Transcript Drug Delivery to Lungs VII

The Influence of Canister Headspace on the Pharmaceutical Performance of a Solution Metered Dose Inhaler Product
Shuguang Hou, Kimberly Kriesel, Todd Alband, Lisa Dick and David Heisler
3M Drug Delivery Systems Division, 3M Center Building 260-4N-12, St Paul, MN 55144
Results
Results
Introduction
The headspace of pressurized metered dose inhaler
(MDI) canisters is filled by the vapor of volatile
components, mainly propellant, contained in the
formulation. Following multiple actuations of the MDI,
the headspace of the canister increases and more
propellant evaporates to fill the headspace, which causes
the concentration of non-volatile components, mainly
the active drug, in the liquid phase of the formulation. If
there are no confounding variables, as seems likely in a
formulation containing dissolved drug, the delivered
dose drug per actuation from the MDI would be
expected to increase through the container life. The
significance of such impacts had been proposed on the
regulatory specification limits of MDI dose content
uniformity (1-3).
A solution formulation HFA MDI product has been
developed. This formulation contains one active drug at
1 mcg/actuation, 15% w/w ethanol as a co-solvent, a
non-volatile mineral acid as a stabilizer, and HFA-134a
as a propellant. The objective of this study is to assess
the influences of the canister headspace on the drug
concentration in the container, drug delivery, and particle
size distribution of the MDI product.
Drug Concentration in Container: The drug
concentration in the container decreased to 94.7% and
86.6% of the beginning at the end of container life for
units with fill weights of 7.3 g (60 actuations) and 11.0 g
(120 actuations) (Figure 1 and Table 1). The 11.0 g fill
weight unit showed a larger decrease of drug
concentration through container life due to its larger fill
weight (i.e. larger number of actuations). Interestingly,
the drug concentration at the middle of the container life
(i.e. after 60 actuations) did not change for the 11.0 g fill
weight unit, while the drug concentration decreased to
94.7% after 60 actuations for the 7.3 g fill weight unit.
This might be explained by the smaller initial canister
headspace for the 11.0 g fill weight unit. A computer
model, developed based on the ideal gas law and
Raoult’s law, was applied to estimate these impacts. The
experimental results had a good agreement with the
theoretical data (Figure 1). These results indicate that
both the initial canister headspace and fill weight have
impacts on the drug concentration remaining in the
canister through container life.
Dose Delivery (DD): For the 7.3 g fill weight units
(with a larger initial canister headspace), the delivered
dose increased approximately 13% at the end of
container life (Table 1), which agreed with the literature
(1 - 2). This was explained by the continuous
equilibration of the liquefied propellant into the
headspace of the canister following the actuations. For
the 11.0 g fill weight units (with a smaller initial canister
headspace), no significant change was observed for the
delivered dose through container life (Table 1).
Theoretically, the 11.0 g fill weight unit has more doses
(120 actuations), thus should show a more significant
increase for the delivered dose per actuation at the end
of container life. The reason for no change of the
delivered dose through container life for the 11.0 g fill
weight unit remains unclear.
Figure 1 Plot of Drug Concentration in the Canister
through Container Life
The initial canister headspace and fill weight had an
effect on the active drug concentration remaining in the
container and the delivered dose. The behavior of a
solution formulation allows the detection of such effects.
Under both headspace conditions, the delivered dose
through the container life should meet the regulatory
guidance of within 80 - 120% of label claim (4). To
achieve a more consistent pharmaceutical performance
for solution MDIs, a smaller initial canister headspace
and smaller fill weight are suggested.
Methods
The drug concentration in the container through
container life was determined by a validated HPLC
method with UV detection. The method precision was
0.5% relative standard deviation (RSD).
The delivered dose (ex-actuator) and particle size
distribution through container life were measured with
the Bespak 0.22 mm orifice diameter actuator. The dose
delivery was tested using a dose unit spray apparatus
(DUSA) tube and the particle size distribution was
measured using Andersen cascade impactor (ACI). The
flow rate was 28.3 liters per minute for both tests. The
drug content in the DUSA tube and ACI plates was
assayed by a validated HPLC method with UV
detection. The method precision was 1.7% RSD and the
limit of quantitation (LOQ) was 0.14 mcg/actuation.
Percentage of Drug
Concentration
The MDI solution formulation was filled in 3M
aluminum 15-mL canisters with Bespak BK357 63-µL
valves. The fill weight was either 7.3 grams (60
actuations) or 11.0 grams (120 actuations), resulting in
different head space volumes in the canister.
120.0
100.0
80.0
60.0
11.0g-Theoretical
7.3g-Theoretical
11.0g-Actual
7.3g-Actual
40.0
20.0
Particle Size Distribution: No significant change was
observed for the fine particle fraction (FPF) through
container life for either fill weight (Table 1).
Conclusions
Acknowledgement
0.0
0
20
40
60
80
100
120
140
Actuation Number
Table 1 Summary of Drug Concentration in the
Container, Drug Delivery and Fine Particle Fraction
through Container Life
Parameters
7.3 g Fill Weight
11.0 g Fill Weight
Beginning Middle End Beginning Middle End
% of
100.0
NA
94.5
100.0
99.5
86.3
Drug Conc.
(0.9)
(0.0)
(0.0)
(0.4) (1.9)
DD
0.77
0.81
0.87
0.80
0.79
0.81
(mcg/act.)
(0.06)
(0.06) (0.00)
(0.02)
(0.03) (0.02)
FPF
46.8
NA
48.6
48.3
NA
48.7
(%)
(0.5)
(3.2)
(4.9)
(3.9)
The authors thank Mike Sivigny and Jane M. Pamperin
for providing the computer model program.
References
1. Howlett, D. , Drug Delivery to Lungs VII, 105-109,
1996.
2. Lewis, D., Brambilla, G., Ganderton, D., Howlett, D.
and Meakin., B., Respiratory Drug Delivery VII, 373375, 2000.
3. Zhang L and Adjei A. , Respiratory Drug Delivery IX,
673-676, 2004.
4. FDA Draft Guidance for Industry, “Metered Dose
Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug
Products”, October 1998.
Mean (Standard Deviation)
NA: Not Tested.
n = 3 for FPF and n = 9 for drug concentration and DD
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