Claims for Patent: 5,981,606

Summary for Patent: 5,981,606

Title:	Therapeutic TGF-beta-wound healing compositions and methods for preparing and using same
Abstract:	This invention pertains to therapeutic wound healing compositions for protecting and resuscitating mammalian cells (Embodiment One (I)). This invention also pertains to therapeutic TGF-beta-wound healing compositions for reducing the formation of scar tissue and increasing the proliferation and resuscitation rate of mammalian cells (Embodiment Two (II)). In a first aspect of Embodiment One (I.A), the therapeutic wound healing composition comprises (a) pyruvate, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids. In a second aspect of Embodiment One (I.B), the therapeutic wound healing composition comprises (a) pyruvate, (b) lactate, and (c) a mixture of saturated and unsaturated fatty acids. In a third aspect of Embodiment One (I.C), the therapeutic wound healing composition comprises (a) an antioxidant and (b) a mixture of saturated and unsaturated fatty acids. In a fourth aspect of Embodiment One (I.D), the therapeutic wound healing composition comprises (a) lactate, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids. In Embodiment Two (II), the therapeutic wound healing compositions of Embodiment One (I.A-D) are combined with a therapeutically effective amount of a TGF-beta (GF) to form TGF-beta-wound healing compositions (II.A-D+GF). This invention also pertains to methods for preparing and using the TGF-beta-wound healing compositions and the topical and ingestible pharmaceutical products in which the therapeutic compositions may be used.
Inventor(s):	Martin; Alain (Ringoes, NJ)
Assignee:	Warner-Lambert Company (Morris Plains, NJ)
Application Number:	09/019,316
Patent Claims:	1. A therapeutic TGF-beta-wound healing composition which comprises a therapeutically effective amount of a TGF-beta and a wound healing composition, wherein the wound healing composition comprises: (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof; (b) an antioxidant; and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the resuscitation of injured mammalian cells; wherein components a, b, and c are present in amounts sufficient to synergistically enhance wound healing. 2. The composition according tc claim 1, wherein the TGF-beta is selected from the group consisting of Type 1 TGF-beta, Type 2 TGF-beta, and Type 3 TGF-beta. 3. The composition according to claim 2, wherein the TGF-beta is Type 1 TGF-beta. 4. The composition according to claim 1, wherein the pyruvate is selected from the group consisting of pyruvic acid, lithium pyruvate, sodium pyruvate, potassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate, manganese pyruvate, methyl pyruvate, .alpha.-ketoglutaric acid, pharmaceutically acceptable salts of pyruvic acid, prodrugs of pyruvic acid, and mixtures thereof. 5. The composition according to claim 4, wherein the pyruvate is sodium pyruvate. 6. The composition according to claim 1, wherein the antioxidant is selected from the group consisting of all forms of Vitamin A; all forms of carotene;; all forms of Vitamin C; all forms of Vitamin E; Vitamin E esters which readily undergo hydrolysis to Vitamin E; prodrugs of Vitamin A, carotene, Vitamin C, and Vitamin E; pharmaceutically acceptable salts of Vitamin A, carotene, Vitamin C, and Vitamin E, and mixtures thereof. 7. The composition according to claim 6, wherein the antioxidant is Vitamin E acetate. 8. The composition according to claim 1, wherein the mixture of saturated and unsaturated fatty acids comprises animal and vegetable fats and waxes. 9. The composition according to claim 8, wherein the mixture of saturated and unsaturated fatty acids is selected from the group consisting of human fat, chicken fat, cow fat, sheep fat, horse fat, pig fat, and whale fat. 10. The composition according to claim 9, wherein the mixture of saturated and unsaturated fatty acids comprises lauric acid, myristic acid, myristoleic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, margaroleic acid, stearic, oleic acid, linoleic acid, linolenic acid, arachidic acid, and gadoleic acid. 11. The composition according to claim 1, wherein the TGF-beta is present in the therapeutic wound healing composition in an amount capable of establishing in the tissue a TGF-3 level greater than about 0.25ng/gram tissue. 12. The composition according to claim 1, wherein pyruvate is present in the therapeutic wound healing composition in an amount from about 10% to about 50%, by weight of the therapeutic wound healing composition. 13. The composition according to claim 1, wherein the antioxidant is present in the therapeutic wound healing composition in an amount from about 0.1% to about 40%, by weight of the therapeutic wound healing composition. 14. The composition according to claim 1, wherein the mixture of saturated and unsaturated fatty acids is present in the therapeutic wound healing composition in an amount from about 10% to about 50%, by weight of the therapeutic wound healing composition. 15. A method for treating a wound in a mammal which comprises administering to a mammal in need thereof: a therapeutic TGF-beta-wound healing composition which comprises: (1) a TGF-beta; and (2) a therapeutically effective amount of a wound healing composition comprising: (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof; (b) an antioxidant; and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells; wherein components a, b, and c are present in amounts sufficient to enhance wound. 16. A method for preparing a therapeutic TGF-beta-wound healing composition which comprises the steps of admixing the following ingredients: (1) a TGF-beta; and (2) a therapeutically effective amount of a wound healing composition comprising: (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof; (b) an antioxidant; and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells; wherein components a, b, and c are present in amounts sufficient to synergistically enhance wound healing. 17. An augmented TGF-beta-wound healing composition which comprises: (A) a therapeutic TGF-beta-wound healing composition which comprises: (1) a therapeutically effective amount of a TGF-beta; and (2) a wound healing composition which comprises: (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof; (b) an antioxidant; and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells; wherein components a, b, and c are present in amounts sufficient to synergistically enhance wound healing; and, (B) a medicament useful for treating wounds. 18. The augmented TGF-beta-wound healing composition according to claim 17, wherein the medicament useful for treating wounds is selected from the group consisting of immunostimulating agents, antiviral agents, antikeratolytic agents, anti-inflammatory agents, antifungal agents, acne treating agents, sunscreen agents, dermatological agents, antihistamine agents, antibacterial agents, respiratory bursting inhibitors, inhibitors of prostaglandin synthesis, antimicrobial agents, antiseptic agents, anesthetic agents, cell nutrient media, burn relief medications, sun burn medications, insect bite and sting medications, wound cleansers, wound dressings, scar reducing agents, and mixtures thereof. 19. The augmented TGF-beta-wound healing composition according to claim 18, wherein the medicament useful for treating wounds is selected from the group consisting of immunostimulating, agents, antiviral agents, antikeratolytic agents, anti-inflammatory agents, antifungal agents, acre treating agents, sunscreen agents, dermatological agents, antihistamine agents, and antibacterial agents. 20. The augmented TGF-beta-wound healing composition according to claim 19, wherein the medicament useful for treating wounds is an immunostimulating agent selected from the group consisting of betafectin.RTM. and Freund's complete adjuvant. 21. The augmented TGF-beta-wound healing composition according to claim 17, wherein the medicament useful for treating wounds is a cytotoxic agent selected from the group consisting of epithelial cell cohesiveness reducers, dermatological abradants, anti-inflammatories, lipid regulating agents, centrally acting anticholinesterases, chemotherapeutic drugs, and gastric irritants. 22. The augmented TGF-beta-wound healing composition according to claim 19, wherein the medicament useful for treating wounds is an antiviral agent selected from the group consisting of acyclovir, foscamet sodium, ribavirin, vidarabine, ganeiclovir sodium, zidovudine, phenol, amantadine hydrochloride, and interferon alfa-n3. 23. The augmented TGF-beta-wound healing composition according to claim 19, wherein the medicament useful for treating wounds is an antikeratolytic agent selected from the group consisting of salicylic acid, lactic acid, and urea. 24. The augmented TGF-beta-wound healing composition according to claim 19, wherein the medicament useful for treating wounds is an anti-inflammatory agent selected from the group consisting of ibuprofen, naproxen, sulindac, diflunisal, piroxicam, indomethacin, etodolac, meclofenamate sodium, fenoproben calcium, ketoprofen, mefenamic acid, nabumetone, ketorolac tromethamine, diclofenac, evening primrose oil, acetylsalicylic acid, mesalamine, salsalate, diflunisal, salicylsalicylic acid, choline magnesium trisalicylate, flunisolide, triamcinoline, triamcinoline acetonide, beclomethasone dipropriorate, betamethasone diproprionate, hydrocortisone, cortisone, dexamethasone, prednisone, methyl prednisolone, and prednisolone. 25. The augmented TGF-beta-wound healing composition according to claim 19, wherein the medicament useful for treating wounds is an antifungal agent selected from the group consisting of lactic acid, sorbic acid, miconazole, clotrimazole, tioconazole, terconazole, povidone-iodine, and butoconazole. 26. The augmented TGF-beta-wound healing composition according to claim 19, wherein the medicament useful for treating wounds is tretinoin. 27. The augmented TGF-beta-wound healing composition according to claim 19, wherein the medicament useful for treating wounds is a sunscreen agent selected from the group consisting of ethylhexyl p-methoxycinnamate, octyl methoxycinnamate, octyl dimethyl p-aminobenzoic acid, 2-ethylhexyl salicylate, octyl salicylate, menthyl anthranilate, octocrylene, padimate o, titanium dioxide, urea, and oxybenzone. 28. The augmented TGF-beta-wound healing composition according to claim 19, wherein the medicament useful for treating wounds is a buffering agent to maintain the pH of dermatitis in a range from about 5 to about 8 together with an anti-inflammatory agent. 29. The augmented TGF-beta-wound healing composition according to claim 19, wherein the medicament useful for treating wounds is a topical antihistamine agent selected from the group consisting of diphenhydramine hydrochloride and pramoxine hydrochloride. 30. The augmented TGF-heta-wound healing composition according to claim 19, wherein the medicament useful for treating wounds is an antibacterial agent selected from the group consisting of bismuth compounds, such as bismuth aluminate, bismuth subcitrate, bismuth subgalate, bismuth subsalicylate; the sulfonamides; the nitrofurans, such as nitrofurazone and nitrofurantoin; furazolidone, metronidazole, tinidazole, nimorazole, benzoic acid, the aminoglycosides; such as gentamicin, neomycin, kanamycin, and streptomycin, the macrolides, such as erythromycin, clindamycin, and rifamycin; the penicillins, such as penicillin G, penicillin V, Ampicillin and amoxicillin; the polypeptides, such as bacitracin and polymyxin; the tetracyclines, such as tetracycline, chlorotetracycline, oxytetracycline, and doxycycline; the cephalosporins, such as cephalexin and cephalothin; and chloramphenicol, and clidamycin. 31. A method for treating a wound in a mammal with an augmented TGF-beta-wound healing composition which comprises administering to a mammal in need thereof a therapeutic augmented TGF-beta-wound healing composition which comprises: (1) a therapeutically effective amount of a TGF-beta; (2) a wound healing composition which comprises: (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof; (b) an antioxidant; and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells; wherein components a, b, and c are present in amounts sufficient to synergistically enhance wound healing; and, (3) a medicament useful for treating wounds. 32. The method according to claim 31, wherein the medicament useful for treating wounds is selected from the group consisting of immunostimulating agents, antiviral agents, antikeratolytic agents, anti-inflammatory agents, antifungal agents, acne treating agents, sunscreen agents, dermatological agents, antihistamine agents, antibacterial agents, TGF-betas, respiratory bursting inhibitors, inhibitors of prostaglandin synthesis, antimicrobial agents, antiseptic agents, anesthetic agents, cell nutrient media, burn relief medications, sun burn medications, insect bite and sting medications, wound cleansers, wound dressings, scar reducing agents, and mixtures thereof. 33. A TGF-beta-wound healing pharmaceutical composition which comprises: (A) a therapeutic TGF-beta-wound healing composition which comprises: (1) a therapeutically effective amount of a TGF-beta; and (2) a wound healing composition which comprises: (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof; (b) an antioxidant; and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells; wherein components a, b, and c are present in amounts sufficient to synergistically enhance wound healing; and, (B) a pharmaceutically acceptable carrier selected from the group consisting of pharmaceutical appliances, bioadhesives, and occlusive vehicles.

Details for Patent 5,981,606

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Hemispherx Biopharma, Inc.	ALFERON N INJECTION	interferon alfa-n3 (human leukocyte derived)	Injection	103158	10/10/1989		2011-03-01
Hoffmann-la Roche Inc.	PEGASYS COPEGUS COMBINATION PACK	peginterferon alfa-2a and ribavirin		125083	06/04/2004		2011-03-01
Schering Corporation A Subsidiary Of Merck & Co., Inc.	PEGINTRON/ REBETOL COMBO PACK	peginterferon alfa-2b and ribavirin		125196	06/13/2008		2011-03-01