Biomedical Engineering Reference
In-Depth Information
Biodistribution and Therapeutic Efficacy of Non Liposomal
Inhaled/Instilled Nanoparticles
Between 2001 and 2009, the performance of RIF alone or together with other anti-
biotics, loaded in microspheres and PLGA nanoparticles and administered by nebu-
lisation or instillation, was investigated.
For instance, RIF was loaded in 2.76-3.45 mm PLGA microspheres and insuf-
flated or nebulizated directly to the lungs at 1-1.7 mg/kg in guinea pig infected with
aerosolized low dose (2 × 10
5
CFU/ml) of virulent H37Rv strain of
M. tuberculosis.
There was a dose-effect relationship between insufflated RIF- loaded PLGA micro-
spheres and burden of bacteria in lungs. In addition, guinea pigs treated with
RIF- loaded PLGA microspheres had a significantly smaller number of viable bac-
teria, reduced inflammation and lung damage than lactose, saline control, empty
PLGA microspheres or free RIF treated animals (Suárez et al.
2001
). A further
assay employed RIF, INH and PYZ loaded in mass median aerodynamic diameter
of 1.88 ± 0.11 mm PLGA microspheres, and administered by nebulization at RIF
12 mg/kg, INH 10 mg/kg and PYZ 25 mg/kg bw to guinea pigs. A single nebuliza-
tion resulted in sustained therapeutic drug levels in plasma for 6-8 days and in the
lungs for up to 11 days (Pandey et al.
2003b
). The elimination half-life and mean
residence time of the drugs were significantly prolonged compared to oral free
drugs, resulting in an enhanced relative bioavailability for encapsulated drugs
(12.7-, 32.8- and 14.7-fold for RIF, INH and PYZ, respectively). The absolute bio-
availability (compared to i.v. administration) was also increased by 6.5-, 19.1- and
13.4-fold for RIF, INH and PYZ, respectively. On nebulization of microspheres
containing drugs to
M. tuberculosis
infected guinea pigs at every tenth day, no
tubercle bacilli could be detected in the lung after five doses of treatment whereas
46 daily doses of orally administered drug were required to obtain an equivalent
therapeutic benefit. Hence, these PLGA microspheres could be used for intermitent
treatments.
In another approach, RIF was loaded in 3.5 mm PLGA microspheres that were
i.t. administered to rats i.t. infected with 2 × 10
3
CFU with of
M. tuberculosis
Kurono, at 0.4 and 0.04 mg/kg bw (Yoshida et al.
2006
). These RIF- loaded PLGA
microspheres were superior to free RIF for killing of intracellular bacilli and pre-
venting granuloma formation in some lobes.
Finally, RIF loaded in 213 nm PLGA nanoparticles were incorporated into man-
nitol microspheres in one single step by means of a four-fluid nozzle spray drier.
Encapsulation of the nanoparticles in mannitol improved the
in vivo
uptake of the
drug by alveolar macrophages in rat lungs as compared to RIF-loaded in PLGA
nanoparticles and mannitol microparticles alone (Ohashi et al.
2009
).
Microparticles other than PLGA were also employed in pulmonary delivery,
with simmilar successs. For instance, RIF and INH were loaded in ~5 mm PLA
microparticles by spray-drying. Microparticles showed satisfactory aerosol charac-
teristics (median mass aerodynamic diameter 3.57 mm; geometric standard devia-
tion 1.41 mm; fine particle fraction
< 4.6mm
= 78.91 ± 8.4%) and were administered to
mice using an in-house inhalation apparatus or by i.t. instillation. About 10 mg
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