# US 5,700,482 A · Process for the preparation of a liposome dispersion under elevated pressure contents > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,700,482 A - Document ID: US5700482A - Status: Granted - Kind: A - Application number: 08/483,912 - Filed: 1995-06-07 - Granted: 1997-12-23 - Earliest claimed: 1993-03-24 - Assignees: Ciba-Geigy Corporation - Inventors: Lene Frederiksen; Klaus Anton; Peter van Hoogevest - Web page: https://patentgrep.com/patent/US5700482A ## CPC - A61K 9/1277: Preparation processes; Proliposomes - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract The invention relates to a novel, advantageous process for the preparation of liposomes for the inclusion of water-soluble or hydrophilic substances or mixtures of substances, which process provides the surprising advantage, in comparison with known processes, that the proportion of substances or mixtures of substances actually included is increased and which, when used pharmaceutically, provides the advantage of sterile working conditions. In this process, a mixture consisting of at least one phospholipid and customary lipophilic excipients is subjected to a mobile carrier phase consisting of carbon dioxide and a polar organic solvent (modifier) under supercritical pressure and temperature conditions, the compressed mixed phase is reduced to normal pressure and transferred to an aqueous phase comprising a substance having water-soluble or hydrophilic properties for encapsulation in liposomes. ## Claims ### Claim 1 A process for the preparation of a liposome dispersion comprising subjecting at least one phospholipid of the formula ##STR2## wherein R.sub.1 is C.sub.10-20 acyl, R.sub.2 is hydrogen or C.sub.10-20 acyl, and R.sub.3 is hydrogen, 2-trimethylamino-1-ethyl, 2-amino-1-ethyl, C.sub.1-4 alkyl, C.sub.1-5 alkyl substituted by carboxy, C.sub.2-5 alkyl substituted by hydroxy, C.sub.2-5 alkyl substituted by carboxy and by hydroxy, or C.sub.2-5 alkyl substituted by carboxy and by amino, or a salt of such phospholipid to a mobile carrier phase consisting of carbon dioxide and a polar organic solvent under pressure and temperature conditions which are higher than the critical pressure and the critical temperature of a pure carbon dioxide phase, reducing the compressed mixed phase that is obtainable to normal pressure and transferring it to an aqueous phase comprising water in the purity required for the intended application and a non-proteinaceous substance or a mixture of non-proteinaceous substances having water-soluble or hydrophilic properties for encapsulation in liposomes and removing the organic solvent and/or separating off a fraction of liposomes having a desired diameter range and/or converting the liposome dispersion into a form suitable for the intended application. ### Claim 2 (depends on 1) A process according to claim 1, where the non-proteinaceous substance or mixture of substances for encapsulation is at least one compound selected from the group consisting of a radioactive labelling compound, and a pharmaceutical active ingredient. ### Claim 3 (depends on 2) A process according to claim 2, wherein hydrophilic or water-soluble pharmaceutical active ingredients are used as the non-proteinaceous substance a) for encapsulation. ### Claim 4 (depends on 2) A process according to claim 2, wherein zinc-phthalocyanine tetrasulfonate ›ZnPc(SO.sub.3 H).sub.4 ! is used as the non-proteinaceous substance a) for encapsulation. ### Claim 5 (depends on 1) A process according to claim 1, wherein synthetic, substantially pure 1-n-hexa-decanoyl-2-(9-cis-octadecenoyl)-3-sn-phosphatidyl choline is used as the phospholipid b). ### Claim 6 (depends on 1) A process according to claim 1, wherein sterilized water for injection purposes is used as component c). ### Claim 7 (depends on 1) A process according to claim 1, wherein the liposome composition further comprises cholesterol. ### Claim 8 (depends on 1) A process according to claim 1, wherein the liposome composition further comprises at least one water-soluble excipient for the establishment of isotonic conditions. ### Claim 9 (depends on 1) A process according to claim 1, wherein the polar organic solvent is ethanol. ### Claim 10 (depends on 1) A process according to claim 1, wherein a pressure range of approximately from 72 to 400 bar is used. ### Claim 11 (depends on 10) A process according to claim 10, wherein a pressure range of approximately from 200 to 300 bar is used. ### Claim 12 (depends on 1) A process according to claim 1, wherein an elevated temperature of approximately from 32.degree. to 100.degree. C. is used. ### Claim 13 (depends on 12) A process according to claim 12, wherein an elevated temperature of approximately from 50.degree. to 60.degree. C. is used. ### Claim 14 (depends on 1) A process according to claim 1, wherein the liposome dispersion that is obtainable is convened into a lyophilisate which is then reconstituted by the addition of water in the required injection volume.