formulation Flashcards

1
Q

intranasal anatomy

A

2 nostrils separated by septum

nasal vestibule (hairy)

respiratory region
olfactory region

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2
Q

nasal vestibule

A

exposed to external environment, hair to keep out large particles

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3
Q

respiratory region

A

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
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4
Q

OLFACTORY REGION

A
  • 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
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5
Q

Transcellular

A

active mechanism (absorb through cell) push it out other side, shuttle

Slow, ~13hrs

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6
Q

Paracellular transport

A

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

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7
Q

ADV of intranasal

A

Non-invasive
Can self-admin
Bypass hepatic 1st pass effect
Short onset of effect, faster

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8
Q

criteria for nasal spray

A
  • 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)
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9
Q

7 Barriers intranasal CNS drug delivery — protective mechanism of nose

MuPHCEEV

A
  • 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
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10
Q

Lipinski’s rule of 5: Characteristics of an ideal drug candidate for CNS drug delivery

for solubility & permeability

A

< 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)

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11
Q

other characteristics

A

○ pH 4-7.4
○ Tonicity 300-700 mOsmol
○ Volume (max 200uL)
- Metered dosing is an impt function of device

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12
Q

osmolality

A

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)

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13
Q

Rationalise strategies of drug delivery systems in targeting CNS disorders and conditions

A

○ 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

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14
Q

types of delivery system

A

drug carriers in susp
- nanoparticles
- liposomes
- polymer based, excipients
- nano/ microemulsions

powders, gels (in situ)

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15
Q

list of excipients

A

diluent
Buffer salts/ pH adjustment
Preservatives
chelators
solvent
Stabiliser/ co-solvent/ surfactant
Permeation enhancer
Viscosity modifiers
Tonicity adj
flavouring

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16
Q

diluent

A

add bulk
eg water

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17
Q

buffer salts, pH adjustment

A

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

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18
Q

acidic drug

A
  • Ionised when pH > pKa (they lose a proton and become negatively charged)
  • Unionised when pH < pKa (possess a proton and are neutral)
19
Q

basic drug

A
  • Ionised when pH < pKa (they gain a proton and become positively charged)
  • Unionised when pH > pKa (have a neutral charge)
20
Q

preservatives

A

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

21
Q

chelators

A

Remove microbes and ions, prevent them from interacting with proteins and cellular macromolecules

Edetate disodium (EDTA) 0.01%

22
Q

solvent

A

No replace water

Ethanol, Glycine
Glycerin/ glycerol

PEG <5%
PG <10%
Glyceryl dioleate <10%

23
Q

Stabiliser/ surfactant

A

Enhance solubility of poorly soluble API, incr HLB (hydrophilic, lipophilic balance)
- form micelles

Glyceryl monoleate (<7%)
Lecithin <5%
Polysorbate 20 & 80 <2%
Tyloxapol (-)

24
Q

co-solvent

A

Lq miscible water and also improve the solubility of poorly water soluble material (eg. ethanol)

but not form micelles

25
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
26
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
27
tonicity adj
Maintain conc gradient to force API across mem eg: KCl, NaCl (0.5-0.9%) 300-700mosmol
28
flavouring
Pleasant taste as solution can drip back of throat into mouth eg: Menthol Saccharin sodium Sorbitol (<10%)
29
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
30
eg of intranasal sprays for migraine
Imitrex/ sumatriptan (nasal spray) NOT IN SG Xsail/ sumatriptan (nasal powder) NOT in SG
31
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
32
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
33
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
34
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
35
lack of preservatives in sumatriptan IN
single use, device indiv packed in blister pack
36
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)
37
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)
38
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
39
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
40
in situ gels
Low viscosity sol --> incr viscosity once administered (shear rate) - Enhance retention time - activated by stimulus (pH, ion, conc, temp)
41
temp activation
carboxymethylcellulose pluronic F127 poloxamer 407 poloxamer 188 poloxamer 127
42
ionic activation
chitosan (cationic grps, cause repulsion, extension of polymer chains = VISCOUS) gellan gum (high Na conc)
43
pH activation
carbopol 934 (pH > 5) cellulose acetate phthalate (pH > 7.4) carbomer