Stable Anti-inflammatory Solutions for Injection
The present invention relates to stable liquid formulations of ketoprofen, amitriptyline, and oxymetazoline.
1 . A liquid pharmaceutical formulation comprising 550 μM to 1 M ketoprofen, 55 μM to 1 M amitriptyline, 350 μM to 1 M oxymetazoline, 1-100% (v/v) polyol, and 10-500 mM Na citrate, pH 4.5-7.0, wherein the ketoprofen, amitriptyline, and oxymetazoline are soluble, and wherein the ketoprofen, amitriptyline, oxymetazoline are stable for at least six months when stored at a temperature of between 2° C. and 30° C.
2 . The pharmaceutical formulation of claim 1 , wherein the polyol concentration is 10-70% (v/v).
3 . The pharmaceutical formulation of claim 1 , wherein the polyol concentration is 15-25% (v/v).
4 . The pharmaceutical formulation of claim 1 , wherein the polyol concentration is 20% (v/v).
5 . The pharmaceutical formulation of claim 1 , wherein the polyol is PEG 400.
6 . The pharmaceutical formulation of claim 5 , wherein the polyol is PEG 400.
7 . The pharmaceutical formulation of claim 1 , wherein the formulation is an aqueous formulation comprising 30-90% (v/v) water.
8 . The pharmaceutical formulation of claim 5 , wherein the formulation is an aqueous formulation comprising 75-85% (v/v) water.
9 . The pharmaceutical formulation of claim 5 , wherein the formulation is an aqueous formulation comprising 80% (v/v) water.
10 . The pharmaceutical formulation of claim 1 , wherein the pH is between 5.0 and 6.2.
11 . The pharmaceutical formulation of claim 1 , wherein the pH is between 5.2 and 5.8.
12 . The pharmaceutical formulation of claim 1 , wherein the pH is between 5.4 and 5.6.
13 . The pharmaceutical formulation of claim 1 , wherein the pH is about 5.5.
14 . The pharmaceutical formulation of claim 1 , wherein the ketoprofen, amitriptyline, oxymetazoline are stable for at least twelve months when stored at a temperature of between 2° C. and 30° C.
15 . The pharmaceutical formulation of claim 1 , wherein the ketoprofen, amitriptyline, oxymetazoline are stable for at least eighteen months when stored at a temperature of between 2° C. and 30° C.
16 . The pharmaceutical formulation of claim 1 , wherein the ketoprofen, amitriptyline, oxymetazoline are stable for at least twenty-four months when stored at a temperature of between 2° C. and 30° C.
17 . The pharmaceutical formulation of claim 1 , wherein the ketoprofen, amitriptyline, oxymetazoline are stable for at least thirty month when stored at a temperature of between 2° C. and 30° C. s.
18 . The pharmaceutical formulation of claim 1 , wherein the ketoprofen, amitriptyline, oxymetazoline are stable for at least thirty-six months when stored at a temperature of between 2° C. and 30° C.
19 . The pharmaceutical formulation of claim 1 , wherein the ketoprofen, amitriptyline, oxymetazoline are stable for at least forty-eight months when stored at a temperature of between 2° C. and 30° C.
20 . The pharmaceutical formulation of claim 1 , further comprising 0.002-1.0% (w/v) Na 2 EDTA.
21 . The pharmaceutical formulation of claim 1 , wherein the concentration of Na 2 EDTA is between 0.01-0.5% (w/v).
22 . The pharmaceutical formulation of claim 1 , wherein the concentration of Na 2 EDTA is 0.05% (w/v).
23 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is exposed to N 2 before storage.
24 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is stored in the dark.
25 . The pharmaceutical formulation of claim 1 , wherein the Na Citrate concentration is about 50 mM.
26 . A kit comprising the pharmaceutical formulation of claim 1 and instruction for use thereof.
27 . The kit of claim 26 , wherein the pharmaceutical formulation is packaged in a syringe for direct injection into a localized site of inflammation.
28 . The kit of claim 26 , wherein the pharmaceutical formulation is packaged in a vial.
29 . A liquid pharmaceutical formulation comprising 0.1-1.0 g/L ketoprofen, 0.05-0.5 g/L amitriptyline, 0.05-0.5 g/L oxymetazoline, about 0.002-1.0% (w/v) Na 2 EDTA, and 10-500 mM Na citrate, in a medium comprising 10-70% (v/v) PEG 400 and 30-90% v/v water, with a pH of 5.0-6.2, wherein the ketoprofen, amitriptyline, and oxymetazoline are soluble, and wherein the ketoprofen, amitriptyline, oxymetazoline are stable for at least six months when stored at a temperature of between 2° C. and 30° C.
30 . A liquid pharmaceutical formulation comprising about 0.687 g/L ketoprofen, about 0.227 g/L amitriptyline, about 0.215 g/L oxymetazoline, about 0.05% (w/v) Na 2 EDTA and about 50 mM Na citrate, in a medium comprising about 20% (v/v) PEG 400 and about 80% (v/v) water, with a pH of 5.0-6.2, wherein the ketoprofen, amitriptyline, and oxymetazoline are soluble, and wherein the ketoprofen, amitriptyline, oxymetazoline are stable for at least six months when stored at a temperature of between 2° C. and 30° C.
31 . A method of preventing or treating inflammation at an anatomic site that is inflamed or at risk of inflammation, comprising injecting into the site, a composition comprising the anti-inflammatory agents ketoprofen, amitriptyline and oxymetazoline in a physiologic carrier, in the absence of a surgical procedure such that the composition is retained at the site for a sufficient period, and wherein the agents are injected in an amount sufficient, to inhibit inflammation at the site.