Stabilisation of deoxyribonuclease in hydrofluoroalkanes using miscible vinyl polymers

A mix of biocompatible macromolecules (poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP)) has been shown previously to enhance the physical stability of non-aqueous pharmaceutical suspensions. The aim of this work was to assess the feasibility of employing such a combination to facilitate the formulation of deoxyribonuclease I (DNase I) in a metered dose inhaler (MDI) using hydrofluoroalkane (HFA) propellants. DNase I was combined with the selected excipients and formed into an inhalable microparticle by spray-drying. When spray-dried alone DNase I lost almost 40% of its original biological activity, but stabilising DNase I with trehalose and PVA (DTPVA) retained 85% biological activity and trehalose, PVA and PVP (DTPVAPVP) retained 100%. Suspending the DTPVAPVP microparticles within a HFA pMDI for 24 weeks led to no further reduction in the biological activity of DNase I and the formulation delivered almost 60% of the dose expelled to the second stage of a twin-stage impinger. The solubility of PVP in HFA propellants suggests that the enhanced physical stability observed with PVA and PVP may partially be as a result of steric stabilisation. However, the large zeta potential associated with the suspensions suggested that charge stabilisation may also influence the pMDI physical stability.