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。     

超声波对盐酸青藤碱凝胶经皮渗透的促进作用

目的研究超声波对盐酸青藤碱经皮渗透的影响。 方法取离体Sprague-Dawley大鼠皮肤,置于改良Franz扩散池,皮肤角质层朝上,并均匀涂抹盐酸青藤碱凝胶,保持扩散体系温度为（32±0.5）℃,接受介质采用20%聚乙二醇400生理盐水溶液。实验分为药物被动经皮渗透组（对照组）和药物超声波透入组（超声波组）。对照组不加超声波作用,超声波组按超声波作用参数不同分为Ta组（频率800 kHz,强度0.75 W/cm2,作用时间10 min）、Tb组（频率1 MHz,强度0.70 W/cm2,作用时间10 min）、Tc组（频率1 MHz,强度0.35 W/cm2,作用时间10 min）、Td组（频率800 kHz,强度1.50 W/cm2,作用时间10 min）和Te组（频率800 kHz,强度1.50 W/cm2,作用时间5 min）。每组均同时进行6个平行实验,每个平行实验持续时间为8 h,每隔1 h分别吸取接受室溶液,并加入空白接受介质,测定接受液药物浓度,计算平均累积单位面积渗透量Q（μg/cm2）和平均稳态透皮速率Js（μg/cm2/h）,并进行比较。 结果对照组Q8h值为（20.65±10.23）μg/cm2,Js值为（3.02±0.11）μg/cm2/h;Ta、Tb组的Q8h和Js值均明显高于对照组（P<0.05）;Tb组Q8h和Js值明显高于Tc组（P<0.05）;Td组Q8h和Js值明显高于Ta组和Te组（P<0.05）。超声波透入后,皮肤组织切片经光学显微镜观察没有明显改变,扫描电子显微镜下可见角质层表面呈现粗糙、多孔状。 结论超声波透入对盐酸青藤碱的经皮吸收有明显促进作用,渗透效果与超声波强度、作用时间有关,超声波作用的强度在0~1.5 W/cm2范围内,对皮肤组织比较安全     

柔性纳米脂质体双氯芬酸钠外用透皮吸收的效果

目的:观察双氯芬酸钠柔性纳米脂质体皮肤给药缓释系统体外透皮吸收情况。方法:验于2005-03/11在中南大学湘雅医院中西结合研究所完成。实验材料:双氯芬酸钠柔性纳米脂质体(中南大学化工研究所,将双氯芬酸钠制成纳米粒,并包封于卵磷脂及其有生物膜特性和功能的脂质体中,其粒径为30～100nm),扶他林(双氯芬酸钠)。实验分组:15只健康的SD大鼠按随机数字表法分为3组:质量分数为0.01的扶他林组、质量分数为0.05的外用双氯芬酸钠柔性纳米脂质体组和质量分数为0.1的外用双氯芬酸钠柔性纳米脂质体组,每组5只。将鼠皮装于Franz扩散池,角质层面向供给室,真皮层面向接受池,分别将质量分数为0.05的外用双氯芬酸钠柔性纳米脂质体25mg、质量分数为0.1的外用双氯芬酸钠柔性纳米脂质体12.5mg和质量分数为0.01的扶他林125mg(含双氯芬酸钠均为1.25mg)均匀涂布于大鼠皮肤角质层表面,分别于2,4,6,8,10,12h于接受池取样5mL,用0.45μm微孔滤膜过滤。滤液用生理盐水稀释至10mL,于276nm处测定吸光度值,扣除生理盐水的吸光度值后代入标准曲线,计算累积透过量和12h累积透过率,对比3种制剂经大鼠皮肤的体外透皮吸收差异。结果:质量分数为0.05,0.1的外用双氯芬酸钠柔性纳米脂质体组累积透过量、12h累积透过率均高于质量分数为0.01的扶他林组[12h累积透过率分别为(70.76±0.23)%,(75.2±0.32)%,(33.51±0.29)%],差异有显著性意义(t=317.17,232.54,P<0.01);质量分数为0.05的外用双氯芬酸钠柔性纳米脂质体组与质量分数为0.1的外用双氯芬酸钠柔性纳米脂质体组累积透过量、12h累积透过率差异无显著性意义(P>0.05)。结论:双氯芬酸钠柔性纳米脂质体能有效渗透皮肤组织。     

高频超声波对双氯芬酸钠胶稳定性的影响

超声波药物导入法近年来临床上应用很广 ,它与离子导入法相比 ,具有透入皮肤深 ,治疗时间短 ,所选的药物范围广等特点[1] 。双氯芬酸钠 (ＤＣＦ)是目前广泛使用的非甾体抗炎药 ,具有优良的消炎镇痛作用 ,外用的双氯芬酸钠凝胶(ＤＣＦＧ)不仅避免了口服药物可能引起的消化道副作用 ,而且疗效明显 ,不良反应发生率低[2 ] 。但它是否适用于超声波导入 ,即该药对超声波的敏感性如何 ,研究报道的不多[3] 。我们通过一阶导数分光光度法测定经高频超声波作用过的凝胶剂中ＤＣＦ含量 ,以确定超声波在不同强度和作用时间下 ,对该药物稳定性的影响。1…     

低频超声影响恩纳局部镇痛起效时间的随机对照研究

背景许多动物实验表明,低频超声波可促进药物经皮吸收的速率.本研究已采用低频超声波介导局麻药来测定在人体透皮的速度与深度.目的探讨低频超声波对恩纳局部镇痛起效时间的影响,为临床研究低频超声给药和扩大恩纳的临床应用提供依据.设计采用双盲同体配对随机对照研究.地点和对象研究在解放军第四军医大学秦都医院完成,所有研究对象为解放军第四军医大学学员.干预对24例健康青年志愿者的双上臂采用随机数字分为试验组和对照组,每个试验者两上臂同时涂抹1 g恩纳,10 min后试验组上臂进行低频超声(20 kHz)介导,强度为0.5 W/cm2,介导时间10min.主要观察指标用美国产TranscucerIndication Model 1601C尼龙棒机械压力测痛仪每5 min测量两组镇痛起始时间,共观察2 h.试验结束后观察皮肤组织学变化.结果低频超声干预组平均镇痛起始时间为(34.58±3.87)min,对照组为(43.75±4.72)min.两组镇痛起效时间差异有显著性意义(t=7.62,P＜0.01).低频超声可使角质层间质增宽和疏松.结论低频超声可以促进恩纳透过皮肤,缩短恩纳局部镇痛起效时间.     

低频超声药物透入实验研究

通过实验比较了两种频率的超声经ＳＤ大鼠皮肤透入１３１Ｉ的量和深度，放射免疫技术测定结果，显示低频超声透入药物的量多且深，说明低频超声有利于药物的透入。     

低频脉冲超声对肿瘤细胞内化疗药物浓度影响的体外实验研究

目的 观察低频脉冲式超声波对肿瘤细胞内化疗药物浓度的影响并探讨其作用机制. 方法将肝癌细胞株 HepG2与临床常用化疗药蒽环类抗生素阿霉素( adriamycin, ADM)共孵育,用不同条件的低频脉冲超声波处理,选不同时间点用流式细胞仪检测细胞内 ADM荧光强度,荧光分光光度计测量细胞膜流动性. 结果 低频脉冲超声波能显著提高肿瘤细胞 HepG2内 ADM浓度,且这种效应有明显的频率赖性,以 0.8 MHz的频率最为理想 , 细胞内 ADM荧光强度最大可达 145.12,细胞膜荧光偏振度值由原来的 0.198 5降至 0.162 4,改善细胞膜流动性.另外,细胞内药物浓度与细胞膜流动性呈正相关,提示超声波促进药物进入细胞内的作用是通过提高细胞膜的流动性来实现的. 结论低频脉冲超声可促进化疗药物进入肿瘤细胞内,这种效应有明显的频率敏感性,其机制与超声提高细胞膜的流动性有关.     

低频超声影响恩纳局部镇痛起效时间的随机对照研究

背景：许多动物实验表明，低频超声波可促进药物经皮吸收的速率。本研究已采用低频超声波介导局麻药来测定在人体透皮的速度与深度。目的：探讨低频超声波对恩纳局部镇痛起效时间的影响，为临床研究低频超声给药和扩大恩纳的临床应用提供依据。设计：采用双盲同体配对随机对照研究。地点和对象：研究在解放军第四军医大学秦都医院完成，所有研究对象为解放军第四军医大学学员。干预：对24例健康青年志愿者的双上臂采用随机数字分为试验组和对照组，每个试验者两上臂同时涂抹1g恩纳，10min后试验组上臂进行低频超声(20kHz)介导，强度为0．5W／cm^2，介导时间10win。主要观察指标：用美国产Transcucer Indication Model 1601C尼龙棒机械压力测痛仪每5min测量两组镇痛起始时间，共观察2h。试验结束后观察皮肤组织学变化。结果：低频超声干预组平均镇痛起始时间为(34．58&;#177;3．87)min，对照组为(43．75&;#177;4．72)min。两组镇痛起效时间差异有显著性意义(t=7．62．P&;lt;0．01)。低频超声可使角质层间质增宽和疏松。结论：低频超声可以促进恩纳透过皮肤，缩短恩纳局部镇痛起效时间。     

低频脉冲超声对肿瘤细胞内化疗药物浓度影响的体外实验研究

目的：观察低频脉冲式超声波对肿瘤细胞内化疗药物浓度的影响并探讨其作用机制。方法：将肝癌细胞株HepG2与临床常用化疗药蒽环类抗生素阿霉素(adriamycin，ADM)共孵育，用不同条件的低频脉冲超声波处理，选不同时间点用流式细胞仪检测细胞内ADM荧光强度，荧光分光光度计测量细胞膜流动性。结果：低频脉冲超声波能显著提高肿瘤细胞HepG2内ADM浓度，且这种效应有明显的频率赖性，以0．8MHz的频率最为理想，细胞内ADM荧光强度最大可达145．12，细胞膜荧光偏振度值由原来的0．1985降至0．1624，改善细胞膜流动性。另外，细胞内药物浓度与细胞膜流动性呈正相关，提示超声波促进药物进入细胞内的作用是通过提高细胞膜的流动性来实现的。结论：低频脉冲超声可促进化疗药物进入肿瘤细胞内，这种效应有明显的频率敏感性，其机制与超声提高细胞膜的流动性有关。     

应用双氯芬酸钠后骨质疏松性骨折大鼠的肝肾变化:组织学验证

背景:临床上常用非类固醇类抗炎药治疗骨质疏松症和骨质疏松性骨折引起的疼痛,文献报道非类固醇类抗炎药会引起肝肾功能的损害,但其究竟如何影响肝肾组织尚不清楚.目的:观察双氯芬酸钠对骨质疏松性骨折大鼠肝肾组织的影响.设计、时间及地点:随机对照动物实验,于2007-08/2008-02在上海中医药大学动物实验中心完成.材料:8月龄雌性SD大鼠24只,体质量300-320 g,随机分为生理盐水组、双氯芬酸钠先骨折后药物组和双氯芬酸钠先药物后骨折组,每组8只.方法:大鼠卵巢去势后饲养3个月,建立骨质疏松模型,随机分组.生理盐水组和先骨折后药物组先进行双侧股骨中段骨折造模,再分别灌注生理盐水10 mL/(kg·d)和双氯芬酸钠5 mg/(kg·d).1次/d,共3周;先药物后骨折组先灌注双氯芬酸钠5 mg/(kg·d)3周,再进行骨折造模.主要观察指标:分别于骨折后2,3,4,6周摘取肝脏和双侧肾脏,行苏木精-伊红染色观察.各组大鼠肝脏和肾脏组织学观察.结果:双氯芬酸钠先骨折后药物组肾小球炎症反应;肾小管管腔扩张,上皮细胞水肿,细胞核消失,小管变性坏死,管腔内出现白细胞及细胞碎片和药物结晶;肾间质充血,炎症细胞浸润.双氯芬酸钠组肝小叶结构模糊,肝细胞肿胀,脂肪变性,部分肝细胞坏死:汇管区炎症反应;中央静脉和肝窦隙淤血.双氯芬酸钠先药物后骨折组同样造成肝肾组织损害,持续3周左右.结论:双氯芬酸钠对骨质疏松性大鼠的肝肾组织有一定损害,尤其是肾脏组织.长时间应用双氯芬酸钠造成的肝肾组织损害是不可逆的.     

超声促渗理论在中药经皮给药中的应用进展

查阅近年来超声电导法对中药透皮吸收作用影响的有关文献报道并进行归纳、分析,结果显示超声导入在西药方面的研究较多,中药经皮给药的研究相对较少,但显示了超声电导法对中药经皮给药有一定的促渗透作用,从而为研究超声电导对中药的透皮吸收作用的影响提供了理论依据;揭示中药经皮给药的科学内涵,拓展中医外治法的发展空间。     

Radiofrequency-driven skin microchanneling as a new way for electrically assisted transdermal delivery of hydrophilic drugs.

The aim of this study was to increase the skin penetration of two drugs, granisetron hydrochloride and diclofenac sodium, using a microelectronic device based on an ablation of outer layers of skin using radiofrequency high-voltage currents. These radiofrequency currents created an array of microchannels across the stratum corneum deep into the epidermis. The percutaneous penetration studies were first performed in vitro using excised full thickness porcine ear skin. An array of 100 microelectrodes/cm(2) was used in these studies. The skin permeability of both molecules was significantly enhanced after pretreatment with the radiofrequency microelectrodes, as compared to the delivery through the untreated control skin. Steady state fluxes of 41.6 micro g/cm(2)/h (r=0.997) and 23.0 micro g/cm(2)/h (r=0.989) were obtained for granisetron and diclofenac, respectively. The enhanced transdermal delivery was also demonstrated in vivo in rats. It was shown that diclofenac plasma levels in the pretreated rats reached plateau levels of 1.22+/-0.32 micro g/ml after 3 h to 1.47+/-0.33 micro g/ml after 6 h, as compared to 0.16+/-0.04 micro g/ml levels obtained after 6 h in untreated rats. Similarly, application of granisetron patches (3% in crosslinked hydrogel) onto rats' abdominal skin pretreated with radiofrequency electrodes resulted in an averaged peak plasma level of 239.3+/-43.7 ng/ml after 12 h, which was about 30 times higher than the plasma levels obtained by 24-h passive diffusion of the applied drug. The results emphasize, therefore, that the new transdermal technology is suitable for therapeutic delivery of poorly penetrating molecules.     

Effect of Phonophoresis on Skin Permeation of Commercial Anti-inflammatory Gels: Sodium Diclofenac and Ketoprofen

This study evaluated the use of ultrasound in combination with the commercial anti-inflammatory drugs ketoprofen and sodium diclofenac, according to the parameters used in physiotherapy. Ketoprofen and sodium diclofenac were used in the Franz diffusion cell model adapted to an ultrasound transducer in three conditions: no ultrasound, one application of ultrasound and two applications of ultrasound. High-performance liquid chromatography was used to quantify the total amount of drug permeating skin per unit area, as well as flux and latency. The results showed that for ketoprofen, the amount of drug permeating skin and flux increased with two ultrasound applications. Permeation of sodium diclofenac decreased in the presence of ultrasound. Ultrasound parameters and drug properties must be considered in the use of phonophoresis.     

Quantitative Evaluation of Sonophoresis Efficiency and Its Dependence on Sonication Parameters and Particle Size

Transdermal drug delivery makes a critical contribution to medical practice and some advantages over conventional oral administration and hypodermic injection. Enhancement of percutaneous absorption or penetration of therapeutic agents (ie, drugs and macromolecules) by ultrasound, termed sonophoresis, has been applied and studied for decades. In this study, the penetration percentage through porcine ear skin specimens was determined quantitatively by measuring the fluorescence from nanoparticles of 60, 220, and 840 nm in size in a receptor chamber at different sonication parameters (ie, duty cycle, 20%–100%; acoustic intensity, 0.3–1.0 W/cm²; duration, 7–30 minutes; and frequency, 1 MHz). In general, the sonophoresis efficiency increased with the acoustic intensity, duty cycle, and sonication duration but decreased with the particle size (mean ± SD, 62.6% ± 5.4% for 60‐nm versus 11.9% ± 1.1% for 840‐nm polystyrene nanospheres after 30 minutes of sonication at 0.5 W/cm² and a 100% duty cycle; P < .05). On scanning electron microscopy the pore size remained the same (≈100 μm), but more flakes were observed with the progress of sonication. In summary, sonophoresis efficiency is dependent on the ultrasound parameters and particle size. Sufficient sonication would lead to satisfactory penetration of even submicrometer objects through the pores.     

榄香烯透皮凝胶的制备及体外透皮性能

背景:选择合适的载体材料对药物透皮性能的影响是制备榄香烯透皮制剂首先要解决的问题。目的:建立一种榄香烯透皮凝胶并观察其体外透皮性能。方法:采用具有良好生物相容性的亲水性高分子材料聚乙烯醇和羧甲基纤维素钠制备榄香烯透皮制剂。在体外透皮实验装置上,用鼠背皮肤为屏障进行经皮渗透实验,高效气相色谱检测榄香烯的经皮渗透量。结果与结论:聚乙烯醇和羧甲基纤维素钠的使用比例对榄香烯的透皮能力没有显著影响;两种高分子骨架材料在凝胶基质中的浓度对榄香烯透皮能力有一定的影响,以30%含量(聚乙烯醇与羧甲基纤维素钠总量)为最佳。提示此种透皮凝胶可用作榄香烯的良好载体。     

Novel transdermal drug penetration enhancer: synthesis and enhancing effect of alkyldisiloxane compounds containing glucopyranosyl group.

The syntheses of alkyldisiloxanes containing sugar moiety with various alkyl chain length were investigated, in order to develop a silicone-based transdermal penetration enhancer which was expected to show a low irritation to the skin. 1-Alkyl-3-beta-D-glucopyranosyl-1,1,3,3-tetramethyldisiloxanes (Glc-SiCs) were prepared by two-step hydrosilylations of 1-alkene and 1-allyl-beta-D-glucose tetraacetate with 1,1,3,3-tetramethyldisiloxane in the presence of bis(benzonitrile)platinum dichloride as the catalyst, followed by hydrolysis of the acetyl groups with sodium methoxide. The enhancing effect of Glc-SiCs on the percutaneous drug penetration was evaluated by in vitro experiments using a two-chamber diffusion cell. Antipyrine (ANP) and indomethacin (IND) were used as hydrophilic and hydrophobic model drugs, respectively, and the amount of drug permeating through the rat abdominal skin with or without Glc-SiCs was estimated by HPLC. As a result, Glc-SiCs exhibited a enhancing effect on the permeation of both drugs through the skin, which was influenced by the alkyl chain length of Glc-SiCs. In addition, it was suggested that a suitable balance of polarity would be necessary to appear the high enhancing effect, where Glc-SiCs with octyl and decyl groups exhibited the highest enhancing effect. From the determination of kinetic parameters in the drug permeation, it was also found that this enhancing effect was due to the increase of both partition and diffusion coefficients of drug permeation through the skin. By experiments to determine the amount of cholesterol extracted from the skin, the defatting effect would be one of the functions of Glc-SiCs which resulted in the high enhancing activity. Furthermore, according to the Draize test, it was confirmed that Glc-SiCs showed a low irritation to the skin.     

Transdermal drug delivery using iontophoresis and phonophoresis

Introducing medicines into the human body by way of the skin is an ancient practice, and transdermal delivery has long been a standard for administering medications such as nitroglycerin and scopalamine. Phoresis, another method of transdermal drug delivery, is now being ordered for an increasing number of orthopaedic patients who suffer from inflammation, strains, or sprains. In phoretic drug delivery, enhancers such as electricity or ultrasound are used to stimulate drug absorption in the treatment area. To guide their patients to explore a variety of treatment options, orthopaedic nurses need a greater understanding of these phoretic modalities.