By Paul Hancock

Introduction to Valved Holding Chambers

Presentation outline

1: Background

What is a Valved Holding Chamber ?

VHC patent trends

Marketed VHCs

VHC Attributes • Advantages• Disadvantages

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

VHC patent trends

Click movie to begin(If system doesnt support format see supplimentary slides at end of presentation)

Marketed VHCs

Click movie to begin(If system doesnt support format see supplimentary slides at end of presentation)

VHC attributes

Advantages Disadvantages

Efficacy - Improve clinical effect [1] - holds aerosol cloud - ↓ momentum

Too big - Over-dilution of the drug may occur. Cumbersome

Safety - ↓ oropharyngeal deposition, (cold freon, oral candidiasis)

Too small - Re-aggregation of particles may occur. Large particle entrapment efficiency ↓

Particle size ↓ with evaporation. ↑ % drug delivery on target

Wide variation in drug delivery between spacers

Less emphasis on Patient coordination Electrostatic charge ↓ delivery

Enhanced compliance with face mask for paediatric use

Cleaning required

1: Expert Opin. Drug Deliv. 2009 (6)1 Fedorico Lavorini

2: Guidelines

EMEA & Health Canada

FDA

Comparison

FDA

2006 EMEA CHMP & HC Harmonised GuidelineGUIDELINE 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.

Comparison

2002 FDA CDER Guidance for IndustryNasal Spray and Inhalation Solution, Suspension, and Spray Drug Products — CMC Documentation

Effect of Varying Flow RatesThe 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 SPACERSA 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.

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

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

Delay timeThe use of either AeroChamber-Plus® or Volumatic® has been shown to ↓ the mean coarse drug mass, relative to that for the Bespak actuator alone, from 56-60% (expressed as percent nominal dose) to 1-4% [13] .

In spacer-mode, delivered dose is ↓ to ~60% whilst over the 2-10 second holding period, there is further ↓ to ~35% of that obtained through the conventional Bespak actuator.

Fig.1: Mean delivered dose for BDP 50 Modulite MDI systems; (a) No VHC (b) Aerochamber-Plus, (c) Volumatic [13].

Drug delivery performance (for Modulite-BDP pMDIs) when used in association with Aerochamber-Plus could be similar to that obtained with Volumatic up to holding times of at least 5 seconds.

Decay continues with holding time for Aerochamber-Plus to ~30%, there is little change with Volumatic.

Increased residence time within the spacer may cause significant drug loss due to sedimentation and the effects of electrostatic charge [5].

Size selective function

Size selective function reduces oropharyngeal deposition of large particles

In vitro performance of a combination pMDI with VHCs, showed use of both AeroChamber ‘Z-STAT Plus™’ and AeroChamber ‘Max®’ resulted in a large reduction of throat deposition with little or no effect on fine particle dose [14] .

Fine particle dose also had little dependence on the flow rate (28.3 L/min or 60 L/min). As expected, a delay between actuation and inhalation results in reduced drug delivery. Drug delivery dependence on delay time differs between the two [14]

Fig.2: Throat, FPD and total DD recoveries for active, flow @ 28.3L/min. Recoveries for two

different VHCs and pMDI (n=5) [14] .

The delivery of HFA fluticasone propionate was compared for a small volume VHC (AeroChamber Plus* with mouthpiece) and a large volume VHC (Volumatic™) at flow rates of 28.3, 45 and 60 L/min [15].

At 28.3 L/min the FPD from the AeroChamber was comparable with that from the Volumatic™. At higher flow rates, FPD from the AeroChamber exceeded equivalent values from the Volumatic™[15].

• High surface potentials were found as expected on new AeroChamber Plus spacers since plastics are electrical insulators [7]

• Electrostatic charge on a plastic Volumatic® and AeroChamber spacers has been shown to attract particles to the spacer wall [5-6]

• This influences the drug output and hence reduces the clinical efficacy of drug (Salbutamol [4] Ventolin, Flixotide, Tilade, and QVAR [7] ) in a variable manner [8]

Electrostatic charge• Ionic surfactants were found to perform better than non-ionic ones

• The use of commercial detergents is simple, economical, and relevant to patient use in the community setting.

• VHCs manufactured from charge-dissipative materials to improve compliance.

• Washing non-conducting VHCs in Ionic detergent drip drying, coats the surface, and dissipates charge for at least 24 h leading to ↑ in small particle delivery [7, 9-10]

Minimizing Electrostatic Effect· Use metal chamber/spacer· Use anti-static chamber· Prime chamber with pMDI · Pre-soak spacer in ionic detergent / defined time· Air dry only

Fig.3: Drug delivery of particles <6.8um as % of total amount in spacers (n=4)

Nature of drug & type of spacer

Fig.4: Drug delivery of particles <5um from different spacers with different MDIs [17]

• 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

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.].

4: Moving Forward

Modern Devices Features

Size optimised chamber (OptiChamber - Respironics / L'espace - MarkosMefar)

• More fine particle dose available for inhalation

• 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 (OptiChamber - Respironics / Aerochamber - Trudell)

• High flow warning whistle • Encourages proper inhalation speed • Indicates improper inhalation• Trains individuals in proper technique

Inspiratory / Expiratory Valve system • Prevents exhaled breath from entering the chamber

• Low resistance silicone valve

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 design

• PARI Vortex Masks has toy face• 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

4: Moving Forward

In Summary

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

Pinotubo 1991: SO2 droplets + ‘n’ nozzles (multiple - Paul Crutzen)

Eyjafjallajokull 2010: pDPI + single nozzle

Water droplets + Multiple Nozzles/Spacers (John Latham)

20m tons of SO2 droplets • 8km in height• Ash = 58% SiO2

A few 100m above ocean, cloud reflects 50% incoming sunlight

A large number of small drops reflects (wider angle)

High triboelectric charge from particle collisions

A large number of small drops reflects more than the same amount of water in larger drops

Cools planet by half a degree following year

“Any cooling effect will be very insignificant“ *

• Thicken the clouds up (0.8um) • Doubling the drop number increases cloud Albedo by 5.6%

And Finally.....A wider view of aerosolisation technique and formulation

*The World Meteorological Organisation

VHC patent trendsScreen shots to support video slide

VHC patent trendsScreen shots to support video slide

Marketed VHCsScreen shots to support video slide

Marketed VHCsScreen shots to support video slide

Marketed VHCsScreen shots to support video slide

Marketed VHCsScreen shots to support video slide

Marketed VHCsScreen shots to support video slide