Pulmonary Drug Delivery Systems (PDDS)

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 

  1. 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 
(μm)

Deposition site

Deposition per cent

≥10

Oropharynx

100%

>5

Central airways 
(tracheobronchial)

20%

<3

Peripheral airways 
(alveoli)

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

  1. Targeted
    treatment of lung disorders

  2. Non-invasive
    alternative to injection for macromolecule drugs (biologicals)  such as insulin

  3. 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

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