(M1130-01-04) Hydrogel-Forming Microarray Patches Combined with Poly(ethylene)glycol Reservoirs for the Long-Acting Intradermal Deposition of a Poorly-Soluble Drug

Purpose: Hydrogel-forming microarray patches (HF-MAPs) are used to bypass the skin barrier and facilitate the non-invasive transdermal delivery of many hydrophilic compounds. This is mainly due to the hydrophilic matrix of the hydrogels themselves [1]. However, a high proportion of drugs available in production pipelines and in markets are lipophilic molecules and require relatively high doses [2]. Delivering such drugs is attractive, as we can benefit from their lipophilicity in controlling and sustaining their release to produce long-acting effects. Nevertheless, their delivery using HF-MAPs is a challenging task. Herein, we report for the first time, the successful transdermal long-acting delivery of the hydrophobic drug atorvastatin (ATR) via HF-MAPs using poly(ethylene)glycol (PEG) as a matrix. This novel system offers a promising, minimally-invasive, long-acting alternative delivery system for ATR, capable of enhancing patient compliance and therapeutic outcomes.

Methods: HF-MAPs were prepared from aqueous blends of Gantrez S-97^® and PEG 10,000 as the crosslinker, in the presence or absence of sodium carbonate (Na₂CO₃), as demonstrated in Figure 1 (A-D). Two formulations were evaluated, ‘normal swelling’ (F2) and ‘super-swelling’ (F4). The only difference was the addition of Na₂CO₃ into F4 HF-MAPs as it reduces the crosslinking density and allows the formulation to swell more. Those HF-MAPs were then characterised in terms of their swelling kinetics, mechanical properties and insertion efficiency. Afterwards, ATR reservoirs were fabricated using a solid dispersion (SD) method, as depicted in Figure 1(E-H). Four ATR reservoir formulations were evaluated (RF-1, RF-2, RF-5 & RF-6). The ex vivo delivery of ATR-containing reservoirs across HF-MAPs was tested using the Franz-cells apparatus. The in vivo study was conducted using Sprague Dawley rats over 2 weeks, where each rat received 4 HF-MAPs, each combined with an RF-2 ATR reservoir, containing a total amount of 60 mg of ATR. A control group was given an oral suspension of ATR at a dose of 10 mg/rat. Plasma samples were obtained and analysed using a Waters^® Triple Quadruple Tandem Mass Spectrometer (TQ MS-MS).

Results: HF-MAPs were robust enough to penetrate the skin-simulant, Parafilm M^®, and excised neonatal porcine skin models with finger pressure, and could endure up to 32 N of compression force with < 10% height decrease. F4 demonstrated a significant superiority (p < 0.05) in swelling capacity over F2 (1000% for F4, and 434% for F2 at 30 min following their submersion in PBS at pH 7.4). For the ATR reservoir, RF-2 was selected based on dissolution time and appearance, where it was able to dissolve in less than 90 sec. Ex vivo permeation profiles using Franz cells showed that, upon using F4 MAPs, 2.05±0.23 mg of ATR was delivered to the receiver compartment after 24hs. A significantly lower quantity of only 0.64±0.37 mg was delivered using F2 HF-MAPs. A mere 0.23±0.22 mg was detected in the receiver compartment in control cells which did not contain MAPs. The in vivo study carried out over 2 weeks had shown that ATR was detected and quantified throughout the entire study period. This is the first time to prove the versatility of HF-MAPs in the long-acting delivery of a therapeutic agent. It is also the first time to address the delivery of ATR over 2 weeks following a single-dose administration. Figure 2 presents the plasma profile of ATR for both HF-MAPs and control cohorts.

Conclusion: HF-MAPs were shown to enhance the transdermal delivery of the hydrophobic compound, ATR, compared to control setups, upon its incorporation in a PEG SD matrix. The results of ex-vivo permeation studies showed that the PEG reservoirs could successfully deliver ATR across porcine skin via HF-MAPs. The in vivo study has proven, for the first time, the versatility of HF-MAPs in combination with SD PEG reservoirs to achieve sustained delivery of ATR over two weeks. This novel system can provide a promising long-acting alternative delivery system of ATR, which is non-invasive, easy to self-administer and reduces dosing frequency, thus, enhancing patient quality of life.

References: 1. Migdadi E. M., Courtenay A. J., Tekko I. A., McCrudden M. T. C., Kearney M. C., McAlister E., McCarthy H. O., Donnelly R. F., Hydrogel-forming microneedles enhance transdermal delivery of metformin hydrochloride. J Control Release. 2018 ;285:142-151.
2. Paredes, A. J., McKenna, P. E., Ramöller, I. K., Naser, Y. A., Volpe-Zanutto, F., Li, M., Abbate, M. T. A., Zhao, L., Zhang, C., Abu-Ershaid, J. M., Dai, X., Donnelly, R. F., Microarray Patches: Poking a hole in the challenges faced when delivering poorly soluble drugs. Adv. Funct. Mater. 2021, 31, 2005792.


Figure 1. Schematic representation showing (A-D) casting of HF-MAPs, and (E-H) preparation of PEG reservoirs. (I) The final product of HF-MAP and a PEG reservoir laid on top of it. Black scale bare resembles 2 mm in length.


Figure 2. ATR plasma profiles of the rats from the oral, and HF-MAPs cohorts following the in vivo study for 14 days. (Mean + SD, n=6 at 1, 2, 4 and 6h, n=12 at the remaining time points). The black dashed line represents the therapeutically relevant ATR plasma concentration in humans (20 ng/mL)