Stable drug form for oral administration with benzimidazole derivatives as active ingredient and process for the preparation thereof

Abstract

The invention relates to a stable medicament for oral administration which comprises (a) a core which contains an active ingredient selected from Omeprazole, Lansoprazole and Pantoprazole, together with customary pharmaceutical adjuvants, (b) an intermediate layer applied onto the core, and (c) a gastric juice-resistant outer layer. The intermediate layer in (b) is formed as a reactive layer in which a gastric juice-resistant polymer layer material partially neutralized with alkali with cation exchange capacity is present. Further, a method for the production of the stable medicament is disclosed.

1 . Stable medicament for oral administration which comprises 
 (a) a core which contains an active ingredient selected from Omeprazole, Lansoprazole and Pantoprazole, together with customary pharmaceutical adjuvants,    (b) an intermediate layer applied onto the core, and    (c) a gastric juice-resistant outer layer, characterized in that    a reactive intermediate.layer of a gastric juice-resistant polymer layer material partially neutralized with alkali with cation exchange capacity is present in (b).    
     
     
         2 . Medicament according to  claim 1 , characterized in that the alkali is selected from sodium hydroxide and potassium hydroxide.  
     
     
         3 . Medicament according to  claim 1  or  2 , characterized in that the pharmaceutical adjuvant is selected from mannite and hydroxypropylcellulose.  
     
     
         4 . Medicament according to  claim 1  to  3 , characterized in that the core additionally.comprises a tenside.  
     
     
         5 . Medicament according to  claim 4 , characterized in that the tenside is selected from sodium lauryl sulfate, sorbitan fatty acid ester and polyethylene sorbitan fatty acid ester.  
     
     
         6 . Medicament according to  claim 1  to  5 , characterized in that the core is present in the form of pellet cores, tablets, microtablets or as a granulate.  
     
     
         7 . Medicament according to  claim 1  to  6 , character ized in that the gastric juice-resistant polymer layer material in the reactive intermediate layer is partially neutralized to a pH range of ca. 5.5 to 7.0, preferably 5.5 to 6.5.  
     
     
         8 . Medicament according to  claim 7 , characterized in that the partially neutralized gastric juice-resistant polymer layer material is selected from partially neutralized Eudragit® L100-55, Eudragit® L100, hydroxypropylmethylcellulose phthalate (HPMCP) and cellulose acetate phthalate (CAP).  
     
     
         9 . Medicament according to  claim 1  to  8 , characterized in that the reactive intermediate layer additionally comprises an emollient.  
     
     
         10 . Medicament according to  claim 9 , characterized in that the emollient is selected from triethyl citrate, acetyltriethyl citrate, acetylated monoglycerides, propylene glycol and polyethylene glycols.  
     
     
         11 . Medicament according to  claim 1  to  10 , characterized in that the reactive intermediate layer forms a gel-like layer with penetration of protons through the outer layer.  
     
     
         12 . Medicament according to  claim 1  to  11 , characterized in that the reactive intermediate layer possesses a thickness from 5 to 30 μm.  
     
     
         13 . Medicament according to  claim 1  to  12 , characterized in that the gastric juice-resistant outer layer in (c) contains Eudragit® L100-55, Eudragit® L100, hydroxypropylmethylcellulose phthalate (HPMCP) and/or cellulose acetate phthalate (CAP).  
     
     
         14 . Medicament according to  claim 3 , characterized in that the gastric juice-resistant outer layer contains pharmaceutically acceptable antiblocking agents, dispersion agents, pigments and/or colorants.  
     
     
         15 . Medicament according to  claim 14 , characterized in that the antiblocking agent is talcum.  
     
     
         16 . Medicament according to  claim 1  to  15 , characterized in that the gastric juice-resistant outer layer has a layer thickness from 20 to 60 μm, preferably 30 to 60 μm.  
     
     
         17 . Medicament according to  claim 1  to  16  which comprises 
 (a) a core which contains an active ingredient selected from Omeprazole, Lansoprazole and Pantoprazole, together with mannite and hydroxypropylcellulose as adjuvants without alkaline additives,    (b) a reactive intermediate layer applied on the core with a thickness from 5 to 30 μm of Eudragit® L100-55 partially neutralized with sodium hydroxide to a pH range of ca. 5.5 to ca. 7.0, and    (c) a gastric juice-resistant outer layer of Eudragit® L100-55 with a thickness from 30 to 60 μm.    
     
     
         18 . Medicament according to  claim 1  to  17 , characterized in that the reactive intermediate layer is formed as a plurality of single layers.  
     
     
         19 . Medicament according to  claim 1  to  18 , characterized in that the gastric juice-resistant layer is formed as a plurality of single layers.  
     
     
         20 . Medicament according to  claim 1  to  19 , characterized in that the pH transition at the border of the gastric juice-resistant outer layer to the reactive intermediate layer is formed as a gradient.  
     
     
         21 . Method for the production of a stable medicament for oral administration according to one of  claims 1  to  20 , characterized in that 
 (a) a moulded article is formed as a core-which contains an active ingredient selected from Omeprazole, Lansoprazole and Pantoprazole, together with customary pharmaceutical adjuvants,    (b) an intermediate layer is applied onto the moulded article, and    (c) the moulded article-coated in this manner is laminated with a gastric juice-resistant layer, characterized in that a reactive intermediate layer of a gastric juice-resistant layer material partially neutralized with alkali with cation exchange capacity is applied in (b).    
     
     
         22 . Method according to  claim 21 , characterized in that the gastric juice-resistant polymer layer material is partially neutralized with alkali to a pH range from ca. 5.5 to ca. 7.0 before spraying.  
     
     
         23 . Method according to  claim 21 , characterized in that sodium hydroxide or potassium hydroxide is used as an alkali.  
     
     
         24 . Method according to  claim 21 , characterized in that isopropanol is used as a solvent in step (a).  
     
     
         25 . Pharmaceutical composition which contains Diclofenac as a further active ingredient in addition to a stable medicament according to  claim 1  to  20 .  
     
     
         26 . Pharmaceutical composition according to  claim 25 , characterized in that the Diclofenac is present as a formulation which comprises 
 (a) a Diclofenac containing core together with customary adjuvants,    (b) a reactive intermediate layer of gastric juice-resistant polymer layer material partially neutralized with alkali, and    (c) a gasteric juice-resistant outer layer.    
     
     
         27 . Pharmaceuticcal composition according to  claim 25 , characterized in the the Diclofenac is present as a pellet formulation comprising a mixture of gasturic juice-resistant coated pellets and retarded, permeable pellets.  
     
     
         28 . Pharmaceutical capsule formulation, characterized in that it comprises a stable medicament according to  claim 1  to  20  or a composition according to  claim 25  to  27  as pellets.