Stable benzimidazole formulation

Abstract

A stable composition with a benzimidazole derivative, such as Omeprazole, which does not contain a separating layer between the active compound and an enteric coating layer. Instead, the enteric coating layer is applied as a solution with a pH value of at least 6.5, and more preferably in a range of from about 7 to about 10, directly to the benzimidazole derivative substrate. This solution, with the optional addition of a plasticizer, can be directly coated onto the substrate without any necessity for an intermediate layer. Furthermore, in this pH range, the enteric coating is optionally applicable in an aqueous solution, thereby obviating the need for organic solvents for dissolving the enteric coating material. The resultant formulation maintains the stability of the benzimidazole derivative during storage and at the same time protects the product during passage through the acidic environment of the stomach.

1 - 17 . (canceled) 
     
     
         18 . A stable composition for a benzimidazole derivative, the composition comprising:
 (a) a substrate, said substrate featuring the benzimidazole derivative; and   (b) an enteric coating material layered directly over said substrate, said enteric coating material having a pH value of at least about 6.5, thereby obviating the need for an intermediate layer between said substrate and said enteric coating, with the proviso that said enteric coating material does not include HPMCP (hydroxypropyl methylcellulose phthalate).   
     
     
         19 . The composition of  claim 18 , wherein said substrate is an active core for containing the benzimidazole derivative. 
     
     
         20 . The composition of  claim 19 , wherein said active core is selected from the group consisting of a pellet, a bead and a tablet. 
     
     
         21 . The composition of  claim 20 , wherein said active core is a tablet formed by compression. 
     
     
         22 . The composition of  claim 19 , wherein said substrate features:
 (i) a neutral core; and   (ii) an active coating containing the benzimidazole derivative, said active coating being layered over said neutral core such that the composition is in a form of a pellet   
     
     
         23 . The composition of  claim 18 , wherein said substrate features a core containing the benzimidazole derivative with a suitable binding agent, said core being prepared by spheronisation and pelletization; such that the composition is in a form of a pellet. 
     
     
         24 . The composition of  claim 18 , wherein said enteric coating material includes at least one enteric material selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polymethacrylic acid methyl methacrylate and polymethacrylic acid ethyl methacrylate. 
     
     
         25 . The composition of  claim 24 , wherein said enteric coating material further comprises an alkaline compound, such that said pH value is adjusted by adding said alkaline compound to said enteric material. 
     
     
         26 . The composition of  claim 25 , wherein said alkaline compound is an inorganic alkaline compound. 
     
     
         27 . The composition of  claim 26 , wherein said alkaline compound is selected from the group consisting of basic sodium, potassium and ammonium hydroxide. 
     
     
         28 . The composition of  claim 27 , wherein said enteric coating material is at least about 60% neutralized by adding said alkaline compound. 
     
     
         29 . The composition of  claim 28 , wherein said enteric coating material is at least about 80% neutralized by adding said alkaline compound. 
     
     
         30 . The composition of  claim 28 , wherein said enteric coating material is at least about 95% neutralized by adding said alkaline compound. 
     
     
         31 . The composition of  claim 25 , wherein said pH value is in a range of from about 7 to about 10. 
     
     
         32 . The composition of  claim 25 , wherein said enteric coating material further comprises a plasticizer. 
     
     
         33 . The composition of  claim 32 , wherein said plasticizer is selected from the group consisting of a citric acid ester and a phthalic acid ester. 
     
     
         34 . The composition of  claim 33 , wherein the benzimidazole derivative is selected from the group consisting of Omeprazole, Pantoprazole, Lansoprazole, Leminoprazole, Perprazole, Rabeprazole, and pharmaceutically acceptable salts thereof. 
     
     
         35 . A stable composition for a benzimidazole derivative, the composition consisting essentially of:
 (a) a substrate, said substrate featuring the benzimidazole derivative; and   (b) an enteric coating material layered over said substrate, said enteric coating material having a pH value of at least about 6.5 by an alkaline compound, such that said pH value is adjusted by adding said alkaline compound to said enteric material.   
     
     
         36 . The composition of  claim 35 , wherein said substrate is an active core for containing the benzimidazole derivative. 
     
     
         37 . The composition of  claim 36 , wherein said active core is selected from the group consisting of a pellet, a bead and a tablet, said active core being formed by embedding the benzimidazole derivative in poloxamer. 
     
     
         38 . The composition of  claim 36 , wherein said active core is a tablet formed by compression. 
     
     
         39 . The composition of  claim 35 , wherein said substrate features:
 (i) a neutral core; and   (ii) an active coating containing the benzimidazole derivative, said active coating being layered over said neutral core.   
     
     
         40 . The composition of  claim 35 , wherein said enteric coating material includes at least one enteric material selected from the group consisting of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylic acid methyl methacrylate and polymethacrylic acid ethyl methacrylate. 
     
     
         41 . The composition of  claim 40 , wherein said alkaline compound is an inorganic alkaline salt compound. 
     
     
         42 . The composition of  claim 41 , wherein said alkaline compound is selected from the group consisting of basic sodium, potassium or ammonium hydroxide. 
     
     
         43 . The composition of  claim 42 , wherein said enteric coating material is at least about 60% neutralized by adding said alkaline compound. 
     
     
         44 . The composition of  claim 43 , wherein said enteric coating material is at least about 80% neutralized by adding said alkaline compound. 
     
     
         45 . The composition of  claim 44 , wherein said enteric coating material is at least about 95% neutralized by adding said alkaline compound. 
     
     
         46 . The composition of  claim 41 , wherein said pH value is in a range of from about 7 to about 10. 
     
     
         47 . The composition of  claim 41 , wherein said enteric coating material further comprises a plasticizer. 
     
     
         48 . The composition of  claim 47 , wherein said plasticizer is selected from the group consisting of a citric acid ester and a phthalic acid ester. 
     
     
         49 . The composition of  claim 35 , wherein the benzimidazole derivative is selected from the group consisting of Omeprazole, Pantoprazole, Lansoprazole, Leminoprazole, Perprazole, Rabeprazole, and pharmaceutically acceptable salts thereof. 
     
     
         50 . A method for producing a stable composition for a benzimidazole derivative, the method comprising the steps of:
 (a) forming a substrate with the benzimidazole derivative;   (b) preparing an enteric coating material having a pH value of at least about 6.5; and   (c) layering said enteric coating material directly over said substrate, with the proviso that said enteric coating material does not include HPMCP (hydroxypropyl methylcellulose phthalate).   
     
     
         51 . The method of  claim 50 , wherein said substrate is formed by melting poloxamer and by mixing the benzimidazole derivative into said poloxamer. 
     
     
         52 . The method of  claim 50 , wherein said substrate is formed by direct compression. 
     
     
         53 . The method of  claim 50 , wherein said substrate is formed by wet granulation. 
     
     
         54 . The method of  claim 50 , wherein said substrate is formed by coating on an inert core. 
     
     
         55 . The method of  claim 50 , wherein said enteric coating material is prepared by the steps of
 (i) mixing an enteric material with water to form a mixture; and   (ii) adding an alkaline compound to said mixture to form an aqueous solution having a pH value of from about 7 to about 10.   
     
     
         56 . The method of  claim 50 , wherein said enteric coating material is prepared by the steps of
 (i) mixing an enteric material with water and alcohol to form a mixture; and   (ii) adding an alkaline compound to said mixture to form an aqueous solution having a pH value of from about 7 to about 10.   
     
     
         57 . The composition of claim  1 , wherein the composition is in a form of a tablet, wherein said substrate consists essentially of a core and wherein said enteric coating material consists essentially of a single enteric coating. 
     
     
         58 . The composition of claim  1 , wherein the composition is in a form of a pellet, wherein said substrate consists essentially of a core and wherein said enteric coating material consists essentially of a single enteric coating, such that a combination of said single enteric coating and said core forms said pellet, the composition further comprising a tablet for containing a plurality of said pellets, wherein said plurality of pellets is not compressed. 
     
     
         59 . A method for producing a stable tablet composition for a benzimidazole derivative, the method comprising the steps of:
 (a) forming a single core with the benzimidazole derivative;   (b) preparing neutralized enteric coating material having a pH value of at least about 6.5; and   (c) layering a single layer of said enteric coating material directly over said single core to form the tablet by directly coating said single core, such that each tablet only has said single core.