(M1430-06-35) Sustained Transdermal Delivery of Ropinirole Hydrochloride via Monolayer Dissolving Microneedle Array Patches

Purpose: Parkinson’s disease (PD) is the fastest growing neurological disorder globally ^[1]. Ropinirole hydrochloride (ROP) is a dopamine agonist often employed in PD to combat acute moments of unexpected motor symptom return, otherwise known as ‘OFF’ periods ^[2]. Conventional oral ROP via extended-release tablets suffers with poor bioavailability due to first-pass effect and diminishing efficacy in advanced PD due to onset of dysphagia and gastrointestinal dysfunction ^[3]. Due to the aqueous solubility of ROP, sustained transdermal delivery by easy-to-operate and painless monolayer dissolving microneedle array patches (D-MAPs) may be a novel solution yet to be explored.

Methods: D-MAPs were manufactured via one-step micro-casting aqueous blends of ROP at 2.5, 5.0 and 10.0% (w/w) dissolved with poly(vinylpyrrolidone) (PVP; 58 kDa) and poly(vinyl alcohol) (PVA; 9 – 10 kDa, 13 – 23 kDa or 31 – 50 kDa) into 16x16 (256 pyramidal needles with cuboidal base; 900 μm height, 300 μm base width and 100 μm needle-interspacing) silicone moulds. D-MAPs were characterised via axial compression, optical light microscopy, scanning electron microscopy, differential scanning calorimetry, thermogravimetric analysis and fourier-transform infrared spectroscopy. Ex vivo percutaneous permeation and deposition studies were performed in quintuplicate over 24 hours using dermatomed neonatal porcine skin (~350 μm) and vertical Franz-diffusion cell apparatus thermostatted at 37°C. Quantification of ROP was achieved via a reversed-phase high pressure liquid chromatography method validated in accordance with ICH guidelines.

Results: Displayed in Figure 1A-I are optical light microscope images confirming D-MAPs produced from blends containing up to 5% ROP appear homogenous, dimensionally- and spatially-uniform and sharp. However, 10% ROP produced microneedles that are crooked and uneven, due to the re-crystallisation of drug during drying. Figure 1J illustrates that ROP was distributed in the microneedles and baseplate in roughly a 1:7 ratio, with 2.5% and 5.0% (w/w) ROP D-MAPs containing approximately 4.0 mg and 7.5 mg of drug in total, respectively. Figure 2A-D highlight these formulations produced sharp microneedles with a narrow tip radius. Axial compression determined that inclusion of 2.5% (w/w) ROP in the aqueous blend significantly improved resistance to deformation (p < 0.05), with 5.0% (w/w) ROP having no significant effect, as shown in Figure 2E. 10% (w/w) ROP and all D-MAPs composed of 9-10 kDa PVA were observed to be brittle and fractured during compression (data not shown), and furthermore were significantly less rigid than the aforementioned formulations composed of 13 – 23 kDa or 31 – 50 kDa PVA (p < 0.0001). In addition, Figure 2F-H suggests 9 – 10 kDa PVA D-MAPs appeared to insert less efficiently into an in vitro Parafilm^® M skin model than 13 – 23 kDa or 31 – 50 kDa. Overall, the 13 – 23 kDa and 31 – 50 kDa PVA D-MAPs produced from 2.5% and 5.0% (w/w) ROP aqueous blends were selected for ex vivo percutaneous permeation and deposition studies, achieving sustained transdermal release of ROP continually over 24 hours, as shown in Figure 3A. Due to delivery amounts exceeding 0.5 mg, this confirmed the baseplate acted as a reservoir, from where ROP could diffuse into the aqueous microchannels produced by the microneedles, bypassing the stratum corneum. Figure 3B confirms drug loading to be a significant modifying factor in controlling the flux of ROP (p < 0.001), due to the diffusion gradient being the primary driving force for permeation. Suggestibly, PVA molecular weight may affect flux, with increased molecular weight PVA taking longer to dissolve and producing a more viscous gel through which ROP molecules will have reduced diffusion-velocity, however no significant difference was found between 13 – 23 kDa and 31 – 50 kDa (p > 0.05). Deposition of ROP in the neonatal porcine was significantly higher for 5.0% (w/w) ROP D-MAPs composed of 13-23 kDa in comparison to 2.5% (w/w) ROP (p < 0.05), however no significant difference was observed between different drug loadings of 31 – 50 kDa PVA D-MAPs.

Conclusion: Briefly summarised here is the novel approach of delivering ROP transdermally via monolayer D-MAPs, with the baseplate acting as a reservoir and achieving ex vivo sustained release over 24 hours. Future work will seek to explore these systems in vivo.

References: [1] Dorsey ER, JAMA Neur, (2018) 75(1):9. [2] Ruan X et al., Front in Neurosci, (2021) 15. [3] Fasano A et al., Lancet Neur, (2015) 14(6)625-39.

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


Figure 1. (A-I) Optical light microscope images of monolayer ROP D-MAPs. Top, middle and bottom row show D-MAPs composed of 9 – 10 kDa, 13 – 23 kDa and 31 – 50 kDa PVA, respectively. Left, middle and right column show D-MAPs produced from aqueous blends containing 2.5%, 5.0% and 10.0% (w/w) ROP. (J) Drug loading in monolayer D-MAP needles and baseplate. Two-way ANOVA performed, p > 0.05 ns, p < 0.0001 ****. (Means + SD, n = 4).


Figure 2. (A-D) SEM images of monolayer ROP D-MAPs. Top and bottom row show D-MAPs composed of 13 – 23 kDa and 31 – 50 kDa PVA, respectively. Left and right column show D-MAPs produced from aqueous blends containing 2.5% and 5.0% (w/w) ROP. (E) Reduction in microneedle height post-compression against aluminium block at 32 N for 30 s. Two-way ANOVA performed, p < 0.05 *, p < 0.0001 ****. (Means + SD, n = 60). (F-H) D-MAP insertion efficiency into in vitro Parafilm® M skin model (Means ± SD, n = 3).


Figure 3. (A) Ex vivo permeation of ROP across dermatomed neonatal porcine skin over 24 hours (Means + SD, n = 5). (B) Ex vivo flux of ROP across dermatomed neonatal porcine skin. Two-way ANOVA, p > 0.05 ns, p < 0.001 ***. (Means + SD, n = 5). (C) Ex vivo deposition of ROP in dermatomed neonatal porcine skin. Two-way ANOVA, p > 0.05 ns, p < 0.05 *. (Means + SD, n = 5).