基于 6,8-二甲基-2-哌啶甲基-2,3-二氢噻唑并[2,3-F]黄嘌呤的肝细胞单氧化酶系统诱导剂片剂成分的开发

A. I. Petrakov, V. V. Sheikin, S. Krivoshchekov, E. Bezverkhniaia, A. M. Guryev, M. V. Belousov
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Development of a dosage form for 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine requires evaluation of its technological properties which was the aim of the present study.Aim. Preparation of a tablet dosage form for 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine by direct pressing.Materials and methods. The object of the study was the substance of 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine (DPDX270216001 series). Lactose monohydrate (200-559-2, LLC \"Neftegazkhimkomplekt\", Russia), microcrystalline cellulose (100-32-2, Silverline chemicals Ltd., India), potato starch, hydroxypropyl cellulose (ZW180113, Fengchen Group Co., Ltd., Китай), talc (LLC \"Agat-Med\", Russia), magnesium stearate (209-150-3, Ataman Chemicals) were used as excipients. 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引用次数: 0

摘要

导言。细胞色素 P450 抑制是导致肝炎病因和病理治疗效果不佳的原因。最近的实验和临床研究表明,需要使用肝细胞单氧化酶系统诱导剂来提高慢性肝炎和肝硬化的治疗效果。6,8-二甲基-2-哌啶甲基-2,3-二氢噻唑并[2,3-F]黄嘌呤是一种很有前景的肝细胞单加氧酶系统诱导剂,在急性低压缺氧、肝缺血、未结合高胆红素血症、中毒性肝炎等模型中具有解毒和细胞保护活性。开发 6,8-二甲基-2-哌啶甲基-2,3-二氢噻唑并[2,3-F]黄嘌呤的剂型需要对其技术特性进行评估,这也是本研究的目的所在。通过直接压片法制备 6,8-二甲基-2-哌啶甲基-2,3-二氢噻唑并[2,3-F]黄嘌呤的片剂。研究对象为 6,8-二甲基-2-哌啶甲基-2,3-二氢噻唑并[2,3-F]黄嘌呤(DPDX270216001 系列)。一水乳糖(200-559-2,LLC "Neftegazkhimkomplekt",俄罗斯)、微晶纤维素(100-32-2,Silverline 化学品有限公司,印度)、马铃薯淀粉、羟丙基纤维素(ZW180113,丰臣集团有限公司,Китай)、滑石粉(LLC "Agat-Med",俄罗斯)、硬脂酸镁(209-150-3,Ataman 化学品公司)用作辅料。根据以下指标对物质特性进行评估:外观、干燥损失、成分分数、流动性、体积密度、孔隙率、片剂压缩(内聚力)、片剂从基质中的弹射力。片剂质量根据以下指标进行评价:流动性、体积密度、片剂压缩(内聚力)、片剂从基质中的弹射力。片剂采用直接压片法制备。所得片剂根据以下参数进行分析:平均重量、压碎强度、崩解度。测试按照《俄罗斯联邦国家药典》进行。该物质的压缩性(内聚力)差,流动性低,体积密度低,孔隙率高。添加一水乳糖和微晶纤维素后,内聚力(压缩)参数有所改善,但片剂从基质中弹出的力有所增加。随后加入的硬脂酸镁使片剂从基质中的弹射力降低了 5 倍。片剂的流动性增加到 3.5-4.0 克/秒,片剂的崩解时间延长(13-14 分钟)。在模具中加入 10% 的崩解剂提高了崩解率。根据所研究的物质特性,确定了片剂质量的最佳比例。通过直接压片法获得 6,8-二甲基-2-哌啶甲基-2,3-二氢噻唑并[2,3-F]黄嘌呤片剂的可能性已经显现。
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Development of the Tablet Dosage Form Composition for the Inductor of Hepatocytes Monooxygenase System Based on 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine
Introduction. Cytochromes P450 depression is the reason for the low effectiveness of etiotropic and pathogenetic therapy of hepatitis. Recent experimental and clinical studies demonstrated the need for use of inducers of hepatocytes monooxygenase system to increase the effectiveness of treatment of chronic hepatitis and cirrhosis. 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine is a promising inducer of hepatocytes monooxygenase system with detoxifying and cytoprotective activity demonstrated in models of acute hypobaric hypoxia, liver ischemia, unconjugated hyperbilirubinemia, toxic hepatitis. Development of a dosage form for 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine requires evaluation of its technological properties which was the aim of the present study.Aim. Preparation of a tablet dosage form for 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine by direct pressing.Materials and methods. The object of the study was the substance of 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine (DPDX270216001 series). Lactose monohydrate (200-559-2, LLC "Neftegazkhimkomplekt", Russia), microcrystalline cellulose (100-32-2, Silverline chemicals Ltd., India), potato starch, hydroxypropyl cellulose (ZW180113, Fengchen Group Co., Ltd., Китай), talc (LLC "Agat-Med", Russia), magnesium stearate (209-150-3, Ataman Chemicals) were used as excipients. Evaluation of the substance properties was carried according to the following indicators: appearance, loss on drying, fractional composition, flowability, bulk density, porosity, tablet compression (cohesion), ejection force of the tablet from matrix. Tablet masses were evaluated according to the following indicators: flowability, bulk density, tablet compression (cohesion), ejection force of the tablet from matrix. The tablets were obtained by the method of direct pressing. The analysis of obtained tablets were carried out according to the following parameters: average weight, crushing strength, disintegration. The tests were carried out in accordance with the Russian Federation State Pharmacopoeia.Results and discussion. The substance demonstrated poor compression (cohesion), low flowability, low bulk density and high porosity. The addition of lactose monohydrate and microcrystalline cellulose improved the cohesion (compression) parameter, but increased the ejection force of the tablet from matrix. The subsequent addition of magnesium stearate reduced the ejection force of the tablet from matrix by 5 times. The flowability of the tablet mass increased to 3,5–4,0 g/s, the disintegration time of the tablets increased (13–14 min). The introduction of 10 % disintegrators into the mold improved the disintegration rates.Conclusion. Based on the studied properties of the substance, was developed the optimal ratio of tablet mass. The possibility of obtaining a dosage form – tablets of 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-F]xanthine by direct pressing was show.
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