Nasal Drug Delivery

A - Ciliated columnar cells covered by cilia and microvilli of uniform length;
B - basal cells;
C - goblet cells packed with mucus granules;
D - non-ciliated columnar cells, covered by microvilli of uniform length

Particles >10 mm filtered out the vibrisae in nostrils;
Smaller particles (5-10 mm) deposit in nasal passages and are cleared by the mucociliary clearance process
Particles <2 mm not filtered out and may enter lungs.

Dust + microorganisms are get entrapped within viscoelastic mucus blanket lining nasal passages;
Mucus then propelled by claw-like tips of cilia, beats in coordinated manner within periciliary fluid, towards nasopharynx where mucus is swallowed or expectorated.

Entraps substances entering nasal cavity + participates particulate removal via mucociliary clearance.
The mucus capacity to hold water permits humidification of inspired air +aids heat transfer;
Mucus presents diffusion barrier to drug adsorption.

Nasal mucosa - only location in body that provides direct connection between the CNS + atmosphere.

Advantages:
Large SA (160 cm2) for drug absorption;
Highly vascularised nasal mucosa surface > rapid absorption + onset of action;
Low metabolic activity
Good accessibility Ease of administration
Some cases - drugs can be absorbed directly into CNS after nasal administration bypassing tight BBB.
Disadvantages
Mucociliary clearance
Mucus barrier
Metabolic activity
Limited to potent molecules
Lack of reproducibility (common diseases alter noses conditions)
Adverse reactions (mucosal membranes can be sensitive to irritation)

MW of drug molecules
pH of dosage form
Concentration
Particle size
Tonicity of dosage form
Viscosity

Molecules with MW <1000 Da - good systemic bioavailability, no need in penetration enhancers;
Penetration enhancers increase this MW limit to ~ 6000 Da.
>6000 Da - unlikely large molecules can be absorbed without causing damage to nasal cavity;
Drug absorption after nasal administration higher than after oral delivery.

Mucus layer is slightly acidic (pH 5.5 - 6.5)
Drugs Absorption increased as become less ionised;
Cationic drugs in ionised form - retained through binding to -vely charged mucus glycoproteins - may reduce absorption.
pH effect on absorption of peptides - more complex than on conventional drugs.

Drugs absorption across nasal mucosa - via passive diffusion (paracellular or transcellular);
Absorption rate affected by drug conc in solution at absorbing membrane;
If drug formulated as solution - highest conc possible should be chosen that is compatible with an accurate and reproducible dosing volume;
Care must be taken, as high local drug concs over extended periods of time may cause severe irritation or adverse tissue reactions.

Disperse a drug solution throughout length of nasal cavity from atrium to nasopharynx, offering large area for immediate absorption;

Deposits at front of nasal cavity with little of dose reaching turbinates.
~ 40 % of administered dose - cleared rapidly within 20 minutes, 2nd slower phase of clearance follows (drops clearance - much faster than clearance of spray), as most of spray deposits on non-ciliated regions.

Nasal drops more suitable for rapidly absorbed drugs - faster clearance.
Drugs which diffuse across nasal epithelium slowly need longer contact time + may be better administered as sprays.

Enhance nasal absorbance
Improve nasal residence time
Modify drug structure to change physicochemical properties

Alteration of mucus layer -
Agents that decrease viscoelasticity of mucus (anionic and cationic surfactants)
Alteration of tight junctions -
Substances that sequester extracellular Ca ions- needed to maintain tight junction integrity, can cause them to open (EDTA, bile salts)
Reversed micelle formation
Extraction by co-micellisation
Solubilisation of cell membrane lipids, e.g. removal of cholesterol
Erosion of mucosal surface

Used to solubilise drugs, thus increase the drug conc of drug driving diffusion at the absorption site

Water-soluble polymers (methylcellulose, sodium carboxymethylcellulose, chitosan, Carbopol 934P) decreases mucociliary clearance rate, due to their high viscosity in solutions;
Chitosan - enhances nasal absorption of insulin.

Dry powders of microcrystalline cellulose, starch, dextran, chitosan, carbomer containing drugs - absorb water on contact with nasal mucosa + swell to form viscous gels. Can remain in nasal cavity for as long as 6 hours.

Novel multiuser intranasal Drug Delivery device for liquid + powder formulations;
Nasal administration to reach CNS, systemic + topical nasal formulations + vaccines.

Antimicrobial preservatives (e.g. benzalkonium chloride)
Antioxidants (e.g. butylated hydroxytoluene);
Solubilising agents or cosolvents (e.g. glycol derivatives);
Salts for adjusting pH and tonicity;
Humectants, to minimise irritation to the nose (e.g. glycerol);
Viscosity-increasing agents (e.g. methylcellulose)
Absorption enhancers