Microneedle Mediated Iontophoretic Delivery of Tofacitinib Citrate.

PURPOSE: To investigate in vitro transdermal delivery of tofacitinib citrate across human skin using microporation by microneedles and iontophoresis alone and in combination. METHODS: In vitro permeation studies were conducted using vertical Franz diffusion cells. Microneedles composed of polyvinyl alcohol and carboxymethyl cellulose were fabricated and successfully characterized using scanning electron microscopy. The microchannels created were further characterized using histology, dye binding study, scanning electron microscopy, and confocal microscopy studies. The effect of microporation on delivery of tofacitinib citrate was evaluated alone and in combination with iontophoresis. In addition, the effect of current density on iontophoretic delivery was also investigated. RESULTS: Total delivery of tofacitinib citrate via passive permeation was found out to be 11.04 ± 1 µg/sq.cm. Microporation with microneedles resulted in significant enhancement where a 28-fold increase in delivery of tofacitinib citrate was observed with a total delivery of 314.7±33.32 µg/sq.cm. The characterization studies confirmed the formation of microchannels in the skin where successful disruption of stratum corneum was observed after applying microneedles. Anodal iontophoresis at 0.1 and 0.5 mA/sq.cm showed a total delivery of 18.56 µg/sq.cm and 62.07 µg/sq.cm, respectively. A combination of microneedle and iontophoresis at 0.5 mA/sq.cm showed the highest total delivery of 566.59 µg/sq.cm demonstrating a synergistic effect. A sharp increase in transdermal flux was observed for a combination of microneedles and iontophoresis. CONCLUSION: This study demonstrates the use of microneedles and iontophoresis to deliver a therapeutic dose of tofacitinib citrate via transdermal route.

Microneedle and iontophoresis mediated delivery of methotrexate into and across healthy and psoriatic skin.

Psoriasis is a condition of the skin which involves scales, dry patches, and inflammation. Methotrexate (logP: -1.8, MW:454.44 g/mol) is administered orally or intravenously to treat psoriasis. The first-pass metabolism and systemic toxicity can be avoided by administration via skin. Topical and transdermal delivery of methotrexate using iontophoresis and microneedles, alone and in combination was investigated using full-thickness healthy human skin. It is also equally relevant to evaluate the delivery into and across damaged/diseased skin. Hence, this study investigated the delivery of methotrexate using ex vivo healthy and psoriatic human skin to understand the effect of skin disease condition on delivery of methotrexate via skin. A lower resistance and a higher TEWL for psoriatic skin indicated damaged barrier function, while histology studies indicated epithelial hyperproliferation and elongated rete ridges. Using the optimized iontophoretic parameters, there was no significant difference in receptor delivery for psoriatic skin (39.51 ± 4.45 µg/sq.cm) as compared to healthy skin (43.15 ± 0.83 µg/sq.cm). However, methotrexate delivery into psoriatic skin (126.23 ± 24.65 µg/sq.cm) was significantly higher as compared to healthy skin (12.02 ± 4.89 µg/sq.cm). Thus, significantly higher total delivery was observed from psoriatic skin than healthy skin.

An integrated biophysical model for predicting the clinical pharmacokinetics of transdermally delivered compounds.

The delivery of therapeutic drugs through the skin is a promising alternative to oral or parenteral delivery routes because dermal drug delivery systems (D3Ss) offer unique advantages, such as controlled drug release over sustained periods and a significant reduction in first-pass effects, thus reducing the required dosing frequency and the level of patient noncompliance. Furthermore, D3Ss find applications in multiple therapeutic areas, including drug repurposing. This article presents an integrated biophysical model of dermal absorption for simulating the permeation and absorption of compounds delivered transdermally. The biophysical model is physiologically/biologically inspired and combines a holistic model of healthy skin with whole-body physiology-based pharmacokinetics through the dermis microcirculation. The model also includes the effects of chemical penetration enhancers and hair follicles on transdermal transport. The model-predicted permeation and pharmacokinetics of select compounds were validated using in vivo data reported in the literature. We conjecture that the integrated model can be used to gather insights into the permeation and systemic absorption of transdermal formulations (including cosmetic products) released from novel depots and to optimize delivery systems. Furthermore, the model can be extended to diseased skin with parametrization and structural adjustments specific to skin diseases.

Type of endothelial cells affects HepaRG cell acetaminophen metabolism in both 2D and 3D porous scaffold cultures.

Recent advances in developing in vitro tissue models show that function of hepatocytes is altered in when cultured in 3D configuration and co-culturing with various non-parenchymal cells. However, tissue source for such non-parenchymal cells on viability and metabolic products of hepatocytes have not been explored. In this study, we evaluated the effect of 2D and 3D cultures either with HepaRG cells alone or in combination with liver sinusoidal endothelial cells (LSECs) and human umbilical vein ECs (HUVECs). For 3D cultures, we used chitosan-gelatin porous structures formed by freeze-drying. We cultured cells for 8 days before challenging with 1 mm acetaminophen (APAP) and assessed APAP, APAP-sulfate and APAP-glucuronide for 24 hours at 6-hour time intervals using high-performance liquid chromatography. We used multiple methods (phase contrast, confocal and scanning electron microscopy and histology via hematoxylin and eosin staining) to ensure cell distribution. We also measured total protein content and albumin secretion and viability. HUVEC 3D co-cultures showed the lowest HepaRG cell viability, while both 2D and 3D LSEC co-cultures had highest HepaRG cell viability. In addition, 3D cultures had significantly higher EC viability relative to 2D cultures. Further, HUVEC co-cultures showed reduced total protein content and albumin expression as early as day 4. However, urea production on a total protein content basis did not change. In addition, LSEC 3D co-cultures had the highest APAP conversion with reduced APAP-sulfate and APAP-glucuronide formation. CYP3A4 was higher in co-culture with HUVEC for 2D and 3D cultures. In conclusion, HepaRG cells with EC co-cultures demonstrated sensitivity to the EC line used.