A Review: Nasal Drug Delivery System


Nirav S Sheth* and Rajan B Mistry

Sigma Institute of Pharmacy, Baroda. Gujarat, India.

*Corresponding Author E-mail: niravsheth111@gmail.com



For many years, drugs have been administered intranasally for their local effect on the mucosa (e.g. Antihistamines, decongestant, vasoconstrictors and antibiotics). In more recent years many drugs have been shown to achieve a better systemic bioavailability by self medication through the nasal route than by oral administration.Some of them have been shown to duplicate the plasma profile as i.v. administration. More recently the intranasal route has aroused increasing interest as means of the systemic administration of vaccine, hormones, peptides and certain other drugs. Although traditional nasal drug delivery methods offer significant advantages over injection or oral administration, they face challenges that limit efficacy and applications. Once relegated to treating conditions such as nasal congestion and rhinitis, intranasal drug delivery is now gaining attention for administration of a wide range of pharmaceuticals. Industries are looking at nasal drug delivery options as a viable alternative to traditional routes of administration for systemic drugs. This is due to the high permeability of the nasal epithelium, allowing a higher molecular mass cut-off at approximately 1000 Da, and the rapid drug absorption rate with plasma drug profiles sometimes almost identical to those from intravenous injections.


KEYWORDS: Nose, Nasal Devices, Nasal Vaccine, Nasal Drug Absorption



Therapy through intranasal administration has been an accepted form of treatment in the Ayurvedic system of Indian Medicine. In recent years many drugs have been shown to achieve better systemic bioavailability through nasal route than by oral administration.Advances in biotechnology have made available a large number of protein and peptide drug for the treatment of a variety of diseases. These drugs are unsuitable for oral administration because they are significantly degraded in the gastrointestinal tract or considerably metabolized by first pass effect in the liver. Even the parenteral route is inconvenient for long term therapy. So, many alternate routes tried, intranasal drug delivery is found much promising for administration of these drugs. In the last few years a number of excellent reviews have been published examining in detail some particular aspects concerning to potential therapeutic applications of intranasal route of drug delivery. 1 However, general reviews gathering together information about special characteristics of nasal mucosa, desirable physicochemical properties of drugs for nasal administration and successful technology strategies to develop pharmaceutical formulations for topically or systemically intranasal drug delivery are lacking.


Accordingly, the present review outlines anatomical, physiological and histological features of nasal cavity and the major factors affecting nasal drug delivery, highlighting simultaneously the properties of drugs and formulation characteristics that determine decisively the pharmacokinetics of nasal preparations. Additionally, the rationale for the extensive research of nasal medicines with current and future drug therapies, as well as their therapeutic benefit, will be also considered whenever appropriated. 2


Nasal drug delivery:

Nasal drug delivery is a useful delivery method for drugs that are active in low doses and show no minimal oral bioavailability. The nasal route circumvents hepatic first pass elimination associated with the oral delivery: it is easily accessible and suitable for self-medication. Currently, tow classes of nasally delivered therapeutics are on the market. The first one comprises low molecular weight and hydrophobic drugs for the treatment of the nasal mucosa and sinus, including decongestants, topical steroids, antibiotics and other(OTC) products.The second class encompasses a few drugs, which have sufficient nasal absorption for displaying systemic effects. Important candidates are the compounds, generally administered by injection and hardly absorbed after oral administration, due to their instability in gastrointestinal tract, poor absorption properties, and their rapid and extensive biotransformation.Therefore, nasal delivery is promising alternative route for the administration of peptides and protein drugs in particular. 3


The nasal cavity is divided 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 and the olfactory region are the three main regions of the nasal cavity. The lateral walls of the nasal cavity includes a folded structure which enlarges the surface area in the nose to about 150cm2 .This folded structure includes three turbinates:the superior, the median and the inferior. In the main nasal airway, the passages are narrow, normally only 1-3mm wide, and this narrows structure enables the nose to carry out its main functions.4Anatomy of human nose is shown in Figure 1


Figure 1: Anatomy of Human Nose


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 four main types of cells seen in the respiratory epithelium are ciliated columnar cells, non-ciliated columnar cells, goblet cells and basal cells. Although rare, neurosecretory cells may be seen but, like basal cells, these cells do not protrude into the airway lumen. The proportions of the different cell types vary in different regions of the nasal cavity. In the lower turbinate area, about 15-20% of the total numbers of cells are ciliated and 60-70% is non-ciliated epithelial cells. The numbers of ciliated cells increase towards the nasopharynx with a corresponding decrease in non-ciliated cells. The high number of nonciliated cells indicates their importance for absorption across the nasal epithelium. Both columnar cell types have numerous (about 300-400 per cell) microvilli. The large number of microvilli increases the surface area and this is one of the main reasons for the relatively high absorptive capacity of the nasal cavity. 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. These cells are poorly differentiated and act as stem cellstoreplace other epithelial cells. About 5-15% of the mucosal cells in the turbinates are goblet cells, which contain numerous secretory granules filled withmucin. In conjunction with the nasal glands; the goblet cells produce secretions, which form the mucus layer. 5


The Olfactory region:

In human, the olfactory region is located on the 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. Humans have relatively simple noses, since the primary function is breathing, while other mammals have more complex noses better adapted for the function of olfaction.6


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 Para cellular route. This route is slow and passive. There is an inverse log-log correlation between intranasal absorption and the molecular weight of water-soluble compounds. Poor bioavailability was observed for drug with a molecular weight greater than 1000 Daltons. The second mechanism involves transport through a lipoidal route is also known as the transcellular process and is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. Drug also cross cell membranes by an active transport route via carrier-mediated means or transport through the opening of tight junctions. For examples, chitosan, a natural biopolymer from shellfish, opens tight junctions between epithelial cells to facilitate drug transport.7


Factors Influencing Nasal Drug Absorption:

When a drug is nasally administered to induce systemic effects or to act into CNS it needs to pass through the mucus layer and epithelial membrane before reaching the blood stream or pass directly to the CNS. The passage across the epithelium may occur by transcellular or paracellular mechanisms. The first one includes passive diffusion through the interior of the cell and it is especially involved in the transport of lipophilic drugs. However, it seems that compounds with a molecular weight higher than 1 kDa, such as peptides and proteins, are transcellularly transported by endocytic processes. Furthermore, transcellular transport can be mediated by carriers that exist in the nasal mucosa, including organic cation transporters and amino acids transporters. In contrast, paracellular route is involved in the transport of small polar drugs and it takes place between adjacent epithelial cells through hydrophilic porous and tight junctions. Tight junctions are dynamic structures localized between the cells, which open and close accordingly to (in) activation of signaling mechanisms. Nevertheless, it is well known that their size is comprised between 3.9-8.4 Å avoiding the passage of bigger molecules, being this process of transport highly dependent of drug molecular weight.8 Taking into account previous considerations, it is evident that the molecular weight and lipophilicity of drugs may have a great impact in the rate and extent of its nasal absorption. However, other physicochemical drug properties must be considered as well as the characteristics of drug formulation. In this section all these factors will be discussed after a review of the influence of nasal physiological factors on nasal drug absorption. 9


1) Nasal physiological factors:

a) Blood flow:

Nasal mucosa is richly supplied with blood and presents a large surface area making it an optimal local for drug absorption. The blood flow rate influences significantly the systemic nasal absorption of drugs, so that as it enhances more drug passes through the membrane, reaching the general circulation. Indeed, bearing in mind that most of drug absorption takes place by diffusion, the blood flow is essential to maintain the gradient of concentration from the site of absorption to blood. Hence, it is well known that vasodilatation and vasoconstriction may determine the blood flow and, consequently, the rate and extent of drug to be absorbed. Several studies were made to evaluate this influence. For example, 10 showed that phenylephrine, a vasoconstrictor agent, inhibited the absorption of acetylsalicylic acid in nasal cavity. More recently, 11stated that nasal absorption of dopamine was relatively slow and incomplete probably due to its own vasoconstrictor effect. Based on these observations, it was concluded that vasoconstriction decrease nasal drug absorption by diminishing the blood flow.


b) Mucociliary clearance:

MMC also referred to as mucociliary apparatus or mucociliar clearance (MCC) is the self-clearing mechanism of the bronchi. Nasal mucus layer plays an important role in the defense of respiratory tract because it prevents the lungs from foreign substances, pathogens and particles carried by inhaled air. These agents adhere to the mucus layer and, all together, they are transported to the nasopharynx and, eventually, to the gastrointestinal tract. This elimination is designated MCC and it influences also significantly the nasal drug absorption. The MCC system has been described as a ‘‘conveyer belt’’ wherein cilia provide the driving force whereas mucus acts as a sticky fluid that collects and disposes foreign particles. The efficiency of MCC thereby depends on the length, density and beat frequency of cilia as so as the amount and viscoelastic properties of mucus. Briefly, all factors that increase mucus production, decrease mucus viscosity or increase ciliary beat frequency may increase the MCC. In physiological conditions, mucus is transported at a rate of 5 mm/min and its transit time in human nasal cavity is reported to be 15-20 min. Values out of these references are abnormal and suggestive of impaired MCC. Thus, if MCC decreases, residence time of the drug product in nasal mucosa increase and, therefore, enhances its permeation. The opposite effect is observed when MCC increases. In the last case, a premature discharge of nasally administered drugs from nasal cavity toward the nasopharynx occurs, decreasing the amount of drug absorbed. The clearance of a drug product from the nasal cavity is also influenced by the site of deposition. A drug deposited in a posterior area of the nose is cleared more rapidly from the nasal cavity than a drug deposited anteriorly. This is because MCC is slower in the anterior part of the nose than in the more ciliated posterior part. On the other hand, the site of drug deposition in the nose is highly dependent on the dosage form. Nasal sprays deposit drugs more anteriorly than nasal drops, resulting in a slower clearance for drugs administered from spray formulations.Polar drugs are the most affected by MCC, since they are highly soluble in mucus and their passage across the membrane is very slow. 12 Thus, all factors that influence the efficacy and pace of MCC may modify the drug absorption profile. For instance, environmental factors have a relevant influence in MCC. Temperature and sulphur dioxide seem to cause a significant reduction in MCC, but this the mechanism is not well known. Cigarette smoking also decreases MCC as it enhances the viscosity of the mucus and/or diminishes the number of cilia. In addition, several pathological conditions exist in which MCC does not work properly, as shown in Table 2. Furthermore some components of drug formulations may also alter the MCC system, such as preservatives and nasal absorption enhancers. Finally, it is interesting to stand out the inter-individual variability observed in MCC and the influence of the menstrual cycle and circadian rhythm. Actually, during the periovulatory period MCC is increased and it is reduced at night. 13


c)Enzymatic degradation:

Drugs nasally administered circumvent gastrointestinal and hepatic first-pass effect. However, they may be significantly metabolized in lumen of nasal cavity or during the passage across the nasal epithelial barrier due to the presence of a broad range of metabolic enzymes in nasal tissues. Carboxyl esterases, aldehyde dehydrogenases, epoxide hydrolases and glutathione S-transferases have been found in nasal epithelial cells and are responsible for the degradation of drugs in nasal mucosa. Cytochrome P450 is enzymes are also present here and they have been reported as metabolizers of drugs such as cocaine, nicotine, alcohols, progesterone and decongestants. Similarly, proteolytic enzymes (amino peptidases and proteases) were found and they are believed to be the major barrier against the absorption of peptide drugs, such as calcitonin, insulin and desmopressin. Thus, xenobioticmetabolizing enzymes existent in the nasal mucosa may affect the pharmacokinetic and pharmacodynamic profile of nasally applied drugs. In this context, although the nasal first-pass metabolism is usually weaker than hepatic and intestinal ones it cannot be ignored. 14


2) Effect of drug formulation:

a) Viscosity:

As formulation viscosity increases, the contact time between drug and nasal mucosa enhances and, thereby, the potential of drug absorption increases. At the same time, high viscosity of formulations interferes with normal ciliary beating and/or MCC and, thus, increases the permeability of drugs. This has been observed during nasal delivery of insulin, acyclovir and metoprolol. However, sometimes, enhancing formulation viscosity does not enhance the drug absorption. For example, 15performed a study to evaluate the influence of formulation viscosity on the retention time of metoclopramide hydrochloride in nasal cavity and on its absorption. Interestingly, they observed that although the residence time enhanced as viscosity increased the drug absorption diminished. This observation has been attributed to a decrease in the drug diffusion from the formulation. On the other hand, it has also been reported that the viscosity of the solution may provide a larger therapeutic period of nasal formulations. 15


b) PH:

The extent of nasal absorption depends on the pKa of drug and pH at the absorption site, contributing for that also the pH of formulation. At this point, it should be stated that the pH of formulation must be selected attending to drug stability and if possible should be assured the greatest quantity of non-ionized drug species.However, the pH of formulation can induce nasal mucosa irritation and, hence, it should be similar to that found on human nasal mucosa (5.0-6.5). Besides, the pH often prevents the bacteria growth. In order to evaluate the effect of pH solution on the integrity of nasal mucosa, 16dissolved drugs in phosphate buffer at different pH values in the range of 2-12. The study was performed in rats whose nasal pH is 7.39 17 and the results demonstrated that when pH ranged from 3-10 minimal quantities of proteins and enzymes were released from cells, demonstrating no cellular damages. On the contrary, if pH values were below 3 or above 10 damages were observed intracellular and at membrane level.


c) Pharmaceutical form:

Nasal drops are the simplest and the most convenient nasal pharmaceutical form, but the exact amount of drug delivered is not easily quantified and often results in overdose. Moreover, rapid nasal drainage can occur when using this dosage form.Solution and suspension sprays are preferred over powder sprays because the last one easily prompted the development of nasal mucosa irritation. Recently, gel devices have been developed for a more accurate drug delivery. They reduce postnasal drip and anterior leakage, fixing the drug formulation in nasal mucosa. This enhances the drug residence time and diminishes MCC, thereby, potentially increases the nasal absorption. Over the last years, specialized systems such as lipid emulsions, microspheres, liposomes and films have also been developed to improve nasal drug delivery.4


d) Pharmaceutical excipients:

In nasal formulations, a wide variety of pharmaceutical excipients can be found and they are selected accordingly to their functions. Solubilizers, buffer components, antioxidants, preservatives, humectants, gelling/viscosifying agents, and flavoring or taste masking agents are some of the most usual excipients. Although they are responsible for several nasal irritations, antioxidants, preservatives, humectants and flavoring or taste masking agents are not expected to alter nasal drug absorption. 18

Enhancement of Nasal Drug Absorption:19

Several methods have been used to facilitate the nasal absorption of drugs:

a) Structural modification:

The chemical modification of drug molecule has been commonly used to modify the physicochemical properties of a drug and could also be utilized to improve the nasal absorption of drug.

b) Salt or ester formation:

The drug could be converted to form a salt or ester for a better trans-nasal permeability. For example, nasal absorption could be improved significantly by forming a salt with increased solubility in nasal fluid (Table 1) or ester with the enhanced uptake by nasal epithelium.

c) Formulation design:

Proper selection of pharmaceutical excipients in development of nasal formulation could enhance the formulation stability and/or the nasal bioavailability of drug.

d) Surfactant:

Incorporation of proper surfactants into nasal dosage forms could modify thepermeability of nasal membrane, which may facilitate the nasal absorption of drugs Table 1 below, summarized the surfactant used in nasal drug delivery.

Over the last years, due to the understanding of the positive attributes and appropriate characteristics of the nasal cavity, intranasal route has been increasingly considered for drug delivery when developing new chemical entities or improving the therapeutic profile of existing drugs. However, to assess the therapeutic viability of intranasal drug delivery several approaches should be considered, attending, specifically, to the nature of pathologic condition (acute or chronic) and intended effects of drug treatment (local, systemic or at CNS). Indeed, for acute disease conditions, the advantages afforded by intranasal drug delivery in terms of patient comfort and compliance may not be much relevant when compared with drug delivery by parenteral route. In contrast, this is particularly important to treat or control chronic medical conditions. 4


Table 1: Absorption Enhancers Used in Nasal Drug Delivery




Polyozyethylene-9-lauryl ether (Laureth-9):


Bile salts

Trihydroxy salts (glycol- and taurocholate)

Fusidic acid derivatives



Ethylenediaminetetraacetic acid (EDTA)

Fatty acid salts

Oleic acid, Caprylate(C8)

Caprate(C10), Laurate(C12)


Lysophosphatidylcholine (lyso-PC)

Didecanoyl – PC

Glycyrrhetinic acid





α,β, and γ- cyclodextrins and their derivatives


n- glycofurols

n- ethylene glycols


1) Local delivery:

Intranasal administration of medicines is the natural choice for the treatment of topical nasal disorders. Among the most common examples are antihistamines and corticosteroids for rhino sinusitis, and nasal decongestants for cold symptoms. In these cases, intranasal route is the primary option for drug delivery because it allows a rapid symptom relief with a more favourable adverse-event profile than oral or parenteral routes. In fact, relatively low doses are effective when administered topically, 20 minimizing simultaneously the potential of systemic toxic effects. Recently, for instance, topical antibiotherapy has been considered in chronic rhinosinusitis in an attempt to eradicate biofilm bacteria, often resistant to systemic treatment, and still avoiding systemic toxicity.


2) Systemic delivery:

The intranasal administration is an effective way to systemically delivery of drugs as an alternative to oral and intravascular routes. Actually, it seems to present fast and extended drug absorption, 21and it has been supported by many studies planned to compare intranasal drug delivery against oral and parenteral administration. Consequently, the number of drugs administered as nasal formulations intended to achieve systemic effects has widely increased. Some prominent examples include analgesics (morphine), cardiovascular drugs as propranolol and carvedilol, hormones such as levonorgestrel, progesterone 22 andinsulin, anti-inflammatory agents as indomethacin and ketorolac, and antiviral drugs (acyclovir). Actually, there are some examples already available in the market. These include, for instance, zolmitriptan and sumatriptan for the treatment of migraine and cluster headaches. ). 23


3) Nasal vaccines:

Nasal mucosa is the first site of contact with inhaled antigens and, therefore, its use for vaccination, especially against respiratory infections, has been extensively evaluated. In fact, nasal vaccination is a promising alternative to the classic parenteral route, because it is able to enhance the systemic levels of specific immunoglobulin G and nasal secretory immunoglobulin A. In upper airways, the systemic and local immunological responses are mainly mediated by the nasal associated lymphoid tissue situated underneath the nasal epithelium.The nasal associated lymphoid tissue is composed of agglomerates of dendritic cells, T-cells and B-cells which are involved in the initiation and execution of immune responses. 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 virusandparainfluenza-3 virus.However, human nasal vaccination is not restricted to the upper airways affections. After nasal immunization secretory immunoglobulin A can also be detected in other mucosal secretions, which may be important against virus transmitted through other mucosal sites, such as human immunodeficiency virusand hepatitis B virus. 24


4) CNS delivery through nasal route:

The brain is a delicate organ with many vital functions and it is isolated and protected from the outside environment by several intriguing mechanisms. Unfortunately, those are the same mechanisms that prevent the CNS delivery of therapeutic agents. The tight junctions of the BBB surrounding the brain is one of such mechanisms, 25 resulting in a greater transendothelial electric resistance (1500-2000 Ω.cm2)26 compared to that of other tissues like skin, bladder, colon, lungs (3-33 Ω.cm2). This histological organization impairs, therefore, the systemically delivery of CNS-active drugs. Even though, if drugs or other xenobiotics pass through the BBB, a second line of defense mechanisms, including multidrug efflux protein transporters, may reduce the brain exposure. It is estimated that almost half of drug candidates are substrates to P-glycoprotein (P-gp) efflux pump, presenting reduced potential for systemically CNS penetration.27The obstacle imposed by those brain protective mechanisms has increased the interest in developing strategies to overcome them when brain drug exposure is required. In this context, over the last few years, intranasal route has emerged as a promising approach for brain delivery of drugs. The delivery from the nose to the CNS may occur via olfactory neuroepithelium and may involve paracellular, transcellular and/or neuronal transport.28Although the olfactory pathway presents potential to bypass BBB, P-gp appears to be also functional on this area. 29 Graff et al. confirmed that P-gp is present in both the olfactory epithelium and endothelial cells that surround the olfactory bulb. Moreover, the transport via trigeminal nerve system from the nasal cavity to CNS has also been described. Drug delivery into CNS through intranasal route has been reported either in humans or animal models of Alzheimer’s disease30, brain tumors, epilepsy 31,pain  and sleep disorders.32 However, it should be noted that in other cases evidence is lacking supporting the greater brain exposure via intranasal delivery despite the needless of passage BBB and the absence of gastrointestinal and hepaticpre systemic elimination.33



The selection of delivery system depends upon the drug being used, proposed indication, patient population and last but not least, marketing preferences. Some of these delivery systems and their important features are summarized below:


1) Nasal Drops:

Nasal drops are one of the most simple and convenient systems developed for nasal delivery. The main disadvantage of this system is the lack of the dose precision and therefore nasal drops may not be suitable for prescription products. It has been reported that nasal drops deposit human serum albumin in the nostrils more efficiently than nasal sprays.


2) Nasal sprays:

Both solution and suspension formulations can be formulated into nasal sprays. Due to the availability of metered dose pumps and actuators, a nasal spray can deliver an exact dose from 25 to 200 μm. The particles size and morphology (for suspensions) of the drug and viscosity of the formulation determine the choice of pump and actuator assembly.



Table 2. Delivery Means and Devices for Intranasal Administration of Drugs


Delivery Devices

Adrenal corticosteroids


Nasal spray, nasal drops, nasal insufflators, submucosal injections into the anterior tip of inferior turbine, metered dose aerosol


Nasal spray, nasal drops



Nasal spray, ointment


Nose drops


Nasal spray, nose drops, cotton pledget, gauge packtail, insufflators, rubbing with cocaine mud


Nasal spray

Estradiol- 17β

Nasal spray, nasal drops, microsyringe


Nasal spray


Nasal spray, nasal drops


Metered pump sprayer, metered dose aerosolized spray, fixed volume aerosol spray, nasal spray, nasal drops, cotton pledget


Nasal spray(isomack spray

Naferelin acetate

Nasal spray, tobacco snuff, injected into dogs frontal sinus


Metered dose spray

Instilled through Teflon i.v. Catheter


Nasal spray, nasal drops, cotton pleadget, aerosol activated spray, rhynyl (a plastic application tube), graded polyethylene tube,direct instillation by tuberculin syringe and 25G needle


Nasal spray by an atomizer connected to a respiratory pump, nasal spray by gas atomizer, nasal solution administered by micropipette


Inhalation aerosol, nasal spray, nasal aerosol spray, nebulizer aerosol, nasal drops

Vitamin B12

Nose drops, insufflators


Nasal spray, nose drops



3) Nasal Gels:

Nasal gels are high-viscosity thickened solutions or suspensions. Until the recent development of precise dosing device, there was not much interest in this system. The advantages of a nasal gel includes the reduction of post-nasal drip due to high viscosity, reduction of taste impact due to reduced swallowing, reduction of anterior leakage of the formulation, reduction of irritation by using soothing/emollient excipients and target to mucosa for better absorption.


4) Nasal Powder:

This dosage form may be developed if solution and suspension dosage forms cannot be developed e.g., due to lack of drug stability. The advantages to the nasal powder dosage form are the absence of preservative and superior stability of the formulation.However, the suitability of the powder formulation is dependent on the solubility, particles size, aerodynamic properties and nasal irritancy of the active drug an or excipients. Local application of drug is another advantage of this system.Table 3 given lists the drugs that have been administered intransally for systemic medication and type of drug delivery devices used. 34


Advantages of Nasal Drug Delivery System:35

1) Easy accessibility and needle free drug application without the necessity of trained personnel facilitates self medication, thus improving patient compliances compared to parenteral routes.

2) Good penetration of, especially lipophilic, low molecular weight drugs through the nasal mucosa. For instance the absolute nasal bioavailability of fentanyl is about 80%.

3) Rapid absorption and fast onset of action due to relatively large absorption surface and high vascularization. Thus the Tmax of fentanyl after nasal administration was less than or equal to 7 minute comparable to intravenous [i.v]. Nasal administration of suitable drug would therefore be effective in emergency therapy as an alternative to parenteral administration routes.

4) Avoidance of the harsh environmental conditions in the gastrointestinal tract (chemical and enzymatic degradation of drugs).

5) Avoidance of hepatic first pass metabolism and thus potential for dose reduction compared to oral delivery.

6) Potential for direct delivery of drug to the central nervous system via the olfactory region, thus by-passing the blood brain barrier.

7) Direct delivery of vaccine to lymphatic tissue and induction f a secretory immune response at distant mucosal site.



1) The histological toxicity of absorption enhancers used in nasal drug delivery system is not yet clearly established.

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

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

4) There is a risk of local side effects and irreversible damage of the cilia on the nasal mucosa, both from the substance and from constituents added to the dosage form.

5) The common cold or any pathological conditions involving mucociliary dysfunction, can greatly affect the rate of nasal Clearance and subsequently the therapeutic efficacy of the drug administered nasally.

6) There could be a mechanical loss of the dosage form into the other parts of the respiratory tract like lungs because of the improper technique of administration



The scientific community has reached a new stage of nasal drug delivery.The nasal drug delivery is a promising alternative to injectable route of administration. It is very likely that in the near future more drugs will come in the market intended for systemic absorption in the form of nasal formulation.Several formulation factors willinfluence the development of a drug with a drug delivery system, on a longer term;novel nasal products for treatment of long illnesses such as diabetes, growthdeficiency, osteoporosis, fertility treatment and endometriosis are also expected to bemarketed.Itis advisable that the bioavailability of nasal drug products is one of the major challenges for pharmaceutical companies to bring their product in market. The circumstances, which do not favor clinical applicability of nasal drug product is the lack of enough basic research in the area of nasal drug delivery. In contrast, pharmaceutical companies are investing a huge amount of money in the development of nasal drug products because of growing demand of nasal drug products in global pharmaceutical market. This research environment will lead to serious of adverse effects in the society in future. To avoid such backdrops, biomedical scientists, formulation researchers, pharmaceutical companies, funding agencies, and government along with regulatory bodies should pay attention to basic research in nasal drug delivery such as nasal pathophysiology, invention of new excipients to improve the nasal bioavailability, drug delivery devices, toxic dynamic studies of drugs and excipients and in vitro methods for nasal drug metabolism and bioavailability.



1.        CheinYW , Su KSE and Chang SF. Nasal systemic drug delivery. Dekker. 1989; 1-77

2.        Beht et al. Optimization of systemic nasal drug delivery with pharmaceutical excipients. Advansed  Drug Delivery  Review. 1998; 29: 117-13

3.        Wearle LL. Crit.Rev.her.Drug carrier. Sst.  1991; 8: 331-394

4.        J Pharm PharmaceutSci (www.cspsCanada.org) .2009; 12(3): 288 - 311

5.        Schipper, et al. The nasal mucociliary clearance: relevance to nasal drug delivery. Pharma Res. 1991; 7: 807-814

6.        Junginger. Bioadhesive polymer system for peptide delivery.  ActaPharma Tech.1990; 36: 110-12

7.        Su KSE, Moore LC and Chien YW.  Pharmacokinetic and bioavailability of hydromorphine: Effect of various routes of administration. Pharm Res.1988; 5: 718-725

8.        McMartin C. Analysis of structural requirements for the absorption of drugs and macromolecules from the nasal cavity. J Pharm Sci. 1987; 76 :535-540

9.        Arora P, Sharma SandGarg S. Permeability issues in nasal drug delivery. Drug Discovery Today. 2002; 7: 967-975

10.     Huang CH, Kimura R, Nassar RB, Hussain A. Mechanism of nasal absorption of drugs. I: Physicochemical parameters influencing the rate of in situ nasal absorption of drugs in rats. J Pharm Sci. 1985; 74: 608-611

11.     Kao HD, et al. Enhancement of the systemic and CNS specific delivery of L-dopa by the nasal administration of its water soluble prodrugs. Pharm Res. 2000; 17: 978-984

12.     Merkus FW, et al. Nasal mucociliary clearance as a factor in nasal drug delivery. Adv Drug Delivery Rev. 1998; 29: 13-38

13.     Illum L, et al. Intranasal delivery: Physicochemical and therapeutic aspects. Int J Pharm. 2007; 337: 1-24

14.     Lee VH, Yamamoto A. Penetration and enzymatic barriers of peptide and protein absorption. Adv Drug Deliv Rev. 1990; 4: 171-207

15.     Zaki NM, et al. Rapid-onset intranasal delivery of metoclopramide hydrochloride. Part I. Influence of formulation variables on drug absorption in anesthetized rats. Int J Pharm. 2006; 327: 89-96

16.     Pujara CP, et al. Effects of formulation variables on nasal epithelial cell integrity: Biochemical evaluations. Int J Pharm, 1995; 114:197-203

17.     Hirai S, Yashiki T and  Mima H.  Effect of surfactants on nasal absorption of insulin in rats, Int. J. Pharm. 1981; 9: 165-171

18.     Romeo VD, et al . Effects of physicochemical properties and other factors on systemic nasal delivery. Adv Drug Deliv Rev. 1998; 29: 89-116

19.     http://e-jst.teiath.gr

20.     Salib RJ, et al. Basophil activation in the upper airways of rhinitis subjects indicated by the secretion of basogranulin. RespCrit Care Med. 2003; 167(7): 478

21.     FurubayashiT,et al. Evaluation of the Contribution of the Nasal Cavity and Tract to Drug Absorption Following Nasal Application to Rats. Biol Pharm Bull. 2007; 30: 608-611

22.     Rathnam G, Narayanan N and Ilavarasan R. Carbopol-based gels for nasal delivery of progesterone. AAPS Pharm Sci Tech. 2008; 9: 1078-1082

23.     Shao Z,et al. The physicochemical properties, plasma enzymatic hydrolysis, and nasal absorption of acyclovir and its 2’-ester prodrugs. Pharm Res. 1994; 11: 237-242

24.     Costantino HR, et al. Intranasal delivery: Physicochemical and therapeutic aspects. Int J Pharm. 2007; 337: 1-24

25.     Graff  LC, Pollock GM. Nasal drug administration: potential for targeted central nervous system delivery. J Pharm Sci. 2005; 94: 1187-1195

26.     Graff CL, Zhao R and Pollack GM. Pharmacokinetics of substrate uptake and distribution in murine brain after nasal instillation. Pharm Res. 2005; 22: 235-244

27.     VyasTK,et al. Intranasal drug delivery for brain targeting. Curr Drug Deliv. 2005; 2: 165-175

28.     Illum L, et al. Bioadhesive starch microspheres and absorption enhancing agents act synergistically to enhance the nasal absorption of polypeptides.Int J Pharm. 2001; 222: 109-119

29.     Graff CL, Pollack GM. P-Glycoprotein attenuates brain uptake of substrates after nasal instillation. Pharm Res. 2003; 20: 1225- 1230

30.     Jogani VV, et al. Nose-to-brain delivery of tacrine. J Pharm Pharmacol. 2007; 59: 1199-1205

31.     Barakat NS, Omar SA and Ahmed AA. Carbamazepine uptake into rat brain following intra-olfactory transport. J Pharm Pharmacol. 2006; 58: 63-72

32.     Yamada K, et al. Nose-to-brain delivery of TS-002, prostaglandin D2 analogue. J Drug Target. 2007; 15: 59-66

33.     Van den Berg MP, et al. Uptake of melatonin into the cerebrospinal fluid after nasal and intravenous delivery: studies in rats and comparation with a human study. Pharm Res. 2004; 21: 799-802

34.     Chanler SG, Illum,L and Thomas,NW. int J Pharm. 1991; 76: 61-70

35.     Kao HD, et al. Enhancement of the systemic and CNS specific delivery of L-dopa by the nasal administration of its water soluble prodrugs. Pharm Res. 2000; 17: 978-984

36.     Hirai S, et al. Absorption of drugs from the nasal mucosa of rats. Int J Pharm. 1981; 7: 317-325








Received on 24.10.2010          Modified on 03.11.2010

Accepted on 12.11.2010         © RJPT All right reserved

Research J. Pharm. and Tech. 4(3): March 2011; Page 349-355