Novel pharmaceutical formulation with controlled release of active substances

Abstract

There is disclosed a method for stabilizing active substances that are unstable in acidic medium, unstable when stored for longer periods of time in the presence of water and at the same time sensitive to heating, by means of anhydrous granulation of active substances and dried pharmaceutically acceptable auxiliary substances for the preparation of pellet cores or granules. All pharmaceutically acceptable auxiliary substances employed are dried before use so that their weight loss at drying is less than 1.0% of the total weight of the pharmaceutically acceptable auxiliary substance, preferably less than 0.5%. Organic solvents used in process of anhydrous granulation should contain less than 0.2% of water. A novel pharmaceutical formulation with controlled release of active substances that are unstable in acidic medium, unstable when stored for longer periods of time in the presence of water and at the same time sensitive to heating, is disclosed as well.

1 . A pharmaceutical formulation with controlled release of a therapeutically active substance comprising a benzimidazole derivative, comprising an anhydrously-granulated core and a gastro-resistant coating, said core comprising a therapeutically active substance comprising a benzimidazole derivative, a binder soluble in an organic solvent, a cellulose ether, a surfactant, and one or more other pharmaceutically acceptable auxiliary substances.  
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein said core is devoid of alkaline substances.  
     
     
         3 . The pharmaceutical formulation of  claim 1 , wherein the structure of said formulation consists of said core and said coating.  
     
     
         4 . Pharmaceutical formulation according to  claim 1 , characterized in that said therapeutically active substance comprises a compound selected from the group consisting of omeprazol, an optically active isomer of omeprazol, a pharmaceutically acceptable salt of omeprazol, an optically active isomer of said salt, and combinations thereof.  
     
     
         5 . Pharmaceutical formulation according to  claim 1 , characterized in that said therapeutically active substance comprises a compound selected from the group consisting of lansoprazol, an optically active isomer of lansoprazol, a pharmaceutically acceptable salt of lansoprazol, an optically active isomer of said salt, and combinations thereof.  
     
     
         6 . Pharmaceutical formulation according to  claim 1 , characterized in that said therapeutically active substance comprises a compound selected from the group consisting of pantoprazol, an optically active isomer of pantoprazol, a pharmaceutically acceptable salt of pantoprazol, an optically active isomer of said salt, and combinations thereof.  
     
     
         7 . Pharmaceutical formulation according to  claim 1 , characterized in that said therapeutically active substance is present in an amount of 0.1 to 95.0 wt. % with regard to the total weight of the core of the pharmaceutical formulation.  
     
     
         8 . Pharmaceutical formulation according to  claim 1 , characterized in that the core of the pharmaceutical formulation contains a binder soluble in organic solvents with K value of 10 to 95.  
     
     
         9 . Pharmaceutical formulation according to  claim 1 , characterized in that the core of the pharmaceutical formulation contains polyvinylpyrrolidone as a binder with an average molecular weight in the range from 2000 g/mole to 1100000 g/mole.  
     
     
         10 . Pharmaceutical formulation according to  claim 1 , characterized in that the core of the pharmaceutical formulation contains polyvinylpyrrolidone as a binder in an amount of 1 to 30 wt. % with regard to the total weight of the core of the pharmaceutical formulation.  
     
     
         11 . Pharmaceutical formulation according to  claim 1 , characterized in that the core of the pharmaceutical formulation contains a binder soluble in organic solvents, which is the polymer polyvinylpyrrolidone.  
     
     
         12 . Pharmaceutical formulation according to  claim 1 , characterized in that the core of the pharmaceutical formulation contains a cellulose ether in an amount of 2 to 60 wt. % with regard to the total weight of the core of the pharmaceutical formulation.  
     
     
         13 . Pharmaceutical formulation according to  claim 1 , characterized in that the core of the pharmaceutical formulation contains a cellulose ether selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, propyl cellulose, hydroxypropyl cellulose, lower-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, and combinations thereof.  
     
     
         14 . Pharmaceutical formulation according to  claim 1 , characterized in that the core of the pharmaceutical formulation contains a cellulose ether, which is a lower-substituted hydroxypropyl cellulose having a content of hydroxypropoxy groups in the range of 5 to 16%.  
     
     
         15 . Pharmaceutical formulation according to  claim 1 , characterized in that the core of the pharmaceutical formulation contains a surfactant in an amount of 0.1 to 20.0 wt. % with regard to the total weight of the core of the pharmaceutical formulation.  
     
     
         16 . Pharmaceutical formulation according to  claim 1 , characterized in that the core of the pharmaceutical formulation contains a surfactant selected from the group consisting of sodium lauryl sulfate, poloxamers, natural and synthetic lecitins, esters of sorbitan and fatty acids, esters of polyoxyethylene sorbitan and fatty acids, polyoxyethylated hydrogenated castor oils, polyoxyethylene stearates and combinations thereof.  
     
     
         17 . Pharmaceutical formulation according to  claim 1 , characterized in that the core of the pharmaceutical formulation contains one or more other pharmaceutically acceptable auxiliary substances selected from the group consisting of fillers, binders, disintegrators, glidants, lubricants, and combinations thereof.  
     
     
         18 . Pharmaceutical formulation according to  claim 1 , characterized in that the gastro-resistant coating is present in an amount of 5 to 30 wt. % with regard to the total weight of the core of the pharmaceutical formulation.  
     
     
         19 . Pharmaceutical formulation according to  claim 1 , characterized in that the gastro-resistant coating consists of one or more cellulose derivatives and one or more other pharmaceutically acceptable auxiliary substances.  
     
     
         20 . Pharmaceutical formulation according to  claim 19 , characterized in that a cellulose derivative is selected from the group consisting of cellulose acetophthalate, hydroxypropylmethyl cellulose phthalate, and combinations thereof.  
     
     
         21 . Pharmaceutical formulation according to  claim 19 , characterized in that one or more other pharmaceutically acceptable auxiliary substances is selected from the group consisting of polyethylene glycols, triethyl citrate, dibutyl sebacate, tributyl citrate, cetyl alcohol, olive oil, castor oil, monoglycerides, talc, Polysorbate 80, pigments, magnesium stearate, and combinations thereof.  
     
     
         22 . Pharmaceutical formulation according to  claim 1 , characterized in that it is in the form of a capsule, bag, or tablet.  
     
     
         23 . Pharmaceutical formulation according to  claim 1 , characterized in that the anhydrously-granulated core has a water content such that the weight loss at drying is less than 1.0% of the total weight of the core.  
     
     
         24 . Pharmaceutical formulation according to  claim 23 , characterized in that the anhydrously-granulated core has a water content such that the weight loss at drying is less than 0.5% of the total weight of the core.  
     
     
         25 . Pharmaceutical formulation according to  claim 1 , characterized in that the anhydrously-granulated core dried at a temperature of 35 to 45° C. has a water content such that the weight loss at drying is less than 1.0% of the total weight of the core.  
     
     
         26 . Pharmaceutical formulation according to  claim 25 , characterized in that the anhydrously-granulated core dried at a temperature of 35 to 45° C. has a water content such that the weight loss at drying is less than 0.5% of the total weight of the core.  
     
     
         27 . Pharmaceutical formulation according to  claim 1 , characterized in that the gastro-resistant-coated core dried at a temperature of 30 to 35° C. has a water content such that the weight loss at drying is less than 1.0% of the total weight of the formulation.  
     
     
         28 . Pharmaceutical formulation according to  claim 27 , characterized in that the gastro-resistant-coated core dried at a temperature of 30 to 35° C. has a water content such that the weight loss at drying is less than 0.5% of the total weight of the formulation.  
     
     
         29 . A method for stabilizing a therapeutically active substance comprising a benzimidazole derivative, the method comprising the steps of: 
 anhydrously granulating an active substance comprising a benzimidazole derivative and a dried pharmaceutically acceptable auxiliary substance with an organic solvent; and    coating the granulation with a gastro-resistant coating.    
     
     
         30 . The method of  claim 29 , further comprising compressing the granulation into tablets under addition of a second dried pharmaceutically acceptable auxiliary substance, same or different, prior to said coating step.  
     
     
         31 . The method of  claim 29 , further comprising pelletizing said granulation prior to said coating step.  
     
     
         32 . The method of  claim 29 , wherein said dried pharmaceutically acceptable auxiliary substance comprises a binder soluble in an organic solvent, a cellulose ether, and a surfactant.  
     
     
         33 . A method according to  claim 29 , characterized in that each pharmaceutically acceptable auxiliary substance employed is dried before use so that its weight loss at drying is in the range from 1.0% to 0.2% of the total weight of the pharmaceutical auxiliary substance.  
     
     
         34 . A method according to  claim 29 , characterized in that each pharmaceutically acceptable auxiliary substance employed is dried before use so that its weight loss at drying is in the range from 0.5% to 0.2% of the total weight of the pharmaceutical auxiliary substance.  
     
     
         35 . A method according to  claim 46 , characterized in that the organic solvent used in the process of anhydrous granulation, contains less than 0.2% of water.  
     
     
         36 . Process according to  claim 29 , characterized in that pellet cores or granules are dried in a fluidized bed or in a chamber drier at the temperature of inlet air of from 35 to 45° C. until the weight loss at drying is in the range from 0.5% to 0.2% of the total weight of pellet cores or granules.  
     
     
         37 . Process according to  claim 29 , characterized in that after the completed process of coating with a gastro-resistant coating the pellets are dried in a fluidized bed at the temperature of inlet air of from 30 to 35° C. until the weight loss at drying is in the range from 1.0% to 0.2% of the total pellet weight.  
     
     
         38 . Process according to  claim 29 , characterized in that after the completed process of coating with a gastro-resistant coating the pellets are dried in a fluidized bed at the temperature of inlet air from 30 to 35° C. until the weight loss at drying is in the range from 0.5% to 0.2% of the total pellet weight.  
     
     
         39 . Process according to  claim 29 , characterized in that each pharmaceutically acceptable auxiliary substance employed is dried before use so that its weight loss at drying is in the range from 1.0% to 0.2% of the total weight of the pharmaceutical auxiliary substance.  
     
     
         40 . Process according to  claim 29 , characterized in that each pharmaceutically acceptable auxiliary substance employed is dried before use so that its weight loss at drying is in the range from 0.5% to 0.2% of the total weight of the pharmaceutical auxiliary substance.  
     
     
         41 . Process according to  claim 29 , characterized in that an organic solvent used in the process of anhydrous granulation contains less than 0.2% of water.  
     
     
         42 . Process according o  claim 29 , characterized in that an organic solvent in the process of anhydrous granulation is selected from the group consisting of alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated hydrocarbons, cycloaliphatic solvents, aromatic solvents, heterocyclic solvents, and mixtures thereof.  
     
     
         43 . Pharmaceutical formulation according to  claim 29 , characterized in that an active substance is selected from the group consisting of rabeprazol, an optically active isomer of rabeprazol, a pharmaceutically acceptable salt of rabeprazol, an optically active isomer of said salt, and combinations thereof.  
     
     
         44 . A method according to  claim 29 , characterized in that the active substance comprises a compound selected from the group consisting of omeprazol, an optically active isomer of omeprazol, a pharmaceutically acceptable salt of omeprazol, an optically active isomer of said salt, and combinations thereof.  
     
     
         45 . A method according to  claim 44 , characterized in that the active substance comprises omeprazol.  
     
     
         46 . A method according to  claim 29 , characterized in that the active substance comprises a compound selected from the group consisting of lansoprazol, an optically active isomer of lansoprazol, a pharmaceutically acceptable salt of lansoprazol, an optically active isomer of said salt, and combinations thereof.  
     
     
         47 . A method according to  claim 46 , characterized in that the active substance comprises lansoprazol.  
     
     
         48 . A method according to  claim 29 , characterized in that the active substance comprises a compound selected from the group consisting of pantoprazol, an optically active isomer of pantoprazol, a pharmaceutically acceptable salt of pantoprazol, an optically active isomer of said salt, and combinations thereof.  
     
     
         49 . A method according to  claim 48 , characterized in that the active substance comprises pantoprazol.  
     
     
         50 . A method according to  claim 29 , characterized in that said therapeutically active substance comprises a compound selected from the group consisting of rabeprazol, an optically active isomer of rabeprazol, a pharmaceutically acceptable salt of rabeprazol, an optically active isomer of said salt, and combinations thereof.  
     
     
         51 . A method according to  claim 29 , characterized in that the active substance comprises rabeprazol.