Nagaraja Rao

Dose emission characteristics of placebo PulmoSphere® particles are unaffected by a subject's inhalation maneuver.

BACKGROUND Good compliance to the prescribed dosing regimen and inhaler instructions for use are critical for asthma/chronic obstructive pulmonary disease (COPD) patients to achieve good control of their disease. We investigated the extent to which a system comprising porous particles delivered with a passive dry powder inhaler could be designed to achieve significant reductions in dose inhalation errors. METHODS Porous placebo particles were prepared by an emulsion-based spray-drying method (PulmoSphere® technology). The formulations were administered as dry powders with a portable, blister-based dry powder inhaler (Simoon Inhaler). The inhalation profiles of 69 asthma/COPD subjects were determined with an inhaler simulator with resistance comparable to that of the Simoon Inhaler. Powder emptying from the device was assessed by laser photometry. Aerosol performance was assessed on a Next Generation Impactor, and with the idealized Alberta mouth-throat model using both square-wave and subject-inhalation profiles generated in the breathing study. RESULTS Virtually all subjects could achieve a pressure drop of at least 1 kPa and an inhaled volume of at least 500 mL with the Simoon Inhaler. In vitro measures of particle deposition were found to be largely independent of the inhalation maneuver (flow rate, inhaled volume, ramp time) across the broad range of inhalation profiles observed in the breathing study. The rapid emptying of powder from the Simoon Inhaler minimizes the impact of dose-related errors, such as failure to exhale before inhalation and failure to breath-hold post inhalation. CONCLUSIONS Inertial impaction that is largely independent of a subjects inhalation maneuver can be achieved with a drug/device combination product comprising a porous particle formulation and blister-based inhaler.

In Vitro Assessment of Dose Delivery Performance of Dry Powders for Inhalation

The aerosol performance of engineered porous particles (PulmoSphere™) for inhalation as a function of powder properties (particle size and density) was assessed using an idealized replica of the adult human upper respiratory tract (URT) known as the Alberta mouth-throat model. Engineered placebo powders were prepared using the PulmoSphere™ technology, which is based on spray-drying an emulsion feedstock and produces porous particles with well-controlled size and density. These placebo powders are useful surrogates for a class of potent active formulations, and covered a range of particle sizes and densities, representing a particle design space relevant to dry powder inhalers. The Alberta idealized mouth-throat model was used for in vitro measurement of oropharyngeal (mouth and throat) losses and to estimate the total lung dose for different inhalation drug products. The in vitro lung doses measured with the mouth-throat model were compared to predictions of lung dose from semi-empirical numerical models of oropharyngeal deposition. Data from the mouth-throat model and numerical models were used to rank order oropharyngeal losses and flow-rate dependence in the 1–6 kPa pressure drop range. Aerosol performance of the PulmoSphere™ powders was favored by low-particle density and large geometric size, with the oropharyngeal deposition and flow rate dependence being lower for powders with median particle diameter ≥2.5 microns. In comparison, data from lactose-blend formulations showed significantly higher oropharyngeal deposition and flow rate dependence. The idealized mouth-throat model provides a reasonable in vitro estimate of dose delivered to the lungs, and is a useful tool for studying the effect of factors such as drug/device and inhalation airflow. Copyright 2014 American Association for Aerosol Research

Design of spray dried insulin microparticles to bypass deposition in the extrathoracic region and maximize total lung dose

Inhaled drugs all too often deliver only a fraction of the emitted dose to the target lung site due to deposition in the extrathoracic region (i.e., mouth and throat), which can lead to increased variation in lung exposure, and in some instances increases in local and systemic side effects. For aerosol medications, improved targeting to the lungs may be achieved by tailoring the micromeritic properties of the particles (e.g., size, density, rugosity) to minimize deposition in the mouth-throat and maximize the total lung dose. This study evaluated a co-solvent spray drying approach to modulate particle morphology and dose delivery characteristics of engineered powder formulations of insulin microparticles. The binary co-solvent system studied included water as the primary solvent mixed with an organic co-solvent, e.g., ethanol. Factors such as the relative rate of evaporation of each component of a binary co-solvent mixture, and insulin solubility in each component were considered in selecting feedstock compositions. A water-ethanol co-solvent mixture with a composition range considered suitable for modulating particle shell formation during drying was selected for experimental investigation. An Alberta Idealized Throat model was used to evaluate the in vitro total lung dose of a series of spray dried insulin formulations engineered with different bulk powder properties and delivered with two prototype inhalers that fluidize and disperse powder using different principles. The in vitro total lung dose of insulin microparticles was improved and favored for powders with low bulk density and small primary particle size, with reduction of deposition in the extrathoracic region. The results demonstrated that a total lung dose >95% of the delivered dose can be achieved with engineered particles, indicating a high degree of lung targeting, almost completely bypassing deposition in the mouth-throat.