(W0930-02-10) Evaluation of the Effect of the Backing Layer Formulation on Dissolvable Microneedle Properties

Purpose: Dissolvable microneedle (DMN) patches, also termed microarray patches (MAPs), deliver the active pharmaceutical ingredient (API) of interest by incorporating it in a formulation that dissolves when the microneedle is inserted into the body. A key challenge in microneedle-mediated drug and vaccine delivery is to maximise the dose of API delivered into the body and minimise the amount remaining in the patch and on the skin surface. Three critical factors that influence this requirement are location of API within the microneedle, patch mechanical robustness and time of application. Here, our primary objective was to develop a mechanically robust microneedle where the API is located at the tip of the microneedle ("two-layered DMN”), based on the hypothesis that a greater proportion of API is delivered into the skin when it is in a two-layered microneedle compared to when it is incorporated throughout the microneedle (“single-layered DMN”).

Methods: Fluorescent nanoparticles, “fluospheres”, were used as a model nanoparticle-based API. Three fluosphere concentrations; 0.5% (v/v), 1.0% (v/v) or 1.5% (v/v), were incorporated into a trehalose and PVA formulation to make DMN. Single- and two-layer patches were made by micromoulding in PDMS moulds. PVP/glycerol or PVPVA were assessed as backing layers. Ethanol was used as the solvent for the backing layers to prevent dissolution of the water-based fluosphere tip into the backing layer. Microneedles were 500-µm in height. Each 1 cm² patch had 25 DMN. Patch quality was determined using a scoring system. Mechanical robustness was quantified using a texture analyser. Full-thickness ex vivo pig skin was used to assess API skin delivery. DMN dissolution kinetics were determined using Franz cells. One tape strip of the skin was used to determine the amount of API on the skin. API-free formulation was added to tape strips or DMN to recover API, which was quantified by fluorescence spectroscopy. Stability studies were conducted at 21 °C, 80% relative humidity for 3 months.

Results: The upper concentration of fluospheres that could be incorporated into single-layered DMN without compromising patch quality and mechanical robustness was 0.5% (v/v). However, an API concentration of 1.0% (v/v) was chosen for subsequent studies due to the limit of sensitivity in the fluorescence assay. Single-layer patches that did not contain fluospheres withstood a force of 22N, whereas patches with 0.5% (v/v) and 1.0% (v/v) DMN withstood forces of 19N and 12N, respectively, before failure. The backing layer was next developed. The composition of the backing layer significantly impacted the mechanical robustness of two-layered DMN. Patches with a PVP-based backing layer withstood a force of 2N before breaking. However, patches with a PVPVA backing layer withstood forces of 20N. The mechanical properties of PVPVA-based backing layer did not change when stored at 21 °C for 3 months. When examined on a Franz cell, the single-layer patches and tip layers of two-layer patches dissolved within 2 minutes of skin insertion. The backing layer dissolved in 10 minutes. The high limit of sensitivity and interference by PVA confounded the accuracy of the fluorescence assay. As a result, substantial inter- and intra-batch variability was observed when quantifying the amount of API remaining on the patch and present on the skin during skin insertion studies. Although lower amounts of API remained on two-layer patches compared to single-layer patches after skin insertion, this was not significantly different (Table 1).

Conclusion: In this study, we designed a dissolvable microneedle array patch consisting of a novel formulation in the backing layer. Our approach ensures that the API does not dissolve from the microneedle tip into the backing layer when the backing layer is added to the patch. Our data demonstrates stable mechanical robustness of this patch and fast dissolution of the active layer in skin. The influence of the backing layer on mechanical robustness has not previously been demonstrated. Current data, using a fluorescent nanosphere as a model API, demonstrates similar delivery efficiency, of just under 50%, to ex vivo skin by single-layer and two-layer patch designs. Future studies will examine the delivery efficiency of this new two-layer microneedle design using a clinically relevant API and an assay with low limits of sensitivity. This study advances the field by identifying a novel, mechanically robust and stable two-layer microneedle design for API delivery into skin and by highlighting assay-related issues in determining skin delivery efficiency.

Acknowledgements: Funding is acknowledged from SSPC, the Science Foundation Ireland Research Centre for Pharmaceuticals. We thank Dr. Edgar Garcia Manzanilla at Teagasc for providing pig samples and Dr. Conor O’Mahony, Tyndall National Institute for microneedle moulds.

Figure 1: Image of a two-layered DMN. The tip layer consists of a PVA/trehalose-based formulation containing Congo Red for visualisation. Backing layer consists of a PVPVA-based formulation.

Table 1: Delivery studies assessing the delivery of fluospheres loaded into single-layer PVA/trehalose-based DMN compared to PVP- or PVPVA-based two-layer DMN into whole thickness pig skin. Results are pooled across 4 studies.