Pulmonary Drug Delivery
Pulmonary Drug Delivery
Pulmonary Drug Delivery
1
Department of Pharmaceutics, Institute of Pharmaceutical Education, Boradi,
Shirpur, 425 428 (M.S.), India,
2
College of Pharmacy, I.P.S. Academy, Rajendra Nagar, Indore, 452 012,(M.P.),India.
Abstract: Pulmonary drug delivery is primarily use to treat conditions of the airways, delivering locally acting
drugs directly to their site of action. These routes of drug delivery may give the advantages like small amount of
drug, less adverse reaction and rapid onset of action. The human respiratory system is complicated organ system
these system consist of two reagions conducting airways and respiratory region. The airway further divided in to
many folds such as nasal cavity, nasopharynx, oropharynx, larynx, trachea, bronchi, and bronchioles. The
respiratory region consists of respiratory, bronchioles, alveolar ducts and alveolar sac. Pulmonary drug delivery
may show that many molecule are absorbed through the deep lung in ton the bloodstream naturally with high
bioavailability and without the need for enhancer used by other noninvasive route. In these inhalation therapy most
common device use such as nebulizer which consist of two types such as Jet nebulizer and Ultrasonic nebulizer,
Metered dose inhaler (MDI), and Dry powder inhaler(DPI). Pulmonary drug delivery is used for management of
COPD and Asthma only but due to advancement in application nowadays Pulmonary drug delivery is useful to
treat Diabetes, angina pectoris, cancer, bone disorders, tuberculosis, migraine acute lung injury and others. We also
describe here the various evaluation parameter for pulmonary drug devices. In these review we study the
pulmonary disease, different devices use on it, and there application with its evaluation parameter.
Key Words:- Pulmonary, lungs, Inhalers, asthma, COPD, Apllications.
3) Drug absorption may be limited by the physical that patients learn how to organize exhalation and
barrier of the mucus layer. inhalation with actuation of the device. By using the
4) Various factors affect the reproducibility on drug spacer device it may solve the problem moderately
delivery on the lungs, including physiological and the bulky size of the device can be prevention for
pharmaceutical barrier. patients who have need of use of MDIs outside their
5) The lungs are not only accessible surface for drug homes. In near the beginning 1990, attempts were
delivery complex but also delivery devices are actively made to reformulate MDIs as a result of the
required to target drug delivery. mandatory ban on the use of propellant
chlorofluorocarbons (CFCs), which have been
RECENT TECHNOLOGIES OF PULMONARY concerned in the depletion of the Earths ozone layer.
DRUG DELIVERY Optional propellants, such as hydrofluoroalkane 134a
Nebulizer: Nowadays the many physicians are (HFA-134), have be extensively investigated for their
mostly use nebulizer for the treatment of acute potentials to change CFCs since 1990.
asthma in an emergency care unit or for treating
patients with severe asthma at home. In jet
nebulizers, an aerosol is prepared by a high velocity
air stream from a pressurized source directed against
a thin layer of liquid solution. Ultrasonic nebulizers
include the vibration of a piezoelectric crystal
aerosolizing the solution. The nebulizer can transport
more drugs to the lungs than MDI or DPI, the most
common disadvantage of nebulizer are lack of
possibility, higher costs of drug delivery as a result of
the larger need for assistance from healthcare
professionals, and the need for higher drug doses to
achieve a therapeutic result 8.
Metered Dose Inhaler (MDI): These are the most Fig 4: Metered-dose inhalers
common device for administration of aerosolized
drugs. In this technique, a medication is mixed in a
canister with a propellant, and the preformed mixture
is expelled in exact measured amounts upon
actuation of the device. Correct use of MDIs requires
Karhale Ashish A.et al /Int.J.PharmTech Res.2012,4(1) 299
Powder Inhaler (DPI): Dry powder systems use drug and potential for condensed dose through enhanced
single or its blends with a suitable carrier, mainly as dispersibility.
lactose, for delivery to the lungs. The three main
factors Drug, Carrier, and device may affecting the act
EVALUATION OF PULMONARY
of pulmonary delivery of drugs. Unlike MDIs, delivery
of medication with a DPI require minimum patient DRUG DELIVERY DEVICES
coordination and collaboration of breathing following
1) Cascade impactors
actuation of the device. In addition, DPIs are small,
Cascade impastos determine the aerodynamic
portable devices that can be easily carried in a purse or
activities of aerosol particles by size-separating the
pouch. There is also not require to use spacers. In
dose in impactor plates. Cascade impactors give up
addition, DPIs are devoid of environmentally injurious
valuable aerosol parameters such as the fine particle
CFC propellants, as normally necessary in MDI
fraction (FPF) mass median aerodynamic diameter
formulation. Since both MDI and DPI have been
(MMAD). In vitro particle sizing data obtained from
exposed to afford comparable efficacy in delivering
impactors plan first at scheming the quality of the
the similar drug and in view of the mandatory ban of
pharmaceutical product and next at provide an analysis
CFCs use in MDIs by the United Nations, it is not
tool for product improvement. It is projected that
shocking that DPIs have become increasingly
outcome from cascade impactors forecast human lung
significant as a pulmonary drug delivery system over
deposition data as particle aerodynamic size
the precedent decade. The aerosol drug delivery is
determines aerosol deposition in the human respiratory
undergo dramatic changes in both inhaler device and
tract. In wide-ranging the FPF thoroughly
formulation aspects 10. There is a rapid move from the
overestimates whole lung authentication in humans.
traditional propellant-driven metered dose inhalers to
Dimensions in cascade impactors are prepared at room
the high presentation liquid atomizers and dry powder
temperature and at low absolute humidity, which is not
inhalers. The inhaler devices are particularly attractive
representative of human airways ambient
as dry powders. Because of dry powder show the
circumstances.
greater chemical stability than the liquids are use in
atomizers. On the other hand, formulation and
e2) In vitro:-
production of dry powders for inhalation can be
In this respect, in vitro models for pulmonary drug
difficult and challenging due to the potential physical
delivery studies propose another as it convey up fewer
instability of the powder.
moral questions but also because they allow a fast
screening of drugs. In both cellular models, it is
significant that epithelial cells form a tense monolayer
in order to characterize the natural epithelial barrier.
Monolayer tension and reliability are classically
assessed by measuring Trans epithelial electrical
resistance (TEER) and potential difference crosswise
the monolayer. Monolayers of lung epithelial cells
permit the categorization of drug transport and
evaluation of potential drug and formulation toxicity.
Drug transport is classically calculated in the apical to
basolateral direction, and vice versa, in order to ensure
for active transport mechanisms.
4) Primary cell cultures 12 pigs have been generally used as an animal form of
The majority primary cell cultures used as allergic asthma and infectious diseases (e.g.,
models for pulmonary drug delivery and convey tuberculosis) since the airway anatomy and the
studies consist of alveolar epithelial cells. Type II respond to inflammatory stimuli are similar to the
pneumocytes for primary culture can be removed from human case. The dissimilar mammals do not show to
the lung of different species. Human cells are the present related mucociliary clearance and alveolar
mainly representative of the clinical circumstances, but macrophage morphometry. In large mammals, the rate
they are less available than cells from other mammals. of mucus permission in millimetres per minute is
Human type II pneumocytes are removed from normal elevated compared with small rodents. Though, huge
lung tissue of patients undergoing partial lung mammals also have longer airways than minute
resection. In culture, the cells experience segregation rodents and thus, worldwide, the bronchial permission
into type I-like cells, as indicated by morphological of inhaled particles is comparatively slow in humans
and histochemical change. In premature stages of the (> 24 h). By contrast, bronchial clearance of particles
cell culture, the cells create elevated levels of is relatively quick and early in rats and mice. The
surfactant protein C and little levels of caveolin 1, a number of macrophages per alveolus and the alveolar
marker of type I pneumocytes, and on the other hand at macrophage volume are superior in human and canine
later stages. On day 8 of culture, the cells form a tight lungs than in small rodents lungs.
monolayer consisting mainly of type I cells and some
interspersed type II cells, with TEER > 2000 cm2 7) Passive inhalation:-
and potential difference > 10 mV. During passive inhalation of aerosolised drugs,
animals are kept awake and allowed to breathe
5) Air-interface cultures normally. Aerosolised drugs are delivered using an
Air-interface cultures (AIC) are models that permit aerosolisation chamber in whole body, head-only or
aerosol particles to place straight onto semi-dry apical nose-only exposure systems. The devices most
cell surface. Drug deposition and dissolution take frequently used for generating aerosols are nebulisers.
place in a small volume of cell lining fluid, a Passive inhalation is principally used in the mouse and
circumstances that mimics more directly deposition on less frequently in larger animals (rat, guinea-pig, dog ).
the lung surface in vivo. The AIC show greater This method is more representative of drug delivery to
similarity to airways epithelial morphology, with the human lungs than intratracheal instillation of large
superior glycoprotein discharge, more prominent volumes of liquids. The drug concentration in the
microvilli and the construction of a pseudo stratified aerosol is determined by sampling the test atmosphere
layer of columnar cells, while the liquid-covered and quantifying the drug in the sample.
culture created a monolayer of cells.
8) Whole body exposure system:-
6) In vivo In whole body aerosol exposure system, animals
Before new drugs are deliver to the human lungs, are placed in a sealed plastic box that is connected to a
animal studies need to be passed out. The morals of nebuliser or a generator of dry powder aerosol.
any animal experiment require to be accepted by an Although this system allows a less stressful pulmonary
Institutional Animal Care and Use Committee. drug administration to an important number of
Experiment perform in an animal model can afford animals, there is potential drug absorption across the
information on drug declaration, metabolism, skin after deposition on the animal fur, from the nasal
assimilation and kinetic profile as well as on drug and mucosa and from the gastrointestinal tract.
rats and guinea-pigs) are frequent formulation
acceptability. So, non-human primates are use only in 9) Head-only or nose-only exposure systems:-
advanced research. By contrast, small rodents (mice, In the head-only or nose-only exposure systems,
models for preliminary studies on pulmonary drug the animal is attached to the exposure chamber and
delivery because they can be used in large numbers. only the head or the nose is in contact with the aerosol.
Mice have been used less often for assessing The systems can be designed for delivering drugs to
pulmonary release of systemically performing drugs one or to several animals. Compared with the whole
because pharmacokinetic studies are not optimally body exposure system, the head-only or nose-only
perform in mice. Owing to its small size, one mouse exposure systems offer several advantages. Skin
can offer only one blood sample at a time (1 ml whole exposure to the drug and its uptake by the transdermal
blood sample is withdrawn by cardiac puncture and route are avoided. The low volume of the
mouse euthanasia must be done at each time point of aerosolisation chamber reduces the amount of drug
the plasma drug concentrationtime curve. Guinea- needed to generate the aerosol. Potential drug
Karhale Ashish A.et al /Int.J.PharmTech Res.2012,4(1) 301
reactivity with excreta is avoided. Variable durations treatment of COPD titropium inhalers are present in
of animal exposure are possible in one single test. market.
marrow transplantation but controlled trials are needed pulmonary embolism. This pulmonary therapy is
to better clarify efficacy. noninvasive because it is needle free.
17) Delivery of Gentamycin by pulmonary route 22) Recent use of pulmonary delivery for bone
For chronic Pseudomonas aeruginosa(PA) disorders 29
infections in CF gentamycin given by pulmonary route Disease such as osteoporosis and Pagets disease of
play as important role. It was observed daily bones can be treated by pulmonary delivery. The
inhalations of gentamicin delays the acquisition of predicted increase in the number of patients with
chronic PA infections and decreases disease osteoporosis and the lack of ideal therapies dictates the
progression in children with zanamivir, made by GSK, need for better treatments. Clinical evidence from a
was the first inhaled anti-viral medication approved by variety of other peptides and proteins indicates that
the FDA in1999. For treatment of flue dose of dry pulmonary delivery is safe, efficient, well tolerated and
powder inhalers is twice daily for 5 days24. preferred by patients so pulmonary route is better
option to treat bone disorders. Following are drugs
18) Diagnostic application pulmonary drug delivery used to treat osteoporosis are the naturally occurring
26
peptides calcitonin and parathyroid hormone, which
Pulmonary drug delivery is not only useful for regulate bone metabolism.
therapeutic purpose but also for diagnosis purpose. For
example, inhalation of aerosols of methacholine and 23) Current use of pulmonary delivery of opioids as
histamine is responsiveness in asthma. pain therapeutics 30
To avoid pain associated with inject able pain
19) Nicotine aerosol for smoking cessation killer Pulmonary opioid delivery is better alternative.
As we know that smoking is injurious to health. It Early clinical studies involving in haled opioids were
is very difficult to aces such habit. From ancient times focused on treatment of dyspnoea and not pain
people smokes cigarette and get addicted with management, but theyshowed that inhalation of
smoking. Primary reason for cigarette smoking is various opioid compounds is safe, even in severely ill
Nicotine addiction, and nicotine replacement is patients. The advent of specialized and efficient
appealing as a means of reducing cigarette use to pulmonary drug delivery systems has facilitated the
ultimately achieve cessation. evaluation of inhaled opioids, such as morphine and
fentanyl, for management of severe pain associated
20) Inhaled drug delivery for tuberculosis therapy with surgery or malignant disease. Studies are going
27
on to introduce new molecules for management of pain
Tuberculosis is most infectious diseases cause by trough pulmonary route Studies with efficient
Mycobacterium tuberculosis. Administering drugs by pulmonary delivery systems, designed for systemic
the pulmonary route to the lung sallows higher drug drug applications, conclusively show that inhaled
concentrations in the vicinity of these lesions. opioids are rapidly, completely and reproducibly
Supplementing conventional therapy with inhaled absorbed into the bloodstream. Thus, the pulmonary
antiTB therapy may allow therapeutic concentrations route has excellent potential for treating non-
of drug to penetrate effectively into lung lesions and invasively severe pain in the postoperative setting and
treat the resident mycobacterium. in malignant disease.
of device and formulation combinations that will target increase clinical effectiveness and patient compliance.
specific cells or regions of the lung, avoid the lungs Some of the key determinants for successful dispersion
clearance mechanisms and be retained within the lung of pharmaceutical powders suitable for inhalation are
for longer periods. The more efficient, user-friendly reviewed with an emphasis on the practical
delivery devices may allow for smaller total significance.
deliverable doses, decrease unwanted side-effects and
27. Pavan M. Chenchen W. and Anthony J. H., 29. John S. P., Pulmonary delivery of drugs for bone
Inhaled Drug Delivery for Tuberculosis disorders, Advanced Drug Delivery Reviews
Therapy, Pharmaceutical Research, 2009, 26, 11. ,2000, 42, 239248.
28. Tianzhi Y. Fatima M.& Shuhua B., Pulmonary 30. Stephen J. F. and Babatunde A. O., Pulmonary
Delivery of Low Molecular Weight Heparins, delivery of opioids as pain therapeutics,
Pharmaceutical Research, 2004 , 19, 2009 -2014. Advanced Drug Delivery Reviews 2006, 58,
10761088.
*****