Thursday, January 26, 2012

1940-2012: The dry powdered inhaler (DPI) rewriting

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:

Aerohaler:  Released by Abbot laboratories in 1949 as the first marketed dry powdered inhaler (DPI).  The medicine was Norisodrine, isoprenaline sulphate.  It was the first rescue inhaler. It didn't really get much of a chance to gain the love of asthmatics mainly due to the invention of the metered dose inhaler (MDI) in 1957. Just imagine, if the MDI wasn't invented, asthmatics everywhere would probably have an aerohaler.

A.R. Clark, in a 1995 article for Aerosol Science and Technology, described this inhaler 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." (2, page 382)
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.  There were some disadvantages to this device, the most significant was 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 countries, yet it has little in common with the original.

1971: Spinhaler:

The Intal Spinhaler was introduced by Fison in 1971. It was a neat little contraption. Once a physician prescribed the medicine, the patient received a box of Intal Spincaps and an Intal Spinhaler. The spoinhaler was taken apart and the spincap placed on a holder. The spinhaler was put back together. The blue part (see figure) was clicked forward to crush the capsule and release the powder. The patient then put his mouth over the white mouthpiece to inhale the medicine. If the patient was lucky he did not cough.

Warnings on the packaging warned that the produce may incite a cough and bronchospasm. This occurred as the powder impacted the back of the throat, triggering the cough reflex. This may result in bronchospasm and asthma attack. Warnings also noted that the product must be used daily as an asthma controller medicine, and not as a rescue medicine.

Another problem with the medicine is that the patient had to handle each dose. Proper technique also had to be used in order to assure an adequate dose and to prevent the medicine from triggering a cough. A CFC inhaler was available for Intal, and it was approved by the FDA in 1992.  This provided a more convenient and safer delivery device. It also probably improved compliance.

Chromolyn was very popular during the 1980s and 1990s. The spinhaler was ultimately phased out due to the inhaler. The inhaler was phased out due to the Montreal Protocol. A non-CFC chromolyon was never made. One theory for this was declining sales due to better asthma controller medicines that were on the market by the 2000s. It was set to be phased out by December 31, 2010.

It was also available as a solution to be inhaled by nebulizer. It initially came in a glass vial that had to be snapped open, and was probably mainly used in hospitals. Eventually a plastic vial was available. I do not know if the solution was available for home use, although I would imagine so.

By the time I became a respiratory therapist in 1995 I had not used the medicine in over 10 years. I quit on my own because I didn't feel it did any good. In the hospital setting it was mainly just prescribed for children. A reason for this might have been reluctance to prescribing inhaled steroids for kids.




Intal Spinhaler and Intal Gelcap
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 

2 comments:

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  2. You are missing Aptar Pharma's Prohaler from your list of available DPI's.

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