The Aerosol Drug Management Improvement Team ADMIT Slide Deck 2018

Part 6 Aerosol device options Federico Lavorini

Evolution of Aerosol Drug Delivery Devices Courtesy by M. Dolovich

Devices generating drug aerosols Pressurised Metered-Dose Inhalers (pMDI) with and without spacers Breath-actuated Metered-Dose Inhalers Dry powder inhalers (DPIs) Soft mist inhaler (SMI) Nebulisers

Formulation Components Metering chamber Formulation Components Active drug Propellent Co-solvent Valve Metering of a single dose Pressing the stem disconnects the metering chamber Discharge of the dose from the metering chamber Courtesy by M. Dolovich

pMDI Technology Changes Propellant Suspension CFC BDP/FP Solution HFA QVAR Hardware valves, seals, canister Formulation Excipients, co-solvents Dose counter Spacers/Valved holding chambers

pMDI technology changes: HFA-driven pMDIs producing extrafine particles Low velocity “soft” spray; long plume duration Small droplet size and high lung deposition Clinically effective at half the dose of traditional pMDI

Spacers Spacers are extensions to a pMDI with a port at one end to which the pMDI is attached, a facemask or mouthpiece being fitted at the other end These devices constitute a volume into which the patient actuates the pMDI and from which the patient inhales without necessarily having to coordinate the two manoeuvres.

Categories of spacers Open tube spacers, that simply distance the inhaler from the patient’s oropharynx Holding chambers, which include a one-way inhalation valve, intended to retrain the aerosol within the device until the patient inhales Reverse-flow devices, in which the spray is fired either into a collapsible bag or into a small volume through which outside air is entrained Home-made spacer

Spacers increase lung deposition When a pMDI is used alone, medicine ends up in the mouth, throat, stomach and lungs When a pMDI is used with a spacer more medicine is delivered to the lungs Newman SP et al. Chest 1986

Reduction in respirable particles Spacers do not obviate all errors of inhalation technique Lengthy delay between pMDI actuation and inhalation from the spacer Reduction in respirable particles Firing multiple puffs into the spacer before inhaling Barry PW, O’Callaghan C. Brit J Clin Pharmacol , 1996

pMDI poor coordination Breath-actuated metered dose inhalers Advantages No hand-mouth co-ordination needed Usually higher lung deposition than a pMDI Disadvantages Contain propellants “Cold Freon” effect Only short-acting bronchodilator and BDP available pMDI poor coordination BA-pMDI same patient

Breath-actuated pMDIs: potential clinical benefits Review of a large number of patients in “real-life” primary care setting; Patients using breath-actuated pMDI: Better asthma control Trend to fewer asthma exacerbations Possibly used fewer healthcare resources Price et al, Respir Med 2003; 97: 12-19

DPI design

Turbulent Energy: √P= Q x R Mechanism of dispensing powder from a DPI Turbulent Energy: √P= Q x R Q=Inhalation flow, R= Inhaler resistance

DPI Resistance Handihaler 0.16 cmH2O1/2 Lmin-1 Diskus /Accuhaler 0.07 cmH2O1/2 Lmin-1 Turbohaler 0.12 Aerolizer 0.05 0 20 40 60 80 100 120 Inhalation Flow (L/min) 12 10 8 6 4 2 03 Pressure Drop (kPa) + - The lower the resistance, the higher the inhalation flow the higher the resistance, the lower the inhalation flow Al-Showair et al Respir Med 2007

DPI lung dose alters with inhalation flow 10 20 30 40 50 60 70 80 90 100 Inhalation Flow (l/min) Fine Particle Dose (%) THROAT DEPOSITION Turbohaler Aerolizer Accuhaler Palander, Clin Drug Invest 2000; Weuthen, J Aerosol Med 2002

Soft mist inhalers Multi-dose inhalers containing liquid formulations similar to those in nebulisers: Dose delivered in single breath Propellant-free Portable Higher lung deposition than traditional pMDI Low velocity (“soft”) sprays: likely reduction in coordination problems Only one marketed device so far: the Respimat®

Propellant-Free technologies under investigation (Dolovich) The Respimat is a marriage of pMDI portability with small-volume nebuliser ease of use. «metered dose liquid inhaler»

Nebulised aerosol is dynamic! Nebulised aerosol size is unstable in entrained ambient air and rapidly loses water vapour, decreasing size Nebulised aerosol is dynamic!

Drug Losses with Nebulisers Efficiency of conventional nebulizers Drug Losses with Nebulisers 60% 60 % 40 % 60% 40 % 36% Fill Dose Emitted Inhaled Lung Periphery 14% 6%

New generation nebulisers MicroAIR U22 Pari e-flow Aeroneb Respimat Developed over the past 10 years; evaluated in over 55 clinical trials in more than 1,400 subjects Bronchodilator, steroids, Insulin, morphine, interferon High lung deposition; portable, self-contained; EXPENSIVE

Breath enhanced (open vent) Nebuliser design variations Constant output Breath enhanced (open vent) Dosimetric (breath actuated)

Rau JL, et al. Respir Care 2004

Which inhaler is right for your patient? Inhaler devices & drugs > 250 = confusion! Which inhaler is right for your patient? “The proliferation of inhalation devices has resulted in a confusing number of choices for the health-care provider and in confusion for both clinicians and patients trying to use these devices correctly.” Crompton GK et al. Respir Med, 2006

Conscious inhalation possible Conscious inhalation not possible Prescription of inhalers in asthma and COPD: towards a rational, rapid and effective approach Patient Conscious inhalation possible Conscious inhalation not possible Inspiratory flow >30 L/min Inspiratory flow <30 L/min Hand breath coordination Hand breath discoordination Hand breath coordination pMDI + spacer DPI Ba-pMDI pMDI SMI pMDI +/- spacer pMDI +spacer Nebuliser P.N.R. Dekhuijzen, W. Vincken, J.C. Virchow, N. Roche, A. Agusti, F. Lavorini, W.M. van Aalderen, D. Price - Respiratory Medicine (2013) 107, 1817-1821