Nanosuspension-Loaded Dissolving Microneedle Patches for Enhanced Transdermal Delivery of a Highly Lipophilic Cannabidiol.

Purpose: Transdermal Drug Delivery System (TDDS) offers a promising alternative for delivering poorly soluble drugs, challenged by the stratum corneum's barrier effect, which restricts the pool of drug candidates suitable for TDDS. This study aims to establish a delivery platform specifically for highly lipophilic drugs requiring high doses (log P > 5, dose > 10 mg/kg/d), to improve their intradermal delivery and enhance solubility. Methods: Cannabidiol (CBD, log P = 5.91) served as the model drug. A CBD nanosuspension (CBD-NS) was prepared using a bottom-up method. The particle size, polydispersity index (PDI), zeta potential, and concentration of the CBD-NS were characterized. Subsequently, CBD-NS was incorporated into dissolving microneedles (DMNs) through a one-step manufacturing process. The intradermal dissolution abilities, physicochemical properties, mechanical strength, insertion depth, and release behavior of the DMNs were evaluated. Sprague-Dawley (SD) rats were utilized to assess the efficacy of the DMN patch in treating knee synovitis and to analyze its skin permeation kinetics and pharmacokinetic performance. Results: The CBD-NS, stabilized with Tween 80, exhibited a particle size of 166.83 ± 3.33 nm, a PDI of 0.21 ± 0.07, and a concentration of 46.11 ± 0.52 mg/mL. The DMN loaded with CBD-NS demonstrated favorable intradermal dissolution and mechanical properties. It effectively increased the delivery of CBD into the skin, extended the action's duration in vivo, and enhanced bioavailability. CBD-NS DMN exhibited superior therapeutic efficacy and safety in a rat model of knee synovitis, significantly inhibiting TNF-α and IL-1ß compared with the methotrexate subcutaneous injection method. Conclusion: NS technology effectively enhances the solubility of the poorly soluble drug CBD, while DMN facilitates penetration, extends the duration of action in vivo, and improves bioavailability. Furthermore, CBD has shown promising therapeutic outcomes in treating knee synovitis. This innovative drug delivery system is expected to offer a more efficient solution for the administration of highly lipophilic drugs akin to CBD, thereby facilitating high-dose administration.

Industrializable approach for preparing hydrogel microneedles and their application in melanoma treatment.

Microneedles (MNs) technology has been studied in transdermal drug delivery for more than 20 years with hundreds of clinical trials conducted. However, there are currently no commercially available MNs in medicine due to challenges in materials safety, cost-effective fabrication, and large-scale manufacturing. Herein, an approach for rapid and green fabrication of hydrogel microneedles (HMNs) based on infrared irradiation process was proposed for the first time. The optimized formulation consisted of polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP), which acted as cross-linked materials and pore-forming agents, respectively. The manufacturing method involved placing MNs patches under infrared irradiation at 70 °C for 2 min and annealing to obtain HMNs with excellent swelling behavior, mechanical strength, and biocompatibility. When model drugs azelaic acid (AZA) and matrine (MAT) were loaded into HMNs systems, the chemical stability of MAT was significantly improved. Ex vivo transdermal delivery experiments indicated that HMNs could achieve synchronous release of AZA and MAT, and the 24-hour percutaneous permeability rates of both drugs were 73.09 ± 0.48 % and 71.56 ± 1.23 %, respectively. In-vivo pharmacokinetic studies, HMNs administration presented dose-dependent stable blood drug concentrations for both drugs. Additionally, prominent anti-tumor efficacy and biosecurity were observed in the drug-loaded HMNs group in the pharmacodynamic evaluation. In summary, the efficient, convenient, and low-cost fabrication method based on infrared irradiation offers the possibility of mass production of drug-loaded HMNs, showing potential for industrial manufacturing development.