US5213804A
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Solid tumor treatment method and composition
Assignee: Alza Corp
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Filing: 1991-01-15
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Granted: 1993-05-25
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Expires: 2011-01-15
Abstract
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 mu g agent/ mu mole 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.
Inventors
- 👤 Francis J. Martin
- 👤 Martin C. Woodle
- 👤 Carl Redemann
- 👤 Annie Yau-Young
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 13:00
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/10; A61K9/127; C; C07; C07F; C07F9/00; C07F9/02; C07F9/547; C07F9/553; C07F9/5537; A61K47/00; A61K47/50; A61K47/69; A61K47/6905; A61K47/6911; A61K9/1271; A61P; A61P31/00; A61P31/04; A61P35/00; Y; Y02; Y02A; Y02A50/00; Y02A50/30
Claims Analysis
Total Claims: 20
Claim 1
Independent Claim
114 words
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.
Claim 2
Dependent Claim
114 words
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.
Claim 3
Dependent Claim
19 words
The composition of claim 1, wherein the hydrophilic polymer is polyethyleneglycol having a molecular weight between about 1,000-5,000 daltons.
Claim 4
Dependent Claim
22 words
The composition of claim 2, wherein the hydrophilic polymer is selected from the group of polylactic acid, polyglycolic acid, and copolymers thereof.
Claim 5
Dependent Claim
24 words
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.
Claim 6
Dependent Claim
32 words
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 μg compound/μmole liposome lipid.
Claim 7
Dependent Claim
26 words
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.
Claim 8
Dependent Claim
115 words
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 μg agent/μmole 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.
Claim 9
Dependent Claim
115 words
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 μg agent/μmole 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.
Claim 10
Independent Claim
119 words
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.
Claim 11
Independent Claim
119 words
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.
Claim 12
Dependent Claim
48 words
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 μg agent/μmole liposome lipid.
Claim 13
Dependent Claim
26 words
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.
Claim 14
Independent Claim
185 words
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.
Claim 15
Independent Claim
185 words
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.
Claim 16
Dependent Claim
19 words
The method of claim 11, wherein the hydrophilic polymer is polyethyleneglycol having a molecular weight between about 1,000-5,000 daltons.
Claim 17
Independent Claim
163 words
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 μg drug/μmole 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.
Claim 18
Independent Claim
163 words
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 μg drug/μmole 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.
Claim 19
Dependent Claim
41 words
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.
Claim 20
Dependent Claim
26 words
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.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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