9. Formulations Flashcards
where are the drugs absorbed in the nose
olfactory region (connected to CNS, highly vascularised, 15 cm2 surface area)
3 types of intranasal transport
- Paracellular transport (passive)
- Transcellular transport (active)
- Intraneuronal transport (active)
describe paracellular transport
(passive): rapid uptake, passive transport through gaps between cells
how does high turnover of olfactory sensory neurons affect paracellular transport
high turnover of olfactory sensory neurons can leave more gaps → increase paracellular transport
describe transcellular transport
(active): slow process
describe intraneuronal transport
(active) - interact with surface of synapses
advantages of intranasal delivery (4)
- non-invasive
- self-administered
- bypass hepatic first-pass effect
- short onset of effect (short distance btw nose and brain)
barriers to intranasal delivery (7)
- Nasal epithelial layer - drug need to penetrate the epithelial layer
- Nasal mucus - trap the drug
- Metabolic enzymes - can breakdown drug
- Efflux pump - decrease drug absorption
- Hair - trap drugs
- Mucociliary CL - sweep drug out of nose
- Volume - dilute the concentration of drug at site of absorption (olfactory region)
Characteristics of an ideal drug candidate for CNS drug delivery
Lipinski’s rule of 5
- ≤ 5 hydrogen bond donor
- ≤ 10 hydrogen bond acceptor
- < 500Da
- < 300Da for N2B access of hydrophilic drugs
- < 1kDa for N2B access of lipophilic drugs
- Log P < 5 (higher log P more lipophilic)
- Unionised
size of hydrophilic drug for N2B access
< 300Da
size of lipophilic drug for N2B access
< 1kDa
how can delivery systems help to deliver drug to CNS
- make drug physically manageable - API too small in quantity (make into tablets/ liquids)
- improve drug solubility
- improve drug absorption/ permeation
- protect drug from degradation (by macrophages) and excretion (decrease renal excretion of larger drugs)
- improve drug retention (drug stay longer in the body = increase opportunity to interact with target)
- reduce off target SE through targeting
- increase dosing (can add more drugs in)
- reduce frequency of administration → increase compliance
CNS drug formulations
- solutions
- suspensions (nano/microemulsions, liposomes /lipid bilayers, nanoparticles)
- powders
- gels (more viscous can last longer in the nose)
excipients
are ingredients aside from API, pharmacologically inert
diluent eg
water
buffer salts eg
(weak acid/base to maintain pH) - acetic and citric acids, acetate, phosphate
pH adjuster eg
(strong acid/base) - NaOH, HCl
preservatives eg
benzalknoium chloride, benzyl alcohol, chlorhexidine, chlorobutanol, parabens, phenylethyl alcohol
tonicity adjusters eg
(salts) - KCl, NaCl
stabilisers/ co-solvent (increase solubility of drug in diluent)
ethanol, ether, glycol, glycerol, glycine, PEG, glyceryl dioleate
surfactant eg
glyceryl monoleate, lecithin, polysorbate, tyloxapol
permeation enhancers function
increase absorption of drug
viscosity modifiers eg
microcrystalline cellulose
flavouring agents eg
menthol, saccharin sodium, sorbitol
considerations for intranasal formulation
- pH 4-7.4
- tonicity 300-700 mOsm
- volume 200uL max
packaging and storage
- container material should not have chemical or physical interactions with drugs and excipients
- protect formulation from contamination and degradation
- store in cool and low moisture environment, not in fridge/ freezer
excipients in sumatriptan nasal spray:
- monobasic potassium phosphate
- anhydrous dibasic sodium phosphate
- sulfuric acid and NaOH (strong acid and base)
- purified water
- monobasic potassium phosphate: buffer salts (since drug is ionisable, need to have buffering agent to control pH)
- anhydrous dibasic sodium phosphate: buffer salts
- sulfuric acid and NaOH (strong acid and base): pH adjusters
- purified water: diluent
why are there no tonicity adjusters in sumatriptan nasal spray formulation?
drug is providing the osmolarity hence there is no tonicity adjusters
requirements for nasal spray
- formulation must be stable with nasal spray
- user friendly
- reliability in use (mechanism cannot fail)
advantages of nasal spray
- single use → no need preservatives
- nozzle bypass nasal vestibule (hair) → less drugs trapped by hair
considerations for nasal spray
spray content uniformity (amt of drug delivered per pump), spray pattern and plume geometry
nasal powder device (blow from mouth, powder enters nose) advantages & disadvantages
- blowing avoids negative pressure and traps powder in nasal cavity → less drug lost
- may cause irritation
midazolam MOA
activation of GABA receptors
SE of midazolam
can cause dependence (do not use more than max dose)
excipients:
- ethanol
- PEG
- propylene glycol
- purified water
- ethanol, PEG, propylene glycol → cosolvent (midazolam poorly soluble in water need cosolvent to increase solubility)
- purified water → diluent
in situ gels
Low viscosity solutions but increase in viscosity once administered → enhance retention time
- activated by salt conc., pH, temperature
