(T1530-01-01) Application of Solid-State NMR and DSC in Evaluating the Effect of Intrinsic and Extrinsic Factors and Surface Energy of the 3D Printed Probe on Adhesion Properties of Transdermal Patches

Purpose: The exposure of transdermal formulation to various extrinsic and intrinsic factors causes the imbalance in these forces and a lack of understanding of skin-adhesive interfacial interactions has led to failures of many patches including Rotigotine (Neupro). Surprisingly, no detailed study has been conducted to understand the physicochemical changes occurring in the patch components as a function of time, storage, and the impact of extrinsic factors. Furthermore, the current in-vitro method of evaluation is based on stainless steel probe which have a higher surface energy ( >700 dyne/cm) than skin and hence may not be very predictive of adhesion properties of the transdermal products. The objective of the present study was to evaluate the effect of intrinsic factors such as excipients specifically used in Rotigotine (Neupro) transdermal patches, and extrinsic factors including temperature and humidity on the adhesion properties. Further another objective of this study was to evaluate the adhesion properties of these patches using skin mimetic novel 3D printed probes.

Methods: Transdermal formulations were developed by mixing silicone adhesives (amine compatible and non-amine compatible) including Liveo BIO-PSA 4501 and Liveo BIO-PSA 4302 with polyvinylpyrrolidone K-30 (PVP K-30), ascorbyl palmitate, DL-alpha-tocopherol and sodium metabisulfite and coated on a backing membrane (3M Scotchpak™ 9735 Backing Polyester Film Laminate) with 10 mg/cm², dry coat weight (Fig 1). Briefly, PVP K-30 was first dissolved in ethanol. All other excipients were then added in PVP k-30 solution and stirred for 5-10 min. Finally, BIO-PSA 4501 was added and kept for stirring overnight. PVP-K30 (1, 4, and 8 % w/w) in BIO-PSA 4501 were prepared by directly adding PVP K-30 into it. Further, formulations were kept for stirring overnight. Formulations were then coated backing membrane at 10 mg/cm². Further all the laminates were tested for their adhesive properties in probe tack test using texture analyzer (TA-XT plus). All the adhesives were tested using TA-57R stainless still (SS) probe. Additionally, probes were fabricated using polypropylene (PP) filaments (having similar surface energy as human skin) using MakerBot Method X FDM 3D printer. All the coated adhesives were then evaluated for their adhesive properties using these new probes.

Results: The tack test results of Formulations D, E and F using SS probe showed that peak adhesive force was significantly (p < 0.01) reduced when 8% (w/w) PVP K30 was combined with PSA 4501 as compared to 1 and 4% (w/w) PVP-K30 combination with PSA 4501. PP probe also showed significant (p < 0.0001) lower adhesive force as compared to the SS probe in the probe tack test. This indicates that the concentration of excipients in transdermal formulation significantly affects the adhesion properties of the PSAs and TDS (Fig. 1). Differential scanning calorimetry (DSC) results showed sharp endothermic peak at about 116⁰ C suggesting that ascorbyl palmitate (0.02% w/w) and PVP K30 (8% w/w) did not solubilize in the formulation. Moreover, our DSC showed that all the excipients were solubilized in formulations containing 1,2 and 4% PVP K-30 (formulations A, B, C and D in Fig 1) (Fig. 2). Solid state NMR showed that C13 chemical shift values (aliphatic carbon chain peaks) were disappeared in region of 0 to 50 ppm in formulation containing combination of silicone PSAs 4501/4302, ascorbyl palmitate, DL alpha tocopherol, PVP-K30 and sodium metabisulfite transdermal formulation as compared to individual excipients. Additionally, shift in ketone functional group of PVP K30 from 175 ppm to 160 ppm was observed in the spectrum which suggests that molecular interaction occurred in the combination transdermal formulation (Fig. 2). Our accelerated stability studies conducted at 40 ± 2⁰ C temperature and 75 ± 5 % relative humidity (as per the ICH guidelines) showed that Formulation A with 1% PVP K30 didn’t show significant difference the peak adhesive force on day 0 vs week 2 when analyzed using SS and PP probes. However, Formulation B (PSA 4302) with 8% PVP K30 showed significant difference the peak adhesive force on day 0 vs week 2 when analyzed using SS and PP probes suggesting that concentration of excipients in the formulation significantly affects the adhesion properties of the transdermal patches (formulations A and D in Fig 1) (Fig 3).

Conclusion: In conclusion, addition of polymer (PVP K-30) significantly decreased the adhesion properties of silicone PSAs and altered the thermal properties of silicone PSAs. This is the first study to show the effect of interaction between adhesive and combination of adhesives with excipients on the adhesion properties of PSAs using numerous techniques including solid state NMR, DSC and novel 3D printed probe. This is the first report of evaluating adhesion properties of transdermal patches using skin mimetic substrate. Our novel 3D printed probes can be used for the in vitro in vivo correlation of transdermal products.

Fig 1 a) Tack testing of PSA 4501 with PVP K-30 (1, 4 and 8% w/w) analyzed using SS probe.
b) Tack testing of PSA 4501 with PVP K-30 (1, 4 and 8% w/w) analyzed using PP probe.
c) Transdermal formulations A, B, C, D, E and F

Fig 2: a) DSC of Transdermal formulations A, B C and D b) DSC of individual excipients c) Solid state NMR spectra of individual excipients and Formulation A: 7 in the spectra represents PSA 4501 combination and 8 represents PSA 4302 combination formulation

Fig 3: a) Formulation D analyzed using SS probe b) Formulation A analyzed using PP probe c) Formulation A analyzed using SS probe