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Claims for Patent: 6,071,534

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Claims for Patent: 6,071,534

Title: Multivesicular liposomes with controlled release of active agents encapsulated in the presence of a hydrochloride
Abstract:Disclosed are multivesicular liposomes containing biologically active substances, and having defined size distribution, adjustable average size, adjustable internal chamber size and number, and a modulated release of the biologically active substance. The liposomes are made by a process comprising 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. A water-in-oil emulsion is made from the two components, the emulsion is immersed into a second aqueous component, and then divided into small solvent spherules which contain even smaller aqueous chambers. The solvents arc finally removed 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: SkyePharma Inc. (San Diego, CA)
Application Number:09/019,337
Patent Claims: 1. A multivesicular liposome having multiple non-concentric chambers with membranes distributed in a matrix produced by a 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, said hydrochloride and biologically active substance 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 liposome of claim 1, wherein the hydrochloride is hydrochloric acid.

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

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

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

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

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

8. The liposome according to claim 7, wherein the phospholipids are selected from the group consisting of phosphatidylcholine, cardiolipin, phosphatidylethanolamine, sphingomyelin, lysophosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, and phosphatidic acid.

9. The liposome according to claim 1 or 2, wherein the lipid component further comprises cholesterol.

10. The liposome according to claim 1 or 2, wherein the lipid component further comprises a lipid selected from the group consisting of stearylamine, diacyl dimethylammoniumpropane, and diacyl trimethylammoniumpropane.

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

12. The liposome according to claim 7, wherein the neutral lipid is a triglyceride.

13. The liposome according to claim 7, wherein the neutral lipid is a diglyceride.

14. The liposome according to claim 7, wherein the neutral lipid is a propylene glycol ester.

15. The liposome according to claim 12, wherein the triglyceride is selected from the group consisting of triolein, tripalmitolein, trimyristolein, trilinolein, tributyrin, tricaproin, tricaprylin, tricaprin, trilaurin, and combinations thereof.

16. The liposome according to claim 13, wherein the diglyceride is selected from the group consisting of diolein and dipalmitolein.

17. The liposome according to claim 14, wherein the propylene glycol ester is mixed diesters of caprylic and capric acids.

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

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

20. The liposome according to claim 1 or 2, wherein 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.

21. The liposome according to claim 1 or 2, wherein 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.

22. The liposome according to claim 1 or 2, wherein 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.

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

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

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

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

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

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

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

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

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

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

33. The liposome of claim 21, wherein the protein is an antibody or a vaccine.

34. The liposome of claim 21, wherein the antiparasitic is an antiviral or an antifungal.

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

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

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

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

39. The liposome according to claim 1 or 2, wherein the biologically active substance is 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, an antineoplastic, an immunomodulator, an antifungal, a tranquilizer, a steroid, a sedative, an analgesic, a vasopressor, an antiviral, an herbicide, a pesticide, a protein, a peptide, a neurotransmitter, a radionuclide, and suitable combinations thereof.
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