Novel Simvastatin Pulmonary Inhalation Formulation and Characterisation

Alaa S. Tulbah, Hui Xin Ong, Paolo Colombo, Paul M. Young, Daniela Traini

Background: Simvastatin (SV) is an inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, used for lowering cholesterol levels in myocardial infarction prevention. Recently, there has been increasing evidence that SV possess anti-inflammatory properties and that these could be useful in decreasing the inflammation processes in chronic obstructive pulmonary disease (COPD). However, SV is chemically unstable in the presence of water/moisture. Hence, the purpose of this study was to develop a stable pressurized metered dose inhaler (pMDI) solution formulation of SV and to investigate its physio-chemical properties and aerosol performance.
Methods: Simvastatin solubility was performed visually using different concentrations of ethanol and HFA134a propellant to determine the most suitable co-solvent concentration for the formulation of a solution based SV pMDI. The short-term stability of the formulation was also evaluated at 4, 25, and 37 °C over a 2-month period and in vitro aerosol performance was characterised using an Andersen Cascade Impactor.
Results: SV was miscible in formulations containing 4 to 12 % w/w of ethanol in HFA. The formulation containing 6 % ethanol was chosen for stability and aerosol performance, since this concentration ensured SV solubility in HFA and did not lower the propellant vapour pressure to such a great extent that will affect aerosol performance. This formulation was found to be stable at all three temperatures up to two months to-date, and produced a fine particle fraction of 31 ± 2.79 %.
Conclusion: This study presents the formulation of a stable solution based pMDI formulation of inhaled simvastatin, which has the potential to open up new exciting anti-inflammatory therapeutic opportunities for the treatment of COPD.

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