Abstract

Inhalation delivery of therapeutics has long history in the pharmaceutical industry with many products established over several decades [1, 2]. Currently available pharmaceutical inhalation devices include nebulizers, dry powder inhalers (DPIs) and metered dose inhalers (MDIs). Nebulizers can only be used to deliver drugs that are stable in water either as solution or suspension. Delivery time requires 15 – 20 min [3]. Dry powder inhalers can deliver insoluble drugs or drugs unstable in solutions, however, aerosol performance is dependent on particle size and inhalation rate. Limited delivery dose particularly with the use of carrier particles [4]. MDIs can only be used for small drug doses as the active ingredients normally represent less than1% with the remaining content being composed of propellent other excipients [5]. Design and develop a dry powder nebulizer (DryNeb™) that can be used for delivery of relatively large doses of dry powders. The device should provide adequate efficiency of powder dispersion and aerosolization independent of the inhalation rate. The aerosol performance of the device design was evaluated using in silico and in vitro experiments, In silico CFD studies CFD study was contracted at Sandia National Laboratories to study the internal flow of the DryNeb™ device. The powder flow through the inhaler device was analyzed using ANSYS Fluent, a commercially available Computational Fluid Dynamics (CFD) software package. Simulations evaluated the performance under two different airflow rates: 45 L/min and 75 L/min. Due to the complexity of simulating the MRE chaotic motion, the simulations did not consider the MREs rotation. Velocity and turbulent kinetic energy were simulated to characterize the device design. Streamlines were plotted from inlet to outlet, providing a quantitative description of fluid flow through the device. Additionally, velocity contour plots were used to provide more details about the air flow. In vitro Aerosolization experiments Initially, the powder emptying was evaluated gravimetrically using lactose powder. In vitro aerosol performance was tested using a next generation impactor (NGI) with a USP induction port and pre-separator. pure micronized powders were used in the assessment of the dry powder nebulizer. Specifically, micronized budesonide (d50 1.80 ± 0.12 µm) and ciprofloxacin free base (d50 2.47 ± 0.24 µm) were used. Device performance parameters assessed included emitted dose (ED), fine particle dose (FPD <5 µm), fine particle fraction (FPF <5 µm) (FPD and FPF were calculated as a fraction of the delivered dose), mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD). Additionally, the aerosol performance of the DryNeb was also tested using micronized amphotericin B to test the ability of DryNeb to deliver relatively high doses of the drug. Amphotericin B is a water insoluble drug normally used at high doses reaching around 50 mg. Testing was done using fast screening impactor for delivery of 30 mg through 6 inhalations each of 4 seconds at flow rate of 60 L/min. Amount of drug in the collection cups of the NGI was assessed using ultraviolet spectroscopy on a Tecan Infinite M200 plate reader. CFD analysis of the DryNeb device showed a unique pattern with four distinct quadrants in the powder container due to the way the air inlet jets impinge. The circulating zones are hypothesized to be responsible for “reaching” down to the powder bed and entraining powder. Figure 2 shows the velocity contours obtained by CFD analysis experiments. Aerosolization experiments showed that flow rate through the device had minimal impact on the aerosol performance metrics with this powder and fine particle dose was not affected. Results are summarized in table 1. The influence of drug type was also investigated (Figure 3). A comparison of pure budesonide and pure ciprofloxacin powder delivery indicates drug powder and physicochemical properties influence powder emission from the device. More cohesive budesonide had slightly lower dose delivery compared to ciprofloxacin. Currently available inhalations devices including DPIs, nebulizers and MDIs have several limitations related to drug stability, drug dose delivered and time required for dosing The DryNeb device can be used for delivery of dry powders with low stability, solubility or that are required to be delivered at high doses. DryNeb is an active DPI device utilizing external power sources to disperse powders using magnetic responsive elements. Powder dispersion is independent of air flow. The use of the DryNeb was tested with various drugs including budesonide, ciprofloxacin and amphotericin B with promising aerosolization performance. Future plans includes optimization of the device parameters for improving aerosol performance. Additionally, the use of carrier particles as lactose will also be investigated. Currently available inhalations devices including DPIs, nebulizers and MDIs have several limitations related to drug stability, drug dose delivered and time required for dosing The DryNeb device can be used for delivery of dry powders with low stability, solubility or that are required to be delivered at high doses. DryNeb is an active DPI device utilizing external power sources to disperse powders using magnetic responsive elements. Powder dispersion is independent of air flow. The use of the DryNeb was tested with various drugs including budesonide, ciprofloxacin and amphotericin B with promising aerosolization performance. Future plans includes optimization of the device parameters for improving aerosol performance. Additionally, the use of carrier particles as lactose will also be investigated.