Stable intranasal formulations of carbetocin

Abstract

The application describes stable aqueous compositions comprising relatively high concentrations of carbetocin and a solubilizer and/or surface active agent. The disclosed carbetocin compositions are effective in the treatment of a neurodevelopmental disorder, such as Prader-Willi syndrome. Additionally, the disclosed carbetocin compositions show improved stability at room temperature and/or under accelerated conditions of stress.

1 . A stable intranasal pharmaceutical preparation comprising:
 (a) an aqueous solution of carbetocin or a pharmaceutically acceptable salt thereof, wherein the carbetocin is present in a concentration of about 10 mg/ml to about 70 mg/ml;   (b) a hydrotrope; and   (c) a viscoelastic polymer, wherein the solution has little to no visible solids;   and wherein the pharmaceutical preparation results in 75-125% of the bioavailability measured by the area under the curve and the maximum concentration, of an aqueous solution consisting of the same concentration of carbetocin in saline,   and further wherein the pharmaceutical preparation does not contain an interfacial stabilizer, a surfactant, or a chelating agent.   
     
     
         2 . The stable intranasal pharmaceutical preparation of  claim 1 , wherein the hydrotrope is nicotinamide; the viscoelastic polymer is HPMC; and the pharmaceutical preparation further comprises one or more additional excipients. 
     
     
         3 . The pharmaceutical preparation of  claim 1 , wherein the concentration of carbetocin ranges from about 10 mg/ml to about 40 mg/ml. 
     
     
         4 . The pharmaceutical preparation of  claim 1 , wherein the concentration of carbetocin ranges from about 25 mg/ml to about 40 mg/ml. 
     
     
         5 . The pharmaceutical preparation of  claim 1 , wherein the concentration of carbetocin is about 34.3 mg/ml. 
     
     
         6 . The pharmaceutical preparation of  claim 1 , wherein the concentration of carbetocin is about 11.4 mg/ml. 
     
     
         7 . The pharmaceutical preparation of  claim 2 , wherein the HPMC is medium viscosity or high viscosity grade. 
     
     
         8 . The pharmaceutical preparation of  claim 1 , wherein the viscoelastic polymer is HPMC and is present in an amount ranging from 0.005% w/v to 0.05% w/v. 
     
     
         9 . The pharmaceutical preparation of  claim 1 , wherein the hydrotrope is nicotinamide, and wherein the nicotinamide is present in a concentration ranging from 50 mM to 500 mM. 
     
     
         10 . (canceled) 
     
     
         11 . The pharmaceutical preparation of  claim 1 , further comprising sorbitol in a concentration ranging from about 100 mM to about 287 mM. 
     
     
         12 . (canceled) 
     
     
         13 . The pharmaceutical preparation of  claim 1 , wherein the solution has little to no visible solids after shaking for 1, 2, or 3 days at 5° C. and/or 25° C. 
     
     
         14 . The pharmaceutical preparation of  claim 1 , in a unit volume of 140 μL. 
     
     
         15 . The pharmaceutical preparation of  claim 2 , comprising:
 (a) carbetocin, wherein the carbetocin is present in a concentration of about 10 mg/ml to about 40 mg/ml;   (b) nicotinamide, wherein the nicotinamide is present in a concentration ranging from about 200 mM to about 400 mM;   (c) HPMC, wherein the HPMC is present in an amount ranging from 0.0075% w/v to 0.05% w/v; and   (d) one or more additional excipients.   
     
     
         16 . The pharmaceutical preparation of  claim 2 , comprising:
 (a) carbetocin, wherein the carbetocin is present in a concentration of about 25 mg/ml to about 35 mg/ml;   (b) nicotinamide, wherein the nicotinamide is present in a concentration ranging from about 200 mM to about 400 mM;   (c) HPMC, wherein the HPMC is present in an amount ranging from 0.0075% w/v to 0.05% w/v; and   (d) one or more additional excipients.   
     
     
         17 . The pharmaceutical preparation of  claim 15 , wherein the carbetocin is present in a concentration of about 10 mg/ml to about 40 mg/ml and the HPMC is present in an amount of about 0.01% w/v; and
 wherein said one or more additional excipients is selected from the group consisting of sorbitol, EDTA, an amino acid, potassium sorbate, and combinations thereof.   
     
     
         18 . The pharmaceutical preparation of  claim 15 , wherein the HPMC is present in an amount ranging from 0.01% w/v to 0.05% w/v; and
 wherein said one or more additional excipients is sorbitol, and   wherein the sorbitol is present in a concentration ranging from about 100 mM to about 287 mM.   
     
     
         19 . The pharmaceutical preparation of  claim 2 , wherein the solution has little to no visible solids after shaking for 1, 2, or 3 days at 5° C. and/or 25° C. 
     
     
         20 . The pharmaceutical preparation of  claim 2 , wherein the preparation has a pH of about 5.4. 
     
     
         21 . The pharmaceutical preparation of  claim 2 , wherein the HPMC has a viscosity of 40 cP or higher. 
     
     
         22 . The pharmaceutical preparation of  claim 2 , wherein the HPMC has a viscosity of 120 cP or higher. 
     
     
         23 . The pharmaceutical preparation of  claim 1 , wherein the interfacial stabilizing agent is methyl-β-cyclodextrin. 
     
     
         24 . The pharmaceutical preparation of  claim 1 , wherein the chelating agent is ethylene diamine tetraacetic acid (EDTA).