A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease.

BACKGROUND: Long-acting muscarinic antagonist/long-acting ß2-agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI). METHODS: This was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD ( NCT01085045 ). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 µg or 36/9.6 µg), GP MDI 36 µg BID, FF MDI 7.2 and 9.6 µg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 µg BID or tiotropium DPI 18 µg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 7 relative to baseline FEV1. Secondary endpoints included pharmacokinetics and safety. RESULTS: GFF MDI 72/9.6 µg or 36/9.6 µg led to statistically significant improvements in FEV1 AUC0-12 after 7 days' treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI (p ≤ 0.0002). GFF MDI 36/9.6 µg was non-inferior to GFF MDI 72/9.6 µg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated. CONCLUSIONS: GFF MDI 72/9.6 µg and 36/9.6 µg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01085045 . Registered 9 March 2010.

Dose-response to inhaled glycopyrrolate delivered with a novel Co-Suspension™ Delivery Technology metered dose inhaler (MDI) in patients with moderate-to-severe COPD.

BACKGROUND: This study forms part of the first complete characterization of the dose-response curve for glycopyrrolate (GP) delivered using Co-Suspension™ Delivery Technology via a metered dose inhaler (MDI). We examined the lower GP MDI dose range to determine an optimal dose for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: This randomized, double-blind, chronic-dosing, balanced incomplete-block, placebo-controlled, crossover study compared six doses of GP MDI (18, 9, 4.6, 2.4, 1.2, and 0.6 µg, twice daily [BID]) with placebo MDI BID and open-label tiotropium dry powder inhaler (18 µg, once daily [QD]) in patients with moderate-to-severe COPD. Patients were randomized into 1 of 120 treatment sequences. Each sequence included 4 of 8 treatments administered for 14-day periods separated by 7- to 21-day washout periods. The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 14. Secondary efficacy endpoints included peak change from baseline (post-dose) in FEV1 and inspiratory capacity (IC) on Days 1, 7, and 14; change from baseline in morning pre-dose trough FEV1 on Days 7 and 14; change from baseline in 12-h post-dose trough FEV1 on Day 14; time to onset of action (≥10 % improvement in mean FEV1) and the proportion of patients achieving ≥12 % improvement in FEV1 on Day 1; and pre-dose trough IC on Days 7 and 14. Safety and tolerability were also assessed. RESULTS: GP MDI 18, 9, 4.6, and 2.4 µg demonstrated statistically significant and clinically relevant increases in FEV1 AUC0-12 compared with placebo MDI following 14 days of treatment (modified intent-to-treat population = 120). GP MDI 18 µg was non-inferior to open-label tiotropium for peak change in FEV1 on Day 1 and morning pre-dose trough FEV1 on Day 14. All doses of GP MDI were well tolerated with no unexpected safety findings. CONCLUSIONS: These efficacy and safety results support GP MDI 18 µg BID as the most appropriate dose for evaluation in Phase III trials in patients with moderate-to-severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01566773 . Registered 27 March 2012.

Cosuspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers.

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.

Co-suspension delivery technology in pressurized metered-dose inhalers for multi-drug dosing in the treatment of respiratory diseases.

Technologies for long-term delivery of aerosol medications in asthma and chronic obstructive pulmonary disease have improved over the past 2 decades with advancements in our understanding of the physical chemistry of aerosol formulations, device engineering, aerosol physics, and pulmonary biology. However, substantial challenges remain when a patient is required to use multiple inhaler types, multiple medications, and/or combinations of medications. Combining multiple drugs into a single inhaler while retaining appropriate dosing of the individual agents in the combination may enhance patient adherence to therapy and reduce device errors that occur when patients are using multiple inhalers. Pressurized metered-dose inhaler (pMDI) devices are widely used by patients for acute symptom relief as well as maintenance treatment, so the pMDI may be a suitable option with which to explore medication combinations. However, optimizing drug formulation remains a key challenge for pMDI delivery systems. This article introduces a new pMDI formulation approach: co-suspension delivery technology, which uses drug crystals with porous, low-density phospholipid particles engineered to deliver combinations of drugs to the airways with accurate and consistent dosing via pMDIs, independent of medication types and combinations. We describe the key characteristics of pMDIs, and discuss the rationale for the co-suspension delivery technology platform based on the limitations associated with traditional formulations. Finally, we discuss the clinical implications of co-suspension delivery technology for developing combination drug therapies administered by pMDIs.

Gamma scintigraphic pulmonary deposition study of glycopyrronium/formoterol metered dose inhaler formulated using co-suspension delivery technology.

This gamma scintigraphy imaging study was the first to assess pulmonary and extrathoracic deposition and regional lung deposition patterns of a radiolabelled long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10µg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6µg), delivered by pressurized metered dose inhaler (pMDI) using novel co-suspension delivery technology. In this Phase I, randomized, single-centre, single-blind, single-dose, two-treatment, crossover, placebo-controlled study (PT003020), 10 healthy male adults received two actuations of GFF pMDI (7.2/5.0µg per actuation) and placebo pMDI (containing phospholipid-based porous particles without active pharmaceutical ingredient), both radiolabelled with 99mTc, up to 5MBq per actuation. Gamma scintigraphy images of lungs, stomach, head and neck were recorded. In addition, images of the actuators after use, collected mouth washings and exhalation filters were acquired. On average, 38.4% of the emitted dose of radiolabelled GFF pMDI, and 32.8% of radiolabelled placebo pMDI, was deposited in the lungs. The percentage emitted dose detected in the oropharyngeal and stomach regions was 61.4% and 66.9% for radiolabelled GFF pMDI and placebo pMDI, respectively. For both treatments, ≤0.25% of the emitted dose was detected in the exhalation filter. The normalized outer/inner ratio was 0.57 and 0.59 for radiolabelled GFF pMDI and placebo pMDI, respectively, and the standardized central/peripheral ratio was 1.85 and 1.94 respectively, indicating delivery of both co-suspension delivery technology formulations throughout the airways. There were no new or unexpected safety findings. In conclusion, both formulations were efficiently and uniformly deposited in the lungs with similar regional deposition patterns, oropharyngeal and stomach deposition, exhalation fraction and actuator-recovered dose.

Erratum: Erratum: Efficacy of Formoterol Fumarate Delivered by Metered Dose Inhaler Using Co-Suspension™ Delivery Technology Versus Foradil® Aerolizer® in Moderate-To-Severe COPD: A Randomized, Dose-Ranging Study.

[This corrects the article DOI: 10.15326/jcopdf.4.1.2016.0158.].

Efficacy of Formoterol Fumarate Delivered by Metered Dose Inhaler Using Co-Suspension™ Delivery Technology Versus Foradil® Aerolizer® in Moderate-To-Severe COPD: A Randomized, Dose-Ranging Study.

Background: Co-Suspension™ Delivery Technology offers a novel pharmaceutical platform for inhaled drug therapy. This randomized, double-blind, placebo-controlled, single-dose study (NCT01349868) evaluated the efficacy of a range of doses for formoterol fumarate (FF) delivered using Co-Suspension delivery technology via a pressurized metered dose inhaler (MDI) versus placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Secondary objectives included determination of non-inferior efficacy and systemic exposure compared with open-label Foradil® 12 µg (Foradil® Aerolizer®; formoterol fumarate dry powder inhaler). Methods: Patients received each of the 6 study treatments (FF MDI [7.2, 9.6 and 19.2µg], placebo MDI and open-label Foradil® [12 and 24µg]), separated by 3-10 days. Spirometry was performed 60 and 30 minutes prior to and at regular intervals up to 12 hours post-administration of study drug. The primary outcome measure was the change in forced expiratory volume in 1 second (FEV1) area under the curve between 0 and 12 hours (AUC0-12) relative to test day baseline. Results: A total of 50 patients were randomized to study treatment sequences. All doses of FF MDI demonstrated superiority to placebo (p<0.0001) and non-inferiority to Foradil® 12µg, on bronchodilator outcome measures. No serious adverse events were reported during the study. Conclusions: This study demonstrates non-inferiority of bronchodilator response and bioequivalent exposure of FF MDI 9.6µg to Foradil® 12µg, with both agents exhibiting a similar safety profile in patients with moderate-to-severe COPD. This study supports the selection of FF MDI 9.6µg for further evaluation in Phase III trials.

Novel cosuspension metered-dose inhalers for the combination therapy of chronic obstructive pulmonary disease and asthma.

Pressurized metered dose inhaler is the most common inhaled dosage form, ideally suited for delivering the highly potent compounds that medicinal chemists typically discover for respiratory therapeutic targets. The clinical benefit of combination therapy for asthma and chronic obstructive pulmonary disease has been well established, and many of the new discovery candidates are likely to be studied in the clinic as combination drugs even at early stages of development. We present a novel pressurized metered dose inhaler formulation approach to enable consistent aerosol performance of a respiratory therapeutic whether it is emitted from a single-, double- or triple-therapy product. This should enable rapid nonclinical and clinical assessment whether alone or in combination with other drugs, without the challenge of in vitro performance dissimilarity across product types.

Increase in the specific surface area of budesonide during storage postmicronization.

PURPOSE: To evaluate an anomalous increase in the specific surface area of budesonide during storage postmicronization. METHODS: Budesonide was micronized using a conventional air-jet mill. Surface areas and total pore volumes were measured using nitrogen sorption. Porosity was measured using mercury intrusion porosimetry. Particle size was measured using laser diffraction. RESULTS: Budesonide exhibited a surface area increase of 22 +/- 2% when stored at 25 degrees C following micronization. The rate of surface area increase was lower at 20 degrees C. suggesting a temperature-dependent stress relaxation mechanism for the micronized particles. The increase in surface area was accompanied by: (a) an increase in total pore volume: (b) a shift of the pore size distribution to smaller pore sizes; (c) a decrease in size of particles above approximately 1 microm; and (d) an increase in rugosity/surface roughness. CONCLUSIONS: Freshly micronized budesonide exhibited an unusual and significant postmicronization increase in specific surface area upon storage under ambient conditions. Postmicronization stress-relief by intraparticle crack formation, crack propagation with time, and particle fracture seems to be the primary mechanism behind this surface area increase.