NASAL DRUG DELIVERY SYSTEM: A COMPLETE REVIEW

About Authors:
Dharmendra Kumar^*1, Sumedha Bansal^1
1Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology,
Meerut, Uttar Pardesh, India, 250005
*rvnimiet@gmail.com

Abstract:
In present era, nasal drug delivery system has been considered as potential and favourable route of drug delivery because it provides patient compliance, easy to administration, bypass first pass metabolism, excellent penetration, low dose required, rapid absorption and gives desirable effects. So many times nasal drug delivery has been considered as alternative of parenteral route. The purpose of this review, to provide a complete information about nasal drug delivery system such as advantage, limitations, anatomy of nose, mechanism of drug absorption, factors affecting of nasal drug delivery, absorption improvement aspects, novel drug formulations, types of nasal drug delivery system with uses of nasal drug delivery in various disease. So we have expectation, that researches and others cited person get benefitted from this review.

Reference Id: PHARMATUTOR-ART-1593

Intoroduction:
Generally nose is the important part of body for inhalation process. But when it is used as the route of drug delivery attained the great attraction for various drugs. Because nose provides faster and higher level of drug absorption with possibility of self-administration [1].

In recentmany of drugs are used via nasal route but many have various disadvantage such as poor contact of formulation with nasal mucosa, fast clearance and solid dosage formulations also be difficult via nasal route [2].

Researchers have also attempted delivery of drugs to the CNS via nasal route cross the blood brain barrier allowing the direct drug delivery in the bio phase of central nervous system active compound. NDDS also be administration route for vaccines[3-6].

Hydrophobic and low molecular drugs can easily penetrate through nasal mucosa with less degradation. Fast absorption can be achieved due to large absorption surface area and high vascularisation. In emergency nasal route can be used as alternative route of parenteral[7-8].

Advantage of nasal drug delivery system

Limitations of nasal drug delivery system.

Anatomy of nose:
Breathing and olfaction are the major function of human nose[13]. But it also functioned as filtration and humidify of inhaled air before reaching in lowest airways. Nasal cavity has mucus layer and hairs, those helpful in filtration of particles trapped in inhaled air. Additionally metabolism of endogenous substances, mucociliary clearance also a function of nose[14-17].

An nasal cavity has about a 20 ml capacity with a large surface area (about 180 cm²) for the drug absorption afforded by the microvillus present along the pseudo-stratified columnar epithelia cells of the nasal mucosa. Nasal cavity is divided by septum into two equal parts[18].

P^H of mucosal secretions:-
In children – 5.0 to 6.7[19-20]
In adult - 5.5 to 6.5[19-20]

Human nasal cavity have three functional regions called vestibular, olfactory ,and respiratoryareas.the vestibular area provides as a baffle system, and functioned as filter of airborne particle, it has Keratinized and squamous epithelial cells with nasal hairs, it has poor permeability of drug particles. Olfactory epithelium is helpful to metabolizing drugs,it has sustentacular cells, olfactory receptor and basal cells. Drugs can be direct access to CNS from olfactory region. Respiratory region also an important in nasal drug delivery system and provided optimum drug absorption. Respiratory region contains columnar ciliated cells, columnar non ciliated cells, goblet cells and basal cells[21-24].

Figure:- External view of Human Nose

(A).Nasal vestibule:-
- It is the anterior part of nasal cavity.
-Surface area is 0.6cm²[24].
-Nasal portion is covered by a stratified squamous keratinized epithelial with sebaceous gland.
-Drug absorption is very difficult in this region but it afforded high resistance against toxic environment [25].

(B). Atrium-
- The area between nasal vestibule and respiratory region is called Atrium.
- The anterior part consists – stratified squamous
- The posterior part consists- pseudostratified columnar cells.

(C). Respiratory region.
- It is the largest part of nasal cavity and also known as conchae.
- Humidification and temperature is the function of it
- Drug delivery is very good in this region
-It consist pseudo stratified columnar epithelial, globet cells, basal cells, mucous and serous glands.
- Microvilli are important to enhance the respiratory surface area.

(D). Olfactory region.
- It located in the roof of the nasal cavity.
-It has neuroepithelium
-Neuroepithelium is the cavity part of the CNS is directly exposed the external environment [26].
-It has pseudostratified.

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Mechanism of drug absorption[27-28]:-

Figure -: Mechanism of Drug Absorption     

Types of drug mechanism:
1.      Paracellular mechanism – in which process drug transported between cell and transcytosis by vesicle carrier. It is slow process. In which passive diffuse take place. It is suitable mechanism for hydrophilic drugs[28].
2.      Transcellular mechanism – in which process drug diffuse through membrane. It is an active transport process. It is more suitable for lipophilic drugs[28-29].

Factors affecting nasal drug delivery system:

Figure-: Various dosage form of Nasal Drug delivery System

Nasal absorption improvement aspects[59]:-
On the basis of researchers work and literature review can say that absorption of nasal drug improved by various methods. These methods can be divided in two classes.

1. Physicochemical effects:- in which method  drug absorption can be improved by modification of  physicochemical properties of drugs. And by using absorption enhancers. This method includes drug solubility, drug partition, weak ionic interactions etc.

2. Membrane effects: - nasal mucosal surface also be helpful in improving nasal absorption.

Following approaches also have been used for improvement of nasal drug absorption [60-65].
*  Prodrugs
*  Enzymatic inhibitors
*  Absorption enhancers
*  Mucoadhesive drug delivery system
*  Novel formulation forms

These approaches are used in following problems:-following problem  may take place in the nasal absorption or affect the bioavailability of drug-
1.      Poor physiological properties of drug and/or formulation
2.      Enzymatic degradation
3.      Low permeability through nasal membrane

Figure-: Problems and their Solutions for Nasal improvement.

Figure-:  Advantage of Prodrug formulations.

Enzymatic inhibitors[70-76]- nasal mucus layer and nasal mucosa act as enzymatic barriersin the nasal drug delivery. Enzymatic degradation can be avoided by use of protease and peptidases inhibitors.

Absorption enhancers[77-83]- various types of absorption enhancers are used in nasal drug delivery but mechanism of action is not known. Absorption enhancers are as surfactants, bile salts, fatty acids, and polymeric enhancers. These are change permeability of epithelial cell layer by modifying the phosphlipidic bilayer, and increasing paracellular transport because it opening the tight junction between epithelial cells. On the basis of researchers and reviews chitosan and cyclodextran are significantly used with low toxic effect[84-93].

Mucoadhesive drug delivery system[94-97]- by using mucoadhesive agent residence time of drug on mucosa increased. Nasal gel preparations are based on these agents. On the basis of resource these are grouped in two category namely natural mucoadhesive agent[98] and synthetic mucoadhesive[99-101].

Table No. 1- Natural Mucoadhesiveagent used in Nasal drug delivery.

Novel drug formulations:- liposomes, microspheres, and nanoparticles are widely used novel drug formulation. These formulation improved stability, increased bioavailability, so gives better result than other formulations.

1.      Liposomes-[111-119] these are phospholipid vesicles composed by bilayer enclosingone or more aqueous compartments, in these compartments drug can be entrapped or adsorbed.
2.      Microspheres^.-[120-121] microsphere has important role in nasal drug delivery with enhance absorption, sustained release, and also has great importance because it protects drug from enzymatic degradation.
3.      Nanoparticles-[122-132].

Types of nasal drug delivery:-on the basis of anatomy and physiology, many researchers have been developed various nasal drug delivery systems. These systems depend on the conditions of disease such as acute and chronic. And other various factors are discussed in this review previously [133].

1.      Local delivery:[134-140]
-Favourable for topical nasal disorder.
-Low dose required
-Minimizing toxic effects.
-Recently topical ant biotherapy has been used.

For example-

DrugsDisorders

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2.      systemic delivery:
-Fast and extended drug absorption [141].
-Nasal formulation gives more system effect than other routes [142-143].

For example-

3.      Nasal vaccines: nasal vaccines are generally used against respiratory infections. In vaccinationnasal route is the choice of route and also used as alternative of parenteral route because it increaseslevel of immunoglobulin G and immunoglobulin A [155-157]. Nasal vaccines are used against various infection such as-
a.      Influenza A and B, proteasomes-influenza[158]
b.      Adenovirus-vectored influenza[159]
c.      Group B meningococcal native[160]
d.      Attenuated respiratory syncytial virus[161]
e.      Para influenza 3 virus[162]
f.       Human immunodeficiency virus[163]
g.      Hepatitis B virus[164]

4.      CNS delivery through nasal route:
-Brain is the delicate organ and performs vital functions.
-Brain surrounding with tight junction of BBB, it has greater transendothelial electric resistance compared to other tissue such as skin, bladder, lungs [165].
-When drugs/xenobiotics pass through BBB reduce the brain exposure [166-167].
-Olfactory neuroepithelium delivers the drugs nose to CNS, paracellur, trascellular and/or neuronal transport take place [168].
-Olfactory pathways present potential to bypass BBB[169-172].
-Drug delivery into CNS via nasal route has been presented by many researchers in human as well as in animal [173-176].

For example- Animal model of Alzheimer’s disease[177-178].
-Brain tumours[179-180],epilepsy[181], pain, sleep disorder[182],

Greater brain exposure via nasal delivery, needleless of passage BBB but in that other cases lacking of evidence recorded[183-187].

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