JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY
`Volume 30, Number 1, 2017
`Mary Ann Liebert, Inc.
`Pp. 20–41
`DOI: 10.1089/jamp.2016.1297
`
`The History of Therapeutic Aerosols:
`A Chronological Review
`
`Stephen W. Stein, MS1, and Charles G. Thiel, BA2
`
`Abstract
`
`In 1956, Riker Laboratories, Inc., (now 3 M Drug Delivery Systems) introduced the first pressurized metered dose
`inhaler (MDI). In many respects, the introduction of the MDI marked the beginning of the modern pharmaceutical
`aerosol industry. The MDI was the first truly portable and convenient inhaler that effectively delivered drug to the lung
`and quickly gained widespread acceptance. Since 1956, the pharmaceutical aerosol industry has experienced dramatic
`growth. The signing of the Montreal Protocol in 1987 led to a surge in innovation that resulted in the diversification of
`inhaler technologies with significantly enhanced delivery efficiency, including modern MDIs, dry powder inhalers,
`and nebulizer systems. The innovative inhalers and drugs discovered by the pharmaceutical aerosol industry,
`particularly since 1956, have improved the quality of life of literally hundreds of millions of people. Yet, the delivery
`of therapeutic aerosols has a surprisingly rich history dating back more than 3500 years to ancient Egypt. The delivery
`of atropine and related compounds has been a crucial inhalation therapy throughout this period and the delivery of
`associated structural analogs remains an important therapy today. Over the centuries, discoveries from many cultures
`have advanced the delivery of therapeutic aerosols. For thousands of years, therapeutic aerosols were prepared by the
`patient or a physician with direct oversight of the patient using custom-made delivery systems. However, starting
`with the Industrial Revolution, advancements in manufacturing resulted in the bulk production of therapeutic aerosol
`delivery systems produced by people completely disconnected from contact with the patient. This trend continued
`and accelerated in the 20th century with the mass commercialization of modern pharmaceutical inhaler products. In
`this article, we will provide a summary of therapeutic aerosol delivery from ancient times to the present along with a
`look to the future. We hope that you will find this chronological summary intriguing and informative.
`
`Keywords: atropine, dry powder inhaler, inhaler, metered dose inhaler, nebulizer, therapeutic aerosol
`
`The Delivery of Therapeutic Aerosols in Ancient Times
`
`T he delivery of therapeutic vapors and aerosols
`
`through inhalation has been used for thousands of years
`in various cultures. The first known reference to therapeutic
`aerosol delivery is an ancient Egyptian papyrus scroll (Ebers
`papyrus) dating back to *1554 BC, which purportedly was
`discovered between the legs of a mummy in the Assassif
`district of the Theban necropolis.(1) This papyrus describes
`having patients struggling to breathe to inhale the vapor
`formed when black henbane (Hyoscyamus niger) plants were
`placed onto hot bricks. After placing the herbs onto the stone,
`a jar with a hole was place over the herbs and the patient
`
`inhaled the fumes through a stalk of reed that was placed into
`the hole. The instructions as translated by Ebbell(2) are ‘‘Thou
`shalt fetch 7 stones and heat them by the fire, thou shalt take one
`thereof and place (a little) of these remedies on it and cover it
`with a new vessel whose bottom is perforated and place a stalk
`of a reed in this hole; thou shalt put thy mouth to this stalk so that
`thou inhalest the smoke of it.’’ Figure 1 shows a representation
`of the aerosol delivery described in the Ebers papyrus.
`Black henbane is a leafy flowering plant native to Europe
`and northern Africa. The therapeutic properties of the in-
`haled vapor have been attributed to the tropane alkaloids,
`including atropine, contained in all parts of the henbane
`plant.(3,4) The anticholinergic properties of atropine and
`
`13 M Drug Delivery Systems, St. Paul, Minnesota.
`2Retired, Tucson, Arizona.
`
`ªStephen W. Stein and Charles G. Thiel, 2016. Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the
`terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
`reproduction in any medium, provided the original work is properly credited.
`
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`THE HISTORY OF THERAPEUTIC AEROSOLS
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`21
`
`structurally similar alkaloids combined with their promi-
`nence in various plants around the world have resulted in
`this class of compounds playing a critical role in the history
`of therapeutic aerosol delivery.
`The most prominent ancient form of respiratory drug
`delivery was the smoking of opium for therapeutic and
`recreational purposes using incense burners and pipes.
`While the earliest known reference of smoking opium dates
`back to 1100 BC in China,(5) the practice likely had earlier
`origins due to the prominence of opium cultivation by that
`time. It is believed that cultivation of the opium poppy
`originated among the Sumerian people of lower Mesopota-
`mia and was passed on to the Assyrian and Babylonians who
`in turn passed the practice on to the Egyptians.(5) By 1300
`BC, opium cultivation had spread to Egypt, Carthage, and
`Europe. In 1025 AD, the Persian physician, Avicenna (Abu
`‘Ali al-Husayn ibn Sina), in his influential medical ency-
`clopedia entitled Canon of Medicine, described the use of
`opium for a variety of medical purposes, including analge-
`sia, treatment of diarrhea, and treatment of severe cough.
`Avicenna described a variety of forms of administration,
`including smoking and nasal inhalation.(6) Avicenna exten-
`sively described the toxicity of opioids and generally dis-
`couraged their use. He recommended, ‘‘If you have no other
`option but to use opioids, closely monitor patient’s pulse to
`avoid overdosing.’’(6)
`The inhalation of therapeutic aerosols for the treatment of
`asthma is described in the writings of the influential Indian
`physicians, Charaka and Sushruta, which date back to *600
`BC. These writings provide detailed instructions for pre-
`paring herbal compositions, including Datura that could be
`smoked in a pipe or in a cigarette(3) to relieve asthma
`symptoms. Charaka also described the burning of herbal
`compositions in a bowl fitted with a second bowl on top and
`a tube fitted to allow inhalation of the fumes.(7) The thera-
`peutic effects and toxicity described by Sushruta are con-
`sistent with atropine, which is a known active ingredient of
`the Datura stramonium species.(3) While the oldest existing
`documents describing smoking of Datura stramonium for
`treatment of asthma come from about 600 BC, Gandevia
`proposes that the origins of this therapy may date as far back
`as 2000 BC with early traditional Ayurvedic medicine.(7)
`In addition to inhaled Datura, Indian physician Charaka
`Samhita describes in his first century AD medical book a range
`of asthma therapies that include steam inhalation and smoking
`cigars made of the paste of turmeric, cassia, cinnamon, the
`roots of the castor plant, lac, red arsenic, deodar, yellow or-
`piment, and nardus, smeared with ghee.(8) The Ayurvedic texts
`provide instructions on how to modify the strength of the dose,
`give clear instructions on the optimal inhalation technique, and
`provide contraindications to this therapy.(7)
`The famous Greek physician, Hippocrates (460–377 BC),
`describes a device for enabling the inhalation of various
`vapors for the treatment of a number of maladies. This device
`consisted of a pot with a lid that had a hole through which a
`reed could be placed to enable the vapors to be inhaled.(9)
`Vapors generated from herbs and resins that had been boiled
`in vinegar and oil were inhaled through the reed.(3)
`In the second century AD, the Greek physician, Galen of
`Pergamon, described the inhalation of powdered drugs for
`relief of nasal and chest troubles.(10) In particular, Galen
`described the inhalation of myrrh and nutgall powders into
`
`the larynx through a bent reed to treat angina and credited
`the origin of this early practice of powder inhalation to
`Aesculapius, the God of medicine and healing.(11) Around
`the same time frame, another Greek physician, Aretaeus of
`Cappadocia, utilized a similar instrument for powder inha-
`lation to treat laryngeal ailments of children.(12)
`While not normally delivered through inhalation, ephedra
`(known in China as Ma Huang) played a key role in the
`treatment of asthma for thousands of years. The Chinese
`medial book Nei Ching written by Huang-Ti in *1000 BC
`describes the use of Ma Huang remedies for the treatment of
`asthma.(13) Ma Huang, which was usually delivered orally as
`a tea or a pill, was later shown to contain the active ingre-
`dient ephedrine.(3) Ephedra was a mainstay in asthma ther-
`apy in the Roman Empire. The noted Roman historian, Pliny
`the Elder (23–79 AD), recommended ephedra mixed with
`red wine as a remedy for asthma. Interestingly, Pliny re-
`commended a number of other asthma remedies that prob-
`ably did not significantly advance the treatment of asthma
`(e.g., drinking the blood of wild horses, bear’s gall mixed
`with water, or millipedes soaked in honey!), but he made the
`significant contribution of identifying a link between pollen
`exposure and respiratory distress [The Natural History of
`Pliny; translated in 1856 by Bostock and Riley(14)].
`Ephedrine, which would later be isolated from ephedra by
`Japanese chemist Nagayoshi Nagai in 1885,(15) remained
`widely used for treatment of cough and respiratory disease
`until the 1950s when it began to be displaced by other
`bronchodilators with improved safety profiles.(15) Ephedrine
`sulfate is still available over the counter in the United States,
`but with significant restrictions and regulation.
`By the first century AD, the smoking of tobacco and other
`plants in Central and South American cultures using ornate
`pipes had become common.(3) It is believed that these cul-
`tures also had identified the smoking of Datura as a thera-
`peutic remedy for the treatment of asthma(7) and had used
`the inhalation of cannabis for recreational and therapeutic
`purposes, including the use as a sedative.(10)
`In the fourth or fifth century AD, the Roman physician,
`Caelius Aurelianus, provided a clear description of the
`symptoms of bronchial asthma and proposed the inhalation
`of steam as a technique to treat asthmatic episodes. He also
`proposed inhaling sea air as a technique for preventing ep-
`isodes.(8) The warm steamy air in Roman public bath sys-
`tems that were widely developed at that time in major cities
`was recommended by Roman physicians for treatment of
`various ailments, including asthma.(10)
`
`Delivery of Therapeutic Aerosols from the Middle
`Ages to the Industrial Revolution (476–1760 AD)
`
`There were relatively few major innovations in the de-
`livery of therapeutic aerosols during the period between the
`fall of Rome (476 AD) and the start of the Industrial Re-
`volution (c. 1760 AD). The recorded examples of the de-
`livery of therapeutic vapors and aerosols through inhalation
`during this period relied heavily on practices developed
`before the fifth century AD, such as the smoking of Datura
`or opium and directing the fumes and vapors of burning
`herbs into the lung of the patient.
`The seventh century AD Greek physician, Paulus Aegi-
`neta, catalogued a host of ingredients to be inhaled for the
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`22
`
`STEIN AND THIEL
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`FIG. 1. A schematic representation of the oldest known reference (c. 1554 BC) of therapeutic
`aerosol delivery in which smoke of henbane plants was inhaled through the stalk of a reed.
`
`treatment of persistent cough. His recommended treatment
`consisted of placing a complex herbal remedy onto coals
`and inhaling the fumes through a funnel. Aegineta’s in-
`structions are recorded as, ‘‘To be inhaled for a continued
`cough: storax, pepper, mastic, Macedonian parsley, of each
`one ounce; sandarach, 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.’’(9,16) The resultant vapor contained ar-
`senic since sandarac is the Greek and Roman name for red
`arsenic sulfide.(9,16)
`Rhazes, the Arab physician who lived in Baghdad from
`850 to 932 AD, proposed some of the more innovative ap-
`proaches for pulmonary delivery during the Middle Ages. He
`utilized sponges that had been soaked in a solution of narcotic
`plants (opium, hyoscyamus, mandrake, and henbane) and
`then allowed to dry. Then, just before the surgery, the
`sponge was moistened and placed over the mouth and nose
`of patient in order that the vapors be inhaled as anesthesia
`during surgery.(10) Rhazes also advocated for the inhalation
`of arsenic for the treatment of respiratory conditions.(3)
`The figure with the greatest influence on the inhalation of
`therapeutic aerosols during the Middle Ages was the Spanish-
`born physician, Maimonides (1138–1204 AD), who fled
`Spain and eventually became the personal physician to Sal-
`adin, the sultan of Egypt (1137 or 1138–1193 AD). Maimo-
`nides was responsible to care for the king’s asthmatic son and
`wrote the first known book on asthma (A Treatise on Asthma)
`in 1190. His recommendations for management of asthma
`included inhaling herbs burned on a fire, abstaining from sex,
`and eating chicken soup.(3) Maimonides provided numerous
`other dietary recommendations for the management of
`asthma and recognized the link between air pollution and
`asthma.(13) Maimonides reasoned, ‘‘Town air is stagnant,
`turbid, and thick. Air winds carry stealthily inside the
`houses and many become ill with asthma without noticing.
`Concern for clean air is a foremost rule in preserving the
`health of one’s body and soul’’ [quoted in Brenner(13)].
`There were limited advancements in the understanding of
`asthma and the delivery of therapeutic aerosols between the
`time of Maimonides and the start of the Industrial Revolu-
`tion. The most notable contributions came from the Indian
`physician, Yogaratnakara, who in the 17th century provided
`
`further description and modification of Datura smoking
`therapy for treatment of asthma(7) and English physician,
`Christopher Bennet, whose 1654 drawing (Fig. 2) is the
`oldest known illustration of an inhalation device.(3)
`
`FIG. 2. The oldest known drawing of a therapeutic inhaler
`device developed in 1654 by the English physician Chris-
`topher Bennet. Image courtesy of Mark Sanders.
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`THE HISTORY OF THERAPEUTIC AEROSOLS
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`23
`
`The Delivery of Therapeutic Aerosols from 1760 to 1955
`
`With the dawn of the industrial revolution in 1760,
`new manufacturing capabilities and technical discoveries
`paved the way for significant advances in the delivery of
`therapeutic aerosols. Before this time frame, therapeutic
`aerosols were primarily prepared directly by the physician
`or patient, but during this era, devices and therapeutic
`aerosol preparations began to be mass produced by indi-
`viduals completely removed from the treatment of the pa-
`tient. In addition, this was an era where new therapeutic
`entities were identified and techniques were developed for
`enhancing the potency and safety of these therapeutic enti-
`ties by isolating the active ingredient. New delivery systems
`such as nebulizers and early dry powder inhalers (DPIs)
`were also introduced during this period. These advances set
`the stage for the beginning of the modern era of pharma-
`ceutical aerosols, which began in 1956.
`
`Advances in the delivery of medicated vapors
`
`In the late 1700s, respiratory drug delivery continued to
`rely on inhaling medicated vapors. It should be noted that the
`phrase ‘‘medicated vapor’’ is probably simplistic since some
`of the techniques described below that were utilized during
`this period undoubtedly resulted in some aerosol droplets
`being formed either through condensation of saturated water
`vapor in the system or through atomization of the medicated
`solution (e.g., when air is bubbled through the solution or the
`solution is boiled). As a result, the therapeutic benefit of these
`techniques was likely a result of both the vapor and aero-
`solized droplets. Nevertheless,
`these therapeutic aerosols
`were commonly referred to as medicated vapors and are
`similarly described in this article.
`In his 1764 book, Medical Advice to the Consumptive and
`Asthmatic Peoples of England, English physician Philip
`Stern prescribed his personal recipe for inhalation of bal-
`
`samic vapors for the treatment of asthma. Stern’s book was
`groundbreaking in that it was intended to provide instruction
`for the general public rather than physicians.(3) English
`physician John Mudge advocated for inhaling the aerosol
`from heated water containing opium for the treatment of
`catarrhal cough.(3,9) In his book, A Radical and Expeditious
`Cure for a Recent Catarrhous Cough, he coined the term
`inhaler to describe a clever inhalation device for generating
`and delivering steam-based aerosols.(17) The inhaler device,
`first
`introduced in 1778, consisted of a pewter tankard
`having a volume of approximately one pint with a lid that
`had a cover on the top with an adapter that could be coupled
`to a 5- or 6-inch-long flexible tube through which the patient
`inhaled for the 20–30-minute duration of the dosing (Fig. 3).
`The device had holes in the handle through which air was
`drawn in and bubbled through the warm liquid.(17) Through
`use of a clever valve design, the patients were able to keep
`their lips surrounding the mouthpiece tube and breathe in
`and out through the tube in a way similar to many modern
`nebulizers. The Mudge inhaler marked the first known
`commercialization of an inhaler device with Mudge detail-
`ing in his book the name of a local pewterer that he part-
`nered with and from whom the inhaler could be obtained.
`Throughout the 1800s, the inhalation of medicated vapor
`from aqueous solutions continued to be a primary mode of
`treatment of respiratory ailments. Various ceramic inhalers
`with similar functionality to the Mudge inhaler were com-
`mercialized for generated medicated vapors and gained
`popularity in England in the 19th century. Prominent among
`these ceramic inhalers was the Nelson inhaler, which was
`commercialized by S Maw and Sons in London.(9) Other
`approaches were used to generate medicated vapors, such as
`pouring the medicated solution over a sponge.(18)
`As devices for generating medicated vapors proliferated,
`so too did the recommended therapies. In 1834, Sir Charles
`Scudamore proposed heating iodine and hemlock (conium)
`
`FIG. 3. A drawing (a) and photo (b) of the Mudge Inhaler.(17) As the patient inhaled through the flexible
`mouthpiece, air was drawn through the three holes on the handle and the air was bubbled through the
`medicated liquid before exiting the mouthpiece. The right side of the drawing shows the valve configuration,
`which utilized a small cork that moved and allowed the exhaled breath of the patient to exit the tankard.
`Images courtesy of Mark Sanders.
`
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`24
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`STEIN AND THIEL
`
`in water to 120 F and having the patient inhale the vapor for
`15–20 minutes three times per day for the treatment of tu-
`berculosis or other lung diseases.(3) The 1867 British Phar-
`macopoeia listed detailed instructions for the generation of
`various medicated solutions to be inhaled, including hy-
`drocyanic acid for the treatment of cough, chlorine for
`treatment of tuberculosis, hemlock for the treatment of
`cough, creasote for the treatment of tuberculosis and bron-
`chitis, and iodine for the treatment of tuberculosis, phar-
`yngitis, and laryngitis. The inclusion of these therapies in
`the British Pharmacopoeia demonstrates that these therapies
`had received widespread acceptance by that time.(19)
`The inhalation of anesthetic gases through makeshift face
`masks emerged in the 1840s.(10) There is a debate over
`whether the use of inhaled ether as surgical anesthetic was
`introduced by American physicians Crawford Long in 1842
`or William Morton and John Collin Warren in 1846, but the
`practice gained rapid acceptance.(3,20,21) Due to the side
`effect of nausea associated with ether, physician James
`Young Simpson introduced inhaled chloroform as a surgical
`anesthetic in 1847.(10) The use of nitrous oxide for dental
`anesthesia was first demonstrated by American dentist
`Horace Wales in several dental operations in 1844(10) and
`then gained widespread acceptance due to the influence of
`New York dentist Gardner Qunicy Colton.(22)
`
`The diversification of technologies for inhalation delivery
`in the last half of the 19th century
`
`The last half of the 19th century saw unprecedented in-
`novation in the area of pharmaceutical aerosol delivery
`technologies. The introduction of nebulizers, DPIs, advances
`in the commercialization of asthma cigarettes, and a number
`of other delivery technologies dramatically reshaped the
`practice of delivering drugs to the respiratory tract. Other
`innovations, although less influential, are worthy of mention.
`One innovation was direct spraying of medicated solutions
`into the respiratory tract. By 1852, Ira Warren (the inventor of
`the first DPI) was selling a kit consisting of a laryngeal,
`pharyngeal, and nasal shower syringe for applying an aque-
`ous solution of silver nitrate for treatment of various respi-
`ratory conditions such as nasal catarrh and diseases of the
`throat.(23) At the 1890 Annual Meeting of the American
`Medical Association, J. Mount Bleyer published an article
`describing a similar approach that he claimed was capable of
`administering medications such as silver nitrate, iodine, tan-
`nic acid, and hydrogen peroxide deeper into the bronchia.(24)
`Inhaling the fumes of burning niter paper (which gener-
`ates ammonia as it burns) was recommended by Henry Hyde
`Salter in his famous 1860 book, On Asthma its Pathology
`and Treatment, as a form of inhalation therapy.(3) In the
`1890s, the Wyeth Pencil Inhaler was commercialized as a
`portable and convenient treatment of various ailments, in-
`cluding catarrh, bronchitis, and croup. This inhaler con-
`tained menthol crystals and a rotatable cap with holes,
`which when in the proper orientation allowed air to pene-
`trate through the holes and over the crystals to vaporize the
`menthol (which has a vapor pressure of 8.5 Pa at 25°C) so as
`to allow the vapor to be inhaled by the patient.(25)
`Another interesting innovation during this period was a
`patent by Helbing and Pertch(26) in 1899 of a propellant-
`based liquid aerosol generator that used ethyl or methyl
`
`chloride (now considered toxic via inhalation) as the pro-
`pellant to atomize the liquid. The invention utilized heat of
`the hand to increase the vapor pressure of these liquids (135
`and 506 kPa at 20°C, respectively) and provided sufficient
`pressure to atomize the formulation through a small orifice.
`Clark(27) points out that the Helbing and Pertch inhaler was
`in many respects a precursor to the pressurized metered dose
`inhaler (MDI) that would reshape the treatment of lung
`diseases when introduced in 1956. However, Helbing and
`Pertch did not recognize the value of this invention for in-
`halation therapy and instead targeted applications requiring
`a medicated spray to be applied during surgery.
`
`Asthma cigarettes
`
`Smoke therapies for the treatment of respiratory ailments
`originated in India and date back to at least 600 BC. After
`being introduced in the United States by Philadelphia phy-
`sician Samuel Cooper in 1797 and in Great Britain in 1802
`by General Gent upon his return from India,(28) smoked
`stramonium rapidly became a popular asthma therapy in the
`1800s in Europe and the United States. Traditionally, these
`therapies were individually assembled for the specific pa-
`tient (either by the patient or a physician). However, at the
`turn of the 20th century, there was a change to large-scale
`commercial manufacturing of cigarettes to be sold to un-
`known patients. A number of commercially available asth-
`ma cigarettes with stramonium were widely used in Europe,
`the United States, and China(28,29) (Fig. 4). Some of the
`cigarettes included other herbs such as tea leaves, kola nuts,
`lobelia, and atropine-containing atropa belladonna leaves.(9)
`Given the abundance of data demonstrating health risks
`associated with cigarette smoking, it may seem surprising to
`the 21st century reader that cigarettes would be a preferred
`therapeutic option for patients with lung ailments. Clearly, the
`smoke from asthma cigarettes contained tar and a number of
`other toxic substances that would prove detrimental to lung
`function. However, the detrimental impact on lung function of
`
`FIG. 4. Page’s asthma cigarettes containing stramonium,
`tea leaves, chestnut leaves, and gum benzoin. Image cour-
`tesy of Mark Sanders.
`
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`THE HISTORY OF THERAPEUTIC AEROSOLS
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`25
`
`cigarette smoking occurs gradually over time and is most
`severe with long-term use.(30) On the other hand, the thera-
`peutic impact of the atropine-containing smoke from ciga-
`rettes was significant and relatively rapid.(31)
`The anticholinergic drug atropine is an extremely effec-
`tive drug for treating asthma and chronic obstructive pul-
`monary disease (COPD). Atropine and its structural analog
`drugs, ipratropium and tiotropium, remain critical compo-
`nents of asthma and COPD therapy with annual sales in
`2014 of greater than $7 billion.(32) In addition, the extrafine
`nature of combustion aerosols such as cigarette smoke(33)
`results in exceptional lung deposition that was likely sig-
`nificantly superior to the lung deposition provided by other
`delivery systems in the first half of the 20th century. As a
`result, the therapeutic benefit provided by asthma cigarettes
`may have significantly outweighed their potential harm.
`
`The emergence of atomizers and nebulizers
`
`A significant advancement in the delivery of therapeutic
`aerosol was the invention and refinement of devices that re-
`duce a medicated liquid to fine droplets for inhalation. These
`devices can be categorized into atomizers and nebulizers.
`Atomizer devices can use various approaches to cause the
`liquid to be broken into fine particles, but lack the baffle
`system of later nebulizer devices and generated coarse aerosol
`sprays of which only a small portion of the droplets that were
`small enough to deposit in the lung.(19) Nebulizer devices are
`atomizers that contain a baffle system to remove coarse
`droplets from the air stream(9,34) and thus provide aerosols that
`are more likely to deposit in the lung. Often the formulation
`contained in the large droplets that impact on the baffle falls
`back into the reservoir to be atomized again.(19)
`The first atomizer device was developed in 1849 in
`France by Dr. Auphon in which he directed a jet of the water
`at a mineral spring against the walls of the Spa at Euzet Les
`Baines to break the liquid into fine droplets to be in-
`haled.(9,35) In 1858, Jean Sales-Girons invented a portable
`atomizer that utilized a pump handle to draw liquid solution
`from a reservoir and atomize it through a small nozzle and
`direct
`it
`toward an impaction plate to produce a fine
`spray.(19) Sale-Giron’s nebulizer, called the pulverisateur, is
`shown in Figure 5.
`In 1862, the German physician, Bergson, developed a
`different approach to break liquid into fine droplets. His
`device, called Hydrokonium, was an air jet atomizer in
`which a high-velocity air jet generated using a rubber
`squeeze bulb passed directly over another tube through
`which liquid was drawn up and atomized.(19) This air jet
`atomizer approach, which would be widely applied on many
`other atomizers and nebulizers, applied the principle de-
`scribed in 1738 by the Swiss physicist Daniel Bernoulli and
`leveraged by Italian physicist Giovanni Battista Venturi that
`showed that suction could be obtained on a tube when a
`high-velocity fluid was placed directly over the tube.(19)
`Atomizers and nebulizers rapidly became a key thera-
`peutic option for treatment of a wide range of respiratory
`diseases. The rapid popularity is demonstrated by number of
`devices described in two key books from 1867 [Jacob Solis-
`Cohen(11) and John M. Scudder(36)]. These two books provide
`excellent summaries of the state of the art in terms of atomizers
`and nebulizers at that time. They describe a number of novel
`
`FIG. 5. The pulverisateur developed by Jean Sales-Girons
`in 1858. Image courtesy of Mark Sanders.
`
`devices that utilize a venturi principle to atomize medicated
`solutions using high-velocity airflow. These devices used a
`variety of sources for providing the pressurized airflow to at-
`omize the liquid. In addition to Bergson’s Hydrokonium,
`which utilized foot bellows to provide the airflow, Solis-Cohen
`described Siegle’s steam atomizer, which utilized fire to create
`steam as the source of pressurized airflow.(11) Atomizer de-
`signs based on Siegle’s fire-powered steam nebulizer became
`popular in Europe, the United States, and Japan throughout the
`late 1800s.(19) Early nebulizer systems with baffles are de-
`scribed in 1862 by the German physician, L. Waldenburg, and
`in Solis-Cohen’s book published in 1867.(11,19)
`At the dawn of the 20th century, improvements in the
`manufacturing of rubber allowed for the development of
`convenient, portable glass nebulizers that were powered by
`rubber squeeze bulbs.(19) In the early 1930s, a nebulizer, the
`Pneumostat, using compressed air to power the atomization,
`was developed in Germany. Other compressed gas-powered
`nebulizers followed shortly thereafter.(9) The first plastic
`nebulizer,
`the Wright nebulizer, was introduced in the
`1950s. Plastic molding enabled improved precision of the
`venturi orifice and produced much finer sprays capable of
`reaching the deep lung and resulted in performance similar
`to modern nebulizers.(28) Thus, in the century from 1850 to
`1950, nebulizer technology had advanced from infancy to
`devices capable of delivering highly respirable aerosols for
`effective treatment of lung diseases.
`
`Liquidia's Exhibit 1019
`Page 6
`
`

`

`26
`
`STEIN AND THIEL
`
`FIG. 6. A drawing of the first DPI invented by Ira Warren
`in 1852.
`
`Early DPIs
`
`The first known DPI was invented by Boston physician
`Ira Warren in 1852(37) (Fig. 6 below). The glass inhaler
`consists of an inner tube pierced with fine holes and in
`which the powdered medicine is placed. The inner tube was
`enclosed in an outer tube with a mouthpiece (on the right
`side of Fig. 6). The inner tube was twirled by hand as the
`patient
`inhaled, causing the powder
`to be aerosolized
`through the holes in the inner tube and delivered to the
`patient through the mouthpiece. In the patent, Warren states
`that the powder inhaler is designed for the purpose of in-
`haling medicine into the throat and lungs and, at the same
`time, to prevent any of the said medicine from lodging in the
`mouth. The inhaler sold for $1 along with vials of powder to
`be inhaled, which could be purchased for $0.50 per vial.
`Powders available for purchase included silver nitrate,
`copper sulfate, and mercury nitrate (advertisement in The
`Boston Medical and Surgical Journal, November 3, 1852).
`Perhaps the most interesting early DPI device was the
`Carbolic Smoke Ball, which was invented by Frederick Roe
`in 1889.(3) The device consisted of an *5 cm hollow ball
`made of India rubber and a 1.5-cm-long nozzle made of vul-
`canite with a fine gauze placed *0.5 cm from the end of the
`nozzle.(38) Inside the ball was a powder composition consisting
`of glycyrrhiza, hellebore, and carbolic acid.(3,38) When the
`patient squeezed the rubber ball, the powder was aerosolized
`and deagglomerated by shear forces as it passed through the
`sieve in a manner similar to the Rotahaler DPI device intro-
`duced approximately a century later. The patient was instructed
`to inhale the smoke-like aerosol that was formed.(38)
`The device was marketed by the London-based Carbolic
`Smoke Ball Company, which certainly did not lack boldness
`
`in their marketing department! Advertisements for the de-
`vice provided a long list of diseases that they claimed could
`be cured with the Carbolic Smoke Ball and even provide the
`time required to achieve the cure—‘‘Carbolic Smoke Ball
`positively will cure: Coughs (cured in 1 week), cold in the
`head (cured in 12 hours), cold on the chest (cured in
`12 hours), catarrh (cured in 1–3 months), asthma (relieved in
`10 minutes), bronchitis (cured in every case), hoarseness
`(cured in 12 hours), loss of voice (fully restored), sore throat
`(cured in 12 hours), throat deafness (cured in 1–3 months),
`snoring (cured in 1 week), sore eyes (cured in 2 weeks),
`influenza (cured in 24 hours), hay fever (cured in every
`case), headache (cured in 20 minutes), croup (cured in 5
`minutes), whooping cough (relieved first application), and
`neuralgia (cured in 20 min