The above benzimidazole compounds are very effective drugs for the treatment of gastric and duodenal ulcers, gastroesophageal reflux disease, severe erosive esophagitis, Zollinger-Ellison syndrome and H pylori eradication. However, it is well known that these compounds have poor stability. In the solid state they are susceptible to heat, moisture and light, and in aqueous solution or suspension their stability decreases with decreasing pH. The degradation of these compounds is catalyzed by acidic reacting compounds.
Pharmaceutical preparations containing acid-labile compounds have to be subcoated in order to avoid a reaction between the active ingredient and the outer acidic enteric coating which reaction--if occurring--would result in degradation, destabilization and consequently discoloration of the active ingredient.
The use of a barrier layer to protect the pharmaceutical from degradation caused by an enteric coating is well known from the prior art. Nevertheless, it is not possible to use conventional enteric coatings in a conventional way for acid labile benzimidazole compounds since decomposition takes place and the preparations become discolored and lose the active ingredient content with time. Prior art partially avoids the above mentioned stability problem by including an alkaline salt form of the benzimidazole compound or incorporating an alkaline reacting compound into an enteric coated preparation (U.S. Pat. No. 4,786,505, U.S. Pat. No. 5,232,706, EP 237200, EP 124495), the alkaline reacting compound being present within or on the surface of the nucleus together with the benzimidazole compound. Also the alkaline reacting compound is being used in the composition of a second isolation layer to ensure stability of these forms. Thus, the association of an alkaline substance to the neutral form of the benzimidazole compound is taught in order to improve the stability of the active compound, especially for solid dosage forms, and enteric coating is recommended. Nevertheless, a superior stability of the preparations would be required to ensure the stability of the drug for long term storage.
USPTO Backgrounds
USPTO Backgrounds