Analgesic immediate and controlled release pharmaceutical composition

• US 6,194,000 B1
• Filed: 04/17/1998
• Issued: 02/27/2001
• Est. Priority Date: 10/19/1995
• Status: Expired due to Term

• Current Assignee: Mayne Pharma International Pty Limited (Mayne Pharma)
• Original Assignee: FH Faulding & Co. Ltd. (Mayne Pharma)
• Inventors: Heinicke, Grant Wayne, Smith, Ian Keith
• Primary Examiner(s): Spear, James M.
• Application Number:
  US09/062,060
• Time in Patent Office: 1,047 Days
• Field of Search: 424/464, 424/468, 424/490, 424/422, 424/423, 424/436, 424/449, 424/451, 424/457, 424/458, 424/483, 424/473, 424/455, 424/489, 424/472, 424/465, 424/484, 424/485, 424/486, 424/487, 424/488
• US Class Current: 424/458
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077

Abstract

Disclosed is a method for the therapeutic treatment of pain related to wind up in a human or animal. The method of the invention is practiced by administering to the subject an effective amount of an analgesic pharmaceutical composition which includes a NMDA receptor antagonist in an immediate release form combined with an NMDA receptor antagonist in a sustained release form. The immediate release form and sustained release forn are present in sufficient amounts to diminsh or abolish wind up.

Claims

1. A method of preparing an analgesic pharmaceutical composition for the administration of an NMDA receptor antagonist to a human or animal subject for the treatment of pain, comprising:

providing a matrix or coated core containing an NMDA receptor antagonist to provide sustained release of a NMDA receptor antagonist;

providing a mixture containing a NMDA receptor antagonist to provide an immediate release of a NMDA receptor antagonist; and

combining the matrix or coated core with the mixture,

the immediate release form and sustained release form being present in sufficient amounts to diminish or abolish wind-up.

2. The method of claim 1 wherein the matrix core is a matrix composition selected from the group consisting of a wax;

an insoluble matrix polymer;

water soluble matrix materials and mixtures thereof.

3. The method of claims 1 wherein the coated core is a core of NMDA receptor antagonist coated with a pharmaceutically acceptable polymer including diffusion barrier polymers with or without porosity enhancers selected from the group consisting of ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials, sugars, lactose, sucrose, fructose and mannitol, salts, sodium chloride, potassium chloride, organic acids, fumaric acid, succinic acid, lactic acid and tartaric acid and mixires thereof, enteric polymers, hydroxypropyl ceUlluose, hydroxypropyl methyl cellulose, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, and polymethacrylates containing carboxyl groups.

4. The method of claim 1 further comprising compressing the core and the mixture into a tablet form and wherein the core and the mixture are dispersed throughout the tablet form.

5. The method of claim 1 wherein the core and the mixture are combined and compressed into a tablet form such that the core and the mixture form a multilayer tablet form.

6. The method of claim 1 wherein the core and the mixture are combined into a capsule.

42. The method of claim 2 wherein the wax is selected from the group consisting of carnauba, bees wax, paraffin wax, ceresine, shellac, fatty acids, fatty alcohols;

oils, hardened oils or fats, hardened rapeseed oil, castor oil, beef tallow, palm oil and soya bean oil;

the insoluble matrix polymer is selected from the group consisting of ethyl cellulose, celulose acetate butyrate, cellulose acetates, polymethacrylates cotaining quaternary ammonium groups; and

the water soluble matrix material is selected from the group consisting of polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials selected from the group consisting of sugars, salts, and organic acids.

47. The method of claim 42 wherein the sugar is selected from the group consisting of lactose, sucrose, fructose and mannitol;

the salt is selected from the group consisting of sodium chloride and potassium chloride, and the organic acid is selected from the group consisting of fumaric acid, succinic acid, lactic acid and tartaric acid.

7. A method for the therapeutic or prophylactic treatment of pain related to wind-up in a human or animal subject, the method comprising administering to the subject an effective amount of an analgesic pharmaceutical composition including an NMDA receptor antagonist in an immediate release form combined with an NMDA receptor antagonist in a sustained release form, the immediate release form and sustained release form being present in sufficient amounts to diminish or abolish wind-up.

8. The method of claim 7 wherein the analgesic pharmaceutical composition is in an unit dosage form.

9. The method of claim 7 for the treatment of chronic or acute pain.

10. The method of claim 9 wherein the analgesic pharmaceutical composition is administered pre-operatively.

11. The method of claim 7 wherein the pain is related to hyperalgesia or alkodynia.

13. The method of claim 7 wherein the NMDA receptor antagonist is present in an amount of from about 1 to 5000 mg.

14. The method of claim 7 wherein the NMDA receptor antagonist is present in an amount of from about 1 to 1000 mg.

15. The method of claim 7 wherein the NMDA receptor antagonist is present in an amount of from about 100 to 800 mg.

19. The method of claim 7 wherein the NMDA receptor antagonist in an immediate release form is combined in a singe dosage form with an NMDA receptor antagonist in a sustained released form.

20. The method of claim 19 wherein a portion of the NMDA receptor antagonist is immediately released following administration and a portion is sustained released to provide a therapeutic effect over a period of greater than 6 hours.

21. The method of claim 20 wherein the therapeutic effect is provided over a period of 8 to 24 hours.

22. The method of claim 21 wherein the therapeutic effect is provided over a period of 8 to 12 hours.

23. The method of claim 21 wherein the therapeutic effect is provided over a period of 12 to 24 hours.

24. The method of claim 7 wherein the NMDA receptor antagonist in the immediate release or sustained release form is the same or different.

25. The method of claim 7 wherein the immediate release or sustained release form are in a form selected from the group consisting of active cores comprising;

tablets;

multi-layered tablets;

capsules containing coated active cores and/or uncoated active cores;

liquids;

powder;

coated or uncoated granules;

coated or uncoated pellets;

suspensions;

an injectable solution;

a suppository;

implant;

transdermal patch; and

osmotic pump.

26. The method of claim 25 wherein the immediate release and sustained release form of the NMDA receptor antagonist are separate components in a multi-layer tablet and one or more layers include the NMDA receptor antagonist in an immediate release form and one or more layers include the NMDA receptor antagonist in a sustained release form.

27. The method of claim 26 wherein the immediate release and sustained release forms of the NMDA receptor antagonist are dispersed throughout the tablet.

28. The method of claim 25 wherein the immediate release and sustained release form of the NMDA receptor antagonist are separate components in a capsule and one or more components include the NMDA receptor antagonist in an immediate release form and one or more components include the NMDA receptor antagonist in a sustained release form.

29. The method of claim 28 wherein one or more of the components are active cores or pellets and wherein the active cores are uncoated or coated for immediate or sustained release and wherein the pellets are coated for sustained release.

30. The method of claim 29 comprising a blend of cores and pellets wherein a ratio of cores to pellets is 25/75.

31. The method of claim 7 wherein the NMDA receptor antagonist is a morphinan selected from the group consisting of dextromethorphan and dextrorphan, ketamine, amantadine, memantine, eliprodil, ifenprodil, dizocilipine, remacemide, lamotrigine, riluzole, aptiganel, phencyclidine, flupirtine, celfotel, felbamate, spermine, spermidine, levemopamil, a pharmaceutically acceptable salt or ester thereof or a metabolic precursor of any of the foregoing.

32. The method of claim 7 wherein the sustained release form of the NMDA receptor antagonist is in a matrix composition selected from the group consisting of waxes;

insoluble matrix polymer; and

water soluble matrix material and mixtures thereof.

33. The method of claim 32 wherein the sustained release form farther includes an enteric polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trirellitate, shellac, zein, polymethacrylates containing carboxyl groups and combinations thereof.

34. The method of claim 33 wherein the composition further includes a binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, cellulose acetate butyrate, or an enteric binding material, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate or mixtures thereof.

35. The method of claim 7 wherein the immediate release or sustained release form is coated with a pharmaceutically acceptable coating composition selected from the group consisting of ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups, pharmaceutically acceptable polymers, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials, sugars, lactose, sucrose, fructose and mannitol, salts, sodium chloride, potassium chloride and derivatives, organic acids fumaric acid, succinic acid, lactic acid and tartaric acid and mixtures thereof and enteric polymers, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, and polymethacrylates containing carboxyl groups.

36. The method of claim 35 wherein the coating composition comprises from 0 to 50% by weight of a material selected from the group consisting of silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, MCC, polacrilin potassium, or mixtures thereof.

37. The method of claim 36 wherein the composition further comprises 0 to 200 wt. −

% of a filler selected from the group consisting of silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, microcrystalline cellulose, polacrilin potassium, or mixtures thereof.

38. The method of claim 37 wherein the composition fer comprises a swelling/gelling polymer selected from the group consisting of hydroxypropyl cellulose in the range of 0-50 wt. −

% or a hydrophobic material, in the range 10-90 wt. −

%.

39. The method of claim 7 wherein the analgesic pharmaceutical composition is in a form suitable for oral or rectal administration or for administration by transdermal, intravenous, intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular means.

40. The method of claim 38 wherein the swelling/gelling polymer is cetyl alcohol.

41. The method of claim 35 wherein the enteric polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate phthalate, cellulose acetate phihalate, cellulose acetate trimellitate, shellac, zein, polymethacrylates containing carboxyl groups and mixtures thereof.

43. The method of claim 7 wherein the immediate release form of the NMDA receptor antagonist is particles admixed with at least one component selected from the group consisting of cellulose, hydroxypropyl methyl cellulose;

a surfactant selected from the group consisting of sodium lauryl sulphate, chremophor, tweens, spans, pluronics;

an insoluble component selected from the goup consisting of microcrystalline cellulose, Ca₃(PO₄)₂, talc, fumed silica;

a coating material selected from the group consisting of polyethylene glycol, hydroxypropyl methyl cellulose, wax, fatty acids and combinations thereof.

45. The method of claim 32 wherein the wax is selected from the group consisting of carnauba, bees wax, paraffin wax, ceresine, shellac, fatty acids, fatty alcohols, oils, hardened oils or fats, rapeseed oil, castor oil, beef tallow, palm oil, soya bean oil;

the insoluble matrix polymer is selected from the group consisting of ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups, pharmaceutically acceptable polymers; and

the water soluble matrix material is selected from the group consisting of, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, monomeric materials, sugars, lactose, sucrose, fructose, mannitol, salts, sodium chloride, potassium chloride, organic acids, fumaric acid, succinic acid, lactic acid, tartaric acid and mixtures thereof.

46. The method of claim 7 wherein the intermediate release form of the NMDA receptor is a dispersion in a suitable material selected from the group consisting of wax;

polymers;

hardened oils or fats including, hardened rapeseed oil, hardened castor oil, hardened beef tallow, palm oils and soya bean oil;

a soluble agent and combinations thereof.

48. The method of claim 46 wherein the soluble agent is selected from the group consisting of lactose, mannitol, sorbitol and combinations thereof.

12. A method for the treatment of Huntington'"'"'s disease amyotrophic lateral sclerosis (ALS), AIDS-related dementia, Alzheimer'"'"'s disease, schizophrenia, motoneurone diseases and CNS and brain injuries resulting from a number of causes including trauma, stroke and neurosurgery in a human or animal subject, the method comprising administering to the subject an effective amount of an analgesic pharmaceutical composition including an NMDA receptor antagonist in an immediate release form combined with an NMDA receptor antagonist in a sustained release form, the immediate release form and sustained release form being present in sufficient amounts to diminish or abolish wind-up.

16. The method of claim 12 wherein the NMDA receptor antagonist in the immediate release form comprises 5% to 90% of the total amount of the NMDA receptor antagonist.

17. The method of claim 16 wherein the NMDA receptor antagonist in the immediate release form comprises 10%-60% of the total amount of the NMDA receptor antagonist.

18. The method of claim 17 wherein the NMDA receptor antagonist in the immediate release form comprises 15%-50% of the total amount of the NMDA receptor antagonist.

44. A method for the therapeutic or prophylactic treatment of pain related to wind-up in a human or animal subject, the method comprising administering to the subject an effective amount of an analgesic pharmaceutical composition including an NMDA receptor antagonist in an immediate release form combined with an NMDA receptor antagonist in a sustained release form, the immediate release form and sustained release form being present in sufficient amounts to diminish or abolish wind-up wherein the analgesic pharmaceutical composition comprises dextromorphan or a salt thereof in a dosage form wherein the dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method at 100 rpm at 900 ml aqueous buffer at a pH of between 1.6 and 7.2 at 37°

C. is between 22 and 33 wt. −

% dextromorphan released after 0.5 hr, between 24 and 36 wt. −

% dextromethorphan released after 1 hour, between 28 and 42 wt. −

% dextromethorphan released after 2 hours, between 36 and 54 wt. −

% dextromethorphan released after 4 hours, between 44 and 66 wt. −

% dextromethorphan released after 6 hours, between 52 and 78 wt. −

% dextromethorphan released after 8 hours, between 68 and 100 wt. −

% dextromethorphan released after 12 hours, and greater than 80 wt. −

% dextromethorphan released after 16 hours.