Materials and methods for treating bacterial infections using C-1 gentamicin
Inventors
Molitoris, Bruce A. • Wagner, Mark C. • Sandoval, Ruben M. • GOEBL, Mark Gerard
Assignees
Indiana University Research and Technology Corp • US Department of Veterans Affairs
Publication Number
US-10555961-B2
Publication Date
2020-02-11
Expiration Date
2036-06-03
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Abstract
Various aspects relate to the use of C-1 gentamicin as an antibiotic effective for the treatment of a bacterial infection, a genetic disorder, or cancer in a subject.
Core Innovation
The invention relates to the use of the C-1 congener of gentamicin as an antibiotic effective for treating bacterial infections, genetic disorders, and cancer in subjects. The invention encompasses compositions comprising C-1 gentamicin or a pharmaceutically acceptable acid addition salt thereof, preservatives, and chelating agents formulated as liquids substantially free of C-1a gentamicin and C-2a gentamicin. The C-1 gentamicin exhibits lower nephrotoxicity compared to native gentamicin formulations while retaining good antibacterial activity.
The background problem addressed by the invention is the widespread clinical limitation of aminoglycosides, including native gentamicin, due to their nephrotoxicity. Although aminoglycosides are effective antibiotics against gram-negative bacteria and mycobacteria, their use is constrained by the high incidence of kidney damage marked by elevated serum creatinine and reduced glomerular filtration rate. Prior studies failed to isolate pure gentamicin congeners, and existing approaches to reduce nephrotoxicity have been inadequate.
The discovery that the C-1 congener of gentamicin is both non-nephrotoxic and potently bactericidal allows for formulations that can be administered safely, even to patients at high risk of kidney disease. The invention further details compositions with specific impurity ratios of other gentamicin congeners, dose regimens, and methods of administration. Thereby, it expands the therapeutic application of gentamicin to treat bacterial infections, genetic diseases caused by premature stop codons, and cancers characterized by such mutations.
Claims Coverage
The patent includes one independent method claim directed to treating conditions with compositions of C-1 gentamicin and one independent composition claim directed to pharmaceutical compositions comprising C-1 gentamicin.
Method of treating bacterial infections, monogenic genetic diseases, and cancer with C-1 gentamicin
A method comprising administering a composition comprising C-1 gentamicin or a pharmaceutically acceptable acid addition salt thereof, wherein the composition is substantially free of C-1a, C-2, and C-2a gentamicin congeners, and treating conditions selected from bacterial infections, monogenic genetic diseases, and cancer.
Composition comprising C-1 gentamicin with specific impurity limits
A liquid pharmaceutical composition comprising C-1 gentamicin or its pharmaceutically acceptable acid addition salt, a preservative, and a chelating agent, wherein the composition is substantially free of C-1a, C-2, and C-2a gentamicin congeners, and has less than 1000 ppm of C-1a and C-2a gentamicin.
The independent claims focus on methods of treatment using compositions highly enriched in C-1 gentamicin with minimal presence of other gentamicin congeners and compositions of these purified C-1 gentamicin formulations suitable for pharmaceutical use, highlighting low nephrotoxicity and therapeutic efficacy against bacterial infections, genetic diseases, and cancers.
Stated Advantages
The C-1 gentamicin compositions exhibit lower nephrotoxicity compared to native gentamicin formulations.
The invention provides gentamicin formulations with effective antibacterial activity against both gram-positive and multi-drug-resistant gram-negative bacteria.
The lower cytotoxicity allows use of gentamicin in patients previously considered unsuitable due to kidney disease or risk factors for kidney problems.
The compositions enable treatment of genetic diseases and cancers via suppression of premature termination codons with reduced toxicity.
Documented Applications
Treatment of bacterial infections caused by gram-positive and gram-negative bacteria, including infections by Bacillus subtilis, Klebsiella pneumonia, multi-drug resistant Klebsiella pneumoniae, and others.
Treatment of monogenic genetic diseases caused by premature stop codons such as cystic fibrosis, Hurler Syndrome, Scheie syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, nephrogenic diabetes insipidus, hemophilia, dystrophic epidermolysis bullosa, and Kabuki syndrome.
Treatment of cancers wherein cancer cells contain premature stop codons, including cancers of various organs and tissues such as head and neck, skin, lung, colon, prostate, breast, ovary, brain, blood, and lymphoid tissues.
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