Claims for Patent: 8,334,281

Summary for Patent: 8,334,281

Title:	Nasal formulations of metoclopramide
Abstract:	Nasal formulations of metoclopramide, which remain stable and/or colorless upon storage over a period of time, are provided. Also provided are methods of treating disorders treatable with metoclopramide, comprising administering the nasal solutions to patients in need thereof.
Inventor(s):	D'Onofrio; Matthew J. (San Diego, CA), Gonyer; David A. (Cardiff, CA), Shah; Shirish A. (Phoenix, AZ), Madden; Stuart J. (Ellicott City, MD)
Assignee:	Evoke Pharma, Inc. (San Diego, CA)
Application Number:	12/645,108
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,334,281
Patent Claims:	1. A pharmaceutical composition comprising metoclopramide, or a pharmaceutically-acceptable salt thereof, a citrate buffer, and benzalkonium chloride; wherein the composition is a nasal solution that is clear to pale yellow when compared to standard E, 32 USP <631> on storage at a temperature of 40.degree. C. for at least about 4 weeks; and wherein the composition has a citrate concentration ([citrate]=[citric acid]+[dihydrogen citrate ion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10 millimolar. 2. The pharmaceutical composition of claim 1, having a starting pH of at least about 4.5. 3. The pharmaceutical composition of claim 1, having a starting pH of at least about 5.0. 4. The pharmaceutical composition of claim 1, wherein the composition is substantially free of any additional antioxidant. 5. The pharmaceutical composition of claim 1, wherein the composition further comprises at least one member of the group consisting of a salt, EDTA, sorbitol, a sugar (including a reduced sugar, such as sorbitol) or a flavoring agent. 6. The pharmaceutical composition of claim 1, having a concentration of metoclopramide, or a pharmaceutically-acceptable salt thereof, of from about 20.0% (w/v) to about 30.0% (w/v). 7. The composition of claim 1, having a concentration of benzalkonium chloride from about 0.005% (w/v) to about 0.05% (w/v). 8. The composition of claim 1, having an osmolality of from about 500 mOsm/kg to about 1400 mOsm/kg. 9. The composition of claim 1, wherein the composition is a nasal solution that remains clear to pale yellow when compared to standard E, 32 USP <631> on storage at a temperature of about 40.degree. C. for at least about 8 weeks. 10. A pharmaceutical composition comprising metoclopramide, or a pharmaceutically-acceptable salt thereof, a buffer, and benzalkonium chloride; wherein the composition is a nasal solution that is clear to pale yellow when compared to standard E, 32 USP <631> on storage at a temperature of 40.degree. C. for at least about 4 weeks; and wherein the composition has a pH of above about 4.5. 11. The composition of claim 10, having a starting pH of at least about 4.6. 12. The composition of claim 10, wherein the composition remains clear to pale yellow when compared to standard E, 32 USP <631> on storage at a temperature of about 40.degree. C. for at least about 8 weeks. 13. The composition of claim 10, wherein the buffer is selected from the group consisting of citric acid/phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, McIlvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE (1,3-bis(tris(hydroxymethyl)methylamino)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS (3-(N-morpholino)propanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS (4-(N-morpholino)butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2-hydroxy-propanesulfonic acid), tris(hydroxymethylaminomethane, HEPPSO(N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid), POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS(N-(2-hydroxyethyl)piperazine-N'-(3-propane-sulfonic acid), TWINE (N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N'-(4-butanesulfonic acid)), TAPS(N-tris(hydroxy-methypmethyl-3-aminopropanesulfonic acid), or AMPD (2-amino-2-methyl-1,3-propanediol) buffer. 14. A method of treating a patient, comprising intranasally administering to the patient an effective amount of a composition of claim 1. 15. The method of claim 14, wherein the patient has a disorder that is treatable with metoclopramide. 16. The method of claim 15, wherein said disorder that is treatable with metoclopramide is at least one member of the group consisting of gastroparesis, emesis, delayed emesis and nausea. 17. A pharmaceutical composition comprising metoclopramide, or a pharmaceutically-acceptable salt thereof, a citrate buffer, benzalkonium chloride, and less than about 1% w/v benzyl alcohol; wherein the composition is a nasal solution that is clear to pale yellow when compared to standard E, 32 USP <631> on storage at 40.degree. C. for at least about 4 weeks; and wherein the composition has a citrate concentration ([citrate]=[citric acid]+[dihydrogen citrate ion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10 millimolar. 18. The pharmaceutical composition of claim 17, wherein the concentration of benzyl alcohol is about 0.01 to about 0.8% w/v. 19. The pharmaceutical composition of claim 17, wherein said composition remains clear to pale yellow when compared to standard E, 32 USP <631> on storage at a temperature of about 40.degree. C. for at least about 8 weeks. 20. The pharmaceutical composition of claim 17, having a starting pH of at least about 4.5. 21. The pharmaceutical composition of claim 20, having a starting pH of at least about 5.0. 22. The pharmaceutical composition of claim 17, wherein the composition is substantially free of any additional antioxidant. 23. The pharmaceutical composition of claim 17, wherein the composition further comprises at least one member of the group consisting of a salt, EDTA, sorbitol, a sugar (including a reduced sugar, such as sorbitol) or a flavoring agent. 24. The composition of claim 17, having a concentration of metoclopramide, or a pharmaceutically-acceptable salt thereof, of from about 20.0% (w/v) to about 30.0% (w/v). 25. The composition of claim 17, having a concentration of benzalkonium chloride from about 0.005% (w/v) to about 0.05% (w/v). 26. The composition of claim 17, having an osmolality of from about 500 mOsm/kg to about 1400 mOsm/kg. 27. A method of treating a patient, comprising intranasally administering to the patient an effective amount of a composition of claim 17. 28. The method of claim 27, wherein the patient has a disorder that is treatable with metoclopramide. 29. The method of claim 28, wherein said disorder that is treatable with metoclopramide is at least one member of the group consisting of gastroparesis, emesis, delayed emesis and nausea.