(M0930-06-35) Dissolving Microneedles Based on Carboxylmethylcellulose and Surfactant Systems for Enhanced Delivery of Itraconazole

Purpose: Dissolving microneedles (DMNs) represent a promising technology to enhance skin permeation by bypassing the stratum corneum and promoting drug deposition in the viable skin layers. In this study, DMNs were developed for the local delivery of itraconazole (ITZ), a hydrophobic broad-spectrum antifungal agent used in the treatment of cutaneous candidiasis. Carboxymethylcellulose (CMC), a biodegradable, dissolvable, and FDA-approved polymer, was selected for microneedle fabrication. To improve itraconazole incorporation into the CMC aqueous blend, two surfactants, Tween® 80 and Soluplus®, were evaluated. The microneedles were characterised for morphology, mechanical strength, insertion ability, and dissolution behaviour.

Methods: CMC-based DMNs were fabricated using a double-layer casting method. The microneedle (MN) tips were made by dissolving CMC (250 kDa) with different degrees of substitution, 1.2 and 0.7, and concentrations (B1: 10% CMC w/w for 0.7 DS and B2: 15% w/w for 1.2 DS) in deionised water. The selected polymer system (B2) was used to prepare three drug-loaded formulations: ITZ dispersed in CMC alone (F1), CMC with 0.5% w/w Tween® 80 (F2), and CMC with 0.5% w/w Soluplus® (F3). ITZ was ground and incorporated at 5% w/w in the aqueous blends. The mixtures were homogenised using a SpeedMixer at 3500 rpm for 5 minutes. Approximately 100 mg of each blend was poured into 16×16 silicone moulds (pyramidal needle shape, 850 μm height, 300 μm base width, and 300 μm interspacing), centrifuged at 3500 rpm for 5 minutes to ensure proper filling of the cavities and left to dry for 24 hours. A PVP (30% w/w, 90 kDa) and glycerol (1.5% w/w) solution was then poured into the moulds to form the baseplate, centrifuged at 3500 rpm for 15 minutes and left to dry overnight. The DMNs were then cured in an oven at 37°C for 6 hours. The manufactured DMNs from formulations F1, F2, and F3 were examined using both a Leica digital light microscope and a scanning electron microscope (SEM). They were subsequently characterised for mechanical properties and insertion capacity into eight layers of Parafilm M® using a TA.XT2 Texture Analyzer under a compression force of 32 N applied for 30 seconds. The dissolution time of the needles was tested ex vivo by inserting the DMNs into a neonatal porcine skin and incubating them at 37°C. After different time points (15, 30, 60 and 90 minutes) the DMNs were removed, and the residual needle height was measured using a Leica digital light microscope.

Results: The blank formulation B2, with a higher degree of substitution, produced complete and sharp needles, while formulation B1, with a lower degree of substitution, exhibited higher viscosity, which prevented complete filling of the mould cavities, resulting in poorly shaped needles. Based on these observations, formulation B2 was selected as the polymer for the microneedles. The mechanical properties and insertion capability of the formulation were tested, showing a height reduction of 10.8% after compression against a flat stainless-steel block and 2.53% after insertion into eight layers of Parafilm® M, achieving an insertion depth of 378 µm. The manufactured DMNs containing surfactants displayed improved morphological properties, resulting in more uniform and well-defined microneedles. The three drug-loaded formulations were evaluated for mechanical and insertion properties. Formulations containing TWEEN® 80 (F2) showed a slightly lower height reduction percentage after compression (7.94%) compared to F3 and F1, with a percentage of reduction of 8.32% and 8.26%, respectively. Despite this, the insertion capacity remained effective for all formulations, with penetration across eight layers of Parafilm® M reaching an average depth of 378 µm for approximately 30% of the microneedles. Real-time monitoring using optical coherence tomography (OCT) confirmed successful insertion into three Parafilm® layers and full-thickness neonatal porcine skin, verifying the microneedles' capability to bypass the stratum corneum. Ex vivo dissolution studies in full-thickness neonatal porcine skin showed that formulations containing surfactants (F2 and F3) exhibited a significantly faster dissolution rate compared to the non-surfactant formulation (F1), achieving complete dissolution of the microneedle tips within 90 minutes.

Conclusion: In this study, CMC-based dissolving microneedles (DMNs) were successfully developed for the localised delivery of itraconazole. Optimisation of the polymer composition, particularly the selection of a higher degree of substitution CMC, enabled the production of well-defined, mechanically robust microneedles capable of effective skin insertion. Incorporation of surfactants (Tween® 80 and Soluplus®) led to improved microneedle morphology and significantly enhanced the dissolution rate without adversely affecting insertion properties. Ex vivo evaluations confirmed rapid microneedle dissolution within 90 minutes and successful penetration across the stratum corneum. Future work will focus on selecting the optimal surfactant and comparing dermatokinetic profiles to quantify drug deposition within the epidermis and dermis. Additionally, microbiological assays against Candida albicans will be conducted to assess the potential therapeutic efficacy of the DMN formulations.

References: Lee, Jeong W., Jung-Hwan Park, and Mark R. Prausnitz. "Dissolving microneedles for transdermal drug delivery." Biomaterials 29.13 (2008): 2113-2124. Anjani, Qonita Kurnia, et al. "Elucidating the impact of surfactants on the performance of dissolving microneedle array patches." Molecular Pharmaceutics 19.4 (2022). Anjani, Qonita Kurnia, et al. "Dissolvable microarray patches of levodopa and carbidopa for Parkinson’s disease management." European Journal of Pharmaceutics and Biopharmaceutics 199 (2024) ): 114304


Figure 1: (A–B) Digital light microscope images of blank formulations B1 (A) and B2 (B); (C–D) comparison of the needles height before and after a compression force of 32 N against a flat stainless-steel block (C) and after insertion into an eight-layer Parafilm® stack (D) for formulation B2 (mean ± SD, n = 12); (E) insertion profile of formulation B2 (mean ± SD, n = 4); (F–G) comparison of needle height before and after compression force of 32 N (F) and insertion profiles (G) for formulations F1, F2, and F3 (mean ± SD, n = 12, statistical significance: *p < 0.05, **p < 0.01, ***p < 0.001); (H) needle tip height reduction after ex vivo dissolution testing for formulations F1, F2, and F3 (mean ± SD, n = 3. Statistical significance: *p < 0.05, **p < 0.01, ***p < 0.001)



Figure 2: (A–C) Digital light microscope images of formulations F1 (A), F2 (B), and F3 (C); (D–F) OCT images showing the penetration of formulations F1 (D), F2 (E), and F3 (F) into eight layers of Parafilm®; (G–I) OCT images displaying the insertion of formulations F1 (G), F2 (H), and F3 (I) into full-thickness neonatal porcine skin; (L–N) SEM images of ITZ-loaded DMNs for formulations F1 (L), F2 (M), and F3 (N).