Stable benzimidazole formulation

Abstract

A benzimidazole formulation which lacks an intermediate layer and yet which is stable both during storage and during the passage through the stomach, and which has low levels of residual volatile excipients, including but not limited to residual alkalinizing agents and/or residual solvents.

What is claimed is: 
     
         1 . A stable composition for a benzimidazole derivative, the composition comprising:
 a substrate, said substrate comprising the benzimidazole derivative, and   a single coating layer consisting essentially of one or more enteric polymers selected from the group consisting of cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, cellulose acetate trimellitate, poly(methacrylic acid, methyl methacrylate (1:1)), poly(methacrylic acid, ethyl acrylate (1:1)), poly(methacrylic acid, methyl methacrylate (1:2)), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sodium alginate, and alginic acid or mixtures thereof; the one or more enteric polymers being neutralized by at least two alkalizing agents comprising at least one volatile alkalizing agent prior to applying over the substrate to give a pH of at least 6.5;   wherein the alkalizing agents are selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide, methanolamine, monoethanol amine, propanolamine, arginine, lysine, methylene diamine, ethylene diamine, and propylene diamine;   wherein said composition comprises less than 500 parts per million of residual volatile alkalizing agents relative to composition weight;   and wherein the pH of said coating layer after being applied to said substrate is in the range of from about 4.5 to about 6.5 as measured in 30 ml of distilled water at 20-25° C.   
     
     
         2 . The composition of  claim 1 , wherein the pH of said coating layer after being applied to said substrate is in the range of from about 5 to about 6. 
     
     
         3 . The composition of  claim 2 , wherein the pH is about 5. 
     
     
         4 . The composition of  claim 1 , wherein said enteric polymer is dissolved in an organic solvent prior to application. 
     
     
         5 . The composition of  claim 4 , comprising less than about 1000 parts per million of residual organic solvent. 
     
     
         6 . The composition of  claim 4 , wherein said organic solvent is selected from the group consisting of acetone, ethanol, isopropanol and a mixture thereof. 
     
     
         7 . The composition of  claim 1 , wherein said substrate is an active core containing the benzimidazole derivative. 
     
     
         8 . The composition of  claim 7 , wherein said active core is selected from the group consisting of a pellet, a bead and a tablet. 
     
     
         9 . The composition of  claim 8 , wherein said active core is a tablet formed by compression. 
     
     
         10 . The composition of  claim 1 , 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.   
     
     
         11 . The composition of  claim 1 , 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.   
     
     
         12 . The composition of  claim 1 , wherein the benzimidazole derivative is selected from the group consisting of Omeprazole, Pantoprazole, Lansoprazole, Leminoprazole, Perprazole, Rabeprazole, and pharmaceutically acceptable salts thereof. 
     
     
         13 . The composition of  claim 1 , wherein said substrate further comprises a filler. 
     
     
         14 . The composition of  claim 13 , wherein said filler is selected from the group consisting of microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, starch, lactose, glucose, fructose, sucrose, dicalcium phosphate, sorbitol, mannitol, maltitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates, or a mixture thereof. 
     
     
         15 . The composition of  claim 1 , wherein said substrate further comprises a disintegrant. 
     
     
         16 . The composition of  claim 15 , wherein said disintegrant is selected from the group consisting of low-substituted carboxymethyl cellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, or a mixture thereof. 
     
     
         17 . The composition of  claim 1 , wherein said substrate further comprises a lubricant. 
     
     
         18 . The composition of  claim 17 , wherein said lubricant is selected from the group consisting of sodium stearyl fumarate, polyethylene glycol, silica colloidal anhydrous and magnesium stearate, or a mixture thereof. 
     
     
         19 . The composition of  claim 1 , wherein said substrate further comprises an alkalizing agent. 
     
     
         20 . The composition of  claim 19 , wherein said alkalizing agent is selected from the group consisting of sodium stearate, meglumine, disodium phosphate, and ammonia, or a mixture thereof. 
     
     
         21 . The composition of  claim 1 , wherein said coating layer further comprises a plasticizer. 
     
     
         22 . The composition of  claim 21 , wherein said plasticizer is selected from the group consisting of a citric acid ester and a phthalic acid ester. 
     
     
         23 . The composition of  claim 1 , wherein said coating layer further comprises a surfactant. 
     
     
         24 . The composition of  claim 23 , wherein said surfactant is selected from the group consisting of polysorbate 80 and sodium lauryl sulfate. 
     
     
         25 . The composition of  claim 1 , wherein said coating layer further comprises a glidant. 
     
     
         26 . The composition of  claim 25 , wherein said glidant is selected from the group consisting of talc and titanium dioxide. 
     
     
         27 . The composition of  claim 1 , wherein said coating layer further comprises at least one of a coloring agent and a polishing agent. 
     
     
         28 . The composition of  claim 1 , wherein said single coating layer being neutralized by at least two alkalizing agents to give a pH in the range of from about 7 to about 10. 
     
     
         29 . The composition of  claim 1 , wherein said composition comprises between 6 to 500 parts per million of residual volatile alkalizing agents relative to composition weight. 
     
     
         30 . The composition of  claim 1 , wherein said residual volatile alkalizing agent comprises an ammonia solution. 
     
     
         31 . A stable composition for a benzimidazole derivative, the composition comprising:
 a substrate, said substrate comprising the benzimidazole derivative; and   a single coating layer consisting essentially of at least one neutralized enteric polymer comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS), wherein said enteric polymer is neutralized to a pH of at least 6.5 by at least two alkalizing agents prior to applying to said substrate, wherein the two alkalizing agents are selected from the group consisting of ammonium hydroxide, methanolamine, monoethanol amine, propanolamine, methylene diamine, ethylene diamine, propylene diamine, arginine and lysine,   said single coating layer being layered directly over said substrate, without an intermediate layer between said substrate and said enteric coating,   wherein said composition comprises less than about 500 parts per million of residual volatile alkalizing agent relative to the total weight of the composition.   
     
     
         32 . The composition of  claim 31 , wherein said alkalizing agents are ammonium hydroxide and monoethanol amine.