9. Formulations

Question 1

where are the drugs absorbed in the nose

Answer 1

olfactory region (connected to CNS, highly vascularised, 15 cm2 surface area)

Question 2

3 types of intranasal transport

Answer 2

• Paracellular transport (passive)
• Transcellular transport (active)
• Intraneuronal transport (active)

Question 3

describe paracellular transport

Answer 3

(passive): rapid uptake, passive transport through gaps between cells

Question 4

how does high turnover of olfactory sensory neurons affect paracellular transport

Answer 4

high turnover of olfactory sensory neurons can leave more gaps → increase paracellular transport

Question 5

describe transcellular transport

Answer 5

(active): slow process

Question 6

describe intraneuronal transport

Answer 6

(active) - interact with surface of synapses

Question 7

advantages of intranasal delivery (4)

Answer 7

• non-invasive
• self-administered
• bypass hepatic first-pass effect
• short onset of effect (short distance btw nose and brain)

Question 8

barriers to intranasal delivery (7)

Answer 8

• 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)

Question 9

Characteristics of an ideal drug candidate for CNS drug delivery

Answer 9

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

Question 10

size of hydrophilic drug for N2B access

Answer 10

< 300Da

Question 11

size of lipophilic drug for N2B access

Answer 11

< 1kDa

Question 12

how can delivery systems help to deliver drug to CNS

Answer 12

• 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

Question 13

CNS drug formulations

Answer 13

• solutions
• suspensions (nano/microemulsions, liposomes /lipid bilayers, nanoparticles)
• powders
• gels (more viscous can last longer in the nose)

Question 14

excipients

Answer 14

are ingredients aside from API, pharmacologically inert

Question 15

diluent eg

Answer 15

water

Question 16

buffer salts eg

Answer 16

(weak acid/base to maintain pH) - acetic and citric acids, acetate, phosphate

Question 17

pH adjuster eg

Answer 17

(strong acid/base) - NaOH, HCl

Question 18

preservatives eg

Answer 18

benzalknoium chloride, benzyl alcohol, chlorhexidine, chlorobutanol, parabens, phenylethyl alcohol

Question 19

tonicity adjusters eg

Answer 19

(salts) - KCl, NaCl

Question 20

stabilisers/ co-solvent (increase solubility of drug in diluent)

Answer 20

ethanol, ether, glycol, glycerol, glycine, PEG, glyceryl dioleate

Question 21

surfactant eg

Answer 21

glyceryl monoleate, lecithin, polysorbate, tyloxapol

Question 22

permeation enhancers function

Answer 22

increase absorption of drug

Question 23

viscosity modifiers eg

Answer 23

microcrystalline cellulose

Question 24

flavouring agents eg

Answer 24

menthol, saccharin sodium, sorbitol

Question 25

considerations for intranasal formulation

Answer 25

- pH 4-7.4 - tonicity 300-700 mOsm - volume 200uL max

Question 26

packaging and storage

Answer 26

- 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

Question 27

excipients in sumatriptan nasal spray: - monobasic potassium phosphate - anhydrous dibasic sodium phosphate - sulfuric acid and NaOH (strong acid and base) - purified water

Answer 27

- 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

Question 28

why are there no tonicity adjusters in sumatriptan nasal spray formulation?

Answer 28

drug is providing the osmolarity hence there is no tonicity adjusters

Question 29

requirements for nasal spray

Answer 29

- formulation must be stable with nasal spray - user friendly - reliability in use (mechanism cannot fail)

Question 30

advantages of nasal spray

Answer 30

- single use → no need preservatives - nozzle bypass nasal vestibule (hair) → less drugs trapped by hair

Question 31

considerations for nasal spray

Answer 31

spray content uniformity (amt of drug delivered per pump), spray pattern and plume geometry

Question 32

nasal powder device (blow from mouth, powder enters nose) advantages & disadvantages

Answer 32

- blowing avoids negative pressure and traps powder in nasal cavity → less drug lost - may cause irritation

Question 33

midazolam MOA

Answer 33

activation of GABA receptors

Question 34

SE of midazolam

Answer 34

can cause dependence (do not use more than max dose)

Question 35

excipients: - ethanol - PEG - propylene glycol - purified water

Answer 35

- ethanol, PEG, propylene glycol → cosolvent (midazolam poorly soluble in water need cosolvent to increase solubility) - purified water → diluent

Question 36

in situ gels

Answer 36

Low viscosity solutions but increase in viscosity once administered → enhance retention time - activated by salt conc., pH, temperature