A Guide To
`Aerosol Delivery Devices
`for Respiratory Therapists
` 4th Edition
`
`Douglas S. Gardenhire, EdD, RRT-NPS, FAARC
`
`Dave Burnett, PhD, RRT, AE-C
`
`Shawna Strickland, PhD, RRT-NPS, RRT-ACCS, AE-C, FAARC
`
`Timothy R. Myers, MBA, RRT-NPS, FAARC
`
`Copyright ©2017 by the American Association for Respiratory Care
`
`Platinum Sponsor
`
`IPR2021-00406
`United Therapeutics EX2033
`Page 1 of 61
`
`

`

`A Guide to Aerosol
`Delivery Devices for
`Respiratory Therapists,
`4th Edition
`
`Douglas S. Gardenhire, EdD, RRT-NPS, FAARC
`
`Dave Burnett, PhD, RRT, AE-C
`
`Shawna Strickland, PhD, RRT-NPS, RRT-ACCS, AE-C, FAARC
`
`Timothy R. Myers, MBA, RRT-NPS, FAARC
`
`With a Foreword by
`Timothy R. Myers, MBA, RRT-NPS, FAARC
`(cid:38)(cid:75)(cid:76)(cid:72)(cid:73)(cid:3)(cid:37)(cid:88)(cid:86)(cid:76)(cid:81)(cid:72)(cid:86)(cid:86)(cid:3)(cid:50)(cid:73)(cid:386)(cid:70)(cid:72)(cid:85)
`American Association for Respiratory Care
`
`DISCLOSURE
`Douglas S. Gardenhire, EdD, RRT-NPS, FAARC has served as a consultant for the following
`companies: Westmed, Inc. and Boehringer Ingelheim.
`
`Produced by the
`American Association
`for Respiratory Care
`
`2
`A Guide to Aerosol Delivery Devices for Respiratory Therapists, 4th Edition
`American Association for Respiratory Care, © 2017
`
`IPR2021-00406
`United Therapeutics EX2033
`Page 2 of 61
`
`

`

`Foreward
`
`Aerosol therapy is considered to be one of the corner-
`(cid:86)(cid:87)(cid:82)(cid:81)(cid:72)(cid:86)(cid:3)(cid:82)(cid:73)(cid:3)(cid:85)(cid:72)(cid:86)(cid:83)(cid:76)(cid:85)(cid:68)(cid:87)(cid:82)(cid:85)(cid:92)(cid:3)(cid:87)(cid:75)(cid:72)(cid:85)(cid:68)(cid:83)(cid:92)(cid:3)(cid:87)(cid:75)(cid:68)(cid:87)(cid:3)(cid:72)(cid:91)(cid:72)(cid:80)(cid:83)(cid:79)(cid:76)(cid:386)(cid:72)(cid:86)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:81)(cid:88)(cid:68)(cid:81)(cid:70)(cid:72)(cid:86)(cid:3)
`of both the art and science of 21st century medicine. As
`respiratory therapists are the only health care providers
`who receive extensive formal education and who are tested
`for competency in aerosol therapy, the ability to manage
`patients with both acute and chronic respiratory disease as
`the experts in aerosol therapy allows the concept of “art”
`and “science” to take on a practical reality.
`Respiratory therapists continue to be the experts when it
`comes to the art and science of aerosol therapy. With the
`(cid:85)(cid:68)(cid:83)(cid:76)(cid:71)(cid:79)(cid:92)(cid:3)(cid:70)(cid:75)(cid:68)(cid:81)(cid:74)(cid:76)(cid:81)(cid:74)(cid:3)(cid:386)(cid:72)(cid:79)(cid:71)(cid:3)(cid:82)(cid:73)(cid:3)(cid:68)(cid:72)(cid:85)(cid:82)(cid:86)(cid:82)(cid:79)(cid:3)(cid:80)(cid:72)(cid:71)(cid:76)(cid:70)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:71)(cid:72)(cid:79)(cid:76)(cid:89)(cid:72)(cid:85)(cid:92)(cid:3)
`systems, it is imperative that we not only share this expertise
`with patients but also other members of the health care
`delivery team across the continuum of care. With a renewed
`focus on wellness and prevention within the U.S. health care
`system and a determined focus to minimize cost and waste,
`the choice of appropriate respiratory medications and deliv-
`ery devices makes selection of both the drug and optimum
`delivery device even more critical.
`How does a therapeutic intervention around for centuries
`still combine the art with science in the context of aerosol
`therapy? The “science” component includes many different
`aspects such as pharmacology, cardiopulmonary anatomy
`and physiology, physics, and a thorough understanding of
`the different aerosol delivery technologies on the market
`today. In order to claim expertise in the science of aerosol
`therapy and optimize it for patients, the respiratory therapist
`must have concrete knowledge and understanding of the
`numerous drug formulations, their mode of action, and an
`understanding of the respiratory conditions where the drug
`(cid:68)(cid:81)(cid:71)(cid:3)(cid:71)(cid:72)(cid:79)(cid:76)(cid:89)(cid:72)(cid:85)(cid:92)(cid:3)(cid:76)(cid:86)(cid:3)(cid:85)(cid:72)(cid:70)(cid:82)(cid:80)(cid:80)(cid:72)(cid:81)(cid:71)(cid:72)(cid:71)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:86)(cid:88)(cid:83)(cid:83)(cid:82)(cid:85)(cid:87)(cid:72)(cid:71)(cid:3)(cid:69)(cid:92)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:86)(cid:70)(cid:76)(cid:72)(cid:81)(cid:87)(cid:76)(cid:386)(cid:70)(cid:3)
`evidence.
`While the “art” of aerosol delivery is much more abstract
`than the science, it is as equally important to the appropri-
`ate delivery of respiratory medications for optimal outcomes.
`For aerosol therapy, the interaction between technology
`and human behavior is where “art” comes into play. There
`(cid:76)(cid:86)(cid:3)(cid:68)(cid:80)(cid:83)(cid:79)(cid:72)(cid:3)(cid:86)(cid:70)(cid:76)(cid:72)(cid:81)(cid:87)(cid:76)(cid:386)(cid:70)(cid:3)(cid:72)(cid:89)(cid:76)(cid:71)(cid:72)(cid:81)(cid:70)(cid:72)(cid:3)(cid:82)(cid:73)(cid:3)(cid:86)(cid:88)(cid:69)(cid:16)(cid:82)(cid:83)(cid:87)(cid:76)(cid:80)(cid:68)(cid:79)(cid:3)(cid:82)(cid:85)(cid:3)(cid:76)(cid:81)(cid:72)(cid:73)(cid:73)(cid:72)(cid:70)(cid:87)(cid:76)(cid:89)(cid:72)(cid:3)
`use of aerosols when self-administered in large part due to
`lack of knowledge about proper technique by patients. All
`too often, patients do not receive optimum (or sometimes
`
`(cid:68)(cid:81)(cid:92)(cid:12)(cid:3)(cid:69)(cid:72)(cid:81)(cid:72)(cid:386)(cid:87)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)(cid:87)(cid:75)(cid:72)(cid:76)(cid:85)(cid:3)(cid:83)(cid:85)(cid:72)(cid:86)(cid:70)(cid:85)(cid:76)(cid:69)(cid:72)(cid:71)(cid:3)(cid:80)(cid:72)(cid:87)(cid:72)(cid:85)(cid:72)(cid:71)(cid:16)(cid:71)(cid:82)(cid:86)(cid:72)(cid:3)(cid:76)(cid:81)(cid:75)(cid:68)(cid:79)(cid:72)(cid:85)(cid:86)(cid:15)(cid:3)
`dry-powder inhalers, and nebulizers simply because they are
`not adequately trained or evaluated on their proper use.
`The combination of the right medication and the most
`optimal delivery device with the patient’s cognitive and
`physical abilities is the critical juncture where science inter-
`sects with art. For aerosol therapy to be effective, the appro-
`priate delivery system for the medication must be matched
`to the patient’s ability to use it correctly. The art of aerosol
`therapy does indeed arise from the science. When these two
`different, but synergistic components of medicine do not
`properly align, patient adherence decreases. Medication is
`(cid:90)(cid:68)(cid:86)(cid:87)(cid:72)(cid:71)(cid:17)(cid:3)(cid:48)(cid:76)(cid:81)(cid:76)(cid:80)(cid:68)(cid:79)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:3)(cid:69)(cid:72)(cid:81)(cid:72)(cid:386)(cid:87)(cid:3)(cid:76)(cid:86)(cid:3)(cid:71)(cid:72)(cid:85)(cid:76)(cid:89)(cid:72)(cid:71)(cid:17)(cid:3)
`Because aerosol therapy is integral to our scope of prac-
`tice and because we are considered the experts in this area,
`we have a professional obligation to our patients to continue
`our learning and competencies in the delivery of aerosolized
`medicines. Respiratory therapists must take advantage of
`this opportunity to reinforce their value by updating their
`knowledge of aerosol delivery systems and combining that
`knowledge with effective assessment of patients requiring
`this therapy. Recommending an appropriate delivery system
`(cid:87)(cid:68)(cid:76)(cid:79)(cid:82)(cid:85)(cid:72)(cid:71)(cid:3)(cid:86)(cid:83)(cid:72)(cid:70)(cid:76)(cid:386)(cid:70)(cid:68)(cid:79)(cid:79)(cid:92)(cid:3)(cid:87)(cid:82)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:338)(cid:86)(cid:3)(cid:68)(cid:69)(cid:76)(cid:79)(cid:76)(cid:87)(cid:76)(cid:72)(cid:86)(cid:3)(cid:76)(cid:86)(cid:3)(cid:83)(cid:68)(cid:85)(cid:87)(cid:3)(cid:82)(cid:73)(cid:3)(cid:87)(cid:75)(cid:68)(cid:87)(cid:3)
`assessment.
`This guide will provide you the opportunity to advance
`your knowledge and expertise in aerosol delivery. Mastery
`of both the art and science of aerosol delivery can have a
`profound impact on appropriately matching medications and
`delivery devices to optimize your patients’ clinical outcomes.
`You will also contribute to more cost-effective use of health
`care system resources.
`The fourth edition of this Aerosol Guide delivers detailed
`and comprehensive information that, when combined with
`your dedication and commitment to be the professional
`experts in this important area, will empower you to provide
`guidance to your physician, nurse, and pharmacist colleagues
`— but, most importantly, to your patients.
`
`Timothy R. Myers, MBA, RRT-NPS, FAARC
`(cid:38)(cid:75)(cid:76)(cid:72)(cid:73)(cid:3)(cid:37)(cid:88)(cid:86)(cid:76)(cid:81)(cid:72)(cid:86)(cid:86)(cid:3)(cid:50)(cid:73)(cid:386)(cid:70)(cid:72)(cid:85)
`American Association for Respiratory Care
`
`i
`A Guide to Aerosol Delivery Devices for Respiratory Therapists, 4th Edition
`American Association for Respiratory Care, © 2017
`
`IPR2021-00406
`United Therapeutics EX2033
`Page 3 of 61
`
`

`

`Continuing Respiratory
`Care Education (CRCE)
`
`(cid:36)(cid:86)(cid:3)(cid:83)(cid:68)(cid:85)(cid:87)(cid:3)(cid:82)(cid:73)(cid:3)(cid:92)(cid:82)(cid:88)(cid:85)(cid:3)(cid:80)(cid:72)(cid:80)(cid:69)(cid:72)(cid:85)(cid:86)(cid:75)(cid:76)(cid:83)(cid:3)(cid:69)(cid:72)(cid:81)(cid:72)(cid:386)(cid:87)(cid:86)(cid:3)(cid:76)(cid:81)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:36)(cid:80)(cid:72)(cid:85)(cid:76)(cid:70)(cid:68)(cid:81)(cid:3)
`Association for Respiratory Care® (AARC), the Association:
`
`• provides you with continuing education opportunities;
`• keeps track of all the CRCE® hours you earn from CRCE-
`approved programs; and
`• allows you to print online a transcript of your CRCE
`records.
`
`These services are available to you 24 hours a day, seven
`days a week, on the AARC web site (www.AARC.org).
`
`The contents of this book are approved for six CRCE con-
`tact hours; and as an AARC member, there is no charge to
`you. To earn those CRCE contact hours, please go to the
`AARC web site at:
`http://c.aarc.org/go/adu
`
`Further instructions will be given on that web site, including:
`• how to register to take an examination to assess your
`mastery of course objectives;
`• how to update your e-mail address so that registration
`(cid:70)(cid:82)(cid:81)(cid:386)(cid:85)(cid:80)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:70)(cid:68)(cid:81)(cid:3)(cid:69)(cid:72)(cid:3)(cid:86)(cid:72)(cid:81)(cid:87)(cid:3)(cid:87)(cid:82)(cid:3)(cid:92)(cid:82)(cid:88)(cid:17)
`
`Learning Objectives
`
`3.
`
`4.
`
`As you read this book, you will be able to:
`1.
`Identify the terminology used in aerosol medicine.
`2.
`State approximate amount of aerosol deposited in
`the lower respiratory tract for nebulizers, pressurized
`metered-dose inhalers (pMDIs), and dry-powder
`inhalers (DPIs).
`List advantages and disadvantages of inhalation
`compared to other routes of drug administration.
`Identify hazards of aerosol therapy that can impact the
`patient receiving therapy as well as care providers and
`bystanders.
`List advantages and disadvantages of nebulizers for
`aerosol delivery.
`6. Compare the principle of operation of a jet nebulizer,
`mesh nebulizer, and ultrasonic nebulizer.
`7. Describe types of pneumatic jet nebulizer designs and
`methods that are used to decrease aerosol loss from a
`jet nebulizer during exhalation.
`
`5.
`
`8.
`
` 10.
`
` 15.
`
` 16.
`
` 18.
`
`Learn steps for correct use of jet, ultrasonic, and mesh
`nebulizers.
`9. Describe the basic components of a metered-dose
`inhaler.
`List advantages and disadvantages of metered-dose
`inhalers.
` 11. Compare and contrast performance of pMDIs with HFA
`and CFC propellants.
` 12. Discuss factors affecting the pMDI performance and
`drug delivery.
` 13. Explain the importance of priming and tracking the
`number of doses for a metered-dose inhaler.
` 14. Compare and contrast the design of holding chambers
`and spacers.
`Identify factors that affect dose delivery from a holding
`chamber/spacer.
`List advantages and disadvantages of dry-powder
`inhalers.
` 17. Describe the principle of operation of various
`commercially available dry-powder inhalers.
`Identify factors affecting the DPI performance and drug
`delivery.
` 19. Explain how you know that each DPI is empty.
` 20.
`List the correct steps for use of a nebulizer, metered-
`dose inhaler, metered-dose inhaler with holding
`chamber/spacer, and dry-powder inhaler.
`21. Describe causes and solutions of problems seen with
`nebulizers, pMDIs, and DPIs.
`22. Discuss criteria to assist clinicians in selecting an
`aerosol delivery device.
`Identify special considerations for neonatal and pediat-
`ric drug delivery.
`24. Explain how to establish an infection control manage-
`ment system in aerosol drug delivery.
`25. Describe the proper technique of cleaning aerosol
`delivery devices.
`26. Discuss the importance of occupational health and
`safety for respiratory therapists.
`List common problems and errors with each type of
`inhaler.
`28. Describe how to instruct and evaluate patients in the
`use of inhaler devices.
`
`23.
`
`27.
`
`ii
`A Guide to Aerosol Delivery Devices for Respiratory Therapists, 4th Edition
`American Association for Respiratory Care, © 2017
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`

`

`Table of Contents
`
`Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i
`Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv
`The Science of Aerosol Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
`Terminology
`Mechanisms of Aerosol Deposition and Particle Sizes
`Types of Aerosol Generators
`Where Does an Inhaled Aerosol Drug Go?
`Equivalence of Aerosol Device Types
`Advantages and Disadvantages of Inhaled Aerosol Drugs
`Hazards of Aerosol Therapy
`Currently Available Aerosol Drug Formulations
`Small-Volume Nebulizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
`Advantages and Disadvantages of SVNs
`Types of SVNs
`Factors Affecting Jet Nebulizer Performance and Drug Delivery
`(cid:49)(cid:72)(cid:69)(cid:88)(cid:79)(cid:76)(cid:93)(cid:72)(cid:85)(cid:86)(cid:3)(cid:73)(cid:82)(cid:85)(cid:3)(cid:54)(cid:83)(cid:72)(cid:70)(cid:76)(cid:386)(cid:70)(cid:3)(cid:36)(cid:83)(cid:83)(cid:79)(cid:76)(cid:70)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)
`Continuous Aerosol Therapy
`Drug-Delivery Technique
`Inhalers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
`Pressurized Metered-Dose Inhalers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
`Advantages and Disadvantages of pMDIs
`Types of pMDIs
`Currently Available pMDI Formulations
`Factors Affecting pMDI Performance and Drug Delivery
`Drug-Delivery Technique
`Metered-Dose Inhaler Accessory Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
`Advantages and Disadvantages of pMDI Inhaler Accessory Devices
`Spacers
`Valved Holding Chambers
`Drug-Delivery Technique
`Dry-Powder Inhalers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
`Advantages and Disadvantages of DPIs
`Types of DPIs
`Currently Available DPI Formulations
`Factors Affecting the DPI Performance and Drug Delivery
`Drug-Delivery Technique
`Criteria to Select an Aerosol Generator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
`Patient-Related Factors
`Drug-Related Factors
`Device-Related Factors
`Environmental and Clinical Factors
`Neonatal and Pediatric Aerosol Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
`Age and Physical Ability
`Age and Cognitive Ability
`Aerosol Drug Delivery in Distressed or Crying Infants
`Patient-Device Interface
`Parent and Patient Education
`Infection Control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
`IC Management System in Aerosol Drug Delivery
`Preventing Infection and Malfunction of Aerosol Generators at Hospitals or Clinics
`Occupational Health and Safety of Respiratory Therapists
`Educating Patients in Correct Use of Aerosol Devices. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
`Patient Adherence
`Common Patient Errors with pMDIs
`Common Patient Errors with Holding Chambers/Spacers
`Common Patient Errors with DPIs
`Common Patient Errors with SVNs
`Instructing and Evaluating Patients in the Use of Inhaler Devices
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
`
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`Acronyms
`
`CDC
`CDER
`CDRH
`(cid:38)(cid:41)(cid:3)
`DPI
`FDA
`(cid:41)(cid:51)(cid:41)(cid:3)
`GSD
`(cid:43)(cid:41)(cid:36)(cid:3)
`IC
`MMAD
`MMD
`pMDI
`SPAG
`SVN
`VHC
`
`Centers for Disease Control and Prevention
`Center for Drug Evaluation and Research
`Center for Devices and Radiological Health
`(cid:70)(cid:92)(cid:86)(cid:87)(cid:76)(cid:70)(cid:3)(cid:386)(cid:69)(cid:85)(cid:82)(cid:86)(cid:76)(cid:86)
`dry-powder inhaler
`U.S. Food and Drug Administration
`(cid:386)(cid:81)(cid:72)(cid:16)(cid:83)(cid:68)(cid:85)(cid:87)(cid:76)(cid:70)(cid:79)(cid:72)(cid:3)(cid:73)(cid:85)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)
`Geometric Standard Deviation
`(cid:75)(cid:92)(cid:71)(cid:85)(cid:82)(cid:387)(cid:88)(cid:82)(cid:85)(cid:82)(cid:68)(cid:79)(cid:78)(cid:68)(cid:81)(cid:72)
`infection control
`mass median aerodynamic diameter
`mass median diameter
`pressurized metered-dose inhaler
`small particle aerosol generator
`small-volume nebulizer
`valved holding chamber
`
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`The Science of
`Aerosol Drug Delivery
`
`Aerosols exist everywhere there is gas to breathe. From
`pollen and spores, to smoke and pollution, to man-made
`(cid:70)(cid:75)(cid:72)(cid:80)(cid:76)(cid:70)(cid:68)(cid:79)(cid:86)(cid:15)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:68)(cid:72)(cid:85)(cid:82)(cid:86)(cid:82)(cid:79)(cid:3)(cid:70)(cid:68)(cid:87)(cid:72)(cid:74)(cid:82)(cid:85)(cid:92)(cid:3)(cid:76)(cid:81)(cid:70)(cid:79)(cid:88)(cid:71)(cid:72)(cid:86)(cid:3)(cid:68)(cid:81)(cid:92)(cid:3)(cid:386)(cid:81)(cid:72)(cid:3)(cid:79)(cid:76)(cid:84)(cid:88)(cid:76)(cid:71)(cid:3)(cid:82)(cid:85)(cid:3)
`solid particles. A “medical aerosol” is any suspension of liq-
`uid (nebulizer or pMDI) or solid drug particles (pMDI or DPI)
`in a carrier gas.1 Our respiratory systems evolved to have
`(cid:386)(cid:79)(cid:87)(cid:85)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:72)(cid:79)(cid:76)(cid:80)(cid:76)(cid:81)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:86)(cid:92)(cid:86)(cid:87)(cid:72)(cid:80)(cid:86)(cid:3)(cid:87)(cid:75)(cid:68)(cid:87)(cid:3)(cid:80)(cid:88)(cid:86)(cid:87)(cid:3)(cid:69)(cid:72)(cid:3)(cid:82)(cid:89)(cid:72)(cid:85)(cid:70)(cid:82)(cid:80)(cid:72)(cid:3)
`or bypassed in the process of providing local delivery of
`medications to the lung. Methods for generating aerosols,
`formulating drugs, and administering medications effec-
`tively to the desired site of action constitute the science of
`(cid:68)(cid:72)(cid:85)(cid:82)(cid:86)(cid:82)(cid:79)(cid:3)(cid:71)(cid:85)(cid:88)(cid:74)(cid:3)(cid:71)(cid:72)(cid:79)(cid:76)(cid:89)(cid:72)(cid:85)(cid:92)(cid:17)(cid:3)(cid:36)(cid:86)(cid:3)(cid:76)(cid:86)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:70)(cid:68)(cid:86)(cid:72)(cid:3)(cid:76)(cid:81)(cid:3)(cid:68)(cid:81)(cid:92)(cid:3)(cid:86)(cid:70)(cid:76)(cid:72)(cid:81)(cid:87)(cid:76)(cid:386)(cid:70)(cid:3)(cid:71)(cid:76)(cid:86)(cid:70)(cid:76)-
`(cid:83)(cid:79)(cid:76)(cid:81)(cid:72)(cid:15)(cid:3)(cid:82)(cid:81)(cid:72)(cid:3)(cid:80)(cid:88)(cid:86)(cid:87)(cid:3)(cid:386)(cid:85)(cid:86)(cid:87)(cid:3)(cid:88)(cid:81)(cid:71)(cid:72)(cid:85)(cid:86)(cid:87)(cid:68)(cid:81)(cid:71)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:87)(cid:72)(cid:85)(cid:80)(cid:86)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:71)(cid:72)(cid:386)(cid:81)(cid:76)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)
`used to describe the principles of aerosol medicine in order
`to subsequently master its methods.
`
`Terminology
`(cid:39)(cid:72)(cid:386)(cid:81)(cid:76)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86)(cid:3)(cid:82)(cid:73)(cid:3)(cid:78)(cid:72)(cid:92)(cid:3)(cid:87)(cid:72)(cid:85)(cid:80)(cid:86)(cid:3)(cid:88)(cid:86)(cid:72)(cid:71)(cid:3)(cid:76)(cid:81)(cid:3)(cid:68)(cid:72)(cid:85)(cid:82)(cid:86)(cid:82)(cid:79)(cid:3)(cid:71)(cid:85)(cid:88)(cid:74)(cid:3)(cid:71)(cid:72)(cid:79)(cid:76)(cid:89)(cid:72)(cid:85)(cid:92)(cid:3)(cid:68)(cid:85)(cid:72)(cid:3)
`listed in alphabetical order below.
`
`aerosol: a suspension of liquid and solid particles produced
`by an aerosol generator such as the small-volume
`nebulizer (SVN), the pressurized metered-dose inhaler
`(pMDI), or the dry-powder inhaler (DPI)
`aerosol deposition: process of aerosol particles depositing
`on absorbing surfaces
`aerosol generator: a device used for producing aerosol
`particles
`aerosol output: mass of medication exiting an aerosol gen-
`erator
`aerosol therapy: delivery of solid or liquid aerosol particles
`to the respiratory tract for therapeutic purposes
`dead volume (or residual volume): the amount of medica-
`tion that remains in the nebulizer after a treatment is
`complete
`diffusion: the mechanism of aerosol deposition for small
`particles less than 3 μm (Diffusion is also called
`Brownian motion.)
`dry-powder inhaler: an aerosol device that delivers the
`drug in a powdered form, typically with a breath-actu-
`ated dosing system
`emitted dose: the mass of medication leaving an aerosol
`generator as aerosol
`
`(cid:386)(cid:81)(cid:72)(cid:16)(cid:83)(cid:68)(cid:85)(cid:87)(cid:76)(cid:70)(cid:79)(cid:72)(cid:3)(cid:73)(cid:85)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:11)(cid:41)(cid:51)(cid:41)(cid:12)(cid:29)(cid:3)percentage of the aerosol
`between 1–5 μm that deposits in the lung
`heterodisperse: aerosol particles of different sizes
`(cid:75)(cid:92)(cid:71)(cid:85)(cid:82)(cid:387)(cid:88)(cid:82)(cid:85)(cid:82)(cid:68)(cid:79)(cid:78)(cid:68)(cid:81)(cid:72)(cid:3)(cid:11)(cid:43)(cid:41)(cid:36)(cid:12)(cid:29)(cid:3)(cid:68)(cid:3)(cid:81)(cid:82)(cid:81)(cid:87)(cid:82)(cid:91)(cid:76)(cid:70)(cid:3)(cid:79)(cid:76)(cid:84)(cid:88)(cid:72)(cid:386)(cid:72)(cid:71)(cid:3)(cid:74)(cid:68)(cid:86)(cid:3)(cid:83)(cid:85)(cid:82)(cid:83)(cid:72)(cid:79)-
`lant developed to be more environmentally friendly
`than CFCs and used to administer the drug from a
`pMDI
`inhaled dose: the proportion of nominal or emitted dose
`that is inhaled
`inhaled mass: the amount of medication inhaled
`inhaler: device used to generate an aerosolized drug for a
`single inhalation
`inertial impaction: the mechanism of aerosol deposition
`for particles larger than 5 μm
`gravitational sedimentation (gravitational settling): the
`settling rate of an aerosol particle due to gravity, parti-
`cle size, and time
`geometric standard deviation (GSD): one standard devi-
`ation above and below the median particle sizes in
`an aerosol distribution that indicates the variability in
`aerosol particle size
`mass median aerodynamic diameter (MMAD): average
`aerosol particle size as measured by a cascade impac-
`tor
`monodisperse: aerosol particles of same or similar sizes
`nebulizer: an aerosol generator producing aerosol particles
`from liquid-based formulations
`nominal dose: the total drug dose placed in the nebulizer
`plume: a bolus of aerosol leaving the pMDI or other aero-
`sol devices
`pressurized metered-dose inhaler (pMDI): a drug device
`combination that dispenses multiple doses by means
`of a metered value; used interchangeably with pMDI
`respirable mass: (cid:87)(cid:75)(cid:72)(cid:3)(cid:83)(cid:85)(cid:82)(cid:71)(cid:88)(cid:70)(cid:87)(cid:3)(cid:82)(cid:73)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:386)(cid:81)(cid:72)(cid:3)(cid:83)(cid:68)(cid:85)(cid:87)(cid:76)(cid:70)(cid:79)(cid:72)(cid:3)(cid:73)(cid:85)(cid:68)(cid:70)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)
`multiplied by the inhaled mass
`residual volume (or dead volume): the amount of med-
`ication that remains in the nebulizer at the end of a
`treatment
`spacer: a valveless extension device that adds distance
`between the pMDI outlet and the patient’s mouth
`valved holding chamber: a spacer with a one-way valve
`used to contain aerosol particles until inspiration occurs
`
`1
`A Guide to Aerosol Delivery Devices for Respiratory Therapists, 4th Edition
`American Association for Respiratory Care, © 2017
`
`IPR2021-00406
`United Therapeutics EX2033
`Page 7 of 61
`
`

`

`Mechanisms of Aerosol Deposition and
`Particle Sizes
`The major mechanisms of aerosol deposition include
`inertial impaction, gravitational sedimentation (settling),
`and diffusion. Inertial impaction occurs with larger (>3 μm),
`fast-moving particles. Gravitational settling is a function of
`particle mass and time, with the rate of settling proportion-
`al to particle size and mass. Diffusion occurs with particles
`smaller than 1 μm. These mechanisms come into play as
`aerosol particles are inhaled orally or through the nose.
`Larger particles (> 10 μ(cid:80)(cid:12)(cid:3)(cid:68)(cid:85)(cid:72)(cid:3)(cid:386)(cid:79)(cid:87)(cid:72)(cid:85)(cid:72)(cid:71)(cid:3)(cid:76)(cid:81)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:81)(cid:82)(cid:86)(cid:72)(cid:3)(cid:68)(cid:81)(cid:71)(cid:18)(cid:82)(cid:85)(cid:3)
`the oropharynx, largely by inertial impaction; particles of
`5–10 μm generally reach the proximal generations of the
`lower respiratory tract, and particles of 1–5 μm reach to
`the lung periphery.
`Particle size plays an important role in lung deposition,
`along with particle velocity and settling time. As particle
`size increases above 3 μm, aerosol deposition shifts from
`the periphery of the lung to the conducting airways.
`Oropharyngeal deposition increases as particle size increas-
`es above 6 μm. Exhaled loss is high with very small particles
`of 1 μm or less. Consequently, particle sizes of 1–5 μm are
`best for reaching the lung periphery, whereas 5–10 μm
`particles deposit mostly in the conducting airways, and
`10–100 μm particles deposit mostly in the nose.
`Aerosol devices in clinical use produce heterodisperse
`(also termed polydisperse) particle sizes, meaning that
`there is a mix of sizes in the aerosol. Monodisperse
`aerosols, which consist of a single particle size, are rare
`(cid:76)(cid:81)(cid:3)(cid:81)(cid:68)(cid:87)(cid:88)(cid:85)(cid:72)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:80)(cid:72)(cid:71)(cid:76)(cid:70)(cid:76)(cid:81)(cid:72)(cid:17)(cid:3)(cid:36)(cid:3)(cid:80)(cid:72)(cid:68)(cid:86)(cid:88)(cid:85)(cid:72)(cid:3)(cid:87)(cid:75)(cid:68)(cid:87)(cid:3)(cid:84)(cid:88)(cid:68)(cid:81)(cid:87)(cid:76)(cid:386)(cid:72)(cid:86)(cid:3)(cid:68)(cid:3)
`polydisperse aerosol is the mass median diameter (MMD).
`This measure determines the particle size (in μm) above
`and below which 50% of the mass of the particles is con-
`tained. This is the particle size that evenly divides the mass,
`or amount of the drug in the particle size distribution. This
`is usually given as the mass median aerodynamic diameter,
`or MMAD, due to the way sizes are measured. The higher
`the MMAD, the more particle sizes are of larger diameters.
`As seen in Figure 1, larger particles between 10–15 μm
`deposit mostly in the upper airways, particles within the
`5–10 μm range reach the large bronchi, and particles of
`1–5 μm penetrate to the lower airways and lung periph-
`ery.2
`
`Figure 1. (cid:36)(cid:3)(cid:86)(cid:76)(cid:80)(cid:83)(cid:79)(cid:76)(cid:386)(cid:72)(cid:71)(cid:3)(cid:89)(cid:76)(cid:72)(cid:90)(cid:3)(cid:82)(cid:73)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:72)(cid:73)(cid:73)(cid:72)(cid:70)(cid:87)(cid:3)(cid:82)(cid:73)(cid:3)(cid:68)(cid:72)(cid:85)(cid:82)(cid:86)(cid:82)(cid:79)(cid:3)(cid:83)(cid:68)(cid:85)(cid:87)(cid:76)(cid:70)(cid:79)(cid:72)(cid:3)
`(cid:86)(cid:76)(cid:93)(cid:72)(cid:3)(cid:82)(cid:81)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:86)(cid:76)(cid:87)(cid:72)(cid:3)(cid:82)(cid:73)(cid:3)(cid:83)(cid:85)(cid:72)(cid:73)(cid:72)(cid:85)(cid:72)(cid:81)(cid:87)(cid:76)(cid:68)(cid:79)(cid:3)(cid:71)(cid:72)(cid:83)(cid:82)(cid:86)(cid:76)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:76)(cid:81)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:68)(cid:76)(cid:85)(cid:90)(cid:68)(cid:92)(cid:86)
`(cid:11)(cid:41)(cid:85)(cid:82)(cid:80)(cid:3)(cid:53)(cid:72)(cid:73)(cid:72)(cid:85)(cid:72)(cid:81)(cid:70)(cid:72)(cid:3)(cid:21)(cid:15)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)(cid:83)(cid:72)(cid:85)(cid:80)(cid:76)(cid:86)(cid:86)(cid:76)(cid:82)(cid:81)(cid:12)
`
`Types of Aerosol Generators
`Three common types of aerosol generators are used for
`inhaled drug delivery: the small-volume nebulizer (SVN), the
`pressurized metered-dose inhaler (pMDI), and the dry-pow-
`der inhaler (DPI). Each device type is described below.
`Small-Volume Nebulizer: The SVN is an aerosol gener-
`•
`ator that converts liquid drug solutions or suspensions
`into aerosol and is powered by compressed air, oxy-
`gen, a compressor, or an electrically powered device.
`Pressurized Metered-Dose Inhaler: The pMDI is a
`small, portable self-contained drug device combina-
`tion that dispenses multiple doses by a metered value.
`Because of high medication loss in the oropharynx and
`(cid:75)(cid:68)(cid:81)(cid:71)(cid:16)(cid:75)(cid:72)(cid:79)(cid:71)(cid:3)(cid:70)(cid:82)(cid:82)(cid:85)(cid:71)(cid:76)(cid:81)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:71)(cid:76)(cid:73)(cid:386)(cid:70)(cid:88)(cid:79)(cid:87)(cid:92)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)(cid:83)(cid:48)(cid:39)(cid:44)(cid:86)(cid:15)(cid:3)(cid:75)(cid:82)(cid:79)(cid:71)(cid:76)(cid:81)(cid:74)(cid:3)
`chambers and spacers are often used as ancillary devic-
`es with the pMDI.
`Dry-Powder Inhaler: The DPI is an aerosol device that
`delivers drug in a powdered form, typically with a
`breath-actuated dosing system.
`
`•
`
`•
`
`Where Does an Inhaled Aerosol Drug Go?
`Lung deposition may range from 1–50% with clinical
`aerosol delivery systems.3–7 Deposition is dependent on a
`variety of factors such as the device, the patient, the drug,
`and the disease. For example, out of 200 micrograms (μg)
`of albuterol in two actuations or puffs from a pMDI, only
`about 20–40 μg reach the lungs with correct technique.
`The remaining drug is lost in the oropharynx, in the device,
`or in the exhaled breath. Figure 2 indicates the percentag-
`es of drug deposition for different aerosol systems, show-
`ing that oropharyngeal loss, device loss, and exhalation/
`ambient loss differ among aerosol device types, as do lung
`doses.
`
`2
`A Guide to Aerosol Delivery Devices for Respiratory Therapists, 4th Edition
`American Association for Respiratory Care, © 2017
`
`IPR2021-00406
`United Therapeutics EX2033
`Page 8 of 61
`
`

`

`Table 1. Differences in nominal (total) dose between a pMDI and an SVN
`for different drug formulations (cid:11)(cid:48)(cid:82)(cid:71)(cid:76)(cid:386)(cid:72)(cid:71)(cid:15)(cid:3)(cid:90)(cid:76)(cid:87)(cid:75)(cid:3)(cid:83)(cid:72)(cid:85)(cid:80)(cid:76)(cid:86)(cid:86)(cid:76)(cid:82)(cid:81)(cid:15)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)(cid:53)(cid:72)(cid:73)(cid:72)(cid:85)(cid:72)(cid:81)(cid:70)(cid:72)(cid:3)(cid:20)(cid:12)
`
`Drug
`Albuterol
`Ipratropium
`Levalbuterol
`
`pMDI Nominal Dose
`0.2 mg (200 μg)
`0.04 mg (40 μg)
`0.045 mg – 0.09 mg
`
`SVN Nominal Dose
`2.5 mg
`0.5 mg
`0.31 mg – 1.25 mg
`
`It is important to realize that different types of aerosol
`devices deposit a different fraction of the total dose of a
`given drug (also termed “nominal” dose) in the lungs. In
`addition, different types of aerosol devices such as nebuliz-
`ers and pMDIs do not have the same nominal dose. Using
`albuterol as an example, the typical pMDI nominal dose is
`two actuations, or about 200 μg, while the typical nebuliz-
`er nominal dose is 2.