INTRANASAL ROUTE-AN INNOVATIVE TECHNIQUE FOR BRAIN …

www.wjpr.net Vol 6, Issue 17, 2017.

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Joshi et al. World Journal of Pharmaceutical Research

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.


301


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.

https://www.myvmc.com/medical-dictionary/bowmans-glands/4497

https://www.myvmc.com/medical-dictionary/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


306


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


311


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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INTRANASAL ROUTE-AN INNOVATIVE TECHNIQUE FOR BRAIN …