Metered dose inhalers in the transition to low GWP propellants: what we know and what is missing to make it happen

ABSTRACTIntroduction The urgency to replace the propellants currently in use with the new sustainable ones has given rise to the need for investigation and reformulation of pMDIs.Areas covered The reformulation requires in-depth knowledge of the physico-chemical characteristics of the new propellants, which impact the atomization capacity and the plume geometry. Among the investigated propellants, HFA 152a, due to its lower vapor pressure and higher surface tension compared to HFA 134a, deliver larger particles and has a higher solvent capacity toward lipophilic drugs. On the other hand, HFO 1234ze seems to be more like HFA 134a, but with lower reproducibility of the generated spray, indicating a possible high susceptibility to variation in the consistency of the dose delivered. In addition, the hardware components currently in use are compatible with the new propellants. This allowed promising preliminary results in the re-formulation of pMDIs by academia and pharma companies. However, there is little information about the clinical studies required to allow the marketing of these new products.Expert opinion Overall, studies conducted so far show that the transition is technically possible, and the main obstacle will be represented by the full investment required to put the product on the market.KEYWORDS: Metered dose inhalersHFA 152aHFO 1234zeinhalation producteco-sustainable propellantsDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsIndication of the timescales required by the regulations for the replacement of the propellants of current pMDIs with sustainable ones;Impact of the chemical-physical properties of the new propellants on atomization (phase I of aerosol formation);Description of the formulation approaches of pMDI products with HFA152a and HFO1234ze: effect on phase II of aerosol formation (droplet evaporation);IP landscape of patent filed focused on HFA152a and HFO1234ze;Overview of the regulatory aspects suggested to date and clinical trials currently underway (safety, local tolerability and PK).Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.AcknowledgmentsThe authors would like to thank Gaetano Brambilla for his kind availability in providing valuable suggestions and comments on the manuscript.Additional informationFundingThis paper was not funded.