载穿心莲内酯核-壳型Ca-Alg/pNIPAM微球的制备及性能

针对穿心莲内酯(AND)口服给药存在药物苦极问题,拟制备一种有效掩蔽药物苦味且能实现药物控释的微球载体。以海藻酸钠(Na-Alg)和N-异丙基丙烯酰胺(NIPAM)为制备材料,采用静电液滴偶联单体聚合工艺制备了核-壳型AND/Ca-Alg/pNIPAM微球。采用扫描电微观测、红外光谱分析、溶胀实验和体外释药实验等表征微球结构与性能。结果表明:与Ca-Alg微球相比,Ca-Alg/pNIPAM微球具有清晰的核-壳结构;微球平衡溶胀率在32—36℃突降14.6%;微球在模拟胃液中2 h内药物累积释放率低于10%,而在模拟肠液中6—8 h即达到释放平衡且释药动力学符合Reter-Peppas模型。核-壳结构使Ca-Alg/pNIPAM微球在高效负载药物的同时掩蔽了药物苦味,并赋予微球温度/pH双重响应特性,实现了药物肠靶向释放。     

双乳化-凝胶法制备单分散海藻酸钙微球及其载BSA研究

采用双乳化-凝胶法制备了单分散的海藻酸钙凝胶微球,并通过正交试验系统考察了海藻酸钠浓度、氯化钙浓度、表面活性剂浓度、搅拌速度和油水比对海藻酸钙凝胶微球粒径及形貌的影响。在优化的条件下,制备出了平均粒径为4μm、单分散和球形度好的海藻酸钙凝胶微球。包埋模型药物牛血清白蛋白(BSA)的过程中,以去离子水作为洗涤液洗涤海藻酸钙微球时,BSA的包封率仅为13%左右;当水洗液的pH值为3.2时,BSA的包封率提高到66%左右,载药率可达16%,这是海藻酸钙pH值响应溶胀和BSA与海藻酸盐之间静电作用的结果。微球中BSA的体外释放曲线表明,该系统具有在模拟胃液中释药速率慢、释药量低、模拟肠液中释药迅速的特性。因此,双乳化-凝胶法制备海藻酸钙微球有望成为制备蛋白类药物控释制剂的一种新方法,以达到靶向快速给药的目的。     

一种新型的负载蛋白质药物微球的制备和释药性能

为了制备具有蛋白药物结肠靶向释放性能的新型药物载体,采用了水相溶液滴定反应法,分别以牛血清白蛋白(BSA)和乳铁蛋白(LF)为模型蛋白质药物,制得壳聚糖/纤维素磷酸钠(NaCS)/三聚磷酸钠(TPP)载药微球。利用电镜SEM和显微镜观测拍照,对微球的表面和截面形貌进行了表征,发现微球球形规则且颗粒大小均一。同时进行了体外药物模拟释放试验,考察了载药微球先后经过模拟胃液、模拟小肠液和模拟结肠液时的释药性能,及不同的释放条件和制造条件对于微球释药性能的影响,尤其考察了不同蛋白药物和不同干燥方式的影响。结果表明由临界点干燥法制得的负载乳铁蛋白(LF)微球在模拟胃液和小肠液释放量中5 h内只释放出不到20%的蛋白药物,而后在结肠模拟液中4 h内释放出蛋白药物80%以上。这些结果表明,壳聚糖/NaCS/TPP体系具有一定的作为结肠靶向药物释放载体的应用潜力。     

丝素-羟丙基壳聚糖微球的结构和释药性能

以胰岛素为目标药物,以丝素(SF)和羟丙基壳聚糖(HPCS)为包药材料,复凝聚法制备SF-HPCS载药微球。采用红外光谱(FTIR)、扫描电镜(SEM)、X射线衍射(XRD)、热重分析(TGA)等对载药微球的结构、外部形貌及热性能等进行了表征。结果表明,所制备的载药微球表面密实,平均粒径22.4μm,呈正态分布;载药微球对胰岛素的包埋率达73.6%,大于HPCS载药微球(64.3%)及壳聚糖(CS)载药微球(57.1%);SF-HPCS载药微球在人工胃液中4h内累计释药率为21.3%,在人工肠液中24h内累计释药率达81.2%,48h累计释药率为92.2%,释放过程平稳、缓慢。     

蒙脱石微球的可控制备及其载药性能EI北大核心CSCD

针对口服给药体系如何保护药物分子免受人体内环境影响这一挑战,采用乳化凝胶法设计合成了一种pH值敏感性的海藻酸钠(SA)-蒙脱石(MMT)复合微球MMT/SA,用以负载抗癌药物盐酸阿霉素(DOX),在保护药物分子的同时克服了胃肠道的生物化学屏障。探索了MMT处理工艺和合成配比的不同对微球形貌的影响,最终控制微球尺寸在20μm以内,且分布均一。复合载药微球DOX/MMT/SA的载药率为14.7%,在模拟人工胃液和人工肠液环境中表现出不同的药物缓释效果,在模拟人工肠液中的累计释放率(31.7%)明显高于在人工胃液中的释放率(15.8%),且对人结肠癌细胞有明显的杀伤效果。     

紫胶树脂铵盐为壁材的微胶囊制备及性能研究

以紫胶树脂铵盐为壁材,红霉素为芯材,采用乳化-固化法制备了红霉素-紫胶树脂铵盐微胶囊,采用SEM、DSC、FTIR进行形貌和结构表征。结果表明,以紫胶树脂铵盐为壁材的微球表面光滑致密、形态圆整,粒度分布较为均匀,酸化过程中部分紫胶树脂铵盐在微球表面析出,形成致密的树脂膜对芯材起到良好的保护作用,且芯材与壁材并没有发生化学反应。对微胶囊载药率和模拟条件下体胃和体肠环境目标药物释放特性的研究表明,微胶囊载药率为1. 19%,在模拟体胃环境中,70 min内,红霉素释放量仅为载药率的2. 07%;模拟体肠环境中,微胶囊能够在10～120 min内实现红霉素药物的均匀释放,累积释放量达到79. 75%。可见,紫胶树脂铵盐在亲水性肠溶性药物包衣材料中有较强的应用潜力和价值。     

MCM-41/PAA的制备及释药性能

采用微波辅助法合成介孔分子筛(mesoporous molecular sieve)MCM-41,将其与丙烯酸(acrylic acid,AA)经原位聚合,制备具有pH敏感性的新型复合材料MCM-41/聚丙烯酸(polyacrylic acid,PAA)。通过X射线衍射、Fourier红外分析、热重分析、N2吸附/脱附等表征材料的结构和性能,证明合成了一种新型高分子复合材料。以抗压利尿药物氢氯噻嗪为模型药物,通过液体紫外法研究复合材料的载药性能及其在人工胃液(pH=1.2)和人工肠液(pH=6.8)条件下的释药性能。结果显示:MCM-41/PAA的载药量达51.75%,在人工胃液和人工肠液的体外模拟释药过程中显示出良好的pH控释的敏感性。这种材料可以用于肠道靶向控释领域。     

乳化-溶剂挥发法制备乙基纤维素/萘普生复合微球

以乙基纤维素（EC）为载体材料,萘普生为包埋药物,采用O/W型乳化-溶剂挥发法制备了包封率较高的EC/萘普生复合载药微球,利用正交试验优化制备工艺,得出当EC与萘普生的质量比为3：1,EC用量2.5%,聚乙烯醇用量0.8%,吐温-80用量0.4%时是复合微球的最佳制备工艺,在该工艺条件下药物包封率达到88.97%。通过扫描电子显微镜（SEM）、激光粒度分析、傅里叶变换红外光谱（FT-IR）对复合微球的形态和结构进行了分析表征。SEM显示复合微球的形态顺滑,激光粒度分析表明复合微球平均粒径为14.014μm,复合微球的FT-IR谱图中既有EC的特征峰,又有萘普生的特征峰,但没有新基团产生,表明EC包覆萘普生过程中未产生新化合物。体外释放实验表明复合微球的累积释药率随溶出介质pH值的增大而增大,在溶出介质pH值为9时,复合微球的累积释药率最大,达到82.5%,缓释性能较好。     

载牛血清白蛋白凝胶微球体液环境下释药性能的研究

研究可在体内缓释并口服的蛋白多肽类药物是国内外医药界目前广泛关注的问题。利用毒性较低但力学性能差的海藻酸钠和水溶性较低但机械性能良好的聚乙烯醇共混制备凝胶微球,在模拟体液环境(p H=7.4),以空白微球作对照,来对载牛血清白蛋白凝胶微球进行释药性能研究,可看到凝胶微球在白蛋白药物的控释方面是有良好效果的,4 h时可达到牛血清白蛋白药物释放增速最快,12 h时牛血清白蛋白药物累计释放达到55%,这可以为可口服的蛋白多肽类药物口服体内靶向缓释的临床应用提供相关的参考依据,具有重大意义。     

干扰素壳聚糖/海藻酸钠微囊控释制剂载体的初步研究

目的研究蛋白质类药物口服控释给药的可行性。方法壳聚糖与海藻酸钠通过聚电解质络合反应制备成壳聚糖/海藻酸钠微囊,以干扰素为模型药物,研究不同pH条件下,药物的控制释放情况。结果微囊的粒径为1 mm左右,其干扰素的包封率达90.0%以上,微囊在模拟胃液(pH1.0)中,3h药物释放不到5%;在模拟肠液(pH7.4)中,3h药物释放近100%。结论壳聚糖/海藻酸钠微囊有可能成为蛋白质类药物口服控释制剂的载体。     

海藻酸钙/埃洛石载药微球的制备与缓释盐酸二甲双胍性能

缓释可提高药物利用率,降低其毒副作用。采用交联法制备了海藻酸钙/埃洛石载药微球,以载药微球对盐酸二甲双胍（MH）药物的包封率和缓释效果为考察对象,研究了载药微球的制备工艺和缓释性能,并通过SEM、FTIR和TGA对其结构进行了表征。结果表明：在交联温度为0℃、海藻酸钠用量为1g、埃洛石添加量为2g时,能得到较优的载药微球包封率（79.23%）。上述条件下制得的复合载药微球在pH=6.8的磷酸盐缓冲液中能有效缓释,且720min后缓释度可达85.83%,说明其具有较好的pH敏感性和缓释效果。SEM表明海藻酸钙颗粒与埃洛石在载药微球内部形成复合结构,FTIR表明MH主要以物理包埋的形式于载药微球中,TGA表明添加埃洛石可以提高复合材料在200℃以上的热稳定性。     

快速膜乳化与热固化法制备粒径均一的pH敏感壳聚糖季铵盐凝胶微球

以具有升温自固化特性的壳聚糖季铵盐/甘油磷酸钠混合溶液为水相,利用快速膜乳化与热固化法制备了粒径均一、pH敏感的壳聚糖季铵盐凝胶微球,考察了跨膜压力、水油相组成、水油相体积比及微孔膜孔径等对微球粒径、结构和药物包埋率的影响. 结果表明,得到粒径698±57.33, 1145±71.48, 2021±53.63及3984±191.72 nm、粒径分布窄(多分散系数<0.1)、药物包埋率高达75.49%±2.62%的凝胶微球. 所制微球生物相容性好,有明显的pH敏感性,中性和碱性环境下结构稳定,药物缓释,pH=7.4时24 h内药物累计释放率为34.6%;酸性环境下微球崩解,药物快速释放,pH=5.5时1 h内药物累计释放率高达79.6%.     

快速膜乳化法制备胸腺法新长效缓释微球

采用快速膜乳化技术结合溶剂蒸发法制备以生物可降解聚乳酸-羟基乙酸(PLGA)为载体的胸腺法新载药微球,考察了PLGA分子量、油相中PLGA和乳化剂浓度、外水相pH值和内水相体积等对微球包埋率和粒径的影响. 结果表明,制备粒径均一的PLGA载药微球的优化条件为：PLGA分子量51 kDa,油相中PLGA和乳化剂浓度为100和10 g/L,内水相体积0.5 mL,外水相pH值为3.5. 该条件下所制载药微球粒径均一性好(Span<0.7),药物包埋率高达80%以上,突释率24 h内低于20%,线性持续稳定释药时间长达30 d.     

阿司匹林壳聚糖-明胶载药微胶囊的制备及性能研究

以阿司匹林为囊芯,壳聚糖和明胶为壁材,采用乳化交联法制备了明胶-壳聚糖微胶囊,考察了芯壁比、水油体积比、乳化剂用量、交联时间等因素对微胶囊性能的影响.采用高效液相色谱法来测定微胶囊的载药量、包封率和释放性能.研究发现,当芯壁比为1∶1,水油体积比为1∶3,乳化剂Span-80用量为5％,交联时间为2h的条件下制备的微胶囊形状规整,载药量为47.99％,包封率为83.18％,且在人工肠液中具有明显的缓释效果.     

二甲酸钾微胶囊的构建与缓释抑菌性

以自制沸石分子筛为载体,通过水热法将二甲酸钾负载形成芯材,海藻酸钠、壳聚糖为壳材,以复凝聚法制备出缓释微胶囊。通过FTIR、XPS对微胶囊进行了结构表征,通过缓释及抑菌率测试对其性能进行表征。结果表明:沸石分子筛与二甲酸钾之间可形成复配效应,构成微胶囊的芯材;壳聚糖和海藻酸钠发生静电作用,形成聚电解质膜,构成微胶囊的壳材;制备的微胶囊在pH=2.0的模拟胃环境中稳定,在pH=7.2的模拟肠道环境中二甲酸钾得到了释放,并在3 h内可释放完全;微胶囊包封率为68.33%,二甲酸钾的释放量为137.50 mg/g。微胶囊对大肠杆菌的生长具有一定的抑制作用,并随着微胶囊浓度的增大对大肠杆菌的抑制率呈现增长的趋势,最高抑菌率可以达到85%。     

快速膜乳化法制备载醋酸曲普瑞林PLGA微球

以生物可降解聚合物聚(乳酸?羟基乙酸)(PLGA)为载体,以160 g/L明胶水溶液为内水相、含500 g/L PLGA的二氯甲烷为油相,采用快速膜乳化和溶剂蒸发法制备了粒径均一的载醋酸曲普瑞林PLGA微球,微球粒径约30 mm,粒径分布系数Span<0.8,醋酸曲普瑞林包埋率达80.12%,药物在磷酸盐缓冲液中释放36 d的释放率为72.60%,体外释放行为良好.     

重组人粒细胞-巨噬细胞集落刺激因子壳聚糖-海藻酸钠微囊的制备

目的以壳聚糖和海藻酸钠为原料,制备重组人粒细胞-巨噬细胞集落刺激因子(rhGM-CSF)微囊,探讨开发口服蛋白多肽类药物的可行性。方法以rhGM-CSF为药物模型,通过壳聚糖与海藻酸钠聚电解质的络合反应制备rhGM-CSF壳聚糖-海藻酸钠微囊,观察微囊的形态大小,测定其包封率,不同pH值下的膨胀度和体外释放率。结果制备的rhGM-CSF壳聚糖-海藻酸钠微囊呈均匀、完整的圆球形,平均直径1mm左右;包封率达80%以上;在模拟肠液(磷酸盐缓冲液,pH7.4)中浸泡3h,膨胀度可达600%,药物释放率达85%以上。结论壳聚糖-海藻酸钠微囊具有肠溶控释作用,有望成为rhGM-CSF等蛋白类口服药物的控释载体。     

In vitro release study of diltiazem hydrochloride from poly(vinyl pyrrolidone)/sodium alginate blend microspheres

Polymeric blend microspheres of poly(vinyl pyrrolidone) (PVP) with sodium alginate (NaAlg) were prepared by cross‐linking with calcium ions and used to deliver a calcium channel blocker drug, diltiazem hydrochloride (DT). The prepared microspheres were characterized by Fourier transform infrared spectroscopy and scanning electron microscopy. Scanning electron microscopy confirmed the spherical nature of the particles. Preparation conditions for the microspheres were optimized by considering the percentage entrapment efficiency, particle size, and swelling capacity. Effects of variables such as PVP/NaAlg ratio, molecular weight of PVP, cross‐linker concentration, and drug/polymer ratio on the release of DT were discussed at two different pH values (1.2, 6.8) at 37°C. It was observed that DT release from the microspheres decreased with increasing molecular weight of PVP and extent of cross‐linking. However, DT release increased with increasing PVP content and drug/polymer ratio (d/p) of the blend microspheres. The highest DT release percentage was obtained as 99% for PVP/NaAlg ratio of 1/2 with d/p ratio of 1/2 at the end of 4 h. It was also observed from release results that DT delivery from the microspheres through the external medium are much higher at low pH (1.2) value than that of high pH (6.8) value. The drug release from the microspheres mostly followed Fickian transport. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Poly(L‐histidine)‐chitosan/alginate complex microcapsule as a novel drug delivery agent

Novel poly(L ‐histidine)‐chitosan/alginate complex microcapsules were prepared from biodegradable polymers poly(L ‐histidine) (PLHis) in the presence of chitosan at acetate buffer solution pH 4.6. Microcapsules obtained are spherical and well‐dispersed with a smooth surface and a narrow size distribution. The microcapsules can encapsulate the protein model drug hemoglobin (Hb) efficiently. The results show that the complex microcapsules with low, medium, or high molecular weight of chitosan (0.05%, w/v), the highest encapsulation efficiencies obtained are 91.3%, 85.9%, and 94.2% with loading efficiencies of 47.8%, 44.3%, and 39.7%, respectively. The release profiles indicate that Hb‐loaded microcapsules conform to first‐order release kinetic in whole procedure, and 84.8%, 71.4%, and 87.3% of Hb were released during 72‐h incubation in PBS pH6.8 for microcapsules with low, medium, and high molecular weight chitosan (0.05%, w/v), respectively. The results also indicate that particle size and drug loading efficiency have a significant influence on the release profile and encapsulation efficiency. Our results reveal that the PLHis‐chitosan/alginate complex microcapsules are able to encapsulate and release Hb and are potential carriers for protein drugs. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Preparation,characterization, and salicylic acid release behavior of chitosan/poly(vinyl alcohol) blend microspheres

Blend microspheres of chitosan (CS) with poly(vinyl alcohol) (PVA) were prepared as candidates for oral delivery system. CS/PVA microspheres containing salicylic acid (SA), as a model drug, were obtained using the coacervation‐phase separation method, induced by addition of a nonsolvent (sodium hydroxide solution) and then crosslinked with glutaraldehyde (GA) as a crosslinking agent. The microspheres were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy. Percentage entrapment efficiency, particle size, and equilibrium swelling degree of the microsphere formulations were determined. The results indicated that these parameters were changed by preparation conditions of the microspheres. Effects of variables such as CS/PVA ratio, pH, crosslinker concentration, and drug/polymer (d/p) ratio on the release of SA were studied at three different pH values (1.2, 6.8, and 7.4) at 37°C. It was observed that SA release from the microspheres increased with decreasing CS/PVA ratio and d/p ratio whereas it decreased with the increase in the extent of crosslinking. It may also be noted that drug release was much higher at pH 1.2 than that of at pH 6.8 and 7.4. The highest SA release percentage was obtained as 100% for the microspheres prepared with PVA/CS ratio of 1/2, d/p ratio of 1/2, exposure time to GA of 5 min, and concentration of GA 1.5% at the end of 6 h. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009