甲氨蝶呤柔性纳米脂质体的构建及表征

采用甘草酸二钾为膜软化剂,以逆向蒸发法制备甲氨蝶呤柔性纳米脂质体.并以包封率为评价指标,采用正交设计优化处方.结果表明,优化后的甲氨蝶呤柔性纳米脂质体呈球形,平均粒径(212.7±3.9)nm,ζ电位(-19.7±0.2)mV,平均包封率(25.62±0.18)％.初步稳定性研究显示,制品在4℃放置10d,外观、平均粒径、ζ电位和包封率无显著改变.采用离体乳猪皮肤为渗透屏障,对比了甲氨蝶呤柔性纳米脂质体凝胶及其普通凝胶的透皮情况.结果表明,两种制剂的24 h累积透过量分别为(4.22±1.74)和(25.38±30.60)μg/cm2,皮肤滞留量分别为(301.30±69.87)和(138.89±49.56) μg/g.     

环孢素脂质微粒经小鼠皮肤给药的渗透机理研究

目的　研究普通纳米脂质体、柔性纳米脂质体及胆酸钠-磷脂混合胶团对环孢素经小鼠皮肤给药的渗透机理。方法　将含药载体非封闭性应用于离体或在体小鼠皮肤,测定了皮肤、接收介质和血液中环孢素含量。结果 离体条件下,应用柔性纳米脂质体和混和胶团后均能在接收液中检测到药物,但普通脂质体却不能。在体条件下,应用柔性纳米脂质体后8 h血药浓度到达峰值,而应用普通脂质体和混合胶团后在血中几乎未检测到药物。结论 柔性纳米脂质体在皮肤水合压力下发生变形,携药透过皮肤;普通脂质体主要与皮肤发生融合产生蓄积作用;混合胶团在水溶液状态下发挥其渗透促进作用。     

酮洛芬二元醇质体凝胶的研制及其质量考察

目的:研制酮洛芬二元醇质体凝胶,并对其质量进行考察.方法:采用乙醇注入法制备酮洛芬二元醇质体,采用研和法制备醇质体凝胶;透析法测定包封率;Franz扩散池进行离体皮肤渗透试验,测定其体外累积渗透量及皮内滞留量;并对其体外稳定性进行了初步考察.结果:酮洛芬二元醇质体形态圆整,平均粒径为(289.86±44.75)nm,平均包封率为(73.85±2.62)%.体外透过皮肤进入接收液中的二元醇质体(乙醇/丙二醇=7:3)累积渗透量为一元醇质体的1.8倍,24 h时二元醇脂质体和醇质体皮肤中药物滞留量分别为(52.33±3.12)μg·cm-2和(40.25±2.85)μg·cm-2.在实验期内,体外稳定性较好.结论:酮洛芬二元醇质体具更好的透皮吸收性及皮肤滞留性,且质量稳定.     

紫杉醇纳米脂质体凝胶剂的制备及体外透皮研究

目的制备紫杉醇纳米脂质体凝胶剂,考察其粒径、粒径分布、包封率、体外释放度及透皮特性。方法采用薄膜蒸发高压微射流法制备紫杉醇纳米脂质体,以卡波姆为凝胶基质,研制紫杉醇纳米脂质体凝胶剂,采用正交试验探索最佳工艺。用粒径测定仪测定脂质体的粒径及其粒径分布,低速-超速相结合法测定包封率,透析膜扩散法进行体外释放试验,以离体小鼠皮结合改良Franz扩散装置考察其体外透皮特性。结果紫杉醇纳米脂质体的最佳工艺:卵磷脂的含量为2%,药物与磷脂质量比为1∶30,磷脂与胆固醇的质量比为10∶1。测得的粒径为81.8 nm;粒径分布系数为0.180;平均包封率73.2%。纳米脂质体凝胶剂72 h累积释放百分率为79.04%;48 h的单位面积累积渗透量为429.68μg·cm?2。结论该制剂制备工艺简单,易于涂布,具有较高的包封率,粒径较小且分布均匀,体外释放缓慢。纳米脂质体能促进脂溶性药物紫杉醇透过皮肤。     

人表皮活性因子柔性纳米脂质体的制备及相关性质研究

目的 制备人表皮活性因子（EGF）柔性纳米脂质体,并对其相关性质进行研究.方法 利用逆相蒸发-冷冻干燥法制备EGF柔性纳米脂质体,采用酶联免疫吸附法（ELISA）测定EGF的含量,电镜观察其形态,并考察其包封率或载药量、变形性及稳定性.结果 所制备的EGF柔性纳米脂质体为多室脂质体.其平均粒径为（81.62±3.67） nm,Zeta电位为（60.12±7.58） mV;平均包封率为（37.86±4.77）％;平均载药量为（6.58±1.27）％.证实了EGF柔性纳米脂质体具有高度的变形性;冻干的EGF柔性纳米脂质体具有较高的稳定性.结论 EGF柔性纳米脂质体的制备方法可行,含量测定方法简单、可靠,稳定性和变形性高,可能成为透皮转运的有效载体.     

丹皮酚脂质体凝胶剂的透皮作用机制考察

目的 研究丹皮酚脂质体凝胶的体外透皮扩散作用。方法 采用Franz扩散池,以大鼠皮肤进行体外经皮渗透试验,考察丹皮酚脂质体凝胶的经皮渗透行为及皮肤内药物滞留量。结果 制得的丹皮酚脂质体凝胶包封率为78.62%,平均粒径为127 nm。体外经皮渗透试验表明,与丹皮酚凝胶相比,丹皮酚脂质体凝胶透皮速率较慢,但皮肤中药物滞留量明显增加。结论 丹皮酚脂质体凝胶制备工艺可行,其体外释放有明显缓释特征,有望成为丹皮酚应用的新剂型。     

双氯芬酸钠柔性纳米脂质体的制备及离体透皮扩散的研究

目的：制备双氯芬酸钠柔性纳米脂质体并研究柔性纳米脂质体对双氯芬酸钠离体透皮扩散速率的影响。方法：用旋转蒸发超声法制备柔性脂质体，采用改良的Franz扩散池进行体外透皮吸收试验，结果：五种处方的柔性纳米脂质体可不同程度地增加双氯芬酸钠的透皮速率，其中处方IV的透皮速率最大，为双氯芬酸钠饱和溶液的8倍，结论：柔性纳米脂质体可显地促进双氯芬酸钠的透皮吸收。     

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。     

尼美舒利醇质体的体外经皮渗透特性及皮肤刺激性

目的:考察醇质体作为尼美舒利经皮给药载体的体外渗透性及刺激性。方法:采用注入法制备尼美舒利醇质体,采用Franz扩散池和鼠皮进行体外渗透实验,HPLC测定药物浓度并计算药物稳态透皮速率、12 h累积释放量及皮内滞留量;采用小鼠皮肤红斑平均积分考察尼美舒利醇质体刺激性。结果:测得尼美舒利醇质体的稳态经皮渗透速率和12 h累积释放量分别是(16.28±1.68)μg.(cm2.h)-1,(195.38±19.89)μg/cm2,与脂质体相比提高了1.9倍(P<0.05);而醇质体的皮内滞留量为(318.67±38.57)μg/cm2,仅是脂质体的1.07倍(P>0.05)。皮肤刺激性实验显示,NIM醇质体的红斑指数与生理盐水的差异并不明显(P>0.05)。结论:尼美舒利醇质体的经皮渗透性和皮肤刺激性都优于脂质体,是一种有效的经皮给药制剂。     

姜黄素醇质体体外透皮及其稳定性研究

目的：对姜黄素醇质体体外透皮及其稳定性进行考察方法：采用透皮扩散仪进行体外透皮实验,比较姜黄素醇质体、溶液、脂质体经小鼠离体皮肤的累积渗透量及皮肤滞留量;并将姜黄素醇质体4℃条件下冷藏,考察其稳定性。结果：姜黄素醇质体12h内单位面积皮肤的累计渗透量和皮肤滞留量是其溶液（含0．5％吐温-80）的2．71倍和2．81倍;但与其脂质体无显著差异。姜黄素醇质体4℃条件下冷藏1个月,其外观、包封率、粒径及多分散指数（PDI）变化较小。结论：醇质体作为透皮给药载体能促进姜黄素的透皮吸收,并能增加皮肤中的滞留量;姜黄素醇质体具有一定的稳定性。     

Effect of penetration enhancers on the release and skin permeation of bupranolol from reservoir-type transdermal delivery systems

A reservoir-type transdermal delivery system (TDS) of bupranolol (BPL) was designed and evaluated for different formulation variables like gel reservoirs (made with anionic and nonionic polymers), rate controlling membranes and penetration enhancers on the drug release and in vitro skin permeation kinetics of the devices. Keshary-Chien type diffusion cells and pH 7.4 phosphate buffered saline (PBS) were used for drug release studies and excised rat skin was used as a barrier for permeation experiments. The release rate of BPL from nonionic polymer gel reservoirs [hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC)] was much higher than anionic polymer gel reservoirs [carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (Na CMC) and sodium alginate)]. Among different rate controlling membranes, Cotran-polyethylene microporous membrane demonstrated highest release rate for BPL than all other membranes. An optimized TDS formulation with HPC gel and Cotran-polyethylene microporous membrane was used to study the effect of penetration enhancers on the release and skin permeation rate of BPL from the TDS. Permeation rates of the devices containing 5% (w/v) pyrrolidone (PY) or 1-methyl-2-pyrrolidone (MPY) were about 3- and 1.5-fold higher than control (no enhancer, P<0.01) indicating PY to be better penetration enhancer for BPL than MPY. The permeation rates of devices containing partially methylated beta-cyclodextrin (PMbetaCD) and PMbetaCD-BPL complex were about 2.5- and 1.4-fold higher than control (P<0.01). Inclusion of 10 and 30% w/v propylene glycol (PG) in the devices increased the permeation rate by 1.4- and 1.8-fold higher than control (P<0.05). In conclusion, reservoir-type TDS of BPL was developed and penetration enhancers increased the skin permeation of BPL at 4-5 times higher levels than the desired target delivery rate.     

Use of solid phase extraction (SPE) to evaluate in vitro skin permeation of aescin

The aim of this work was to evaluate the feasibility of assessing aescin in vitro permeation through human skin by determining the amount of aescin permeated using conventional HPLC procedures after extraction of skin permeation samples by means of solid phase extraction (SPE). Aescin in vitro skin permeation was assessed from aqueous solutions and gels using both Franz-type diffusion cells and flow-through diffusion cells. The SPE method used was highly accurate (mean accuracy 99.66%), highly reproducible (intra-day and inter-day variations lower than 2.3% and 2.2%, respectively) and aescin recovery from normal saline was greater than 99%. The use of Franz-type diffusion cells did not allow us to determine aescin flux values through excised human skin, therefore aescin skin permeation parameters could be calculated only using flow-through diffusion cells. Plotting the cumulative amount of aescin permeated as a function of time, linear relationships were obtained from both aqueous solution and gel using flow-through diffusion cells. Aescin flux values through excised human skin from aqueous gel were significantly lower than those observed from aqueous solution (p < 0.05). Calculating aescin percutaneous absorption parameters we evidenced that aescin partition coefficient was lower from the aqueous gel with respect to the aqueous solution. Therefore, the SPE method used in this study was suitable to determine aescin in vitro skin permeation parameters from aqueous solutions and gels using a conventional HPLC method for the analysis of the skin permeation samples.     

Microemulsion-based gel of fluorouracil for transdermal delivery

This study is to prepare the microemulsion-based gel based on the W/O microemulsion and fluorouracil (5-Fu) as a model drug to study the transdermal characterization and observe its skin irritation of the microemulsion-based gel in vitro. IPM acted as oil phase, AOT as surfactant, Tween 85 as cosurfactant, water was added dropwise to the oil phase to prepare W/O microemulsion at room temperature using magnetic stirring, then 5-Fu powder was added. The gelatin was used as substrate to prepare 5-Fu microemulsion-based gel. The permeation flux of 5-Fu from 5-Fu microemulsion-based gel across excised mice skin was determined in vitro using Franz diffusion cell to study the influence of the amount of gelatin and the drug loading capacity. Refer to 5-Fu cream, the irritation of microemulsion and microemulsion-based gel on the rat skin was studied. Based on the water/AOT/Tween 85/IPM microemulsion, only the gelatin can form the microemulsion-based gel. At 25 degrees C, 32 degrees C and 40 degrees C, the amount of gelatin required for the formation of microemulsion-based gel were 7%, 14% and more than 17%, respectively. The 12 h transdermal cumulated permeation amount of 5-Fu from microemulsion-based gel containing 14% gelatin and 0.5% drug loading were (876.5 +/- 29.1) microg x cm(-2), 12.3 folds and 4.5 folds more than 0.5% 5-Fu aqueous solution and 2.5% (w/w) 5-Fu cream, respectively. Microemulsion-based gel exhibited some irritation, but could be subsided after drug withdrawal. Microemulsion-based gel may be a promising vehicle for transdermal delivery of 5-Fu and other hydrophilic drug.     

塞来昔布脂质体凝胶的研制及其体外经皮渗透动力学考察

目的研制塞来昔布脂质体凝胶,并对其体外经皮渗透动力学进行考察。方法采用薄膜分散法制备塞来昔布脂质体,均匀设计筛选最佳处方及制备工艺,并以卡波姆940为基质制成脂质体凝胶;用Franz扩散池研究塞来昔布脂质体凝胶与塞来昔布普通凝胶的经皮渗透规律。结果塞来昔布脂质体凝胶的平均粒径为(369.5±10.8)nm,平均包封率为(81.6±2.2)%(n=3);体外透皮试验表明塞来昔布脂质体凝胶的累积透过量显著大于普通凝胶(P<0.05),药物透皮速率与皮肤蓄积量显著大于普通凝胶(P<0.01)。结论塞来昔布脂质体凝胶制备简单,能促进药物透皮吸收,值得进一步研究。     

博莱霉素脂质体凝胶的制备和体外透皮性比较

目的：研制博莱霉素（BLM）脂质体凝胶,并对其皮肤靶向性进行体外评价。方法：采用逆相蒸发-冻融法制备BLM脂质体,再用卡渡姆940为基质制成BLM脂质体凝胶;以离心法测定BLM脂质体的包封率;以体外透皮渗透释药法,比较BLM脂质体凝胶与BLM普通凝胶的透过作用。结果：BLM脂质体平均粒径为（885．20±12．08）nm,平均包封率为（66．80±1．38）％。在24h内,BLM脂质体凝胶累积透过量（Q）及稳态透皮速率（J）与BLM普通脂质体相比,均明显提高,而在皮肤中的滞留药量也显著提高（P〈0．05）。结论：BLM脂质体凝胶在体外可显著增加BLM的透皮吸收,增加皮肤中的滞留量,值得进一步研究。     

氧化苦参碱凝胶体外经皮渗透及大鼠药动学研究

目的 研究氧化苦参碱凝胶的体外经皮渗透影响因素,并对其在大鼠体内的药动学进行研究。方法 采用Valia-Chien 双室扩散池,以大鼠离体皮肤为渗透屏障,HPLC测定氧化苦参碱浓度,以药物累积渗透量为指标,对药物及渗透促进剂的浓度进行筛选。结果 氧化苦参碱经皮凝胶的最优处方12 h累积渗透量为(18.094±1.253)mg·cm^-2,大鼠静注与经皮给药的血浆药动学研究表明,经皮给药的AUC_(0-t)是注射给药的1.9倍(P<0.01)。结论 氧化苦参碱凝胶的经皮吸收能力良好,能长时间持续释放药物,有望成为新的给药剂型。     

超声波促进盐酸利多卡因经皮渗透的研究

目的 研究低频超声波对盐酸利多卡因凝胶经皮渗透的促进作用。方法 制备2.5%盐酸利多卡因凝胶;应用单室扩散池和乳猪皮肤,测定盐酸利多卡因凝胶在20 kHz超声波作用下,利多卡因的经皮渗透性能,并以复方利多卡因乳膏作为对照品,用HPLC测定接受液中的盐酸利多卡因浓度;考察超声强度和作用持续时间等因素的影响。结果 超声波能明显促进盐酸利多卡因的经皮渗透,且随着超声强度的增加和超声作用持续时间的延长,促渗效果明显增强;功率为2.26 W·cm-2,持续时间5 min的超声波处理皮肤,盐酸利多卡因凝胶的2 h累积经皮渗透量是被动扩散的9.3倍,是复方利多卡因乳膏的2.4倍。结论 超声波能显著促进盐酸利多卡因凝胶的经皮渗透,2 h内的体外透皮速率大于复方利多卡因乳膏,可发展成为血管穿刺止痛的新给药方法。     

Analysis of skin disposition and metabolism of ethyl nicotinate after topical application using dual agar gel disc-inserted rats

The skin disposition and metabolism of topically applied ethyl nicotinate (EN) were evaluated in dual agar gel disc-inserted hairless rats, which have two agar gel discs subcutaneously inserted into the abdominal region as drug receptors, and a topical formulation containing EN placed on either side of the gel disc through the skin. Plasma and agar levels of EN and its metabolite, nicotinic acid (NA), were followed every 2 h over 6 h. EN permeated through the skin barrier and partly metabolized to NA with 89.4% of the metabolite ratio [NA/(EN+NA)] at 6 h. Some EN and NA in the skin moved to the systemic circulation, and the remainder migrated into the agar gel below the formulation. The total amount (EN+NA) in the skin that distributed from the formulation directly to the systemic circulation and the application side of the gel corresponded to 95.2% and 4.8% of the total skin permeation at 6 h, respectively. Only NA was distributed from the systemic circulation to both agar gel discs. The NA fraction in the application side of the gel from the circulation was only 1% of the total amount in the agar gel. The metabolite ratio on the application side of the agar gel was higher than that in the receiver for the in vitro skin permeation using excised hairless rat skin. This difference was probably related to a lower EN ratio in viable skin in situ than in vitro. These results suggest that the present in situ method is useful to evaluate the skin disposition and metabolism of topically applied drugs.     

Topical vehicles based on natural surfactant/fatty alcohols mixed emulsifier: The influence of two polyols on the colloidal structure and in vitro/in vivo skin performance

There is a growing need for in-depth research into new skin- and environment-friendly surfactants, such as alkylpolyglucosides. The aim of this study was to assess whether, to which extent and by what mechanism the two commonly used hydrophilic excipients, propylene glycol (PG) and glycerol (GL), affect the colloidal structure of emulsions formed by a natural mixed emulsifier, cetearyl glucoside and cetearyl alcohol. Furthermore, the study was concerned with the effect of these changes on in vitro permeation profiles of two model drugs (diclofenac sodium and caffeine) and in vivo skin performance of the test samples. The results have shown that the emulsion vehicles consisted of a complex colloidal structure of lamellar liquid crystalline and lamellar gel crystalline type. PG addition produced a stronger hydrophilic lamellar gel phase than GL, which was independent on the model drug used. PG-containing vehicles have revealed a considerable amount of interlamellar PG/water mixture, with incorporated drug. In vitro permeation data obtained using artificial skin constructs (ASC) confirmed the relationship between rheological profiles of vehicles and the extent of skin delivery. Higher permeation profiles of both drugs from PG-containing formulations coincided with a higher increase in transepidermal water loss observed in in vivo study on human volunteers, which confirms the penetration/permeation enhancer effect of PG. It also indicates the existence of the vehicle/ASC interactions analogous to those between the vehicle and the skin, thus affirming the use of ASC as a reliable tool for permeation studies. Contrary to the effect of PG, the results obtained with GL suggest that it may have a permeation-retarding rather than a permeation-enhancing effect in topical vehicles of this type.     

固体脂质纳米粒作为水杨酸经皮给药载体的研究

目的 考察固体脂质纳米粒作为经皮给药载体对水杨酸经皮吸收的促渗透作用.方法 采用薄膜超声法制备水杨酸固体脂质纳米粒,以改良的Franz扩散池考察其体外透皮特性;并与水杨酸软膏剂比较,考察其促渗作用.结果 制备的水杨酸固体脂质纳米粒均匀圆整,包封率为46.4%,体外透皮特性优于普通软膏剂,24 h后皮肤药物累积透过量为654.3 μg/cm2,皮肤中药物残留量为22.99 μg,均分别显署高于软膏剂组(128.0 μg/cm2和0.84 μg,P<0.05).结论 固体脂质纳米粒作为水杨酸经皮给药载体,可有效促进药物透皮吸收和增加药物在皮肤中储留量,而且可延缓药物的释放,从而有效提高药物疗效及患者依从性.