(T1330-06-35) Transdermal Administration of Rivastigmine Using Hydrogel-Forming Microneedles as a Potential Treatment for Alzheimer’s disease

Purpose: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, accounting for 60-70% of dementia cases and emerging as a significant global health burden. Rivastigmine (RVA), a cholinesterase inhibitor, is recognized as one of the first-line therapeutic agents of AD [1]. Currently, RVA is predominantly available in the form of capsules and transdermal patches. However, low patient adherence, a hallmark of AD progression, presents significant challenges for oral administration. Patients will miss the frequent tablets they should take, and as the disease advances, dysphagia further compromises the feasibility of oral drug delivery. The development of once-daily transdermal RVA patches offer a promising alternative, potentially enhancing patient compliance and achieving improved therapeutic outcomes [2]. However, as the disease progresses, the required dosage increases, necessitating a proportional enlargement of the patch surface area. This expansion may further reduce patient compliance and increase the risk of potential skin irritations. Microneedles (MNs) offer a non-invasive drug delivery method, bypassing the stratum corneum by creating microchannels for transdermal administration [3]. Hydrogel forming microarray patches (HMAPs), first introduced in 2012, represent a novel class of microneedles distinguished by their unique mechanism of action. Upon application to the skin, the HMAPs rapidly imbibe interstitial fluid, causing them to swell. This swelling behavior facilitates the diffusion of therapeutic agents from an attached drug reservoir above HMAPs into the dermal microcirculation, providing an efficient transdermal drug delivery system [3]. In this study, incorporating rivastigmine were developed for sustained transdermal drug delivery, aiming to provide a novel therapeutic approach for the management of AD.

Methods: HMAPs were prepared using poly (vinyl pyrrolidone) (PVP) (K29/32 58k), poly (vinyl alcohol) (PVA)(85-124k), and citric acid (10%w/w, 15%w/w, and 1.5%w/w) according to Fig.1.(a). The aqueous mixtures were then cast into the silicone moulds (11 x 11 pyramidal needle density on 0.49 cm² area with 600 µm needle height). After drying at room temperature for 48 hours, HMAPs were demoulded and subsequently crosslinked by heating in an oven at 130 °C for 3 hours. Obtained HMAPs were characterized through insertion and mechanical strength studies. Two types of RVA reservoirs were developed as shown in Fig.1.(b). RVA freeze-dried tablets were fabricated by combining RVA, mannitol, gelatine, and (hydroxypropyl)methyl cellulose (HPMC) in deionized water, followed by a freeze-drying process. RVA films were prepared by casting an aqueous gel composed of RVA, PVA (9–10 kDa), and PVP (K29/32) in the ratio of (5%w/w, 47.5%w/w, and 47.5%w/w) into needle-free silicone moulds similar to those used for HMAPs. Ex-vivo permeation study was conducted as Fig.2. using Franz diffusion cells with dermatomed neonatal porcine skin (obtained from stillborn piglets, 350µm). HMAPs were inserted into the skin, samples were collected at predetermined time points.

Results: As shown in Fig.3. (a), (b). Acceptable mechanical properties were demonstrated as HMAPs were able to effectively penetrate through folded Parafilm® layers equivalent to a depth of 360 μm. According to Fig.3. (c), Upon insertion into the skin, the HMAPs facilitated the sustained delivery of RVA over 24 hours. The incorporation of HPMC effectively slowed the release rate of RVA, with RVA tablets delivering approximately 12.4 mg (41%) after 24 hours, while HPMC-containing tablets (1% w/w) delivered around 7.6 mg (25%). These findings demonstrate the potential of HMAPs combined with RVA to develop a long-acting transdermal drug delivery system. RVA films delivered approximately 13.4 mg (45%) of the loaded drug over 24 hours, achieving an equivalent dosage to that of commercial rivastigmine patches (13.3 mg/24h, 27 cm²) while utilizing a significantly smaller surface area. This strategy may substantially reduce skin-related complications associated with oversized transdermal patches.

Conclusion: RVA-loaded HMAPs were developed and evaluated through ex vivo permeation studies. The microneedles successfully achieved the daily dosage requirements of commercial rivastigmine patches while utilizing a smaller application area, which could effectively enhance patient compliance, thereby improving therapeutic outcomes. Furthermore, the incorporation of HPMC demonstrated the ability to sustain rivastigmine release over an extended period. These findings highlight the potential of microneedle systems as a promising platform for the transdermal delivery of rivastigmine. Subsequent in vivo studies will be conducted using RVA-loaded HMAPs to further evaluate the feasibility of employing this platform for the treatment of AD.

References: [1]. Anand, P. and Singh, B. (2013) ‘A review on cholinesterase inhibitors for Alzheimer’s disease’, Archives of Pharmacal Research, 36(4), pp. 375–399. [2]. Molinuevo, JL . and Arranz, FJ. (2012) ‘Impact of transdermal drug delivery on treatment adherence in patients with Alzheimer's disease’, Expert Review of Neurotherapeutics, 12(1), pp. 31-37. [3]. Donnelly, R.F. et al. (2012) ‘Hydrogel-Forming Microneedle Arrays for Enhanced Transdermal Drug Delivery’, Advanced Functional Materials, 22(23), pp. 4879–4890.


Fig.1. (a) Schematic representation of the HMAPs manufacturing process. (b) Schematic representation of the RVA freeze dried tablets (1) and films (2) manufacturing process (c) Schematic representation of the characterization process of HMAPs (1) insertion study (2) mechanical strength study.


Fig.2. Schematic representation of the ex vivo permeation study.


Fig.3. (a) Insertion profile of the HMAPs (Means ± SD, n = 3) (b) Mechanical strength profile of the HMAPs (Means ± SD, n = 3) (c) Ex vivo permeation profile of RVA through the HMAPs, across dermatomed neonatal porcine skin within 24 hours (Means ± SD, n = 6)