Drug delivery through the nasal route has been used for the treatment of local diseases such as nasal congestion, allergies, and infections. An assessment has been made on various nasal formulations to find the feasibility of drug delivery via the nasal cavity into the systemic circulation. Nasal route can be successfully exploited for systemic delivery of drugs and vaccines, and more specifically, for preferential targeting of drugs to the CNS . The blood-brain-barrier (BBB), a dense packing arrangement of endothelial cells, is the major influencing factor in drug delivery to the brain. Drugs to be therapeutically active should reach the brain via the BBB in management of CNS disorders. BBB comprise of various cells present at the level of BBB contributing function. The tight junctures between endothelial cells in brain has very high trans-endothelial electric resistance of 1500-2000 W cm2 compared to 3-33 W cm2 of other tissues like skin, bladder, colon, lung etc. which significantly affects transport of drugs. Lipophilic drugs are readily cross BBB. Systemically administered drug encounters blood-cerebrospinal fluid barrier (BCB) before entering the CNS. A double-layered structure called the arachnoid membrane covering of brain acts as a barrier between blood and CSF and restricts passage of hydrophilic substances from the blood brain due to tight junctions. The BBB is prime rate-limiting barrier (rate and extent of drug diffusion) into and within the CNS.

Irrespective of aggressive research ongoing in the treatment of central nervous system diseases, such as epilepsy, analgesia, migraine, brain tumors, human immuno-deficiency encephalopathy, cerebro-vascular diseases, brain hemorrhage, depression, and Alzheimer's syndrome, the clinical failure results from limited drug concentration at target site. Various approaches such as BBB disruption, receptor mediated transport, cell penetrating peptides and targeted delivery using prodrugs, have been investigated to target drugs to CNS. Since first patent granted to William Frey in 1989, the nasal mucosa has been investigated extensively as an alternative route of drug administration to achieve faster and more complete drug uptake in the CNS and peripheral circulation. Intranasal drug delivery is convenient, amenable for self-administration, reliable, and provides rapid onset of action, explaining the significance of attention from academic and industrial researchers in the last few years. The nasal route can be exploited as a potential alternative drug delivery route for delivering drugs such as low molecular weight polar compounds, P-glycoprotein substrates, or peptides and proteins to CNS. The CNS delivery of these molecules is limited due to lack of effective absorption or inactivation in the gastro-intestinal tract, ineffectiveness if administered by other non-parenteral route of administration, or where rapid onset of action is desired to manage emergencies.

This review highlights the significance of nasal drug delivery in the treatment of CNS diseases/disorders, the mechanism of transport, and novel drug delivery approaches to enhance bioavailability of therapeutics delivered via nasal route.

Nasal route: Drug delivery to CNS
A unique connection of the nose and the CNS, intranasal route can deliver therapeutic agents to the CNS by passing the BBB. The nose is a complex organ since three different processes - deposition, clearance, and absorption of drugs - occur simultaneously within the nasal cavity. Absorption of drug across the olfactory region of the nose provides a unique feature and superior option to target drugs to brain. For effective transport of drugs across nasal mucosa, the anatomy and physiology must be taken into consideration in designing promising delivery systems for the CNS.

Nasal anatomy and physiology
The nostrils are a pair of nasal cavities divided by a nasal septum. The human nasal cavity has a total volume of about 16 to 19 mL, and a total surface area of about 180 cm2, and is divided into two nasal cavities via the septum. The volume of each cavity is approximately 7.5 mL, having a surface area around 75 cm2. Nasal cavity filters, warms, and dehumidifies the air prior to reaching the lower airways. The nasal cavities are covered by a mucosa of 2-4 mm in thickness, and it has both respiratory (80%) and olfactory (20%) functions . The respiratory region consists of three nasal turbinates - the superior, the middle, and the inferior. These turbinates are primarily responsible for creating a turbulent airflow throughout the nasal passages which facilitates improved contact between the inhaled air and the mucosal surface. Moreover, the human nasal cavity is lined with three types of epithelia: squamous, respiratory, and olfactory. Anterior part of the nose has squamous mucosa and absence of cilia. Transitional epithelium precedes the respiratory epithelium present within the anterior nostrils and the olfactory epithelium is located in the posterior part of nasal cavity.

The respiratory epithelium is a major lining of the human nasal cavity, which is primarily responsible for systemic transport or absorption of the drugs administered via the intranasal route. This respiratory epithelium consists of ciliated and non-ciliated columnar cells and globet cells. Basal cells are located adjacent to the basal lamina on the basolateral side of the epithelium and the lamina propia is located beneath the blood vessel-, nerve-, and gland-rich basal lamina.

The nasal passage epithelium is covered by a mucus layer that is renewed every 10 to 15 minutes. The pH of the mucosal secretions ranges from 5.5 to 6.5 in adults and 5.0 and 6.7 in children, which entrap particles clearing them from the nasal cavity by cilia. The mucus moves through the nose at an approximate rate of 5 to 6 mm/min resulting in particle clearance within the nose every 15-20 minutes. In addition, numerous enzymes such as cytochrome P450 enzyme isoforms, including CYP1A, CYP2A, CYP2E, carboxylesterases, and glutathione S-transferases are found in the nasal cavity, which can breakdown and/or alter the drugs administered in the nasal cavity.

Post drug administration into the nasal cavity, a solute can be deposited at one or more of three anatomically distinct regions, the vestibular, respiratory or olfactory region. The vestibular region, primarily filter out the air borne particles, is located at the opening of the nasal passages. Vestibular is considered to be the least important of three regions within the context of drug absorption. The respiratory region is the largest of the three regions and has a high degree of vascularity that facilitates absorption of the administered drug. The olfactory region has an area of about 6,500 mm2 and thus plays a decisive role in nose-to-CNS/-CSF transport of drugs.

Mechanism of drug transport
The nasal mucosa has respiratory and olfactory mucosa, principally responsible for transport of drugs across the nasal mucosa. Nasal cavity is rich in vasculature, which is located on and underneath the mucosal membrane. Lipophillic (non-polar) drugs are generally well-absorbed from the nasal cavity resulting in a comparable bioavailability to that observed following intravenous administration. Polar molecules are not well absorbed and transverse across the nasal mucosa to the systemic circulation or are transported across the nasal mucosa to the central nervous system.Polar compounds transport dependent on molecular weight, diffusion mechanism, concentration gradients, or receptor mediated, transcellular, or paracellular transport.Compounds with low molecular weight, usually less than 1,000 daltons, will generally transverse and cross the nasal mucosa using the paracellular mode of transport, whereas polar compounds would normally use endocytic transport mechanisms. Hence, changing lipophillicity of the drugs either by chemical modification of drug, by forming a complex, or by designing a relatively more lipophillic formulation, can improve bioavailability. Another prime factor which can account for poor bioavailability across nasal mucosa is the rapid mucociliary clearance from the nasal cavity.

Mucociliary clearance is usually in the range of 15-20 minutes and hence, the administered formulation can get cleared from the nasal cavity within this time-frame, which results in limited contact time with the vasculature or the epithelium. Enzymatic degradation is a potential factor that can influence drug transport across the nasal mucosa especially for peptides and proteins. The nasal cavity contains endopeptidases and exopeptidases, which are responsible for the cleavage of the N and C terminals of the peptides and proteins. The problem of premature degradation can be circumvented or reduced by designing product development strategy using a prodrug approach or by combining enzyme inhibitors in the formulation. Another important factor to enhance the rate and extent of absorption of nasally administered drugs is to incorporate absorption promoters such as surfactants, co-surfactants, bile salts and bile salt derivatives, fatty acids and its derivatives, and cyclodextrins. Generally, these promoter or permeability enhancers act by changing or enhancing the permeability across the epithelial cell layer through modifying the phospholipids bilayer. In some cases, these promoters may influence the tight junctions or prevent enzymatic degradation. However, selection of the absorption promoter is to be done carefully looking towards toxic effect on the nasal mucosa cells and cause permanent alteration or damage to the nasal mucosa.


Intranasal drug delivery is a non-invasive route of administration and offers several advantages such as rapid absorption and bioavailability profiles identical to intravenous administration

Intranasal drug delivery for CNS targeting
The pathways by which intranasally delivered drugs reach the CSF and/or CNS are predominantly via the olfactory transport and/or the trigeminal pathway. Following intranasal administration of insulin like growth factor-1 and other neurotrophic factors, the drugs bypassed the blood-brain barrier and reached the brain / central nervous system alongside the trigeminal / olfactory pathways directly from the nasal cavity. In mice, it was recently shown that dopamine reached the right olfactory bulb after nasal administration into the right nostril. Moreover, micro-radiography of the olfactory region of the mouse showed the presence of drug molecules along the olfactory neuron bundles, indicating either trans-neural transport or transport via CSF surrounding the bundles.

Gizurarson, et al., investigated distribution of insulin between blood and brain compartments in mice. The insulin concentrations were found to be significantly higher in the brain following intra-olfactory administration as compared to subcutaneous injection. The absorption was also found to be very rapid (ten minutes after the administration) and 487% higher than that achieved following subcutaneous injection. They concluded that it may be possible to achieve absorption directly into the brain, by-passing the blood-brain barrier, following nasal administration for many types of neuro-active peptide and protean drugs. The drug can reach the CNS via the nasal cavity across the olfactory membrane and the arachnoid membrane pathways, which are surrounded by the arachnoid space containing CSF.

Mechanisms of drug transport via nasal route
The drug uptake into the brain from the nasal mucosa mainly occurs via three different pathways. One is the systemic pathway by which some of the drug is absorbed into the systemic circulation subsequently reaches the brain by crossing the BBB. The two other direct pathways are through the olfactory pathway and the trigeminal neural pathway by which the drug partly travels from the nasal cavity to the CSF and the brain tissue. The mechanisms of transport of drugs from nose-to-brain, CSF, and the peripheral circulation are not yet completely understood. However, the drug can cross the olfactory path by one or a combination of mechanisms. These include transcellular or simple diffusion across the membrane, paracellular transport via movement between cells, and transcytosis by vesicle carriers. Three mechanisms of transnasal transport mentioned in this section are considered to be predominant.

Possible transport pathways
The first mechanism involves an aqueous route of transport, generally termed as paracellular route. This route is slow, passive, and there seem to be an inverse log-log correlation between intranasal absorption and the molecular weight of hydrophilic compounds. Incomplete and slow absorption frequently result in poor bioavailability for drugs with a molecular weight greater than 1,000 daltons.

The second mechanism involves transport via the lipoidal route, also familiar as the transcellular process. It 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 interstitial spaces of tight junctions. For example, chitosan, a naturally occurring cationic biopolymer, opens up the tight junctions between epithelial cells and facilitates the drug transport from the interstitial spaces.

The third mechanism is mainly due to drug transport through the olfactory neuron cells by intercellular axonal transport primarily through the olfactory bulb.

Advantages and limitations
Intranasal drug delivery is a non-invasive route of administration and offers several advantages such as rapid absorption and bioavailability profiles identical to intravenous administration. Furthermore, drugs delivered through the intranasal route, also to some extent, avoid a systemic dilution effect and first pass metabolism. Nasal delivery route is convenient, patient friendly, prevents risk of gastrointestinal tract irritation, cost effectiveness and offers self medication options to manage emergency situations. However, there are limitations such as low dose and low volume, particularly when compounds have restricted aqueous solubility or stability. The other drawback associated with intranasal delivery is that it could result in poor bioavailability, especially when the drugs are highly susceptible to enzymatic degradation or if they have a larger molecular weight.

Crucial factors for development of nasal formulations
The deposition of drug and deposition area is mainly dependant on the delivery system and the delivery device because of nasal cavity has the peculiar anatomy and physiology. The deposition is influenced by factors such as mode of administration, particle size of the formulation, velocity of the delivered particles, spray angle and cone. A wider spray cone could result in loss of the formulation while narrower spray cones would lead to limited deposition with respect to the available absorption surface area. An optimal spray cone may effectively and rapidly deliver the drug from the formulation at desired specific site/s present within nasal cavity. The selection of delivery system depends upon the drug used, therapeutic indication, patient population, and last but not least, marketing preferences. In addition to dosage form design, pharmacokinetics and bioavailability of drugs may be governed by several factors following intranasal administration. Some of the physico-chemical, formulation, and physiological factors must be considered prior to designing an intranasal delivery system for CNS targeting.

Physicochemical properties of drugs
Physicochemical properties are one of the important aspect in design of formulation.

Chemical form
The chemical form of a drug is important in determining absorption. For example, conversion of the drug into a salt or ester form can alter its absorption. Huang et. al., reported that in-situ nasal absorption of carboxylic acid esters of L-tyrosine was significantly greater than that of unmodified L-tyrosine.

Polymorphisms
Polymorphs are known to affect the dissolution rate and solubility of drugs and thus their absorption through biological membranes.

Molecular weight
A linear inverse correlation has been reported between the absorption of drugs and molecular weight up to 300 daltons. Absorption decreases significantly if the molecular weight is greater than 1,000 daltons except with the use of absorption enhancers. Nasal drug absorption is affected by molecular weight, size, formulation pH, pKa of molecule, and delivery volume among other formulation characteristics. Furthermore, linear molecules have lower absorption than cyclic-shaped molecules.

Particle size
It has been reported that particles greater than 10 µm in size are deposited in the nasal cavity. Particles that are 2 to 10 µm can be retained in the lungs, and particles of less than 1 µm are exhaled.

Solubility and dissolution rate
Drug solubility and dissolution rates are important factors in determining nasal absorption from powders and suspensions. The particles deposited in the nasal cavity need to dissolve prior to absorption.

Formulation factors
pH of formulation
Both the pH of the nasal cavity and pKa of a particular drug need to be considered to rationalize systemic absorption. Nasal irritation is minimized when products are delivered with a pH ranging between 4.5 and 6.5. The delivery volume is limited by the size of the nasal cavity. An upper limit of 25 mg/dose and a volume of 25-150 µL/nostril have been suggested.

Buffer capacity
Nasal formulations are generally administered in small volumes ranging from 25 to 200 µL (commonly practiced volume -100 µL). Hence, nasal secretions may alter the pH of the administrated dose. This can affect the concentration of unionized drug available for absorption; therefore, an adequate formulation buffer capacity may be required to maintain the pH in-situ.

Osmolarity
Drug absorption can be affected by tonicity of the formulation. Shrinkage of epithelial cells has been observed in the presence of hypertonic solutions. Hypertonic saline solutions are also known inhibit or cease ciliary activity. Low pH has a similar effect on cells as hypertonic solutions.

Gelling agents
Retention of the nasal formulation in the nasal cavity can enhance therapeutic effect by virtue of enhancing rate and extent of drug absorption. According to a study by Jansson et al. revealed that increasing the viscosity of the solution is an important factor in prolonging the therapeutic effect of nasal preparations. A study performed by Suzuki, et al., showed that a drug carrier, hydroxypropyl cellulose in this case, was effective for improving the absorption of low molecular weight drugs but did not produce the same effect for high molecular weight peptides.

Solubilizers
The aqueous solubility of a drug is always a limitation for nasal drug delivery in solution. Conventional solvents or co-solvents such as glycols, small quantities of alcohol, Transcutol (diethylene glycol monoethyl ether), medium chain glycerides and Labrasol (saturated polyglycolyzed C8-C10 glyceride) can be used to enhance the solubility of drugs. Other options include the use of surfactants or cyclodextrins such as hydroxypropyl-beta-cyclodextrin that serve as biocompatible solubilizers and stabilizers in combination with lipophilic absorption enhancers. In such cases, impact of the solubilizers on nasal irritancy should be considered.

Preservatives
Most nasal formulations are aqueous-based and, therefore, will require preservatives to prevent microbial growth. Parabens, benzalkonium chloride, phenyl ethyl alcohol, EDTA and benzyl alcohol are some of the commonly used preservatives in nasal formulations.

Antioxidants
A small quantity of antioxidants may be required to prevent oxidation of active compounds. Commonly used antioxidants include sodium metabisulfite, sodium bisulfite, butylated hydroxytoluene and tocopherol.

Humectants
Many allergic and chronic diseases can be connected with crusts and drying of the mucous membrane. Certain preservatives/antioxidants, among other excipients, are also likely to cause nasal irritation especially when used in larger quantities. Adequate intranasal moisture is essential for preventing dehydration. Common examples of humectants include glycerin, sorbitol and mannitol.

Drug concentration, required dose, and dose volume
Drug concentration, dose and volume of administration are three interrelated parameters that impact the performancezof the nasal delivery system.

Role of absorption enhancers
The selection of absorption enhancers is based upon their acceptability by regulatory agencies and their impact on nasal physiological function. Absorption enhancers may be required when a drug exhibits poor membrane permeability, large molecular size, lack of lipophilicity and susceptibility to enzymatic degradation by aminopeptidases.

Physiological factors Effect of deposition on absorption
Deposit of the formulation in the anterior portion of the nose provides a longer nasal residence time. The anterior portion of the nose is an area of low permeability while the posterior portion of the nose, where the drug permeability is generally higher, provides shorter residence time. The method of administration and properties of the formulation eventually determine the deposit site.

Nasal blood flow
The nasal mucosal membrane is very rich in vasculature and plays a vital role in the thermal regulation and humidification of inhaled air. Drug absorption will depend upon the vasoconstriction and vasodilatation of these blood vessels.

Effect of mucociliary clearance
It is important that the integrity of the nasal clearance mechanism is maintained to perform normal physiological functions such as the removal of dust, allergens and bacteria. The absorption of drugs is influenced by the residence time between the drug and the epithelial tissue. The mucociliary clearance is inversely related to the residence time and therefore inversely proportional to the absorption of drugs administered. A prolonged residence time in the nasal cavity may also be achieved by using bioadhesive polymers, microspheres, chitosan, and polycarbophil, or by increasing the viscosity of the formulation.

Effect of enzymatic activity
Several enzymes that are present in the nasal mucosa might affect the stability of drugs. For example, proteins and peptides are subjected to degradation by proteases and amino-peptidase at the mucosal membrane.

Effect of pathological condition
Intranasal pathologies such as allergic rhinitis, infections, or previous nasal surgery may affect the nasal mucociliary transport process and/or capacity for nasal absorption. During the common cold, the efficiency of an intranasal medication is often compromised. Nasal clearance is also reduced in insulin-dependent diabetes. Nasal pathology can also alter mucosal pH and thus affect absorption of drugs.

Intranasal formulations for CNS targeting
The deposition and deposition area are mainly a function of the delivery system and delivery device. Different dosage forms and their application to delivery the drugs to the central nervous system following intranasal drug delivery are discussed in this section.

Liquid dosage forms
Liquid dosage forms either in form of soluble, suspended or colloidal systems are normally used for formulating nasal delivery systems.

Nasal drops
Nasal drops are one of the most simple and convenient delivery systems among all formulations. The main disadvantage of this system is the lack of dose precision. It has been reported that nasal drops deposit human serum albumin in the nostrils more efficiently than nasal sprays.

Nasal sprays
Both solution and suspension formulations can be formulated into nasal sprays. Due to the availability of metered dose pumps and actuators, a nasal spray can deliver an exact dose anywhere from 25 to 200 µL. The particle size and morphology (for suspensions) of the drug and viscosity of the formulation determine the choice of pump and actuator assembly.

Nasal emulsions, microemulsions and nanoparticles
Intranasal emulsions and nanoparticles have not been studied as extensively as other liquid nasal delivery systems. Nasal emulsions offer the advantages for local application mainly due to the viscosity. One of the major disadvantages is poor patient acceptability. The physical stability of emulsion formulations and precise delivery are some of the main formulation issues.

Semi-solid dosage forms
Semi-solid systems, for example gels, ointments and liquid systems containing polymers that gel at particular pH changes are usually employed for designing the nasal drug delivery systems.

Nasal gels
Nasal gels are thickened solutions or suspensions, of high-viscosity. The advantages of a nasal gel include the reduction of post-nasal dripping due to its high viscosity, reduction of the taste impact due to reduced swallowing, reduction of anterior leakage of the formulation, reduction of irritation by using soothing/emollient excipients, and target delivery to the mucosa for better absorption. vitamin B12 and apomorphine gel have been successfully employed to achieve desired therapeutic concentrations following nasal administration.

Solid dosage forms
Solid dosage forms are also becoming popular for intranasal drug delivery, although these formulations are more suitable for pulmonary drug delivery and similar applications, since it can cover the vasculature within the epithelium of nasal mucosa.

Nasal powders
Powder dosage forms may be developed if solution and suspension dosage forms cannot be developed, mainly due to lack of drug stability. The advantages of a nasal powder dosage form are the absence of preservative and superior stability of the drug in the formulation. However, the suitability of the powder formulation is dependent on the solubility, particle size, aerodynamic properties and nasal irritancy of the active drug and/or excipients. An additional advantage of this system is local application of drug, but nasal mucosa irritancy and metered dose delivery are some of the challenges for formulation scientists and device manufacturers who are interested in powder dosage forms.

To formulate a nasal formulation with ideal performance and commercial attributes, the drug properties, delivery system and nasal physiology should all be considered and understood from the early stages of product development

Microspheres, including mucoadhesive microspheres, are specialized systems that are becoming increasingly popular for designing nasal products. Microspheres may provide more prolonged contact with the nasal mucosa and thus enhance rate and extent of drug absorption. Microspheres or nanoparticles for nasal applications are usually prepared using biocompatible materials, such as starch, albumin, dextran, and gelatin. However, their toxicity/irritancy on the nasal mucosa cells due to the presence of a variety of polymers/excipients must be critically evaluated. It has been observed that in the presence of starch microspheres, the nasal mucosa is dehydrated due to moisture uptake by the microspheres. This results in reversible "shrinkage" of the cells, providing a temporary physical separation of the tight (intercellular) junctions that increases the absorption of drugs.Novel formulations for CNS therapy using intranasal administration

To formulate a nasal formulation with ideal performance and commercial attributes, the drug properties, delivery system and nasal physiology should all be considered and understood from the early stages of product development. It is advisable to focus on maximizing the residence time and ensuring efficient absorption of drug. A successful nasal formulation program involves detailed consideration of the interactions between formulation composition, device design, delivery system and the patient's pathological condition. Currently, metered-dose systems provide the greatest dose accuracy and reproducibility.

Differences also exist in force of delivery, emitted droplet size, and spray patterns. A study by Suman et al., evaluated spray pattern and plume geometry in vitro and compared those measurements to those of in vivo deposition within the nasal cavity. Currently, tip aperture design pumps are available to administer formulations in an upward direction. Since, the turbinates are located at the sides of the nostrils (not upward); the entire dose volume cannot be administered to the target site of absorption. This also leads to swallowing of part of the dose. It may be possible to design a side aperture pump to direct the entire dose volume directly to the absorption site, the turbinates, for more efficient (target) nasal delivery.

Delivery devices are important not only for delivering medication, but also for providing an appropriate environment for storage. This would include protection from microbial contamination and chemical degradation. The device and formulation should be compatible so as to avoid potential leaching or adsorption.

Research trend in intranasal drug delivery to CNS
A few studies have been highlighted in this section to present the potential for and significance of intranasal drug delivery for CNS therapy. Gizurarson, et al., studied selective delivery of insulin into the brain following instilling the drug to the olfactory region of the nasal cavity.

They concluded that direct transport of insulin by passing BBB may play a key role in the prevention and treatment of obesity and other diseases associated with hypoinsulinemia in the brain. Krauland, et al., have developed a microparticulate delivery system based on a thiolated chitosan conjugate for the nasal application of peptides.

In another study, nasal delivery of insulin using chitosan microspheres was attempted by Varshosaz, et al. These authors reported that the microspheres containing 400 mg of chitosan and 70 mg ascorbyl palmitate resulted in 44% absolute bioavailability of insulin and caused 67% reduction of blood glucose as compared to delivery via the intravenous route. In a study conducted on another peptide compound, Lerner, et al., observed enhanced delivery of octreotide to the brain via transnasal iontophoretic administration. They found that octreotide was present in samples extending from the olfactory bulb to the cerebellum with 2- to 13-fold increases in the concentration of the active compared to control/passive animals. Gavini, et al., formulated mucoadhesive microspheres for nasal administration of an antiemetic drug metoclopramide. This study demonstrated that alginate/chitosan spray-dried microspheres have promising properties for use as mucoadhesive nasal carriers for extending the residence time of an antiemetic drug.

Bertram and Bodmeier have reported on an in-situ gelling, bioadhesive nasal inserts for extended drug delivery. They found that the drug release of inserts prepared from high molecular weight polymers (carrageenan, carbopol, chitosan, hydroxypropyl methylcellulose (HPMC), sodium- carboxymethylcellulose (NaCMC), xanthan gum was a complex interplay of osmotic forces, water uptake and electrostatic interactions between the drug and the polymer.

Also, a study conducted by Cerchiara, et al., showed interesting results from propranolol hydrochloride microparticle formulation developed using chitosan and poly(methyl vinyl ether-co-maleic anhydride) and found to lower the release rate of drug and can thus be used for nasal sustained delivery systems. We have studied the pharmacokinetics and direct nose-to-brain transport efficiency of mucoadhesive microemulsions of sumatriptan and clonazepam. We found that pharmacokinetic profile, mucoadhesive microemulsions of both the drugs reached their maximum concentration faster with profiles comparable to intravenous administration.

Investigational and marketed products
Administration of intranasal medication under emergency circumstances is a rapid and safe method not only for the patient but also for the provider, however to date it has been under utilized. Nevertheless, due to aggressive research in the last decade, numerous conspicuous merits and features have attracted pharmaceutical industries to design the products in intranasal drug delivery format.

Therapeutic moieties under investigation for intranasal delivery to the CNS
Intranasal drug delivery has an exciting novel, non-invasive and convenient approach of delivering a wide range of therapeutics directly to the CNS. Many drug delivery systems for intranasal administration have been explored and are reached to market and many are under phase I/II/III clinical stages. The emergence of peptide and protein moieties in the therapeutics has certainly attracted scientific and industrial attention to exploit intranasal route for targeting CNS. The limitations with respect to CNS drug delivery, i.e., low bioavailability, local irritation and toxicity upon long-term usage, even though has great potential. A better understanding of the mechanism of nose-to-brain transport, correlation between transport and properties of drug molecules, and formulation development aspects to enhance residence time, inhibit degradation, and further amplify the amount of drug delivered, nasal delivery for CNS therapy has tremendous potential in the near future.
(The author professor of pharmaceutics head, Pharmacy Department and Coordinator TIFAC-CORE in NDDS, Faculty of Technology and Engineering, The Maharaja Sayajirao University of Baroda, Gujarat State- India.)