Hydrogel-forming microarray patches combined with powder-based reservoir for labetalol hydrochloride transdermal delivery

Abstract

Hypertension is the most common pregnancy disorder and can lead to life-threatening conditions for both mother and fetus. However, managing this condition with oral and intravenous labetalol can be challenging, highlighting the need for alternative delivery methods. This study presents, for the first time, the development of novel powder-based reservoirs incorporated with hydrogel-forming microarray patches (MAPs) to facilitate the transdermal delivery of labetalol hydrochloride (HCl). A holder, created from poly(propylene) using a 3D printer, was designed to house labetalol HCl powder, which was then combined with hydrogel-forming MAPs. This novel system improved the insertion profile of MAPs into Parafilm® layers and excised full-thickness neonatal porcine skin, achieving up to 85 % of needle height penetration without compromising needle integrity (only 8 % height reduction after applying 32 N of force). The current holder design was able to load 50 mg of labetalol HCl and allowed for single or multiple injections of deionised water to dissolve the powder and facilitate permeation through dermatomed neonatal porcine skin in in vitro studies using a Franz cell setup. The results showed that this powder-based reservoir design delivered labetalol HCl more effectively over 24 h compared to directly compressed tablets. Additionally, poly(vinyl alcohol)/poly(vinyl pyrrolidone)/citric acid-based hydrogel-forming MAPs delivered more labetalol HCl than Gantrez® S-97/poly(ethylene glycol)-based MAPs (9 mg vs. 5 mg) in 24 h. This novel system holds promise for improving the delivery of compounds in a simple manner, though further design modifications for one-step application are needed.

Introduction

Hypertension complicates 1 in 10 pregnancies in the UK and is recognised as the most common pregnancy disorder (Prevalence | Background information | Hypertension in pregnancy | CKS | NICE, n.d., Hopkins, 2000, Braunthal and Brateanu, 2019). This condition poses significant risks to both the mother and fetus, with the severity of the risks closely correlating with the level of blood pressure. Untreated hypertension during pregnancy can lead to other disorders, such as preeclampsia, which affects 3–4 % of all pregnancies worldwide (Brown and Garovic, 2014, Fox et al., 2019). Treating severe hypertension is crucial to prevent cerebrovascular, cardiac, and renal complications in the mother. Consequently, the choice of therapy is limited to medications that are relatively safe, have a long history of clinical use, and possess a side-effect profile deemed acceptable by most obstetricians (Croke, 2019). Labetalol, a beta-blocker, is recommended during pregnancy as it effectively lowers blood pressure while maintaining normal placental blood flow (Roccella, 2000, Magee et al., 2003).

Hypertension during pregnancy typically develops within the first 20 weeks (High blood pressure and pregnancy: Know the facts – Mayo Clinic, n.d., Whelton et al., 2017). However, oral administration of labetalol tablets can be challenging if the mother experiences morning sickness, compounded by the need to manage high blood pressure. Although labetalol is also available as an injection, this option requires healthcare intervention and is generally reserved for emergency situations where rapid blood pressure reduction is necessary. Therefore, transdermal delivery of labetalol has emerged as a promising alternative, addressing the limitations of both oral and intravenous administration.

Hydrogel-forming microarray patches (MAPs) offer a potential platform for administering labetalol hydrochloride (HCl) transdermally. This minimally-invasive approach could potentially be self-applied by the patient, reducing the need for frequent clinic or hospital visits for drug administration. Hydrogel-forming MAPs have been shown to deliver high-dose drugs across the stratum corneum to reach the dermal microcirculation (Bin Sabri et al., 2022, Naser et al., 2023, Himawan et al., 2023, Anjani et al., 2021, Ramadon et al., 2020, Volpe-Zanutto et al., 2022, Reyna et al., 2023), making them a viable option for labetalol HCl delivery in this study. Previous studies have explored various drug reservoirs that can be incorporated with hydrogel-forming MAPs, including lyophilised wafers, direct compressed tablets, and poly(ethylene glycol) reservoirs (Anjani et al., 2021, Donnelly et al., 2014, McAlister et al., 2021). In this study, we aim to evaluate a novel drug reservoir alternative for combination with hydrogel-forming MAPs.

In the present work, we introduce and develop, for the first time, a powder-based reservoir to simplify the transdermal delivery of labetalol HCl, which can also be applied to other compounds. This reservoir allows drug powder to be loaded into a holder prepared using a simple 3D-printing technique. We evaluated the novel powder-based reservoir for its effect on the mechanical properties and swelling capacity of hydrogel-forming MAPs, as well as its performance in in vitro permeation studies across dermatomed neonatal porcine skin using a Franz cell setup. The results were compared with those obtained from direct compressed tablets. This study provides a preliminary design of a powder-based reservoir that could potentially simplify the transdermal delivery of various compounds via hydrogel-forming MAPs.

Download the full article as PDF here Hydrogel-forming microarray patches combined with powder-based reservoir for labetalol hydrochloride transdermal delivery

or read it here

Materials

Labetalol hydrochloride (HCl, 98 % purity), poly(vinyl alcohol) (PVA, 87–89 % hydrolyzed, MW 85–124 kDa), and anhydrous citric acid were sourced from Sigma-Aldrich (Dorset, UK). Gantrez® S-97, a copolymer of methyl vinyl ether and maleic acid (PMVE/MA, MW 1,500 kDa), along with Plasdone™ K-29/32 (PVP, MW 58 kDa), were gifted from Ashland (Kidderminster, UK). Additional materials, including poly(ethylene glycol) (PEG, MW 10 kDa), sodium bicarbonate, and phosphate-buffered saline tablets (PBS, pH 7.4), were also obtained from Sigma-Aldrich (Dorset, UK). All solvents used in the study were of analytical grade and supplied by Sigma-Aldrich (Dorset, UK).

Qonita Kurnia Anjani, Usanee Detamornrat, Eneko Larrañeta, Ryan F. Donnelly, Hydrogel-forming microarray patches combined with powder-based reservoir for labetalol hydrochloride transdermal delivery, International Journal of Pharmaceutics, 2024, 125061, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.125061.