Download 08_Nasal Drug Delivery

Nasal Drug Delivery
Dr Mohammad Issa
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Nasal physiology
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The nasal cavity is divided by the nasal
septum (comprised of bone and cartilage),
with each half opening at the face (via the
nostrils)
There is also a connection to the oral cavity
provided by the nasopharynx
The lateral walls comprise a folded structure
(refered to as the nasal labial folds or
conchae) providing a total surface area of
about 150 cm2 in humans
The three main areas of the nasal cavity are:
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The anterior and the posterior vestibules
The respiratory region
The olfactory region
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Nasal physiology
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Nasal physiology
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The epithelial tissue within the nasal cavity is
relatively highly vascularized, and thus provides
a potential conduit for drug delivery
The cellular makeup of the nasal epithelial
tissue consists mainly of ciliated columnar cells,
non-ciliated columnar cells, goblet cells and
basal cells, with the proportions varying in
different regions of the nasal cavity
Ciliated cells facilitate the transport of mucus
towards the nasopharynx. Basal cells, which are
poorly differentiated, act as stem cells to
replace other epithelial cells. Goblet cells, which
contain numerous secretory granules filled with
mucin, produce the secretions that form the
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mucus layer
Nasal delivery: Local delivery
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Intranasal administration of medicines is the
natural choice for the treatment of topical
nasal disorders.
Among the most common examples are
antihistamines and corticosteroids for
rhinosinusitis, and nasal decongestants for
cold symptoms
In these cases, intranasal route is the
primary option for drug delivery because it
allows a rapid symptom relief with a more
favorable adverse-event profile than oral or
parenteral routes
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Nasal delivery: Local delivery
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In fact, relatively low doses are effective
when administered topically, minimizing
simultaneously the potential of systemic toxic
effects. Recently, for instance, topical
antibiotherapy has been considered in chronic
rhinosinusitis in an attempt to eradicate
biofilm bacteria, often resistant to systemic
treatment, and still avoiding systemic toxicity
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Nasal delivery: Systemic delivery
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This route is easier and more comfortable for
the patient than the parenteral route and it
avoids enterohepatic recirculation and gut
enzymes
This naturally makes it attractive for the
delivery of peptides and recombinant DNA
technology
However, absorption rates fall off sharply
when the molecular weight exceeds 1000
Daltons which probably explains why
desmopressin is delivered successfully (m. w.
1069 Daltons), whilst insulin (m. w. 6000
Daltons approx.) is not
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Nasal delivery: Systemic delivery
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The nasal mucosa demonstrates typical
absorption mechanisms. Water soluble drugs
enter via passive diffusion through aqueous
channels. As the diffusion path through the
nasal mucosa is short, intranasally
administered drugs demonstrate a rapid rise
to peak plasma concentrations, but the rapid
clearance from the mucosa limits available
time for absorption
Amino acids such as tyrosine and
phenylalanine are absorbed by active
transport, presumably by similar mechanisms
to those observed in the blood brain barrier
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Nasal delivery: Systemic delivery
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Currently, commercial products which
utilize this route for systemic delivery exist
for some gonadorelin analogues, which are
hypothalmic hormones
These include buserelin for prostatic cancer,
oestradiol dependent endometriosis and
infertility, and nafarelin also for
endometriosis and infertility
Other commercial products includes
desmopressin for diabetes insipidus and
primary nocturnal enuresis and lypressin
for diabetes insipidus
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Nasal delivery: Systemic delivery
-Penetration enhancers
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The drive to increase the absorption of large
molecular weight molecules has lead to the
use of penetration enhancers
Bile salts, e.g. sodium deoxycholate, sodium
glycocholate and sodium taurocholate,
decrease the viscosity of mucus and create
transient hydrophilic pores in the membrane
bilayer
EDTA, and fatty acid salts such as sodium
caprate and sodium laurate, increase
paracellular transport by removal of luminal
calcium, thus increasing permeability of the
tight junctions
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Nasal delivery: Systemic delivery
-Penetration enhancers
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Non-ionic detergents e.g. Laureth-9 alter
membrane structure and permeability
It should be remembered that the
penetration enhancers are generally nonspecific and there remains the potential that
any large molecule can enter the systemic
circulation once the epithelial barrier is
breached
Some penetration enhancers, e.g. Laureth-9
and bile salts, have been reported to be toxic
to the nasal mucosa
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Nasal delivery: Systemic delivery
-Penetration enhancers
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Cyclodextrins have been used as solubilizers
and absorption enhancers for nasal drug
delivery
Methylated ß-cyclodextrins have been used to
promote absorption of peptides and proteins,
but mainly in animals
Limited studies show that the cyclodextrins
are well tolerated in humans
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Nasal delivery: vaccination route
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Advantages include: highly vascular mucous
membranes, low enzymatic degradation
compared to oral vaccines, and greater
acceptability to patients
Disadvantages: mucociliary clearance and
inefficient uptake of soluble antigens.
Therefore, nasal vaccines require potent
adjuvants and delivery systems to enhance
their immunogenicity and to protect their
antigens
It is important to note that even for active
antigens, intranasal delivery may not elicit an
immune response in the absence of an
effective adjuvant
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Nasal delivery: vaccination route
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Presentation of a suitable antigen with an
appropriate adjuvant to the nasal-associated
lymphoid tissue (NALT) has the potential to
induce humoral and cellular immune
responses
This approach may be a particularly effective
approach to achieving rapid mass
immunization, for instance in children and/or
in developing countries and disaster areas
Intranasal immunization may lead to
development of local, as well as systemic,
immunity.
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Nasal delivery: vaccination route
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Vaccination via the intranasal route does not
require a sterile product or a sterile dosing
technique (a distinct advantage in developing
areas of the world).
An example of an intranasal vaccine is
FluMist®, a cold-adapted live influenza virus:
This product is given as one or two doses
over the influenza season via a syringe
sprayer
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Nasal delivery: vaccination route
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Additional examples of human efficacy testing
of intranasal vaccines includes those targeted
against
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adenovirus-vectored influenza
proteosome-influenza
influenza A
influenza B
meningococcal outer membrane vesicle
a combination respiratory syncytial virus (RSV)
and parainfluenza 3 virus (PIV3) live,
attenuated intranasal vaccine
Effective nasal immunization requires an
effective antigen and/or a potent mucosal
adjuvant or carrier
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Mechanisms to increase nasal
residence time of formulations
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Two basic approaches have been used to
increase the nasal residence times of drugs:
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to use viscosity enhancers such as
hydroxypropylmethylcellulose and
methylcellulose
to use a “bioadhesive” excepients such as
albumin, Sephadex, starch, dextran,
hyaluronan, and chitosan
Chitosan has been shown to exhibit
advantages as a vaccine carrier due to its
immune stimulating activity and bioadhesive
properties that enhance cellular uptake,
permeation and antigen protection, as well as
being well tolerated by humans
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Intranasal drug delivery to the central
nervous system
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Drugs delivered intranasally are transported
along olfactory sensory neurons to yield
significant concentrations in the CSF and
olfactory bulb
Small molecules such as cocaine and
cephalexin can be transported directly to the
CNS from the nasal cavity
Cephalexin preferentially entered the CSF
after nasal administration compared to
intravenous (IV) and intraduodenal
administration in rats. The levels of
cephalexin in CSF were 166-fold higher 15
minutes after nasal administration than those
of the other two routes
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Intranasal drug delivery to the central
nervous system
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The ratio of the methotrexate AUCCSF value
between the intranasal route and the IV
injection was over 13-fold
A number of protein therapeutic agents, such
as neurotrophic factors and insulin, have
been successfully delivered to the CNS using
intranasal delivery in a variety of species
Insulin-like growth factor I (IGF-I) could be
delivered to the brain directly from the nasal
cavity, even though IGF-I did not cross the
BBB efficiently by itself. As a consequence,
intranasal IGF-I markedly reduced infarct
volume and improved neurological function
following focal cerebral ischemia
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Intranasal drug delivery to the central
nervous system
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Research in humans has also provided
evidence for direct delivery of therapeutic
agents to the CNS from the nasal cavity.
CNS effects of intranasal insulin in humans
was demonstrated without altering plasma
glucose or insulin level
Intranasal administration is a promising
approach for rapid-onset delivery of
medications to the CNS bypassing the BBB.
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Intranasal drug delivery : limitations
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One of the biggest limitations is insufficient
drug absorption through the nasal mucosa.
Many drug candidates cannot be developed
for the nasal route because they are not
absorbed well enough to produce therapeutic
effects
Another limitation concerning nasal
administration is that a small administration
volume is required, beyond which the
formulation will be drained out into the
pharynx and swallowed
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