Emulsion formulations of an NK-1 receptor antagonist and uses thereof
Disclosed herein are novel pharmaceutical formulations of a neurokinin-1 (NK-1) receptor antagonist suitable for parenteral administration including intravenous administration. Also included are formulations including both the NK-1 receptor antagonist and dexamethasone sodium phosphate. The pharmaceutical formulations are stable oil-in-water emulsions for non-oral treatment of emesis and are particularly useful for treatment of subjects undergoing highly emetogenic cancer chemotherapy.
1. An injectable pharmaceutical emulsion comprising:
a neurokinase-1 (NK-1) receptor antagonist;
11 wt/wt % to 15 wt/wt % of an emulsifier;
an oil;
a co-surfactant which comprises an alcohol;
a tonicity agent;
a pH modifier; and
water;
wherein the pH of the emulsion ranges from about 7.5 to 9.0, and the ratio of the emulsifier to the NK-1 receptor antagonist ranges from about 18:1 to 22:1 (wt/wt %).
2. The emulsion according to claim 1 , wherein the ratio of the oil to the NK-1 receptor antagonist ranges from about 5:1 to 15:1 (wt/wt %).
3. The emulsion according to claim 1 , wherein the ratio of the oil to the NK-1 receptor antagonist ranges from about 10:1 to 15:1 (wt/wt %).
4. The emulsion according to claim 1 , wherein the ratio of emulsifier to oil ranges from about 1:1 to 3:1 (wt/wt %).
5. The emulsion according to claim 1 , wherein the emulsifier is a phospholipid.
6. The emulsion according to claim 1 , wherein the emulsifier is an egg lecithin.
7. The emulsion according to claim 1 , further comprising dexamethasone sodium phosphate, wherein the dexamethasone sodium phosphate is present in the aqueous phase.
8. The emulsion according to claim 1 , wherein the NK-1 receptor antagonist is selected from the group consisting of rolapitant, netupitant, ezlopitant, vestipitant, serlopitant, maropitant, casopitant, befetupitant, and orvepitant.
9. The emulsion according to claim 1 , wherein the pH modifier is oleic acid or a salt thereof.
10. The emulsion according to claim 1 , wherein the pH modifier is a buffer.
11. The emulsion according to claim 10 , wherein the buffer is Tris buffer.
12. The emulsion according to claim 1 , wherein the oil is soybean oil.
13. The emulsion according to claim 1 , wherein the alcohol is ethanol.
14. The emulsion according to claim 13 , wherein the ethanol is present in the emulsion at less than 10 wt/wt %.
15. The emulsion according to claim 1 , wherein the NK-1 receptor antagonist is not aprepitant.
16. A method for preparing an injectable pharmaceutical emulsion comprising:
(a) combining a NK-1 receptor antagonist, an emulsifier, and an alcohol with an oil to generate an oil phase;
(b) combining water, a tonicity agent, a pH modifier, and optionally a buffer to generate an aqueous phase;
(c) homogenizing the oil phase with the aqueous phase to generate the pharmaceutical emulsion; and
(d) sterilizing the pharmaceutical emulsion.
17. The method according to claim 16 , wherein step (c) comprises homogenizing the oil phase with the aqueous phase to generate a crude emulsion, and step (c) further comprises homogenizing the crude emulsion to generate a fine emulsion wherein the fine emulsion is the pharmaceutical emulsion.
18. The method according to claim 17 , wherein homogenizing the crude emulsion comprises using a microfluidizer at a pressure between 10,000 to 30,000 psi.
19. The method according to claim 18 , wherein homogenizing the crude emulsion comprises 4 to 15 passes through the microfluidizer.
20. The method according to claim 16 , wherein the sterilizing comprising passing the pharmaceutical emulsion through a filter having a pore size of about 0.2 microns.
21. The method according to claim 16 , further comprising adding a solution of dexamethasone sodium phosphate to the pharmaceutical emulsion prior to sterile filtration.
22. The method according to claim 16 , wherein the receptor antagonist is selected from the group consisting of rolapitant, netupitant, ezlopitant, casopitant, befetupitant, vestipitant, serlopitant, maropitant, and orvepitant.
23. The method according to claim 16 , wherein the NK-1 receptor antagonist is not aprepitant.