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) NALOXONE 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 opioid-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 analgesic effect of the opioids 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 opioid antagonist, 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 oxycodone 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 opiate 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 analgesics 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 naloxol.