星点设计法优化盐酸小檗碱树脂复合胃黏附给药系统的研究

本文以离子交换树脂(IER)作为载体吸附盐酸小檗碱，通过包衣将其制成胃黏附微囊，并以胃黏附微囊的载药量，胃滞留时间和体外释药时间作为评价指标，对处方进行优化。考察不同型号载体与不同浓度、温度和pH值的药物溶液对IER载药量的影响；以卡伯姆934与IER的比例(X₁)、丙烯酸树脂(Eudragit)与IER的比例(X₂)、Eudragit RL与Eudragit RS的比例(X₃)为自变量，以制剂累计释放量85%的时间点(Y₁)、制剂在大鼠胃体外黏附滞留百分比(Y₂)为因变量，通过星点设计—效应面法优化胃黏附包衣处方。优化后载药工艺为在37 ℃、pH 5左右条件下，用IRP88离子交换树脂对1.0 mg·mL^-1盐酸小檗碱溶液载药；优化后的包衣液组成为X₁=0.75、 X₂=0.9、 X₃=0.6，所得制剂单位质量载药量高，可在300 min左右达到累计释放总量的85%，同时在所设计条件范围内胃黏附作用最强。     

三七总皂苷油包水微乳的处方筛选及体内外评价

筛选口服油包水(W/O)微乳处方以提高三七总皂苷(panax notoginsenoside，PNS)中人参皂苷Rb₁的体内肠吸收，分别采用大鼠体内肠吸收、脂质体和平行人工膜(parallel artificial membrane permeability assay，PAMPA)等模型分别研究微乳的体内药代动力学及体外对膜流动性和药物膜转运性质的影响。主要以磷脂/乙醇(SP/EtOH)为表面活性剂，与PNS水溶液(400 mg·mL^-1)和不同油相分别制备11个W/O微乳处方。多数微乳处方可提高药物的大鼠体内肠吸收，其吸收促进作用除与所含表面活性剂有关外，不同油相的选用也会产生一定影响，其吸收促进作用大小为月桂酸甘油酯≈肉蔻豆酸异丙脂>棕榈酸异丙脂>棕榈酸异辛酯。长链(>C₁₄)脂肪酸酯的吸收促进作用低于中链脂肪酸酯(C₈~C₁₄)。多数微乳处方可不同程度的提高脂质体的膜流动性。PAMPA研究中，稀释后微乳(D-ME)中药物的有效透过系数(P_e)多数高于PNS对照溶液，表明微乳中的组分可以提高药物的膜透过能力，稀释前微乳(ME)的P_e与大鼠体内肠吸收具有相对较好的直线相关性(r=0.774 0)。W/O微乳可以促进人参皂苷Rb₁的肠吸收，吸收促进作用与其提高生物膜流动性有一定关系。PAMPA可以尝试引入制剂处方研究(如吸收促进剂等)的某些领域中。     

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。     

通过体外自乳化性能及体内药代动力学评价优化葛根素自乳化制剂

本文将水不溶性药物葛根素制备成自乳化制剂。测定了葛根素在不同油相及表面活性剂的溶解度，结果表明葛根素在油酸、Tween 80中的溶解度较好，1，2-丙二醇不但能增加药物的溶解度，而且能够提高自乳化能力。以油酸为油相，Tween 80为表面活性剂，1，2-丙二醇为助表面活性剂，配制一系列混合物，通过绘制三元相图得到自乳化区，考察不同自乳化处方的自乳化性质，采用激光粒度散射仪测定乳化后粒子大小，在体外评价基础上选择较好的3个处方进行比格犬体内药动学研究，比较不同处方自乳化制剂在比格犬体内的生物利用度包括药代动力学参数Cmax， Tmax， AUC0-t。结果表明处方2和处方3的AUC0-t值［(5.201±0.511) ng·mL^-1·h， (5.174±0.498) ng·mL^-1·h］和Cmax值［(1.524±0.125) ng·mL^-1， (1.513±0.157) ng·mL^-1］显著高于处方4［(3.013±0.623) ng·mL^-1·h， (0.939±0.089) ng·mL^-1］，通过体内研究结果获得较优处方为油酸(17.5%)、Tween 80(34.5%)、1，2-丙二醇(34.5%)。自乳化释药系统提供了水不溶性药物口服给药的新途径。     

桂枝、当归挥发油微囊处方优化及体内药动学研究

目的 优化桂枝、当归挥发油微囊的处方，对处方优化后制备的微囊进行相关表征和大鼠体内药动学研究。方法 采用喷雾干燥法制备桂枝、当归挥发油微囊。以载药量和包封率为指标，通过Box-Behnken设计-效应面法优化处方。采用傅里叶变换红外光谱和扫描电镜方法对处方优化后制备的微囊进行表征。按照100 mg·kg^-1的剂量灌胃给药后采血，HPLC测定血药浓度，比较体内药动学行为。结果 最佳处方为芯材-囊材比1∶1.7，囊材浓度为10.25%，复合囊材辛烯基琥珀酸淀粉钠/麦芽糊精比为3.8∶1，高压均质压力为20 MPa，喷雾干燥进口温度为185 ℃。在该条件下，测得微囊的载药量为(18.94±1.09)%，包封率(96.03±2.91)%。傅里叶变换红外光谱和扫描电镜结果表明，挥发油已成功被包覆在囊壁材料中，微囊基本形状为球形，表面凹陷但无明显裂缝。体内药动学结果显示，微囊组的达峰时间(t_max)、半衰期(t_1/2)、清除率(CL)、时间-曲线下面积(AUC_0-t)、药物从中央室消除的一级速率常数(k₁₀)、药物从中央室向周边室转运的一级速率常数(k₁₂)、药物从周边室向中央室转运的一级速率常数(k₂₁)等药动学参数与挥发油组的差异均具有统计学意义(P<0.05或P<0.01)。药动学结果表明微囊有效延长了桂枝、当归挥发油在体内滞留时间，促进药物在体内的吸收，口服相对生物利用度提高至2.62倍。结论 Box-Behnken设计-效应面法所建立的模型能较好地优化桂枝、当归挥发油微囊的处方工艺，具有良好预测性。处方优化后制备的微囊具有良好载药性能，提高了挥发油的生物利用度。     

蒲地蓝消炎口服液对头孢克洛在大鼠肠道吸收的影响

目的 建立小肠灌流液中头孢克洛的高效液相色谱(HPLC)分析方法, 考察蒲地蓝消炎口服液对头孢克洛在大鼠小肠吸收的影响, 为临床联合用药的合理性提供实验依据。方法 采用大鼠在体单向肠灌流实验模型, 应用重量法校正灌流液体积, HPLC测定灌流液中头孢克洛, 计算头孢克洛肠吸收参数。结果 头孢克洛在各肠段均有良好吸收, 小肠不同部位头孢克洛的吸收速率常数(K_a)与有效渗透系数(P_eff)大小为十二指肠> 空肠≈回肠, 各肠段间的吸收无统计学差异;联合应用蒲地蓝消炎口服液时, 头孢克洛在全场段的吸收均有所减少, 十二指肠处显著减少(P<0.05), 其他肠段处无统计学差异(P> 0.05)。结论 研究结果表明蒲地蓝消炎口服液会影响头孢克洛的小肠吸收, 因此两药联合使用时产生较好的药效不是通过促进头孢克洛的吸收而实现的, 而是二者共同作用的结果。     

盐酸地尔硫延迟起释型缓释片的研制

目的制备盐酸地尔硫(diltiazam hydrochloride,DIL)延迟起释型缓释片,解析释药机制,并考察外衣层组成对药物释放的影响。方法用干压包衣技术制备盐酸地尔硫的延缓片,用释药时滞(T_lag)及释药速率常数(k)将各因素(外衣层中的HPMC用量和粘度,PVP K30用量、EC粘度及压片压力)对药物的释放效果进行评价。结果 HPMC用量或粘度增大,T_lag延长,k减慢;PVP K30用量增大,T_lag减短,k加快;在一定范围内EC粘度及压片压力波动对释药行为无影响。结论延缓片中药物主要是通过溶蚀机制释放,外衣层的溶蚀速率是决定释药时滞的关键因素。     

难溶性药物盐酸奈必洛尔口服自微乳化给药系统的制备以及体外评价

目的 制备盐酸奈必洛尔(hydrochloride,NBH)自微乳化给药系统(self-microemulsifying drug delivery system,SMEDDS),并进行体外评价。方法 通过测定NBH在不同油相、表面活性剂和助表面活性剂中的溶解度以及运用伪三元相图对空白自微乳化的处方组成进行确定,使用星点设计-效应面法对处方用量进行筛选和优化,并加入过量NBH原料药对该处方的载药量进行确定。结果 NBH-SMEDDS处方组成为中链甘油三酸酯∶辛酸癸酸聚乙二醇甘油酯∶二乙二醇单乙基醚=20∶48∶32,该处方的载药量为20.05 mg,该处方的粒径、自乳化时间、粒径分布范围符合预测值,溶出度试验显示,NBH-SMEDDS在介质中溶出度的整体趋势对比NBH粉末和NBH普通片有一定的提升,在1,2,3月的加速条件下稳定性良好。结论 SMEDDS可用于提高NBH的体外溶出度,且稳定性良好。     

阿托伐他汀钙自微乳化释药系统的制备与评价

摘 要 目的：开发并优化阿托伐他汀钙自微乳化释药系统,改善阿托伐他汀钙的溶出度。方法: 通过溶解度和伪三元相图实验确定油相,表面活性剂和助表面活性剂的种类和用量范围,并通过D 最优混料实验设计优化阿托伐他汀钙自微乳化释药系统的处方,评价了自微乳化释药系统经水稀释后形成微乳的外观,微观形态,粒径分布,Zeta电位;比较市售阿托伐他汀钙片与自制阿托伐他汀钙自微乳化释药系统的体外溶出情况。结果: 阿托伐他汀钙自微乳化释药系统的处方组成为：Capmul MCM作为油相,Labrasol作为表面活性剂,Transcutol P作为助表面活性剂,最佳配比为：13.0〖KG*9〗∶〖KG-*2〗43.5〖KG*9〗∶〖KG-*2〗43.5。自微乳化释药系统经水稀释后形成的微乳外观呈微泛蓝光的澄清透明状液体;透射电镜下显示其呈圆整,规则球状分布;平均粒径为（34.2±13.6）nm,PdI为（0.169±0.04）,Zeta电位为（-21.1±1.3）mV;阿托伐他汀钙自微乳化释药系统在45 min内药物可完全溶出。结论: 运用D 最优混料实验设计方法成功开发了阿托伐他汀钙自微乳化释药系统,可以有效提高药物的溶出速度。     

响应面法优化西罗莫司胶束及其促小肠吸收作用

目的 制备和优化西罗莫司（sirolimus，SRL）聚合物胶束，考察其对大鼠在体肠吸收动力学的影响。方法 以去氧胆酸修饰的壳聚糖（deoxycholic acid grafted chitosan，CS-DCA）为载体，采用溶剂蒸发法制备SRL CS-DCA胶束。以包封率、载药量、粒径和电位作为考察指标，结合星点设计-效应面法优化处方。建立大鼠在体单向肠灌流模型，并通过肠腔有效吸收系数（P_eff）、吸收速率常数（K_a）和药物吸收剂量分数（f_a）研究不同浓度SRL CS-DCA的肠吸收特性。结果 SRL CS-DCA最优处方：载体浓度（CS-DCA）为10 mg·mL^-1，药物与载体质量比为20%，该条件下制备得到的SRL CS-DCA带正电荷（37.0±2.7）mV，粒径（182.2±5.7）nm，包封率>90%，载药量（15.8±0.5）%。SRL CS-DCA经大鼠全肠后，反映药物肠吸收程度的评价指标P_eff、K_a和f_a均较SRL有显著提高（P<0.05）；不同浓度的SRL CS-DCA在大鼠全肠段的P_eff、K_a、f_a值无显著性差异，提示胶束在10~100 μg·mL^-1吸收无浓度抑制，吸收特征为被动转运的线性动力学过程，推测其可能的吸收机制为被动扩散。结论 SRL制备成聚合物胶束后，对其在大鼠小肠的吸收具有明显的促进作用，从侧面证明SRL CS-DCA能有效改善SRL口服生物利用度。     

Optimization and in situ intestinal absorption of self-microemulsifying drug delivery system of oridonin

The objective of this study was to optimize and characterize an oridonin self-microemulsifying drug delivery system (SMEDDS) formulation. A central composite design (CCD) was used to investigate the influence of factors (oil percentage and surfactant to co-surfactant ratio (Sur/Co-s ratio)) on the responses including droplet size, polydispersity, equilibrium solubility and in situ intestine absorption rate. Furthermore, the desirability function approach was applied to obtain the best compromise among the multiple responses. It was found that oil percentage played a significant role on the droplet size and polydispersity. The drug equilibrium solubility was mainly contributed to oil percentage and less to Sur/Co-s ratio. The in situ intestinal absorption was influenced by both of the two factors, whereas the oil percentage played a more important role in absorption. The practical response values under the optimized formulation were in good accordance with the predicted values. Our results demonstrate CCD is of value in optimizing the SMEDDS formulation and understanding the effects of formulation compositions on SMEDDS properties.     

微粉硅胶对固体自微乳化给药系统小肠吸收的影响

固体载体对固体自微乳化给药系统(solid self-microemulsifying drug delivery systems,S-SMEDDS)的体内外性质有重要影响。本文探讨微粉硅胶对S-SMEDDS药物吸收的影响,为选择适宜固体载体提供依据。通过研究微粉硅胶对小肠脂解和S-SMEDDS体外释放的影响,并采用新型体外脂解-吸收模型研究微粉硅胶对S-SMEDDS离体小肠吸收的影响。结果发现微粉硅胶既能提高脂解速率,增加脂解后水性分散相中药物分配,促进药物吸收;又会延缓S-SMEDDS体外释药,影响药物的吸收速度;最终导致对S-SMEDDS的离体小肠吸收没有显著性影响。而且微粉硅胶对脂解和释药的影响都与其用量有关,这提示微粉硅胶适合作为S-SMEDDS的固体载体,其用量需要进一步筛选优化。     

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.     

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.     

Self-microemulsifying drug delivery system (SMEDDS) of vinpocetine: formulation development and in vivo assessment

A new self-microemulsifying drug delivery system (SMEDDS) has been developed to increase the solubility, dissolution rate and oral bioavailability of vinpocetine (VIP), a poor water-soluble drug. The formulations of VIP-SMEDDS were optimized by solubility assay, compatibility tests, and pseudo-ternary phase diagrams analysis. The optimal ratio in the formulation of SMEDDS was found to be Labrafac : oleic acid : Cremophor EL : Transcutol P=40 : 10 : 40 : 10 (w/w). The average particle diameter of VIP was less than 50 nm. In vitro dissolution study indicated that the dialysis method in reverse was better than the ultrafiltration method and the dialysis method in simulating the drug in vivo environment. Comparing with VIP crude drug power and commercial tablets, (-)VIP-SMEDDS caused a 3.4- and 2.9-fold increase in the percent of accumulated dissolution at 3 h. Further study on the absorption property of VIP-SMEDDS employing in situ intestine of rats demonstrated that VIP in SMEDDS could be well-absorbed in general intestinal tract without specific absorption sites. In addition, the developed SMEDDS formulations significantly improved the oral bioavailability of VIP in rats. Relative bioavailability of (-)VIP-SMEDDS and (+)VIP-SMEDDS increased by 1.85- and 1.91-fold, respectively, in relative of VIP crude powder suspension. The mechanisms of enhanced bioavailability of VIP might contribute to the improved release, enhanced lymphatic transport, and increased intestinal permeability of the drug.     

Systematic development of design of experiments (DoE) optimised self-microemulsifying drug delivery system of Zotepine

The aim of present investigation is to improve dissolution rate of poor soluble drug Zotepine by a self-microemulsifying drug delivery system (SMEDDS). Ternary phase diagram with oil (Oleic acid), surfactant (Tween 80) and co-surfactant (PEG 400) at apex were used to identify the efficient self-microemulsifying region. Box–Behnken design was implemented to study the influence of independent variables. Principal Component Analysis was used for scrutinising critical variables. The liquid SMEDDS were characterised for macroscopic evaluation, % Transmission, emulsification time and in vitro drug release studies. Optimised formulation OL1 was converted in to S-SMEDDS by using Aerosil^® 200 as an adsorbent in the ratio of 3:1. The S-SMEDDS was characterised by SEM, DSC, globule size (152.1?nm), zeta-potential (?28.1?mV), % transmission study (98.75%), in vitro release (86.57%) at 30?min. The optimised solid SMEDDS formulation showed faster drug release properties as compared to conventional tablet of Zotepine.     

Preparation and evaluation of self-microemulsifying drug delivery system of oridonin

The objective of this study was to develop self-microemulsifying drug delivery system (SMEDDS) to enhance the oral bioavailability of the poorly water-soluble drug, oridonin. The influence of the oil, surfactant and co-surfactant types on the drug solubility and their ratios on forming efficient and stable SMEDDS were investigated in detail. The SMEDDS were characterized by morphological observation, droplet size and zeta-potential determination, cloud point measurement and in vitro release study. The optimum formulation consisted of 30% mixture of Maisine 35-1 and Labrafac CC (1:1), 46.7% Cremopher EL, and 23.3% Transcutol P. Invitro release test showed a complete release of oridonin from SMEDDS in an approximately 12h. The absorption of oridonin from SMEDDS showed a 2.2-fold increase in relative bioavailability compared with that of the suspension. Our studies demonstrated the promising use of SMEDDS for the delivery of oridonin by the oral route.     

自微乳释药系统及其制剂的研究进展

根据近期报道的自微乳释药系统最新研究进展,详细阐述自微乳释药系统的特点、性质、机制、处方工艺和质量评价,并介绍了有代表性的自微乳制剂。自微乳释药系统能显著增加某些药物的吸收和生物利用度,在药学领域将有很好的应用前景。     

双氯芬酸钠自乳化给药系统的研制

目的研制双氯芬酸钠自乳化给药系统。方法通过测定双氯芬酸钠在各种溶剂中的平衡溶解度,选择适宜油相、乳化剂、助乳化剂,并在此基础上绘制伪三元相图。通过对各处方比例的筛选,结合各处方载药量以及所形成微乳的稳定性,确定最佳处方。结果以油相为三辛酸/癸酸甘油酯,乳化剂为Cremophor EL,助乳化剂为丙二醇,Km1为4∶1,Km2为1∶9,双氯芬酸钠在微乳中的质量浓度为25g.L-1,该处方为最佳处方。结论所研制的自乳化给药系统具有粒径小、载药量高、性质稳定的优势,可作为进一步研究的基础。     

星点设计效应面法优化非洛地平自微乳给药系统

目的 设计非洛地平自微乳给药系统，并进行体外评价。方法 测定非洛地平的溶解度，考察油相与乳化剂的相容性，绘制伪三元相图，初步设计自微乳处方；运用星点设计效应面法优化自微乳处方；评价自乳化性能和体外溶出行为。结果 非洛地平自微乳处方：油相LABRAFIL M 1944CS为4.4 g，乳化剂Cremophor EL35为5.5 g，助乳化剂PEG400为1.1 g，非洛地平1.0 g；自乳化效率高，乳液澄明稳定，平均粒径为30.4 nm，PDI为0.16；水中溶出很快，5 min内平均溶出度>85%，30 min达99%，24 h后乳滴依然稳定。结论 星点设计-效应面法优化的非洛地平自微乳，自乳化性能高，乳液稳定，显著提高非洛地平的体外溶出度。