Extraction of levetiracetam for therapeutic drug monitoring by transdermal reverse iontophoresis.

Recently, transdermal reverse iontophoresis across the skin has been investigated as a novel technology for the purpose of diagnosis as well as therapeutic drug monitoring. Accordingly, the objective of this study was to investigate ex vivo and in vivo transdermal extraction of levetiracetam, an antiepileptic drug, across the pig ear skin by reverse iontophoresis. Reverse iontophoresis experiments were performed using three chambered diffusion cells. Extractions profiles were generated in phosphate buffers at different current intensities, pH and ionic strength as well donor drug concentrations. This was followed by ex vivo extraction in gels and in vivo extractions using New Zealand rabbits. Results indicate that levetiracetam was extracted at both anode and cathode. Flux values were unaffected by increase in current intensities (0.5 mA and 0.6 mA) but affected by pH and ionic strength. Neither in cathodal nor in anodal extraction, flux values did show a proportional relationship with the donor drug concentration. At low and medium concentration levels, flux values did not show any major change but the extraction flux at high donor concentration was much higher. In contrast, in vivo experiment with rabbits resulted in wide variation of fluxes with very high fluxes recorded at the cathodal end. Reasons attributed to this difference may include lower current intensity, and species variation. The most significant finding of this study is that measurable amounts of the levetiracetam were extracted at both the ends indicating its feasibility for non-invasive drug monitoring.

Reverse Iontophoretic Extraction of Gabapentin: A Mechanistic Study.

BACKGROUND: For the narrow therapeutic index anti-epileptic drugs, monitoring of plasma concentration is a necessity for avoiding complications related to fluctuation of plasma level. OBJECTIVE: The work was aimed at extracting gabapentin by transdermal reverse iontophoresis to investigate its feasibility for noninvasive therapeutic drug monitoring. METHODS: Gabapentin was delivered in phosphate buffer (pH 7.4) at a therapeutic concentration range of 2-10 µg/ml. The same media was also used in receiver compartment. Extractions were carried out under an electric field of 5 V (current intensity range 0.3 -0.5 mA/cm2), provided by a custom-made power source for a period of 4 h. Samples were withdrawn at hourly intervals and drug content was analyzed by HPLC. RESULTS: Results indicated that gabapentin extraction occurred at both anode and cathode with cathodal extractions showing higher value at all concentrations. Extraction rates at both the chambers were affected by time, the first hour extraction was notably higher than the later hours. Highest extraction rate was noted at pH 5. Surprisingly, anodal extraction was found to show greater positive correlation with current intensity compared to cathodal extraction. CONCLUSIONS: As gabapentin carried no net charge at pH 7.4, orientation mediated electromigration was suggested to be the cause.

Transdermal reverse iontophoresis: A novel technique for therapeutic drug monitoring.

Application of transdermal reverse iontophoresis for diagnostic purpose is a relatively new concept but its short span of research is full of ups and downs. In early nineties, when the idea was floated, it received a dubious welcome by the scientific community. Yet to the disbelief of many, 2001 saw the launching of GlucoWatch® G2 Biographer, the first device that could measure the blood sugar level noninvasively. Unfortunately, the device failed to match the expectation and was withdrawn in 2007. However, the concept stayed on. Research on reverse iontophoresis has diversified in many fields. Numerous in vitro and in vivo experiments confirmed the prospect of reverse iontophoresis as a noninvasive tool in therapeutic drug monitoring and clinical chemistry. This review provides an overview about the recent developments in reverse iontophoresis in the field of therapeutic drug monitoring.

Understanding type 1 diabetes: etiology and models.

Type 1 diabetes is a complex disease involving a combination of factors, such as genetic susceptibility, immunologic dysregulation and exposure to environmental triggers. Animal models serve an important function both in elucidating the pathophysiology and preliminary screening of antidiabetic molecules. Hence, the development of models for type 1 diabetes can be broadly divided into 3 categories, namely: identification of spontaneously developing type 1 diabetes mellitus strains, creating diabetes-prone species through gene transfer techniques and forced destruction of islet cells through chemical or surgical means. This review discusses the models used to study type 1 diabetes with special emphasis on genetics.

Prospects of iontophoresis in cardiovascular drug delivery.

Clinical benefits, industry interest, regulatory precedence, and strong market potential have made transdermal research the fastest growth area in drug delivery. As most drugs permeate poorly through skin, a major challenge is achieving the therapeutic level by enhancement of permeation rate. Iontophoresis, utilizing a minimal amount of current, is found to affect the skin permeation process drastically. Ideally suited for protein drugs, attempts have been made to utilize the technology for accelerating the low-molecular-weight drugs for chronic administration. However, because of the difficulty associated with the energy supply, commercialization was not feasible until recent times. Fortunately, the unprecedented growth of microelectronics has bridged this lacuna and brought the technology right into limelight. This article analyses the advantages of electrically assisted drug delivery in relation to passive permeation, with special reference to some cardiovascular drugs, for which there is already a demand in the market.

In vitro iontophoretic delivery of nicorandil.

The present investigation is aimed at assessing the iontophoretic permeability of nicorandil to evaluate its feasibility for the development of an actively delivered transdermal system. Excised porcine skin was used for permeation study, and steady state flux was optimized with respect to donor concentration, current density, and voltage. Constant current iontophoresis was carried out at 0.3, 0.5, and 0.7 mA/cm(2), whereas constant voltage studies were carried out at 3, 5, and 6.5 V. The effect of donor drug concentration (11.8, 55.8, and 104.8 mg/mL) was studied at the optimized condition of 5 V. An apparent increase in steady state flux was observed in constant current studies, but the increment over the passive diffusion was statistically insignificant (P > 0.05). In contrast, steady state flux was found to be higher than that of passive fluxes when permeation was carried out at 5 and 6.5 V (P < 0.001). Incorporation of alcohol in the donor vehicle increased solubility, but there was a tradeoff in terms of lag time. Conformity with the Nernst-Planck convective transport model suggested that electroosmosis was the dominant mechanism of permeation.

Passive and iontophoretic permeation of glipizide gel: an in vitro and in vivo study.

The purpose of the present work was to formulate and evaluate skin permeability of a glipizide gel to assess its suitability for transdermal delivery. A polymer gel was prepared by soaking hydroxypropyl methyl cellulose (5 g) overnight in phosphate buffer: ethanol (50:50, v/v) and mixing it with separately prepared glipizide solution in the same vehicle to bring the concentration to 2 mg /ml. In vitro skin permeability was assessed in full thickness skin of rabbits and pigs. For in vivo studies New Zealand rabbits were used. In vitro passive permeation was carried out in Franz diffusion cell but for iontophoresis, diffusion cell was modified according to Glikfield design. Iontophoresis was performed at a current density of 0.5 mA/cm2 via silver/silver chloride electrodes with the passive controls but for in vivo study current density was reduced to 0.125 mA/cm2. Blood samples were analyzed for drug content by HPLC and blood sugar levels were also recorded periodically during in vivo permeation. Results of the in vitro study indicated that iontophoresis considerably increased the permeation rate of glipizide compared to passive controls in both the skin types (P<0.05). For in vivo studies current densities and drug concentration had to be lowered to 0.125 mA/cm2 as excessive permeation resulting in hypoglycemic shocks were noted when study was carried out at a current density of 0.5 mA/cm2. The low intensity current was well tolerated. The plasma concentration of glipizide was significantly higher (P<0.05) than that obtained in the passive controls. The study indicated even at very low current density, iontophoresis could enhance the permeation of glipizide significantly.

Screening of venlafaxine hydrochloride for transdermal delivery: passive diffusion and iontophoresis.

The objective of the study was to investigate in vitro transdermal delivery of venlafaxine hydrochloride across the pigskin by passive diffusion and iontophoresis. For passive diffusion, experiments were carried out in Franz diffusion cell whereas for iontophoretic permeation, the diffusion cell was modified to contain both the donor and return electrode on the same side of skin. Anodal iontophoresis was carried out using a current density of 0.5 mA/cm(2). Donor concentrations used were 585.5 mg/ml (saturated solution) and 100 mg/ml. Experiments initially performed to determine the transport efficiency of venlafaxine ions showed promising results. Iontophoresis increased the permeation rate at both concentration levels over their passive counterparts (P < 0.01), but surprisingly higher steady-state flux was obtained from lower donor drug load (P < 0.01). The favorable pH of the unsaturated solutions is suggested to be the cause for this effect. Mild synergistic effect was observed when iontophoresis was carried out incorporating peppermint oil in the donor but the same was not found in passive diffusion. Highest steady-state flux obtained in the experiment was 3.279 mumol/cm(2)/h when peppermint oil (0.1%) was included in the donor. As the maintenance requirement of venlafaxine hydrochloride is approximately 9.956 mumol/h, the results suggested that the drug is a promising candidate for iontophoretic delivery.

Passive and iontophoretic permeation of glipizide.

In vitro iontophoretic delivery of glipizide across the pigskin was investigated. The experiment was carried out at three different donor drug concentrations using cathodal iontophoresis (current density 0.5 mA cm(-2)) with corresponding passive controls. At all concentration levels, iontophoresis showed enhanced permeation rate compared to passive controls (P<0.01). For passive permeation, the steady-state flux significantly increased with the increase in donor drug concentration (P<0.01). Passive process followed zero-order profile while the profile was nonlinear in iontophoresis. Competition by chloride ions released in the cathode compartment could be the reason. Flux enhancement was highest at the lowest drug load and lowest at the highest drug load. The target flux of glipizide was calculated to be 0. 4147 micromol h(-1). As the highest flux obtained was 0.2727 micromol cm(-2) h(-1), it can be said that glipizide is a promising candidate for iontophoretic delivery.