Modified release opioid analgesics

Question 1

what is a sustained release formulation?

Answer 1

ormulations/therapeutic agents that should

prolong biological activity

Question 2

what is a controlled release formulation?

Answer 2

formulations that control the rate at which
the therapeutic agent is released into the
biological milieu

Question 3

what is the difference between controlled and sustained release?

Answer 3

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.

Question 4

what are the advantages of controlled release dosage forms?

Answer 4

reduced frequency of dosage
more effective utilisation of the therapeutic agent
lower incidence of side effects
improved control of disease state

Question 5

what does the controlled release plasma curve entail?

Answer 5

one repeat action dosage form containing two doses

one controlled release dosage form containing the same drug

Question 6

what are the disadvantages of controlled release dosage forms?

Answer 6

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

Question 7

what are the general principles for obtaining controlled/extended release prep?

Answer 7

• 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

Question 8

what are the 3 diffusion controlled drug delivery systems?

Answer 8

reservoir
matrix
miscellaneous

Question 9

what is a resevoir system? how does it work?

Answer 9

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

Question 10

what are the key physiochemical parameters that affect drug diffusion and rate of release for resevoir systems?

Answer 10

– 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)

Question 11

what is a matrix diffusion controlled drug delivery system? how does it work?

Answer 11

• 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

Question 12

how are the release kinetics altered in a matrix diffusion controlled system?

Answer 12

Drug dispersed as a solid in the membrane phase

instead of being dissolved

Question 13

what is the total concentration of drug in a matrix diffusion controlled system?

Answer 13

total concentration of drug larger than the solubility of the drug in the matrix

Question 14

what equation describes matrix diffusion controlled system?

Answer 14

higuchi equation

Question 15

what are the consequences of the higuhi equation?

Answer 15

• 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

Question 16

how may the rate of release in the higuchi equation be altered?

Answer 16

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

Question 17

what does the release of a drug from a granular matrix involve?

Answer 17

– the simultaneous penetration of the surrounding
liquid
– dissolution of drug
– leaching out of the drug through interstitial channels
or pores

Question 18

define a granule

Answer 18

A granule is defined as a porous rather than a homogeneous

matrix

Question 19

what is included in the second form of the higuchi equation?

Answer 19

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

Question 20

why is tortuosity introduced into the equation?

Answer 20

to account for an
increase in path length of diffusion due to branching and
bending of the pores

Question 21

what effect does an increase in tortuosity have?

Answer 21

Increased tortuosity decreases the mass of drug released

Question 22

what does a tortuosity score indicate?

Answer 22

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

Question 23

what are the assumptions of the second higuchi equation?

Answer 23

• 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

Question 24

how may matrices be formulated?

Answer 24

Matrices may be formulated that form pores following the
dissolution of water soluble salts or alternatively,
hydrophilic polymers

Question 25

how is drug release controlled in dissolution and diffusion controlled systems?

Answer 25

– solubility (rate and extent) of the pore forming
materials
– resultant porosity of the matrix
– drug diffusion within the aqueous filled pores

Question 26

what is the mechanism of release for barrier coating?

Answer 26

diffusion eg beewax

Question 27

what is the mechanism of release for fat embedment?

Answer 27

erosion, hydolysis of fat, diffusion

eg beewax

Question 28

what is the mechanism of release for plastic matrix?

Answer 28

leaching, diffusion

Question 29

what is the mechanism of action for repeated action?

Answer 29

dissolution of enteric coating

eg cellulose acetylphthallate

Question 30

what is the mechanism of release for ion exchange?

Answer 30

dissociation of drug-resin complex

eg amberlite

Question 31

what is the design of a resevoir system?

Answer 31

coating of tabs/ granules with a hydrophilic/phobic polymer

Question 32

what is the design of a matrix system?

Answer 32

composed of a hydrophilic/hydrophobic polymer

Question 33

ideally, what order release should the extended- release drug formulation follow?

Answer 33

zero order

Question 34

what is taken into consideration when designing oral formulations?

Answer 34

releasing the drug at the desired place- ie stomach or intestines

Question 35

how does the ph affect drug release?

Answer 35

If the drug is unstable at the low pH (1–4) of the stomach, formulationscan be coated with an enteric coating, which contains carboxylic acidgroups that are protonated and insoluble at the low pH of the stomach,and will dissolve in the higher pH (7–9) range of the intestines (e.g.Cellulose Acetate Phthalate)

Question 36

What is SODAS technology?

Answer 36

This formulation consists of a gelatin capsule that contains both
immediate-release (IR) and extended-release (ER) beads of morphine in
a ratio of 9:1 (w/w), which allow to reach a therapeutic level of morphine
within 30 minutes (IR beads) while maintaining the plasmatic
concentration for 24 hours (ER beads).

Question 37

what does kadian capsules contain?

Answer 37

Kadian® capsules only contain one type of
pellets that provide both immediate and
sustained release of morphine.
• The coating used in this system is formed of
an insoluble ethylcellulose layer containing
two different polymers:
Polyethylene glycol 6000 (PEG with a molar
mass of 6000/mol)
Eudragit

Question 38

describe the release of kadian capsules

Answer 38

• Once the capsule is administered, the gelatincapsule dissolves and releases the pellets into theGI fluid.
• In the acidic medium of the stomach only PEG6000 is dissolved forming small pores into theethylcellulose layer leading to immediate releaseof a small fraction of the morphine.
• Carboxylic acid groups of eudragit are protonatedat the low pH making it insoluble in the stomach.
• As the pH increases in the intestine, dissolution ofeudragit results in the formation of bigger pores
• As such, the drug can continue to diffuse fromthe pellets providing a constant therapeuticconcentration of drug over 24 hours

Question 39

what is the release profile for the sustained release tablets

Answer 39

• Drug reservoir composed of the drug (hydromorphone),polyethylene glycol and polyvinylpyrrollidone
• Osmotic push layer consisting of polyethylene glycol,sodium chloride and hydroxypropylcellulose
• Coated by a semipermeable shell membrane consisting ofcellulose acetate and polyethylene glycol
• Once in the GI tract, the fluid flows through the membraneat a controlled rate, allowing the push layer to expand andeject the suspended drug from the drug layer out of thetablet through the delivery orifice.
• This formulation provides a sustained release over 24 hoursand is suitable for poorly water soluble compounds.

Question 40

what metabolism does transdermal administration follow?

Answer 40

transdermal drug delivery also by-passes first-
pass hepatic metabolism common to the use
of oral analgesics.

Question 41

why is fentantyl a suitable analgesic for transdermal delivery?

Answer 41

Low molecular weight (286 Da), high lipophilicity (LogP = 717),
and optimal skin flux (around 1000 times higher than
morphine)

Question 42

what does the fentanyl resevoir patch consist of?

Answer 42

It consists of a backing layer, formed by apolyester film that protects the patch from theenvironment, a liquid drug reservoir withdehydrated alcohol gelled withhydroxyethylcellulose
• a membrane, constituted of an ethylene-vinylacetate copolymer, which controls the rate ofrelease of fentanyl from the reservoir
• a silicone adhesive layer to adhere the patch tothe skin surface.

Question 43

how was the concern about a reservoir patch drug leakage addressed?

Answer 43

To address this concern, a matrix transdermal
patch was developed
• The drug is directly dissolved into a matrix
composed of a semi-solid formulation of a
polyacrylate adhesive.
• Fentanyl matrix patches with a lower drug
load were found to be superior to and as safe
as established standard oral and transdermal
opioid treatments