Yong Pei Gie, Segorean Ana-Manuela, Cordeiro Ana Sara
Leicester Institute of Pharmaceutical, Health and Social Care Innovations, Leicester School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK.
Drug Deliv Transl Res. 2025 Jan 3. doi: 10.1007/s13346-024-01758-9.
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.
在过去几十年里，使用可溶解微针阵列（dMNA）进行皮内和透皮给药在该领域一直是一种不断发展的趋势。然而，缺乏具体的监管标准仍然阻碍着它们的临床开发和推向市场。众所周知，dMNA的组成会显著影响其性能，每一种新配方都可能给开发者、制造商和监管机构带来挑战。一种诸如质量源于设计（QbD）的系统方法，从产品开发过程的一开始就融入质量理念，能够设计和优化具有良好特性的载药dMNA配方。在这项工作中，我们定义了载利多卡因dMNA的质量目标产品概况（QTPP），并通过实验设计（DoE）的顺序方法优化了它们的组成。第一步（DoE_1）证实了所有配方成分（聚乙烯吡咯烷酮、聚乙烯醇和蔗糖）对阵列性能的影响，并为DoE_2预先优化了它们的设置。阵列表征聚焦于先前定义的关键质量属性（药物含量、溶解时间、机械强度、皮肤插入和物理属性）。在其最大合意度（85.15%）下，预计在DoE_2中获得的优化设计空间将生产出具有高机械强度（针高降低<10%）、皮肤插入率（针高>90%）和利多卡因盐酸盐负载量（约5毫克）、良好物理属性且在最多60分钟内溶解的Li-dMNA。所获得的灵活设计空间允许生产始终符合QTPP的dMNA，减少了在更为严格的GMP方法中常见的批次失败和最终产品测试。总体而言，将QbD原则应用于配方开发有望提高产品质量并促进dMNA进入临床。
