Розробка складу та технології комбінованих ректальних супозиторіїв з індол-3-карбінолом

Abstract

Робота присвячена розробці нового вітчизняного препарату комбінованого складу з індол-3-карбінолом та мелоксикамом у формі ректальних супозиторіїв для лікування доброякісних захворювань передміхурової залози. На підставі результатів органолептичних, фізико-хімічних, фармако-технологічних, структурно-механічних, біофармацевтичних та фармакологічних досліджень обґрунтовано склад допоміжних речовин супозиторіїв, а саме: ПЕО-основа у співвідношенні ПЕО-1500 : ПЕО-400 – 95 : 5 та ПАР – Montanox 80 у концентрації 3 %. Розроблено раціональну технологію супозиторіїв для лікування ДЗПЗ та досліджено їх основні показники якості. Розроблено проекти ТР і МКЯ на препарат «Індоксам».

Работа посвящена разработке нового отечественного препарата комбинированного состава с индол-3-карбинолом и мелоксикамом в форме ректальных суппозиториев для лечения доброкачественных заболеваний предстательной железы. На основании результатов органолептических, физико-химических, фармако-технологических, структурно-механических, биофармацевтических и фармакологических исследований обоснован состав вспомогательных веществ суппозиториев, а именно: ПЭО-основа в соотношении ПЭО-1500 : ПЭО-400 – 95 : 5 и ПАВ – Montanox 80 в концентрации 3%. Разработана рациональная технология суппозиториев для лечения доброкачественных заболеваний предстательной железы и исследованы их основные показатели качества. Разработаны проекты ТР и МКК на препарат «Индоксам».

The work is devoted to the development of a new combined domestic drug of indole-3-carbinol and meloxicam in the form of rectal suppositories for the treatment of benign prostatic diseases. Perspectives of the use of the combination of indole-3-carbinol and meloxicam in the composition of rectal suppositories for the treatment of BPD, which can simultaneously affect various pathogenesis of these diseases, have a polyvalent pharmacological effect on the patient's body have been reviewed. The results of theoretical and experimental researches on the choice of concentration of active pharmaceutical ingredients and auxiliary substances in the suppositories are given. Taking into account the results of microscopic analysis and solubility of indole-3-carbinol and meloxicam in various solvents, a rational way of administering APIs to the suppository mass has been determined. On the basis of physico-chemical and pharmacological studies, an optimal suppository basis was chosen and its rational composition was justified: PEO-1500 : PEO-400 as 95 : 5. Taking into account the results of surfactants influence on the organoleptic, physico-chemical, technological and osmotic properties of model suppository samples, an optimal emulsifier – Montanox 80 at a concentration of 3.0 % was selected, which allowed obtaining the most aggregatively stable systems and provided the necessary osmotic activity of the drug. The results of the development of the composition and technology of the preparation under the conditional name "Indoxam" are presented. Structural-mechanical properties of developed suppositories were investigated and their non-Newtonian type of flow and thixotropy have been confirmed. The optimum temperature range of suppository pouring has been established – 50-55 °C, which allowed obtaining a high-quality preparation in terms of homogeneity. With the help of modern methods of analysis, techniques of selected APIs identification and quantification have been developed. It has been established that the developed method of high-performance liquid chromatography allows not only to quantify indole-3-carbinol and meloxicam in suppositories, but also to assess the homogeneity of their distribution. Validation of the developed methodology has been carried out, its suitability and repeatability for simultaneous quantitative determination of both meloxicam and indole-3-carbinol in the final dosage form have been proved. Quality indicators of developed suppositories according to the requirements of the SPU have been determined: description, identification and quantitative content of API, homogeneity of dosage units, homogeneity of mass, homogeneity, pH, disintegration, stability of suppositories to fracture and MBP. Based on the conducted studies, the stability of the developed suppositories has been proved and the shelf life of them was set to 2 years at a temperature of 8-15 °С, when stored in finished forms of foil and light protective polyvinylchloride film. The study of microbiological purity of the drug showed compliance with the requirements of the SPU: 1 g of the preparation is allowed to have 1000 CFU of aerobic microorganisms (TAMC) and 100 CFU of yeast and mold fungi (TYMC), while taking into account all the colonies of bacteria and fungi. The presence of Escherichia coli in 1.0 g of the drug is not allowed. Based on microbiological studies, suppositories with a combination of indole-3-carbinol and meloxicam have a pronounced antibacterial effect in relation to gram-positive and gram-negative bacteria and antifungal action, which allows the use of "Indoxam" suppositories for the treatment of abacterial and bacterial forms of prostatitis. By conducting preclinical pharmacological studies, it has been proved that suppositories of this composition have a positive effect on the state of the prostate gland, effectively inhibit the inflammatory process, show a pronounced prostate- protective action, have no toxic effect and are suitable for prolonged use. For the first time on the basis of organoleptic, physico-chemical, pharmacotechnological, structural-mechanical, biopharmaceutical, microbiological and pharmacological studies, the composition and technology of rectal suppositories "Indoxam" have been theoretically and experimentally substantiated. The TR and MQC projects have been developed and tested in the industrial conditions of PJSC "Lekhim-Kharkiv" (approval test certificate dated September 24, 2018).