formulation Flashcards
intranasal anatomy
2 nostrils separated by septum
nasal vestibule (hairy)
respiratory region
olfactory region
nasal vestibule
exposed to external environment, hair to keep out large particles
respiratory region
3 turbinates/ conchae (Superior, middle, inferior)
- Creates a vortex to regulate air temperature to body temp, prevent damage to lungs
- Access to CNS:
□ Ciliated columnar epithelial cells
□ Drug dissolve in mucous layer —> paracellular/ transcellular/ intraneuronal
OLFACTORY REGION
- In olfactory recess, uppermost area. Target for direct nose-brain delivery
- Direct connection to CNS
- Highly vascularised. ~15cm2 (makes up 10% of nasal SA)
- Access to CNS:
1) Transcellular
2) Paracellular
3) Intraneuronal, shuttle through neurons, not as common
Transcellular
active mechanism (absorb through cell) push it out other side, shuttle
Slow, ~13hrs
Paracellular transport
a) in interstitial space, tight junction between cells. Small molecules
b) Rapid uptake
c) High turnover of olfactory sensory neurons, leave large gaps for bigger molecules
ADV of intranasal
Non-invasive
Can self-admin
Bypass hepatic 1st pass effect
Short onset of effect, faster
criteria for nasal spray
- stability with formulated pdt
- user friendly design for pt compliance
(access olfactory region, bypass vestibular (hair) no need adjust etc) - reliability (reproducible same dose)
(specific metering, spray-producing pump mechanism, spray content uniformity, spray pattern & plume geometry)
7 Barriers intranasal CNS drug delivery — protective mechanism of nose
MuPHCEEV
- Nasal epithelial layer
- Nasal mucus (~5um)
□ Viscous layer, incr hydration in nose - Metabolic enzymes
□ Not as extensive as rest of body - Efflux pumps
- Hair
□ When mole size too large, irritate nose hair = SNEEZE - Mucociliary clearance
□ Push down into GIT, 10-15mins CL - Volume
□ Olfactory region is only 10% SA, 15cm2 limited drug conc, vol
Lipinski’s rule of 5: Characteristics of an ideal drug candidate for CNS drug delivery
for solubility & permeability
< 500 Da (<300Da for hydrophilic, <1kDa for lipo)
log P <5
unionised
=/< 5 H bond donors (H linked to e/w grp)
=/< 10 H bond acceptors (e/w)
other characteristics
○ pH 4-7.4
○ Tonicity 300-700 mOsmol
○ Volume (max 200uL)
- Metered dosing is an impt function of device
osmolality
higher osmolarity facilitates conc gradient
high conc of mucus layer where drug deposited —> area of low conc (epithelial, semi permeable mem in cerebral space)
** better to have higher osmolarity in formulation, as dilution in IN cavity. range of (300-700 mOsmol)
Rationalise strategies of drug delivery systems in targeting CNS disorders and conditions
○ Make the drug physically manageable
○ Improve drug solubility
○ Improve drug absorption, permeability
○ Protect drug candidate from degradation and excretion
○ Improve drug retention
- Prevent mucociliary action, incr duration of action
○ Reduce SE (through targeting)
- Prevent interaction with receptors in other organs
○ Incr dosing
- Reduce freq of admin – improve pt compliance
types of delivery system
drug carriers in susp
- nanoparticles
- liposomes
- polymer based, excipients
- nano/ microemulsions
powders, gels (in situ)
list of excipients
diluent
Buffer salts/ pH adjustment
Preservatives
chelators
solvent
Stabiliser/ co-solvent/ surfactant
Permeation enhancer
Viscosity modifiers
Tonicity adj
flavouring
diluent
add bulk
eg water
buffer salts, pH adjustment
Maintain pH, Integrity, stability by conjugate acid-base pair
added H+ – removed by CB
added OH- – removed by CA
eg:
acetic, citric, hcl acids (0.12/ 0.10%)
NaOH, sodium borate, sodium acetate, citrate, phosphates
acidic drug
- Ionised when pH > pKa (they lose a proton and become negatively charged)
- Unionised when pH < pKa (possess a proton and are neutral)
basic drug
- Ionised when pH < pKa (they gain a proton and become positively charged)
- Unionised when pH > pKa (have a neutral charge)
preservatives
Safety, microbial growth
- esp for multidose formulation
eg: BZC 0.01-0.02% w/v
benzyl alcohol, chlorhexidine, phenylethyl alcohol
affect cilia: chlorobutanol, methylparaben, propylparaben
chelators
Remove microbes and ions, prevent them from interacting with proteins and cellular macromolecules
Edetate disodium (EDTA) 0.01%
solvent
No replace water
Ethanol, Glycine
Glycerin/ glycerol
PEG <5%
PG <10%
Glyceryl dioleate <10%
Stabiliser/ surfactant
Enhance solubility of poorly soluble API, incr HLB (hydrophilic, lipophilic balance)
- form micelles
Glyceryl monoleate (<7%)
Lecithin <5%
Polysorbate 20 & 80 <2%
Tyloxapol (-)
co-solvent
Lq miscible water and also improve the solubility of poorly water soluble material (eg. ethanol)
but not form micelles
Permeation enhancer (FYI)
Make cell mem more permeable, incr junction
eg: saponins, Laureth-9 (surfactant); fusidic acid derivatives, trihydroxy salts (bile salts); oleic acid, caprylate, laurate (fatty acid); EDTA, salicylic acid (chelators); phospholipids
Viscosity modifiers
More viscous than mucus to incr retention - long polymer, fibers to entangle into mucus
eg: <1%
Me-OH-Pr cellulose
Na CMC (heat)
Microcrystalline cellulose
tonicity adj
Maintain conc gradient to force API across mem
eg: KCl, NaCl (0.5-0.9%)
300-700mosmol
flavouring
Pleasant taste as solution can drip back of throat into mouth
eg:
Menthol
Saccharin sodium
Sorbitol (<10%)
packaging of intranasal spray
- Container vessel material
- Not have chemical or physical interaction with drug and excipients
- Protect formulation from contamination and degradation
- Kept in cool and low moisture environments, not in fridge/ freezer
eg of intranasal sprays for migraine
Imitrex/ sumatriptan (nasal spray) NOT IN SG
Xsail/ sumatriptan (nasal powder) NOT in SG
sumatriptan dosing
5/10/20 mg in 0.1mL
1/2 sprays into 1 nostril, 1 spray per nostril
2hrs between each spray
Max: 40mg in 24hr
avail: tablet, sc inj, IN
composition of sumatriptan IN
2 diff acid-base conjugate as sumatriptan consists of 3*N likely to ionise.
excipients to increase permeability, maintain unionised form
1) Monobasic potassium phosphate NF
1) Anhydrous dibasic sodium phosphate USP
2) Sulfuric acid
2) NaOH
3) Purified water - diluent
formulation property linking to the API
pH 5.5
Osmolality 372 - 742 mOsmol for 5mg/ 20mg
- >700mOsmol but will be more diluted in mucosal layer of nose
API: is ionisable, has bond acceptor
PK of sumatriptan
Absorption: paracellular
* Small hydrophilic molecules
* Peak conc 60% at 30mins after admin
2nd peak from GIT absorption
* Drip back into mouth, GIT
lack of preservatives in sumatriptan IN
single use, device indiv packed in blister pack
delivery design considerations for
disperse droplets into resp & olfactory sections
DPGVVV
1) droplet size distribution
2) viscosity (affects force of spray)
3) spray pattern (how droplet deposited on nasal surface)
4) plume geometry (how droplet deposited on nasal surface)
5) dose vol (how much can region hold)
6) velocity (damage nasal tissues)
nasal powder (sumatriptan)
1) mouth nozzle, nasal nozzle
2) blow through mouth nozzle, push powder into nose
- avoid neg P, trap powder in nasal cavity (not breathing out)
- CAUSE IRRITATION (sneeze, lost of drug)
nayzilam/ midazolam
benzodiazepine dose (for seizure, muscle relaxant, ANX)
1 dose/ spray with ONSET of sx
- extra dose if sx persists after 10mins
- no more than 2 dose/ episode
Max dose: no more every 3 days & < 5/mnth
formulation in midazolam — link to API
- Ethanol (co-solvent)
- Propylene glycol (co-solvent)
- Purified water (diluent)
- PEG-6 methyl ether (stabiliser)
- Polyethylene glycol 400 (stabiliser)
No buffer as no ionizable grp
Single use as expose to air, CO2 –> acidic
in situ gels
Low viscosity sol –> incr viscosity once administered (shear rate)
- Enhance retention time
- activated by stimulus (pH, ion, conc, temp)
temp activation
carboxymethylcellulose
pluronic F127
poloxamer 407
poloxamer 188
poloxamer 127
ionic activation
chitosan (cationic grps, cause repulsion, extension of polymer chains = VISCOUS)
gellan gum (high Na conc)
pH activation
carbopol 934 (pH > 5)
cellulose acetate phthalate (pH > 7.4)
carbomer
