Methods of use of emulsion formulations of an NK-1 receptor antagonist
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: aprepitant, egg lecithin, soybean oil, ethanol, sucrose, sodium oleate, and water, wherein the ratio of the egg lecithin to aprepitant ranges from about 18:1 to 22:1 (wt/wt %).
2. The emulsion according to claim 1 , wherein the egg lecithin is present at a concentration of about 14 wt/wt % to 15 wt/wt %.
3. The emulsion according to claim 2 , wherein the ratio of egg lecithin to aprepitant is about 20:1.
4. The emulsion according to claim 1 , wherein the soybean oil is present at a concentration of about 9 wt/wt % to 10 wt/wt %.
5. The emulsion according to claim 1 , wherein the soybean oil is present at a concentration of about 9.5 wt/wt %.
6. The emulsion according to claim 1 , wherein the ethanol is present at a concentration of about 2 wt/wt % to 3 wt/wt %.
7. The emulsion according to claim 1 , wherein the sucrose is present at a concentration of about 3 wt/wt % to 8 wt/wt %.
8. The emulsion according to claim 1 , wherein the sucrose is present at a concentration of about 5 wt/wt %.
9. The emulsion according to claim 1 , wherein the sodium oleate is present at a concentration of about 0.4 wt/wt % to 0.5 wt/wt %.
10. The emulsion according to claim 1 , wherein the sodium oleate is present at a concentration of about 0.45 wt/wt %.
11. The emulsion according to claim 1 , wherein the ratio of soybean oil to aprepitant ranges from about 13:1 to 14:1 (wt/wt %).
12. The emulsion according to claim 1 , wherein the ratio of (egg lecithin plus soybean oil) to aprepitant ranges from about 32:1 to 34:1.
13. An injectable pharmaceutical emulsion, comprising:
a neurokinin-1 (NK-1) receptor antagonist;
about 14 wt/wt % to 15 wt/wt % of an emulsifier selected from the group consisting of egg phospholipids and soy phospholipids;
about 9 wt/wt % to 10 wt/wt % of an oil selected from the group consisting of coconut oil, olive oil, soybean oil, safflower oil, triglycerides, octyl and decyl glycerate, ethyl oleate, glyceryl linoleate, ethyl linoleate, glyceryl oleate, cholesteryl oleate, cholesteryl linoleate, and mixtures thereof;
about 2 wt/wt % to 3 wt/wt % of a co-surfactant comprising an alcohol;
about 3 wt/wt % to 8 wt/wt % of an osmotic agent selected from the group consisting of glycerol, sorbitol, xylitol, mannitol, glucose, trehalose, maltose, sucrose, raffinose, lactose, dextran, polyethylene glycol, or propylene glycol;
about 0.4 wt/wt % to 0.5 wt/wt % of a pH modifier, wherein the pH modifier is oleic acid or a salt thereof; and
water;
wherein the ratio of the emulsifier to NK-1 receptor antagonist ranges from about 18:1 to 22:1 (wt/wt %).
14. The emulsion according to claim 13 , wherein the NK-1 receptor antagonist is aprepitant.
15. The emulsion according to claim 13 , wherein the emulsifier is egg lecithin.
16. The emulsion according to claim 13 , wherein the oil is soybean oil.
17. The emulsion according to claim 13 , wherein the co-surfactant is ethanol.
18. The emulsion according to claim 13 , wherein the osmotic agent is sucrose.
19. The emulsion according to claim 13 , wherein the pH modifier is sodium oleate.
20. The emulsion according to claim 11 , wherein:
the oil is present at a concentration of about 9.5 wt/wt %;
the pH modifier is present at a concentration of about 0.45 wt/wt %;
the ratio of the emulsifier to NK-1 receptor antagonist is about 20:1 (wt/wt %);
the ratio of oil to NK-1 receptor antagonist ranges from about 13:1 to 14:1 (wt/wt %); and
the ratio of (emulsifier plus oil) to NK-1 receptor antagonist ranges from about 32:1 to 34:1.
21. The emulsion according to claim 20 , wherein:
the NK-1 receptor antagonist is aprepitant;
the emulsifier is egg lecithin;
the oil is soybean oil;
the co-surfactant is ethanol;
the osmotic agent is sucrose; and
the pH modifier is sodium oleate.
22. A method for preventing post-operative nausea and vomiting in a subject, comprising:
intravenously administering an injectable pharmaceutical emulsion comprising:
aprepitant;
about 14 wt/wt % to 15 wt/wt % of egg lecithin;
about 9 wt/wt % to 10 wt/wt % of soybean oil;
about 2 wt/wt % to 3 wt/wt % of ethanol;
about 3 wt/wt % to 8 wt/wt % of sucrose;
about 0.4 wt/wt % to 0.5 wt/wt % of sodium oleate; and
water;
wherein the ratio of the egg lecithin to aprepitant ranges from about 19:1 to 20:1 (wt/wt %).
23. The method according to claim 22 , wherein the ratio of egg lecithin to aprepitant is about 20:1 (wt/wt %).
24. The method according to claim 22 , wherein the egg lecithin is present at a concentration of about 14.5 wt/wt %.
25. The method according to claim 22 , wherein the soybean oil is present at a concentration of about 9.5 wt/wt %.
26. The method according to claim 22 , wherein the ethanol is present at a concentration of about 2 wt/wt % to 3 wt/wt %.
27. The method according to claim 22 , wherein the sucrose is present at a concentration of about 5 wt/wt %.
28. The method according to claim 22 , wherein the sodium oleate is present at a concentration of about 0.45 wt/wt %.
29. The method according to claim 22 , wherein the ratio of soybean oil to aprepitant ranges from about 13:1 to 14:1 (wt/wt %).
30. The method according to claim 22 , wherein the ratio of (egg lecithin plus soybean oil) to aprepitant ranges from about 32:1 to 34:1.