Investigations of Tiotropium pMDI Suspension Formulations

Cuong Hoa Tran, Chen Zheng, Simon Warren, Glyn Taylor

The anticholinergic, tiotropium (Tio) is a long-acting muscarinic agent (LAMA) that has gained acceptance as the first line of therapy for many patients with chronic obstructive pulmonary disease (COPD). In this study, we evaluated the key aerosol parameters of some pressurised metered dose inhaler (pMDI) suspension formulations of Tio. The pMDI formulations contained a particulate excipient intended to aid manufacturing processes and to stabilise the Tio suspensions. The objective was to investigate the effects of excipient particle size, Tio:excipient blend ratios, and excipient physicochemical properties on the performance of suspension systems formulated in HFA 134a and HFA 227 propellants.
Formulations were prepared using commercially available inhalation grades of lactose (with different particle size ranges), (Lac, Respitose SV003 and SV010) combined in different ratios (i.e. 1:5, 1:10 and 1:25 w/w, Tio:excipient) and with two propellants (HFA 134a and 227). Initial aerosol characterisation tests indicated that the 1:5 (Tio:Lac) ratio was the most effective compared to higher excipient ratios and that the larger particulate Lac material (SV010) in HFA 227 improved performance further. Additional refinement of dose content uniformity and aerosol performance was achieved by substituting the excipient L-Leucine (Leu) in place of Lac. Leu (90 –
106 μm sieved fraction) in HFA 134a formulations produced consistent emitted dose data through canister life.  The improved emitted dose performance may be a consequence of more closely matching the density of the excipient and the propellant.

In vitro aerosol properties of some novel suspension formulations showed similar characteristics to those of the Spiriva ® HandiHaler.

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