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.

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 at least one neutralized enteric polymer, 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 said at least two alkalizing agents are is selected from the group consisting of amino alcohols, alkylene diamines, ammonia solution, arginine and lysine, said single coating layer 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 alkalizing agent relative to the total weight of the composition.   
     
     
         2 . A stable composition for a benzimidazole derivative, the composition comprising:
 a substrate, said substrate comprising the benzimidazole derivative and   a single coating layer consisting of one or more enteric polymers treated by at least one volatile alkalizing agent prior to applying over the substrate to give a pH of at least 6.5;   wherein said composition comprises less than 500 parts per million of residual volatile alkalizing agents relative to composition weight,   and wherein a 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.   
     
     
         3 . The composition of  claim 2 , wherein said pH of said coating layer after being applied to said substrate is in the range of from about 5 to about 6. 
     
     
         4 . The composition of  claim 3 , wherein said pH is about 5. 
     
     
         5 . The composition of  claim 1 , wherein said alkalizing agent is selected from the group consisting of basic sodium, potassium, methanolamine, ammonium solution, amino alcohols, arginine, lysine, and alkylene diamines. 
     
     
         6 . The composition of  claim 5 , wherein said amino alcohol is selected from the group consisting of methanolamine, monoethanol amine, and propanolamine. 
     
     
         7 . The composition of  claim 5 , wherein said alkylene diamine is selected from the group consisting of methylene diamine, ethylene diamine, and propylene diamine. 
     
     
         8 . The composition of  claim 5 , wherein said ammonium solution comprises ammonium hydroxide. 
     
     
         9 . The composition of  claim 1 , wherein said enteric polymer is dissolved in an organic solvent prior to application. 
     
     
         10 . The composition of  claim 9 , comprising less than about 1000 parts per million of residual organic solvent. 
     
     
         11 . The composition of  claim 9 , wherein said organic solvent is selected from the group consisting of acetone, ethanol, isopropanol and a mixture thereof. 
     
     
         12 . The composition 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) Eudragit™ S hydroxypropyl methylcellulose acetate succinate (HPMCAS), sodium alginate, and alginic acid or mixtures thereof. 
     
     
         13 . The composition of  claim 1 , wherein said substrate is an active core for containing the benzimidazole derivative. 
     
     
         14 . The composition of  claim 13 , wherein said active core is selected from the group consisting of a pellet, a bead and a tablet. 
     
     
         15 . The composition of  claim 14 , wherein said active core is a tablet formed by compression. 
     
     
         16 . 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 
   
     
     
         17 . 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. 
     
     
         18 . 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. 
     
     
         19 . The composition of  claim 1 , wherein said substrate further comprises a filler. 
     
     
         20 . The composition of  claim 19 , 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. 
     
     
         21 . The composition of  claim 1 , wherein said substrate further comprises a disintegrant. 
     
     
         22 . The composition of  claim 21 , 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. 
     
     
         23 . The composition of  claim 1 , wherein said substrate further comprises a lubricant. 
     
     
         24 . The composition of  claim 23 , 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. 
     
     
         25 . The composition of  claim 1 , wherein said substrate further comprises an alkalinizing agent. 
     
     
         26 . The composition of  claim 25 , wherein said alkalinizing agent is selected from the group consisting of sodium stearate, meglumine, disodium phosphate, and ammonia, or a mixture thereof. 
     
     
         27 . The composition of  claim 1 , wherein said coating layer further comprises a plasticizer. 
     
     
         28 . The composition of  claim 24 , wherein said plasticizer is selected from the group consisting of a citric acid ester and a phthalic acid ester. 
     
     
         29 . The composition of  claim 1 , wherein said coating layer further comprises a surfactant. 
     
     
         30 . The composition of  claim 29 , wherein said surfactant is selected from the group consisting of polysorbate 80 and sodium lauryl sulfate. 
     
     
         31 . The composition of  claim 1 , wherein said coating layer further comprises a glidant. 
     
     
         32 . The composition of  claim 31 , wherein said glidant is selected from the group consisting of talc and titanium dioxide. 
     
     
         33 . The composition of  claim 1 , wherein said coating layer further comprises at least one of a coloring agent and a polishing agent. 
     
     
         34 . 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 one volatile alkalizing agent; and   layering said one or more enteric polymers over a substrate comprising the benzimidazole derivative to form a coating layer, the composition comprising said substrate and said coating layer, such that the composition comprises less than 1000 parts per million of residual volatile alkalizing agents relative to composition weight.   
     
     
         35 . The method of  claim 34 , wherein said at least one alkalizing agent comprises one or more of amino alcohols, alkylene diamines, arginine, lysine, and ammonia solution. 
     
     
         36 . A method for preparing a stable composition for a benzimidazole derivative, comprising:
 Dissolving one or more enteric polymers in an organic solvent;   neutralizing said one or more enteric polymers to a pH of at least 6.5 with at least one volatile alkalizing agent; and   layering said one or more enteric polymers over a substrate comprising the benzimidazole derivative to form a coating layer, the composition comprising said substrate and said coating layer, such that the composition comprises less than 1000 parts per million of residual solvent relative to composition weight.   
     
     
         37 . The method of  claim 36 , wherein said neutralizing said one or more enteric coating layers comprises forming an enteric polymer suspension having a pH value of at least about 6.5. 
     
     
         38 . The method of  claim 37 , wherein said pH value of said enteric polymer suspension is from about 7 to about 10. 
     
     
         39 . The method of  claim 1 , wherein said pH is in the range of from about 7 to about 10. 
     
     
         40 . 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, 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 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,   said single coating layer 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 alkalizing agent relative to the total weight of the composition.   
     
     
         41 . The composition of  claim 40 , wherein at least one of said alkilizing agents is selected from the group consisting of amino alcohols, alkylene diamines, arginine and lysine. 
     
     
         42 . The composition of  claim 40 , wherein at least one of said alkilizing agents is ammonia.