吲哚美辛柔性纳米脂质体与普通纳米脂质体体外透皮速率的比较

背景:吲哚美辛口服副作用大,将其制成软膏局部应用,透皮扩散速率较慢,影响吸收.柔性纳米脂质体是一种新型的经皮给药载体,对药物的皮肤渗透有显著的促进作用.目的:制备吲哚美辛柔性纳米脂质体并舰察柔性纳米脂质体对吲哚美辛离体透皮扩散速率的影响.设计、时间及地点:体外对照观察,于2008-07/2009-01在中南大学卫生部纳米生物技术重点实验室完成.材料:用薄膜超声法制备吲哚美辛纳米柔性脂质体.方法:采用小鼠体外皮肤的Franz扩散池作为渗透屏障进行体外透皮吸收实验,对比柔性纳米脂质体和普通脂质体的药物渗透速率.主要观察指标:粒径、回收率、包封率、药物累积渗透速率.结果:纳米脂质体作为载体粒径小,包封率高,具有可变形性,能顺利携带药物透过皮肤,提高吲哚美辛的透皮速率;与普通纳米脂质体相比,柔性纳米脂质体透皮速率更高.结论:柔性纳米脂质体可显著地促进吲哚美辛的透皮吸收.     

低相对分子质量透明质酸脂质体的制备及透皮性能

背景:透明质酸是一种用途广泛的高分子材料,在实际应用中,由于其相对分子质量较大,透皮吸收效果不理想,利用脂质体作为其载体可以改善其传输效果,具有较好的应用前景。目的:观察包裹低相对分子质量透明质酸脂质体的透皮性能。方法:采用薄膜法制备低相对分子质量透明质酸脂质体,设计正交实验,采用蛇蜕研究其透皮吸收性能。结果与结论:温度35℃、胆固醇与卵磷脂的比例为0.15∶1,透明质酸与卵磷脂的比例为0.03∶1、水合介质PBS的pH值为7.5,可制备包封率较高的低相对分子质量透明质酸脂质体;脂质体包裹低相对分子质量透明质酸,能有效得提高透明质酸透过蛇蜕的能力,达到了提高透明质酸透皮吸收率的作用。     

低相对分子质量透明质酸脂质体的制备及透皮性能

背景：透明质酸是一种用途广泛的高分子材料,在实际应用中,由于其相对分子质量较大,透皮吸收效果不理想,利用脂质体作为其载体可以改善其传输效果,具有较好的应用前景。目的：观察包裹低相对分子质量透明质酸脂质体的透皮性能。方法：采用薄膜法制备低相对分子质量透明质酸脂质体,设计正交实验,采用蛇蜕研究其透皮吸收性能。结果与结论：温度35℃、胆固醇与卵磷脂的比例为0.15∶1,透明质酸与卵磷脂的比例为0.03∶1、水合介质PBS的pH值为7.5,可制备包封率较高的低相对分子质量透明质酸脂质体;脂质体包裹低相对分子质量透明质酸,能有效得提高透明质酸透过蛇蜕的能力,达到了提高透明质酸透皮吸收率的作用。     

苦参碱醇质体的制备及其体外透皮性能

背景:醇质体是一种新型脂质体,具有高变形性、高包封率的优点,能完整地透过皮肤,尤其适合作为外用给药和透皮给药载体.目的:采用卵磷脂和乙醇制备苦参碱醇质体,观察其在体外大鼠皮肤的透皮性能.设计、时间及地点:对比观察实验,于2007-08/2008-03在中南大学卫生部肝胆肠外科研究中心实验室完成.材料:苦参碱原料药由西安华鹏天然植物开发有限公司生产.大豆卵磷脂由美国Avanti Polar Lipids Inc.生产.方法:苦参碱醇质体由10～30 g/L卵磷脂、体积分数为30%～45%的乙醇、10 g/L苦参碱和水组成,采用乙醇注入超声法制备.采用Franz扩散池检测体外透皮效果,供给池给药后,从接收池取样采用高效液相法检测药物透皮量.主要观察指标:苦参碱醇质体的粒径、包封率及苦参碱在体外大鼠皮肤的透皮量.结果:醇质体的粒径随乙醇体积分数增加而下降,随磷脂质量浓度增加而增加.与其他剂型相比,苦参碱醇质体的24 h透皮累积量(60.5%)最大,而没有透皮延迟时间.结论:成功制备了苦参碱醇质体,其在体外实验中能增加苦参碱的经皮渗透性.     

二黄凝胶贴膏与软膏的体外释放及透皮性能比较

目的比较二黄凝胶贴膏与软膏的体外释放及透皮性能。方法采用Strat-M膜及改进的Franz扩散池进行体外释放及透皮试验,用高效液相色谱法定量分析制剂中君药独活的有效成分蛇床子素含量,测定两种剂型的体外释放度、透皮量及透皮率。结果二黄凝胶贴膏的透皮方程为Ln=0.443 6t+1.350 9,r=0.964 4,体外累积释放度、透皮量、透皮率分别为62.90%、0.067 2 mg/g、20.82%;二黄软膏的透皮方程为Ln=0.205 1t-0.244 7,r=0.995 6,体外累积释放度、透皮量、透皮率分别为77.64%、0.013 1 mg/g、9.36%。结论二黄凝胶贴膏的透皮量、透皮率均优于二黄软膏,透皮性能明显优于原剂型,且凝胶贴膏不易过敏,贴敷方便。     

透皮吸收促进剂对冰黄凝胶治疗作用的影响

目的比较氮酮、丙二醇、樟脑、十二烷基硫酸钠对冰黄凝胶透皮作用的影响,为选择该制剂的透皮吸收促进剂提供依据。方法用RYJ-6A型药物透皮扩散试验仪,通过测定不同时间点的吸光度A值来考察各促进剂对冰黄凝胶透皮作用的影响,并根据考察结果选择最理想的促进剂进行药效学实验。结果4种促进剂增加冰黄凝胶透皮吸收速率顺序为:氮酮>樟脑>丙二醇>十二烷基硫酸钠>不加促进剂的原药物。结论选择氮酮作为冰黄凝胶的促进剂是比较合理的。     

不同浓度氮酮对双氯灭痛凝胶剂的透皮扩散影响

目的：为双氯灭痛凝胶剂筛选一定浓度的氮酮（Azone)作为渗透促进剂。方法：本实验采用改良Franz扩散装置及离体鼠皮为屏障．以生理盐水为接受介质，研究了不同浓度的氯酮(0％，1％．2％．3％，5％Azone)对双氯灭痛凝胶剂透皮吸收的影响。结果：双氯灭痛凝胶剂12小时累积透皮释药百分率依次分别为38.42％、62.35％、72.80％、32．10％、55.36％。结论．筛选了含氯酮2％作为促进剂，制备了有良好的经皮吸收性能的凝胶剂。     

不同浓度氮酮对双氯灭痛凝胶剂的透皮扩散影响

目的：为双氯灭痛凝胶剂筛选一定浓度的氮酮（Ａｚｏｎｅ）作为渗透促进剂。方法：本实验采用改良Ｆｒａｎｚ扩散装置及离体鼠皮为屏障，以生理盐水为接受介质，研究了不同浓度的氮酮（０％，１％，２％，３％，５％Ａｚｏｎｅ）对双氯灭痛凝胶剂透皮吸收的影响。结果：双氯灭痛凝胶剂１２小时累积透皮释药百分率依次分别为３８．４２％、６２．３５％、７２．８０％、３２．１０％、５５．３６％。结论：筛选了含氮酮２％作为促进剂，制备了有良好的经皮吸收性能的凝胶剂。     

盐酸哌唑嗪缓释贴片的释药行为及其生物相容性评价

背景:盐酸哌唑嗪半衰期短,首剂效应明显,国内仅有普通片上市.目的:研制以聚乙烯醇和明胶为骨架材料的盐酸哌唑嗪缓释贴片,并考察其释药行为和生物相容性.设计、时间及地点:随机设计,动物对照实验,于2007-01/08在重庆医科大学约学院实验室进行.材料:采用水性分散体法,以聚乙烯醇、明胶为骨架材料制备盐酸哌唑嗪亲水性凝胶骨架缓释贴片.方法:①随机选用新两兰大白兔6只,取腹部皮肤进行体外透皮实验,以氮酮、丙二醇、骨架材料配比、载药量为影响因素,稳态透皮速率、时滞为指标,采用正交设计筛选最侍处方.②验证最佳处方,考察贴片物理特性、黏性及透皮行为,并采用差示扫描量热法对其进行差热分析.③随机选用新两兰大白兔12只,通过皮肤刺激性实验,考察贴片的生物相容性.主要观察指标:①贴片最佳处方筛选及验证.②贴片的物理特性评价.③贴片的差热分析.④皮肤刺激性反应.结果:①正交实验筛选的最佳处方为氮酮2%,丙二醇15%,骨架材料配比为5∶4,载药昔1.0%.②按最佳处方制备的贴片外观、黏性良好;其稳态透皮速率、时滞和综合评分分别为(8.92±0.58)μg?(cm2·h),(3.38±1.17)h,81.58±8.42,其体外72 h内释药行为符合Higuchi方程模式(r=0.995 7),并趋近于零级释药模式(r=0.987 3),经皮渗透曲线重现性良好(P>0.05);差热分析表明,盐酸哌唑嗪在骨架材料中以分子或无定形存在.③贴片生物相容性良好,对兔皮肤无刺激性.结论:制备的亲水性凝胶骨架盐酸哌唑嗪缓释贴片生物相容性良好,具有持续平稳释药的特性.     

3种促透剂对天麻体外透皮吸收的影响

目的比较3种促透剂对天麻体外透皮吸收的影响。方法采用改良Franz扩散池,选择大鼠背皮为渗透屏障,从接受池取样,用HPLC法测定样品中天麻素含量,比较5%薄荷脑、5%冰片、5%氮酮对天麻透皮吸收的影响。结果天麻提取液分别加5%薄荷脑、5%冰片、5%氮酮后透皮速率分别为14.277、17.495、29.089μg/(cm2·h-1)。结论5%氮酮对天麻主要活性成分天麻素促渗透作用最强。     

低频超声波对双氯芬酸钠体外经皮渗透的影响

背景:双氯芬酸钠是临床上常用的强效非类固醇抗炎镇痛药物,经皮渗透可以避免肝的首过作用和胃肠道破坏,但受角质层影响,渗透量小;低频超声波能够改善皮肤通透性,促进药物经皮吸收。目的:通过对低频超声对促进双氯芬酸钠药物经皮的吸收效果研究,确定适合该类药物的低频超声经皮渗透物理参数。方法:30只大鼠随机均分为10组,9组用于正交试验,1组用于不加超声波时的对照试验。取大鼠背部皮肤进行透皮实验,以超声波的频率、强度及作用时间为影响因素,渗透量为指标,采用正交试验法,对双氯芬酸钠进行大鼠离体皮肤体外渗透试验,考察双氯芬酸钠渗透效果最好时,低频超声波各个参数值最优配比,并与空白组对比,观察其显著意义。结果与结论:渗透量随着超声波的作用时间的延长而增加,且超声波频率和强度都对渗透量有一定的影响。正交试验筛选的低频超声波最佳配比的参数为频率20kHz,强度0.75W/cm2,作用时间15min。结果提示,低频超声波频率、强度、作用时间均对渗透量的影响显著(P<0.01),三者相比较,作用时间对双氯芬酸钠渗透性的影响最大。     

低频超声波对双氯芬酸钠体外经皮渗透的影响

背景：双氯芬酸钠是临床上常用的强效非类固醇抗炎镇痛药物,经皮渗透可以避免肝的首过作用和胃肠道破坏,但受角质层影响,渗透量小;低频超声波能够改善皮肤通透性,促进药物经皮吸收。目的：通过对低频超声对促进双氯芬酸钠药物经皮的吸收效果研究,确定适合该类药物的低频超声经皮渗透物理参数。方法：30只大鼠随机均分为10组,9组用于正交试验,1组用于不加超声波时的对照试验。取大鼠背部皮肤进行透皮实验,以超声波的频率、强度及作用时间为影响因素,渗透量为指标,采用正交试验法,对双氯芬酸钠进行大鼠离体皮肤体外渗透试验,考察双氯芬酸钠渗透效果最好时,低频超声波各个参数值最优配比,并与空白组对比,观察其显著意义。结果与结论：渗透量随着超声波的作用时间的延长而增加,且超声波频率和强度都对渗透量有一定的影响。正交试验筛选的低频超声波最佳配比的参数为频率20kHz,强度0.75W/cm2,作用时间15min。结果提示,低频超声波频率、强度、作用时间均对渗透量的影响显著（P〈0.01）,三者相比较,作用时间对双氯芬酸钠渗透性的影响最大。     

聚羟基脂肪酸酯和聚酰胺-胺树状高分子构筑的经皮给药系统

背景：聚羟基脂肪酸化合物具有黏着性及与药物分子混合、分散的特性,可作为体外给药剂型的基质;树状高分子具有独特的物理、化学性质,能够作为药物的载体。目的：将聚羟基脂肪酸化合物与聚酰胺-胺树状高分子混合,构筑能够促进难溶型药物的透皮的经皮给药系统。方法：将恶臭假单胞菌 KT2442在含有NH4Cl的培养基中30℃培养72 h,然后在培养体系中添加5 g/L辛烷酸培养24 h,用氯仿抽提聚羟基脂肪酸化合物。各取10 mg聚羟基脂肪酸化合物基质与含聚酰胺-胺与苯乙胺树状高分子的聚羟基脂肪酸化合物基质,分别与5 mg磺酰胺衍生物Tamsulosin混合,构建经皮给药系统;同时构建体外渗透研究装置,研究基质促进药物渗透的效果。X射线衍射分析Tamsulosin、聚羟基脂肪酸化合物基质、基质聚羟基脂肪酸化合物-Tamsulosin 及含聚酰胺-胺树状高分子聚羟基脂肪酸化合物基质-Tamsulosin的内部原子空间分布状况。结果与结论：聚羟基脂肪酸化合物及聚羟基脂肪酸化合物与聚酰胺-胺树状高分子的混合物都能作为经皮给药的基质,促进难溶药物的透皮作用;并且在相同的条件下,聚羟基脂肪酸化合物与聚酰胺-胺树状高分子的混合物作为基质的经皮给药系统能够满足药物的临床血药浓度。聚羟基脂肪酸化合物与聚酰胺-胺树状高分子的混合物能够使模型药物很好地晶体化并呈现高度有序的方向性。     

New microemulsion vehicle facilitates percutaneous penetration in vitro and cutaneous drug bioavailability in vivo.

Microemulsion systems possessing a potentially improved skin bioavailability of lidocaine were designed and explored for some characteristics. The existence of microemulsion regions was investigated in quaternary systems composed of glyceryl oleate+polyoxyl 40 fatty acid derivatives (surfactants)/tetraglycol (co-surfactant)/isopropyl palmitate/water by constructing pseudo-ternary phase diagrams at fixed co-surfactant/surfactants (CoS/S) ratios. Light scattering measurements used to determine the diameter of the internal phase revealed that lidocaine in the microemulsions increased the droplet size, implying a drug tendency to accumulate in the interfacial layers. Percutaneous penetration studies using rat skin in vitro showed that the transdermal flux of lidocaine was significantly improved by microemulsion composed of the glyceryl oleate-PEG-40 stearate combination rather than glyceryl oleate-PEG-40 hydroxylated castor oil. Two principal factors were found to govern the transdermal penetration of lidocaine from the microemulsion: water content and the CoS/S ratio. By analyzing skin layers (epidermis and dermis) for lidocaine content, significantly higher concentrations were found after rats were treated in vivo with liquid microemulsions (CoS/S=1.8, 30 wt.% water) or patches compared to those measured after application of EMLA cream. It has been suggested, therefore, that these microemulsions loaded with lidocaine would provide adequate analgesia in relatively shorter periods of time.     

超快效液相色谱与液面法测定榄香烯微乳的含量及包封率

背景:超快速液相色谱法具有快速、准确的优点,可以用来检测榄香烯微乳的含量.榄香烯微乳的包封率目前尚没有较好检测方法.目的:采用超快效液相色谱与液面法测定榄香烯微乳的含量及包封率.方法:应用超快速液相色谱法检测榄香烯微乳含量,根据榄香烯不溶于水而浮于水面的原理,设计液面法检测榄香烯微乳的包封率.结果与结论:色谱条件下β-榄香烯与辅料分离良好,β-榄香烯在3.94~27.58 mg/L范围内线性关系良好.榄香烯微乳中β-榄香烯平均含量为(8.273±0.018) g/L,平均包封率为(99.81±0.24)%.提示超快速液相色谱和液面法可用于检测榄香烯微乳的含量和包封率,简单、快速且准确,榄香烯微乳包封率好.     

Transdermal delivery of levonorgestrel I: Alkanols as permeation enhancers in vitro

The effect of alcoholic penetration enhancers on the transdermal delivery of levonorgestrel (LN) was investigated. A series of albanais was tested in vitro it for their ability to enhance the delivery of LN through excised rat skins. The steady-state flux of LN was measured using donor phase compositions of water fethanol mixtures, and the neat straight chain alkanols ethanol, propanol, butanol, pentanol, hexanol, and octanol. The steady-state flux of LN was found to increase as the alkyl chain length increased from C₂ to C₄. This was followed by a decrease in the steady-state flux as the alkyi chain length increased above 1 -butanol. Three secondary alkanols, 2-propanol, 2-butanol, and 2-pentanol were also tested as penetration enhancers. The same trend was evident: steady-state flux was highest for 2-butanol with 2-propanol and 2-pentanol giving lower steady-state fluxes. The flux of LN was lower for secondary alkanols relative to the corresponding primary alkanol. Propylene glycol was also tested as an enhancer. Overall, the steady-state flux using this penetration enhancer was about that of water, which was low relative to all the alkanols. Flux of LN through human cadaver skin from pure ethanol was about four times lower than through rat skin. A mechanism for permeability enhancement based on the alkanol structure and water-solubility is presented as well as a discussion of the data as it relates to development of a transdermal delivery system for LN.     

纳米银缓释壳聚糖／聚乙烯醇伤口敷料的制备及表征

背景：临床上传统治疗创面感染主要使用抗生素药物敷料,但长期使用会诱导细菌耐药;同时纳米创伤敷料生物相容性差,无法降解,不宜长期覆盖创面。目的：制备一种具有抗蔺作用、牛物相容性良好的伤口敷料,并表征分析其生物学性能。方法：采用缩醛化反应制得含纳米银,聚乙二醇的壳聚糖,聚乙醇酸海绵,检测材料的物理性能、表面形貌、体外释放及抗菌性能。结果与结论：制得的纳米银粒径小,分散性良好,体外释放实验表明纳米银粒子可持续不断地从辅料释放出来,作用于细菌。含纳米银,聚乙二醇的壳聚糖,聚乙烯醇海绵孔隙致密均匀,大小孔相巧．贯通;吸水性大、保湿性高、透气性适中：吸水牢和透气率邰随聚乙烯醇1799含最增加而增大：保湿率坫本不变;对金黄色葡萄杆菌、大肠杆菌、白色念珠菌、铜绿假单胞菌、变伤寒沙门菌5种实验菌种均有良好杀菌效累。表明该敷料物理性能好,生物相容性及杀菌效果好。     

Polymeric transdermal drug penetration enhancer. The enhancing effect of oligodimethylsiloxane containing a glucopyranosyl end group.

Oligodimethylsiloxanes (ODMSs) containing a beta-D-glucopyranosyl group at one chain end (Glc-ODMSs) with various molecular weights were prepared to develop a silicone-based polymeric transdermal penetration enhancer with a non-ionic polar end group. Glc-ODMSs were prepared by hydrosilylation of hydrosilyl-terminated ODMS with 1-allyl-beta-D-glucose tetraacetate in the presence of bis(benzonitrile)platinum dichloride as the catalyst, followed by hydrolysis of the acetyl groups with sodium methoxide. The enhancing effect in the drug penetration was evaluated by in vitro experiments using a two-chamber diffusion cell. Antipyrine was used as a model drug, and the amount of drug permeating through the rat abdominal skin with or without Glc-ODMS was determined by HPLC. These enhancers were effective for the penetration of antipyrine. On the other hand, the enhancing effects were influenced by the concentration of Glc-ODMS coexisted regardless of its ODMS chain length. The enhancing effect was also observed by the pretreatment of the skin with Glc-ODMS before the drug permeation, the results of which suggested that the induction periods to appear the enhancing effects were different between Glc-ODMSs with the short and the long ODMS chain lengths. Furthermore, according to the Draize test, Glc-ODMSs exhibited no irritation to the skin regardless of the ODMS chain length.     

Evaluation of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) gels as a release vehicle for percutaneous fentanyl.

The primary objective of this study was to investigate the feasibility of PEO-PPO-PEO copolymer gel as a release vehicle for percutaneous administration of fentanyl in vitro and in vivo. A cellulose membrane and nude mouse skin with series concentrations of PEO-PPO-PEO block copolymers were used to examine the sustained-release pattern and permeation of fentanyl. The in vivo percutaneous absorption was examined using rabbits to evaluate the preliminary pharmacokinetics of fentanyl with 46% PEO-PPO-PEO copolymer formulation patches. The micelle formation ability of this block copolymer and the penetration ability of PEO-PPO-PEO copolymer over time were also studied by pyrene fluorescence probe methods and the dynamic light scattering test. At a concentration of 46% at 37 degrees C, PEO-PPO-PEO copolymers formed a gel and showed a pseudo-zero-order sustained-release profile. With increasing concentration of copolymer in the cellulose membrane transport, the apparent release flux of fentanyl (200 microgram/ml) decreased to 1. 09+/-0.19 microgram cm(-2) h(-1). Assessment of the effect of the copolymer on nude mouse skin also showed a decrease in the apparent permeability coefficient [(P(H(2)O))=2.24+/-0.47x10(-6) cm s(-1) vs. (P(46% block copolymer))=0.93+/-0.23x10(-7) cm s(-1)]. The preliminary pharmacokinetics of the fentanyl patch was shown to be in steady state within 24 h, and this was maintained for at least 72 h with an elimination half-life (t(1/2)) of 10.5+/-3.4 h. A fluorescence experiment showed polymeric micelle formation of PEO-PPO-PEO copolymers at 0.1% (w/w) within 50 nm micelle size and the PEO-PPO-PEO copolymers were able to penetrate nude mouse skin within 24 h. Thus, it appears that fentanyl preparations based on PEO-PPO-PEO copolymer gel might be practical for percutaneous delivery.     

Development of a reservoir-type transdermal enantioselective-controlled delivery system for racemic propranolol using a molecularly imprinted polymer composite membrane

The aims of this study were to develop a transdermal patch for selective controlled delivery of the active S-enantiomer from racemic propranolol, and to evaluate its performance in vivo using Wistar rats. A molecularly imprinted polymer (MIP) thin-layer composited cellulose membrane with selectivity for S-propranolol was employed as the enantioselective-controlled release system. The effect of gel reservoir (poloxamer and chitosan) on enantioselective delivery was investigated. The chitosan gel allowed excellent selectivity for delivery of the S-propranolol enantiomer, whilst the more rheologically structured poloxamer gel formulation provided no selective release of S-propranolol. The chitosan gel exhibited high flux and had the ability to enantioselective deliver S-propranolol across excised rat skin. The results from confocal laser scanning microscopy study, carried out with the R- and S-propranolol enantiomers labeled with a 1-pyrenebutyric acid probe as fluorescent markers, suggested that the MIP composite membrane selectively regulated the release of the recognised S-enantiomer via a facilitated transport pathway through complex formation with the selective receptor sites, while the release of the R-enantiomer was via a non-selective route. The reservoir patch for enantiomer-controlled delivery of propranolol was therefore fabricated by incorporating the chitosan gel formulation containing racemic propranolol hydrochloride into the MIP composite membrane laminated backing. These patch devices were shown to exhibit the significant stereoselectivity uptake of propranolol when attached to the skin, using pharmacokinetic studies in rats. S-Propranolol enantiomer plasma concentration profiles for the transdermal patch in the in vivo study were comparable to data for the gel formulations that were applied directly to skin, and containing a single S-enantiomer of propranolol. The results demonstrate that the transdermal patch based on the MIP composite membrane-controlled release system may have potential in the enantioselective-controlled delivery of the S-isomer of racemic propranolol.