Intravenous Infusion of Curcumin and a Calcium Channel Blocker

Abstract

Compositions and methods for treating systemic diseases by intravenous administration of formulations of synthesized curcumin (diferuloylmethane) and concomitantly a calcium channel blocker to human subjects with neoplastic and neurodegenerative diseases are disclosed herein. The diseases are treated by prolonged administration of sub-optimal doses of liposomal curcumin or polymeric nanocurcumin or the sustained release curcumin from PLGA nanocurcumin at dosages below systemic hemolytic thresholds concomitantly with or without calcium channel blockers.

What is claimed is:  
     
         1 . A formulated pharmaceutical composition comprising
 a therapeutically effective amount of an intravenous formulation of curcumin enveloped by a polylactic glycolic acid (PLGA) copolymer and a layer of lipids to form a liposome.   
     
     
         2 . The composition of  claim 1 , wherein the composition is adapted for administration in a human subject for a treatment of one or more proliferative selected from the group consisting of neoplastic disorders, neurodegenerative diseases, drug induced tardif dyskinesia, parasitic diseases and abnormal ophthalmic disorders such as cataract and macular degeneration. 
     
     
         3 . The composition of  claim 2 , wherein the neoplastic disorders comprise breast cancer, uterine cancer, cervical cancer, ophthalmic tumors, brain tumors, and pancreatic cancer. 
     
     
         4 . The composition of  claim 2 , wherein the neurodegenerative diseases comprise neuropathologic disorders, Parkinson's disease, Alzheimer's disease (AD), senile dementia, vascular dementias, Pick's disease, and Creutzfeldt-Jacobs disease. 
     
     
         5 . The composition of  claim 1 , wherein the composition further comprises one or more calcium channel blockers selected from at least one of verapamil, ethylisopropylameloride, niflamic acid, NPPB, dihydropyridines, phenylalkylamines, Benzothiozepines, Diltiazem, nonselective blockers comprising mibefradil, bepridil, fendeline, fluspirilene, catecholamines, and erythropoietin agents. 
     
     
         6 . The composition of  claim 1 , wherein the curcumin is a synthetic curcumin. 
     
     
         7 . The composition of  claim 1 , wherein the composition comprises one or more optional pharmaceutically acceptable excipients, diluents, extended or controlled release agents, lubricants, preservatives or any combinations thereof. 
     
     
         8 . The composition of  claim 1 , wherein the polymer further comprises another polymer selected from at least one of polyesters, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyorthoesters, polyphosphoesters, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), copolymers, terpolymers, and combinations or mixtures thereof. 
     
     
         9 . A method comprising intravenous administration to a subject of a therapeutically effective amount of an intravenous composition of curcumin, wherein the synthesized curcumin is enveloped by a polylactic glycolic acid (PLGA) copolymer and a layer of lipids to form a liposome. 
     
     
         10 . The method of  claim 9 , further comprising the step of providing a calcium channel blocker prior to or concomitantly with the synthesized curcumin. 
     
     
         11 . The method of  claim 10 , wherein the one or more calcium channel blockers are selected from the group consisting of verapamil, ethylisopropylameloride, niflamic acid, NPPB, dihydropyridines, phenylalkylamines, Benzothiozepines, Diltiazem, nonselective blockers comprising mibefradil, bepridil, fendeline, fluspirilene, catecholamines, and erythropoietin agents. 
     
     
         12 . A method of treating a subject afflicted with one or more proliferative disorders comprising the steps of:
 identifying the subject in need of treatment against the one or more proliferative disorders; and   administering a therapeutically effective amount of an intravenous formulation of curcumin enveloped by a polylactic glycolic acid (PLGA) copolymer and a layer of lipids to form a liposome sufficient to treat the proliferative disorder.   
     
     
         13 . The method of  claim 12 , wherein the one or more proliferative diseases comprise breast, uterine cervical, ophthalmic and pancreatic cancer. 
     
     
         14 . The method of  claim 12 , wherein the formulation mitigates a curcumin induced red blood cell (RBC) hemolysis. 
     
     
         15 . The method of  claim 12 , wherein the liposomal curcumin is infused continuously for 1-72 hours weekly for four weeks, or for 24 hours every other day weekly for 12 doses in combination with a calcium channel blocker. 
     
     
         16 . The method of  claim 12 , wherein the liposomal curcumin is infused for 1 hour weekly for four weeks in combination with a calcium channel blocker. 
     
     
         17 . The method of  claim 12 , further comprising the step of providing a calcium channel blocker selected from at least one of verapamil, ethylisopropylameloride, niflamic acid, NPPB, dihydropyridines, phenylalkylamines, Benzothiozepines, Diltiazem, nonselective blockers comprising mibefradil, bepridil, fendeline, fluspirilene, catecholamines, and erythropoietin agents. 
     
     
         18 . A method of treating one or more diseases or conditions in a subject comprising the steps of:
 identifying the subject in need of treatment against the disease or the condition; and   administering a therapeutically effective amount of an intravenous formulation of curcumin enveloped by a polylactic glycolic acid (PLGA) copolymer and a layer of lipids to form a liposome.   
     
     
         19 . The method of  claim 18 , wherein the disease or the condition comprises proliferative diseases selected from the group consisting of breast cancer, uterine cancer, cervical cancer, ophthalmic tumors, brain tumors, pancreatic cancer, neuropathologic disorders, Parkinson's disease, drug induced tardif dyskinesia, parasitic diseases, and abnormal ophthalmic disorders such as cataract and macular degeneration. 
     
     
         20 . A method of treating a tumor in a human subject comprising the step of:
 identifying the subject in need of the treatment against the tumor; and   administering a therapeutically effective amount of an intravenous formulation of curcumin enveloped by a polylactic glycolic acid (PLGA) copolymer and a layer of lipids to form a liposome to treat the tumor.   
     
     
         21 . The method of  claim 20 , wherein the conjugate is adapted for administration in situ into a breast for treatment of a ductal carcinoma, into an aqueous humor of an eye for the treatment of a retinoblastoma or uveal melanoma, for intravesicular administration for the treatment of a bladder cancer or for direct application to an uterine cervix marked by a dysplasia or a cancer. 
     
     
         22 . A method of treating an ophthalmic tumor, an age related condition comprising macular degeneration and cataract or both in a subject comprising the step of:
 identifying the subject in need of treatment against the tumor or the age related condition; and   administering a therapeutically effective amount of an intravenous formulation of curcumin enveloped by a polylactic glycolic acid (PLGA) copolymer and a layer of lipids to form a liposome for the treatment of the tumor or the age related condition.