In vivo evaluation of skin of children with LC-OCT: An objective assessment.

BACKGROUND: Several non-invasive skin imaging methods have been developed in recent years. Line-field confocal optical coherence tomography (LC-OCT) is one of them, leading to the best compromise in terms of resolution and penetration depth. Skin biopsies are an essential technique in paediatric dermatology, but they are a major stressful event for the child and their parents. Current LC-OCT studies have not been dedicated to a paediatric population. If, however, LC-OCT proves to be helpful in children, it may help guide and decrease a certain number of skin biopsies. OBJECTIVES: (1) To evaluate the feasibility of using LC-OCT in paediatric patients, and (2) to assess the maturation of skin structures in children over time with this method. METHODS: In vivo LC-OCT images were collected on six specific body regions (forehead, forearm, chest, back, dorsum of the hand and palmar surface) and in six age groups (between the ages of 0 and 16 years). RESULTS: In all body areas and age groups assessed, 9 of 10 images were rated as good-to-excellent, the only exception were the images acquired on the palmar surface. LC-OCT allowed visualizing very well the skin structures up to a penetration of 500 µm. We observed that the body regions located on the upper extremities of the body (forearm, dorsum of the hand and palmar surface) showed both a maturation on their structure and differences in thickness with respect to the other regions evaluated. CONCLUSIONS: LC-OCT can easily be used for non-invasive imaging of children's skin and allows to document progressive skin changes in the different age groups. It may be a useful asset for imaging and diagnosing superficial skin disorders and as such reducing the number of invasive procedures while increasing the speed of diagnosis in the paediatric population.

Transdermal therapeutic systems for memantine delivery. Comparison of passive and iontophoretic transport.

Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist used in the treatment of moderate to severe dementia including the symptoms of Alzheimer's disease (AD). It is administered orally but compliance, swallowing problems and the routine use of multiple medications in elderly AD patients means that an alternative route of administration would be of interest. The aim of the present study was to develop memantine hydrochloride occlusive transdermal therapeutic systems (TTS) for passive and iontophoretic delivery across the skin. Polyvinyl pyrrolidone (PVP) and a mixture with polyvinyl alcohol (PVA) were employed as polymeric matrices. The study involved the TTS characterization in addition to quantification of the memantine transport across porcine skin in vitro. The evaluation of the TTS physical properties suggested that systems were made more mechanically resistant by including PVA (6%) or high concentrations of PVP (24%). Moreover, a linear correlation was observed between the concentration of PVP and the bioadhesion of the systems. Drug delivery experiments showed that the highest transdermal flux provided by a passive TTS (PVP 24% w/w limonene) was 8.89±0.81µgcm-2h-1 whereas the highest iontophoretic transport was 46.4±3.6µgcm-2h-1. These innovative TTS would enable two dosage regimens that could lead to therapeutic plasma concentrations.

Topical delivery of diclofenac into and across equine skin from a novel liquid diclofenac epolamine formulation.

The aim was to investigate diclofenac delivery into and across equine skin in vitro using Franz diffusion cells from a novel diclofenac epolamine (DIC-EP; 1.3%) formulation and to compare the results to those of Surpass® (1% diclofenac sodium liposomal cream) and a 1% aqueous solution of diclofenac sodium. Skin was harvested from the lower legs of Freiberger geldings immediately after slaughter and sliced to a thickness of ~2 mm. Skin samples were divided into two groups [Group 1: 1 year old (n = 2) and Group 2: 6-8 years old (n = 3)]. Cumulative permeation of diclofenac in Groups 1 and 2 after 24 h using diclofenac sodium solution was 1.91 ± 0.27 and 1.76 ± 0.34 µg/cm2 , respectively. The values for Surpass® and DIC-EP were 3.2 ± 0.8/3.3 ± 0.7 µg/cm2 and 230 ± 59/89.2 ± 32.5 µg/cm2 , respectively. Thus, diclofenac permeation from DIC-EP was significantly greater and appeared to show an age-dependent effect. Mathematical modelling showed that the DIC-EP formulation significantly increased diclofenac partitioning into the skin and a linear correlation was observed between steady-state flux and the partition parameter. Greater skin deposition of diclofenac was also observed with DIC-EP. These preliminary results suggest that the DIC-EP formulation may be effective in treating inflammatory conditions in horses.

Development of antimigraine transdermal delivery systems of pizotifen malate.

The aim of this study was to develop and evaluate a transdermal delivery system of pizotifen malate. Pizotifen is frequently used in the preventive treatment of migraine, but is also indicated in eating disorders. In the course of the project, the effects of chemical enhancers such as ethanol, 1,8-cineole, limonene, azone and different fatty acids (decanoic, decenoic, dodecanoic, linoleic and oleic acids) were determined, first using a pizotifen solution. Steady state flux, diffusion and partition parameters were estimated by fitting the Scheuplein equation to the data obtained. Among the chemical enhancers studied, decenoic acid showed the highest enhancement activity, which seemed to be due to the length of its alkyl chain and unsaturation at the 9th carbon. The influence of iontophoresis and the involvement of electrotransport in said process was determined. The absorption profile obtained with iontophoresis was similar to that obtained with fatty acids and terpenes, though skin deposition of the drug was lower with the former. Transdermal delivery systems (TDS) of pizotifen were manufactured by including chemical enhancers, decenoic acid or oleic acid, and were subsequently characterized. When the results obtained with solutions were compared with those obtained with the TDS, a positive enhancement effect was observed with the latter with respect to the partitioning and diffusion of the drug across the skin. Our findings endorse the suitability of our TDS for delivering therapeutic amounts of pizotifen malate.

Transdermal absorption of memantin--effect of chemical enhancers, iontophoresis, and role of enhancer lipophilicity.

The transdermal administration of memantine may have advantages with respect to oral therapy when treating advanced stages of Alzheimer's disease. With the ultimate objective of administrating memantine through a transdermal patch, the absorption of the drug across skin was evaluated by means of in vitro permeation studies. The effect of several chemical enhancers was studied in order to enhance percutaneous absorption of the memantine. The iontophoretic transdermal transport of memantine hydrochloride using a current density of 0.5 mA/cm(2) was also investigated. Results demonstrated that pre-treatment of the skin with R-(+)-limonene, laurocapram, decenoic acid, or oleic acid produced a statistically significant increment in the transdermal flux of memantine hydrochloride with respect to the control. Iontophoresis exhibited the greatest ability to enhance the flux of drug with respect to the control; nevertheless, the results obtained with R-(+)-limonene indicate that this compound could be of great use as a percutaneous enhancer in a memantine transdermal delivery system. In this study, the relationship between enhancement activity and lipophilicity was also studied. Satisfactory correlations have been obtained between the optimum lipophilicity of the enhancer and n-octanol/water partition coefficients of drugs. This relationship is a very useful tool that could allow to reduce time and to optimize the selection of appropriate enhancers for transdermal formulations.

HPLC-UV analytical method for determination of pizotifen after in vitro transdermal diffusion studies.

Pizotifen malate is an antihistamine and serotonin inhibitor used in the preventive treatment of migraine and eating disorders. A simple, rapid, accurate and precise high-performance liquid chromatography (HPLC) method involving ultraviolet detection was validated for the quantitative analysis of pizotifen malate in samples from in vitro transdermal diffusion studies. The method was validated for specificity, linearity, accuracy, precision, limit of detection, limit of quantification and robustness. Drug stability in the solution was also determined under different conditions. Separation was carried out using a 250 × 4.0 mm Kromasil(®) C(18) column at room temperature. The detector response, fitted at 254 nm, was found to be linear in a concentration range between 0.24 and 24.0 µg/mL. The limit of detection was 0.02 µg/mL and the limit of quantification was 0.07 µg/mL. Finally, in vitro transdermal diffusion of pizotifen malate was characterized using the validated HPLC method.

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 0.50mA/cm(2). 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 0.50mA/cm(2) 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±24µg/cm(2)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 7.2cm(2)) patch.

Sumatriptan succinate transdermal delivery systems for the treatment of migraine.

We have successfully obtained sumatriptan transdermal systems with different polymer compositions: methyl cellulose (MC), polyvinyl pyrrolidone (PVP) and a polyvinyl pyrrolidone (PVP)-polyvinyl alcohol (PVA) mixture. The systems contained 1,2-propylenglycol (MC) or sorbitol as a plasticizer (PVP and PVP-PVA), methacrylate copolymer as an adhesive agent, and an occlusive liner. Azone (5%, w/w) was incorporated into all the systems as a percutaneous enhancer. Transdermal systems are thin, transparent and non-adhesive when in a dry state. The permeation of sumatriptan succinate across pig ear skin was studied using the systems prepared. The formulation with MC polymer produced a statistically significant increment with respect to the PVP and PVP-PVA formulations (p < 0.05). Azone incorporation into the systems produced an increment in the sumatriptan flux values of all three transdermal systems with respect to those of the controls (p < 0.05). In addition, the application of iontophoresis to the wet methyl cellulose-Azone formulation produced a much higher increase of sumatriptan transdermal flux.