Hiep X. Nguyen

Microneedle-mediated intradermal delivery of epigallocatechin-3-gallate.

Epigallocatechin‐3‐gallate (EGCG) is the physiologically most active and abundant flavanol, accounting for 50–80% of green tea catechins. It is an anti‐inflammatory, antioxidant, chemopreventive and skin photoprotective agent. However, light sensitivity and low permeability of EGCG across the stratum corneum due to its high molecular weight as well as strong binding to the lipid bilayers in the skin make it difficult to be used as a key ingredient in cosmetic products. This study aimed to formulate a photostable hydrogel of EGCG with good rheological properties for dermal application and investigate the effect of skin microporation using maltose microneedles on its permeation through dermatomed porcine skin.

Fabrication, characterization and application of sugar microneedles for transdermal drug delivery

AIM This study aimed to fabricate, characterize and use maltose microneedles for transdermal delivery of doxorubicin. MATERIALS & METHODS Microneedles were fabricated by micromolding technique and evaluated for dimensions, mechanical properties and in situ dissolution. Microporation of human cadaver skin was confirmed by dye binding, histology, pore uniformity, confocal laser microscopy and skin integrity measurement. In vitro permeation studies were performed on vertical Franz diffusion cells. RESULTS Maltose microneedles were sharp, mechanically uniform and rapidly dissolvable. Microneedle insertion resulted in a marked decrease in lag time and a significant increase in the permeation across and into human skin (p < 0.05). The skin delivery profile was used to predict the steady-state plasma concentration. CONCLUSION Maltose microneedles are a promising physical technique to increase skin delivery.

Dihydroergotamine mesylate-loaded dissolving microneedle patch made of polyvinylpyrrolidone for management of acute migraine therapy

&NA; Migraine is a widespread neurological disease with negative effects on quality of life and productivity. Moderate to severe acute migraine attacks can be treated with dihydroergotamine mesylate (DHE), an ergot derivative that is especially effective in non‐responders to triptan derivatives. To overcome limitations of current DHE formulations in subcutaneous injection and nasal spray such as pain, adverse side effects and poor bioavailability, a new approach is needed for DHE delivery enabling painless self‐administration, quick onset of action, and high bioavailability. In this study, we developed a dissolving microneedle patch (MNP) made of polyvinylpyrrolidone, due to its high aqueous solubility and solubility enhancement properties, using a MNP design previously shown to be painless and simple to administer. DHE‐loaded MNPs were shown to have a content uniformity of 108 ± 9% with sufficient mechanical strength for insertion to pig skin ex vivo and dissolution within 2 min. In vivo pharmacokinetic studies were carried out on hairless rats, and DHE plasma levels were determined by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). The area under curve (AUC) value after DHE delivery by MNP (1259 ± 917 ng/mL min) was not significantly different (p > 0.05) as compared to subcutaneous injection, with a relative bioavailability of 97%. Also, appreciable plasma levels of DHE were seen within 5 min for both delivery methods and tmax value of MNPs (38 ± 23 min) showed no significant difference (p > 0.05) compared to subcutaneous injection (24 ± 13 min). These results suggest that DHE‐loaded MNPs have promise as an alternative DHE delivery method that can be painlessly self‐administered with rapid onset and high bioavailability. Graphical abstract Figure. No caption available.

Methods to simulate rubbing of topical formulation for in vitro skin permeation studies

Rubbing a topical formulation on skin is generally assumed to enhance drug penetration. The aim of this study was to demonstrate different techniques such as using glass rod, rheometer, and gloved finger for rubbing a 2% salicylic acid gel on skin and investigate their effect on in vitro permeation of salicylic acid through dermatomed porcine ear skin. The studies included evaluation of the gels rheological properties, gel distribution on skin surface, in vitro permeability, drug distribution in skin, skin extraction recovery, and mass balance. Rubbing with a gloved finger resulted in a uniform gel layer with a thickness of 49.61±15.33μm on the skin surface. No significant difference between the different test groups was observed in terms of the cumulative amount of drug that permeated in 24h (p>0.05). Drug levels in stratum corneum, epidermis, and dermis were also analyzed. Rubbing with gloved finger delivered significantly higher amount of drug into the skin layers as compared to other test groups (p<0.05). Amount of drug extracted from skin was reliably correlated to the actual drug levels in skin (R2=0.99). Considering drug amounts in different compartments, mass balance ranged from 75.86±2.90% to 80.44±2.99%.

Effect of ablative laser on in vitro transungual delivery

ABSTRACT Topical therapy of nail psoriasis using methotrexate has not been realized due to the high molecular weight and low permeability of the compound. In this study, we used a 2940 nm fractional ablative laser to disrupt the nail barrier to enhance the in vitro transungual delivery of methotrexate. Bovine hoof membrane—an in vitro model of the human nail—was treated by the laser at different energy levels and pore densities. A successful microporation was characterized by mechanical properties, scanning electron microscopy, Fourier transform infrared spectrophotometer, dye binding, histology, pore uniformity, confocal laser microscopy, nail integrity measurement, and permeation studies. No significant difference in the pore dimension was found in different treatment groups (p > 0.05). Increases in pore depth corresponded with increases in the laser energy. Laser ablation was found to affect the mechanical properties of the hoof membrane. In in vitro permeation studies, laser ablation resulted in a significant increase in the drug cumulative delivery, flux, and permeability coefficient as compared to the untreated group (n = 3, p < 0.05). A change in the laser energy and pore density was found to alter the drug permeability. Thus, transungual methotrexate delivery was enhanced by the fractional laser ablation.

Qualitative and quantitative analysis of lateral diffusion of drugs in human skin

Graphical abstract Rate of diffusion in (A) vertical direction into the central probe and (B) horizontal direction into the lateral probe Untreated skin (PASSIVE), PLGA microneedles‐treated skin (MN), Ablative laser‐treated skin (LASER) (*, # indicated statistical difference between groups, p < 0.05, p < 0.01, respectively). Figure. No Caption available. Abstract This study aimed to qualitatively and quantitatively analyze lateral diffusion of drugs in dermatomed human skin. Lateral diffusion of calcein and methylene blue dyes in skin was investigated using confocal laser microscopy, calcein imaging, and histology studies. In in vitro permeation studies, two linear microdialysis probes were inserted into the dermis of untreated, poly lacto‐glycolic acid microneedle‐treated, and ablative laser‐treated skin such that one was in the center of the diffusion area and the other was parallel, at 8 mm from the central probe. Skin was mounted on Franz cells, sandwiched between donor containing diclofenac sodium solution and receptor containing phosphate buffered saline, pH 7.4. Qualitative techniques revealed faster lateral diffusion of the dyes in microneedle‐treated skin than laser‐treated skin. Rate of drug diffusion in the central probe in the microneedle‐treated skin (11.8 ± 2.5 &mgr;g/h) was significantly higher than untreated and laser‐treated skin (p < 0.05). Rate of lateral diffusion in untreated group (0.7 ± 0.1 &mgr;g/h) was significantly lower than microneedle and laser‐treated skin (p < 0.05). Overall, in vitro microdialysis was demonstrated as a novel and valuable tool that can be employed for quantitative investigation of rate of vertical and lateral diffusion of drugs in intact and microporated skin.

Poly (vinyl alcohol) microneedles: Fabrication, characterization, and application for transdermal drug delivery of doxorubicin

Graphical abstract Figure. No caption available. &NA; Poly (vinyl alcohol) microneedles were fabricated, characterized, and applied to enhance in vitro transdermal delivery of doxorubicin. The microneedles were fabricated using the micromolding technique with the drug load in different locations within the needle array. The polymer solution was assessed for rheological properties, drug dissolution, and chemical structurestudies. Microneedles (unloaded) and drug‐loaded microneedles were characterized by optical microscopy, fluorescent microscopy, scanning electron microscopy, and drug release kinetics. Successful microporation of dermatomed human cadaver skin was demonstrated by dye binding, pore uniformity, histology, confocal laser microscopy, and skin integrity studies. The microneedles‐mediated transdermal delivery of doxorubicin was investigated using vertical Franz diffusion cells. The fabricated microneedles were sharp, strong, and uniform. In vitro permeation studies showed that the microneedle‐treated skin (4351.55 ± 560.87 ng/sq.cm) provided a significantly greater drug permeability than the untreated group (0.00 ± 0.00 ng/sq.cm, n = 4, p < 0.01). The drug location within the needle array was found to affect the drug release profile as well as its permeation into and across human skin. Skin microporation achieved by poly (vinyl alcohol) microneedles was found to enhance transdermal delivery of doxorubicin in vitro.

Electrically and Ultrasonically Enhanced Transdermal Delivery of Methotrexate

In this study, we used sonophoresis and iontophoresis to enhance the in vitro delivery of methotrexate through human cadaver skin. Iontophoresis was applied for 60 min at a 0.4 mA/sq·cm current density, while low-frequency sonophoresis was applied at a 20 kHz frequency (2 min application, and 6.9 W/sq·cm intensity). The treated skin was characterized by dye binding, transepidermal water loss, skin electrical resistance, and skin temperature measurement. Both sonophoresis and iontophoresis resulted in a significant reduction in skin electrical resistance as well as a marked increase in transepidermal water loss value (p < 0.05). Furthermore, the ultrasonic waves resulted in a significant increase in skin temperature (p < 0.05). In permeation studies, the use of iontophoresis led to a significantly higher drug permeability than the untreated group (n = 4, p < 0.05). The skin became markedly more permeable to methotrexate after the treatment by sonophoresis than by iontophoresis (p < 0.01). A synergistic effect for the combined application of sonophoresis and iontophoresis was also observed. Drug distribution in the skin layers revealed a significantly higher level of methotrexate in the sonicated skin than that in iontophoresis and untreated groups. Iontophoresis and low-frequency sonophoresis were found to enhance the transdermal and intradermal delivery of methotrexate in vitro.