Novel formulation of pegylated-liposome encapsulated glycopeptide antibiotics

Abstract

This invention is directed to a novel method of treating an individual suffering from a bacterial infection, such as bacterial infections of various tissues or organs of an individual. In general, the method of treatment involves administering to an individual a pharmaceutical formulation that comprises a liposome-encapsulated antimicrobial agent, wherein polyethylene glycol (PEG) molecules are covalently attached to the surface of the liposomes.

The claimed invention is: 
     
         1 . A pharmaceutical formulation comprising an antimicrobial agent or combination of antimicrobial agents, wherein the antimicrobial agent is encapsulated in a liposome, and wherein at least one polyethylene glycol (PEG) molecule is attached covalently to the surface of the liposome. 
     
     
         2 . The pharmaceutical formulation according to  claim 1 , wherein, one or more antimicrobial agents are glycopeptide antibiotics. 
     
     
         3 . The pharmaceutical formulation according to  claim 1 , wherein the one or more glycopeptide antibiotics are selected from: vancomycin; avoparcin; ristocetin; teicoplanin; derivatives of vancomycin, avoparcin, ristocetin, and teicoplanin; or mixtures thereof. 
     
     
         4 . The pharmaceutical formulation according to  claim 3 , wherein derivatives of vancomycin derivatives include: multivalent vancomycin; vancomycin disulfide; mono- or di-dechlorovancomycin; glutamine analogs of vancomycin; aspartic acid analogs of vancomycin; desvancosamine derivatives of vancomycin; chlorine derivatives of vancomycin; benzylic amino sugar derivatives of vancomycin; N-acyl vancomycin; N-aracyl vancomycins; and N-alkyl vancomycin; or mixtures thereof. 
     
     
         5 . The pharmaceutical formulation according to  claim 1 , wherein the liposome comprises a lipid selected from: 1,2-dimyristroyl-sn-glycero-3-phosphocholine; 1,2-dilauroyl-sn-glycero-3-phosphocholine; 1,2-distearoyl-sn-glycero-3-phosphocholine; 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine; 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine; 1,2-dioleoyl-sn-glycero-3-phosphate monosodium salt; 1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-(1-glycerol)]sodium salt; 1,2-dimyristoyl-sn-glycero-3-[phospho-L-serine]sodium salt; 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-glutaryl sodium salt; and 1,1′,2,2′-tetramyristoyl cardiolipin ammonium salt; or mixtures thereof. 
     
     
         6 . The pharmaceutical formulation according to  claim 1 , wherein the PEG molecule is selected from: methylpolyethyleneglycol-1,2-distearoyl-phosphatidyl ethanolamine conjugate (MPEG-2000-DSPE); monomethoxypolyethylene glycol (MPEG-OH), monomethoxypolyethylene glycol-succinate (MPEG-S), monomethoxypolyethylene glycol-succinimidyl succinate (MPEG-S-NHS), monomethoxypolyethylene glycol-amine (MPEG-NH 2 ), monomethoxypolyethylene glycol-tresylate (MPEG-TRES), and monomethoxypolyethylene glycol-imidazolyl-carbonyl (MPEG-IM); or mixtures thereof. 
     
     
         7 . The pharmaceutical formulation according to  claim 1 , wherein the liposome also comprises cholesterol or cholesterol derivatives. 
     
     
         8 . The pharmaceutical formulation according to  claim 1 , wherein the liposome comprises: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); methylpolyethyleneglycol-1, 2-distearoyl-phosphatidyl ethanolamine conjugate (MPEG-2000-DSPE); and cholesterol or a cholesterol derivative. 
     
     
         9 . The pharmaceutical formulation according to  claim 8 , wherein the molar ratio of DSPC, cholesterol, and MPEG-2000-DSPE, respectively, ranges from 0.1:0.1:0 to 30:10:2. 
     
     
         10 . The pharmaceutical formulation according to  claim 9 , wherein the molar ratio of DSPC, cholesterol, and PEG, respectively, is from 3:1:0 to 3:1:0.5. 
     
     
         11 . A method of treatment for an infection of a tissue or organ of a patient by at least one bacterium comprising administering to the patient an effective amount of the pharmaceutical formulation according to  claim 1 . 
     
     
         12 . The method of treatment according to  claim 11 , wherein the at least one bacterium is gram-positive. 
     
     
         13 . The method of treatment according to  claim 12 , wherein the at least one gram-positive bacterium is Methicillin-resistant  Staphylococcus aureus  (MRSA). 
     
     
         14 . The method of treatment according to  claim 11  wherein the at least one bacterium infects the intracellular compartment of a cell. 
     
     
         15 . The method of treatment according to  claim 11 , wherein the infected tissue or organ is lung, liver, spleen, kidney, or blood, including all blood cell populations, or any combination of the foregoing tissues or organs. 
     
     
         16 . The method of treatment according to  claim 15 , wherein the infected tissue or organ is lung.