ic8 - pharmacy technology

Question 1

what is the nostril separated by

Answer 1

septum

Question 2

what are the three main regions of the nasal cavity

Answer 2

nasal vestibule, respiratory region and olfactory region

[nasal vestibule] hairy, first contact with external environment thus hair helps to keep out large particulates

[respiratory region] has three turbinates (superior, middle, inferior) which creates a vortex when you breathe in air

[olfactory region] located in olfactory recess (upper most area) which has direct connection to CNS via olfactory neurons, region is highly vascularised despite small surface area of approx 15cm2 (approx 10% of nasal surface area)

Question 3

what kind of cells does the olfactory epithelium comprise of and what is its function

Answer 3

olfactory epithelium lined with epithelial and mucosal cells where drugs and small molecules will solubilise into then interact with receptors

Question 4

what kind of cells does the respiratory epithelium comprise of and what is its function

Answer 4

respiratory epithelium lined with ciliated columnar cells that have a large surface area to enhance drug delivery once it solubilises in mucus layer, it can then interact with the cells via various transports to be shuttered across to interact with blood vessels and the trigeminal nerve which is another direct route to the brain

Question 5

what kind of permeation routes allows for access to CNS from olfactory and respiratory regions

Answer 5

transcellular transport, paracellular transport and intraneuronal transport

[transcellular] through active mechanisms through the cells, slow (approx 13h)

[paracellular] rapid uptake, passive transport through gaps between cells, high turnover (always being recycled) of olfactory sensory neurons that can leave more gaps

[intraneuronal] shuttering across neurons

Question 6

what is the property of olfactory neurons that helps with paracellular transport

Answer 6

high turnover rate of olfactory neurons which can leave more gaps between cells to help facilitate paracellular transport

Question 7

what are the advantages of intranasal delivery

Answer 7

non invasive, can be self administered, bypasses hepatic first pass effect (where there is metabolic enzymes that breaks down certain drugs thus decr effective conc of drug and decr therapeutic outcome), shorter onset of effect due to close proximity to CNS (which is our target site of action)

Question 8

what are the inherent barriers to intranasal delivery

Answer 8

nasal epithelial layer, nasal mucus of approx 5microm, metabolic enzymes, efflux pumps, hair, volume

[nasal epithelial layer] layer of cells the drugs have to diffuse through to get access to the brain

[nasal mucus] viscous aq layer, drug movement here is slow, drugs are often water based

[metabolic enzymes] present in mucus layer (though not extensive) and will breakdown substances

[efflux pumps] present in mucus layer which ejects certain foreign material

[hair] drug has to be delivered past hair else it causes irritation and risk being sneezed out which results in loss of product and thus decr therapeutic effect

[volume] small volume, esp olfactory region, have to balance conc and vol bc risk of irritation

Question 9

what rule determines the characteristics of an ideal drug candidate and what are the components of this rule

Answer 9

lipinski’s rule of 5

5 or less H bond donors
10 or less H bond acceptors
<500Da (<300Da for N2B access of hydrophilic drugs, <1kDa for N2B access of lipophilic drugs)
LogP <5
unionised

Question 10

what are the functions of a delivery system

Answer 10

1. make the drug physically manageable
2. improve drug solubility
3. improve drug absorption
4. protect drug from degradation and excretion
5. improve drug retention
6. reduce s/e (through targeting)
7. incr dosing
8. reduce freq of administration which can improve pt compliance

Question 11

what are the types of delivery systems

Answer 11

solutions, suspensions, powders, gels

Question 12

what is an added advantage of using a gel delivery system

Answer 12

gels have higher viscosity and contains water which can be hydrating, apart from enhancing solubility and delivery of drugs

Question 13

what are some types of suspensions that can be used as delivery systems

Answer 13

nano/micro emulsions, liposomes, nanoparticles, other lipid based self assembled structures

Question 14

what are “excipients”

Answer 14

ingredients aside from active ingredients

are pharmacologically inert

have different functions

Question 15

what must be done when including excipients into delivery systems

Answer 15

important to test compatibility of excipients with active ingredients

Question 16

list examples of some nasal sprays, nasal powders and nasal gels currently on the market

Answer 16

nasal sprays: sumatriptan (imitrex) for migraine, midazolam (nayzilam) for seizures, naloxone (narcan) for opioid overdose

nasal powders: sumatriptan (xsail) for migraine

nasal gels: in development

Question 17

what are some common excipients of nasal sprays and list some examples for each type of excipients

Answer 17

diluent, buffer salts, preservatives, stabiliser/ co-solvent, permeation enhancers, viscosity modifiers

Question 18

what might a viscosity modifier do for a drug

Answer 18

increase viscosity of drug formulation such that it can retain on epithelial layer and be less affected by flowing mucus thus providing enough time for drug to diffuse across the membrane

Question 19

what are the considerations for excipients (pH, tonicity, volume, container, storage)

Answer 19

pH 4-7.4
tonicity 300-700mOsm
volume max 200microL

container vessel material should not have chemical or physical interactions with drugs and excipients, protects the formulation from contamination and degradation

store in cool, low moisture environment, but not in fridge or freezer

opaque

Question 20

what are in situ gels and list some common polymers that would be used to formulate in situ gels

Answer 20

in situ gels are gels with low viscosity solution initially but viscosity increases once administered due to activation by stimulus

stimulus can be salt conc, pH, temp etc
(eg. low viscosity at pH4 but when pH5 incr by 3x)

common polymers used are carbopol 934, hydroxymethyl cellulose K4M, buffer components (triethanolamine, potassium dihydrogen orthophosphate, NaOH), hydroxypropyl-beta-cyclodextrin, paliperidone, pluronic F127, chitosan

Question 21

what is the benefit of in situ gels

Answer 21

it allows for longer retention on epithelium which helps increase absorption

Question 22

what is the moa of sumatriptan and its indication

Answer 22

serotonin receptor agonist, induces inhibitory action in CNS to relief migraine

indicated for migraine

Question 23

what is the dosing for imitrex

Answer 23

imitrex is sumatriptan

dosed at 5/10/20mg in 0.1mL, one to two sprays into one nostril (max 40mg in 24h)

another spray may be used after at least 2h since last spray

Question 24

what is the composition and role of each ingredient in imitrex

Answer 24

imitrex is sumatriptan

monobasic potassium phosphate NF – a conjugate acid base pair to serve as buffer

anhydrous dibasic sodium phosphate USP – conjugate acid base pair to serve as buffer

sulfuric acid NF – buffer

NaOH – buffer

purified water USP – diluent to bulk up formulation

note no preservatives bc single use

Question 25

what is the pH and tonicity of imitrex

Answer 25

imitrex is sumatriptan

pH 5.5
tonicity is 372mOsm for 5mg and 742mOsm for 20mg

Question 26

does the drug in imitrex fit the ideal characteristics based on the rule

Answer 26

imitrex is sumpatriptan

based on lipinski’s rule of 5

MW is 285.4
LogP is 0.93
2 H bond donors
3 H bond acceptors
has an ionisable amine group (thus need buffer to maintain pH)

Question 27

what are the PK characteristics of imitrex

Answer 27

imitrex is sumatriptan

suspected paracellular transport (bc drug is small and hydrophilic)

two peaks (60% of peak conc after 30mins of administration, second peak due to gut absorption)

Question 28

what are the requirements, considerations for device design and regulations for a nasal spray

Answer 28

[requirements] stability with formulated product, user friendly design for patient compliance, reliability in its use

[considerations] droplet size distribution (shape and diameter of nozzle), viscosity (affect how it ejects from nozzle, if more viscous need more force), spray pattern, plume geometry, dose volume, velocity (if too fast, force of spray hitting nasal tissue can cause damage)

[regulations] pump delivery (durability of device and reproducibility of pump spray weight), spray content uniformity (amount of drug delivered per pump), spray pattern and plume geometry (from top down view, will affect how droplets deposit on nasal surface area)

Question 29

what are the key features of the imitrex nasal spray

Answer 29

imitrex is sumatriptan

1. consists of a nozzle and a plunger
2. single use (comes in blister pack)
3. elongated nozzle bypasses nasal vestibule and allows direct and deeper access into nasal cavity to access olfactory region
4. specific metering and spray producing pump mechanisms (complete push of plunger required to force solution or suspension through orifice in the nozzle)
5. disperses droplets into respiratory and olfactory sections

Question 30

what are the key features of powder imitrix

Answer 30

imitrix is sumatriptan

1. mouth nozzle to blow powder through, another nozzle inserted in nostril -> blowing through mouth avoids negative pressure and traps powder in nasal cavity thus less loss of drug but may cause irritation bc solid powder
2. force from breathing out forces powder into nose and since no air comes out of nose when exhaling, air is continuously circulating in nasal cavity thus allowing product to be trapped within nasal cavity and decr opportunity for it to be cleared

Question 31

draw structure of sumatriptan and identify the H bond acceptors and donors and the ionisable group and what is the pKa of the ionisable group (thus explain how this affects pH of formulation)

Answer 31

2 H bond donors
3 H bond acceptors
amine is ionisable (tertiary amine) with pKa of 4.9 thus pH kept above pKa to prevent it from ionising

Question 32

what is the moa and indication for midazolam

Answer 32

midazolam is a benzodiazepine that activates GABA receptors which causes muscle relaxation

indicated for seizures

Question 33

what is the dosing for midazolam

Answer 33

1 dose or spray with onset of sx

extra dose if sx persist after 10mins, no more than 2 doses per episode
(max dose is no more than once q3d and no more than 5x/m)

Question 34

does the drug in nayzilam fit the ideal characteristics based on the rule

Answer 34

nayzilam is metronidazole

MW is 325
LogP is 3.97
no H bond donors
2 H bond acceptors
unionisable

Question 35

what are the excipients in nayzilam and its function in the formulation

Answer 35

nayzilam is metronidazole

1. ethanol – co solvent
2. PEG-6 methyl ether – stabiliser
3. polyethylene glycol 400 – stabiliser
4. propylene glycol – co-solvent
5. purified water – diluent

Question 36

draw the structure of midazolam and identify the H bond acceptors

Question 37

draw structure of PEG-6 methyl ether and propylene glycol

Question 38

should a drug for nasal administration be hydrophilic or lipophilic

Answer 38

balance both

hydrophilic bc need to be soluble in nasal mucus

lipophilic to pass through lipid membrane

Question 39

what is a property of PEG-6 methyl ether

Answer 39

has a slightly hydrophobic region which can latch onto hydrophobic molecule and incr its solubility