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.     

Poloxamer gel as vehicle for transdermal iontophoretic delivery of arginine vasopressin: evaluation of in vivo performance in rats

The present study describes the formulation and evaluation for pharmacokinetic and pharmacodynamic activity of arginine vasopressin (AVP), a nanopeptide with antidiuretic activity on being delivered by transdermal iontophoresis. Poloxamer 407 was used to form stable gels that did not reduce the release of AVP. The release rate from the gel followed Higuchi kinetics indicating that the dominant mechanism of release is diffusion. Iontophoresis alone and in combination with chemical enhancers was used to augment the transdermal permeation of AVP. The results of both pharmacokinetic and pharmacodynamic studies emphasize the dimension of 'rapid onset' achieved by iontophoresis. The correlation between pharmacokinetic data and pharmacodynamic activity was only qualitative. Histopathological studies revealed that skin toxicity caused by either iontophoresis or chemical enhancers when used alone could be reduced by using a combination of both the techniques in tandem.     

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.     

Passive and active strategies for transdermal delivery using co-encapsulating nanostructured lipid carriers: In vitro vs. in vivo studies

This work aimed at designing a formulation based on nanostructured lipid carriers (NLC) for transdermal co-administration of olanzapine and simvastatin, using passive and active strategies in a combined in vitro/in vivo development approach. NLC were prepared by two distinct methods, namely solvent emulsification–evaporation (SE/E) and high pressure homogenization (HPH). HPH was selected on the basis of a better performance in terms of drug loading and in vitro permeation rate. Several mathematical models were used to elucidate the release mechanisms from lipid nanoparticles. In vitro release kinetics was shown to be driven by diffusion, but other mechanisms were also present, and supported the feasibility of using NLC for sustained drug delivery. The in vitro skin studies showed that the chemical penetration enhancers, limonene and ethanol, added to the NLC formulations, promoted a synergistic permeation enhancement of both drugs, with olanzapine exhibiting a higher permeation than simvastatin. Transdermal administration to rats resulted in steady-state levels reached at around 10 h and maintained for 48 h, again with olanzapine exhibiting a better permeation rate. The pharmacokinetic parameters indicated that the NLC dispersion displayed a better in vivo performance than the gel, which was consistent with the in vitro results. These differences were, however, negligible in the flux values, supporting the use of gel as a final, more convenient, formulation. The in vivo experiments in rats correlated well with in vitro findings and revealed that the combined use of ethanol and limonene, incorporated in the NLC formulation, provided the main driving force for drug permeation. The Dermaroller® pretreatment did not significantly enhance drug permeation, supporting the use of passive methods as suitable for a transdermal delivery system. Furthermore, this work may provide a promising proof-of-concept for further clinical application in the treatment of schizophrenia and associated disorders, combined with dyslipidemia.     

Effect of amino acid sequence on transdermal iontophoretic peptide delivery

The objective of this study was to investigate the effect of amino acid sequence on the transdermal delivery of peptides by iontophoresis. Structurally related, cationic tripeptides based on the residues at positions (i) 6–8 in LHRH (Ac-X-Leu-Arg-NH₂) and (ii) 3–5 in octreotide (Ac-X-dTrp-Lys-NH₂) were studied. Iontophoretic transport experiments were conducted using porcine skin in vitro to investigate the dependence of flux on peptide concentration. Co-iontophoresis of acetaminophen enabled deconvolution of the contributions of electromigration (EM) and electroosmosis (EO) and the calculation of an electroosmotic inhibition factor (IF). A two-fold increase in donor peptide concentration increased iontophoretic flux for most peptides, and electroosmotic inhibition for dNal-containing tripeptides. The improvement in transport and the impact on the EM and EO components were peptide-specific. A reduction in the number of competing ions in the formulation significantly increased transport and, specifically, the EM contribution; it also increased IF of compounds with a propensity to interact with the membrane. No monotonic dependence of flux on either molecular weight or lipophilicity was observed. Iontophoretic peptide transport could not be rationalized in terms of either peptide molecular weight or computational 2D estimates of lipophilicity. Data suggest that a more complex three-dimensional approach is required to develop structure permeation relationships governing iontophoretic peptide delivery.     

In vitro and in vivo evaluation of the transdermal iontophoretic delivery of sumatriptan succinate.

The objective was to evaluate the transdermal delivery of the 5-HT(1B/1D) agonist, sumatriptan from an iontophoretic patch system, in vivo. Initial in vitro experiments were conducted to optimize formulation parameters prior to iontophoretic delivery in Yorkshire swine. It was found in vitro that increasing drug load in the patch from 9.7 to 39 mg had no statistically significant effect on cumulative delivery (cf. 305.6+/-172.4 vs. 389.4+/-80.4 microg cm(-2), respectively). However, for a given drug load (39 mg) increasing formulation pH from pH 4.7 to 6.8 significantly increased the cumulative amount of sumatriptan delivered across the skin (389.4+/-80.4 vs. 652.4+/-94.2 microg cm(-2)). A biphasic current profile comprising intensities of 1.8 mA from t=0 to t=180 min and 0.8 mA from t=181 min to t=360 min was used for the in vivo experiments. Drug levels in the blood were 13.7+/-4.5 and 53.6+/-10.2 ng ml(-1) at the 30 and 60 min time-points, rising to 90-100 ng ml(-1) during the 90-180 min time-period. The in vivo results show that the pharmacokinetics following transdermal iontophoretic delivery are comparable to those after oral, nasal or rectal administration, but do not match those upon subcutaneous injection.     

In vitro transdermal iontophoretic delivery of leuprolide-mechanisms under constant voltage application

The transdermal iontophoretic delivery of Leuprolide, a nonapeptide LHRH agonist was studied with the aim of understanding the mechanisms of iontophoresis. Permeation studies were carried out at pH 4.5 and 7.2, at which the average ionic valence of the drug molecule was roughly 2 and 1, respectively. Heat-separated human epidermal membrane was subjected to constant voltage within the range of 250 to 1000 mV during the iontophoretic phase. Iontophoretic enhancement at pH 7.2 was greater than at 4.5. A model for iontophoretic enhancement was developed that takes into consideration the membrane alterations caused by iontophoresis depicted as increased porosity and the permeation through lipid pathways of the stratum corneum. Model-based evaluation yielded that first, the porosity increased with the applied voltage to as much as three times the original at 1000 mV. Second, the lipid pathways contributed approx. 20% to the total permeation during the passive phase. Third, the electro-osmotic flow contributed significantly to the enhancement and its direction was from anode to cathode at pH 7.2 and the opposite at pH 4.5. The magnitude of the electro-osmotic flow was at pH 4.5 somewhat lower than at pH 7.2. Addition of a negatively charged water soluble peptide, Acetyl leucine leucinolyl phosphate as an adjuvant led to twofold increase in the enhancement factor at pH 4.5 and a decrease in the magnitude of the electro-osmotic flow from cathode to anode. Repeated iontophoretic applications of 250 mV on the same skin specimen resulted in same enhancement every time and did not cause any barrier alterations when applied for 1 h every 24 h, which was not the case if the duration between the two iontophoretic applications was only 3 h.     

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.     

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.     

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.     

Rivastigmine exposure provided by a transdermal patch versus capsules

ABSTRACT

Objectives: The rivastigmine transdermal patch is the first transdermal treatment for Alzheimer's disease (AD) and dementia associated with Parkinson's disease. The objective of this study was to evaluate the pharmacokinetics of rivastigmine following transdermal delivery by a patch versus oral delivery with conventional capsules in a population of AD patients.

Methods: Both non-compartmental and compartmental analyses were performed on the same database showing relatively large inter-patient variations in pharmacokinetic parameters (up to 73% for the capsule group). The compartmental analysis provided model-based predictions of pharmacokinetic parameters, with the aim of comparing the two modes of administration when adjusting for confounding factors such as patient body weight and gender.

Results: According to both non-compartmental and compartmental analyses, the patch provided significantly lower peak rivastigmine plasma concentrations (C_max) and slower times to C_max (t_max), compared with capsules. However, drug exposure (area under the curve; AUC) was not significantly different between the 4.6?mg/24 hour (5?cm²) patch and 3?mg BID (6?mg/day) capsule doses, or between the 9.5?mg/24 hour (10?cm²) patch and 6?mg BID (12?mg/day) capsule doses, according to both analyses. This suggests comparable exposure from these two rivastigmine delivery systems.

Conclusion: The analyses were consistent with previous reports of a markedly less fluctuating, more continuous drug delivery with the rivastigmine patch. This characteristic delivery profile is associated with similar efficacy yet improved tolerability, compared with capsules.     

Effect of iontophoresis on in vitro transdermal absorption of almotriptan

The aim of the present work was to characterize the in vitro transdermal absorption of almotriptan through pig ear skin. The passive diffusion of almotriptan malate and its iontophoretic transport were investigated using current densities of 0.25 and 0.50 mA/cm². In vitro iontophoresis experiments were conducted on diffusion cells with an agar bridge without background electrolytes in the donor compartment. Although both current densities applied produced a statistically significant increment with respect to passive permeation of almotriptan (p < 0.01), that of 0.50 mA/cm² proved to be the best experimental condition for increasing the transport of almotriptan across the skin. Under these experimental conditions, the transdermal flux of the drug increased 411-fold with respect to passive diffusion, reaching 264 ± 24 μg/cm² h (mean ± SD). Based on these results, and taking into account the pharmacokinetics of almotriptan, therapeutic drug plasma levels for the management of migraine could be achieved via transdermal iontophoresis using a reasonably sized (around 7.2 cm²) patch.     

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.     

Enhanced transdermal delivery of meloxicam by nanocrystals: Preparation,in vitro and in vivo evaluation

 Meloxicam (MLX) is efficient in relieving pain and inflammatory symptoms, which, however,is limited by the poor solubility and gastrointestinal side effects. The objective of thisstudy is to develop a nanocrystal formulation to enhance transdermal delivery of MLX. MLXnanocrystals were successfully prepared by the nanoprecipitation technique based on acidbaseneutralization. With poloxamer 407 and Tween 80 (80/20, w/w) as mixed stabilizers,MLX nanocrystals with particle size of 175 nm were obtained. The crystalline structure ofMLX nanocrystals was confirmed by both differential scanning calorimetry and X-ray powderdiffractometry. However,the nanoprecipitation process reduced the crystallinity of MLX.Nanocrystals increased both in vitro and in vivo transdermal permeation of MLX comparedwith the solution and suspension counterparts. Due to the enhanced apparent solubilityand dissolution as well as the facilitated hair follicular penetration, nanocrystals present ahigh and prolonged plasma MLX concentration. And 2.58- and 4.4-fold increase in AUC0→24hwas achieved by nanocrystals comparing with solution and suspension, respectively. In conclusion,nanocrystal is advantageous for transdermal delivery of MLX.     

Formulation,optimization and evaluation of transferosomal gel for transdermal insulin delivery

The present study deals with the development of transferosomal gel containing insulin by reverse phase evaporation method for painless insulin delivery for use in the treatment of insulin dependent diabetes mellitus. The effect of independent process variables like ratio of lipids (soya lecithin:cholesterol), ratio of lipids and surfactants, and ratio of surfactants (Tween 80:sodium deoxycholate) on the in vitro permeation flux (μg/cm²/h) of formulated transferosomal gels containing insulin through porcine ear skin was optimized using 2³ factorial design. The optimal permeation flux was achieved as 13.50 ± 0.22 μg/cm²/h with drug entrapment efficiency of 56.55 ± 0.37% and average vesicle diameter range, 625–815 nm. The in vitro insulin permeation through porcine ear skin from these transferosomal gel followed zero-order kinetics (R² = 0.9232–0.9989) over a period of 24 h with case-II transport mechanism. The in vitro skin permeation of insulin from optimized transferosomal gel by iontophoretic influence (with 0.5 mA/cm² current supply) also provided further enhancement of permeation flux to 17.60 ± 0.03 μg/cm²/h. The in vivo study of optimized transferosomal gel in alloxan-induced diabetic rat has demonstrated prolonged hypoglycemic effect in diabetic rats over 24 h after transdermal administration.     

氟康唑脂质体凝胶的制备及体外透皮实验（英文）

目的制备氟康唑脂质体凝胶,并研究其性质。方法以薄膜分散法制备氟康唑脂质体,透射电镜观察脂质体的形态,粒度分布仪测定粒径,透皮吸收扩散池测定脂质体凝胶的透皮吸收。结果氟康唑脂质体的包封率为47.68%。脂质体粒径均匀,平均粒径为250±8nm。氟康唑脂质体凝胶的累积透过量（25.27%）低于非脂质体凝胶（36.72%）,而脂质体凝胶的药物皮内滞留量（162±15μg·cm^-2于非脂质体凝胶（48±6μg·cm^-2结论氟康唑脂质体凝胶剂可显著提高药物的皮内滞留量,有望成为氟康唑的一种外用新剂型。     

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.     

In vitro iontophoretic transport of ketorolac: synthetic membrane as a barrier

The effect of different factors on the iontophoretic transport of ketorolac was analyzed. In vitro experiments were performed in a diffusion cell with a cellulose membrane as a barrier. The results indicated that an increase in current density or drug concentration enhanced the transmembrane permeation of the drug. The presence of extraneous ions (such as NaCl) or an increase in viscosity of the donor medium slowed down the iontophoretic transport of the drug. The pH does not seem to be an important factor determining iontophoretic transport of ketorolac as statistically insignificant difference was observed in flux at pH 5.6, 7.2, and 8. Also, the relative importance of the transport contributions involved in iontophoresis, namely diffusive iontophoretic and electro-osmotic fluxes, was investigated using glucose as a nonionizable drug. The results indicated that the total flux of ketorolac is a result of two contributions: passive diffusion and iontophoretic flux. The contribution of electro-osmosis appears to be negligible.