Aerosols in Medicine

Transcription

1 Aerosols in Medicine Principles, Diagnosis and Therapy Second, revised edition Edited by F. Moren M.B. Dolovich M.T. Newhouse S.P. Newman 1993 ELSEV1ER AMSTERDAM - LONDON - NEW YORK TOKYO

2 Contents Preface List of Contributors v vii Chapter 1. Upper airway: structure, function and therapy, by Niels Mygind 1 1. Introduction 1 2. Anatomy of the nose Surface epithelium Blood vessels 4 Submucosal glands Nerves 8 3. Applied physiology of the nose Nasal airways Heating and humidification Filtration Pathology of rhinitis Allergic rhinitis Primary ciliary dyskinesia The common cold Aerosol therapy in the nose Drug absorption Rhinitis therapy Systemic drug delivery in the nose Spray types Drop-bottle pipette Aqueous pump spray Preservatives Pressurized metered-dose inhaler Side effects Nasal inhalation for the treatment of airway disease Pharynx and larynx 22 References 25 xi

3 Chapter 2. Lower airway: structure and function, by James B. Forrest Introduction 2. General organization of lung structure 2.1. Lung structural units Lobes Bronchopulmonary segments Lobules Acinus 2.2. Airway morphology and geometry Conducting airways Acinus Lung development 1. Development of cell types in the lung Acknowledgments References Primitive fetal cell Ciliated cells Primary cilia Ciliated cells (surface border cilia) Mucus-secreting and serous-secreting cells Intermediate cell Basal cells Lymphocytes Mast cell (globule leucocyte) Kultschitsky cell (clear or argyrophilic) Clara cell Brush cell Nerve cells.14. Submucous gland Smooth muscle Connective tissue Parenchymal cells Structure of the alveolar capillary barrier Alveolar epithelium Type 1 pneumonocyte Type 2 pneumonocyte Type 3 pneumonocyte (alveolar brush cell; Capillary endothelium Pericyte Interstitial elements and cells Alveolar macrophage Other migratory cells Functional airway morphology Structural aspects of airway compliance Airway innervation Bronchial circulation Summary Chapter 3. Aerosol characterization and generation, by David L. Swift Characteristics of aerosols 1.1. Definitions xn

4 1.2. Properties of single particles Collective properties of aerosols Mathematical description of aerosols Measurement of aerosol properties Aerosol generation General principles Liquid aerosol formation by comminution 73 Liquid generation of solutions and suspensions Generation of solids 80 References 82 Chapter 4. Airflow dynamics in the human airways, by H.K. Chang and A.S. Menon Introduction Airway models Flow in the large airways (trachea, main and lobar bronchi) Steady axial velocity profiles Secondary velocities in steady flow Velocity profiles in oscillatory flow Quasi-steadiness in oscillatory flows Peak oscillatory velocity profiles Effect of the larynx on the oscillatory profiles Flow in the upper airways (nose, nasopharynx, mouth, oropharynx, pharynx and anterior larynx) Relevence of fluid dynamics to particle deposition 113 References 115 Chapter 5. Mechanisms of particle deposition and clearance, by Joseph D. Brain and James D. Blanchard Introduction Particle transport and deposition mechanisms Sedimentation Inertial impaction 120 Diffusion Electrostatic attraction Interception and other deposition processes Characterizing and delivering therapeutic aerosols Factors influencing particle deposition Anatomy of the respiratory tract Choice of pathway Particle size and distribution I2S 4.4. Hygroscopicity and evaporation Breathing pattern Disease 133

5 5. Selecting deposition patterns? Drug targeting ] Ai 5.2. Local distribution of deposited dose ' " 5.3. The bronchial circulation and the redistribution of deposited dose ' 3" 6. Clearance and retention of particles Mucociliary transport l-> 6.2. Non-ciliated regions 1 7. Cough ]f 14U 7.1. Two-phase flow 8. Measuring particle retention Modeling Photometry and filter collection 8.3. Bronchoalveolar lavage I Radioactivity l /-Cameras 8.6. Tomography ' 4^ 8.7. Magnetopneumography l 4^ 9. Conclusions ' 46 References I 47 Chapter 6. Models of aerosol behavior in airways and alveoli, by Paul E. Morrow and C.P. Yu Introduction Particle deposition General features of particle deposition Head or extrathoracic deposition 159 Lung deposition Compartmental model Continuous model Semi-empirical model Other factors affecting deposition Deposition in children Particle charge Particle polydispersity Particle hygroscopicity Lung assessment using aerosols Particle removal from the respiratory system General features of particulate retention Historical review Objectives of retention kinetics Kinetic analyses of particle retention Nasal airways Tracheobronchial airways Pulmonary region 181 Acknowledgment 188 References 188 xiv

6 Chapter 7. Aerosols in diagnosis: ventilation, airway penetrance, epithelial permeability, mucociliary transport and airway responsiveness, by Myrna B. Dolovich, Donald W. Cockcroft and Geoffrey Coates Introduction Instrumentation Aerosols and the assessment of ventilation Pulmonary embolism Aerosol ventilation technique Aerosol 'penetrance' in the assessment of airway obstruction Aerosols and airway pharmacological responses Lung deposition and bronchodilation Lung deposition and induced bronchoconstriction Aerosols in the assessment of pulmonary epithelial permeability Aerosols in the assessment of mucociliary transport Radioactive aerosol technique for lung clearance Tracheal mucus velocity Use of aerosols in assessment of airway responsiveness Measurement of non-allergic airway (hyper-)responsiveness: histamine and methacholine inhalation tests Histamine and methacholine inhalation test methods Technical factors Aerosol generation Method of inhalation 219. Handling of solutions Measurement of response Expression of results Tidal breathing method Hand-held nebulizer system Non-technical factors Comparison of results by different methods Clinical relevance Diagnosis of asthma Assessment of occupational asthma Severity of asthma Monitoring treatment Measurement of responsiveness to sensitizing stimuli Allergen inhalation tests Occupational challenges 228 Acknowledgement 229 References 229 Chapter 8. Epithelial permeability, by Richard M. Effros Introduction Correlation of structure and permeability 235

7 3. Indicator properties which affect transport Reflection coefficients of the pulmonary epithelium Radioaerosol studies Active transport across the pulmonary epithelium Clinical applications of radioaerosol clearance 244 References 244 Chapter 9. Airway mucus clearance and mucociliary transport, by Per Camner and Bj'drn Mossberg Introduction Basic data Importance of mucociliary clearance Lung diseases General aspects Bronchiectasis Chronic bronchitis Bronchial asthma Lung cancer Other chronic diseases Acute infections Interventions Environmental factors 256 References 257 Chapter 10. Bronchial asthma, chronic bronchitis and pulmonary parenchymal diseases, by Olof Selroos Introduction Drugs for inhalation /?-Receptor-stimulating agents Anticholinergic bronchodilators 264 Disodium cromoglycate Nedocromil sodium Corticosteroids r Antitrypsin Mucolytics Water and saline aerosols Diuretics Surfactant Delivery systems Metered-dose inhalers Spacers attached to metered-dose inhalers Tube spacers Holding chambers 272 xvi

8 3.3. Dry-powder inhalers Nebulizers Clinical indications Reversible airway obstruction Acute asthma Maintenance treatment for stable asthma Irreversible airway obstruction Pulmonary parenchymal diseases Pulmonary sarcoidosis Other parenchymal diseases 285 References 285 Chapter 11. Pulmonary infections, by Caroline Breese Hall and John T. McBride Introduction Aerosolized antibacterial agents Aerosolized chemoprophylactic therapy for Pneutnocystis carinii Aerosolized antiviral agents Environmental considerations Summary 300 References 300 Chapter 12. Systemic therapy with aerosols, by Dieter K'dhler Introduction Nasal administration Pulmonary administration Drugs Aerosol generation and delivery Inhalation Deposition Transport into blood Outlook 315 Acknowledgements 316 References 316 Chapter 13. Aerosol dosage forms and formulations, by Folke More'n Oral and nasal inhalation of drugs Powder systems Drug substance Size reduction Drug carriers Powder inhalers Devices for oral inhalation 324 xvii

9 Devices for nasal inhalation 327 Testing of powder systems Dose of drug Particle size Water absorption Airflow 329 Pressurized aerosols Formulation CFC propellants Restrictions to CFCs Alternative propellants Formulation aspects Filling technique Metering valve Aerosol generation Formulation factors Actuator design for oral inhalation Nasal inhalation Testing of pressurized aerosols Particle size Dose measurement Assay Leakage rate Actuator characterization Aqueous systems 4.1. Formulation Solvents and solubility enhancement Liposomes ph and tonicity Antioxidants and preservatives Package 4.2. Aerosol generation Nebulizers Nasal pumps 4.3. Testing of aqueous systems Particle size Dose characterization Microbiological conditions References 348 Chapter 14. Particle size analysis of therapeutic aerosols, by G.W. Hallworth Introduction Drug and excipient powders Microscopy and dispersion Laser diffraction 353 Electro/one and photozone counters Disc centrifuge Pressurized metered-dose inhalers: spray droplet size Spra> characteristics and general methods 354 xviii

10 3.2. Laser diffraction Microscopy, holography and other imaging methods Laser optical array and phase Doppler sizers Pressurized metered-dose inhalers: aerosol particle size Microscopy and holography Inertial impaction and cascade impactors Two-stage impingers Single-particle optical sizers Light scattering single particle sizers GalaiCIS Aerodynamic particle sizers Sedimentation Powder inhalers Introduction Non-impaction cloud methods Inertial impaction Nebulizers Nebulization Measurement of dried aerosols Measurement of unevaporated aerosols Comparison of methods for sizing nebulized aerosols 370 References 370 Chapter 15. Therapeutic aerosol deposition in man, by Stephen P. Newman Therapeutic aerosol delivery systems Types of devices Potential importance of deposition Difficulty of predicting deposition Drug recovery and pharmacokinetics Labelling techniques Drugs labelled with /if-ray emitters Drug studies with y-ray emitters Inert particles and droplets Monitoring techniques /-Camera Other measurements Control of breathing manoeuvre Deposition studies with nebulizers Percentage of dose reaching the lungs Type of nebulizer Breathing pattern Selective deposition and targeting Deposition studies with pressurized metered-dose inhalers Percentage of dose reaching the lungs 3X Changes in inhalation mode - w * 6.3. Auxiliary devices 3XK 6.4. Physicochemical factors 390 xix

11 7. Dry-powder inhalers Deposition from nasal delivery systems Efficient nasal deposition Relationship between deposition, clearance and efficacy Metered-dose inhalers versus aqueous pump spray Other factors Concluding remarks 395 References 396 Chapter 16. Occupational and environmental aerosols. Characterization and clinical relevance, by David C.F. Muir and Dave K. Verma Introduction Size-selective dust sampling The association of particulates with other pollutants The extent of the health problem The working environment Sampling strategy Personal sampling where a portable sampling device is carried by the worker Breathing zone sampling General area sampling Size-selective sampling Total dust sampling Respirable dust sampling Airborne dust-sampling devices Methods based on counting particles Thekonimeter Impingers Thermal precipitators Gravimetric sampling The horizontal elutriator Cyclones Inhalable dust samplers Direct reading instruments and automated counting Measurements of fibrous aerosols Correlation between various dust-measuring devices Community air polution The smoke stain Hi-volume dust sampler Size-selective samplers Correlation between different sampling systems Indoor air pollution Summary 421 References 422 Subject index 425 xx