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.

What is claimed is: 
     
         1 - 10 . (canceled) 
     
     
         11 . A pharmaceutical composition comprising metoclopramide, or a pharmaceutically-acceptable salt thereof, a buffer, and benzalkonium chloride; wherein the composition is stable, substantially free of color, and/or substantially clear; and wherein the composition has a pH of above about 4.5. 
     
     
         12 . The composition of  claim 11 , having a starting pH of at least about 4.6. 
     
     
         13 . The composition of  claim 11 , wherein the composition remains stable, substantially free of color and/or substantially clear on storage at a temperature of about 25° C. to about 40° C. for at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks or at least about 12 weeks. 
     
     
         14 . The composition of  claim 11 , 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), AD(Original) A (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)), TE(Original) A (triethanolamine), EPPS(N-(2-hydroxyethyl)piperazine-N′-(3-propane-sulfonic acid), TRICINE (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-methyl)methyl-3-aminopropanesulfonic acid), or AMPD (2-amino-2-methyl-1,3-propanediol) buffer. 
     
     
         15 - 17 . (canceled) 
     
     
         18 . An article of manufacture comprising:
 (a) 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° C. for at least about 4 weeks; and wherein the composition has a citrate concentration of at least about 10 millimolar; and   (b) a means for nasal administration of said composition to a patient.   
     
     
         19 . The article of manufacture of  claim 18 , wherein the means for nasal administration comprises a reservoir that contains the composition, a pump in fluid communication with the composition in the reservoir and a nozzle in fluid communication with the pump, wherein activation of the pump withdraws a predetermined amount of said composition from the reservoir and causes said predetermined amount of said composition to be expelled from said nozzle. 
     
     
         20 . The article of manufacture of  claim 19 , wherein said predetermined amount of composition is about 10 μL to about 500 μL, about 50 μL to about 250 μL, about 50 μL, about 75 μL, about 100 μL, about 125 μL, about 150 μL, about 175 μL, about 200 μL, about 225 μL or about 250 μL per activation (“spray”). 
     
     
         21 . The article of manufacture of  claim 20 , wherein the composition is within an opaque container. 
     
     
         22 . A pharmaceutical composition comprising metoclopramide, or a pharmaceutically-acceptable salt thereof, and citric acid as a stabilizer, wherein the composition is stable, substantially free of color, and/or substantially clear. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the composition has a citric acid concentration of at least about 5 millimolar. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the composition has a citric acid concentration of about 5-100 millimolar. 
     
     
         25 . The pharmaceutical composition of  claim 22 , wherein the composition is substantially free of any additional antioxidant. 
     
     
         26 . The pharmaceutical composition of  claim 22 , 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. 
     
     
         27 . The composition of  claim 22  having a concentration of metoclopramide, or a pharmaceutically-acceptable salt thereof, of from about 20.0% (w/v) to about 30.0% (w/v). 
     
     
         28 . The composition of  claim 22 , wherein the composition further contains benzalkonium chloride at a concentration from about 0.005% (w/v) to about 0.05% (w/v). 
     
     
         29 . The composition of  claim 22 , having an osmolality of from about 500 mOsm/kg to about 1400 mOsm/kg. 
     
     
         30 . The composition of  claim 22 , wherein the composition remains stable, substantially free of color, and/or substantially clear on storage at a temperature of about 25° C. to about 40° C. for at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks or at least about 12 weeks. 
     
     
         31 . A method of treating a patient, comprising administering to the patient an effective amount of a composition of  claim 22 . 
     
     
         32 . The method of  claim 31 , wherein the patient has a disorder that is treatable with metoclopramide. 
     
     
         33 . The method of  claim 32 , wherein said disorder that is treatable with metoclopramide is at least one member of the group consisting of gastroparesis, emesis, delayed emesis and nausea. 
     
     
         34 . An article of manufacture comprising a composition of  claim 11  and a means for nasal administration of said composition to a patient. 
     
     
         35 . The article of manufacture of  claim 34 , wherein the means for nasal administration comprises a reservoir that contains the composition, a pump in fluid communication with the composition in the reservoir and a nozzle in fluid communication with the pump, wherein activation of the pump withdraws a predetermined amount of said composition from the reservoir and causes said predetermined amount of said composition to be expelled from said nozzle. 
     
     
         36 . The article of manufacture of  claim 35 , wherein said predetermined amount of composition is about 10 μL to about 500 μL, about 50 μL to about 250 μL, about 50 μL, about 75 μL, about 100 μL, about 125 μL, about 150 μL, about 175 μL, about 200 μL, about 225 μL or about 250 μL per activation (“spray”). 
     
     
         37 . The article of manufacture of  claim 36 , wherein the composition is within an opaque container. 
     
     
         38 - 51 . (canceled) 
     
     
         52 . An article of manufacture comprising a composition of claim  38  and a means for nasal administration of said composition to a patient. 
     
     
         53 . The article of manufacture of  claim 52 , wherein the means for nasal administration comprises a reservoir that contains the composition, a pump in fluid communication with the composition in the reservoir and a nozzle in fluid communication with the pump, wherein activation of the pump withdraws a predetermined amount of said composition from the reservoir and causes said predetermined amount of said composition to be expelled from said nozzle. 
     
     
         54 . The article of manufacture of  claim 53 , wherein said predetermined amount of composition is about 10 μL to about 500 μL, about 50 μL to about 250 μL, about 50 μL, about 75 μL, about 100 μL, about 125 μL, about 150 μL, about 175 μL, about 200 μL, about 225 μL or about 250 μL per activation (“spray”). 
     
     
         55 . The article of manufacture of  claim 54 , wherein the composition is within an opaque container.