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INTRANASAL ROUTE-AN INNOVATIVE TECHNIQUE FOR BRAIN …
Transcript of INTRANASAL ROUTE-AN INNOVATIVE TECHNIQUE FOR BRAIN …
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INTRANASAL ROUTE-AN INNOVATIVE TECHNIQUE FOR BRAIN
TARGETTING
Preeti Joshi* and Aushotosh Badola
Shri Guru Ram Rai Institute of Technology and Sciences, Dehradun.
ABSTRACT
The complex arrangement of Blood-Brain Barrier(BBB) restricts the
entry of drugs into the brain. The intranasal route is widely accepted
route for the delivery of many therapeutic agents due to a reason it
bypasses BBB. Direct nose to brain drug delivery has been proved to
be an excellent platform for brain targeting through surface
engineering of neurotherapeutic-loaded carrier systems resulting in
enhanced product performance. There is a unique pathway through
nasal mucosa to brain by which many upcoming therapeutic agents
will also delivered through this route to brain which have brain as
target site. Nowdays, macromolecules, stem cells, DNA plasmids,
chemotherapeutic agents etc are delivered by intranasal route.
KEYWORDS: Noninvasiveness, Intranasal drug delivery, Brain targeting, Blood Brain
Barrier, Central nervous system.
INTRODUCTION
Intranasal therapy has been an accepted form of treatment in the Ayurveda system of Indian
medicine since early. Nasal therapy also called “NASYA KARMA”. It is one of the
PANCHAKARMA mentioned in Ayurveda. It is the process by which drug is administered
through the nostrils. If „Nasyakarma‟ is done properly and regularly alleviate disease like
cervical spondylitis, headache, facial paralysis, hemiplegia, diseases of nose frozen shoulder,
mental disorder and skin complaints. Nasyakarma will enhance the activity of sense organs
and prevent the disease of head (URDHWANGA).[1]
The early 1980s saw the introduction of
nasal route as a promising systemic delivery alternative to other conventional drug delivery
system. Nasal mucosa has been considered as potential co-administration route to achieve
faster and higher level of drug absorption because it is permeable to more compounds then
World Journal of Pharmaceutical Research SJIF Impact Factor 7.523
Volume 6, Issue 17, 300-316. Review Article ISSN 2277– 7105
Article Received on
29 October 2017,
Revised on 19 Nov. 2017,
Accepted on 09 Dec. 2017
DOI: 10.20959/wjpr201717-10309
*Corresponding Author
Preeti Joshi
Shri Guru Ram Rai Institute
of Technology and Sciences,
Dehradun.
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Joshi et al. World Journal of Pharmaceutical Research
the gastrointestinal tract due to lack of pancreatic and gastric enzymatic activity, neutral pH
of the nasal mucous and less dilution by gastrointestinal contents.[2]
It is useful delivery
method for drugs that are active in low doses and show no minimal oral bioavailability such
as proteins and peptides.[3]
ADVANTAGES[4][5][6][7]
1. Rapid absorption, higher bioavailability, therefore, lower dose.
2. Fast onset of therapeutic action.
3. Avoidance of liver first pass metabolism & metabolism by GIT.
4. Minimum irritation to the gastrointestinal membrane.
5. Reduced risk of overdose.
6. Non-invaive, ease of convenience along with self medication.
7. Improved patient compliance.
8. It can be a beneficial adjunct product to an existing product.
DISADVANTAGES[8][9]
1. Concentration achievable in different regions of the brain and spinal cord varies with each
agent.
2. Delivery is expected to decrease with increasing molecular weight of drug.
3. Some therapeutic agents may be susceptible to partial degradation in the nasal mucosa or
may cause irritation to the mucosa.
4. The absorption enhancers used to improve nasal drug delivery system may have
histological toxicity which is not yet clearly established.
5. Absorption surface area is less when compared to GIT.
6. Once the drug administered can not be removed.
7. Nasal irritation.
NASAL ANATOMY & PHYSIOLOGY
Externally, nose consist of paired nasal bones and upper and lower lateral cartilages. Nasal
cavity is divided by nasal septum. The lateral nasal wall consists of inferior and middle
turbinates and occasionally a superior or supreme turbinate bone. The nasal membrane
composed of ciliated pseudostratified glandular columnar epithelium. Mucociliary transport
relies on mucus production and ciliary function.[10]
The level of congestion & nasal
membrane s controlled by Blood and autonomic nerve supply. Contributions of nerve supply
are from the facial nerve originating at the inferior salivatory nucleus and following along the
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distribution of the facial nerve through the sphenopalatine ganglion. internal and external
carotid artery systems supplies blood to the nose.[11]
ophthalmic artery of the internal carotid
artery system supply the posterior aspect of the nasal cavity. Olfactory nerve endings
originate in the olfactory bulb under the frontal lobe and pass directly through the cribriform
plate as second-order neurons entering the nasal cavity. Olfactory nerves are found on the
superior portion of the septum, superior turbinates, and cribriform region.[12][13]
Figure 1: Anatomy of nose.
NASAL VESTIBULE
The nasal vestibule is a small dilated space just internal to the naris, that is lined by skin and
contains hair follicles.
RESPIRATORY SECTION
The respiratory section of the nasal cavity refers to the passages through which air travels
into the respiratory system. The respiratory section of each nostril contains
four conchae (protrusions or bumps) which are also referred to as turbinate bones or lobes
and are covered by the nasal mucosa. conchae (also named turbinates) are the curved bony
projections pointed downwards and medially. Below and lateral to every concha is a
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corresponding meatus. Superior and middle nasal conchae are the projections from the medial
surface of the ethmoidal labyrinth. Inferior concha is a separate bone, The superior concha is
smallest and inferior concha is largest in size. Meatuses are the passages (recesses) below the
overhanging conchae.[14]
They‟re visualized once conchae are removed. Inferior meatus is the
largest and is located underneath the inferior nasal concha. Middle meatus is located
underneath the middle concha. The meatuses of the nasal cavity connect to the paranasal
sinuses.[15]
OLFACTORY REGION
The olfactory receptors (receptors for smell sensations) are found in this section of the nasal
cavity. Bowman‟s glands are also found in this section of the nasal cavity.
Three types of cells constitute olfactory epithelium i.e basal, supporting, and olfactory
receptor cells. Stem cells are the basal cells that give rise to olfactory receptor cells. The
continuous turnover and new supply of these neurons are unique to the olfactory system.
Supporting cells are scattered over the receptor cells and have numerous microvilli and
secretory granules, which empty their contents onto the mucosal surface[16][17]
. The receptor
cells are actually bipolar neurons contains specialized cilia which provide the transduction
surface for odorous stimuli.
The conchae (turbinate bones) of the nasal mucosa expand the total surface area of the
mucosa and create turbulence in air entering the respiratory passage. This causes air to swirl
as it moves through the nasal cavity and increases contact between infiltrating air and the
nasal mucosa, allowing particles in the air to be trapped before entering other parts of the
respiratory system (e.g. the lungs).[18]
The olfactory system functions to process sensory information related to smell.
BOWMAN‟S GLAND-Bowman‟s glands secrete the majority of the mucus which overlies
the nerves of the olfactory system. They also secrete the pigment which gives this mucus its
yellow colour. Mucus secreted by these glands dissolves odours as they enter the nose,
enabling them to interact with the olfactory receptors.
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PATHWAYS OF NASAL DRUG DELIVERY
Olfactory pathway: The possible mechanism by which drugs are transported from nose to
brain has not yet clear but olfactory pathway contributes a vital role. Basal cells and neural
cells replace each other during their constant motion and due to this constant motion and
replacement nasal mucosa becomes permeable resulting in enhanced delivery of drug to
brain. Three different pathways across the olfactory epithelium includes:
Paracellular pathway: Through the tight junctions between between sustentacular cells and
olfactory neurons. Hydrophillic drugs most probably absorbed by diffusion through aqueous
channels (pores). This pathway is slow and passive. This route is responsible for transport of
hydrophilic drugs and it shows rate dependency on the molecular weight of a drug.[19]
Drugs
with a molecular weight up to 1000 Da without absorption enhancer shows good
bioavailability which can be extended to drugs with molecular weight up to 6000 Da with
absorption enhancer.[20]
Transcellular pathway: Across the sustentacular cells most likely by receptor-mediated
endocytosis, fluid phase endocytosis or by passive diffusion. Passive diffusion is a common
transport pathway for lipophilic drugs.
Olfactory nerve pathway: In this drug is taken up into the neuronal cell by endocytosis or
pinocytosis mechanisms and transported by intracellular axonal transport to the olfactory
bulb.[21]
Figure 2: Olfactory & Trigeminal pathway.
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Trigeminal pathway: Trigeminal nerve which connects the nasal passages to the brain plays
an important role in IN delivery of drug. Respiratory region occupies major portion of nasal
cavity and innervated by trigeminal nerves.[22][23]
Trigeminal nerve is fifth (V) cranial nerve
having three branches; ophthalmic nerve, maxillary nerve and mandibular nerve and is
responsible for sensation in nasal cavity. Olfactory pathway delivers drug to rostal area of
brain, whereas trigeminal pathway not only targets rostal but also caudal area of brain,
making it difficult to differentiate whether intranasally administered drug is translocated to
rostal area by olfactory or trigeminal pathway. A unique feature of the trigeminal nerve is that
it enters the brain from the respiratory epithelium of the nasal passages at two sites: i) through
anterior lacerated foramen near the pons and ii) through the cribriform plate near olfactory
bulb, creating entry points into both caudal and rostral brain areas following intranasal
administration.[24][25]
FIGURE 3
Figure 3: Nose to brain transport.
BRAIN TARGETTING STRATEGIES
There are various techniques which are used to distrupt the BBB & helps in the transport of
drug molecules across this barrier to the CNS have been studied. These includes:-
Nasal Cavity
Olfactory
Region
Blood
CSF
Brain
Tissue
Tissues/Organ
Elimination
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Figure4: Drug delivery strategies to brain.
INVASIVE STRATEGIES
Distruption of BBB by chemicals: Various invasive techniques are used for the disruption
of the BBB and enhance the delivery of drug to Brain Osmotic disruption of BBB is one of
the invasive techniques in which shrinkage of endothelial cells takes place for a short period
of time & leakage of drug to the CNS through opening of tight junctions.[26]
On injecting
intracarotid hypotonic solution of mannitol, tight junctions were opened and subsequently
promoted the delivery of chemotherapeutic agents to the brain. This technique is less specific
DRUG DELIVERY STRATEGIES FOR
BRAIN TARGETTING
INVASIVE
STRATEGI
ES
NON-
INVASIVE
STRATEGIES
NEW
ADVANCEMENT
Distruption of
BBB by
chemicals
Focus
ultrasound
enhanced
delivery
Craniotomy
based drug
delivery
Use of
Polymeric
wafers
Prodrug
approach
Efflux pump
inhibition
Cell based
therapy
Intranasal
drug delivery
Antibodies
mediated drug
delivery
Laser light
based
technology
Facial
intradermal
injection
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and inefficient and major drawbacks are transport of plasma protein to CNS, disturbed
glucose uptake, neurotoxicity of cerebral tissues, altered brain functions and technicality
related issues. Bradykinin and histamine act as vasoactive agents which disturb the BBB &
improve the transportation of drugs to CNS. Role of bradykinin are the activation of B2
receptors, leakage of endothelial cells based on modulation of caveolin-1 and caveolin-2 and
permeability enhancement of brain tumor microvessels via (KATP) channels.[27]
Focus Ulrasound enhanced Delivery: Another versatile approach for enhancing of drug
transportation to the CNS by the use of ultrasound waves which reversibly and transiently
open the BBB. In this type of drug delivey microbubbles (MBs) is used as a contrast agent.
These bubbles were administered systemically and worked on acoustic energy principle to
exert pressure on endothelial cells and open the tight junctions, resulted in increased
permeability of BBB and improved delivery of drug to the brain. These MBs operate in
collaboration with low intensity Focus Ultrasound (FUS) and this combined system is called
MB facilitated FUS.
MB-FUS system decreases the acoustic energy requirement, focusing the acoustic energy
within blood vessels. Different antitumor agents such as trastuzumab[28]
, temozolomide[29]
,
methotrexate[30]
, neucleotides i.e. siRNA[31]
and stem cells[32]
have been successfully
delivered with the help of FUS. FUS-MB system is effectively used with other DDSs for
brain targeted delivery.
Craniotomy-based drug delivery: Craniotomy-based drug delivery is the direct way of
targeting the specific part of the brain without exposure to peripheral organs via Intracerebral
or intraventricular injection. In intraventricular delivery, drug reservoir implanted in the scalp
provided the controlled release of a drug and is connected to the ventricles in the brain
through catheter[33, 34]
. Higher concentration of drugs is achieved without distribution to the
interstitial fluid of brain. Intraventricular system directly delivers the drug to the ventricles
and subarachnoidal part of the brain and is suitable for therapy of meningioma and metastatic
cells of CSF[35]
. Intracerebral system directly injects or infuses the drug into brain
parenchyma through catheter[36]
and controlled devices maintain the delivery[37]
. This system
depends on the diffusion mechanism and provides slow distribution of drugs within the brain,
as diffusion decreases with the increase of distance. Hence, intracerebral delivery requires
large doses of a drug to achieve desired therapeutic response[38]
.
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Convection-enhanced Delivery: This system involves continuous infusion method and
pressure gradient to distribute large volume of drugs at target tissues via intracranial catheter.
This delivery overcomes the disadvantages of intracereberal delivery system. It has certain
limitations of drug entry to surrounding tissue, difficult to design, instability of drug and low
therapeutic level of drug in the target area. Coupling of CED with liposomes improved the
efficiency of CED for brain tumor targeting. Liposomal delivery, significantly, inhibited
tumor volume and increased the survival rate.
Polymeric wafers based delivery systems: Development of polymeric devices for targeted
and controlled delivery of therapeutic moieties lead to advancement in polymer technology.
This involves the controlled release of drug at targeted site. Wafers based on polyanhydride
were implanted in tumor resection area, crossed the BBB, gradually released and distributed
the drug into the brain and targeted site.[39][40]
Polyanhyride based polymer shows effective
results in animals with minimum toxicity. Wafers have certain limitations of less penetration
into deep brain tissue, cyst formation, meningitis, impaired wound healing and abscess
formation.
NON-INVASIVE STRATEGIES
These strategies utilizes the endogenous mechanism for transport of drug across the BBB.
Prodrug approach: With increase in lipophilic characters in drug molecule, it facilitates
better permeation. This approach based on chemical modifications in the drug molecule to
modulate its lipophilic behavior, increase permeability & water solubility. Targeted prodrugs
contain chemical entity along with parent drugs designed to approach enzymes or transport
system at the targeted site to be converted to active moiety. Peptidase enzymes in the brain
removed the spacer and released the active drug[41]
. Prodrug approach has been successfully
utilized for delivery of neurotherapeutics to treat neurological disorders. This approach
retains the drug at brain for longer period of time.
Efflux Pump inhibition: The presence of efflux pump in the BBB which is another barrier
for effective drug transportation to the brain. Efflux by the active P-glycoprotein (P-gp)
presents on the apical membrane of the endothelial cells of BBB results in poor drug
availability at the targeted brain tissues. P-gp has more affinity for lipophillic and cationic
drugs[42]
. Most of the low molecular weight drugs such as nitrosoureas are substrate for P-gp
and are restricted to enter the brain. Inhibition of P-gp efflux is the useful approach to save
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the therapeutic efficacy of potent drugs. Dopamine, pharmacologically effective for the
treatment of Parkinson′s disease, is unable to cross BBB disease. L-dopa is transported
through L-amino acid transporter crossed BBB and converted to dopamine in the brain.
Cell based therapy: This therapy utilizes macrophages and many types of stem cells as
carriers for delivery to brain. An effective delivery for neurological disorders and brain
tumors. In this macrophages with phagocytosis property migrated towards to brain by
transcellular or paracellular transport. During brain tumor and inflammatory conditions
macrophages are attracted and infiltrated towards brain. Macrophages are suitable candidates
for targeted delivery of NPs and diagnostic and imaging agents to the brain tumor and
neurodegenerative diseases. Stem cells could be used as vector for delivery of cytokines,
oncolytic viruses, and suicide genes to brain[43][44][45]
. Stem cells could be effective cargo for
oncolytic virus to treat the glioma. In a study, Mesenchymal Stem Cells carrying oncolytic
herpes simplex virus exhibited efficacious results in glioma-bearing mice[46]
.
Intranasal drug delivery: Drug administered through nasal route of administration is
absorbed into the systemic circulation. Drug absorption through nasal respiratory epithelium
follows transcellular and paracellular absorption, carrier-mediated transport, and absorption
through trancytosis mechanism[47]
. Nasal drug delivery to the brain posed a big challenge of
BBB-mediated restriction. Administration of drug deep into the nasal cavity approached nasal
mucosa, led to direct transmission of drug into brain via olfactory pathway. Olfactory
pathway consists of olfactory neurons that carry drugs from olfactory mucosa to the brain and
is slow process of drug transmission. Olfactory epithelium pathway is faster way of drug
transportation[48]
. Drug is passed through olfactory epithelium via paracellular mechanism
into perineural space and transferred directly to the brain.
RECENT ADVANCEMENTS IN BRAIN TARGETED DRUG DELIVERY SYSTEM
Antibodies mediated drug delivery: Restriction posed by the BBB and low brain
permeability of the antibodies limited the potential of antibody mediated therapy for
neurological diseases. mAbs are much large in size and unlike small molecules, unable to
cross BBB and approach target sites in the brain[49,50]
. Although, no mAb has been approved
for brain targeted therapy but several mAbs are under clinical trials especially for the
treatment of Alzheimer‟s disease.
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Bispecific antibody (bsAb) is newly designed Ab with two different binding specificities.
bsAbs are introduced for chemotherapy with one binding specificity targets the tumor cell
and other targets the antigen on immune cells[51]
. Recent application of bsAbs is the targeted
delivery across BBB. bsAbs constructed with one specificity to promote transportation across
BBB via receptor mediated transport and second specificity to target the specific site in the
brain for desired therapeutic effect. Several BBB crossing bsAbs were formulated and
evaluated for brain targeted delivery such as bsAb with transferrin receptor (TfR) binding
domain to cross BBB and single-chain variable region fragments (scFv) specificity against
amyloid beta peptide.
Laser light based technology: This technology is beneficial in distrupion of BBB & helpful
in glioma targeted delivery. Due to this laser light defects are created in endothelial cells & it
becomes leaky, allow transport of therapeutic agents to parenchymal tissues. Combination
therapy of 5-aminolevulinic acid (5-ALA) with laser light opened the tight junctions between
the endothelial cells for longer period of time. Laser could be combined with other strategies
to potentiate BBB disruption. Ultrashort laser pulses are successfully transport nanoparticles,
genetically engineered viruses and numerous therapeutic agents to the brain.
APPLICATION
Delivery of macromolecules: Large molecular size and susceptibility to enzymatic
degradation is the prime reason behind low bioavailability of such compounds. Proteins and
peptides are generally administered parenterally owing to their physicochemical instability
and susceptibility to hepatogastrointestinal first-pass elimination. IN delivery of large number
of protein based molecules to brain, such as corticotropin-releasing hormone (CRH),
neurotrophic factors, insulin and MSH/ACTH[52]
.
Delivery of stem cell & DNA plasmids: By nasal administration of DNA plasmids, the level
of plasmid in brain was 3.9 -- 4.8 times higher than the plasmid concentration in lungs and
spleen & reaches the brain within 15 min following intranasal administration. IN delivery of
Neural stem/progenitor cells (NSPC) rapidly migrate to malignant glioma via olfactory
pathway. IN delivery of NSPC provides non- invasive and chronic therapy for treating
gliomas and other CNS disorders.
Delivery of chemotherapeutic agents: Anticancer drugs when administrated by parenteral
or oral route to target the brain tumors not only limited the efficacy of these agents by BBB
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but also caused serious side effects on other organs; therefore, the nasal route of drug delivery
has been explored by researchers. chemotherapeutic agents such as Perillyl alcohol (POH)[53]
,
NSPCs[54]
, glioma-adapted vesicular stomatitis virus strain (VSVrp30)[55]
, methotrexate[56]
and telomerase inhibitors (GRN163)[57]
have been successfully delivered to target brain
tumors by nasal route.
CONCLUSION
An innovative drug delivery system is one which delivers the desired concentration of drug at
the required site. Intranasal delivery bypasses the BBB to target CNS, reducing systemic
exposure of drug, thereby reducing the systemic side effects & target the particular area.
Direct nose to brain drug delivery system is a potential strategy to overcome the obstacles
presented by the BBB. It is an attractive option of drug delivery due to its non-invasiveness.
A variety of neurotherapeutic agents including small drug molecules, proteins, peptides,
hormones and biological cells such as stem cells can be delivered by this route, thereby
yielding new insights into prevention and management of different neurological disorders. It
is uncertain, however, whether the drug is being released from the carrier system in the nasal
cavity and transported to CNS, or the carrier system is transported along olfactory and/or
trigeminal nerve pathways into the CNS where the drug is released. Thus, more basic
research is required to determine the possible transport pathway of therapeutic carrier to the
CNS and their further fate into the biological system.
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