Calcipotriol Nanosuspension-Loaded Trilayer Dissolving Microneedle Patches for the Treatment of Psoriasis: In Vitro Delivery and In Vivo Antipsoriatic Activity Studies

Abstract

Psoriasis, affecting 2-3% of the global population, is a chronic inflammatory skin condition without a definitive cure. Current treatments focus on managing symptoms. Recognizing the need for innovative drug delivery methods to enhance patient adherence, this study explores a new approach using calcipotriol monohydrate (CPM), a primary topical treatment for psoriasis. Despite its effectiveness, CPM's therapeutic potential is often limited by factors like the greasiness of topical applications, poor skin permeability, low skin retention, and lack of controlled delivery. To overcome these challenges, the study introduces CPM in the form of nanosuspensions (NSs), characterized by an average particle size of 211 ± 2 nm. These CPM NSs are then incorporated into a trilayer dissolving microneedle patch (MAP) made from poly(vinylpyrrolidone) and w poly(vinyl alcohol) as needle arrays and prefrom 3D printed polylactic acid backing layer. This MAP features rapidly dissolving tips and exhibits good mechanical properties and insertion capability with delivery efficiency compared to the conventional Daivonex ointment. The effectiveness of this novel MAP was tested on Sprague-Dawley rats with imiquimod-induced psoriasis, demonstrating efficacy comparable to the marketed ointment. This innovative trilayer dissolving MAP represents a promising new local delivery system for calcipotriol, potentially revolutionizing psoriasis treatment by enhancing drug delivery and patient compliance.

Keywords: calcipotriol; microneedle; nanocrystal; nanosuspension; psoriasis.

Figure 1

Schematic illustration of the process of fabricating NSs.

Figure 2

Schematic illustration of the fabrication process of dissolving MAPs.

Figure 3

(A) Diagrammatic illustration of the six treatment cohorts investigated in the in vivo experiments. The skin and spleen were excised after the animals were sacrificed for the investigation of antipsoriatic activities. Created with BioRender.com. (B) Schematic illustration of the treatment schedule for psoriasis. After the establishment of the model, IMQ was applied every morning, and the treatments were applied every evening. Created with ProcessOn.com.

Figure 4

(A) Particle size of the CPM NSs at different time points (mean + SD, n = 3), (B) PDI of the CPM NSs at different time points (mean ± SD, n = 3), (C) changes in the CPM content during the NS milling progress (mean ± SD, n = 3), and (D) changes in the particle size stability of the CPM NSs under different storage conditions over a period of 28 days (mean ± SD, n = 3).

Figure 5

(A) Distribution profile of crude CPM (mean, n = 6), (B) SEM images of crude CPM powder, (C) DLS reports of the CPM NSs, and (D) SEM images of lyophilized CPM NSs. (E) FTIR, (F) DSC, and (G) XRD data of bulk CPM powder, 9–10 kDa poly(vinyl alcohol), a physical mixture of CPM and PVA (at 5/7, w/w) and lyophilized CPM NSs. (H) In vitro cumulative release profiles of lyophilized CPM NSs and bulk CPM powder (mean ± SD, n = 3).

Figure 6

(A) Representative SEM and digital microscopy images of NS MAPs and powder MAPs. (B) Percentage reductions in the height of individual NS microneedles after compression by a force of 32 N/MAP. (C) Insertion of NS MAPs into an artificial skin model consisting of eight layers of Parafilm M with a force of 32 N/MAP. (D) Representative OCT images of NS MAPs following their insertion into full-thickness excised neonatal porcine skin. (E) In-skin dissolution state of NS MAPs. The black scale bar indicates a length of 2 mm, and (F) drug content and distribution of NSs and powder MAPs (mean + SD, n = 4). (G) Drug content of CPM MAPs for 6 months (mean ± SD, n = 6).

Figure 7

Drug distribution at different times after the application of (A) CPM NS MAPs and (B) CPM powder MAPs (mean + SD, n = 4). (C) Drug deposition in the skin after CPM MAP application at different times (mean ± SD, n = 4). (D) Drug permeation across full-thickness skin after CPM MAP application at different times (mean ± SD, n = 4). Representative digital images of skins after applying (E) CPM NS MAPs, (F) CPM powder MAPs, (G) CPM marketed ointment, or (H) CPM marketed ointment for 24 h. The black scale bar indicates a length of 0.2 μm.

Figure 8

Representative images of (A) skin morphology, (B) H&E staining of the dorsal skin, and (C) spleen from each group of rats. (D) Percentage of body weight change during the therapy period (mean ± SD, n = 5). PASI scores were recorded every day until the end of the experiment. (E) Cumulative score (erythema plus induration plus desquamation), (F) erythema score, (G) induration score, and (H) desquamation score (mean ± SD, n = 5). (I) Skin thickness, (J) skin moisture at the end of the treatments, (K) spleen length, and (L) spleen index after sacrifice (mean + SD, n = 5). Each dot symbol represents an individual rat.