Enhanced brain bioavailability of galantamine by selected formulations and transmucosal administration of lipophilic prodrugs

Abstract

A method of treating a subject for a brain disease associated with cognitive impairment, including administering to a subject a chemical substance according to GLN-1062 or salt thereof: wherein the GLN-1062 or salt thereof is in a multi-layered tablet with a digestive acid resistant coating.

What is claimed is: 
     
         1 . A method of treating a subject for a brain disease associated with cognitive impairment, comprising administering to the subject a therapeutically effective amount of GLN 1062 or salt thereof in a multi-layered tablet with a digestive acid resistant coating. 
     
     
         2 . The method according to  claim 1 , wherein the digestive acid resistant coating comprises a poly(meth)acrylate coating. 
     
     
         3 . The method according to  claim 1 , wherein the tablet comprises a tablet core, wherein said core comprises a therapeutically effective amount of GLN 1062 or salt thereof, microcrystalline cellulose (MCC), corn starch, hydroxypropyl methylcellulose (HPMC), and magnesium stearate. 
     
     
         4 . The method according to  claim 1 , wherein the tablet comprises a tablet core, wherein said core comprises microcrystalline cellulose (MCC), and wherein the tablet comprises an active pharmaceutical ingredient layer (API layer) comprising a therapeutically effective amount of GLN 1062 or salt thereof and hydroxypropyl methylcellulose (HPMC). 
     
     
         5 . The method according to  claim 1 , wherein GLN1062 is administered as a salt. 
     
     
         6 . The method according to  claim 4 , wherein the salt comprises stoichiometric and/or non-stoichiometric salts and/or hydrates of GLN 1062, whereby the salt is described as: GLN 1062·n HX·m H2O; wherein n, m=0-5 and n and m can be the same or different, and HX=an acid. 
     
     
         7 . The method according to  claim 4 , wherein the GLN1062 salt has a solubility in water of at least 10% weight per volume (w/v). 
     
     
         8 . The method according to  claim 4 , wherein the GLN1062 salt is a gluconate salt, saccharate salt, maleate salt, or lactate salt. 
     
     
         9 . The method according to  claim 1 , wherein GLN1062 or salt thereof is administered at a dosage of 1 to 100 mg one to three times daily. 
     
     
         10 . The method according to  claim 1 , wherein the brain disease to be treated is selected from the group consisting of Alzheimer's disease, Parkinson's disease, dementia, schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy, oxygen and nutrient deficiencies in the brain after hypoxia, anoxia, asphyxia, cardiac arrest, chronic fatigue syndrome, poisoning, anaesthesia, spinal cord disorders, central inflammatory disorders, postoperative delirium, subsyndromal postoperative delirium, neuropathic pain, abuse of alcohol and drugs, addictive alcohol and nicotine craving, and effects of radiotherapy. 
     
     
         11 . A method of treating a subject for a brain disease associated with cognitive impairment, comprising administering to the subject a therapeutically effective amount of GLN 1062 or salt thereof via transmucosal administration, selected from intranasal, sublingual or buccal administration, in an emulsion or self-microemulsifying drug delivery (SMEDD) system. 
     
     
         12 . The method according to  claim 11 , wherein the emulsion or SMEDD comprises additionally one or more surfactants, oils and co-surfactants and is prepared under stirring and/or ultrasound. 
     
     
         13 . The method according to  claim 11 , wherein the emulsion or SMEDD comprises additionally glyceryl caprylate, polyethyleneglycol, propyleneglycol and/or diethyleneglycolemonoethylether. 
     
     
         14 . The method according to  claim 11 , wherein GLN1062 is administered as a salt. 
     
     
         15 . The method according to  claim 14 , wherein the salt comprises stoichiometric and/or non-stoichiometric salts and/or hydrates of GLN 1062, whereby the salt is described as: GLN 1062·n HX·m H2O; wherein n, m=0-5 and n and m can be the same or different, and HX=an acid. 
     
     
         16 . The method according to  claim 14 , wherein the GLN1062 salt has a solubility in water of at least 10% weight per volume (w/v). 
     
     
         17 . The method according to  claim 14 , wherein the GLN1062 salt is a gluconate salt, saccharate salt, maleate salt, or lactate salt. 
     
     
         18 . The method according to  claim 11 , wherein GLN1062 or salt thereof is administered at a dosage of 1 to 100 mg one to three times daily. 
     
     
         19 . The method according to  claim 11 , wherein the brain disease to be treated is selected from the group consisting of Alzheimer's disease, Parkinson's disease, dementia, schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy, oxygen and nutrient deficiencies in the brain after hypoxia, anoxia, asphyxia, cardiac arrest, chronic fatigue syndrome, poisoning, anaesthesia, spinal cord disorders, central inflammatory disorders, postoperative delirium, subsyndromal postoperative delirium, neuropathic pain, abuse of alcohol and drugs, addictive alcohol and nicotine craving, and effects of radiotherapy. 
     
     
         20 . A method of treating a subject for a brain disease associated with cognitive impairment, comprising administering to the subject a therapeutically effective amount of GLN 1062 or salt thereof via transmucosal administration, selected from intranasal, sublingual or buccal administration, in a micronized powder formulation. 
     
     
         21 . The method according to  claim 11 , wherein the micronized powder formulation comprises nanocrystals of GLN 1062 and polymeric micro-particles to which GLN 1062 is adsorbed. 
     
     
         22 . The method according to  claim 11 , wherein the micronized powder formulation is obtained by co-precipitation of polymer and GLN 1062, by pearl milling and homogenization in water. 
     
     
         23 . The method according to  claim 11 , wherein GLN1062 is administered as a base. 
     
     
         24 . The method according to  claim 1 , wherein GLN1062 or salt thereof is administered at a dosage of 1 to 100 mg one to three times daily. 
     
     
         25 . The method according to  claim 1 , wherein the brain disease to be treated is selected from the group consisting of Alzheimer's disease, Parkinson's disease, dementia, schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy, oxygen and nutrient deficiencies in the brain after hypoxia, anoxia, asphyxia, cardiac arrest, chronic fatigue syndrome, poisoning, anaesthesia, spinal cord disorders, central inflammatory disorders, postoperative delirium, subsyndronal postoperative delirium, neuropathic pain, abuse of alcohol and drugs, addictive alcohol and nicotine craving, and effects of radiotherapy.