(W0930-11-63) Improving Adhesion Evaluation of Transdermal Rotigotine Patches: Utilizing Skin-Mimicking Substrates for Accurate Assessment

Purpose: The effectiveness of transdermal rotigotine patches for Parkinson's disease is influenced by various skin conditions such as micro-delaminations, wrinkles, and roughness, which can differ based on age and sex. These differences can lead to inadequate delivery of therapeutic doses into the bloodstream and may result in severe side effects if the patches start to peel off and come into contact with clothing or children. Additionally, the current evaluation of patch adhesion using conventional stainless steel (SS) substrates lacks similarity to the human skin. Therefore, this study aims to develop rotigotine matrix transdermal patches and assess their adhesion properties using innovative skin-mimicking substrates (acrylonitrile butadiene styrene (ABS)). These substrates having similar surface energy as skin will replicate specific skin conditions like micro-delamination, and wrinkles. The primary objective of the study was to develop a new adhesion testing method for transdermal patches to prevent them from detaching from the skin.

Methods: Preliminary probe tack and peel adhesion studies were performed on plain PSA-4302. Briefly, PSA-4302 was coated onto a 9744-release liner with a dry coat weight of 5 mg/cm². It was then dried at 90°C for 30 minutes and laminated with a 9735-backing membrane. The rotigotine matrix patch formulation was prepared by dissolving 8% (w/w) polyvinyl pyrrolidone-K30 (PVP-K30) and 4.5% (w/w) rotigotine in absolute ethanol on a magnetic stirrer. The remaining excipients (0.02% (w/w) ascorbyl palmitate, 0.25% (w/w) sodium metabisulfite, and 0.07% (w/w) DL-alpha-tocopherol) were then incorporated into the mixture before adding 87.11% (w/w) 4302 silicone pressure-sensitive adhesive (PSA). The formulation was stirred overnight at 50 rpm and then evenly coated onto a 9744-release liner with a targeted dry coat weight of 10 mg/cm2. It was then dried at 90°C for 30 minutes and laminated with a 9735 backing membrane to produce the final Rotigotine matrix patches. Custom-designed skin-mimetic substrates (made from ABS) were created using FDM printing technology (MethodX FDM 3D-printer) for conducting adhesion tests, including probe tack and peel adhesion tests, for transdermal patches (Figure 1 a&b). ABS probes were initially designed using computer-aided design (CAD) software Autodesk Fusion 360 to align with the dimensions of the TA-57R stainless steel probe (7mm diameter) currently employed for in vitro tack analysis for transdermal patches. Further, CAD files of ABS probes with micro-delaminations on the surface were designed by creating elliptical impressions (2mm minor axis, 4mm major axis, and 40µm depth based on the literature data) across the probe surface. Wrinkled probes were crafted by adding triangular protrusions of uniform height but varying widths, generating probes with diverse wrinkle patterns including arc length (length of the rounded surface of the wrinkle) of 0.098 mm, 0.446 mm and 0.810 mm for fine, moderate, and coarse wrinkles based on the literature data. Peel adhesion ABS plates were designed using Autodesk Fusion 360 software (Dimensions: 200mm length, 50mm width, and 1.2mm thick) and imported to the FDM 3D printer as an STL file. Finally, patches were analyzed in probe tack and (90⁰) peel adhesion test using SS and ABS substrates using a texture analyzer instrument.

Results: Our preliminary data of probe tack and peel adhesion test showed a significant (p < 0.01) decrease in peak and peel adhesive force, respectively, required to unbind the ABS substrate as compared to the SS substrate (Figure 1 c&d). This suggests that the SS substrate overestimates the adhesion properties of the patches and may not correlate with in vivo studies. The visual appearance of the Rotigotine formulation was found to be translucent, with no evidence of particle sedimentation. Microscopic images of the probes confirmed the micro-delamination and wrinkles features which were originally created in CAD design.  Tack analysis of rotigotine matrix patches revealed a notable decrease in peak adhesive force with micro-delaminated probes as compared to probes with no micro-delaminations suggesting that adhesion properties of the patches significantly decreased (p < 0.001) with an increase in micro-delaminations (Figure 2). Similar observations were observed in peel adhesion testing.  Probe tack testing using ABS probes with coarse, moderate, and fine wrinkles showed a significant decrease (p < 0.001) in adhesion properties of the rotigotine patches as compared to the probe with no wrinkles (Figure 3). This suggests that wrinkled skin affects the adhesion properties of the patches.

Conclusion: Our study demonstrates that the adhesion properties of rotigotine matrix patches are significantly influenced by the test substrate and surface features. SS substrate overestimates adhesion compared to ABS, potentially leading to inaccurate predictions of in vivo performance. Furthermore, the presence of micro-delaminations and wrinkles on the skin significantly decreases the adhesion property of the patches. These findings suggest that adhesion test methods for Transdermal patches should incorporate more realistic skin-like substrates and account for surface irregularities to accurately assess patch performance. This to be the first investigation to utilize novel skin-mimetic substrates incorporating micro-delaminations and wrinkles to assess the adhesion properties of transdermal patches.

References: 1. Cilurzo F, Gennari CG, Minghetti P. Adhesive properties: a critical issue in transdermal patch development. Expert opinion on drug delivery. 2012;9(1):33-45.
2. Wokovich AM, Prodduturi S, Doub WH, Hussain AS, Buhse LF. Transdermal drug delivery system (TDDS) adhesion as a critical safety, efficacy and quality attribute. European Journal of Pharmaceutics and Biopharmaceutics. 2006;64(1):1-8.
3. Minghetti P, Cilurzo F, Casiraghi A. Measuring adhesive performance in transdermal delivery systems. American Journal of Drug Delivery. 2004;2:193-206.
4. Elshoff J-P, Bauer L, Goldammer N, Oortgiesen M, Pesch H, Timmermann L. Randomized, double-blind, crossover study of the adhesiveness of two formulations of rotigotine transdermal patch in patients with Parkinson’s disease. Current Medical Research and Opinion. 2018;34(7):1293-1299.
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Acknowledgements: This work was supported by NSFCREST Center for Complex Materials Design for Multidimensional Additive Processing (CoManD), Grant/Award Number:1735968.


Figure 1: a) Probe tack test setup showing replacement of stainless steel with ABS probe used for adhesion testing; b) Peel adhesion setup showing replacement of stainless steel with ABS plate used for adhesion testing; c) Probe tack test of PSA 4302 using SS and ABS probe (n=5, p<0.001); d) Peel adhesion test of PSA 4302 using SS and ABS probe (n=5, p<0.05).


Figure 2: a) 3D CAD models of the micro-delaminated ABS probes with 2, 3, and 4 micro-delaminations b) Probe tack test of rotigotine patch using ABS probe with 0, 2, 3, and 4 micro-delaminations showing a significant decrease in peak adhesive force in case of micro-delaminated probes as compared to probe with no micro-delaminations. (n=5, p<0.0001).


Figure 3: a) 3D CAD model created and used to simulate three different wrinkle conditions (coarse, moderate, and fine) in the 3D-printed ABS probe; b) Probe tack test of rotigotine patch using ABS probe with fine, moderate, and coarse showing a significant decrease in peak adhesive force in case of wrinkled probes as compared to probe with no wrinkles. (n=5, p<0.0001).