(W0930-03-17) Enhanced Transdermal Delivery of Tizanidine Using Novel Cavity Hydrogel-Forming Microneedles

Purpose: Tizanidine (TZN), a centrally acting skeletal muscle relaxant, suffers from limited oral bioavailability (20–34%) due to extensive first-pass hepatic metabolism, necessitating frequent administration to maintain therapeutic plasma concentrations [1]. Transdermal drug delivery (TDD) presents a compelling alternative by circumventing hepatic metabolism, with hydrogel-forming microneedles (HF-MNs) offering a minimally invasive means to enhance TDD [2]. In contrast to conventional patches, which are hindered by slow drug partitioning and prolonged lag times, HF-MNs rapidly penetrate the stratum corneum and swell to facilitate efficient drug diffusion [2]. Recent advances in cavity-forming microneedle design have reduced the polymeric barrier, significantly minimizing lag time and accelerating drug absorption, approaching the pharmacokinetic profiles achieved by intramuscular or subcutaneous injections [3]. This study explores the potential of cavity-HF-MNs for TZN and TZN HCl to optimize their TDD, aiming for improved pharmacokinetic profiles and enhanced therapeutic outcomes.

Methods: HF-MNs were prepared from aqueous mixtures using poly (vinyl pyrrolidone) (PVP K29/32 58k), poly (vinyl alcohol) (PVA 85-124k) and citric acid (ratio 10:15:1.5). Small (F2) and large (F3) cavity-HF-MNs were prepared and compared to conventional HF-MNs(F1) (Fig. 1). A 9x9 pyramidal needle with 1000 µm needle height and a base width of 0.460 mm was used. Two types of drug reservoirs were prepared following previously described methods [4]. Poly(ethylene) glycol (PEG)-based solid dispersion (SD) reservoirs of TZN were formulated using PEG 200, TZN, and PEG 6000 in a weight ratio of 79.5:1:19.5. TZN HCl lyophilized wafers were prepared using TZN HCl, mannitol, gelatin, and deionized water in a weight ratio of 4:3:1:12. The skin permeation profile of all the formulations was then studied using Franz diffusion cells [5].

Results: All HF-MNs formulations were successfully fabricated and demonstrated accepted mechanical strength with less than 20% height reduction after compression (Fig. 2). Furthermore, all the HF-MNs formulations completely penetrate the first four layers of the Parafilm^® M skin model (Fig 2). This insertion at the first layer confirms stratum corneum penetration capability [2]. Skin permeation profiles demonstrated a more improved transdermal delivery of both TZN and TZN HCl using the cavity-HF-MNs in comparison to the conventional HF-MNs (Fig. 2). Furthermore, large cavity-HF-MNs (F3) were more efficient than small cavity-HF-MNs (F2) in delivering both TZN and TZN HCl achieving ~1.8mg and ~14mg, respectively when the same drug reservoirs were used.

Conclusion: In this study, both conventional and cavity-HF-MNs were developed with accepted mechanical and insertion properties. Cavity-HF-MNs demonstrated the potential for a more effective TDD for both TZN and TZN HCl as evidenced by ex-vivo study results. Notably, the large cavity-HF-MNs exhibited superior drug delivery capacity and thus improved the delivery efficiency.

References: [1]. Hord, A. H., Chalfoun, A. G., Denson, D. D., & Azevedo, M. I. (2001). Systemic tizanidine hydrochloride (Zanaflex) relieves thermal hyperalgesia in rats with an experimental mononeuropathy. Anesthesia and analgesia, 93(5), 1310–1315.
[2]. Larraneta E, Lutton RE, Woolfson AD, Donnelly RF. Microneedle arrays as transdermal and intradermal drug delivery systems: materials science, manufacture and commercial development. Materials Science and Engineering: R: Reports. 2016;104:1-32.
[3] Cárcamo-Martínez, Á., Mallon, B., Anjani, Q. K., Domínguez-Robles, J., Utomo, E., Vora, L. K., Tekko, I. A., Larrañeta, E., & Donnelly, R. F. (2021). Enhancing intradermal delivery of tofacitinib citrate: Comparison between powder-loaded hollow microneedle arrays and dissolving microneedle arrays. International journal of pharmaceutics, 593, 120152.
[4]. Thakkar, H., Pandya, K., & Patel, B. (2020). Microneedle-Mediated Transdermal Delivery of Tizanidine Hydrochloride. Methods in molecular biology (Clifton, N.J.), 2059, 239–258.
[5]. Zhu, L. L., Wang, Y. H., & Zhou, Q. (2024). Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations. Journal of pain research, 17, 1257–1271.


Fig.1. (a) Schematic representation of the conventional HF-MNs (F1) manufacturing process. (b) Schematic representation of the small cavity HF-MNs (F2) manufacturing process. (c) Schematic representation of the large cavity HF-MNs (F3) manufacturing process.


Fig.2. (a) Digital images of the HF-MNs tips of F1, F2 and F3. (b) Comparison of the percentage of height reduction of 3 different HF-MNs (means + S.D., n = 3, p<0.05). (c) Insertion depths, number of Parafilm®M layers penetrated and percentage of holes created on each Parafilm®M layer by the different HF-MNs (F1-F3) (means ± S.D., n = 3). (d) Ex-vivo cumulative amount (mg) of TZN HCl across dermatomed neonatal porcine skin obtained from still born piglets from the different HF-MNs (F1-F3), compare the same concentration TZN HCl lyophilized reservoirs within 24h (Means ± SD, n = 3, p<0.05). (e) Ex-vivo cumulative amount (mg) of TZN across dermatomed neonatal porcine skin obtained from still born piglets from the different HF-MNs (F1-F3), compare the same concentration PEG-based TZN reservoirs within 24h (Means ± SD, n = 3, p<0.05).