Sign in to NCBI
`
`Search
`
`Help
`
`Formats:
`Article | PubReader | ePub (beta) | PDF
`(1.1M) | Citation
`
`Share
` Facebook
`
`Save items
`
` Twitter
`
` Google+
`
`Add to Favorites
`
`Similar articles in PubMed
`The inhalation of drugs: advantages and
`[Respir Care. 2005]
`problems.
`
`The Evolution of Pressurized Metered-Dose
`[J Aerosol Med Pulm Drug Deliv....]
`Inhalers from Early to Modern Devices.
`
`In vitro tests for aerosol deposition. III: effect of
`[J Aerosol Med Pulm Drug Deliv....]
`inhaler insertion angle on aerosol deposition.
`
`The use of computational fluid dynamics in inhaler
`[Expert Opin Drug Deliv. 2013]
`design.
`
`History of aerosol therapy: liquid nebulization to
`[Respir Care. 2005]
`MDIs to DPIs.
`
`See reviews...
`
`See all...
`
`Cited by other articles in PMC
`
`Links
`
`Recent Activity
`
`Turn Off
`The History of Therapeutic Aerosols: A
`Chronological Review
`
`Clear
`
`See more...
`
`The History of Therapeutic aerosols: a chronological Review
`
`Resources
`
`How To
`
`PMC
`
`US National Library of Medicine
`National Institutes of Health
`
`Advanced
`
`Journal list
`
`Journal List
`
`J Aerosol Med Pulm Drug Deliv PMC5278812
`
`JOURNAL OF AEROSOL MEDICINE AND
`PULMONARy DRUG DELIvERy
`
`J Aerosol Med Pulm Drug Deliv. 2017 Feb 1; 30(1): 20–
`41.
`Published online 2017 Feb 1.
`doi: 10.1089/jamp.2016.1297
`
`PMCID: PMC5278812
`PMID: 27748638
`
`The History of Therapeutic Aerosols: A Chronological
`Review
`1
`2
`Stephen W. Stein, MS and Charles G. Thiel, BA
`
`▸ Author information ▸ Article notes ▸ Copyright and License information Disclaimer
`
`This article has been cited by other articles in PMC.
`
`Go to:
`
`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,
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMc5278812/[2/12/2019 11:17:33 aM]
`
`

`

`The History of Therapeutic aerosols: a chronological Review
`
`nebulizer, therapeutic aerosol
`
`Go to:
`
`The Delivery of Therapeutic Aerosols in Ancient Times
`THE 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
`(1)
`the legs of a mummy in the assassif district of the Theban necropolis.
` 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
`(2)
`placed into the hole. The instructions as translated by Ebbell
` 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.
`
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`Review Black henbane and its toxicity - a descriptive review.
`[Avicenna J Phytomed. 2014]
`
`Medicinal aspects of opium as described in Avicenna's Canon
`[Acta Med Hist Adriat. 2013]
`of Medicine.
`
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`Historical review of the use of parasympatholytic agents in the
`[Postgrad Med J. 1975]
`treatment of respiratory disorders.
`
`Historical review of the use of parasympatholytic agents in the
`[Postgrad Med J. 1975]
`treatment of respiratory disorders.
`
`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.
`
`Black henbane is a leafy flowering plant native to Europe and northern africa.
`The therapeutic properties of the inhaled vapor have been attributed to the
`tropane alkaloids, including atropine, contained in all parts of the henbane
`(3,4)
`plant.
` The anticholinergic properties of atropine and structurally similar
`alkaloids combined with their prominence 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
`(5)
`1100 Bc in china,
` 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 Mesopotamia
`and was passed on to the assyrian and Babylonians who in turn passed the
`(5)
`practice on to the Egyptians.
` By 1300 Bc, opium cultivation had spread to
`Egypt, carthage, and Europe. In 1025 aD, the Persian physician, avicenna
`(abū ‘alī al-Husayn ibn Sina), in his influential medical encyclopedia entitled
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMc5278812/[2/12/2019 11:17:33 aM]
`
`

`

`The History of Therapeutic aerosols: a chronological Review
`
`Canon of Medicine, described the use of opium for a variety of medical
`purposes, including analgesia, treatment of diarrhea, and treatment of severe
`cough. avicenna described a variety of forms of administration, including
`(6)
`smoking and nasal inhalation.
` avicenna extensively described the toxicity of
`opioids and generally discouraged their use. He recommended, “If you have no
`other option but to use opioids, closely monitor patient's pulse to avoid
`(6)
`overdosing.”
`
`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
`preparing herbal compositions, including Datura that could be smoked in a
`(3)
`pipe or in a cigarette
` to relieve asthma symptoms. charaka also described
`the burning of herbal compositions in a bowl fitted with a second bowl on top
`(7)
`and a tube fitted to allow inhalation of the fumes.
` The therapeutic effects and
`toxicity described by Sushruta are consistent with atropine, which is a known
`(3)
`active ingredient of the Datura stramonium species.
` 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
`(7)
`may date as far back as 2000 Bc with early traditional ayurvedic medicine.
`
`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
`(8)
`orpiment, and nardus, smeared with ghee.
` 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
`(7)
`therapy.
`
`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
`(9)
`which a reed could be placed to enable the vapors to be inhaled.
` vapors
`generated from herbs and resins that had been boiled in vinegar and oil were
`(3)
`inhaled through the reed.
`
`In the second century aD, the Greek physician, Galen of Pergamon, described
`(10)
`the inhalation of powdered drugs for relief of nasal and chest troubles.
` 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
`(11)
`healing.
` around the same time frame, another Greek physician, aretaeus of
`cappadocia, utilized a similar instrument for powder inhalation to treat
`(12)
`laryngeal ailments of children.
`
`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
`(13)
` Ma
`describes the use of Ma Huang remedies for the treatment of asthma.
`Huang, which was usually delivered orally as a tea or a pill, was later shown to
`(3)
`contain the active ingredient ephedrine.
` Ephedra was a mainstay in asthma
`therapy 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 recommended a number of other asthma remedies that
`probably 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
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMc5278812/[2/12/2019 11:17:33 aM]
`
`History of aerosol therapy: liquid nebulization to MDIs to DPIs.
`[Respir Care. 2005]
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`
`The history of Ephedra (ma-huang).
`[J R Coll Physicians Edinb. 2011]
`
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`Historical review of the use of parasympatholytic agents in the
`[Postgrad Med J. 1975]
`treatment of respiratory disorders.
`
`History of aerosol therapy: liquid nebulization to MDIs to DPIs.
`[Respir Care. 2005]
`
`Review Inhalation therapy: an historical review.
`
`

`

`[Prim Care Respir J. 2007]
`
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`
`Historical review of the use of parasympatholytic agents in the
`[Postgrad Med J. 1975]
`treatment of respiratory disorders.
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`
`The History of Therapeutic aerosols: a chronological Review
`
`honey!), but he made the significant contribution of identifying a link between
`pollen exposure and respiratory distress [The Natural History of Pliny;
`(14)
`translated in 1856 by Bostock and Riley
`].
`
`Ephedrine, which would later be isolated from ephedra by Japanese chemist
`(15)
`nagayoshi nagai in 1885,
` remained widely used for treatment of cough and
`respiratory disease until the 1950s when it began to be displaced by other
`(15)
`bronchodilators with improved safety profiles.
` 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
`(3)
`South american cultures using ornate pipes had become common.
` It is
`believed that these cultures also had identified the smoking of Datura as a
`(7)
`therapeutic remedy for the treatment of asthma
` and had used the inhalation
`of cannabis for recreational and therapeutic purposes, including the use as a
`(10)
`sedative.
`
`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
`(8)
`proposed inhaling sea air as a technique for preventing episodes.
` The warm
`steamy air in Roman public bath systems that were widely developed at that
`time in major cities was recommended by Roman physicians for treatment of
`(10)
`various ailments, including asthma.
`
`Go to:
`
`Delivery of Therapeutic Aerosols from the Middle Ages
`to the Industrial Revolution (476–1760 AD)
`There were relatively few major innovations in the delivery of therapeutic
`aerosols during the period between the fall of Rome (476 aD) and the start of
`the Industrial Revolution (c. 1760 aD). The recorded examples of the delivery
`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 aegineta, catalogued a host
`of ingredients to be inhaled for the 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 instructions 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
`(9,16)
`affected with the cough may inhale the vapor through a funnel.”
` The
`resultant vapor contained arsenic since sandarac is the Greek and Roman name
`(9,16)
`for red arsenic sulfide.
`
`Rhazes, the arab physician who lived in Baghdad from 850 to 932 aD,
`proposed some of the more innovative approaches 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
`(10)
`anesthesia during surgery.
` Rhazes also advocated for the inhalation of
`(3)
`arsenic for the treatment of respiratory conditions.
`
`The figure with the greatest influence on the inhalation of therapeutic aerosols
`during the Middle ages was the Spanish-born physician, Maimonides (1138–
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMc5278812/[2/12/2019 11:17:33 aM]
`
`

`

`The History of Therapeutic aerosols: a chronological Review
`
`1204 aD), who fled Spain and eventually became the personal physician to
`Saladin, the sultan of Egypt (1137 or 1138–1193 aD). Maimonides 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
`(3)
`from sex, and eating chicken soup.
` Maimonides provided numerous other
`dietary recommendations for the management of asthma and recognized the
`(13)
`link between air pollution and asthma.
` 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
`(13)
`Brenner
`].
`
`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 Revolution. 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
`(7)
`asthma
` and English physician, christopher Bennet, whose 1654 drawing (
`(3)
`Fig. 2) is the oldest known illustration of an inhalation device.
`
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`History of aerosol therapy: liquid nebulization to MDIs to DPIs.
`[Respir Care. 2005]
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMc5278812/[2/12/2019 11:17:33 aM]
`
`

`

`The History of Therapeutic aerosols: a chronological Review
`
`FIG. 2.
`
`The oldest known drawing of a therapeutic inhaler device developed in 1654 by
`the English physician christopher Bennet. Image courtesy of Mark Sanders.
`
`Open in a separate window
`
`Go to:
`
`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 individuals completely removed from the treatment of the patient.
`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 entities 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 pharmaceutical 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 aerosolized
`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 balsamic vapors for the treatment of asthma. Stern's book was
`groundbreaking in that it was intended to provide instruction for the general
`(3)
`public rather than physicians.
` English physician John Mudge advocated for
`inhaling the aerosol from heated water containing opium for the treatment of
`(3,9)
` In his book, A Radical and Expeditious Cure for a Recent
`catarrhal cough.
`Catarrhous Cough, he coined the term inhaler to describe a clever inhalation
`(17)
`device for generating and delivering steam-based aerosols.
` 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
`(17)
`through the warm liquid.
` 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 detailing in his book the name of a local pewterer that he partnered
`with and from whom the inhaler could be obtained.
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMc5278812/[2/12/2019 11:17:33 aM]
`
`History of aerosol therapy: liquid nebulization to MDIs to DPIs.
`[Respir Care. 2005]
`
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`The early history of anaesthesia in Canada: the introduction of
`[Can Anaesth Soc J. 1977]
`ether to upper Canada, 1847.
`
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`
`

`

`The History of Therapeutic aerosols: a chronological Review
`
`FIG. 3.
`
`(17)
`a drawing (a) and photo (b) of the Mudge Inhaler.
` 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.
`
`The inhalation of drugs: advantages and problems.
`[Respir Care. 2005]
`Delivery options and devices for aerosolized therapeutics.
`[Chest. 2001]
`History of aerosol therapy: liquid nebulization to MDIs to DPIs.
`[Respir Care. 2005]
`
`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
`commercialized for generated medicated vapors and gained popularity in
`England in the 19th century. Prominent among these ceramic inhalers was the
`(9)
`nelson inhaler, which was commercialized by S Maw and Sons in London.
`Other approaches were used to generate medicated vapors, such as pouring the
`(18)
`medicated solution over a sponge.
`
`as devices for generating medicated vapors proliferated, so too did the
`recommended therapies. In 1834, Sir charles Scudamore proposed heating
`iodine and hemlock (conium) in water to 120 F and having the patient inhale
`the vapor for 15–20 minutes three times per day for the treatment of
`(3)
`tuberculosis or other lung diseases.
` The 1867 British Pharmacopoeia listed
`detailed instructions for the generation of various medicated solutions to be
`inhaled, including hydrocyanic acid for the treatment of cough, chlorine for
`treatment of tuberculosis, hemlock for the treatment of cough, creasote for the
`treatment of tuberculosis and bronchitis, and iodine for the treatment of
`tuberculosis, pharyngitis, and laryngitis. The inclusion of these therapies in the
`British Pharmacopoeia demonstrates that these therapies had received
`(19)
`widespread acceptance by that time.
`
`The inhalation of anesthetic gases through makeshift face masks emerged in
`(10)
`the 1840s.
` 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
`(3,20,21)
`gained rapid acceptance.
` Due to the side effect of nausea associated
`with ether, physician James Young Simpson introduced inhaled chloroform as
`(10)
`a surgical anesthetic in 1847.
` The use of nitrous oxide for dental anesthesia
`was first demonstrated by american dentist Horace Wales in several dental
`(10)
`operations in 1844
` and then gained widespread acceptance due to the
`(22)
`influence of new York dentist Gardner Qunicy colton.
`
`The diversification of technologies for inhalation delivery in the last half
`of the 19th century
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMc5278812/[2/12/2019 11:17:33 aM]
`
`

`

`High cumulative risk of lung cancer death among smokers and
`[Am J Epidemiol. 2006]
`nonsmokers in Central and Eastern Europe.
`The clinical pharmacology of a herbal asthma cigarette.
`[Br J Clin Pharmacol. 1980]
`
`History of aerosol therapy: liquid nebulization to MDIs to DPIs.
`[Respir Care. 2005]
`
`History of aerosol therapy: liquid nebulization to MDIs to DPIs.
`[Respir Care. 2005]
`Principles and, practice of aerosol therapy of the lungs and
`[Ann Allergy. 1946]
`bronchi.
`
`The History of Therapeutic aerosols: a chronological Review
`
`The last half of the 19th century saw unprecedented innovation 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 aqueous solution of silver nitrate for treatment of
`various respiratory conditions such as nasal catarrh and diseases of the
`(23)
`throat.
` 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,
`(24)
`iodine, tannic acid, and hydrogen peroxide deeper into the bronchia.
`
`Inhaling the fumes of burning niter paper (which generates ammonia as it
`burns) was recommended by Henry Hyde Salter in his famous 1860 book, On
`(3)
`Asthma its Pathology and Treatment, as a form of inhalation therapy.
` In the
`1890s, the Wyeth Pencil Inhaler was commercialized as a portable and
`convenient treatment of various ailments, including catarrh, bronchitis, and
`croup. This inhaler contained menthol crystals and a rotatable cap with holes,
`which when in the proper orientation allowed air to penetrate through the holes
`and over the crystals to vaporize the menthol (which has a vapor pressure of
`(25)
`8.5 Pa at 25°c) so as to allow the vapor to be inhaled by the patient.
`
`another interesting innovation during this period was a patent by Helbing and
`(26)
`Pertch
` in 1899 of a propellant-based liquid aerosol generator that used ethyl
`or methyl chloride (now considered toxic via inhalation) as the propellant 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
`(27)
`sufficient pressure to atomize the formulation through a small orifice. clark
`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 inhalation 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 physician Samuel cooper in 1797 and in Great Britain in 1802
`(28)
`by General Gent upon his return from India,
` 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
`patient (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 unknown patients. a number of commercially available
`asthma cigarettes with stramonium were widely used in Europe, the united
`(28,29)
`States, and china
` (Fig. 4). Some of the cigarettes included other herbs
`such as tea leaves, kola nuts, lobelia, and atropine-containing atropa belladonna
`(9)
`leaves.
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMc5278812/[2/12/2019 11:17:33 aM]
`
`

`

`The History of Therapeutic aerosols: a chronological Review
`
`FIG. 4.
`
`Page's asthma cigarettes containing stramonium, tea leaves, chestnut leaves, and
`gum benzoin. Image courtesy of Mark Sanders.
`
`Given the abundance of data demonstrating health risks associated with
`st
`cigarette smoking, it may seem surprising to the 21 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 cigarette
`(30)
`smoking occurs gradually over time and is most severe with long-term use.
`On the other hand, the therapeutic impact of the atropine-containing smoke
`(31)
`from cigarettes was significant and relatively rapid.
`
`The anticholinergic drug atropine is an extremely effective drug for treating
`asthma and chronic obstructive pulmonary disease (cOPD). atropine and its
`structural analog drugs, ipratropium and tiotropium, remain critical
`components of asthma and cOPD therapy with annual sales in 2014 of greater
`(32)
`than $7 billion.
` In addition, the extrafine nature of combustion aerosols
`(33)
`such as cigarette smoke
` results in exceptional lung deposition that was
`likely significantly 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 reduce 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
`(19)
`the droplets that were small enough to deposit in the lung.
` nebulizer
`devices are atomizers that contain a baffle system to remove coarse droplets
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMc5278812/[2/12/2019 11:17:33 aM]
`
`History of aerosol therapy: liquid nebulization to MDIs to DPIs.
`[Respir Care. 2005]
`The inhalation of drugs: advantages and problems.
`[Respir Care. 2005]
`
`

`

`The History of Therapeutic aerosols: a chronological Review
`
`(9,34)
` and thus provide aerosols that are more likely to
`from the air stream
`deposit in the lung. Often the formulation contained in the large droplets that
`(19)
`impact on the baffle falls back into the reservoir to be atomized again.
`
`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
`(9,35)
`inhaled.
` 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
`(19)
`spray.
` Sale-Giron's nebulizer, called the pulverisateur, is shown in Figure 5.
`
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`
`The Carbolic smoke ball.
`
`[Pharm Hist (Lond). 1984]
`
`FIG. 5.
`
`Open in a separate window
`
`The pulverisateur developed by Jean Sales-Girons in 1858. Image courtesy of
`Mark Sanders.
`
`The inhalation of penicillin dust; its proper role in the
`management of respiratory infections.[Am Pract Dig Treat. 1949]
`
`Review Inhalation therapy: an historical review.
`[Prim Care Respir J. 2007]
`
`In 1862, the German physician, Bergson, developed a different approach to
`break liquid into fine droplets. His device, called Hydrokonium, was an ai