Dermal acrylic and silicone patches  the effect of liquid additives

Transdermal adhesive patches may contain liquid excipients which help to disperse the active pharmaceutical ingredient (API) in the polymer matrix, but also modify internal matrix structure and the release rate and skin absorption of API. Moreover, application properties of the product can be influenced, such as adhesion, skin tolerance or occlusion. The aim of the study was to evaluate the effects of liquid components of dermal patches on their biopharmaceutical, morphological and application properties (Mikolaszek et al., 2022). Different types of polymers forming the matrix were tested, classified as silicones (SSA) or acrylates (DT) and liquid excipients were: silicone oil (SO), polyoxyethylene glycol (PEG), propylene glycol (GP), isopropyl myristate (MIP) and triethyl citrate (TEC), triacetin (TA).


Introduction
Transdermal adhesive patches may contain liquid excipients which help to disperse the active pharmaceutical ingredient (API) in the polymer matrix, but also modify internal matrix structure and the release rate and skin absorption of API. Moreover, application properties of the product can be influenced, such as adhesion, skin tolerance or occlusion. The aim of the study was to evaluate the effects of liquid components of dermal patches on their biopharmaceutical, morphological and application properties (Mikolaszek et al., 2022). Different types of polymers forming the matrix were tested, classified as silicones (SSA) or acrylates (DT) and liquid excipients were: silicone oil (SO), polyoxyethylene glycol (PEG), propylene glycol (GP), isopropyl myristate (MIP) and triethyl citrate (TEC), triacetin (TA).

Preparation of the patches
The silicone patches (SSA) were prepared by mixing two components with polymerization catalysts (LiveoTM Soft Skin Adhesive MG 7-9850 DuPont, Brussels, Belgium). Acrylic patches DT were prepared by casting and evaporation method using DuroTak® polymers: 87-4098 (DT8), 87-2852 (DT2) Henkel, Brussels, Belgium). Polyethylene (PE) membrane (Esselte, Warsaw, Poland) was used as a backing layer for DT and silicone elastic film for SSA. Placebo patches and containing indomethacin (IND, 5% w/w) were prepared. Liquid components (10% w/w, alone or with IND) were mixed with the polymers in a planetary mixer Thinky assuring good homogeneity of the mass.

Adhesion test in vitro
The test was performed according to the USP method "Peel adhesion test" using TA.XT Plus texture analyzer (Stable Micro Systems, Godalming, UK). The patch was peeled from the glass plate under 90° angle. Based on the acquired force-distance curve, the initial peel force, as well as mean peel force were evaluated.

Oxygen permeation
100 cm 2 patches were examined with coulometric method according to ASTM F1927-98.

In vivo performance
Placebo patches were applied to the arms of volunteers for 24 h. The experiment was performed according to the permission of the Bioethical Commission. The force of detachment was measured using a Texture analyzer and the removed patches were observed under microscope. Moreover, Transepidermal Water Loss (TEWL) was measured. The irritation test was performed by Eurofins Dermscan (Gdansk, Poland).

In vitro drug release
Pharmaceutical development and manufacturing Maced. pharm. bull., 69 (Suppl 1) 95 -96 (2023) The experiments were carried out for the patches with IND using a pharmacopoeial paddle over disk apparatus and phosphate buffer pH 7.4. Concentration of IND in the acceptor medium was assayed with HPLC/UV.
Before the experiment and after 48-96 h exposure to the dissolution medium the patches were analyzed: microscopically (SEM and Raman microscopy), by FTIR spectroscopy and wet and dry weight was measured to evaluate swelling and erosion.

Results and discussion
Microscopic analysis of the placebo formulations showed good compatibility in acrylate-based samples, except for compositions containing SO. The silicone-based patches showed very limited compatibility exhibiting no signs of phase separation only with MIP and SO. Besides, most of liquid excipients, except SO and GP, caused almost complete loss of adhesiveness in SSA patches. On the other hand, IND appeared to slightly improve the peel parameters previously reduced by liquids.
TEC, TA and PEG caused increase in the initial peel force of DT2 placebo compositions, but the effect of MIP and GP was opposite. In DT8-based formulations with PEG a reduction of peel adhesion was observed.
No irritation in vivo was observed after application of the patches without additives or with MIP. Additional tests were performed with SSA patches and significant irritation was observed in the case of SSA-PG patch, while SSA-SO was the best tolerated. Due to different backing membranes there was a large difference in oxygen permeability through SSA and DT patches (43688 and 603 cm³/m²/24h), however large inter-individual deviations in TEWL values were observed in vivo and no conclusion was obtained regarding the relationship between type of the patch and this parameter.
Irrespective of the liquid added IND was dissolved in DT type patches but remained suspended in SSA patches. The liquid additives promoted the drug release with the most pronounced effect of MIP both in SSA and DT. In Fig. 1 the effect of PEG, GP, MIP and TEC on the release of IND from the acrylic patch is presented. Modification of the SSA matrices with MIP or SO affected the drug diffusion even in more visible way than observed for DT.
In Table 1 changes in the mass of the acrylic patches immersed in the dissolution medium are presented. It can be seen that the promotion of in vitro drug release by MIP can be explained by neither better swelling nor by special erosion of the patch.
After the release test the patches were dried and were tested for adhesiveness. It was found that the adhesive properties were significantly reduced. The Raman maps showed much lower fraction of IND visible on the patch surface after the release test. Addition of the liquid excipients resulted in the increase of the dissolved fraction of IND within the polymeric matrix. FTIR spectra were compatible with the drug release test since the absence of IND bands was more evident in the patches containing liquid additives.

Conclusion
The results indicate that liquid excipients can be used to intentionally modify the properties of the patches. Higher compatibility with liquid excipients, as well as better adhesive properties were exhibited by the patches based on acrylates. Unfortunately, even if the liquid excipient is apparently compatible with the polymer and promotes drug release, the adhesive properties can still be significantly reduced.