Quality-by-design principles applied to the development and optimisation of lidocaine-loaded dissolving microneedle arrays - a proof-of-concept.

The use of dissolving microneedle arrays (dMNA) for intradermal and transdermal drug delivery has been a growing trend in the field for the past decades. However, a lack of specific regulatory standards still hinders their clinical development and translation to market. It is also well-known that dMNA composition significantly impacts their performance, with each new formulation potentially presenting a challenge for developers, manufacturers and regulatory agencies. A systematic approach such as quality-by-design (QbD), which embeds quality from the very beginning of the product development process, allows the design and optimisation of a drug-loaded dMNA formulation with promising features. In this work, we defined the Quality Target Product Profile (QTPP) for lidocaine-loaded dMNA and optimised their composition through a sequential design of experiments (DoE) approach. The first step (DoE_1) confirmed the influence of all formulation components (PVP, PVA and sucrose) in the properties of the arrays and pre-optimised their settings for DoE_2. The array characterisation focused on previously defined critical quality attributes (drug content, dissolution time, mechanical strength, skin insertion and physical attributes). At its maximum desirability (85.15%), the optimised design space obtained in DoE_2 is predicted to produce Li-dMNA with high mechanical strength (< 10% needle height reduction), skin insertion (> 90% needle height) and Li-HCl loading (~ 5 mg), good physical attributes and dissolving in a maximum of 60 min. The flexible design space obtained allows for the production of dMNA that consistently meet the QTPP, reducing batch failure and end-product testing, which are common in the more rigid GMP approach. Overall, applying QbD principles to formulation development shows promise to increase product quality and facilitate translation of dMNA into the clinic.