两种介孔二氧化硅载体用于改善西洛他唑溶出度的比较

目的研究两种介孔二氧化硅(MCM-48和MCM-41)作为西洛他唑(cilostazol,CLT)的载体在改善药物溶出度方面的作用。方法分别采用3种方法制备CLT/MCM-48和CLT/MCM-41固体分散体,以紫外分光光度法测定样品的载药量。以溶出度为评价指标,对载药方法、药物与载体的质量比和固体分散体粒径等因素进行了优化,并应用氮气吸附和低温DSC法分析样品中药物的存在状态。结果当药物与载体质量比为1∶3时,以共沉淀法制备的CLT/MCM-48和CLT/MCM-41样品,经150μm孔径筛处理后,药物的溶出度最高,分别达到78%和85%。与以PEG4000为载体制备的CLT/PEG相比,显示了更加优良的药物溶出的稳定性。氮气吸附结果表明药物已经成功分散于载体孔道中;DSC分析显示,药物极有可能以无定形存在,且介孔孔道对药物向稳定型转变有延缓和阻滞作用。结论 MCM-48和MCM-41作为药物载体制备固体分散体能够不同程度地提高CLT的溶出度。     

基于HPMCAS载体的依非韦伦固体分散体溶出模式研究

目的 以依非韦伦为原料药、不同规格（L、M、H）HPMCAS为载体，采用喷雾干燥法制备固体分散体并对其溶出模式进行初步探究。方法 通过X射线粉末衍射（XRPD）、扫描电子显微镜（SEM）对固体分散体理化性质进行制剂学表征；以动力溶解度为指标考察不同药载比、不同规格HPMCAS固体分散体的溶出情况；通过粒度分析仪和透射电子显微镜（TEM）、SEM探讨固体分散体溶出时的不同模式。结果 XRPD分析显示，固体分散体中药物以无定形的形态分散在HPMCAS中；SEM分析显示，L、M、H规格HPMCAS与依非韦伦形成的固体分散体均具有"萎缩葡萄干"形态；在pH 6.8磷酸缓冲盐溶液中溶出时，药载比1：6的固体分散体溶出好，药载比1：1.5的固体分散体溶出差且相同药载比时L规格HPMCAS的固体分散体溶出更快。结论 以不同规格HPMCAS为载体制备的依非韦伦固体分散体在pH 6.8磷酸缓冲盐溶液中溶出时，存在多种溶出模式。药载比1：6时，L、M规格HPMCAS的固体分散体以药物纳米颗粒的形式溶出；药载比1：1.5时，L、M规格HPMCAS的固体分散体存在类似溶蚀的溶出模式，药物从载体骨架中释放。     

田口设计筛选硝苯地平喷雾干燥分散体的处方研究

目的 考察喷液处方对硝苯地平喷雾干燥分散体（spray dried dispersion,SDD）的表征和非漏槽条件下溶出度的影响。方法 采用minitab DOE（design of experiment）中的田口设计（Taguchi design）方法,以120 min以内的溶出度曲线下面积（AUC0~120 min）及120 min时的溶出浓度和最大浓度的比值（C₁₂₀/C_max）为评价指标,考察载体材料的种类和用量及喷雾溶液的固含量对硝苯地平SDD的药物存在状态和体外溶出度的影响。结果 硝苯地平与聚合物的比例对固体分散体中药物的存在状态和体外溶出度均有显著影响,固含量对结果影响较小。以共聚维酮为载体材料时,可以获得比醋酸羟丙甲基纤维素琥珀酸酯（HPMCAS）更高的最大溶出浓度（C_max）,但是HPMCAS的抑制药物重结晶的效果明显优于共聚维酮,其中药物-HPMCAS LG 1∶4时可以获得最大的C_max和AUC_{0~120 min}。结论 硝苯地平与HPMCAS LG按照1∶4的比例配成固含量10%的溶液进行喷雾干燥,可以制得溶出度显著改善的SDD。     

Soluplus®、PVP VA64为载体的氟苯尼考固体分散体的制备及体外评价

目的 采用新型载体材料Soluplus^®和PVP VA64制备氟苯尼考固体分散体,以增加其溶解度及体外溶出度。方法 应用溶解度参数法初步预测药物与载体材料的相容性,进一步采用溶剂蒸发法制备氟苯尼考-Soluplus^®和氟苯尼考-PVP VA64固体分散体,并采用差示扫描量热法（DSC）、X-射线粉末衍射法（XPRD）、傅里叶变换红外光谱法（FTIR）对所得固体分散体进行表征,且与PVP K30进行比较。以溶解度和体外溶出度为评价指标,对不同载体制备的氟苯尼考固体分散体进行比较。结果 DSC、XPRD和FTIR结果表明,不同高分子材料制得的氟苯尼考固体分散体中药物均呈无定型状态;几种载体材料均能增加氟苯尼考的溶解度及溶出速率,增溶效果为PVP VA64>PVP K30>Soluplus^®,其中PVP VA64固体分散体的溶解度增加最为显著,25℃在标准硬水、自来水、纯化水中的溶解度约为原料药的3倍,且自来水中5 min时累积溶出率可达88.23%,为氟苯尼考原料药的20.56倍。结论 采用溶剂蒸发法制备氟苯尼考-PVP VA64固体分散体可以显著提高药物的溶解度及体外溶出度。     

以泊洛沙姆188或聚乙二醇8000为载体制备槲皮素晶体分散体系的表征及体外溶出行为研究

目的 制备不同高分子材料的槲皮素（QUR）结晶固体分散体（QUR-CSD）,探讨高分子材料对QUR-CSD体外溶出行为的影响及其可能的分子机制。方法 分别以泊洛沙姆188（P188）或聚乙二醇8000（PEG8000）为载体,QUR为模型药物,采用旋转蒸发法制备2种QUR-CSD（CSD-P188-QUR、CSD-PEG-QUR）。扫描电子显微镜（SEM）观察样品的微观结构;粉末X-射线衍射法（PXRD）观察晶体学特性;差示扫描量热法（DSC）测定起始熔融温度（T_c,onset）;通过粉末溶出、本征溶出、片剂pH转换溶出实验考察体外溶出行为。结果 CSD表征结果显示,2种QUR-CSD中QUR均以结晶态存在,晶体粒径、晶畴尺寸和结晶度均较原料药有所减小,且以P188为载体的CSD对药物上述性质的影响更明显。3种不同的体外溶出实验结果均显示CSD-P188-QUR溶出行为最佳,其次是CSD-PEG-QUR,QUR最差。结论 2种高分子材料均可通过影响CSD中QUR的微观结构来改善其体外溶出行为,且以P188为载体的CSD对药物微观结构的影响更为显著。     

托伐普坦固体分散体的制备及体外溶出特性考察

目的 采用固体分散技术提高难溶性药物托伐普坦的体外溶出度。方法 选用聚维酮K_29/32为载体材料,以溶剂蒸发法制备托伐普坦固体分散体。采用差示扫描量热法(DSC)、X-射线粉末衍射法(XRPD)对所得固体分散体进行鉴定, 并进行溶解度、体外溶出实验。结果 固体分散体的DSC 图谱及X-射线粉末衍射确定了托伐普坦以无定形态分散在载体中, 体外溶解实验表明其溶出较原料药、物理混合物均有明显提高。结论 将托伐普坦与PVP K_29/32制成固体分散体,其分散状态发生了改变,溶出性能明显提高。     

卡维地洛固体分散体的制备与溶出度测定

目的：制备卡维地洛固体分散体,增加其溶解度和溶出速度。方法：以聚乙烯吡咯烷酮（PVP）、聚乙二醇－6000（PEG－6000）为载体,溶剂法和溶剂熔融法制备固体分散体,并进行体外溶出度研究。结果：载体比例越大,药物溶出愈快;且载体比例愈小,差异愈显著。载体为PVP所制固体分散体的体外溶出为总体优于载体为PEG－6000的固体分散体。结论：本试验所制卡维地洛固体分散体能加速体外溶出,为难溶于水药物提高生物利用度开辟一条途径。     

卡维他洛固体分散体的研制及其体外溶出实验

目的：制备卡维他洛固体分散体,增加其溶解度和溶出速度。方法：以聚乙烯吡咯烷酮（PVP）、聚乙二醇-6000（PEG-6000）为载体,溶剂法和溶剂熔融法制备固体分散体,并进行体外溶出度研究。结果：载体比例越大,药物溶出愈快;且载体比例愈小,差异愈显著。载体为PVP所制固体分散体的体外溶出行为总体优于载体为PEG-6000的固体分散体。结论：本试验所制卡维地洛固体分散体能加速体外溶出,为难溶于水药物提高生物利用度开辟一条途径。     

提高原人参二醇口服生物利用度的固体分散体及其片剂的制备与评价

目的 本文拟研究一种加水复溶后可转化为纳米混悬液的新型固体分散体片剂,提高原人参二醇（PPD）口服给药的溶解度和生物利用度。方法 通过将药物、聚合物载体和表面活性剂按10:14:6的比例溶解于乙醇后,减压真空干燥制备固体分散体,然后将固体分散体、乳糖、交联聚乙烯吡咯烷酮和硬脂酸镁按300:16:60:4的比例混合后,直接压成片重400 mg的片剂。结果 发现含泊洛沙姆188和维生素E聚乙二醇琥珀酸酯（TPGS）的原人参二醇固体分散体加水复溶后可转变为纳米混悬液。以乙烯基吡咯烷酮/醋酸乙烯共聚物64（PVP-VA）为载体,维生素E聚乙二醇琥珀酸酯为表面活性剂的固体分散体加水复溶后可转变为平均粒径小于120 nm的纳米混悬液,该混悬液放置8 h后粒径基本稳定。固体分散体经压制成片剂后可在15 min内溶出超过90%的药物,且其溶出的药物可稳定维持至少8 h。固体分散体经大鼠灌胃给药后,其最高血药浓度和生物利用度是原型药物及辅料物理混合物的6.59倍和2.54倍。结论 该研究表明可转化为纳米混悬液的固体分散体片剂是一种可提高原人参二醇口服生物利用度的新制剂方法。     

混合溶剂对喷雾干燥制备伊曲康唑固体分散体物理性质的影响

目的 研究二氯甲烷-乙醇混合溶剂组分比对喷雾干燥制备伊曲康唑固体分散体物理性质的影响。方法 采用HPLC测定室温下伊曲康唑在不同体积比的二氯甲烷-乙醇混合溶剂中的平衡溶解度。以PVP VA64为载体,体积比分别为100：0、90：10、70：30、50：50的二氯甲烷-乙醇混合液为溶剂,采用喷雾干燥法制备伊曲康唑固体分散体,通过扫描电镜、差示扫描量热法、接触角测定仪和体外溶出试验对制得的固体分散体进行表征。采用差示扫描量热法考察固体分散体在90℃放置48,96,192 h后的物理稳定性。结果 伊曲康唑溶解度的大小取决于二氯甲烷-乙醇混合溶剂的组成,在不同体积比的二氯甲烷-乙醇混合溶剂中的溶解度差别很大。喷雾干燥制得的4种伊曲康唑固体分散体均为无定形固体分散体,具有单一的玻璃化转变温度、不同的形态和润湿性。体外溶出试验表明相对于原料药,制备得到的4种伊曲康唑固体分散体溶出速率显著提高。90℃高温加速稳定性试验放置后的固体分散体显示不同的物理稳定性。结论 二氯甲烷-乙醇混合溶剂组分比会对喷雾干燥制备伊曲康唑固体分散体的物理性质产生显著影响,其原因是由于伊曲康唑在混合溶剂中的溶解度差异会导致药物沉淀析出的时间不同,并进一步影响药物在固体分散体中的分布行为和物理稳定性。     

Nanostructure-loaded mesoporous silica for controlled release of coumarin derivatives: A novel testing of the hyperthermia effect

The synthesis of three types of mesoporous materials is reported: pure mesoporous silica (MCM-41), a nanocomposite of mesoporous silica with hydroxyapatite (MCM-41-HA) and mesoporous silica/gold nanorods nanocomposite (MCM-41-GNRs). The mesoporous materials were characterized by X-ray diffraction, N₂ adsorption isotherms, FTIR spectroscopy, transmission electron microscopy, and scanning electron microscopy. The samples were loaded with coumarin thiourea derivatives (I-IV) having functional groups of varying sizes and the in vitro release assays were monitored, and the release behavior was investigated as a function of soaking time in simulated body fluid. Two release stages were obtained in MCM-41, MCM-41-HA and MCM-41-GNRs loaded samples with the early release stages accounting for about 30% of loaded derivatives. These early release stages are characterized by Higuchi rate constant values nearly twice the values associated with the second release stages. The influence of substituent size on the release rate constants was explained in terms of sorption sites and hydrogen bonding with silanol groups on silicates. The release of coumarin derivatives loaded on MCM-41, MCM-41-HA and MCM-41-GNRs occurs over remarkably long time of the order of about 260 h with faster release rates in loaded MCM-41 and MCM-41-GNRs samples compared with MCM-41-HA ones. The role of hyperthermia effect in enhancing release rates was investigated by subjecting loaded MCM-41-GNRs to near infrared (NIR) radiation at 800 nm. This would be of significance in targeted drug release using hyperthermia effect. Unlike hydroxyl apatite, loading MCM-41 with gold nanorods does not affect the release kinetics. Only when these samples are irradiated with NIR photons, does the release occur with enhanced rates. This property could be valuable in selected targeting of drugs.     

索拉非尼固体分散体的制备及性质研究

目的制备索拉非尼(sorafenib,SFN)/介孔硅的固体分散体,并进行体内外性质研究。方法利用溶剂挥发法制备固体分散体,以溶出度为指标筛选药物和介孔硅比例;采用差示扫描量热法(DSC)和粉末X射线衍射(XRD)技术,考察药物存在状态及物理稳定性;通过电镜观察样品形貌;以大鼠为实验动物,以自制SFN粉末为对照,对固体分散体进行体内药动学研究。结果原料药为结晶态,溶出度<10%;随着介孔硅的比例增大,固体分散体的溶出度增加,当SFN与介孔硅的比例为1∶5时,SFN以非晶态存在,溶出度>90%,在6个月的加速实验中,药物存在状态和溶出度未见明显改变。固体分散体组的cmax是SFN粉末组的1.8倍,相对生物利用度为175%。结论 SFN/介孔硅固体分散体物理稳定性良好,能提高SFN的溶出度,改善其口服吸收效果。     

介孔二氧化硅微球的制备及用于吲哚美辛载药与溶出性质

目的制备介孔二氧化硅微球,以期提高吲哚美辛的溶出速率。方法以表面活性剂十六烷基三甲基溴化铵和普兰尼克三嵌段共聚物P123作为双模板,用软膜板法制备具有介孔孔道的介孔二氧化硅微球药物载体,采用扫描电镜及氮气吸附-脱附手段表征载体形貌、比表面积及孔径分布。用吸附平衡挥干法载药制得吲哚美辛固体分散体,并对该固体分散体的溶出性质进行研究。结果制得的介孔二氧化硅载体由粒径相对均一的球形粒子组成。其粒径主要集中在2～5μm,载体的比表面积为502.87 m²·g2·g^(-1),孔容为2.23 cm(-1),孔容为2.23 cm³·g3·g^(-1),孔径为23.75 nm。吲哚美辛/介孔二氧化硅固体分散体的药物溶出速率与累积溶出度与吲哚美辛原料药相比均有了显著提高。结论吲哚美辛已高度分散于微球载体中,药物的溶出速率明显加快,为提高吲哚美辛生物利用度的研究打下了基础。     

介孔二氧化硅纳米粒的制备及对载药与药物溶出度的影响

目的为提高水难溶性药物的分散性及溶出度,制备介孔二氧化硅纳米粒作为水难溶性药物的载体。方法探索得到简单有效地制备球状介孔二氧化硅纳米粒的工艺条件,采用扫描电镜及氮气吸附-脱附等手段分析表征载体的外观形貌,比表面积及孔径分布,并选取水难溶性药物西洛他唑作为模型药物,以溶剂浸渍挥干法载药制得药物固体分散体,采用热分析、氮气吸附-脱附曲线以及溶出度实验研究药物固体分散体的基本性质。结果制得的二氧化硅载体的形貌近球状,粒径大小分布在200～250 nm,载体的比表面积最高可达1 101.54 m2.g-1,孔径分布主要集中在3.0～4.0 nm。载药过程对西洛他唑在载体中的存在形式没有影响,固体分散体中西洛他唑的溶出度得到显著提高,当药物与载体的质量比为1∶3时,药物60 min累计溶出达85%。结论介孔二氧化硅纳米粒有望成为水难溶性药物的优良载体。     

Amino functionalized chiral mesoporous silica nanoparticles for improved loading and release of poorly water-soluble drug

In the present paper, chiral mesoporous silica nano-cocoon (A-CMSN) functionalized with amino group was synthesized, and its loading and release of indomethacin (IMC), a poorly soluble drug, was studied. Due to the use of chiral anionic surfactants as a template, A-CMSN possessed 2D hexagonal nano-cocoon morphology with curled channels on its surface, which was quite different from another 2D hexagonal mesoporous silica nanoparticles (MCM-41) with straightway channels. After being loaded into the two silica carriers by hydrogen bond, crystalline IMC converted to amorphous form, leading to the improved drug dissolution. And IMC loading capacity of A-CMSN was higher than MCM-41 because curled loading process originating from curvature chiral channels can hold more drug molecules. Compared with IMC, IMC loaded A-CMSN presented obviously fast release throughout the in vitro release experiment, while IMC loaded MCM-41 released faster than IMC at the initial 5 h then showed controlled slow release afterwards, which was closely related to the mesoporous silica nanoparticles and different channel mesostructures of these two carriers. A-CMSN possessed nano-cocoon morphology with curled 2D hexagonal channel and its channel length was shorter than MCM-41, therefore IMC molecules can easily get rid of the constraint of A-CMSN then to be surrounded by dissolution medium.     

Econazole Nitrate-Loaded MCM-41 for an Antifungal Topical Powder Formulation

The aim of this article was to prepare a topical powder for the treatment of fungal infections, such as Candida intertrigo and tinea pedis. Thus, an econazole nitrate (ECO) formulation with improved drug dissolution and proper moisture adsorption was designed. ECO was melt with the mesoporous silicate MCM-41 (drug/MCM-41 1/3) and the resulting inclusion compound was characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The drug loading was confirmed by the decrease of specific surface area and pore volume between MCM-41 and the inclusion compound. Formulations containing the inclusion compound were prepared and submitted to in vitro dissolution test and in vitro antifungal activity. A remarkable dissolution rate improvement as well as a higher antifungal activity was observed for the inclusion compound if compared to a commercial product. Moisture sorption properties for MCM-41 and formulations were evaluated as well.     

High drug load,stable, manufacturable and bioavailable fenofibrate formulations in mesoporous silica: a comparison of spray drying versus solvent impregnation methods

Encapsulation of drugs in mesoporous silica using co-spray drying process has been recently explored as potential industrial method. However, the impact of spray drying on manufacturability, physiochemical stability and bioavailability in relation to conventional drug load processes are yet to be fully investigated. Using a 2³ factorial design, this study aims to investigate the effect of drug-loading process (co-spray drying and solvent impregnation), mesoporous silica pore size (SBA-15, 6.5 nm and MCM-41, 2.5 nm) and percentage drug load (30% w/w and 50% w/w) on material properties, crystallinity, physicochemical stability, release profiles and bioavailability of fenofibrate (FEN) loaded into mesoporous silica. From the scanning electronic microscopy (SEM) images, powder X-ray diffraction and Differential scanning calorimetry measurements, it is indicated that the co-spray drying process was able to load up to 50% (w/w) FEN in amorphous form onto the mesoporous silica as compared to the 30% (w/w) for solvent impregnation. The in vitro dissolution rate of the co-spray dried formulations was also significantly (p?=?0.044) better than solvent impregnated formulations at the same drug loading. Six-month accelerated stability test at 40?°C/75% RH in open dish indicated excellent physical and chemical stability of formulations prepared by both methods. The amorphous state of FEN and the enhanced dissolution profiles were well preserved, and very low levels of degradation were detected after storage. The dog data for the three selected co-spray-dried formulations revealed multiple fold increment in FEN bioavailability compared to the reference crystalline FEN. These results validate the viability of co-spray-dried mesoporous silica formulations with high amorphous drug load as potential drug delivery systems for poorly water soluble drugs.     

熔融法制备布洛芬固体分散体

目的提高布洛芬的体外溶出速率。方法以亲水性Sylysia 730为载体,采用熔融法制备布洛芬-Sylysia 730固体分散体;利用体外溶出度实验确定熔融法制备固体分散体的制备条件;采用粉末X射线衍射法、差示扫描量热法、扫描电子显微镜分析法对制备的固体分散体进行物相鉴别。结果熔融法制备的布洛芬-Sylysia 730固体分散体中布洛芬均以非晶态存在于载体中。结论用Sylysia 730制备布洛芬固体分散体后显著提高了布洛芬的溶出速率,可进一步进行体内释药行为考察。     

Study on formulation variables of methotrexate loaded mesoporous MCM-41 nanoparticles for dissolution enhancement

The aim of this study was to develop methotrexate loaded mesoporous MCM-41 nanoparticles for improved dissolution of methotrexate. The mesoporous MCM-41 nanoparticles act as carrier for drug and increase the solubility of the drug. In order to achieve this objective small pore size MCM-41 nanoparticles have been synthesized followed by drug loading process. The process of drug loading was optimized using full 33 factorial design. With a view to obtain maximum drug loading three variables, concentration of drug solution, stirring rate, and drug:carrier ratio were optimized using a full 33 factorial design. Using statistically designed experiments, the inclusion of methotrexate in MCM-41 nanoparticles was successfully carried out to obtain a drug loading of about 48%. X-ray powder diffraction and differential scanning calorimetry revealed the presence of methotrexate in amorphous form and FT-IR spectroscopy showed the presence of light interactions between the silicate silanols and the drug. The decrease of Brunauer, Emmett and Teller specific surface area and pore volume between free MCM-41 and the inclusion compound was the proof of the presence of methotrexate inside the mesopores. The inclusion compound was submitted to in vitro dissolution tests and a remarkable dissolution rate improvement was observed in comparison to the crystalline drug in all tested conditions.     

Preparation, characterization and in vitro dissolution of aceclofenac-loaded PVP solid dispersions prepared by spray drying or rotary evaporation method

This study was conducted to enhance dissolution rate of aceclofenac (ACF) with extremely low solubility and high permeability (BCS class II) in water using poly vinyl pyrrolidone (PVP) and sodium lauryl sulfate as carriers. Solid dispersions were prepared by spray drying method and rotary evaporation method using different ratios of ACF and polymers. The characterization of solid dispersions was evaluated by scanning electron microscopy, Fourier transformation infrared spectroscopy, differential scanning calorimetry and powder X-ray diffractometer. The dissolution behavior of solid dispersions was compared with pure ACF (API) and Airtal^® (Deawoong, Co, Korea) as control groups in simulated phosphate buffer at pH 6.8. The dissolution rate of the drug was affected by nature and amount of polymer used. The prepared solid dispersion of ACF/PVP (1:5) appeared to have the highest dissolution rate. Therefore, solid dispersion techniques of spray drying and rotary evaporation method can be successfully used for the enhancement of the dissolution rate of ACF.