Patent EA-002978-B1 (EA)
Title: Process for preparation phospholipid suspension and process for preparation phospholipid mixture
Inventor: HUI POH K
IPC: A61K9/127
Filed: 1999-01-14
Abstract: 1. A process for preparing a phospholipid suspension, comprising: (a) contacting at least two lipids with a first non-aqueous solvent forming a solution; (b) concentrating the solution to a thick gel; (c) contacting the thick gel with a second non-aqueous solvent; (d) concentrating the solution from step (c) forming a lipid blend; (e) contacting the lipid blend with a third non-aqueous solvent, whereby the lipid blend substantially dissolves in the third non-aqueous solvent forming a solution; and (f) contacting the solution from step (e) with an aqueous solution forming a phospholipid suspension. 2. The process according to Claim 1, wherein in step (a), the first non-aqueous solvent is a mixture of methanol and toluene. 3. The process according to Claim 1, wherein in step (c), the second non-aqueous solvent is a methyl t-butyl ether. 4. The process according to Claim 1, wherein in step (a), the solution is warmed to a temperature sufficient to complete dissolution of the lipids into the solvent. 5. The process according to Claim 1, wherein in step (a), the solution is warmed to about 25 to 75 degree C. 6. The process according to Claim 1, wherein in step (d), the solids collected are washed with methyl t-butyl ether and dried in vacuo. 7. The process according to Claim 1, wherein the non-aqueous solvent is selected from propylene glycol, ethylene glycol, and polyethylene glycol 300. 8. The process according to Claim 7, wherein the nonaqueous solvent in step (e) in step (e) is propylene glycol. 9. The process according to Claim 7, wherein the lipid blend, comprises: (a) 1, 2-dipalmitoyl-sn-glycero-3-phosphatidylcholine; (b) 1, 2-dipalmitoyl-sn-glycero-3-phosphotidic, mono sodium salt; and (c) N- (methoxypolyethylene glycol 5000 carbamoyl)-1,2dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, mono sodium salt. 10. The process according to Claim 7, wherein the non-aqueous solvent in step (e) is heated to a temperature of about 30 to 70 degree C prior to contacting with the lipid blend. 11. The process according to Claim 10, wherein the nonaqueous solvent is heated to a temperature of about 50 to 55 degree C prior to contacting with the lipid blend. 12. The process according to Claim 7, wherein the ratio of lipid blend to non-aqueous solvent in step (e) is from about 5 mg of lipid blend per mL of non-aqueous solvent to about 15 mg/mL. 13. The process according to Claim 12, wherein the ratio of lipid blend to non-aqueous solvent is about 10 mg/mL. 14. The process according to Claim 7, wherein in step (f), the aqueous solution is selected from water, saline, a saline/glycerin mixture, and a saline/glycerin/non-aqueous solvent mixture. 15. The process according to Claim 14, wherein the aqueous solution is a saline and glycerin mixture. 16. The process according to Claim 14, wherein the aqueous solution is a saline, glycerin, and propylene glycol mixture. 17. The process according to Claim 16, wherein 6.8 mg/mL of sodium chloride are present, 0.1 mL/mL of glycerin are present, 0.1 mL/mL of propylene glycol are present, and about 0.75 to 1.0 mg/mL of the lipid blend are present. 18. The process according to Claim 17, wherein 0.75 mg/mL of lipid blend are present. 19. The process according to Claim 17 wherein 1.0 mg/mL of lipid blend are present. 20. The process according to Claim 7, wherein in step (f), the aqueous solution is heated to a temperature of about 45 to 60 degree C prior to contacting with the solution from step (e). 21. The process according to Claim 20, wherein the aqueous solution is heated to a temperature of about 50 to 55 degree C prior to contacting with the solution from step (e). 22. The process according to Claim 1, wherein the process further comprises: (g) heating the lipid suspension from step (f) to a temperature about equal to or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the suspension. 23. The process according to Claim 22, wherein in step (g), the lipid suspension is heated to a temperature of at least about 67 degree C. 24. The process according to Claim 22, wherein the process further comprises: (h) filtering the lipid suspension through a sterilizing filter. 25. The process according to Claim 24, wherein in step (h), the filtration is performed using two sterilizing filter cartridges. 26. The process according to Claim 25, wherein in step (h), the sterilizing filter cartridges are at a temperature of from about 70 to 80 degree C. 27. The process according to Claim 26, wherein in step (h), 0.2 μm hydrophilic filters are used. 28. The process according to Claim 24, wherein the process further comprises: (i) dispensing the filtered solution from step (h) into a vial. 29. The process according to Claim 28, wherein the process further comprises: (j) exchanging the headspace gas of the vial from step (i) with a perfluorocarbon gas. 30. The process according to Claim 29, wherein the perfluorocarbon gas is perfluoropropane. 31. The process according to Claim 30, wherein exchange of headspace gas is performed using a lyophilizing chamber. 32. The process according to Claim 29, wherein the process further comprises: (k) sterilizing the vial from step (j). 33. The process according to Claim 32, wherein in step (k), the vial is sterilized at about 126-130 degree C for 1 to 10 minutes. 34. The phospholipid suspension, comprising: (a) contacting at least two phospholipids with a first non-aqueous solvent forming a solution; (b) concentrating the solution to a thick gel; (c) contacting the thick gel with a second non-aqueous solvent; (d) concentrating the solution from step (c) to solid phospholipids; (e) collecting the resulting solids, wherein the first non-aqueous solvent is a mixture of methanol and toluene and the second non-aqueous solvent is a methyl t-butyl ether.