Transdermal iontophoretic drug delivery: advances and challenges

The stratum corneum continues to pose considerable impediment to transdermal drug delivery. One of the effective ways of circumventing this challenge is through the use of iontophoresis. Iontophoresis uses low-level current to drive charged compounds across the skin. This review discusses progress made in the field of iontophoretic transport of small and large molecules. The major obstacles are also touched upon and advances made in the last few decades described. A number of iontophoretic systems approved for clinical use by regulatory authorities is also discussed.     

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.     

电穿孔技术促进萘普生经皮渗透的研究

目的：研究电穿孔技术对小分子离子型药物经皮渗透的影响。方法：应用双室扩散池方法研究电穿孔技术对萘普生在离体大鼠腹部皮肤经皮渗透的影响。并与被动扩散和离子导入进行比较。结果：外加电脉冲（指数衰减型脉冲,脉冲幅度为４００Ｖ,电容器电容为２．２ｕＦ,脉冲率为２０ｐｕｌｓｅｓ．ｍｉｎ＾－１,脉冲宽度τ≈６．０ｍｓ）或离子导入（１ｍＡ．ｃｍ＾－２,６ｈ）时,萘普生的渗透速率和累积渗透量均大于被动扩散。外加脉     

多肽蛋白质类药物离子导入经皮给药的研究进展

论述了多肽蛋白质类药物离子导入经皮给药的特点及主要影响因素,重点介绍了近年来国际上对胰岛素、降血钙素、促黄体(生成)激素释放激素、精氨酸抗利尿激素(加压素)等多肽蛋白质类药物离子导入经皮给药的研究进展.     

复方妥布霉素眼凝胶中地塞米松磷酸钠的含量测定

目的建立复方妥布霉素眼凝胶中地塞米松磷酸钠的含量测定方法。方法流动相超声破胶后用高效液相色谱法测定地塞米松磷酸钠的含量。结果地塞米松磷酸钠在20~100μg.mL-1浓度范围内色谱峰面积(A)与浓度(C)之间线性关系良好(r=0.9994),平均回收率102.37±0.70%,RSD=1.57%(n=6)。结论本法可快速、准确地测定眼凝胶中地塞米松磷酸钠的含量。     

地塞米松磷酸钠注射液对注射用头孢地嗪钠稳定性的影响

目的考察地塞米松磷酸钠注射液在50g·L-1葡萄糖注射液中对注射用头孢地嗪钠稳定性的影响。方法观察配伍液的外观、测定不溶性微粒、pH值,采用HPLC法测定头孢地嗪钠含量。结果配伍液在室温时6h内无明显外观、pH值、含量的变化,不溶性微粒数符合规定。结论地塞米松磷酸钠注射液室温时于6h内对头孢地嗪钠稳定性无影响。     

肺靶向地塞米松微球的制备及体外释药

目的:研究水溶性药物地塞米松磷酸钠肺靶向微球制备工艺的优化。方法:以油/水型乳化-溶剂挥发法制备微球,考察微球的性质及肺靶向性。维持其他条件不变,内相中加入甲醇和改变外相中氯化钠的加入量后,考察微球的载药量变化。结果:所制的微球的平均粒径为(8.37±4.0)μm。突释性好,最初0.5h释药量达48.28%。各器官石蜡切片中,肺组织中有较多微球嵌顿。随着内相中加入甲醇和外相中加入氯化钠,微球载药量提高。结论:地塞米松微球有良好的肺靶向性。采用油/水型乳化-溶剂挥发法制备水溶性地塞米松微球时,内相中加入甲醇和外相中加入氯化钠有助于提高微球的载药量。     

地塞米松磷酸钠注射剂与甲钴胺注射剂在氯化钠注射剂中的稳定性考察

目的考察地塞米松磷酸钠注射剂与甲钴胺注射剂在氯化钠注射剂中的稳定性。方法监测地塞米松磷酸钠注射剂与甲钴胺注射剂在氯化钠注射剂中配伍后于4℃、常温时自然光照射下及避光条件下12 h内的含量变化,同时考察配伍液pH值与外观的变化情况。结果与配伍后0 h比较,在避光条件下12 h内,pH、外观及两者含量均无显著变化;未避光条件下,地塞米松磷酸钠在12 h内无显著变化,5min内甲钴胺含量有显著变化,50%以上已降解。结论建议地塞米松磷酸钠注射剂不要与甲钴胺注射剂在氯化钠注射剂中配伍后用于静脉滴注。     

葡萄糖酸钙注射液与注射用地塞米松磷酸钠的输液配伍相容性

目的：考察葡萄糖酸钙注射液和注射用地塞米松磷酸钠在输液袋中的配伍相容性。方法：模拟临床输液实际情况,在室温（25℃）下,将临床常用量葡萄糖酸钙在10%葡萄糖注射液或0.9%氯化钠注射液输液袋中与注射用地塞米松磷酸钠混合配伍,分别在0,0.5,1,3 h考察外观、pH及葡萄糖酸钙和地塞米松磷酸钠的药物浓度。结果：上述配伍输液在3 h内均无浑浊、变色、沉淀和气体产生等,pH保持稳定,而地塞米松磷酸钠的浓度随时间在输液中呈现不同程度的变化。结论：临床常用量葡萄糖酸钙注射液与注射用地塞米松磷酸钠在常用输液中存在配伍禁忌。     

异烟肼比色法测定麻地喷雾剂中地塞米松磷酸钠含量

目的建立异烟肼比色法测定麻地喷雾剂中地塞米松磷酸钠含量的方法.方法根据地塞米松磷酸钠具有△1,4-3-酮甾体结构,与异烟肼发生缩合反应显黄色,在404 nm处有紫外吸收峰的特点,测定其含量.结果地塞米松磷酸钠在77.8～116.7 mg*L-1范围内,吸收度与浓度呈良好的线性关系( r=0.9 998, n=5 ).平均回收率100.4%,RSD为0.64%.日内RSD=1.35%,日间RSD=1.88%(n=5).结论方法简便易行、快速准确,可作为该制剂的质量控制方法.     

高效液相色谱法测定注射用复方粉针剂中地塞米松磷酸钠和去甲万古霉素的含量

目的建立高效液相色谱法同时测定复方粉针剂中地塞米松磷酸钠和去甲万古霉素的含量.方法采用SphereSorb C18色谱柱(4.6mm×250mm,10μm),甲醇-0.01mol·L-1磷酸氢二铵(20:80,磷酸调pH6.0)为流动相,检测波长:214nm,流 /min,柱温为30℃,进样量20μL.结果地塞米松磷酸钠线性范围为9.6～48mg·L-1,回归方程Y=30605.3X速:1.0mL16315.8,r=0.9999,平均回收率98.1%,RSD为0.92%(n=9);去甲万古霉素线性范围20～100mg·L-1,回归方程Y=5171.6X-8435.4,r=0.9993,平均回收率100.5%,RSD为1.0%(n=9).结论方法简便、可靠、结果准确,可用于本制剂的含量测定和质量控制.     

医院药剂科的新药开发

目的：建立不经分离同时测定地塞米松磷酸钠及干扰组分尼泊金乙酯含量的测定方法。方法：以蒸馏水为空白,采用褶合光谱法。结果：平均回收率为１００８％,９９３９％;ＲＳＤ为１００％,０６１％。结论：本法方便准确,适用于紫外吸收有干扰的多组分制剂的常规分析。     

Non-invasive iontophoretic delivery of peptides and proteins across the skin

Introduction: Peptides and proteins are playing an increasingly important role in modern therapy. Their potency and specificity make them excellent therapeutic agents; however, their physicochemical properties and stability requirements almost invariably necessitate their administration by subcutaneous, intramuscular or intravenous injection. Controlled non-invasive administration using more patient-friendly advanced delivery technologies may combine the precision afforded by parenteral administration with improved compliance and the potential for individualized therapy.

Areas covered: Transdermal iontophoresis enables hydrophilic charged molecules to be administered through the skin in an effective, non-invasive, patient-friendly manner. This review presents the basic concepts and an analysis of the effect of iontophoretic parameters and molecular properties on electrotransport rates across the skin along with a summary of experimental studies with peptides and proteins. The last section covers other techniques used in conjunction with iontophoresis.

Expert opinion: It has long been known that iontophoresis can administer therapeutic amounts of biologically active peptides into the body. More recent studies have shown that it is also capable of delivering structurally intact, functional proteins non-invasively into and across intact human skin. The next step is to develop cost-effective and easy-to-use iontophoretic patch systems that ensure biomolecule stability, optimize delivery efficiency and address unmet therapeutic needs.     

高效液相色谱法测定氯氟液中氯霉素和地塞米松磷酸钠的含量

目的建立高效液相色谱法同时测定氯氟液中氯霉素和地塞米松磷酸钠含量。方法色谱柱为Inertsil C8-3,流动相为甲醇-乙腈-水(72∶3∶25),流速为1.0mL·min-1,柱温为40℃,检测波长为240nm。结果氯霉素和地塞米松磷酸钠检测质量浓度分别为62.1～745.2mg·L-1(r=0.9999)和6.22～74.64mg·L-1(r=0.9999),平均加样回收率分别为101.02%(RSD为2.0%)和100.05%(RSD为1.6%)。结论方法简便易行、准确可靠,可用于该制剂的含量测定。     

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.     

兔眼玻璃体腔地塞米松磷酸钠的高效液相色谱法测定

目的:建立高效液相色谱法测定新西兰大白兔眼玻璃体地塞米松磷酸钠含量.方法:玻璃体溶液0.1 mL经70 ℃干燥变性蛋白并浓缩标本,流动相20 μL溶解浓缩回收,离心.色谱条件为流动相:甲醇-0.34%磷酸二氢钾(55∶45),流速:0.20 mL·min-1,C18色谱柱,柱温:25 ℃,检测波长:240 nm.结果:地塞米松磷酸钠在0.062 5～2.5 mg·L-1内线性关系良好(r=0.998 8),方法回收率为100.2%～106.3%,绝对回收率为70.7%～80.1%,日内、日间RSD分别为2.9%～4.4%,5.1%～8.3%;检测灵敏度0.020 mg·L-1.结论:标本前处理可以有效去除蛋白,过程简单,方法稳定,灵敏度高,结果可靠,适用于兔眼玻璃体腔地塞米松磷酸钠的定量分析.     

HPLC法测定麻地滴鼻液中两组分含量

目的建立HPLC法测定麻地滴鼻液中盐酸麻黄碱和地塞米松磷酸钠的含量。方法采用Hypersil ODS2(4.6 mm×250mm,5μm)色谱柱,以甲醇∶0.025 mol.L-1磷酸二氢钠溶液(54∶46)为流动相,流速1.0 m l.m in-1,检测波长258 nm。结果盐酸麻黄碱和地塞米松磷酸钠的线性范围分别为102~510 mg.L-1,(r=0.999 9),2.5~12.5 mg.L-1,(r=1.0);平均加样回收率分别为100.9%(RSD=1.1%),101.1%(RSD=1.5%)。结论该方法简便、准确,适用于麻地滴鼻液的质量控制。     

盐酸帕洛诺司琼注射液与注射用地塞米松磷酸钠的配伍相容性研究

目的：考察盐酸帕洛诺司琼注射液与注射用地塞米松磷酸钠在输液中的配伍相容性。方法：在室温（25℃）不避光的环境条件下,对盐酸帕洛诺司琼和地塞米松磷酸钠配伍液,于0,3,6,24 h时间点观察配伍液的外观,同时测定配伍液的pH值和微粒的变化,并采用高效液相法测定配伍液中的药物浓度。结果：上述配伍输液在24 h内均无浑浊、无变色、无沉淀和气体产生,不溶性微粒符合规定标准,pH和2种药物浓度保持恒定。结论：在室温下,盐酸帕洛诺司琼与地塞米松磷酸钠在常用输液中稳定,可在临床中配伍使用。     

两种辅料对地塞米松磷酸钠注射液中杂质的影响

目的:分析对比依地酸二钠与亚硫酸氢钠对地塞米松磷酸钠注射液中杂质的影响.方法:建立地塞米松磷酸钠注射液杂质Ⅰ(C22 H30 FNa2 O11 PS)的定量分析方法,以杂质Ⅰ、地塞米松的含量和总杂质的峰面积占比来评价制剂的安全性.结果 与结论:以依地酸二钠为辅料的地塞米松磷酸钠注射液中杂质Ⅰ含量更低,总杂质也相对更少.