Formulation of PEGylated-liposome encapsulated glycopeptide antibiotics
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.
1. A liposome-encapsulated antimicrobial agent,
wherein the liposome consists of a (A) phospholipid, (B) cholesterol, and (C) methylpolyethyleneglycol-1,2-distearoylphosphatidyl ethanolamine (DSPE-mPEG) which are present in weight ratios (A:B:C) ranging from (0.8-1.2):(0.16-0.20):(0.018-0.022), and encapsulates an aqueous solution of the antimicrobial agent.
2. A liposome-encapsulated antimicrobial agent according to claim 1 , wherein the antimicrobial agent is a glycopeptide antibiotic.
3. A liposome-encapsulated antimicrobial agent according to claim 2 , wherein the glycopeptide antibiotic is vancomycin, avoparcin, ristocetin, teicoplanin, a derivative of vancomycin, avoparcin, ristocetin, or teicoplanin.
4. A liposome-encapsulated antimicrobial agent according to claim 3 , wherein the derivative of vancomycin is a multivalent vancomycin, vancomycin disulfide, mono- or di-dechlorovancomycin, a glutamine analog of vancomycin, an aspartic acid analog of vancomycin, a desvancosamine derivative of vancomycin, a chlorine derivative of vancomycin, a benzylic amino sugar derivative of vancomycin, N-acyl vancomycin, N-aracyl vancomycins, and N-alkyl vancomycin.
5. A liposome-encapsulated antimicrobial agent according to claim 1 , wherein the phospholipid is 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, or 1,1′,2,2T-tetramyristoyl cardiolipin ammonium salt.
6. A liposome-encapsulated antimicrobial agent according to claim 5 , wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).
7. A liposome-encapsulated antimicrobial agent according to claim 1 , wherein the weight ratios of (A:B:C) are 1:0.18:0.02.
8. A method of treating a bacterial infection of a tissue or organ of a patient comprising administering to the patient an effective amount of the liposome-encapsulated antimicrobial agent according to claim 1 .
9. A method of treating a bacterial infection according to claim 8 , wherein the bacterial infection is caused by gram-positive bacteria.
10. A method of treating a bacterial infection according to claim 9 , wherein the gram-positive bacteria are Methicillin-resistant Staphylococcus aureus (MRSA).
11. A method of treating a bacterial infection according to claim 8 wherein the gram-positive bacteria is in the intracellular compartment of a cell.
12. A method of treating a bacterial infection according to claim 8 , wherein the infected tissue or organ is lung, liver, spleen, kidney, or blood.
13. A method of treating a bacterial infection according to claim 12 , wherein the infected tissue or organ is lung.
14. A liposome-encapsulated antimicrobial agent according to claim 1 , wherein the DSPE-mPEG is DSPE-mPEG(550), a DSPE-mPEG(750), DSPE-mPEG(1000), DSPE-mPEG(2000), DSPE-mPEG(3000), or DSPE-mPEG(5000).
15. A liposome-encapsulated antimicrobial agent according to claim 14 , wherein the DSPE-mPEG is DSPE-mPEG(2000).
16. A liposome-encapsulated glycopeptide antibiotic, wherein the liposome comprises: (A) 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), (B) cholesterol, and (C) DSPE-mPEG(2000) which are present in weight ratios (A:B:C) ranging from (0.8-1.2):(0.16-0.20):(0.018-0.022), and encapsulates an aqueous solution of the glycopeptide antibiotic.
17. A liposome-encapsulated glycopeptide antibiotic according to claim 16 , wherein the glycopeptide antibiotic is vancomycin.
18. A liposome-encapsulated glycopeptide antibiotic according to claim 17 , wherein the weight ratios (A:B:C) are 1:0.18:0.02.
19. A liposome-encapsulated glycopeptide antibiotic according to claim 17 or 18 , wherein the aqueous solution of vancomycin comprises 10 mg/ml vancomycin.