IC9- Pharm Tech I Flashcards
Which part of the nose has direct connection to the CNS?
Describe its vascularisation and the surface area
The olfactory region.
Highly vascularized, SA ~15 cm^2
What are the various permeation routes from the nose to the brain? (3)
- Paracellular transport (in between cells)
- Intraneuronal transport
- Transcellular transport
Compare transcellular transport and paracellular transport
Transcellular transport:
- Slow (upwards of 13 hours)
- Through active mechanisms through the cell
Paracellular transport
- Rapid uptake
- Passive transport through gaps between cells
- High turnover of olfactory sensory neurons can leave more gaps to help facilitate more paracellular transport
Advantages of intranasal delivery route? (4)
- Non-invasive
- Can be self-administered
- Bypasses the hepatic first-pass effect
- Short onset of effect
What are the barriers to intranasal delivery? (7)
- Nasal epithelial layer
- Nasal mucus (~5 μm)
- Metabolic enzymes
- Efflux pumps
- Hair
- Mucociliary clearance
- Volume
State the Lipinski’s rule of 5 for ideal drug candidates
- ≤ 5 hydrogen bond donors
- ≤ 10 hydrogen bond acceptors
- < 500 Da (< 300 Da for nose to brain access of hydrophilic drugs; <1 kDa for nose to brain access of lipophilic drugs)
- Log P < 5
- Unionised
What happens if the drug candidate does not meet the Lipinski’s rule of 5?
Failure to do so may require help from a delivery system
What are the advantages of delivery systems? (8)
- Make the drug physically manageable
- Improve drug solubility
- Improve drug absorption
- Protect the drug candidate from degradation and excretion
- Improve drug retention
- Reduce side effects (through targeting)
- Increasing dosing
- Reduce frequency of administration (improves pt compliance)
What are the different types of delivery systems for intranasal delivery? (4)
- Solutions
- Suspensions
- Powders
- Gels
What are the 3 types of suspensions for intranasal delivery systems?
- Nano/microemulsions
- Liposomes and other lipid-based self-assembled structures
- Nanoparticles
What are the intranasal products available on the market? (3)
- Nasal sprays
- Nasal powders
- Nasal gels (in development for
Alzheimer’s, Parkinson’s and
schizophrenia)
Which nasal sprays are found in the market? (3)
And their indication?
- Imitrex/sumatriptan – migraine
- Nayzilam/midazolam – seizures
- Narcan/naloxone – opioid overdose
Which nasal powder is found in the market? (1)
And its indication?
Xsail/sumatriptan – migraine
What are the common excipients of nasal sprays? (6)
- Diluent
- Buffer salts
- Preservatives
- Stabiliser/co-solvent
- Permeation enhancers
- Viscosity modifiers
Characteristics of nasal cavity which may affect choice of excipients for intranasal delivery? (3)
- pH (pH 4 – 7.4)
- Tonicity (300 – 700 mOsm)
- Volume (max 200 μL)
With regards to packing and storage, what must the container vessel material containing the intranasal product fulfill? (2)
- Should not have chemical or physical interactions with drug and excipients
- Protects the formulation from contamination and degradation
Packaging and storage instructions for intranasal delivery?
Typically kept in cool and low moisture environments, and not in the fridge/freezer
MOA of Imitrex/sumatriptan?
Serotonin receptor agonist that induces inhibitory action in CNS to relieve migraines
What is the dosing for Imitrex/sumatriptan? Max dose?
1 spray per nostril, another spray may be used after at least 2 hours since the last spray if migraine not resolved
Max dose: do not use > 40mg of imitrex within a 24h period
How should Imitrex/sumatriptan be stored?
Away from light, between 2-30°C
Does Imitrex/sumatriptan MOSTLY follow the Lipinski’s rule of 5?
Which factor does not satisfy the rule? Is it still ok? Why?
Yes
Imitrex/sumatriptan is ionisable which does not follow the Lipinski’s rule of 5 of ‘unionisable’. But still okay as it has a buffering agent to control whether it’s ionised or unionised
What is the composition of Imitrex/sumatriptan? (5)
State the role of each excipient
- Monobasic potassium phosphate: pH adjustment
- Anhydrous dibasic sodium phosphate: buffer
- Sulfuric acid: pH adjustment
- Sodium hydroxide: pH adjustment
- Purified water: diluent
What is the pH and osmolality of Imitrex/sumatriptan?
- pH ~ 5.5
- Osmolality: 372 or 742 mOsmol for the 5-and 20-mg IMITREX nasal spray, respectively
What is the PK of Imitrex/sumatriptan?
- How is it transported from N2B?
- How much of its peak concentration is reached 30 mins after administration?
- Suspected (but unconfirmed) paracellular transport of the drug (route for small hydrophilic molecules)
- ~60% of peak concentration 30 mins
after administration (second peak after absorption from gut)
What are the requirements for a nasal spray as a delivery device? (3)
- Stability with the formulated product
- User-friendly design for patient compliance
- Reliability in use
What is the difference between singledose and multidose nasal sprays?
Single unit dose sprays do not require preservatives as no concern for microbial growth
In nasal sprays, which barrier in the nose does the nozzle bypass?
It bypasses the nasal vestibule (hair)
Describe how the droplets are dispersed in the nose via nasal sprays
Nasal sprays disperses droplets into respiratory and olfactory sections
What are the considerations for device design of nasal sprays? (6)
- Droplet size distribution
- Viscosity
- Spray pattern
- Plume geometry
- Dose volume
- Velocity
What are the unique regulations for nasal sprays? (3)
- Pump delivery
- Durability of device
- Reproducibility of pump spray weight - Spray Content Uniformity (SCU)
- Amount of drug delivered per pump - Spray pattern and plume geometry
Which 2 formulations is Imitrex/sumatriptan available in?
Nasal spray and nasal powder
Advantage (1) and disadvantage (1) of nasal powder?
Advantage: blowing through the mouth avoids negative pressure and “traps” powder in nasal cavity → less loss of drug
Disadvantage: may cause irritation
MOA of Nayzilam/midazolam?
(include drug class)
Benzodiazepine
Activation of GABA receptors → relaxes muscles, anti-anxiety, treatment of seizure
Dosing of Nayzilam/midazolam?
What is the max dose?
- 1 dose/spray with onset of symptoms
- Extra dose if symptoms persist after 10 mins (but NO MORE THAN 2 doses per episode)
- Max dose: treat no more than one episode every 3d; no more than 5 episodes per month
Storage of Nayzilam/midazolam?
Store at controlled room temp (20-25°C)
Does Nayzilam/midazolam follow the Lipinski’s rule of 5?
Yes
What is the composition of Nayzilam/midazolam? (5)
- Ethanol (co-solvent to enhance solubility)
- PEG-6 methyl ether
- Polyethylene glycol 400
- Propylene glycol
- Purified water
DDIs with Nayzilam/midazolam?
What may happen if there is concomitant use?
Concomitant use of Nayzilam/midazolam with opioids may result in profound sedation, respiratory depression, coma and death
ADEs of Nayzilam/midazolam?
*Cardiorespiratory ADEs (hypotension, respiratory depression)
What is something to note about the class of drugs benzodiazepines? (Nayzilam/midazolam)
Has abuse potential, pts may develop physical dependence to it (withdrawal symptoms)
How does the viscosity of in situ nasal gels work once they are administered?
How is this a benefit in terms of retention time?
Low viscosity solutions initially but increase in viscosity once administered
Can enhance retention
time in the nasal cavity
What factors cause nasal gels to increase in viscosity once administered?
Activated by stimulus such as changes in salt concentrations, pH, temperature etc
Are there any products of nasal gel on the market yet?
No
What are the benefits of nasal gel? (5)
- Higher drug absorption
- Increased bioavailability
- Higher contact with nasal mucosa
- Protection from enzymatic degradation
- Reduced mucociliary clearance (MCC)
What are the different types of stimuli for nasal gels?
- Physiological temp (viscosity increases when temp increases to body temp)
- Ionic (responsive to different salt conc)
- pH
Given that the stimuli of nasal gel paliperidone is pH, what is the function of the buffer components?
Buffer components help to maintain the gel at the correct pH to begin with, such that only when it is exposed to the correct pH in the envt then it can increase in viscosity
