Cosuspensions of Microcrystals and Engineered ... - ACS Publications

Sep 17, 2012 - Respiratory therapeutics can be delivered to the lung using nebulizers, dry powder inhalers, or pressurized metered dose inhalers (pMDI...
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Cosuspensions of Microcrystals and Engineered Microparticles for Uniform and Efficient Delivery of Respiratory Therapeutics from Pressurized Metered Dose Inhalers Reinhard Vehring,# David Lechuga-Ballesteros,* Vidya Joshi, Brian Noga, and Sarvajna K. Dwivedi Pearl Therapeutics, Inc., Redwood City, California 94063, United States S Supporting Information *

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 longstanding 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.

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INTRODUCTION Chronic respiratory diseases and lung infections are among the largest causes of mortality and morbidity worldwide, with substantial economic burden to the health care system. More than three million people lose their life per year due to asthma or chronic obstructive pulmonary disease (COPD), with their lives cut short by an average of 14 years.1 It is well-established that diseases of the lung are best treated by local delivery of drugs to the airways.2,3 Current clinical research has shown the benefits of using more than one class of drugs to manage asthma or COPD, and it is not unusual to have patients inhaling drugs from three different inhalers or combining inhaled therapy with oral medications.4 Adherence to the consistent use of more than one inhaled treatment is challenging for most patients, and recently approved products contain two drugs that can be administered concomitantly. Respiratory therapeutics can be delivered to the lung using nebulizers, dry powder inhalers, or pressurized metered dose inhalers (pMDI). By far, the most prevalent delivery device is the pMDI, with about 80% market share in the industrialized world and nearly exclusive usage in the developing world.5,6 Although many pMDI products suffer from significant technical shortcomings, they are widely accepted by physicians and patients to manage asthma and COPD.7 Frequently cited problems are substantial drug deposition in the mouth and © 2012 American Chemical Society

throat of the patient, correlated with increased potential of unwanted side effects, and low lung deposition.8 Only 20% of the dose emitted from pMDIs typically reaches the lungs, which has been correlated with poor inhaler technique.9,10 Dosing uniformity is confounded by improper timing of the administration steps by the patient. Even properly trained patients, e.g., those participating in a clinical trial, may experience poor dose reproducibility,11,12 particularly with poorly performing formulations. Most pMDI products use drug microcrystals which are suspended in a propellant.13 Typically, a small volume of the suspension, 25 to 100 μL, is metered upon actuation of the device and atomized through a small orifice with a diameter of 0.2 to 0.5 mm, resulting in a drug-containing propellant spray.14 The propellant evaporates rapidly and the remaining aerosolized drug crystals are inhaled by the patient. In the first generation of pMDIs, drug microcrystals were suspended in chlorofluorocarbon (CFC) propellants. To achieve uniform dosing, soluble surfactants were added to the suspension to decrease the tendency of the drug crystals to agglomerate in the propellant.15 The ozone depletion potential Received: June 5, 2012 Revised: August 21, 2012 Published: September 17, 2012 15015

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stabilization.28 Engineered microparticles have also been used to improve suspension MDI performance. In the PulmoSphere technology based approach, active pharmaceutical ingredients are incorporated into low-density, phospholipid microparticles by spray-drying an emulsion containing the dissolved or suspended drug.29,30 These drug-containing microparticles are then suspended in the propellant. Here, we present a new formulation approach based on engineered microparticles in which the drug crystals are not incorporated into the microparticles during the spray-drying process, but rather, porous microparticles and drug crystals are added separately into the propellant, where they form a physically stable, uniform cosuspension by irreversible physical association of drug crystals with the porous particles, despite their buoyancy differences, while preserving the benefits of engineered particles and the natural physicochemical stability of drug crystals.

of the CFC propellants led to a switch to hydrofluoroalkane (HFA) propellants in the past decade. Introduction of the HFAs to replace the CFC propellants resulted in unanticipated formulation challenges because of the increased solubility of many classes of drugs in them, and incompatibility with previously used surfactants.16 Many of the drug microcrystal based HFA pMDI suspensions have poor colloidal stability leading to dosing variability,13,17 which is aggravated further due to improper patient coordination or timing during actuation, even if the inhalers are shaken well immediately prior to use, and the patient actuates the inhaler within seconds after shaking. These negative effects of poor colloidal stability are amplified in combination products due to differences in the density and particle size distribution of multiple drug microcrystals.13,18,19 The poor colloidal stability results in agglomeration, followed by creaming or sedimentation. Drug crystals suspended in propellant tend to form large agglomerates to minimize their surface energy with respect to the propellant. The agglomerates either rise or sink quickly due to true density differences with the propellant. This creaming or sedimentation results in concentration gradients causing variability in the amount of drug metered into the pMDI valve,20 because the dose is metered by volume of suspension irrespective of the mass of suspended particles. The agglomeration behavior of the suspension is driven by interparticle forces which can be expressed using interfacial energy parameters.21 The rate of agglomeration and sedimentation is affected by buoyancy and gravitational forces, and depends on drug suspension concentration, particle size distribution of the microcrystals, and the number of drugs in the suspension. This leads to pMDIs which have a variable ratio of fine particle dose to suspension concentration, when formulated in different strengths, using different microcrystal size, or when combined with another drug component.19 Such lack of dosing proportionality complicates the development of new combination pMDI products, and impedes their clinical evaluation, which requires a comparative clinical testing of the combination inhaler along with each of the respective single component inhalers, administered alone or coadministered sequentially in several dose strengths.22 Several approaches have been developed or proposed to improve the colloidal stability in pMDIs. One option is the use of HFA-soluble polymers such as poly(ethylene glycol) or polyvinyl pyrrolidone as suspension stabilizers.19 Certain combination products have been formulated in the suspension pMDI format using this approach.13,23 Alternatively, surfactants such as oleic acid can be solubilized in HFA using ethanol as a cosolvent. The polymers or surfactant increase suspension stability by reducing the surface energy of the drug crystal surface with respect to the propellants.24 However, combination products based on these approaches tend to deliver fine particle doses different from those of the individual components.19 Other approaches to improve colloidal stability of pMDI suspensions are at a research stage. Formulation techniques have been described, in which stable suspensions are created via a space-filling, network-like structure of the drug and the excipients.25,26 In another approach, to improve delivered dose variability submicrometer particles of α-lactose monohydrate have been used as bulking agents in pMDIs.27 Recently, chitosan nanoparticles, with HFA-philic oligo(lactide) chains grafted on them, were proposed for HFA suspension

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MATERIALS AND METHODS

Cosuspension metered dose inhalers containing glycopyrrolate (GP), formoterol fumarate dihydrate (FF), or Mometasone furoate (MF), and their corresponding binary or ternary combinations, were prepared by simultaneously suspending spray-dried lipid porous particles with micronized, mostly crystalline drug particles. Drug microcrystals were produced by air-jet milling. The manufacturing process for phospholipid microparticles has been described before.31 Briefly, an emulsion feedstock with a composition of 93.4% DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) and 6.6% anhydrous calcium chloride (equivalent to a 2:1 DSPC/CaCl2 molar ratio) was prepared. During the emulsion preparation, DSPC and CaCl2 were dispersed into a vessel containing heated water and PFOB (perfluorooctyl bromide or perflubron) using a high-shear mixer. The coarse emulsion was then further processed with a high-pressure homogenizer before spray-drying using a spraydryer.32 Commercially available pressure filling equipment was used (Pamasol Willi Mäder AG, Pfäffikon Switzerland) for pMDI manufacturing.33 Porous particles and microcrystalline drugs were added to a drug addition vessel in a humidity controlled environment. The drug addition vessel was then connected to a suspension vessel and flushed with HFA 134a propellant and mixed gently to form a slurry. The slurry was then transferred back to the suspension mixing vessel and adjusted to the target suspension concentration. The suspension was filled into 14 mL fluorinated ethylene polymer-coated aluminum canisters (Presspart, Blackburn, UK) through 50 μL valves (Bespak, King’s Lynn, UK), which are standard pMDI components. Sample canisters were selected at random for total canister analysis to ensure correct formulation quantities. MDIs were quarantined for one week before undergoing analytical testing. Optical particle size distributions of the micronized drug crystals and porous particles were determined by laser diffraction (Sympatec GmbH, Clausthal-Zellerfeld, Germany). Key parameters of the cumulative distribution of the drug microcrystals and the porous particles are shown in Table 1. dn refers to the relative amount, n, in percent of total volume, under diameter, d, in the cumulative volume distribution. The span is defined as d90 − d10.

Table 1. Descriptive Parameters of the Particle Size Distribution of All Formulation Components

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materials

d10 (μm)

d50 (μm)

d90 (μm)

span (μm)

MF Microcrystals GP Microcrystals FF Microcrystals spray dried lipid porous particles

0.4 0.5 0.5 0.9

1.0 1.7 1.4 2.3

2.3 3.5 2.7 4.7

1.9 2.1 1.9 1.7

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The particle density of the porous particles was assessed by measuring the compressed bulk density of the associated powders (Micromeritics Geopyc 1360). Aerosol performance was tested using the method described in United States Pharmacopoeia (USP) chapter ⟨601⟩. A Next Generation Impactor (NGI) operated at an air flow rate of 30 L/ min was used for determination of aerodynamic particle size distribution. Sample canisters were seated into actuators with two waste priming actuations and two additional seating waste actuations. Five actuations were collected in the NGI with a USP induction port attached. The valve, actuator, induction port, NGI collection cups, stages, and filter were rinsed with volumetrically dispensed solvent. The sample solutions were assayed using a drug-specific chromatographic method. The fine particle dose was defined as the sum of drug masses on stages 3 through filter. To allow comparison of inhalers with different dose strengths, the fine particle fraction was used, which is the sum of drug masses on stages 3 through filter normalized by the delivered dose. Delivered dose uniformity through canister life testing was performed using a Dose Uniformity Sampling Apparatus as described by USP ⟨601⟩. Inhalers were seated and primed as described before. Two actuations were collected and assayed at the beginning, middle, and end of canister actuation life (120 actuations). Micrographs were obtained either on a Zeiss EVO MA 15 scanning electron microscope using an Everhart-Thornley detector for Secondary Electron images or on a field emission SEM (JEOL 6301F) for high-resolution studies. An overall field of view at low magnification was selected and then divided into a 4 × 4 grid for collection of higher-resolution images at a higher magnification. These high-resolution images were overlapped slightly to allow the images to be combined to obtain a high-resolution, large field of view, containing several hundred individual agglomerates each. Electron-dispersive Xray spectroscopy (EDS) was conducted subsequently on the same field of view. A silicon drift detector (Bruker XFLASH 5010) was used to collect the EDS spectra. Elemental mapping of seven elements (carbon, nitrogen, oxygen, phosphorus, calcium, chlorine, and bromine) was used to identify the microcrystals and porous particles. Glycopyrrolate, i.e., glycopyrronium bromide, was identified using the Lβ transition of bromine. Chlorine’s KLII,III transition was used to identify Mometasone furoate. Formoterol fumarate contains neither chlorine nor bromine and was identified using the 392 eV Kα nitrogen transition. The phospholipid particles were verified using the KLII,III transition of phosphorus. Samples for microscopy work were prepared by actuating pMDIs on sample holders in a dosing tube and were coated with carbon (Leica SCD005), instead of gold or palladium to avoid interference by them in the EDS analysis.

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RESULTS The spray-dried porous lipid microparticles are shown in Figure 1. The porous nature of the particles is a consequence of the particle formation process during spray-drying.34 The microparticles are manufactured by spray-drying a phospholipidstabilized emulsion of PFOB nanodroplets. Upon evaporation of water, most of the phospholipid in the atomized droplets solidifies, while the PFOB is still present as nanodroplets because it evaporates more slowly than water. After the PFOB finally evaporates, a dry particle with a solid-foam nanostructure is created,30 shown schematically in the top panel of Figure 1, and also observed in the high-magnification electromicrograph in the bottom panel. It is apparent that this process yields particles with low particle density. The compressed bulk density of porous particle powders used in this study was found to be ∼0.2 kg/L. Visual observation of suspensions in glass vials showed excellent colloidal stability, in agreement with previously reported results.35 As can be observed in the electromicrographs of Figure 1, the particle surface is corrugated, and the substructure detail suggests that the particle surface is formed of

Figure 1. Top: Schematic of typical cross section for porous microparticles derived from multiple micrographs of broken particles. Middle: Micrograph of a porous microparticle. Bottom: Internal substructure.

a layer with thickness of less than 100 nm. This surface layer is expected to be amphiphilic due to its phospholipid nature. Surface corrugation and the amphiphilic nature of surfaces have been shown to reduce cohesion between particles,6,36 which contributes to the observed low aggregation rate in the propellant. In the drug microcrystal−porous particle cosuspensions, the drug crystals adhered to the corrugated surface of the larger phospholipid microparticles through shape-fitting contact similar to that which was described for other systems by Weiler et al.,37 thereby reducing the surface area exposed to the 15017

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red, and MF in green. Note that the porous particles, colored in gold, appeared geometrically larger than the crystals, but due to their low particle density had a small median aerodynamic diameter of 1.7 μm, suitable for efficient respiratory delivery. As can be observed in Figure 3, all drug microcrystals remained attached to the porous particles after actuation from the device. Analysis of a larger field of view yielded a positive elemental identification of 644 drug microcrystals, of which 96% were found attached to porous particles after actuation. A repeat of the experiment with metered dose inhalers stored for 3 month at 40 °C and 75% RH under moisture protection showed the same observations, allowing us to conclude that the crystals remain attached to the porous particles and are delivered from the pMDIs in the form of respirable agglomerates. A Raman spectroscopy study40 on agglomerates emitted from cosuspension MDIs showed no changes in the internal molecular vibrations of the components, indicating that the microcrystals adhere to the porous particles by physisorption. The results displayed in Figure 4 show the aerosol performance of a triple combination pMDI product containing three drugs of different therapeutic classes. The drugs were formulated according to their distinct dose requirements (approximately 10, 40, and 100 μg per actuation for FF, GP, and MF, respectively). Approximately 300 μg per actuation of porous particles were used in all cosuspensions. These drugs differ in their physicochemical and pharmacological properties: GP is a long-acting muscarinic receptor antagonist (LAMA), an anticholinergic bronchodilator used to open constricted airways; FF is a long-acting β2-adrenergic receptor agonist (LABA) that causes bronchodilation by smooth muscle relaxation, and MF is an inhaled corticosteroid (ICS) indicated to reduce lung airways inflammation. For FF, GP, and MF, respectively, the solubility in propellant is 0.015, 0.16, and 3.2 μg/g at 25 °C; and density is 1.307, 1.372, and 1.377 kg/L at 25 °C. The drug microcrystal sizes are given in Table 1. The leftmost columns in Figure 4 show the fraction of the assayed drug mass that remained in the device upon actuation. The second set of columns, labeled “inlet”, describes a fraction that was pre-separated in the USP induction port of the impactor due to large particle size or high propellant droplet velocity. It should be noted that the actual extrathoracic deposition in the patient is larger than the fraction collected in the induction port.41 The remaining columns report the mass fractions

propellant and the associated surface energy. The strong adhesion was verified by observing various cosuspensions of drug crystals with porous particles in glass vials. A typical example is shown in Figure 2. At ambient temperature, the

Figure 2. Micronized GP alone (left vial) and micronized GP cosuspended with phospholipid microparticles (right vial) demonstrating formation of drug−microparticle agglomerates.

density of the propellant, 1.206 kg/L, is higher than that of the phospholipid microparticles, 1.066 kg/L, and lower than that of the drug crystals, in this case, glycopyrrolate, 1.372 kg/L; therefore, if the drug and porous particles were not attached to each other in the cosuspension they would separate over time, i.e., the drug crystals would sediment, as shown in the left vial in Figure 2, and the porous particles would cream. However, even when gravitational acceleration was amplified 200-fold by centrifugation, no drug crystals sedimented, but rather rose to the surface together with the phospholipid microparticles, as can be observed in the right vial in Figure 2. Figure 3 shows the result of an experiment that was conducted to verify whether the drug crystals remain attached to the porous particles even after actuation of the metered dose inhaler. A triple combination cosuspension of GP, FF, and MF was prepared for this experiment. Such triple combination therapy may be preferred for the treatment of chronic obstructive pulmonary disease,38,39 but has not been successfully formulated before. The triple cosuspension was actuated under dry conditions from the MDI onto a sample holder for ultramicroscopy analysis. The particles were identified and color-coded based on an elemental analysis using energy dispersive X-ray spectroscopy. GP was colored in blue, FF in

Figure 3. Color-coded micrograph of agglomerates emitted from a pMDI containing micronized crystals from three different drugs cosuspended with porous microparticles. 15018

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therapy. A known problem caused by insufficient colloidal stability of the drug suspension is that the delivered dose from the first usable actuation may be different from that obtained in the last usable actuation.43 Priming instructions and product overages44 are prescribed for pMDI products to minimize this effect. The delivered dose from a pMDI may also be affected by deposition of drug crystals on the walls of the container or on the metering valve surfaces. The delivered dose throughout the life of the cosuspension pMDIs is shown in Figure 5 for the triple cosuspension of GP,

Figure 4. Aerodynamic size distribution of pMDI cosuspensions delivering glycopyrrolate (GP) from single, dual (with formoterol fumarate), and triple (with added Mometasone furoate) configurations. The mass is expressed as a percentage of total assayed mass, which corresponds to the metered dose. Error bars correspond to ±1 standard deviation (n = 3). Figure 5. Delivered dose uniformity represented by the individual doses of a triple cosuspension containing GP, FF, and MF at the beginning of the use of the pMDI, halfway through its use, and at the end of use, when the canister is nearly empty. Regulatory limits of ±15% for the mean and 25% for the individual data are shown by broken and closed lines, respectively.

deposited in the impactor in different aerodynamic diameter ranges. The mass represented by the rightmost six sets is termed the fine particle dose. While there is no direct correlation, it can be considered to be a good in vitro surrogate of the dose that would reach the lung of a patient under normal breathing conditions. Low device deposition, high fine particle fractions of 61 ± 4%, and low deposition in the induction port of less than 33% were achieved for all three drugs (shown for GP only in Figure 4), which represents a significant improvement compared to corresponding performance parameters for recently developed pMDIs.42 More importantly, the fine particle fraction and particle size distribution obtained for the GP microcrystals remained the same whether delivered from a single component cosuspension pMDI, 68%, from a double combination with FF microcrystals, 66%, or from a triple combination with the addition of FF and MF microcrystals, 64%. Similar results were achieved for the other two drug components in their respective cosuspensions (data available in the Supporting Information). The aerosol performance of the drug crystals in cosuspension was very similar to that of the porous particles alone. Thus, it can be concluded that the formation of the mixed agglomerates of drug microcrystals and porous particles in the cosuspension minimizes the impact of variations in suspension concentration of the drug microcrystals, providing a manufacturing advantage not previously available for the development of respiratory therapeutics. PMDIs containing GP microcrystal suspensions without porous particles were prepared and tested as a control. In the aerosol performance assay, these inhalers showed high variability in the recovered mass of GP relative to the nominal dose. No further development of this formulation type was conducted, because several GP-only pMDIs retained a significant part of the nominal dose in the inhaler upon actuation. Patients suffering from chronic lung disease are typically prescribed pMDIs with enough doses for one month of

FF, and MF. All three drugs, delivered concomitantly, met the regulatory requirements for chronic use by patients. The slight rise of delivered dose throughout the life of the pMDI is expected even for suspensions that do not cream or sediment at all. At the end of use, the headspace in the canister above the suspension is larger than at the beginning. It contains more propellant vapor that must be supplied from the liquid propellant volume, increasing the suspension concentration accordingly. A second effect can also cause a rise in delivered dose for a creaming suspension, because the valve meters from the bottom of the suspension volume, where the suspension concentration could be leaner than at the top, depending on the timing of such metering relative to shaking of the inhaler. This latter effect would lead to low doses at the beginning of use and an increase in average suspension concentration with repeated actuations. A statistical analysis of the data shown in Figure 5 revealed that the same trend in delivered dose was observed for each of the three drugs throughout the use of the device in spite of their differences in density, particle size, and nominal dose. Moreover, the random dose fluctuations associated with individual actuations were found to be correlated for the three drugs. To assess the level of covariance the sample Pearson’s correlation coefficients for the pairwise correlation of the individual drug doses in the triple combination were calculated using the results of each individual dose determination as sample set. Pearson’s correlation coefficients ranged from 0.52, which is considered a strong positive correlation, for the covariance of MF and FF doses to a near-perfect correlation of 0.96 for MF with GP. This shows that the dose ratios of the 15019

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three individual drugs in the triple combination remained nearly constant from actuation to actuation, which proves the high degree of homogeneity in the cosuspensions. This again supports the conclusion that the microcrystals of the three drugs remain attached to the phospholipid microparticles upon emission and in the cosuspension throughout the use of the inhaler. Current drugs used in the treatment of chronic lung disease are highly potent with doses that range from 400 μg/ day; and even more potent molecules, with doses approaching the nanogram range, are in drug discovery and development stages.45 Finding a no-effect level in clinical dose ranging studies often requires formulation and precise administration of doses that are significantly smaller than the final therapeutic dose. Formulating such small quantities of drug in a conventional pMDI, or even with any other current lung delivery device, poses significant challenges, because the amount of drug deposited on internal device surfaces is expected to be independent of the total amount of drug present. If only a very small quantity of drug is present in the suspension, such fixed losses due to device become very significant, leading to large deviations from the target dose, and unacceptable variability in delivered dose to the patient. This can become a severe obstacle in the clinical development of potent therapeutics. Figure 6 shows the dose uniformity results of two formoterol fumarate cosuspensions that were formulated to submicrogram

Figure 7. Aerodynamic particle size distribution of glycopyrrolate cosuspension pMDIs with nominal doses ranging from 0.3 to 18 μg per actuation presented as a percent of assayed mass. Error bars correspond to ±1 standard deviation (n = 3).

low as 300 ng per actuation, and the fine particle fraction remained constant over the entire dose range. Various aspects of the aerosol performance of 18 cosuspensions that were formulated to contain one, two, or three drugs in a wide range of drug microcrystal doses are shown in Figures 7, 8, and 9. In all cases, the same type of

Figure 8. Fine particle fraction of drugs delivered from cosuspension pMDIs with similar valve and actuator components. The open symbols represent the fine particle fraction of the indicated drug in a double or triple combination formulation.

Figure 6. Delivered dose uniformity of formoterol fumarate, formulated to target doses of 960 ng and 480 ng per actuation, respectively. Regulatory limits of ±15% for the mean and 25% for the individual data are shown by broken and closed lines, respectively.

phospholipid microparticles was used at a concentration that was higher than the concentration of the drug crystals. Figure 7 shows an example of aerodynamic particle size distributions, device, and throat depositions, as described previously for Figure 4, for a series of GP cosuspensions. Figure 8 shows the fine particle fraction, and Figure 9 displays the mass median aerodynamic diameter, MMAD, of the aerosol emitted from the device, tested after the induction port. The MMAD is a measure of the aerosol particle size distribution; half of the mass of the aerosol is contained in particles with an aerodynamic diameter smaller than the MMAD. The GP cosuspension pMDI aerosol performance parameters shown in Figures 7−9 were independent of nominal dose over a dose range of more than 2 orders of magnitude (300 ng to 40 μg). No statistically significant differences in the size distributions were detected. In general, the MMAD of an

doses. A comparison of the data shown in Figures 5 and 6 demonstrates similar delivered dose trends throughout device use, in spite of a nearly 100-fold difference in drug microcrystal dose (480 ng FF to 50 μg MF per actuation). Even at the lowest doses, the results met regulatory requirements for mean and individual dose consistency (Figure 6). In the cosuspension approach, drug losses due to adhesion of particles to internal container surfaces are minimized by the presence of a constant amount of phospholipid microparticles. For the cosuspensions presented above, the surface area of the porous particles is more than 10 000 times larger than that of the container and valve. Hence, the drug crystals preferentially attach to the porous particles. This is further supported by the data presented in Figure 7 for a nearly 60-fold dose range of GP cosuspensions. The device deposition of GP did not increase even at doses as 15020

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fraction obtained from the inhaler is mostly decoupled from the physicochemical properties of the drug, the strength of the dose, and the number of drugs in the cosuspension. Formulations of highly potent drugs at nanogram dose levels and combination therapies, including a triple therapy, were found to be feasible. Combination metered dose inhaler therapeutics based on the cosuspension technology have advanced to midstage clinical trials in COPD patients, proving the viability of this novel formulation approach in iterative product development for chronic respiratory illnesses.

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ASSOCIATED CONTENT

* Supporting Information S

A micrograph of micronized glycopyrrolate raw material, experimental parameters for drug specific assays, the spraydrying process, and determination of drug solubility in propellant, aerodynamic size distribution expressed in absolute assayed mass, as well as aerodynamic size distributions of formoterol fumarate and Mometasone furoate in mono, dual, and triple configurations. This material is available free of charge via the Internet at http://pubs.acs.org.

Figure 9. Mass median aerodynamic diameter of drugs delivered from cosuspension pMDIs in monotherapy, double, and triple combinations. Nominal dose refers to the metered dose per actuation.

aerosol generated by a pMDI is influenced by properties of the container closure system, for example, actuator orifice diameter, and by properties of the suspension, such as particle size of the dispersed phase and suspension concentration. In cosuspensions, the total suspension concentration is largely determined by the concentration of porous particles, which is typically higher than that of the drug microcrystals. This provides an opportunity to tune the aerosol performance of cosuspensions by varying the suspension concentration of the porous particles. For the dose range studied here, the suspension concentration of the porous particles was kept constant and was 6 to 1000 times higher than that of the drugs. Hence, the changes in concentration of the drug microcrystals have no measurable impact on aerosol performance. Figures 8 and 9 also show that the performance of the cosuspensions was unaffected by the presence of other drugs in double and triple combination pMDIs. Both fine particle fraction and MMAD remain very consistent for all three drugs, irrespective of the number of drugs in the cosuspension. Aerosol performance and dosing uniformity of the cosuspensions remained stable on isothermal storage and after six-week thermal cycling trials.31,46 In addition to the formulations presented above, several other drugs indicated for the treatment of asthma or COPD, including salmeterol xinafoate, fluticasone propionate at doses up to 150 μg, tiotropium bromide, and budesonide were also rapidly and successfully formulated using the cosuspension approach (results not shown). Cosuspension pMDI for the treatment of COPD have been tested in several clinical studies to date,47−50 including dose ranging studies of FF and GP cosuspension pMDIs in COPD patients, and studies of the GP/ FF combination in healthy volunteers, to assess safety and efficacy of the individual agents and the combination.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Present Address #

Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada T6G 2G8. Notes

The authors declare the following competing financial interest(s): All the authors are employees of Pearl Therapeutics, Inc.

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REFERENCES

(1) Beaglehole, R.; Irwin, A.; Prentice, T. The World Health Report: 2004: Changing History; World Health Organization: Geneva, 2004. (2) Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA), 2011; http://www.ginasthma.org. (3) Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Inititiative for Chronic Obstructive Lung Disease (GOLD), 2011; http://www.goldcopd.org. (4) Cazzola, M.; Gabriella Matera, M. The additive effect of theophylline on a combination of formoterol and tiotropium in stable COPD: a pilot study. Respiratory Medicine 2007, 101 (5), 957−962. (5) Newman, S. P. Principles of Metered-Dose Inhaler Design. Respiratory Care 2005, 50 (9), 1177−1190. (6) Wu, L.; da Rocha, S. R. P. Biocompatible and biodegradable copolymer stabilizers for hydrofluoroalkane dispersions: a colloidal probe microscopy investigation. Langmuir 2007, 23 (24), 12104− 12110. (7) Virchow, J.; Crompton, G.; Dal Negro, R.; Pedersen, S.; Magnan, A.; Seidenberg, J.; Barnes, P. Importance of inhaler devices in the management of airway disease. Respiratory Medicine 2008, 102 (1), 10−19. (8) Everard, M. L. Aerosol therapy past, present, and future: a clinician’s perspective. Respiratory Care 2000, 45 (6), 769. (9) Rootmensen, G. N.; van Keimpema, A. R. J.; Jansen, H. M.; de Haan, R. J. Predictors of incorrect inhalation technique in patients with asthma or COPD: a study using a validated videotaped scoring method. Journal of Aerosol Medicine and Pulmonary Drug Delivery 2010, 23 (5), 323−328. (10) McFadden, E. Improper patient techniques with metered dose inhalers: clinical consequences and solutions to misuse. Journal of Allergy and Clinical Immunology 1995, 96 (2), 278−283.

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CONCLUSION A cosuspension formulation approach for pMDI is reported, where drug crystals associate with engineered porous microparticles to form stable agglomerates in HFA propellants. The cosuspensions have excellent uniformity and colloidal stability, and the agglomerates remain intact upon actuation. Hence, product performance parameters such as particles size distribution, dose uniformity, and fine particle fraction are largely dominated by the properties of the engineered microparticles. For suitably micronized drugs, the fine particle 15021

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