Iontophoretic transdermal delivery of buspirone hydrochloride in hairless mouse skin

The transdermal delivery of buspirone hydrochloride across hairless mouse skin and the combined effect of iontophoresis and terpene enhancers were evaluated in vitro using Franz diffusion cells. Iontophoretic delivery was optimized by evaluating the effect of drug concentration, current density, and pH of the vehicle solution. Increasing the current density from 0.05 to 0.1 mA/cm² resulted in doubling of the iontophoretic flux of buspirone hydrochloride, while increasing drug concentration from 1% to 2% had no effect on flux. Using phosphate buffer to adjust the pH of the drug solution decreased the buspirone hydrochloride iontophoretic flux relative to water solutions. Incorporating buspirone hydrochloride into ethanol:water (50:50 vol/vol) based gel formulations using carboxymethylcellulose and hydroxypropylmethylcellulose had no effect on iontophoretic delivery. Incorporation of three terpene enhancers (menthol, cineole, and terpineol) into the gel and when combined with iontophoresis it was possible to deliver 10 mg/cm²/day of buspirone hydrochloride.     

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.     

Polycyclic aromatic hydrocarbon levels in three pelagic fish species from Atlantic Ocean: inter-specific and inter-season comparisons and assessment of potential public health risks

The concentrations of 18 polycyclic aromatic hydrocarbons (PAHs) were determined in three commercially valuable fish species (sardine, Sardina pilchardus; chub mackerel, Scomber japonicus; and horse mackerel, Trachurus trachurus) from the Atlantic Ocean. Specimens were collected seasonally during 2007–2009. Only low molecular weight PAHs were detected, namely, naphthalene, acenaphthene, fluorene and phenanthrene. Chub mackerel (1.80–19.90 μg/kg ww) revealed to be significantly more contaminated than horse mackerel (2.73–10.0 μg/kg ww) and sardine (2.29–14.18 μg/kg ww). Inter-specific and inter-season comparisons of PAHs bioaccumulation were statistically assessed. The more relevant statistical correlations were observed between PAH amounts and total fat content (significant positive relationships, p ? 0.05), and season (sardine displayed higher amounts in autumn–winter while the mackerel species showed globally the inverse behavior). The health risks by consumption of these species were assessed and shown to present no threat to public health concerning PAH intakes.     

脉冲电流对胰岛素经皮渗透的促进作用

实验结果表明,脉冲电流能有效地提高胰岛素的透皮扩散速率,并随着释放池中胰岛素浓度的递增,透皮扩散速率呈线性增加。同时,胰岛素在pH值偏离等电点的酸性溶液(pH3.6)中透皮速率最高,为324.2±33.4μU/(cm²·h),而在pH值高于等电点的溶液(pH7.4)中其透皮速率降至143.7±27.3μU/(cm²·h),在pH值接近等电点(pH5.3)时,胰岛素的透皮速率最低,为78.4±21.9μU/(cm²·h)。     

Transdermal Permeation of Alniditan by Iontophoresis: In Vitro Optimization and Human Pharmacokinetic Data

Purpose. The aim of this paper was to assess the feasibility of electrically enhanced transdermal delivery of alniditan, a novel 5 HT_1D agonist for the treatment of migraine. Methods. An in vitro study was first performed to optimize the different parameters affecting iontophoresis efficiency. The mechanism of alniditan permeation by iontophoresis was investigated. Finally, a phase I clinical trial was performed to assess systemic delivery of alniditan by iontophoresis. Results. i) In vitro: The optimal conditions were found with a buffer like ethanolamine at a pH of 9.5, with Ag/AgCl electrodes and a direct current application. Alniditan permeation was enhanced when increasing the current density, the duration of current application and the drug concentration. Iontophoresis slightly increased drug quantities in stratum corneum compared to passive diffusion but it strongly increased alniditan quantities in viable skin, ii) The objective to deliver in vivo 0.5 mg of alniditan within less than 1 h was reached but an erythema was detected at the anode. Conclusions. This study demonstrates the feasibility of iontophoretic delivery system for antimigraine compounds.     

lontophoretic Delivery of a Telomeric Oligonucleotide

Purpose. To evaluate the feasibility of iontophoretically enhanced transdermal delivery of a phosphorothioate oligonucleotide across hairless mouse skin. Methods. The phosphorothioate sequence, 5-d(TTAGGG)-3 (TAG-6) which mimics the repeat sequence of the telomere was used as a model compound. Iontophoresis was performed on hairless mouse skin using an in vitro flow-through diffusion system. Both 5-FITC and uniformly ³⁵S labeled oligonucleotide were used to monitor transdermal flux. Results. Cathodal delivery of TAG-6 resulted in substantial oligonucleotide flux. The molecular label did not alter transport properties. No flux was measured with either anodal or passive delivery. The oligonucleotide was not degraded as it crossed the skin. Molecular transport was donor condition dependent, with pH and salt concentration both having significant effects. Pre-treating the skin with ethanol reduced iontophoretic transport. Conclusions. These data demonstrate that iontophoresis can enhance transdermal flux of an intact phosphorothioate oligonucleotide and that this penetration is donor condition dependent. Furthermore, iontophoretically enhanced transdermal delivery is a feasible apprach to the administration of phosphorothioate oligonucleotides.     

Stability indicating ion chromatography method for the simultaneous determination of ibandronate sodium drug substance and its impurities

A simple and sensitive ion chromatography method has been developed for the simultaneous assay of ibandronate sodium drug substance and the determination of its impurities. The separation was achieved on Allsep™ anion column 150 mm × 4.6 mm, 7 μm particle diameter. The mobile phase consisted of 1% (v/v) aqueous formic acid and acetone 98:2% (v/v); flow rate 1.0 ml min⁻¹ at ambient temperature. The analytes were monitored by conductometric detector. The drug substance was subjected to stress conditions of hydrolysis, oxidation, photolytic, thermal and humidity degradation. Considerable degradation was achieved only under oxidative conditions. Mass balance was demonstrated in all stress conditions. The method was validated for specificity, precision, linearity, solution stability and accuracy. The limits of detection (LOD) and limits of quantification (LOQ) for impurities were in the range of 0.36–0.80 μg ml⁻¹ and 1.00–2.40 μg ml⁻¹, respectively. For ibandronate LOD was 38 μg ml⁻¹ and LOQ was 113 μg ml⁻¹. The average recoveries for impurities and ibandronate were in the range of 99.0–103.1% and the method can be successfully applied for the routine analysis of ibandronate sodium drug substance.     

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.     

Iontophoresis Enhances the Transport of Acyclovir Through Nude Mouse Skin by Electrorepulsion and Electroosmosis

Purpose. Iontophoresis was employed for enhancing the transdermal delivery of acyclovir through nude mouse skin in vitro, with the aim of understanding the mechanisms responsible for drug transport, in order to properly set the conditions of therapeutical application. Methods. Experiments were done in horizontal diffusion cells, using as donor a saturated solution of acyclovir at two different pH values (3.0 and 7.4). Different electrical conditions (current density and polarity) were employed. Results. At pH 3.0, acyclovir anodal transport was due to electrorepulsion, since acyclovir was 20% in the protonated form. In acyclovir anodal iontophoresis at pH 7.4 the main mechanism involved was electroosmosis, since the drug was substantially unionized and the negative charge of the skin at this pH caused the electroosmotic flow to be from anode to cathode. In the case of cathodal iontophoresis at pH 3.0, acyclovir transport was enhanced approx. seven times, due to the presence of an electroosmotic contribution caused by the reversal of the charge of the skin. At pH 7.4 during cathodal iontophoresis acyclovir transport was not enhanced because the electroosmotic flow was in the opposite direction, compared to drug electric transport, i.e. anode to cathode. The increased skin permeability caused by current application was demonstrated to be less important than electrorepulsion and electroosmosis. Conclusions. Anodal iontophoresis shows potential applicability for enhancing acyclovir transport to the skin, considering that both electric transport and electroosmosis can be used by appropriately setting the pH of the donor.     

Iontophoretic drug delivery using the IOMED Phoresor® system

Iontophoresis, or electromotive drug administration, is a process that enhances the delivery of drugs through a biological membrane via the application of low-intensity electrical current. This technology offers several advantages over oral and injection drug delivery. Key advantages of iontophoretic drug delivery include the avoidance of pain and potential for infection associated with needle injection, the ability to control the rate of drug delivery, the ability to programme the drug-delivery profile and the minimisation of local tissue trauma. Research using iontophoresis has shown delivery of a number of drug classes. By controlling the applied electric current one can tailor a dosage regimen with a drug delivery profile specific for an indication and the needs of the patient. Advances in iontophoretic electrode design, microelectronics and methods to optimise iontophoretic drug delivery have improved the ability to safely deliver both older, off-patent drugs, as well as new chemical entities being developed to treat a variety of diseases. In addition to transdermal applications, current research indicates that iontophoresis may prove to be a viable noninvasive drug delivery method for treating conditions that affect the back of the eye.     

Effect of Electroporation on Transdermal lontophoretic Delivery of Luteinizing Hormone Releasing Hormone (LHRH) in Vitro

Electroporation, the creation of transient, enhanced membrane permeability using short duration (microseconds to millisecond) electrical pulses, can be used to increase transdermal drug delivery. The effect of an (electroporative) electric pulse (1000 V, = 5 msec) on the iontophoretic transport of LHRH through human skin was studied in vitro. Fluxes achieved with and without a pulse under different current densities (0- 4 mA/cm²) were compared. The results indicated that the application of a single pulse prior to iontophoresis consistently yielded higher fluxes (5—10 times the corresponding iontophoretic flux). For example, at 0.5 mA/cm² fluxes were 0.27 ± 0.08 and 1.62 ± 0.05 µg/hr/cm² without and with the pulse, respectively. At each current density studied, the LHRH flux decreased after iontophoresis, approaching pre-treatment values. The results show that electroporation can significantly and reversibly increase the flux of LHRH through human skin. These results also indicate the therapeutic utility of using electroporation for enhanced transdermal transport.     

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.     

Drug Reservoir Composition and Transport of Salmon Calcitonin in Transdermal Iontophoresis

Purpose. The aim of the work was to study iontophoretic transdermal administration of salmon calcitonin (sCt) in rabbits, with particular attention to drug reservoir composition. A dry sCt disc, to be dissolved on the application site, was used for preparing the reservoir for transdermal iontophoresis. As a reference drug reservoir, a pad wetted with drug solution was used. Methods. Experiments were done in rabbits depositing 100 IU of salmon calcitonin on skin and applying anodal iontophoresis. Serum calcium concentration was measured during iontophoresis, passive diffusion and after i.v. administration. Parameters such as pH value and reservoir type were examined. Results. Transdermal iontophoresis of sCt elicited a decrease in the serum calcium level, whereas, in the absence of electric current, no significant fall was measured. Using the reservoir prepared from drug solution, anodal iontophoresis at pH 4.2 was more effective than at pH 7.4, probably due to higher sCt net positive charge. Using the reservoir prepared from dry disc, similar kinetics and extent of drug effect were observed at both pH values. The reservoir prepared from solid drug deposit concentrated sCt next to the skin. Conclusions. Anodal iontophoresis for transdermal calcitonin administration shows therapeutical applicability. The type of reservoir is an important parameter affecting sCt transdermal iontophoresis.     

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.     

Simultaneous determination of nine flavonoids in Polygonum hydropiper L. samples using nanomagnetic powder three-phase hollow fibre-based liquid-phase microextraction combined with ultrahigh performance liquid chromatography-mass spectrometry

A simple, inexpensive, and efficient nanomagnetic powder three-phase hollow fibre-based liquid-phase microextraction (HF-LPME) technique combined with ultrahigh performance liquid chromatography–mass spectrometry (UPLC–MS) was developed for the simultaneous analysis of nine flavonoids in Polygonum hydropiper L. samples. The final, optimised extraction conditions were as follows: an organic solvent of ethyl acetate, a donor phase of aqueous KH₂PO₄ at pH 3.0, an acceptor phase of aqueous NaHCO₃ at pH 8.5, a stirring rate of 1000 rpm, and an extraction time of 50 min. Under these conditions, analyte calibration curves were all linear, with correlation coefficients ≥0.9994. The relative standard deviation for all analytes in intra-day (0.8–2.2%) and inter-day (1.7–3.5%) precision tests was well within the acceptable ranges, as were the limits of quantitation (LOQ < 0.054 μg/L) and detection (LOD < 0.170 μg/L). Recoveries for all standard compounds were between 95.17% and 99.82%, with a RSD of no more than 2.3%. Correlative analyses demonstrated that the physicochemical parameters of the compounds themselves also influenced the extraction efficiency. This technology proved to be rapid, sensitive, and reliable for the quality control of P. hydropiper L. samples.     

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.     

离子导入对卡托普利透皮吸收的促进作用(英文)

目的:研究离子导入技术对卡托普利透皮吸收的促进作用。方法:应用离子导入技术研究了卡托普利体外透过大鼠离体皮肤的影响因素,并进行了卡托普利水凝胶贴片大鼠在体的试验,测定了血药浓度的变化。结果:离子导入技术可以有效地促进卡托普利的透皮吸收,透皮速率增加约7倍。药物贮库中的各种因素如pH,离子强度,药物浓度和电流强度均影响药物的透皮速率。随着pH的增加,离子强度的减小,药物浓度的增加及电流强度的增加,透皮速率也增加。大鼠在体试验也表明用药1h后血药浓度即可达到坪值(约0.9μg/mL),并在整个试验阶段维持稳定。结论:离子导入可以有效地促进卡托普利的透皮吸收。     

Organogels in drug delivery

In the last decade, interest in physical organogels has grown rapidly with the discovery and synthesis of a very large number of diverse molecules, which can gel organic solvents at low concentrations. The gelator molecules immobilise large volumes of liquid following their self-assembly into a variety of aggregates such as rods, tubules, fibres and platelets. The many interesting properties of these gels, such as their thermoreversibility, have led to much excitement over their industrial applications. However, only a few organogels are currently being studied as drug/vaccine delivery vehicles as most of the existing organogels are composed of pharmaceutically unacceptable organic liquids and/or unacceptable/untested gelators. In this paper a brief overview of organogels is presented, followed by a more in-depth review of the gels that have been investigated for drug and/or vaccine delivery. These include microemulsion-based gels and lecithin gels (studied for transdermal delivery), sorbitan monostearate organogels and amphiphilogels (studied as vaccine adjuvants and for oral and transdermal drug delivery, respectively), gels composed of alanine derivatives (investigated as in situ forming gels) and Eudragit organogels (studied as a matrix for suppositories). Finally, pluronic lecithin organogels, descendents of lecithin gels but which are not really organogels, are briefly discussed for their interesting history, their root and the wide interest in these systems.     

The effects of pH and ionic strength on topical delivery of a negatively charged porphyrin (TPPS4)

Meso-tetra-[4-sulfonatophenyl]-porphyrin (TPPS(4)) is a charged porphyrin derivate used in photodynamic therapy (PDT) by parenteral administration. This study means to investigate potential enhancement for its topical delivery by determining the TPPS(4) dependence on the environmental characteristics and applying iontophoresis. In order to accomplish this task, cathodal and anodal iontophoresis as well as passive delivery of the drug were studied in vitro and in vivo in function of its concentration, pH and ionic strength. A reduction in drug concentration as well as the NaCl elimination from donor formulation at pH 2.0 increased TPPS(4) passive permeation through the skin in vitro. Iontophoresis improved TPPS(4) delivery across the skin when applied in solutions containing NaCl at pH 2.0, regardless electrode polarity. However, at pH 7.4, the amount of TPPS(4) permeated by iontophoresis was not different from that one permeated after passive experiments from a solution containing NaCl. Despite the fact that iontophoresis did not improve TPPS(4) transdermal delivery at this specific condition, in vivo experiments showed that 10 min of iontophoresis quickly and homogeneously delivered TPPS(4) to deeper skin layers when compared to passive administration, which is an important condition for topical treatment of skin tumors with PDT.