Liposome formulation of fluticasone furoate and method of preparation
The present invention is directed to a liposomal formulation having a lipid ingredient encapsulating fluticasone furoate, and a method for preparing the liposomal formulation. The liposome formulation comprises a lipid and a sterol. The method of preparing the liposomes comprises the steps of (1) mixing fluticasone furoate with lipid ingredients comprising a lipid and a sterol, (2) injecting the mixture into normal saline solution, and (3) ultrafiltering and concentrating the resulting solution. This preparation method can produce a liposome formulation having desirable properties and compositions, for example, the ratio of the lipid ingredient, the drug to lipid ratio, and the pH value, which is suitable for nebulization inhalation.
1. A formulation comprising a suspension of a plurality of liposomes in a solvent, wherein the liposomes comprise a lipid ingredient that encapsulates fluticasone furoate, wherein the lipid ingredient comprises DPPC and cholesterol in a DPPC:cholesterol molar ratio of about 0.8:1 to about 1.2:1, the weight ratio of fluticasone furoate to lipid ingredient is about 1:30, the concentration of fluticasone furoate is about 1 mg/100 mL, and the solvent is normal saline.
2. The formulation according to claim 1 , wherein the liposomes have an average size of about 130 nm.
3. The formulation according to claim 1 , having a pH ranging from about 4.0 to about 7.0.
4. The formulation according to claim 1 , wherein the composition has a pH of about 5.7.
5. The formulation according to claim 1 , wherein the composition has an encapsulation efficiency of at least 90%.
6. The formulation according to claim 1 , wherein the formulation when nebulized forms droplets with a D50 value ranging from about 3.9 μm to about 4.8 μm.
7. The formulation according to claim 1 , wherein the formulation when nebulized forms droplets with a D90 value ranging from about 7.3 μm to about 11.2 μm.
8. The formulation according to claim 1 , further comprising an antioxidant selected from the group consisting of a water-soluble antioxidant and an oil-soluble antioxidant.
9. The formulation according to claim 8 , wherein the oil-soluble antioxidant is selected from the group consisting of alpha-tocopherol, alpha-tocopherol succinate, alpha-tocopherol acetate and mixtures thereof, and the water-soluble antioxidant is selected from the group consisting of ascorbic acid, sodium bisulfate, sodium sulfite, sodium pyrosulfite, L-cysteine, and mixtures thereof.
10. A method of preparing the formulation of claim 1 comprising:
(1) dissolving fluticasone furoate, DPPC, and cholesterol in ethanol, wherein the fluticasone furoate is present in an amount of about 1 mg/30 mL of ethanol, the DPPC is present in an amount of about 19.6 mg/30 mL of ethanol, and the cholesterol is present in about 10.4 mg/30 mL of ethanol, to provide a first mixture;
(2) injecting the first mixture into a normal saline solution with stirring, wherein the ratio of the first mixture to the saline solution is about 30:50 (v/v) to form a second mixture comprising liposome vesicles;
(3) adding normal saline to the second mixture comprising liposome vesicles in an amount sufficient to provide a volume of about 100 mL for each 30 mL of ethanol to provide a third mixture; and
(4) ultrafiltering and concentrating the third mixture to a volume of 10 mL per each 100 mL of the third mixture to provide the formulation.
11. The method according to claim 10 , wherein the formulation has a pH ranging from about 4.0 to about 7.0.
12. The method of claim 10 , wherein the first mixture is heated to a temperature ranging from about 40° C. to about 80° C.
13. The method of claim 11 , wherein the first mixture is heated to a temperature of about 50° C.
14. The method of claim 10 , wherein the ultrafiltering uses a hollow fiber membrane.