WO2016091805A2

WO2016091805A2 - Naloxone monopreparation and multi-layer tablet

Info

Publication number: WO2016091805A2
Application number: PCT/EP2015/078827
Authority: WO
Inventors: Hélène Rey; Olaf MUNDSZINGER; Isabelle GOLFIER; Silvia JAKOB; Oliver RUSCH
Original assignee: Develco Pharma Schweiz Ag
Priority date: 2014-12-08
Filing date: 2015-12-07
Publication date: 2016-06-16
Also published as: CN107205943A; EP3229785A2; WO2016091805A3

Abstract

The present invention relates to a solid, oral pharmaceutical composition comprising naloxone, or a pharmaceutically acceptable salt thereof as the active ingredient, the composition having a delayed release of said active ingredient. The composition can comprise a matrix containing glycerol di-behenic acid esters as matrix formers, with a mass ratio of naloxone to matrix former(s) of between 1:1 and 1:10, whereby the active ingredient naloxone has a delayed release. According to the invention, in order to provide a composition suitable for a dosage covering at least twelve hours for treating opioid-induced obstipation, the composition has an in-vitro release rate of the active ingredient, measured using a vane stirrer method according to Eur. Ph. at 75 U/min in 500 ml of 0.1 N hydrochloric acid at 37 °C, of 0 % to 75 % in 2 h, 3 % to 95 % in 4 h, 20 % to 100 % in 10 h, 30 % to 100 % in 16 h, 50 % to 100 % in 24 h and more than 80 % in 36 h, said composition having an IC₅₀/C_max value of at least 40. Preferably, the composition comprises a value for t_max (naloxone) / t_max (naloxone-3-glucuronoid) of at least 5. In an alternative embodiment, the composition can take the form of a multi-layer tablet.

Description

NALOXONE-MONOPRÄPARAT AND MULTILAYER TABLET

BACKGROUND OF THE INVENTION

Constipation is a major side effect in the treatment of painkillers of the opioid type. It is one of the most common side effects and is an undesirable concomitant in over 85% of patients, especially in long-term opioid therapy. In contrast to other opioid-induced side effects, opioid-induced constipation is a chronic condition that does not lose its intensity during treatment. The effect of opioids on gut motility is presumably based on the binding of opioids to opioid receptors of the gastrointestinal tract, which are found there in relatively high density.

The aim of a suitable therapy is to eliminate this peripheral side effect of the opioids, since the opioid-induced constipation can be uncomfortable and very painful, often leads to the discontinuation of opioid therapy, and thus endangers the treatment success of the opioids. Since opioid-induced constipation is believed to be directly and locally effected throughout the intestine by the occupancy of opioid receptors, this side effect should be reversed by the use of opioid antagonists. However, the use of opioid antagonists only makes sense if the antagonistic effect on the intestine is limited and the central analgesic effect is not abolished.

A suitable opioid antagonist for the treatment of opioid-induced constipation is naloxone. Following oral administration, naloxone is absorbed rapidly and completely, and since the substance is subject to very pronounced first-pass metabolism, only small amounts of unaltered naloxone are systemically available. The majority of the administered substance is present in the blood in the form of non or only weakly effective metabolites such as naloxone-3-glucuronide or beta-6-naloxol. Naloxone in an appropriate dose is an ideal candidate for the treatment of opioid-induced constipation: it is an active substance in the intestine and can thus neutralize the paralytic activity of the opioid on the gastrointestinal tract, whereas it is highly metabolised after absorption at the first passage through the liver and becomes ineffective. Thus, the analgesic effect of opioids is not affected. Opioid-induced constipation can not be successfully treated with a fast-release naloxone formulation because it paralyzes the entire gastrointestinal tract and not just

Duodenum and upper parts of the small intestine are concerned. WO 2011/117306 discloses a

Two-layer tablet which contains an opioid agonist in one layer and an opioid antagonist in the other layer, the tablet rapidly releasing both active ingredients. The advantage of this bilayer tablet is indeed the suppression of caused by opioid agonists

Side effects, but here the opioid-induced constipation is not in the foreground.

Although the combination preparation ^{Targin® available} on the market, in which the opioid agonist oxycodone in the form of the hydrochloride salt and the opioid antagonist naloxone are also mixed in the form of its hydrochloride salt, releases the active substances in a sustained release and is thus used for the parallel treatment of pain and opioid -induced constipation. However, this monolithic formulation has the disadvantage that the release kinetics for both drugs is not variable and therefore the individual treatment success is difficult to optimize.

In addition to infusion solutions for the treatment of opioid poisoning only Naloxone combination preparations are available in the market, in which naloxone and opiate in a fixed ratio side by side. For the treatment of opioid-induced constipation but it would be desirable to have a naloxone Monopräparat, since this can be administered independently of the nature of the opiate and on the other in a variable amount, whereby the desired amount of naloxone administered exactly and so optimal Treatment success can be achieved. Although in the patent literature naloxone Monopräparate described as in WO 98/25613 A2. However, these preparations release the naloxone specifically depending on the ambient pH of the gastrointestinal tract, which is why a locally uniform supply over the entire gastrointestinal tract away with naloxone and thus optimal treatment success is not possible.

SCOPE OF THE INVENTION

It is an object of the present invention to provide a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient naloxone in a sustained release and thus is suitable for at least twelve hours administration for the treatment of opioid-indicated constipation.

This object is achieved by a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient naloxone in a sustained release and an in vitro release rate of the active ingredient naloxone, measured using the paddle stirrer method according to Eur. Ph. at 75 rpm in 500 ml 0.1 N

Hydrochloric acid at 37 ° C, from 0% to 75% in 2 h, from 3% to 95% in 4 h, from 20% to 100% in 10 h, of

30% to 100% in 16 h, from 50% to 100% in 24 h and more than 80% in 36 h.

It has been found that the composition according to the invention having said release profile is suitable for at least twelve hours administration for the treatment of opioid-indicated constipation and accordingly has a relatively high patient compliance.

The in-vitro release rate is determined using the blade stirrer apparatus (Apparatus 2) and the blade stirrer method according to Eur.Ph. (European Pharmacopoeia, 7th edition, 3rd supplement, 2.9.3 "Release of active ingredient from solid dosage forms", pp 5519-5526) at 75 rev / min in 500 ml of 0.1 N hydrochloric acid at 37 ° C. The amount of Released active ingredient is preferably determined by UV detection at 220 nm.

Through the matrix, the active ingredient is released in a sustained release, and the in vitro release rate of the active ingredient naloxone, measured using the paddle stirrer method according to Eur. Ph. At 75 rev / min in 500 ml of 0.1 N hydrochloric acid at 37 ° C 0% to 75% in 2 h, from 3% to 95% in 4 h, from 20% to 100% in 10 h, from 30% to 100% in 16 h, from 50% to 100% in 24 h and more than 80% in 36 h.

The opioid-induced constipation that may be treated by the composition of the present invention may be derived from any opioid analgesics or opioid analogues analgesics, their salts, and mixtures thereof. Examples of corresponding analgesics are: alfentanil, allylprodin, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, besomorphine, dextromoramide, decocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, Dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophin, narcein, nicomorphine, Norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, propperidine, propoxyphene, sufentanil, tilidine, and tramadol Hydrocodone, morphine, hydromorphone, oxycodone, bupren orphin, codeine, fentanyl, levorphanol, Meperidine, methadone, levomethadone and dextromethadone are particularly preferred in the invention.

According to a preferred embodiment of the composition according to the invention, it is provided that the composition has an in vitro release rate of the active ingredient from 0% to 50% in 2 h, from 5% to 95% in 4 h, from 20% to 90% in 10 h of more than 70% in 18 hours and more than 80% in 24 hours.

According to a further preferred embodiment of the composition according to the invention, it is provided that the composition has an in vitro release rate of the active ingredient of 0% to 38% in 2 h, of 5% to 55% in 4 h and of 20% to 75% in 10 h.

According to a further preferred embodiment of the composition according to the invention, it is provided that the composition has an in vitro release rate of the active ingredient of 0% to 50% in 1 h, 10% to 95% in 4 h, 35% to 100% in 8 h, from 55% to 100% in 12 h, from 70% to 100% in 16 h and of more than 90% in 24 h.

According to a further preferred embodiment of the composition according to the invention, it is provided that the composition has an in vitro release rate of the active ingredient of 0% to 30% in 1 h, 0% to 40% in 2 h, 3% to 55% in 4 h, from 10% to 65% in 8 h, from 20% to 75% in 12 h, from 30% to 88% in 16 h, from 50% to 100% in 24 h and of more than 80% in 36 h having.

According to a further preferred embodiment of the composition according to the invention, it is provided that the composition has an in vitro release rate of the active ingredient of 10% to 30% in 1 h, 17% to 37% in 2 h, 27% to 47% in 4 h, from 40% to 60% in 8 h, from 50% to 70% in 12 h, from 60% to 80% in 16 h, from 80% to 100% in 24 h.

According to a particularly preferred embodiment of the composition according to the invention, it is provided that the composition releases the active ingredient naloxone regardless of the ambient pH of the gastrointestinal tract. This ensures that the entire gastrointestinal tract can be supplied with naloxone or a salt thereof uniformly and continuously, independently of the respective local pH environment, whereby a further optimization of the treatment success can be achieved. The pH-independent release of active ingredient of the composition according to the invention can be known to the person skilled in the art by selection pharmaceutical excipients are obtained, wherein in the gastrointestinal tract local pH values of about 1.2 (stomach) prevail to about 6.8 colon.

According to the invention, a release of the active ingredient of the composition according to the invention independent of the ambient pH of the gastrointestinal tract is preferably understood according to the invention as meaning that the similarity factor f2 of a first in vitro release is at a pH of 1.2 to 6.8 and a second in vitro release at any other pH of 1.2 to 6.8 is greater than or equal to 50.

The similarity factor f2 is determined according to SHAH V.P., TSONG Y., SATHE P., & LIU J.P. (1998), "In vitro dissolution profile comparison statistics and analysis of the similarity factor, f2", Pharmaceutical Research, 15, 889-896. Namely, the similarity factor f2 (English, similarity factor) is calculated according to the following formula:

/ ₂ = 50 - tep _lc ([!

In this equation, Rt and Tt represent the amounts of drug released at time t at the first pH and at the second pH, respectively. N is the number of times. The f2 factor is determined under the following conditions: a) the minimum number of times for release is 3 (time 0 is excluded), b) the times for the first and second pH should be the same; (c) for the released quantities for each time point, an average value of 12 measurements is given for each pH; (d) not more than an average measured above a release of 85% may be included in the calculation, (e) the relative standard deviation or Coefficient of variation of release at one pH should be less than 20% for the first time and less than 10% for the second and any further time.

For the f2 factor calculation, the in vitro release profiles are determined using the paddle stirrer apparatus (Apparatus 2) and the paddle stirrer method according to Eur.Ph. (European Pharmacopoeia, 7th edition, 3rd supplement, 2.9.3 "release of active ingredient from solid dosage forms", pp 5519-5526) at 75 rev / min in 500 ml buffer (according to European Pharmacopoeia, 7th edition, 7th supplement, 4.1.3 "Buffer Solutions", p. 7671-7679) at 37 ° C. The amount of drug released is determined by UV detection at 220 nm. According to a further preferred embodiment of the composition according to the invention, it is provided that the composition comprises a matrix which releases the active ingredient in a retarded manner.

In particular, the active ingredient can be released in a delayed-release manner if it is contained in a sustained release matrix.

The composition of the invention may comprise a matrix which releases the naloxone or the pharmaceutically acceptable salt thereof retarded. According to the invention, the matrix may preferably be a so-called scaffold matrix, which may be swellable or non-swellable, or a so-called eroding matrix. The matrix may also have properties of both skeleton matrix and eroding matrix.

In a scaffold matrix, the active ingredient is incorporated in a matrix scaffold. During transport of the loaded scaffold matrix through the gastrointestinal tract, the active ingredient is gradually leached out of the matrix scaffold by the digestive juices. After this is done, the matrix framework is eliminated in a more or less unchanged or swollen form. In the case of an eroding matrix, on the other hand, the matrix is degraded or eroded, as a result of which active ingredient particles reach the surface and dissolve. The release rate depends on the extent of the matrix degradation or its erosion.

In terms of the formation of a largely stable scaffold matrix with suitable release of active ingredient, it is provided according to a further preferred embodiment of the composition according to the invention that the matrix comprises one or more water-insoluble matrix formers. In an alternative embodiment, it is provided that the matrix comprises one or more water-soluble matrix formers.

According to a further preferred embodiment of the composition according to the invention, it is provided that the matrix is water-insoluble.

According to a further preferred embodiment of the composition according to the invention, it is provided that the matrix comprises as matrix former one or more compounds selected from the group consisting of cellulose esters, cellulose ethers, polyethylene oxide, polyvinylpyrrolidone / polyvinyl acetate mixtures, methacrylate-acrylate copolymers, waxes, fats such as for example, glycerol esters and fatty alcohols. The substance classes mentioned are particularly suitable as matrix formers for the composition according to the invention, wherein, according to the invention, preference is given in particular to polyvinyl acetate mixed with a polyvinylpyrrolidone and / or a glycerol-di-behenic acid ester as matrix former. It is preferred that the solid oral pharmaceutical composition include a glycerol di-behenic acid ester matrix as one of the matrix formers.

In this case, the preferred mass ratio of naloxone to the matrix image (s) comprises values between 1: 1 and 1:10.

With respect to the naloxone matrix, in a preferred embodiment, the composition includes glycerol di-behenic acid ester as a matrix former in an amount of 10-50% by weight. More preferably, the composition includes glycerol di-behenic acid ester in an amount of 10-50% by weight, preferably in an amount of 15-45% by weight, more preferably 20-35%, and most preferably 25-30% by weight.

Preferred is glycerol di-behenic acid ester in an amount of 29.4% by weight relative to the naloxone matrix.

According to a further preferred embodiment of the composition according to the invention, it is provided that the composition is free of film-coated, naloxone-containing particles, wherein the filming causes the sustained release of the naloxone.

According to a further preferred embodiment of the composition according to the invention, it is provided that the composition is directly tabletted, since this is particularly cost-effective.

According to a further preferred embodiment of the composition according to the invention, it is provided that the composition is in the form of a tablet, capsule, granules, a microtablet, extruded particles or granules compressed into a tablet.

According to a further preferred embodiment of the composition according to the invention, it is provided that the composition is in the form of a once-a-day (once-a-day-formulation) or a twice-a-day-formulation.

In the composition of the present invention, the active ingredient is naloxone or a pharmaceutically acceptable salt thereof, with naloxone hydrochloride being particularly preferred because of its solubility and stability. One or more further active ingredients may be present in the composition. The naloxone or the pharmaceutically acceptable salt thereof is preferably contained in the composition of the present invention in an amount of 0.1 to 500 mg, more preferably in an amount of 1 mg to 50 mg, and most preferably in an amount of 3 mg, 6 mg , 12 mg, 24 mg, 36 mg or 48 mg.

The present invention further relates to the use of the composition of the invention for the treatment of opioid-induced constipation.

With regard to a composition which is particularly suitable for twice daily administration, the present invention further relates to a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient in a retarded manner and an in vitro Release rate of the active ingredient, measured using the paddle stirrer method according to Eur. Ph. At 75 rpm in 500 ml of 0.1 N hydrochloric acid at 37 ° C., from 5% to 50% in 1 h, from 10% to 75% in 2 h, from 20% to 95% in 4 h, from 40% to 100% in 8 h, of more than 50% in 12 h, of more than 70% in 18 h and of more than 80% in 24 h having.

With regard to a composition which is particularly suitable for twice daily administration, the present invention further relates to a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient in a retarded manner and an in vitro Release rate of the active ingredient, measured using the paddle stirrer method according to Eur. Ph. At 75 rpm in 500 ml of 0.1 N hydrochloric acid at 37 ° C., from 20% to 50% in 1 h, from 40% to 75% in 2 h, from 60% to 95% in 4 h, from 80% to 100% in 8 h and from 90% to 100% in 12 h.

With regard to a composition which is particularly suitable for once-daily administration, the present invention further relates to a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient in a retarded manner and an in vitro Release rate of the active ingredient, measured using the paddle stirrer method according to Eur. Ph. At 75 rpm in 500 ml of 0.1 N hydrochloric acid at 37 ° C., from 0% to 50% in 1 h, from 0% to 75% in 2 h, from 10% to 95% in 4 h, from 35% to 100% in 8 h, from 55% to 100% in 12 h, from 70% to 100% in 16 h and of more than 90% in 24 h. With regard to a composition particularly suitable for once-daily administration, the present invention further relates to a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the

Composition releases the drug retarded and an in vitro release rate of

Active ingredient, measured using the paddle stirrer method according to Eur. Ph. At 75 rpm in

500 ml of 0.1 N hydrochloric acid at 37 ° C, from 0% to 30% in 1 h, from 0% to 40% in 2 h, from 3% to 55% in

4 h, from 10% to 65% in 8 h, from 20% to 75% in 12 h, from 30% to 88% in 16 h, from 50% to 100% in 24 h and of more than 80% in 36 h.

With regard to a composition which is particularly suitable for once-daily administration, the present invention further relates to a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient in a retarded manner and an in vitro Release rate of the active ingredient, measured using the paddle stirrer method according to Eur. Ph. At 75 rpm in 500 ml of 0.1 N hydrochloric acid at 37 ° C., from 10% to 30% in 1 h, from 17% to 37% in 2 h, from 27% to 47% in 4 h, from 40% to 60% in 8 h, from 50% to 70% in 12 h, from 60% to 80% in 16 h, from 80% to 100% in 24 hours.

In the interests of good patient compliance, it is provided according to a further preferred embodiment of the composition according to the invention that the composition, preferably a tablet or a capsule, a in wiro-release rate of the active ingredient, measured using the Blattrührer method according to Eur. Ph In 500 ml of 0.1 N hydrochloric acid at 37 ° C, from 0% to 75% in 2 h, from 3% to 95% in 4 h, from 20% to 100% in 10 h, from 30% to 100% in 16 h, from 50% to 100% in 24 h and more than 80% in 36 h.

According to a further preferred embodiment of the composition according to the invention, with a view to providing a composition which is suitable for at least 12 h for the treatment of opioid-induced constipation, the composition is intended to have an in vitro release rate of the active ingredient of 0% to 50% % in 2 h, from 5% to 95% in 4 h, from 20% to 90% in 10 h, of more than 70% in 18 h and of more than 80% in 24 h.

According to the invention, the rate of release is regulated by adjusting the mass ratio of naloxone to matrix former. In a preferred embodiment, the mass ratio of naloxone to matrix images is 1: 1, more preferably 1: 2, even more preferably 1: 3, even more preferably 1: 4, more preferably 1: 5, more preferably 1: 6, even more preferably 1: 7, even more preferably 1: 8, more preferably 1: 9 and most preferably 1:10.

The composition according to the invention is characterized in that the concentration of naloxone in the plasma is extremely low due to the retardation. Compared with a non-sustained-release composition, the maximum plasma concentration (C _max ) over the course of action is about 20 times lower and 100 times lower compared to an intravenous composition.

The inhibition of the receptors, however, is better overall over the course of action. The low bioavailability in the system therefore ensures, in addition to the anti-obstruction effects of naloxone, a reduced probability and / or severity of side effects.

Since the inhibitory concentrations (IC ₅₀ ) of naloxone are known for the opioid receptors (μ, δ and κ), a new IC ₅₀ / C _{ma <} value results, which allow an estimation of the risks of the tablet. When using the IC ₅₀ for the μ receptor, for a tablet according to the invention with naloxone at 48 mg, an IC ₅₀ / C _max value of 54 is obtained. Generally, the higher the IC ₅ o / C value, the lower are the risks of the tablet according to the invention. In the following, all information refers to the IC ₅₀ for the μ receptor.

In a preferred embodiment, the composition has an IC ₅₀ / C _max of at least 30. In a more preferred embodiment, the composition has an IC ₅₀ / _Cmax of at least 35. In a more preferred embodiment, the composition has an IC ₅₀ / C _max of at least 40. In the most preferred embodiment, the composition has an IC ₅₀ / C _max of at least 50.

In addition, a particularly high value for the ratio t _{max of} the active substance naloxone, to the t _{max of} its metabolite naloxone-3-glucuronide, is characteristic of the present composition. T _max is a classic parameter in pharmacokinetics and describes the time to maximum plasma concentration of a substance.

The higher the value of the ratio T _max (naloxone) to T _max (naloxone-3-glucuronide), the slower the active ingredient is released from the composition and metabolized. Thus, the effect of the antagonist lasts longer. Surprisingly, the inventors have found that so too are the side effects of

Antagonists are lower. For example, the reduction of the opioid effect is lower and also the

Withdrawal symptoms.

It is preferred that the composition comprises a t _max (naloxone) / t _max (naloxone-3-glucuronoid) value of at least 5.

In a further embodiment, the composition additionally comprises at least one stabilizer which protects the active ingredient. In a preferred embodiment, this is at least one stabilizer selected from the list comprising sulfur dioxide, sodium sulfite, sodium bisulfite, ascorbic acid and derivatives thereof and tocopherol and its water and fat soluble derivatives such. As tocopherol acetate, sulfites, bisulfites and hydrogen sulfites of alkali earth alkaline and other metals, PHB esters, BHA, BHT, gallates and lower fatty acids, fruit acids, phosphoric acids, sorbic and benzoic acid and their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate , Lecithins, mono- and polyhydroxylated benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cystine, conidendrines, diethyl carbonates, methylenedioxyphenols, cephalins, β, β'-dithiopropionic acid, biphenyl and other phenyl derivatives.

In a further embodiment, the composition additionally comprises at least one stabilizer which protects the matrix. In a preferred embodiment, this is at least one stabilizer selected from the list comprising butylhydroxytoluene, sulfur dioxide, sodium sulfite, sodium bisulfite, ascorbic acid and derivatives thereof and tocopherol and its water and fat soluble derivatives such. As tocopherol acetate, sulfites, bisulfites and hydrogen sulfites of alkali earth alkaline and other metals, PHB esters, BHA, BHT, gallates and lower fatty acids, fruit acids, phosphoric acids, sorbic and benzoic acid and their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate , Lecithins, mono- and polyhydroxylated benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cystine, conidendrines, diethyl carbonates, methylenedioxyphenols, cephalins, β, β'-dithiopropionic acid, biphenyl and other phenyl derivatives.

In a further embodiment, the composition comprises at least one additive, wherein the additive is an emetic or a Scharf substance drug. In a preferred embodiment, the composition comprises an additive, which is a drug substance selected from the group comprising Allii sativi Bulbus, Asari Rhizoma c. Herba, Calami Rhizoma, Capsici Fructus (Paprika), Capsici Fructus acer (Cayenne pepper), Curcumae longae Rhizoma, Curcumae xanthorrhizae Rhizoma, Galangae Rhizoma, Myristicae Semen, Piperis nigri Fructus (pepper), Sinapis albae (Erucae)

Semen, Sinapis nigri Semen, Zedoariae Rhizoma and Zingiberis Rhizoma, more preferably from the group consisting of Capsici Fructus (paprika), Capsici Fructus acer (cayenne pepper) and

Piperis nigri Fructus (pepper).

In a preferred embodiment, the composition comprises at least one additive, which is an emetic. In a preferred embodiment, the emetic is based on one or more ingredients of Radix Ipecacuanhae (vomiting root). In a preferred embodiment, the emetic is based on the ingredient emetine, in an alternative embodiment, the emetic is apomorphine.

In another embodiment, the composition comprises a dye. In a preferred embodiment, this dye is selected from the group comprising red iron oxide, black iron oxide and indigo carmine.

In a further embodiment, the composition additionally comprises at least one non-steroidal anti-inflammatory or antihistamine.

In an alternative embodiment, the composition additionally comprises at least one water-soluble lubricant. In a preferred embodiment, the composition comprises at least one water-soluble lubricant selected from the group comprising adipic acid, fumaric acid, sodium benzoate and macrogols.

It is also an object of the present invention to provide a tablet comprising as active ingredients an opioid agonist or a pharmaceutically acceptable salt thereof and an opioid antagonist or a pharmaceutically acceptable salt thereof which is suitable for the parallel treatment of pain and opioid induced constipation , wherein by means of the tablet, an individual treatment success can be easily optimized.

This object is achieved by a multi-layer tablet comprising at least

a first drug layer containing as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof; and

a second active ingredient layer containing as active ingredient an opioid antagonist or a

contains pharmaceutically acceptable salt thereof, wherein at least the second active ingredient layer releases the active ingredient in a retarded manner. In a preferred

Embodiment put the first and the second drug layer releases the drug retarded. The

Multi-layer tablet may also comprise other active ingredients.

The multilayer tablet according to the invention is suitable for the parallel treatment of pain and opioid-induced constipation, wherein a variable release kinetics for each active ingredient can be easily realized and therefore an individual treatment success can be easily optimized.

The multilayer tablet according to the invention also has the advantage that in each layer a different etardierungssystem, e.g. can be used with a sustained-release layer coated pellets or a retarded releasing matrix. As a result, a specific release kinetics for each active ingredient and a variable ratio of the active ingredients individually adapted to a specific patient can be realized particularly easily.

In addition, the multilayer tablet according to the invention has the advantage that much more precise dosages of the two active substances are possible by means of the same. This comes into play especially for small doses.

In addition, the tablet according to the invention is advantageous if the two active ingredients are incompatible with one another.

According to a particularly preferred embodiment of the multilayer tablet according to the invention, it is provided that the multilayer tablet is a two-layer tablet. The multilayer tablet according to the invention can be realized in the form of a two-layer tablet in terms of process technology, simply and thus cost-effectively.

According to a further preferred embodiment of the multilayer tablet according to the invention, it is provided that the second active substance layer comprises a matrix which retards the release of the opioid antagonist or the pharmaceutically acceptable salt thereof. A retardant-acting matrix can be produced in terms of process technology simply and thus inexpensively. According to the invention, the matrix may preferably be a so-called scaffold matrix, which may be swellable or non-swellable, or a so-called eroding matrix. The matrix may also have properties of both skeleton matrix and eroding matrix. In a scaffold matrix, the active ingredient is incorporated in a matrix scaffold. During the

Transport the loaded skeletal matrix through the gastrointestinal tract, the drug is gradually dissolved out of the digestive juices from the matrix framework. After this is done, the matrix framework is eliminated in a more or less unchanged or swollen form. In the case of an eroding matrix, on the other hand, the matrix is degraded or eroded, as a result of which active ingredient particles reach the surface and dissolve. It is the

Rate of release depends on the extent of the matrix degradation or its erosion.

According to a further preferred embodiment of the multilayer tablet according to the invention, it is provided that the matrix contains one or more water-insoluble matrix formers. In an alternative embodiment it is provided that the matrix contains one or more water-soluble matrix formers.

According to a further preferred embodiment of the multilayer tablet according to the invention, it is provided that the matrix comprises as matrix former one or more constituents selected from the group consisting of cellulose esters, cellulose ethers, polyvinylpyrrolidone / polyvinyl acetate mixtures, methacrylate-acrylate copolymers, polyethylene oxide waxes, fats such as glycerol esters , and fatty alcohols. Said constituents are particularly suitable as matrix formers for the tablet according to the invention, wherein according to the invention it is preferred in particular to use polyvinyl acetate mixed with a polyvinylpyrrolidone and / or a glycerol-di-behenic acid ester as matrix former.

According to the invention, the rate of release is regulated by adjusting the mass ratio of naloxone to matrix former. In a preferred embodiment, the mass ratio of naloxone to matrix images is 1: 1, more preferably 1: 2, even more preferably 1: 3, even more preferably 1: 4, more preferably 1: 5, more preferably 1: 6, even more preferably 1: 7, even more preferred 1: 8, more preferably 1: 9 and most preferably 1:10.

With respect to the naloxone matrix, in a preferred embodiment, the multilayer tablet contains glycerol di-behenic acid ester as a matrix former in an amount of 10-50% by weight. More preferably, the multi-layer tablet contains glycerol di-behenic acid ester in an amount of 15-45% by weight, more preferably 20-35%, and most preferably 25-30% by weight.

Preferred is glycerol di-behenic acid ester in an amount of 29.4% by weight relative to the naloxone matrix. According to a further preferred embodiment of the multilayer tablet according to the invention, it is provided that the second active substance layer releases the active ingredient, ie the opioid antagonist or the pharmaceutically acceptable salt thereof, independently of the ambient pH of the gastrointestinal tract. This ensures that the entire gastrointestinal tract is supplied with the opioid antagonist or a salt thereof, regardless of the particular local pH environment, so that a further optimization of the treatment success can be achieved. The pH-independent release of active ingredient of the composition according to the invention can be achieved by selecting suitable components, with local pH values in the gastrointestinal tract of about 1.2 (stomach) to about 7.0 colon.

According to a further preferred embodiment of the multilayer tablet according to the invention, it is provided that the opioid antagonist is selected from the group consisting of naloxone, N-methylnaloxone and N-methylnaltrexone and pharmaceutically acceptable salts thereof, wherein naloxone hydrochloride is particularly preferred according to the invention.

According to a further preferred embodiment of the multilayer tablet according to the invention, it is provided that the opioid agonist or the pharmaceutically acceptable salt thereof is contained in the first active ingredient layer in the form of pellets containing the opioid agonist and to which the release of the opioid agonist Agonist retarding layer is applied.

According to a further preferred embodiment, the multilayer tablet has an IC ₅ o / C value for naloxone of at least 30. In a preferred embodiment, the multilayer tablet has an IC ₅₀ / C _max value of at least 35. In a more preferred embodiment, the multilayer tablet has an IC ₅₀ / C _max value of at least 40. In the most preferred embodiment, the multilayer tablet has an IC ₅₀ / C _{ma) <} value of at least 50.

It is preferred that the multi-layer tablet comprises a t _max (naloxone) / t _max (naloxone-3-glucuronoid) value of at least 5.

According to a further preferred embodiment of the multilayer tablet according to the invention, it is provided that opioid agonist is selected from the group comprising: alfentanil, allylprodin, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, besomorphine, dextromoramide, decocin, Diampromid, diamorphone, Dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,

Dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,

Etonitazen, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,

Ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocin,

Methadone, Metopon, Morphine, Myrophin, Narcein, Nicomorphine, Norlevorphanol, Normethadone,

Nalorphine, nalbuphen, normorphin, norpipanone, opium, oxycodone, oxymorphone, papaveretum,

Pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodin, piritramide,

Propheptazine, promedol, propranidine, propoxyphene, sufentanil, tilidine, and tramadol and their pharmaceutically acceptable salts, hydrocodone, morphine, hydromorphone, oxycodone,

Buprenorphine, codeine, fentanyl, levorphanol, meperidine, methadone, levomethadone and

Dextromethadone and their pharmaceutically acceptable salts are particularly preferred according to the invention.

According to a further preferred embodiment of the multilayer tablet according to the invention, it is provided that at least the second active ingredient layer is directly tabletted, since this is so particularly inexpensive to produce.

In a further embodiment, the multilayer tablet additionally comprises at least one stabilizer which protects the active ingredient naloxone. In a preferred embodiment, this is at least one stabilizer selected from the list comprising sulfur dioxide, sodium sulfite, sodium bisulfite, ascorbic acid and derivatives thereof and tocopherol and its water and fat soluble derivatives such. As tocopherol acetate, sulfites, bisulfites and hydrogen sulfites of alkali earth alkaline and other metals, PHB esters, BHA, BHT, gallates and lower fatty acids, fruit acids, phosphoric acids, sorbic and benzoic acid and their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate , Lecithins, mono- and polyhydroxylated benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cyctin, conidendrins, diethyl carbonates, methylenedioxyphenols, cephalins, ß, ß'-dithiopropionic acid, biphenyl and other phenyl derivatives.

In a further embodiment, the multilayer tablet additionally comprises at least one stabilizer which protects the matrix. In a preferred embodiment, this is at least one stabilizer selected from the list comprising butylhydroxytoluene, sulfur dioxide, sodium sulfite, sodium bisulfite, ascorbic acid and derivatives thereof and tocopherol and its water and fat soluble derivatives such. As tocopherol acetate, sulfites, bisulfites and hydrogen sulfites of alkali earth alkaline and other metals, PHB esters, BHA, BHT, gallates and lower fatty acids, fruit acids, phosphoric acids, sorbic and benzoic acid and their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate, lecithins, mono- and polyhydroxylated

Benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cystine,

Conidendrines, diethyl carbonates, methylenedioxyphenols, cephalins, ß, ß'-dithiopropionic acid,

Biphenyl and other phenyl derivatives.

In a further embodiment, the multilayer tablet comprises at least one additive, wherein the additive is an emetic or a Scharf substance drug. In a preferred embodiment, the composition comprises an additive, which is a drug substance selected from the group comprising Allii sativi Bulbus, Asari Rhizoma c. Herba, Calami Rhizoma, Capsici Fructus (Paprika), Capsici Fructus acer (Cayenne), Curcumae longae Rhizoma, Curcumae xanthorrhizae Rhizoma, Galangae Rhizoma, Myristicae Semen, Piperis nigri Fructus (pepper), Sinapis albae (Erucae) Semen, Sinapis nigri Semen, Zedoariae Rhizoma and Zingiberis Rhizoma, particularly preferred from the group consisting of Capsici Fructus (paprika), Capsici Fructus acer (cayenne pepper) and Piperis nigri Fructus (pepper).

In a preferred embodiment, the multilayer tablet comprises at least one additive, which is an emetic. In a preferred embodiment, the emetic is based on one or more ingredients of Radix Ipecacuanhae (vomiting root). In a preferred embodiment, the emetic is based on the ingredient emetine, in an alternative embodiment, the emetic is apomorphine.

In a further embodiment, the multilayer tablet comprises a dye. In a preferred embodiment, this dye is selected from the group comprising red iron oxide, black iron oxide and indigo carmine.

In an alternative embodiment, the composition additionally comprises at least one water-soluble lubricant. In a preferred embodiment, the composition comprises at least one water-soluble lubricant selected from the group comprising adipic acid, fumaric acid, sodium benzoate and macrogols. According to a further preferred embodiment of the invention

Multi-layer tablet, it is provided that the tablet is designed for once-daily administration

(Once-daily-formulation).

According to a further preferred embodiment of the multilayer tablet according to the invention, it is provided that the tablet is designed for twice-daily administration (twice-daily-formulation).

According to a further preferred embodiment of the multilayer tablet according to the invention, it is provided that the multilayer tablet contains from 0.1 mg to 500 mg of the opioid agonist or a pharmaceutically acceptable salt thereof and from 0.1 mg to 500 mg of the opioid antagonist or of a pharmaceutically acceptable salt thereof, according to the invention particularly preferably in a ratio (agonist: antagonist) of 1:10 to 10: 1.

The present invention further relates to a first method for producing the multilayer tablet according to the invention, comprising the steps

Providing a first tableting composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof, and optionally a doping agent;

Providing a second tableting composition comprising as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof, and a

retarding agent;

- Filling a first filling shoe of a tablet pressing tool with the first

Tablettiermasse and a second filling shoe of the tablet press tool with the second Tablettiermasse;

- Pressing the first and second Tablettiermasse to obtain a multilayer tablet.

The present invention further relates to a second method for producing the multilayer tablet according to the invention, comprising the steps

Providing a first tableting composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof, wherein the opioid agonist or the pharmaceutically acceptable salt thereof is contained in the first tabletting mass in the form of pellets containing and containing the opioid agonist a layer releasing the release of the opioid agonist is applied; Providing a second tabletting composition comprising as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof and a doping agent;

- Filling a first filling shoe of a tablet pressing tool with the first

- Pressing the first and second Tablettiermasse to obtain a multilayer tablet.

In a preferred embodiment, the second tabletting mass has an IC ₅₀ / C _max value of at least 30. In a more preferred embodiment, the second tabletting mass has an IC ₅ o / C value of at least 35. In a further preferred embodiment, the second tabletting compound has an IC ₅₀ / C _max value of at least 40. In the most preferred embodiment, the second tabletting mass has an IC ₅₀ / C _{ma) <} value of at least 50.

Furthermore, it is preferred that the second tabletting mass comprises a matrix with at least one matrix former as retarding agent. In this case, the preferred mass ratio of antagonist in the second tableting mass to the matrix image or images comprises values between 1: 1 and 1:10.

With respect to the naloxone matrix, in a preferred embodiment, the second tableting mass contains glycerol di-behenic acid ester as a matrix former in an amount of 10-50% by weight.

More preferably, the second tabletting mass comprises glycerol di-behenic acid ester in an amount of 15-45% by weight, more preferably 20-35%, and most preferably 25-30% by weight.

Furthermore, it is preferred that the multilayer tablet produced by one of the methods comprises a t _max (naloxone) / t _max (naloxone-3-glucuronoid) value of at least 5.

The present invention further relates to the use of the multilayer tablet according to the invention for the treatment of pain and for the simultaneous treatment of opioid-induced constipation. The following embodiments serve to explain the invention.

EXAMPLES

ORAL COMPOSITION

The following embodiments serve in conjunction with the drawings to explain the invention. It shows:

Fig. 1: Release profiles of the tablets according to the embodiments 1 and 2.

Embodiment 1

Tablets of the following composition were prepared:

The ingredients naloxone hydrochloride and glycerol di-benzenic acid ester were sieved and mixed together. To the resulting mixture was added first the colloidal silica in sieved form and then the magnesium stearate. The mixture thus obtained was compressed to tablets by means of a conventional tablet press. Embodiment 2:

Tablets of the following composition were prepared analogously to Example 1:

Kollidon ^® SR consisting of 80% by weight of polyvinyl acetate, 19% by weight of povidone, 0.8% by weight of sodium lauryl sulfate and 0.2% by weight of colloidal silica.

Embodiment 3

Two-layer coated tablets of the following composition were prepared:

Placebo layer

Sugar pellets (diameter: 500-600 carriers 10.00 μηι)

Hypromellose filler 10.00 microcrystalline cellulose filler 10.00 colloidal silica flow control agent 0.25

Magnesium stearate lubricant 0.25

Total weight of placebo layer 30.50

Total weight of 56.00 two-layer tablet core

Opadry tablet film 3.00

Total weight of the 59.00 two-layer tablet

The components of the naloxone-layer, ie, naloxone hydrochloride, Kollidon ^® SR, glycerol-di- behenic acid, colloidal silica and magnesium stearate were sieved and mixed together to form a first powdery mixture. Further, the ingredients of the placebo layer, ie, sugar pellets, hypromellose, microcrystalline cellulose, colloidal silica and magnesium stearate were sieved and mixed together to form a second powdered mixture.

The first and second mixtures were compressed by means of a conventional two-layer tablet press into two-layer tablet cores. The two-layer tablet cores thus obtained were dissolved in a coater using Opadry ^® film-coated in water at a temperature of 30 ° C to 50 ° C to give two-layer tablets.

release profiles

The in vitro release profiles of the tablets according to embodiments 1 and 2 were determined using the paddle stirrer apparatus (apparatus 2) and the Blattrüh rer method according to Eur.Ph. (European Pharmacopoeia, Seventh Edition, 3rd Amendment, 2.9.3 "Release of Active Substance from Solid Pharmaceutical Forms", pp. 5519-5526) at 75 rpm in 500 ml of 0.1 N hydrochloric acid at 37 ° C. The amount released drug was determined by UV detection at 220 nm. The in vitro release profiles of the tablets according to the embodiments 1 (♦) and 2 (x) are shown in FIG.

MULTI-LAYER TABLET

Embodiment 1

Two-layered coated tablets of the following composition were prepared:

The components of the oxycodone layer, ie the retarded oxycodone pellets, microcrystalline

Cellulose, colloidal silica and magnesium stearate were screened and mixed together to a first mixture.

Further, the components of the naloxone layer were ie naloxone hydrochloride, Kollidon ^® SR, colloidal silicon dioxide and magnesium stearate sieved and mixed together to form a second powdery mixture.

The first and second mixtures were compressed to two-layer tablet cores using a conventional two-layer tablet press. The two-layer tablet cores thus obtained were dissolved in a coater using Opadry II ^® film-coated in water at a temperature of 30 ° C to 50 ° C.

The retarded oxycodone pellets had the following composition and were prepared as known in the art.

Opadry II ^® consists of polyvinyl alcohol, iron oxide or titanium dioxide, macrogol and talc. Embodiment 2:

There were prepared double-layered coated tablets of the following composition as in Example 1:

Embodiment 3

List of Figures

Figure 1: Release profile of naloxone from a composition according to the invention.

Claims

De WO 2016/091805 Weiz AG CH ilger Anwalt pCT / Ep2015 / 078827Switzerland Fasanenstraße 29Our sign: B193-0007WO1 10719 Berlin PATENT CLAIMS

1. A solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, the composition comprising a matrix with glycerol di-behenic acid ester as matrix former, in a mass ratio of naloxone to matrix image (s) between 1: 1 and 1: 10, wherein retarded by the matrix the drug is release, and when in i // ^{'froFreisetzungsrate} of the drug naloxone, measured using the Paddle method described in accordance with Eur. Ph. at 75 U / min in 500 ml of 0.1 N hydrochloric acid 37 ° C, from 0% to 75% in 2 h, from 3% to 95% in 4 h, from 20% to 100% in 10 h, from 30% to 100% in 16 h, from 50% to 100% in 24 hours and more than 80% in 36 hours, and the composition has an IC ₅₀ / C _max of at least 40.

A composition according to claim 1 wherein the composition is glycerol di-behenic acid ester, in

With respect to the naloxone matrix, in an amount of 10-50% by weight (w / w), preferably 15-45% w / w, 20-40% w / w, and 25-35% w / w.

The composition of claim 1, wherein the composition includes glycerol di-behenic acid ester in an amount of 29.4% with respect to the naloxone matrix.

A composition according to any one of the preceding claims, wherein the composition comprises a t _max (naloxone) / t _max (naloxone-3-glucuronoid) value of at least 5.

A composition according to any one of the preceding claims wherein the composition releases the active ingredient naloxone independently of the ambient pH of the gastrointestinal tract.

Composition according to any one of the preceding claims, characterized in that the composition has an in vitro release rate of naloxone from 0% to 50% in 2 h, from 5% to 95% in 4 h, from 20% to 90% in 10 h, of more than 70% in 18 h and of more than 80% in 24 ha.

7. Composition according to one of claims 1 to 5, characterized in that the

Composition has an in vitro release rate of the active ingredient from 0% to 38% in 2 h, from 5% to 55% in 4 h and from 20% to 75% in 10 h.

8. Composition according to one of claims 1 to 5, characterized in that the

Composition an in vitro release rate of the active ingredient from 0% to 50% in 1 h, from 10% to 95% in 4 h, from 35% to 100% in 8 h, from 55% to 100% in 12 h, of 70 % to 100% in 16 hours and more than 90% in 24 hours.

9. Composition according to one of claims 1 to 5, characterized in that the

Composition an in vitro release rate of the active ingredient from 0% to 30% in 1 h, from 0% to 40% in 2 h, from 3% to 55% in 4 h, from 10% to 65% in 8 h, of 20 % to 75% in 12 h, from 30% to 88% in 16 h, from 50% to 100% in 24 h and of more than 80% in 36 h.

Composition according to any one of the preceding claims, characterized in that the composition is directly tabletted.

11. Composition according to one of the preceding claims, characterized in that the composition is formed as a once-daily formulation.

12. Composition according to one of the preceding claims 1 to 10, characterized in that the composition is designed as a twice-daily formulation.

13. multilayer tablet comprising at least

a second active substance layer containing as active ingredient an opioid antagonist in a matrix with at least one matrix former,

wherein the first and second drug layer release the drug retarded and the second drug layer has an IC50 / Cmax value of at least 40 and a mass ratio of antagonist to matrix image (s) between 1: 1 and 1:10 comprises.

14. multilayer tablet, comprising at least:

a second active substance layer which as active ingredient is an opioid antagonist wherein the first and the second active substance layer release the active substance in a retarded manner and the second

Drug layer has an IC50 / Cmax value of at least 40, and a tmax (antagonist) / tmax (antagonist metabolite) value of at least 5.

15. The multilayer tablet according to claim 13 or 14, wherein the composition comprises glycerol di-behenic acid ester as a matrix former.

The multilayer tablet of claim 15, wherein the composition comprises glycerol di-behenic acid ester in an amount of 20-40% weight / weight with respect to the naloxone matrix.

The multilayer tablet of claim 16, wherein the composition comprises glycerol di-behenic acid ester in an amount of 29.4% with respect to the naloxone matrix.

18. multilayer tablet according to any one of the preceding claims 13 to 17, characterized

in that the opioid agonist or the pharmaceutically acceptable salt thereof is contained in the first active substance layer in the form of pellets containing the opioid agonist and to which a release-inhibiting opioid agonist layer is applied.

19. multilayer tablet according to any one of the preceding claims 13 to 18, characterized

characterized in that the opioid agonist is selected from the group consisting of

Hydrocodone, morphine, hydromorphone, oxymorphone, oxycodone, buprenorphine, codeine, fentanyl, levorphanol, meperidine, methadone, levomethadone and dextromethadone and theirs

pharmaceutically acceptable salts.

20. A method for producing a multilayer tablet according to any one of claims 13 to 19,

comprising the steps:

Providing a first tabletting composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof and a doping agent;

Providing a second tableting composition comprising as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof and at least one retarding agent, characterized in that the second tableting composition has an IC ₅₀ / C _max value of at least 40 and a mass ratio of antagonist to retardant (n) between 1: 1 and 1:10. - Filling a first filling shoe of a Ta blettenpresswerkzeuges with the first

- Pressing the first and second Tablettiermasse to obtain a multilayer tablet.

21. A process for producing a multilayer tablet according to any one of claims 13 to 19,

comprising the steps

Providing a first tableting composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof, wherein the opioid agonist or the pharmaceutically acceptable salt thereof is contained in the first tabletting mass in the form of pellets containing and containing the opioid agonist a layer which releases the release of the opioid agonist is applied,

Providing a second tabletting composition comprising as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof and a labeling agent, characterized in that the second tabletting mass has an IC50 / Cmax value of at least 40 a mass ratio of antagonist to retarding agent (s) between 1 : 1 and 1:10.

- Filling a first filling shoe of a Ta blettenpresswerkzeuges with the first Tablettiermasse and a second filling shoe of the tablet pressing tool with the second Tablettiermasse;

- Pressing the first and second Tablettiermasse to obtain a multilayer tablet.

22. A method for producing a multilayer tablet according to any one of claims 13 to 19,

comprising the steps:

Providing a first tableting composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof and a retarding agent;

Providing a second tableting composition comprising as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof and a retarding agent, characterized in that the second tabletting mass has an IC ₅₀ / C _{ma) <} value of at least 40 and a value of at least 5 for t _max (antagonist) / t _max (antagonist metabolite).

- Pressing the first and second Tablettiermasse to obtain a multilayer tablet.

23. A method for producing a multilayer tablet according to any one of claims 13 to 19, comprising the steps

Providing a second tabletting composition comprising as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof and a retarding agent, characterized in that the second tableting composition has an IC50 / Cmax value of at least 40 and a value of at least 5 for tmax (antagonist) / tmax (antagonist metabolite).

- Pressing the first and second Tablettiermasse to obtain a multilayer tablet.

24. A solid oral pharmaceutical composition according to any one of claims 1 to 12 for

Use in the treatment of opioid-induced constipation.

25. A multilayer tablet according to any one of claims 13 to 19 for use in the treatment of opioid-induced constipation.