AeroChamber Mitchell, J., Coppolo, D.C., Nagel, M.W. Khan Y, Tang Y, Hochhaus G, Shuster JJ, Spencer T, Chesrown S, Hendeles L.

Transcription

1 AeroChamber Anti-Static Clinical Summary The following summaries have been extracted from various journals and resources to produce a comprehensive analysis of clinical data available. Mitchell, J., Coppolo, D.C., Nagel, M.W. Electrostatics and Inhaled Medications: Influence on Delivery Via Pressurized Metered-Dose Inhalers and Add-On Devices. J. Pediatri Dec; 149(6): The movement of inhaler-generated aerosols is significantly influenced by electrostatic charge on the particles and on adjacent surfaces. Particle charging arises in the aerosol formation process. Since almost all inhalers contain nonconducting components, these surfaces can also acquire charge during manufacture and use. Spacers and valved holding chambers used with pressurized metered dose inhalers to treat obstructive lung diseases are particularly prone to this behavior, which increases variability in the amount of medication available for inhalation, and this is exacerbated by low ambient humidity. This may result in inconsistent medication delivery. Conditioning the device by washing it with a conductive surfactant (detergent) or using devices made of charge dissipative/ conducting materials can mitigate electrostatic charge. This review discusses sources of electrostatic charge, the processes that influence aerosol behavior, methods to mitigate electrostatic charge, and potential clinical implications. Khan Y, Tang Y, Hochhaus G, Shuster JJ, Spencer T, Chesrown S, Hendeles L. Lung bioavailability of hydrofluoroalkane fluticasone in young children when delivered by an antistatic chamber/mask. Clin Pharmacokinet. 2006;45(7): OBJECTIVE: To determine whether an antistatic valved holding chamber/mask improves lung bioavailability of hydrofluoroalkane (HFA) fluticasone in young children. STUDY DESIGN: Twelve patients, age 1 to 6 years, with well-controlled asthma were treated with an HFA fluticasone metered-dose inhaler (Flovent HFA) twice daily (440 microg/day). The drug was delivered by tidal breathing through conventional (AeroChamber Plus) and antistatic (AeroChamber MAX) valved holding chambers (VHCs) with masks in a randomized, crossover manner, each for 3 to 7 days. When adherence was 100% at home, blood was collected for measurement of steady-state fluticasone plasma concentration (FPC) 1 hour after the last dose was administered in the clinic. FPC indicates systemic exposure directly and airway delivery indirectly. It was measured by liquid chromatography-mass spectrometry. Data was analyzed by regression analysis. RESULTS: The mean +/- SD FPC was 107 +/- 30 pg/ml after conventional VHC and 186 +/- 134 pg/ml after the antistatic VHC (P =.03). In 5 patients (40%), the antistatic VHC increased FPC by >/= 100%, to potentially excessive levels in 4 of them; it had little effect in 7 patients. CONCLUSIONS: HFA fluticasone was delivered to the airways by both devices even though the patients could not inhale deeply and breath hold. The antistatic VHC variably increased lung bioavailability. To reduce systemic exposure, the dose should be weaned to the minimum required to maintain asthma control.

2 Drollmann A, Nave R, Steinijans VW, Baumgärtner E, Bethke TD. Equivalent pharmacokinetics of the active metabolite of ciclesonide with and without use of the AeroChamber Plus spacer for inhalation. ALTANA Pharma AG, Konstanz, Germany. BACKGROUND: Ciclesonide is an inhaled corticosteroid that provides safe and effective control of persistent asthma. Ciclesonide is administered as an aerosol solution in a metered-dose inhaler, using hydrofluoroalkane-134a as a propellant. It is activated in the lung to form its only active metabolite, desisobutyryl-ciclesonide (des-cic). A spacer may be used in combination with the hydrofluoroalkane metered-dose inhaler (HFA-MDI) to maintain inhaled corticosteroid delivery to the lung in patients with poor inhalation technique. OBJECTIVE: To determine if the pharmacokinetics of des-cic and ciclesonide are altered when a spacer is used for ciclesonide inhalation. METHODS: A randomised, open-label, 2-period crossover, single-center pharmacokinetic study was conducted in 30 patients with asthma (forced expiratory volume in 1 second > or = 70% predicted). A single dose of ciclesonide (320 microg ex-actuator; equivalent to 400 microg ex-valve) was administered via the HFA-MDI with and without an AeroChamber Plus spacer (Trudell Medical International, London, ON, Canada). Serum concentrations of ciclesonide and des- CIC were measured before inhalation and at various intervals until 14 hours after treatment using high-performance liquid chromatography with tandem mass spectrometric detection. RESULTS: The pharmacokinetic properties of the active metabolite, des-cic, were equivalent after inhalation of ciclesonide with and without the AeroChamber Plus spacer. Point estimates and 90% confidence intervals (CIs) for the ratio of des-cic pharmacokinetic properties in the presence or absence of a spacer were within the conventional bioequivalence range of (area under the serum concentration time curve from time zero to infinity 0.96 [0.85, 1.07]; peak serum concentration 1.05 [0.94, 1.18]; elimination half-life 1.04 [0.92, 1.18]). Furthermore, there was no relevant difference in the point estimate and 90% CI of the difference of the time to reach peak serum concentration of des-cic with or without a spacer. CONCLUSION: The AeroChamber Plus spacer did not influence the pharmacokinetics of the pharmacologically active des-cic. Thus, systemic exposure to the active metabolite is similar when ciclesonide is inhaled with or without a spacer. Furthermore, these results are indicative of comparable lung deposition of ciclesonide in both the presence and absence of a spacer. F. Chambers, A. Ludzik, Charnwood. [Poster Board #K29] Comparative Performance Evaluation of the Aero- Chamber MAX*VHC with AeroChamber Plus* Using Budesonide and Formoterol (BUD/FM) in One Pressurized Metered-Dose Inhaler (pmdi), [Publication Page: A196]. Leicestershire, England. Pediatr Allergy Immunol Aug;18(5): Rationale: We compared the performance of the AeroChamber MAX* VHC (Trudell Medical International, London, Ontario, Canada), a new valved holding chamber (VHC) with improved antistatic properties, with the AeroChamber Plus* (Trudell) when used with a pmdi containing BUD/FM at 2 strengths (80/4.5 or 160/4.5 g per actuation). Methods: The effect of different administration techniques on delivered dose and particle size distribution as measured by Andersen cascade impactor (ACI) was investigated. Three spacer administration techniques were investigated: 2 actuations of BUD/FM into the VHC connected to the impactor/filter with applied continuous airflow, 2 actuations with a 2-second delay between each actuation and collection, and 2 actuations together followed by a 2-second delay before collection. For comparison purposes, 2 actuations from the pmdi (no delay) were fired into the ACI. Results: The fine particle dose (FPD) profiles of both (BUD/FM)/VHC combinations were similar to that of BUD/FM pmdi alone when delay between actuation and administration was minimized. There were no significant differences in the FPD profiles of either BUD or FM. AeroChamber MAX* VHC was found to be more robust when delays between actuation and administration were encountered, although a reduction in BUD/FM FPD was observed from both VHCs when delays between actuation and collection were introduced. Conclusions: Both AeroChamber MAX* VHC and AeroChamber Plus* can be used effectively with BUD/FM pmdi. Performance of the (BUD/FM)/VHC combination is similar to BUD/FM pmdi alone when delay between actuation and administration is kept to a minimum. The FPD profile of the AeroChamber MAX* VHC is more robust than that of the AeroChamber Plus* when delays between actuation and administration are encountered, possibly due to the antistatic properties of the construction materials.

3 von Berg A, Engelstätter R, Minic P, Sréckovic M, Garcia Garcia ML, Lato_ T, Vermeulen JH, Leichtl S, Hellbardt S, Bethke TD. Comparison of the efficacy and safety of ciclesonide 160 microg once daily vs. budesonide 400 microg once daily in children with asthma. Marienhospital Wesel, Wesel, Germany. Ciclesonide is an onsite-activated inhaled corticosteroid (ICS) for the treatment of asthma. This study compared the efficacy, safety and effect on quality of life (QOL) of ciclesonide 160 microg (ex-actuator; nominal dose 200 microg) vs. budesonide 400 microg (nominal dose) in children with asthma. Six hundred and twenty-one children (aged 6-11 yr) with asthma were randomized to receive ciclesonide 160 microg (ex-actuator) once daily (via hydrofluoroalkane metered-dose inhaler and AeroChamber Plus spacer) or budesonide 400 microg once daily (via Turbohaler) both given in the evening for 12 wk. The primary efficacy end-point was change in forced expiratory volume in 1 s (FEV1). Additional measurements included change in daily peak expiratory flow (PEF), change in asthma symptom score sum, change in use of rescue medication, pediatric and caregiver asthma QOL questionnaire [PAQLQ(S) and PACQLQ, respectively] scores, change in body height assessed by stadiometry, change in 24-h urinary cortisol adjusted for creatinine and adverse events. Both ciclesonide and budesonide increased FEV1, morning PEF and PAQLQ(S) and PACQLQ scores, and improved asthma symptom score sums and the need for rescue medication after 12 wk vs. baseline. The non-inferiority of ciclesonide vs. budesonide was demonstrated for the change in FEV1 (95% confidence interval: -75, 10 ml, p = , one-sided non-inferiority, per-protocol). In addition, ciclesonide and budesonide showed similar efficacy in improving asthma symptoms, morning PEF, use of rescue medication and QOL. Ciclesonide was superior to budesonide with regard to increases in body height (p = 0.003, two-sided). The effect on the hypothalamic-pituitary-adrenal axis was significantly different in favor of ciclesonide treatment (p < 0.001, one-sided). Both ciclesonide and budesonide were well tolerated. Ciclesonide 160 microg once daily and budesonide 400 microg once daily were effective in children with asthma. In addition, in children treated with ciclesonide there was significantly less reduction in body height and suppression of 24-h urinary cortisol excretion compared with children treated with budesonide after 12 wk. Coppolo, D.P.,Mitchell, J.P., Doyle, C.C., Avvakoumova, V.A., Nagel, M.W. A Valved Holding Chamber from Non Electrostatic Materials Has More Effective Medication Delivery Compared with a Similar-Sized Non Conducting Device When Used Out-of-Package. ATS International Conference. San Francisco, Proc. Amer Thoracic Soc. 4(abstracts issue) [Publication Page: A639]. Manufacturers advise pre-conditioning VHCs with detergent to mitigate electrostatic charge that reduces medication delivery. These instructions may not be followed in hospital where time-to-treat is critical, or at home due to noncompliance. We report a study in which the delivery of an anticholinergic agent used to treat COPD (Atrovent -HFA, Boehringer Ingelheim (Canada) Ltd. 20- g/actuation ipratropium bromide ex metering valve) via a VHC manufactured from electrostatic charge-dissipative materials (AeroChamber Z-Stat Plus, Monaghan Medical Corp., Plattsburgh, NY) was compared with a similar-sized non-conducting VHC (OptiChamber Advantage, Respironics Inc., Cedar Grove NJ, USA), evaluated directly from their packaging (n=3 devices/group). Measurements of the fine particle fraction (FPF) contained in particles < 4.0 m aerodynamic diameter were made at 30 L/min using a Next Generation Pharmaceutical Impactor with no delay, 2-s and 5-s delay between pmdi actuation and sampling. The total emitted mass (TEM) of ipratropium bromide was quantified by HPLC-UV spectrophotometry, and fine particle mass (FPM) was determined as the product of TEM and FPF. FPF was <82% for both VHC groups. Values of FPM (mean SD, g/actuation) for the AeroChamber Z-Stat plus VHCs were: no delay; s delay, s delay). Equivalent data for the OptiChamber Advantage VHCs were: no delay; s delay; s delay. FPM ex OptiChamber Advantage was significantly less that from the charge-dissipative AeroChamber Z-Stat Plus VHC (un-paired t-test at each condition, p 0.018). Clinicians should be aware of the dosing implications, especially where there is the likelihood that pre-washing will not be performed.

4 Louca E, Leung K, Coates A, Mitchell J, Nagel M. Comparison of Three Valved Holding Chambers for the Delivery of Fluticasone Propionate to an Infant Face Model. J Aerosol Med Summer; 19 (2): The purpose of this study was to compare drug delivery efficiency of three valved holding chambers (VHC) with facemasks. The AeroChamber MAX* made of electrostatic dissipative material was compared with two non-conducting VHCs, the OptiChamber Advantage and ProChamber. The OptiChamber Advantage and ProChamber were washed with a mild ionic detergent and dripped dried to minimize electrostatic charge. The AeroChamber MAX* was tested out of the package and after wash, rinse and drying. A realistic infant face model with an electrostatic filter in the oral cavity was connected to a breath simulator set for a standard waveform for a small child. Facemask fit was demonstrated by agreement of simulator settings with inspiratory flow measurements from a flow pneumotachograph connected to the system. Randomized and blinded studies were performed using an HFA-fluticasone propionate MDI (125µg/dose), and filters were assayed using high-pressure liquid chromatography (HPLC). Drug delivery efficiency expressed as a percentage of the total dose of fluticasone propionate (250µg) for the Aero- Chamber MAX* out-of-the-package was 22.0(0.9)% (mean (95% CI)) and 20.5(1.3)% when pre-washed/rinsed. Results for the ProChamber and OptiChamber Advantage were 10.4(1.9)% and 7.8(1.9)% respectively. Improved delivery of medication via VHCs made from electrostatic charge dissipative materials should be considered when choosing appropriate doses for small children. Geller DE, Kesser KC. Effects of Pretreatment of Static and Nonstatic Holding Chambers (HC) on the Delivery of Flovent 110-HFA (F) in an Infant Airway Model. Presented at the American Thoracic Society Conference, May, Infants often receive inhaled drugs via metered dose inhalers and HCs with masks. Static within HCs reduces the drug available for inhalation. Priming or washing of HCs may reduce static, and newer HCs incorporate antistatic surfaces in their design. Purpose: To compare predicted lung delivery to infants of F using 3 different HC types under 3 conditions: unused, primed, and washed. Methods: HCs were AeroChamber MAX* (AM; antistatic polymer), PARI Vortex (PV; antistatic coating), and the Optichamber Advantage (OA; no antistatic tx), all with proprietary facemasks. HCs were tested in this order: 1) out-of-package; 2) primed with 14 puffs of F110; 3) washed with detergent, rinsed and air-dried. The SAINT (9 mo-old nose-throat model) was coated with Brij/glycerol to mimic a mucus coating; simulated breath pattern was Vt 100 ml, rate 30, I:E 1:1.3. F-110 was actuated into the chamber 2 seconds prior to inspiration, 6 breaths/puff, 4 puffs per test. F was captured on an absolute filter distal to the SAINT. Drug captured on the filter represents lung dose; drug rinsed from the SAINT is throat dose. F was assayed by HPLC. Results: The highest lung dose was achieved with the AM. Lung dose with AM was consistent whether out-of package, primed or washed (14.8, 18.7, 15.3 µg per actuation respectively). The lung dose was substantially higher with the AM than the PV, which in turn was higher than the OA, under all pretreatment conditions. The inhaled dose (lung + throat) was also highest with AM, suggesting lower chamber static, better valve design, and/or better facemask design and fit. Conclusion: The AM delivers significantly more F using this lung model and is consistent whether new, primed or washed. This large improvement in efficiency may be clinically significant. Caregivers should individualize dose to achieve minimal effective dose and monitor for side effects of medications. Coppolo D.P., Mitchell, J.P., Nagel, M.W. Levalbuterol Aerosol Delivery with a Non-Electrostatic Versus a Non- Conducting Valved Holding Chamber. Respiratory Care, May 2006, Vol 51, No 5. BACKGROUND: Hydrofluoroalkane-propelled levalbuterol (Xopenex) aerosol is a recently approved formulation for delivery via metered-dose inhaler for the treatment or prevention of bronchospasm in adults, adolescents, and children 4 years of age who have reversible obstructive airway disease. Valved holding chambers (VHCs) made from conventional polymers are susceptible to accumulation of electrostatic charge, which can be minimized by rewashing with ionic detergent, but it may be desirable to be able to use the product straight from the package, without pretreatment, especially during an exacerbation. METHODS: We studied the performance of the AeroChamber Plus* VHC and AeroChamber MAX* VHCs in delivering hydrofluoroalkane-propelled levalbuterol. Both VHCs were prewashed, rinsed and drip-dried before testing. The AeroChamber MAX* VHC is manufactured from charge-dissipative material and was therefore also evaluated without prewashing.

5 [continued] Aerosol samples were collected at 28.3 L/min with an Andersen 8-stage cascade impactor, per the procedure specified in Chapter 601 of the United States Pharmacopeia. RESULTS: The mean ± SD fine-particle mass (mass of aerosol particles < 4.7 µm aerodynamic diameter) values were 33.5 ± 1.4 µg and 36.3 ± 1.1 µg with the AeroChamber MAX* VHC, without and with wash/rinse pretreatment, respectively, and 28.5 ± 2.4 µg with the prewashed AeroChamber Plus* VHC. CONCLUSIONS: We think the small differences we observed are unlikely to be of clinical importance, given the inter-patient variability seen with inhaled drug delivery. The performance of the AeroChamber MAX* VHC was substantially comparable whether or not it was prewashed. Rau JL, Coppolo DP, Nagel MW, Avvakoumova V, Doyle CC, Wiersema KJ, Mitchell JP. The Importance of Nonelectrostatic Materials in Holding Chambers for Delivery of Hydrofluoroalkane Albuterol. Respiratory Care, May 2006, Vol 51, No 5. INTRODUCTION: Electrostatic attraction of aerosolized particles to the inner walls of an aerosol holding chamber (HC) made from a nonconducting material can reduce medication delivery, particularly if there is a delay between actuation and inhalation. OBJECTIVE: Compare total emitted mass and fine-particle mass (mass of particles < 4.7 µm) of hydrofluoroalkane-propelled albuterol from similar-sized HCs manufactured from conductive material (Vortex), charge-dissipative material (AeroChamber MAX* VHC), and nonconductive material (OptiChamber Advantage, ProChamber, Breathrite, PocketChamber, and ACE), with and without wash/rinse pretreatment of the HC interior with ionic detergent, and with 2-s and 5-s delays between actuation and inhalation. METHODS: All the HCs were evaluated (1) directly from their packaging (with no wash/rinse pretreatment) and (2) after washing with ionic detergent and rinsing and drip-drying. We used an apparatus that interfaced between the HC mouthpiece and the induction port of an 8-stage Andersen cascade impactor to simulate a poorly coordinated patient, with delays of 2 s and 5 s between actuation and inhalation/sampling at 28.3 L/min. RESULTS: With the 2-s delay, the delivered fine-particle mass per actuation, before and after (respectively) wash/rinse pretreatment was: AeroChamber MAX* VHC: 23.8 ± 4.8 µg, 21.5 ± 3.2 µg; Vortex: 16.2 ± 1.7 µg, 15.5 ± 2.0 µg; OptiChamber Advantage: 2.6 ± 1.2 µg, 6.7 ± 2.3 µg; ProChamber: 1.6 ± 0.4 µg, 5.1 ± 2.5 µg; Breathrite: 2.0 ± 0.9 µg, 3.2 ± 1.8 µg; PocketChamber: 3.4 ± 1.6 µg, 1.7 ±1.6 µg; ACE: 4.5 ± 0.9 µg, 5.4 ± 2.9 µg. Similar trends, but greater reduction in aerosol delivery, were observed with the 5-s delay. Significantly greater fine-particle mass was delivered from HCs made from conducting or chargedissipative materials than from those made from nonconductive polymers, even after wash/rinse pretreatment (p < 0.01). The fine-particle mass was also significantly greater from the AeroChamber MAX* VHC than from the Vortex, irrespective of wash/rinse pretreatment or delay interval (p < 0.01). CONCLUSION: HCs made from electrically conductive materials emit significantly greater fine-particle mass, with either a 2-s or 5-s delay, than do HCs made from nonconducting materials, even with wash/rinse pretreatment. Khan YR. Relative Amount of Fluticasone Delivered by HFA-MDI to Children of Different Ages. J Allergy Clin Immunol, Vol 117, #2, S91, February RATIONALE: We hypothesized that less fluticasone propionate (FP) is delivered by MDI to the airways of children <5 yr who passively inhale through a mask/valved holding chamber (VHC) than to older children who inhale deeply and breath hold. The 1-hr steady-state FP plasma concentration was used as an indirect measure of the relative amount deposited in the lungs and a direct measure of systemic exposure. METHODS: Sixty children with well controlled persistent asthma received FP 2x110 µg BID for 3 days, delivered by HFA-MDI through a device they used effectively. This higher dose is routine in our clinic. 100% adherence, documented by electronic monitor, was required. Five groups of 12 each were studied; 1) yr by actuator alone; 2) 5-9 yr by actuator alone; 3) 5-9 yr by antistatic VHC/mouthpiece (AeroChamber MAX*); 4) 5-9 yr by antistatic VHC/mask; and 5) 1-4 yr by antistatic VHC/mask. FP was measured by an LC-MS/MS assay with a 13% CV for precision at 5 pg/ml. RESULTS: The mean±sd concentrations in pg/ml were: yr actuator, 76±61; 5-9 yr actuator, 87±80; 5-9 yr VHC/mouthpiece, 207±149; 5-9 yr VHC/mask, 140±61; and 1-4 yr VHC/mask, 165±58. The mean concentration in the yr actuator group was significantly lower than VHC groups (p=0.003), but not different from the 5-9 yr actuator alone group. CONCLU- SIONS: There was a device but not an age-related difference in deposition. The antistatic VHC improved deposition of HFA-FP and compensated for passive inhalation in children 1-4 yr.

6 Mitchell JP, Wiersema KJ, Doyle CC, Nagel MW, Coppolo DP. Fine Particle Delivery of Levalbuterol is substantially comparable from valved holding chambers (VHCs), one of which is manufactured from a transparent, but electrostatic charge dissipative polymer. Presented at AARC Open Forum, December, Xopenex HFA (45 µg/actuation levalbuterol tartrate ex actuator) inhalation aerosol (Sepracor Inc., Marlborough, MA, USA), is a recently approved hydrofluoroalkane (HFA) formulation for delivery by pressurized metered-dose inhaler (pmdi) for the treatment or prevention of bronchospasm in adults, adolescents and children 4 years of age and older with reversible obstructive airway disease. VHCs are prescribed for patients that have difficulty coordinating pressurized metered-dose pmdi use, but those made from conventional polymers are susceptible to accumulation of electrostatic charge during manufacture. Whereas such charge can be minimized by pre-washing with ionic detergent, it may be desirable to be able to use the product straight from the packaging without pre-treatment, especially in the case of an acute exacerbation. We report a study in which two VHCs (AeroChamber Plus* VHC and AeroChamber MAX* VHC with mouthpiece, Monaghan Medical Corp., Plattsburgh, NY (n=10 devices/group)) were evaluated with Xopenex HFA. Both VHCs were pre-washed, rinsed and drip-dried before testing in accordance with the manufacturer s instructions. The AeroChamber MAX* VHC is manufactured from charge dissipative materials, and was therefore also evaluated without pre-washing. Measurements were made at 28.3 L/min ± 5% by Andersen 8-stage cascade impactor equipped with USP induction port in accordance with the procedure in <601> of the US Pharmacopeia. 10- actuations of medication were delivered via the VHC on test, and the mass of levalbuterol collecting in the induction port and on each stage of the impactor was subsequently assayed by HPLC-UV spectrophotometry. Fine particle mass (particles < 4.7 µm aerodynamic diameter), considered most likely to penetrate to the airways of the lungs, was 28.8 ± 2.4 µg, 33.5 ± 1.5 and 36.5 ± 1.0 µg for the AeroChamber Plus* VHC (pre-washed), AeroChamber MAX* VHC (pre-washed) and AeroChamber MAX* VHC (no pretreatment) VHCs respectively. Although small differences existed between these results, they are unlikely to be of clinical significance given the inter-patient variability seen with inhaled drug delivery (1). The performance of the AeroChamber MAX* VHC was substantially comparable whether or not the devices were pre-washed. (1) Cripps,A.; Riebe,M.; Schulze,M. et al., Respir. Med. 2000; 94Suppl.B:3-9. Nagel MW, Wiersema KJ, Avvakoumova V, Mitchell JP. A More Meaningful Test for Valved Holding Chamber (VHC) Performance Based on Delay Following Inhaler Actuation. Presented at DDL XVI, December, 2005 A recently introduced Canadian Standard introduced the concept of a 2-s delay for the in vitro evaluation of VHC performance in terms of fine particle delivery, since this approach provides a closer approximation of reality when used by the poorly coordinated patient. We present results from a study carried out in accordance with this standard, in which two variants of the AeroChamber MAX* VHC (n=3/group, 3 replicates/device), were evaluated with an HFA-solution formulation (Qvar ). Values of fine particle mass (FPM) from the mouthpiece and medium facemask variants (particles < 4.7 µm aerodynamic diameter) with the 2-s delay were 43.1 ± 4.3 µg and 39.8 ± 6.1 µg respectively. These values compared with 37.1 ± 2.3 µg from pmdi alone (no delay). The incorporation of a delay following inhaler actuation meets the goal of providing meaningful data for clinicians at the patient interface as guidance to establish a dosing regimen for the uncoordinated patient. Mitchell JP, PhD 1, Avvakoumova V, BSc1, Doyle CC, BSc1, Wiersema KJ, BA1, Nagel MW, HBSc1, Cripps AL, PhD2 and Malcolm H, BSc. CANADA and 2Inhalation Product Development, GlaxoSmithKline plc, Ware, UNIT- ED KINGDOM. A Small Volume Valved Holding Chamber (VHC) Manufactured From Charge Dissipative Materials Has Comparable In Vitro Performance with a Large Volume Non-Conducting Plastic Spacer for Both Bronchodilator and Anti-Inflammatory Formulations. Presented at the European Respiratory Society (ERS) Annual Congress, September, It is important for VHC users to have a device that is convenient and as compact as possible. We report a study in which a new small non-electrostatic VHC (AeroChamber MAX* VHC (ACMax), Trudell Medical International,

7 [continued] Canada, 198-mL) was compared with a traditional large VHC (Volumatic (VOL), GlaxoSmithKline (GSK), UK, 850-mL) for the delivery of two strengths of salmeterol (SX)/fluticasone propionate (FP) (Seretide -HFA 50 and 250, GSK plc), as well as with salmeterol (Serevent -HFA, Serevent -CFC, GSK plc). Measurements of fine particle mass ( µm aerodynamic diameter)/actuation (FPM, µg) were made by Andersen 8-stage impactor at 28.3 L/min in accordance with the compendial procedure in Ph.Eur. All VHCs (n=5/group) were pre-washed with detergent, rinsed and drip-dried. Although there were small differences between mean values for the VHCs that were typically < 20%, neither group delivered consistently greater FPM (Table). FPM (µg) delivery comparison Formulation ACMax- FPM (mean SD) VOL-FPM (mean SD) Seretide 50-FP Seretide 50-SX Seretide 250-FP Seretide 250-SX Serevent -HFA Serevent -CFC Mitchell J, Avvakoumova V, Doyle C, Wiersema K, Nagel M, Cripps A, Malcolm H. Large and small volume valved holding chambers (VHCs) have comparable in vitro performance with HFA formulation. Presented at the World Allergy Conference, June, Background: VHCs are an important adjunct in the delivery of medication in the form of particles finer than about 5 µm aerodynamic diameter from a pressurized metered dose inhaler (pmdi) to the lower respiratory tract. For some patients, they facilitate the use of a pmdi, but there are advantages for the patient if the device can be kept small, yet deliver medication efficiently. Methods: We report a study in which a new VHC (AeroChamber MAX* VHC 198ml, Trudell Medical International) manufactured from transparent electrostatic charge dissipative materials was compared with a large volume VHC (Volumatic ml, GlaxoSmithKline plc) for the fine particle delivery of a variety of HFAbased formulations commonly prescribed to treat lung disease involving broncho-constriction and inflammation. The particle size distribution was determined using an Andersen 8-stage cascade impactor operated at 28.3 L/min ± 5% and assays for active pharmaceutical ingredient(s) (APIs) were undertaken by HPLC-UV spectrophotometry, except for salmeterol xinafoate, which was assayed using fluorescence detection. The VHCs (n=5 group) were pre-washed in mild detergent, rinsed and drip-dried to minimize any influence of electrostataic charge, although the AeroChamber MAX* VHC can also be used out of the package with comparable performance in cases where the patient does not comply with instructions to pre-wash (Mitchell, JP et al (2004). Respiratory Drug Delivery 9; ). Results: The results are summarized in the table (n=5 replicates/condition; mean ± SD). Formulation Drug Substance AeroChamber MAX* Volumatic FPM (µg) FPM (µg) Flixotide - HFA 50 fluticasone propionate 25.1 ± ± 3.0 Flixotide - HFA 250 fluticasone propionate ± ± 14.0 Ventolin - HFA salbutamol 36.7 ± ± 1.8 Seretide - 50 fluticasone propionate 22.0 ± ± 2.7 Seretide - 50 salmeterol 10.3 ± ± 1.4 Seretide fluticasone propionate ± ± 8.6 Seretide salmeterol 12.1 ± ± 0.9 Fine particle mass (FPM) is the summed deposition on stages 3 to 5 of the cascade impactor, representing particles in the range from 1.1 to 4.7 µm aerodynamic diameter. Conclusions: Both small and large volume VHCs delivered substantially equivalent FPM with all of the formulations that were evaluated.

8 Mitchell JP, Rau JL, Coppolo D, Nagel MW, Avvakoumova V, Doyle CC, Wiersema KJ. Is the Use of Electrostatic Charge-Dissipative Materials Effective as a means of Improving Aerosol Delivery by Valved Holding Chamber (VHC) to the Poorly Coordinated Patient? American Thoracic Society 101st International Conference, May, Particle deposition caused by electrostatic attraction to the walls of VHCs made from nonconducting materials can reduce performance, particularly if inhalation is delayed. We report a study in which delivery of Ventolin -HFA via a new VHC (AeroChamber MAX* (Trudell Medical International)) manufactured from charge-dissipative materials was compared with other non-conducting VHCs (OptiChamber Advantage (Respironics), ProChamber (Respironics), Breathrite (Ventlab Corp.), PocketChamber (Ferraris Medical Inc.) and ACE (DHD) as well as with a metal device with some non-conducting parts (Vortex (PARI Respiratory Equipment Inc.). All VHCs (n=5 devices/group) were washed in mild detergent, rinsed and drip-dried before use in accordance with manufacturers instructions and FDA requirements. An apparatus that interfaced between the VHC mouthpiece and induction port leading to an 8-stage Andersen cascade impactor was used to simulate 2- and 5-s delay intervals between pmdi actuation and the onset of sampling at 28.3 L/min. Values of fine particle mass (FPM ( g/actuation)) are summarized in the table. FPM for the pmdi alone (no delay) was 28.5 ± 2.5 µg. The AeroChamber MAX* VHCs significantly outperformed the other devices even after pre-washing to mitigate electrostatic charge (1- way ANOVA at each delay interval, p < 0.05). Fine particle mass < 4.7 μm aerody.namic diameter ( μg): mean ±SD VHC 2-s delay 5-s delay AeroChamber MAX* 21.2 ± ± 0.8 Vortex 15.5 ± ± 2.7 OptiChamber Advantage 6.7 ± ± 1.3 ProChamber 5.1 ± ± 0.3 Breathrite 3.2 ± ± 0.4 PocketChamber 1.7 ± ± 0.5 ACE 5.4 ± ± 1.4 Mitchell JP, Avvakoumova V, Doyle CC, Wiersema KJ, Nagel MW, Cripps AL, Malcolm H. Large and Small Volume Valved Holding Chambers (VHCs) have comparable In Vitro Performance with HFA Formulations. Drug Delivery to the Lungs XV, December, We report a study using an Andersen 8-stage cascade impactor operated at 28.3 L/min in which a new VHC (AeroChamber MAX* -198-ml, Trudell Medical International) manufactured from transparent electrostatic charge dissipative materials was compared with a large volume VHC (Volumatic ml, GlaxoSmithKline plc) for the fineparticle delivery of a variety of hydrofluoroalkane (HFA)-based formulations commonly prescribed to treat lung disease involving broncho-constriction and inflammation (Ventolin-HFA, Flixotide-HFAand Seretide). The VHCs (n=5/ group) were prewashed in mild detergent, rinsed and air-dried to minimize any influence of electrostatic charge. Both small and large volume VHCs delivered substantially equivalent fine particle mass (FPM) with all of the formulations that were evaluated. Nagel MW, Mitchell JP, Louca E, Leung K, Coates AL. Comparison of Three Valved Holding Chambers (VHCs) for thedelivery of HFA-Fluticasone Propionate to an Infant Face Model. Drug Delivery to the Lungs XV, December, We report a study in which a new artificial infant face with realistic surface texture (ADAM) was evaluated with three different pediatric VHCs, each equipped with its facemask. Each VHC (n=3/group) was applied to the face with 1.6 kg force, based on optimum measurements made in an asthma clinic, and sealing of the mask to the face was cofirmed. A filter located behind the lips was connected to a breathing simulator that was operated representing a small child (155-ml tidal volume, 0.8 s inspiration, 1.6 s expiration). Drug delivery expressed as a percentage of the total dose of fluticasone propionate (250 μg/2 actuations) delivered was: AeroChamber MAX* VHC out-of package 22.0(0.9)% (mean (95% CI)) and 20.5(1.3)% pre-washed/rinsed/drip-dried ; ProChamber 10.4(1.9)% pre-washed/drip-dried ; OptiChamber Advantage VHCs 7.8(1.9)% (pre-washed/drip-dried).

9 Mitchell JM, Wiersema KJ, Doyle CC, Nagel MW. Improved Performance from a Valved Holding Chamber (VHC) with Body Manufactured from a Transparent, but Electrostatic Charge Dissipative Polymer. Presented at the AARC Open Forum, New Orleans, December, Resp Care Journal, 49(11), Particle deposition caused by electrostatic attraction to the walls of VHCs made from nonconducting polymer can significantly reduce pressurized metered dose inhaler (pmdi) medication delivery, especially at first use (1). This study explored the potential for improved performance with a new VHC with body manufactured from a transparent custom charge dissipative polymer (AeroChamber MAX*, Monaghan Medical Corp., Plattsburgh, NY), compared with a conventional transparent, but non-conducting VHC (ProChamber, Respironics Inc., Cedar Grove, NJ). Before testing, both groups of devices (n=3/group) were pre-washed in ionic detergent following each manufacturer s instructions. Fine particle mass/actuation (FPM), based on particles < 4.7 µm aerodynamic diameter, was determined by Andersen 8-stage cascade impactor at 28.3 L/min ± 5% in accordance with <601> of the US Pharmacopeia. A 2-s delay was introduced between pmdi actuation and sampling via the impactor to simulate use by poorly coordinated patients. 15-actuations of Combivent (Boehringer-Ingelheim (Canada) Ltd., Mississauga, ON (18 µg ipratropium bromide (IPR) + 90 µg albuterol base equivalent (ALB)) were delivered at 30-s intervals from a pre-primed canister. This formulation carried a significant electrostatic charge (+170 ± 80 pc (mean ± SD)), based on 5 separate actuations from a single pmdi into a Faraday cup electrometer. Values of FPM (mean ± SD) are summarized in the Table. VHC type FPM (μg) Mass Retained by VHC (μg) ALB IPR ALB IPR AeroChamber MAX* 41.4 ± ± ± ± 0.3 ProChamber 18.1 ± ± ± ± 0.9 FPM from the AeroChamber MAX* VHCs was significantly greater than that from the ProChamber VHCs (unpaired ttest, p < 0.001), and was associated with decreased retention of both ALB and IPR by the VHC by the former chamber (p < 0.001). The use of charge dissipative materials is more effective than pre-washing a nonconducting device for the delivery of this formulation, and is likely to lead to a better therapeutic outcome for the uncoordinated patient prescribed a VHC. (1) Piérart, F., Wildhaber, J.H., Vrancken, I. et al., Eur. Respir J. 1999;13: Coates AL, Louca E, Leung K, Nagel MW, Mitchell JP. In Vitro Comparison of Valved Holding Chambers (VHCs) with Facemasks Using an Infant Face Model. American College of Chest Physicians Annual Meeting, in CHEST, 2004, 126, 910s. The delivery of aerosolized medication from pressurized metered-dose inhalers (pmdis) by VHC with facemask that is often prescribed for infants and small children is influenced by surface electrostatic charge. Our study attempted to examine medication delivery via VHC with facemask attached, using a model infant face (ADAM) based on a Laerdal head mannequin, modified to simulate natural facial texture. VHCs manufactured from a transparent, electrostatic charge dissipative polymer (AeroChamber MAX* with child mask, Monaghan Medical Corp., Plattsburgh NY) were compared with similar sized VHCs manufactured from non-conducting polymer (OptiChamber Advantage with medium facemask, Respironics Inc., Cedar Grove, NJ.) The AeroChamber MAX* VHCs were tested out-ofthe-package and pre-washed with detergent solution followed by rinsing. The OptiChamber Advantage VHCs were pre-washed but not rinsed to confer the maximum benefit of detergent coating as a means of reducing electrostatic charge. 2 actuations of fluticasone propionate ((FP), 125 µg/actuation, Flovent HFA, GSK Inc., Canada) were delivered s apart. Total mass via AeroChamber MAX* VHC with no pre-treatment was 55.1 (2.29) µg (mean (95% CI)), comparable with 51.3 (3.29) µg with pre-treatment. Total mass via OptiChamber Advantage VHCs was 19.4 (4.76) µg. The use of electrostatic charge dissipative materials for the VHC is more effective than pre-treatment of a non-conducting VHC by washing in ionic detergent.

10 Mitchell JP, Doyle CC, Avvakoumova V, Nagel MW. In vitro performance of a new non-electrostatic, transparent valved holding chamber (VHC) for the poorly coordinated patient. European Respiratory Society Conference, September, VHCs are often prescribed for pediatric patients having difficulty coordinating pressurized metered dose inhaler (pmdi) use. Electrostatic charge results in loss of medication during the interval after inhaler actuation before inhalation takes place. We report a study in which a new non-electrostatic VHC (AeroChamber MAX*, Trudell Medical International, Canada (AC-MAX)) was compared with metal-bodied non-electrostatic (Vortex, PARI, USA) and transparent non-electrostatic VHCs (OptiChamber Advantage, Respironics, USA (OPT)) (n=5 devices/group) for the delivery of Flovent HFA (125 µg/actuation fluticasone propionate, GSK Inc., Canada). Each VHC was washed in ionic detergent and rinsed before use in accordance with manufacturer cleaning instructions. Fine particle mass/actuation (FPM < 4.7 µm aerodynamic diameter) was determined by Andersen 8-stage impactor (CI) operated at 28.3 L/min in accordance with the European Pharmacopeia (EP). A novel apparatus interposed a shutter between the VHC and the EP induction port entry to the CI that opened 5-s after pmdi actuation, simulating delayed inhalation. Fine particle fraction of the emitted dose with delay was close to 95% for each VHC. FPD for AC-MAX (mean SD) was 48.4 ± 2.0 µg, significantly greater than 26.2 ± 3.7 µg (Vortex) and 8.3 ± 2.8 µg (OPT) (1-way ANOVA, p < 0.001), and only slightly less than 55.3 ± 4.0 µg for the pmdi alone with no delay (p = 0.008), representing perfect coordination. This in vitro study may have significant clinical implications. Asmus MJ, Hochhaus G, Tang Y, Spencer LT, Sturtz P, Hendeles L. Impact of a New Anti-Static Valved Holding Chamber on Airway Delivery of Inhaled Fluticasone Propionate in Asthmatic Children. American Thoracic Society 100th International Conference, May, The only effective way to administer fluticasone propionate (FP) to young asthmatic children in the United States is via metered-dose inhaler (MDI) attached to a valved holding chamber (VHC) with mask. Using this method, several factors potentially influence the amount of FP delivered to the patient s airways, including electrostatic charge on the VHC. Since FP peak plasma concentrations are directly proportional to inhaled dose, we used the 1-hour post-dose FP plasma concentration to estimate relative airway delivery in young children from a MDI attached to a conventional VHC with mask, and a new VHC with mask made from electrostatic charge resistant plastic. FP plasma concentrations were determined in 12 children ( yr) with adequately-controlled persistent asthma 1-hour after inhaling 2x110 µg/puffs of FP MDI with HFA-134a propellant BID for at least 3 days through a conventional VHC with mask (AeroChamber Plus*, Monaghan) and the new anti-static VHC with mask (AeroChamber MAX*, Trudell) in a randomized crossover fashion. An electronic monitor confirmed perfect adherence. Subjects and parents were trained to adequately use each device. FP plasma concentrations were quantified by a novel LC-MS/MS assay. A paired student t-test was used to compare observed differences in the mean 1-hour FP plasma concentration after each device. Mean ±SD 1-hour FP plasma concentration was 185.6±134.2 pg/ml from the new anti-static VHC with mask, and 106.9±29.5 pg/ml from the conventional VHC with mask (p=0.035). The new anti-static VHC with mask improved delivery of FP to the airways by 70% in young children. FP concentrations after the anti-static VHC were in the same range as those measured in a previous study of older children (6-9 yr) using InspirEase with more efficient inhalation technique. Mitchell JP, Nagel MW, Doyle CC, Varallo VM. Performance of a New Valved Holding Chamber (VHC) with Non- Electrostatic Body: The Effect of Delay of Inhalation Following Actuation of the Pressurized Metered-Dose Inhaler (pmdi). American Thoracic Society 100th International Conference, May, VHCs made from conventional transparent polymers are susceptible to accumulation of electrostatic charge during manufacture. Whereas such charge can be removed by washing with ionic detergent, it is desirable to be able to use the product straight from the packaging without pre-treatment, especially in the case of an acute exacerbation of asthma. We report a study in which a new VHC (AeroChamber MAX*, Monaghan Medical Corp., Plattsburgh, NY) manufactured from a custom transparent polymer was compared with a metal-walled VHC ((Vortex, PARI Respiratory Equipment Inc., Monterey, CA) n=5 devices/group) for the delivery of an inhaled corticosteroid

11 [continued] (Flovent HFA, 125 µg/actuation fluticasone propionate (FP), GSK Inc., Mississauga, Canada). All devices were tested immediately after removal from their packaging with minimal handling. Measurements of fine particle dose (FPD, particles < 4.7 µm aerodynamic diameter) were made with no delay by Andersen 8-stage impactor at 28.3 L/min in accordance with Chapter 601 of the US Pharmacopeia. A purpose-built apparatus was used to enable equivalent measurements to be made with a 5-s delay following pmdi actuation without manipulating the VHC on test, and with the impactor operating continuously. Assay for FP was undertaken by HPLC-UV spectrophotometry. FPD for the AeroChamber MAX* and Vortex VHCs were 45.7 ± 1.5 µg and 33.8 ± 6.4 µg respectively with no delay and 37.2 ± 3.5 µg and 13.4 ± 2.2 µg with 5-s delay. Both groups of devices provided similar FPD with no delay as might be expected, given the use of non-electrostatic materials for their bodies. However, the AeroChamber MAX* VHCs were less susceptible to subsequent aerosol deposition within the chamber during the delay period. The finding may lead to a better therapeutic outcome especially for the poorly coordinated patient. Mitchell JP, Morton R, Schmidt JN, Snyder S, Doyle CC, Nagel MW. Overcoming Electrostatic Charge Retention in a New Valved Holding Chamber (VHC): In Vitro Performance Comparison with Current Devices. Respiratory Drug Delivery IX, April 2004; Particle deposition caused by electrostatic attraction to the walls of VHCs made from non-conducting polymer can significantly reduce pressurized metered dose inhaler (pmdi) medication delivery, especially at first use. Washing in ionic detergent followed by drip-drying to coat the interior surfaces with a conducting layer of surfactant is effective at counteracting these losses, but the process is time consuming and therefore inconvenient, especially in the hospital setting. A new VHC (AeroChamber MAX*, Trudell Medical International) has been designed in which the body is manufactured from an electrostatic dissipative but transparent custom polymer so that it can be used without pre-treatment. Aerosol formation is therefore visible to both health-care giver and patient. VHC volume (198 ml) has also been chosen to optimize the delivery of medication. The design intent is to ensure that most of the aerosol delivered to the VHC at MDI actuation remains suspended if a poorly coordinated patient delays inhalation for several seconds. An in vitro comparison of the AeroChamber MAX* VHC with similar sized OptiChamber Advantage (Respironics Inc., Cedar Grove, NJ) and Vortex (Pari Respiratory Equipment, Monterey, CA) VHCs (n=5/group) was undertaken with Flovent-HFA (125 µg/actuation fluticasone propionate (FP) to investigate use out of the packaging (i.e., no pre-wash) both with no delay between pmdi actuation and inhalation and with a 5-s delay. Both fine particle mass (FPM) and total emitted mass/actuation (TEM) (mean ± SD) for Flovent-HFA were greater for the group of AeroChamber MAX* VHCs both with and without delay (1-way ANOVA at each condition, p < 0.001). FPM decreased by 19% with delay for this group of VHCs, compared with 94% and 60% for the OptiChamber and Vortex VHCs, respectively. This decline was associated with increased internal deposition that was 40.8 ±3.4 µg for the AeroChamber MAX*, 93.9 ±4.0 µg for the OptiChamber, and 72.8 ±4.6 µg for the Vortex VHCs after the delay period. Nagel MW, Schmidt JN, Doyle CC, Varallo VM, Mitchell JP. Delay Testing of Valved Holding Chambers (VHCs) With a New Apparatus. Drug Delivery to the Lungs-XIV, December, We report a study in which VHCs (AeroChamber MAX* and OptiChamber Advantage were evaluated with HFA-fluticasone propionate (125µg/actuation), simulating inhalation delay. A microphone sensed pmdi actuation, starting a timer. Total emitted dose (TED) was determined by attaching the VHC mouthpiece to a filter during the delay interval using an adapter containing a shutter temporarily interposed so that airflow to the filter (28.3 L/min) was sampled outside the VHC. After the delay, the shutter fell away and the contents of the VHC were inhaled. TED was 71.7 ±4.1µg (no delay), 54.2 ±4.5 µg (2-s delay) and 43.0 ±1.8 µg (10-s delay) with the AeroChamber MAX* and 35.7 ±3.9 µg (no delay), 15.9 ±3.0 µg (2-s delay) and 5.6 ±2.7 µg (10-s delay) with the OptiChamber. This finding could have clinical implications for uncoordinated patients.

12 Nagel MW, Schmidt JN, Doyle CC, Varallo VM, Mitchell JP. In Vitro Performance of a New Non-Electrostatic Transparent Valved Holding Chamber (VHC). Drug Delivery to the Lungs-XIV, December, In J Aerosol Med., 2004, 17(3), 288. We report a study in which a VHC manufactured from a high conductivity optically transparent custom polymer (AeroChamber MAX*, Trudell Medical International, London, Canada) was compared with a metal VHC (NebuChamber, Astra-Zeneca, Lund, Sweden) for the delivery of budesonide (Pulmicort: 200 µg/actuation) by pressurized metered-dose inhaler. We evaluated each VHC (n=5/group) at 12 L/min by low-flow Marple-Miller Impactor with zero and 5-s delay between inhaler actuation and sampling. Fine particle dose <4.7 µm aerodynamic diameter was 51.9 ±2.8 µg and 44.3 ± 4.2 µg for the AeroChamber MAX* and Nebuchamber VHCs respectively with no delay, decreasing to 35.8 ±4.1 µg and 32.7 ± 3.9 µg respectively with delay. The performance of the optically transparent VHC compared favorably with that of the metal chamber. *AeroChamber MAX, AeroChamber AreoChamber Plus and AeroChamber Plus Z STAT are trademarks and registered trademarks of Monaghan Medical and Trudell Medical International. PN /08