PHARMACEUTICAL COMPOSITION

• US 20090162450A1
• Filed: 03/06/2009
• Published: 06/25/2009
• Est. Priority Date: 06/19/2006
• Status: Active Grant

• Current Assignee: Alpharma Pharmaceuticals LLC (Pfizer Inc.)
• Original Assignee: Alpharma Pharmaceuticals LLC (Pfizer Inc.)
• Inventors: Boehm, Garth, Liang, Alfred, Matthews, Frank, Tang, Lijuan
• Granted Patent: US 7,682,633 B2
• Time in Patent Office: Days
• US Class Current: 424/497
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Provided herein is a pharmaceutical composition comprising an antagonist, an agonist, a seal coat, and a sequestering polymer, wherein the antagonist, agonist, seal coat and at least one sequestering polymer are all components of a single unit, and wherein the seal coat forms a layer physically separating the antagonist from the agonist from one another. Methods for manufacturing such a pharmaceutical composition are also provided.

Claims

1. A method of treating pain in a human, the method comprising:

the human orally taking an intact multi-layer composition in an amount sufficient to treat the pain,

wherein the multi-layer composition comprises;

a. a water-soluble core;

b. an antagonist containing layer comprising naltrexone or a pharmaceutically acceptable salt of naltrexone coating the core;

c. a sequestering polymer layer coating the antagonist containing layer;

d. an agonist layer comprising morphine or a pharmaceutically acceptable salt of morphine coating the sequestering polymer layer; and

,

e. a controlled release layer coating the agonist layer;

wherein the multi-layer composition sequesters at least 80% of the naltrexone or the pharmaceutically acceptable salt of naltrexone as determined at 73 hours by first placing the multi-layer composition in 500 mL of a 0.1 N HCl solution for 1 hour at 37°

C. using USP paddle method, 100 rotations per minute, and then placing the multi-layer composition in 500 mL of a pH 7.5, 0.05 M phosphate buffer, for 72 hours at 37°

C. using USP paddle method, 100 rotations per minute, and then determining the amount of the naltrexone or the pharmaceutically acceptable salt thereof sequestered; and

wherein one of the following conditions are met;

i) the agonist layer comprises sodium chloride;

or

ii) the multilayer composition further comprises, immediately beneath the agonist layer, an osmotic pressure regulating agent layer comprising sodium chloride.

2. The method of claim 1, wherein, in the multi-layer composition,

the antagonist containing layer comprises the pharmaceutically acceptable salt of naltrexone, wherein the pharmaceutically acceptable salt of naltrexone is naltrexone HCl;

the sequestering polymer layer comprises copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, sodium lauryl sulfate in an amount from 1.6% to 6.3% of the copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups on a weight-to-weight basis, and talc in an amount of from 75% to 125% of the copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups on a weight-to-weight basis coating the antagonist containing layer; and

the agonist layer comprises morphine sulfate and hydroxypropylmethyl cellulose.

3. The method of claim 2, wherein condition i) is met.

4. The method of claim 2, wherein condition ii) is met.

5. The method of claim 4, wherein the osmotic pressure regulating agent layer further comprises hydroxypropylmethyl cellulose.

6. The method of claim 1, wherein the human is in the fed state when orally taking the multi-layer composition, and wherein the area under the plasma concentration versus time curve for 6-beta-naltrexol for the human, at 168 hours (AUC_last) after administration of the multi-layer composition, is 1057 pg*h/mL.

7. The method of claim 1, wherein the time to maximum concentration for 6-beta-naltrexol (T_max) in the human'"'"'s plasma, after orally taking the multi-layer composition, is 57.29 hours.

8. The method of claim 1, wherein the maximum concentration of 6-beta-naltrexol (C_max) in the human'"'"'s plasma, after orally taking the multi-layer composition, is 25 pg/mL.

9. The method of claim 1, wherein in the multi-layer composition, the controlled release layer comprises a cellulose;

a polyalkylene glycol;

an anionic copolymer based on methacrylic acid and ethylacrylate; and

a plasticizer.

10. The method of claim 1, wherein the multi-layer composition does not contain a bittering agent, a gelling agent, an irritant, or an emetic.

11. The method of claim 1, wherein in the multi-layer composition, the composition contains the antagonist only in the antagonist containing layer.

12. The method of claim 1, wherein in the multi-layer composition, the composition contains the agonist only in the agonist layer.

13. The method of claim 1, wherein in the multi layer composition, the only agonist is the morphine or the pharmaceutically acceptable salt thereof.

14. The method of claim 1, wherein in multi-layer composition, the only antagonist is the naltrexone or the pharmaceutically acceptable salt thereof.

15. The method of claim 2, wherein in the multi-layer composition, the sodium lauryl sulfate is only contained in the sequestering polymer layer.

16. The method of claim 1, wherein in the multi-layer composition, the sodium chloride is contained only in the agonist layer.