Modified Release Flashcards
L.O:
* To understand, recognise, describe and assess the strategies available for the design of modified-release drug delivery systems.
* To identify the advantages and limitations of controlled release formulations
* To understand the release profiles afforded by these mechanisms
* To distinguish between first order, zero order release kinetics of modified release formulation
* To appreciate the design variables which enable release rates to be controlled
* To identify the effects of device geometry on release profile
* Where appropriate, to quote a product which uses each mode of control above
* To deduce the likely control mechanism of modified release systems from SmPC or patient information sheets
what is a MR dosage form? (and how is it different to IR)
Dosage forms that release drugs in a fashion other than the conventional IR
describes drug released differently from conventional
why are MR dosage forms used over conventional IR? (3)
- delivering drug at specific rate/time
- extending drug release over specific duration
- delaying drug release to a pre-determined time point
why would we delay a drug release to a pre-determined time point (2)
to target a drug release to a specific area
or
avoid drug release in a specific area (e.g. drugs acid labile and would be rendered inactive to stomach conditions/ drugs that irritate stomach and cause unwanted SEs)
What are the 2 subcategories of a modified release dosage form?
Extended release
Delayed release
3 subcategories within the subcategory: EXTENDED release?
- sustained release
- controlled release
- long acting
What is a sustained release dosage form?(how does it work)
will extend the peak/time that drug is therapeutic
… prolongs duration of action
how does sustained release differ from IR?
similar to IR but will continue for longer period of time, prolong action
what does controlled release dosage form do?
controls amount of drug released into blood for predetermined time.
Can control plasma conc of drug in blood for that time
long acting dosage form is a combination of what 2 types of df?
sustained and controlled release (the other 2 in subcategory of extended release
What are the 2 types of delayed release dosage forms?
- Site specific targetting
- Enteric coating
benefit of enteric coating?
protect drug from stomach/ stomach from drug
advantages of extended release dosage forms? 4
- Less frequent dosing (reduce by 50%)
- More stable plasma conc than IR - Less fluctuations … better pain management
- Better px compliance
- chronotherapy - administering drug related to the body rhythm e.g. circadian rhythm (sleep wake cycle) so dont need to admin when asleep + effect maintained overnight
What is the purpose of DELAYED release dosage forms?
Drug release into different location than stomach
DELAYED release dosage forms protect?
acid sensitive (labile) drugs from the stomach
and
stomach from irritating drugs e.g. NSAIDs
IR dosage form has highest/lowest drug plasma conc?
highest
5 advantages of delayed release?
- protect labile drugs
- protect stomach from irritating drugs
- remain intact in small intestine to release drug in colon for local action
- time lag before drug release
- can also have DR followed by IR or extended release
what advantage does MR have over IR?
Less SE as conc wont get to higher levels
what is the most common design for delayed release? why?
enteric coating as it is pH sensitive
… will enable the drug to reach the small intestine for release in the colon
MR advantages
cost effective
better convenience + compliance
lower frequency of administration
reduced side effects
Protect acid sensitive drugs, dissolve later/ elsewhere
Fluctuations in Cp eliminated
Maintains MEC over 24hrs (minimum effective conc)
what are the different types of MR release kinetics? 3
zero order
first order
higuchi √ time
what is zero order release?
where rate of drug release is INDEPENDANT of drug conc in dosage form, because constant conc gradient maintained
constant conc gradient maintained between what?
and what does this influence?(zero order release)
barrier of dosage formulation (interface) and surrounding environments (gastric fluids).
As long as kept constant, amount of drug release also kept constant :)
when do kinetics of a drug that follow zero order change to first? and why?
follow zero order until next dosing interval, the drug conc depletes, therefore changing release profile into first order
what kinetic order has the best control over the drug plasma concentration?
zero order
what order of kinetics does controlled release formulations have?
zero order
Constant amount of drug released per time
whats the equation of drug release with zero order?
Q = Q0 + K0 t
(Y=mx+c)
Q = amount of drug released
Q0 = initial amount of drug in solution (usually zero) if starts at origin
K0 = zero order release constant
(see graphs!!)
3 examples of zero order formulation designs?
- osmotic systems
- matrix tablets with poorly soluble drugs
- reservoir systems
what is first order release?
where rate of drug release is DEPENDANT on the drug conc in dosage form.
describe first order graph
Initial rapid drug release then decline in release rate (match up w amount of drug left in dosage form until eventually exhaust all of drug from it)
what kind of kinetics does sustained release follow?
first order release
how does rate of drug release change with drug conc in first order?
Rate of drug release decreases with a decrease in drug conc
2 examples of first order formulation designs?
conventional tablets
water soluble drugs in a porous matrix system
what does Higuchi of √ time release profile describe?
drug release from matrix systems
When there is a change in drug release because there is a change in distance over time that the drug molecules have to travel
what is the higuchi release profile?
Longer the distance (for drug mol to travel) - longer for drug to leave matrix system
So when change in distance/time… follows model
e.g. time for lecture hall people outer quicker to leave than middle
Other release patterns for MR? 2
Delayed release
Bimodal release
When is a bimodal release graph seen in dosage formulations?
in long acting formulations
What is the equation for zero order drug release where there is a constant drug release over time?
M infinity = Initial [ ] of drug in formulation
Ft = Kt
(check notes)
What is the equation for release profiles other than zero order?
Where the value of n will vary according to the type of release profile i.e. first order or higuchi
(check notes !!!)
What is the equation for first order release profiles?
Ft = e^Kt
Ft = fraction of dose released at time t
What system follows the first order release profile?
A water soluble drug in a porous matrix
What is the equation for higuchi release profiles?
and what systems follow it?
Ft = Kt^0.5
This is seen in systems with a matrix
zero order equation used for what systems?
osmotic
‘drug conc in formulation is much higher than in surroundings’ for what model?
all 3: zero, first, higuchi
‘drug release from formulation starts fast and slows down as drug conc in formulation decreases’ for which models?
first order and higuchi
…
zero order: drug release from formulation is rapid, changes to first order
Why are poorly soluble drugs not appropriate for MR drugs?
release of drug already delayed (rate limiting step) so making the drug MR would delay it further and make the drug show less therapeutic effect
4 things to consider about the MR formulation?
drug substance
disease condition
GI physiology
px
What 5 factors of ‘drug substances’ must be considered for MR dosage forms?
- sufficient solubility +permeability
- Dose: lower = better as further excipients need to be added otherwise would be too bulky
- Good GI stability: withstand harsh conditions
- Half life shouldn’t be too long
Why should some drugs not be MR in terms of the DISEASE CONDITION that they have?
Some treatments require rapid onset/ prolonged response so long acting/combination better
E.g for diarrhoea then MR not best as you want quick action
MR better for acute or chronic therapy?
Good for chronic diseases where you want reduced frequency
Why is the GI transit time important in MR dosage forms?
GI transit time: set time, if drug not released then, will exit body without achieving active component = no therapeutic effect
Why is the patient’s ability to use the MR product as directed so important?
reduced dosage frequency should improve px adherence as becomes more convenient to take med
do not crush: reduces therapeutic effect :(
why is it important to counsel your patient on MR formulations? how?
do not crush etc. so release profile for drug remains intact + subtherapeutic effects felt
by making sure px comfortable using drug/ may prefer diff formulation
MR lec 2
the 4 release mechanisms of ER formulations?
- Dissolution controlled formulations
- Diffusion controlled formulations
- Osmotically controlled formulations
- Ion exchange systems formulations
Dissolution controlled formulations
What is the dissolution mechanism of extended release formulations?
And explained by which equation?
drug solutes dissolve into the surrounding medium AKA the bulk which is explained by the Noyes Whitney equation
What does the dissolution of the ER drug depend on? 4
(see eqn)
- Drug solubility: higher solubility faster dissolution (thickness of boundary and how linked to drug sol)
- solvent into which the ER drug dissolves into
- particle size - Larger particles diffuse slower as they have less SA
How does the enteric coating control dissolution of ER drug?
polymer chosen to coat the API for ER will ensure it does not dissolve in stomach but the desired site in the GIT e.g. SI/LI
What are MUPS and why are they used in ER tablets?
Multiunit particulate systems
multiple sized particles. thickness = diff rates of dissolving and drug release. with MUPS can extend release of API
what formulation is extended release?
multiunit particluate systems (MUPS)
what formulations are delayed release?
MUPS or tablet with an enteric coating to prevent dissolution within the stomach
… How are the enteric coating of ER and DR formulations different?
both types of MRs can be MUPS but:
delayed tablets could also just be tablets as all that needs to be achieved is an enteric coating enough to protect content from stomach and later be released where needed in GIT
Diffusion controlled formulations:
What 3 simple factors affect the rate of diffusion?
- SA + DISTANCE that particles are moving to
- How STEEP conc gradient is
- diffusion coefficient
describe Diffusion controlled formulations
how it works
- Diffusion of dissolved drug controls release
- Drug dissolves in surrounding fluid
- Conc grad drives diffusion: High conc in dosage form and low outside = imbalance so moves out into fluid –> Low conc.
what is flux and how calculated? (see notes)
rate of diffusion.
M/t = CAKD/l
conc grad
surface area
partition coefficient
diffusion coefficient
over memb thickness
what are the two types of systems diffusion controlled dosage forms used?
matrix systems
reservoir systems
describe matrix system in an MR dosage form? + describe the kinetics involved
drug evenly dispersed within a polymer matrix = zero order.
change in conc. gradient –> first order kinetics
change in diffusion distance –> higuchi release
What is a matrix system in an MR dosage form?
where drug dispersed within a polymer matrix which creates a barrier between the API and the dissolution medium
release profile of ER with a matrix system if there is a change in concentration gradient?
first order release profile
as rate of release is dependent on the concentration of the drug
release profile of ER with a matrix system if there is a change in diffusion distance?
higuchi release profile
as drug release dependent on distance that drug particles moving through medium
what are reservoir systems? and relation to kinetics order
drug present in the core of a semi-permeable membrane
constant conc. gradient = zero order
why are reservoir systems zero order?
membrane acts as channel of release. Constant conc gradient over time = zero order.
when cant be maintained towards end, release profile change to first order