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。     

低频超声促进双氯芬酸钠经皮渗透的研究

目的研究低频超声对双氯芬酸钠体外经皮渗透的促进作用,并比较连续型和脉冲型超声波对经皮渗透的影响。方法应用改进Franz扩散池,以大鼠皮肤为透皮屏障,以低频超声波为促渗手段,通过紫外可见光分光光度法研究双氯芬酸钠的经皮渗透性能;考察超声波作用时间和耦合介质等因素的影响,并比较连续型和脉冲型超声波作用的差异。结果低频超声波能明显促进双氯芬酸钠的经皮渗透,且在1~5min内,随着超声波作用时间的延长,药物经皮渗透量会逐渐增加。当耦合介质为生理盐水,超声作用时间为5 min时,5 h内双氯芬酸钠的累积渗透量是被动扩散的3.02倍;连续型和脉冲型超声分别作用后的累积渗透量几乎相等。结论低频超声波能明显促进双氯芬酸钠的经皮渗透;连续型和脉冲型超声波对双氯芬酸钠促渗效果差异无统计学意义,这些试验结果对经皮给药治疗仪的开发具有重要的参考价值。     

超声波导入的促渗作用及其对皮肤微观结构的影响

目的 考察超声波导入对高乌甲素水凝胶经皮渗透的促进作用及其对皮肤角质层微细结构的影响。方法 制备了高乌甲素卡波姆凝胶,分别采用频率为800 kHz和1 MHz的超声波在体外进行了经鼠皮渗透实验,定时测定接受室药物浓度并计算经皮渗透参数。制备皮肤切片,分别采用光镜和扫描电镜观察皮肤及角质层微细结构的改变。结果 800 kHz和1 MHz的超声波导入对高乌甲素稳态透皮速率的促渗倍数分别达到约7倍和23倍。角质层微细结构观察发现超声波引起了皮肤表面空隙的增加和结构的改变。结论 超声波导入显著促进了高乌甲素的经皮渗透,并提示空化效应是引起促渗作用的重要因素。     

超声波导入的促渗作用及其对皮肤微观结构的影响

目的考察超声波导入对高乌甲素水凝胶经皮渗透的促进作用及其对皮肤角质层微细结构的影响。方法制备了高乌甲素卡波姆凝胶,分别采用频率为800 kHz和1 MHz的超声波在体外进行了经鼠皮渗透实验,定时测定接受室药物浓度并计算经皮渗透参数。制备皮肤切片,分别采用光镜和扫描电镜观察皮肤及角质层微细结构的改变。结果800 kHz和1 MHz的超声波导入对高乌甲素稳态透皮速率的促渗倍数分别达到约7倍和23倍。角质层微细结构观察发现超声波引起了皮肤表面空隙的增加和结构的改变。结论超声波导入显著促进了高乌甲素的经皮渗透,并提示空化效应是引起促渗作用的重要因素。     

黄体酮透皮给药系统体外经皮渗透特性的研究

目的研究黄体酮透皮给药系统的体外经皮渗透特性。方法采用聚丙烯酸酯为骨架制备黄体酮透皮贴片,以离体人皮为透皮模型,采用Valia-Chien扩散池和高效液相色谱法研究促渗剂、药物含量对黄体酮透皮给药系统经皮渗透的影响。结果23%单月桂酸甘油酯与15%棕榈酸乙酯合用对黄体酮促渗效果明显,经皮渗透速率为1.50±0.64μg·cm-2·h-1,增渗倍数达到了21.4倍。贴片中黄体酮含量由0.75mg·cm-2提高到1.0mg·cm-2时,经皮渗透速率明显增大;含量提高到1.25mg·cm-2时,经皮渗透速率无明显变化。结论单月桂酸甘油酯和棕榈酸乙酯联用对黄体酮透皮给药系统体外经皮渗透具有显著的促进作用,黄体酮的最佳含量是1.0mg·cm-2。     

低频超声辐照对顺铂抑制人肝癌细胞体内外生长增效作用的实验研究

目的观察低频超声辐照对顺铂抑制人肝癌细胞的体内外生长增效作用,探讨低频超声在肿瘤化学治疗增效中的应用价值。方法①体外实验：将人肝癌细胞SMMC7721分为A组（实验空白对照）;B组（SMMC7721细胞常规培养）;C组（单纯使用顺铂治疗,药物终浓度为2．5和5mg／L;D组（低频超声治疗,频率为30kHz,强度分别为1．4和2．8W／cm2,每个强度分别辐照2min、5min）;E组（顺铂＋低频超声,用法同c组和D组）。计算联合治疗指数值,用噻唑蓝比色法检测对人肝癌细胞SMMC7721生长抑制率。②体内实验：16只裸鼠体内移植人肝癌肿瘤SMMC7721模型分为对照组、顺铂组、低频超声组和观察组（顺铂＋低频超声）,各4只。采用裸鼠体内移植人肝癌细胞SMMC7721,用低频超声波（频率30000Hz,超声强度2．8W／cm2）对腹腔内注射顺铂（5m/kg）的裸鼠进行肿瘤局部辐射,测量肿瘤体积,绘制肿瘤生长曲线,实验结束称瘤重和体重,计算肿瘤抑制率。结果D组1．4W／cm。和2．8w／cm2辐照2min的生长抑制率分别为5．3％和8．0％,辐照5min的生长抑制率分别为12．2％和23．8％;E1组（顺铂终浓度2．5mg／L＋低频超声强度1．4W／cm2）辐照2和5min的生长抑制率分别为55．4％和69．5％,E2组（顺铂终浓度2．5mg／L＋低频超声强度2．8w／cm。）分别为70．9％和77．9％,E3（顺铂终浓度5．0mg／L＋低频超声强度1．4W／cm2）分别为70．8％和75．5％,E4组（顺铂终浓度5．0mg／L＋低频超声强度2．8W／cm。）分别为80．1％和84．9％。低频超声波联合顺铂对SMMC7721细胞生长抑制率明显高于单独低频超声。体内实验中,不同治疗方法干预后,对照组、顺铂组、低频超声组和观察组裸鼠平均瘤重分别为（0．65±0．31）、（0．42±0．19）、（0．50±0．17）、（0．29±0．18）g,观察组与对照组间差异有统计学意义（P〈0．05）。顺铂组、低频超声组和观察组的肿瘤抑制率分别为36．0％、23．8％、55．2％,低频超声组和顺铂组的差异无统计学意义（P〉0．05）,观察组与低频超声组的差异有统计学意义（P〈0．05）。结论低频超声在体内、外均明显增强抗癌药顺铂对人肝癌细胞SMMC7721的抑制作用。低频超声波的作用时间是增加化学治疗药物细胞毒作用的关键因素,低频超声波局部透射可以增加全身给药化学治疗的疗效,有望成为临床治疗的新方法。     

氟比洛芬压敏胶分散型贴剂的制备及体外经皮渗透性考察

目的:研制氟比洛芬压敏胶分散型贴剂并考察其体外经皮渗透性。方法:将氟比洛芬及各种促渗剂直接溶于压敏胶中制备压敏胶分散性贴剂,采用卧式双室扩散池,研究其体外经皮渗透行为。结果:由Duro-Tak 87-9301型压敏胶制备的贴刺具有较好的稳态渗透速率。5%氯酮与10%豆蔻酸异丙酯合用对氟比洛芬促渗效果明显,经皮渗透速率为（3.35±0.53）μg·cm^-2·h^-1,促渗倍率达2.68倍。贴剂中氟比洛芬的含量由5%增加到10%,经皮渗透速率明显增大,含量增加到15%和20%时,渗透速率无明显变化。结论:所得处方中各因素的组合有利于氟比洛芬的经皮吸收。     

喷他佐辛压敏胶分散型贴剂的制备研究

目的研制喷他佐辛压敏胶分散型贴剂并考察其体外经皮渗透性。方法将喷他佐辛及各种促渗剂直接溶于压敏胶中制备压敏胶分散型贴剂,采用卧式双室扩散池,研究其体外经皮渗透行为。结果由Duro-Tak 87-9301型压敏胶制备的贴剂具有较好的稳态渗透速率。5%氮酮与10%豆蔻酸异丙酯合用对喷他佐辛促渗效果明显,经皮渗透速率为(11.28±0.63)μg/(cm2.h),促渗倍率达3.01倍。贴剂中喷他佐辛的含量由2%增加到4%,经皮渗透速率明显增大,含量增加到6%和8%时渗透速率无明显变化。结论所得处方中各因素的组合有利于喷他佐辛的经皮吸收。     

薄荷醇及其二组分系统对5-氟脲嘧啶经皮渗透和贮库效应的影响

目的：探讨薄荷醇及其二组分系统对氟脲嘧啶(5—Fu)经皮渗透和贮库效应的影响。方法：在离体透皮吸收装置上，测定不同时间5—FU的透过量，计算累积透过量、渗透系数和增渗倍数，并考察其贮库效应。结果：不同浓度薄荷醇对5—FU经皮渗透均有明显的促进作用，其增渗倍数分别为1．25、1.45和1．37倍。其中含2％浓度的薄荷醇组作用最强；含2％和4％薄荷醇的组有显的贮库效应。几种促透剂单独应用或与薄荷醇联合应用时，5—FU的经皮渗透均有显或极显的增加。结论：薄荷醇及其二组分系统能显增强5—FU经皮渗透，加强其贮库效应。     

促渗剂对贴剂中双氯芬酸二乙胺的经皮促渗作用

目的 制备双氯芬酸二乙胺(DDEA)水凝用胶贴剂,研究不同促渗剂对水凝胶贴剂中DDEA体外透皮吸收的影响.方法 以具有良好生物相容性的亲水性高分子材料为基质材料制备DDEA水凝胶贴剂;用离体大鼠腹部皮肤为模型,采用改良Franz扩散池装置进行经皮渗透实验.HPLC法测定不同时间点接收池中DDEA的浓度,计算药物的累积渗透量和经皮渗透动力学参数.结果 不同促渗剂对DDEA的经皮渗透有不同程度的促进作用,其中薄荷脑的促渗作用最为显著.薄荷脑对DDEA的促渗在1%～5%,呈正相关剂量效应关系,薄荷脑用量为5%时,药物的稳态透皮速率可达18.121 μg·cm-2·h-1,与空白对照组相比增渗倍数为5.45.结论 薄荷脑可作为DDEA水凝胶贴剂的促渗剂,并可开发此新型水凝胶贴剂.     

Low Intensity Ultrasound as a Probe to Elucidate the Relative Follicular Contribution to Total Transdermal Absorption

Purpose. To investigate the effect of ultrasound on the histological integrity and permeability properties of whole rat skin in vitro. Methods. A defined, field-free source of ultrasound was used to irradiate excised rat skin prior to in vitro transport studies in Franz-type cells using sucrose, mannitol, hydrocortisone, 5-fluorouracil and aminopyrine. Results. High intensity ultrasound irradiation (1 to 2 W cm^–2) irreversibly damaged cutaneous structures and increased the percutaneous transport rate of permeants. In contrast, skin integrity was largely maintained with low intensity ultrasound (0.1 to 1 W cm^–2) which merely discharged sebum from the sebaceous glands so as to fill much of the hair follicle shafts. This effect caused the transfollicular absorption pathway to be blocked for hydrophilic molecules that penetrate via this route and reduced the transport rate significantly. Conclusions. This phenomenon may be used as a probe to elucidate the relative follicular contribution to total penetration for hydrophilic permeants. It was demonstrated that the shunt pathway was responsible for virtually all mannitol and sucrose penetration, perhaps half of hydrocortisone transport but negligible aminopyrine and 5-fluorouracil penetration.     

Effect of Ultrasound Application on Skin Metabolism of Prednisolone 21-Acetate

Purpose. The effect of ultrasound on skin penetration and metabolism of prednisolone (PN) and prednisolone 21-acetate (PNA) was investigated in the hairless mouse skin in vitro. Methods. The abdominal skin excised freshly was pretreated under different ultrasound intensities (4.32, 2.88, and 1.50 W/cm²) for 10, 30, and 60 min. The penetration/metabolism rate of PNA and its metabolite (PN) was then measured using a side-by-side diffusion cell. Results. The skin penetration of PN was enhanced by the ultrasound pretreatment. This enhancement was attributed to the decrease in the stratum corneum barrier capacity by ultrasound energy. The steady-state appearance rate of PN following the skin bioconversion of PNA decreased appreciably with increasing the product of the duration of pretreatment (D_p, min) and the intensity of ultrasound applied (I_u W/cm²). When the product value was less than 40 W/cm² min, the steady-state appearance rate of the PN hardly increased in spite of the penetration enhancement of PNA. Conclusions. These findings indicated a possible deactivation of the skin enzymes by ultrasound energy.     

Reducing Systemic Absorption from Monochloracetic Acid Exposure Through Dermal Decontamination: Use of the Pig Ear Organ Culture System

Abstract

Severe systemic intoxication may occur after skin contamination with monochloracetic acid (MCA). For this reason the effects of decontaminating with either water (most commonly used) or bicarbonate on the rates of percutaneous penetration and dermal accumulation of radiolabeled MCA were measured using the blood-perfused pig ear model. The rate of percutaneous penetration of a 40% solution of MCA was measured after exposure times of 1, 3, and 10 min. Maximal rates of percutaneous penetration (ng/min/cm²; mean ± SEM) were 891 ± 335 for a 1 min exposure; 947 ± 191 for a 3 min exposure; and 3221 ± 515 for a 10 min exposure. Although the initial rate of percutaneous absorption (first 30 min) was directly related to the exposure time, there was no difference in maximal rates of percutaneous penetration for 1 and 3 min exposures. It appears, that for short exposure times, the percutaneous penetration rate is determined by both the rate of penetration into the skin and the rate of diffusion from dermal stores into the blood.

A saturated sodium bicarbonate solution and water proved equally effective in decontaminating the skin after a 10 min exposure to MCA. However, a saturated bicarbonate solution was a slightly more effective decontaminant than water after a 1 min exposure. Our data indicate that decontamination should take place as soon as possible after dermal contamination with MCA. Furthermore, decontamination should continue for as long as possible in order to reduce the systemic burden. In view of the toxicity of MCA and the speed with which dermal deposits can accumulate, it is essential that decontamination facilities (e.g., a shower or bath filled with decontaminant) are available at all points in the workplace where MCA is handled.     

Phonophoresis of Methyl Nicotinate: A Preliminary Study to Elucidate the Mechanism of Action

The skin penetration enhancement effect of ultrasound (phonophoresis) on methyl nicotinate was investigated in 10 healthy volunteers in a double-blind, placebo-controlled, crossover clinical trial. Each treatment consisted of the application of ultrasound massage (3.0 MHz, 1.0 W/cm² continuous output) or placebo massage (0 MHz) for 5 min to the forearms of the volunteers, followed by a standardized application of methyl nicotinate at intervals of 15 sec, 1 min, and 2 min postmassage. Percutaneous absorption of methyl nicotinate was monitored using laser Doppler velocimetry. Ultrasound treatment applied prior to methyl nicotinate led to enhanced percutaneous absorption of the drug, for example, ultrasound treatment data versus control data at 2 min showed significant increases (P < 0.05; analysis of variance) in the peak blood flow (125.8 ± 12.0 vs 75.3 ± 10.4% flux) and in the area under the curve for blood flow (2630.3 ± 387.5 vs 1567.6 ± 183.5% flux · min). The results of this study suggest that ultrasound affects the skin structure to provide skin penetration enhancement. This finding is consistent with the proposed hypothesis that phonophoresis acts by disordering the structured lipids in the stratum corneum.     

Use of the skin sandwich technique to probe the role of the hair follicles in sonophoresis

The human skin sandwich technique was used to explore the effect of brief ultrasound exposure on the transfollicular pathway of absorption. Hydrocortisone was used as a model drug. In order to calculate the permeability coefficient of hydrocortisone, its concentration at saturation in the PBS donor solution was determined. Skin samples were prepared by sandwich technique with total hydration of the epidermal and sandwich membranes. The skin was sonicated for 0 s (control), 30 s or 45 s using a pulsed mode (10% duty cycle) with the spatial and temporal average intensity (SATA) of 3.7 W/cm². The transducer was then removed and permeation was allowed to proceed for 52 h. Then the percentage follicular contribution was determined. It was determined that without ultrasound, drug entry into follicles accounted for 46% of total penetration. As the duration of sonication increased, the follicular contribution fell to zero even though total transepidermal flux dramatically increased. This is explained by ultrasound exposure causing sloughing off of the uppermost stratum corneum. This permeabilises the continuous surface but at the same time the disturbed cornceocytes will plug hair follicle orifices.     

Influence of ultrasound on the percutaneous absorption of ketorolac tromethamine in vitro across rat skin

The influence of ultrasound on percutaneous absorption of ketorolac tromethamine was studied in vitro across rat skin. Sonication was carried out with a continuous mode, at an intensity of 1-3 W/cm² and a frequency of 1 MHz for 30 min. A significant increase in permeation of ketorolac through rat skin was observed with the applied sonication at 3 W/cm² when compared with permeation at 1 and 2 W/cm². Enhanced ketorolac penetration at 3 W/cm² can be explained by the mechanical and/or thermal action of ultrasound waves. The distance of the ultrasound probe from the skin surface did not influence the flux of the drug. Pretreatment of skin by 5% d-limonene in ethanol for 2 hr followed by sonication at 3 W/cm² (30 min) significantly enhanced the permeation of ketorolac when compared with passive flux with or without enhancer pretreatment.     

Low frequency sonophoresis mediated transdermal and intradermal delivery of ketoprofen

The objective of this study was to test low frequency sonophoresis at 20 kHz for delivery of ketoprofen into and across the skin. Permeation studies were carried out in vitro on excised hairless rat skin over a period of 24 h using Franz diffusion cells after which, skin samples were subjected to skin extraction to quantify the amount of drug present in skin. Parameters like ultrasound application time, duty cycle coupling medium and distance of ultrasound horn from skin were optimized. Transepidermal water loss (TEWL) was measured to indicate the extent of barrier disruption following sonophoresis. Confocal microscopy was used to visualize dye penetration through sonophoresis treated skin. Application of ultrasound significantly enhanced permeation of ketoprofen from 74.87 ± 5.27 μg/cm² for passive delivery to 491.37 ± 48.78 μg/cm² for sonophoresis. Drug levels in skin layers increased from 34.69 ± 7.25 μg following passive permeation to 212.62 ± 45.69 μg following sonophoresis. TEWL increased from 31.6 ± 0.02 (passive) to 69.5 ± 12.60 (sonophoresis) indicating disruption of barrier properties. Confocal microscopy images depicted enhanced dye penetration through sonophoresis treated skin confirming barrier disruption. Low frequency sonophoresis with optimized ultrasound parameters can be effectively used to actively enhance transdermal and topical delivery of ketoprofen.     

Topical Delivery of Anti-sense Oligonucleotides Using Low-Frequency Sonophoresis

No HeadingPurpose. Topical delivery of oligonucleotides, though attractive for the treatment of skin disorders, is limited by the low permeability of the stratum corneum. Herein, we assessed the potential of low-frequency ultrasound (20 kHz, 2.4 W/cm²) in delivering therapeutically significant quantities of anti-sense oligonucleotides into skin.Methods. Dermal penetration of oligonucleotides penetration was quantified in vitro using radiolabeled oligonucleotides.Results. Estimated concentrations of oligonucleotides (ODNs) in the superficial layers of the skin ranged from ~0.5% to 5% of the donor concentration after a 10-min application of ultrasound and ODN. Microscopic evaluations using fluorescently labeled oligonucleotides and sulforhodamine B revealed heterogeneous penetration into the skin. Heterogenous penetration led to the formation of localized transport pathways (LTPs), which occupied about 5% of the total exposed skin area. Immuno-histochemical studies using an oligonucleotide that reacts specifically with an antibody also confirmed penetration of ODNs into LTPs. Histologic studies revealed that no gross structural changes were induced in the skin due to ultrasound application.Conclusions. These results show successful delivery of anti-sense oligonucleotides using low-frequency ultrasound.     

In vitro study of low-frequency ultrasound-enhanced transdermal transport of fentanyl and caffeine across human and hairless rat skin

The effect of low-frequency sonophoresis on fentanyl and caffeine permeation through human and hairless rat skin was studied in vitro. Experiments were performed using 20 kHz ultrasound applied at either continuous or discontinuous mode and with an average intensity of 2.5 W/cm(2). The results showed that low-frequency ultrasound enhanced the transdermal transport of both fentanyl and caffeine across human and hairless rat skin. This was explained by both increasing flux during sonication and shortening the lag time. Discontinuous mode was found to be more effective in increasing transdermal penetration of fentanyl while transdermal transport of caffeine was enhanced by both continuous and pulsed mode. Histological and electron microscopy studies showed that human and hairless rat skin was unaffected by ultrasound exposure. Further studies will be necessary to determine the relative contribution of ultrasound parameters in low-frequency ultrasound-induced percutaneous enhancement of drug transport.