(19) TZZ¥¥___T (11) EP 3 311 667 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 25.04.2018 Bulletin 2018/17 A01N 43/42 (2006.01) A61K 31/44 (2006.01) (21) Application number: 17194444.0 (22) Date of filing: 08.07.2010 (84) Designated Contracting States: • SCHACHTEL, Bernard AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Jupiter, FL Florida 33477 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • TAKIGIKU, Ray PL PT RO SE SI SK SM TR Loveland, OH Ohio 45140 (US) (30) Priority: 08.07.2009 US 223999 P (74) Representative: Avidity IP 09.07.2009 US 224424 P Broers Building Hauser Forum (62) Document number(s) of the earlier application(s) in 21 JJ Thomson Avenue accordance with Art. 76 EPC: Cambridge CB3 0FA (GB) 10797879.3 / 2 451 274 Remarks: (71) Applicant: Charleston Laboratories, Inc. •This application was filed on 02-10-2017 as a Jupiter, FL 33477 (US) divisional application to the application mentioned under INID code 62. (72) Inventors: •Claims f iled aft er the date of fil ing of the • BOSSE, Paul application/after the date of receipt of the divisional Jupiter, FL Florida 33469 (US) application (Rule 68(4) EPC) • AMELING, John Cincinnati, OH 45252-1051 (US) (54) PHARMACEUTICAL COMPOSITIONS (57) Methods and compositions are provided which comprise effective amounts of analgesic to treat a subject, including reducing or eliminating an adverse effect associated with the analgesic. EP 3 311 667 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 311 667 A1 Description CROSS-REFERENCE 5 [0001] This application claims the benefit of U.S. Provisional Application No. 61/223,999, filed July 8, 2009, and U.S. Provisional Application No. 61/224,424, filed July 9, 2009, which are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION 10 [0002] Available pain medications may have adverse effects, such as nausea, vomiting, and skin rashes and sedation. As a result of such adverse effects, many subjects are unable to tolerate recommended dosages needed for effective pain relief because of adverse effects. Accordingly, there remains a need for effective therapeutics with reduced adverse effects. 15 INCORPORATION BY REFERENCE [0003] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. 20 SUMMARY OF THE INVENTION [0004] In one aspect, provided herein is a bi-layer tablet comprising: (1) a controlled-release layer comprising (a) from about 6.5 mg to about 8.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof, (b) from about 135 mg to 25 about 170 mg of silicified microcrystalline cellulose, (c) from about 12 mg to about 20 mg of hydroxy methyl propyl cellulose, (d) about 10 mg of croscarmellose sodium (e) from about 1 mg to about 4 mg of magnesium stearate, (f) from about 1mg to about 4 mg of stearic acid, and (g) from about 250 mg to about 402 mg of acetaminophen or a pharma- ceutically acceptable salt thereof; and (2) an immediate release layer comprising (a) from about 11 mg to about 14 mg of promethazine or a pharmaceutically acceptable salt thereof, (b) from about 100 mg to about 140 mg of silicified 30 microcrystalline cellulose, (c) from about 12 mg to about 18 mg of croscarmellose sodium and (d) from about 0.8 mg to about 1.5 mg of magnesium stearate. In one embodiment the controlled-release layer comprises about 7.5 mg of hy- drocodone or a pharmaceutically acceptable salt thereof; and wherein the immediate-release layer comprises about 12.5 mg of promethazine or a pharmaceutically acceptable salt thereof. In another embodiment, the controlled-release layer further comprises about 325 mg of acetaminophen or a pharmaceutically acceptable salt thereof. In another 35 embodiment, the tablet has a hardness of about 9.5 kilopond and thickness from about 6.9 to about 7.0 mm. In another embodiment, the hydrocodone salt is hydrocodone bitartrate. In another embodiment, the promethazine salt is promet- hazine HCl. In another embodiment, the effective amount of the hydrocodone or pharmaceutically acceptable salt thereof is an amount effective for treating or preventing pain for a period of 8-12 hours immediately following administration to a subject. In another embodiment, the controlled release layer is formulated to release in a subject in need thereof said 40 hydrocodone or a pharmaceutically acceptable salt thereof, or said acetaminophen or a pharmaceutically acceptable salt thereof at a rate that maintains a higher blood plasma level of said hydrocodone or a pharmaceutically acceptable salt thereof or said acetaminophen or a pharmaceutically acceptable salt for 4-8 hours compared to the blood plasma level after administration of an equivalent dosage of hydrocodone or a pharmaceutically acceptable salt thereof or acetaminophen or a pharmaceutically acceptable salt thereof in a non-controlled release formulation. In another em- 45 bodiment, the immediate release layer is formulated to release, after administration in a subject in need thereof, said promethazine or a pharmaceutically acceptable salt thereof at a rate that produces a peak plasma concentration of promethazine or a pharmaceutically acceptable salt thereof in the subject’s blood about 30-120 minutes earlier compared to peak plasma concentrations after administration to the subject of an equivalent dosage of promethazine or a phar- maceutically acceptable salt thereof in a non-immediate-release formulation. In another embodiment, the promethazine 50 or a pharmaceutically acceptable salt thereof potentiates the analgesic effect of said hydrocodone or a pharmaceutically acceptable salt thereof or said acetaminophen or a pharmaceutically acceptable salt thereof. [0005] In another aspect, provided herein is a method for treating or preventing pain comprising, administering to a subject in need thereof a bi-layer tablet comprising: (1) a controlled- release layer comprising (a) from about 6.5 mg to about 8.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof, (b) from about 250 to about 402 mg of 55 acetaminophen or a pharmaceutically acceptable salt thereof, (c) from about 135 mg to about 170 mg of silicified microcrystalline cellulose, (d) from about 12 mg to about 20 mg of hydroxy methyl propyl cellulose, (e) from about 1 mg to about 4 mg of magnesium stearate (f) from about 1mg to about 4 mg of stearic acid, and (g) about 10 mg of croscar- mellose sodium; and(2) an immediate release layer comprising (a) from about 11 mg to about 14 mg of promethazine 2 EP 3 311 667 A1 or a pharmaceutically acceptable salt thereof, (b) from about 100 mg to about 140 mg of silicified microcrystalline cellulose, (c) from about 12 mg to about 18 mg of croscarmellose sodium and (d) from about 0.8 mg to about 1.5 mg of magnesium stearate. [0006] In another aspect, provided herein is a method for treating or preventing pain comprising, administering to a 5 subject in need thereof a bi-layer tablet comprising: (1) a controlled- release layer comprising about 7.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof, about 325 mg of acetaminophen or a pharmaceutically acceptable salt thereof, about 149.5 mg of silicified microcrystalline cellulose, about 15.5 mg of hydroxy methyl propyl cellulose, about 10 mg of croscarmellose sodium, about 2.7 mg of magnesium stearate, and about 2.7 mg of stearic acid; and (2) an immediate release layer comprising about 12.5 mg of promethazine or a pharmaceutically acceptable salt thereof, about 10 121.5 mg of silicified microcrystalline cellulose, about 15 mg of croscarmellose sodium and about 1 mg of magnesium stearate. [0007] In another aspect, provided herein is a bi-layer tablet comprising: (1) a controlled-release layer comprising (a) from about 6.5 mg to about 8.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof, (b) from about 135 mg to about 170 mg of silicified microcrystalline cellulose, (c) about 15.7 mg of hydroxy methyl propyl cellulose, (d) about 15 10 mg of croscarmellose sodium (e) from about 1 mg to about 4 mg of magnesium stearate, (f) from about 1mg to about 4 mg of stearic acid, and from about 250 mg to about 402 mg of acetaminophen or a pharmaceutically acceptable salt thereof; and (2) an immediate release layer comprising (a) from about 11 mg to about 14 mg of promethazine or a pharmaceutically acceptable salt thereof, (b) from about 100 mg to about 140 mg of silicified microcrystalline cellulose, (c) from about 12 mg to about 18 mg of croscarmellose sodium and (d) from about 0.8 mg to about 1.5 mg of magnesium 20 stearate. [0008] In another aspect, provided herein is a bi-layer tablet, comprising a a controlled-release layer and an immediate release layer, wherein the controlled-release layer comprises about 7.5 mg of hydrocodone or a pharmaceutically ac- ceptable salt thereof, about 325 mg of acetaminophen or a pharmaceutically acceptable salt thereof, about 149.5 mg of silicified microcrystalline cellulose, about 15mg to 16 mg of hydroxy methyl propyl cellulose, about 9.5mg to 10.5 mg 25 of croscarmellose sodium, about 2.7 mg of magnesium stearate, and about 2.7 mg of stearic acid; and the immediate release layer comprises about 12.5 mg of promethazine or a pharmaceutically acceptable salt thereof, about 121.5 mg of silicified microcrystalline cellulose, about 15 mg of croscarmellose sodium and about 1 mg of magnesium stearate.