Multiple-unit pharmaceutic composition of modifiable release

The present invention relates to an oral, multi-unit modified release pharmaceutical composition for administering an analgesic effective amount of opioid, providing both a relatively rapid onset of analgesic effect and persistence of analgesic effective plasma concentration for a relatively long period of time and a method for preparing such composition. The modified release multi-unit composition contains at least two fractions in which individual opioid-containing units are coated with a sustained release coating, designed to release the active ingredient in such a way as to achieve both a relatively rapid onset of analgesia and persistence of effective analgesic concentration in plasma for a relatively long period of time, making the composition suitable for once or twice daily administration.

It is possible to maintain drug levels above the lower therapeutic plasma level for relatively long periods of time by administering higher doses of conventionally formulated drug forms. However, increasing doses is not an appropriate approach, since such doses may produce undesirably high and toxic drug levels. An alternative alternative approach is to administer the drug at certain intervals, resulting in the oscillation of drug levels, the so-called peak and valley effect. This approach is generally associated with a number of potential serious problems, such as strong peak effect (toxic effect) and valley (inactive drug level), as well as lack of patient compliance, which can lead to ineffective or unsuccessful therapy. However, if the plasma concentration is kept constant above the therapeutic level when using conventional tablets, then if an opioid is not administered very frequently, an unacceptably high daily dose is required.

Controlled release formulations are known which are designed to immediately release a portion of the total drug dose. This loading dose is the amount of drug that will provide the desired pharmacological response as soon as possible according to the biopharmaceutical properties of the drug. Such preparations that initially release the therapeutic agent charge and then release the therapeutic agent at a substantially constant rate are described in International Application Publication No. WO95 / 14460, published June 1, 1995. The composition described therein relates to an opioid sustained release formulation comprising a plurality of substrates containing the active ingredient in a sustained release matrix or coated with a sustained release coating containing a retarding substance. Sustained release beads are then coated with the opioid in an immediate release form, or in the case where the composition is in the form of gelatin capsules, ordinary opioid is introduced into the gelatin capsule by inclusion in the capsule of a sufficient amount of immediate-release opioid in powder or granular form. In another alternative, the gelatin capsule itself is coated with an immediate release opioid layer.

A major drawback of the above formulation is that the introduction of a conventional opioid into gelatin capsules without a protective coating on the opioid can easily lead to a lack of control of the exact dose, especially if the capsule leaks or the patient tears the capsule. In addition, it is not possible to modify the release of the sustained release fraction, and the only way to avoid toxic plasma concentrations or to control peak plasma concentrations is to reduce the exact amount of opioid in the immediate release portion.

The above-described controlled-release preparations have a long-lasting effect and release the drug in a prolonged manner. However, these types of formulations can lead to an undesirable decrease in bioavailability, probably because the active ingredient is not released in good time.

The purpose of the multi-unit preparation technique of the invention is to modify the release of the active substance according to a previously established scheme to reduce and delay the peak plasma concentration (peak) without affecting the degree of drug availability. The frequency of undesirable side effects may be reduced, and the frequency of administration may be reduced by delaying the time needed to reach a peak in blood concentration and by prolonging the duration of therapeutically effective plasma concentration.

188 919 up to a dose given only twice or once a day. It also aims to improve patient compliance. Another advantage of the multi-unit modified release form is that high local concentrations of the active substance in the gastrointestinal tract are avoided due to the fact that the units are freely distributed in the gastrointestinal tract, regardless of its emptying.

In addition, patients with chronic pain very often require high daily doses of an analgesic, for example about 100 mg morphine. If such a high dose of opioid is to be administered once a day, release from the drug form must be safe. The preparation must also be very stable during storage, because immediate release associated with accidental damage to, for example, a high dose coating or capsule can lead to undesirably high plasma concentrations, so-called emptying of the dose, which could cause death of the patient. When using a coated multi-unit dosage form, the risk of dose emptying, associated for example with tearing of the coating, is reduced because the amount of active ingredient in each of the coated units is negligible.

However, the major disadvantage of the prior art once-daily treatment may be the low peak plasma concentration at the end of the day and therefore no analgesic effect. As the treatment of pain is based on the balance of pain relief on the one hand and on the other hand the risk of side effects, for example associated with drug accumulation, the dosage interval is usually calculated so that the drug concentration is significantly reduced at the time of taking the next dose. Thus, the patient very often suffers from increasing pain before the drug concentration reaches therapeutic level after the next dose. In addition, it should be noted that relatively high doses, corresponding to a relatively higher peak concentration, are often needed in the treatment of pain in pain crises. Thus, relatively higher initial analgesic plasma concentrations may be necessary compared to plasma concentrations that allow pain relief to be maintained.

Since the treatment of chronic pain is very often a life-long treatment and therefore very expensive, dosage forms for once-a-day administration should not require an expensive and complicated method of production, since the higher cost of such a product compared to the cost of a conventional product would reduce the chance of such a drug being successful.

However, no oral analgesic pharmaceutical composition has been disclosed that can be prepared in an easy, cheap and reproducible manner and at the same time provides an adequate release profile of the active substance, giving a prolonged effect such that pain is relieved quickly after administration and prevented for a period of about 12 to 24 hours.

Therefore, there is a need for a preparation containing an opioid substance that allows the administration of both large and small daily doses only once or twice a day in a safe and reliable manner that is easy to produce, preferably by conventional production methods and the least number of steps possible. . It is also important that the once-daily opioid formulation contains the active ingredient in such a way that the formulation has a reliable dissolution rate because unexpectedly rapid dissolution of the opioid would be dangerous to the patient.

The purpose of the invention is to provide a multi-unit oral modified release formulation for administration of a daily dose of opioid in a form that requires administration of at most twice a day, preferably once a day, and which does not have the disadvantages of previously suggested modified release formulations, which is manifested in that that the dosage form provides both rapid release from the first fraction containing the modified release opioid multiunits as well as delayed and prolonged release from the second fraction of the modified release multiunits, which results in a pain relief that lasts for at least 12 hours, preferably 24 hours after administration.

In a further aspect, the object of the invention is to provide a method for the preparation of an oral multi-unit modified release pharmaceutical composition.

188 919

Thus, the subject of the invention is an oral, multi-unit composition of a modified release pharmaceutical preparation for administering an analgesic effective amount of an opioid to obtain both a relatively rapid onset of an analgesic effect and maintaining effective analgesic plasma concentration for a relatively long period of time, characterized in that it is in a dosage unit contains at least the following two multi-unit fractions:

- the first fraction of coated multi-units with relatively fast release for relatively fast release of opioid in vivo to obtain therapeutically active plasma concentration in a relatively short period of time; and

- a second fraction of coated delayed release multi-units for delayed release of opioid in vivo to maintain analgesic plasma concentration for a period of at least 12 hours;

wherein the form of the first and second fraction in terms of delayed release from them and the ratio of the first to the second fraction in the dosage unit is selected such that:

(i) relatively fast in vitro opioid release from the first relatively fast release multiunit fraction. measured dissolution method using a paddle apparatus according to the US Pharmacopoeia (USP) / European Pharmacopoeia (F. Eur.) at a rotor speed of 100 rpm at 37 ° C and using 900 ml 0.1N HCl as the dissolving fluid;

(ii) delayed in vitro release of opioid from the second fraction of delayed release multi-units relative to the in vitro release of the first modified-release multi-unit fraction, measured by the dissolution method as defined above;

wherein rapid release and delayed in vitro release are selected such that the first fraction is significantly released when the second fraction is released, which corresponds to the release of at least 50% of the opioid contained in the first fraction when 10% of the opioid is released contained in the second fraction, measured by the dissolution method as defined above.

The multi-unit modified-release dosage forms of the invention ensure that therapeutic levels are obtained and maintained, while at the same time reducing side effects, such as nausea, vomiting and lethargy, considered to be associated with high levels of analgesic opioids in the blood. It is also believed that the use of the dosage forms of the invention leads to a reduction in the risk of drug addiction compared to prior forms of therapy. Furthermore, the multi-unit modified-release dosage forms of the invention preferably release analgesic opioids at a rate that is independent of pH, thereby avoiding pH-dependent accumulation of dose after oral administration.

Since also the first, relatively fast fraction of the formulation composition of the invention contains opioid in coated form, the release of the fraction can be modified to the desired release profile, which is of great importance for the safety of the drug. First, avoid "free opioid" in the capsule or coating, which may be degraded or leaking from the formulation.

Since the coating of each fraction can be carried out using essentially identical procedures and materials, the cost of production can be kept low.

The invention also relates to a method for producing a dosage unit of an oral multi-unit modified release pharmaceutical composition as defined above, characterized in that at least two of the following coated multi-unit fractions are introduced into the dosage unit:

- the first fraction of coated multi-units with relatively fast release for relatively fast release in vivo of opioid to obtain therapeutically active plasma concentration over a relatively short period of time; and

- a second fraction of coated delayed-release multi-units for in vivo opioid delayed release to maintain active analgesic plasma concentrations for a period of at least 12 hours;

188 919 wherein the form of the first and second fraction, in terms of release from them and the ratio of the first to the second fraction in the dosage unit is selected such that:

(i) relatively fast release of opioid in vitro from the first fraction of relatively fast release multiunits, as measured by the dissolution method as defined in claim 1. (Ii) in vitro delayed release from the second fraction of delayed release multiunits as compared to the in vitro release from the first opioid fraction, measured by the dissolution method according to claim 1. 1, wherein the rapid release and delayed in vitro release are selected such that the first fraction is significantly released when the second fraction is released, which corresponds to the release of at least 50% of the first fraction when 10% of the second fraction is released , measured by the dissolution method by the dissolution method as defined above.

In one embodiment, the composition may contain modified release multiunits for which the in vitro dissolution characteristics of the first fraction of modified modified multiunits within 0.5 hours provide release, determined by the dissolution method III described herein, at least 30%, such as at least 40%, preferably at least 50%, more preferably at least 60%, even more preferably at least 70%, most preferably at least 90%.

In addition, the composition may contain modified release multiunits for which the in vitro dissolution characteristics of the first fraction of modified release multiunits within 1 hour provide release determined by the dissolution method III described herein, at least 50%, such as at least 60%, preferably at least 70%, more preferably at least 80%, even more preferably at least 90%, most preferably at least 95%.

The in vitro dissolution characteristics of the second fraction of modified release multiunits can provide release in one embodiment within 1 hour as determined by dissolution method III as described herein in the range of 0% -30%, such as in the range of 0% -20%, preferably in the range of 0% -10%, most preferably about 5%.

In addition, the in vitro dissolution characteristics of the second fraction of modified release multiunits can provide release within 3 hours, determined by dissolution method III described herein, in the range of 10% -70%, such as in the range of 15% -60%, preferably in the in the range of 20% -50%, more preferably in the range of 25% -45%, most preferably about 35%.

Within 6 hours, the in vitro dissolution characteristics of the second fraction of modified release multiunits can provide release, determined by dissolution method III described herein, in the range of 35% -95%, such as in the range of 50% -90%, preferably in the range 60% -80%, more preferably in the range of 65% -75%, most preferably about 70%.

In addition, within 9 hours, the in vitro dissolution characteristics of the second fraction of modified release multiunits may provide release, determined by dissolution method III described herein, in the range 50% -100%, such as in the range 60% -98%, preferably in the range of 70% -95%, more preferably in the range of 80% -90%, most preferably about 85%.

To ensure that the release of the second fraction has the desired delay time relative to the release of the first fraction, the in vitro dissolution characteristics of the first and second fractions are chosen in one embodiment such that the first fraction is significantly released when the release of the second fraction begins, which corresponds to the release at least 50% of the first fraction while 5% of the second fraction is released, measured by the dissolution method described in the description.

In addition, the in vitro dissolution characteristics of the first and second fractions in the same or second embodiment are chosen such that the first fraction is significantly released when the second fraction is released, which corresponds to the release of at least 70% of the first fraction when the second fraction is released. % of the second fraction, measured using the dissolution method described in the description III.

Two fractions of modified release multiunits can be selected in terms of modified release from each of the fractions and the ratio between the two fractions of 188,919 mi, so that the in vitro dissolution characteristics of the composition within 1 hour ensures the release of opioid in the first and second fraction, determined by the dissolution method V , described herein, in the range of 5% -50%, such as in the range of 5% -45%, preferably in the range of 15% -40%, more preferably in the range of 20% -35%, just like around 27%.

In addition, two fractions of modified release multiunits can be selected in terms of modified release from each of the fractions and the ratio between the two fractions so that the 3-hour in vitro dissolution characteristics of the composition provides the release determined by the dissolution method V described herein, in the range of 20% -80%, such as in the range of 25% -70%, preferably in the range of 30% -60%, more preferably in the range of 35% -55%, such as about 50%.

In a further aspect, the two fractions of modified release multiunits can be selected in terms of modified release from each of the fractions and the ratio between the two fractions so that the in vitro dissolution characteristics of the composition within 6 hours provides the release determined by the dissolution method V described herein description, in the range of 40% -98%, such as in the range of 50% -95%, preferably in the range of 60% -90%, more preferably in the range of 65% -85%, most preferably in the range of 70% -83%, such as about 80%.

In addition, two fractions of modified release multiunits can be selected in terms of modified release from each of the fractions and the ratio between the two fractions so that the in vitro dissolution characteristics of the composition within 9 hours provide the release determined by the dissolution method V described herein, in the range of 50% -100%, such as in the range of 60% -99%, preferably in the range of 70% -98%, more preferably in the range of 75% -97%, most preferably in the range of 80% -95%, just like in the range of 85% -96%, like around 95%.

In a preferred embodiment, the composition meets the above criteria for dissolution characteristics of the composition over the full period of time given.

The ratio between the first and second fractions of the modified release multiunits in the composition of the invention may be in the range of 1: 120-1: 2, such as in the range of 1: 10-1: 3, preferably in the range of 1: 8-1: 3, more preferably in the range of 1: 7-1: 3.5, even more preferably in the range of 1: 3.5-l: 4.5, and most preferably in the range of 1: 4.

In a preferred embodiment, the multi-units are coated, substantially homogeneous cross-section pellets.

The individual units of the first and second fractions differ in their modified release properties, for example due to the amount of coating applied to each of the multiunits of each fraction. However, the individual units of the two fractions are preferably of the same size.

Preferably, the modified release multiunits of the first fraction give a plasma opioid concentration peak that is substantially the same as the concentration peak resulting from the second fraction. Since the peak plasma concentration of the second fraction is chosen such that the peak has an extended character due to the fraction dissolution characteristics described herein, the peak of this second fraction should preferably generally represent a lower level of therapeutic plasma concentration. In this preferred embodiment, the plasma concentration level is such that opioid is not present in excess.

Because the total amount of opioid contained in the first fraction is generally relatively small (e.g. about 20%) compared to the total amount of opioid in the composition, the plasma concentration peak from the first fraction, which is higher than the concentration peak resulting from the second fraction, does not necessarily correspond significant loss of opioid.

However, the peak in the first fraction should not exceed the peak in the second fraction for an extended period of time unless the patient suffers from severe breakthrough pain when higher plasma concentration than the plasma concentration needed to maintain pain relief appears.

Even in circumstances where the peak of the first fraction is preferably higher than the peak of the second fraction, it is easy to avoid inappropriate high plasma concentrations (within the toxic level) originating from the first fraction due to the modified release.

188 919

In another embodiment, for example, in circumstances where the patient is treated well by once or twice daily administration of the dosage composition of the invention, the first fraction may be adjusted to give a plasma opioid concentration peak that is lower than the concentration peak resulting from the second fractions. This does not have to cause breakthrough pain because the opioid remaining in the plasma from the previously administered dose may contribute to maintaining sufficiently high plasma concentration until release from the second fraction of the composition. In other cases, the daily dose may be given at the appropriate time of the day, when the patient feels less need for an analgesic, for example, before going to bed.

Thus, an important aspect of the invention is its embodiment when the first fraction results in a therapeutically active plasma opioid level until the sustained release of the opioid from the second fraction of modified release multiunits contributes to maintaining therapeutically active plasma opioid concentration.

Preferably, the modified release coating of each of the fractions contains substantially the same components. The delayed release time of the second fraction relative to the first fraction can be achieved by a modified release coating of the first fraction which is present in the range of about 10% to about 80%, based on the dry weight of the amount of the modified release coating of the second fraction.

It is also preferred that the modified release coating of both fractions is essentially insoluble in water, but diffusible in water and substantially independent of pH, resulting in absorption independent of the presence of food in the stomach.

The amount of opioid in the modified release multi-unit composition of the present invention can be selected to correspond to doses of about 5 mg, 10 mg, 20 mg, 30 mg, 50 mg, 60 mg, 100 mg, 200 mg or 300 mg morphine, which all are known they are from the state of the art. However, the composition of the invention preferably contains an amount of opioid, which is a daily, analgesically effective dose of opioid.

Generally, it is not always possible to obtain identical release profiles when administering different doses for ordinary dosage forms, such as tablets containing plain opioid, and the loading dose of the active ingredient may vary depending on the tablet size. The release profile for 100 mg given as a single dose may therefore differ from the release profile for 100 mg given as 5 doses of 20 mg each. Even with commercially available modified release forms, a substantially identical release profile for different doses is not always observed.

It is now possible to administer different doses with identical release profiles with the composition of the invention. If only each multi-unit modified release composition of the invention is made of the same type of coated multi-units of the first and second fraction and with the same ratios, each dosage form may be administered together to achieve any desired total dose without altering the total release profile of the total dose. Accordingly, reliable and predictable plasma concentrations can be obtained, irrespective of the total dose, throughout the entire period between administrations.

Thus, another advantage of the compositions of the invention is that the composition can be prepared in various series of dosage forms, e.g. 10 mg, 30 mg, etc., having each individual property resulting from the design of modified release of the first and second fractions, as well as from the ratio between factions. You can then get any appropriate total dose from the appropriate doses in each series.

The preferred dosage form according to the invention is in the form of a capsule. The size of the capsule is adapted to the amount of opioid in the composition.

The dose amounts suggested above should not be considered as limiting the scope of the invention, since it is obvious to the skilled person that any desired amount of opioid can be used and is limited only by the size of the composition.

The overall object of the invention is to provide a unit dose for administering an analgesic effective amount of opioid only once a day. However, because some patients may still need or prefer to receive the medicine twice a day, the invention does not

188 919 may be limited to once-daily dosage form compositions as long as each unit dose of the composition meets the dissolution criteria given above.

The term "multi-unit modified release composition" is defined as releasing the drug at such a rate that plasma levels are maintained for as long as possible above the therapeutic (analgesic) level but below the toxic level.

The term "fraction" of multi-units in the present application refers to parts of a multi-unit dose unit. The fraction is generally different from the other multi-unit fraction in the dosage unit. Even if only two fractions are defined, the scope of the invention also includes more than two fractions in a dosage unit. Accordingly, the dosage unit of the invention contains at least two different fractions.

The term "dosage unit" as used herein refers to one single unit, for example capsules. The dosage unit represents many individual units, which according to the general state of the art may be in the form of capsules, tablets, sachets, etc.

The term "opioid" in this application refers to a group of drugs that are similarly similar to morphine or opium in their properties. The term includes natural and synthetic opioids as well as active metabolites such as morphine 6-glucuronide and morphine 3-glucuronide, and mixtures of opioids. The definition of opioids also includes pharmaceutically acceptable salts and / or complexes of opioids.

Further examples of opioids include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocin, desomorphine, dextromoramide, deocinetin, diampromid, dihydrocorphinone, dimepromothin, dimeprimene , ethoheptazine, ethylmethylthiatinbuten, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isometadone, dextropropoxyphene, ketobemidone, levallorphan, levorfanol, levofenacylmorphan, lofentanil, meperidine, meptazine, metazocin, methadone, methopone, morphine, myrofin, nalbufen, narcein, nicomorphine, norlevorfanol, normetiponone, nalporfin pentazocine, fenadoxone, fenomorphan, fenazocine, phenoperidine, piminodine, pyramidamide, proheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine, tratnadol, their salts, mixtures of any of the above mixed μ-agonists / antagonists, (and / or K-agonists, combinations of the foregoing and the like.

The oral multi-unit opioid modified release pharmaceutical composition of the invention preferably contains morphine as a therapeutically active ingredient in an amount corresponding to 5 mg to 800 mg morphine sulfate by weight. Alternatively, the dosage form may contain molar equivalent amounts of morphine salt. In preferred embodiments, when the opioid analgesic is other than morphine, the dosage form contains a suitable amount that provides a substantially equivalent therapeutic effect.

Generally, opioids are easily absorbed from the gastrointestinal tract after oral administration. Many opioids, including morphine, undergo first-pass metabolism in the liver. Satisfactory analgesic effect in cancer patients is associated with a very wide range of steady-state morphine plasma concentrations of 16 to 364 ng / ml (Goodman and Gilmans; The Pharmacological Basis of Therapeutics, 8th ed., 1990, p. 496). The half-life of morphine is about 1.5-2 hours, however, morphine is metabolized to active products such as morphine 6-glucuronide, which has a longer half-life. The average duration of action for the first single dose of 10 mg morphine orally, im or sc is about 4-5 hours. Examples of dosing of other opioid analgesics providing approximately the same analgesic effect as 10 mg morphine are well known and for example are given in the book Goodman and Gilmans; The Pharmacological Basis of Therapeutics, ed. 8, 1990, p. 497.

The term "bioavailability" means the extent to which a drug is absorbed from a multi-unit modified release composition.

In the context of the present invention, the term "therapeutically active plasma concentration for a period of at least 12 (24) hours" includes the situation in which the opioid administered has

188 919 metabolized to active products, exerting an analgesic effect for the given period of time. Accordingly, opioid exactly as administered may not be directly detectable in plasma in an amount generally considered to be an analgesic effective level.

The patient's daily dose is generally calculated based on cumulative oral doses pn (= as needed) over several days. Accordingly, if the demand for a particular opioid over a period of 48 hours was 120 mg, then the daily dose is 60 mg, regardless of whether the administration reflects a specific regimen, such as the need for higher doses during the day.

In one embodiment of the invention, the first multi-unit fraction contains an amount of opioid corresponding to about 25% to about 17% (between 1/4 and 1/6) of the daily dose. For patients in whom 4 daily doses of a conventional sustained release preparation are satisfactory, the first fraction may contain in one example an amount of opioid corresponding to 25% of the daily dose. The second fraction may then contain the remaining 75% of the daily dose.

However, the preferred amount of the first fraction may be 20% of the daily dose and the second fraction 80% of the daily dose.

In another embodiment of the invention, the first fraction of the multiunits contains an amount of opioid corresponding to the amount of opioid necessary to achieve an analgesic effect after the first single oral dose of a conventional sustained release formulation.

The individual units of the multi-unit formulation according to the invention are usually pellets or beads with a size (average diameter) from 0.1 to 2 mm. The most preferred pellet size is between 0.5 and 0.8 mm. Pellets or beads contain a combination of the active substance, opioid and excipients. When the pellets or beads are not coated, the combination of active substance and excipient is referred to as the core.

In the context of the present invention, the term "cores that are substantially homogeneous in cross-section" means cores in which the active substance is not limited to the outer layer of the core mass, i.e. in other words normal cores which in cross-section contain essentially the mass of the core the same type of composition, which is smaller particles containing the active substance, in contrast to non-pareil cores, each of which consists of an excipient and the active substance is applied to its surface. From this definition it follows that cores that are substantially homogeneous in cross-section will normally consist of a mixture of the active substance with excipients, which mixture is not necessarily qualitatively or quantitatively homogeneous throughout the entire cross-sectional area of ​​the core, but may for example have a concentration gradient of the opioid substance or may consist essentially of the opioid substance itself. In the following description and claims, such cores that are substantially uniform in cross-section will simply be referred to as cores for simplicity.

The core containing the opioid substance in a substantially uniform form provides more reproducible release of the active ingredient compared to, for example, particles in which the active ingredient forms part of the coating.

Preferably, the individual release core profile of the individual unit is substantially non-limiting in terms of the desired release profile of the coated pellet, i.e. the core itself provides about 100% release within 1 hour, preferably within 45 minutes, as measured by the in vitro dissolution test described in the examples . However, pellet cores exhibiting slower release are also within the scope of the invention.

The oral multi-unit composition of the modified release pharmaceutical preparation of the invention is typically a capsule containing multiple units, typically above 100, a sachet containing multiple units, typically above 1000 or a tablet made of multiple units, typically above 100 so that the tablet will generally disintegrate, essentially directly after ingestion in the stomach into many individual units, which are freely distributed in the gastrointestinal tract.

In the context of the present invention, the term "once a day" means that in order to achieve an adequate therapeutic and / or prophylactic response it is necessary to administer the composition of the pharmaceutical preparation only once a day; however, each administration

188 919 may consist of the simultaneous administration of more than one dosage unit, such as 2-4 dosage units, if the required amount of active ingredient cannot be formulated in one unit of the composition or if a smaller size unit of the composition is more preferred.

According to the above definition of the term "once a day", the term "twice a day" means that in order to obtain a suitable therapeutic and / or prophylactic response it is necessary to administer the composition of the pharmaceutical preparation only twice a day.

In this regard, a significant advantage of the compositions of the invention is that the release profile of each dosage unit is constant, regardless of the total amount of active ingredient in the dosage unit, as long as the ratios of substantially identical pellets having "fast" and "slow" release are constant.

Notwithstanding the above definitions of the terms "once and twice a day", a dosage unit constructed to provide the active ingredient when administered only once a day is preferred. However, due to individual circumstances, some patients may need a new dose, for example 12 or 18 hours, if the patient has, for example, atypical absorption or intestinal transit time. If the subject has a relatively fast intestinal transit time, some of the active ingredient may be secreted before releasing the full dose or it may be released in the colon from which absorption is reduced.

The multi-unit pharmaceutical formulation according to the invention is preferably made as a unit dosage form which, after oral administration, disintegrates into many individual units. The dosage unit form is preferably a solid form, such as, for example, a capsule or sachet, especially a capsule form.

The actual opioid load in the pharmaceutical preparation of the invention, i.e. the concentration in wt% of opioid, calculated relative to the total weight of the pellet, may depend on the specific opioid used in the preparation. When the opioid load in individual pellets of the two fractions and the ratio of the two fractions for one dosage unit, containing, for example, 10 mg morphine, is identical to another dosage unit containing, for example, 100 mg of opioid, the release profile for each dose will be identical. Consequently, a particular total dose can be administered to a patient by combining the appropriate dosage units, e.g. selected with 10, 30 and 100 mg opioid, without changing the total release profile of the total amount of opioid administered.

Preferably, the pellets of the pharmaceutical preparation of the invention contain about 10% by weight or more of opioid based on the total weight of the pellet.

The compositions discussed above can be prepared by conventional methods known in the art. This method can generally be as follows:

(a) the individual units containing the active substance are coated with an internal film-forming mixture containing the film-forming substance, the first fraction of the individual dosage unit units coated with the amount of coating, calculated on the dry matter, which corresponds to from about 10% to about 90%, calculated on dry mass, amount of coating of the second fraction of individual dose units;

b) the units thus coated are optionally provided with an outer film layer containing a film-forming agent;

c) a mixture of the individual units of the first and second fractions is formulated into a dosage form in the desired ratio of the two fractions.

The film-forming agent in step b) can be selected to prevent adhesion between the units at elevated temperatures, after which the coated units are heated to a temperature above 40 ° C, preferably not higher than 65-75 ° C, thereby producing a continuous phase in outer layer in a homogeneous mixture with the film-forming substance. In some cases, this crosslinking process can also take place before applying the outer coating layer.

As mentioned above, the opioid containing pellets used in the composition of the invention are coated with a modified release coating. The modified release coating is applied to the pellets from the solution and / or suspension, preferably in an aqueous solvent, but an organic coating composition can also be applied.

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Examples of film-forming substances that are suitable for use in the present invention are substances selected from the group consisting of cellulose derivatives, such as, for example, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose valerate, cellulose acetate propionate, such as an example of polymethyl methacrylate, vinyl polymers such as, for example, polyvinyl acetate, polyvinylformal, polyvinylbutyryl, vinyl chloride-vinyl acetate copolymer, ethylene-vinyl acetate copolymer, vinyl chloride-propylene-vinyl acetate copolymer, silicone polymers, such as, for example, sesquiphenylsiloxane ladder polymer and colloidal silica, polycarbonate, polystyrene, polyester, coumarone-indene polymer and other polybutadium high molecular synthetic polymers.

In some preferred embodiments, the acrylic polymer is one or more ammonium methacrylate copolymer. Ammonium methacrylate copolymers are well known in the art and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.

In a preferred embodiment, the acrylic coating is an acrylic resin lacquer used in the form of an aqueous dispersion, such as resins commercially available from Rohm Pharma under the name Eudragn®. In another preferred embodiment, the acrylic coating comprises a mixture of two commercially available acrylic varnishes from Rohm Pharma under the names Eudragit® RL SOD and Eudragit® RS 30 D, respectively. Eudragit® RL 300 and Eudragit® RS 30 D are copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to other neutral ester groups (methacrylate is 1:20 for Eudragit® RL 30d and 1 : 40 for Eudragit® RS 30 D. Eudragit® RL / RS mixtures are insoluble in water and digestive fluids. However, the coatings formed from them swell in aqueous solutions and digestive fluids and are permeable to them. Eudragit® RL / RS dispersions can be mixed together in any desired ratio to give a modified release formulation having the desired dissolution profile. The most desirable modified release formulations can be obtained from a delay coating, based on Eudragit® NE30D, which is an inert resin having a molecular weight of 800,000.

The amount of coating applied is selected so as to obtain a predetermined dissolution characteristic of the composition fraction. The weight content of the modified release coating in the individual pellet will be for the fraction providing the prolonged opioid substance action a maximum of 15% by weight on average, such as for example 12% by weight, preferably at most about 10% by weight on average, more preferably in the range of about 6% on average up to 9% by weight, based on the weight of the individual uncoated pellet. The amount of coating applied depends on the predetermined dissolution characteristics of the particular core composition and the desired fraction release profile. For the immediate release opioid fraction, the amount of coating may be at most an average of 8 wt.%, Such as, for example, 6 wt.%, Preferably at most an average of about 5 wt.%, Preferably about 4 wt.%, Such as about 3.5 wt.% , preferably on average about 3% by weight, based on the weight of the individual uncoated pellet. However, the amount of coating applied should also be adjusted so that there are no problems with its tearing.

The coating can in a known manner be mixed with various excipients such as plasticizers, release agents such as colloidal silicon dioxide, inert fillers and pigments.

The sticking of water-dispersible film-forming agents can be prevented by simply incorporating an anti-adhesive agent into the coating. Preferably, finely divided, substantially insoluble, pharmaceutically acceptable, non-wettable powder with anti-adhesive properties is used as the release agent. Examples of anti-adhesive agents are metal stearates such as magnesium stearate or calcium stearate, microcrystalline cellulose or mineral substances such as calcite, substantially water insoluble calcium phosphates, or substantially water insoluble calcium sulfates, colloidal silica, titanium dioxide, barium sulfates, nitrate domed aluminum silicates, hydrated potassium aluminum silicates and talc. Talc is the preferred release agent. The release agent or agents is preferably incorporated into the coating in an amount of about 0.1-70% by weight, in particular about 1-60% by weight and preferably about 8-50% by weight of the inner membrane layer. By choosing a small size of talc particles, a larger surface area is obtained; as a consequence, a greater release effect is possible, enabling the introduction of smaller amounts of a particular release agent.

Individual coated controlled release multi-units may additionally comprise a second coating. Such a coating can be adapted to stabilize coated controlled release multiunits and to prevent unwanted changes in the release profile of each coated unit. Accordingly, a second varnish or coating may contribute to the stability of the release profile of the dosage unit.

It has surprisingly been found that if calcium is added to the second coating, for example in the form of calcium sulfate, improved storage stability is observed.

Thus, multi-units may additionally comprise an outer membrane layer.

In one aspect, the outer film layer comprises a water-based film-forming agent, which prevents adhesion between units at elevated temperature and gives the units a flowable, wherein the water-based film-forming agent is non-adhesive at temperatures above about 50 ° C, such as a temperature between about 60 ° C a about 120 ° C and is selected from diffusive coatings, such as ethyl cellulose or enteric coatings, such as anionic poly (meth) acrylic acid esters, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, polyvinyl acetate phthalate-crotonic acid copolymers or mixtures thereof or water-soluble coating substances such as water-soluble cellulose derivatives, for example, hydroxy cellulose , carboxymethyl cellulose, methyl cellulose, propyl cellulose, hydroxyethyl cellulose, carboxy ethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxymethyl cellulose, carboxymethyl ethyl cellulose, methyl hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

Examples of plasticizers used according to the invention are triacetin, acetylated monoglyceride, rapeseed oil, olive oil, sesame oil, tributyl acetyl citrate, triethyl acetyl citrate, glycerin, sorbitol, diethyl oxalate, diethyl malate, diethyl maleate, diethyl succinate, diethyl malonate dioctyl phthalate, dioctyl sebacate, triethyl citrate, tributyl citrate, glyceryl trimethylate, polyethylene glycol, propylene glycol and mixtures thereof. The plasticizer is normally used in an amount of less than 10% by weight based on the dry weight of the coating composition.

In addition to the active substance in the form of coated pellets, the pharmaceutical composition may additionally contain pharmaceutically acceptable excipients.

In the context of the present invention, the term "pharmaceutically acceptable excipient" means any substance that is inert in the sense that it essentially exerts no therapeutic and / or prophylactic effect alone.

A pharmaceutically acceptable excipient may be added to the active substance to allow a pharmaceutical preparation with acceptable technical properties to be obtained. Although a pharmaceutically acceptable excipient may have some effect on the release of the active substance, the substances used to obtain modified release are not covered by this definition.

Fillers / diluents / fillers such as sucrose, sorbitoc mannitol, lactose (e.g. spray-dried lactose, α-lactose, β-lactose, Tablettose, various types of Pharmatosc®, Microtose® or Fast-Floc®), microcrystalline cellulose ( for example, various Avicel® grades such as Avicel® PH101, Avicel® PH102 or Avicel® PHW5, Ełcema® P100, Emcocel®, Vivacel®, Ming Tai® and Solka-Floc®), L-hydroxypropyl cellulose (low substitution) (e.g. L-HPC-CH31 and L-HpC-LH11), dextrin, maltodextrin (e.g. Lodex®5 and Lodex®10), starches or modified starches (including potato starch, corn starch or rice starch), sodium chloride, sodium phosphate, calcium phosphate (e.g. basic calcium phosphate), calcium sulfate, calcium carbonate. In the pharmaceutical preparations according to the invention particularly suitable

188 919 proved to be microcrystalline lose, L-hydroxypropyl cellulose, dextrins, maltodextrins, starches and modified starches.

Disintegrants such as cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium (i.e. sodium cross-linked carboxymethylcellulose, e.g. Ac-Di-So® '), alginic acid or alginates, insoluble polyvinylpyrrolidone (e.g. Polyvidon® CL, Polyvidon® CL-M, Kollidon® CL, Polyplasdone® XL, Polyplasdone® XL-10), sodium carboxymethyl starch (e.g. Primogc® and Explotab®).

Other suitable pharmaceutically acceptable excipients include dyes, fragrances, surfactants and buffering agents.

The following examples further illustrate the invention.

Short description of the figures

Figure 1 is a diagram of the release profile of coated modified release cores produced according to example 1.

Figure 2 is a diagram of the release profile of coated modified release cores produced according to example 2.

Figure 3 is a diagram of the release profile of coated modified release cores produced according to example 3.

Figure 4 is a diagram of the release profile of coated modified release cores produced according to example 19.

Figure 5 is a diagram of the release profile of coated modified release cores manufactured according to example 22, gray No. 1.

Figure 6 is a diagram of the release profile of coated modified release cores produced according to example 22, gray No. 2.

Figure 7 is a diagram of the release profile of coated modified release cores manufactured according to example 22, gray No. 3.

Figure 8 is a diagram of the release profile of coated modified release cores produced according to example 22, gray No. 4.

Figure 9 is a diagram of the release profile of coated modified release cores made according to example 22, batch No. 5.

Figure 10 is a diagram of the release profile of coated modified release cores produced according to example 23.

Figure 11 is a diagram of the release profile of coated modified release cores produced according to example 24.

Figure 12 is a diagram of the plasma concentration of morphine (morphine sulfate) in arbitrary concentration units after administration of identical total amounts of morphine. The second fraction of both preparations is identical and has essentially slow release. The preparation illustrated with small white squares contains 10% plain morphine sulfate (unmodified). The second formulation, illustrated with filled squares, contains a similar amount of morphine in the form of a modified release multi-unit fraction according to the invention. The diagram was prepared based on the assumption of a single-compartment open model in which the elimination rate constant (Ke) for morphine is 0.5; the absorption rate constant (Ka) for ordinary morphine is 10; the absorption rate constant for multi units with slow modified release of the second fraction is 0.2 and 0.8 for multi units with fast modified release of the first fraction. This model is intended to illustrate the effect of the first fraction containing modified release multiunits as compared to unmodified release.

Figure 13 is a diagram similar to the one in Fig. 12, but in which the ratio between the first and second fraction of each formulation is 2/10. The preparation containing 20% ​​ordinary morphine is illustrated by crosses, and the preparation containing the same amount of the first fraction of modified release multiunits is illustrated by stars. The second fraction of each preparation is identical.

Figure 14 is a diagram similar to the diagram in Fig. 12, but in which the ratio between the first and second fraction of each formulation is 5/10. The preparation containing ordinary morphine is illustrated by stars, and the preparation containing

188 919 the first fraction of modified release multiunits is illustrated by a filled window.

Figure 15 is a diagram of three preparations in which the ratio between the two fractions is 2/10. The curve illustrated with crosses contains normal morphine in the fast fraction, and the curve illustrated with the asterisk includes modified release multi-units having a constant absorption rate of 0.8 as the fast fraction, and the curve illustrated with filled triangles includes the faster fraction of modified release multi-units having a constant absorption rate of 2. The modified release multiunits of the second fraction of all three preparations have an absorption rate constant of 0.2. The delay time for the absorption of this second fraction is three hours, similar to the formulations illustrated in Figures 12, 13 and 14.

Figure 16 is a diagram of the morphine plasma concentration after administration of three different morphine compositions. Further details are described in test 1.

Figure 17 shows in vivo and in vitro dissolution profiles for Repro-Dose® morphine, see test 1.

Figure 18 shows the correlation between iri vivo dissolution and in vitro for Repro-Dose® morphine, see test 1.

Figure 19 is a Levy diagram for Repro-Dose® morphine, see test 1.

Figure 20 shows estimated plasma morphine levels; further details are provided in test 1.

Figure 21 is a diagram of the morphine plasma concentration after one dose of a modified release multi-unit capsule prepared according to example 12, compared to the Repro-Dose® morphine (RDM) and mSd Continus® (MST) preparation, taken without food (fasting) and with food (food). Further details are provided in test 2.

Figure 22 is a diagram corresponding to the diagram in Figure 21, except that the plasma concentrations of 6-glucuronide morphine are shown.

Figure 23 is a diagram corresponding to the diagram in Figure 21, except that the plasma concentrations of 3-glucuronide morphine are shown.

Figure 24 is a diagram of morphine plasma concentrations after administration of two different morphine compositions. Details are given in test 3.

Figure 25 is a diagram of the mean pain intensity; further details are provided in test 3.

Figure 26 shows the result of the treatment preference evaluation; details are given in test 3

Materials and methodology

The following materials were used in the preparations examined during the work on the invention. Where reference is made to the official pharmacopoeia, this applies to the current edition of that pharmacopoeia.

The following abbreviations have been used:

F. Eur .: European Pharmacopoeia

B. R: Brttish Phamiacopoeia

USP: Untted States ΡΙκίΓηκκοροείίΐ

NF: National Formulary

<td>Substance</td><td>Quality</td><td>Manufacturer</td>

<td> 1</td><td> 2</td><td> 3</td>

<td>Morphine sulfate</td><td>BP</td><td>Macfarlan</td>

<td>Natriumalginate LF 200S</td><td>F Eur</td><td>Protan Biopolymer</td>

<td>aspartame</td><td>NF</td><td>Holland Sweetner Company</td>

<td>Maydis Amylum</td><td>F Eur.</td><td>Cerestar</td>

<td>N atria Citras</td><td>F Eur.</td><td>Kirsch</td>

188 919 table continues

<td> 1</td><td> 2</td><td> 3</td>

<td>Natrii Hydrogencarbonas</td><td>F. Eur.</td><td>Solvay</td>

<td>Titanii Dioxidum</td><td>F Eur.</td><td>bayer</td>

<td>Acidum Tartaricum</td><td>F. Eur.</td><td>Vinal</td>

<td>Lemon juice</td><td></td><td>Givaudan Dubendorf</td>

<td>Lemon aroma</td><td></td><td>Givaudan Dubendorf</td>

<td>Polyvidonum K30</td><td>F. Eur</td><td>ISP and BASF</td>

<td>Cellulosum microcrystallinum</td><td>F Eur.</td><td>FMC</td>

<td>Carboxymethylcellulosum natricum</td><td>F Eur.</td><td>Henkel</td>

<td>Lactosum monohydricum</td><td>F Eur.</td><td>Hollandse Melksvirkerfabrik and DMV</td>

<td>Aqua Purificate</td><td>F Eur</td><td>Shin-Etsu</td>

<td>Methylhydroxypropylcellulosum (Pharma Coat 606)</td><td>F. Eur.</td><td>dow</td>

<td>Methylhydroxypropylcellulosum (Methocel E5 Premium)</td><td>F. Eur.</td><td>Akcros Chemicals</td>

<td>Magnesia Stearas</td><td>F. Eur</td><td>Whittaker, Clark &amp; ​​Daniels</td>

<td>talcum</td><td>F. Eur.</td><td>Dow Corning</td>

<td>Simethicone emulsion</td><td>USP</td><td>Rbhm Pharma Gmbh, Darmstadtd, Germany</td>

<td>EudragitNE30D</td><td></td><td>Giullim Chemie</td>

<td>Calcium sulphate</td><td>NF</td><td>Hefti</td>

<td>Polysorbatum 20</td><td>F Eur.</td><td>Grace</td>

<td>Syloid 244</td><td>F Eur</td><td>Meggle</td>

<td>Tablettose</td><td>F. Eur.</td><td>Colorcon</td>

<td>Pre-gelatinised starch</td><td>NF</td><td></td>

Dissolution method I for opioid (morphine sulfate) (morphine units)

<td>The camera</td><td>USP / F Eur. dissolution apparatus + PERKIN ELMER fully automated dissolution system</td>

<td>Fiberglass filter</td><td>Whatman GF / D</td>

<td>Dissolution medium</td><td>900.0 ml 0.1N HCl</td>

<td>Rotation speed</td><td>100 rpm</td>

<td>Stirrer</td><td>vane</td>

<td>Sampling times</td><td>as given in the table</td>

<td>Detection wavelength</td><td>X = 284 nm</td>

<td>Measuring equipment</td><td>UV spectrophotometer, 1 cm cuvette</td>

<td>The temperature of the dissolution medium</td><td>37.0 ° C ± 0.5 ° C</td>

188 919

Preparation of reagents: Medium dissolving 0.1N HCl: 83.0 ml deg. HCl (37%) diluted with purified water to 10.00 1.

Standard stock solution S (2 solutions prepared): 100 mg (= q, mg) of morphine sulfate R was dissolved in 50.00 ml of 0.1 IN HCl.

Control of 2 standards: 3.00 ml S was diluted with 0.1N HCl to 200.00 ml (b).

Blank test: 0.1N HCl (c).

Measurement: At a maximum of about 284 nm, the absorbance difference between the solutions b and c (kj) was measured. F. Eur. vol. 6.19.

Calculations: for each of the kj measurements the response was calculated (with 3 significant digits)

R

<img file="PL188919B1_D0001.tif" />

kl 2

The deviation between R] and R2 should not exceed 2%.

Designation E^1%/ 1 cm.

Stock solutions 1 and 2 were mixed in a 1: 1 ratio. 4.00 ml of this solution was diluted with 0.1N HCl to 200.00 ml. Stock solution and blank (0.1N HCl) were heated to 37 ° C. When both solutions reached 37 ° C, a blank (0.1N HCl) was pumped into the measuring chamber. Pumping was carried out until all possible air bubbles were removed from the chamber.

A background correction procedure was performed and the standard control solution was pumped.

The absorbance of the standard was measured and El% / 1 cm calculated:

1% _ ab_s]x50x10 Icm q_xx4 abs_st= absorbance of the standard used qx = average weight (mg) of morphine sulphate R weighed into two standard solutions

The calculated E1% / 1 cm was entered into the PEDS-PC program. The PEDS program was programmed according to the Perkin-Elmer manual.

Procedure: 900.0 ml 0.1N HCl dissolution medium was poured into each of 7 measuring vessels. They were heated to 37.0 ° C ± 0.5 ° C. The dissolution medium from 7 vessels was pumped into the UV spectrophotometer measuring chambers and a background correction procedure was performed. Six 25 morphine sulfate units and one placebo unit were weighed into 25 ml containers. The placebo unit was used as a blank.

The procedure for manufacturing and moving units

1. Mix the contents of the containers thoroughly.

2. Pour 10.0 ml of tap water into the measuring glass. Pour water into the container and mix until the mixture has a homogeneous appearance. The mixture is ready for use after 1 minute.

3. Mix the mixture immediately before transferring to the USP vessel. Prepared 7 units move to separate vessels. Rinse each container with the dissolution medium from the vessel to transfer the entire mixture to the vessel.

4. Immediately after transferring all units to the vessels, start dissolution.

Dissolution method II for opioid (morphine sulfate) (10 mg, 30 mg and 60 mg morphine capsules).

188 919

<td>The camera</td><td>USP / F.Eur. dissolution apparatus + autosampler (ISCO / Sotax dissolution sampler) or the PERKIN ELMER fully automated dissolution system</td>

<td>Fiberglass filter</td><td>as for method I</td>

<td>Dissolving medium</td><td>as for method I</td>

<td>Rotation speed</td><td>as for method I</td>

<td>Stirrer</td><td>as for method I</td>

<td>Sampling times</td><td>as for method 1</td>

<td>Sampling</td><td>Automatic, approximately 9.00 ml (v), removed liquid not replenished (compensation was carried out by calculation) Fully automated PERKIN-ELMER dissolution system, UV measurements every 10 minutes for 16 hours of the test</td>

<td>Detection wavelength</td><td>as for method I</td>

<td>Measuring equipment</td><td>as for method 1</td>

<td>The temperature of the dissolution medium</td><td>as for method I</td>

Preparation of reagents: Dissolving medium 0.1N HCl: as for method I. Standard stock solution S (2 solutions were prepared): as for method I. Solutions for standard dilution:

mg: 1 empty capsule size 5 dissolved in 900.0 ml 0.1N HCl.

mg: 1 empty capsule size 3 dissolved in 900.0 ml 0.1N HCl.

mg: 1 empty capsule size 1 dissolved in 900.0 ml 0.1N HCl.

These solutions were used to dilute the standard and as blank.

Standard solution:

mg: 5.00 ml S diluted with 0.1N HCl to 50.00 ml. 10.00 ml was diluted with 0.1N HCl to 100.00 ml (b).

mg: 3.00 ml S was diluted with 0.1N HCl to 200.00 ml (b).

mg: 3.00 ml S was diluted with 0.1N HCl to 100.00 ml (b).

Test solutions: Samples were measured undiluted (a).

Measurement: at a maximum of about 284 nm, the absorbance difference between solutions b and c (k) and between solutions a and c (k2) was measured. F. Eur. vol. 6.19.

Measurement: At a maximum of about 284 nm, the absorbance difference between the solutions b and c (kj) was measured. R Eur. vol. 6.19.

Calculations: as in method I.

Manual calculations:

GSR = (Ri + R2)

The released amount of morphine sulfate (y) in mg was calculated by the formula:

mg:

1h:

k₂xnx900xl0 GSRxl00x50x50xl00

3h:

k₂xnx (-&gt; 00-v) x5x10 GSRx 100x50xn0x100 (released mg of moffin sulfate) y₃= z₃+ Y, xv

900 v^, =

188 919

6h:

k₂xnx (900 - 2v) x5x10 GSRx100x50x50x100

V

900 + y₃xv

900-v

9h:

_ k₂xnx (900-3v) x5xl0 ^FROM'~ GSRxl00x50x50xl00 y₉ = z₉ + Y, xv

900 + y₃xv

900 vv

s₆x-900-2xv mg:

lh:

k xnx900x3

GSRx100x50x50x200 (released mg of morphine sulfate)

3h:

k₂xnx (900 - v) x3 GSRx100x50x50x200 y₃ = z₃ + y, x

900

6h:

k₂xnx (900-2v) x3

GSRxl00x50x50x200 vvy_fi = from₆ + yx -—- + y₃x⁶ 6 71 ₉₀₀ 7 3 _9θ0-_ν

9h:

k_?xnx (900-3v) x3 ν vvz₉ =—^and- y₉= Zn + y, x- + y₃x- + y₆x^&gt; GSRx 100x50x50x200 ⁹ ’ ⁷¹ 900 900-v 900-2xv mg:

lh:

Yi = k₂xnx900x3

GSRx 100x50x50x100 (released mg morphine sulfate)

3h:

k₂xnx (900 - v) x3 GSRxl00x50x50xl00 y₃ = z₃+ Y, x

900

6h:

k₂xnx (900 - 2v) x3 GSRx 100x50x50x and 00 y₆ = from₆ + Y, x

900 ©3*

V

900-v

9h:

_ k ₂ xnx (900 - 3 v) x3 ^FROM'~ GSRx100x50x50x100 y₉ = Zn + y, x - + y₃x79 9 7i _90θ 73 ₉₀₀__v + live *

900-2xv n = purity of the morphine sulfate standard as a percentage v = sample taken in ml Results in% = (yx 100) / \ x = given content (10, 30 or 60)

188 919

Procedure: 900.0 ml of 0.1N HCl dissolution medium was poured into each of the desired number of vessels, e.g. 6, and the vessels were heated to 37.0 ° C ± 0.5 ° C. One capsule was transferred to each dish.

Autosampler setting: according to the camera instructions.

Dissolution method using fully automated equipment

Apparatus: USP / F. Eur. dissolution apparatus + PERKIN ELMER dissolution system (PEDS) + PEDS-PC program.

Control of two standards: as for method I.

Measurement: as for method I.

Calculations: as for method I.

Determination E1% 1 cm: as for method I.

Procedure: 900.0 ml 0.1N HCl dissolution medium was poured into each of 7 measuring vessels. They were heated to 37.0 ° C ± 0.5 ° C. The dissolution medium from 7 vessels was pumped into the UV spectrophotometer measuring chambers and a background correction procedure was performed. A capsule was transferred to each of the 6 vessels. A suitable clean capsule was added to the vessel 7 and used as a blank during the measurement.

mg: 1 pure capsule, size 5.

mg: 1 clean capsule, size 3.

mg: 1 pure capsule, size 1.

Dissolution method III for multi-units with modified opioid release (morphine sulfate)

<td>The camera</td><td>As for method II</td>

<td>Fiberglass filter</td><td>As for method I</td>

<td>Dissolving medium</td><td>As for method I</td>

<td>Rotation speed</td><td>As for method I</td>

<td>Stirrer</td><td>As for method I</td>

<td>Sampling times</td><td>Dissolution system according to USP / F Eur + autosampler multi-unit with slow modified release 13.6, 9h Multi-units with fast modified release: 12.1h Mixture of multi-units with slow and fast modified release · 1, 3, 6, 9h</td>

<td>Sampling</td><td>As for method II. Completely automated PERKIN ELMER dissolution system as in method II</td>

<td>Detection wavelength</td><td>As for method I</td>

<td>Measuring equipment</td><td>As for method I</td>

<td>The temperature of the dissolution medium</td><td>As for method 1</td>

Preparation of reagents: as for method I.

Standard stock solution S (2 solutions prepared): as for method I. Standard solution: 3.00 ml. S diluted with 0.1N HCl to 100.00 ml (b).

Test solutions: Measurements of undiluted samples (a) were carried out. Blank test: 0.1 1N HCl (c).

Measurement: as for method I.

Calculations: as in method I.

Manual calculations:

GSR = 12 (R, + R₂)

188 919

The released amount of morphine sulfate (y) in mg was calculated by the formula:

Multi-units with slow modified release of 1h:

k₂xnx900x3.

y, = --- (mg morphine sulfate released)

GSRxl00x50x50xl00

3h:

k_?xnx (900 - v) x3 vz, = --i —-- y, = z, + y, xGSRx 100x50x50x100 '^{3 J 1} 900

6h:

_ k₂xnx (900 -2v) x3 ^v , ^v^Zo ~ GSRxl00x50x50xl00 ^s6 - ^from6 + ^s'^x+ ^s3^x9Q0. _v

9h:

k₂xnx (900-3v) x3 ν vvz₉ = —-- y_g= z_g+ Y | X + y₂x- + y₆x-GSRx 100x50x50x100 ^{79 9 1} 900 900-v 900-2xv

Slow modified multi-units * /₂h:

k₂xnx900xvx3. , . _.

y_/2 =-^from- (mg mg morphine sulphate released) ^71/2 GSRx 100x50x50x100 lh:

k₂xnx (900 - v) xvx3 vz, = -—^and- y, = z, + y_1/2x¹ GSRxl00x50x50xl00 ^{71 1 1/2} 900 n = purity of the morphine sulfate standard in percent v = sample taken in ml

Procedure: 900.0 ml 0.1N HCl dissolution medium was poured into each of 6 vessels and the vessels were heated to 37.0 ° C ± 0.5 ° C. An amount of modified release multi-units (= p, mg) corresponding to 60 mg morphine sulfate was transferred to each vessel.

Autosampler setting: according to the camera instructions.

Dissolution method using fully automated equipment

Apparatus: USP / F. Eur. dissolution apparatus + PERKIN ELMER dissolution system (PEDS) + PEDS-PC program.

Control of two standards: as for method I.

Procedure: 900.0 ml 0.1N HCl dissolution medium was poured into each of 6 measuring vessels. They were heated to 37.0 ° C ± 0.5 ° C. An amount of modified release multi-units (= p, mg) corresponding to 60 mg morphine sulfate was transferred to each vessel. A standard solution of 0.07 mg / ml (60 mg / 900 ml) was added to vessel 7.

Programming the PEDS program according to the PERKIN ELMER manual

IV dissolution method for opioid (morphine sulfate) (40 mg morphine tablets and modified release multi-units for tablets)

188 919

<td>The camera</td><td>As for method I</td>

<td>Fiberglass filter</td><td>As for method I</td>

<td>Dissolution medium</td><td>As for method I</td>

<td>Rotation speed</td><td>As for method 1</td>

<td>Stirrer</td><td>As for method I</td>

<td>Sampling times</td><td>As in the tables</td>

<td>The temperature of the dissolution medium</td><td>As for method I</td>

Preparation of reagents:

Dissolving medium 0.1N HCl: as for method I.

Standard stock solution S (2 solutions prepared): as for method I.

Control of 2 standards: as for method I.

Measurement: as for method I.

Calculations: as for method I.

Measurement 1 cm: as for method I.

Procedure: 900.0 ml 0.1N HCl dissolution medium was introduced into the desired number of vessels. They were then heated to 37 ° C ± 0.5 ° C.

Tablets: One tablet was added to each dish. Modified release units: A quantity of units, corresponding to 40 mg morphine sulfate, was added to each vessel.

Dissolution method V for opioid (morphine sulfate) (10 mg, 20 mg, 30 mg, 50 mg, 60 mg and 100 mg morphine capsules)

<td>The camera</td><td>USP / F dissolution apparatus. Eur + autosampler (ISCO / Sotax)</td>

<td>Fiberglass filter</td><td>As for method I</td>

<td>Dissolution medium</td><td>As for method 1</td>

<td>Rotation speed</td><td>As for method I</td>

<td>Stirrer</td><td>As for method I</td>

<td>Sampling times</td><td>As in the tables</td>

<td>Sampling</td><td>As in method 11</td>

<td>The temperature of the dissolution medium</td><td>As for method 1</td>

Preparation of reagents:

Dissolving medium 0.1N HCl: as for method I Procedure: as for method II

Standard stock solution S (2 solutions prepared): as for method I.

Calibration curve: Each of two standard stock solutions (solution

S) was diluted with the dissolution medium to obtain standard solutions covering three concentration levels.

<td>Level, calibration curve</td><td>Concentration</td>

<td> 1</td><td>approx. 18% of the declared content</td>

<td> 2</td><td>about 60% of the declared content</td>

<td> 3</td><td>about 105% of the declared content</td>

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Measurement: Standard and test solutions were measured by HPLC.

<td>Column</td><td>Superspher RP 18 100, 250 · 4.6 mm.</td>

<td>Detector</td><td>UV absorption detector, X = 287 nm.</td>

<td>Mobile phase</td><td>11.54 g of sodium lauryl sulfate and 15.60 g of NafyPGa · 2H20 were dissolved in 500 ml of HPLC grade H2O, 500 ml of acetonitrile and 5.00 ml of diethylamine and mixed thoroughly. The pH was then adjusted to 3.6 ± 0.05 by means of a phosphoric acid concentration (about 3 ml). Vacuum filtration through Whatman GF / A filter.</td>

<td>Flow</td><td>1, 0 pl / min.</td>

<td>injection</td><td>20 pl for 50, 60 and 100 mg capsules; 100 pl for 10, 20 and 30 mg capsules.</td>

Chromatography time for standard and test solution: approximately 1.75 * tr morphine [minutes] (= approximately 10 minutes).

Note: The sample of the test solution for HPLC assay (= test solution) and solutions for the calibration curve were filtered before analysis through Whatman GF / F filters. Test solutions were not diluted.

Calculation: The six solutions described in the "Calibration Curve" section were analyzed before sample injection and linear regression of concentration responses was performed. The slope (slope and vice versa) and the intersection point (intersection cam) were used for the calculations

The 95% intercept confidence interval must contain the original function.

The amount of morphine sulfate (yj, y3, y6, y9) dissolved as a percentage of the contents of each capsule was calculated using the following equations:

lh:

(AND₂ - intersection_k._rzyuka|,_b) xnx900xl00 nachyleme_krzywkallbxl00xx

3h:

(AND₂ - intersection_krzywkahb) xnx (900- v) xioo _ y nachyleme_krzywkallbxl00xx ^{Υ3 Z3 + y, X}900

6h:

(AND₂ -cut_krzywkal,_b) xnx (900-2v) xl00 nachylente_krzywkallbxl00xx ^{y6 = Z6 + y | X}900 ^{+ Y3X} v

900

9h:

(AND₂ - intersection_kr2ywka,_lb) xnx (900 - 3v) x100 inclination_kl2ywkallbxl00xx y₉ = from₉ + yi^xx7g ⁺ y3^x7xx⁺y6x

900

900 v

900 - 2xv

AND₂ = surface area of ​​the morphine peak in the chromatogram of the test solution n = purity of the morphine sulphate standard in percent v = amount of sample in ml x = stated content in capsule

Example 1

In Example 1, coated cores with modified morphine sulfate release were prepared by forming the cores and coating them with 13.5% (% of core weight).

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Cores were made using an extrusion / spheronization technique. The ingredients are given in Table 1. The ingredients were mixed and wetted in a Diosna high shear mixer, in which the water was applied by means of a nozzle (Delevan CJ type pressure nozzle with a 4.0 mm hole size).

Table 1

<td>Ingredients</td><td>Quantity (kg)</td>

<td>Morphine sulfate</td><td> 8,10</td>

<td>Microcrystalline cellulose</td><td> 7,26</td>

<td>Lactose</td><td> 29,16</td>

<td>Sodium carboxymethyl cellulose</td><td> 0,45</td>

<td>Purified Water</td><td> 12,60</td>

The wetted mass was extruded using a Nica E14O extruder through a 0.6 mm sieve. The extrudate was spheronized in a Fuji-Paudal marimerizer for 4 min. The cores thus produced were dried in trays for approximately 13 h at 40 ° C.

The dried cores were fractionated in a Swecco apparatus equipped with a 0.500 mm lower screen and a higher 0.790 mm screen.

21.9 kg of these cores were coated with an outer coating, middle coating and inner coating in a Glatt WSG 30 fluidized bed apparatus with a spray head 1.8 mm and spray pressure of 3 bar for the inner coating and 3.5 bar for the middle and outer coating. The composition of the coating is shown in Table 2.

Table 2

<td>Ingredients</td><td>Quantity (kg)</td>

<td> 1</td><td> 2</td>

<td></td><td>Internal coating</td>

<td>hydroxypropyl methylcellulose</td><td> 0,163</td>

<td>Magnesium stearate</td><td> 0,034</td>

<td>Talc</td><td> 0,304</td>

<td>Simethicon emulsion</td><td> 0,025</td>

<td>EudragitNE 300</td><td> 10,800</td>

<td>Purified Water</td><td> 13,674</td>

<td>Together</td><td> 25,000</td>

<td></td><td>Middle coating</td>

<td>Calcium sulphate</td><td> 1,817</td>

<td>hydroxypropyl methylcellulose</td><td> 0,230</td>

<td>Simethicon emulsion</td><td> 0,012</td>

<td>Polysorbatum 20</td><td> 0,017</td>

<td>Eudragit NE 30D</td><td> 2,428</td>

<td>Purified Water</td><td> 6,941</td>

188 919 table continues

<td> 1</td><td> 2</td>

<td></td><td>Outer shell</td>

<td>hydroxypropyl methylcellulose</td><td> 0,360</td>

<td>Talc</td><td> 0,360</td>

<td>Purified Water</td><td> 8,280</td>

<td>Together</td><td> 9,000</td>

Middle shell Outer shell

The following amounts of inner, middle and outer coatings were used in the coating process. The amount of dry matter calculated as a percentage of the core mass is also given below.

Internal coating 15.82 kg of the solution above surface (dry mass: 8.5% of the core mass) 4.59 kg of coating solution (dry mass: 4.0% πμ)) '^ ζ6γ ^) 3 , 49 kg of coating solution (dry weight: 1.0% maa) core) During the coating process, the bed temperature was kept in the range from 19.5 to

20.9 ° C by controlling the liquid flow rate. The inlet air temperature was maintained at around 43 ° C. After coating, the coated cores were crosslinked at a bed temperature of about 70 ° C for 30 minutes, after which the coated cores were cooled to a bed temperature below 35 ° C.

The desired dissolution profile (target) and lower and lower limits of dissolution rate are shown below.

<td></td><td>Goal</td><td>Lower boundary</td><td>Upper boundary</td>

<td>1h</td><td> 5,0%</td><td> 0,0%</td><td> 21,0%</td>

<td>3h</td><td> 33,0%</td><td> 11,0%</td><td> 55,0%</td>

<td>6h</td><td> 68,0%</td><td> 52,0%</td><td> 84,0%</td>

<td>9h</td><td> 84,0%</td><td> 73,0%</td><td> -</td>

After coating, the coated cores were sieved through a 1.2 mm sieve. The overlaid material was discarded. The coated cores thus produced had the dissolution rate shown in Table 3 (determined by the dissolution method III described above).

Table 3

<td>1h</td><td> 2,1%</td>

<td>2h</td><td> 9,9%</td>

<td>3h</td><td> 19,9%</td>

<td>4h</td><td> 31,3%</td>

<td>5h</td><td> 42,8%</td>

<td>6h</td><td> 53,4%</td>

<td>7h</td><td> 62,6%</td>

<td>8h</td><td> 70,3%</td>

<td>9h</td><td> 76,2%</td>

<td>Loh</td><td> 80,7%</td>

<td>11H</td><td> 86,8%</td>

<td>12h</td><td> 92,5%</td>

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Example 2

In Example 2, coated cores with modified morphine sulfate release were prepared by forming cores and coating them with 11.5% (% by weight of the core).

Cores were manufactured and coated as described in Example 1, with the difference that in Example 2 30 kg of cores were coated with the inner, middle and outer coating as follows:

Inner coating 13.01 kg of coating solution (dry weight: 6.5% core weight

4.94 kg of coating solution (dry weight: 4.0% core weight 3.75 kg of coating solution (dry weight: 1 /)% core weight During the coating process, the bed temperature was maintained in the range from 19.0 to

20.8 ° C by controlling the liquid flow rate.

The coated cores thus produced had the dissolution rate shown in Table 4 (determined by the dissolution method III described above).

Middle shell Outer shell

Table 4

<td>1h</td><td> 18,2%</td>

<td>2h</td><td> 37,4%</td>

<td>3h</td><td> 53,3%</td>

<td>4h</td><td> 65,8%</td>

<td>5h</td><td> 75,3%</td>

<td>6h</td><td> 82,1%</td>

<td>7h</td><td> 86,8%</td>

<td>8h</td><td> 90,1%</td>

<td>9h</td><td> 92,4%</td>

<td>Loh</td><td> 94,0%</td>

<td>12h</td><td> 95,9%</td>

<td>16h</td><td> 97,5%</td>

Example 3

In Example 3, coated cores with modified morphine sulfate release were prepared by forming cores and coating them with 8% (% of core weight).

Cores were made and coated as described in Example 1, with the difference that in Example 3, 30 kg of cores were coated with the inner, middle and outer coating as follows:

Inner coating 6.00 kg of coating solution (dry weight: 3.0% of core weight)

Middle coating 4.94 kg of coating solution (dry weight: 4.0% of core weight)

Outer shell 3.75 kg of coating solution (dry weight: 1.0% of core weight)

The desired dissolution profile (target) and lower and lower dissolution rate limits are shown below.

Goal Lower limit Upper limit

0.5h 67.0% 47.0% 95.0% 1.00.0 91.0% 71.0% During the coating process, the bed temperature was kept in the range from 19.3 to 20.5 ° C by controlling the liquid flow rate.

The coated cores thus produced had the dissolution rate shown in Table 5 (determined by the dissolution method III described above).

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Table 5

<td>10 min</td><td> 49,0%</td>

<td>20 min</td><td> 77,6%</td>

<td>30 minutes</td><td> 89,5%</td>

<td>40 min</td><td> 94,6%</td>

<td>50 min</td><td> 97,2%</td>

<td>60 min</td><td> 98,4%</td>

Example 4

In Example 4, coated cores with modified morphine sulfate release were prepared by forming the cores and coating them with 12.5% ​​(% of core weight).

The cores were made and coated as described in Example 1, except that in Example 4 the amount of liquid added during wetting in the Diosna mixer was 12.83 kg and 30 kg of the cores were coated with an inner coating, and an outer coating below:

Internal coating 15.01 kg of coating solution (dry weight: 7.5% of the core weight)

Middle coating 4.94 kg of coating solution (dry weight: 4.0% of core weight)

3.7 outer coating (5 kg coating solution (dry weight: 1.0% of core weight)

During the coating process, the bed temperature was maintained in the range of 18.0 to 19.6 ° C by controlling the liquid flow rate.

The coated cores thus produced had the dissolution rate shown in Table 6 (determined by the dissolution method III described above).

Table 6

<td>1h</td><td> 10,3%</td>

<td>2h</td><td> 24,9%</td>

<td>3h</td><td> 40,2%</td>

<td>4h</td><td> 54,4%</td>

<td>5h</td><td> 66,7%</td>

<td>6h</td><td> 76,1%</td>

<td>7h</td><td> 83,1%</td>

<td>8h</td><td> 88,1%</td>

<td>9h</td><td> 91,6%</td>

<td>Loh</td><td> 94,1%</td>

<td>12h</td><td> 97,3%</td>

<td>16h</td><td> 100,1%</td>

Example 5

In Example 5, coated cores with modified morphine sulfate release were prepared by forming the cores and coating them with 13.5% (% by weight of the core).

Cores were made and coated as described in Example 4, with the difference that in Example 5 30 kg of cores were coated with an inner, middle and outer coating as follows:

Internal coating 17.01 kg coating solution (dry weight: 8, (5% of core weight)

Middle coating 4.94 kg of coating solution (dry weight: 4.0% core weight)

Outer shell 3.75 kg of coating solution (dry weight: 1.0% core weight)

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During the coating process, the bed temperature was maintained in the range of 18.3 to 19.8 ° C by controlling the liquid flow rate.

The coated cores thus produced had the dissolution rate shown in Table 7 (determined by the dissolution method III described above).

Table 7

<td>1h</td><td> 3,4%</td>

<td>2h</td><td> 10,1%</td>

<td>3h</td><td> 19,8%</td>

<td>4h</td><td> 31,3%</td>

<td>5h</td><td> 43,5%</td>

<td>6h</td><td> 54,9%</td>

<td>7h</td><td> 64,9%</td>

<td>8h</td><td> 72,9%</td>

<td>9h</td><td> 79,1%</td>

<td>10h</td><td> 83,7%</td>

<td>12h</td><td> 90,0%</td>

<td>16h</td><td> 95,8%</td>

Example 6

In Example 6, coated cores with modified morphine sulfate release were prepared by forming cores and coating them with 8.0% (% by weight of the core).

Cores were prepared and coated as described in Example 4, but with the desired dissolution profile as described in Example 3. In addition, with the difference that in Example 6, 30 kg of cores were coated with an inner, middle and outer coating as follows: 0 kg coating solution (suaha weight a: 1.0s / core weight)

Middle coating 4.94 kg coating solution (dry weight: 4.0% with core weight)

Outer shell 3.75 kg solution after '^ vll ^ l ^ ίyίo ^ (tgtt (dry weight: 1.0% of core weight)

During the coating process, the bed temperature was maintained in the range of 18.2 to 19.8 ° C by controlling the liquid flow rate.

The coated cores thus produced had the dissolution rate shown in Table 8 (determined by the dissolution method III described above).

Table 8

<td>10 min</td><td> 51,0%</td>

<td>20 min</td><td> 79,1%</td>

<td>30 minutes</td><td> 90,5%</td>

<td>40 min</td><td> 95,5%</td>

<td>50 min</td><td>98.0% of</td>

<td>60 min</td><td> 99,2%</td>

Example 7

In Example 7, coated cores with modified morphine sulfate release were prepared by forming cores and coating them with 13.0% (% by weight of the core).

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Cores were made and coated as described in example 1, with the difference that in example 7 the amount of liquid added during wetting in the Diosna mixer was

12.38 kg and 30 kg of cores were coated with the inner, middle and outer coating as below:

Internal coating 115.01 kg of coating solution (dry weight: 8.0% of core weight)

Middle coating 4.94 kg of coating solution (dry weight: 4.0% of core weight)

Outer shell 3.75 kg of coating solution (dry weight: 1.0% of core weight)

During the coating process, the bed temperature was kept in the range of 20.5 to 22.5 ° C by controlling the liquid flow rate.

The coated cores thus produced had the dissolution rate shown in Table 9 (determined by the dissolution method described above).

Table 9

<td>1h</td><td> 4,3%</td>

<td>2h</td><td> 12,3%</td>

<td>3h</td><td> 24,3%</td>

<td>4h</td><td> 38,6%</td>

<td>5h</td><td> 52,6%</td>

<td>6h</td><td> 64,4%</td>

<td>7h</td><td> 73,6%</td>

<td>8h</td><td> 80,5%</td>

<td>9h</td><td> 85,4%</td>

<td>Loh</td><td> 88,9%</td>

<td>12h</td><td> 93,4%</td>

<td>16h</td><td> 97,4%</td>

Example 8

In Example 8, coated cores with modified morphine sulfate release were prepared by forming cores and coating them with 8.0% (% by weight of the core).

Cores were prepared and coated as described in example 7, but with the desired dissolution profile as described in example 3 and with the difference that in example 8 30 kg of cores were coated with an inner, middle and outer coating as follows:

Internal coating 6.0 kg of coating solution (dry weight: 3.0% of core weight)

Middle coating 4.94 kg of coating solution (dry weight: 4.0% of core weight)

Outer shell 3, T5 kg of coating solution (dry weight: 1 /)% of core weight) and during the tamperuture coating process, the tyrosis was held in the range from 20.0 to 22.2 ° C by controlling the liquid flow rate.

The coated cores thus produced had the dissolution rate shown in Table 10 (determined by the dissolution method III described above).

Table 10

<td>10 min</td><td> 41,1%</td>

<td>20 min</td><td> 70,7%</td>

<td>30 minutes</td><td> 84,9%</td>

<td>40 min</td><td> 92,2%</td>

<td>50 min</td><td> 96,0%</td>

<td>60 min</td><td> 98,1%</td>

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Example 9

In Example 9, coated cores with modified morphine sulfate release were prepared by forming cores and coating them with 12.2% (% of core weight).

Cores were made and coated as described in example 7, with the difference that in example 9 30 kg of cores were coated with the inner, middle and outer coating as follows:

Internal coating^ęPowija wed wed^dknew outer shell

14.41 rotevor / aevteiin leagues to dry (dry weight: 7,: 2% of core weight)

4.94 kg of solution / coatings (dry weight: 4.0% of core weight)

3.75 kg of solution / solution with salt (dry weight: 1.0% of core weight) and during the coating process the bed temperature was kept in the range from 20.0 to 22.2 ° C by controlling the liquid flow rate.

The coated cores thus produced had the dissolution rate shown in Table 11 (determined by the dissolution method III described above).

Table 11

<td>1h</td><td> 12,2%</td>

<td>2h</td><td> 28,7%</td>

<td>3h</td><td> 44,6%</td>

<td>4h</td><td> 59,1%</td>

<td>5h</td><td> 70,5%</td>

<td>6h</td><td> 78,6%</td>

<td>7h</td><td> 84,2%</td>

<td>8h</td><td> 88,1%</td>

<td>9h</td><td> 90,5%</td>

<td>Loh</td><td> 92,3%</td>

<td>12h</td><td> 94,7%</td>

<td>16h</td><td> 96,4%</td>

Example 10

In Example 10, coated cores with modified morphine sulfate release were prepared by forming the cores and coating them with 13.5% (% of core weight).

Cores were made using an extrusion / spheronization technique. The ingredients are given in Table 12. The ingredients were mixed and wetted in a Diosna high shear mixer, in which water was applied by means of a nozzle (Delfvan CJ type pressure nozzle with 2.5 mm hole size).

Table 12

<td>Ingredients</td><td>Quantity (kg)</td>

<td>Morphine sulfate</td><td> 7,20</td>

<td>Microcrystalline cellulose</td><td> 6,48</td>

<td>Lactose</td><td> 25,92</td>

<td>K. sodium carboxymethyl cellulose</td><td> 0,40</td>

<td>Purified Water</td><td> 10,60</td>

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The wetted mass was extruded using a Nica EMO extruder through a screen size

0.6 mm. The extrudate was spheronized in a Fuji-Paudal marimerizer for 3.5 min. The cores thus produced were dried in trays for approximately 7 h at 40 ° C.

The dried cores were fractionated in a Sweco apparatus equipped with a lower screen

0.500 mm and a higher 0.790 mm screen.

The above procedure was repeated 4 times, obtaining a total capacity of 147 kg of cores.

28.0 kg of these cores were coated with an outer shell, middle shell and inner shell in a Glatt WSG 30 fluidized bed apparatus with a spray head 1.8 mm and spray pressure of 3 bar for the inner shell and 3.5 bar for the middle and outer shell. The composition of the coating is shown in Table 13.

Table 13

<td>Ingredients</td><td>Quantity (kg)</td>

<td></td><td>Internal coating</td>

<td>Hydrąksykrokyląmetylącoluląpa</td><td> 0,104</td>

<td>Magnesium stearate</td><td> 0,022</td>

<td>Talc</td><td> 0,194</td>

<td>Simethicon emulsion</td><td> 0,016</td>

<td>Eudragit NE 30D</td><td> 6,912</td>

<td>Purified Water</td><td> 8,752</td>

<td>Together</td><td> 16,000</td>

<td></td><td>Middle coating</td>

<td>Calcium sulphate</td><td> 0,790</td>

<td>Hydrąksykrokyląmotylocoluląza</td><td> 0,100</td>

<td>Simethicon emulsion</td><td> 0,005</td>

<td>Polysorbatum 20</td><td> 0,0075</td>

<td>Eudragit NE 30D</td><td> 1,055</td>

<td>Purified Water</td><td> 3,0425</td>

<td>Together</td><td> 5,000</td>

<td></td><td>Outer shell</td>

<td>Hydrąksykrącyląmetylącoluląza</td><td> 0,160</td>

<td>Talc</td><td> 0,160</td>

<td>Purified Water</td><td> 3,680</td>

<td>Together</td><td> 4,000</td>

The following amounts of inner, middle and outer coatings were used in the coating process.

Internal coating

Middle coating

Outer shell

15.88 kg coating solution / suspension (dry weight: 8.5% of core weight)

4.61 kg coating solution / suspension (dry weight: 4.0% of core weight)

3.50 kg solution / slurry for coating (dry weight: 1.0% of core weight)

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During the coating process, the bed temperature was maintained in the range of 18.0 to 20.5 ° C by controlling the liquid flow rate. The inlet air temperature was maintained at about 30 ° C. After coating, the coated cores were crosslinked at a bed temperature of about 70 ° C for 30 minutes, after which the coated cores were cooled to a bed temperature below 35 ° C.

After coating, the coated cores were sieved through a 1.00 mm sieve. The overlaid material was discarded.

The coated cores thus produced had the dissolution rate shown in Table 14 (determined by the dissolution method III described above).

Table 14

<td>1h</td><td> 5,4%</td>

<td>2h</td><td> 15,6%</td>

<td>3h</td><td> 29,1%</td>

<td>4h</td><td> 43,6%</td>

<td>5h</td><td> 57,4%</td>

<td>6h</td><td> 68,6%</td>

<td>7h</td><td> 77,2%</td>

<td>8h</td><td> 83,6%</td>

<td>9h</td><td> 88,1%</td>

<td>Loh</td><td> 91,3%</td>

<td>12h</td><td> 95,4%</td>

<td>16h</td><td> 99,0%</td>

Example 11

In Example 11, coated cores with modified morphine sulfate release were prepared by coating the cores with 8.0% (weight% of the core).

Cores were prepared as described in Example 10. The cores were coated with the inner, middle and outer coating as follows:

Internal coating

Middle coating

Outer shell

5.6 kg coating solution / suspension (dry weight: 3.0% of core weight)

4.61 kg coating solution / suspension (dry weight: 4.0% of core weight)

3.50 kg solution of Sausage for softening (dry matter: 1.0% of core weight)

During the coating process, the bed temperature was kept in the range of 18.5 to 22.0 ° C by controlling the liquid flow rate.

The coated cores thus produced had the dissolution rate shown in Table 15 (determined by the dissolution method III described above).

Table 10

<td>10 min</td><td> 38,5%</td>

<td>20 min</td><td> 70,2%</td>

<td>30 minutes</td><td> 86,6%</td>

<td>40 min</td><td> 94,0%</td>

<td>50 min</td><td> 97,8%</td>

<td>60 min</td><td> 99,6%</td>

188 919

Example 12

In Example 12, the coated cores of Example 10 and Example 11 were mixed for minutes in a tumble mixer.

The mixing ratio was as follows:

Example 10: 20.009 kg

Example 11: 4.73 kg

These proportions were calculated assuming that 80.0% of the morphine sulfate in the mixture should be in the form of coated cores prepared according to example 10, and 20.0% of the morphine sulfate in the mixture should be in the form of coated cores prepared according to example 11.

The core mixture was mixed in a tumble mixer for 5 minutes with 0.186 kg of talc.

The thus-prepared mixture of coated cores had the dissolution rate shown in Table 16 (determined by the dissolution method III described above).

Table 16

<td>1h</td><td> 24,0%</td>

<td>2h</td><td> 31,8%</td>

<td>3h</td><td> 41,7%</td>

<td>4h</td><td> 52,7%</td>

<td>5h</td><td> 63,5%</td>

<td>6h</td><td> 73,1%</td>

<td>7h</td><td> 80,1%</td>

<td>8h</td><td> 85,6%</td>

<td>9h</td><td> 89,8%</td>

<td>10h</td><td> 92,8%</td>

<td>12h</td><td> 96,8%</td>

<td>16h</td><td> 100,5%</td>

The mixture of coated cores was filled into capsules using a Zanasi AZ 40 capsule filling machine. The characteristics of the capsules are given in Table 17 (determined by the dissolution method II, described below).

Table 17

<td>Capsule size</td><td> 5</td><td> 3</td><td> 1</td>

<td>Number of coated cores (mg)</td><td> 62,5</td><td> 187,4</td><td> 374,8</td>

<td>Morphine Sulfate Dose (mg)</td><td> 10</td><td> 30</td><td> 60</td>

<td>Dissolution after 1h (%)</td><td> 23,1</td><td> 22,1</td><td> 22,9</td>

<td>Dissolution after 3h (%)</td><td> 41,3</td><td> 40,0</td><td> 40,8</td>

<td>Dissolution after 6h (%)</td><td> 72,9</td><td> 71,8</td><td> 72,4</td>

<td>Dissolution after 9h (%)</td><td> 91,3</td><td> 88,9</td><td> 89,8</td>

Example 13

In Example 13, coated cores with modified morphine sulfate release were prepared by forming cores and coating them with 12.5% ​​(% by weight of the core).

188 919

Cores were prepared and coated as described in Example 10, with the difference that in Example 13 the cores were coated with the inner, middle and outer coating as follows:

Internal coating ^Pthat^Labout^kand ^śro^dkHalf of

Exterior coating

14-, 0 kg coating solution / suspension (dry weight: 7.5% of core weight)

4-, 61 kg coating solutions / suspensions (dry weight: 4.0% of core weight)

3.50 kg Γοζί \ νοπ.ι / ζίηνίΰ8ίην to a cracking coating (dry mass: 1.0% of core weight) and during the coating process the bed temperature was kept in the range from 18.0 to 22.0 ° C by controlling the flow rate of the liquid.

The coated cores thus produced had the dissolution rate shown in Table 18 (determined by the dissolution method III described above).

Table 18

<td>1h</td><td> 10,5%</td>

<td>2h</td><td> 26,5%</td>

<td>3h</td><td> 42,0%</td>

<td>4h</td><td> 55,9%</td>

<td>5h</td><td> 67,5%</td>

<td>6h</td><td> 76,8%</td>

<td>7h</td><td> 83,7%</td>

<td>8h</td><td> 88,4%</td>

<td>9h</td><td> 91,8%</td>

<td>10h</td><td> 94,5%</td>

<td>12h</td><td> 97,4%</td>

<td>16h</td><td> 99,9%</td>

Internal coating

Middle coating

Outer shell

Example 14

In Example 14, coated cores with modified morphine sulfate release were prepared by forming cores and coating them with 14.5% (% by weight of the core).

Cores were prepared and coated as described in Example 10, with the difference that the cores were coated with the inner, middle and outer coating as follows:

17.75 kg solution / suspension for coating (dry matter: 9.5% of core weight)

4.61 kg of melon / zaeviksin rio eyelid (dry matter: 4.0% of core weight)

3.50 kg of solution, suspended in a coated coating (Dry mass: 1.0% by weight of l ^ c ^^^ n ^^) and the slurry process iαmpore (alura using a solid from 18, with 22.2 ° C by controlling the liquid flow rate.

The coated cores thus produced had the dissolution rate shown in Table 19 (determined by the dissolution method III described above).

188 919

Table 19

<td>1h</td><td> 3,3%</td>

<td>2h</td><td> 9,4%</td>

<td>3h</td><td> 18,3%</td>

<td>4h</td><td> 30,4%</td>

<td>5h</td><td> 43,7%</td>

<td>6h</td><td> 56,8%</td>

<td>7h</td><td> 67,1%</td>

<td>8h</td><td> 75,4%</td>

<td>9h</td><td> 81,7%</td>

<td>Loh</td><td> 86,6%</td>

<td>12h</td><td> 92,6%</td>

<td>16h</td><td> 98,0%</td>

Example 15

In Example 15, modified-release morphine sulfate sachets were prepared by forming cores and then coating with 15.0% (% of core weight).

Cores were made by extrusion / spheronization. The ingredients are listed in Table 20. The ingredients were mixed and wetted in a Fielder high shear mixer.

Table 20

<td>Ingredients</td><td>Quantity (kg)</td>

<td>Morphine sulfate</td><td> 0,900</td>

<td>Microcrystalline cellulose</td><td> 1,200</td>

<td>Corn starch</td><td> 1,800</td>

<td>Lactose</td><td> 1,980</td>

<td>polyvidone</td><td> 0,120</td>

<td>Purified Water</td><td> 2,550</td>

The wetted mass was extruded using a Nica EMO extruder through a 0.6 mm sieve. The extrudate was spheronized in a Fuji-Paudal marimerizer for 1.75 min. The cores thus produced were dried in trays for approximately 5 h at 40 ° C.

The dried cores were fractionated in a Retsch apparatus equipped with a lower 0.500 mm sieve and a higher 0.800 mm sieve.

100 g of these cores were coated with an outer coating, a middle coating and an inner coating in a laboratory fluidized bed apparatus with a spray head of 0.7 mm and a spray pressure of 0.6 bar. The composition of the coating is shown in Table 21.

188 919

Table 21

<td>Ingredients</td><td>Quantity (kg)</td>

<td></td><td>Internal coating</td>

<td>Hydroksypropylomatylacaloloza</td><td> 6,50</td>

<td>Magnesium stearate</td><td> 1,35</td>

<td>Talc</td><td> 12,15</td>

<td>Sime ^ icm emulsion</td><td> 1,00</td>

<td>Eudragit NE 30D</td><td> 432,00</td>

<td>Purified Water</td><td> 547</td>

<td>Together</td><td> 1000,00</td>

<td></td><td>Middle coating</td>

<td>Sulphate increased</td><td> 79,00</td>

<td>Hydroksyprapylamatylacaluloza</td><td> 10,00</td>

<td>Sime ^ icm emulsion</td><td> 0,50</td>

<td>Palysorbatom 20</td><td> 0,75</td>

<td>Eudragit NE 30D</td><td> 105,50</td>

<td>Purified Water</td><td> 304,25</td>

<td>Together</td><td> 500,00</td>

<td></td><td>Outer shell</td>

<td>Hydraksyprakylametylacalolaoa</td><td> 10,00</td>

<td>Talc</td><td> 10,00</td>

<td>Purified Water</td><td> 230,00</td>

<td>Together</td><td> 250,00</td>

Internal coating

Middle coating

Outer shell

The following amounts of inner and middle coatings were used in the coating process

66.70 kg solution ^ coating coats (dry weight: 10, Z^θ^ masyrdzeninj

15.50 kg coating solution / suspension (dry weight: 4.0% of core weight)

12.50 kg IΌztworι2'zawtseiao w powiejcznym czgo (dry matter: 1 ^ ha of core weight am

During the coating process, the inlet air temperature was kept at around 40 ° C and the outlet air temperature at around 30 ° C. After coating, the coated cores were crosslinked at a bed temperature of about 70 ° C for 30 minutes, after which the coated cores were cooled to a bed temperature below 35 ° C.

After coating, the coated cores were sieved through a 1.0 mm sieve. The overlaid material was discarded.

45.0 g of the prepared core and and 35 g of the composition pozedsjawίonce in abeela 22 were poured into sachets, giving to each sachet 230 mg of the coated core and 171 mg of the mixture shown in Table 22.

188 919

Table 22

<td>Sodium Citrate</td><td>41.00 mg</td>

<td>Sodium bicarbonate</td><td>77.80 mg</td>

<td>Titanium dioxide</td><td>51.10 mg</td>

<td>Tartaric acid</td><td>45.00 mg</td>

<td>Lemon juice</td><td>4.10 mg</td>

<td>Lemon aroma</td><td>4.10 mg</td>

<td>aspartame</td><td>4.10 mg</td>

<td>Sodium alginate LF 200S</td><td>122.80 mg</td>

Sodium citrate, sodium bicarbonate and titanium dioxide were ground in a Fritzh laboratory mill equipped with a 0.2 mm sieve. Tartaric acid was also ground in a Fritzh apparatus.

The mixture of coated core and powder from the sachets had the dissolution rate shown in Table 23 (determined by the dissolution method I described above).

Table 23

<td>1h</td><td> 5,4%</td>

<td>2h</td><td> 17,5%</td>

<td>3h</td><td> 32,8%</td>

<td>4h</td><td> 47,1%</td>

<td>5h</td><td> 58,8%</td>

<td>6h</td><td> 68,3%</td>

<td>7h</td><td> 75,1%</td>

<td>8h</td><td> 80,7%</td>

<td>9h</td><td> 84,2%</td>

<td>12h</td><td> 91,1%</td>

<td>16h</td><td> 95,5%</td>

Internal coating

Middle coating

Outer shell

Example 16

In Example 16, modified-release morphine sulfate sachets were prepared by forming cores and then coating them with 11% (% of core weight).

The sachets were made as described in Example 15, except that the cores were coated with the following amounts of inner, middle and outer coatings.

40.0 kg coating solution / suspension (dry weight: 6.0% of core weight)

16.5 kg coating solution / suspension (dry weight: 4.0% of core weight)

12.5 kg coating solution / suspension (dry weight: 1.0% of core weight)

The mixture of coated cores and powder from the sachets had the dissolution results shown in Table 24 (determined using the dissolution method I described above).

188 919

Table 24

<td>0.5h</td><td> 19,6%</td>

<td>1,0h</td><td> 47,2%</td>

<td>1.5 hours</td><td> 66,4%</td>

<td>3,0h</td><td> 91,5%</td>

<td>6,0h</td><td> 101,1%</td>

Example 17

In Example 17, 4 gray modified-release morphine cores were prepared by forming the cores and then coating with 7.0% or 9.0%, or 11.0%, or 13.0% (% of core weight).

Cores were made by extrusion / spheronipation. The ingredients are listed in Table 25. The ingredients were mixed and wetted in a Kenwood laboratory mixer.

Table 25

<td>Ingredients</td><td>Quantity (g)</td>

<td>Morphine sulfate</td><td> 75,00</td>

<td>Microcrystalline cellulose</td><td> 85,00</td>

<td>Lactose</td><td> 340,00</td>

<td>Purified Water</td><td> 180,00</td>

The wetted mass was extruded using a Nica EMO extruder through a 0.6 mm sieve. Spheroid extrudate in a laboratory device for 2 min. The cores thus produced were dried in a laboratory fluid bed drier for about 8 minutes at 40 ° C.

The dried cores were fractionated in a Retsch apparatus equipped with a 0.500 mm lower screen and a 0.800 mm higher screen.

100 g of these cores were coated with an outer coating and an inner coating in a laboratory fluidized bed apparatus with spray head 0.7 mm and spray pressure 0.6 bar. The composition of the coating is shown in Table 26.

Table 26

<td>Ingredients</td><td>Quantity (kg)</td>

<td> 1</td><td> 2</td>

<td></td><td>Internal coating</td>

<td>Hydrąksyprąkylomotyloceluloza</td><td> 1,30</td>

<td>Magnesium stearate</td><td> 0,27</td>

<td>Talc</td><td> 2,43</td>

<td>Simethicon emulsion</td><td> 0,20</td>

<td>Eudragit NE 30D</td><td> 86,40</td>

<td>Purified Water</td><td> 109,40</td>

<td>Together</td><td> 200,00</td>

188 919

<td> 1</td><td> 2</td>

<td></td><td>Outer shell</td>

<td>hydroxypropyl methylcellulose</td><td> 4,00</td>

<td>Talc</td><td> 4,00</td>

<td>Purified Water</td><td> 92,00</td>

The following amounts of internal and external coatings were used in the coating process.

AND

Internal coating

Outer shell II

Internal coating

Outer shell

III

Internal coating

Outer shell

IV

39.84 kg coating solution / suspension (dry weight: 6.0% of core weight)

12.50 kg coating solution / suspension (dry weight: 1.0% of core weight)

53.12 kg coating solution / suspension (dry weight: 8.0% of core weight)

12.5 kg coating solution / suspension (dry weight: 1.0% of core weight)

66.40 kg coating solution / suspension (dry weight: 10.0% of core weight)

12.5 kg coating solution / suspension (dry weight: 1.0% of core weight)

Inner shell Outer shell

79.70 kg coating solution / suspension (dry weight: 12.0% of core weight)

12.50 kg coating solution / suspension (dry weight: 1.0% of core weight)

During the coating process, the inlet air temperature was maintained at about 40 ° C and the outlet air temperature about 33 ° C. After coating, the coated cores were crosslinked at a bed temperature of about 70 ° C for 30 minutes, after which the coated cores were cooled to a bed temperature below 35 ° C.

After coating, the coated cores were sieved through a 1.0 mm sieve. The overlaid material was discarded.

The coated cores thus produced had the dissolution rate shown in Table 27 (determined by the dissolution method III described above).

Table 27

<td></td><td> 1 (%)</td><td>II (%)</td><td>III (%)</td><td>IV (%)</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>

<td>lh</td><td> 15,4%</td><td> 8,9%</td><td> 7,4%</td><td> 2,7%</td>

<td>2h</td><td> 29,4%</td><td> 15,9%</td><td> 11,9%</td><td> 4,8%</td>

<td>3h</td><td> 43,1%»</td><td> 23,7%</td><td> 15,6%</td><td> 7,1%</td>

<td>4h</td><td> 55,9%.</td><td> 33,9%</td><td> 21,6%</td><td> 10,8%</td>

<td>6h</td><td> 75,1%</td><td> 55,6%</td><td> 41,7%</td><td> 26,9%.</td>

<td>9h</td><td> 88,7%.</td><td> 77,2%</td><td> 67,7%&gt;</td><td> 56,2%</td>

188 919 table continues

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>

<td>Loh</td><td> 90,9%</td><td> 81,5%</td><td> 73,6%</td><td> 63,4%</td>

<td>lih</td><td> 92,3%</td><td> 84,5%</td><td> 77,8%</td><td> 69,2%</td>

<td>12h</td><td> 93,8%</td><td> 87,5%</td><td> 81,9%</td><td> 74,0%</td>

<td>16h</td><td> 96,2%</td><td> 92,8%</td><td> 90,0%</td><td> 85,3%</td>

Example 18

In Example 18, coated cores with modified morphine sulfate release were prepared by forming cores and coating them with 13.0% (% by weight of the core). The cores thus produced were pressed into tablets.

Cores were made by pumping / spheronization. The ingredients are listed in Table 28. The ingredients were mixed and wetted in a Kenwood Major laboratory mixer.

Table 28

<td>Ingredients</td><td>Quantity (g)</td>

<td>Morphine sulfate</td><td> 37,50</td>

<td>Microcrystalline cellulose</td><td> 42,50</td>

<td>Lactose</td><td> 170,00</td>

<td>Purified Water</td><td> 90,00</td>

^Pthat^Linner eye^ęExternal

The wetted mass was extruded using a Nica E14O extruder through a 0.6 mm sieve. The extrudate was spheronized in a laboratory device for 2 min. The cores thus produced were dried in a laboratory fluid bed drier for about 10 minutes at 40 ° C.

The dried cores were fractionated in a Retsch apparatus equipped with a 0.500 mm lower screen and a higher 0.800 mm screen.

100 g of these cores were coated as described in example 17, using the following amounts of outer coating and inner coating.

79.70 kg coating solution / suspension (dry weight: 12.0% of core weight)

Outer shell R⁵,° ^kS ^d° r (dry matter: 1.0% of core weight)

These coated cores were mixed in a cubic mixer with two batches of approximately 100 g of coated cores prepared as described in Example 17 (using 12.0% + 1.0% of dry matter), resulting in a total batch of about 300 g of coated cores.

These coated cores were used for dry granulation. The composition of this granulate is given in Table 29.

The coated cores thus produced had the dissolution rate shown in Table 27 (determined by the dissolution method III described above).

Table 29

<td>Ingredients</td><td>Quantity (g)</td>

<td> 1</td><td> 2</td>

<td>Morphine sulfate, coated cores</td><td> 67,50</td>

<td>Starch 1500</td><td> 6,03</td>

188 919 table continues

<td> 1</td><td> 2</td>

<td>Microcrystalline cellulose</td><td> 12,06</td>

<td>Tablettose</td><td> 1,53</td>

<td>Syloid</td><td> 1,08</td>

<td>Magnesium stearate</td><td> 0,18</td>

<td>Talc</td><td> 1,62</td>

Mixing was carried out in a cubic mixer. Dry granulation was repeated to obtain a total of 180 g of granulate.

Tablets were made from this granulate using a Fette exacta compression device. The compression force used was either 17 kN (denoted 1) or about 9 kN (denoted 2) and the weight of the tablets approximately 400 mg.

The tablets thus prepared had the solubility shown in Table 30 (determined by the IV dissolution method described above).

Release data for the corresponding coated cores are shown in Table 31 (determined by the IV dissolution method described above).

Table 30

<td></td><td> (1)(%)</td><td> (2) (%)</td>

<td>1h</td><td> 35,2%</td><td> 32,1%</td>

<td>3h</td><td> 60,9%</td><td> 57,1%</td>

<td>6h</td><td> 77,6%</td><td> 75,4%</td>

<td>9h</td><td> 87,2%</td><td> 87,3%</td>

<td>12h</td><td> 94,0%</td><td> 94, 4%</td>

<td>15h</td><td> -</td><td> 100,4%</td>

<td>16h</td><td> 97,2%</td><td> -</td>

Table 31

<td>1h</td><td> 8,9%</td>

<td>3h</td><td> 18,8%</td>

<td>6h</td><td> 38,7%</td>

<td>9h</td><td> 59,5%</td>

<td>12h</td><td> 74,3%</td>

<td>16h</td><td> 82,4%</td>

Example 19

In example 19, the coated cores of examples 1, 2 and 3 were mixed for 5 minutes in a tumble mixer. The mixing ratio was as follows:

Example 1: 29.5 kg

Example 2: 20.5 kg

Example 3: 12.1 kg

188 919

These proportions were calculated assuming that 80.0% of the morphine sulfate in the mixture should come from the preparations prepared according to Example 1 and Example 2, and 20.0% of the morphine sulfate in the mixture should come from the preparation from Example 3.

The amounts of the formulations of Examples 1 and 2 were selected to obtain the dissolution of the mixture as close as possible to the purpose described in Example 1.

The core mixture was mixed in a drum mixer for 5 minutes with 0.466 kg of talc.

The thus-obtained mixture of p coated cores had the dissolution rate shown in Table 32 (determined by the dissolution method III described above).

Table 32

<td>lh</td><td> 29,7%</td>

<td>2h</td><td> 41,2%</td>

<td>3h</td><td> 52,2%</td>

<td>4h</td><td> 62,3%</td>

<td>5h</td><td> 71,2%</td>

<td>6h</td><td> 78,5%</td>

<td>7h</td><td> 84,8%</td>

<td>8h</td><td> 88,9%</td>

<td>9h</td><td> 92,2%</td>

<td>12h</td><td> 94,8%</td>

<td>16h</td><td> 98,1%</td>

The mixture of coated cores was filled into capsules using a Zanasi AZ 40 capsule filling machine. The characteristics of the capsules are given in Table 33 (determined by the dissolution method V, described below).

Table 33

<td>Capsule size</td><td> 3</td><td> 1</td>

<td>Number of coated cores (mg)</td><td> 125,8</td><td> 377,5</td>

<td>Morphine Sulfate Dose (mg)</td><td> 20</td><td> 60</td>

<td>Dissolution after 1h (%)</td><td> 30,3</td><td> 29,6</td>

<td>Dissolution after 3h (%)</td><td> 53,7</td><td> 52,2</td>

<td>Dissolution after 6h (%)</td><td> 80,3</td><td> 79,7</td>

<td>Dissolution after 9h (%)</td><td> 94,4</td><td> 94,5</td>

Example 20

In example 20, the coated cores of examples 4, 5 and 6 were mixed for 5 minutes in a tumble mixer.

The mixing ratio was as follows:

Example 4: 31.2 kg

Example 5: 30.1 kg

Example 6: 14.5 kg

188 919

These proportions were calculated assuming that 80.0% of the morphine sulfate in the mixture should be in the form of coated cores prepared according to Example 4 and Example 5, and 20.0% of the morphine sulfate in the mixture should come from the preparation of Example 6.

The amounts of the formulations of Examples 4 and 5 were selected to obtain the dissolution of the mixture as close as possible to the purpose described in Example 1.

The core mixture was mixed in a drum mixer for 5 minutes with 0.569 kg of talc.

The thus-prepared mixture of coated cores had the dissolution rate shown in Table 34 (determined by the dissolution method III described above).

Table 34

<td>lh</td><td> 23,3%</td>

<td>2h</td><td> 33,4%</td>

<td>3h</td><td> 44,3%</td>

<td>4h</td><td> 55,2%</td>

<td>5h</td><td> 65,3%</td>

<td>6h</td><td> 73,2%</td>

<td>7h</td><td> 80,2%</td>

<td>8h</td><td> 85,1%</td>

<td>9h</td><td> 88,8%</td>

<td>Loh</td><td> 91,3%</td>

<td>12h</td><td> 94,9%</td>

<td>16h</td><td> 98,0%</td>

The mixture of coated cores was filled into capsules using a Zanasi AZ 40 capsule filling machine. The characteristics of the capsules are given in Table 35 (determined by the dissolution method V, described below).

Table 35

<td>Capsule size</td><td> 00</td>

<td>Number of coated cores (mg)</td><td> 629,1</td>

<td>Morphine Sulfate Dose (mg)</td><td> 100,0</td>

<td>Dissolution after 1h (%)</td><td> 26,5</td>

<td>Dissolution after 3h (%)</td><td> 48,0</td>

<td>Dissolution after 6h (%)</td><td> 77,5</td>

<td>Dissolution after 9h (%)</td><td> 93,5</td>

Example 21

In Example 21, the coated cores of Examples 7, 8 and 9 were mixed for 5 minutes in a tumbler.

The mixing ratio was as follows:

Example 7: 32.2 kg

Example 8: 13.3 kg

Example 9: 25.0 kg

188 919

These proportions were calculated assuming that 80.0% of the morphine sulfate in the mixture should be in the form of coated cores prepared according to Example 7 and Example 9, and 20.0% of the morphine sulfate in the mixture should be from Example 8.

The amounts of examples 7 and 8 were selected to obtain the dissolution of the mixture as close as possible to the purpose described in example 1.

The core mixture was mixed in a tumbler for 5 minutes with 0.530 kg of talc.

The thus-prepared mixture of coated cores had the dissolution rate shown in Table 36 (determined by the dissolution method III described above).

Table 36

<td>1h</td><td> 24,7%</td>

<td>2h</td><td> 36,2%</td>

<td>3h</td><td> 47,2%</td>

<td>4h</td><td> 59,3%</td>

<td>5h</td><td> 69,3%</td>

<td>6h</td><td> 77,1%</td>

<td>7h</td><td> 83,1%</td>

<td>8h</td><td> 86,9%</td>

<td>9h</td><td> 89,7%</td>

<td>Loh</td><td> 91,8%</td>

<td>12h</td><td> 94,4%</td>

<td>16h</td><td> 96,6%</td>

The mixture of coated cores was filled into capsules using a Zanasi AZ 40 capsule filling machine. The characteristics of the capsules are given in Table 37 (determined by the V-thinner method described below).

Table 37

<td>Capsule size</td><td> 4</td><td> 3</td><td> 1</td>

<td>Number of coated cores (mg)</td><td> 62,9</td><td> 188,7</td><td> 314,6</td>

<td>Morphine Sulfate Dose (mg)</td><td> 10</td><td> 30</td><td> 50</td>

<td>Razkosocoenia after 1H (%)</td><td> 23,9</td><td> 25,4</td><td> 23,8</td>

<td>Dissolution after 3h (%)</td><td> 44,6</td><td> 47,5</td><td> 47, 6</td>

<td>Dissolution after 6h (%)</td><td> 76,2</td><td> 79,3</td><td> 78,6</td>

<td>Dissolution after 9h (%)</td><td> 90,2</td><td> 92,5</td><td> 92,9</td>

Example 22

In Example 22, modified release morphine sulfate cores were prepared and then coated as described in Example 1.

The number of coated cores, the amount of internal coating applied and the dissolution data (determined by the method of knock-out III, described above) are shown in table 38.

188 919

Table 38

<td>Gray No.</td><td> 1</td><td> 3</td>

<td>Number of coated cores (kg)</td><td> 27,7</td><td> 27,7</td>

<td>The amount of internal coating (% of cores)</td><td> 7,5</td><td> 8,9</td>

<td>Product temperature, coating (approx., ° C)</td><td> 19,0-21,8</td><td> 19,4-21,6</td>

<td>Dissolution after 1h (%)</td><td> 9,9</td><td> 3,9</td>

<td>Dissolution after 2h (%)</td><td> 25,9</td><td> 10,8</td>

<td>Dissolution after 3h (%)</td><td> 41,7</td><td> 21,5</td>

<td>Dissolution after 4h (%)</td><td> 56,7</td><td> 34,6</td>

<td>Dissolution after 5h (%)</td><td> 69,0</td><td> 48,9</td>

<td>Dissolution after 6h (%)</td><td> 78,3</td><td> 61,0</td>

<td>Dissolution after 9h (%)</td><td> 92,3</td><td> 83,7</td>

<td>Dissolving after 10h (%)</td><td> 94,6</td><td> 87,7</td>

<td>Dissolving after 14h (%&gt;)</td><td> -</td><td> 95,8</td>

<td>Dissolution after 16h (%)</td><td> 99,7</td><td> -</td>

<td>Charge No.</td><td> 4</td><td> 5</td>

<td>Number of coated cores (kg)</td><td> 27,7</td><td> 27,9</td>

<td>The amount of internal coating (% of cores)</td><td> 8,0</td><td> 8,4</td>

<td>Product temperature, coating (approx., ° C)</td><td> 18,8-22,0</td><td> 19,5-21,6</td>

<td>Dissolution after 1h (%)</td><td> 6,3</td><td> 4,7</td>

<td>Dissolution after 2h (%)</td><td> 18,0</td><td> 11,7</td>

<td>Dissolution after 3h (%)</td><td> 32,4</td><td> 22,2</td>

<td>Dissolution after 4h (%)</td><td> 47,6</td><td> 35,5</td>

<td>Dissolution after 5h (%)</td><td> 61,2</td><td> 49,4</td>

<td>Dissolution after 6h (%)</td><td> 72,0</td><td> 61,7</td>

<td>Dissolution after 7h (%)</td><td> -</td><td> 71,4</td>

<td>Dissolution after 9h (%)</td><td> 89, 9</td><td> 84,2</td>

<td>Dissolving after 10h (%)</td><td> 92,8</td><td> 87,8</td>

<td>Dissolving after 15 h (%)</td><td> 99,3</td><td> -</td>

<td>Dissolution after 16h (%)</td><td> -</td><td> 97,2</td>

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<td>Charge No.</td><td> 2</td>

<td>Number of coated cores (kg)</td><td> 27,7</td>

<td>The amount of internal coating (% of cores)</td><td> 3,0</td>

<td>Product temperature, coating (approx., ° C)</td><td> 19,0-21,9</td>

<td>Dissolving after 10 min (%)</td><td> 50,9</td>

<td>Dissolving after 20 min (%)</td><td> 78,9</td>

<td>Dissolving after 30 min (%)</td><td> 91,0</td>

<td>Dissolving after 40 min (%)</td><td> 96,2</td>

<td>Dissolving after 50 min (%)</td><td> 98,7</td>

<td>Dissolving after 60 min (%)</td><td> 100,1</td>

Example 23

In example 23, the coated cores of example 22, batches 1, 2 and 3 were mixed for 5 minutes in a tumble mixer.

The mixing ratio was as follows:

Example 22, gray 1: 27.3 kg

Example 22, batch 2: 13.2 kg

Example 22, gray 3: 28.4 kg

These proportions were calculated assuming that 80.0% of the morphine sulfate in the mixture should be in the form of coated cores prepared according to Example 22, batches 11 2, and 20.0% of the morphine sulfate in the mixture should be from Example 22, run 3.

The amounts of Example 22, grayer than Example 22, Batch 3, were selected to obtain dissolution of the mixture as close as possible to the purpose described in Example 1.

The core mixture was mixed in a drum mixer for 5 minutes with 0.520 kg of talc.

The thus-obtained mixture of coated cores had the dissolution rate shown in Table 39 (determined by the dissolution method III described above).

Table 39

<td>1h</td><td> 23,0%</td>

<td>2h</td><td> 32,2%</td>

<td>3h</td><td> 43,1%</td>

<td>4h</td><td> 54,6%</td>

<td>5h</td><td> 65,0%</td>

<td>6h</td><td> 73,6%</td>

<td>7h</td><td> 79,9%</td>

<td>8h</td><td> 84,6%</td>

<td>9h</td><td> 87,9%</td>

<td>10h</td><td> 90,3%</td>

<td>12h</td><td> 93,3%</td>

<td>16h</td><td> 96,0%</td>

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The mixture of coated cores was filled into capsules using a Zanasi AZ 40 capsule filling machine. The characteristics of the capsules are given in Table 40 (determined by the dissolution method V, described below).

Table 40

<td>Capsule size</td><td> 00</td>

<td>Number of coated cores (mg)</td><td> 629,1</td>

<td>Morphine Sulfate Dose (mg)</td><td> 100,1</td>

<td>Dissolution after 1H (%)</td><td> 25,1</td>

<td>Dissolution after 3h (%)</td><td> 45,6</td>

<td>Dissolution after 6h (%)</td><td> 76,1</td>

<td>Dissolution after 9h (%)</td><td> 90,4</td>

Example 24

In example 24, the coated cores of example 22, batches 2, 4 and 5, were mixed for 5 minutes in a tumble mixer.

The mixing ratio was as follows:

Example 22, gray 2: 12.1 kg

Example 22, batch 4: 29.0 kg

Example 22, gray 5: 21.9 kg

These proportions were calculated assuming that 80.0% of the morphine sulfate in the mixture should be in the form of coated cores prepared according to Example 22, batch 4 and 5, and 20.0% of the morphine sulfate in the mixture should come from the preparation of Example 22, gray 2.

The amounts from example 22, gray 4 and from example 22, gray 5 were chosen so as to obtain the dissolution of the mixture as close as possible to the purpose described in example 1.

The core mixture was mixed in a drum mixer for 5 minutes with 0.470 kg of talc.

The thus-prepared mixture of coated cores had the dissolution rate shown in Table 41 (determined by the dissolution method III described above).

Table 41

<td>1h</td><td> 21,8%</td>

<td>2h</td><td> 30,7%</td>

<td>3h</td><td> 40,3%</td>

<td>4h</td><td> 51,2%</td>

<td>5h</td><td> 61,3%</td>

<td>6h</td><td> 70,3%</td>

<td>7h</td><td> 77,3%</td>

<td>8h</td><td> 81,9%</td>

<td>9h</td><td> 85,4%</td>

<td>Loh</td><td> 88,1%</td>

<td>12h</td><td> 91,9%</td>

<td>16h</td><td> 94,6%</td>

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The coated core mixture was filled into capsules using a Zanasi AZ 40 capsule filling machine. The characteristics of the capsules are given in Table 42 (determined by the dissolution method V, described below).

Table 42

<td>Capsule size</td><td> 4</td><td> 0</td>

<td>Number of coated cores (mg)</td><td> 62,9</td><td> 377,9</td>

<td>Morphine Sulfate Dose (mg)</td><td> 10,0</td><td> 60,0</td>

<td>Dissolution after 1 h (%)</td><td> 22,7</td><td> 25,0</td>

<td>Dissolution after 3h (%)</td><td> 40,9</td><td> 44,1</td>

<td>Dissolution after 6h (%)</td><td> 71,7</td><td> 73,8</td>

<td>Dissolution after 9h (%)</td><td> 88,4</td><td> 89,2</td>

Clinical tests

In the following tests, modified-release capsules prepared according to Example 12 are referred to as Repro-Dose® morphine.

Test ltcode PDMO-012)

Comparative, single-dose, open, randomized, three-phase, cross-over studies in healthy volunteers, assessing the bioavailability of two modified-release preparations: ReproDose® morphine (RDM) and KapanoPu® (KAP) compared to a normal morphine tablet, Morfin DAK® (MOR) ).

Research Center:

Daw Park Repatriation Hospital, Daw Park, Adelaide, South Australia 5041.

Research objectives:

The aim of the study was (i) to study the pharmacokinetic profiles of one dose of Repro-Dose morphine (RDM), KapanoPu® and morphine DAK® morphine (MOR) to compare the rate and extent of absorption and the in vivo release characteristics of a single dose of three formulations; and (ii) to study the in vitro / in vivo correlation and to assess adverse effects during the test period.

Number and type of volunteers

The study was a single-dose, open, randomized, three-phase cross-over study in 24 healthy volunteers. All people who withdrew from the study were excluded.

volunteers:

Healthy volunteers of both sexes, 18-45 years old, weight ± 10% of the ideal body weight for the given age, height and build who gave their written consent. Volunteers who took another medicine, who abused or addicted to drugs, who donated blood in the 3 months prior to the study, who participated in the last three months, who had a history of emotional instability or psychiatric disorders, were not eligible for the study. which were likely not to succumb to the test report, who have taken any opiates (other than codeine) whose alcohol consumption exceeded 40 g of alcohol (4 standard alcoholic drinks) for men and 20 g of alcohol (2 standard alcoholic drinks) for women who had positive antigen results in the last 6 months before the study surface Hepatitis B and / or Hepatitis C or HIV who have had an allergy or intolerance to compounds who have suffered from acute or chronic diseases, which may affect the health of the volunteer or the test result, who had clinically significant abnormal laboratory test results, or who were pregnant or lactating.

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Drugs used in the test:

Morphine Repro-Dose® 30 mg modified-release capsules, Kapano® 20 mg modified-release capsules, or Morfin DAK® 30 mg tablets.

Single doses of 60 mg Morphine Repro-Dose® and Kapanol® and 30 mg Morphine DAK® were administered with 240 ml of water.

Basic variables:

Area under the plasma concentration curve - morphine time from zero to 36 hours (AUC⁰'6⁶) (RDM and KAP) and from zero to 16 hours (AUC⁰'^) (MOR) are the primary variables in the bioavailability test.

Secondary variables:

Other pharmacokinetic variable derivatives were considered as secondary test variables (AUC0-36) (M-6-G, M-3-G), (AUC0-⁰⁰), C ™_x, T ™ T_Ug, MRT, HVD, T&gt; 75% Cm, ke).

Safety parameters:

Volunteers were asked to inform the researcher of any changes in their normal state of health. The researcher recorded in the CRF the event, date and time of occurrence and withdrawal, frequency, severity, results, classification and all actions taken.

Conducting the test:

Each volunteer underwent initial screening tests within 4 weeks before the first dose of study medication. Screening included medical history, physical examination, and laboratory testing.

In the evening of the day before the study, the volunteer reported at 1800 at Daw Park Repatriation Hospital and was asked to confirm his readiness to undergo the tests. A urine sample was then taken for drug abuse testing.

In the morning of the day when the dose was given to the women, a pregnancy test was carried out, which had to be negative.

Volunteers had physiological tests (pulse, blood pressure, respiration rate and pulse oximetry) prior to dosing and at 2, 4, 6, 8, 10, 12, 16, 23 and 36 hours after dosing in periods when Kapanol® was administered and Repro-Dose® morphine and pre-dose, 0.5.1, 1.5, 2, 3, 4, 6, 10 and 16 hours post-dose in periods in which Morfin DAK® was administered. Volunteers had to remain at Daw Park Repatriation Hospital for 36 hours after dosing. Volunteers had to be fasting from supper at 10 pm the day before and until sample collection after 4 hours. Fluid uptake from 1 hour before to 4 hours after dose was standardized. Meals were standardized for the first 24 hours. During the periods when two modified-release preparations were administered, blood samples were taken immediately before the dose and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 23, 27, 31 and 36 hours after dose. Blood samples during periods when volunteers took a regular morphine tablet were taken before dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10 , 12 and 16 hours after dose. Samples were analyzed at PMC in Sweden.

One week between study periods, volunteers had a washout period.

Volunteers were subjected to post-test screening, including laboratory tests, within 3-10 days of the end of the last study period.

Results of bioavailability studies:

A total of 26 volunteers were qualified for the study. Two volunteers gave up during the first period (RDM and KAP) and were excluded. A total of 24 volunteers completed the study. Of the volunteers who completed the study, there were 15 men and 9 women. Their age ranged from 18-38 years with an average age of 24.1 ± 5.3 years. Their average weight was in the range of 50-82 kg with an average weight of 66.1 ± 9.1 kg.

Plasma concentration curves - time for morphine are shown in Figure 16. It was found that the mean ± SD AUC0 'for morphine³6 (nmol / 1 xh) is 467 ± 191 (RDM) and 445 ± 175 (KAP), and the AUC ° '' 6 is 201 ± 64 (MOR 30 mg) and 402 ± 128 (mOr normalized to 60 mg).

The ratio (%) and 90% confidence limits for RDM / KAP was 104.1% [97.1; 111.6], for RDM / MOR (60) the ratio was 113.0% [105.4; 121.1]. RDM is absorbed to the same extent as KAP and slightly more than MoR, however both confidence limits were within the 80-125% bioavailability limits.

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For morphine, mean ± SD C_{m, x} (nmol / 1xh) was 29.8 ± 12.3 (RDM), 34.4 ± 20.6 (KAP), 84.4 ± 35.0 (MOR 30 mg) and 188.4 ± 69.9 ( MOR normalized to 60 mg). The effect of reduced peak concentrations after RDM and KAP compared to MOR was to flatten plasma concentration curves.

Median (range) T._ma (hours: minutes) for morphine was 5:00 (1:00) 4:00) for RDM, 8:00 (1: 00-12: 00) for KAP and 0:45 (0: 15-1: 30 ) for mOr. A significant time delay to maximum concentration was observed for KAP compared to RDM, which were both significantly delayed relative to MOR.

The results for T ^ g also showed a slight delay in KAP absorption compared to RDM.

Sustained release profiles of RDM and KAP compared to MOR are confirmed by the differences detected in MRT, HVD and T&gt; 75%, Cmo, determined for three preparations.

Pharmacokinetic profiles for morphine metabolites were as expected for morphine levels for the three preparations.

Of the 24 volunteers who completed the study, 16 had 38 adverse events (AEs).

Much more volunteers reported side effects during the KAP period than during the RDM period (p &lt;0.014).

The AEs described in all three treatments were mainly mild, few were moderate and only 2 were described as severe. AEs described as probably related to morphine are common and well known side effects of morphine, i.e. vomiting, nausea, headache and dizziness.

None of the pharmacokinetic profiles for individual volunteers gave rise to evidence of evacuation following any of the treatment protocols.

There were no fertile heavy or unexpected AEs.

Conclusion:

The amount of morphine absorbed from RDM was found to be approximately 104% (90% confidence interval 97.1-111.6%) of morphine zooborbed with KAP when the preparations were administered in single, equal doses in the fasting state. Preporots can therefore be considered equivalent (the 90% confidence interval is in the range 80-125%) under these conditions.

Plasma profiles for morphine after RDM and KAP administration show a prolonged effect and milder plasma concentration curves than MOR.

The concentration peak occurs earlier for RDM than for KAP and RDM tends to be more prolonged than KAP.

Fewer volunteers experienced side effects in the case of RDM than in the case of KAP.

The pharmacokinetic and side effects described in these studies indicate that RDM may be a valuable solution for daily administration and may offer clinically significant advantages over KAP.

In vitro-in vivo correlation results

Using deconvolution techniques for plasma data for RDM and KAP compared to MOR and oral solution data (internal data), in vivo dissolution profiles were obtained (Figure 17). These profiles correlate well with in vitro dissolution data at level A.

% released in vivo = bx% released in vitro + a

<td>Preparot</td><td>b</td><td>about</td><td>R2</td><td>N</td>

<td>RDM</td><td> 0, 9535</td><td> -1,0054</td><td> 0,9926</td><td> 19</td>

<td>KAP</td><td> 0, 6635</td><td> -3,7095</td><td> 0,9530</td><td> 5</td>

Dsne indicate a good correlation between the in vitro and in vivo dissolution profiles for the RDM preparation (Fig 18) and the weaker correlation to the KAP preparation.

188 919

Using Levy plots (Fig. 19) covered with the following formula: T ™ = bx + a, the following correlations are obtained:

<td>Preparation</td><td>b</td><td>and</td><td>R²</td><td>N</td>

<td>RDM</td><td> 1,0920</td><td> 0,2149</td><td> 0,9844</td><td> 11</td>

<td>KAP</td><td> 1,6085</td><td> 0,3360</td><td> 0,9966</td><td> 11</td>

For both preparations, the intersection point (z) is close to zero, for RDM the slope (b) is close to 1 and for both preparations the correlation coefficients are rather high, which means that the in vitro and in vivo dissolution profiles are very similar and close to correlation 1 1.

By using convection techniques for in vitro dissolution, it is possible to estimate lower and higher goat plasma which surrounds the obtained plasma profiles for RDM very well (Fig. 20).

Test 2 (code PDMO-013)

Single-dose, open-label, cognophoresis, cross-over studies in healthy volunteers, assessing the bioavailability of Repro-Dose® and MST Continus® morphine on an empty stomach and in food.

Research Center:

Leicester Clinical Research Center Limited, 72 Hospital Close, Evington, Leicester, LE5 ​​4WW, United Kingdom.

Research objectives:

The aim of the study was (i) to compare the bio-tendency of Repro-Dose® morphine on healthy volunteers and MST Continus®, and (ii) to investigate the effect of food on the absorption of Repm-Dose® and MST Continus® morphine and to assess adverse effects during the test period.

Number and type of volunteers

The study was a single dose, open, randomized, four-phase cross-over study in 16 healthy volunteers. All people who withdrew from the study were excluded.

volunteers:

Healthy volunteers of both sexes, 18-50 years old, weight 55-110 kg, who gave their written consent. Volunteers who took another medicine, who abused or addicted to drugs, who donated blood in the 3 months prior to the study, who participated in the last three months, who had a history of emotional instability or psychiatric disorders, were not eligible for the study. which were likely to fail the test report, who have taken any opiates (other than codeine) whose alcohol consumption exceeded 40 g of alcohol (4 standard alcoholic drinks) for men and 20 g of alcohol (2 standard alcoholic drinks) for women who had positive antigen results in the last 6 months before the study surface Hepatitis B and / or Hekztitis C or HIV who have had an allergy or intolerance to compounds who have suffered from acute or chronic diseases, which may affect the health of the volunteer or the test result, who had clinically significant abnormal laboratory test results, or who were pregnant or lactating.

Drugs used in the test:

Morphine Repro-Dose® 30 mg modified-release capsules or MST Continus® 30 mg modified-release tablets.

Single doses of 60 mg were administered with or without standardized breakfast.

Basic variables:

Area under the plasma concentration curve - time for morphine from zero to 36 hours (AUCe '³⁶) is the primary variable in the bio-tendency test.

188 919

Secondary variables:

Other fyrmαkokiaetocyae derivatives were considered as secondary test variables (AUC ° -³⁶) (M-6-G, M-3-G), AUC j C ™ x, Tmx, Tag MRT, HVD, ke).

Safety parameters:

Volunteers were asked to inform the researcher of any changes in their normal state of health. ΒιΡιπ recorded in the CRF the event, date and time of occurrence and resignation, frequency, severity, results, cause-effect relationships, classification and all actions taken.

Conducting the test:

Each volunteer underwent initial screening tests within 3 weeks before the first dose of study medication. Screening included medical history, physical examination, and laboratory testing.

On the evening of the day before the study, the volunteer reported at 1900 to the LCRC and was asked to confirm his readiness to undergo the tests. A urine sample was then taken for drug abuse testing.

In the morning of the day when the dose was given to the women, a pregnancy test was carried out, which had to be negative.

Volunteers had physiological tests (pulse, blood pressure and repulsion rate) before dose and 2, 8, 24 and 48 hours after dose. In addition, volunteers were fitted with a pulse oximeter during sleep during the first 24 hours after dosing. Volunteers had to remain in the LCRC for 48 hours after dosing. Volunteers had to be fasting oP supper at 10 pm the previous day until sample collection 4 hours after Pawka. In the Trunks of the study with food, a standardized breakfast was served no more than 20 minutes before taking the drug, which took place in the morning together with 240 ml of water. Fluid uptake from 1 hour before. After 3 hours post-dose, it was sterilized. Styndaroy meals for the first 24 hours'. Blood samples were taken immediately before dose (- / 2) and 12 1, 1 12, 2, 214, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 28 and 36 hours after dose. Samples were analyzed at PMC in Sweden.

One week between study periods, volunteers had a washout period.

Volunteers were subjected to post-test screening, including laboratory tests, within 3-10 days of the end of the last study period.

Findings:

A total of 17 volunteers were qualified for the study. One volunteer gave up prior to dosing and was excluded. 16 volunteers completed the research. Of the volunteers who completed the study, there were 9 men and 7 women. Their age ranged from 19-49 years with an average age of 28.2 ± 8.7 years. Their average weight was in the range of 54.6-89 kg with an average weight of 70.8 ± 9.9 kg.

Plasma concentration-time curves for morphine are shown in Figure 21. It was found that the mean ± SD AUC0'36 (amol / 1 xh) for morphine is 426 ± 127 (fasting RDM), 416 ± 116 (RDM after eating), 473 ± 138 (MST fasted) and 483 ± 126 (MST fasted).

The ratio (%) and 90% confidence limits for RDM / MST was 89.6% [84.1; 95.5] (fasting), 86.1% [80.8; 91.7] (after driving). By comparison, the fasting / on-diet ratio for RDM was 98.5% [92.5; 105.0]. RDM is absorbed to the same extent as MST, which results from the fact that the confidence limits wereⁱⁿ 80-125% range of light availability limits.

For morphine, the mean ± SD Cmx (nmol / 1 xh) was 34.2 ± 12.2 (fasting RDM), 33.0 ± 11.7 (fasting RDM), 82.8 ± 35.5 (fasting MST) and 68.3 ± 26.6 (MST after driving). The effect of reduced peak concentrations after RDM was to flatten plasma concentration curves.

Median (range) Tmx (gopyino: miauto) for morphine was 1:48 (1: 00-6: 00) for fasting RDM, 2:30 (1: 00-8: 00) for RDM after eating, 1:30 ( 0: 30-2: 30) for MST fasting and 2:30 (1: 00-5: 00) for MST after eating. A significant time delay to maximum concentration was observed when RDM and MST were administered by eating.

The results for Tlag also showed a slight delay in RDM absorption when administered with a high-fat breakfast.

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Sustained release profiles of RDM compared to MST are confirmed by the differences detected in MRT, HVD and T&gt; 75% Cmax, determined for two preparations.

There was no significant effect of food on either morphine or its two metabolites in RDM.

Pharmacokinetic profiles for morphine metabolites were as expected for morphine levels for two formulations.

Of the 16 volunteers who completed the study, 12 had 83 adverse events (AEs). Much more volunteers reported side effects during the MST period during both fasting and post-RDM periods (p &lt;0.046), but there was no difference in the occurrence of side effects during fasting and post-RDM periods.

AEs reported in all three treatments were mainly mild, few were moderate and only 3 were described as severe. AEs described as probably related to RDM and MST are common and well known side effects of morphine, i.e. vomiting, nausea, headache and dizziness. There has been a trend towards a lower incidence of drug-related side effects in RDM compared to MST.

None of the pharmacokinetic profiles for individual volunteers gave rise to a dose-emptying follow-up to any of the treatment protocols.

No severe or unexpected AEs occurred.

Conclusion:

The amount of morphine absorbed from RDM was found to be approximately 90% (90% confidence interval 84.1-95.5%) of morphine absorbed from MST when both preparations were administered in single, equal fasting doses. The preparations can therefore be considered equivalent (90% confidence interval is in the range 80-125%) under these conditions.

Plasma profiles for morphine after RDM administration show a prolonged effect and milder plasma concentration-time curves than MST.

There was no effect of food on the RDM bioavailability.

Fewer volunteers experienced side effects in RDM than in MST.

The pharmacokinetic and side-effect data described in these studies indicate that RDM may be a valuable once-a-day preparation and may offer clinically significant advantages over MST.

Test 3 (code PDMO-018)

Single-dose, open, randomized, four-phase, cross-over studies in healthy volunteers assessing the bioavailability of Repro-Dose® morphine once a day and MST Continus® twice a day at steady state.

Research Center:

Leicester Clinical Research Center Limited, 72 Hospital Close, Evington, Leicester, LE5 ​​4WW, United Kingdom.

Research objectives:

The aim of the study was (i) to compare bioavailability at steady state in healthy volunteers of Repro-Dose® morphine once daily and MST Continus twice daily, and (ii) to assess adverse effects during the test period.

Number and type of volunteers

The study was a multidose, open, randomized, biphasic cross-over study in 16 healthy volunteers. All people who withdrew from the study were excluded.

volunteers:

Healthy volunteers of both sexes, 18-50 years old, weight 55-110 kg, who gave their written consent. Volunteers who took another medicine, who abused or were addicted to drugs, who donated blood in the 3 months prior to the study, who participated in the last three months, who had a history of emotional instability or psychiatric disorders, were not eligible for the study. for which there was a likelihood that they would not succumb to the test report, who in the last 6 months

188 919 before the study they took any opiates (other than codeine) whose alcohol consumption exceeded 40 g of alcohol (4 standard alcoholic drinks) for men and 20 g of alcohol (2 standard alcoholic drinks) for women who had positive Hepatitis B surface antigen results or Hepatitis C or HIV who have had an allergy or intolerance to compounds who have suffered from acute or chronic diseases that may affect the health of the volunteer or the test result, who had clinically significant laboratory abnormalities or who were pregnant or lactating.

Drugs used in the test:

Mor ^ ine Repro-Dose® 30 mg modified-release capsules or MST Continus® 30 mg modified-release tablets.

Single doses of 60 mg Moi-phine Repro-Dose® were administered each morning for 5 days.

Single doses of 30 mg MST Continus® were administered each morning and evening for 5 days.

Basic variables:

Area under the plasma concentration - time curve for morphine from zero to 24 hours (AUC ^) is the primary variable in the bio-bioassay test.

Secondary variables:

Other pharmacokinetic derivative derivatives were considered as secondary test variables (AUC024) (M-6-G, M-3-G), (AUC ^), (AUC¹²^), C_max, C._rom. Cthrough, Cav,% PTF, T._mand_X,

HVD, T&gt; 75% c,_{1 ix ;;}).

Safety parameters:

Volunteers were asked to inform the researcher of any changes in their normal state of health. The researcher recorded in the CRF the event, date and time of occurrence and withdrawal, frequency, severity, results, cause-effect relationships, classification and all actions taken.

Conducting the test:

Each of the volunteers underwent preliminary skeletal tests within 3 weeks before the first dose of study drug. Skriąmg included medical history, physical examination, and laboratory testing.

In the evening of the day before the study, the volunteer checked into the LCRC 26 hours before the first dose and was asked to confirm his readiness to undergo the trials. Then a urine sample was taken to conduct drug abuse testing and a pregnancy test was carried out for female volunteers. In the event that the drug abuse test and pregnancy test were negative, volunteers were given only direct iv injection of approximately 0.5 ml naloKone 0.4 mg / ml (Narcan®) in the first period. If no side effects occurred at least 15-20 minutes after injection, 2 naltrexone tablets (100 mg) were orally administered approximately 24 hours before the first dose of morphine.

Volunteers had a physiological examination (pulse, blood pressure and respiratory rate) before dosing and 2 and 8 hours after the morning dose of the day and 4 hours after the morning dose on days 2-5. In addition, volunteers were fitted with a pulse oximeter each night during sleep up to 24 hours after the last morning dose in each period. Volunteers had to remain in the LCRC for 48 hours after the last morning dose. Rekro-Dose® morphine was administered in the morning and MST Continus® in the morning and evening (day 5 after the H-hour sample). NaltreKone was administered within 24 hours of each morphine dose and 24 hours after the last morphine dose. Doses of naltrexone and morphine were separated by at least 60 minutes. Volunteers had to be fasting from supper at 10 pm (day 4) before sampling (day 5), and until the end of 4 hours after sampling. Volunteers were fasting from 10 hours to 16 hours sampling when a light snack was served. The next morning, breakfast was served after sampling after 24 hours. Meals were standardized at both study periods. Day 5 was not allowed to take meals from 1 hour before the morning dose to 1 hour after the dose and again from 1 hour before the evening dose to 1 hour after the dose, only allowing 240 ml of water along with the dose of morphine. On day 3 and 4, blood samples were taken immediately before the morning dose in each study period. On day 5, a blood sample was taken before dose (0 o'clock) and 1, 2, 3, 4, 5, 6, 8, 10, 12, 13, 14, 16, 18, 20, 22 and 24 hours after the morning dose. Samples were analyzed at the Drug Distribution Department at Linz.

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Volunteers had a washout period of two weeks between study periods.

Volunteers were subjected to a post-test examination, including laboratory tests, within 3-10 days of the end of the last study period.

Findings:

A total of 19 volunteers were qualified for the study. Three volunteers gave up, one after one but before dosing and two during the MST period. All three volunteers were excluded. 16 volunteers completed the research. Of the volunteers who completed the study, there were 9 men and 7 women. Their age ranged from 22-46 years with an average age of 31.4 ± 7.2 years. Their average weight was in the range of 55.0-88.6 kg with an average weight of 68.4 ± 10.1 kg.

The mean transient Cthrough concentration on days 3-5 indicates that steady state levels have been reached for both treatment periods.

Plasma concentration curves - time for morphine are shown in Figure 24. It was found that the mean ± SD AUC0'2 for morphine⁴ is 657 nmol / 1 x h. The ratio obtained by pairwise comparison was 101% with a confidence interval of 92-111%. Equivalence with AUC0'24 (99% confidence interval in the 80125% range) was also found for metabolites.

For all three analyzed substances, AUC0'24 was higher for RDM compared to MST. Conversely, the area under the curve was higher for MST in the range of 12 to 24 hours.

C_max for RDM and MST were 50 ± 20 and 62 ± 30 mol / L, respectively

No equivalence was found for this parameter. Higher plasma metabolite peaks were also found in MST.

Median T._max occurred 1.5 hours later in the RDM period; MST reached its peak after a median of 2 hours.

Fluctuations in morphine levels during the RDM and MST periods were 135% and 185%, respectively. M-6-G and M-3-G fluctuations were also more clearly marked during the MST period.

HVD morphine for RDM (14.1 hours) was twice as high as HVD for MST (7.3 hours). T support data&gt; 75% Cmax found for morphine was 6.5 hours (RDM) and 3.3 hours (MST). The results of these parameters for metabolites were consistent with the results for morphine.

Of the 19 volunteers who started the study, 14 had 44 adverse events (AEs); 13 aE (RDM), 14 AE (MST), 13 AE (naltrexone) and 4 Ae (before or after the test).

There was no significant difference in the number of volunteers reporting AE between RDM and MST treatment.

The AEs described in all three treatments were mainly mild and most were opioid side effects, especially gastrointestinal disorders. The safety profile for MST did not seem to differ from that of RDM, although a few more AEs were noted for RDM. Unlike the MST period, no mental disorders were noted during the RDM period. In addition, more vomiting was reported during the MST period. None of the pharmacokinetic profiles for individual volunteers gave grounds for dose emptying following any of the treatment protocols.

No severe or unexpected AEs occurred.

Conclusion:

Studies have shown that chronic once-daily RDM and MST twice daily administration were equivalent in AUC for both morphine and its metabolites (M-6-G and M-3-G) under steady state conditions. Although the effect of RDM treatment was lower Cmax, which occurred later than Cm for MST, RDM gave initial plasma concentrations comparable to those during the MST period. However, the RDM preparation prolonged the release of morphine and therefore contributed to smoother and more elongated plasma release profiles. In addition, RDM successfully minimized fluctuations during the 24-hour dosing period compared to MST. These features indicate that RDM may offer significant clinical advantages over MST and allow once daily administration.

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In this body, naltrexone was used to antagonize possible side effects of chronic morphine administration. This made research on volunteers safe. There were no serious or unexpected side effects. Safety profiles for these two treatment periods were indistinguishable.

Test 4 (PDMQ-OOl code)

Randomized double-blind cross-over studies in patients suffering from chronic pain assessing the bioavailability of Repro-Dose® and MST Continus® at steady state.

Research Center:

King's College Hospital, Denmork Hill, London SE5 9RS, United Kingdom, St. Christopher's Hospice, 51-59 Lawrie Park Road, Sydenham, London SE 26, United Kingdom and St. Francis Hospice, The Holi, Broxhill Rond, Hoveringatte-Bower, Romford, Essex, United Kingdom.

Research objectives:

The aim of the study was (i) to compare the analgesic efficacy and side effects profile of Repro-Dose® morphine compared to MST Continus® in patients with stable chronic opioid-responsive pain, and (ii) to study the pharmacokinetic profile of Repro-Dose® morphine compared to MST Continus ®.

Number and type of volunteers

The study was a cross-over study and 40 patients were randomly assigned to one of the test groups after a 5-day screening period. All persons who withdrew from bsdoń were excluded.

Group A: MST Continus® for 5 days, followed by Repro-Dose® morphine for 5 days.

Group B: Morphine Repro-Dose® for 5 days, then MST Continus® for 5 days.

Obs preparations were administered in daily doses of 20, 40, 60, 90 or 120 mg.

Up to 10 patients with a daily requirement of 40, 60, 90 or 120 mg morphine were included in the pharmacokinetic part of the study.

patients:

Patients included in the study were inpatient or outpatient patients suffering from cancer-related pains, severe vascular disease, or other chronic pains requiring morphine treatment. They were men and women at least 18 years of age, and the body weight of patients included in the pharmacokinetic part was 40-90 kg. Before entering the study, they should receive MST Continus® in stable doses for a 5-day screening period. Their morphine requirement should be 20, 40, 60, 90 or 120 mg daily during the study period. Patients were allowed to take other medications (e.g. NSAIDs, corticosteroids, anti-convuls) for soreness, tricyclic antidepressants), this medicine should be taken at stable doses during the screening period and during the trial. No other concurrent treatment (e.g. radiation, chemotherapy) was allowed. Patients suffering from gastrointestinal diseases or with impaired liver and / or kidney function were excluded from this study because it may affect absorption, metabolism and / or excretion of the drug. Pregnant or lactating women were excluded from badoń.

Drugs used in the test:

Morphine Repro-Dose® modified release capsules at 20, 40, 60, 90 or 120 mg daily doses were to be compared with MST Continus® modified release tablets twice daily at the daily doses mentioned above. However, MST Continus® was administered at doses of 10, 20, 30, 45 or 60 mg twice a day.

Both preparations were encapsulated in red gelatin capsules and administered orally.

An escape drug is provided, that is Palfium (dextromoramide) 5 mg tablets.

188 919

Basic variables:

The primary variable in this test was the number of therapy failures. Patient therapy was considered unsuccessful if he had used more escape medicine during the last three days of the Morphine Repro-Dose® period than during the last three days of the MST Continus® period.

Secondary variables:

The secondary variables examined are: time to first use of the escape medicine after each dose (morning, evening) over the last three days of each period, average pain intensity index in the last three days of each period, total assessment of each therapy by the patient, patient preferences for each from periods of therapy.

Safety parameters:

The researcher asked patients every evening if they experienced any side effects, if the answer was yes, the researcher wrote down the type, severity, duration, result, adjunctive treatment and recorded the report on the side effects form.

Conducting the test:

Five days before the patient's enrollment, patients were screened for the study and given written and oral information about the study. If after the screening period the patient wanted to be included in the examination, he was asked for written permission. During this screening visit, the patient's demographic data, medical history, administered drugs, pain site, and liver and kidney function after blood sampling were recorded.

During the 5-day screening period, the researcher monitored the patient's pain intensity and administered drugs, and if they turned out to be stable, the patient was qualified for testing.

On day 0, patients were enrolled in the study, giving study medication and escape drug (Palfium tablets) for the next 5 days.

On day 5, patients were transferred to the second therapy group and returned to all other drugs (including escape medicine) for the remaining 5 days.

During the entire study period, patients assessed pain intensity twice a day before taking study medication and in the evening wrote in a notebook or experienced any side effects.

At the end of each study period, patients expressed their general opinion about the therapy, and at the end of the study they expressed their preferences for any therapy, if possible.

On day 10 (at the end of the study), patients' total bilirubin and s-creatinine levels were determined to determine if the patient's renal and liver function was stable throughout the study period.

Patients participating in the pharmacokinetic part of the study received blood samples during the 24-hour period on days 4-5 and 9-10. In addition, urine was collected from these 24-hour periods.

Test results - clinical part:

The study was conducted from February 19, 1994 to February 8, 1996. A total of 55 patients were screened and 47 patients qualified for the study. Forty patients were examined in the "intent-to-treat" (ITT) population and 31 patients in the population according to protocol. The ITT population consisted of 19 men and 21 women; 30 of them were cancer patients and 10 other patients; mean age 68.3 years (range 42.5-86.3) and average weight

63.9 kg (± 12.1). Seven patients abandoned the study or were withdrawn, including 3 patients who withdrew due to side effects, 1 due to lack of effect, 2 due to problems with study drugs and 1 due to comorbid disease. The analysis was performed as if the data were from one center, using data from all dose levels administered.

Fourteen patients (35%) consumed less Palfium during the RDM period than during the MST period and 15 (38%) consumed equal amounts in both periods. A total of 29 (72.5%) patients were successful (95% confidence interval 56.1-85.4%). This means that at least 56% of patients did not need any escape medicine at all or needed less than or equal amounts of escape medicine during the RDM period compared to the MST period and their treatment could be considered to be successful at 97.5% confidence level .

188 919

Twenty-five (63%) patients have taken escape medication during the last 3 days in the RDM period and 27 (68%) patients in the MST period. The difference between the percentage of patients who took the escape medicine in both periods is not significant.

In the last 3 days of the RDM period, the median time to first escape was between 22 and 25 hours. In the last 3 days of the MST period, the median time to first escape was between 10 and 13 hours at night and 13 hours at all day periods.

The mean pain intensity (numerical rating scale) and the 90% confidence interval over the last 3 days of therapy were 2.7 (2.2-3.2) in the rDm period and 2.5 (2.0-3.1) in the period MST (Fig. 25). There was no significant difference between mean pain intensities over the two study periods.

The mean total rating ± standard deviation was 3.2 ± 0.9 during the RDM period and 3.0 ± 0.9 during the MST period. There was no difference in patients' overall assessment of therapy.

Eighteen (45%) patients preferred the RDM therapy period, 9 (22.5%) patients the MST period and 13 (32.5%) patients had no preference (Figure 26). The percentage of patients who preferred RDM plus the percentage of patients who did not have preferences was significantly higher than the percentage of patients who preferred MST therapy (p = 0.0003).

No effect-dose relationship was observed in this study.

Thirty-eight out of 47 qualified patients reported a total of 158 side effects (AEs), of which 42 occurred in patients who had discontinued therapy or were withdrawn. A total of 116 side effects occurred in a population of 31 intent-to-treat patients, including 24 patients who reported 56 side effects during the RDM period and 26 patients who reported 60 side effects during the MST period.

No SAEs occurred during the study periods. Two SAE cases occurred during RDM follow-up therapy; none of them was drug dependent.

Patients' AEs are well known opioid or disease related effects. It was considered that for a significant proportion of the AEs described, it is unlikely that they would be associated with the study drug. AEs were mainly moderate or mild, and some were severe. AEs were evenly distributed among treatment groups. The most common AEs were nausea and vomiting.

Conclusions: clinical part

The results indicate that RDM administered once a day is as effective and well tolerated as an equal dose of MST administered in two divided doses.

RDM administered once daily was preferred by more patients than twice daily MST.

The consistency of the data obtained in these studies indicates that the studies were designed correctly for this type of efficacy studies and are of major importance. There is a good correlation between relevant parameters used to assess efficacy.

The RDM security profile is similar to the MST profile.

All AEs classified as drug-related were previously described for morphine therapy. SAE was not observed during the study periods. Two SAE cases were observed during RDM follow-up therapy, none of which were drug-related.

Results - pharmacokinetic part

The first patient was enrolled on January 28 and the study is still ongoing. The last patient was enrolled on May 22, 1996. Five patients were enrolled in the interim clinical report, of which 4 completed the study. Samples from one of the qualified patients have not been analyzed yet. All eligible patients were men in the 55-72 year range (p = 8), weight 50-68 kg. One patient dropped out because he stopped taking the study drug.

All patients had the same overall scores for RDM and MST. One patient preferred RDM, the others had no preference.

The following RDM / MST ratios were calculated for patients nr. 137, 140 and 155 respectively: AUC⁰^ (0.86, 0.85, 0.84), AUC⁰'¹² (1.22; 1.51; 1.18), AUC¹^¹(0.47; 0.47; 0.58), C_mand_X

188 919 (0.83, 0.72, 0.60), Cmm (0.89, 1.98, 0.57), C_th_rough (0.78; 1.38; 0.62), fluctuation index (0.95, 0.72, 0.72) and Xu total (1.63 0.83, 0.68).

The following differences in hours (RDM-MST) were calculated for patients No. 137, 140 and 155, respectively: Tma (0; -3; -2), HVD (5.45; -0.63; 1.93), and (3.53; -1.88; -5.03).

Four patients reported 23 episodes of side effects (AEs). Three patients who completed the study gave 20 AE, including 2 patients given 10 AE during the RDM period and 3 patients administered AE during the MST period.

SAE was not recorded in this part of the study.

Test 5 (code PDMO-O09)

Three-phase, double-blind, double-phase, cross-over studies in patients suffering from chronic pain assessing the efficacy and bioavailability of Repro-Dose® and Contalgin® morphine at steady state.

Research Center:

Geriatrie Treatment Center, Trznehzven, Schioldannsvej 31, DK-2920 Charlottenlund, Denmark.

Research objectives:

The aim of the study was (i) to investigate the analgesic efficacy and side effects profile of ReproDose® morphine administered once or twice daily compared to Contalgin® administered twice daily in patients with stable chronic opioid-responsive pain, and (ii) to study the pharmacokinetic profile of morphine Repro-Dose® compared to Contalgin® in the given dose range.

Number and type of volunteers

The study was a three-phase cross-over study and 42 patients were randomly assigned to one of the test groups after a 5-day screening period. All people who withdrew from the study were excluded.

Each of these drugs was administered for a period of 5 days.

ABC

ACB

BAC

BCA

CAB

CBA

Group A: Contalgm®. Half the daily dose of morphine was administered in the morning and half the daily dose in the evening.

Group B: Morphine Repro-Dose® (once daily dosing). The total daily dose of morphine was given in the evening and placebo capsules were given in the morning.

Group C: Re ^ o-Dose® morphine (twice daily dosing). Half the daily dose of morphine was administered in the morning and half the daily dose in the evening.

The preparations were administered in daily doses of 20, 40, 60, 80 or 120 mg.

Eighteen patients with a daily requirement of 60, 80 or 120 mg morphine were included in the pharmacokinetic part of the study.

patients:

Patients included in the study were inpatient or outpatient patients suffering from chronic pain requiring morphine treatment associated with osteoarthritis, rheumatoid arthritis or prostate cancer. They were men and women at least 18 years of age, and the body weight of patients included in the pharmacokinetic part was 40-100 kg. Before entering the study, they should receive Doltard® or Contalgin® at stable doses for a 5-day screening period. Their morphine requirement should be 20, 40, 60, 80 or 120 mg daily during the study period. Patients were allowed to take other medications to relieve pain (e.g. NSAID, kartosteIΌidy, anticonvulsant ^}, tricyclic antidepressants) and disease modifying agents (DMARDs, including corticosteroids) but this drug should be taken at stable doses during the screening period and during research. No other concurrent treatment (e.g. radiation, chemotherapy) was allowed. Patients suffering from gastrointestinal disease62

188 919 food or those with impaired liver and / or kidney function were excluded from this study because it may affect absorption, metabolism and / or excretion of the drug.

Drugs used in the test:

Mor-phine Repro-Dose® modified-release capsules at 20, 40, 60, 80 or 120 mg daily doses (administered once or twice daily) were to be compared with Contalem® modified-release tablets twice daily at the daily doses mentioned above . However, Conta ^ was administered in doses of 10, 20, 30, 40 or 60 mg twice a day. Both preparations were encapsulated in red gelatin capsules and administered orally. An escape drug is provided, that is Palfium (dextromoramide) 5 mg tablets.

Basic variables:

The primary variable for Morphine Repro-Dose® (once daily) in this test was the number of treatment failures. Patient therapy was considered unsuccessful if he had used more escape medicine during the last three days of the Morphine Repro-Dose® period (once daily administration) than during the last three days of the Contalgm® period.

The primary variable for Morphine Repro-Dose® (twice daily) in this test was the escape drug use during the last three days of the Morphine Rekro-Dose® period (twice daily administration) than during the last three days of the Contalgm period.

Secondary variables:

The secondary variables examined are: time to first escape after each dose (morning, evening) over the last three days of each period, mean pain intensity index over the last three days of each period, total assessment of each therapy by the patient, patient preferences for each of the periods of therapy.

Safety parameters:

The researcher asked patients every evening if they experienced any side effects, if the answer was yes, the researcher wrote down the type, severity, duration, result, adjunctive treatment and recorded the report on the side effects form.

Conducting the test:

Five days before enrollment, patients were screened for the study and given written and oral information about the study. If after a complaint period the patient wanted to be included in the study, he was asked for written permission. During this screening visit, the patient's demographics, medical history, medication administered, pain site, and liver and kidney function after blood sampling were recorded.

During the S-day screening period, the investigator monitored the patient's pain intensity and administered drugs, and if they turned out to be stable, the patient was qualified for testing.

On day 0, patients were enrolled in the study, giving study medication and escape drug (Palfium tablets) for the next 5 days.

On day 5 and day 10, patients were transferred to the group with the next therapy from the sequence and returned to all other drugs (including escape medicine) for the remaining 5 days.

During the entire study period, patients assessed pain intensity twice a day before taking study medication and in the evening wrote in a notebook or experienced any side effects.

At the end of each study period, patients expressed their general opinion about the therapy, and at the end of the study they expressed their preferences for any therapy, if possible.

On day 15 (at the end of the study), patients' total bilirubin and s-creatinine levels were determined to determine whether the patient's renal and liver function was stable throughout the study period.

Patients also participating in the pharmacokinetic part of the study received blood samples during the 24 hours period on days 4-5, 9-10 and 14-15. In addition, urine was collected from these 24-hour periods.

Repro-Dose® morphine; total applications

Clinical study results indicate that Rekro-Dose® morphine has a more elongated plasma concentration profile than MST Continus® and at the same time provides a very early plasma concentration profile that produces a clinical effect. Comparison between Repro-Dose® morphine

188 919 once a day and MST Continus® twice Pyienaie in patients with chronic pain shows the efficacy and safety of both therapies. However, more patients preferred the Repro-Dose® period, although this was blind, with twice daily dosing (placebo administered in the morning). When administered once a day, even a larger number of patients may prefer Repro-Dose® morphine, due to the convenient administration regimen, and greater patient compliance can be expected.

Compared to Kapano® morphine, Repro-Dose® 'morphine exhibits the same extension of the plasma concentration profile, but earlier the concentration peak, which can be an advantage to avoid pain breakthrough.

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188 919

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188 919

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188 919

EFFICACY AND SAFETY STUDIES ON PATIENTS WITH CHRONIC PAIN

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188 919

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Department of Publications of the Republic of Poland. Edition of 50 copies

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