The important of inhalers device in asthma management? นายแพทย์ธีระศักดิ์ แก้วอมตวงศ์ หน่วยโรคระบบการหายใจและเวช บำบัดวิกฤต ภาควิชาอายุรศาสตร์ โรงพยาบาล รามาธิบดี

Respiratory pharmacology Inhaled drug administrations are widely used in pulmonary medicine Asthma COPD Bronchiectasis Cystic fibrosis Drugs available for respiratory care Anti-inflammation: corticosteroids Anti-infective agents : antibiotics, antifungal Bronchodilators : β adrenergic agonist and muscarinic receptor antagonist Mucoregulator : Dornase alpha

Medication for asthma and COPD AsthmaCOPD Anti-inflammatory drugs -Corticosteroids -Anti-leukotriene -Cromone -Theophylline Bronchodilators -Short and long acting β2-agonits -Short and long acting anticholinergic -Theophylline Bronchodilator -Short and long acting β2-agonits -Short acting anticholinergic Anti-inflammatory drugs -corticosteroid ICS/LABA combination Anti-immunoglobulin EMucolytic drugs Antibiotic s Vaccination

Advantages of inhaled therapy Providing local effect of medications that optimizes the desired therapeutic effects Requiring the lower dose Preferred characteristics Fast onset of action Low systemic bioavailability Less side effects than orally or intravenously administered drugs American Association of Respiratory Care Aerosol Consensus Statement. Respir Care 1991

Pulmonary drug delivery Lewis RA, Fleming JS. Br J Dis Chest 1985; 79(4):

Respiratory drugs

Development of inhalers 1930s s Compressed-air nebulizer Medihaler® (first MDI) Ultrasonic nebulizer Spinhaler® (first DPI) Breath- actuated MDI Diskhaler® Rotadisk ® ( DPI) Turbuhaler ® (DPI) Autohaler ® Breath- actuated MDI Diskus ® (DPI) Novolizer ® (DPI)

The effectiveness of aerosol The effectiveness of an aerosol is dependent on how much of the medication actually reaches the small peripheral airways of the lungs In vitro : Fine particle fraction (FPF) In vivo: camera scintigraphy Burton G. Respiratory Care. A guide to clinical practice 1992

Airway anatomy (tree) Wiebel Upper & lower respiratory tractConducting & gas exchange

Airway generation and flow relationship

Lung deposition of drugs

Factors affecting lung deposition Particle size Speed of inspiration (inspiratory flow) Integrity of airway Proper inhaled device technique

Particle dynamics in respiratory tract Impact Sedimentation Diffusion Impaction Diffusion Sedimentation

Physical mechanism of drug movement & deposition Speed of inspiration (Ideal speed or flow is L/min) High flow facilitate central impaction but low flow facilitate sedimentation of particle Sedimentation (0.5-5 µm) Impact (> 5 µm) at upper airway and high flow rate Diffusion (< 0.5 µm) high speed movement and short haul exhaled

Fine-particle fraction (FPF) Fine-particle fraction (FPF) is percentage of the aerosol between 1–5 μm that deposits in the lung

Mean aerodynamic diameter (MMAD) Deposit of particles by size Particles > 8 µm are deposited in the oropharynx (90% absorbed) Particles with size 5-8 µm are deposited in the large airways Particles with size 2-5 µm are deposited in tracheobronchial region Particles with size 1-2 µm are deposited in the alveolar region Particles with size < 1 µm are passed expiration Rau JL Jr. Respiratory care pharmacology. 2002

MMAD and GSD Mass Median Aerodynamic Diameter (MMAD) is defined as the diameter at which 50% of the particles by mass are larger and 50% are smaller Geometric Standard Deviation (GSD) is a measure of the spread of an aerodynamic particle size distribution. Typically calculated as follows: GSD = (d 84 /d 16 ) 1/2. d84 and d16 represent the diameters at which 84% and 16% of the aerosol mass are contained, respectively, in diameters less than these diameters.

Particle size distribution (Histogram)

Particle size distribution Histogram of particle size distribution Histogram of logarithmic particle size distribution MMAD =1 µm

MMAD (d 50 ) MMAD =1 µm

MMAD =5 µm means ? The calculated aerodynamic diameter that divides the particles of an aerosol in half, based on the weight of the particles. By weight, 50% of the particles will be larger than the MMAD and 50% of the particles will be smaller than the MMAD. MMAD of 5 μm =? 50 % of the total sample mass will be present in particles having diameters less than 5 μm, and that 50 % of the total sample mass will be present in particles having an diameter larger than 5 μm.

Lung deposition and MMAD Leach C et al. Particle size of inhaled corticosteroids: Does it matter? J Allergy Clin Immunol 2009

Inhaler devices Metered-dose inhaler (MDIs) Conventional pressurized inhaler Activated by pressurized inhaler inspiration Dry-powder inhaler (DPI) Single dose Multi-dose Nebulizers Jet Ultrasonic

pMDI and plum mechanism

HFA and CFC propellant pMDI HFA pMDI CFC pMDI

HFA improve lung deposition

MDI with spacing device or VHC

การใช้ยาสูดร่วมกับ Spacer ชนิดของ spacer แบ่งเป็น Aerosol Cloud Enhancer (ACE) Volumetric spacer

Aerochamber (VHC) vs Ventahaler Aerochamber plusVentahaler 1) a 145-mL rigid cylinder made of polyester (Trudell Medical, London, ON) 2) Adapter that makes it compatible with most pMDIs 3) Is available with a mouthpiece or a mask 1) An elliptical-shaped device made of rigid, transparent plastic 2) Capacity of 750 Ml 3) Designed to fit GlaxoSmithKline Products Not fit all pMDIs.

Spacer decrease orapharyngeal deposition

Build in dose counter

MDI and spacer use

Types of dry powder inhaler (DPI) Single dose dry powder (SD-DPI) Multi-dose dry powder (MD-DPI) HandihalerBreezhaler Accuhaler Turbuhaler

Basic design & functional elements (DPI) Powder formulation Dose mechanism containing (measuring) Powder de-agglomeration principle (Dispersing powder into inhaled air stream) Inhaler mouthpiece

Powder formulation Active drug particles with 1-5 µm are extremely adhesive Drug stick together or surface of inhaler Excipients (micronized or agglomerate) Adhesive mixture ( α lactose monohydrate) The detach of active drug from carriers

Powder formulation Adhesive mixtureNuclear conglomerateSpherical pellet type 100 µm 500 µm The carrier molecules of excipient 1)Similar size to drugs (micronized) 2)Large size than drug (carrier)

Micronized drug and carrier particles Active drug 3-5 µMLarge carrier lactose particle 500 µM Active drug 3-5 µM Micronized lactose molecule

Adhesive and removal force balance The Fine Particle Fraction As a result of the balance between separate force (from de-agglomeration) and adhesive force (drug-carrier interaction)

Basic design & functional elements (DPI) Powder formulation Dose mechanism containing (measuring) Powder de-agglomeration principle (Dispersing powder into inhaled air stream) Inhaler mouthpiece

Dose measuring system

De-agglomeration principles DPI

Multi-dose dried powder

Dose mechanism containing (measuring)

DPI Inhaler performance Inspiratory flow performance ‘Intrinsic resistance of device’ Patients inspiratory flow ability Humidity and moister exposure

Inpiratory flow range of DPI Flow dependence DPI Turbuhaler Flow independent DPI Accuhaler

Flow rate and FPF from inhalers

Intrinsic resistance of DPI (kPa0.5/min/L)

Inhalers and airflow resistance sis Inspiratory effort (kPa) Flow rate (L/min) Breezhaler2.2  kPa 1/2 L -1 min Diskus 2.7  kPa 1/2 L -1 min Turbuhaler 3.4  kPa 1/2 L -1 min Handihaler 5.1  kPa 1/2 L -1 min Increasing tan re ce Singh D et al. ATS 2010 (poster)

Factors affect adhesion de-agglomeration Drug: - Type of drug -Size of distribution -Conditioning -Play-load on carrier Carrier: -Surface properties -Bulk properties -Conditioning -Stability (aging) Mixing: -Type of mixer -Mixing time -Batch size Mixing: -Type of mixer -Homogeneity -Conditioning Inhalation test: -Type of inhaler -Inhalation manouvor -Test system Fine particle fraction De Boer Ah Int J Pharm 2003

Tubuhaler as flow dependent Necessary inspiratory flow rate (L/m) Drug deposition in lungs (%) Drug deposition in oropharyns     13.0 Dolovich M. AJRCCM 1988;137:A433.

DPI design -powder formulation -dose system -dose de-agglomeration principle Airflow resistance Inhalation effort Patient factors -instruction -clinical parameters -age, gender, training -smoker, nonsmokers Flow maneuvers -peak flow rate -flow increase rate -inhalation time Performance - Dose entrainment -Fine particle fraction -Lung deposition + Scheme of the major variable and interaction in DPI performance

Accuhaler use

Turbuhaler use

Recommended age for inhalation therapy SVN with mask SVN with mouthpiece pMDI with holding chamber/spacer and mask pMDI with holding chamber/spacer Dry-powder inhaler Metered-dose inhaler Breath-actuated MDI (e.g., Autohaler™) Breath-actuated nebulizers ≤3 years  3 years < 4 years  4 years ≥ 4 years ≥ 5 years Rau JL Jr. Respiratory care pharmacology. 2002

Time after medication (hours) FEV 1 (% of predicted) 1 mg terbutaline* mg terbutaline via Turbuhaler ® Mean PIF of Turbuhaler (L/min) min after administration of 1mg terbutaline via Nebuhaler treatment. Turbuhaler ® is fully effecitve at flow rate ≥ 30L/min at patients aged ≥ 6 years of age Pederson S, et al. Arch Dis Child 1990; 65:

4.0 0 FEV 1 (litres) Terbutaline (mg) Standard inhalation conditions at peak inspiratory flow of 83.9L/min Low inspiratory flow rate (30L/min) through entire inhalation Turbuhaler ® is clinically effecitve at both standard & low inspiratory flow rate similar level of bronchodilation & FEV 1 Meijer RJ, et al. Thorax 1996; 51:

0 % of metered dose (L) pMDI Turbuhaler 40 Borgström L, et al. Am J Respir Crit Care Med 1996; 153: Fine particle dose Lung deposition FEV 1 Higher proportion fine particle dose and lung deposition leads to better efficacy 0.25 mg terbutaline

Turbuhaler gives better central lung deposition as same as pMDI with spacer ® Thorsson L, et al. Int J Pharmaceut 1998; 168: % (Central lung deposition 11%) 26% (Central lung deposition 11%) 38%

Lung deposition of budesonide is greater than that of fluticasone via Diskus or pMDI Thorsson L, et al. Br J Clin Pharmacol 2001; 52: Lung deposition budesonide turbuhaler 36% fluticasone Diskus 12% fluticasone pMDI 20%

Fine particle dose (% of labeled dose) MMAD (µm) BUD/FOR Turbuhaler SAL/FLU Disku Budesonide Fluticasone Formoterol Salmeterol Granlund KM, et al. Eur Respir J 2000; 16 (suppl. 31): 455s MMAD = mass median aerodynamic diameter BUD/FOR turbuhaler delivers higher % of fine particle dose on both BUD & FORM

Asking L, et al. J Aerosol M 2001; 14: 502 Fine particle dose (% of label claim) Inspiratory flow at 40 L/min. SAL/FLU Diskus, fluticasone BUD/FOR Turbuhaler, budesonide Inspiratory flow at 49 L/min. Higher % of fine particle dose with BUD/FOR turbuhaler even at low inspiratory flow

Gustafsson PM, et al. Am J Respir Crit Care Med 2003; 167: A117 Fine particle dose (% of label claim) % fine particle mass at low flow rates in young asthmatic children is also higher with turbuhaler SAL/FLU Diskus 50/100 µg (LABA component) BUD/FOR Turbuhaler 80/4.5 µg (LABA component)

Lipniunaset al, /100 Fine particle dose (% of labelled dose) 160/250320/500 Nominal dose of budesonide / fluticasone (µg) budesonide fluticasone Fine particle size of BUD via Turbuhaler is consistent at all strengths; & higher than FP via Diskus Lipniunas P, et al. Eur Respir J 2002; 20 (suppl. 38): 541s

Spiral channels Turning grip Desiccant store Air inlets Dose counter Turbuhaler ® The air enters through air inlets and passes through desiccant store to keep humidity out Air inlets

Diskus ® The device should be discarded after removal from the moisture-protective foil overwrap pouch Diskus ® itself does NOT contain desiccant

Asking L, et al. J Aerosol Med 1999; 12 (No 3): °C/60%RH* 40°C/75%RH* Months storage Fine particle dose % of label claim Serevent ® Diskus TM, 50 µg/dose *RH – relative humidity Aluminum blisters may fail to protect against humidity in Diskus TM

1.0 Budesonide viaTurbuhaler Relative lung deposition Fluticasone via Diskus in vivo lung deposition of budesonide via Turbuhaler is higher even when the inhaler is stored under hot & humid condition ( 40 ° /75%) Borgström L, et al. Am J Respir Crit Care Med 2003; 167(suppl. 7): A896

Borgström and Lipniunas, 2003 Initial value Proportion of initial value (%) 3 months Turbuhaler ® Diskus ™ Delivered dose Fine particle dose Turbuhaler ® Diskus ™ Fine particle dose via Turbuhaler at 40 ° /75% over 3 months is higher Lipniunas P, et al. Eur Respir J 2003; 22 (suppl. 45): 237s

Drug deposition from various inhalers Rau JL Jr. Respiratory care pharmacology. 2002

Hand function in elderly and device

Age related physical change

Potential effects of inhalation technique in elderly

Advantages and disadvantages AdvantagesDisadvantages pMDI -Quick to use -compact and portable -multi-dose -Difficult inhalation technique -propellant required -High oropharyngeal deposition pMDI +Space (VHC) -Practical advantages as p MDI -Easier to use effectively than p MDI -Reduced oro-pharyngeal deposition -More bulky than p MDI -Propellant required -Susceptible to effect of static charge DPI -Practical advantages similar to p MDI (Multidose/multiple single dose) -No propellant needed -Inspiratory flow-actuated -Easy to use than p MDI -Usually more costly than p MDI -Some may be moisture sensitive -Inspiratory flow-driven (potential problem of low inspiratory force)

Treatment include medication Symptoms and side effect HRQL and functionality Expectation Satisfaction with medication Other influence on satisfaction Physical communication Disease history Treatment history Direct consumer advising Other influence on expectation