Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Patent
1993-06-23
1998-06-02
Kishore, Gollamudi S.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
A61K 9127, A61K 9133
Patent
active
057595712
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/US93/04501, filed May 11, 1993, which is a Continuation-in-Part application of PCT/US92/10591, filed Dec. 2, 1992.
FIELD OF THE INVENTION
This invention relates to the fields of biochemistry and medicine, and particularly to a liposome formulation. More specifically, it relates to a liposomal formulation containing an aminoglycoside, its process of manufacture and its use. This invention also relates to formulations having reduced toxicity, longer stability, and superior efficacy. This invention further relates to liposomal formulations containing amikacin and its use in treating drug susceptible and drug resistant strains of bacterial infections.
BACKGROUND OF THE INVENTION
The discovery of aminoglycosides began in the 1940s with the isolation of streptomycin from Streptomyces griseus. Since the 1940s, other aminoglycosides have been discovered and synthesized. These include neomycin which is obtained or isolated from Streptomyces fradiae; kanamycin which is isolated from Streptomyces kanamyceticus; gentamicin which is isolated from Micromonospora purpurea; tobramycin which is isolated from Streptomyces tenedrarius; sisomicin isolated from micromonospora inyoesis; amikacin which is a semisynthetic derivative of Kanamycin A; and netilmicin which is a semisynthetic derivative of sisomicin. Amikacin has the broadest spectrum of antimicrobial activity of all the aminoglycosides. It also has a unique resistance to the immunoglycoside-inactivating enzymes.
The aminoglycosides are polar-cations which consist of two or more amino sugars joined in a glycosidic linkage to a hexose nucleus, which is usually in a central position. The aminoglycosides are used primarily to treat infections caused by gram-negative bacteria. However, aminoglycosides have been used in recent years to treat bacteria from the genera Mycobacteria. For example, amikacin has shown to be effective against Mycobacterium tuberculosis. Aminoglycosides have also been tested against M.avium infections including M. avium-intracellulare complex (MAC) which is a group of related acid-fast organisms that grow only slightly faster than M. tuberculosis and can be divided into a number of serotypes. At the beginning of the twentieth century, tuberculosis was the most prevalent cause of death in the United States. By the late 1940s, with the advent of streptomycin, tuberculosis infection had decreased substantially. Since the mid-1980s with the appearance of the acquired immune deficiency syndrome, tuberculosis again began to emerge as a major health problem. Further, the new cases of tuberculosis showed resistance to many of the available antibiotic therapies. Similarly MAC, once considered rare, is now the most common systemic bacterial type infections in patients suffering from acquired immune deficiency syndrome. Hence, the search for an effective antibiotic has intensified.
Although the aminoglycosides have been useful in treating infections, the use of these antibiotics is not free from toxicity and side effects. Aminoglycosides may produce irreversible vestibular, cochlear, and renal toxicity. The two main toxic effects of aminoglycosides are ototoxicity and nephrotoxicity. Studies have found that the aminoglycosides antibiotics may cause polyuria, decreased urinary osmolality, proteinuria, enzymuria, glycosuria, and a decrease in the rate of glomerular filtration. Some investigators believe that nephrotoxicity results from the accumulation of the aminoglycosides in the renal cortex because of the long half-life of the agents in that tissue.
Liposomes are microscopic vesicles made, in part, from phospholipids which form closed, fluid filled spheres when dispersed with water. Phospholipid molecules are polar, having a hydrophilic ionizable head and two hydrophobic tails consisting of long fatty acid chains. Thus, when sufficient phospholipid molecules are present with water, the tails spontaneously associate to exclude water while the hydrophilic phosphate heads interact with water. The result is a bilayer membrane in which
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Bracken Kevin R.
Chiang Su-Ming
Hersch Evan M.
Petersen Eskild A.
Proffitt Richard T.
Kishore Gollamudi S.
NeXstar Pharmaceuticals, Inc.
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