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Mucoadhesive Targeted Pulmonary Delivery of Nanoparticulated Dry Powder Insufflators - A Revolt in TB Therapy
Mucoadhesive Targeted Pulmonary Delivery of Nanoparticulated Dry Powder Insufflators - A Revolt in TB Therapy
, 7(1), 87-94
ISSN: 0975-7538
Review Article
www.ijrps.pharmascope.org
ABSTRACT
The emergence of multidrug-resistant TB (MDR-TB) against rst-line drugs and extensively drug resistant TB (XDR-
TB) due to misuse of second-line anti tubercular drugs (ATDs) is a further concern. Recommended treatment in-
volves long term and multiple drug therapy with severe side effects. Due to this concern nanoparticle-based sys-
tems have significant potential for treatment and prevention of tuberculosis (TB) to overcome the need to admin-
ister ATDs at high and frequent doses, would assist in improving patient compliance and circumvent hepatotoxic i-
ty and/or nephrotoxicity/ocular toxicity/ototoxicity associated with the prevalent rst-line chemotherapy.
Nanostructured delivery systems constitute a wide range of systems varying from liposomes, micelles, micro - and
nanoemulsions, to polymeric nanoparticles (PNPs ) and solid lipid nanoparticles (SLNs). Pulmonary administration
of inhaled nanoparticles in the form of dry powder inhalers offer particular advantages for pulmonary administra-
tion of anti tubercular drugs (ATDs). Present review comprehensively about different approaches of nanobased
drug delivery, devises and techniques for pulmonary delivery of nanoparticle encapsulated ATD.
Keywords: Anti tubercular drugs (ATDs); Nanoparticle-based systems; Dry powder inhalers.
INTRODUCTION cobacteria for its survival in alveoli i.e., macrophages
(iii) alleviating drug toxicity and (iv) enhanced patient
Universally Tuberculosis (TB) exists as a foremost infec-
compliance. The current article embarks on the devel-
tious cause of death. The bacteria underlying for this
opment achieved in inhalation therapy of ATDs that are
disease is Mycobacterium tuberculosis that can gener-
designed in to appropriate delivery systems (Rajesh
ate either a quiet, latent infection or a growing, vigor-
Pandey and G. K. Khuller, 2005).
ous disease. If not or inappropriately cured, it causes
continuous tissue degeneration and, ultimately, de- A novel device with simplified and innovative technol-
mise (WHO, 1998, C.D. Mitnick et al., 2008). ogy that comprehends the scientific growth at a
nanolevel is nanotechnology. This aids in curing alarm-
An effectual diagnosis and treatment exist as oral anti
ing diseases like tuberculosis with nanospheres em-
tubercular drugs (ATDs), but is nevertheless allied with
bedded micro particles targeted to pulmonary mucosa
innumerable substantial disadvantages. Among all the
as dry powder insufflators as an extended release drug
types of TB pulmonary tuberculosis is the major one
delivery of ATDs (T.S. Hauck., et al 2010).
and large dosage is needed to be given as the amount
of drug reached at site of target is less to that of total Tuberculosis
dose administered. Yet this small amount of drug is
Transmission
eliminated within a couple of hours hence amplifying
the requisite to prescribe multiple ATDs daily, the Nevertheless TB is treatable. Universally millions of
treatment that is difficult to stick on by greater part of citizens have been infected and killed in a year (WHO,
TB patients. Obviously, systems that deliver ATD to 1998, Iseman MD 2000, McCray E et al., 1997). The
pulmonary route can evade daily dosage and in addi- influence of TB on world healthiness is major; in 2006,
tion will aid in: (i) straight drug release to the infected billions of death cases were reported due to TB (Da-
tissue/organ; (ii) targeting the safest host cells of my- vidsons Principles and Practice of Medicine, 2010,
886).
* Corres ponding Author
Clinical features
Ema i l: srivys hu.pharma@gmail.com
Conta ct: +91-9705070901 The significant route that the tubercle bacilli desires for
Received on: 09-01-2016 its infection is respiratory tract. Besides the periodic
Revi sed on: 10-02-2016 pulmonary or trache bronchial lymph node cal cifica-
Accepted on: 14-02-2016
tion, lesions developed in lungs are generally get rid off
ing of ATDs. There was a marked raise in buildup of without inclusion of lipids. Niosomes are liposome like
ATDs bio distribution from 5.1% for conventional lipo- vesicles with charged phospholipids (stearyl amine and
somes to 31% for PEG formulated liposomes after 30 diacetylphosphate) and nonionic surfactants (mono-
min of IV administration in normal and TB induced alkly or dialkyl polyoxyethylene ether) ensue after cho-
mice (Deol P,Khuller GK, 1997). lesterol hydration (M. Smola et al., 2008). Stability,
easy scaling up and less cost productivity are the ad-
Solid nanoparticles (SLN)
vantages of niosomes over liposomes. They can host
Solid nanoparticles are lipid based aqueous nanocrys- lipophobic drugs within their core and have propensity
talline suspensions that are solids at normal tempera- to entrap hydrophobic drugs in lipophilic regions. A
ture and are novel carriers next to l iposome, lipid range of surfactants (viz. Spans 20, 40, 60, 80, 85) were
emulsion, and polymeric nanoparticle (PNP) (V. Jenning used with various sized niosomes for effective delivery
et al., 2002). They have better acceptability, scaling-up of loaded rifampicin to the lungs (D.A. Mitchison et al.,
possibility, lipophilic or lipophobic drug integration 2010, G. Scheuch et al., 2006).
capability, and an enhanced stability of encapsulated
Polymeric nanoparticles (PNP)
drugs. Hence solid nanoparticles are unique in the im-
pression that correlates the qualities of nanoparticles PNP are specific target drug delivering carriers with
by eliminating their few difficulties (R.H. Muller et al., good solubility and s tability (P.K. Gaur et al., 2010).
2004). Large scale manufacturing with feasibility pre- Potentiality of lipophobic and lipophilic drug loading,
venting organic solvents and composition are the im- easiness of administration through different routes
pressive benefits of solid nanoparticles (P.M. Bummer popularize as one of the most valued methods for drug
2004). entrapment (L. Brannon-Peppas, 1995).They form two
types of systems based on their productive technique
Micelles
such as nanocapsules and nanospheres. In nanocap-
Micelles are liquid colloidal submicroscopic aggregates sules the drug is dissolved in aqueous or non-aqueous
of surfactants of 20-80nm in size (Jiang W et al., 2007). solvents and is encased under a polymeric membrane.
Its layer is formed by the interaction of lipophobic sec- Perversely, nanospheres are with homogeneous dis-
tions with the aqueous medium stabilizing the aggre- persion of active molecules in solid matrices of variable
gate by facilitating the solubilization of amphiphile in porosity throughout the particle. Biomaterials of broad
water. Alternatively, lipophilic sections create the in- range been known for PNPs were phased out from the
ternal micellar layer that allows the solubilization of system by opsonization and phagocytosis (D.E. Owens
inadequately aqueous soluble drugs (J.R.Koup et al., III and N.A. Peppas, 2006). In an effort to mask host
1986) protecting these by chemical and biological de- immune system recognition and to increase circulatory
struction. In order to enhance the enclosed drug incur- time, the external surface is modified with hydrophilic
sion in to mycobacterium and its anti tubercular activi- chains (PEG). It is one of the most considerably investi-
ty, micelles have been significantly lipophilized .The gated approaches with respect to anti tubercular drug
major and important micellar forming materi als in- delivery systems.
clude poly ethylene-polypropylene oxide (PEO-PPO)
Delivery approaches with nanoparticles
block copolymers (linear poloxamers and branched
polaxamines), (D.A. Chiappetta et al., 2007). Intra and extra pulmonary diseases are treated by
pulmonary route of drug delivery system as the lungs
Dendrimers
have distinctive features like large surface area, thin
Dendrimers are 3D configured nanoparticles with tree epithelial layer, high vascularization and escape of first
designed assortment of process, low molecular weight pass metabolism (Al-Hallak KM et al., 2010).
and multi dispersible and extremely flexible capacity.
Pulmonary delivery of nanoparticle encapsulated ATD
Previous decades have sprouted this concept by the
earliest synthesis of dendrimers namely polyamidoam- Nanoparticles posses the capability to attain a maxi-
ines (PAMAM), (D.A. Tomalia et al., 2005). With the mum drug filling, reduce the usage of polymers, barrier
advantage of dendrimeric core, intrication and conju- cross permeability and better therapeutic efficacy. Al-
gation on their texture they were efficient of drug en- veoli targeted net drug delivery is easily approachable
capsulation (A.D. Emanuele et al., 2005). Encapsulation by their mucosal adherence by inhalation (Jacobs, C. &
of drug chiefly relies on lipophilic interactions and hy- Muller, R. H, 2002). PLGA is the most possibly investi-
drogen bonding providing physical binding of the drug gated nanoparticulate drug transporter (Bala, I., Hari-
to the core. A mannosylated fifth generation (5G) PPI haran, S. & Kumar, M. N. V. R, 2004). PLGA are exten-
dendrimer is discovered for transport of RIF to macro- sively used for the preparation of self reinforced prep-
phages (Kumar PV et al., 2006). arations and ATD carrier due to their biodegradability
and biocompatibility (Anderson J.M. and Shive M.S,
Niosomes
1997- Ain Q et al., 2003). In a murine TB Model the
Equimanner to that of liposomes, niosomes were pri- dose frequency was reduced for PLGA nanoparticle
marily made up of non-ionic surfactant plus with or (PLGA-NP) encapsulated first line TB drugs (Pandey R.
et al., 2003).A commonly occuirng glycoprotein called solution is provided at ambient temperature and in-
wheat germ agglutinin (lectin) was combined with for- jected to the nozzle in which it is atomized by the noz-
mulation for additional refinement. Similar to drug zle gas. Then this solution is dry up by pre-heated dry-
bounded liposomes, lectin based PLG nanoparticles ing gas in a unique compartment to eliminate liquid
were also investigated for their chemotherapeutic po- humidity from the system creating dry particles of 2
tential due to widely distribution of lectin receptors in m size. Large scale production of such particles can be
lungs (Abu-Dahab, R, 2001, Vyas, S. P. et al., 2004). easily achieved by this method due to its fine ma n-
Natural polymer based antitubercular drug therapy agement on particle formation. As this method is avoid
was explored with chitosan loaded DNA delivery to of mechanical high energy input it is also appropriate
alveoli encoding TB bacilli T cell epitopes (Bivas-Benita, for heat sensitive materials like proteins and peptides
M et al., 2004). (Gilani K et al., 2005, Rogers T et al., 2001).
Devices for drug delivery Spray freeze drying method
Nebulizers or pressurized metered dose inhalers This method is a combination of spray drying and
(pMDIs) and dry powder inhalers are the three tech- freeze drying development steps spraying drug solu-
niques to inhaled drug delivery each with their exclu- tion in to a freezing medium (liquid nitrogen) accom-
sive potency and properties (Chow AH et al., 2007). panied with lyophilization (Maa YF et al., 2000) making
Different types of inhalable nanoparticles can be deliv- light, fine and porous particles having enhanced aero-
ered by nebulizers but the disadvantage of compressed sol efficiency with 100% productivity (Yu Z et al., 2004).
air source necessity restricted their use to hospitals Heat sensitive substances like insulin (Kuo JH et al.,
and ambulatory care settings (Dailey LA et al., 2003- 2004) and plasma DNA, could even get developed in
Ostrander KD et al., 1999). dry powder inhalation designs. Nevertheless it is a
costly process constrained for exclusively costly drug
Though pMDI is the best preferred inhaled drug-
(Chattopadhyay P et al., 2007).
delivery system, certain down sides made an obstacle
to formulate nanoparticles and less ideal for delivery of Supercritical fluid technology
inhalable nanoparticles. These include instability due
This process is designed as the controlled crystalliza-
to sedimentation, crystal growth and polymorphism
tion of drug from dispersion in carbon dioxide (super-
and chances of accumulation in oropharynx due to high
critical fluid) for generation of microparticles, nanopar-
dose velocity (Rance RW, 1974, Timsina MP et al.,
ticles, liposomes and i nclusion complexes. This tech-
1994).
nique is employed concerning drug delivery to lower
Hence to conquer the down sides of pMDI dry powder respiratory tract including proteins and peptides and
inhalers (DPIs) were presented because of their high for the enhancement of formulation characteristics of
formulation stability alveolar deposit (Crompton GK, specific drugs (Rehman M et al., 2004, Rasenack N et
1991- Vidgren MT, 1988). Designing of significant po- al., 2003).
rous particles with little density and huge geometrical
Solvent precipitation method
dimension contributed a stage ahead in the pulmonary
delivery of DPIs. Their physical characteristics equipped This particular technique entails sonocrystallization
them to avoid natural clearance from lungs and allow plus micro precipitation by contradicting liquid jets.
alveolar drug release even (Edwards DA, 1997). Diseas- Crystallized drug molecules at narrow size distribution
es like TB, cystic fibrosis and lung cancer were treated might be developed by direct controlled crystallization.
well due to combined benefits of nanoscale formula- Accelerated precipitation through aqueous solutions
tion and localized delivery of nanoparticles from DPIs using anti solvents will generate inhalable particles. In
(Sung JC et al., 2007- Roa WH et al., 2011). recent times, ultrasonic radiation was practiced to reg-
ulate the precipitation. By using sonocrystallization
Methodologies for producing particulate matter for
technique different drugs were designed for asthma
lung delivery
disease (Gratton SE et al., 2007).
A nanojet milling instrument is employed for producing
Double emulsion/solvent evaporation technique
nanoparticles implied for pul monary drug delivery us-
ing nitrogen gas. Few techniques of such were pointed This technique includes oil in water emulsion prepara-
out shortly. tion with following elimination of the oil phase via va-
porization. The organic solvent diffuses out from poly-
mer phase to aqueous phase, made evaporated devel-
Spray drying technique oping drug-loaded poymeric nanoparticles.An exten-
sive research on biodegradable polymers as carriers for
Spray drying is an advanced technique for producing
pulmonary solid nanoparticulate drug delivery was
solid state respirable colloidal particles (Mosen K et al.,
carried out by the help of this method.
2004, Duddu SP et al., 2002). It was discovered around
three decades past for creating fine particles for lower Particle replication in non-wetting templates (PRINT)
respiratory tract drug delivery. In this strategy the drug
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