(T1530-03-18) Ionic Liquid-Based Dissolving Microarray Patches for Controlled Release of Isoniazid: A Proof-of-Concept Study

Purpose: Microarray patches (MAPs) are minimally invasive devices that can circumvent the outermost skin barrier, the stratum corneum (SC), allowing drug delivery to the rich dermal microcirculation [1]. Ionic liquids (ILs) are salts that exist in a liquid state at or near room temperature. They are salts, typically composed of a bulky organic cation and an inorganic or organic anion [2]. In such an approach, active pharmaceutical ingredients (APIs) may also be ionised as one of the components of an IL (API-ILs), presenting with tailor-made physiochemical properties through wise-pairing with suitable organic counterions. Both MAPs and API-ILs have demonstrated promising potentials in transdermal drug delivery, but there is a lack of work combining the two formulations together for controlled drug release. Therefore, in this work, we proposed the concept of loading API-ILs into dissolving MAPs for controlled transdermal delivery of an anti-tuberculosis antibiotic, isonicotinic acid hydrazide (INH).

Methods: Figure 1 displays the synthesis of INH-ILS via protonation using appropriate organic acids. Sodium hexanesulfonate and sodium docusate were converted to their acidic forms through ion-exchange resins. The resulting acids were then added to an INH solution to yield INH hexanesulfonate (INH-HS) and INH Docusate (INH-DS). The solubilities of INH, INH-HS, INH-DS in phosphate buffer saline (PBS, pH 7.4) at 37^oC were determined by a previously described HPLC-UV method. As illustrated in Figure 2a, a ‘two-step’ casting approach was utilised to fabricate the INH-ILs loaded dissolving MAPs, ensuring the majority of the ‘drug-containing’ shaft of the needles could be inserted beneath the aforementioned SC barrier and facilitate drug delivery to the viable skin layers [3]. The ex vivo permeation and deposition profiles of the formulated dissolving MAPs were evaluated via a Franz cell apparatus, using full-thickness skin obtained from stillborn piglets (~ 500 μm).

Results: The ionisation of the INH-ILs was confirmed via ATR-FTIR and ¹H NMR spectroscopies by comparative analysis of the characteristic signals of INH and its protonated counterpart (data not shown in the abstract). NMR analysis confirmed the desired 1:1 stoichiometry through the relative integrals of the signals of INH and respective organic anions. Furthermore, there was a colour change from the white INH powder to the yellow INH-ILs (Figure 2b), indicating successful protonation of INH [4]. The solubilities of the formulated INH-HS (7.823 ± 2.677 mg/ml) and INH-DS (34.836 ± < 0.144 mg/ml) were determined to be significantly less than that of the INH powder form (94.775 ± 6.906 mg/ml) (p < 0.05 in both cases). The individual needles on INH-ILs based dissolving MAPs were found to be intact, sharp and well-formed. Figure 2e illustrates the ex vivo permeation and deposition profiles of the formulated INH-HS and INH-DS dissolving MAPs. Table 1 presented drug content and ex vivo permeation and deposition profiles of the INH-ILs dissolving MAPs. After 24 h patch application, the amount of INH permeated from the INH-HS MAPs (the less soluble salt form) was significantly reduced (0.921 <± 0.050 mg, 50.707 ± 2.768% of INH loaded) in comparison to that of the INH MAPs (1.387 ± 0.166, 68.147 ± 8.172% of INH loaded) (p = 0.0098). Additionally, it was revealed that a greater amount of INH was deposited in the skin from the INH-HS MAP in Figure 1f (p < 0.05 in all comparisons), which further indicates controlled transdermal and intradermal INH delivery.

Conclusion: This work describes the concept of the combinatorial approach of dissolving MAPs and ILs, for controlled transdermal and intradermal INH delivery by modifying the aqueous solubility. An enhanced intradermal deposition and reduced transdermal permeation were found with the dissolving MAPs incorporated with the less soluble INH-HS compared with the more soluble INH-DS. Further in vivo studies will be performed now to investigate the pharmacokinetic profiles in suitable animal models.

References: 1. Donnelly, R.F., T.R.R. Singh, and A.D. Woolfson, Microneedle-based drug delivery systems: Microfabrication, drug delivery, and safety. Drug Delivery, 2010. 17(4): p. 187-207.
2. Shamshina, J.L. and R.D. Rogers, Ionic liquids: New forms of active pharmaceutical ingredients with unique, tunable properties. Chemical Reviews, 2023. 123(20): p. 11894-11953.
3. Li, Y., et al., Dissolving microarray patches loaded with a rotigotine nanosuspension: A potential alternative to Neupro® patch. Journal of Controlled Release, 2024. 372: p. 304-317.
4. Santos, F., L.C. Branco, and A.R.C. Duarte, Organic salts based on isoniazid drug: Synthesis, bioavailability and cytotoxicity studies. Pharmaceutics, 2020. 12(10): p. 952.


Figure 1. A schematic illustration of synthesis of the INH-ILs.


Figure 2. (a) A schematic illustration of the ‘two-layered’ casting process of the MAPs. (b) Visual appearance of INH powder and the formulated INH-ILs. (c) and (d) Representative digital microscopic images of the INH-ILs dissolving MAPs. (e) Ex vivo permeation profiles of the INH-ILs MAPs (Means  S.D., n = 3). (f) Ex vivo deposition profiles of the INH-ILs MAPs (Means  S.D., n = 3).


Table 1. Ex vivo permeation and deposition profiles of the INH-ILs dissolving MAPs.