IC9 Flashcards
description of olfactory region for drug delivery
highly vascularised - direct connetion to CNS
15cm2 (10% of nasal surface)
access to CNS via the respiratory and olfactory regions? methods of transport
paracellular (needs to be nano size)
- rapid
- passive transport through cell gaps
- high turnover of olfactory sensory neurons can leave more gaps.
- however has proteins in between them that prevent passive movement.
transcellular
- through active mechanisms through cell.
- slow (>13h)
intraneuronal
- interact w synapse surface and shuttered through nerves.
transcellular and intraneuronal are more active and require some form of trigger/interaction.
advantages of intranasal delivery
1) non invasive
2) can self administer
3) bypass hepatic first pass effect
4) short onset of effect
barriers to intranasal delivery
1) nasal epithelial layer
2) nasal mucus (appx 5um) = viscous and traps foreign matter
3) metabolic enzymes = remove foreign matter
4) efflux pumps
5) hair
6) mucociliary clearance (villi)
7) volume = disperses drug and prevent concentrating at area of absorption.
ideal drug candidate?
lipinski’s rule of 5
≤5 HBD
≤10 HBA
<500Da (<300 for hydrophilic, <1KDa for lipophilic)
logp <5
unionised
functions of drug delivery systems
1) make drug physically manageable
2) improve drug solubility
3) improve drug absorption
4) protect the drug candidate from degradation and excretion (eg macrophages)
5) improve drug retention
6) reduce side effects (through targeting)
7) increasing dosing
8) reduce freq of admin
types of intransal delivery systems (formulations)
solutions
suspensions: nano/microemulsions, liposome (surfactant bilayer) and other lipid-based self assembled structures (internal lattices), nanoparticles (drug attached to solid particles eg iron oxide, silicon, polymers).
powders
gels
considerations for nasal sprays (values)
pH 4 - 7.4 (far extremes may cause irritation)
tonicity (300-700 mOsm)
volume (max 200uL)
what are some common ph adjustment excipients in nasal sprays
acetic acid, citric acid
sodium hydroxide, hydrochloric acid
sodium borate, boric acid
in general any acids or bases
what are some common buffer excipients in nasal sprays
acetic acid, citric acid
sodium acetate/citrate/phosphate
potassium phosphate
what are some common metal chelator excipients in nasal sprays
edetate disodium (is also a preservatie enhancer)
what are some common preservative excipients in nasal sprays
benzalkonium chloride
benzethonium chloride
chlorhexidine (di)gluconate
chlorobutanol
methylparaben
propylparaben
phenyl ethyl alcohol
benzyl alcohol
what are some common tonicity adjuster excipients in nasal sprays
potassium chloride
sodium chloride
glycerin/glycerol/glycine (also act as solvent)
what are some viscosity adjuster excipients in nasal sprays
Me-OH-Pr cellulose
Na CMC
Microcrystalline cellulose
what are some solvent excipients in nasal sprays
Ethanol
Glycerin/glycerol/glycine (also act as tonicity adjustments)
PEG
PG
Glyceryl dioleate
what are some surfactant excipients in nasal sprays
Glyceryl monoleate
Lecithin
Polysorbate 20 AND 80
Tyloxapol
what are some flavoring agent excipients in nasal sprays
menthol
saccharin sodium (sweetener)
sorbitol (sweetener)
what excipient has a known effect on cillia?
BAC
chlorobutanol
methylparaben
propylparaben
packaging material for intransal delivery?
VESSEL MATERIAL
should be chemically and physically inert from drug and excipients eg drug should not absorb to the sides fo the storing vessel
(stable with formulated product)
should protect the drug from contamination and degradation
user-friendly design for patient compliance
reliability in use (e.g if 20 uses then there should be slightly more than 20 in dose)
storage for intransal delivery?
STORAGE
kept in cool, low moisture environments
DO NOT STORE IN FRIDGE OR FREEZER (this does not slow down degradation)
dosing and admin for imitrex
5, 10, 20mg in 0.1mL
1 or 2 sprays into one nostril
another spray used at least 2 hours after
max 40mg in 24 hours
PK of imitrex
suspected but unconfirmed paracellular transport of the drug due to the high donor and acceptor values AND low logP = small hydrophilic molecule
60% of peak conc at 30min after admin and second peak after absorption from gut
delivery design for imitrex (specific)
1) single-use and device individually packed in a blister pack =
- no preservatives
- MAINTAIN freshness
- no concern for microbial growth
2) nozzle and plunger design = nozzle bypasss nasal vestibule (hair) = hair prevents contact of drug
3) specific metering and spray producing pump mechanisms to spray a specific volume each time
considerations for nasal sprays
disperse droplets into respiratory and olfactory sections.
REPRODUCIBILITY
- droplet size distribution
- viscosity
- spray pattern
- plume geometry
- dose volume
- velocity
pump should be durable and reproduce same pump spray weight.
the spray content uniformity (SCU) should be the same, ie amount of drug delivered per pump is equal. spray pattern and plume geometry should be similar and reach target site in nose.
powder nasal sprays, how does it work?
for patients who are not well coordinated and cannot press and inhale sprays at the same time.
- has a mouth nozzle where patient blows powder through another nozzle inserted in the nostril.
- avoids negative pressure and traps powder in the nasal cavity
DISADVANTAGE = may cause irritation
dose and admin for nayzilam
1 dose with onset of symptoms
extra dose if persist after 10min
no more than 2 doses per episode
max dose: no more than once every 3 days and no more than 5 times per month
how do in-situ gels work
low viscosity solution but increase in viscosity once administered due to activation by stimulus (salt, pH, temp…)
- enhanced retention time?
- consider pH of nose (5.5-6.5)
