难溶性药物logP值对纳米脂肪乳载药特性的影响

目的 考察难溶性药物油/水分配系数(log P值)对纳米脂肪乳载药量、体外释药特性、相分布等载药特性的影响。 方法 选取6种难溶性药物:尼莫地平(NIM)、多西紫杉醇(DTX)、姜黄素(CUR)、紫杉醇(PTX)、替尼泊苷(TEN)、水飞蓟宾(SLB),分别考察其log P值与PEG400中溶解度、载药纳米脂肪乳的载药量、粒径、Zeta电位、体外释药特性以及相分布等的关系。 结果 随着log P值的增加,药物在PEG400中的溶解度呈先上升后下降的趋势,在纳米脂肪乳中的载药量增高,体外释放速率减慢,在油相中的分布增加,在乳化剂层的分布减小;药物log P值与载药纳米脂肪乳的粒径及Zeta电位无关。 结论 可综合考虑药物的log P值及PEG400中的溶解度,用以初步判断纳米脂肪乳的载药特性。     

Box-Behnken效应面法优化布洛芬缓释滴丸的处方

摘 要 目的：制备布洛芬缓释滴丸,考察其体外累积释放度,并验证药物在基质中存在的状态。方法: 以含药量、水溶性与难溶性基质比、硬脂酸与单硬脂酸甘油脂用量比为考察因素,以2 h和10 h累积溶出率的综合评分为评价指标,应用Box Behnken 效应面法筛选布洛芬缓释滴丸的最优处方。采用差示扫描量热法（DSC）考察药物在基质中存在的状态。结果: 布洛芬缓释滴丸的最优处方为：含药量10%,水溶性与难溶性基质比为4∶1,硬脂酸与单硬脂酸甘油酯用量比为3∶1。制得的布洛芬缓释滴丸10 h的最大累积溶出率可达78.85%。DSC分析表明,在缓释滴丸中药物结晶峰消失,形成了固体分散体。结论:所制得的布洛芬缓释滴丸具有良好的缓释效果,且制备工艺简单。     

一种新型普鲁兰微球的制备及其释药性能研究

目的 构建一种白血病治疗药物甲氨蝶呤（MTX）的新载体,探讨其对MTX的负载效率及其缓释性。方法 采用动态光散射（DLS）和扫描电镜（SEM）对载体载药前后的粒径、电位及形貌进行表征,紫外分光光度法测定MTX的含量。结果 平均粒径大小为1098 nm,Zeta电位为0.835 mV,载药后分别为1324 nm、0.727 mV,载药后粒径略有增加。MTX的载药量和包封率分别未（13.44±2.13）%、（58.7±4.6）%。SEM显示,该载体载药前后均为球形结构,证明微球制备成功。体外释放研究表明,微球负载的药物释放明显减缓,游离药物在10 h内可完全释放,但此时微球中的药物释放量仅30.0%左右,72 h仅释放78.6%。结论 负载MTX的胆甾醇疏水改性普鲁兰（CHP）微球属于微米级,具有较高的载药量和明显的缓释性。     

用疏水改性的白及多糖制备载紫杉醇纳米粒并对其表征

目的 讨论白及多糖作为药物递送载体的可行性。方法 制备疏水性胆甾醇琥珀酰基白及多糖（CHSB）后,以紫杉醇（PTX）为模型药物,采用透析法制备载药纳米粒子,然后在透射电镜（TEM）下观察其形态;用动态光散射仪（DLS）检测其粒径、粒径分布和Zeta电位;用高效液相色谱法（HPLC）测定其包封率和载药量,并考察其体外释放情况;采用差示量热扫描法（DSC）确证药物在载药纳米粒子中的存在形式;采用MTT法考察纳米粒子的体外抗肿瘤活性,用荧光标记法观察肝癌细胞QGY-7703对纳米粒子的摄取情况。结果 制备的纳米粒呈规则球形,粒度分布均匀,药物包载于纳米粒内部,载药量和包封率在一定范围受CHSB的影响,载药纳米粒对肝癌细胞的杀伤性强于游离药物,在细胞内可观察到罗丹明B标记的纳米粒呈现的荧光。结论 CHSB作为难溶性药物载体具有较高的可行性,因此可作为一种极具潜力的纳米载体材料。     

三维有序大孔淀粉材料改善达比加群酯的溶出行为

目的 制备三维有序大孔淀粉材料（three-dimensional ordered macroporous starch material,3DOMS）,改善难溶性药物达比加群酯（dabigatran etexilate,DBET）的溶出度。方法 通过硬模板法制备3DOMS;溶剂挥发法进行载药;借助X射线衍射法、差示扫描量热法和傅里叶红外光谱法表征考察药物存在状态;溶出度实验验证DBET溶出度改善情况。结果 3DOMS具有三维有序的纳米级连通孔道结构,借助其纳米级空间抑制效应能够有效抑制难溶性药物的结晶度,载药样品（DBET-3DOMS）中DBET以无定形态存在,体外溶出度实验表明药物溶出效果明显改善。结论 3DOMS能够有效改善DBET的溶出,作为生物可降解材料在改善难溶性药物水溶性方面具有较大潜力。     

羧基化三维有序大孔炭载体用于提高羟基喜树碱的溶出度

目的制备羧基化三维有序大孔炭载体,提高水难溶性药物羟基喜树碱的溶出度。方法采用硬模板法制备三维有序大孔炭载体,以扫描电子显微镜(scanning electron microscopy,SEM)进行表征。采用表面氧化法进行羧基化修饰,对修饰前后的载体进行IR表征及Zeta电位测定。采用溶剂挥发法载药,测定载药量并对载药体系的水分散性进行考察。以DSC考察药物于载体中的存在状态,对原料药及羧基化修饰前后的载药体系的药物溶出度进行测定。结果制得的三维有序大孔炭载体孔道呈互相连通的三维结构,外孔孔径为500nm,内孔孔径为200nm。羧基化修饰后载体的Zeta电位显著降至-16mV,IR谱图中可见明显的羧基吸收峰。羟基喜树碱的载药量质量分数约为24%,羧基化修饰的载药体系水分散性显著提高,DSC显示其中所载药物的结晶峰明显减弱。原料药1h累计释放度仅为24.7%,羧基化修饰的载药体系药物累计释放度升至83.6%。结论制备的羧基化三维有序大孔炭载体可利用其独特的结构特征及改善的水分散性显著提高羟基喜树碱的溶出度。     

有序介孔硅胶提高难溶性药物白藜芦醇的溶出速率

本研究的目的是制备有序介孔硅胶并考察其作为难溶性药物载体的体外药物释放特点。以十六烷基三甲基溴化铵为模板合成了有序介孔硅胶, 以白藜芦醇为模型药物, 采用扫描电镜、透射电镜、N₂吸附-脱附、X-射线衍射和红外光谱对载药前后的有序介孔硅胶进行表征, 并考察药物体外释放行为。结果表明, 合成的有序介孔硅胶比表面积大、粒度均匀, 具有有序六方孔道结构, 载药后药物以无定形态或分子态存在, 释放速率明显提高。有序介孔硅胶有望成为新型的难溶性药物载体。     

磷酸川芎嗪pH调控长时微孔渗透泵控释片的制备

目的 制备24 h长时释放磷酸川芎嗪微孔渗透泵控释片。方法 根据不同时间累积释放度考察药物体外释放情况;利用单因素考察和正交试验设计,筛选出最佳处方。结果 单因素考察找出对16 h内体外累积释放度影响较为显著的因素：pH调节剂（枸橼酸钠、酒石酸钠）用量、聚乙二醇-400（PEG-400）用量、柠檬酸三乙酯（TEC）用量、包衣增重。采用L₉（3⁴）正交试验的优化实验,直观分析结果得到最优处方：按照两个最佳处方进行中试放大试验制备3批样品,其体外累计释放度曲线拟合结果符合零级模型,拟合度好（r=0.995 0）,16 h累计释放度达85%以上。24 h释放结果批间相似因子（f₂）为84～97,重现性好。结论 该处方制备工艺简单有效,所制磷酸川芎嗪微孔渗透泵片在16 h内零级释放特征显著,并可达到24 h的长时控释释药。     

氧氟沙星/蒙脱土纳米复合体的制备及其对药物缓释作用的研究

目的 制备氧氟沙星/蒙脱土（OFLO/MMT）插层化复合物,为寻求新型药物载体材料及氧氟沙星新剂型提供依据。方法 采用溶液离子交换法制备OFLO/MMT复合体系,利用单因素法考察药物浓度、反应温度、时间等因素对蒙脱土载药量的影响,优化插层反应条件,通过紫外光谱、傅立叶变换红外（FTIR）、DTA曲线手段对插层复合体进行表征。并进一步研究OFLO/MMT纳米复合物在不同pH值释放介质中的释放行为。结果 在初始浓度2.60 mg·mL^-1,25℃反应2 h时药物载药量最大,体外释放实验表明OFLO/MMT插层药物在释放介质中具有缓释作用,且OFLO/MMT在酸性和碱性条件下的释放动力学明显不同,复合体更倾向于在盐酸溶液（pH 1.2）中进行释放。结论 插入蒙脱土层间的氧氟沙星具有明显的缓释作用,且具有一定pH值敏感性,蒙脱土可作为一种非常好的缓释制剂载体材料。     

难溶性药物新型速崩片的研究进展

摘 要难溶性药物由于其溶解度低,导致吸收差,生物利用度低,临床应用受到很大局限。运用各种增溶技术,增加难溶性药物的溶解度,进而提高其生物利用度十分必要。然而现有的增溶技术常常会造成增溶后含药量低、粘度高等问题,容易造成服用量的增大以及制剂困难。速崩片可通过局部快速释放达到提高患者顺应性以及增溶的目的。本文针对近年来出现的难溶性药物速崩片增溶技术,综述了固体分散体速崩片、包合物速崩片、乳剂冻干片、自微乳分散片、纳米混悬剂冻干片、微丸速崩片、水分散体冻干片等制剂新技术在增加难溶性药物溶解度、改善生物利用度、提高患者用药依从性等方面的应用。     

Angiopep-2修饰载神经毒素介孔二氧化硅脂质囊纳米粒的制备及其体内外评价

目的 制备Angiopep-2（ANG）修饰的载神经毒素（neurotoxin,NT）介孔二氧化硅脂质囊纳米粒（mesoporous silica nanoparticles,MSN）（ANG-LP-MSN-NT）,并进行体内外评价。方法 利用改进的Stober法制备介孔二氧化硅纳米粒,然后运用薄膜水化法制备ANG-LP-MSN-NT。考察其形态、粒径、Zeta电位、载药量和包封率;通过小角粉末衍射、氮气吸-脱附法等技术对其进行表征;透析袋法考察其体外释药特性;热板法和醋酸扭体法考察其镇痛效果。结果 制备的MSN比表面积为557 m²·g^-1,孔径和孔容积（V_p）分别为2.94 nm和0.58 cm³·g^-1。ANG-LP-MSN-NT分布均一,无团聚现象,粒径为（123.37±3.76）nm（PDI 0.20±0.02）,Zeta电位为（-16.57±1.59）mV,载药量与包封率分别为（10.75±0.54）%与（91.82±3.12）%。ANG-LP-MSN-NT较MSN-NT体外突释降低,缓释特性明显;药效学实验结果表明ANG-LP-MSN-NT起效快、最大镇痛效应优于其他组别。结论 ANG-LP-MSN-NT解决了二氧化硅易团聚、易突释的问题,且更有利于NT在脑部富集,发挥更好的镇痛效果,该纳米递药系统作为神经毒素载体在镇痛方面具有较好的应用前景。     

载吉西他滨介孔二氧化硅纳米粒的制备及其抗肿瘤活性评价

目的：制备载吉西他滨(gemcitabine,GemC)的介孔二氧化硅纳米粒(MSN),并对其体内外抗肿瘤活性进行评价。方法：采用聚合法制备了GemC-MSN,采用激光粒度仪测定了纳米粒的粒度分布和电位,并通过透射电镜对纳米粒的形态进行了表征。应用紫外可见分光光度法评价了纳米粒的载药量、包封率及体外释放特性。采用MTT染色法,考察了GemC-MSN对A549细胞的体外细胞毒性。建立了体内肿瘤动物模型,评价纳米粒的体内抗肿瘤活性。结果：纳米粒分布均一,平均粒径为107.29 nm,PDI为0. 167,Zeta电位为0.107mV;药物的载药量和包封率分别为(37.31±1.25)%和(87.37±2.12)%;体外释放结果显示,纳米粒具有一定的缓释作用,96h时释放达到平衡;体内外抗肿瘤试验结果表明,GemC-MSN较游离GemC具有更强的抗肿瘤活性。结论：MSN作为药物的新型载体,具有良好的生物相容性,并能显著提高GemC的载药量,控制药物的缓慢释放,能显著提高GemC的体内外抗肿瘤活性,将为GemC新型给药系统的深入研究提供参考。     

Capped mesoporous silica nanoparticles as stimuli-responsive controlled release systems for intracellular drug/gene delivery

Importance of the field: The incorporation of stimuli-responsive properties into nanostructured systems has recently attracted significant attention in the research of intracellular drug/gene delivery. In particular, numerous surface-functionalized, end-capped mesoporous silica nanoparticle (MSN) materials have been designed as efficient stimuli-responsive controlled release systems with the advantageous ‘zero premature release’ property.

Areas covered in this review: Herein, the most recent research progress on the design of biocompatible, capped MSN materials for stimuli-responsive intracellular controlled release of therapeutics and genes is reviewed. A series of hard and soft caps for drug encapsulation and a variety of internal and external stimuli for controlled release of different cargoes are summarized. Recent investigations on the biocompatibility of MSN both in vitro and in vivo are also discussed.

What the reader will gain: The reader will gain an understanding of the challenges for the future exploration of biocompatible stimuli-responsive MSN devices.

Take home message: With a better understanding of the unique features of capped MSN and its behaviors in biological environment, these multifunctional materials will find a wide variety of applications in the field of drug/gene delivery.     

Surface Functionalization of Mesoporous Silica Nanoparticles Controls Loading and Release Behavior of Mitoxantrone

Purpose

To investigate the effect of surface functionalization of mesoporous silica nanoparticles (MSN) on crystallization, loading, release and activity of mitoxantrone (MTX).

Methods

Thiol-, amine-, and mixed thiol/amine-functionalized MSN were synthesized and characterized by electron microscopy, thermogravimetry, surface area analysis, elemental analysis and zeta potential. MTX loading and release kinetics were determined in phosphate and acetate buffers (pH 7.4 and 4.5). The crystalline state of MTX in MSN was determined by differential scanning calorimetry and X-ray diffraction. Cytotoxicity and activity of MTX loaded MSN were determined by MTS assay in MDA-MB-231 cells.

Results

Our results demonstrate that loading of MTX depends strongly on the type of surface functional groups in MSN. Thiol-MSN showed the highest MTX loading (18?% w/w) when compared with thiol/amine-MSN (6?% w/w) and amine-MSN (1?% w/w). MTX release was strongly dependent on the pH of the release medium and the type of surface functional group. MTX was found in the amorphous form when loaded in thiol-functionalized MSN. No significant effect of surface modification of MSN on particle toxicity was observed. MTX loaded in MSN exhibited comparable anticancer activity in vitro as free MTX.

Conclusion

Surface modifications of MSN have significant effect on MTX crystallization and release behavior.     

载阿霉素介孔二氧化硅纳米粒的细胞毒性及细胞摄取

目的制备载阿霉素的介孔二氧化硅纳米粒(mesoporous silica nanoparticles,MSN),对其理化性质及细胞摄取行为进行初步研究。方法通过聚合法制备MSN,透射电镜表征纳米粒的形态,动态光散射粒径测定仪测定粒子的平均粒径及分布。紫外分光光度计测定阿霉素的负载行为,MTT比色分析法研究粒子的细胞毒性,激光共聚焦显微镜观察其人乳腺癌MCF-7细胞对载药粒子的摄取。结果纳米粒分布均一,平均粒径约70 nm(PDI<0.1),载药量质量分数达到20%。MCF-7细胞对载药粒子的摄取较快,空白纳米粒具有较低的细胞毒性。结论介孔二氧化硅纳米粒具有较高的药物载药量和良好的生物相容性,能较快地被对人乳腺癌MCF-7细胞摄取,有望成为一种新型的药物化疗载体。     

Solubility enhancement of ethyl p-methoxycinnamate under nanoscale confinement

The low solubility of ethyl p-methoxycinnamate (EPMC) inhibits its absorption in the gastrointestinal tract, impairing its pharmacological effect. The solubility of EPMC can be increased by utilizing a carrier in the type of mesoporous silica nanoparticles (MSN). In the present study, we aimed to confine EPMC under the nanoscale of MSN (MSN-EPMC) to increase the water solubility of EPMC. MSN was prepared using sodium silica as a precursor and Tween 80 and Span 80 as templates. Briefly, 500 mg MSN was dispersed into 2% w/v EPMC solution, stirred at 100 r/min for 24 h, and dried at 60 °C. The results showed that the MSN formed had a particle size of 87.1305 nm, a surface area of 68.86 m²/g, a pore diameter of 20.45 nm, and a pore volume of 0.352 cm³/g. EPMC was successfully confined under the nanoscale of MSN. MSN-EPMC had an amorphous structure, a loading capacity of 10.6%, and a loading efficiency of 18.18%. The solubility of MSN-EPMC was increased by 2.63 folds at 30 min compared with EPMC. The amorphous structure of MSN-EPMC was responsible for the enhancement of the water solubility. It could be concluded that the confining of EPMC in MSN had the potential to increase the solubility of a water-soluble isolate of a plant.     

pH responsive cylindrical MSN for oral delivery of insulin-design,fabrication and evaluation

Objective: The objective of the present study was to develop novel PMV [poly (methacrylic acid-co-vinyl triethoxylsilane)]-coated mesoporous silica nanoparticles (MSN) with improved hypoglycemic effect for oral insulin (INS) delivery.

Methods: MSN was synthesized under acidic condition using Pluronic® P 123 and Tetra ethoxy orthosilane. Surfactant was removed by calcination. Calcined MSN was coated with pH sensitive polymer PMV. Cytotoxicity of this coated MSN was evaluated by MTT assay using CHO-K1 cell line. Different MSN samples were characterized with BET surface area analyzer, FESEM, TEM, FT-IR, XRD, TG-DTA. In vivo study was performed using male rats. Pharmacokinetic study was conducted using HPLC.

Results and discussion: Highest surface area (304.3921 m²/g) was observed in case of calcined sample. Adsorption pore width of final coated sample was highest (64.7844?nm) compared with others. No noticeable cytotoxicity was observed for this coated support. The entrapment efficiency of insulin was found to be 39.39%. In vitro studies were done at different pH using Franz-diffusion cell. Results showed significant release at pH 7.4. Cumulative drug release over a period of 6?h was more than 48% at this systemic pH. Effect of this MSN-PMV-INS on blood glucose level was retained for 16?h. This novel formulation has shown 73.10% relative bioavailability of insulin.

Conclusion: A novel-coated mesoporous silica support was successfully developed for delivery of insulin through oral route.     

基于固体分散技术的山楂叶总黄酮缓释胶囊的研制及释药机制研究

目的 研制山楂叶总黄酮缓释胶囊,并考察其释药机制。方法 采用喷雾干燥法制备山楂叶总黄酮缓释固体分散体,以乙基纤维素等为载体,以2,6,12 h的释放度为指标,筛选最佳缓释固体分散体处方;采用X-射线衍射、扫描电镜和红外光谱法考察固体分散体中药物分散状态;拟合川北方程,以粉体流动性参数为指标,筛选缓释胶囊的处方辅料,制备山楂叶总黄酮缓释固体分散体胶囊,考察缓释胶囊释药机制,拟合释放动力学方程。结果 山楂叶总黄酮缓释固体分散体最佳处方组成为山楂叶总黄酮：乙基纤维素：卡波姆940P=4：1：0.5;X-射线衍射和扫描电镜结果表明,药物以无定形或分子形式分散于固体分散体中;红外光谱法结果表明,乙基纤维素峰强度增强;缓释胶囊最佳处方组成为固体分散体：微粉硅胶=1：0.3%,所制备缓释胶囊释放度2,6,12 h分别为27.56%,69.50%和96.78%。结论 该缓释胶囊在12 h内呈现良好缓释特征,释放行为符合一级动力学方程,释放机制为扩散和溶蚀相结合机制,且为降解控释型。     

Mesoporous silica formulation strategies for drug dissolution enhancement: a review

Introduction: Silica materials, in particular mesoporous silicas, have demonstrated excellent properties to enhance the oral bioavailability of poorly water-soluble drugs. Current research in this area is focused on investigating the kinetic profile of drug release from these carriers and manufacturing approaches to scale-up production for commercial manufacture.

Areas covered: This review provides an overview of different methods utilized to load drugs onto mesoporous silica carriers. The influence of silica properties and silica pore architecture on drug loading and release are discussed. The kinetics of drug release from mesoporous silica systems is examined and the manufacturability and stability of these formulations are reviewed. Finally, the future prospects of mesoporous silica drug delivery systems are considered.

Expert opinion: Substantial progress has been made in the characterization and development of mesoporous drug delivery systems for drug dissolution enhancement. However, more research is required to fully understand the drug release kinetic profile from mesoporous silica materials. Incomplete drug release from the carrier and the possibility of drug re-adsorption onto the silica surface need to be investigated. Issues to be addressed include the manufacturability and regulation status of formulation approaches employing mesoporous silica to enhance drug dissolution. While more research is needed to support the move of this technology from the bench to a commercial medicinal product, it is a realistic prospect for the near future.     

载阿霉素海藻酸钠纳米粒的制备及体外释药行为研究

目的以海藻酸钠(sodium alginate,ALG)为材料,制备载阿霉素海藻酸钠纳米粒(doxorubicin loading nanoparticles,DOX-ALG-NPs),并对其载药、释药特性进行研究。方法采用微乳-离子交联法制备空白海藻酸钠纳米粒(ALG-NPs),以吸附法载药制备阿霉素海藻酸钠纳米粒(DOX-ALG-NPs)。采用效应面法对ALG-NPs的处方进行优化,并考察ALG-NPs悬液浓度、药载比、孵育时间及孵育温度对ALG-NPs载药性能的影响。对DOX-ALG-NPs的基本性质及体外释药行为进行考察。结果成功制备了粒径为(262.0±4.5)nm的ALG-NPs及粒径为(159.8±8.1)nm、包封率及载药量分别为(94.2±0.5)%和(19.05±0.085)%的DOX-ALG-NPs。与原料药DOX相比,DOX-ALG-NPs在生理盐水与PBS(pH=7.4)中均呈现明显的缓释作用,在生理盐水和PBS中2 h与5 h时分别释放药物(38.1±1.5)%与(55.5±1.1)%、(40.0±1.8)%与(48.1±2.5)%,24 h时分别释放(73.1±3.2)%、(60.3±3.4)%。结论所制备的DOX-ALG-NPs形态圆整,粒径小且分布均匀,包封率及载药量较高,具有缓释性能,有望用作抗癌药物传递系统。