Preparation of a lipid blend and a phospholipid suspension containing the lipid blend

Abstract

The present invention describes processes for the preparation of a lipid blend and a uniform filterable phospholipid suspension containing the lipid blend, such suspension being useful as an ultrasound contrast agent.

1 . A process for preparing a phospholipid suspension, comprising:
 (1) contacting a lipid blend with a non-aqueous solvent, whereby the lipid blend substantially dissolves in the non-aqueous solvent; and,   (2) contacting the solution from step (1) with an aqueous solution to form a lipid suspension.   
     
     
         2 . A process according to  claim 1 , wherein the non-aqueous solvent is selected from propylene glycol, ethylene glycol, and polyethylene glycol 300. 
     
     
         3 . A process according to  claim 2 , wherein the non-aqueous solvent is propylene glycol. 
     
     
         4 . A process according to  claim 2 , 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)-1,2-dipalmitoyl-sn-glycero--3-phosphatidylethanolamine, mono sodium salt.   
     
     
         5 . A process according to  claim 2 , wherein the non-aqueous solvent is heated to a temperature of about 30 to 70° C. prior to contacting with the lipid blend. 
     
     
         6 . A process according to  claim 5 , wherein the non-aqueous solvent is heated to a temperature of about 50 to 55° C. prior to contacting with the lipid blend. 
     
     
         7 . A process according to  claim 2 , wherein the ratio of lipid blend to non-aqueous solvent is from about 5 mg of lipid blend per mL of non-aqueous solvent to about 15 mg/mL. 
     
     
         8 . A process according to  claim 7 , wherein the ratio of lipid blend to non-aqueous solvent is about 10 mg/mL. 
     
     
         9 . A process according to  claim 2 , wherein in step (2), the aqueous solution is selected from water, saline, a saline/glycerin mixture, and a saline/glycerin/non-aqueous solvent mixture. 
     
     
         10 . A process according to  claim 9 , wherein the aqueous solution is a saline and glycerin mixture. 
     
     
         11 . A process according to  claim 9 , wherein the aqueous solution is a saline, glycerin, and propylene glycol mixture. 
     
     
         12 . A process according to  claim 11 , 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. 
     
     
         13 . A process according to  claim 12 , wherein 0.75 mg/mL of lipid blend are present. 
     
     
         14 . A process according to  claim 12 , wherein 1.0 mg/mL of lipid blend are present. 
     
     
         15 . A process according to  claim 2 , wherein in step (2), the aqueous solution is heated to a temperature of about 45 to 60° C. prior to contacting with the solution from step (1). 
     
     
         16 . A process according to  claim 15 , wherein the aqueous solution is heated to a temperature of about 50 to 55° C. prior to contacting with the solution from step (1). 
     
     
         17 . A process according to  claim 1 , wherein the process further comprises: (3) heating the lipid suspension from step (2) to a temperature about equal to or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the suspension. 
     
     
         18 . A process according to  claim 17 , wherein in step (3), the lipid suspension is heated to a temperature of at least about 67° C. 
     
     
         19 . A process according to  claim 17 , wherein the process further comprises:
 (4) filtering the lipid suspension through a sterilizing filter.   
     
     
         20 . A process according to  claim 19 , wherein in step (4), the filtration is performed using two sterilizing filter cartridges. 
     
     
         21 - 44 . (canceled)