Development of 4-phenylbutyric acid microsponge gel formulations for the treatment of lewisite-mediated skin injury.

Lewisite, a chemical warfare agent, causes skin blisters, erythema, edema, and inflammation, requiring mitigation strategies in case of accidental or deliberate exposure. 4-phenyl butyric acid (4-PBA), a chemical chaperone, reduces endoplasmic reticulum stress and skin inflammation. The study aimed to encapsulate 4-PBA in microsponges for effective, sustained delivery against lewisite injury. Porous microsponges in a topical gel would potentially sustain delivery and improve residence time on the skin. Microsponges were developed using the quasi-emulsion solvent diffusion method with Eudragit RS100. Optimized formulation showed 10.58%w/w drug loading was incorporated in a carboxymethylcellulose (CMC) and Carbopol gel for in vitro release and permeation testing using dermatomed human skin. A sustained release was obtained from all vehicles in the release study, and IVPT results showed that compared to the control (41.52 ± 2.54 µg/sq.cm), a sustained permeation profile with a reduced delivery was observed for microsponges in PBS (14.16 ± 1.23 µg/sq.cm) along with Carbopol 980 gel (12.55 ± 1.41 µg/sq.cm), and CMC gel (10.09 ± 1.23 µg/sq.cm) at 24 h. Optimized formulation showed significant protection against lewisite surrogate phenyl arsine oxide (PAO) challenged skin injury in Ptch1+/-/SKH-1 hairless mice at gross and molecular levels. A reduction in Draize score by 29%, a reduction in skin bifold thickness by 8%, a significant reduction in levels of IL-1ß, IL6, and GM-CSF by 54%, 30%, and 55%, respectively, and a reduction in apoptosis by 31% was observed. Thus, the translational feasibility of 4-PBA microsponges for effective, sustained delivery against lewisite skin injury is demonstrated.

Transdermal Delivery of Baclofen Using Iontophoresis and Microneedles.

Baclofen, a GABAb agonist, is used in the treatment of multiple sclerosis, a neurodegenerative disease. Currently available dosage forms to deliver baclofen are through the oral and the intrathecal routes. The disadvantage of oral baclofen is that it requires administering the drug multiple times a day, owing to baclofen's short half-life. On the other hand, intrathecal baclofen pumps are invasive and cannot be an alternative to oral baclofen. Hence, there is a need to develop a dosage form that can deliver baclofen non-invasively and for an extended period at a steady rate, increasing the dosing interval. A transdermal baclofen delivery system might be the solution to this problem. Hence, this research focuses on evaluating microneedles, iontophoresis, and a combination of microneedles-iontophoresis as transdermal delivery enhancement strategies for baclofen. In vitro permeation studies were conducted on dermatomed porcine ear skin using vertical Franz diffusion cells to evaluate transdermal baclofen delivery. Anodal iontophoresis was applied at a current density of 0.5 mA/cm2, and transdermal delivery was assessed from pH 4.5 (45.51±0.76 µg/cm2) and pH 7.4 (68.84±10.13 µg/cm2) baclofen solutions. Iontophoresis enhanced baclofen delivery but failed to reach target delivery. Maltose microneedles were used to create hydrophilic microchannels on the skin, and this technique enhanced baclofen delivery by 89-fold. Both microneedles (447.88±68.06 µg/cm2) and combination of microneedles - iontophoresis (428.56±84.33 µg/cm2) reached the target delivery range (222-1184 µg/cm2) for baclofen. The findings of this research suggest that skin could be a viable route for delivery of baclofen. Graphical Abstract.

In vitro percutaneous absorption studies of cannabidiol using human skin: Exploring the effect of drug concentration, chemical enhancers, and essential oils.

Cannabidiol, a non-psychoactive constituent of cannabis, has garnered much attention after United States Food and Drug Administration approved Epidiolex® for oral use. Although therapeutic effect of cannabidiol after systemic absorption has been investigated extensively, its therapeutic potential in treating skin disorders after local delivery still needs further exploration. Our study has investigated the effect of cannabidiol concentration, chemical enhancers, and essential oils on percutaneous absorption of cannabidiol. In vitro permeation tests were conducted on human skin. The 24 h study results suggest no significant difference in amount of drug absorbed into skin, between 5% (242.41 ± 12.17 µg/cm2) and 10% (232.79 ± 20.82 cm2) cannabidiol solutions. However, 1% delivered (23.02 ± 4.74 µg/cm2) significantly lower amount of drug into skin than 5% and 10%. Transcutol and isopropyl myristate did not enhance delivery of cannabidiol. However, oleic acid was found to be useful as chemical enhancer. Oleic acid (43.07 ± 10.11 µg/cm2) had significantly higher cannabidiol delivery into skin than the group without oleic acid (10.98 ± 3.40 µg/cm2) after a 4 h in vitro permeation study. Essential oils at concentrations tested had lower total cannabidiol delivery when compared to control. This study's findings will help guide future research on the pharmacological effect of percutaneously delivered cannabidiol on inflammatory skin disorders.

The pharmacokinetics of 3-fluoroamphetamine following delivery using clinically relevant routes of administration.

3-Fluoroamphetamine (also called PAL-353) is a synthetic amphetamine analog that has been investigated for cocaine use disorder (CUD), yet no studies have characterized its pharmacokinetics (PK). In the present study, we determined the PK of PAL-353 in male Sprague Dawley rats following intravenous bolus injection (5 mg/kg). Plasma samples were analyzed using a novel bioanalytical method that coupled liquid-liquid extraction and LC-MS/MS. The primary PK parameters determined by WinNonlin were a C0 (ng/mL) of 1412.09 ± 196.12 and a plasma half-life of 2.27 ± 0.67 h. As transdermal delivery may be an optimal approach to delivering PAL-353 for CUD, we assessed its PK profile following application of 50 mg of transdermal gel (10% w/w drug over 5 cm2). The 10% w/w gel resulted in a short lag time, sustained delivery, and a rapid clearance in plasma immediately after removal. The rodent PK data were verified by examining in vitro permeation through human epidermis mounted on Franz diffusion cells. An in vitro-in vivo correlation (IVIVC) analysis was performed using the Phoenix IVIVC toolkit to assess the predictive relationship between rodent and human skin absorption/permeation. The in vitro permeation study revealed a dose-proportional cumulative and steady-state flux with ~ 70% of drug permeated. The fraction absorbed in vivo and fraction permeated in vitro showed a linear relationship. In conclusion, we have characterized the PK profile of PAL-353, demonstrated that it has favorable PK properties for transdermal administration for CUD, and provided preliminary evidence of the capacity of rodent data to predict human skin flux.