INTRODUCTION:

Nasal Absorption Mechanism:

The nasal absorption of the drug mainly considered taking place in respiratory region consisting of the turbinates and part of nasal septum. The respiratory region consists of inferior, middle and superior turbinate attached to lateral wall.

A drug may cross the nasal mucosa by different mechanisms

There are two routes potentially involved in drug absorption across the nasal epithelial barrier: ¹

1) Transcellular route

The transcellular route of nasal mucosa has been simply viewed as primarily crossing the “lipoidal barrier,” in which the absorption of a drug is determined by the magnitude of its partition coefficient and molecular size.

a. Transcellular passive diffusion

Molecular size of drugs is known to be one of the important factors in determining the passive diffusion. It was reported that nasal absorption sharply decreased for a drug with molecular weight higher than 1,000 Da . Because the degree of ionization of a given drug is also an important property for absorption via this route, transport is dependent on the pKa of the drug and pH of the environment (e.g. the pH of nasal secretions is normally in the region 5.5–6.5).

b. Carrier mediated process:

The existence of a carrier-mediated transport in nasal mucosa was 1^stsuggested by Kimura et al. P-glycoprotein, organic cation transporter, dopamine transporter, and amino acid transporters have all been identified in the nasal mucosa, especially in the olfactory mucosa .These transporters determine the polarized absorption and excretion of their substrates including amino acids, amines, and cations.

c. Endocytic process: (particle internalization by vesicles).

Since the uptake of particles in nasal epithelial tissue is known to be mostly mediated by M cells, nasal administration has been investigated as a noninvasive delivery of vaccines However, since the uptake of naked DNA by endocytocis is limited, use of either nanoparticles as mucosal delivery systems or hypotonic shock is reported for the efficient transfection of gene and vaccine into the nasal epithelium.

2) Paracellular route: (Movement through the spaces between cells and tight junctions.)

This refers to the transport taking place between adjacent epithelial cells by passive diffusion or solvent drag mechanisms. Thus, small hydrophilic molecules can passively diffuse through paracellular routes between adjacent nasal epithelial cells. Passive diffusion of hydrophilic solutes via paracellular routes is driven by a concentration gradient across the epithelium with the rate of absorption governed by the Fick’s 1^st law of diffusion. Polar and charged drugs with molecular weights below 1,000 Da are thought to permeate the nasal epithelium via this paracellular route. A major limiting site of paracellular pathways is known to be the tight junctional region, which is characterized as the joining of contiguous cells via various tight junctional proteins.

Transcellular way is a fast rate which is lipophilicity dependent and paracellular is slower rate which is sensitive to variation in molecular weight. Lipophilic drug are transported by concentration dependent passive diffusion process, receptor or carrier mediation and by vesicular transport mechanism. Polar drug pass through epithelium via the gaps and pores between the cells. Diffusion of penetrant molecule through aqueous channel between nasal mucosa imposes a molecular size dependent nasal permeability.

Factors influencing nasal absorption:

1. Physiological Factor:

a. Mucociliary clearance.

b. Pathololgical condition like infection, allergy, nasal inflammation

c. Atmospheric condition in nasal cavity (temperature, humidity).

d. Speed of mucus flow, nasal blood flow.

e. Enzymatic degradation

2. Dosage form factors:

a. Physicochemical properties of active drug

b .Concentration of active drug

c. Physicochemical properties of pharmaceutical excipient used.

d. Density, viscosity and pH characteristic of formulation

e. Toxicity of dosage form.

3. Administration factors:

a. Size of dose

b. Site of deposition

c. Loss from nasal cavity after administration.

4. Other factors:

a. Variability of intranasal dosing.

b. Effect of delivery system.

1. Physiological Factor

a. Mucociliary clearance:

Nasal mucociliary clearance is a fundamental function required to maintain the health and defense of nose.² This process is responsible for rapid clearance of nasally administered drugs from nasal cavity to nasopharynx and therefore interfering with absorption of drug following intranasal administration.³Mucociliary clearance system it transport the agent backward in the nose and downward in to the throat This action is related with beat of cilia present in respiratory epithelial cell. The mucociliary clearance system has been known as a “conveyer belt” in which ciliated cells provide the driving force, and mucus performs as a sticky fluidic belt that collects and disposes of foreign particles.

The absorption of drugs from the nasal mucosa is influenced by the contact time between drug and epithelial tissue. Nasal mucociliary clearance, limits the residence time of drugs administered into the nasal cavity, decreasing the time available for the drug to be absorbed. The normal half-time of clearance in humans is about 20 min.⁴

Nasal mucociliary clearance is affected by drug and additives used in nasal formulations. Cholinergic agonists, such as acetylcholine and methacholine, beta-Adrenergic agonists stimulate ciliary activity in a dependent manner in vivo and in vitro. Salmeterol and isoprenaline, beta-adrenergic receptor agonists, were found to reduce the decrease in ciliary beat frequency of human mucosa in vitro caused by a ciliotoxin.

Atropine is the only for the mucociliary transport rate on human nasal cholinergic antagonist known to decrease mucociliturbinates in vitro and the saccharin clearance time in ary clearance and ciliary activity.⁴

The preservatives, such as chlorobutol and hydroxybenzoates, cause reversible inhibition of mucociliary clearance. Preservatives such as cresol, chlorocresol, and phenyl mercuric salts showed irreversible inhibition of mucociliary clearance, whereas nasal mucociliary transport was not altered by benzalkonium chloride.

b. Pathololgical condition like infection, allergy, nasal inflammation :

Diseases such as the common cold, rhinitis, atrophic rhinitis and nasal polyposis are usually associated with mucociliary dysfunctioning, hypo or hypersecretions, and irritation of the nasal mucosa, which can influence drug permeation.

Inflammation of the nasal mucosa may affect the drug absorption. Various studies suggest that intranasal drug pharmacokinetics and pharmacodynamics are not affected by inflammation of nasal mucosa.³ E.g. zolmitriptan, butarphenol ³

c. Atmospheric condition in nasal cavity (temperature, humidity):

The blood vessels in the nasal mucosal membrane play an important role in the thermal regulation and humidification of the inhaled air and hence on the drug absorption.

d. Speed of mucus flow, nasal blood flow:

The vestibule, atrium and the beginning of the turbinates are covered by non-ciliated surfaces. Mucus flow in this anterior third of the nasal cavity is only 1–2 mm/h.

The main nasal passages are highly vascularized and ciliated. Here the rate of mucus flow is 8–100 mm/min. It is assumed that in this region, with increased surface area, highest air flow resistance particles, and ciliated cells, the main drug absorption takes place.⁵

The nasal mucosa is supplied by rich vasculature. The highly vascular nature of the mucosa makes it a good membrane for drug absorption The blood flow and therefore drug absorption will depend upon the vasodilation and vasoconstriction of the blood vessels. The nasal blood flow is affected by several external and physiological factors as ambient temperature, humidity, presence of drugs, trauma, and inflammation as well as some psychological factors such as emotion, fear, anxiety, and frustration .The nasal blood flow is sensitive to a variety of compounds. This is true for both locally or systemically acting drugs.⁶Such effects are important in determining nasal drug absorption due to their effects on blood flow.

e. Enzymatic degradation:

One of the major barriers in nasal absorption of drug is posed by nasal mucosal lining and enzymes present in nasal cavity. The existence of this enzyme influences the transnasal absorption of both lipophilic and hydrophilic drug. Various enzymes are found to exist in nasal mucosa like aldehyde cytochrome P-450-dependent monooxygenhormones .Other enzymes such as amino peptidases have been shown to result in systemic degradation of peptides and proteins. Carboxylesterases are another class of enzymes which have the highest activity reported in the nasal epithelia.⁷

Cytochrome P-450 dependent monooxygenase is reported to catalyse the metabolism of different xenobiotics. It metabolizes many drug in nasal mucosa like nasal decongestant, nicotine, cocaine, phenacetin, progesterone.

2. Dosage form factors:

a. Physicochemical properties of active drug:

The rate and extent of drug absorption may depend upon many physicochemical factors including the aqueous-to-lipid partition coefficient of the drug, the pKa, the molecular weight of the drug, perfusion rate and perfusate volume.⁸

1. Molecular size: It has been reported that nasal absorption falls off sharply for a drug molecule with a molecular weight greater than 1000 Dalton. Based on the reports by Fisher et al. and Yamamto et al , it can be concluded that the permeation of drugs less than 300 Da is not significantly influenced by the physicochemical properties of the drug, which will mostly permeate through aqueous channels of the membrane. By contrast, the rate of permeation is highly sensitive to molecular size for compounds with MW = >300 Da⁹.

2. Chemical form: Conversion of a drug into a salt or ester can alter its absorption. Huang et.al studied the structural modification of a drug on absorption. In-situ nasal absorption of carboxylic acid ester of L –Tyrosine was significantly greater than that of L-tyrosine.¹⁰

3. Particle Size:

Particles larger than 30 mm are removed as there is a large degree of air-mucosa contact time due to cilia air turbulence in the nasal airway which increases with a faster respiratory rate. A substantial proportion of smaller particles down to 12 mm are also filtered.¹¹ It has been reported that particle greater than 10um is deposited in nasal cavity and less than 1µm are exhaled.

4. Solubility and dissolution:

Intranasal drugs are administered to nasal mucosa as a molecularly dispersed form e.g. in solution form. The allowable volume for intranasal administration is very low and therefore drug with low aqueous solubility and requiring high doses may present a problem the drug dissolve in fluid present in nasal cavity. If drug remains as it is particles it is cleared away and no absorption not occurs. Thus the drug should have sufficient solubility in nasal secretion.

5. Lipophilicity:

For nasal mucosal membranes, a range of studies evaluating the effect of lipophilicity and pH on nasal absorption of small molecular weight drugs has been performed in the rat model. It was found that the largest absorption of the drugs occurred when they were in their non-ionized state, in which drugs have a higher apparent partition coefficient, i.e., are more lipophilic. However, significant absorption was also seen when the drugs were ionized.¹²

Nasal absorption of drugs through olfactory bulb has received more attention in recent days. The lipophilicity of the drug molecule is the first prerequisite for centrally acting drugs. However, direct nose to brain pathway allows the transportation of drug without sufficient lipophilicity. Most of the drug are either weakly acidic or weakly basic and their absorption depends on the degree of ionization at nasal pH of between 4.5 and 6.5. Thus pH is essential for physiological defense mechanism against microbial organisms. Lysozyme is present in nasal secretion, which is responsible for destroying certain microorganism at acidic pH. Lysozyme inactivation at alkaline condition leads to nasal infection and hence it affects the nasal mucociliary clearance and bioavailability of nasal formulations.¹³

6. Effect of perfusion rate:

The results of nasal perfusion studies on nasal administration of Phenobarbital showed that as the perfusion rate increases nasal absorption first increases and then reaches a plateau level that is independent of perfusion rate.

b .Concentration of active drug:

Nasal absorption of 1-tyrosyl-L-tyrosine was shown to increase with drug concentration in an ex with vivo nasal perfusion experiment in rats. In another study by Brannan et al., a nasal spray of beclomethasone dipropionate was administered to patients with allergic rhinitis, in two concentrations, 0.042% and 0.084%. No effect in the systemic absorption of this drug was observed as a function of its concentration. If the primary mechanism of absorption was passive, there should be a clear positive relationship between absorption and drug concentration. Such a relationship is not always observed.⁶

From the above studies one cannot judge the effect of drug concentration on absorption and bioavailability. However, the absorption of drug and its concentration cannot be correlated with the mechanism of drug absorption from the nasal mucosa.

c. Physicochemical properties of pharmaceutical excipient used:

Several promising drug candidates cannot be exploited for the nasal route because they are not absorbed well enough to produce therapeutic effects. This has led researchers to search for the ways to improve drug absorption through the nasal route. The most widely used approach is the incorporation of excipients in formulations which will allow improved drug absorption.

Formulation excipients are chosen for various reasons. The most common reasons follow.

1. Solubilizer: It is necessary to use solubilizer in formulation, in case of poorly water soluble drug, One can use the cosolvents like glycols in formulation to improve nasal absorption.

2.Buffer components: Various conventional buffer systems can be used to buffer nasal formulations. An important parameter for consideration is the buffer capacity of a formulation.

3. Antioxidants: It may be necessary to use antioxidants to prevent drug degradation. Typically, sodium metabisulfite, sodium bisulfite, and tocopherol are used. Usually, antioxidants are used in small quantities and they may not affect drug absorption or cause any nasal irritation.

4. Absorption promoters: Either a drug does not absorb at all or has poor absorption or the C_max or T_max are not adequate. Invariably, a formulator will be faced with a situation where drug absorption will need to be optimized. The use of absorption promoters may be done.

d. Density, viscosity and pH characteristic of formulation:

The extent of absorption is pH dependent, being higher at a pH lower than pKa and decreases as the pH increases beyond the pKa.The rate of absorption is increased because of ionization of penetrent molecule.

The variation in solution pH was also observed to affect the nasal absorption of peptide-based drugs, such as insulin.

It is important to adjust nasal formulations pHs for the following reasons:

· To avoid irritation of the nasal mucosa;

· To obtain efficient drug absorption;

· To prevent growth of pathogenic bacteria in the nasal passage.

To avoid nasal irritation, formulation pH should be adjusted between 4.5 and 6.5.

3. Administration factors

Drug distribution in the nasal cavity is an important factor that affects the efficiency of nasal absorption. Three mechanisms are usually considered in assessing particle deposition in the respiratory tract, i.e., inertia, sedimentation and diffusion, the first being the dominant mechanism in nasal deposition. Any particle with an aerodynamic diameter of 50 mm or greater does not enter the nasal passage. Result suggested regarding drug concentration, dose, is that high concentration for better bioavailability, maximum dose in minimum volume vehicle (less than 200 µl), is preferable .The mode of administration also influences the distribution of drug in nasal cavity, which determines the efficiency of its absorption. Drug administered by different types of nasal delivery systems, like nose drop, plastic bottle nebuliser, an atomized pump and metered dose pressurized aerosol. Depending on the type of formulation, a variety of devices have been used to give drugs intranasally. over-dosage. Their angle of insertion into the nostril can influence the part of the nasal cavity that the formulation comes in contact with initially and as such the overall deposition pattern¹⁴. Deposition of formulation in anterior portion of the nose provides a prolonged nasal residential time and better absorption. One should avoid deposition in both the poorly absorptive stratified epithelium of the anterior atrium and in the posterior nasopharyngeal region, which leads to drug loss to stomach by swallowing.

The site of deposition within nasal cavity depends upon the type of delivery system used and the technique of administration applied. The density, shape and hygroscopicity of the particle and the pathological conditions in the nasal passage influence the deposition of particle, whereas particle size distribution determines the site of deposition. Metered-dose nebulizers and metered-dose aerosols are superior to other devices in terms of accuracy and reproducibility (Dondeti 1996). However, the duration and condition of storage, as well as the physicochemical characteristics of the formulation such as viscosity, surface tension and homogeneity (e.g. of suspensions) affect metering accuracy. Technical aspects of criteria for choosing a particular device should take the following factors into account: physicochemical properties of the drug in the dosage form that can be delivered from a particular device; and device performance with respect to accuracy and reproducibility of dosing as well as resistance to microbial contamination. The device should be compatible with the formulation components.¹⁴

4. Other factors

a. Variability of intranasal dosing:

Inter- and intra-subject variability in pharmacokinetics and/or pharmacodynamics is an important consideration when choosing the delivery route. For low-molecular-weight drugs, intranasal dosing can provide pharmacokinetics with relatively high bioavailability and relatively low variability, which in many cases is similar to or lower than oral or even injection administration¹⁵ (e.g., Coda et al., 2003). However, for high-molecular-weight drugs such as peptides and proteins, intranasal pharmacokinetics exhibit relatively low bioavailability and relatively high variability compared to injections¹⁶ (Adjei et al., 1992).

b. Effect of delivery system:

Several types of drug delivery devices are used for delivering dug to nasal cavity, such as nasal dops, nasal spray,aerosol spray and insufflator. An inflatable nasal device with it’s wall constructed from a microporous membrane was developed to provide the long acting, controlled delivery of drug. The dose of active ingredient administered intranasally depends on the volume of drug solution delivered at each actuation of device and concentration of drug in formulation.

The effect of delivery devices on nasal administration can be seen from the results of the study of progesterone delivered to rabbits by the controlled release device was compared to that attained by an immediate release nasal spray. The result indicate that with nasal spray produces peak plasma level within 2 min whereas controlled release nasal device lead to gradual increase in plasma progesterone concentration which reaches to plateau level within 20-30min.The systemic bioavailability of progesterone by an immediate nasal spray was 82.5% and a controlled release nasal device was 72.4%.This reveals that nasal devices also having effect on nasal absorption of drug.

Enhancement of nasal drug absorption

Mechanism:

There are many mechanism are proposed for absorption enhancement

1) Physicochemical effect:

Some enhancer can alter the physicochemical properties of drug in formulation. This can be done with following methods,

a. Structural modification: The chemical modification of the molecular structure of a drug used to modify the physicochemical properties of a drug and hence it could also be utilized to enhance nasal absorption of a drug.

b. Salt or ester formation: Drug can be converted to a salt or an ester form for achieving better transnasal permeability, such as formation of salt with increased solubility or an ester with better nasal membrane permeability.

c. Formulation design: Formulation excipients could improve the stability and enhance nasal absorption of drug.

d. Surfactant: Incorporation of Surfactant into nasal formulation could modify the permeability of nasal mucosa, which may facilitate nasal absorption of drug.

2) Membrane effect:

Many enhancers show their effect by affecting the nasal mucosal surface. The major mechanism proposed include

-Alteration of the properties of the mucus.

- Inhibition of ciliary beat frequency,¹⁷(Morimoto et al 1991),

- Enhancement of both transcellular and paracellular transport¹⁸ (O'Hagan et al 1990; Uchida et al 1991) with the latter as a result of the influence on tight junction regulation ¹⁹(LeuBen et al 1994; Ganem-Quintanar et al 1997)

- Enzyme inhibition ²⁰ (Morimoto et al 1991b; LeuBen et al 1994)

- Increasing fluidity of the membrane lipid bilayer²¹ (Ganem-Quintanar et al 1997).

Absorption enhancement due to an effect on cilia results in increased local drug residence time. Mucolytic agents alter mucus rheology, making it more permeable to drug molecules. The nasal mucus is negatively charged. Alteration of its charge characteristics could potentially increase or decrease absorption of a charged molecule. The nasal mucosa is also an active enzymatic barrier. Protease inhibitors have been used to increase the nasal bioavailability of many drugs. It is very important that the effects of substances that alter tight junction and membrane lipid bilayer fluidity, or extract membrane proteins, be transient and completely reversible to allow proper cell /epithelial barrier functioning.¹⁴

Strategies to improve nasal absorption of drug:

1. Nasal enzyme inhibitor

e.g. bestatin, fusidic acid and bile salt

2. Nasal permeation enhancer

e. g. Cyclodextrin, surfactanta, saponins, phospholipids.

3. Prodrug approach

e.g. Cyclic prodrug, esters.

4. Nasal mucoadhesive delivery

e.g. Carbopol. polycarbophil, lecithin, chitosan.

5. Particulate drug delivery

e.g. microsphere, nanoparticleand ,liposome.

6.Physiological modifying agent

Ciliary movement and the resulting clearance of the delivered drug / dosage form towards the throat are challenges when developing a prolonged release dosage form. Also a considerable enzyme activity, though lower than in the gastrointestinal tract, must be considered. Nevertheless, a number of approaches have been used to overcome these limitations such as the use of bioadhesive formulations to increase the nasal residence time of dosage forms, addition of absorption enhancers to increase the membrane permeability, and the use of protease / peptidase inhibitors to avoid enzymatic degradation of peptide and protein drugs in the nasal cavity. Several nasal dosage forms are under investigation including solutions (drops or sprays), gels, suspensions and emulsions, liposomal preparations, powders and microspheres, as well as inserts.

1. Nasal enzyme inhibitor:

Although enzymes are known to exist in the nasal tissues they do not appear to have a significant effect on the extent of absorption of most compounds except peptides.

Since the nasal administration of some of compounds resulted in complete absorption, one can attribute the above observations to one of the following reasons:

1. The rate of absorption is very fast making the exposure time of the drug to the enzyme very short;

2. The level of the enzymes in the nasal tissue (mg/g) is very low and can be easily saturated with the drug.²²

Some guidelines that may be adhered to enhance drug delivery through nasal route:

Minimizing metabolism; this can be achieved by chemical modification, covalent bonding to a polymer backbone, encapsulation in to a protective material, coadministration with enzyme inhibitor or pretreatment with an enzyme inactivator, such as bestatin, amastatin, boroleucin, borovaline, aprotinin, and trypsin inhibitors,fusidic acid derivative ⁷.e.g fusidic acid consist of sodium salt of fusidic acid (STDHF) . STDHF was considered a good candidate for the transnasal delivery of macromolecules such as insulin, calcitonin, growth hormone, etc. In study reported by Baldwin STDHF at a concentration of 0.5% enhanced the absorption of human growth hormone across the nasal mucosa. The increase in bioavailability was 11-fold in rats and rabbits and 21-fold in sheep. Thus it can be concluded that the efficacy of STDHF as an absorption enhancer is influenced by interspecies differences as well as its concentration in the test formulations.

Bile salt (e.g. sodium glycocholate, sodium deoxycholate) inhibits aminopeptidase activity in nasal mucosa .It forms transient hydrophilic pores in membrane bilayer and enhances the absorption.

2. Nasal permeation enhancer

e .g. Cyclodextrin, surfactant, saponins, phospholipids.

In order to solve the insufficient absorption of drugs, absorption enhancers are employed. Surfactants, bioadhesive polymer materials, drug delivery systems, cyclodextrins, bile salts, phosphatidylcholines and fusidic acid derivatives are known as absorption enhancers.

Fig 1. Nasal Absorption pathways.

Cyclodextrins have been used in drug delivery over the past decades. Cyclodextrins are cyclic oligomers of glucose and form so-called inclusion complexes with any drug whose molecules can fit into lipophilic cavities of the cyclodextrin molecules. An example of cyclodextrin used as an absorption enhancer, several compounds have been investigated etc.for their nasal absorption enhancement using cyclodextrins as the optimizers. They include calcitonin, cortisone, diazepam, naproxen, leuprolide.²³

An ‘ideal’ absorption promoter should have the following characteristics:

a) It should be pharmacologically inert.

b) It should be non-allergic, non-toxic, and non-irritating.

c) It should be highly potent.

d) It should be compatible with a wide variety of drugs and excipients.

e) It should be odorless, tasteless, and colorless.

f) It should be inexpensive and readily available in highest purity.

g) It should be accepted by many regulatory agencies all around the world.

Enhancers like surfactants, bile salts, fatty acids and most phospholipids are chemical enhancer which work by modifying the phospholipids bilayer structure of cells, leaching out protein or even stripping off the outer layer of mucosa.

For other enhancer those work by transiently opening tight junctions between cells such as chitosan, selected cyclodextrins and phospholipids. For example, nasal oestradiol marketed recently by Servier in Europe has used Cyclodextrin to solubilise the drug and thus enhanced permeation. Cyclodextrins are observed as the best-studied group of enhancers. The most-studied of them are: α cyclodextrin, β cyclodextrin, methylcyclodextrin and hydroxypropyl β cyclodextrin. Among these, β cyclodextrin is being considered forpossessing a GRAS (Generally Recognized as Safe) Cyclodextrins have been used successfully to increase the absorption of many substances including salmon calcitonin, insulin and human growth hormone.

3. Prodrug approach:⁷

Delivery of xenobiotics via the nasal route has received increasing attention as this offers several advantages, i.e. high systemic availability, rapid onset of action. Both charged and uncharged forms of drugs can be transported across the nasal epithelium. This mucosa is rich in various metabolizing enzymes such as aldehyde dehydrogenase, glutathione transferases, epoxide hydrolases, cyt-P450-dependent monooxygenases. The presence of these enzymes may make it possible for pharmaceutical scientists to design prodrugs for better absorption and high systemic availability.

A major obstacle to the application of peptides in clinical settings is their poor biomembrane penetration, rapid enzymatic degradation, and short biological half lives. A possible approach that has been suggested for a variety of peptide agents to solve these delivery problems is derivatization of peptides to produce prodrugs or transport forms that are lipophilic as the parent peptides and capable of protection against degradation by enzymes. The ideal prodrug of a peptide would exhibit enhanced membrane permeation characteristics and increased stability against metabolic degradation. After crossing the membrane barrier, the prodrug should undergo spontaneous or enzymatic transformation to release the peptide, which then can exhibit its pharmacological effect. It was shown that, by preparing cyclic prodrugs using the functional groups of the N- and C-terminal ends of a peptide, metabolic degradation mediated by exopeptidases should be minimized. In addition, cyclization of a peptide may also restrict the conformation flexibility of the molecule, leading to a more compact structure with altered physicochemical properties.

The following basic physicochemical properties need to be determined to develop a successful prodrug:

(a) Solubility, (b) stability, (c) compatibility, (d) enzymes stability, and (e) toxicity

4. Nasal mucoadhesive delivery

Bioadhesive polymers such as methylcellulose, carboxymethylcellulose, and hydroxypropylcellulose or polyacrylic acid can enhance the transnasal delivery of drug. The enhancement presumely results from increase in residence time in nasal cavity and higher local drug concentration in the mucus lining on the nasal mucosal surface. One of the properties of bioadhesive polymer is the ability to swell by absorbing water from the mucus layer in the nasal cavity thereby forming a gel like layer in which the polymer forms a bond with the glycoprotein chain of the mucin. Apart from these synthetic and natural polymers, there is now a new class of promising compounds, the lectins, often referred to as second generation mucoadhesive materials. These are non-immunogenic proteinsor glycoproteins capable of specific recognition and reversible binding to carbohydrate moieties of complex glycoconjugates without altering the covalent nature of any of the recognized glycosyl ligands.¹⁴

Mucoadhesive drug delivery has been used to improve the therapeutic efficacy of local as well as systemic drug delivery. The bioavailability of nasally administered drugs was improved with all kinds of therapeutic substances such as small organic molecules, antibiotics, vaccines, DNA, proteins, and other macro molecules.¹³

Nasal mucoadhesive gels are the lucrative ways of improving the nasal residential time.

Gels can offer the following advantages over other dosage forms:

1. Gels reduce post nasal drip into the back of the throat and therefore minimize any bad taste problems and loss of drug formulation from the nasal cavity;

2. Gels reduce anterior leakage of the drug out of the nasal cavity;

3. Gels also help localize formulation on the mucosa thereby providing a better chance for the drug be absorbed;

4. For certain drugs, the irritation potential from the drug itself or from other necessary formulation excipients can also be reduced because gels can afford the use of certain soothing agents or emollients which may not be suitable for solution, suspension, or powder dosage forms.

Gels can be developed for both systemic as well as local drug delivery. For example, a Cyanocobalamin (vitamin B12) Gel has been developed by Nastech Pharmaceutical Company for systemic administration to patients who are suffering from Vitamin B12 deficiency anemia.⁶

Mucoadhesive powder dosage form also offers the advantage of increased nasal residence time. Enhancement of nasal absorption of insulin was demonstrated in dogs by using powder formulation prepared from hydroxypropylmthylcellulose and neutralized polyacrylic acid, which forms a gel in contact with nasal mucosa.

5. Particulate drug delivery:

For the enhancement of nasal bioavailability, a drug delivery system should have the following properties:

• It should adhere to the nasal mucosa;

• It should pass through the mucus;

• It should cause the formation of viscous layer;

• It should have low clearance;

• It should keep the stability of the drug; and

• It should release the drug slowly.

Microsphere:

Microsphere drug delivery system has the ability to control the rate of drug clearance from the nasal cavity as well as protect drug from enzymatic degradation in nasal secretion thereby providing a potential for increasing the systemic bioavailability of drugs. Recently, microsphere technology has been applied in designing formulations for nasal drug delivery. The primary rationale for such work is to provide a better chance for the drug to be absorbed by allowing a more intimate and prolonged contact between the drug and the mucosal membrane. It is well known that solutions, suspensions and powders are rapidly cleared from the nasal cavity. Drugs which are not absorbed from such dosage forms, stand better chance for absorption when formulated in ‘gelling’ microspheres made by using biocompatible materials e.g. starch.⁶

The microsphere prepared from bioadhesive polymer ,such as starch, albumin, gelatin and dextran retain in nasal cavity with half life of clearance increased to 3hr or longer. Degredable Starch Microspheres (DSM) is the most frequently used microsphere system for nasal drug delivery and has been shown to improve the absorption of insulin in particular and other bioactive compounds in general. Human growth hormone (hGH)-loaded microparticles prepared by polycarbophilcysteine (PCP-Cys) in combination with glutathione (GSH) represented a promising tool for the delivery of hGH for nasal bioavalability.⁸

Liposomes:

Liposomes have been delivered by nasal route; the amphiphilic nature of liposome is well characterized for favorable permeation of drugs through biological membranes. The permeability of liposome entrapping insulin through nasal mucosa of rabbits has been studied with and without incorporating sodium glychoate as a permeation enhancer. The comparative pharmacokinetics in rats showed high permeability of liposome pretreated with permeation enhancer than solution containing the same quantity of permeation enhancer.

Alpar et al studied the potential adjuvant effect of liposomes on tetanus toxoid, when delivered via the nasal, oral and I.M. routes compared to delivery in simple solution in relation to the development of a non-parenteral immunization procedure, which stimulates a strong systemic immunity. Intranasal administration of calcitonin-containing charged liposomes in rabbits was investigated to evaluate the in vivo calcitonin absorption performance. Significant level of accumulation of positively charged liposomes on the negatively charged nasal mucosa surface was reported⁸.

Liposomes were effectively used for intranasal delivery of peptides such as insulin and desmopressin. Intranasal immunization with liposomal vaccines results in increased antigen-specific antibody responses.

Delivery of liposome-associated antigen through nasal route offers many advantages compared to the oral route

· Less antigen required to produce similar effect

· Eliminates the problems associated with low pH of the GIT

In the field of gene therapy, recent studies report efficient gene transfer through delivery of DNA/cationic liposome complex to the nasal epithelium of humans with cystic fibrosis.

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Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 634-641

Class	Enhancing Efficiency	Safety	Example
I	Strong and fast reaction with tissue, with fast recovery of functional property	Comparatively safe	Fatty acids (caproic, linoleic) acylcarnitines, azone.
II	Moderate and fast reaction with tissue, fast fast recovery of functional property	Comparatively safe	Bile salts (STDHF),salicylates, homovanilate
III	Strong or moderate reaction with tissue with a slow recovery of functional properties	Tissue disturbance remains, thus not very safe.	Strong surfactants, chelating agent, citric acid.
IV	Moderate reaction with tissue	Comparatively safe but with possibility of systemic side effects	Dimethyl sulphoxide, N, N-Dimethylformamide. ethanol