Martin J. Telko

Inhaled Large Porous Particles of Capreomycin for Treatment of Tuberculosis in a Guinea Pig Model

ABSTRACT Capreomycin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB), but it is limited therapeutically by its severe side effects. The objectives of the present studies were (i) to design low-density porous capreomycin sulfate particles for efficient pulmonary delivery to improve local and systemic drug bioavailability and capacity to reduce the bacillary load in the lungs in a manner similar to that achieved with intramuscular injections; (ii) to determine pharmacokinetic parameters after pulmonary administration of these capreomycin particles; and (iii) to evaluate the efficacy of these particles in treating animals in a small-aerosol-inoculum guinea pig model of TB. Capreomycin particles were manufactured by spray drying and characterized in terms of size and drug content. Pharmacokinetic parameters were determined by noncompartmental methods with healthy guinea pigs after administration of capreomycin particles by insufflation. The efficacy of the particles was evaluated by histopathological analysis and in terms of wet organ weight and bacterial burden in TB-infected animals. Lungs of animals receiving a 14.5-mg/kg dose of capreomycin particles showed significantly lower wet weights and smaller bacterial burdens than those of animals receiving any other treatment. These results were supported by histopathological analysis. The feasibility of inhaling capreomycin in a novel powder form, with the ultimate objective of the treatment of MDR-TB, is demonstrated by pharmacokinetic and pharmacodynamic studies with guinea pigs. If applied to humans with MDR-TB, such a therapeutic approach might simplify drug delivery by eliminating injections and might reduce adverse effects through lowering the dose.

Prediction of dry powder inhaler formulation performance from surface energetics and blending dynamics.

The purpose of these studies was to investigate the ability of surface energy measurements and rates of mixing in dry powder inhaler (DPI) formulations to predict aerosol dispersion performance. Two lactose carrier systems comprising either spray-dried or milled particles were developed such that they had identical physical characteristics except for surface morphology and surface energies avoiding confounding variables common in other studies. Surface energy measurements confirmed significant differences between the powder systems. Spray-dried lactose had a higher surface entropy (0.20 vs. 0.13 mJ/m2K) and surface enthalpy (103.2 vs. 79.2 mJ/m2) compared with milled lactose. Mixing rates of budesonide or fluorescein were assessed dynamically, and significant differences in blending were observed between lactose systems for both drugs. Surface energies of the lactose carriers were inversely proportional to dispersion performance. In addition, the root mean square (RMS) of blending rates correlated positively with aerosol dispersion performance. Both techniques have potential utility in routine screening of DPI formulations.

Aerodynamic and Electrostatic Properties of Model Dry Powder Aerosols: a Comprehensive Study of Formulation Factors

ABSTRACTThe impact of formulation variables on aerodynamic and electrostatic properties of dry powder aerosol particles is of great importance to the development of efficient and reproducible inhaler products. Systematic evaluation requires a well-designed series of experiments using appropriate methods. A factorial experimental design was employed. In broad terms, the conditions considered were two drugs, albuterol and budesonide, in combination with different excipients, drug concentrations, delivered doses, and metering system (capsule composition) and sampled under different flow conditions using standard entrainment tubes. Samples were collected in an electrical low-pressure impactor, to evaluate distribution of electrostatic properties, and an Andersen eight-stage nonviable cascade impactor, to estimate aerodynamic particle size distribution, concurrently. The deposition studies allowed calculation of approximate per particle charge levels for drug. The results showed very high particle charge levels, often in the 1,000–10,000 of elementary charges per particle range, orders of magnitude higher than charge levels predicted by the Boltzmann charge distribution. The charge levels are considerably higher than had previously been estimated (200e per particle).