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。     

薄荷脑和樟脑对复方苯海拉明乳膏透皮作用的影响

目的研究薄荷脑和樟脑对复方苯海拉明乳膏中盐酸苯海拉明和苯佐卡因透皮作用的影响。方法采用改良Franz直立式扩散池,以离体乳猪皮肤为渗透屏障进行体外透皮扩散试验,以盐酸苯海拉明和苯佐卡因的累积渗透量、稳态流量及皮肤滞留量为指标,考察薄荷脑和樟脑在处方中的透皮调节作用。结果薄荷脑和樟脑对盐酸苯海拉明的累积渗透量、稳态流量及皮肤滞留量均无显著影响(P>0.05);对苯佐卡因的累积渗透量、稳态流量有显著抑制作用(P<0.01),并能提高其12 h皮肤滞留量(P<0.05)。结论薄荷脑和樟脑在复方苯海拉明乳膏中除发挥其药理活性外,还能调节药物的透皮吸收,其对苯佐卡因经皮渗透的抑制及皮肤滞留量的增加可能更有利于复方苯海拉明乳膏发挥局部治疗作用。     

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。     

低频超声波促进重酒石酸卡巴拉汀经皮渗透的研究

目的研究低频超声波对重酒石酸卡巴拉汀(rivastigmine hydrogen tartrate,RHT)经皮渗透的促进作用。方法通过对小鼠、大鼠、小型猪和乳猪皮肤性能的考察,选择乳猪腹部皮肤进行经皮渗透实验。采用20 k Hz的超声波,于单室扩散池中测定2%的RHT水溶液的经皮渗透速率,考察超声波强度和暴露时间的影响。结果当超声波暴露时间为3 min时,超声波强度从2 W·cm?2增加到11 W·cm?2,超声波对RHT的促渗倍数从9.15倍增加到84.79倍。超声波强度为2 W·cm?2时,超声时间从3 min增加到30 min,促渗倍数从9.15倍增加到42.85倍。结论低频超声波对RHT有很强的经皮渗透促进作用,增加超声的功率或者延长超声的时间,均能够明显增强超声对RHT的促渗作用。     

盐酸利多卡因凝胶剂处方优化及稳定性考察

目的:考察多种渗透促进剂对盐酸利多卡因凝胶经皮渗透的影响,并从中筛选其最佳处方组成。方法:采用离体皮肤渗透实验,以渗透速率为指标,均匀设计优化处方工艺,考察不同渗透促进剂对羧甲基纤维素钠(CMC-Na)基质的凝胶剂中利多卡因的经皮渗透效果。结果:含1.5%月桂氮(?)酮,4%聚乙二醇-400,2%泊洛沙姆和25%丙二醇(PG)的盐酸利多卡因凝胶剂具有最佳的经皮渗透速率,且处方稳定,对皮肤无刺激性。结论:渗透促进剂对盐酸利多卡因经皮渗透有显著的促进作用。     

不同扩散膜对布洛芬乳膏体外经皮扩散实验研究

目的研究布洛芬乳膏在不同扩散膜上的经皮扩散情况以及氮酮(Azone)对其扩散的影响.方法使用流通扩散池对含氮酮和不含氮酮的布洛芬乳膏进行体外经皮扩散实验,测定累积渗透量,计算其经皮扩散速率.结果鼠皮的经皮扩散速率明显高于蛇蜕的经皮扩散速率(P＜0.01),不加促透剂的经皮扩散速率,鼠皮是蛇蜕的6倍;加促透剂的经皮扩散速率,鼠皮是蛇蜕的3.5倍;氮酮对蛇蜕的促透作用比鼠皮强.结论蛇蜕作为体外透皮实验的扩散膜其实验数据会更有实际意义.     

复方盐酸萘替芬乳膏对离体豚鼠皮肤的透皮吸收研究

目的:研究复方盐酸萘替芬乳膏对离体豚鼠皮肤的透皮作用及皮肤组织中的药物浓度。方法:采用静态渗透室装置,皮片涂不同浓度盐酸萘替芬、酮康唑单一及复方乳膏制剂(盐酸萘替芬1%、2%、4%,酮康唑0.25%、0.5%、1%)后36h内不同时间(6、12、24、36h)取样,采用高效液相色谱法测定样品中及皮肤组织中盐酸萘替芬、酮康唑浓度。结果:盐酸萘替芬、酮康唑经离体豚鼠皮的透过率随时间的延长而缓慢增加。36h时,高浓度复方制剂中盐酸萘替芬、酮康唑经离体豚鼠皮的平均透过率分别为(9.3±8.6)×10-3%、(1.39±0.20)%;豚鼠皮中二者浓度分别为(29.81±12.16)、(60.76±5.47)μg.g-1。结论:复方盐酸萘替芬乳膏局部皮肤给药36h后,药物在皮肤组织中浓度较高,表明其透过皮肤吸收较少。     

滚轮微针技术对黄柏提取物乳膏中盐酸小檗碱经皮渗透的促进作用

采用回流法制备黄柏提取物,再制成o/w型乳膏.用HPLC法测定盐酸小檗碱的含量.以离体裸鼠皮肤为屏障,用改良Franz扩散池法考察乳膏中盐酸小檗碱的体外透皮性能,探讨滚轮微针技术对黄柏提取物乳膏中盐酸小檗碱体外经皮渗透行为和皮肤滞留量的影响.结果显示,不用或采用微针处理组乳膏中盐酸小檗碱12h的累积渗透量为(0.161±0.008)、(0.978±0.034) mg/cm2,经皮渗透速率为(0.035±0.007)、(0.197±0.018) mg·cm-2·h-1,皮肤滞留量为(0.373±0.021)、(1.364±0.342)mg/cm2.可见,滚轮微针技术能显著提高外用黄柏提取物乳膏中盐酸小檗碱的经皮渗透量(P＜0.05),增加皮肤内药物滞留量(P＜0.05).     

离体皮肤渗透试验重复优化盐酸利多卡因凝胶剂处方工艺

目的 :考察多种渗透促进剂对盐酸利多卡因凝胶经皮渗透的影响 ,并从中筛选其最佳处方组成。方法 :采用离体皮肤渗透试验 ,以渗透速率常数 (Y)和渗透率 (J)为指标 ,均匀设计和正交设计优化处方工艺 ,考察不同渗透促进剂对卡波普 (Carbopol)凝胶中利多卡因的经皮渗透效果。结果 :含氮酮 (Azone) 1.5 %、聚乙二醇 -4 0 0 (PEG-4 0 0 ) 0 .5 %、泊洛沙姆 (F-68) 4%、丙二醇 (PG) 2 5 %的盐酸利多卡因凝胶的经皮渗透效果最佳 ,并具有良好的稳定性 ,对皮肤无刺激性。结论 :通过重复优化法筛选出渗透促进剂对凝胶中盐酸利多卡因的最佳处方。     

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.     

Sonophoresis. I. The Use of High-Frequency Ultrasound to Enhance Transdermal Drug Delivery

Previous attempts to use ultrasound (1-MHz frequency and 1 to 3-W/cm² intensity) to enhance transdermal drug delivery (so-called sonophoresis) have produced inconsistent results. Theoretical analysis of ultrasound propagation in tissue predicts that higher-frequency ultrasound (>1 MHz) will increase the concentration of energy deposition in the stratum corneum (SC) (typically, the rate-limiting barrier to percutaneous penetration). This hypothesis was tested by comparing the passive transdermal delivery of salicylic acid with that under the influence of ultrasound at 2-, 10-, and 16-MHz frequency; measurements were performed in vivo in hairless guinea pigs. Total drug absorbed was quantified by determining the amount of salicylic acid (1) present in SC tape strips and (2) eliminated in urine. Sonophoresis for 20 min at 2 MHz caused no significant increase in salicylic acid delivery over passive diffusion; treatment with ultrasound at 10 and 16 MHz, on the other hand, significantly elevated salicylic acid transport, by 4-fold and 2.5-fold, respectively. Kinetic analysis of the sonophoretic data at 10 and 16 MHz also revealed that the diffusion lag time associated with transdermal drug delivery (TDD) was reduced. A shorter period (5 min) of sonophoresis again resulted in enhanced TDD (relative to the corresponding control) at the higher frequencies; the delivered dose, and the level of enhancement, however, were lower than those after the 20-min treatment. In a separate series of experiments, it was shown that (a) ultrasound did not alter the release kinetics of salicylic acid from the gel formulation used and (b) pretreatment of the skin with ultrasound at 10 and 16 MHz lowered skin barrier function such that the subsequent delivery of salicylic acid was enhanced compared to passive transport without sonophoresis pretreatment. It follows that the enhancing effect of sonophoresis is due to a direct effect of ultrasound on (presumably) the stratum corneum.     

A combined approach of chemical enhancers and sonophoresis for the transdermal delivery of tizanidine hydrochloride

The effects of chemical enhancers and sonophoresis on the transdermal permeation of tizanidine hydrochloride (TIZ) across mouse skin were investigated. Parameters including drug solubility, apparent partition coefficient (APC), drug permeation, and degradation in skin were determined. Low frequency ultrasound was also applied in the presence and absence of chemical enhancers to assess whether drug permeation improved. APC values indicated that TIZ preferentially partitions into intercellular spaces and does not form a reservoir, with the drug also exhibiting good enzymatic stability in skin. Most of the enhancers studied significantly increased the permeation rate of TIZ through full thickness mouse skin in comparison with TIZ formulated in phosphate buffer. Maximum enhancement was observed for TIZ formulated as a suspension in 50% v/v aqueous ethanol containing 5% v/v citral. Sonophoresis significantly (p < 0.05) increased the cumulative amount of TIZ permeating through the skin at 15 and 30 min in comparison to passive diffusion. A synergistic effect was noted when sonophoresis was applied in the presence of chemical enhancers. The results suggest that the formulation of TIZ with an appropriate penetration enhancer may be useful in the development of a therapeutic system to deliver TIZ across the skin for a prolonged period, i.e. 24 hr. The application of ultrasound in association with chemical enhancers, such as the combination of 5% v/v citral in 50% v/v aqueous ethanol, could further serve as a non-oral and non-invasive drug delivery modality for the immediate therapeutic effect of muscle relaxants such as TIZ.     

Lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel delivery by combined microneedle and ultrasound

Abstract

A study that combines microneedles (MNs) and sonophoresis pre-treatment was explored to determine their combined effects on percutaneous delivery of lidocaine from a polymeric hydrogel formulation. Varying ratios of carboxymethylcellulose and gelatine (NaCMC/gel ranges 1:1.60–1:2.66) loaded with lidocaine were prepared and characterized for zeta potential and particle size. Additionally, variations in the formulation drying techniques were explored during the formulation stage. Ex vivo permeation studies using Franz diffusion cells measured lidocaine permeation through porcine skin after pre-treatment with stainless steel MNs and 20?kHz sonophoresis for 5-and 10-min durations. A stable formulation was related to a lower gelatine mass ratio because of smaller mean particle sizes and high zeta potential. Lidocaine permeability in skin revealed some increases in permeability from combined MN and ultrasound pre-treatment studies. Furthermore, up to 4.8-fold increase in the combined application was observed compared with separate pre-treatments after 30?min. Sonophoresis pre-treatment alone showed insignificant enhancement in lidocaine permeation during the initial 2?h period. MN application increased permeability at a time of 0.5?h for up to ～17 fold with an average up to 4 fold. The time required to reach therapeutic levels of lidocaine was decreased to less than 7?min. Overall, the attempted approach promises to be a viable alternative to conventional lidocaine delivery methods involving painful injections by hypodermic needles. The mass transfer effects were fairly enhanced and the lowest amount of lidocaine in skin was 99.7% of the delivered amount at a time of 3?h for lidocaine NaCMC/GEL 1:2.66 after low-frequency sonophoresis and MN treatment.     

Identification and assessment of permeability enhancing vehicles for transdermal delivery of glucosamine hydrochloride

As an initial step to develop the transdermal delivery system of glucosamine hydrochloride (GL-HCl), the permeation study across the rat skin in vitro was performed to identify the most efficient vehicle with regard to the ability to deliver GL-HCl transdermally. The GL-HCl formulations such as o/w cream, liposome suspension, liposomal gel, and liquid crystalline vehicles were prepared and compared for transdermal flux of GL-HCl. The liquid crystalline vehicles were more effective in increasing the skin permeation of GL-HCl than o/w cream and liposomal vehicles. Of the liquid crystalline vehicles tested, the permeation enhancing ability of the cubic phase was greater than that of the hexagonal phase when the nanoparticle dispersion was used. The skin permeation enhancing ability of the cubic nanoparticles for GL-HCl was further increased by employing both oleic acid and polyethylene glycol 200. Therefore, the cubic liquid crystalline nanodispersion containing oleic acid and PEG 200 can provide a possibility of clinical application of transdermal GL-HCl.     

Transdermal iontophoresis of sodium nonivamide acetate. V. Combined effect of physical enhancement methods

The effect of iontophoresis combined with treatment of other physical enhancement methods such as electroporation, low frequency ultrasound, and erbium:YAG (yttrium-aluminum-garnet) laser on the transdermal delivery of sodium nonivamide acetate (SNA) was examined in this present study. Iontophoresis increased the transdermal flux of SNA in vitro as compared to the passive diffusion without any enhancement. Furthermore, iontophoresis was always the most potent enhancement method for SNA permeation among the physical enhancement methods tested. Pulsing of high voltages (electroporation) followed by iontophoresis did not result in increased transport over iontophoresis alone. However, electroporation shortened the onset of transdermal iontophoretic delivery of SNA. Pretreatment of low frequency ultrasound (sonophoresis) alone on skin did not increase the skin permeation of SNA. The combination of iontophoresis and sonophoresis increased transdermal SNA transport more than each method by itself. The enhancement of drug transport across shunt routes and reduction of the threshold voltage in the presence of an electric field may contribute to this synergistic effect. Use of an erbium:YAG laser was a good method for enhancing transdermal absorption of SNA because it allows precise control of stratum corneum (SC) removal, and this ablation of SC could be reversible to the original normal status. The combination of laser treatment and iontophoresis also synergized the skin permeation of SNA, possibly due to a gradual drop in the electric resistance of the skin. The results in this present study point out that the choice of certain conditions with suitable physical enhancement methods can induce a synergistic effect on transdermal delivery of SNA during iontophoresis.     

The effect of formulation vehicles on the in vitro percutaneous permeation of ibuprofen

Background

The transdermal application of substances represents an elegant approach to overcome side effects related to injections or oral treatment. Due to benefits like a constant plasma level, no pain during application and a simple therapeutic regime, the optimization of formulations for transdermal drug delivery has gained interest in the last decades. Ibuprofen is a non-steroidal anti-inflammatory compound which is nowadays often used transdermally. The objective of this work was to conduct a study on the effect of different 5% ibuprofen containing formulations (Ibutop^? cream, Ibutop^? gel, and ibuprofen solution in phosphate buffered saline) on the in vitro-percutaneous permeation of ibuprofen through skin to emphasise the importance of the formulation on percutaneous permeation and skin reservoir.

Methods

The permeation experiments were conducted in Franz-type diffusion cells according to OECD guideline 428 with 2 mg/cm² ibuprofen formulation on each skin sample. Ibuprofen was analysed in the receptor fluid and extracted skin samples by UV-VIS high-performance liquid-chromatography at 238 nm. The plot of the cumulative amount of ibuprofen permeated versus time was employed to calculate the apparent permeability coefficient, the maximum flux and the lagtime, all of which were statistically analysed by One-way ANOVA.

Results

Although ibuprofen permeation out of the gel increases rapidly within the first four hours, the cream produced the highest ibuprofen delivery through the skin within 28 hours, followed by the solution and the gel. A significant shorter lagtime was found after gel treatment compared with the cream and the solution. After 28 hours 59% of the applied ibuprofen was found in the receptor fluid of the cream treated samples, 26% in the solution treated samples and 21% in the samples treated with the gel. Fourfold higher ibuprofen reservoirs were found in the solution and gel treated skin samples compared to the cream treated skin samples.

Conclusion

The present study demonstrates the importance of the formulation on transdermal drug delivery of ibuprofen and emphasises the differences of drug storage within the skin due to the formulation. Thus, it is a mistaken assumption that formulations comprising the same drug amount are equivalent regarding skin permeability.     

Single-layer transdermal film containing lidocaine: modulation of drug release.

We have recently described an innovative drug delivery system, a water-based and vapor permeable film intended for dermal and/or transdermal delivery. The aim of this work was to modulate the delivery of the model drug lidocaine hydrochloride from the transdermal film across rabbit ear skin. The effect of drug loading, of film-forming polymer type and content, of adhesive and plasticizer on lidocaine transport across the skin was evaluated. Additional objective was to evaluate the effect of occlusion on the kinetics of lidocaine transport, by applying an occlusive backing on the surface of the transdermal film. From the data obtained it can be concluded that the transdermal film acts as a matrix controlling drug delivery. The film-forming polymer molecular weight had a negligible effect on drug penetration, while its content was more effective. The choice of the adhesive seems to be the most important variable governing drug transport. In particular, the presence of lauric acid combined with a basic drug, such as lidocaine, can produce a relevant improvement in permeation, because of the formation of an ion pair. Concerning the kinetics, drug depletion is responsible for the declining permeation rates observed in the late times of permeation.     

Transdermal Drug Delivery Using Low-Frequency Sonophoresis

Purpose. Application of therapeutic ultrasound (frequency: 1–3 MHz and intensity: 0–2 W/cm²) enhances transdermal drug transport, although typically by a factor of less than 10. In this paper, we show that application of ultrasound at 20 KHz induces transdermal transport enhancements of up to 1000 times higher than those induced by therapeutic ultrasound. Methods. In vitro (human cadaver epidermis) as well as in vivo (hairless rat skin) permeation experiments were performed to assess the effect of low-frequency ultrasound on transdermal transport. Results. Application of low-frequency ultrasound (20 KHz, 125 mW/cm², 100 msec pulses applied every second) enhanced transdermal transport of several permeants, including estradiol, salicylic acid, corticosterone, sucrose, aldosterone, water, and butanol, across human cadaver skin by a factor in the range of 3 to 3000 and that of salicylic acid across hairless rat skin in vivo by a factor of up to 300. Low-frequency ultrasound did not induce a long-term loss of the barrier properties of the skin (in vitro) or damage to living skin of hairless rats. At a mechanistic level, it is hypothesized that application of low-frequency ultrasound enhances transdermal transport through aqueous channels in the SC generated by cavitation-induced bilayer disordering. Support for this hypothesis is provided using experimental and theoretical analyses of low-frequency sonophoresis. Conclusions. Low-frequency ultrasound enhances transdermal transport of drugs more effectively than that induced by therapeutic ultrasound.     

Bacterial cellulose membranes applied in topical and transdermal delivery of lidocaine hydrochloride and ibuprofen: in vitro diffusion studies

Bacterial cellulose (BC) is a biomaterial with unique physical and mechanical properties that triggered considerable interest, but there are few studies addressing the use of such membranes for drug loading and controlled release. This study aimed to investigate the applicability of BC membranes in topical or transdermal drug delivery systems. To assess its therapeutic feasibility, the permeation through human epidermis of two model drugs (lidocaine hydrochloride and ibuprofen) in BC and other formulation systems was compared in vitro. A uniform distribution of both drugs in the BC membranes was achieved. Diffusion studies with Franz cells showed that the incorporation of lidocaine hydrochloride in BC membranes provided lower permeation rates than those obtained with the conventional formulations. However, the results obtained with the lipophilic drug were quite different, since permeation of ibuprofen in BC was almost three times higher than that of the drug in the gel or in a PEG400 solution. These results indicate that this technology can be successfully applied to modulate the bioavailability of drugs for percutaneous administration, which could be particularly advantageous in the design of delivery systems that have, simultaneously, the ability to absorb exudates and to adhere to irregular skin surfaces.