黄体酮通过乙烯—醋酸乙烯共聚物膜扩散机制的研究

本文研究了黄体酮通过乙烯-醋酸乙烯共聚物(EVA)膜的扩散机制。黄体酮的渗透常数和分配系数均随EVA膜中醋酸乙烯含量增加呈非线性增大,扩散系数则与醋酸乙烯含量无关。即黄体酮自水相通过EVA膜的渗透常数完全决定于分配系数。后者同膜中醋酸乙烯含量间的非线性关系,是由于非羟基化合物黄体酮能够与醋酸乙烯形成1∶1和1∶2复合物,其稳定常数为K_(1∶1)=0.11(mol/L)~(-1),K_(1∶2)=0.09(mol/L)~(-2)。通过黄体酮在己烷-醋酸乙酯等共溶剂系统中的溶解度特性研究,进一步支持了该结论。     

Monoliths with chiral surface functionalization for enantioselective capillary electrochromatography

The state-of-the-art in CEC enantiomer separations with monolithic capillary columns is comprehensively reviewed. The various types of monolithic columns comprising in situ organic polymer monoliths, molecularly imprinted polymer (MIP) monoliths, silica monoliths and monoliths made from particles are discussed with a focus on materials’ synthesis, chemistry and properties as well as column aspects. Monolithic MIP-type porous layer open-tubular (PLOT) columns are treated herein as well. From this survey of the literature, the authors come to the conclusion that monolithic silica capillaries appear to become the preferred column type for CEC enantiomer separations of low-molecular drugs and other chiral pharmaceuticals or chemicals.     

In vivo evaluation of thiolated poly(acrylic acid) as a drug absorption modulator for MRP2 efflux pump substrates

Recently, several polymers have been reported to modulate drug absorption by inhibition of intestinal efflux pumps such as multidrug resistance proteins (MRPs) and P-glycoprotein (P-gp). The aim of the present study was to evaluate the efficiency of thiolated poly(acrylic acid) (PAA-Cys) to act as a drug absorption modulator for MRP2 efflux pump substrates in vivo, using sulforhodamine 101 as representative MRP2 substrate. In vitro, the permeation-enhancing effect of unmodified PAA and PAA₂₅₀-Cys_, displaying 580 μmol free thiol groups per gram polymer, was evaluated by using freshly excised rat intestinal mucosa mounted in Ussing-type chambers. In comparison to that of the buffer control, the sulforhodamine 101 transport in the presence of 0.5% unmodified PAA₂₅₀ and 0.5% (w/v) PAA₂₅₀-Cys was 1.3- and 4.0-fold improved, respectively. In vivo, sulforhodamine 101 solutions containing 4% (w/v) unmodified PAA₂₅₀ or 4% (w/v) thiolated PAA₂₅₀ were orally given to rats. The PAA₂₅₀-Cys solution increased the area under the plasma concentration-time curve (AUC_0-12) of sulforhodamine 101 3.8-fold in comparison to control and 2.2-fold in comparison to unmodified PAA₂₅₀. This in vivo study revealed that PAA₂₅₀-Cys significantly increased the oral bioavailability of MRP2 substrate sulforhodamine 101.     

Poly( -histidine)–PEG block copolymer micelles and pH-induced destabilization

Poly(L-histidine)-poly(ethylene glycol) diblock copolymers (polyHis-b-PEG) were prepared and used for the construction of polymeric micelles responding to local pH changes in the body. PolyHis was synthesized by ring opening polymerization of L-histidine N-carboxyanhydride, the imidazole amine group of which was protected by the dinitrophenyl group. The resulting polymer (M(n): 5,000 g/mole) was coupled to poly(ethylene glycol) (M(n): 2,000 g/mole) via an amide linkage using the dicyclohexyl carbodiimide and N-hydroxysuccinimide-mediated reaction. The block copolymer in dimethyl sulfoxide formed polymeric micelles on diafiltration against a borate buffer at pH 8. Dynamic light scattering and atomic force microscopy showed the micelles were spherical, diameter approximately 114 nm, with a unimodal distribution. The critical micelle concentration (CMC) at pH 8.0 was 2.3 mg/l. The CMC increased markedly on decreasing the pH of the diafiltration medium below 7.2. Micelles prepared at pH 8.0 were gradually destabilized below pH 7.4, as evidenced by a slight increase in light transmittance, an alteration in size distribution, and a decrease in the pyrene fluorescence intensity. It was concluded that the ionization of the polyHis block forming the micelle core determined the pH-dependent CMC and stability. After further optimization of the pH-sensitivity, pH-sensitive micelles are expected to have application for solid tumor treatment, exploiting the fact that most solid tumors have an acidic extracellular pH.     

Preparation and pharmaceutical evaluation of acetaminophen nano-fiber tablets: Application of a solvent-based electrospinning method for tableting

In this study, we developed nano-fiber-based tablets with acetaminophen (AAP; Log P_ow = 0.51) for controlled-release delivery systems and evaluated in vitro drug dissolution and in vivo pharmacokinetics in rats. Nano-fibers made from methacrylic acid copolymer S (MAC; EUDRAGIT^® S100) and containing AAP were prepared using a solvent-based electrospinning (ES) method. In vitro dissolution rate profiles of AAP showed tableting pressure-dependent decreases and pH-dependent increases. The results of tablet tracking by X-ray irradiation showed tablets based on MAC nano-fibers did not disintegrate in the upper intestinal lumen and had the properties of a long-term-acting tablet. In addition, the in vitro release profiles of AAP from nano-fiber tablets prepared by dissolving MAC with AAP (NFT), nano-fiber tablets prepared by adsorbing AAP to drug-free MAC nano-fibers (NFT_adso), and tablets prepared by adsorbing half the amount of AAP to MAC nano-fibers containing the remaining amount of AAP (NFT_half) showed independent controlled-release aspects of AAP compared with physical mixture tablets (PMT). In vivo pharmacokinetic studies in rats after intraduodenal administration of 14 mg/rat AAP in NFT, NFT_adso, and NFT_half demonstrated that all these tablets based on MAC nano-fibers showed sustained-release profiles compared with PMT, and showed ultra-sustained release properties for AAP. These new tablets based on MAC nano-fibers did not disintegrate in the intestine in the lower pH region, and the tablets could regulate the release of AAP in a pH-dependent manner. The ES method is a useful technique to prepare nano-fibers and showed promising results as an oral delivery system for sustained-release regulation.     

pH-responsive nanoparticles releasing tenofovir intended for the prevention of HIV transmission

This study is designed to test the hypothesis that tenofovir (TNF) or tenofovir disoproxil fumarate (TDF) loaded nanoparticles (NPs) prepared with a blend of poly(lactic-co-glycolic acid) (PLGA) and methacrylic acid copolymer (Eudragit® S-100, or S-100) are noncytotoxic and exhibit significant pH-responsive release of anti-HIV microbicides in the presence of human semen fluid simulant (SFS). After NPs preparation by emulsification diffusion, their size, encapsulation efficiency (EE%), drug release profile, morphology, and cytotoxicity are characterized by dynamic light scattering, spectrophotometry, transmission electron microscopy, and cellular viability assay/transepithelial electrical resistance measurement, respectively. Cellular uptake was elucidated by fluorescence spectroscopy and confocal microscopy. The NPs have an average size of 250 nm, maximal EE% of 16.1% and 37.2% for TNF and TDF, respectively. There is a 4-fold increase in the drug release rate from the 75% S-100 blend in the presence of SFS over 72 h. At a concentration up to 10 mg/ml, the PLGA/S-100 NPs are noncytotoxic for 48 h to vaginal endocervical/epithelial cells and Lactobacillus crispatus. The particle uptake (∼50% in 24 h) by these vaginal cell lines mostly occurred through caveolin-mediated pathway. These data suggest the promise of using PLGA/S-100 NPs as an alternative controlled drug delivery system in intravaginal delivery of an anti-HIV/AIDS microbicide.     

基于星形嵌段共聚物的药物载体和控制释放研究

目的：研究合成的星形嵌段共聚物（PEI-PLGA-b-PEG）对模型化合物结晶紫和模型药物阿霉素的装载及pH敏感释放。方法：将PEI—PLGA-b-PEG与模型化合物混合体系对水溶液做充分透析以测定装载量;将共聚物一模型化合物复合体对不同pH的水溶液透析,测定模型化合物释放速率。结果：PEI—PLGA-b—PEG可实现对模型化合物的有效稳定俘获以及明显的pH敏感释放。结论：合成的PEI-PLGA-b—PEG可用作酸度敏感释放的药物载体。     

聚甲丙烯酸铵酯Ⅰ动力黏度测定

考察了聚甲丙烯酸铵酯Ⅰ的流体特性并建立了其动力黏度的测定方法.采用马尔文Kinexus Ultra同轴圆筒式流变仪,测定温度20℃,剪切速率10s-1.结果表明聚甲丙烯酸铵酯Ⅰ为牛顿流体,动力黏度为6.78 mPa(.)s,RSD为0.19％.     

基于β-环糊精和二茂铁主客体作用的超分子聚合物的制备及其凝胶化

以β-环糊精修饰的壳聚糖（CDCS）和二茂铁修饰的聚乙二醇（FcPEG）为构筑单元,以β-环糊精和二茂铁的主客体相互作用为驱动 ,构筑了水溶性的超分子聚合物CDCS-FcPEG。在此基础上,加入α-环糊精（α-CD）,通过其对聚乙二醇的穿环络合诱导结晶作用,制备 了壳聚糖基水凝胶。使用核磁（1H-NMR）、紫外可见光谱法（UV-Vis）、X射线衍射分析（XRD）和循环伏安法（CV）等手段进行了验证。 结果表明：超分子聚合物CDCS-FcPEG与共价键连接的传统聚合物一样可以和α-CD形成凝胶。     

异戊二烯-甲基丙烯酸甲酯的阴离子嵌段共聚合

在四氢呋喃(THF)与环己烷的混合溶剂中,以正丁基锂(n-BuLi)为引发剂,采用具有较大空间位阻和特定电荷环境的P配合物为添加剂,实现了异戊二烯(Ip)和甲基丙烯酸甲酯(MMA)的阴离子嵌段共聚。分别采用GPC、1H-NMR对聚合物的结构进行了分析表征。结果表明：随着THF与环己烷体积比的增大,单体的转化率呈现下降的趋势;同时空间位阻较大的P配合物的加入,堵塞了正、负离子对之间的部分通道,有效地抑制了MMA段聚合副反应的发生,在易于工业化的0 ℃之下成功合成了分子量分布窄(1.21)的聚异戊二烯聚甲基丙烯酸甲酯嵌段共聚物(PI-b-PMMA),并且共聚物中PI嵌段以3,4结构链节为主。