本文關(guān)鍵詞： 肺動脈高壓 制備工藝 質(zhì)量標準 穩(wěn)定性研究　出處：《河南大學》2014年碩士論文　論文類型：學位論文

【摘要】：肺動脈高壓作為目前臨床非常見的疾病之一,具有較高的致死率和致殘率,其臨床診治一直是醫(yī)學界的重要難題。臨床研究證實,肺動脈高壓的發(fā)病與血管收縮、原位血栓的形成等有著密切的關(guān)系,降低患者的心臟負荷和改善其血運情況是治療肺動脈高壓的重要途徑。隨著臨床研究的不斷深入,內(nèi)皮素受體拮抗劑在治療肺動脈高壓方面的臨床療效備受關(guān)注。TY-202作為血管內(nèi)皮素拮抗劑,可通過抑制ETA受體和ETB受體發(fā)揮較為明顯的抗肺血管收縮和抑制血管重構(gòu)的臨床效果。TY-202的各類制劑已獲FDA批準在美國及周邊國家上市,其臨床效果頗受肯定。因此,開發(fā)以TY-202為活性成分的藥物制劑對于緩解肺動脈高壓臨床用藥缺乏及降低肺動脈高壓患者醫(yī)療經(jīng)濟成本具有重要的意義。 通過對TY-202溶解性、油水分配系數(shù)、熔點等理化性質(zhì)進行考察,歸屬其為BCS二類藥物。建立體外溶出度評價方法,照溶出度測定法(中國藥典二部附錄XC,第二法)優(yōu)先以pH5.0醋酸緩沖液900ml為溶劑,轉(zhuǎn)速50轉(zhuǎn)/分,于220nm的波長處檢測,以HPLC法計算每片溶出量,并與國外市售品進行對比,評價原研一致性。處方工藝主要包括片劑制備以及包衣操作。通過正交試驗,以片重差異、溶出度、硬度為綜合指標,篩選最佳處方,并進行優(yōu)化,確定最終素片處方,并對片劑進行包衣工藝研究,以包衣效率為考察指標正交試驗優(yōu)化包衣參數(shù),以確定的片劑處方及包衣參數(shù)進行中試三批樣品生產(chǎn)。 通過建立高效液相色譜法,對TY-202片劑質(zhì)量進行研究,測定有關(guān)物質(zhì)、含量和溶出度,并對三批中試樣品進行加速試驗,在6個月內(nèi)TY-202片的外觀、含量、溶出度未出現(xiàn)明顯差異,有關(guān)物質(zhì)隨放置時間有不同程度的變化,但均符合規(guī)定；以市售包裝樣品長期穩(wěn)定性試驗9個月各項指標均未發(fā)生明顯變化,均在質(zhì)量控制范圍內(nèi)。
[Abstract]:Pulmonary hypertension, as one of the most common diseases, has a high mortality and disability rate. The clinical diagnosis and treatment of pulmonary hypertension has been an important problem in the medical field. Clinical studies have confirmed that the pathogenesis of pulmonary hypertension and vasoconstriction. There is a close relationship between the formation of in situ thrombosis and so on. It is an important way to treat pulmonary hypertension to reduce the cardiac load and improve the blood flow of the patients. The clinical efficacy of endothelin receptor antagonist in the treatment of pulmonary hypertension has attracted much attention. TY-202 is used as endothelin antagonist. The clinical effects of anti-pulmonary vasoconstriction and vascular remodeling by inhibiting ETA receptor and ETB receptor .TY-202 have been approved by FDA to be listed in the United States and neighboring countries. The development of drug preparation with TY-202 as the active component is of great significance in alleviating the shortage of pulmonary hypertension and reducing the medical cost of patients with pulmonary hypertension. The solubility of TY-202, oil / water partition coefficient, melting point and other physicochemical properties were investigated. The method of dissolution evaluation in vitro was established. PH5.0 acetic acid buffer (900ml) was used as solvent in the second appendix of Chinese Pharmacopoeia, and was detected at 220 nm wavelength. The dissolution of each tablet was calculated by HPLC method, and compared with that of foreign market. To evaluate the consistency of original research. The prescription process mainly includes tablet preparation and coating operation. Through orthogonal test, the optimum prescription was screened and optimized to determine the final prescription by taking the weight difference of tablets, dissolution and hardness as the comprehensive index. The coating process of tablets was studied and the coating parameters were optimized by orthogonal test with coating efficiency as the index. The tablet formulation and coating parameters were produced in the pilot-scale three batches of samples. The quality of TY-202 tablets was studied by high performance liquid chromatography (HPLC). The related substances, contents and dissolution were determined, and accelerated tests were carried out on three pilot-scale samples. The appearance and content of TY-202 tablets were determined within 6 months. There was no significant difference in dissolution, the relative substances varied with the time of storage, but all of them were in accordance with the regulations, and the indexes of the long-term stability test of the package samples on the market for 9 months did not change obviously, all of them were within the range of quality control.
【學位授予單位】：河南大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R943

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