Patent EA-001637-B1 (EA)
Title: Pharmaceutical preparation comprising lyophilized liposomes encapsulating an active principle which is highly insoluble in water, and the process for preparing the said preparation
Inventor: CAVALLIO GIOVANNI
IPC: A61K47/26
Filed: 1998-02-12
Abstract: 1. Lyophilized composition comprising trehalose and lipid liposomes in hich a biologically-active principle has been incorporated, characterized in that the biologically-active principle is highly insoluble in water, the trehalose/lipid weight ratio is <= 1.5, and all of the trehalose was added to the outside of the liposomes already formed before lyophilization. 2. Lyophilized composition according to Claim 1, characterized in that the biologically-active principle which is highly insoluble in water is chosen from the group comprising lonidamine, melatonin cyclosporin A and bindarit. 3. Lyophilized composition according to Claim 1 or 2, characterized in that the lipids are chosen from the group comprising phosphoglycerides, glycerides, diglycerides, triglycerides, phospholipids, galactosyl and glucosyl lipids, cholesterol and its derivatives, sphingolipids and their mixtures. 4. Lyophilized composition according to Claim 3, characterized in that the lipids are phospholipids. 5. Lyophilized composition according to any one of Claims 1 to 4, characterized in that the trehalose/lipid weight ratio is between 1:2 and 1:1. 6. Lyophilized composition according to any one of Claims 1 to 5, characterized in that the average size of the liposomes is between 50 and 250 nm. 7. Lyophilized composition according to Claim 6, characterized in that the average size of the liposomes is between 50 and 100 nm. 8. Process for lyophilizing a composition comprising trehalose and lipid liposomes, in which there has been incorporated a biologically-active principle characterized in that: a) from 0.2 to 1.5 parts in weight of trehalose are added for each part in weight of lipids of an aqueous liposome composition in which the average size of the liposomes is between 50 and 250 nm, said liposomes comprising a biologically-active principle which is highly insoluble in water; b) said composition is chilled by means of the chilling plate of the lyophilizer to a temperature between -5 degree  and -70 degree C, at a chilling rate of between 0.5 and 2 degree C/min.;c) once the predetermined freezing temperature has been reached, said composition is kept at said temperature for between 2 and 5 hours; d) a vacuum of between 5 x 10.1 and 8 x 102 millibar is applied, leaving the temperature of the chilling plate at the chilling temperature defined in point b) for a period of between 2 and 5 hours; e) the temperature of the chilling plate is brought to -15 C, and kept there until the water is completely removed. 9. Lyophilization process according to Claim 8, characterized in that, in Phase b), the freezing temperature is between -20 degree  and -30 degree C. 10. Lyophilization process according to Claim 8 or 9, characterized in that, in Phase b), the chilling rate is 0.77 degree C/min. 11. Lyophilization process according to any one of Claims 8 to 10, characterized in that, in Phase c), the time is 3 hours. 12. Lyophilization process according to any one of Claims 8 to 11, characterized in that, in Phase d), the vacuum is 6 x 10<-2> millibar.