Background to the area of Valved Holding Chambers

1. Introduction to Valved Holding Chambers
By Paul Hancock

2. Presentation outline

3. 1: Background
What is a Valved Holding Chamber ?
VHC patent trends
Marketed VHCs
VHC Attributes
•Advantages
•Disadvantages

4. What is a Valved Holding Chamber ?
A VHC is a device used with a pMDI to improve the delivery of
aerosol medication into the lungs
Improving drug delivery to lungs in a coordinated fashion
Serves as a reservoir to hold the aerosol cloud for the patient to inhale through
a one-way valve
Removing larger particles of medication to reduce throat deposition
Droplets evaporate to a smaller size before inhalation for improved delivery
into the lungs
Decelerate the medication coming from a pMDI to allow better deposition into
the lungs rather than the mouth and throat

5. VHC patent trends
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6. Marketed VHCs
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7. VHC attributes
Advantages Disadvantages
Efficacy - Improve clinical effect [1] - holds Too big - Over-dilution of the drug may occur.
aerosol cloud - ↓ momentum Cumbersome
Safety - ↓ oropharyngeal deposition, (cold Too small - Re-aggregation of particles may
freon, oral candidiasis) occur. Large particle entrapment efficiency ↓
Particle size ↓ with evaporation. ↑ % drug Wide variation in drug delivery between
delivery on target spacers
Less emphasis on Patient coordination Electrostatic charge ↓ delivery
Enhanced compliance with face mask for Cleaning required
paediatric use
1: Expert Opin. Drug Deliv. 2009 (6)1 Fedorico Lavorini

8. 2: Guidelines
EMEA & Health Canada
FDA
Comparison

9. 2006 EMEA CHMP & HC Harmonised Guideline
GUIDELINE ON THE PHARMACEUTICAL QUALITY OF INHALATION AND
NASAL PRODUCTS
Fine particle mass with spacer/holding chamber use (CTD 3.2.P.2.4)
For inhalation products that may be administered with a spacer or holding
chamber, a study should be conducted to determine whether the use of the
spacer or holding chamber changes the FPM.
If the instructions accompanying the spacer or holding chamber include an in-use
cleaning schedule (e.g., weekly cleaning), the FPM should be tested before and
after cleaning the spacer or holding chamber according to the instructions provided
with the device.
Any differences in FPM should be assessed for their clinical relevance, with
support from any clinical data obtained with the spacer or holding chamber.
FDA

10. 2002 FDA CDER Guidance for Industry
Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products — CMC
Documentation
Effect of Varying Flow Rates
The effect of varying flow rate should be studied for inhalation spray drug products
and should address the following:
For drug products with an expansion or holding chamber, spacer, or similar
component, a separate study is encouraged to assess the effect of increasing
waiting periods (e.g., 0, 5, 10 seconds) between actuation and initiation of inflow,
at a specified flow rate, on the SCU and particle/droplet size distribution.
MDI, ACTUATOR, AND SPACERS
A spacer device must be directly compared to a predicate spacer as well as
directly compared to an MDI alone without the spacer attached. Particle size
distribution data should be gathered for the predicate device and the new device
utilizing the identical MDI attached to the devices.
Each spacer must have particle size distribution data for each drug classification
type for which it is intended.
Comparison

11. Table 1. Comparison of FDA and EMEA/Health Canada Orally Inhaled Drug
Product Performance Characterization Studies

12. 3: Effect of different conditions of use on VHCs
Effect of spacers on drug deposition
Delay time
Size selective function
Electrostatic charge
Nature of drug & type of spacer

13. The use of either Delay time Drug delivery
AeroChamber-Plus® performance (for
or Volumatic® has Modulite-BDP pMDIs)
been shown to ↓ the when used in
mean coarse drug association with
Aerochamber-Plus
mass, relative to that
could be similar to that
for the Bespak obtained with Volumatic
actuator alone, from up to holding times of at
56-60% (expressed least 5 seconds.
as percent nominal
dose) to 1-4% [13] . Decay continues with
holding time for
In spacer-mode, Aerochamber-Plus to
delivered dose is ↓ ~30%, there is little
change with Volumatic.
to ~60% whilst over Fig.1: Mean delivered dose for BDP 50
the 2-10 second Modulite MDI systems; (a) No VHC (b) Increased residence
holding period, there Aerochamber-Plus, (c) Volumatic [13]. time within the spacer
is further ↓ to ~35% may cause significant
of that obtained drug loss due to
through the sedimentation and the
conventional Bespak effects of electrostatic
charge [5].
actuator.

14. Size selective function Fine particle
dose also had
little dependence
Size selective on the flow rate
function reduces (28.3 L/min or 60
oropharyngeal L/min). As
deposition of large expected, a delay
particles between actuation
and inhalation
In vitro results in reduced
performance of a drug delivery.
combination pMDI Drug delivery
with VHCs, showed dependence on
use of both Fig.2: Throat, FPD and total DD recoveries for delay time differs
AeroChamber ‘Z- active, flow @ 28.3L/min. Recoveries for two between the two
STAT Plus™’ and different VHCs and pMDI (n=5) [14] . [14]
AeroChamber
‘Max®’ resulted in a The delivery of HFA fluticasone propionate was compared for a small
large reduction of volume VHC (AeroChamber Plus* with mouthpiece) and a large
volume VHC (Volumatic™) at flow rates of 28.3, 45 and 60 L/min [15].
throat deposition
with little or no At 28.3 L/min the FPD from the AeroChamber was comparable with
effect on fine that from the Volumatic™. At higher flow rates, FPD from the
particle dose [14] . AeroChamber exceeded equivalent values from the Volumatic™[15].

15. Electrostatic charge
• High surface • Ionic surfactants were
potentials were found found to perform better
as expected on new than non-ionic ones
AeroChamber Plus
spacers since plastics • The use of commercial
are electrical insulators detergents is simple,
[7]
economical, and relevant
to patient use in the
• Electrostatic charge on community setting.
a plastic Volumatic® and
AeroChamber spacers • VHCs manufactured from
has been shown to Fig.3: Drug delivery of particles <6.8um as % charge-dissipative
attract particles to the of total amount in spacers (n=4) materials to improve
spacer wall [5-6] compliance.
• This influences the Minimizing Electrostatic Effect
• Washing non-conducting
drug output and hence · Use metal chamber/spacer VHCs in Ionic detergent
reduces the clinical · Use anti-static chamber drip drying, coats the
efficacy of drug · Prime chamber with pMDI surface, and dissipates
(Salbutamol [4] Ventolin, · Pre-soak spacer in ionic charge for at least 24 h
Flixotide, Tilade, and QVAR
[7] ) in a variable manner detergent / defined time leading to ↑ in small
[8]
· Air dry only particle delivery [7, 9-10]

16. Nature of drug & type of spacer
The amount of drug can be affected by:
• The correct choice of spacer
• Size, length, diameter and shape of spacer
• Inhalation technique, coordination & incorrect
spacer use.
• For example, five actuations of steroid into large
vol. spacer resulted in same amount drug
delivered as a single actuation into the same
spacer [20 T.C.D.].
• Increasing spacer length can decrease oral
deposition of drug but not affect total delivery [18]
• Considerable differences have been found in
drug delivery from different spacers (Fig. 4) [17, 19]
• In-vitro tests use constant flow. Breathing
patterns representative of patients (esp children)
may be more appropriate
Fig.4: Drug delivery of particles <5um from different spacers with different MDIs [17]

17. 4: Moving Forward

18. 4: Moving Forward
Modern Devices Features
Size optimised chamber • More fine particle dose available for inhalation
(OptiChamber - Respironics
/ L'espace - MarkosMefar) • Drug output less sensitive to variations in patient technique
• Enhanced suspension and distribution of the atomized drug
• Enhances deposition in the lower airways
Patient feedback • High flow warning whistle
(OptiChamber - Respironics • Encourages proper inhalation speed
/ Aerochamber - Trudell) • Indicates improper inhalation
• Trains individuals in proper technique
Inspiratory / Expiratory • Prevents exhaled breath from entering the chamber
Valve system
• Low resistance silicone valve

19. 4: Moving Forward
Modern Devices Features
Chamber • High-impact polycarbonate (non-conducting - Volumatic™ )
•Due to the water rinsing method employed by the Volumatic™ PIL, there
is a greater potential for static build up affecting the dose and FPM [12] .
• Clear copolyester (non-conducting - AeroChamber Plus*[3] ), the PIL
adopts a detergent wash method to coat the inner surface
• Washing with ionic detergents has been shown to minimise/eliminate
static [2] due to their conductive nature
• Aerosol plume visible (OptiChamber / Volumatic™ / AeroChamber Plus*)
• AeroChamber Max™ -198-ml is manufactured from transparent
electrostatic charge dissipative materials
• PARI Vortex antistatic metallic chamber
Child-centric • PARI Vortex Masks has toy face
design • Using vivid colours and a shape like a toy animal
• Watchhaler™ has a more childlike and welcoming look
• Watchhaler™ has a protective outer chamber around the aerosol
balloon so that the balloon cannot be touched reducing electrostatic
charge

20. In Summary

21. References
[1] Expert Opin. Drug Deliv. 2009 (6)1 Fedorico Lavorini
[2] Kwok PCL, Aerosol Science 37 (2006) 1671 - 1682
[3] Asmus, M.J., (2003) Pharmacotherapy, 23, 1538-1544
[12] Mitchell, J.P. Drug Delivery to the Lungs-18, The Aerosol Society Edinburgh, UK, 2007:90-93,
[4] Eur Respir J, 1996, 9, 1943-1946 J.H. Wildhaber et. Al
[5] O'Callaghan C et al. Thorax 1993; 48: 603-606
[6] Barry PW et al. J Clin Pharmacol 1995; 40: 76-78
[7] Philip Chi Lip Kwok et al. Aerosol Science 37 (2006) 1671 – 1682
[8] Chuffart, A.A., et al Swiss Med. Wkly. 2001;131:14-18
[9] Wildhaber, J.H, Br. J. Clin. Pharmacol. 2000;50:277-280.
[10] Wildhaber, J.H., Pediatr. Pulmonol. 2000;29:389-393.
[11] British Thoracic Society/Scottish Intercollegiate Guidance Network (SIGN). 2008. British guideline on the management of asthma. Publication 101.
[12] Mitchell, J.P. Drug Delivery to the Lungs-18, The Aerosol Society Edinburgh, UK, 2007:90- 93
[13] Respiratory Drug Delivery 2008 - Church et al. (Vectura Group plc, Chippenham, UK, Chiesi Farmaceutici SpA, Parma, Italy)
[14] Respiratory Drug Delivery 2008 - Li et al.
[15] Mitchell JP, Nagel MW, Wiersema KJ, Bates SL, Morton RW. Performance of Larg and Small Volume Valved Holding Chambers as a function of flow
rate. Journal of Aerosol Med., 14(1), 122, 2001
[16] P.W.Barry , O'Callaghan C, Advanced drug Delivery Reviews 55 (2003) 879-923
[17] P.W.Barry , O'Callaghan C et al. Thorax 1996; 51: 835-840
[18] F.Moren, Int. J. Pharm. 1 (1978) 205 – 212
[19] R.Ahrens et al. J. Allergy Clin. Immunol. 96 (1995) 288-294
[20] P.W.Barry , O'Callaghan C, Eur. Respir. J. 7 (1994) 1707-1709

22. And Finally.....
A wider view of aerosolisation technique and formulation
Pinotubo 1991: SO2 Eyjafjallajokull 2010: pDPI Water droplets + Multiple
droplets + ‘n’ nozzles + single nozzle Nozzles/Spacers (John Latham)
(multiple - Paul Crutzen)
20m tons of SO2 droplets • 8km in height A few 100m above ocean, cloud
• Ash = 58% SiO2 reflects 50% incoming sunlight
A large number of small drops High triboelectric charge from A large number of small drops
reflects (wider angle) particle collisions reflects more than the same
amount of water in larger drops
Cools planet by half a degree “Any cooling effect will be • Thicken the clouds up (0.8um)
following year very insignificant“ * • Doubling the drop number
increases cloud Albedo by 5.6%
*The World Meteorological Organisation

23. VHC patent trends
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24. VHC patent trends
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25. Marketed VHCs
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26. Marketed VHCs
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27. Marketed VHCs
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28. Marketed VHCs
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29. Marketed VHCs
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