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Metered-dose inhaler

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A metered-dose inhaler (MDI) is a device that delivers a specific amount of medication to the lungs in the form of a short burst of aerosolized medicine that is usually self-administered by the patient via inhalation. It is the most commonly used delivery system for treating asthma, chronic obstructive pulmonary disease (COPD) and other respiratory diseases. The medication in a metered dose inhaler is most commonly a bronchodilator, corticosteroid or a combination of both for treating asthma and COPD. Other medications less commonly used but also administered by MDI are mast cell stabilizers, such as cromoglicate or nedocromil.

Metered-dose Inhaler

Description

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MDI canister and actuator components from H&T Presspart

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.[1][2] 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.[3]

Uses

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Nicorette 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.[4]

  • 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.[5] 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.[5] A study found that "levels of carcinogens and toxins in e-cigarettes typically exceeded those measured in an FDA-approved nicotine inhaler."[5] 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.[6]

History

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Before the invention of the MDI, asthma medication was delivered using a fragile and unreliable squeeze bulb nebulizer.[7] 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.[2] 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.[7] 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.[8] The initial design by Riker used a glass canister coated with vinyl plastic to improve its resilience.[7] By 1956, Riker had developed two MDI-based products, the Medihaler-Ept containing epinephrine and the Medihaler-Iso containing Isoprenaline.[2] 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.

Spacers

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Main article: 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.[9]

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.[10]

Lifespan and replacement

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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.

Inhaler technique and use

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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.[11][12] Incorrect inhaler technique has been associated with poorer outcomes.[12][13] 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.[14][15]

Propellants

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CFC-free Asthalin HFA inhaler

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,[16] 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 [17]
  • have a density of approximately 1.2 to 1.5 g cm−3 (approximately that of the drug to be suspended or dissolved)[16]
  • have a vapour pressure of 40 to 80 psig [18]
  • have no toxicity to the patient [16][18]
  • be non-flammable [16][18]
  • be able to dissolve common additives (active ingredients should be either fully soluble or fully insoluble)[16]

Chlorofluorocarbons (CFCs)

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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.[19] This followed from U.S. decision to agree to the 1987 Montreal Protocol on Substances that deplete the ozone layer.[20]

Hydrofluorocarbons

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Hydrofluorocarbon propellants have replaced CFC propellants.[21] 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.[22]

Surfactant lipids

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Phospholipids are important natural surfactant lipids.[23] used to enhance penetration and bioavailability.[24] 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.

Colours

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

Name Use United Kingdom New Zealand United States
Salbutamol Reliever Light Blue Light Blue (Ventolin, Respigen); Gray (Salair) Bright Red (generics); Light Blue (brand name)
Beclometasone Steroid Brown Brown Light Green
Seretide (Advair in US) Combination Purple Purple Purple
Fostair Combination Pink
Epinephrine Brown

See also

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References

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  1. ^ Hickey AJ, da Rocha SR (2021). Pharmaceutical Inhalation Aerosol Technology (Third ed.). CRC Press. ISBN 978-1-03-209322-2.
  2. ^ a b c Swarbrick J (2007). Encyclopedia of Pharmaceutical Technology (3rd Illustrated ed.). Informa Health Care. p. 1170. ISBN 978-0-8493-9394-5.
  3. ^ Finlay WH (June 2001). The Mechanics of Inhaled Pharmaceutical Aerosols: An Introduction. Academic Press. ISBN 978-0-08-051137-5.
  4. ^ Busse W, Colice G, Hannon S (1998). "CFC-BDP require 2.6 times the dose to achieve equivalent improvement in FEV1 as HFA-BDP". Am J Respir Crit Med. 157: A405.
  5. ^ a b c Drummond MB, Upson D (February 2014). "Electronic cigarettes. Potential harms and benefits". Annals of the American Thoracic Society. 11 (2): 236–242. doi:10.1513/annalsats.201311-391fr. PMC 5469426. PMID 24575993.
  6. ^ van Geffen WH, Douma WR, Slebos DJ, Kerstjens HA (August 2016). "Bronchodilators delivered by nebuliser versus pMDI with spacer or DPI for exacerbations of COPD". The Cochrane Database of Systematic Reviews. 2016 (8): CD011826. doi:10.1002/14651858.cd011826.pub2. PMC 8487315. PMID 27569680.
  7. ^ a b c Purewal TS, Grant D (1997). Metered Dose Inhaler Technology (Illustrated ed.). Informa Health Care. ISBN 978-1-57491-065-0.
  8. ^ Clark AR (1995). "Medical Aerosol Inhalers: Past, Present, and Future". Aerosol Science and Technology. 22 (4): 374–391. Bibcode:1995AerST..22..374C. doi:10.1080/02786829408959755.
  9. ^ Togger DA, Brenner PS (October 2001). "Metered dose inhalers". The American Journal of Nursing. 101 (10): 26–32. doi:10.1097/00000446-200110000-00020. PMID 11680341.
  10. ^ Hickey AJ, ed. (2007). Inhalation Aerosols: Physical and Biological Basis for Therapy (2nd ed.). NY: Informa Healthcare. ISBN 978-1-351-66052-5.
  11. ^ Vanderman AJ, Moss JM, Bailey JC, Melnyk SD, Brown JN (February 2015). "Inhaler misuse in an older adult population". The Consultant Pharmacist. 30 (2): 92–100. doi:10.4140/TCP.n.2015.92. PMID 25695415.
  12. ^ a b Gregoriano C, Dieterle T, Breitenstein AL, Dürr S, Baum A, Maier S, et al. (December 2018). "Use and inhalation technique of inhaled medication in patients with asthma and COPD: data from a randomized controlled trial". Respiratory Research. 19 (1): 237. doi:10.1186/s12931-018-0936-3. PMC 6276152. PMID 30509268.
  13. ^ Maricoto T, Monteiro L, Gama JM, Correia-de-Sousa J, Taborda-Barata L (January 2019). "Inhaler Technique Education and Exacerbation Risk in Older Adults with Asthma or Chronic Obstructive Pulmonary Disease: A Meta-Analysis". Journal of the American Geriatrics Society. 67 (1): 57–66. doi:10.1111/jgs.15602. hdl:10400.6/9162. PMID 30291745.
  14. ^ Tay ET, Needleman JP, Avner JR (March 2009). "Nebulizer and spacer device maintenance in children with asthma". The Journal of Asthma. 46 (2): 153–155. doi:10.1080/02770900802538244. PMID 19253121. S2CID 22194306.
  15. ^ Caufield M (8 November 2019). "How Properly To Clean Your Blue Asthma Inhaler". e-Surgery. Retrieved 2019-12-21.
  16. ^ a b c d e Noakes T (2002). "Medical Aerosol Propellants". Journal of Fluorine Chemistry. 118 (1–2): 35–45. Bibcode:2002JFluC.118...35N. doi:10.1016/S0022-1139(02)00191-4.
  17. ^ Gore W, Patton D, Dabruzzi C, Geduldig L, Maginley R, Stone S, et al. (IPAC Editorial Panel) (2009). Tansey I, Byron P, Dalby R, Noakes T, Schultz R, Tansey I, Van Campen L, Vogelsberg T (eds.). "Ensuring Patient Care: The Role of the HFC MDI" (PDF) (2nd ed.). International Pharmaceutical Aerosol Consortium (IPAC). Archived (PDF) from the original on 7 December 2017. Retrieved 2009-04-14.
  18. ^ a b c Leach LC (1995). "Approaches and Challenges to Use Freon Propellant Replacements". Aerosol Science and Technology. 22 (4): 328–334. Bibcode:1995AerST..22..328L. doi:10.1080/02786829408959750.
  19. ^ Young S (September 22, 2011). "No more Primatene Mist in the U.S. after this year". The Chart (blog). CNN. Archived from the original on 2011-09-22. Retrieved 2011-09-22.
  20. ^ "The Montreal Protocol on Substances that Deplete the Ozone Layer" (PDF). United Nations Environment Programme. Archived from the original (PDF) on 2009-02-27.
  21. ^ "Metered Dose Inhalers (MDIs)". European FluoroCarbons Technical Committee (EFCTC). Retrieved 2019-04-09.
  22. ^ Bodkin H (2019-04-08). "Asthma inhalers as bad for the environment as 180-mile car journey, health chiefs say". The Telegraph. ISSN 0307-1235. Retrieved 2019-04-09.
  23. ^ EP 1658851, Hills BA, Woodcock DA, Staniforth JN, "Anti-asthmatic combinations comprising surface active phospholipids", published 24 June 2006, assigned to Britannia Pharmaceuticals Ltd. 
  24. ^ US US8591954, Somaraju S, Suman J, Ganguly S, Dalby R, "Phospholipid-based inhalation system", issued 26 November 2013, assigned to Next Breath LLC. 
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