醋氯芬酸醇质体的制备及体外经皮渗透考察

目的:制备醋氯芬酸(ACF)醇质体并考察其对离体大鼠的透皮能力。方法:采用乙醇注入均质法制备醋氯芬酸醇质体,利用正交试验优化处方;对其粒径、包封率、形态及大鼠离体皮肤经皮渗透量进行考察。结果:优选处方为乙醇用量45%,大豆磷脂用量3%,醋氯芬酸用量0.35%。制备的醇质体平均粒径为102 nm,包封率为48%。醋氯芬酸醇质体的24 h经皮渗透量为821.8μg.cm-2是其45%乙醇溶液的6.36倍。结论:醇质体能显著提高醋氯芬酸经皮渗透量,是经皮给药的优良载体。     

青藤碱微乳处方及其透皮性能研究

 目的：筛选青藤碱微乳最佳处方,同时考察不同体系的微乳体外透皮能力。方法：以大鼠离体皮肤渗透速率及累积渗透量为指标,采用均匀设计法确定最佳处方。结果：最佳处方为：聚山梨酯-20与乙醇为1∶2,含青藤碱2%,油酸2%,混合表面活性剂50%,水46%。结论：优选处方的青藤碱微乳透皮性能良好。     

麝香壮骨膏中不同极性药物的体外释放与透皮对比

摘要：目的:考察麝香壮骨膏中盐酸苯海拉明、水杨酸甲酯的体外释放和透皮规律。方法:采用垂直式Franz扩散池进行体外释放和透皮试验,HPLC法测定释放液和透皮接受液中盐酸苯海拉明、水杨酸甲酯含量,计算单位面积累积释放率和累积透过率。结果:麝香壮骨膏中盐酸苯海拉明、水杨酸甲酯24h单位面积累积释放率均值分别为19.75%,73.50%,释放过程均符合Higuchi模型;单位面积累积透过率分别为12.48%,45.62%,透皮过程均符合零级模型;麝香壮骨膏样品中水杨酸甲酯单位面积平均累积释放率、累积透过率显著高于盐酸苯海拉明（P＜0.05）。结论:麝香壮骨膏中,脂溶性药物较水溶性药物具有更高的体外释放和经皮渗透性能。     

自溶性微针的制备及其对盐酸青藤碱凝胶透皮性能的影响

目的：优选出自溶性微针的处方工艺,并考察所制备的微针对盐酸青藤碱凝胶透皮性能的影响。方法采用浇注法制备自溶性微针,穿刺试验考察其机械性能,并采用改良Franz扩散池考察自溶性微针预处理皮肤,对盐酸青藤碱凝胶透皮性能的影响。结果采用浇注法制备自溶性微针,其最佳处方为：基质材料硫酸软骨素和聚乙烯吡咯烷酮（PVP）按照1∶1的比例混合,加入重量比60％的水;所制得的微针针形完整、机械强度良好,能够很好的穿刺铝箔和大鼠皮肤;体外透皮实验显示,自溶性微针使得盐酸青藤碱凝胶的累积渗透量增加了3．62倍。结论优选的自溶性微针的处方与制备工艺简单、可行,可显著提高盐酸青藤碱凝胶的透皮性能,为载药微针的进一步研究提供参考依据。     

酮洛芬醇质体体外经皮渗透研究

目的:考察酮洛芬醇质体的体外经皮渗透特性。方法:乙醇注入法制备酮洛芬醇质体,采用Franz扩散池,以离体小鼠皮为皮肤屏障,对酮洛芬醇质体的体外经皮渗透量、稳态透皮速率进行研究,并测定24 h时皮肤中的滞留量。结果:酮洛芬醇质体体外24 h累积渗透量Q为(720.88±2.04)μg.cm-2,稳态透皮速率J为(28.15±0.20)μg.cm-2.h-1,24 h皮肤中的滞留量(50.86±1.44)μg.cm-2,与同剂量酮洛芬脂质体及其30%醇溶液相比,均有明显提高(P<0.05)。结论:醇质体可显著增加酮洛芬的体外经皮渗透,值得进一步研发。     

全反式维A酸醇质体的处方优化及评价

目的：制备全反式维A酸(all-trans retinoic acid,ATRA)醇质体并对其稳定性及体外经皮渗透等进行考察。方法：采用注入法制备ATRA醇质体,通过正交设计优化制备工艺;同时测定其Zeta电位及粒径;以改进的Franz扩散池法,进行体外小鼠经皮渗透实验,测定药物累积渗透量及透皮速率。结果：优选处方组成为20%乙醇（w/w）,4%磷脂（w/w）,磷脂[DK]∶胆固醇（w/w）2[DK]∶1,磷脂[DK]∶维A酸（w/w）10[DK]∶1,检测平均粒径为237.3nm,Zeta电位为-36.31mV;ATRA醇质体放置1,10,20d后,7h累积透皮量分别为（210.6±1.7）,（196.2±3.8）和（181.1±4.2）μg[DK]?cm-2,而水醇混合物累积透皮量仅为（120.4±5.4）μg[DK]?cm-2。结论：ATRA醇质体制备工艺简单可行,所得传递体粒径较小且均匀,室温放置较稳定,透皮效果较好并可以促进维A酸经皮转运。     

氨甲环酸醇质体的制备及体外评价

目的： 制备氨甲环酸醇质体（TA@ES）,并初步考察其体外透皮性能。方法：采用乙醇注入-挤出法制备TA@ES。通过单因素考察和Box-Behnken设计-响应面法对处方进行筛选及优化;按最优处方制备TA@ES,对其进行质量评价,并进行体外透皮试验。结果：优化后的TA@ES处方脂药比为3.20∶1,胆固醇用量为0.62%,乙醇用量为19.37%。制得的TA@ES为类球形,平均粒径为（194.3 ± 4.1）nm,Zeta 电位为（-32.2 ± 2.6）mV,包封率为（17.20 ± 0.89）%。体外透皮试验结果表明,与氨甲环酸水溶液相比,TA@ES不仅提高了药物经皮渗透量（4.98倍）,而且还增加了深层皮肤滞留量（1.74倍）。结论：制备的TA@ES能够提高氨甲环酸的经皮渗透量和深层皮肤滞留量,有望成为黄褐斑治疗药物的新载体。     

葛根素立方液晶的制备及在微针作用下的体外透皮特性研究

目的:制备葛根素立方液晶,研究其在微针作用下的体外透皮特性。方法:以单油酸甘油酯、乙醇、葛根素、纯化水为材料,采用注入法制备葛根素立方液晶;用偏光显微镜和小角X射线衍射进行表征。采用改进的Franz扩散池比较葛根素10%乙醇水溶液和葛根素立方液晶的体外透皮特性;考察葛根素立方液晶在微针作用下的体外透皮特性。结果:所制葛根素立方液晶在偏光显微镜下无明显晶体分布,呈暗绿色,显各向同性;其散射峰位之比为6~(1/2)∶8~(1/2),证明其内部结构为螺旋型晶格。葛根素10%乙醇水溶液和葛根素立方液晶的透皮速率分别为15.306、29.101μg/(cm~2·h),20 h内的累积透皮量分别为190、545μg/cm~2;200μm微针预处理皮肤后,葛根素立方液晶的透皮速率为78.15μg/(cm~2·h),20 h内的累积透皮量为1 450μg/cm~2。结论:成功制得葛根素立方液晶,其具有较葛根素乙醇水溶液更强的透皮能力,且联合微针给药具有更好的透皮性能。     

氢溴酸加兰他敏贴剂的制备及体外释放和透皮特性研究

目的：制备氢溴酸加兰他敏贴剂,并对其体外释放度和体外透皮特性进行考察。方法：采用丙烯酸酯乳液型压敏胶为基质制备氢溴酸加兰他敏贴剂,按《中华人民共和国药典》规定方法进行贴剂的体外释放度测定;采用改良Franz扩散池,以离体小鼠皮肤为屏障进行氢溴酸加兰他敏贴剂的体外透皮特性研究。结果：氢溴酸加兰他敏贴剂的体外释放符合Higu-chi方程,24 h累积释药量占总药量的41.81%;体外透皮符合零级方程,24 h累积渗透量占总药量的19.99%。结论：采用丙烯酸酯乳液型压敏胶为基质制备的氢溴酸加兰他敏贴剂具有较好的体外释放和透皮特性。     

延胡索乙素贴剂处方研究

目的对延胡索乙素透皮贴剂基质进行优选,确定处方组成。方法以PVA（X1）,PVP（X2）、甘油（X3）、羧甲基纤维素钠（X4）、氮酮（X5）、丙二醇（X6）为因素,用量为水平,采用U6（66）均匀设计,以累积渗透量为考察指标,优选基质。结果透皮贴剂的最优处方比为PVA-PVP-甘油-羧甲基纤维素钠-氮酮-丙二醇=14.44∶5.87∶11.53∶3.00∶4.97∶4.62。结论上述基质处方制备的透皮贴剂的渗透效果较好。     

Enhancement of skin penetration of vitamin K using monoolein-based liquid crystalline systems.

Application of vitamin K (vitK) to the skin has been used for suppression of pigmentation and resolution of bruising. However, there is no report concerning the extent of its penetration in the skin. In this study, we investigated the in vitro skin penetration and transdermal delivery of vitK, and whether these parameters may be enhanced by lipid-based drug delivery systems. The lipid formulation used in this study contains monoolein (MO), which is structured as a liquid crystalline phase, named hexagonal phase. The skin penetration of vitK was assessed in vitro using porcine ear skin mounted in a Franz diffusion cell. VitK (2.5%, w/w) was incorporated in either of three formulations: liquid vaseline, MO-based hexagonal phase gel (MO-vitK-water at 77.5/2.5/20, w/w/w) and MO-based nanodispersion of hexagonal phase (MO-vitK-poloxamer-water at 15/2.5/0.9/81.6, w/w/w/w). When vaseline was used, vitK was delivered mainly to the stratum corneum (SC): 9.50+/-0.97 microg/cm(2) of vitK was delivered to the SC at 12 h post-application, whereas 4.90 +/- 1.28 microg/cm(2) of vitK was delivered to the epidermis (E)+dermis (D) at the same time point. The hexagonal phase gel and the nanodispersion delivered approximately 2 times more vitK to the SC and 2.0-3.7 times more vitK to the [E+D] than the vaseline solution. The nanodispersion (but not the gel) also increased the transdermal delivery of vitK at 9 h ( approximately 3-fold increase). These results demonstrate that the topical delivery of vitK incorporated in a lipophilic vehicle is small, but it may be enhanced by MO-based systems, which might be useful to increase the effectiveness of topical vitK therapy.     

促渗剂对复方黄芩巴布剂透皮吸收的影响

目的:研究不同促渗剂对复方黄芩巴布剂透皮吸收的影响。方法:在离体透皮实验装置上,以生理盐水为接受液,通过高效液相色谱法测定释放液中黄芩苷的含量以确定最佳促渗剂配比。结果:几种促渗剂对复方黄芩巴布剂均有促渗作用;采用混合透皮促进剂促渗作用较强,其中以油酸∶丙二醇∶氮酮=2∶2∶1为最强。结论:采用混合促渗剂对复方黄芩巴布剂中黄芩苷的经皮渗透有较好的促进作用。     

Development and characterisation of modified poloxamer 407 thermoresponsive depot systems containing cubosomes

The purpose of this study is to develop a thermoresponsive sustained release delivery system combining phytantriol cubosomes and poloxamer 407 (P407). P407 undergoes thermoreversible gelation, where it exists as a free-flowing liquid at low temperature and gels upon heating. However, this polymer has the major draw back of fast erosion in aqueous environments which needs to be addressed. Three different concentrations of P407 (12%, 15% and 17% (w/v)) were formulated with various additives (methyl cellulose (MC), dextran, carrageenan and Pluronic-R (25R4)). The rheological characteristics and in vitro stability were investigated. The sol-gel transition temperature of P407 was lowered in the presence of the phytantriol cubosomes. The addition of MC and dextran did not affect the sol-gel transition temperature whereas 25R4 increased the gelation temperature. No transition was observed for the carrageenan formulations. The presence of 25R4 allowed the development of formulations that were free flowing liquid at working temperature (22 °C), gelled at body temperature (37 °C) and had improved stability in an aqueous environment. Both rheological and in vitro stability studies suggested that cubosome-loaded 17% (w/v) P407 with 25R4 in 1:1 molar ratio may have a potential as sustained release delivery system.     

运用裂区设计寻找塞来昔布凝胶最佳配方

目的：寻找塞来昔布（celecoxib,CLX）凝胶的最佳配方。方法：采用三裂式裂区设计,主区为羟丙基甲基纤维素、海藻酸钠及卡波姆3种基质,副处理为透皮剂月桂氮芯卓酮（氮酮）的两种水平（1.0%和2.0%）,亚副处理为透皮剂薄荷醇的两种水平（0.5%和1.0%）,重复3次实验。运用改良的Franz扩散池,选用不同配方塞来昔布制剂作促渗性试验,采用HPLC法测定和计算药物12 h累积释放量（Q）。结果：裂区分析发现区组之间并无显著差异,但各种基质之间存在显著差异;透皮剂氮酮及薄荷醇均对CLX透过皮肤起着非常重要的促进作用,氮酮、薄荷醇均与基质存在显著的协同交互作用;薄荷醇与氮酮之间,以及薄荷醇、基质和氮酮三者之间均存在显著的协同交互作用。进一步的析因设计的方差分析发现在以羟丙基甲基纤维素为基质的凝胶中,氮酮在促进CLX透过皮肤的过程中发挥主要作用;薄荷醇则对CLX透过皮肤无明显作用,但氮酮与薄荷醇合用对CLX透过皮肤表现出显著的协同增效作用。在海藻酸钠为基质的凝胶中,氮酮、薄荷醇均可显著促进CLX透过皮肤;两者合用,对CLX透过皮肤表现出显著的协同增效作用。在以卡波姆为基质的凝胶中,氮酮以及薄荷醇均无显著促进CLX透过皮肤的作用;氮酮与薄荷醇合用也无显著的协同或拮抗作用。结论：本研究结果提示,塞来昔布凝胶配方以6号（海藻酸钠+1.0%氮酮和0.5%薄荷醇）为最佳。同时也表明一种化学物质透过皮肤的量,既与其本身的性质有关,也与透皮剂的种类及性质有关,还与凝胶基质的性质有关。     

Effect of penetration enhancers on gel formulation of Zidovudine: in vivo and ex vivo studies

To overcome many challenges associated with antiretroviral drug therapy, novel drug delivery systems present an opportunity for formulation scientists to improve the management of patients with HIV/AIDS. The purpose of this study was to prepare a transdermal delivery system for zidovudine using different penetration enhancers incorporated in carbopol 971P gel and to evaluate the same for rheology, percent drug content, drug deposition, in vitro, ex vivo, and in vivo permeation across rat skin. The rheology studies indicated that 1% w/w carbopol gel had a higher linear viscoelastic region, good creep recovery, and desirable viscosity. Among all gel formulations, gel containing cineole and menthol as penetration enhancers attained a steady-state flux of 5.9 mg/cm(2)/h and 5.4 mg/cm(2)/h of zidovudine, respectively, leading to plasma concentration in the therapeutic range. The drug deposition was also found to be highest in the case of gel containing cineole and menthol as penetration enhancers. The results indicated a linear relationship between in vitro flux and in vivo bioavailability of zidovudine transdermal gel.     

Preparation of phytantriol cubosomes by solvent precursor dilution for the delivery of protein vaccines

Different delivery strategies to improve the immunogenicity of peptide/protein-based vaccines are currently under investigation. In this study, the preparation and physicochemical characterisation of cubosomes, a novel lipid-based particulate system currently being explored for vaccine delivery, was investigated. Cubosomes were prepared from a liquid precursor mixture containing phytantriol or glycerylmonooleate (GMO), F127 for particle stabilisation, and a hydrotrope (ethanol or polyethylene glycol (PEG₂₀₀) or propylene glycol (PG)). Several liquid precursors were prepared, and the effect of varying the concentrations of F127 and the hydrotrope on cubosome formation was investigated. Formulations were prepared by fragmentation for comparison. The model protein ovalbumin (Ova) was also entrapped within selected formulations. Submicron-sized particles (180-300 nm) were formed spontaneously upon dilution of the liquid precursors, circumventing the need for the preformed cubic phase used in traditional fragmentation-based methods. The nanostructure of the phytantriol dispersions was determined to be cubic phase using SAXS whilst GMO dispersions had a reverse hexagonal nanostructure coexisting with cubic phase. The greatest entrapment of Ova was within phytantriol cubosomes prepared from liquid precursors. Release of Ova from the various formulations was sustained; however, release was significantly faster and the extent of release was greater from fragmented dispersions compared to liquid precursor formulations. Taken together, these results suggest that phytantriol cubosomes can be prepared using liquid precursors and that it is a suitable alternative to GMO. Furthermore, the high entrapment and the slow release of Ova in vitro highlight the potential of phytantriol cubosomes prepared using liquid precursors as a novel vaccine delivery system.     

Quercetin in w/o microemulsion: In vitro and in vivo skin penetration and efficacy against UVB-induced skin damages evaluated in vivo.

The present study evaluated the potential of a w/o microemulsion as a topical carrier system for delivery of the antioxidant quercetin. Topical and transdermal delivery of quercetin were evaluated in vitro using porcine ear skin mounted on a Franz diffusion cell and in vivo on hairless-skin mice. Skin irritation by topical application of the microemulsion containing quercetin, and the protective effect of the formulation on UVB-induced decrease of endogenous reduced glutathione levels and increase of cutaneous proteinase secretion/activity were also investigated. The w/o microemulsion increased the penetration of quercetin into the stratum corneum and epidermis plus dermis at 3, 6, 9 and 12h post-application in vitro and in vivo at 6h post-application. No transdermal delivery of quercetin occurred. By evaluating established endpoints of skin irritation (erythema formation, epidermis thickening and infiltration of inflammatory cells), the study demonstrated that the daily application of the w/o microemulsion for up to 2 days did not cause skin irritation. W/o microemulsion containing quercetin significantly prevented the UVB irradiation-induced GSH depletion and secretion/activity of metalloproteinases.     

倍他司汀醇质体的制备与评价

目的:研究倍他司汀醇质体最佳处方工艺,并考察其体外透皮特性。方法:采用乙醇注入法制备倍他司汀醇质体,以大豆卵磷脂用量、乙醇用量和水浴温度作为考察因素,粒径、包封率为测定指标,采用星点设计-效应面法优化处方,并考察该制剂的初步稳定性;应用Franz扩散池进行体外透皮吸收试验,比较不同给药形式对倍他司汀经皮渗透的影响。结果:最佳处方工艺为倍他司汀100 mg、大豆卵磷脂311 mg、乙醇4.1 m L、水浴温度为39℃,制备的倍他司汀醇质体外观为泛有蓝光的澄清液体,包封率为(67.1±2.23)%,粒径为(59.6±4.81) nm,与预测值相差比例均<5%。倍他司汀醇质体的经皮渗透速率为10.76μg·cm^-2·h^-1,是水溶液的8.47倍、普通脂质体的3.09倍、体积分数为45%乙醇溶液的1.63倍。结论:制备的倍他司汀醇质体粒径小、分布均匀、稳定性较高,具有良好的透皮吸收特性。     

Topical delivery of cyclosporin A: an in vitro study using monoolein as a penetration enhancer.

Topical delivery of cyclosporin A (CysA) is of great interest for the treatment of autoimmune skin disorders, but it is frequently ineffective due to poor drug penetration in the skin. The present study was aimed at investigating whether the presence of monoolein (a lipidic penetration enhancer) in a preparation of propylene glycol can improve CysA delivery to the skin. CysA was incorporated in a propylene glycol preparation containing 5-70% (w/w) of monoolein. The topical (to the skin) and transdermal (across the skin) delivery of CysA were evaluated in vitro using porcine ear skin mounted in a Franz diffusion cell. CysA was quantified by UV-HPLC. At 5%, monoolein increased only the transdermal delivery of CysA. At 10%, it increased both topical and transdermal delivery. When the concentration of monoolein was further increased (20-70% w/w), an interesting phenomenon was observed: the topical delivery of CysA was still elevated but its transdermal delivery was substantially reduced. It was concluded that monoolein (in propylene glycol formulations) can promote the topical delivery of CysA, with reduced transdermal delivery.