Pharm tech

intranasal delivery - nasal anatomy

Two nostrils, separated by a septum

Nasal vestibule (hairy)

Respiratory region

3 turbinates/conchae

Superior, middle, inferior

Olfactory region

Located in the olfactory recess

Direct connection to CNS

Highly vascularized

~15 cm2 (10% of nasal surface

Access to CNS via respiratory & olfactory regions:

Nose to brain access via various permeation routes

intranasal delivery - mode of transport

Transcellular transport

Through active mechanisms through the cell

Slow (upwards of 13 hours)

Paracellular transport

Rapid uptake

Passive transport through gaps between cells

High turnover of olfactory sensory neurons can leave more gaps

Intraneuronal transport

intranasal delivery - advantages

Non-invasive

Can be self-administered

Bypasses the hepatic first-pass effect

Short onset of effect

intranasal delivery - barriers

Nasal epithelial layer

Nasal mucus (~5 μm)

Metabolic enzymes

Efflux pumps

Hair

Mucociliary clearance

Volume

intranasal delivery - ideal drug candidates

intranasal delivery - types of delivery systems

intranasal delivery - Common excipients of nasal sprays

intranasal delivery - Packaging and storing

Container vessel material

Should not have chemical or physical interactions with drug and excipients

Protects the formulation from contamination and degradation

Typically kept in cool and low moisture environments, and not in the fridge/freezer

intranasal delivery - Imitrex/sumatriptan

IN Imitrex/sumatriptan - composition

IN Imitrex/sumatriptan - PK

Suspected (but unconfirmed) paracellular transport of the drug. Route for small hydrophilic molecules

60% of peak concentration 30 mins after administration

Second peak after absorption from gut

IN Imitrex/sumatriptan - delivery device (nasal spray)

IN Imitrex/sumatriptan - Unique regulations for nasal sprays

Pump delivery

Durability of device

Reproducibility of pump spray weight

Spray Content Uniformity (SCU)

Amount of drug delivered per pump

Spray pattern and plume geometry

IN Imitrex/sumatriptan - Delivery device (powder)

Mouth nozzle to blow powder through another nozzle inserted in the nostril

Blowing through the mouth avoids negative pressure and "traps" powder in nasal cavity

Less loss of drug

May cause irritation

intranasal delivery - Nayzilam/midazolam

IN Nayzilam/midazolam - midazolam

Molecular weight = 325.77 g/mol

LogP = 3.97

Hydrogen bond donors = 0

Hydrogen bond acceptors = 3

Ionisable: no

IN Nayzilam/midazolam - composition

Ethanol

PEG-6 methyl ether

Polyethylene glycol 400

Propylene glycol

Purified water

Why no buffers/pH adjusting agents?

intranasal delivery - in situ gels

Low viscosity solutions initially but increase in viscosity once administered

Activated by stimulus such as changes in salt concentrations, pH, temperature etc.

Can enhance retention time

No products on market yet

in situ gels - composition