Modified release opioid analgesics Flashcards
what is a sustained release formulation?
ormulations/therapeutic agents that should
prolong biological activity
what is a controlled release formulation?
formulations that control the rate at which
the therapeutic agent is released into the
biological milieu
what is the difference between controlled and sustained release?
Controlled release is a perfectly zero-order release; that is, the drug
releases constantly over time irrespective of concentration.
Sustained release implies slow release of the drug over a time
period. It may or may not be controlled release.
what are the advantages of controlled release dosage forms?
reduced frequency of dosage
more effective utilisation of the therapeutic agent
lower incidence of side effects
improved control of disease state
what does the controlled release plasma curve entail?
one repeat action dosage form containing two doses
one controlled release dosage form containing the same drug
what are the disadvantages of controlled release dosage forms?
More difficult and expensive to manufacture
• Potentially fatal if there is a problem with the
manufactured product
• Prolongation of side-effects following
administration
• If the drug is eliminated at a low rate, there is
a danger of accumulation
• Potentially dangerous for drugs that have a
narrow therapeutic window
what are the general principles for obtaining controlled/extended release prep?
• Utilisation of Chemical Reactions– insoluble salts –e.g. triamcinolone diacetate vs triamcinolone
– Prodrugs –e.g. 5-fluoro-2-deoxyuridine
• Utilisation of the Pharmacokinetic Phase
– prolongation of absorption
-prolongation of metabolism
-prolongation of excretion
what are the 3 diffusion controlled drug delivery systems?
reservoir
matrix
miscellaneous
what is a resevoir system? how does it work?
In this system, a water-insoluble polymeric material encases a core of drug. Drug will partition into the membrane and exchange with the fluid surrounding the particle or tablet • Additional drug will enter the membrane, diffuse to the periphery, and exchange with the surrounding media
what are the key physiochemical parameters that affect drug diffusion and rate of release for resevoir systems?
– drug diffusion coefficient (D) – partition coefficient (ratio of the concentration of drug in the coating to that in the core) (K) – area of the coating (A) – thickness of the coating (l) – concentration of drug in the core (C)
what is a matrix diffusion controlled drug delivery system? how does it work?
• Consider the situation in which a powdered drug is
homogeneously dispersed (e.g. dissolved) through a matrix tablet
• The drug will dissolve in the polymer matrix and diffuse out from
the surface of the matrix
• As the drug is released, the distance for diffusion becomes
increasingly greater
• The boundary that forms between the drug and empty matrix
therefore recedes into the tablet as drug is eluted
how are the release kinetics altered in a matrix diffusion controlled system?
Drug dispersed as a solid in the membrane phase
instead of being dissolved
what is the total concentration of drug in a matrix diffusion controlled system?
total concentration of drug larger than the solubility of the drug in the matrix
what equation describes matrix diffusion controlled system?
higuchi equation
what are the consequences of the higuhi equation?
• The amount of drug released is therefore proportional to:
– √2A, the total amount of drug in unit volume of the matrix
– √D, the diffusion coefficient of the drug in the matrix
– √Cs, the solubility of the drug in the polymer matrix
– √t, time
how may the rate of release in the higuchi equation be altered?
increasing or decreasing the solubility of the drug in the
polymer (salts forms, complexation)
increasing or decreasing the total concentration of drug
altering the crystallinity of the polymer
what does the release of a drug from a granular matrix involve?
– the simultaneous penetration of the surrounding
liquid
– dissolution of drug
– leaching out of the drug through interstitial channels
or pores
define a granule
A granule is defined as a porous rather than a homogeneous
matrix
what is included in the second form of the higuchi equation?
e and t
• Porosity is the fraction of the matrix that exist as pores or
channels into which the surrounding liquid can penetrate
• The porosity term is the porosity of the matrix following
complete extraction of the drug
why is tortuosity introduced into the equation?
to account for an
increase in path length of diffusion due to branching and
bending of the pores
what effect does an increase in tortuosity have?
Increased tortuosity decreases the mass of drug released
what does a tortuosity score indicate?
A straight channel pore has a tortuosity of 1 whereas a
channel through a packed mass of spherical beads of uniform
size has a tortuosity of 2 - 3
what are the assumptions of the second higuchi equation?
- A pseudo-steady state is maintained during release
- A»Cs, i.e. excess solute is present
- C = 0 at all times (perfect sink conditions)
- Drug particles are much smaller than the matrix itself
- The diffusion coefficient remains constant
- There is no interaction between the drug and the matrix
how may matrices be formulated?
Matrices may be formulated that form pores following the
dissolution of water soluble salts or alternatively,
hydrophilic polymers
