Modified Release Flashcards
What are considered USP interchangeable with extended release?
Define them
Controlled release:
- release drug at a constant rate and plasma concentrations remain constant
Prolonged release
- drug is provided for absorption over a long period of time; onset is delayed (initial dose + replenishment)
Sustained release:
- an initial release of drug sufficient to provide a therapeutic effect followed by a gradual release of the drug (maintenance dose)
advantages of modified release
- Reduced dosing frequency and decreased accumulation of drugs in body
- less fluctuation at plasma drug levels
- Reduced GI side effects
- Improved efficacy/safety ratio
- may reduce cost
Disadvantages of modified release
- dose dumping
- may become lodged in the GI tract
- additional patient education
- variable physiological factors (pH differences, GI motility)
- removal of the drug from system may be hard
What dose size make it difficult for extended release products?
500mg+
What are drugs more prone to when they stay longer in the GI tract?
to undergo acid-base hydrolysis and enzymatic biotransformation
What occurs to API solubility when it is low vs high
Low aqueous solubility (0.1mg/mL or less)
- not suitable to diffuse through a membrane
High aqueous solubility
- rapid dissolution
- difficult to decrease the rate, to modify absorption
What is the ideal Log K value for extended release candidates
Log K between 1-3
What does API half-life refer to? what is ideal half life?
describes the rate of drug elimination
- ideal between 2-8h
What are the physiochemical factors that can affect modified release drugs
- Dose size
- Drug stability in the GI
- API solubility
- Partition coefficient
- API half-life
- Polymer structure
What is the most absorptive region in the GI tract
Small intestine
What are the biopharmaceutical factors that can affect modified release drugs?
- anatomical factors of the GI
- Dietary Factors
- Physiological Factors
What are safety and risk management factors for dose-dumping
- integrity of dosage form
- Must have a robust formulation
- problematic with highly potent drugs with narrow therapeutic index
Explain zero-order kinetics
Equation
Drug release is INDEPENDENT of amount of drug in dosage form and is constant over time
Equation (sum of exponents = 0)
- no concentration dependence
- same amount of drug release/unit of time
Explain First order kinetics
Equation
Most extended release drugs
- release is DEPENDENT on the amount of drug remaining in the dosage form
- as amount of drug drops, release rate also drops
Equation (sum of exponents = 1)
- concentration dependence
What are the units of reaction rate
- mol/(L s)
- negative sign
What are the types of modified release systems (5)
- Diffusion controlled (reservoir + matrix)
- Osmotically controlled
- Ion-exchange resin
- Gastric retentive systems
- Colonic oral delivery system (pH-controlled)
Explain reservoir diffusion system
- drug is in a reservoir surround by INSOLUBLE polymeric membrane
- can be monolithic or multiparticulate
- rate governed by Fick’s law
- can be prepared by fluidized-bed coating, rotary granulation, solvent free coating
What are advantages of multiparticulates
- minimized risk of dose dumping
- more consistent in vivo performance
- tailored released kinetics
What are components of a reservoir system in the core and coating
Core
- Active drug
- filler
- lubricant/glidant
Coating
- Membrane polymer: HPC, ethyl cellulose, polyvinyl acetate
- Pore former: PEG
- Plasticizer
- Colour/opacifier
Explain matrix diffusion systems in genera
Consists of drug dispersed homogenously throughout an inert insoluble or swellable/erodible polymer (the matrix)
- no coating
- monolithic only
- most common Extended Release products
Explain hydrophilic or swellable matrix systems
- mixed with hydrophilic gel-forming polymer (HPMC, methylcellulose, acrylic copolymers)
- controlled by diffusion of the drug out the gel layer
- zero or first order
- cost effective
Explain erosion-controlled matrix systems
- drug release rate controlled by erosion of a matrix in which the drug is dispersed or dissolved it
- can also be called hydrophilic matrix systems
- bioerodible matrices: copolymers of lactic and glycolic acid, lipids, waxes
Explain inert polymer matrix systems
- first order release, porous matrix
- hydrophobic matrices: ethylcellulose, carnuba wax (lipid based) - it can include PEG (pore-forming)
What are formulation factors that can affect the release rate of matrix diffusion systems? (4)
- Amount of drug in matrix
- the porosity of the release unit
- the length of the pores in release unit
- the solubility of the drug
