Modified Release Flashcards
How does conventional/immediate release oral dosage form effect absorption and duration of action?
Drug is rapidly released and absorbed in the GI track, peaking plasma concentrations very quickly for a short duration of action
Define extended release (ER).
Releases drug slowly over a long time and maintains drug plasma level at a therapeutic level
Define delayed release (DR)
Delays release for a period of time to target a specific site in the body
What is the goal of modified release oral dosage forms?
To improve therapeutic profile of the drug and minimize side effects
What are other names are there for extended release according to USP?
Controlled release → release drug at a constant rate
Prolonged release → onset is delayed and drug is provided for absorption over a longer period of time
Sustained release → initial release of drug provides therapeutic effect followed by gradual release of the drug
What are some of the advantages of the modified release dosage form? (7)
- reduced dosing frequency and accumulation of drug in the body
- better patient acceptance and compliance
- less fluctuation at plasma drug levels
- reduced GI side effects
- improved efficacy/safety ratio
- usage of less total drug
- may reduce cost of treatment for chronic diseases
What are some of the disadvantages of the modified release dosage form? (5)
- dose dumping
- tablets that remain intact may become lodged at some site in the GI tract
- need of additional patient education
- variable physiological factors (pH differences, GI motility)
- removal of drug from system is difficult if not impossible
What are the physiochemical factors that must be taken into consideration when designing MRSDF? (6)
- Dose size
- Drug stability in the GI tract
- API solubility
- Partition coefficient
- API half-life
- Polymer structure
MRSDF design considerations: dose size
Large doses (>500mg) are hard to make into ER products because it requires 2 or more times the amount of drug as IR
MRSDF design considerations: drug stability in the GI tract
In MR, drugs stay in the GI tract for longer → more prone to acid-base hydrolysis and enzymatic biotransformation
MRSDF design considerations: API solubility
LOW (<0.1mg/mL) → not suitable to diffuse through a membrane
HIGH → rapid dissolution, difficult to decrease the rate to modify absorption
MRSDF design considerations: partition coefficient
Log K 1-3 = ideal for ER drug candidates
MRSDF design considerations: API half life
should be 2-8h
MRSDF design considerations: polymer structure
Effects the diffusion coefficient and release rate of a drug
What are the biopharmaceutical factors to be taken into consideration when designing MRSDF? (3)
- Anatomical factors of GI
- Dietary factors
- Physiological factors
MRSDF design considerations: anatomical factors of GI tract
- absorption window is the specific region of the GI tract where absorption takes place
- most absorptive region is the small intestine → short transit time ~3h
MRSDF design considerations: dietary factors
food intake will influence drug release rate, absorption rate and amount absorbed
MRSDF design considerations: physiological factors
metabolic enzymes and efflux mechanisms
What does grapefruit juice inhibit?
P-glycoprotein efflux and intestinal metabolism, enhancing bioavailability with some drugs
When is dose dumping very problematic?
Highly potent drugs with narrow therapeutic indexes
Drug release rate should balance rate of ______ to rate of _____
Balance rate of absorption to rate of elimination
What is required to balance rate of absorption and rate of elimination?
Drug release must be independent of amount of drug left in the dosage form and is constant over time (zero order kinetics)
What kinetics do most ER systems show?
FIRST ORDER → release is dependent on the amount of drug remaining in the dosage form over time
What does reaction rate describe?
The change in concentration of a drug as a function of time
Describes the increase or decrease in the concentration of A within a time interval dt
Rate = +/- d[A]/dt
What are the units of reaction rate?
Concentration versus time; mol/(L s)
What are the types of modified release systems? (5)
- diffusion controlled → reservoir and matrix devices
- osmotically controlled systems
- ion-exchange resins
- gastric retentive systems
- pH-sensitive delivery systems (delayed release)
How is a reservoir diffusion system made?
Drug is in a core/reservoir surrounded by an inert water insoluble polymeric membrane (non-porous or with porous-forming polymers)
→ can be monolithic(1 unit or layer) or multi-particulate (granules)
What is the rate controlling mechanism in a reservoir diffusion system?
drug partitioning into membrane with release into surrunding fluid by diffusion; rate of release is governed by Fick’s law for non-porous type
What are some of the advantages of multiparticulates in the reservoir diffusion system?
- minimized risk of dose dumping
- more consistent in vivo performance
- tailored release kinetics (depending on how many IR and ER pellets there are)
What are the components of the core in a reservoir system?
- active drug
- filler
- lubricant/glidant
What are the components of the coating in a reservoir system?
- membrane polymer (HPC, ethyl cellulose, polyvinyl acetate)
- pore former (PEG)
- plasticizer
- colour/opacifier
What is different in a reservoir system for low and high dose strength API?
HIGH → drug containing core, functional coat on top
LOW → placebo core with drug layer around it, functional coat on top
What are the two preparation methods for reservoir diffusion systems?
- Coated granules or pellets by: extrusion-spheronization, rotary granulation, fluidized-bed coating, hot-melt coating
- Encapsulate in hard capsule or compress into tablets (multiple-unit pellet system/MUPS)
What is a matrix diffusion system?
Made of drug dispersed homogenously throughout an inert, insoluble, swellable, or erodible polymer (matrix)
→ ONLY monolithic
What is the rate controlling step for matrix diffusion systems?
Diffusion of drug out of the matrix
Do matrix diffusion systems have a membrane?
NO
What are some formulation factors that can affect the rate of release in a matrix system?
- amount of drug in the matrix
- porosity of the release unit
- length of the pores in the release unit
- solubility of the drug
What are the three types of matrix diffusion systems
- Hydrophilic matrix systems/swellable soluble matrices
- Erosion controlled
- Inert polymer
What are the properties of hydrophilic/swellable matrix systems?
- drug is mixed with hydrophilic gel-forming polymer
- HPMC
- methylcellulose
- acrylic copolymers
- drug release controlled by diffusion of drug out of the gel layer
- zero or fist order release
- cost effective
What are the properties of erosion-controlled matrix systems?
- drug release rate is controlled by erosion of the matrix
- first order release
- can also be called hydrophilic matrix systems
- bio-erodable matrices:
- co-polymers of lactic and glycolic acid
- lipids
- waxes
What are the properties of inert polymer matrix systems?
- first order release, porous matrix
- hydrophobic matricies:
- ethylcellulose
- carnauba wax
- can include PEG → pore forming
How do osmotically controlled systems work?
Uses osmotic pressure as the driving force to generate a constant release of a drug → water diffuses in and increases osmotic pressure forcing drug out through a laser drill hole
What is the order of release for osmotically controlled systems?
ZERO → constant release over time
***membrane is permeable to water but not to the drug so it must come out through the pores
What are the two types of osmotically controlled systems?
- Elemental osmotic pump (EOP): single-layer tablet
- Push-pull osmotic pump (PPOP): bilayer tablet
What is the semi-permeable membrane of osmotically controlled pumps most commonly made of?
cellulose acetate and PEG
What is an ion-exchange resin system?
Insoluble copolymers matrix containing ionizable groups capable of exchanging ions → reversible process
Resin and drug are prepared in beads or pellets
What types of resins are there for IER?
- Strong cation IERs; sulphonic acid functional groups
- Weak cation IERs; carboxylic acid functional groups
- Strong anion IERs; trimethyl ammonium chloride
- Weak anion IERs; ammonium chloride or primary amine
How does IER work?
- Loading of basic drug onto cation exchange resin
- Release of drug from resinate
What are gastric retentive systems used for?
Retention of DF in the stomach for drugs that:
- have narrow absorption window
- act locally in the stomach
- unstable in the colon
- low solubility at high pH
What are the advantages of gastric retentive systems?
- reduce variability of drug release
- local delivery and action
- enhanced bioavailability
What are the four types of gastric retentive systems?
- Floating delivery systems
- Muco-adhesive system
- Expandable system
- High density system
How do pH controlled systems work and what are some examples of polymers used in these systems?
Change in pH results in a swelling or de-swelling of polymer → hydroxypropylmethylcellulose phthalate and polymethylmethacrylate (eudragit)
What is the application of pH-controlled systems?
Colonic delivery systems: local delivery for the treatment of inflammatory diseases, infections, diarrhea and systemic delivery
What is the process of release for pH-controlled systems?
- Acid insoluble cap and coating dissolves in intestinal fluids
- hydrogel plug expands in intestinal fluids
- hydrogel plug is ejected
- drug is released in colon
***this mechanism is hard to make and there are very few of these systems available
What are the USP requirements for these types of dosage forms?
- Drug release → individual monographs have specific criteria for compliance with the test and test procedures
- In vitro-In vivo correlations (IVIVC) → process for developing this model is as follows:
- develop formulations with different release rates
- obtain in vitro dissolution and in vivo plasma concentration profile
- estimate the in vivo absorption or dissolution time course for each formulation
What are the differences in methylphenidate release forms?
Concerta → osmotic pressure
Biphentin → capsule containing multi-layered beads
Ritalin → film coated, extended release tablets
