title: Stabilisation of deoxyribonuclease in hydrofluoroalkanes using miscible vinyl polymers.
abstract: 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.
authors.affiliation: Department of Pharmacy, Pharmaceutical Sciences Research Division, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NN, UK. stuart.jones@kcl.ac.uk <stuart.jones@kcl.ac.uk>
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Jones
authors.forename: Gary P
authors.initials: GP
authors.lastname: Martin
authors.forename: Marc B
authors.initials: MB
authors.lastname: Brown
mesh_terms: D000465:Algorithms; D002138:Calibration; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D003850:Deoxyribonuclease I / Q000008:administration & dosage / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D004356:Drug Storage; D004563:Electrochemistry; D005465:Fluorocarbon Polymers / Q000737:chemistry*; D005612:Freeze Drying; D049329:Nanostructures; D010316:Particle Size; D011142:Polyvinyl Alcohol / Q000737:chemistry; D011205:Povidone / Q000737:chemistry; D012995:Solubility; D013535:Suspensions; D014753:Vinyl Compounds / Q000737:chemistry*
chemical_list: D005465:Fluorocarbon Polymers; D013535:Suspensions; D014753:Vinyl Compounds; D011142:Polyvinyl Alcohol; D003850:Deoxyribonuclease I; D011205:Povidone