本文選題：有機(jī)凝膠 + 長(zhǎng)鏈脂肪酸�。� 參考：《吉林大學(xué)》2014年碩士論文

【摘要】：本研究針對(duì)上市長(zhǎng)效制劑存在生產(chǎn)成本高，工藝復(fù)雜，制劑中溶劑的生物毒性等問題，設(shè)計(jì)開發(fā)一種生物相容性好、能平穩(wěn)釋藥的小分子原位有機(jī)凝膠系統(tǒng)。選擇藥用的注射用大豆油作為凝膠基質(zhì)，生物相容性輔料脂肪酸及脂肪酸酯作為凝膠因子，非典型性精神分裂癥藥物帕潘立酮為模型藥物，研制能以液態(tài)注射，給藥后立即轉(zhuǎn)變?yōu)榘牍虘B(tài)藥物貯庫(kù)的注射型原位有機(jī)凝膠系統(tǒng)，并對(duì)其進(jìn)行凝膠性質(zhì)評(píng)價(jià)和釋藥行為研究。 選擇4種不同鏈長(zhǎng)的商品化長(zhǎng)鏈脂肪酸（肉豆蔻酸、棕櫚酸、硬脂酸、花生酸），和2種硬脂酸酯（單硬脂酸甘油酯、三硬脂酸甘油酯）作為有機(jī)凝膠因子，進(jìn)行凝膠因子的性質(zhì)表征和成膠性研究。采用倒流法測(cè)定不同凝膠體系的凝膠化轉(zhuǎn)變溫度（Tsg）和凝膠化轉(zhuǎn)變時(shí)間（tsg）；應(yīng)用差示掃描量熱法（DSC）對(duì)凝膠體系進(jìn)行熱分析；通過粘度測(cè)定來評(píng)價(jià)該凝膠體系的機(jī)械性能。結(jié)果表明，隨著脂肪酸中烷烴鏈的增長(zhǎng)，對(duì)注射用大豆油的膠凝能力增強(qiáng)。同時(shí)考察了不同凝膠因子添加量制備的凝膠劑的性質(zhì)，其中分別以7.5%(w/v)硬脂酸和5.0%(w/v)花生酸制備的凝膠體系具有較適宜的凝膠化轉(zhuǎn)變溫度，較高的膠凝效率和一定的凝膠機(jī)械強(qiáng)度。而采用兩種硬脂酸酯制備，不能得到均一的凝膠體系。顯微鏡觀察有機(jī)凝膠劑具有緊密且均一的空間網(wǎng)狀結(jié)構(gòu)。凝膠初步穩(wěn)定性實(shí)驗(yàn)表明此凝膠劑在常溫、離心及反復(fù)升降溫條件保持穩(wěn)定。 以優(yōu)選的凝膠體系制備帕潘立酮載藥有機(jī)凝膠，并進(jìn)行體外釋藥研究。建立了帕潘立酮的體外定量方法，制備載藥有機(jī)凝膠，測(cè)定凝膠化轉(zhuǎn)變溫度和時(shí)間，結(jié)果表明，，藥物引入可以加快凝膠化轉(zhuǎn)變速度，而不影響凝膠體系的凝膠化轉(zhuǎn)變溫度。對(duì)7.5%(w/v)硬脂酸和5.0%(w/v)花生酸制備的凝膠體系進(jìn)行釋藥行為研究，考察體外釋藥行為的影響因素，結(jié)果表明，兩種脂肪酸制備的凝膠體系對(duì)模型藥物帕潘立酮均具有緩釋效果，體外釋藥周期為1至3周；花生酸制備的凝膠體系對(duì)藥物的緩釋作用強(qiáng)于硬脂酸制備的凝膠體系。 對(duì)帕潘立酮有機(jī)凝膠進(jìn)行體內(nèi)評(píng)價(jià)，考察凝膠劑的體內(nèi)釋藥行為、形態(tài)變化和生物相容性。以大鼠為實(shí)驗(yàn)動(dòng)物，于背部皮下注射優(yōu)選帕潘立酮原位凝膠處方，考察凝膠劑的體內(nèi)藥代動(dòng)力學(xué)行為。結(jié)果表明，凝膠劑在動(dòng)物體內(nèi)可以均勻釋放1周，且無突釋效應(yīng)。采用Ritger-Peppas模型對(duì)體內(nèi)釋藥曲線進(jìn)行擬合，推斷該制劑的釋藥機(jī)制為藥物擴(kuò)散和骨架溶蝕的共同作用。采用小動(dòng)物活體成像系統(tǒng)觀察給藥后注射部位凝膠劑的變化，結(jié)果顯示，于給藥9天后，凝膠徹底消失，即釋藥結(jié)束后凝膠劑完全被體內(nèi)攝取。用背部除毛的小鼠進(jìn)行凝膠的組織刺激性實(shí)驗(yàn)，凝膠注射6天后，大鼠注射部位周圍組織無明顯炎癥反應(yīng)，證明凝膠劑具有良好的生物相容性。 本研究開發(fā)的帕潘立酮原位有機(jī)凝膠長(zhǎng)效注射劑制備工藝簡(jiǎn)單，生物相容性好，在體內(nèi)可平穩(wěn)釋藥一周，具備良好的實(shí)用價(jià)值和應(yīng)用前景，也為長(zhǎng)效緩釋制劑的開發(fā)提供理論支持。
[Abstract]:In this study, we designed and developed a small molecular in situ organogels system with good biocompatibility and stable release, aiming at the problems of high production cost, complex process and the biological toxicity of solvent in the preparation of the long-acting preparation. For the gel factor, parpinone, an atypical schizophrenia drug, was used as a model drug to develop an injection in situ organogels system that could be injected into a liquid state by liquid injection into a semisolid drug store immediately after the drug was given, and the gel properties and drug release behavior were evaluated.
4 kinds of commercialized long chain fatty acids (myristic acid, palmitic acid, stearic acid, arachidic acid), and 2 kinds of stearate (glycerol monostearate, three stearic acid glyceride) were selected as organic gelatin factors to study the properties and gelation of gelation factors. The gel transition temperature of different gel systems was determined by reflux method. Tsg) and gelation time (TSG); thermal analysis of the gel system by differential scanning calorimetry (DSC); the mechanical properties of the gel system were evaluated by viscosity measurement. The results showed that the gelation capacity of soybean oil for injection was enhanced with the increase of alkane chain in fatty acids. The addition of different gel factors was also investigated. The gel properties of the gel prepared with 7.5% (w/v) stearic acid and 5% (w/v) arachidic acid have better gelation temperature, higher gelation efficiency and certain gel mechanical strength. The gel system can not be obtained by using two kinds of stearic esters. The microscope observation of organogels is tight. The gel initial stability test showed that the gel remained stable at room temperature, centrifugation and repeated heating and cooling conditions.
The Papin risperidone carrier organogels were prepared by the optimized gel system and the drug release in vitro was studied. The in vitro quantitative method of Papin risone was established to prepare the drug loaded organogels and to determine the gelation temperature and time. The results showed that the gelation speed of the gel could be accelerated by the introduction of the drug without affecting the gelation temperature of the gel system. The drug release behavior of 7.5% (w/v) stearic acid and 5% (w/v) arachidic acid was studied and the influencing factors of the release behavior in vitro were investigated. The results showed that the gel system prepared by two fatty acids had a sustained release effect on parpant model drug, and the release period was 1 to 3 weeks in vitro; the gel system prepared by arachidic acid The sustained release effect of the material is stronger than that of the stearic acid gel system.
The in vivo evaluation of Papin risperidone organogels was conducted in vivo to investigate the drug release behavior, morphological changes and biocompatibility of the gel in vivo. Taking the rat as the experimental animal, the prescription of Papin risone in situ gel was optimized by subcutaneous injection on the back, and the pharmacokinetic behavior of the gel in vivo was investigated. The results showed that the gel could release 1 evenly in the animal body. Ritger-Peppas model was used to fit the drug release curve in vivo. It was concluded that the release mechanism of the drug was the common effect of drug diffusion and skeleton dissolution. The gel agent of the injection site was observed by the living imaging system of small animals. The results showed that the gel disappeared completely after 9 days of administration, that is, the drug release knot. After 6 days of gel injection, there was no obvious inflammatory reaction in the tissue around the injection site of the rat, which proved that the gel had good biocompatibility.
The preparation of Papin risperidone in situ organogels has a simple preparation process, good biocompatibility, a stable release of drug in the body for a week, and has good practical value and application prospects. It also provides theoretical support for the development of long-acting sustained-release preparation.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R943

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