THE PRESS-AND-BREATHE pmdi ADDITIONAL TECHNOLOGIES FOR PRESSURIZED METERED DOSE INHALERS Steve Newman Scientific Consultant Nottingham, UK steve.newman@physics.org Compact, portable, convenient Asthma and chronic obstructive pulmonary disease (COPD) Reformulation with HFA propellants on-going But.many patients unable to use correctly Poor inhaler technique: variable lung dose Crucial errors may result in zero lung dose May give low lung dose even with correct technique ADDITIONAL pmdi TECHNOLOGIES Objectives More reliable lung dose Improved clinical response Novel actuators Breath-actuated pmdis Velocity-modifying devices Add-on devices Spacer devices Holding chambers Reverse-flow devices BREATH-ACTUATED pmdis Novel compact pmdis actuators Designed to overcome problem of poor coordination Contain standard pmdi canisters Fire the pmdi or release the dose automatically as the patient inhales Several already marketed Autohaler (developed by 3M Pharmaceuticals) EasiBreathe (developed by Ivax) MD Turbo (developed by Respirics) Other devices in development AUTOHALER BREATH-ACTUATED pmdi Image courtesy of 3M Pharmaceuticals Trigger: Latch Spring At rest Prepared for use Rocker Catch Re-setting Dose release Vane 1
AUTOHALER IMPROVES LUNG DEPOSITION IN POOR COORDINATORS Mean and SD data from Newman, S.P. et. al., (1991), Thorax 46, 712-716 AUTOHALER (3M PHARMACEUTICALS) Early model introduced circa 1970 Made loud click when triggered Non-selective bronchodilator isoproterenol Current model introduced 1988 Triggers at 20 to 40 L/min Virtually silent operation Marketed with both beta-2 agonist bronchodilator and corticosteroid products K-HALER (CLINICAL DESIGNS) Images courtesy of Clinical Designs Ltd. SMARTMIST (ARADIGM) Image courtesy of Aradigm Corporation K-Valve Mouthpiece cover Valve at rest Valve retains dose Valve releases dose Contains microprocessor Senses inhalation Only actuates at correct inhaled volume and flow rate Provides patient with feedback and can monitor adherence Probably too bulky and expensive for routine asthma therapy Potentially more useful for specialized applications BENEFITS OF BREATH-ACTUATED pmdis Primary health-care review* of > 5000 asthma patients showed those using breath-actuated pmdi Needed fewer prescriptions & physician consultations Had better controlled asthma Used fewer health-care resources More expensive than press-and-breathe pmdis, but more cost-effective? Ensure a lung dose in poor coordinators May be used more widely in future for expensive drugs, or drugs with narrow therapeutic windows ERRORS WITH BREATH-ACTUATED pmdis Breath-actuated pmdis correct for poor coordination But still possible to make crucial errors resulting in zero lung dose Failure to prepare device correctly Inhalation too slow to trigger device (but triggering flow only 30 L/min in marketed models) Stopping inhalation / inhaling through nose Breath-actuated pmdis considered inappropriate for young children Importance of patient education * Price, D. et. al. (2003), Respir. Med., 97, 12-19 2
VELOCITY-MODIFYING DEVICES TEMPO TM INHALER (MAP PHARMACEUTICALS) Image courtesy of MAP Pharmaceuticals pmdi spray velocity may be 5 to 8 m/sec at 10 cm from nozzle May contribute to crucial errors in pmdi technique Velocity-modifying pmdi devices aim to deliver a lowvelocity spray to the patient First device with several brand names: Gentlehaler (US), Spacehaler (UK), Neohaler (India) Potential benefits: Reduced incidence of crucial errors Lower oropharyngeal deposition / higher lung deposition Some new HFA pmdis already have reduced spray velocity DEPOSITION OF FLUTICASONE PROPIONATE FROM TEMPO INHALER IN GAMMA SCINTIGRAPHY STUDY Mean and SD data from Mohsen, N., (2002), Respiratory Drug Delivery VIII, 593-597 TYPES OF ADD-ON DEVICE TUBE SPACER HOLDING CHAMBERS REVERSE-FLOW DEVICE ONE-WAY VALVE EXHALATION HOLE TUBE SPACERS Simple tube extensions to inhaler mouthpiece Azmacort spacer (Abbott Laboratories), 113 ml Inhalet spacer (AstraZeneca), 80 ml Place time and distance between pmdi and patient Allows spray to evaporate and slow down First pmdi products in 1956 had 8 cm mouthpieces (Riker Laboratories, now 3M Pharmaceuticals) Exhalation into spacer may blow dose away HOLDING CHAMBERS Variety of sizes and shapes Volumes 100 ml to 750 ml Small holding chambers include AeroChamber (Trudell), 149 ml and 198 ml OptiChamber Advantage (Respironics), 218 ml Some smaller devices designed for infants Large holding chambers include Nebuhaler (AstraZeneca), 750 ml Volumatic (GlaxoSmithKline), 700 ml Some have universal adaptors Many have transparent body One-way valve prevents dose being blown away 3
REVERSE-FLOW DEVICES (1) InspirEase (Schering-Plough) 660 ml bag made of stiff plastic Inhalation of dose collapses the bag Provides patient with visual feedback that dose has been inhaled Audio signal if inhaled flow rate > 20 L/min REVERSE-FLOW DEVICES (2) OptiHaler (Respironics) 70 ml plastic chamber Actuation opens vents in rear of device Inhalation entrains dose in ambient air Sometimes described as a breath-coordinated device Stiff plastic bag Reed EFFECT OF SPACER DIMENSIONS ON IN VITRO FINE PARTICLE MASS (FPM) OF CROMOLYN SODIUM Mean data from Barry, P.W. and O Callaghan, C. (1995), J. Aerosol Med., 8, 303-305 SMALL HOLDING CHAMBERS Images courtesy of Trudell, Respironics and PARI AEROCHAMBER VORTEX FPM, mg 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 3920 ml 35 ml 5 10 20 50 Diameter 3 cm 5 cm 8 cm 10 cm OPTICHAMBER ADVANTAGE Add-on device length, cm OTHER DESIGN ISSUES IN ADD-ON DEVICES One-way valve design Include flat plates, shuttles, duckbills Must open and close easily May be a site of drug deposition Facemask design Must fit tightly Avoidance of eye deposition Dead-space as small as possible VALVES AND FLOW INDICATORS Images by courtesy of Trudell Medical International Flow indicators OptiChamber Advantage image courtesy of Respironics, Inc. Donut valve Duckbill valve 4
FINE PARTICLE FRACTION (%) FOR TWO pmdi FORMULATIONS DELIVERED VIA NINE ADD-ON DEVICES % Mean data from Holzner, P.M. and Muller, B.W. (1994), Int. J. Pharm., 106, 69-75 40 30 20 10 ROLES OF ADD-ON DEVICES Each add-on device is different, but as a class they have some common properties Making pmdis easier to use correctly Dissociate pressing and breathing Fine particle fraction varied according to add-on device and pmdi Each pmdi / add-on combination potentially unique Any pmdi / add-on combination more reliable than press-and-breathe MDI Further studies required to assess relevance of in vitro findings Improving drug delivery Targeting inhaled corticosteroids Alternative to nebulizers OptiChamber Advantage image courtesy of Respironics, Inc. MAKING pmdis EASIER TO USE CORRECTLY Possible to press, and then breathe LUNG DEPOSITION FROM pmdi vs pmdi PLUS HOLDING CHAMBER pmdi pmdi + Chamber Tidal breathing of each dose from a holding chamber may be possible More reliable lung dose pmdi plus holding chamber: Recommended device for children < 6 y Facemask preferred for infants Add-on devices improve therapeutic response in patients with poor inhaler technique OptiChamber Advantage image courtesy of Respironics, Inc. Images from Newman, S.P. et al. (1996), J.Pharm. Sci. 85, 960-964, and Newman, S.P. (1998), Pharm. Technol. 22 (June), 78-94 TARGETING INHALED CORTICOSTEROIDS Higher lung deposition and lower oropharyngeal deposition especially useful for inhaled corticosteroids Allows daily dose to be titrated downwards Maintain lung dose while reducing total body dose Potential to reduce systemic side-effects Lower oropharyngeal deposition reduces local sideeffects (candidiasis and dysphonia) Holding chambers may allow more patients to have oral corticosteroids withdrawn ALTERNATIVE TO NEBULIZERS FOR DELIVERY OF LARGE BRONCHODILATOR DOSES Delivering inhaled drugs in severe acute asthma Difficult to use pmdi correctly Nebulizer therapy allows reliable delivery of large doses But nebulizers are bulky, expensive, easy to contaminate Many studies show that pmdi plus holding chamber is equally effective for delivery of large doses Significant cost-benefits May allow earlier discharge from emergency department Easier to clean Incorporation into breathing circuits for intubated patients (e.g. OptiVent, Respironics) 5
FINE PARTICLE MASS OF BUDESONIDE MEASURED IN VITRO FROM NEBUHALER HOLDING CHAMBER Mean data from Barry, P.W. and O Callaghan, C. (1995), Br.J.Clin.Pharmacol., 40, 76-78 20 sec delay 10 sec delay INHALATION FROM ADD-ON DEVICES Add-on devices can be used with significant delay times between actuation and inhalation and by inhaling multiple doses in one breath 5 sec delay 5 actuations 2 actuations 1 actuation 0 5 10 15 20 25 30 35 Fine particle mass, µg But may lead to reduced lung dose Optimal inhalation technique No delay between actuation and inhalation Inhale one dose at a time Tidal breathing often possible, but slow deep breaths ideal STATIC CHARGE IN ADD-ON DEVICES Add-on devices usually made of insulating polymers Most acquire static charge during handling Most aerosols acquire charge by tribo-electrification as they are formed Aerosol is attracted to walls of add-on device Supplements losses within add-on device that occur by impaction and sedimentation HALF-TIME OF AIRBORNE AEROSOL IN HOLDING CHAMBERS Mean data from Bisgaard, H. et. al. (1995), Arch. Dis. Childhood, 73, 226-230 Clearance by sedimentation and by electrostatic attraction Half-time: time for concentration in chamber to be halved Treated 150 ml Treated 350 ml Treated 750 ml Untreated 750 ml 10 20 30 Half-time (seconds) EFFECT OF STATIC VOLTAGE ON FINE PARTICLE FRACTION FROM A HOLDING CHAMBER Mean data from Dewsbury, N.J. et. al. (1996), Int. J. Pharm., 137, 261-264 40 Fine 30 Particle Fraction 20 % 10 5 10 15 20 Static Voltage kv MINIMIZING STATIC CHARGE EFFECTS IN ADD-ON DEVICES Coat internal surface with antistatic lining Use precise washing and drying technique Wash with ionic detergent, allow to air-dry Prime internal surface by actuating pmdi into add-on device many times before use: coats walls with drug and excipients Static charge leads to variable lung dose Use non-static add-on device Static-free plastic: AeroChamber Max, Trudell Metal add-on device: NebuChamber, AstraZeneca Metal add-on device: Vortex, PARI 6
LUNG DEPOSITION FROM PLASTIC AND METAL HOLDING CHAMBERS MEASURED BY GAMMA SCINTIGRAPHY Mean and SD data from Kenyon, C.J., et. al. (1998), Eur. Respir. J., 11, 606-610 NebuChamber, 250 ml, metal UNPRIMED PRIMED N.S. IMPROVED FINE PARTICLE MASS (FPM) OF ALBUTEROL IN VITRO FOR NON-ELECTROSTATIC HOLDING CHAMBERS FPM, µg 20 Mean data from Rau, J.L, et al., (2006), Respir. Care, 51, 503-510 No wash/rinse After wash/rinse Nebuhaler, 750 ml, plastic UNPRIMED PRIMED P< 0.01 10 Volumatic, 700 ml, plastic UNPRIMED PRIMED P < 0.02 10 20 30 40 Lung deposition, % Non-electrostatic chambers Non-conducting chambers CONCLUDING REMARKS (1) Add-on devices have many advantages as drug delivery devices, and are amongst the most reliable of inhalers Large versus small holding chambers Static charge is a major potential source of variable dosing in add-on devices Most important future uses of add-on devices: Inhalation therapy in young children Targeted delivery of inhaled corticosteroids Convenient delivery of large bronchodilator doses (instead of nebulizers) CONCLUDING REMARKS (2) Compact pmdi auxiliary devices, e.g. breathactuated inhalers and velocity-modifiers, are more portable and convenient than add-on devices Breath-actuated pmdis predicted to become more widely used, especially for non-asthma, non-copd applications Additional technology for pmdis can help to ensure that virtually any patient can benefit from pmdi therapy 7