Pressurized metered dose inhalers (pMDIs) are widely utilized to manage diseases of the lungs, such as asthma and chronic obstructive pulmonary disease. They can be formulated such that the drug and/or nonvolatile excipients are dissolved or dispersed in the formulation, rendering a solution or suspension formulation, respectively. While the formulation process for solution pMDIs is well defined, the formulation process of pMDIs with any type of suspended entity can be lengthy and empirical. The use of suspended drug or the addition of a second drug or excipient in a suspension pMDI formulation may non-linearly impact the product performance of the drug of interest in the formulation; this requires iterative testing of a series of pMDIs in order to identify a formulation with the most potential for success. One of the primary attributes used to characterize the product performance and quality control of inhaled medications is the residual aerodynamic particle size distribution (APSD) of the aerosolized drug. Along with clinical factors, formulation and device parameters have a significant impact on APSD. In this study, a computational model was developed using the principles of statistics and physical chemistry to predict the residual APSD generated by suspension pMDIs based on formulation, device, and raw drug or excipient substance considerations. The formulations modeled and experimentally evaluated consist of a suspended drug or excipient with/without a dissolved drug or excipient in a cosolvent-propellant system. The in silico model enables modeling a process that is difficult to delineate experimentally and contributes to understanding the link between pMDI formulation and device to product performance. The ability to identify and understand the variables that affect atomization and/or aerosol disposition , such as initial droplet size, suspended micronized drug or excipient size, and drug or excipient concentration, facilitates defining the design space for suspension pMDIs during development and improves recognizing the sensitive of the APSD is on each hardware and formulation variable. This model can later be applied to limit batch-to-batch variation in the manufacturing process and selecting plausible suspension pMDI formulations with quality design as the end goal.

No / Determining bioequivalence for solution pressurized metered dose inhalers (pMDI) is difficult because the critical characteristics of such products are poorly defined. The aim of this study was to elucidate the non-aerodynamic properties of the emitted aerosol particles from two solution pMDI products that determine their biopharmaceutical differences after deposition. Novel particle capture and analysis techniques were employed to characterize the physicochemical and biopharmaceutical properties of two beclomethasone dipropionate (BDP) products: QVAR and Sanasthmax. The BDP particles emitted from the Sanasthmax inhaler were discernibly different those emitted from QVAR in terms of size (50% larger, less porous), solid state (less crystalline) and dissolution (20-fold slower). When deposited onto the surface of respiratory epithelial cell layers, QVAR delivered ∼50% more BDP across the cell layer in 60 min than Sanasthmax. Biopharmaceutical performance was not attributable to individual particle properties as these were manifold with summative and/or competing effects. The cell culture dissolution− absorption model revealed the net effect of the particle formed on drug disposition and was predictive of human systemic absorption of BDP delivered by the test inhalers. This illustrates the potential of the technique to detect the effect of formulation on the performance of aerosolized particles and contribute to assessment of bioequivalence. / This work was in part funded by a grant from the Safety and Environmental Assurance Centre, Unilever Colworth, U.K. Particle sizing was performed by Steve Ingham, Institute of Pharmaceutical Science, King’s College London.

Drug administration through the pulmonary route is an ancient technique that evolved from inhaling the smoke of certain leaves as a medicine. The optimum droplet diameter for the pulmonary system deposition has been identified to be in the range from 2 to 3.5 μm, with potential deposition rates of up to 80% of this size range. Currently, the most used aerosol generator methods are the pressurized metered dose inhalers. However, they generally exhibit low deposition efficiency with less than 20 % of the spray reaching the target area of the lungs as most of the drug deposited in the upper airways. This is for the most part due to the droplet size polydispersity that is inherent in these systems. The droplets of the biggest diameter will deposit in the upper airways, and then the deposited medicine will be swallowed and absorbed in the gastrointestinal tract. This can produce adverse medical side effects. Electrospray (ES) or electrohydrodynamic atomization (EHDA) is a promising atomization process due to its ability to produce a spray with monodisperse droplet size. The current study will investigate the feasibility of using electrospray in a pulmonary drug delivery system. Assessments, selection and characterization of suitable biocompatible solvents that can be used as a lung obstruction relief drug were carried out. Tests to identify the electrospray setup necessary to produce droplet sizes in the appropriate range for deposition in the lungs were carried out. The study found that both stable and pulsating cone jet modes can produce the required droplet size and the pulsating mode can produce at least four times higher flow than stable cone jet mode. A low-cost image analysis technique developed for this work gave satisfactory results that could be compared to droplet size scaling laws from the literature. However, it proved to be relatively time consuming and further automation of this technique would make it more suitable for large-scale studies. The image analysis results show a correlation between the cone length, cone angle and the applied voltage. The droplet scaling laws discrepancies such as the solution flow rate exponent and the constant that is used by some scaling laws may be attributed to the droplet evaporation time which is quite short for the water/ ethanol solutions. The emitter diameter and the conductivity effect on the I(Q) power law and the sensitivity of the onset voltage (Vonset) to the liquid flow rate (Q), were demonstrated for solutions of triethylene-glycol (TEG), and for an ethanol-water mixture solution.