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.
Product performance test data are presented on Glycopyrrolate (GP), a LAMA, and Formoterol Fumarate (FF), a LABA, and their combination in Pearl's HFA MDI format (GP MDI, FF MDI, and GP/FF combination MDI). GP and FF MDIs consistently deliver 18 and 2.4 µg GP and FF per actuation, respectively, with over 50% of the delivered dose in a particle size range suitable for uniform deposition in human airways. Their aerodynamic particle size distributions show excellent long term stability when stored at refrigerated (2-8°C), room temperature (25°C/60% RH) or stressed (40°C/75% RH) conditions. The delivered doses and aerosol properties of GP MDIs remain unchanged upon repeat thermal excursions between-5°C and 40°C for several weeks, demonstrating the robustness of Pearl's novel HFA MDI suspensions. GP/FF MDIs also show excellent stability without any physical or chemical interaction between the two actives under a broad range of test conditions. The overall performance attributes for the two drugs in GP/FF MDI combination remain unchanged from the monotherapy GP and FF MDIs. Conclusions Pearl is well positioned to further develop its MDI products. Pearl's MDI products demonstrate the following characteristics: Physical and chemical stability even under stressed conditions across a wide range of products Ability to develop very low doses of potent molecules High fine particle fraction (>50%) with low throat deposition for all products Excellent dose content uniformity No pharmaceutical effect observed when developing combination drug products High speed of development; < 9 months from first formulation to dosing patients Pearl's porous particle platform is ideal for the development of robust MDI products in timelines not previously attainable.
Rationale: This first-inhuman study provided safety and pharmacokinetic (PK) data on a novel fixed dose combination of Glycopyrrolate and Formoterol Fumarate metered dose inhaler (MDI). Pearl's novel porous particle based suspension technology allows better targeting of drugs to the airways via pressurized metered dose inhaler (MDI), and enables the development of combination products with improved physical stability, content uniformity, and aerodynamic size distribution similarity across the combination drug components. The objective of this study was to provide safety and PK evidence in support of further clinical studies in patients with COPD. Methods: Study PT0030901 was a randomized, double-blind, single-dose, 4-period crossover, single-center study in healthy subjects that evaluated a single administration of 4 inhaled treatments: glycopyrrolate 72 µg (GP), formoterol fumarate 9.6 µg (FF), the fixed combination GP/FF from a single MDI, and the loose combination of GP + FF administered from two separate MDIs. At each treatment visit, subjects were assessed for 12 hours after dosing. There was a minimum 7 day washout period between treatments. Evaluations included adverse events (AEs), dry mouth and tremor assessments, hematology, clinical chemistry, vital signs, 12-lead electrocardiograms (ECG), spirometry, physical examinations, and PK parameters. Results: Sixteen subjects (11 females, 5 males), average age 27 years (range 19 to 47), were enrolled with 13 subjects completing all treatment periods. No important safety trends or signals were noted for GP/FF MDI fixed dose combination in terms of AEs, changes in serum potassium or other laboratory values, vital signs, ECGs, or spirometry parameters. Conclusions: The novel GP/FF MDI fixed dose combination was safe and well-tolerated, with a safety profile similar to that observed with the components administered individually or at the same time as a loose combination. These safety findings support further evaluation of GP/FF MDI in patients with COPD. Conclusions In this healthy volunteer study, the combination of 72 µg of glycopyrrolate and 9.6 µg of formoterol fumarate [administered as a fixed combination (GP/FF MDI) and as a loose combination from two separate inhalers (GP MDI + FF MDI)] was observed to be safe and well tolerated with a similar safety profile to that of GP MDI and FF MDI administered alone. Administration of drug as a loose or fixed combination resulted in similar PK profiles for GP; similar findings were observed for FF. The data from this study support the further evaluation of GP/FF MDI in patients with COPD.
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