(T0930-08-54) Design of Dissolving Microneedles Based on Amorphous Salt Formation for Controlled Drug Release

Purpose: A dissolving microneedle is fabricated from biodegradable materials that dissolve in the body, enabling drug delivery into the systemic circulation by needle dissolution after insertion¹⁾. Therefore, the rate of drug absorption depends on the solubility and diffusion of the drug within the skin. In many reports, drugs are dispersed within water-soluble polymers. However, since the needle portion is very small, the drug loading is low, which limits the types of drugs that can be applied²⁾. In this study, microneedles were prepared without using polymers to increase drug loading. Furthermore, by combining the drug with additives to form amorphous salts, the potential for controlled drug release was examined.

Methods: Donepezil (DPZ), a cholinesterase inhibitor commonly used in the treatment of Alzheimer’s disease, was employed as a model drug. Given its basic nature (pK_a ≈ 8.9), eight acidic compounds—including sorbic acid and maleic acid—were selected as counterions for salt formation. Physical mixtures of DPZ and each acid were prepared at a 1:1 molar ratio via manual trituration using a mortar and pestle. The propensity for amorphous salt formation was assessed by differential scanning calorimetry (DSC). Microneedles were fabricated using a Vacuum Compression Molding (VCM), which facilitates the melting and subsequent cooling of powder formulations within a mold. The physical mixtures were loaded into microneedle molds, subjected to thermal processing at 180 °C for 10–20 minutes, and subsequently cooled. This procedure was repeated up to five times per sample. The morphological integrity of the fabricated microneedles and the absence of crystalline residues were confirmed via polarized light microscopy. Drug release kinetics were evaluated using Franz diffusion cells equipped with 0.2 μm membrane filters.

Results: DSC measurements with heating–cooling–heating cycles showed that DPZ remained amorphous throughout the process. Physical mixtures of DPZ and acidic compounds also remained amorphous during cycling, although the acidic compounds alone recrystallized during cooling. A single glass transition temperature was observed, indicating that DPZ and the acidic compounds were miscible (Figure 1). Under polarized light microscopy observation of DPZ alone and DPZ-sorbic acid, needle formation was confirmed and no residual crystals were observed on the needle surfaces (Figure 2). In the mixture of DPZ and maleic acid, needle formation was insufficient. The donepezil content was evaluated by varying the number of VCM processing cycles. Compared to a single operation, repeated processing markedly increased the DPZ content. After one cycle, the DPZ content in the needles was approximately 400 mg, whereas after five cycles, it increased to about 1600 mg. In the microneedle mold, the cavity for needle formation is extremely small. Because this space is not much larger than the powder particle size, a single cycle often leaves large voids. In contrast, with repeated cycles, the melted and cooled powder was thought to accumulate in layers, progressively filling the cavity and thereby increasing drug content. In the release test, microneedles containing only DPZ showed faster dissolution, with approximately 65% released after 180 minutes (Figure 3). By contrast, when DPZ was combined with sorbic acid, the dissolution rate was about 39%. Given that the p<em>K_a difference between DPZ and sorbic acid exceeds 4, it is considered that an amorphous salt was formed within the microneedles and that the differences in the salts’ dissociation constants affected the initial dissolution behavior.

Conclusion: Dissolving microneedles containing the drug alone can be prepared using VCM. Furthermore, it was demonstrated that the formation of amorphous salt can control the drug release from microneedle.

References: 1) Zheng, L., Chen, Y., Gu, X., Li, Y., Zhao, H., Shao, W., Ma, T., Wu, C., Wang, Q., 2024. Co-delivery of drugs by adhesive transdermal patches equipped with dissolving microneedles for the treatment of rheumatoid arthritis. Journal of Controlled Release 365, 274–285.
2) Yadav, P.R., Hingonia, P., Das, D.B., Pattanayek, S.K., 2024. Modeling of Dissolving Microneedle-Based Transdermal Drug Delivery: Effects of Dynamics of Polymers in Solution. Mol. Pharmaceutics 21, 5104–5114.

Acknowledgements: There are no fundings and conflict of interest.

Figure 1. DSC thermograms of physical mixtures of donepezil (DPZ) and acidic compounds.

Figure 2. Polarized light microscopy images of the prepared microneedles: (a) donepezil (DPZ) alone, (b) DPZ–sorbic acid and (c) DPZ-maleic acid.

Figure 3. Release profile of donepezil (DPZ) from microneedle containing DPZ alone or DPZ-sorbic acid. (n=3)