Controlled release galantamine composition

Abstract

The present invention is concerned with controlled release compositions for oral administration comprising galantamine; and with processes of preparing such controlled release compositions.

1 . A controlled release formulation comprising particles comprising galantamine or a pharmaceutically acceptable acid addition salt thereof as the active ingredient and a water soluble pharmaceutically acceptable excipient, said particles being coated by a release rate controlling membrane coating.  
     
     
         2 . A formulation according to  claim 1  wherein the active ingredient is galantamine hydrobromide (1:1).  
     
     
         3 . A formulation according to  claim 1  wherein the water soluble excipient is a film forming polymer.  
     
     
         4 . A formulation according to  claim 3  wherein the water soluble film forming polymer is a polymer that has an apparent viscosity of 1 to 100 mPa·s when dissolved in a 2% aqueous solution at 20° C. solution.  
     
     
         5 . A formulation according to  claim 4  wherein the water soluble polymer is selected from the group comprising 
 alkylcelluloses such as methylcellulose,    hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose,    hydroxypropylcellulose and hydroxybutylcellulose,    hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose,    carboxyalkylcelluloses such as carboxymethylcellulose,    alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose,    carboxyalkylalkylcelluloses such as carboxymethylethylcellulose,    carboxyalkylcellulose esters,    starches,    pectines such as sodium carboxymethylamylopectine,    chitine derivates such as chitosan,    polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, traganth, agar-agar, gummi arabicum, guar gummi and xanthan gummi,    polyacrylic acids and the salts thereof,    polymethacrylic acids and the salts thereof, methacrylate copolymers,    polyvinylalcohol,    polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate    polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.    
     
     
         6 . A formulation according to  claim 5  wherein the water soluble polymer is hydroxypropyl methylcellulose HPMC 2910 5 mPa·s.  
     
     
         7 . A formulation according to  claim 6  wherein the weight-by-weight ratio of hydroxypropyl methylcellulose HPMC 2910 5 mPa·s to galantamine is in the range of 17:1 to 1:5.  
     
     
         8 . A formulation according to  claim 2  wherein galantamine hydrobromide (1:1) and the water soluble, film forming polymer are layered or coated on an inert sphere.  
     
     
         9 . A formulation according to  claim 8  wherein the inert spheres are 16-60 mesh (1,180-250 μm) sugar spheres.  
     
     
         10 . A formulation according to  claim 1  wherein the release rate controlling membrane coating comprises a water insoluble polymer and optionally a plasticizer.  
     
     
         11 . A formulation according to  claim 10  wherein the water insoluble polymer is ethylcellulose and the plasticizer is selected from the group consisting of dibutyl sebacate, diethyl phthalate and triethyl citrate.  
     
     
         12 . A formulation according to  claim 11  wherein the weight of the release rate controlling membrane coating ranges from 3% to 15% of the uncoated particle.  
     
     
         13 . A formulation according to  claim 1  wherein a seal coat lies between the drug core and the release rate controlling membrane coating.  
     
     
         14 . A formulation according to  claim 1  further comprising a topcoat comprising galantamine and water-soluble polymer.  
     
     
         15 . A formulation according to  claim 14  capable of releasing in USP buffer pH 6.8 at 37° C. in an Apparatus 2 (USP 23, <711> Dissolution, pp 1791-1793, paddle, 50 rpm) from 20 to 40% of the total amount of galantamine.HBr in 1 hour, and more than 80% of the total amount of galantamine.HBr in 10 hours  
     
     
         16 . A dosage form comprising a therapeutically effective amount of the controlled release formulation of  claim 1 .  
     
     
         17 . A dosage form according to  claim 16  which delivers a therapeutically effective amount of galantamine to a patient during the 24 hours following a single once daily administration.  
     
     
         18 . A dosage form according to  claim 16  wherein part of the galantamine is present in an immediate release form.  
     
     
         19 . A dosage form according to  claim 18  wherein said immediate release form comprises particles as lacking the release rate controlling membrane.  
     
     
         20 . A dosage form according to  claim 18  wherein said immediate release form comprises immediate release minitablets.  
     
     
         21 . A dosage form according to  claim 18  wherein said immediate release form comprises a topcoat comprising galantamine or a pharmaceutically acceptable salt thereof and a water-soluble polymer.  
     
     
         22 . A dosage form according to  claim 16  providing a mean maximum plasma concentration of galantamine from 10 to 60 ng/ml and a mean minimum plasma concentration from 3 to 15 ng/ml after repeated administration every day through steady-state conditions.  
     
     
         23 . (canceled)  
     
     
         24 . (canceled)  
     
     
         25 . (canceled)  
     
     
         26 . A process of preparing a formulation according to  claim 1  comprising admixing galantamine or a pharmaceutically acceptable salt form thereof with a water soluble excipient to form a drug core, and thereafter applying the release rate controlling membrane coating.  
     
     
         27 . A method of treating Alzheimer's dementia and related dementias in a human while substantially reducing adverse effects associated with acetyl cholinesterase inhibitors, comprising administering to a human in need of such treatment, a therapeutically effective amount of the controlled release formulation as claimed in  claim 1 , said amount being sufficient to alleviate said Alzheimer's dementia and related dementias, but insufficient to cause said adverse effects.  
     
     
         28 . A method according to  claim 27  wherein the related dementia belongs to the group consisting of vascular dementia, Lewy body disease, autism, mental retardation, bipolar disorder psychiatric conditions, disruptive behaviour, attention deficient, hyperactivity disorder, substance abuse, and extreme aggression, especially conduct disorder.  
     
     
         29 . A method according to  claim 27  wherein the adverse effects is selected from the group consisting of nausea, vomiting, sweating, restlessness, and insomnia.  
     
     
         30 . A method according to  claim 27 , wherein the adverse effects is selected from the group consisting of nausea and vomiting.  
     
     
         31 . A method of treating Alzheimer's disease in a human while substantially reducing adverse effects associated with acetyl cholinesterase inhibitors comprising administering to a human in need of such treatment a therapeutically effective amount of the formulation of  claim 1 .  
     
     
         32 . A method according to  claim 31 , wherein the adverse effects is selected from the group consisting of nausea and vomiting.  
     
     
         33 . A formulation according to  claim 1 , wherein the formulation provides a therapeutically effective amount of the active ingredient while substantially reducing an adverse effect selected from the group consisting of nausea and vomiting upon administration of the formulation to a human.  
     
     
         34 . A formulation according to  claim 1 , wherein the formulation provides a therapeutically effective amount of the active ingredient while substantially reducing adverse effects of nausea upon administration of the formulation to a human.  
     
     
         35 . A formulation according to  claim 1 , wherein the formulation provides a therapeutically effective amount of the active ingredient while substantially reducing adverse effects of vomiting upon administration of the formulation to a human.  
     
     
         36 . A dosage form according to  claim 16 , wherein the dosage form provides a therapeutically effective amount of the active ingredient while substantially reducing an adverse effect selected from the group consisting of nausea and vomiting upon administration of the dosage form to a human.  
     
     
         37 . A dosage form according to  claim 16 , wherein the dosage form provides a therapeutically effective amount of the active ingredient while substantially reducing adverse effects of nausea upon administration of the dosage form to a human.  
     
     
         38 . A dosage form according to  claim 16 , wherein the dosage form provides a therapeutically effective amount of the active ingredient while substantially reducing adverse effects of vomiting upon administration of the dosage form to a human.