oral modified release

Question 1

listen some advantages of modified release therapy

Answer 1

1. improved treatment due the plasma levels being controlled
2. improved compliance as less doses needed taken
3. economic savings. fewer doses = lower volume

Question 2

what are some limitations of modified release delivery?

Answer 2

1. variable physiological factors affect release (pH, food etc)
2. GI transit time usually less than 12 hours. (limits time for therapeutic levels to be reached & maintained.)
3. can become lodged at some site in GIT
4. Dose size. dose > 500mg is too bulky to swallow
5. dose dumping possible. large dose deposited quickly in GIT due to bad manufacturing.

Question 3

list some required drug characteristics for modified release

Answer 3

• used for chronic rather than acute
• half life should be between 2 and 8 hours. too short means too large dose.
• absorption should be fast enough such that the release rate controls the conc of drug in plasma not rate of absorption.
• drug must have intermediate solubility. very high makes it difficult to formulate. poor solubility limits absorption.

Question 4

(SAMPLE Q) explain the difference in plasma conc vs time profile for MR and conventional release and how this affects dosing.

Answer 4

• conventional makes plasma conc of drug fluctuate between sub and super therapeutic levels frequently.
  it doesnt remain in therapeutic levels for long. this means more frequent dosing
• MR takes longer to reach therapeutic levels but drug level in plasma does not fluctuate and remains in therapeutic window for long periods. this requires taking a dose 1-2 times a day

Question 5

why are multiple unit dosage forms more desirable in Modified release.

Answer 5

there is a lower isk of drug dumping and evens out potential fluctuations in drug release

Question 6

what are the two types of MUDF and SUDF structures

Answer 6

1. reservoir: pellet, particle, or tablet coated with varying thickness and composition of polymers
2. matrix: drug particles dispersed evenly in a polymer.

Question 7

explain the drug release process of MR drug.

Answer 7

when ingested, gi fluid erodes polymer and water penetrates into device and dissolves drug. drug passes out of polymer matrix/coating to enter GIT and is absorbed

Question 8

two example of polymers used

Answer 8

ethylcellulose and eudragit RS and RL

Question 9

why might matrix systems be preferred over reservoir system

Answer 9

• less of a risk of drug dumping
• cheaper and easier to make
• simpler design

Question 10

what is higuchi’s power law and why is it used

Answer 10

fraction of drug release = K(constant) X Time squared by ‘n’ (the release exponent)

its used because if your equation fits the higuchi law it is safe to assume that its diffusion controlled release

Question 11

if my equation fits the Hickson - crowell eqn, what does that indicate to us about the drug release

Answer 11

it is dissolution/erosion only. NO diffusion

Question 12

what is zero order release and why is that desirable

Answer 12

shows that drug release is constant, which means the plasma level should also be constant throughout the drug release.

the drug release rate should be the only thing that controls the plasma level

Question 13

list factors that are involved in not being able to achieve zero order release

Answer 13

1. drug solubility in GI fluid
2. dosage form surface area
3. solubility of polymer and whether it varies over time
4. thickness of polymer coating
5. is the drug dispersed homogenously in the dosage form? (matrix systems only)

Question 14

During erosion/dissolution, which type of modified dosage form are u most likely to get zero order release from and what criteria must be met to achieve it

Answer 14

a matrix device,

1. if its homogenously dispersed in the polymer
2. rate of polymer matrix dissolution/erosion is constant
3. if the drug is only released on erosion/dissolution of the polymer.

Question 15

During diffusion, which type of modified dosage form are u most likely to get zero order release from and why

Answer 15

reservoir system more likely

during diffusion, the drug particles in the centre of the matrix system has much longer to travel to be released.

the reservoir membrane surface should not be affected too much at all.

Question 16

what is mucoadhesion in terms of modified release and why is it useful

Answer 16

• a drug carrier system attaching to the mucus layer of mucosal epithelium (membranes)
• prolongs residence time in GIT, by adhering to GI membrane and control drug release.

Question 17

explain the three stages of mucoadhesion.

Answer 17

1. contact between mucoadhesive and mucus membrane. (must be rapid)
2. mucoadhesive penetrates into crevices of tissue surface and entanglement of glycoprotein chains.
3. secondary chemical bonds form between mucus and adhesives. (VDW, H bonding, electrostatic.)

Question 18

list three factors in mucoadhesion and give examples for each

Answer 18

1. polymer related factors.(molecular weight, polymer conc, polymer chain flexibility.)
2. environment-related factors (pH, initial contact time, degree of swelling.)
3. physiological variables (mucin turnover, disease states.)

Question 19

list methods used to study mucoadhesion

Answer 19

1. in vitro/ ex vivo methods
   (a) based on tensile strength
   (b) based on shear strength
2. in vivo methods (measurement of residence time at application site or transit times through GIT)

Question 20

list the ideal characteristics of mucoadhesive polymers

Answer 20

1. non-toxic
2. non-irritant
3. biodegradable
4. forms strong bonds with mucosa and adheres quickly
5. viscosity of it not affected by body temp
6. relatively cheap

Question 21

give one example of anionic and non-ionic mucoadhesives

Answer 21

anionic:
- carbomer

nonionic
- hydroxyethylcellulose (HEC)

Question 22

what is enzyme-dependent release specifically for, and why is advantageous?

Answer 22

colonic delivery

• more soluble and stable pH in colon
• lower protease levels than rest of GIT

Question 23

give an example of an enteric polymer

Answer 23

Eudragits

Question 24

(SAMPLE Q) explain why we dont formulate all drugs as MR in terms of 1. Gi transit time, 2. Drug half-life, 3.Drug solubility

Answer 24

1. transit time usually less than 12 hours which limits time for therapeutic levels to be reached and maintained
2. too short a half life can require too large a dose. half life of 4-6 hours make ideal CR candidates. longer half life drugs are MR
3. v poor aqueous solubility means dissolution rate limits absorption rate. intermediate is ideal. highly soluble drugs are hard to formulate

Question 25

(SAMPLE Q) why arent all drugs made as MR in terms of: 1. dose size, 2. Cost, 3. disease state ?

Answer 25

1. dose needs to be <500mg, if more too bulky to swallow.
   also dose dumping possible and more dangerous with MR as large dose may be deposited quickly in GIT due to bad manufacture. (overdose).
2. MR more costly typically than conventional.
3. only appropriate for chronic conditions, not acute.

Question 26

(SAMPLE Q) Why dont we make all drugs as MR in terms of : 1.drug absorption, 2. therapeutic index of drug, 3. stability in GI tract.

Answer 26

1. drug must have neither very slow nor very fast rates of absorption & excretion. very fast release requires too large a dose. absorption should be fast enough that the release rate controls conc of drug in plasma and not rate of absorption.
2. if too narrow, then levels may be out with the safe or effective plasma concs. if dose dumping occurs with narrow index, then overdose
3. the drug shouldnt degrade due to pH or enzymatic activity because at any given time the conc in gi fluid is lower than that of an intermediate release dosage form

Question 27

(SAMPLE Q) explain whether SUDF OR MUDF is more suited to MR

Answer 27

• MUDF as they lessen risk of dose dumping and even out fluctuations in release.
• dose is spread out among many individual particles, so if any particles are defective this can be made up by rest of dosage form.
• with SUDF, if theres a design fault, then the whole tablet will have an undesired release profile

Question 28

(SAMPLE Q) give an example of a polymer used in (a) dissolution/erosion controlled release and (b) diffusion controlled release

Answer 28

(a) HPMC
(B) Ethylcellulose

Question 29

(SAMPLE Q) define zero order release

Answer 29

where drug release is independent of both time and concentration of drug within the dosage form.