Ligand-targeted emulsions carrying bioactive agents

Abstract

A composition for use in delivering a bioactive agent to targeted tissues or cells comprises: (a) a site-specific targeting ligand; (b) a lipid encapsulated oil in water emulsion; and (c) a bioactive agent in or on the surface of the outer monolayer of the emulsion; the ligand being conjugated directly or indirectly to the emulsion and the composition providing facilitated delivery of the bioactive agent through prolonged association and increased contact of the ligand-bound lipid encapsulated emulsion particles with the lipid bilayer of the target tissues or cells. The composition may also comprise a lipid encapsulated oil in water emulsion and a combination site-specific targeting ligand/bioactive agent. Methods for improved delivery of a bioactive agent to targeted tissues or cells are also disclosed.

What is claimed is:  
     
         1 . A composition for use in delivering a bioactive agent to targeted tissues or cells comprising: 
 (a) a site-specific targeting ligand;    (b) a lipid encapsulated oil in water emulsion; and    (c) a bioactive agent in or on the surface of the outer monolayer said emulsion; said ligand being conjugated directly or indirectly to said emulsion and said composition providing facilitated delivery of said bioactive agent through prolonged association and increased contact of the ligand-bound, lipid encapsulated emulsion particles with the lipid bilayer of said target tissues or cells.    
     
     
         2 . A composition as set forth in  claim 1  wherein said site-specific targeting ligand is selected from the group consisting of antibodies, antibody fragments, peptides, asialoglycoproteins, polysaccharides, aptamers, small molecules, nucleic acids, peptidomimetics, mimetics and drugs.  
     
     
         3 . A composition as set forth in  claim 2  wherein said site-specific targeting ligand is an antibody.  
     
     
         4 . A composition as set forth in  claim 1  wherein said oil in water emulsion contains a fluorochemical.  
     
     
         5 . A composition as set forth in  claim 4  wherein said fluorochemical is a fluorocarbon.  
     
     
         6 . A composition as set forth in  claim 4  wherein said fluorocarbon is perfluorooctylbromide.  
     
     
         7 . A composition as set forth in  claim 4  wherein said fluorochemical is a liquid with a boiling point above approximately 30° C.  
     
     
         8 . A composition as set forth in  claim 7  wherein said fluorochemical liquid has a boiling point above approximately 90° C.  
     
     
         9 . A composition as set forth in  claim 1  wherein said bioactive agent is selected from the group consisting of chemotherapeutic agents, drugs, genetic materials, nucleic acid-based therapy, protein or peptide therapy, radioactive isotopes or combinations thereof.  
     
     
         10 . A composition as set forth in  claim 9  wherein said bioactive agent is a chemotherapeutic agent.  
     
     
         11 . A composition as set forth in  claim 1  wherein said lipid encapsulated emulsion has an outer coating or outer monolayer composed of a material selected from the group consisting of a natural or synthetic phospholipid, a fatty acid, cholesterol, lysolipid, sphingomyelin, tocopherol, glucolipid, stearylamine, cardiolipin, a lipid with ether or ester linked fatty acids and a polymerized lipid.  
     
     
         12 . A composition as set forth in  claim 1  wherein said outer monolayer of said emulsion also contains an additional surfactant incorporated therein for stabilizing said emulsion.  
     
     
         13 . A composition as set forth in  claim 12  wherein said additional surfactant is selected from the group consisting of nonionic and amphoteric surfactants.  
     
     
         14 . A composition as set forth in  claim 12  wherein said surfactant contains a cationic lipid to facilitate adhesion of said bioactive agent to said emulsion particles.  
     
     
         15 . A composition as set forth in  claim 14  wherein said cationic lipid is selected from the group consisting of N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride, 1,2-dioleoyloxy-3-(trimethylammonio)propane, 1,2-dioleoyl-3-(4′-trimethylammonio)butanoyl-sn-glycerol, 1,2-diacyl-3-trimethylammonium-propane, 1,2-diacyl-3-dimethylammonium-propane, 1,2-diacyl-sn-glycerol-3-ethylphosphochloine, and 3β-[N′,N′-dimethylaminoethane)-carbamol]cholesterol-HCl.  
     
     
         16 . A composition as set forth in  claim 1  wherein said emulsion contains an emulsifying and/or solubilizing agent.  
     
     
         17 . A composition as set forth in  claim 1  wherein said emulsion particles have a diameter in the range of approximately 0.01 to 10 microns.  
     
     
         18 . A composition as set forth in  claim 17  wherein said emulsion particles have a diameter in the range of approximately 0.1 to 0.5 microns.  
     
     
         19 . A composition as set forth in  claim 1  wherein said emulsion contains a primer material incorporated into the outer monolayer thereof to covalently bond said ligand with said emulsion.  
     
     
         20 . A composition as set forth in  claim 19  wherein said primer material is selected from the group consisting of 1-ethyl-3-(3-N-N-dimethylaminopropyl)carbodiimide hydrochloride, 1-cyclohexyl-3-(2-morpholinoethyl)carbodimide methyl-p-toluenesulfonate, phosphatidylethanolamine, N-caproylamine phosphatidylethanolamine, N-dodecanylamine phosphatidylethanolamine, phosphotidylthioethanol, 1,2-diacyl-sn-glycerol-3-phosphoethanolamine-N-[4-p-maleimidephenyl)-butyramide, N-succinyl-phosphatidylethanolamine, N-glutaryl-phosphatidylethanolamine, N-dodecanyl-phosphatidylethanolamine, N-biotinyl-phosphatidylethanolamine, N-biotinylcaproyl-phosphatidylethanolamine, and phosphatidylethylene glycol.  
     
     
         21 . A composition as set forth in  claim 1  wherein said ligand is conjugated directly to said emulsion by direct adsorption of said ligand to the oil/aqueous interface of said emulsion.  
     
     
         22 . A composition for use in delivering a bioactive agent to targeted tissues or cells comprising: 
 (a) a lipid encapsulated oil in water emulsion; and    (b) a combination site-specific targeting ligand/bioactive agent in or on the surface of the outer monolayer of said emulsion; said combination ligand/bioactive agent being conjugated directly or indirectly to said emulsion and said composition providing facilitated delivery of said bioactive agent through prolonged association and increased contact of the ligand-bound, lipid encapsulated emulsion particles with the lipid bilayer of said target tissues or cells.    
     
     
         23 . A composition as set forth in  claim 22  wherein said combination ligand/bioactive agent is selected from the group consisting of antibodies, peptide fragments and mimetics.  
     
     
         24 . A composition as set forth in  claim 23  wherein said combination ligand/bioactive agent is an antibody.  
     
     
         25 . A composition as set forth in  claim 22  wherein said oil in water emulsion contains a fluorochemical.  
     
     
         26 . A composition as set forth in  claim 25  wherein said fluorochemical is a fluorocarbon.  
     
     
         27 . A composition as set forth in  claim 25  wherein said fluorochemical is a liquid with a boiling point above approximately 30° C.  
     
     
         28 . A composition as set forth in  claim 27  wherein said fluorochemical liquid has a boiling point above approximately 90° C.  
     
     
         29 . A composition as set forth in  claim 22  wherein said lipid encapsulated emulsion has an outer coating or outer monolayer composed of a material selected form the group consisting of a natural or synthetic phospholipid, a fatty acid, cholesterol, lysolipid, sphingomyelin, tocopherol, glucolipid, stearylamine, cardiolipin, a lipid with ether or ester linked fatty acids and a polymerized lipid.  
     
     
         30 . A composition as set forth in  claim 22  wherein said outer monolayer of said emulsion also contains an additional surfactant incorporated therein for stabilizing said emulsion.  
     
     
         31 . A composition as set forth in  claim 30  wherein said surfactant contains a cationic lipid to facilitate adhesion of said ligand/bioactive agent to said emulsion particles.  
     
     
         32 . A composition as set forth in  claim 22  wherein said emulsion contains an emulsifying agent and/or solubilizing agent.  
     
     
         33 . A composition as set forth in  claim 27  wherein said emulsion particles have a diameter in the range of approximately 0.01 to 10 microns.  
     
     
         34 . A composition as set forth in  claim 33  wherein said emulsion particles have a diameter in the range of approximately 0.1 to 0.5 microns.  
     
     
         35 . A composition as set forth in  claim 22  wherein said emulsion contains a primer material incorporated into the outer lipid monolayer thereof to covalently bond said ligand/bioactive agent with said emulsion.  
     
     
         36 . A composition as set forth in  claim 22  wherein said ligand/bioactive agent is conjugated directly to said emulsion by direct adsorption of the ligand/bioactive agent to the oil/aqueous interface of said emulsion.  
     
     
         37 . A method for improved delivery of a bioactive agent to targeted tissues or cells comprising administering to said tissues or cells a composition comprising: 
 (a) a site-specific targeting ligand;    (b) a lipid encapsulated oil in water emulsion; and    (c) a bioactive agent in or on the surface of the outer monolayer of said emulsion; said ligand being conjugated directly or indirectly to said emulsion; whereby said composition provides facilitated delivery of said bioactive agent through prolonged association and increased contact of the ligand-bound, lipid encapsulated emulsion particles with the lipid bilayer of said target tissues or cells.    
     
     
         38 . A method as set forth in  claim 37  wherein said site-specific targeting ligand is selected from the group consisting of antibodies, antibody fragments, peptides, asialoglycoproteins, polysaccharides, aptamers, small molecules, nucleic acids, peptidomimetics, mimetics and drugs.  
     
     
         39 . A method as set forth in  claim 38  wherein said site-specific targeting ligand is an antibody.  
     
     
         40 . A method as set forth in  claim 37  wherein said oil in water emulsion contains a fluorochemical.  
     
     
         41 . A method as set forth in  claim 40  wherein said fluorochemical is a fluorocarbon.  
     
     
         42 . A method as set forth in  claim 41  wherein said fluorocarbon is perfluorooctylbromide.  
     
     
         43 . A method as set forth in  claim 40  wherein said fluorochemical is a liquid with a boiling point above approximately 30° C.  
     
     
         44 . A method as set forth in  claim 43  wherein said fluorochemical liquid has a boiling point above approximately 90° C.  
     
     
         45 . A method as set forth in  claim 37  wherein said bioactive agent is selected from the group consisting of chemotherapeutic agents, drugs, genetic materials, nucleic acid-based therapy, protein or peptide therapy, radioactive isotopes or combinations thereof.  
     
     
         46 . A method as set forth in  claim 45  wherein said bioactive agent is a chemotherapeutic agent.  
     
     
         47 . A method as set forth in  claim 45  wherein said lipid encapsulated emulsion has an outer coating composed of a material selected from the group consisting of a natural or synthetic phospholipid, a fatty acid, cholesterol, lysolipid, sphingomyelin, tocopherol, glucolipid, stearylamine, cardiolipin, a lipid with ether or ester linked fatty acids and a polymerized lipid.  
     
     
         48 . A method as set forth in  claim 33  wherein said outer monolayer of said emulsion also contains an additional surfactant incorporated thereon for stabilizing said emulsion.  
     
     
         49 . A method as set forth in  claim 48  wherein said additional surfactant is selected from the group consisting of nonionic and amphoteric surfactants.  
     
     
         50 . A method as set forth in  claim 37  wherein said surfactant contains a cationic lipid to facilitate adhesion of said bioactive agent to said emulsion particles.  
     
     
         51 . A method as set forth in  claim 37  wherein said emulsion contains an emulsifying and/or solubilizing agent.  
     
     
         52 . A method as set forth in  claim 37  wherein said emulsion particles have a diameter in the range of approximately 0.01 to 10 microns.  
     
     
         53 . A method as set forth in  claim 52  wherein said emulsion particles have a diameter in the range of approximately 0.1 to 0.5 microns.  
     
     
         54 . A method as set forth in  claim 37  wherein said emulsion contains a primer material incorporated into the outer monolayer thereof to covalently bond said ligand with said emulsion.  
     
     
         55 . A method as set forth in  claim 37  wherein said ligand is conjugated directly to said emulsion by direct adsorption of said ligand to the oil/aqueous outerface of said emulsion.  
     
     
         56 . A method for improved delivery of a bioactive agent to targeted tissues or cells comprising administering to said tissues or cells a composition comprising: 
 (a) a lipid encapsulated oil in water emulsion; and    (b) a combination site-specific targeting ligand/bioactive agent in or on the surface of the outer monolayer of said emulsion; said combination ligand/bioactive agent being conjugated directly or indirectly to said emulsion and said composition providing facilitate delivery of said bioactive agent through prolonged association and increased contact of the ligand-bound, lipid encapsulated emulsion particles with the lipid bilayer of said target tissues or cells.    
     
     
         57 . A method as set forth in  claim 50  wherein said combination ligand/bioactive agent is selected from the group consisting of antibodies, antibody fragments, peptides, asialoglycoproteins, polysaccharides, aptamers, small molecules, nucleic acids, peptidomimetics, mimetics and drugs.  
     
     
         58 . A method as set forth in  claim 57  wherein said combination ligand/bioactive agent is an antibody.  
     
     
         59 . A method as set forth in  claim 56  wherein said oil in water emulsion contains a fluorochemical.  
     
     
         60 . A method as set forth in  claim 59  wherein said fluorochemical is a fluorocarbon.  
     
     
         61 . A method as set forth in  claim 59  wherein said fluorochemical is a liquid with a boiling point above approximately 30° C.  
     
     
         62 . A method as set forth in  claim 61  wherein said fluorochemical liquid has a boiling point above approximately 90° C.  
     
     
         63 . A method as set forth in  claim 56  wherein said lipid encapsulated emulsion has an outer coating or outer monolayer composed of a material selected from the group consisting of a natural or synthetic phospholipid, a fatty acid, cholesterol, lipolipid, sphengomyelin, tocopheral, glucolipid, stearylamine, cardiolipin, a lipid with ether or ester linked fatty acids and a polymerized lipid.  
     
     
         64 . A method as set forth in  claim 56  wherein said outer monolayer of said emulsion also contains an additional surfactant incorporated therein for stabilizing said emulsion.  
     
     
         65 . A method as set forth in  claim 64  wherein said surfactant contains a cationic lipid to facilitate adhesion of said ligand/bioactive agent to said emulsion particles.  
     
     
         66 . A method as set forth in  claim 56  wherein said emulsion contains an emulsifying agent and/or solubilizing agent.  
     
     
         67 . A method as set forth in  claim 56  wherein said emulsion particles have a diameter in the range of approximately 0.01 to 10 microns.  
     
     
         68 . A method as set forth in  claim 67  wherein said emulsion particles have a diameter in the range of approximately 0.1 to 0.5 microns.  
     
     
         69 . A method as set forth in  claim 56  wherein said emulsion contains a primer material incorporated into the outer lipid monolayer thereof to covalently bond said ligand/bioactive agent with said emulsion.  
     
     
         70 . A method as set forth in  claim 56  wherein said ligand/bioactive agent is conjugated directly to said emulsion by direct adsorption of the ligand/bioactive agent to the oil-aqueous interface of said emulsion.