Liposomal compositions and methods of using the same to treat dyslipidemias

Abstract

The present invention provides a liposomal composition for treating dyslipidemias in human subjects, a method of using a liposomal composition, and devices and modes of operation of the devices and of the compositions, and kits related thereto. The invention provides for the reverse transport of cholesterol from peripheral tissues to the liver in a warm blood mammal while controlling plasma atherogenic lipoprotein concentrations, including LDL concentrations. A method described above and mode of operation of the devices includes the step of administering an effective amount of a multiplicity of acceptors comprised of phospholipids substantially free of sterol. A method described above optionally includes the step of periodically assaying atherogenic lipoprotein concentrations with an assay during the treatment period to assess atherogenic lipoprotein concentrations and obtain an atherogenic lipoprotein profile, and adjusting the administration in response to the profile. The large liposomes are dimensioned larger than fenestrations of an endothelial layer lining hepatic sinusoids in the liver so that the liposomes are too large to readily penetrate the fenestrations of one variant. The therapeutically effective amounts are in the range of about 10 mg to about 1600 mg phospholipid per kg body weight per dose. A pharmaceutical composition and related kit for mobilizing peripheral cholesterol and sphingomyelin that enters the liver of a subject consisting essentially of liposomes of a size and shape larger than fenestrations of an endothelial layer lining hepatic sinusoids in the liver is also provided. The invention also provides for control of cholesterol related genes and other compounds. The present invention also provides compositions and methods for treating atherosclerosis. In one embodiment, the compositions comprise unilamellar liposomes having an average diameter of 100-150 nanometers. Methods for treating atherosclerosis employing the compositions of the present invention are also provided.

1 . A pharmaceutical composition consisting essentially of: 
 unilamellar liposomes having an average diameter in the range of about 100 to about 150 nanometers, which liposomes are not bound to a drug: and    a pharmaceutically acceptable carrier.    
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the liposomes are bound to apoproteins.  
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the liposomes have an average diameter of about 125 nanometers.  
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the liposomes comprise at least one phospholipid.  
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the phospholipid is phosphatidylcholine, phosphatidylglycerol, distearoylphosphatidylcholine or distearoylphosphatidylglycerol.  
     
     
         6 . The pharmaceutical composition of  claim 4 , wherein the liposome comprises phosphatidylcholine and phosphatidylglycerol.  
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the liposome is liquid-crystalline at 37° C.  
     
     
         8 . A method for treating atherosclerosis in an animal comprising administering a liposome composition to the animal, which liposome composition consists essentially of unilamellar liposomes having an average diameter in the range of about 100 to about 150 nanometers.  
     
     
         9 . The method of  claim 8 , wherein the unilamellar liposomes have an average diameter of about 125 nanometers.  
     
     
         10 . The method of  claim 8 , wherein the liposomes comprise at least one phospholipid.  
     
     
         11 . The method of  claim 10 , wherein the phospholipid is phosphatidylcholine, phosphatidylglycerol, distearoylphosphatidylcholine or distearoylphosphatidylglycerol.  
     
     
         12 . The method of  claim 11 , wherein the liposome comprises phosphatidylcholine and phosphatidylglycerol.  
     
     
         13 . The method of  claim 8 , wherein the liposome is liquid-crystalline at 37° C.  
     
     
         14 . The method of  claim 8 , wherein the liposome composition is administered parenterally.  
     
     
         15 . The method of  claim 14 , wherein the liposome composition is administered intravenously.  
     
     
         16 . The method of  claim 8  further comprising repeating the administration of the liposome composition.  
     
     
         17 . The method of  claim 16 , wherein the liposome composition is administered every 7-14 days.  
     
     
         18 . The method of  claim 16 , wherein the liposome composition is administered at least twice.  
     
     
         19 . The method of  claim 9 , wherein the liposomes comprise at least one phospholipid.  
     
     
         20 . The method of  claim 19 , wherein the phospholipid is phosphatidylcholine, phosphatidylglycerol, distearoylphosphatidylcholine or distearoylphosphatidylglycerol.  
     
     
         21 . The method of  claim 20 , wherein the liposomes comprise phosphatidylcholine and phosphatidylglycerol.  
     
     
         22 . The method of  claim 21 , wherein the liposome comprises phosphatidylcholine.  
     
     
         23 . A method of treating a dyslipidemic human subject comprising administering a therapeutically effective amount of a dosage formulation of a multiplicity of large, unilamellar liposomes comprised of phospholipids substantially free of sterol to a human in need thereof for a treatment period.  
     
     
         24 . The method of  claim 23 , wherein the therapeutically effective amount is in the range of about 10 mg to about 1600 mg of phospholipid per kg body weight per dose.  
     
     
         25 . The method of  claim 23 , wherein the liposomes are given periodically during said treatment period.  
     
     
         26 . The method of  claim 23 , wherein the liposomes have diameters larger than about 50 nm.  
     
     
         27 . The method of  claim 23 , wherein the liposomes have diameters larger than about 80 nm.  
     
     
         28 . The method of  claim 23 , wherein the liposomes have diameters in the range of about 100 nm to about 200 nm.  
     
     
         29 . The method of  claim 23  further comprising a step of enhancing tissue penetration of a cholesterol acceptor and increasing extraction of tissue cholesterol and other exchangeable material by co-administration of an effective amount of a compound, said compound selected from the group consisting of a small acceptor of cholesterol and a drug that increases endogenous small acceptors of cholesterol.  
     
     
         30 . The method of  claim 29 , wherein said small acceptor is selected from the group consisting of a high-density lipoprotein, a phospholipid protein complex having a group selected from a group consisting of apoA-I, apoA-I milano, apoA-II, apoA-IV, apoE, synthetic fragments thereof, natural fragments thereof, an amphipathic compound, including amphipathic compounds that are not a protein, an amphipathic protein, and an amphipathic peptide, said protein substantially free of phospholipid, small phospholipid liposomes, and a small cholesterol acceptor.  
     
     
         31 . The method of  claim 29 , wherein said drug comprises an agent that raises physiologic HDL concentrations, said agent selected from the group consisting of nicotinic acid, ethanol, a fibric acid, a cholesterol synthesis inhibitor, a drug that increases HDL concentrations, and derivatives thereof.  
     
     
         32 . The method of  claim 23 , wherein said dosage formulation comprises liposomes having the structure of large unilamellar vesicles obtainable by extrusion of phospholipid which is in a liquid-crystalline phase at about 37° C. through polycarbonate filters having a pore diameter of about 0.1 micron, the formulation containing between about 7 and about 105 grams of lipid.  
     
     
         33 . The dosage formulation of  claim 32 , wherein the liposomes are bound to proteins or peptides.  
     
     
         34 . The dosage formulation of  claim 33  wherein the proteins are selected from the group consisting of paraoxonase, lipoprotein lipase, and lipid binding proteins.  
     
     
         35 . The dosage formulation of  claim 32 , wherein the liposomes have a diameter of about 125 plus or minus 30 nanometers.  
     
     
         36 . The dosage formulation of  claim 32 , wherein the liposomes comprise at least one phospholipid selected from the group consisting of phosphatidylcholine, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, oleoyl palmitoyl phosphatidylcholine, palmitoyl-oleoyl phosphatidylcholine, dioleoyl phosphatidylcholine, sphingomyelin, phsophatidylglycerol, and mixtures thereof.  
     
     
         37 . The dosage formulation of  claim 36 , wherein the liposome comprises phosphatidylcholine and phosphatidylglycerol.  
     
     
         38 . The dosage formulation of  claim 37 , wherein the phospholipid is phosphatidylcholine.  
     
     
         39 . The dosage formulation of  claim 32  wherein the liposomes are bound to molecules which enhance liposome stability or half-life.