Pulmonary Drug Delivery Systems
Session
Outcomes
At the end of the
session students will be to:
• Explain
significance of drug delivery to lungs
• Describe
anatomical and histological aspects of lungs
• Enlist
advantages and disadvantages of pulmonary route for drug delivery
• Appraise
challenges in pulmonary drug delivery
• Discuss
various pulmonary drug delivery systems
• Recall
latest develolpments in PDDS
Pulmonary Drug
Delivery Systems
• Pulmonary
route used to treat different respiratory diseases from last decade.
• The
inhalation therapies involved the use of leaves from plants, vapours from
aromatic plants, balsams, and myhrr.
• Pulmonary
drug delivery is primarily used to treat conditions of the airways, delivering
locally acting drugs directly to their site of action.
• Delivery
of drugs directly to their site of action reduces the dose needed to produce a
pharmacological effect.
• The
respiratory tract is one of the oldest routes used for the administration of
drugs.Over the past decades inhalation therapy has established itself as a
valuable tool in the local therapy of pulmonary diseases such as asthma or COPD
(Chronic Obstructive Pulmonary Disease).
• This
type of drug application in the therapy of these diseases is a clear form of
targeted drug delivery.
• Currently,
over 25 drug substances are marketed as inhalation aerosol products for local
pulmonary effects and about the same number of drugs are in different stages of
clinical development.
• The
drug used for asthma and COPD e.g..- β2-agonists such as salbutamol (albuterol), Terbutalin
formoterol, corticosteroids such as
budesonide, Flixotide or beclomethasone and mast-cell stabilizers
such as sodium cromoglycate or
nedocromi,.
• The
latest and probably one of the most promising applications of pulmonary drug
administration is
1) Its
use to achieve systemic absorption of the administered drug substances.
2) Particularly
for those drug substances that exhibit a poor bioavailability when administered
by the oral route, as for example peptides or proteins, the respiratory tract might
be a convenient port of entry.
Anatomy of
Respiratory system
´ The
human respiratory system is divided into upper and lower respiratory tracts
´ The
upper respiratory system consists of the external nose, nasal cavities, nasopharynx and oropharynx mouth, trachea,
nasal secretions
´ The
lower respiratory tract consists of the larynx, bronchi, and alveoli, which are composed of respiratory tissues
• The
human respiratory system is a complicated organ system of very close
structure–function relationships.
The system consisted
of two regions:
1. The
conducting airway
- The
respiratory region.
·
The airway is further divided into many folds:
nasal cavity and the associated sinuses, and the nasopharynx, oropharynx,
larynx, trachea, bronchi, and bronchioles.
·
The respiratory region consists of respiratory
bronchioles, alveolar ducts, and alveolar sacs
·
The human respiratory tract is a branching
system of air channels with approximately 23 bifurcations from the mouth to the
alveoli.The major task of the lungs is gas exchange, by adding oxygen to, and removing
carbon dioxide from the blood passing the pulmonary capillary bed.
Lung region
1.
Nasopharynx region: (NP)
2.
Tracheobronchial region: (TB)
3.
Alveolar region: (AV)
Types of cells present in lungs
Bronchi
1) Ciliated
cells
2) Goblet
cells
3) Serous
cells
4) Brush
cells
5) Clara
cells
Bronchioles
1) Ciliated
cells
2) Clara
cells
Alveoli
1) Type-1
pneumocytes
2) Type-2
pneumocytes
Factors
determining the deposition of inhaled particles
Advantages
of Pulmonary Route Systemic acting drugs
ü A
large surface area for drug absorption
ü Convenience
and good patient compliance
ü Rapid
attainment of therapeutic drug levels in the blood
ü High
drug permeability, especially for lipophilic and low molecular weight drugs
ü Avoidance
of harsh environmental and gastrointestinal conditions
ü Bypassing
of hepatic first-pass metabolism
ü Potential
direct drug delivery to the brain along the olfactory nerves
ü Direct
contact site for vaccines with lymphatic tissues
Disadvantages
• Complex
delivery devices are required to target drugs to the airways and these devices
may be inefficient.
• Aerosol
devices can be difficult to use
• Various
factors affect the reproducibility of drug delivery to the lungs, including
physiological (respiratory maneuver) and pharmaceutical (device, formulation)
variables.
• Drug
absorption may be limited by the physical barrier of the mucus layer and the
interactions of drugs with mucus.
• Mucociliary
clearance reduces the retention time of drugs within the lungs. Efficient drug
delivery of slowly absorbed drugs must
overcome the ability of the lung to remove drug particles by mucociliary
transport
Advantages
of Pulmonary Route Locally acting drugs
Targeted Delivery
•
Drug is deposited its site of action
•
Systemic absorption and distribution throughout
the body not required
•
Effectiveness not limited by poor absorption or hepatic
first-pass metabolism
Clinical advantages
•
Low dose compared to oral therapy
•
Low incidence of systemic side-effects
•
Rapid onset of drug action
CHALLENGES IN PULMONARY DRUG DELIVERY
q Low
Efficiency of inhalation system
Aerosol system should have to produce optimum size particles
because they are too small, they will be exhaled. If the particles are too
large, they effects on the oropharynx and larynx. (0.5-1mm)
q Less
drug mass per puff
To get adequate effect with the pulmonary drug delivery
practical delivery of many drug which require milligram doses but with most
existing systems, the total amount of drug per puff delivered to the lower
respiratory tract is too low less than 1000 mcg.
q Poor
formulation stability for drug
Most traditional drugs are crystalline, in the case of
corticosteroids, and highly moisture sensitive drugs are unstable.
q Improper
dosing reproducibility
Reason for Poor dosing reproducibility like worsening of
diseases’, problem in device, unstabality of formulation.
Nasal Preparations for systemic effect
Ø Butorphanol
Ø Sumatriptan
Ø Desmopressin
Ø Insulin
Butorphanol
It is a potent synthetic mixed agonist-antagonist opioid
analgesic
Butorphanol for nasal administration is marketed as Stadol
NS Nasal spray
It is a metered spray having an aqueous solution of butorphanol
tartrate with sodium chloride, citric acid and benzelthonium chloride
Sumatriptan
Ø It
is a serotonin receptor agonist,
Ø used
in the treatment of migraine and cluster
headache
Ø It
offers several advantages:
Ø Ease
of self- administration unlike
injections
Ø Better
bioavailability in comparison to oral (only 14%)
Ø Convenient
in cases of nausea and vomiting unlike oral tablets
Ø A
marketed nasal formulation of sumatriptan is Imigran (Glaxo Wellcome)
Desmopressin
´ It
is the synthetic analogue of the naturally occurring antidiuretic hormone, vasopressin
´ It
is one of the First example of peptide drugs that were administered nasally
for systemic effects
´ Traditionally,
it was administered using the rhinyl catheter method as drops or by metered –dose pump as spray
´ DDAVP®
Nasal spray (desmopressin acetate) or DDAVP® Rhinal Tube are
available as aqueous solutions containing
desmopressin acetate
Insulin
It is used in the therapy of diabetes mellitus
Till date, several trials have been carried out with
intranasal formulations but only with low and variable bioavailability and
uncertainty about long- term safety
Challenges
in Pulmonary Drug Delivery
Assessment of
Pulmonary Drug Delivery
Lung Deposition (radionuclide imaging)
Pulmonary bioavailability (pharmacokinetic)
Inhaler Devices
Correct inhaler technique
Non suitable devices for >1 mg drug dose
Lung defense
mechanisms
Evolved to prevent entry of inhaled materials
To remove them once deposited
·
Controlled pulmonary drug delivery is a big
challenge because different parts of the respiratory tract are cleared by
different mechanisms
·
PLGA nanoparticles have been investigated for
pulmonary delivery of anti-TB drugs
Dosage forms
for pulmonary drug delivery
Aerosol
• Aerosol
is a pressurized dosage forms containing one or more therapeutic active ingredients which upon
actuation emit a fine dispersion of
liquid or solid materials in a gaseous form
• The
particle size of aerosols important in
determining the disposition site
Aerosol particle size
on the dispersion pattern
|
Particle diameter |
Deposition site |
Deposition per cent |
|
≥10 |
Oropharynx |
100% |
|
>5 |
Central airways |
20% |
|
<3 |
Peripheral airways |
60% |
|
Extrathoracic |
~10% |
Determination
of Particle Size
a) Cascade
Impactor
Principle– Stream of
particles projected through a series of nozzles and glass slides at high
velocity larger particles are impacted first on lower velocity stage and
smaller particles are collected at higher velocity stage
b) Light
Scattering Decay
Principle– As aerosol
settles under turbulent conditions the change in the light intensity of a
Tyndall beam is measured
Advantages
•
A dose can be removed without contamination of materials
•
Ease and convenience of application
•
Rapid response to the medicament
•
Irritation produced by mechanical application is eliminated or reduced
Disadvantages
•
Expensive
•
Inflammability
•
Toxicity
•
Explositivity
•
Bronchoconstriction
Inhalation Drug
Delivery System
The respiratory tract has been largely used for treatment of
obstructive airway diseases (e.g. Asthma)
It can be classified into:
1. Nebulisers
2. Metered dose inhalers
3. Dry powder inhalers
Nebulizers
• ´Nebulizers
have been successfully employed for drug delivery to lungs
• ´It
has also been examined for local drug delivery to the trachea as for local anaesthesia for bronchoscopy
Metered
Dose Inhalers
´The development of first pressurised MDI in the mid- 1950s
has been major advance in the administration of drugs locally to the lungs
especially for the treatment of asthmatics
• MDI
composed of four components viz
Ø Base
formulations (drug, propellant, excipients)
Ø The
container
Ø The
metering valve
Ø The
actuator (mouthpiece)
Metered Dose Inhalers Merits
Ø Multi-dose
capabilities
Ø Quick
delivery
Ø Pressurised
inhaler protects from ingress of both
moisture and pathogens
Metered Dose Inhalers Demerits
Ø Difficult
for people with osteoarthritis affecting
hands
Ø May
be unsuitable for patients with severe
COPD with poor inspiratory flow rate
Ø pMDIs
require coordinating your breath with
medication release (inhaling technique)
Ø Much
of the dose is deposited in the
oropharynx
Ø An
inspiration flow rate of 25L/min is
required
Dry powder Inhalers
´ DPIs
are an alternative to the aerosol based inhalers commonly MDIs, that deliver a powder dosage form to the lungs
´ These
devices are environmental friendly since they do not require CFC propellants for drug dispersion
´ DPIs
are also versatile devices
´ They
are commercially available in two types
ü Unit
dose devices
ü Multidose
devices
Inhalation
Drug Delivery System Applications
- Targeted
treatment of lung disorders - Non-invasive
alternative to injection for macromolecule drugs (biologicals) such as insulin - Efficacious
and patient-friendly vaccines (pain free)
Novel
Approaches for Pulmonary Delivery
·
´Polymeric nanoparticles
·
´Liposome
·
´Solid lipid nanoparticles
·
´Submicron emulsion
·
´Dendrimer-based nanoparticle
Polymeric
Nanoparticles
´ Carriers
for drug molecule
´ Prevent
drug from degradation
´ Control
of drug release
´ Due
to their biocompatibility, surface modification capability, and sustained- release properties, polymeric nanoparticles
are intensively studied using various
important pulmonary drugs
´ Additionally,
In-vitro lung surfactant models and In-vivo studies are required to establish the pulmonary acceptability of
polymeric nanocarrier systems
Liposomes
·
´Most extensively investigated systems for
controlled delivery of drug to the lung
·
´Appropriate for therapeutic agent delivery to
lung, since these vesicles can be prepared from compounds endogenous to the
lungs, such as the components of lung surfactant, and these properties make
liposome attractive candidate as drug delivery vehicles
·
´Synthetic lung surfactant Alveofact® for
pulmonary instillation for the treatment of respiratory distress syndrome
·
´Typically, liposomal formulations have been
delivered to the lung in the liquid state, and nebulizers have been used
extensively for the aerosol delivery of liposomes in the liquid state
·
´Liposomal dry powder formulations have been
intensively examined in order to successfully circumvent these issues and some
of them are in clinical trials
·
´Liposomes conjugated with cell-penetrating
peptides are recognized as potential nanocarrier systems for intracellular
delivery of macromolecules to the lung
Solid Lipid
Nanoparticles
·
´The advantages of drug release from SLNs in the
lung are control of the release profile, achievement of a prolonged release and
having a faster In-vivo degradation compared to particles made from PLA or PLGA
·
´Pulmonary applications of SLNs as local
delivery carriers for small molecules or as systemic delivery carriers for
macromolecules have been reported
·
´SLNs incorporating rifampicin, isoniazid and
pyrazinamide are evaluated against experimental tuberculosis, and observed the
slow and sustained-release of drugs from the SLNs both In-vitro and In-vivo
- Deposition and clearance
of SLNs were assessed after inhalation of aerosolized insoluble particles using gamma-scintigraphy
imaging analysis - Inhaled material began
to translocate to regional lymph nodes indicating that inhalation can be an effective route to
deliver drug-containing lipid particles to
the lymphatic systems and lipid particles can be used as potential
drug carriers for lung cancer
therapy, as well as for vaccine delivery
Submicron
emulsions
´ Submicron
emulsions are promising carriers for DNA vaccines to the lung since they are able to transfect pulmonary
epithelial cells, which possibly induce
cross priming of antigen-presenting cells and directly activate dendritic cells, resulting in stimulation of
antigen-specific T-cells
´ Submicron
emulsion loaded with Mycobacterium tuberculosis Ag85B DNA vaccine was explored for the purpose of
pulmonary mucosal vaccination
Dendrimer-based
nanoparticles
• Cationic
dendrimers can be used as pulmonary delivery carriers for a relatively large molecular weight anionic drug
• Binds
anionic drug molecules most likely via electrostatic interactions and
increase drug absorption through charge
neutralization
• Half-life
and absorption of LMWH administered via the pulmonary route can be increased by encapsulating the drug in
dendrimeric micelles
• LMWH
loaded in the mPEG–dendrimer could potentially be used as noninvasive delivery
system for the treatment of thromboembolic disorder
Emerging
Delivery Techniques
The AERx® System (Aradigm Corporation)
“Intelligent” inhaler
•
Records inhaled flow rate
•
Breath-actuated at pre- determined volume / flow
•
Dose titration
•
Dose-recording history Aerosol formation
•
Heater helps control aerosol size
•
Nozzle hole diameter 1.2 μm Drug doses > 20 mg in 45 μL possible
•
Nano-suspensions also possible
Respimat® Soft MistTM Inhaler
(Boehringer Ingelheim)
• Respimat
SMI is a “press and breathe” device
• Low
spray velocity and long duration aerosol
cloud assumed to make coordination
easier
• Clinical
trials demonstrate clinical efficacy
with ¼ to ½ of the pMDI or Handihaler®
DPI dose
• Corresponds
to improved lung deposition
• Being developed
primarily for
• drugs
to treat COPD
• Launched
2004: fenoterol / ipratropium bromide
(Berodual®)
Advantages of AERx®
System
Ø Lighter
and smaller than electronic device
Ø Similar
efficiency and reproducibility
Ø No
heater, dose titration, dosing history recording
Ø 600
nm diameter nozzle
Ø holes
by laser photoablation
Future
Prospects
Lung Model
•
Weibel Model of
Lung
Simulation studies
•
Device Characteristics
•
Deposition Behavior
Conclusion
´Drug delivery through the respiratory tract has been used
for local and systemic effects, it offers considerable advantages over
alternative routes of administration for delivering drugs to systemic
circulation
´The success of various novel drug delivery carries
nasopulmonary delivery ultimately depends on the ability to produce
sufficiently stable formulation that can be practically administered through
available devices
