Development of a new method of determining pharmaceutical aerosol plume geometry based on drug mass and inhalation flow




Moraga-Espinoza, Daniel Francisco

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The ability of a pharmaceutical inhalation medicine to penetrate the airways once entrained in the patient’s inhalation flow is a function of the physics of particle motion, airflow dynamics, and the physical structures of the airways. Therefore, development of in vitro characterization techniques capable of predicting in vivo aerosol performance and assisting in the understanding of inhaler performance is critical. Plume geometry for pressurized metered dose inhalers (pMDIs) and nasal sprays has been a long-standing characterization technique that is used, for example, to evaluate the integrity of the metered valve and the nozzle. High-speed laser imaging (HSLI) is the preferred method to characterize the geometry of the aerosol plume from these devices. However, current methods do not allow for simulation of inhalation airflow and do not use drug mass quantification to determine plume angles. Chapter 1 presents a review on the state of the art of pressurized metered dose inhaler (pMDI) technology. Different variables affecting the aerosol performance such as formulation and device are presented. Additionally, we compare compendial characterization techniques used for predicting the efficiency of the device. Chapter 2 presents an investigation on the effect of airflow on plume geometry utilizing a novel technique. A modified induction port called the Plume Induction Port Evaluator (PIPE) was developed and used to characterize the geometry of the plume under airflow conditions by drug mass quantification and compared to plume angles determined via droplet illumination methods. Characterization using PIPE revealed that the plume angle was significantly reduced in the presence of airflow, thus demonstrating that plume geometry is affected by patient’s inhalation. Chapter 3 presents an investigation on the use of the PIPE apparatus to evaluate the effect of airflow on the plume geometry of commercially-available suspension pMDIs. An equation was developed to consider the geometry of the actuator in the calculation of the effective angles between the nozzle and the sections in PIPE. This led to the finding that the Mass Median Plume Angles (MMPA) of the suspension formulations were significantly narrower in the presence of airflow. Chapter 4 presents a study on the adaptation of the PIPE apparatus to the analysis of nasal sprays and enabled a quantification of the effect of formulation and inhalation flow rates on plume geometry. Nasal replica casts were used to evaluate the effect of different inhalation maneuvers on the turbinate deposition. A correlation between plume angles and turbinate depositions under flow demonstrated that plume angles of nasal sprays are reduced when exposed to the patient inhalation forces. Chapter 5 presents an investigation on the correlation between plume geometry and drug delivery efficiency of solution pMDIs. Plume Efficiency, and Mass Median Plume Angle based on emitted dose are two parameters developed to correlate the angle of the droplets within the plume with the fraction of aerosol with an aerodynamic particle size < 5μm. Both parameters showed good correlation with fine particle fraction and provide the means to assess the degree of interaction between the plume and the induction port. We propose the use of these variables to predict the interaction of the plume with the oral cavity and therefore, predict oropharyngeal deposition


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