Mohylyuk V. Scientific and practical substantiation of formulation and technology of sustained release matrix tablets. Case study: Trimetazidine dihydrochloride.

A thesis for the Candidate of Pharmacy Degree in specialty 15.00.01. - Technology of drugs, organization of pharmaceutical business and forensic pharmacy. - Shupyk National Medical Academy of Postgraduate Education, Kyiv, 2016. Dissertation is dedicated to the study of factors affecting the release kinetics of freely soluble active pharmaceutical ingredient trimetazidine dihydrochloride (TMZo2HCl) in vitro from matrix tablets produced using direct compression method. Effect of soluble matrix formers on TMZo2HCl release profile from matrix tablets was conducted. It was experimentally established that matrix former release prolongation possibility increased with increasing of possibility to form viscous solutions in water: Klucel HXF > Methocel K15M > Polyox WSR-301 > Kollidon K-90 for different polymers and Methocel K100M > K15M > K100LV for same polymers with different molecular weight. Slowdown of release in the release medium with pH 6.8 was due to the interaction of TMZo2HCl and Carbopol 71G with rubber-like layer formation. It was experimentally established that effect of insoluble matrix formers on TMZo2HCl release profile from matrix tablets was in sequence: Ethocel 10 > Precirol ATO 5 ? Kollidon SR > Eudragit RSPO. Swelling of Kollidon SR matrix was due to elastic recovery of spherical shape of polymer particles and polyvinyl acetate swelling upon hydration. Diluents type effect on TMZo2HCl dissolution profile was investigated. Soluble (sorbitol), insoluble (calcium hydrogen phosphate dihydrate), insoluble and swellable (cellulose microcrystalline) diluents were used. Faster TMZo2HCl release from Ethocel 10, Kollidon SR and Methocel K4M matrix tablets with sorbitol than Emcompress and Avicel PH-101 was established. During determination of Emcompress and Avicel PH-101 effect on release kinetics from matrix tablets with different matrix formers were established that release was faster using: Avicel PH-101 in insoluble unswellable matrix of Ethocel 10; Emcompress in insoluble swellable matrix of Kollidon SR; Avicel PH-101 in soluble swellable matrix of Methocel K4М. It was established that TMZo2HCl release kinetics from matrix tablets with Ethocel 10, Kollidon SR and Methocel K4M and Emcompress diluent was higher in pH 1 medium than in pH 6.8 which is consistent with pH-dependent Emcompress solubility. Soluble diluents particle size effect on TMZo2HCl dissolution profile was also investigated. Decreasing of TMZo2HCl dissolution kinetics from Ethocel 10 matrix tablets with lactose and sorbitol particle size increasing was established. The dissolution kinetics from Kollidon SR matrix tablets was decreased with increasing of soluble diluent particle size from 17 to 110 µm, but increasing of sorbitol particle size from 110 to 513 µm had no effect on dissolution profile. Particle size of soluble diluents had no significant effect on dissolution kinetics from Methocel K4M matrix tablets. The dissolution kinetics from tablets with Ethocel 10, Kollidon SR and Methocel K4 as matrix formers was decreased with diluent solubility decreasing. Effect of tablet diameter increasing and height decreasing without tablet mass changing and tablet size increasing with simultaneous tablet mass increasing on in vitro release of TMZo2HCl and caffeine from matrix tablets was investigated. It was found that drug release from Ethocel-10, Kollidon SR and Methocel K4M matrix tablets was increased with tablet surface area to volume ratio increasing. Time of total matrix tablet erosion in disintegration test which mimic influence of peristaltic movement in stomach antrum increased with increasing of higher molecular weight portion of soluble polymer Methocel K. Using different diluents in Methocel K4M matrix tablet the time of total matrix tablet erosion decreased in sequence Avicel PH-101 > Emcompress > Granulac 200. Mechanical loading (2 N during 1 min) of tablets after predetermined time points (1, 2 and 4 h) was used to mimic pyloric sphincter mechanical influence on tablet's release profiles. Resistance of matrix tablets dissolution profile to mechanical loading decreased in sequence: Ethocel 10 > Kollidon SR > Methocel K4М for matrix formers; Avicel PH-> Granulac 200 for diluents in Kollidon SR matrix tablets; caffeine (20 mg/ml) > TMZo2HCl (620 mg/ml) for model drugs with different solubility. Key words: matrix tablets, trimetazidine dihydrochloride, matrix former, diluent, drug release, mechanical loading.