Antitubercular inhaled therapy
Abstract
Pulmonary tuberculosis remains the commonest form of this diseaseand
the development of methods for delivering antituberculardrugs
directly to the lungs via the respiratory route is a rational
therapeutic goal. The obvious advantages of inhaled therapyinclude
direct drug delivery to the diseased organ, targetingto alveolar
macrophages harbouring the mycobacteria, reducedrisk of systemic
toxicity and improved patient compliance. Researchefforts have
demonstrated the feasibility of various drug deliverysystems
employing liposomes, polymeric microparticles and nanoparticlesto
serve as inhalable antitubercular drug carriers.
In particular,
nanoparticles have emerged as a remarkably useful tool for this
purpose. While some researchers have preferred dry powder inhalers,
others have emphasized nebulization. Beginning with the respiratory
delivery of a single antitubercular drug, it is now possibleto
deliver multiple drugs simultaneously with a greater therapeutic
efficacy. More experience and expertise have been observed with
synthetic polymers, nevertheless, the possibility of using natural
polymers for inhaled therapy has yet to be explored. Severalkey
issues such as patient education, cost of treatment, stabilityand
large scale production of drug formulations, etc. need tobe
addressed before antitubercular inhaled therapy finds itsway from
theory to clinical reality.
Keywords: tuberculosis , liposomes, polymers , nebulization , drug delivery
Introduction
A Greek pharmacist, Pedanus Discorides, introduced the conceptof
inhaled fumigation during the first century. Antiseptic aerosol
therapy, e.g. boiling tar vapours, became a popular antitubercular
medication in the middle of the 20th century, although it hardlyhad
any therapeutic value.
Since then, antitubercular inhaledtherapy has come a long way to a
stage of experimental realitywith potential clinical applications.
The importance of thesubject stems from the fact that tuberculosis
(TB) continuesto be a leading killer disease causing 3 million
deaths annually
and has emerged as an occupational disease in the health care
system.
Oral therapy using the currently employed antituberculardrugs (ATDs)
is very effective, but is still associated witha number of
significant drawbacks. More than 80% of TB casesare of pulmonary TB
alone and high drug doses are required tobe administered because
only a small fraction of the total dosereaches the lungs after oral
administration. Even this smallfraction is cleared in a matter of a
few hours thus explainingthe necessity to administer multiple ATDs
on a regular basis,a regimen which the majority of TB patients find
difficult toadhere to. Clearly, ATD delivery systems which can be
administeredvia the pulmonary route and can avoid the daily dosing,
wouldbe a vast improvement because they would help in: (i) directdrug delivery to the diseased organ; (ii) targeting to alveolar
macrophages which are used by the mycobacteria as a safe sitefor
their prolonged survival; (iii) reduced systemic toxicityof the
drugs; and (iv) improved patient compliance. The presentreview
highlights the progress made in antitubercular inhaledtherapy
especially with the ATDs formulated into suitable deliverysystems.
Modes of respiratory drug delivery
A convenient way of delivering drugs to the lungs is the aerosolizationof the drugs as fine powders with the aid of dry powder inhalers(DPIs). Alternatively, the drug may be first solubilized/suspendedin an aqueous medium and subsequently aerosolized (liquid aerosolizationor nebulization) through a nebulizer. A nebulizer requires a
dispersing force (either a jet of gas or ultrasonic waves) for
aerosolization.
A drug may also be delivered to the lungsdirectly, i.e. without
prior aerosolization, using a devicecalled an insufflator. Compared
with a nebulizer, a DPI is moreefficient in terms of drug delivery
and less time consuming.
However, nebulizers can be designed to make the best use ofa
patient's breathing pattern, the so-called �breath-assisted
nebulizers�.
Further, with jet nebulizers, adjustmentsin drug dosing are easier
to achieve.
Although nebulizationis the most common method of aerosol delivery
of antibiotics,other factors such as nebulizer technology, breath
holding patterns,degree of airway disease, pulmonary function as
well as theaerodynamics of the pharmaceutical aerosol, are all known
toaffect the efficiency of drug delivery.,
An important aerodynamicparameter is the mass median aerodynamic
diameter (MMAD), thediameter above and below which 50% of the mass
of aerosolizedparticles are contained. The smaller the diameter, the
betterare the chances that particle deposition would occur in thedeeper parts of the lungs, i.e. the alveoli. The optimum range
is defined as 0.5�5.0 �m (the respirable range)because particles <
0.5 �m are usually exhaled whereasparticles > 5.0 �m are impacted in
the oropharynx.
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