Patent EA-001721-B1 (EA)
Title: Sustained-release microgranules containing diltiazem as the active principle
Inventor: DEBREGEAS PATRICE
IPC: A61K9/54
Filed: 1996-12-23
Abstract: 1. Sustained-release (SR) microgranules containing Diltiazem, characterised in that they comprise: - a neutral granular support coated with an active layer comprising: - Diltiazem or a pharmaceutically acceptable salt thereof as active principle, - a surfactant, and - a binder, and a layer which ensures sustained release of the active principle (SR layer) and further characterised in that the microgranules solution degree is defined in vitro with water as a solvent and has the following characteristics: <=15% in one hour, 25-55% in 6 hours, 30-60% in 10 hours, 55-85% in 16 hours and >=80% in 22 hours. 2. Microgranules according to Claim 1, characterised in that the SR layer ensures slow sustained release of the active principle and is itself coated with another active layer comprising: - Diltiazem or a pharmaceutically acceptable salt thereof as active principle, - a surfactant, and - a binder, itself coated with an external layer which ensures rapid sustained release of the active principle contained in this active layer. 3. Microgranules according to Claim 2, characterised in that they also comprise an intercalating layer between the SR layer which ensures slow release of the active principle and the active layer coating this SR layer. 4. Microgranules according to Claim 2 or 3, characterised in that each active layer also comprises a plasticiser, preferably a phthalic acid ester. 5. Microgranules according to Claim 1, characterised in that they comprise a mixture consisting of two categories: slow sustained release microgranules with solution degree defined in vitro with water as a solvent and having the following characteristics: <=30% in 12 hours and >=45% in 20 hours, and rapid sustained release microgranules with solution degree defined in vitro with water as a solvent and having the following characteristics: <=30% in 2 hours and >=65% in 6 hours. 6. Microgranules according to Claim 5, characterised in that each active layer also comprises a plasticiser, preferably a phthalic acid ester. 7. Microgranules according to any one of Claims from 1 to 6, characterised in that the surfactant is an anionactive, nonionogenic, cationactive or amphoteric surfactant. 8. Microgranules according to Claim 7, characterised in that the surfactant is an anionactive surfactant selected in particular from alkali metal (C10-C20) alkylsulfates, preferably from soduim laurylsulfate, alkali metal (C10-C20) alkylsulfonates or alkali metal (C10-C20) alkylbenzenesulfonates. 9. Microgranules according to any one of Claims from 1 to 8, characterised in that the binder consists of any pharmaceutically acceptable binder which is useful for coating neutral granular supports, in particular pharmaceutically acceptable polymers such as polyvinylpyrrolidone. 10. Microgranules according to any one of Claims from 1 to 9, characterised in that the active principle/surfactant weight ratio is between 99/1 and 95/5, preferably about 98/2. 11. Microgranules according to any one of Claims from 1 to 10, characterised in that the active principle/binder weight ratio is between 99/1 and 90/10, preferably about 97/3. 12. Microgranules according to Claim 6, characterised in that they comprise the following components (weight %): neutral granular support 20-25% active principle 70-75% surfactant 0.5-5% binder 0.5-10% plasticiser 0-5%. 13. Microgranules according to Claim 4, characterised in that they comprise the following components (weight %): neutral granular support 10-20% active principle 75-85% surfactant 0.5-5% binder 0.5-10% plasticiser 0.5-5%. 14. Microgranules according to any one of Claims from 1 to 13, characterised in that each SR layer consists of a coating agent which ensures sustained release. 15. Microgranules according to Claim 14, characterised in that the coating agent is combined with one or more common additives, in particular with a bioavailability adjuvant and/or a plasticiser and/or a lubricant. 16. Microgranules according to Claim 14 or 15, characterised in that the coating agent ensuring the sustained release is a water-insoluble film-forming polymer such as polymethacrylates. 17. Microgranules according to any one of Claims from 14 to 16, characterised in that the bioavailability adjuvant is preferably a fatty acid ester and polyoxyethylene, in particular such as described as Polysorbate. 18. Microgranules according to any one of Claims from 14 to 17, characterised in that the lubricant is talc. 19. Microgranules according to any one of Claims from 14 to 18, characterised in that the plasticiser is a pharmaceutically acceptable common plasticiser used for the preparation of microgranules, in particular esters of citric, phthalic and sebacic acids such as triethylcitrate, dibutylsebacate or diethylphthalate and mixtures thereof. 20. Microgranules according to Claim 6, characterised in that they comprise the following components (weight %): - neutral granular support 10-20% - active layer: - active principle 45-65% - binder 0.5-2% - surfactant 0.5-1% - plasticiser 0.5-1% - SR layer: - coating agent 10-30% - bioavailability adjuvant 0.05-0.15% - plasticiser 2-10% - lubricant 2-10%. 21. Microgranules according to Claim 4, characterised in that they comprise the following components (weight %): - neutral granular support 5-15% - active layers: - active principle 45-65% - binder 0.5-2.5% - surfactant 0.75-1.25% - plasticiser 0.75-1.25% - SR layers: - coating agent 15-35% - bioavailabihty adjuvant 0.02-0.15% - plasticiser 2-10% - lubricant 2-10%. 22. Gelatin capsules comprising microgranules according to any one of Claims from 1 to 21.