Improved stability and release control of levodopa and metaraminol using ion-exchange fibers and transdermal iontophoresis

Achievement of controlled drug delivery and stability of drugs during storage is a problem also in transdermal drug delivery. The objective of this study was to determine, whether an easily oxidized drug, levodopa, could be stabilized during storage using pH-adjustment and ion-exchange fibers. Controlled transdermal delivery of the zwitterionic levodopa was attempted by iontophoresis and ion-exchange fiber. Ion-exchange kinetics and transdermal permeation of a cationic (presumably more stable) model drug, metaraminol, were compared to the corresponding data of levodopa. Levodopa was rapidly oxidized in the presence of water, especially at basic pH-values. At acidic pH-values the stability was improved significantly. Ion-exchange group and the pH had a clear effect on the release of both the levodopa and metaraminol from the ion-exchange fiber. The adsorption/release kinetics of metaraminol were more easily controllable than the corresponding rate and extent of levodopa adsorption/release. Iontophoretic enhancement of drug permeation across the skin was clearly more significant with the positively charged metaraminol than with the zwitterionic levodopa. Ion-exchange fibers provide a promising alternative to control drug delivery and to store drugs that are degraded easily.     

Trials and tribulations of skin iontophoresis in therapeutics

Iontophoresis is a method of non-invasive transdermal drug delivery based on the transfer of charged molecules using a low-intensity electric current. Both local and systemic administration are possible; however, the skin pharmacokinetics of iontophoretically delivered drugs is complex and difficult to anticipate. The unquestionable theoretical advantages of the technique make it attractive in several potential applications. After a brief review of the factors influencing iontophoresis, we detail the current applications of iontophoresis in therapeutics and the main potential applications under investigation, including systemic and topical drugs and focusing on the treatment of scleroderma-related ulcerations. Finally, we address the issue of safety, which could be a limitation to the routine clinical use of iontophoresis.     

A novel electronic skin patch for delivery and pharmacokinetic evaluation of donepezil following transdermal iontophoresis

The nature of Alzheimer's disease limits the effectiveness of available oral treatments. The aim of this study was to assess the feasibility of transdermal iontophoretic delivery of donepezil in a hairless rat model as a potential treatment modality in Alzheimer's and to evaluate the effect of current densities on its pharmacokinetics. Donepezil loaded integrated Wearable Electronic Drug Delivery (WEDD^®) patches supplied current levels of 0, 0.13, 0.26 and 0.39 mA. Plasma extracted donepezil was analyzed by HPLC. Noncompartmental analysis was used to characterize disposition of the drug. The amount delivered across hairless rat skin and areas under the curve (AUC) were found to rise in proportion to the current levels. Peak plasma levels of 0.094, 0.237 and 0.336 μg/ml were achieved at 0.13, 0.26 and 0.39 mA respectively. Time to peak plasma concentrations was after termination of current and same for all current levels. Transdermal elimination half-life was significantly increased from the true value of 3.2 h due to depot formation, prolonging complete absorption of the drug. Donepezil was successfully delivered iontophoretically at levels sufficient to produce pharmacodymanic effect. Pharmacokinetic analysis demonstrated linear kinetics at the current levels used and flip flop kinetics following iontophoretic administration.     

青藤碱贴剂透皮吸收实验接收液的筛选

目的:筛选青藤碱贴剂的接收液.方法:采用体外透皮实验法,以生理盐水-乙醇、PBS缓冲液、PBS缓冲液-乙醇溶液为考察对象,在不同时间点取样接收液,HPLC测定青藤碱浓度,以单位面积累积透皮量对时间进行零级、一级、Higuchi方程拟合,计算透皮速率常数.结果:表明零级拟合效果较好,Higuchi方程和一级拟合效果不佳.结论:PBS-ethanol接收液透皮速率较快,符合透皮吸收实验对接收液的要求.     

酮洛芬贴片体外透皮释放方法学研究

目的:建立酮洛芬贴片体外透皮释放方法学。方法 :采用HPLC法测定释放液中酮洛芬的含量,测定条件:DiamonsilC18色谱柱(150 mm×4.6 mm,5μm),流动相为pH 3.5磷酸盐缓冲液-乙腈-水(2∶53∶45),检测波长为253 nm,流速为1.0mL.min-1,柱温25℃。以裸鼠皮肤为实验皮肤,采用Frans扩散池方法进行三批酮洛芬贴片样品的体外透皮实验。结果:在该HPLC条件下,酮洛芬与其他杂质分离良好,进样量在0.509~40.72μg.mL-1时,酮洛芬浓度与峰面积呈良好的线性关系(r=0.999 9),回收率为101.09%,RSD为1.23%。三批酮洛芬贴片样品的透皮释放速率分别为18.157,17.973,20.001μg.cm-2.h-1,药物透皮释放符合零级动力学过程。结论:本文建立的酮洛芬贴片体外透皮释放方法简便,重现性好,可以用于控制产品质量。     

Transdermal iontophoresis of ranitidine: an opportunity in paediatric drug therapy

The objective of this study was to examine the use of transdermal iontophoresis for the delivery of ranitidine hydrochloride in children. Constant, direct current, anodal iontophoresis of ranitidine was performed in vitro across dermatomed pig skin. The effect of donor vehicle, current intensity, and drug concentration were first examined using aqueous solutions. It was found that drug delivery was higher at pH 7 (donor: 5 mM Tris) than pH 5.6 (donor: water). In the presence of low levels of competing background electrolyte, ranitidine delivery increased linearly with applied current but was independent of the donor drug concentration. The second part of the study evaluated two Pluronic^® F-127 gels as potential vehicles for ranitidine delivery. The formulations were characterised in terms of apparent viscosity, conductivity and passive permeation measurements. Iontophoretic delivery of ranitidine was only slightly affected when delivered from the gels relative to aqueous solutions. Overall the results demonstrated that therapeutic paediatric doses of ranitidine (neonates: 0.09–0.17 μmol/kg h; 1 month to 12 years: 0.36–0.71 μmol/kg h) could be easily achieved by transdermal iontophoresis with simple gel patches of practical surface area (0.2–1.5 cm²/kg).     

Potential and problems of developing transdermal patches for veterinary applications

A new frontier in the administration of therapeutic drugs to veterinary species is transdermal drug delivery. The primary challenge in developing these systems is rooted in the wide differences in skin structure and function seen in species ranging from cats to cows. The efficacy of a transdermal system is primarily dependent upon the barrier properties of the targeted species skin, as well as the ratio of the area of the transdermal patch to the species total body mass needed to achieve effective systemic drug concentrations. A drug must have sufficient lipid solubility to traverse the epidermal barrier to be considered for delivery for this route. A number of insecticides have been developed in liquid ‘pour-on’ formulations that illustrate the efficacy of this route of administration for veterinary species. The human transdermal fentanyl patch has been successfully used in cats and dogs for post-operative analgesia. The future development of transdermal drug delivery systems for veterinary species will be drug and species specific. With efficient experimental designs and available transdermal patch technology, there are no obvious hurdles to the development of effective systems in many veterinary species.     

Non-invasive monitoring of phenytoin by reverse iontophoresis

Transdermal iontophoresis offers a non-invasive sampling method for therapeutic drug monitoring. This study examined whether iontophoretic extraction (a) is concentration dependent, (b) reflects the subdermal level of unbound drug, (c) follows protein binding changes, and (d) becomes truly non-invasive when a co-extracted compound is used as an internal standard for calibration. Iontophoresis was conducted in vitro using dermatomed pig-ear skin. The subdermal solution was a buffer containing phenytoin at therapeutic concentrations, an internal standard at fixed level, human albumin and/or valproic acid. The ionized form of phenytoin was recovered at the anode by electro-migration, while the neutral form was extracted to the cathode by electroosmosis. A satisfactory correlation between the reverse iontophoretic extracted amount of phenytoin and the subdermal concentration was observed. Iontophoresis extracted only the free fraction of phenytoin. At steady state, reverse iontophoresis monitored changes in free drug concentration provoked in the subdermal compartment. Acetate was introduced at a fixed concentration into the subdermal compartment to act as an ‘internal standard’. Subsequently, acetate and the ionized form of phenytoin were co-extracted to the anode. The ratio of the extracted amounts was proportional to the subdermal concentration ratio demonstrating a means by which the method may become truly non-invasive.     

Effect of iontophoresis and fatty acids on permeation of Arginine Vasopressin through rat skin

The aim of this study was to assess the effects of fatty acids and iontophoretic mode of penetration enhancement on transdermal delivery of Arginine Vasopressin (AVP). Sprague-Dawley (SD) rat skin was pretreated with fatty acids (e.g. 5% w/v, lauric acid, oleic acid, and linoleic acid in ethanol:water (EtOH:W, 2:1 system) for 2h and iontophoresis in vitro, separately or together. The results indicate that all fatty acids studied increased (P<0.05) the flux of AVP in comparison to control (not pretreated with enhancer) and their effectiveness in flux enhancement was comparable. Further, oleic acid in combination with iontophoresis significantly increased the permeation of AVP both in comparison to pretreatment with fatty acids and iontophoresis alone. However, iontophoresis did not further increase the permeation of AVP through linoleic acid pretreated skin. Fourier transform infrared (FT-IR) spectroscopic studies revealed that EtOH:W (2:1) system is not effective in lipid extraction. The shift to higher wavenumbers of the symmetric and asymmetric stretching peaks at 2850 and 2920cm(-1) revealed that at the concentration used, oleic acid and linoleic acid caused fluidization of stratum corneum (SC) lipids. This study provides direct evidence that oleic acid in EtOH:W (2:1) system causes disruption of the SC lipid lamellae and that a combination of oleic acid with iontophoresis further enhances the effects of oleic acid in a synergistic manner.     

氮酮对双氯灭痛透皮吸收作用的研究

本实验采用简单小室法,以离体小白鼠皮肤为透皮屏障,用生理盐水为接受液,研究了不同浓度的氮酮对双氯灭痛透皮吸收的影响。实验结果表明:含2%、1.5%、1.0%、0.5%氮酮的双氯灭痛擦剂与不含氮酮的双氯灭痛擦剂间,其透皮吸收有极显著性差异(P<0.01);含不同浓度氮酮的双氯灭痛擦剂间,其透皮吸收有显著性差异(P<0.05);其中以含1.5%氮酮的双氯灭痛擦剂,其透皮吸收为最好。     

In vitro and in vivo iontophoretic transdermal delivery of an anti-parkinsonian agent

To objective of this work was to study the feasibility of iontophoretic delivery of SLV 318 (7-(4-benzyl-1-piperazinyl)-2(3H)-benzoxazolone methanesulfonate) across hairless rat skin in vitro and in vivo. The effect of counter-ions and temperature were investigated for optimizing SLV 318 solubility. The effect of electrode efficiency and total current applied on the delivery of SLV 318 were studied using Franz diffusion cells and samples were analyzed using HPLC. Delivery increased with increasing concentration. For current-time combinations, electrode had to be replaced every 9 h. Passive, iontophoretic (0.1 mA/cm² for 1 h) and intravenous studies were performed in vivo. Blood samples collected were analyzed using LC-MS/MS. SLV 318 had higher solubility with NaCl (75 mM) as a counter-ion at 25 °C than with other counter-ions tested. In vivo iontophoresis significantly enhanced the permeation and also reduced its lag time (P < 0.05). The C_max of SLV 318 during 1 h iontophoresis was 6.56 ± 0.68 ng/mL at 1.31 ± 0.29 h (T_max) as compared to 2.96 ± 0.29 ng/mL at 25.32 ± 0.67 h (T_max) by 24 h passive permeation. The in vitro and in vivo data has shown the feasibility to enhance delivery of SLV 318 by iontophoresis.     

Stability of a transdermal salmon calcitonin formulation

This study was designed to monitor the stability of salmon calcitonin during storage conditions, under the electric fields generated during iontophoresis and electroporation, in contact with transdermal glass diffusion cells, and during transport through skin. The formulation in a citrate buffer (pH 4.0) was stable in storage for short-term studies but degraded significantly on extended storage. Albumin was able to minimize adsorption in contact with glass surfaces, and aprotinin was able to minimize proteolytic degradation in contact with skin. The formulation was stable under electric field, but there was a loss due to adsorption if salt bridges were used.     

氮酮用量对莫诺苯宗乳膏离体透皮吸收的影响

目的 研究渗透吸收促进剂氮酮用量对莫诺苯宗乳膏体在外经皮渗透的影响,并拟定氮酮的最佳浓度.方法 以30%乙醇-水溶液为接收液,小鼠离体皮肤为屏障,采用改良的Franz扩散池进行体外渗透实验,HPLC法测定接收液中莫诺苯宗的含量.结果 24 h内,不同浓度的氮酮对莫诺苯宗乳膏透皮吸收均有一定的促进作用,其促渗作用为2%氮酮>5%氮酮>1%氮酮>0氮酮.结论 氮酮能促进莫诺苯宗乳膏中莫诺苯宗的透皮吸收,以2%的氮酮促透效果最佳.     

Passive and iontophoretic transdermal delivery of phenobarbital: Implications in paediatric therapy

The objective of this investigation was to evaluate phenobarbital transdermal delivery for possible use in paediatric care. In vitro experiments were performed using intact pig skin and barriers from which the stratum corneum had been stripped to different extents to model the less resistant skin of premature babies. Cathodal iontophoretic delivery of phenobarbital was superior to anodal transport and optimised delivery conditions were achieved by reduction of competing co-ion presence in the drug formulation. Phenobarbital transport across intact or partially compromised skin was controlled by iontophoresis which was more efficient than passive diffusion. Across highly compromised skin, however, passive diffusion increased drastically and iontophoretic control was lost. Overall, this study demonstrates the feasibility of phenobarbital transdermal delivery for paediatric patients.     

Investigation of the carbopol gel of solid lipid nanoparticles for the transdermal iontophoretic delivery of triamcinolone acetonide acetate

The purpose of this study was to investigate solid lipid nanoparticles (SLN) hydrogel for transdermal iontophoretic drug delivery. Triamcinolone acetonide acetate (TAA), a glucocorticoids compound, was employed as the model drug. SLN containing the drug triamcinolone acetonide acetate (TAA-SLN) and their carbopol gel with stable physicochemical properties were prepared. The use of TAA-SLN carbopol gel as a vehicle for the transdermal iontophoretic delivery of TAA was evaluated in vitro using horizontal diffusion cells fitted with porcine ear skin. We found that the TAA-SLN gel possessed good stability, rheological properties, and high electric conductance. Transdermal penetration of TAA from TAA-SLN gel cross the skin tissue was significantly enhanced by iontophoresis. The enhancement of the cumulative penetration amount and the steady-state penetration flux of the penetrated drug were related to the particle size of TAA-SLN and the characteristics of the applied pulse electric current, such as density, frequency, and on/off interval ratio. These results indicated that SLN carbopol gel could be used as a vehicle for transdermal iontophoretic drug delivery under suitable electric conditions.     

Iontophoresis: a potential emergence of a transdermal drug delivery system

The delivery of drugs into systemic circulation via skin has generated much attention during the last decade. Transdermal therapeutic systems propound controlled release of active ingredients through the skin and into the systemic circulation in a predictive manner. Drugs administered through these systems escape first-pass metabolism and maintain a steady state scenario similar to a continuous intravenous infusion for up to several days. However, the excellent impervious nature of the skin offers the greatest challenge for successful delivery of drug molecules by utilizing the concepts of iontophoresis. The present review deals with the principles and the recent innovations in the field of iontophoretic drug delivery system together with factors affecting the system. This delivery system utilizes electric current as a driving force for permeation of ionic and non-ionic medications. The rationale behind using this technique is to reversibly alter the barrier properties of skin, which could possibly improve the penetration of drugs such as proteins, peptides and other macromolecules to increase the systemic delivery of high molecular weight compounds with controlled input kinetics and minimum inter-subject variability. Although iontophoresis seems to be an ideal candidate to overcome the limitations associated with the delivery of ionic drugs, further extrapolation of this technique is imperative for translational utility and mass human application.     

An in vivo investigation of the rabbit skin responses to transdermal iontophoresis

To optimize the benefits of transdermal iontophoresis, it is necessary to develop a suitable animal model that would allow for extensive assessments of the biological effects associated with electro-transport. Rabbit skin responses to iontophoresis treatments were evaluated by visual scoring and by non-invasive bioengineering parameters and compared with available human data. In the current density range 0.1–1.0 mA/cm² applied for 1 h using 0.9% w/v NaCl and 0.5 mA/cm² for up to 4 h, no significant irritation was observed. 2 mA/cm² applied through an area of 1 cm² for 1 h resulted in slight erythema at both active electrode sites but without significant changes in transepidermal water loss (TEWL) and laser Doppler velocimetry (LDV). A value of 4 mA/cm² under similar conditions caused moderate erythema at the anode and cathode with TEWL and LDV being significantly elevated at both sites; 1 mA/cm² current applied for 4 h, caused moderate erythema at both anode and cathode; and 1 mA/cm² applied for 1 h caused no irritation when the area of exposure was increased from 1 to 4.5 cm². When significant irritation and barrier impairment occurred, the erythema was resolved within 24 h with barrier recovery complete 3–5 days post-treatment. Rabbit skin thus shows promise as an acceptable model for iontophoresis experiments.     

N-三甲基壳聚糖对甲氧沙林脂质体凝胶的透皮吸收促进作用研究

目的 观察N-三甲基壳聚糖(TMC)对药物初级制剂凝胶的透皮吸收促进作用.方法 以季铵化程度为60％的TMC(TMC60)为促渗剂,加入到甲氧沙林脂质体(LMOP)凝胶中或对LMOP进行包衣处理,再制备成凝胶.采用Franz扩散池,以不含促渗剂的LMOP凝胶为阴性对照,1％氮酮+丙二醇为促渗剂的LMOP凝胶为阳性对照,考察游离TMC及TMC包衣对LMOP凝胶的体外透皮促进作用.结果 三种含促渗剂的LMOP凝胶与阴性对照相比,透皮效果及24h后皮肤蓄积量差异均有统计学意义(x2=8.65,P＜0.05),且以游离的TMC60促渗作用最优.结论 TMC可促进LMOP凝胶的体外透皮吸收,值得进一步研究.     

A validated reversed phase HPLC method for the determination of process-related impurities in almotriptan malate API

An isocratic reversed phase liquid chromatographic (RP-LC) method has been developed and subsequently validated for the determination of almotriptan malate and its process-related impurities. Separation was achieved with a Phenomenex, Gemini, C-18 column and sodium phosphate buffer (pH adjusted to 7.6): acetonitrile (80:20, v/v) as eluent, at a flow rate of 1.5 mL/min. UV detection was performed at 227 nm. The method is simple, rapid, selective, accurate and stability indicating. The described method is linear over a range of LOQ, 1.5 ug/mL (150% of the specification limit) for all the process-related impurities. The method precision for the determination of related compounds was below 1.0% R.S.D. The accuracy of the method demonstrated at 4 levels in the range of 25-150% of the specification limit and the recovery of impurities were found to be in the range of 96-102%. The method is useful in the quality control of bulk manufacturing.     

Transdermal iontophoresis of 5-fluorouracil combined with electroporation and laser treatment

The influence of iontophoresis and other physical enhancement methods such as electroporation and erbium:yttrium-aluminum-garnet (YAG) laser on the skin permeation of 5-fluorouracil (5-FU) was examined. Iontophoresis increased the in vitro transdermal transport of both the anionic and non-ionic forms of 5-FU. A combination of electroporation pretreatment and subsequent iontophoresis resulted in a higher permeation of 5-FU than either technique alone. It appeared that electroporation treatment exerted a disruptive influence on the stratum corneum (SC). The SC layers in the skin were partly ablated by the laser, resulting in a great enhancement effect on the skin permeation of 5-FU. Application of iontophoresis further increased the drug permeation across laser-pretreated skin. The laser was consistently the most potent technique to enhance 5-FU delivery among the physical enhancement methods examined in this study.