Özet:

             Introduction. Nowadays, due to limited resources for health care is increasing attention to the use in medical practice of generic medicinal products (MP) of various pharmaco-therapeutical groups, among which attracts attention anti-ischemic drugs, because treatment of cardiovascular diseases for a long time occupies one of the leading places in the medical practice. To increase the saturation of the pharmaceutical market and satisfying the needs of patients in MPs of this group it is necessary to create high-quality, safe and effective generic drugs of domestic production, which have much more cheaper price in comparison to innovative drugs.          According to international regulatory practice, registration of generic MP is subject to proof its bioequivalence to reference product by various methods, one of which is biowaiver - simplified procedure of registration of generic drugs based on biopharmaceutical classification system (BCS) and the results of in vitro comparative studies using test "Dissolution". The biowaiver procedure involves in vivo bioequivalence study, if equivalence of MPs is justified by appropriate in vitro data, which are based on results of three main research of definition: solubility of active substance, the degree of permeability of the active substance, dissolution profiles of generic and reference drugs. This work is dedicated to conducting complex in vitro studies of medicinal product Mildralex-Zdorovye, capsules 250 mg and 500 mg, active ingredient of which is meldonium dihydrate, in order to determine the possible application of biowaiver procedure for state registration of generic MP.          Objects and methods of the study. Objects of study: meldonium dihydrate substance, manufactured by «China Chem Co., Ltd» (China) Mildralex-Zdorovye, capsules 250 mg and 500 mg manufactured by "Pharmaceutical company "Zdorovye", LLC (Ukraine), reference drug Mildronat, hard capsules 250 mg and 500 mg, manufactured by Joint Stock Company «Grindeks» (Latvia). All studies were performed according to standardized procedure developed in accordance with the recommendations of Ministry of Health ST-N 42-7.1: 2014. «Medicinal products. Bioequivalence Studies» and approved by the company. Solubility of active ingredient was determined in three buffer solutions (pH 1.2; 4.5; 6.8) at (37 ± 1)°C by shaking in a thermostatic flask (shake-flask method) of the highest single dose of API (1.0 g) to complete dissolution. The study was carried out by using apparatus for dissolution test PHARMA TEST, PTWS 3SE (Germany) in following conditions: paddle device, volume of dissolution medium - 900 ml, dissolution medium temperature - (37 ± 1)°C, stirring speed - 50 rpm, buffer solutions with pH 1.2; 4.5; 6.8, sampling time: 10, 15, 30 and 45 minutes. For each study 12 units of MP were used for statistical evaluation. Assay of meldoniym in all studies was conducted by developed and validated method by liquid chromatography. Throughout the experiment pH of buffer solutions with MP was controlled.          Results and discussion. Performance of general conditions of the possibility of biowaiver procedure application for test products was analyzed and it was found that generic and reference drugs are in solid dosage form (hard capsules) of systemic action with immediate release for oral use, containing the same drug substance (meldonium), in the same quantity 250 mg or 500 mg and excipients, don't have narrow therapeutic index, and all criteria conform to specified requirements.          According to results of meldonium solubility study was confirmed full solubility of it's highest single dose to a less volume than 250 ml of each of the three buffer solutions, i.e the substance relates to compounds with high solubility. Degree of permeability of meldonium was established in the Department of Experimental Therapy and Pharmacokinetics department of SI "Institute of Pharmacology and Toxicology NAMS of Ukraine" using method of measuring the permeability through monolayer of cell culture Caco-2. Average penetration factor for meldonium dihydrate substance was (1,29 ± 0,12) E-05 cm/s, which corresponds to the criterion of "high degree of penetration."Thus, it was found that meldonium dihydrate belongs to I class according to BCS.          Release of meldonium from generic capsules 250 mg and 500 mg and reference drugs in all 3 recommended dissolution media is more than 85% of the labeled amount of active ingredient in 15 minutes. This means that the drugs being studied belong to rapidly soluble drugs in all recommended dissolution media. Considering established dissolution profiles of objects being studied and reliability of results, confirmed by RSD value, similarity of meldonium capsules was approved without mathematical calculation of similarity factor.          Conclusions. Conducted complex of studies to determine bioequivalence between the generic and reference MP of meldonium, which included analysis of the general conditions of the possibility of bioveyver procedure applicability, the study of solubility and degree of permeability of active substance, determination and comparison of dissolution profiles of the generic and reference products. The study found meldonium belonging to I class according to BCS, and generic and reference drugs of meldonium are quickly soluble drugs in all recommended dissolution media. The similarity of dissolution profiles demonstrates the equivalence of generic and reference drugs of meldonium. The results obtained allowed to make decision regarding registration of generic MP by biowaiver procedure without conducting in vivo bioequivalence studies.

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