辛苯聚醇陰道用殼聚糖溫敏緩釋凝膠的研制
發(fā)布時(shí)間：2018-08-15 13:43
【摘要】：辛苯聚醇(Octoxynol-9,O-9)是應(yīng)用廣泛的壬苯醇醚(Nonoxynol-9,N-9)的類似物,也是一種非離子型表面活性劑類陰道用殺精劑,但其毒性較N-9小[1-2]。而現(xiàn)今的外用避孕制劑多存在易于泄漏,難以鋪展覆蓋陰道表面,在陰道內(nèi)滯留時(shí)間短,生物利用度低的問(wèn)題。溫敏凝膠是在位凝膠的一種,可響應(yīng)溫度變化發(fā)生相變而具有獨(dú)特的溶液-凝膠轉(zhuǎn)變性質(zhì),從而有著給藥方便、黏附力強(qiáng)、長(zhǎng)時(shí)間滯留的特點(diǎn),因此尤其適用于黏膜給藥[3-4]。殼聚糖(Chitosan,CS)也是溫敏凝膠體系中一種常見(jiàn)的材料,有著良好的生物降解性、生物相容性、無(wú)毒與抑菌性,是一種優(yōu)良的生物粘附性材料,有延緩藥物釋放的作用[5-6]。因此本研究將安全性更高的O-9與優(yōu)良的生物粘附材料CS結(jié)合,制備具有溫度敏感性的新型陰道用制劑,可使制劑在陰道表面廣泛覆蓋,延長(zhǎng)藥物在陰道中的滯留時(shí)間,得到更安全、有效、使用方便的新型外用避孕制劑。本研究選擇藥用輔料泊洛沙姆(Poloxamer)與CS結(jié)合作為溫敏凝膠基質(zhì),采用冷溶法制備辛苯聚醇陰道用溫敏性凝膠[(O-9)-VTG],并用星點(diǎn)設(shè)計(jì)-效應(yīng)面法優(yōu)化處方,篩選出最優(yōu)處方的基質(zhì)配比為P407:P188:甘油:CS=16.3:5.7:5:0.6,按處方制備的(O-9)-VTG的膠凝溫度為33℃,膠凝時(shí)間約1.6min。采用高效液相色譜法建立了(O-9)-VTG質(zhì)量控制方法,并對(duì)3批樣品進(jìn)行了質(zhì)量評(píng)價(jià),含量分別為標(biāo)示量的99.83%、100.69%、99.31%(n=3)。為探討(O-9)-VTG的體外釋放行為,采用無(wú)膜溶出法進(jìn)行體外釋放度的研究。結(jié)果表明,(O-9)-VTG釋藥模型擬合遵循零級(jí)方程。通過(guò)影響因素試驗(yàn)、加速實(shí)驗(yàn)及長(zhǎng)期穩(wěn)定性試驗(yàn),以外觀性狀、pH、膠凝溫度、O-9含量為指標(biāo)對(duì)制劑進(jìn)行初步穩(wěn)定性考察,結(jié)果表明(O-9)-VTG具有良好的穩(wěn)定性。采用試管倒置法可測(cè)得膠凝完全時(shí)的膠凝溫度,但無(wú)法對(duì)凝膠的相變行為及凝膠強(qiáng)度等進(jìn)行表征,因此采用動(dòng)態(tài)流變學(xué)實(shí)驗(yàn)測(cè)定溫敏凝膠在相變過(guò)程中的流變參數(shù),可測(cè)得(O-9)-VTG的膠凝溫度為32.6℃,與試管倒置法測(cè)得結(jié)果基本一致,其在室溫下(25℃)具有良好的流動(dòng)性,粘度小,為牛頓流體,易于注射入陰道內(nèi);置于陰道后可迅速鋪展,在一定時(shí)間內(nèi)膠凝后,凝膠粘度增大,具有假塑性流體特征。另外模擬了陰道液的稀釋作用對(duì)(O-9)-VTG膠凝行為的影響,證實(shí)了(O-9)-VTG在體溫條件下仍可形成凝膠。通過(guò)分別陰道給予雌性大鼠自制辛苯聚醇普通凝膠[(O-9)-gels]及(O-9)-VTG,收集含藥陰道沖洗液,建立陰道沖洗液中藥物含量測(cè)定方法,并采用DAS軟件對(duì)陰道沖洗液中藥物量進(jìn)行處理得到(O-9)-gels和(O-9)-VTG的陰道內(nèi)滯留時(shí)間,結(jié)果與(O-9)-gels相比,制備的(O-9)-VTG具有明顯的陰道內(nèi)粘附滯留性能。為評(píng)價(jià)制劑的有效性,以市售壬苯醇醚凝膠(N-9 Jelly)為對(duì)照,采用改良的Sander-cramer方法觀察(O-9)-VTG的最低有效殺精濃度(MEC)對(duì)大鼠精子的作用,結(jié)果表明,(O-9)-VTG的MEC為0.50mg·ml-1,與N-9 Jelly的效果相當(dāng)。大鼠陰道內(nèi)給藥后,使雌雄鼠合籠,觀察避孕效果,得到(O-9)-VTG與N-9 Jelly均有較高的避孕率的結(jié)論,與自然對(duì)照組及空白凝膠組之間的差異具有顯著性,表明(O-9)-VTG陰道用藥具有較好的抗生育作用。陰道粘膜刺激性試驗(yàn)及陰道急性毒性試驗(yàn)以SD雌性大鼠為對(duì)象,通過(guò)肉眼和陰道病理切片觀察,采用Eckstein刺激性評(píng)價(jià)標(biāo)準(zhǔn)評(píng)價(jià)刺激性,結(jié)果顯示(O-9)-VTG對(duì)大鼠陰道無(wú)明顯的刺激作用,局部急性毒性實(shí)驗(yàn)表明經(jīng)陰道用藥也無(wú)毒性。綜上所述,本研究制備的(O-9)-VTG膠凝溫度適宜,溫度敏感性好,制劑質(zhì)量穩(wěn)定,具有一定的緩釋作用,體內(nèi)滯留時(shí)間長(zhǎng),組織相容性好,制備得到更安全、有效、使用方便的新型外用避孕藥,也為辛苯聚醇陰道局部用藥制劑的進(jìn)一步開(kāi)發(fā)研究提供依據(jù)和基礎(chǔ)。
[Abstract]:Octoxynol-9 (O-9) is a widely used analogue of nonoxynol-9 (N-9) and a nonionic surfactant vaginal spermicide, but its toxicity is less than that of N-9 [1-2]. Temperature-sensitive gel is a kind of in-situ gel, which can respond to temperature change and has a unique solution-gel transition properties, so it has the characteristics of convenient administration, strong adhesion and long retention, so it is especially suitable for mucosal administration [3-4]. Chitosan (CS) is also a common kind of temperature-sensitive gel system. Material, with good biodegradability, biocompatibility, non-toxicity and bacteriostasis, is an excellent bioadhesive material, has the effect of delaying drug release [5-6].Therefore, this study will be safer O-9 and excellent bioadhesive material CS combined to prepare a new temperature-sensitive vaginal preparation, can make the preparation in the negative. A new type of external contraceptives with more safety, effectiveness and convenience was obtained by extending the drug retention time in vagina. In this study, the thermosensitive gel [(O-9) -VTG] for octylene polyol vagina was prepared by cold-dissolving method with the combination of Poloxamer and CS as the thermosensitive gel matrix. The optimal matrix ratio was P407:P188:glycerol:CS=16.3:5.7:5:0.6. The gelling temperature and gelling time of (O-9) -VTG prepared according to the prescription were 33 C and 1.6 min. The quality control method of (O-9) -VTG was established by high performance liquid chromatography, and the quality of three batches of samples was evaluated. In order to investigate the release behavior of (O-9) - VTG in vitro, the release rate of (O-9) - VTG in vitro was studied by membrane-free dissolution method. The results showed that (O-9) - VTG release model followed zero-order equation. The results showed that (O-9) - VTG had good stability. The gelation temperature of the gel could be measured by inverted tube method, but the phase transition behavior and gel strength could not be characterized. Therefore, the rheological parameters of the thermosensitive gel during phase transition could be measured by dynamic rheological experiment. The gelling temperature of 9-VTG is 32.6, which is basically the same as that measured by tube inversion method. It has good fluidity at room temperature (25) and low viscosity. It is a Newtonian fluid and is easy to be injected into vagina. It can be spread quickly after being put into vagina. After gelling for a certain period of time, the gel viscosity increases and has the characteristics of pseudoplastic fluid. The effect of dilution of vaginal fluid on the gelation behavior of (O-9) - VTG proved that (O-9) - VTG could still form gel at body temperature. The normal gel [(O-9) - gels] and (O-9) - VTG were administered to female rats vaginally respectively, and the vaginal flushing fluid containing drugs was collected to establish a method for the determination of drug content in vaginal flushing fluid. The intravaginal retention time of (O-9) - gels and (O-9) - VTG in vaginal flushing solution was compared with that of (O-9) - gels. To evaluate the effectiveness of the preparation, the modified Sander-Cramer method was used to observe the intravaginal retention of (O-9) - VTG. The effect of the lowest effective spermicidal concentration (MEC) of (O-9) - VTG on rat spermatozoa was studied. The results showed that the MEC of (O-9) - VTG was 0.50mg Vaginal mucosal irritation test and vaginal acute toxicity test were conducted in SD female rats. The stimulation was evaluated by Eckstein irritation evaluation criteria. The results showed that (O-9) - VTG had no effect on vaginal irritation in SD female rats. To sum up, the prepared (O-9) - VTG gelling temperature is suitable, the temperature sensitivity is good, the quality of the preparation is stable, it has a certain sustained-release effect, the retention time in vivo is long, the tissue compatibility is good, the preparation is safer, more effective, and more convenient to use. The use of contraceptives also provides a basis for further development and research of octylene polyol vaginal topical preparations.
【學(xué)位授予單位】：湖北中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R943
本文編號(hào)：2184379
[Abstract]:Octoxynol-9 (O-9) is a widely used analogue of nonoxynol-9 (N-9) and a nonionic surfactant vaginal spermicide, but its toxicity is less than that of N-9 [1-2]. Temperature-sensitive gel is a kind of in-situ gel, which can respond to temperature change and has a unique solution-gel transition properties, so it has the characteristics of convenient administration, strong adhesion and long retention, so it is especially suitable for mucosal administration [3-4]. Chitosan (CS) is also a common kind of temperature-sensitive gel system. Material, with good biodegradability, biocompatibility, non-toxicity and bacteriostasis, is an excellent bioadhesive material, has the effect of delaying drug release [5-6].Therefore, this study will be safer O-9 and excellent bioadhesive material CS combined to prepare a new temperature-sensitive vaginal preparation, can make the preparation in the negative. A new type of external contraceptives with more safety, effectiveness and convenience was obtained by extending the drug retention time in vagina. In this study, the thermosensitive gel [(O-9) -VTG] for octylene polyol vagina was prepared by cold-dissolving method with the combination of Poloxamer and CS as the thermosensitive gel matrix. The optimal matrix ratio was P407:P188:glycerol:CS=16.3:5.7:5:0.6. The gelling temperature and gelling time of (O-9) -VTG prepared according to the prescription were 33 C and 1.6 min. The quality control method of (O-9) -VTG was established by high performance liquid chromatography, and the quality of three batches of samples was evaluated. In order to investigate the release behavior of (O-9) - VTG in vitro, the release rate of (O-9) - VTG in vitro was studied by membrane-free dissolution method. The results showed that (O-9) - VTG release model followed zero-order equation. The results showed that (O-9) - VTG had good stability. The gelation temperature of the gel could be measured by inverted tube method, but the phase transition behavior and gel strength could not be characterized. Therefore, the rheological parameters of the thermosensitive gel during phase transition could be measured by dynamic rheological experiment. The gelling temperature of 9-VTG is 32.6, which is basically the same as that measured by tube inversion method. It has good fluidity at room temperature (25) and low viscosity. It is a Newtonian fluid and is easy to be injected into vagina. It can be spread quickly after being put into vagina. After gelling for a certain period of time, the gel viscosity increases and has the characteristics of pseudoplastic fluid. The effect of dilution of vaginal fluid on the gelation behavior of (O-9) - VTG proved that (O-9) - VTG could still form gel at body temperature. The normal gel [(O-9) - gels] and (O-9) - VTG were administered to female rats vaginally respectively, and the vaginal flushing fluid containing drugs was collected to establish a method for the determination of drug content in vaginal flushing fluid. The intravaginal retention time of (O-9) - gels and (O-9) - VTG in vaginal flushing solution was compared with that of (O-9) - gels. To evaluate the effectiveness of the preparation, the modified Sander-Cramer method was used to observe the intravaginal retention of (O-9) - VTG. The effect of the lowest effective spermicidal concentration (MEC) of (O-9) - VTG on rat spermatozoa was studied. The results showed that the MEC of (O-9) - VTG was 0.50mg Vaginal mucosal irritation test and vaginal acute toxicity test were conducted in SD female rats. The stimulation was evaluated by Eckstein irritation evaluation criteria. The results showed that (O-9) - VTG had no effect on vaginal irritation in SD female rats. To sum up, the prepared (O-9) - VTG gelling temperature is suitable, the temperature sensitivity is good, the quality of the preparation is stable, it has a certain sustained-release effect, the retention time in vivo is long, the tissue compatibility is good, the preparation is safer, more effective, and more convenient to use. The use of contraceptives also provides a basis for further development and research of octylene polyol vaginal topical preparations.
【學(xué)位授予單位】：湖北中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R943
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