难溶性药物与介孔二氧化硅纳米粒载体的相互作用对于释放速率的影响

目的 研究介孔二氧化硅纳米粒（MSN）载体与装载的难溶性药物间的相互作用,探索对释放速率具有重要影响的因素,归纳总结可预测难溶性药物-MSN给药系统释放行为的数学模型。方法 以溶胶凝胶法制备的MSN作为载体,通过溶剂挥干法进行药物装载,利用扫描电子显微镜（SEM）、透射电子显微镜（TEM）分析载体的外观形貌及孔道结构,通过比表面积分析仪研究载体的比表面积及孔径分布。选取载药量及药物的氢键受体数量作为因素进行释放行为分析,通过Design Expert软件进行2因素3水平析因设计,完成体外释放实验;2、24 h累积释放度作为因变量,拟合数学模型。结果溶胶凝胶法制备的MSN为均一的球形,粒径约为400 nm,孔道呈放射状,孔径均一为3.6 nm。拟合模型显示,载药量比氢键受体数量对2 h累计释放度影响更大,随着载药量的增加,2 h累计释放度逐渐下降;在研究范围内,氢键受体数为6,载药量为50%具有最小的2 h累计释放度,为50.31%。24 h累计释放度则根据载药量的不同随着氢键受体数的改变呈现相反趋势,当载药量较低时,与氢键受体数呈正相关;当载药量较高时,与氢键受体数呈负相关。氢键受体数为6,载药量小于10%时具有最大的24 h累计释放度,可达99.44%。结论 相对药物的氢键受体数量,载药量对于难溶性药物-MSN给药系统的速缓释放具有重要调控作用,低载药量可以实现药物的2 h快速释放及24 h完全释放,高载药量则反之。     

Genotoxicity evaluation of nanosized titanium dioxide,synthetic amorphous silica and multi-walled carbon nanotubes in human lymphocytes

Toxicological characterization of manufactured nanomaterials (NMs) is essential for safety assessment, while keeping pace with innovation from their development and application in consumer products. The specific physicochemical properties of NMs, including size and morphology, might influence their toxicity and have impact on human health. The present work aimed to evaluate the genotoxicity of nanosized titanium dioxide (TiO₂), synthetic amorphous silica (SAS) and multiwalled carbon nanotubes (MWCNTs), in human lymphocytes. The morphology and size of those NMs were characterized by transmission electron microscopy, while the hydrodynamic particle size-distributions were determined by dynamic light scattering. Using a standardized procedure to ensure the dispersion of the NMs and the cytokinesis-block micronucleus assay (without metabolic activation), we observed significant increases in the frequencies of micronucleated binucleated cells (MNBCs) for some TiO₂ NMs and for two MWCNTs, although no clear dose–response relationships could be disclosed. In contrast, all forms of SAS analyzed in this study were unable to induce micronuclei. The present findings increase the weight of evidence towards a genotoxic effect of some forms of TiO₂ and some MWCNTs. Regarding safety assessment, the differential genotoxicity observed for closely related NMs highlights the importance of investigating the toxic potential of each NM individually, instead of assuming a common mechanism and equal genotoxic effects for a set of similar NMs.     

Inclusion of fenofibrate in a series of mesoporous silicas using microwave irradiation

A selection of porous silicas were combined with a model drug using a recently developed, controlled microwave heating process to determine if the application of microwave irradiation could enhance subsequent drug release. Five mesoporous silica types were investigated (core shell, core shell rehydrox, SBA-15, silica gel, SYLOID®) and, for comparison, one non-porous silica (stober). These were formulated using a tailored microwave heating method at drug/excipient ratios of 1:1, 1:3 and 1:5. In addition, all experiments were performed both in the presence and absence of water, used as a fluidising media to aid interaction between drug and support, and compared with results obtained using more traditional heating methods. All formulations were then characterised using differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier transformation infrared spectroscopy (FT-IR). Pharmaceutical performance was investigated using in vitro drug release studies. A significant enhancement in the release profile of fenofibrate was observed for formulations prepared using microwave heating in the absence of water for five of the six silica based formulations. Of all the formulations analysed, the greatest extent of drug release within the experimental 30 min was the 1:5 core shell rehydrox achieving a total of 86.6 ± 2.8%. The non-porous (stober) particles did not exhibit an increased release of the drug under any experimental conditions studied. This anomaly is thought to be a result of the comparatively small surface area of the silica particles, thus preventing the adsorption of drug molecules.     

胶态二氧化硅固化的银杏黄酮组分磷脂复合物微丸的制备工艺研究

目的：制备胶体二氧化硅固化粉末微丸,并对制备工艺进行研究。方法：首先制备银杏黄酮组分磷脂复合物,并利用胶体二氧化硅进行固化得到固化粉末。以其为主药,通过单因素实验筛选制备微丸的润湿剂、载药量和崩解剂,以微丸的圆整度和收率为评价指标,采用正交实验设计筛选出最佳制备工艺。结果：选择30%乙醇作为润湿剂,确定载药量为70%,选择CMC-Na作为崩解剂。最佳制备工艺确定为滚圆时间为4min,滚圆频率30Hz,挤出频率为30Hz。结论：制备的微丸稳定,验证试验结果表明制备工艺科学合理。     

Facile synthesis of PEI-based crystalline templated mesoporous silica with molecular chirality for improved oral delivery of the poorly water-soluble drug

The aim of this study was to build up a novel chiral mesoporous silica called PEIs@TA-CMS through a facile biomimetic strategy and to explore its potential to serve as a drug carrier for improving the delivery efficiency of poorly water-soluble drug. PEIs@TA-CMS was synthesized by using a chiral crystalline complex associated of tartaric acid and polyethyleneimine (PEIs) as templates, scaffolds and catalysts. The structural features including morphology, size, pore structure and texture properties were systematacially studied. The results showed that PEIs@TA-CMS was monodispersed spherical nanoparticles in a uniformed diameter of 120–130 nm with well-developed pore structure (S_BET: 1009.94 m²/g, pore size <2.21 nm). Then PEIs@TA-CMS was employed as nimodipine (NMP) carrier and compared with the drug carry ability of MCM41. After drug loading, NMP was effectively transformed from the crystalline state to an amorphous state due to the space confinement in mesopores. As expected, PEIs@TA-CMS had superiority in both drug loading and drug release compared to MCM41. It could incorporate NMP with high efficiency, and the dissolution-promoting effect of PEIs@TA-CMS was more obvious because of the unique interconnected curved pore channels. Meanwhile, PEIs@TA-CMS could significantly improve the oral adsorption of NMP to a satisfactory level, which showed approximately 3.26-fold higher in bioavailability, and could effectively prolong the survival time of mice on cerebral anoxia from 10.98 to 17.33 min.     

几种预制硅胶薄层层析板的性能考察

本文考察了几种预制硅胶薄层层析板的性能,结果表明实验所用四川省中药研究所研制的薄层铺板器与瑞士Camag公司铺板器所预制硅胶薄层板的性能相近似,质量较好,优于国内某厂所产硅胶预制板。     

Exploration of Novel Co-processed Multifunctional Diluent for the Development of Tablet Dosage Form

The aim of this investigation was to develop a novel multifunctional co-processed diluent consisting of microcrystalline cellulose (Avicel PH 102), crospovidone (Polyplasdone XL) and polyethylene glycol 4000. Colloidal silicon dioxide and talc were also incorporated as minor components in the diluent to improve tableting properties. Melt granulation was adopted for preparation of co-processed diluent. Percentage of Avicel PH 102, Polyplasdone XL and polyethylene glycol 4000 were selected as independent variables and disintegration time was chosen as a dependent variable in simplex lattice design. The co-processed diluent was characterised for angle of repose, bulk density, tapped density, Carr''s index, percentage of fines and dilution potential study. Acetaminophen and metformin were used as poorly compressible model drugs for preparation of tablets. The blend of granules of drug and extra-granular co-processed diluent exhibited better flow as compared to the blend of drug granules and physical mixture of diluents blend. The diluent exhibited satisfactory tableting properties. The tablets exhibited fairly rapid drug release. In conclusion, melt granulation is proposed as a method of preparing co-processed diluent. The concept can be used to bypass patents on excipient manufacturing.     

淫羊藿组分缓释制剂的研究

筛选淫羊藿组分缓释片的处方,建立体外释放评价方程.采用胶态二氧化硅辅助喷雾干燥淫羊藿组分,并以其为主药制备缓释片.以主要成分宝藿苷Ⅰ的溶出度为评价指标考察骨架材料类型、填充剂、致孔剂、润滑剂等辅料对缓释片质量的影响,并采用干法压片工艺制备出淫羊藿组分缓释片.所筛选的缓释片处方为主药35％,羧甲基纤维素HPMC K4M20％和HPMC K15M10％为骨架材料,微晶纤维素31％,PEG6000 2％,硬脂酸镁2％.该处方条件下制备的淫羊藿组分缓释片体外持续8h释药达80％.零级方程、一级方程及Higuchi方程等都能较好模拟缓释片体外释放特征,其相关系数r均大于0.96.其中一级方程与体外释放特征最相似,其相关系数r为0.995 0.该制备方法操作简单,处方筛选结果真实可靠,可为淫羊藿组分缓释制剂的生产制备提供思路和方法指导.     

Ordered mesoporous silica induces pH-independent supersaturation of the basic low solubility compound itraconazole resulting in enhanced transepithelial transport

The majority of innovative drug candidates are poorly water soluble and exhibit basic properties. This makes them highly dependent on the in vivo encountered acid–neutral pH sequence to achieve a sufficient dissolution and thus absorption. In this study, we evaluated the pH-independent generation of intraluminally induced supersaturation of the model compound itraconazole and its beneficial effect on the extent of absorption in the Caco-2 system and the rat in situ perfusion system. Local supersaturation was obtained by means of a solvent shift method and a novel formulation strategy based on ordered mesoporous silica (OMS) as a carrier. In vitro results evidenced that both methods were capable of creating a supersaturated state of itraconazole in fasted state simulated intestinal fluid (FaSSIF) when no preceding acidic dissolution was simulated. The extent of supersaturation exceeded 21.9 and 9.6 during at least 4 h for the solvent shift method and OMS as a carrier, respectively. As compared to saturation conditions (0.09 ± 0.01 μg), supersaturation induced by the solvent shift method as well as by the use of OMS increased transport across a Caco-2 cell monolayer more than 16-fold, resulting in the basolateral appearance of 2.20 ± 0.29 μg and 1.46 ± 0.03 μg itraconazole after 90 min, respectively. In the absence of an acid–neutral pH sequence, the performance of the marketed product Sporanox^® was inferior with total transport amounting to 0.12 ± 0.03 μg after 90 min. Enhanced absorption was confirmed in the in situ perfusion model where OMS was able to boost total transport of itraconazole after 60 min from 0.03 ± 0.01 nmol cm⁻¹ to 0.70 ± 0.09 nmol cm⁻¹ compared to saturated equilibrium conditions in FaSSIF. The solid dosage form Sporanox^® again failed to achieve a similar extent of absorption enhancement (0.29 ± 0.01 nmol cm⁻¹). These findings suggest that intraluminal supersaturation can be created by the use of OMS and that preceding dissolution of basic compounds in the acidic medium of the stomach is not required to allow for efficient intestinal absorption. The use of OMS appears to be a promising strategy for the delivery of especially basic low solubility compounds in patients suffering from hypochlorhydria; the pH independency may also result in a more reproducible systemic exposure.     

胶体金免疫层析法同时检测肉类食品中八种兽药残留物

目的研制八联盘检测肉类食品中多种兽药残留物。方法将应用胶体金免疫层析法制备好的8种试纸条组装成多联检测盘,评价该盘检测兽药残留物的灵敏度、准确度、特异性和稳定性。结果通过在空白样本中加标,确定了不同样本(猪肉、牛肉和羊肉)中14种兽药的检测限;60份样本的八联盘检测结果与仪器确证结果一致,检出禁用药和限用药各6份,符合率达100%;检测盘中的试纸条与类似药物之间无交叉反应,特异性好;八联盘在室温条件下可保存至少12个月,稳定性较好。结论该八联盘操作简便、快速、检测结果准确、稳定,为兽药残留现场监控提供了有力工具。