本文選題：藻酸雙酯鈉(PSS)　切入點：緩釋片　出處：《中國海洋大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：藻酸雙酯鈉(Propylene glycol alginate sodium sulfate, PSS)是中國自主研發(fā)的第一個海洋多糖藥物,在臨床上主要用于缺血性心腦血管疾病的治療。但目前PSS的藥物制劑僅僅有普通片劑及注射劑,且質(zhì)量標(biāo)準(zhǔn)不夠完善,尤其是其固體制劑缺少對溶出度的考察,不能滿足日益增長的臨床需求。同時,PSS普通片劑存在需多次給藥,血藥濃度波動較大,生物利用度低,患者順應(yīng)性差等問題,因此研究和開發(fā)PSS的緩釋制劑等新劑型是臨床上的迫切需要。本文以目前使用較為廣泛的羥丙基甲基纖維素(HPMC)、羧甲基纖維素鈉(CMC-Na)、十八醇作為骨架材料,分別采用濕法制粒和熔融制粒兩種方法對PSS緩釋片的制備工藝進(jìn)行了研究；并對兩種方法的片重差異,片劑硬度和工藝操作過程進(jìn)行了比較,結(jié)果表明熔融制粒方法更適合于PSS緩釋片的制備。根據(jù)PSS的結(jié)構(gòu)和理化性質(zhì)特點,本文分別采用高效凝膠滲透色譜(HPGPC)方法和柱前衍生高效液相色譜(PC-HPLC)法對PSS緩釋片的含量和體外釋放度測定進(jìn)行了較為系統(tǒng)的研究。采用HPGPC法在多種凝膠色譜柱上未能將PSS與輔料完全分離,PSS與輔料色譜峰存在部分重疊；但將Shodex OHpak SB-806 HQ色譜柱與TSK gel G3000 PWXL色譜柱進(jìn)行串聯(lián),可使PSS與各輔料的分離得到明顯改善,而且采用峰高定量因可有效降低色譜峰少量重疊的影響,比采用峰面積定量具有更好的線性關(guān)系,該方法適合PSS緩釋片的含量測定。采用PC-HPLC法將PSS緩釋片進(jìn)行降解和衍生后測定,各輔料不影響PSS的含量測定,在0.3～12 mg/mL濃度范圍內(nèi)與峰面積呈現(xiàn)良好的線性關(guān)系(R2=0.9983),精密度RSD為1.4%(n=5),重復(fù)性RSD為3.4%(n=5),具有專屬性強,靈敏度高和重現(xiàn)性好的特點,適合PSS緩釋片體外釋放度的測定。通過單因素試驗考察了HPMC、CMC-Na和十八醇用量對體外藥物釋放的影響,進(jìn)一步運用正交設(shè)計法對處方進(jìn)行了優(yōu)化,并采用釋藥動力學(xué)模型對PSS緩釋片的體外藥物釋放特性進(jìn)行了擬合。結(jié)果表明,PSS緩釋片的最適處方為HPMC、CMC-Na和十八醇的用量分別為片重的15%,10%和10%(W/W)。按最適處方制備的PSS緩釋片在2、6、12 h內(nèi)可分別釋放藥物30.3%,70.9%和95.5%,其藥物釋放行為符合一級方程,并以Fickian擴散和骨架溶蝕兩種機制協(xié)同作用釋放藥物。本文對PSS緩釋片的制備工藝、輔料對藥物釋放的影響和處方的優(yōu)化進(jìn)行了系統(tǒng)的研究,成功制備得到了藥物釋放行為符合一級方程的PSS緩釋片；并建立了適用于PSS緩釋片含量測定的高效凝膠滲透色譜法；建立了適用于PSS緩釋片體外釋放度測定的柱前衍生高效液相色譜方法。這些研究結(jié)果為PSS及其它海洋多糖藥物緩釋制劑的應(yīng)用開發(fā)提供了基礎(chǔ)和參考,在降低PSS臨床應(yīng)用中的不良反應(yīng),改善患者的順應(yīng)性方面具有重要的積極作用。
[Abstract]:Sodium alginate glycol alginate sodium sulfate (PSSs) is the first marine polysaccharide drug developed by China, which is mainly used in the treatment of ischemic cardio-cerebrovascular diseases. The quality standard is not perfect, especially its solid preparation is lack of the investigation of dissolution, and can not meet the increasing clinical demand. At the same time, the common tablets of PSS need to be given many times, the blood concentration fluctuates greatly, the bioavailability is low. Patients' compliance is poor, so it is an urgent need to study and develop new dosage forms of PSS, such as sustained-release formulations. In this paper, the widely used hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose sodium (CMC-Na), octadecanol (octadecanol) were used as skeleton materials. The preparation process of PSS sustained-release tablets was studied by wet granulation and melt granulation, and the weight difference, hardness and operation process of the two methods were compared. The results showed that the melt granulation method was more suitable for the preparation of PSS sustained-release tablets. The content and in vitro release of PSS sustained-release tablets were studied by high performance gel permeation chromatography (HPGPC) and precolumn derivatization high performance liquid chromatography (PC-HPLC), respectively. HPGPC method was used to determine the content and in vitro release rate of PSS sustained-release tablets on various gel chromatographic columns. The chromatographic peaks of PSS and excipients were partially overlapped; But when the Shodex OHpak SB-806 HQ column and the TSK gel G3000 PWXL column were connected in series, the separation of PSS and the excipients could be improved obviously, and the effect of a little overlap of the chromatographic peaks could be effectively reduced by using the quantitative factor of peak height. This method is suitable for the content determination of PSS sustained-release tablets. The PSS sustained-release tablets are degraded and derivatized by PC-HPLC method. The contents of PSS are not affected by the excipients. There is a good linear relationship between the peak area and the peak area in the concentration range of 0.3 ~ (12) mg/mL. The precision RSD is 1. 4% and the reproducible RSD is 3. 4%. It has the characteristics of high specificity, high sensitivity and good reproducibility. The effects of the dosage of HPMC, CMC-Na and octadecanol on drug release in vitro were investigated by single factor test, and the formulation was optimized by orthogonal design. The pharmacokinetic model was used to simulate the drug release characteristics of PSS sustained-release tablets in vitro. The results showed that the optimal formulation of PSS sustained-release tablets was that the dosage of HPMC- CMC-Na and octadecanol was 15g / 10% and 10g / W / WN of the tablet weight, respectively. Sustained release tablets could release 30. 30.9% and 95. 5% of the drugs within 12 h, respectively. The drug release behavior of the tablets was in accordance with the first order equation. In this paper, the preparation process of PSS sustained release tablets, the effect of excipients on drug release and the optimization of formulation were systematically studied. PSS sustained-release tablets with first-order equation were successfully prepared, and a high performance gel permeation chromatography was established for the determination of PSS sustained-release tablets. A precolumn derivatization high performance liquid chromatography (HPLC) method for the determination of in vitro release of PSS sustained-release tablets was established. These results provide a basis and reference for the application and development of PSS and other marine polysaccharide drug sustained-release preparations. It plays an important role in reducing adverse reactions in clinical application of PSS and improving compliance of patients.
【學(xué)位授予單位】：中國海洋大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R943

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