Modified Release Dosage Forms

Question 1

Explain the blood concentration curve.

Answer 1

1. drug conc. in blood begins at zero–>all drug is still in dosage form
2. conc. begins to rise–>no effect yet
3. conc. crosses minimum effective conc–>therapeutic effect
4. conc. is at its peak–>maximum therapeutic effect/minimum toxic conc.
5. conc. starts to decline–>reduced therapeutic activity
6. conc. falls below MEC–>drug elimination, no therapeutic activity

Question 2

What is the definition of the following?
toxic concentration
therapeutic window
onset of action

Answer 2

toxic concentration: onset of adverse effects
therapeutic window: concentration between MEC and MTC
onset of action: time at which MEC is reached

Question 3

What are the challenges of the conventional dosage forms?

Answer 3

do not maintain blood concentration within therapeutic range for extended period of time
controllable drug release is not possible

Question 4

What are the approaches if drug levels have to be maintained using conventional dosage forms?

Answer 4

increase initial dose to increase duration of action:
-challenge: blood conc will rise, earlier MTC and to a greater extent
-final consequence: increased potential of toxicity
administer repeatedly using a constant dosing interval:
-mainstay of conventional regimen
-challenge: patient inconvenience
-final consequence: missed doses or made-up doses or non adherence

Question 5

What is the rationale for MRDFs?

Answer 5

to prolong or control drug availability or release with the intent of improving efficacy of drug therapy

Question 6

Differentiate between delayed action and extended action.

Answer 6

delayed action:
-lag period between admin and release
-release of drug at particular site
-mostly enteric coated
extended action
-release the med in a controlled manner at a pre-determined
rate, duration and location to achieve and maintain levels

Question 7

What are sustained-release systems?

Answer 7

any drug delivery system that achieves slow release of drug over extended period of time

Question 8

When does a sustained-release system become considered a controlled-released system?

Answer 8

if the sustained-released system is successful at maintaining constant drug levels in the target organ

Question 9

When does a sustained-release system become considered a prolonged-released system?

Answer 9

if the sustained-release system prolongs the therapeutic levels of the drug

Question 10

What are extended release systems?

Answer 10

allow reduction in dosing frequency from that necessitated by a conventional dosage form

Question 11

What are delayed release systems?

Answer 11

release the drugs at a time other than promptly after administration
the delay may be influenced by pH

Question 12

What is targeted release?

Answer 12

isolates or concentrates the drugs in a specific boy region, tissue, or organ

Question 13

What are repeated action forms?

Answer 13

usually contain two or more single doses of the drug, one for immediate release and the second for delayed release

Question 14

What is the rationale for extended release formulation?

Answer 14

XL products provide an immediate release of drug, which promptly produces the desired therapeutic effect, which is then followed by a gradual and continual release of drug to maintain effect over time
eliminates the need for night dosing

Question 15

Where does the difference lie when a drug is available in both SR and XL formulation?

Answer 15

duration of action
ex: Wellbutrin (bupropion)

Question 16

True or false: the terms controlled release, sustained release, and extended release are used interchangeably

Answer 16

true

Question 17

What are the advantages of MRDFs?

Answer 17

less fluctuation of drug levels
-controlling rate of release eliminates peaks and valleys
reduced dosing frequency
-extended release delivers more than one single dose, usually
taken OD or BID
enhanced patient compliance
-less missed dose, neglected dose, etc
reduction in adverse side effects
-fewer blood level peaks outside therapeutic range
reduction in health care costs
-initial costs are greater but overall treatment cost may be less

Question 18

What are the limitations of MRDFs?

Answer 18

initially they are costly for patients
immediate termination of drug action is not possible
usually contain higher drug amount than in conventional dosing–>abuse potential
higher probability for drug-excipient interaction
more complicated formulation design
not suitable when rapid action is required like breakthrough pain or anxiety attacks
not flexible

Question 19

True or false: MRDFs can be split

Answer 19

false

Question 20

What are the variables on the design of MRDFs?

Answer 20

route of delivery
type of delivery system
disease being treated
the patient
length of therapy
properties of the drug (physicochemical, biological)

Question 21

Which solubility is preferred for MRDFs?

Answer 21

medium solubility
no need for MRDFs for low water solubility

Question 22

What solubility is it not possible to make MRDFs?

Answer 22

<0.01mg/mL solubility
-difficult diffusion through layers of polymer

Question 23

What is the difficulty of using very high water solubility drugs for MRDFs?

Answer 23

difficult to reduce their dissolution rate to an acceptable range

Question 24

What is the partition coefficient?

Answer 24

potential of drugs to cross biological membrane (ratio of drug in lipid phase vs aqueous phase)
-affects the ability of drugs to diffuse through polymers used in
the design of MRDFs

Question 25

What is the importance of stability for MRDFs?

Answer 25

stability of drug in the dosage form outside the body stability of the drug in the dosage form inside the body -drugs remain in the dosage form for extended times -drug is trapped in the system-->penetrating fluids should not degrade the drug

Question 26

What should be the rate of absorption and excretion for MRDFs?

Answer 26

not very slow neither very fast slow kinetics-->inherently long-acting-->not necessary to prepare MRDFs fast kinetics-->very short half-lives (<2hrs)-->very large amounts will be required to design MRDFs

Question 27

Regarding complexation, which types of drugs are not suitable for MRDFs?

Answer 27

drugs which show high levels of protein binding in the blood *only free unbound drug can diffuse through tissues and hence can be controlled*

Question 28

What is an undesired margin of safety for MRDFs?

Answer 28

narrow therapeutic window

Question 29

Are MRDFs for acute conditions?

Answer 29

acute conditions-->immediate release is required more dosage adjustments, MRDFs are difficult for dosage adjustments

Question 30

What is the maximum dose for MRDFs?

Answer 30

0.5-1g

Question 31

True or false: MRDFs are intended to minimize dosing frequency, thus contains a greater amount of drug than a corresponding single conventional dose

Answer 31

true

Question 32

How do we determine the dose size of MRDFs?

Answer 32

consider dose of drug in conventional form to determine amount required in SR products

Question 33

What are the mechanisms for modified release?

Answer 33

membrane dissolution membrane diffusion matrix dissolution matrix diffusion membrane-matrix hybrids osmotic pressure

Question 34

What are dissolution systems?

Answer 34

controlled release products are prepared by controlling the the dissolution rate of drugs that are readily soluble -two categories: membrane or matrix

Question 35

Describe membrane dissolution systems.

Answer 35

different groups of particles with different membrane thickness and composition are made, that will release the drug at different rates -more uniform blood level of drug can be obtained another type is a layer of drug is coated on a sugar core and then coated with the slowly dissolving membrane material -another layer of the drug is applied, followed by another coat -the outer most layer is typically a layer of drug that will serve as a loading dose

Question 36

True or false: uncoated particles can be used for MRDFs

Answer 36

false uncoated particles=immediate release form of drug

Question 37

What is Spansule technology?

Answer 37

capsule filled with granules -initial dose is promptly released and remaining medication is released gradually over a prolonged period of time

Question 38

Describe matrix dissolution systems.

Answer 38

drug is dispersed in a series of different sized granules made of the matrix material -different size granules will have different dissolution times -matrix granules often combined with granules with no matrix material=providing a loading dose

Question 39

How are matrix dissolution systems prepared?

Answer 39

compressing the drug with a slowly soluble polymer carrier (hydrophilic cellulose polymers) into a tablet form release process: hydration of the cellulose polymer; gel formation on the polymers surface; tablet erosion; subsequent release of drug

Question 40

What are diffusion systems?

Answer 40

release rate of drug is determined by its diffusion through a water-insoluble polymer two types: -membrane (core is surrounded by a polymeric membrane) -matrix (drug is distributed uniformly in an inert polymeric matrix)

Question 41

What is usually involved in the drug release of reservoir devices?

Answer 41

dissolution of drug inside the reservoir diffusion of drug across membrane (rate controlling step)

Question 42

Describe matrix diffusion devices.

Answer 42

drug is dispersed homogenously in the matrix which does not dissolve or erode diffusion of the drug from the matrix to outside-->rate limiting step matrix devices can be excreted in the feces

Question 43

What are membrane-matrix hybrids used for?

Answer 43

used mainly for non-oral routes -NuvaRing -Mirena IUD for much prolonged delivery times

Question 44

What are osmotic systems?

Answer 44

osmotic pressure can be employed as the driving force to generate a constant release of drug, provided that constant osmotic pressure is maintained

Question 45

How do osmotic pressure systems work?

Answer 45

water moves in-->dissolves or suspends the drug-->membrane is not permeable to the drug-->the system pushes the drug out through the orifice

Question 46

What are points to discuss about MRDFs during patient counseling?

Answer 46

advise of the dose and dosing frequency of MRDFs not to use them interchangeably or concomitantly with IR of the same drug patient should not be changed back to IR without consideration of any existing blood levels of the drug once stabilized, patients should not be changed to another XL product unless there is assurance of equivalent bioavailability dont chew or crush patients fed by an NG feeding tube may receive conventional or modified release nonerodible plastic matrix shells and osmotic tablets remain intact throughout the GI transit and the empty shells from osmotic tablets may be seen in the stool