INTRODUCTION:

Although various advantage of brain research, brain and central nervous system disorders leading cause of disability and account for more hospitalization and prolonged care almost all other disease combination. Problem with that present of BBB. The drug that are effective against CNS disease and reach to brain via blood compartment must pass BBB. For development of drugs which penetrate the BBB to expected CNS therapeutics effective. It is important to understand the mechanism involved in uptake and efflux from the brain. BBB functionally regulated by various cell present in different portion of BBB(1). This realization implies better understanding relationship of transport at BBB to drug structure and physicochemical properties.

This review will prove invaluable to researchers interested in fundamental function of BBB and those pharma person interested in rational drug delivery directed to brain via olfactory region(nasal route).

1. Barrier to CNS drug delivery

Failure to effectively delivery drug to treat CNS disease due to various barrier inhibit drug delivery to CNS.

1.1 Blood brain barrier:

Is a unique membrane that tightly segregates the brain from blood circulation. CNS consist of blood capillaries that is different from the other blood capillaries present in other tissues. This result in permeability barriers between blood with in brain capillaries and extracellular fluid in blood tissue. Capillaries present in spinal cord and brain due to lack of small pores that allow rapid movement of solutes from circulation from other organ; these cappilaries contain lining of layer of special endothelial cell that lack of fenestration and sealed with tight junctions. This tight junction epithelium similar to the berrier that found in different organ of body (2). The permeability barrier containing brain capillaries endothelium is also known as BBB. Ependymal cell (in cerebral ventricles and glial cells) containing three types.

1. Astrocytes: frame work structure as similar as neuron and maintain biochemical environment. There foot processes and spread out and abutting one other to form encapsulate environment of capillaries these are closely associated to blood capillaries and form BBB.

2. Oligodendrocytes: to formation and maintenance of myelin sheath, which surround axons and is essential for fast transmission of action potential by salutatory conduction.

3. Microglias: mononuclear macrophages mainly derived from blood.

Tight junction between endothelial cells results in high trans endothelial electrical resistance as compared to other tissues. Tissue other than this reduces the aqueous based paracellular diffusion.(3,4).

Micro vessels upto 95% of toral surface area of BBB, and represent principal route by chemical enter the brain. Vessels in brain were found to have somewhat smaller diameter and thinner wall than other organ vessels. Microchondrial density in brain found to be higher than in other capillaries not because of more enormous or large microchondria, but due to smaller diameter of the brain micro-vessels and consequently smaller cytoplasmic area. In bran capillaries, intracellular cleft, pinocytosis, and fenestrate are virtually nonexistent; exchange due to the trans cellular. There for lipid-soluble solutes can freely diffuse throughout capillaries and may passively cross BBB.

Some, region not involve in BBB classical endothelial cells. But, have micro-vessels similar to periphery. These area are adjust to ventrical of the brain and are termed as circumventrical organ(CVOs). This portion include the choroid plexus, medium eminence, subcommisaral organ and area of posterma. In this region capillaries more permeable to solute. Epithelium cell of plexus and tanycytes form tight junction to prevent transport from the abluminal extracellular fluid (ECF) to the brain ECF. Plexus mainly involve in transport of peptide drug due to major site of cerebrospinal fluid(CSF) production and freely highly exchange of CSF and ECF (5).

BBB region have also a enzymatic aspect .solute molecule that cross this membrane subsequently pass to various degradation by various enzyme present inside endothelial cells and also contain large densities of mitochondria, metabolically highly active organelles(6).

Efflux transport also responsible for removes a broad range of drug molecule from endothelial cell cytoplasm before cross to brain parenchyma. Fig.1 shows representation of all BBB properties and comparison with general capillaries.

1.2 Blood cerebrospinal fluid barrier

Another most critical barrier for systemically administrate drug encounters before entering the CNS. So, these can be responsible for exchange drug molecule with in interstitial fluid of brain parenchyma, blood flow also be regulated by blood cerebrospinal fluid barrier(BCB), physiologically found in epithelium of the choroids plexus, which arrange in manner that limits the passage of molecules and cells into the CSF. The choroid plexus and arachnoid membrane act together at the barriers between the blood and CSF. On external surface of the brain the ependymal cell fold over to form double layered structure, which lie between the dura and pia,this called as aranchnoid membrane. With in double layer this can be responsible for CSF drainage. Passage of substance that can be prevented by tight junction present in membrane(7). This can be generally impermeable to hydrophilic substance and its role to forming the CSF-blood barrier is passive. The choroid plexus forms the CSF and help to regulate the concentration of molecule inside. This consist of highly vascularized,“cauliflower like” masses of pia mater tissue that dip into pockets formed by parenchymal cells. The preponderance of choroid plexus is distributed throughout the forth ventrical near the base of brain and in lateral ventricles inside the right and left cerebral hemispheres. However, these epithelial like cells have shown a low resistance as compared to cerebral endothelial cells(8).

1.3 Blood- tumor barrier

Intracranial delivery have a advantage when targeting CNS function diffidiency but difficult to target brain tumor. BBB in the microvasculature of CNS tumor has clinical consequences.

Example when chemotherapeutic agent delivery through cardiovascular system that can be response when given in primary and secondary stage but when CNS malignancies where the BBB is significant compromised, a variety of physiological barrier common to all solid tumor is compromised, a variety of physiological barrier can inhibit drug delivery through cardiovascular system. due large tumor grows vascular surface area decreases leading to decrease in vascular surface area and they can be effect on trans-vascular exchange of blood borne molecules. At that time also increase in intra-capillary distances, leading to greater diffusional requirement for drug delivery to neoplastic cells due to high interstitial tumor pressure and association with increase in hydrostatic pressure of normal brain, as a result the cerebral microvasculature in these tumor region may less permeable to drug than normal brain endothelium and have produce less drug concentration inside tumor (9). There is a locally as well as nonhomogeneous disturbance of BBB by present of tumor cells. (10).

Above all barrier can be conclude that delivery through cardiovascular to CNS often preincluded by a various barrier like BBB, BCB, Brain tumor barrier.

2. Mechanism for drug transport to the brain

Mainly two way that can be responsible for the transport of drug to the CNS that is efflux and uptake mechanism. Most of the in vivo experimental study shows that drug uptake into the brain will automatically incorporate any activity of CNS efflux into their apparent determination of brain penetration. With in CNS there is a no. of efflux mechanism influence on drug concentration. Some of this involve passive and active. Active efflux mainly involve specific transporters may often reduce the penetration of drug at the BBB to level that are lower and that might effected by physiological properties of drug molecule. Noticeably drug exposure not enhancing by efflux mechanism but by restricting through BBB membrane, hence strategies directed toward the brain uptake of drug that are substrates for specific efflux mechanism need to focused on desining reactivity with a transporter out of drug molecule(11,12)..

3. Physicochemical factor that influence on brain uptake

Tab 1. Physiological factor that affect on transport across BBB.

Factors Affecting Drug Transport Across BBB

● Concentration gradient of drug/polymer

● Molecular weight of the drug

● Lipophilicity of the drug

● Sequestration by other cells

● Affinity for efflux proteins (e.g. Pgp

● Pathological status

● Flexibility, conformation of drug/polymer

● Molecular charge

● Affinity for receptors or carriers

● Cerebral Blood flow

● Systemic enzymatic stability

● Metabolism by other tissues

● Clearance rate of drug/polymer

● Cellular enzymatic stability

Biological activity generally measure of brain uptake. Hypnotic activity of a number of congeneric series of CNS depressants reached at maximum when log octanol – water partition coefficient near to 2. (13), difficulty with biological activity depend on at least two factor:

1. Rate of transfer from blood to brain or distribution between blood and brain.

2. Interaction between drug and some receptors in brain.

The log P _{o/w represents} more informative physicochemical parameter used in medicinal chemistry. On other side increase lipophilicity with the intent to improve membrane permeability might not effect on chemical handling difficulty but also effecton volume of distribution in plasma and tends to effect on pharmacokinetic parameter.

4. Strategies for enhanced CNS drug delivery (14 - 16)

To overcome the multitude of barriers restricting CNS drug delivery of potential therapeutic agents, numerous drug delivery strategies have been developed. These strategies generally fall into one or more of the following categories: invasive, non-invasive or miscellaneous techniques (13). The CNS drug delivery tree encompassing the various possible strategies is given below in the Fig. 2.

4.1 Non invasive techniques:

Variety of non invasive technique for brain drug delivery is investigated now a day in market. This can be use to gain widespread of drug distribution throughout brain capillaries. This can mainly delivery by two way that is chemical or biological nature of compound. Such method involve drug manipulation which may include prodrugs, lipophilic analogs, chemical drug delivery, carrier mediated drug delivery, receptor/vector mediated drug delivery etc(17).

4.1.1 Chemical method:

Main premises for chemicalmethod remain prodrug apparoach. In this method use of chemical transformation of drugs by changing in various functionalities. The chemical change is usually designed to improve deficient physicochemical property such as permeability or solubility of compound. Due to the poor selectivity and poor tissue retention of some of these molecules not modified to prepeare prodrug . and also they require longer duration time to convert their inactive moiety to form active form. Besides, the lipidization strategy involves the addition of lipid-like molecules through modification of the hydrophilic moieties in the drug structure. Lipid-soluble molecules are believed to be transported through the BBB by passive diffusion but the lipidization of molecules generally increases the volume of distribution, particularly due to to plasma protein-binding which affects all other pharmacokinetic parameters. Furthermore,increasing lipophilicity tends to increase the rate of oxidative metabolism by cytochrome P-450 and enzymes.While increased lipophilicity may improve diffusion across the BBB, it also tends to increase uptake into other tissues, causing an increased tissue burden(18). Caging compounds within glycosyl-, maltosyl-, diglucosyland dimaltosyl-derivatives of cyclodextrin is reported by Bodor in US Patent 5017566 (19). In other reference described that biomolecular complexes comprising of a therapeutic, prophylactic and diagnostic agent. The complexes are further covalently bonded with cationic carriers and permeabilizer peptides for delivery across the BBB and with targeting moieties for uptake by target brain cells. Invented complexes are particularly useful for delivery of a biologically active agent to the glial tissue of the brain as well as to the cortical, cholinergic and adrenergic neurons. The mentioned therapeutic complexes or conjugates comprise of an ome. in U.S. patent application 20060211628A1(20). disclosed a method of treating multiple sclerosis, using effective amount of a compound having: (a) A combination of molecular weight and membrane miscibility properties for permitting the compound to cross the BBB of the organism; (b) A readily oxidizable chemical group for exerting antioxidant properties; and (c) A chemical make-up for permitting the compound or its intracellular derivative to accumulate within the cytoplasm of cells(21).

4.1.2 Biological method:

This apparoach primilariy emanate from the understanding the physiological and anatomical nuances of the BBB transportation. on that many available apparoach , shows that conjugation of drug molecule with antibodies is the most commonly and effectively used method. Other method that can be use to deliver directly to ligand in the form of sugar and lectin forms which can be directed to various specific receptor found on cell surface(22). a Antibodies are particularly well suited for targeting BBB receptor-mediated transcytosis systems given their high affinity and specificity for their ligands (23). As examples, appropriately-targeted antibodies that recognize extracellular epitopes of the insulin and transferrin receptors can act as artificial transporter substrates that are effectively transported across the BBB and deposited into the brain interstitium via the transendothelial route (24). Megalin ligands are carriers or vectors for the delivery of active agents via transcytosis to brain and are patented by Starr et al. who disclosed RAP (receptor-associated protein), which serves to increase the transport of the therapeutic agent. In some embodiments, the megalin ligand or megalin-binding fragment of such a ligand may be modified as desired to enhance its stability or pharmacokinetic properties (e. g. PEGylation of the RAP (receptor-associated protein) moiety of the conjugate, mutagenesis of the RAP moiety of the conjugate) (25). In another patent Neuwelt. Disclosed monoclonal antibody conjugated for the delivery of the drugs across the BBB (26). In patent number WO2007036022 disclosed subunits and multimers of subunits suitable for use in inducing the transport of one or more cargo substances into a cell and in some instances across a cell. The subunits may have a targeting domain, such as an antibody or antibody fragment; a multimerization domain, such as a verotoxin Bsubunit mutant scaffold, and a cargo molecule such as a drug or imaging agent, which may be directly linked to the subunit or may be packaged in a liposome, nanoparticle, or the like. In some instances, the targeting domain may have affinity for a blood brain barrier antigen and may be capable of inducing cell-mediated transcytosis to facilitate the delivery of cargo molecule across the blood brain barrier. In some instances, the targeting region may have affinity for a cancer antigen and may be capable of inducing cell-mediated endocytosis (27). In other research they invented polypeptides derived from aprotinin and aprotinin analogues as well as conjugates and pharmaceutical compositions comprising of these polypeptides for treating a patient of a neurological disease. The invention also related to the use of these polypeptides for transporting a compound or drug across the blood brain barrier (28). In another apparoach author discovered that the NgRHl cell surface receptor, an antigen preferentially expressed in endothelial cells, is involved in regulating blood-brain barrier (BBB) permeability. Invention provides a method of modulating BBB permeability comprising of the step of administering an agent to a subject, wherein the said agent targets a human NgRHl cell surface receptor that is present in the brain. Non- limiting examples of the agents useful for modulating BBB permeability via NgRHl include inorganic molecules, peptides, peptide-mimetics, antibodies, liposomes, small interfering RNAs, antisense protiens, aptamers and external guide sequences(29). In US patent number 4801575 shows that the preparation of chimeric peptides by coupling or conjugating the pharmaceutical agent to a transportable peptide. The chimeric peptide purportedly passes across the barrier via receptors for the transportable peptide. Trans-portable peptides, or vectors, mentioned as suitable for coupling to the pharmaceutical agent include insulin, transferrin, insulinlike growth factors I and II, basic albumin and prolactin.(30). The peptide to be delivered is bonded to a water soluble, non-peptidic polymer to form a conjugate. The conjugate is then administered into the blood circulation of an animal so that the conjugate passes across the blood-brain barrier and into the brain. The water-soluble non-peptidic polymer can be selected from the group consisting of polyethylene glycol and copolymers of polyethylene glycol and polypropylene glycol activated for conjugation by covalent attachment to the peptide (31). US Patent number 5833988 give various method for delivering a neuropharmaceutical or diagnostic agent across the blood-brain barrier employing an antibody against the transferrin receptor. A nerve growth factor or a neurotrophic factor is conjugated to a transferrin receptorspecific antibody. The resulting conjugate is administered to an animal and is capable of crossing the BBB (32). In another apparoach author described use of taxoid for treatment of brain cancers, in this molecule can be conjugated with at least one taxol derivative bound to at least one vector peptide capable of increasing the solubility of derivative and advantageously of to be transported across the BBB. The invention also relates to the preparation of these compounds and to the pharmaceutical compositions containing them, useful for the treatment of cancers, most particularly of brain cancers (33).

4.1.3 CNS drug delivery through novel carrier:

I. Colloidal drug delivery

in general this delivery mainly involve micelles, microemulsion, liposome, and nanopaticles (nanocapsule and nanosphere).in general due to method of preparation and easy to scale up of formulation only liposomal formulation and nanoparticles are most widely used now a day (34). The enormous advantage of this like, increase specificity toward specific legand , to improve bioavailability of drug, increase diffusion rate through biological membrane and also protect from enzymatic degradation. The fate of various colloidal system can be determinate by using intravenous administration to determine by combination of various biological and physicochemical even and on the bases of above event varioud drug delivery carrier can be formulated. After administration of compound this can be followed opsonization. Thus, particles have a hydrophobic surface properties affectively coated with plasma component (opsonins) and rapidly removed from the circulation via various route present in liver and spleen area. When., colloidal particles that are small and hydrophilic enough can escape, at least partially, from the opsonization process and consequently, remain in the circulation for a relatively longer period of time. In other concept of “steric hindrance” has been mostly applied to avoid the deposition of plasma proteins either by adsorbing some surfactant molecules at the surface of the colloids or by providing a sterical stability by the direct chemical link of polyethyleneglycol (PEG) at the surface of the particles. In addition, active targeting can be achieved by the attachment of a specific ligand (such as a monoclonal antibody) onto the surface of the colloidal particle, preferentially at the end of the PEG molecules, since the targeted colloidal particles will be much more efficient if they are also sterically stabilized (35 – 36 ).

The fate of various colloidal system after administration given in below figure.3.

II. Polymeric micelles and microemulsion:

Drug delivery system mainly formulated by using amphiphilic copolymers having A-B diblock in that A mainly contain hydrophilic and B contain hydrophobic polymers in size range from several tens nanometer. This are thermodynamically and kinetically stable in aqueous compartment. Several reviews have analyzed in great detail, the properties of the different copolymers used in the preparation of the polymeric micelles, as well as the physical chemistry of these systems, which may influence their properties such as their size distribution, stability, drugloading capacity, drug release kinetics, blood circulation time and biodistribution (37 - 38). studies have shown that poloxamer (PluronicTM) micelles conjugated with antibodies may improve brain distribution of haloperidol, a neuroleptic agent. This approach has resulted in a dramatic improvement of drug efficacy. This result indicates that PluronicTM micelles provide an effective transport of solubilized neuroleptic agents across the BBB (39). In various patented technology involve a method of producing a delivery vehicle by the miniemulsion method, comprising of nanoparticles made by the said method, optionally also having a surface-modifying agent and a pharmaceutical agent to cross one or more physio-logical barriers, in particular the blood-brain-barrier. This subsequently showed modified-release characteristics such as sustained-release or prolonged-release of a pharmaceutical agent in the target tissue (40).

III. Polymeric nanoparticle

Due to present of tight junction at endothelial cell it is difficult to prove therapeutic strategies to CNS. So, to overcome this polymeric biocompatible carrier are formulated e.g: nanoparticles, liposome have been applied to cancer treatment on brain. Nanoparticle consist of polymers are about 10 to 200nm in size. Some research article shows that they can be effectively rapid transport of drug charged particle across the BBB. In some research found a cationic polymer (polyethylenimine) with which the drug can bypass the BBB and which uses an intramuscular injection in the tongue to introduce drugs into the brain using retrograde axonal transport. In other way transported doxorubicin across the BBB using a peptide vector. The drug to be transported is covalently bound to D-penetrantin, a peptide, and synB1, which facilitate transport across the BBB without causing efflux by the P-glycoprotein.

Tab.2 Ideal properties of nanoparticles for crossing CNS

Ideal properties of nanoparticles for brain drug delivery

· Nontoxic, biodegradable, and biocompatible

· Particle dieameter between 10-100 nm

· Physical stability in vivo and in vitro

· Avoidance from RES (Reticulo-endothelial system) leads to prolonged blood circulation time

· Cns targeted delivery via receptor-mediated transcytosis across brain capillary endothelial cells

· Scalable and cost-effective manufacturing process

· Amenable to small molecules, peptides,. Proteinsor nucleic acids

· Formulation stability. Minimal nanoparticle excipient-induced drug alteration (chemical degradation/alteration. Protein denaturation

· Controlled – drug release profiles

Other ways include transporting nanoparticles via the transferrin receptor by binding them to ligands. This system however has the setback that the particles can be charged with a small quantity of the substance to be transported only(41). Ideal properties for drug loaded nanoparticle for transport through the brain can be maintention in table.2.

In US2006051423 patent shows that use a chitosan-based transport system for overcoming the BBB. The transport system contains at least one substance selected from the group consisting of chitin, chitosan, chitosan oligosaccharides, glucosamine and derivatives thereof (molecular weights ranging from 179 Da to 400 kDa), and optionally one or more active agents and/or one or more markers and/or one or more ligands (42). In another patent shows US6419949 involve use of pharmaceutical compositions in the form of nanoparticles suitable for passage through the intestinal mucosa, the BBB and the BCFB. Said nanoparticles have a size ranging from 40 to 150 nm, and are formed by one or more lipids optionally in combination with a steric stabilizer and by a drug. They are prepared dispersion in an aqueous medium at 2-4°C, a hot prepared oil/water or water/oil/water microemulsion comprising one or more lipids, a surfactant agent, a cosurfactant and optionally a steric stabilizer (43). Solid lipid nanoparticles (SLN) were developed as an alternative carrier system to emulsions, liposomes, and polymeric nanoparticles. SLN can provide advantages including stabilization of incorporated compounds, controlled release, and occluviseness. The solid lipid nanoparticles by virtue of surface functionalization, neutral lipid character and nanoscale particle size can effectively transport a delivery package such as biologically active agents, pharmaceutically active agents, magnetically active agents, and/or imaging agents across the BBB and into the brain tissue(44). In patent WO2006044660 shows that methods of delivering at least one biologically, pharmaceutically or magnetically active agent, or imaging agent across the BBB, cellular lipid bilayer and into a cell, and to a subcellular structure with functionalized solid lipid nanoparticles comprising a neutral lipid and functionalized polymer comprising of at least one ionic or ionizable moiety. The patent also discloses method of SLN preparation, as lipids and pharmaceutically active agents for preparing the solid lipid nanoparticles (45).

IV. Liposomes for CNS drug delivery

It can be defind liposomes can enhance drug delivery to the brain across the BBB. Liposomes are small vesicles (usually submicron-sized) comprising of one or more concentric bilayers of phospholipids separated by aqueous compartments. Although liposomes have been reported to enhance the uptake of certain drugs into the brain after intravenous injection (46). US patent 20020025313A1 disclosed immunoliposomes and pharmaceutical compositions capable of targeting pharmacological compounds to the brain. Liposomes are coupled to an antibody binding fragment such as Fab, F(ab').sub.2, Fab'or or a single chain polypeptide antibody which binds to a receptor molecule present on the vascular endothelial cells of the mammalian BBB (47). a non-invasive gene targeting to brain by liposomes. Liposomes containing therapeutic genes are conjugated to multiple brain barrier and brain cell membrane targeting agents to provide transport of the encapsulated gene across the BBB. After crossing the BBB, the encapsulated gene expresses the encoded therapeutic agent within the brain to provide therapeutic effect and diagnosis of neurological disorders (48). liposomes for transporting the therapeutic agents across the CNS. Invention discusses brain specific targeting vehicle for transporting neuropharmacological agents across the BBB. Liposomes are sterically stabilized by attaching ligands to the surface of the liposomes (49).

4.2 Invasive method:

Despite various ease and complain of non-invansive method is not associated with direct or invasive delivery of drug to brain, it often shows up as the sole alternative wherein the drug elicit right physicochemical properties. Generally only low molecule weight, lipid soluble molecule, and few peptides and nutrient can cross this barrier either by passive diffusion or using suitable transport mechanism(50). So, for most drug not achieve therapeutics level with in the brain tissue followed by intravenous and oral administration. due to high potency of dosage form they produce high toxicity on the side of administration. Drug directly administrated into brain tissue by many ways are exposed for directly intracranial delivery by intracereblovascular, intracerebral, intrathecal administration by creating holes on head or disturbing BBB(51).

4.2.1 Distuption of the BBB

Theoretically with the BBB weakened by systemic administred drugs can undergo enhance extravasation rates in cerebral endothelium, leading to increase parenchymal drug concentration. A variety of technique available for this but due to some drawback of this like, induction on pathological condition, in technique mainly involve use of infusion of solvent; X-irradiation.

I. Osmotic : In treatment of patient with rapidly growing, high grade gliomas, osmotic opening of the BBB was developed. Intracarotid injection of hypertonic solution(such as mannitol, arabinose) and ministrated so that they can produce shrinkage of endothelial cells and opening new path in BBB for period of few hours. This can be help in deliver of molecule to brain. They produce break down of self defense mechanism of brain and level it vulnerable to damage from all circulating chemical and toxins.

II. Biochemical: Intracaroid infusion of leukotriene C4 was achieved with out disturbing the BBB. In contrast with osmotic this can be opening the novel observation that normal brain capillaries being unaffected when vasoactive leukotriene treatment used to increase permeability. But, tumor capillaries or injured capillaries being sensitize by leukotriene and permeability dependent on molecule weight.

4.2.2 Direct drug delivery

One strategy to overcome the BBB that has been used extensively in clinical trials is the direct administration of drugs by intraventricular and intracerebral routes. The drugs can be infused intraventricularly using a plastic reservoir (Ommaya reservoir) implanted subcutaneously in the scalp and connected to the ventricles within the brain via an outlet catheter.Unfortunately, there are several problems, apart from the surgical intervention required. Firstly, in the human brain the diffusion distances from cerebrospinal fluid (CSF) to a drug target site may only be several centimeters, and for drugs relying only on diffusion for penetration, insufficient concentration of drug may reach the target site Secondly, the microvessels of the brain secrete interstitial fluid at a low but finite rate, generating a flow towards the CSF spaces, which also works against diffusive drug penetration. Finally, the high turnover rate of the CSF (total renewal every 5-6 hrs in humans) means that injected drug is being continuously cleared back into the blood. In practice, drug injection into the CSF is a suitable strategy only for sites close to the ventricles. For drugs that need to be at elevated levels for long periods for an effective action, continuous or pulsatile infusion may be necessary. WO2004043334 disclosed an apparatus for delivering a non steroidal anti -inflammatory drug (NSAID) supplied to the body of a subject for delivery to at least a portion of a CNS of the subject via the systemic blood circulation, including a stimulator adapted to stimulate at least one site of the subject, during at least a portion of the time when the NSAID is present in the blood. The apparatus uses electrical, chemical, mechanical and/or odorant stimulation (52). US 7241283 Putz disclosed a method of treating a tissue region in the brain of a patient comprising: inserting into the brain an outer catheter having a passageway extending between a proximal end and at least one port, the outer catheter guiding the inner catheter to the tissue region; and transferring fluids between the tissue region and the proximal end through the passageway (53).

5. Alternative route of Administration (nasal route)

Currently, Nasal drug delivery has been recognized as a very promising route for delivery of therapeutic compounds including biopharmaceuticals. Due to avoid various proteolytic action involve by oral administration as well as to provide a rapid onset of action for various emergency condition.anatomy and physiology of the nasal passage indicate that nasal administration has potential practical advantages for the introduction of therapeutic drugs into the systemic circulation. The concentration-time profiles achieved after nasal administration are often similar to those after intravenous administration, resulting in a rapid onset of pharma- cological activity(54). showed that the sedative propiomazine, for which a rapid onset of action is desirable. and it absorbed within 5 minutes after nasal administration to rats. Later the use of the nasal route for delivery of vaccines, especially against respiratory infections such as influenza, is attracting interest from vaccine delivery scientists (55). In table.3 shows that various formulartion based on nasal delivery.

Tab.3 Formulation based on intranasal drug delivery.

Drug	Treatment	Author
Sumatriptan	Migraine	Duquesnoy et al; eur j pharma sci: 1998; 6;99-104
Dismopressin	Diabetic	Aller N et al; int I clin pharmacol; 1998; 6, 99-104.
Oxytosin	Milk secretion	Slot WB eta l; gasterolody, 1997; 36(9), 430 – 500.
Apomorphin	Parkinsonism	Sam E et al; eur j drug metab, 1995; 20(1), 27-33.
Nicotin	Smoking cessation	Market

5.1 Advantage of nasal drug delivery system (56):

Ø Large nasal mucosal surface area for dose absorption

Ø Rapid drug absorption via highly vascularized mucosa

Ø Rapid onset of action

Ø Ease of administration, noninvasive

Ø By pass the BBB

Ø Avoidance of the gastrointestinal tract and first pass metabolism

Ø Improved bioavailability

Ø Direct transport into systemic circulation and CNS is possible

Ø Lower dose/reduced side effects

Ø Improved convenience and compliance

Ø Self-administration

5.2 Disadvantage of nasal drug delivery system (56):

Ø Volume that can be delivered into nasal cavity is restricted to 25-200 μl.

Ø Not feasible for high molecular weight more than 1k Da

Ø Adversely affected by pathological conditions

Ø Drug permeability may alter due to ciliary movement

Ø Drug permeability is limited due to enzymatic inhibition

Ø Nasal irritants drugs cannot be administered through this route

Ø Exact mechanism is not yet clearly known

5.3 Anatomy and physiology of nose (57):

Nose can be devided maily in three portion medium septum, central portion bone, and cartilage. Each portion can be open into half part of face and connected by nostril and in mouth at nasopharynx. The nasal vestribule can be divided into three part like: respiratory region, olfactory region, and nasal vestibule. Total surface area are covered by folded structure of around 150cm². Folded structure can be divided into superior, medium, inferior. Sub nasal mucosal zone extremely vascular and this network drain blood from the nasal mucosa directly to systemic circulation and thus avoiding first pass metabolism. In figure 4. Represent schematic diagram anatomy of nose from the right cross section.

5.3.1 Respiratory Region (58): Epithelium mainly contain four type of cell mainly non-ciliated, ciliated columnar, basal cells and floblet cells. This can be help in passive transport of compound from the cell and motility of cilia. This can also be help to prevent drying of mucosa by tapping moisture.15 – 20% of cell covered with layer of cilia and use to move proper way for mucus toward phayrynx. Mucus also facilitated mucociliary clearance. Fig.5(a) shows respiratory epithelium contain all type of cells. viscous gel produce on mucosa move with the help of cilio terminal during energy dependent effective stock of ciliomotion.cilio are upto 7mm in size fully extended but folded to half in their length. The cilio beat around 1000 strokes per minute. Hence mucous move from anterior to posterior region in nasal cavity to nasopharynx. Fig.5(b) give mucociliary clearance relationship between cilio motion and mucus layer.

5.5 Crusial factor for CNS targeting via nasal route:

Physiological properties of drugs : This is one of the important factor for formulation of most of the nasal formulation. In that various parameter can be involve.

5.5.1 Factor related to drug:

I. Lipophilicity: absorption mainly dependent on hydrophilic lipophilic balance of molecule. Compound with higher absorption with increase in lipophillicity. Lipophilic compound readily cross biological membrane via transcellular route since able to partition into and traverse the cell in the cell cytoplasm. Nasal absorption of steroids was directly correlated with lipophillicity of drug molecule and found to pH independent (62).

II. Partition coefficient and pKa: based on pH partition theory unionized molecule well absorbed compared to ionized drug from the absorption site. In a experiment on diltiazem and paracetamol shows that quantitative relationship existed between partion coefficient and nasal absorption constant (63).

III. Chemical form: chemical form mainly effect on absorption of molecule. For ex, conversion into salt and ester form mainly effect on that. On research shows that absorption of carboxylic acid ester of L- tyrosine higher than the L-tyrosine natural form(64).

IV. Molecule weight: linear invers relationship observe between molecule weight upto 300 daltons. And decrese with molecule weight more than 1000 daltons. During that they require absorption enhancer for better absorption on molecule(65).

V. Particle size: greter then 10µm deposited in nasal cavity. While 2 to 10 µm can be retain into lungs, less than 1 µm exhaled.

VI. Solubility and Dissolution rate: in determing nasal absorption from powder and suspension. The particle deposited on absorption side first they can be dissolve for the absorption. For that solubility of compound can be a crucial factor. While in nasal cavity fluid available for dissolution of compound is less than the fluid available at absorption through thr git (66).

5.5.2 Formulation factors

I. pH of formulation: both pH and pKa of the formulation effect on the absorption of compound. Nasal irritation minimized by pH is between- 4.5 – 6.5. due to present of lysosome in nasal mucosa they can be destroys certain bacteria in acidic pH. By maintain alkaline pH lysosome is inactivate and nasal mucosa is susceptible for microbial infection. The pH of nasal formulation important due to following reason (67):

ü To avoid irritation of nasal mucosa

ü To allow the drug to be available in unionized form for absorption

ü To prevent growth of pathogenic bacteria in the nasal passage

ü To maintain functionality of excipients such as preservatives

ü To sustain normal physiological ciliary movement

II. Osmolarity: absorption of molecule also be effected by tonicity of the formulation. In present study in rat shows that sodium chloride concentration is 0.462M is required to achive maximum absorption of molecule. Because of shrinkage of nasal epithelial mucosa due to hypertonic solution (68).

III. Gelling agent: retention nasal formulation on nasal cavity can be enhance therapeutical response and can be also enhancing rate and extent of drug absorption. On study shows that increasing viscosity of formulation can prolong the action of nasal formulation (69).

IV. Solubilizers: aqueous solubility of drug molecule can always limitation for nasal formulation in solution. Conventional solvent and cosolvent can be use in some case surfactant use to enhance the aqueous solubility of molecule.

V. Drug concentration, required dose, and dose volume: This are all interrelated parameter that can be effect on the performance of the formulation. In one article shows that absorption of salicylic acid can be decrease with increase in concentration of administrated drug and low absorption at high concentration of salicylic acid and also lines to produce nasal cilio toxicity (70).

5.5.3 Physiological Factor:

I. Effect of deposition on absorption: this can provide longer residence time and better absorption of compound. Also when compound stay on this portion can under goes mucociliaray clearace and hence shows low bioavailability.size and patter of diposition can be depend on device, mode of administration, physiological properties of drug.

II. Nasal blood flow: mucosal surface rich of vasculature and play role in thermal regulation and humidification. Absorption of molecule can be dependent of vasocontraction and vasodilation of compound.

III. Effect of mucociliary clearance: nasal clearance mechanism is maintained to perform normal physiological functions such as the removal of dust, allergens and bacteria. Absorption of molecule can be depend on residual time between nasal epithelium and formulation. Mucociliary clearance is inversely related to the residence time hence can be effect on absorption of molecule. Prolong residence time can be achieved by using bioadhesive molecule (71).

IV. Effect of enzyme activity: this can mainly effect on stability of drug. For ex. Protein and peptide are subjected to degradation by proteases and aminopeptidases at mucosa membrane.

5.5.4 Nasal formulation:

Deposition and deposition area are mainly function of delivery system and delivery devices. Different dosage form and their application to delivery drug via nasal route are as following.

I. Liquid dosage form (72): either in solution, suspended particle, colloidal system.

Nasal drops: simple and convenient delivery device than all other formulation, due to lack of dose precision not widely use, it has been reported that nasal drop deposit on human serum albumin nostril mucosa more effectively than nasal spray.

Nasal sprays: in that both suspension and solution formulation incorporated as compared to powder due to mucosal irritation nature of powder form.by using meter dose pump and actuator actual dose can be deliver (25 to 200 µl) from this and can be selected based on particle size and morphology (for suspension formulation) of particular formulation.

Nasal emulsion, microemulsion and nanoparticles: intranasal and nanoparticle not been studied extensively as other liquid formulation, nasal emulsion have a benefit like high viscosity but due to some issue like stability, poor patient compliance, price delivery of formulation.

II. Semi solid dosage form (73): mainly involve gels, ointment, liquid system containing polymer that get gel at particular pH. Nasal gel formulation most widely use due to benefit like post-nasal dripping is less due to high viscosity of particular formulation, reduce taste impact, reduction of irritation by using smoothing and emollient compound.

III. Solid dosage form(74): this also being popular for intranasal drug delivery but this can be a most popular for pulmonary drug delivery of particular compound. Powder formulation have a benefits like absence of preservative and superior stability of dosage form. However suitability of powder dosage for this is mainly dependent on particlesize, aerodynamic properties, irritation properties of formulation and solubility. But nasal mucosal irritation and meter dose formulation is most challenge for scientist.

5.6 Application of nasal drug delivery system:

5.6.1 Delivery of vaccines through nasal route:

Nasal delivey of vaccines reported not only for produce systemic immune response , but also local immune response in the nasal lining, providing additional barrier of protection. Most of the pathogen can be enter in the body via mucosal layer. Therefore this route is potential route as well as first line of defect against entering pathogens. In Table. 4. Explain various marketed available product for vaccines delivery through nasal mucosa.

5.6.2. Delivery of peptides and nonpeptides drugs for systemic effect through nasal route.

Most peptides and proteins, being hydrophilic polar molecules of relatively high molecular weight, that’s via poorly absorbed across biological membranes with bio-availability obtained in the region of 1–2% concentrations when administered as simple solutions. This low uptake may be adequate for the development of some commercial products like desmopressin and calcitonin because they have a wide therapeutic index. But for certain peptide drugs such as insulin which does not have the luxury of wide therapeutic index it is essential to develop the novel formulation strategies. In order to produce a product with a good bioavailability that can provide sufficient reliability in dosing and overcome these problems much research has been carried out in the areas of absorption enhancers and bioadhesive agents. Absorption enhancers are used to increase the bioavailability, and these enhancers are basically surfactants, glycosides, cyclodextrin and glycols. Recent studies have shown that the high bioavailability achieved with absorption enhancers for the delivery of polar compounds across mucosal membranes can be associated with tissue damage. In table 5&6 explain various marketed available protein and peptide drug delivery and nonpeptide drug delivery in market.

5.7. Various patent for nasal drug delivery.

In table 7. Various patent pertaining to intranasal brain drug delivery.as nasal route of administration is found to be a validated route of drug delivery to brain many scientists have revealed that ocular route can be the next alternative route of drug delivery.

Tab.4, Marketed Available Nasal Drug Product For Vaccination

Vaccine	Product name	Dosage form	Status	Manufacturer
Human influenza vaccine	Nasaflu Berna	Virosomes (spray)	Marketed	Berna Biotech
Equine influenza vaccine	Flu Avert	Drops	Marketed	Heska
Feline bordetella bronchiseptica vaccine	Nobivac Bp	Suspension drops	Marketed	Intervet
Human streptococcus A vaccine	Strep Avax	Nanoparticulate	Phase 2	ID Biomedical
Human influenza vaccine	FluINsuru	Nanoparticulate	Phase 2	ID Biomedical
Human influenza vaccine	-	Non indicated	Phase ½	West PS
Human influenza vaccine	FluMist	Spray	Marketed	Medlmmune inc.
Feline trivalent vaccine against calici herpes – I and parvovirus	-	Drops	Marketed	Heska

Tab.5, Marketed Available Nasal Drug Product For Protein And Peptide.

Drug {Sols (spray)}	Disease	Product name	Status	Manufacturer
Salmon calcitonin	osteoporosis	koril 200 I.E	Marketed	Novartis Pharma
Desmopressin	Antidiuretic	Minirin nasenspray	Marketed	Ferring Arzneimmited
Buserelin	Prostate cancer	Profact nasal	Marketed	Aventis Pharma
Nafarelin	Endometriosis	Synarela	Marketed	Pharmacia
Oxytocin	Lactation induction	Syntocinon	Marketed	Novartis Pharma
Protirelin	Thyroid diagnostics	Relefact8* TRH nasal	Marketed	Sanofi-synthelabo Aventis Pharma

Tab.6, Marketed Available Nasal Drug Product For Non-Peptide.

Drug {Sols (spray)}	Disease	Product name	Status	Manufacturer
Zolmitriptan	Migraine	AscoTOP* nasal	Marketed	Astra Zeneca
Sumatriptan	Migraine	Imigran* nasal	Marketed	Glaxo SmithKline
Dihyfroergotamin	Migraine	Migranal* nasal spray	Marketed	Novartis Pharma
Estradiol	Hormone replacement	Aerodiol*	Marketed	Servier

The ability of engineered liposomes to enter into brain tumours makes them potential delivery systems for brain targeting. Biodegradable polymers are also making their place in the area of matrix type sustained-release of neurotherapeutics. Table 8 presented below summarizes the drugs available for brain disorders along with their routes of administration.

CONCLUSION:

For treatment of CNS disease is more challenging for scientist because of delivery of drug molecule to the brain is often precluded by a variety of physiological, biochemical, metabolic situation that collectively compromising the BBB, BCB and BTB. In present situation patient suffering from various type of CNS disease remain poor, but recent developments in the drug delivery provide responsible barriers to overcome this. Drug delivery directly to brain interstitium has recently enhanced by rational design polymer based design, noninvasive , invasive nad also intranasal drug delivery through the olfactory and trigeminal neuronal pathway. More this is a noninvasive method, self administrative, patient confort and compliance which can be hurdled intravenous drug therapy of various polymer based and other invasive therapy. However continuous and vigorous research efforts to develop more therapeutic and less toxic molecule are paralleled by the aggressive pursuit of more effective mechanism for delivery drug molecule to target particular part of CNS.

REFERENCES:

1. Pardridge WM, et al. peptid drug delivery to the brain, raven press, New York, U.S.A, 1991.

2. Crone c, et al. the blood brain barrier , a modified tight epithelium, elis harwood,chicheter, 17-40,1986.

3. Brightman M et al, ultra structure of brain endothelium in Bradbury MWB physiology and pharmacology, springer verlag, berlin,1-22,1992.

4. Loe H et al, drug delivery to damaged brain, brain res rev,38 : 140-148,2001.

5. Davson h et sl, physiology of the CNS and BBB, crs press, USA,1995.

6. Brownless J et al, peptides, peptidases and mammalian BBB, J comp neurol, 60:1089 – 1096,1993.

7. Nabershima S et al, junction in the meaning and marginal glia, J comp neurol 164:2, 127- 169,1975.

8. Saito Y et al, bicarbonate transport across the frog choroid plexus and cerebrospinal fluid of mice, prog brain res, 29: 19 – 40, 1968.

9. Conford EM et al, comparison of lipid mediated BBB penetrability in neonates and adult, Am J physiology, 243,1982.

10. Siegal T et al, strategies for increasing drug delivery to brain, focus on brain lymphoma, clin pharmakinetic, 41: 141-186,2002.

11. Sadeque et al, increased drug delivery to brain by P- glycoprotein inhibitor, clin pharmacol ther: 68: 231-237; 2000.

12. Salvolainen J et al, effect of P- glycoprotein inhibitor on brain and plasma conc of antihuman immunodeficiency virus drug administration in rats, drug metabolism dispos,31 ; 479-482;2002.

13. Gupta SP et al, QSAR studies on drug delivery at CNS, chem rev, 89, 1765 – 1800; 1989.

14. Reddy JS et al, novel delivery system for drug targeting to brain, drug future, 29: 63-69,2004.

15. Misra A et al, drug delivery to the CNS: a review, J pharma sci, 6(2): 252-273, 2003.

16. Kabanov AV et al, nowel technologies for drug delivery across the BBB, curr pharma des, 10: 1355-1363:2004.

17. Abbott NJ, Romero IA. Transporting therapeutics across the bloodbrain barrier. Mol Med Today; 2: 106-113, 1996.

18. Han HK, Amidon GL. Targeted prodrug design to optimize drug delivery. AAPS Pharm Sci; 2: E6, 2000.

19. Bodor, N.S.: US4540564 (1985).

20. Katz, R., Tomoaia-Cotisel, M.: US20066005004 (2006).

21. Atlas, D., Melamed, E., Offen, D.: US20060211628 A1 (2006).

22. Bergley DJ. The blood-brain barrier: principles for targeting peptides and drugs to the central nervous system. J Pharm Pharmacol; 48: 136-146, 1996.

23. Walus LR, Pardridge WM, Starzyk RM, Friden PM. Enhanced uptake of rsCD4 across the rodent and primate blood-brain barrier following conjugation to anti- transferring receptor antibodies. J Pharmacol Exp Ther; 277: 1067-1075, 1996.

24. Pardridge WM, Kang YS, Buciak JL, Yang J. Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid trans-cytosis through the blood-brain barrier in vivo in the primate. Pharm Res; 12: 807-816, 1995.

25. Starr, C.M., Zankel, T., Gabathuler, R.: CA2525236 (2005).

26. Neuwelt, E.A.: US5124146 (1991).

27. Abulrob, A., Zhang, J.: WO2007036022 (2007).

28. Beliveau, R., Che, C., Regina, A., Demeule, M.: CA2597958(2002).

29. Daneman, R., Barres, B.: WO2007137303 (2007).

30. Pardridge, W.M.: US4801575 (1989).

31. Bentley, M.D., Roberts, M.J.: US20030139346A1 (2003).

32. Friden, P.M.: US5833988 (1998).

33. Temsamani, J., Rees, A.R.: US20060293242A1 (2006).

34. Garcia-Garcia E, Andrieux K, Gil S, Couvreur P. Colloidal carriers and blood-brain barrier (BBB) translocation: A way to deliver drugs to the brain? Int J Pharm; 298: 274-292, 2005.

35. Peracchia MT, Vauthier C, Desmaele D, et al. Pegylated nanoparticles from a novel methoxypolyethylene glycol cyanoacrylatehexadecyl cyanoacrylate amphiphilic copolymer. Pharm Res; 15: 550-556, 1998.

36. Peracchia MT, Harnisch S, Pinto AH, et al. Visualization of in vitro protein rejecting properties of PEGylated stealth polycyanoacrylate nanoparticles. Biomaterials; 20: 1269-1275, 1999.

37. Jones M, Leroux J. Polymeric micelles-a new generation of colloidal drug carriers. Eur J Pharm Biopharm; 48: 101-111, 1999.

38. Allen C, Maysinger D, Eisenberg A. Nano-engineering block copolymer aggregates for drug delivery. Colloids Surf B Biointerfaces; 16: 3-27, 1999.

39. Kabanov AV, Batrakova EV, Melik-Nubarov NS, et al. New classes of drug carries: micelles of poly(oxyethylene) – poly (oxypropylene block copolymersas microcontainers for drug targeting form blood in brain. J Control Release; 22: 141-158, 1992.

40. Ringe, K., Radunz, H. : WO2006056362 (2006).

41. Kreuter J. Nanoparticulate systems for brain delivery of drugs. Adv Drug Del Rev; 47: 65-81, 2001.

42. Heppe, K., Heppe,A., Schliebs, R.: US2006051423 (2006).

43. Gasco, M.R.: US20026419949 (2002).

44. Mehnert W, Mäder K. Solid lipid nanoparticles - production, characterization and applications. Adv Drug Deliv Rev; 47: 165-196, 2001.

45. Shastri, V.P., Sussman, E., Jayagopal, A.: WO2006044660 (2006).

46. Huwyler J, Wu D, Pardridge WM. Brain drug delivery of small molecules using immunoliposomes. Proc Natl Acad Sci USA; 93: 14164-14169. 1996.

47. Micklus, M.J., Greig, N.H., Rapoport, S.I.: US20020025313A1 (2002).

48. Pardrige, W.M.: WO01182900A1 (2001).

49. Pardrige, W.M., Huwyler, J.: WO022092A1 (1998).

50. Grieg NH. Optimizing drug delivery to brain tumors. Cancer Treat Rev; 14: 1-28, 1987.

51. Langer R. Polymer implants for drug delivery in the brain. J Control Release; 16: 53- 60, 1991.

52. Shalev, A.: WO2004043334 (2004).

53. Putz, D.A.: US20077241283 (2007).

54. Arun Kumar Singh et al. Nasal cavity: a promising transmucosal platform for drug delivery and research approaches from nasal to brain targeting, Journal of Drug Delivery & Therapeutics;, 2(3): 22-33, 2012.

55. Illum L. Nasal drug delivery-possibilities, problems and solutions. J Control Release; 87:87–198, 2003.

56. Singh et al. nasal cavity: a promising transmucosal platform for drug delivery and research apparoaches from nasal to brain targeting, journal of drug delivery and therapeutics; 2(3): 22-33,2012.

57. Mygind N et al. anatomy, physiology and function of nasal cavities in health and disease. Adv drug delivery reviews; 29: 3-12, 1998.

58. Chein YW et al. anatomy and physiology of the nose. In nasal systemic delivery: drug and pharmaceutical sciences, new York.1-26: 1989.

59. Talegaonka S et al. intranasal drug delivery: An approach to bypass the BBB, indian J pharma; 36(3),140-147,2004.

60. Illum L. nasal drug delivery: new strategies and development. Drug discovery today. 7(23):1184-1189:2002.

61. Illum L et al. transport of drug from nasal cavity to the CNS, European journal of pharmaceutical sciences 11; 1-18, 2000.

62. Ohwaki T, Ando H, Watanabe S, Miyake Y. Effect of dose, pH ,osmolarity on nasal absorption on nasal absorption of secretin in rat. J pharm sci . 74:550-2,1985.

63. Jiang XG, Lu X, Cui JB, Qiu L, Xi NZ. Studies on octanol-water partition coefficient and nasal drug absorption. Yao Xue Xue Bao; 32: 458-460, 1997.

64. Huang C, Kimura R, Nassar A, Hussain A. Mechanism of nasal drug absorption of drug II: absorption of L-tyrosine and the effect of structural modification on its absorption. J Pharm Sci. 74:1298-1301,1985.

65. Fisher A, Illum L, Davis S, Schacht E. Di-iodo-L-tyrosine labeled dextrans as molecular size markers of nasal absorption in the rat. J Pharm Pharmacol; 44: 550-554, 1992.

66. Johnes N. The nose and para nasal sinuses physiology and anatomy.adv Drug Deliv Rev;51:5-19, 2001.

67. Thompson R. Lysozyme and its relation to antibacterial properties of various tissues and secretions. Arch Pathol. 1940;30:1096

68. Ohwaki T, Ando H, Kakimoto F. Effects of dose, pH, and osmolarity on nasal absorption of secretin in rats. II: Histological aspects of the nasal mucosa in relation to the absorption variation due to the effects of pH and osmolarity. J Pharm Sci; 76: 695-698, 1987.

69. Suzuki Y, Makino Y. Mucosal drug delivery using cellulose derivatives as a functional polymer. J Controlled Release; 62:101-107, 1999.

70. Hirai S, Yashika T, Matsuzawa T, Mima H. Absorption of drugs from the nasal mucosa of rat. Int J Pharm.;7: 317-325, 1981.

71. Kublik H, Vidgren MT. Nasal delivery systems and their effect on deposition and absorption. Adv Drug Deliv Rev.; 29: 157-177, 1998.

72. Hardy JC, Lee SW, Wilson CG. Intranasal drug delivery by nasal spray and drops.J Pharm Pharmacol; 37: 294-7, 1985.

73. Junginger HE. Mucoadhesive hydrogels. Pharmazeutische Industrie; 53: 1056-1065, 1956.

74. Ishikawa F, Katsura M, Tamai I, Tsuji A. Improved nasal bioavailability of elcatonin by insoluble powder formulation. Int J Pharm; 224: 105-114, 2001.

Received on 10.06.2014 Modified on 20.08.2014

Res. J. Pharm. Dosage Form. and Tech. 6(4):Oct.- Dec.2014; Page 253-266

Drug	Application	Delivery system	References
Benzodiazapines Valporicacid carbamezapine	Epilepsy	Nasoadhesive microemulsion	Ambikanandan et al, 1061/MUM/2005
Sedative	Insomnia	Nasoadhesive microemulsion	Ambikanandan et al, 1124/MUM/2005
Triptan, caffeine	Migraine	Nasoadhesive microemulsion	Ambikanandan et al, 1125/MUM/2005
Lorazepam	Epilepsy	Spray	Wermwling DP: US20016610271(2001)
Zolpidem	Insomnia	Chitosan sols	Castile. US2007140981A1(2007)
Diazepam	Epilepsy	Microemulsion	Choi et al, US20050002987A1(2005)
Neurotropic agent	Brain disorders	Liposome, sustain release matrix tablet	Frey et al, WO000033814(2000) Frey II: WO00033813A1 (2000) Frey II: US20030072793 (2003) Frey II : EP1137401B1 (2005)
Proteasomes glatiramer	Neurodegenerative diorders	Nanoemulsion	Frenkel et al, US20060229233A1 (2006)
clotrimazole	Huntington’s	-	Cummings et al, US20070037800A1(2007)
Catecholic butane	Obesity, diabetes, hypertension	-	Heller et al, US20060141029A1 (2006) Heller et al, US20060141047A1 (2006) Heller et al, US20060141025A1 (2006)
Galantamine		Liquid, gel, powder	Quary SC, US20060003989A1 (2006)

Brain Disorder	Molecule Patented Or Under Investigation
Cerebral Ischemia / Stroke	Deferoxamine, Trientine, Ebselen, Hereguline, Cobalt, Remacemide
Alzheimer’s Disease	Ambenonium, Edrophonium, Neostigmine, Tacrine, Rivastigmine, Galantamine
Migraine	Frovartriptan, Ergotamine, Sumatriptan, Rizatriptan, Zolmitriptan
AIDS	Zidovudine, Efavirenz, Tenofovir, Saquinavir
Epilepsy	Phenytoin, Ethosuximide, Topiramate, Gabapentin, Carbamazepine, Lamotrigine
Schizorphenia	Chlorpromazine, Clozapine, Risperidone, Olanzapine
Depression	Imipramine, Fluoxentine, Sertraline, Moclobemide, Phenelzine
Narcotic Addiction	Mecamylamine, Pempidine, Succinylchloride, Trimethaphean, Chlorisondamine, Hexamethonium, Pentolinium, Methadone
Parkinsonism	Selegiline, Rimantadine, Amantadine, Levodopa, Ropinirole, Entacapone, Talocapone, Pramipexole
Anxiety	Flurazepam, Alprazolam, Diazepam, Lorazepam, Clonazepam, Buspirone
Obesity	Diltizem, Phentermine, Sibutramine, Rimonabant