Pharmacokinetics of Ethionamide Delivered in Spray-Dried Microparticles to the Lungs of Guinea Pigs.

The use of ethionamide (ETH) in treating multidrug-resistant tuberculosis is limited by severe side effects. ETH disposition after pulmonary administration in spray-dried particles might minimize systemic exposure and side effects. To explore this hypothesis, spray-dried ETH particles were optimized for performance in a dry powder aerosol generator and exposure chamber. ETH particles were administered by the intravenous (IV), oral, or pulmonary routes to guinea pigs. ETH appearance in plasma, bronchoalveolar lavage, and lung tissues was measured and subjected to noncompartmental pharmacokinetic analysis. Dry powder aerosol generator dispersion of 20% ETH particles gave the highest dose at the exposure chamber ports and fine particle fraction of 72.3%. Pulmonary ETH was absorbed more rapidly and to a greater extent than orally administered drug. At Tmax, ETH concentrations were significantly higher in plasma than lungs from IV dosing, whereas insufflation lung concentrations were 5-fold higher than in plasma. AUC(0-t) (area under the curve) and apparent total body clearance (CL) were similar after IV administration and insufflation. AUC(0-t) after oral administration was 6- to 7-fold smaller and CL was 6-fold faster. Notably, ETH bioavailability after pulmonary administration was significantly higher (85%) than after oral administration (17%). These results suggest that pulmonary ETH delivery would potentially enhance efficacy for tuberculosis treatment given the high lung concentrations and bioavailability.

Pharmacokinetics of Inhaled Rifampicin Porous Particles for Tuberculosis Treatment: Insight into Rifampicin Absorption from the Lungs of Guinea Pigs.

Tuberculosis (TB) is a life-threatening infection that requires a lengthy treatment process that is often associated with adverse effects. Pulmonary delivery of anti-TB drugs has the potential to increase efficacy of treatment by increasing drug concentrations at the lungs, the primary site of infection. The aim of the present study is to evaluate the disposition of rifampicin (RIF) after its pulmonary administration as porous particles (PPs) to guinea pigs and contrast it to that after oral administration. RIF microparticles were prepared by spray drying a solution of RIF and L-leucine (9:1), and the resulting particles were characterized for their physicochemical properties. Animals received RIF either as intravenous solution (iv), as oral suspension of micronized RIF (ORS) and RIF-PPs (ORPP), or by insufflation of the PPs (IRPP). Plasma samples were collected at preselected time points, and bronchoalveolar lavage (BAL) was performed at the end of the study. RIF concentrations in biological samples were analyzed by HPLC. Plasma concentration versus time data was analyzed by compartmental and noncompartmental methods. RIF PPs were thin walled porous particles with mass median aerodynamic diameter (MMAD) of 4.8±0.1 µm, GSD=1.29±0.03, and fine particle fraction below 5.8 µm of 52.9±2.0%. RIF content in the resulting particles was 91.8±0.1%. Plasma concentration vs time profiles revealed that the terminal slope of the iv group was different from that of the oral or pulmonary groups, indicating the possibility of flip-flop kinetics. RIF from IRPP appeared to be absorbed faster than that of ORPP or ORS as evidenced by higher RIF plasma concentrations up until 2 h. Notably, similar AUC (when corrected by dose), similar CL, λ, and half-life were obtained after oral administration of RIF at 40 mg/kg and pulmonary administration of RIF at 20 mg/kg. However, RIF in the IRPP group had a shorter Tmax and higher bioavailability than orally dosed groups. In addition, RIF concentrations in the BAL of animals in the IRPP group were 3-4-fold larger than those in the orally dosed groups. The disposition in ORS and ORPP were best described by a model with two sequential compartments, whereas the disposition of IRPP was best described by a two parallel compartment model. The advantages of delivering RIF by the pulmonary route are demonstrated in the present study. These include achieving higher RIF concentrations in the lungs and similar systemic levels after pulmonary delivery of one-half of the oral nominal dose. This is expected to result in a more effective treatment of pulmonary TB, as shown previously in published efficacy studies.

Dry powder PA-824 aerosols for treatment of tuberculosis in guinea pigs.

Novel treatments for multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB), or latent TB are needed urgently. Recently, we reported the formulation and characterization of the nitroimidazo-oxazine PA-824 for efficient aerosol delivery as dry powder porous particles and the subsequent disposition in guinea pigs after pulmonary administration. The objective of the present study was to evaluate the effects of these PA-824 therapeutic aerosols on the extent of TB infection in the low-inoculum aerosol infection guinea pig model. Four weeks after infection by the pulmonary route, animals received daily treatment for 4 weeks of either a high or a low dose of PA-824 dry powder aerosol. Animals received PA-824 cyclodextrin/lecithin suspensions orally as positive controls, and those receiving placebo particles or no treatment were negative controls. The lungs and spleens of animals receiving the high dose of inhaled PA-824 particles exhibited a lower degree of inflammation (indicated by wet tissue weights), bacterial burden, and tissue damage (indicated by histopathology) than those of untreated or placebo animals. Treatment with oral PA-824 cyclodextrin/lecithin suspension resulted in a more significant reduction in the bacterial burden of lungs and spleen, consistent with a dose that was larger than inhaled doses (eight times the inhaled low dose and four times the inhaled high dose). However, histopathological analysis revealed that the extent of tissue damage was comparable in groups receiving the oral or either inhaled dose. The present studies indicate the potential use of PA-824 dry powder aerosols in the treatment of TB.

Formulation and pharmacokinetics of self-assembled rifampicin nanoparticle systems for pulmonary delivery.

PURPOSE: To formulate rifampicin, an anti-tuberculosis antibiotic, for aerosol delivery in a dry powder 'porous nanoparticle-aggregate particle' (PNAP) form suited for shelf stability, effective dispersibility and extended release with local lung and systemic drug delivery. METHODS: Rifampicin was encapsulated in PLGA nanoparticles by a solvent evaporation process, spray dried into PNAPs containing varying amounts of nanoparticles, and characterized for physical and aerosol properties. Pharmacokinetic studies were performed with formulations delivered to guinea pigs by intratracheal insufflation and compared to oral and intravenous delivery of rifampicin. RESULTS: The PNAP formulations possessed properties suitable for efficient deposition in the lungs. In vitro release showed an initial burst of rifampicin, with the remainder available for release beyond eight hours. PNAPs delivered to guinea pigs by insufflation achieved systemic levels of rifampicin detected for six to eight hours. Moreover, rifampicin concentrations remained detectable in lung tissue and cells up to and beyond eight hours. Conversely, after pulmonary delivery of an aerosol without nanoparticles, rifampicin could not be detected in the lungs at eight hours. CONCLUSIONS: Our results indicate that rifampicin can be formulated into an aggregated nanoparticle form that, once delivered to animals, achieves systemic exposure and extends levels of drug in the lungs.

Dry powder nitroimidazopyran antibiotic PA-824 aerosol for inhalation.

We formulated PA-824, a nitroimidazopyran with promise for the treatment of tuberculosis, for efficient aerosol delivery to the lungs in a dry powder porous particle form. The objectives of this study were to prepare and characterize a particulate form of PA-824, assess the stability of this aerosol formulation under different environmental conditions, and determine the pharmacokinetic parameters for the powder after pulmonary administration. The drug was spray dried into porous particles containing a high drug load and possessing desirable aerosol properties for efficient deposition in the lungs. The physical, aerodynamic, and chemical properties of the dry powder were stable at room temperature for 6 months and under refrigerated conditions for at least 1 year. Pharmacokinetic parameters were determined in guinea pigs after the pulmonary administration of the PA-824 powder formulation at three doses (20, 40, and 60 mg/kg of body weight) and compared to those after the intravenous (20 mg/kg) and oral (40 mg/kg) delivery of the drug. Oral and inhaled delivery of PA-824 achieved equivalent systemic delivery at the same body dose within the first 12 h of dosing. However, animals dosed by the pulmonary route showed drug loads that remained locally in the lungs for 32 h postexposure, whereas those given the drug orally cleared the drug more rapidly. Therefore, we expect from these pharmacokinetic data that pulmonary delivery may achieve the same efficacy as oral delivery at the same body dose, with a potential improvement in efficacy related to pulmonary infection. This may translate into the ability to deliver lower body doses of this drug for the treatment of tuberculosis by aerosol.

Immunization by a bacterial aerosol.

By manufacturing a single-particle system in two particulate forms (i.e., micrometer size and nanometer size), we have designed a bacterial vaccine form that exhibits improved efficacy of immunization. Microstructural properties are adapted to alter dispersive and aerosol properties independently. Dried "nanomicroparticle" vaccines possess two axes of nanoscale dimensions and a third axis of micrometer dimension; the last one permits effective micrometer-like physical dispersion, and the former provides alignment of the principal nanodimension particle axes with the direction of airflow. Particles formed with this combination of nano- and micrometer-scale dimensions possess a greater ability to aerosolize than particles of standard spherical isotropic shape and of similar geometric diameter. Here, we demonstrate effective application of this biomaterial by using the live attenuated tuberculosis vaccine bacille Calmette-Guérin (BCG). Prepared as a spray-dried nanomicroparticle aerosol, BCG vaccine exhibited high-efficiency delivery and peripheral lung targeting capacity from a low-cost and technically simple delivery system. Aerosol delivery of the BCG nanomicroparticle to normal guinea pigs subsequently challenged with virulent Mycobacterium tuberculosis significantly reduced bacterial burden and lung pathology both relative to untreated animals and to control animals immunized with the standard parenteral BCG.

Preparation and in vivo evaluation of a dry powder for inhalation of capreomycin.

PURPOSE: To develop an aerosol system for efficient local lung delivery of a tuberculostatic drug. METHODS: The antibiotic, capreomycin sulfate, was spray dried to form a dry powder aerosol. The chemical content and physical properties of resulting particles were assessed under various storage conditions. Plasma concentrations of capreomycin after insufflation into guinea pigs were evaluated at three doses, and compared to IV and IM administration of a capreomycin solution. RESULTS: Dry powder aerosols containing capreomycin were formulated to enable efficient delivery of large drug masses to the lungs of guinea pigs. Aerosols loaded with 73% CS were shown to possess good aerosolization properties and physical-chemical stability for up to 3 months at room temperature. Upon insufflation into guinea pigs, the amount of CS reaching the bloodstream was significantly lower compared to IV or IM administration, but resulted in a significantly longer drug half-life. CONCLUSIONS: The results indicate that large doses of capreomycin in dry powder form can be efficiently delivered to the lungs of guinea pigs, which may result in high local drug exposure but significantly reduced systemic exposure as suggested by plasma concentrations in the present studies. These systems have considerable potential to provide more effective therapy for MDR-TB.