诺氟沙星阴道用温度敏感原位凝胶的制备及体外释放度研究

摘 要 目的：制备诺氟沙星阴道用温度敏感原位凝胶,并考察其体外药物释放行为。方法: 以泊洛沙姆为基质,采用冷溶法制备诺氟沙星阴道用温度敏感原位凝胶,考察泊洛沙姆407与泊洛沙姆188的用量对胶凝相变温度的影响,采用星点设计 效应面法优化其处方,并考察其体外药物释放行为。结果: 在一定浓度范围内,随着泊洛沙姆407用量的增大胶凝化温度逐渐降低,随着泊洛沙姆188用量的增大胶凝化温度逐渐升高,通过优化得到诺氟沙星阴道用温度敏感原位凝胶的最佳处方为：泊洛沙姆407的浓度为20.6%（w/v）,泊洛沙姆188的浓度为5.7%（w/v）,在温度为36.5 ℃以上可发生胶凝。药物在温度敏感原位凝胶中呈持续缓慢释放,6 h药物的累积释放度为87.5%±5.4%。结论: 诺氟沙星阴道用温度敏感原位凝胶具有很好的温度敏感性,可以延缓药物释放,有望开发成为一种新型阴道给药制剂。     

硫酸阿托品眼用温敏凝胶的制备及体外释放研究

摘 要 目的：制备硫酸阿托品眼用温敏凝胶并考察其体外药物释放行为。方法: 以泊洛沙姆407（P407）和泊洛沙姆188（P188）的用量为考察因素,模拟泪液稀释前后的胶凝温度为考察指标,采用星点设计 效应面法优化处方并进行验证;采用无膜溶出模型考察凝胶的体外溶蚀与药物释放行为。结果: 以处方中含有P407 23%、P188 5%为最佳处方,效应面法优化处方的预测值和实测值偏差均小于5%;凝胶溶蚀速率决定药物释放速率,且两者均符合零级动力学方程。结论: 星点设计 效应面法可用于硫酸阿托品眼用温敏凝胶的处方优化,所建立的模型预测性良好;最优处方的制剂体外释放缓慢,符合设计要求。     

星点设计-效应面法对左氧氟沙星泊洛沙姆407/188眼用凝胶的制备工艺优化

目的 应用星点设计-效应面法研制左氧氟沙星温度敏感型眼用凝胶,优化处方工艺,以期获得可用于白内障术后感染的眼用制剂。方法 选择泊洛沙姆407(P407)和泊洛沙姆188(P188)作为凝胶温敏材料,以凝胶温度为响应值,通过星点设计-效应面法进行模型拟合;采用无膜溶出模型考察药物的体外溶蚀行为与释放度。结果 模型拟合获得优化处方：P407浓度25.23%、P188浓度1.89%,胶凝温度的实测值与预测值相对偏差<5%。泪液溶蚀是影响药物释放的主要因素。结论 星点设计-效应面法得到的左氧氟沙星眼用温敏型凝胶处方精密度较高,可作进一步推广应用研究。     

温控型胰岛素液体肛门栓药剂学研究

目的 温控型胰岛素液体肛门栓药剂学性质的研究。 方法 采用正交试验法,以形成凝胶时间、胶凝强度、生物黏附力、黏度、胶凝温度作为评价指标,对处方中的泊洛沙姆407和泊洛沙姆188的比例、壳聚糖质量分数和pH值3个因素进行考察,确定最优处方工艺;测定最优处方液体栓剂的胶凝强度、生物黏附力、黏度、胶凝温度。 结果 泊洛沙姆407:泊洛沙姆188(15:25),壳聚糖质量分数0.4%,pH值为5±0.2。 结论 经验证结果良好,液体栓剂强度及生物黏附力良好。     

他克莫司阳离子微乳原位凝胶的制备及体外释放研究

目的 为了改善他克莫司水溶性差、眼部生物利用度低的问题,研制了他克莫司阳离子微乳原位凝胶,并研究其体外药物释放行为,为后期进一步研究提供基础。方法 通过高压均质法制得他克莫司阳离子纳米乳,并将其分散于泊洛沙姆407和泊洛沙姆188中制备他克莫司阳离子微乳原位凝胶。采用无膜溶出模型研究其体外释放行为。结果 采用玻璃瓶倒置法测定胶凝温度,筛选出最优凝胶基质处方为26%泊洛沙姆407和12%泊洛沙姆188;体外释药结果显示凝胶溶蚀速率是决定体外释药速率的关键。结论 成功制备了他克莫司阳离子微乳原位凝胶,其体外释药稳定,能满足眼用制剂要求,展现出良好的眼部应用前景。     

正交试验优选甲硝唑阴道用温敏凝胶的处方工艺

摘 要 目的：优选甲硝唑温敏凝胶的处方工艺。方法: 以胶凝温度和24 h累积释放度为评价指标,采用正交试验考察泊洛沙姆407（P407）、泊洛沙姆188（P188）、海藻酸钠和聚乙二醇4000（PEG4000）用量4个因素,筛选温敏凝胶的最佳处方。采用HPLC法测定甲硝唑温敏凝胶的体外释放度,并与市售普通凝胶剂进行比较。结果: 温敏凝胶最佳处方组成为： 20% P407,18% P188,0.1%海藻酸钠,1.5% PEG4000。制得的甲硝唑温敏凝胶累积释放度高,胶凝温度适宜。与市售凝胶相比,阴道滞留性明显提高。结论:该处方设计合理,制备工艺可行。     

星点设计-效应面法优化氨来呫诺眼用温敏凝胶的处方

目的研制氨来呫诺眼用温敏凝胶。方法采用冷法工艺制备氨来呫诺眼用温敏凝胶,以泊洛沙姆407和泊洛沙姆188为温敏凝胶材料,以二者用量为考察因素,以人工模拟泪液稀释前后的胶凝温度为考察指标,采用星点设计-效应面法进行处方优化并验证。结果氨来呫诺眼用温敏凝胶优化处方P407和P188的质量浓度配比为190∶40,胶凝温度为28.37℃,经模拟泪液稀释后胶凝温度为32.63℃。结论星点设计-效应面法优化处方的方法可行,建立的数学模型预测性好,该眼用温敏凝胶满足眼部用药的设计要求,可进一步研究开发。     

盐酸美普他酚鼻用温敏型凝胶的制备及其体外释放度考察

目的:制备盐酸美普他酚鼻用温敏型凝胶并考察其体外释放特性。方法:以盐酸美普他酚为主药,泊洛沙姆P407为凝胶材料制备凝胶;以影响制剂胶凝温度的泊洛沙姆P407、P188及PEG6000用量为考察因素,胶凝温度为考察指标进行正交试验优选处方;同时采用改良的Franz扩散池法,以生理盐水为介质进行体外释放特性评价。结果:以处方中含有泊洛沙姆P407为20%、泊洛沙姆P188为3%、PEG6000为2%为最佳处方,平均胶凝温度为32.4℃。所制制剂15min即释药约25%,体外释药行为符合Higuchi方程。结论:该制剂处方设计和工艺方法可行,并具有一定的缓释特性,适合鼻腔给药。     

白藜芦醇原位漂浮凝胶的制备及体外评价

目的:采用安全性高、生物相容性好的常用凝胶材料制备白藜芦醇原位漂浮凝胶,并对处方进行优化,获得具有温敏性质的可漂浮于膀胱内并长时间持续释放药物的凝胶剂,用于膀胱癌的膀胱灌注化疗。方法:以泊洛沙姆407、泊洛沙姆188、海藻酸钠、碳酸钙、碳酸氢铵为辅料,冷溶法制备凝胶;以胶凝温度、胶凝时间为指标,采用星点设计-响应面法对泊洛沙姆407、泊洛沙姆188、碳酸氢铵的用量进行优化;对优化处方进行温敏性能、漂浮性能和释药性能评价。结果:最优处方为白藜芦醇30%,泊洛沙姆407 17.2%,泊洛沙姆188 5.5%,海藻酸钠0.15%,碳酸钙0.06%,碳酸氢铵0.15%。该处方的胶凝温度为28℃～29℃,胶凝时间为50 s,药物以扩散方式从漂浮凝胶中缓慢释放,持续释放时间超过48 d。结论:白藜芦醇原位漂浮凝胶具有膀胱内长时间持续释放药物的性质,可以作为膀胱癌治疗中膀胱灌注化疗的替代给药形式,具有提高患者依从性的优点。     

辛苯聚醇温敏凝胶的制备及其体外释放研究

目的：制备辛苯聚醇阴道用温敏凝胶[（O-9）-VTG],并对其释放机制进行探讨。方法：采用冷溶法以泊洛沙姆407（P407）和泊洛沙姆188（P188）为温敏凝胶材料制备凝胶,倒置法测定其胶凝温度（T_GEL）,再应用星点设计-效应面法优化处方,并采用无膜溶出模型考察其体外溶蚀及释药情况。结果：优化的处方基质配比为P407：P188：甘油：壳聚糖=16.3：5.7：5：0.6,胶凝温度为33℃,胶凝时间约1.6 min;辛苯聚醇体外释放符合零级动力学方程。结论：效应面法筛选辛苯聚醇温敏凝胶处方合理,（O-9）-VTG作为新型阴道用避孕制剂前景良好。     

氯霉素温敏型眼用原位凝胶的研制

目的制备氯霉素泊洛沙姆眼用原位温敏型凝胶并建立其质量控制方法。方法以泊洛沙姆P407和P188为温敏材料,通过测定溶液-凝胶相转变温度优化处方;采用紫外分光光度法测定氯霉素含量。结果氯霉素温敏型原位凝胶的胶凝温度随P407浓度增大而降低,随P188浓度增加先升高后降低,模拟泪液的稀释可使胶凝温度升高,建立了泪液稀释后相变温度与泊洛沙姆浓度的拟合方程,经Design-Expert软件优化出的氯霉素温敏型原位凝胶最佳处方为25%P407和4.19%P188;优化处方在29.5℃时为自由流动的液体,泪液稀释后在34.6℃能够发生相变形成凝胶。结论该眼用温敏凝胶符合眼部应用要求,体现出良好的应用前景。     

奥洛他定温度敏感眼用原位凝胶的制备

目的:研制奥洛他定温度敏感眼用原位凝胶。方法:采用泊洛沙姆P407和P188为温敏材料,以胶凝温度为指标,通过星点设计-效应面法优化处方。结果:经过优化筛选出的处方在室温条件下是自由流动的液体,在生理条件下发生胶凝形成凝胶。结论:所研制奥洛他定眼用温度敏感原位凝胶符合眼部应用要求,体现出良好的临床应用前景。     

D-Optimal Design in the Development of Rheologically Improved In Situ Forming Ophthalmic Gel

In situ forming ophthalmic gels need to be fine tuned considering all the biopharmaceutical challenges of the front of the eye in order to increase drug residence time at the application site resulting in its improved bioavailability and efficacy. The aim of this study was to develop in situ forming ophthalmic poloxamer P407/poloxamer P188/chitosan gel fine tuned in terms of polymer content, temperature of gelation, and viscosity. Minimizing the total polymer content while retaining the advantageous rheological properties has been achieved by means of D-optimal statistical design. The optimal in situ forming gel was selected based on minimal polymer content (P407, P188, and chitosan concentration of 14.2%, 1.7%, and 0.25% w/w, respectively), favorable rheological characteristics, and in vitro resistance to tear dilution. The optimal in situ forming gel was proved to be robust against entrapment of active pharmaceutical ingredients making it a suitable platform for ophthalmic delivery of active pharmaceutical ingredients with diverse physicochemical properties.     

Properties of bioadhesive ketoprofen liquid suppositories: preparation,determination of gelation temperature,viscosity studies and evaluation of mechanical properties using texture analyzer by 4 × 4 factorial design

Abstract

Context: Development and evaluation of thermosensitive and bioadhesive liquid suppositories containing ketoprofen (KP).

Objective: This study was conducted to develope thermosensitive and bioadhesive liquid suppositories containing KP using poloxamer and different bioadhesive polymers and to investigate their gelation temperature, viscosity and mechanical properties.

Materials and methods: Bioadhesive liquid suppositories were prepared by the cold method using poloxamer 407 (P 407), Poloxamer 188 (P 188) and various amounts of different bioadhesive polymers. Their gelation temperatures, viscosity values and mechanical properties were determined using texture analyzer by 4?×?4 factorial design.

Results: It was seen that in presence of KP, gelation temperature of formulation P 407/P 188 (4/20%) significantly decreased from 64 to 37.1?°C. It is to be noted that addition of increasing concentrations of bioadhesive polymers lowered gelation temperature and its decrease was highest with addition of Carbopol 934 P (C). Results of texture profile analysis (TPA) showed that formulations containing C have significantly higher hardness and adhesiveness values than other bioadhesive formulations. According to TPA, gel structure of liquid suppository formulation F5, containing P 407/P 188/KP/C (4/20/2.5/0.8%), exhibited the greatest hardness, compressibilty, adhesiveness and besides greatest viscosity.

Discussion and conclusion: According to mechanical properties and viscosity values, it was concluded that F5 could be a promising formulation.     

吡嘧司特钾眼用原位温度敏感凝胶的制备及其体外释放度的研究

目的：以吡嘧司特钾为模型药物,制备眼用原位温度敏感凝胶,考察其体外释放度。方法：以泊洛沙姆407/188为基质,筛选最佳处方以达到合适的胶凝温度,建立高效液相色谱法测定吡嘧司特钾含量并以无膜溶出模型考察体外释放度。结果：处方中以5%甘露醇为溶媒,0.1%吡嘧司特钾（w/v）、0.01%苯扎溴铵（v/v）、6%泊洛沙姆188（w/v）和20%泊洛沙姆407（w/v）的组成可以达到最适胶凝温度,经影响因素试验考察证明该制剂性质稳定,体外释放度考察结果表明药物的释放与时间成线性关系。结论：本文制备的吡嘧司特钾眼用原位温度敏感凝胶具有很好的温度敏感性,能够延长药物在眼部停留时间且给药方便,有望开发成为一种新型眼用给药制剂。     

复方甲硫酸新斯的明眼用原位凝胶的处方工艺研究

目的 筛选用于治疗近视的复方甲硫酸新斯的明眼用原位凝胶处方。方法 温度敏感型凝胶以泊洛沙姆P407和泊洛沙姆P188为基质;离子敏感型凝胶以去乙酰结冷胶为基质;pH敏感型凝胶以卡波姆P934、卡波姆P940和羟丙基甲基纤维素为基质,以胶凝的黏度与成分的相溶性为考察指标,筛选最佳基质处方。采用美国药典溶出度测定法第三法的改良法,作缓释制剂的释放度考察。结果 以温度敏感型的泊洛沙姆P407 24%和P188 10%合用的基质制备复方甲硫酸新斯的明眼用原位凝胶最为适合。结论 本法制备眼用原位凝胶的工艺可行,并具有较好的缓释效果。     

Doxycycline and hydroxypropyl-β-cyclodextrin complex in poloxamer thermal sensitive hydrogel for ophthalmic delivery

The present study aimed to prepare a chemically and physically stable formulation of doxycycline (Doxy) in an in situ thermally sensitive hydrogel for ophthalmic delivery. An inclusion complex of Doxy and hydroxypropyl-β-cyclodextrin (HP-β-CD) was first developed to increase the stability of Doxy in aqueous solution. The physical characteristics (phase solubility profiles, thermal analysis, X-ray powder diffractograms and infrared spectra) of the Doxy-HP-β-CD inclusion complex indicated the formation of a stable 1:1 complex. Poloxamers P407 (16–22%) and P188 (0–5%) were mixed to obtain a hydrogel with an appropriate gelation temperature for opthalmic use. Formulation of the inclusion complex in the poloxamer hydrogel exhibited a suitable gelation temperature (33.3 °C) after dilution with simulated tear fluid (Gel:STF=40:7, v/v). The release of Doxy from the poloxamer hydrogel followed a zero order equation suggesting it occurs through corrosion of the poloxamer hydrogel. Stability studies demonstrated that the inclusion of Doxy by HP-β-CD markedly improved its stability in aqueous solution both at 8 and 40 °C. This formulation of a doxycycline-HP-β-CD inclusion complex in an in situ thermally sensitive poloxamer hydrogel represents a potentially effective ophthalmic Doxy delivery system.     

Stimuli-Responsive in situ Spray Gel of Miconazole Nitrate for Vaginal Candidiasis

Vaginal candidiasis is a common form of infection in women caused by Candida species. Due to several drawbacks of conventional treatments, the current research is attempted to formulate and optimize a miconazole nitrate-loaded in situ spray gel for vaginal candidiasis. The stimuli-responsive (pH and thermo-responsive) polymers selected for the in situ gel were chitosan and poloxamer 407, respectively, whereas hydroxypropyl methylcellulose (HPMC) was introduced in the formulation to further improve the mucoadhesive property. The dispersion of each polymer was carried out using the cold method, whereas the optimization of the formulation was achieved using Box-Behnken statistical design considering viscosity and gelation temperature as dependent variables. Present design achieved the optimized outcome with HPMC, poloxamer and chitosan at 0.52% (w/v), 18.68% (w/v) and 0.41% (w/v), respectively. Evaluation of drug-excipients compatibility was performed using differential scanning calorimetry, Fourier transform infrared spectroscopy, and thermogravimetric analysis where the results showed the absence of any chemical interaction between the polymers and drug component. The optimized formulation showed gelation temperature at 31°C allowing in situ phase transition in a vaginal environment; pH of 4.21 is suitable for use in the vaginal cavity, and appropriate viscosity (290 cP) at storage temperature (below 30°C) would allow spraying at ease, whereas strong mucoadhesive force (22.4±0.513 g) would prevent leaking of the formulation after application. The drug release profile showed sustained release up to 24 h with a cumulative drug release of 81.72%, which is significantly better than the marketed miconazole nitrate cream. In addition, an improved antifungal activity could be correlated to the sustained release of the drug from the formulation. Finally, the safety of the formulation was established while tested on HaCaT cell lines. Based on our findings, it could be concluded that the in situ hydrogel formulation using stimuli-responsive polymers could be a viable alternative to the conventional dosage form that can help to reduce the frequency of administration with ease of application to the site of infection, thus will provide better patient compliance.