Metered-dose inhaler

File:MDI components.jpg

A metered-dose inhaler consists of three major components: the canister, which is produced in aluminum or stainless steel by means of deep drawing, where the formulation resides; the metering valve, which allows a metered quantity of the formulation to be dispensed with each actuation; and an actuator (or mouthpiece) which enables the patient to operate the device and directs the aerosol into the patient's lungs.{{cite book | vauthors = Hickey AJ, da Rocha SR |title=Pharmaceutical Inhalation Aerosol Technology |date=2021 |publisher=CRC Press |isbn=978-1-03-209322-2 |edition=Third}} The formulation comprises the drug, a liquefied gas propellant and, in many cases, stabilizing excipients. The actuator contains the mating discharge nozzle and generally includes a dust cap to prevent contamination.

To use the inhaler, the patient presses down on the top of the canister, with their thumb supporting the lower portion of the actuator. Actuation of the device releases a single metered dose of the formulation, which contains the medication either dissolved or suspended in the propellant. Breakup of the volatile propellant into droplets, followed by rapid evaporation of these droplets, results in the generation of an aerosol consisting of micrometer-sized medication particles that are then inhaled.{{cite book | vauthors = Finlay WH | title = The Mechanics of Inhaled Pharmaceutical Aerosols: An Introduction. | publisher = Academic Press | date = June 2001 | isbn = 978-0-08-051137-5}}

File:Nicorette Inhalator.jpg Inhalator is a vapour inhalator.]]

Metered-dose inhalers are only one type of inhaler, but they are the most commonly used type. The replacement of chlorofluorocarbons propellants with hydrofluoroalkanes (HFA) resulted in the redesign of metered-dose inhalers in the 1990s. For one variety of beclomethasone inhalers, this redesign resulted in considerably smaller aerosol particles being produced and increased in potency by a factor of 2.6.{{cite journal |vauthors=Busse W, Colice G, Hannon S | year = 1998 | title = CFC-BDP require 2.6 times the dose to achieve equivalent improvement in FEV1 as HFA-BDP | journal = Am J Respir Crit Med | volume = 157 | page = A405 }}

• Asthma inhalers contain a medication that treats the symptoms of asthma.
• Nicotine inhalers allow cigarette smokers to get nicotine without using tobacco, much like nicotine gum or a nicotine patch. The US Food and Drug Administration (FDA) has approved some nicotine inhaler products for smoking cessation.{{cite journal | vauthors = Drummond MB, Upson D | title = Electronic cigarettes. Potential harms and benefits | journal = Annals of the American Thoracic Society | volume = 11 | issue = 2 | pages = 236–242 | date = February 2014 | pmid = 24575993 | pmc = 5469426 | doi = 10.1513/annalsats.201311-391fr }} Nicotine inhalers that are marketed as nicotine replacement therapy should not be confused with electronic cigarettes, which produce an aerosol, usually from a tobacco extract, using a heating coil, while nicotine inhalers produce a noncombusted nicotine aerosol. A study found that "levels of carcinogens and toxins in e-cigarettes typically exceeded those measured in an FDA-approved nicotine inhaler." Nicotine inhalers are also known by their nickname of "the puffer." These devices are made of thin plastic, sometimes resembling a cigarette or a cylinder shape. They contain a porous nicotine-filled plug located at the base of the product. When you puff on the inhaler, nicotine aerosol is inhaled and absorbed in the mouth's lining. Every inhaler delivers almost four hundred puffs of this nicotine vapor. The nicotine inhaler is also temperature-sensitive. In cooler weather, less nicotine is delivered. The nicotine inhaler is considered more straightforward to use than the electronic cigarette as it is usually disposable and contains fewer parts than the electronic cigarette.
• Nicotine inhalers also exist as non-MDIs; for example, the format for the Nicorette Inhalator is an "inhalation vapour solution."
• Dry powder inhalers involve micronized powder, often packaged in single-dose quantities in blisters or gel capsules containing the powdered medication to be drawn into the lungs by the user's breath. These systems tend to be more expensive than the MDI, and patients with severely compromised lung function, such as those that occur during an asthma attack, may find it difficult to generate enough airflow to get good function from them.
• Metered-dose inhalers can be used to treat COPD, both in a stable state and during lung attacks.{{cite journal | vauthors = van Geffen WH, Douma WR, Slebos DJ, Kerstjens HA | title = Bronchodilators delivered by nebuliser versus pMDI with spacer or DPI for exacerbations of COPD | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 8 | pages = CD011826 | date = August 2016 | pmid = 27569680 | pmc = 8487315 | doi = 10.1002/14651858.cd011826.pub2 }}

Before the invention of the MDI, asthma medication was delivered using a fragile and unreliable squeeze bulb nebulizer.{{cite book| vauthors = Purewal TS, Grant D |title=Metered Dose Inhaler Technology|publisher=Informa Health Care|year=1997|edition=Illustrated|isbn=978-1-57491-065-0}} The relatively crude nature of these devices also meant that the particles that they generated were relatively large, too large for effective drug delivery to the lungs.{{Cite book| edition = 3rd Illustrated| publisher = Informa Health Care| isbn = 978-0-8493-9394-5| pages = 1170| vauthors = Swarbrick J | title = Encyclopedia of Pharmaceutical Technology| year = 2007}} Nonetheless, these nebulizers paved the way for inhalation drug delivery, inspiring the MDI.

MDIs were first developed in 1955 by Riker Laboratories, now a subsidiary of 3M Healthcare. At that time, MDIs represented a convergence of two relatively new technologies, the CFC propellant and the Meshburg metering valve, originally designed for dispensing perfume.{{Cite journal| doi = 10.1080/02786829408959755| volume = 22| issue = 4| pages = 374–391| vauthors = Clark AR | title = Medical Aerosol Inhalers: Past, Present, and Future| journal = Aerosol Science and Technology| year = 1995| bibcode = 1995AerST..22..374C| doi-access = free}} The initial design by Riker used a glass canister coated with vinyl plastic to improve its resilience. By 1956, Riker had developed two MDI-based products, the Medihaler-Ept containing epinephrine and the Medihaler-Iso containing Isoprenaline. Both products are agonists that provide short-term relief from asthma symptoms and have now largely been replaced in asthma treatment by salbutamol, which is more selective.

{{main|Asthma spacer}}

Metered-dose inhalers are sometimes used with add-on devices referred to as holding chambers or spacers, tubes attached to the inhaler that act as a reservoir or holding chamber and reduce the speed at which the aerosol enters the mouth. They serve to hold the medication that is sprayed by the inhaler. This makes it easier to use the inhaler and helps ensure that more of the medication gets into the lungs instead of just into the mouth or the air. Proper use of a spacer can make an inhaler more effective in delivering medicine.{{cite journal | vauthors = Togger DA, Brenner PS | title = Metered dose inhalers | journal = The American Journal of Nursing | volume = 101 | issue = 10 | pages = 26–32 | date = October 2001 | pmid = 11680341 | doi = 10.1097/00000446-200110000-00020 }}

Spacers can be especially helpful to adults and children who find a regular metered dose inhaler hard to use. People who use corticosteroid inhalers should use a spacer to prevent getting the medicine in their mouth, where oral yeast infections and dysphonia can occur.{{cite book | title = Inhalation Aerosols: Physical and Biological Basis for Therapy | veditors = Hickey AJ | edition = 2nd | publisher = Informa Healthcare | location = NY | date = 2007 | isbn = 978-1-351-66052-5 }}

The deposition of the content of drug formulation on the canister surface can result in a shorter shelf life of an MDI inhaler. Applying a suitable surface coating to the components helps to extend this shelf life. Over the years, various coating processes have been developed that can be applied to both the canister and valve to protect the contents from deposition and degradation.

Gas plasma processing is an industrial technique carried out in a vacuum to coat the entire MDI inhaler. It involves constant or pulsed gas excitation by radio frequency (RF) or the microwave field to produce an energetic plasma. This coating ensures that the drug formulation does not stick to the interior wall of the MD inhaler and results in the patient receiving the prescribed dose of medication, extending the product's shelf-life.

A metered dose inhaler contains enough medication for a certain number of actuations (or "puffs") printed on the canister. Even though the inhaler may continue to work beyond that number of uses, the amount of medication delivered may not be correct. It is important to keep track of the number of times an inhaler is used so that it can be replaced after its recommended number of uses. For this reason, several regulatory authorities have requested that manufacturers add a dose counter or dose indicator to the actuator. Several inhalation products are now sold with a dose counter-actuator. Depending on the manufacturer and the product, inhalers are sold as a complete unit or the individual canister as a refill prescription.

While MDIs are commonly used in the treatment of lung-based disorders, their use requires dexterity to complete the required sequential steps to achieve the application of these devices. Incorrect completion of one or more steps in using an MDI can substantially reduce the delivery of the administered medication and, consequently, its effectiveness and safety. Numerous studies have demonstrated that between 50-100% of patients do not use their inhaler devices correctly, with patients often unaware that they are using their inhaled medication incorrectly.{{cite journal | vauthors = Vanderman AJ, Moss JM, Bailey JC, Melnyk SD, Brown JN | title = Inhaler misuse in an older adult population | journal = The Consultant Pharmacist | volume = 30 | issue = 2 | pages = 92–100 | date = February 2015 | pmid = 25695415 | doi = 10.4140/TCP.n.2015.92 }}{{cite journal | vauthors = Gregoriano C, Dieterle T, Breitenstein AL, Dürr S, Baum A, Maier S, Arnet I, Hersberger KE, Leuppi JD | title = Use and inhalation technique of inhaled medication in patients with asthma and COPD: data from a randomized controlled trial | journal = Respiratory Research | volume = 19 | issue = 1 | pages = 237 | date = December 2018 | pmid = 30509268 | pmc = 6276152 | doi = 10.1186/s12931-018-0936-3 | doi-access = free }} Incorrect inhaler technique has been associated with poorer outcomes.{{cite journal | vauthors = Maricoto T, Monteiro L, Gama JM, Correia-de-Sousa J, Taborda-Barata L | title = Inhaler Technique Education and Exacerbation Risk in Older Adults with Asthma or Chronic Obstructive Pulmonary Disease: A Meta-Analysis | journal = Journal of the American Geriatrics Society | volume = 67 | issue = 1 | pages = 57–66 | date = January 2019 | pmid = 30291745 | doi = 10.1111/jgs.15602 | hdl-access = free | doi-access = free | hdl = 10400.6/9162 }} Incorrect maintenance and cleaning of metered dose inhalers is also an issue identified by many users, highlighting the need for clear guidance for patients prescribed MDIs.{{cite journal | vauthors = Tay ET, Needleman JP, Avner JR | title = Nebulizer and spacer device maintenance in children with asthma | journal = The Journal of Asthma | volume = 46 | issue = 2 | pages = 153–155 | date = March 2009 | pmid = 19253121 | doi = 10.1080/02770900802538244 | s2cid = 22194306 }}{{Cite web|url=https://e-surgery.com/how-to-clean-a-ventolin-and-salbutamol-asthma-inhaler/|title=How Properly To Clean Your Blue Asthma Inhaler| vauthors = Caufield M |website=e-Surgery|date=8 November 2019 |language=en-GB|access-date=2019-12-21}}

File:Cipla inhaler.jpg

One of the most crucial components of an MDI is its propellant. The propellant provides the force to generate the aerosol cloud and is also the medium where the active component must be suspended or dissolved. Propellants in MDIs typically make up more than 99% of the delivered dose,{{Cite journal | vauthors = Noakes T | title = Medical Aerosol Propellants | journal = Journal of Fluorine Chemistry | volume = 118 | issue = 1–2 | pages = 35–45 | year = 2002 | doi = 10.1016/S0022-1139(02)00191-4 | bibcode = 2002JFluC.118...35N }} so the properties of the propellant dominate more than any other individual factor. This is often overlooked in literature and in industry because so few propellants are used, and their contribution is often taken for granted. Suitable propellants must pass a stringent set of criteria, and they must:

• have a boiling point in the range of -100 to +30 °C{{cite web |url= https://unfccc.int/files/methods/other_methodological_issues/interactions_with_ozone_layer/application/pdf/ipacat2.pdf | archive-url = https://web.archive.org/web/20171207044706/http://unfccc.int/files/methods/other_methodological_issues/interactions_with_ozone_layer/application/pdf/ipacat2.pdf | archive-date = 7 December 2017 |title=Ensuring Patient Care: The Role of the HFC MDI | edition = 2nd | vauthors = Gore W, Patton D, Dabruzzi C, Geduldig L, Maginley R, Stone S, Wright P | collaboration = IPAC Editorial Panel | date = 2009 | veditors = Tansey I, Byron P, Dalby R, Noakes T, Schultz R, Tansey I, Van Campen L, Vogelsberg T |publisher = International Pharmaceutical Aerosol Consortium (IPAC) |access-date=2009-04-14 |url-status=live }}
• have a density of approximately 1.2 to 1.5 g cm⁻³ (approximately that of the drug to be suspended or dissolved)
• have a vapour pressure of 40 to 80 psig{{Cite journal | vauthors = Leach LC | title = Approaches and Challenges to Use Freon Propellant Replacements | journal = Aerosol Science and Technology | volume = 22 | issue = 4 | pages = 328–334 | year = 1995 | doi = 10.1080/02786829408959750| bibcode = 1995AerST..22..328L | doi-access = free}}
• have no toxicity to the patient
• be non-flammable
• be able to dissolve common additives (active ingredients should be either fully soluble or fully insoluble)

In the early days of MDIs, the most commonly used propellants were the chlorofluorocarbons CFC-11, CFC-12 and CFC-114.

In 2008, the Food and Drug Administration announced that inhalers using chlorofluorocarbons as a propellant, such as Primatene Mist, could no longer be manufactured or sold as of 2012.{{cite news|url=http://thechart.blogs.cnn.com/2011/09/22/no-more-primatene-mist-in-the-u-s-after-this-year/|title=No more Primatene Mist in the U.S. after this year| vauthors = Young S |date=September 22, 2011|work=The Chart (blog)|access-date=2011-09-22|publisher=CNN|archive-date=2011-09-22|archive-url=https://web.archive.org/web/20110922181217/http://thechart.blogs.cnn.com/2011/09/22/no-more-primatene-mist-in-the-u-s-after-this-year/|url-status=dead}} This followed from U.S. decision to agree to the 1987 Montreal Protocol on Substances that deplete the ozone layer.{{cite web|url=http://www.undp.org/gef/05/documents/publications/MontrealProtocol_WEB.pdf|title=The Montreal Protocol on Substances that Deplete the Ozone Layer|publisher=United Nations Environment Programme|archive-url=https://web.archive.org/web/20090227134139/http://www.undp.org/gef/05/documents/publications/MontrealProtocol_WEB.pdf|archive-date=2009-02-27|url-status=dead}}

Hydrofluorocarbon propellants have replaced CFC propellants.{{Cite web|url=https://www.fluorocarbons.org/metered-dose-inhalers-mdis/|title=Metered Dose Inhalers (MDIs) | work = European FluoroCarbons Technical Committee (EFCTC) |language=en-US|access-date=2019-04-09}} Concerns about the use of hydrofluorocarbon propellants have, however, since arisen since these compounds are potent greenhouse gases; propellants released during the use of a single inhaler result in a greenhouse footprint equivalent to greenhouse gases released during a 180-mile car journey.{{Cite news|url=https://www.telegraph.co.uk/news/2019/04/08/asthma-inhalers-bad-environment-180-mile-car-journey-health/|title=Asthma inhalers as bad for the environment as 180-mile car journey, health chiefs say| vauthors = Bodkin H |date=2019-04-08|work=The Telegraph|access-date=2019-04-09|language=en-GB|issn=0307-1235}}

Phospholipids are important natural surfactant lipids.{{cite patent | country = EP | number = 1658851 | inventor = Hills BA, Woodcock DA, Staniforth JN | assign = Britannia Pharmaceuticals Ltd. | pubdate = 24 June 2006 | url = https://patents.google.com/patent/EP1658851A1/en?oq=EP1658851A1 | title = Anti-asthmatic combinations comprising surface active phospholipids }} used to enhance penetration and bioavailability.{{cite patent | country = US | number = US8591954 | inventor = Somaraju S, Suman J, Ganguly S, Dalby R | assign = Next Breath LLC. | gdate = 26 November 2013 | title = Phospholipid-based inhalation system | url = https://patents.google.com/patent/US8591954B2/en }} Phospholipids reduce the high surface tension forces at the air-water interface within the alveoli, thereby reducing the pressure needed to expand the lungs. Thus, commercially available formulations of phospholipids have been designed to spread rapidly over an air-aqueous interface, thereby reducing what is otherwise a very high surface tension of water.

For ease of identification, many MDI's are colour-coded

• Inhaler
• Dry powder inhaler
• Asthma
• Spray bottle

{{reflist}}

• [http://www.uptodate.com/patients/content/topic.do?topicKey=~qqnO9LIC/_PY_l UpToDate Patient Information: Metered dose inhaler techniques in adults]
• [http://www.aboutkidshealth.ca/En/ResourceCentres/Asthma/AsthmaMedicines/Pages/Using-a-Metered-Dose-Inhaler-MDI-with-a-Spacer.aspx Using a metered-dose inhaler with a spacer: techniques for children, illustrated]
• [http://www.aboutkidshealth.ca/En/ResourceCentres/Asthma/AsthmaMedicines/Pages/Using-a-Metered-Dose-Inhaler-MDI-without-a-Spacer.aspx Using a metered-dose inhaler without a spacer: techniques for children, illustrated]
• {{cite web | title=Aerosol Properties of Metered-Dose Inhalers | website=U.S. Food and Drug Administration (FDA) | date=23 May 2022 | url=https://www.fda.gov/drugs/regulatory-science-action/effects-realistic-in-vitro-test-factors-aerosol-properties-metered-dose-inhalers | archive-url=https://web.archive.org/web/20220523201809/https://www.fda.gov/drugs/regulatory-science-action/effects-realistic-in-vitro-test-factors-aerosol-properties-metered-dose-inhalers | url-status=dead | archive-date=May 23, 2022 }}

{{Dosage forms|state=expanded}}

{{Portal bar|Medicine}}

{{DEFAULTSORT:Metered-Dose Inhaler}}

Category:Asthma

Category:Drug delivery devices

Category:Smoking cessation

Category:Dosage forms