Transdermal permeation of selegiline from hydrogel-membrane drug delivery systems

In the present work, we attempted to design a transdermal system for delivering selegiline using a hydrogel-based drug reservoir and a rate-controlling membrane (Solupor polyethylene membranes). The appearances of these preparations were evaluated by scanning electron microscopy (SEM), and the in vitro skin permeation of selegiline across porcine skin was examined. Both the R- and S-forms of selegiline were examined in this study to elucidate the stereoselectivity of skin to selegiline. Solupor membranes and hydrogels exhibited a cross-linking structure with micropores. R-Selegiline revealed a flux of 1.13 μg/cm²/h across porcine skin. Solupor membranes were rate limiting for skin permeation of selegiline. Around a 2-fold reduction in the drug flux was determined after Solupor membrane incorporation. There were no significant differences in drug flux across the four Solupor membranes tested. The flux of R-selegiline from cellulose hydrogels approximated that from the aqueous solution (control). Both the membrane and hydrogel greatly reduced the inter-subject variations in skin permeation. According to the results of skin permeation and the partition coefficient between the skin and water (log P_skin/water), the S-enantiomer may be preferable for permeation into the skin. However, the R- and S-forms demonstrated equal absorption of the drug fluxed in the presence of the membrane and/or the hydrogel. The results of this study encouraged us to further investigate hydrogel-membrane delivery systems for transdermal selegiline administration.     

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.     

Pharmacokinetic evaluation of a selegiline pulsatile oral delivery system

Selegiline is a selective, irreversible inhibitor of MAO-B, used in the treatment of Parkinson's disease, either alone or as an adjunct to L-DOPA. The sole recommended dosing regimen is 5 mg given in the morning and at noon with breakfast and lunch. A pulsatile oral dosage form was developed to mimic the conventional tablet release from two oral administrations separated by 4 h, to permit once-daily dosing and increase compliance. The pharmacokinetics of the pulsatile delivery system was studied in six healthy male volunteers. The plasma concentration–time profile from the pulsatile system of selegiline and metabolites is dissimilar to that obtained from the 5 mg bid administration of the conventional tablet and cannot be considered to be bioequivalent. The initial pulse of the delivery system is rapidly absorbed but to a lesser extent than the conventional regimen; the second pulse exhibits absorption which is delayed and prolonged. The decrease in the selegiline concentration may be due to the less absorptive surface of the lower GI tract which is available to the second pulse. Another reason could be the disparity between the in vitro and in vivo release profiles from the second pulse. Compartmental analysis indicates that the ratio of formation–absorption rate constant for the selegiline to N-desmethylselegiline pathway decreases from 1·57±1·04 for the first pulse to 0·61±0·54 for the second pulse of the pulsatile delivery system, suggesting that the upper portion of the GI tract has a greater capacity to convert selegiline to N-desmethylselegiline than the lower GI tract. The lack of in vivo and in vitro correlation is most likely due to site specific absorption/metabolism. Regimen has been previously shown to be a significant factor in estimating the extent of selegiline and metabolite exposure following oral administration. The inequivalence of dosing regimens of the same total daily dose may ultimately be linked to the saturability of gut wall metabolism. This phenomenon may preclude the development of novel delivery systems designed to mimic the recommended dosing regimen of the conventional Eldepryl^™ tablet. © 1997 John Wiley & Sons, Ltd.     

Transdermal and intradermal iontophoretic delivery of dexamethasone sodium phosphate: quantification of the drug localized in skin

In this study, the effect of iontophoresis on the transdermal and intradermal delivery of dexamethasone sodium phosphate (DEX-P) was examined in vitro and in vivo in the hairless rat model by skin permeation studies, tape stripping, and skin extraction. Cathodal or anodal iontophoresis (ITP) was performed and samples were analyzed by HPLC. In vitro experiments revealed that cathodal ITP significantly enhanced the cumulative amount of DEX-P permeating through the skin when compared to passive and anodal delivery. Tape stripping and skin extraction studies performed in vivo after ITP showed enhanced deposition of the drug in the stratum corneum and underlying skin when compared to passive delivery. The DEX-P and DEX depot formed in the stratum corneum and underlying skin were retained for at least 48?h and 24?h, respectively. In conclusion, ITP demonstrated potential as a feasible enhancement technique to drive the drug into and through the skin in significant amounts as compared to passive delivery.     

Transdermal iontophoretic delivery of triptorelin in vitro

The feasibility of delivering triptorelin ([D-Trp6]LHRH) by transdermal iontophoresis was evaluated in vitro. Peptide electrotransport at different current densities and donor concentrations was measured across porcine ear skin. The concomitant delivery of an electroosmotic marker enabled calculation of the respective contributions of electromigration (EM) and electroosmosis (EO) to iontophoretic delivery. At a given concentration (3 mM), a threefold increase in current density produced a corresponding increase in the cumulative amount of peptide present in the receptor compartment. Conversely, doubling the concentration to 6 mM produced a twofold reduction in the amount of peptide delivered, partly due to a concentration-dependent inhibition of EO. EM was revealed to be the predominant transport mechanism, accounting for 80% of overall delivery. Finally, despite the inhibition of EO, the results indicate that application of an iontophoretic current of 0.8 mA over a relatively small contact area (4 cm2) would provide a delivery rate of 36 microg/h, largely sufficient for therapeutic requirements.     

Controlled non-invasive transdermal iontophoretic delivery of zolmitriptan hydrochloride in vitro and in vivo

The objective was to investigate the transdermal delivery kinetics of zolmitriptan from an iontophoretic patch system in Yorkshire swine in vivo. Preliminary in vitro experiments showed that cumulative drug transport during a 6-h current application (0.25 mA cm⁻²) was independent of patch load (263.7 ± 92.7, 357.2 ± 85.9, 374.9 ± 74.3 and 335.9 ± 27.7 μg cm⁻² for 7.5, 15, 45 and 90 mg patch loads, respectively; ANOVA, p < 0.05); the steady-state flux was ∼92 μg cm⁻² h⁻¹. The in vivo studies used multistep current profiles to demonstrate (i) rapid drug uptake and (ii) the effect of superposing a bolus input on basal drug levels. In both studies, zolmitriptan was detected in the blood after 2.5 min; drug levels were 7.1  1.7 and 10.4 ± 3.5 ng ml⁻¹ at t = 30min in Studies 1 and 2, respectively. In Study 2, increasing current intensity from 0.2 to 1.4 mA (0.05-0.35 mA cm⁻²) at t = 180 min caused zolmitriptan levels to rise from 9.38 ± 0.93 ng ml⁻¹ at t = 180 min to 13.57 ± 1.85 ng ml⁻¹ at t = 190 min; a ∼50% increase in 10 min. Extrapolation of these results to humans suggests the feasibility of delivering therapeutic amounts of zolmitriptan at faster rates than those from existing dosage forms.     

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     

Transdermal and transbuccal drug delivery systems: enhancement using iontophoretic and chemical approaches

We investigated the enhancement effect of chemical enhancers and iontophoresis on the in vitro transdermal and transbuccal delivery of lidocaine HCl (LHCl), nicotine hydrogen tartrate (NHT), and diltiazem HCl (DHCl) using porcine skin and buccal tissues. Dodecyl 2-(N,N-dimethylamino) propionate (DDAIP), dodecyl-2-(N,N-dimethylamino) propionate hydrochloride (DDAIP HCl), N-(4-bromobenzoyl)-S,S-dimethyliminosulfurane (Br-iminosulfurane), and azone (laurocapram) were used as chemical enhancers. The study results showed that the application of iontophoresis at either 0.1 mA or 0.3 mA significantly enhanced transdermal and transmucosal delivery of LHCl, NHT and DHCl. It was also demonstrated that iontophoresis had a more pronounced enhancement effect on transdermal delivery than on transbuccal delivery of LHCl, NHT and DHCl. In addition, DDAIP HCl was found to be the most effective enhancer for transbuccal delivery of LHCl and NHT.     

盐酸司来吉兰的合成

以1-苯基-2-丙胺为原料,经N-甲基化、拆分、N-炔基化、成盐共4步反应合成盐酸司来吉兰,总收率为42.2%.文中设计了盐酸司来吉兰的第一步合成路线,并按此路线合成了中间体3.     

Transdermal delivery of levosimendan

The aim of this study was to determine if transdermal penetration of levosimendan, a novel positive inotropic drug, could be enhanced and controlled by formulation modifications. Penetration of levosimendan across human epidermis in vitro was determined using abdominal excised skin and diffusion cells. Predicted steady-state plasma concentrations of levosimendan were estimated using permeabilities and pharmacokinetic parameters of levosimendan. For penetration enhancement we used different pH values, co-solvents, cyclodextrins, surfactants, penetration enhancers, liposomes, and iontophoresis. Sodium lauryl sulfate, ethanol, oleic acid, and soya phosphatidylcholine or their combinations clearly increased levosimendan permeation across the skin in vitro. Iontophoresis was also an efficient method to increase transdermal permeation of levosimendan. A hydrophilic co-solvent/penetration enhancer is needed to achieve better permeability of levosimendan across the skin. In conclusion, transdermal delivery of levosimendan can be significantly increased by formulation modification. Based on kinetic calculations, therapeutic plasma concentrations may be achievable transdermally.     

Transdermal iontophoretic delivery of methylphenidate HCl in vitro

Methylphenidate is prescribed orally for Attention Deficit Disorder in children and adults, and for narcolepsy patients. Methylphenidate has a short plasma half-life (1-2 h) and thus needs to be frequently administered for effective therapy. Such therapy has limitations in terms of patient compliance, particularly in young children. For such reasons, the development of a transdermal dosage form of methylphenidate may be useful. This study was undertaken to evaluate the passive and electrically assisted transport (iontophoresis) of methylphenidate from aqueous methylphenidate hydrochloride solutions across excised human skin. A maximum flux of 12.0 micrograms/(cm2 h) of protonated methylphenidate was estimated from the passive transport data at pH 3.5. Iontophoresis significantly enhanced protonated methylphenidate transport as compared with passive delivery. From the present experiments, the efficiency of iontophoretic delivery of methylphenidate was approximately 700 micrograms/(mA h). Based on in vitro skin flux data, the daily dose of 15-40 mg methylphenidate can be achieved using a current density of 0.5 mA/cm2 and a minimum transport area of 2-5 cm2 for 24-h application, or an area of 4-10 cm2 for 12-h (daytime) application. From methylphenidate skin flux values, methylphenidate mobility of 2.2 x 10(-4) cm2/(V s) was estimated, which compares reasonably with its free solution mobility of 6.6 x 10(-4) cm2/(V s).     

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.     

Transdermal delivery of diclofenac using microemulsions

A transdermal preparation containing diclofenac diethylammonium (DDA) was developed using an O/W microemulsion system. Of the oils tested, lauryl alcohol was chosen as the oil phase of the microemulsion, as it showed a good solubilizing capacity and excellent skin permeation rate of the drug. Pseudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant and cosurfactant for microemulsion formation, and the effect of these additives on skin permeation of DDA was evaluated with excised rat skins. The optimum formulation of the microemulsion consisted of 1.16% of DDA, 5% of lauryl alcohol, 60% of water in combination with the 34.54% of Labrasol (surfactant)/ethanol (cosurfactant) (1:2). The efficiency of formulation in the percutaneous absorption of DDA was dependent upon the contents of water and lauryl alcohol as well as Labrasol:ethanol mixing ratio. It was concluded that the percutaneous absorption of DDA from microemulsions was enhanced with increasing the lauryl alcohol and water contents, and with decreasing the Labrasol:ethanol mixing ratio in the formulation.     

The effect of pretreatment with terpenes on transdermal iontophoretic delivery of arginine vasopressin

This study investigates the effects of terpenes and iontophoresis on the in vitro permeation of arginine vasopressin (AVP) through rat skin and the biophysical changes induced by the chemical enhancers in the stratum corneum (SC) lipids by FT-IR spectroscopy. Pretreatment with terpenes (e.g. 5% w/v, carvone, pulegone, cineole and menthol in EtOH:W (2:1) system) increased (P < 0.05) the flux of AVP in comparison to control (not pretreated with enhancer) but was not significantly different (P > 0.05) in comparison to iontophoresis. Amongst different terpenes studied maximum enhancement ratio was observed with cineole. In combination, iontophoresis did not further increase (P > 0.05) the permeation of AVP through the enhancer pretreated epidermis in comparison to pretreatment with enhancer or iontophoresis alone. Hence it was concluded that although the combination was effective in flux enhancement compared to control, there was no synergism in action between terpenes and iontophoresis. FT-IR spectroscopic studies revealed that EtOH:W (2:1) system is not effective in lipid extraction. The area under the symmetric and asymmetric stretching peaks at 2850 and 2920 cm(-1) revealed that at the concentration used terpenes did not extract any lipids from the epidermis. The mode of action of terpenes is attributed to the breaking of hydrogen bonds between the ceramide head groups of lipids in the SC leading to greater fluidization of the SC lipids.     

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.     

Transdermal iontophoretic delivery of salmon calcitonin

Electrically enhanced transdermal delivery of salmon calcitonin could be useful for chronic treatment of postmenopausal osteoporosis and other clinical indications as a superior alternative to parenteral delivery. Calcitonin (50 microg/ml) formulation was prepared in citrate buffer (pH 4.0). Epidermis separated from human cadaver skin was used. Most iontophoresis studies were done at a current density of 0.5 m A cm2. Silver/silver-chloride electrodes were used and calcitonin was found to be best delivered under the anode. The relationship between calcitonin flux and current density during iontophoresis was linear. Passive flux was zero. Flux increased with increasing concentration up to 250 microg/ml but then it levels off. Thus, transdermal delivery of salmon calcitonin may be accomplished to achieve therapeutic levels.     

Integrated pharmacokinetic and metabolic modeling of selegiline and metabolites after transdermal administration

Selegiline (SEL) is a selective, irreversible inhibitor of MAO-B, used in the treatment of Parkinson's disease, either alone or as an adjunct to L-DOPA. Selegiline hydrochloride (HCl) undergoes significant first-pass metabolism following oral administration. Transdermal delivery avoids the first-pass effect and provides greater and more prolonged levels of unchanged SEL and reduced levels of metabolites (N-desmethylselegiline (DES), L-amphetamine (AMP), and L-methamphetamine (MET)) compared to the oral regimen. An integrated pharmacokinetic–metabolic model which predicts plasma concentrations of SEL and metabolites following a single 24 h application of a selegiline transdermal system (STS) is proposed. The model is based on the metabolic conversion of SEL to DES and MET and subsequently to AMP. The input function is described by a zero-order constant for the delivery of SEL from the STS system based on in vitro studies of penetration of SEL across human skin. The elimination–non-metabolic constants for each analyte account for the urinary elimination. Plasma concentration data from a pilot pharmacokinetic study in which six healthy male volunteers were administered single 24 h applications of a 1·8 mg cm², 10 cm² STS were used to examine this model. The coefficient of determination was 0·98 and model selection criterion was 3·4 for mean data fits, supporting the goodness of fit of the model. The pharmacokinetic parameters obtained by non-compartmental analysis were comparable to those predicted by a compartmental model. The model also predicted urinary recoveries for AMP and MET and negligible recovery for SEL and DES consistent with recent studies with the STS in which urine was collected. The metabolic conversion constant from SEL to DES was significantly lower than the conversion constant from SEL to MET, indicating that metabolism of SEL is primarily driven towards MET following transdermal administration. The metabolic conversion from MET to AMP was less than the conversion from DES to AMP. This simultaneous prediction of the SEL and metabolites is essential as the metabolic ratios have been linked to the neuroprotective effects of SEL. These findings support the proposed regional delivery advantage attributed to the transdermal route compared to the conventional therapy with the oral tablet. Future model applications may also help identify significant covariates (i.e. age, gender, and disease state) in upcoming clinical trials. © 1997 John Wiley & Sons, Ltd.     

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.     

盐酸奥丹西酮离子导入的研究(英)

本文研究了奥丹西酮在不同电流密度下经小鼠全皮的渗透动力学。当电流密度从0.05mA．cm-2升高到0.3mA．cm-2时，药物的稳态流量从30．29μg．cm-2.h-1增加到160.70μg．cm-2.h-1。研究中药物稳态流量和应用电流之间不严格呈线性关系。铂在供药池中作阳极时，可导致药物溶液变色；而应用银电极代替铂电极，则可以避免此问题的出现。应用铂电极时，供药池和接受池中均发现有pH变化。文章对以上问题以及解决的方法进行了讨论。