STABLE INTRANASAL FORMULATIONS OF CARBETOCIN
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.
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.