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3153 Patho+Anat > IC8 Intranasal > Flashcards

IC8 Intranasal Flashcards

1
Q

Describe the nasal anatomy

A
  • Two nostrils, separated by a septum
  • Nasal vestibule (hair)
  • Respiratory region (3 turbinates/chonchae - superior, middle, inferior)
  • Olfactory region (located in the olfactory recess)
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2
Q

Describe the nasal physiology of the respiratory region

A

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
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3
Q

Describe the access to CNS via respiratory region

  • Transport into respiratory epithelium
  • Access to CNS
A

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
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4
Q

Describe the nasal physiology of the olfactory region

A

Olfactory region

  • Direct connection to CNS via olfactory neurons
  • Highly vascularized (more so than respi region)
  • Area: 15cm2 (10% of nasal surface area)
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5
Q

Describe the access to CNS via olfactory region

  • Transport into olfactory epithelium
  • Access to CNS
A

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)
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6
Q

Advantages of intranasal delivery

A
  • Non-invasive
  • Self-administered
  • Bypass hepatic first-pass effect
  • Short onset of effect
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7
Q

Physiological BARRIERS to intranasal delivery
M2E3HV

A
  • 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)
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8
Q

Intranasal delivery is limited by:

A
  1. Concentration
  • high conc can cause irritation to nasal mucosa, must be within certain pH and osmolality
  • pH 4 - 7.4
  • Tonicity 300-700 mOsm
  1. Volume
  • small volume of drug, max 200uL
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9
Q

What makes an ideal drug candidate for intranasal delivery?

A

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)
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10
Q

Importance of a delivery system:

A

(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)
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11
Q

Common excipients used in nasal sprays include:

A
  • 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)
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12
Q

pH adjustment/buffers

A
  • Acetic and citric acids
  • Sodium hydroxide/hydrochloric acid
  • Sodium borate/boric acid
  • Sodium acetate, citrate, phosphates, potassium phosphate
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13
Q

Preservatives

A
  • Edetate disodium (EDTA) - also a metal chelator
  • Benzalkonium chloride
  • Benzethonium chloride
  • Benzyl alcohol
  • Chlorhexidine
  • Chlorobutanol
  • Methylparaben
  • Phenylethyl alcohol
  • Propylparaben
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14
Q

Tonicity adjustment

A

(salts)

  • Potassium chloride
  • Sodium chloride
  • Glycerin/glycerol
  • Glycine
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15
Q

Viscosity adjustment

A
  • Me-OH-Pr cellulose
  • Na carboxymethylcellulose
  • Microcrystalline cellulose (long polymer fibers)
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16
Q

Solvent

A
  • 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.

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17
Q

Surfactants (Stabilizers - able to form micelles)

A
  • 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).

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18
Q

Flavoring agents

  • Also explain why they might be needed?
A
  • Menthol
  • Saccharin sodium
  • Sorbitol

Drug in nasal cavity can drip back down throat, into mouth

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19
Q

Packing and storage of intranasal drugs

A
  • 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
20
Q

What dosage forms does Sumatriptan come in?

A
  • Oral
  • Subcutaneous injection
  • Intranasal
21
Q

Imitrex (Sumatriptan) - Migraine

Dosage and administration

A

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
22
Q

Imitrex (Sumatriptan) - Migraine

Formulation-specific side effect

A

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
23
Q

Imitrex (Sumatriptan) - Migraine

Absorption of IN spray

A
  • 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
24
Q

Imitrex (Sumatriptan) - Migraine

Storage

A
  • between 2 to 30 degree celsius
  • store away from light
  • do not test or prime before use
25
Q

Imitrex (Sumatriptan) - Migraine

  • pH
  • Osmolality
A

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
26
Q

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
A

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
27
Q

Imitrex (Sumatriptan) - Migraine

Does Sumatriptan exist as an ion at pH 5.5?

A

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

28
Q

Imitrex (Sumatriptan) - Migraine

  • Molecular weight
  • LogP
  • H bond donors
  • H bond acceptors
  • Ionizable
A
  • Molecular weight: 295.4g/mol
  • LogP: 0.93
  • H bond donors: 2
  • H bond acceptors: 4
  • Ionizable: Yes
29
Q

Imitrex (Sumatriptan) - Migraine

PK

  • What kind of drug transport?
A

Probably paracellular transport, as it is a small hydrophilic molecule

*Paracellular transport <10um (microns)

30
Q

Imitrex (Sumatriptan) - Migraine

Delivery device components:

A
  • 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
31
Q

Imitrex (Sumatriptan) - Migraine

Considerations for delivery device to disperse droplets into respiratory and olfactory regions:

A
  • 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)
32
Q

Imitrex (Sumatriptan) - Migraine

Unique regulations for nasal spray:

A
  • 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
33
Q

Imitrex (Sumatriptan) - Migraine

Delivery device - powder (breath-powered delivery device)

  • Describe how this device works and its advantages
A
  • 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
34
Q

Nayzilam (Midazolam) - Seizures

Dosage and administration

A

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

35
Q

Nayzilam (Midazolam) - Seizures

Warning and precautions

A
  1. Risk from concomitant use with opioids (fatal additive effects)
  • Profound sedation, respiratory depression, coma, death
  1. 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
36
Q

Nayzilam (Midazolam) - Seizures

Abuse and dependence

A

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
37
Q

Nayzilam (Midazolam) - Seizures

Storage

A
  • Room temperature between 20-25 (15-30) degree celsius
  • Do not test or prime before use
38
Q

Nayzilam (Midazolam) - Seizures

  • Molecular weight
  • LogP
  • H bond donors
  • H bond acceptors
  • Ionizable
A
  • 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)
39
Q

Nayzilam (Midazolam) - Seizures

Excipients:

  • Ethanol
  • PEG-6 methyl ether
  • Polyethylene glycol 400
  • Propylene glycol
  • Purified water
A

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)

40
Q

How might pH of water change overtime?

A

Become acidic, due to CO2 diffusing into the water, becoming carbonic acid

41
Q

[In situ gels]

Describe how they work?

Advantage:

A

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)

42
Q

[In situ gels]

Activated by temperature:

A
  • Pluronic F127
  • Carboxymethylcellulose
  • Hydroxy methyl propyl cellulose (HPMC)
  • Poloxamer
43
Q

[In situ gels]

Activated by ion concentration:

A
  • Gellan gum
44
Q

[In situ gels]

Activated by pH

A
  • Carbopol
  • Cellulose acetate phthalate
45
Q

What is the use of cyclodextrin excipient?

A

Inclusion complex - permeation enhancer

  • Improves solubility and enhances bioavailability by encapsulating hydrophobic compounds

3153 Patho+Anat (10 decks)

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