intranasal delivery Flashcards
nasal anatomy and physiology
1) nasal vestibule contain hair
2) respiratory region
- 3 turbinate/conchae
** create vortex when air breathed in -> cycle air to bring it to body temperature
** superior, middle, inferior - paracellular or transcellular transport
3) olfactory region
- directly connected to CNS
- highly vascularised
- paracellular, transcellular, intraneural transport
modes of transport
1) paracellular
- passive through gaps between cell
- rapid but require small molecule ( < 2 microm)
2) transcellular
- active mechanism through cell
- slow process
3) intraneuronal transport
- shuttled along neurons
advantages of intranasal
1) non invasive
2) self-administered
3) bypass hepatic first pass
4) short onset of effect
disadvantages of intranasal
barrier to entry
1) nasal epithelial layer: need to diffuse through
2) nasal mucous
3) metabolic enzyme
4) efflux pump
5) hair
6) MCC
7) volume
- olfactory small volume
- irritation if concentration of drug too high
lipinski’s rule of 5
1) ≤ 5 H bond donor
2) ≤ 10 H bond acceptor
3) < 500 Da
- < 300 Da for N2B access for hydrophilic drugs
- < 1kDa for N2B access for lipophilic drugs
4) log P < 5
what to do if drug don’t meet requirement?
1) make drug physically capable
2) improve drug solubility, absorption, retention
3) protect drug candidate from degradation, excretion
4) reduce SE by specific targeting
5) increase dosing
6) reduce frequency of administration
conditions for ideal intranasal delivery
1) pH 4 - 7.4
2) tonicity 300 - 700 mOsm
3) max volume 200 microL
common excipients
1) pH adjustment: acetic acid, NaOH
2) buffer: sodium acetate, phosphates
3) metal chelator/preservative enhancer: edetate disodium
4) preservative
- effect on cilia: benzalkonium chloride, chlorobutanol, methylparaben
- benzyl alcohol, chlorhexidine
5) tonicity adjustment: NaCl, KCl
6) viscosity adjustment: Me-OH-Pr cellulose, Na CMC, MCC
7) solvent: ethanol, PEG, PG
8) solvent/tonicity adjustment: glycerine, glycerol, glycine
9) surfactant: glyceryl monoleate, polysorbate 20 or 80
10) flavouring agents
requirements for packaging and storage
1) container vessel material
- X chemical or physical interaction with drug and excipients
- protect formulation from contamination and degradation
2) cool, low moisture environment
3) X fridge or freezer
imitrex/sumatriptan - composition
1) buffer (conjugate acid base pair)
- monobasic potassium phosphate NF
- anhydrous dibasic sodium phosphate USP
2) pH adjuster
- sulfuric acid NF
- NaOH NF
3) diluent
- purified water USP
imitrex/sumatriptan - drug characteristic
1) pH 5.5
2) weight = 294.5 g/mol
3) LogP = 0.93
4) H bond donor = 2
5) H bond acceptor = 3
5) ionisable
imitrex/sumatriptan - PK
1) paracellular transport
2) 2 peak concentration
- 1st: drug directly through nose
- 2nd: drug absorbed from gut
types of delivery device used for imitrex/sumatriptan
1) nasal spray
- nozzle, plunger: single use
- nozzle bypass nasal vestibule = direct access to olfactory region
- disperse droplets into respiratory and olfactory sections
2) powder
- mouth nozzle to blow powder
- another nozzle inserted into nostril
- may cause irritation
- advantages of blowing through mouth
** avoid negative pressure
** trap powder in nasal cavity = lesser loss of drug
nayzilam/midazolam (benzodiazepine) - drug characteristics
1) molecular weight = 325.77 g/mol
2) LogP = 3.97
3) H bond donor = 0
4) H bond acceptor = 2
5) non-ionisable
nayzilam/midazolam (benzodiazepine) - composition
1) co-solvent: ethanol, propylene glycol
2) stabiliser: PEG-6 methyl ether, polyethylene glycol 400
3) diluent: purified water
- why don’t need buffering/pH adjustment agent?
** non-ionisable, single use
