盐酸异丙肾上腺素的颊粘膜渗透

利用单室扩散池研究了盐酸异丙肾上腺素通过金黄地鼠颊粘膜的药物渗透。结果表明,在12h 内,30mg/ml 的药物水溶液渗透速率为5.51μg/(cm²·h),以20% PG 和1%Tween20为溶媒30mg/ml 的药物溶液的渗透速率为9.78μg/(cm²·h),增加0.8倍。含60mg 药物贴剂渗透速率为14.94μg/(cm²·h),当在贴剂中加10%Azone 时,其渗透速率为545.96μg/(cm²·h),增加35.4倍。     

利拉萘酯喷雾剂的经皮渗透研究

目的 研究利拉萘酯喷雾剂的经皮渗透性。方法 采用改良Franz扩散池,以小型猪皮肤为渗透屏障,高效液相色谱法测定利拉萘酯含量。结果 利拉萘酯喷雾剂和乳膏剂的稳态透皮速率分别为(0.017±0.006),(0.014±0.003)μg·cm^-2·h^-1;利拉萘酯喷雾剂和乳膏剂的24 h累积渗透量分别为(0.60±0.23),(0.44±0.15)μg·cm^-2;利拉萘酯喷雾剂和乳膏剂在皮肤中的药物残留量分别为(8.2±1.3),(7.7±1.6)μg·g^-1。结论 利拉萘酯喷雾剂的稳态透皮速率、24 h累积渗透量、在皮肤中的药物残留量均稍大于利拉萘酯乳膏剂,但2种剂型之间没有显著性差异。     

十一酸睾酮二元醇质体凝胶剂体内外透皮特性研究

摘 要 目的：对十一酸睾酮（TU）二元醇质体凝胶进行体内外透皮考察。方法: 采用注入法制备TU二元醇质体,以卡波姆941为凝胶基质,制备TU二元醇质体凝胶剂;以小鼠皮肤为屏障,采用Franz扩散池法对其体外透皮特性进行考察;以大鼠为实验动物,背部给予TU二元醇质体凝胶剂后,于设定的时间点测定血浆中TU浓度,计算药动学参数,并与TU二元醇质体进行比较。结果: TU二元醇质体及其凝胶的体外累积透皮百分率Q与时间t均符合一级动力学模型,线性方程分别为：Q=8.68t+6.78（r=0.998 2）和Q=6.09t+3.09（r=0.999 3）,稳态透皮速率分别为8.68 μg·cm^-2·h^-1和6.09 μg·cm^-2·h^-1,24 h后TU在皮肤中的滞留量分别为（208.80±55.26）μg·g^-1和（225.60±38.90）μg·g^-1;大鼠体内TU二元醇质体及其凝胶的主要药动学参数分别为：Cmax（18.50±2.75）mg·L^-1和（20.80±2.42）mg·L^-1;tmax（6.20±0.14）h和（9.54±0.52）h;AUC0-48h（336.74±2.05）h和（486.30±1.68）h。结论:TU二元醇质体及其凝胶均呈现较好的体内外透皮特性,且在缓释性上凝胶剂表现更优。     

依达拉奉凝胶的制备及体外透皮性能研究

目的 考察依达拉奉凝胶体外经皮渗透性,筛选凝胶剂最佳处方。方法 采用Valin-Chien双室渗透扩散池,以大鼠离体皮肤为渗透屏障,以HPLC测定依达拉奉的浓度,考察含药量、月桂氮（艹卓）酮用量、环糊精的型号和含量对依达拉奉凝胶剂经皮渗透性的影响。结果 凝胶剂最佳处方为6%依达拉奉、10%月桂氮（艹卓）酮、10% β-环糊精、2%羧甲基纤维素钠,依达拉奉12 h累积渗透量平均值为(501.95±27.59)μg·cm^-2,渗透速率平均值为(42.25±7.39)μg·cm^-2·h^-1。结论 依达拉奉凝胶剂具有较好的经皮渗透特性,有望成为新的给药制剂。     

离子导入对降纤酶经皮渗透的影响

目的研究离子导入对降纤酶经皮渗透的影响。方法利用水平式扩散池，对降纤酶进行离子导入透过大鼠皮肤和人尸表皮的渗透性试验，对电极极性、渗透介质的pH以及离子强度等影响进行考察。结果离子导入阳极转运时，在pH 6.4的磷酸盐缓冲介质中，降纤酶的表观经皮渗透系数为（1.2±0.4）×10^-4 cm·h^-1，明显高于阴极转运［（4.3±1.4）×10^-5 cm·h^-1］；在pH 7.4磷酸盐缓冲介质中，降纤酶阳极离子导入经皮渗透量为（25±5）×10^-14 mol·cm^-2高于pH 6.4介质经皮渗透量［(15±4)×10^-14 mol·cm^-2］。结论离子导入阳极转运能够促进降纤酶的经皮渗透，电渗作用有重要影响。     

十一酸睾酮二元醇质体体外透皮特性及其安全性研究

摘 要 目的： 对十一酸睾酮（TU）二元醇质体的体外透皮特性进行考察,并对其皮肤安全性进行研究。方法: 采用注入法制备TU二元醇质体;以小鼠皮肤为屏障,采用Franz扩散池法对其体外透皮特性进行考察;以豚鼠为实验动物,对其皮肤刺激性、过敏性、毒性进行考察。结果: TU二元醇质体平均包封率为（79.14±0.66）%;体外透皮实验中,累积释药百分率Q与时间t的关系符合一级动力学方程：Q=8.57t+8.26（r=0.998 6）,稳态透皮速率为8.57 μg·cm^-2·h^-1;24 h后TU在皮肤中的滞留量为（208.8±55.26）μg·g^-1;TU二元醇质体无明显局部刺激性、致敏性及急性毒性。结论: TU二元醇质体表现出较好的体外透皮渗透性,且安全性理想,值得进一步研究。     

黄体酮热熔压敏胶透皮贴剂的制备及其体外释药性能研究

目的 制备黄体酮热熔压敏胶透皮贴剂并考察其体外释药性能。 方法 采用苯乙烯-异戊二烯-苯乙烯热塑性弹性体热熔压敏胶为骨架材料,以大鼠离体皮肤为渗透屏障,采用改良Freeze扩散池,用HPLC法测定接收液浓度,筛选促渗剂的种类、浓度和涂布厚度,确定贴剂处方。 结果 促渗剂选择肉豆蔻酸异丙酯(IPM),含量为2%;选择涂布厚度为300 μm,得到累积渗透曲线为Q=6.172 1 t-5.457 7(r=0.998 8);24 h药物累积渗透量为144.17 μg/cm²;稳态渗透速率为(6.17±0.49) μg/(cm²·h)。 结论 制备的黄体酮热熔压敏胶透皮贴剂中的有效成分黄体酮体外经皮渗透良好,具有较好的临床应用前景。     

基于透皮离子导入技术的戒烟药物金雀花碱的可控递送研究

目的 探索烟碱乙酰胆碱受体部分激动剂金雀花碱(cytisine，CTS)经阳极离子导入透过离体猪皮。方法 采用HPLC-PDA建立并验证CTS的分析方法。研究了电流密度、药物浓度和药物基质对CTS透皮离子导入的影响。采用标志物对乙酰氨基酚解析CTS离子导入过程中电迁移和电渗的贡献。结果 CTS从水溶液中被动透皮不佳，但在离子导入条件下CTS的透皮递送量显著增加，将电流密度从0.15 mA·cm^–2增加到0.5 mA·cm^–2可使离子导入CTS的稳态流量呈线性增加(J=452.8I+31.51，r=0.998 3)。在使用0.5 mA·cm^–2电流密度的条件下，给药池药物浓度的增加(2.5，5.0，10.0 mg·mL^–1)可使累积透皮递送量显著增加。共离子导入对乙酰氨基酚证实了电迁移是CTS的主要递送机制(˃90%)。CTS的传导效率良好(6.63%~8.82%)。递送效率，即递送药物占所给予的制剂中的药物的百分数较高(在0.5 mA·cm^–2时>40%)。CTS从离子导入贮库HEC水凝胶中递送时的累积透皮递送量为(1 551.94±322.19)μg×cm^–2，与从CTS溶液中递送时的累积透皮递送量无统计学差异。结论 体外数据表明，使用较小面积的凝胶贴片通过透皮离子导入可以方便地递送治疗剂量的CTS。     

盐酸罗哌卡因透皮凝胶剂的处方优化

摘 要 目的：筛选盐酸罗哌卡因透皮凝胶剂的最佳处方。方法: 以盐酸罗哌卡因凝胶的稳态透皮速率和24 h累积透皮率为考察指标,采用3因素3水平进行正交试验设计,并采用Design Expert 8.0.5.0软件对试验结果进行分析,确定最佳处方。结果: 最佳处方的组成为：卡波姆2%,丙二醇10%,氮酮5%。以最佳处方制得的凝胶稳态透皮速率为0.695 1 mg·h^-1·cm^-2,24 h累积透皮率为91.04%,与相同浓度的盐酸罗哌卡因药物溶液相比,24 h累积透皮率提高了22.79%。Design Expert 8.0.5.0软件对最佳处方的稳态透皮速率和24 h累积透皮率预测值良好。结论:该处方设计合理,性质良好,适合作为皮肤局部用药。     

9-硝基喜树碱在Caco-2细胞模型中的体外摄取、转运及外排动力学

目的研究9-硝基喜树碱(9-NC)的细胞摄取、转运及外排特性。方法一种体外培养的人小肠上皮细胞模型Caco-2应用于9-NC的小肠上皮细胞的摄取、跨膜转运及外排动力学研究。评价了时间、温度、pH,P-糖蛋白(P-glycoprotein, P-gp)抑制剂对细胞摄取的影响。采用HPLC测定药物含量。结果9-硝基喜树碱以被动扩散为主要方式被细胞摄取和转运。药物的摄取与时间呈正相关，与温度、pH呈负相关。P-gp抑制剂环孢菌素和维拉帕米增加9-NC细胞摄取(P<0.05)。药物从Basolateral(B,基底面)到Apical(A,肠腔面)的渗透系数P_app大于A到B(2.6-6.9倍)。9-NC外排符合二级外排动力学过程，A侧m₀［(148.0±2.2) pmol·cm^-2］和外排速率(41.1 pmol·cm²·min^-1)高于B侧的m₀［(121±7) pmol·cm^-2(P<0.05)和外排速率(29.2 pmol·cm²·min^-1)(P<0.01)。结论 9-NC是以被动扩散方式为主要方式被小肠上皮细胞摄取和转运，并受到P-糖蛋白强烈的外排作用。     

Human Calcitonin Delivery in Rats by Iontophoresis

Abstract— In-vitro iontophoresis (0·33 mA cm⁻²) of calcitonin (50 μg mL⁻¹, pH 4) was performed with the hairless rat skin model. Direct current was as potent as pulse current (2·5 kHz on/off 1/1) iontophoresis in promoting transdermal permeation of calcitonin. Increase in duration of current application from 20 min to 1 h did not increase calcitonin flux. Results suggest that calcitonin can be blocked in the skin pores through which it travels or can accumulate in the skin and be progressively released from the depot. Invivo experiments showed that transdermal iontophoretic administration of calcitonin induced a hypocalcaemic effect in rats.     

Transdermal iontophoresis of insulin. Part 1: A study on the issues associated with the use of platinum electrodes on rat skin

We have studied the issues associated with the use of platinum electrodes for transdermal iontophoretic delivery of peptides, using insulin as a model peptide. Insulin permeation was studied using full-thickness rat skin by varying the donor solution pH as a function of electrode polarity. The stability of insulin under the iontophoretic conditions was studied using TLC, SDS-polyacrylamide gel electrophoresis and HPLC. Large pH shifts were observed during anodal iontophoresis (AI), when the donor solution pH was above the isoelectric point of insulin and in cathodal iontophoresis (CI), when the donor solution pH was below the isoelectric point of insulin. The direction and magnitude of electroosmotic flow was influenced by pH of the donor solution and the electrode polarity. On the other hand, the buffer used to maintain the pH governed the contribution of electrorepulsion to the overall transport of insulin. Electrochemical degradation of insulin was significant during AI at pH 7.4. Among the pH investigated, AI of insulin at pH 3.6 and CI at pH 8.35 were better, as the pH shift was relatively less and electrochemically more stable during iontophoresis as compared with other pH. In summary, the pH shift caused by platinum electrodes had a significant influence on the permeation and stability of insulin.     

Controlled delivery of ropinirole hydrochloride through skin using modulated iontophoresis and microneedles

Abstract

The objective of this study was to investigate the effect of modulated current application using iontophoresis- and microneedle-mediated delivery on transdermal permeation of ropinirole hydrochloride. AdminPatch® microneedles and microchannels formed by them were characterized by scanning electron microscopy, dye staining and confocal microscopy. In vitro permeation studies were carried out using Franz diffusion cells, and skin extraction was used to quantify drug in underlying skin. Effect of microneedle pore density and ions in donor formulation was studied. Active enhancement techniques, continuous iontophoresis (74.13?±?2.20?µg/cm²) and microneedles (66.97?±?10.39?µg/cm²), significantly increased the permeation of drug with respect to passive delivery (8.25?±?2.41?µg/cm²). Modulated iontophoresis could control the amount of drug delivered at a given time point with the highest flux being 5.12?±?1.70?µg/cm²/h (5–7?h) and 5.99?±?0.81?µg/cm²/h (20–22?h). Combination of modulated iontophoresis and microneedles (46.50?±?6.46?µg/cm²) showed significantly higher delivery of ropinirole hydrochloride compared to modulated iontophoresis alone (84.91?±?9.21?µg/cm²). Modulated iontophoresis can help in maintaining precise control over ropinirole hydrochloride delivery for dose titration in Parkinson’s disease therapy and deliver therapeutic amounts over a suitable patch area and time.     

Transdermal Iontophoretic Delivery of Propofol: A General Anaesthetic in the Form of its Phosphate Salt

The main objective of this study was to investigate the feasibility of delivery of propofol phosphate (PP), a prodrug of propofol, via transdermal route using iontophoresis in combination with chemical permeation enhancers (CPEs). PP, a prodrug, was synthesized and its structure was characterized. In vitro passive and iontophoretic drug transport studies were carried out using Franz diffusion cell across freshly excised hairless rat skin at different concentrations of PP in combination with CPE. Among all the CPEs screened, 0.1% sodium dodecyl sulfate (SDS) increased the passive transdermal flux to 13.43 ± 0.73 μg/(cm² h) from 8.52 ± 0.82 μg/(cm² h) (control). Cathodal iontophoresis in combination with 0.1% SDS synergistically enhanced the flux [249.24 ± 6.12μg/(cm² h)] of PP. The Pharmacokinetic studies were performed in rat model to assess the feasibility of transdermal delivery of PP. The amount of propofol present in plasma samples in control group (passive) was below the detectable levels at all the time points during the study. The plasma concentration—time profile of iontophoresis group of rats was fit to a noncompartmental model and the pharmacokinetic parameters were calculated. These studies suggest the plausibility of achieving therapeutically relevant levels of propofol when delivered via transdermal route by combining iontophoresis with CPE.     

Response Surface Method: A Novel Strategy to Optimize lontophoretic Transdermal Delivery of Thyrotropin-releasing Hormone

Purpose. To maximize the iontophoretic transdermal delivery rate of thyrotropin-releasing hormone (TRH) facilitated by periodically monophase-pulsed current across excised skin. Methods. The pH of the buffer, the ionic strength in the solution, the frequency of the periodically monophase-pulsed current and the current on/off ratio were chosen as the key variables. A response surface method was applied to optimize the transdermal delivery rate of TRH under different operational conditions. Results. The optimum operating conditions were achieved via experimentation based on the response surface method by systematically adjusting the pH of the buffer, the ionic strength in the solution, the current amplitude, frequency and the active temporal ratio of the pulsed current. The rate of permeation of TRH crossing the skin during iontophoresis varied from two to ten-fold, depending on operating conditions. Conclusions. Only a few steps, two in this work, were needed to reach the optimal. The response surface near the region of the maximal point was thoroughly described with a quadratic function. A maximal transdermal rate of permeation of TRH, 103.2 µg h^–1 cm^–2, was obtained when the donor solution was at pH = 7.0, ionic strength = 0.037, and with a periodically monophase-pulsed current iontophoresis with duty cycle = 75%. The effect of pulse frequency was not statistically significant.     

Transdermal iontophoretic delivery of selegiline hydrochloride,in vitro

Transdermal iontophoretic delivery of selegiline hydrochloride (SH) across dermatomed human skin was studied. Electrochemical stability and various factors affecting the skin permeation were investigated. SH was stable under the influence of an electrical field. The permeation of SH was very low by passive delivery (2.29?±?0.05 μg/cm²/h) as compared to iontophoresis at 0.5 mA/cm² (65.10?±?5.04 μg/cm²/h). An increase in drug concentration from 1 to 20?mg/mL increased the iontophoretic flux by 13-fold. Optimal pH and salt (NaCl) concentration for iontophoretic delivery of SH were found to be pH 5 and 100?mM, respectively. Overall, with 20?mg/mL SH and a current density of 0.4 mA/cm², a maximum flux of 305.5?μg/cm²/h was obtained. Based on reported pharmacokinetic parameters, input target delivery rate to achieve effective plasma concentration of SH (2.2?ng/mL) was calculated. With a surface area of 40?cm², iontophoretic delivery can provide six to seven times higher levels of SH than the target delivery rate, which enables lowering of the dose and/or patch surface area. Further in vivo studies will be required to prove the efficacy of ionophoresis for enhanced delivery of SH.     

电致孔和离子导入对胰岛素经皮渗透的促进作用

目的研究电致孔(EP)和离子导入(ION)对胰岛素经皮渗透的影响。方法以水平双室扩散池的方法,研究电致孔与离子导入联合应用对胰岛素经皮渗透的促进作用,并与单独使用离子导入或电致孔进行比较。结果 电致孔与离子导入联用比单独离子导入显著增加胰岛素的经皮渗透性(P<0.05),且高电压比低电压电致孔离子导入显著增加胰岛素的渗透速率(P<0.01)。胰岛素离子导入前,500 V电压,给90次脉冲(指数衰减脉冲,每次脉冲持续时间20～24 ms,3次·min^-1),导致了透皮流速(Flux)的快速稳定增加。结论电致孔和离子导入联用能明显促进大分子胰岛素的经皮渗透性。     

Effect of PEG6000 on the In Vitro and In Vivo Transdermal Permeation of Ondansetron Hydrochloride from EVA1802 Membranes

The objective was to evaluate ethylene vinyl acetate (EVA) copolymer membranes with vinyl acetate content of 18% w/w (EVA1802) for transdermal delivery of ondansetron hydrochloride. The EVA1802 membranes containing selected concentrations (0, 5, 10 and 15% w/w) of PEG6000 were prepared, and subjected to in vitro permeation studies from a nerodilol-based drug reservoir. Flux of ondansetron from EVA1802 membranes without PEG6000 was 64.1 ± 0.6 μg/cm^2·h, and with 10%w/w of PEG6000 (EVA1802-PEG6000-10) it increased to 194.9 ± 4.6 μg/cm^2·h. However, with 15%w/w of PEG6000, EVA1802 membranes produced a burst release of drug which in turn decreased drug flux. The EVA1802-PEG6000-10 membrane was coated with an adhesive emulsion, applied to rat epidermis and subjected to in vitro permeation studies against controls. Flux of ondansetron from transdermal patch across rat epidermis was 111.7 ± 1.3 μg/cm^2·h, which is about 1.3 times the required flux. A TTS was fabricated using adhesive-coated EVA1802-PEG6000-10 membrane and other TTS components, and subjected to in vivo delivery in human volunteers against a control. It was concluded from the comparative pharmacokinetic study that TTS of ondansetron, prepared with EVA1802-PEG6000-10 membrane, provided average steady-state plasma concentration on par with multiple-dosed oral tablets, but with a low percent of peak-to-trough fluctuation.     

A Review of: “Excipient Development for Pharmaceutical,Biotechnology, and Drug Delivery Systems”

The feasibility of delivering hydromorphone by transdermal iontophoresis to obtain therapeutically effective analgesic concentrations for the management of cancer-related pain was evaluated. Anodal iontophoresis was performed, and the effect of current strength, current duration, solution pH, presence of buffer ions, and drug concentration on the transdermal permeation of hydromorphone was investigated in vitro. Freshly excised full‐thickness hairless rat skin and side-by-side permeation cells connected to the Phoresor II^TM with Ag/AgCl electrodes was used. The flux of hydromorphone was observed to significantly increase (P < 0.05) from 72.04–280.30 μg/cm²/h with increase in current strength from 0.10–0.50 mA. A linear relationship was obtained between hydromorphone flux and current strength. Furthermore, the flux of hydromorphone was influenced by solution pH and presence of buffer ions. Also, the in vitro permeation flux of hydromorphone was observed to significantly increase (P < 0.05) with a 10-fold increase in hydromorphone hydrochloride concentration from 0.01–0.10 M. However, with further increase to 0.50 M, there was no significant difference in flux. These results show that by manipulating electronic and formulation variables, the transdermal iontophoretic delivery of hydromorphone can be controlled, and therapeutically effective concentrations of hydromorphone for the management of cancer-related pain can be obtained.     

In-vitro and in-vivo transdermal iontophoretic delivery of tramadol, a centrally acting analgesic

Objectives The feasibility of transdermal delivery of tramadol, a centrally acting analgesic, by anodal iontophoresis using Ag/AgCl electrodes was investigated in vitro and in vivo. Methods To examine the effect of species variation and current strength on skin permeability of tramadol, in‐vitro skin permeation studies were performed using porcine ear skin, guinea‐pig abdominal skin and hairless mouse abdominal skin as the membrane. In an in‐vivo pharmacokinetic study, an iontophoretic patch system was applied to the abdominal skin of conscious guinea pigs with a constant current supply (250 µA/cm²) for 6 h. An intravenous injection group to determine the pharmacokinetic parameters for estimation of the transdermal absorption rate in guinea pigs was also included. Key findings The in‐vitro steady‐state skin permeation flux of tramadol current‐dependently increased without significant differences among the three different skin types. In the in‐vivo pharmacokinetic study, plasma concentrations of tramadol steadily increased and reached steady state (336 ng/ml) 3 h after initiation of current supply, and the in‐vivo steady‐state transdermal absorption rate was 499 µg/cm² per h as calculated by a constrained numeric deconvolution method. Conclusions The present study reveals that anodal iontophoresis provides current‐controlled transdermal delivery of tramadol without significant interspecies differences, and enables the delivery of therapeutic amounts of tramadol.