1. INTRODUCTION:

In current time, the nasal drug delivery received a huge deal of attention for its convenient, promising, and reliable way of systemic administration for drugs, especially for those drugs which are ineffective orally and those which must be administered by injections¹. This route provides a large surface area, porous endothelial membrane, high total blood flow, bypassing the first-pass metabolism, as well as ready accessibility. In addition nasal mucosa is permeable to more compounds than the gastrointestinal tract owing to the absence of pancreatic, gastric enzymatic activities, plus interference by gastrointestinal contents².

The early recorded historical application of nasal drug delivery was limited to topical applications of drugs intended for only local effects. However in recent times, its application grown to include a wide range of targeted areas in the body to produce local and systemic effects. Nasal drug delivery too finds a particular place in the traditional system of medicine such as the Ayurvedic system of Indian medicine which is called as “Nasya karma” and is a well-recognized way of treatment³.

In therapeutics, nose forms an vital part of the body for faster and elevated level of drug absorption with the possibility of self-administration. Drugs range from small micromolecules to large macromolecules such as peptide/proteins, hormones, and vaccines, are delivered through the nasal cavity. It is reported that lipophilic drugs are generally well absorbed from the nasal cavity with pharmacokinetic profiles frequently identical to those obtained subsequent to intravenous injection with a bioavailability approaching up to 100% in numerous cases⁴. Large absorption surface area in addition to elevated vascularisation leads to speedy absorption. In emergency, nasal route can be used as a alternative route of parenteral administration. Drugs are quickly absorbed from the nasal cavity after intranasal administration, ensuing in rapid systemic drug absorption. An approach if made for increasing the residence time of drug formulations in the nasal cavity can result in enhanced nasal drug absorption⁵. Depending on the required site of drug action, the drug to be inhaled needs to be adjusted to particle size, concentration, and chemical form to make sure a local or else systemic drug action.

1.1 Possible Nasal Drug Delivery:

A. Local Delivery:

Nasal delivery can be used for local (or topical) treatment as it provides the minimal potential for systemic adverse effects when compared to the oral route of administration. Therefore relatively low doses are effective when administered through nasal route with low systemic toxic effects⁶. Well-known therapeutic classes of drugs delivered are decongestants for cold nasal symptoms moreover antihistamines and corticosteroids for allergic rhinitis⁷.

B. Systemic Delivery:

The intranasal administration of drugs is an effective means for the systemic availability of drugs as compared to oral along with intravascular routes of administration. It provides fast and extended drug absorption than oral and parenteral administration⁸. Therapeutic classes of drugs delivered comprise analgesics, cardiovascular drugs as propranolol and carvedilol, hormones such as levonorgestrel, progesterone, and insulin, anti‐inflammatory agents as indomethacin and ketorolac, and antiviral drugs (acyclovir). Some examples which are available in the market include zolmitriptan and sumatriptan for the treatment of a migraine and cluster headaches.

C. Nasal Vaccines:

During inhalation nasal mucosa is the first site of contact with inhaled antigens, and therefore, its use for vaccination, mainly for respiratory infections, has been comprehensively evaluated⁹. In fact, nasal vaccination is a promising alternative to the classic parenteral route as it can improve the systemic levels of specific immunoglobulin G and nasal secretory immunoglobulin A. Examples of the human efficacy of intranasal vaccines include those against influenza A and B virus, proteosoma‐influenza, adenovirus‐vectored influenza, Group B meningococcal native, attenuated respiratory syncytial virus, and parainfluenza 3 virus.

Central Nervous System (CNS) Delivery through Nasal Route:

The intranasal route approach can deliver the drugs to the brain¹⁰. The delivery of drugs to CNS from the nasal route occurs through olfactory neuroepithelium. Drug delivery through nasal route into CNS has been reported for Alzheimer’s disease, brain tumors, epilepsy, pain, and sleep disorders¹¹.

1.2 Advantages of Nasal Drug Delivery System:

1. Drug degradation that is observed in the gastrointestinal tract is not present.

2. Hepatic first – pass metabolism is lacking¹².

3. Fast drug absorption and speedy onset of action can be achieved.

4. The bioavailability of larger drug molecules can be enhanced by using absorption enhancer or by other approach.

5. The nasal bioavailability for smaller drug molecules is excellent.

6. Drugs that are orally not absorbed can be delivered to the systemic circulation by nasal drug delivery.

7. Large nasal mucosal surface area for dose absorption¹³.

8. Rapid drug absorption via highly-vascularised mucosa.

9. Ease of administration, non-invasive.

10. Enhanced bioavailability.

11. Lesser dose/reduced side effects¹³.

12. Minimal aftertaste.

13. Improved convenience and compliance.

14. Self-administration.

1.3 Limitations:

1. The histological toxicity of absorption enhancers used in nasal drug delivery system is not so far clearly established. Certain surfactants used as chemical enhancers could disrupt as well as even dissolve the membrane in elevated concentration¹⁴.

2. Relatively inconvenient to patients when compared to oral delivery systems as there is a possibility of nasal irritation.

3. Nasal cavity provides lesser absorption surface area when compared to GIT.

4. Delivery volume in nasal cavity is constrained to 25–200µL.

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

1.4 Anatomy of Human Nose:

The nasal cavity is separated into two symmetrical halves by the nasal septum, a central partition of bone and cartilage; each side opens at the face via the nostrils and connects with the mouth at the naso pharynx. The nasal vestibule, the respiratory region with the olfactory region are the three chief regions of the nasal cavity. The lateral walls of the nasal cavity comprises a folded structure which increases the surface area in the nose to about 150 cm². This folded structure includes three turbinates: the superior, the median and the inferior¹⁵. In the main nasal airway, the passages are narrow, usually only 1-3mm wide, and this narrow structure allows the nose to bring out its key functions. Parts of nasal cavity is shown in Figure 1.

Figure 1: Parts of nasal cavity consists of a) nasal vestibule, b) palate, c–inferior turbinate, d) middle turbinate, e) superior turbinate (olfactory mucosa), f) nasopharynx

The Respiratory region:

In general, the nasal respiratory epithelium is described as a pseudo-stratified ciliated columnar epithelium. This region is considered to be the main site for drug absorption into the systemic circulation¹⁶. The four main types of cells seen in the respiratory epithelium are ciliated columnar cells, non-ciliated columnar cells, goblet cells as well as basal cells. Even though rare, neurosecretory cells may possibly be seen but, like basal cells, these cells do not project into the airway lumen. The proportions of the different cell types differ in diverse regions of the nasal cavity. In the lower turbinate area, about 15-20% of the total numbers of cells are ciliated moreover 60-70% is non-ciliated epithelial cells. The numbers of ciliated cells enlarge towards the nasopharynx with a corresponding decline in non-ciliated cells. The elevated number of nonciliated cells indicates their importance for absorption across the nasal epithelium¹⁷. Both columnar cell types have many (about 300-400 per cell) microvilli. The large number of microvilli amplifies the surface area and this is one of the major reasons for the relatively elevated absorptive capacity of the nasal cavity. The role of the ciliated cells is to transport mucus towards the pharynx. Basal cells, which differ greatly in both number and shape, never reach the airway lumen. These cells are poorly differentiated and act as stem cells to replace other epithelial cells. About 5-15% of the mucosal cells in the turbinates are goblet cells, which include numerous secretory granules filled with mucin. In conjunction with the nasal glands; the goblet cells generate secretions, which form the mucus layer.

The Olfactory region:

In human, the olfactory region is situated on the roof of the nasal cavities, just beneath the cribriform plate of the ethmoid bone, which divides the nasal cavities from the cranial Cavity. The olfactory tissue is often yellow in colour in contrast to the surrounding pink tissue¹⁸. Humans have relatively simple noses, as the primary function is breathing, whereas other mammals have more complex noses better adapted for the function of olfaction.

1.5 Mechanism of Nasal Drug Absorption:

Several mechanisms have been proposed for absorption of drug through nasal route, but following are high lighted here.

1. The first mechanism involves an aqueous route of transport, which is also known as the paracellular route. This route is slow and passive. There is an inverse relationship between intranasal absorption and the molecular weight of water-soluble compounds. Poor bioavailability was observed for drug with a molecular weight greater than 1000 Daltons¹⁹.

2. The second mechanism involves transport through a lipoidal route is identified as transcellular process and is liable for the transport of lipophilic drugs that show a rate dependency on their lipophilicity.

2. Barriers to Nasal Absorption:

Subsequent factors are the barriers to the absorption of drugs through nasal cavity.

i) Low bioavailability:

Lipophilic drugs are normally well absorbed from the nasal cavity compared to polar drugs. The most essential factor restraining the nasal absorption of polar drugs and especially large molecular weight polar drugs such as peptides and proteins is the little membrane permeability. Polar drugs with molecular weights less than 1000 Daltons will normally pass the membrane using paracellular route. Larger peptides and proteins have been shown to be able to pass the nasal membrane using an endocytotic transport process however only in low amounts²⁰.

ii) Low membrane transport:

One more significant factor for low membrane transport is the rapid clearance of the administered formulation from the nasal cavity as a result of the mucociliary clearance mechanism. This is in particular the case for drugs that are not simply absorbed across the nasal membrane. It has been shown that for both liquid and powder formulations, that are not mucoadhesive, the half life of clearance is in the order of 15 - 20 min. It has further been suggested that the deposition of a formulation in the anterior part of the nasal cavity can diminish clearance and endorse absorption as compared to deposition further back in the nasal cavity. Most nasal sprays of diverse makes have revealed to deliver the formulation to a restricted area in the anterior part of the nasal cavity as contrasting to nasal drops which will be delivered to a larger area further back in the nasal cavity²¹. The use of bioadhesive excipients in the formulations is an approach to triumph over the rapid mucociliary clearance. The clearance might also be reduced by depositing the formulation in the anterior, less ciliated part of the nasal cavity consequently leading to better absorption.

iii) Enzymatic Degradation:

A further contributing factor to the low transport of particularly peptides and proteins across the nasal membrane is the possibility of an enzymatic degradation of the molecule either within the lumen of the nasal cavity or during passage across the epithelial barrier. These sites both contain exo-peptidases and endopeptidases. The use of enzyme inhibitors and/or saturation of enzymes might be approaches to beat this barrier.

3. Factors Influencing Nasal Drug Absorption:

Numerous factors influence the systemic bioavailability of drugs which are administered through the nasal route. The factors comprise physiochemical properties of the drugs, the anatomical and physiological properties of the nasal cavity and the type and characteristics of selected nasal drugs delivery system. These factors play key role for most of the drugs in turn to reach therapeutically effective blood levels after nasal administration²². The factors influencing nasal drug absorption are described as follows.

1) Physiochemical properties of drug.

· Molecular size.

· Lipophilic-hydrophilic balance.

· Enzymatic degradation in nasal cavity.

2) Nasal Effect

· Membrane permeability.

· Environmental pH

· Mucociliary clearance

· Cold, rhinitis.

3) Delivery Effect

· Formulation (Concentration, pH, osmolarity)

· Delivery effects

· Drugs distribution and deposition.

· Viscosity

1) Physiochemical properties of drug:

Molecular size:

The molecular size of the drug influence absorption of the drug through the nasal route. The water soluble drugs have inverse relationship between the molecular weight and drug permeation. The rate of permeation is very sensitive to molecular size for compounds with MW ≥ 300 Daltons.

Lipophilic-hydrophilic balance:

The hydrophilic and lipophilic nature of the drug also influences the process of absorption. By increasing lipophilicity, the permeation of the compound in general boosts through nasal mucosa.

Enzymatic degradation in nasal cavity:

In case of peptides and proteins, they have low bioavailability across the nasal cavity, as these drugs have a possibility to go through enzymatic degradation in the lumen of the nasal cavity otherwise during passage through the epithelial barrier. These both sites contain exopeptidases and endopeptidases, exo-peptidases are mono-aminopeptidases and di-aminopeptidases. These have ability to cleave peptides at their N and C terminal and endopeptidases such as serine and cysteine, which can attack internal peptide bonds.

2) Nasal effect factors:

Membrane permeability:

Nasal membrane permeability is the most significant factor, which affect the absorption of the drug through the nasal route. The water soluble drugs and large molecular weight drugs like peptides and proteins are having the low membrane permeability. Hence the compounds like peptides and proteins are mainly absorbed through the endocytotic transport process in little amounts (Inagaki M et al., 1985). Water soluble high molecular weight drugs cross the nasal mucosa mainly by passive diffusion through the aqueous pores (i.e. tight junctions).

Environmental pH:

The environmental pH plays a main role in the effectiveness of nasal drug absorption. Small water soluble compounds like benzoic acid, salicylic acid, and alkaloid acid illustrate that their nasal absorption in rat occurred to the maximum extent at those pH values where these compounds are in the nonionised form. However, at pH values where these compounds are partially ionized, substantial absorption was found. This implies that the nonionised lipophilic form crosses the nasal epithelial barrier via transcellular route, while the more lipophilic ionized form passes through the aqueous paracellular route²³.

Mucociliary clearance (MCC):

Mucociliary clearance is one of the functions of the upper respiratory tract to avoid noxious substances (allergens, bacteria, viruses, toxins etc.) from attainment to lungs. When such materials stick on to, or dissolve in the mucus lining of the nasal cavity, they are transported on the way to the nasopharynx for eventual release into the gastrointestinal tract. Clearance of this mucus as well as the adsorbed/dissolved substances into the GIT is called the MCC. This clearance mechanism persuade the absorption process due to the dissolved drugs in the nasal cavity discharge by both the mucus and the cilia and the mucus transport rate is 6mm/min. It is of extreme importance that the MCC is not damaged in turn to avoid lower respiratory tract infections²⁴.

Cold, rhinitis:

Rhinitis is a most common disease that influences bioavailability of the drug. The allergic rhinitis is the allergic airway disease, which affects 10% of population and the symptoms include hypersecretion, itching and sneezing largely caused by the viruses, bacteria or irritants. It is caused by chronic otherwise acute inflammation of the mucous membrane of the nose. These circumstances affect the absorption of drug through the mucus membrane owing to the inflammation.

3) Delivery effect factors:

Factors that affect the delivery of drug across nasal mucosa are surfactants, dose, pH, osmolarity, viscosity, particle size and nasal clearance and drug structure.

Formulation (pH, Osmolarity):

The pH of the formulation and nasal surface, can affect drugs permeation. To avoid nasal irritation, the pH of the nasal formulation should be adjusted to 4.5–6.5 as lysozyme is found in nasal secretions, which is accountable for destroying certain bacteria at acidic pH. Under alkaline conditions, lysozyme is inactivated and the tissue is vulnerable to microbial infection. In addition to avoiding irritation, it results in obtaining efficient drug permeation and avoids the growth of bacteria.

The osmolarity of the dosage form affects the nasal absorption of the drug; it was studied in the rats by using model drug. The sodium chloride concentration of the formulation affects the nasal absorption. The maximum absorption was achieved by 0.462 M sodium chloride concentration; the higher concentration not only causes increased bioavailability but also leads to the toxicity to the nasal epithelium.

Drugs distribution and deposition:

The drug distribution in the nasal cavity is one of the main factors, which affect the efficiency of nasal absorption. The mode of drug administration could effect the distribution of drug in nasal cavity, which in turn will establish the absorption efficiency of a drug. The absorption and bioavailability of the nasal dosage forms chiefly depends on the site of disposition. The anterior portion of the nose presents a prolonged nasal residential time for disposition of formulation, it enhances the absorption of the drug. And the posterior chamber of nasal cavity will use for the deposition of dosage form; it is eliminated by the mucociliary clearance process and hence shows low bioavailability. The site of disposition and distribution of the dosage forms mainly depends on delivery device, mode of administration and physicochemical properties of drug molecule²⁵.

Viscosity:

A higher viscosity of the formulation rises contact time between the drug and the nasal mucosa thus increasing the time for permeation. At the same time, extremely viscous formulations interfere with the normal functions like ciliary beating or else mucociliary clearance and therefore modify the permeability of drugs.

4. Strategies to Improve Nasal Absorption:

A variety of strategies used to improve the bioavailability of the drug in the nasal mucosa which includes

1. To improve the nasal residence time

2. To increase nasal absorption

3. To modify drug structure to alter physicochemical properties

1. To improve the Nasal Residence Time:

Mucocilliary clearance acts to eliminate the foreign bodies as well as substances from nasal mucosa as quickly as possible. One way to hold-up clearance is to apply the drug to the anterior part of the nasal cavity, an effect that is basically determined by the type of dosage form used. The preparation can also be formulated with polymers such as methylcellulose, hydroxy propyl methyl cellulose or polyacrylic acid, in which inclusion of polymer augments viscosity of the formulation and as well acts as a bio adhesive with mucus.

2. To increase the Nasal Absorption:

The mechanism of action of absorption enhancer is raising the rate at which drug passes through the nasal mucosa. Several enhancers act by changing the structure of epithelial cells in some way, however they should achieve this while causing no damage or permanent change to nasal mucosa.

3. To modify drug structure to alter physicochemical properties:

Modification of drug structure without changing pharmacological activity is one of the lucrative ways to improve the nasal absorption. Here modification of physiochemical properties such as molecular size, molecular weight, pka and solubility are favourable for nasal drug absorption²⁵.

Any one or blend of above approaches are used for the enhancing the absorption and bioavailability of the formulations. Numerous methods have been used to facilitate the nasal absorption of drugs which include:

Nasal enzyme inhibitors:

Nasal metabolism of drugs can be removed by using the enzyme inhibitors. Primarily for the formulation of proteins and peptide molecule development enzyme inhibitors like peptidases and proteases are used. The absorption enhancers like salts and fusidic acid derivatives as well proves enzyme inhibition activity to augment the absorption and bioavailability of the drug. The other enzyme inhibitors generally used for the enzymatic activity are tripsin, aprotinin, borovaline, amastatin, bestatin and boroleucin inhibitors.

Permeation enhancers:

The permeation enhancers are essentially used for the enhancement of absorption of the active medicament. By and large the absorption enhancers act via one of the next mechanisms:

· Inhibit enzyme activity;

· Lessen mucus viscosity or elasticity;

· Decrease mucociliary clearance;

· Open tight junctions; and

· Solubilize or else stabilize the drug.

The mechanism of action of absorption enhancer is rising the rate at which drug passes through the nasal mucosa. Several enhancers act by altering the structure of epithelial cells in some way, however they should accomplish this while causing no damage or permanent change to nasal mucosa²⁶. General requirement of an ideal penetration enhancer are as follows.

1. It should lead to an effective increase in the absorption of the drug.

2. It must not cause permanent damage or alteration to the tissues.

3. It should be non irritant and nontoxic.

4. It has to be effective in small quantity.

5. The enhancing effect should occur when absorption is required.

6. The effect should be temporary and reversible.

7. It should be compatible with other excipients.

A variety of penetration enhancers have been evaluated for organic drugs including surfactants, bile salts, chelators, fatty acid salts, phospholipids, glycyrrhetenic acid derivatives, cyclodextrins in addition to glycols.

Classification of chemical penetration enhancer includes:

Surfactants: Polyozyethylene-9-lauryl ether (Laureth-9), Saponin

Bile salts: Trihydroxy salts (glycol- and taurocholate), Fusidic acid derivatives (STDHF)

Chelators: Salicylates, Ethylenediaminetetraacetic acid (EDTA)

Fatty acid salts: Oleic acid, Caprylate (C8), Caprate (C10), Laurate (C12)

Phospholipids: Lysophosphatidylcholine (lyso-PC), Di-decanoyl – PC

Glycyrrhetinic acid derivates: Carbenozolone, Glycyrrhizinate

Cyclodextrins: α, ß, and γ- cyclodextrins and their derivatives

Glycols: n-glycofurols and n-ethylene glycols

Prodrug approach:

Prodrug approach is chiefly meant for optimizing favourable physicochemical properties such as solubility, taste, odor, stability, etc. Prodrug is typically referred as promoiety, it is to cover the undesired functional groups with another functional groups. This prodrug approach is essentially for improving the nasal bioavailability particularly for the proteins and peptides to increase the membrane permeability along with improved enzymatic stability. The prodrug goes through enzymatic transformation to liberate the active medicament, while it crosses the enzymatic and membrane barrier. The absorption of peptides like angiotensin II, bradykinin, caulein, carnosine, enkephalin, vasopressin and calcitonin are enhanced by preparing into enamine derivatives, these agents demonstrated absorption enhancement with prodrug approach.

Structural modification:

Modification of drug structure without altering pharmacological activity is one of the lucrative ways to progress the nasal absorption. The chemical modification of drug molecule has been normally used to alter the physicochemical properties of a drug such as molecular size, molecular weight, pka and solubility are favourable to develop the nasal absorption of drug²⁷. For example, chemical modification of salmon calcitonin to ecatonin (C-N bond replaces the S-S bond) confirmed better bioavailability than salmon calcitonin.

Particulate drug delivery:

Particle design plays an important role in absorption enhancement. Microspheres, nanoparticles and liposomes are all systems which can be used as carriers to encapsulate an active drug. The properties of these can be varied to maximize therapeutic efficacy. On the whole, this can effect in increased absorption efficacy in addition to stability and reduced toxicity of the active ingredient. Systems can be designed to be mucoadhesive to enhance the retention time and make possible sustained release.

Microspheres primarily enhance the absorption and bioavailability by adhering to the nasal mucosa and enhance the nasal residence time of drug. The microspheres prepared by using polymers like dextran, chitosan, biodegradable starch microspheres efficiently improved the bioavailability of various drugs. Liposomes are ampliphilic in nature are well characterized for favourable permeation of drugs through the biological membranes, so the water soluble drugs have been delivered to nasal region. Cationic liposomes are having superior permeation capacity than negatively charged anionic liposomes.

Bioadhesive polymer:

To improve the nasal residence and absorption of the drug bioadhesive polymers are used. They improve the retention time of the drug inside the nasal cavity by making an adhesive force between formulation and nasal mucosa, which leads to minimization of mucociliary clearance of formulation.

In situ gel:

These are the formulations which get changed into gel upon instillation into nasal cavity by the influence of stimuli which includes temperature, pH in addition to ionic concentration. Consistency of the gel is thick which makes the formulation difficult to drain by the influence of ciliate movement.

5. Excipients Used in Nasal Formulations:

There are various types of excipients used in nasal formulations. Commonly used excipients are as follows:

Bioadhesive polymers:

Compound that is capable of interacting with biological material through interfacial forces as well as being retained on such material for long-lasting periods of time is called as bioadhesive polymer. They are also called as mucoadhesive if biological material is mucus membrane. On molecular level, process of mucoadhesion can be made clear on the basis of attractive molecular interactions involving forces such as Vander Waals, electrostatic interactions, hydrogen bonding, and hydrophobic interactions. The bioadhesive force of a polymer material is dependent on the nature of the polymer, the surrounding medium (pH), swelling and physiological factors (mucin turnover, disease state).

Gelling agent:

Gelling agent augments solution viscosity which aids in lengthening the therapeutic effect of nasal preparations. Drug carrier such as hydroxyl propyl cellulose was effective for improving the absorption of low molecular weight drugs however not for high molecular weight peptides²⁸.

Penetration enhancer:

Chemical penetration enhancers are generally used in the nasal drug delivery. Classification of chemical penetration enhancer includes, following

1) Solvents

2) Alkyl methyl sulphoxides

3) Pyrrolidones

4) 1- Dodecyl azacycloheptan-2-one

5) Surfactants.

Buffers:

Nasal formulations are in general administered in small volumes ranging from 25 to 200µL with 100µL being the most frequent dose volume. Hence, nasal secretions may change the pH of the administrated dose which can affect the concentration of unionized drug obtainable for absorption. Hence, an adequate formulation buffer capacity may be necessary to maintain the pH in-situ.

Solubilizers:

Aqueous solubility of drug is always a constraint for nasal drug delivery in solution. Conventional solvents or co-solvents like glycols, small quantities of alcohol, Transcutol (diethylene glycol monoethyl ether), medium chain glycerides and Labrasol (saturated polyglycolyzed C8- C10 glyceride) can be used to enhance the solubility of drugs. Other compounds can be used like, the use of surfactants or cyclodextrins such as HP- β -Cyclodextrin that serve as a biocompatible solubilizer and stabilizer in combination with lipophilic absorption enhancers. In these cases, their impact on nasal irritancy should be considered.

Preservatives:

Most nasal formulations are aqueous based therefore needs preservatives to avoid microbial growth. Parabens, phenyl ethyl alcohol, benzalkonium chloride, EDTA and benzoyl alcohol are some of the generally used preservatives in nasal formulations²⁹.

Antioxidants:

A small quantity of antioxidants may be necessary to avoid drug oxidation. Generally used antioxidants are sodium bisulfite, butylated hydroxytoluene, sodium metabisulfite and tocopherol. Typically, antioxidants do not affect drug absorption or cause nasal irritation. Chemical/physical interaction of antioxidants and preservatives with drugs, excipients, manufacturing equipment and packaging components must be considered as part of the formulation development program.

Humectants:

Owing to allergic and chronic diseases there can be crusts and drying of mucous membrane. Certain preservatives/ antioxidants are also likely to cause nasal irritation particularly when used in high quantities. Sufficient intranasal moisture is necessary for avoiding dehydration. Hence, humectants can be added especially in gel-based nasal products. Humectants evade nasal irritation and do not affect drug absorption. Common used humectants include glycerin, sorbitol and mannitol.

Surfactants:

Surfactant inclusion into nasal dosage forms can alter the permeability of nasal membranes, which may assist the nasal absorption of drug.

6. Nasal Formulations:

Liquid dosage forms:

a) Nasal drops

Nasal drops are one of the most simple and convenient delivery systems among all formulations. The main disadvantage of this system is the lack of dose precision.

b) Nasal sprays

Both solution and suspension formulations can be formulated into nasal sprays. Due to the accessibility of metered dose pumps and actuators, a nasal spray can deliver a precise dose anywhere from 25 - 200 µL.

c) Nasal emulsions, micro emulsions

Intranasal emulsions have not been studied as extensively as other liquid nasal delivery systems. Nasal emulsions offer the advantages for local application mainly due to the viscosity³⁰.

Semi-solid dosage forms:

Semi-solid systems such as gels, ointments and liquid systems containing polymers that gel at particular pH changes are typically utilized for designing the nasal drug delivery systems.

a) Nasal gels

Nasal gels are thickened solutions or suspensions, of elevated viscosity. The advantages of a nasal gel include the lessening of post-nasal dripping due to its high viscosity, reduction of the taste impact due to reduced swallowing, decline of anterior leakage of the formulation.

Solid dosage forms:

Solid dosage forms are more appropriate for pulmonary drug delivery and similar applications, since it can cover the vasculature within the epithelium of nasal mucosa.

a) Nasal powders

Powder dosage forms may be developed if solution and suspension dosage forms cannot be developed, primarily due to lack of drug stability. The advantages of a nasal powder dosage form are the absence of preservative and better stability of the drug in the formulation. However, the appropriateness of the powder formulation is dependent on the solubility, particle size, aerodynamic properties and nasal irritancy of the active drug and/or excipients.

Novel drug formulations:

A number of claims have been made in favour of developing nasal formulations containing liposomes, microspheres and nanoparticles for intranasal drug delivery. These systems can include, besides the drug, enzymatic inhibitors, nasal absorption enhancers or/and mucoadhesive polymers in order to get better the stability, membrane penetration and retention time in nasal cavity.

a) Liposomes:

Liposomes are phospholipids vesicles composed by lipid bilayers enclosing one or more aqueous compartments and wherein drugs and other substances can be incorporated. Liposomal drug delivery systems present a variety of advantages such as the efficient encapsulation of small and large molecules with a broad range of hydrophilicity and pKa values. Indeed they have been found to improve nasal absorption of peptides such as insulin and calcitonin by increasing their membrane penetration. This has been attributed to the increasing nasal retention of peptides. Protection of the entrapped peptides from enzymatic degradation and mucosal membrane disruption.

b) Microspheres:

Microsphere technology has been broadly applied in designing formulations for nasal drug delivery. Microspheres are typically based on mucoadhesive polymers (chitosan, alginate), which present advantages for intranasal drug delivery. Moreover microspheres might as well protect the drug from enzymatic metabolism as well as sustain drug release, extending its effect.

c) Nanoparticles:

Nanoparticles are solid colloidal particles with diameters raging from 1-1000nm. They consist of macromolecular materials and can be therapeutically used as adjuvant in vaccines or as drug carriers, in which the active substance is dissolved, entrapped, encapsulated, adsorbed or chemically attached. Nanoparticles might offer several advantages because of their small size, however only the smallest nanoparticles penetrate the mucosal membrane by paracellular route and in a limited quantity as the tight junctions are in the order of 3.9 - 8.4 A.

7. Evaluation of Nasal Drug Formulations:

1. In vitro Nasal Permeation Studies:

A variety of approaches used to determine the drug diffusion through nasal mucosa from the formulation. The two important methodologies to study the diffusion profile of the drug are discussed below.

In vitro Diffusion Studies:

The nasal diffusion cell is fabricated in glass. The water-jacketed recipient chamber has overall capacity of 60ml and a flanged top of about 3mm; the lid has 3 opening, each for sampling, thermometer, and a donor tube chamber. The 10cm long donor chamber, and a donor tube chamber has overall capacity of 60ml and a flanged top of about 3mm; the lid has 3 openings, each for sampling, thermometer, and a donor tube chamber the 10 cm long donor chamber tube has internal diameter of 1.13cm. The nasal mucosa of sheep was detached from sub layer bony tissues and stoned in distilled water having few drops at gentamycin injection. Following the complete removal of blood from mucosal surface, is attached to donor chamber tube. The donor chamber tube is placed such a way that it just touches the diffusion medium in recipient chamber. At predetermined intervals, samples (0.5ml) from recipient chamber are removed and transferred to amber colored ampoules. The samples withdrawn are correctly replaced. The samples are estimated for drug content by proper analytical technique. All through the experiment the temperature is maintained at 37˚C.

In vivo Nasal Absorption studies:

Animal Models for Nasal Absorption Studies:

The animal models employed for nasal absorption studies can be of two types, viz., whole animal or in vivo model and an isolated organ perfusion or ex vivo model. In vivo models are Rat model, Rabbit model, monkey model and dog model.

Ex vivo Nasal Perfusion Models:

Surgical preparation is the same as that is for in vivo rat model. During the perfusion studies, a funnel is placed between the nose and reservoir to lessen the loss of drug solution. The drug solution is placed in a reservoir maintained at 37°C and is circulated through the nasal cavity of the rat with a peristaltic pump. The perfusion solution passes out from the nostrils (through the funnel) and runs again into the reservoir. The drug solution in the reservoir is always stirred. The amount of drug absorbed is estimated by measuring the residual drug concentration in the perfusing solution. The drug activity due to stability problems might be lost during the course of experiment³¹.

8. CONCLUSION:

Nasal drug delivery is a novel platform and it is a promising substitute to injectable route of administration. The nasal cavity has a large surface area and a greatly vascularised mucosa. Drugs absorbed by the rich network of blood vessels pass directly into the systemic circulation, thus avoiding the first pass metabolism. This delivery system is valuable in conditions like Parkinson’s disease, Alzheimer’s disease or pain since it requires rapid and/or specific targeting of drugs to the brain and it is a appropriate route to produce immune response against a variety of diseases like anthrax, influenza etc., by delivering the vaccines through the nasal mucosa. There is possibility in the near future that more drugs will come in the market in the form of nasal formulation intended for systemic treatment. In future, the extensive research is essential to build this route of delivery more competent and accepted.

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Received on 02.03.2022 Modified on 23.04.2022

Asian J. Pharm. Res. 2022; 12(3):249-258.

DOI: 10.52711/2231-5691.2022.00041