AN OVERVIEW TO THE RECENT TRENDS IN NASAL DRUG DELIVERY SYSTEMS
MHG Dehgan, Satapathy Asis Amitav*
Y.B.Chavan College of Pharmacy,
Dr. Rafiq Zakaria Campus,
Nasal route for the administration of drugs is used as an alternative route for the systemic availability of drugs restricted to intravenous administration. This is due to the large surface area, porous endothelial membrane, high total blood flow, the avoidance of first-pass metabolism, and ready accessibility. The nasal administration of drugs, including many biotechnological compounds like hormones, vaccines, peptide and protein drugs to give enhanced bioavailability. Many drug delivery methods for nasal availability of liquid, semisolid and solid formulation are investigated to avail the drugs to treat most CNS diseases (i.e., Parkinson’s disease, Alzheimer’s disease, Migraine attack) because it requires rapid and/or specific targeted delivery of drugs to the brain.
In this review we discuss some factors affecting nasal absorption, bio-availability barriers, and strategies to improve nasal absorption, new developments in nasal dosage form design and applications of nasal drug delivery system and the effects of microspheres, liposomes and other bioadhesive drug delivery systems on nasal drug absorption.
REFERENCE ID: PHARMATUTOR-ART-1278
Nasal drug delivery system which has been practiced for thousands of years, has been given a new ray of life. Nasal therapy, is one of the recognized form of treatment in the Ayurvedic systems of Indian medicine, it is also called “NASAYA KARMA” . It is a useful drug delivery method for drugs that are active in low doses and show less oral bioavailability such as proteins and peptides. One of the reasons for the low degree of absorption of peptides and proteins via the nasal route is rapid movement away from the absorption site in the nasal cavity due to the mucociliary clearance mechanism. The nasal route overcomes hepatic first pass metabolism associated with the oral delivery. During the past several decades, the availability of drug via the nasal route has received maximum attention from pharmaceutical scientists and clinicians. Drug candidates ranging from small to large molecules to macromolecular proteins have been tested in various animal subjects. It has been documented that nasal administration of certain hormones and steroids have resulted in a more complete absorption . This indicates the potential value of the nasal route for administration of systemic medications as well as utilizing this route for local effects. Nasal routesoffers lower doses, more rapid attainment of therapeutic blood levels, quicker onset of pharmacological activity fewer side effects, high total blood flow per cm3, porous endothelial membrane is easily accessible, and drug is delivered directly to the brain along the olfactory nerves [4-6].However the primary function of the nose is olfaction, it heats and humidifies inspired air and also filters airborne particulates. Consequently, the nose functions as a protective system against foreign material. There are three distinct functional zones in the nasal cavity, namely: vestibular, olfactory, and respiratory areas. The vestibular area serves as a baffle system; it functions as a filter of airborne particles.The olfactory epithelium is capable ofmetabolizing drugs. The respiratory mucosa is the region where drug absorption is optimal.To optimize nasal administration, bioadhesive hydrogels, bioadhesive microspheres (dextran, albumin and degradable starch) and liposomes have been studied.
FACTORS INFLUENCING NASAL DRUG ABSORPTION
There are various factors that affect the systemic bioavailability of drugs that are administered through the nasal route. The factors can be affecting to the physiochemical properties of the drugs, the anatomical and physiological properties of the nasal cavity and the type and characteristics of selected nasal drugs delivery system. These factors play key role for most of the drugs in order to reach therapeutically effective blood levels after nasal administration. The factors influencing nasal drug absorption are described as follows.
1) Physiochemical properties of drug.
* Lipophilic-hydrophilic balance.
* Enzymatic degradation in nasal cavity
* Molecular size.
2) Delivery Effect
* Delivery effects
* Formulation (Concentration, pH, osmolarity)
* Drugs distribution and deposition.
3) Nasal Effect
* Mucociliary clearance
* Cold, rhinitis.
* Membrane permeability.
* Environmental pH
1) Physiochemical properties of drug
The HLB nature of the drugs affects the absorption process. By increasing lipophilicity, the permeation of the compound normally increases through nasal mucosa. 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 membranes. Lipophilic drugs like naloxone, buprenorphine, testosterone and 17a-ethinyl- oestradiol are almost completely absorbed when administered intranasal route [11-12].
Enzymatic degradation in nasal cavity
Drugs like peptides and proteins are having low bio-availability across the nasal cavity, so these drugs may have possibility to undergo enzymatic degradation of the drug molecule in the lumen of the nasal cavity or during passage through the epithelial barrier. These both sites are having exo-peptidases and endo-peptidases, exo-peptidases are mono-aminopeptidases and di-aminopeptidases. These are having capability to cleave peptides at their N and C termini and endo-peptidases such as serine and cysteine, which can attack internal peptide bonds .
The molecular size of the drug influence absorption of the drug through the nasal route. The lipophilic drugs have direct relationship between the MW and drug permeation whereas water soluble compounds depict an inverse relationship. The rate of permeation is highly sensitive to molecular size for compounds with MW ≥ 300 Daltons .
2) Delivery effect factors
Factors that affect the delivery of drug across nasal mucosa such as surfactants, dose pH, osmolarity, viscosity, particle size and nasal clearance, drug structure can be used to advantage to improve absorption.
Formulation (Osmolarity, , pH, Concentration)
The osmolarity of the dosage form affects the nasal absorption of the drug; it was studied in the rats by using model drug. The sodium chloride concentration of the formulation affects the nasal absorption. The maximum absorption was achieved by 0.462 M sodium chloride concentration; the higher concentration not only causes increased bioavailability but also leads to the toxicity to the nasal epithelium .
The pH of the formulation and nasal surface, can affect a drug’s permeation. To avoid nasal irritation, the pH of the nasal formulation should be adjusted to 4.5–6.5 because lysozyme is found in nasal secretions, which is responsible for destroying certain bacteria at acidic pH. Under alkaline conditions, lysozyme is inactivated and the tissue is susceptible to microbial infection. In addition to avoiding irritation, it results in obtaining efficient drug permeation and prevents the growth of bacteria .
Concentration gradient plays very important role in the absorption / permeation process of drug through the nasal membrane due to nasal mucosal damage. Examples for this are nasal absorption of L-Tyrosine was shown to increase with drug concentration in nasal perfusion experiments. Another is absorption of salicylic acid was found to decline with concentration. This decline is likely due to nasal mucosa damage by the permanent .
Drugs distribution and deposition
The drug distribution in the nasal cavity is one of the important factors, which affect the efficiency of nasal absorption. The mode of drug administration could effect the distribution of drug in nasal cavity, which in turn will determine the absorption efficiency of a drug. The absorption and bioavailability of the nasal dosage forms mainly depends on the site of disposition. The anterior portion of the nose provides a prolonged nasal residential time for disposition of formulation, it enhances the absorption of the drug. And the posterior chamber of nasal cavity will use for the deposition of dosage form; it is eliminated by the mucociliary clearance process and hence shows low bioavailability . The site of disposition and distribution of the dosage forms are mainly depends on delivery device, mode of administration, physicochemical properties of drug molecule.
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.
3) Nasal effect factors
Particles entrapped in the mucus layer are transported with it thus, effectively cleared from the nasal cavity. The combined action of mucus layer and cilia is called mucociliary clearance. This is an important, nonspecific physiological defence mechanism of the respiratory tract to protect the body against noxious inhaled materials. The normal mucociliary transit time in humans has been reported to be 12 to 15 minutes[.The factors that affect mucocilliary clearance include physiological factors (age, sex, posture, sleep,exercise ,common environmental pollutants (sulphur dioxide and sulphuric acid, nitrogen dioxide, ozone, hairspray and tobacco smoke, diseases (immotile cilia syndrome, primary ciliary dyskinesia- Kartagener.s syndrome, asthma, bronchiectasis, chronic bronchitis, cystic fibrosis, acute respiratory tract infection and drugs and additives .
Rhinitis is a most frequently associated common disease, it influence the bioavailability of the drug. It is mainly classified into allergic rhinitis and common, the symptoms are hyper secretion, itching and sneezing mainly caused by the viruses, bacteria or irritants. Allergic rhinitis is the allergic airway disease, which affects 10% of population. It is caused by chronic or acute inflammation of the mucous membrane of the nose. These conditions affect the absorption of drug through the mucus membrane due the inflammation
Nasal membrane permeability is the most important factor, which affect the absorption of the drug through the nasal route. The water soluble drugs and particularly large molecular weight drugs like peptides and proteins are having the low membrane permeability. So the compounds like peptides and proteins are main-ly absorbed through the endocytotic transport process in low amounts . Water-soluble high molecular weight drugs cross the nasal mucosa mainly by passive diffusion through the aqueous pores (i.e. tight junctions).
The environmental pH plays an important role in the efficiency of nasal drug absorption. Small water-soluble compounds such as benzoic acid, salicylic acid, and alkaloid acid show that their nasal absorption in rat occurred to the greatest extent at those pH values where these compounds are in the nonionised form. However, at pH values where these compounds are partially ionized, substantial absorption was found. This means that the nonionised lipophilic form crosses the nasal epithelial barrier via transcellular route, whe-reas the more lipophilic ionized form passes through the aqueous paracellular route .
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