半胱氨酸修饰的荷载紫杉醇聚离子复合物胶束口服给药的体内体外研究

本文合成了普朗尼克F127-壳聚糖(F127-CS)和普朗尼克F127-半胱氨酸(F127-CT)共聚物,采用薄膜分散法以F127-CS、F127-CT和胆酸钠(Na C)为材料构建了聚离子复合物胶束,并以该复合物胶束作为药物载体运载紫杉醇进行口服给药。通过物理化学性质研究,包括粒径分布、Zeta电位、外观形态和临界胶束浓度,进一步证实形成了纳米级球形结构的胶束,并对胶束的体外释放及体内药动力学进行考察。与普朗尼克胶束的载药量(3.35%)相比,F127-CS/F127-CT/Na C胶束载药量提高到12.77%。通过临界胶束浓度的测定证实:在水溶液中F127-CS/F127-CT/Na C胶束比Na C胶束更稳定。药物动力学实验结果显示F127-CS/F127-CT/Na C紫杉醇载药胶束的药-时曲线下的面积是紫杉醇溶液的4倍。因此,F127-CS/F127-CT/Na C胶束是一种理想的紫杉醇口服给药系统。     

多西他赛Pluronic F127聚合物胶束的制备与表征

目的制备多西他赛(DTX)的F127聚合物胶束,对其药剂学特征进行评价。方法薄膜分散法制备胶束,并在单因素考察的基础上,以正交试验优化处方;透射电镜观察胶束形态;粒度分布测定仪测定其粒径、粒度分布;离心过滤法测定胶束的包封率和载药量;以DTX注射液作对照,采用动态膜透析法考察载药胶束的体外释药情况。结果薄膜分散法制备的胶束呈球形或类球形,平均粒径为(30.2±2.56)nm,平均包封率为(86.66±2.46)%,平均载药量为(0.42±0.01)%;体外释放实验结果表明该胶束具有一定的缓释能力。结论该胶束制备工艺简单,成型好,包封率高,具有一定的缓释能力。     

白藜芦醇胶束的制备及初步质量评价

摘要：目的:制备白藜芦醇聚合物胶束（RES-M）并对其进行初步的质量评价。方法:采用薄膜分散法,以普朗尼克F127（pluronic F127）作为载体材料,制备RES-M;以包封率和载药量为指标,通过单因素考察对RES-M的处方及工艺进行优化,并对最优处方制剂进行质量评价。结果:最优处方为pluronic F127与RES投料量比例为8∶1,旋蒸温度为45℃,旋蒸时间为25 min,水化介质为超纯水,水化体积为10 ml。最优处方的RES-M粒径为21.79 nm,多分散系数（PDI）为0.049,Zeta电位为-6.26 mV,包封率为（99.96±0.57）%,载药量为（10.67±0.37）%;RES-M的抗氧化能力与RES本身相当。结论:本试验成功制备RES-M,制备工艺简单,包封率与载药量均较高,为白藜芦醇制剂的研发提供了一定的理论基础。     

多西他赛普朗尼克P123胶束的制备

摘 要 目的： 优化以普朗尼克P123为载体材料的多西他赛胶束处方工艺。方法: 采用薄膜水化法制备多西他赛普朗尼克P123胶束。采用星点设计 效应面法优化胶束处方工艺,以包封率作为评价指标,考察投药量、有机溶剂体积、水化体积、水化温度。采用透射电镜观察胶束形态,并测定胶束的粒径和Zeta电位,以透析法进行胶束体外释放特性考察。结果: 以多元线性回归和二次、三次多项式拟合指标与因素之间的数学关系,结果表明三次多项式拟合度较好,制备出的胶束形态圆整,平均粒径和Zeta电位分别为108.3 nm和 3.99 mV,多分散指数为0.265,平均包封率和载药率分别为（97.91%±0.28％）和（3.72%±0.12％）,多西他赛胶束120 h的累积释放率达95.03%,具有一定的缓释能力。结论:采用薄膜水化法制备的多西他赛胶束工艺简单可行,具有较高的包封率,在体外具有较好的缓释效果。     

阿霉素-五味子乙素pH敏感聚合物胶束的制备与制剂学性质

目的以p H敏感聚合物聚乙二醇-聚乳酸-聚组氨酸[poly(ethyleneglyco1)-poly(D,L-lactide)-poly(L-histidine),m PEG-PLA-PHis]胶束为载体,联合包载抗肿瘤药物阿霉素与多药耐药逆转剂五味子乙素制备聚合物胶束,并对其制剂学性质进行研究。方法采用薄膜分散法制备阿霉素-五味子乙素p H敏感聚合物胶束,以包封率、载药量和稳定性(载药胶束24 h的包封率和载药量变化)为评价指标,采用单因素试验及Box-Behnken效应面法筛选最优处方;应用透射电子显微镜观察载药胶束的外观形态,动态光散射法测定载药胶束的粒径及zeta电位;透析法考察载药胶束在不同p H条件下的释药行为。结果制备的阿霉素-五味子乙素p H敏感聚合物胶束平均粒径为64.73 nm,zeta电位为-8.7 m V。最优处方中阿霉素包封率为95.3%,载药量为8.7%,五味子乙素包封率为76.1%,载药量为3.4%,载药胶束稳定性较好。体外释放结果表明,所制备的阿霉素-五味子乙素p H敏感聚合物胶束在弱酸性条件下,药物释放速率明显加快。结论采用星点设计-效应面法优化处方与制备工艺,所制备的阿霉素-五味子乙素p H敏感聚合物胶束粒径分布均匀,包封率和载药量良好,具有明显的p H响应行为。     

他克莫司载药胶束的制备与制剂学性质

目的以聚乙二醇单甲醚-聚乳酸[methoxy poly(ethylene glycol)-poly(lactide),m PEG-PLA]嵌段共聚物为载体材料,制备他克莫司载药胶束,考察其制剂学性质。方法采用薄膜分散法制备他克莫司载药胶束。超速离心法测定他克莫司载药胶束的载药量和包封率。以载药量、包封率、粒径以及粒径分布为评价指标,采用单因素试验和正交试验优化他克莫司载药胶束制备处方。应用透射电镜、粒度测定仪和zeta电位分析仪对他克莫司载药胶束的形态、粒径和电位进行表征。结果在优化条件下制备的他克莫司载药胶束载药量为7.77%,包封率为84.31%,胶束粒子外观圆整且分散良好,平均粒径为23.20 nm,PDI为0.058,zeta电位为-0.831 m V。结论单因素试验联合正交试验可有效地优化他克莫司m PEG-PLA胶束处方和制备工艺。优化条件下制备的他克莫司载药胶束具有较高的载药量和包封率,粒径较小且分布均匀,24 h内稳定性良好。     

阿霉素共聚物胶束的制备及体外性质研究

目的制备阿霉素共聚物胶束并研究其体外性质。方法采用开环聚合法合成聚乙二醇单甲醚-聚乳酸羟基乙酸（mPEG—PLGA）嵌段共聚物;用透析法、溶剂蒸发法制备空白及载阿霉素胶束;动态光散射仪（DLS）测定其粒径分布;采用紫外分光光度法测定胶束的包封率和载药量。通过体外释药实验研究了载阿霉素胶束的释药特性。结果采用透析法制备载阿霉素胶束大小均匀,平均粒径为（91．1±15．8）nm;药物胶束的包封率为85．2％,载药量为10．4％;与市售阿霉素注射剂相比,载阿霉素胶束具有良好的缓释性能。结论共聚物胶束可作为疏水性药物阿霉素的载体。     

姜黄素聚合物胶束的制备及体外评价

目的:制备姜黄素的Soluplus聚合物胶束,并对其进行体外评价。方法:采用薄膜分散法制备姜黄素聚合物胶束;采用粒径测定仪、透射电镜、X-射线衍射(XRD)对其进行表征;采用紫外分光光度法测定胶束的包封率和载药量;采用动态膜透析法考察载药胶束的体外释药特性。结果:薄膜分散法制备的胶束呈球形或类球形,平均粒径为(65.54±2.57)nm,平均包封率为(87.73±2.94)%,平均载药量(7.96±2.13)%;XRD结果表明姜黄素以无定型状态或分子状态包载在聚合物胶束中;体外释放结果表明姜黄素的soluplus聚合物胶束具有缓释作用。结论:该胶束制备工艺简单,其粒径、包封率、载药量可控,具有缓释作用。     

紫杉醇普朗尼克稳定化胶束的制备

目的:制备载紫杉醇的普朗尼克(Pluronic)稳定化胶束。方法:采用插入交联的方法,以普朗尼克P123为材料插入交联剂聚氰基丙烯酸正丁酯制备紫杉醇稳定化胶束。并对其理化性质如粒径,载药量,体外释放度等进行了测定。同时测定了该胶束对HepG-2肝癌细胞的细胞毒性。结果:所制备的载药胶束,多倍冲稀后仍能稳定存在。细胞毒性实验结果表明,稳定胶束对HepG-2肝癌细胞的细胞毒性显著高于原料药。结论:所制备的载紫杉醇胶束性质稳定,细胞毒性增加。     

喷雾干燥法制备三七皂苷缓释微球

目的 制备三七皂苷缓释微球.方法 以壳聚糖、丙烯酸树脂为载体材料,采用喷雾干燥法制备三七皂苷缓释微球.以载药量和包封率为指标,采用均匀设计法优化处方.结果 所制三七皂苷缓释微球的外观圆整,平均粒径为11.80μm,包封率70.4%,载药量9.1%,在磷酸缓冲液中三七皂苷12 h释放缓慢、平稳,释放均遵循Weibull方程.结论 所制三七皂苷缓释微球符合预期,具有很好的缓释效果.     

Preparation and evaluation of icariside II-loaded binary mixed micelles using Solutol HS15 and Pluronic F127 as carriers

An effective anti-cancer drug, icariside II (IS), has been used to treat a variety of cancers in vitro. However, its poor aqueous solubility and permeability lead to low oral bioavailability. The aim of this work was to use Solutol®HS15 and Pluronic F127 as surfactants to develop novel mixed micelles to enhance the oral bioavailability of IS by improving permeability and inhibiting efflux. The IS-loaded mixed micelles were prepared using the method of ethanol thin-film hydration. The physicochemical properties, dissolution property, oral bioavailability of the male SD rats, permeability and efflux of Caco-2 transport models, and gastrointestinal safety of the mixed micelles were evaluated. The optimized IS-loaded mixed micelles showed that at 4:1 ratio of Solutol®HS15 and Pluronic F127, the particle size was 12.88?nm with an acceptable polydispersity index of 0.172. Entrapment efficiency (94.6%) and drug loading (9.7%) contributed to the high solubility (11.7?mg/mL in water) of IS, which increased about 900-fold. The SF-IS mixed micelle release profile showed a better sustained release property than that of IS. In Caco-2 cell monolayer models, the efflux ratio dramatically decreased by 83.5%, and the relative bioavailability of the mixed micelles (AUC_0–∞) compared with that of IS (AUC_0–∞) was 317%, indicating potential for clinical application. In addition, a gastrointestinal safety assay also provided reliable clinical evidence for the safe use of this micelle.     

Pharmaceutical evaluation of genistein-loaded pluronic micelles for oral delivery

The purpose of the present study was to determine whether Pluronic F127 polymeric micelles could improve the oral bioavailability of a poor water-soluble drug, such as genistein. Genistein is a phytoestrogen that has estrogenic activity. F127 triblock copolymer consists of PEO100-PPO65-PEO100. Genistein was incorporated in the Pluronic F127 polymeric micelles by a solid dispersion method. The genistein release of genistein-loaded polymeric micelles was studied in vitro (in pH 1.2 and pH 6.8). And the oral bioavailabilities of genistein powder and genistein-loaded micelles were estimated at a dose of 4.0 mg/kg as genistein in rats. Drug loading amount and drug loading efficiency were 11.18% and 97.41%, respectively. The average size of the genistein-loaded polymeric micelles was 27.76 nm. And genistein release of the genistein-loaded polymeric micelles in vitro was 58% (pH 1.2) and 82% (pH 6.8). The bioavailability of genistein-loaded polymeric micelles was better than genistein powder. Consequently, Pluronic F127 polymeric micelles are an effective delivery system for the oral administration of genistein.     

Preparation of sodium cholate-based micelles through non-covalent ıbonding interaction and application as oral delivery systems for paclitaxel

In present study, two types of micelles based on sodium cholate (NaC) were prepared through non-covalent bonding interaction and the potential of micelles as oral drug delivery systems for paclitaxel (PTX) was evaluated. Pluronic–chitosan (F127–CS) and Pluronic–poly (acrylic acid) (F127–PAA) copolymers were synthesized. Electrostatic interaction and hydrogen bond were used to prepare F127–CS/NaC micelles and F127–PAA/NaC micelles, respectively. The physicochemical characteristics of micelles were determined. An average diameter of 67.5?nm and unimodal pattern of size distribution were observed for F127–CS/NaC micelles. While for F127–PAA/NaC micelles, an average diameter of 85.89?nm and non-unimodal pattern of size distribution were observed. The results revealed that F127–CS/NaC micelles were more integrated than F127–PAA/NaC micelles. Further experiments showed that the F127–CS/NaC micelles had a higher drug-loading content of 12.8% and a lower critical micelle concentration (CMC) of 2.5?×?10^?3?mol/L compared with F127–PAA/NaC micelles. In vitro cytotoxicity analysis demonstrated that the PTX-loaded F127–CS/NaC micelles were of great efficiency in inhibiting the growth of drug-resistant breast cancer MCF-7 cells (MCF-7/Adr). The intragastric administration of the PTX-loaded F127–CS/NaC micelles in rats provided a 4.33-fold higher absolute bioavailability compared to commercial Taxol®, indicating an efficient oral absorption of PTX delivered by micelles. These findings signify that F127–CS/NaC micelle may be a promising carrier for the delivery of PTX.     

Adoption of polymeric micelles to enhance the oral bioavailability of dexibuprofen: formulation,in-vitro evaluation and in-vivo pharmacokinetic study in healthy human volunteers

Abstract

This work aimed to incorporate Dexibuprofen (DXI), the pharmacologically active and more potent form of ibuprofen, into polymeric micelles based tablets with enhanced oral bioavailability. Thin film hydration technique was employed to prepare DXI polymeric micelles using Pluronic® F127 and/or P123 solutions in different ratios (ranging from 1:1 up to 1:10). Prepared micelles were characterized regarding particle size, drug loading and entrapment efficiency. Selected formulae were lyophilized in presence of cryoprotectants and subjected to solid-state characterization as well as scanning and transmission electron microscopy. Subsequently, tablets were prepared and evaluated in-vitro regarding physical properties and drug release. An in-vivo pharmacokinetic study was performed in six healthy human volunteers in comparison to the commercially available tablet of DXI. Solid-state characterization proved that DXI was homogenously dispersed in Pluronic micelles’ matrices. Formula TF5 tablets comprising lyophilized micelles (F5; DXI: Pluronic F127 in 1:1 ratio and 0.25% mannitol) showed higher C_max and earlier t_max values than those of the commercial formula, where the relative bioavailability was calculated to be 160.15%. The experimental evidence in this research leads to the conclusion that polymeric micelles present enabling properties for oral delivery of drugs with low solubility.     

Synthesis and characterization of novel poly(sebacic anhydride-co-Pluronic F68/F127) biopolymeric microspheres for the controlled release of nifedipine

Amphiphilic block copolymers composed of prepoly(sebacic anhydride) and Pluronic-F68/F127 have been synthesized in different molar compositions via melt-polycondensation reaction. Poly(sebacic anhydride-co-PLF68/PLF127) thus formed was characterized by Fourier transform infrared spectroscopy (FTIR), gel permeation chromatography (GPC) and nuclear magnetic resonance spectroscopic (NMR) techniques. The amphiphilic block copolymers were used to prepare microspheres and to encapsulate nifedipine (NFD) by the solvent evaporation technique. Differential scanning calorimetry (DSC) was used to confirm the incorporation of Pluronic into polyanhydrides, while X-ray diffraction (XRD) was performed on the drug-loaded microspheres to investigate the crystalline nature of the drug after encapsulation. Scanning electron micrograph (SEM) pictures indicated spherical nature of the microspheres. Microspheres obtained were in the size range of 10-50microm as measured by the laser particle size analyzer. In vitro release studies of NFD from poly(sebacic anhydride-co-Pluronic-F68/F127) microspheres performed in pH 7.4 phosphate buffer indicated sustained release rates of NFD at higher amounts of Pluronic in polyanhydride copolymers; there was no significant difference obtained between the release patterns of NFD from Pluronic-F68 and Pluronic-F127 copolyanhydride microspheres when same amount of Pluronics were used.     

丙泊酚mPEG-PLA/普朗尼克混合胶束的制备和性质(英文)

采用生物相容性聚合物胶束材料聚乙二醇-聚乳酸(mPEG-PLA)和普朗尼克P105(P105),构建了全新的混合胶束体系,用于提高难溶性麻醉药—丙泊酚的溶解度。相对于单纯由mPEG-PLA构建的载药胶束,该载药混合胶束能有效提高药物溶解度。最优化处方为mPEG-PLA:P105:丙泊酚=10:4:5(w/w/w),粒径约为90nm,多分散指数为0.2左右。载药混合胶束中游离药物浓度显著低于市售品脂肪乳(P<0.05)。此混合胶束于4oC条件下放置6个月,其粒径、多分散指数、游离药物浓度和载药量均无明显变化,说明4oC条件下该体系在6个月内是稳定的。混合胶束在各时间点的体外释放百分率显著高于市售品脂肪乳,这可能有利于更快发挥药效。睡眠/苏醒试验结果表明,混合胶束、单一胶束以及市售品脂肪乳的翻正反射消失时间和恢复时间没有显著性差异(P>0.05)。上述结果表明该混合胶束有望成为静脉给药系统应用于临床。     

Preparation and characterization of polymeric micelles for solubilization of poorly soluble anticancer drugs.

The objective of this study is to investigate the solubilization of poorly water-soluble anticancer drugs, octaethylporphine (OEP), meso-tetraphenyl porphine (mTPP) and camptothecin (CPT), in Pluronic and polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) polymeric micelles. Three different Pluronic and PEG-DSPE polymers with various chain lengths were chosen and micelle formulations were prepared by using various drug:polymer ratios. Formulations were characterized by critical micellization concentration (CMC) values of copolymers, micelle particle size and distribution, zeta potential, loading efficiency and stability. Polymers formed very stable, low CMC micelles with smaller sizes than 100 nm. It was shown that drug loading efficiency highly depends on the polymer type, drug type and their ratios. The most efficient drug loading was obtained by loading mTPP in PEG2000-DSPE and Pluronic F127 micelles. This result is attributed to phenyl groups in mTPP might lead to attraction between alkyl groups in the polymer and increase drug incorporation. PEG-DSPE formulations had higher zeta potential values indicating that they would be more stable against aggregation than Pluronic micelles. From the drug assay aspect Pluronic micelles remained more stable in 3-month long stability test. These results showed that besides their solubilizing effects, polymeric micelles could be useful as novel drug carriers for hydrophobic drugs.     

Thermoreversible mucoadhesive ophthalmic in situ hydrogel: Design and optimization using a combination of polymers

The purpose of the study was to develop an optimized thermoreversible in situ gelling ophthalmic drug delivery system based on Pluronic F 127, containing moxifloxacin hydrochloride as a model drug. A 3(2) full factorial design was employed with two polymers: Pluronic F 68 and Gelrite as independent variables used in combination with Pluronic F 127. Gelation temperature, gel strength, bioadhesion force, viscosity and in vitro drug release after 1 and 10 h were selected as dependent variables. Pluronic F 68 loading with Pluronic F 127 was found to have a significant effect on gelation temperature of the formulation and to be of importance for gel formation at temperatures 33-36 °C. Gelrite loading showed a positive effect on bioadhesion force and gel strength and was also found helpful in controling the release rate of the drug. The quadratic mathematical model developed is applicable to predicting formulations with desired gelation temperature, gel strength, bioadhesion force and drug release properties.     

载喜树碱普郎尼克/TPGS混合胶束的制备与质量评价

目的制备装载喜树碱的普朗尼克105和维生素E琥珀酸聚乙二醇酯(TPGS)混合胶束,并对其性质及体外释药特性进行评价。方法根据两种材料的比例选择4个处方,采用薄膜形成法制备混合胶束;透射电镜观察聚合物胶束形态;激光动态散射法测定胶束的粒径及其分布;荧光分光光度法考察含药胶束的载药量,确定最佳处方;透析袋法进行胶束体外释药行为研究。结果混合胶束大小均匀,具有球形核-壳结构,粒径分布范围在4~9 nm,并且随着维生素E琥珀酸聚乙二醇酯用量的增加,聚合物胶束的粒径分布更加集中;混合胶束显著提高了喜树碱的溶解度;喜树碱混合胶束体外释放缓慢,符合双向动力学特征。结论普朗尼克105和维生素E琥珀酸聚乙二醇酯混合胶束可以作为疏水性药物的纳米级长循环载体,具有很好的应用前景。