Morphine polymer release system

• US 8,808,745 B2
• Filed: 08/23/2013
• Issued: 08/19/2014
• Est. Priority Date: 09/21/2001
• Status: Expired due to Fees

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Fischer, Gina, Bar-Shalom, Daniel, Slot, Lillian, Andersen, Christine
• Primary Examiner(s): ROGERS, JAMES WILLIAM
• Application Number:
  US13/974,346
• Publication Number:
  US 20140093569A1
• Time in Patent Office: 361 Days
• Field of Search: None
• US Class Current: 424/486
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

A pharmaceutical composition for controlled release of an active substance is provided. The active substance is released into an aqueous medium by erosion of at least one surface of the composition. The composition comprises i) a matrix comprising a) polymer or a mixture of polymers, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients, and ii) a coating.

Claims

1. A pharmaceutical composition for controlled release of an opioid into an aqueous medium by erosion of at least one surface of the composition, the composition consisting of:

a matrix composition consisting of;

(a) one or more polyglycol homopolymers having an average molecular weight of from at least about 100,000 daltons to about 700,000 daltons,

(b) a block copolymer of ethylene oxide and propylene oxide having up to about 30% w/w of the propylene oxide based block, based on the total weight of the block copolymer, wherein the block copolymer has an average molecular weight of from about 5,000 to about 15,000 daltons,

(c) an opioid,

(d) one or more pharmaceutically acceptable excipients selected from the group consisting of cellulose derivatives, release modifiers, and antioxidants,

the matrix having a coating having at least one opening exposing at least one surface of said matrix, the coating being insoluble in and impermeable to body fluids,

wherein any matrix surface exposed to the aqueous medium erodes at a substantially constant rate, so that a zero order release is obtained of at least about 60% w/w of the opiod from the pharmaceutical composition when subject to an in vitro dissolution test according to USP 24, NF 19, 711 Dissolution, employing Apparatus 2 equipped with a paddle, using 0.1 N hydrochloric acid as the dissolution medium during the first 120 minutes and thereafter substituting a pH 6.8 buffer solution.

2. The composition of claim 1, wherein the one or more polyglycol homopolymers is comprised of one or more polyethylene oxides having an average molecular weight of from at least about 100,000 daltons to about 700,000 daltons.

3. The composition of claim 1, wherein the one or more polyglycol homopolymers is comprised of one or more polyethylene oxides having an average molecular weight selected from the group consisting of about 100,000 daltons, about 200,000 daltons, about 300,000 daltons, and about 400,000 daltons, and mixtures thereof.

4. The composition of claim 1, wherein the one or more polyglycol homopolymers is comprised of a polyethylene oxide having an average molecular weight selected from the group consisting of about 200,000 daltons and about 300,000 daltons.

5. The composition of claim 1, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, aniloridine, benzylmorphine, bezitramide, buprenorphine, butophanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diapromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimephetanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, dextropropoxyphene, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, morphine 6-glucuronide, morphine 3-glucuronide, myrophine, nalbuphine, narccine, nicomorphine, norlevorphanol, normethadone, nalorphine, nonmorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.

6. The composition of claim 1, wherein the opioid is selected from the group consisting of oxycodone and pharmaceutically acceptable salts thereof.

7. The composition of claim 1, wherein the cellulose derivative is selected from the group consisting of microcrystalline cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose.

8. The composition of claim 1, wherein the cellulose derivative is selected from the group consisting of hydroxypropylmethylcellulose and methyl cellulose.

9. The composition of claim 1, wherein the cellulose derivative is hydroxypropylmethylcellulose.

10. The composition according to claim 1, wherein the release modifier is selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and methacrylic acid copolymers.

11. The composition according to claim 1, wherein the release modifier is selected from the group consisting of methacrylic acid copolymers.

12. The composition of claim 1, wherein the antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), t-butyl hydroquinone, 1,3,5-trihydroxybenzene, calcium ascorbate, sodium ascorbate, gallic acid, dodecyl gallate, octyl gallate, hydroquinone, maltol, sodium sulfite, sodium bisulfite, sodium metabisulfite, citric acid, tartaric acid, ascorbic acid, erythorbic acid, etidronic acid, phosphite, hypophosphorous acid, nordihydroguairetic acid, propionic acid, potassium bisulphite, potassium metabisulphite, dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate, tocopherols, and tocopheryl acetates.

13. The composition of claim 1, wherein the antioxidant is selected from the group consisting of BHA and BHT.

14. The composition of claim 1, wherein the antioxidant is BHT.

15. The composition of claim 1, wherein the coating comprises one or more polymers selected from the group consisting of cellulose acetate, polyamide, polyethylene, polyethylene terephthalate, polypropylene, polyurethane, polyvinyl acetate, polyvinyl chloride, silicone rubber, latex, polyhydroxybutyrate, polyhydroxyvalerate, teflon, polylactic acid or polyglycolic acid and copolymers thereof, ethylene vinyl acetate (EVA), styrene-butadienestyrene (SBS) and styrene-isoprene-styrene (SIS).

16. The composition of claim 1, wherein the coating comprises one or more polylactic acid polymers.

17. The composition of claim 15, wherein the coating further comprises one or more substantially water-soluble crystalline polymers.

18. The composition of claim 1, having a cylindrical shape optionally with one or more tapered ends.

19. The composition of claim 1, wherein about 50% w/w opioid is released from the composition within 3-5 hours as measured by the dissolution test recited in claim 1.

20. The composition of claim 1, wherein about 75% w/w opioid is released from the composition within 3-12 hours as measured by the dissolution test recited in claim 1.

21. The composition of claim 1, wherein the coating does not completely crumble or erode before the matrix has completely eroded.

23. The composition of claim 1, wherein the opioid is selected from the group consisting of hydrocodone and pharmaceutically acceptable salts thereof.

24. The composition of claim 3, wherein the opioid is selected from the group consisting of hydrocodone and pharmaceutically acceptable salts thereof.

25. The composition of claim 4, wherein the opioid is selected from the group consisting of hydrocodone and pharmaceutically acceptable salts thereof.

26. The composition of claim 3, wherein the opioid is selected from the group consisting of oxycodone and pharmaceutically acceptable salts thereof.

27. The composition of claim 4, wherein the opioid is selected from the group consisting of oxycodone and pharmaceutically acceptable salts thereof.

22. A method for treating pain, comprising orally administering a pharmaceutical composition to a patient in need thereof, wherein the pharmaceutical composition provides controlled release of an opiod into an aqueous medium by erosion of at least one surface of the composition, and consists of:

a matrix composition consisting of;

(a) one or more polyglycol homopolymers having an average molecular weight of from at least about 100,000 daltons to about 700,000 daltons,

(b) a block copolymer of ethylene oxide and propylene oxide having up to about 30% w/w of the propylene oxide based block, based on the total weight of the block copolymer, wherein the block copolymer has an average molecular weight of from about 5,000 to about 15,000 daltons,

(c) an opiod,

(d) one or more pharmaceutically acceptable excipients selected from the group consisting of cellulose derivatives, release modifiers, and antioxidants,

the matrix having a coating having at least one opening exposing at least one surface of said matrix, the coating being insoluble in and impermeable to body fluids,

wherein an matrix surface exposed to the aqueous medium erodes at a substantially constant rate, so that a zero order release is obtained of at least about 60% w/w of the opiod from the pharmaceutical composition when subject to an in vitro dissolution test according to USP 24, NF 19, 711 Dissolution, employing Apparatus 2 equipped with a paddle, using 0.1 N hydrochloric acid as the dissolution medium during the first 120 minutes and thereafter substituting a pH 6.8 buffer solution.