Hydrophilic/ lipophilic polymeric matrix dosage formulation

Abstract

An oral dosage form comprising a pharmaceutical tablet of one or more layers, one of which carries a biologically active substance; the formulation of said tablet includes different percentages of hydrophilic and lipophilic polymeric materials, and adjuvant substances. The tablets of the present invention show a release rate which is independent from the amounts of active substance present in the tablet.

1 . A multi-layer controlled-release tablet comprising: 
 (a) one active layer containing: (i) an active substance, (ii) hydrophilic polymeric substances which swell and/or gel and/or erode upon contact with aqueous liquids, (iii) lipophilic substances, and (iv) adjuvant substances, wherein the weight ratio of the hydrophilic polymeric substances to the lipophilic substances contained in said active layer is in the range of 10:1 to 0.5:1; and    (b) one or more barrier layers containing one or more of: hydrophilic polymeric substances which swell and/or gel and/or erode upon contact with aqueous liquids, lipophilic substances, and adjuvant substances.    
     
     
         2 . A multi-layer tablet as claimed in  claim 1 , in which the weight ratio of the hydrophilic polymeric substances to the lipophilic substances contained in said active layer is in the range of 7:1 to 1:1  
     
     
         3 . A multi-layer tablet as claimed in  claim 1  or  claim 2 , in which said hydrophilic polymeric substances (ii) are contained in a percentage between 1% and 75%, preferably between 5% and 65%, of the weight of the active layer.  
     
     
         4 . A multi-layer tablet as claimed in any one of  claims 1  to  3 , in which said lipophilic substances (iii). are contained in a percentage between 1% and 70%, preferably between 5 and 55% of the weight of said active layer.  
     
     
         5 . A multi-layer tablet as claimed in any one of  claims 1  to  4 , in which said adjuvants. (iv) are contained in a percentage between 5% to 50%, preferably from 10% to 40%, of the weight of said active layer.  
     
     
         6 . A multi-layer tablet as claimed in any one of  claims 1  to  5 , in which the weight ratio between said active substance (i) and said adjuvant substances (iv) in the active layer is in the range of 0.001:1 to 4:1, preferably from 0.003:1 to 3:1.  
     
     
         7 . A multi-layer tablet as claimed in any preceding claim, in which said one or more barrier layers are applied to one or both surfaces (bases) of the active layer.  
     
     
         8 . A multi-layer tablet as claimed in any preceding, claim, in which the weight ratio of hydrophilic swelling and/or gelling and/or erodible polymeric substances to lipophilic substances contained in the barrier layer is in the range of 1:1 to 7.5:1, suitably, from 1.5:1 to 4:1, and preferably between 2:1 and 3.5:1.  
     
     
         9 . A multi-layer tablet as claimed in any preceding claim, in which the active substance (i) is contained in a weight percentage between 0.01% to 70%, preferably between 0.05% to 50% by weight of the active layer.  
     
     
         10 . A multi-layer tablet as claimed in  claim 9 , in which the active substance (i) is contained in a percentage of 0.05% to 20% by weight of the active layer.  
     
     
         11 . A multi-layer tablet as claimed in any preceding claim, in which the active layer contains polymeric material with slow swelling and/or gelification and/or erosion and/or solubility properties.  
     
     
         12 . A multi-layer tablet as claimed in any preceding claim, in which the active layer further contains polymeric substances of a lipophilic nature.  
     
     
         13 . A multi-layer tablet as claimed in any preceding claim, in which said hydrophilic polymeric substances comprise a pharmaceutically acceptable biocompatible and/or biodegradable material, including non-cross-linked polyvinylpyrrolidone, hydroxypropylcellulose with a molecular weight of 100,000 to 4,000,000, sodium carboxymethylcellulose, carboxymethylstarch, potassium methacrylate-divinylbenzene copolymer, hydroxypropylmethylcellulose of molecular weight between 2,000 and 4,000,000, a polyethyleneglycol of molecular weight between 200 and 15,000, a polyoxyethylene with molecular weight of up to 20,000,000, a carboxyvinylpolymer, a poloxamer (polyoxyethylene-polyoxypropylene copolymer), a polyvinylalcohol, a glucane(glucan), a carrageenan, a scleroglucane (scleroglucan), a mannan, a galactomannan, gellans, xanthans, alginic acid and/or a derivative thereof, polyaminoacids, methyl vinyl ether/maleic anhydride copolymer, carboxymethylcellulose and/or a derivative thereof, ethylcellulose, methylcellulose, starch, a starch derivative, alpha, beta, or gamma cyclodextrin and/or a dextrin derivative.  
     
     
         14 . A multi-layer tablet as claimed in any preceding claim, in which said lipophilic substances include a natural fat (for example coconut, soya, cocoa) as such or totally or partially hydrogenated, beeswax, polyethoxylated beeswax, a mono-, bi- or tri-substituted glyceride, glyceryl palmitostearate, glyceryl behenate, diethyleneglycol palmitostearate, a polyethyleneglycol stearate, a polyoxyethyleneglycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, polyethyleneglycol palmitostearate, mono- or di-glyceryl behenate, a fatty alcohol associated with a polyethoxylate fatty alcohol, cetyl alcohol, stearic acid, a saturated or unsaturated fatty acid or a hydrogenated derivative thereof, and/or hydrogenated castor oil.  
     
     
         15 . A multi-layer tablet as claimed in any preceding claim, in which the active substance(s) are therapeutic agents for the treatment of chronic diseases, for example drugs acting on the cardiovascular system, anti-arrhythmics, cardiac stimulants, vasodilators, anti-hypertensives, anti-adrenergic substances of central and peripheral action or substances acting on the arteriolar musculature, substances acting on the renin-angiotensin system, anti-hypertensives and diuretics in association, anti-Parkinson's Disease agents, diuretics and drugs for the treatment of Alzheimer's disease.  
     
     
         16 . A multi-layer tablet as claimed in any preceding claim, in which the active substance(s) is selected from: propranolol, atenolol, pindolol, ropinirole, prazosin, ramipril, spirapril; spironolactone, metipranolol, molsidomine, moxonidina, nadolol, nadoxolol, levodopa, metoprolol, or timolol, inclusive of pharmaceutically acceptable salts thereof.  
     
     
         17 . A multi-layer tablet as claimed in any preceding claim, in which the tablet preparation is carried out by compression of the powder or granular mixture and working between 1000 and 5000 Kg/cm 2 .  
     
     
         18 . A multi-layer tablet as claimed in any preceding claim, in which the lipophilic substance present in the active layer is selected from hydrogenated castor oil and glyceryl behenate.  
     
     
         19 . A multi-layer tablet as claimed in any preceding claim, in which the active substance comprises or is ropinirole, inclusive of pharmaceutically acceptable salts thereof.  
     
     
         20 . A multi-layer tablet as claimed in  claim 19 , in which the amount of ropinirole present, inclusive of pharmaceutically acceptable salts thereof, is up to 12.0 mg, measured as the amount of ropinirole base present.  
     
     
         21 . A multi-layer tablet as claimed in  claim 19 , in which the amount of ropinirole present, inclusive of pharmaceutically acceptable salts thereof, is from 0.75 mg to 12.0 mg, measured as the amount of ropinirole base present.  
     
     
         22 . A multi-layer tablet as claimed in any preceding claim, in which the active layer consists of components (i) to (iv) wherein the active substance is contained in a percentage of 0.05% to 20% by weight of the active layer, the adjuvant substances are contained in a percentage of 5% to 50% by weight of the active layer, and the weight ratio of the hydrophilic polymeric substances to the lipophilic substances contained in the active layer is in the range of from 7:1 to 1:1.  
     
     
         23 . A multi-layer tablet as claimed in any preceding claim, in which the active layer consists essentially of components (i) to (iv) wherein the active substance is contained in a percentage of 0.05% to 20% by weight of the active layer, the adjuvant substances are contained in a percentage of 5% to 50% by weight of the active layer, and the weight ratio of the hydrophilic polymeric substances to the lipophilic substances contained in the active layer is in the range of from 7:1 to 1:1.  
     
     
         24 . A multi-layer tablet as claimed in any preceding claim, in which the hydrophilic polymeric substance comprises hydroxypropylmethylcellulose of molecular weight 2,000 to 4,000,000, sodium carboxymethylcellulose or calcium carboxymethylcellulose.  
     
     
         25 . A multi-layer tablet as claimed in any preceding claim, in which (i) the active substance is ropinirole contained in a percentage of 0.05% to 20% by weight of the active layer, (ii) the hydrophilic polymeric substance comprises hydroxypropylmethylcellulose, sodium carboxymethylcellulose or calcium carboxymethylcellulose, (iii) the lipophilic substance comprises hydrogenated castor oil or glyceryl behenate, and (iv) the adjuvant substances are contained in a percentage of 5% to 50% by weight of the active layer, and the weight ratio of the hydrophilic polymeric substances to the lipophilic substances contained in the active layer is in the range of from 7:1 to 1:1.  
     
     
         26 . A multi-layer tablet as claimed in any preceding claim, wherein the active substance is ropinirole contained in a percentage of 0.05 to 20% by weight of the active layer, and wherein the hydrophilic polymeric substances in the active layer comprise hydroxypropylmethylcellulose and sodium carboxymethylcellulose.  
     
     
         27 . A multi-layer tablet as claimed in any preceding claim, in which the active layer consists of components (i) to (iv) wherein: 
 the active substance is ropinirole contained in a percentage of 0.05% to 20% by weight of the active layer,    the adjuvant substances are contained in a percentage of 5% to 50% by weight of the active layer,    the hydrophilic polymeric substances in the active layer comprise hydroxypropyl-methylcellulose and sodium carboxymethylcellulose, and    the weight ratio of the hydrophilic polymeric substances to the lipophilic substances contained in the active layer is in the range of from 7:1 to 1:1    
     
     
         28 . A method of treating Parkinson's Disease comprising administering to a human in need of such treatment one or more multi-layer tablets as defined in any one of  claims 19  to  27 .  
     
     
         29 . A method as claimed in  claim 28 , in which one or more multi-layer tablets as defined in any one of  claims 19  to  27  are administered once per day to the human in need of such treatment.  
     
     
         30 . A method as claimed in  claim 28 , in which a single multi-layer tablet as defined in any one of  claims 19  to  27  is administered once per day.  
     
     
         31 . A multi-layer tablet as claimed in any one of  claims 1  to  27 , in which the one or more barrier layers: 
 are applied to one or both surfaces (bases) of the active layer,  
 contain hydrophilic polymeric substances which swell and/or gel and/or erode upon contact with aqueous liquids, as defined in  claim 13 , and  
 contain lipophilic substances.  
 
     
     
         32 . A multi-layer tablet as claimed in any one of  claims 1  to  27  or  31 , in which the one or more barrier layers: 
 are applied to one or both surfaces (bases) of the active layer,  
 contain hydrophilic polymeric substances which swell and/or gel and/or erode upon contact with aqueous liquids, as well as lipophilic substances, and  
 are such that during the first-hour after oral administration or immersion in aqueous liquids (e.g. water), release of the active substance occurs substantially only from the surface of the tablet not covered by the one or more barrier layers.  
 
     
     
         33 . A multi-layer tablet as claimed in any one of  claims 1  to  27  or  31  to  32  wherein a barrier layer is applied to both surfaces (bases) of the active layer.