Nasal Medication: A Potential Alternative Route


Sharma Akshat*, Pachoriya Rahul and Sharma Ratnesh

Department of Pharmaceutics, V.N.S Institute of Pharmacy, Neelbud, Bhopal (M.P.) India

*Corresponding Author E-mail:



The nasal mucosa deliberated as a potential administration route. Because of large surface area, porous endothelial membrane, rapid blood flow, first pass metabolism avoidance and quick accebility the drug absorption has been faster and also higher. Protein and peptides, low molecular weight polar molecules antiparkinson’s drugs and macromolecular polysaccharides. The major hurdle in nasal route of administration is the poor contact of formulation with mucosa of nose. But using absorption enhancer and mucoadhesive polymer the increase in residence time of drug in nasal mucosa. Many researchers became interested in the nasal route for the systemic delivery of medication due to high degree of vascularization and permeability.




It is essential to understand the anatomical, physiological, and functional features of the nasal cavity. The description as below1.



The total surface area of human nasal cavity about 150 cm2 and a total volume of about 15 ml midline septum are divided into two non-connected parts. As a cross-sectional view of human nose as schematically shown in Figure.1.


Figure 1: A cross-sectional view of human nose




The nasal cavity having many differentiated regions2, 3. The nasal vestibule is situated just inside of the nostrils, with an area of about 0.6 cm2. The epithelial cells in this region are stratified, squamous, and keratinized. The atrium located at the back of the vestibule is the narrowest region, and has stratified squamous cells anteriorly and pseudostratified cells with microvilli posteriorly. The olfactory region lies in the roof of the nasal cavity, and covers about 10% of the total surface area. The nasopharynx is a passage to the esophagus, and receives nasal cavity drainage. Finally, the respiratory region constitutes the remaining large percentage of the nasal cavity. The respiratory region is dominated by three nasal turbinates: the superior, middle, and inferior turbinates, which project from the lateral walls of each half of the nasal cavity. This anatomical structure is important for creating a turbulent flow through the nasal passage, which ensures better contact between the inhaled air and the mucosal surface, and facilitates humidification and temperature regulation of the inhaled air. Similar complicated turbinate structures, more or less, are seen in all animal models normally used for nasal delivery studies.



The respiratory region is highly supplied with blood and having a large surface area, which suggests suitability as an absorption site for drugs. Four different types of cells constitute the nasal epithelium, with a thickness of about 100 mm First, basal cells, which are precursor cells of the other cell types, lie on the basement membrane and do not front the nasal cavity4. These cells have desmosomes and hemidesmosomes, which seem to mediate adhesion between adjacent cells and the basement membrane, respectively. Two different types of columnar cells, ciliated and non-ciliated cells, are predominating cells on the nasal permeability by forming apical tight junctions between neighboring cells and inter digitations of the cell membrane in the uppermost part. These cells have an abundance of mitochondria in the apical part, showing an active metabolism. The entire apical surface of all columnar cells is covered with approximately 400 microvilli, which increase the surface area of the nasal mucosa for effective exchange through the epithelium5. The microvilli also play a major part in maintaining a wet environment by retaining mucus layers, which will be explained later. Ciliated and non-ciliated cells have non-uniformity in their distribution in the nasal cavity, corresponding well with the nasal airflow (i.e., the percentage of ciliated cells is inversely proportional to the inspiratory air flow rate). Specifically, there are more ciliated cells in the lower surface of the nasal cavity than in the upper surface, and there are fewer ciliated cells in the anterior part, with low temperature and humidity, than in the deeper part of the cavity, with high temperature and humidity. Each ciliated cell has approximately 100 cilia, 0.3 mm in width and 4–6 mm in length, which are beating about 1000 times per minute. The fourth typical cell type of the epithelium in the respiratory region is the goblet cell, having many secretory vesicles in the cytoplasm, which is related to production of the mucus layer on the surface. Although little is known about the mechanisms of nasal secretion from the goblet cells, they may play a role in response to physical and chemical irritants in microenvironments. The goblet cells exist in a larger number in the posterior region than in the anterior region of the nasal cavity; 4000–7000 cells/mm2 is the average concentration, which is similar to their distribution in the trachea and main bronchi. The highly vascularized basement of the epithelium receives an arterial blood flow of about 40 ml/min/ 100 g. Differing from the gastrointestinal (GI) tract, the venous blood deriving from the nose flows directly into the systemic circulation, indicating that the hepatic first-pass effect is circumvented, allowing a high bioavailability of administered drugs. The apical surface of the epithelium is covered with sol-state and gel-state mucus layers.



Anterior serous and seromucus glands, and the goblet cells to a lesser degree, are responsible for the production of nasal secretions. Approximately 1.5–2ml of mucus is secreted daily. The mucus layer is reported to exist as a double layer of 5 mm in thickness, consisting of a periciliary sol layer and a gel layer covering the sol layer. The nasal mucus having different constituents are shown in table.1.


Table 1: The nasal mucus constituents





Mucus glycoproteins (mucin)


Other proteins (Albumin, immunoglobulins, lysozyme, lactoferrin)


Inorganic salts





The mucus glycoprotein, consisting of a protein core (20%) and oligosaccharide side chains (80%), is cross-linked by a disulfide and hydrogen bond, providing appropriate viscosity and elasticity with the mucus gel layer. The mucus is continuously moved forward by the forefront of the cilia in the order of 5mm/min, which is a mucociliary clearance. Mucus as well as for removing substances adhering to the nasal mucosa6,7,8. In the normal state, a substance administered nasally will be cleared by this system in 15–20 min. In pathological conditions such as common colds, rhinitis, and nasal polyposis, the nasal function may be modified as exemplified with mucociliary dysfunctioning, hyposecretions or hypersecretions, and irritation of the nasal mucosa. When considering nasal drug delivery, this defensive function of the nose must be taken into account.



·         When drug will be given through nasal cavity (nasal administration) it passes through nasal epithelium and goes into the systemic circulation (blood). Then it will cross blood brain barrier as well as also crosses the blood-cerebrospinal fluid barrier and finally reach to the brain.

·         When drug will be given through nasal cavity (nasal administration). Then it passes through olfactory region and goes into cerebrospinal fluid and finally reaches to the brain.

·         When drug will be given through nasal cavity (nasal administration) the drug passing through mucociliary clearance and enzymatic barrier. Then drug passing through this barrier will be absorbed across nasal epithelium and reach the systemic circulation. Then it will be eliminated by a normal clearance mechanism and showing its pharmacological effect at the tissue/organ. The mucociliary clearance will transport a drug towards the gastrointestinal tract via the nasopharynx, and give the possibility that the drug will be absorbed from gastrointestinal tract. The nasal absorption pathways are shown in figure. 2.



The main barriers in the mucosal absorption of different drugs like peptide and protein etc are penetration and an enzymatic barrier, environmental ph which are relevant to nasal delivery9. These are discussed as below:-



The molecular weight of a drug, in particular peptide and protein drugs, is one of the most predominating factors to any kind of mucosal penetration barrier10. Researchers suggest that the water-soluble and high-molecular weight compounds can penetrate the nasal mucosa mainly by passive diffusion (i.e., through the transcellular route such as aqueous pores and tight junctions). Moreover, the bioavailability of a compound can be estimated from its molecular weight only if the issue of enzymatic degradation can be ignored.


Table 2: Different enzymes and its examples



oxidative enzymes

cytochrome P450, carboxy esterase, aldehyde dehydrogenase, and carbonic anhydrase

conjugative enzymes

glucuronyl transferase and glutathione transferase

exopeptidases and endopeptidases

aminopeptidase, carboxypeptidase, trypsinlike activities, and cathepsins

Figure 2: Mechanisms of drugs after nasal administration






The nasal epithelium also acts as an enzymatic barrier to nasally administered drugs (peptide and protein)11. Nasal cavity contains many enzymes which seem to be common in GI tract or liver including. The enzymes and examples are shown in Table. 2.


This wide variety of enzymes is creating a pseudo-first-pass effect, the absorption of drugs (peptide and protein). The degradation mechanisms of some small peptides such as vasopressin, calcitonin, and LHRH analogues in the nasal cavity are elucidated by experiments using specific enzyme inhibitors12-15.



The pH of the nasal formulation may influence absorption efficiency. Small water-soluble compounds having dissociable functional groups, their absorption depends on environmental pH (i.e., a greater drug permeation is usually expected at a pH that is lower than the drug’s intrinsic pKa because under such conditions, the molecules exist as a unionized, hydrophobic form). The pH of nasal mucus layer, which varies between 5.5 and 6.5 in adults and between 5.0 and 7.0 in infants. This physiological pH of the nasal cavity may neutralize the pH of the formulation by its buffering capacity, and can affect microenvironmental pH surrounding drug molecules during the absorption process. The environmental pH may be an important key factor when facing the enzymatic barrier because some endogenous enzymes have specific optimal pH for exerting their activities. Therefore the pH in the formulation tested must be considered when interpreting the experimental results.


Figure 3. Basic concept for improving nasal drug( peptide and protein) delivery


1.                    Increased residence time.

2.                    Increased accessibility to membrane by removal of mucus (water).

3.                    Protection from enzymatic degradation.

4.                    Penetration enhancement with minimal and reversible damage with maximal potency.

5.                    Realization of local high concentration (sharp concentration gradient).





Most of the drugs (proteins and peptides) show insufficient nasal bioavailability, which may be one of the reasons for difficulties in development. The basic concept for improving nasal drug (peptide and protein) deliveryas shown in figure 3.


To improve the nasal absorption of peptide and protein drugs, several strategies classified as follows have been discussed below:

·         Use of absorption enhancers.

·         Use of enzyme inhibitors.

·         Synthesis of more lipophilic analogues.

·         Formulation approach includes device-related approach.


Absorption Enhancers:

The most rapidly used approach to improve the bioavailability of nasally administered drugs (proteins and peptides) is the use of absorption enhancers16, 17. The functions of absorption enhancers are elucidated and demonstrated in several ways by increasing membrane fluidity (either by causing disorders in the phospholipid domain or by facilitating the leaching of membrane proteins), opening tight junctions, or inhibiting enzymatic activities in the nasal tissue. The absorption enhancers based on their chemical classification as shown in Table 3.


Table 3: Different examples of nasal absorption enhancers



Bile salts( and derivative)

Sodium glycocholate, sodium deoxycholate


Saporin, sodium lauryl sulphate

Fatty acids

Sodium caprylate, phospholipids, sodium laurate

Chelating agent

Salicylates, Ethylene diamine tetraacetic acid



Bioadhesive materials powders

Carbopol, starch microspheres, chitosan


Chitosan, carbopol

Figure 4: The properties of ideal absorption enhancer



Absorption-enhancing agents have been tried in mucosal delivery as well as in nasal delivery only sodium caprate used in rectal suppositories of antibiotics18–23. Bile salts have been recognized as safe and effective enhancers, and have been used for nasal delivery. The ideal requirements for absorption enhancer are shown in figure. 3.



Chitosan, derived from crustacean chitin by a partial deacetylation process, is a type of polysaccharide consisting of glucosamine and N-acetyl-glucosamine, and has been widely investigated in the pharmaceutical field. Chitosan is a positively charged polymer, and can form salts with inorganic and organic acids. Although the chitosan of a pharmaceutical (good manufacturing practices, or GMP) grade is a glutamate salt with an average molecular mass of approximately 250 kDa, a broad range of molecular weights and salt forms is currently available24, 25. Chitosan is prove that it can improve the nasal absorption of various drugs (peptide and protein) such as leuprolide (1300 Da), salmon calcitonin (3500 Da), and parathyroid hormone (PTH) (4000 Da). Chitosan powder formulations, in the form of microspheres or powders, can, in many cases, provide a better absorption enhancing effect than chitosan solutions. One of the important features of chitosan for nasal application is its bioadhesiveness. Because of the positive charge, it can interact with the negatively charged sialic acid residues in the mucus layer, which can modify the mucociliary transport system. Another mechanism of action elucidated is a transient opening of the tight junctions in the cell membranes to allow polar drugs to pass through residues in the mucus layer, which can modify the mucociliary transport system. Another mechanism of action elucidated is a transient opening of the tight junctions in the cell membrane to allow polar drugs to pass through. Chitosan itself is not absorbed across the mucosa because of its high molecular weight, and its toxicity by the nasal administration.



The most upcoming strategy for an improved nasal delivery of drugs (proteins and peptides) is the formulation approach. Normally, the nasal residence time is rather short because of mucociliary clearance. Although the nasal route of administration provides fast absorption of drugs into the circulation and quick onset of therapeutic efficacies, the rapid clearance of the dosage form may be a disadvantage to obtaining reproducible absorption kinetics. For the purpose of improving absorption efficiency by prolonging nasal retention, recent progress based on the formulation approach should be noted.


Sprays vs. drops:

The site of drug deposition in the nasal cavity highly depends on the method of administration. When administering solution formulation, it is important to consider the particle/droplet size. The limitation is that the entire dose must be given in a volume of 25–200 ml, depending on the formulation. Nasal drops are the simplest and most convenient form. The exact volume of dosing is more difficult to determine, which may be a device-related matter, and rapid drainage is new problem with drops. Droplets administered by sprays reach a more posterior region of the nose than do drops. The posterior region is rich in ciliated cells, indicating a larger surface area contributing to the absorption of drugs26. The viscosity of the formulation can also influence the clearance of a drug. Nasal sprays containing a viscous polymer such as methylcellulose or hydroxycellulose showed decreased clearance of the formulation from the nasal cavity, resulting in the delayed absorption of drugs (proteins and peptides) 27, 28, 29.


Solutions vs. powders:

The powder dosage forms of drugs (proteins and peptides) based on materials such as microcrystalline cellulose, starch, and hyaluronic acid, can having merits over solution formulations30. The major advantages of the powder formulation are a higher chemical stability than the solution, which leads to the possible administration of large amounts of the drug and excipients. At the time of designing powder formulation for nasal peptide delivery, substantial care must be taken when controlling the particle size. Various types of inhalers for nasal powder administration, such as monodose inhaler, multidose dry powder system, pressurized metered dose inhaler, and so on, are available. The utility of water insoluble calcium carbonate (CaCO3) to formulate a powder formulation of (Asu1.7)-eel calcitonin (ECT)65. The insoluble powder formulation was prepared simply by adding ECT solution to the CaCO3 powder, followed by drying and milling. Fascinatingly, absorption occurred more quickly with the powder form than with the liquid form, but CaCO3 itself was found to have no effect on the permeability of ECT. They conclude that an insoluble powder form may improve the overall nasal absorption of ECT, mainly by increase in the residence of the drug at the mucosal surface.

The powder systems have been shown the mucociliary clearance and, in some cases, to affect the paracellular pathway by removal of water from the cell membrane.



The additives used in the formulation don’t have any side effects before permitting by regulatory agencies. Exact guidelines are asses for the toxicity as well as irritancy of pharmaceutical additives were used in nasal formulation. Mainly it divided in 3 categories:-

·         Influences on the morphology

·         Function of the nasal tissue, irritancy/tolerability,

·         Systemic toxicities.

The first class explains the histological absorption observation of the nasal membrane, protein leakage study, measurement of mucociliary transport rate, and ciliary beat frequency. The second and third class explain the transient and reversible nature of the membrane- damaging effect and direct clinical approach in human volunteers for irritancy and tolerability issues.



1.       Vaccines delivery through nasal route:-

Mucosa of nasal is highly rich in specialized cells and organized lymphatic tissue involved in the first line defense against airborne microorganism. Delivery of vaccines through nasal produce systemic immune response, but also local immune response in the nasal lining, providing additional barrier of protection31. Vaccines delivery to the nasal cavity also stimulates production of local secretory IgA antibodies as well as IgG, providing an additional first line of defense, which helps to eliminate the pathogen before it becomes established32. Major reasons for exploiting the nasal route for vaccine delivery:

·         The first sight of contact with inhaled pathogens in nasal mucosa.

·         The nasal route highly rich in lymphatic tissue.

·         Increase in both mucosal and systemic immune responses.

·         Low cost, patient friendly, non-injectable, safe.

The nasal drug products for the vaccination which is available in the market have been shown in table 4.


Table 4: The different vaccines with their product name and manufacturer





Human influenza vaccine



Medlmmune Inc.

Equine influenza vaccine

Flu Aver



Porcine Bordetella bronchiseptica vaccine

Maxi/ Guard Nasal Vaccine


Addison Biological Laboratory

Human influenza vaccine


Proteosomes   (nanoparticulate)

ID Biomedical

Feline Bordetella bronchiseptica vaccine

Nobivac Bp

Suspension drops



Table 5: Delivery of different drugs into brain via nasal route




Treatment of Diabetes Mellitus

Insulin like Growth factor (IGF-1)


Treatment of Alzheimer disease

Activity-dependent neuro-trophic Factor (ADNF12)


Diagnosis and treatment of central diabetes insipid us prevention and treatment of postoperative abdominal distention






Supplementation of insufficient secretion of progesterone in women participating in fertilization programmes



Relief from pain



Management of anxiety



deficiency symptoms in young

women after oophorectomy



Prevention from bacterial infection




2.       Delivery of drugs to the brain via nasal cavity:-

In therapeutic situations a rapid targeting of drug to brain is required where the nose to brain delivery is beneficial. Development of nasal delivery system increase the fraction of drug that reaches the CNS after nasal delivery, benefit conditions such as Parkinson’s disease, Alzheimer’s disease or pain would be benefited from the development of nasal delivery systems, which will increase the fraction of drug that reach the CNS after nasal delivery in the nasal passage, olfactory region is located at the upper remote part. It offers certain compounds to circumvent the blood brain barrier and enters into the brain. The different drugs given through this route have been shown in table 5.



There is no doubt that the nasal route of administration of drugs (peptide and protein) is one of the most attractive alternatives to injections because of its convenience, which should assure good compliance by patients. The administration of drug through nasal route show quick absorption and therapeutic advantages. Safety aspects of excipients especially absorption enhancers is also a challenging issue, in the formulation part. Most enhancers show a direct relationship exists between absorption enhancing ability and local toxic effect. The efficacy of some kinds of absorption enhancers may not be necessarily related to their damaging effects on the nasal epithelium. In conclusion, a better absorption mechanisms and also assure the safety as well as efficacy of the formulation will be needed.



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Received on 20.07.2010          Modified on 30.07.2010

Accepted on 11.08.2010         © RJPT All right reserved

Research J. Pharm. and Tech. 4(2): February 2011; Page 189-196