Details for Patent: 5,891,467

Title:	Method for utilizing neutral lipids to modify in vivo release from multivesicular liposomes
Abstract:	The rate of release of encapsulated active compound from a multivesicular liposomal (MVL) formulation is modified by selection of a neutral lipid component. A family of MVL formulations containing different slow:fast release neutral lipid molar ratios display different release rates depending upon the molar ratio of the fast release neutral lipid to the slow release neutral lipid in each member. Incubation in plasma or a plasma-like medium at in vivo temperatures so as to obtain a release rate curve for each allows selection from among the members of the family of a liposomal formulation with a desired rate of release in vivo.
Inventor(s):	Willis; Randall C. (Solana Beach, CA)
Assignee:	Depotech Corporation (San Diego, CA)
Filing Date:	Jan 31, 1997
Application Number:	08/792,566
Claims:	1. A method for modifying the rate of release of a biologically active compound encapsulated in a multivesicular liposome having a neutral lipid component comprising: (1) forming an emulsion from a) a lipid component comprising an organic solvent, an amphipatlic lipid, and a neutral lipid component coanprising a molar ratio of from 1:0 to 0:1 of a slow release rate neutral lipid to a fast release rate neutral lipid, and b) an immiscible first aqueous component wherein at least one biologically active compound is incorporated into either the lipid component or the first aqueous component, or both; (2) mixing the emulsion with a second aqueous component to form solvent spherules, and (3) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating the biologically active compound; wherein the molar ratio of the slow release neutral lipid to the fast release neutral lipid is selected to increase or decrease the rate of release of the biologically active compound, with all increase tin the ratio corresponding to a decrease in release rate and wherein the slow release neutral lipid is selected from the group consisting of triolein, tripalmitolein, trimyristolein, trilaurin, tricaprin, and mixtures thereof, and the fast release neutral lipid is selected from the group consisting of tricaprylin, tricaproin, and mixtures thereof. 2. The method of claim 1, wherein the molar ratio of the neutral lipid component to all the lipids in the liposome is in the range from about 0.01 to about 0.21. 3. The method of claim 1, wherein the molar ratio of the slow release neutral lipid to the fast release neutral lipid is selected in the range from about 1:1 to 1:100. 4. The method of claim 1, wherein the molar ratio of the slow release neutral lipid to the fast release neutral lipid is in the range from about 1:4 to 1:27. 5. The method of claim 1, wherein the slow release neutral lipid is tripalmitolein. 6. The method of claim 1, wherein the slow release neutral lipid is triolein. 7. The method of claim 1, wherein the slow release neutral lipid is tricaprin. 8. The method of claim 6, wherein the fast release neutral lipid is tricaprylin or a mixture of tricaprylin and tricaproin. 9. A method for modifying the rate of release of a biologically active compound encapsulated in a multivesicular liposome, said method comprising utilizing a blend of triolein or tripalmitolein and a fast release neutral lipid as the neutral lipid component in a multivesicular formulation in which an active compound is encapsulated; wherein the rate of release of the biologically active compound increases in proportion with the molar ratio of the fast release neutral lipid to the triolein or tripalmitolein in the neutral lipid component, wherein the fast release neutral lipid is selected from the group consisting of tricaprylin, tricaproin, and mixtures thereof. 10. The method of claim 9, wherein the rate of release is in vivo, and the neutral lipid component has a melting point about or below an in vivo temperature. 11. The method of claim 9, wherein the release is at storage temperature, and the melting point of the neutral lipid component is about or above the storage temperature. 12. The method of claim 9, wherein when the fast release neutral lipid is tricaprylin, the molar ratio of triolein or tripalmitolein to tricaprylin is in the range from about 1:1 to 1:100. 13. The method of claim 9, wherein the molar ratio of the triolein or tripalmitolein to the fast release neutral lipid is in the range from about 1:1 to 1:27. 14. The method of claim 9, wherein the release is in vivo, and the fast release neutral lipid is tricaprylin. 15. A method for modifying the rate of release of a biologically active coinpound encapsulated in a multivesictLIar liposome having a neutral lipid component comprising: (1) forming an emulsion from a) a lipid component comprising an organic solvent, an amphipathic lipid, and a neutral lipid component comprising a molar ratio of from 1:0 to 0:1 of a slow release rate neutral lipid to a fast release rate neutral lipid, and b) an immiscible first aqueous component wherein at least one biologically active compound is incorporated into either the lipid component or the first aqueous component, or both; (2) mixing the emulsion with a second aqueous component to form solvent spherules, and (3) removing the organic solvent from the solvent spherules to form multivesicular liposomes encapsulating the biologically active compound; wherein the molar ratio of the slow release neutral lipid to the fast release neutral lipid is selected to increase or decrease the rate of release of the biologically active compound, with an increase in the ratio corresponding to a decrease in release rate and wherein the slow release neutral lipid is selected from the group consisting of propylene glycol diesters with eight and ten carbon acyl moieties and cholesterol esters; and the fast release neutral lipid is tricaprylin or tricaproin.