IC8 Intranasal Flashcards
Describe the nasal anatomy
- Two nostrils, separated by a septum
- Nasal vestibule (hair)
- Respiratory region (3 turbinates/chonchae - superior, middle, inferior)
- Olfactory region (located in the olfactory recess)
Describe the nasal physiology of the respiratory region
Respiratory region
- Superior, middle, and inferior turbinates
- Creates a vortex, cycles the air to bring it to a similar temp as body temp to prevent damage to cells as we breathe in
- Presence of cilia increases surface area
- Highly vascularized
- Access to CNS
Describe the access to CNS via respiratory region
- Transport into respiratory epithelium
- Access to CNS
Transport into respiratory epithelium:
- Paracellular transport (rapid, passive through gaps, <10um)
- Transcellular transport (slow, active)
Access to CNS:
- Trigeminal nerve in the respiratory epithelium
- Access to CNS not as efficient as there are many other blood vessels that the drug may interact with
Describe the nasal physiology of the olfactory region
Olfactory region
- Direct connection to CNS via olfactory neurons
- Highly vascularized (more so than respi region)
- Area: 15cm2 (10% of nasal surface area)
Describe the access to CNS via olfactory region
- Transport into olfactory epithelium
- Access to CNS
Transport into olfactory epithelium:
- Paracellular transport (rapid, passive through gaps)
- Transcellular transport (slow, active)
- Intraneuronal transport (fastest)
Access to CNS:
- Paracellular transport (high turnover of olfactory sensory neurons leave more gaps for drug transport into olfactory epithelium and CNS)
- Intraneuronal transport (drug shuttled along neuron -> axon, directly into olfactory bulb via the olfactory nerve)
Advantages of intranasal delivery
- Non-invasive
- Self-administered
- Bypass hepatic first-pass effect
- Short onset of effect
Physiological BARRIERS to intranasal delivery
M2E3HV
- Nasal epithelial layer
- Nasal mucus (~5um) - can hydrate nose, solubilize drug
- Metabolic enzymes
- Efflux pumps
- Hair
- Mucociliary clearance
- Volume (small vol of drug - only 10% of nasal surface area able to absorb into olfactory region)
Intranasal delivery is limited by:
- Concentration
- high conc can cause irritation to nasal mucosa, must be within certain pH and osmolality
- pH 4 - 7.4
- Tonicity 300-700 mOsm
- Volume
- small volume of drug, max 200uL
What makes an ideal drug candidate for intranasal delivery?
Lipinski’s (modified) rule of 5:
- =<5 H bond donors (acids)
- =<10 or less H bond acceptors (bases)
- <500Da (for N2B access - <300Da for hydrophilic drugs, <1000Da for lipophilic drugs)
- Log P <5 (more lipophilic, but cannot be too lipophilic)
- Unionized (cross lipid membrane)
Importance of a delivery system:
(Made up of excipients)
- Make drug physically manageable
- Improve drug solubility
- Improve drug absorption
- Protect drug candidate from degradation and excretion
- Improve drug retention
- Reduce side effects (though specific targeting)
- Increasing dosing (so as to dcr frequency)
- Reduce frequency of administration (improve compliance)
Common excipients used in nasal sprays include:
- Diluents
- Buffer salts (acid + base => absorb acid/base contaminants to maintain pH)
- Preservatives (multidose formulation)
- Stabilizer/cosolvent (enhance solubility, form micelles)
- Permeation enhancers (interfere w integrity of membrane)
- Viscosity modifiers (incr/dcr flow)
pH adjustment/buffers
- Acetic and citric acids
- Sodium hydroxide/hydrochloric acid
- Sodium borate/boric acid
- Sodium acetate, citrate, phosphates, potassium phosphate
Preservatives
- Edetate disodium (EDTA) - also a metal chelator
- Benzalkonium chloride
- Benzethonium chloride
- Benzyl alcohol
- Chlorhexidine
- Chlorobutanol
- Methylparaben
- Phenylethyl alcohol
- Propylparaben
Tonicity adjustment
(salts)
- Potassium chloride
- Sodium chloride
- Glycerin/glycerol
- Glycine
Viscosity adjustment
- Me-OH-Pr cellulose
- Na carboxymethylcellulose
- Microcrystalline cellulose (long polymer fibers)
Solvent
- Ethanol
- Glycerin/glycerol
- Glycine
- PEG (polyethylene glycol)
- Propylene glycol
- Glyceryl dioleate
Co-solvents are solvents/liquids that are miscible in water and also improve the solubility of poorly water soluble material (eg. ethanol), and these are generally incapable of forming micelles.
Surfactants (Stabilizers - able to form micelles)
- Glyceryl monoleate
- Lecithin
- Polysorbate 20 and 80
- Tyloxapol
- Polyethylene glycol PEG (polymer)
Stabilisers will form structures (ie. micelles) or will sit at the interface between two immiscible/insoluble components to increase the solubility of the poorly water-soluble material (eg. lecithin).
Flavoring agents
- Also explain why they might be needed?
- Menthol
- Saccharin sodium
- Sorbitol
Drug in nasal cavity can drip back down throat, into mouth
Packing and storage of intranasal drugs
- Container vessel material should not have chemical or physical interactions with the drug and its excipients
- Container vessel should protect the formulation from contamination and degradation
- Store in cool and low moisture environment, not in fridge/freezer
- If sensitive to light, use opaque/amber bottles, and store away from light
What dosage forms does Sumatriptan come in?
- Oral
- Subcutaneous injection
- Intranasal
Imitrex (Sumatriptan) - Migraine
Dosage and administration
Formulation comes in 5mg or 20mg unit dose nasal spray devices
- Recommended adult dose: 5mg, 10mg, 20mg (in 0.1ml)
- 5mg and 20mg given as single spray in 1 nostril
- 10mg given by administering single 5mg dose in each nostril (shown to be equivalent to single 10mg dose in 1 nostril)
If migraine not resolved in 2h or returns after transient improvement,
- 1 additional dose may be administered at least 2h after the first dose
- Max daily dose in 40mg in 24h period
Imitrex (Sumatriptan) - Migraine
Formulation-specific side effect
Local irritation
- burning, numbness, paresthesia (tingling sensation), nasal discharge, pain, soreness
- transient symptoms, generally resolved in less than 2h
Other common symptoms
- unusual/bad taste in the mouth
- N/V
- dizziness
Imitrex (Sumatriptan) - Migraine
Absorption of IN spray
- Cmax following 5mg and 20mg intranasal dose was 5 and 16ng/mL respectively
- Cmax (6mg S/C): 71ng/mL
- Cmax (oral 25mg, 100mg): 18ng/mL, 51ng/mL
Imitrex (Sumatriptan) - Migraine
Storage
- between 2 to 30 degree celsius
- store away from light
- do not test or prime before use
Imitrex (Sumatriptan) - Migraine
- pH
- Osmolality
pH 5.5
Osmolality of 5mg dose: 372 mOsmol
Osmolality of 20mg dose: 742 mOsmol
Why can the osmolality be >700 mOsmol?
- Drug is diluted by mucosa when administered (account for dilution)
- Creates concentration gradient for drug to be absorbed by olfactory epithelium
Imitrex (Sumatriptan) - Migraine
Explain the role of each excipient:
- Monobasic potassium phosphate NF
- Anhydrous dibasic sodium phosphate USP
- Sulfuric acid NF
- Hydroxide NF
- Purified water USP
Monobasic potassium phosphate NF + Anhydrous dibasic sodium phosphate USP
- pH buffers
- monobasic acids donate one H+ ion, while dibasic acids donate two H+ ions, therefore dibasic is more acidic
- monobasic = dihydrogen
Sulfuric acid NF + Hydroxide NF
- pH buffers
Purified water USP
- solvent
Imitrex (Sumatriptan) - Migraine
Does Sumatriptan exist as an ion at pH 5.5?
It is unionized at pH 5.5
- Tertiary amine (ionizable, pKa 4.9; hence at a pH of 5.5, it remains unionized as a base)
Therefore, aids its ability to cross the lipid membrane
Imitrex (Sumatriptan) - Migraine
- Molecular weight
- LogP
- H bond donors
- H bond acceptors
- Ionizable
- Molecular weight: 295.4g/mol
- LogP: 0.93
- H bond donors: 2
- H bond acceptors: 4
- Ionizable: Yes
Imitrex (Sumatriptan) - Migraine
PK
- What kind of drug transport?
Probably paracellular transport, as it is a small hydrophilic molecule
*Paracellular transport <10um (microns)
Imitrex (Sumatriptan) - Migraine
Delivery device components:
- Consist of a nozzle + plunger
- Single use, individually packed in a blister pack
- Specific metering and spray producing pump mechanism (push plunger to force solution/suspension through orifice in the nozzle)
- Nozzle bypasses nasal vestibule (hair), to access olfactory region
Imitrex (Sumatriptan) - Migraine
Considerations for delivery device to disperse droplets into respiratory and olfactory regions:
- Droplet size distribution
- Viscosity (more viscous, more force needed)
- Spray pattern
- Plume geometry (spray angle, plume width)
- Dose-volume
- Velocity (too fast, force may damage tissue)
Imitrex (Sumatriptan) - Migraine
Unique regulations for nasal spray:
- Pump delivery (durability of device for multidose preparations, reproducibility of pump spray weight)
- Spray content uniformity (amt of drug delivered per pump)
- Spray pattern and plume geometry
Imitrex (Sumatriptan) - Migraine
Delivery device - powder (breath-powered delivery device)
- Describe how this device works and its advantages
- Mouth nozzle to blow powder through another nozzle inserted in the nostril
- Blow through the mouth, which helps to avoid negative pressure, and traps powder in nasal cavity, resulting in less loss of drug
- However, may cause irritation
Nayzilam (Midazolam) - Seizures
Dosage and administration
Single dose nasal spray unit containing 5mg midazolam in 0.1ml solution, in individual blister pack
- Initial dose: 5mg into one nostril
- Second dose (if needed): 5mg into opposite nostril, after 10 minutes of first dose
*Do not administer second dose if pt has trouble breathing, or if there is excessive sedation
Max dose: two 5mg doses to treat a single episode
Recommended to treat no more than one episode every three days, and no more than 5 episodes per month
NOT recommended for chronic daily use
Nayzilam (Midazolam) - Seizures
Warning and precautions
- Risk from concomitant use with opioids (fatal additive effects)
- Profound sedation, respiratory depression, coma, death
- Risk of cardiorespiratory adverse reactions
- Respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest, cardiac arrest
- May result in death or permanent neurologic injury
- Rare reports of hypotensive episodes
- Pt with COPD are highly sensitive to the respiratory depressant effect of Midazolam
Nayzilam (Midazolam) - Seizures
Abuse and dependence
Midazolam is a controlled substance (schedule IV)
- Subject to abuse potential
- Physical dependence
- Withdrawal effects following abrupt discontinuation/rapid dose reduction: disturbed sleep, rebound anxiety, tremor, convulsions
Nayzilam (Midazolam) - Seizures
Storage
- Room temperature between 20-25 (15-30) degree celsius
- Do not test or prime before use
Nayzilam (Midazolam) - Seizures
- Molecular weight
- LogP
- H bond donors
- H bond acceptors
- Ionizable
- Molecular weight: 325.77 g/mol
- LogP: 3.97
- H bond donors: 0
- H bond acceptors: 3
- Ionizable: No (none of the lone pairs on N are available for protonation)
Nayzilam (Midazolam) - Seizures
Excipients:
- Ethanol
- PEG-6 methyl ether
- Polyethylene glycol 400
- Propylene glycol
- Purified water
Ethanol
- cosolvent
PEG-6 methyl ether
- stabilizer (polymers)
Polyethylene glycol 400
- stabilizer (polymers)
Propylene glycol
- cosolvent
Purified water
- solvent
(Notice how no buffering/pH adjusting agents are added since the molecule is unionizable)
How might pH of water change overtime?
Become acidic, due to CO2 diffusing into the water, becoming carbonic acid
[In situ gels]
Describe how they work?
Advantage:
Low viscosity solutions increase in viscosity once administered, and activated by stimulus such as concentration, pH, and temperature
Advantage: enhance retention time (delay mucociliary clearance, sustained drug release profile, enhance drug permeability)
[In situ gels]
Activated by temperature:
- Pluronic F127
- Carboxymethylcellulose
- Hydroxy methyl propyl cellulose (HPMC)
- Poloxamer
[In situ gels]
Activated by ion concentration:
- Gellan gum
[In situ gels]
Activated by pH
- Carbopol
- Cellulose acetate phthalate
What is the use of cyclodextrin excipient?
Inclusion complex - permeation enhancer
- Improves solubility and enhances bioavailability by encapsulating hydrophobic compounds
