Methods and Compositions for Delivery of Catecholic Butanes for Treatment of Tumors

Abstract

The present invention provides kits, methods and compositions for the treatment of diseases such as cancers. The compositions herein contain a substantially pure preparation of at least one catecholic butane, including, for example, NDGA compounds in a pharmaceutically acceptable carrier or excipient. The catecholic butane such as NDGA or its derivatives are administered to one or more subjects in need of treatment by a route other than direct injection into the affected tissues or topical application on affected tissues.

1 . A method for treatment of a disease in a subject comprising:
 (a) providing a composition comprising at least one catecholic butane other and a pharmaceutically acceptable carrier or excipient, wherein the wherein the catecholic butane has the formula:   
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently —H, a lower alkyl, a lower acyl, an alkylene or an unsubstituted or substituted amino acid residue or salt thereof; 
         R 3 , R 4 , R 5 , R 6 , R 10 , R 11 , R 12  and R 13  are independently —H or a lower alkyl; and 
         R 7 , R 8  and R 9  are independently —H, —OH, a lower alkoxy, a lower acyloxy, or any two adjacent groups together may be an alkyene dioxy, or an unsubstituted or substituted amino acid residue or salt thereof, provided that the catecholic butane is not NDGA.
 (b) administering the composition to the subject systemically by a route of administration selected from the group consisting of: oral administration; inhalation administration; intra-arterial administration, with or without occlusion; intracranial administration; intraventricular administration; intravenous administration; intramuscular administration; implantation administration; and central venous administration. 
 (c) wherein the disease is selected from the group consisting of: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, astrocytoma, bile duct cancer, bladder cancer, bone cancer osteosarcoma/malignant fibrous histiocytoma, brain stem glioma, brain tumor ependymoma, brain tumor medulloblastoma, breast cancer, carcinoid tumor gastrointestinal, carcinoma adrenocortical, carcinoma islet cell, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, clear cell sarcoma of tendon sheaths, colon cancer, cutaneous T-cell lymphoma, endometrial cancer, epithelial cancer ovarian, esophageal cancer, Ewing's family of tumors, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, eye cancer retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, germ cell tumor extragonadal, germ cell tumor, ovarian tumor, gestational trophoblastic tumor, glioma, hairy cell leukemia, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell carcinoma (endocrine pancreas), Kaposi's sarcoma, laryngeal cancer, leukemia acute lymphoblastic cancer, leukemia acute myeloid cancer, leukemia chronic lymphocytic cancer, leukemia chronic myelogenous cancer, leukemia hairy cell cancer, liver cancer, lung cancer non-small cell, lung cancer small cell, male breast cancer, malignant mesothelioma, medulloblastoma, melanoma, merkel cell carcinoma, multiple endocrine neoplasia syndrome, mycosis fungoides, myeloma multiple, nasal cavity, paranasal and sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and lip cancer, oropharyngeal cancer, osteosarcoma/malignant fibrous histiocytoma of bone, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, parathyroid cancer, penile cancer, pheochromocytoma, pineal and supratentorial primitive neuroectodermal tumors, pituitary tumor, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal, pelvis and ureter transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma soft tissue adult, Sezary syndrome, skin cancer, small intestine cancer, stomach (gastric) cancer, testicular cancer, thymoma, thyroid cancer, urethral cancer, uterine cancer endometrial, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor., other than an inflammatory disease; other than an inflammatory disease that is associated with microglial cell activation or stimulation., a proliferative disease., a proliferative disease is malignant, pre-malignant or benign cancer, a disease resulting from or is associated an infection selected from the group consisting of HIV infection, HPV infection and HSV infection. 
 
       
     
     
         2 . The method of  claim 1 , wherein the composition comprises a carrier or excipient selected from the group consisting of dimethyl sulfoxide (DMSO), phosphate buffered saline, saline, a lipid based formulation, a liposomal formulation, a nanoparticle formulation, a micellar formulation, a water soluble formulation, and a biodegradable polymer. 
     
     
         3 . The method of  claim 1 , wherein R 1  and R 2  are independently —CH 3 , —(C═O)CH 2 N(CH 3 ) 2  or —(C═O)CH 2 N + H(CH 3 ) 2 .Cl −  and R 8  and R 9  are independently —OCH 3 , —O(C═O)CH 2 N(CH 3 ) 2  or —O(C═O)CH 2 N + H(CH 3 ) 2 .Cl −  or wherein R 1  and R 2  are independently —CH 3  and R 8  and R 9  are independently —OCH 3 . 
     
     
         4 . The method of  claim 1 , wherein the pharmaceutically acceptable carrier or excipient comprises dimethyl sulfoxide or at least one dietary fat or oil selected from the group consisting of castor oil and peanut oil. 
     
     
         5 . The method of  claim 1 , wherein the composition is administered to a human in an amount of about 10 mg/kg to about 375 mg/kg per dose. 
     
     
         6 . The method of  claim 1 , wherein the composition is administered on a schedule selected from the group consisting of: daily, daily for 5 or more days to a week, daily for 5 or more days to 2 weeks, daily for 5 or more days to 3 weeks. 
     
     
         7 . A method of treating leukemia in a subject comprising:
 a) administering a composition consisting essentially of one catecholic and a pharmaceutically acceptable carrier or excipient, wherein the wherein the catecholic butane has the formula:   
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently —H, a lower alkyl, a lower acyl, an alkylene or an unsubstituted or substituted amino acid residue or salt thereof; 
         R 3 , R 4 , R 5 , R 6 , R 10 , R 11 , R 12  and R 13  are independently —H or a lower alkyl; and 
         R 7 , R 8  and R 9  are independently —H, —OH, a lower alkoxy, a lower acyloxy, or any two adjacent groups together may be an alkyene dioxy, or an unsubstituted or substituted amino acid residue or salt thereof, provided that the catecholic butane is not NDGA; and
 (b) administering the composition to the subject systemically by a route of administration selected from the group consisting of: oral administration; inhalation administration; 
 
         intra-arterial administration, with or without occlusion; intracranial administration; intraventricular administration; intravenous administration; intramuscular administration; implantation administration; and central venous administration. 
       
     
     
         8 . The method of  claim 7 , wherein R 1  and R 2  are independently —CH 3 , —(C═O)CH 2 N(CH 3 ) 2  or —(C═O)CH 2 N + H(CH 3 ) 2 .Cl −  and R 8  and R 9  are independently —OCH 3 , —O(C═O)CH 2 N(CH 3 ) 2  or —O(C═O)CH 2 N + H(CH 3 ) 2 .Cl −  or wherein R 1  and R 2  are independently —CH 3  and R 8  and R 9  are independently —OCH 3 . 
     
     
         9 . The method of  claim 7  wherein the leukemia is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia; hairy cell leukemia; leukemia acute myeloid cancer, leukemia chronic lymphocytic cancer, leukemia chronic myelogenous cancer, leukemia hairy cell cancer. 
     
     
         10 . The method of  claim 7 , wherein the pharmaceutically acceptable carrier or excipient is an oil. 
     
     
         11 . The method of  claim 7 , wherein the composition is administered on a schedule selected from the group consisting of: daily, daily for 5 or more days to a week, daily for 5 or more days to 2 weeks, daily for 5 or more days to 3 weeks. 
     
     
         12 . The method of  claim 7 , wherein the amount of chatecholic butane administered is at least 30 mg per dose. 
     
     
         13 . The method of  claim 7  wherein the amount of chatecholic butane administered is at least 90 mg per dose. 
     
     
         14 . The method of  claim 7 , wherein the chatecholic butane is present in the composition at a concentration of 20 mg/mL. 
     
     
         15 . The method of  claim 7 , wherein the pharmaceutically acceptable carrier or excipient comprises Cremaphor EL, ethanol and saline. 
     
     
         16 . The method of  claim 8 , wherein the Cremaphor EL concentration is 6%. 
     
     
         17 . The method of  claim 8 , wherein the ethanol concentration is 6%. 
     
     
         18 . The method of  claim 8 , wherein the composition administered to the subject comprises at least 2 mg of per dose. 
     
     
         19 . The method of  claim 8 , wherein the composition is administered to a human in an amount of about 10 mg/kg to about 375 mg/kg per dose. 
     
     
         20 . A method of treating leukemia in a subject comprising:
 a) administering a composition consisting essentially of tetra-O-methyl NDGA and a pharmaceutically acceptable carrier or excipient, and
 (b) administering the composition to the subject systemically by a route of administration selected from the group consisting of: oral administration; inhalation administration; intra-arterial administration, with or without occlusion; intracranial administration; intraventricular administration; intravenous administration; intramuscular administration; implantation administration; and central venous administration.