Conference Proceedings
`
`History of Aerosol Therapy: Liquid Nebulization to MDIs to DPIs
`
`Paula J Anderson MD
`
`Introduction: Origins of Inhaled Therapies
`Ceramic Inhalers (19th Century)
`Early Atomizers and Nebulizers (Mid-to-Late 19th Century)
`Asthma Cigarettes and Powders
`Hand-Bulb Nebulizer and Early Electric and Compressor Nebulizers
`(1930s–1940s)
`Early DPIs and MDIs (1940s–1950s)
`Advances in Aerosol Science
`Theoretical Models
`Indirect Measures of Lung Deposition
`Particle Sizing Techniques and in Vitro Measurements
`Scintigraphy
`Pharmacokinetics and Pharmacodynamics
`1987 Montreal Protocol
`Summary
`
`Inhaled therapies have been used since ancient times and may have had their origins with the
`smoking of datura preparations in India 4,000 years ago. In the late 18th and in the 19th century,
`earthenware inhalers were popular for the inhalation of air drawn through infusions of plants and
`other ingredients. Atomizers and nebulizers were developed in the mid-1800s in France and were
`thought to be an outgrowth of the perfume industry as well as a response to the fashion of inhaling
`thermal waters at spas. Around the turn of the 20th century, combustible powders and cigarettes
`containing stramonium were popular for asthma and other lung complaints. Following the discov-
`ery of the utility of epinephrine for treating asthma, hand-bulb nebulizers were developed, as well
`as early compressor nebulizers. The marketing of the first pressurized metered-dose inhaler for
`epinephrine and isoproterenol, by Riker Laboratories in 1956, was a milestone in the development
`of inhaled drugs. There have been remarkable advances in the technology of devices and formu-
`lations for inhaled drugs in the past 50 years. These have been influenced greatly by scientific
`developments in several areas: theoretical modeling and indirect measures of lung deposition,
`particle sizing techniques and in vitro deposition studies, scintigraphic deposition studies, pharma-
`cokinetics and pharmacodynamics, and the 1987 Montreal Protocol, which banned chlorofluoro-
`carbon propellants. We are now in an era of rapid technologic progress in inhaled drug delivery and
`applications of aerosol science, with the use of the aerosolized route for drugs for systemic therapy
`and for gene replacement therapy, use of aerosolized antimicrobials and immunosuppressants, and
`interest in specific targeting of inhaled drugs. Key words: aerosol, nebulizer, inhaler, metered-dose
`inhaler, dry powder inhaler, asthma, lung disease, bronchodilator, scintigraphy, drug delivery.
`[Respir
`Care 2005;50(9):1139 –1149. © 2005 Daedalus Enterprises]
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`HISTORY OF AEROSOL THERAPY: LIQUID NEBULIZATION TO MDIS TO DPIS
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`Introduction: Origins of Inhaled Therapies
`
`Although the term “aerosol” was not coined until around
`1920, inhaled therapy for medicinal purposes dates back at
`least 4,000 years. The origins of inhalation therapy for asthma
`and other lung complaints may have arisen in the traditional
`therapies of Ayurvedic medicine in India around 2000 BC.1
`The compounds smoked included herbal preparations, most
`notably datura species, which contain potent alkaloids with
`anticholinergic bronchodilating properties. The datura roots
`were powdered together with other materials such as ginger
`and pepper, made into a paste for smearing on a reed that
`could be dried and smoked through a pipe.
`Around 1500 BC in Egypt, the vapor of black hen-
`bane was inhaled after being thrown onto a hot brick.
`Henbane is of the genus Hyoscyamus, which is in the
`nightshade family and contains hyoscyamine, another
`anticholinergic compound. One of the earliest inhaler de-
`vices is a design attributed to Hippocrates (Greece, 460 –
`377 BC) that consisted of a simple pot with a reed in the
`lid, through which vapors could be inhaled. Native cul-
`tures from Central and South America also fashioned pipes
`and devices for inhaling the smoke of tobacco and other
`plants (Fig. 1).
`In 1190 AD, a famous Spanish physician and philoso-
`pher Maimonides wrote Treatise on Asthma and recom-
`mended inhalation of fumes generated from herbs thrown
`on a fire, in addition to a modest lifestyle, which included
`chicken soup.2 Various ingredients have been documented
`in these inhaled recipes from antiquity, as evidenced by
`this quotation from Paulus Aegineta (Greece, 7th century
`AD): “To be inhaled for a continued cough: storax, pep-
`per, mastick, Macedonian parsley, of each one ounce; san-
`darach [an arsenical preparation], 6 scruples; 2 bayberries;
`mix with honey; and fumigate by throwing them upon
`coals so that the person affected with the cough may inhale
`the vapor through a funnel.”3 Commonly used materials
`for these ancient inhaled remedies included plants with
`
`Paula J Anderson MD is affiliated with the Division of Pulmonary and
`Critical Care Medicine, University of Arkansas for Medical Sciences,
`Central Arkansas Veterans Healthcare System, Little Rock Arkansas.
`
`Paula J Anderson MD presented a version of this article at the 36th
`RESPIRATORY CARE Journal Conference, Metered-Dose Inhalers and Dry
`Powder Inhalers in Aerosol Therapy, held April 29 through May 1, 2005,
`in Los Cabos, Mexico.
`
`Correspondence: Paula J Anderson MD, Division of Pulmonary and Crit-
`ical Care Medicine, University of Arkansas for Medical Sciences, Central
`Arkansas Veterans Healthcare System, 4301 W Markham, Slot 555, Lit-
`tle Rock AR 72205. E-mail: pjanderson@uams.edu.
`
`Fig. 1. Arica inhaler from coastal regions of northern Chile and
`southern Peru, dating from about 1500 AD. A tobacco-like mixture
`was prepared on the decorated wooden receptacle and inhaled
`through the hollow wooden mouthpiece. (Courtesy of Mark Sand-
`ers, Inhalatorium.com.)
`
`anticholinergic properties, such as datura, henbane, lobe-
`lia, and belladonna, in addition to arsenicals, balsams, and
`gum resins.
`Throughout the ages, many terms have been used to
`describe inhaled substances. Common terms and defini-
`tions are listed in Table 1.
`
`Ceramic Inhalers (19th Century)
`
`Variations on Hippocrates’s pot-and-reed design were
`used in the late 18th and early 19th century. The English
`physician John Mudge described his invention of an in-
`haler based on a pewter tankard, in his 1778 book A Rad-
`ical and Expeditious Cure for a Recent Catarrhous Cough
`(Fig. 2). Dr Mudge is thought to be the first person to use
`the term “inhaler,” and describes using his device for in-
`haling opium vapor for the treatment of cough.4 Numerous
`models of ceramic inhalers followed this design and were
`popular from the 19th century onward (Fig. 3). The design
`caused air to be drawn through warm water or an infusion
`prior to inhalation; one of the most popular models, the
`Nelson’s inhaler, manufactured by S Maw and Sons in
`London, was described in a Lancet article in 1863. Dr
`Scudding, in his 1895 treatise on inhalation therapy, re-
`lated that “the most efficient apparatus for the inhalation
`either of simple steam or of medicated vapors is that which
`is know by the name of Nelson’s Inhaler: it is constructed
`of earthenware, and, in addition to its complete adaptation
`to the purpose for which it is intended, possesses the triple
`recommendation of cleanliness, portability, and cheap-
`ness.”5 Those are certainly qualities that are valued in
`modern inhalation devices.
`The earliest use of inhaled datura for asthma in Britain
`was recorded in 1802 by Dr Sims, who had learned of this
`treatment from General Gent, an asthmatic posted to Ma-
`dras, who had adopted the practice for his own use.1,6
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`Table 1. Definitions of Common Terms Applied to Inhaled Therapies
`
`Aerosol
`Atomizer
`
`Nebulizer
`Fume
`Vapor
`Smoke
`Dust
`Powder
`Suspension
`Solution
`Gas
`
`Mist
`
`Solid or liquid particles suspended in a gas
`Device used to form a mist of fine droplets from a liquid. A high-velocity air jet passes over a liquid feed tube and draws
`liquid to the surface by the Bernoulli effect. The liquid is then propelled forward as a thin sheet, from which it breaks up
`into droplets by shear-induced instability.
`An atomizer modified with a baffle or impactor in front of the jet to remove large particles from the air stream
`Solid-particle aerosol produced by the condensation of vapors or gaseous combustion products
`The gaseous state of substances that are normally in the liquid or solid state (at normal room temperature and pressure)
`Visible aerosol resulting from incomplete combustion; the particles can be solid or liquid
`Solid-particle aerosol formed by mechanical disintegration of a parent material, such as by crushing or grinding
`A solid substance in the form of tiny, loose particles
`Mixture in which particles are suspended in a fluid and the particles are large enough that gravity causes the particles to settle
`Homogeneous mixture of 2 or more substances; frequently a liquid solution
`State of matter distinguished from the solid and liquid states by (1) relatively low density and viscosity, (2) relatively great
`expansion and contraction with changes in pressure and temperature, (3) the ability to diffuse readily, and (4) the
`spontaneous tendency to distribute uniformly throughout any container.
`Liquid-particle aerosol formed by condensation or atomization
`
`Early Atomizers and Nebulizers
`(Mid-to-Late 19th Century)
`
`Atomizers (also known as nebulizers) were developed
`in the mid-1800s in France and were thought to be an
`outgrowth of the perfume industry as well as a response to
`the fashion of inhaling thermal waters at spas. Dr Auphon
`Euget-Les Bain invented the atomizer in 1849, and in 1858
`Jean Sales-Girons introduced a portable nebulizer (Fig. 4).
`Dr Sales-Girons won the silver prize of the Paris Academy
`of Science in 1858 for his invention, which used a pump
`handle to draw liquid from the reservoir and force it through
`a nozzle against a plate.7 At that time, spa therapy was
`very popular in France, and the Sales-Girons “pulverisa-
`teur” was invented to allow those patients who could not
`attend the thermal baths to benefit from treatment. The
`thermal spas in France and elsewhere in Europe had long
`been used for therapeutic purposes, and the waters were
`inhaled as aerosols as well as ingested.6,8 These waters
`contained minerals, bicarbonate, and arsenicals, and occa-
`sionally substances were added that were harmful to the
`lungs, such as turpentine and petroleum. An improvement
`on the Sales-Girons device has been attributed to Bergsen,
`of Berlin, “whose apparatus consists of 2 glass tubes, hav-
`ing capillary openings at one end—these 2 ends being
`placed almost at a right angle with each other. The more
`open end of the perpendicular tube is immersed in the
`medicated fluid, and, as the compressed air is forced through
`the horizontal tube, the air in the perpendicular one be-
`comes exhausted, and the medicated solution then rises in
`it, and, when it arrives at the capillary opening, is dis-
`persed in very fine spray by the force of the compressed
`air passing along the other tube.”9 This is an early but
`accurate description of the Venturi system employed by
`today’s jet nebulizer.
`
`Fig. 2. The Mudge inhaler, invented by Dr John Mudge in 1778,
`was a pewter tankard with a mouthpiece covering the top and an
`air passage drilled through the handle. As the patient breathed
`through the mouthpiece, air was drawn through the holes in the
`handle and passed through the liquid at the bottom of the vessel.
`(Courtesy of Mark Sanders, Inhalatorium.com.)
`
`Reportedly, General Gent may have become a victim of
`his own inhaled therapy, with toxic manifestations leading
`to his untimely demise. There are other reports of datura
`use being brought back to Britain from the Far East, and
`the drug may have been used for its hallucinatory effects
`as well. The drug entered orthodox pharmacopoeias in
`Europe during the first part of the 19th century; its alkaloid
`component was identified as atropine in 1833.
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`HISTORY OF AEROSOL THERAPY: LIQUID NEBULIZATION TO MDIS TO DPIS
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`Fig. 3. Examples of earthenware inhalers from the late 19th century for inhalation of infusions. Left: The Alexandra inhaler, which has a vertical
`air channel at the back, through which air is drawn; a cover with a mouthpiece would complete the item. (Courtesy of Mark Sanders, Inhalato-
`rium.com.) Right: The Maw’s (or Nelson) inhaler, which would have had a stopper with a tube extending down into the liquid infusion.
`
`Fig. 4. The Sales-Girons “pulverisateur,” which won the 1858 silver prize of the Paris Academy of Science. The pump handle draws liquid
`from the reservoir and forces it through an atomizer. (Courtesy of Mark Sanders, Inhalatorium.com.)
`
`Siegle’s steam spray inhaler, developed in Germany in
`the 1860s, was based on the same principle, but it used
`steam rather than compressed air to disperse the medicated
`liquid. During that period, there were some authorities
`
`who doubted that spray solutions actually reached the lungs.
`In what might have been one of the first deposition ex-
`periments, Demarquay studied a woman with a tracheal
`fistula and demonstrated by doing chemical tests at the
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`Fig. 5. Asthma powder and asthma cigarettes were popular around the turn of the 20th century. One of the active ingredients was
`stramonium, which has anticholinergic bronchodilating properties.
`
`tracheal opening that the inhaled substances had at least
`penetrated as far as the trachea.9
`
`Asthma Cigarettes and Powders
`
`Around the turn of the 20th century, combustible pow-
`ders and cigarettes for the treatment of asthma and other
`lung complaints were popular (Fig. 5).6,10 These cigarettes
`contained stramonium (from Datura stramonium) as well
`as other ingredients, such as tea leaves, belladonna, kola
`nuts, and lobelia. A spoonful of powder was placed in a
`saucer and burned, and the smoke was inhaled through the
`mouth or with a funnel. The instructions for the asthma
`cigarette were to “exhaust the lungs of air, then fill the
`mouth with smoke and take a deep breath, drawing the
`smoke down into the lungs. Hold for a few seconds and
`then exhale through the mouth and nostrils,” which are
`similar to instructions given in modern clinics for metered-
`dose inhalers (MDIs) and dry powder inhalers (DPIs). Dur-
`ing that period, inhaled treatments were very popular and
`many of dubious benefit. Some devices employed the in-
`halation of vapors of menthol, creosote, turpentine, cam-
`phor, eucalyptus, balsam, pine, or mustard. A few inhaler
`advertisements even claimed great benefit from the regular
`inhalation of dry air.
`Of note is the Carbolic Smoke Ball, patented in 1889,
`for the inhalation of medicated powders.11 This device was
`a hollow rubber ball with a sieve across the orifice to
`deaggregate the powder inside. The ball was squeezed to
`produce a powder aerosol of Glycyrrhiza, hellebore, and
`
`carbolic acid, and a £100 reward was offered to anyone
`who contracted influenza while using the Carbolic Smoke
`Ball according to directions. This may have been one of
`the first examples of a DPI. Throughout history, and es-
`pecially in the 19th and early 20th centuries, much of the
`popularity and advertisements for inhalation therapies and
`devices were driven by the current lung conditions. Many of
`these devices were advertised as treatment for consumption,
`catarrh, croup, bronchitis, pertussis, diphtheria, or influenza,
`as asthma was less commonly diagnosed.
`
`Hand-Bulb Nebulizer and Early Electric and
`Compressor Nebulizers (1930s–1940s)
`
`Although the herb ma-huang had been used since 3000
`BC in Chinese medicine for the treatment of bronchos-
`pasm, advances were made around the turn of the 20th
`century, with the recognition of adrenal extract as a bron-
`chodilator. In 1899, epinephrine was named by Abel, and
`this was followed by its synthesis by Stolz and Dakin.12,13
`Solis-Cohen reported the use of adrenal extract to treat
`asthma patients in 1900, and the first use of epinephrine as
`an aerosol was reported in 1910 by Barger and Dale. It’s
`of interest that the 1932 edition of the Oxford Medicine
`does not mention inhaled adrenalin as a treatment for
`asthma, but states “. . .if the patient himself cannot use
`hypodermic medication he tends to rely upon patent med-
`icines and so-called asthma cures. The most serviceable
`among these seem to be the ones that contain stramonium
`leaves and saltpeter in the form of a powder, the fumes of
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`vice was also used in the 1950s by Abbot for administra-
`tion of norisodrine powder for treatment of asthma.
`The development of the pressurized MDI (pMDI) was a
`revolution in inhaler design. In 1955, Dr George Maison,
`the president of Riker Labs (now 3M Pharmaceuticals, St
`Paul, Minnesota), stimulated the development of the pMDI
`at the suggestion of his asthmatic teenage daughter, who
`got the idea from perfume spray devices.10,17 Researchers
`at Riker Labs developed a metered-dose valve and worked
`with DuPont, which manufactured propellants to produce
`an alcohol-based solution MDI. In March 1956, new drug
`applications were approved for Medihaler-Epi (epineph-
`rine) and Medihaler-Iso (isoproterenol). Three months later,
`these products were packaged for marketing. In 1957 the
`first oral suspension pMDIs of epinephrine and isoproter-
`enol were produced.
`There have been remarkable advances in the technology
`of devices and formulations for inhaled drugs in the 50
`years since the development of the first pMDI (Fig. 7). Jet
`and ultrasonic nebulizers have advanced, with devices that
`are breath-enhanced, breath-actuated, and dosimetric. Sev-
`eral new devices use vibrating-mesh technology in porta-
`ble, efficient nebulizers. MDI development has proceeded
`in several directions to address the problems posed by
`improper inhalation technique and coordination, high oro-
`pharyngeal deposition, and the need to replace chlorofluo-
`rocarbon (CFC) propellants. This has resulted in market-
`ing of accessory devices, breath-actuated MDIs, DPIs,
`non-CFC MDIs, and metered-dose liquid inhalers. Some
`early developments warrant mention, such as the first
`breath-actuated inhaler, the Duo-Haler, manufactured by
`3M in 1970.11 This device did not gain clinical acceptance
`because of its large size and the fact that it made a loud
`click on actuation.
`Early DPIs included the Spinhaler for cromolyn, intro-
`duced by Fisons in 1971, and the Rotahaler for albuterol,
`introduced by Glaxo in 1977. Also, the ultrasonic nebu-
`lizer, which uses a transducer made from a piezoelectric
`crystal, was put into production in the 1960s, but was
`never as commercially successful as the jet nebulizer.
`Another device that was in widespread use in the 1970s
`and 1980s was the intermittent positive-pressure breathing
`machine for delivery of bronchodilator solutions. Reports
`suggested that this device was not an improvement over
`the nebulizer or pMDI, and, in fact, it was associated at
`times with worsening asthma, worsening gas exchange,
`and barotrauma, so use of this device declined.18,19
`A milestone in the clinical use of inhaled drug therapy
`that deserves mention took place in 1974: the Conference
`on the Scientific Basis of Respiratory Therapy, also known
`as the “Sugarloaf Conference,”20 at which many experts in
`pulmonary medicine and respiratory care came together to
`examine the scientific basis for respiratory care and spe-
`cifically address aerosol therapy.
`
`Fig. 6. AsthmaNefrin hand-bulb nebulizer from the 1940s. The
`nebulizer was constructed of a plastic-like material and used for
`the inhalation of epinephrine.
`
`which, when burned, are inhaled for the relief of the par-
`oxysm. These fumes seem to be antispasmodic in action
`and following their inhalation thick sputum is raised and
`temporary relief results.”14
`Adrenalin chloride solution was supplied in the 1930s
`as a bronchodilator and was nebulized via glass-bulb nebu-
`lizers such as the Parke-Davis Glaseptic, and in the 1940s,
`via plastic-bulb nebulizers such as the AsthmaNefrin (Fig.
`6). The AsthmaNefrin instructions state that “the appliance
`reduces the solution to a mist so fine it actually floats in
`air. You breathe it as easily as you would a moist sea
`breeze, and the inhalant accomplishes its work because it
`can really be inhaled.”
`In the early 1930s, a compressor nebulizer, the Pneu-
`mostat, was manufactured in Germany.15 This piece of
`equipment had a rheostat for the power supply, allowing
`adjustment of the electrical voltage powering the compres-
`sor. Also around that time, the London Inhalatorium of-
`fered a treatment room that utilized a nebulizer powered
`by a cylinder of compressed oxygen, for inhalation of
`adrenalin, menthol, eucalyptus, turpentine, and other in-
`gredients.16
`
`Early DPIs and MDIs (1940s–1950s)
`
`Abbot Laboratories developed the Aerohaler for inhaled
`penicillin G powder and launched this device in 1948.
`Each small sifter cartridge contained 100,000 units of pen-
`icillin powder, which was inserted in the inhaler; the in-
`halation air intake caused a metal ball to strike the car-
`tridge and shake out powder into the airstream. The device
`could also be used for nasal inhalation, and the instructions
`strongly exhort against exhaling into the device. This de-
`
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`HISTORY OF AEROSOL THERAPY: LIQUID NEBULIZATION TO MDIS TO DPIS
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`Fig. 7. The evolution of inhaler devices.
`
`Advances in Aerosol Science
`
`Theoretical Models
`
`During the 20th century several scientific advances had
`major impacts on inhaled-drug delivery. These include (1)
`theoretical models and predictions, (2) indirect measures
`of lung deposition, (3) particle sizing techniques and in
`vitro measurements, (4) scintigraphic measurement of lung
`deposition, (5) pharmacokinetics and pharmacodynamics,
`and (6) the 1987 Montreal Protocol, which banned CFC
`propellants. In the early part of the 20th century it was not
`the medical field that stimulated investigations into mea-
`surements of respiratory-tract particle deposition, but chem-
`ists working on toxic aerosols used in warfare during and
`after World War I and industrial hygienists concerned with
`environmental and occupational particle exposure. The first
`mathematical model of respiratory deposition of aerosols
`was presented by Findeisen in 1935.21,22 He used a simple
`9-generation lung model, excluding the upper airway, and
`using 7 different particle diameters (from 0.03 ␮m to 30
`␮m), and assumed deposition from the mechanisms of
`impaction, sedimentation, and Brownian diffusion. He
`found that as particle size increased, the site of deposition
`moved proximally, toward the trachea. Landahl modified
`Findeisen’s model by adding a mouth and pharynx, an
`alveolar duct generation, and several different breathing
`conditions.23 There were subsequent refinements of these
`models in the years that followed, but one of the most
`widely used models was developed and reported24,25 by
`the Task Group on Lung Dynamics to the International
`Commission on Radiation Protection (Fig. 8). The model
`divided respiratory tract deposition into 3 zones, the na-
`
`sopharyngeal, tracheobronchial, and pulmonary zones, and
`performed calculations for particles from 0.01 ␮m to 100
`␮m, with several breathing patterns. Although the task
`group’s model was intended for radiation-protection pur-
`poses, it was widely applied to other situations. For all of
`the models, the particles were assumed to be spherical and
`of unit density (1 g/cm3), and the concept of aerodynamic
`particle diameter was established. In 1963, Weibel pub-
`lished lung anatomical schemes with 23 generations, based
`on detailed anatomic examination of several excised nor-
`mal adult human lungs, which were used in many of the
`subsequent theoretical models.26
`Much more sophisticated models are now available, use
`more accurate lung anatomy and 3-dimensional simulations,
`and incorporate factors such as airway narrowing and hygro-
`scopic particle growth. In contrast to the original stimulus of
`modeling in toxicology and occupational hygiene, there is
`much more interest at present in modeling delivery of ther-
`apeutic aerosols. Therapeutic aerosols present many more
`challenges for modeling, in that they take different physical
`forms and can be generated in many different ways. The
`physical form may be liquid drops, solutions, micronized
`drug in suspension, or dry particles. Some are physically
`unstable and may be subject to evaporation, growth, agglom-
`eration, or repulsion as they pass from the delivery device
`into the humid respiratory tract. Models are currently evolv-
`ing to account for these variables.27,28
`
`Indirect Measures of Lung Deposition
`
`During the period of theoretical model development,
`experimental studies of aerosol deposition in humans were
`also taking place. These studies utilized laboratory-gener-
`
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`Fig. 8. Task Group on Lung Dynamics theoretical model. The model divided respiratory-tract deposition into 3 zones: the nasopharyngeal,
`tracheobronchial, and pulmonary zones. (From Reference 25, with permission.)
`
`ated monodisperse aerosols, normal subjects, and tech-
`niques that compared fractions of inhaled and exhaled air
`to estimate particle retention.29,30 Techniques for aerosol
`analysis included light scattering measurements and chem-
`ical analysis of inhaled and exhaled air. Several different
`aerosols were used, including triphenyl phosphate, CaCO3,
`ZnO, sebacate, and NaCl particles. In general, these early
`measurements were in reasonable agreement with the avail-
`able theoretical models. Over the next 20 –30 years, the
`technology and experimental data improved as theoretical
`models improved and the effect of particle size and breath-
`ing pattern on the deposition of inhaled aerosols became
`more clear.31,32
`
`Particle Sizing Techniques and in Vitro
`Measurements
`
`During the period of development of theoretical depo-
`sition models and early deposition experiments, advance-
`ments were also made in respirable mass sampling of aero-
`sols and particle sizing. The concept of respirable mass
`was developed for industrial hygiene purposes, to indicate
`what portion of a harmful dust could penetrate deep into
`the lung and cause lung disease. Several definitions were
`put forth in the 1950s and 1960s and the decades that
`followed.22 Early sizing of harmful mineral dusts was via
`microscopy, but mechanical samplers were developed that
`divided particles that were nonrespirable from those that were
`respirable.33 These fractions can be gravimetrically measured,
`and this technology is still used today in the workplace.
`More sophisticated methods for determination of parti-
`cle size distribution were developed using inertial impac-
`tion and optical devices, which have become the standard
`for pharmaceutical aerosols.34 The cascade impactor draws
`
`the aerosol through a series of stages, each containing a
`plate or filter upon which the particles deposit according to
`their sizes. Optical methods use light scattering, diffrac-
`tion, phase Doppler, and time-of-flight measurements to
`derive particle size distribution. From these measurements
`a mean aerodynamic diameter and the variability around
`that mean (geometric standard deviation) can be deter-
`mined. These measurements are important for quality con-
`trol and comparison of devices, and they can be used to
`estimate the amount of deposition in the respiratory tract.
`Characteristically, cascade impactors or multistage im-
`pingers are used to quantitate the respirable fraction or
`fine-particle dose (usually the percentage of particles ⬍ 5– 6
`␮m diameter) as an estimate of lung delivery.
`Cascade impactor measurement with drug-specific as-
`say is the method of choice in the United States, and a
`standard inlet manifold should be used. Recommendations
`are available for assessment of particle size distributions
`and mass output of nebulizers, MDIs, and DPIs.35,36 In
`vitro systems have been added to particle sizing devices in
`ways that more closely simulate the clinical scenario. An-
`atomic throats have been used with impactors or impingers
`instead of standard inlet manifolds. Radiolabeled aerosols
`have been delivered to anatomic lung models using sim-
`ulated breathing patterns. Other measurements of “inhaled
`mass” from a nebulizer have used a patient or patient
`surrogate (piston pump) breathing from a nebulizer through
`filters.
`
`Scintigraphy
`
`The gamma camera was invented and reported by An-
`ger in 1958,37 and radionuclide imaging of the human
`body was initially done in hospitals for diagnostic pur-
`
`1146
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`RESPIRATORY CARE • SEPTEMBER 2005 VOL 50 NO 9
`
`Liquidia's Exhibit 1067
`Page 8
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`HISTORY OF AEROSOL THERAPY: LIQUID NEBULIZATION TO MDIS TO DPIS
`
`ments can be made from plasma or urinary levels. These
`measurements can provide confirmation of in vitro and
`scintigraphic assessments and can often add insights into
`the relationship between drug delivery and clinical effi-
`cacy and toxicity. Borgstro¨m et al used scintigraphy and
`urinary drug levels to measure differences in terbutaline
`lung deposition between an MDI and a DPI in asthmat-
`ics.41 Spirometry showed that at the lower dose of ter-
`butaline, improvement in forced expiratory volume in the
`first second was significantly greater with the device that
`had greater lung deposition, but that at the higher dose
`there was no difference in forced expiratory volume in the
`first second, despite higher deposition. This is an example
`of how pharmacokinetics/pharmacodynamics data can clar-
`ify that higher deposition may not improve the clinical
`outcome and may cause toxicity. These types of measure-
`ments are used to assess new formulations and devices, to
`determine the most clinically appropriate dose of drug, and
`to improve the therapeutic ratio of the drug/device com-
`bination.
`
`1987 Montreal Protocol
`
`MDIs were initially developed with CFC propellant sys-
`tems. Because of CFC’s deleterious effects on the ozone
`layer, the Montreal Protocol was developed by the United
`Nations in 1987, which banned substances that deplete the
`ozone layer.42 This ban phased out the use of CFCs by
`1996, although pharmaceutical companies had exemptions.
`While the contribution of CFC inhaler propellants has a
`minute environmental impact, this ban had a large effect
`on the development of inhaler technology. Hydrofluoroal-
`kane (HFA) propellants were found to be effective substi-
`tutes, and HFA134a was developed as an alternative to
`CFC. The substitution of HFA propellants has changed the
`properties of the aerosols produced by pMDIs, and HFA-
`propelled aerosol is, in general, a “softer” spray that exits
`the pMDI at a lower velocity. Also, the spray temperature
`from a HFA-propellant pMDI is above freezing—much
`warmer than that of a CFC-propellant pMDI.
`HFA-propelled beclomethasone required reformulation
`as a solution rather than as a suspension, and the resulting
`aerosol contains a much higher fraction of fine particles,
`which exit the inhaler at a lower velocity.43 This results in
`higher lung deposition and lower oropharyngeal deposi-
`tion. The improved drug deposition is of sufficient mag-
`nitude that pharmacokinetic studies found that the label
`dose could be cut in half and achieve results similar to that
`of the CFC formulation. The phasing-out of CFC propel-
`lants has stimulated the development of CFC-free MDIs,
`DPIs, and MDI liquid inhalers. The United States Food
`and Drug Administration recently issued a final rule that,
`as of December 31, 2008, all CFC devices will be phased
`out.
`
`Fig. 9. Early scintigraphy study showing the relationships between
`breathing pattern and the lung deposition and lung function re-
`sponse with bronchodilator from a pressurized metered-dose in-
`haler. (From Reference 38, with permission.)
`
`poses. In the late 1970s it was recognized that scintigraphy
`could be used to assess drug delivery to various organs,
`including the lungs.38 Total and regional deposition and
`clearance of therapeutic aerosols can be measured nonin-
`vasively by the use of inhaled radiolabeled particles and
`scintigraphic scanning techniques. The distribution as well
`as quantity of label in the oropharynx, lun