Modified release Flashcards
why are modified release dosage forms used over conventional immediate release?
- delivering drug at a specific rate/time
- extending the drug release over a specific duration
- delaying drug release to a pre-determined time point
why would we delay a drug release to a pre-determined time point
to target a drug release to a specific area or avoid drug release in a specific area
what are the types of modified releases
- Extended release
- sustained release
- controlled release
- long acting - delayed release
- site specific targeting
- enteric coating (protecting the stomach from the drug or the drug from the stomach)
what are the advantages of extended release?
- more stable plasma concentration than immediate release
- reduced dosing frequency
- better pt compliance and adherence
- chronotherapy - administring a drug related to the body rhythm e.g. circadian rhthym
Immediate release is the dosage form with the HIGHEST/LOWEST drug plasma conc?
Highest
whats advantage does MR have over IR?
less side effects
what is the most common design for delayed release? why?
enteric coating as it is pH sensitive
why are delayed release dosage forms used?
to release in other locations than the stomach, this means that the enteric coating must protect acid liabile drugs
MR advantages
- cost effective
- better compliance
- lower frequency of administration
- reduced side effects
what are the different types of MR kinetics?
- zero order
- first order
- higuchi
what is zero order release?
where the rate of drug release is independent of the concentrations of drug in the dosage form, which has a CONSTANT drug release.
what happens to the kinetics of a drug that follow zero order? and why?
they follow zero order til the next dosing interval, the drug concentrations depletes, therefore changing the release profile into the 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
whats the equation of drug release with zero order?
what are some examples of zero order formulation designs?
- osmotic systems
- matrix tablets with poorly soluble drugs
- reservoir systems
what is first order release?
the rate of drug release is dependent on the concentration of the drug in dosage form.
there is a rapid initial drug release, followed by a decline in release rate. the release rate slows as the concentration of the drug decreases
what kind of kinetics does sustained release follow?
first order release
what are examples of first order formulation designs?
- conventional tablets
- water soluble drugs in a porous matrix system
what is the higuchi release profile?
the longer the distance the drug molecule has to travel the longer the time for the drug to be released from the matrix system
what is to consider about the MR formulation?
- GI transit time
- pt convenience and ability to use product as directed
why is it important to counsel your patient on MR formulations? how?
to make sure they do not crush etc. so that the release profile for the drug remains intact so subtherapeutic effects are felt.
by making sure the pt is comfortable using the drug or may prefer an alternate formulation
what are the release mechanisms of ER formulations?
- dissoultion controlled formulations
- diffusion controlled formulations
- osmotically controlled formulations
- ion exchange systems formulations
what is dissolution controlled formulations controlled by ?
Noyes Whitney, therefore, …
what formulation is extended release?
multiunit particluate systems (MUPS)
what formulation is used in delayed release?
MUPS or tablet with an enteric coating to prevent dissolution within the stomach
What is multi-unit particulate systems? what is the significance?
the use of different concentration of polymers within the drug.
the lower the concentration of polymers the faster the dissolution
how is flux calculated?
what are the two types of systems diffusion controlled dosage forms used?
- matrix systems
- reservoir systems
what are matrix systems and the type of kinetics involved?
drug evenly dispersed within a polymer matrix = zero order.
a change in conc. gradient causes first order kinetics
a change in diffusion distance causes higuchi release
what are reservoir systems? and relation to kinetics order
a drug present in the core of a semi-permeable membrane. a constant conc. gradient = zero order
why are reservoir systems zero order?
as the drug releases is from one point (one exit way) therefore there is a constant amount of drug release as the gradient will remain the same due to the constant drug concentration on the outer layer ready to diffuse out.
what are examples of matrix systems?
- insoluble polymer matrix
- soluble (erodible) polymer matrix
- soluble (swellable) polymer matrix
- lipid matrix
what factors affect drug release in an insoluble polymer matrix?
- polymer porosity
- polymer tortuosity
- drug solubility
what polymers are used in insoluble polymer matrix?
ethyl cellulose
methyl acrylate metacrylate copolymer
polyvinyl chloride
polyethylene
dont dissolve or change shape in water
what are ghost tablets? what must you do when starting medication that has ghost tablets?
insoluble tablets in water, therefore, pass the body without any changes. however api will dissolve.
the outer layer remains, therefore, appropriate counselling must occur to stop confusion if patients notice tablets within their faeces
how are soluble polymer matrix used
prep: drug disperse in a water soluble polymer
Use: polymer dissolves and erodes in contact with the fluid
how is drug dissolution affected in soluble polymer matrix?
increases in dissolution time the smaller the formulation size due to the increase in surface area.
what order do hydrophobic and homogenous polymers follow
zero order
what order do hydrophilic polymers follow?
first order
what type or erosion do hydrophobic or hydrophilic powders follow?
hydrophobic - surface erosion
hydrophilic - bulk erosion
what factors effect soluble polymer matrix?
polymer concentration
drug vs polymer dissolution rate
additional erosion from GI motility
what examples of soluble polymer matrix?
water soluble polymers
poly(lactic acid)
poly vinyl caprolactone
polyethylene glycol
polyethylene glycol monostearate
what is soluble (swellable) polymer matrix?
prep: drug dispersed in swellable and water soluble polymer
use: polymer swells to form a gel layer once in contact with fluid
gel erodes and drug dissolves
what are factors affecting drug release in soluble (swellable) polymer matrix?
- polymer hydration/swelling rate
- environmental factors
- Chemical interactions between the drug and the polymer
- tortuosity and porosity of polymer gel
- polymer concentration
what polymers are used for swellable matrix
HPMC
hydroxyethylcellullose
sodium carboxymethyl cellulose
what is a lipid matrix
similar to insoluble polymer matrix. no pores so a channeling agent is needed and API needs to have a suitable water solubility
what is an example of a channeling agent?
water soluble
e.g. NaCl
what order of kinetics does lipid matrix follow?
higuchi
what are reservoir systems?
membrane controlled
what are factors affecting drug release in reservoir systems?
polymer thickness
polymer porosity
drug solubility
why is membrane integrity important in reservoir systems?
otherwise dose dumping is caused causing an severe increase in plasma drug concentrations which can cause toxicity
how can we avoid dose dumping within reservoir systems?
using pellets rather than tablets
or using MUPS
what are osmotic systems?
what are ion-exchange formulations?
what is the release rate of the ion exchange formulation controlled by?
diffusion of ions into the resin
what are cation exchangers?
resin ionisable group is acid (sulfonic, carboxylic or phenolic)
where will ion exchange occur for cation exchangers?
in basic solutions
what are anion exchangers?
Anion exchangers are a type of ion-exchange material used to remove or replace anions (negatively charged ions) from solutions.
where will ion exchange happen for anion exchangers?
in the stomach at low pH
what are the different GI tract transit times within the stomach, small intestine, larger intestine and oro-anal transit?
how does the size of a gastrointestinal drug affect transit time within the stomach ?
the larger the size of the drug the longer the transit time within the stomach, this is due to the tablets inability to crack. remaining intact takes longer to fully digest.
why will MUPS move faster than intact tablets?
due to lower effect of gastric emptying
where is majority of the drug from MR tablets absorbed from? why is this important?
the small intestine. to make sure our formulations met desired characteristics thast allow optimise drug absorption at this site
how long can tablets be absorbed for in the small intestine and why?
6 hours due to the length of transit time, this means there can be a 6 hour drug release.
Where must your drug be absorbed if you want to deliver the drug to your colon?
large intestine
what is the fluid volume in the colon, therefore what is the dose volume thatll be soluble?
20-50ml,
dose soluble <50ml
coating importance for MR colon delivery?
pH of coating important to release the drug,
coating integrity to stop dose dumping.
when is the colon targetted for drug delivery?
local treatment of disease e.g. inflammatory bowel disease (ulcerative colitis)
what are the different drug mechanisms to target the colon?
pH triggered drug release
time triggered drug release
microbiologically triggered drug release
how does pH triggered drug release occur?
achieved by the use of pH sensitive polymers
either coat a compressed tablet/pellet/beads.
what are the polymers and pH threshold?
whats the importance of enteric coating?
3 reasons
to prevent drug release in the stomach, stay intact
- protect the stomach from the drug
- protect the drug from the stomach
- release the drug after the stomach (e.g. in the intestines)
what are some examples of acidic polymers?
methyl acrylate-methacrylic acid copolymers
cellulose acetate succinate
hydroxy propyl methyl cellulose phthalate
polyvinyl aceteta phthalate (PVAP)
when are acidic polymers for enteric coated formulations used?
dissolve at higher pH’s (more basic environments)
e.g. large intesting pH 6.1-7.4
effect of food when taking MR medication
gastric emptying
fasted state 1-2 hours but post eating non disintegating tablets may remain in the stomach for longer periods
delaying the drugs onset
effects of additional GI motility in fed state and alcohol
increase drug degratation, lowering the efficacy and therapeutic effects
gastro retentive dosage formulations must be…
acid stable and withstand GI motility
what are some dosing mechanisms for gastro-retensive formulations?
- floating dosage forms
- bioadhesive multiparticulates
- swelling single unit systems
why are floating dosage forms not used as much clinically?
due to the limitation of not knowing if the DF is floating within the stomach
how do swelling single unit systems work?
the polymers swell in the stomach, becoming larger than the pyloric opening. this means that there is an increase in the bioavailiabilty of the drug being absorbed by active transporters
how to counsel patients about delayed release solids ?
to take with water or apple juice ( increases onset)
take on an empty stomach
do not chew/crush
how to counsel patients about extended release solids?
to take with water or apple juice
food does not impact bioavailibility
do not chew/crush
appearance of ghost tablets
confirm storage/onset/frequency
