RS51162B

Tamper resistant oral pharmaceutical dosage forms comprising an opioid analgesic

Abstract

The process of preparing a solid oral pharmaceutical dosage form, extended release, characterized in that it comprises at least the steps of: (a) combining at least (1) at least one polyethylene oxide having, based on rheological measurements, an morarnu weight of at least 1,000,000, and (2) at least one active agent, to form a composition; (b) shaping the composition, the formation of formulations of the extended release matrix; and (c) curing said matrix formulation for extended release, comprising at least a curing step of subjecting the formulations of the extended release matrix jenajmanje a temperature equal to the softening temperature of said polyethylene oxide for a time period of at least about 1 min.Prijava 58 further comprising the dependent claims.

RS51162B, drawing sheet 1 — Sheet 1 of 27

Term

0.9 yearsleft in the term

Expires 24 August 2027.

59 claims: 4 independent, 55 dependent

1
ΡΑΤΕΝΤΝΙ ZAHTEVI 1. Proces za dobijanje čvrstog oralnog farmaceutskog oblika za doziranje sa produženim oslobađanjem, naznačen time, što se sastoji najmanje od koraka:(a) kombinovanja bar (1) najmanje jednog polietilen-oksida, koji na osnovu reoloških merenja ima morarnu masu od najmanje 1,000,000, i (2) najmanje jednog aktivnog agensa, formirajući kompoziciju;(b) oblikovanja ove kompozicije, formiranjem formulacije matrice za produženo oslobađanje;i (c) očvršćavanja pomenute formulacije matrice za produženo oslobađanje, koje se sastoji najmanje od koraka očvršćavanja, podvrgavanjem formulacije matrice za produženo oslobađanje temperaturi koja je najmanje jednaka temperaturi omekšavanja pomenutog polietilenoksida, tokom perioda vremena od najmanje oko 1 min.
2
Proces prema Zahtevu 1, naznačen time, što se u koraku c) formulacija matrice za produženo oslobađanje podvrgava temperaturi koja je najmanje jednaka temperaturi omekšavanja pomenutog polietilen-oksida, tokom perioda vremena od najmanje oko 5 min.
3
Proces prema Zahtevu 1, naznačen time, što se u koraku c) formulacija matrice za produženo oslobađanje podvrgava temperaturi koja je najmanje jednaka 225 51162 Β temperaturi omekšavanja pomenutog polietilen-oksida, tokom perioda vremena od najmanje oko 15 min.
4
Proces prema Zahtevu 1, 2 ili 3, naznačen time, što se u koraku b) kompozicija oblikuje, formiranjem formulacije matrice za produženo oslobađanje u obliku tablete.
5
Proces prema Zahtevu 4, naznačen time, što se u koraku b) kompozicija oblikuje direktnim komprimovanjem pomenute kompozicije.
6
Proces prema bilo kom od Zahteva 1 do 5, naznačen time, što se u koraku c) formulacija matrice za produženo oslobađanje podvrgava temperaturi od najmanje oko 60°C, ili najmanje oko 62°C, poželjno najmanje oko 68°C, najmanje oko 70°C, najmanje oko 72°C, ili najmanje oko 75°C.
7
Proces prema Zahtevu 6, naznačen time, što se formulacija matrice za produženo oslobađanje podvrgava temperaturi od oko 62°C do oko 90°C, od oko 65°C do oko 90°C, ili od oko 68°C do oko 90°C.
8
Proces prema Zahtevu 6, naznačen time, što se formulacija matrice za produženo oslobađanje podvrgava temperaturi od najmanje oko 62°C ili najmanje oko 68°C, tokom perioda vremena od oko 1 min do oko 5 h, ili od oko 5 min do oko 3 h.
9
Proces prema Zahtevu 6, naznačen time, što se formulacija matrice za produženo oslobađanje podvrgava temperaturi od najmanje oko 62°C ili najmanje oko 68°C, tokom perioda vremena od najmanje oko 15 min.
10
Proces prema Zahtevu 6, naznačen time, što se oblik za doziranje podvrgava temperaturi od najmanje oko 60°C, ili najmanje oko 62°C, poželjno najmanje oko 68°C, najmanje oko 70°C, najmanje oko 72°C ili najmanje oko 75°C, ili od oko 62°C 226 51162 Β do oko 85°C, tokom perioda vremena od najmanje oko 15 min, najmanje oko 30 min, najmanje oko 60 min, ili najmanje oko 90 min.
11
Proces prema bilo kom od Zahteva 1 do 10, naznačen time, što se formulacija matrice za produženo oslobađanje u koraku c) podvrgava temperaturi od najmanje oko 60°C, ili najmanje oko 62°C, ali manjoj od oko 90°C, ili manjoj od oko 80°C.
12
Proces prema bilo kom od Zahteva 1 do 11, naznačen time, što se korak očvršćavanja odigrava na temperaturi unutar neke sušnice.
13
Proces prema Zahtevu 12, naznačen time, što temperaturu koraka c) predstavlja ciljana temperatura unutar sušnice, a pri tome korak očvršćavanja počinje kada temperatura unutar sušnice dostigne pomenutu temperaturu, dok se korak očvršćavanja završava ili kada prestane zagrevanje ili kada se bar smanji, pa temperatura unutar sušnice padne za više od oko 10°C, ili ispod oko 62°C, kod profila temperature nalik platou, ili temperatura unutar sušnice padne ispod pomenute temperature, kod profila temperature nalik paraboli ili trouglu.
14
Proces prema Zahtevu 13, naznačen time, što profil temperature tokom koraka očvršćavanja pokazuje oblik nalik platou, a pri tome je poželjno da pomenuta temperatura bude najmanje oko 68°C, a vreme očvršćavanja poželjno je da bude unutar opsega od oko 30 min do oko 20 h.
15
Proces prema bilo kom od Zahteva 1 do 11, naznačen time, što se korak očvršćavanja c) odigrava u nekom konvektivnom uređaju za očvršćavanje, koga karakterišu ulazna temperatura vazduha, izlazna temperatura vazduha i/ili temperaturna proba.
16
Proces prema Zahtevu 15, naznačen time, što se temperatura koraka c) definiše kao ciljana temperatura ulaznog vazduha, a pri tome korak očvršćavanja počinje kada temperatura ulaznog vazduha dostigne pomenutu temperaturu, dok se 227 51162 Β korak očvršćavanja završava, ili kada prestane zagrevanje, ili kada se bar smanji, pa zatim temperatura ulaznog vazduha padne ispod pomenute temperature, ili za više od oko 10°C, ili ispod oko 62°C, kada je profil temperature nalik platou, ili kada temperatura ulaznog vazduha padne ispod pomenute temperature, kada je profil temperature nalik paraboli ili trouglu.
17
Proces prema Zahtevu 16, naznačen time, što profil temperature tokom когака očvršćavanja pokazuje oblik nalik platou, a pri tome poželjno je da pomenuta temperatura bude najmanje oko 72°C, a vreme očvršćavanja poželjno je bude unutar opsega od oko15 min do oko 2 h.
18
Proces prema Zahtevu 15, naznačen time, što temperatura koraka očvršćavanja c) predstavlja ciljanu temperaturu izlaznog vazduha, a pri tome когак očvršćavanja počinje kada temperatura izlaznog vazduha dostigne pomenutu temperaturu, dok se korak očvršćavanja završava, ili kada zagrevanje prestane, ili se bar smanji, pa zatim temperatura izlaznog vazduha padne ispod pomenute temperature za više od oko 10°C, ili ispod oko 62°C, kada je profil temperatura nalik platou, ili kada temperatura izlaznog vazduha padne ispod pomenute temperature, kada je profil temperate nalik paraboli ili trouglu.
19
Proces prema Zahtevu 18, naznačen time, što profil temperature tokom когака očvršćavanja pokazuje oblik nalik platou, a pri tome poželjno je da pomenuta temperatura bude najmanje oko 68’C, a vreme očvršćavanja poželjno je da bude unutar opsega od oko 1 min do oko 2 h.
20
Proces prema Zahtevu 15, naznačen time, što temperaturu koraka c) predstavlja ciljana temperatura formulacije matrice za produženo oslobađanje, a pri tome korak očvršćavanja počinje kada temperatura formulacije matrice za produženo oslobađanje dostigne pomenutu temperaturu, dok se korak očvršćavanja završava ili kada zagrevanje prestane ili kada se bar smanji, pa zatim temperatura formulacije matrice za produženo oslobađanje padne ispod pomenute temperature za više od 228 51162 Β око 10°С, ili ispod oko 62°C, kada je profil temperature nalik platou, ili kada temperatura formulacije matrice za produženo oslobađanje padne ispod pomenute temperature, kada je profil temperature nalik paraboli ili trouglu.
21
Proces prema Zahtevu 15, naznačen time, što temperaturu koraka c) predstavlja ciljana temperatura, koja se meri upotrebom temperaturne probe, a pri tome korak očvršćavanja počinje kada temperatura izmerena upotrebom temperaturne probe dostigne pomenutu temperaturu, dok se korak očvršćavanja završava, ili kada zagrevanje prestane, ili se bar smanji, pa temperatura merena upotrebom temperaturne probe zatim padne ispod pomenute temperature za više od oko 10°C, ili ispod oko 62°C, kada je profil temperature nalik platou, ili kada temperatura merena upotrebom temperaturne probe padne ispod pomenute temperature, kada je profil temperature nalik paraboli ili trouglu.
22
Proces prema Zahtevu 21, naznačen time, što profil temperature tokom koraka očvršćavanja pokazuje oblik nalik platou, i pri tome je poželjno da pomenuta temperatura bude najmanje oko 68°C, a vreme očvršćavanja poželjno je da bude unutar opsega od oko15 min do oko 2 h.
23
Proces prema bilo kom od Zahteva 1 do 11 i 15 do 22, naznačen time, što se korak očvršćavanja c) odigrava u sloju formulacija matrice za produženo oslobađanje koje se slobodno kreću.
24
Proces prema Zahtevu 23, naznačen time, što se očvršćavanje odigrava u sudu za oblaganje.
25
Proces prema bilo kom od Zahteva 1 do 24, naznačen time, što sadrži još i korak oblaganja očvrsle formulacije matrice za produženo oslobađanje.
26
Proces prema Zahtevu 25, naznačen time, što se sastoji od koraka:(a) kombinovanja bar 229 51162 Β (1) najmanje jednog polietilen-oksida koji, na osnovu reoloških merenja, ima molarnu masu od najmanje 1,000,000, i (2) najmanje jednog aktivnog agensa, formirajući kompoziciju;(b) oblikovanja pomenute kompozicije formiranjem formulacije matrice za produženo oslobađanje u obliku tablete, direktnim komprimovanjem;(c) očvršćavanja pomenute tablete - podvrgavanjem sloja tableta koje se slobodno kreću temperaturi od oko 62°C do oko 90°C, tokom perioda vremena od najmanje oko 1 min, u sudu za oblaganje, i - zatim hlađenja sloja tableta koje se slobodno kreću na temperaturu ispod oko 50°C;i zatim (d) oblaganja oblika za doziranje u pomenutom sudu za oblaganje.
27
Proces za dobijanje čvrstog oralnog oblika za doziranje sa produženim oslobađanjem, naznačen time, što se sastoji najmanje od koraka:(a) kombinovanja bar (1) najmanje jednog polietilen-oksida koji, na osnovu reoloških merenja, ima molarnu masu od najmanje 1,000,000, i (2) najmanje jednog aktivnog agensa, formirajući kompoziciju;(b) oblikovanja ove kompozicije formiranjem formulacije matrice za produženo oslobađanje;i (c) očvršćavanja pomenute formulacije matrice za produženo oslobađanje, koje se sastoji najmanje od koraka očvršćavanja, pri čemu se pomenuti polietilen-oksid bar delimično istopi.
28
Proces prema Zahtevu 27, naznačen time, što se kompozicija u koraku b) oblikuje formiranjem formulacije matrice za produženo oslobađanje u obliku tablete. 230 51162 Β
29
Proces prema Zahtevu 28, naznačen time, što se kompozicija u koraku b) oblikuje direktnim komprimovanjem pomenute kompozicije.
30
Proces prema Zahtevu 29, naznačen time, što se istopi najmanje oko 20%, najmanje oko 40%, ili najmanje oko 75% polietilen-oksida visoke molarne mase.
31
Proces prema Zahtevu 30, naznačen time, što se istopi oko 100% polietilenoksida visoke molarne mase.
32
Proces prema bilo kom od Zahteva 27 do 31, naznačen time, što se когак očvršćavanja c) odigrava u nekoj sušnici.
33
Proces prema bilo kom od Zahteva 27 do 31, naznačen time, što se korak očvršćavanja c) odigrava u nekom konvektivnom uređaju za očvršćavanje.
34
Proces prema bilo kom od Zahteva 27 do 31, naznačen time, što se korak očvršćavanja c) odigrava u sloju formulacija matrice za produženo oslobađanje koje se slobodno kreću.
35
Proces prema Zahtevu 34, naznačen time, što očvršćavanje odigrava u nekom sudu za oblaganje.
36
Proces prema bilo kom od Zahteva 27 do 35, naznačen time, što se sastoji još od koraka oblaganja očvrsle formulacije matrice za produženo oslobađanje.
37
Proces prema bilo kom od Zahteva 1 do 36, naznačen time, što aktivni agens predstavlja neki opijatni analgetik.
38
Proces prema Zahtevu 37, naznačen time, što se opijatni analgetik bira iz grupe koju čine alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, 231 51162 Β dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimetilthiambutene, dioxaphetyl butyrat, dipipanone, eptazocine, ethoheptazine, etilmetilthiambutene, etilmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl i derivati, hydrocodone, hydromorphone, hidroksipethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, охутогрћопе, papaveretum, pentazocine, phenadoksone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, njihove farmaceutski prihvatljive soli, hidrati i solvati, smeše bilo kog od prethodnih.
39
Proces prema Zahtevu 37, naznačen time, što se opijatni analgetik bira iz grupe koju čine codeine, morphine, oxycodone, hydrocodone, hydromorphone, ili охутогрћопе ili njihove farmaceutski prihvatljive soli, hidrati i solvati, i smeše bilo kog od prethodnih.
40
Proces ргета Zahtevu 39, naznačen time, što opijatni analgetik predstavlja oxycodone hidrohlorid, a oblik za doziranje sadrži od oko 5 mg do oko 500 mg oxycodone hidrohlorida.
41
Proces prema Zahtevu 40, naznačen time, što oblik za doziranje sadrži 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 60 mg, ili 80 mg, 90 mg, 120 mg ili 160 mg oxycodone hidrohlorida.
42
Proces prema bilo kom od Zahteva 39 do 41, naznačen time, što aktivni sastojak predstavlja oxycodone hidrohlorid, a oxycodone hidrohlorid poseduje nivo 14-hidroksikodeinona koji je manji od oko 25 ppm, poželjno manji od oko 15 ppm, manji od oko 10 ppm, ili manji od oko 5 ppm. 232 51162 Β
43
Proces prema Zahtevu 37, naznačen time, što opijatni analgetik predstavlja oxymorphone hidrohlorid, a oblik za doziranje sadrži od oko 1 mg do oko 500 mg oxymorphone hidrohlorida.
44
Proces prema Zahtevu 43, naznačen time, što oblik za doziranje sadrži 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30, mg, 40 mg, 45 mg, 60 mg, ili 80 mg, 90 mg, 120 mg ili 160 mg of охутогрћопе hidrohlorida.
45
Proces prema Zahtevu 37, naznačen time, što opijatni analgetik predstavlja hydromorphone hidrohlorid, a oblik za doziranje sadrži od oko 1 mg do oko 100 mg hydromorphone hidrohlorida.
46
Proces prema Zahtevu 45, naznačen time, što oblik za doziranje sadrži 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, 48 mg ili 64 mg hydromorphone hidrohlorida.
47
Proces prema bilo kom od Zahteva 1 do 46, naznačen time, što najmanje jedan polietilen-oksid, na osnovu reoloških merenja, ima približnu molarnu masu od 2,000,000 do 8,000,000.
48
Proces prema Zahtevu 47, naznačen time, što najmanje jedan polietilen-oksid koji, na osnovu reoloških merenja, ima približnu molarnu masu 2,000,000, 4,000,000, 7,000,000 ili 8,000,000.
49
Proces prema bilo kom od Zahteva 1 do 48, naznačen time, što ova kompozicija sadrži još najmanje jedan polietilen-oksid koji, na osnovu reoloških merenja, ima molarnu masu manju od 1,000,000.
50
Proces prema Zahtevu 49, naznačen time, što ova kompozicija sadrži još najmanje jedan polietilen-oksid koji, na osnovu reoloških merenja, ima približnu molarnu masu od 100,000 do 900,000. 233 51162 Β
51
Proces prema Zahtevu 50, naznačen time, što ova kompozicija sadrži još najmanje jedan polietilen-oksid koji, na osnovu reoloških merenja, ima približnu molarnu masu od 100,000.
52
Proces prema bilo kom od Zahteva 1 do 51, naznačen time, što je ukupni sadržaj polietilen-oksida u kompoziciji jednak najmanje oko 80 mas%.
53
Proces prema bilo kom od Zahteva 1 do 52, naznačen time, što aktivni agens predstavlja oxycodone hidrohlorid, a ukupni sadržaj oxycodone hidrohlorida u kompoziciji je veći od oko 5 mas%.
54
Proces prema bilo kom od Zahteva 1 do 53, naznačen time, što sadržaj u kompoziciji najmanje jednog polietilen-oksida koji, na osnovu reoloških merenja, ima molarnu masu od najmanje 1,000,000, iznosi najmanje oko 80 mas%.
55
Proces prema bilo kom od Zahteva 1 do 54, naznačen time, što ova kompozicija sadrži najmanje jedan polietilen-oksid koji, na osnovu reoloških merenja, ima molarnu masu od najmanje 1,000,000, i najmanje jedan polietilen-oksid koji, na osnovu reoloških merenja, ima molarnu masu manju od 1,000,000, a pri tome ova kompozicija sadrži najmanje oko 10 mas%, iii najmanje oko 20 mas% polietilenoksida koji, na osnovu reoloških merenja, ima približnu molarnu masu manju od 1,000,000.
56
Proces prema Zahtevu 55, naznačen time, što se oblik za doziranje podvrgava temperaturi nižoj od oko 80°C, ili nižoj od oko 77°C.
57
Proces prema bilo kom od Zahteva 1 do 56, naznačen time, što korak očvršćavanja c) dovodi do smanjenja gustine formulacije matrice za produženo oslobađanje. 234 51162 Β
58
Proces prema Zahtevu 57, naznačen time, što je gustina očvrsle formulacije matrice za produženo oslobađanje, u poređenju sa gustinom neočvrsle formulacije matrice za produženo oslobađanje, manja za najmanje oko 0.5%, poželjno najmanje za oko 0.7%.
59
Čvrst oralni farmaceutski oblik za doziranje sa produženim oslobađanjem, dobijen pomoću nekog procesa, prema bilo kom od Zahteva 1 do 58.

Independent claims59

3,725 paragraphs in 143 sections, as filed

FIELD OF THE INVENTION

The present invention relates to pharmaceutical dosage forms, for example, to abuse-resistant dosage forms containing opiate analgesics, and to their manufacturing, use and treatment processes.

BACKGROUND OF THE INVENTION

Pharmaceutical products are sometimes the subject of abuse. For example, the observed dose of opiate agonist may be stronger when administered parenterally, compared to the same dose when administered orally. Some formulations may be misused so that the opiate agonist contained therein may be used in an unauthorized manner. Controlled-release opiate agonist formulations, those that abuse drugs are sometimes crushed or subjected to solvent extraction (e.g. ethanol), so that after oral or parenteral use, the opiate contained in them becomes for immediate use.

51162 Β

Controlled-release opioid agonist dosage forms, which may release some of the opiate after exposure to ethanol, may also cause the patient to release this dose more rapidly than anticipated if the patient does not follow the instructions for use and uses alcohol with this form at the same time. dosing.

There is a constant need in the art for oral dosage forms containing an opiate agonist, in which there will be no significant change in the release properties of the opiates, when they are in contact with alcohol and / or if they have resistance to crushing.

DISCLOSURE OF THE ESSENCE OF THE INVENTION

It is an object of some embodiments of the present invention to provide a sustained release oral dosage form containing an active agent, such as an opiate analgesic, which is resistant to abuse.

It is an object of some embodiments of the present invention to provide a sustained release oral dosage form comprising an active agent, such as an opiate analgesic, which is resistant to crushing.

It is an object of some embodiments of the present invention to provide a sustained release oral dosage form comprising an active agent, such as an opiate analgesic, which is resistant to alcohol extraction and dose robbery, when used concomitantly with or in contact with alcohol.

51162 Β in 900 mL of simulated enzyme-free gastric fluid (CSF), at 37 ° C, characterized by the percentage of active substance released during 0.5 hours of dissolution, which does not deviate by more than about 20% from the corresponding in vitro release rate of the in vitro reference tablet or reference beads which are not crushed.

In some embodiments, the present invention relates to a solid oral pharmaceutical dosage form, comprising a sustained release matrix formulation in the form of a tablet or granules, wherein the tablet or individual bead can be crushed without tearing, characterized by the thickness of the tablet or single bead after of this kneading, which is not more than about 60% of the thickness of that tablet or individual granule of rge than they are crushed, wherein this crushed or uncrushed tablet or crushed or uncrushed granules have an in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid without enzyme (SZF), containing 40 % ethanol, at 37 ° C, characterized by the percentage of active substance released during 0.5 hours of dissolution, which does not deviate by more than about 20% from the corresponding in vitro release rate, measured in USP Apparatus 1 (at the basket), at 100 o / min, in 900 ml of simulated enzyme-free gastric fluid (CSF), at 37 ° C, alcohol-free, if crushed or uncrushed reference tablet or crushed or uncrushed reference granules are used, respectively.

In some embodiments, the present invention relates to a solid oral sustained release dosage form comprising a sustained release matrix formulation, and the sustained release matrix formulation comprises a composition comprising at least:

(1) at least one polyethylene oxide having, based on rheological measurements, an approximate molar mass of at least 1,000,000; and (2) at least one active agent; wherein said composition comprises at least about 80% by weight of polyethylene oxide.

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

51162 Β

In some embodiments, the present invention relates to a solid sustained release oral dosage form comprising a sustained release matrix formulation, and the sustained release matrix formulation comprises a composition comprising at least:

(1) at least one active agent;

(2) at least one polyethylene oxide having, based on rheological measurements, a molar mass of at least 1,000,000; and (3) at least one polyethylene oxide having, based on rheological measurements, a molar mass of less than 1,000,000.

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

(a) combining at least (1) at least one polyethylene oxide, which based on rheological measurements has an approximate molar mass of at least 1,000,000, and (2) at least one active agent, forming a composition;

(b) shaping this composition to form a sustained release matrix formulation; and (c) curing said sustained release matrix formulation, comprising at least the curing step, by subjecting the sustained release matrix formulation to a temperature at least equal to the softening temperature of said polyethylene oxide, for a period of time of at least about 1 min.

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

(a) combining bar

51162 Β (1) at least one polyethylene oxide, which on the basis of rheological measurements has an approximate molar mass of at least 1,000,000, and (2) at least one active agent, forming a composition;

(b) shaping this composition, forming a sustained release matrix formulation; and (c) curing said sustained release matrix formulation, comprising at least a curing step, wherein said polyethylene oxide is at least partially melted.

In some embodiments, the present invention relates to a solid sustained release oral dosage form, comprising a sustained release matrix formulation comprising the active agent in tablet or granular form, wherein the tablet or individual granules can be crushed without tearing, characterized in the thickness of that tablet or individual bead after kneading, which corresponds to not more than 60% of the thickness of this tablet or individual bead before kneading, wherein said crushed tablet or crushed granules have an in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SZF), at 37 ° C, characterized by the percentage of the amount of active ingredient released during 0.5 h of dissolution, which does not deviate by more than about 20% from the corresponding in vitro dissolution rate of the uncrushed reference tablet or reference beads.

51162 Β

900 mL of simulated gastric fluid, without enzyme (CZF), at 37 ° C, between about 5 and about 40% by weight of released active agent after 0.5 h.

In some embodiments, the present invention relates to a solid sustained release oral dosage form, comprising a sustained release matrix formulation comprising the active agent in the form of a tablet or granules, wherein the tablet or individual granules can be crushed without tearing, characterized by a thickness a tablet or single bead after kneading, corresponding to not more than about 60% of the thickness of this tablet or single bead before kneading, wherein the crushed or uncrushed tablet or crushed or uncrushed granules have an in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SZF), containing 40% ethanol, at 37 ° C, characterized by the percentage of the amount of active ingredient released during 0.5 h of dissolution, which does not deviate by more than about 20% from the corresponding in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, enzyme-free (SZF), at 37 ° C, ethanol-free, using a crushed or uncrushed reference tablet or crushed or uncrushed reference beads, respectively.

51162 Β

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; and (2) at least one active agent, selected from opiate analgesics; wherein the composition contains at least about 80% by weight of polyethylene oxide.

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; and (2) 10 mg oxycodone hydrochloride;

and wherein the composition contains at least about 85% by weight of polyethylene oxide.

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; and (2) 15 mg or 20 mg of oxycodone hydrochloride;

wherein said composition comprises at least about 80% by weight of polyethylene oxide.

In some embodiments, the present invention relates to a solid sustained release oral dosage form, comprising a sustained release matrix formulation,

51162 Β and this sustained release matrix formulation contains a composition consisting of at least:

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; and (2) 40 mg oxycodone hydrochloride;

wherein said composition comprises at least about 65% by weight of polyethylene oxide.

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; and (2) 60 mg or 80 mg of oxycodone hydrochloride;

wherein said composition comprises at least about 60% by weight of polyethylene oxide.

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; and (2) 8 mg of hydromorphone hydrochloride;

and wherein the composition contains at least about 94% by weight of polyethylene oxide.

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; i

51162 Β (2) 12 mg hydromorphone hydrochloride;

and wherein the composition contains at least about 92% by weight of polyethylene oxide.

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; and (2) 32 mg of hydromorphone hydrochloride;

wherein the composition comprises at least about 90% by weight of polyethylene oxide.

In some embodiments, the present invention relates to a solid sustained release oral dosage form, comprising a sustained release matrix formulation, and the sustained release matrix formulation comprises a composition comprising at least:

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

(2) at least one polyethylene oxide, having, based on rheological measurements, a molar mass of at least 1,000,000; and (3) at least one polyethylene oxide, which based on rheological measurements has an approximate molar mass of less than 1,000,000.

(1) at least one polyethylene oxide, having a molar mass of at least 800,000 based on rheological measurements; and (2) at least one active agent selected from opiate analgesics;

51162 This composition contains at least about 80% by weight of polyethylene oxide.

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; and (2) at least one active agent;

and this sustained release matrix formulation, when subjected to an indentation test, has a crack-forming force of at least about 110 N.

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; and (2) at least one active agent;

and this sustained release matrix formulation, when subjected to the indentation test, has a distance along the crack penetration depth ”of at least about 1.0 mm.

In some embodiments, the present invention relates to a method of treatment, wherein the dosage form according to the present invention, comprising an opiate analgesic, is administered to a patient in need thereof for the treatment of pain.

In some embodiments, the present invention relates to the use of a dosage form in accordance with the present invention, comprising an opiate analgesic, for the manufacture of a medicament for the treatment of pain.

51162 Β

In some embodiments, the present invention relates to the use of a high molar mass polyethylene oxide having, based on rheological measurements, an approximate molar mass of at least 1,000,000, as a matrix-forming material, in the manufacture of a solid oral sustained release dosage form comprising an active a component selected from opiates, imparting to this solid oral sustained release dosage form resistance to extraction with alcohol.

In some embodiments, the present invention relates to a process for preparing a solid sustained release oral dosage form, comprising at least

<td>steps:</td><td>(a) combining bar (1) at least one polyethylene oxide having a molar mass of at least 1,000,000 based on rheological measurements, and (2) at least one active agent, forming a composition; (b) shaping this composition to form a sustained release matrix formulation; i (c) curing said sustained release matrix formulation, comprising at least one curing compound, by subjecting the sustained release matrix formulation to a temperature at least equal to the softening temperature of said polyethylene oxide, for a period of time of at least 5 min.</td>

In accordance with some embodiments of the present invention, the solid sustained release pharmaceutical dosage form is used as a suppository.

The term "sustained release" as defined for the purposes of the present invention, refers to products that are formulated to make a drug that is available after ingestion over an extended period of time, thereby allowing a reduction

51162 Β frequency of dosing, compared to the drug when it is a conventional dosage form (eg as a solution or immediate release dosage form).

The term "immediate release", as defined for the purposes of the present invention, refers to products that are formulated to allow a drug to dissolve in gastrointestinal contents without the intention of delaying or prolonging the dissolution or absorption of that drug.

The term "solid oral sustained release pharmaceutical dosage form" refers to a dosage form containing a unit dose of active agent in a sustained release form, such as a sustained release matrix formulation, and optionally other adjuvants and additives, which are conventional in prior art, such as a protective coating or a capsule and the like, and optionally any additional properties or components, used in such a dosage form. Unless specifically noted, the term "solid oral sustained release dosage form" refers to said intact dosage form, i. before any abuse. The sustained release pharmaceutical dosage form may be, for example, a tablet containing a sustained release matrix formulation, or a capsule containing a sustained release matrix formulation in the form of granules. This "sustained release pharmaceutical dosage form" may contain one part of the active agent in a sustained release form and the other part of the active agent in a sustained release form, e.g. as a layer of active immediate release agent surrounding the dosage form, or an immediate release component included in the dosage form.

The term "sustained release matrix formulation" is defined for the purposes of the present invention such that the molded solid formulation contains at least one active agent and at least one sustained release ingredient, such as a sustained release matrix material, such as e.g. high molar mass polyethylene oxide. This composition may optionally contain more than two of these

Compounds, namely other active agents and additional retardants and / or other materials, including, but not limited to, low molar mass polyethylene oxides, and other adjuvants and additives, which are conventional in the art.

The term bioequivalence / bioequivalence, as defined for the purposes of the present invention, refers to a dosage form that provides geometric mean values for Stoh, AUCt, and AUCjnf for active agent, where 90% confidence intervals, estimated for the ratio (tested / reference) fall within the range of 80.00% to 125.00%. Preferably, the mean values for Cmax, AUCt and AUCinf fall within the range of 80.00% to 125.00%, determined in states of both full and empty stomach.

The term polyethylene oxide is defined for the purposes of the present invention as having a molar mass of at least 25,000, measured in a conventional manner in the prior art, and preferably having a molar mass of at least 100,000. Compositions with a lower molar mass are usually referred to as polyethylene glycols.

The term high molar mass polyethylene oxide is defined for the purposes of the present invention by having an approximate molar mass of at least 1,000,000. For the purposes of the present invention, the approximate molar mass is obtained on the basis of rheological measurements. Polyethylene oxide is considered to have an approximate molar mass of 1,000,000 when a 2% by weight solution in water of said polyethylene oxide, using a Brookfield viscometer, Model RVF, axis no. 1, at 10 rpm, at 25 ° C, shows a viscosity range of 400 to 800 mPa s (cP). Polyethylene oxide is considered to have an approximate molar mass of 2,000,000, when a 2% by weight solution in water of said polyethylene oxide, using a Brookfield viscometer, Model RVF, axis no. 3, at 10 rpm, at 25 ° C, shows a viscosity range of 2000 to 4000 mPa s (cP). Polyethylene oxide is considered to have an approximate molar mass of 4,000,000 when 1 wt% solution in water of said polyethylene oxide, using a Brookfield viscometer, Model RVF, axis no. 2, at 2 rpm, at 25 ° C, shows a viscosity range of 1650 to 5500 mPa s (cP). Polyethylene oxide is considered to have an approximate molar mass of 5,000,000 when 1 wt% solution in water of said polyethylene oxide, using Brookfield's

51162 Β viscometer, Model RVF, shaft no. 2, at 2 rpm, at 25 ° C, shows a viscosity range of 5500 to 7500 mPa s (cP). Polyethylene oxide is considered to have an approximate molar mass of 7,000,000 when 1 wt% solution in water of said polyethylene oxide, using a Brookfield viscometer, Model RVF, axis no. 2, at 2 rpm, at 25 ° C, shows a viscosity range of 7500 to 10,000 mPa s (cP). Polyethylene oxide is considered to have an approximate molar mass of 8,000,000 when 1 wt% solution in water of said polyethylene oxide, using a Brookfield viscometer, Model RVF, axis no. 2, at 2 rpm, at 25 ° C, shows a viscosity range of 10,000 to 15,000 mPa s (cP). With respect to polyethylene oxide lower molar mass; polyethylene oxide is considered to have an approximate molar mass of 100,000 when a 5 wt% solution in water of said polyethylene oxide, using a Brookfield viscometer, Model RVT, axis no. 1, at 50 rpm, at 25 ° C, shows a viscosity range of 30 to 50 mPa s (cP), and polyethylene oxide is considered to have an approximate molar mass of 900,000 when a 5% by weight solution in water of said polyethylene oxide, using Brookfield viscometer, Model RVF, axis no. 2, at 2 rpm, at 25 ° C, shows a viscosity range of 8800 to 17,600 mPa s (cP).

The term low molar mass polyethylene oxide is defined for the purposes of the present invention such that, based on the rheological measurements mentioned above, it has an approximate molar mass of less than 1,000,000.

The term direct compression is defined for the purposes of the present invention by referring to a tableting process, wherein the tablet, or any other compressed dosage form, is made in a process comprising the steps of dry mixing the compound and compressing the dry aperture to form a form. for dosing, e.g. using a diffusion aperture and / or a convective mixing process (see e.g. Guidance for industry, SUPAC-IR / MR: Immediate Release and Modified Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum ”).

The term "free-moving tablet layer", as defined for the purposes of the present invention, refers to a batch of tablets that are kept in motion, relatively one

51162 Β to another, such as in a coating apparatus, at a suitable rotation speed or in a fluidized bed of tablets. Preferably, the layer of freely movable tablets reduces or prevents the tablets from sticking to each other.

The term "kneading" and related terms used in the context of kneading tablets or other dosage forms in accordance with the present invention means that the tablet is subjected to a force applied from a substantially vertical to diameter direction and substantially aligned with the thickness, e.g. tablets. This force can be applied by means of an ordinary blade-like press (unless explicitly stated otherwise) to the extent necessary to achieve the target crushed / reduced thickness. In accordance with some embodiments of the present invention, this kneading does not cause the tablet to tear into pieces, however, it may crown and crack at the edges. This crushing is described by the thickness of the crushed tablet, compared to the thickness of the uncompressed tablet, expressed in% of thickness, calculated according to the thickness of the uncrushed tablet. In addition to tablets, this crushing can be applied to any dosage form. essentially aligned with the rental diameter (ie thickness) of that shape, when that shape is different from the spherical, and from any direction when that shape is spherical. Crushing is then described by the thickness / smallest diameter of the crushed form, compared to the thickness / smallest diameter of the uncrushed form, expressed in% thickness, based on the thickness / smallest diameter of the uncrushed form, if the initial form is not spherical, or in% thickness, based on uncrushed diameter, if the initial shape is spherical. This thickness is measured using a thickness gauge (eg, a digital thickness gauge or a digital vernier). Figures 4 to 6 show tablets that were crushed using a table press with a blade. The initial form of the tablet is shown in Figures 1 to 3, on the left side of the photo.

In some embodiments of the present invention, in addition to using a table press, a tablet / dosage hammer may be used. In this process of kneading with a hammer, it is struck by hand, from a direction that is essentially aligned with the thickness, e.g. tablets. Crushing is then also described by the thickness / smallest diameter of the crushed form, compared to the uncrushed form, expressed in% of thickness, at

51162 Β basis of thickness / minimum diameter of uncrushed form, if the initial form is not spherical, or in% of thickness, in relation to uncrushed diameter, if the form is spherical. Thickness is measured using a thickness gauge (eg a digital thickness gauge or digital vernier).

In contrast, when tear strength is expressed or a tablet hardness test is performed, as described in Remington’s Pharmaceutical Sciences ”, 18th edition, 1990, chapter 89, “Oral Solid Dosage Forms”, pages 1633-1665, which is incorporated herein by reference, using an apparatus, model Schleuniger Apparatus, tablet / dosage form is placed between pairs of flat plates, placed in parallel, and compresses with these flat plates, so that the force is applied substantially vertically to the thickness, and substantially aligned with the diameter of the tablet, thus reducing the diameter in that direction. This reduced diameter is described as% of diameter, based on the diameter of the tablet before performing the tear strength test. The breaking strength or hardness of a tablet is defined as the force at which the tablet / test dosage form is tested. Tablets / dosage forms that do not break, but that deform due to the applied force, are considered to be resistant to tearing with the observed force.

Another test for the quantitative expression of tablet strength / dosage form is the embossing test, which uses a Texture Analyzer apparatus, such as the TA-HT2 Texture Analyzer model (Texture Technologies Corp., 18 Fairview Road, Scarsdale, NY 10583). In this process, tablets / dosage forms are placed on top of a stainless steel stand, with a slightly concave surface, and then pierced using a drop-down sample of a Texture Analyzer, such as the TA-8A, which consists of a stainless steel ball about 3 mm. Before the start of the measurement, the tablets are aligned directly below the sample, so that the falling sample pierces the tablet in the middle, ie. in the center of the tablet, so that the force of the falling sample is applied substantially vertically to the diameter and substantially aligned with the thickness of the tablet. First, a test of the Texture Analyzer begins to move toward the tablet sample at a pre-tested speed. When the test touches the surface of the tablet, and the starting force is reached, the test continues its movement at the tested speed and penetrates the tablet. For each depth of penetration

51162 Β test, which will then be expressed as the distance ”, the appropriate force is measured, and the data are collected. When the sample reaches the desired maximum penetration depth, it changes direction and moves back at the tested speed, so that the following data can be collected. The crack force is defined as the force of the first local maximum reached on the corresponding force / distance diagram, and is calculated using software, for example “Texture Analyzer Software”, “Texture Expert Exceed, Version 2.64 English”. Without wishing to be bound by any theory, structural damage to the tablet / dosage form is considered to occur in the form of a crack. However, cracked tablets / dosage forms, in accordance with some embodiments of the present invention, remain cohesive, indicating continued resistance to the falling sample. The corresponding distance at the first local maximum is then defined as the crack penetration depth distance.

For purposes of some embodiments of the present invention, the term "tensile strength" refers to the hardness of tablets / dosage forms, which is preferably measured using a Schleuniger apparatus, wherein the term "crack force reflects the strength of tablets / dosage forms, which is preferably measured by an embossing test, using a Texture Analyzer apparatus.

Another parameter of the extended release matrix formulations, which can be derived from the embossing test described above, is the work of the extended release matrix formulation used in the embossing test described above. The value of this work corresponds to the integral of the force over the distance.

The term "crushing resistant", as defined for some embodiments of the present invention, refers to dosage forms that can be at least crushed without tearing, using a table press as described above, at no more than about 60% of thickness, preferably not more than about 50% of thickness, more preferably at not more than about 40% of thickness, more preferably at not more than about 30% of thickness, and most preferably at not more than about 20% of thickness, 10% of thickness, or 5% of thickness.

51162 Β

For some embodiments of the present invention, dosage forms are considered "resistant to alcohol extraction" when the observed dosage form provides an in vitro dissolution rate, measured in a USP Apparatus 1 (with basket), at 100 rpm, in 900 mL simulated gastric fluid, without enzyme (SJF), containing 40% ethanol, at 37 ° C, characterized by the percentage of active substance released in 0.5 h, preferably 0.5 and 0.75 h, more preferably 0.5, 0.75 and 1 h, even more preferably for 0.5, 0.75, 1 i

1.5 h, and most preferably for 0.75, 1, 1.5 and 2 h dissolution, which does not deviate by more than about 20% or preferably not more than about 15%, at each mentioned time, from the corresponding in vitro dissolution rate, measured in the USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (FF), at 37 ° C, without ethanol.

The term "abuse resistant", for the purposes of the present invention, refers to dosage forms that provide crushing resistance or resistance to alcohol extraction, and preferably both, as defined above, and may possess additional anti-abuse characteristics.

For the purposes of the present invention, the term active agent is defined as a pharmaceutically active substance, which includes, but is not limited to, opiate analgesics.

For the purposes of the present invention, the term "opiate anagenetic" encompasses individual compounds and compositions of compounds selected from the group of opiates that provide an analgesic effect, such as an individual opiate agonist, or a combination of opiate agonists, a single mixed opiate agonist. antagonist, or a combination of mixed opiate agonists-antagonists, or a single partial opiate agonist, or a combination of partial opiate agonists, mixed opiate agonist-antagonists and partial opiate agonists with one or more opiate antagonists, their stereoisomers, ethers or esters, salts, hydrates and solvates, compositions of any of the foregoing, and the like.

51162 Β

The present invention, which is described herein, specifically encompasses the use of opiate analgesics in the form of any pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts are, but are not limited to, inorganic 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, asparginate, glutamate and the like, and metal salts such as sodium salt, potassium salt, cesium salt, and the like; alkaline earth metals, such as calcium salt, magnesium salt, and the like; salts of organic amines, such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, and the like.

The opiates used in accordance with the present invention may contain one or more asymmetric centers, and may give enantiomers, diastereomers or other stereoisomeric forms. The present invention also encompasses the use of all these possible forms, as well as their racemic and dissociated forms and their compositions. If the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, it is intended to include both E and Z geometric isomers. Likewise, all tautomers are encompassed by this invention.

As used herein, the term stereoisomers is a general term for all isomers of individual molecules, which differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center, which do not relate to each other as an object and a mirror image (diastereomers).

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

51162 Β

The term enantiomer, or enantiomeric, refers to a molecule that cannot overlap with its mirror image and is therefore optically active, with the enantiomer rotating the plane of polarized light in one direction and its mirror image rotating the plane of polarized light in the opposite direction. .

The term racemic refers to a mixture of equal parts of enantiomers, which is optically inactive.

The term separation refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.

Opiate agonists useful in the present invention include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezithramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezoidene diihine, , dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, methopon, morphine, myrophine, narcanine, ncene, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, pyritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing, and the like.

Opioid antagonists, useful in combination with the opiate agonists described above, are e.g. naloxones, naltrexones and nalmephenes or pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing, and the like.

51162 Β

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

In some embodiments, the opiate anagletic is selected from codeine, morphine, oxycodone, hydrocodone, hydromorphone, or oxymorphone, or a pharmaceutically acceptable salt, hydrate, and solvate thereof, a mixture of any of the foregoing, and the like.

In some embodiments, the opiate analgesic is oxycodone, hydromorphone, or oxymorphone, or a salt thereof, 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 may be used, including but not limited to hydrates and solvates or free bases. 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 of oxycodone hydrochloride or an equimolar amount of any other pharmaceutically acceptable salt, derivatives or forms, including, but not limited to, hydrates and solvates or a free base. This 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 of oxymorphone hydrochloride or an equimolar amount of any other pharmaceutically acceptable salt , derivatives or forms, including, but not limited to, hydrates and solvates or the free base. This dosage form contains e.g. 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, 48 mg or 64 mg of hydromorphone hydrochloride or equimolarnequalities of any other pharmaceutically acceptable salt, derivative or form, including, but not limited to, hydrates and solvates, or free base.

WO 2005/097801 A1, US 7,129,248 B2 and US 2006/0173029 A1, all of which are incorporated herein by reference, describe a process for preparing oxycodone hydrochloride, having a 14-hydroxycodeinone level of less than about 25 ppm, preferably less than about 15 ppm ppm,

51162 Β less than about 10 ppm, or less than about 5 ppm, more preferably less than about 2 ppm, less than about 1 ppm, less than about 0.5 ppm, or less than about 0.25 ppm.

The term "ppm", as used herein, means "parts per million". With respect to 14-hydroxycodeinone, "ppm" means parts per million of 14-hydroxycodeinone, more specifically specified in the product sample. The level of 14-hydroxycodeinone can be determined by any method known in the art, preferably by HPLC analysis, using UV detection.

In some embodiments of the present invention, wherein the active agent is oxycodone hydrochloride, oxycodone hydrochloride is used to have a 14-hydroxycodeinone level of less than about 25 ppm, preferably less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm, more preferably less than about 2 ppm, less than about 1 ppm, less than about 0.5 ppm or less than about 0.25 ppm.

In some other embodiments, in accordance with the present invention, other therapeutic agents may be used, either in combination with opiates or instead of opiates. Examples of such therapeutic agents are antihistamines (e.g. dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), non-steroidal anti-inflammatory agents (e.g. pargohep, diclofenac, indomethacin, ibuprofen, sulindac-emetic and soh-2). (prg. metoclopramide, methylnaltrexone), anti-epileptics (e.g., phenytoin, meprobmate, and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem, and nicardipine), antitussives, and expectorants (e.g., codeine-phosphate). theophylline), antacids, anti-spasmodics (e.g. atropine, scopolamine), antidiabetics (e.g. insulin), diuretics (e.g. ethacrynic acid, bendrofluthiazide), anti-hypotensives (e.g. propranoloi, clonidine), antihypertensives. clonidine, methyldopa), bronchodilators (eg albuterol), steroids (eg hydrocortisone, triamcinolone, prednisone), antibiotics (eg tetracycline), antihemorrhoids, hypnotics, psychotropics, antidiareals, mucolytics, sedatives, decongestants (eg dogs) , vitamins, stimulants (including appetite suppressants, such as

51162 Β phenylpropanolamine) and cannabinoids, as well as pharmaceutically acceptable salts, hydrates and solvates thereof.

In some embodiments, the present invention relates to the use of Soh-2 inhibitors as active agents, in combination with opiate analgesics, or instead of opiate analgesics, for example, the use of Soh-2 inhibitors, such as meloxicam (4-hydroxy-2-methyl-A N- (5-methyl-2-thiazolyl) -2H-1,2,2-benzothiazine-3-carboxamide-1,1-dioxide), as described in US Serial No. 10 / 056,347 and 11 / 825,938, which are incorporated herein by reference, nabumetone (4- (6-methoxy-2-naphthyl) -2-butanone), as described in U.S. Pat. Serial No. 10 / 056,348, which is incorporated herein by reference, celecoxib (4- [5- (4-methylphenyl) -3 (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide), as described in U.S. Serial No. 11 / 698,394, which is incorporated herein by reference, nimesulide (N- (4-Nitro-2-phenoxyphenyl) methanesulfonamide), as described in U.S. Serial No. 10 / 057,630, which is incorporated herein by reference, and N- [3- (formylamino) -4-oxo-6-phenoxy-4H-1-benzopyran-

7-yl] methanesulfonamide (T-614), as described in U.S. Serial No. 10 / 057,632, which is incorporated herein by reference.

The present invention also relates to dosage forms using active agents, such as, for example, benzodiazepines, barbiturates or amphetamines. These can be combined with the respective antagonists,

The term "benzodiazepines" refers to benzodiazepines and drugs that are derivatives of benzodiazepines, which are able to calm the central nervous system. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepat, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, metazolamine and solvates, and mixtures thereof. Benzodiazepine antagonists that can be used in the present invention include, but are not limited to, flumazenil, as well as pharmaceutically acceptable salts, hydrates, and solvates thereof.

51162 Β

Barbiturates are sedative-hypnotic drugs, which are derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, as well as pharmaceutically acceptable salts, hydrates and solvates thereof, and mixtures thereof. Barbiturate antagonists that can be used in the present invention include, but are not limited to, amphetamines, as well as pharmaceutically acceptable salts, hydrates, and solvates thereof.

Stimulants refer 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 their pharmaceutically acceptable salts, hydrates and solvates, and mixtures thereof. Stimulant antagonists that can be used in the present invention are, but are not limited to, benzodiazepines, as well as pharmaceutically acceptable salts, hydrates, and solvates thereof, described herein.

SHORT DESCRIPTION OF IMAGES

Figure 1 is a photograph showing a top view (view aligned with the thickness of the tablet) of the tablets from Example 7.1, before (left side) and after (right side) the tear strength test, in which an instrument, the Schleuniger Model 6D apparatus, was used.

Figure 2 is a photograph showing the top view (view aligned with the thickness of the tablet) of the tablets from Example 7.2 before (left side) and after (right side) the tear strength test, in which an instrument, the Schleuniger Model 6D apparatus, was used.

Figure 3 is a photograph showing the top view (the view is aligned with the tablet thickness) of the tablets from Example 7.3, before (left side) and after (right side) the tear strength test, in which an instrument, the Schleuniger Model 6D apparatus, was used.

51162 Β

Figure 4 is a photograph showing a top view (the view is aligned with the thickness of the tablet) of the tablet from Example 7.1 after kneading with a Carver hand-held press (hydraulic, model # 3912).

Figure 5 is a photograph showing a top view (the view is aligned with the thickness of the tablet) of the tablet from Example 7.2 after kneading with a Carver hand-held press (hydraulic, model # 3912).

Figure 6 is a photograph showing a top view (the view is aligned with the thickness of the tablet) of the tablet from Example 7.3 after kneading with a Carver hand-held press (hydraulic, model # 3912).

Figure 7 is a photograph showing a top view (the view is aligned with the thickness of the tablet) of the tablets from Example 7.1 after 10 manual hammer blows.

Figure 8 is a photograph showing a top view (the view is aligned with the thickness of the tablet) of the tablets from Example 7.2 after 10 manual hammer blows.

Figure 9 is a photograph showing a top view (the view is aligned with the thickness of the tablet) of the tablets from Example 7.3 after 10 hand-made hammer blows.

Figure 10 is a diagram showing the temperature profile of the curing process in the Example

13.1.

Figure 11 is a diagram showing the temperature profile of the curing process in the Example

13.2.

Figure 12 is a diagram showing the temperature profile of the curing process in the Example

13.3.

51162 Β

Figure 13 is a diagram showing the temperature profile of the curing process in the Example

13.4.

Figure 14 is a diagram showing the temperature profile of the curing process in the Example

13.5.

Figure 15 is a diagram showing the temperature profile of the curing process in the Example

14.1.

Figure 16 is a diagram showing the temperature profile of the curing process in the Example

14.2.

Figure 17 is a diagram showing the temperature profile of the curing process in the Example

14.3.

Figure 18 is a diagram showing the temperature profile of the curing process in the Example

14.4.

Figure 19 is a diagram showing the temperature profile of the curing process in the Example

14.5.

Figure 20 is a diagram of the embossing test in Example 20 performed with the tablet of

Example 13.1 (cured for 30 min, uncoated).

Figure 21 is a diagram of the embossing test in Example 20 performed with the tablet of

Example 13.2 (cured for 30 min, uncoated).

Figure 22 is a diagram of the embossing test in Example 20, performed with the tablet of

Example 13.3 (cured for 30 min, uncoated).

51162 Β

Figure 23 is a diagram of the embossing test in Example 20, performed with the tablet of

Example 13.4 (cured for 30 min, uncoated).

Figure 24 is a diagram of the embossing test in Example 20, performed with the tablet of

Example 13.5 (cured for 30 min, uncoated).

Figure 25 is a diagram of the embossing test in Example 20, performed with the tablet of

Example 17.1 (cured for 15 min at 72 ° C, coated).

Figure 26 is a diagram of the embossing test in Example 20, performed with

Example 18.2 (cured for 15 min at 72 ° C, coated).

tablet from

Figure 27 is a diagram of the embossing test in Example 20, performed with the tablet of

Example 14.1 (cured for 1 h, coated).

Figure 28 is a diagram of the embossing test in Example 20, performed from Example 14.2 (cured for 1 h, coated).

Figure 29 is a diagram of the embossing test in Example 20, performed from Example 14.3 (cured for 1 h, coated).

Figure 30 is a diagram of the embossing test in Example 20, performed from Example 14.4 (cured for 1 h, coated).

tablet from tablet from tablet from

Figure 31 is a diagram of the embossing test in Example 20, performed from Example 14.5 (cured for 1 h, coated).

Figure 32 is a diagram of the embossing test in Example 20, performed from Example 16.1 (cured for 15 min, coated).

tablet from tablet from

51162 Β

Figure 33 is a diagram of the embossing test in Example 20, performed with the tablet of Example 16.2 (cured for 15 min, coated).

Figure 34 is a diagram of the injection test in Example 21, performed with the tablet of Example 16.1 (cured for 15 min, coated) and with a commercial Oxycontin ™ 60 mg tablet.

Figure 35 is a diagram of the injection test in Example 21, performed with the tablet of Example 16.2 (cured for 15 min, coated) and with a commercial Oxycontin cont 60 mg tablet.

Figure 36 shows the mean plasma oxycodone concentration versus time profile, on a linear scale [population: complete analysis (empty stomach status)] according to Example 26.

Figure 37 shows the mean concentration of oxycodone in plasma as a function of time profile, on a log-linear scale [population: complete analysis (empty stomach status)] according to Example 26.

Figure 38 shows the mean plasma concentration of oxycodone as a function of time profile and then on a linear scale [population: complete analysis (empty stomach status)] according to Example 26.

Figure 39 shows the mean plasma oxycodone concentration versus time profile, on a log-linear scale [population: complete analysis (empty stomach status)] according to Example 26.

Figure 40 shows representative views of a 10 mg OxyContin zg crushed tablet and the crushed tablets of Example 7.2, according to Example 27.

51162 Β

Figure 41 shows representative views of the ground tablets of Example 7.2 and OxyContin ™ of 10 mg, before and after 45 min of dissolution, according to Example 27.

Figure 42 shows the dissolution profiles of the ground tablets of Example 7.2 and the crushed OxyContin ™ 10 mg tablets, according to Example 27.

Figure 43 shows graphs of the particle size distribution of ground tablets (OxyContin ™ 10 mg tablets, from Example 7.2 and Example 14.5), according to Example 27.

DETAILED DESCRIPTION OF THE INVENTION

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

(b) shaping this composition, forming a sustained release matrix formulation; and (c) curing said sustained release matrix formulation, comprising at least some curing, by subjecting the sustained release matrix formulation to a temperature at least equal to the softening temperature of said polyethylene oxide, for a period of time of at least about 1 min.

Preferably, the curing is performed at atmospheric pressure.

In one embodiment, the present invention relates to a process for preparing a solid sustained release oral dosage form, comprising at least the steps of:

(a) combining bar zo

51162 Β (1) at least one polyethylene oxide, which, based on rheological measurements, has a molar mass of at least 1,000,000; and (2) at least one active agent, forming a composition;

(b) shaping this composition to form a sustained release matrix formulation; and (c) curing said sustained release matrix formulation comprising at least a curing step by subjecting the sustained release matrix formulation to a temperature at least equal to the softening temperature of said polyethylene oxide for a period of time of at least 5 min. Preferably, this curing is performed at atmospheric pressure.

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

(b) shaping this composition to form a sustained release matrix formulation; and (c) curing said sustained release matrix formulation, comprising at least a curing step, wherein said polyethylene oxide is at least partially melted.

It is desirable that this curing be performed at atmospheric pressure.

In some embodiments, the composition is formed in step b) to form a sustained release matrix formulation in the form of a tablet. A direct release process can be used to shape the sustained release matrix formulation into a tablet form

51162 Β compression. Direct compression is an efficient and simple tablet-forming process, avoiding process steps, such as wet granulation. However, any other process for the production of tablets known in the art can be used, such as wet granulation and then compressing these granules to form tablets.

In one embodiment, the curing of the sustained release matrix formulation in step c) comprises at least a curing step, wherein the high molar mass polyethylene oxide in the sustained release matrix formulation is at least partially melted. For example, in a sustained release matrix formulation, at least about 20%, or at least about 30%, of high molar mass polyethylene oxide is melted. 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% of the high molar mass polyethylene oxide is melted in the sustained release matrix formulation. In a preferred embodiment, about 100% of the high molar mass polyethylene oxide is melted.

In other embodiments, the curing of the sustained release matrix formation in step c) comprises at least a curing step, wherein the sustained release matrix formulation is subjected to an elevated temperature for a period of time. In these embodiments, the temperature used in step c), i.e., the curing temperature, is at least as high as the softening temperature of the high molar mass polyethylene oxide. Without wishing to be bound by any theory, curing at a temperature as high as at least as the softening temperature of high molar mass polyethylene oxide is considered to cause the least adhesion of the polyethylene oxide particles to each other, or even fusion. 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 62'0 to about 8 ° 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. Preferably, the curing temperature ranges 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 ° C, or from about 70 ° C to about 80 ° C, most preferably from

51162 Β 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 less than about 90 ° C or less than about 80 ° C. It is preferably in the range from about 62 ° C to about 72 ° C, and in particular from about 68 ° C to about 72 ° C. Preferably, the curing temperature is as high as at least the lower limit of the softening temperature of the high molar mass polyethylene oxide, or at least about 62 ° C or at least about 68 ° C. More preferably, the curing temperature is within the range of the softening temperature of the high molar mass polyethylene oxide, or at least about 70 ° C. More preferably, the curing temperature is at least as high as the upper limit of the softening temperature range of the high molar mass polyethylene oxide, or at least about 72 ° C. In one alternative embodiment, the curing temperature is higher than the upper limit of the high molar mass softening temperature range, for example, the curing temperature is at least about 75 ° C, or at least about 80 ° C.

In those embodiments in which the curing of the sustained release matrix formation in step c) comprises at least a curing step, in which the sustained release matrix formulation is subjected to an elevated temperature for a period of time, this time period will hereinafter be referred to as curing time. When measuring the curing time, the starting point and the end point of the curing time are defined. For the purposes of the present invention, the starting point of the curing time is defined by the point at the time when the curing temperature is reached.

In some embodiments, the temperature profile during curing shows a plateau-like shape between the starting point and the end point of curing. In these embodiments, the end point of the curing step is defined by a point at the time when the heating ends or at least decreases, e.g. by interrupting or reducing the heating and / or beginning the next cooling step, when the temperature falls below the curing temperature by more than about 10 ° C and / or below the lower limit of the softening temperature range of high molar mass polyethylene oxide, for example below about 62 ° C. When it is reached

51162 Β the curing temperature and thus the curing step begins, there may be a deviation from the curing temperature during the curing step. These deviations are tolerated until they exceed a value of 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 rise to a value of about 85 ° C, preferably about 8 ° C, and more preferably about 78 ° C, and the measured temperature may also temporarily drops to a value of about 65 ° C, preferably about 69 ° C, and more preferably about 72 ° C. In cases of greater temperature reduction and / or in case the temperature falls below the lower limit of the softening temperature range of high molar mass polyethylene oxide, for example below about 62 ° C, the curing step is interrupted, ie the end point is reached. Curing can be restarted by reaching the curing temperature again.

In other embodiments, the temperature profile during the curing step shows a parabolic or triangular shape between the starting point and the curing end point. This means that after the starting point, i.e. the point at the time when the curing temperature is reached, the temperature further rises reaching a maximum and then decreases. In these embodiments, the end point of the curing step is defined by a point at the time when the temperature falls below the curing temperature.

In this context, it should be noted that depending on the curing apparatus used, hereinafter referred to as the curing apparatus, various types of temperature may be measured within the curing apparatus to characterize the curing temperature.

In some embodiments, the curing step may take place in an oven. In these embodiments, the temperature inside the dryer is measured. Based on this, if the curing step takes place in the oven, the curing temperature is defined as the target internal temperature in the oven, and the starting point of the curing step is defined as the point at which the internal dryer temperature reaches the curing temperature. The end point of the curing step is defined as (1) the point u

51162 Β the time when the heating is stopped, or at least reduced, and the temperature in the oven then falls below the curing temperature by more than about 10 ° C and / or below the lower limit of the softening temperature range of high molar mass polyethylene oxide, for example below about 62 ° C, in the case of a plateau-like temperature profile, or (2) a point in time when the temperature inside the dryer falls below the curing temperature, in the case of a parabola or triangle-shaped temperature profile. Preferably, the curing step begins when the temperature inside the dryer 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 shows a plateau-like shape, wherein the curing temperature, i. the internal temperature in the oven, preferably at least about 68 ° C, for example about 70 ° C, them about 72 ° C, or about 73 ° C, or to be within the range of about 70 ° C to about 75 ° C, and the curing time is preferably within the range of about 30 min to about 20 h, more preferably from about 30 min to about 15 h, or from about 30 min to about 4 h, or from about 30 min to about 2 h. Most preferably, the curing time is within the range of about 30 min to about 90 min.

In some other embodiments, the curing takes place in curing devices that are heated by air flow and comprise a heated air supply (inlet) and an exhaust outlet, such as in a coating vessel or in a fluidization column. Such curing devices will hereinafter be referred to as convective curing devices. In these curing devices, it is possible to measure the inlet air temperature, ie. the temperature of the heated air entering the convective curing device, and / or the temperature of the exhaust air, i.e. the temperature of the air leaving the convective curing device. It is also possible to determine, or at least estimate, the temperature of the formulations within the convective curing device during the curing step, e.g. using infrared temperature measuring instruments, such as an IR gun, or by measuring a temperature using a temperature probe, which is placed inside the curing device, in the vicinity of the sustained release matrix formulations. Based on this, when the curing step takes place in a convective curing device,

51162 Β The curing temperature can be defined and the curing time can be measured as follows.

In one embodiment, in which the curing time is measured according to method 1, the curing temperature is defined by the target inlet air temperature, and the starting point of the curing step is defined by a point at the time when the inlet air temperature reaches the curing temperature. The end point of the curing step is defined as (1) the point at the time when heating is stopped or at least reduced, and the inlet air temperature then falls below the curing temperature by more than about 10 ° C and / or below the lower limit of the polyethylene oxide softening temperature range. molar mass, for example below about 62 ° C, in the case of a plateau-like temperature profile, or (2) a point at the time when the inlet air temperature falls below the curing temperature, at a temperature profile resembling a parabola or triangle. Preferably, the curing step according to process 1 begins 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. C. In a preferred embodiment, the temperature profile during the curing step has a plateau-like shape, wherein the curing temperature, i. the target inlet air temperature, preferably at least about 72 ° C, for example about 75 ° C, and the curing time, measured according to process 1, is preferably within the range of about 15 min to about 2 h, for example about 30 min, or about 1 h.

In another embodiment, when the curing time is measured according to method 2, the curing temperature is defined by the target exhaust air temperature, and the starting point of the curing step is defined by the point at the time when the exhaust air temperature reaches the curing temperature. The curing end point is defined as (1) a point at the time when heating stops, or at least decreases, and then the exhaust air temperature falls below the curing temperature by more than about 10 ° C and / or below the lower limit of the polyethylene softening temperature range. -oxide of high molar mass, and an example below about 62 ° C, at a plateau-like temperature profile, or (2) a point at the time when

51162 Β the temperature of the exhaust air falls below the curing temperature, in the case of a paraboia or triangle shape temperature profile. Preferably, according to process 2, the curing step begins when the exhaust 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, from at least about 72 ° C, or at least about 75 ° C. In preferred embodiments, the temperature profile during the curing step shows a plateau-like shape, wherein the curing temperature, i. the target temperature of the exhaust air is, preferably at least about 68 ° C, at least about 70 ° C or at least about 72 ° C, for example the target temperature of the exhaust air is about 68 ° C, about 70 ° C, about 72 ° C , about 75 ° C, or about 78 ° C, and the curing time, measured according to method 2, is preferably within the range of about 1 min to about 2 h, preferably from about 5 min to about 90 min, for example the curing time is about 5 min, about 10 min, about 15 min, about 30 min, about 60 min, about 70 min, about 75 min, or about 90 min. In a more preferred embodiment, the curing time, which is measured according to method 2, is within the range of about 15 min to about 1 h.

In another embodiment, in which the curing time is measured according to method 3, the curing temperature is defined by the target temperature of the sustained release matrix formulation, and the starting point of the curing cog is defined by the point at which the temperature of the sustained release matrix formulation can be measured. , for example using an IR gun, reaches the curing temperature. The end point of the curing step is defined as (1) a point at the time when heating stops, or at least the heating decreases, and then the temperature of the extended release matrix formulation falls below the curing temperature by more than 10'C and / or below the lower temperature range. softening of high molar mass polyethylene oxide, for example below about 62 ° C, at a plateau-like temperature profile, or (2) a point at the time when the temperature of the sustained release matrix formulation falls below the curing temperature, at the parabot or triangle shape temperature profile. Preferably, according to method 3, the curing step begins when the temperature of the sustained release matrix formulation reaches a curing temperature of at least about 62 ° C, at least

51162 Β about 68 ° C or at least about 70 ° C, more preferably from at least about 72 ° C, or at least about 75 ° C.

In another embodiment, when the curing time is measured according to method 4, the curing temperature is defined as a target temperature measured using a temperature probe, such as a thermocouple wire, located inside the curing device, close to the sustained release matrix formulation, and the starting point the curing step is defined by the point at the time when the temperature, measured by the temperature of the sample placed inside the curing device, close to the sustained release matrix formulation, it reaches the curing temperature. The end point of the curing step is defined as (1) the point at the time when the heating stops or decreases and the temperature measured by the test temperature then falls below the curing temperature by more than about 10 ° C and / or below the lower polyethylene oxide softening temperature range. high molar masses, for example, below about 62 ° C, at a plateau-like temperature profile, or (2) a point at the time when the temperature measured by the temperature test falls below the curing temperature, at the temperature profile the shape of a parabola or triangle. Preferably, according to method 4, the curing process begins when the temperature measured by the temperature of the sample placed inside the curing device, close to the sustained release matrix formulation, reaches a curing temperature of at least about 62 ° C, at least about 68 ° C or at least about 70 ° C, more preferably from at least about 72 ° C or at least about 75 ° C. In a preferred embodiment, the temperature profile during the curing step shows a plateau-like shape, wherein the curing temperature, i. the target temperature measured using a temperature probe placed inside the curing device, close to the sustained release matrix formulation, is preferably at least about 68 ° C, for example about 70 ° C, and the curing time, which is measured according to method 4, is preferred. to be within the range of about 15 min to about 2 h, for example the curing time is about 60 min or about 90 min.

51162 Β

If curing is maintained in a convective 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 by method 2.

In some embodiments, the curing temperature is defined by a range of the target temperature, for example, the curing temperature is defined as a range of the target inlet air temperature, or as a range of the target exhaust air temperature. In these embodiments, the starting point of the curing step is defined as the point and 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 when heating stops or at least decreases, and the temperature then falls below the lower limit of the target. a temperature range of more than about 10 ° C and / or below the lower limit of the softening temperature range of high molar mass polyethylene oxide, for example, below about 62 ° C.

The curing time, i.e. the period of time during which the sustained release matrix formulation is subjected to the curing temperature, which can, for example, be measured according to the methods 1,2, 3 and 4 described above, is at least about 1 min or at least about 5 min. The curing time may vary from about 1 min to about 24 h, or from about 5 min to about 20 h, or from about 10 min to about 15 h, or from about 15 min to about 10 h, or from about 30 min to about 5 h, depending on the specificity of the composition and on the formulation and curing temperature. The composition parameter, curing time and curing temperature are selected to achieve the abuse resistance described herein. According to some embodiments, the curing time varies from about 15 minutes to about 30 minutes. According to other embodiments, wherein the curing temperature is at least about 60 ° C, they are 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 ranging from about 62 ° C to about 85 ° C, or from about 65 ° C to about 85 ° C, preferably the curing time is at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 75 minutes min, at least about 90 min or about 120 min. In preferred embodiments, when the curing temperature is, for example, at least about

51162 Β

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 the range of about 62 ° C to about 80 ° C, of about 65 ° C C to about 80 ° C, from about 68qC to about 80 ° C, from about 70 ° C to about 80 ° C, or from about 72 ° C to about 80 ° C, preferably the curing time is at least about 1 min, or at least about 5 min. More preferably, the curing time is at least about 10 minutes, at least about 15 minutes, or at least about 30 minutes. In some embodiments, the curing time may be selected to be as short as possible while still achieving the desired resistance to abuse. For example, it is preferred that the curing time does not exceed about 5 hours, more preferably not more than about 3 hours, and most preferably not more than about 2 hours. Preferably, the curing time is within the range of about 1 min to about 5 h, from about 5 min to about 3 h, from about 15 min to about 2 h, or from about 15 min to about 1 h. Any combination of curing temperatures and curing times described herein is within the scope of this invention.

In some embodiments, the composition is subjected to a curing temperature until the high molar mass polyethylene oxide present in the sustained release matrix formulation reaches its softening temperature and / or at least partially melts. In some such embodiments, the curing time may be less than about 5 minutes, for example the curing time may vary from about 0 minutes to about 3 hours, or from about 1 minute to about 2 hours, or from about 2 minutes to about 1 hour. Instant curing is also possible, by choosing a curing device that allows instantaneous heating of the high molar mass polyethylene oxide in the sustained release matrix formulation to at least its softening temperature, so that the high molar mass sepolyethylene oxide at least partially melts. Such curing devices are, for example, microwave dryers, ultrasonic devices, a light irradiation apparatus such as a UV irradiation apparatus, ultra-high frequency (UHF) fields, or any method known to a person skilled in the art.

The person skilled in the art is aware that the size of the sustained release matrix formulation can determine the required curing time and curing temperature, in order to achieve the desired resistance to abuse. No desire to bond with anything

51162 Β by some theory, it is considered that in the case of a large sustained release matrix formulation, such as a large tablet, a longer curing time is required, during which heat is conducted to the interior of such a formulation, than in the case of a corresponding smaller formulation. Higher temperature increases the rate of thermal conductivity, and therefore reduces the required curing time.

When curing c) can take place in the dryer. Suitably, the curing step c) takes place in a sustained-release sustained release matrix formulation layer, e.g. in a coating vessel. The coating vessel allows the batch curing step to be performed, which can then be followed by a coating coating, without the need to switch dosage forms, e.g., tablets. Such a process may include the following steps:

(b) shaping said composition by forming a sustained release matrix formulation in the form of a tablet, by direct compression;

- subjecting the free-flowing tablet layer to a temperature 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 min, or at least about 5 min, preferably from at least about 30 min, in a coating pan, and

- then cooling the free-moving tablet layer to a temperature below about 50 ° C;

and then (d) coating this dosage form in said coating container.

In some embodiments, an additional curing step may follow the coating of the dosage form in step d). An additional curing step can be done as

51162 Β is described in curing step c). In some such embodiments, the curing temperature in this additional curing step is preferably at least about 70 ° C, at least about 72 ° C, or at least about 75 ° C, and the preferred curing time is in the range of about 15 min to about 1 h , for example about 30 min.

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

In some embodiments, the curing step c) reduces the density of the sustained release matrix formulation formulation, so that the density of the cured sustained release matrix formulation is lower than the density of the cured sustained release matrix formulation of the curing step c). Preferably, the density of the cured sustained release matrix formulation is reduced by at least about 0.5% compared to the density of the uncured sustained release matrix formulation. More preferably, the density of the cured sustained 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%, compared to the density of the uncured sustained release matrix formulation. . Without wishing to be bound by any theory, it is believed that the sustained release matrix formulation, due to the absence of elevated pressure during curing c), expands, leading to a decrease in density.

According to another aspect of the present invention, the density of the sustained release matrix formulation in a solid oral sustained release pharmaceutical dosage form, preferably in a dosage form containing oxycodone HCl 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 / cm 23, equal to or less than about 1.18 g / cm3, or equal to or less than about 1.17 g / cm3 For example, the density of the sustained release matrix formulation is in the range of about 1.10 g / cm3 up to about 1.20 g / cm3, of about 1.11 g / cm3 up to about 1.20 g / cm3, or from about 1.11 g / cm3 to about 1.19 g / cm3. Preferably it is within the range of

51162 Β about 1.12 g / cm3 to about 1.19 g / cm3, or from about 1.13 g / cm3 to about 1.19 g / cm3, more preferably about 1.13 g / cm 23 to about 1.18 g / cm3.

The density of the sustained release matrix formulation is preferably determined by the Archimedean principle, using a liquid of known density (p0). The mass of the sustained release matrix formulation is first weighed in air and then immersed in a liquid, then the mass is measured. From these two masses, the density of the sustained release matrix formulation, p can be determined using the equation:

A p = - po

A - B where p represents the density of the sustained release matrix formulation, A is the mass of the sustained release matrix formulation in air, B is the mass of the sustained release matrix formulation when immersed in the liquid, and p0 is the density of a liquid at a given temperature. A suitable liquid of known density, for example, is hexane.

Preferably, the density of the extended release matrix formulation is measured using a special scale, a Top-loading Mettler Toledo balance model, Model # AB 135-S / FACT, Serial # 1127430072, and a density determination kit 33360. It is preferable to use hexane, as a liquid of known density, p0.

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

The density of the sustained release matrix formulation is preferably related to the density of the uncoated formulation, for example the density of the tablet core. In those embodiments in which the sustained release matrix formulation is coated, for example when the sustained release matrix formulation is subjected to coating step d, after curing step c), the density of the extended release matrix formulation is preferably measured before performing the coating step, or by removal

51162 Β coatings from the coated sustained release matrix formulation, followed by measuring the density of the uncoated sustained release matrix formulation.

In the embodiments described above, high molar mass polyethylene oxide can be used, which based on rheological measurements has an approximate molar mass of from 2,000,000 to 15,000,000, or from 2,000,000 to 8,000,000. In particular, polyethylene oxides can be used, which, based on rheological measurements, have an approximate molar mass of 2,000,000, 4,000,000, 7,000,000 or 8,000,000. In particular, polyethylene oxides can be used which, based on rheological measurements, have an approximate molar mass of 4,000,000.

In embodiments in which the composition may further comprise at least one low molar mass polyethylene oxide, a polyethylene oxide having an approximate molar mass of less than 1,000,000 based on rheological measurements is used, such as polyethylene oxides based on rheological measurements. have an approximate molar mass of 100,000 to 900,000. The addition of such low molar mass polyethylene oxides can be used specifically to adjust the release rate, such as increasing the release rate of the formulation, which otherwise provides a release rate that is too low for the observed purposes. In such embodiments, at least one polyethylene oxide may be used, which, based on rheological measurements, has an approximate molar mass of 100,000.

In some such embodiments, the composition comprises at least one polyethylene oxide having an approximate molar mass of at least 1,000,000 based on rheological measurements, and at least one polyethylene oxide having an approximate molar mass of less than 1,000,000 based on rheological measurements, wherein the composition comprises at least about 10% by weight, or at least about 20% by weight of polyethylene oxide, which based on rheological measurements has an approximate molar mass of less than 1,000,000. In some such embodiments, the curing temperature is less than about 80 ° C, or even less than about 77 ° C.

51162 Β

In some embodiments, the total polyethylene oxide content of the composition is at least about 80% by weight. Without wishing to be bound by any theory, it is believed that the high polyethylene oxide contents provide the abuse resistance described herein, such as tensile strength and resistance to alcohol extraction. According to some such embodiments, the active ingredient is oxycodone hydrochloride, and the composition contains more than about 5% by weight of oxycodone hydrochloride.

In some such embodiments, the composition comprises at least one polyethylene oxide, which based on rheological measurements has an approximate molar mass of at least 1,000,000, in an amount of at least about 80% by weight. In some embodiments, the content in the composition of at least one polyethylene oxide, which based on rheological measurements has an approximate molar mass of at least 1,000,000, is at least about 85%, or at least about 90% by weight. In such embodiments, polyethylene oxide can be used, which based on rheological measurements has an approximate molar mass of at least 4,000,000, or at least 7,000,000. In some such embodiments, the active agent is ohusobope hydrochloride or hydromorphone hydrochloride, although other active agents may also be used in accordance with this aspect of the present invention, and the composition comprises more than about 5% by weight of oxycodone hydrochloride or hydromorphone hydrochloride.

In some embodiments in which the drug content of the composition is at least about 20% by weight, the polyethylene oxide content may be low, such as 75% by weight. In another embodiment, wherein the drug content of the composition is in the range of about 25 wt% to about 35 wt%, the polyethylene oxide content may be in the range of about 65 wt% to about 75 wt%. For example, in embodiments in which the drug content of the composition is about 32% by weight, the polyethylene oxide content may be about 67% by weight.

In some embodiments of the present invention, magnesium stearate is added, during or after the curing process / curing step, to avoid sticking between the tablets. In some such embodiments, magnesium stearate is added at the end of the curing process / curing step, prior to cooling the tablets, or during cooling of the tablets. Other anti-caking agents may be used, such as talc,

51162 Β silicon dioxide, evaporated silica, colloidal silicon dioxide, calcium stearate, carnauba wax, long chain fatty alcohols and waxes such as stearic acid and stearyl alcohol, mineral oil, paraffin, microcrystalline cellulose, glycerin and propylene glycol polyethylene glycol. Additionally, or alternatively, coating may begin at high temperatures.

In some embodiments, in which the curing step c) is performed in a coating vessel, the adhesion of the tablets can be avoided, or the adhered tablets can be disassembled by increasing the rotation speed of the container, during the curing step or after curing, in the latter case, for example before or during tablet cooling. The speed of rotation of the vessel increases to such a value when all the tablets are disassembled and no sticking occurs.

In some embodiments of the present invention, an initial coating film or fraction film of a coating is applied prior to performing the curing c). Coating with this film gives the sustained release matrix formulation or tablet a "coating", which functions as an anti-caking agent, i.e. with the aim of avoiding mutual adhesion of the formulations or tablets. In some such embodiments, the coating film that is applied prior to hardening is a coating with an Opadry film. After the curing step c), the film can be applied in the next step.

The present invention also encompasses any solid oral sustained release dosage form obtainable in the process, which is in accordance with any of the processes described above.

Independently, the present invention also relates to solid oral sustained release dosage forms.

In some embodiments, the present invention relates to solid oral sustained release pharmaceutical dosage forms comprising a sustained release matrix formulation comprising the active agent in tablet or granular form, wherein

51162 Β this tablet or individual granules can be crushed without tearing, which is characterized by the thickness of the tablet or individual granule after kneading, which corresponds to no more than 60% of the thickness of this tablet or individual granule before kneading, said crushed tablet or crushed granules having a dissolution rate in vitro, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid without enzyme (SZF), at 37 ° C, characterized by the percentage of the amount of active ingredient released during 0.5 h, or for 0.5 and 0.75 h, or for 0.5, 0.75 and 1 h, or for 0.5, 0.75, 1 and 1.5 h, or for 0.5, 0.75, 1, 1.5 and 2 h dissolution, which does not deviate by more than about 20% at each said time from the corresponding in vitro dissolution rate of the uncrushed reference tablet or reference beads.

In some such embodiments, the tablet or individual granules may be crushed without tearing, characterized by a thickness of the tablet or individual granule after kneading, which corresponds to no more than about 50%, or no more than about 40%, or no more than about 30%, or not more than about 20%, or not more than about 16% of the thickness of this tablet or individual bead before kneading, said crushed tablet or crushed beads having an in vitro dissolution rate measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SZF), at 37 ° C, characterized by the percentage of the amount of active substance released during 0.5 h, or for 0.5 and 0.75 h, or for 0.5, 0.75 and 1 h , or during 0.5, 0.75, 1 and 1.5 h or during 0.5, 0.75, 1,

1.5 and 2 h of dissolution, which does not deviate by more than about 20%, or no more than about 15%, at each said time from the corresponding in vitro dissolution rate of the uncrushed reference tablet or reference beads.

51162 Β have an in vitro dissolution rate, measured in a USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SŽF), at 37 ° C, which is between about 5 and about 40 % by weight of active agent released after 0.5 h.

In some such embodiments, the tablet or individual bead may be crushed without tearing, characterized by a thickness of the tablet or single bead after kneading, which corresponds to no more than about 50%, or no more than about 40%, or no more than about 30%, or not more than about 20%, or not more than about 16% of the thickness of this tablet or single bead of rge kneading, wherein said crushed tablet or crushed granules and uncrushed reference tablet or uncrushed reference granules have an in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 ml of simulated gastric fluid, without enzyme ( SJF), at 37 ° C, which is between about 5 and about 40% by weight of active agent released after 0.5 h, or is between about 5 and about 30% by weight of active agent released after 0.5 h, or is between about 5 and about 20% by weight of active agent released after 0.5 h, or is between about 10 and about 18% by weight of active agent released after 0.5 h.

In some embodiments, the present invention relates to a solid sustained release oral dosage form comprising a sustained release matrix formulation comprising the active agent in tablet or granular form, wherein the tablet or individual bead can be crushed without tearing, characterized in the thickness of the tablet or single bead after kneading, which corresponds to no more than about 60% of the thickness of this tablet or single bead before kneading, wherein the crushed or uncrushed tablet or crushed or uncrushed granules have an in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SZF), containing 40% ethanol, at 37 ° C, characterized by the percentage of the amount of active substance released during 0.5 h or for 0.5 and 0.75 h, or for 0.5, 0.75 and 1 h, or for 0.5, 0.75, 1 and 1.5 h, or for 0.5, 0.75, 1,

1.5 and 2 h of dissolution, which does not deviate by more than about 20% at any time from the corresponding in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzymes (SGF)

51162 Β at 37 ° C, without ethanol, using a crushed or uncrushed reference tablet or crushed or uncrushed reference beads, respectively.

In some such embodiments, the tablets or granules may be crushed without tearing, characterized by a thickness of the tablet or individual bead after kneading, which corresponds to no more than about 60%, or no more than about 50%, or no more than about 40%, or no more than about 30%, or not more than about 20%, or not more than about 16% of the thickness of this tablet or individual bead before kneading, wherein the crushed or uncrushed tablet or individual beads have an in vitro dissolution rate, measured in a USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (CZF), containing 40% ethanol, then 37 ° C, characterized by the percentage of the amount of active substance released during 0.5 h, or during 0.5 and 0.75 h, or during 0.5, 0.75 and 1 h, or during 0.5, 0.75, 1 and 1.5 h, or during 0.5, 0.75, 1, 1.5 and 2 h of dissolution, which does not deviate more than about 20% or not more than about 15% at each said time of the appropriate in vitro dissolution rate, measured in a USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, enzyme-free (SZF), at 37 ° C, without ethanol, using a crushed or uncrushed reference tablet or reference beads, respectively.

In some embodiments, the present invention relates to a solid sustained release oral dosage form, comprising a sustained release matrix formulation comprising the active agent in tablet or granular form, wherein the tablet or individual granules can be crushed without tearing, characterized in the thickness of the tablet or single bead after kneading, which corresponds to no more than about 60% of the thickness of this tablet or single bead before kneading, wherein the crushed or uncrushed tablet or crushed or uncrushed granules have an in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SZF), containing 40% or 0% ethanol, at 37 ° C, which is between about 5 and about 40% by weight of active agent released after 0.5 h.

51162 Β

In some such embodiments, the tablet or individual bead may be crushed without tearing, characterized by a tablet or single bead thickness after kneading, corresponding to no more than about 50%, or pe more than about 40%, or no more than about 30%, or not more than about 20%, or not more than about 16% of the thickness of this tablet or individual granule before kneading, wherein the crushed or uncrushed tablet or crushed or uncrushed granules have an in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric juice without enzyme (SJF), containing 40% or 0% ethanol, at 37 ° C, which is between about 5, and about 40 wt% released active agent after 0.5 h, or is between about 5 and about 30 wt% released active agent after 0.5 h, or is between about 5 and about 20 wt% released active agent after 0.5 h, Hi is between about 10 and about 18% by weight of active agent released after 0.5 h.

Such dosage forms can be prepared as described above.

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; and (2) at least one active agent, preferably selected from opiate analgesics;

wherein said composition comprises at least about 80% by weight of polyethylene oxide. This composition may also contain at least about 85 or 90% by weight of polyethylene oxide. According to some such embodiments, the composition comprises at least about 80% by weight of polyethylene oxide, the active agent is oxycodone hydrochloride or hydromorphone hydrochloride, and the composition contains more than about 5% by weight of oxycodone hydrochloride or hydromorphone hydrochloride.

51162 Β

In some such embodiments, the composition comprises at least about 80% by weight of polyethylene oxide, which based on rheological measurements has an approximate molar mass of at least 1,000,000.

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; and (2) 10 mg oxycodone hydrochloride;

and wherein the composition contains at least about 85% by weight of polyethylene oxide.

(1) at least one polyethylene oxide, which, based on rheological measurements, has an approximate molar mass of at least 1,000,000; and (2) 15 mg or 20 mg oxycodone hydrochloride;

wherein said composition comprises at least about 80% by weight of polyethylene oxide.

(1) at least one polyethylene oxide, which, based on rheological measurements, has a molar mass of at least 1,000,000; and (2) 40 mg oxycodone hydrochloride;

wherein said composition comprises at least about 65% by weight of polyethylene oxide.

51162 Β

(1) at least one polyethylene oxide, having a molar mass of at least 1,000,000 based on rheological measurements; and (2) 60 mg or 80 mg oxycodone hydrochloride;

wherein said composition comprises at least about 60% by weight of polyethylene oxide.

(1) at least one polyethylene oxide, having a molar mass of at least 1,000,000 based on rheological measurements; and (2) 8 mg of hydromorphone hydrochloride;

and wherein the composition contains at least about 94% by weight of polyethylene oxide.

(1) at least one polyethylene oxide, having a molar mass of at least 1,000,000 based on rheological measurements; and (2) 12 mg hydromorphone hydrochloride;

and wherein the composition contains at least about 92% by weight of polyethylene oxide.

51162 Β (1) at least one polyethylene oxide, having a molar mass of at least 1,000,000 based on rheological measurements; and (2) 32 mg of hydromorphone hydrochloride;

wherein the composition comprises at least about 90% by weight of polyethylene oxide.

In some embodiments, the present invention also relates to a solid sustained release oral dosage form comprising a sustained release matrix formulation, and the sustained release matrix formulation comprises a composition comprising at least:

(1) at least one active agent, preferably selected from opiate analgesics;

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

51162 Β (1) at least one polyethylene oxide, which, based on rheological measurements, has a molar mass of at least 800,000 or at least 900,000; and (2) at least one active agent, selected from opiate analgesics; and wherein the composition comprises at least about 80% by weight of polyethylene oxide.

In some embodiments of the present invention, the sustained release matrix has a density equal to or less than about 1.20 g / cm3. In some such embodiments, the density of the sustained release matrix formulation is equal to or less than about 1.19 g / cm3, preferably equal to or less than about 1.18 g / cm 23, or equal to or less than about 1.17 g / cm3. For example, the density of the sustained release matrix formulation is in the range of about 1.10 g / cm3 up to about 1.20 g / cm3, of about 1.11 g / cm3 up to about 1.20 g / cm3, or from about 1.11 g / cm3to about 1.19 g / cm3. Prefer a range of about 1.12 g / cm3 to about 1.19 g / cm3, or from about 1.13 g / cm3 to about 1.19 g / cm3, more preferably about 1.13 g / cm3 to about 1.18 g / cm3. Preferably, the density is determined using the Archimedes principle, as described above.

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

wherein the sustained release matrix formulation, when subjected to the embossing test, has a crack-forming force of at least about 110 N.

In some embodiments of the present invention, the sustained release matrix formulation has a crack-forming force of at least about 110 N, preferably of at least about 120 N, at least about 130 N, or at least about 140 N, more preferably than

51162 Β at least about 150 N, at least about 160 N, or at least about 170 N, most preferably from at least about 180 N, at least about 190 N, or at least about 200 N.

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

wherein the sustained release matrix formulation, when subjected to the embossing test, has a penetration depth distance along the crack of at least about 1.0 mm.

In some embodiments of the present invention, the sustained release matrix formulation has a crack penetration depth distance of at least about 1.0 mm, or at least about 1.2 mm, preferably from at least about 1.4 mm, at least about 1.5 mm, or at least about 1.6 mm, more preferably from at least about 1.8 mm, at least about 1.9 mm or at least about 2.0 mm, most preferably from at least about 2.2 mm, at least about 2.4 mm or at least about 2.6 mm.

In some such embodiments of the present invention, the sustained release matrix formulation has a crack-forming force of at least about 110 N, preferably of at least about 120 N, at least about 130 N, or at least about 140 N, more preferably of at least about 150 N, at least about 160 N , or at least about 170 N, most preferably from at least about 180 N, at least about 190 N, or at least about 200 N, and / or a distance "along the crack penetration depth" of at least about 1.0 mm or at least about 1.2 mm, preferably of at least about 1.4 mm, at least about 1.5 mm, or at least about 1.6 mm, more preferably from at least about 1.8 mm, at least about 1.9 mm, or at least about 2.0 mm, most preferably from at least about 2.2 mm, at least about 2.4 mm, or at least about 2.6 mm. A combination of any of the above-mentioned crack force values and

51162 The "distance" along the crack penetration depth is within the scope of the present invention.

In some such embodiments, the sustained release matrix formulation, when subjected to the embossing test, resists operation of at least about 0.06 J, or at least about 0.08 J, preferably of at least about 0.09 J, at least about 0.11 J, or at least about 0.13 J, more preferably of at least about 0.15 J, at least about 0.17 J, or at least about 0.19 J, most preferably from at least about 0.21 J, at least about 0.23 J, or at least about 0.25 J, without cracking.

The parameters “crack formation force”, “distance along crack penetration depth” and “operation” are determined using the indentation test, as described above, using the Texture Analyzer instrument, model -Α-ΧΤ2 Texture Analyzer (Texture Technologies Corp., 18 Fairview Road , Scarsdale, NY 10583). The crack formation force and / or the distance “along the crack penetration depth” can be determined using an uncoated or coated sustained release matrix formulation. Preferably, the crack formation force and / or the distance “along the crack penetration depth” is determined on an uncoated sustained release matrix formulation. Without wishing to be bound by any theory, a coating, such as the coating performed in step d) of the manufacturing process of the solid oral sustained release dosage form described above, is not considered to contribute significantly to the observed crack formation force and / or distance "along the depth of crack penetration". Therefore, the crack formation force and / or the distance “along the crack penetration depth” determined for the specific coated sustained release matrix formulation is not expected to vary substantially from the corresponding uncoated sustained release matrix formulation.

In some embodiments, the sustained release matrix formulation is in the form of a tablet or granules, and the tablet or individual bead can be crushed without tearing, characterized by the thickness of the tablet or single bead after kneading, corresponding to no more than 60% of the thickness of this tablet or single bead. kneading. It is desirable that

51162 Β the tablet or individual bead can be crushed without tearing, which is characterized by the thickness of the tablet or individual bead after kneading, which corresponds to not more than about 50%, or not more than about 40%, or not more than about 30%, or not more than about 20%, or not more than about 16%, of the thickness of this tablet or single bead before kneading.

Preferably, the crushing of tablets or individual granules is performed with a table press, such as a table press, a blade type, or with a hammer, as described above.

In some such embodiments, the sustained release matrix formulation is in the form of a tablet or granules, and the tablet or individual bead can be crushed without tearing, characterized by the thickness of the tablet or single bead after kneading, corresponding to no more than 60% of the thickness of this tablet or single bead. before kneading, said crushed tablet or crushed granules having an in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm , in 900 mL of simulated gastric fluid, without enzyme (SŽF), at 37 ° C, characterized by the percentage of the amount of active substance released during 0.5 h, or for 0.5 and 0.75 h, or for 0.5, 0.75 and 1 h, or for 0.5, 0.75 , 1 and 1.5 h, or during 0.5, 0.75, 1, 1.5 and 2 h of dissolution, which deviates by more than about 20% at each said time from the corresponding in vitro dissolution rate of the uncrushed reference tablet or uncrushed reference beads. Preferably, the tablet or individual bead can be crushed without crushing, characterized by the thickness of the tablet or individual bead after kneading, which corresponds to no more than about 50%, or no more than about 40%, or no more than about 30%, or not more than about 20%, or not more than about 16%, of the thickness of this tablet or a single bead of rge kneading, said crushed tablet or crushed beads having an in vitro dissolution rate, measured in a USP Apparatus 1 (with a basket), with 100 r / min, in 900 mL of simulated gastric fluid, without enzyme (SŽF), at 37 ° C, characterized by the percentage of the amount of active substance released during 0.5 h, or for 0.5 and 0.75 h, or for 0.5, 0.75 and 1 h, or for 0.5, 0.75 , 1 and 1.5 h, or during 0.5, 0.75, 1, 1.5 and 2 h of dissolution, which does not deviate more than about 20%, or pe more than about 15%, in each mentioned

51162 Β the time from the appropriate in vitro dissolution rate of the uncrushed reference tablet or uncrushed reference beads.

In some embodiments, the present invention relates to a solid sustained release oral dosage form, comprising a sustained release matrix formulation, wherein the sustained release matrix formulation is in the form of a tablet or granules, and the tablet or individual granules can be crushed without tearing. , characterized by the thickness of the tablet or single bead after kneading, which corresponds to no more than 60% of the thickness of this tablet or single bead before kneading, wherein the crushed or uncrushed tablet or crushed or uncrushed granules have an in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SZF), containing 40% ethanol, at 37 ° C, characterized by the percentage of the amount of active substance released during 0.5 h, or for 0.5 and 0.75 h, or for 0.5, 0.75 and 1 h, or for 0.5, 0.75, 1 and 1.5 h, or for 0.5 , 0.75, 1, 1.5 and 2 h of dissolution, which deviates more than about 20% at any one time, from the corresponding in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (CZF), at 37 ° C, without ethanol, using a crushed or uncrushed reference tablet or crushed or uncrushed reference beads, respectively. Preferably, the tablet or granules can be crushed without tearing, characterized by the thickness of the tablet or individual bead after kneading, which corresponds to no more than about 60%, or no more than about 50%, or no more than about 40%, or no more of about 30%, or not more than about 20%, or not more than about 16% of the thickness of this tablet or individual bead before kneading, wherein the crushed or uncrushed tablet or individual beads have an in vitro dissolution rate, measured in a USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SŽF), containing 40% ethanol, then 37 ° C, characterized by the percentage of the amount of active substance released during 0.5 h, or during 0.5 and 0.75 h, or during 0.5, 0.75 and 1 h, or during 0.5, 0.75, 1 and 1.5 h, or during 0.5, 0.75, 1, 1.5 and 2 h of dissolution, which does not deviate by more than about 20% or not more than about 15% in each mentioned time, from the appropriate in vitro dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL

51162 Β simulated gastric fluid, enzyme-free (SZF), at 37 ° C, ethanol-free, using crushed and uncompressed reference tablets or reference granules, respectively.

In some such embodiments, the formation of the sustained release matrix does not break when subjected to a maximum force of about 196 N or about 439 N in the tablet hardness test.

Preferably, the tablet hardness test, which determines the breaking strength of the sustained release matrix formulation, is performed in an apparatus, model Schleuniger Apparatus, as described above. For example, the breaking strength is determined using an apparatus, model Schleuniger 2E / 106 Apparatus, using a maximum force of about 196 N, or an apparatus, model Schleuniger Model 6D Apparatus, applying a maximum force of about 439 N.

It has been observed that the formulations of the present invention are storage stable, wherein the sustained release matrix formulation, after storage at 25 ° C and 60% relative humidity (RH), or at 40 ° C and 75% relative humidity (RH), for at least 1 month, more preferably for at least 2 months, for at least 3 months, or for at least 6 months, gives the dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric juice without enzymes ( SŽF), at 37 ° C, characterized by the percentage of the amount of active substance released during 1 h, or for 1 and 2 h, or for 1 and 4 h, or for 1, 2 and 4 h, or for 1, 4 and 12 h, or for 1, 2, 4 and 8 h, or during 1, 2, 4, 8 and 12 h of dissolution, which does not deviate by more than about 15%, preferably not more than about 12%, or not more than about 10%, more preferably not more than about 8% , or not more than about 6%, most preferably not more than about 5% at each mentioned time, from the appropriate in vitro dissolution rate of the reference formulation before storage. Preferably, the sustained release matrix formulation is stored in bottles, such as 100 labeled bottles. Any combination of the aforementioned storage times, dissolution times, and tolerance limits is within the scope of this invention.

51162 Β

According to another aspect of storage stability, a sustained release matrix formulation, after storage at 25 ° C and 60% relative humidity (RH), or at 40 ° C and 75% relative humidity (RH), for at least 1 month, is more preferred. for at least 2 months, for at least 3 months, or for at least 6 months, contains an amount of at least one active agent, in wt%, relative to the specification of the active agent in the sustained release matrix formulation, not deviating more than about 10%, preferably not more than about 8%, or pe more than about 6%, more preferably not more than about 5%, Hi not more than about 4%, or not more than about 3% of the corresponding the amount of active agent in wt%, relative to the specification of the active agent in the sustained release formulation matrix of the reference formulation prior to storage. Preferably, the sustained release matrix formulation is stored in bottles, such as 100 labeled bottles. Any combination of the above-mentioned storage times and tolerance limits is within the scope of the present invention.

According to these embodiments, the active agent is oxycodone hydrochloride.

Preferably, the amount of at least one active agent, in wt%, relative to the specification specification in the sustained release matrix formulation, is determined by extracting at least one active agent from the sustained release matrix formulation and then analyzing using high performance liquid chromatography. In some embodiments, in which the at least one active agent is oxycodone hydrochloride, it is preferred that the oxycodone hydrochloride content, by weight%, relative to the specification of oxycodone hydrochloride in the sustained release matrix formulation, is determined by extracting oxycodone hydrochloride from the sustained release matrix formulation. : 2 with a mixture of acetonitrile and simulated gastric fluid, without enzymes (SZF), with constant stirring with a magnetic stirrer, until the sustained release matrix formulation is completely dispersed, or overnight, and then analyzed using high performance liquid chromatography, preferably high performance reverse phase high performance chromatography. In some such realizations, and in doing so

51162 Β prolonged-release matrix formulation in tablet form, preferably oxycodone hydrochloride content, by weight, relative to oxycodone hydrochloride specification in tablets, is determined by extracting oxycodone hydrochloride from two sets of tablets, each with 900 mL of a 1: 2 mixture of acetonitrile and simulated gastric fluid, without enzymes (SZF), with constant stirring with a magnetic stirrer, while the tablets are completely dispersed, or overnight, and then analyzed using high performance liquid chromatography, preferably with reverse phase. It is desirable that the results of this test are mean values from two measurements.

In some embodiments, the present invention relates to a solid oral sustained release dosage form, wherein the dosage form has a dissolution rate, measured in a USP Apparatus 1 (with a basket), at 100 rpm, in 900 mL of simulated gastric juice. without enzyme (SŽF), at 37 ° C, which is between 12.5 and 55 wt.% released active agent after 1 h, between 25 and 65 wt.% released active agent after 2 h, between 45 and 85 wt.% released active agent after 4 h h and between 55 and 95% by weight of active agent released after 6 hours, optionally between 75 and 100% by weight of active agent released after 8 hours. Preferably, the dosage form has a dissolution rate, measured in a USP Apparatus 1 (with a basket), at 100 rpm, in 900 mL of simulated gastric juice without enzyme (SZF), at 37 ° C, which 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 of active agent released after 4 hours, and between 60 and 90% by weight of active agent released after 6 hours, optional between 80 and 100% by weight of active agent released after 8 h. More preferably, the dosage form has a dissolution rate, measured in USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric juice without enzyme (SZF), at 37 ° C, which is between 17.5 and 35 % by weight of 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, optional between 85 and 100% by weight of active agent released after 8 h.

51162 Β

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

These dosage forms can be prepared by the process described herein.

In the embodiments described above, the tablet may be formed by directly compressing the composition and curing by subjecting said 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 period of time of at least about 1 min, at least about 5 min, or at least about 15 min.

In some embodiments of the present invention, the tablet described above may be coated with a powder layer by applying a layer of polyethylene oxide powder to a cured or uncured tablet so as to surround its core, and then curing the tablet with a layer of this powder as described above. Such an outer layer of polyethylene oxide provides a delay in the time of onset of release of the active ingredient and / or a reduction in the overall dissolution rate.

In some embodiments of the present invention, an integral bilayer or multilayer tablet is produced, wherein at least one of the layers comprises a sustained release formulation as described above, and at least one of the other layers comprises a sustained release formulation of the active agent contained within the sustained release formulation. by release, or some other active agent. In some such embodiments, the tablet is a bilayer tablet, with a sustained release formulation layer, as described herein, and an immediate release formulation layer. In some such embodiments, particularly bilayer tablets, opiate analgesics are contained in the sustained release layer, and additional non-opiate analgesics are contained in the immediate release layer. Non-opiate analgesics may be nonsteroidal anti-inflammatory agents, but also non-opiate analgesics, such as acetaminophen. Eg. acetaminophen can be used in combination with hydrocodone as an opiate analgesic. Such tablets can be obtained

51162 Β specific tablet compression techniques, which allow the compression of at least two tablet forming compositions with at least two different bonded layers, each of which contains one of at least two compositions. For example, such tablets may be produced in a tablet press by filling a compression tool with the first composition, then compressing said first composition, then over the compressed first composition by filling the second composition, then compressing the two compositions and forming a final layered tablet. The immediate release composition may be any composition known in the art.

The present invention also encompasses the use of high molar mass polyethylene oxide, which, based on rheological measurements, has a molar mass of at least 1,000,000, as a matrix-forming material, in the manufacture of a solid sustained release oral dosage form containing the active ingredient of choice. between opiates, giving the solid sustained release dosage form resistance to alcohol extraction. This use can be accomplished as described herein, in connection with the process or formulations described, or in any other manner conventional in the art.

It has been observed that the compositions of the present invention, which contain high molar mass polyethylene oxide, can be crushed to a thickness of between about 15 and about 18% of the thickness of the uncrushed formulation, while the crushed tablet partially or substantially retains the initial uncrushed tablet form during dissolution, neglecting swelling that also occurs during dissolution, i.e., the thickness of the tablet increases and the diameter of the tablet decreases significantly during dissolution. Without wishing to be bound by any theory, high molar mass polyethylene oxide is considered to have the property of memorizing shape and the ability to retain its initial shape after deformation, e.g., after kneading, in an environment that allows regeneration, such as an aqueous medium used in dissolution tests. This property is believed to contribute to the abuse resistance, in particular the alcohol resistance, of the dosage form of the present invention.

51162 Β

The present invention also encompasses a method of treatment, wherein the dosage form is administered to treat a disease or condition of a patient in which pain treatment is specifically required, and the use of a dosage form according to the present invention for the manufacture of a medicament for treating a disease or a patient condition in which pain treatment is specifically required.

In one aspect of the present invention, a solid oral sustained release dosage dosage form is administered twice daily, which after administration to human patients provides a steady state with a mean tmax of from about 2 to about 6 hours, or from about 2.5 to about 5.5 hours, or from about 2.5 to about 5 h, for a single dose. This dosage form may contain oxycodone or a salt thereof, or a hydromorphone or a salt thereof.

In one aspect of the present invention, a solid oral sustained release dosage form is administered once a day, which, after administration to human patients, provides a steady state with a mean tmax from about 3 to about 10 h, or from about 4 to about 9 h, or from about 5 to about 8 h, for a single dose. This dosage form may contain oxycodone or a salt thereof, or a hydromorphone or a salt thereof.

In another aspect of the present invention, there is administered a solid oral sustained release dosage form twice a day, wherein the dosage form comprises oxycodone or a salt thereof, in a content of about 10 mg to about 160 mg, wherein the dosage form is provides a mean maximum plasma concentration of oxycodone (Cmax) at steady state, and up to about 240 ng / mL, or from about 6 ng / ml_ to about 240 ng / mL, after administration or after a single dose to human patients.

In another aspect of the present invention, there is provided a solid oral extended release dosage form, wherein the dosage form comprises oxycodone or a salt thereof, in a content of about 10 mg to about 40 mg, wherein the dosage form is

51162 Β provides the mean maximum plasma concentration of oxycodone (Cmax), at steady state, from about 6 ng / mL to about 60 ng / mL, after administration or after a single dose to human patients.

In another aspect of the present invention, there is provided a solid sustained release oral dosage form that is bioequivalent to the commercial product OxyContin®.

In another aspect of the present invention, there is provided a solid oral sustained release dosage form that is bioequivalent to the commercial product Palladone ™, marketed since 2005 in the United States.

In another aspect of the present invention, there is provided a solid sustained release oral dosage form, wherein the active agent is oxycodone hydrochloride, wherein the dosage form comprises 10 mg of oxycodone hydrochloride, which, after testing in a comparative clinical study, is bioequivalent to the reference tablet containing 10 mg of oxycodone hydrochloride in matrix formulation, consisting of:

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 (solid): 10.0 mg / tablet

e) Triacetin®: 2.0 mg / tablet

f) Stearyl alcohol: 25.0 mg / tablet

d) Talk: 2.5 mg / tablet

h) Magnesium stearate: 1.25 mg / tablet;

and this reference table is obtained in the following steps:

First Eudragit® RS 30D and Triacetin® are combined by passing through a 60 mesh sieve, then stirring for 5 min with low shear, or until a uniform dispersion is obtained.

51162 Β

Second Oxycodone HCl, lactose and povidone are placed in a fluidization column which is a granulator / dryer (FBD), and this suspension is sprayed into a powder in a fluidization column.

Third After spraying, the granulate is passed through sieve # 12, if it is necessary to reduce clots.

4th This dry granulate is transferred to a mixer.

5th Meanwhile, dissolve the required amount of stearyl alcohol, at a temperature of approximately 70 ° C.

6th The molten stearyl alcohol is added to the granulate with stirring.

7th The waxed granulate thus transferred to a fluidization column, which is at the same time a granulator / dryer, or to trays, and allowed to cool to room or lower temperature.

8th The granulate thus cooled is passed through a # 12 sieve.

9th This wax granulate is transferred to a mixer / blender, and lubricated with the required amount of talc and magnesium stearate for approximately 3 minutes.

10th This granulate is compressed into 125 mg tablets in a suitable tableting machine.

Pharmacokinetic parameters, such as Cmax and tmax> AUCt, AUCinf, etc. describing the blood plasma curve, can be obtained in clinical trials, first by administering a single dose of the active agent, e.g., oxycodone, to a number of test subjects, such as healthy human subjects. Plasma values of individual test subjects are then averaged, eg as AUC, Cmax itmax> and thus the mean values are obtained. In the context of the present invention, pharmacokinetic parameters, such as AUC, CmAndxitmax refer to mean values. Further, in the context of the present invention, in vivo parameters, such as AUC, C valuesmax, tmax, or analgesic efficacy, refer to steady-state parameters or values obtained after administration or after a single dose to human patients.

51162 Β

Value Cmax shows the maximum concentration of the active agent in the blood plasma. The value of tmax shows the time in which C is reachedmax. In other words, tmax is the time when the maximum plasma concentration is observed.

The AUC value (from the area under the curve) corresponds to the area of the concentration curve. The AUC value is proportional to the total amount of active agent absorbed into the bloodstream, and therefore represents a measure of bioavailability.

AUC valuet corresponds to the area under the plasma-time concentration curve, from the time of administration to the last measurable plasma concentration, and is calculated using an ascending linear / descending logarithmic trapezoidal rule.

AUCjnf is the area under the plasma-time concentration curve, extrapolated to infinity, and is calculated using the formula:

AUC „, = AUC, +The

L-u where Ct represents the last measurable plasma concentration, and λζ is the apparent rate constant of the terminal phase.

λζ represents the apparent rate constant of the terminal phase, where λζ the slope value of the linear regression profile of the concentration logarithm from time, during the terminal phase.

ti / 2z represents the half-life of the apparent terminal phase, and is usually defined as ti / 2z = (In2) / λζ.

Delay time youag is estimated as the time immediately before the first measurable plasma concentration value.

The term "healthy human person" refers to a male or female person, with average values of height, weight and physiological parameters, such as blood pressure, etc. Healthy human persons for the purposes of the present invention are selected according to inclusion and exclusion criteria, which are based on and in accordance with the recommendations

51162 Β International Body, International Conference for Harmonization of Clinical Trials (ICH).

Thus, the inclusion criterion includes male and female persons between the ages of 18 and 50, in conclusion, body mass ranging from 50 to 100 kg, and with a Body Mass Index (BMI)> 18 and <342), and those individuals are healthy and free of significant abnormalities, based on medical history, physical examination, signs of vitality, and electrocardiograms, and women, who have the potential to give birth, must use an adequate and reliable contraceptive procedure, such as a barrier with additional spermicidal foam or gel, some intra-uterine device, hormonal contraception (hormonal contraceptives alone, are not acceptable), that women whose menstruation has stopped, they must be menopausal for 1 year and have an elevated serum follicle-stimulating hormone (FSH) content, and all of these subjects are willing to eat all the food given to them during the test.

The next criterion for inclusion may be that individuals refrain from strenuous exercise throughout the examination and will not begin a new exercise program, nor participate in any unusually strenuous physical exertion.

Exclusion criteria include women who are pregnant (positive for a beta human chorionic gonadotropin test) or are breastfeeding, any history and current drug or alcohol abuse during the previous five years, a history of any current condition that may interfere with absorption, distribution, metabolism, or drug excretion, use of a drug containing an opiate for the past thirty (30) days, history of known susceptibility to oxycodone, naltrexone, or related compounds, any history of frequent nausea or vomiting, regardless of etiology, any history of head injuries or trauma with immediate consequences, participation in any clinical trial of the drug for thirty (30) days prior to the first dose in this trial, any significant illness during thirty ( 30) days before the first dose in this study, use of any drugs as a therapy to replace the hormone thioride (hormonal contraception is allowed), then vitamins, herbal, and / or

51162 Β mineral supplements, for 7 days before the first dose in this study, refusal and abstinence from food for 10 h before and 4 h after administration of the tested drugs, and complete abstinence from caffeine and xanthine during each restriction, alcohol consumption within forty-eight ( 48) h from the beginning of drug administration (1. day), or at any time after the start of the drug administration trial, history of smoking or use of nicotine products within 45 days of the drug administration trial, or a positive urinary cotinine test, voluntary donation of blood or blood products during the 30 days prior to drug administration or at any time during the study, unless required by the clinical test protocol, positive urine test results, alcohol testing during the test in each period, and hepatitis B surface antigen (HBsAg), hepatitis B surface antibody HBsAb (if not immunized), hepatitis C antibody (anti-HCV), positive test for Naloxone HCl, presence of Gilbert's syndrome or any known hepatobiliary abnormalities, and if the Examiner considers the person unsuitable for some reasons not listed above.

Persons who meet all the inclusion criteria and none of the exclusion criteria are included statistically distributed in the survey.

An enrolled group is a group of persons who have been informed and who have given written consent.

A statistically safe group is a group of subjects who are statistically distributed, who receive a drug and have at least one post-dose safety evaluation.

A complete analysis of this group on PK-metry, is for the group of subjects statistically selected, receiving the drug, and has at least one valid PK-metry. Subjects who vomit within 12 h after dosing may be included based on visual examination of the PK profile, prior to database closure. Subjects and profiles / metrics excluded from the analysis are documented in the Statistical Analysis Plan.

51162 Β

In the Naloxone HCI exposure test, vital signs and pulse oximetry (SPO)2) are taken before the Naloxone HCI exposure test. Exposure to Naloxone HCl can be performed by intravenous or subcutaneous administration. For intravenous administration, the needle or cannula should remain in the hand during administration. 0.2 mg Naloxone HCl (0.5 mL) was administered by intravenous injection. The person is observed for 30 s to record signs of exclusion or symptoms. 0.6 mg of Naloxone HCl (1.5 mL) was then administered by intravenous injection. This person is observed for 20 min for signs and symptoms of exclusion. For subcutaneous administration, 0.8 mg of Naloxone HCl (2.0 mL) was administered and the person was observed for 20 min for signs and symptoms of exclusion. After 20 min of observation after exposure to Naloxone HCI, vital signs and SPO are tested.2.

Vital signs are systolic blood pressure, diastolic blood pressure, pulse, respiratory rate, and oral temperature.

Through the Questionnaire "How are you feeling?", For each measurement of a vital sign, people are examined through the non-suggestive question "How are you feeling?", Such as "Are there any changes in your health after testing / since the last question?". The person's response is assessed to determine if any adverse effects should be noted. Individuals are also encouraged to voluntarily report adverse effects that occur at any other time during the trial.

Each person receiving food treatment will eat a standard high-fat meal, in accordance with the Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies (US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, December 2002). This meal is given 30 min before dosing, and is eaten at a steady rate over a period of 25 min, so that it is completed 5 min before dosing.

51162 Β

Clinical laboratory evaluations performed during these clinical trials include biochemistry (no food for at least 10 h), hematology, serology, urine analysis, drug abuse test, and other tests.

Biochemical tests (without food for at least 10 h) are determination of albumin, alkaline phosphatase, alanine aminotransferase (alanine transaminase, ALT), asparagine aminotransferase (asparagine transaminase, AST), calcium, chloride, creatinine, glucose, inorganic phosphate phosphate, bilirubin, total protein, urea, lactate dehydrogenase (LDH), direct bilirubin and CO2.

Haematological examinations include determination of hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell count, differential white blood cell count (% and absolute): basophils, eosinophils, lymphocytes, monocytes and neutrophils.

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

Urinary analyzes include determination of color, appearance, pH, glucose, ketone, urobilinogen, nitrite, invisible blood, protein, eukocyte esterase, microscopic and macroscopic evaluation, specific gravity.

Drug abuse testing includes urine testing for opiates, amphetamines, cannabinoids, benzodiazepines, cocaine, cotinine, barbiturates, phenylcyclidines, methadone, and propoxyphene, and alcohol tests such as blood alcohol and breath tests.

Additional tests for women include only the serum pregnancy test, the urine pregnancy test, and the serum follicle-stimulating hormone (FSH) test (only for women who self-report postmenopause).

51162 Β

DETAILED DESCRIPTION OF DESIRABLE REALIZATIONS

The present invention will now be more fully described by reference to the accompanying examples. However, the following description is intended to be illustrative only and should not be construed as limiting the invention in any way.

Example 1

In Example 1, a 200 mg tablet was obtained, with 10 mg of oxycodone HCl, using high molar mass polyethylene oxide, in combination with hydroxypropylcellulose. composition:

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

<td>Oxycodone HCI</td><td> 10</td><td> 5</td>

<td>Polyethylene oxide (MW: approx. 4,000,000; Polyox ™ VVSR-301)</td><td> 160</td><td> 80</td>

<td>Hydroxypropylcellulose (Klucel ™ HXF)</td><td> 30</td><td> 15</td>

<td>In total</td><td> 200</td><td> 100</td>

Production process:

The steps in the production of tablets are as follows:

First Ohusobope HCl, polyethylene oxide and hydroxypropylcellulose are mixed dry in a low / high shear mixer, model Black & Decker Handy Chopper dual blade mixer, capacity 355 mL.

Second The aperture from step 1 is compressed into the target mass, in a single tablet press, model Manesty Ture F 3.

Third The tablets from Step 2 are spread out on a tray and placed in an oven, Hotpack Model 435304, at 70 ° C, and held for approximately 14.5 h for the tablets to harden.

In vitro testing, including abuse resistance testing (hammer and tear strength test) and alcohol extraction resistance, was performed as follows.

51162 Β

Tablets were tested in vitro, using a USP Apparatus 2 (spatula), at 50 rpm, in 900 mL of simulated gastric fluid, without enzyme (SZF), at 37 ° C, using a spectrometer, model Perkin Elmer UVA / IS Spectrometer Lambda 20, with UV detection at 230 nm. These results are given in Table 1.1.

Uncured tablets, hardened tablets and abused tablets, ie crushed, hardened tablets, were tested. The hardened tablets are crushed with a hammer, using 7 hand-made hammer blows, to cause abused physical damage. The dimensions of the tablets before and after kneading were taken on these samples, and certain dissolution profiles on separate samples. These results are given in Table 1.1.

Next, an abuse resistance test was performed, hardened tablets were subjected to a tear strength test, using a maximum force of 196 N, using an apparatus, model Schleuniger 2E / 106 Apparatus, to assess tear resistance. These results are also shown in Table 1.1.

In addition, the hardened tablets were tested in vitro using ethanol / SJF medium, with ethanol concentrations of 0%, 20% and 40%, to evaluate the power of alcohol extraction. Testing was performed using a USP Apparatus 2 (paddle), at 50 rpm, in 500 mL medium, at 37 ° C, using a spectrometer, model Perkin Elmer UV / VIS Spectrometer Lambda 20, with UV detection and then 220 nM. Sampling times are 0.5 and 1 h. These results are also given, in Table 1.2.

51162 Β

TABLE 1.1

<td colspan="2"></td><td></td><td colspan="2">Hardened</td>

<td colspan="2"></td><td>Uncured whole</td><td>Celcom</td><td>Crushed with 7 hammer blows</td>

<td rowspan="4">Tablet dimensions</td><td>Thickness (mm)</td><td></td><td> 4.39 1</td><td> ” 2.232</td>

<td>Diameter (mm)</td><td> -</td><td> 7.56 1</td><td> 10.27 2</td>

<td>Tear strength (N)</td><td> -</td><td> 196+ 3</td><td> -</td>

<td>Diameter (mm) after tear strength test</td><td> -</td><td> 7.33 1</td><td> -</td>

<td rowspan="6">dissolution (Released, %) (n = 3 tablets per dish)</td><td>0.5 h</td><td> 13</td><td> 34</td><td> 33</td>

1 η = median 3 measurements 2 η = median 5 measurements 3196+ means that, subjected to a maximum force of 196 N, the tablets did not break, n = median 3 measurements.

TABLE 1.2

<td colspan="7">dissolution (released,%) (p = 2 tablets / cup)</td>

<td>time</td><td colspan="2">Ethanol concentration in NWF</td><td colspan="2">Ethanol concentration in NWF</td><td colspan="2">Ethanol concentration in NWF</td>

<td></td><td>uncured</td><td>hardened</td><td>uncured</td><td>hardened</td><td>uncured</td><td>hardened</td>

51162 Β

Example 2

In Example 2, three different 100 mg tablets were obtained, with 10 and 20 mg of Oxycodone HCl, using high molar mass polyethylene oxide, and optionally hydroxypropylcellulose. compositions:

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

<td>Ingredient</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td>

<td>Oxycodone HCI</td><td> 10</td><td> 20</td><td> 10</td>

<td>Polyethylene oxide (MW: approx. 4,000,000; Polyox ™ VVSR301)</td><td> 90</td><td> 80</td><td> 85</td>

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

<td>In total</td><td> 100</td><td> 100</td><td> 100</td>

Production process:

The steps of the tablet production process are as follows:

First Oxycodone HCl, polyethylene oxide and hydroxypropylcellulose are mixed dry, in a low / high shear mixer, model Black & Decker Handy Chopper dual blade mixer, capacity 355 mL.

Second The aperture from 1. Kogak is compressed into the target mass, in a single tablet press, model Manesty Ture F 3 press.

Third The tablets from 2. Kogaka are spread out on a tray, placed in an oven, Hotpack model 435304, at 70 - 75 ° C, and kept for approximately 6 to 9 hours for the tablets to harden.

In vitro testing, including abuse resistance testing (table press and tear strength test) is performed as follows.

The hardened tablets are tested in vitro, using a USP Apparatus 2 (spatula), at 50 rpm, in 500 mL of simulated gastric fluid, without enzyme (SZF), at 37 ° C, using a spectrometer, model Perkin Elmer UV / VIS Spectrometer Lambda 20, UV

51162 Β detection at 220 nm. Hardened tablets and hardened crushed tablets are tested. The tablets are kneaded using a pressure of 172 bar in a table press, model Carver style bench press, to commit physical abuse. These results are given in Table 2.

Then, an abuse resistance test was performed, the hardened tablets were subjected to a tear strength test, applying a maximum force of 196 N, using an apparatus, model Schleuniger 2E / 106 Apparatus, to determine the tear resistance. These results are given 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>cele (n = 6)</td><td>crushed table a press</td><td>cele (n = 2)</td><td>crushed table press</td><td>cele (n = 5)</td><td>Crushed by a table a press</td>

<td rowspan="4">Tablet, dimensions</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> 658</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>Tear strength (N)</td><td> 196+ 1</td><td>on</td><td> 196+ 1</td><td>on</td><td> 196+ 1</td><td>on</td>

<td rowspan="6">Dissolution (released, %) (n = 1)</td><td>0.5 h</td><td> 34</td><td> 46</td><td> 42</td><td> 50</td><td> 40</td><td> 56</td>

1 196+ means that, subjected to a maximum force of 196 N, the tablets did not break

51162 Β

Example 3

In Example 3, 200 mg tablets were obtained, with 10 mg oxycodone HCl and high molar mass polyethylene oxide.

composition:

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

<td>Oxycodone HCI</td><td> 10</td><td> 5</td>

<td>Polyethylene oxide (MW: approximately 4,000,000; Polyox ™ WSR301)</td><td> 188</td><td> 94</td>

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

<td>In total</td><td> 200</td><td> 100</td>

Production process:

The steps in tablet production are as follows:

First Oxycodone HCl, polyethylene oxide and magnesium stearate are mixed dry, in a low / high shear mixer, model Black & Decker Handy Chopper dual blade mixer, capacity 355 mL.

Second The aperture from Step 1 is compressed to the target weight in a single tablet press, model Manesty Ture F 3 press.

Third The tablets from Step 2 are placed on a tray, transferred to an oven, Hotpack model 435304, at 70 ° C, where the tablets harden from 1 to 14 h.

In vitro testing, including abuse resistance testing (tear strength test) was performed as follows:

Tablets were tested in vitro, using a USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SZF), at 37 ° C, using a Perkin Elmer UV / VIS Spectrometer Lambda. 20 USP Apparatus, with UV detection at 220 nm, as they were subjected to curing for 2, 3, 4, 8, and 14 h. The dimensions of uncured and hardened tablets and dissolution results are given in Table 3.

51162 Β

As an additional test of resistance to abuse, hardened and non-hardened tablets are subjected to a tear strength test, applying a maximum force of 196 N, using an apparatus, model Schleuniger 2E / 106 Apparatus. Tear resistance was determined. These results are given in Table 3.

TABLE 3

<td colspan="2" rowspan="2"></td><td rowspan="2">Not- hardened 2</td><td colspan="5">Curing time (h)</td>

<td rowspan="4">Tablet, dimensions</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>Tear strength (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,%) (p = 2)</td><td>0.5 h</td><td rowspan="6">Not tested</td><td rowspan="6">Not tested</td><td> 16</td><td> 11</td><td> 15</td><td> 33</td>

1 Tablet dimensions n = 4 2 Tablet dimensions n = 10 3196+ means that, subjected to a maximum force of 196 N, the tablets did not break.

Example 4

In Example 4, six different 100 mg tablets (Examples 4.1 to 4.6) were obtained, with 10 mg oxycodone HCl, with variable amount and molar mass of polyethylene oxide used.

compositions:

51162 Β

<td rowspan="2">Ingredient</td><td>mg /</td><td>mg /</td><td>mg /</td><td>mg /</td><td>mg /</td><td>mg /</td>

<td>Oxycodone HCI</td><td> 10</td><td> 10</td><td> 10</td><td> 10</td><td> 10</td><td> 10</td>

<td>Polyethylene oxide (MW: approx. 4,000,000; Polyox ™ WSR 301)</td><td> 89.5</td><td> 79.5</td><td> 69.5</td><td> 89.0</td><td> 0</td><td> 0</td>

<td>Polyethylene oxide (MW; approx. 100,000; Polyox ™ N10)</td><td> 0</td><td> 10</td><td> 20</td><td> 0</td><td> 0</td><td> 0</td>

<td>Polyethylene oxide (MW: approx 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>Polyethylene oxide MW; približno7,000,000; Polyox SR 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>In total</td><td> 100</td><td> 100</td><td> 100</td><td> 100</td><td> 100</td><td> 100</td>

<td>Aperture size (g)</td><td> 125</td><td> 125</td><td> 125</td><td> 125</td><td> 157.5</td><td> 155.5</td>

<td>Total aperture batch (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 steps of tablet production were as follows:

First Oxycodone HCl and polyethylene oxide (and BHT, if necessary) are mixed for 30 s, then dry, in a low / high shear mixer, model Black & Decker Handy Chopper dual blade mixer

Second Magnesium stearate is added to the blend from Step 1 and mixed for another 30 s.

Third Aperture from 2. Kogaka is compressed to the desired mass, in a single tablet press, model Manesty Ture F 3 press, using a standard concave tool (6.75 mm)

4th Tablets from Z. Kogak are transferred to a 38 cm coating container (model LCDS Vector Laboratory Development Coating System), with 38 rpm, equipped with one compartment. The temperature probe (thermocouple wires) is placed inside the coating vessel, near the layer

51162 Β tablet, to monitor the temperature of the layer. The tablet layer was heated to a temperature of about 70 to about 80 ° C (this temperature, for each Example can be obtained from Tables 4.1 to 4.6), for a minimum of about 30 min and a maximum of 2 h. The tablet layer is then cooled and the container emptied.

In vitro testing, including abuse resistance testing (tear strength and hammer test) is performed as follows:

Uncured and cured tablets, with 0.5, 1, 1.5 and 2 h cure, were tested in vitro, using a USP Apparatus 1 (with a basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzymes (SZF), at 37 ° C, using a Perkin Elmer UV / VIS Spectrometer Lambda 20, with Ude detection at a wavelength of 220 nm. Tablet dimensions and dissolution results, corresponding to the respective curing times and temperature, are given in Tables 4.1 to 4.6.

As an additional test of abuse resistance, hardened and uncured tablets were subjected to a tear strength test, using a maximum force of 196 N, using an apparatus, model Schleuniger 2E / 106 Apparatus, to determine tear resistance. These results are given in Tables 4.1 to 4.6.

In addition, the tablets were crushed with a hammer, using 10 hand-made hammer blows, to cause physical damage (hammer test).

TABELA4.1

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

<td rowspan="2">uncured (n = 10)</td><td colspan="4">Curing time (h) (n = 5)</td>

<td rowspan="3">Tablet, 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>

51162 Β

<td rowspan="2"></td><td>Tear strength ! 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 tear strength test (directly measured after test)</td><td>crushed1</td><td> 5.15</td><td> 5.38</td><td> 5.23</td><td> 5.44</td>

<td rowspan="2">Curing process</td><td>0 min</td><td></td><td> 19.7</td><td> -</td><td></td><td> -</td>

<td rowspan="2">Tablet layer temperature</td><td>20 min</td><td> -</td><td> 68.6</td><td> -</td><td> -</td><td> -</td>

<td rowspan="3">(temperature test, inside the vessel)</td><td>60 min</td><td> -</td><td> -</td><td> 78.9</td><td> -</td><td> -</td>

η = 33222

<td rowspan="6">Dissolution (released,%)</td><td>0.5 h</td><td> 19</td><td> 21</td><td> 18</td><td> 18</td><td> 19</td>

η = 111

<td rowspan="3">Subsequent hammer test3 (10 strokes done manually), thickness (mm)</td><td rowspan="3">and</td><td rowspan="3"> 1.70</td><td> 2.18</td><td> 2.37</td><td> 2.09</td>

1Tablets crushed and crushed during the tear strength test 2196+ means that, subjected to a maximum force of 196 N, the tablets did not break 3 10 hammer blows were applied, the tablets were crushed, but they did not break, the hammer blow caused the appearance of cracks on the edge.

51162 Β

TABLE 4.2

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

<td rowspan="2">Uncured (n = 10)</td><td colspan="4">Curing time (h) (n = 5)</td>

<td></td><td>Weight (mg)</td><td> 108</td><td> 109</td><td> 109</td><td> 109</td><td> 107</td>

<td></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></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></td><td>Tear strength (N)</td><td> 93</td><td> 196+3</td><td> 196+3</td><td> 196+3</td><td> 196+3</td>

<td>Tablet, dimensions</td><td>Diameter (mm) after tear strength test (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 Ddmaranje (mm) after tear strength test (NLT 15 min d□maranje period)</td><td> -</td><td> 5.60</td><td> 5.52</td><td> 5.48</td><td> 5.73</td>

<td rowspan="2">Curing process</td><td>0 min</td><td></td><td> 20.2</td><td> -</td><td> -</td><td> -</td>

<td rowspan="2">Tablet layer temperature</td><td>20 min</td><td></td><td> 74.9</td><td> -</td><td> -</td><td> -</td>

<td>(temperature</td><td>90 min</td><td></td><td> -</td><td> -</td><td> 76.4</td><td> -</td>

<td>rehearsals within the court)</td><td>120 min</td><td></td><td> -</td><td> -</td><td> -</td><td> 77.5</td>

<td rowspan="6">Dissolution (released,%) (n = 3)</td><td>0.5 h</td><td></td><td> 20</td><td> 20</td><td> -</td><td> 29</td>

η =

<td rowspan="3">After the hammer test (10 strokes performed manually) thickness (mm)</td><td rowspan="3">and</td><td> 1.98</td><td> 2.00</td><td> 1.80</td><td> 1.62</td>

51162 Β 2 Tablets crushed and crushed during the tear strength test 3196+ means that, subjected to a maximum force of 196 N, the tablets did not break.

TABELA4.3

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

<td rowspan="2">Uncured (n = 10)</td><td colspan="4">Curing time (h) (n = 5)</td>

<td rowspan="6">Tablet, dimensions</td><td>Pile (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>Tear strength (N)</td><td> 91</td><td> 196+ 'J</td><td> 196+ 0</td><td> 196+ 3</td><td> 196+ 3</td>

<td>3vocabulary (mm) after tear strength test (measured directly after the test)</td><td>crushed2</td><td> 5.58</td><td> 5.60</td><td> 5.56</td><td> 5.72</td>

<td>Diameter after rest (mm) after tear strength test (NLT 15 min rest period)</td><td> -</td><td> 5.77</td><td> 5.75</td><td> 5.68</td><td> 5 82</td>

<td rowspan="8">Curing process Tablet layer temperature ° C (test temperature inside the vessel)</td><td>0 min</td><td></td><td> 20.3</td><td> -</td><td> -</td><td> -</td>

n =

<td rowspan="6">Dissolution (released, %)</td><td>0.5 h</td><td></td><td> 22</td><td> 23</td><td></td><td> 33</td>

51162 Β η = 1111

<td rowspan="3">After the test with a hammer (10 strokes performed manually) thickness (mm)</td><td rowspan="3">on</td><td> 2.16</td><td> 1.95</td><td> 1.43</td><td> 1.53</td>

2 The tablets were crushed and crushed during the tear strength test 3196+ means that, subjected to a maximum force of 196 N, the tablets did not break.

TABELA4.4

<td colspan="2" rowspan="3"></td><td colspan="5">Primer4.4</td>

<td rowspan="2">Uncured (n = 10)</td><td colspan="4">Curing time (h) (p = 5)</td>

<td></td><td>Weight (mg)</td><td> 101</td><td> 101</td><td> 101</td><td> 101</td><td> 101</td>

<td></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></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></td><td>Tear strength (N)</td><td> 81</td><td> 196+ 3</td><td> 196+ 3</td><td> 196+ 3</td><td> 196+ 3</td>

<td>Tablet, dimensions</td><td>Diameter (mm) after tear strength test (measured directly after the test)</td><td>crushed2</td><td> 5.39</td><td> 5.39</td><td> 5.39</td><td> 547</td>

<td></td><td>Diameter after rest (mm) after tear strength test (NLT 15 min rest period)</td><td> -</td><td> 5.58</td><td> 5.59</td><td> 5.58</td><td> 5.63</td>

<td rowspan="2">Curing process</td><td>0 min</td><td></td><td> 37.3</td><td></td><td></td><td></td>

<td rowspan="2">Tablet layer temperature ° C</td><td>20 min</td><td></td><td> 74.6</td><td> -</td><td></td><td></td>

<td rowspan="2">(test temperature inside</td><td>60 min</td><td></td><td> -</td><td> 78.7</td><td></td><td></td>

<td>Court)</td><td>120 min</td><td></td><td> -</td><td> -</td><td> -</td><td> 79.3</td>

51162 Β

<td rowspan="6">Dissolution (released,%) (n = 3)</td><td>0.5 h</td><td> -</td><td> 17</td><td> 16</td><td> -</td><td></td>

η = 1111

<td rowspan="3">After the test with a hammer (10 done by hand) thickness (mm)</td><td rowspan="3"> -</td><td> 2.11</td><td> 2.42</td><td> 2.14</td><td> 2.18</td>

2 The tablets were crushed and crushed during the tear strength test 3196+ means that, subjected to a maximum force of 196 N, the tablets did not break.

TABELA4.5

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

<td rowspan="2">Uncured (n = 10)</td><td colspan="4">Curing time (h) (n = 5)</td>

<td></td><td>Weight (mg)</td><td> 108</td><td> 108</td><td> 107</td><td> 107</td><td> 107</td>

<td></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></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 rowspan="2">Tablet, dimensions</td><td>Tear strength (N)</td><td> 116</td><td> 196+ 3</td><td> 196+ 3</td><td> 196+ 3</td><td> 196+ 3</td>

<td>Diameter (mm) after tear strength test (measured directly 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 tear strength test (NLT 15 min rest period)</td><td> -</td><td> 5.67</td><td> 5.76</td><td> 5.67</td><td> 5.68</td>

<td rowspan="2">Curing process</td><td>0 min</td><td></td><td> 19.8</td><td></td><td></td><td></td>

<td rowspan="2">Temperature layer of tablets 0C</td><td>20 min</td><td> -</td><td> 74.6</td><td> -</td><td> -</td><td> -</td>

51162 Β

<td rowspan="3">(test temperature inside the vessel)</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 h</td><td> -</td><td> 21</td><td> 20</td><td> -</td><td> -</td>

η = 1111

<td>After the hammer test</td><td></td><td> 2.19</td><td> 2.31</td><td> 2.36</td><td> 2.45</td>

<td>(10 strokes done manually)</td><td></td><td> 2.15</td><td> 2.48</td><td> 242</td><td> 2.08</td>

<td>thickness (mm)</td><td></td><td> 2.10</td><td> 2.28</td><td> 2.19</td><td> 2.28</td>

2 The tablets were crushed and crushed during the tear strength test 3196+ means that, subjected to a maximum force of 196 N, the tablets did not break.

TABELA4.6

<td></td><td></td><td colspan="7">Primer4.6</td>

<td></td><td></td><td></td><td colspan="6">Curing time (n = 5)</td>

<td></td><td></td><td>uncured (n = 6)</td><td>10 min</td><td>20 min</td><td>0.5 h</td><td>1.0 h</td><td>1.5 h</td><td>2.0 h</td>

<td rowspan="5">Tablet dimensions</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>Tear strength (N)</td><td> 128</td><td colspan="6"> 196+ 2</td>

<td>Diameter (mm) after tear test (measured directly after test)</td><td>crushed 1</td><td> 5.27</td><td> 5.47</td><td> 5.51</td><td> 5.51</td><td> 5.56</td><td> 563</td>

51162 Β

<td></td><td>Diameter (mm) post Tear strength test [NLT 15 min d ma dmaranja)</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 rowspan="2">Curing process</td><td>0 min</td><td></td><td> 30.8</td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2">Tablet layer temperature ° C</td><td>10 min</td><td> -</td><td> 79.5</td><td> -</td><td> -</td><td> -</td><td> -</td><td> -</td>

<td rowspan="2">(test temperature inside</td><td>40 min</td><td></td><td></td><td></td><td> -</td><td> 80.0</td><td> -</td><td> -</td>

<td>court</td><td>90 min</td><td></td><td></td><td></td><td> -</td><td> -</td><td> 80.2</td><td> -</td>

<td rowspan="2">Dissolution (released,%)</td><td>1 h</td><td> -</td><td> -</td><td></td><td> 30</td><td> 30</td><td></td><td> -</td>

<td colspan="2">After the hammer test 3</td><td></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>

<td colspan="2">(10 strokes done manually)</td><td></td><td> 1.19</td><td> 220</td><td> 2.34</td><td> 2.39</td><td> 2.26</td><td> 2.40</td>

<td colspan="2">thickness (mm)</td><td></td><td> 1.24</td><td> 2.18</td><td> 2.03</td><td> 2.52</td><td> 2.50</td><td> 2.16</td>

1 The tablets were crushed and crushed during the tear strength test 2196+ means that, subjected to a maximum force of 196 N, the tablets did not break.

3 The tablets were crushed, but did not break, and the hammer blows caused some damage along the edge.

Example 5

In Example 5, three more tablets were obtained, with 10 wt% oxycodone HCl.

51162 Β

compositions:

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

<td>Tablet</td><td>mg / dish. (%)</td><td>mg / dish. (%)</td><td>mg / dish. {%)</td>

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

<td>Polyethylene oxide (MW: approx. 4,000,000; Polyox ™ WSR301)</td><td> 106.8 (89)</td><td> 178 (89)</td><td> 82.8(69)</td>

<td>Polyethylene oxide (IMW. approximately 100,000; 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>In total</td><td> 120</td><td> 200</td><td> 120</td>

<td>Total batch size (kg)</td><td> 100</td><td> 100</td><td> 100</td>

<td>(quantity produced)</td><td></td><td></td><td></td>

<td>lining</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td>

<td>Coating, white film Opadry concentrate, formula Υ-5-18024-Α</td><td> 3.6 (3)</td><td> 6.0 (3)</td><td> 3. (3)</td>

The steps for the production of talents were as follows:

First Polyethylene oxide is sieved through a Sweco Sifter, equipped with a 20 mesh sieve, υ suitable separate containers.

Second Blender, model Gemco "V" (with I movable bar) - from 283 L, in the following order:

Approximately half of the polyethylene oxide WSR 301

Oxycodone hydrochloride

Polyethylene oxide N10 (Example 5.3 only)

Residual polyethylene oxide WSR 301

Third Blend the materials from Step 2 for 10 min, (Example 5.1) or 20 min (Example 5.2) and 15 min (Example 5.3) with the movable switch on.

51162 Β

4th Batch the magnesium stearate in a Gemco V blender.

5th Blend the materials from Step 4 for 3 minutes, with the movable rod turned off.

6th The aperture from Step 5 is charged into clean, tared stainless steel containers.

7th The aperture from Step 5 is compressed to the target mass, using a 40-tablet press, model Masaon 40 station tablet press, at 135,000 tablets per hour, using a standard, round, concave (flat) mold of 23/81 cm.

8th The tablets from Step 7 were transferred to a 122 cm coating pan, model Accela-Coat coating pan, with 7 rpm and a batch of 98.6 kg (Example 5.1), 92.2 kg (Example 5.2) and 96.9 kg (Example 5.3). ), so the tablet layer is heated until the inlet air temperature reaches approximately 80 ° C (Examples 5.2 and 5.3), or 75 ° C (Example 5.1), and cures for 1 h at the target inlet temperature.

9th Continue with the vessel rotation speed of 7 to 10 rpm, and the tablet layer is cooled, using the outlet air temperature, until the inlet temperature pe reaches 25 ° C and the layer temperature reaches 30 - 34 ° C.

10th The tablet layer is heated using the outlet air temperature until the inlet temperature reaches 55 ° C. When film coating begins, the outlet temperature approaches 39 ° C and continues until the target weight gain of 3% is reached.

11th After coating, the vessel speed is set to 1.5 rpm and the outlet air temperature is set to 27 ° C, the air flow is maintained at the set value, until the system cools to an outlet air temperature of 27 - 30 ° C.

12th The tablets are emptied.

51162 Β

In vitro testing, including testing for resistance to abuse (strength and tearing and hammer test) and resistance to alcohol extraction, is performed as follows:

Tablets hardened for 0.5 h and tablets hardened for 1.0 h and coated, tested in vitro, using USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SŽF), at 37 ° C , using Agilent UV / VIS Spectrometer Model HP8453, UV wavelength detection 220 nm. Tablet dimensions and dissolution results corresponding to the respective times and temperatures are given in Tables 5.1 to 5.3.

Tablets hardened 1.0 h and coated were tested in vitro, using ethanol / SZF medium, with an ethanol concentration of 40%, to evaluate the possibility of alcohol extraction. Testing was performed using a USP Apparatus 1 (with a basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SZF), at 37 ° C, using an Agilent UV / VIS Spectrometer Model HP8453, detection with UV wavelength 230 nm. The tablet dissolution results are given in Table 5.3.

As a further test of abuse resistance, uncured tablets and hardened tablets were subjected to a tear strength test, using a maximum force of 439 N, using an apparatus, model Schleuniger Model 6D, to assess resistance to tearing. These results are given in Tables 5.1 to 5.3.

In addition, the tablets were crushed with a hammer, using 10 hammer blows performed by hand, to perform physical damage (hammer test).

51162 Β

TABELA5.1

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

<td>uncured</td><td>Hardening 30 min (n = 10)</td><td>Hardening 1 h / coated (n = 10)</td>

<td rowspan="5">Tablet, dimensions</td><td>Weight (mg)</td><td> 119.7 1</td><td> 120</td><td> 122</td>

<td>Thickness (mm)</td><td> 3.63 2</td><td> 3.91</td><td> 3.88</td>

<td>Diameter (mm)</td><td> -</td><td> 7.03</td><td> 7.02</td>

<td>Tear strength (N)</td><td> 54 3</td><td> 439 4</td><td> 438 4</td>

<td>Diameter (mm) after tear strength test</td><td> -</td><td> 4.18</td><td> 4.26</td>

<td rowspan="2">Curing process</td><td>10 min</td><td></td><td> 75.8</td><td> 75.8</td>

<td>Input</td><td>40 min</td><td></td><td> -</td><td> 74.5</td>

<td rowspan="2">temperature ° C</td><td>50 min</td><td></td><td> -</td><td> 73.5</td>

<td rowspan="2">dissolution</td><td>0.5 h</td><td></td><td> 19</td><td> 19</td>

<td>(Released,</td>

<td rowspan="2">Hammer test (10 strokes wrapped by hand) Tablet thickness (mm), measured before and after the test (p = 3)</td><td rowspan="2"> -</td><td>rge</td><td>polse</td><td>before</td><td>after</td>

1 Fourteen samples were taken from the process (40 tablets per sample), and each sample was averaged. The stated value is the average of these averages.

2 p = 39 3n = 130 4 n = 10; The tablets do not break when subjected to a maximum force of 438 N / 439 N.

51162 Β

TABLE 5.2

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

<td>uncured</td><td>Hardening 30 min (n = 10)</td><td>Hardening 1 h / coated (P = 10)</td>

<td rowspan="5">Tablet, dimensions</td><td>Weight (mg)</td><td> 200.4 1</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>Tear strength (N)</td><td> 85 3</td><td> 4394</td><td> 439 4</td>

<td>Diameter (mm) after tear strength test</td><td> -</td><td> 5.52</td><td> 5.72</td>

<td rowspan="2">Curing process</td><td>10 min</td><td></td><td> 79.7</td><td> 79.7</td>

<td>Input</td><td>40 min</td><td></td><td> -</td><td> 79.5</td>

<td rowspan="2">temperature ° C</td><td>50 min</td><td></td><td> -</td><td> 80.9</td>

<td rowspan="6">Dissolution Released,%) (n = 3)</td><td>0.5 h</td><td></td><td> 14</td><td> 15</td>

<td rowspan="2">Hammer test (10 strokes performed manually) Tablet thickness (mm) measured before and after the test (n = 3)</td><td rowspan="2"> -</td><td>before</td><td>after</td><td>rge</td><td>after</td>

1 Nine samples were taken from the process (40 tablets per sample) so each sample was averaged. The stated value is the average of these averages.

2 n = 27 3n = 90 4 n = 10; The tablets do not break when subjected to a maximum force of 438 N / 439 N.

51162 Β

TABLE 5.3

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

<td>uncured</td><td>Hardening 30 min (n = 10)</td><td>Hardening 1 h / coated (n = 10)</td>

<td rowspan="5">Tablet, dimensions</td><td>Weight (mg)</td><td> 120.5 1</td><td> 122</td><td> 125</td>

<td>Thickness (mm)</td><td> 3.64 2</td><td> 3.85</td><td> 3.77</td>

<td>Diameter (mm)</td><td> -</td><td> 7.03</td><td> 7.01</td>

<td>Tear strength (N)</td><td> 563</td><td> 438 4</td><td> 439 4</td>

<td>Diameter (mm) after tear strength test</td><td> -</td><td> 3.96</td><td> 4.28</td>

<td rowspan="2">Curing process</td><td>10 min</td><td> -</td><td> 80.0</td><td> 80.0</td>

<td>Input</td><td>40 min</td><td> -</td><td> -</td><td> 79.5</td>

<td rowspan="2">temperature ° C</td><td>50 min</td><td> -</td><td> -</td><td> 79.5</td>

<td rowspan="6">Dissolution (released,%) (n = 3)</td><td>0.5 h</td><td> -</td><td> 20</td><td> 23</td><td> 21</td>

<td rowspan="2">Hammer test (10 strokes performed manually) Tablet thickness (mm) measured before and after the test (n - 3)</td><td rowspan="2"> -</td><td>before</td><td>after</td><td>before</td><td>after</td>

1 Twelve samples were taken from the process (40 tablets per sample) so each sample was averaged. The stated value is the average of these averages.

2n = 33 3n = 130

51162 Β 4 η = 10; The tablets do not break when subjected to a maximum force of 438 N / 439 N.

Example 6

In Example 6, tablets containing Naltrexone HCl were obtained.

compositions:

<td>Tablet</td><td>mg / dish.</td>

<td>Naltrexone HCl</td><td> 10</td>

<td>Polyethylene oxide (MW: approx. 4,000,000; Polyox ™ WSR 301)</td><td> 89.0</td>

<td>Magnezijiim stearate</td><td> 1.0</td>

<td>In total</td><td> 100</td>

Total batch size (kg) (quantity produced)

<td>Total batch size (kg) (quantity produced)</td><td> 20</td>

<td>lining</td><td>mg / unit</td>

<td>Base coating Red film of Opadry coating, concentrations of formula Υ-5-1-15139</td><td> 3.0</td>

<td>Special and coating effects Opadry FX - silver, formula 62VV28547</td><td> 3.0</td>

These tablets were obtained as described in Example 5, using a blender, a Gemco V 'blender (with 1 movable rod) - 56 L, and an 8-tablet rotary press set at 24,000 tablets per hour, with a standard round with a concave (flat) tool of 22/81 cm (the upper one is embossed / the lower one is flat), and a 60 cm device, model Compu-Lab, was used for coating. Blending time in

Second The step was 8 min, the batch in the vessel was 9.2 kg, and the curing time was 2 h.

Example 7

The following three Examples were prepared, each containing 10 mg of oxycodone hydrochloride.

51162 Β

compositions:

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

<td>Tablet</td><td>mg / Unit (%)</td><td>mg / unit (%)</td><td>mg / unit (%)</td>

<td>Oxycodone HCI</td><td> 10(5)</td><td> 10(6.67)</td><td> 10(10)</td>

<td>Polyethylene oxide (MW: approx. 4,000,000; Polyox ™ WSR 301)</td><td> 188 (94)</td><td> 138.5(92.3)</td><td> 69 (69)</td>

<td>Polyethylene oxide (MW; approx 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>In total</td><td> 200</td><td> 150</td><td> 100</td>

<td>Total batch size (kg) (quantity produced)</td><td> 100</td><td> 100</td><td> 100</td>

Total batch size (kg) (quantity produced)

<td>Coated film</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td>

<td>Opadry white coating film, concentrate of formula Υ-5-18024-Α</td><td> 6</td><td> 4.5</td><td> 3</td>

The steps of tablet production are as follows:

First Magnesium stearate is sieved through a Sweco Sifter, equipped with a mesh sieve, into separate suitable containers.

Second Batch blender, model Gemco "V" blender (with movable and bar) - from 283 L, in the following order:

Approximately half of the polyethylene oxide WSR 301

Oxycodone hydrochloride

Polyethylene oxide N10 (Example 7.3 only)

Residual polyethylene oxide WSR 301

Third Blend the materials from the 2nd Kogak for 10 minutes, with the movable and crossbar included.

4th Batch the magnesium stearate in a Gemco V blender.

51162 Β

5th The materials from the 4th cocoon are blended for 3 minutes, with the movable and barbed off.

6th The aperture is loaded from step 5 into clean, tared stainless steel containers.

7th Compress the aperture from Step 5 to the target mass, in a 40-tablet tablet press, set at 135,000 tablets per hour, using a standard 23/81 cm round, concave (flat) mold.

7.1 and 7.2) and a standard round, concave (flat) 64 mm mold (Example 7.3).

8th Tablets from Step 7 were loaded into a 22 cm coating pan, model Accela-Coat coating pan, with a batch of 97,388 kg (Example 7.1), 91,051 kg (Example 7.2) and 89,527 kg (Example 7.3).

9th The vessel speed is set to 7 rpm and the tablet layer is heated by adjusting the outlet air temperature until an inlet temperature of approximately 75 ° C is reached. The tablets were cured for 1 h at the target inlet temperature (Examples 7.1 and 7.2), and 30 min for (Example 7.3).

10th The vessel is continued to rotate at 6 to 8 rpm, and the tablet layer is cooled using an outlet air temperature until an inlet temperature of 25 ° C is reached and the outlet temperature reaches 30 - 34 ° C.

11th The tablet layer is heated using the outlet air temperature until the inlet temperature reaches the target 55 ° C. When film coating begins, the outlet temperature approaches 39 ° C, and continues until the target mass growth reaches 3%.

12th Upon completion of the coating, the vessel speed is set to 1.5 rpm and the outlet air temperature is set to 27 ° C, while maintaining the air flow at the set value, to cool the system so that the outlet temperature is 27 - 30 ° C.

13th The tablets are emptied,

51162 Β

In vitro tests are performed, including abuse resistance testing (strength then tearing, hammer test and tablet kneading test) and resistance to alcohol extraction, as well as stability tests, as follows:

Hardened, coated tablets (whole and kneaded) are tested in vitro, using a USP Apparatus 1 (with a basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SZF), at 37QC. Samples were analyzed by reverse phase liquid performance high performance (HPLC), then a VVaters Atlantis dC18 3.0x150 mm, 3 pm column, using a mobile phase consisting of a mixture of acetonitrile and non-basic potassium phosphate buffer (pH 3.0), with UV detection at 230 nm. Sampling times are 0.5, 0.75, 1.0, 1.5 and 2.0 h. Additional sampling times are 1.0, 4.0 and 12 h.

Hardened, coated tablets (whole and kneaded) are tested in vitro, using ethanol / CFC medium, with concentrations of 0% and 40% to assess the possibility of alcohol extraction. Testing was performed using a USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric juice without enzyme (SZF), at 37 ° C. Samples were analyzed by reverse phase liquid performance (HPLC) on a VVaters Atlantis dC18 3.0x150 mm, 3pm column using a mobile phase consisting of a mixture of acetonitrile and non-basic potassium phosphate buffer (pH 3.0), with UV detection at 230 nm. Sampling times are 0.5, 0.75, 1.0, 1.5 and 2.0 h.

The hardened tablets are subjected to a tear strength test, applying a maximum force of 439 N, using a Schleuniger Model 6D apparatus, to assess the tear resistance of the tablets.

The hardened tablets were subjected to high pressure, using a table hand press, model Carver (hydraulic, model # 3912), in order to do physical damage by kneading the tablets.

51162 Β

The hardened tablets are also subjected to a tear strength test, using 10 hammer blows, performed manually, in order to perform physical damage.

Hardened, coated tablets were subjected to a stability test, storage in 100 labeled bottles, under different storage conditions (25 ° C / 60% relative humidity, or 40 ° C / 75% relative humidity), for a period of time, followed by testing the tablets in in vitro, as described above. Sample times in terms of storage include the initial sample (i.e. before storage), one month, two months, three months and six months of storage, and the sample times in terms of dissolution test are 1.0, 4.0 and 12.0 h.

The hardened, coated tablets were also subjected to a stability test by storage in 100 labeled bottles under different storage conditions (25 ° C / 60% relative humidity or 40 ° C / 75% relative humidity) for a period of time, followed by testing the tablets to determine oxycodone HCl content in tablet samples, in percent, relative to the indicated specification. Sample times in terms of storage are the initial sample (i.e. before storage), one month, two months, three months and six months of storage. In this test, oxycodone hydrochloride was extracted from two sets of ten tablets each, with 900 mL of a 1: 2 mixture of acetonitrile and simulated gastric fluid, without enzyme (SZF), with constant stirring with a magnetic stirrer, in a 1000 mL volumetric flask, while the tablets are completely dispersed, or overnight. Samples of the solution were diluted and analyzed by reverse phase high performance liquid homography (HPLC) on a Waters Atlantis dCi column.8 3.0 x 250 mm, 5 μΐη, held at 60 ° C, using a mobile phase consisting of acetonitrile and a monobasic potassium phosphate buffer with a pH of 3.0, and UV detection at 280 nm.

51162 Β oxycodone-N-oxide degradation products, in percentages, relative to the specified oxycodone HCl specification, Sample storage times are the initial sample (ie before storage), one month, two months, three months and six months of storage. In the ONO test, oxycodone hydrochloride and its degradation products were extracted from a set of ten tablets, with 900 mL of a 1: 2 mixture of acetonitrile and simulated gastric fluid, without enzyme (SZF), with constant stirring with a magnetic stirrer, in a 1000 mL volumetric flask. until the tablets are completely dispersed, or overnight. Samples of the solution were diluted and analyzed by reverse phase high performance liquid homography (HPLC) on a 3.0 x 250 mm, 5 pm VVaters Atlantis dC-is column, held at 60 ° C, using a mobile phase consisting of acetonitrile and buffer. monobasic potassium phosphate with pH 3.0, and UV detection at 206 nm.

These results are given in Tables 7.1 to 7.3

TABLE 7.1.1

<td colspan="2" rowspan="2"></td><td colspan="3">Example 7.1</td>

<td>Whole (n = 10)</td><td colspan="2">Crushedfn = 3) (applied 6800 kg)</td>

<td rowspan="6">Tablet, dimensions</td><td>Weight (mg)</td><td> 205</td><td> 207</td><td> 204</td>

<td>Thickness (mm)</td><td> 5.95</td><td>GoG</td><td> (1961</td>

<td>% Thickness</td><td></td><td> 17.0</td><td> 16.1</td>

<td>Diameter (mm)</td><td> 7.02</td><td> 17.13 2</td><td> 17.35 2</td>

<td>Tear strength (N)</td><td> >4383</td><td colspan="2" rowspan="2"></td>

<td>Diameter (mm) after tear strength test</td><td> 5.84</td>

<td rowspan="4">Before and after the hammer test Measured tablet thickness (mm)</td><td>before</td><td>after</td><td colspan="2" rowspan="4"></td>

<td rowspan="2"></td><td>cele</td><td>cele</td><td>crushed</td><td>crushed</td>

51162 Β

<td rowspan="5">Dissolution (released,%) (n = 3)</td><td>0.5 h</td><td> 11</td><td> 9</td><td> 17</td><td> 13</td>

_____________________Cele

0.5 h

<td rowspan="6">Dissolution (released,%) (n = 6)</td><td>0.5 h</td><td> -</td>

1 3 measurements per tablet 2 2 measurements per tablet 3the tablets break when subjected to a maximum force of 438 N

TABLE 7.1.2

<td></td><td></td><td colspan="5">Stability tests for Example 7.1</td>

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

<td></td><td></td><td>initially</td><td>1 Month 40/75</td><td>2 Months 40/75</td><td>3 Months 25/60</td><td>3 Months 40/75</td>

<td rowspan="3">Dissolution (released, %) (n = 6) SJF</td><td>1 h</td><td> 22</td><td> 21</td><td> 21</td><td> 20</td><td> 21</td>

<td rowspan="3">Test (% oxycodone HCt)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>

1 [Mes = Month (s)];2 relative to the oxycodone HCl specification.

TABLE 7.2.1

<td colspan="2" rowspan="2"></td><td colspan="3">Primer7.2</td>

<td>Whole (n = 10)</td><td colspan="2">Crushed (n = 3) (applied 9000 kg)</td>

<td>Tablet,</td><td>Weight (mg)</td><td> 154</td><td> 154</td><td> 153</td>

100

51162 Β

<td rowspan="5">dimensions</td><td>Thickness (mm)</td><td> 4.68</td><td> 0.75</td><td> 0.771</td>

<td>% Thickness</td><td></td><td> 16.0</td><td> 16.5</td>

<td>Diameter (mm)</td><td> 702</td><td> 17.14 2</td><td> 16.902</td>

<td>Tear strength (N)</td><td> 4383</td><td colspan="2" rowspan="2"></td>

<td>Diameter (mm) after strength test and tearing</td><td> 4.93</td>

<td colspan="2" rowspan="4">Before and after the hammer test, Measured tablet thickness (mm)</td><td>rge</td><td>after</td><td colspan="2" rowspan="4"></td>

<td colspan="2" rowspan="2"></td><td>cele</td><td>cele</td><td>crushed</td><td>crushed</td>

<td rowspan="5">Dissolution (released,%) (n = 3)</td><td>0.5 h</td><td> 14</td><td> 10</td><td> 21</td><td> 15</td>

cele

<td rowspan="6">Dissolution (released,%) (p = 6)</td><td>0.5 h</td><td> -</td>

1 3 measurements per tablet 2 2 measurements per tablet 3 The tablets do not break when subjected to a maximum force of 438 N

TABLE 7.2.2

<td colspan="9">Stability tests for Example 7.2</td>

<td></td><td></td><td colspan="5">Storage conditions (° C /% RH) and time sk</td><td colspan="2">adištenia1</td>

<td></td><td></td><td>initially</td><td>1 Month 40/75</td><td>2 Months 40/75</td><td>3 Months 25/60</td><td>3 Months 40/75</td><td>6 Months 25/60</td><td>6 Months 40/75</td>

<td>dissolution</td><td>1 h</td><td> 26</td><td> 24</td><td> 22</td><td> 23</td><td> 24</td><td> 25</td><td> 25</td>

101

51162 Β

<td rowspan="2">(Released, %) (n = 6) SJF</td><td>4h</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 (% oxycodone HCl)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 (% oxycodone Noxide)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>

1 [Mes = Month (s)];2 relative to the oxycodone HCl specification.

TABLE 7.3.1

<td colspan="2" rowspan="2"></td><td colspan="3">Example 7.3</td>

<td>Whole (n = 10)</td><td colspan="2">Crushed (n = 3) (applied 6800 kg)</td>

<td rowspan="5">Tablet, dimensions</td><td>Weight (mg)</td><td> 103</td><td> 102</td><td> 104</td>

<td>Thickness (mm)</td><td> 3.92</td><td>bJzG (15.6)</td><td> 0.661 (16.8)</td>

<td>Diameter (mm)</td><td> 6.25</td><td> 15.36 2</td><td> 15.24 2</td>

<td>Tear strength (N)</td><td> 4393</td><td colspan="2" rowspan="2"></td>

<td>Diameter (mm) after tear strength test</td><td> 3.80</td>

<td colspan="2" rowspan="4">Before and after the test with a hammer Measured tablet thickness (mm)</td><td>before</td><td>after</td><td colspan="2" rowspan="4"></td>

<td colspan="2" rowspan="2"></td><td>cele</td><td>cele</td><td>crushed</td><td>crushed</td>

<td rowspan="5">Dissolution (released,%) (n = 3)</td><td>0.5 h</td><td> 19</td><td> 15</td><td> 26</td><td> 19</td>

cele

102

51162 Β

<td rowspan="6">Dissolution (released%) (n = 6)</td><td>0.5 h</td><td></td>

1 3 measurements ρο tablets 2 2 measurements per tablet 3 The tablets do not break when subjected to a maximum force of 439 N.

TABLE 7.3.2

<td colspan="6">Stability tests for Example 7.3</td>

<td></td><td></td><td colspan="4">Storage conditions (° C /% RH) and storage time1</td>

<td></td><td></td><td>initially</td><td>1 Month 40/75</td><td>2 Months 40/75</td><td>3 Months 25/60</td>

<td rowspan="3">Dissolution (% released) (n = 6) SJF</td><td>1 h</td><td> 32</td><td> 29</td><td> 30</td><td> 31</td>

<td rowspan="3">Test (% oxycodone HCl)2</td><td>Testl</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>

1 [Mes = Month (s)];2 relative to the oxycodone HCl specification

Example 8

Two more tablets of 160 mg oxycodone hydrochloride were produced (Examples 8.1 and 8.2).

compositions:

<td></td><td colspan="2">Example 8.1</td><td colspan="2">Example 8.2</td>

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

<td>Oxycodone Hydrochloride</td><td> 160</td><td> 25</td><td> 160</td><td> 25</td>

<td>Polyethylene oxide (high M, quality 301)</td><td> 476.8</td><td> 74.5</td><td> 284.8</td><td> 44.5</td>

<td>Polyethylene oxide (low M, quality N10)</td><td> 0</td><td> 0</td><td> 192</td><td> 30</td>

103

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<td>Magnesium stearate</td><td> 3.2</td><td> 0.5</td><td> 3.2</td><td> 0.5</td>

<td>In total</td><td> 640</td><td> 100</td><td> 640</td><td> 100</td>

The steps of tablet production are as follows:

First Oxycodone HCl and polyethylene oxide are mixed dry, in a low / high shear mixer, model Black & Decker Handy Chopper dual blade mixer, capacity 355 ml_, for 30 s.

Second Magnesium stearate is added and mixed for another 30 s with the blend from Step 1.

Third The aperture from Step 2 is compressed into the target mass, in a single tablet press, model Manesty Ture F 3 press, using a molding mold (7,937 x 14,290 mm).

4th Tablets from 2. Kogaka are placed on a tray, transferred to an oven, model Hotpack Mesdel 435304 ram, at 73 ° C, for 3 h to harden the tablets.

In vitro testing, including abrasion resistance (tear strength test), is performed as follows:

Tablets were tested in vitro, using a USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric juice without enzyme (SZF), at 37 ° C, using an Agilent UV / VIS Spectrometer Mesdel HP8453 spectrometer, detection with a UV wavelength of 280 nm, after 3 h of curing. The dimensions of uncured and hardened tablets and dissolution results are given in Table 8.

As a further test of abuse resistance, hardened and uncured tablets are subjected to a tear strength test, applying a maximum force of 196 N, using an apparatus, model Schleuniger 2E / 106 Apparatus, to assess tear resistance. These results are given in Table 8.

In addition, the tablets were crushed with a hammer, using 10 hammer blows performed by hand, to obtain physical damage (hammer test). The results are given in Table 8.

104

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TABLE 8

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

<td>Uncured (n = 12)</td><td>3h hardening (n = 5)</td><td>Uncured (n = 12)</td><td>3 h hardening (n = 10)</td>

<td rowspan="4">Tablet, dimensions</td><td>Weight (mg)</td><td> 648</td><td> 648</td><td> 643</td><td> 643</td>

<td>Thickness (mm)</td><td> 7.07</td><td> 7.42</td><td> 7.01</td><td> 7.20</td>

<td>Width (mm)</td><td> 7.96</td><td> 7.97</td><td> 7.96</td><td> 7.91</td>

<td>Tear strength (N)</td><td>196+ ' John =?) -..........</td><td> 196+1(n = 1)</td><td> 196+ 1.. LRg2) ......</td><td> 196+1(p = 2)</td>

<td rowspan="6">Dissolution (released %)</td><td>0.5 h</td><td rowspan="6">Not tested</td><td> 9</td><td rowspan="6">Not tested</td><td> 13</td>

<td colspan="2">After hammer test (10 strokes performed manually) Thickness (mm)</td><td>It breaks easily</td><td> -</td><td>It breaks easily</td><td> 3.80</td>

1 The hardness tester has a maximum at 20+ Kp, which is 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

Three Primers were produced and tested, each with 12 mg of hydromorphone hydrochloride.

compositions:

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

<td>Tablet</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td>

<td>Hydromorphone HCI</td><td> 12</td><td> 12</td><td> 12</td>

<td>Polyethylene oxide (M: approx. 7,000,000; 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>In total</td><td> 500</td><td> 700</td><td> 850</td>

105

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<td>Total batch size (kg) (quantity produced)</td><td> 100</td><td> 100</td><td> 100</td>

Total batch size (kg) (quantity produced)

<td>Film coating</td><td>mg / dish.</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 film coating of Orabgu concentrate of formula Υ-5-18024-Α</td><td> 15</td><td> 21</td><td> 25.5</td>

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

The steps of tablet production are as follows:

First Hydromorphone HCl and magnesium stearate are sieved through a Sweco Sifter, equipped with a 20 mesh sieve, into suitable separate containers.

Second Blender, model Gemco "V (with I movable bar) - from 283 L, is charged in the following order:

Approximately 25 kg of polyethylene oxide WSR 303

Hydromorphone hydrochloride

Approximately 25 kg of polyethylene oxide WSR 303

Third Blend the materials from the 2nd Kogak for 10 minutes, with the movable rod included.

4th The remaining polyethylene oxide WSR 303 is loaded into a Gemco “V” blender.

5th Blend the materials from Step 4 for 10 minutes, with the movable rod included.

6th Batch the magnesium stearate in a Gemco V blender.

7th Blend the materials from Step 6 for 3 minutes, with the movable switch off.

8th The 7th Step aperture is loaded into clean, tared stainless steel containers.

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9th The aperture of Step 8 is compressed to the desired mass, in a tablet press with 40 places, at a rate of 133,000 tablets per hour, using a standard round, concave (flat) mold of 12 mm.

10th The tablets from Step 9 were loaded into a 120 cm coating pan, model AcCele-Coat coating pan, with a batch of 80 kg (Examples 9.1 and 9.3) and 79 kg (Example 9.2).

11th The rotation speed is set to 2 rpm and the tablet layer is heated by adjusting the outlet air temperature until the target inlet temperature of approximately 75 ° C is reached. The tablets are cured for 1 h and 15 min, at the following inlet temperature range, 75 - 87 ° C (Example 9.1), 75 - 89 ° C (Example 9.2) and 75 - 86 ° C (Example 9.3).

12th At the beginning of cooling the vessel, the rotation speed is increased from 7 rpm, and the whole tablet is cooled using the outlet air temperature, so that the inlet temperature is 25 ° C and the outlet temperature reaches 30 - 34 ° C. During this cooling process, magnesium stearate is added to the tablet layer to reduce tablet adhesion.

13th The tablet layer is heated, using the exhaust air temperature, so that the inlet air temperature reaches the target 55 ° C. Film coating begins when the outlet temperature approaches 39 ° C, and continues until the target weight gain of 3% is reached.

14th Upon completion of the coating, the vessel rotation speed is set to 1.5 rpm and the outlet temperature is set to 27 ° C, while maintaining the air flow as currently set, so the system is cooled to an outlet temperature of 27-30 ° C.

15th The tablets are emptied.

Example 10

The following tablet containing 12 mg of hydromorphone hydrochloride was obtained. composition:

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<td></td><td>example</td>

<td>Tablet</td><td>mg / unit</td>

<td>Hydromorphone HCI</td><td> 12</td>

<td>Polyethylene oxide (M: approx. 7,000,000; Polyox ™ WSR 303)</td><td> 483</td>

<td>Magnesium stearate</td><td> 5</td>

<td>In total</td><td> 500</td>

Total batch size (kg) (quantity produced)

<td>Total batch size (kg) (quantity produced)</td><td> 119.98</td>

The steps of tablet production are as follows:

First Hydromorphone HCl and magnesium stearate are sieved through a Sweco Sifter, equipped with a 20 mesh sieve, into suitable separate containers.

Second Blender, model Gemco "V" blender (with I movable rod) - from 283 L, charged in the following order:

Approximately 60 kg of polyethylene oxide WSR 303

Hydromorphone hydrochloride

Third The materials from Step 2 are blended for 10 minutes with the bar included.

4th The remaining polyethylene oxide WSR 303 is loaded into a Gemco “V” blender.

5th Blend for 10 min the materials from 4. Kogaka with the movable and crossbar included.

6th Batch the magnesium stearate in a Gemco "V" blender.

7th Blend the materials from the 6th Kogak for 3 minutes, with the movable switch off.

8th Aperture the 7th Kogaka into clean, tared stainless steel containers.

9th Compress the aperture from Step 8 to the target mass, on a forty-tablet press, at a rate of 150,000 tablets per hour, using a standard 12 mm round, concave (flat) mold.

I08

51162 Β

10th The tablets from Step 9 are loaded into a 120 cm coating pan, model AcCele-Coat coating pan, with a batch of 92,887 kg.

11th The rotation speed of the vessel is set to 1.9 rpm, and the tablet layer is heated by adjusting the outlet air temperature until the target inlet temperature of approximately 80 ° C is reached. These tablets are cured for 2 h at the next inlet temperature range of 80 - 85 ° C.

12th At the end of hardening and the beginning of cooling, the layer of tablets begins to agglomerate (the tablets stick together). The speed of rotation of the vessel is adjusted to 2.8 rpm, and the tablet layer is completely agglomerated and cannot be returned for coating.

It has been suggested that tablet agglomeration can be avoided, for example by lowering the curing temperature, increasing the speed of rotation of the vessel, using magnesium stearate as an anti-caking agent, or applying a pre-coating prior to curing.

However, part of the tablets was taken before cooling, as a sample for in vitro testing, which is performed as follows:

The hardened tablets are tested in vitro, using a USP Apparatus 2 (spatula), at 75 rpm, in 900 mL of simulated gastric fluid, without enzyme (SZF), at 37 ° C, using the VVaters Alliance System, equipped with a VVaters column. Novapak C18

3.9 mm x 150 mm, and a mobile phase consisting of a mixture of acetonitrile, SDS and monobasic sodium phosphate buffer (pH 2.9). Detection was performed with a PDA detector. Sampling times are 1, 2, 4, 8, 12, 18, and 22 h.

TABLE 10

<td colspan="2"></td><td>USP Apparatus 2</td>

<td rowspan="4">Dissolution (released%) (n = 6)</td><td>1 h</td><td> 19</td>

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51162 Β

Example 11

The following tablet containing 12 mg of hydromorphone hydrochloride was obtained.

composition:

<td>Tablet</td><td>mg / unit</td>

<td>Hydromorphone HCI</td><td> 12</td>

<td>Polyethylene oxide (M: Approximately 7,000,000; Polyox ™ WSR 303)</td><td> 681</td>

<td>Magnesium stearate</td><td> 7</td>

<td>In total</td><td> 700</td>

Total batch size (kg) (quantity produced)

<td>Total batch size (kg) amount)</td><td> 122.53</td>

<td>Film coating</td><td>mg / unit</td>

<td>White film coating of Opadry concentrate of formula Υ-5-18024-Α</td><td> 21</td>

<td>Coating batch size (kg)</td><td> 80</td>

The steps of tablet production are as follows:

First Hydromorphone HCl and magnesium stearate are sieved through a Sweco Sifter, equipped with a 20 mesh sieve, into suitable separate containers.

Second Blender, model Gemco "V" (with I movable rod) - from 283 L, in the following order:

Approximately 60 kg of polyethylene oxide WSR 303

Hydromorphone hydrochloride

Third The remaining polyethylene oxide WSR 303 is loaded into a Gemco V blender ”.

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4th Blend the materials from Step 4 for 10 minutes, with the movable rod included.

5th Batch the magnesium stearate in a Gemco "V" blender.

6th The materials from Step 5 are blended for 3 minutes, with the movable switch off.

7th The aperture from Step 6 is loaded into clean, tared stainless steel containers.

8th The aperture from Step 7 is compressed to the target mass in a 40-tablet press at a rate of 150,000 tablets per hour, using a standard 12 mm round, concave (flat) mold.

9th The tablets from Step 9 are loaded into a 120 cm coating pan, model AcCele-Coat coating pan, with a batch of 80,000 kg.

10th The rotation speed of the vessel is adjusted to 1.8 rpm and the tablet layer is heated by adjusting the outlet air temperature so as to achieve an inlet temperature of approximately 80 ° C. These tablets solidify 1.25 h in the following inlet temperature range of 75 - 85 ° C.

11th At the end of hardening, and at the beginning of cooling, the layer of tablets begins to agglomerate (the tablets stick together). The speed of rotation of the vessel is increased to 10 rpm, and the tablets are separated.

12th The vessel is continued to rotate at approximately 10 rpm and the tablet layer is cooled, using the outlet air temperature until the inlet temperature of 25 ° C is reached and the outlet temperature reaches 30 - 34 ° C.

13th The tablet layer is heated, using an outlet air temperature to reach the target inlet temperature of 55 ° C. When film coating begins and the outlet temperature approaches 39 ° C, continue until a weight gain of 3% is achieved.

14th After coating, the vessel speed is set to 1.5 rpm and the outlet temperature is set to 27 ° C, the air flow is maintained at the set value and the system is cooled to an outlet temperature of 27 - 30 ° C.

15th The tablets are emptied.

III

51162 Β! P in vitro testing is performed as follows:

The coated tablets were tested in vitro, using a USP Apparatus 2 (spatula) at 75 rpm, in 900 mL of simulated gastric juice without enzyme (SZF), at 37 ° C, using the VVaters Alliance System, equipped with a VVaters Novapak Ci column.8

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). Detection is performed using a PDA detector. Sampling times are 1, 2, 4, 8, 12, 18, 22, and 24 h. These results are given in Table 11.

TABLE 11

<td colspan="2"></td><td>USP Apparatus 2</td>

<td rowspan="8">Dissolution (% released) (medium n - 6)</td><td>1 h</td><td> 12</td>

Example 12

Two more specimens were produced, containing 10 mg of oxycodone hydrochloride, having the tablet cores given in Example 2.3, coated with a polyethylene oxide coating that provides delayed release.

Composition: Tablet core

<td>Ingredient</td><td>mg / unit</td>

<td>Oxycodone HCI</td><td> 10</td>

<td>Polyethylene oxide (M: Approximately 4,000,000; Polyox ™ WSR301)</td><td> 85</td>

<td>hydroxypropylcellulose (Klucel ™ HXF)</td><td> 5</td>

<td>Total tablet core</td><td> 100</td>

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Composition: Compressed coating over the tablet core

<td></td><td>Example 12.1</td><td>Example 12.2</td>

<td>Ingredient</td><td>mg / unit</td><td>mg / unit</td>

<td>Polyethylene oxide (M: approx. 4,000,000; Polyox ™ VVSR301)</td><td> 200</td><td> 100</td>

<td>Tablet core</td><td> 100</td><td> 100</td>

<td>Total weight of the tablet</td><td> 300</td><td> 200</td>

Production process: The steps of tablet production are as follows:

First The tablet from Example 2.3 is used for the tablet core.

Second The single tablet press, model Manesty Ture F 3, is equipped with a round, standard 7.94 mm concave flat mold.

Third In Example 12.1, approximately 100 mg of polyethylene oxide is placed in the mold, and the tablet core is manually centered in the mold (on top of the powder layer), and another 100 mg of polyethylene oxide is placed in the mold over this tablet.

4th These materials are manually compressed by turning the compression lever.

5th In Example 12.2, approximately 50 mg of polyethylene oxide is placed in the mold, and the tablet core is manually centered in the mold (on top of the powder layer), and another 50 mg of polyethylene oxide is placed in the mold over this tablet.

6th These materials are manually compressed by turning the compression lever.

7th The tablets from Steps 4 and 6 are placed on a tray and transferred to an oven, model Hotpack Mesdel 435304, set at 75 ° C, to harden these compression-coated tablets for 3 h.

In vitro testing is performed as follows:

The tablets are tested in vitro, using a USP Apparatus 1 (with a basket), at 100 rpm, in 900 mL of simulated gastric fluid, without enzyme (SZF), at 37 ° C,

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51162 Om using a spectrometer, model Perkin Elmer UV / VIS Spectrometer Lambda 20 USP Apparatus, with UV determination at 220 nm. The dimensions and dissolution results of the hardened, compression-coated tablets are given 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 h</td><td> 0</td><td> 1</td>

In Example 13, five different 156 mg tablets (Examples 13.1 to 13.5) with 10, 15, 20, 30 and 40 mg of Oxycodone HCl were obtained, using high molar mass polyethylene oxide.

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 / unit</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td>

<td>Oxycodone HCI</td><td> 10</td><td> 15</td><td> 20</td><td> 30</td><td> 40</td>

<td>Polyethylene oxide (M: approximately 4,000,000; 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 tablet core weight (mg)</td><td> 150</td><td> 150</td><td> 150</td><td> 150</td><td> 150</td>

<td>Total batch size</td><td>10 kg</td><td>10 kg</td><td>10 kg</td><td>10 kg</td><td>10 kg</td>

1Ι4

51162 Β

<td>lining</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td><td>mg / unit</td>

<td>Coating with Opadry film</td><td> 6</td><td> 6</td><td> 6</td><td> 6</td><td> 6</td>

<td>Total tablet weight <m9)</td><td> 156</td><td> 156</td><td> 156</td><td> 156</td><td> 156</td>

<td>Coating batch size (kg)</td><td> 8.754</td><td> 9.447</td><td> 9.403</td><td> 8.717</td><td> 8.902</td>

The steps of tablet production are as follows:

First Batch blender, model Patterson Kelly V 'blender (with I movable rod) - from 15 L, in the following order:

Approximately half of the polyethylene oxide WSR 301

Oxycodone hydrochloride

Residual polyethylene oxide WSR 301

Second The materials from Step 1 are blended for 5 minutes with the movable bar turned on.

Third Batch the magnesium stearate in a "B" blender.

4th The materials from Step 3 are blended for 1 min with the movable switch off.

5th The aperture from step 4 is charged into a plastic bag.

6th The aperture from Step 5 is compressed to the target mass, in an 8-tablet press, at a rate of 35,000 tablets per hour, using a standard 22/81 cm round, concave (embossed) mold.

7th The tablets from step 6 were loaded into a 60 cm coating pan, model Compu-Lab coating pan, with a batch 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).

8th The temperature test (thermocouple wire) is placed directly above the tablet layer in the container, so that the top of the test is near the moving tablet layer.

9th The rotation speed of the vessel is set to 7 rpm, and the tablet layer is heated by adjusting the inlet temperature so as to reach the target test temperature of 75 ° C. The start of curing (described by method 4) is initiated when the sample temperature shows approximately 70 ° C (Example

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13.1 at 68.3 ° C, Example 13.2 at 69.9 ° C, Example 13.3 and 13.4 at 70.0 ° C, and Example 13.5 at 71.0 ° C). When the target test temperature is reached, the inlet temperature is set to maintain the target test temperature. These tablets harden for 90 minutes. The speed of rotation of the vessel is increased to 12 rpm during approximately 60 min of curing (except in Example 13.5, when the speed of rotation of the vessel is maintained at 7 rpm during curing). Samples are taken after 30 min, 60 min and 90 min curing. The temperature profile of the curing process in the Examples

13.1 to 13.5 are given in Tables 13.1.1 to 13.5.1 and then in Figures 10 to 14.

10th After curing, magnesium stearate is added to the moving tablets as an anti-caking agent. The amount of magnesium stearate added was 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 measuring tray and manually dispersed (powdered) as a powder over a moving layer of tablets. Continue rotating the vessel at 12 rpm (Example 13.5 at 7 rpm), and cool the tablet layer by adjusting the inlet temperature to 21 ° C. The tablet layer was cooled to an outlet temperature of <41 ° C.

11th The tablet layer is heated by adjusting the inlet to 55 ° C. When film coating begins, the outlet temperature reaches approximately 43 ° C, and is continued until a weight gain of 4% is achieved.

12th When the film coating is completed, the speed of the vessel is reduced (3 to 6 rpm), and the inlet temperature is set to 21 ° to 25 ° C to cool the system and maintain the air flow at the set value.

13th The tablets are emptied.

In vitro testing, including tear strength and density measurement, is performed as follows:

Tablets cured for 30 min and 60 min, and tablets cured for 90 min and coated were tested in vitro, using a USP Apparatus 1 (with basket), at 100 rpm, in

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900 mL of simulated enzyme-free gastric juice (SJF), at 37 ° C. Samples were analyzed by reverse phase high performance liquid homography (HPLC) on a VVaters Atlantis dC18 3.0 x 150 mm, 3pm column using a mobile phase consisting of a mixture of acetonitrile and non-basic potassium phosphate buffer (pH 3.0), with detection at 230 nm UV. Sampling times are 1.0, 2.0, 4.0, 8.0 and 12.0 h. Tablet dimensions and dissolution results, corresponding to the respective curing times and temperature, are given in Tables 13.1.2 to 13.5.2.

Uncured tablets, hardened tablets and hardened coated tablets are subjected to a tear strength test, applying a maximum force of 439 N, using a device, model Schleuniger Mesdel 6D apparatus, to assess the resistance of tablets to tearing, tear strength test, applying a maximum force of 196 N, using an apparatus, model Schleuniger 2E / 106 Apparatus, to assess tear resistance.

Density of uncured tablets and tablets hardened over various periods of time (samples from

30, 60 and 90 min) is determined according to the Archimedes principle, using a scale, model Top-loading Mettler Toledo balance Mesdel # AB 135-S / FACT, Serial #

1127430072 and a density determination kit 33360, according to the following procedure:

Adjust the Mettler Toledo balance with the density kit. The appropriate beaker was filled with hexane (200 mL).

The mass of the tablet in the air is measured and recorded as Mass A.

Transfer this same tablet to a lower coil inside a beaker filled with hexane.

Determine the mass of the tablet in hexane and register as Mass B.

The density is calculated in accordance with the equation

AA p = —--- po.gde su

Α- B

R; Tablet density

A: The mass of the tablet in the air

B: The mass of the tablet when immersed in the liquid

117

51162 Β r0: Density of liquid at a given temperature (density of hexane at 20 ° C = 0.660 g / mL (Merck lndex))

7th Density is registered.

The listed density values are mean values for 3 tablets and all refer to uncoated tablets.

These results are given in the following tables.

TABLE 13.1.1: HARDENING PROCESS TEMPERATURE PROFILE

EXAMPLE 13.1

<td>Total time (min.)</td><td>Curing time (min.j1</td><td>Set inlet temperature GS)</td><td>Actual inlet temperatureMRWITH)2</td><td>Test temperature (° C)3</td><td>Output temperature GS)4</td><td>Objections</td>

<td> 15</td><td> 0</td><td> 85</td><td> 84,8</td><td> 68,3</td><td> 65,5</td><td>The beginning hardened.</td>

<td> 45</td><td> 30</td><td> 83</td><td> 83</td><td> 74,8</td><td> 74,7</td><td>sample of 30 min</td>

<td> 75</td><td> 60</td><td> 81</td><td> 81,1</td><td> 75</td><td> 75,9</td><td>sample of 60 min</td>

<td> 105</td><td> 90</td><td> 81</td><td> 80,9</td><td> 74,9</td><td> 76</td><td>End hardened, sample 90 min</td>

1 determined in accordance with procedure 4, 5 inlet temperature measured; 3 temperature measured using a temperature test (thermocouple wire) 4 temperature measured at the outlet.

TABLE 13.1.2

<td></td><td></td><td colspan="4">Primer13.1</td>

<td></td><td></td><td>uncured (p = 5)</td><td>30 min hardened. (n = 5)</td><td>60 min hardened. (p = 5)</td><td>90 min hardened. coated (n = 5)</td>

<td rowspan="2">Tablet, dimensions</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>

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<td rowspan="2"></td><td>Diameter (mm)</td><td> 7.14</td><td> 7.00</td><td> 6.98</td><td> 6.98</td>

<td>Tear strength (N)</td><td> 80</td><td> 196 1</td><td> 196 1</td><td> 438 2</td>

<td rowspan="5">Dissolution (released %) SGF</td><td>1 h</td><td></td><td> 25 (9.5)</td><td> 24 (8.4)</td><td> 27 (7.3)</td>

1 maximum force of the hardness tester, the tablets do not break when subjected to a maximum force of 196 N.

2 maximum hardness tester force, the tablets do not break when subjected to a maximum force of 438 N.

TABLE 13.2.1: HARDENING PROCESS TEMPERATURE PROFILE

EXAMPLE 13.2

<td>Total time (min.)</td><td>Time hardens. (Min.)1</td><td>Set inlet temperature (° C)</td><td>Actual inlet temperature (° c)2</td><td>Temperature probe (° C)3</td><td>Output temperature (° C)4</td><td>Objections</td>

<td> 21</td><td> 0</td><td> 85</td><td> 84,8</td><td> 69,9</td><td> 69,1</td><td>The beginning hardens.</td>

<td> 51</td><td> 30</td><td> 82</td><td> 82</td><td> 74,8</td><td> 75,8</td><td>sample of 30 min</td>

<td> 81</td><td> 60</td><td> 81</td><td> 80,8</td><td> 75</td><td> 75,9</td><td>sample of 60 min</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 of hardening, sample of 90 min</td>

<td colspan="2">1 determined in sk</td><td colspan="2">hell with procedure 4, 2</td><td colspan="3">inlet temperature measured; 3 temperature</td>

measured using a temperature probe (thermocouple wire) 4temperature measured at the outlet.

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TABLE 13.2.2

<td></td><td></td><td colspan="4">Primer13.2</td>

<td></td><td></td><td>Uncured (n = 5)</td><td>30 min hardened. (n = 5)</td><td>60 min hardened. (n = 5)</td><td>90 min hardened. coated (n = 5)</td>

<td rowspan="4">Tablet, dimensions</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>Tear strength (N)</td><td> 62</td><td> 196 1</td><td> 196 1</td><td> 196 1</td>

<td rowspan="5">Dissolution (released %) SŽF</td><td>1 h</td><td> -</td><td> 23 (10.6)</td><td> 22 (8.5)</td><td> 25 (5.2)</td>

1 maximum force of the hardness tester, the tablets do not break when subjected to a maximum force of 196 N.

TABLE 13.3.1: CURING PROCESS TEMPERATURE PROFILE

EXAMPLE 13.3.

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Set inlet temperature (° C)</td><td>Actual inlet temperature (° C)2</td><td>Test temperature (° C)3</td><td>Outlet temperature co4</td><td>Objections</td>

<td> 13</td><td> 0</td><td> 90</td><td> 90,1</td><td> 70</td><td> 68,3</td><td>The beginning hardened.</td>

<td> 43</td><td> 30</td><td> 83</td><td> 83,1</td><td> 75,4</td><td> 76,5</td><td>sample of 30 min</td>

<td> 73</td><td> 60</td><td> 81,5</td><td> 81,5</td><td> 74,7</td><td> 76,1</td><td>sample of 60 min</td>

<td> 103</td><td> 90</td><td> 81,5</td><td> 81,3</td><td> 75</td><td> 76,1</td><td>End of hardening, sample of 90 min</td>

120

51162 Β 1 determined in accordance with procedure 4, 2 inlet temperature measured, 3 temperature measured using a temperature probe (thermocouple wire) ”temperature measured at the outlet.

TABLE 13.3.2

<td></td><td></td><td colspan="4">Example 13.3</td>

<td></td><td></td><td>uncured (n = 5)</td><td>30 min hardened. (n = 5)</td><td>60 min hardened. (n = 5)</td><td>90 min hardened, coated (n = 5)</td>

<td rowspan="4">Tablet, dimensions</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>Stroke strength (N)</td><td> 83</td><td> 196 1</td><td> 196 1</td><td> 196 1</td>

<td rowspan="5">Dissolution (released%) SZF</td><td>1 h</td><td> -</td><td> 22 (5.8)</td><td> 26 (9.2)</td><td> 23(5 7)</td>

1 maximum hardness tester force, the tablets do not break when subjected to a maximum force of 196N.

TABLE 13.4.1: HARDENING PROCESS TEMPERATURE PROFILE

EXAMPLE 13.4:

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Set inlet temperature GS)</td><td>Actual inlet temperature (° C)2</td><td>Test temperature (° C)3</td><td>Output temperature (° C)4</td><td>Objections</td>

<td> 16</td><td> 0</td><td> 90</td><td> 90,1</td><td> 70</td><td> 69,5</td><td>The beginning hardened.</td>

<td> 46</td><td> 30</td><td> 84</td><td> 84</td><td> 75,4</td><td> 77,2</td><td>sample of 30 min</td>

<td> 76</td><td> 60</td><td> 82</td><td> 81,7</td><td> 74,7</td><td> 76,3</td><td>sample of 60 min</td>

<td> 106</td><td> 90</td><td> 82</td><td> 82,1</td><td> 75,1</td><td> 76,4</td><td>End hardened, sample 90 min</td>

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1 determined in accordance with procedure 4, 2 inlet temperature measured; 3 temperature measured using test temperature (thermocouple wire) 4temperature measured at the outlet.

TABLE 13.4.2

<td></td><td></td><td colspan="4">Example 13.4</td>

<td></td><td></td><td>Uncured (n = 5)</td><td>30 min hardened. (n = 5)</td><td>60 min hardened. (n = 5)</td><td>90 min hardened, coated (n = 5)</td>

<td rowspan="4">Tablet, dimensions</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>Squeezing strength (N)</td><td> 65</td><td> 196 1</td><td> 196 1</td><td> 196 1</td>

<td rowspan="5">Dissolution (released%) SZF</td><td>1 h</td><td></td><td> 29 (3.2)</td><td> 25 (7.9)</td><td> 24 (5.5)</td>

1 maximum hardness tester force, the tablets do not break when subjected to a maximum force of 196 N.

TABLE 13.5.1: HARDENING PROCESS TEMPERATURE PROFILE

EXAMPLE 13.5:

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Set inlet temperature (° C)</td><td>Actual inlet temperature (° C)2</td><td>Test temperature (° C)3</td><td>Output temperature (° C)4</td><td>Objections</td>

<td> 20</td><td> 0</td><td> 90</td><td> 90,2</td><td> 70,9</td><td> 71</td><td>The beginning hardened.</td>

<td> 50</td><td> 30</td><td> 85</td><td> 85</td><td> 75,2</td><td> 77,5</td><td>sample of 30 min</td>

<td> 80</td><td> 60</td><td> 83</td><td> 83,1</td><td> 75,1</td><td> 76,5</td><td>sample of 60 min</td>

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<td> 110</td><td> 90</td><td> 80</td><td> 80,1</td><td> 73,6</td><td> 74,7</td><td>End hardened, sample 90 min</td>

Ύ determined in accordance with procedure 4, temperature measured at the inlet; temperature measured using a temperature test (thermocouple wire)4 temperature measured at the outlet.

TABLE 13.5.2

<td></td><td></td><td colspan="5">Example 13.5</td>

<td></td><td></td><td>Uncured (n = 5)</td><td>30 min hardened. (n = 5)</td><td>60 min hardened. (n = 5)</td><td>90 min hardened. (n = 5)</td><td>90 min hardened. coated (n = 5)</td>

<td rowspan="5">Tablet, dimensions</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>Tear strength (N)</td><td> 90</td><td> 438 1</td><td> 438 1</td><td> 438 1</td><td> 438 1</td>

<td>Relaxed diameter (mm) after tear strength test (NLT 15 min relaxation period)</td><td> -</td><td> 4.57</td><td> 4.68</td><td> 4.69</td><td> 4.67</td>

<td rowspan="5">Dissolution (released%) SZF</td><td>1 h</td><td></td><td> 28 (5.0)</td><td> 29 (5.9)</td><td></td><td> 26(1.4)</td>

1 maximum force of the hardness tester, the tablets do not break when subjected to a maximum force of 196 N.

TABELA13.6

<td></td><td></td><td>Density</td><td>(G / CMT</td><td></td><td>change</td>

<td></td><td>uncured</td><td>30 min hardened.</td><td>60 min hardened.</td><td>90 min hardened.</td><td>density after curing (%)2</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>

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<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>

1 The density value is the mean value of 3 measured tablets; 2 The change in density after curing corresponds to the observed change in density in% of tablets cured for 90 min, compared to non-cured tablets.

Example 14

In Example 14, five different 156 mg tablets (Examples 14.1 to 14.5) with 10, 15, 20, 30 and 40 mg oxycodone HCl were obtained, using high molar mass polyethylene oxide, with a larger batch size, compared to Example 13. .

compositions:

<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 / dish.</td><td>mg / dish.</td><td>mg / dish.</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Oxycodone HCI</td><td> 10</td><td> 15</td><td> 20</td><td> 30</td><td> 40</td>

<td>Polyethylene oxide (M: approx. 4,000,000; 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 tablet core massage (mg)</td><td> 150</td><td> 150</td><td> 150</td><td> 150</td><td> 150</td>

<td>Total batch size</td><td>100 kg</td><td>100 kg</td><td>100 kg</td><td>100 kg</td><td>100 kg</td>

<td>lining</td><td>mg / dish.</td><td>mg / dish.</td><td>mg / dish.</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Coating with Opadry film</td><td> 6</td><td> 6</td><td> 6</td><td> 6</td><td> 6</td>

<td>Total tablet weight (mg)</td><td> 156</td><td> 156</td><td> 156</td><td> 156</td><td> 156</td>

<td>Coating batch size (kg)</td><td> 97.480</td><td> 98.808</td><td> 97.864</td><td> 99.511</td><td> 98.788</td>

The steps of tablet production are as follows:

First Magnesium stearate is sifted through a sieve, model Sweco Sifter, equipped with a sieve of 20 mesh, in a special separate container.

Second Blender, model Gemco "V" (with I pocket stick) - from 283 L, is charged in the following order:

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Approximately half of the polyethylene oxide WSR 301

Oxycodone hydrochloride

Residual polyethylene oxide WSR 301

Third The materials from Step 2 are blended for 10 minutes with the bar included.

4th Batch the magnesium stearate in a Gemco "V" blender.

5th Blend the materials from Step 4 for 3 minutes, with the iron turned off.

6th The aperture from Step 5 is loaded into clean, tared stainless steel containers.

7th The aperture from Step 6 is compressed to the target mass in a press for 40 tablets, at a rate of 135,000 tablets per hour, using a standard round, concave (embossed) mold of 22/81 cm.

8th The 7-step tablets are charged to a 120 cm coating pan, model AcCele-Coat coating pan, with a batch of 97,480 kg (Example 14.1), 98,808 kg (Example 14.2), 97,864 kg (Example 14.3), 99,511 kg 14.4) and 98,788 kg (Example 14.5).

9th The rotation speed of the vessel is set to 7 rpm, and the tablet layer is heated by adjusting the outlet air temperature so as to reach an inlet temperature of 75 ° C. The tablets were cured for 1 h at the target inlet temperature (Examples 14.1 to 14.5). The starting point, used to determine the curing time, according to method 1, was the time when the inlet temperature reached the target temperature of 75 ° C. The temperature profile of the curing process of Examples 14.1 to 14.5 is given in Tables 14.1.1 to 14.5.1 and in Figures 15 to 19.

10th Continue with the rotation speed of the vessel of 7 rpm in Examples 14.2, 14.4 and 14.5. The speed of the court is increased to 10 rpm, in Example 14.1, and to 8 rpm in Example 14.3. In Examples 14.2 to 14.5, 20 g of magnesium stearate was added as an anti-caking agent. The tablet layer is cooled by slightly lowering the outlet temperature (Example 14.1), or by directly adjusting the outlet temperature to 25 ° C (Example 14.2), or 30 ° C (Examples 14.3 to 14.5), until a specific outlet temperature of 30 to 34 is reached. ° C.

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11th The tablet layer is heated using an air outlet temperature so that the target inlet temperature of 55 ° C is reached. When film coating begins, the outlet temperature approaches 39 ° C and continues until a weight gain of 4% is achieved.

12th After coating, the vessel speed is set to 1.5 rpm and the outlet temperature is set to 27 ° C, the air flow is maintained at the set value and the system is cooled to an outlet temperature of 27 - 30 ° C.

13th The tablets are emptied.

In vitro testing, which includes tensile strength tests and stability tests, is performed as follows:

Tablets hardened 1 h and coated were tested in vitro, using a USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric juice without enzyme (SZF), at 37 ° C. Samples were analyzed by reverse phase high performance liquid homatography (HPLC) on a VVaters Atlantis dC18 3.0 x 150 mm, 3pm column using a mobile phase consisting of a mixture of acetonitrile and non-basic potassium phosphate buffer (pH 3.0), with UV detection at 230 nm. Sampling times are 1.0, 2.0, 4.0, 6.0, 8.0 and 12.0 h. Tablet dimensions and dissolution results, corresponding to the respective curing times and temperature, are given in the Tables.

14.1.2 to 14.5.2.

Uncured tablets were subjected to a tear strength test using a maximum force of 196 N, using a Schleuniger 2E / 106 Apparatus, to assess the tear resistance of the tablets.

Hardened, coated tablets were subjected to a stability test, storage in 100 labeled bottles under different storage conditions (25 ° C / 60% relative humidity or 40 ° C / 75% relative humidity) for a period of time, followed by in vitro tablet testing as is described above. And the sample times, in terms of storage,

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51162 Β are the initial sample (ie before storage), one month, two months, three months and six months of storage, and the sample times in terms of dissolution test are 1.0, 2.0, 4.0, 8.0 and 12.0 h.

The hardened, coated tablets were also subjected to a stability test by storage in 100 labeled bottles under different storage conditions (25 ° C / 60% relative humidity or 40 ° C / 75% relative humidity) for a period of time, followed by testing the tablets to determine oxycodone HCl content in tablet samples. And the sample times in terms of storage are the initial sample (ie before storage), one month, two months, three months and six months of storage. In the test, oxycodone hydrochloride was extracted from two sets of ten tablets each, with 900 mL of a 1: 2 mixture of acetonitrile and simulated gastric fluid, without enzyme (SZF) with constant stirring with a magnetic stirrer in a 1000 mL volumetric flask, while the tablets do not disperse completely, or overnight. Samples of the solution were diluted and analyzed by reverse phase high performance liquid homography (HPLC) on a Waters Atlantis dCis 3.0 x 250 mm, 5 pm column held at 60 ° C using a mobile phase consisting of acetonitrile and monobasic potassium phosphate buffer. , with pH 3.0, and UV detection at 280 nm.

The cured, coated tablets were also subjected to a stability test by storage in 100 labeled bottles under different storage conditions (25 ° C / 60% relative humidity or 40 ° C / 75% relative humidity) for a period of time, followed by the tablets being subjected to the oxycodone test. N-oxide (ONO), to determine the content of oxycodone-N-oxide decomposition products, and unknown decomposition products in weight percent, relative to the indicated oxycodone HCl specification. And the sample times, in terms of storage, are the initial sample (ie before storage), one month, two months, three months and six months of storage. In the ONO test, oxycodone hydrochloride and its decomposition products were extracted from a set of ten tablets, with 900 mL of a 1: 2 mixture of acetonitrile and simulated gastric fluid, without enzyme (SZF), with constant stirring with a magnetic stirrer in a 1000 mL volumetric flask, while the tablets do not disperse completely, or overnight. Samples

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51162 Β the solutions are diluted and analyzed by reverse phase high performance liquid homography (HPLC) on a VVaters Atlantis dC column18 3.0 x 250 mm, 5 ct, held at 60 ° C, using a mobile phase consisting of acetonitrile and a monobasic potassium phosphate buffer with a pH of 3.0, and UV detection at 206 pt.

The densities of uncured tablets, cured tablets and cured / coated tablets were determined as described in Example 13.

These results are given in the following Tables.

TABLE 14.1.1: CURING PROCESS TEMPERATURE PROFILE

EXAMPLE 14.1

<td>Total time (min.)</td><td>Time was running out. (Min.)1</td><td>Input temp. (° C)2</td><td>Set a output temp. (° C)</td><td>Actual output temp. CO '</td><td>Court rotation speed (rpm)</td><td>Objections</td>

<td> 0</td><td> -</td><td> -</td><td> -</td><td> -</td><td> 7</td><td>Batch loading, start heating</td>

<td> 36</td><td> 0</td><td> 75,0</td><td> 65</td><td> 65</td><td> 7</td><td>Start of curing sample of 0 min</td>

<td> 51</td><td> 15</td><td> 72,2</td><td></td><td></td><td> 7</td><td>sample of 15 min</td>

<td> 66</td><td> 30</td><td> 75,0</td><td> 68</td><td> 68</td><td> 8</td><td>sample of 30 min</td>

<td> 81</td><td> 45</td><td> 74,8</td><td></td><td></td><td> 8</td><td>sample of 45 min</td>

<td> 96</td><td> 60</td><td> 71,0</td><td> 69</td><td> 69</td><td> 8</td><td>End of curing, 60 min sample, Mgstearate not used, start of cooling, tablet flow was sticky</td>

<td> 101</td><td> -</td><td> 62,0</td><td></td><td></td><td> 8</td><td>The flow of tablets becomes lumpy</td>

<td> 104</td><td> -</td><td> 59,2</td><td></td><td></td><td> 9</td><td>The flow is very lumpy ("tablet layer covered")</td>

<td> 109</td><td> -</td><td> 54,9</td><td></td><td></td><td> 9</td><td>Tablet flow still</td>

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<td></td><td></td><td></td><td></td><td></td><td></td><td>a little lumpy, but better</td>

<td> 110</td><td> -</td><td> 53,2</td><td></td><td></td><td> 8</td><td>Return to normal tablet flow</td>

1 determined in accordance with procedure 1, 2 inlet temperature measured, 3 temperature measured at the outlet.

TABLE 14.1.2

<td></td><td></td><td colspan="3">Example 14.1</td>

<td></td><td></td><td>uncured</td><td>60 min curing (n = 5)</td><td>60 min curing, coated (n = 5)</td>

<td></td><td>Weight (mg)</td><td>150 (n = 120)</td><td> 150</td><td> 158</td>

<td rowspan="3">Tablet, dimensions</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>Stroke strength (N)</td><td>68 (n = 100)</td><td> 196 1</td><td> 196 ’</td>

<td>dissolution</td><td>1 h</td><td> -</td><td></td><td> 25</td>

<td rowspan="3">(released%) SZF</td><td>2h</td><td> -</td><td></td><td> 42</td>

1 maximum force of the hardness tester, the tablets do not break when subjected to a maximum force of 196 N.

TABLE 14.1.3

Stability tests for Example 14.1, storage at 25 ° C / 60% RH

<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>dissolution</td><td>2h</td><td> 42</td><td> 40</td><td> 38</td><td> 38</td><td> 39</td>

<td>(released</td><td>4h</td><td> 67</td><td> 64</td><td> 61</td><td> 61</td><td> 64</td>

<td>(mg oxycodone</td><td>test2</td><td> 9.8</td><td> 9.9</td><td> 9.8</td><td> 9 9</td><td> 9.8</td>

<td>HCl)</td><td>average</td><td> 9.8</td><td> 9.8</td><td> 9.8</td><td> 9.9</td><td> 9.8</td>

<td></td><td>oxycodone Noxide (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

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<td rowspan="2">Decomposition product test</td><td>Each individually unknown (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>Total decomposition products (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

1 relative to the oxycodone HCl specification.

TABLE 14.1.4

<td colspan="7">Stability tests for Example 14.1, storage at 40 ° C / 75% RH</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) SJF</td><td>1 h</td><td> 25</td><td> 25</td><td> 25</td><td> 24</td><td> 23</td>

<td rowspan="3">Test (mg oxycodone HCl)</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>average</td><td> 9.8</td><td> 9.9</td><td> 9 7</td><td> 9.7</td><td> 9.8</td>

<td rowspan="3">Decomposition product test</td><td>oxycodone Noxide (%)1</td><td> <0.1</td><td> < 0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>Each individually unknown (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>Total decomposition products (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

1 relative to the oxycodone HC specification

TABLE 14.2.1: HARDENING PROCESS TEMPERATURE PROFILE

EXAMPLE 14.2

<td>total time (min.)</td><td>Time hardened. (Min.)1</td><td>Input temp. (° C)2</td><td>Set output temp. (° C)</td><td>Actual output temp. (° C)3</td><td>Court rotation speed (rpm)</td><td>Objections</td>

<td> 0</td><td> -</td><td> 18</td><td> 50</td><td> 20</td><td> 7</td><td>Batch loading, start heating</td>

<td> 8</td><td> -</td><td> 67,7</td><td> 51,0</td><td> 50,5</td><td> 7</td><td>Slowly adjust the output</td>

<td> 14</td><td> 0</td><td> 75,0</td><td> 61,7</td><td> 61,9</td><td> 7</td><td>Start of curing, sample of 0 min</td>

<td> 21</td><td> 7</td><td> 77,8</td><td></td><td></td><td> 7</td><td>High input, then drop to 7GS</td>

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<td> 29</td><td> 15</td><td> 70,6</td><td> 66,1</td><td> 65,5</td><td> 7</td><td>sample of 15 min</td>

<td> 44</td><td> 30</td><td> 73,3</td><td> 67,0</td><td> 67,4</td><td> 7</td><td>sample of 30 min</td>

<td> 54</td><td> 40</td><td> 71,7</td><td> 67,5</td><td> 67,3</td><td> 7</td><td>Several tablets were glued to the dish carriers, without permanent gluing</td>

<td> 59</td><td> 45</td><td> 74,3</td><td> 68,0</td><td> 67,9</td><td> 7</td><td>sample of 45 min</td>

<td> 74</td><td> 60</td><td> 73,0</td><td> 68</td><td> 68</td><td> 7</td><td>End of curing, 60 min sample, 20 g of Mgstearate added, slightly sticky tablet flow (based on cascade flow observation), flow immediately improved after addition of Mg-stearate</td>

<td> 75</td><td></td><td> 73</td><td> 25</td><td> 68</td><td> 7</td><td rowspan="6">Normal tablet flow was observed during cooling</td>

1 determined in accordance with procedure 1,2 temperature measured in azu, 5 temperature measured at the outlet.

TABLE 14.2.2

<td></td><td></td><td colspan="3">Example 14.2</td>

<td></td><td></td><td>uncured</td><td>60 min curing (0 = 5)</td><td>60 min curing, coated (n = 5)</td>

<td rowspan="4">Tablet, dimensions</td><td>Weight (mg)</td><td>150 (n = 120)</td><td> 149</td><td> 156</td>

<td>Thickness (mm)</td><td>4.38 (p = 5)</td><td> 4.68</td><td> 4.70</td>

<td>Diameter (mm)</td><td>7.13 (p = 5)</td><td> 7.07</td><td> 7.09</td>

<td>Stroke strength (N)</td><td>70 (η = 100)</td><td> 196 1</td><td> 196 1</td>

<td rowspan="3">Dissolution (% released)</td><td>1 h</td><td> -</td><td> -</td><td> 23</td>

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1 maximum force of the hardness tester, the tablets do not break when subjected to a maximum force of 196 N.

TABLE 14.2.3

Stability tests for Example 14.2, storage at 25 ° C / 60% RH

<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) SŽF</td><td>1 h</td><td> 23</td><td> 24</td><td> 26</td><td> 22</td><td> 24</td>

<td rowspan="3">Test (mg oxycodone HCl)</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>average</td><td> 14.7</td><td> 14.9</td><td> 14.7</td><td> 14.7</td><td> 14.8</td>

<td rowspan="3">Decomposition product test</td><td>oxycodone Noxide (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>Each individually unknown (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>Total decomposition products (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

1 relative to the oxycodone HCL specification

TABLE 14.2.4

Stability tests for Example 14.2, storage at 40 ° C / 75% RH

<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 h</td><td> 23</td><td> 25</td><td> 26</td><td> 22</td><td> 24</td>

<td rowspan="3">Test (mg oxycodone HCl)</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>

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<td rowspan="3">Decomposition product test</td><td>oxycodone Noxide (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>Each individually unknown (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>Total decomposition products (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td>S0.1</td>

1 relative to the oxycodone HCl specification.

TABLE 14.3.1: TEMPERATURE PROFILE OF THE HARDENING PROCESS

EXAMPLE 14.3

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Input temp. (° C)2</td><td>Set output temp. (° C)</td><td>Actual output temp. (° C)3</td><td>Court rotation speed (rpm)</td><td>Objections</td>

<td> 0</td><td> -</td><td> 17,1</td><td> 50</td><td> 18</td><td> 7</td><td>Batch loading, start heating</td>

<td> 15</td><td> 0</td><td> 75,0</td><td> 61,6</td><td> 61,9</td><td> 7</td><td>Start of curing, sample of 0 min</td>

<td> 22</td><td> 7</td><td> 79,0</td><td> 62,8</td><td> 66,3</td><td> 7</td><td>High entrance</td>

<td> 30</td><td> 15</td><td> 68,4</td><td> 66,0</td><td> 65,3</td><td> 7</td><td>Sample of 15 min</td>

<td> 45</td><td> 30</td><td> 76,9</td><td> 68,0</td><td> 67,9</td><td> 7</td><td>Sample of 30 min</td>

<td> 60</td><td> 45</td><td> 73,9</td><td> 68,6</td><td> 68,4</td><td> 7</td><td>Sample of 45 min</td>

<td> 68</td><td> 53</td><td> -</td><td> -</td><td></td><td> 7</td><td>Several tablets (1 -4) stuck to the container carriers, good flow of tablets</td>

<td> 75</td><td> 60</td><td> 77,0</td><td> 70,5</td><td> 70,8</td><td> 8</td><td>End of curing, 60 min sample, 20 g of Mgstearate added, tablet flow instantly improved</td>

<td> 76</td><td></td><td> 76</td><td> 30</td><td> 71</td><td> 8</td><td rowspan="5">During cooling, normal tablet flow was observed. No sticking</td>

1 determined in accordance with the procedure, 2 inlet temperature measured, 3 temperature measured at the outlet.

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TABLE 14.3.2

<td></td><td></td><td colspan="3">Example 14.3</td>

<td></td><td></td><td>uncured</td><td>60 min curing (n = 5)</td><td>60 min curing, coated (n = 5)</td>

<td rowspan="4">Tablet, dimensions</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 (p = 5)</td><td> 7.08</td><td> 7.10</td>

<td>Stroke strength (N)</td><td>64 (n = 110)</td><td> 196 1</td><td> 196 1</td>

<td rowspan="5">Dissolution (released%) SZF</td><td>1 h</td><td></td><td> -</td><td> 24</td>

They will not break when subjected to a maximum force of the hardness tester, a maximum force of 196 N.

TABLE 14.3.3

Stability tests for Example 14.3, storage at 25AndC / 60% RH

<td colspan="2" rowspan="2"></td><td colspan="5">Time stored yes</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) SJF</td><td>1 h</td><td> 24</td><td> 25</td><td> 22</td><td> 24</td><td> 21</td>

<td rowspan="3">Test (mg oxycodone HCl)</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>average</td><td> 19.5</td><td> 19.4</td><td> 19.4</td><td> 19.4</td><td> 19.6</td>

<td rowspan="3">Decomposition product test</td><td>oxycodone Noxide (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>Each individually unknown (%)1</td><td> <0.1</td><td> <0.1</td><td> 20 1</td><td> <0.1</td><td> <0.1</td>

<td>Total decomposition products (%)1</td><td> <0.1</td><td> 20.1</td><td> 20.1</td><td> <0.1</td><td> <0.1</td>

1 relative to the oxycodone HCl specification.

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TABLE 14.3.4

Stability tests for Example 14.3, storage at 40 ° C / 75% RH

<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 h</td><td> 24</td><td> 27</td><td> 24</td><td> 23</td><td> 22</td>

<td rowspan="3">Test (mg oxycodone HCl)</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>average</td><td> 19.5</td><td> 19.3</td><td> 19.6</td><td> 19.4</td><td> 19.6</td>

<td rowspan="3">Decomposition product test</td><td>oxycodone Noxide (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>Each individually unknown (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> 2 0.1</td><td> <0.1</td>

<td>Total decomposition products (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

1 relative to the oxycodone HCl specification.

TABLE 14.4.1: HARDENING PROCESS TEMPERATURE PROFILE

EXAMPLE 14.4

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Input temp. (° C)2</td><td>Temp. layer ('C)3</td><td>Set output temp. (° C)</td><td>Actual output temp. (° C)4</td><td>Primedbe®</td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td>Batch loading, start 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>Start of curing, sample of 0 min</td>

<td> 24</td><td> 15</td><td> 69,2</td><td> 66,7</td><td> 65,7</td><td> 64,9</td><td>Sample of 15 min</td>

<td> 39</td><td> 30</td><td> 76,5</td><td> 70,2</td><td> 67,7</td><td> 67,7</td><td>Sample of 30 min</td>

<td> 47</td><td> 38</td><td> 76,7</td><td> 71,0</td><td> 68,8</td><td> 68,4</td><td>Several tablets were glued to the dish carriers, without permanent gluing</td>

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<td> 54</td><td> 45</td><td> 79,1</td><td> 72,1</td><td> 70,0</td><td> 69,5</td><td>Sample of 45 min</td>

<td> 69</td><td> 60</td><td> 74,0</td><td> 74,5</td><td> 71,7</td><td> 71,3</td><td>Kgaj curing, 60 min sample, added 20 g Mgstearate, onset of cooling, tablet flow slightly sticky (based on cascade flow observation), several tablets still stuck to vessel carriers, flow / cascade currently improved, after addition of Mg-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 tablet flow was observed during cooling</td>

1 determined in accordance with procedure 1, 2 inlet temperature measured, 3 Tablet layer temperature, ie the temperature of the sustained release matrix formulation, measured using an IR gun,4 temperature measured at the outlet,5 The rotation speed of the vessel was 7 rpm during the entire curing process.

TABLE 14.4.2

<td></td><td></td><td colspan="3">Example 14.4</td>

<td></td><td></td><td>uncured</td><td>60 min curing (n = 5)</td><td>60 min curing, coated (n = 5)</td>

<td rowspan="4">Tablet, dimensions</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>Stroke strength (N)</td><td>61 (n = 100)</td><td> 196 ’</td><td> 196 1</td>

<td rowspan="5">Dissolution (released%) SZF</td><td>1 h</td><td></td><td> -</td><td> 22</td>

1 maximum hardness tester force, the sheets shall not break when subjected to a maximum force of 196 N.

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TABLE 14.4.3

Stability tests for Example 14.4, storage at 25AndC / 60% RH

<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) SŽF</td><td>1 h</td><td> 22</td><td> 23</td><td> 24</td><td> 24</td><td> 23</td>

<td rowspan="3">Test (mg oxycodone HCl)</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>average</td><td> 29.0</td><td> 28.9</td><td> 28.6</td><td> 28.8</td><td> 29.2</td>

<td rowspan="3">Decomposition product test</td><td>oxycodone Noxide (%)1</td><td> 50.1</td><td> <0.1</td><td> 50.1</td><td> <0.1</td><td> <0.1</td>

<td>Each individually unknown (%)1</td><td> <0.1</td><td> <0.1</td><td> < 0.1</td><td> <0.1</td><td> <0.1</td>

<td>Total decomposition products (%)1</td><td> <0.1</td><td> 5 0.1</td><td> <0.1</td><td> 5 0.1</td><td> <0.1</td>

1 relative to the oxycodone HCl specification.

TABLE 14.4.4

<td colspan="7">Stability tests for Example 14.4, storage at 40 ° C / 75% RH</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 %) (p = 6) SŽF</td><td>1 h</td><td> 22</td><td> 26</td><td> 24</td><td> 24</td><td> 24</td>

<td rowspan="3">Test (mg oxycodone HCl)</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>average</td><td> 29.0</td><td> 29.3</td><td> 28.1</td><td> 28.9</td><td> 28.5</td>

<td rowspan="3">Decomposition product test</td><td>oxycodone Noxide (%)1</td><td> 5 0.1</td><td> 50.1</td><td> 5 0.1</td><td> 5 0.1</td><td> <0.1</td>

<td>Each individually unknown (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>In the total decay products (%)1</td><td> <0.1</td><td> <0.1</td><td> < 0.1</td><td> <0.1</td><td> <0.1</td>

<td colspan="3">1 relative to the oxycodone specification</td><td colspan="4">HCI.</td>

TABLE 14.5.1: HARDENING TEMPERATURE PROFILE PROFILE

EXAMPLE 14.5

<td>Total time (min.)</td><td>Time about solid. (Min.)1</td><td>Input temp. ( 'C)2</td><td>Temp. layer fC)3</td><td>Set output temp. (° C)</td><td>Actual output temp. (° C)4</td><td>Objections5</td>

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<td> 0</td><td> -</td><td> 16,6</td><td> 30</td><td> 60,0</td><td> 19,7</td><td>Batch loading, start 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>Start of curing, sample of 0 min</td>

<td> 32</td><td> 15</td><td> 83,1</td><td> 70,8</td><td> 70,0</td><td> 68,7</td><td>Sample of 15 min</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 tablet flow and 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>Sample of 30 min</td>

<td> 52</td><td> 35</td><td> 71,2</td><td> 73,8</td><td> 72,2</td><td> 71,4</td><td>Tablet flow slightly sticky, 12 tablets glued to the dish carriers</td>

<td> 62</td><td> 45</td><td> 75,4</td><td> 75,3</td><td> 72,2</td><td> 72,9</td><td>Sample of 45 min</td>

<td> 66</td><td> 49</td><td> 73,4</td><td> 74,5</td><td> 72,2</td><td> 71,8</td><td>Tablet flow slightly sticky, 12 tablets cured for container carriers (no permanent sticking)</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 curing, sample of 60 min, added 20 g of Mgstearate, instantaneous improvement of flow / cascade start of cooling, no sticking for vessel carriers</td>

<td> 80</td><td> -</td><td> 46,8</td><td> 64,9</td><td> 30,0</td><td> 64,7</td><td>Cooling</td>

<td> -</td><td> -</td><td> -</td><td> -</td><td> 30,0</td><td> -</td><td>2 tablets glued to the dish carriers (no permanent gluing)</td>

<td> 82</td><td> -</td><td> 40,3</td><td> 58,6</td><td> 30,0</td><td> 57,4</td><td>The tablets still look mobile, no sticking was observed</td>

<td> 84</td><td> -</td><td> 35,8</td><td> 57,4</td><td> 30,0</td><td> 55,6</td><td rowspan="3">Normal tablet flow was observed during the cooling period. Continued cooling until</td>

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<td> 89</td><td> -</td><td> 28,8</td><td> 51,8</td><td> 30,0</td><td> 51,3</td><td>outlet temperature of 30-</td>

<td> 91</td><td> -</td><td> 26,9</td><td> 47,2</td><td> 30,0</td><td> 47,9</td><td>34 ° C, before coating</td>

<td> 97 _</td><td></td><td> -</td><td> ~ 29</td><td> 30,0</td><td> -</td><td>Top layer 30.3 ° G, bottom layer 28.5 ° C</td>

Tdetermined in accordance with procedure 1, 2 inlet temperature measured,3 Tablet layer temperature, ie prolonged release matrix formulation temperature, measured with an IR gun,4 temperature measured at the outlet,5 The rotation speed of the vessel was 7 rpm during the entire curing process.

TABLE 14.5.2

<td></td><td></td><td colspan="3">Example 14.5</td>

<td></td><td></td><td>uncured</td><td>60 min curing (n = 5)</td><td>60 min curing, coated (n = 5)</td>

<td rowspan="4">Tablet, dimensions</td><td>Weight (mg)</td><td>150 (n = 120)</td><td> 149</td><td> 155</td>

<td>Thickness (mm)</td><td>4.30 (n = 5)</td><td> 449</td><td> 4.52</td>

<td>Diameter (mm)</td><td>7.15 (n = 5)</td><td> 7.10</td><td> 7.15</td>

<td>Stroke strength (N)</td><td>55 (p = 110)</td><td> 196’</td><td> 196 1</td>

<td rowspan="5">Dissolution (released%) SZF</td><td>1 h</td><td></td><td> -</td><td> 24</td>

1 maximum hardness tester force, the sheets shall not break when subjected to a maximum force of 196 N.

TABLE 14.5.3

Stability tests for Example 14.5, storage at 25 ° C / 60% RH

<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 h</td><td> 24</td><td> 25</td><td> 27</td><td> 23</td><td> 25</td>

<td rowspan="3">Test (mg oxycodone HCl)</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>average</td><td> 37.8</td><td> 38.0</td><td> 36.7</td><td> 37.9</td><td> 39.2</td>

<td rowspan="2">Decomposition product test</td><td>oxycodone Noxide (%) '</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>Each individually unknown (%) '</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

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<td>Total products [decay (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

1 relative to the oxycodone HCl specification.

TABLE 14.5.4

Stability tests for Example 14.5, storage at 40 ° C / 75% RH

<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) SJF</td><td>1 h</td><td> 24</td><td> 26</td><td> 27</td><td> 25</td><td> 25</td>

<td rowspan="3">Test (mg oxycodone HCl)</td><td>Testl</td><td> 37.8</td><td> 38.3</td><td> 37.3</td><td> 37.6</td><td> 37.9</td>

<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">Decomposition product test</td><td>oxycodone Noxide (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>Each individually unknown (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

<td>Total decomposition products (%)1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td><td> <0.1</td>

1 relative to the oxycodone HCl specification.

TABELA14.6

<td></td><td colspan="3">Density (g / cmJ)</td><td rowspan="2">Density change after curing (%)</td><td rowspan="2">Density change after curing and coating (%)</td>

<td></td><td>uncured</td><td>Hardened</td><td>Hardened and coated</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, two different tablet formulations were obtained with Oxycodone HCl, and high molar mass polyethylene oxide. One formulation is a 234 mg tablet (Example 15.1) with 60 mg Oxycodone HC, and one formulation is a 260 mg tablet (Example 15.2) with 80 mg Oxycodone HCl.

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compositions:

<td></td><td>Example 15.1</td><td>Example 15.2</td>

<td>Ingredient</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Oxycodone HCI</td><td> 60</td><td> 80</td>

<td>Polyethylene oxide (M: approximately 4,000,000, 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>Total tablet core weight (mg)</td><td> 225</td><td> 250</td>

<td>Total batch size</td><td>10 kg</td><td>10 kg</td>

<td>lining</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Coating with Opadry film</td><td> 9</td><td> 10</td>

<td>Total tablet weight (mg)</td><td> 234</td><td> 260</td>

<td>Coating batch size (kg)</td><td> 8.367</td><td> 8.205</td>

The steps of tablet production are as follows:

First Batch blender, model Patterson Kelly V 'blender (with I movable rod) - from 16 L, in the following order:

Approximately half of the polyethylene oxide WSR 301

Oxycodone hydrochloride (sieved through a 20 mesh sieve)

Residual polyethylene oxide WSR 301

Second The materials from Step 1 are blended for 5 minutes with the movable bar turned on.

Third Batch the magnesium stearate in a "B" blender (sieved through a 20 mesh sieve).

4th The materials from Step 3 are blended for 1 min with the movable switch off.

5th The aperture from step 4 is loaded into a plastic bag (note: two 5 kg apertures were prepared to provide a 10 kg aperture for tablet compression).

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6th The aperture from Step 5 is compressed to the target mass, in an 8-tablet press at a rate of 35,000 tablets per hour, using a standard 7/20 cm round, concave (embossed) mold. A sample of the tablet core is taken.

7th The tablets from step 6 were loaded into a 60 cm coating pan, model Compu-Lab coating pan, with a batch of 8,367 kg (Example 15.1) and 8,205 kg (Example 15.2).

8th The temperature test (thermocouple wire) is placed directly above the tablet layer in the container, so that the top of the test is near the falling tablet layer.

9th The rotation speed of the vessel is set to 10 rpm, and the tablet layer is heated by adjusting the inlet temperature to reach the target outlet temperature of 72 ° C. The start of curing (described by method 2) is taken when the outlet temperature reaches 72 ° C. The inlet temperature is set to maintain the target outlet temperature. These tablets harden in 15 minutes. The speed of rotation of the vessel is maintained at 10 rpm. The temperature profile of the curing process for Examples 15.1 and 15.2 is given in Tables 15.1.1 and 15.2.1.

10th Continue with the vessel turning speed of 10 rpm. The inlet temperature is set to 22 ° C and the tablet layer is cooled until the outlet temperature reaches 30.0 ° C. At the end of cooling, a sample of hardened tablets is taken.

11th The tablet layer is heated by adjusting the inlet to 53 ° C. Film coating begins when the outlet temperature reaches approximately 41 ° C and continues until a weight gain of 4% is achieved. During film coating, the speed of rotation of the vessel is increased to 20 rpm.

12th Upon completion of the film coating, the rotation speed of the vessel is reduced and the inlet temperature is adjusted to 22 ° C, the air flow is maintained at the set value and the system is cooled to an outlet temperature <30 ° C. A sample of hardened / coated tablets is taken.

13th The tablets are emptied.

In vitro testing, including the tear strength test, is performed as follows:

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Tablet cores (uncured), 15 min curable tablets and cured / coated tablets are tested in vitro, using a USP Apparatus 1 (with a basket, with a safety spring placed on top of the basket, to reduce the tendency of the tablets glued to the bottom of the shaft), at 100 rpm, in 900 mL of simulated enzyme-free gastric juice (SZF), at 37.0 ° C. Samples were analyzed by reverse phase high performance liquid homography (HPLC) on a VVaters Atlantis dC18 3.0 x 250 mm, 5pm column using a mobile phase consisting of a mixture of acetonitrile and polybasic potassium phosphate buffer (pH 3.0), with UV detection at 230 nm. Sampling times are 1.0,2.0,4.0, 6.0,8.0, 12.0 and 16.0 h.

Tablet cores (uncured), 15 min curable tablets and cured / coated tablets were subjected to a tear strength test, applying a maximum force of 196 N, using a device, model Schleuniger 2E / 106 apparatus, to assess tablet resistance to tearing.

Tablet dimensions and dissolution results are given in Tables 15.1.2 to 15.2.2.

TABLE 15.1.1; HARDENING PROCESS TEMPERATURE PROFILE

EXAMPLE 15.1

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Set input (° C)</td><td>Actual inlet (° C)2</td><td>rehearsals (° C)3</td><td>Output (° C)4</td><td>Objections</td>

<td> 0</td><td> -</td><td>22 to 85</td><td> 47.4</td><td> -</td><td> 26.4</td><td>Start warming up</td>

<td> 20</td><td> -</td><td> 85</td><td> 848</td><td> 73.7</td><td> 70.4</td><td>Good tablet flow, no sticking</td>

<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>Start of hardening; 74 ° C set at input too low, output dropped to 70.9 ° C, reset 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 tablet flow, no sticking</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 tablet flow, no sticking</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 of curing, good flow of tablets, no sticking, start of cooling</td>

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At the end of cooling, no sticking was observed during cooling, good flow of tablets, a sample of _____________________ hardened tablets is taken: temperature measured at the inlet, 3 temperature determined according to method 2, measured using a temperature probe (thermocouple wire) 4 temperature measured at the outlet.

TABLE 15.1.2

<td></td><td></td><td colspan="3">Example 15.1</td>

<td></td><td></td><td>uncured</td><td>15 min curing</td><td>coated</td>

<td rowspan="7">Dissolution (released%) SZF</td><td>1 h</td><td> 28</td><td> 28</td><td> 24</td>

TABLE 15.2.1: HARDENING PROCESS TEMPERATURE PROFILE

EXAMPLE 15.2

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total time (min.)</td><td>Time hardened. (Min)1</td><td>Set input (° C)</td><td>Actual input MRWITH)2</td><td>rehearsals (° C)3</td><td>Output (° C)4</td><td>Objections</td>

<td> 0</td><td> -</td><td>22 to 80</td><td> 23.3</td><td> 27.7</td><td> 25.5</td><td>Start warming up</td>

<td> 20</td><td> -</td><td> 80</td><td> 80.0</td><td> 70.1</td><td> 68.4</td><td>Good tablet flow, no sticking</td>

<td> 30</td><td> -</td><td> 80</td><td> 80.1</td><td> 72.5</td><td> 70.6</td><td>Good tablet flow, no sticking</td>

<td> 35</td><td> 0</td><td> 80</td><td> 79.9</td><td> 73.6</td><td> 72.0</td><td>Start of hardening; Good tablet flow, no sticking</td>

<td> 38</td><td> 3</td><td> -</td><td> -</td><td> -</td><td> 72.7</td><td>Maximum output temp.</td>

<td> 45</td><td> 10</td><td> 74</td><td> 73.9</td><td> 71.9</td><td> 72.3</td><td>Good tablet flow, no sticking</td>

<td> 50</td><td> 15</td><td>74 to 22</td><td> 742</td><td> 72.0</td><td> 72.4</td><td>End of curing, start of cooling</td>

<td> 71</td><td> -</td><td> 22</td><td> 21.7</td><td> 28.4</td><td> 30.0</td><td>At the end of cooling, no sticking was observed during cooling, good flow of tablets, a sample of hardened tablets is taken</td>

144

51162 Β 1 determined in accordance with procedure 2, 2 inlet temperature measured, 3 Temperature measured using the Temperature probe (thermocouple wire) 4 temperature measured at the outlet.

TABLE 15.2.2

<td></td><td></td><td colspan="3">Example 15.2</td>

<td></td><td></td><td>uncured (p = 25)</td><td>15 min curing (n = 5)</td><td>Coated (n = 5)</td>

<td rowspan="3">Tablet, dimensions</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>Tear strength (N)</td><td> 92</td><td> 196 1</td><td> 194 2</td>

<td rowspan="7">Dissolution (released%) SZF</td><td>1 h</td><td> 26</td><td> 28</td><td> 25</td>

1 maximum strength of the hardness tester, the tablets do not break when subjected to a maximum force of 196 N.

2 Four tablets do not break when subjected to a maximum force of 196 N, one tablet gives a breaking strength of 185 N (sample average, n - 5, 194 N).

Example 16

In Example 16, two different Oxycodone HCl tablet formulations were prepared using high molar mass polyethylene oxide. One formulation has a tablet weight of 234 mg (Example 16.1), with 60 mg of Oxycodone HCl, and one formulation has a tablet weight of 260 mg (Example 16.2), with 80 mg of Oxycodone HCl. These formulations were produced in a larger batch, compared to Example 15.

compositions:

<td></td><td>Example 16.1</td><td>Example 16.2</td>

<td>Ingredient</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Oxycodone HCI</td><td> 60</td><td> 80</td>

<td>Polyethylene oxide (M: approximately 4,000,000; Polyox SR WSR- 301, LEO)</td><td> 162.75</td><td> 167.5</td>

<td>Magnesium stearate</td><td> 2.25</td><td> 2.50</td>

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<td>Total tablet core weight (mg)</td><td> 225</td><td> 250</td>

<td>Total batch size</td><td>100 kg</td><td>100 kg</td>

<td>lining</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Coating with Opadry film</td><td> 9</td><td> 10</td>

<td>Total tablet weight (mg)</td><td> 234</td><td> 260</td>

<td>Coating batch size (kg)</td><td> 94.122</td><td> 93.530</td>

The steps of tablet production are as follows:

First Oxycodone HCl and magnesium stearate are sieved through a sieve, model Sweco Sifter, equipped with a 20 mesh sieve, into suitable separate containers.

Second Blender, model Gemco V blender (with I movable rod) - from 283 L, charged in the following order:

Approximately half of the polyethylene oxide WSR 301

Oxycodone hydrochloride

Residual polyethylene oxide WSR 301

Third The materials from Step 2 are blended for 10 min with the ignition on.

4th Batch the magnesium stearate in a Gemco "V" blender.

5th Blend the materials from Step 4 for 2 minutes, with the ignition off.

6th The aperture from Step 5 is loaded into clean, tared stainless steel containers.

7th Aperture from 6. Kogaka is compressed to the target mass in a press for 40 tablets, at a rate of 135,000 tablets per hour, using a standard round, concave relief mold, of 7/20 cm and a compression force of 16.5 kN for Example 16.1, and a compression force of 16.0 kN for Example 16.2. A sample of the tablet core is taken.

8th The tablets from step 7 were loaded into a 120 cm coating pan, model AcCele-Coat Coating pan, with a batch of 94,122 kg (Example 16.1) and 93,530 kg (Example 16.2).

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9th The rotation speed of the vessel is adjusted to 7 rpm, and the tablet layer is heated by adjusting the outlet air temperature so as to achieve an outlet temperature of 72 ° C. The start of curing (described by method 2) is taken when the outlet temperature reaches 72 ° C. The tablets are cured at the target outlet temperature for 15 minutes. The temperature profile of the curing process of Examples 16.1 and 16.2 is shown in Tables 16.1.1 and

16.2.1.

10th Continue at a speed of 7 rpm. The outlet temperature is set to 25 ° C and the tablet layer is cooled until the outlet temperature reaches 30 ° C.

11th The tablet layer is heated using an outlet temperature set at 30 ° to 38 ° C. Film coating begins when the outlet temperature reaches 40 ° C and continues until a weight gain of 4% is achieved. During film coating, the speed of rotation of the vessel is maintained at 7 rpm.

12th Upon completion of the film coating, the vessel speed is reduced to 1.5 rpm, the outlet temperature is adjusted to 27 ° C, and the air flow is maintained at the set value until the tablet layer is cooled to an outlet temperature <30 ° C.

13th The tablets are emptied.

In vitro testing, including the tear strength test, is performed as follows:

The coated tablets are tested in vitro, using a USP Apparatus 1 (with a safety spring basket placed on top of the basket to reduce the adhesive properties of the tablets), at 100 rpm, in 900 mL of simulated gastric juice without enzyme (FF), at 37.0 ° C. Samples were analyzed by reverse phase high performance liquid homography (HPLC) in a Waters Atlantis dC18 3.0 x 250 mm, 5pm column using a mobile phase consisting of a mixture of acetonitrile and monobasic potassium phosphate buffer (pH 3.0), with UV detection at 230 nm. Sampling times are 1.0, 2.0, 4.0, 8.0, and 12.0 h.

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Uncured tablets are subjected to online tests of weight, thickness and hardness using an apparatus, model Keu Checkweigher.

Tablet dimensions and dissolution results are given in Tables 16,1.2 to 16.2.2.

TABLE 16.1.1: CURING PROCESS TEMPERATURE PROFILE

EXAMPLE 16.1

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Input (° C)2</td><td>IR gun (° C)3</td><td>Set output (° C)</td><td>Output (° C)4</td><td>Objections</td>

<td> 0</td><td></td><td> 34</td><td> 32</td><td> 65</td><td> 24</td><td>Start warming up</td>

<td> 21</td><td> 0</td><td> 92</td><td> 79</td><td> 72</td><td> 72</td><td>Start of hardening</td>

<td> 37</td><td> 16</td><td> 80</td><td> 77</td><td>72 to 25</td><td> 73</td><td>Kgaj hardening, good flow of tablets, no sticking, start of cooling</td>

<td> 57</td><td> -</td><td> 22</td><td> 26</td><td> 25</td><td> 29</td><td>At the end of cooling, no sticking was observed during cooling, good flow of tablets</td>

1 determined in accordance with procedure 2, 2 inlet temperature measured, 3 temperature measured with an IR gun, 4 temperature measured at the outlet.

TABLE 16.1.2

<td></td><td></td><td colspan="2">Example 16.1</td>

<td></td><td></td><td>Uncured (n = 70)</td><td>coated</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>Tearing strength (Kp)</td><td> 5.7</td><td> -</td>

<td>dissolution</td><td>1 h</td><td> -</td><td> 24</td>

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<td rowspan="4">(released%) SZF</td><td>2 h</td><td> -</td><td> 41</td>

TABLE 16.2.1: CURING PROCESS TEMPERATURE PROFILE

EXAMPLE 16.2

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total time (min.)</td><td>Time hardened. (min.f</td><td>Input (° C)2</td><td>IR gun (° C)3</td><td>GS output set)</td><td>Output (° C)4</td><td>Objections</td>

<td> 2</td><td></td><td> -</td><td> -</td><td>20 to 65</td><td> -</td><td>Start warming up</td>

<td> 22</td><td> 0</td><td> 91</td><td> 77</td><td> 68</td><td> 72</td><td>Start of hardening</td>

<td> 28</td><td> 6</td><td> 82</td><td> 83</td><td> 72</td><td> 78</td><td>Good tablet flow, no sticking</td>

<td> 37</td><td> 15</td><td> 81</td><td> 76</td><td>72 to 25</td><td> 72</td><td>End of curing, good flow of tablets, no sticking, start of cooling</td>

<td> 47</td><td> -</td><td> 25</td><td> 50</td><td> 25</td><td> 48</td><td>Good tablet flow, no sticking</td>

<td> 56</td><td> -</td><td> 21</td><td> 29</td><td> 25</td><td> 30</td><td>After cooling, no sticking was observed during cooling, good flow of tablets</td>

1 determined in accordance with procedure 2, 2 inlet temperature 3 temperature measured with an IR gun,4 temperature measured at the outlet.

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TABLE 16.2.2

<td></td><td></td><td colspan="2">Example 16.2</td>

<td></td><td></td><td>Uncured (n = 60)</td><td>coated</td>

<td rowspan="3">Tablet, dimensions</td><td>Weight (mg)</td><td> 250.8</td><td> -</td>

<td>Thickness (mm)</td><td> 4.05</td><td> -</td>

<td>Tearing strength (Kp)</td><td> 6.8</td><td> -</td>

<td rowspan="5">Dissolution (released%) SZF</td><td>1 h</td><td> -</td><td> 22</td>

Example 17

In Example 17, two formulations of Oxycodone HCl tablets containing 60 mg of Oxycodone HCl were given using high molar mass polyethylene oxide. Example 17.1 is the same formulation given in Example 15.1. The second formulation (Example 17.2) contains 0.1% butylated hydroxytoluene. Each formulation was cured for 15 min at a target outlet temperature of 72 ° C and 75 ° C, then film coated, then cured again for 30 min at the target outlet temperature.

compositions:

<td></td><td>Example 17.1</td><td>Example 17.2</td>

<td>Ingredient</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Oxycodone HCI</td><td> 60</td><td> 60</td>

<td>Polyethylene oxide (M: approximately 4,000,000; 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>Total tablet core weight (mg)</td><td> 225</td><td> 225</td>

<td>Total batch size</td><td>Lks</td><td> _</td>

<td>lining</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Coating with Opadry film</td><td> 9</td><td> 9</td>

<td>Total tablet weight (mg)</td><td> 234</td><td> 234</td>

<td rowspan="2">Coating batch size (kg)</td><td>2 kg at 72 ° C</td><td>6 kg and 72 ° C</td>

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The steps of tablet production are as follows:

First Blender, model Patterson Kelly "V '(with I movable rod) - from 15 L, is charged in the following order:

Approximately half of the polyethylene oxide WSR 301

Oxycodone hydrochloride (sieved through a 20 mesh sieve) Residual polyethylene oxide WSR 301

Second The materials from Step 1 are blended for 5 minutes with the movable bar turned on.

Third Batch the magnesium stearate in a "B" blender.

4th The materials from Step 3 are blended for 1 min with the movable switch off.

5th The aperture from step 4 is loaded into a plastic bag (note: two 5 kg apertures were prepared for Example 17.2, to provide a 10 kg aperture for tablet compression).

6th The aperture from Step 5 is compressed to the target mass, in an 8-tablet press, at a rate of 30,000 tablets per hour, using a standard 7/20 cm round, concave (embossed) mold. Example 17.1 with a compression force of 12 kN, and Example 17.2 with 6 kN, 12 kN and 18 kN.

7th The tablets from step 6 are loaded into a 38 cm coating pan (for a 2 kg batch), or 60 cm, (for a 6 kg batch), model AcCele-Coat Coating pan.

8th The temperature test (thermocouple wire) is placed directly above the tablet layer in the container, so that the top of the test is near the falling tablet layer.

9th The rotation speed of the vessel is adjusted to 7 or 10 rpm, and the tablet layer is heated by adjusting the inlet temperature so as to achieve a target outlet temperature of 72 ° C or 75 ° C. The onset of curing (described by Method 2) is assumed to be when the outlet temperature reaches the target. The inlet temperature is set to maintain the target outlet temperature. These tablets harden in 15 minutes. The speed of rotation of the vessel is maintained at the existing number of rpm. The temperature profile of the curing process for Examples 17.1 and 17.2 is given in Tables 17.1.1 and 17.2.1.

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10th Continue at speed with the existing rpm. The inlet temperature is set to 20 ° or 22 ° C and the tablet layer is cooled until an outlet temperature of approximately 30 ° C is reached. Note: Magnesium stearate was not used.

11th The tablet layer is heated by adjusting the inlet to 52 ° - 54 ° C. Film coating begins when the outlet temperature reaches approximately 39 ° - 42 ° C and continues until a weight gain of 4% is achieved. During film coating, the rotation speed of the vessel is increased to 15 or 20 rpm.

12th Upon completion of the film coating, the rotation speed of the vessel is reduced to the level used during curing. The tablet layer is heated by adjusting the inlet temperature so as to achieve a target outlet temperature of 72 ° C or 75 ° C. The onset of curing (described by Method 2) begins when the outlet temperature reaches the target. The inlet temperature is set to maintain the target outlet temperature. The coated tablets harden for another 30 minutes. The speed of rotation of the vessel is maintained at the existing number of rpm. The temperature profile of this additional curing process, for Examples 17.1 and 17.2, is given in Tables 17.1.1 and 17.2.1.

13th The tablets are emptied.

In vitro testing, including the tear strength test, is performed as follows:

Tablet cores (non-cured), cured tablets and cured / coated tablets are tested in vitro, using USP Apparatus 1 (with a spring-loaded basket mounted on top of the cobra to reduce the tendency of the tablets to stick to the bottom of the shaft), with 100 rpm, in 900 mL of simulated gastric juice without enzyme (SZF), at 37.0 ° C. Samples were analyzed by reverse phase high performance liquid homatography (HPLC) on a VVaters Atlantis dC18 3.0 x 250 mm, 5pm column using a mobile phase consisting of a mixture of acetonitrile and monobasic potassium phosphate buffer (pH 3.0), with UV detection at 230 nm. Sampling times are 1.0,2.0, 4.0, 6.0, 8.0, 12.0 and 16.0 h.

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Uncured tablets are subjected to a tear strength test, using a maximum force of

196 N, using an apparatus, model Schleuniger 2E / 106 apparatus, to assess the tear resistance of tablets.

Tablet dimensions and dissolution results are given in Tables 17.1.2 to 17.2.2.

TABLE 17.1.1

<td colspan="7">72 ° C curing process for Example 17.1</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Set input (° C)</td><td>Actual input ('C)2</td><td>rehearsals (° C)3</td><td>Output (° C)4</td><td>Objections</td>

<td> 0</td><td> -</td><td>22 to 80</td><td> 25.5</td><td> 28.4</td><td> 28 5</td><td>Start warming up</td>

<td> 19</td><td> 0</td><td>80 to 78</td><td> 80.0</td><td> 73.2</td><td> 72.0</td><td>Start of hardening</td>

<td> 34</td><td> 15</td><td> 75</td><td> 75.0</td><td> 72.3</td><td> 72.0</td><td>End of curing, start of cooling</td>

<td> 50</td><td> -</td><td> 22</td><td> 22.8</td><td> 28.2</td><td> 29.2</td><td>End of cooling, ready for coating</td>

<td colspan="4">Application of 4% coated film on tab</td><td colspan="3">here, when the start of heating is reached</td>

<td> 0</td><td> -</td><td>48 to 80</td><td> 47.8</td><td> 45.1</td><td> 43.1</td><td>Start heating for additional hardening</td>

<td> 13</td><td> 0</td><td>80 to 76</td><td> 80.1</td><td> 73.2</td><td> 72.0</td><td>The beginning of extra hardening.</td>

<td> 28</td><td> 15</td><td> 75</td><td> 74.9</td><td> 72.0</td><td> 72.4</td><td>15 min additional hardening.</td>

<td> 43</td><td> 30</td><td>74 to 22</td><td> 74.0</td><td> 71.5</td><td> 72.1</td><td>30 min additional hardening, start of cooling</td>

<td> 55</td><td> -</td><td> 22</td><td> 24.6</td><td> 32.2</td><td> 34</td><td>End of cooling, discharge</td>

<td colspan="7">Curing process at 75 ° C for Example 17.1</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td> 0</td><td> -</td><td>42 to 80</td><td> 42.1</td><td> 38.6</td><td> 38.5</td><td>Start warming up</td>

<td> 21</td><td> 0</td><td> 82</td><td> 81.5</td><td> 75.1</td><td> 75.0</td><td>Start of hardening</td>

<td> 36</td><td> 15</td><td>77.5 to 22</td><td> 77.6</td><td> 74.1</td><td> 75.2</td><td>End of curing, start of cooling</td>

<td> 53</td><td> -</td><td> 22</td><td> 23.1</td><td> 29.5</td><td> 29.6</td><td>End of cooling, ready for coating</td>

<td colspan="4">Apply 4% film coating to the boards</td><td colspan="3">is when the start of heating is reached</td>

<td> 0</td><td></td><td>48 to 83</td><td> 48.1</td><td> 44.4</td><td> 41.5</td><td>Start heating for additional hardening</td>

I53

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<td> 12</td><td> 0</td><td> 83</td><td> 83.1</td><td> 75.1</td><td> 75.0</td><td>The beginning of additional hardening.</td>

<td> 27</td><td> 15</td><td> 78</td><td> 78.11</td><td> 74.4</td><td> 75.4</td><td>15 min additional hardening.</td>

<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 min additional hardening, start of cooling</td>

<td> 56</td><td> -</td><td> 22</td><td> 23.9</td><td> 30.3</td><td> 30.0</td><td>End of cooling, discharge</td>

1 determined in accordance with procedure 2, 2 inlet temperature measured, 3 Temperature measured using a temperature probe (thermocouple wire) 4 temperature measured at the outlet.

TABLE 17.1.2

<td></td><td></td><td colspan="5">Example 17.1</td>

<td></td><td></td><td>Uncured (n = 25)</td><td colspan="2"></td><td colspan="2"></td>

<td rowspan="3">Tablet, dimensions</td><td>Weight (mg)</td><td> 225</td><td colspan="2"> -</td><td colspan="2"> -</td>

<td>Thickness (mm)</td><td> 3.86</td><td colspan="2"> -</td><td colspan="2"> -</td>

<td>Tear strength (N</td><td> 75</td><td colspan="2"> -</td><td colspan="2"> -</td>

<td></td><td></td><td></td><td colspan="2">Example 17.1 hardened to 72 ° C</td><td colspan="2">Example 17.1 solidified at 75 ° C</td>

<td></td><td></td><td></td><td>15 min hardened.</td><td>coated</td><td>15 min hardened.</td><td>coated</td>

<td rowspan="7">Dissolution (released %) SGF</td><td>1 h</td><td> 27</td><td> 27</td><td> 26</td><td> 28</td><td> 26</td>

TABLE 17.2.1

<td colspan="7">Curing process then 72 ° C for Example 17.2</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Set input (° C)</td><td>Actual inlet ° C)2</td><td>rehearsals (° C)3</td><td>Output (° C)4</td><td>Objections</td>

<td> 0</td><td> -</td><td> 80</td><td> 34.8</td><td> 33.8</td><td> 32.1</td><td>Batch of vessel 6 kg; Start warming up</td>

<td> 27.5</td><td> 0</td><td> 80</td><td> 80.3</td><td> 73.0</td><td> 72.0</td><td>Start of hardening</td>

<td> 42.5</td><td> 15</td><td>73.6 dO 22</td><td> 73.5</td><td> 70.6</td><td> 72.1</td><td>Kgaj hardening, start cooling</td>

<td> 61</td><td> -</td><td> 22</td><td> 22.7</td><td> 30.1</td><td> 30</td><td>End of cooling, ready for coating</td>

<td colspan="2">Application 4%</td><td>film coatings</td><td colspan="4">per tablet, when the onset of warming is reached</td>

<td> 0</td><td> -</td><td>80 to 53</td><td> 53</td><td> -</td><td> 39.5</td><td>Start warming up for</td>

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<td></td><td></td><td></td><td></td><td></td><td></td><td>additional hardening</td>

<td> 18</td><td> 0</td><td> 80</td><td> 79.9</td><td> 74.1</td><td> 72.0</td><td>The beginning of extra hardening.</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 min additional hardening.</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 min additional hardening, start of cooling</td>

<td> 64</td><td> -</td><td> 23.0</td><td> 23.9</td><td> -</td><td> 30.0</td><td>End of cooling, discharge</td>

<td colspan="7">Curing process at 75 ° C for Example 17.2</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total Time (min.)</td><td>Time hardened. (Min.)1</td><td>Set input (° C)</td><td>Actual inlet (° C)2</td><td>rehearsals (° C)3</td><td>Output (° C)4</td><td>Objections</td>

<td> 0</td><td> -</td><td> 82</td><td> 52.9</td><td> 53</td><td> 48.4</td><td>Batch of dish 2 kg, Start of heating</td>

<td> 23.5</td><td> 0</td><td>85 to 82</td><td> 81.8</td><td> 76.4</td><td> 75.0</td><td>Start of hardening</td>

<td> 38.5</td><td> 15</td><td> 78</td><td> 78</td><td> 75.6</td><td> 76.1</td><td>End of curing, start of cooling</td>

<td> 53</td><td> -</td><td> 20</td><td> 32.4</td><td> 30.0</td><td> 32.1</td><td>End of cooling, ready for coating</td>

<td colspan="3">Application of 4% film coating</td><td colspan="4">per tablet, when the onset of warming is reached</td>

<td> 0</td><td> -</td><td>53.5 to 83</td><td> 53.7</td><td> -</td><td> 46.5</td><td>Start heating for additional hardening</td>

<td> -</td><td> 0</td><td> 83</td><td> 83</td><td> 73.7</td><td> 75</td><td>The beginning of extra hardening.</td>

<td> -</td><td> 15</td><td> 78</td><td> 77.9</td><td> 74.3</td><td> 75.9</td><td>15 min additional hardening.</td>

<td> -</td><td> 30</td><td>78 to 22</td><td> 78</td><td> 75.1</td><td> 76.4</td><td>30 min additional hardening, start of cooling</td>

<td></td><td> -</td><td> 22</td><td> 23.6</td><td> 31.0</td><td> 32.1</td><td>Kgaj cooling (15 min cooling), draining</td>

TABLE 17.2.2

<td></td><td></td><td colspan="6">Example 17.2</td>

<td></td><td></td><td colspan="6">Uncured tablet cores (n = 5)</td>

<td></td><td>Compression force (kN)</td><td> 6</td><td> 12</td><td> 18</td><td> 12</td><td></td><td></td>

<td rowspan="3">Tablet, dimensions</td><td>Weight (mg)</td><td> 226</td><td> 227</td><td> 227</td><td> 226</td><td></td><td></td>

<td>Thickness (mm)</td><td> 3.93</td><td> 3.87</td><td> 3.86</td><td> 3.91</td><td></td><td></td>

<td>Tearing strength (N)</td><td> 43</td><td> 71</td><td> 83</td><td> 72</td><td></td><td></td>

<td></td><td></td><td colspan="3">Example 17.2 hardened to 72 ° C (6 kg batch)</td><td colspan="3">Example 17.2 hardened to 75 ° C (2 kg batch)</td>

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<td></td><td colspan="2"></td><td colspan="3">15 min hardened, coated</td><td>Uncured (core)</td><td colspan="2">15 min hardened.</td><td colspan="2">coated</td>

<td></td><td colspan="2">Compression force (kN)</td><td> 6</td><td> 12</td><td> 18</td><td colspan="5"> 12</td>

<td rowspan="6">Dissolution (released%) SZF No spring</td><td colspan="2">1 h</td><td> 25</td><td> 23</td><td> 23</td><td> 26</td><td colspan="2"> 27</td><td colspan="2"> 24</td>

<td colspan="2" rowspan="7">Dissolution (released%) SZF With basket and spring</td><td>1 h</td><td></td><td> 26</td><td> 24</td><td></td><td></td><td colspan="2"></td><td rowspan="7"></td>

Example 18

In Example 18, four different Oxycodone HCl tablet formulations were obtained, containing 80 mg of Oxycodone HCl, using high molar mass polyethylene oxide, with a tablet weight of 250 mg. The two formulations (Examples 18.2 and 18.3) contained 0.1% butylated hydroxytoluene. One of the formations (Example 18.4) contained 0.5% butylated hydroxytoluene. The three formulations (Examples 18.1, 18.2, and 18.4) contained 1% magnesium stearate. One of the formulations (Example 18.3) contained 0.5% magnesium stearate.

compositions:

<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 / dish.</td><td>mg / dish.</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Oxycodone HCI</td><td> 80 (32%)</td><td> 80 (32%)</td><td> 80 (32%)</td><td> 80 (32%)</td>

<td>Polyethylene oxide (M: approx. 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>

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<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 tablet core weight (mg)</td><td> 250</td><td> 250</td><td> 250</td><td> 250</td>

<td>Total batch size (kg)</td><td>5 and 6.3</td><td> 5</td><td> 5</td><td> 5</td>

<td>lining</td><td>mg / dish.</td><td>mg / dish.</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Coating with Opadry film</td><td>on</td><td> 7.5</td><td> 10</td><td>on</td>

<td>Total tablet weight (mg)</td><td>on</td><td> 257.5</td><td> 260</td><td>on</td>

<td>Coating batch size (kg)</td><td>on</td><td> 1.975</td><td> 2.0</td><td>on</td>

The steps of tablet production are as follows:

First Blender, model Patterson Kelly "V ', (with I movable rod) - from 15 L, is charged in the following order:

Approximately half of the polyethylene oxide WSR 301

Oxycodone hydrochloride

BHT (needed)

Residual polyethylene oxide WSR 301

Second The materials from Step 1 are blended: 10 min (Example 18.1, batch size 6.3 kg), 6 min (Example 18.2), or 5 min (Example 18.1, batch size 5 kg, Examples 18.3 and 18.4), with the movable switch off .

Third Batch the magnesium stearate in a "B" blender.

4th The materials from Step 3 are blended for 1 min with the movable switch off.

5th The aperture from step 4 is charged into a plastic bag.

6th The aperture from Step 5 is compressed to the target mass, in a press for 8 tablets. The compromise parameters are given in Tables 18.1 to 18.4.

7th The tablets from step 6 are loaded into a 45 cm coating pan, model Compu-Lab coating pan, with a batch of 1.5 kg (Example 18.1 curing at 72 ° C), 2.0 kg (Example 18.1 curing at 75 ° and 78 ° C) ), 1,975 kg (Example 18.2 curing at 72 ° C and 75 ° C), 2.0 kg (Example 18.3), 2.0 kg (Example 18.4 curing at 72 ° C and 75 ° C).

8th The temperature test (thermocouple wire) is placed directly above the tablet layer in the container, so that the top of the test is near the moving tablet layer.

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9th In Examples 18.1 to 18.4, the tablet layer was heated by adjusting the inlet temperature so as to achieve a target outlet temperature of 72 ° C, 75 ° C or 78 ° C. The start of curing (described by method 2) is taken when the outlet temperature reaches the target outlet temperature. When the target outlet temperature is reached, the inlet temperature is set to maintain the target outlet temperature. These tablets harden in 15 minutes to 90 minutes. After curing, the tablet layer is cooled. Temperature profiles for the curing process for Examples

18.1 to 18.4 are given in Tables 18.1.1 to 18.4.1.

10th After cooling, the tablet layer was heated, adjusting the inlet to 53 ° C (Examples 18.2 and 18.3, and film coating was not performed for Examples 18.1 and 18.4). When film coating begins, the outlet temperature reaches approximately 40 ° C and continues until a mass increment of 3% (Example 18.2) and 4% (Example 18.3) is achieved.

11th When the film coating is completed (Example 18.2), the tablet layer is heated by adjusting the inlet temperature to reach the target outlet temperature (72 ° C for one batch and 75 ° C for the second batch). The start of curing (described by method 2) is taken when the outlet temperature reaches the target outlet temperature. When the target outlet temperature is reached, the inlet temperature is set to maintain the target outlet temperature. The film-coated tablets harden for another 30 minutes. After this additional curing, the tablet layer is cooled. The temperature profile of the curing process for Example 18.2 is given in the Table

18.2.1.

12th The speed of the vessel is reduced and the inlet temperature is set to 22 ° C. The system is cooled to an outlet temperature of 30 ° C.

13th The tablets are emptied.

In vitro testing, including strength and tear testing, is performed as follows:

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Tablet cores (non-cured), cured tablets, and cured / coated tablets are tested in vitro, using the USP Apparatus 1 (some tests are with a safety spring basket placed on top of the basket to reduce the tendency of the tablets to stick to the bottom of the property), at 100 rpm, in 900 mL of simulated enzyme-free gastric juice (SJF), at 37.0 ° C. Samples were analyzed by reverse phase high performance liquid homography (HPLC) on a VVaters Atlantis dC18 3.0 x 250 mm, 5pm column using a mobile phase consisting of a mixture of acetonitrile and monobasic potassium phosphate buffer (pH 3.0), with UV detection at 230 nm. Sampling times are 1.0, 2.0,4.0, 6.0, 8.0 and 12.0 h.

Uncured tablets are subjected to a tear strength test, using a maximum force of 196 N, using an apparatus, model Schleuniger 2E / 106 apparatus, to assess the resistance of the tablets to tearing.

Tablets of Example 18.4 (cured at 72 ° C and 75 ° C, respectively) were subjected to a stability test by storage in 6 labeled bottles under different storage 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. And the sample times, in terms of storage, are: initial sample (ie. rge storage), two weeks and one month, and the sampling times in terms of dissolution test are 1.0, 2.0,4.0, 6.0, 8.0 and 12.0 h.

Tablet dimensions and dissolution results are given in Tables 18.2.2 to 18.4.2.

TABLE 18.1.1

<td colspan="7">72 ° C curing process for Example 18.1</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Set input (° C)</td><td>Actual inlet (° C)2</td><td>Probe (eC)3</td><td>Output (° C)4</td><td>Objections</td>

<td> 0</td><td> -</td><td>23 to 80</td><td> 24.8</td><td> 28.4</td><td> 28.9</td><td>Batch of vessel 1.5 kg; Start warming up</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>Start of hardening</td>

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<td> 35</td><td> 15</td><td> 75</td><td> 75</td><td> 71.4</td><td> 72.0</td><td>Sample</td>

<td> 50</td><td> 30</td><td> 75</td><td> 74.9</td><td> 72.0</td><td> 72.7</td><td>Sample</td>

<td> 65</td><td> 45</td><td> 74</td><td> 74</td><td> 71.5</td><td> 72.1</td><td>Sample</td>

<td> 80</td><td> 60</td><td> 74</td><td> 74</td><td> 71.2</td><td> 71.8</td><td>Sample</td>

<td> 95</td><td> 75</td><td> 74</td><td> 73.9</td><td> 71.7</td><td> 72.3</td><td>Sample</td>

<td> 110</td><td> 90</td><td>74 to 22</td><td> 74</td><td> 71.7</td><td> 72.3</td><td>End of solidification, sample taken, 0.3 g of magnesium stearate added, start of cooling</td>

<td> 129</td><td> -</td><td> 22</td><td> 23.1</td><td> 27.4</td><td> 26.9</td><td>End of cooling, no sticking during cooling, emptying</td>

Curing process at 75 ° C for Example 18.1

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total Time (min.)</td><td>Time hardened. (Min.)1</td><td>Set input (° C)</td><td>Actual inlet (° C)2</td><td>Probe ('cf</td><td>Output (° C)4</td><td>Objections</td>

<td> 0</td><td> -</td><td>23 dO 85</td><td> 24.1</td><td> 25.0</td><td> 24.9</td><td>Batch of dish 2.0 kg, Start of heating</td>

<td> 19</td><td> 0</td><td>85 to 82</td><td> 85.1</td><td> 76.2</td><td> 75</td><td>Start of hardening</td>

<td> 34</td><td> 15</td><td> 78</td><td> 78.2</td><td> 73.6</td><td> 75.1</td><td>Sample</td>

<td> 49</td><td> 30</td><td> 78</td><td> 77.8</td><td> 74.5</td><td> 75.5</td><td>Sample</td>

<td> 64</td><td> 45</td><td> 77.5</td><td> 77.6</td><td> 74.8</td><td> 75.4</td><td>Sample</td>

<td> 79</td><td> 60</td><td> 77.5</td><td> 77.6</td><td> 74.6</td><td> 75.1</td><td>Sample</td>

<td> 94</td><td> 75</td><td> 77.5</td><td> 77.5</td><td> 74.5</td><td> 75.1</td><td>Sample, little sticking</td>

<td> 109</td><td> 90</td><td> 77.5</td><td> 77.6</td><td> 75.0</td><td> 75.6</td><td>End of curing, sample taken, start of cooling</td>

<td> 116</td><td> -</td><td> 22</td><td> 30.6</td><td> 42.6</td><td> 46.7</td><td>less sieving on court carriers</td>

<td> 122</td><td> -</td><td> 22</td><td> 25</td><td> -</td><td> 33.5</td><td>End of cooling</td>

<td colspan="7">78 ° C curing process for Example 18.1</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td> 0</td><td> -</td><td> 82</td><td> 35</td><td> 37.6</td><td> 35.9</td><td>Batch of dish 2 kg, Start of heating</td>

<td> 17.5</td><td> 0</td><td>85 to 83</td><td> 85.1</td><td> 77.4</td><td> 78.0</td><td>Start of hardening</td>

<td> 32.5</td><td> 15</td><td> 82</td><td> 81.9</td><td> 76.9</td><td> 78.4</td><td>Sample</td>

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<td> 47.5</td><td> 30</td><td> 81</td><td> 80.9</td><td> 77.4</td><td> 78.3</td><td>Sample</td>

<td> 62.5</td><td> 45</td><td> 80.5</td><td> 80.7</td><td> 77.4</td><td> 78.2</td><td>Sample</td>

<td> 69.5</td><td> 52</td><td> 80.5</td><td> 80.4</td><td> 77.5</td><td> 78.2</td><td>Less sticking</td>

<td> 77.5</td><td> 60</td><td> 80.5</td><td> 80.6</td><td> 77.6</td><td> 78.3</td><td>Pattern, gluing</td>

<td> 87.5</td><td> 70</td><td> -</td><td> -</td><td> -</td><td> -</td><td>0.3 g of magnesium stearate was added</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>Sample, adhesion continued, brief improvement in tablet flow with magnesium stearate</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, start cooling</td>

TABLE 18.1.2

<td></td><td></td><td colspan="3">Example 18.1 (6.3 kg batch)</td>

<td></td><td></td><td>Uncured core of the tablet</td><td colspan="2"></td>

<td></td><td>Compression force (kN)</td><td> 15</td><td colspan="2"></td>

<td 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>Breaking strength (N)</td><td> 87</td><td colspan="2"></td>

<td></td><td></td><td></td><td colspan="2">Example 18.1, curing at 72 ° C</td>

<td></td><td></td><td>uncured</td><td>15 min curing</td><td>60 min curing</td>

<td>dissolution</td><td>1 h</td><td> 25</td><td> 26</td><td> 25</td>

<td rowspan="4">(released %) SŽF No spring</td><td>2h</td><td> 40</td><td> 40</td><td> 40</td>

<td></td><td></td><td colspan="2">Example 18.1 (batch of 5.0 kg)</td>

<td></td><td></td><td colspan="2">Uncured tablet core</td>

<td></td><td>Compression force (kN)</td><td> 15</td><td></td>

<td rowspan="3">Tablet, dimensions</td><td>Weight (mg)</td><td> 253</td><td></td>

<td>Thickness (mm)</td><td> 4.13</td><td></td>

<td>Tear strength (N)</td><td> 92</td><td></td>

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<td></td><td></td><td></td><td colspan="2">Example 18.1 curing at 75 ° C</td><td>Example 18.1 curing at 78 ° C</td>

<td></td><td></td><td>uncured</td><td>15 min hardened.</td><td>60 min hardened.</td><td>30 min curing</td>

<td rowspan="5">Dissolution (released%) SZF No spring</td><td>1 h</td><td> 26</td><td> 26</td><td> 26</td><td> 26</td>

TABLE 18.2.1

<td></td><td></td><td></td><td colspan="8">72 ° C curing process for Example 18.2</td>

<td></td><td></td><td></td><td></td><td></td><td colspan="3">Temperature</td><td></td><td></td><td>Ί</td>

<td>Total time (min.)</td><td colspan="2">Time hardened. imine.)1</td><td colspan="2">Adjusted input co</td><td colspan="2">Actual inlet (° C)2</td><td colspan="2">rehearsals (° C)3</td><td>Output (° C)4</td><td>and Objections</td>

<td> 0</td><td></td><td> -</td><td colspan="2">42 to 80</td><td> 41.9</td><td></td><td colspan="2"> 37.4</td><td> 37.8</td><td>Batch of dish 1,975 kg, Start of heating</td>

<td> 18</td><td></td><td> 0</td><td> 80</td><td></td><td> 80.1</td><td></td><td colspan="2"> 71.6</td><td> 72.0</td><td>Start of hardening</td>

<td> 33</td><td></td><td> 15</td><td colspan="2">75 to 22</td><td> 75.0</td><td></td><td colspan="2"> 71.1</td><td> 72.3</td><td>End of curing, start of cooling</td>

<td> 47.5</td><td></td><td> -</td><td> 22</td><td></td><td> 22.5</td><td></td><td colspan="2"> 30.4</td><td> 30.0</td><td>End of cooling, Sample, ready for coating</td>

<td colspan="3">Application 3% f</td><td>ma obloc</td><td colspan="7">is by tablets, when the onset of heating is reached</td>

<td> 0</td><td></td><td> -</td><td>50 to 80</td><td></td><td> 50</td><td colspan="2"> 48.0</td><td></td><td> 43.0</td><td>Start heating for additional hardening</td>

<td> 12</td><td></td><td> 0</td><td>80 to 77</td><td></td><td> 80.0</td><td colspan="2"> 72.1</td><td></td><td> 72.0</td><td>The beginning of extra hardening.</td>

<td> 27</td><td></td><td> 15</td><td> 75</td><td></td><td> 74.9</td><td colspan="2"> 71.0</td><td></td><td> 72.4</td><td>Sample, 15 min additional curing</td>

<td> 42</td><td></td><td> 30</td><td>74 to 22</td><td></td><td> 73.9</td><td colspan="2"> 70.7</td><td></td><td> 72.1</td><td>Sample, 30 min additional curing, start of cooling</td>

<td> 61</td><td></td><td> -</td><td> 22</td><td></td><td> -</td><td></td><td></td><td></td><td> 30</td><td>End of cooling, discharge, Sample</td>

<td colspan="7">Curing process then 75 ° C for Example 18.2</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Set input (° C)</td><td>Actual inlet (° c)2</td><td>rehearsals (° C)3</td><td>Output (° C)4</td><td>Objections</td>

<td> 0</td><td> -</td><td>42 to 82</td><td> 41.8</td><td> 39.7</td><td> 40.1</td><td>Batch of dish 1,975 kg, Start of heating</td>

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<td> 18</td><td> 0</td><td>82 to 80</td><td> 81.9</td><td> 75.2</td><td> 75.0</td><td>Start of hardening</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 hardening, beginning of cooling, no sticking</td>

<td> 49</td><td> -</td><td> 22</td><td> 22.5</td><td> 28.8</td><td> 29.5</td><td>End of cooling, Sample, ready for coating</td>

<td colspan="7">Application of 3% film of coating per tablet, when the onset of heating is reached</td>

<td> 0</td><td> -</td><td>48 to 83</td><td> 48.0</td><td> 44.5</td><td> 41.5</td><td>Start heating for additional hardening</td>

<td> 13</td><td> 0</td><td> 83</td><td> 83.3</td><td> 75.6</td><td> 75.4</td><td>The beginning of extra hardening.</td>

<td> 28</td><td> 15</td><td> 78</td><td> 78.0</td><td> 74.6</td><td> 75.4</td><td>The sample was further cured for 15 min.</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>The sample is further hardened for 30 minutes, cooling begins</td>

<td> 58.5</td><td> -</td><td> 22</td><td> 24.2</td><td> -</td><td> 30</td><td>End of cooling, discharge, Sample</td>

TABLE 18.2.2

<td></td><td></td><td colspan="6">Example 18.2</td>

<td></td><td></td><td colspan="6">Uncured tablet core</td>

<td></td><td>Mold size, round (cm)</td><td colspan="2"> 7/20</td><td colspan="2"> 7/20</td><td colspan="2"> 33/56</td>

<td></td><td>Compression force (kN)</td><td colspan="2"> 8</td><td colspan="2"> 15</td><td colspan="2"> 15</td>

<td rowspan="3">Tablet, dimensions</td><td>Weight (mg)</td><td colspan="2"> 253</td><td colspan="2"> 253</td><td colspan="2"> 252</td>

<td>Thickness (mm)</td><td colspan="2"> 4.24</td><td colspan="2"> 4.21</td><td colspan="2"> 3.77</td>

<td>Tear strength (N)</td><td colspan="2"> 50</td><td colspan="2"> 68</td><td colspan="2"> 55</td>

<td></td><td></td><td colspan="6">Example 18.2 curing at 72 ° C</td>

<td></td><td>Compression force (kN)</td><td colspan="2"> 8</td><td colspan="2"> 15</td><td colspan="2"> 15</td>

<td></td><td></td><td colspan="2">15 min curing, coated</td><td colspan="2">15 min curing, coated</td><td colspan="2">15 min curing, coated</td>

<td></td><td>Dissolving with basket *</td><td>Beige spring</td><td>With spring</td><td>No spring</td><td>With spring</td><td>No spring</td><td>With spring</td>

<td rowspan="4">dissolution1 (released%) SZF</td><td>1 h</td><td> 22 (4.9)</td><td> 23 (6.5)</td><td> 22 (4.8)</td><td> 24 (5.6)</td><td> 23 (2.2)</td><td></td>

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* Some tests include the use of a safety spring placed on top of the basket to reduce the tendency of the tablet to stick to the bottom of the shaft; 1 the values in parentheses show the relative standard deviation.

TABLE 18.3.1

<td colspan="7">Curing process at 72 ° C for Example 18.3</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Set input (° C)</td><td>Actual inlet (° C)2</td><td>rehearsals ( 'C)3</td><td>OutputMRWITH)4</td><td>Objections</td>

<td> 0</td><td> -</td><td>22 to 80</td><td> 25.1</td><td> 29.4</td><td> 30.1</td><td>Batch of dish 2 0 kg, Start of heating</td>

<td> 19</td><td> 0</td><td> 80</td><td> 80.0</td><td> 71.8</td><td> 72.0</td><td>Start of hardening</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 of curing, start of cooling</td>

<td> 49</td><td> -</td><td> 22</td><td> 22.9</td><td> 29 1</td><td> 29.7</td><td>End of cooling</td>

determined in accordance with procedure 2, 2 inlet temperature measured, 3 temperature met using a temperature test (thermocouple wire) 4 temperature measured at azu.

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>Mold</td><td colspan="2">Round 7/20 cm</td><td>Oval 1.5 / 0.69 cm</td>

<td></td><td>Compression force (kN)</td><td colspan="2"> 15</td><td> 10-11</td>

<td rowspan="3">Tablet, dimensions</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>Tear strength (N)</td><td colspan="2"> 83-110</td><td> 71 -76</td>

<td></td><td></td><td colspan="3">Example 18.3 curing at 72 ° C</td>

<td></td><td></td><td colspan="2">15 min curing, coated</td><td>15 min curing, coated</td>

<td></td><td></td><td colspan="2">Round 7/20 cm</td><td>Oval 1.5 / 0.69 cm</td>

<td></td><td>Dissolving with basket *</td><td>No spring</td><td>With spring</td><td>No spring</td>

<td rowspan="3">Dissolution '(% released)</td><td>1 h</td><td> 23 (7.0)</td><td> 23 (4.9)</td><td> 24 (7.2)</td>

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* Some tests were with a protective spring, placed on top of the basket to reduce the tendency of the tablets to stick to the bottom of the shaft.

1 the values in parentheses show the relative standard deviation.

TABLE 18.4.1

<td colspan="7">Curing process at 72 ° C for Example 18.4</td>

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Set input ('C)</td><td>Actual inlet (° C)2</td><td>rehearsals (° C)3</td><td>Output (° C)4</td><td>Objections</td>

<td> 0</td><td> -</td><td> 82</td><td> 35.6</td><td> 37.3</td><td> 36.3</td><td>Batch of vessel 2.0 kg; Start warming up</td>

<td> 13.5</td><td> 0</td><td> 82</td><td> 82</td><td> 72.6</td><td> 72.0</td><td>Start of hardening</td>

<td> 28.5</td><td> 15</td><td> 75</td><td> 75</td><td> 70.9</td><td> 72.4</td><td>Sample</td>

<td> 43.5</td><td> 30</td><td> 75</td><td> 75</td><td> 71.1</td><td> 72.6</td><td>Sample</td>

<td> 58.5</td><td> 45</td><td> 75</td><td> 75</td><td> 71.4</td><td> 72.8</td><td>Sample</td>

<td> 73.5</td><td> 60</td><td> 75</td><td> 75</td><td> 71.5</td><td> 73</td><td>End of curing, Sample, start of cooling</td>

<td> 78.5</td><td> -</td><td> 23</td><td> 37.4</td><td> 48</td><td> 52.2</td><td>Continue cooling</td>

<td colspan="7">Curing process at 75 ° C for Example 18.4</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>Batch of dish 2.0 kg, Start of heating</td>

<td> 17.5</td><td> 0</td><td> 85</td><td> 85</td><td> 76.2</td><td> 75</td><td>Start of hardening</td>

<td> 32.5</td><td> 15</td><td> 78</td><td> 77.9</td><td> 74.5</td><td> 75.9</td><td>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>Sample</td>

<td> 62.5</td><td> 45</td><td> 77</td><td> 77</td><td> 73.9</td><td> 75.3</td><td>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 curing, Sample, start of cooling</td>

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51162 Β 1 determined in accordance with procedure 2, 2 inlet temperature measured, 3 temperature measured using a temperature probe (thermocouple wire) 4 temperature measured at the outlet.

TABLE 18.4.2

<td></td><td></td><td colspan="5">Example 18.4</td>

<td></td><td></td><td>Uncured tablet core</td><td colspan="4"></td>

<td></td><td>Compression force (kN)</td><td> 15</td><td colspan="4"></td>

<td rowspan="3">Tablet, dimensions</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>Tear strength (N)</td><td> 85</td><td colspan="4"></td>

<td></td><td></td><td></td><td colspan="2">Example 18.4 curing at 72 ° C</td><td colspan="2">Example 18.4 curing at 75 ° C</td>

<td></td><td></td><td>uncured</td><td>15 min hardened.</td><td>60 min hardened.</td><td>15 min hardened.</td><td>60 min hardened.</td>

<td rowspan="5">Dissolution (released%) SZF No spring</td><td>1 h</td><td> 26</td><td> 26</td><td> 26</td><td> 26</td><td> 25</td>

<td></td><td></td><td colspan="4">Example 18.4, stability after 2 weeks; 15 min curing at 72 ° C</td>

<td></td><td></td><td>Initial</td><td> 25 / 601</td><td> 40 / 751</td><td>50 ° C</td>

<td rowspan="6">Dissolution (released%) SŽF Without spring</td><td>1 h</td><td> 26</td><td> 26</td><td> 26</td><td> 27</td>

<td></td><td></td><td colspan="4">Example 18.4, stability after 2 weeks; 15 min curing at 75 ° C</td>

<td></td><td></td><td>Initial</td><td> 25 / 601</td><td> 40 / 751</td><td>50 ° C</td>

<td rowspan="3">Dissolution (% released)</td><td>1 h</td><td> 26</td><td> 25</td><td> 26</td><td> 25</td>

I66

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<td rowspan="3">No spring</td><td>6h</td><td></td><td></td><td> -</td><td> -</td>

<td></td><td></td><td></td><td colspan="3">Example 18.4, stability after 1 month 15 min curing at 72 ° C</td>

<td></td><td></td><td>Inicijaina</td><td> 25/601</td><td> 40 / 75</td><td>50 ° C</td>

<td rowspan="3">Dissolution (% released)</td><td>1 h</td><td> 26</td><td> 26</td><td> 26</td><td> 26</td>

<td>No spring</td><td>8h</td><td> 89</td><td> 89</td><td> 91</td><td> 93</td>

<td>1 warehouse conditions</td><td colspan="3">25 ° C / 60% RH or 40 ° C / 75%</td><td colspan="2">RH</td>

Example 19

In Example 19, two different formulations of Oxycodone HCl tablets were obtained, containing 80 mg of Oxycodone HCl, using high molar mass polyethylene oxide, with a tablet weight of 250 mg. One of these formulations (Example 19.1) contained polyethylene oxide N60K, and the other formulation (Example 19.2) contained polyethylene oxide N12.

compositions:

<td></td><td>Example 19.1</td><td>Example 19.2</td>

<td>Ingredient</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Oxycodone HCI</td><td> 80 (32%)</td><td> 80 (32%)</td>

<td>Polyethylene oxide (M. approx. 2,000,000; Polyox ™ WSR-N60K)</td><td> 168.75 (67.5%)</td><td> 0</td>

<td>Polyethylene oxide (M: approx 1,000,000; Polyox ™ WSR- N12K)</td><td> 0</td><td> 168.75 (67.5%)</td>

<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>Total batch size (kg)</td><td> 2.0</td><td> 2.0</td>

<td>lining</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Coating with Opadry film</td><td> 10</td><td> 10</td>

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<td>Total tablet weight (mg)</td><td> 260</td><td> 260</td>

<td>Circulation batch size (kg)</td><td> 1.4</td><td> 1.4</td>

The steps of tablet production are as follows:

First Blender, model Patterson Kelly “V 'blender (with I movable bar) - from

7.5 L, Charged in the following order:

About half of polyethylene oxide

Oxycodone hydrochloride

Residual polyethylene oxide

Note: polyethylene oxide was sieved through a 20 mesh sieve, no residual material was used.

Second The materials from Step 1 are blended for 5 minutes with the movable bar turned on.

Third Batch the magnesium stearate in a "B" blender.

4th The materials from Step 3 are blended for 1 min with the movable switch off.

5th The aperture from step 4 is charged into a plastic bag.

6th The aperture from Step 5 is compressed to the target mass, in an 8-tablet press at a rate of 30,000 tablets per hour, using a standard 7/20 cm round, concave (embossed) mold. The compression parameters are given in the Tables

19.1 and 19.2.

7th The tablets from step 6 are loaded into a 45 cm coating pan, model Compu-Lab coating pan.

8th The temperature of the test (thermocouple wire) is placed directly above the tablet layer in the container, so that the top of the test is near the moving tablet layer.

9th The tablet layer is heated by adjusting the inlet temperature to reach the target outlet temperature of 72 ° C. The start of curing (described by method 2) is taken when the outlet temperature reaches the target temperature. When the target outlet temperature is reached, the inlet temperature is set to maintain the target outlet temperature. These tablets harden in 15 minutes. After solidification, the inlet temperature rises

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51162 Β set to 22 ° C and the tablet layer is cooled. The temperature profiles for the curing process for Examples 19.1 and 19.2 are given in Tables 19.1.1 and 19.2.1.

10th After cooling, the tablet layer is heated by adjusting the inlet to 53 ° C. When film coating begins, the outlet temperature reaches approximately 4GS and continues until a weight gain of 4% is achieved.

11th When the film coating is complete, the tablet layer is cooled by adjusting the inlet temperature to 22 ° C. The tablet layer is cooled to an outlet temperature of 30 ° C or lower.

12th The tablets are emptied.

In vitro testing, including the tear strength test, is performed as follows:

Tablet cores (non-cured), cured tablets, and cured / coated tablets are tested in vitro, using the USP Apparatus 1 (with a safety spring-mounted basket on top of the cobra to reduce the tendency of the tablets to stick to the bottom of the shaft), with 100 o / min, in 900 mL of simulated enzyme-free gastric juice (SJF), at 37.0 ° C. Samples were analyzed by reversed-phase high-performance liquid homography (HPLC) to a VVaters Atlantis dC18 3.0 x 250 mm, 5pm column using a mobile phase consisting of a mixture of acetonitrile and monobasic potassium phosphate buffer (pH 3.0), with UV detection at 230 nm. Sampling times are 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 16.0 h.

Uncured tablets are subjected to a tear strength test, using a maximum force of 196 N, using an apparatus, model Schleuniger 2E / 106 apparatus, to assess the resistance of the tablets to tearing.

Tablet dimensions and dissolution results are given in Tables 19.1.2 and 19.2.2.

TABLE 19.1.1

<td colspan="4">Example 19.1 (PEO N60K)</td>

<td></td><td></td><td>Temperature</td><td></td>

<td>In total</td><td>time</td><td>Configured Actual Rehearsal Output</td><td>Objections</td>

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<td>time (Min.)</td><td>hardens. (Min.)1</td><td>inlet (° C)</td><td>input (° C)2</td><td>(° C)3</td><td>(° C)4</td><td></td>

<td>on</td><td> -</td><td>22 to 80</td><td> 25.3</td><td> 26.4</td><td> 26.9</td><td>Batch 1.4 kg; Start warming up</td>

<td> 21</td><td> 0</td><td> 80</td><td> 79.9</td><td> 70.0*</td><td> 72.0</td><td>Start of hardening</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 tablet flow, no sticking</td>

<td> 36</td><td> 15</td><td>75.5 to 22</td><td> 75.4</td><td> 69.5*</td><td> 72.4</td><td>End of curing, start of cooling</td>

<td> 50</td><td> -</td><td> 22</td><td> 22.6</td><td> 27.5</td><td> 30.0</td><td>End of cooling, sample</td>

1 determined in accordance with procedure 2, 2 inlet temperature measured, 3 temperature measured using a temperature probe (thermocouple wire) 4 outlet temperature measured; * Values at low temperatures, compared to the outlet temperature. Battery changed before performing the process for Example 19.2.

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 tablet core</td>

<td></td><td>Compression force (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>Tear strength (N)</td><td> 112</td><td colspan="2"></td>

<td></td><td></td><td></td><td colspan="2">Example 19.1 curing on 72 ° C</td>

<td></td><td></td><td>uncured</td><td>15 min curing</td><td>Hardened / coated</td>

<td rowspan="7">Dissolution (released%) SZF With spring basket</td><td>1 h</td><td> 25 (2.3)</td><td> 25 (2.1)</td><td> 25 (3.7)</td>

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TABLE 19.2.1

Example 19.2

<td></td><td></td><td colspan="4">Temperature</td><td></td>

<td>Total time (rnin.)</td><td>Time hardened. (Min.)1</td><td>Set input (° C)</td><td>Actual inlet (° C)2</td><td>rehearsals (° C)3</td><td>Output (° C)4</td><td>Objections</td>

<td> 0</td><td> -</td><td>22 to 80</td><td> 27.0</td><td> 31.4</td><td> 30.9</td><td>Batch 1.4 kg; Start warming up</td>

<td> 19.5</td><td> 0</td><td> 80</td><td> 80.1</td><td> 71.5</td><td> 72.0</td><td>Start of hardening</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 tablet flow, no sticking</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>Kgaj hardening, start cooling</td>

<td> 49</td><td> -</td><td> 22</td><td> 22.4</td><td> 30.0</td><td> 30.0</td><td>End of cooling, sample</td>

TABLE 19.2.2

<td></td><td></td><td colspan="3">Example 19.1 (PEO N12K)</td>

<td></td><td></td><td colspan="3">Uncured tablet core</td>

<td></td><td>Compression force (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>Tear strength (N)</td><td> 107</td><td colspan="2"></td>

<td></td><td></td><td></td><td colspan="2">Example 19.2 curing on 72 ° C</td>

<td></td><td></td><td>uncured</td><td>15 min curing</td><td>Hardened / coated</td>

<td rowspan="7">Dissolution (released%) SŽF With basket With spring</td><td>1 h</td><td> 277 (7.6)</td><td> 25(1.0)</td><td> 26 (4.0)</td>

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Example 20: Impression test

In Example 20, the tablets obtained according to Examples 13.1 to 13.5, 14.1 to 14.5, 16.1, 16.2, 17.1 and 18.2 were subjected to an embossing test, in an apparatus, Texture Analyzer, to quantify the strength of the tablets.

The embossing tests are performed in an apparatus, model ΤΑ-ΧΤ2 Texture Analyzer (Texture Technologies Corp., 18 Fairview Road, Scarsdale, NY 10583), equipped with a spherical test made of stainless steel, TA-8A, diameter 3.2 mm. The height of the sample was calibrated to 6 mm above the stainless steel base with a slightly concave surface. The tablets are placed on top of this stainless steel stand and placed directly under the test. Each type of tablet is tested at least once. Values for individual measurement are given. Testing performed on the same type of tablet gives similar results, unless the tablet and the test were not aligned. In that case, the data is rejected, after receiving confirmation by visual examination of the tested tablet.

Embossing tests are performed with the following parameters:

<td>speed before the test</td><td>0.5 mm / s,</td>

<td>test speed</td><td>0.5 mm / s,</td>

<td>automatically activated force</td><td>10 grams,</td>

<td>speed after test</td><td>1.0 mm / s,</td>

<td>test distance</td><td>3.0 mm.</td>

These results are given in Tables 20.1 to 20.3 and in Figures 20 to 33.

TABELA20.1

Values of crack formation force, distance “along the depth of crack penetration” and work

<td></td><td colspan="4">Penetration test results</td>

<td></td><td>Crack force</td><td>maximum force (N)6</td><td>Distance (mm) *</td><td>Work <J)8</td>

<td>Example 13.11</td><td> -</td><td> 189</td><td> 3.00</td><td> 0284</td>

<td>Primer13.2 '</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> > 250b</td><td> -</td><td> > 2.0</td><td> > 0.250</td>

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<td>Primer18.2with</td><td> 194</td><td></td><td> 1.80</td><td> 0.175</td>

<td>Example 14.14</td><td> 213</td><td></td><td> 2.52</td><td> 0.268</td>

<td>Example 14.2L</td><td> 196</td><td></td><td> 2.27</td><td> 0.222</td>

<td>Example 14.3J</td><td> 161</td><td></td><td> 1.90</td><td> 0.153</td>

<td>Example 14.4 °</td><td> 137</td><td></td><td> 1.51</td><td> 0.103</td>

<td>Example 14.5 °</td><td> 134</td><td></td><td> 1.39</td><td> 0.093</td>

<td>Primer16.r</td><td> 227</td><td></td><td> 2.23</td><td> 0.253</td>

<td>Primer16.24</td><td> 224</td><td></td><td> 2.17</td><td> 0.243</td>

1 the embossing test was performed on tablets cured for 30 min and uncoated (curing time was determined according to method 4, curing begins when the sample temperature reaches 70 ° C, see Example 13).

2 the embossing test was performed on tablets cured for 15 min at 72 ° C and coated (curing time was determined according to method 2, curing begins when the outlet temperature reaches 72 ° C, see Examples 17 and 18).

3 the embossing test was performed on tablets cured 1 h and coated (curing time was determined according to method 1, curing begins when the inlet air temperature reaches 75 ° C, see Example 14).

4 the embossing test was performed on tablets cured for 15 min and coated (curing time was determined according to method 2, curing begins when the outlet air temperature reaches 72 ° C, see Example 16).

5 The maximum force exceeded the detection limit.

6 In the injection tests, in which the tablets did not crack under the test conditions given above, the maximum force at a penetration depth of 3.0 mm is given, instead of the crack force; 7distance "depth of crack penetration.

8 approximate value, calculated using the equation:

Rad «half · Force [N] h Distance [m].

TABELA20.2

Selected force values for the increment of distance change of 0.1 mm

<td rowspan="2">Distance (mm)</td><td colspan="7">Siia (N)</td>

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1 Force value at a distance of 2.0825 mm

TABLE 20.3

Selected force values for 0.1 mm distance change increment

<td rowspan="2">Distance (mm)</td><td colspan="7">Force (N)</td>

174

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Example 21: Testing

In Example 21, the tablets corresponding to Examples 16.1 (60 mg Oxycodone HCl) and 16.2 (80 mg oxycodone HCL) and the commercial tablets Oxycontin ™ with 60 mg and Oxycontin ™ with 80 mg were subjected to an embossing test in a Texture Analyzer apparatus, to quantitatively determine the strength of the tablet.

Embossing tests were performed as described in Example 20.

These results are given in Table 21 and Figures 34 and 35.

TABLE 21: SELECTIVE VALUE VALUES FOR INCREASE CHANGE

DISTANCES OF 0.1 mm

<td rowspan="2">Distance (mm)</td><td colspan="4">Force (N)</td>

<td>Pr.16.1</td><td>Oxycontin 'M 60 mg</td><td>Pr.16.2</td><td>OxycontinTHEM 80 mg</td>

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Comparative Example 22

In Comparative Example 22, five different 150 mg tablets (Examples 22.1 to 22.5) with 10, 15, 20, 30 and 40 mg oxycodone HCl were prepared using the composition described in Example 13, with the addition of the manufacturing process of Example 13 by tablets subjected to a melting step, instead of a curing step.

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 / dish.</td><td>mg / dish.</td><td>mg / dish.</td><td>mg / dish.</td><td>mg / dish.</td>

<td>Oxycodone HCI</td><td> 10</td><td> 15</td><td> 20</td><td> 30</td><td> 40</td>

<td>Polyethylene oxide (M: approx. 4,000,000; 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 tablet core weight (mg)</td><td> 150</td><td> 150</td><td> 150</td><td> 150</td><td> 150</td>

| The total size of the Shar already | 10 kg 10 kg 10kg | 10kg | 10 kg

The steps of tablet production are as follows:

First Blender, model Patterson Kelly V blender, (with I movable rod)

- of 15 L, charged in the following order:

Approximately half of the polyethylene oxide WSR 301

Oxycodone hydrochloride

Residual polyethylene oxide WSR 301

Second The materials from Step 1 are blended for 5 minutes with the movable bar turned on.

Third Batch the magnesium stearate in a "B" blender.

4th The materials from Step 3 are blended for 1 min with the movable switch off.

5th The aperture from step 4 is charged into a plastic bag.

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6th Aperture from 5. Kogaka is compressed to the target mass, in an 8-tablet press, at a rate of 35,000 tablets per hour, using a standard 22/81 cm round, concave (embossed) mold.

7th The tablets from step 6 are melted in a temperature-controlled press, model Specac press. The compressed tablets of Step 6 are placed between two heated plates, preheated to 120 ° C, then compressed using a compression device set to 1000 kg, and held for 3 min. The molten tablets are cooled to room temperature before measuring the density.

Density measurement is performed as follows:

The density of the tablets, before and after the melting step, was determined by the Archimedes principle, using a scale, the model Top-loading Mettler Toledo balance Mesdel # AB 135-S / FACT, Serial # 1127430072, and the density determination kit 33360, according to the following procedure:

First Adjust the scale, model Mettler Toledo, with a set for determining the density.

Second Fill a beaker of appropriate volume (200 mL) with hexane.

Third The mass of the tablet in the air is measured and recorded as Mass A.

4th Transfer the same tablet to the lower spool inside a beaker filled with hexane.

5th The mass of the tablet in hexane is measured and recorded as Mass B.

6th The density is calculated according to the equation

A p = - po, where are p AB And p; tablet density

A: mass of the tablet in air

B: mass of the tablet immersed in the liquid p0: density of liquid at a given temperature (density of hexane at 20 ° C = 0.660 g / mL) (Megsk lndex)

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7th Density is registered.

The listed density values are mean values for 3 tablets and all refer to uncoated tablets.

These results are given in Table 22.1.

TABELA22.1

<td></td><td colspan="2">Density (g / cm3)1</td><td rowspan="2">Density change after melting (%)3</td>

<td></td><td>Tablet that has not been melted2</td><td>Melted tablet</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>

1 The density value is the mean value measured for 3 tablets; 2The density of the “unrefined tablet” corresponds to the density of the “uncured tablet” of Examples 13.1 to 13.5; 3 The change in density after melting corresponds to the observed change in density, in%, of melted tablets compared to non-melted tablets.

EXAMPLE 23

In Example 23, 154.5 mg tablets with 30 mg Hydromorphone HCl were obtained using high molar mass polyethylene oxide.

composition:

<td>Ingredient</td><td>mg / dish.</td><td>g / batch</td>

<td>Hydromorphone HCI</td><td> 30</td><td> 1000</td>

<td>Polyethylene oxide (M: 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 rowspan="2"></td>

<td>Total batch size</td><td>10 kg (2 * 5 kg)</td>

<td>lining</td><td>mg / dish.</td>

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<td>Coating with Opadry film</td><td> 4.5</td>

<td>Total tablet weight (mg)</td><td> 154.5</td>

<td>Coating batch size (kg)</td><td>8,835 kg</td>

The steps of tablet production are as follows:

First Blender, model PK V-blender (with l-movable rod) - from 15 L, charged in the following order:

Approximately half of polyethylene oxide 301

Hydromorphone HCI

Residual polyethylene oxide 301

Second The materials from Step 1 are blended for 5 min with the mixing intensifier on.

Third Batch the magnesium stearate in a PK V-blender.

4th The materials from Step 3 are blended for 1 min with the mixing intensifier switched off.

5th The aperture from step 4 is loaded into a plastic bag (Note: two apertures of 5 kg each were made, to provide the 10 kg required for compression).

6th The aperture of Step 5 is compressed to the target mass, in a rotary press using a standard round, concave (embossed) mold, 22/81 cm, at a rate of 35,000 to 40,800 tablets per hour, using a compression force of 5-8 kN.

7th The tablets from step 6 are loaded into a 60 cm coating pan, model CompuLab coating pan, with a batch of 9.068 kg.

8th The rotation speed of the vessel is adjusted to 10 rpm, and the tablet layer is heated by adjusting the inlet air temperature so as to achieve an outlet temperature of approximately 72 ° C. The onset of curing (described by method 2) begins when the outlet temperature reaches 72DC. The tablets are cured at the target outlet temperature for 1 h. Sample tablets are taken after 30 minutes of curing.

9th After 1 h of curing at the target outlet temperature of 72 ° C, the inlet temperature is set to 90 ° C to raise the outlet temperature (layer temperature).

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51162 Β lO.After 10 min of intensified heating, the outlet temperature reaches 82 ° C. The tablets continue to maintain good flow / movement in the layer. No sticking was observed.

H. The temperature is adjusted to 22 ° C to initiate cooling. During the cooling period (up to an outlet temperature of 42 ° C), no sticking or agglomeration of the tablets was observed.

12th The tablets from Step 11 are loaded into a 60 cm coating pan, model Compu-Lab coating pan, with a batch of 8,835 kg.

13th The tablet layer is heated by adjusting the inlet air temperature to 55 ° C. When film coating begins, the outlet temperature approaches 42 ° C, and is continued until a weight gain of 3% is achieved.

14.0 film coating is performed at a spray rate of 40-45 g / min, with a target air flow of 5.7 L / min, and a vessel rotation speed, initially 10 rpm, with an increase to 15 rpm. After coating, the rotation speed of the vessel was adjusted to 3.5 rpm and the tablets were allowed to cool.

15. The tablets are emptied.

In vitro testing, which includes dissolution, content testing and content uniformity test, is performed as follows:

Tablets cured for 30 min (uncoated) were tested in vitro, using a USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric juice without enzyme (SZF), at 37.0 ° C. Samples were analyzed by reversed-phase high-performance liquid homography (HPLC) and then columns of VVaters Atlantis dC18 3.0 x 250 mm, 5pm, using a mobile phase consisting of a mixture of acetonitrile and monobasic potassium phosphate buffer (pH 3.0), with detection at 220 nm . Sampling times are 1.0, 2.0,4.0, 8.0 and 12.0 h.

The 30 min (uncoated) tablets were subjected to a content test. Oxycodone hydrochloride was extracted from two sets of ten tablets each, with 900 mL of a 1: 2 mixture of acetonitrile and simulated gastric fluid, without enzyme (CZF), with

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51162 Β Stirring constantly with a magnetic stirrer, in a 1000 mL volumetric flask, until the tablets are completely dispersed, or overnight. Samples of the solution were diluted and analyzed by reverse phase high performance liquid homography (HPLC) on a VVaters Atlantis dCi column.8 3.0 x 250 mm, 5 [mu] m, held at 60 [deg.] C., using a mobile phase consisting of acetonitrile and a monobasic potassium phosphate buffer with pH 3.0, and UV detection at 280 nm.

The 30 min (uncoated) tablets were subjected to a uniformity test. Oxycodone hydrochloride was extracted from ten separate tablets, each with 90 mL of a 1: 2 mixture of acetonitrile and simulated gastric fluid, without enzyme (SZF), with constant stirring with a magnetic stirrer in a 100 mL volumetric flask until the tablets were completely dispersed, or over night. Samples of the solution were diluted and analyzed by reverse phase high performance liquid homography (HPLC) to a Waters Atlantis dC column.18 3.0 x 250 mm, 5 [mu] m, held at 60 [deg.] C., using a mobile phase consisting of acetonitrile and a monobasic potassium phosphate buffer with pH 3.0, and UV detection at 280 nm.

These results are given in Table 23.

TABLE 23

<td></td><td>Example 23 30 min curing</td>

<td>Composition test (% oxycodone HCl)1</td><td> 98.9</td>

<td>Content uniformity (% oxycodone HCI)1</td><td> 97.9</td>

<td rowspan="2">dissolution</td><td>2 h</td><td> 42</td>

<td>(released%)</td>

1 relative to the Oxycodone HCI specification

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51162 Β

Example 24

In Example 24, 150 mg tablets were obtained, with 2 mg of Hydromorphone HCl, using high molar mass polyethylene oxide.

composition:

<td>Ingredient</td><td>mg / dish.</td><td>g / batch</td>

<td>Hydromorphone HCI</td><td> 2</td><td> 66.5</td>

<td>Polyethylene oxide (M: 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>Total batch size</td><td>10 kg (2 * 5 kg)</td>

The steps of tablet production are as follows:

First Blender, model PK V-blender (with l-movable rod) - from 3.8 L, charged in the following order:

Approximately 600g of polyethylene oxide 301

Hydromorphone HCI

Approximately 600g of polyethylene oxide 301

Second The materials from Step 1 are blended for 2 min with the l-movable rod turned on, and then emptied.

Third Blender, model PK V-blender (with l-movable rod) - from 15 L, charged in the following order:

Approximately half of the remaining polyethylene oxide 301

Pre-aperture material (from Step 2)

Residual polyethylene oxide 301

4th The materials from Step 3 are blended for 5 min, with the mixing intensifier on.

5th Magnesium stearate is charged to a PK V-blender.

6th The materials from Step 5 are blended for 1 min, with the mixing intensifier switched off.

7th The aperture from Step 6 is loaded into a plastic bag (Note: two apertures of 5 kg were produced, to obtain the 10 kg required for compression).

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8th The aperture from Step 7 is compressed to the target mass, in a rotary press for 8 tablets, using a standard round, concave (embossed) mold, 22/81 cm, at a rate of 40,800 tablets per hour, using a compressive force of 2 kN.

9th Tablets from 8. Kogaka are loaded into a 60 cm coating container, model CompuLab coating pan, with a batch of 9,146 kg.

10th The rotation speed of the vessel is adjusted to 10 rpm, and the tablet layer is heated by adjusting the inlet air temperature so as to reach an outlet temperature of approximately 72 ° C. The onset of curing (described by Method 2) begins when the outlet temperature reaches 72 ° C. The tablets are cured at the target outlet temperature for 1 h. Sample tablets are taken after 30 minutes of curing.

H.The speed of rotation of the vessel increases to 15 rpm, when the outlet temperature reaches 72 ° C.

12th After 1 h of curing at the target outlet temperature, the inlet temperature was adjusted to 22 ° C to initiate cooling. After 3 min of cooling, the tablet layer begins to form large agglomerates of tablets. Coating is not feasible.

13th The tablets are emptied.

It is contemplated that agglomeration of the tablets can be avoided, for example by increasing the speed of rotation of the vessel, by using magnesium stearate as an anti-caking agent, or by applying a coating to a sublayer prior to curing.

In vitro testing includes dissolution tests, content testing and content uniformity, which are performed as follows:

Tablets cured for 30 min (uncoated) were tested in vitro, using a USP Apparatus 1 (with a basket), at 100 rpm, in 900 mL of simulated gastric juice without enzyme (SZF), at 37.0 ° C. Samples were analyzed by reverse phase high performance liquid homatography (HPLC) on a VVaters Atlantis dC18 3.0 x 250 mm, 5pm column using a mobile phase consisting of a mixture of acetonitrile and monobasic buffer.

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51162 Β potassium phosphate (ρΗ 3.0), with detection at 220 nm. Sampling times are 1.0, 2.0, 4.0, 8.0 and 12.0 h.

The 30 min (uncoated) tablets were subjected to a content test. Oxycodone hydrochloride was extracted from two sets of ten tablets in each, with 900 mL of 1: 2 mixture of acetonitrile and simulated gastric fluid, without enzyme (SJF), with constant stirring with a magnetic stirrer, in a 1000 mL volumetric flask, until the tablets were completely do not disperse, or overnight. Samples of the solution were diluted and analyzed by reverse phase high performance liquid homography (HPLC) on a VVaters Atlantis column dC ^ 3.0 x 250 mm, 5 μπι, held at 60 ° C, using a mobile phase consisting of acetonitrile and monobasic buffer. potassium phosphate with pH 3.0, and UV detection at 280 nm.

The 30 min (uncoated) tablets are subjected to a uniformity test. Oxycodone hydrochloride is extracted separately from ten tablets, each with 90 mL of a 1: 2 mixture of acetonitrile and simulated gastric fluid, without enzyme (CZF), with constant stirring with a magnetic stirrer, in a 100 mL volumetric flask until the tablets are completely dispersed, or over night. Samples of the solution were diluted and analyzed by reverse phase high performance liquid homography (HPLC) on a Waters Atlantis dCi column.8 3.0 x 250 mm, 5 cgp, held at 60 ° C, using a mobile phase consisting of acetonitrile and a monobasic potassium phosphate buffer with a pH of 3.0, and UV detection at 280 nm.

These results are given in Table 24.

TABLE 24

<td></td><td>Example 24 30 min curing</td>

<td>Composition test (% oxycodone HCl)1</td><td> 95.7</td>

<td>Content uniformity (% oxycodone HCI)1</td><td> 94.9</td>

Dissolve 1 x 26

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Example 25

In Example 25, two different 400 mg tablets were obtained, with 60 mg (Examples 25.1 and 25.2) and 80 mg (Examples 25.3 and 25.4) of oxycodone HCl, using high molar mass polyethylene oxide and low molar mass polyethylene oxide. Two batches of 100 kg were obtained for each formulation.

<td></td><td colspan="4">Example 25</td>

<td>Ingredient</td><td colspan="2">mg / dish.</td><td colspan="2">mg / dish.</td>

<td>Oxycodone HCI</td><td colspan="2"> 60</td><td colspan="2"> 80</td>

<td>Polyethylene oxide (M: approx. 4,000,000; Polyox ™ WSR-301)</td><td colspan="2"> 229.7</td><td colspan="2"> 216</td>

<td>Polyethylene oxide (M: approx. 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>Total tablet core weight (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>Total batch size</td><td>100 kg</td><td>100 kg</td><td>100 kg</td><td>100 kg</td>

<td>lining</td><td colspan="2">mg / dish.</td><td colspan="2">mg / dish.</td>

<td>Coating with Opadry film</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>Coating batch size (kg)</td><td> 91.440</td><td> 96.307</td><td> 95.568</td><td> 98.924</td>

The steps of tablet production are as follows:

First Magnesium stearate is sifted through a sieve, model Sweoo Sifter equipped with a sieve of 20 mesh, in a special separate container.

Second Blender, model Gemco "V" blender (with I movable rod) - from 283 L, charged in the following order:

Approximately half of the polyethylene oxide WSR 301

Oxycodone hydrochloride

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Polyethylene oxide WSR N10

Residual polyethylene oxide WSR 301

Third The materials from Step 2 are blended for 10 minutes with the bar included.

4th Batch the magnesium stearate in a Gemco "V" blender.

5th Blend the materials from Step 4 for 2 minutes, with the movable switch off.

6th The 5-aperture is loaded into a clean, tared stainless steel container.

7th The aperture of Step 6 is compressed to the target mass in a press of 40 tablets, at a rate of 124,000 tablets per hour, using a standard 33/81 cm round, concave (embossed) mold.

8th Tablets from 7. Kogaka are loaded into a 120 cm coating pan, model AcCele-Coat coating pan, with a batch of 91,440 kg (Example 25.1), 96,307 kg (Example 25.2), 95,568 kg (Example 25.3) and 98,924 kg 25.4).

9th The rotation speed of the vessel is adjusted to 6 to 10 rpm, and the tablet layer is heated by using an outlet air temperature to obtain a target inlet air temperature of 55 ° C. Film coating begins when the outlet temperature approaches 40 ° C and continues for another 10, 15 or 16 min. This initial coating film is applied to provide the tablets with a "coating" that acts as an anti-caking agent during the curing process.

10th Upon completion of this "coating", the tablet layer is heated by adjusting the outlet air temperature to achieve an inlet air temperature of 75 ° C (Examples 25.1 and 25.3) or to achieve a target outlet temperature of 78 ° C (Examples 25.2 and 25.4). The tablets were cured at this target temperature for 65 min (Example 25.1), 52 min (Example 25.2), 80 min (Example 25.3) and 55 min (Example 25.4). For Primee 25.1 and 25.3, the start of curing (described by Method 1) is when the inlet temperature reaches the target inlet temperature. For Examples 25.2 and 25.4, the start of curing (described by Method 2) is when the outlet temperature

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51162 Β reaches the target outlet temperature. The temperature profile of the curing process of Examples 25.1 to 25.4 is given in Tables 25.1.1 to 25.4.1.

11th During the curing process, the rotation speed of the vessel is increased from 7 to 9 rpm (Examples 25.1 and 25.3) and from 10 to 12 rpm (Examples 25.2 and 25.4). For Examples 25.1 to 25.4, 20 g of magnesium stearate was added as an anti-caking agent. The tablet layer is cooled by adjusting the outlet temperature to 30 ° C.

12th After cooling, the tablet layer is heated by adjusting the inlet to 53 ° C. When film coating begins, the outlet temperature reaches approximately 39 ° C and continues until a weight gain of 4% is achieved,

13th When the film coating is complete, the tablet layer is cooled by adjusting the outlet temperature to 27 ° C. The tablet layer is cooled until an outlet temperature of 30 ° C or lower is reached.

14th The tablets are emptied.

In vitro testing, including the tear strength test, is performed as follows.

The hardened and coated tablets were tested in vitro, using a USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated gastric juice without enzyme (SZF), at 37 ° C. Samples were analyzed by reverse phase high performance liquid homatography (HPLC) on a VVaters Atlantis dC18 3.0 x 150 mm, 3pm column using a mobile phase consisting of a mixture of acetonitrile and non-basic potassium phosphate buffer (pH 3.0), with UV detection at 230 nm. Sampling times are 1.0, 2.0, 4.0, 6.0, 8.0 and 12.0 h.

Uncured tablets are subjected to a tear strength test, using a maximum force of 196 N, using an apparatus, model Schleuniger 2E / 106 apparatus, to assess the resistance of the tablets to tearing.

These results are given in Tables 25.1.2 to 25.4.2

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TABLE 25.1.1:

TEMPERATURE PROFILE OF THE CURING PROCESS OF THE EXAMPLE 25.1

<td>Total time (min.)</td><td>Time hardened. (Min.)1</td><td>Input temp. ( 'C)2</td><td>Set output temp. (° C)</td><td>Actual output temp. (° C)3</td><td>Court rotation speed (rpm)</td><td>Objections</td>

<td> 5</td><td> 0</td><td> 75</td><td> 60</td><td> 59</td><td> 7</td><td>Start of hardening</td>

<td> 70</td><td> 65</td><td> 75</td><td> 72</td><td> 72</td><td> 9</td><td>After curing, add 20 g of Mg-St</td>

<td> 71</td><td> -</td><td> 74</td><td> 30</td><td> 72</td><td> 9</td><td>Start cooling</td>

<td> 94</td><td> -</td><td> 23</td><td> 30</td><td> 30</td><td> 9</td><td>End of cooling</td>

1 determined in accordance with procedure 1,2 inlet temperature measured, 3 temperature measured at the outlet.

TABLE 25.1.2

<td></td><td colspan="2"></td><td colspan="2">Example 25.1</td>

<td></td><td colspan="2"></td><td>uncured</td><td>hardened, coated</td>

<td></td><td colspan="2">Weight (mg)</td><td>401 (n = 120)</td><td> -</td>

<td>Tablet, dimensions</td><td>Tear strength</td><td>(N)</td><td>112 (p = 50)</td><td> -</td>

TABLE 25.2.1:

TEMPERATURE PROFILE OF THE CURING PROCESS OF THE EXAMPLE 25.2

<td>Total time (min.)</td><td>Time hardening, (Min.)1</td><td>Input temp. fC)2</td><td>Set output temp. (° C)</td><td>Actual output temp. (° C)3</td><td>Court rotation speed (rpm)</td><td>Objections</td>

<td> 33</td><td> 0</td><td> 90</td><td> 77</td><td> 77</td><td> 10</td><td>Start of hardening</td>

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<td> 85</td><td> 52</td><td> 80</td><td> 77</td><td> 77</td><td> 12</td><td>End of curing, add 20 g of Mg-St</td>

<td> 86</td><td> -</td><td> 80</td><td> 30</td><td> 77</td><td> 12</td><td>Start cooling</td>

<td> 116</td><td> -</td><td> 24</td><td> 25</td><td> 30</td><td> 12</td><td>End of cooling</td>

1 determined in accordance with procedure 2, 2 inlet temperature measured, 3 temperature measured at the outlet.

TABLE 25.2.2

<td></td><td></td><td colspan="3">Example 25.2</td>

<td></td><td></td><td>uncured</td><td>hardened, coated Initial data</td><td>hardened, coated data for 2nd test</td>

<td rowspan="2">Tablet, dimensions</td><td>Weight (mg)</td><td>400 (n = 120)</td><td> -</td><td> -</td>

<td>Stroke strength (N)</td><td>103 (n = 40)</td><td> -</td><td> -</td>

<td rowspan="6">Dissolution (% released) SGF</td><td>1 h</td><td></td><td> 23</td><td> 24</td>

TABLE 25.3.1:

TEMPERATURE PROFILE OF THE CURING PROCESS OF THE EXAMPLE 25.3

<td> 5</td><td> 0</td><td> 75</td><td> 65</td><td> 58</td><td> 7</td><td>Start of hardening</td>

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<td> 85</td><td> 80</td><td> 74</td><td> 72</td><td> 72</td><td> 9</td><td>End hardened, adding 20 g of Mg-St</td>

<td> 86</td><td> -</td><td> 75</td><td> 30</td><td> 72</td><td> 9</td><td>Start cooling</td>

<td> 112</td><td> -</td><td> 23</td><td> 30</td><td> 30</td><td> 9</td><td>End of cooling</td>

1 determined in accordance with procedure 1, 2 temperature measured in azu, 3 temperature measured at the outlet.

TABLE 25.3.2

<td></td><td></td><td colspan="3">Example 25.3</td>

<td></td><td></td><td>Neočvrsie</td><td>hardened, coated Initial data</td><td>hardened, coated Data 2. test</td>

<td rowspan="4">Tablet, dimensions</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>Tear strength (N)</td><td>111 (P = 40)</td><td> -</td><td> -</td>

TABLE 25.4.1:

TEMPERATURE PROFILE OF THE CURING PROCESS OF THE EXAMPLE 25.4

<td> 33</td><td> 0</td><td> 88</td><td> 78</td><td> 78</td><td> 10</td><td>Start of hardening</td>

<td> 88</td><td> 55</td><td> 80</td><td> 78</td><td> 78</td><td> 12</td><td>What hardened., Adding 20 g Mg-St</td>

<td> 89</td><td> -</td><td> 79</td><td> 30</td><td> 78</td><td> 12</td><td>Start cooling</td>

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113 I - | 23 | 25 | 34 | 12 | End of cooling j1 determined in accordance with procedure 2,2 inlet temperature measured,3 temperature measured at the outlet.

TABLE 25.4.2

<td></td><td></td><td colspan="3">Example 25.4</td>

<td></td><td></td><td>uncured</td><td>hardened, coated Initial data</td><td>hardened, coated Data for 2nd test</td>

<td rowspan="4">Tablet, dimensions</td><td>Weight (mg)</td><td>400 (p = 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>Stroke strength (N)</td><td>101 (n = 40)</td><td> -</td><td> -</td>

<td rowspan="6">Dissolution (released%) SZF</td><td>1 h</td><td></td><td> 25</td><td> 29</td>

TABLE 25.5

<td></td><td colspan="3">Density (g / cm3)1</td><td>Density change after curing (%)2</td>

<td></td><td>uncured</td><td>30 min curing</td><td>60 min curing</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>

1 The density was measured as described in Example 13. The density value was the mean measurement value for 3 tablets; 2 The change in density after curing corresponds to the observed change in density, in%, of tablets cured for 60 min, compared to uncured tablets.

Example 26

In Example 26, a statistical study, open-label, single-dose, quadruple treatment, in four periods, a quadruple crossover study, on healthy human subjects was performed to examine the pharmacokinetic characteristics and relative

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51162 Β Bioavailability of three abuse-resistant oxycodone formulations (10 mg oxycodone HCl tablets from Examples 7.1 to 7.3), compared to the commercial OxyContin® formulation (10 mg), on an empty and full stomach.

The test treatments were as follows:

Test treatments:

Treatment 1A: 1x 10 mg Oxycodone HCl tablet

Examples

7.3 (Fiormulation 1A) on an empty and full stomach.

Treatment 1B: 1x 10 mg Oxycodone HCl tablet from

Examples

7.2 (Formulation 1B) on an empty and full stomach.

Treatment 1C: 1x 10 mg Oxycodone HCl tablet from

Examples

7.1 (Formulation 1C) on an empty and full stomach.

Reference treatment:

OC treatment: 1x tablet of Oxycodone HCI 10 mg administered on an empty and full stomach.

Each of these treatments was administered orally with 240 mL of water, as a single dose, on an empty and full stomach.

Since this study was performed in healthy human subjects, the opiate antagonist naltrexone hydrochloride was administered to minimize opiate-related adverse effects.

Choice of persons

Testing procedures

The following testing procedures were performed on all potential subjects, during the study, 28 days before the first dose was administered:

- Voluntary consent.

- Weight, height, body mass index (BM1), and demographics.

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- Rating criteria for on / off.

- Medical history and history of treatment, including concomitant treatment.

Vital signs - blood pressure, respiratory indicators, mouth temperature, and pulse (after sitting for about 5 min) and blood pressure and pulse after standing for about 2 min - pulse oximetry (SPO2), including the question How do you feel? ”.

- Routine physical examination (alternatively can be done in Period 1 upon admission).

Clinical laboratory tests (including biochemistry, hematology and urine analysis [UA]).

- 12-channel electrocardiogram (ECG).

- Tests for hepatitis (including hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], hepatitis C antibody [anti-HCV]), and abuse of selected drugs.

- Serum pregnancy test (women only).

- Serum follicle hormone stimulation test (FSH) (after menopause, only in women)

Inclusion criteria

The study included individuals who met the following criteria.

Males and females, ages 18 to 50, inclusive.

- Body weight, ranging from 50 to 100 kg, and BMI> 18 a <34 (kg / m2).

- Healthy and without significant abnormal findings, which is determined through medical history, physical examination, signs of vitality, and ECG.

- Women, potential mothers must use some adequate and reliable contraceptive procedure (eg barrier with additional spermicidal foam or gel, intra-uterine device, hormonal contraception (only hormonal contraceptives are not acceptable) .Menopausal women must have menopause> 1 year and have elevated serum FSH.

- Consent to eat food given to them during the examination.

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Exclusion criteria

The following criteria exclude potential individuals from this study.

Women who are pregnant (positive test for beta human chorionic gonadotropin) or who are breastfeeding.

Any history or current abuse of drug or alcohol in the last 5 years.

- History or any current conditions that may interfere with the absorption, distribution, metabolism or excretion of the drug.

Use any opiate-containing medication for the past 30 days.

- History of known sensitivity to oxycodone, naltrexone, or related compounds.

- Any history of frequent nausea or vomiting, regardless of etiology.

- Any history of head injuries or trauma with current consequences.

- Participate in a clinical trial of the drug 30 days before receiving the initial dose in this trial.

- Any significant illness during the 30 days prior to receiving the initial dose in this study.

- Use of any treatment, including thyroid hormone replacement therapy (hormonal contraception is allowed), vitamins, herbs, and / or mineral supplements, for the 7 days prior to receiving the initial dose.

- Refusal or abstinence from food for 10 hours before and 4 hours after administration of the investigational drugs, and complete abstinence from caffeine or xanthine, during each restriction.

- Drinking alcohol within 48 hours of the initial administration of the investigational medicinal product (Day 1), or at any time after the initial administration of the investigational medicinal product.

- History of smoking or use of nicotine products within 45 days of drug administration, or a positive urine nicotine test.

- Donation of blood and blood products 30 days before the administration of the investigational drugs, or at any time during the trial, unless required by this protocol.

- Positive results on drug testing in urine, alcohol test in any period of Admission and HBsAg, HBsAb (if not immunized), anti-HCV.

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Positive test for Naloxone HCl.

- Presence of Gilbert's syndrome or any known hepatobiliary abnormality.

- If the examiner considers that the person is unsuitable for any reason not specifically stated in the exclusion criteria.

Persons who meet the inclusion criteria, and none of the exclusion criteria, are statistically assigned to the survey. Approximately 34 individuals were expected to be statistically distributed, with 30 individuals completing the study. Any person who interrupts the interrogation shall be replaced.

Individuals were assigned according to the Statistical Classification Plan (RAS) in a 2: 1 ratio of non-intake and food intake conditions, with twenty individuals randomly classified as non-food intake and 10 individuals randomly classified as food intake.

Admission procedures

On the first day (Day 1) of the 1st period, persons admitted to this study were tested for Naloxone HCl. The results of this test must be negative for persons continuing this test. Signs of vitality and SPO are measured2 before and after the Naloxone HCl test.

The following procedures were also performed for all persons at admission, in each of the periods:

- Verification of inclusion / exclusion criteria, including verification of voluntary compliance with caffeine or xanthene restriction criteria.

- Routine physical and interrogation during admission only in the 1st Period (if not performed during testing).

- Signs of vitality-blood pressure, respiratory indicators, and pulse (after sitting approximately 5 min) and SPO2, including the “How are you feeling?” questionnaire.

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Examination for alcohol abuse (through a breath analysis test), cotinine, and selected drugs.

Urine pregnancy test (for all women).

- Checking medication and medical history.

- Monitoring and registration of current medication.

- Monitoring and registration of harmful phenomena.

For subjects who continue to participate in this study, drug test results (including alcohol and nicotine) should be available and negative prior to dosing. In addition, compliance with current medication and other restrictions on admission and testing is checked in the appropriate source documentation.

Prior to the first dose in Period 1, individuals were statistically distributed according to the order of treatment, in which the tested and reference treatments were received in that order. The order of treatment, in accordance with the statistical schedule (RAS) is determined by the biostatistician, who does not participate in the evaluation of the results of this study. Statistical assay is used in this study to improve the value of statistical comparisons during treatment.

The treatment sequences in this study are given in Table 26.1:

TABLE 26.1

<td></td><td>Period 1</td><td>Period 2</td><td>Period 3</td><td>Period 4</td>

<td>order</td><td>Treatment</td><td></td><td></td><td></td>

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Test procedures

Each trial contains four trial periods, each with a single dose. There is a wash or cleanse period of seven days, between the administration of the dose in each test period. During each period, individuals arrive at the test site the day before the administration of the study drugs, 48 hours after the administration of the study drugs, and return to the test site in 72-hour procedures.

In each study period, subjects were administered one of the tested formulations of oxycodone (10 mg), or 10 mg (OC) OxyContin® tablets, with 240 mL of water, after 10 h of no food intake overnight (for empty stomach treatments). . People who receive treatment on an empty stomach, continue not to take food for another 4 hours after dosing. People who receive treatment on a full stomach, start with a standard meal (high-fat breakfast, FDA) 30 minutes of drug administration. Individuals are dosed 30 minutes after the start of this meal, and no food intake is allowed for the next at least 4 hours after dosing.

Individuals receive 50 mg naltrexone HCl tablets at times -12, 0, 12, 24, and 36 h, relative to the dosage of each formulation or OxyContin® tested.

Individuals stand or sit in an upright position while receiving their dose of study drug. Persons remain upright for at least another 4 hours.

Clinical laboratory sampling is preceded by non-intake of food (ie at least 10 h) before food intake (this does not include water). No food intake is required on test days when there is no dosing.

During this study, adverse events and concomitant treatment, signs of vitality (including blood pressure, body temperature, pulse, and respiratory rate) and SPO are recorded and monitored.2.

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Blood samples for determination of oxycodone plasma concentrations are taken from each person before dosing 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 h after dosing, in each of the periods.

For each sample, 6 mL of blood is taken from a vein, via an implanted catheter and / or taken directly from a vein, into tubes containing K2EDTA as anticoagulant (evacuated Vacutainer® collection tubes to take 6 ml_, with K2EDTA). Oxycodone plasma concentrations were quantified by convenient liquid chromatography in tandem with mass spectrometry.

Test completion procedures

The following procedures were performed clinically, for all subjects at the end of this trial (Completion of the trial) or after termination of the trial:

Assessment of concomitant treatment.

- Signs of vitality and SPO2, including the questionnaire How are you feeling? ”..

- Physical examination.

- 12-channel ECG.

- Clinical laboratory evaluation (including biochemistry [not eating for at least 10 h], hematology and urine analysis).

- Assessment of adverse events.

- Serum pregnancy test (women only).

The results of this test are shown in Tables 26.2 to 26.5.

TABELA26.2:

Mean data from pharmacokinetic measurements in plasma

Treatments 1A, 1B, 1C and OC (on a full stomach)

Treatment1A-full stomach

<td></td><td>^ tah</td><td>^ tah</td><td>AUCt</td><td>AUCinf</td><td>tl / 2z</td><td>λζ</td><td>t | ag</td>

<td>MEDIUM</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>

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<td>MEDIJANA</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>GEOMSRED</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">Treatment1B-full stomach</td>

<td></td><td>Cmax</td><td>^ tah</td><td>AUCt</td><td>AUCinf</td><td>G / 2z</td><td>Cwith</td><td>Tlaga</td>

<td>MEDIUM</td><td> 14.2</td><td> 5.25</td><td> 133</td><td> 134</td><td> 4.37</td><td> 0.164</td><td> 0.0833</td>

<td>MEDIJANA</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>GEOMSRED</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">Treatment 1C-full stomach</td>

<td></td><td>Cmax</td><td>tmax</td><td>AUCt</td><td>AUCinf</td><td>t | / 2z</td><td>λζ</td><td>Tlaga</td>

<td>MEDIUM</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>MEDIJANA</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>GEOMSRED</td><td> 16.5</td><td>ON</td><td> 133</td><td> 134</td><td>ON</td><td>ON</td><td>ON</td>

<td colspan="8">OC-full stomach treatment</td>

<td></td><td>c '- * max</td><td>tmax</td><td>AUCt</td><td>AUCinf</td><td>tl / 2z</td><td>λζ</td><td>^ IAG</td>

<td>MEDIUM</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>MEDIJANA</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>GEOMSRED</td><td> 12.8</td><td>ON</td><td> 137</td><td> 138</td><td>ON</td><td>ON</td><td>ON</td>

ΝΑ = not performed.

TABLE 26.3:

Mean data from pharmacokinetic measurements in plasma

Treatments 1A, 1B, 1C and OC (empty stomach condition)

<td colspan="8">Treatment 1A-empty stomach</td>

<td></td><td>^ tah</td><td>tmax</td><td>AUCt</td><td>AUCLNF</td><td>Il / 2Z</td><td>λζ</td><td>tag</td>

<td>MEDIUM</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>

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<td>MEDIJANA</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>GEOMSRED</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">Treatment 1B-empty stomach</td>

<td></td><td>^ tah</td><td>^ tah</td><td>AUCt</td><td>AUCLNF</td><td>tl / 2z</td><td>λζ</td><td></td>

<td>MEDIUM</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>MEDIJANA</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>GEOMSRED</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">Treatment 1C-empty stomach</td>

<td></td><td>^ tah</td><td>tmax</td><td>AUCt</td><td>AUCinf</td><td>tl / 2z</td><td>λζ</td><td>tag</td>

<td>MEDIUM</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>MEDIJANA</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>GEOMSRED</td><td> 13.2</td><td>ON</td><td> 108</td><td> 109</td><td>ON</td><td>ON</td><td>ON</td>

<td colspan="8">OC-empty stomach treatment</td>

<td></td><td>^ tah</td><td>Vnax</td><td>AUCt</td><td>AUCinf</td><td>tl / 2z</td><td>λζ</td><td>Tlaga</td>

<td>MEDIUM</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>MEDIJANA</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>GEOMSRED</td><td> 9.60</td><td>ON</td><td> 112</td><td> 113</td><td>ON</td><td>ON</td><td>ON</td>

ΝΑ = not performed.

TABLE 26.4: Statistical results of pharmacokinetic measurements for Oxycodone: Bioavailability of tablets from Examples 7.1 to 7.3 relative to OxyContin® of 10 mg in the full stomach (Population: Complete analysis)

<td rowspan="2">Comparison (Test vs. Ref)</td><td colspan="2">^ tah</td><td colspan="2">AUCt</td>

<td>LS MEDIUM, Ratio (test / reference)And</td><td>90% Confidence Interval ”</td><td>LS MEDIUM Ratio (test / reference)And</td><td>90% Confidence intervalb</td>

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51162 Β And Medium squares for MEDIUM from ANOVA. The natural log (1p) for the measured AVERAGE values was calculated by transforming In (MEDIUM) back to the linear scale, i.e., the geometric values of the AVERAGE; Ratio of measured values of AVERAGE ln-transformed measurements (expressed as a percentage). Ln-transformed ratio transformed back to linear scale (test = Treatment 1A, 1B, 1C; reference = Treatment OC);b 90% confidence interval for the MEASUREMENT value ratio (expressed as a percentage). Ln-transformed confidence limits transformed back to the linear scale.

TABLE 26.5: Statistical results of pharmacokinetic measurements for Oxycodone: Bioavailability of tablets from Examples 7.1 to 7.3 relative to OxyContin® of 10 mg on an empty stomach (Population: Complete analysis)

<td rowspan="2">Comparison (Test vs. Ref)</td><td colspan="2">Cmax</td><td colspan="2">AUC,</td>

<td>LS MEDIUM Ratio (test / reference)And</td><td>90% Confidence intervalb</td><td>LS MEDIUM Ratio (test / reference)And</td><td>90% Confidence intervalb</td>

<td colspan="4">And Medium squares for MEDIUM from ANOVA. Natural log (In) for measured SR</td><td>EDNJE value</td>

are calculated by transforming In (MEDIUM) back to the linear scale, i.e., the geometric values of MEDIUM; Ratio of measured values of AVERAGE In-transformed measurements (expressed as a percentage). Ln-transformed ratio transformed back to a linear scale (test = Treatment 1A, 1B, 1C; reference - Treatment OC);b 90% confidence interval for the MEASUREMENT value ratio (expressed as a percentage). Ln-transformed confidence limits transformed back to a linear scale.

Example 27

In Example 27, the oxycodone HCl tablets of Examples 7.2, and Examples 14.2 to 14.5, containing 10, 15, 20, 30, and 40 mg of oxycodone HCl, respectively, were subjected to various tests of resistance to abuse, using mechanical force and chemical extraction. , to assess their resistance to physical and chemical manipulations.

The test results were compared with control data, and defined as the percentage of active pharmaceutical ingredient (AFS) released from intact tablets, after dissolution in vitro in simulated enzyme-free effluent (CZF), over 45 min. This comparison was chosen as the reference point for estimating the amount of AFS

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51162 Β present in the body (after 45 min), when the product is taken as prescribed. Available data for the current market formulation, OxyContin ™, are given for comparison.

Five tablets of different breaking strengths were produced (with 10, 15, 20, 30 and 40 mg oxycodone HCl, corresponding to Example 7.2 and Examples 14.2 to 14.5). All tablet strengths were approximately the same size and weight, so all tests were performed with tablet tear strength with the lowest AFS to excipient ratio (10 mg, Example 7.2) and the highest AFS to excipient ratio (40 mg, Example 14.5). In addition, Test Level 1 was performed with medium-strength tablets (15, 20, and 30 mg, Examples 14.2, 14.3, and 14.4) to test resistance to physical manipulation and then chemical extraction, using a pestle and mortar. Further testing on these tablets was not performed, because higher levels of testing use a coffee grinder, which gives a similar particle distribution and a similar amount of extracted AFS for tablets broken by grinding (Examples 7.2 and 14.5).

The experimental techniques used in this testing are designed to represent procedures for simulating and evaluating common abusive practices. Four levels of resistance to abuse are broadly defined, giving an approximation of the relative level of resistance to abuse. Several approaches to abuse were considered; to are mechanical force (applied to damage the drug product), availability and toxicity of solvent for extraction, and heat treatment. Each higher level of resistance to abuse represents an increased difficulty, which needs to be overcome for successful abuse of the drug product. Definitions of levels of resistance to abuse, including examples of equipment and reagents, are given in Table 27.1.

TABLE 27.1: Definitions and examples of testing

<td>Level</td><td>Definition</td><td>Degree of difficulty</td><td>Examples of equipment</td><td>Reagent examples</td>

<td> 0</td><td>It is able to be abused directly without preparation</td><td>Negligible</td><td>ON</td><td>No</td>

<td> 1</td><td>It is easily misused by various means without reagents or with ease</td><td>Minimal</td><td>Crushing tools (hammer, shoe,</td><td>water, distilled alcohols (vodka, gin, etc.), wine</td>

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<td></td><td>available reagent The reagents are directly edible and the extraction time is shorter</td><td></td><td>crusher for pills, etc.)</td><td>vinegar, baking powder, cooking oil</td>

<td> 2</td><td>Simple misuse with additional preparation, which requires some planning Reagents are directly edible, although more harmful, the extraction time is shorter, and heat treatment is applied</td><td>moderate</td><td>Accessories for IV preparation, grinding device (coffee grinder, blender), microwave oven</td><td>100% ethanol (grain alcohol, Everclear) strongly acidic and basic solutions</td>

<td> 3</td><td>Preparation of abuse requires knowledge of drug chemistry, includes more difficult-to-access reagents, may require industrial tools, involves complex processes (eg two-phase extraction) Some reagents are harmful and not directly edible, extraction time and temperature are increased</td><td>Considerable</td><td>Impact mill (e.g. Fitzmill)</td><td>In addition to the previously mentioned solvents: these are methanol, ether, isopropanol, acetone, ethyl acetate</td>

Test results

Control data (“taken as directed”) and specification limits

Dissolution testing of the intact tablets of Examples 7.2 and Examples 14.2 to 14.5 was performed in vitro, using a USP Apparatus 1 (with a basket), at 100 rpm, in 900 mL of simulated gastric juice without enzyme (SZF), at 37 ° C. . Samples were taken after 45 min of dissolution and analyzed by reverse phase high performance liquid homatography (HPLC). The average results of the triplicate analysis are given in Table 27.2, and compared with equivalent data for OxyContin 10 mg tablets.

TABLE 27.2: Control results -% AFS released after 45 min

<td rowspan="2">Sample preparation</td><td colspan="6">% oxycodone HCl1 released after 45 min</td>

<td>OxyContin ™ 10 mg</td><td>Pr.7.2 (10 mg)</td><td>Pr.14.2 (15 mg)</td><td>Pr.14.3 (20 mg)</td><td>Pr.14.4 (30 mg)</td><td>Pr 14.5 (40 mg)</td>

<td>None (intact tablets) 1 ___________</td><td> 34</td><td> 19</td><td> 20</td><td> 20</td><td> 18</td><td> 19</td>

Trelative to the specification on the label

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In addition, Table 27.3 contains a specification of the dissolution limits of one hour, for each of the tested tablets. This illustrates the range of acceptable drug release in one hour, for all formulations tested in this study. It should be noted that the upper acceptable limit for in vitro dissolution, after one hour, for oxycodone HCl, a tablet with 10 mg of OxyContin, is 49%.

TABLE 27.3: Dissolution limit specification (released%)

<td>Product</td><td>Boundary specification after 1 h</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>

Level 1 testing

Level One testing involves crushing in a mortar with a pestle and simple extraction.

Results for Level 1 - Crushing

After crushing in a mortar with a pestle, in vitro dissolution testing was performed in triplicate, for each of the products, using a USP Apparatus 1 (with a basket), at 100 rpm, in 900 mL of simulated gastric juice without enzymes (SZF), at 37 ° C, as described above for control data. The tablets of Example 7.2 could not be crushed using a mortar and pestle, and therefore the release of AFS was not significantly increased, compared to the control results. Although difficult, tablets from Primera

14.2 to 14.5 (15, 20, 30 and 40 mg tablets) can be broken into larger pieces, using a mortar and pestle, but with little or no powder. This reduction in particle size results in greater AFS release; however, swelling of the tablet matrix, when dissolved in the CFC, provides protection against drug release, as less than half of the AFS is released after 45 min. Tablets containing OxyContin lako are easily crushed into powder, using a mortar and pestle, which leads to the release of most AFS. Figure 40 contains representative representations of crushed tablets. Table 27.4 contains the average results for the percentage of AFS released after crushing.

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51162 Β The tablets of Examples 7.2 and 14.5 became viscous after the addition of water, which gave a small amount of liquid (<0.3 mL) that could be drawn into an insulin syringe and analyzed for AFS content. Very little AFS has been regenerated. Approximately 1 mL, contains half of the AFS, regenerated from 10 mg OxyContin crushed tablets. Table 27.8 contains the results of the intravenous preparation simulation.

TABLE 27.8: Results of IV simulation -% released AFS

<td colspan="4">% released ohusoaope HCi1</td>

<td>Sample preparation</td><td>OxyContin 'M(10 mg)</td><td>Pr.7.2 (10 mg)</td><td>Pr.14.5 (40 mg)</td>

<td>Simulation IV preparation</td><td> 49</td><td> 1</td><td> 4</td>

<td>Control - intact tablets (released after 45 min)</td><td> 34</td><td> 19</td><td> 19</td>

1 relative to the specification on the label

Results Novoa 2 - Heat treatment

Heat treatment was attempted in a microwave oven; however, testing was unsuccessful with small water volumes. Material of ground tablets from Example 7.2 i

14.5 cannot be contained in 10 - 20 mL of boiling water, so the water volume is increased to 100 mL. After 3 min, at a maximum microwave oven power of 800 W (model, GE Mesdel JE835), the resulting liquid was analyzed for AFS content. In addition, small-volume boiling water extraction was tested by adding 10 mL of boiling water to a vial containing a ground tablet. This vial is shaken vigorously for 15 minutes. As shown in Table 27.9, after the application of the heat treatment, the ground tablet retains the controlled release properties, which prevented complete rupture of the dose. This microwave experiment was not performed on crushed OxyContin tablets; However, comparative data from the boiling water experiment are given.

TABLE 27.9: Heat treatment results -% released AFS

Sample preparation

Ground tablets, in 100 mL hot water (microwave heating, 3 min)% released oxycodone HCl1

OxyContin Pr.7.2 Pr.14.5 (10 mg) (10 mg) (40 mg)

N / A 44 52

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TABLE 27.4: Crushing results -% of released AFS after 45 min

<td rowspan="2">Sample preparation</td><td colspan="6">% oxycodone NSG released after 45 min.</td>

<td>OxyContin 'm 10 mg</td><td>Rg.7.2 (10 mg)</td><td>Rg.14.2 (15 mg)</td><td>Rg.14.3 (20 mg)</td><td>Fr 14.4 (30 mg)</td><td>Pr.14.5 (40 mg)</td>

<td>Crushed tablets</td><td> 92</td><td> 20</td><td> 41</td><td> 44</td><td> 42</td><td> 43</td>

<td>Control - intact tablets (release after 45 min)</td><td> 34</td><td> 19</td><td> 20</td><td> 20</td><td> 18</td><td> 19</td>

1 relative to the specification of the label

In addition, the tablets of Example 14.5 cannot be crushed between two spoons, indicating the need to use additional tablet crushing kits. Conversely, OxyContin ™ tablets are easily crushed between two spoons.

Level 1 Results - Simple Extraction

The tablets of Examples 7.2 and Examples 14.2 to 14.5 were crushed in a mortar with a pestle and shaken vigorously in a hand shaker (shaker), at an angle greater than 10 °, for 15 min, in various solvents, at room temperature. As previously mentioned, crushing in a mortar with a pestle had no effect on the tablets of Example 7.2, and therefore the extracted amounts were not increased. The tablets of Examples 14.2 to 14.5 were crushed before extraction using a mortar and pestle. Due to the swelling of the tablet matrix in the tested solvents, the crushed tablets remained resistant to wider dose release, while the OxyContin® tablets released almost all AFS. Table 27.5 contains the average amounts of AFS released in each solvent.

TABLE 27.5: Results of free extraction -% AFS released after 15 min% released0š> xycodone HČf

<td>Crushed tablets in solvent for extraction</td><td>OxyContin ™ (10 mg)</td><td>Pr.7.2 (10 mg)</td><td>Pr.14.2 (15 mg)</td><td>Pr.14.3 (20 mg)</td><td>Pr.14.4 (30 mg)</td><td>Pr.14.5 (40 mg)</td>

<td>Water</td><td> 92</td><td> 8</td><td> 32</td><td> 30</td><td> 28</td><td> 51</td>

<td>vinegar</td><td> 102</td><td> 11</td><td> 28</td><td> 35</td><td> 41</td><td> 54</td>

<td>Cooking oil</td><td> 79</td><td> 0</td><td> 2</td><td> 1</td><td> 2</td><td> 6</td>

<td>0.026M solution</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>baking powder</td><td> 95</td><td> 6</td><td> 26</td><td> 25</td><td> 29</td><td> 50</td>

<td>Control - intact</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>tablets (released</td><td> 34</td><td> 19</td><td> 20</td><td> 20</td><td> 18</td><td> 19</td>

after 45 min)

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51162 Β 1 relative to the specification on the label

Level 2 testing

Level 2 testing includes grinding, simulation of intravenous (IV) preparation, heat treatment, and extraction.

Results Novoa 2 - Grinding

The tablets of Example 7.2 and Example 14.5 were ground for 1 min in a Cuisanart® coffee grinder with a stainless steel blade (Mesdel DCG-12BC). The energy consumption of the coffee grinder was determined to be 10.5 kJ (for 1 min). The material, equivalent to one unit dose, was taken in triplicate and analyzed by dissolution testing, using a USP Apparatus 1 (with basket), at 100 rpm, in 900 mL of simulated enzyme-free gastric juice (SZF), at 37 ° C, as described above for control data. After one minute, the tablets of Example 7.2 and Example 14.5 were ground to a similar particle size distribution, resulting in the release of approximately half of the AFS from both tablets. OxyContin te tablets were ground into a mixture of larger pieces with some powder, which resulted in the release of almost complete AFS. Table 27.6 contains the average amount of AFS released from such ground tablets. As mentioned earlier, the ground tablets of Examples 7.2 and 14.5 swell and become gelatinous. This phenomenon provides protection against dose withdrawal. Figure 41 contains representative views of the ground tablets before and after reconstitution.

TABLE 27.6: Grinding results -% AFS released after 45 min

<td colspan="4">% released oxycodone NSG</td>

<td>Sample preparation</td><td>OxyContin (10 mg)</td><td>Pr.7.2 (10 mg)</td><td>Rg14.5 (40 mg)</td>

<td>Ground tablets</td><td> 93</td><td> 47</td><td> 52</td>

<td>Control - intact tablets (released after 45 min)</td><td> 34</td><td> 19</td><td> 19</td>

1 relative to the specification on the label

Relative dissolution rate in vitro

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To test the relative dissolution rate of AFS, dissolution samples were taken every 5 min, from t = 0 to t = 40 min, for the ground tablets of Example 7.2 (coffee grinder) and for the crushed OxyContin ™ 10 mg tablets. with a pestle). The OxyContin ™ tablet is easier and more efficient to crush using a mortar and pestle. Although approximately half of the AFS was released over 45 min from the ground tablets of Example 7.2, opa was released gradually, which is characteristic of a controlled release product. No dose robbery was observed. In contrast, dissolution of the ground OxyContin mle tablets leads to complete robustness of the dose for 10 min. This is illustrated in Figure 42.

Particle size distribution in ground tablets

The ground tablets of Examples 7.2 and 14.5 (coffee grinder) and the crushed OxyContin 10 10 mg tablets (avan and pestle) were analyzed by sieving to evaluate the particle size distribution of the ground material. The tablets are sown for 12 minutes, using vibration. The sieves used and the corresponding values in mesh units are given in Table 27.7. As shown by the particle size distribution graphs in Figure 43, 70-80% of the ground tablets of Examples 7.2 and 14.5 are larger than 600 [mu] m. Such large dimensions of the particles of ground material probably do not correspond to snorting. OxyContin ™ of 10 mg gave the distribution of much smaller particles.

TABLE 27.7: Sieve dimensions and corresponding sizes in mesh units

<td>Vgoj sieve</td><td>The value of mesh (Mm)</td>

Level 2 Results - Simulation of intravenous preparation

The tablets of Examples 7.2 and 14.5 were ground in a coffee grinder (as described above) and placed in a spoon. OxyContin ™ 10 mg tablets were crushed between two spoons. To each slurry was added 2 mL of water to extract or dissolve the drug product. ground

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Ground tablets, in 10 mL of hot water (shaking, 15 min) _______________

Control - intact tablets (released after 45 min) ___________ 1 relative to the specification on the label

Level 2 Results - Extraction

The tablets of Examples 7.2 and 14.5 were ground in a coffee grinder (as in the procedure described above) and then shaken for 15 min in various solvents, at room temperature. OxyContin te tablets were crushed using a mortar and pestle. Table 27.10 contains the average amounts of AFS released in each solvent. The ground tablets remained resistant to increased dose edging in various solvents.

TABLE 27.10: Extraction results -% released AFS after 15 min

<td></td><td colspan="3">% released oxycodone NSG</td>

<td>Ground tablets</td><td>OxyContin</td><td>Pr.7.2</td><td>Pr.14.5</td>

<td>Extraction solvent</td><td>(10 mg)</td><td>(10 mg)</td><td>(40 mg)</td>

<td>Control - intact tablets (released after 45 minutes)</td><td> 34</td><td> 19</td><td> 19</td>

1 relative to the specification on the label

Level 3 Testing

Level 3 testing involves extraction for 60 min at room temperature (ST) and at 50 ° C.

Level 3 Results - Enhanced Extraction (ST, 50 ° C)

The tablets of Examples 7.2 and 14.5 were ground in a coffee grinder (as in the procedure described above) and then shaken vigorously in various solvents for 60 minutes at room temperature. In addition, the ground tablets were extracted in various solvents, kept at 50 ° C, for 60 min, using a heated water bath. Stirrers were placed in each vial to move the liquid. After 1 h of extraction, the ground tablets retained some of the controlled release properties, which prevented complete rupture of the dose. Extraction at elevated temperatures is not significant

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51162 Β more efficient, due to the increased solubility of the tablet matrix at higher temperatures in most of the tested solvents. In Table 27.11, the released contents of the tablets from Examples 7.2 and 14.5 were compared with crushed OxyContin ™ 10 mg tablets during extraction for 15 min.

TABLE 27.11: Results of enhanced extraction -% released AFS in 60 min

<td rowspan="2">Ground tablets and extraction solvent</td><td colspan="3">% released Oxycodone1(ST)</td><td colspan="3">% oslobođenog Ohuss ^ ope1 (50 "S)</td>

<td>* OxyContin (10 mg)</td><td>Rg.7.2 (10 mg)</td><td>Pr.14.5 (40 mg)</td><td>* OxyContin 10 mg</td><td>Pr.7.2 (10 mg)</td><td>Pr.14.5 (40 mg)</td>

<td>40 vol% Ethanol</td><td> 101</td><td> 55</td><td> 56</td><td></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>Cooking oil</td><td> 79</td><td> 2</td><td> 4</td><td></td><td> 7</td><td> 4</td>

<td>isopropanol</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>acetone</td><td> 60</td><td> 37</td><td> 38</td><td></td><td>ON</td><td>ON</td>

<td>methanol</td><td> 92</td><td> 71</td><td> 82</td><td></td><td> 72</td><td> 61</td>

<td>Ethyl acetate</td><td> 83</td><td> 25</td><td> 5</td><td></td><td> 39</td><td> 30</td>

<td>Ether</td><td> 78</td><td> 10</td><td> 2</td><td></td><td>ON</td><td>ON</td>

<td>Control -</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>intact tablets</td><td> 34</td><td> 19</td><td> 19</td><td> 34</td><td> 19</td><td> 19</td>

<td>(released</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>after 45 min)</td><td></td><td></td><td></td><td></td><td></td><td></td>

relative to the specification on the label; Data for crushed OxyContin tablets, over 15 min, for comparison

Example 28

In Example 28, a statistically controlled, single-center, single-dose, dual-treatment, two-way, two-way crossover study was performed on healthy human subjects to test the bioequivalence of the formulation of Example 14.1 with oxycodone HCl (10 mg), relative to to the commercial formulation OxyContin® (10 mg), in a full stomach.

The treatment of this study was as follows:

Test treatment: 1 χ tablet from Example 14.1 (10 mg oxycodone HCl)

Reference treatment: 1x 10 mg OxyContin® tablet

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51162 Β

Each of the treatments was administered orally with 240 mL of water, as a single dose, in a full stomach state.

Since this study was performed in healthy human subjects, the opiate antagonist naltrexone hydrochloride was administered to minimize Opioid-related adverse effects.

Choice of persons

Testing procedures were performed as described in Example 26.

This study included individuals who met the inclusion criteria described in Example 26. All potential individuals were excluded from this study, in accordance with the exclusion criteria described in Example 26, with the exception of point 11 of the exclusion criteria in this study. , which refers to "refusal or abstinence from food for 4 hours after administration of the study drug, and complete abstinence from caffeine and xanthine during each intake."

Individuals who met all inclusion criteria, and none of the exclusion criteria, were statistically assigned to the study. Approximately 84 people are expected to be statistically distributed, with a target of approximately 76 people completing the study.

Admission procedures

Admission procedures were performed on the first day, in Period 1, and admission in each period was performed as described in Example 26. Pre-dosing (Day 1, Period 1 only) laboratory samples (hematology, biochemistry, and urine analysis) were taken after signs of vitality and SPO2, and were measured after abstinence from food overnight (10 h).

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51162 Β

Prior to the first dosing in Period 1, subjects were statistically distributed according to the treatment order, according to the statistical distribution plan (RAS), as described in Example 26. The treatment sequences in this study are given in Table 28.1.

TABELA28.1

<td></td><td>Period 1</td><td>Period 2</td>

<td>order</td><td colspan="2">Treatment</td>

<td> 1</td><td>1x OxyContin®10 mg</td><td>1x Example 14.1</td>

<td> 2</td><td>1x Example 14.1</td><td>1x OxyContin® 10 mg</td>

Test procedures

This study included two test periods, each with a single dose. There was a washout period of at least six days between dosing doses, in each test period. During each period, subjects were detained at the study site for one day prior to administration of the investigational drugs until 48 hours after administration of the investigational drugs, and persons returned to the study site in 72-hour procedures.

In each study period, after 10 h of not eating overnight, subjects took a standard meal (high-fat breakfast, FDA) 30 min before administration, either the formulation from Example 14.1 or OxyContin® 10 mg tablets, with 240 mL of water. It is not allowed to take food for at least 4 hours after the dose.

Subjects received 25 naltrexone HCl tablets at times -12, 0, and 12 h, relative to the dosage of the formulation of Example 14.1 or OxyContin®.

Subjects stood or were in an upright sitting position when receiving their dose of the formulation from Example 14.1 or OxyContin®. The subjects remained in an upright position for the next at least 4 h.

No food intake was not required on test days when there was no dosing.

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51162 Β

During this study, adverse events and concomitant medication were reported, and signs of vitality (including blood pressure, body temperature, pulse, and respiratory rate) and SPO2 were monitored.

Blood samples for determination of plasma oxycodone concentration were taken from each person before dosing and at times 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 h post-dose, in each period.

Each sample contained 6 mL of blood from a vein, taken through an implanted catheter and / or directly from a vein, into tubes containing K2EDTA as an anticoagulant. Plasma oxycodone concentrations were quantified by appropriate liquid chromatography in tandem with mass spectrometry.

The test completion procedure was performed as described in Example 26.

The results of this test are given in Table 28.2.

TABLE 28.2: Statistical results of pharmacokinetic measurements of Oxycodone Bioavailability of the formulation from Example 14.1, relative to OxyContin® of 10 mg, in the full stomach condition (population: complete analysis)

<td></td><td colspan="2">LS</td><td colspan="2">MEDIUM3</td><td rowspan="2">Test / Referencec</td><td rowspan="2">90% Confidence intervald</td>

<td>measuring</td><td>N</td><td>(Test)D</td><td>N</td><td>(Reference)D</td>

<td>AUCinf (Ng * h / mL)</td><td> 79</td><td> 139</td><td> 81</td><td> 146</td><td> 95.6</td><td> (93.73 ; 97.53)</td>

And The smallest squares for MEDIUM are from ANOVA. The natural log (In) measurements of the mean value were calculated by transforming the value of In (mean) back to the linear scale, i.e., to the geometric mean value.

b Test = tablet from Example 14.1; Reference = 10 mg OxyContin® tablet.

c Ratio of measured values AVERAGE for ln-transformed measurements (expressed as a percentage). The Ln-transformed relation is transformed backwards to a linear scale.

d 90% Confidence interval for the ratio of measured values AVERAGE (expressed as a percentage). The Ln-transformed confidence limit is transformed back to a linear scale.

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51162 Β

These results show that the tablets of Example 14.1 are bioequivalent to OxyContin® 10 mg tablets, in a full stomach.

Example 29

In Example 29, a statistically averaged, open-label, single-center, single-dose, dual-treatment, two-period, two-way study was performed on healthy human subjects to examine the bioequivalence of the formulation of Example 14.1 with oxycodone HCl (10 mg), in relative to the commercial formulation OxyContin® (10 mg), on an empty stomach.

The treatment of this study was as follows:

<td>Test treatment:</td><td>1 * tablet Primera 14.1 (10 mg oxycodone HCl)</td>

<td>Reference treatment:</td><td>1 h tablet OxyContin® 10 mg</td>

Each of these treatments was administered orally, with 240 mL of water, as a single dose, on an empty stomach.

Since this study was performed in healthy human subjects, the opiate antagonist naltrexone hydrochloride was administered to minimize opiate-related adverse effects.

Choice of persons

Testing procedures were performed as described in Example 26.

This study included individuals who met the inclusion criteria, as described in Example 26. Potential individuals were excluded from this study, according to the exclusion criteria described in Example 26.

Individuals who met the inclusion criteria, and none of the exclusion criteria, were statistically distributed in this study. It is predicted that approximately

214

51162 Β Persons are statistically distributed, with the target of approximately 76 people completing this survey.

Admission procedures

Admission procedures were performed on the first day, Period 1, and admission in each period was performed as described in Example 26. Pre-dosing (Day 1, Period 1 only) and laboratory samples (hematology, biochemistry, and urine analysis) were taken after measurements of signs of vitality and SPO2, after not eating during the night (10 h).

Prior to the first dose in Period 1, subjects were statistically distributed according to the treatment order, according to the statistical distribution plan (RAS) described in Example 26. The treatment sequences in this study are given in Table 29.1.

TABELA29.1

<td></td><td>Period 1</td><td>Period 2</td>

<td>order</td><td colspan="2">Treatment</td>

<td> 1</td><td>1x OxyContin® 10 mg</td><td>1x Example 14.1</td>

<td> 2</td><td>1x Example 14.1</td><td>1x OxyContin®10 mg</td>

Test procedures

This trial involves two trial periods, each with a single dose. There is a washout period of at least six days between dosing in each test period. During each period, subjects are retained at the test site for one day prior to the administration of the investigational drugs, up to 48 hours after the administration of the investigational drugs, and the persons return to the test site in 72-hour procedures.

In each study period, subjects were administered the formulation of Example 14.1 or a 10 mg OxyContin® tablet, with 240 mL of water, after 10 hours of fasting overnight. People continue not to eat for at least 4 hours after the dose.

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51162 Β

Subjects received 25 mg paKgehope HCl tablets, at times -12, 0 and 12 h, relative to the dosage of the formulation of Example 14.1 or OxyContin®.

Subjects stand or are in an upright sitting position while receiving their doses of the formulation of Example 14.1 or OxyContin®. Persons remain in the administrative position for at least another 4 hours.

Clinical sampling of laboratory samples (Day 1) is preceded by non-intake of food (ie for at least 10 h) (water is not included). No food intake is required on test days when no dose is received.

During this test, adverse events and concomitant medication are recorded, and signs of vitality (including blood pressure, body temperature, pulse, and respiratory rate) and SPO are monitored.2.

Blood samples for determination of oxycodone plasma concentration were taken for each person, before dosing and at times 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 h post-dose, in each period.

Test completion procedures are described in Example 26.

The results of this test are shown in Table 29.2.

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51162 Β

TABLE 29.2:

Statistical results of pharmacokinetic measurements of Oxycodone:

Bioavailability of the formulation from Example 14.1 Relative to OxyContin® of 10 mg on an empty stomach (population: complete analysis)

<td></td><td colspan="4">LS SREDNJE '</td><td rowspan="2">Test / Referencec</td><td rowspan="2">90% Confidence intervald</td>

<td>measuring</td><td>N</td><td>(testfil</td><td>N</td><td>(Reference)0</td>

<td>AUCjnf (ng * h / mL)</td><td> 81</td><td> 108</td><td> 81</td><td> 110</td><td> 98.0</td><td> (94.94,101.19)</td>

<td>And Least squares</td><td colspan="2">for MEDIUM</td><td>E su</td><td>from ANOVA.</td><td>3native log (In)</td><td>value measurements</td>

MEDIUMS were calculated by transforming the value of In (MEDIUM) back to the linear scale, ie, to the value geometrically AVERAGE.

b Test = tablet from Example 14.1; Reference = 10 mg OxyGontin® tablet.

c Ratio of measured values AVERAGE for ln-transformed measurements (expressed as a percentage). The Ln-transformed ratio is transformed back to the linear scale.

d 90% Confidence interval for the ratio of measured values AVERAGE (expressed as a percentage). The Ln-transformed confidence limit is transformed back to a linear scale.

These results show that the tablets of Example 14.1 are bioequivalent to OxyContin® 10 mg tablets, on an empty stomach.

EXAMPLE 30

In Example 30, a statistically averaged, open-label, single-dose, two-treatment, two-way crossover study was performed in healthy human subjects to examine the bioequivalence of the oxycodone HCl formulation (40 mg) of Example 14.5, relative to the commercial OxyContin® formulation ( 40 mg) in a full stomach.

The treatment for this study was as follows:

<td>Test treatment:</td><td>1 h Tablet from Example 14.5 (40 mg oxycodone HCl)</td>

<td>Reference treatment:</td><td>1 h 40 mg OxyContin® tablet</td>

Each of the treatments is administered orally with 240 mL of water, as a single dose, in a full stomach.

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51162 Β

Since this study is performed in healthy humans, the opiate antagonist naltrexone hydrochloride is administered to minimize opiate-related adverse effects.

Selection of persons

Testing procedures were performed as described in Example 26.

This study included individuals who met the inclusion criteria as described in Example 26. Potential individuals were excluded from this study, according to the exclusion criteria described in Example 26, with the exception of point 11 of the exclusion criteria from this study, which refers to the refusal or abstinence from food, for 4 hours after the administration of the drugs from this study, and complete abstinence from caffeine and xanthine during each abstinence ”.

Individuals who met the inclusion criterion, and none of the exclusion criteria, were statistically distributed in this study. Approximately 84 individuals were predicted to be statistically distributed, with a target of approximately 76 individuals completing this study.

Admission procedures

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51162 Β

TABELA30.1

<td></td><td>Period 1</td><td>Period 2</td>

<td>order</td><td colspan="2">Treatment</td>

<td> 1</td><td>1 h OxyContin®40 mg</td><td>1 h Example 14.5</td>

<td> 2</td><td>1 h Example 14.5</td><td>1 h OxyContin®40 mg</td>

Test procedures

The trial involves two trial periods, each with a single dose. There is a washout period of at least six days between dosing in each test period. During each period, subjects are retained at the test site for one day prior to the administration of the investigational drugs, up to 48 hours after the administration of the investigational drugs, and the persons return to the test site in 72-hour procedures.

In each study period, after 10 h of overnight food intake, subjects were given a standard meal (FDA breakfast, 30 min before administration, or the formulation of Example 14.5, or a 40 mg OxyContin® tablet, with 240 mL of water. It is not allowed to take food for at least 4 hours after the dose.

Subjects received 25 mg naltrexone HCl tablets, at times -12, 0, 12, 24 and 36 h, relative to the dosage of the formulation of Example 14.5 or OxyContin®.

Subjects stand or are in an upright sitting position while receiving their doses of the formulation of Example 14.5 or OxyContin®. Persons remain in the administrative position for at least another 4 hours.

No food intake is required on test days when no dose is received,

219

51162 Β

Blood samples for determination of plasma oxycodone concentration were taken for each person at different dosages and at times 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 h post-dose, in each period.

Each is taken 6 mL of blood from a vein, through an implanted catheter and / or directly from a vein, into tubes containing K2EDTA as an anticoagulant. Oxycodone plasma concentrations are quantified by appropriate liquid chromatography in tandem with mass spectroscopy.

The procedures for completing this test were performed as described in Example 26.

The results of this test are shown in Table 30.2.

TABLE 30.2:

Statistical results of pharmacokinetic measurements of Oxycodone:

Bioavailability of the formulation of Example 14.5 relative to OxyContin® of 40 mg in the full stomach (population: complete analysis)

<td></td><td colspan="4">LS SREDNJE '</td><td rowspan="2">Test / Referencec</td><td rowspan="2">90% Confidence intervald</td>

<td>measuring</td><td>N</td><td>(Test) °</td><td>N</td><td>(Reference)0</td>

<td>AUCjnf (ng * h / 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="3">And Least squares for MEDIUM</td><td colspan="4">E are from ANOVA. Natural log (In) value measurement</td>

MEDIUMS were calculated by transforming the value of In (MEDIUM) back to the linear scale, ie “to the value geometric AVERAGE.

b Test = tablet from Example 14.5; Reference = 40 mg OxyContin® tablet.

c Ratio of measured values AVERAGE for Ιπ-transformed measurements (expressed as a percentage). The Ln-transformed ratio is transformed back to the linear scale.

d 90% Confidence interval for the ratio of measured values AVERAGE (expressed as a percentage). The Ln-transformed confidence limit is transformed back to a linear scale.

These results indicate that the tablets of Example 14.5 are bioequivalent to OxyContin® 40 mg tablets, in a full stomach state.

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51162 Β

Example 31

In Example 31, a statistically averaged, open-label, single-dose, two-treatment, two-way crossover study was performed on healthy human subjects to examine the bioequivalence of the Oxycodone HCl Formulation (40 mg) of Example 14.5, relative to the commercial OxyContin® formulation (40 mg). ) on an empty stomach.

The treatment for this study was as follows:

<td>Test treatment:</td><td>1 h Tablet from Example 14.5 (40 mg oxycodone HCl)</td>

<td>Reference treatment:</td><td>1 h 40 mg OxyContin® tablet</td>

Each of the treatments is administered orally with 240 mL of water, as a single dose, on an empty stomach.

Since this study is performed in healthy humans, the opiate antagonist naltrexone hydrochloride is administered to minimize opiate-related adverse effects.

Selection of persons

Testing procedures were performed as described in Example 26.

This study included individuals who met the inclusion criteria, as described in Example 26. Potential individuals were excluded from the study according to the exclusion criteria described in Example 26.

Individuals who met all inclusion criteria, and none of the exclusion criteria, were statistically assigned to this study. Approximately 84 individuals were predicted to be statistically distributed, with a target of approximately 76 individuals completing this study.

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51162 Β

Admission procedures

Admission procedures were performed on Day 1 of Period 1, and admission in each period was described in Example 26. Pre-dosing (Day 1, Period 1 only) and laboratory samples (hematology, biochemistry, and urine analysis) were collected after measurement of vital signs and SPO2, after not eating for at least 4 h.

Prior to the first dose in Period 1, individuals were statistically distributed according to the treatment order, according to the statistical classification plan (RAS), as described in Example 26. The treatment sequences in this study are given in Table 31.1.

TABELA31.1

<td></td><td>Period 1</td><td>Period 2</td>

<td>order</td><td colspan="2">Treatment</td>

<td> 1</td><td>1 h OxyContin®40 mg</td><td>1 h Example 14.5</td>

<td> 2</td><td>1 h Example 14.5</td><td>1 h OxyContin®40 mg</td>

Test procedures

In each administration period, the formulation of Example 14.5, or a 40 mg OxyContin® tablet, with 240 mL of water, was administered to the subjects after 10 hours of no food intake overnight. People continue not to eat for at least the next 4 hours after the dose.

Subjects received naltrexone HCl 50 mg tablets at times -12, 0, 12, 24, and 36 h, relative to the dosage of the formulation of Example 14.5 or OxyContin®.

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51162 Β

Individuals stand or are in an upright sitting position while receiving their dose of the formulation of Example 14.5 or OxyContin®. Persons remain upright for at least another 4 hours.

No food intake is required on test days when no dose is received.

During this study, adverse events and treatment with concomitant medications were registered, and signs of vitality (including blood pressure, body temperature, pulse, and respiratory rate) and SPO2 were monitored.

Blood samples for determination of oxycodone plasma concentration were taken for each person before dosing and at times 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 h post-dose, in each period.

Each is taken 6 mL of blood from a vein, through an implanted catheter and / or directly from a vein, into tubes containing K2EDTA as an anticoagulant. Plasma oxycodone concentrations are quantified by appropriate liquid chromatography in tandem with mass spectroscopy.

The procedures for completing this test were performed as described in Example 26.

The results of this test are shown in Table 31.2.

TABELA31.2:

Statistical results of pharmacokinetic measurements of Oxycodone:

Bioavailability of the formulation from Example 14.5 relative to OxyContin® of 40 mg on an empty stomach (population: complete analysis)

<td></td><td colspan="4">LS SREDNJE '</td><td rowspan="2">Test / Referencec</td><td rowspan="2">90% Confidence intervald</td>

<td>measuring</td><td>N</td><td>(Test)0</td><td>N</td><td>(Reference)0</td>

223

51162 Β And The smallest squares for MEDIUM are from ANOVA. The natural log (In) measurements of the mean value were calculated by transforming the value of In (mean) back to the linear scale, i.e., to the geometric mean value.

b Test = tablet from Example 14.5; Reference = 40 mg OxyContin® tablet.

c Ratio of measured values AVERAGE for ln-transformed measurements (expressed as a percentage). The Ln-transformed ratio is transformed back to the linear scale.

d 90% Confidence interval for the ratio of measured values AVERAGE (expressed as a percentage). The Ln-transformed confidence limit is transformed back to a linear scale.

These results indicate that the tablets of Example 14.5 are bioequivalent to 40 mg OxyContin® tablets on an empty stomach.

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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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