羧甲基壳聚糖阴道温敏性原位凝胶的研制及体外质量考察

摘要：目的:优化羧甲基壳聚糖（CCS）阴道温敏性原位凝胶的处方,并对其体外性质进行考察。方法:拟定CCS质量分数为1.0%,以pH 4.2乳酸-乳酸钠为缓冲体系,在单因素试验的基础上,以胶凝温度(Tgel)为评价指标,以正交试验优化泊洛沙姆407（P407）、泊洛沙姆188（P188）、甘油及聚卡波菲（PCP）的用量。对最佳处方制备的CCS温敏性原位凝胶的pH、胶凝时间、黏度及体外释药特性进行考察。结果:优化的最佳处方为18%P407,5%P188,5%甘油及0.4%PCP。最佳处方制备的CCS温敏性原位凝胶平均Tgel为29.5℃,pH为4.12,胶凝时间为22.6 s,在8个温度单位内完成黏度的增加,体外释药符合一级动力学过程,且主要由基质溶蚀控制。结论:CCS温敏性原位凝胶体外性质符合阴道给药制剂的要求,并可迅速发生相转变,可望在阴道局部发挥缓释长效作用。     

尼莫地平泊洛沙姆188纳米胶束的制备工艺研究

目的探讨制备尼莫地平泊洛沙姆188纳米胶束的优良工艺。方法采用乳化-溶剂蒸发法制备尼莫地平泊洛沙姆188纳米胶束,考察影响尼莫地平泊洛沙姆188纳米胶束包封率的主要因素,即有机溶剂的种类、尼莫地平溶液滴加速率、有机相与水相的体积比以及尼莫地平与泊洛沙姆188的质量比,并在此基础上采用正交设计优化尼莫地平泊洛沙姆188纳米胶束的制备工艺。结果尼莫地平泊洛沙姆188纳米胶束的制备最优处方为尼莫地平滴加速率为0.2 ml/min,有机相与水相的体积比为1∶5,尼莫地平与泊洛沙姆188的质量比为1∶3。结论通过正交试验,能够获得尼莫地平泊洛沙姆188纳米胶束的最佳制备工艺。     

星点设计-响应面法优选肝癌介入栓塞用香叶木苷温敏凝胶基质处方的研究

目的:优选肝癌介入栓塞用香叶木苷温敏凝胶的基质处方.方法:以胶凝温度为指标,基于单因素分析,采用星点设计-响应面法优化并验证肝癌介入栓塞用香叶木苷温敏凝胶基质处方中泊洛沙姆407、泊洛沙姆188、羟丙甲基纤维素的最优配比.结果:肝癌介入栓塞用香叶木苷温敏凝胶最优处方为泊洛沙姆407:泊洛沙姆188:羟丙基甲基纤维素=2...     

星点设计-效应面法优化托吡卡胺温敏型原位凝胶处方

目的：优化托吡卡胺眼用温敏型原位凝胶的制备工艺。方法：采用星点设计法考察温敏材料泊洛沙姆407和泊洛沙姆188质量分数对指标相变温度的影响,并以相变温度（T。）和模拟泪液稀释后的相变温度（L）为指标对结果进行模型拟合;采用效应面法优化处方并进行验证,测定300rain内的体外累积降放度。结果：泊洛沙姆407和泊洛沙姆188质量分数分别为20％、5％,以T·和Tz为指标进行多元线性回归的相关系数分别为（1．9187、0．8899;效应面法优化处方的实测值与预测值偏差绝对值均〈5％,300min内的体外累积释放度为65％。结论：星点设计一效应面法所建立的模型实现了该眼用温敏型原位凝胶的处方优化．数学模型预测性良好。     

盐酸布替萘芬阴道用温敏水凝胶的制备及体外释放度的考察

目的:制备盐酸布替萘芬阴道用温敏水凝胶并考察其体外释放度。方法:以泊洛沙姆为基质,筛选最佳处方以达到合适胶凝温度,并利用高效液相色谱法(HPLC)建立含量测定方法考察体外释放度。结果:结果显示以1%盐酸布替萘芬、0.1%山梨酸钾、2%甘油、5%聚山梨酯80、12%泊洛沙姆407及5%泊洛沙姆188为配方制备的温敏水凝胶在35℃时产生胶凝,体外释放度考察结果显示8 h可释放超过90%的药物。结论:本研究制备的盐酸布替萘芬阴道用温敏水凝胶具有很好的温度敏感性及黏附性,具有缓释特性且给药方便,是一种值得开发的药物制剂。     

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。     

泊洛沙姆407水溶液的流变学性质

本文对泊洛沙姆407(商品名为普朗尼克F127)进行了流变学性质的考察。通过剪切速率触变性实验、温度敏感性实验和多次升温后表观黏度复原性实验得到了泊洛沙姆407各项流变学参数。结果表明,随着泊洛沙姆407水溶液浓度的提高,其由牛顿流体转变为假塑性流体,触变性和胶凝温度均逐渐降低(15.25%泊洛沙姆407可在体温下形成凝胶)。本文为泊洛沙姆407作为凝胶剂基质的应用提供了可参考的流变学数据。     

星点设计-效应面法优选连芩清热温敏凝胶制备工艺

目的 优化连芩清热温敏凝胶剂的制备工艺。方法 以泊洛沙姆407用量、泊洛沙姆188用量、连芩清热洗剂原液用量为考察变量,以胶凝温度为考察指标,采用星点设计-效应面法确定优选制备工艺条件,并进行预测分析。结果 连芩清热温敏凝胶剂的最优制备为：泊洛沙姆407用量17%,泊洛沙姆188用量3%,连芩清热洗剂原液用量比例为46%,连芩清热温敏凝胶的凝胶温度为30.4℃,凝胶时间为（14.8±2.1）s,凝胶长度（0.5±0.1）cm。结论 连芩清热温敏凝胶剂制备工艺简便,稳定性好,凝胶时间和凝胶长度合理。     

一种治疗牙周疾病的温控凝胶剂的制备

目的：采用泊洛沙姆作为基质,制备一种治疗牙周疾病的温控凝胶剂。方法：调整泊洛沙姆407和188的比例,使凝胶剂在36℃开始胶凝。结果：本凝胶剂中,泊洛沙姆407质量分数为22%,泊洛沙姆188质量分数为12%时,凝胶剂的胶凝温度为36℃。结论：本方法制备温控凝胶剂简单可靠,可行性大。     

复方黄芩温敏凝胶的制备与质量标准研究

目的：制备复方黄芩温敏凝胶,并建立了温敏凝胶中黄芩苷含量测定的质量标准。方法以泊洛沙姆作为凝胶材料,考察含有不同泊洛沙姆407（Pluronic F127）和泊洛沙姆188（Pluronic F68）浓度配比的处方对凝胶胶凝温度的影响。采用高效液相色谱法测定凝胶中黄芩苷的含量：色谱柱为Acclaim 120 C18柱（4.6mm ×250mm,5μm）;流动相为甲醇-水-磷酸（57∶43∶0.2）,流速1.0mL· min －1;检测波长280nm,柱温30℃。结果选择胶凝温度为29.5℃的凝胶基质：22％P407／8％P188。黄芩苷在0.0253～0.1508（mg· mL －1）范围内线性关系良好,平均加样回收率为103.74％,RSD为1.26％。结论泊洛沙姆温敏凝胶的制备工艺简便易行,筛选得到的凝胶处方适于临床皮肤给药。所建立的质量标准结果准确,可靠,重现性好,可用于复方黄芩温敏凝胶的质量控制。     

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。     

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。     

雌二醇阴道用生物黏附性温敏型凝胶的处方筛选及流变学考察

目的:研制雌二醇阴道用生物黏附性温敏型凝胶(E₂-VTISG),并进行热力学和流变学考察。方法:采用冷法工艺制备E₂-VTISG。采用倒试管法测定胶凝温度(T_gel),以T_gel为考察指标,泊洛沙姆P407,泊洛沙姆P188为主要影响因素,用星点设计-效应面法进行处方筛选。采用黏度计测定表观粘度,采用动态流变学实验测定温敏凝胶在相变过程中的流变参数。结果:雌二醇阴道用生物黏附性温敏型凝胶的最优处方的基质配比为P407:P188:甘油:PCP:尼泊金乙酯=18:2.96:5:0.2:0.2,实测胶凝温度为33.4℃。结论:星点设计-效应面法筛选E₂-VTISG处方预测性良好,流变学结果显示优化后的雌二醇温敏凝胶符合阴道局部用药要求。     

马来酸噻吗洛尔眼用温敏凝胶的处方筛选与体外释放评价

目的:筛选马来酸噻吗洛尔眼用温敏型凝胶优化处方,并对其体外释放进行评价。方法:选用泊洛沙姆P407、P188为载体材料制备眼用温敏凝胶,测定不同处方的凝胶前体溶液分别在未经处理和经人工泪液稀释条件下,从溶液态转变为凝胶态的胶凝温度,通过星点设计-效应面法筛选优化处方,并考察胶凝时间和释放行为。结果:根据温敏凝胶保存和使用的温度要求,筛选出优化处方为P407:P188(24.25%:1.56%)。前体溶液能够在34℃人工泪液中迅速形成凝胶,并在体外缓慢释放6 h以上。结论:经过筛选并制备出的噻吗洛尔温敏型凝胶具有良好的载药能力、稳定性及释放性能,满足眼用制剂质量要求和实际应用要求。     

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。     

Thermally reversible in situ gelling carbamazepine liquid suppository

Carbamazepine (CBZ), indicated for the control of epilepsy, undergoes extensive hepatic first-pass elimination after oral administration. A rectal dosage form of CBZ is not commercially available, although it is of particular interest when oral administration is impossible. Conventional suppositories can cause patient discomfort and may reach the end of the colon; consequently, the drug can undergo the first-pass effect. Mucoadhesive liquid suppositories of CBZ were prepared by adding carbopol to formulation of thermally gelling suppositories that contain 20% poloxamer 407 and either 15% poloxamer 188 or 1% methylcellulose. Gellan gum was also tried instead of 20% poloxamer. All formulations contained 10% CBZ. The characteristics of the suppositories differed depending on the formulation. The formula containing 20% poloxamer 407, 1% methylcellulose, and 0.5% carbopol showed reasonable gelation temperature, gel strength and bioadhesive force. The analysis of release mechanism showed that CBZ released from the suppositories by Fickian diffusion. In vivo evaluation of the same formulation showed higher peak plasma concentration of CBZ compared with the orally administered suspension containing the equivalent amount of drug. However, there was no statistical significant difference (p > 0.05) in extent of bioavailability between the liquid suppository and oral suspension as indicated by the values of AUC(0 - infinity), 17.9 and 18.8 micro g x h/ml, respectively. These results suggested that mucoadhesive in situ gelling liquid suppository could be an effective and convenient delivery system of carbamazepine.     

Thermally Reversible In Situ Gelling Carbamazepine Liquid Suppository

Carbamazepine (CBZ), indicated for the control of epilepsy, undergoes extensive hepatic first-pass elimination after oral administration. A rectal dosage form of CBZ is not commercially available, although it is of particular interest when oral administration is impossible. Conventional suppositories can cause patient discomfort and may reach the end of the colon; consequently, the drug can undergo the first-pass effect. Mucoadhesive liquid suppositories of CBZ were prepared by adding carbopol to formulation of thermally gelling suppositories that contain 20% poloxamer 407 and either 15% poloxamer 188 or 1% methylcellulose. Gellan gum was also tried instead of 20% poloxamer. All formulations contained 10% CBZ. The characteristics of the suppositories differed depending on the formulation. The formula containing 20% poloxamer 407, 1% methylcellulose, and 0.5% carbopol showed reasonable gelation temperature, gel strength and bioadhesive force. The analysis of release mechanism showed that CBZ released from the suppositories by Fickian diffusion. In vivo evaluation of the same formulation showed higher peak plasma concentration of CBZ compared with the orally administered suspension containing the equivalent amount of drug. However, there was no statistical significant difference (p > 0.05) in extent of bioavailability between the liquid suppository and oral suspension as indicated by the values of AUC_{0 - ∝}, 17.9 and 18.8 μ g.h/ml, respectively. These results suggested that mucoadhesive in situ gelling liquid suppository could be an effective and convenient delivery system of carbamazepine.     

Solubility enhancement of desloratadine by solid dispersion in poloxamers

The present study investigates the possibility of using poloxamers as solubility and dissolution rate enhancing agents of the poorly water soluble drug substance desloratadine that can be used for the preparation of immediate release tablet formulation. Two commercially available poloxamer grades (poloxamer P 188 and poloxamer P 407) were selected, and solid dispersions (SDs) containing different weight ratio of poloxamers and desloratadine were prepared by a low temperature melting method. All SDs were subjected to basic physicochemical characterization by thermal and vibrational spectroscopy methods in order to evaluate the efficiency of poloxamers as solubility enhancers. Immediate release tablets were prepared by direct compression of powdered solid dispersions according to a General Factorial Design, in order to evaluate the statistical significance of two formulation (X(1) - type of poloxamer in SD and X(2) - poloxamer ratio in SD) and one process variable (X(3) - compression force) on the drug dissolution rate. It was found that desloratadine in SDs existed in the amorphous state, and that can be largely responsible for the enhanced intrinsic solubility, which was more pronounced in SDs containing poloxamer 188. Statistical analysis of the factorial design revealed that both investigated formulation variables exert a significant effect on the drug dissolution rate. Increased poloxamer ratio in SDs resulted in increased drug dissolution rate, with poloxamer 188 contributing to a faster dissolution rate than poloxamer 407, in accordance with the results of intrinsic dissolution tests. Moreover, there is a significant interaction between poloxamer ratio in SD and compression force. Higher poloxamer ratio in SDs and higher compression force results in a significant decrease of the drug dissolution rate, which can be attributed to the lower porosity of the tablets and more pronounced bonding between poloxamer particles.     

安乃近原位凝胶的制备及体外评价

目的 制备安乃近原位凝胶,延长安乃近在体内的作用时间.方法 以泊洛沙姆407(P407)和泊洛沙姆188(P188)作为载体材料,采用冷溶法制备安乃近原位凝胶,考察P407和P188的含量、亚硫酸氢钠及安乃近浓度对胶凝温度的影响,并用透析袋法考察凝胶的体外释药情况.结果 当P407浓度为23％、P188浓度为6％、亚硫酸氢钠的浓度为0.2％时,所制得的安乃近原位凝胶注射剂的胶凝温度合适,为35.3℃时,该凝胶在1h内的平均体外累积释放率为40.57％,较安乃近水溶液同时间内的累积释放率低50.39％.结论 安乃近原位凝胶的温敏性明显,其胶凝温度适合体内给药;安乃近原位凝胶对安乃近药物的释放显示出了明显的缓释效应,可以进一步用于临床.