Intranasal Route: A Novel Approach for CNS Delivery

 

Moon R. S., Mitkare S.S., Kshirsagar R.V, Kale A.G.*, Shinde N.D., Malewar A.S. and  Pawde P.K.

School of Pharmacy, SRTM University, Nanded (Maharashtra)

*Corresponding Author E-mail: abhijitkale20@gmail.com

 

ABSTRACT:

This review aims to evaluate the evidence for the existence of a direct nose to brain delivery. Blood brain barrier (BBB) represents one of the strictest barriers for delivery of drugs to brain due to restricted exchange of hydrophilic compounds, proteins between plasma and central nervous system (CNS).

 

From last few years due to restricted entry of many therapeutic agents to CNS, the diseases of CNS like Alzheimer’s, parkinsonism, brain tumors, anxiety, neuronal disorders, depression etc. can’t be treated efficiently. Different attempts were made for CNS drug delivery, but the fraction of drug reach to brain is too less due to BBB. Intranasal brain targeting is a new attempt for CNS delivery which bypasses the BBB and increases the fraction of drug reaches to CNS. This is because of direct contact of olfactory and trigeminal nerves with CNS. Here olfactory epithelium acts as channel for drug entering to brain. This pathway is novel, simple and non-invasive approach which eliminates the need for systemic delivery and unwanted systemic side effects. A wide variety of therapeutic agents without any modification can be delivered to brain by this route.

 

Therefore present study critically tries to evaluate the evidence of nasal-brain transport with a focus on drug carriers, transport pathways, formulation aspects and to suggest future strategies that may contributes in the field of nasal brain drug delivery.

 

KEYWORDS: Blood brain barrier (BBB), Central nervous system (CNS), olfactory epithelium, non-invasive.

 


INTRODUCTION:

Diseases of the Central Nervous System (CNS) such as schizophrenia, meningitis, migraine, Parkinson’s disease and Alzheimer’s disease require delivery of the drug to the brain for treatment. However such transport remains problematic, especially for hydrophilic drugs and large molecular weight drugs, due to the impervious nature of the endothelial membrane separating the systemic circulation and central interstitial fluid, the Blood–Brain Barrier (BBB). Hence, many therapeutic agents may have been abandoned because sufficient drug levels in the brain cannot be achieved via the systemic circulation.1

 

Macromolecular drugs such as peptides and proteins, termed ‘biologics,’ are too large and too hydrophilic to penetrate the BBB from the systemic circulation and would be rapidly degraded by gastrointestinal enzymes or the liver cytochromes, if taken orally. A non-invasive therapy would be desirable for patients particularly for diseases that require chronic dosing such as those related to dementia1, 2.

 

It has been shown in the literature from animal and human investigations, that transport of exogenous materials directly from nose-to-brain is a potential route for by-passing the BBB. This route, involves the olfactory or trigeminal nerve systems which initiate in the brain and terminate in the nasal cavity at the olfactory neuroepithelium or respiratory epithelium, respectively2.

 

They are the only externally exposed portions of the CNS and therefore represent the most direct method of non-invasive entry into the brain. However, the quantities of drug administered nasally that have been shown to be transported directly from nose-to-brain are very low, normally less than 0.1%, and hence the system is not currently used therapeutically and no product is licensed specifically via this route. 2

 

The strategy of applying drugs that are encapsulated into particulate vectors (such as synthetic nanoparticles) to the olfactory epithelium could potentially improve the direct CNS delivery of drugs—including biologics. If drugs could reach the CNS in sufficient quantity by this route, it could generate interest in previously abandoned drug compounds and enable an entirely novel approach to CNS drug delivery3.

 

Therefore, the present study aims to critically evaluate the evidence of nose-to-brain transport with a focus on drug carriers, transport pathways, formulation aspects and to suggest future strategies that may benefit progress in the field of nose-to-brain drug delivery1.

 

NEED FOR STUDY

Considering the wealth of activity and interest in the area of nasal drug delivery, together with the potential benefits from this route of administration, we should expect to see a range of novel nasal products reaching the market in the near future. These products will, in the first instance, most probably comprise products for crisis treatments, such as erectile dysfunction, sleep induction, acute pain (migraine), panic attacks, nausea, heart attacks and Parkinson’s disease because of the ability to provide rapid absorption of drug from the nasal cavity into the systemic circulation. On a longer term, novel nasal products for treatment of long-term illnesses, such as diabetes, growth deficiency, osteoporosis, fertility treatment and endometriosis, will also be marketed. Most of the new drugs used for these treatments are proteins, peptides; hence normally only given by injection4.

 

It will also be interesting to follow the developments in the area of nose to brain delivery of drugs and whether it will prove possible to develop nasal delivery systems that will enable a rapid and efficient concentration of drug in the brain necessary for the treatment of selected diseases of the brain or the CNS and to circumvent the blood–brain barrier5.

 

Advantages of Intranasal Delivery 6, 7

·        Direct transport into systemic circulation and CNS is possible.

·        Direct delivery of vaccine to lymphatic tissue and induction of a secretory immune response at distant mucosal site.

·        Avoids degradation of drug in GI tract resulting from acidic or enzymatic degradation.

·        Avoids degradation of drug resulting from hepatic first pass metabolism.

·        Results in rapid absorption and onset of effect.

·        Results in higher bioavailability thus use lower doses of drug.

·        Easily accessible, non-invasive route, self-medication is possible

·         Needle free drug application 

·        Improves patient compliances compared to parenteral routes.

·        Offers lower risk of overdose (Steady state conc.)

·        Does not have any complex formulation requirement

·        Effective in emergency as an alternative to parenteral route of administration.

 

Limitations of Nasal Delivery

·        Limited understanding of mechanisms and less developed models at this stage.

·        Volume that can be delivered into nasal cavity is restricted to 25–200 ul

·        High molecular weight compounds cannot be delivered through this route (mass cut off ~1 kDa)

·        Adversely affected by pathological conditions

·        Large interspecies variability is observed in this route

·        Normal defence mechanisms like mucocillary clearance and ciliary beating affects the permeability of drug

·        Enzymatic barrier to permeability of drugs

·        Irritation of nasal mucosa by drugs

 

NASAL ANATOMY AND PHYSIOLOGY:

1)      The external nose and the nasal cavity1,3:

The main functions of the nose are olfaction, regulation of humidity and temperature of inhaled air, and removal of large particulates including microorganisms from the inhaled air. In humans, the total surface area and volume of the two sides of the nasal cavity has been measured using computed tomography (CT) scans as 150.4cm2 (made possible by three protrusions or ‘turbinates’ within the cavity) and 13.0 ml, respectively1,3.

 

Fig.1: The external nose and nasal cavity,

A) Nasal vestibule, B) Internal ostium, C) Inferior concha (inferior turbinate and orifice of the nasolacrimal duct), D) Middle concha (middle turbinate and orifices of frontal sinus, anterior ethmoidal sinuses and maxillary sinus), E) Superior concha (super turbinate and orifices of posterior ethmoidal sinuses), hatched area: olfactory region.

 

Fig. 2: Nasal mucosa contains ciliated epithelial cells and mucous-producing goblet cells

a)                 Cilia b) Ciliated columnar cells c) non-ciliated cells d) goblet cells e)Basal cells

Fig.3: Olfactory Region of brain

 

Fig.4: Olfactory area showing the olfactory epithelium, bulb and tract.

 

Fig.5: Delivery of Drugs to Brain through Nasal Cavity

 

Fig.6: Various regions showing Nasal Cavity

 

The nasal septum divides the nasal cavity along the centre into two halves open to the facial side and to the rhino pharynx, through the anterior and via the posterior nasal apertures, respectively. Each nasal cavity can be divided into three regions; the nasal vestibule, the olfactory region and the respiratory region. The olfactory epithelium is located high in the nasal cavity in man. It partly overlies the cribriform plate, a bony structure that contains many pores that allow the passage of neuronal bundles from the olfactory epithelium to pass into the CNS. Olfactory epithelium may also lie partly on the nasal septum and on the superior turbinate. It is above the normal path of the airflow which means that odorant molecules normally reach the sensitive receptors by diffusion. The act of sniffing enhances the diffusional process by increasing the airflow rate and changing it from continuous to pulsatile in nature. This behavior increases the turbulence within the nasal cavity and therefore allows greater interaction of the inspired air with the olfactory region at the roof of the nasal cavity. The respiratory region is dominated by the large inferior turbinate, the middle turbinate and further back in the nasal cavity, the superior turbinate3,6,7.

 

Fig.7: Pathway of olfactory transfer of drug from nose to brain.

 

The respiratory epithelium and mucociliary clearance

The respiratory epithelium is composed of four types of cells, namely, non-ciliated and ciliated columnar cells, basal cells and goblet cells. These cells facilitate active transport processes such as the exchange of water and ions between cells and motility of cilia (where applicable). They may also serve to prevent drying of the mucosa by trapping moisture. About 15–20% of the respiratory cells are covered with a layer of long cilia, which move in a coordinated way to propel mucus towards the pharynx3.

 

Mucus (or nasal secretion) is a complex mixture of materials consisting of approximately 95% water, 2% mucin, 1% salts, 1% of other proteins such as albumin, immunoglobulins, lysozymes and lactoferrin, and <1% lipids3.

 

Mucus is present in two layers on the epithelium in order to facilitate mucociliary clearance. The cilia beat with a frequency of 1000 strokes per min. Hence the mucus moves only in one direction from the anterior to the posterior part of the nasal cavity to the nasopharynx. Therefore, particles applied to the nasal respiratory mucosa will be transported on the mucus to the back of the throat with a speed of 5mm per min3,5.

 

3) Olfactory epithelium and neuronal supply to the nasal cavity

The olfactory epithelial layer predominantly contains three cell types: the olfactory neural cells, the sustentacular (also known as supporting) cells and the basal cells. Basal cells are progenitor cells (of supporting cells) that also provide mechanical support via anchorage to other cells3,11.

 

The olfactory neural cells or the axons are un-myelinated and interspaced between the supporting cells (Fig.4). They originate at the olfactory bulb in the CNS and terminate at the apical surface of the olfactory epithelium3.

 

The olfactory knob (or vesicle) protrudes out from and above the apical surface of the olfactory epithelium (Fig.4). Approximately 10–23 cilia project from the basal bodies of the knob, each of length up to 200 m. The cilia contain chemical detectors that, once activated by odorants, initiate depolarisation of the olfactory axon by either direct ion-gated channels or cAMP operated ion-channels3.


Table no.1: Structural features of different sections of nasal cavity and their relative impact on  permeability 15

Region

Structural features

Permeability

Nasal Vestibule

Nasal hairs, epithelial cells are stratified, squamous and keratinized, sebaceous glands are present

Least permeable because of presence of kerastinized cells

Atrium

Transepithelial region, stratified squamous cells are present anterioly and pseudostratified cells with microvilli present posteriorly, Narrowest region of nasal cavity

Less permeable as it has small surface area and stratified cells are present anteriorly

Respiratory Region (Inferior turbinate, middle turbinate, superior turbinate)

Pseudostratified ciliated columnar cells with microvilli (300 per cell), large surface area, Receives max. nasal secretions because of seromucus glands, nasolacrimal ducts and goblet cells, Richly supplied with blood for heating and humidification of inspired air.

Most permeable region because of large surface area and rich vasculature

Olfactory region

Specilized ciliated olfactory nerves cells for smell perception, Receives ophthalmic and maxillary divisions of trigeminal nerves, Direct access to CSF

Direct  access to CSF

Nasopharynx

Upper part contains ciliated cells and lower part contains squamous epithelium

Receives nasal cavity drainage

 


 

Junctional complexes (cell-to-cell contact areas) found between both respiratory and olfactory epithelial cells in the nasal cavity.

 

VARIABLE FACTORS AFFECTING THE PERMEABILITY OF DRUGS THROUGH NASAL MUCOSA6,7,15:

 

A. Biological factors

·        Structural features

·        Biochemical changes

B. Physiological factors

·        Blood supply and neuronal regulation

·        Nasal secretions

·        Nasal cycle

·        pH of the nasal cavity

·        Mucociliary clearance and ciliary beat frequency

·        Pathological conditions

C. Environmental factors

·        Temperature

·        Humidity

 

D. Formulation factors

a) Physicochemical properties of drug

·        Molecular weight

·        Size

·        Solubility

·        Lipophilicity

·        pKa and partition coefficient

b) Physicochemical properties of formulation

·        pH and mucosal irritancy

·        Osmolarity

·        Viscosity/Density

·        Drug distribution

·        Area of nasal membrane exposed

·        Area of solution applied

·        Dosage form

E. Device related

·        Particle size of the droplet/powder

·        Site and pattern of disposition

F. Patient Population Related

·        Effect of nasal inflammation

·        Nasal physiology

·         Variability in I N dosing

 

The factors affecting permeability of drug through the nasal mucosa can broadly be classified as follows

 

Biological factors

Although efforts are being made to skillfully modify and explore the structural features and mechanisms of nasal mucosa to increase permeability, this is not advisable because of anticipated alterations in the normal physiology of the nasal cavity, especially during chronic application. These alterations could cause unintended adverse effects and result in pathological implications15.

 

Ø  Structural features

The nasal cavity can anatomically be segregated into five different regions: nasal vestibule, atrium, respiratory area, olfactory region and the nasopharnyx as earlier. The structural features of the regions that are responsible for the permeability of the nasal cavity are listed in table.

 

Ø  Biochemical changes

Nasal mucus acts as an enzymatic barrier to the delivery of drugs because of the presence of a large number of enzymes, which include oxidative and conjugative enzymes, peptidases and proteases. These enzymes are responsible for the degradation of drugs in the nasal mucosa and result in creation of a pseudo-first-pass effect, which hampers the absorption of drugs. The nasal P450-dependent monoxygenase system has been implicated in nasal metabolism of nasal decongestants, alcohols, nicotine and cocaine. Similarly, protease and peptidase were found to be responsible for the presystemic degradation and subsequent lower permeation of various peptide drugs, such as calcitonin, insulin and desmopressin. In spite of these hurdles, the nasal route is still considered to be superior to the oral route7, 17.

 

Physiological factors

Ø  Nasal secretions

Anterior serous and seromucous glands are responsible for the production of nasal secretions. Approximately 1.5–2 l ml of mucus is produced daily. The mucus layer probably exists as a double layer (5 μm thick) consisting of ericiliary sol phase in which the cilia beat and a superficial blanket of gel is moved forwards by the tip of the cilia.

 

The permeability of drug through the nasal mucosa is affected by:

• Viscosity of nasal secretion

• Solubility of drug in nasal secretions

• Diurnal variation

 

 

 


Table no.2: Excipients used in nasal dosage forms 6,7

Pharmaceutical Excipients

Type of dosage form

Comments

Permeation enhancers

e.g. 1. Cyclodextrins

2. Fusidic acid derivatives

3. Phosphatidylcholines

4. Microspheres and  liposomes

5. Bile salts and surfactants

 

 

Powders, gels, solutions

 

 

Improves the bioavailability of drugs particularly molecular weight above 1000 Da Causes nasal epithelial toxicity

Solvents

e.g.  ethanols, polyethylene, propylene glycols etc.

Gels, solutions

To increase conc. of drug in vehicle and reduce the dose volume, may act as permeation enhancers

Viscosity modifiers

e.g. cellulose derivatives

Gels, solutions

To improve the nasal residential time

Mucoadhesive polymers

e.g. carbopol, polycabophil, cellulose derivatives, lecithin, and chitosan

 

Powders, gels, solutions

To improve the nasal residential time

Preservatives

e.g. benzalkonium chloride

Gels, solutions

To maintain sterility of dosage form, may alter the nasal residential time

Enzyme inhibitors

e.g. bestatin, amastatin, boroleucine, fusidic acid, and bile salts

 

Powders, gels, solutions

 

To improve the bioavailability of protein and peptides

Tonicity modifies/buffers

e.g. sodium chloride, citrate buffer

 

Solutions

 

To avoid the nasal epithelial toxicity

 


Table No.3:  Strategies to Improve Bioavailability 6,7

Strategy

Examples

Nasal enzyme inhibitors

Bestatin, amastatin, boroleucine, fusidic acid, and bile salts

Nasal permeation enhancers

Cyclodextrins, surfactants, saponins, fusidic acids, and phospholipids

Prodrug approach

Cyclic prodrugs, esters, and derivatization of C and N termini

Nasal mucoadhesives

Carbapol, polycarbophil, cellulose derivatives, lecithin and chitosan

Particulate drug delivery

Microspheres, nanoparticles, and liposomes

 

Ø  pH of nasal cavity

 It varies between 5.5–6.5 in adults and 5.0–7.0 in infants. A greater drug permeation is usually achieved at a nasal pH that is lower than the drug’s pKa because under such conditions the penetrant molecules exist as unionized species. A change in the pH of mucus can affect the ionization and thus increase or decrease the permeation of drug, depending on the nature of the drug. Because the pH of the nasal cavity can alter the pH of the formulation and vice-versa, the ideal pH of a formulation should be within 4.5–6.5 and if possible the formulation should also have buffering capacity15.

 

Ø  Mucociliary clearance (MCC) and ciliary beating

These are normal defence mechanisms of the nasal cavity that clear mucus as well as substances adhering to the nasal mucosa bacteria, allergens, and so on) and drain them into the nasopharnyx for eventual discharge into the gastrointestinal tract. Whenever a substance is nasally administered, it is cleared from the nasal cavity in ~21 min by MCC. Reduced MCC increases the time of contact between a drug and the mucus membrane and subsequently enhances drug permeation; whereas, increased MCC decreases drug permeation. Some drugs, hormonal changes of the body, pathological conditions, environmental conditions and formulation factors (especially rheology are reported to affect the MCC and in turn exert significant influence on drug permeability15.

 

Ø    Pathological conditions

Diseases such as the common cold, rhinitis, atropic rhinitis and nasal polyposis are usually associated with mucociliary dysfunctioning, hypo or hypersecretions, and irritation of the nasal mucosa, which can influence drug permeation. Merkes et al. recently screened and later classified drugs as cilio0friendly or cilio-inhibitory and thus provided a valuable tool in the design of safe nasal drugs15.

 

Environmental conditions15

Temperatures in the range of 24°C cause a moderate reduction in the rate of MCC whereas on the whole it has been seen that a linear increase in ciliary beat frequency occurs with increase in temperature.

 

Formulation factors15

A nasal formulation is usually composed of drug, vehicle, and excipients.

 

a) Physicochemical properties of drug

MW and size MW and lipophilicity or hydrophilicity act together to determine drug permeation. A large number of therapeutic agents, peptides and proteins in particular, have shown that for compounds >1 kDa, bioavailability can be directly predicted from knowledge of MW. In general, the bioavailability of these large molecules ranges from 0.5% to 5%. In the case of lipophilic compounds, a direct relationship exists between the MW and drug permeation whereas water-soluble compounds depict an inverse relationship.

 

Permeation of drugs less than 300 Da is not significantly influenced by the physicochemical properties of the drug, which will mostly permeate through aqueous channels of the membrane. By contrast, the rate of permeation is highly sensitive to molecular size for compounds with MW >300 Da. Solubility Drug solubility is a major factor in determining absorption of drug through biological membranes. However, very few reports are available regarding the relationship between the solubility of a drug and its absorption via the nasal route. As nasal secretions are more watery in nature, a drug should have appropriate aqueous solubility for increased dissolution

 

Ø  Lipophilicity

On increasing lipophilicity, the permeation of the compound normally increases through nasal mucosa.

Ø  Partition coefficient and pKa

As per the pH partition theory, unionized species are absorbed better compared with ionized species and the same holds true in the case of nasal absorption.

 

b) Physicochemical properties of the formulation 15

Ø pH and mucosal irritancy

The pH of the formulation, as well as that of nasal surface, can affect a drug’s permeation. To avoid nasal irritation, the pH of the nasal formulation should be adjusted to 4.5–6.5. In addition to avoiding irritation, it results in obtaining efficient drug permeation and prevents the growth of bacteria.

 

Ø  Viscosity

 A higher viscosity of the formulation increases contact time between the drug and the nasal mucosa thereby increasing the time or permeation. At the same time, highly viscous formulations interfere with the normal functions like ciliary beating or mucociliary clearance and thus alter the permeability of drugs.

 

Ø  Area of nasal mucus membrane exposed

In a study conducted using 40 mg progesterone ointment, absorption was compared between applications to one nostril with application to both nostrils. Increased bioavailability was observed when ointment was applied in both the nostrils concluding that as the area of mucus membrane exposed increases, it should result in increased permeation.

 

Ø  Volume of solution applied

The volume that can be delivered to the nasal cavity is restricted to 0.05–0.15 ml. Different approaches have been explored to use this volume effectively including the use of solubilizers, gelling, or viscofying agents. The use of solubilizer increases the aqueous solubility of insoluble compounds and can even promote the nasal absorption of the drug. Gelling agents decrease drainage and result in an increase in the retention time of the drug in contact with mucus membranes.

 

Ø  Dosage form

Nasal drops are the simplest and most convenient dosage form but the exact amount that can be delivered cannot be easily quantified and often results in overdose. Moreover, rapid nasal drainage is a problem with drops. Solution and suspension sprays are preferred over powder sprays because powder results in mucosal irritation. Recently, metered-dose gel devices have been developed that accurately deliver drug. Gels reduce the postnasal drip and anterior leakage, and localize the formulation in mucosa. A limited amount of work has been reported on the use of emulsions and ointments as nasal formulations. Specialized systems such as lipid emulsions, microspheres and niosomes have been developed for nasal delivery.

 

Device related factor15

Different types of device are used to deliver formulations to nasal cavity. Shape and size of the device affects:

 

Ø  Particle size of the droplet or powder

The particle size of the droplet produced depends on the shape and size of the device used. If the particle size produced is <10 μm, then particles will be deposited in the upper respiratory tract, whereas if particle size is <0.5 μm then it will be exhaled. Particles or droplets with size between 5–7 μm will be retained in the nasal cavity and subsequently permeated.

 

Ø  Site and pattern of deposition

The site and pattern of deposition is affected by formulation composition, the physical form of the formulation (liquid, viscous, semisolid, solid), the device used, the design of actuators and adapters, and administration technique. The permeability of the site at which the formulation is deposited and the area of nasal cavity exposed affects the absorption of drugs. Retention of the drug in the nasal cavity is also dictated by the above factors.

 

Factors related to patient population

Ø  Effect of nasal inflammation

A common question regarding IN dosing and the intended patient population is whether inflammation of the nasal mucosa (e.g., patients with rhinitis) affects drug bioavailability. Various studies suggest that intranasal drug pharmacokinetics and/or pharmacodynamics are not affected by the presence of rhinitis. These studies include the examination of intranasal formulations of low-molecular-weight compounds (e.g., dihydroergotamine, zolmitriptan, and butorphanol, as well as peptide drugs (e.g., buserelin and desmopressin.)

 

Ø  Nasal physiology

Various aspects of nasal physiology and their workings, such as nasal anatomy, airflow, resistance, and the nasal cycle may have a potential impact on IN delivery.

 

Variability of IN dosing

Inter-and intra-subject variability in pharmacokinetics and/or pharmacodynamics is an important consideration when choosing the delivery route. Different administration routes should be compared (e.g., IN, oral, injection), and viable options are those with variability commensurate with the expected therapeutic window. Variability can be affected by numerous factors, including those arising from the patient, delivery device, formulation, and the drug itself. For low-molecular-weight drugs, IN dosing can provide pharmacokinetics with relatively high bioavailability and relatively low variability, which in many cases is similar to or lower than oral or even injection administration. However, for high-molecular-weight drugs such as peptides and proteins, IN pharmacokinetics exhibit relatively low bioavailability and relatively high variability compared to injections. This can be ameliorated by the use of permeation enhancers (vide infra) which can enhance bioavailability and reduce variability.

 

OPPORTUNITIES FOR NASAL DELIVERY:

Nasal delivery – what are the possibilities?

Local delivery:

·        Nasal allergy

·        Nasal congestion

·        Nasal infection

 

Systemic delivery:

·        Crisis treatments – rapid onset is needed

·        Long term treatment – daily administration

·        Peptides and proteins – difficult to administer

 

 

Vaccine delivery:

·        Antigens (whole cells, split cells, surface antigens)

·        DNA vaccines

Access to CNS:

·        To reach local receptors

·        To circumvent the blood-brain barrier

 

INTRANASAL BRAIN DELIVERY:

The nose to brain delivery would be beneficial in therapeutic situations where a rapid and/or specific targeting of drugs to the brain is required. Conditions such as Parkinson’s disease, Alzheimer’s disease or pain would be benefited from the development of nasal delivery systems, which will increase the fraction of drug that reach the CNS after nasal delivery.1

 

Olfactory Region in Relation to the Brain

The olfactory region located at the upper remote parts of the nasal passages offers the potential for certain compounds to circumvent the blood-brain barrier and enter into the brain.

 

Neurotrophic factors such as NGF [72-74] IGF-I [75] FGF [76] and ADNF [77] have been intranasally delivered to the CNS in rodents. Studies in humans, with proteins such as AVP, CCK analog, MSH/ACTH and insulin have revealed that they are delivered directly to the brain from the nasal cavity. Frey declared that by nasally administering insulin like growth factor (IGF-1) the drug could bypass the blood brain barrier and reach the central nervous system directly from the nasal cavity. Reports in the literature of studies in animal models and in man have shown this to be a distinct possibility with results showing the uptake of drugs into the cerebrospinal fluid and the brain tissue being dependent upon molecular weight and the lipophilicity. Various studies in animal models have confirmed that, at early time points after nasal administration, the concentration of cocaine in the brain was higher after nasal administration than after intravenous administration, thereby showing the existence of a pathway from the nose to the brain.1,2

 

Mechanism of Drug Transport to CNS

The first step in the absorption of drug from the nasal cavity is passage through the mucus. Small, unchanged articles easily pass through this layer. However, large or charged particles may find it more difficult to cross. Mucin, the principle protein in the mucus, has the potential to bind to solutes, hindering diffusion. Additionally, structural changes in the mucus layer are possible as a result of environmental changes (i.e. pH, temp., etc.).6,7

 

Subsequent to a drug’s passage through the mucus, there are several mechanisms for absorption through the mucosa. These include

1.      Transcellular or simple diffusion across the membrane,

2.      Paracellular transport via movement between cell and

3.      Transcytosis by vesicle carriers.

 

Obstacles to drug absorption are potential metabolism before reaching the systemic circulation and limited residence time in the cavity. Several mechanisms have been proposed but the following two mechanisms have been considered predominantly6.

 

Ø  The first mechanism involves an aqueous route of transport, which is also known as the paracellular route. This route is slow and passive. There is an inverse log-log correlation between intranasal absorption and the molecular weight of water-soluble compounds. Poor bioavailability was observed for drugs with a molecular weight greater than 1000 Daltons6,7.

 

Ø  The second mechanism involves transport through a lipoidal route that is also known as the transcellular process and is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. Drugs also cross cell membranes by an active transport route via carrier-mediated means or transport through the opening of tight junctions6,7.

 

Ø  Other mechanism / Cellular mechanisms for transmucosal drug delivery

Nanoparticles (when larger than about 20 nm) are thought to pass transcellularly (apical to basolateral transport through epithelial cell) in nose-to-brain drug delivery. The transcellular route of cell transport is less well characterized than the paracellular route. Novel spectroscopy and microscopy techniques such as electron energy loss spectroscopy and energy filtering transmission electron microscopy have recently provided new insights into endocytosis and the cellular mechanism responsible for the transcellular transport of particles

 

Ø  Endocytosis is also one of the mechanism found for nasal CNS delivery.

 

FORMULATION STRATEGIES FOR DIRECT NOSE-TO-BRAIN DRUG TRANSPORT 

Platform technology

As platform technology opens a possibility to efficiently deliver a number of different drugs. Here the nanoparticles, nanoemulsions, microspheres, prodrugs.etc. can be effectively delivered to CNS. Here the main intention is given to the compatibility of API and excipients in the formulations.3  

 

Surface modification

Another approach used is surface modification. Here drug delivery properties of the formulation are determined by the interaction of the surface coating with the biological system and not that of the biophysical properties of the drug molecule itself. This strategy could potentially standardize the utility of this drug delivery route so that it would be more predictable. These surface modification by chitosan, PEG and lectins.

 

APPLICATIONS

Delivery of protein therapeutic agents/ Macromolecules to CNS

In the age of advanced protein, peptides and vaccine research, nasal administration of such drugs provides an attractive route. In case of oral administration, the bioavailability of protein molecules tends to be relatively low due to their large molecular size and rapid enzymatic degradation. Because of their physicochemical instability susceptibility to hepato-gastrointestinal “first-pass” elimination, peptide/protein drugs are generally administered parenterally It is on this background that intranasal administration seems a promising option6,7.

 

Recently most nasal formulations of peptides/protein drugs have been made up in simple aqueous or saline solutions with preservatives. Delivery of protein therapeutic agents to the CNS clearly involves the extraneuronal transport as it occurs within minutes rather than hours. A number of protein therapeutic agents have been successfully delivered to CNS using intranasal delivery in a variety of species. e.g. Neurotropic factors such as NGF, IGF-I in rhodents, proteins such as MSH/ACTH, insulin in humans7.

 

The bioavailability of protein molecules tends to be relatively low due to their large molecular size and rapid enzymatic degradation. As the number of amino acids increases beyond 20, bioavailability becomes very low. To overcome this problem, absorption enhancers (surfactants, glycosides, cyclodextrin, glycols), and bioadhesive agents (carbapol, cellulose agents, starch, dextran and chitosan) may be used7.

 

Liu et.al has demonstrated the therapeutic benefits of intranasal delivery of proteins in stroke studies. Here IGF-I reduces the infaract volume and improves the neurologic function with middle cerebral artery occlusion (MCAO)6,7.

 

Delivery of DNA Plasmids to the CNS

Of the several routes available for immunization, the nasal route is particularly attractive because of the ease of the administration and induction of potent immune responses, particularly in respiratory tract. However effective delivery system is required to enhanced immune responses following nasal immunization6.

 

It has been reported that after nasal administration of DNA plasmids, the level of plasmids in the brain was, 3.9 to 4.8 times higher than the plasmids concentrations in the spleen and lungs. Plasmid DNA reached the brain within 15 minutes after intranasal administration. The higher distribution of plasmids to the brain after intranasal administration indicates that nasal administration might be a potential route for the delivery of therapeutic genes to the CNS with reduced side effects in other organs.7

 

Delivery of small molecules to the CNS

Many small molecules have been shown to be transported directly to the brain and /or CSF from the nasal cavity. e.g. estrogen, progesterone, cocaine have higher CSF and olfactory bulb concentration after nasal administration than that obtained after parenteral administration. The properties of small molecules such as size and lipophilicity affect delivery to the CNS after intranasal delivery. e.g. CSF conc. of Cephalexin was found to be 166 fold higher after intranasal administration compare to systemic route7.

 

In Alzheimer’s disease

Here intranasal route used for delivery of water soluble prodrug form of 17-beta-estradiol in Alzheimer’s disease. The concentration of drug in CSF after intranasal route is higher than IV route for the same dose. 6, 7

 

CONCLUSION:

Studies on this topic may suggest that intranasal brain drug delivery has a great potential to treat both acute and chronic diseases, neurological diseases. Intranasal brain drug delivery could be a critical advance for establishing effective therapeutic strategies for CNS diseases including Alzheimer’s disease and Parkinsonism.

 

For a drug to be successfully administered through the nasal cavity, it has to overcome the challenges created by the enzymatic barrier of the nasal mucosa, the physical barrier of nasal epithelium, mucociliary clearance and the mucus layer itself before reaching the systemic circulation. Previous study suggests that large molecules like insulin, proteins having specific effects on various function of brain can be transported rapidly from nasal cavity to CNS1. The formulation and the permeability aspects of drug molecules greatly affect the bioavailability of drugs. From the formulation scientist’s perspective, a better understanding of permeation pathways is required so that a correlation can be established between the physicochemical properties of the drug and formulation with that of permeation rate. This will not only aid in the optimal design of formulation but also cut down the experimental efforts involved. Further, extensive research for alternatives at the molecular level is required to increase the permeation of drugs through the nasal mucosa without compromising normal functioning of nose which ultimately results in larger fraction of drug delivery to CNS3.

 

One of the most important factors hindering the quality of nasal product is inter and intra subject variability in pharmacokinetics of dosage forms. Bioavailability of nasal products is one of the major challenges for pharmaceutical companies to bring their products in market. The circumstances, which do not favor clinical applicability of nasal drug product is the lack of enough basic research in the area of nasal drug delivery. The researchers and pharmaceutical companies should invest enough money in further development of intranasal brain delivery1,6,7.

 

The era of nasal drug delivery has started but efforts need to be done to make it more popular and efficient. The researchers, biomedical scientists, formulation researchers, pharmaceutical companies, funding agencies and government along with regulatory bodies should pay attention to basic research in nasal brain drug delivery such as nasal pathophysiology, invention of new excipients to improve the nasal bioavailability, drug delivery devices, toxicodynamic studies of drugs and excipients and in vitro methods for nasal drug metabolism and bioavailability which makes delivery of drugs to brain more simpler and efficient2.

 

FUTURE PERSPECTIVE

Although the major progress has been made regarding the intranasal drug delivery, there is still a distinct lack of information regarding this important topic. The studies searching for this information should be done urgently because of rapid increase in aging population and number of patients suffering from CNS disorders, especially neurological diseases around the world.

 

The following future studies may be of particular interest.

Ø  It is essential to search for the mechanisms underlying the direct drug transport from nose-to-brain after intranasal drug delivery, particularly those mechanisms in humans.

Ø  Second, methods for intranasal drug administration to treat CNS diseases must be improved.8, 20

Ø  Previous studies have suggested potential pathways to further increase the efficacy of intranasal drug delivery. For example, it was reported that carriers of drug such as methoxy poly (ethylene glycol)-poly (lactic acid) nanoparticles, can further increase the efficacy of intranasal drug delivery to brain7,8,20.

Ø  The optimum body positions for intranasal drug delivery have to be focused and some advanced tools for intranasal drug administration has to be invented. Future investigations along these research directions are to optimize the intranasal drug delivery approach.8, 20.

Ø  It appears increasingly necessary to conduct clinical trials to determine if intranasal drug delivery may be used to treat neurological diseases, which has been distinctly insufficient.1,3,8,20

 

Thus future studies should evaluate the possibility of improving the effectiveness of nose-to brain transport by drug delivery and drug formulation approaches.

 

REFERENCES:

                   

1.       L. Illum, Transport of drugs from the nasal cavity to the CNS:Eur.J.Pharm.Sci.2000:11:1-18

2.       L. Illum, Is nose-to-brain transport of drugs in man a reality? : J. Pharm. Pharmcol 2004:56:3-17

3.       Alpesh Mistry, Snjezana Stolnik, Lisbeth Illum, Nanoparticles for direct nose-to-brain delivery of drugs:Int.J. Pharm. 2009:379:146-157

4.       L. Illum, Nasal drug delivery- possibilities, problems and  solutions: J.Controlled Release 2003:87: 187-198

5.       L. Illum, Nasal Drug Delivery-new developments and strategies: Drug Discovery Today 2002:7: 1184-1189

6.       S. Talegaonkar, P. R. Mishra, Intranasal delivery: An approach to bypass the BBB: Indian J. Pharmacol 2004:36:140-147

7.       Satish B. Bhise, A.V. Yadav, Amelia Makrand Avachat, Rajkumar Malyandi,  Bioavailability of intranasal drug delivery system: Asian J. Pharm. 2008 (Oct-Dec):201-215

8.       Priyanka Arora, Shringi Sharma, Sanjay Garg, Permeability issues in nasal  drug delivery: Drug Discovery Today 2002:7:967-975

9.       Anwar A. Hussain, Intranasal drug delivery: Advanced drug delivery review 1998:29: 39-49

10.     Charan R. Behl, Nasal drug delivery- Unique opportunities and challenges: Pros and Cons Practical considerations: June 09, 2005

11.     Ulrika Westin, Elena Piras, Bjorn Jansson, Ulrika Bergstrom, Maria Dahlin, Eva Brittebo, Erik Bjork, Transfer of morphine along the olfactory pathway to the CNS after nasal administration to rodents: Eur.J.Pharm.Sci.2005:24:565-573.

12.     Maria Dahlin, Bjom Jansson, Erik Bjork, Levels of dopamine in blood and brain following nasal administration to rats: Eur. J. Pharm.Sci.2001:14:75-80

13.     Ramesh Krishnamoorthy, Ashim K. Mitra, Prodrugs for nasal drug delivery: Advanced Drug Delivery Reviews 1998: 29: 135-146

14.     S.T. Charlton, S.S. Davis, L. Illum, Nasal administration of an angiotensin antagonist in the rat model: Effect of bioadhesive formulations on the distribution of drugs to the systemic and CNS: Int. J. Pharm. 2007:338:94-103

15.     Kisan R. Jadhav, Manoj J. Gambhire, Ishaque M. Shaikh, Vilasrao J. Kadam, Sambhaji S. Pisal, Nasal Drug Delivery System- factors affecting and applications: Current Drug Therapy 2007:2: 27-38

16.     Cecilia Wadell, Erik Bjork, Ola Camber, Nasal Drug Delivery-Evaluation of an in vitro model using porcine nasal mucosa: Eur. J. Pharm. Sci 1999:7:197-206

17.     Morten Aavad Bagger, Erik Bechgaard, The potential of nasal applicationfor delivery  to the central brain- a microdialysis study of fluorescein  in rats: Eur. J. Pharm. Sci 2004:21:235-242

18.     Henry R. Costantino, LIsbeth Illum, Gordon Brandt, Paul H. Johnson, Steven C. Quay, Intranasal delivery- Physiochemical and therapeutic aspects: Int. J. Pharm 2007:337:1-24

19.     S.T. Charlton, S.S. Davis, L. Illum, Evaluation of bioadhesive polymers as delivery systems for nose to brain delivery- In vitro characterization studies: J. Controlled Release 2007:118:225-234

20.     Weibai Ying, The nose may help the brain- intranasal drug delivery for treating neurological diseases: Future Neural. 2008:3:1-4

 

 

 

Received on 11.02.2010       Modified on 28.02.2010

Accepted on 20.03.2010      © RJPT All right reserved

Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 970-978