USOO945.6986B2

(12) United States Patent (10) Patent No.: US 9.456,986 B2 Rey et al. (45) Date of Patent: Oct. 4, 2016

(54) MONO PREPARATION AND (56) References Cited MULTILAYER TABLET U.S. PATENT DOCUMENTS (71) Applicant: Develco Pharma Schweiz AG, Pratteln (CH) 8,846,090 B2 * 9/2014 Brogmann et al...... 424/484 (72) Inventors: Hélène Rey, Rosenau (FR); Olaf FOREIGN PATENT DOCUMENTS Mundszinger,s Efringen-Kirchen (DE);s WO WO95/20947 8, 1995 Isabelle Golfier, Bantzenheim (FR): WO WO 98.25613 6, 1998 Sylvia Jakob, Bernau (DE); Oliver WO WO O3,OOT8O2 1, 2003 Rusch, Basel (CH) WO WO 2009/085778 T 2009 WO WO 2011, 117306 9, 2011 (73) Assignee: Develco Pharma Schweiz AG, Pratteln WO WO 2012/0521.69 4/2012 (CH) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this European Pharmacopoeia 7.3, 29.3, "Dissolution Test for Solid patent is extended or adjusted under 35 Dosage Forms”, 2012 U.S.C. 154(b) by 0 days. European Pharmacopoeia 7.7, 4.1.3, “Buffer Solutions', 2013. Shah, Vinod P. “In Vitro Dissolution Profile Comparison—Statis (21) Appl. No.: 14/563,555 tics and Analysis of the Similarity Factor, f,”, Pharmaceutical Research, vol. 15(6), 1998, pp. 889-896. (22) Filed: Dec. 8, 2014 * cited by examiner (65) Prior Publication Data US 2015/0238420 A1 Aug. 27, 2015 Primary Examiner — Susan Tran (74) Attorney, Agent, or Firm — Ballard Spahr LLP: (30) Foreign Application Priority Data Scott Marty Dec. 11, 2013 (EP) ...... 13005759 (57) ABSTRACT Dec. 11, 2013 (EP). ... 13005,760 The present invention relates to a solid oral pharmaceutical Dec. 11, 2013 (EP) ...... 13005761 composition comprising naloxone, or a pharmaceutically acceptable Salt thereof, as an active Substance, wherein the (51) Int. Cl. composition releases the active Substance in a prolonged A6 IK 9/14 (2006.01) manner. In order to provide a composition that is Suitable for A6 IK 9/24 (2006.01) an administration period of at least twelve-hours for the A6 IK 9/00 (2006.01) treatment of -induced constipation, it is proposed that A6 IK 9/20 (2006.01) the composition should have an in vitro release rate of the A 6LX 9/50 (2006.01) active Substance measured using the paddle stirrer method A6 IK 3/485 (2006.01) according to Ph. Eur, at 75 rpm in 500 ml 0.1 N hydrochloric (52) U.S. Cl. acid at 37° C., of 0% to 75% in 2 h, of 3% to 95% in 4 h, CPC ...... A61K 9/209 (2013.01); A61K 9/0004 of 20% to 100% in 10 h, of 30% to 100% in 16 h, of 50% (2013.01); A61 K9/2077 (2013.01); A61 K to 100% in 24 h, and of more than 80% in 36 h, wherein the 9/2095 (2013.01); A61K 9/5084 (2013.01); composition has a ICso/C value of at least 40. In an A61K 31/485 (2013.01) alternative embodiment, the composition can be a multilayer (58) Field of Classification Search tablet. None See application file for complete search history. 18 Claims, 1 Drawing Sheet U.S. Patent Oct. 4, 2016 US 9,456,986 B2

US 9,456,986 B2 1. 2 NALOXONE MONO PREPARATION AND paralysing effect of the opioid on the gastrointestinal tract, MULTILAYER TABLET while after absorption it is largely metabolised during the first passage in the liver, and thereby becomes inactive. The CROSS-REFERENCE TO RELATED effect of the is thus not affected. APPLICATION 5 Since the paralysis does not only affect the duodenum and the upper part of the Small intestine, but the entire gastro This application claims priority to European Patent Appli intestinal tract, the opioid-induced constipation cannot be cation No. 13005761.5, which was filed Dec. 11, 2013, treated Successfully with a composition that releases the European Patent Application No. 13005760.7, which was naloxone rapidly. WO 2011/117306 discloses a two-layer filed Dec. 11, 2013, and European Patent Application No. 10 tablet, which in one layer contains an opioid agonist, and in 13005759.9, which was filed Dec. 11, 2013, the disclosures another layer an , wherein the tablet of each of which is incorporated herein by reference in its quickly releases both active Substances. The advantage of entirety. this double-layer is to suppress the side effects of the opioid BACKGROUND 15 agonist, but it does not focus on Suppression of the opioid induced constipation. The present invention relates to a solid oral pharmaceu The combined preparation Targin R) is available on the tical composition comprising naloxone, or a pharmaceuti market and comprises a mixture of the opioid agonist cally acceptable salt thereof, wherein the composition in the form of a hydrochloric salt, and the opioid releases the active Substance in a prolonged manner. 2O antagonist naloxone also in the form of a hydrochloric salt. The present invention also relates to a solid oral pharma In this preparation, the active substances are released in a ceutical composition comprising naloxone, or a pharmaceu prolonged manner. It is therefore suitable for the parallel tically acceptable salt thereof, for the treatment of opioid treatment of pain and opioid-induced constipation. How induced constipation. ever, this monolithic formulation has the disadvantage that The present invention relates to a tablet comprising an 25 the release rates of the two active substances are fixed. opioid agonist, or a pharmaceutically acceptable salt thereof, Individualised treatments are therefore difficult to optimise. as well as an opioid antagonist, or a pharmaceutically In addition, infusion solutions available on the market for acceptable salt thereof, as active Substances, wherein the the treatment of opioid poisoning are only naloxone com tablet releases the active Substances in a prolonged manner. bined preparations, in which naloxone and the are The present invention also relates to a solid oral pharma- 30 present in a fixed proportion to each other. However, for the ceutical composition comprising naloxone, or a pharmaceu treatment of opioid-induced constipation, it would be desir tically acceptable salt thereof, for use in for the treatment of able to have single agent naloxone preparations, since this opioid-induced constipation. would allow administering naloxone both independently of Constipation is a major side effect of opioid the nature of the opiate and in variable doses. The desired administration. It is one of the most common side effects and 35 quantity of naloxone could therefore be applied, which is particularly predominant in long-term opioid administra would lead to an optimal treatment. Naloxone single agent tion therapies, occurring in approximately 85% of patients. preparations are described in the patent literature, such as in In contrast to other opioid-induced side effects, opioid WO 98/25613 A2. However, the release of naloxone from induced constipation is a chronic phenomenon, the intensity these compositions is dependent on the ambient pH in the of which does not decrease over the course of the treatment. 40 gastrointestinal tract. A uniform application of naloxone to The effect of the opioids on the gut mobility is probably due the entire gastrointestinal tract, and therefore an optimal to binding of the opioids to the opioid receptors of the treatment, are thus not possible with Such products. gastrointestinal tract, which are present there at a relatively high density. DESCRIPTION OF THE INVENTION The aim of the atherapy proposed here is to neutralize this 45 peripheral side effect of opioids because opioid-induced The objective of the present invention is to provide a solid constipation can be uncomfortable and very painful, and oral pharmaceutical composition comprising naloxone, or a often leads to the discontinuation of the opioid-based pharmaceutically acceptable salt thereof, as an active Sub therapy, and thus endangers the Success of the treatment with stance, wherein the composition releases the active Sub the opioids. Since it can be assumed that the opioid-induced 50 stance naloxone in a prolonged manner, and is Suitable for constipation is caused directly and locally over the entire an administration period of at least twelve-hours, for the intestine through binding to the opioid receptors, this side treatment of opioid-induced constipation. effect should be eliminated through the use of opioid antago This objective is achieved by a solid oral pharmaceutical nists. However, the use of opioid antagonists only makes composition comprising naloxone, or a pharmaceutically sense if the antagonistic effect is limited to the intestine and 55 acceptable Salt thereof, as an active Substance, wherein the does not cancel the main analgesic effect. composition releases the active Substance in a prolonged Naloxone is a Suitable opioid antagonist for the treatment manner, and the in vitro release rate of the active Substance of opioid-induced constipation. Naloxone is rapidly and naloxone, measured using the paddle stirrer method accord completely absorbed after oral administration and because ing to Ph. Eur, at 75 rpm in 500 ml 0.1 N hydrochloric acid the Substance is subject to extensive first-pass metabolism, 60 at 37° C., is of 0% to 75% in 2 h, of 3% to 95% in 4 h, of only Small amounts of unmetabolised naloxone are available 20% to 100% in 10 h, of 30% to 100% in 16 h, of 50% to to the system. The vast majority of the applied Substance is 100% in 24 h, and of more than 80% in 36 h. found in blood in the form of inactive or only mildly active It was observed that the composition according to the metabolites such as naloxone-3-glucuronide or beta-6- invention, with its release profile, was Suitable for an admin . In Suitable doses, naloxone is an ideal candidate for 65 istration period of at least twelve-hours for the treatment of remedying opioid-induced constipation: in the intestine it is opioid-induced constipation. Accordingly it possesses a rela present as an active Substance and can thus counter the tively high level of patient compliance. US 9,456,986 B2 3 4 The in vitro release rate is determined using the paddle be achieved through the choice of suitable pharmaceutical stirrer apparatus (apparatus 2) with the paddle stirrer method excipients that will be known to the person skilled in the art. according to Ph. Eur. (Europäisches Arzneibuch, 7th edition, Local pH values in the gastrointestinal tract are from about 3rd supplement, 2.9.3 “Wirkstofffreisetzung aus festen 1.2 (in the stomach), to about 6.8 in the colon. Arzneiformen, pages 5519-5526) at 75 rpm in 500 ml 0.1 5 The release of the active substance from the composition N hydrochloric acid at 37°C. The amount of released active of the invention that is independent from the pH of the substance is preferably determined by UV-detection at 220 gastrointestinal is preferably understood to mean that the . similarity factor f2 between a first in vitro release at a pH of The opioid-induced constipation which can be treated by 1.2 to 6.8 and a second in vitro release at any other pH of 1.2 the composition according to the invention can be caused by 10 any opioid analgesic or opioid analgesic analogue, or by any to 6.8 is larger or equal to 50. of their salts or mixtures. Examples of Such analgesics are The similarity factor f2 is determined according to SHAH the following: , , alphaprodine, anile V. P., TSONG Y., SATHE P., & LIU J. P. (1998), “In vitro ridine, , , , butor dissolution profile comparison-statistics and analysis of the phanol, , , besomorphine, dextromor 15 similarity factor, f2., Pharmaceutical Research, 15, 889 amide, , , diamorphone, 896. Specifically, the similarity factor f2 is calculated by the , , , following formula: , , , , , , ethylmeth ylthiambutene, , , , , 0.5 , , , isometha f = solo- : lo done, , , levophenacylmorphane, , meperidine, , , , metopone, , , narceline, , In this equation, Rt and Tt represent the released quanti , , , nalbuphene, 25 ties of active substance at time point t at the first and second , , , oxycodone, oxymor pH. n is the number of time points. The f2 factor is phone, , , , phenom determined under the following conditions: a) the minimal orphane, , , , piritr number of time points for one release is 3 (time point 0 is amide, propheptazine, promedol, , excluded); b) the time points for the first and the second pH propoxyphene, , , and , wherein 30 should be equal; c) for each time point, and for each pH, the hydrocodone, morphine, hydromorphone, oxycodone, released quantity is indicated as the mean value of 12 buprenorphine, codeine, fentanyl, levorphanol, meperidine, measurements; d) no more than one mean value measured methadone, , and are par above a release of 85% can be taken into account for the ticularly preferred according to the invention. calculation; e) the relative standard deviation or coefficient In a preferred embodiment of the invention, the compo 35 of variation of the release at a given pH should be smaller sition has an in vitro release rate of the active substance of than 20% for the first time point and smaller than 10% for 0% to 50% in 2 h, of 5% to 95% in 4 h, of 20% to 90% in the second, and every Subsequent time point. 10 h, of more than 70% in 18 h, and of more than 80% in The in vitro release profiles used for the calculation of the 24 h. f2 factor are determined using the paddle stirrer apparatus In a more preferred embodiment of the invention, the 40 (apparatus 2) with the paddle stirrer method according to Ph. composition has an in vitro release rate of the active Sub Eur. (Europaisches Arzneibuch, 7th edition, 3rd supplement, stance of 0% to 38% in 2h, of 5% to 55% in 4 h, and of 20% 2.9.3 “Wirkstofffreisetzung aus festen Arzneiformen’, pages to 75% in 10 h. 5519-5526) at 75 rpm in 500 ml buffer (according to the According to another preferred embodiment of the inven Europaisches Arzneibuch, 7th edition, 7th supplement, 4.1.3 tion, the composition has an in vitro release rate of the active 45 “Pufferlösungen”, pages 7671-7679) at 37° C. The amount substance of 0% to 50% in 1 h, of 10% to 95% in 4h, of 35% of released active substance is determined by UV-detection to 100% in 8 h, of 55% to 100% in 12 h, of 70% to 100% at 220 nm. in 16 h, and of more than 90% in 24 h. In a further preferred embodiment of the invention, the According to another preferred embodiment of the inven composition comprises a matrix, which releases the active tion, the composition has an in vitro release rate of the active 50 ingredient in a prolonged manner. The active Substance can substance of 0% to 30% in 1 h, of 0% to 40% in 2 h, of 3% be released in a prolonged manner inexpensively, particu to 55% in 4 h, of 10% to 65% in 8 h, of 20% to 75% in 12 larly when it is contained in a matrix that prolongs its h, of 30% to 88% in 16 h, of 50% to 100% in 24 h, and of release. more than 80% in 36 h. The composition according to the invention may comprise In a further preferred embodiment of the invention, the 55 a matrix, which releases naloxone, or a pharmaceutically composition has an in vitro release rate of the active Sub acceptable salt thereof, in a prolonged manner. The matrix stance of 10% to 30% in 1 h, of 17% to 37% in 2 h, of 27% according to the invention is preferably a so-called scaffold to 47% in 4 h, of 40% to 60% in 8 h, of 50% to 70% in 12 matrix, which can be Swelling or non-Swelling, or can be a h, of 60% to 80% in 16 h, of 80% to 100% in 24 h. so-called eroding matrix. The matrix can also have proper In a particularly preferred embodiment of the invention, 60 ties of both scaffold and eroding matrixes. the composition releases the active Substance naloxone In the case of a scaffold matrix, the active Substance is independently of the ambient pH of the gastrointestinal tract. incorporated into the matrix structure. The active Substance This ensures that the entire gastrointestinal tract can be is gradually dissolved by the digestive juices from the evenly and continuously supplied with naloxone, or an loaded scaffold matrix during the transport through the acceptable salt thereof. A further optimisation of the treat 65 gastrointestinal tract. At the end of the process, the matrix ment is thereby achieved. The pH-independent release of the scaffold is excreted in more or less unchanged form, or in a active Substance from the composition of the invention can Swollen form. In contrast, with an eroding matrix, the matrix US 9,456,986 B2 5 6 is degraded, or eroded, which leads to active Substance active Substance in a prolonged manner, and the in vitro particles being exposed at the Surface, and dissolved. The release rate of the active Substance, measured using the release rate therefore depends on the matrix degradation or paddle stirrer method according to Ph. Eur, at 75 rpm in 500 erosion rate. ml 0.1 N hydrochloric acid at 37° C., is of 20% to 50% in For the purpose of forming a largely stable scaffold matrix 5 1 h, of 40% to 75% in 2 h, of 60% to 95% in 4 h, of 80% with an appropriate active substance release rate, a further to 100% in 8 h, and of 90% to 100% in 12 h. preferred embodiment of the invention is a composition with Regarding the composition which is particularly Suited for a matrix that comprises one or several water-soluble matrix a once-a-day administration, the present invention further forming agents. relates to a solid oral pharmaceutical composition compris According to a further preferred embodiment of the 10 ing naloxone, or a pharmaceutically acceptable salt thereof, invention, the matrix of the composition is water-insoluble. as an active Substance, wherein the composition releases the In another preferred embodiment of the invention, the active Substance in a prolonged manner, and the in vitro matrix of the composition comprises one or several matrix release rate of the active Substance, measured using the forming agents selected from the group consisting of cellu paddle stirrer method according to Ph. Eur, at 75 rpm in 500 lose esters, polyethylene oxide, polyvinylpyrrolidone/poly- 15 ml 0.1 N hydrochloric acid at 37° C., is of 0% to 50% in 1 vinyl acetate mixtures, methacrylate-acrylate copolymers, h, of 0% to 75% in 2 h, of 10% to 95% in 4 h, of 35% to waxes, fats such as glycerol esters, and fatty alcohols. The 100% in 8 h, of 55% to 100% in 12 h, of 70% to 100% in Substance classes mentioned here are particularly suitable as 16 hand of more than 90% in 24 h. matrix-forming agents for the composition of the invention. Regarding the composition which is particularly Suited for However, particularly preferred is the use of a mixture of 20 a once-a-day administration, the present invention further polyvinyl acetate and polyvinylpyrrolidone, and/or a glyc relates to a solid oral pharmaceutical composition compris erol dibehenic acid ester as matrix-forming agent. ing naloxone, or a pharmaceutically acceptable salt thereof, In a further preferred embodiment of the invention, the as an active Substance, wherein the composition releases the composition is free of film-coated, naloxone-containing active Substance in a prolonged manner, and the in vitro particles, wherein the coating causes the prolonged release 25 release rate of the active Substance, measured using the of the naloxone. paddle stirrer method according to Ph. Eur, at 75 rpm in 500 According to a further preferred embodiment of the ml 0.1 N hydrochloric add at 37° C., is of 0% to 30% in 1 invention, the composition can be formed by direct com h, of 0% to 40% in 2 h, of 3% to 55% in 4 h, of 10% to 60% pression, since this is particularly inexpensive. in 8 h, of 20% to 75% in 12 h, of 30% to 88% in 16 h, of According to another preferred embodiment of the inven- 30 50% to 100% in 24 h, and of more than 80% in 36 h. tion, the composition is in the form of a tablet, capsule, Regarding the composition which is particularly Suited for granule, a micro tablet, extruded particles or granules com a once-a-day administration, the present invention further pressed into a tablet. relates to a solid oral pharmaceutical composition compris In a further preferred embodiment of the invention, the ing naloxone, or a pharmaceutically acceptable salt thereof, composition is designed as a once-a-day formulation, or a 35 as an active Substance, wherein the composition releases the twice-a-day formulation. active Substance in a prolonged manner, and the in vitro Naloxone, or a pharmaceutically acceptable salt thereof, release rate of the active Substance, measured using the is the active Substance of the composition according to the paddle stirrer method according to Ph. Eur, at 75 rpm in 500 invention, wherein naloxone hydrochloride is particularly ml 0.1 N hydrochloric acid at 37° C., is of 10% to 30% in preferred due to its solubility and stability. One or several 40 1 h, of 17% to 37% in 2 h, of 27% to 47% in 4 h, of 40% additional active Substances can be present in the composi to 60% in 8 h, of 50% to 70% in 12 h, of 60% to 80% in 16 tion. h, and of 80% to 100% in 24 h. Naloxone, or a pharmaceutically acceptable salt thereof, In accordance with good patient compliance, a further in the composition according to the invention is preferably preferred embodiment of the invention is a composition, present in an amount from 0.1 to 500 mg, more preferably 45 wherein the composition is preferably a tablet or a capsule, from 1 mg to 50 mg and even more preferably in an amount which has an in vitro release rate of the active substance, from 3 mg, 6 mg, 12 mg, 24 mg or 48 mg. measured using the paddle stirrer method according to Ph. The present invention further relates to the use of the Eur, at 75 rpm in 500 ml 0.1 N hydrochloric acid at 37°C., composition according to the invention for the treatment of of 0% to 75% in 2 h, of 3% to 95% in 4 h, of 20% to 100% opioid-induced constipation. 50 in 10 h, of 30% to 100% in 16 h, of 50% to 100% in 24 h, Regarding the composition which is particularly Suited for and of more than 80% in 36 h. a twice-a-day administration, the present invention further A further preferred embodiment of the invention is pro relates to a solid oral pharmaceutical composition compris viding a composition that is suitable for the treatment of ing naloxone, or a pharmaceutically acceptable salt thereof, opioid-induced constipation for at least 12 h, provided that as an active Substance, wherein the composition releases the 55 the composition has an in vitro release rate of the active active Substance in a prolonged manner, and the in vitro substance of 0% to 50% in 2 h, of 5% to 95% in 4h, of 20% release rate of the active Substance, measured using the to 90% in 10 h, of more than 70% in 18 h, and of more than paddle stirrer method according to Ph. Eur, at 75 rpm in 500 80% in 24 h. ml 0.1 N hydrochloric acid at 37° C., is of 5% to 50% in 1 The release rate is, in accordance with the invention, h, of 10% to 75% in 2 h, of 20% to 95% in 4 h, of 40% to 60 controlled by adjusting the mass ration of naloxone to 100% in 8 h, of more than 50% in 12 h, of more than 70% matrix-forming agent. In a preferred embodiment, the mass in 18 h, and of more than 80% in 24 h. ratio of naloxone to matrix-forming agent is 1:1, more Regarding the composition which is particularly Suited for preferably 1:2, more preferably 1:5, more preferably 1:6, a twice-a-day administration, the present invention further more preferably 1:7, even more preferably 1:8, yet more relates to a solid oral pharmaceutical composition compris- 65 preferably 1:9 and most preferably 1:10. ing naloxone, or a pharmaceutically acceptable salt thereof, The composition of the invention is characterised in that as an active Substance, wherein the composition releases the through the prolonged release the concentration of naloxone US 9,456,986 B2 7 8 in the plasma is low. Its maximum plasma concentration rhizae rhizoma, Galangae rhizoma, Semen Myristicae, Pip (C) is about 20x lower during the active course compared eris nigrifructus (pepper), Sinapis albae (Erucae) Semen, to a composition without prolonged release, and about 100x Sinapis migrae semen, Zedoariae rhizoma and Zingiberis lower compared with an intravenously administered com rhizoma, preferably from the group consisting of capsici position. 5 fructus (capsicum), capsici fructus acer (cayenne pepper) However, the inhibition of the receptors over the active and Piperis nigrifructus (pepper). course is better. In addition to providing the constipation In a preferred embodiment, the composition comprises at prevention effect of naloxone, the low bioavailability in the least one additive, wherein this additive is an emetic. In a system also ensures a reduced likelihood and/or severity of preferred embodiment, the emetic is based on one or several the side effects. 10 Substances from radix ipecacuanha (ipecac). In a preferred Since the naloxone inhibitory concentrations (ICs) for opioid receptors (L, 8 and K) are known, the assessment of embodiment, the emetic is based on the Substance emetine, the risk factor of a tablet can be calculated with the ratio in an alternative embodiment, the emetic is apomorphine. ICs/C. With the ICs of LL receptor, the value of ICs/ In a further embodiment, the composition comprises a C for a tablet according to the invention with 48 mg of 15 dye. In a preferred embodiment, the dye is selected from a naloxone is 54. In general, the higher the value of ICs/C. group comprising red iron oxide, black iron oxide and indigo the lower the risk factor of the tablet according to the carmine. invention. Hereafter all values relating to the ICs are for the In a further embodiment, the composition additionally receptor. comprises at least one non-steroid antirheumatic or an In a preferred embodiment, the composition has an ICso/ antihistamine. C. value of at least 30. In a more preferred embodiment, In an alternative embodiment, the composition addition the composition has an ICso/C value of at least 35. In an ally comprises at least one water-soluble lubricant. In a even more preferred embodiment, the composition has an preferred embodiment, the composition comprises at least ICso/C value of at least 40. In the most preferred embodi one water-soluble lubricant selected from the group com ment, the composition has an ICs/C value of at least 50. 25 prising adipic acid, fumaric acid, sodium benzoate and In a further embodiment, the composition additionally macrogol. comprises at least one stabilizer, which protects the active The aim of the present invention is also to provide a tablet, Substance. In a preferred embodiment, the at least one which comprises an opioid agonist, or a pharmaceutically stabilizer is selected from the list comprising sulphur diox acceptable salt thereof, and an opioid antagonist, or a ide, Sodium Sulphite, sodium bisulphite, ascorbic acid and its 30 pharmaceutically acceptable salt thereof, as active Sub derivatives and tocopherol, as well as its water- and fat stances, and is suitable for the parallel treatment of pain and soluble derivatives, such as, for example, tocopherol acetate, opioid-induced constipation, wherein the treatment can be Sulphites, bisulphites and hydrogen Sulphites of alkali, alka easily optimised by means of the tablet. line earth metals or other metals, paraben, BHA, BHT, The invention fulfils this aim through a multilayer tablet gallates, as well as lower fatty acids, fruit acids, phosphoric 35 comprising at least acids, Sorbic and benzoic acids as well as their salts, esters, a first active Substance-containing layer, which contains derivatives and isomeric compounds, ascorbyl palmitate, as an active Substance an opioid agonist, or a pharma lecithins, mono- and polyhydroxylated derivatives, ceutically acceptable salt thereof; and ethylenedlaminetetraacetic acid and salts thereof, citraconic a second active Substance-containing layer, which con acid, cysteine, L-cysteine, conidendrin, diethyl carbonate, 40 tains as an active Substance an opioid antagonist, or a methylenedioxyphenols, cephalin, B.f3'-dithiopropionic acid, pharmaceutically acceptable salt thereof, biphenyl and other phenyl derivatives. wherein at least the second active Substance-containing layer In a further embodiment, the composition additionally releases the active Substance in a prolonged manner. In a comprises at least one stabilizer, which protects the matrix. preferred embodiment, both the first and the second active In a preferred embodiment, the at least one stabilizer is 45 Substance-containing layers release the active Substance in a selected from the list comprising butylated hydroxytoluol, prolonged manner. The multilayer tablet can also comprise Sulphur dioxide, Sodium Sulphite, Sodium bisulphite, ascor additional active Substances. bic acid and its derivatives and tocopherol, as well as its The multilayer tablet according to the invention is suitable water- and fat-soluble derivatives, such as, for example, for the parallel treatment of pain and opioid-induced con tocopherol acetate, Sulphites, bisulphites and hydrogen Sul 50 stipation, wherein variable release kinetics for each active phites of alkali, alkaline earth metals and other metals, Substance are easily achieved and individualised treatments paraben, BHA, BHT. gallates as well as lower fatty acids, can therefore easily be optimised. fruit acids, phosphoric acids, Sorbic and benzoic acids and The multilayer tablet of the invention has the further their salts, esters, derivatives and isomeric compounds, advantage that in each layer a different release retarding ascorbyl palmitate, lecithins, mono- and polyhydroxylated 55 system can be used, such as Sustained-release pellets coated benzene derivatives, ethylenediaminetetraacetic acid and with a release retardant, or a Sustained-release matrix. This their salts, citraconic acid, cysteine, L-cysteine, conidendrin, allows to easily and independently vary the release kinetics diethyl carbonate, methylenedioxyphenole, cephalin, B.B'- for each active substance and the proportion of the active dithiopropionic acid, biphenyl and other phenyl derivatives. Substances, for tailoring the treatment to a patient. In a further embodiment, the composition comprises at 60 The multilayer tablet of the invention also has the advan least one additive, wherein the additive is an emetic or a tage that it enables a much more accurate dosage of the pungent agent drug. In a preferred embodiment, the com active substances. This is particularly important for Small position comprises an additive, wherein this additive is a doses. pungent agent, selected from the group comprising Allii The tablet of the invention is also advantageous when the sativi bulb, Asari rhizome cum herba, Calami rhizoma, 65 two active Substances are not compatible with one another. capsici fructus (capsicum) capsici fructus acer (cayenne According to a particularly preferred embodiment of the pepper), Rhizoma Curcunae Longae, Curcunae xanthor invention, the multilayer tablet is a two-layer tablet. The US 9,456,986 B2 10 multilayer tablet of the invention can be obtained as a In a further preferred embodiment of the multilayer tablet two-layer tablet by a simple and therefore inexpensive according to the invention, the opioid agonist, or the phar process. maceutically acceptable salt thereof, of the first active sub In a further preferred embodiment of the multilayer tablet stance-containing layer is present in the form of pellets according to the invention, the second active Substance 5 which contain the opioid agonist and onto which a release containing layer comprises a matrix, which prolongs the retardant layer is applied. release of the opioid antagonist, or a pharmaceutically In a preferred embodiment, the multilayer tablet of the acceptable salt thereof. A release-prolonging matrix can be invention has an ICso/C value for naloxone of at least 30. obtained by a simple and therefore inexpensive process. The In a more preferred embodiment, the multilayer tablet has an matrix can, according to the invention, preferably be a 10 ICs/C value of at least 35. In an even more preferred so-called scaffold matrix, which can be Swelling or non embodiment, the multilayer tablet has an ICso/C value of Swelling, or a so-called eroding matrix. The matrix can also at least 40. In the most preferred embodiment, the multilayer have properties of both scaffold and eroding matrixes. tablet has an ICs/C value of at least 50. In a scaffold matrix, the active Substance is incorporated In a further preferred embodiment of the multilayer tablet into the matrix structure. The active Substance is gradually 15 according to the invention the opioid agonist is selected dissolved by the digestive juices from the loaded scaffold from a group consisting of alfentanil, allylprodine, alp matrix during the transport through the gastrointestinal tract. haprodine, anilleridine, benzylmorphine, bezitramide, When this is done, the matrix scaffold is excreted in more or buprenorphine, , clonitaZene, codeine, besomor less unchanged form, or in a Swollen form. In contrast, with phine, , dezocine, diampromide, diamor an eroding matrix, the matrix is degraded, or eroded, which phone, dihydrocodeine, dihydromorphine, dimenoxadol, leads to active substance particles being exposed at the Dimepheptanol, dimethylthiambutene, dioxaphetyl surface, and dissolved. The release rate therefore depends on butyrate, dipipanone, eptazocine, ethoheptazine, ethylmeth the matrix degradation or erosion rate. ylthiambutene, ethylmorphine, etonitaZene, fentanyl, heroin, According to a further preferred embodiment of the hydrocodone, hydromorphone, hydroxypethidine, isometha multilayer tablet of the invention, the matrix contains one or 25 done, ketobemidone, levorphanol, levophenacylmorphane, several water-insoluble matrix-forming agents. In an alter lofentanil, meperidine, meptazinol, metazocine, methadone, native embodiment, the matrix contains one or several metopone, morphine, myrophine, narceline, nicomorphine, water-soluble matrix-forming agents. norievorphanol, normethadone, nalorphine, nalbuphene, In another preferred embodiment of the multilayer table normorphine, norpipanone, opium, oxycodone, oxymor of the invention, the matrix of the composition comprises 30 phone, papaveretum, pentazocine, phenadoxone, phenom one or several matrix-forming agents selected from the orphane, phenazocine, phenoperidine, piminodine, piritr group consisting of cellulose esters, polyethylene oxide, amide, propheptazine, promedol, properidine, polyvinylpyrrolidone/polyvinyl acetate mixtures, methacry propoxyphene, Sufentanil, tilidine, and tramadol, wherein late-acrylate copolymers, waxes, fats Such as glycerol esters, hydrocodone, morphine, hydromorphone, oxycodone, and fatty alcohols. The Substance classes mentioned here are 35 buprenorphine, codeine, fentanyl, levorphanol, meperidine, particularly Suitable as matrix-forming agents for the com methadone, levomethadone, and dextromethadone, as well position of the invention. However, particularly preferred is as pharmaceutically acceptable salts thereof, are particularly the use of a mixture of polyvinyl acetate and polyvinylpyr preferred. rolidone, and/or a glycerol dibehenic acid ester as matrix In a further preferred embodiment of the multilayer tablet forming agent. 40 according to the invention, at least the second active The release rate is, in accordance with the invention, Substance layer is formed by direct compression, since this controlled by adjusting the mass ration of naloxone to is particularly inexpensive. matrix-forming agent. In a preferred embodiment, the mass In a further embodiment, the multilayer tablet additionally ratio of naloxone to matrix-forming agent is 1:1, more comprises at least one stabilizer, which protects the nalox preferably 1:2, more preferably 1:5, more preferably 1:6, 45 one. In a preferred embodiment, the at least one stabilizer is more preferably 1:7, even more preferably 1:8, yet more selected from the list comprising Sulphur dioxide, sodium preferably 1:9 and most preferably 1:10. Sulphite, Sodium bisulphite, ascorbic acid and its derivatives According to a further preferred embodiment of the and tocopherol, as well as its water- and fat-soluble deriva multilayer tablet of the invention, the second active sub tives, such as, for example, tocopherol acetate, Sulphites, stance-containing layer releases the active Substance, the 50 bisulphites and hydrogen Sulphites of alkali, alkaline earth opioid antagonist, or the pharmaceutically acceptable salt metals or other metals, paraben, BHA, BHT. gallates, as well thereof, independently of the ambient pH of the gastroin as lower fatty acids, fruit acids, phosphoric acids, Sorbic and testinal tract. This ensures that the entire gastrointestinal benzoic acids as well as their salts, esters, derivatives and tract can be evenly and continuously supplied with nalox isomeric compounds, ascorbyl palmitate, lecithins, mono one, or an acceptable salt thereof. A further optimisation of 55 and polyhydroxylated benzene derivatives, ethylenediam the treatment is thereby achieved. The pH-independent netetraacetic acid and salts thereof, citraconic acid, cysteine, release of the active substance from the multilayer tablet of L-cystelne, conidendrin, diethyl carbonate, methylenedioxy the invention can be achieved through the choice of suitable phenols, cephalin, B.f3'-dithiopropionic acid, biphenyl and pharmaceutical excipients that will be known to the person other phenyl derivatives. skilled in the art. Local pH values in the gastrointestinal tract 60 In a further embodiment, the multilayer tablet additionally are from about 1.2 (in the stomach), to about 7 in the colon. comprises at least one stabilizer, which protects the matrix. In a further preferred embodiment of the multilayer tablet In a preferred embodiment, the at least one stabilizer is of the invention, the opioid antagonist is selected form a selected from the list comprising butylated hydroxytoluol, group consisting of naloxone, N-methylmalaxone and Sulphur dioxide, Sodium Sulphite, sodium bisulphite, ascor N-methyinaltrexone, as well as pharmaceutically acceptable 65 bic acid and its derivatives and tocopherol, as well as its salts thereof, wherein naloxone hydrochloride is particularly water- and fat-soluble derivatives, such as, for example, preferred. tocopherol acetate, Sulphites, bisulphites and hydrogen Sul US 9,456,986 B2 11 12 phites of alkali, alkaline earth metals and other metals, pressing of the first and second table mass to obtain a paraben, BHA, BHT. gallates as well as lower fatty acids, multilayer tablet. fruit acids, phosphoric acids, Sorbic and benzoic acids and The present invention further relates to a method for their salts, esters, derivatives and isomeric compounds, producing the multilayer tablet of the invention, comprising ascorbyl palmitate, lecithins, mono- and polyhydroxylated at least the steps of benzene derivatives, ethylenediaminetetraacetic acid and providing a first tablet mass that comprises an opioid their salts, citraconic acid, cysteine, L-cysteine, conidendrin, agonist, or a pharmaceutically acceptable salt thereof, diethyl carbonate, methylenedioxyphenole, cephalin, B.B'- as an active Substance, wherein the opioid agonist, or dithiopropionic acid, biphenyl and other phenyl derivatives. the pharmaceutically acceptable salt thereof, in the first In a further embodiment, the multilayer tablet comprises 10 tablet mass is present in the form of pellets which at least one additive, wherein the additive is an emetic or a contain the opioid agonist and onto which a release pungent agent drug. In a preferred embodiment, the com retardant layer is applied; position comprises an additive, wherein this additive is a providing a second tablet mass that comprises an opioid pungent agent, selected from the group comprising Allii 15 antagonist, or a pharmaceutically acceptable salt sativi bulb, Asari rhizome cum herba, Calami rhizoma, thereof, as an active Substance, as well as a release capsici fructus (capsicum) capsici fructus acer (cayenne retardant; pepper), Rhizoma Curcunae Longae, Curcunae xanthor filling a first filling shoe of a tablet pressing tool with the rhizae rhizoma, Galangae rhizoma, Semen Myrtisticae, Pip first tablet mass and a second filling shoe of the tablet eris nigrifructus (pepper), Sinapis albae (Erucae) Semen, 2O pressing tool with the second tablet mass; Sinapis migrae semen, Zedoariae rhizoma and Zingiberis pressing of the first and second table mass to obtain a rhizoma, preferably from the group consisting of capsici multilayer tablet. fructus (capsicum), capsici fructus acer (cayenne pepper) and Piperis nigrifructus (pepper). The present invention further relates to the use of the multilayer tablet of the invention for the treatment of pain In a preferred embodiment, the multilayer tablet com 25 and for the simultaneous treatment of opioid-induced con prises at least one additive, wherein this additive is an stipation. emetic. In a preferred embodiment, the emetic is based on one or several Substances from radix ipecacuanha (ipecac). In a preferred embodiment, the second tablet mass has a In a preferred embodiment, the emetic is based on the ICs/C value of at least 30. In a more preferred embodi Substance emetine, in an alternative embodiment, the emetic 30 ment, the second tablet mass has an ICso/C value of at is apomorphine. least 35. In an even more preferred embodiment, the second In a further embodiment, the multilayer tablet comprises tablet mass has an ICs/C value of at least 40. In the most a dye. In a preferred embodiment, the dye is selected from preferred embodiment, the second tablet mass has an ICso/ a group comprising red iron oxide, black iron oxide and C. value of at least 50. indigo carmine. 35 The following examples serve to illustrate the invention. In a further embodiment, the multilayer tablet additionally comprises at least one non-steroid antirheumatic or an EXAMPLES antihistamine. In an alternative embodiment, the multilayer tablet addi tionally comprises at least one water-soluble lubricant. In a 40 Oral Composition preferred embodiment, the multilayer tablet comprises at least one water-soluble lubricant selected from the group The following examples are used in conjunction with the comprising adipic acid, fumaric acid, Sodium benzoate and drawing to illustrate the invention. It shows: macrogols. FIG. 1: Release profiles of the tablets according to In a further preferred embodiment of the invention, the 45 examples 1 and 2. multilayer tablet is designed as a once-a-day formulation. In a further preferred embodiment of the invention, the multilayer tablet is designed as a twice-a-day formulation. Example 1 In a further preferred embodiment, the multilayer tablet is contains from 0.1 to 500 mg of opioid agonist, or of a 50 Tablets with the following composition were produced: pharmaceutically acceptable salt thereof, and from 0.1 to 500 mg of opioid antagonist, or of a pharmaceutically acceptable salt thereof, particularly preferred is a ratio Weight (agonist:antagonist) of 1:10 to 10:1. Substance Function ng The present invention further relates to a method for SS Naloxone hydrochloride Active Substance 48.OO producing the multilayer tablet of the invention, comprising Glycerol dibehenic acid ester Release retardant 2O4.64 at least the steps of Colloidal silicon dioxide Flow regulator 19.00 providing a first tablet mass that comprises an opioid Stearate Lubricant 2.36 agonist, or a pharmaceutically acceptable salt thereof, Total weight of the tablet 274.00 as an active Substance, as well as a release retardant; 60 providing a second tablet mass that comprises an opioid antagonist, or a pharmaceutically acceptable salt The components naloxone hydrochloride and glycerol thereof, as an active Substance, as well as a release dibehenic acid ester were sieved and mixed together. First retardant; the sieved Colloidal silicon dioxide and then the magnesium filling a first filling shoe of a tablet pressing tool with the 65 stearate were mixed into the resulting mixture. The thus first tablet mass and a second filling shoe of the tablet obtained mixture was pressed into a tablet using a conven pressing tool with the second tablet mass; tional tablet pressing tool. US 9,456,986 B2 13 14 Example 2 3rd supplement, 2.9.3 “Wirkstofffreisetzung aus festen Arzneiformen, pages 5519–5526) at 75 rpm in 500 ml 0.1 Tablets with the following composition were produced N hydrochloric acid at 37° C. The amount of released with the same method as in example 1: naloxone was determined by UV-detection at 220 nm. The in vitro release profiles of the tablets according to examples 1 (0) and 2 (x) are shown in FIG. 1. Weight Substance Function ng Multilayer Tablets Naloxone hydrochloride Active Substance 12.00 Kollidon (R) SR Release retardant 63.16 10 Example 1 Vivapur 200 Filler 7.00 Colloidal silicon dioxide Flow regulator 1.24 Magnesium Stearate Lubricant O.60 Coated two-layer tablets of the following composition were produced: Gesamtgewicht der Tablette 84.OO 15 Kollidon(R) SR consisting of 80 wt.-% polyvinyl acetate, Weight 19 wt.-% povidone, 0.8 wt.-% sodium lauryl sulfate and 0.2 Substance Function ng wt.-% Colloidal silicon dioxide. Oxycodone layer Example 3 Sustained-release oxycodone Active Substance 10.00 pellets (containing 3 mg oxycodone HCI) Coated two-layer tablets with the following composition microcrystalline cellulose Filler 24.50 were produced: Colloidal silicon dioxide Flow regulator O.25 Magnesium Stearate Lubricant O.25 25 Total weight of the oxycodone 35.00 Weight ayer Substance Function ng Naloxone layer Naloxone layer Naloxone hydrochloride Active Substance 3.00 Naloxone Hydrochloride Active Substance 3.00 30 Kollidon (R) SR Release retardant 21.75 Kollidon (R) SR Release retardant 17.00 Colloidal silicon dioxide Flow regulator O.SO Glycerol dibehenic acid Release retardant 4.75 Magnesium Stearate Lubricant O.25 ester Colloidal silicon dioxide Flow regulator O.60 Total weight of the naloxone 25.50 Magnesium Stearate Lubricant O.15 ayer 35 Total weight of the two-layer 6O.SO Total weight of the naloxone layer 25.5 ablet core Placebo layer Opadry IIR) Tablet coating 2.50 Sugar pellets (diameter: Carrier 10.00 Total weight of the two-layer 63.00 500-600 m) ablet Hypromellose Filler 10.00 40 microcrystalline cellulose Filler 10.00 Colloidal silicon dioxide Flow regulator O.25 Magnesium Stearate Lubricant O.25 The components of the oxycodone layer, that is, Sustained release oxycodone pellets, microcrystalline cellulose, col Total weight of the placebo layer 30.50 loidal silicon dioxide and magnesium Stearate were sieved Total weight of the two-layer tablet 56.00 45 and blended together to form a first powdery mixture. CO Further, the components of the naloxone layer: naloxone Opadry(R) Tablet coating 3.00 hydrochloride, Kollidon R. SR, colloidal silicon dioxide and Total weight of the two-layer tablet 59.00 magnesium Stearate were sieved and mixed together to form a second powdery mixture. 50 The first and the second mixture were pressed with a The components of the naloxone layer, that is, naloxone conventional two-layer tablet press to obtain the two-layer hydrochloride, Kollidon R. SR, glycerol dibehenic acid ester, colloidal silicon dioxide and magnesium Stearate were tablet core. The thus obtained two-layer tablet core was sieved and blended together to form a first powdery mixture. coated with the coating material Opadry II(R) that had been Further, the components of the placebo layer: Sugar pellets, 55 dissolved in water at a temperature of 30° C. to 50° C. to hypromellose, microcrystalline cellulose, colloidal silicon obtain the two-layer tablet. dioxide and magnesium Stearate were sieved and mixed The sustained-release oxycodone pellets had the follow together to form a second powdery mixture. ing composition and were prepared as known in the art: The first and the second mixture were pressed with a conventional two-layer tablet press to obtain the two-layer 60 Weight tablet core. The thus obtained two-layer tablet core was Substance Function ng coated to obtain the two-layer tablet. Release Profile Oxycodone pellets The in vitro release profiles of the tablets according to Oxycodone hydrochloride Active Substance 3.00 examples 1 and 2 were determined using a the paddle stirrer 65 Pellets neutral Carrier 2.50 apparatus (apparatus 2) with the paddle stirrer method Povidone Binder O.SO according to Ph. Eur. (Europtisches Arzneibuch, 7th edition, US 9,456,986 B2

-continued -continued Weight Weight Substance Function ng Substance Function ng Retardant layer microcrystalline cellulose Filler 242.00 Colloidal silicon dioxide Flow regulator 4.OO Ethylcellulose Retarding agent 3.00 Magnesium Stearate Lubricant 4.OO Hydroxypropylcellulose OSO Triethyl citrates OSO Total weight of the oxycodone 330.00 ayer Total weight of the Sustained 1O.OO 10 Naloxone layer release oxycodone pellets Naloxone hydrochloride Active Substance 48.00 microcrystalline cellulose Filler 84.00 Kollidon (R) SR Release retardant 204.00 Kollidon(R) SR consists of 80 wt.-% polyvinyl acetate, 19 Colloidal silicon dioxide Flow regulator 1O.OO wt.-% povidone, 0.8 wt.-% sodium lauryl sulfate and 0.2 Magnesium Stearate Lubricant 2.00 wt.-% Colloidal silicon dioxide. 15 Opadry IIR) consists of polyvinyl , iron oxide or Total weight of the naloxone 348.00 titanium dioxide, Macrogol and talc. ayer Gesamtgewicht des 678.00 Zweischichtitablettenkerns Example 2 Opadry(R) Tablet coating 22.00 Total weight of the two-layer 700.00 Coated two layer tables of the following composition tablet were produced as in example 1: 25 Weight FIGURE LEGEND Substance Function ng Oxycodone layer FIG. 1: Release profile of naloxone from the composition according to the invention; (X) example 1 (0) example 2. Sustained-release oxycodone Active Substance 3O.OO 30 pellets (containing 9 mg oxycodone HCI) The invention claimed is: microcrystalline cellulose Filler 3O.OO 1. A Solid oral pharmaceutical composition comprising Colloidal silicon dioxide Flow regulator 1.OO naloxone, or a pharmaceutically acceptable salt thereof, as Magnesium Stearate Lubricant 1.OO 35 an active Substance, wherein the composition releases the Total weight of the oxycodone 62.00 active Substance in a prolonged manner, and the in vitro ayer release rate of the active Substance naloxone, measured Naloxone layer using the paddle stirrer method according to Ph. Eur, at 75 Naloxone hydrochloride Active Substance 6.OO rpm in 500 ml 0.1 N hydrochloric acid at 37° C., of 0% to Glycerol dibehenic acid ester Release retardant 23.00 40 75% in 2 h, of 3% to 95% in 4 h, of 20% to 100% in 10 h, microcrystalline cellulose Filler 2O.OO of 30% to 100% in 16 h, of 50% to 100% in 24 h, and of Colloidal silicon dioxide Flow regulator 1...SO more than 80% in 36 h, wherein the composition has a Magnesium Stearate Lubricant OSO ICs/C value of at least 40, wherein the composition Total weight of the naloxone 51.00 comprises a matrix, wherein the matrix comprises glycerol ayer 45 dibehenic acid ester as matrix-forming agent, and wherein Total weight of the two-layer 113.00 the mass ratio of naloxone to glycerol dibehenic acid ester ablet core is 1:5. Opadry IIR) Tablet coating 8.OO 2. A composition according to claim 1, wherein the Total weight of the two-layer 121.00 composition releases the active Substance naloxone inde 50 pendently of the ambient pH of the gastrointestinal tract. ablet 3. A composition according to claim 1, wherein the composition has an in vitro release rate of the active Sub stance naloxone of 0% to 50% in 2 h, of 5% to 95% in 4 h, Example 3 of 20% to 90% in 10 h, of more than 70% in 18 h, and of 55 more than 80% in 24 h. 4. A composition according to claim 1, wherein the Coated two layer tables of the following composition composition has an in vitro release rate of the active Sub were produced as in example 1: stance naloxone of 0% to 38% in 2 h, of 5% to 55% in 4 h, and of 20% to 75% in 10 h. Weight 60 5. A composition according to claim 1, wherein the Substance Function ng composition has an in vitro release rate of the active Sub stance of 0% to 50% in 1 h, of 10% to 95% in 4 h, of 35% Oxycodone layer to 100% in 8 h, of 55% to 100% in 12 h, of 70% to 100% Sustained-release oxycodone Active Substance 80.00 in 16 h, and of more than 90% in 24 h. pellets (containing 24 mg 65 6. A composition according to claim 1, wherein the oxycodone HCI) composition has an in vitro release rate of the active Sub stance of 0% to 30% in 1 h, of 0% to 40% in 2 h, of 3% to US 9,456,986 B2 17 18 55% in 4 h, of 10% to 65% in 8 h, of 20% to 75% in 12 h, 15. A method for the production of a multilayer tablet of 30% to 88% in 16 h, of 50% to 100% in 24 h, and of more according to claim 12, comprising the steps of than 80% in 36 h. providing a first tablet mass that comprises an opioid 7. A composition according to claim 1, wherein the matrix agonist, or a pharmaceutically acceptable salt thereof, releases the active ingredient in a prolonged manner. 5 as an active substance, as well as a release retardant; 8. A composition according to claim 7, wherein the matrix providing a second tablet mass that comprises an opioid comprises one or several matrix-forming agents selected antagonist, or a pharmaceutically acceptable salt from the group consisting of cellulose esters, polyvinylpyr thereof, as an active substance, as well as a release rolidone/polyvinyl acetate mixtures, methacrylate-acrylate retardant, characterised in that the second table mass copolymers, waxes, fats such as glycerol esters, and fatty 10 has a ICso/C of at least 40; alcohols. filling a first filling shoe of a tablet pressing tool with the 9. A composition according to claim 1, wherein the first tablet mass and a second filling shoe of the tablet composition is formed by direct compression. pressing tool with the second tablet mass; 10. A composition according to claim 1, wherein the pressing of the first and second table mass to obtain a composition is designed as a once-a-day formulation. 15 multilayer tablet. 11. A composition according to claim 1, wherein the 16. A method for the production of a multilayer tablet composition is designed as a twice-a-day formulation. according to claim 12, comprising the steps of 12. A multilayer tablet comprising at least providing a first tablet mass that comprises an opioid a first active substance-containing layer, which contains agonist, or a pharmaceutically acceptable salt thereof, naloxone, or a pharmaceutically acceptable salt thereof as an active substance, wherein the opioid agonist, or as an active substance; and the pharmaceutically acceptable salt thereof, in the first a second active substance-containing layer, which con tablet mass is present in the form of pellets which tains as an active substance an opioid antagonist, or a contain the opioid agonist and onto which a release pharmaceutically acceptable salt thereof, retardant layer is applied: wherein the first and the second active substance-contain 25 providing a second tablet mass that comprises an opioid ing layers release the active substance in a prolonged antagonist, or a pharmaceutically acceptable salt manner, and the second active substance-containing thereof, as an active substance, as well as a release layer has a ICso/C value of at least 40 U, wherein the retardant, characterised in that the second table mass multilaver tablet comprises a composition wherein the has a ICso/C of at least 40; composition comprises a matrix, wherein the matrix 30 filling a first filling shoe of a tablet pressing tool with the comprises glycerol dibehenic acid ester as matrix first tablet mass and a second filling shoe of the tablet forming agent, and wherein the mass ratio of naloxone pressing tool with the second tablet mass; to glycerol dibehenic acid ester is 1:5. pressing of the first and second table mass to obtain a 13. A multilayer tablet, wherein the second active sub multilayer tablet. stance-containing layer comprises a composition according 35 17. A method of treating opioid-induced constipation to claim 1. comprising administering the solid oral pharmaceutical 14. A multilayer tablet according to claim 12, wherein the composition of claim 1 to a subject in need thereof. opioid agonist, or the pharmaceutically acceptable salt 18. A method of treating opioid-induced constipation thereof, in the first active substance-containing layer is comprising administering the multilayer tablet according to present in the form of pellets which contain the opioid 40 claim 12 to a subject in need thereof. agonist and onto which a release retardant layer is applied.