NASAL DRUG DELIVERY SYSTEM: DESIGNING OF NASAL PRODUCT-POSSIBILITY & PROBLEM

Abstract:

NASAL DRUG DELIVERY SYSTEM: DESIGNING OF NASAL PRODUCT-POSSIBILITY & PROBLEM
Dharmendra singh*, Shrikant Nirwan
*Department of pharmaceutics (Assist. Professor ), Gyan Vihar School of Pharmacy,
Suresh Gyan Vihar University Jaipur.
ABSTRACT
In recent year, the nasal rout has been considered as an administration rout to have a faster & higher level of drug absorption. The richly supplied vascular nature of nasal mucosa coupled with its drug permeation make the nasal rout of administration attractive for many drug like ,peptides, protein, insulin, vaccines,etc. In order to formulate a nasal formulation with desirable performance and commercial attributes, the drug properties, delivery system and nasal physiology should all be considered and understood from the early stage of a product development. In nasal drug delivery Physicochemical properties of drugs affecting the drug absorption, The selection of delivery system such as Nasal emulsion & ointments; Nasal drops; Nasal spray; Nasal gel; Micro sphere technology depends upon the drug being used, proposed indication, marketing preferences.

Notes:

NASAL DRUG DELIVERY SYSTEM: DESIGNING OF NASAL PRODUCT-POSSIBILITY & PROBLEM
Dharmendra singh*, Shrikant Nirwan
*Department of pharmaceutics (Assist. Professor ), Gyan Vihar School of Pharmacy,
Suresh Gyan Vihar University Jaipur.
ABSTRACT
In recent year, the nasal rout has been considered as an administration rout to have a faster & higher level of drug absorption. The richly supplied vascular nature of nasal mucosa coupled with its drug permeation make the nasal rout of administration attractive for many drug like ,peptides, protein, insulin, vaccines,etc. In order to formulate a nasal formulation with desirable performance and commercial attributes, the drug properties, delivery system and nasal physiology should all be considered and understood from the early stage of a product development. In nasal drug delivery Physicochemical properties of drugs affecting the drug absorption, The selection of delivery system such as Nasal emulsion & ointments; Nasal drops; Nasal spray; Nasal gel; Micro sphere technology depends upon the drug being used, proposed indication, marketing preferences.

1. INTRODUCTION:

ANATOMY AND PHYSIOLOGY OF NOSE:
ANATOMY
The most efficient area for drug absorption is the highly vascularized lateral wall of the nasal cavity: the mucosa lined over the turbinate or conchae: 1.superior turbinate 2.middle turbinate 3.inferior turbinate.
PHYSIOLOGY OF NOSE:
1. Effect of deposition on absorption:
• anterior portion of nose → longer residence time → low permeability
• posterior portion of nose → shorter residence time → greater permeability
2. Effect of mucociliary clearance:
• It is important that the 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 secretory transport in the nose to constantly remove particles that are trapped on the mucus blanket using inhalation
3. Effect of enzymatic activity:
• Several enzymes that are present in the nasal mucosa might affect the stability of drug. For example, proteins and peptides are subjected to degradation by proteases and amino-peptidase at the mucosal membrane.
ADVANTAGES OF NASAL ROUTE:
 Non-invasive
 Rapid onset of action
 Avoidance of first-pass metabolism
 Potential for direct delivery to brain
 Ability to deliver large molecules such as peptides, protein& nucleic acid.
LIMITATION OF NASAL ROUTE:
 Design of inhaler device
 sterility & stability
 toxicology & reproducible of delivery

2. MECHANISM OF DRUG ABSORPTION:
I. It involves aqueous route of transport; also known as paracellular process → slow&passive → inverse relation between intranasal absorption &the molecular weight of water soluble compounds →poor bioavailability with MW1000 Da
II. It involves lipoidal route of transport: also known as transcellular process → depend upon lipophilicity of drug → transported through passive diffusion or active transport via carrier-mediated route or through opening of tight junction.
III. It involves tight junctions function → polar drug are transported → through epithelium via the gaps or pores between cells.
IV. It involves direct transport across the olfactory region, (situated at the left of the nasal cavity) →direct membrane between nose & brain.
3. FACTORS AFFECTING DRUG ABSORPTION:
Physicochemical properties of drugs:
1. Chemical form: the chemical form of a drug can be important in determining absorption. For example, conversion of the drug into a salt or ester form can alter its absorption. The effect of structural modification of drug on absorption. It was observed that in-situ nasal absorption of carboxylic acid ester of L-Tyrosin was significantly greater than that of L-Tyrosin.
2. Polymorphism: polymorphism is known to affect the dissolution rate and solubility of drug and thus their absorption through biological membranes. It is therefore advisable to study the polymorphic stability and purity of drug for nasal powder and /or suspensions.
3. Molecular weight: a linear inverse correlation has been reported between the absorption of drug and molecular weight up to 300 Daltons. Absorption decreases significantly if molecular weight is greater than 1000 Daltons except with the use of absorption enhancers.
4. Particle size: it has been reported that particle sizes greater than 10 µmare deposited in the nasal cavity. Particles that are 2 to 10 µm can be retained in the lungs and particles of less than 1µm are exhaled.
5. Solubility & dissolution rate: drug solubility and dissolution rates are important factor in determining nasal absorption from powders and suspensions. The particles deposited in the nasal cavity need to be dissolved prior to absorption. If a drug remains as particles or is cleared away, no absorption occurs.
Pathological condition:
 Intranasal pathologies such as allergic rhinitis, infections, 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 clearance is reduced in insulin –dependent diabetes.
 Nasal pathology can also alter mucosal pH and mucosal pH and thus affect absorption of drug.
4. FORMULATION:
pH the pH of a nasal formulation for the following reasons:
• To avoid irritation of nasal mucosa
• To allow the drug to be available in unionized form for absorption
• To prevent growth of pathogenic bacteria in the nasal passage
• To sustain normal physiological ciliary movement.
Lysozyme is found in nasal secretion, which is responsible for destroying certain bacteria at acidic pH . Under alkaline condition, lysozyme is inactivated and the nasal tissue is susceptible to microbial infection. It is therefore advisable to keep the formulation at a pH of 4.5 to 6.5 keeping in mind the physicochemical properties of the drug as drugs are absorbed in un-ionized form.
Buffer capacity: Nasal formulations are generally administered in small volume ranging from 25 to 200 µl with 100 µl being the most common dose volume. Hence, nasal secretion may alter the pH of administrated dose. This can affect the concentration of un-ionized drug available for absorption.
Osmolarity: drug absorption can be affected by tonicity of the formulation. Shrinkage of epithelial cell has been observed in the presence of hypertonic solutions. Hypertonic saline solutions also inhibit or cease ciliary activity. Low pH has a similar effect as that of a hypertonic solution.
Gelling/viscosifying agent or gel-forming carriers: increasing solution viscosity may provide a means of prolonging the therapeutic effect of nasal preparations. A drug carrier such as hydroxylpropyl cellulose was effective for improving the absorption of low molecular weight drug but did not produce the same effect of high molecular weight drug but did not produce the same effect for high molecular weight peptides. Use of a combination of carriers is often recommended from a safety point of view.
Solubilizers’: aqueous solubility of drug is always a limitation for nasal drug delivery in solution.conventiional solvent and co solvents such as glycols, small quantities of alcohol, transcutol, medium chain glyerides and labrasol can be used to enhance the solubility of drug. Other option includes the use of surfactants or cyclodextrins such as HP-ß-Cyclodextrin that serve as a biocompatible solubilizer and stabilizer in combination with lipophilic absorption enhancers.
Preservatives: most nasal formulations are aqueous based and need preservative to prevent microbial growth. Parabens, benzalkonium chloride, phenyl ethyl alcohol, EDTA and bezoyl alcohol are some of the commonly used preservatives in nasal formulations. Mercury-containing preservative have a fast and irreversible effect on ciliary movement and should not be used in nasal system.
Antioxidants: a small quantity of antioxidants may required to prevent drug oxidation. Commonly used antioxidants are sodium metabisulfite; sodiumbisulfite, butylated hydroxytoluene and tocopherol.usually antioxidants donot affect drug absorption or cause nasal irritation.
Humectants: many allergic and chronic diseases are often connected with crusts and drying of mucous membrane. Certain Preservatives /antioxidants among other excipients are also likely to cause nasal irritation especially when used in higher quantities. Adequate intranasal moisture is essential for preventing dehydration.therfore; Humectants can be added especially in gel –based nasal products. Humectants avoid nasal irritation and are not likely to affect drug absorption. Common examples include glycerin, sorbitol and mannitol.
Role of absorption enhancers: when it becomes difficult for a nasal product to achieve its required absorption profile, the use of absorption enhancers is recommended. They are act by one of the following mechanism:
a) Inhibit enzyme activity
b) Reduce mucus activity or elasticity
c) Decrease mucociliary clearance
d) Open tight junctions: and
e) Solubilize or stabilize the drug
They are generally of two types:
1. Physical enhancer’s → affect nasal clearance reversibly by forming a gel → continue until the gel is swallowed.
2. Chemical enhancer’s → act by destructing the nasal mucosa very often in an irreversible way → e.g. chelating agents, fatty acid, bile acid salts, surfactants, etc.
5. VARIOUS DRUG DELIVERYS:
The selection of delivery system depends upon the drug being used, proposed indication, marketing preferences. Some of these delivery system and their important features are summarized below:
Nasal emulsion & ointments: nasal emulsion and ointments have not been studied in detail as other nasal delivery system. They offer advantages for local application mainly due to their viscosity. One of the major disadvantages is poor patient acceptability.
Nasal drops: nasal drops are one of the most simple and convenient system developed for nasal delivery. The main disadvantage of this system is lack of 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 sprays.
Nasal spray: both solution and suspension formulation can be formulated into nasal sprays. Due to the availability of meter dose pumps and actuators, a nasal sprays can deliver an exact dose from 25 to 200 µ. The particle size and morphology (suspension) of the drug and viscosity of the formulation determine the choice of pump and actuator assembly.
Nasal gel: nasal gels are high viscosity thickened solutions or suspensions. The advantages of a nasal gel include 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. A vitamin B12 gel has been recently developed as a prescription product.
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 oftheformulation.however, the solubility of the powder formulation is dependent on the solubility, particle size and nasal irritancy of the active drug and/or excipients.
Specialized delivery system: microsphere technology is one of the specialized systems becoming popular for designing nasal products.microsphere may provide more prolonged contact with the nasal mucosa and thus enhance absorption. Microspheres for nasal applications have been prepared using biocompatible materials such as starch, albumin, dextran and gelatin. It was hypothesized that in the presence of starch microspheres, the nasal mucosa is dehydrated due to moisture uptake by the microspheres, this results in reversible “shrinkage” of cells, providing a temporary physical separation of the tight (intracellular) junctions that increases the absorption of drugs.
6. APPLICATIONS OF NASAL ROUTE:
1. Nasal delivery of vaccines: it produces not only systemic immune response but also local immune response in nasal lining, providing additional barrier of protection. Delivering the vaccine to the nasal cavity itself stimulates the production of local secretory IgA antibodies as well as IgG, providing an additional first line of defense. The main problem is that drugs in particular proteins&peptides are poorly absorbed across the nasal mucosa, with less than 1% of the doses enter the bloodstream. The delivery with chitosan, a nasal vaccine produces the same level of IgG as an injection together with high level of IgA.It also stimulate an antibody production directly: nasal vaccination also elicit the more powerful cell mediated immune response in which cytokines stimulate killer cell activity & production of antibodies at cell level.Eg. US FDA has granted marketing approval for Flumist TM for active immunization for prevention of disease caused by Influenza A&B viruses. It is a live attenuated influenza virus vaccine & contains recombinant cold adopted strain of Influenza A&B.
7. NOSE TO BRAIN DELIVERY
 It is well known that the euphorics derived from the sniffing of cocaine in conscious subject occurs rapidly, with in 3 to 5 min.
 It has been suggested that, the rapid nasal absorption isdueto the presence of a direct pathway from the nasal cavity to the CNS.
M/A
 Drugs have been shown to reach CNS from the nasal cavity by directly transport across the olfactory region situated at the left of nasal cavity.
 There is a transcellular route through the cells swell as paracellular route between the cells, as is the case of normal epithelium.
 The intracellular axonal pathway is a slow pathway that can take hours to deliver drug to the CNS, whereas the two other pathways are fast & enable drug transport.
1. Eg. (3H)-Dopamine reached the olfactory lobe after nasal administration & that at 4 hour after administration the concentration in the tissue after nasal administration was 27 times higher than after IV injection.

8. INTRANASAL DELIVERY OF PEPTIDES & PROTEINS
PROBLEMS OF PEPTIDES &PROTEINS AS DRUGS:
1. Not readily absorbed by GIT, due to the presence of photolytic enzyme & the low permeability of the gut membrane to such generally hydrophilic high molecule weight compounds.
2. Often prescribed for chronic & life long disease. But due to its extensive first pass elimination & short biological half-life, the parental rout has limited stability.
3. A single, peptide hasn’t just one activity, but affects several biological functions. After parenteral or oral administration they are distributed via the circulation & thereafter can interact simultaneously with receptor in the different body compartments.

FEATURES OF NASAL ROUT OF ADMINISTRATION
1. The sinuses of the nasal cavity increase surface area, which is further increased by microvilli in the mucous membrane.
2. The subepitheliallayers of the mucous is highly vascularised with large & fenestrated capillaries facilitating rapid absorption with low metabolism of drug through the vascular wall.
3. The drug passes directly in the systemic circulation & portal circulation is avoided thus first-pass effect is eliminated.
4. Although, absorption efficiency by nasal route is lower than IV route for peptides: the absorption is reproducible.
LIMITATIONSOF NASAL ROUTE FOR PEPTIDE DELIVERY:
1. Low bioavailability
2. unreliable dosing
3. It is not suitable for long term treatment as it may cause pathogenic change of the mucosa.
4. Adjuvant in the preparation might interfere with the ciliary’s activity of the membrane, causes irritation &local toxicity.
5. Unwanted immunogenic effects might arise with this route.

9. SUMMARY & CONCLUSION
In order to formulate a nasal formulation with desirable performance and commercial attributes, the drug properties, delivery system and nasal physiology should all be considered and understood from the early stage of a product development. It is advisable to focus on maximizing the residence time and ensuring an efficient absorption of drug. A successful nasal formulation program involves detailed consideration of the interactions between formulation composition, device design delivery system and the patients pathological condition.
10. REFERENCES:
1. www.drugdeliverytech.com/cgi-bin
2. Transdermal delivery of peptides: through the eastern pharmacist: July ’93, p.no 47.
3. www.nastech.com/nastech/junctions-biology
4. www.nastech.com/nastech/nasal
5. nasal drug absorption: through Indian drug: june’96,33(6) p.no243
6. Encyclopedia of pharmaceutical technology: second edition, volume I: p.no. 854