title: Cosuspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers.
abstract: Engineered porous phospholipid microparticles with aerodynamic diameters in the respirable range of 1-2 μm were cosuspended in 1,1,1,2-tetrafluoroethane, a propellant, with microcrystals of glycopyrrolate, formoterol fumarate dihydrate, or Mometasone furoate-three drugs with different solubilities in the propellant, and different physical, chemical, and pharmacological attributes. The drug microcrystals were added individually, in pairs, or all three together to prepare different cosuspensions, contained in a pressurized metered dose inhaler (pMDI). The drug microcrystals irreversibly associated with the porous particles, and the resultant cosuspensions possessed greatly improved suspension stability compared with suspensions of drug microcrystals alone. In general, all cosuspensions showed efficient dose delivery of the drugs, with fine particle fractions of more than 60% for a wide range of doses, including those as low as 300 ng per inhaler actuation. In the cosuspension pMDIs, comparable fine particle fractions were delivered for all tested drugs, whether or not they were emitted from an inhaler containing one, two, or three drugs. We demonstrate that the cosuspension approach solves at least three long-standing problems in the clinical development of pMDI-based products: (1) dose and drug dependent delivery efficiency, (2) inability to formulate dose strengths below 1 μg to fully explore drug efficacy and safety, and (3) combination suspensions delivering a different fine particle fraction than individual drug suspensions.
authors.affiliation: Pearl Therapeutics, Inc., Redwood City, California 94063, United States.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Vehring
authors.forename: David
authors.initials: D
authors.lastname: Lechuga-Ballesteros
authors.forename: Vidya
authors.initials: V
authors.lastname: Joshi
authors.forename: Brian
authors.initials: B
authors.lastname: Noga
authors.forename: Sarvajna K
authors.initials: SK
authors.lastname: Dwivedi
mesh_terms: D016503:Drug Delivery Systems; D004983:Ethanolamines / Q000737:chemistry*; D000068759:Formoterol Fumarate; D005650:Fumarates / Q000737:chemistry*; D006024:Glycopyrrolate / Q000737:chemistry*; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry; D036501:Metered Dose Inhalers; D000068656:Mometasone Furoate; D010316:Particle Size; D010743:Phospholipids / Q000737:chemistry*; D016062:Porosity; D011244:Pregnadienediols / Q000737:chemistry*; D012138:Respiratory Therapy; D012995:Solubility; D013499:Surface Properties; D014867:Water / Q000737:chemistry; D004980:Ethane / Q000031:analogs & derivatives; D005466:Fluorocarbons
chemical_list: D004983:Ethanolamines; D000068759:Formoterol Fumarate; D005650:Fumarates; D006024:Glycopyrrolate; D006845:Hydrocarbons, Fluorinated; D000068656:Mometasone Furoate; D010743:Phospholipids; D011244:Pregnadienediols; D014867:Water; C063006:norflurane; D004980:Ethane; D005466:Fluorocarbons