透皮介导肽及其经皮吸收机制研究进展

传统给药方式常因胃肠道降解作用、肝脏首过效应,以及病人顺应性差,无法持续稳定给药等而使药物、营养性食物的应用受到很大限制。透皮介导肽(TMPs)能够携带大分子"货物"进入皮肤真皮层,克服传统给药方式的弊端,展示了广阔的发展前景。目前处于研究热点的TMPs主要有TAT,ANTP,PEP-1,TD-1,SPACE,富精氨酸短肽等,透皮输送的"货物"包括亲水性关节炎药物、麻醉药、疫苗、免疫抑制剂、胰岛素、肉毒杆菌神经毒素(Bo NT-A)等,对于相关疾病表现了良好的应用价值。本文综述了透皮介导肽的透皮路径和经皮吸收机制,并展望透皮介导肽的发展前景。     

鹿筋胶原蛋白多肽透皮吸收试验研究

研究2种酶解法制备得到的鹿筋胶原蛋白多肽对体外皮肤吸收的影响。采用单酶法和双酶法制备得到2种鹿筋胶原蛋白多肽DSCP-1和DSCP-2,以离体小鼠的皮肤为透皮屏障,应用透皮吸收仪,分别于不同时间取样,测定透皮液中蛋白质的透皮率和分子量分布。结果表明,鹿筋胶原蛋白多肽经透皮试验后,透皮液中分子质量主要分布在5~26 k Da之间,约占80%以上;DSCP-1的透皮率为3.83%,DSCP-2的透皮率为6.15%。2种酶解方法制备得到的胶原蛋白多肽均可透过皮肤,双酶法制备得到的鹿筋胶原蛋白多肽更易于透过皮肤。     

不同渗透促进剂对双氯芬酸钠凝胶的透皮作用

目的 研究月桂氮革酮、薄荷油、冰片、桉油和松节油等5种渗透促进剂促双氯芬酸钠凝胶透皮的作用.方法 采用改良Franz扩散池,用离体家兔皮肤为透皮屏障,紫外分光光度法测定累积透皮量.结果 5种渗透促进剂均有促进双氯芬酸钠凝胶经皮渗透的作用,增渗倍数分别为1.20,1.98,1.82,1.97和3.63.结论 薄荷油、冰片、桉油、松节油透皮促渗作用好于月桂氮革酮,松节油的促渗作用尤为显著.     

不同渗透促进剂对双氯芬酸钠凝胶的透皮作用

目的 研究月桂氮革酮、薄荷油、冰片、桉油和松节油等5种渗透促进剂促双氯芬酸钠凝胶透皮的作用.方法 采用改良Franz扩散池,用离体家兔皮肤为透皮屏障,紫外分光光度法测定累积透皮量.结果 5种渗透促进剂均有促进双氯芬酸钠凝胶经皮渗透的作用,增渗倍数分别为1.20,1.98,1.82,1.97和3.63.结论 薄荷油、冰片、桉油、松节油透皮促渗作用好于月桂氮革酮,松节油的促渗作用尤为显著.     

神经酰胺修饰醇质体的制备与表征

为了提高醇质体的稳定性，作者采用神经酰胺Ⅲ（ceramide III，Cer3） 修饰醇质体，首先考察了Cer3质量浓度对醇质体稳定性的影响，后将视黄醇棕榈酸酯（retinyl palmitate，RP） 作为脂溶性活性物载入Cer3醇质体，研究了RP-Cer3醇质体的稳定性、稳定机制及体外释放性能。结果显示，当Cer3质量浓度为1 mg/mL时，Cer3醇质体的稳定性最好。RP-Cer3醇质体的RP质量浓度为2 mg/mL时，粒径为（68.4±1.1） nm，室温储存120 d，外观和粒径均无明显变化。X射线衍射和全反射傅里叶红外光谱表明RP被很好地包载于醇质体中，同时，红外光谱图也说明了RP与醇质体存在氢键相互作用。研究表明，Cer3的加入会降低醇质体流动性从而提高其稳定性，且RP-Cer3醇质体具有较好的体外释放性能。     

青花椒挥发油固体脂质纳米粒的制备及质量评价

制备青花椒固体脂质纳米粒,并考察其小鼠离体皮肤中的透皮吸收特征。微乳法制备SLNs,通过单因素考察,以挥发油为油相,硬脂酸聚乙二醇甘油酯(gelucire 50/13)为脂质载体,吐温80为乳化剂,丙三醇为助乳化剂,使用Box-Behnken设计-响应面法优化处方,Franz扩散池法比较青花椒挥发油与其SLNs的体外透皮吸收特征。结果表明,青花椒挥发油纳米粒最佳处方为丙三醇质量浓度3.67 g/L、药脂比6︰1、吐温80质量浓度4.67 g/L;测得SLNs平均粒径28.76±1.56 nm,多分散指数0.108±0.023,包封率92.24%±3.48%,纳米粒积累渗透量25.02μg/cm²,是原料的3.16倍。SLNs粒径小,分布均匀,包封率高,可促进药物的体外透皮吸收。     

2,4-二氯苄醇消毒性能研究

目的研究2,4-二氯苄醇的消毒性能。方法采用载体定量杀菌实验和文献调研相结合的方式,研究2,4-二氯苄醇有效杀菌浓度和安全性。结果 2,4-二氯苄醇浓度在0.2%~0.3%之间,对大肠杆菌、白色念珠菌、金黄色葡萄球菌作用1min,菌落杀灭对数值均3.00。经文献检索,大鼠经口LD50为3000 mg/kg,亚急性毒性结果为阴性;1%的2,4-二氯苄醇对皮肤无刺激。结论 2,4-二氯苄醇可用于皮肤消毒和卫生手消毒,具有良好的安全性。     

静电纺丝制备阿昔洛韦载药超细纤维垫

 采用高压静电纺丝技术制备载有阿昔洛韦的聚丙烯腈（PAN）超细纤维垫并对其进行表征。扫描电子显微镜观察结果表明,随着载药量增加,纤维直径呈增大趋势,当阿昔洛韦与PAN的质量比为20:100时,纤维中有少量药物颗粒析出;红外扫描结果表明阿昔洛韦与PAN之间具有较好相容性;体外溶出试验结果表明,载药纤维垫有明显的初期突释现象,随着载药量增加,初期突释更加明显,而药物释放度相应提高。不同载药量的纤维垫均能控制药物通过扩散机制缓慢释放60%以上的药物。静电纺丝载药纤维垫可为制备新型透皮给药系统或皮肤局部给药系统的研究开发提供新策略。     

基于CAR T免疫治疗方法用PHA包裹pomalidomide构筑医用纺织品功能后整理剂

利用中链聚羟基脂肪酸酯(mcl-PHA)的黏着性作为后整理剂基质,构筑含有pomalidomide经皮给药的后整理剂,并用其整理纺织品。通过后整理剂缓释pomalidomide及透皮吸收改善CAR T细胞治疗实体瘤的效果。使用mcl-PHA作为基质构筑经皮给药系统,检测药物透皮量;并使用CD133-CAR T细胞作为效应细胞,U251 CD133-OE luc(转入萤火虫荧光素酶基因且过表达CD133的人胶质瘤细胞)作为靶细胞,探究pomalidomide是否可以在体外调节CAR T细胞的功能。结果表明:mcl-PHA构筑的具有经皮给药功能的后整理剂具有缓释、促进药物透皮吸收功能,且药物量能达到体外实验的需求;pomalidomide可显著增强CD133-CAR T细胞杀伤肿瘤细胞的能力,并提高CD133-CAR T细胞的细胞因子分泌水平。mcl-PHA作为后整理基质构筑的含有pomalidomide药物系统的医用纺织品联合CAR T细胞治疗可能成为实体瘤治疗的一种新策略。     

柚皮多糖在不同烟叶载体上保润特性的变化

本文以柚子果皮为材料,采用热水提取结合低温醇沉制备柚皮多糖。通过扫面电镜和化学方法分析研究六种烟叶载体物理结构和化学成分的差异,并研究柚皮多糖在不同烟叶载体上保润动力学。扫面电镜表明不同载体表面光滑度不同,表皮气孔数量也不相同,上部叶B3F表皮气孔排布要比中部叶C2F致密一些,中部叶C2F表皮气孔排布又比下部叶B1F要致密一些。化学成分有机酸含量DY2含量最高为28.1%,DY3最低为16.2%。多酚含量由2.2 mg/kg增加至5.58 mg/kg,品种间有显著差异。总糖含量最高是C2F为26.37%,显著高于其它几种,烟碱含量DY1最低为2.82%,B3F最高为5.12%。保润特性表明:自身保润特性呈现一定的差异,柚皮多糖在六种烟叶载体上保润动力学呈现不同的变化趋势,对B3F载体的保润效果最佳,对B1F载体的保润效果相对较差。     

RS4型抗消化淀粉载体的靶向控制释放特性

采用In-Vitro模型及结合扫描电子显微技术,在模拟人体结肠环境中,考察了RS4型抗消化淀粉薄膜的结肠微生物降解性能。结果表明,RS4型抗消化淀粉能够被结肠中的微生物特异性降解,具有良好的结肠靶向降解性,可以控制生物活性物质的释放。同时,以牛血清白蛋白为模型生物活性物质,建立了以RS4型抗消化淀粉为载体的BSA口服结肠靶向控释系统,经体外释放特性研究,该系统能保护生物大分子牛血清白蛋白(BSA)穿过模拟人体上消化道,并在人工模拟结肠环境中具有良好的释放特性。     

Formulation effects of topical emulsions on transdermal and dermal delivery

It has been recognized that the vehicle in which a permeant is applied to the skin has a distinctive effect on the dermal and transdermal delivery of active ingredients. The cutaneous and percutaneous absorptions can be enhanced, e.g. by an increase in thermodynamic activity, supersaturation and penetration modifiers. Furthermore, dermal and transdermal delivery can be influenced by the interactions that may occur between the vehicle and the skin on the one hand, and interactions between the active ingredient and the skin on the other hand. Emulsions are widely used as cosmetic and pharmaceutical formulations because of their excellent solubilizing capacities for lipophilic and hydrophilic active ingredients and application acceptability. This review focuses, in particular, on the effect of emulsions on the dermal and transdermal delivery of active ingredients. It is shown that the type of emulsion (w/o vs. o/w emulsion), the droplet size, the emollient, the emulsifier as well as the surfactant organization (micelles, lyotropic liquid crystals) in the emulsion may affect the cutaneous and percutaneous absorption. Examples substantiate the fact that emulsion constituents such as emollients and emulsifiers should be selected carefully for optimal efficiency of the formulation. Moreover, to understand the influence of emulsion on dermal and transdermal delivery, the physicochemical properties of the formulation after application are considered.     

Biodegradable polymers as encapsulation materials for cosmetics and personal care markets

The topical and transdermal delivery of active cosmetic ingredients requires safe and non‐toxic means of reaching the target sites without causing any irritation. Preservation of the active ingredients is also essential during formulation, storage and application of the final product. As many biologically active substances are not stable and sensitive to temperature, pH, light and oxidation, they require encapsulation to protect against unwanted degradation and also to target specific and controlled release of the active substance. The use of biodegradable polymers as encapsulation materials offers several advantages over other carrier materials. Encapsulation of active ingredients using biodegradable polymeric carriers can facilitate increased efficacy and bioavailability and they are also removed from the body via normal metabolic pathways. This article reviews current research on biodegradable polymers as carrier or encapsulation materials for cosmetic and personal care applications. Some of the challenges and limitations are also discussed. Examples of biodegradable polymers reviewed include polysaccharides, poly α‐esters, polyalkylcyanoacrylates and polyamidoamine dendrimers.     

Effectiveness of transdermal, needle-free injections for reducing pork carcass defects

A needle-free, transdermal injection device was evaluated for effectiveness of vaccine delivery and for injection site lesions in swine. A total of 130 pigs were vaccinated for pseudorabies virus (PRV) and Mycoplasma hyopneumoniae (M. hyopneumoniae). Pigs were divided into three groups; one group served as unvaccinated controls, the second group was vaccinated with conventional hypodermic needles and the third group was vaccinated with a needle-free, airpowered transdermal injection device. Blood samples collected for up to 36 days post-injection showed that both injection methods produced similar serological responses that were significantly greater than for unvaccinated controls. Injection sites, collected at slaughter from each carcass, showed minimal development of lesions and no carcass defects. The results show the needle-free, transdermal injection system to be effective and safe. Elimination of needles will prevent residual needle fragments in carcasses and associated carcass defects that develop from needle-induced injection-site lesions.     

淀粉基胃漂浮控释载体的制备及其控释特性

通过在淀粉分子中引入羧甲基基团,制备了淀粉基胃漂浮控释系统载体材料。系统考察了不同羧甲基取代度对淀粉基胃漂浮控释系统载体结构和性能的影响规律。结果显示,随着取代度的提高,羧甲基淀粉的结晶程度降低,溶胀性能先增大后降低,当取代度为0.08时,其溶胀性能比原淀粉提高了10倍。在此基础上,选择维生素B1作为模型功能活性物质,羧甲基淀粉作为胃漂浮控释系统载体材料,制备了胃靶向漂浮控释系统,并考察了其对维生素B1在体外模拟胃液中的释放性能。结果表明,羧甲基淀粉胃漂浮控释系统具有良好的漂浮性能和控缓释性能。以取代度为0.08的羧甲基淀粉为载体,所制得的淀粉基胃漂浮控释系统起漂时间小于2 min,持续漂浮时间可达8 h。体外释放动力学研究显示,此羧甲基淀粉胃漂浮控释系统可使维生素B1释放时间延长至6 h,释放行为符合零级动力学。     

基于CRISPR/Cas9系统对乳酸乳球菌进行绿色荧光蛋白标记

乳酸乳球菌是治疗剂在体内运送的良好载体,研究其在体内的真实运送情况需对其进行标记。该实验利用CRISPR/Cas9系统对乳酸乳球菌(Lactococcus lactis)NZ9000进行增强型绿色荧光蛋白(enhanced green fluorescent protein, eGFP)标记,用于研究乳酸乳球菌在体内的运送,评价其作为益生菌的功能。基于该实验室已构建的乳酸乳球菌CRISPR/Cas9编辑质粒pLL25构建重组质粒pYSH,其上携带eGFP及同源臂,电转入乳酸乳球菌NZ9000感受态细胞中,将基因组中的乳酸脱氢酶基因(ldh)替换为绿色荧光蛋白基因,从而使Lactococcus lactis NZ9000获得标记,表达绿色荧光蛋白。对绿色荧光标记的Lactococcus lactis NZ9000突变株,酶标仪定量分析eGFP的表达强度。荧光强度定量分析结果表明,在乳酸乳球菌不同生长阶段,eGFP基因均能稳定表达。     

基于CRISPR/Cas9系统对乳酸乳球菌进行绿色荧光蛋白标记

乳酸乳球菌是治疗剂在体内运送的良好载体,研究其在体内的真实运送情况需对其进行标记。该实验利用CRISPR/Cas9系统对乳酸乳球菌(Lactococcus lactis)NZ9000进行增强型绿色荧光蛋白(enhanced green fluorescent protein, eGFP)标记,用于研究乳酸乳球菌在体内的运送,评价其作为益生菌的功能。基于该实验室已构建的乳酸乳球菌CRISPR/Cas9编辑质粒pLL25构建重组质粒pYSH,其上携带eGFP及同源臂,电转入乳酸乳球菌NZ9000感受态细胞中,将基因组中的乳酸脱氢酶基因(ldh)替换为绿色荧光蛋白基因,从而使Lactococcus lactis NZ9000获得标记,表达绿色荧光蛋白。对绿色荧光标记的Lactococcus lactis NZ9000突变株,酶标仪定量分析eGFP的表达强度。荧光强度定量分析结果表明,在乳酸乳球菌不同生长阶段,eGFP基因均能稳定表达。     

Novel transdermal drug delivery system with polyhydroxyalkanoate and starburst polyamidoamine dendrimer

In search of an efficient transdermal drug delivery system (TDDS), a polyhydroxyalkanoate (PHA)-based system with a polyamidoamine dendrimer was examined. Tamsulosin was used as the model drug. The dendrimer was found to act as the weak enhancer. By adding the dendrimer, the dendrimer-containing PHA matrix achieved the clinically required amount of tamsulosin permeating through the skin model. This is also the first report of the application of PHA and dendrimer to the TDDS.     

固体脂质纳米粒的研究及应用

固体脂质纳米粒(SLN)作为新型的脂质药物传输载体而备受关注。现报告本课题组的研究,结合复习文献对SLN的基因传递、蛋白多肽类药物非注射给药、难溶性药物增溶及靶向给药系统的研究和应用作一综述。     

Mechanism of enhancement effect of dendrimer on transdermal drug permeation through polyhydroxyalkanoate matrix

The possible application of polyhydroxyalkanoate (PHA) in transdermal drug delivery systems (TDDSs) for tamsulosin was previously reported. PHAs containing the drugs, ketoprofen, clonidine and tamsulosin showed good adhesiveness to the skin model used, that is, shed snake skin, and dispersed well all model drugs tested. The model drugs hardly permeated through snake skin in solution form. However, these drugs permeated well through snake skin from the PHA matrix. It was previously reported that the addition of a dendrimer, a polymeric permeation enhancer, is effective for the TDDS for tamsulosin to establish an effective clinical TDDS. The effect of dendrimer addition was examined in TDDSs for ketoprofen and clonidine. The dendrimer added did not show an enhancement effect on the TDDSs for the two drugs. To investigate the mechanism of the enhancement effect of a dendrimer on the tamsulosin TDDS, X-ray analyses were performed. With dendrimer addition, drug crystallization in PHA was promoted. The crystal in PHA had highly ordered and changed its space group. These findings are very important for exploiting high-performance PHA-based TDDSs.