US5013556A
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Liposomes with enhanced circulation time
Assignee: Liposome Technology Inc
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Filing: 1989-10-20
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Granted: 1991-05-07
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Expires: 2009-10-20
Abstract
Abstract A liposome composition which contains between 1-20 mole percent of an amphipathic lipid derivatized with a polyalkylether, as exemplified by phosphatidylethanolamine derivatized with polyethyleneglycol. The derivatized lipid enchances the circulation time of the liposomes severalfold, and this enhancement is achieved with either fluid or membrane-rigidifying liposome components. Also disclosed are methods for delivering a drug for slow release from the bloodstream, and for targeting a selected tissue or cells with liposomes, via the bloodstream.
Inventors
- 👤 Martin C. Woodle
- 👤 Francis J. Martin
- 👤 Annie Yau-Young
- 👤 Carl T. Redemann
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 13:20
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: 38
Claim 1
Independent Claim
65 words
A liposome composition for use in delivering a compound via the bloodstream comprising liposomes composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic, vesicle-forming lipid derivatized with a polyethyleneglycol, and containing the compound in liposome-entrapped form, and characterized by a blood level, 24 hours after intravenous injection, which is severalfold times that of the liposomes in the absence of the derivatized lipid.
Claim 2
Dependent Claim
65 words
A liposome composition for use in delivering a compound via the bloodstream comprising liposomes composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic, vesicle-forming lipid derivatized with a polyethyleneglycol, and containing the compound in liposome-entrapped form, and characterized by a blood level, 24 hours after intravenous injection, which is severalfold times that of the liposomes in the absence of the derivatized lipid.
Claim 3
Dependent Claim
23 words
The composition of claim 1, wherein the liposomes have a selected average size in the size range between about 0.05 and 0.5 microns.
Claim 4
Dependent Claim
19 words
The composition of claim 2, wherein the polyethyleneglycol has a molecular weight is between about 1,000 to 5,000 daltons.
Claim 5
Dependent Claim
64 words
The composition of claim 2, wherein the amphipathic lipid is a phospholipid having a polar head group at which the polyethyleneglycol is derivatized, and the liposomes are characterized by a blood circulation lifetime, as measured by the percent liposome marker retained in the blood 24 hours after intravenous injection of the liposomes, which is greater than about 5 percent of the total amount administered.
Claim 6
Dependent Claim
53 words
The composition of claim 4, wherein the amphipathic lipid is a phospholipid and the liposomes are characterized by a blood circulation lifetime, as measured by the percent liposome marker retained in the blood 24 hours after intravenous injection of the liposomes, which is greater than about 10 percent of the total amount administered.
Claim 7
Dependent Claim
23 words
The composition of claim 4, wherein the phospholipid is phosphatidylethanolamine, and the polyethyleneglycol is coupled to the phospholipid through a lipid amine group.
Claim 8
Dependent Claim
23 words
The composition of claim 5, wherein the phospholipid contains acyl chains which are predominantly 18-carbon acyl chains with at least one unsaturated bond.
Claim 9
Dependent Claim
24 words
The composition of claim 7, wherein the phospholipid is a phosphatidylethanolamine, and the polyethyleneglycol is coupled to the phospholipid through a lipid amine group.
Claim 10
Dependent Claim
26 words
The composition of claim 1, wherein the liposomes contain 10-40 mole percent cholesterol, 40-85 mole percent neutral phospholipid, and 5-15 mole percent phospholipid derivatized with polyethyleneglycol.
Claim 11
Dependent Claim
38 words
The composition of claim 1, which is characterized by a blood/RES ratio, 24 hours after intravenous administration, which is at least about tenfold greater than that of the same liposomes in the absence of the derivatized amphipathic lipid.
Claim 12
Dependent Claim
32 words
The composition of claim 10, wherein the vesicle-forming lipids making up the liposomes are selected to produce a selected rate of release of the drug from the liposomes circulating in the bloodstream.
Claim 13
Dependent Claim
18 words
The composition of claim 11, for the treatment of malignancy, wherein the drug is an amphipathic anti-tumor compound.
Claim 14
Dependent Claim
18 words
The composition of claim 12, wherein the drug is doxorubicin or a pharmacologically acceptable analog or salt thereof.
Claim 15
Dependent Claim
19 words
The composition of claim 1, wherein the polyalkylether is linked to the amphipathic lipid through an esterase-or peptidase-sensitive linkage.
Claim 16
Dependent Claim
36 words
The composition of claim 1, wherein the liposomes include a surface-bound ligand which is effective to bind specifically and with high affinity to ligand-binding molecules carried on the surface of specific cells circulating in the bloodstream.
Claim 17
Dependent Claim
36 words
The composition of claim 15, wherein the surface-bound ligand is an antibody effective to bind specifically and with high affinity to an antigen which is expressed in a cell in the bloodstream in a disease state.
Claim 18
Dependent Claim
24 words
The composition of claim 15, wherein the surface-bound ligand is CD4 peptide which is effective to bind to HIV-infected T cell or B cells.
Claim 19
Independent Claim
70 words
A method of producing a severalfold increase in the blood-circulation time of intravenously administered liposomes formed of vesicle-forming lipids and containing an entrapped compound, as measured by the percent liposome marker retained in the blood 24 hours after intravenous injection, substantially independent of the degree of saturation of said vesicle-forming lipids, comprising forming the liposomes to include between about 1-20 mole percent an amphipathic, vesicle-forming lipid derivatized with a polyethyleneglycol.
Claim 20
Independent Claim
70 words
A method of producing a severalfold increase in the blood-circulation time of intravenously administered liposomes formed of vesicle-forming lipids and containing an entrapped compound, as measured by the percent liposome marker retained in the blood 24 hours after intravenous injection, substantially independent of the degree of saturation of said vesicle-forming lipids, comprising forming the liposomes to include between about 1-20 mole percent an amphipathic, vesicle-forming lipid derivatized with a polyethyleneglycol.
Claim 21
Independent Claim
63 words
A method of enhancing the uptake, by the reticuloendothelial system, of cells carrying surface-specific ligand-binding molecules which are characteristic of a disease state, comprising preparing a suspension of liposomes containing between 1-20 mole percent of an vesicle-forming lipid derivatized with a polyethyleneglycol, and a surface-bound ligand effective to bind specifically and with high affinity to said ligand-binding molecule, and administering said suspension intravenously.
Claim 22
Independent Claim
63 words
A method of enhancing the uptake, by the reticuloendothelial system, of cells carrying surface-specific ligand-binding molecules which are characteristic of a disease state, comprising preparing a suspension of liposomes containing between 1-20 mole percent of an vesicle-forming lipid derivatized with a polyethyleneglycol, and a surface-bound ligand effective to bind specifically and with high affinity to said ligand-binding molecule, and administering said suspension intravenously.
Claim 23
Dependent Claim
23 words
The method of claim 19, wherein the liposomes have a selected average size in the size range between about 0.05 and 0.5 microns.
Claim 24
Dependent Claim
70 words
The method of claim 19, for increasing the blood-circulation time of intravenously administered liposomes, as measured by the percent liposome marker retained in the blood 24 hours after intravenous injection of the liposomes, to a level which is greater than about 10 percent of the total amount of lipid administered, wherein the amphipathic lipid is a phospholipid, and the polyethyleneglycol has a molecular weight between about 1,000 to 5,000 daltons.
Claim 25
Dependent Claim
40 words
The method of claim 19, wherein adding is effective to enhance the blood circulation lifetime 24 hours after intravenous administration, by at least about tenfold over that observed with the same liposomes in the absence of the derivatized amphipathic lipid.
Claim 26
Independent Claim
81 words
A method of administering a compound intravenously, to achieve a level of compound in the bloodstream, 24 hours after drug administration, which is at least about 5 percent of the total amount of compound administered, comprising preparing a suspension of liposomes composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic, vesicle-forming lipid derivatized with a polyethyleneglycol, and the compound, in liposome-entrapped form, and intravenously administering an amount of the suspension containing a pharmacologically acceptable amount of the drug.
Claim 27
Independent Claim
81 words
A method of administering a compound intravenously, to achieve a level of compound in the bloodstream, 24 hours after drug administration, which is at least about 5 percent of the total amount of compound administered, comprising preparing a suspension of liposomes composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic, vesicle-forming lipid derivatized with a polyethyleneglycol, and the compound, in liposome-entrapped form, and intravenously administering an amount of the suspension containing a pharmacologically acceptable amount of the drug.
Claim 28
Dependent Claim
19 words
The method of claim 23, wherein the polyethyleneglycol has a molecular weight of between about 1,000 and 5,000 daltons.
Claim 29
Dependent Claim
36 words
The method of claim 23, wherein the vesicle-forming lipid is a phospholipid, and the level of compound in the bloodstream, 24 hours after liposome administration, is at least about 10 percent of the total compound administered.
Claim 30
Independent Claim
72 words
A method of delivering a drug selectively to a target tissue containing surface-bound tissue-specific ligand-bind molecules, comprising preparing a suspension of liposomes containing between 1-20 mole percent of an vesicle-forming lipid derivatized with a polyethyleneglycol, a surface-bound ligand effective to bind specifically and with high affinity to said ligand-binding molecule, and the drug, in liposome-entrapped form, and intravenously administering an amount of the suspension containing a pharmacologically acceptable amount of the drug.
Claim 31
Independent Claim
72 words
A method of delivering a drug selectively to a target tissue containing surface-bound tissue-specific ligand-bind molecules, comprising preparing a suspension of liposomes containing between 1-20 mole percent of an vesicle-forming lipid derivatized with a polyethyleneglycol, a surface-bound ligand effective to bind specifically and with high affinity to said ligand-binding molecule, and the drug, in liposome-entrapped form, and intravenously administering an amount of the suspension containing a pharmacologically acceptable amount of the drug.
Claim 32
Dependent Claim
19 words
The method of claim 26, wherein the polyethyleneglycol has a molecular weight of between about 1,000 and 5,000 daltons.
Claim 33
Dependent Claim
12 words
The method of claim 27, wherein the vesicle-forming lipid is a phospholipid.
Claim 34
Dependent Claim
28 words
The method of claim 26, wherein the target tissue is a solid tumor carrying a tumor specific antigen, and the ligand is an antibody specific against such antigen.
Claim 35
Dependent Claim
26 words
The method of claim 26, wherein the target tissue is a solid tumor, and the drug is doxorubicin or a pharmacologically acceptable analog or salt thereof.
Claim 36
Dependent Claim
19 words
The method of claim 19, wherein the polyethyleneglycol has a molecular weight of between about 1,000 and 5,000 daltons.
Claim 37
Dependent Claim
12 words
The method of claim 19, wherein the vesicle-forming lipid is a phospholipid.
Claim 38
Dependent Claim
19 words
The method of claim 19, wherein the cells are HIV-infected T-cells or B cells and the surface-bound D4 peptide.
References Cited (Backward Citations)
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