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。     

丹皮酚凝胶剂体外经皮渗透性研究

目的研究丹皮酚凝胶剂中丹皮酚的经皮渗透性。方法把小鼠离体皮肤夹在Fran′s扩散池供给室和接收池间做经皮渗透试验。结果丹皮酚从凝胶中扩散出,并穿过皮肤渗透到接收池中,24 h透过率约为46.73%。结论丹皮酚凝胶剂中的丹皮酚具有良好的渗透性。因丹皮酚具有杀菌、抗炎等功效,可将其制备成凝胶剂用于皮肤疾病的治疗,故有进一步研究和推广的价值。     

不同基质及促渗剂对姜黄素脂质体凝胶经皮渗透的影响

考察了凝胶基质种类及浓度和促渗剂对姜黄素脂质体凝胶经小鼠离体皮肤的累积渗透量及皮肤滞留量的影响.所得优化处方为:以1％卡波姆为凝胶基质,加入2％月桂氮草酮和2％薄荷醇为复合促渗剂.所得制品的24h累积渗透量、稳态渗透速率及皮肤滞留量均显著高于姜黄素脂质体.     

丹皮酚自微乳处方设计研究

目的 研究丹皮酚自微乳的处方设计.方法 采用测定溶解度,绘制伪三元相图和星点设计法筛选及优化处方.结果 以油酸乙酯(EO)为油相、聚氧乙烯辛基苯基醚(OP-10)为乳化剂、二乙二醇单乙基醚(HP)为助乳化剂,比例为24.47％∶50.35％∶25.18％时能形成稳定的丹皮酚自微乳.结论 丹皮酚自微乳处方设计方法简单,结果可靠,性质稳定.     

基于微乳凝胶新载体的丹皮酚经皮给药系统的构建及药代动力学研究

为构建基于微乳凝胶 (microemulsion-based gels, MBGs) 新载体的丹皮酚经皮给药系统, 采用皮肤、血液双位点同步微透析结合LC/MS联用技术测定丹皮酚微乳、微乳凝胶及市售丹皮酚软膏在大鼠皮肤、血液中的药物浓度随时间的变化过程, 并对其药代动力学参数进行比较分析。方法学研究表明, 丹皮酚线性探针体内回收率 (R_{in vivo}) 为 (69.7 ± 4.8) %, 同心圆探针体内回收率为 (51.6 ± 7.2) %。大鼠腹部脱毛, 分别给予丹皮酚微乳 (1% 丹皮酚)、微乳凝胶和市售丹皮酚软膏, 以PBS (pH 7.4) 溶液作为灌流液, 灌流速度为5 μL·mL⁻¹, 每隔20 min收集1次微透析样品, 共收集12 h, 透析液采用LC/MS进行测定。皮肤药动学结果表明丹皮酚微乳、微乳凝胶与市售软膏相比, 显著提高了药物在皮肤组织中的浓度; 血液药动学结果表明微乳凝胶与市售软膏具有相近的生物利用度, 但前者的血药浓度更平稳。本研究所构建的丹皮酚微乳凝胶有望为皮肤湿疹的治疗提供一种新的制剂; 所建立的微透析/LC-MS联用技术能够在体、同步、实时监测大鼠皮肤、血液中的药物浓度, 为经皮给药药代动力学研究提供了新的方法。     

电化学法研究几种丹皮酚凝胶剂的体外经皮渗透率

目的 采用电化学分析法对丹皮酚水凝胶、丹皮酚复乳凝胶、丹皮酚脂质体凝胶、丹皮酚β-糊精(β-CD)包合物凝胶中丹皮酚的体外经皮渗透率进行研究.方法 将离体小鼠皮肤夹在Fran's扩散池的供给室和接收池之间,注入一定量不同丹皮酚凝胶剂于供给室,测定其经皮渗透率.结果 用电化学法测得的上述4种不同丹皮酚凝胶24 h经皮渗透率分别为48.68%、14.01%、34.44%和10.43%.结论 采用电化学法检测丹皮酚经皮渗透率具有快速、方便、灵敏的优点.丹皮酚水凝胶剂具有良好的经皮渗透性.     

自乳化基质乙氧苯柳胺乳膏的研制及透皮研究

目的：制备自乳化基质乙氧苯柳胺乳膏并对其体外透皮吸收行为进行考察。方法：采用Tefose63为自乳化基质制备乙氧苯柳胺乳膏并考察其稳定性，采用改进的Franz扩散池，以大鼠离体腹部皮肤为透皮模型，用HPLC法测定药物在透皮接收液中的浓度及皮肤中药物滞留量。结果：自乳化基质乳膏具有较好的稳定性，在皮肤中的渗透系数及药物滞留量明显大干市售软膏，离体条件下，自乳化基质乳膏8h渗透系数是市售软膏的1．56倍，皮肤中药物滞留量是市售软膏的2．31倍。结论：自乳化基质乙氧苯柳胺乳膏能促进药物渗透到皮肤并增加药物在皮肤中的滞留量，有望成为新型经皮给药制剂。     

丹皮酚传递体的制备及其稳定性研究

目的制备丹皮酚传递体并进行质量评价。方法采用薄膜分散-超声法制备丹皮酚传递体,以粒径为考察指标,通过单因素考察和正交试验设计优选最佳处方和工艺;考察其多分散度、Zeta电位、包封率,并对传递体稳定性进行研究。结果丹皮酚传递体分散于0．9％氯化钠注射用水中,室温放置20d稳定,粒径变化较小。最佳配方为磷脂／胆固醇3：1,磷脂／吐温-802：1,磷脂／丹皮酚10：1;水合温度为37℃,平均粒径为89．34nm。结论丹皮酚传递体制备工艺简单可行,所得传递体粒径较小且均匀。     

盐酸特比萘芬醇类脂泡囊凝胶离体和在体透皮特点研究

目的:研究盐酸特比萘芬醇类脂泡囊凝胶在体和离体透皮特点。方法:采用Franz扩散池进行体外透皮实验,考察盐酸特比萘芬醇类脂泡囊凝胶、脂质体凝胶和普通凝胶经皮渗透性和皮肤滞留量;以小鼠为实验动物,3种凝胶腹部经皮给药,考察盐酸特比萘芬的血药浓度和皮肤滞留量,对比不同类型凝胶剂的透皮效果。结果:离体透皮扩散实验中,透皮速率排序为:脂质体凝胶>醇类脂泡囊凝胶>普通凝胶;皮肤内24 h累积滞留量排序为:醇类脂泡囊凝胶>脂质体凝胶>普通凝胶。在体透皮吸收实验中,皮肤内6 h累积滞留量排序为:醇类脂泡囊凝胶>脂质体凝胶>普通凝胶。3种凝胶中的盐酸特比萘芬在皮肤深层中的滞留量均远远大于角质层,醇类脂泡囊凝胶中药物在皮肤深层的滞留量远大于另外两种凝胶,而脂质体凝胶和普通凝胶在皮肤深层的滞留量无明显差异。结论:醇类脂泡囊对盐酸特比萘芬透皮吸收具有一定的促进作用,同时也能显著提高盐酸特比萘芬在皮肤内特别是皮肤深层中的滞留量,为治疗深部皮肤真菌感染提供了一种新方法。     

双氯芬酸钠巴布剂的制备及体外透皮研究

目的：制备双氯芬酸钠（DCS）的巴布剂,并对其体外释药特性进行考察。方法：制备1％的DCS巴布剂及凝胶剂,考察两者对小鼠离体皮肤的渗透性。结果：与同剂量DCS凝胶相比,DCS巴布剂的离体皮肤累积渗透量及渗透速率均有显著提高（P〈0．05）。结论：DCS巴布剂体外渗透性能优于其凝胶剂,值得进一步研制,以期为DCS新型外用制剂的研制奠定基础。     

Development of a topical ointment of betamethasone dipropionate loaded nanostructured lipid carrier

The purpose of this study was to design an innovative topical ointment containing betamethasone dipropionate loaded nanostructured lipid carrier (BD-NLC) for the treatment of atopic dermatitis (AD). BD-loaded NLC was produced with precirol ATO 5 and oleic oil (OA) by melt emulsification method. Effects of surfactant concentration, amount of solid lipid and liquid lipid on skin retention and skin penetration were investigated by in vitro percutaneous permeation experiment. The optimized BD-NLC showed a homogeneous particle size of 169.1 nm (with PI = 0.195), negatively charged surface (−23.4 mV) and high encapsulation efficiency (85%). Particle morphology assessed by TEM revealed a spherical shape. In vitro skin permeation study was carried out to investigate the percutaneous behaviors of W/O ointment with BD-NLC and Carbopol emulgel ointment with BD-NLC. W/O ointment with BD-NLC showed high skin retention (35.43 µg/g) and low penetration (0.87 µg/ml). In vitro drug release studies were carried out to demonstrate the drug releasing properties of the two ointments. W/O ointment with BD-NLC showed an advantage for skin retention as it was better for drug release. The tissue distribution test suggested that BD distribution was skin > muscle > blood. Self-made topical ointment in mice showed no skin irritation. The animal experiments indicated that BD-loaded NLC ointment was effective and safe for topical use.     

Influence of solid lipid microparticle carriers on skin penetration of the sunscreen agent, 4-methylbenzylidene camphor

The objective of this study was to prepare lipid microparticles (LMs) loaded with the sunscreen agent, 4-methylbenzylidene camphor (4-MBC), to achieve decreased skin penetration of this UV filter. The microparticles were produced by the melt dispersion technique using tristearin as lipidic material and hydrogenated phosphatidylcholine as the surfactant. The obtained microparticles were characterized by scanning electron microscopy and differential scanning calorimetry. Release of 4-MBC from the LMs was found to be slower than its dissolution rate. The influence of the LMs' carrier system on percutaneous penetration was evaluated after their introduction in a model topical formulation (emulsion). In-vitro measurements were performed with cellulose acetate membranes in Franz diffusion cells. The 4-MBC release and diffusion was decreased by 66.7-77.3% with the LM formulation, indicating that the retention capacity of the microparticles was maintained after incorporation into the emulsion. In-vivo human skin penetration of 4-MBC was investigated by tape stripping, a technique for selectively removing the upper cutaneous layers. The amount of sunscreen penetrating into the stratum corneum was greater for the emulsion containing non-encapsulated 4-MBC (36.55% of the applied dose) compared with the formulation with the sunscreen-loaded microparticles (24.57% of the applied dose). The differences between the two formulations were statistically significant in the first (2-4) horny layer strips. Moreover, the LMs' effect measured in-vivo was less pronounced than in-vitro. The increased 4-MBC retention on the skin surface achieved by its incorporation in the LMs should enhance its efficacy and reduce the potential toxicological risk associated with skin penetration.     

Effect of vehicles and penetration enhancers on the in vitro percutaneous absorption of celecoxib through human skin

The aim of this study was the comparison of three different formulations (gel, o/w emulsion, oleagenous cream) and two penetration enhancers (oleic acid and menthol) as vehicle systems for celecoxib in respect of release and penetration through excised human skin in vitro. The influence of the vehicle on the release rate was studied in vitro using a cellulose acetate membrane. The release rate could be increased by up to 6.5 and 2.5 times with gel and o/w emulsion compared to oleagenous cream respectively. Further in vitro penetration measurements using human skin on Franz diffusion cells were performed with and without oleic acid and menthol as enhancers. It was shown that the penetration rate is strongly dependent upon the enhancer type and concentration but not on the vehicle itself and could be increased by 48% when 5% oleic acid was used in oleagenous cream. In all formulations tested, celecoxib was released and penetrated into human skin more quickly and to a greater extent from the gel formulations. There is no topical formulation available of celecoxib and its penetration properties through human skin have not been investigated. Since celecoxib creates some gastrointestinal disturbances, topical formulations of celecoxib preferably in gel form including 5% oleic acid could be suggested as an alternative.     

微乳法制备丹皮酚纳米结构脂质载体

目的以丹皮酚为模型药物,微乳法制备纳米结构脂质载体（NLC）。方法采用伪三元相图法对构建纳米脂质载体的初乳液进行筛选,经体外透皮试验确定处方。结果硬脂酸为固态脂质（占初乳处方的1％）,油酸乙酯为液态脂质（占初乳处方的1％）,LabrasoL为乳化剂,TranscutoLP为助乳化剂,Km：2：1,含水量50％,采用注射器滴入法分散于0℃冷水中,可以快速制得载药量10％的丹皮酚纳米脂质载体。结论微乳法制备的丹皮酚纳米脂质载体制备．f-艺简单、操作方便,不需使用有机溶剂（如二氯甲烷、氯仿等）和复杂设备,适合纳米结构脂质载体的研究和小规模制备。     

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.     

辣椒碱纳米乳的制备及大鼠透皮实验研究

目的:制备辣椒碱纳米乳并评价其透皮作用。方法:以具有两亲性的苯甲醇作油相,分别以乙醇、1,2-丙二醇和正丁醇作助表面活性剂,以三元相图确定微乳区域,以辣椒碱透皮速率为指标,用单纯形法优化处方。比较优化处方所得辣椒碱纳米乳与其乳膏和水凝胶制剂经大鼠皮肤的稳态透皮速率(Js)。结果:以乙醇和1,2-丙二醇作助表面活性剂的纳米区域面积相当,均大于正丁醇的纳米乳面积。单纯形法可较准确地优化处方,优选处方辣椒碱纳米乳及乳膏和水凝胶的Js分别为17.54、2.78、7.35μg·cm-2·h-1(P<0.01)。结论:所制备的辣椒碱纳米乳具有良好透皮作用。     

Study of tolnaftate release from fatty acids containing ointment and penetration into human skin ex vivo

Five fatty acids (oleic, linoleic, myristic, lauric and capric) were incorporated in 10% (w/w) into ointment formulation and their influence on lipophilic model drug tolnaftate release in vitro and enhancing effect on tolnaftate penetration into epidermis and dermis of human skin ex vivo were investigated. The prepared ointments were tested for homogeneity, pH and theological properties. In vitro release studies and ex vivo skin penetration experiments were carried out using Hanson and Bronaugh-type flow-through diffusion cells, respectively. Tolnaftate cumulative amount liberated from semisolids was assayed using UV-Vis spectrophotometer. After in vitro skin penetration studies, appropriately extracted human skin layers were analyzed for tolnaftate content using a validated HPLC method. Statistical analysis revealed that release rate of tolnaftate from control ointment and ointments with fatty acids was not significantly different and only 7.34-8.98% of drug was liberated into an acceptor medium after 6 h. Tolnaftate amount penetrating into 1 cm2 of epidermis from ointments containing oleic, linoleic, myristic and lauric acids was significantly greater (p < 0.05) than from the control ointment. Penetration enhancing ratios for these fatty acids for tolnaftate penetration into epidermis ranged from 1.48 to 1.75. In conclusion, fatty acids did not increase the liberation of tolnaftate from ointment formulation, but demonstrated their enhancing effect on tolnaftate penetration into human epidermis in vitro. Results from in vitro release experiments do not suit for prediction of the situation in the skin in vitro, if chemical penetration enhancers are incorporated into the ointment formulation.     

Polymeric microparticles-based formulation for the eradication of cutaneous candidiasis: development and characterization

Abstract

Cutaneous candidiasis is a common topical fungal infection which may be more prominent in patients associated with AIDS. It is usually treated by conventional formulations such as cream, gel, which show various adverse effects on skin along with systemic absorption. To overcome these drawbacks, various novel drug delivery systems have been explored. Poly(lactic-co-glycolic acid) (PLGA)-based microparticulate systems have shown good dermal penetration after topical application. Therefore, in the present study clotrimazole-loaded PLGA microspheres were prepared for targeted dermal delivery. Microspheres were prepared by using a single emulsification (oil-in-water, O/W) evaporation technique and characterized for different parameters. Prepared microparticulate systems were dispersed in Carbopol 934® gel and antifungal activity was carried out on experimentally induced cutaneous candidiasis in immunosuppressed guinea pigs. Particle size of optimized formulation was 2.9?µm along with 74.85% entrapment of drug. Skin retention studies revealed that drug accumulation in the skin was higher with microspheres gel as compared to marketed gel. Confocal microscopy of skin further confirmed penetration of microspheres up to 50?µm into the dermal region. In-vivo antifungal activity studies demonstrated that microsphere gel showed better therapeutic activity, lowest number of cfu/ml was recorded, as compared to marketed gel after 96?h of application. Based on the results of the study, it can be concluded that PLGA microparticles may be promising carriers to deliver clotrimazole intradermally for the treatment of invasive fungal infections.     

Transdermal Permeation and Skin Retention of Diclofenac and Etofenamate/Flufenamic Acid From Over-the-Counter Pain Relief Products

Topical pain relief products differ in the type of drug, concentration, and formulation. All these factors influence the drug transit through the skin barrier, and its eventual retention in the skin as a reservoir for subsequent release. In addition, the drug potency can be different, which is important for the product efficacy. We studied here ex vivo human skin permeation and retention of five over-the-counter NSAID gels containing 2.32% diclofenac (DIC) and 5–10% etofenamate (ETF). The potency of the permeated/retained drug amounts were compared using a composite parameter, the Index of Relative Topical Anti-inflammatory Activity (IRTAA), which is calculated as the product of the skin permeation/retention and the drug relative potency. The IRTAAs of the DIC gel were 94–667-fold higher and 72–208-fold higher for transdermal delivery and skin retention, respectively, than IRTAAs of the ETF gels. These superior IRTAAs indicate that DIC delivered by this topical formulation would achieve a higher bioactivity and would form a potent drug reservoir relevant for its subsequent long-lasting release.     

Effect of natural penetration enhancers on dermal delivery of hydrocortisone acetate

The purpose of the research work was to develop microemulsion (ME) of hydrocortisone acetate (HCA) using natural penetration enhancers and to determine its possibility in effective dermal delivery. Eucalyptus oil, clove oil and lemon grass oil were selected as natural penetration enhancers and pseudo-ternary phase diagrams were plotted using Tween 80 as surfactant and ethanol as cosurfactant. ME of each penetration enhancer was optimized using three factors, three levels Box–Behnken design, with independent variables as penetration enhancer, Tween 80 and ethanol. Formulations were assessed for percentage drug release as dependent variable. Response of these formulations decreased as the concentration of oil ranged from high to low and the response showed positive effect with increase in concentration of Tween 80 and ethanol. The globule size of optimized batches of eucalyptus oil, clove oil and lemon grass oil were found to be 226.1, 129.04 and 818.9 nm respectively. Optimized batches of MEs were then incorporated in carbopol 940 to form ME based gel without affecting their structure. Ex vivo permeation studies showed that amount of drug permeated from ME based gels was less than ME formulation indicating greater retention of HCA into skin layers. Retention of drug in skin layers both dermis and epidermis was higher for all three natural penetration enhancer. Hence natural penetration enhancers can be used for effective delivery of topical corticosteroids to the skin for improved treatment of several skin diseases and can be a better choice over synthetic penetration enhancers in terms of safety.