Transcript Figure 9. Fine particle mass for Taper albuterol sulfate DPI

3M Drug Delivery Systems
Comparative Performance of the 3M™ Taper Dry Powder Inhaler Device
Jean Kelly1, Steve Stein1, Tom Robison1, Zhaolin Wang1, Allan Bohlke1, John Simons1, Jacqueline Ganser1,Tucker Silberhorn1, Randy Bay2;
13M Drug Delivery Systems, St. Paul MN, 23M Corporate Research Process Lab, St. Paul MN
STABILITY OF TAPER DRUG PRODUCTS
TAPER PERFORMANCE USING BIOLOGICALLY
RELEVANT FLOW PROFILES
2.0
High Volume and Peak Flow
High Volume and Low Peak Flow
Flow Rate (L/sec)
Average Volume and Peak Flow
Figure 1:. 3M™ Taper DPI
An informal stability study was performed with albuterol sulfate to
evaluate device performance over 6 month long-term storage. The MCT
dose content was about 200 mg which provided a target emitted dose of
194 mg. Devices sealed in foil pouches were stored at 25oC/65%RH
and tested periodically over a 26-week period. Taper demonstrated
excellent dose content uniformity with essentially no change in mean
emitted dose (refer to Figure 7). Additionally, all 49 emitted doses
measurements throughout the stability study were within ±15% of the
target emitted dose. Similarly, through-life testing at 26 weeks showed
minimal trending over 120 actuations with all results well within ±15%
of target (see Figure 8). Particle size of the emitted dose also remained
stable with the mean fine particle mass < 5 mm within 10% of initial for
each timepoint through 26 weeks (refer to Figure 9).
1.5
Low Volume and Peak Flow
1.0
0.5
1.40
1.20
3M™ Taper
Δ = 23%
1.0
2.0
3.0
4.0
0.80
3M™ Taper
DISKUS®
0.60
0.40
0.00
High Volume High Volume
Average
Low Volume
and Peak and Low Peak Volume and
and Peak
Flow
Flow
Peak Flow
Flow
5.0
GID 157716
60
50
3M™ Taper
DISKUS®
Turbohaler®
Easyhaler®
40
30
20
10
The number and dimension of the dimples in the dosing zone of the
MCT (approximately 2 cm2) predominately determines the dose
delivered from Taper. MCTs with varying dimple patterns were filled
with albuterol sulfate to assess Taper dose range capabilities. Emitted
doses were collected per USP <601> using Apparatus B at 85 lpm,
which is equivalent to a pressure drop of 4 kPa across the device.
Devices were constructed with approximately 0.005-2 mg albuterol
sulfate per actuation. The corresponding delivered doses from these
devices are shown in Figure 5, demonstrating Taper’s broad dose range
capability. The high correlation between loaded and emitted dose
indicates effective drug release from the MCT and low device hold-up
(~11% on average) across the dose range. Fine particle fractions were
measured using the NGI apparatus (85 LPM/4 kPa). Figure 6
demonstrates high fine particle fractions for drug loaded at ~0.005-2
mg/actuation with an overall average of 58%.
2000
R² = 0.9996
1500
1000
500
Steroid
Figure 1. Fine Particle Fractions for 3M Taper
Relative to Advair DISKUS, Ventolin DISKUS2,
Turbohaler2,3, and Easyhaler2
Emitted Dose (mg)
100
50
0
0
4
8
12
16
20
150
100
24
50
0
0
60
Timepoint (Weeks)
Target Emitted Dose
±15% of Target
120
Actuation Number
Mean Emitted Dose
Target emitted dose
GID 160547
±15% of Target
Mean Emitted Dose
GID 160547
Figure 7. Emitted dose content
uniformity for Taper albuterol sulfate
DPI over 26 weeks storage at long term
conditions (25oC/60% RH). N=9-10 per
pull point.
Figure 8. Through-life dose content
uniformity for Taper albuterol sulfate
after 26 weeks storage at 25oC/60% RH.
N=3 at beginning, middle (60 actuations)
and end of life (120 actuations).
120
100
80
60
40
20
0
0
4
8
12
16
20
24
Timepoint (Weeks)
Mean Fine Particle Mass (≤ 5 mcm)
Initial FPM + 10%
Initial FPM - 10%
GID 160547
The 3M™ Taper DPI has demonstrated high efficiency with typical FPF
of ~50%, a two-fold improvement over DISKUS®, Turbohaler®, and
Easyhaler®. Predicted Taper lung dose is relatively insensitive to
inhalation flow profile, similar to DISKUS®. Doses from 0.005 to 2
mg/actuation have been loaded and consistently delivered from Taper.
Excellent stability was observed in the Taper device through 6 months
storage (25oC/60% RH).
REFERENCES
1. Palander, A., et al. (2000), “In vitro Comparison of Three Salbutamol-Containing
Multidose Dry Powder Inhalers Buventol Easyhaler, Inspiryl Turbohaler and Ventoline
Diskus,” Clin Drug Invest., 20(1), pp 25-33.
FPF(avg) = 58%
70
2. Feddah, M.R., et al. (2000), “In-Vitro Characterization of Metered Dose Inhaler Versus
Dry Powder Inhaler Glucocorticoid Products: Influence of Inspiratory Flow Rates,” J. Pharm.
Pharmaceut. Sci., 3(3), pp 317–324.
60
50
40
30
3. Grgic, B., Finlay, W. H. and Heenan, A. F. (2004), "Regional Aerosol Deposition and
Flow Measurements in an Idealized Mouth and Throat", J. Aerosol Sci., 35(1), pp 21-32.
20
10
0
0
LABA
150
CONCLUSIONS
80
0
Albuterol
200
Figure 9. Fine particle mass for Taper albuterol sulfate DPI
measured over 26 weeks storage at long term conditions
(25oC/60% RH), N=5.
TAPER DRUG DOSING RANGE
0
GID 160547
200
GID 160547
Fine Particle Fraction (%)
Fine Particle Fraction (%)
70
Figure 3. Taper specific flow profiles
Figure 4. Impact of In-Vitro Simulated Breath
recorded from four subjects (two female and Profile on Predicted Lung Dose for Taper and
two male)
DISKUS® (N=3). Predicted lung doses were
normalized by dividing by the average lung
dose. ED=emitted dose
Emitted Dose (mg/actuation)
For all DPI devices, non-respirable drug particles (generally aerodynamic
diameters > 5 mm) impact on the throat and are swallowed. Reducing
non-respirable drug has the potential to reduce undesired side effects.
Improving DPI delivery efficiency also has economic benefits since the
same respirable mass can be delivered while loading less drug into the
device. Aerodynamic particle size distribution measurements were
performed for Taper devices loaded with either albuterol sulfate, a longacting beta agonist (LABA), or a corticosteroid. The Next Generation
Pharmaceutical Impactor (“NGI”, MSP Corporation, Shoreview, MN) was
used at 85 LPM, which resulted in a pressure drop of 4 kPa for both Taper
and Advair DISKUS®. Similar assessments for DISKUS®, Turbohaler®,
and Easyhaler® using multi-stage impactors/impingers (at least 4 kPa
pressure drop) were reported elsewhere1,2. Taper generally demonstrated
a two-fold improvement in fine particle fractions (FPF, % of emitted dose <
5 mm) over the other DPI devices (see Figure 2).
250
140
GID 160547
TAPER EFFICIENCY RELATIVE TO MARKETED DPIs
250
0.20
Time (sec)
GID 157716
Predicted Lung Dose
3M™ Taper = 46.2% of ED (Avg)
DISKUS = 21.7% of ED (Avg)
1.00
0.0
0.0
DISKUS
Δ = 29%
Emitted Dose (µg)
Variation in patient inhalation flow profile can impact the amount of drug
delivered to the lung from a DPI device. Flow rate sensitivity was
evaluated for the 3M Taper device and compared with Advair DISKUS®
using individual inhalation profiles recorded by a mini Pulmonary Wave
Generator (mPWG). Device specific inhalation profiles were selected from
four subjects (two female and two male) based on physiologically
differentiable parameters of peak inspirational flow rate and total
inspirational volume (see Figure 3). In-vitro drug delivery testing was
conducted using the mPWG, an idealized Alberta throat3 and the dose
sampling apparatus (sample collection tube) from USP <601> . The
amount of drug captured by the sample collection tube provided an
estimate of lung dose3,4. Taper demonstrated superior efficiency with, on
average, 46.2% of the Taper emitted dose targeted for lung delivery versus
only 21.7% for DISKUS®. Both Taper and DISKUS® were relatively
insensitive to variation in biologically relevant inhalation flow profiles.
Maximum differences in predicted lung dose were 23% for Taper and 29%
for DISKUS® (refer to Figure 4).
Normalized Predicted Lung Dose
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“dimples” (50-200 mm diameters and 25-100 mm depth) that are filled
with micronized drug. Dimple density predominantly defines the dose
with drug loading demonstrated from 0.005 to 2 mg/actuation. Winding
drug filled MCT onto a spool allows for up to 120 doses to be stored in
a compact pocket-sized device with integrated moisture protection
(humidity maintained typically 30-60% RH, tailored to product
requirements). Cohesive forces (primarily van der Waals) maintain the
drug inside the dimples until breath-actuated delivery imparts sufficient
energy for drug release from the MCT. The Taper device shown in
Figure 1 also contains a dose counter, a dose ready-indicator and
patient feedback (visual and audible) confirming that a dose was
delivered.
Fine Particle Mass (mg)
OVERVIEW OF 3M™ TAPER DPI
500
1000
1500
Loaded Dose (mg/actuation)
Figure 5. Taper dose range
demonstrated with albuterol sulfate
(N=5-20)
2000
GID 160547
0
500
1000
1500
2000
Loaded Dose (mg/actuation)
Figure 6. Taper fine particle fractions for
albuterol sulfate (N=2-3)
4. Olsson, B., Borgstrom, L., Svensson, M. and Lundback, H. (2008), "Modeling
Oropharyngeal Cast Deposition to Predict Lung Delivery from Powder Inhalers," Dalby,
R.N., Bryon, P.R., Peart, J., Farr, S.J., Suman, J.D. and Young, P.M. (eds), Respiratory
Drug Delivery 2008, 197-206.
Advair, DISKUS and Ventolin DISKUS are registered trademarks of GlaxoSmithKline
Turbohaler is a registered trademark of Astra Zeneca
Easyhaler is a registered trademark of Orion Pharma