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

Abstract

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-1β 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.

Keywords: cannabidiol; dissolving microneedle; highly lipophilic drugs; knee synovitis; nanosuspension.

Graphical abstract

Figure 1

Chemical structures of CBD.

Figure 2

The scheme of CBD-NS and CBD-NS DMN preparation.

Figure 3

Different formulations of (A) the particle size; (B) PDI (C) zeta potential; (D) the particle size distributions; (E) magnification 100 kx SEM image and (F) magnification 100 kx TEM image of Tween 80-CBD-NS, scale bar = 200 nm.

Figure 4

(A) SEM images of Blank DMN (A1) magnification 60x; (A2) magnification 1000x and (A3) magnification 5000x. (B) CBD (pure drug). (B) Scanning microscopy images of CBD-NS DMN (B1) magnification 60x; (B2) magnification 1000x and (B3) magnification 5000x. (C) Images of Blank DMN dissolution in skin over time (C1) 0 min; (C2) 1 min; (C3) 5 min and (C4) 10 min, scale bar = 500 μm. (D) Images of CBD-NS DMN dissolution in skin over time (D1) 0 min; (D2) 1 min; (D3) 5 min and (D4) 10 min, scale bar = 500 μm.

Figure 5

(A) Mechanical performance of CBD-NS DMN. (B) DSC analysis of CBD (pure drug), Blank DMN and CBD-NS DMN. (C) XRD analysis of CBD (pure drug), Blank DMN and CBD-NS DMN. (C1) 2 Theta range 5–60° and (C2) 2 Theta range 5–20°.

Figure 6

(A) Images of porcine skin after treatment with C6 DMN (A1) Bright-field image; (A2) Fluorescence microscopy. (B) Insert depth obtained by CLSM 3D reconstruction, scale bar = 500 μm. (C) In vivo imaging of rats after being treated with C6, (C1) In vivo images throughout 48 h and (C2) the curve of fluorescence intensity with time.

Figure 7

(A) In vitro cumulative release curve of CBD-NS DMN in 2% Tween 80. (B) The residual ratio of CBD above the skin (blue line), and the accumulative amount of CBD entering the skin (red line). Data are represented as mean ± S.D., n = 4.

Figure 8

Treatment of rat model of knee synovitis induced by kaolin/λ-carrageenan. (A) Images of the knee joints from the Model, MTX S.C. and CBD-NS DMN; (B) Statistics of knee swelling degree and (C) Changes in body weight of rats after one week of treatment with different groups. (D) The serum of rats was used to detect inflammatory factors, including (D1) TNF-α and (D2) IL-1β. (E) Histopathological evaluation of knee joint in kaolin/carrageenan-induced knee synovitis model rats. H&E staining images of Naive, Model, MTX S.C. and CBD-NS DMN (Magnification 10×). Scale bar = 200 μm. Data are represented as mean ± S.D., n = 5. The “*” represents the significant difference between each group and the model group, specifically *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001. The “ns” represents no significant difference between the groups and the naive group.

Figure 9

CBD pharmacokinetic curves in the blood of SD rats after oral administration and administration of DMN (A) 0–72h; (B) 0–24h. Data are represented as mean ± S.D., n = 5.