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Claims for Patent: 5,807,572

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Claims for Patent: 5,807,572

Title: Multivesicular liposomes having a biologically active substance encapsulated therein in the presence of a hydrochloride
Abstract:Disclosed are multivesicular liposomes containing biologically active substances, the multivesicular liposomes having defined size distribution, adjustable average size, adjustable internal chamber size and number, and a modulated rate of the biologically active substance in contrast to the previous art. The process comprises dissolving a lipid component in volatile organic solvents, adding an immiscible aqueous component containing at least one biologically active substance to be encapsulated, and adding to either or both the organic solvents and the lipid component, a hydrochloride effective to control the release rate of the biologically active substance from the multivesicular liposome, making a water-in-oil emulsion from the two components, immersing the emulsion into a second aqueous component, dividing the emulsion into small solvent spherules which contain even smaller aqueous chambers, and then removing the solvents to give an aqueous suspension of multivesicular liposomes encapsulating biologically active substances.
Inventor(s): Kim; Sinil (Solana Beach, CA), Howell; Stephen B. (Del Mar, CA)
Assignee: DepoTech Corporation (La Jolla, CA)
Application Number:08/473,019
Patent Claims: 1. A process for producing a multivesicular liposome having multiple non-concentric chambers with membranes distributed in a matrix, the process comprising the steps of:

(a) forming a water-in-oil emulsion from two immiscible components, the two immiscible components being (1) a lipid component comprising at least one organic solvent, at least one amphipathic lipid, and a neutral lipid lacking a hydrophilic head group, and (2) a first aqueous component; said water-in-oil emulsion further comprising a hydrochloride selected from the group consisting of hydrochloric acid, arginine hydrochloride, histidine hydrochloride, lysine hydrochloride and pyridine hydrochloride, and combinations thereof, in a concentration in the range from about 10 mM to about 500 mM and at least one biologically active substance selected from the group consisting of an anesthetic, an antiasthmatic agent, a cardiac glycoside, an antihypertensive, a nucleic acid, an antibiotic, a vaccine, an antiarrhythmic, an antiangina, a hormone, an antidiabetic, at antineoplastic, an immunomodulator, an antifungal, a tranquilizer, a steroid, a sedative, an analgesic, a vasopressor, an antiviral, a herbicide, a pesticide, a protein, a peptide, a neurotransmitter, a radionuclide, and suitable combinations thereof, said hydrochloride and biologically active agent being independently incorporated into either the lipid component or the first aqueous component, or into both;

(b) dispersing the water-in-oil emulsion containing the hydrohalide into a second aqueous component to form solvent spherules; and thereafter

(c) removing the organic solvent from the solvent spherules to form the multivesicular liposomes suspended in the second aqueous component;

wherein the hydrohalide concentration in the water-in-oil emulsion is chosen to modulate the in vivo release rate of the biologically active substance.

2. The process of claim 1 wherein, the hydrohalide is hydrochloric acid.

3. The process of claim 1 wherein, the hydrochloride is chosen from the group consisting of lysine hydrochloride, histidine hydrochloride, arginine hydrochloride, and combinations thereof.

4. The process of claim 1 wherein, the amphipathic lipid comprises at least one zwitterionic amphipathic lipid.

5. The process of claim 1 wherein, the amphipathic lipid comprises at least one cationic amphipathic lipid.

6. The process of claim 1 wherein, the amphipathic lipid comprises at least one anionic amphipathic lipid.

7. The process of claim 1 wherein, the amphipathic lipid comprises at least one zwitterionic and at least one cationic amphipathic lipid.

8. The process of claim 1 wherein, the amphipathic lipid comprises at least one zwitterionic and at least one anionic amphipathic lipid.

9. The process according to claim 4, 5, 6, 7, or 8 wherein, the amphipathic lipid is selected from the group consisting of phospholipids.

10. The process according to claim 9 wherein, the phospholipids are selected from the group consisting of phosphatidylcholine, cardiolipin, phosphatidylethanolamine, sphingomyelin, lysophosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, and phosphatidic acid.

11. The process according to claim 1 or 2 wherein, the lipid component further comprises.

12. The process according to claim 1 or 2 wherein, the lipid component further comprises stearylamine, or diacyl dimethylammoniumpropane, or diacyl trimethylammoniumpropane.

13. The process according to claim 1 or 2 wherein, the biologically active substance is lipophilic and is incorporated into the lipid component.

14. The process according to claims 4, 5, 6, 7, or 8 wherein, the neutral lipid is a triglyceride.

15. The process according to claims 4, 5, 6, 7, or 8 wherein, the neutral lipid is a diglyceride.

16. The process according to claims 4, 5, 6, 7, or 8 wherein, the neutral lipid is a propylene glycol ester.

17. The process according to claim 14 wherein, the triglyceride is selected from the group consisting of triolein, tripalmitolein, trimyristolein, trilinolein, tributyrin, tricaproin, tricaprylin, tricaprin, trilaurin, and combinations thereof.

18. The process according to claim 15 wherein, the diglyceride is selected from the group consisting of diolein and dipalmitolein.

19. The process according to claim 16 wherein, the propylene glycol ester is mixed diesters of caprylic and capric acids.

20. The process according to claim 1 or 2 wherein, the organic solvent is selected from the group comprising ethers, hydrocarbons, esters, and combinations thereof.

21. The process according to claim 1 or 2 wherein, the biologically active substance is hydrophilic and is incorporated into the first aqueous component.

22. The process according to claim 1 or 2 wherein, the emulsification of the two immiscible components is carried out using a method selected from the group consisting of mechanical agitation, ultrasonic energy, and nozzle atomization.

23. The process according to claim 1 or 2 wherein, the formation of the solvent spherules is carried out using methods selected from the group consisting of mechanical agitation, ultrasonic energy, nozzle atomization, and combinations thereof.

24. The process according to claim 1 or 2 wherein, the removing of the organic solvent is by a method selected from the group consisting of sparging, rotary evaporation, passing gas over the solvent spherules, and combinations thereof.

25. The process according to claim 1 or 2 wherein, the biologically active substance is cytarabine.

26. The process according to claim 1 or 2 wherein, the biologically active substance is morphine.

27. The process according to claim 1 or 2 wherein, the biologically active substance is hydromorphone.

28. The process according to claim 1 or 2 wherein, the biologically active substance is leuprolide.

29. The process according to claim 1 or 2 wherein, the biologically active substance is a nucleic acid.

30. The process according to claim 1 or 2 wherein, the biologically active substance is interleukin-2.

31. The process according to claim 1 or 2 wherein, the biologically active substance is amikacin.

32. The process according to claim 1 or 2 wherein, the biologically active substance is granulocyte colony stimulating factor.

33. The process according to claim 1 or 2 wherein, the biologically active substance is insulin.

34. The process according to claim 1 or 2 wherein, the biologically active substance is hepatitis B vaccine.

35. The process of claim 23 wherein, the protein is an antibody or a vaccine.

36. The process of claim 23 wherein, the antiparasitic is an antiviral or an antifungal.

37. The process according to claim 1 or 2 wherein, the biologically active substance is .alpha.-interferon.

38. The process according to claim 1 or 2 wherein, the biologically active substance is methotrexate.

39. The process according to claim 1 or 2 wherein, the biologically active substance is granulocyte-macrophage colony stimulating factor.

40. The process according to claim 1 or 2 wherein, the lipid component further comprises plant sterols.
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