Understanding fundamental formulation properties to demonstrate the feasibility of reformulating a salbutamol pMDI containing the low GWP propellant HFO1234ze(E)
Alex Slowey, Phil Cocks and Ben Myatt
Kindeva Drug Delivery, Charnwood Campus, Loughborough, UK
Summary
The most widely used salbutamol sulphate rescue medications are pMDIs containing propellant HFA134a, which has a global warming potential (GWP) of >1400. It is therefore economically and environmentally desirable to develop new pMDI products, including rescue medications, using low GWP propellant alternatives.
Kindeva Drug Delivery (Kindeva) has demonstrated that a low GWP salbutamol pMDI product could be developed that achieves comparable in-vitro pharmaceutical performance to Ventolin™ Evohaler™. The propellant chosen for reformulation was HFO1234ze(E) primarily due to its low GWP of <1.
Initial investigations demonstrated that it was not possible to just change the propellant from HFA134a to HFO1234ze(E) due to high levels of drug deposition on the internal surfaces of the container closure system (CCS), which resulted in a low and variable delivered dose relative to Ventolin™ Evohaler™.
After the inclusion of small quantities of ethanol in the alternative product formulation, delivered dose was significantly improved and comparable DCU performance to Ventolin was achieved. However, it was recognised that differences in the properties of the two propellants and the inclusion of ethanol, would significantly affect atomisation behaviour and plume evolution of the reformulated test product.
Based on a fundamental understanding of the thermophysical properties of both propellants, in particular, HFO1234ze(E)/ethanol binary mixtures, key actuator dimensions (exit orifice diameter and jet length) were selected to enable the APSD performance of the reformulated test product to match that of Ventolin. The test product was confirmed to be physically and chemically stable following 13 weeks storage at accelerated conditions (40ºC/75% relative humidity).
In conclusion, this study successfully demonstrated that a reformulated salbutamol sulphate pMDI product with low GWP propellant HFO1234ze(E), containing 5% w/w ethanol, resulted in comparable in-vitro pharmaceutical performance to Ventolin Evohaler.