Claims for Patent: 6,558,695

Summary for Patent: 6,558,695

Title:	Topical and transdermal administration of peptidyl drugs using hydroxide releasing agents as permeation enhancers
Abstract:	A method is provided for increasing the permeability of skin or mucosal tissue to a topically or transdermally administered pharmacologically or cosmeceutically active peptide, polypeptide or protein. The method involves use of a specified amount of a hydroxide-releasing agent, the amount optimized to increase the flux of the peptide, polypeptide or protein through a body surface while minimizing the likelihood of skin damage, irritation or sensitization. Formulations and drug delivery devices employing hydroxide-releasing agents as permeation enhancers are provided as well.
Inventor(s):	Luo; Eric C. (Plano, TX), Hsu; Tsung-Min (San Diego, CA)
Assignee:	Dermatrends, Inc. (San Diego, CA)
Application Number:	09/737,831
Patent Claims:	1. A method for enhancing the flux of a peptidyl drug through a body surface, comprising administering the peptidyl drug to a localized region of a human patient's body surface in combination with a hydroxide-releasing agent applied to the body surface in a predetermined amount effective to enhance the flux of the drug through the localized region of the body surface without causing damage thereto, and effective to provide a pH in the range of approximately 8.5 to 11.5 at the localized region of the body surface, during drug administration, wherein the peptidyl drug and hydroxide-releasing agent are present in a formulation and the amount of hydroxide-releasing agent in the formulation applied to the body surface is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.25 wt. % to 25.0 wt. % of the formulation. 2. The method of claim 1, wherein the body surface is skin. 3. The method of claim 1, wherein the body surface is mucosal tissue. 4. The method of claim 1, wherein the formulation is aqueous. 5. The method of claim 4, wherein the formulation has a pH in the range of approximately 8.0 to 13. 6. The method of claim 5, wherein the pH is in the range of approximately 8.0 to 11.5. 7. The method of claim 6, wherein the pH is in the range of approximately 8.5 to 11.5. 8. The method of claim 4, wherein the aqueous formulation is selected from the group consisting of a cream, a gel, a lotion, and a paste. 9. The method of claim 8, wherein the formulation is a cream. 10. The method of claim 8, wherein the formulation is a gel. 11. The method of claim 1, wherein the formulation is nonaqueous. 12. The method of claim 11, wherein the formulation is an ointment. 13. The method of claim 1, wherein the hydroxide-releasing agent releases free hydroxide ions in the presence of an aqueous fluid. 14. The method of claim 1, wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof. 15. The method of claim 14, wherein the hydroxide-releasing agent is an inorganic hydroxide. 16. The method of claim 15, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof. 17. The method of claim 16, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and mixtures thereof. 18. The method of claim 17, wherein the inorganic hydroxide is sodium hydroxide. 19. The method of claim 18, wherein the inorganic hydroxide is potassium hydroxide. 20. The method of claim 14, wherein the hydroxide-releasing agent is an inorganic oxide. 21. The method of claim 20, wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof. 22. The method of claim 14, wherein the hydroxide-releasing agent is a metal salt of a weak acid. 23. The method of claim 22, wherein the hydroxide-releasing agent is selected from the group consisting of sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, tribasic sodium phosphate, dibasic sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, dibasic potassium phosphate, tribasic potassium phosphate, dibasic ammonium phosphate, and mixtures thereof. 24. The method of claim 23, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.25 wt. % to 7.0 wt. % of the formulation. 25. The method of claim 24, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.5 wt. % to 4.0 wt. % of the formulation. 26. The method of claim 25, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.75 wt. % to 2.0 wt. % of the formulation. 27. The method of claim 26, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 1.0 wt. % of the formulation. 28. The method of claim 20, wherein the formulation contains up to approximately 25 wt. % of the hydroxide-releasing agent. 29. The method of claim 28, wherein the formulation contains up to approximately 20 wt. % of the hydroxide-releasing agent. 30. The method of claim 1, wherein the peptidyl drug and hydroxide-releasing agent are administered by applying a drug delivery device to the localized region of the patient's body surface thereby forming a body surface-delivery device interface, the device comprising the peptidyl drug and the hydroxide-releasing agent, and having an outer backing layer that serves as the outer surface of the device during use. 31. The method of claim 30, wherein the peptidyl drug and hydroxide-releasing agent are present in an adhesive, gel or liquid formulation contained within the device. 32. The method of claim 30, wherein the outer backing layer is occlusive. 33. The method of claim 1, wherein the peptidyl drug is administered in combination with an additional permeation enhancer. 34. The method of claim 1, wherein the peptidyl drug is systemically acting and administration is transdermal. 35. The method of claim 1, wherein the peptidyl drug and hydroxide-releasing agent are administered without any additional permeation enhancer. 36. The method of claim 1, wherein the peptidyl drug is a peptide. 37. The method of claim 1, wherein the peptidyl drug is a polypeptide. 38. The method of claim 1, wherein the peptidyl drug is a protein. 39. The method of claim 1, wherein the peptidyl drug is selected from the group consisting of coagulation modulators, cytokines, endorphins, kinins, peptidyl hormones, LHRH analogs and combinations thereof. 40. The method of claim 39, wherein the peptidyl drug is a coagulation modulator. 41. The method of claim 40, wherein the peptidyl drug is selected from the group consisting of .alpha..sub.1 -antitrypsin, .alpha..sub.2 -macroglobulin, antithrombin III, factor I, factor II, factor III, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XII, heparin cofactor II, kallikrein, plasmin, plasminogen, prekallikrein, protein C, protein S, thrombomodulin and combinations thereof. 42. The method of claim 39, wherein the peptidyl drug is a cytokine. 43. The method of claim 42, wherein the peptidyl drug is selected from the group consisting of colony stimulating factor 4, heparin binding neurotrophic factor, interferon-.alpha., interferon .alpha.-2a, interferon .alpha.-2b, interferon .alpha.-n3, interferon-.beta., interferon-.gamma., interleukin-1, interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, interleukin-7, interleukin-8, interleukin-9, interleukin-10, interleukin-11, interleukin-12, interleukin-13, interleukin-14, interleukin-15, interleukin-16, interleukin-17, tumor necrosis factor, tumor necrosis factor-.alpha., granuloycte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, midkine, thymopoietin and combinations thereof. 44. The method of claim 39, wherein the peptidyl drug is an endorphin. 45. The method of claim 44, wherein the peptidyl drug is selected from the group consisting of dermorphin, dynorphin, .alpha.-endorphin, .beta.-endorphin, .gamma.-endorphin, .sigma.-endorphin [Leu.sup.5 ]enkephalin, [Met.sup.5 ]enkephalin, substance P, and combinations thereof. 46. The method of claim 39, wherein the peptidyl drug is a kinin. 47. The method of claim 46, wherein the peptidyl drug is selected from the group consisting of bradykinin, potentiator B, bradykinin potentiator C, kallidin and combinations thereof. 48. The method of claim 39, wherein the peptidyl drug is a peptidyl hormone. 49. The method of claim 48, wherein the peptidyl drug is selected from the group consisting of activin, amylin, angiotensin, atrial natriuretic peptide, calcitonin, calcitonin gene-related peptide, calcitonin N-terminal flanking peptide, cholecystokinin, ciliary neurotrophic factor, corticotropin, corticotropin-releasing factor, epidermal growth factor, follicle-stimulating hormone, gastrin, gastrin inhibitory peptide, gastrin-releasing peptide, ghrelin, glucogon, gonadotropin-releasing factor, growth hormone releasing factor, human chorionic gonadotropin, inhibin A, inhibin B, insulin, leptin, lipotropin, luteinizing hormone, luteinizing hormone-releasing hormone, .alpha.-melanocyte-stimulating hormone, .beta.-melanocyte-stimulating hormone, .gamma.-melanocyte-stimulating hormone, melatonin, motilin, oxytocin, pancreatic polypeptide, parathyroid hormone, placental lactogen, prolactin, prolactin-release inhibiting factor, prolactin-releasing factor, secretin, somatotropin, somatostatin, thyrotropin, thyrotropin-releasing factor, thyroxine, triiodothyronine, vasoactive intestinal peptide, vasopressin and combinations thereof. 50. The method of claim 49, wherein the peptidyl drug is oxytocin. 51. The method of claim 39, wherein the peptidyl drug is an LHRH analog. 52. The method of claim 51, wherein the peptidyl drug is selected from the group consisting of buserelin, deslorelin, fertirelin, goserelin, histrelin, leuprolide, lutrelin, nafarelin, tryptorelin and combinations thereof. 53. The method of claim 52, wherein the peptidyl drug is leuprolide. 54. The method of claim 1, wherein the peptidyl drug is selected from the group consisting of abarelix, adenosine deaminase, anakinra, ancestim, alteplase, alglucerase, asparaginase, bivalirudin, bleomycin, bombesin, desmopressin acetate, des-Q14-ghrelin, dornase-.alpha., enterostatin, erythropoeitin, exendin-4, fibroblast growth factor-2, filgrastim, .beta.-glucocerebrosidase, gonadorelin, hyaluronidase, insulinotropin, lepirudin, magainin I, magainin II, nerve growth factor, pentigetide, thrombopoietin, thymosin .alpha.-1, thymidin kinase, tissue plasminogen activator, tryptophan hydroxylase, urokinase, urotensin II and combinations thereof.

Details for Patent 6,558,695

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	01/15/1974		2019-12-16
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	12/27/1984		2019-12-16
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	02/15/1985		2019-12-16
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	02/16/1990		2019-12-16
Bel-mar Laboratories, Inc.	CHORIONIC GONADOTROPIN	chorionic gonadotropin	Injection	017054	03/26/1974		2019-12-16
Fresenius Kabi Usa, Llc	CHORIONIC GONADOTROPIN	chorionic gonadotropin	For Injection	017067	03/05/1973		2019-12-16
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	05/05/2004		2019-12-16