苦参碱壳聚糖微球的制备及体外释药

目的:以壳聚糖为囊材制备苦参碱结肠靶向给药微球及评价其体外释药情况。方法:用乳化化学交联法制备微球,以微球的粒径分布百分数、载药量及包封率为优化指标对影响微球制备的主要因素用正交试验设计优化制备条件;并对最佳制备工艺制得的微球进行3种不同递质(人工胃液、人工肠液及大鼠结肠液)中的体外释放度评价。结果:制得的苦参碱壳聚糖微球在电镜下,球形表面圆整,粒径分布适宜,微球平均粒径为(68.3±2.7)μm,平均载药量为(16.0±0.5)%,平均包封率为(66.3±4.2)%。苦参碱壳聚糖微球在人工胃液中2h不释药;在人工肠液中4h内释放不到1%,96h释药不到10%;在含大鼠结肠内容物的磷酸盐缓冲液(pH6.8)中4h释放10%左右,36h释药近50%,此后释药趋于缓慢,96h释药近80%。结论:苦参碱壳聚糖微球几乎不在上消化道释药,而是在结肠靶向释药。     

盐酸小檗碱微囊的制备及其体外释放研究

目的:为改善口感、减小对胃黏膜的刺激,制备盐酸小檗碱微囊,并考察其体外释药特性。方法:以阿拉伯胶、明胶为囊材,采用复凝聚法制备盐酸小檗碱微囊,以包封率、载药量、外形为指标,采用正交设计试验对囊心(盐酸小檗碱)-囊材质量比、囊材质量分数、搅拌速度进行优化,并进行验证。考察所制制剂的粒径分布及在人工肠液中5 h内的体外释药率。结果:最优处方为囊心-囊材质量比为1∶3,阿拉伯胶和明胶的质量分数均为2.50%,搅拌速度为200 r/min,成囊温度为53℃。所制盐酸小檗碱微囊的包封率为38%,载药量为41.71%;微囊圆整光滑,无粘连,粒径均匀,外形评分50.6;80%以上分布在3~9μm;3 h的累积释药率即达90%。结论:成功制得盐酸小檗碱微囊。     

2种骨架材料制备盐酸小檗碱囊泡的比较

目的 比较胆固醇和β-谷甾醇作为囊材制备的盐酸小檗碱囊泡的特性和体外释药差异。方法 采用薄膜蒸发法用2种囊材分别制备盐酸小檗碱囊泡,光学显微镜观察比较囊泡形态,微粒分析仪评价囊泡粒径分布差异;采用HPLC测定盐酸小檗碱囊泡包封率和载药量,比较2种囊泡的体外释放情况,并考察温度对囊泡稳定性的影响。结果 镜下观察2种囊材制备的囊泡圆整度均较好,粒径分布范围比较相似;用胆固醇和β-谷甾醇制备的囊泡包封率分别为28.5%和25.21%,载药量分别为1.32%和1.26%;体外释放试验中,在人工肠液和人工胃液中的胆固醇囊泡12 h累积释放百分率在50%左右,而β-谷甾醇囊泡的累积释放百分率>70%;40℃以下放置8 h,温度对2种小檗碱囊泡的包封率影响较小,当温度高于40℃时,2种小檗碱囊泡的包封率均显著降低。结论 用薄膜分散法制备的2种小檗碱囊泡镜下形态相似,包封率近似;用β-谷甾醇制备的囊泡释药快,释药量多;40℃以下放置稳定性均较好。β-谷甾醇作为载体材料制备囊泡具有可行性。     

5-氟尿嘧啶共聚物纳米粒的制备及其药剂学性质

目的 以生物可降解材料Pluronic P105-PAGA共聚物制备5-氟尿嘧啶(5-FU)纳米粒,并考察纳米粒的药剂学特性.方法 采用透析法制备纳米粒,以包封率和载药量为指标,应用星点设计效应面优化法优化处方,并考察其表面特征、包封率、载药量、粒径、体外释放等性质.结果 5-FU-Pluronic P105-PAGA纳米粒为圆整的类球形实体粒子,平均粒径为175 nm,载药量为22.37%,包封率为95.26%,有突释现象,体外12 h累积释放率为80.4%.结论 所制纳米粒具有高包封率和载药量,粒径适宜,具有一定的缓控释作用.     

TRH-03肠溶微丸的制备及其处方优化

目的研究TRH-03肠溶微丸的处方优化及制备工艺。方法采用流化床包衣法,以载药量及释放量为考察指标,对TRH-03肠溶微丸的处方、上药和包衣工艺进行了优化。结果制得的3批肠溶微丸圆整度好,其载药率分别为35.63%、35.04%、35.64%;在人工胃液中保持不释药,人工肠液中45min内释放率分别为89.58%、88.96%、88.36%,载药量稳定且重现性好,体外释放度符合中国药典2010年版二部的要求。结论本方法制备工艺简单易行,重复性好,适合进一步的工业化生产。     

甲硝唑缓释微球结肠溶胶囊的制备及体外释放

目的：研制甲硝唑缓释微球并装于结肠溶胶囊，评价其体外释放特性。方法：用乳化交联法制备甲硝唑羧甲基壳聚糖微球，测定平均粒径、载药量、包封存率等指标；将微球和原料药分别装于结肠溶胶囊，测定微球、原料药及结肠溶胶囊剂型在人工胃液、人工小肠液、人工结肠液中的释放性能。结果：重复制备6批微球，微球平均粒径为（197．1±3．9）μm，载药量为（48．2±1．5）％，包封率为（37．5±1．9）％；体外释放甲硝唑原料药0．75h释放完全，甲硝唑微球7h释放完全；甲硝唑原料药结肠溶胶囊和甲硝唑微球结肠溶胶囊，在人工胃液、人工小肠液5h均无释放，移至人工结肠液后，前者于6．25h释放完全，后者于13h释放完全。结论：甲硝唑羧甲基壳聚糖微球的制备工艺稳定，甲硝唑羧甲基壳聚糖微球结肠囊胶囊具有结肠定位及缓释性能。     

兰索拉唑肠溶微丸胶囊的制备

目的:制备兰索拉唑肠溶微丸胶囊。方法:采用流化床包衣技术,在空白丸芯上依次包以主药层、隔离层和肠溶层,制备成兰索拉唑肠溶微丸,将肠溶微丸装入普通胶囊制成兰索拉唑肠溶微丸胶囊,并考察3批制剂的载药率及在人工肠液和人工胃液中的释放情况。结果:所制微丸圆整度高,外观亮泽,载药均匀、载药率高(平均值在96%以上),包衣效果好;其在人工肠液中45min的体外累积释放率大于(94.3±0.76)%,在人工胃液中2h的释放量小于(6.2±1.6)%。结论:所制兰索拉唑肠溶微丸胶囊工艺可行,重现性良好,质量稳定可靠,具有良好的体外释药性和耐酸力。     

青蒿琥酯纳米粒的制备及其体外细胞抑制试验

目的:制备青蒿琥酯纳米粒,并对其性质及体外细胞抑制作用进行研究。方法:以聚乳酸-羟基乙酸共聚物(PLGA)为载体,采用自乳化方法制备青蒿琥酯纳米粒。扫描电镜观察纳米粒的形态,激光粒度仪测定纳米粒的粒径及其分布;考察纳米粒的载药量、包封率、体外释放情况;MTT法考察纳米粒对人白血病细胞株K562在不同时间(24、48、72h)的体外细胞抑制率,并与青蒿琥酯(原料药)比较。结果:所制青蒿琥酯纳米粒为圆球形,表面光滑,平均粒径为(144±3.0)nm,Zeta电位是-31.5mV,平均载药量和包封率分别为14%、84%;体外释放试验前期有明显突释现象,前24h累积释放度为46%,其后释放均匀,120h累积释放度达65%,具有缓释作用;其在72h时对细胞抑制率高于青蒿琥酯组(76.4%vs.59.1%),有较强抑制作用(P<0.05)。结论:所制青蒿琥酯纳米粒在体外具有较好的缓释性,对K562细胞有较强的抑制作用。     

对乙酰氨基酚/MCM-41载药体系的制备及其缓释性能的研究

目的制备对乙酰氨基酚/MCM-41缓释体系,并考察其体外释放行为。方法在碱性和室温条件下制备MCM-41介孔材料;采用浸渍法将解热镇痛药物对乙酰氨基酚组装到MCM-41的孔道中,通过XRD、IR、低温N2吸附对MCM-41介孔材料及药物组装体进行表征;测定组装体的载药量、载药时间以及在人工胃液中的释放行为。结果介孔材料MCM-41作为药物载体具有较短的载药时间(7 h)、较大的载药量(46.65%)、较低的释放速率(6 h仅释放35.6%)。结论通过测定组装体在体外模拟人工胃液和人工肠液中的释放速率,结果表明制得了对乙酰氨基酚/MCM-41缓释释放体系。     

吲哚美辛结肠定位凝胶微丸的研究

目的制备吲哚美辛凝胶微丸实现结肠定位给药。方法采用滴制法制备海藻酸钙微丸,以微球圆整度、包封率、载药量为质量指标,通过正交试验选出优化处方,并用丙烯酸树脂Eudragit S100进行包衣。结果凝胶微丸在人工胃液和人工肠液中6 h累积释放率小于15%,而在人工结肠液中2 h达80%以上。结论所制得的吲哚美辛凝胶微丸符合结肠定位的基本要求。     

胸腺肽α1结肠释放片的制备及其体外释药研究

目的:制备胸腺肽α1结肠释放片(Tα1片),评价其体外释药性能。方法:将Tα1制成片芯,2次包衣,内层为壳聚糖盐酸盐,外层为尤特奇L100-55。高效液相色谱(HPLC)法进行含量及含量均匀度测定,扫描电镜法评价壳聚糖盐酸盐包衣膜在模拟大肠液中的降解作用。以荧光剂FD-4为模型化合物,同法制备模拟结肠片,荧光分光光度法检测其在pH 1.2盐酸溶液,pH 6.8磷酸盐缓冲液及模拟大肠液中的体外释放性能。结果:Tα1片的含量及含量均匀度符合《中国药典》相关规定;电镜扫描结果表明,壳聚糖盐酸盐包衣膜在模拟大肠液中具有显著降解作用;模拟结肠片在pH 1.2盐酸溶液和pH 6.8磷酸盐缓冲液中的累积释药量6 h内小于23％,而在模拟大肠液中4 h基本释药完全。结论:本研究所制备的Tα1结肠释放片具有潜在的结肠靶向释药效果。     

小檗碱壳聚糖纳米粒的制备及其体外释药特性研究

目的:制备小檗碱壳聚糖纳米粒,并考察其外观、粒径和体外释药特性。方法:以离子凝胶法制备小檗碱壳聚糖纳米粒,紫外分光光度法测定小檗碱含量并计算其在不同递质中的累积释放度。结果:壳聚糖纳米粒呈球形或类球形,平均粒径267.9nm,多分散系数0.264,平均包封率(65.4±0.7)%。纳米粒6h内释放度为(56.8±1.7)%,8h以后趋于平缓,24h释放度为(65.6±1.1)%;在人工胃液、人工肠液和pH7.4磷酸盐缓冲液3种溶出递质6h内释放度依次为(75.3±1.3)%、(55.7±0.9)%、(45.8±1.6)%。结论:离子凝胶法适用于小檗碱壳聚糖纳米粒的制备,释药递质对释药程度影响显著,呈pH依赖性。     

盐酸去氢骆驼蓬碱在人工胃液、肠液及蒸馏水中的稳定性考察

目的:考察盐酸去氢骆驼蓬碱在人工胃液、人工肠液及蒸馏水中的稳定性。方法:采用高效液相色谱法测定盐酸去氢骆驼蓬碱的含量,用经典恒温加速法考察温度对其在不同条件下稳定性的影响。结果:盐酸去氢骆驼蓬碱检测浓度的线性范围为1.8～30.0μg.mL-1,在人工胃液、人工肠液、蒸馏水中的降解符合一级动力学过程,预测的有效期分别为566、69、22d。结论:盐酸去氢骆驼蓬碱在人工胃液、人工肠液、蒸馏水中的稳定性均较好。     

Formulation of controlled release microspheres containing nicardipine: the role of pharmacokinetic modeling and computer simulation.

Nicardipine is an antihypertensive drug of the dihydropyridine series. It has high solubility in an acidic and low solubility in an alkaline medium. It is rapidly absorbed, extensively presystemically metabolized and excreted in the urine and faeces, mainly as inactive metabolites. Since the duration of its action can be extended by prolonging the absorption interval, the design of controlled release formulation is reasonable. The aim of the present study was to prepare microspheres which would release nicardipine at a decreased rate in gastric and increased rate in intestinal juice during a 12 h interval. Pharmacokinetic modeling based on compartment analysis and supported by analog computer and digital simulation technique showed that the target steady state peak plasma concentrations of 32 microg/l and trough plasma concentration of 7 microg/l would be maintained if nicardipine were incorporated in a formulation releasing the drug as follows: 25% after 1 h, 40% after 2 h, 65% after 4 h, 80% after 6 h, 90% after 8 h and 100% by 12 h. Microspheres have been prepared from hydroxypropylmethylcellulose phthalate polymer using the solvent evaporation method. Drug content, scanning electron micrographs, particle size distribution and dissolution profile were determined. In vitro nicardipine release was described by a biphasic square root of time kinetics and was in accordance with the above values relating to the dissolution. Furthermore, a composed first-pass pharmacokinetic model with derived release function as an input was developed to predict nicardipine plasma concentrations after single- and 12 h multiple-dosage-regimen scheme administration of controlled release microspheres.     

盐酸青藤碱肠溶缓释微丸的制备

目的：制备盐酸青藤碱肠溶缓释微丸。方法：分别以Eudragit NE30D为缓释膜材，HPMC E5为隔离层膜材，Eudragit L30D-55为肠溶层膜材，采用流化床包衣法制备盐酸青藤碱肠溶缓释微丸，并考察缓释层、隔离层和肠溶层包衣增重对药物释放的影响。结果：制备的肠溶缓释微丸在人工胃液中释放度<10%，人工肠液中缓慢释放8 h。结论：该制备工艺简单易行，重现性好，有望应用于工业化生产。     

Micromeritic studies on nicardipine hydrochloride microcapsules

In this study, nicardipine hydrochloride (N.HCl) microcapsules were prepared by means of coacervation phase separation technique using ethylcellulose (EC) as a coating material. Micromeritic investigations were carried out on nicardipine hydrochloride, ethylcellulose and nicardipine hydrochloride microcapsules in order to standardize the microcapsule product and to optimize the pilot production of dosage forms prepared with these microcapsules. Microcapsules we prepared had the ratio of 2:1 core:wall and then by sieving, were divided into two groups according to their particle sizes which were > 840 μm and 476–840 μm. The bulk volume and weight, tapping volume and weight, fluidity, angle of repose, weight deviation, particle size distribution, density and porosity of nicardipine hydrochloride, ethylcellulose and nicardipine hydrochloride microcapsules were studied. To determine flowability, Hausner ratio and Consolidation index were also calculated from the results obtained. The findings of the study suggested that the micromeritic properties of the crude materials were significantly changed by the microencapsulation process. In addition, it was shown by scanning electron microscopy, that the changes were due to changes in the physicochemical properties of drug particles.     

盐酸倍他洛尔-树脂混悬剂制备工艺研究

目的:考察药物-树脂混悬剂的制备工艺。方法:以阳离子交换树脂(大、小粒径)为载体,盐酸倍他洛尔为模型药物,设计正交试验考察药物与大、小粒径树脂结合的复合物的包封率和载药量,以沉降体积比和再分散性为评价指标筛选出合适的助悬剂,并在人工泪液中比较包衣后药物-树脂混悬剂盐酸倍他洛尔滴眼液的释药动力学。结果:制备的药物-树脂(小粒径)复合物包封率为82.86%、载药量为41.43%,优于大粒径(78.95%、39.48%);以加入卡波姆为助悬剂时混悬剂沉降体积比大,再分散性好,混悬剂稳定。由包衣后的药物-树脂复合物所制备的混悬剂,在人工泪液中的释药动力学与盐酸倍他洛尔滴眼液相似。结论:初步建立了药物-树脂混悬剂的制备工艺,为进一步制备出安全、有效、稳定的药物-树脂眼用混悬剂提供了一定的参考。     

Insulin‐loaded nanocapsules for oral administration: In vitro and in vivo investigation

The purpose of this work was to investigate the ability of poly(isobutylcyanoacrylate) nanocapsules to protect insulin from degradation by proteolytic enzymes providing biologically active insulin by the oral route. Insulin was labeled with Texas Red^® for release studies and microscopy observations. The fluorescent marker was mostly retained by the nanocapsules incubated in the reconstituted gastric medium but the release was 75% within 30 min when the nanocapsules were incubated in the reconstituted intestinal medium. Turbidimetric measurements and electron microscopy observations confirmed that the nanocapsules were degraded in the reconstituted intestinal medium, whereas nanocapsule integrity was preserved in the reconstituted gastric medium. In vivo studies of the gastrointestinal distribution of insulin‐loaded nanocapsules after oral feeding showed that nanocapsules were retained by the stomach for 30 min. One hour after oral administration, nanocapsules reached the lower part of the intestine (ileum). Fluorescence microscopy and confocal microscopy carried out on portions of the small intestine revealed the presence of concentrated fluorescent spots into the mucosa and even in the lamina propia, suggesting that insulin‐loaded nanocapsules could cross the intestinal epithelium. These data suggest that PIBCA nanocapsules can efficiently protect insulin when given orally. In addition, they seemed to be significantly involved in the absorption mechanism. Drug Dev. Res. 49:109–117, 2000. © 2000 Wiley‐Liss, Inc.     

法莫替丁脉冲控释片的研制

［摘要］目的 制备法莫替丁脉冲控释片. 方法 以脉冲控释片在人工胃液和人工肠液中的释放度为指标,采用正交设计进行处方筛选和优化. 结果 按优化处方成功制备法莫替丁脉冲控释片.释放度实验表明,4 h 内有一个速释过程,经约8 h的时滞后,又产生一个符合Higuchi动力学模型的释药过程. 结论 该制剂体外释药具有脉冲释药特点,有利于提高消化性溃疡疾病的治疗效果.     

蛇床子素及其β-环糊精包合物在不同溶出介质中的溶出速率研究

目的:考察蛇床子素及其β-环糊精包合物在不同溶出介质中的溶出行为.方法:用紫外分光光度法测定蛇床子素和包合物分别在人工胃液、人工肠液、15%乙醇、30%乙醇、0.2%十二烷基硫酸钠的人工胃液、0.5%十二烷基硫酸钠的人工胃液中的溶出速率.结果:蛇床子素和包合物在人工胃液、人工肠液中溶出太少,不能满足测定条件,在0.5%十二烷基硫酸钠的人工胃液中,溶出很快,不能完全区分二者的溶出度差异,用含0.2%十二烷基硫酸钠的人工胃液作溶出介质,效果较好.结论:介质对蛇床子素及包合物的溶出有很大影响,但在所有溶出介质中包合物的溶出速率均快于蛇床子素,且具有显著性差异(P＜0.05).