Claims for Patent: 10,624,911

Summary for Patent: 10,624,911

Title:	Physiologically balanced injectable formulations of fosnetupitant
Abstract:	Injectable dosages and formulations of fosnetupitant and pharmaceutically acceptable salts thereof are provided that are efficacious, chemically stable and physiologically balanced for safety and efficacy.
Inventor(s):	Venturini; Alessio (Varese, IT), Cannella; Roberta (Varese, IT)
Assignee:	Helsinn Healthcare SA (Lugano/Pazzallo, CH)
Application Number:	15/611,785
Patent Claims:	1. A pharmaceutically stable injectable liquid formulation of fosnetupitant comprising: a) from 2.3 to 30 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) from 5 to 50 .mu.g/mL palonosetron hydrochloride based on the weight of the free base; c) sodium hydroxide; d) disodium edetate; e) optionally hydrochloric acid; and f) mannitol. 2. A pharmaceutically stable injectable lyophilized formulation of fosnetupitant comprising: a) from 2.3 to 30 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) from 5 to 50 .mu.g/mL palonosetron hydrochloride based on the weight of the free base; c) sodium hydroxide; d) disodium edetate; e) optionally hydrochloric acid; and f) mannitol. 3. A pharmaceutically stable liquid injectable solution formulation of fosnetupitant at a pH of 7.0-10.0 comprising: a) from 2.3 to 30 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) from 5 to 50 .mu.g/mL palonosetron hydrochloride based on the weight of the free base; c) from 0.05 to 0.9 mg/mL disodium edetate; d) from 10 to 100 mg/mL mannitol; e) NaOH; optionally HCl; and g) water q.s. 4. A pharmaceutically stable lyophilized powder injectable formulation of fosnetupitant at a pH of 7.0-10.0 comprising: a) from 2.3 to 30 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) from 5 to 50 .mu.g/mL palonosetron hydrochloride based on the weight of the free base; c) from 0.1 to 2.0 mg/mL disodium edetate; d) from 10 to 100 mg/mL mannitol; and e) NaOH and optionally HCl; based on a reconstitution in a suitable water volume. 5. The lyophilized powder formulation of claim 4 at a pH of 7.0-10.0, comprising: a) from 2.3 to 30 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) from 5 to 50 .mu.g/mL palonosetron hydrochloride based on the weight of the free base; c) from 0.1 to 2.0 mg/mL disodium edetate; d) from 10 to 100 mg/mL mannitol; and e) NaOH and HCl; based on a reconstitution in a suitable water volume. 6. The lyophilized powder formulation of claim 4 at a pH of 8.5-9.5, comprising: a) about 13.0 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) about 14.04 .mu.g/mL palonosetron hydrochloride based on the weight of the salt; c) about 0.32 mg/mL disodium edetate; d) about 38 mg/mL mannitol; and e) NaOH and optionally HCl; based on a reconstitution in water volume of 20 mL. 7. A method of manufacturing a liquid injectable or lyophilized formulation of fosnetupitant comprising: a) simultaneously admixing the chloride hydrochloride salt of fosnetupitant with sodium hydroxide in water at a basic pH of from approximately 11 to 14 to form a solution; b) reducing the pH of the solution to a basic pH of from approximately 7 to 10 by the addition of one or more acidic pH adjusting agents; and c) optionally admixing the solution with one or more pharmaceutically acceptable excipients. 8. An intravenous formulation of fosnetupitant made by a process of mixing the fosnetupitant formulation of claim 2 with 0.9% saline or 5% glucose. 9. The liquid formulation of claim 1 comprising palonosetron hydrochloride and HCl. 10. The liquid formulation of claim 3, comprising: a) from 2.3 to 30 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) from 5 to 50 .mu.g/mL palonosetron hydrochloride based on the weight of the free base; c) from 0.1 to 2.0 mg/mL disodium edetate; d) from 10 to 100 mg/mL mannitol; and e) NaOH and HCl. 11. The liquid formulation of claim 3 at a pH of 8.5-9.5, comprising: a) about 13.0 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) about 14.04 .mu.g/mL palonosetron hydrochloride based on the weight of the salt; c) about 0.32 mg/mL disodium edetate; d) about 38 mg/mL mannitol; and e) NaOH and HCl. 12. The lyophilized powder formulation of claim 2 comprising: a) from 2.3 to 30 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) from 5 to 50 .mu.g/mL palonosetron hydrochloride based on the weight of the free base; c) from 0.1 to 2.0 mg/mL disodium edetate; d) from 10 to 100 mg/mL mannitol; and e) NaOH and optionally HCl; based on a reconstitution in a suitable water volume. 13. The lyophilized powder formulation of claim 2 comprising: a) about 13.0 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) about 14.04 .mu.g/mL palonosetron hydrochloride based on the weight of the salt; c) about 0.32 mg/mL disodium edetate; d) about 38 mg/mL mannitol; and e) NaOH and HCl; based on a reconstitution in a suitable volume of water. 14. The liquid formulation of claim 1 at a pH of from 7.5 to 10.0. 15. The lyophilized powder formulation of claim 2 having a pH of from 7.5 to 10.0 upon reconstitution in water. 16. The lyophilized powder formulation of claim 12 having a pH of from 7.5 to 10.0 upon reconstitution in water. 17. The lyophilized powder formulation of claim 13 having a pH of from 7.5 to 10.0 upon reconstitution in water. 18. The method of claim 7, wherein the acidic pH adjusting agent comprises hydrochloric acid. 19. A pharmaceutically stable injectable liquid formulation of fosnetupitant comprising: a) from 2.3 to 30 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) from 5 to 50 .mu.g/mL palonosetron hydrochloride based on the weight of the free base; c) an alkalizing agent; and d) an alkaline pH. 20. The pharmaceutically stable injectable liquid formulation of claim 19 comprising: a) about 13.0 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) about 14.04 .mu.g/mL palonosetron hydrochloride based on the weight of the salt; c) sodium hydroxide as the alkalizing agent; and d) a pH of from 7 to 10. 21. The pharmaceutically stable injectable liquid formulation of claim 19 comprising sodium hydroxide as the alkalizing agent and a pH of from 7 to 10.