(T1430-03-17) Development of Microneedle Array Patch Systems for Transdermal Delivery of Dopamine Agonists for Treatment of ‘OFF’ Periods in Parkinsons Disease

Purpose: Apomorphine hydrochloride (APO) and ropinirole hydrochloride (ROP) are dopamine agonists that are often employed in Parkinson’s Disease (PD) to combat acute moments of unexpected motor symptom return, otherwise known as ‘OFF’ periods ^[1]. Conventional subcutaneous administration of APO by hypodermic needle or pneumatic pump brings challenging self-operation, pain and injection site reactions ^[2]. Oral ROP suffers with poor bioavailability due to first-pass effect, and diminishing efficacy in advanced PD due to onset of dysphagia and gastrointestinal dysfunction ^[3]. Transdermal delivery of these agents by easy-to-operate and painless dissolving or hydrogel-forming microneedle array patches (MAPs) may bypass these issues ^[4].

Methods: Dissolving APO MAPs were fabricated via aqueous micro-casting in 16 x 16 silicone moulds using two layers; in Table 1 is summarised each of the aqueous blends used to prepare the 1st layer, consisting of poly(vinyl alcohol) (PVA) 9-10 kDa and poly(vinylpyrrolidone) (PVP) 58 kDa, with APO loaded at 9, 15, or 21% (w/w), applied under 4.5 bars positive pressure followed by drying at room temperature for 24 hours. An aqueous blend consisting of 32.9% (w/w) PVP K90, 1.75% (w/w) glycerol and 0.35% (w/w) ascorbic acid, was then cast over the mould and centrifuged at 2880 g for 10 minutes, then dried for a further 24 hours at room temperature. MAP morphology, integrity and in vitro insertion were characterised by optical light microscopy and optical coherence tomography. Ex vivo permeation of APO through excised neonatal porcine skin was carried out using modified Franz-diffusion cells. Screening of excipients for directly-compressed ROP tablet reservoirs included microcrystalline cellulose (MCC), sorbitol, mannitol, Soluplus^®, PVP 58 kDA, croscarmellose sodium, sodium starch glycolate and crospovidone (CPV), through 1 minute of continuous pressure at 5 tonnes. The tablets were characterised based on dissolution time and hardness. Hydrogel MAPs and films were fabricated and characterised as previously published ^[5]. Permeation of ROP through hydrogel-forming films was performed using a side-bi-side diffusion cell apparatus in PBS (pH 7.4) equilibrated at 37.4 °C. All quantitative analysis of APO or ROP was performed using a validated RP-HPLC method.

Results: As shown in Figure 1A - D, sharp, homogenous dissolving MAPs were successfully fabricated with 2, 3 and 4 mg APO localised in the microneedle tips, which were capable of penetrating >400 μm into an in vitro Parafilm^® M model and were of high integrity ( < 10% height reduction post-compression against aluminium block at 32 N). During ex vivo permeation studies, up to 1 mg of APO was delivered into the receptor compartment after 24 hrs, as illustrated in Figure 1E. Figure 2A and B reveal that preliminary screening of excipients by mixture-DOE for use in the directly-compressed ROP tablet reservoir formulation identified MCC and CPV should be included based on their tablet hardness and dissolution properties. Both excipients provided optimal tablet integrity, and hypothetically may allow for a precisely tailored dispersion time / ROP release profile by varying the ratio of CPV and MCC in the tablet reservoir formulation. Figure 2C and D visually confirm these excipients produce well-formed tablets by direct-compression. In Figure 2E<, the hydrogel-forming film formulation that provided optimal permeation of ROP (p < 0.001) was Gantrez ^® S-97 (poly(methylvinylether-co-maleic acid)) crosslinked with PEG 10 kDa at 80 °C for 24 hours. Thus, it may be a suitable hydrogel-forming MAP for future ex vivo permeation studies of ROP through excised neonatal porcine skin.

Conclusion: Demonstrated here is the potential viability of MAP technology for transdermal delivery of APO and ROP, as a patient-friendly alternative to the conventional yet challenging parenteral and oral therapies. The scope of this project now looks to optimise the directly-compressed ROP tablet reservoir formulation by mixture-DOE, and investigate ex vivo permeation via hydrogel-forming MAPs. Additionally, exploration of the performance of these MAP systems in an appropriate in vivo model will be a key step for future work.

References: [1] Ruan X et al., Front in Neurosci, (2021) 15. [2] Carbone F et al., CNS Drugs, (2019) 33, 905-18. [3] Mochizuki H et al., Parkinsonism Relat Disord, (2021) 83:105-9. [4] Waghule T et al., Biomed & Pharm, (2019) 109, 1249-58. [5] Donnelly RF et al., Adv Funct Mat, (2012) 22, 4879-90.

Acknowledgements: The authors would like to thank the Department for the Economy (NI) and Janssen Pharmaceuticals for the provision of support for undertaking this work.


Table 1. Composition of the various aqueous blends used to prepare the 1st-layer of dissolving APO-MAPs.


Figure 1 (A) Optical light microscope profile images 9% (w/w) APO-loaded MAP. (B) APO content per patch (Means + SD, n = 3). (C) Needle height reduction post-compression (Means + SD, n = 3). (D) Insertional efficiency into Parafilm® (Means + SD, n = 3). (E) Permeation of APO across full thickness porcine skin (Means ± SD, n = 4).


Figure 2 Piepel trace plots derived from mixture-DOE, illustrating each excipients linear effects on the following responses: (A) hardness (n = 4) and; (B) dispersion time (n = 4). (C) and (D) show optical light microscope images of directly-compressed tablets composed of CPV and MCC respectively. (E) Cumulative permeation-time graph of ROP dissolved in PBS (pH 7.4) through various hydrogel-forming film formulations. One-way ANOVA comparison reveals significant difference in total ROP permeated after 24 hrs (***, p < 0.001) between Gantrez S-97/PEG 10 kDa and PVA/PVP/CA at various crosslinking times between 0.5 – 3 hrs (Means ± SD, n = 5).