Transcript (Can in Can) Canister

DEVELOPMENT OF CICLESONIDE 60 ACTUATION HFA pMDIs TO MATCH
THE PHARMACEUTICAL PERFORMANCE OF THE 120 ACTUATION PRODUCT
USING SLEEVED CAN (CAN IN CAN) TECHNOLOGY
M.R. Butler 1, H. Müller 2, and A. Bell 3
1 3M Health Care Ltd., Loughborough, Leicestershire, UK,
2 ALTANA Pharma AG, Konstanz, Germany,3 sanofi-aventis, Crewe, Cheshire, UK
Header Figure 2: X-ray Images of Sleeved Canister
Figure 3. Comparison of TLMD for 60 and 120 Actuation Ciclesonide inhalers
– 18pts Bold White
Image of base of
can reaching the
internal depth stop
In-vitro TLMD Dose Proportionality of
Ciclesonide 60 and 120 Actuation
Inhalers
180
100
Mean TLMD (mcg/actuation)
Ciclesonide is a corticosteroid, which is converted to an active
metabolite (desisobutyryl-ciclesonide) in the lungs. In clinical trials,
ciclesonide solution HFA based metered dose inhalers have been
shown to be effective in the treatment of persistent asthma in adults
(18 years and over), with lung deposition estimated to be
approximately 52%.
Comparison of Ciclesonide 80mcg TLMD for 60
and 120 Actuation Inhalers
TLMD (mcg / actuation)
Introduction
90
80
70
140
60 Actuation
120
120 Actuation
60
40
20
10ml
Canister
5ml Sleeved
(Can in can)
canister
An in-vitro feasibility exercise was performed to demonstrate
whether comparability in pharmaceutical performance between the
two pack sizes could be achieved. A key consideration in this exercise
was whether the headspace, defined as the percentage of the canister
that does not contain formulation in the liquid phase, could be made
consistent between the pack sizes.
Enabling your success
40
60
80
100
120
140
160
Product Strength (mcg/actuation)
180
In-vitro FPD Dose Proportionality
of Ciclesonide 60 and 120
Actuation Inhalers
Comparison
n of Ciclesonide 40mcg FPD for 60 and
120 Actuation Inhalers
The consideration of headspace is important since, if not matched,
the amount of propellant in the vapour phase would be different
leading to slightly differing concentrations of active drug in the
formulation (possibly leading to non-comparability in the in-vitro
pharmaceutical performance between product pack sizes). The use of
the sleeved canister successfully enables the matching of the
headspace between the two pack sizes. The output of the exercise to
maintain comparable headspace is detailed in Table 1 [2].
Product
120 actuation
60 actuation
Total
Volume in
Empty
Canister
(ml)
16.25
10.29
Target Fill
Weight (g)
Target Fill
Volume (ml)
Fill Volume
(%)
9.6
6.1
8.09
5.14
49.78
49.95
Comparison of Pharmaceutical Performance
Represents volume of
formulation in canister
at first use
20
Figure 4. Comparison of FPD for 60 and 120 Actuation Inhalers
Table 1. Matching of Headspace Between Ciclesonide Inhalers 120 and
60 actuation Pack Sizes
Figure 1. Schematic Diagram of a 10ml Canister and a 5ml
Sleeved (Can in Can) Canister
0
60 Actuation Pack Size
In vitro performance for both the 60 and 120 actutation pack sizes
was evaluated to confirm equivalence. Through Life Medication
Delivery (TLMD) (Uniformity of Content) and particle size
analysis were determined following pharmacopeial guidelines [3, 4
and 5]. Figure 3 compares the TLMD for 80 mcg Ciclesonide
pMDIs for the 120 and 60 actutation packs. Figure 4 compares the
Fine Particle Dose (defined as the dose < 5 μm) for 40 mcg
Ciclesonide pMDIs for the 120 and 60 actutation packs. For both
the TLMD and FPD, the in-vitro dose proportionality was
determined to confirm that the pack sizes remained comparable
across the different product strengths.
140.0
35
120.0
FPD (mcg/actuation)
Ciclesonide inhalers are formulated with propellant HFA 134a and
ethanol in three strengths delivering individual doses of 40, 80
and 160 mcg/actuation and are available in two pack sizes
delivering a minimum of 60 and 120 actuations. The container
and closure for both pack sizes are the same except for the size of
the canister used. The 120-actuation product uses a 10mL
aluminium canister. For the 60-actuation product, a ‘sleeved’ (can
in can) canister was developed, which incorporates a 5mL canister
inserted inside an aluminium sleeve (refer to Figures 1 and 2).
Therefore, by maintaining the same external dimensions for both
product pack sizes, it became feasible to use the same actuator,
labelling and packaging, as well as the same automated product
manufacturing and packaging processes [1].
Error bars
represent 1SD
Error bars
represent 1SD
80
0
120 Actuation Pack Size
FPD (mcg / actuation)
Background
R2 = 1
100
60
Interference fit of
aluminium sleeve onto
5ml aluminium canister
R2 = 1
160
30
25
20
120 Actuation
60 Actuation
R 2 = 0.9999
100.0
R2 = 1
80.0
60.0
Error bars
represent 1SD
40.0
20.0
15
0.0
0
120 Actuation Pack Size
20
60 Actuation Pack Size
40
60
80
100
120
140
160
180
Product Strength (mcg/actuation)
Conclusions
The investigations have demonstrated that the in-vitro
pharmaceutical performance of ciclesonide 60 and 120 actuation
inhalers is comparable across the three product strengths. This
comparability was obtained for the 60-actuation product by the use of
the sleeved canister, which ensured that the headspace between the
two canisters was equivalent.
References
[1]. J.M.Moore, L. Bradley, P.Charnock and S.Brown (2004),
“Container Closure System Solutions for Delivering Low
Numbers of Doses from a Pressurised Metered Dose Inhaler”,
Respiratory Drug Delivery IX, 333-336
[2]. M. Butler and H. Müller (2004), “Development of Alvesco®
60 Actuation pMDIs to Match the Pharmaceutical Performance of
the 120 Actuation Product Using Sleeved Can (can in can)
Technology”, DDL 15 Proceedings, 61-64
[3]. ”Uniformity of Delivered Dose”, Preparations for Inhalation,
General Dosage Forms, European Pharmacopoeia 4th edition, 552556, 2002
[4]. “Preparations for Inhalation: Aerodynamic Assessment of
Fine Particles”, Methods of Analysis (2.9.18), European
Pharmacopoeia 4th Edition, 216-219, 2002
[5]. “Metered Dose Inhalers and Dry Powder Inhalers”, <601>
Aerosols Physical Tests, USP 24, 1896-1912, 2000
3 Drug Delivery Systems