modified release 1+2 Flashcards
what is a modified release dosage form?
Dosage forms that contain special excipients or are prepared by a special process designed to modify the rate, the place or the time at which the active substance(s) are released
what are the different types of immediate release dosage units?
-disintegrating/ chewable/ effervescent/ sublingual/ buccal
what are the different types of modified release tablets?
delayed release repeated release prolonged release sustained release extended release controlled release modified release
how does repeat action and modified release dosage form compare?
modified release- constant between MEC and MSC
repeated action- spikes- up and down- risk of under or over dosing
what are some of the advantages of MR?
•Improved treatment of chronic illnesses–
Steady plasma concentration between MEC and MSC –Reduction in systemic side effects
•Reduction in dosage frequency
improved patient compliance
what are some of the limitations of MR dosage forms?
GI tract physiology
require drug properties
possibility of overdose due to dose dumping
what are the selection criterial for MR formulations?
optimum water solubility - 10mg/mL if diffused controlled system
ideal half life= 4-6hr
wide absorption window
low first pass metabolism
what does a low half life (less than one hour) and a high half life ( more than 6 hours) mean?
low= need for high doses high= slow elimination and potential toxicity
what are the 4 classifications of the biopharmaceutical classification system?
- High solubility & high permeability (best for MR) e.g. propranolol
- Low solubility and high permeability e.g. ketoprofen, carbamazepine
- High solubility and low permeability e.g. ranitidine, atenolol
- Low solubility and low permeability (not for MR) e.g. frusemide, hydrochlorothiazide
what is high and low solubility?
high= highest dose strength is greater than or equal to 250ml of aq media over ph 1-8 low= highest dose strength is soluble in less than or equal to 250ml of aq media over ph 1-8 or less than 1mg/ml
what is high and low permeability?
high permeabillity= more than 90% if administratered dose is absorbed in vivo
low= less than 20% of administered dose is absorbed in vivo
how do you determine the apparent drug permeability?
-Caco2 cell lines
resembles cells of the small intestine
At regular time intervals the drug concentration at the receiver chamber is determined
Papp=dQ/dt(1/CoA)
what is the different mechanisms of drug released from MR tablets?
diffusion controlled release
dissolution controlled release
erosion- controlled release
osmosis- controlled release
what is diffusion controlled release?
- GI fluids dissolve the drug
- Dissolved drug molecules diffuse out of the dosage form via 1-pores of the release unit or 2- the surrounding membrane
what is dissolution-controlled release?
-it can be achieved by:
sparingly water sol drug
slowly dissolving carrier
slowly dissolving coating or ph dependent coating
-pulsatile release and delayed release tablets
what is erosion controlled release?
- matrix is gradually liberated from dosage unit surface exposing the drug to the GI fluids
what is osmosis-controlled release?
osmotic pump systems
what is a hydrophillic colloid matrix?
- Swellable‐soluble matrix systems
- Drug
- Water‐swellable hydrophilic polymer
what is the initial burst effect of a surface drug?- from hydrophilic matrix
initial bit released
Polymer swelling and dissolution are synchronised
•Constant thickness of gel layer
•Zero‐order release
what happens if the polymer swelling and dissolution are not synchronised?
- Increasing thickness of gel layer
- Insoluble drug
- Cannot diffuse through gel layer
- Released after matrix erosion
what are the types of hydrophilic colloid matrices?
True gel
•A cross linked polymeric structure is formed on contact with water e.g. gelatin
Viscous or “viscolised” matrix •A very viscous solution rather than a gel e.g HPMC
what does a hydrophilic colloid matrix system consist of?
•Drug Water‐swellable hydrophilic polymer •Compression aid •Lubricant •(Matrix / gel modifier) •(Solubiliser/ pH modifier) •(Glidant)
what are super-porous hydrogels?
Hydrogels with a 3‐D network of large pores (> 100 μm)
•Fast uptake of water due to capillary forces
•Swell in seconds up to 200 times their original size
•Due to rapid swelling, protective outer shell needed e.g. hard shell capsules, blister packs
•Improved gastric retention of dosage form due to increased size
what are insoluble polymer matrices?
- Inert polymer, insoluble in GI fluids •PVA, ethyl cellulose
- Drug diffusion via fluid‐filled pores of the matrix
- Suitable for drugs with high aqueous solubility
how do we measure the drug release from insoluble polymer matrices?
Higuchi Square Root model
what are lipid matrices?
•Wax material, solid at room & body temperature–Hydrogenated vegetable oils, microcrystalline wax, carnauba wax
•Chanelling agent–Water‐soluble e.g. NaCl, glucose–Leaches out of the matrix–Formation of tortuous capillaries
•Other components
–Solubilisers & pH modifiers–Antiadherent / glidant–No need for lubricant
what are membrane controlled systems?
- drug resevoir is coated with a membrane
- GI fluids diffuse across the membrane
- dissolved drugs diffuse out of the core through the membrane
what is the composition of membrane-controlled systems?
drug reservoir
-active drug/ filler/ solubilizing agent( optional)/ lubricant or glidant
coating
-membrane polymer/ plasticizer/ membrane modifier/ coloring agent
what are single unit systems?
Compressed tablet formulation with a polymer coating
•Tablet core dissolves on contact with GI fluids
•Water‐soluble filler
-solubilising agent
-surfactants/PEGS
what are multiple-unit systems?
> 1 discreet units form one single dose
hard shell capsule-filled with pellets or mini-tablets
compressed tablet
-multiple unit pellet systems/ filled with pellets/ MMC as a cushioning agent
what are the different types of film-coated pellets?
homogeneous pellet- uniform distribution of the drug and high drug loading
heterogeneous pellet- inert sugar sphere, coated with the drug
what was the first pellet-based MR prep on the market?
inderal 160mg
how was inderal made up?
•Pellet formulation –Propranolol hydrochloride 50% –Microcrystalline cellulose (MCC) 50% •Film coating –Ethyl celluloce (EC) 80% –Hydroxypropyl methylcellulose (HPMC) 20%
how is monomax sustained release capsules made up?
- Pellet core–Isosorbide mononitrate 40mg–Sugar sphere (sucrose)
- Film coating–1/3 of pellets: EudragitL100 (soluble) –2/3 of pellets: Eudragit RS (insoluble)
how would you use microcrystalline cellulose as cushioning material in MUPs?
Film coated pellets are mixed with coarse grade MCC or with granules made from MCC
•Example: LosecMUPS®
how is pentasa slow release 500mg tablet made up?
•MUPS® technology •Pellet core –Mesalazine500mg –MCC500mg •Film coat –Ethyl Cellulose
what did the tableting process for pentasa slow release 500mg tablet look like?
- pellets are mixed with cushioning material, magnesium stearate and talc
- cushioning material. granules made of MCC and PVP
how are pentasa slow release tablets released in the stomach?
- Rapid dispersion in the stomach
* Pellets release drug in a pH‐independent manner fromduodenumtocolon
what are the advantages of multiple unit systems?
–Consistent GI transit
–Total dose dumping is not a problem
–Optimised drug release mechanism that can incorporate more than one drugs
what are the disadvantages of a multiple-unit system?
–“Build‐up” of static charge during capsule filling process
–Difficult to retain in higher GI tract
what is an EOP system?
elementary osmotic pump (EOP) system
•Drug is suspended in water‐soluble tablet core
•Coating
•Semi‐permeable membrane with 1 or 2 small laser‐drilled exit holes (50‐100 μm)
how does the drug release process work with EOP?
–Water diffuses into the tablet core
–Core dissolves and hydrostatic pressure builds up and pumps drug solution (or suspension) via the hole.
how does as osmotic pump system compare with a classic membrane controlled system?
Membrane‐controlled system
•Two‐way diffusion process
•“Water in” and “drug out”
•No osmotic effect of core polymer material
•Membrane is permeable to both water & drug molecules
•No holes on membrane but unintentional pinholes may be present
Osmotic pump system
•One‐way diffusion process
•Water is the diffusing entity “water in” only
•Semi‐permeable membrane: allows diffusion of water molecules only
•Core swelling must cause osmotic effect –soluble excipient may be included to create osmotic pressure
•Drilled‐hole on membrane but no unintentional holes should be present
what affects the rate of drug release?
1- rate of water diffusion into the membrane
2-pumping rate of drug suspension/ solution
what are the components of an osmotic pump system?
•Core–Drug–Filler with osmotic properties ( NaCl,
KCl‐osmogens)–(Viscosity modifier)–(Solubiliser)–Lubricant / glidant
•Coating–Membrane polymer–Plasticiser–(Membrane modifier)
what are the advantages of osmotic pump systems?
- Well characterised system
- Water diffusion is easy to control
- Release mechanism is independent of drug properties
- Suitable for a wide range of drugs
- Straightforward coating technology
- Zero‐order release profile
what are the disadvantages of osmotic pump systems?
- Size of laser‐drilled hole(s) is critical
- Laser drilling is expensive
- Membrane integrity is vital
what order does osmotic pump release follow?
zero-order release after initial lag time
what is the ‘push-pull’ osmotic pump?
expanded push compartment with osmotic core drug during operation
