Metered dose inhalers represent a large proportion of inhaled products used in the treatment and prevention of asthmaand chronic obstructive lung disease. These products were developed in the middle of the last century and havechanged little in the intervening period. One significant change was the replacement of ozone depletingchlorofluorocarbon (CFC) propellants with more environmentally friendly hydrofluoroalkanes as both the suspendingmedium and the means by which drug is generated as an aerosol. The role of co-solvent and surfactants in theperformance and the quality of the product is significant. The pharmaceutical industry performed the Herculean task ofreformulating all of their inhaled products into the new propellants quickly and efficiently to accommodate theimpending international phase out and elimination of CFCs. Despite the success of their endeavors there remains a needfor a systematic evaluation of excipient effects on the efficacy of metered dose inhaler products. It is proposed that controlling key manufacturing variables and measuring a range of quality and performanceattributes will highlight factors contributing to accuracy and reproducibility of the delivered dose and aerodynamicparticle size distribution. These outcomes are relevant to efficacy, and important for development of predictive models.
The specific aims of the proposal are: Selection of drug and preparation in a range of primary sizes suitable fordelivery as a respirable aerosol; evaluation of the effects of (a) different amounts of co-solvent (ethanol) and surfactant(oleic acid) will be evaluated. A multivariate statistical design will be employed to optimize the manufacture andmaintain efficiency without losing study power. A range of concentrations of the additives will be employed to exploreprocess design space within and outside the Q2 acceptance limits of 5% and (b) other surfactants will be studied basedon the experience gained with oleic acid and principles of physical chemistry; construction and utilization ofmathematical models to describe the influence of formulation and device variables on performance of the metered doseinhalers. The important variables in pMDI product manufacture that may impact on performance include: drug substance andits intrinsic physico-chemical properties; particle size and distribution of milled particles for suspension formulations;composition of the formulation with respect to: Propellant; Co-solvent; Surfactant; formulation, device (canister, valveand actuator) interactions. Important quality and performance variables include: delivered dose and uniformity;aerodynamic particle size distribution; plume geometry and spray pattern and; potentially dissolution (for poorly solubleor delayed dissolution materials) The intent by regulatory agencies to design quality into products based on sound scientific and engineeringprinciples requires that the manufacturing variables and the testing protocols and procedures are suitable to achieve thedesired monitoring and control of the product. It is the intent of this project to develop a framework from which todevelop criteria for product performance based on control of input process and product variables.

Public Health Relevance

Formulation additives and composition influence quality and performance of metered dose inhalers(MDIs). A systematic approach to understanding the sources of variability and deviation from dosedelivery is important to product development and regulatory approval. A comprehensive approach toproduct manufacturing processes and analytical testing using principles of quality by design will beemployed to prepare and characterize MDIs. Data collected will be used in predictive models based onphysical chemistry and design features that support rapid product development and the 'weight ofevidence' approach promoted by the US Food and Drug Administration to demonstrate productperformance similarity.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1-SRC (99))
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University of Florida
Schools of Pharmacy
United States
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