Consequences of not-shaking and shake-fire delays on the emitted dose of some commercial solution and suspension pressurized metered dose inhalers

Figures & data

Figure 1. Gravitational stability of pMDI formulated as solutions or suspensions: solution-based formulations contain the drug solubilized in a hydrofluoroalkane (HFA) propellant with or without co-solvents. HFA suspensions contain suspended drug particles subjected to creaming or sedimentation according to the difference between the density of the drug and the density of the system.

Table 1. Characteristics and therapeutic indications in European Union of fixed-dose combination (FDC_pMDIs), high dose strength fixed-dose combination (HD_FDC_pMDIs) and monocomponent pMDIs drug products.

pMDI commercial name	Drug and Label Claim	Drug density (g/ml)	Number of doses	Propellant	Propellant density (g/ml)	Drug/propellant density difference (g/ml)	Formulation type and excipients included	Authorized EU therapeutic indication *
FDC_pMDIs
Foster®	BDP, 100 μg	1.26	120	HFA134a	1.22	solution, no difference	Solution and excipients (ethanol anhydrous, hydrochloric acid)	Maintenance in asthma and COPD; Maintenance and reliever in asthma
	FF, 6 μg	1.24
Symbicort®	BUD, 160 μg	1.31	120	HFA227	1.41	−0.10 –0.17	Suspension and excipients (povidone, macogrol 1000)	Maintenance in COPD
	FF, 4.5 μg	1.24
Seretide®	FP, 125 μg	1.33	120	HFA134a	1.22	0.11 0.00	Suspension	Maintenance in asthma
	SX, 25 μg	1.22
Serzyl®	FP, 125 μg	1.33	120	HFA134a	1.22	0.11 0.00	Suspension and excipients (ethanol anhydrous)	Maintenance in asthma
	SX, 25 μg	1.22
Trimbow®	BDP, 100 μg	1.26	120	HFA134a	1.22	solution, no difference	Solution and excipients (ethanol anhydrous, hydrochloride acid)	Maintenance in COPD
	GLY, 12.5 μg	1.32
	FF, 6 μg	1.24
Flutiform®	FP, 125 μg	1.33	120	HFA227	1.41	−0.08 –0.17	Suspension and excipients (ethanol anhydrous, sodium cromoglycate)	Maintenance in asthma
	FF, 5 μg	1.24
HD_FDC_pMDIs
Foster ®	BDP, 200 μg	1.26	120	HFA134a	1.22	solution, no difference	Solution and excipients (ethanol anhydrous, hydrochloric acid)	Maintenance in asthma
	FF, 6 μg	1.24
Seretide®	FP, 250 μg	1.33	120	HFA134a	1.22	0.11 0.00	Suspension	Maintenance in asthma
	SX, 25 μg	1.22
Serzyl®	FP, 250 μg	1.33	120	HFA134a	1.22	0.11 0.00	Ssuspension and excipients (ethanol anhydrous)	Maintenance in asthma
	SX, 25 μg	1.22
Flutiform®	FP, 250 μg	1.33	120	HFA227	1.41	−0.08 –0.17	Suspension and excipients (ethanol anhydrous, sodium cromoglycate)	Maintenance in asthma
	FF, 10 μg	1.24
Monocomponent pMDIs
Clenil®	BDP, 100 μg	1.26	200	HFA134a	1.22	solution, no difference	Solution and excipients (ethanol anhydrous, glycerol)	Maintenance in asthma
Aircort®	BUD, 200 μg	1.31	200	HFA134a	1.22	0.09	Suspension and excipients (oleic acid, ethanol anhydrous)	Maintenance in asthma
Ventolin®	SS, 100 μg	1.30	200	HFA134a	1.22	0.08	Suspension	Reliever in asthma
Flixotide®	FP, 50 μg	1.33	120	HFA134a	1.22	0.11	Suspension	Maintenance in asthma

BDP: Beclomethasone dipropionate; BUD: Budesonide; FF: Formoterol fumarate; FP: Fluticasone propionate; GLY: Glycopirronium; HFA134a: hydrofluoroalkane 134a; HFA227: hydrofluoroalkane 227; SS: Salbutamol sulfate; SX: Salmeterol xinafoate.

*There may be changes in the indications from Country to Country.

Figure 2. Emitted dose (µg) without shaking the canister at different level of canister content for fixed-dose combination (FDC) pMDIs: Foster (BDP-FF) 100 + 6 µg, Symbicort (BUD-FF) 160 + 4.5 µg, Seretide (FP-SX) 125 + 25 µg, Trimbow (BDP-FF-GLY) 100 + 6 + 10 µg, Serzyl (FP-SX) 125 + 25 µg, Flutiform (FP-FF) 125 + 5 µg (n = 9; mean ± st.dev).

Figure 3. Emitted dose (µg) without shaking the canister at different level of canister content for high dose strength fixed-dose combination (HD_FDC) pMDIs: Foster (BDP-FF) 200 + 6 µg, Seretide (FP-SX) 250 + 25 µg, Serzyl (FP-SX) 250 + 25 µg, Flutiform (FP-FF) 250 + 10 µg (n = 9; mean ± st.dev).

Figure 4. Emitted dose (µg) without shaking the canister at different level of canister content for monocomponent pMDIs: Clenil (100 µg BDP), Aircort (200 µg BUD), Ventolin (100 µg SS) and Flixotide (50 µg FP) (n = 9; mean ± st.dev).

Figure 5. Emitted dose (µg) applying increasing time delays after shaking for fixed-dose combination (FDC) pMDIs: Foster (BDP-FF) 100 + 6 µg, Symbicort (BUD-FF) 160 + 4.5 µg, Seretide (FP-SX) 125 + 25 µg, Trimbow (BDP-FF-GLY) 100 + 6 + 10 µg, Serzyl (FP-SX) 125 + 25 µg, Flutiform (FP-FF) 125 + 5 µg (n = 9; mean ± st.dev;*p < 0.05;**p < 0.01;***p < 0.001).

Figure 6. Emitted dose (µg) applying increasing time delays after shaking for high dose strength fixed-dose combination (HD_FDC) pMDIs: Foster (BDP-FF) 200 + 6 µg, Seretide (FP-SX) 250 + 25 µg, Serzyl (FP-SX) 250 + 25 µg, Flutiform (FP-FF) 250 + 10 µg (n = 9; mean ± st.dev;p < 0.05;**p < 0.01; ***p < 0.001).

Figure 7. Emitted dose (µg) applying increasing time delays after shaking for monocomponent pMDIs: Clenil (100 µg BDP), Aircort (200 µg BUD), Ventolin (100 µg SS) and Flixotide (50 µg FP) (n = 9; mean ± st.dev; p < 0.05; **p < 0.01; ***p < 0.001).

Figure 8. Overall summary data obtained in this study: emitted dose value of each API, released by a fixed-dose, high dose strenght fixed-dose combinations or monocomponent formulation, expressed as percentage in relation to the label claim. The data were collected during canister life cycle without shaking. The number of plotted values for each product were #135, #90 or #45 for triple-, double- or mono-component MDI product, respectively.

Figure 9. Overall summary data obtained in this study: emitted dose value of each API, released by a fixed-dose, high dose strenght fixed-dose combination or monocomponent formulation, expressed as percentage in relation to the label claim. The data were collected applying time delay after shaking. The number of plotted values for each product were #117, #72, or #36 for triple-, double- or mono-component MDI product, respectively.