Formulation having controlled, delayed release of active ingredient

Abstract

The present invention relates to novel pharmaceutical formulations which have controlled, delayed release of active ingredient, and to a process for the preparation of such formulations. The invention additionally relates to the use of these novel pharmaceutical administration forms as medicaments for the treatment of diseases which require delayed release of the active ingredient, such as hypertension, or asthmatic diseases.

1 - 26 . (canceled) 
     
     
         27 . A process for preparing a pharmaceutical administration form of a composition having extended release of active ingredient, comprising
 a) grinding a polyvinyl alcohol which has been approved for use in pharmaceutical formulations at low temperatures in the range from minus 30° C. to 0° C. to give a finely divided powder having an average particle size Dv50 in the range 50-100 μm, preferably in the range Dv50 60-95 μm, and sieving through an 800 μm sieve, and   b) mixing intensively with microcrystalline cellulose having an average particle size Dv50 in the range 100 to 150 μm,   c) mixing the resultant mixture from b) with an adequate amount of an active ingredient,   e) optionally adding additives which are advantageous for further processing, such as flow-control agents or lubricants, and   f) after adequate mixing of the resultant mixture and optionally after sieving in order to remove coarse particulate material still present, tabletting the mixture by pressing at a suitable pressure,   
       giving, after pressing with a pressing force in the range from 5 to 32 kN, tablets having hardnesses in the range from 50 to 290 N, which have an average release rate of 80% of the active ingredient in a time of at least 9 to 12 hours. 
     
     
         28 . The process according to  claim 27 , wherein extended release tablets are produced which have a virtually unchanged active-ingredient release profile over a very broad range of pressing forces and tablet hardnesses. 
     
     
         29 . The process according to  claim 27 , wherein extended release tablets which have hardnesses in the range from 50 to 290 N and, in spite of the modified hardness, have a virtually identical active-ingredient release profile are produced with a pressing force in the range from 5 to 32 kN. 
     
     
         30 . The process according to  claim 27 , wherein polyvinyl alcohol and microcrystalline cellulose are mixed intensively with one another in the ratio 2:1 to 1:2, preferably in the ratio 1.5:1 to 1:1.5, in particular 1:1, based on the total amount of the co-mixture. 
     
     
         31 . The process according to  claim 27 , wherein, as additives, small amounts of silicon dioxide as flow-control agent and magnesium stearate as lubricant are added to the mixture and mixed therewith. 
     
     
         32 . The process according to  claim 27 , wherein in c) the active ingredient propranolol and/or pharmaceutically tolerated salts, hydrates or solvates thereof or theophylline, anhydrous or the monohydrate thereof, in an effective amount is added and mixed therewith. 
     
     
         33 . The process according to  claim 33 , wherein the propranolol-containing mixture is pressed with a pressing force in the range from 10 to 30 kN to give tablets having hardnesses in the range from 100 to 260 N which have an average release rate of 80% of the active ingredient in a time of at least 9 to 12 hours. 
     
     
         34 . A pharmaceutically active composition having extended release of active ingredient, prepared by a process according to  claim 27 , comprising the active ingredient propranolol and/or pharmaceutically tolerated salts, hydrates or solvates thereof as antihypertensive β-blocker and a co-mixture of microcrystalline celluloses and polyvinyl alcohols
 or 
 the active ingredient theophylline and/or pharmaceutically tolerated salts, hydrates or solvates thereof, preferably the anhydrate thereof, and a co-mixture of microcrystalline celluloses and polyvinyl alcohols. 
 
     
     
         35 . The composition according to  claim 34 , comprising propranolol in the form of the hydrochloride or succinate. 
     
     
         36 . The composition according to  claim 34 , comprising co-mixture of microcrystalline celluloses and polyvinyl alcohols in the ratio 2:1 to 1:2, preferably in the ratio 1.5:1 to 1:1.5, in particular 1:1, based on the total amount of the co-mixture, and in which the polyvinyl alcohols are selected from grades 18-88, 26-88, 40-88, 48-88 and all grades in between in accordance with the requirements of the Ph. Eur., USP or JPE pharmacopoeias, including grade 28-99 in accordance with the requirements of the JPE or Ph. Eur., and have average particle-size fractions in the co-mixture in the range Dv50 50-100 μm, preferably in the range Dv50 60-95 μm. 
     
     
         37 . The composition according to  claim 34 , comprising a co-mixture of microcrystalline celluloses and polyvinyl alcohol of grade 26-88 and/or 40-88, where the polyvinyl alcohols in the co-mixture have, before pressing, average particle-size fractions in the range Dv50 60-95 μm. 
     
     
         38 . The composition according to  claim 34 , comprising a co-mixture of microcrystalline celluloses and polyvinyl alcohols, where the polyvinyl alcohols employed have, before pressing, a bulk density in the range from 0.40 to 0.65 g/ml, preferably from 0.45 to 0.60 g/ml, and a tapped density in the range from 0.50 to 0.80 g/ml, in particular in the range from 0.55 to 0.75 g/ml. 
     
     
         39 . The composition according to  claim 34 , which has been pressed to give tablets having hardnesses in the range from 50 to 290 N, where the latter have, independently of the hardness, an average release rate of 80% of the active ingredient in a time of at least 9 to 12 hours;
 or   which comprises propranolol as active ingredient and has been pressed to give tablets having hardnesses in the range from 100 to 260 N, where the latter have, independently of the hardness, an average release rate of 80% of the active ingredient in a time of at least 9 to 12 hours;   or   which comprises theophylline as active ingredient and has been pressed to give tablets having hardnesses in the range from 50 to 290 N, where the latter have, independently of the hardness, an average release rate of 80% of the active ingredient in a time of at least 9 to 12 hours.   
     
     
         40 . The composition according to  claim 34 , which has a moderate initial release and subsequently a uniform release of active ingredient, thus preventing undesired dose dumping of active ingredient;
 or   comprises silicon dioxide as flow-control agent;   or   comprises magnesium stearate as lubricant.   
     
     
         41 . The composition according to  claim 34 , which is in a pharmaceutical administration form having extended release of active ingredient and which is for oral administration. 
     
     
         42 . The composition according to  claim 41 , which comprises the active ingredient in a matrix which releases the active ingredient by diffusion and/or gradual erosion in the presence of liquid in the gastrointestinal system. 
     
     
         43 . The composition according to  claim 41 , which comprises 10 to 140 mg of the active ingredient, calculated as propranolol, per dose;
 or   100 to 600 mg of the active ingredient, calculated as theophylline, per dose;   or   propranolol hydrochloride as active ingredient in an amount of 80 or 160 mg per dose;   or   anhydrous theophylline as active ingredient.