Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product.

Microneedle Array Patches (MAPs) are an emerging dosage form that creates transient micron-sized disruptions in the outermost physical skin barrier, the stratum corneum, to facilitate delivery of active pharmaceutical ingredients to the underlying tissue. Numerous MAP products are proposed and there is significant clinical potential in priority areas such as vaccination. However, since their inception scientists have hypothesized about the risk of a clinically significant MAP-induced infection. Safety data from two major Phase 3 clinical trials involving hundreds of participants, who in total received tens of thousands of MAP applications, does not identify any clinically significant infections. However, the incumbent data set is not extensive enough to make definitive generalizable conclusions. A comprehensive assessment of the infection risk is therefore advised for MAP products, and this should be informed by clinical and pre-clinical data, theoretical analysis and informed opinions. In this article, a group of key stakeholders identify some of the key product- and patient-specific factors that may contribute to the risk of infection from a MAP product and provide expert opinions in the context of guidance from regulatory authorities. Considerations that are particularly pertinent to the MAP dosage form include the specifications of the finished product (e.g. microbial specification), it's design features, the setting for administration, the skill of the administrator, the anatomical application site, the target population and the clinical context. These factors, and others discussed in this article, provide a platform for the development of MAP risk assessments and a stimulus for early and open dialogue between developers, regulatory authorities and other key stakeholders, to expedite and promote development of safe and effective MAP products.

Coated microneedles for transdermal delivery of a potent pharmaceutical peptide.

Minimally invasive delivery of peptide and protein molecules represents a significant opportunity for product differentiation and value creation versus standard injectable routes of administration. One such technology utilizes microneedle (MN) patches and it has made considerable clinical advances in systemic delivery of potent macromolecules and vaccines. A sub-class of this technology has focused on preparation of solid dense MN arrays followed by precision formulation coating on the tips of the MN. The objective of this study was to develop a drug product using the MN technology that has similar bioperformance when compared to subcutaneous route of delivery and can provide improved stability under storage. Therapeutic peptide (Peptide A, Merck & Co., Inc., Kenilworth, NJ, USA) is being developed as a subcutaneous injection for chronic dosing with a submilligram estimated therapeutic dose. Peptide A has chemical and physical stability challenges in solution and this led to exploration of a viable drug product which could provide therapeutic dosages while overcoming the stability issues seen with the compound. This work focused on developing a coated solid microstructure transdermal system (sMTS) for Peptide A followed by detailed in vitro and preclinical evaluation for two different coating formulations. Based on initial assessment, ~250 µg of Peptide A could be coated with precision on a 1.27cm2 patch which contained 316 MN's. The delivery from these systems was achieved with absolute bioavailability being similar to the subcutaneous delivery (88% and 74% for coated sMTS 1 & 2 and 75% for subcutaneous delivery). Stability of Peptide A was also found to be significantly improved when coated on the sMTS system with minimal degradation recorded at room temperature storage as compared to the subcutaneous liquid formulation. Additionally, skin irritation (on pig skin) was also measured in this study and it was found to be minimal and self-resolving. This evaluation provided a viable option for developing a drug product with improved stability and successful delivery of the investigated molecule. Graphical abstractSchematic showing uncoated sMTS, resulting product with coated peptide, successful skin penetration with high delivery efficiency and bioavailability.