1957: The invention of the rescue inhaler

When Americans unite and put their minds and imaginations together in a quest to obtain a united goal, anything can be accomplished.  This was what occurred during WWII.  While war is bad, it can bring about many good things.  In this way, the metered dose inhaler — the rescue inhaler you have in your pocket right now — is a byproduct of war.

A 1957 ad for the Riker inhaler (a)

Allied troops fighting in the fields of Europe were often infested with bugs that caused Malaria.  This was impeding the war effort.

To remedy this problem the U.S. Government hired researchers to come up with a bug repellent that would help allied soldiers attack bugs.

Lyle Goodhue and William Sullivans must have first looked to the past to find a solution.  They would have learned that in 1790 pressurized aerosols were introduced in France to create carbonated beverages.

They would have learned that in 1837 the first spray can was made of heavy steal in Perpigna.  The can had a valve in it that allowed it to create the spray.  Several prototypes were tested in 1862, although nothing ever came of it. (1)

They would have learned that in 1927 a Norwegian man named Erik Rotheim patented the first spray can that was capable of holding pressurized contents and spraying them.  It’s now considered the forerunner of modern spray cans.

Goodhue and Sullivans then took these old ideas and combined them with ideas of their own and came up with a design capable of carrying a pressurized propellant called flurocarbon.  The bug spray was added to the propellent and the spray can allowed for the bugs to be sprayed and killed.

So while the first spray cans were used to hold bug sprays during the war, the concept soon evolved to other products, such as paint and perfume.  It was the perfume market that Riker Laboratories (a subsidiary of what is now 3M Pharmaceuticals) was thinking of when it started tinkering with this product.  They wanted to create a spray perfume. (2)

Yet Riker researchers soon realized there was a demand by asthmatics for a convenient to use and portable spray can for asthma medicine.  This was how the first inhaler came to fruition.  In 1956 Riker inventors created the asthma inhaler market with a Medihaler-Epi that contained epinepherine and medihaler Iso that contained Isophrenaline.

The Riker inhaler was a major breakthrough.  This product was incorporated with the first ever actuator with a one-way valve that allowed for the medicine and propellant to be sprayed in a uniform dose (a metered dose), and soon became known as the metered dose inhaler (MDI).  The Medi-Iso delivered a metered dose of 0.15 mg and the Medi-Epi delivered a dose of 0.06 mg.  The inhalers were  easy to use, provided fast relief, and were easy to lug around. (2)

The design of this original inhaler was very similar to many of the inhalers we lug around today, such as the Ventolin inhaler.  It could easily fit into a boy’s front pocket or a mom’s purse, and using it was as as easy as squeezing the actuator.

Electric nebulizers in the 1950s were large, bulky and made of glass.  They were also expensive, so many asthmatics had less expensive nebulizers that required them to squeeze a bulb to aerosolize the medicine.  Many asthmatics continued to smoke asthma cigarettes, insents, or other palliative asthma remedies.

So getting asthma relief was inconvenient when the medihaler was introduuced, and the relief given wasn’t very good. So this was the market advertisers for Riker Laboratories aimed for when they started their first advertising campaign.

1956 ad for the Medihaler (b)

An old advertisement for the Medihaler (see image) used the inconvenience of these other devices as a marketing ploy:

Medihaler with your favorite bronchodilator:

• No rubber bulbs to deteriorate


• No breakage of costly glass nebulizers


• No spilling of solution in pocket or purse

The Medihaler became an instant hit.  It, coupled with the discovery of theophylline, caused the market for asthma medicines to boom.

Gregg Mitman, in his book “Breathing Space: How allergies shape our lives and landscapes,” explained that between 1972 and 1985 prescription drugs in the United States showed a modest 7 percent increase in the number of prescriptions filled.

During the same period, prescriptions for asthma drugs increased 200 percent.”  The market for asthma inhalers was so bullish that other pharmaceutical companies raced to make their asthma remedies available as an inhaler.  (3)

Mitman further explained that the sale of asthma inhalers alone (both beta adrenergics and others), accounted for “25 percent of all prescriptions dispensed for the treatment of asthma in 1985.”

So it didn’t take long at all for pharmaceuticals, doctors and asthmatics to catch on to the convenience of the rescue inhaler.  Life for asthmatics changed forever, and for the better.

Click here for more asthma history.

References:

1.  About.com, “History of spray cans,”  http://inventors.about.com/od/astartinventions/a/aerosol.htm (provides a good history of the spray can)


2. Brenner, Barry E, ed., ”Emergency Medicine,” 1998, from chapter one “Where have we been?  A history of acute asthma,” page 23


3.  Mitmann, Gregg, “Breathing Space:  How allergies shape our lives and landscape, 2007,  page 237 (a great read if you want to learn more about the history of asthma/ allergies)

Pictures:

1. (a)  Deco Dog, http://www.decodog.com/inven/medical2.html, you can purchase or check out old asthma inhaler ads here 


2. (b)  Deco Dog, ibid

1864: Alfred Newton"s Dry Powdered Inhaler

Maybe the first real dry powdered inhaler was patented in 1864 by Alfred E. Newman.  After correspondence with Dr. James in New York, he put together an inhaler that was designed after a mantle clock “with an orifice at one side, inside was a mesh and a crank shaft with feather beaters. Powder was placed into the bottom of the box and the patient would put their mouth to the orifice and inhale while the handle was cranked causing the feathers to beat the powder creating a dust, which would pass through the mesh toward the mouth.”

Newman realized the powder must be “pulverized” and that it “must be kept dry,” and this is a similar concept to modern dry powder inhalers.  The Newton device was designed for potassium chlorate, and it was mainly designed for diseases of the throat. Yet still it was a revolutionary concept.  (1)

According to Mark Sanders, it was also used for tuberculosis.  (2)

Assuming my links hold up, you can see a picture of this inhaler both here and here.

References:

1. Smyth, Hugh D.C., Anthony J. Hickey, editors, “Controlled Pulmonary Delivery,” 2011, New York, Springer, page 60-61


2. Sanders, Mark, “Pioneers of Inhalation: Vapour Trails and Powder Monkey,” from Inhalatorium.com: Online Museum of inhaler technology, slide show presentation, accessed on 11/13/12

james powder

more

1940-2012: The dry powdered inhaler (DPI)

For almost 8,000 years asthmatics inhaled medicine by smoking it.  This changed in the 1930s with the invention of the electric nebulizer and again in the 1950s with the invention of the metered dose inhaler (MDI).  A third option that has been slowly gaining momentum is the Dry Powder Inhaler (DPI). 

A DPI allows you to inhale the powdered version of a medicine, which comes in the form of a capsule or blister that is cracked open inside the inhaler.  There is no propellant, and instead the medicine is breath actuated.  This means the medicine enters your airway as you inhale.  

There are advantages to DPIs:

1. Since they are breath actuated no propellant is needed


2. Coordination is generally easy


3. They are easier to use than MDIs


4. Dose is easily measured

Of course there are also disadvantages:    

1. The patient must be able to generate enough flow


2. Each company markets its own device, which means there may be many to learn


3. You will have to place the capsule into the device prior to inhaling the medicine


4. The devicess tend to be expensive to manufacture and expensive to purchase

To learn about the history of DPIs we actually have to travel back to before the first MDIs hit the market in the 1950s.  In fact, according to Mark Sanders in his 2007 article, “Inhalation Therapy: an historic review,” the first patent for a DPI was made in 1964 by Newton.  The medicine he used was potassium chlorate, a medicine Sanders notes was ultimately determined to be a lung irritant.

However, while Newton’s device wasn’t a commercial success, “He observed that the powder needed to be finely pulverized and that it had to be kept dry — principles that still apply to dry powder inhalers today.”  (1)

According to A.R. Clark in his 1995 article, “Medical Aerosol Inhalers: Past, Present, and Future, Aerosol Science and Technology , the first DPI was patented in 1939.  I would imagine he’s referring to DPIs that resemble what we use today, as opposed to the Newton’s device.  

Clark explained that the 1939 inhaler  was not used as an asthma inhaler, though, but to inhale “aluminum dust  for the chelation of inhaled silica.  It was intended for use by miners who suffered from silicosis induced by inhaling dust.”  Yet the product never gained popularity and was never marketed.  (2)

By the 1940s pharmaceutical companies learned that systemic injection of asthma medicines like epinephrine and atropine caused significant side effects.  They were in an all out race to develop a device that allowed asthmatics to inhale medicine and, thus, generate an immediate effect with fewer side effects. 

In 1949 the Aerohaler was introduced as the first marketable DPI, and also the first rescue inhaler.    The medicine was Isoprenaline sulphate.  Yet it never gained popularity and was later overshadowed when the first MDIs hit the market in 1957 in the form of the Medihaler Epi and the Medihaler Iso.

For all practical purposes, it was ultimately realized DPIs don’t work well with rescue medicine because when the medicine is needed many asthmatics have trouble generating enough flow to suck up the medicine.  While Ventolin is available overseas as a DPI, none are currently approved by the FDA for sale in the U.S.

When the CFC propellant (see lexicon) used in MDIs was determined to harm the environment in the 1990s, DPIs were determined to be a solid delivery device for asthma controller medications, and this is the main reason they have become a common site in asthmatic homes.

Aerolator with glass vial containing 3 small epi/ penicillin vials

So, without further adieu, here are your DPIs:

1.  Aerohaler:  Released by Abbot laboratories  in 1949 as the first marketed DPI.  The medicine was Norisodrine, isoprenaline sulphate.  It was the first rescue inhaler.  Clark described the Aerohaler this way:  ”The device consisted of ‘sifter’ cartridges containing the powdered dose out of the cartridge and a mouthpiece through which the aerosol was inhaled.  There was very little control over the delivered dose, other than patient symptoms titration, and there was no dispersion mechanism inside the device to aid aerosol generation.”  (3)  Each glass vile contained three smaller vials (sifter cartridges) that were set on the inhaler device.  The patient then inhaled the powder through the nose.  The disadvantages of this inhaler were later outshadowed by the release of the MDI in 1957.  The Aerohaler was also used in the late 1940s and 50s as a means to deliver penicillin.  A modern version of the Aerohaler was remarketed and available in some countires, yet it has little in common with the original.  



Intal Spinhaler and Intal Gelcap

2.  Spinhaler:  Fisons introduced this device in 1971 as the mechanism to deliver disodium cromoglycate (sodium cromolyn or simply cromolyn).  It was approved by the FDA in .  The product was marketed as the Intal Spinhaler to be used with the Intal Spincaps, and remedied many of the problems of the Aerohaler.  It was the first commercially successful DPI.  The caps were made of a hard gelatin and guaranteed the same dose with each inhaletion (a metered dose).  They had to be removed from the foil package and placed in the spinhaler by the patient.  The patient then cocks the outer shell of the inhaler and needles inside the device pierce the capsule.  The patient then places his mouth on the mouthpiece and inhales.  The flow generated causes a fan inside the device to rotate, and as this occurs the powder is inhaled.  The Intal Spinhaler was very popular as an asthma controller medicine during the 1980s and 90.  It was ultimately phased out because the powder caused some patients to cough and this caused some asthma attacks.  It was replaced by the Intal inhaler in the late 1990s.  I wrote more about the Spinhaler here.

Ventolin Rotahaler and Rotacaps

3.  Rotahaler:  In the early 1960s Allen and hanbury introduced the Ventolin Rotacap to go along with the Ventolin Rotahaler.  The product was marketed throughout the 1980s and 1990s but was ultimately discontinued because some asthmatics who needed the rescue medicine had trouble generating enough flow to suck in the medicine.  Another problem was that each individual unit dose Rotacap had to be handled by the patient and carefully inserted into the device.  The Ventolin Rotahaler was a failed experiment, and since it was discontinued only asthma controller medicines have been available as DPIs.  The Rotahaler was later refined so it contained a month supply of capsules and re-marketed as the Becotide Rotohaler and the Spiriva Handihaler in 2009.

4.  Turbuhaler:  Astra Zeneca introduced this product as one of the first multi dose DPIs in the early 1990s. The Pulmicort Turbuhaler was approved by the FDA in 1997, and the Symbicort Turbohaler in 2000, according to FDA.gov.  Various other products have been marketed in other countries such as the Bricanyl Turbuhaler (terbutaline) and Formoterol Oxis Turbuhaler.  The Pulmicort DPI has since been discontinued.

Diskhaler

5.  Diskhaler:  GlaxoSmithKline intruduced the disk in the early 1990s and asked for FDA approval in 1992. The original discus contained 4-8 blisters per cartridge, which made it so the patient didn’t have to worry about handling each dose.  The device has since been refined so each discus contains 60 capsules, or two capsules for each day, or one month supply.  The recommended dose is one puff twice daily.  Each disc is equivalent to two puffs of the MDI version of the medicine.  A blister of capsules are stored in a roll, or disc inside the device.  All the patient has to do to prepare a dose is to open the device and pull down a lever.  This moves a new capsule into the delivery chamber and decreases the counter by one so the patient knows how many doses are left. The Serevent Discus was FDA approved in 1997 and the Advair Discus in 2000 according to fda.gov.  The Flovent Discus was approved in 2000 but was never marketed. The Serevent Discus may also be referred to as Seritide, Viani, ForAir, and Foxair in some countries.  Advair is a combination of Serevent and Flovent.  The Advair Discus is currently the most popular asthma controller medicine on the market.  The discus is referred to as the autohaler or diskus in some countries.  Other products available but not approved by the FDA are the Becodisk which contains beclomethasone, and the Ventolin Autohaler

6.  Inhalator:  The device is marketed by Novaris.  I’ve found various articles that mention studies comparing salmeterol (Serevent) inhaler with the formoterol inhalator (Barotec) from as far back as 1985, although I’m not certain it was actually approved for use in any country at this time.  The inhaler was improved upon by 2001 and renamed the Centihaler.  It was this product that was finally approved by the FDA in 2001 as the Foradil Centihaler.  In 2006 the FDA approved the Foradil Aerolizer which will be under patent until 2019.  (3)  The recommended dose is two puffs of the inhaler twice daily or one puff on the DPI.  As a note here, the FDA seems to have the strictest policy for drug approval.  As a rule of thumb, if the FDA approves a medicine chances are it’s been run through the gambit and is proven relatively safe, or at least the benefits far outweigh the disadvantages.  I believe this product was slow to be approved by the FDA due to it being linked to asthma related deaths.  However, many believe it wasn’t the medicine so much as poor education that resulted in the deaths, yet it was never proven either way.  A similar problem plagues salmeterol.  The problems was addressed in 2003 with a black box warning on the packaging. 

7.  Cyclohaler:   This is another DPI introduced to the market in the early 1990s.  The medicine is stored in hard gelcaps that are inserted into the cyclohaler with each use.  The mouthpiece is long to optimize drug distribution even if the patient isn’t able to generate enough flow. Several puffs were often necessary to get an optimal dose.  The initial product was marketed as the Aerolizer Cyclohaler, and the products available were albuterol and ipatropium bromide.  Since the product wasn’t marketed in the U.S. the medicine was referred by it’s non-U.S. name, such as the Salbutamol Cyclohaler and Salbutamol Cyclocaps.  The product has since been refined and marketed with other medicines such as  salbutamol (Sultanol), beclomethasone (Becotide), Formoterol (Foradil) and  budesonide (Miflonide).  The latest version is marketed as the cyclohaler 400.

8.  Other:  By 2008 there would be over 20 different DPIs on the market (4), and by 2012 that number would rise to 35.  While many are available for use in Europe, only a select few have been approved by the FDA.  DPIs currently on the market (as of 2012) are (you can view pictures of the various devices here):

• 
  Acu-Breathe (Respirics)


• 
  Aerolizer (Novartis)


• AIR (Civitas/Alkermes)


• 
  Airmax (Teva)


• Aspirair (Vectura)


• Axahaler (S.M.B.)


• Breezhaler (Novartis)


• Clickhaler (Vectura)


• Conix Dry (3M)


• Cricket (Mannkind)


• Cyclohaler (Teva)


• Diskhaler (GlaxoSmithKline)


• Diskus (GlaxoSmithKline)


• Dreamboat (Mannkind)


• Easyhaler (Orion)


• EZ Aer (Aerovance)


• Flexhaler (AstraZeneca) — Pulmicort


• Genuair (Almirall)


• Gemini (GSK)


• Handihaler (Boehringer Ingelheim)


• MicroDose (MicroDose Therapeutx)


• Next DPI (Chiesi)


• Novolizer (Meda)


• Oximax (Mantecorp)


• Podhaler (Novartis)


• Pulmojet (sanofi-aventis)


• Pulvinal (Chiesi)


• Skyehaler (SKyepharma)


• Solis (Sandoz/Novartis)


• Taifun (Akela)
  


• 
  Taper Dry (3M)


• Trivair (Trimel Bipharma)


• Twincaps/Flowcaps (Hovione)


• Twisthaler (Schering /Merck)


• Turbuhaler (AstraZeneca) (5)


• 
  Dura Spiros (3M) — battery powered (introduced in 1990s)

Click here for more asthma history.

References:

1. Sanders, Mark, “Inhalation therapy:  an historic review,” Primary Care Respiratory Journal, 2007, 16 (2), pages 71-81


2. Clark, A.R., “Medical Aerosol Inhalers: Past, Present, and Future, Aerosol Science and Technology, 1995, 22:4, 374-91


3. Foradil Aerolizer Briefing Document, Available to the public without redaction, pulmonary drug advisory committee on the safety of long acting beta agonist bronchodilators, fda.gov, http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4148B1_02_01-Novartis-Foradil.pdf, page 9


4. Patterson, Roy, “Patterson’s Allergic Diseases,” 7th ed., page 610


5. “Dry Powder Inhalation: Technology, Devices, Markets and Opportunities,” prnewswire.com, Jan. 19, 2012, New York, http://www.prnewswire.com/news-releases/dry-powder-inhalation-technology-devices-markets-and-opportunities-137656553.html