3.0 Anatomy and physiology of Nose:⁴

The nose is complex organ from a kinetic point of view because of three different processes –deposition, clearance or translocation and absorption of the drug that take place inside the nose. The nasal cavity (Fig-1) is divided into two symmetrical halves by the nasal septum, a central portion of bone and cartilage, each side opens at the face via the nostrils and connects with the mouth at nasopharynx. The nasal vestibule, the respiratory region and the olfactory region are the three main region of nasal cavity. The lateral walls of the nasal cavity include a folded structure which enlarges the surface area in the nose to about 150 cm².This folded structure includes three turbinate; the superior, the median and the inferior. In the main nasal airway, the passages are narrow, normally only 1-3 mm wide and this narrows structure enables the nose to carry out its main function. During inspiration, the air comes into close contact with the nasal mucosa and particles such as dust and bacteria are trapped in the mucous. Additionally, the inhaled air is warmed and moistened as it passes over the mucosa; and the high blood supply epithelium.

The submucosal zone of the nasal mucosa directly to the systemic circulation, thus avoiding first pass metabolism. Another, perhaps more familiar, major function of the nose is olfactory region is located on the roof of the nasal cavity.

The nasal cavity is covered with a mucous membrane which can divide into nonolfactory and olfactory epithelium areas. The nonolfactory area includes the nasal vestibule, which is lined with skin-like cell, and respiratory region, which has a typical airway epithelium.

Figure No: 1 Anatomy of nasal cavity

(A) Saggital section of the nasal cavity showing the nasal vestibule, (B) atrium, (C) respiratory area: (C1) inferior turbinate, (C2)middle turbinate and (C3)superior turbinate, (D) the olfactory region, and (E)Nasopharynx.

3.1 The Respiratory region:

The nasal respiratory epithelium is generally described as a pseudo- stratified ciliated columnar epithelium. This region is considered to be the major site for drug absorption into the systemic circulation. The 4 main types of cells seen in the respiratory epithelium are ciliated columnar cells, non ciliated columnar cells, goblet cells and basal cell. Although rare, neurosecretory cells may be seen but, like basal cell, these cells do not protrude into the airway lumen. The numbers of ciliated cells increase towards the nasopharynx with a corresponding decrease in non-ciliated cells. The high number of non-ciliated cells indicates their importance for absorption across the nasal epithelium. The role of the ciliated cells is to transport mucus towards the pharynx. Basal cells, which vary greatly in both number and shape, never reach the airway lumen.

3.2 The olfactory region:

In human, the olfactory region is located on roof of the nasal cavities, just below the cribriform plate of the ethmoid bone, which separates the nasal cavities from the cranial cavity. The olfactory tissue is often yellow in color, in contrast to the surrounding pink tissue. Human have relatively simple nose, since the primary function is breathing, while other mammals have more complex noses better adapted for the function of olfaction.

4.0 Mechanism of Drug Absorption:

Several mechanisms have been proposed but the following two mechanisms have been considered predominantly.

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

The second mechanism involves transport through a lipoidal route is also known as the transcellular process and is responsible for the transport of lipophilic drug that show a rate dependency on their lipophlicity.Drug also cross cell membranes by an active transport route via carrier-mediated means or transport through the opening of tight junction.

5.0 Factors affecting the nasal permeability of drugs:

The factors affecting permeability of drug through the nasal mucosa can broadly be classified into three categories as shown below.

A) Physicochemical characteristics of drug

B) Formulation related factor

C) Physiological factor

A) Physicochemical characteristics of drug:⁵

Molecular Weight and size:

A linear inverse correlation has been reported between the absorption of drug and molecular weight up to 300 Dalton. A large number of therapeutic agents, peptides and proteins in particular, have shown that for compounds1 Dalton, bioavailability can be directly predicted from knowledge of MW. In general, the bioavailability of these large molecules ranges from 0.5% to 5%⁶.

Solubility and Dissolution rate:

Drug solubility is a major factor in determining absorption of drug through biological membranes. However, very few reports are available regarding the relationship between the solubility of a drug and its absorption via the nasal route. As nasal secretions are more watery in nature, a drug should have appropriate aqueous solubility for increased dissolution.

Lipophilicity:

On increasing lipophilicity, the permeation of the compound normally increases through nasal mucosa. In a study conducted to characterize the barrier properties of mucosal membranes, it was found that the nasal mucosa had the highest in vitro transport both of the model hydrophilic compound, mannitol, and the model lipophilic compound, progesterone. Although the nasal mucosa was found to have some hydrophilic character, it appears that these mucosae are primarily lipophilic in nature and the lipid domain plays an important role in the barrier function of these membranes⁷. In one study on intranasally administered corticosteroids, a high degree of lipophilicity diminished the water solubility of corticosteroids in the nasal mucosa and, therefore, the amount of drug swept away by mucociliary clearance increased considerably⁸. However, excess hydrophilicity is also known to decrease the systemic bioavailability of many drugs. Prodrugs such as testosterone 17 -N,Ndimethylglycinate hydrochloride have been synthesized to overcome the poor solubility problem⁹.

Partition coefficient and pKa:

As per the pH partition theory, unionized species are absorbed better compared with ionized species and the same holds true in the case of nasal absorption. Jiang et al. (1997) conducted a study to find out the quantitative relationship between the physicochemical properties of drugs and their nasal absorption, using diltiazem hydrochloride and paracetamol as model drugs. The results showed that a quantitative relationship existed between the partition coefficient and the nasal absorption constant¹⁰. Various studies indicate that drug concentrations in the cerebrospinal fluid (CSF) rise with an increase in lipophilicity or the partition coefficient of the drugs. The nasal absorption of weak electrolytes such as salicylic acid and aminopyrine was found to be highly dependent on their degree of ionization. Although for aminopyrine, the absorption rate increased with the increase in pH and was found to fit well to the theoretical profile, substantial deviations were observed with salicylic acid. The authors concluded that perhaps a different transport pathway, along with the lipoidal pathway, existed for salicylic acid¹¹. Similarly, when the absorption of benzoic acid was studied at pH 7.19 (99.9% of the drug existed in ionized form) it was found that 10% of drug was absorbed indicating that the ionized species also permeates through nasal mucosa¹². Based on all of these observations, the authors discounted partition coefficients as a major factor governing nasal absorption and supported that other transport pathways for hydrophilic drugs might be of importance.

B) Formulation related factor:

pH and mucosal irritancy:

The pH of the formulation, as well as that of nasal surface, can affect a drug’s permeation. To avoid nasal irritation, the pH of the nasal formulation should be adjusted to 4.5–6.5¹³. In addition to avoiding irritation, it results in obtaining efficient drug permeation and prevents the growth of bacteria. Osmolarity Ohwaki et al. studied the effect of osmolarity on the absorption of secretin in rats and found thatabsorption reached a maximum at a sodium chloride concentration of 0.462 M¹⁴, because shrinkage of the nasal epithelial mucosa was observed at this salt concentration¹⁵.

Viscosity:

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

Area of nasal mucus membrane exposed:

In a study conducted using 40 mg progesterone ointment, absorption was compared between applications to one nostril with application to both nostrils. Increased bioavailability was observed when ointment was applied in both the nostrils¹⁶ concluding that as the area of mucus membrane exposed increases, it should result in increased permeation.

Volume of solution applied:

The volume that can be delivered to the nasal cavity is restricted to 0.05–0.15 ml. Different approaches have been explored to use this volume effectively including the use of solubilizers¹⁷, gelling, or viscofying agents. The use of solubilizer increases the aqueous solubility of insoluble compounds can even promote the nasal absorption of the drug. Gelling agentsdecrease the drainage and result in an increase in the retention time of the drug in contact with mucus membranes.¹⁸

Dosage form:

Nasal drops are the simplest and most convenient dosage form but the exact amount that can be delivered cannot be easily quantified and often results in overdose¹⁹. Moreover, rapid nasal drainage is a problem with drops. Solution and suspension sprays are preferred over powder sprays because powder results in mucosal irritation²⁰. Recently, metered-dose gel devices have been developed that accurately deliver drug. Gels reduce the postnasal drip and anterior leakage, and localize the formulation in mucosa²¹. A limited amount of work has been reported on the use of emulsions and ointments as nasal formulations.

C) Physiological Factor:²²

Effect of Enzymatic Activity:

Several enzymes that present in the nasal mucosa might affect the stability of drug. For example, protein and peptides are subjected to degradation by proteases and amino-peptidase at the mucosal membrane. Peptides may also form complexes with immunoglobulin (Ig) in the nasal cavity leading to an increase to and the molecular weight and a reduction of permeability.

Effect of Pathological Condition:

Intranasal pathologies such as allergic rhinitis, infection or previous nasal surgery may affect the nasal mucociliary transport process and or capacity for nasal absorption. During the common cold, the efficiency of an intranasal medication is often compromised. Nasal pathology can also alter mucosal pH and thus affect absorption of drug.

Effect of Mucociliary Clearance:

It is important that integrity of the nasal clearance mechanism is maintained to perform normal physiological function such as the removal of dust, allergens and bacteria. The ciliary activity is the driving force of the secretary transport in the nose to constantly remove particles that are trapped on the mucous blanket during inhalation.

6.0 Physiological barrier:
6.1Nasal.Mucus:
Airway mucus is composed of primarily water (95%), mucus glycoprotein (2%) and other proteins including albumin, immunoglobulin, and lysozyme (1%), inorganic salts and lipids. Mucus glycoprotein, well known as mucin is the major component of the mucus. This compound is primarily responsible for the viscoelastic properties of mucus. The visco-elastic properties also depend on the percentage content of mucin, water, and other ions. The pH of the nasal secretion also determines the viscoelastic properties of mucus. It is important to consider the interaction between the drug and mucus. There may be a chance of change in viscoelastic properties due to drug - mucus interaction that could be effectively utilized to improve the bioavailability of nasal dosage forms. The mode of transportation of drug molecule across the mucus barrier is principally based on drug diffusion mechanism. The drug diffusion across the nasal mucus is governed by factors such as molecular weight of drug, viscosity of mucus, surface charge, drug-mucus interaction, and etc.^[23] Small unionized molecules readily cross the mucosal barrier.

6.2Nasal.epithelium:
The nasal membrane can be classified into olfactory and nonolfactory epithelia. The olfactory epithelium is pseudostratified columnar in type, and consists of specialized olfactory cells, supporting cells, and both serous and mucous glands, whereas the nonolfactory epithelium is a highly vascular tissue covered by a ciliated pseudostratified columnar epithelium.²⁴ The olfactory cells contain bipolar neurons and act as peripheral receptors and first-order ganglion cells.²⁵ The nasal respiratory epithelium consists of loosely packed cells with high permeability and vasculature. The permeability of environmental toxins is restricted by nasal epithelium. Nasal absorption is achieved by different mode of transportations such as passive diffusion, carrier mediated transport, and transcytosis. However, nasal absorption was hindered by efflux transporters such as glycoprotein. Low molecular lipophilic compounds rapidly get permeated through nasal mucosa. For example, the bioavailability of nasal absorption of ondansetron was comparable with intravenous route in rats.²⁶ This study revealed complete and rapid absorption of drugs through nasal epithelium. Various reasons are suggested for high permeability of nasal mucosa including high vasculature, non keratinized epithelium, low metabolic activity and high perfusion rate.²⁷

6.3Mucociliary.clearance:
Nasal mucociliary clearance is the most important physiological barrier, which reduces the nasal residential time of drugs and/or dosage forms.²⁸ Bioavailability of nasal dosage form depends on the residential time of the drug in the nasal cavity. The nasal mucociliary clearance system transports the mucus layer that covers the nasal epithelium towards the nasopharynx by ciliary beating. In true sense, mucociliary clearance is one of the defense mechanism of the respiratory tract to protect the body against any noxious material that is inhaled.²⁹ Ciliated mucous cells present in the nasal mucosal membrane are responsible for mucociliary clearance. Nasal clearance precedes at an average rate of 5-6 mm/min.³⁰ Nasal mucociliary clearance carries the airway secretion backward to the nasopharynx. This material is dispatched by wiping action of the palate to the stomach, periodically through swallowing.³¹ A large number of factors influence the nasal mucociliary clearance, which include nasal pathophysiology, temperature and moisture of inhaled air, drugs, pollutants, and pH of the nasal secretion.³² A wide variety of methods are used to determine the mucociliary clearance.³³Total clearance of the deposited dose is monitored by the clearance of radio labeled dosage form, which is measured by gamma camera. Mucus flow rate is measured by the transport time or speed of marker placed on the nasal mucosa.

6.4Nasal.pathophysiology:

The influence of physiology of abnormal nose on bioavailability of nasal drug products has not been studied in sufficient details. The most frequent and common disease associated with nose is rhinitis; hence pathology of rhinitis and its influence in drug bioavailability is briefly discussed in this section. Rhinitis is classified as allergic rhinitis and common cold. Allergic rhinitis is the allergic airway disease, which affects 10% of population.³⁴ Numerous allergens are constantly present in our environment, and any one of them can cause allergic rhinitis. In this condition, air borne allergic particles including pollens, molds, animal allergens are deposited on the nasal mucosa. Allergic rhinitis, is also known as hay fever, may be acute, seasonal or chronic and perennial. Allergic rhinitis is characterized by hypersecretion, itching, and sneezing³⁵.

6.5Nasal.metabolism :

Although nasal secretions consist of enzymes, they do not have a significant effect on the extent of absorption of most of compounds except protein and peptide molecules.³⁶ The low metabolic environment offers nasal drug delivery as a lucrative route for both conventional and protein molecules. Nasal bioavailability of a significant number of drugs such as progesterone, testosterone, estradiol, naloxane, propranolol, and butorpheanol is almost 100%,³⁷ whereas the oral bioavailability of the above mentioned drugs is almost nil except propranolol, which has oral bioavailability ranging from 20 to 30%.³⁸ Presystemic metabolism is the major rate limiting step in the bioavailability of oral drug product; which is particularly true for highly lipophilic compounds.³⁹ The nasal administration of these compounds resulted in complete absorption because of a) the rate of absorption was very fast, hence enzymatic exposure time is very short and b) the level of enzymes in nasal cavity is very low and can be easily saturated with drugs.⁴⁰

7.0) Strategies to improve bioavailability in Nasal Drug Delivery:

7.1) Enzyme Inhibiter:

A number of studies have described the role of enzyme inhibitors on bioavailability of nasal formulations.⁴¹^,⁴² Particularly, enzyme inhibitors are essential components of formulation, while developing a dosage form for protein and peptide molecules. Mostly peptidase and protease inhibitors are widely used to improve the bioavailability of protein and peptide molecules. Enzymatic activity can also be reduced by addition of enzyme inhibitors such as bestatin, amastatin, boroleucin, borovaline, aprotinin, and trypsin inhibitors.⁴³ Clinical studies are costly and time consuming and there is no guarantee for success of drug product, so these methods for enzyme inhibition are considered as non-lucrative approach for pharmaceutical companies.

7.2) Nasal permeation enhancer

Various mechanisms such as increase in the membrane fluidity, creating transient hydrophilic pores, decreasing the viscosity of mucous layer and opening up of tight junctions are the proposed mechanisms of permeation enhancers, which improve the bioavailability of nasal dosage forms.⁴⁴ Some of the permeation enhancers like bile salts and fusidic acid derivatives can also inhibit the enzymatic activity in the membrane, thereby improving bioavailability. Even though nasal permeation enhancers can improve the therapeutic efficacy of drug products, its toxicity should be considered while developing dosage form. One of the most common and frequently reported problems with permeations enhancer is the nasal irritation during administration of nasal dosage form.⁴⁵

The ideal characteristics of nasal permeation enhancers are as follows:

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.

7.3) Prodrug approach:

In recent days, designing of prodrug is used to improve the physicochemical properties such as solubility and compound lipophilicity to overcome the pharmacokinetic demerits associated with drug molecules. However, prodrug approach has also been used to reduce the presystemic metabolism and chemical decomposition. The basic principle associated with prodrug is to cover the undesired functional group(s) with another functional group, which usually are referred as promoiety.

8.0) Applications of Nasal Drug Delivery:⁴⁶^-
48

8.1 Nasal Delivery of organic-Based pharmaceutical

Drug with extensive presystemic metabolism, such as progesterone, Estradiol, Testoserone, Propranolol, Cocaine, Naloxone and Nitroglycerine can be rapidly absorbed through nasal mucosa with a systemic bioavailability of approximately 100%.

8.2 Nasal Delivery of Peptide-Based pharmaceutical

Most of nasal formulations of peptide and proteins pharmaceutical have been simple prepared in simple aqueous solution with preservatives. Peptide and protein pharmaceutical have generally low oral bioavailability and are normally administered by parenteral route due to their physicochemical instability and susceptibility to hepatic first pass elimination.

The extent of systemic delivery of peptide or proteins by transnasal permeation may depend on

a. The structure and of the molecules.

b. The partition coefficient.

c. The susceptibility to proteolysis by nasal enzymes

d. Nasal residence time

e. Formulation variables ( pH, viscosity and osmolarity)

Recently development has been made to increase the nasal absorption of protein and peptide drug using following agent:

Ø Viscosity enhancing agent- methyl cellulose, HPMC, polyethylene glycol etc.

Ø Bile salt- sodium salt of deoxycholic acid.

Ø Surfactants – polyoxyethylene-9-laurylether

Ø Enzyme inhibitors- aprotinin or amastatin

Ø Mucoadhesive or bioadhesive polymer- starch, albumin, gelatin.

9.0 Animal models:

9.1 Rat models⁴⁹:

The rat is anesthetized by intraperitoneal injection of sodium pentobarbital. After an incision is made in the neck, the trachea is cannulated with a polyethylene tube. Another tube is inserted through the esophagus towards the posterior part of nasal cavity. The passage of nasopalatine tract is sealed surgically to prevent the drainage of drug solution from the nasal cavity to the mouth. The drug solution is delivered to the nasal cavity through either the nostril or the esophageal tubing.

In this model the rabbit is anesthetized by an intramuscular injection of a combination of ketamine and xylazine. The drug solution is delivered by nasal spray into each nostril while the rabbits head is held in upright position. During the study the rabbit is permitted to breath normally through the nostrils and the body temperature is maintained at 37°c by a heating pad. The blood samples are collected via IV indwelling catheter in the marginal ear vein.

9.3 Dog model:⁵⁰

The dog is anesthetized by intravenous injection of thiopental sodium and is maintained in an anesthetized state with Phenobarbital sodium. A positive pressure pumps provides ventilation the cuffed endotracheal tube and a heating pad keeps the body temperature at 37°_+0.5.

9.4 Sheep model:⁵¹

The sheep model for studying nasal drug delivery is prepared by using the same procedure as described for dog model. A male in-house-bread sheep is used because it lacks nasal infection diseases.

Because of their larger nostril and body compared to the rat model, rabbit and dog , sheep are suitable and practical animal models for the evaluation of the pharmacokinetics and pharmaceutical parameter involved in the nasal delivery of drug from sophisticated formulation.

9.5 Monkey model:

The monkey tranquilized by intramuscular injection of Ketamine HCl solution or is anesthetized by intravenous injection of sodium Phenobarbital. While holding the head in upright position, the drug solution is delivered into each nostril. The monkey is then placed in the supine position in a metabolism chair for 5-10 min. following intranasal administration. Blood sample are collected via indwelling catheter in the vein.

9.0 CONCLUSION:

Targeted drug delivery systems have decreased the dosages requirement and it is an alternative to IV route. The Nasal mucoadhesive microspheres have increased the bioavailability of protein and peptide drug. It is very likely that in near future more drugs will come in market intended for systemic absorption in the form of nasal formulation. The nasal mucosa has been considered as an administration route to achieve faster and higher level of drug absorption. The targeted nasal drug delivery with the help of specially designed pumps has increased the nasal absorption of the drug and decreased the dosages requirement.

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Received on 13.03.2011

Accepted on 14.04.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(5): Sept.-Oct. 2011, 159-166

Sr. no	Product	Drug	Indication	Manufacturer
1	Beconase® AQ Nasal Spray	Beclomethasone dipropionate monohydrate	Symptomatic treatment of seasonal and perennial allergic rhinitis	Allen and Hanbury’s/Glaxo Wellcome Inc.
2	Vancenase® AQ Nasal Spray	Beclomethasone dipropionate monohydrate	Symptomatic treatment of seasonal or perennial allergic rhinitis	Schering Plough Corp
3	Rhinocort® Nasal Inhaler	Budesonide	Management of symptoms of seasonal and perennial allergic rhinitis and non-allergic perennial rhinitis	Astra USA, Inc.
4	Stadol NS® Nasal Spray	Butorphanol tartrate	Management of pain including migraine headache pain	Bristol Myers Squibb
5	Miacalcin® Nasal Spray	Calcitonin — salmon	Post-menopausal osteoporosis	Sandoz Pharmaceutical Corp
6	Nasalcrom® Nasal Solution	Cromolyn sodium	Symptomatic prevention and treatment of seasonal or perennial rhinitis	Fisons Corp. Prescription Products
7	DDAVP® Nasal Spray	Desmopressin acetate	polydipsia, polyurea, and dehydration in patients with diabetes insipidusPrevention and control of	Rhone Poulenc Rorer
8	Stimate® Nasal Spray	Desmopressin acetate	Hemophilia A, von Willebrand’s disease (type 1)	Rhone Poulenc Rorer
9	Decadron® PhosphateTurbinaire®	Dexamethasone	Treatment of inflammatory nasal conditions or nasal polyps	Merck and Co., Inc
10	Nasalide® Nasal Solution	Flunisolide	Symptomatic treatment of seasonal or perennial rhinitis	Roche Laboratories
11	Flonase® Nasal Spray	Fluticasone propionate	Management of seasonal and perennial rhinitis	Allen and Hanbury’s/Glaxo Wellcome Inc
12	Synarel® Nasal Solution	Nafarelin acetate	Central precocious puberty ; endometriosis	Roche Laboratories
13	Syntocinon® Nasal Spray	Oxytocin	Promote milk ejection in breast feeding mothers	Sandoz Pharmaceutical Corp.
14	Nasacort® Nasal Inhaler	Triamcinolone acetonide	Treatment of seasonal and perennial allergic rhinitis	Rhone Poulenc Rorer