Composition and method for the treatment of neurological diseases and cerebral injury

Abstract

Methods and compositions which include or include the administration of a hydrophobic drug, prodrug thereof, salt thereof, isoform thereof, or a combination thereof; cyclodextrin, prodrug thereof, salt thereof, or a combination thereof; polyethylene glycol, propylene glycol, or combination thereof; and optionally, a pharmaceutically acceptable carrier.

What is claimed is: 
     
         1 . A method for treating or preventing a disease or injury, comprising administering to a subject a composition, comprising:
 a hydrophobic drug, prodrug thereof, salt thereof, isoform thereof, or a combination thereof;   cyclodextrin, prodrug thereof, salt thereof, or a combination thereof;   polyethylene glycol, propylene glycol, or combination thereof; and   optionally, a pharmaceutically acceptable carrier.   
     
     
         2 . The method of  claim 1 , wherein the hydrophobic drug is an HDAC inhibitor. 
     
     
         3 . The method of  claim 1 , wherein the hydrophobic drug is a Class I, Class IIa, Class IIb, or Class IV HDAC inhibitor, or a combination thereof. 
     
     
         4 . The method of  claim 1 , wherein the hydrophobic drug is a Class I or Class II HDAC inhibitor, or a combination thereof. 
     
     
         5 . The method of  claim 1 , wherein the hydrophobic drug is vorinostat. 
     
     
         6 . The method of  claim 1 , wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, dimethyl-β-cyclodextrin, hydroxypropyl-α-cyclodextrin, or hydropropyl-γ-cyclodextrin, or a combination thereof. 
     
     
         7 . The method of  claim 1 , wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin. 
     
     
         8 . The method of  claim 1 , wherein the hydrophobic drug is administered in an amount of 0.1-500 mg/kg. 
     
     
         9 . The method of  claim 1 , wherein the cyclodextrin is administered in an amount of 1000-40,000 mg/kg. 
     
     
         10 . The method of  claim 1 , wherein the composition comprises a hydrophobic drug:cyclodextrin:polyethylene glycol or propylene glycol molar ratio of 1-100:1-1000:1-1000. 
     
     
         11 . The method of  claim 1 , wherein the hydrophobic drug is vorinostat, and the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin. 
     
     
         12 . The method of  claim 1 , wherein the composition comprises the pharmaceutically acceptable carrier. 
     
     
         13 . The method of  claim 1 , comprising polyethylene glycol. 
     
     
         14 . The method of  claim 1 , wherein the disease or injury is one or more of disease of the brain, cerebral injury, brain and systemic disease, brain and systemic disease for which the liver read out, neurological disease, cerebral injury, disease associated with loss or reduction of level of calbindin, neurotoxicity, Niemann-Pick disease, Niemann-Pick Type C disease, neurodegenerative disorder, TBI, autism, Alzheimer's, cutaneous T cell lymphoma, B cell lymphoma, inflammatory disorder, neuroinflammatory disorder, neuroinflammation due to lysosomal storage disorder, lysosomal storage disorder, Sezary syndrome, Gliobastoma multiforme, Myeloddysplastic syndrome, non small cell lung cancer, HIV, non-neurological disease, brain tumor, disease responsive to treatment with histone deacetylase (HDAC) inhibitor, disease involving plasma concentration of vorinostat (SAHA), disease responsive to treatment with SAHA, disease where effect of SAHA is observed in animal model, encephalopathy, epilepsy, cerebrovascular disease, disease responsive to penetration of drug through the blood-brain barrier, Parkinsons, Amyotrophic Lateral Sclerosis, activator deficiency/GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, Gaucher's disease, Gaucher disease (types I-III), GM1 gangliosidosis, I-cell disease/mucolipidosis II, infantile free sialic acid storage disease/ISSD, juvenile hexosaminidase A deficiency, Krabbe disease, metachromatic leukodystrophy, mucopolysaccharidoses disorders, pseudo-Hurler polydystrophy/mucolipidosis IIIA, MPSI Hurler syndrome, MPSI Scheie syndrome, MPS I Hurler-Scheie syndrome, MPS II Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, MPS IX hyaluronidase deficiency, MPS VI Maroteaux-Lamy, MPS VII Sly syndrome, mucolipidosis I/sialidosis, multiple sulfatase deficiency, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, Salla disease, Tay-Sachs, Wolman disease, advanced solid tumors, treatment-resistant multiple myeloma, chronic lymphocytic leukemia or lymphoma, advanced hematological indications, multiple myeloma, solid refractory tumors, polycythemia vera, essential thrombocythemia, myelofibrosis, acute myocardial infarction, pancreatic cancer, cervical cancer, ovarian cancer, spinal muscular atrophy, relapsed ovarian cancer, follicular lymphoma, Huntington's disease, Hodgkin lymphoma, acute myeloid leukemia, sarcoma, lymphoma, lung cancer, breast cancer, recurrent or metastatic prostate cancer, hepatocellular carcinoma, ovarian cancer spleen metastasis, or a combination thereof. 
     
     
         15 . A pharmaceutical composition, comprising:
 a hydrophobic drug, prodrug thereof, salt thereof, isoform thereof, or a combination thereof;   cyclodextrin, prodrug thereof, salt thereof, or a combination thereof,   polyethylene glycol, propylene glycol, or combination thereof; and   optionally, a pharmaceutically acceptable carrier.   
     
     
         16 . The composition of  claim 15 , wherein the composition comprises a hydrophobic drug:cyclodextrin:polyethylene glycol or propylene glycol molar ratio of 1-100:1-1000:1-1000. 
     
     
         17 . The composition of  claim 15 , wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin. 
     
     
         18 . The composition of  claim 15 , wherein the hydrophobic drug is vorinostat. 
     
     
         19 . The composition of  claim 15 , wherein the polyethylene glycol or polypropylene glycol is polyethylene glycol. 
     
     
         20 . A pharmaceutical composition, comprising:
 a hydrophobic drug, prodrug thereof, salt thereof, isoform thereof, or a combination thereof;   cyclodextrin, prodrug thereof, salt thereof, or a combination thereof;   polyethylene glycol, propylene glycol, or combination thereof; and   optionally, a pharmaceutically acceptable carrier;   wherein the hydrophobic drug is present in an administration amount of 0.1-500 mg/kg; and   wherein cyclodextrin is present in an administration amount of 1000-40,000 mg/kg.