# US 9,433,582 B2 · Gastric retentive extended release pharmaceutical compositions > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,433,582 B2 - Document ID: US9433582B2 - Status: Granted - Kind: B2 - Application number: 14/301,658 - Filed: 2014-06-11 - Published: 2014-10-02 - Granted: 2016-09-06 - Earliest claimed: 2011-05-17 - Assignees: Mallinckrodt Inc. - Applicants: Mallinckrodt LLC - Inventors: Krishna R. Devarakonda; Michael J. Giuliani; Vishal K. Gupta; Ralph A. Heasley; Susan Shelby - Web page: https://patentgrep.com/patent/US9433582B2 ## CPC - A61K 9/2031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers} - A61K 9/0065: {Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus} - A61K 9/209: {containing drug in at least two layers or in the core and in at least one outer layer} - A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol - A61K 31/485: Morphinan derivatives, e.g. morphine, codeine - A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract The present disclosure provides extended release pharmaceutical compositions comprising an opioid and an additional active pharmaceutical ingredient, wherein the composition exhibits gastric retentive properties which are achieved by a combination of a physical property of the composition and release of the opioid, wherein upon administration to a subject, the composition has at least one pharmacokinetic parameter that differs by less than about 30% when the subject is in a fasted state as compared to a fed state. ## Claims ### Claim 1 A pharmaceutical composition comprising: (a) at least one immediate release portion comprising about 125 mg to about 325 mg of acetaminophen and about 1.5 mg to about 4.0 mg hydrocodone or a pharmaceutically acceptable salt thereof; and (b) at least one extended release portion comprising about 125 mg to about 325 mg of acetaminophen and about 4.5 mg to about 6.5 mg hydrocodone or a pharmaceutically acceptable salt thereof, and an extended release-component; wherein the total amount of acetaminophen in the composition is about 325 mg to about 650 mg, and the total amount of hydrocodone or a pharmaceutically acceptable salt thereof in the composition is about 7.5 mg to about 10 mg, wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at a paddle speed of about 100 rpm in 900 mL of 0.1N HCl using a USP type II apparatus at a constant temperature of about 37° C., about 20% to about 40% of the total amount of hydrocodone or a pharmaceutically acceptable salt thereof in the composition is released at about 15 minutes in the test and about 50% to about 55% of the total amount of acetaminophen in the composition is released at about 15 minutes in the test. ### Claim 2 (depends on 1) The pharmaceutical composition of claim 1, wherein upon oral administration of a single dose of the composition to a subject, the composition provides a Cmax for hydrocodone from about 0.9 ng/mL/mg to about 2.0 ng/mL/mg, a Cmax for acetaminophen from about 4.0 ng/mL/mg to about 11.0 ng/mL/mg, a Tmax for hydrocodone from about 2 hours to about 8 hours, and a Tmax for acetaminophen from about 0.5 hour to about 6 hours. ### Claim 3 (depends on 1) The pharmaceutical composition of claim 1, wherein from about 45% to about 65%, by weight, of the hydrocodone or a pharmaceutically acceptable salt thereof is released from the composition at about 2 hours in the test, from about 60% to about 85%, by weight, of the hydrocodone or a pharmaceutically acceptable salt thereof is released from the composition at about 4 hours in the test, from about 80% to about 100%, by weight, of the hydrocodone or a pharmaceutically acceptable salt thereof is released from the composition at about 8 hours in the test, from about 60% to about 75%, by weight, of the acetaminophen is released from the composition at about 2 hours in the test, and from about 75% to about 85%, by weight, of the acetaminophen is released from the composition at about 4 hours in the test. ### Claim 4 (depends on 1) The pharmaceutical composition of claim 1, wherein upon oral administration of multiple doses to a subject in need of analgesia, the composition produces a blood plasma profile characterized by a mean AUC for hydrocodone from about 10.0 ng·hr/mL/mg to about 22.0 ng·hr/mL/mg, a steady state AUC for hydrocodone from about 13.0 ng·hr/mL/mg to about 18.0 ng·hr/mL/mg, a mean AUC for acetaminophen from about 35.0 ng·hr/mL/mg to about 80.0 ng·hr/mL/mg, and a steady state AUC for acetaminophen from about 37.0 ng·hr/mL/mg to about 42.0 ng·hr/mL/mg. ### Claim 5 (depends on 1) The pharmaceutical composition of claim 1, wherein upon oral administration of multiple doses to a subject in need of analgesia, the composition produces a blood plasma profile characterized by a median Tmax for hydrocodone from about 3.0 hours to about 6.0 hours, a steady state Tmax for hydrocodone from about 2.0 hours to about 4.0 hours, a median Tmax for acetaminophen from about 1.0 hour to about 5.0 hours, and a steady state Tmax for acetaminophen from about 0.5 hour to about 1.0 hours. ### Claim 6 (depends on 1) The pharmaceutical composition of claim 1, wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at a paddle speed of about 100 rpm in 900 mL of 0.1N HCl using a USP type II apparatus at a constant temperature of about 37° C, about 35% to about 40% of the hydrocodone or a pharmaceutically acceptable salt thereof is released at about 30 minutes in the test and about 51% to about 58% of the acetaminophen is released at about 30 minutes in the test. ### Claim 7 (depends on 1) The pharmaceutical composition of claim 1, Wherein the extended release component comprises polyethylene oxide. ### Claim 8 (depends on 7) The pharmaceutical composition of claim 7, wherein the polyethylene oxide has a molecular weight from about 500,000 Daltons to about 10,000,000 Daltons. ### Claim 9 (depends on 1) The pharmaceutical composition of claim 1, wherein the at least one immediate release portion comprises from about 20% to about 30% of the total amount of hydrocodone or a pharmaceutically acceptable salt thereof in the composition and from about 40% to about 60% of the total amount of acetaminophen in the composition, and the at least one extended release portion comprises the balance of each of the hydrocodone or a pharmaceutically acceptable salt thereof and the acetaminophen. ### Claim 10 (depends on 1) The pharmaceutical composition of claim 1, wherein the immediate release portion comprises, by weight of the immediate release portion, from about 70% to about 80% acetaminophen and from about 0.5% to about 1% of hydrocodone or a pharmaceutically acceptable salt thereof;and the extended release portion comprises, by weight of the extended release portion, from about 30% to about 50% of the extended release component, from about 20% to about 40% of acetaminophen, and from about 0.5% to about 2% of hydrocodone or a pharmaceutically acceptable salt thereof. ### Claim 11 (depends on 1) The pharmaceutical composition of claim 1, wherein the extended release component comprises a polymer selected from the group consisting of linear, branched, dendrimeric, or star polymers, hydrophilic polymers, and mixtures thereof. ### Claim 12 (depends on 1) The pharmaceutical composition of claim 1, wherein the extended release component comprises a polymer selected from the group consisting of a polyalkylene oxide, poly(ethylene oxide), polyethylene glycol and poly(ethylene oxide) poly(propylene oxide), methylcetlulose, hydroxymethylcellulose, laydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylceliulose, carboxymethylcellulose, microcrystalline cellulose, acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, aminoethyl acrylate, maleic anhydride copolymer, polymaleic acid, poly(acrylamide), poly(methacrylanaide), poly(dimethylacrylamide), poly(N-isopropyl-acrylamide), poly(oiefinic alcohol), poly(vinyi alcohol), poly(N-vinyl lactam), poly(vinyl pyrrolidone), poly(N-vinyl caprolactam), polyol, glycerol, polyglycerol, propylene glycol, trimethylene glycol, mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, mono- and di-polyoxyethylated trirnethylene glycol, polyoxyethylated sorbitol, polyoxyethylated glucose, polyoxazolines, poly(methyloxazoline), poly(ethyloxazoline), polyvinylamine, polyvinylacetate, ethylene-vinyl acetate copolymer, polyvinyl acetate phthalate, polyimines, polyethyleneimine, starch, starch-based polymer, polyurethane hydrogel, chitosan, polysaccharide gums, xanthan gum, zein, shellac, ammoniated shellac, shellac-acetyl alcohol, shellac n-butyl, stearate, and mixtures thereof. ### Claim 13 A pharmaceutical composition comprising: (a) at least one immediate release portion comprising about 125 mg to about 325 mg of acetaminophen and about 1.5 mg to about 4.0 mg hydrocodone or a pharmaceutically acceptable salt thereof; and (b) at least one extended release portion comprising about 125 mg to about 32.5 mg of acetaminophen and about 4.5 mg to about 6.5 mg hydrocodone or a pharmaceutically acceptable salt thereof, and an extended release component; wherein the total amount of acetaminophen in the composition is about 325 mg to about 650 mg, and the total amount of hydrocodone or a pharmaceutically acceptable salt thereof in the composition is about 7.5 mg to about 10 mg; and wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at a paddle speed of about 150 rpm in 900 mL of 0.1N HCl using a USP type II apparatus at a constant temperature of about 37° C, the drug release profile substantially corresponds to the following: after 15 minutes, no more than about 35%, by weight, of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof is released and no more than about 55%, by weight, of the total amount of the acetaminophen is released; after 1 hour, no more than about 50%, by weight, of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof is released and no more than about 63%, by weight, of the total amount of the acetaminophen is released; after 2 hours, no more than about 65%, by weight, of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof is released and no more than about 75%, by weight, of the total amount of the acetaminophen is released; after 4 hours, from about 65% to about 85%, by weight, of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof is released and from about 70% to about 90%, by weight, of the total amount of the acetaminophen is released; after 8 hours, from about 85% to about 100%, by weight, of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof is released and from about 85% to about 100%, by weight, of the total amount of the acetaminophen is released; and after 12 hours, from about 95% to about 100%, by weight, of the total amount of the hydrocodone or a pharmaceutically acceptable salt thereof is released and from about 90% to about 100%, by weight, of the total amount of the acetaminophen is released. ### Claim 14 (depends on 13) The pharmaceutical composition of claim 13, wherein the composition comprises about 325 mg of acetaminophen and about 7.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof. ### Claim 15 (depends on 13) The pharmaceutical composition of claim 13, wherein when orally administered to a subject, the composition produces a blood plasma concentration profile characterized by a biphasic increase in blood plasma concentrations of hydrocodone and acetaminophen. ### Claim 16 (depends on 15) The pharmaceutical composition of claim 15, wherein the biphasic increase in blood plasma concentrations of hydrocodone is characterized by a plasma concentration-time profile for hydrocodone in which the slope of a line drawn between 0 hour and about 2 hours is greater than the slope of a line drawn between about 2 hours and about 5 hours. ### Claim 17 A pharmaceutical composition as a solid oral dosage form comprising: (a) at least one immediate release portion comprising about 125 mg to about 325 mg of acetaminophen and about 1.5 mg to about 4.0 mg hydrocodone or a pharmaceutically acceptable salt thereof; and (b) at least one extended release portion comprising about 125 mg to about 325 mg of acetaminophen and about 4.5 mg to about 6.5 mg hydrocodone or a pharmaceutically acceptable salt thereof, and an extended release component; wherein the total amount of acetaminophen in the composition is about 325 mg and the total amount of hydrocodone or a pharmaceutically acceptable salt thereof in the composition is about 7.5 mg; and wherein upon oral administration of two solid oral dosage forms of the composition wherein upon oral administration of two solid oral dosage forms of the composition, the composition provides the composition provides an AUC0-1.7h for acetaminophen of about 5.0 ng·h/mL/mg to about 13.0 ng·h/mL/mg; an AUC1.7-48h for acetaminophen of about 25.0 ng·h/mL/mg to about 75.0 ng·h/mL/mg, an AUC0-2.44h for hydrocodone or a pharmaceutically acceptable salt thereof of about 1.0 ng·h/mL/mg to about 4.25 ng·h/mL/mg; and AUC2.44-36h of about 10 ng·h/mL/mg to about 20.0 ng·h/mL/mg. ### Claim 18 (depends on 17) The pharmaceutical composition of claim 17 wherein the AUC0-1hr for acetaminophen is from about 1.25 ng·hr/mL/mg to about 3.25 ng·hr/mL/mg. ### Claim 19 (depends on 17) The pharmaceutical composition of claim 17 wherein the AUC0-2hr for acetaminophen is from about 4.25 ng·hr/mL/mg to about 8.75 ng·hr/mL/mg. ### Claim 20 (depends on 17) The pharmaceutical composition of claim 17 wherein the AUC0-4hr for acetaminophen is from about 10.0 ng·hr/mL/mg to about 20.0 ng·hr/mL/mg. ### Claim 21 (depends on 17) The pharmaceutical composition of claim 17 wherein the AUC0-3hr for hydrocodone is from about 1.0 ng·hr/mL/mg to about 5.0 ng·h/mL/mg. ### Claim 22 (depends on 21) The pharmaceutical composition of claim 21 wherein the AUC3-36hr for hydrocodone is from about 5.0 ng·h/mL/mg to about 25.0 ng·hr/mL/mg. ### Claim 23 A pharmaceutical composition as a solid oral dosage form comprising: (a) at least one immediate release portion comprising about 125 mg to about 325 mg of acetaminophen and about 1.5 mg to about 4.0 mg hydrocodone or a pharmaceutically acceptable salt thereof; and (b) at least one extended release portion comprising about 125 mg to about 325 mg of acetaminophen and about 4.5 mg to about 6.5 mg hydrocodone or a pharmaceutically acceptable salt thereof thereof, and an extended release component; wherein the total amount of acetaminophen in the composition is about 325 mg to about 650 mg, and the total amount of hydrocodone or a pharmaceutically acceptable salt thereof in the composition is about 7.5 mg to about 10 mg; and wherein upon oral administration of two solid oral dosage forms of the composition wherein upon oral administration of two solid oral dosage forms of the composition, the composition maintains the composition maintains a therapeutic blood plasma concentration of hydrocodone of at least about 5 ng/mL from about 0.75 hours to about 10 hours after administration of the composition, and wherein at least about 90% of the acetaminophen is released from the composition by about 8 hours after administration of the composition such that, by about 10 hours after administration of the composition, acetaminophen has a blood plasma concentration that is less than about 30% of acetaminophen's maximum plasma concentration. ### Claim 24 (depends on 23) The pharmaceutical composition of claim 23, wherein the AUCTmax-t for acetaminophen is from about 20.0 ng·hr/mL/mg to about 40.0 ng·hr/mL/mg. ### Claim 25 (depends on 23) The pharmaceutical composition of claim 23, wherein the AUC(1.7-48hr) for acetaminophen is from about 25.0 ng·hr/mL/mg to about 75.0 ng·hr/mL/mg. ### Claim 26 (depends on 23) The pharmaceutical composition of claim 23, wherein the composition is administered to a subject as a bilayer tablet. ### Claim 27 (depends on 26) The pharmaceutical composition of claim 26, wherein the bilayer tablet comprises about 325 mg of acetaminophen and about 7.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof. ### Claim 28 (depends on 27) The pharmaceutical composition of claim 27, wherein a single dose comprises two bilayer tablets. ### Claim 29 (depends on 23) The solid oral dosage form of claim 23, wherein the solid oral dosage form is a tablet or capsule. ### Claim 30 (depends on 23) The solid oral dosage form of claim 23, wherein the solid oral dosage form is used in the treatment of acute pain.