Pulmonary
delivery of nanoparticle-encapsulated ATDs
Nanoparticles range in size from 10 to 1000 nm whereas microparticles
lie in the size range of 1 and 1000 �m.
The differencebetween microparticles and nanoparticles lies not
merely inthe size, but also in the ability of nanoparticles to
achievea high drug loading, minimize the consumption of polymers,
crosspermeability barriers and elicit a better therapeutic response.,
Furthermore, inhalable nanoparticles stand better chancesof
mucosal adherence, particle(s) delivery and hence net drugdelivery
to the lungs.
For the reasons discussed in thecase of microparticles, PLG is the
most intensively studiednanoparticulate drug carrier.
We prepared PLG-nanoparticlesaccording to the double
emulsion/solvent evaporation technique,
co-encapsulating rifampicin, isoniazid and pyrazinamide. The
particle size ranged from 186 to 290 nm. Upon aerosolization,the
MMAD (as determined on a 7-stage Andersen Cascade Impactor)was found
to be 1.88 �m and thus suitable for deep lungdelivery. It is known
that high surface hydrophobicity can resultin particle aggregation
during nebulization especially on ajet nebulizer. Because the
PLG-nanoparticles were stabilizedby polyvinyl alcohol thereby
imparting hydrophilicity to theformulation, particle aggregation was
not a problem.
A single nebulization of the formulation to guinea pigs wasable
to maintain a therapeutic drug concentration in the plasmafor 6�8
days and in the lungs for 9�11 days. Therewas a striking improvement
in the half-life, mean residencetime and relative/absolute
bioavailability of encapsulated drugscompared with free drugs. It
may be asked that if one is aimingat pulmonary deposition of ATDs,
how the improvement in systemicbioavailability would be advantageous
following inhaled therapy?The argument was that the enhanced
bioavailability would leadto more of the drugs reaching the lungs by
way of the circulation,i.e. the systemic spillover could not be
considered as a drugwastage.
Repeated administration of the formulation failedto elicit
hepatotoxicity as assessed on a biochemical basis.In M.
tuberculosis H37Rv infected guinea pigs, five nebulizeddoses of the formulation spaced 10 days apart, resulted in undetectablecfu in the lungs replacing 46 conventional doses. This was the
first report of PLG-nanoparticles as an inhalable ATD carrier.
The advantage of the system over inhalable microspheres was
clear cut; firstly, it was possible to co-administer multipleATDs
encapsulated in nanoparticles and secondly, a better therapeutic
response was elicited in the case of nanoparticles.
The formulation was further refined and improved by couplingit to
lectin (wheat germ agglutinin, a commonly occurring plant
glycoprotein). With the knowledge that lectin receptors arewidely
distributed in the respiratory tract,
it was worthwhileto evaluate the chemotherapeutic potential of
lectin-functionalizedPLG-nanoparticles,
a somewhat similar approach to ligand-appendedliposomes.
Upon nebulization to guinea pigs, therapeuticdrug concentrations
were maintained in the plasma/organs for6�15 days. Most of the
pharmacokinetic parameters wereupgraded compared with uncoated
PLG-nanoparticles. Most importantly,when nebulized to TB-infected
guinea pigs every fortnight, threedoses of the formulation produced
undetectable cfu in the lungsas well as spleens.
The series of experiments proved that46 conventional doses could be
reduced to five nebulized dosesof PLG-nanoparticles and further to
just three doses with lectin-PLG-nanoparticles.
A new concept in nanotechnology is that of solid lipid nanoparticles(SLNs), i.e. lipid nanocrystals in water possessing a solid
core into which drugs are incorporated. The SLNs combine thevirtues
of more traditional drug carriers such as liposomesor polymeric
nanoparticles while eliminating some of their disadvantages,e.g. the
issues of burst release and long-term stability inthe case of
liposomes as well as the problems of residual solventsand bulk
production in the case of polymeric nanoparticles.,
Furthermore, although PLG is completely biodegradable and
biocompatible, the degradation rate is slow and repeated administrationof the formulation carries a likelihood of accumulation of the
polymer or its degradation products in the respiratory tract.The
polymer is known to elicit a mild inflammatory responselasting 2�3
weeks,
however, the implications for inhaledtherapy and possible influence
on lung function have yet tobe evaluated.
Although the pulmonary delivery of SLNs is in its infancy,
our experiments with inhalable ATD-loaded SLNs have produced
encouraging results in a guinea pig TB model.
Seven weeklyinhaled doses of the formulation resulted in
undetectable bacilliin the lungs of M. tuberculosis infected
guinea pigs. Anotheraspect yet to be explored is that of natural
polymer (e.g. alginate,chitosan) based ATD delivery systems. A
recent report describingthe pulmonary delivery of chitosan-loaded
DNA encoding M. tuberculosisT cell epitopes
might well serve as the starting point inthis area. Work is in
progress in our laboratory to encapsulateATDs in chitosan-stabilized
alginate nanoparticles for pulmonarydelivery.
Future perspectives
Based on the experimental data, it is clear that respiratorydrug
delivery systems certainly have the potential for antitubercular
inhaled therapy (). The requirements for fewer drug dosesas well as a low dosing
frequency are definite advantages. However,there are some key issues
that still need to be addressed. Thepossibility of variable
deposition of an inhaled formulationin the lungs needs to be
considered and is a matter of concernbecause it could result in
suboptimal drug concentrations incertain lung regions. If this does
occur to a significant extentthen treatment response could be
impaired. However, deliveryvehicles with good systemic
bioavailability could overcome thispotential problem. Indeed, whilst
inhaled therapy would probablybe most beneficial to patients with
pulmonary TB, formulationswith a good systemic bioavailability of
ATDs (e.g. nanoparticles)might also be of benefit for patients with
extra-pulmonary TB.Concerns regarding toxicity consequent on
systemic absorptionmay be offset by the fact that these formulations
are intendedfor intermittent therapy, with the net drug dose
administeredactually being reduced compared with oral therapy.
Patients suffering from endobronchial TB may be particularly
suitable for inhaled therapy in future.
MDR-TB not respondingto conventional treatment is another scenario
where inhaledtherapy may come to have a significant future role. For
patientswho do not fit into the categories above, the future role ofinhaled therapy is less clear. Potentially, a few inhaled doses
at the start of treatment for uncomplicated pulmonary TB couldhelp
to significantly reduce the pulmonary bacterial burdenand hence
improve on the efficacy of conventional oral therapy.However,
inhaled therapy will need to fit in with existing NationalTB
programmes, and with initiatives such as the Directly Observed
Treatment Shortcourse (DOTS) programme. Increased costs, together
with the need for strict control of infection precautions toprevent
device-associated cross-infections and/or risk to healthpersonnel,
may limit the extent to which such technologies cometo be widely
available, particularly in developing countries.The large-scale
production of stable drug formulations at anaffordable cost will be
the fundamental and decisive obstaclewhich will need to be overcome
before contemplating human trials.However, the rationale behind
antitubercular inhaled therapyis persuasive. Hopefully, current and
future research effortswill eventually result in this concept moving
from the benchto the bedside.
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