Radiolabelling of Low GWP pMDI Formulations for Scintigraphy
Simon J Warren1, Chen Zheng1, Aneta Obirek1, Rebecca Price-Davies2 & Glyn Taylor1
1Cardiff Scintigraphics Ltd., Cardiff Medicentre, Cardiff, CF14 4UJ, UK
2Simbec Research Ltd., Merthyr Rd, Merthyr Tydfil, CF48 4DR, UK
Pressurised metered dose inhalers (pMDIs) use hydrofluorocarbon (HFC) propellants, some of which have noteworthy global warming potential (GWP). HFC uses are regulated and an international phase down has been implemented through the Kigali Amendment to the Montreal Protocol.
Some pharmaceutical companies have already stated their intention to transition to low GWP propellants, e.g. Chiesi (HFC 152a) and AstraZeneca (HFO 1234ze).
Marketing approvals for pMDIs with low GWP propellants will be dependent, in part, upon establishing bioequivalence with reference products. For locally acting medications gamma scintigraphy offers an accurate and fully quantifiable technique to conduct comprehensive in vivo characterisation of inhalers i.e. lung deposition / distribution, swallowed and exhaled fractions and the impact of patient factors.
To achieve these objectives radiolabelling methods for low GWP formulations must be developed. Trace amounts of Technetium-99m (Tc-99m) are incorporated into the formulations, without changing the pharmaceutical properties, so that the radiotracer acts as an accurate surrogate for the active pharmaceutical ingredients (APIs). Standard pharmacopoeial inertial impaction tests were conducted to characterise both the API and Tc-99m aerosol properties.
Two model triple combination pMDI formulations, using the APIs in commercial HFA 134a products i.e. in Chiesi’s Trimbow® (beclometasone/ formoterol/ glycopyrronium in solution) and AstraZeneca’s Trixeo® (budesonide/ formoterol /glycopyrronium in suspension) were produced using HFC 152a and HFO 1234ze respectively, then radiolabelled with Tc-99m. Using acceptance criteria recommended for the validation of radiolabelled orally inhaled products (Devadason et al. 2012) the radiolabel was shown to be an accurate surrogate for the APIs in both formulation types.
Tc-99m was used to radiolabel pMDIs formulated with low GWP propellants. Tc-99m was an accurate surrogate for drugs dissolved in HFC 152a or suspended in HFO 1234ze. Radiolabelled products can be used in clinical studies to evaluate in vivo bioequivalence between reference products and those reformulated in next generation propellants.