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 method for preparing a stable composition for a benzimidazole derivative, comprising:
 neutralizing one or more enteric polymers to a pH of at least 6.5 with at least two alkalizing agents, wherein at least one of said at least two alkalinizing agents is a volatile alkalinizing agent and at least one of said at least two alkalinizing agents is a non-volatile alkalinizing agent;   layering said one or more enteric polymers over a substrate comprising the benzimidazole derivative, wherein said pH of said single 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., wherein said one or more enteric polymers is layered directly over said substrate, without an intermediate layer between said substrate and said one or more enteric polymers; and   forming a single coating layer of said one or more enteric polymers over said substrate such that said composition comprises less than 500 parts per million of residual volatile alkalizing agents relative to composition weight and wherein said composition comprises at least one residual non-volatile alkalizing agent.   
     
     
         2 . The method of  claim 1 , wherein said pH of said coating layer after being applied to said substrate is in the range of from about 5 to about 6. 
     
     
         3 . The method of  claim 2 , wherein said pH is about 5. 
     
     
         4 . The method of  claim 1 , wherein said non-volatile alkalizing agent is selected from the group consisting of basic sodium, potassium, amino alcohols, arginine, lysine, and alkylene diamines. 
     
     
         5 . The method of  claim 4 , wherein said amino alcohol is selected from the group consisting of methanolamine, monoethanol amine, and propanolamine. 
     
     
         6 . The method of  claim 4 , wherein said alkylene diamine is selected from the group consisting of methylene diamine, ethylene diamine, and propylene diamine. 
     
     
         7 . The method of  claim 1 , comprising dissolving said one or more enteric polymers in an organic solvent prior to layering said one or more enteric polymers over said substrate. 
     
     
         8 . The method of  claim 7 , wherein said organic solvent is selected from the group consisting of acetone, ethanol, isopropanol and a mixture thereof. 
     
     
         9 . The method of  claim 1 , wherein said enteric polymer is 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) (Eudragit L100™), poly((methacrylic acid, ethyl acrylate)1:1) (Eudragit L30D-55) or Eudragit L100-55™, (poly(methacrylic acid, methyl methacrylate)1:2) and Eudragit™ S hydroxypropyl methylcellulose acetate succinate (HPMCAS), or mixtures thereof. 
     
     
         10 . The method of  claim 1 , comprising adding said benzimidazole derivative into an active core to form said substrate. 
     
     
         11 . The method of  claim 10 , wherein said active core is selected from the group consisting of a pellet, a bead and a tablet. 
     
     
         12 . The method of  claim 11 , comprising compressing a tablet to form said active core. 
     
     
         13 . The method of  claim 1 , further comprising layering an active coating containing said benzimidazole derivative over a neutral core to form said substrate in a form of a pellet. 
     
     
         14 . The method of  claim 1 , further comprising using spheronisation and pelletization on a core containing the benzimidazole derivative with a suitable binding agent to form said substrate in a form of a pellet. 
     
     
         15 . The method 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. 
     
     
         16 . The method of  claim 1 , further comprising adding a filler into said substrate. 
     
     
         17 . The method of  claim 16 , wherein said filler is selected from the group consisting of microcrystalline cellulose, sodium carboxymethycellulose, ethylcellulose, cellulose acetate, starch, lactose, glucose, fructose, sucrose, dicalcium phosphate, sorbitol, manitol, mantitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates, or a mixture thereof. 
     
     
         18 . The method of  claim 1 , further comprising adding a disintegrant into said substrate. 
     
     
         19 . The method of  claim 18 , 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, and low substituted hydroxypropyl cellulose magnesium aluminum silicate, or a mixture thereof. 
     
     
         20 . The method of  claim 1 , further comprising adding a lubricant into said substrate. 
     
     
         21 . The method of  claim 20 , wherein said lubricant is selected from the group consisting of sodium stearyl fumarate, polyethylene glycol, and magnesium stearate, or a mixture thereof. 
     
     
         22 . The method of  claim 1 , further comprising adding an alkalinizing agent into said substrate. 
     
     
         23 . The method of  claim 22 , wherein said alkalinizing agent is selected from the group consisting of sodium stearate, meglumine, disodium phosphate, and ammonia, or a mixture thereof. 
     
     
         24 . The method of  claim 1 , further comprising adding a plasticizer into said substrate. 
     
     
         25 . The method of  claim 24 , wherein said plasticizer is selected from the group consisting of a citric acid ester and a phthalic acid ester. 
     
     
         26 . The method of  claim 1 , further comprising adding a surfactant into said coating layer. 
     
     
         27 . The method of  claim 26 , wherein said surfactant is selected from the group consisting of polysorbate 80 and sodium lauryl sulfate. 
     
     
         28 . The method of  claim 1 , further comprising adding a glidant into said coating layer. 
     
     
         29 . The method of  claim 28 , wherein said glidant is selected from the group consisting of talc and titanium dioxide. 
     
     
         30 . The method of  claim 1 , wherein said residual volatile alkalizing agent comprises an ammonia solution.