The invention provides a method of producing a highly stable pharmaceutical aerosol suspension formulation suitable for use in a metered dose inhaler, the formulation comprising formoterol fumarate di-hydrate in suspension, a steroid in suspension, a propellant and ethanol, the method comprising the steps of drying the formoterol fumarate di-hydrate to a water content of 4.8 to 4.28%.

The following formulation was prepared (FF denotes formoterol fumarate di-hydrate; FP represents fluticasone propionate; and DSCG represents disodium cromoglycate).

Formoterol Fumarate Di-hydrate is dried at 20 to 40° C. and at a maximum of 100 mbar reduced air pressure.

DSCG is dried at 80° C. and a maximum 100 mbar to a water content of less than 4%.

The dried materials are deposited along with the fluticasone propionate in a filling vessel and the vessel is evacuated to less than 100 mbar air pressure.

Absolute ethanol (anhydrous) and pharmaceutical grade EPA 227 are pre-blended in another container. The blending container is then connected to the filling vessel and the blend is fed into the vessel. The resultant filled vessel is homogenised for 30 minutes at 300 rpm.

An aliquot from the filling vessel is pressure-filled into the aluminium can in a quantity sufficient for a one month medication. Filled aluminium cans formed in this fashion are weight-checked and allowed to rest for an equilibration period before testing.

(Measurement of Particle Size Distribution and Fine Particle Fraction)

The formulations employed are those formed according to Example 1 above.

The aerodynamic particle size distribution is determined using an Andersen Scale Impactor (ACI) fitted with the universal induction port (as set forth in the USP) at 28.3 L/minute.

20 shots (equivalent to 10 doses) of a formulation formed according to Example 1, are discharged into the ACI. Fractions of the dose are deposited at different stages of the ACI, in accordance with the particle size of the fraction. Each fraction is washed from the stage and analysed using HPLC.

HPLC analysis showed that the fine particle fraction of the dose delivered to the ACI apparatus is greater than 50% both for the formoterol fumarate di-hydrate and the fluticasone propionate.

Formulations of Example 1 are tested for Delivered dose Uniformity according to the following method.

Canisters containing formulations are stored at 40° C. and 75% rh for 6 months.

After the appropriate storage period, MDI devices containing formulations of Example 1 are connected with the Funnel Apparatus described herein above.

3 doses (6 shots) are discharged into the apparatus at the beginning of the life of the container; 4 doses (8 shots) are discharged in the middle life of the container; and 3 doses (6 shots) are discharged at the end of the container life. The intermediate doses/shots are discharged to waste. The delivered dose is collected by washing the glass scinter, and the dose is analysed by HPLC.

Analysis shows that after the storage period, variance of the delivered dose does not exceed +/−25% of the mean delivered dose, +/−20% of the mean delivered dose.

Formulations of Example 1 are tested for Delivered dose Uniformity according to the following method.

Canisters containing formulations are stored at 40° C. and 75% rh for 1, 3 and 6 months.

After the appropriate storage period, MM devices containing formulations of Example are connected with the Funnel Apparatus described herein above.

For each container, 1 dose (two shots) are discharged into the Funnel Apparatus. This is repeated for 10 containers. After washing the Funnel Apparatus and analysing using HPLC, results show that no delivered dose varies by more than +/−25% of the mean delivered dose, and more particularly +/−20% of the mean delivered dose.