Evaluation of physical and chemical modifications to drug reservoirs for stimuli-responsive microneedles

Abstract

Hydrogel-forming microneedle (MN) arrays are minimally-invasive devices that can penetrate the stratum corneum, the main barrier to topical drug application, without causing pain. However, drug delivery using hydrogel-forming MN arrays tends to be relatively slow compared to rapid drug delivery using conventional needles and syringes. Therefore, in this work, for the first time, different physical and chemical delivery enhancement methods were employed in combination with PVA-based hydrogel-forming MN arrays. Using a model drug, ibuprofen (IBU) sodium, the designed systems were assessed in terms of the extent of transdermal delivery.

Iontophoresis (ITP) and heat-assisted drug delivery technology were investigated as physical permeation enhancement techniques. Ex vivo studies demonstrated that the ITP (0.5 mA/cm²)-mediated combination strategy significantly enhanced the transdermal permeation of IBU sodium over the first 6 h (~ 5.11 mg) when compared to MN alone (~ 1.63 mg) (p < 0.05). In contrast, heat-assisted technology showed almost no promoting effect on transdermal delivery. Furthermore, IBU sodium-containing rapidly dissolving lyophilised and effervescent reservoirs, classified as chemical modification methods, were prepared. Both strategies achieved rapid and effective ex vivo IBU sodium permeation, equating to ~ 78% (30.66 mg) and ~ 71% (28.43 mg) from lyophilised and effervescent reservoirs, respectively.

Moreover, in vivo pharmacokinetic studies showed that the IBU sodium plasma concentration within lyophilised and effervescent groups reached a maximum concentration (C_max) at 4 h (~ 282.15 µg/mL) and 6 h (~ 140.81 µg/mL), respectively. These strategies not only provided rapid achievement of therapeutic levels (10–15 µg/ml), but also resulted in sustained release of IBU sodium for at least 48 h, which could effectively reduce the frequency of administration, thereby improving patient compliance and reducing side effects of IBU sodium.

Introduction

Transdermal drug delivery (TDD), as an alternative to oral and parenteral administration, can circumvent associated issues such as first-pass effect and needle phobia. However, due to the skin barrier effect, only drugs with specific properties, such as low molecular weight (MW) (< 500 Da) and balanced lipophilicity (LogP 1–3), can passively diffuse through the stratum corneum (SC), thereby limiting the application of TDD [1] Microneedle (MN) arrays offer an option to overcome this obstacle, as they exhibit the ability to bypass the SC and allow drugs to diffuse into the deep skin layers [2]. Hydrogel-forming MN arrays represent one of the five designs within MN technology and permit the delivery of high doses of drug molecules across the skin. Within this MN design, the active substances are loaded into a separate drug reservoir meaning that the loading capacity is not limited to the MN needles themselves [3, 4]. The structure of hydrogel-forming MNs and their mechanism are schematically in Fig. 1. Previous studies have shown that a wide range of drug reservoirs can be integrated into hydrogel-forming MN arrays for different transdermal delivery purposes [3,4,5,6,7,8,9,10,11]. However, when compared to conventional needles and syringes, hydrogel-forming MN technology typically exhibits a lag phase, resulting in a slower rate of drug delivery. Therefore, the present work highlights different physical and chemical modification methods to drug reservoirs in combination with hydrogel-forming MN arrays, to further improve the amount and rate of delivery of a small molecule water-soluble model drug, ibuprofen (IBU) sodium, to enable rapid TDD.

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Materials

Gantrez® S-97, a copolymer of methylvinylether and maleic acid (PMVE/MA), MW 1.5 × 106 Da and Plasdone® K-29/32, poly(vinyl pyrrolidone) (PVP) MW 5.8 × 104 Da, were gifts from Ashland Specialties UK Ltd, Kidderminster, Worcestershire. Gelatin, sold under product brand name Cryogel® SG/3 was provided from PB Gelatins GmbH, Nienburg/Weser, Germany. Mannitol, sold under product brand name Pearlitol® 50 C, was purchased from Roquette, (Lestrem, France). All other chemicals and materials were of analytical grade and purchased from Sigma-Aldrich (Dorset, UK) or Fisher Scientific (Loughborough, UK).

Li, L., Anjani, Q.K., Hutton, A.R.J. et al. Evaluation of physical and chemical modifications to drug reservoirs for stimuli-responsive microneedles. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01737-0

Read also our introduction article on Mannitol here: