The effect of temperature-dependent drug viscosity on needle-free jet injection

Abstract

Highly viscous drugs cannot be delivered through a needle. Typically, this means that these drugs are formulated at lower concentrations, demanding higher delivery volumes, which often must be delivered intravenously. Jet injection may provide an important solution for viscous drug delivery. Jet injection is a needle-free drug delivery technique whereby a liquid drug is formed into a hair-thin (∼200 µm) high-speed (>100 m/s) jet that penetrates and delivers itself into tissue. While it may seem that it would be just as difficult to form a viscous drug into a high-speed jet as it is to force it down a needle, this is not the case. Recent work has revealed that ‘viscous-heating’ during jet injection can result in significant temperature increase, and resultant viscosity decrease, in a thin outer-layer of the jet; this phenomenon effectively results in the drug ‘self-lubricating’ as it passes through a jet injection orifice. Despite the potential for this finding to revolutionise the subcutaneous delivery of high-viscosity drugs, little further work in this area has since been reported on. In this work we develop finite element models of needle-free injection to investigate how viscous heating affects jet production, how heat exchange with the orifice material influences this process, and to what extent jet production is affected by the initial temperature of the fluid. We then conduct novel high-speed measurements of jet and orifice temperature changes due to viscous heating. We find that viscous heating is responsible for approximately doubling the speed of jets that can be produced with very viscous fluid (1 Pa·s) at room temperature. The thermal conductivity of the orifice can transfer heat away from the perimeter of the jet, and thus reduce the lubricating effect of viscous heating. We then show that by preheating 99 % glycerol (1 Pa·s) from 7 °C to 37 °C the jet speed can be increased 6-fold. We also demonstrate the successful delivery of a very viscous glycerol solution using preheated jet injection into ex vivo porcine tissue. Given that 99 % glycerol is 10- to 100-fold more viscous than current protein therapeutics, our findings demonstrate the potential for jet injection, with or without additional drug preheating, to deliver drug formulations, needle-free, that are much more viscous than those currently delivered through needles.