青霉属生物中分离出的抗真菌四肽的固相合成

目的以固相合成法合成抗真菌四肽D-Phe-Val-D-Val-Tyr-OH。方法采用固相合成法通过4步反应顺利获得目标四肽,所得化合物的结构通过MS、1H NMR等光谱确证。结果合成得到了抗真菌四肽D-Phe-Val-D-Val-Tyr-OH,总收率为47.0%。结论合成方法具有可行性,操作简便、总收率高,目标化合物可用于抗真菌药物研究。     

抗肿瘤肽AP-9的固相合成

建立了抗肿瘤肽AP-9的Fmoc固相全合成方法，产品纯度大于98％。着重研究了Fmoc-Arg（Pbf）-OH与H—Pro—Trt树脂的缩合反应。结果表明，以THF-NMP（1：1）为溶剂，于30℃微波辐射反应6min，缩合产率达80．2％。     

奥曲肽固相合成工艺研究

目的优化奥曲肽固相合成工艺。方法本研究采用Fmoc保护基固相合成策略合成奥曲肽直链肽[D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr(ol)],并在此基础上进行裂解、成环、纯化、制备奥曲肽。本研究着重对裂解条件进行优化,包括裂解液成分、比例、反应温度和时间等。结果与结论以TFA∶TIS∶H_2O∶DTT=90∶2.5∶2.5∶8为裂解体系,在10℃下反应2～3 h得到纯度92%(HPLC)的直链肽粗品。本文优化的裂解条件提高了奥曲肽直链肽纯度,同时避免了乙二硫醇的使用,使得生产过程对环境更加友好,更适合工业化生产。     

鳖甲抗肝纤维化活性多肽的固相合成

目的固相合成鳖甲抗肝纤维化活性多肽,为开发抗肝纤维化多肽药物提供结构明确的受试品。方法采用固相合成法,以Fmoc保护氨基酸和Wang树脂为原料,经1 氧 3 双二甲胺羧基苯骈三氮唑四氟化硼盐、N 甲基吗啡啉缩合,以20%哌啶的N,N 二甲基甲酰胺溶液进行脱保护,用三氟乙酸切割试剂将多肽粗品从Wang树脂上切割下来。结果经反相高效液相色谱分析纯化,可得纯度>98%的目的肽,经质谱鉴定其相对分子质量与理论值一致。结论该合成方法条件温和、副反应少,操作简便,纯化效率高,可用于大规模合成目的肽。     

普兰林肽的固相合成

目的:探索普兰林肽的固相合成、氧化条件及纯化方法。方法:采用Fmoc固相多肽合成法,以Rink Amide-AM树脂做载体,HBTU/HOBt/DIEA做缩合剂,逐步缩合得到全保护线性普兰林肽树脂,以TFA/苯甲硫醚/苯酚/H2O/EDT/TIS配比的裂解液脱除保护基团,分别采用空气,二甲基亚砜,双氧水氧化两个半胱氨酸的巯基形成一对二硫键,半制备反相高效液相色谱法纯化。结果:合成含37个氨基酸以及一对二硫键的普兰林肽经RP-HPLC和MALDI-TOF-MS确证,粗品纯度在50.0%以上,粗品经半制备型反相高效液相色谱纯化,所得精肽的纯度大于95.0%,总收率为30.5%。结论:该方法简单,合成的产品成本低,纯度高,可为工业化生产提供借鉴。     

微波辅助固相合成苄基保护的天冬氨酸六肽

目的 固相合成天冬氨酸六肽.方法 以Fmoc-Asp(OBzl)-OH为原料,苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯为缩合剂,微波辅助逐步接肽法固相合成,三氟醋酸切割产物肽,纯化得保护的天冬氨酸六肽.结果 产物结构经1HNMR,MS确证.结论 微波法可以显著缩短固相合成反应的时间,提高产率.     

醋酸奥曲肽的固相合成

目的设计并合成醋酸奥曲肽.方法采用固相多肽合成法,使用逐步缩合的战略合成奥曲肽.结果与结论合成了醋酸奥曲肽,纯品总收率为30%(以连到树脂上的第一个氨基酸计).关键中间体及最终产物的结构经质谱、红外光谱、核磁共振氢谱及碳谱得到确证.     

Fmoc法固相合成普兰林肽

以Fmoc保护的氨基酸为原料,Amide Rink MBHA树脂为载体,按照氨基酸序列进行耦合制得普兰林肽,同时考察了裂解条件.应用反相高效液相色谱得到纯度98%以上的样品.     

抗肝癌药物酪丝亮肽的工艺研究

［摘要］目的 探索一类抗肝癌新药酪丝亮肽的固相合成路线,并与申报的液相合成路线进行优缺点比较. 方法 采用Fmoc/Wang树脂固相合成方法,逐步接肽,然后用裂解液（TFA：Tis:H2O,95.0：2.5：2.5）从树脂切割得到粗品,最后制备液相纯化脱盐,冻干得到产品. 结果 终产品经质谱、磁共振检测确证,纯度为99.5%,产率为82.0%. 结论 Fmoc固相合成方法可以得到与液相合成一致的产品,相比液相路线,该合成方法便捷易操作,生产周期短,产率高,但是成本相对较高.     

新型经皮给药载体——醇质体的研究进展

醇质体作为一种新的经皮给药载体,是一种具有高变形性、高包封率、能完整地渗透过皮肤的新型脂质体。它性质稳定、制备简单,与普通脂质体相比,显著提高了透皮速率,能更有效地运送药物通过角质层进入皮肤更深层甚至血液循环,也为亲水和亲脂性药物提供有效的细胞内传递,近年已成为经皮给药研究的热点。文中根据国内外文献,对醇质经皮给药的促渗机制、特点及其应用现状进行综述,同时指出了其存在的问题和可能的发展趋势。     

Vesicular systems for delivering conventional small organic molecules and larger macromolecules to and through human skin

The history of using vesicular systems for drug delivery to and through skin started nearly three decades ago with a study utilising phospholipid liposomes to improve skin deposition and reduce systemic effects of triamcinolone acetonide. Subsequently, many researchers evaluated liposomes with respect to skin delivery, with the majority of them recording localised effects and relatively few studies showing transdermal delivery effects. Shortly after this, transfersomes were developed with claims about their ability to deliver their payload into and through the skin with efficiencies similar to subcutaneous administration. Since these vesicles are ultradeformable, they were thought to penetrate intact skin deep enough to reach the systemic circulation. Their mechanisms of action remain controversial, with diverse processes being reported. Parallel to this development, other classes of vesicles were produced, with ethanol being included into the vesicles to provide flexibility (as in ethosomes); vesicles were constructed from surfactants and cholesterol (as in niosomes). The ultradeformable vesicles showed variable efficiency in delivering low-molecular-weight and macromolecular drugs. This article will critically evaluate vesicular systems for dermal and transdermal delivery of drugs, considering both their efficacy and their potential mechanisms of action.     

Vesicles as tools for the modulation of skin permeability

Human skin is a remarkably efficient barrier designed to keep our insides in and the outside out. The modulation of this efficient barrier's properties, including its permeability to chemicals, drugs and biologically active agents is the prime target for various dermal, transdermal, drug, antigen and gene delivery approaches. Therefore, several methods have been attempted to enhance the permeation rate of biologically active agents, temporarily and locally. One of the approaches is the application of drug-laden vesicular formulations. This review presents various mechanisms involved in increasing drug transport across the skin via different vesicular approaches, such as liposomes, elastic vesicles and ethosomes, along with compiling the research work conducted in this field.     

多肽蛋白质类药物离子导入经皮给药的研究进展

论述了多肽蛋白质类药物离子导入经皮给药的特点及主要影响因素,重点介绍了近年来国际上对胰岛素、降血钙素、促黄体(生成)激素释放激素、精氨酸抗利尿激素(加压素)等多肽蛋白质类药物离子导入经皮给药的研究进展.     

Drug Delivery by Phonophoresis

Phonophoresis is defined as the migration of drug molecules, contained in a contact agent, through the skin under the influence of ultrasound. Several drugs have been introduced into the body by this technique. The design of a phonophoretic drug delivery system is in developmental stages in various research laboratories. Parameters affecting the delivery of drugs by this technique and devices available for drug delivery purposes are discussed in this review.     

Synthesis of Conjugated Chitosan and its Effect on Drug Permeation from Transdermal Patches

The aim of this study was to synthesis the conjugated chitosan by covalent attachment of thiol moieties to the cationic polymer, mediated by a carbodiimide to improve permeation properties of chitosan. Thioglycolic acid was covalently attached to chitosan by the formation of amide bonds between the primary amino groups of the polymer and the carboxylic acid groups of thioglycolic acid. Hence, these polymers are called as thiomers or thiolated polymers. Conjugation of chitosan was confirmed by Fourier transform-infrared and differential scanning calorimetric analysis. Matrix type transdermal patches of carvedilol were prepared using the different proportions of chitosan and chitosan-thioglycolic acid conjugates (2:0, 1.7:0.3, 1.4:0.6, 1:1, 0.6:1.4 and 0.3:1.7) by solvent casting technique. Prepared matrix type patches were evaluated for their physicochemical characterization followed by in vitro evaluation. Selected formulations were subjected for their ex vivo studies on Wistar albino rat skin and human cadaver skin using the modified Franz diffusion cell. As the proportion of conjugated chitosan increased, the transdermal patches showed increased drug permeation. The mechanism of drug release was found to be nonFickian profiles. The present study concludes that the transdermal patches of carvedilol using conjugated chitosan with different proportions of chitosan were successfully developed to provide improved drug permeation. The transdermal patches can be a good approach to improve drug bioavailability by bypassing the extensive hepatic first-pass metabolism of the drug.     

Synthesis of 6- and 9-Ethylocatadecanoic Acids

Specific branched fatty acids are of great interest in the search of a new type of drug penetration enhancers across human skin for transdermal drug delivery and in gaining an understanding of structure-activity relationships with skin lipids. A convenient synthesis has therefore been developed especially for ethyloctadecanoic acids. The successful syntheses of 6- and 9-ethyloctadecanoic acids are reported here.     

微针经皮给药应用的新进展

微针有助于改善患者的用药依从性,提高药物的生物利用度.近年来,微针在疫苗接种、蛋白质和多肽给药、DNA给药、皮肤美容、眼科用药、局部麻醉、微量取样等领域均有应用.微针在胰岛素给药和局部麻醉中的研究已进入临床试验阶段,在皮肤美容、疫苗接种和蛋白质给药方面已有上市产品.     

Transdermal delivery of low molecular weight heparin loaded in flexible liposomes with bioavailability enhancement: comparison with ethosomes

Low molecular weight heparin (LMWH)-loaded flexible liposomes (flexosomes) were formulated for transdermal delivery, and their physicochemical and pharmacokinetic parameters were compared with LMWH-loaded ethosomes. Flexosomes had similar particle size compared with ethosomes, but their deformability was higher than that of ethosomes (76.7% vs. 46.8%). In vitro, flexosomes demonstrated 2.6-fold higher permeability coefficient than ethosomes. In comparison to LMWH aqueous solution, skin deposition of flexosome increased 3.2-fold, while that of ethosome increased only 2.0-fold. In vivo, after the topical application of flexosome to hairless mouse, [anti-Xa]_max was 1.11?IU/mL, while ethosomes showed only 0.32?IU/mL. Moreover, AUC_0–24?h of flexosomes was 2.5-fold higher than ethosomes. In conclusion, the enhanced skin permeation and bioavailability of LMWH can be achieved with flexosomes in comparison with ethosomes. The LMWH transdermal delivery via flexosomes has the potential to replace the parenteral dosage forms for the treatment of venous thromboembolism, pulmonary embolism and cardiovascular events.     

纳米药物载体在经皮给药系统中应用的研究进展

目的介绍纳米药物载体在经皮给药系统中的应用。方法查阅国内外文献共31篇,从纳米药物载体在经皮给药系统中的应用及各自的优势和不足等方面进行综述。结果纳米药物载体具有提高药物的化学稳定性、促进药物经皮吸收、控制药物释放以及定位给药等优点,在药物的经皮吸收方面具有广阔应用前景。结论纳米药物载体为药物的经皮通透提供了新的途径和方法,但是其安全性和有效性仍需进一步研究。