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.
Jones
Stuart A
SA
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>
Martin
Gary P
GP
Brown
Marc B
MB
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*
D005465:Fluorocarbon Polymers; D013535:Suspensions; D014753:Vinyl Compounds; D011142:Polyvinyl Alcohol; D003850:Deoxyribonuclease I; D011205:Povidone