The development of a single-use, capsule-free multi-breath tobramycin dry powder inhaler for the treatment of cystic fibrosis.

The aerosol performance and delivery characteristics of tobramycin for the treatment of respiratory infection were evaluated using the Orbital™, a multi-breath, high dose, dry powder inhaler (DPI). Micronised tobramycin was prepared and tested in the Orbital and in the commercially available TOBI Podhaler (Novartis AG). Furthermore, the TOBI Podhaler formulation containing tobramycin as Pulmospheres was tested in both the commercial Podhaler device (T-326) and Orbital for comparison. By varying the puck geometry of the Orbital, it was possible to deliver equivalent doses of micronised tobramycin (114.09±5.86mg) to that of the Podhaler Pulmosphere product (116.01±2.59mg) over 4 sequential simulated breaths (60Lmin-1 for 4s) without the need for multiple capsules. In general, the aerosol performance of the micronised tobramycin from the Orbital was higher than the T-326 Podhaler device, with fine particle fraction (FPF) of 44.99%±1.09% and 37.03%±0.86%, respectively. When testing the Pulmosphere powder in the two devices, the T-326 had marginally better performance with a FPF of 68.77%±2.10% compared to 61.30%±3.45%. This is to be expected since the TOBI Podhaler and Pulmosphere are an optimised powder and device combination. The Orbital was shown to be capable of delivering high efficiency, high dose antibiotic therapy for inhalation without the need for the use of multiple capsules as used in current devices. This approach may pave the way for a number of antibiotic therapies and medicaments where high dose respiratory deposition is required.

Measuring Bipolar Charge and Mass Distributions of Powder Aerosols by a Novel Tool (BOLAR).

The Bipolar Charge Analyzer (BOLAR) was evaluated for measuring bipolar electrostatic charge and mass distributions of powder aerosols generated from a dry powder inhaler. Mannitol powder (5, 10, and 20 mg) was dispersed using an Osmohaler inhaler into the BOLAR at air flow rates of 30 or 60 L/min. As the aerosol sample was drawn through the BOLAR, the air flow was divided into six equal fractions. Five of them entered individual detection tubes with a defined cutoff diameter in the range of 0.95 to 16.36 µm (depending on the flow rate) and the remaining (i.e., the sixth) fraction passed through a reference chamber. The aerosols that entered the detection tubes were separated according to the particle charge polarity (positive, negative, or neutral) and charge was measured by separate electrometers. The deposited powder of a single actuation from the inhaler was chemically assayed using high performance liquid chromatography. Additionally, the aerosol measurements were conducted on a modified Classic Electrical Low Pressure Impactor (ELPI) for comparison of the net specific charge per size fraction. Spray-dried mannitol carried significantly different positively and negatively charged particles in each of the five defined particle size fractions. The charge-to-mass ratio (q/m) of positively charged particles ranged from +1.11 to +32.57 pC/µg and negatively charged particles ranged from -1.39 to -9.25 pC/µg, resulting in a net q/m of -3.08 to +13.34 pC/µg. The net q/m values obtained on the modified ELPI ranged from -5.18 to +4.81 pC/µg, which were comparable to the BOLAR measurements. This is the first full report to utilize the BOLAR to measure bipolar charge and mass distributions of a powder aerosol. Positively and negatively charged particles were observed within each size fraction, and their corresponding q/m profiles were successfully characterized. Despite some potential drawbacks, the BOLAR has provided a new platform for investigating bipolar charge in powder aerosols for inhalation.

Tuning aerosol performance using the multibreath Orbital® dry powder inhaler device: controlling delivery parameters and aerosol performance via modification of puck orifice geometry.

The current study presents a new approach to tackle high-dose lung delivery using a prototype multibreath Orbital® dry powder inhaler (DPI). One of the key device components is the "puck" (aerosol sample chamber) with precision-engineered outlet orifice(s) that control the dosing rate. The influence of puck orifice geometry and number of orifices on the performance of mannitol aerosols were studied. Pucks with different orifice configurations were filled with 400 mg of spray-dried mannitol and tested in the Orbital® DPI prototype. The emitted dose and overall aerodynamic performance across a number of "breaths" were studied using a multistage liquid impinger. The aerosol performances of the individual actuations were investigated using in-line laser diffraction. The emptying rate of all pucks was linear between 20% and 80% cumulative drug released (R(2) > 0.98), and the amount of formulation released per breath could be controlled such that the device was empty after 2 to 11 breath maneuvers. The puck-emptying rate linearly related to the orifice hole length (R(2) > 0.95). Mass median aerodynamic diameters of the emitted aerosol ranged from 4.03 to 4.62 µm and fine particle fraction (≤6.4 µm) were 50%-66%. Laser diffraction suggested that the aerosol performance and emptying rates were not dependent on breath number, showing consistent size distribution profiles.

Inhalable tranexamic acid for haemoptysis treatment.

PURPOSE: An inhalable dry powder formulation of tranexamic acid (TA) was developed and tested in a novel high-dose Orbital® multi-breath inhaler. The formulation was specifically intended for the treatment of pulmonary haemorrhage and wound healing associated with haemoptysis. METHODS: Inhalable TA particles were prepared by spray drying and the powder characterised using laser diffraction, electron microscopy, thermal analysis, moisture sorption and X-ray powder diffraction. The aerosol performance was evaluated using cascade impaction and inline laser diffraction and interaction with epithelia cells and wound healing capacity investigated using Calu-3 air interface model. RESULTS: The spray dried TA particles were crystalline and spherical with a D0.5 of 3.35 µm. The powders were stable and had limited moisture sorption (0.307%w/w at 90%RH). The Orbital device delivered ca. 38 mg powder per 'inhalation' at 60 l · min(-1) across four sequential shots with an overall fine particle fraction (⩽ 6.4 µm) of 59.3 ± 3.5% based on the emitted mass of ca. 150 mg. The TA particles were well tolerated by Calu-3 bronchial epithelia cells across a wide range of doses (from 1 nM to 10nM) and no increase in inflammatory mediators was observed after deposition of the particles (a decrease in IL-1ß, IL-8 and INFγ was observed). Time lapse microscopy of a damaged confluent epithelia indicated that wound closure was significantly greater in TA treated cells compared to control. CONCLUSION: A stable, high performance aerosol of TA has been developed in a multi-breath DPI device that can be used for the treatment of pulmonary lesions and haemoptysis.

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 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 physico-chemical properties and aerosol performance when delivered via a novel high-payload dry powder Orbital(™) 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 µm) 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.

Overcoming dose limitations using the orbital(®) multi-breath dry powder inhaler.

PURPOSE: A new approach to delivering high doses of dry powder medicaments to the lung is presented. The Orbital(®) dry powder device is designed to deliver high doses of drugs to the respiratory tract in a single dosing unit, via multiple inhalation maneuvers, overcoming the need to prime or insert multiple capsules. METHODS: The Orbital was tested in its prototype configuration and compared with a conventional RS01 capsule device. Three formulations were evaluated: 200 mg of spray-dried ciprofloxacin formulation for respiratory infection, 200 mg of spray-dried mannitol formulation for mucus clearance, and 100, 200, and 400 mg of co-spray-dried 1:8 formulations containing ciprofloxacin and mannitol as combination therapy. The systems were evaluated in terms of physicochemical properties and tested using a multistage liquid impinger at 60 L/min. Emptying rates were evaluated, and the aerosolization performance compared with 10 capsules used sequentially in the RS01. RESULTS AND DISCUSSION: The systems were different in terms of morphology, thermal response, moisture sorption, and stability; however, they had similar sizes when measured by laser diffraction, making them suitable for comparison in the Orbital and RS01 devices. The aerosolization performance from the Orbital device and RS01 was dependent on the formulation type; however, the fine particle fraction (FPF) produced by the Orbital device was higher than that by the RS01. The FPFs for ciprofloxacin, mannitol, and co-spray-dried formulation were 67.1±1.8, 47.1±2.2, and 42.0±1.8, respectively. For the Orbital, 90% of the loaded dose was delivered within 10 inhalation maneuvers, with the profile being dependent on the formulation type. CONCLUSION: The Orbital provides a means of delivering high doses of medicine to the respiratory tract through multiple breath maneuvers after a single actuation. This approach will allow the delivery of a wide range of high-payload formulations (>100 mg) for the treatment of a variety of lung disorders. To date, no such passive device exists that meets these crucial criteria.

Particle aerosolisation and break-up in dry powder inhalers: evaluation and modelling of the influence of grid structures for agglomerated systems.

This study aimed to investigate the influence of grid structures on the break-up and aerosol performance of a model inhalation formulation through the use of standardised entrainment tubes in combination with computational fluid dynamics (CFD). A series of entrainment tubes with grid structures of different aperture size and wire diameters were designed in silico and constructed using three-dimensional printing. The flow characteristics were simulated using CFD, and the deposition and aerosol performance of a model agglomerate system (496.3-789.2 µm agglomerates containing 3.91 µm median diameter mannitol particles) were evaluated by chemical analysis and laser diffraction, respectively. Analysis of the mannitol recovery from the assembly indicated that mass deposition was primarily on the grid structure with little before or after the grid. Mass deposition was minimal down to 532 µm; however, for smaller grid apertures, significant blockage was observed at all airflow rates (60-140 L · min(-1)). Analysis of the particle size distribution exiting the impactor assembly suggested that mannitol aerosolisation was dependent on the void percentage of the grid structure. It is proposed that initial particle-grid impaction results in a shearing force causing agglomerate fragmentation followed by immediate re-entrainment into the turbulent airstream within the grid apertures which causes further dispersion of the fine particles. Such observations have significant implications in the design of dry powder inhaler devices.

Particle aerosolisation and break-up in dry powder inhalers: evaluation and modelling of impaction effects for agglomerated systems.

This study utilised a combination of computational fluid dynamics (CFD) and standardised entrainment tubes to investigate the influence of impaction on the break-up and aerosol performance of a model inhalation formulation. A series of entrainment tubes, with different impaction plate angles were designed in silico and the flow characteristics, and particle tracks, were simulated using CFD. The apparatuses were constructed using three-dimensional printing. The deposition and aerosol performance of a model agglomerate system (496.3-789.2 µm agglomerates containing 3.91 µm median diameter mannitol particles) were evaluated by chemical analysis and laser diffraction, respectively. Analysis of the mannitol recovery from the assembly and CFD simulations indicated that mass deposition on the plate was dependent on the impactor angle (45°-90°) but independent of the airflow rate (60-140 L·min(-1)). In comparison, wall losses, perpendicular to the impactor plate were dependent on both the impactor angle and flow rate. Analysis of the particle size distribution exiting the impactor assembly suggested mannitol aerosolisation to be independent of impactor angle but dependent on the air velocity directly above the impactor plate. It is proposed that particle-wall impaction results in initial agglomerate fragmentation followed by reentrainment in the airstream above the impaction plate. Such observations have significant implications in the design of dry powder inhaler devices.

Particle aerosolisation and break-up in dry powder inhalers 1: evaluation and modelling of venturi effects for agglomerated systems.

PURPOSE: This study utilized a combination of computational fluid dynamics (CFD) and standardized entrainment tubes to investigate the influence of turbulence on the break-up and aerosol performance of a model inhalation formulation. METHODS: Agglomerates (642.8 mum mean diameter) containing 3.91 mum median diameter primary spherical mannitol particles were prepared by spheronisation. A series of entrainment tubes with different Venturi sections were constructed in silico, and the flow pattern and turbulence/impaction parameters were predicted using CFD. The entrainment models were constructed from the in silico model using three-dimensional printing. The aerosol performance of the mannitol was assessed by entraining the agglomerates into the experimental tubes at a series of flow rates and assessing the size distribution downstream of the venturi via in-line laser diffraction. RESULTS: A series of parameters (including Reynolds number (Re), turbulence kinetic energy, turbulence eddy frequency, turbulence length-scale, velocity and pressure drop) were calculated from the CFD simulation. The venturi diameter and volumetric flow rate were varied systematically. The particle size data of the agglomerated powders were then correlated with the CFD measurements. No correlation between turbulence and aerosol performance could be made (i.e. at a Reynolds number of 8,570, the d(0.1) was 52.5 mum +/- 19.7 mum, yet at a Reynolds number of 12,000, the d(0.1) was 429.1 mum +/- 14.8 mum). Lagrangian particle tracking indicated an increase in the number of impactions and the normal velocity component at the wall, with increased volumetric airflow and reduced venturi diameter. Chemical analysis of the mannitol deposited on the walls showed a linear relationship with respect to the theoretical number of impactions (R(2) = 0.9620). Analysis of the relationship between the CFD results and the experimental size data indicated a critical impact velocity was required to initiate agglomerate break-up ( approximately 0.4 m.s(-1)). CONCLUSION: While this study focussed on the effect of turbulence on agglomerate break-up, the small amount of impaction, which inevitably occurs in the venturi assembly, appeared to dominate agglomerate break-up in this dry powder system.

Does electrostatic charge affect powder aerosolisation?

To study if electrostatic charge initially present in mannitol powder plays a role in the generation of aerosols, mannitol was unipolarly charged to varying magnitudes by tumbling the powder inside containers of different materials. The resulting charge in the powder was consistent with predictions from the triboelectric charging theories, based on the work function values from literature and electron transfer tendencies from measurement of contact angle. The latter generated a parameter, gamma(-)/gamma+, which is a measure of the electron-donating capacity relative to the electron-accepting tendency of material. Lowering the work function value or increasing the gamma(-)/gamma+ ratio of the container material resulted in mannitol being more negatively charged, and vice versa. After charging, the powder was dispersed from an Aerolizer(R), at 30 and 60 L/min, to study the aerosol performance. Irrespective of the charge level, the powder showed similar fine particle fraction, emitted dose and device retention at a given flow rate, indicating that charge induced by different containers during tumbling does not play a significant role in mannitol powder aerosolisation.

Pharmacopeial methodologies for determining aerodynamic mass distributions of ultra-high dose inhaler medicines.

Three different impactor methodologies, the Andersen cascade impactor (ACI), next-generation impactor (NGI) and multistage-liquid impinger (MSLI) were studied to determine their performance when testing ultra-high dose dry powder formulations. Cumulative doses of spray-dried mannitol (Aridol) were delivered to each impactor at a flow rate of 60Lmin(-1) (up to a max dose of 800mg delivering 20 sequential 40mg capsules). In general, total drug collected in both the ACI and NGI falls below the range 85-115% of label claim criteria recommended by the United States of America Food and Drug Administration (FDA) at nominal mannitol doses exceeding 20mg and 200mg, respectively. In comparison analysis of the MSLI data, over a 5-800mg cumulative dosing range, indicated that the percentage of nominal dose recovered from the MSLI was within the +/-15% limits set in this study. Furthermore all samples, apart from the 5mg and 10mg analysis were within 5% of the nominal cumulative dose. While the MSLI is not routinely used for regulatory submission, the use of this impinger when studying ultra-high dose formulations should be considered as a complementary and comparative source of aerosol deposition data.