IC9

Question 1

description of olfactory region for drug delivery

Answer 1

highly vascularised - direct connetion to CNS
15cm2 (10% of nasal surface)

Question 2

access to CNS via the respiratory and olfactory regions? methods of transport

Answer 2

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.

Question 3

advantages of intranasal delivery

Answer 3

1) non invasive
2) can self administer
3) bypass hepatic first pass effect
4) short onset of effect

Question 4

barriers to intranasal delivery

Answer 4

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.

Question 5

ideal drug candidate?

Answer 5

lipinski’s rule of 5
≤5 HBD
≤10 HBA
<500Da (<300 for hydrophilic, <1KDa for lipophilic)
logp <5
unionised

Question 6

functions of drug delivery systems

Answer 6

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

Question 7

types of intransal delivery systems (formulations)

Answer 7

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

Question 8

considerations for nasal sprays (values)

Answer 8

pH 4 - 7.4 (far extremes may cause irritation)

tonicity (300-700 mOsm)

volume (max 200uL)

Question 9

what are some common ph adjustment excipients in nasal sprays

Answer 9

acetic acid, citric acid
sodium hydroxide, hydrochloric acid
sodium borate, boric acid

in general any acids or bases

Question 10

what are some common buffer excipients in nasal sprays

Answer 10

acetic acid, citric acid
sodium acetate/citrate/phosphate
potassium phosphate

Question 11

what are some common metal chelator excipients in nasal sprays

Answer 11

edetate disodium (is also a preservatie enhancer)

Question 12

what are some common preservative excipients in nasal sprays

Answer 12

benzalkonium chloride
benzethonium chloride

chlorhexidine (di)gluconate
chlorobutanol

methylparaben
propylparaben

phenyl ethyl alcohol
benzyl alcohol

Question 13

what are some common tonicity adjuster excipients in nasal sprays

Answer 13

potassium chloride
sodium chloride

glycerin/glycerol/glycine (also act as solvent)

Question 14

what are some viscosity adjuster excipients in nasal sprays

Answer 14

Me-OH-Pr cellulose
Na CMC
Microcrystalline cellulose

Question 15

what are some solvent excipients in nasal sprays

Answer 15

Ethanol
Glycerin/glycerol/glycine (also act as tonicity adjustments)
PEG
PG
Glyceryl dioleate

Question 16

what are some surfactant excipients in nasal sprays

Answer 16

Glyceryl monoleate
Lecithin
Polysorbate 20 AND 80
Tyloxapol

Question 17

what are some flavoring agent excipients in nasal sprays

Answer 17

menthol
saccharin sodium (sweetener)
sorbitol (sweetener)

Question 18

what excipient has a known effect on cillia?

Answer 18

BAC
chlorobutanol
methylparaben
propylparaben

Question 19

packaging material for intransal delivery?

Answer 19

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)

Question 20

storage for intransal delivery?

Answer 20

STORAGE

kept in cool, low moisture environments
DO NOT STORE IN FRIDGE OR FREEZER (this does not slow down degradation)

Question 21

dosing and admin for imitrex

Answer 21

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

Question 22

PK of imitrex

Answer 22

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

Question 23

delivery design for imitrex (specific)

Answer 23

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

Question 24

considerations for nasal sprays

Answer 24

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.

Question 25

powder nasal sprays, how does it work?

Answer 25

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

Question 26

dose and admin for nayzilam

Answer 26

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

Question 27

how do in-situ gels work

Answer 27

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)