Download Pulmonary Drug Delivery

BIOMATERIAL DEVICES
And the Epithelium
Pulmonary
BBB
PULMONARY PHYSIOLOGY
Functions
Ventilation/Conduction
Conduction Pathway
The relaxation/contraction
of circular smooth muscle
lining these “airways’”
determines how easily
airflow can occur
(bronchodilation vs.
bronchoconstriction).
Most gas exchange
occurs in the
~8,000,000
alveolar sacs.
Functions of Conduction Pathway
Alveolar/Capillary Structural Relationship
Abundance of pulmonary capillaries
Ventilated air is brought into close proximity to the “pulmonary” blood
Efficient and thorough gas exchange between the air and the blood.
Extensive branching of alveoli:
Increased surface area
for exchange between
air and blood.
Alveolar and capillary walls:
Thin
Permit rapid
diffusion of gases
Airflow in the lungs:
Ventilation.
[AIR]
EXCHANGE
[BLOOD]
Gases exchange
by diffusion.
Bloodflow through the
pulmonary capillaries is
driven by the contraction
of the right ventricle.
PULMONARY DRUG DELIVERY
Pulmonary drug delivery. Part I: Physiological factors affecting
therapeutic effectiveness of aerosolized medications
N. R. Labiris & M. B. Dolovich
Table 1
Advantages of pulmonary delivery of drugs to treat respiratory and systemic disease.
Treatment of Respiratory Diseases
Treatment of Systemic Diseases
Deliver high drug concentrations directly to the disease site
Minimizes risk of systemic side-effects
Rapid clinical response
I
Bypass the barriers to therapeutic efficacy, such as poor
gastrointestinal absorption and first-pass metabolism in
the liver
A noninvasive ‘needle-free’ delivery
system.
Suitable for a wide range of substances
from small molecules to very large
protein[20, 21]
Enormous absorptive surface area (100
meters squared) and a highly permeable
membrane(0.2–0.7micrometer thickness)
n the alveolar region [22, 23].
Large molecules with very low absorption
rates can be absorbed in significant
quantities; the slow mucociliary clearance
in the lung periphery results in
prolonged residency in the lung [72].
Achieve a similar or superior therapeutic effect at a fraction
of the systemic dose. For example, oral salbutamol
2–4 mg is therapeutically equivalent to 100–200
Microgram by MDI
A less harsh, low enzymatic environment
that is devoid of hepatic first-pass
metabolism.
Reproducible absorption kinetics.
Pulmonary delivery is independent of
dietary complications, extracellular
enzymes and interpatient metabolic
differences that affect gastrointestinal
absorption [21].
LUNG IS THE ONLY ORGAN
THROUGH WHICH THE
ENTIRE CARDIAC OUTPUT
PASSES
BASIC FACTS ABOUT INHALED
DRUGS
•
Optimal site of deposition depends upon infection being
treated
• Sometimes difficult to deliver to target site due to obstructions
resulting from pathologies
•
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Inhalation of drugs for asthma, chronic obstructive pulmonary
disease, cystic fibrosis, chronic bronchitis-Common place
Inhalation of drugs for diabetes, cancer, migraines, hepatitis
C, pain management-In development
Therapeutic effect of aerosolized therapies depends upon dose
deposited and distribution
Surface concentration of drug affects response
• Particle size affects deposition
• Small particles penetrate more deeply into lung
• Larger particles filtered out of upper airways
OPTIMAL SITE OF DEPOSITION
•
•
Historically aerosol drug delivery limited to topical therapy for lung
and nose
Major contributing factor was inefficiencies of available inhalation
devices that deposit only 10-15% emitted dose in lung
•
•
•
Adequate for doses of steroids and bronchodilators
Inadequate for systemic therapies-Systemic therapies require large
amounts of drug in order to achieve therapeutic drug levels
Design of more efficient systems
•
MDI
• Metered dose inhalers
• Pressurized hand-held devices
• Use propellants
•
DPI
• Dry powder inhalers
•
•
LPI
Advair Diskus
• Liquid dose inhalers
AEROSOL PARTICLE SIZE
•
Defines dose and distribution of drug
•
Heterodispersity
• Fine aerosols deposit on peripheral airways but deposit less drug
per unit surface area
• Larger particle aerosols deposit on central airways and deposit
more drug per unit surface area
INHALATION OF PROTEINS
•
1925-Demonstration that insulin can be absorbed from lung
•
Macromolecules <40kDa (,5-6nm in diameter) rapidly appear in blood
(15-60 minutes after inhalation)
•
Macromolecules >40kDa are slower to adsorb (hours)
MECHANISMS OF DEPOSITION
•
Inertial impaction
•
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Gravitational sedimentation
•
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First 10 generations of lung
Tracheobroncial region and bends and
bifurcations
Air velocity is high
Airflow is turbulent
Particles >10 microns deposited in
oropharyngeal region
Delivered by DPI, forward velocity
MDI
Last 5-6 generations of lung
Air velocity is low
Diffusion (Brownian motion)
•
•
Alveolar region
Air velocity is negligible
Hygroscopic drugs swell as they come in
contact with humidified air in lung
(99.5%)
Large porous particles (LPPs) are a drug delivery platform that
manipulates particle properties by increasing geometric diameter and
lowering particle mass density while maintaining an aerodynamic
diameter that allows for entry and deposition in the lungs.
LPPs disperse more readily than classical small dense particles of
inhaled pharmaceutical formulations, allowing efficient delivery of
large drug masses from a relatively simple inhaler.
These dry powders are also manufactured inexpensively and at large
commercial scales using processes such as spray drying.
The result is a free-flowing powder that is shelf-stable and easily
delivered in large doses.
Drugdeliverytech.com
CLEARANCE MECHANISMS
•
Inhaled drugs (once deposited) are
cleared from lungs, absorbed into
systemic circulation, enzymatically
degraded
•
Particles deposited in conducting
airways removed by mucociliary
clearance or absorbed through
epithelium (passive diffusion,
extracellular pathways, endocytosis)
into blood or lymph
•
•
Goblet cells
•
Submucosal glands
•
Impaired in lung diseases such
as CF and asthma
Vanderbilt.edu
Particles deposited in alveolar region
phagocytosed and cleared by
alveolar macrophages or absorbed
into systemic circulation
•
Rate of absorption of proteins
is size dependent
Nanomedicine
BARRIERS TO ABSORPTION
• Drug absorption
regulated by alveolarvascular permeable
barrier
• Number of alveoli-200600 million
• Enormous surface area
• Barriers to absorption
•
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Lung surfactant
Surface lining fluid
Epithelium
Interstitium
Basement membrane
Endothelium
MECHANISMS FOR DELIVERY
TO BLOODSTREAM
•
Cell absorptive transcytosis (adsorptive/receptor mediated)
•
Paracellular transport (bijunctions, trijunctions)
•
Large transitory pores
• Bioavailability of macromolecules deposited in lung 10-200 times
greater than nasal or GI values
• Due to enormous surface area and very small diffusion
distances, slow surface clearance
CENTRAL NERVOUS SYSTEM
BLOOD BRAIN BARRIER
THE BRAIN AND SPINAL CORD
WHY IS IT SO DIFFICULT
TO TREAT PATHOLOGIES IN
THE BRAIN/CNS?
Blood Brain Barrier
VASCULATURE OF THE BRAIN
Blood vessels in human brain. A
plastic emulsion was injected into
brain vessels and brain
parenchymal tissue was dissolved
(photo on left).
Zlokovic & Apuzzo: Neurosurgery
43(4):877-878, 1998. (provided by
permission from Lippincott
Williams & Wilkins)
Alzheimer’s Assoc. Org.
BLOOD-BRAIN BARRIER
BASIC ANATOMICAL BARRIER
• CNS blood capillaries
structurally different from
blood capillaries in other
tissues
• Barrier between blood
within brain capillaries and
extracellular fluid
• Capillaries lack pores that
allow rapid movement of
solutes from circulation
into tissue
• Endothelial cell lining lacks
fenestrations
• Endothelial cells lining
vessels are joined by tight
junctions
• High transendothelial
electrical resistance
BBB
BBB
•
Micro-vessels make up 95% of total surface area of BBB
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650km, total surface area 12 meters squared
Intercellular clefts, pinocytosis, fenestrae- nonexistent
Exchange must be trans-cellular
Only lipid-soluble solutes can passively cross
• Drugs used to treat virtually all brain-related pathologies have been lipidsoluble if administered IV
• Exception-lipophilic anti-cancer agents have difficulty entering interstitium
due to efflux mechanisms (discussed in later slides)
•
Areas adjacent to the ventricles have microvessels similar to those
found in periphery
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Circumventricular organs- ex. choroid plexus, neurohypophysis
Exchange between cerebrospinal fluid and brain extracellular fluid
Enzymes
•
Endothelial cells contain large numbers of enzymes
• Rapidly degrade most peptides
THE BBB PRESENTS THE SAME EFFLUX
MECHANISM AS THE GI TRACT
• Multi-drug transporters
• P-glycoprotein (Pgp) active-drug-efflux-transporter
protein
• Multi-drug resistance protein (MRP)
• Multi-specific anion transporter
• Luminal membranes of cerebral capillary endothelium
• Efflux of drug molecules from endothelial cell cytoplasm
before entering brain parenchyma
• Active efflux via specific transporters
• Efflux of lipid-soluble molecules
• Restricting efflux may increase brain exposure to drugs
• Co-administration of a competitive or non-competitive
inhibitor of the efflux pump together with desired drug
• Co-administration of Pgp blocker, valspodor, improves
therapeutic effect of paclitaxel in mice.
EFFLUX MECHANISM
P-GLYCOPROTEIN (PGP) ACTIVE-DRUG-EFFLUXTRANSPORTER PROTEIN
BLOOD-CEREBROSPINAL BARRIER
CEREBROSPINAL FLUID BATHS THE BRAIN TISSUE AND
PROVIDES YET ANOTHER BARRIER TO TRANSPORT INTO BRAIN
PARENCHYMA FROM THE BLOOD
• Regulation of passage of blood-borne
molecules into CSF
• Found in epithelium of choroid plexus
• Choroid plexus and arachnoid mater act together
as barrier between blood and CSF
• Choroid plexus very vascular, forms CSF and regulates
contents of CSF
• Passage of substances from blood through
arachnoid membrane prevented by tight junctions
• Ependymal cells (choroidal epithelial cells) form
continuous sheet around the ventricles
• Microvilli, basolateral interdigitations, abundant
mitochondria
Three layers of meninges
Dura mater
Arachnoid mater
Pia mater
CSF located within the ventricles and
within sub-arachnoid space
Surrounded by ependymal
cells that are connected by tight
junctions
The choroid plexus and arachnoid mater
provide barrier to transport between blood
(circulating in vessels of arachnoid mater)
and CSF in ventricles
VENTRICLES OF THE BRAIN
IN ADDITION TO MECHANICAL BARRIERS, THE
CHOROID EPITHELIUM PRESENT MOLECULAR
BARRIERS TO TRANSPORT
•
•
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Fortification by active
organic acid transporter
system in choroid plexus
capable of driving CSFborne organic acids into
blood
Therapeutic organic acids
such as Penicillin,
methotrexate (anti-cancer),
zidovudine(anti-viral) are
actively removed from CSF
and are prevented from
diffusing into brain tissue
Substantial diffusion
distance between CSF and
brain parenchyma also
hinders entry of molecules
deep into brain tissue
BLOOD-TUMOR BARRIER
• CNS malignancies-BBB compromised
• Physiological barriers prevent delivery of
drugs via cardiovascular system
• Inconsistencies in microvasulature of tumor results
in spatially inconsistent drug delivery
• Vascular surface area decreases as tumor size
increases
• Intracapillary distances within tumor increase
• Increased hydrostatic pressure/interstitial tumor
pressure inhibits transport of molecules into tumor
GLIOMA
DRUG DELIVERY TO THE BRAIN
Chemistryworld/Issues
INTERSTITIAL DELIVERY
INJECTIONS, CATHETERS, PUMPS
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Ommaya reservoir/implantable pump for intraventricular or
intrathecal routes
Continuous drug delivery
Three pumps available
• Infusaid pump
• Vapor pressure of compressed Freon to deliver drug solution at
constant rate
• MiniMed PIMS system
• Solenoid pumping mechanism
• Medtronic SynchroMed system
• Peristaltic mechanism
•
Epidural delivery device
• Depofoam drug delivery system
• Epidural delivery of morphine encapsulated in multivesicular
liposomes
INTERSTITIAL DELIVERY
BIODEGRADABLE POLYMER WAFERS AND MICROSPHERES
•
Direct delivery to brain interstitium using polyanhydride
wafers
•
Conjugation of polymerically delivered chemotherapeutic
agents to a water-soluble macromolecule
• Increases drug penetration by increasing drug
retention
• Hanes et al.-IL-2-loaded biodegradable polymer
microspheres
• Stereotaxic implantation of microparticles containing
drug into specific areas of brain
• Gliadel-Polymeric delivery system containing
BCNU for treatment of glioma patients
DELIVERY FROM BIOLOGICAL TISSUE
• Implantation of tissue
that synthesizes and
secretes protein
therapeutic agents
Encapsulated Neural Grafts
• Implantation of
embryonic neural grafts
for the treatment of
Parkinsons
Nature Nanotechnology
Philip R. LeDuc, Michael S. Wong, Placid M. Ferreira, Richard E. Groff, Kiryn Haslinger,
Michael P. Koonce, Woo Y. Lee, J. Christopher Love, J. Andrew McCammon, Nancy A.
Monteiro-Riviere, Vincent M. Rotello, Gary W. Rubloff, Robert Westervelt & Minami Yoda
Nature Nanotechnology 2, 3 - 7 (2007)