Numerical And Experimental Study On The Transport And Deposition Mechanisms Of Inhaled Dry Powders In Upper Respiratory Tracts

Dry powder inhalers(DPIs)refer to devices that generates dispersion and aerosolization of drug dry powder by active inhalation of patients,which are widely used in the treatment of respiratory diseases.However,most of the doses of DPIs are remained in the devices and deposited in the extrathoracic region with the delivery efficiencies to lungs generally in a range of 20%?40%,which is not only related to the physicochemical characteristics of the powder prescription,but also depends on the design of the devices,the usage of patients and the structure of respiratory tracts.Therefore,to maximize the dose delivered to the lungs,it is essential to conduct research on the transport and deposition mechanism of particles emitted from DPIs in the upper respiratory tracts.In this thesis,in vitro experiments and in silico simulations were employed to systematically evaluate the effects of inhalation parameters and inhaler characteristics on deposition patterns.Meanwhile,mathematical models for predicting the aerosol deposition pattern in upper respiratory tracts were proposed under the conditions of considering the intersubject variability between individuals.The computational fluid dynamics(CFD)and discrete phase model(DPM)were applied to study the effects of inhalation parameters,such as mouth-throat geometry,particle size and airflow rate,on the deposition profiles of fine particles in the United States Pharmacopeia throat(USP),idealized mouth throat(IMT)and a realistic mouth throat(RMT)constructed from CT scan.In silico results indicated that the deposition fraction increased with the increases in particle size and airflow rate.The complex geometry of the mouth throat corresponded to unstable flow field(jet and recirculation),resulting in more particle deposition due to the impaction with inner the wall.The effect of geometrical variation on the particle deposition was dominant.Although the total deposition fractions between IMT and RMT were similar,the particle spatial deposition distribution was clearly different.The main regions for deposition were larynx and pharynx for IMT and RMT,respectively,and particles tended to be more uniformly and dispersedly deposited in RMT.In vitro testing and CFD-DPM approach were conducted to evaluate the effects of particle release on mouth-throat deposition based on the Handihaler^?,USP and RMT models.Results indicated that,compared with the tubular USP model,the complex anatomic feature of RMT model led to an increase of inner surface exposed to the drug aerosols,resulting in more aerosol impaction and deposition,as well as lower fine particle dose(FPD).Increasing airflow rate corresponded to better drug aerosolization but not higher inhalation dose.The accelerated aerosols entered the oral cavity with a high momentum,leading to more inertial impaction and drug waste in the mouth-throat region.Moreover,the consideration of inhalers made particles enter the mouth in a form of central spray with varied momentum,and the collision deposition in the oral cavity increased significantly and mainly occurred on the front side of the tongue and the palate.Based on the commercial Handihaler^?,a Generic inhaler was designed with changes in the airway structure.Then,CFD-DPM simulation,in vitro delivery experiments and laser particle size analysis were employed to study the effect of DPI structure design on powder aerosolization and delivery efficiency.Results indicated that although the Generic inhaler could obtain consistent airway volume as the Handihaler^?,changes in the air intake position and size,central airway structure and shape of screen would directly affect the flow field and particle aerodynamic behavior in inhalers.In vitro data indicated that even though the resistance of the Generic matched the reference inhaler,it was still not enough to achieve the equivalent aerosolization performance.Under the same experimental conditions,Generic inhaler could achieve the similar FPD as the reference one,but the relatively low number of collisions of particles in the central airway directly resulted in unsatisfactory aerosolization of dry powders.Subsequently,the retention and collision deposition of large drug powders in the inhaler and mouth-throat increased obviously.To investigate the effect of usage of the inhaler on its delivery performance,according to the instructions for use of Handihaler^?,the aerosol deposition in RMT models with variations in insertion angle and mouthpiece position of the inhaler were simulated via CFD-DPM.Results indicated that inhaler usage had strong impacts on airflow and particle deposition profiles,especially for collision deposition in oral cavities.Small(-15°and 0°)or large(30°and 45°)insertion angles would shorten the collision time between the high-speed jet and the tongue of the palate,resulting in more deposition via impaction in the corresponding areas.Deeper position of the mouthpiece meant lower arch of tongue and lower deposition fraction via impaction in oral cavity.When using the DPIs,in order to reach the balance of reducing particle loss in mouth-throat,improving dose to the lungs and the comfort of the patients,better performance could be achieved by controlling the aerosol entering the mouth with the flow streamlines parallel to the tongue with deeper mouthpiece position.Finally,to propose mathematical models for predicting the aerosol deposition pattern in upper respiratory tracts,fourteen RMT models with significant intersubject variability were constructed and the deposition profiles of particles emitted from Handihaler^?were studied by CFD-DPM approach.Results indicated that the variations in geometrical factors,such as oral volume,airway curvature and glottis aperture,between individuals significantly affected the aerodynamic behavior and deposition fraction of inhaled particles.For the mathematical models derived to predict particle deposition in RMTs,the impaction parameter((9²₍₆₀₎)showed good correlation with deposition fraction,whereas the parameter did not consider the anatomical dimensions of the mouth-throat among individuals;the correlation between Stokes number and deposition fraction was highly sensitive to the characteristic diameter of the mouth-throat,and considering the complex morphology of pharyngeal and laryngeal regions could more accurately estimate the aerosol deposition;the correlations based on Stokes and Reynolds numbers showed good performance for predicting aerosol deposition with high determination coefficients(R²),while the applications were dependent on particle aerodynamic diameter.In summary,this thesis systematically studied the delivery and deposition process of inhaled dry powder in the upper respiratory tracts,which provided crucial theoretical basis for the development of new inhalers,the in vitro testing and the optimization on the use of DPIs.Meanwhile,the proposed mathematical models for predicting the aerosol deposition pattern profiles could contribute as a data reference for assessing the in vivo-in vitro correlation of DPIs.