http://informahealthcare.com/ddi ISSN: 0363-9045 (print), 1520-5762 (electronic) Drug Dev Ind Pharm, Early Online: 1–7 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2014.909841

RESEARCH ARTICLE

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Multi-breath dry powder inhaler for delivery of cohesive powders in the treatment of bronchiectasis Paul M. Young1, Rania O. Salama1, Bing Zhu1, Gary Phillips2, John Crapper2, Hak-Kim Chan3, and Daniela Traini1 1

Department of Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, NSW, Australia, 2Pharmaxis Pty Ltd, Frenchs Forest, Sydney, NSW, Australia, and 3Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, NSW, Australia Abstract

Keywords

A series of co-engineered macrolide–mannitol particles were successfully prepared using azithromycin (AZ) as a model drug. The formulation was designed to target local inflammation and bacterial colonization, via the macrolide component, while the mannitol acted as mucolytic and taste-masking agent. The engineered particles were evaluated in terms of their physicochemical properties and aerosol performance when delivered via a novel high-payload dry powder Orbitalä inhaler device that operates via multiple inhalation manoeuvres. All formulations prepared were of suitable size for inhalation drug delivery and contained a mixture of amorphous AZ with crystalline mannitol. A co-spray dried formulation containing 200 mg of 50:50 w/w AZ: mannitol had 57.6% ± 7.6% delivery efficiency with a fine particle fraction (6.8 mm) of the emitted aerosol cloud being 80.4% ± 1.1%, with minimal throat deposition (5.3 ± 0.9%). Subsequently, it can be concluded that the use of this device in combination with the co-engineered macrolide–mannitol therapy may provide a means of treating bronchiectasis.

Bronchiectasis, dry powder inhaler, inhalation, macrolides, mucolytics, orbital

Introduction Bronchiectasis is an irreversible obstructive pulmonary disease resulting from exposure to inhaled pathogens or toxins. The respiratory tissue becomes severely damaged and patients develop inflammation, hyper-mucosal secretion and reoccurring infection. While there is no direct cure for bronchiectasis, the use of mucociliary clearance agents, anti-inflammatory and antibiotics are commonly used therapies1. Of recent interest is the use of antibiotic macrolides to control inflammation. There is mounting evidence that this class of antibiotic not only is effective against local infection but also has therapeutic benefits for reducing respiratory inflammation via their immunomodulatory effects1–3. In order to be effective against infection and inflammation, macrolides need to be formulated for local treatment at the lung epithelia. Relatively high doses are required for treating infection (milligram quantities), and macrolides are inherently bitter tasting4, causing potential patient compliance issues when considering oral inhalation therapy. One approach to overcome this limitation would be to incorporate a taste-masking agent; however, this would further stress the requirement for efficient delivery of high doses to the lung. Mannitol is an approved pharmaceutical excipient used as a taste-masking agent and sweetener5–7 and is also used as an active pharmaceutical

Address for correspondence: Paul M. Young, Department of Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, NSW, Australia. Tel: +61 2 9114 0350. E-mail: [email protected]

History Received 2 February 2014 Revised 24 March 2014 Accepted 25 March 2014 Published online 9 May 2014

ingredient as a respiratory mucolytic8,9. Thus, it is hypothesized that a co-formulated mannitol–macrolide formulation may be useful in the treatment of bronchiectasis since the mannitol would reduce the bitter taste of the macrolide and concurrently increase mucus clearance, while the macrolide would simultaneously treat inflammation and local infection. In order to achieve this, a highdose inhaler device would be required with minimal oral-pharynx deposition and high respiratory tract penetration and deposition. The OrbitalÔ device was designed as a single use disposable dry powder inhaler capable of delivering high payloads to the respiratory tract over a number of inhalation maneuvers10,11. The device (Figure 1) consists of four main components: (1) a mouth piece, (2) dispersion grid, (3) aerosolization chamber with tangential air inlets and (4) a sample compartment ‘‘puck’’, which rotates within the aerosolization chamber, releasing the formulation through a precision engineered sample orifice. By controlling the size of the puck and orifice, a range of doses can be incorporating (ranging up to 500 mg) and can be emptied over a number of inhalation maneuvers (i.e. breaths). In this study, a model macrolide, azithromycin (AZ) alone and co-engineered powder systems containing the AZ and mucolytic/ taste masker mannitol in different ratios were formulated. Co-spray drying was used, since this method has previously been used to co-engineer inhaled microparticles containing a number of molecules including antibiotics with mannitol12. The physico-chemical properties of each powder were evaluated, and the aerosol performance in a prototype OrbitalTM device studied to assess the potential of this device and formulation approach for treatment of bronchiectasis.

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Particle size analysis Samples were analyzed for their particle size distribution by laser diffraction using a Mastersizer 2000 with Scirocco 2000 dry powder feeder (Malvern Instruments, Malvern, UK). Approximately 3 mg of powder was dispersed using 4-bar pressure. Each sample was analyzed in triplicate. X-ray powder analysis

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The crystal structure of the raw and spray-dried samples were characterized using X-ray powder diffraction (D5000, Siemans, Karlsruhe, Germany). Settings were as follows: 5–40 2y, step size 0.04 2y, step time 1 s and temperature 25  C. Differential scanning calorimetry

Figure 1. Schematic of the prototype Orbital DPI device. (1) Mouthpiece, (2) dispersion grid, (3) tangential air inlets and (4) puck-containing inhaled formulation.

The thermal response of each of the powders was analyzed using differential scanning calorimetery (DSC, Model 821e; Mettler Toledo, Greifensee, Switzerland). Samples (3–5 mg) were crimp-sealed in DSC sample pans and thermal properties analyzed at 10  C min1 over a temperature ramp between 40 and 400  C. Exothermal and endothermic peak temperatures, onset temperature and heat of enthalpy for each peak were determined using STARe software, V.9.0x (Mettler Toledo). Dynamic vapor sorpion studies

Materials and methods Materials Raw AZ was purchased from Sigma-Aldrich (Sydney, Australia). Water was purified by reverse osmosis (Merk Millipore, Billerica, Õ MA). Mannitol was supplied by Roquette (Pearlitol 160C, Lestrem, France). All solvents were obtained from Thermo Fisher Scientific (Sydney, Australia) and were of analytical/HPLC grade. Prototype OrbitalTM dry powder inhaler devices were supplied by Pharmaxis Pty Ltd. (Sydney, Australia).

Dynamic vapor sorption (DVS) was used to investigate the relative moisture sorption and stability of each powder formulation, with respect to humidity. Humidity can play an important role in terms of powder cohesion13 and amorphous stability14,15. Samples (ca. 8 mg) were added to glass sample pans, which were placed in the sample chamber of a DVS (DVS-1, Surface Measurement Systems Ltd., London, UK). Each sample was dried at 0% RH before being exposed to 10% RH increments for two 0–90% RH cycles (25  C). Equilibrium moisture content at each humidity step was determined by a dm/dt of 0.002% min1.

Microparticle production Three AZ:mannitol formulations were prepared by co-spray drying AZ and mannitol at ratios of 100:0, 50:50 and 20:80 w/ w. A Buchi B-290 spray dryer (Flawil, Switzerland) was utilized to prepare the particles. Spray drying of AZ and azithromycin– mannitol (AZ–Man) co-formulations was performed using the closed loop configuration with Buchi-296 dehumidifier and B-295 inert-loop (Bu¨chi, Flawil, Switzerland), using N2 as the drying gas. The feed solution was composed of ethanol:water 60:40 v/v and dissolved drug and mannitol mass at a concentration of 40 mg mL1. The inlet temperature was 110  C, feed rate 4 mL min1, spray air flow 700 l hr1 and aspiration rate 100% (approximately 35 m3/h). The outlet temperature was 70  C. In addition, mannitol alone was spray dried. Samples were stored for a minimum of 24 h at 45% relative humidity (RH) and 20  C prior to further study. Scanning electron microscopy Scanning electron photomicrographs of the microparticles were collected using a field emission scanning electron microscope (Zeiss Ultra Plus, Carl Zeiss NTS GmbH, Oberkochen, Germany) at 3 kV. Prior to analysis, samples were mounted on adhesive carbon tape (pre-mounted on aluminum stubs) and coated with gold to a thickness of approximately 15 nm using a sputter coater (Sputter coater S150B, Edwards High Vacuum, Sussex, UK).

Impaction studies and aerosolization performance In vitro aerosolization performance of the microparticles was assessed using a multi-stage liquid impinger (MSLI) (Copley Scientific, Nottingham, UK) equipped with a USP throat. The first four MSLI stages were filled with 20 mL of rinsing solvent (50:50 v/v acetonitrile:water for AZ–man and micronized AZ). The filter stage had a 0.2 mm glass filter (Pall Corporation, Surry Hills, Australia). The MSLI airflow was equilibrated to 60 L min1, using a GAST Rotary vein pump (Erweka GmbH, Heusenstamm, Germany) and calibrated flow meter (TSI 3063, TSI instruments Ltd., Buckinghamshire, UK); 60 L min1 was chosen as a fixed flow rate to allow comparison with previous published data within the field. A prototype Orbital device10,11 was used filled with 200 mg of powder. The original weight of loaded device was recorded, and device fired into the MSLI at 60 L min1 for 4 s, simulating one breath. The device was reweighed after each experiment to assess the delivered dose and the process repeated 10 times for each formulation, until the weight difference between two consecutive actuations was smaller than 0.2 mg. After complete actuation, the puck, device, mouthpiece, throat and filter stage were washed using recovery solution and diluted so that their concentration was within the calibration range for high-performance liquid chromatography (HPLC) analysis. Each formulation was tested in triplicate.

DOI: 10.3109/03639045.2014.909841

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Chromatographic methodology Quantification of AZ was performed using a Shimadzu HPLC system comprising CBM-20A controller, LC-20AT pump, SPD20A UV/VIS detector, SIL-20A HT autosampler and LC Solution software (all from Shimadzu Corporation, Kyoto, Japan). AZ was assayed using an XBridge Shield RP18 5 mm 4.6  150 mm column (Waters, Milford, MA). The mobile phase consisted of 20 mM ammonium acetate solution and acetonitrile (50:50 v/v) adjusted to pH 8.7 with ammonia solution. The recovery and standard dilution solutions were 50:50 v/v water:acetonitrile. A flow rate of 1 mL min1 and a wavelength of 210 nm were used to detect AZ at a retention time of 4 min. The HPLC quantification method was validated in terms of the linearity, precision (relative standard deviation; RSD), limit of quantification (LOQ) and tailing factor across the calibration range of 5–200 mg mL1. Statistical analysis Data were subjected to statistical analysis (SPSS 17.0, IBM, Armonk, NY) using ANOVA one-way analysis. Significant differences between formulations were analyzed using multiple comparisons (Tukeys post-hoc test), and p values of 50.05 were considered to be significant.

Results and discussion Scanning electron microscopy Scanning electron micrographs of the spray-dried AZ and co-spray dried AZ:mannitol samples are shown in Figure 2. In general, AZ had a corrugated surface morphology consistent with rapid particle drying, cavity formation and particle collapse. As the mannitol concentration was increased in the feed solution, the microparticles became smoother and more spherical. Particle size analysis Particle size distributions of the spray-dried AZ and co-spray dried AZ:mannitol samples are shown in Figure 3. All particle sizes were similar with d0.5 of 1.6 ± 0.1 mm for 100:0, 1.6 ± 0.1 mm for 50:50 and 1.8 ± 0.3 mm for 20:80 AZ:mannitol powders, respectively. Such observations suggest the particles to be of a suitable size for inhalation and were equivalent to allow comparison in the prototype Orbital device. X-ray powder analysis The X-ray powder diffraction patterns of the spray-dried AZ and co-spray dried 50:50 AZ:mannitol sample are shown in Figure 4, along-side spray-dried mannitol. Analysis of the data suggested that the AZ spray-dried showed a single broad diffuse peak, suggesting the material to be predominately amorphous. In comparison, the co-spray-dried formulations containing mannitolcontained peaks characteristic of the stable mannitol b-form16–18, with no peaks characteristic of either the less stable a-form (as shown by a peak at 13.8 2y in the spray dried mannitol alone) or peaks representative of AZ, between 10 and 15 2y19. Consequently, it may be assumed that the co-spray dried formulations are composed of both crystalline mannitol and amorphous AZ. Differential scanning calorimetry The differential scanning calorimetry thermograms of the spraydried AZ and co-spray dried 50:50 AZ:mannitol sample are shown alongside a spray dried mannitol sample in Figure 5. In general, the single spray-dried mannitol had a characteristic endothermic peak of melting at approximately 168–171  C.

Figure 2. Scanning electron microscopy images of spray-dried azithromycin and co-spray-dried azithromycin–mannitol mixtures.

In comparison, the amorphous AZ exhibited no exothermic or endothermic transitions until a broad peak of degradation at around 250  C, correlating well with previous studies of noncrystaline AZ19. The influence of the heat flow on the thermal properties of the co-spray dried sample showed a exothermic response at 125  C followed by endothermic response at 168  C. Such observations suggest a recrystallization phenomena that is most likely attributed to the AZ (since it was evident mannitol was already present as the stable b form from XRPD data) followed by complex endothermic event, likely related to simultaneous melting of both AZ and mannitol between 150 and 180  C (multiple endothermic events were detected by first derivative analysis). As with the spray-dried AZ alone, a broad endothermic event occurred at 250  C corresponding to degradation.

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Figure 3. Particle size distribution of spray-dried azithromycin and co-spray-dried azithromycin–mannitol mixtures.

Drug Dev Ind Pharm, Early Online: 1–7

Figure 5. DSC thermogram for spray-dried mannitol, azithromycin and 50:50 azithromycin:mannitol.

dried powders at various concentrations are shown in Figures 6 and 7. The spray-dried mannitol (100%) adsorbed 0.7% w/w water between 0% RH and 90% RH. This process was fully reversible, indicating the material was crystalline, and the cycle was repeatable, showed by conducting a second moisture sorption cycle (data not shown). In comparison, the 100% spray-dried AZ presented a sorption profile characteristic of water absorption. Specifically, moisture sorption increased with respect to increase in humidity until 5.2% w/w was absorbed at 90% RH. Unlike the 100% mannitol sample, the 100% AZ desorption isotherm from 90% to 0% RH contained hysteresis, suggesting absorption into the amorphous mass rather than simply surface adsorption, as observed with the mannitol. The sample did return to a 0% w/w value, indicative of a reversible process, suggesting that crystallization did not occur. A second moisture sorption cycle for the 100% AZ sample indicated a reproducible isotherm that followed the primary desorption isotherm. For the 20% w/w and 50% w/w samples, sorption cycles 1 and 2 differed. This was particularly evident for the 50% w/w sample where a mass loss was observed between 50 and 60% RH during the first sorption sample. Such observations are indicative of a re-crystallization process occurring. Analysis of the equilibrium moisture sorption at 40 and 90% RH as a function of %w/w AZ is shown in Figure 7. It is evident that the presence of mannitol in the formulation resulted in an increase in equilibrium moisture uptake, greater than for the mannitol or AZ alone. Specifically, the 50% w/w powder adsorbed ca. 12% water at 90% RH compared to 0.7 and 5.5% for the spray-dried mannitol and AZ alone, respectively. The moisture sorption at 40% RH for the 50% w/w co-spray-dried powder was 2.31% w/w. It is likely that the presence of mannitol throughout the amorphous matrix enhances water uptake into the powder since there is likely a mixture of both crystalline and amorphous mannitol. Subsequently, moisture protection should be taken into consideration when designing the final commercial Orbital device. Impaction studies and aerosolization performance Figure 4. X-ray powder diffractograms of azithromycin, mannitol and a 50% w/w co-spray dried particle system.

DVS studies To investigate the relative solid-state stability of the spray-dried and co-spray dried powders, the influence of humidity on moisture sorption was investigated. Representative moisture sorption isotherms for spray-dried mannitol, AZ and co-spray

The current HPLC quantification method for AZ across the concentration range studied showed a linearity regression value (R2) of 0.9999, RSD of 1.4% (n ¼ 8) and tailing factor of 1.28, respectively. The LOQ was reported to be 1.62 mg/mL, suitable for AZ quantification purpose. The in vitro drug deposition and aerosolization performance of each formulation were tested. Mass deposition of each formulation from the Orbital device on each stage of the MSLI expressed as a percentage of the total mass recovered is shown in Figure 8.

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Figure 6. Dynamic vapor sorption isotherms of spray-dried mannitol, azithromycin and co-spray-dried azithromycin–mannitol mixtures.

Figure 7. The relative moisture sorption at 40 and 90% RH as a function of AZ:mannitol ratio.

To further analyze the aerosol performance, the emptying efficiency as a function of shot number and aerosol performance parameters are shown in Figure 9(A) and (B), respectively. For the performance parameters, the cumulative drug deposition of the different formulations, from stage 3 to filter of the MSLI was calculated as the fine particle fraction of the loaded and emitted dose (FPFLD and FPFED; particles with an aerodynamic diameter 6.8 mm, calculated as a function of drug recovered from all stages and device components). In general, AZ was cohesive and had relatively poor emptying efficiency through the orbital puck (41.4% ± 9.0% was emptied after 10 shots). However, the aerosol performance of the emitted powder was high, with 82% ± 2.1% of the generated aerosol cloud having an aerodynamic diameter 6.8 mm (i.e. the FPFED). It is also interesting to note that 50% of the total emitted dose was generated in the first shot. As increased amounts of mannitol were incorporated into the formulation, the emptying efficiency increased proportionally. The output efficiency of the particles containing 50% and 80% w/w mannitol were 57.6% ± 7.6% and 62.9% ± 10%, respectively. Interestingly, for the 20:80 AZ:mannitol formulation, no significant change in emptying was observed after the first shot, whilst the 50:50 had a linear emptying profile after the first shots (Figure 10).

Figure 8. MSLI stage deposition of spray-dried azithromycin and co-spray-dried azithromycin–mannitol mixtures from the Orbital DPI device (n ¼ 3, ±SD).

The FPFLD of the mannitol containing particles was significantly higher than for the AZ alone formulation (ANOVA; p50.05); however, the overall efficiency of the generated aerosol cloud did not change to any large degree; the FPFED for the 50:50 and 20:80 AZ:mannitol formulations were 80.4% ± 1.1% and 74.1% ± 4.4%, respectively. While 40–60% of the loaded dose remained in the Orbital, the induction port (IP) deposition remained very low with 8.3% ± 3% of the formulation being deposited in this stage of the MSLI. This is important since the Orbital effectively ‘‘sieves out’’ the larger cohesive agglomerates (e.g. AZ-only formulation) that would be deposited in the oralpharynx region and cause potential tolerability issues. Ultimately, the aerosol cloud that is generated has a high respirable fraction with reduced IP impaction and increased stage deposition profiles (Figure 8). The particles released from the mannitol-containing formulation may contain large agglomerates that are potentially not suitable for inhalation delivery, causing a reduction in the FPFED.

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should investigate the influence of puck size, fill weight and orifice size, shape and numbers, on aerosolization efficiency, as well as undertake preliminary taste-masking studies in human volunteers.

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Conclusions A series of co-engineered macrolide–mannitol formulations were successfully prepared using AZ as a model drug. The formulations were incorporated into a novel Orbital device that demonstrated high-dose respiratory deposition efficiency and low throat deposition. The use of this device in combination with a the co-engineered macrolide–mannitol therapy may provide a means of treating bronchiectasis and local infection via the antiinflammatory and antibacterial effects of the macrolide coupled with the mucolytic and taste-masking function of mannitol.

Declaration of interest Authors report no declaration of interest. This research was supported under Australian Research Council’s Linkage Projects funding scheme (project number LP100100451). A/Professor Young is the recipient of an Australian Research Council Future Fellowship (project number FT110100996). A/Professor Traini is the recipient of an Australian Research Council Future Fellowship (project number FT12010063).

References

Figure 9. (A) Emptying profiles for 200 mg-loaded powder and (B) aerosolization efficiency of spray-dried azithromycin and co-spray-dried azithromycin–mannitol mixtures from the Orbital DPI device (n ¼ 3, ±SD).

Figure 10. Average emptying profile of the 50:50 AZ:mannitol formulation, starting from inhalation manoeuvre number two.

In general, the Orbital device reproducibly delivered 100 mg of formulation with a respirable fraction 6.8 mm of ca. 80%. For the 50:50 formulation, this would be equivalent to a dose of 40 mg AZ and 40 mg mannitol, respectively, to the lung. Future studies

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18. Lee YY, Wu JX, Yang M, et al. Particle size dependence of polymorphism in spray-dried mannitol. Eur J Pharm Sci 2011;44: 41–8. 19. Bayod JMS, Fernandez MF, Llorente GI, inventors; Astur-Pharma, S.A., assignee. Preparation of non-crystalline and crystalline dihydrate forms of azythromycin. EP 1103558 A2. Spain, 1999. Available from: http://www.google.st/patents/EP1103558A2?cl=en

Multi-breath dry powder inhaler for delivery of cohesive powders in the treatment of bronchiectasis.

A series of co-engineered macrolide-mannitol particles were successfully prepared using azithromycin (AZ) as a model drug. The formulation was designe...
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