Alouache, Amina Imen; (2008) Novel Phospholipid-Based Pressurised Metered Dose Inhaler Formulations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A novel formulation which involves the use of phospholipids and ethanol has been shown to produce physically stable pressurised metered dose inhaler (pMDI) solutions. Two model drugs salbutamol base and budesonide were soluble in the investigated amounts of phosphatidylcholine (PC), ethanol and 1,1,1,2-tetrafluoroethane (HFA 134a). A one phase solution system was formed in the propellant. Extending delivery of therapeutically active agents in the optimum quantity, at a desired location within the respiratory tract is the principal aim of inhalation therapy. This was achieved with the right combination of PC and cosolvent. Both drugs were entrapped within spontaneously formed liposomes in vitro: the rate of efflux from the liposomes determined drug availability. The results obtained from the current investigation can serve as a model for an approach that can be used to optimise phospholipid-containing pMDI formulations, thus enabling formulation of a therapeutically effective phospholipid-containing solution pMDI. In a separate study, the stability of 1H,1H,2H,2H-perfluorooctan-1-ol (PFOH) and PEG-phospholipid suspension pMDIs containing budesonide, formoterol fumarate or terbutaline sulphate suspended in HFA 134a was investigated. The focus was on the suspension stabilising abilities of the fluorinated alcohol, PFOH. All formulations formed a stable suspension system. Settling properties of these formulations were investigated as a function of cosolvent PFOH concentration. The settling kinetics were examined by Turbiscan measurements and were also investigated with the naked eye at different temperatures. At the lowest PFOH concentration used (5% w/w), sedimentation and creaming were observed. Correspondingly, the higher PFOH concentration (15% w/w) resulted in increased 10th 50th and 90th percentiles (Dv10, Dv50, and Dv90) undersize values for HFA-based suspension pMDIs compared to 5% and 10% w/w PFOH, as determined using a Malvern Spraytec. PFOH cosolvent successfully stabilised PEG-phospholipid suspension pMDIs and led to the production of a finer suspension, reduction of particles adhesion to the can walls and inhibition of particle flocculation. The spray performance of PFOH and PEG-phospholipids suspension pMDIs was investigated. All formulations produced aerosol clouds in the respirable range. Suspensions containing PEG-phospholipid and PFOH produced a significantly larger (P≤0.05) stage 2 deposition in the twin impinger (TI) compared to drug alone in HFA 134a. All formulations produced aerosol clouds in the respirable range. Incomplete evaporation of PFOH may cause a reduction in fine particle fraction (FPF).

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