Liquid oral formulations of netupitant and palonosetron
Orally administered liquid formulations of netupitant and palonosetron, and suitable pharmaceutical excipients, in a solvent system that allows for the netupitant to be suspended and the palonosetron to be dissolved, that are efficacious, chemically stable and physiologically balanced for safety and efficacy.
1 . An orally administered antiemetic composition in a mixed suspension/solution solvent system comprising:
a) from 0.01 to 0.2 mg/mL palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a dissolved state and from 10 to 100 mg/mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a solid suspended state; and
b) a solvent system in which the netupitant or pharmaceutically acceptable salt thereof is insoluble and in a solid state but homogenously suspended and the palonosetron or pharmaceutically acceptable salt thereof is soluble and in a dissolved state comprising water, one or more miscibilized wetting agents, one or more miscibilized suspending agents, one or more pH modifiers, optionally one or more miscibilized sweetening agents, and optionally one or more miscibilized preservatives.
2 . The composition of claim 1 , wherein the solvent system comprises one or more miscibilized sweetening agents; and one or more miscibilized preservatives.
3 . The composition of claim 1 , wherein the palonosetron is present as palonosetron HCl and the netupitant is present as the free base.
4 . The composition of claim 1 , wherein the netupitant is present as a free base and has a particle size distribution defined by a d(50) of 1-8 μm and a d(90) of not more than 24 μm or a d(50) of 2-4 μm and a d(90) of not more than 12 μm.
5 . The composition of claim 1 , having a pH of from 4 to 7 or from 5 to 6.
6 . The composition claim 1 , comprising 30 mg/mL of netupitant free base and 0.056 mg/mL of palonosetron HCl.
7 . The composition of claim 1 , wherein the wetting agent is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, ethanol, and combinations thereof.
8 . The composition of claim 1 , comprising from 25 to 100 mg/mL, from 35 to 75 mg/mL, or 50 mg/mL glycerin as a wetting agent.
9 . The composition of claim 1 , wherein the suspending agent is selected from the group consisting of cellulose derivatives, acacia, xanthan gum, and combinations thereof.
10 . The composition of claim 1 , comprising from 2 to 4 mg/mL, from 2.5 to 3.5 mg/mL, or 3 mg/mL xanthan gum as a suspending agent.
11 . The composition of claim 1 , wherein the pH modifier is selected from the group consisting of citric acid anhydrous and sodium citrate tribasic and combinations thereof.
12 . The composition of claim 1 , comprising:
a) from 25 to 100 mg/mL, from 35 to 75 mg/mL, or 50 mg/mL glycerin; and
b) from 2 to 4 mg/mL, from 2.5 to 3.5 mg/mL, or 3 mg/mL xanthan gum.
13 . The composition of claim 1 , comprising:
a) from 2 to 4 mg/mL, from 2.5 to 3.5 mg/mL, or 3 mg/mL xanthan gum;
b) from 800 mg/mL to 950 mg/mL, from 850 to 900 mg/mL, or 886.333 mg/mL sorbitol syrup n.c. 70%; and
c) from 0.5 to 1.5 mg/mL, from 0.75 to 1.25 mg/mL, or 1 mg/mL potassium sorbate.
14 . A method of preventing chemotherapy induced nausea and vomiting in a human patient in need thereof comprising orally administering to the patient 300 mg of netupitant or pharmaceutically acceptable salt thereof (based on the weight of the free base) and 0.5 mg palonosetron or pharmaceutically acceptable salt thereof (based on the weight of the free base) from the composition of claim 1 .
15 . The method of claim 14 , further comprising administering highly emetogenic chemotherapy or moderately emetogenic chemotherapy within 2 hours of administering the netupitant and palonosetron.
16 . A method of manufacturing an orally administered antiemetic composition in a mixed suspension/solution solvent system comprising:
a) making a bulk formulation comprising from 0.01 to 0.2 mg/mL palonosetron or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a dissolved state and from 10 to 100 mg/mL of netupitant or a pharmaceutically acceptable salt thereof (based on the weight of the free base) in a solid suspended state; and
b) filling the bulk formulation into a plurality of unit dose packages while continuously stirring the formulation to minimize or prevent foaming.
17 . The method of claim 16 , wherein the bulk formulation comprises a solvent system in which the netupitant or pharmaceutically acceptable salt thereof is insoluble but homogenously suspended and the palonosetron or pharmaceutically acceptable salt thereof is soluble comprising water, one or more miscibilized wetting agents, one or more miscibilized suspending agents, one or more pH modifiers, optionally one or more miscibilized sweetening agents, and optionally one or more miscibilized preservatives.
18 . The method of claim 16 , comprising filling about 10 mL of the bulk formulation into each unit dose package comprising 300 mg of netupitant or a pharmaceutically acceptable salt thereof at a concentration of 30 mg/mL, and 0.5 mg of palonosetron or a pharmaceutically acceptable salt thereof at a concentration of 0.05 mg/mL, wherein the doses and concentrations are based on the free form of the netupitant and palonosetron.
19 . The method of claim 16 , wherein the netupitant is present as a free base and has a particle size distribution defined by a d(50) of 1-8 μm and a d(90) of not more than 24 μm or a d(50) of 2-4 μm and a d(90) of not more than 12 μm.
20 . The method of claim 16 , wherein the netupitant is present as a free base and has a particle size distribution defined by a d(50) of 1-8 μm and a d(90) of not more than 24 μm or a d(50) of 2-4 μm and a d(90) of not more than 12 μm.
21 . The composition of claim 1 , wherein the netupitant is present as a free base and has a particle size distribution defined by a d(50) of less than about 8 μm.