Morphine polymer release system

• US 8,609,143 B2
• Filed: 03/28/2008
• Issued: 12/17/2013
• 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:
  US12/078,312
• Publication Number:
  US 20080254123A1
• Time in Patent Office: 2,090 Days
• Field of Search: 424/486, 424/484
• 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 at least one therapeutically, prophylactically and/or diagnostically active substance into an aqueous medium by erosion of at least one surface of the composition, the composition comprising:

a matrix composition comprising;

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) an opiod active substance, and, optionally,

c) one or more pharmaceutically acceptable excipients,

with the proviso that the matrix composition does not contain a water dispersible or water soluble surface active agent that has at least one domain which is compatible with the polymer in the matrix composition and at least one other domain which is lipophilic, and which has a melting point that is lower than the polymer in the matrix,

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 and comprising a polymer, 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 active substance 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,

the composition having a cylindrical shape optionally with one or more tapered ends.

2. A composition according to 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, normorphine, 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.

3. A composition according to claim 2, wherein the opioid is morphine, morphine 6-glucuronide, morphine 3-glucuronide, dihydromorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone or mixtures thereof.

4. A composition according to claim 1, wherein the release of the opioid from the composition is zero order and about 50% w/w opioid is released from the composition within 3-5 hours as measured by the dissolution test described in claim 1.

5. A composition according to claim 1, wherein the release of the opioid from the composition is zero order and about 75% w/w opioid is released from the composition within 3-12 hours as measured by the dissolution test described in claim 1.

6. A composition according to claim 1, wherein the polyglycol homopolymer comprises a polyethylene oxide.

7. A composition according to claim 1, wherein the matrix composition further comprises a block copolymer of ethylene oxide and propylene oxide that is comprised of up to about 30% w/w of the propylene oxide based block, and has an average molecular weight of from about 8,000 to about 15,000 daltons.

8. A composition according to claim 1, wherein the opioid has a water-solubility of at least 3 mg/ml.

9. A composition according to claim 1, wherein the matrix composition comprises a pharmaceutically acceptable excipient having a water-solubility of at the most 3 mg/ml.

10. A composition according to claim 1, wherein the matrix composition comprises a pharmaceutically acceptable excipient selected from the group consisting of cellulose, microcrystalline cellulose, methyl cellulose, ethyl cellulose, ethylhydroxyethyl cellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, hydroxypropylmethyl cellulose, amylopectin, pectin, starch, sodium starch, kaolin, bentonit, acacia, alginic acid, sodium alginate, calcium alginate, gelatin, molasses, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, veegum, glycollate, magnesium stearate, calcium stearate, stearic acid, talc, titanium dioxide, silicium dioxide, clays, croscarmellose, gums, and agar.

11. A composition according to claim 1, wherein the opioid has a water-solubility of at the most 3 mg/ml.

12. A composition according to claim 11, wherein the matrix composition comprises a pharmaceutically acceptable excipient having a water-solubility of at least 1 mg/ml.

13. A composition according to claim 1, wherein the matrix composition comprises a pharmaceutically acceptable excipient having a water-solubility of at least about 10 mg/ml in water at ambient temperature.

14. A composition according claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of inorganic acids, inorganic bases, inorganic salts, organic acids or bases and pharmaceutically acceptable salts thereof, monosaccharides, disaccharides, oligosaccharides, and polysaccharides.

15. A composition according to claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of inorganic or organic acids and pharmaceutically acceptable salts thereof.

16. A composition according to claim 15, wherein the organic acid is selected from the group consisting of acetic acid, ethanoic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, adipic acid, ascorbic acid/vitamin C, carbamic acid, cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid, gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolic acid, glyoxylic acid, lactic acid, levulinic acid, malonic acid, mandelic acid, oxalic acid, pimelic acid, pyruvic acid, aspartic acid, and glutamic acid.

17. A composition according to claim 16, wherein the organic acid is selected from the group consisting of acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, and sorbic acid.

18. A composition according to claim 14, wherein the inorganic acid is pyrophosphoric acid, glycerophosphoric acid, ortho phosphoric acid, meta phosphoric acid, boric acid, hydrochloric acid, or sulfuric acid.

19. A composition according to claim 18, wherein the inorganic acid is ortho phosphoric acid or meta phosphoric acid.

20. A composition according to claim 14, wherein the organic bases are selected from the group consisting of p-nitrophenol, succinimide, benzenesulfonamide, 2-hydroxy-2-cyclohexenone, imidazole, pyrrole, diethanolamine, ethyleneamine, tris(hydroxymethyl)aminomethane, hydroxylamine, sodium citrate, aniline, and hydrazine.

21. A composition according to claim 14, wherein the inorganic bases are selected from the group consisting of aluminium oxide, aluminium oxide trihydrate, alumina, sodium hydroxide, potassium hydroxide, calcium carbonate, ammonium carbonate, and ammonium hydroxide.

22. A composition according to claim 14, wherein the pharmaceutically acceptable salt of an organic or inorganic acid is selected from the group consisting of sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogenphosphate, potassium hydrogenphosphate, dicalcium phosphate, sodium sulfate, potassium sulfate, calcium sulfate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, calcium carbonate, magnesium carbonate, sodium acetate, potassium acetate, calcium acetate, sodium succinate, potassium succinate, calcium succinate, sodium citrate, potassium citrate, calcium citrate, sodium tartrate, potassium tartrate, calcium tartrate, and zinc sulphate.

23. A composition according to claim 22, wherein the inorganic salt is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, or magnesium chloride.

24. A composition according to claim 14, wherein the pharmaceutically acceptable excipient is selected from glucose, ribose, arabinose, xylose, lyxose, allose, altrose, inositol, sorbitol, mannose, gulose, idose, galactose, talose, mannitol, fructose, lactose, sucrose, dextrin, dextran, amylose, xylan, and dextrose.

25. A composition according to claim 14, wherein the pharmaceutically acceptable excipient is selected from mannitol, xylitol, sorbitol, sucrose and inositol.

26. A composition according to claim 1, wherein the active substance is present in the matrix composition in a concentration of from about 0.1 to about 98% w/w.

27. A composition according to claim 1, wherein the active substance is present in the matrix composition in a concentration of at the most about 65% w/w.

28. A composition according to claim 1, wherein the active substance is a pharmaceutically active powder.

29. A composition according to claim 28, wherein the powder has a particle size of from about 0.1 μ

m to about 500 μ

m.

30. A composition according to claim 1, wherein the polymer in the coating is selected from the group consisting of ethylcellulose, cellulose acetate, cellulose propionate, cellulose nitrate, 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, styrene-butadienstyrene and styrene-isoprene styrene.

31. A composition according to claim 1, wherein the coating does not completely crumble or erode before the matrix has completely eroded.

32. A composition according to claim 1, wherein the matrix composition does not contain polyethylene glycol 2000 monostearate or polyethylene glycol 400 monostearate.

33. A composition according to claim 1 comprising one or more antioxidants.

34. A composition according to claim 1 further comprising a second pharmaceutically acceptable excipient selected from the group consisting of fillers, diluents, disintegrants, glidants, pH-adjusting agents, viscosity adjusting agents, solubility increasing or decreasing agents, osmotically active agents and solvents.

35. A composition according to claim 1, wherein the matrix composition further comprises a block copolymer of ethylene oxide and propylene oxide having an average molecular weight of from about 5,000 to about 30,000 daltons.

36. A composition according to claim 1, wherein the matrix composition further comprises a polymer selected from the group consisting of poly(ethylene-glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol (PEG-PLGA PEG), poly((DL-lactic acid-co-glycolic acid)-g-ethylene glycol) (PLGA-g-PEG), and polyethylene oxide-polypropylene oxide (PEO-PPO).

37. A composition according to claim 1, wherein the opening of the coating exposes a surface at an end of the cylindrically shaped matrix, the opening having an area equivalent to the volume of the cylindrically shaped matrix divided by the length of the cylindrically shaped matrix.

38. A composition according to claim 1, consisting of said matrix composition having said coating.