Mebendazole polymorph for treatment and prevention of tumors

Abstract

Mebendazole is an antiparasitic drug with over 40 years of safe use. Recently mebendazole was repurposed for glioblastoma therapy. Three polymorphs of mebendazole exist, but the relative polymorph content for existing drugs varies, and the therapeutic anti-cancer relevance of the different polymorphs was unknown. As an oral drug mebendazole polymorph C is a superior form, and it reaches the brain and brain tumors in effective concentrations. Efficacy is further improved by combining mebendazole with a P-glycoprotein inhibitor. Mebendazole may also be used for therapy of other cancers, as well as a chemo-preventative agent.

We claim: 
     
         1 . A pharmaceutical formulation of mebendazole wherein at least 90% of the mebendazole in the formulation is polymorph C, and wherein the formulation is granulated. 
     
     
         2 . The pharmaceutical formulation of  claim 1  wherein the granulated formulation is coated. 
     
     
         3 . The pharmaceutical formulation of  claim 1  wherein is at least 95% of all mebendazole in the formulation is polymorph C. 
     
     
         4 . The pharmaceutical formulation of  claim 1  wherein is at least 98% of all mebendazole in the formulation is polymorph C. 
     
     
         5 . The pharmaceutical formulation of  claim 1  wherein is at least 99% of all mebendazole in the formulation is polymorph C. 
     
     
         6 . The pharmaceutical formulation of  claim 1  further comprising an inhibitor of P-glycoprotein. 
     
     
         7 . The pharmaceutical formulation of  claim 6  wherein the inhibitor of P-glycoprotein is elacridar. 
     
     
         8 . The pharmaceutical formulation of  claim 1  further comprising a non-steroidal anti-inflammatory drug (NSAID). 
     
     
         9 . The pharmaceutical formulation of  claim 8  wherein the NSAID is sulindac. 
     
     
         10 . A pharmaceutical formulation of mebendazole comprising polymorph C and an inhibitor of P-glycoprotein. 
     
     
         11 . The pharmaceutical formulation of  claim 10  wherein the formulation is granulated. 
     
     
         12 . The pharmaceutical formulation of  claim 11  wherein the formulation is coated. 
     
     
         13 . The pharmaceutical formulation of  claim 10  wherein the inhibitor of P-glycoprotein is elacridar. 
     
     
         14 . A pharmaceutical formulation of mebendazole and an NSAID. 
     
     
         15 . The pharmaceutical formulation of  claim 14  wherein the formulation is granulated. 
     
     
         16 . The pharmaceutical formulation of  claim 15  wherein the formulation is coated. 
     
     
         17 . The pharmaceutical formulation of  claim 14  wherein the NSAID is sulindac. 
     
     
         18 . The pharmaceutical formulation of  claim 14  wherein the mebendazole comprises polymorph C. 
     
     
         19 . A method of administering the pharmaceutical formulation of one of  claims 1 ,  10 , and  14 , comprising:
 applying the formulation to food prior to ingestion of the food.   
     
     
         20 . The method of  claim 19  wherein the food comprises lipids. 
     
     
         21 . The method of  claim 19  wherein the pharmaceutical composition comprises a P-glycoprotein inhibitor and the P-glycoprotein inhibitor is elacridar. 
     
     
         22 . The method of  claim 19  wherein the pharmaceutical composition comprises an NSAID and the NSAID is sulindac. 
     
     
         23 . The method of  claim 19  wherein the food is ingested by a cancer patient. 
     
     
         24 . The method of  claim 19  wherein the food is ingested by a cancer patient with a brain tumor. 
     
     
         25 . The method of  claim 19  wherein the food is ingested by a cancer patient with a one of breast, colorectal cancer, and lung tumor. 
     
     
         26 . The method of  claim 19  wherein the food is ingested by a cancer patient with a tumor that has a multidrug resistant pump. 
     
     
         27 . The method of  claim 19  wherein the food is ingested by an individual at elevated risk of developing colorectal cancer. 
     
     
         28 . The method of  claim 27  wherein the individual has familial adenomatous polyposis. 
     
     
         29 . The method of  claim 27  wherein the individual has non-hereditary polyposis coli. 
     
     
         30 . A method to monitor anti-cancer potency of a pharmaceutical formulation of mebendazole, comprising:
 assaying the pharmaceutical formulation and determining amount of polymorph C and amount of polymorph A.   
     
     
         31 . The method of  claim 30  wherein the step of assaying comprises infrared spectroscopy. 
     
     
         32 . The method of  claim 30  wherein the step of assaying is performed at a plurality of times. 
     
     
         33 . A method of treating, or reducing risk of developing, a tumor in a human comprising:
 administering to the human or dispensing for oral ingestion by the human the pharmaceutical formulation of one of  claims 1 ,  10 , and  14 .   
     
     
         34 . The method of  claim 33  wherein the tumor is a brain tumor. 
     
     
         35 . The method of  claim 34  wherein the brain tumor is a medulloblastoma. 
     
     
         36 . The method of  claim 34  wherein the brain tumor is a glioma. 
     
     
         37 . The method of  claim 33  wherein the tumor is selected from the group consisting of breast, colorectal, and lung tumors. 
     
     
         38 . The method of  claim 33  wherein the tumor has a multidrug resistant pump. 
     
     
         39 . A kit for treating or reducing risk of tumors, comprising:
 mebendazole; and   an inhibitor of P-glycoprotein or a non-steroidal, anti-inflammatory drug.   
     
     
         40 . The kit of  claim 39  wherein the mebendazole comprises polymorph C. 
     
     
         41 . The kit of  claim 39  wherein the polymorph C comprises at least 90% of all mebendazole in the kit. 
     
     
         42 . The kit of  claim 39  which comprises an inhibitor of P-glycoprotein. 
     
     
         43 . The kit of  claim 39  which comprises an NSAID. 
     
     
         44 . The kit of  claim 42  wherein the inhibitor of P-glycoprotein is elacridar. 
     
     
         45 . The kit of  claim 43  wherein the NSAID is sulindac. 
     
     
         46 . A method of treating or reducing risk of a tumor in a human comprising:
 administering or dispensing to the human for oral ingestion:
 polymorph C of mebendazole, and 
 an inhibitor of P-glycoprotein or a non-steroidal, anti-inflammatory drug. 
   
     
     
         47 . The method of  claim 46  wherein an inhibitor of P-glycoprotein is administered or dispensed. 
     
     
         48 . The method of  claim 47  wherein the inhibitor of P-glycoprotein is elacridar. 
     
     
         49 . The method of  claim 46  wherein the polymorph C comprises at least 90% of all mebendazole administered. 
     
     
         50 . The method of  claim 46  wherein a brain tumor is treated. 
     
     
         51 . The method of  claim 50  wherein the brain tumor is a medulloblastoma. 
     
     
         52 . The method of  claim 50  wherein the brain tumor is a glioma. 
     
     
         53 . The method of  claim 46  wherein a tumor is treated, said tumor selected from the group consisting of breast, colorectal, and lung tumors. 
     
     
         54 . The method of  claim 53  wherein the tumor has a multidrug resistant pump. 
     
     
         55 . The method of  claim 46  wherein a NSAID is administered or dispensed. 
     
     
         56 . The method of  claim 55  wherein the NSAID is sulindac. 
     
     
         57 . The method of  claim 46  wherein the human has an elevated risk of developing a cancer. 
     
     
         58 . The method of  claim 46  wherein the human has an elevated risk of developing a colorectal cancer. 
     
     
         59 . A method of reducing risk of a tumor in a human comprising:
 administering or dispensing to the human for oral ingestion:
 mebendazole, and 
 a non-steroidal, anti-inflammatory drug.