Solid tumor treatment method and composition

• US 5,213,804 A
• Filed: 01/15/1991
• Issued: 05/25/1993
• Est. Priority Date: 10/20/1989
• Status: Expired due to Term

• Current Assignee: SEQUUS Pharmaceuticals, Inc. (Johnson & Johnson)
• Original Assignee: Liposome Technology, Inc.
• Inventors: Martin, Francis J., Yau-Young, Annie, Redemann, Carl, Woodle, Martin C.
• Primary Examiner(s): Page, Thurman K.
• Application Number:
  US07/642,321
• Time in Patent Office: 861 Days
• Field of Search: 424/450, 260/403, 428/402.2, 264/4, 264/4.1
• US Class Current: 424/450
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07F 9/5537 the heteroring containing the structure -C(=O)-N-C(=O)- (both carbon atoms belong to the heteroring)

Abstract

A liposome composition for localizing an anti-tumor compound to a solid tumor via the bloodstream. The liposomes, which contain the agent in entrapped form, are composed of vesicle-forming lipids and between 1-20 mole percent of a vesicle-forming lipid derivatized with hydrophilic biocompatible polymer, and have sizes in a selected size range between 0.07 and 0.12 microns. After intravenous administration, the liposomes are taken up by the tumor within 24-48 hours, for site-specific release of entrapped compound into the tumor. In one composition for use in treating a solid tumor, the compound is an anthracycline antibiotic drug which is entrapped in the liposomes at a concentration of greater than about 50 μg agent/μmole liposome lipid. The method results in regression of solid colon and breast carcinomas which are refractory to anthracycline antibiotic drugs administered in free form or entrapped in conventional liposomes.

Claims

1. A liposome composition for use in localizing a compound in a solid tumor via the bloodstream, by liposome extravasation into the tumor, comprising

liposomes (i) composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic vesicle-forming lipid derivatized with a hydrophilic polymer selected from the group consisting of polyethyleneglycol, polylactic acid, polyglycolic acid and polylactic acid/polyglycolic acid copolymers, and (ii) having a selected mean particle diameter in the size range between about 0.07 to 0.12 microns, and

the compound in liposome-entrapped form,

and characterized by a liposome blood lifetime, 24 hours after intravenous injection, that is several times greater than the blood lifetime of liposomes in the absence of the derivatized lipid.

2. The composition of claim 1, wherein the hydrophilic polymer is polyethyleneglycol having a molecular weight between about 1,000-5,000 daltons.

3. The composition of claim 2, wherein the hydrophilic polymer is selected from the group of polylactic acid, polyglycolic acid, and copolymers thereof.

4. The composition of claim 1, wherein the compound is an anti-tumor agent, and at least about 80% of the compound is in liposome-entrapped form.

5. The composition of claim 4, wherein the anti-tumor agent is an anthracycline antibiotic, and the concentration of compound which is entrapped in the liposomes is greater than 50 μ

g compound/μ

mole liposome lipid.

6. The composition of claim 4, wherein the anthracycline is selected from the group consisting of doxorubicin, epirubicin, and daunorubicin, including pharmacologically acceptable salts and acids thereof.

7. A liposome composition for use in localizing an anthracycline anti-tumor drug in a solid tumor via the bloodstream by liposome extravasation into the tumor, comprising,

liposomes (i) composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic vesicle-forming lipid derivatized with polyethyleneglycol, and (ii) having an average size in a selected size range between about 0.07 to 0.12 microns, and

the drug, at least about 80% in liposome-entrapped form, and having a concentration in the liposomes greater than 50 μ

g agent/μ

mole liposome lipid,

and characterized by a liposome blood lifetime, 24 hours after intravenous injection, that is several times greater than the blood lifetime of liposomes in the absence of the derivatized lipid.

15. The composition of claim 7, wherein the drug is selected from the group consisting of doxorubicin, epirubicin, and daunorubicin, including pharmacologically acceptable salts and acids thereof.

8. A method of preparing an agent for localization in a solid tumor by extravasation of liposomes containing the agent into the solid tumor, when the agent is administered by IV injection, comprising

entrapping the agent in liposomes which are characterized by:

(a) a lipid composition which includes between 1-20 mole percent of an amphipathic vesicle-forming lipid derivatized with a hydrophilicpolymer selected from the group consisting of polyethyleneglycol, polylactic acid, polyglycolic acid and polyactic acid/polyglycolic acid copolymers,

(b) an average liposome size in a selected size range between about 0.07-0.12 microns; and

(c) a liposome blood lifetime 24 hours after intravenous injection, that is several times greater than the blood lifetime of liposomes in the absence of the derivatized lipid.

9. The method of claim 8, wherein the agent is an anthracycline antibiotic drug, and said entrapping includes loading the agent into preformed liposomes by remote loading across an ion or pH gradient, to a final concentration of lipisome-entrapped material of greater than about 50 μ

g agent/μ

mole liposome lipid.

10. The method of claim 9, wherein the drug is selected from the group consisting of doxorubicin, epirubicin, and daunorubicin, including pharmacologically acceptable salts and acids thereof.

11. A method of localizing a compound in a solid tumor in a subject by extravasation of liposomes containing the agent into the solid tumor comprising,

preparing a composition of liposomes (i) composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic vesicle-forming lipid derivatized with a hydrophilic polymer selected from the group consisting of polyethyleneglycol, polylactic acid, polyglycolic acid and polylactic acid/polyglycolic acid copolymers, said liposomes having a blood lifetime, as measured by the percent of a liposome marker present in the blood 24 hours after intravenous administration, which is several times greater than that of liposomes in absence of the derivatized lipids, (ii) having an average size in a selected size range between about 0.07-0.12 microns, and (iii) containing the compound in liposome-entrapped form,

injecting the composition intravenously in the subject in an amount effective to localize a therapeutically effective quantity of the agent in the solid tumor, and

by said injecting, achieving a localization of the liposomes in the solid tumor, 48 hours after intravenous administration, that is substantially greater than that of liposomes in the absence of the derivatized lipid.

12. The method of claim 11, wherein the hydrophilic polymer is polyethyleneglycol having a molecular weight between about 1,000-5,000 daltons.

13. A method of treating breast or colon carcinoma in a subject with an anthracycline antibiotic drug, comprising

entrapping the drug in liposomes (i) composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic vesicle-forming lipid derivatized with a hydrophilic polymer selected from the group consisting of polyethyleneglycol, polylactic acid, polyglycolic acid and polylactic acid/polyglycolic acid copolymers, said liposomes having a blood lifetime, as measured by the percent of a liposome marker present in the blood 24 hours after intravenous administration, which is several times greater than that of liposomes in absence of the derivatized lipids, and (ii) having an average size in a selected size range between about 0.07-0.12 microns at a concentration of entrapped drug of greater than about 50 μ

g drug/μ

mole liposome lipid, with at least about 80% of the drug entrapped in the liposomes, and

injecting the composition intravenously in the subject in an amount effective to localize a therapeutically effective quantity of the agent in the carcinoma.

14. The method of claim 13, wherein the hydrophilic polymer is polyethyleneglycol having a molecular weight between about 1,000-5,000 daltons, and the agent is selected from the group consisting of doxorubicin, epirubicin, and daunorubicin, including a pharmacologically acceptable salts and acids thereof.