Patent EA-002502-B1 (EA)
Title: Pharmaceutical formulation comprising a 2-[[(2-pyridinyl) methyl] sulfinyl] benzimidazole having anti-ulcer activity and a process for the preparation of such formulation
Inventor: HENRIKSEN KRISTIAN LUND
IPC: A61K9/64
Filed: 1999-03-17
Abstract: 1. An oral pharmaceutical formulation comprising a 2-[[(2-pyridinyl)methyl]sulfinyl]benzimidazole having anti-ulcer activity as active ingredient, said formulation comprising granules having a substantially inert core coated with i) an inner coating layer comprising the benzimidazole, a disintegrant and a surfactant in a matrix of a melt coating substance essentially consisting of one or more esters of glycerol and fatty acids, ii) an outer coating layer being an enteric coating, and iii) an intermediate coating layer separating the enteric coating layer from the inner coating layer. 2. The formulation of claim 1, wherein the melt coating substance has a melting point in the range from 30 to 60 degree C, in particular in the range from 30 to 50 degree C, and more definite from 35 to 45 degree C. 3. The formulation according to claim 1, wherein the melt coating substance consists essentially of a mixture of hard fat and glyceryl monostearate 40-50. 4. The formulation according to claim 3, wherein the ratio by weight between hard fat and glyceryl monostearate 40-50 is in the range from 100:1 to 1:2, and preferably in the range from 20.1 to 5:2. 5. The formulation according to any preceding claim, wherein the disintegrant is a superdisintegrant, in particular crospovidone. 6. The formulation according to any preceding claim, wherein the benzimidazole is micronized. 7. The formulation according to any preceding claim, wherein the surfactant is an anionic or a nonionic surfactant, in particular sodium lauryl sulfate. 8. The formulation according to any preceding claim, wherein the substantially inert cores are nonpareils made from saccharose and starch and of a size in the range from 200 to 1500 .mu.m, in particular size in the range from 850 to 1000 .mu.m. 9. The formulation according to any preceding claim, wherein the enteric coating layer comprises a copolymer of methacrylic acid and methylmethacrylate, optionally in a combination with a plasticizer, in particular triethyl citrate , and/or other auxiliary agents, in particular micronized talc. 10. The formulation according to any preceding claim, wherein the intermediate coating layer comprises hydroxypropyl methylcellulose, optionally in a combination with titanium dioxide or micronized talc and/or other auxiliary agents. 11. The formulation according to any preceding claim, wherein the intermediate coating layer comprises a layer of the melt coating substance consisting essentially of one or more esters of glycerol and fatty acids, optionally comprising auxiliary agents, such as a disintegrant or a surfactant, but free of benzimidazole. 12. The formulation according to ny preceding claim, wherein the benzimidazole is omeprazole, pantoprazole or lansoprozole. 13. The formulation according to any preceding claim, being provided as a unit dose in a gelatine capsule, in particular as the unit dose, wherein the unit dose is 10, 20 or 40 mg of omeprazole, 40 mg of pantoprazole or 15 or 30 mg of lansoprazole. 14. A process for the preparation of an oral pharmaceutical formulation according to any preceding claim comprising the step of providing substantially inert cores with a coating layer comprising the benzimidazole, a disintegrant and a surfactant in a matrix of a melt coating substance consisting essentially of one or more esters of glycerol and fatty acids, by a melt coating technique. 15. The process according to claim 14, further comprising the steps of i) mixing the benzimidazole with the surfactant and the disintegrant, ii) blending the mixture obtained in step i) with the substantially inert cores while heating to a temperature above the melting point of the melt coating substances, iii) adding the melt coating substance to the blend obtained in step ii) while blending and heating to a temperature above the melting point of the melt coating substance, iv) continuing the blending and heating to a temperature above the melting point of the melt coating substance until an adequate coating of the cores has been obtained, and v) cooling the coated cores obtained in step iv) to room temperature. 16. The process according to claim 15, wherein the substantially inert cores are heated temperature above the melting point of the melt coating substance prior to blending the mixture obtained in step ii) 17. The process according to claim 15 or 16, wherein the melt coating substance is added as a melt in step (iii). 18. The process according to claim 15 or 16, wherein the melt coating substance is added as a finely divided solid in step (iii). 19. The process according to any of claims 15-18, wherein the cooling to room temperature in step v) is carried out in two steps, the first step being carried out under continued blending until a temperature slightly above the melting point of the melt coating substance has been reached, and the second step being carried out by tray cooling. 20. The process according to any of claims 14-19, comprising the further steps of coating the obtained substantially inert cores, coated with the coating layer comprising the benzimidazole, a disintegrant and a surfactant in a matrix of a melt coating substance, with an intermediate coating layer and an outer coating layer, the outer coating layer being an enteric coating.