星点设计-效应面法优化PLGA-PEG纳米粒的处方工艺

摘要：目的:采用星点设计-效应面法优化载体基质为PLGA-PEG的siRNA纳米粒的制备工艺。方法:采用复乳法制备载药纳米粒,以二氯甲烷体积、吐温-80的质量分数和复乳的超声时间为试验因素,纳米粒的平均粒径、包封率和突释量为考察指标,根据星点设计原理安排实验和处方工艺优化。结果:成功制备了纳米粒。最佳工艺为二氯甲烷体积13 ml,乳化剂吐温-80的质量分数为3.1%,复乳的超声时间为2.8 min;按优化处方工艺制备的纳米粒的平均粒径（101.5±6.3）nm,包封率（57.6±4.8）%,体外48 h累积释放度高于80%。结论:星点设计-效应面法适用于PLGA-PEG纳米粒的工艺优化,所建立的数学模型预测性良好。     

效应面法优化盐酸昂丹司琼微球的制备工艺

目的：优化盐酸昂丹司琼聚乳酸乙醇酸嵌段共聚物（PLGA）微球的处方工艺。方法：o／o型乳化溶剂挥发法制备微球，采用小复合设计安排实验，考察盐酸昂丹司琼和PLGA的重量比（X1）、PLGA在内相中的浓度（X2）以及正己烷加入的时间（X3）对微球性质的影响。微球性质的评价指标是包封率（Y1）、载药量（Y2）、粒径（Y3）、体外释曲曲线零级方程拟合的相关系数（Y4）和16d的累积释放度（Y5）。根据最佳数学模型绘制效应面图，通过效应面法优化制备工艺。结果：最优工艺：X1为1：10，X2为32％，X3为65min。按照优化工艺制备的微球的包封率为50．69％，载药量4．6l％，粒径为58μm，体外释药曲线符合零级释放（r=0．99），16d的累积释放度约为91％。优化工艺的预测值和实洲值比较接近。结论：采用效应面法完成了盐酸昂丹司琼微球的多目标优化。     

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。     

Box-Behnken效应面法优化塞来昔布微球制备工艺

目的：制备塞来昔布聚乳酸-羟基乙酸共聚物（PLGA）载药微球,优化其处方和制备工艺,考察其体外释药行为。方法：分别以油相中PLGA浓度、水相PVA浓度和油/水相体积比为考察因素,以包封率为考察指标,采用Box-Behnken效应面法优化塞来昔布微球的处方和工艺;透析袋法评估其体外释放能力。结果：塞来昔布PLGA微球的最佳处方工艺条件为：PLGA浓度75 g·L^-1,水相PVA体积分数1.5%,油/水相体积比1∶30。所制备的微球形态圆整,大小均一,实测包封率为66.1%,与预测值67.3%相比,偏差为1.8%。最优处方体外14 d累积释药56%,体外释放曲线符合Higuchi方程。结论：Box-Behnken效应面法简便可行,可用于优化塞来昔布PLGA微球的制备,微球体外释放具有缓释效果。     

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。     

处方和工艺参数对奥硝唑生物可降解凝胶剂体外释药曲线的影响

目的：考察处方和制备工艺对奥硝唑生物可降解凝胶剂体外释药曲线的影响。方法：以乳酸一羟基乙酸共聚物[poly（lactic-co-glycolic acid），PLGA]为载体材料制备了奥硝唑凝胶剂，采用高效液相色谱法测定凝胶剂中药物的含量，紫外分光光度法测定体外释放度。考察PLGA的型号、溶媒、PLGA与溶媒的比例，药物与PLGA的比例等因素对奥硝唑凝胶体外释放度的影响。结果：以PLGA（50：50，10000）为载体材料，以N-甲基-2-吡咯烷酮为溶媒制备凝胶。当处方中含药物2oA，PLGA（50：50，10000）49％，NMP49％时，奥硝唑凝胶可缓释7d，0～5d以近零级的方式缓释（R^2=0．9943）。结论：奥硝喳凝胶剂具有较好的缓释特征，处方和制备工艺简单可行。     

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。     

重组人血管内皮抑制素壳聚糖纳米粒的制备

目的:通过星点设计-效应面法优化重组人血管内皮抑制素(Endostar)壳聚糖纳米粒的制备工艺。方法:以壳聚糖浓度、三聚磷酸钠(TPP)浓度及壳聚糖溶液与TPP溶液体积比为考察因素,以载药量、包封率和粒径为指标,采用多元线性回归和多元非线性回归拟合选择合适模型,并根据最佳模型绘制效应面图,选择最佳处方,并进行预测分析,同时考察最佳处方的体外释放。结果:用多元非线性回归对实验中各因素和指标进行拟合明显优于线性拟合。最佳处方制备的Endostar载药壳聚糖纳米粒,载药量、包封率及粒径的实测值与预测值的偏差均在±7%以内,体外释放1周累积释放80%。结论:通过星点设计-效应面法可以准确快速优化处方工艺。优化后的工艺制备的纳米粒可以延缓Endostar的释放,达到了缓释效果,符合预期的试验目标。     

星点设计-效应面法优化阿德福韦-β-环糊精包合物制备工艺的研究

目的：星点设计–效应面法优化阿德福韦包合物的制备工艺。方法以饱和水溶液法制备阿德福韦-β-环糊精包合物,采用星点设计优化制备工艺,以β-环糊精与阿德福韦的投料配比、包合时间、包合温度为自变量,包合率、收率为因变量,分别进行多元线性回归和二项式方程拟合,依据最佳数学模型描绘效应面选择最佳处方工艺进行验证试验。结果二项式方程拟合度较高,预测性好,相关系数r＝0.965;效应面法优选出的最佳工艺为：β-环糊精与阿德福韦的投料配比约为3∶1,包合时间为5 h,包合温度为60℃。最佳工艺验证试验结果与二项式拟合方程预测值偏差为（1.31±0.69）%。结论应用星点设计-效应面优化法能够精确有效地优化阿德福韦-β-环糊精包合物的制备工艺,优选出的最佳工艺稳定可行,可用于工业生产。     

紫杉醇mPEG-PLA共聚物胶束的制备及工艺优化

目的：制备紫杉醇mPEG-PLA共聚物胶束（PM-PTX）,优化处方及工艺。方法：采用薄膜水化法制备PM-PTX,通过星点设计一效应面优化法设计和优化处方工艺,并评估药物的体外释放。结果：以投药量和水化体积作为自变量,包封率和载药量作为因变量,行多元线性回归及二次多项式拟合,优选最佳处方工艺并进行验证,得最优工艺条件为投药量2.71 mg,水化体积7.04 mL。按照优化处方制得的PM-PTX包封率为（83.04±1.96）%,载药量为（15.01±0.28）%,与预测值的偏差分别为1.91%和0.99%。PM-PTX溶液为无色透明,透射电镜下显示胶束呈类圆形,胶束粒径为（87.74±2.3）nm,多分散指数为0.259±0.014,Zeta电位为（-1.22±0.133）mV。在3种pH环境下,胶束的药物释放速率无明显差异（P>0.05）,96 h的累积释放率分别为（92.19±3.17）%,（88.37±5.62）%和（86.04±2.16）%（pH=5.8,7.2,7.4）。结论：星点设计-效应面优化法对PM-PTX的制备工艺优化有效,所建立的模型预测性良好。     

星点设计-效应面法优化阿昔洛韦口腔贴片处方

摘 要 目的： 星点设计 效应面法优化阿昔洛韦口腔贴片处方。方法: 以羟丙甲纤维素(HPMC) K4M和卡波姆974P NF的用量为因素,以阿昔洛韦在1 h,5 h和12 h的释放度和黏附力为指标,用多元线性方程、双因素模型和二次多项式模型分别描述各指标与因素的关系,根据较优数学模型绘制效应面图;各指标效应面二维等高线图的重叠部分,即为最佳处方区域,选择最佳处方,并进行预测分析。结果: 二次多项式模型拟合的相关系数和可信度较高。最佳处方各指标的实测值在预期范围内。结论: 星点设计 效应面优化法可以较好地用于阿昔洛韦口腔贴片处方的优化。     

星点设计-效应面法优化健脾颗粒的提取工艺

目的:以星点设计-效应面法优选健脾颗粒的提取工艺。方法:以加水量和提取时间为自变量,以橙皮苷转移率为因变量对自变量各水平进行多元线性回归和二项式拟合,用效应面法选择较佳工艺条件,并进行预测分析。结果:确定较优提取工艺为加11倍量水,提取时间80 min,提取2次,提取率实测值与预测值偏差为0.54%,二项式拟合复相关系数r=0.958 3。结论:采用星点设计-效应面法优选健脾颗粒的提取工艺,方法简便,预测性良好。     

星点设计-效应面法优化异长春花碱脂质体的处方

目的采用星点设计-效应面法优化异长春花碱脂质体的处方。方法以磷脂/药(质量比)、胆固醇/磷脂(摩尔比)、水化温度为考察因素,以脂质体的包封率和脂质体的平均粒径为指标,采用二次多项式方程描述考察指标和影响因素之间的数学关系,根据此数学模型描绘效应面,选择最佳处方,并进行预测分析。结果所建立的考察指标和影响因素之间的数学模型具有较高的可信度。以优化后的处方制备样品,各指标实测值与预测值偏差较小。结论所建立的模型预测性良好,制备的脂质体符合设计要求。     

星点设计-效应面法优化硝酸布康唑缓释乳膏的制备

目的 采用星点设计-效应面法对硝酸布康唑缓释乳膏的处方进行优化。方法 以液体石蜡用量(X₁)、乳化剂用量(X₂)、助乳化剂占乳化剂比例(X₃)为考察因素,以24,48,72 h的累积释放度为考察指标,分别用多元线性模型、二次多项式模型描述考察指标和3个考察因素之间的数学关系,根据模型绘制效应面图和等高线图,通过重叠等高线图确定优化处方,最后进行验证。结果 二次多项式模型比多元线性模型置信度高;根据二次多项式模型,发现 3 个考察因素和 3个考察指标之间存在可信的定量关系;优化处方各设定指标的预测值和实际值非常接近。结论 星点设计-效应面法可用于硝酸布康唑缓释乳膏的处方优化,所建模型具有良好的预测能力。     

星点设计-效应面法优化盐酸巴尼地平自微乳化释药系统

目的：星点设计．效应面法优化盐酸巴尼地平自微乳化释药系统的处方。方法：以油相用量和乳化剂及助乳化剂用量之比为变量,粒径、饱和载药量、自乳化时间为因变量,采用线性方程和二次及三次多项式描述三个因变量和两个变量之间的数学关系,根据最佳数学模型描绘效应面,选择最佳处方。结果：三个因变量和两个变量之间以三项式拟合最佳,相关系数分别为：0．9918,0．9960,0．9825（P〈0．05）,具有较高的可信度。优选的最佳处方组成为：中链甘油三酸酯（MCT）：聚氧乙烯氢化蓖麻油（CremophorRH40）：甘油=32．9：42．9：23．2（w：w：w）,其中药物含量的质量分数为1％。最佳处方的变量理论值与预测值的偏差≤5％。结论：所建立的模型预测性良好。     

Development of thermosensitive chitosan/glicerophospate injectable in situ gelling solutions for potential application in intraoperative fluorescence imaging and local therapy of hepatocellular carcinoma: a preliminary study

Objectives: Thermosensitive chitosan/glycerophosphate (C/GP) solutions exhibiting sol–gel transition around body temperature were prepared to develop a class of injectable hydrogel platforms for the imaging and loco-regional treatment of hepatocellular carcinoma (HCC). Indocyanine green (ICG) was loaded in the thermosensitive solutions in order to assess their potential for the detection of tumor nodules by fluorescence.

Methods: The gel formation of these formulations as well as their gelling time, injectability, compactness and resistance of gel structure, gelling temperature, storage conditions, biodegradability, and in vitro dye release behavior were investigated. Ex vivo studies were carried out for preliminary evaluation using an isolated bovine liver.

Results: Gel strengths and gelation rates increased with the cross-link density between C and GP. These behaviors are more evident for C/GP solutions, which displayed a gel-like precipitation at 4°C. Furthermore, formulations with the lowest cross-link density between C and GP exhibited the best injectability due to a lower resistance to flow. The loading of the dye did not influence the gelation rate. ICG was not released from the hydrogels because of a strong electrostatic interaction between C and ICG. Ex vivo preliminary studies revealed that these injectable formulations remain in correspondence of the injected site.

Conclusions: The developed ICG-loaded hydrogels have the potential for intraoperative fluorescence imaging and local therapy of HCC as embolic agents. They form in situ compact gels and have a good potential for filling vessels and/or body cavities.     

Development of biodegradable in situ implant and microparticle injectable formulations for sustained delivery of haloperidol

The objective of this study is to formulate injectable, biodegradable sustained release in situ implant (ISI), and in situ microparticle (ISM) formulations of haloperidol. Factors affecting the in vitro drug release, pharmacokinetics, and stability of the formulations were investigated. The concentration of the polymer, poly(lactide-co-glycolide) acid (PLGA), and the type of solvents showed a pronounced effect on the in vitro drug release from the ISI and ISM formulations. The ISM formulation [20% PLGA in N-methyl-2-pyrrolidone (NMP)–peanut oil, 1:4] showed reduced maximum plasma concentration (60 versus 44 ng/mL) and longer release (30 days, plasma concentration of 8 ng/mL versus 20 days, plasma concentration of 6 ng/mL) compared with the ISI formulation (20% PLGA in NMP) after intramuscular injection in rats. The delivery of haloperidol can be extended further by changing the concentration, molecular weight, and lactide-to-glycolide ratio of the PLGA. These formulations can be easily administered by both intramuscular and subcutaneous injections. The shelf lives of both systems were found to be 2 years when stored at 4°C. Haloperidol can be formulated as an injectable ISI or ISM systems suitable for 1 month or longer release. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3753–3762, 2012     

Controlled delivery of aspirin: effect of aspirin on polymer degradation and in vitro release from PLGA based phase sensitive systems

The objective of this study was to develop poly (d,l-lactide-co-glycolide) (PLGA) based injectable phase sensitive in situ gel forming delivery system for controlled delivery of aspirin, and to characterize the effect of drug/polymer interaction on the in vitro release of aspirin and polymer degradation. Aspirin was dissolved into PLGA solution in 1-methyl-2-pyrrolidone. Poly(ethylene glycol)400 was used as plasticizer to reduce initial burst release. The solution formulation was injected into aqueous release medium to form a gel depot. Released samples were withdrawn periodically and assayed for aspirin content by high performance liquid chromatography. The effect of aspirin on the degradation of PLGA matrix was evaluated using Proton Nuclear Magnetic Resonance and Gel Permeation Chromatography. PLGA based in situ gel forming formulations controlled the in vitro release of aspirin for 7 days only. Analysis of PLGA matrix residuals revealed that PLGA in aspirin loaded formulations exhibited a significantly (p < 0.05) faster degradation compared to blank formulations. These findings suggest that aspirin causes an unusually faster degradation of PLGA. Such faster degradation of PLGA has not been noticed for any other drugs reported in the literature.     

Nanoparticles laden in situ gel of levofloxacin for enhanced ocular retention

Abstract

Availability of proper concentration of medicament on to the corneal surface is a challenging task. Many novel formulations, i.e. hydrogels, nanoparticles, ocuserts, etc. had been tested to improve ocular bioavailability, out of which our group found, in situ gel and polymeric nanoparticle are the most interesting approach to achieve ocular retention. We found that in situ gel stay only for 12?h and poly(lactic-co-glycolic acid (PLGA) nanoparticles are non mucoadhesive in nature so we try to combine both these formulations and termed it as “Nanoparticle laden in situ gel”. Here we prepare nanoparticle laden in situ gel containing levofloxacin encapsulated PLGA nanoparticle, incorporated in chitosan in situ gel and evaluated its ocular retention by gamma scintigraphy in rabbits. The observations of acquired gamma camera images showed good retention over the entire precorneal area. From static and dynamic gamma scintigraphy evaluation, we can be interpret that developed nanoparticle laden in situ gel formulation cleared at a very slow rate and remained at corneal surface for longer duration than marketed formulation, in situ gel and nanosuspension alone.     

Preparation and Characterization of a Composite PLGA and Poly(Acryloyl Hydroxyethyl Starch) Microsphere System for Protein Delivery

Purpose. To prepare and characterize a novel composite microsphere system based on poly(D,L-lactide-co-glycolide) (PLGA) and poly(acryloyl hydroxyethyl starch) (acHES) hydrogel for controlled protein delivery. Methods. Model proteins, bovine serum albumin, and horseradish peroxidase were encapsulated in the acHES hydrogel, and then the protein-containing acHES hydrogel particles were fabricated in the PLGA matrix by a solvent extraction or evaporation method. The protein-loaded PLGA-acHES composite microspheres were characterized for protein loading efficiency, particle size, and in vitro protein release. Protein stability was examined by size-exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and monitoring the enzymatic activity. Results. Scanning electron microscopy showed discrete PLGA microspheres containing many acHES particles. The composite microspheres were spherical and smooth in size range of 39-93 m. The drug loading efficiency ranged from 51 to 101%. The composite microspheres showed more favorable in vitro release than conventional PLGA microspheres. The composite microspheres showed 20% less initial with a gradual sustained release compared to high burst (60%) followed by a very slow release with the conventional PLGA microspheres. The composite microspheres also stabilized encapsulated proteins from the loss of activity during the microsphere preparation and release. Proteins extracted from the composite microspheres showed good stability without protein degradation products and structural integrity changes in the size-exclusion chromatography and SDS-PAGE analyses. Horseradish peroxidase extracted from microspheres retained more than 81% enzymatic activity. Conclusion. The PLGA-acHES composite microsphere system could be useful for the controlled delivery of protein drugs.