In Vitro Assessment of Dose Delivery Performance of Dry Powders for Inhalation

Figures & data

TABLE 1 Dry powder inhaler and formulations used in the present study

DPI (Resistance) [cm H2O^1/2 LPM^−1]	Product name (treatment)	Drug package	Label claim [μg]	Formulation platform	Composition drug/excipients	Tapped density [g·cm^−3]
Device A Simoon™ (0.20)	Placebo	Unit Dose Blister	N/A	Emulsion Spray-Dry	DSPC, CaCl2	<0.2
Device B HandiHaler® (0.16)	Spiriva® (COPD)	Unit Dose Capsule	18^a	Blend	TB/Lactose	>0.5
Device C Twisthaler® (0.14)	Asmanex® (Asthma)	Multi-Dose Reservoir	220^a	Spheronized	MF/Lactose	>0.5

^aLabel claim of marketed product. TB = Tiotropium Bromide. MF = Mometasone Furoate.

FIG. 1. Emitted powder mass measurement set-up with a customized emitted dose powder collector for Device A and using DUSA tube for Devices B and C.

FIG. 2. Cross-sectional view of the idealized mouth-throat model with an inhaler and filter housing attached upstream and downstream, respectively.

TABLE 2 Stage cut-off diameters for NGI stage 3 at test conditions

Inhaler	Flow resistance [cm·H2O^1/2·LPM^−1]	Pressure drop [kPa]	Flow-rate [L·min^−1]	NGI stage 3^a,b ECD [μm]	d^2·Q [μm^2·L·min^−1]
Device A	0.20	1	16	5.39	465
		2	22	4.62	470
		4	32	3.87	484
		6	40	3.47	482
Device B	0.16	1	20	N/A^c	N/A^c
		2	28	4.13	478
		4	39	3.50	478
		6	47	3.18	475
Device C	0.14	1	23	N/A^c	N/A^c
		2	33	3.80	477
		4	47	3.19	478
		6	57	2.89	476

^aBased on archival calibration for NGI at 15 L·min⁻¹ (Marple et al. 2004).

^bStage cut size-flow calculation for NGI stage 3 covering flow-rate from 30–100 L·min⁻¹(Marple et al. 2003), , where d₅₀ represents new stage cut size-flow, Q, and A is stage cut size at 60 L·min⁻¹.

^cNot reported here as NGI data were not generated at 1 kPa for Devices B and C due to steep drop in aerosol dose delivery.

TABLE 3 Bulk powder properties of spray-dried PulmoSphere™ formulations

Powder Batch No.	Drug loading [%]	Tapped density [g·cm^−3]	Primary particle size, Sympatec X50 [μm]
A	0	0.041	2.49
B	0	0.042	4.20
C	0	0.041	3.50
D	0	0.065	2.00
E	0	0.069	3.16
F	0	0.122	1.68
G*	2	0.036	3.05
H*	6	0.045	2.74

*PulmoSpheres™ formulations of Indacaterol (Novartis AG, Switzerland).

FIG. 3. Three particle morphologies analyzed by scanning electron microscopy: (a) spray-dried PulmoSphere^™ (Batch A), (b) traditional lactose-blend with tiotropium bromide, and (c) spheronized mometasone furoate.

FIG. 4. Effect of tapped density and primary particle size on in vitro aerosol performance: (a) tapped density as function of emitted powder mass (N = 10) and (b) primary particle size, X50, as function of fine particle mass (N = 3) accumulated mass from stage 3 to MOC.

TABLE 4 NGI analysis data and mean

			1 kPa		2 kPa		4 kPa		6 kPa
Inhaler	Formulation platform	Mouthpiece air inlet dimension	MMAD [μm]	GSD^c	MMAD [μm]	GSD^c	MMAD [μm]	GSD^c	MMAD [μm]	GSD^c
Device A	Emulsion spray-dry^a	0.48^b	4.3	2.1	3.9	1.8	3.5	1.8	3.2	1.9
Device B	Blend	0.53^b	Not Tested^d	Not Tested^d	4.0	1.8	3.9	2.1	3.7	1.9
Device C	Spheronized	0.53^b	Not Tested^d	Not Tested^d	2.9	1.9	2.6	1.9	2.4	1.9

^aRepresentative PulmoSphere™ powder batch A (X₅₀ of 2.49 μm and tapped density 0.041 g·cm⁻³) was used for comparison.

^bApproximate inhaler mouthpiece exit diameter in cm.

^c, where d₈₄ and d₁₆ represent the diameters of the aerosol mass at 84 and 16%, respectively.

^dNGI data were not generated at 1 kPa for Devices B and C due to steep drop in aerosol dose delivery.

TABLE 5 ARLA calculator selection input parameters, all others set to default mode

Parameters	Input 1	Input 2	Input 3	Input 4
Particle properties	Particle density = 1 g·cm^−3	Log-normal distribution	MMAD (Table 4)	GSD (Table 4)
Gas properties	Default
Age	Adult
Delivery route	Oral
Breathing conditions	Single inhalation through mouthpiece	Inhalation flow (Table 2)
Respiratory tract geometry	Diameter of MP inhaler (Table 4)
Gravity	Default

FIG. 5. Photographs of DPI mouthpiece showing internal geometry of aerosol flow path.

FIG. 6. In vitro lung dose performance as measured from the mouth-throat model for PulmoSpheres^™ delivered by Device A as a function of mean primary particle size, tested at 1–6 kPa inhaler pressure drops.

TABLE 6 Mean and standard deviation of in vitro aerosol delivered dose for different formulation platforms

Compound Name (Inhaler)	Powder Platform (Lot)	ΔP / Q [kPa/mL·s^−1]	EPM [%LC]	MT IVLD^a [%LC]	[%LC]	[%LC]	Equation (3)[3] LDF [% of ISM]	Equation (3)[3] LDF [% of LC]
Placebo (Device A)	Spray-Dried PulmoSphere^™ (0.04 g/cm^3, 2.49 μm)	1 / 265	85 (3)	70 (4)	44 (3)	58 (3)	52 (2)	34 (1)
		2 / 373	88 (2)	74 (1)	45 (2)	63 (2)	48 (1)	35 (0)
		4 / 530	90 (2)	75 (5)	41(3)	61 (3)	44 (2)	31 (1)
		6 / 660	92 (2)	80 (6)	42 (8)	64 (9)	43 (3)	33 (2)
Tiotropium Bromide (Device B)	Blend (002383B)	1 / 333	No Data^b	No Data^b	No Data^b	No Data^b	No Data^b	No Data^b
		2 / 467	39 (17)	20 (20)	5 (0)	8 (1)	45 (2)	4 (0)
		4 / 650	55 (8)	19 (3)	11 (1)	20 (2)	39 (1)	10 (0)
		6 / 788	49 (6)	16 (3)	9 (3)	17 (5)	36 (2)	8 (0)
Mometasone Furoate (Device C)	Spheronized (OJS5)	1 / 383	67 (3)	12 (5)	No Data^b	No Data^b	No Data^b	No Data^b
		2 / 550	71 (5)	15 (8)	8 (1)	11 (10	56 (1)	7 (0)
		4 / 783	74 (4)	26 (10)	13 (2)	18 (2)	54 (1)	11 (0)
		6 / 950	77 (6)	32 (2)	15 (1)	21 (1)	52 (1)	13 (0)

^aMT: Mouth-throat model; IVLD: in vitro lung dose.

^bNo data generated due to poor aerosol performance.

FIG. 7. Mouth-throat model in vitro aerosol data comparing three different powder technology platforms: (a) mouth-throat deposition and (b) lung dose fraction.

FIG. 8. Comparison of results from the mouth-throat model, in vitro lung dose (experimental data), and inertial impaction parameter model: (a) d²Q < 500 and (b) d²Q < 1300 μm²·L·min⁻¹.