Inhibition of mammalian target of rapamycin

Abstract

Disclosed are microcapsules that include an inhibitor of the mammalian target of rapamycin (mTOR) within the microcapsules, and pharmaceutical compositions and kits that include the microcapsules. Also disclosed are methods for treating or preventing an age-related disease, condition, or disorder in a subject that involve administering to a subject a pharmaceutically effective amount of microcapsules that includes an inhibitor of mTOR within the microcapsules.

We claim: 
     
         1 . A microcapsule pharmaceutical preparation, comprising:
 a) a core component comprising an inhibitor of mammalian target of rapamycin (mTOR) comprising rapamycin or an analog of rapamycin; and   b) a solid excipient matrix comprising an enteric coating material, wherein said inhibitor of mTOR is microencapsulated by said enteric coating material, and wherein said enteric coating material remains intact at a pH level of about or less than 7.   
     
     
         2 . The microcapsule pharmaceutical preparation of  claim 1 , wherein said enteric coating is comprised of Eudragit® S100, cellulose acetate phthalate (CAP), a methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, polyvinyl acetate phthalate (PVAP), or a methyl methacrylate-methacrylic acid copolymer. 
     
     
         3 . The microcapsule pharmaceutical preparation of  claim 1 , wherein said analog of rapamycin is everolimus, tacrolimus, CCI-779, ABT-578, AP-23675, AP-23573, AP23841, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin, or 42-0-(2-hydroxy)ethyl rapamycin. 
     
     
         4 . The microcapsule pharmaceutical preparation of  claim 1 , wherein said microcapsule pharmaceutical preparation further comprises at least one additional compound, wherein the at least one additional compound is vitamin E, vitamin A, an antibacterial antibiotic, an antioxidant, L-carnitine, lipoic acid, metformine, resveratrol, leptine, a non-steroid anti-inflammatory drug, or a COX inhibitor. 
     
     
         5 . A pharmaceutical or nutraceutical composition comprising the microcapsule pharmaceutical preparation of  claim 1  for treating or preventing a malady in a mammalian subject, wherein the lifespan expectancy of said mammalian subject is prolonged. 
     
     
         6 . The pharmaceutical or nutraceutical composition of  claim 5 , wherein said malady is selected from the group consisting of breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, renal cancer, skin cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, lymphatic cancer, stomach cancer, pancreatic cancer, testicular cancer, lymphoma and leukemia. 
     
     
         7 . The pharmaceutical or nutraceutical composition of  claim 6 , wherein said rapamycin analog is everolimus, tacrolimus, CCI-779, ABT-578, AP-23675, AP-23573, AP23841, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin, or 42-0-(2-hydroxy)ethyl rapamycin. 
     
     
         8 . The pharmaceutical or nutraceutical composition of  claim 5 , wherein the core component further comprises at least one additional compound compound. 
     
     
         9 . The pharmaceutical or nutraceutical composition of  claim 8 , wherein said at least one additional compound is vitamin E, vitamin A, an antibacterial antibiotic, an antioxidant, L-camitine, lipoic acid, metformine, resveratrol, leptine, a non-steroid anti-inflammatory drug, or a COX inhibitor. 
     
     
         10 . A method for treating or preventing a malady in a mammalian subject in need thereof comprising administering a pharmaceutically effective amount of the microcapsule pharmaceutical preparation of  claim 1  to the subject. 
     
     
         11 . The method of  claim 10 , wherein the core component comprises rapamycin. 
     
     
         12 . The method of  claim 10 , wherein the core component comprises a rapamycin analog. 
     
     
         13 . The method of  claim 12 , wherein the rapamycin analog is everolimus, tacrolimus, CCI779, ABT-578, AP-23675, AP-23573, AP23841, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin, or 42-0-(2-hydroxy)ethyl rapamycin. 
     
     
         14 . The method of  claim 10 , wherein the microcapsule pharmaceutical preparation further comprises at least one additional compound. 
     
     
         15 . The method of  claim 14 , wherein the at least one additional compound is vitamin E, vitamin A, an antibacterial antibiotic, an antioxidant, L-camitine, lipoic acid, metformine, resveratrol, leptine, a non-steroid anti-inflammatory drug, or a COX inhibitor. 
     
     
         16 . The method of  claim 10 , wherein said malady is selected from the group consisting of breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, renal cancer, skin cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, lymphatic cancer, stomach cancer, pancreatic cancer, testicular cancer, lymphoma and leukemia. 
     
     
         17 . The method of  claim 10 , wherein the microcapsule pharmaceutical preparation is administered orally, by nasogastric tube, rectally, intraperitoneally, topically, subcutaneously, or intravenously. 
     
     
         18 . The method of  claim 10 , wherein the microcapsule pharmaceutical preparation is administered by combining said microcapsules with an edible substance. 
     
     
         19 . The method of  claim 10 , wherein the dose of the inhibitor of mTOR ranges from 1 microgram to 100 mg per kg body weight of the subject. 
     
     
         20 . A method for prolonging the lifespan of a mammalian subject comprising administering a pharmaceutically effective amount of the microcapsule pharmaceutical preparation of  claim 1  to the subject, wherein lifespan is prolonged. 
     
     
         21 . A method for reducing age-related decline in cognition in a mammalian subject comprising administering a pharmaceutically effective amount of the microcapsule pharmaceutical preparation of  claim 1  to the subject, wherein the age-related decline in cognition is reduced. 
     
     
         22 . A kit comprising a first sealed container comprising a microcapsule pharmaceutical preparation, wherein the microcapsule is comprised of a core component comprising an inhibitor of mammalian target of rapamycin (mTOR), wherein said inhibitor of mTOR is rapamycin or a rapamycin analog, and wherein said core component is microencapsulated and encased in an enteric coating material. 
     
     
         23 . The kit of  claim 22 , wherein said enteric coating material is comprised of Eudragit S100, cellulose acetate phthalate (CAP), a methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, polyvinyl acetate phthalate (PVAP), or a methyl methacrylate-methacrylic acid copolymer. 
     
     
         24 . The kit of  claim 22 , wherein the rapamycin analog is everolimus, tacrolimus, CCI-779, ABT-578, AP-23675, AP-23573, AP23841, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epithiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethylrapamycin, or 42-0-(2-hydroxy)ethyl rapamycin. 
     
     
         25 . The kit of  claim 22 , further comprising at least one additional compound comprised in the first sealed container or in a second sealed container. 
     
     
         26 . The kit of  claim 25 , wherein said at least one additional compound is vitamin E, vitamin A, an antibacterial antibiotic, an antioxidant, L-camitine, lipoic acid, metformine, resveratrol, 20 leptine, a non-steroid anti-inflammatory drug, or a COX inhibitor.