Microneedles (MNs) have emerged as a promising solution for pain-free and patient-friendly drug delivery. MNs provide therapeutic benefits with minimal invasiveness, thus reducing patient distress. However, although MNs have been proposed for the sustained delivery of drugs into the central nervous system (CNS), conventional rigid MNs lead to discomfort and fatigue during extended wear. In this study, wearable electrospun web MNs (EW-MNs) inspired by the mechanics of bee stingers are developed. Through the grounding of metal MNs and controlled formation of electrospun fibers, EW-MNs suitable for skin insertion and anchoring are fabricated. The penetration depth and drug diffusion performance are then evaluated. Sustained-release drug delivery along the fiber surface is validated using fluorescent dyes simulating a real therapeutic drug. Finally, the therapeutic mechanism and efficacy of EW-MNs loaded with CNS-targeted drugs, such as rivastigmine, are validated in guinea pig models, confirming their potential for continuous and effective CNS disease management. In vitro and in vivo evaluations showed a 2.5-fold increase in AUC and a fivefold expansion in drug diffusion area, demonstrating the efficacy of EW-MNs in sustained CNS drug delivery.

Microneedles (MNs) have emerged as a promising solution for pain-free and patient-friendly drug delivery. MNs provide therapeutic benefits with minimal invasiveness, thus reducing patient distress. However, although MNs have been proposed for the sustained delivery of drugs into the central nervous system (CNS), conventional rigid MNs lead to discomfort and fatigue during extended wear. In this study, wearable electrospun web MNs (EW-MNs) inspired by the mechanics of bee stingers are developed. Through the grounding of metal MNs and controlled formation of electrospun fibers, EW-MNs suitable for skin insertion and anchoring are fabricated. The penetration depth and drug diffusion performance are then evaluated. Sustained-release drug delivery along the fiber surface is validated using fluorescent dyes simulating a real therapeutic drug. Finally, the therapeutic mechanism and efficacy of EW-MNs loaded with CNS-targeted drugs, such as rivastigmine, are validated in guinea pig models, confirming their potential for continuous and effective CNS disease management. In vitro and in vivo evaluations showed a 2.5-fold increase in AUC and a fivefold expansion in drug diffusion area, demonstrating the efficacy of EW-MNs in sustained CNS drug delivery.

<b><i>Purpose:</i></b> A dexamethasone canalicular insert, Dextenza®, has been used to treat anterior inflammation of the eye, including keratoconjunctivitis sicca. This study aimed to investigate the tear pharmacokinetics and systemic exposure of dexamethasone in New Zealand White rabbits after inserting the preparation into the punctum and to correlate the data with the <i>in vitro</i> dissolution test. <b><i>Methods:</i></b> Dextenza was inserted into the punctum of rabbits. A paper strip serially collected tears, and dexamethasone concentrations in tears and plasma were measured using HPLC-MS/MS. The time courses of tear and plasma dexamethasone concentrations were characterized. <b><i>Results:</i></b> The release of dexamethasone from the insert to tears in rabbits was completed in ∼ 5 days, much faster than in humans and dogs (30 days). The time course of plasma dexamethasone concentration was fully characterized, in contrast to the fact that systemic exposure was merely observed in the other species. The present results might be attributed to the anatomical structure of the lacrimal sac beneath rabbits' canaliculi. The <i>in vitro</i> dissolution pattern represented an excellent correlation with the <i>in vivo</i> release in tears. <b><i>Conclusions:</i></b> We first examined the pharmacokinetic study of the canalicular insert in rabbits, which could be applied to the other insert studies in the species.

Reversible cholinesterase inhibitors have been investigated to address prophylactic and therapeutic outcomes against organophosphorus nerve poisoning, and procyclidine is concomitantly used to compensate for their adverse effects. We designed double-layer patches with microneedles composed of a cream layer for immediate release and a hyaluronic acid-based thin solid layer for sustained release. Rivastigmine and procyclidine were added to the two layers with different doses, and their transdermal absorption was explored in guinea pigs for the first time. The contents of hyaluronic acid and the number of microneedles were also examined to determine the optimal patches, which would achieve the mean target plasma concentrations of the two drugs for 72 h. Plasma concentrations of rivastigmine and procyclidine were determined using a validated HPLC-MS/MS method, and acetylcholinesterase (AChE) activity was monitored and correlated with plasma rivastigmine concentrations. The systemic exposure of both drugs was successfully characterised in guinea pigs, and the change was relevant in terms of different patches with microneedles. The inhibitory effect on AChE was prolonged despite the decay of rivastigmine concentrations. Finally, the preparation of a double-layer patch with microneedles was suggested, and the present results would help explain the prophylactic and therapeutic effects of rivastigmine and procyclidine against biochemical weapons.

Generic drugs offer cost-effective alternatives to brand-name medications while ensuring comparable safety and efficacy. However, narrow therapeutic index drugs (NTIDs), which require precise dosing due to narrow margins between therapeutic and toxic concentrations, present additional regulatory challenges. Concerns regarding the interchangeability of generic NTIDs are amplified by international variation in definitions, bioequivalence (BE) standards, and regulatory approaches. This systematic review compares NTID-related regulatory frameworks across major authorities to inform the development of the ICH M13C guideline and foster global harmonization of evaluation standards for generic NTIDs. A comprehensive comparative analysis was conducted of NTID-related regulatory frameworks in five ICH member countries (United States [US], European Union [EU], Japan, Canada, and South Korea), with Egypt, Jordan, and Saudi Arabia included as reference countries. Data were obtained from literature searches and official regulatory sources, focusing on NTID definitions, BE standards, and NTID lists. Marked regulatory divergence was observed. South Korea uniquely incorporates quantitative pharmacological and toxicological criteria into NTID definitions. The US employs the most stringent NTID BE standards, utilizing a fully replicated design, reference-scaled average bioequivalence (RSABE), and variability assessment. Only cyclosporine and tacrolimus are classified as NTIDs by all five core countries. Variability in NTID lists and evaluation criteria complicates global harmonization efforts. Achieving consistent evaluation and safe international use of generic NTIDs requires global alignment on definitions, BE criteria, and NTID lists. This review supports integrating real-world data into regulatory decision-making and advances the ICH M13C guideline.

<b><i>Purpose:</i></b> Dexamethasone eye implant has been used to treat macular edema and non-infectious uveitis. To date, its ocular pharmacokinetics are not fully characterized, and the development of generic preparations is in progress, as the patent of the original brand expires soon. Therefore, this work was designed to 1) determine the time course of vitreous dexamethasone concentrations following intravitreal implantation in rabbits and 2) explore the alternative use of NDF-SI01 from a pharmacokinetic point of view compared to Ozurdex^®, which is currentlyused in the market. <b><i>Methods:</i></b> Ozurdex^® and NDF-SI01 were implanted into the right and left eyes of the rabbit, respectively. A serial vitreous collection was performed to minimize the sacrifice of animals, and dexamethasone concentrations were measured by HP LC-MS/MS. <b><i>Results:</i></b> After implantation, dexamethasone concentration reaches the maximum concentration (3.1 μg/mL) in 19.5 days and decreases with a half-life of 40.3 h. AUC and clearance are 683.9 μg·h/mL and 1.29 mL/h, respectively. There is no significant difference in pharmacokinetic parameters between NDF-SI01 and Ozurdex^®. The overall patterns of the cumulative release of both implants are similar. <b><i>Conclusions:</i></b> NDF-SI01 could alternate Ozurdex^® in clinics based on the in vivo comparative pharmacokinetic study and in vitro dissolution test.

Propolis is a natural resinous substance made by bees through mixing various plant sources. Propolis has been widely recognized as a functional food due to its diverse range of beneficial bioactivities. However, the therapeutic effects of consuming propolis against atopic dermatitis (AD) remain largely unknown. The current study aimed to investigate the potential efficacy of propolis against AD and explore the active compound as well as the direct molecular target. In HaCaT keratinocytes, propolis inhibited TNF-α-induced interleukin (IL)-6 and IL-8 secretion. It also led to a reduction in chemokines such as monocyte chemoattractant protein-1 (MCP-1) and macrophage-derived chemokine (MDC), while restoring the levels of barrier proteins, filaggrin and involucrin. Propolis exhibited similar effects in AD-like human skin, leading to the suppression of AD markers and the restoration of barrier proteins. In DNCB-induced mice, oral administration of propolis attenuated AD symptoms, improved barrier function, and reduced scratching frequency and transepidermal water loss (TEWL). In addition, propolis reversed the mRNA levels of AD-related markers in mouse dorsal skin. These effects were attributed to caffeic acid phenethyl ester (CAPE), the active compound identified by comparing major components of propolis. Mechanistic studies revealed that CAPE as well as propolis could directly and selectively target MKK4. Collectively, these findings demonstrate that propolis may be used as a functional food agent for the treatment of AD.