Claims for Patent: 5,723,147

Summary for Patent: 5,723,147

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:	08/472,126
Patent Claims:	1. A multivesicular liposome having multiple non-concentric chambers with membranes distributed in a matrix comprising: (a) a biologically active substance selected from 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, a herbicide, a pesticide, a protein, a peptide, a neurotransmitter, a radionuclide, and suitable combinations thereof; (b) an amphipathic lipid; (c) a neutral lipid lacking a hydrophilic head group; and (d) a hydrohalide selected from the group consisting of hydrochloric acid, arginine hydrochloride, histidine hydrochloride, lysine hydrochloride and pyridine hydrochloride in a concentration in the range from about 10 mM to about 500 mM; wherein the concentration of the hydrohalide is sufficient to modulate the release rate of the biologically active substance from the composition. 2. The composition of claim 1, wherein, the hydrochloride is selected from the group consisting of lysine hydrochloride, histidine hydrochloride, arginine hydrochloride, and combinations thereof. 3. The composition of claim 1, wherein the rate is a therapeutically effective rate sufficient to ameliorate a disease following administration of the composition to a living mammal. 4. The composition of claim 1, wherein, the biologically active substance is a pesticide. 5. The composition of claim 1, wherein, the biologically active substance is an herbicide. 6. A method for the treatment of a patient in need thereof with a 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, an antineoplastic, an immunomodulator, an antifungal, a tranquilizers, 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 comprising administering said substance to the patient encapsulated in a multivesicular liposome wherein the encapsulation was done in the presence of a hydrochloride selected from the group consisting of hydrochloric acid, arginine hydrochloride, histidine hydrochloride, lysine hydrochloride, pyridine hydrochloride, and suitable combinations thereof, in a concentration in the range from about 10 mM to about 500 mM; wherein the concentration of the hydrohalide is sufficient to modulate the release rate of the biologically active substance from the composition. 7. The composition of claim 1, wherein the protein is selected from the group consisting of interleukin-2, granulocyte colony stimulating factor, hepatitis B antigen, granulocyte-macrophage colony stimulating factor, insulin-like growth factor-1, and .alpha.-interferon. 8. A composition of claim 1, wherein the hormone is selected from the group consisting of pituitary and hypophyseal hormones. 9. A multivesicular liposome composition comprising: (a) a compound selected from the group consisting of cytarabine, morphine sulfate, hydromorphone, amikacin, methotrexate, and iohexol; (b) an amphipathic lipid; (c) a neutral lipid lacking a hydrophilic head group; and (d) a hydrohalide selected from the group consisting of hydrochloric acid, arginine hydrochloride, histidine hydrochloride, lysine hydrochloride and pyridine hydrochloride in a concentration in the range from about 10 mM to about 500 mM; wherein the amount of the hydrohalide is sufficient to modulate the release rate of the compound from the composition. 10. The composition of claim 9, wherein the rate is a therapeutically effective rate sufficient to ameliorate a disease following administration of the composition to a living mammal. 11. The composition of claim 9, wherein the compound is amikacin, morphine sulfate, or cytarabine. 12. A method for the treatment of a patient in need thereof with a compound selected from the group consisting of cytarabine, morphine sulfate, hydromorphone, amikacin, and methotrexate, comprising administering said compound to the patient encapsulated in a multivesicular liposome wherein the encapsulation was done in the presence of a hydrochloride selected from the group consisting of hydrochloric acid, arginine hydrochloride, histidine hydrochloride, lysine hydrochloride and pyridine hydrochloride in a concentration in the range from about 10 mM to about 500 mM; wherein the amount of the hydrochloride is sufficient to modulate the release rate of the compound from the composition at a therapeutically effective rate. 13. The method of claim 12, wherein the hydrochloride is hydrochloric acid, the compound is cytarabine, and the concentration of the hydrochloric acid is in the range from about 70 mM to about 500 mM to decrease the rate of release of the compound. 14. The method of claim 12, wherein the hydrochloride is hydrochloric acid, the compound is cytarabine, and the concentration of the hydrochloric acid is in the range from about 10 mM to about 70 mM to increase the rate of release of the compound. 15. The method of claim 12, wherein the hydrochloride is hydrochloric acid, the compound is morphine sulfate, and the concentration of the hydrochloric acid is in the range from about 25 mM to about 200 mM to decrease the rate of release of the compound. 16. The method of claim 6, wherein the protein is selected from the group consisting of interleukin-2, granulocyte colony stimulating factor, hepatitis B antigen, granulocyte-macrophage colony stimulating factor, insulin-like growth factor-1, and .alpha.-interferon.