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 Präder-Willi syndrome. Additionally, the disclosed carbetocin compositions show improved stability at room temperature and/or under accelerated conditions of stress.

What is claimed is: 
     
         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; and   (b) a solubilizer and/or hydroxypropyl methylcellulose (HPMC);   wherein the solubilizer is a hydrotrope, and wherein the solution has little to no visible solids.   
     
     
         2 . 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) nicotinamide;   (c) HPMC; and   (d) 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 1 , wherein the HPMC is high viscosity grade. 
     
     
         8 . The pharmaceutical preparation of  claim 1 , wherein the HPMC 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 . The pharmaceutical preparation of  claim 1 , wherein the hydrotrope is sodium salicylate, and wherein the sodium salicylate is present in a concentration ranging from about 200 mM to about 400 mM. 
     
     
         11 . The pharmaceutical preparation of  claim 1 , further comprising sorbitol in a concentration ranging from about 100 mM to about 287 mM. 
     
     
         12 . The pharmaceutical preparation of  claim 1 , further comprising an amino acid. 
     
     
         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.