Understanding key parameters affecting needle-free skin penetration by a parenteral drug delivery system

This thesis seeks to resolve difficulties in the development of a parenteral needle-free drug delivery system. Analysis of the penetration performance of Glide Pharma’s Solid Dose Injector in two clinical trials on man has shown that skin, and likely its inherent variation, was the cause of incomplete deliveries. As indicated by the literature and issues with previous needle-free technologies, a more complete understanding of skin penetration is required before such systems are capable of ensuring delivery across a patient population. Exploratory skin experiments led to the justification, design and build of a novel skin penetration test rig capable of simulating the delivery of a solid dose implant. This test rig, the Penetrometer, required significant software development to both stabilise and validate its performance before use on the in vivo porcine model, an established non-clinical model for drug delivery through human skin. Two non-clinical studies have been performed using the Penetrometer to capture force displacement profiles, using a metal probe equivalent to an implant, for penetration events on multiple test sites on multiple models. Significant levels of variation in key parameters were shown to be present intra- and inter-test site, as well as intra- and inter-model. It is likely that this variation, as detected in the porcine model, was the cause of problematic system performance during human clinical trials. Penetration experiments have also been performed to establish the validity of using in vitro skin or silicone rubber as an alternative test bed to in vivo models. The key parameters measured are the peak force during penetration, the displacement of the skin at penetration and the work required to penetrate the skin, with variations observed of the order of 30%, 100% and 140%, respectively. The results indicate how challenging it will be to reliably administer drugs using needle-free injection. This information should be used to better specify the device design and implant formulation to ensure delivery success. Prior to this thesis there was no quantitative data available, either published or within the collaborator, describing the magnitude and variation of the key parameters affecting needle-free skin penetration. This thesis has used the porcine model, further work must determine the parameters for the breadth of a human patient population.