> 25</td>

<td>2 hours</td><td> 43</td><td> 42</td><td> 39</td>

<td>4 hours</td><td> 65</td><td> 67</td><td> 64</td>

<td>6 hours</td><td> 83</td><td> 83</td><td> 82</td>

<td>8 hours</td><td> 92</td><td> 94</td><td> 92</td>

<td>12 hours</td><td> 101</td><td> 102</td><td> 100</td>

177

<td>16 hours</td><td> 104</td><td> 103</td><td> 102</td>

1 maximum strength of the hardness tester, the tablets did not break after being subjected to a maximum force of 196 N.

2 Four tablets did not break after being subjected to a maximum force of 196 N, one tablet showed resistance to crushing at 185 N (average of samples, n = 5, 194 N).

Example 16

In Example 16, using high molecular weight polyethylene oxide, two different tablets containing oxycodone hydrochloride were prepared. One 234 mg formulation (Example 16.1) contained 60 mg oxycodone hydrochloride and the other 260 mg formulation (Example 16.2) contained 80 mg oxycodone hydrochloride. The formulations were made in a larger number compared to the batch of Example 15.

compositions:

<td></td><td>Example 16.1</td><td>Example 16.2</td>

<td>Ingredient</td><td>mg / unit</td><td>mg / unit</td>

<td>Oxycodone hydrochloride</td><td> 60</td><td> 80</td>

<td>Poly (ethylene oxide) (mass molecular: approximately 4000000; Polyox ™ WSR- 301, LEO)</td><td> 162,75</td><td> 167,5</td>

<td>Magnesium stearate</td><td> 2,25</td><td> 2,50</td>

<td>The total weight of the tablet core (Mg)</td><td> 225</td><td> 250</td>

<td>The weight of the whole batch</td><td>100 kg</td><td>100 kg</td>

<td>Coating layer</td><td>mg / unit</td><td>mg / unit</td>

<td>Opadry coating layer</td><td> 9</td><td> 10</td>

<td>Total tablet weight (mg)</td><td> 234</td><td> 260</td>

<td>Weight of coated lot (kg)</td><td> 94,122</td><td> 93,530</td>

The tablets were made according to the following processing steps:

1. Oxycodone hydrochloride and magnesium stearate were passed through a Sweco screen fitted with a screen

178 20 mesh mesh size into separate appropriate containers.

2. The Gemco "V" mixer (equipped with mixer I) with a capacity of 10 cubic feet was placed in succession:

Approximately 1/2poly (ethylene oxide) WSR 301

Oxycodone hydrochloride

Other poly (ethylene oxide) WSR 301

3. The materials obtained in step 2 were mixed for 10 minutes using the included stirrer I.

4. Magnesium stearate was placed in the Gemco "V" mixer.

5. The materials obtained in step 4 were mixed for 2 minutes using the switched off stirrer I.

6. The mix obtained in step 5 was placed in clean, tared stainless steel containers.

7. The mix obtained in step 6 was compressed to a target mass using a 40 station tablet press at a speed of 135,000 tablets per hour, using standard 3/8 inch rounded, concave embossed tooling, and 16.5 kN compression force in Example 16.1 and 16.0 kN compression force in example 16.2. A sample of the tablet core was taken.

8. The tablets obtained in step 7 were introduced into an Accela-Coat 48-inch coating drum, the drum loading was 94.122 kg (Example 16.1) and 93.530 kg (Example 16.2).

9. The drum rotation speed was set at 7 rpm and the tablet bed was heated to set the outlet air temperature to reach 72 ° C. The curing starting point (as described in method 2) was reached when the outlet air temperature reached 72 ° C. The tablets were cured at the target outlet air temperature for 15 minutes. The temperature profile of curing processes for examples 16.1 and 16.2 is presented in tables 16.1.1 and

16.2.1.

Ten. The drum rotation speed was maintained at 7 revolutions per minute. The outlet air temperature was set to 25 ° C and the tablet bed was cooled such that the outlet air temperature was 30 ° C.

179

11. The bed of tablets was heated by raising the temperature from 30 ° C to 38 ° C. The coating process was started when the outlet air temperature reached 40 ° C and continued until the target mass increased by 4%. During the coating process, the drum rotation speed was maintained at 7 rpm.

12. After coating, the drum rotation speed was reduced to 1.5 revolutions per minute, the outlet air temperature was set to 27 ° C, the air flow was kept constant, and the tablet bed was cooled to an outlet air temperature <30 ° C.

13. The tablets were removed from the drum.

Then, in vitro tests were carried out, including crushing strength tests:

The coated tablets were tested in vitro using USP Apparatus 1 (basket with a blocking spring placed on the surface of the basket to reduce the tendency of the tablets to stick to the base of the stem) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37, 0 ° C. Samples were analyzed by reversed-phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3, 0 x 250 mm column, 5 pm using a mobile phase consisting of a mixture of acetonitrile and monobasic potassium phosphate buffer (pH 3.0), UV detection at 230 nm. Tests were carried out for time points of 1.0, 2.0, 4.0, 8.0, and 12.0 hours.

Uncured tablets were subjected to weight, thickness and hardness tests on an ongoing basis using Key Checkweigher.

Tablet dimensions and dissolution results are presented in tables 16.1.2 to 16.2.2.

Table 16.1.1: temperature profile of the curing process according to example 16.1

180

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>Inlet (° C)2</td><td>Thermometer on infrared type pistol (° C)3</td><td>set temperature on outlet (° C)</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td> -</td><td> 34</td><td> 32</td><td> 65</td><td> 24</td><td>Beginning heating</td>

<td> 21</td><td> 0</td><td> 92</td><td> 79</td><td> 72</td><td> 72</td><td>Beginning curing</td>

<td> 37</td><td> 16</td><td> 80</td><td> 77</td><td>72 to 25</td><td> 73</td><td>End process curing good flow tablets, lack gluing, beginning cooling</td>

181

<td> 57</td><td></td><td> 22</td><td> 26</td><td> 25</td><td> 29</td><td>End cooling, during cooling no observed gluing, good flow tablets</td>

<td colspan="7">1 determined according to method 2,2 inlet temperature measured,3 the temperature was measured using a pistol type infrared thermometer4 outlet temperature measured.</td>

Table 16.1.2

<td></td><td></td><td colspan="2">Example 16.1</td>

<td></td><td></td><td>unpaved (N = 70)</td><td>Covered</td>

<td rowspan="3">Tablet dimensions</td><td>Weight (mg)</td><td> 224,6</td><td> -</td>

<td>Thickness (mm)</td><td> 3,77</td><td> -</td>

<td>Resistance to crushing (Kp)</td><td> 5,7</td><td> -</td>

<td rowspan="5">Dissolving (% released) SGF</td><td>1 hour</td><td> -</td><td> 24</td>

<td>2 hours</td><td> -</td><td> 41</td>

<td>4 hours</td><td> -</td><td> 67</td>

<td>8 hours</td><td> -</td><td> 93</td>

<td>12 hours</td><td> -</td><td> 99</td>

182

Table 16.2.1: Temperature profile of the curing process according to example 16.2

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>Inlet (° C)2</td><td>Thermometer on infrared type pistol (° C)3</td><td>Set temperature on outlet (° C)</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 2</td><td> -</td><td> -</td><td> -</td><td>20 to 65</td><td> -</td><td>Beginning heating</td>

<td> 22</td><td> 0</td><td> 91</td><td> 77</td><td> 68</td><td> 72</td><td>Beginning curing</td>

<td> 28</td><td> 6</td><td> 82</td><td> 83</td><td> 72</td><td> 78</td><td>Good flow tablets, lack bonding</td>

183

<td> 37</td><td> 15</td><td> 81</td><td> 76</td><td>72 to 25</td><td> 72</td><td>End process curing good flow tablets, lack gluing, beginning cooling</td>

<td> 47</td><td></td><td> 25</td><td> 50</td><td> 25</td><td> 48</td><td>good flow tablets, lack bonding</td>

<td> 56</td><td></td><td> 21</td><td> 29</td><td> 25</td><td> 30</td><td>End cooling, during cooling no observed gluing, good flow tablets</td>

Table 16.2.2

<td></td><td></td><td colspan="2">Example 16.2</td>

<td></td><td></td><td>unpaved (N = 60)</td><td>Covered</td>

<td rowspan="2">Tablet dimensions</td><td>Weight (mg)</td><td> 250,8</td><td> -</td>

<td>Thickness (mm)</td><td> 4,05</td><td> -</td>

184

<td></td><td></td><td colspan="2">Example 16.2</td>

<td></td><td></td><td>unpaved (N = 60)</td><td>Covered</td>

<td></td><td>Strength for crushing (Kp)</td><td> 6,8</td><td></td>

<td rowspan="5">dissolution (% released) SGF</td><td>1 hour</td><td> -</td><td> 22</td>

<td>2 hours</td><td> -</td><td> 37</td>

<td>4 hours</td><td> -</td><td> 62</td>

<td>8 hours</td><td> -</td><td> 89</td>

<td>12 hours</td><td> -</td><td> 97</td>

Example 17

In Example 17, using high molecular weight polyethylene oxide 60 mg of 17.1 hydrochloride is such a second preparation of hydroxytoluene, two preparations containing oxycodone were prepared. The formulation of the example is the same as shown in example 15.1.

(example 17.2) contains 0.1% butylated. Each tablet was cured at a target air outlet temperature of 72 ° C and 75 ° C for 15 minutes, then covered with a coating layer, and an additional curing step was carried out at the target air outlet temperature for 30 minutes .

compositions:

<td></td><td>Example 17.1</td><td>Example 17.2</td>

<td>Ingredient</td><td>mg / unit</td><td>mg / unit</td>

<td>Oxycodone hydrochloride</td><td> 60</td><td> 60</td>

<td>Poly (ethylene oxide) (mass molecular: approximately 4000000; Polyox ™ WSR-301)</td><td> 162,75</td><td> 162,525</td>

<td>Butylated hydroxytoluene (BHT)</td><td> 0</td><td> 0,225</td>

<td>Magnesium stearate</td><td> 2,25</td><td> 2,25</td>

<td>The total weight of the tablet core (Mg)</td><td> 225</td><td> 225</td>

<td>The weight of the whole batch</td><td>5 kg</td><td>10 kg</td>

185

<td>Coating layer</td><td>mg / unit</td><td>mg / unit</td>

<td>Opadry coating layer</td><td> 9</td><td> 9</td>

<td>Total tablet weight (mg)</td><td> 234</td><td> 234</td>

<td>Weight of coated lot (kg)</td><td>2 kg in temperature 72 ° C</td><td>6 kg in temperature 72 ° C</td>

<td>Weight of coated lot (kg)</td><td>2 kg in temperature 750 ° C</td><td>2 kg in temperature 75 ° C</td>

The tablets were made according to the following processing steps:

1. In a Patterson Kelly "V" mixer (equipped with mixer I), with a capacity of 16 quarters, were placed in succession:

Approximately 1/2poly (ethylene oxide) WSR 301

Oxycodone hydrochloride (sieved through a 20 mesh sieve)

Other poly (ethylene oxide) WSR 301

2. The materials of step 1 were mixed for 5 minutes using the stirrer I on.

3. Magnesium stearate was placed in the "V" mixer.

4. The materials of step 3 were mixed for 1 minute using the switched off stirrer I.

5. The mix obtained in step 4 was placed in a plastic bag (note: in Example 17.2, two 5 kg of blend were prepared to give a 10 kg blend of compression tablets).

6. The mix obtained in step 5 was compressed to a target mass using an 8-station tablet press operating at 30,000 tablets per hour, using standard 3/8 inch rounded, concave (extruded) tooling. In example 17.1 a compression force of 12 kN was used, in example 17.2 6 kN, 12 kN and 18 kN.

7. The tablets obtained in step 6 were introduced into a 15 inch (for a 2 kg batch) or 24 inch (for a 6 kg batch) Accela-Coat coating drum.

186

8. A temperature probe (wired thermocouple) was placed in the drum directly above the tablet bed so that the probe end was close to the tablet bed.

9. The drum rotation speed was set to 7 or 10 revolutions per minute and the tablet bed was heated to set the inlet air temperature to reach a target outlet air temperature of 72 ° C or 75 ° C. The curing start point (as described in method 2) was reached when the outlet air temperature reached the target value. The inlet air temperature was adjusted to maintain the desired outlet air temperature. The tablets were cured for 15 minutes. The drum rotation speed was kept constant. The temperature profile of the curing processes according to examples 17.1 and 17.2 is presented in tables 17.1.1 and 17.2.1.

Ten. The drum rotation speed was kept constant. The inlet air temperature was set to 20 ° or 22 ° C and the tablet bed was cooled so that the outlet air temperature was approximately 30 ° C. Note: Magnesium stearate was not used.

11. The tablet bed was heated to set an inlet air temperature of 52 ° -54 ° C. The coating process was started when the outlet air temperature reached approximately 39 ° -42 ° C and continued until the target mass increased by 4%. During the coating process, the drum rotation speed was increased to 15 or 20 revolutions per minute.

12. After coating, the drum rotation speed was reduced to the speed set during curing. The tablet bed was heated to set the inlet air temperature to reach a target of 72 ° C or 75 ° C. The curing start point (as described in method 2) was reached when the outlet air temperature reached the target value. The inlet air temperature was adjusted to maintain the desired outlet air temperature. The coated tablets were cured for another 30 minutes. The drum rotation speed was kept constant. Additional process temperature profile

187 curing for examples 17.1 and 17.2 are shown in tables 17.1.1 and 17.2.1.

13. The tablets were removed from the drum.

Then, in vitro tests were carried out, including crushing strength tests:

Tablet core (uncured), cured tablets and cured / coated tablets were tested in vitro using USP Apparatus 1 (basket with a locking spring placed on the surface of the baskets to reduce the tendency of the tablets to stick to the base of the stem) at 100 rpm in 900 ml of simulated gastric fluid without enzymes (SGF) at 37.0 ° C. The samples were analyzed by reversed-phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3.0 x 250 mm column, 5 μm, using a mobile phase consisting of a mixture of acetonitrile and monobasic potassium phosphate buffer (pH 3.0), UV detection at 230 nm. Tests were carried out for time points of 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 16.0 hours.

To assess the tablet's breaking strength, the unhardened tablets were subjected to a crushing strength test using a maximum force of 196N using a Schleuniger 2E / 106 device.

Tablet dimensions and dissolution results are presented in tables 17.1.2 to 17.2.2.

Table 17.1.1

<td colspan="7">Example 17.1 curing process at 72 ° C</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>set temp. air on in flight (° C)</td><td>The actual temp. air on in flight (° C)2</td><td>Probe (° C) 3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td> -</td><td>22 to 80</td><td> 25,5</td><td> 28,4</td><td> 28,5</td><td>Beginning heating</td>

188

<td> 19</td><td> 0</td><td colspan="2">8 0 to 78</td><td colspan="2"> 80,0</td><td colspan="2"> 73,2</td><td> 72,0</td><td>Beginning curing</td>

<td> 34</td><td> 15</td><td colspan="2"> 75</td><td colspan="2"> 75,0</td><td colspan="2"> 72,3</td><td> 72,0</td><td>End of the process curing beginning cooling</td>

<td> 50</td><td></td><td colspan="2"> 22</td><td colspan="2"> 22,8</td><td colspan="2"> 28,2</td><td> 29,2</td><td>End cooling, ready to coating</td>

<td colspan="10">After applying a coating layer (4%) to the tablets, start heating</td>

<td> 0</td><td></td><td>4 8 to 80</td><td colspan="2"> 47,8</td><td colspan="2"> 45,1</td><td colspan="2"> 43,1</td><td>Beginning heating for additional stage curing</td>

<td> 13</td><td> 0</td><td>8 0 to 76</td><td colspan="2"> 80,1</td><td colspan="2"> 73,2</td><td colspan="2"> 72,0</td><td>Beginning additional stage curing</td>

<td> 28</td><td> 15</td><td> 75</td><td colspan="2"> 74,9</td><td colspan="2"> 72,0</td><td colspan="2"> 72,4</td><td>15 minutes additional stage curing</td>

<td> 43</td><td> 30</td><td>74 to 22</td><td colspan="2"> 74,0</td><td colspan="2"> 71,5</td><td colspan="2"> 72,1</td><td>30 minutes additional stage curing beginning cooling</td>

<td> 55</td><td></td><td> 22</td><td colspan="2"> 24,6</td><td colspan="2"> 32,2</td><td colspan="2"> 34</td><td>End cooling, unloading</td>

<td colspan="10">Example 17.1 curing process at 75 ° C</td>

189

<td></td><td></td><td colspan="7">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td colspan="2">Set temperature air on in flight (° C)</td><td colspan="2">The actual temp. air on in flight (° C)2</td><td colspan="2">Probe (° C)3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td> -</td><td colspan="2">42 to 80</td><td colspan="2"> 42,1</td><td colspan="2"> 38,6</td><td> 38,5</td><td>Beginning heating</td>

<td> 21</td><td> 0</td><td colspan="2"> 82</td><td colspan="2"> 81,5</td><td colspan="2"> 75,1</td><td> 75,0</td><td>Beginning curing</td>

<td> 36</td><td> 15</td><td colspan="2">77.5 to 22</td><td colspan="2"> 77,6</td><td colspan="2"> 74,1</td><td> 75,2</td><td>End of the process curing beginning cooling</td>

<td> 53</td><td></td><td colspan="2"> 22</td><td colspan="2"> 23,1</td><td colspan="2"> 29,5</td><td> 29,6</td><td>End cooling, ready to coverage</td>

<td colspan="10">After applying a coating layer (4%) to the tablets, start heating</td>

<td> 0</td><td></td><td>4 8 to 83</td><td colspan="2"> 48,1</td><td colspan="2"> 44,4</td><td colspan="2"> 41,5</td><td>Beginning heating for additional stage curing</td>

<td> 12</td><td> 0</td><td> 83</td><td colspan="2"> 83,1</td><td colspan="2"> 75,1</td><td colspan="2"> 75,0</td><td>Beginning additional stage curing</td>

<td> 27</td><td> 15</td><td> 78</td><td colspan="2"> 78,11</td><td colspan="2"> 74,4</td><td colspan="2"> 75,4</td><td>15 minutes additional stage curing</td>

190

<td> 42</td><td> 30</td><td>76.5 to 22</td><td> 76,5</td><td> 73,9</td><td> 74,9</td><td>30 minutes additional stage curing beginning cooling</td>

<td> 56</td><td></td><td> 22</td><td> 23,9</td><td> 30,3</td><td> 30,0</td><td>End cooling, the tablets were removed from the drum</td>

Table 17.1.2

<td></td><td></td><td colspan="3">Example 17.1</td>

<td></td><td></td><td>unpaved (N = 25)</td><td></td><td></td>

<td rowspan="3">dimensions pills</td><td rowspan="2">Mass (Mg) Thickness (Mm)</td><td> 225</td><td> -</td><td> -</td>

<td>Strength on Crushing (N)</td><td> 75</td><td></td><td></td>

<td></td><td></td><td></td><td>Example 17.1 hardened in at 72 ° C</td><td>Example 17.1 hardened in temperature 75 ° C</td>

191

<td></td><td></td><td></td><td>hardened by 15 minutes</td><td>Covered</td><td>hardened by 15 minutes</td><td>Covered</td>

<td rowspan="7">dissolution (% released) SGF</td><td>1 hour</td><td> 27</td><td> 27</td><td> 26</td><td> 28</td><td> 26</td>

<td>2 hours.</td><td> 44</td><td> 42</td><td> 41</td><td> 44</td><td> 42</td>

<td>4 hours</td><td> 68</td><td> 67</td><td> 66</td><td> 69</td><td> 67</td>

<td>6 hours</td><td> 83</td><td> 83</td><td> 84</td><td> 85</td><td> 83</td>

<td>8 hours</td><td> 93</td><td> 92</td><td> 93</td><td> 95</td><td> 93</td>

<td>12 hours</td><td> 99</td><td> 100</td><td> 100</td><td> 100</td><td> 98</td>

<td>16 hours</td><td> 100</td><td> 102</td><td> 102</td><td> 102</td><td> 99</td>

Table 17.2.1

<td colspan="7">Example 17.2 Curing process at 72 ° C</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>set temp. air on in flight (° C)</td><td>The actual temp. air on in flight (° C)2</td><td>Probe (° C)3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td></td><td> 80</td><td> 34,8</td><td> 33,8</td><td> 32,1</td><td>Load drum 6 kg; beginning heating</td>

<td> 27,5</td><td> 0</td><td> 80</td><td> 80,3</td><td> 73,0</td><td> 72,0</td><td>Beginning curing</td>

192

<td> 42,5</td><td> 15</td><td>7 3.6 to 22</td><td> 73,5</td><td> 70,6</td><td> 72,1</td><td>End of the process curing beginning cooling</td>

<td> 61</td><td></td><td> 22</td><td> 22,7</td><td> 30,1</td><td> 30</td><td>End cooling, ready to coverage</td>

<td colspan="7">After applying a coating layer (4%) to the tablets, start heating</td>

<td> 0</td><td></td><td>8 0 to 53</td><td> 53</td><td></td><td> 39,5</td><td>Beginning heating for additional stage curing</td>

<td> 18</td><td> 0</td><td> 80</td><td> 79,9</td><td> 74,1</td><td> 72,0</td><td>Beginning additional stage curing</td>

<td> 33</td><td> 15</td><td> 73,5</td><td> 73,4</td><td> 70,9</td><td> 72,3</td><td>15 minutes additional stage curing</td>

<td> 48</td><td> 30</td><td> 73,5</td><td> 73,5</td><td> 71,4</td><td> 72,5</td><td>30 minutes additional stage curing beginning cooling</td>

<td> 64</td><td></td><td> 23,0</td><td> 23,9</td><td></td><td> 30,0</td><td>End cooling, unloading</td>

<td colspan="7">Example 17.2 curing process at 75 ° C</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

193

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td colspan="2">set temp. air at the inlet (° C)</td><td colspan="2">The actual temp. air at the inlet (° C)2</td><td colspan="2">Probe (° C)3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td></td><td colspan="2"> 82</td><td colspan="2"> 52,9</td><td colspan="2"> 53</td><td> 48,4</td><td>Load 2 kg drum beginning heating</td>

<td> 23,5</td><td> 0</td><td colspan="2">85 to 82</td><td colspan="2"> 81,8</td><td colspan="2"> 76,4</td><td> 75,0</td><td>Beginning curing</td>

<td> 38,5</td><td> 15</td><td colspan="2"> 78</td><td colspan="2"> 78</td><td colspan="2"> 75,6</td><td> 76,1</td><td>End of the process curing beginning cooling</td>

<td> 53</td><td></td><td colspan="2"> 20</td><td colspan="2"> 32,4</td><td colspan="2"> 30,0</td><td> 32,1</td><td>End cooling, ready to coverage</td>

<td colspan="10">After applying a coating layer (4%) to the tablets, start heating</td>

<td> 0</td><td></td><td>53.5 to 83</td><td colspan="2"> 53,7</td><td colspan="2"></td><td colspan="2"> 46,5</td><td>Beginning heating for additional stage curing</td>

<td></td><td> 0</td><td> 83</td><td colspan="2"> 83</td><td colspan="2"> 73,7</td><td colspan="2"> 75</td><td>Beginning additional stage curing</td>

<td></td><td> 15</td><td> 78</td><td colspan="2"> 77,9</td><td colspan="2"> 74,3</td><td colspan="2"> 75,9</td><td>15 minutes additional stage curing</td>

194

<td></td><td> 30</td><td>7 8 to 22</td><td> 78</td><td> 75,1</td><td> 76,4</td><td>30 minutes additional stage curing beginning cooling</td>

<td></td><td></td><td> 22</td><td> 23,6</td><td> 31,0</td><td> 32,1</td><td>End cooling (15 minutes cooling) unloading</td>

<td colspan="7">1 determined according to method 2, 2 inlet temperature measured, 3 temperature measured using a temperature probe (wired thermocouple) 4 outlet temperature measured.</td>

Table 17.2.2

<td></td><td></td><td colspan="8">Example 17.2</td>

<td></td><td></td><td colspan="8">Uncured tablet core (n = 5)</td>

<td></td><td>Force compression (KN)</td><td> 6</td><td> 12</td><td> 18</td><td> 12</td><td colspan="2"></td><td colspan="2"></td>

<td rowspan="3">dimensions pills</td><td>Weight (mg)</td><td> 226</td><td> 227</td><td> 227</td><td> 226</td><td colspan="2"></td><td colspan="2"></td>

<td>Thickness (mm)</td><td> 3,93</td><td> 3,87</td><td> 3,86</td><td> 3,91</td><td colspan="2"></td><td colspan="2"></td>

<td>Strength for crushing (N)</td><td> 43</td><td> 71</td><td> 83</td><td> 72</td><td colspan="2"></td><td colspan="2"></td>

<td></td><td></td><td colspan="3">In example 17.2 curing temperature was 72 ° C (batch 6 kg)</td><td colspan="5">In example 17.2 curing temperature was 75 ° C (2 kg batch)</td>

<td></td><td></td><td colspan="3">hardened by 15 minutes, covered</td><td colspan="2">uncured (core)</td><td colspan="2">15 min curing</td><td>selected combined</td>

195

<td></td><td>Force compression (KN)</td><td> 6</td><td> 12</td><td> 18</td><td colspan="3"> 12</td>

<td rowspan="6">Dissolution (% released) SGF, without spring</td><td>1 hour</td><td> 25</td><td> 23</td><td> 23</td><td> 26</td><td> 27</td><td> 24</td>

<td>2 hours</td><td> 41</td><td> 39</td><td> 37</td><td> 41</td><td> 43</td><td> 40</td>

<td>4 hours</td><td> 65</td><td> 64</td><td> 59</td><td> 64</td><td> 66</td><td> 64</td>

<td>6 hours</td><td> 80</td><td> 81</td><td> 75</td><td> 79</td><td> 81</td><td> 80</td>

<td>8 hours</td><td> 90</td><td> 91</td><td> 86</td><td> 88</td><td> 91</td><td> 90</td>

<td>12 hours</td><td> 98</td><td> 100</td><td> 97</td><td> 99</td><td> 101</td><td> 100</td>

<td rowspan="7">Dissolution not (% released) SGF Shopping basket with spring</td><td>1 hour</td><td></td><td> 26</td><td> 24</td><td></td><td></td><td></td>

<td>2 hours</td><td></td><td> 42</td><td> 40</td><td></td><td></td><td></td>

<td>4 hours</td><td></td><td> 66</td><td> 66</td><td></td><td></td><td></td>

<td>6 hours</td><td></td><td> 83</td><td> 83</td><td></td><td></td><td></td>

<td>8 hours</td><td></td><td> 93</td><td> 92</td><td></td><td></td><td></td>

<td>12 hours</td><td></td><td> 100</td><td> 98</td><td></td><td></td><td></td>

<td>16 hours</td><td></td><td> 102</td><td> 101</td><td></td><td></td><td></td>

Example 18

In Example 18, four different 250 mg preparations containing 80 mg oxycodone hydrochloride were prepared using high molecular weight polyethylene oxide. Two formulations (Examples 18.2 and 18.3) contained 0.1% butylated hydroxytoluene. One formulation (Example 18.4) contained 0.5% butylated hydroxytoluene. Three formulations (Examples 18.1, 18.2, and 18.4) contained 1% magnesium stearate. One formulation (Example 18.3) contained 0.5% magnesium stearate. compositions:

196

<td></td><td>Example 18.1</td><td>Example 18.2</td><td>Example 18.3</td><td>Example 18.4</td>

<td>Ingredient</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td>

<td>hydrochloride oxycodone</td><td> 80 (32%)</td><td> 80 (32%)</td><td> 80 (32%)</td><td> 80 (32%)</td>

<td>Poly (ethylene oxide) (molecular mass: w approximately 4,000,000; Polyox ™ WSR- 301)</td><td> 167,5 (67%)</td><td> 167,25 (66,9%)</td><td> 166,25 (67,4%)</td><td> 166,25 (66,5%)</td>

<td>butylated hydroxytoluene (BHT)</td><td> 0</td><td> 0,25 (0,1%)</td><td> 0,25 (0,1%)</td><td> 1,25 (0,5%)</td>

<td>Magnesium stearate</td><td> 2,5 (1%)</td><td> 2,5 (1%)</td><td> 1,25 (0,5%)</td><td> 2,5 (1%)</td>

<td>Total Core Mass tablets (mg)</td><td> 250</td><td> 250</td><td> 250</td><td> 250</td>

<td>Whole batch weight (kg)</td><td>5 and 6.3</td><td> 5</td><td> 5</td><td> 5</td>

<td>Coating layer</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td>

<td>Coating layer Opadry</td><td>n / a</td><td> 7,5</td><td> 10</td><td>n / a</td>

<td>Total weight tablets (mg)</td><td>n / a</td><td> 257,5</td><td> 260</td><td>n / a</td>

<td>Weight of coated lot (Kg)</td><td>n / a</td><td> 1,975</td><td> 2,0</td><td>n / a</td>

The tablets were made according to the following processing steps:

1. In a Patterson Kelly "V" mixer (equipped with mixer I), with a capacity of 16 quarters, were placed in succession:

Approximately 1/2poly (ethylene oxide) WSR 301 Oxycodone hydrochloride BHT (if required)

Other polyethylene oxide WSR 301 2. 2. The materials of step 1 were mixed for 10 minutes (example 18.1, batch 6.3 kg), 6 minutes (example 18.2), or

197 minutes (example 18.1, batch 5 kg, examples 18.3 and 18.4), using an agitator I.

3. Magnesium stearate was placed in the "V" mixer.

4. The materials of step 3 were mixed for 1 minute using the switched off stirrer I.

5. The mix obtained in stage 4 was placed in a plastic bag.

6. The mix obtained in step 5 was compressed to the target mass using an 8-station tablet press. Compression parameters are presented in tables 18.1 to 18.4.

7. The tablets obtained in step 6 were introduced into a Compu-Lab 18 inch coating drum with a drum load of 1.5 kg (example 18.1, cured at 72 ° C), 2.0 kg (example 18.1, cured at 75 ° and 78 ° C), 1.975 kg (example 18.2, cured at 72 ° C and 75 ° C), 2.0 kg (example 18.3), 2.0 kg (example 18.4, cured at 72 ° C and 75 ° C) .

8. A temperature probe (wired thermocouple) was placed in the drum directly above the tablet bed so that the end of the probe was close to the moving tablet bed.

9. in examples 18.1 to 18.4, the tablet bed was heated by setting the inlet air temperature to achieve a target outlet air temperature of 72 ° C, 75 ° C or 78 ° C. The curing starting point (as described in method 2) was reached when the outlet air temperature reached the target value. When the target outlet air temperature was reached, the inlet air temperature was adjusted to maintain the desired outlet air temperature. The tablets were cured for 15 to 90 minutes. After curing, the tablet bed was cooled. The temperature profile for curing processes according to examples 18.1 to 18.4 is presented in tables 18.1.1 to 18.4.1.

Ten. After cooling, the tablet bed was heated to set an inlet air temperature of 53 ° C (examples 18.2 and

18.3, no coatings were carried out in examples 18.1 and 18.4). The coating process was started when the outlet air temperature reached approximately 40 ° C and led to

198 the moment when the target mass increased by 3% (example 18.2) and o

4% (example 18.3).

11. After the coating process (example 18.2), the tablet bed was heated to set the inlet air temperature to reach the target outlet temperature (72 ° C for one lot and 75 ° C for the other lot). The curing starting point (as described in method 2) was reached when the outlet air temperature reached the target value. When the target outlet air temperature was reached, the inlet air temperature was adjusted to maintain the desired outlet air temperature. The coated tablets were cured for another 30 minutes. After an additional curing step, the tablet bed was cooled. The temperature profile for the curing process according to example 18.2 is shown in the table

18.2.1.

12. The drum rotation speed was reduced and the inlet air temperature was set to 22 ° C. The system was cooled to an air temperature of 30 ° C.

13. The tablets were removed from the drum.

In vitro tests including crushing strength and durability tests were carried out as follows:

The tablet core (uncured), cured tablets, and cured / coated tablets were tested in vitro using USP Apparatus 1 (some tests included a basket with a locking spring placed on the surface of the basket to reduce the tendency of the tablets to stick to the base of the stem) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37.0 ° C. Samples were analyzed by reverse phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3.0 x 250 mm column, 5 μη using a mobile phase consisting of a mixture of acetonitrile and monobasic potassium phosphate buffer (pH 3.0), UV detection at 230 nm. Samples were taken for time periods of 1.0, 2.0, 4.0, 6.0, 8.0 and 12.0 hours.

To assess the tablet's breaking strength, the uncured tablets were subjected to a strength test

199 crushing with a maximum force of 196 N using a Schleuniger 2E / 106 device.

Tablets according to example 18.4 tablets (cured at 72 ° C and 75 ° C, respectively) were subjected to a stability test by storing them in bottles containing 6 tablets under various conditions (25 ° C / 60% relative humidity or 40 ° C / 75% relative humidity or 50 ° C) for a period of time and then testing the tablets in vitro as described above. Storage testing was performed on the initial sample (i.e. before storage), after two weeks and one month of storage, dissolution tests were carried out for periods of 1.0, 2.0, 4.0, 6.0,

8.0 and 12.0 hours.

Tablet dimensions and dissolution results are presented in tables 18.2.2 to 18.4.2.

Table 18.1.1

<td colspan="7">Example 18.1 curing process at 72 ° C</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>set temp. air at the inlet The actual (° C)</td><td>Inlet (° C)2</td><td>Probe (° C) 3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td></td><td>23 to 80</td><td> 24,8</td><td> 28,4</td><td> 28,9</td><td>Drum load 1.5 kg; beginning heating</td>

<td> 20</td><td> 0</td><td>80 to 78</td><td> 80,0</td><td> 72,3</td><td> 72,0</td><td>Beginning curing</td>

<td> 35</td><td> 15</td><td> 75</td><td> 75</td><td> 71,4</td><td> 72,0</td><td>A sample</td>

<td> 50</td><td> 30</td><td> 75</td><td> 74,9</td><td> 72,0</td><td> 72,7</td><td>A sample</td>

<td> 65</td><td> 45</td><td> 74</td><td> 74</td><td> 71,5</td><td> 72,1</td><td>A sample</td>

<td> 80</td><td> 60</td><td> 74</td><td> 74</td><td> 71,2</td><td> 71,8</td><td>A sample</td>

<td> 95</td><td> 75</td><td> 74</td><td> 73,9</td><td> 71,7</td><td> 72,3</td><td>A sample</td>

200

<td> 110</td><td> 90</td><td colspan="2">74 to 22</td><td colspan="2"> 74</td><td colspan="2"> 71,7</td><td> 72,3</td><td>End of the process curing a sample was taken, 0.3 g was added stearate magnesium beginning cooling</td>

<td> 129</td><td></td><td colspan="2"> 22</td><td colspan="2"> 23,1</td><td colspan="2"> 27,4</td><td> 26,9</td><td>End cooling, lack bonding during cooling, unloading</td>

<td colspan="10">Example 18.1 curing process at 75 ° C</td>

<td></td><td></td><td colspan="7">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>set temp. air on in flight (° C)</td><td colspan="2">The actual temp. air on in flight (° C)2</td><td colspan="2">Probe (° C) 3</td><td colspan="2">Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td></td><td>23 to 85</td><td colspan="2"> 24,1</td><td colspan="2"> 25,0</td><td colspan="2"> 24,9</td><td>Drum load 2.0 kg, beginning heating</td>

<td> 19</td><td> 0</td><td>85 to 82</td><td colspan="2"> 85,1</td><td colspan="2"> 76,2</td><td colspan="2"> 75</td><td>Beginning curing</td>

<td> 34</td><td> 15</td><td> 78</td><td colspan="2"> 78,2</td><td colspan="2"> 73,6</td><td colspan="2"> 75,1</td><td>A sample</td>

<td> 49</td><td> 30</td><td> 78</td><td colspan="2"> 77,8</td><td colspan="2"> 74,5</td><td colspan="2"> 75,5</td><td>A sample</td>

<td> 64</td><td> 45</td><td> 77,5</td><td colspan="2"> 77,6</td><td colspan="2"> 74,8</td><td colspan="2"> 75,4</td><td>A sample</td>

201

<td> 79</td><td> 60</td><td> 77,5</td><td colspan="2"> 77,6</td><td colspan="2"> 74,6</td><td colspan="2"> 75,1</td><td>A sample</td>

<td> 94</td><td> 75</td><td> 77,5</td><td colspan="2"> 77,5</td><td colspan="2"> 74,5</td><td colspan="2"> 75,1</td><td>A sample, slight clumping</td>

<td> 109</td><td> 90</td><td> 77,5</td><td colspan="2"> 77,6</td><td colspan="2"> 75,0</td><td colspan="2"> 75,6</td><td>End of the process curing a sample was taken, beginning cooling</td>

<td> 116</td><td></td><td> 22</td><td colspan="2"> 30,6</td><td colspan="2"> 42,6</td><td colspan="2"> 46,7</td><td>slight sticking on shoulders support</td>

<td> 122</td><td> -</td><td> 22</td><td colspan="2"> 25</td><td colspan="2"> -</td><td colspan="2"> 33,5</td><td>End cooling</td>

<td colspan="10">Example 18.1 curing process at 78 ° C</td>

<td></td><td></td><td colspan="7">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td colspan="2">Set temperature air on in flight (° C)</td><td colspan="2">The actual temp. air on in flight (° C)2</td><td colspan="2">Probe (° C) 3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td></td><td colspan="2"> 82</td><td colspan="2"> 35</td><td colspan="2"> 37,6</td><td> 35,9</td><td>Drum loading 2 kg, beginning heating</td>

<td> 17,5</td><td> 0</td><td colspan="2">85 to 83</td><td colspan="2"> 85,1</td><td colspan="2"> 77,4</td><td> 78,0</td><td>Beginning curing</td>

<td> 32,5</td><td> 15</td><td colspan="2"> 82</td><td colspan="2"> 81,9</td><td colspan="2"> 76,9</td><td> 78,4</td><td>A sample</td>

<td> 47,5</td><td> 30</td><td colspan="2"> 81</td><td colspan="2"> 80,9</td><td colspan="2"> 77,4</td><td> 78,3</td><td>A sample</td>

<td> 62,5</td><td> 45</td><td colspan="2"> 80,5</td><td colspan="2"> 80,7</td><td colspan="2"> 77,4</td><td> 78,2</td><td>A sample</td>

<td> 69,5</td><td> 52</td><td colspan="2"> 80,5</td><td colspan="2"> 80,4</td><td colspan="2"> 77,5</td><td> 78,2</td><td>slight clumping</td>

202

<td> 77,5</td><td> 60</td><td> 80,5</td><td> 80,6</td><td> 77,6</td><td> 78,3</td><td>A sample, bonding</td>

<td> 87,5</td><td> 70</td><td></td><td></td><td></td><td></td><td>0.3 g was added stearate magnesium</td>

<td> 92,5</td><td> 75</td><td> 80,0</td><td> 79,8</td><td> 77,1</td><td> 78,1</td><td>A sample, bonding progressed, slight improvement flow tablets after addition stearate magnesium</td>

<td> 107,5</td><td> 90</td><td> 80,0</td><td> 79,9</td><td> 77,5</td><td> 78,0</td><td>Sample, beginning cooling</td>

203

Table 18.1.2

<td colspan="2"></td><td></td><td colspan="3">Example 18.1 (batch 6.3 kg)</td>

<td colspan="2"></td><td></td><td>uncured core pills</td><td colspan="2"></td>

<td colspan="2"></td><td>Force compression (KN)</td><td> 15</td><td colspan="2"></td>

<td colspan="2" rowspan="3">Tablet dimensions</td><td>Weight (mg)</td><td> 250</td><td colspan="2"></td>

<td>Thickness (Mm)</td><td> 4,08</td><td colspan="2"></td>

<td>Strength for crushing (N)</td><td> 87</td><td colspan="2"></td>

<td colspan="2"></td><td></td><td></td><td colspan="2">Example 18.1, curing in at 72 ° C</td>

<td colspan="2"></td><td></td><td>uncured</td><td>hardened for 15 minutes</td><td>hardened for 60 minutes</td>

<td colspan="2" rowspan="5">dissolution (% released) SGF, without spring</td><td>1 hour</td><td> 25</td><td> 26</td><td> 25</td>

<td>2 hours</td><td> 40</td><td> 40</td><td> 40</td>

<td>4 hours</td><td> 66</td><td> 64</td><td> 62</td>

<td>8 hours</td><td> 95</td><td> 89</td><td> 91</td>

<td>12 hours</td><td> 102</td><td> 97</td><td> 92</td>

<td></td><td></td><td colspan="4">Example 18.1 (5.0 kg batch)</td>

<td></td><td></td><td colspan="4">Uncured tablet core</td>

204

<td></td><td>Force compression (KN)</td><td> 15</td><td colspan="3"></td>

<td rowspan="3">dimensions pills</td><td>Weight (mg)</td><td> 253</td><td colspan="3"></td>

<td>Thickness (Mm)</td><td> 4,13</td><td colspan="3"></td>

<td>Resistance to crushing (N)</td><td> 92</td><td colspan="3"></td>

<td></td><td></td><td></td><td colspan="2">Example 18.1, curing in at 75 ° C</td><td>Example 18.1 curing in temperature 78 ° C</td>

<td></td><td></td><td>uncured</td><td>Cured by 15 minutes</td><td>Cured by 60 minutes</td><td>Cured by 30 minutes</td>

<td rowspan="5">Dissolution % released) SGF without spring</td><td>1 hour</td><td> 26</td><td> 26</td><td> 26</td><td> 26</td>

<td>2 hours</td><td> 40</td><td> 41</td><td> 42</td><td> 41</td>

<td>4 hours</td><td> 63</td><td> 67</td><td> 68</td><td> 66</td>

<td>8 hours</td><td> 90</td><td> 94</td><td> 94</td><td> 93</td>

<td>12 hours</td><td> 101</td><td> 101</td><td> 100</td><td> 101</td>

205

Table 18.2.1

<td colspan="9">In example 18.2, the curing process was carried out at 72 ° C</td>

<td></td><td></td><td colspan="6">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>Set temperature air on in flight (° C)</td><td colspan="2">The actual temp. air on in flight (° C)2</td><td colspan="2">Probe (° C) 3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td></td><td>42 to 80</td><td colspan="2"> 41,9</td><td colspan="2"> 37,4</td><td> 37,8</td><td>Drum loading 1.975 kg, beginning heating</td>

<td> 18</td><td> 0</td><td> 80</td><td colspan="2"> 80,1</td><td colspan="2"> 71,6</td><td> 72,0</td><td>Beginning curing</td>

<td> 33</td><td> 15</td><td>75 to 22</td><td colspan="2"> 75,0</td><td colspan="2"> 71,1</td><td> 72,3</td><td>End of the process curing beginning cooling</td>

<td> 47,5</td><td></td><td> 22</td><td colspan="2"> 22,5</td><td colspan="2"> 30,4</td><td> 30,0</td><td>End cooling, sample, ready to cover</td>

<td colspan="9">After the coating was applied to the tablets, the coating began heating (3%)</td>

<td> 0</td><td></td><td>50 to 80</td><td> 50</td><td colspan="2"> 48,0</td><td colspan="2"> 43,0</td><td>Beginning heating for additional stage curing</td>

<td> 12</td><td> 0</td><td>80 to 77</td><td> 80,0</td><td colspan="2"> 72,1</td><td colspan="2"> 72,0</td><td>Beginning additional stage curing</td>

206

<td> 27</td><td> 15</td><td> 75</td><td> 74,9</td><td> 71,0</td><td> 72,4</td><td>Sample, 15 minutes additional stage curing</td>

<td> 42</td><td> 30</td><td>74 to 22</td><td> 73,9</td><td> 70,7</td><td> 72,1</td><td>Sample, 30 minutes additional stage curing beginning cooling</td>

<td> 61</td><td></td><td> 22</td><td></td><td></td><td> 30</td><td>End cooling, unloading, a sample</td>

<td colspan="7">Example 18.2 curing process at 75 ° C</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>Set temperature air on in flight (° C)</td><td>The actual temp. air on in flight (° C)2</td><td>Probe (° C)3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td></td><td>42 to 82</td><td> 41,8</td><td> 39,7</td><td> 40,1</td><td>Drum loading 1.975 kg, beginning heating</td>

<td> 18</td><td> 0</td><td>82 to 80</td><td> 81,9</td><td> 75,2</td><td> 75,0</td><td>Beginning curing</td>

<td> 33</td><td> 15</td><td>78 to 22</td><td> 77,8</td><td> 74,2</td><td> 75,4</td><td>End of the process curing beginning cooling, lack bonding</td>

207

<td> 49</td><td></td><td> 22</td><td> 22,5</td><td> 28,8</td><td> 29,5</td><td>End cooling, sample, ready to cover</td>

<td colspan="7">After the coating was applied to the tablets, the coating began heating (3%)</td>

<td> 0</td><td></td><td>48 to 83</td><td> 48,0</td><td> 44,5</td><td> 41,5</td><td>Beginning heating for additional stage curing</td>

<td> 13</td><td> 0</td><td> 83</td><td> 83,3</td><td> 75,6</td><td> 75,4</td><td>Beginning additional stage curing</td>

<td> 28</td><td> 15</td><td> 78</td><td> 78,0</td><td> 74,6</td><td> 75,4</td><td>Sample, 15 minutes additional stage curing</td>

<td> 44,5</td><td> 31,5</td><td>77.5 to 22</td><td> 77,4</td><td> 74,4</td><td> 75,4</td><td>Sample 30 minutes additional stage curing beginning cooling</td>

<td> 58,5</td><td></td><td> 22</td><td> 24,2</td><td></td><td> 30</td><td>End cooling, unloading, a sample</td>

Table 18.2.2

<td></td><td></td><td colspan="3">Example 18.2</td>

<td></td><td></td><td colspan="3">Uncured tablet cores</td>

208

<td></td><td>Dimension instrumentation, rounded (all)</td><td colspan="3"> 3/8</td><td colspan="3"> 3/8</td><td colspan="2"> 13/32</td>

<td></td><td>Compression Force (KN)</td><td colspan="3"> 8</td><td colspan="3"> 15</td><td colspan="2"> 15</td>

<td rowspan="3">dimensions pills</td><td>Weight (mg)</td><td colspan="3"> 253</td><td colspan="3"> 253</td><td colspan="2"> 252</td>

<td>Thickness (mm)</td><td colspan="3"> 4,24</td><td colspan="3"> 4,21</td><td colspan="2"> 3,77</td>

<td>Resistance to crushing (N)</td><td colspan="3"> 50</td><td colspan="3"> 68</td><td colspan="2"> 55</td>

<td></td><td></td><td colspan="8">Example 18.2, cured in at 72 ° C</td>

<td></td><td>Compression Force (KN)</td><td colspan="2"> 8</td><td colspan="3"> 15</td><td colspan="3"> 15</td>

<td></td><td></td><td colspan="2">cure for 15 minutes, covered</td><td colspan="3">cure for 15 minutes, covered</td><td colspan="3">cure for 15 minutes, covered</td>

<td></td><td>Cart to dissolving *</td><td>Without spring</td><td>That spring</td><td colspan="2">Without spring</td><td>That spring</td><td colspan="2">Without spring</td><td>That spring</td>

<td rowspan="5">dissolution (% released) SGF</td><td>1 hour</td><td> 22 (4,9)</td><td> 23 (6,5)</td><td colspan="2"> 22 (4,8)</td><td> 24 (5,6)</td><td colspan="2"> 23 (2,2)</td><td></td>

<td>2 hours</td><td> 36 (6,1)</td><td> 38 (5,4)</td><td colspan="2"> 36 (6,7)</td><td> 39 (4,4)</td><td colspan="2"> 37 (3,9)</td><td></td>

<td>4 hours</td><td> 58 (5,8)</td><td> 63 (2,3)</td><td colspan="2"> 58 (7,0)</td><td> 63 (2,3)</td><td colspan="2"> 59 (5,2)</td><td></td>

<td>6 hours</td><td> 75 (4,9)</td><td> 80 (1,2)</td><td colspan="2"> 75 (4,9)</td><td>WHAT s °</td><td colspan="2"> 76 (4,2)</td><td></td>

<td>8 hours</td><td> 87 (4,1)</td><td> 90 (1,2)</td><td colspan="2"> 88 (3,1)</td><td> 90 (1,8)</td><td colspan="2"> 88 (3,2)</td><td></td>

209

<td rowspan="2"></td><td>12 hours</td><td> 96 (1,9)</td><td>PW) What</td><td> 97 (1,2)</td><td> 98 (1,6)</td><td> 97 (1,1)</td><td></td>

<td>16 hours</td><td> -</td><td> 100 (1,4)</td><td> -</td><td> 101 (2,8)</td><td> -</td><td></td>

<td colspan="8">* Some tests require the use of a locking spring placed on the surface of the basket to reduce tendency of the tablets to stick to the base of the stem;1 Values in parentheses indicate relative standard deviation.</td>

Table 18.3.1

<td colspan="7">Example 18.3 Curing process at 72 ° C</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>set temp. air at the inlet The actual (° C)</td><td>The actual temp. air at the inlet (° C)2</td><td>Probe (° C) 3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td></td><td>22 to 80</td><td> 25,1</td><td> 29,4</td><td> 30,1</td><td>Loading drum 2.0 kg, beginning heating</td>

<td> 19</td><td> 0</td><td> 80</td><td> 80,0</td><td> 71,8</td><td> 72,0</td><td>Beginning curing</td>

<td> 34</td><td> 15</td><td>75 to 22</td><td> 74,9</td><td> 70,7</td><td> 72,2</td><td>End process curing beginning cooling</td>

<td> 49</td><td> -</td><td> 22</td><td> 22,9</td><td> 29,1</td><td> 29,7</td><td>End cooling</td>

210 1 determined according to method 2, 2 inlet temperature measured, 3 temperature measured using a temperature probe (wired thermocouple) 4 outlet temperature measured.

Table 18.3.2

<td></td><td></td><td colspan="3">Example 18.3</td>

<td></td><td></td><td colspan="3">Uncured tablet core</td>

<td></td><td>Instrumentation</td><td colspan="2">Round 3/8 inch</td><td>Oval 0,600x0,270 whole</td>

<td></td><td>Compression Force (KN)</td><td colspan="2"> 15</td><td> 10-11</td>

<td rowspan="3">dimensions pills</td><td>Weight (mg)</td><td colspan="2"> 250</td><td> 250</td>

<td>Thickness (mm)</td><td colspan="2"> 4,20</td><td> 3,80-3,84</td>

<td>Resistance to crushing (N)</td><td colspan="2"> 83-110</td><td> 71-76</td>

<td></td><td></td><td colspan="3">Example 18.3, cured in at 72 ° C</td>

<td></td><td></td><td colspan="2">hardened by 15 minutes, covered</td><td>cure for 15 minutes, covered</td>

<td></td><td></td><td colspan="2">Round 3/8 inch</td><td>Oval 0,600x0,270 whole</td>

<td></td><td>Cart to dissolving *</td><td>Without spring</td><td>That spring</td><td>Without spring</td>

<td rowspan="3">Dissolution1 (% released) SGF</td><td>1 hour</td><td> 23 (7,0)</td><td> 23 (4,9)</td><td> 24 (7,2)</td>

<td>2 hours</td><td> 37 (6,2)</td><td> 38 (3,4)</td><td> 40 (6,0)</td>

<td>4 hours</td><td> 59 (4,6)</td><td> 61 (1,9)</td><td> 64 (5,0)</td>

211

<td>6 hours</td><td> 75 (3,5)</td><td> 79 (1,5)</td><td> 81 (2,8)</td>

<td>8 hours</td><td> 87 (2,7)</td><td> 89 (2,1)</td><td> 91 (2,0)</td>

<td>12 hours</td><td> 98 (2,6)</td><td> 98 (2,6)</td><td> 98 (1,6)</td>

* Some tests require the use of a locking spring located on the surface of the basket to reduce the tendency of the tablets to stick to the base of the stem.

1 The values in parentheses indicate the relative standard deviation.

Table 18.4.1

<td colspan="7">Example 18.4 Curing process at 72 ° C</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>Set temperature air on in flight (° C)</td><td>The actual temp. air on in flight (° C)2</td><td>Probe (° C) 3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td></td><td> 82</td><td> 35,6</td><td> 37,3</td><td> 36,3</td><td>Loading 2.0 kg drum; beginning heating</td>

<td> 13,5</td><td> 0</td><td> 82</td><td> 82</td><td> 72,6</td><td> 72,0</td><td>Beginning curing</td>

<td> 28,5</td><td> 15</td><td> 75</td><td> 75</td><td> 70,9</td><td> 72,4</td><td>A sample</td>

<td> 43,5</td><td> 30</td><td> 75</td><td> 75</td><td> 71,1</td><td> 72,6</td><td>A sample</td>

<td> 58,5</td><td> 45</td><td> 75</td><td> 75</td><td> 71,4</td><td> 72,8</td><td>A sample</td>

212

<td> 73,5</td><td> 60</td><td> 75</td><td> 75</td><td> 71,5</td><td> 73</td><td>End of the process curing a sample, beginning cooling</td>

<td> 78,5</td><td> -</td><td> 23</td><td> 37,4</td><td> 48</td><td> 52,2</td><td>Continuation cooling</td>

<td colspan="7">Example 18.4 Curing process at 75 ° C</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td> 0</td><td></td><td> 85</td><td> 26,1</td><td> 31,0</td><td> 29,1</td><td>Load 2.0 kg drum beginning heating</td>

<td> 17,5</td><td> 0</td><td> 85</td><td> 85</td><td> 76,2</td><td> 75</td><td>Beginning curing</td>

<td> 32,5</td><td> 15</td><td> 78</td><td> 77,9</td><td> 74,5</td><td> 75,9</td><td>A sample</td>

<td> 47,5</td><td> 30</td><td> 77,5</td><td> 77,4</td><td> 74,2</td><td> 75,6</td><td>A sample</td>

<td> 62,5</td><td> 45</td><td> 77</td><td> 77</td><td> 73,9</td><td> 75,3</td><td>A sample</td>

<td> 77,5</td><td> 60</td><td> 77</td><td> 77,0</td><td> 73,7</td><td> 75,3</td><td>End of the process curing a sample, beginning cooling</td>

213 1 determined according to method 2, 2 inlet temperature measured, 3 temperature measured using a temperature probe (wired thermocouple) 4 outlet temperature measured.

Table 18.4.2

<td></td><td></td><td colspan="5">Example 18.4</td>

<td></td><td></td><td>Uncured core</td><td colspan="4"></td>

<td></td><td></td><td>pills</td><td colspan="4"></td>

<td></td><td>Force compression (KN)</td><td> 15</td><td colspan="4"></td>

<td rowspan="3">dimensions pills</td><td>Weight (mg)</td><td> 254</td><td colspan="4"></td>

<td>Thickness (mm)</td><td> 4,15</td><td colspan="4"></td>

<td>Strength for crushing (N)</td><td> 85</td><td colspan="4"></td>

<td></td><td></td><td></td><td colspan="2">Example 18.4, hardened in temperature 72 ° C</td><td colspan="2">Example 18.4, hardened in temperature 75 ° C</td>

<td></td><td></td><td>unpaved</td><td>hardened by 15 minutes</td><td>hardened by 60 minutes</td><td>hardened by 15 minutes</td><td>hardened by 60 minutes</td>

<td>dissolution (% released) SGF, without spring</td><td>1 hour</td><td> 26</td><td> 26</td><td> 26</td><td> 26</td><td> 25</td>

214

<td rowspan="4"></td><td colspan="2">2 hours</td><td> 41</td><td> 41</td><td> 41</td><td> 42</td><td> 40</td>

<td colspan="2">4 hours</td><td> 63</td><td> 64</td><td> 65</td><td> 65</td><td> 64</td>

<td colspan="2">8 hours</td><td> 89</td><td> 89</td><td> 94</td><td> 91</td><td> 89</td>

<td colspan="2">12 hours</td><td> 98</td><td> 99</td><td> 100</td><td> 100</td><td> 99</td>

<td></td><td></td><td colspan="5">Example 18.4, 2 weeks durability, hardened for 15 minutes at 72 ° C</td><td></td>

<td></td><td></td><td colspan="2">initially</td><td> 25/601</td><td> 40/751</td><td>50 ° C</td><td></td>

<td rowspan="6">dissolution (% released) SGF, without spring</td><td>1 hour</td><td colspan="2"> 26</td><td> 26</td><td> 26</td><td> 27</td><td></td>

<td>2 hours</td><td colspan="2"> 41</td><td> 40</td><td> 41</td><td> 42</td><td></td>

<td>4 hours</td><td colspan="2"> 64</td><td> 62</td><td> 63</td><td> 65</td><td></td>

<td>6 hours</td><td colspan="2"> -</td><td> -</td><td> -</td><td> -</td><td></td>

<td>8 hours</td><td colspan="2"> 89</td><td> 88</td><td> 90</td><td> 92</td><td></td>

<td>12 hours</td><td colspan="2"> 99</td><td> 99</td><td> 99</td><td> 102</td><td></td>

<td></td><td></td><td colspan="5">Example 18.4, 2 weeks durability, hardened for 15 minutes at 75 ° C</td><td></td>

<td></td><td></td><td colspan="2">initially</td><td> 25/601</td><td> 40/751</td><td>50 ° C</td><td></td>

<td rowspan="6">dissolution (% released) SGF, without spring</td><td>1 hour</td><td colspan="2"> 26</td><td> 25</td><td> 26</td><td> 25</td><td></td>

<td>2 hours</td><td colspan="2"> 42</td><td> 39</td><td> 41</td><td> 40</td><td></td>

<td>4 hours</td><td colspan="2"> 65</td><td> 60</td><td> 64</td><td> 63</td><td></td>

<td>6 hours</td><td colspan="2"> -</td><td> -</td><td> -</td><td> -</td><td></td>

<td>8 hours</td><td colspan="2"> 91</td><td> 84</td><td> 90</td><td> 91</td><td></td>

<td>12 hours</td><td colspan="2"> 100</td><td> 95</td><td> 99</td><td> 99</td><td></td>

215

<td></td><td></td><td></td><td colspan="3">Example 18.4, 1 one month shelf life, cured for 15 minutes at temperature 72 ° C</td><td></td>

<td></td><td></td><td>Initially</td><td> 25/601</td><td> 40/751</td><td>50 ° C</td><td></td>

<td rowspan="5">dissolution (% released) SGF, without spring</td><td>1 hour</td><td> 26</td><td> 26</td><td> 26</td><td> 26</td><td></td>

<td>2 hours</td><td> 41</td><td> 41</td><td> 40</td><td> 41</td><td></td>

<td>6 hours</td><td> -</td><td> 79</td><td> 79</td><td> 83</td><td></td>

<td>8 hours</td><td> 89</td><td> 89</td><td> 91</td><td> 93</td><td></td>

<td>12 hours</td><td> 99</td><td> 98</td><td> 99</td><td> 101</td><td></td>

1 storage conditions, e.g. 25 ° C / 60% relative humidity or 40 ° C / 75% relative humidity

Example 19

In Example 19, using high molecular weight polyethylene oxide, two different formulations were prepared.

250 mg containing 80 mg oxycodone hydrochloride. One formulation (Example 19.1) contained N60K poly (ethylene oxide) and the second formulation (Example 19.2) contained N12K poly (ethylene oxide). compositions:

<td></td><td>Example 19.1</td><td>Example 19.2</td>

<td>Ingredient</td><td>mg / unit</td><td>mg / unit</td>

<td>Oxycodone hydrochloride</td><td> 80 (32%)</td><td> 80 (32%)</td>

<td>Poly (ethylene oxide) (molecular weight: w</td><td> 168,75</td><td> 0</td>

<td>approximately 2,000,000; Polyox ™ WSR- N60K)</td><td> (67,5%)</td><td></td>

<td>Poly (ethylene oxide) (molecular weight: w</td><td> 0</td><td> 168,75</td>

<td>approximately 1,000,000; Polyox ™ WSR- N12K)</td><td></td><td> (67,5%)</td>

216

<td>Magnesium stearate</td><td> 1,25 (0,5%)</td><td> 1,25 (0,5%)</td>

<td>Total tablet core weight (mg)</td><td> 250</td><td> 250</td>

<td>Whole batch weight (kg)</td><td> 2,0</td><td> 2,0</td>

<td>Coating layer</td><td>mg / unit</td><td>mg / unit</td>

<td>Opadry coating layer</td><td> 10</td><td> 10</td>

<td>Total tablet weight (mg)</td><td> 260</td><td> 260</td>

<td>Weight of coated lot (kg)</td><td> 1,4</td><td> 1,4</td>

The tablets were made according to the following processing steps:

1. The Patterson Kelly "V" mixer (equipped with mixer I) with a capacity of 8 quarters was placed in succession:

Approximately 1/2poly (ethylene oxide)

Oxycodone hydrochloride

Other poly (ethylene oxide)

Note: poly (ethylene oxide) was sieved through a 20 mesh screen, no retained material was used.

2. The materials of step 1 were mixed for 5 minutes using the stirrer I on.

3. Magnesium stearate was placed in the "V" mixer.

4. The materials of step 3 were mixed for 1 minute using the switched off stirrer I.

5. The mix obtained in stage 4 was placed in a plastic bag.

6. The mix obtained in step 5 was compressed to the target mass using an 8-station tablet press operating at a speed of 30,000 tablets per hour, using standard 3/8 inch rounded, concave (extruded) tooling. Compression parameters are presented in tables 19.1 and 19.2.

7. The tablets obtained in step 6 were introduced into a Compu-Lab 18 inch coating drum.

8. A temperature probe (wired thermocouple) was placed in the drum directly above the tablet bed so that the end of the probe was close to the moving tablet bed.

217

9. The tablet bed was heated by setting the inlet air temperature to reach a target outlet air temperature of 72 ° C. The curing starting point (as described in method 2) was reached when the outlet air temperature reached the target value. When the target outlet air temperature was reached, the inlet air temperature was adjusted to maintain the desired outlet air temperature. The tablets were cured for 15 minutes. After curing, the inlet air temperature was set to 22 ° C and the tablet bed was cooled. The temperature profile for curing processes according to examples 19.1 and 19.2 is shown in the tables

19.1.1 and 19.2.1.

Ten. After cooling, the tablet bed was heated to set an inlet air temperature of 53 ° C. The coating process was started when the outlet air temperature reached approximately 41 ° C and continued until the target mass increased by 4%.

11. After the coating process, the tablet bed was cooled by setting the inlet air temperature to 22 ° C. The tablet bed was cooled to an outlet air temperature of 30 ° C or less.

12. The tablets were removed from the drum.

Then, in vitro tests were carried out, including crushing strength tests:

Tablet core (uncured), cured tablets, and cured / coated tablets were tested in vitro using USP Apparatus 1 (basket with a blocking spring placed on the surface of the basket to reduce the tendency of the tablets to stick to the base of the stem) at 100 revolutions per minute in 900 ml of simulated Gastric fluid without enzymes (SGF) at 37.0 ° C. The samples were analyzed by reverse phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3.0 x 250 mm column, 5 μm, using a mobile phase consisting of a mixture of acetonitrile and monobasic potassium phosphate buffer (pH 3.0), detection UV at 230 nm. Samples were taken for time periods of 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 16.0 hours.

218

In order to assess the tablet strength against cracks, the unhardened tablets were subjected to a crushing strength test, acting with a force of a maximum value equal to

196 N using the Schleuniger 2E / 106 device.

Tablet dimensions and dissolution results are presented in tables 19.1.2 and 19.2.2.

Table 19.1.1

<td colspan="7">Example 19.1 (PEO N60K)</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>set temp. air at the inlet The actual (° C)</td><td>The actual temp. air on in flight (° C)2</td><td>Probe (° C)3</td><td>Outlet (° C) 4</td><td>Comments</td>

<td> 0</td><td></td><td>22 to 80</td><td> 25,3</td><td> 26,4</td><td> 26,9</td><td>Drum loading 1.4 kg; beginning heating</td>

<td> 21</td><td> 0</td><td> 80</td><td> 79,9</td><td> 70,0*</td><td> 72,0</td><td>Beginning curing</td>

<td> 31</td><td> 10</td><td> 75,5</td><td> 75,5</td><td> 69,1 *</td><td> 72,2</td><td>Good flow tablets, none bonding</td>

<td> 36</td><td> 15</td><td>7 5.5 to 22</td><td> 75,4</td><td> 69,5*</td><td> 72,4</td><td>End of the process curing beginning cooling</td>

<td> 50</td><td></td><td> 22</td><td> 22,6</td><td> 27,5</td><td> 30,0</td><td>End cooling, a sample</td>

219 1 determined according to method 2, 2 inlet temperature measured, 3 temperature measured using a temperature probe (wired thermocouple) 4 outlet temperature measured;

* Low temperature values compared to the outlet air temperature. Before starting the measurements for Example 19.2 batteries were changed.

Table 19.1.2

<td></td><td></td><td colspan="3">Example 19.1 (PEO N60K)</td>

<td></td><td></td><td colspan="3">Uncured core pills</td>

<td></td><td>Force compression (KN)</td><td> 15</td><td colspan="2"></td>

<td rowspan="3">Tablet dimensions</td><td>Weight (mg)</td><td> 252</td><td colspan="2"></td>

<td>Thickness (mm)</td><td> 4,12</td><td colspan="2"></td>

<td>Strength for crushing (N)</td><td> 112</td><td colspan="2"></td>

<td></td><td></td><td></td><td colspan="2">Example 19.1, hardened in at 72 ° C</td>

<td></td><td></td><td>unpaved</td><td>hardened by 15 minutes</td><td>cured /covered</td>

<td rowspan="5">dissolution (% released) SGF Spring basket</td><td>1 hour</td><td> 25 (2,3)</td><td> 25 (2,1)</td><td> 25 (3,7)</td>

<td>2 hours</td><td> 40 (1,8)</td><td> 40 (1,3)</td><td> 40 (3,8)</td>

<td>4 hours</td><td> 67 (0,7)</td><td> 66 (1,5)</td><td> 65 (1,4)</td>

<td>6 hours</td><td> 85 (1,0)</td><td> 86 (3,9)</td><td> 84 (1,0)</td>

<td>8 hours</td><td> 97 (0,8)</td><td> 98 (1,8)</td><td> 95 (0,7)</td>

220

<td></td><td> 12</td><td>hours</td><td> 101 (1,2)</td><td> 103</td><td> 102</td>

<td></td><td> 16</td><td>hours</td><td> 102 (0,7)</td><td> 103</td><td> 103</td>

Table 19.2.1

<td colspan="7">Example 19.2 (PEO N12K)</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td> 0</td><td></td><td>22 to 80</td><td> 27,0</td><td> 31,4</td><td> 30,9</td><td>Drum loading 1.4 kg; beginning heating</td>

<td> 19,5</td><td> 0</td><td> 80</td><td> 80,1</td><td> 71,5</td><td> 72,0</td><td>Beginning curing</td>

<td> 29,5</td><td> 10</td><td> 75</td><td> 75,0</td><td> 70,3</td><td> 72,0</td><td>Good flow tablets, none bonding</td>

<td> 34,5</td><td> 15</td><td>75 to 22</td><td> 75,1</td><td> 70,4</td><td> 72,0</td><td>End of the process curing beginning cooling</td>

<td> 49</td><td></td><td> 22</td><td> 22,4</td><td> 30,0</td><td> 30,0</td><td>End cooling, a sample</td>

221

Table 19.2.2

<td></td><td></td><td colspan="3">Example 19.1 (PEON12K)</td>

<td></td><td></td><td colspan="3">Uncured tablet core</td>

<td></td><td>Force compression (KN)</td><td> 15</td><td colspan="2"></td>

<td rowspan="3">Tablet dimensions</td><td>Weight (mg)</td><td> 257</td><td colspan="2"></td>

<td>Thickness (mm)</td><td> 4,17</td><td colspan="2"></td>

<td>Strength for crushing (N)</td><td> 107</td><td colspan="2"></td>

<td></td><td></td><td></td><td colspan="2">Example 19.2, hardened in at 72 ° C</td>

<td></td><td></td><td>unpaved</td><td>Cured by 15 minutes</td><td>cured /covered</td>

<td rowspan="7">dissolution (% released) SGF Spring basket</td><td>1 hour</td><td> 277 (7, 6)</td><td> 25 (1,0)</td><td> 26 (4,0)</td>

<td>2 hours</td><td> 44 (4,9)</td><td> 42 (0,6)</td><td> 43 (3,7)</td>

<td>4 hours</td><td> 72 (2,5)</td><td> 70 (0,6)</td><td> 71 (1,8)</td>

<td>6 hours</td><td> 92 (1,1)</td><td> 92 (0,6)</td><td> 91 (1,2)</td>

<td>8 hours</td><td> 102 (0,9)</td><td> 101 (1,1)</td><td> 100 (1,4)</td>

<td>12 hours</td><td> 102 (1,1)</td><td> 101 (0,9)</td><td> 101 (1,3)</td>

<td>16 hours</td><td> 103 (0,3)</td><td> 103 (1,3)</td><td> 102 (1,1)</td>

Example 20: Hardness test by indentering In example 20, tablets according to examples 13.1 to

13.5, 14.1 to 14.5, 16.1, 16.2, 17.1 and 18.2, in order to quantify strength, were subjected to hardness test by indentering using a texture analyzer.

Hardness testing of the indenter method was performed using the TA-XT2 texture analyzer

222 (Texture Technologies Corp., 18 Fairview Road, Scarsdale, NY

10583) equipped with a spherical probe made of stainless steel aTA-8A with a diameter of 1/8 inch. The probe height has been calibrated to

6mm above a stainless steel tripod with a slightly concave surface. The tablets were placed on the surface of the tripod and lined up directly under the probe. Each type of tablet was tested at least once. Values from single measurements are presented. Testing on the same type of tablets resulted in similar results unless the tablet and probe were not aligned. In this case, the data were discarded after confirmation of the test tablet by visual inspection.

Hardness tests using the indenter method were carried out with the following parameters:

initial speed 0.5 mm / s, test speed 0.5 mm / s, automatic release force 10 g, final speed 1.0 mm / s, test distance 3.0 mm.

The results are presented in tables 20.1 to 20.3 and figures 20 to 33.

Table 20.1:

<td colspan="5">Crushing force, "penetration depth to distance cracks "and work values</td>

<td></td><td colspan="4">Results of the hardness test by pressing indenter</td>

<td></td><td>Force crushing (N)</td><td>Maximum force (N)6</td><td>Distance (mm) 7</td><td>job (J) 8</td>

<td>Example 13.11</td><td> -</td><td> 189</td><td> 3,00</td><td> 0,284</td>

<td>Example 13.21</td><td> -</td><td> 188</td><td> 3,00</td><td> 0,282</td>

<td>Example 13.31</td><td> 191</td><td> -</td><td> 2,91</td><td> 0,278</td>

<td>Example 13.41</td><td> 132</td><td> -</td><td> 1,81</td><td> 0,119</td>

<td>Example 13.51</td><td> 167</td><td> -</td><td> 1,82</td><td> 0,152</td>

<td>Example 17.12</td><td> >2505</td><td> -</td><td> >2,0</td><td> >0,250</td>

<td>Example 18.22</td><td> 194</td><td> -</td><td> 1,80</td><td> 0,175</td>

<td>Example 14.13</td><td> 213</td><td> -</td><td> 2,52</td><td> 0,268</td>

<td>Example 14.23</td><td> 196</td><td> -</td><td> 2,27</td><td> 0,222</td>

223

<td>Example 14.33</td><td> 161</td><td> -</td><td> 1,90</td><td> 0,153</td>

<td>Example 14.43</td><td> 137</td><td> -</td><td> 1,51</td><td> 0,103</td>

<td>Example 14.53</td><td> 134</td><td> -</td><td> 1,39</td><td> 0,093</td>

<td>Example 16.14</td><td> 227</td><td> -</td><td> 2,23</td><td> 0,253</td>

<td>Example 16.24</td><td> 224</td><td> -</td><td> 2,17</td><td> 0,243</td>

1 the indenter hardness test was carried out on tablets cured for 30 minutes and uncoated (curing time was determined according to method 4, curing started when the temperature probe indicated a temperature of 70 ° C, see Example 13).

2 the indenter hardness test was carried out on tablets cured at 72 ° C for 15 minutes and coated (curing time was determined according to method 2, curing started when the outlet air temperature reached 72 ° C, see Examples 17 and 18), 3 the indenter hardness test was carried out on tablets cured for 1 hour and coated (curing time was determined according to method 1, curing started when the inlet air temperature reached 75 ° C, see Example 14), 4 the indenter hardness test was carried out on tablets cured for 15 minutes and coated (curing time was determined according to method 2, curing started when the outlet air temperature reached 72 ° C, see Example 16), 5 The peak of strength has exceeded the detection limit, 6 In hardness tests by indentering, in cases where the tablets did not break under the test conditions specified above, the tablets, instead of crushing, were subjected to the maximum force at a penetration depth of 3.0 mm;

7 distance "penetration depth to crack" 8 approximate value, calculated using the equation: Work = 1/2.Force [N] x Distance [m].

224

Table 20.2:

<td colspan="8">Selective force values at a distance increasing by 0.1 mm</td>

<td rowspan="2">Distance (Mm)</td><td colspan="7">Force (N)</td>

<td>Example 13.1</td><td>Example 13.2</td><td>Example 13.3</td><td>Example 13.4</td><td>Example 13.5</td><td>Example 17.1</td><td>Example 18.2</td>

225

<td colspan="8">Force value for a distance of 2.0825 mm</td>

Table 20.3:

<td colspan="8">Selective force values at increasing distance 0.1 mm</td>

<td rowspan="2">Distance (Mm)</td><td colspan="7">Force (N)</td>

<td>Example 14.1</td><td>Example 14.2</td><td>Example 14.3</td><td>Example 14.4</td><td>Example 14.5</td><td>Example 16.1</td><td>Example 16.2</td>

226

Example 21: Hardness induction test In example 21, to quantify tablet strength, tablets according to examples 16.1 (60 mg oxycodone hydrochloride) and 16.2 (80 mg oxycodone hydrochloride) and commercially available OxyContin ™ 60 mg and

OxyContin ™ 80 mg was subjected to a hardness test by indentering using a texture analyzer.

Hardness testing of the indenter was carried out as described in example 20.

The results are shown in Table 21 and Figures 34 and

35.

Table 21:

<td colspan="5">Selective force values at increasing distance 0.1 mm</td>

<td rowspan="2">Distance (Mm)</td><td colspan="4">Force (N)</td>

<td>Example 16.1</td><td>OxyContin ™ 60 mg</td><td>Example 16.2</td><td>OxyContin ™ 8 0 mg</td>

227

Comparative Example 22

In Comparative Example 22, five different 150 mg tablets (Examples 22.1 to 22.5) containing 10, 15, 20, and 40 mg oxycodone hydrochloride were prepared using the compositions described in Example 13 and, if the tablets were subjected to a shaping step and curing, the process was changed of production according to example 13.

compositions:

<td></td><td>Example 22.1</td><td>Example 22.2</td><td>Example 22.3</td><td>Example 22.4</td><td>Example 22.5</td>

<td>Ingredient</td><td>mg / one TKE</td><td>mg / one TKE</td><td>mg / one TKE</td><td>mg / one TKE</td><td>mg / one TKE</td>

<td>hydrochloride oxycodone</td><td> 10</td><td> 15</td><td> 20</td><td> 30</td><td> 40</td>

<td>Poly (oxide ethylene) (mass Molecular: approximately 4000000; Polyox ™ WSR-301)</td><td> 138,5</td><td> 133,5</td><td> 128,5</td><td> 118,5</td><td> 108,5</td>

228

<td>stearate magnesium</td><td> 1,5</td><td> 1,5</td><td> 1,5</td><td> 1,5</td><td> 1,5</td>

<td>Total weight tablet core (Mg)</td><td> 150</td><td> 150</td><td> 150</td><td> 150</td><td> 150</td>

<td>The weight of the whole batch</td><td>10 kg</td><td>10 kg</td><td>10 kg</td><td>10 kg</td><td>10 kg</td>

The tablets were made according to the following processing steps:

1. In a Patterson Kelly "V" mixer (equipped with mixer I), with a capacity of 16 quarters, were placed in succession:

Approximately 1/2poly (ethylene oxide) WSR 301

Oxycodone hydrochloride

Other poly (ethylene oxide) WSR 301

2. The materials of step 1 were mixed for 5 minutes using the stirrer I on.

3. Magnesium stearate was placed in the "V" mixer.

4. The materials of step 3 were mixed for 1 minute using the switched off stirrer I.

5. The mix obtained in stage 4 was placed in a plastic bag.

6. The mix obtained in step 5 was compressed to the target mass using an 8-station tablet press operating at 35,000 tablets per hour, using standard 9/32 inch rounded, concave (extruded) tooling.

7. The tablets obtained in step 6 were shaped using a Specac press with temperature control. The compressed tablets obtained according to step 6 were placed between two heated plates, which were pre-heated to 120 ° C, then compressed under a pressure of 1000 kg and held for 3 minutes. Before measuring the density, the molten tablets were cooled to room temperature.

The density measurement was carried out as follows:

The tablet density before and after the shaping step was determined based on the Archimedes principle, using a Mettler Toledo Model # AB 135-S / FACT top loading weight, Serial # 1127430072 and a 33360 density kit, according to the following procedure:

229

1. A Mettler Toledo balance was set up with a density determination kit.

2. The 200 ml beaker was filled with hexane.

3. The tablet was weighed in air and the mass was designated 5 mass A.

4. The tablet was transferred to a lower coil inside a hexane filled beaker.

5. The weight of the tablet in hexane was determined and the mass was designated as mass B.

6. Density was calculated according to the equation

AND r = A - B 'ro in which r: Tablet density

A: Weight of the tablet in the air

B: The weight of the tablet immersed in liquid0: Liquid density at a given temperature (density of hexane at 20 ° C = 0.660 g / ml (Merck's index)

7. Density was recorded.

The density values described are average values of 20 measurements for 3 tablets and all refer to uncoated tablets.

The results are shown in Table 22.1. Table 22.1

<td></td><td colspan="2">Density (g / cm3)1</td><td rowspan="2">Change density after (%) shaping 3</td>

<td></td><td>Pill unshaped2</td><td>shaped pill</td>

<td>Example 22.1</td><td> 1,172</td><td> 1,213</td><td> +3,498</td>

<td>Example 22.2</td><td> 1,174</td><td> 1,213</td><td> +3,322</td>

<td>Example 22.3</td><td> 1,179</td><td> 1,222</td><td> +3,647</td>

<td>Example 22.4</td><td> 1,182</td><td> 1,231</td><td> +4,146</td>

<td>Example 22.5</td><td> 1,222</td><td> 1,237</td><td> +1,227</td>

230 1 The density value is the average of 3 tablets;

2 The density of the "unformed tablet" corresponds to the density of the "uncured tablet" according to examples 13.1 to 13.5;

3 The change in density after shaping corresponds to the observed change in density of the shaped tablet in% compared to the unformed tablet.

Example 23

In Example 23, using high molecular weight polyethylene oxide, 154.5 mg tablets containing were prepared

thirty mg hydromorphone hydrochloride.

Composition:

<td>Ingredient</td><td>mg / unit</td><td>g / batch</td>

<td>Hydromorphone Hydrochloride</td><td> 30</td><td> 1000</td>

<td>Poly (ethylene oxide) (molecular weight: approximately 4,000,000; Polyox ™ WSR- 301)</td><td> 119,25</td><td> 3975</td>

<td>Magnesium stearate</td><td> 0,75</td><td> 25</td>

<td>Total tablet core weight (mg)</td><td> 150</td><td></td>

<td>The weight of the whole batch</td><td>10 kg (2x 5 kg)</td><td></td>

<td>Coating layer</td><td>mg / unit</td><td></td>

<td>Opadry coating layer</td><td> 4,5</td><td></td>

<td>Total tablet weight (mg)</td><td> 154,5</td><td></td>

<td>Weight of coated lot (kg)</td><td>8,835 kg</td><td></td>

The tablets were made according to the following processing steps:

1. In the PK V mixer (with stirrer I) with a capacity of 16 10 quarts were placed in order:

Approximately half of polyethylene oxide 301 Hydromorphone hydrochloride Other polyethylene oxide 301

2. The materials of step 1 were mixed for 5 minutes with the intensifier stirrer turned on.

3. Magnesium stearate was placed in the PK V mixer.

231

4. The materials of step 3 were mixed for 1 minute with the intensifier off.

5. The mix obtained in stage 4 was placed in a plastic bag (note: 2 x 5 kg of mix was made by obtaining 10 kg of mix ready for compression).

6. The mix obtained in step 5 was compressed to the target mass using an 8-station rotary tablet press, using a standard 9/32 inch rounded, concave (extruded) tooling, operating at 35,000 to 40,800 tablets per hour, using a compression force of 5-8 kN.

7. The tablets obtained in step 6 were introduced into a Compu-Lab 24 inch coating drum with a drum load of 9.068 kg.

8. The drum rotation speed was set at 10 rpm and the tablet bed was heated by setting the inlet air temperature to achieve an outlet air temperature of approximately 72 ° C. The curing starting point (as described in method 2) was reached when the outlet air temperature reached 72 ° C. The tablets were cured at the target outlet air temperature for 1 hour. After 30 minutes of curing, tablets were taken.

9. After 1 inlet air temperature

Curing hours were observed with a target outlet of 72 ° C, the temperature was set to 90 ° C to increase the outlet air temperature (bed temperature).

Ten. After 10 minutes of increased heating, the outlet air temperature reached 82 ° C. good tablet flow and bed movement. Do not stick the tablets.

11. The inlet air temperature was set to 22 ° C to start cooling. During the cooling period (until the outlet air temperature reached 42 ° C), no sticking or agglomeration of tablets was observed.

12. The tablets obtained in step 11 were introduced into a 24 inch Compu-Lab coating drum at a drum load of 8.835 kg.

232

13. The tablet bed was warmed by setting the inlet air temperature to 55 ° C. The coating process was started when the outlet air temperature was around 42 ° C and continued until the target mass increased by 3%.

14. The coating process was carried out with a spray speed of 40-45 g / min, with a target air flow of 350 cubic feet per minute and a drum rotation speed initially equal to 10 rpm and then increased to 15 rpm. After coating, the drum rotation speed was set to 3.5 revolutions per minute and the tablets were allowed to cool.

15. The tablets were removed from the drum.

In vitro tests including dissolution, determination and uniformity test were carried out as follows:

Tablets cured for 30 minutes (uncoated) were tested in vitro using USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37.0 ° C. Samples were analyzed by reverse-phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC 18 3, 0 x 250 mm, 5 μΗΐ column using a mobile phase consisting of a mixture of acetonitrile and monobasic potassium phosphate buffer (pH 3.0), detection UV at 220 nm. Tests were carried out for time points of 1.0, 2.0, 4.0, 8.0 and 12.0 hours.

Tablets cured for 30 minutes (uncoated) were subjected to the assay test. Oxycodone hydrochloride was extracted from tablets in two sets of ten, each time 900 ml of a 1: 2 mixture of acetonitrile and simulated gastric fluid without enzyme (SGF), continuously stirring with a magnetic stirrer in a 1000 ml volumetric flask until all the tablets were completely dispersed or overnight. The solutions were diluted and analyzed by reverse phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC column18 3.0 x 250 mm, 5 μm, at 60 ° C, using a mobile phase consisting of acetonitrile and potassium phosphate monobasic buffer at pH 3.0, UV detection at 280 nm.

233

Tablets cured for 30 minutes (uncoated) were subjected to a uniformity test. Oxycodone hydrochloride was extracted from ten separate tablets, each time using 90 ml of a 1: 2 mixture of acetonitrile and simulated gastric fluid without enzyme (SGF), stirring continuously with a magnetic stirrer in a 100 ml volumetric flask until the tablets were completely dissolved or overnight. The solutions were diluted and analyzed by reversed-phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3.0 x 250 mm column, 5 μm, at 60 ° C, using a mobile phase consisting of acetonitrile and monobasic potassium phosphate buffer pH 3.0, UV detection at 280 nm.

The results are shown in Table 23. Table 23

<td colspan="2"></td><td>Example 23, 30 minutes curing</td>

<td colspan="2">Test (% oxycodone hydrochloride)1</td><td> 98,9</td>

<td colspan="2">uniformity (% oxycodone hydrochloride)1</td><td> 97,9</td>

<td rowspan="5">dissolution (% released) (N = 6)</td><td>1 hour</td><td> 26</td>

<td>2 hours</td><td> 42</td>

<td>4 hours</td><td> 66</td>

<td>8 hours</td><td> 92</td>

<td>12 hours</td><td> 101</td>

<td colspan="3">1 in relation to the oxycodone hydrochloride declared on the label</td>

Example 24

In Example 24, using high molecular weight polyethylene oxide, 150 mg tablets were prepared

2mg hydromorphone hydrochloride.

Composition:

<td>Ingredient</td><td>mg / unit</td><td>g / batch</td>

<td>Hydromorphone Hydrochloride</td><td> 2</td><td> 66,5</td>

234

<td>Poly (ethylene oxide) (mass molecular: approximately 4,000,000; Polyox ™ WSR- 301)</td><td> 147,25</td><td> 4908,5</td>

<td>Magnesium stearate</td><td> 0,75</td><td> 25</td>

<td>Total tablet core weight (mg)</td><td> 150</td><td rowspan="2"></td>

<td>The weight of the whole batch</td><td>10 kg (2X5 kg)</td>

The tablets were made according to the following processing steps:

1. In a PK V mixer (with a stirrer I) with a capacity of 4 quarters placed in sequence:

Approximately 600 g of polyethylene oxide 301

Hydromorphone Hydrochloride

Approximately 600g of polyethylene oxide 301

2. The materials of step 1 were mixed for 2 minutes with the stirrer ON and then removed from the mixer.

3. In a PK V mixer (with a mixer I) with a capacity of 16 quarters were placed in order:

Approximately half of the remaining poly (ethylene oxide)

301

Pre-mixed blend (obtained according to step 2)

Other polyethylene oxide 301

4. The materials of step 3 were mixed for 5 minutes with the intensifier stirrer turned on.

5. Magnesium stearate was placed in the PK V mixer.

6. The mix obtained in step 5 was mixed for a minute with the intensifier off.

7. The mix obtained in step 6 was placed in a plastic bag (note: 2 x 5 kg mix was prepared to give 10 kg ready mix).

8. The mix obtained in step 7 was compressed to the target mass using an 8-station rotary tablet press, using a standard 9/32 inch rounded, concave (extruded) tooling, operating at a speed of 40800 tablets per hour, using a compression force of 2 kN.

9. The tablets obtained in step 8 were introduced into a 24 inch Compu-Lab coating drum at a drum load of 9.146 kg.

Ten. The drum rotation speed was set to 10 rpm and the tablet bed was heated to set the temperature

235 inlet air so as to reach an outlet air temperature of approximately 72 ° C. The curing starting point (as described in method 2) was reached when the outlet air temperature reached 72 ° C. The tablets were cured at the target outlet air temperature for 1 hour. After 30 minutes of curing, samples of talets were taken.

11. When the outlet air temperature reached 72 ° C, the drum rotation speed was increased to 15 rpm.

12. After 1 hour of curing at the target outlet air temperature, the inlet air temperature was set to 22 ° C to initiate cooling. After 3 minutes of cooling, the bed stuck together into a large tablet agglomerate. It was not possible to apply a coating layer.

13. The tablets were removed from the drum.

It is believed that the agglomeration of tablets can be avoided, e.g. by increasing the drum rotation rate, using magnesium stearate as an anti-sticking agent, or applying a subcoating prior to curing.

In vitro tests including dissolution, determination and uniformity test were carried out as follows:

Tablets cured for 30 minutes (uncoated) were tested in vitro using USP Apparatus 1 (drum mixer) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37.0 ° C. Samples were analyzed by reversed-phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3, 0 x 250 mm, 5 μΗΐ column using a mobile phase consisting of a mixture of acetonitrile and monobasic potassium phosphate buffer (pH 3.0), UV detection at 220 nm. Tests were carried out for time points of 1.0, 2.0, 4.0, 8.0 and 12.0 hours.

Tablets cured for 30 minutes (uncoated) were subjected to the assay test. Oxycodone hydrochloride was extracted from tablets in two sets of ten, each in 900 ml of a 1: 2 mixture of acetonitrile and simulated gastric fluid without enzyme (SGF), continuously stirring with a magnetic stirrer in a 1000 ml volumetric flask until all the tablets former

236 completely dispersed or overnight. The solutions were diluted and analyzed by reversed-phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3 column, 0 x 250 mm, 5 pm at 60 ° C using a mobile phase consisting of acetonitrile and monobasic potassium phosphate buffer pH 3.0, UV detection at 280 nm.

Tablets cured for 30 minutes (uncoated) were subjected to a uniformity test. Oxycodone hydrochloride was extracted from ten separate tablets, each time using 90 ml of a 1: 2 mixture of acetonitrile and simulated gastric fluid without enzyme (SGF), continuously stirring with a magnetic stirrer in a 100 ml volumetric flask until the tablets were completely dissolved or through the night. The solutions were diluted and analyzed by reverse phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC column18 3.0 x 250 mm, 5 pm, at 60 ° C, using a mobile phase consisting of acetonitrile and monobasic potassium phosphate buffer at pH 3.0, UV detection at 280 nm.

The results are shown in Table 24. Table 24

<td colspan="2"></td><td>Example 24, 30 minutes curing</td>

<td colspan="2">Test (% oxycodone hydrochloride)1</td><td> 95,7</td>

<td colspan="2">Content uniformity (% oxycodone hydrochloride)1</td><td> 94,9</td>

<td rowspan="5">dissolution (% released) (N = 6)</td><td>1 hour</td><td> 26</td>

<td>2 hours</td><td> 39</td>

<td>4 hours</td><td> 62</td>

<td>8 hours</td><td> 89</td>

<td>12 hours</td><td> 98</td>

<td colspan="3">1 in relation to the oxycodone hydrochloride declared on the label</td>

237

Example 25

In Example 25, using a high molecular weight polyethylene oxide and low weight 80 mg polyethylene oxide (Example Each molecular preparation, two different 400 mg containing 60 mg were prepared (Example 25.1 and 25.2) and 25.3 and 25.4) oxycodone hydrochloride. made in two 100 kg batches.

<td></td><td colspan="4">Example 25</td>

<td>Ingredient</td><td colspan="2">mg / unit</td><td colspan="2">mg / unit</td>

<td>Oxycodone hydrochloride</td><td colspan="2"> 60</td><td colspan="2"> 80</td>

<td>Poly (ethylene oxide) (mass molecular: approximately 4000000; Polyox ™ WSR-301)</td><td colspan="2"> 229,7</td><td colspan="2"> 216</td>

<td>Poly (ethylene oxide) (mass molecular: approximately 100,000; Polyox ™ WSR- N10)</td><td colspan="2"> 106,3</td><td colspan="2"> 100</td>

<td>Magnesium stearate</td><td colspan="2"> 4</td><td colspan="2"> 4</td>

<td>The total weight of the tablet core (Mg)</td><td colspan="2"> 400</td><td colspan="2"> 400</td>

<td>Example</td><td> 25,1</td><td> 25,2</td><td> 25,3</td><td> 25,4</td>

<td>The weight of the whole batch</td><td>100 kg</td><td>100 kg</td><td>100 kg</td><td>100 kg</td>

<td>Coating layer</td><td colspan="2">mg / unit</td><td colspan="2">mg / unit</td>

<td>Opadry coating layer</td><td colspan="2"> 16</td><td colspan="2"> 16</td>

<td>Total tablet weight (mg)</td><td colspan="2"> 416</td><td colspan="2"> 416</td>

<td>Example</td><td> 25.1</td><td> 25.2</td><td> 25.3</td><td> 25.4</td>

<td>Weight of coated lot (kg)</td><td> 91,440</td><td> 96, 307</td><td> 95,568</td><td> 98,924</td>

The tablets were made according to the following processing steps:

1. Magnesium stearate was passed through a Sweco screen fitted with a 20 mesh screen in a suitable separate container.

2. In the Gemco mixer "V" (equipped with mixer I) 15 with a capacity of 10 cubic feet were placed in succession:

Approximately 1/2poly (ethylene oxide) WSR 301

Oxycodone hydrochloride

Poly (ethylene oxide) WSR N10

Other poly (ethylene oxide) WSR 301

238

3. The materials obtained in step 2 were mixed for 10 minutes using the included stirrer I.

4. Magnesium stearate was placed in the Gemco "V" mixer.

5. The materials obtained in step 4 were mixed for 2 minutes using the switched off stirrer I.

6. The mix obtained in step 5 was placed in a clean, tared stainless steel container.

7. The mix obtained in step 6 was compressed to a target mass using a 40 station tablet press working at a rate of 124,000 tablets per hour, using standard 13/32 inch rounded, concave (extruded) tooling.

8. The tablets obtained in step 7 were introduced into an Accela-Coat 48-inch coating drum, the drum loading was 91.440 kg (Example 25.1), 96.307 kg (Example 25.2), 95.568 kg (Example 25.3) and 98.924 kg (Example 25.4).

9. The drum rotation speed was set at 6 to 10 rpm and the tablet bed was heated with air at the outlet temperature to achieve a target inlet temperature of 55 ° C. Coating was started when the outlet air temperature was around 40 ° C and was carried out for 10, 15 or 16 minutes. This initial coating step was carried out to form a "coating" for tablets that acts as an anti-sticking agent during the curing process.

Ten. After completing the application of the "overcoat", the tablet bed was heated to set the outlet air temperature to reach a target inlet air temperature of 75 ° C (Example 25.1 and 25.3) or to reach a target outlet air temperature of 78 ° C (Example 25.2 and 25.4). The tablets were cured at the target temperature for 65 minutes (Example 25.1), 52 minutes (Example 25.2), 80 minutes (Example 25.3) and 55 minutes (Example 25.4). In examples 25.1 and 25.3, the curing start point (as described in method 1) was obtained when the inlet air temperature reached the target inlet air temperature. In examples 25.2 and 25.4, the curing start point (as described in method 2) was obtained when the outlet air temperature reached the target value. Temperature profile

239 curing processes for examples 25.1 to 25.4 are presented in tables 25.1.1 to 25.4.1.

11. During the curing process, the drum rotation speed was increased from 7 to 9 rpm (examples 25.1 and 25.3) and from 10 to 12 rpm (examples 25.2 and 25.4). In examples 25.1 to 25.4, 20 g magnesium stearate was added as an anti-sticking agent. The tablet bed was cooled by setting the outlet air temperature to 30 ° C.

12. After cooling, the tablet bed was heated to set an inlet air temperature of 53 ° C. The coating process was started when the outlet air temperature reached approximately 39 ° C and continued until the target mass increased by 4%.

13. After completion of the coating process, the tablet bed was cooled by setting an outlet air temperature of 27 ° C. The tablet bed was cooled to an outlet air temperature of 30 ° C or less.

14. The tablets were removed from the drum.

Then, in vitro tests were carried out, including crushing strength tests.

Cured and coated tablets were tested in vitro using USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C. Samples were analyzed by reversed-phase high performance liquid chromatography (HPLC) on a Waters Atlantis dC18 3.0 x 150 mm column, 3 pm, using a mobile phase consisting of a mixture of acetonitrile and non-basic phosphate buffer (pH 3.0), UV detection 230 nm. Tests were carried out for time points of 1.0, 2.0, 4.0, 6.0, 8.0 and 12.0 hours.

To assess the tablet's breaking strength, the unhardened tablets were subjected to a crushing strength test using a maximum force of 196 N using a Schleuniger 2E / 106 device.

The results are shown in Tables 25.1.2 to 25.4.2.

240

Table 25.1.1: Temperature profile of the curing process according to example 25.1

<td>Time total (Min.)</td><td>Time curing (Min.) 1</td><td>Temperature air on in flight (° C)2</td><td>Set temperature air on exit ( ° C)</td><td>The actual temperature air on outlet (° C)3</td><td>Speed rotation of the drum (turnover on minute)</td><td>Comments</td>

<td> 5</td><td> 0</td><td> 75</td><td> 60</td><td> 59</td><td> 7</td><td>Beginning curing</td>

<td> 70</td><td> 65</td><td> 75</td><td> 72</td><td> 72</td><td> 9</td><td>End curing 20 g added stearate magnesium</td>

<td> 71</td><td> -</td><td> 74</td><td> 30</td><td> 72</td><td> 9</td><td>Beginning cooling</td>

<td> 94</td><td> -</td><td> 23</td><td> 30</td><td> 30</td><td> 9</td><td>End cooling</td>

<td colspan="7">1 determined according to method 1,2 inlet temperature measured,3 outlet temperature measured.</td>

241

Table 25.1.2

<td></td><td></td><td colspan="2">Example 25.1</td>

<td></td><td></td><td>unpaved</td><td>cured, covered</td>

<td rowspan="2">dimensions pills</td><td>Weight (mg)</td><td>401 (n = 120)</td><td> -</td>

<td>Resistance to crushing (N)</td><td>112 (n = 50)</td><td> -</td>

Table 25.2.1: Temperature profile of the curing process according to example 25.2

<td>Time</td><td>Time</td><td>The temperature</td><td>Ustawio-</td><td>Fakty-</td><td>Speed</td><td>Comments</td>

<td>całko-</td><td>curing</td><td>rature</td><td>at the temperature</td><td>Total</td><td>swiveled</td><td></td>

<td>Temples</td><td>management</td><td>powie-</td><td>powie-</td><td>tem-</td><td>present</td><td></td>

<td>(Min.)</td><td>(Min.) 1</td><td>on in flight (° C)2</td><td>on outlet (° C)</td><td>rature air on outlet e (° C)3</td><td>of the drum (turnover on minute)</td><td></td>

<td> 33</td><td> 0</td><td> 90</td><td> 77</td><td> 77</td><td> 10</td><td>Beginning curing</td>

<td> 85</td><td> 52</td><td> 80</td><td> 77</td><td> 77</td><td> 12</td><td>End curing 20 g added stearate magnesium</td>

242

<td> 86</td><td> -</td><td> 80</td><td> 30</td><td> 77</td><td> 12</td><td>Beginning cooling</td>

<td> 116</td><td> -</td><td> 24</td><td> 25</td><td> 30</td><td> 12</td><td>End cooling</td>

<td colspan="7">1 determined according to method 2,2 inlet temperature measured, 3 outlet temperature measured.</td>

Table 25.2.2

<td></td><td></td><td colspan="3">Example 25.2</td>

<td></td><td></td><td>unpaved</td><td>cured, coated, data initial</td><td>cured, coated, data from second test</td>

<td rowspan="2">dimensions pills</td><td>Weight (mg)</td><td>400 (N = 120)</td><td> -</td><td> -</td>

<td>Resistance to crushing (N)</td><td>103 (N = 40)</td><td></td><td></td>

<td rowspan="6">dissolution (% released) SGF</td><td>1 hour</td><td></td><td> 23</td><td> 24</td>

<td>2 hours</td><td> -</td><td> 39</td><td> 43</td>

<td>4 hours</td><td> -</td><td> 62</td><td> 70</td>

<td>6 hours</td><td> -</td><td> 79</td><td> 88</td>

<td>8 hours</td><td> -</td><td> 90</td><td> 99</td>

<td>12 hours</td><td> -</td><td> 97</td><td> 103</td>

<td colspan="5">1 determined according to method 1,2 inlet temperature measured,3 outlet temperature measured.</td>

243

Table 25.3.1: Temperature profile of the curing process according to example 25.3

<td>Time</td><td>Time</td><td>The temperature</td><td>Mouth-</td><td>Fakty-</td><td>Shaft-</td><td>Comments</td>

<td>całko-</td><td>curing</td><td>rature</td><td>Wion</td><td>Total</td><td>bone</td><td></td>

<td>Temples</td><td>management</td><td>powie-</td><td>tem-</td><td>tem-</td><td>to images,</td><td></td>

<td>(Min.)</td><td>(Min.) 1</td><td>on in flight (° C)2</td><td>rature air on outlet (° C)</td><td>rature air on outlet (° C) 3</td><td>torques of the drum (turnover on minute)</td><td></td>

<td> 5</td><td> 0</td><td> 75</td><td> 65</td><td> 58</td><td> 7</td><td>Beginning curing</td>

<td> 85</td><td> 80</td><td> 74</td><td> 72</td><td> 72</td><td> 9</td><td>End curing 20 g added stearate magnesium</td>

<td> 86</td><td> -</td><td> 75</td><td> 30</td><td> 72</td><td> 9</td><td>Beginning cooling</td>

<td> 112</td><td> -</td><td> 23</td><td> 30</td><td> 30</td><td> 9</td><td>End cooling</td>

244

Table 25.3.2

<td></td><td></td><td colspan="3">Example 25.3</td>

<td></td><td></td><td>unpaved</td><td>cured, coated, data initial</td><td>cured, coated, data from second test</td>

<td rowspan="4">dimensions pills</td><td>Weight (mg)</td><td>400 (N = 120)</td><td> -</td><td> -</td>

<td>Thickness (mm)</td><td> -</td><td> -</td><td> -</td>

<td>Diameter (Mm)</td><td> -</td><td> -</td><td> -</td>

<td>Strength for crushing (N)</td><td>111 (N = 40)</td><td></td><td></td>

Table 25.4.1: Temperature profile of the curing process according to example 25.4

<td>Time</td><td>Time</td><td>The temperature</td><td>Mouth-</td><td>Fakty-</td><td>Speed</td><td>Comments</td>

<td>całko-</td><td>curing</td><td>rature</td><td>Wion</td><td>Total</td><td>rotation</td><td></td>

<td>Temples</td><td>management</td><td>powie-</td><td>tem-</td><td>tem-</td><td>of the drum</td><td></td>

<td>(Min.)</td><td>(Min.) 1</td><td>interiors on in flight (° C)2</td><td>rature air on outlet (° C)</td><td>rature air on outlet (° C)3</td><td>(turnover on minute)</td><td></td>

<td> 33</td><td> 0</td><td> 88</td><td> 78</td><td> 78</td><td> 10</td><td>Beginning curing</td>

245

<td> 88</td><td> 55</td><td> 80</td><td> 78</td><td> 78</td><td> 12</td><td>End curing 20 g added stearate magnesium</td>

<td> 89</td><td> -</td><td> 79</td><td> 30</td><td> 78</td><td> 12</td><td>Beginning cooling</td>

<td> 113</td><td> -</td><td> 23</td><td> 25</td><td> 34</td><td> 12</td><td>End cooling</td>

<td colspan="7">1 determined according to method 2,2 inlet temperature measured,3 outlet temperature measured.</td>

Table 25.4.2

<td></td><td></td><td colspan="3">Example 25.4</td>

<td></td><td></td><td>unpaved</td><td>cured, coated, data initial</td><td>cured, coated, data from second test</td>

<td rowspan="4">dimensions pills</td><td>Weight (mg)</td><td>400 (N = 120)</td><td></td><td></td>

<td>Thickness (mm)</td><td></td><td></td><td></td>

<td>Diameter (mm)</td><td></td><td></td><td></td>

<td>Strength for crushing (N)</td><td>101 (N = 40)</td><td></td><td></td>

<td rowspan="4">dissolution (% released) SGF</td><td>1 hour</td><td> -</td><td> 25</td><td> 29</td>

<td>2 hours</td><td> -</td><td> 42</td><td> 47</td>

<td>4 hours</td><td></td><td> 66</td><td> 73</td>

<td>6 hours</td><td> -</td><td> 84</td><td> 91</td>

246

<td rowspan="2"></td><td>8 hours</td><td> -</td><td> 96</td><td> 99</td>

<td>12 hours</td><td> -</td><td> 100</td><td> 101</td>

Table 25.5

<td></td><td colspan="3">Density (g / cm3)1</td><td>Change density after curing (%)2</td>

<td></td><td>unpaved</td><td>hardened by 30 minutes</td><td>hardened by 60 minutes</td><td></td>

<td>Example 25.1</td><td> 1,205</td><td> 1,153</td><td> 1,138</td><td> -5,560</td>

<td>Example 25.3</td><td> 1,207</td><td> 1,158</td><td> 1,156</td><td> -4,225</td>

<td colspan="5">1 The density was measured as described in Example 13. The density value is the average of 3 tablets; the change in density after curing corresponds to the change observed density of tablets cured for 60 minutes in% w compared to uncured tablets.</td>

Example 26

In Example 26, randomized, open, single dose, four types of formulations were performed, over four time periods, four parallel pathways cross-screening in healthy people to assess the pharmacokinetic properties and relative bioavailability of three tamper resistant oxycodone preparations (10 mg tablets oxycodone hydrochloride according to examples 7.1 to 7.3 in relation to the commercially available OxyContin® (10 mg), in fasting state and after eating a meal.

The tested preparations were as follows:

Tested preparations:

Preparation 1A: 1x oxycodone hydrochloride 10 mg tablet according to example 7.3 (preparation 1A) administered on an empty stomach or after a meal.

Preparation 1B: 1x oxycodone hydrochloride 10 mg tablet 20 according to example 7.2 (preparation 1B) administered on an empty stomach or after a meal.

247

Preparation 1C: 1x oxycodone hydrochloride 10 mg tablet according to example 7.1 (preparation 1C) administered on an empty stomach or after a meal.

Reference preparation:

Preparation OC: 1x OxyContin® 10 mg tablet administered on an empty stomach or after a meal.

All preparations were administered orally with 8 oz. (240 ml) of water as a single dose when fasted or after a meal.

Because this study was conducted in healthy people, the opioid antagonist naltrexone hydrochloride was administered to minimize the adverse effects caused by the opioid.

Selection of study participants

Classification methods

The following classification procedures were used for all potential patients during the classification visit, which was 28 days prior to the first dose:

- Informed consent.

- Weight, height, body mass index (BMI), and demographics.

- Estimate the inclusion / exclusion criteria.

- Medical history and treatment history, including associated medications.

- Signs of vital signs - blood pressure, respiratory rate, mouth temperature, and pulse rate (after sitting for about 5 minutes) and blood pressure and pulse rate after standing for about 2 minutes - and pulse oximetry results (SOP2), including the answer to the question "How do you feel?".

- Routine physical examination (may alternatively be carried out upon enrollment in period 1).

- Laboratory clinical studies (including biochemistry, hematology and urinalysis [UA]).

- 12-lead electrocardiogram (ECG).

- Hepatitis screening (including hepatitis B surface antigen [HBsAg], entropy 248 [HBsAb], hepatitis B antibody transient anti hepatitis C antibody [anti-HCV], abuse of selected drugs.

- Pregnancy test based on serum analysis (only female patients).

- Serum vesicular gonadotropin (FSH) test (postmenopausal women only)

Inclusion criteria

Patients who met the following criteria were included in the study.

- Men and women aged 18 to 50 inclusive.

- Body weight in the range of 50 to 100kg (110 to 220 lbs (pounds)) and BMI> 18 and £ 34 (kg / m2).

- Healthy patients who do not have significantly abnormal test results, as determined by analyzing medical history, physical examination, vital signs and electrocardiogram (ECG).

- Women who are able to become pregnant must have a suitable and reliable method of contraception, barrier with additional foam or jelly with spermicide, intrauterine device, hormonal contraception (consecutive hormonal contraceptives used alone are not acceptable). Women who are in postmenopausal age must be in postmenopausal> 1 year have elevated serum FSH levels.

- Consent to accept all food provided during the study.

Exclusion criteria

The following criteria excluded potential patients from the study.

- Women who are pregnant (positive human beta chorionic gonadotropin test) or are feeding.

- Any history or current abuse of drugs or alcohol for 5 years.

- History or any use such as action interfere with the excretion of the drug.

current states that can absorb, break down, metabolize or

249

- Taking opioid medicines in the last 30 days.

- A history of known sensitivity to oxycodone, naltrexone, or related compounds.

- Any history of frequent nausea or vomiting regardless of etiology.

- Any history of epileptic seizures or head injuries with current complications.

- People who participated in the clinical trial of the drug During the 30 days preceding the initial dose in this trial.

- People who had any more serious illness within the 30 days preceding the initial dose in this study.

- People who have taken any drug that is part of a hormone replacement therapy with thyroid hormone (hormonal contraception is allowed), vitamins, herbs, and / or mineral supplements within the 7 days preceding the initial dose.

- Refusal to refrain from taking food for 10 hours before and 4 hours after administration of study drugs and to refrain from taking complete caffeine or xanthine during each study period.

- Persons who received alcoholic beverages within forty-eight (48) hours prior to commencement of the study drug intake (day 1) or at any time after the start of the study by administering the drug.

- A history of smoking or use of nicotine products within 45 days prior to study involving drug administration or a positive urine cotinine test.

- Persons who received blood or blood products within 30 days prior to administration of study drugs or at any time during the study, except as required by this protocol.

- Positive results for screening for urine, alcohol for reporting at all times, and HBsAg, HBsAb (unless the patient was immunized with this antibody), anti-HCV.

- Positive test with Naloxone HCl.

250

- Presence of Gilbert's symptom or any known hepatobiliary abnormalities.

-People who, according to the researcher, are suitable for a reason (s) not specified in the exclusion criteria.

Patients who met all inclusion criteria and none of the exclusion criteria were randomly selected for the study. It was expected that approximately 34 patients would be randomly selected, with 30 patients eventually completing the study. Any patient who interrupts the test can be replaced.

Patients were assigned according to a random allocation schedule (RAS) in a 2: 1 ratio to the fasting group and the post-meal group, twenty patients were randomly assigned to the fasted group and 10 patients were assigned to the post-meal group.

Reporting procedures

On the 1st day of period 1, patients were admitted to the research unit and subjected to tests provoked by Naloxone HCl. The results of this test had to be negative for patients to be able to continue the test. Vital signs and SOP2 measured before and after Naloxone HCl challenge.

The following procedures were also carried out for all patients when reporting in each study period:

- Verification of inclusion / exclusion criteria, including verification of compliance with caffeine or xanthine restriction criteria.

- Routine physical examination only when registering for the test in period 1 (unless it was carried out during the classification).

- Examination of vital signs such as blood pressure, respiratory rate, and pulse rate (after sitting for approximately 5 minutes) - and SOP2, including the answer to the question "How do you feel?".

- Alcohol screening (test using a breath tester), cotinine and abuse of selected drugs.

251

- Pregnancy test based on urine analysis (for all female patients).

- Verification of medical history and treatment history.

- Monitoring and registration of accompanying drugs.

- Monitoring and logging of harmful events.

In order to continue the study, the results of the drug screening (including alcohol and cotinine) had to be available and negative before dosing. In addition, continuous compliance with medication recommendations and other restrictions on reporting and throughout the study was verified and recorded in the appropriate source documentation.

Prior to administration of the first dose in period 1, patients were randomly assigned a preparation sequence, according to which the reference preparations of biostatistics schedule are to be received by the tested preparations and the preparation in the specified order. The sequence of preparations was assigned according to a random assignment (RAS) prepared by which he did not participate in the evaluation of the test results. Randomization was used in this study to increase the reliability of statistical comparisons between formulations.

Preparation sequences for this study are shown in Table 26.1:

Table 26.1

<td></td><td>Period 1</td><td>Period</td><td>2 Period 3</td><td>Period 4</td>

<td>Sequence</td><td></td><td></td><td>Preparation</td><td></td>

Research procedures

The study included four study periods, each involving a single dose. There was a washout period of seven days between dosing in each study period. During each period, patients were confined to the study site from the day prior to administration of the subjects

252 medication and for 48 hours after administration of study medication, and returned to study site for procedures at 72 hours.

In each study period, patients were administered one of the tested oxycodone (10 mg) or 10 mg OxyContin® (OC) tablets with 240 ml of water after a 10-hour fasting overnight (for fasting). Patients receiving fasting had to remain fasting for an additional 4 hours after dosing. Patients receiving post-meal formulations began to eat a standard meal (FDA high-fat breakfast) 30 minutes before drug administration. Patients were dosed 30 minutes after the start of the meal and no food was given for at least 4 hours after the dose.

Patients received 50 mg naltrexone hydrochloride tablets -12, 0, 12, 24, and 36 hours for each dose of study formulation or OxyContin® dose.

Patients were in an upright or upright sitting position while receiving the study medication dose. Patients remained upright for a minimum of 4 hours.

Samples for analysis in the clinical laboratory were taken from patients who were fasting, i.e. not taking food, for at least 10 hours (the term food does not include water). Fasting was not required for testing on days when no doses were taken.

During the study, adverse events and concomitant medications were recorded, and vital signs (including blood pressure, body temperature, pulse rate, and respiratory rate) and SPO were monitored2.

Blood samples for determination of oxycodone plasma concentration were taken from each patient before the dose and 0.5, 1,

1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 28, 32, 36, 48, and 72 hours after dosing in each study period .

For each sample, 6 ml of venous blood was withdrawn through a permanently attached catheter and / or by direct puncture of the vein into tubes containing K2EDTA as an anticoagulant (collection of 6 ml tubes vacuum packed with K2EDTA Vacutainer®). Oxycodone plasma levels were determined

253 quantitatively using a standard compliant method combining liquid chromatography with mass spectrometry.

Procedures for completing the study

The following procedures were carried out at the clinic for all patients at the end of the study (end of study) or after discontinuation of the study:

- Assessment of accompanying treatment.

- Vital signs and SOP2, including the answer to the question "How do you feel?".

- Physical examination.

- 12-lead ECG electrocardiogram.

- Laboratory clinical trials (including biochemistry [fasting, for at least 10 hours], hematology, and urinalysis).

- Adverse event assessments.

- Pregnancy test based on serum analysis (only for female patients).

The results of this study are presented in tables 26.2 to

26.5.

Table 26.2: Average values of plasma pharmacokinetic parameters obtained for preparations 1A, 1B,

1C and OC (after meal)

<td colspan="8">Preparation 1A - condition after a meal</td>

<td></td><td>Cmax</td><td>tmax</td><td>AUCt</td><td>AUCinf</td><td>t1 /2z</td><td>lfrom</td><td>tlag</td>

<td>Average</td><td> 11,3</td><td> 5,08</td><td> 122</td><td> 134</td><td> 4,22</td><td> 0,170</td><td> 0,0833</td>

<td>Standard deviation</td><td> 5,54</td><td> 2,46</td><td> 55,3</td><td> 42,5</td><td> 0,884</td><td> 0,0292</td><td> 0,195</td>

<td>Value minimal</td><td> 0,372</td><td> 1,00</td><td> 1,13</td><td> 86,2</td><td> 3,34</td><td> 0,114</td><td> 0</td>

<td>Median</td><td> 10,7</td><td> 5,00</td><td> 120</td><td> 121</td><td> 3,94</td><td> 0,177</td><td> 0</td>

<td>Value maximal</td><td> 20,5</td><td> 10,0</td><td> 221</td><td> 223</td><td> 6,10</td><td> 0,207</td><td> 0,500</td>

254

<td>Average geometric</td><td> 8,63</td><td>ON</td><td> 85,8</td><td> 128</td><td>ON</td><td>ON</td><td>ON</td>

<td colspan="8">Preparation 1B - after-meal condition</td>

<td></td><td>Cmax</td><td>tmax</td><td>AUCt</td><td>AUCinf</td><td>t1 /2z</td><td>lfrom</td><td>tlag</td>

<td>Value minimal</td><td> 8,11</td><td> 3,00</td><td> 63,7</td><td> 64,5</td><td> 3,28</td><td> 0,0990</td><td> 0</td>

<td>Median</td><td> 14,2</td><td> 5,00</td><td> 126</td><td> 127</td><td> 4,22</td><td> 0,165</td><td> 0</td>

<td>Value maximal</td><td> 18,5</td><td> 8,00</td><td> 205</td><td> 207</td><td> 7,00</td><td> 0,211</td><td> 0,500</td>

<td>Average geometric</td><td> 13,8</td><td>ON</td><td> 127</td><td> 128</td><td>ON</td><td>ON</td><td>ON</td>

<td colspan="8">Preparation 1C - after-meal condition</td>

<td></td><td>Cmax</td><td>tmax</td><td>AUCt</td><td>AUCinf</td><td>t1 /2z</td><td>lfrom</td><td>tlag</td>

<td>Average</td><td> 17,1</td><td> 4,21</td><td> 138</td><td> 139</td><td> 4,41</td><td> 0,162</td><td> 0,0417</td>

<td>Standard deviation</td><td> 4,66</td><td> 1,21</td><td> 42,9</td><td> 42,9</td><td> 0,843</td><td> 0,0263</td><td> 0,144</td>

<td>Value minimal</td><td> 11,6</td><td> 1,50</td><td> 91,4</td><td> 92,5</td><td> 3,43</td><td> 0,107</td><td> 0</td>

<td>Median</td><td> 16,5</td><td> 4,50</td><td> 122</td><td> 123</td><td> 4,03</td><td> 0,173</td><td> 0</td>

<td>Value maximal</td><td> 27,9</td><td> 6,00</td><td> 218</td><td> 219</td><td> 6,49</td><td> 0,202</td><td> 0,500</td>

<td>Average geometric</td><td> 16,5</td><td>ON</td><td> 133</td><td> 134</td><td>ON</td><td>ON</td><td>ON</td>

255

<td colspan="8">OC preparation - condition after a meal</td>

<td></td><td>Cmax</td><td>tmax</td><td>AUCt</td><td>AUCinf</td><td>t1 /2z</td><td>lfrom</td><td>tlag</td>

<td>Average</td><td> 13,2</td><td> 3,17</td><td> 142</td><td> 143</td><td> 4,83</td><td> 0,146</td><td> 0</td>

<td>Standard deviation</td><td> 3,20</td><td> 1,85</td><td> 39,3</td><td> 39,5</td><td> 0,702</td><td> 0,0189</td><td> 0</td>

<td>Value minimal</td><td> 8,85</td><td> 1,00</td><td> 95,2</td><td> 95,9</td><td> 3,93</td><td> 0,105</td><td> 0</td>

<td>Median</td><td> 12,3</td><td> 2,25</td><td> 124</td><td> 125</td><td> 4,76</td><td> 0,146</td><td> 0</td>

<td>Value maximal</td><td> 18,1</td><td> 6,00</td><td> 218</td><td> 219</td><td> 6,59</td><td> 0,176</td><td> 0</td>

<td>Average geometric</td><td> 12,8</td><td>ON</td><td> 137</td><td> 138</td><td>ON</td><td>ON</td><td>ON</td>

<td colspan="8">NA = not applicable.</td>

Table 26.3: Average values of plasma pharmacokinetic parameters obtained for preparations 1A, 1B, 1C and OC (fasted state)

<td colspan="8">Preparation 1A - on an empty stomach</td>

<td></td><td>Cmax</td><td>tmax</td><td>AUCt</td><td>AUCinf</td><td>t1 /2z</td><td>lfrom</td><td>tlag</td>

<td>Average</td><td> 8,84</td><td> 4,60</td><td> 109</td><td> 111</td><td> 4,66</td><td> 0,156</td><td> 0,0250</td>

<td>deviations</td><td> 2,25</td><td> 1,90</td><td> 20,1</td><td> 20,3</td><td> 1,26</td><td> 0,0279</td><td> 0,112</td>

<td>e * Standard in</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Value minimal</td><td> 4,85</td><td> 2,00</td><td> 69,0</td><td> 69,8</td><td> 3,56</td><td> 0,0752</td><td> 0</td>

<td>Median</td><td> 8,53</td><td> 5,00</td><td> 114</td><td> 114</td><td> 4,29</td><td> 0,162</td><td> 0</td>

<td>Value maksymal.</td><td> 13,2</td><td> 10,0</td><td> 138</td><td> 139</td><td> 9,22</td><td> 0,195</td><td> 0,500</td>

256

<td>Average geometric</td><td> 8,56</td><td>ON</td><td> 108</td><td> 109</td><td>ON</td><td>ON</td><td>ON</td>

<td colspan="8">Preparation 1B - on an empty stomach</td>

<td></td><td>Cmax</td><td>tmax</td><td>AUCt</td><td>AUCinf</td><td>t1 /2z</td><td>lfrom</td><td>tlag</td>

<td>Average</td><td> 9,97</td><td> 4,58</td><td> 115</td><td> 116</td><td> 4,67</td><td> 0,156</td><td> 0</td>

<td>Standard deviation</td><td> 1,82</td><td> 1,18</td><td> 23,8</td><td> 23,8</td><td> 1,24</td><td> 0,0309</td><td> 0</td>

<td>Value minimal</td><td> 6,90</td><td> 2,00</td><td> 75,2</td><td> 76,3</td><td> 3,53</td><td> 0,0878</td><td> 0</td>

<td>Median</td><td> 10,0</td><td> 5,00</td><td> 121</td><td> 122</td><td> 4,35</td><td> 0,159</td><td> 0</td>

<td>Value maksymal.</td><td> 14,1</td><td> 6,00</td><td> 152</td><td> 153</td><td> 7,90</td><td> 0,197</td><td> 0</td>

<td>Average geometric</td><td> 9,81</td><td>ON</td><td> 113</td><td> 114</td><td>ON</td><td>ON</td><td>ON</td>

<td colspan="8">Preparation 1C - on an empty stomach</td>

<td></td><td>Cmax</td><td>tmax</td><td>AUCt</td><td>AUCinf</td><td>t1 /2z</td><td>lfrom</td><td>tlag</td>

<td>Average</td><td> 13,6</td><td> 3,75</td><td> 110</td><td> 111</td><td> 4,18</td><td> 0,169</td><td> 0,0227</td>

<td>Standard deviation</td><td> 3,79</td><td> 1,38</td><td> 18,5</td><td> 18,5</td><td> 0,594</td><td> 0,0256</td><td> 0,107</td>

<td>Value minimal</td><td> 8,64</td><td> 1,00</td><td> 70,6</td><td> 71,1</td><td> 2,92</td><td> 0,135</td><td> 0</td>

<td>Median</td><td> 12,9</td><td> 3,75</td><td> 112</td><td> 113</td><td> 4,13</td><td> 0,169</td><td> 0</td>

<td>Value maksymal.</td><td> 23,7</td><td> 6,00</td><td> 142</td><td> 143</td><td> 5,14</td><td> 0,237</td><td> 0,500</td>

<td>Average geometric</td><td> 13,2</td><td>ON</td><td> 108</td><td> 109</td><td>ON</td><td>ON</td><td>ON</td>

257

<td colspan="4">OC preparation</td><td colspan="4">- on empty stomach</td>

<td></td><td>Cmax</td><td>tmax</td><td>AUCt</td><td>AUCinf</td><td>t1 /2z</td><td>lfrom</td><td>tlag</td>

<td>Average</td><td> 9,73</td><td> 2,82</td><td> 114</td><td> 115</td><td> 4,82</td><td> 0,154</td><td> 0</td>

<td>Standard deviation</td><td> 1,67</td><td> 0,960</td><td> 26,0</td><td> 26,2</td><td> 1,41</td><td> 0,0379</td><td> 0</td>

<td>Value minimal</td><td> 7,38</td><td> 1,00</td><td> 76,3</td><td> 77,8</td><td> 3,11</td><td> 0,0839</td><td> 0</td>

<td>Median</td><td> 9,57</td><td> 3,00</td><td> 112</td><td> 112</td><td> 4,37</td><td> 0,159</td><td> 0</td>

<td>Value maksymal.</td><td> 13,2</td><td> 5,00</td><td> 181</td><td> 183</td><td> 8,27</td><td> 0,223</td><td> 0</td>

<td>Average geometric</td><td> 9,60</td><td>ON</td><td> 112</td><td> 113</td><td>ON</td><td>ON</td><td>ON</td>

<td colspan="8">NA = not applicable.</td>

Table 26.4:

<td colspan="5">Statistical results of pharmacokinetic parameters of preparations</td>

<td>oxycodone:</td><td colspan="2">bioavailability of tablets</td><td colspan="2">according to examples 7.1 to</td>

<td colspan="3">7.3 compared to OxyContin® 10</td><td colspan="2">mg after a meal</td>

<td>(Population</td><td colspan="2">full analysis)</td><td></td><td></td>

<td>Comparison</td><td>Ratio</td><td>90% range</td><td>Avg ratio</td><td>90% range</td>

<td>(preparation</td><td>medium LS</td><td>trustb</td><td>LS</td><td>trustb</td>

<td>examined</td><td>(prep. investigates</td><td></td><td>(prep. investigates</td><td></td>

<td>terms of</td><td>ny / odniesi-</td><td></td><td>ny / reference shall</td><td></td>

<td>preparation</td><td>no) and</td><td></td><td>no) and</td><td></td>

<td>reference shall</td><td></td><td></td><td></td><td></td>

<td>present)</td><td></td><td></td><td></td><td></td>

<td>1A relative to</td><td> 67,5</td><td> [47,84;</td><td> 62,6</td><td> [39,30;</td>

<td>1B relative to</td><td> 108,0</td><td> [76,59;</td><td> 92,9</td><td> [58,31;</td>

<td>1C relative to</td><td> 129,0</td><td> [91,54;</td><td> 97,0</td><td> [60,83;</td>

258 and Average calculated by the method of least squares using ANOVA. The natural logarithm (ln) of mean parameters was calculated by converting ln from means back to the linear scale, i.e., to geometric means; Ratio of average parameters to parameters transformed in ln (expressed as a percentage). The ratio converted to Inn was transformed back to the linear scale (test preparations = 1A, 1B, 1C; reference preparation = OC);

b 90% confidence interval for the ratio of average parameters (expressed as a percentage). Transformed into ln, the confidence interval was transformed back to a linear scale.

Table 26.5:

<td colspan="5">Statistical results of pharmacokinetic parameters of preparations</td>

<td colspan="3">oxycodone: bioavailability of tablets 7.3 compared to OxyContin® 10 (Population: full analysis)</td><td colspan="2">according to examples 7.1 to mg in fasting state</td>

<td>Comparison (preparation examined terms of preparation reference)</td><td>Ratio medium LS (prep. test / reference) and</td><td>90% range trustb</td><td>Ratio medium LS (prep. test / reference) and</td><td>90% range trustb</td>

<td>1A relative to OC</td><td> 89,5</td><td> [82,76; 96,89]</td><td> 97,0</td><td> [92,26; 102,79]</td>

<td>1B relative to OC</td><td> 99,0</td><td> [91,33; 107,30]</td><td> 101,0</td><td> [95,42; 106,57]</td>

<td>1C relative to OC</td><td> 133,0</td><td> [123,23; 143,86]</td><td> 96,4</td><td> [91,43; 101,68]</td>

<td colspan="5">and Average calculated by the method of least squares using ANOVA. Natural logarithm (ln) of means parameters were calculated by transforming ln from means of back to the linear scale, i.e., to geometric means; Ratio of average parameters to parameters transformed into ln (expressed as a percentage). Transformed into LN ratio transformed back to the linear scale (test preparations = 1A, 1B, 1C; reference preparation = OC);</td>

259 b 90% confidence interval for the ratio of average parameters (expressed as a percentage). Transformed into ln, the confidence interval was transformed back to a linear scale.

Example 27

In Example 27, oxycodone HCl tablets according to Example 7.2, and Examples 14.2 to 14.5, containing 10, 15, 20, 30, and 40 mg oxycodone hydrochloride were subjected to various interference resistance tests, respectively, using mechanical strength and chemical extraction to assess their strength for physical and chemical manipulation.

Test results were compared with control data defined as the percentage of Pharmaceutically Active Ingredient (API) released from intact tablets after in vitro dissolution in simulated gastric fluid without enzyme (SGF) for 45 minutes. This comparator system was chosen as a reference to determine the approximate amount of API present in the body (after 45 minutes) when the product is taken according to guidelines. For comparison, available results for the OxyContin ™ product currently available on the market are also presented.

Tablets were prepared with five different contents (10, 15, 20, 30 and 40 mg oxycodone hydrochloride, according to example 7.2, and examples 14.2 to 14.5). Tablets at all strengths had approximately the same dimensions and weight, so all tests were performed by grouping tablets with the lowest API and excipient ratio (10 mg, Example 7.2) and the highest API and excipient ratio (40 mg, Example 14.5). ). In addition, level 1 studies were conducted on tablets with intermediate strengths (15, 20 and 30 mg, examples 14.2, 14.3 and 14.4) to assess the resistance to physical manipulation, followed by chemical extraction, when using a mortar and pestle. Further tests were not carried out on these tablets because a coffee grinder was used in the higher levels of the test, resulting in similar particle size distributions and similar amounts of API extracted from

260 ground tablets placed in groups (Example 7.2 and

14.5).

The experimental techniques used in this test were designed to obtain methods suitable for simulating and estimating common abuse methods. Four levels of tamper resistance have been broadly defined to give an approximation of the relative level of tamper resistance. Several approaches to ingenuity were considered;

including the use of mechanical force (used to damage the medicinal product), availability and toxicity of extraction solvents, length of extraction time and thermal treatment. Any higher level of tamper resistance means an increase in the difficulty of successful tampering with the medicinal product. Definitions of tamper resistance levels, including examples of equipment and reagents used, are presented in Table 27.1.

Table 27.1: Definitions and test examples Level Definition Degree Examples Examples of difficulties in equipping reagents 0 Capable of direct skipping N / A No daytime abuse without preparation

<td>Easy to abuse -</td><td>Minimal Tool</td><td>Water,</td>

<td>using it</td><td>down</td><td>alcohols</td>

<td>various means</td><td>crushing</td><td>distilled</td>

<td>no reagent or,</td><td>(hammer,</td><td>(vodka,</td>

<td>using the reagent</td><td>foot</td><td>genie, etc.),</td>

<td>easily possible</td><td>whisk,</td><td>vinegar, soda</td>

<td>get</td><td>crusher for pills, e.t.c.)</td><td>purified</td>

<td>Direct reactants</td><td></td><td>Oil</td>

<td>days are suitable for</td><td></td><td>kitchen</td>

consumption and extraction time is shorter

261

<td> 2</td><td>Easy to abuse -</td><td>moderate</td><td>Tools</td><td>100% ethanol</td>

<td></td><td>with additional</td><td>important to provide</td><td>to prepare</td><td>(alcohol</td>

<td></td><td>preparation</td><td></td><td>celebrate</td><td>cereal,</td>

<td></td><td>demanding</td><td></td><td>preparation</td><td>Everclear)</td>

<td></td><td>use</td><td></td><td>to serve</td><td>strongly</td>

<td></td><td>certain reagents</td><td></td><td>IV (to</td><td>acid and</td>

<td></td><td>directly send</td><td></td><td>venous)</td><td>alkaline</td>

<td></td><td>going to</td><td></td><td>tools</td><td>solutions</td>

<td></td><td>intake, though</td><td></td><td>for grinding</td><td></td>

<td></td><td>more harmful</td><td></td><td>(grinder for</td><td></td>

<td></td><td>time, extra time</td><td></td><td>coffee,</td><td></td>

<td></td><td>the shortcut is shorter,</td><td></td><td>mixer),</td><td></td>

<td></td><td>and apply</td><td></td><td>stove</td><td></td>

<td></td><td>heat treatment</td><td></td><td>Microwave</td><td></td>

<td> 3</td><td></td><td>Considerable</td><td>Mill percussive</td><td></td>

<td></td><td>Preparation for</td><td></td><td>(Eg.</td><td>Except</td>

<td></td><td>abuse</td><td></td><td>Fitzmill)</td><td>previously</td>

<td></td><td>requires knowledge</td><td></td><td></td><td>wyszczegó-</td>

<td></td><td>about chemistry</td><td></td><td></td><td>lnionych</td>

<td></td><td>medicines, includes</td><td></td><td></td><td>dissolution</td>

<td></td><td>harder to access</td><td></td><td></td><td>craftsmen:</td>

<td></td><td>reagents, maybe</td><td></td><td></td><td>methanol,</td>

<td></td><td>require tools</td><td></td><td></td><td>ether,</td>

<td></td><td>industrial,</td><td></td><td></td><td>isopropanol,</td>

<td></td><td>I have a complex pro</td><td></td><td></td><td>acetone,</td>

<td></td><td>cesses (e.g. biphasic extraction). Some reagents they are harmful and not are suitable for consumption, extraction time and temperature are bigger.</td><td></td><td></td><td>ethyl acetate</td>

The research results

Control data (preparation 'taken according to instructions') and boundary conditions

262

The dissolution test of intact tablets according to example 7.2 and examples 14.2 to 14.5 was carried out in vitro using USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C. Samples were taken 45 minutes after dissolution and analyzed by reverse phase high performance liquid chromatography (HPLC). The average results of the three trial analyzes are shown in Table 27.2 and compared with equivalent data for 10 mg OxyContin ™ tablets.

Table 27.2: Control results -% API released after 45 minutes% oxycodone hydrochloride1 released after 45 minutes

<td>prepared</td><td>OxyContin</td><td>Ex.</td><td>Ex.</td><td>Ex.</td><td>Ex.</td><td>Ex.</td>

<td>Nothing</td><td> 34</td><td> 19</td><td> 20</td><td> 20</td><td> 18</td><td> 19</td>

(intact tablets) 1 in relation to the content declared on the label

In addition, Table 27.3 contains limits for dissolution within one hour for each of the tablets tested. This illustrates the extent of acceptable drug release over one hour for all formulations tested in this study. It should be noted that the upper limit of release for one hour in vitro of oxycodone hydrochloride from 10 mg OxyContin tablets is 49%.

Table 27.3: Dissolution limits (% released)

<td>Product</td><td>Boundary conditions for 1 hour</td>

<td>Example 7.2</td><td> 15-35</td>

<td>Example 14.2</td><td> 15-35</td>

<td>Example 14.3</td><td> 15-35</td>

<td>Example 14.4</td><td> 15-35</td>

<td>Example 14.5</td><td> 15-35</td>

<td>OxyContin ™ 10 mg</td><td> 29-49</td>

263

Level 1 study

The first level of the study involved mortar and pestle crushing and simple extraction.

Level 1 - results - crushing

After crushing with a mortar and pestle, the in vitro dissolution test was carried out in three trials for each product using USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C as described above for control data. The tablets of Example 7.2 could not be crushed using a mortar and pestle, so that the release of API did not increase significantly compared to the control results. Although difficult, the tablets of Examples 14.2 to 14.5 (15,

20, 30 and 40 mg tablets) could be broken into large pieces using a mortar and pestle to give little or no powder. This reduction in particle size resulted in increased release of API; however, swelling of the tablet matrix upon dissolution in SGF provided protection against the release of too much dose, resulting in release below half of the API content after 45 minutes. OxyContin ™ tablets were easily crushed to a powder using a mortar and pestle, resulting in the release of most APIs. Fig. 40 shows representative images of crushed tablet. Table 27.4 presents the average results of the percentage of API released after crushing.

<td>Table 45 minutes</td><td colspan="5">27.4: Crushing results -% released</td><td>API after</td>

<td>A sample</td><td colspan="2">% hydrochloride</td><td colspan="4">oxycodone1 released after</td>

<td></td><td></td><td></td><td colspan="2">45 minutes</td><td></td><td></td>

<td colspan="2">Preparation of OxyContin</td><td>Ex.</td><td>Ex.</td><td>Ex.</td><td>Ex.</td><td>Ex.</td>

<td>crushed</td><td> 92</td><td> 20</td><td> 41</td><td> 44</td><td> 42</td><td> 43</td>

<td>pills</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Control -</td><td> 34</td><td> 19</td><td> 20</td><td> 20</td><td> 18</td><td> 19</td>

<td>intact</td><td></td><td></td><td></td><td></td><td></td><td></td>

264 tablets (release after 45 minutes) 1 in relation to the content declared on the label

In addition, the tablets of Example 14.5 could not be crushed between two teaspoons, demonstrating that additional tools may be needed to crush the tablets. Conversely, OxyContin ™ tablets could easily be crushed between two teaspoons.

Level 1 - results - simple extraction

Tablets according to example 7.2, and examples from 14.2 to

14.5 were crushed using a mortar and pestle and vigorously shaken using a hand shaker at an angle of 10 ° for 15 minutes in various solvents at room temperature. As previously stated, the tablets of Example 7.2 were not crushed using a mortar and pestle, so that the extracted amounts did not increase. The tablets according to examples 14.2 to 14.5 were crushed using a mortar and pestle before extraction. Due to the swelling of the tablet matrix in the solvents tested, crushed tablets remained resistant to the release of too much dose, while OxyContin ™ tablets released almost all of the API content. Table 27.5 shows the average amount of API released in each solvent.

Table 27.5: Simple extraction results -% of API released after 15 minutes

<td>% released</td><td colspan="6">oxycodone hydrochloride1</td>

<td colspan="2">Crushed OxyContin ™</td><td>Ex.</td><td>Ex.</td><td>Ex.</td><td>Ex.</td><td>Ex.</td>

<td>tablets w</td><td></td><td> 7.2</td><td> 14.2</td><td> 14.3</td><td> 14.4</td><td> 14.5</td>

<td>dissolution</td><td>(10 mg)</td><td>(10 mg)</td><td>(15 mg)</td><td>(20 mg)</td><td>(30 mg)</td><td>(40 mg)</td>

<td>foreman to</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>extraction</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Water</td><td> 92</td><td> 8</td><td> 32</td><td> 30</td><td> 28</td><td> 51</td>

<td>(volumetric</td><td></td><td></td><td></td><td></td><td></td><td></td>

wo)

265

<td>Vinegar</td><td> 102</td><td> 11</td><td> 28</td><td> 35</td><td> 41</td><td> 54</td>

<td>kitchen</td><td></td><td></td><td></td><td></td><td></td><td></td>

baking soda solution

<td>Control of intact tablets (release after 45 minutes)</td><td> 34</td><td> 19 20</td><td> 20 18</td><td> 19</td>

<td>1 relative to</td><td colspan="2">declared content</td><td>at the label</td><td></td>

Level 2 research

The second level of the study included milling, preparation of a simulated intravenous (IV) preparation, heat treatment and extraction.

Level 2 - results - milling

Example 7.2 and tablets according to Example 14.5 were ground in a Cuisanart® coffee grinder with stainless steel blades (model DCG-12BC) for 1 minute. The output power of the coffee grinder (1 minute) was determined to be 10.5 kJ. In three trials, material equivalent to one unit dosage form was taken and analyzed by dissolution testing using USP Apparatus 1 (drum mixer) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37 ° C as described above for control data. After one minute, the tablets of Example 7.2 and Example 14.5 were milled to give similar particle size distributions, resulting in the release of both tablets with different strengths approximately half of the API content. OxyContin ™ tablets were ground to obtain a mixture containing larger pieces and some powder, resulting in almost complete release of API. Table 27.6 shows the average amounts of API released from milled tablets. As mentioned previously, the milled tablets of examples 7.2 and 14.5 succumbed

266 swollen and became gelatinous. This phenomenon provides protection against the release of too high a dose. Fig. 41 is a representative illustration of the milled tablet before and after dissolution.

Table 27.6: Milling results -% of API released after minutes

<td></td><td colspan="3">% oxycodone hydrochloride1 released</td>

<td>Sample of preparation</td><td>OxyContin (10 mg)</td><td>Ex. 7.2 (10 mg)</td><td>Ex. 14.5 (40 mg)</td>

<td>Ground tablets</td><td> 93</td><td> 47</td><td> 52</td>

<td>Control -</td><td> 34</td><td> 19</td><td> 19</td>

intact tablets (release after 45 minutes) 1 in relation to the content declared on the label

Relative in vitro dissolution rate

To assess the relative release rate of API, dissolution samples were collected every five minutes from t = 0 to t = 40 minutes, for ground tablets according to Example 7.2 (coffee mill) and crushed 10 mg OxyContin ™ tablets (mortar and pestle). OxyContin ™ tablets are easier and more effectively crushed using a mortar and pestle. Although approximately half of the API content is released from the milled tablet of Example 7.2 in 45 minutes, this amount is released at a gradual rate that is characteristic of a controlled release product. No excessive release was observed. Conversely, dissolution of the ground OxyContin ™ tablet resulted in the release of the total high dose within 10 minutes. This is illustrated in Fig. 42.

Particle size distribution of milled tablets

The ground tablets of Examples 7.2 and 14.5 (coffee grinder) and crushed 10 mg OxyContin ™ tablets (mortar and pestle) were analyzed by screening to assess the particle size distribution of the milled material. The tablets were screened for 12 minutes, using vibration. Sieves with appropriate mesh sizes are shown in the table

267

27.7. As shown in the distribution by particle size chart in Fig. 43, 70-80% of the milled tablets according to examples 7.2 and 14.5 had dimensions larger than 600 gm. The large particle size of the ground material is probably unpleasant to inhale (sniff). 10 mg OxyContin ™ tablets resulted in particles with a significantly smaller particle size distribution.

Table 27.7: Screen dimensions and corresponding mesh sizes Screen number Mesh size (gm)

120

200

325

600

425

250

180

125

Level 2 - results - simulated intravenous preparation

The tablets of Examples 7.2 and 14.5 were ground in a coffee grinder (as described above) and placed on a teaspoon. 10 mg OxyContin ™ tablets were crushed between two teaspoons. Two milliliters of water were added to each teaspoon to extract or dissolve the medicine. The milled tablets of Examples 7.2 and 14.5 became viscous when water was added, giving a small amount (<0.3 mL) of liquid capable of being drawn into the insulin syringe, which was analyzed for API content. Very few APIs received. Approximately one milliliter contained half of the API content obtained from crushed 10mg OxyContin tablets. Table 27.8 contains data on the simulated intravenous preparation.

268

Table 27.8: Simulated formulation IV - results -% API released% oxycodone hydrochloride released1

<td>Sample of preparation</td><td>OxyContin ™ (10 mg)</td><td>Ex. 7.2 (10 mg)</td><td>Ex. 14.5 (40 mg)</td>

<td>Simulated preparation IV</td><td> 49</td><td> 1</td><td> 4</td>

<td>Control - intact</td><td> 34</td><td> 19</td><td> 19</td>

<td>tablets (release after 45</td><td></td><td></td><td></td>

<td>minutes)</td><td></td><td></td><td></td>

<td>1 in relation to the content</td><td>declared</td><td>at the label</td><td></td>

Level 2 - results - thermal treatment

The heat treatment was attempted in a microwave oven; however, the test was unsuccessful in a small volume of water. Ground tablets according to examples 7.2 and

14.5 could not be contained in 10-20 ml of boiling water, so the amount of water was increased to 100 ml. After 3 minutes of high energy processing in a microwave oven

800 watts (GE Model JE835), the remaining liquid was analyzed for API content. In addition, extraction in a small amount of boiling water was estimated by adding 10 ml of boiling water to the vial containing the ground tablet. The vial was shaken vigorously for 15 minutes. As shown in Table 27.9, after the heat treatment, the milled tablet retained controlled release properties that prevent the release of the total overdose. The microwave heating experiments were not performed on crushed OxyContin tablets; however, the comparison is a comparison of results from the boiling water experiment.

Table 27.9: Thermal treatment - results -% released

API% of oxycodone hydrochloride released1

<td>Sample of preparation</td><td>OxyContin (10 mg)</td><td>Ex. 7.2 (10 mg)</td><td>Ex. 14.5 (40 mg)</td>

<td>Ground tablets</td><td>in 100 ml N / A</td><td> 44</td><td> 52</td>

269 hot water (microwaves for minutes)

Ground tablets with 10 ml 89 58 61 hot water (shaking for 15 minutes)

<td>Control pills minutes)</td><td>- intact (release after 45</td><td> 34</td><td> 19</td><td> 19</td>

<td colspan="3">1 in relation to the declared content</td><td>at the label</td><td></td>

Level 2 - results - extraction

The tablets of Examples 7.2 and 14.5 were ground in a coffee mill (as in the method described above) and then shaken for 15 minutes in various solvents at room temperature. OxyContin ™ tablets were crushed using a mortar and pestle. Table 27.10 contains the average amounts of API released in each solvent. The ground tablets remained resistant to the release of too much dose in various solvents.

Table 27.10: Extraction results -% of API released after minutes

<td rowspan="2"></td><td colspan="3">% hydrochloride released</td>

<td colspan="2">oxycodone</td><td> 1</td>

<td>Ground tablets with reconstitution</td><td>OxyContin</td><td>Ex. 7.2</td><td>Ex. 14.5</td>

<td>extraction jug</td><td>(10 mg)</td><td>(10 mg)</td><td>(40 mg)</td>

<td>Control - intact</td><td> 34</td><td> 19</td><td> 19</td>

<td>tablets (release after</td><td></td><td></td><td></td>

minutes) 1 in relation to the content declared on the label

Level 3 research

Level 3 of the study involved extraction for 60 minutes at room temperature (room temperature) and 50 ° C.

Level 3 - results - advanced extraction (room temperature, 50 ° C)

Tablets according to examples 7.2 and 14.5 were ground in a coffee grinder (as in the method described above) and then vigorously shaken for 60 minutes in various solvents

270 in room temperature. In addition, the ground tablets were extracted in various solvents at 50 ° C for 60 minutes using a water bath. Agitators were placed in each vial to mix the liquid. After 1 hour of extraction, the milled tablets retained some controlled release properties, providing protection against complete dose release. Extraction at elevated temperatures is not much more effective due to the increased solubility of the tablet matrix at higher temperatures in most of the solvents tested. In Table 27.11, the amounts released from tablets according to Examples 7.2 and 14.5 and from crushed 10 mg OxyContin ™ tablets after a 15-minute extraction were compared.

Table 27.11: Results of advanced extraction -% 15 API released within 60 minutes

<td>ground pills By virtue of</td><td colspan="3">% oxycodone released1 (room temperature)</td><td colspan="2">% released (50 ° C)</td><td>oxycodone1</td>

<td>szczalni</td><td>* OxyContin</td><td>Ex.</td><td>Ex.</td><td>* OxyConti</td><td>Ex</td><td>Ex.</td>

<td>to extraction</td><td>(10 mg)</td><td>7.2 (10 mg)</td><td>14.5 (40 mg)</td><td>n 10 mg</td><td>7.2 (10 mg)</td><td>14.5 (40 mg)</td>

<td>40% ethanol (V)</td><td> 101</td><td> 55</td><td> 56</td><td>N / D</td><td> 61</td><td> 65</td>

<td>100% ethanol</td><td> 96</td><td> 66</td><td> 61</td><td></td><td> 78</td><td> 67</td>

<td>Oil kitchen</td><td> 79</td><td> 2</td><td> 4</td><td></td><td> 7</td><td> 4</td>

<td>70% isopropanol (V)</td><td> 97</td><td> 48</td><td> 35</td><td></td><td> 49</td><td> 69</td>

<td>Acetone</td><td> 60</td><td> 37</td><td> 38</td><td></td><td>N / D</td><td>N / D</td>

271

<td>methanol</td><td> 92</td><td> 71</td><td> 82</td><td> 72</td><td> 61</td>

<td>Acetate</td><td> 83</td><td> 25</td><td> 5</td><td> 39</td><td> 30</td>

<td>ethyl</td><td></td><td></td><td></td><td></td><td></td>

<td>Ether</td><td> 78</td><td> 10</td><td> 2</td><td>N / D</td><td>N / D</td>

Control

- no 34 tablets (releases not after 45 minutes) 1 in relation to the content declared on the label; * Results for crushed OxyContin after 15 minutes, for comparison.

Example 28

In Example 28, randomized, open, one-site, single-dose, two-type, two-time, cross-sectional studies in healthy people were performed to evaluate the bioequivalence of oxycodone hydrochloride (10 mg) according to Example 14.1 on the market OxyContin® (10 mg) in the fed state.

The tested preparations were as follows:

Test preparation: 1x tablet (10 mg oxycodone hydrochloride) according to example 14.1

Reference preparation: 1x 10 mg OxyContin® tablet

All preparations were administered orally with 8 oz. (240 ml) of water as a single dose in a fed state.

Because this study was conducted in healthy people, the opioid antagonist naltrexone hydrochloride was administered to minimize the adverse effects caused by the opioid.

Selection of study participants

Classification procedures were carried out as described in Example 26.

272 section 11 of the exclusion criteria for this study referred to "refusing to refrain from taking food for hours after administration of study drugs and refraining from taking complete caffeine or xanthine during each study period".

Patients who met all inclusion criteria and none of the exclusion criteria were randomly selected for the study. About 84 patients were expected to be randomly selected, with 76 patients eventually completing the study.

Inclusion procedures

Reporting procedures were performed on the 1st day of period 1 and at reporting in each study period as described in Example 26. Prior to dose administration (day 1 only, period 1), samples were taken for laboratory analysis (hematology, biochemistry and urine analysis) after measurement vital signs and SOP2 on an empty stomach, after fasting overnight (10 hours).

Prior to administration of the first dose in period 1, patients were randomly assigned a formulation receiving sequence according to a random allocation schedule (RAS) as described in Example 26. The preparation sequences for this study are shown in Table 28.1.

Table 28.1

<td></td><td>Period 1</td><td>Period 2</td>

<td>Sequence</td><td colspan="2">Preparation</td>

<td> 1</td><td>1x OxyContin® 10 mg</td><td>1x preparation according to example 1411</td>

<td> 2</td><td>1x preparation according to example 14.1</td><td>1x OxyContin® 10 mg</td>

Research procedures

The study included two study periods, each involving a single dose. There was a washout period of at least six days between dosing in each study period. During each period, patients were confined to the study site from the day prior to study drug administration and for 48 hours after study drug administration, and

273 patients returned to the study site for procedures at 72 hours.

In each study period, after a 10-hour fasting overnight, patients received a standard meal (FDA high-fat breakfast) 30 minutes prior to administration of the formulation of Example 14.1 or 10 mg OxyContin® tablets with 240 ml water. No food was given for at least 4 hours after dosing.

Patients received 25 mg naltrexone hydrochloride tablets at -12, 0, and 12 hours relative to the formulation of Example 14.1 or OxyContin®.

Patients were in an upright or upright sitting position while receiving a dose of Example 14.1 or OxyContin®. Patients remained upright for a minimum of 4 hours.

Fasting was not required for testing on days when no doses were taken.

During the study, adverse events and associated treatment, and vital signs (including blood pressure, body temperature, pulse rate and respiratory rate) were recorded and SPO monitored2.

Blood samples for determination of oxycodone plasma concentration were taken from each patient before the dose and 0.5, 1,

1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 28, 32, 36, 48, and 72 hours after dosing in each research period.

For each sample, 6 ml of venous blood was collected via a permanent catheter and / or direct vein puncture into tubes containing K2EDTA as an anticoagulant. Oxycodone plasma concentrations were quantified using a standardized method combining liquid chromatography with mass spectrometry.

The completion procedures were carried out as described in Example 26.

The results of this study are presented in Table 28.2.

274

Table 28.2:

<td colspan="7">Statistical results of pharmacokinetic parameters of preparations oxycodone: bioavailability of the preparation according to example 14.1 in relative to OxyContin® 10 mg in the fed state (Population: full analysis)</td>

<td></td><td colspan="4">Average Lsand</td><td rowspan="2">Prep. test / referencec</td><td rowspan="2">90% compartment trustd</td>

<td>Parameter</td><td>N</td><td>(Test)b</td><td>N</td><td>(Reference) b</td>

<td>AUCinf (Ng * hr. / Ml)</td><td> 79</td><td> 139</td><td> 81</td><td> 146</td><td> 95,6</td><td> (93,73; 97,53)</td>

<td colspan="7">and Average calculated by the method of least squares from using ANOVA. Natural logarithm (ln) of means parameters were calculated by transforming ln from means of back to the linear scale, i.e., to geometric means. b Test = tablet according to example 14.1; Reference = 10 mg OxyContin® tablet.c Ratio of average parameters to transformed parameters in ln (expressed as a percentage). Transformed into LN ratio transformed back to a linear scale.d 90% confidence interval for the ratio of average parameters (expressed as a percentage). Transformed into ln borders the confidence interval has been transformed back to scale liner.</td>

The results show that the tablets of Example 14.1 are bioequivalent to 10 mg OxyContin® tablets in the fed state.

Example 29

In Example 29, randomized, open, single-site, single-dose, two types of preparations, two periods of time, cross-testing was performed

275 in healthy people, to assess oxycodone hydrochloride (10 mg) as described in Example 14.1 against the commercially available OxyContin® (10 mg) when fasted.

The tested preparations were as follows:

Test preparation: 1x tablet according to example 14.1 (10mg oxycodone hydrochloride)

Reference preparation: 1x 10 mg OxyContin® tablet

All preparations were administered orally with 8 oz. (240 ml) of water as a single fasted dose.

Because this study was conducted in healthy people, the opioid antagonist naltrexone hydrochloride was administered to minimize the adverse effects caused by the opioid.

Selection of study participants

Classification procedures were carried out as described in Example 26.

Patients who met the inclusion criteria described in Example 26 were included in the study. Potential patients were excluded from the study according to the exclusions described in Example 26.

Patients meeting all criteria not meeting any of the exclusion criteria were randomly selected for the study. About 84 patients were expected to be randomly selected, with 76 patients eventually completing the study.

Reporting procedures

with inclusion criteria and

276

Table 29.1

<td></td><td>Period 1</td><td></td><td>Period 2</td>

<td>Sequence</td><td></td><td>Preparation</td><td></td>

1x OxyContin® 10 mg 1x formulation according to example 14.1

1x formulation according to 1x OxyContin® 10 mg of Example 14.1

Research procedures

In each study period, patients were administered the formulation of Example 14.1 or 10 mg OxyContin® tablets with 240 mL water, after a 10-hour fasting overnight. Patients still had to refrain from taking food for at least 4 hours after taking the dose.

Patients received 25 mg naltrexone hydrochloride tablets at -12, 0, and 12 hours relative to the formulation of Example 14.1 or OxyContin®.

Patients were in an upright or upright sitting position while receiving a dose of Example 14.1 or OxyContin®. Patients remained upright for a minimum of 4 hours.

Samples for analysis in the clinical laboratory (day -1) were taken from patients who were fasting, i.e. not taking food for at least 10 hours (the term food does not include water). Fasting was not required for testing on days when no doses were taken.

During the study, adverse events and associated treatment, as well as vital signs (including blood pressure, body temperature, pulse rate and respiratory rate) were recorded and SPO monitored2.

Blood samples for determination of oxycodone plasma concentration were taken from each patient before the dose and 0.5, 1,

277

1,5, 2, 2,5, 3, 3,5, 4, 4,5, 5, 6, 8, 10, 12, 16, 24, 28, 32,

36, 48, and 72 hours after dosing in each study period.

For each sample, 6 ml of venous blood was withdrawn via a permanent catheter and / or by direct puncture of the vein into tubes containing K2EDTA as an anticoagulant. Oxycodone plasma concentrations were quantified using a standardized method combining liquid chromatography with mass spectrometry.

The completion procedures were carried out as described in Example 26.

The results of this study are presented in Table 29.2.

Table 29.2:

<td></td><td colspan="4">LS averageand</td><td rowspan="2">Prep. test / referencec</td><td rowspan="2">90% compartment trustd</td>

<td>Parameter</td><td>N</td><td>(Test)b</td><td>N</td><td>(Will no)b</td>

<td>AUCinf (Ng * hr. / Ml)</td><td> 81</td><td> 108</td><td> 81</td><td> 110</td><td> 98,0</td><td> (94,94, 101,19)</td>

278 transformed back to a linear scale.

d 90% confidence interval for the ratio of average parameters (expressed as a percentage). Transformed into ln, the confidence interval was transformed back to a linear scale.

The results show that the tablets of Example 14.1 are bioequivalent to 10 mg OxyContin® tablets in the fasted state.

Example 30

In Example 30, a randomized, open, one-site, single-dose, two-way, two-time cross-sectional study was performed in healthy people to assess the bioequivalence of oxycodone hydrochloride (40 mg) as per Example 14.5 OxyContin® (40 mg) in the market after a meal.

The tested preparations were as follows:

Test preparation: 1x tablet according to example 14.5 (40 mg oxycodone hydrochloride)

Reference preparation: 1x 40 mg tablet OxyContin®

All preparations were administered orally with 8 oz. (240 ml) of water as a single dose in a fed state.

Because this study was conducted in healthy people, the opioid antagonist naltrexone hydrochloride was administered to minimize the adverse effects caused by the opioid.

Selection of study participants

Classification procedures were carried out as described in Example 26.

Patients who met the inclusion criteria described in Example 26 were included in the study. Potential patients were excluded from the study according to the exclusion criteria described in Example 26, except that section 11 of the exclusion criteria for this study referred to "refusing to refrain from taking food for 4 hours after administration of study drugs and abstaining from total taking caffeine or xanthine during each reduction period. "

279

Reporting procedures

Prior to administration of the first dose in period 1, patients were randomly assigned to receive preparations according to a random allocation schedule (RAS) as described in Example 26. The preparation sequences for this study are shown in Table 30.1.

Table 30.1

<td></td><td>Period 1</td><td>Period 2</td>

<td>Sequence</td><td colspan="2">Preparation</td>

<td> 1</td><td>1x OxyContin® 40 mg</td><td>1x preparation according to example 14.5</td>

<td> 2</td><td>1x preparation according to example 14.5</td><td>1x OxyContin® 40 mg</td>

Research procedures

The study included two study periods, each involving a single dose. There was a washout period of at least six days between dosing in each study period. During each period, patients were confined to the study site from the day prior to study medication administration and for 48 hours after study medication administration, and patients returned to study site for procedures at 72 hours.

In each study period, after a 10-hour fasting overnight, patients received a standard meal (FDA high-fat breakfast) 30 minutes prior to administration of the preparation of Example 14.5 or 40 mg tablets

280

OxyContin® with 240 ml of water. No food was given for at least 4 hours after dosing.

Patients received 50 mg naltrexone hydrochloride tablets at -12, 0, 12, 24, and 36 hours relative to the formulation of Example 14.5 or OxyContin®.

Patients were in an upright or upright sitting position while receiving a dose of the formulation of Example 14.5 or OxyContin®. Patients remained upright for a minimum of 4 hours.

Fasting was not required for testing on days when no doses were taken.

During the study, adverse events and associated medications, and vital signs (including blood pressure, body temperature, pulse rate, and respiration rate) were recorded and SPO monitored2.

Blood samples for determination of oxycodone plasma concentration were taken from each patient before the dose and 0.5,

1,1,5, 2, 2,5, 3, 3,5, 4, 4,5, 5, 6, 8, 10, 12, 16, 24, 28, 32, 36, 48, and 72 hours after dosing at each study period.

The completion procedures were carried out as described in Example 26.

The results of this study are shown in Table 30.2.

281

Table 30.2:

<td colspan="7">Statistical results of pharmacokinetic parameters of preparations oxycodone: bioavailability of the preparation according to example 14.5 in relative to OxyContin® 40 mg in a fed state (population: full analysis)</td>

<td></td><td colspan="4">LS averageand</td><td rowspan="2">Prep. test / referencec</td><td rowspan="2">90% compartment trustd</td>

<td>Parameter</td><td>N</td><td>(Test)b</td><td>N</td><td>(Reference) b</td>

<td>ANDUCinf (Ng * hr. / Ml)</td><td> 76</td><td> 516</td><td> 80</td><td> 558</td><td> 92,4</td><td> (90, 00, 94,96)</td>

<td colspan="7">and Average calculated by the method of least squares from using ANOVA. Natural logarithm (ln) of means parameters were calculated by transforming ln from means of back to the linear scale, i.e., to geometric means. b Test = tablet according to example 14.5; Reference = 40 mg OxyContin® tablet.c Ratio of average parameters to transformed parameters in ln (expressed as a percentage). Transformed into LN ratio transformed back to a linear scale.d 90% confidence interval for the ratio of average parameters (expressed as a percentage). Transformed into ln borders the confidence interval has been transformed back to scale liner.</td>

The results show that the tablets of Example 14.5 are bioequivalent to 40 mg OxyContin® tablets in the fed state.

Example 31

In Example 31, a randomized, open, one-site, single-dose, two types of preparation, two periods of time, cross-over study was performed

282 in healthy people, to evaluate oxycodone hydrochloride (40 mg) as described in Example 14.5 against the commercially available OxyContin® (40 mg) when fasted.

The tested preparations were as follows:

Test preparation: 1x tablet according to example 14.5 (40mg oxycodone hydrochloride)

Reference preparation: 1x 40 mg tablet OxyContin®

All preparations were administered orally with 8 oz. (240 ml) of water as a single fasted dose.

Because this study was conducted in healthy people, the opioid antagonist naltrexone hydrochloride was administered to minimize the adverse effects caused by the opioid.

Selection of study participants

Screening procedures were carried out as described in Example 26.

Patients who met the inclusion criteria described in Example 26 were included in the study. Potential patients were excluded from the study according to the exclusions described in Example 26.

Reporting procedures

with inclusion criteria and

283

Table 31.1

<td></td><td>Period 1</td><td></td><td>Period 2</td>

<td>Sequence</td><td></td><td>Preparation</td><td></td>

1x OxyContin® 40 mg 1x formulation according to example 14.5

1x formulation according to 1x OxyContin® 40 mg of example 14.5

Research procedures

The study included two study periods, each involving a single dose. There was a washout period of at least six days between dosing in each study period. During each period, patients were confined to the study site from the day prior to study medication administration and for 48 hours after study medication administration, and patients returned to study site for procedures at 72 hours.

In each study period, patients were administered the formulation of Example 14.5 or 40 mg OxyContin® tablets with 240 ml water, after a 10-hour fasting overnight. Patients still had to refrain from taking food for at least 4 hours after taking the dose.

Patients received 50 mg naltrexone hydrochloride tablets at -12, 0, 12, 24, and 36 hours relative to the formulation of Example 14.5 or OxyContin®.

Patients were in an upright or upright sitting position while receiving a dose of the formulation of Example 14.5 or OxyContin®. Patients remained upright for a minimum of 4 hours.

Fasting was not required for testing on days when no doses were taken.

Blood samples for determination of oxycodone plasma concentration were taken from each patient before the dose and 0.5, 1,

1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 28, 32, 36, 48, and 72 hours after dosing in each research period.

284

The completion procedures were carried out as described in Example 26.

The results of this study are shown in Table 31.2.

Table 31.2:

<td colspan="7">Statistical results of pharmacokinetic parameters of preparations oxycodone: bioavailability of the preparation according to example 14 in relative to OxyContin® 40 mg in an empty stomach (population: full analysis)</td>

<td></td><td colspan="4">LS averageand</td><td rowspan="2">Prep. test / referencec</td><td rowspan="2">90% compartment trustd</td>

<td>Parameter</td><td>N</td><td>(Test)b</td><td>N</td><td>(Reference) b</td>

<td>AUCinf (Ng * hr. / Ml)</td><td> 85</td><td> 444</td><td> 82</td><td> 468</td><td> 94,8</td><td> (92,42, 97,24)</td>

<td colspan="7">and Average calculated by the method of least squares from using ANOVA. Natural logarithm (ln) of means parameters were calculated by transforming ln from means of back to the linear scale, i.e., to geometric means. b Test = tablet according to example 14.5; Reference = 40 mg OxyContin® tablet.c Ratio of average parameters to transformed parameters in ln (expressed as a percentage). Transformed into LN ratio transformed back to a linear scale.d 90% confidence interval for the ratio of average parameters (expressed as a percentage). Transformed into ln borders</td>

285 the confidence interval has been transformed back to a linear scale.

The results show that the tablets of Example 14.5 are bioequivalent to 40 mg OxyContin® tablets in the fasted state.

286

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CO6160317A2	Colombia	A2	2010-05-20
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HK1138498A	Hong Kong, China	A	2010-08-27
HK1138498A1	Hong Kong, China	A1	2010-08-27
CA2661573C	Canada	C	2010-10-26
RS51162B	Serbia	B	2010-10-31
GT200900023A	Guatemala	A	2010-11-05
EP2070538B1	European Patent Office (EPO)	B1	2010-12-01
EP2082742B1	European Patent Office (EPO)	B1	2010-12-01
AT489953T	Austria	T	2010-12-15
AT489954T	Austria	T	2010-12-15
ATE489953T1	Austria	T1	2010-12-15
ATE489954T1	Austria	T1	2010-12-15
DE602007010963D1	Germany	D1	2011-01-13
DE602007010974D1	Germany	D1	2011-01-13
AT11571U1	Austria	U1	2011-01-15
EP2080514B1	European Patent Office (EPO)	B1	2011-02-23
PT2070538E	Portugal	E	2011-03-02
PT2082742E	Portugal	E	2011-03-02
EP2292229A1	European Patent Office (EPO)	A1	2011-03-09
EP2292230A1	European Patent Office (EPO)	A1	2011-03-09
AT499101T	Austria	T	2011-03-15
ATE499101T1	Austria	T1	2011-03-15
DK2070538T3	Denmark	T3	2011-03-21
DK2082742T3	Denmark	T3	2011-03-21
HRP20110130T1	Croatia	T1	2011-03-31
SI2070538T1	Slovenia	T1	2011-03-31
SI2082742T1	Slovenia	T1	2011-03-31
DE602007012747D1	Germany	D1	2011-04-07
EP2311459A1	European Patent Office (EPO)	A1	2011-04-20
ES2357376T3	Spain	T3	2011-04-25
HRP20110147T1	Croatia	T1	2011-04-30
TWI341213B	Taiwan Province of China	B	2011-05-01
ES2358066T3	Spain	T3	2011-05-05
DK2080514T3	Denmark	T3	2011-05-16
PT2080514E	Portugal	E	2011-05-24
PL2070538T3This record	Poland	T3	2011-05-31
PL2082742T3	Poland	T3	2011-05-31
SI2080514T1	Slovenia	T1	2011-05-31
ES2361721T3	Spain	T3	2011-06-21
HRP20110375T1	Croatia	T1	2011-06-30
EP2343071A1	European Patent Office (EPO)	A1	2011-07-13
SA07280459B1	Saudi Arabia	B1	2011-07-20
SA2709B1	Saudi Arabia	B1	2011-07-20
AU2007287341B2	Australia	B2	2011-08-25
RS51591B	Serbia	B	2011-08-31
AU2011213804A1	Australia	A1	2011-09-08
PL2080514T3	Poland	T3	2011-09-30
DOP2011000255A	Dominican Republic	A	2011-10-15
UA96306C2	Ukraine	C2	2011-10-25
ME01187B	Montenegro	B	2011-10-31
RS51664B	Serbia	B	2011-10-31
RS51678B	Serbia	B	2011-10-31
KR20110119847A	Republic of Korea	A	2011-11-02
EP2384754A1	European Patent Office (EPO)	A1	2011-11-09
EP2399579A1	European Patent Office (EPO)	A1	2011-12-28
EP2399580A1	European Patent Office (EPO)	A1	2011-12-28

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Tamper resistant oral pharmaceutical dosage forms comprising an opioid analgesic

Abstract

Term

Priority claims8

Members424

Numbers

Titles2

Classification