Cosuspensions of Microcrystals and Engineered Microparticles for Uniform and Efficient Delivery of Respiratory Therapeutics from Pressurized Metered Dose Inhalers

摘要

Engineered porous phospholipid microparticlesnwith aerodynamic diameters in the respirable range of 1−2 μmnwere cosuspended in 1,1,1,2-tetrafluoroethane, a propellant,nwith microcrystals of glycopyrrolate, formoterol fumaratendihydrate, or Mometasone furoatethree drugs with differentnsolubilities in the propellant, and different physical, chemical,nand pharmacological attributes. The drug microcrystals werenadded individually, in pairs, or all three together to preparendifferent cosuspensions, contained in a pressurized meteredndose inhaler (pMDI). The drug microcrystals irreversiblynassociated with the porous particles, and the resultantncosuspensions possessed greatly improved suspension stabilityncompared with suspensions of drug microcrystals alone. In general, all cosuspensions showed efficient dose delivery of the drugs,nwith fine particle fractions of more than 60% for a wide range of doses, including those as low as 300 ng per inhaler actuation. Innthe cosuspension pMDIs, comparable fine particle fractions were delivered for all tested drugs, whether or not they were emittednfrom an inhaler containing one, two, or three drugs. We demonstrate that the cosuspension approach solves at least three longstandingnproblems in the clinical development of pMDI-based products: (1) dose and drug dependent delivery efficiency, (2)ninability to formulate dose strengths below 1 μg to fully explore drug efficacy and safety, and (3) combination suspensionsndelivering a different fine particle fraction than individual drug suspensions.