Oral modified release formulations Flashcards
discuss the disadvantages of conventional formulations
1) If the drug has a short half-life, it has to be administered frequently, so there are chances of missing the dose.
2) concentration-time profile obtained is not steady.
The fluctuations of drug plasma level that occurs during conventional release may produce under medication or overmedication.
3) Poor patient compliance.
at steady state the average concentration of drug remains constant. what does the time to reach steady state depend on?
1) half time of the drug and is independent of the dose size and the dosing interval
is a once daily formulation the best?
1) Very little evidence that once a day dosing is best!
2) Unless there is a good reason otherwise probably safer to give a drug twice daily rather than od – no possibility of dose dumping
how are modified release formulations classified?
Categorized based on the release profile using plasma concentration plasma curve
describe the first-order kinetics model of drug release for conventional dosage forms.
In First-order model, drug release is dependent on the amount of drug available for release and therefore the rate of release declines exponentially with time.
describe the rate of drug release from Extended release dosage forms
1) Extended release dosage forms are governed by zero-order kinetics in which the rate of release is independent of amount of drug remaining in the dosage form.
2) Therefore a constant amount of drug will be released over time from extended release dosage forms
what are the advantages of modified release formulations?
1) Reduced dosing frequency
2) Dose reduction
3) Improved patient compliance
4) A constant level of drug concentration in blood plasma
5) Reduced toxicity due to overdose
6) Reduces the fluctuation of peak-value
7) night time dosing can be avoided
one advantage of modified release formulations is that the total amount of drug administered can be reduced. what are the benefits of this?
1) Maximizing availability with minimum dose
2) Minimize or eliminate local side effects
3) Minimize or eliminate systemic side effects
4) Minimize drug accumulation with repeated dosing.
outline the disadvantages of modified release formulations
1) Possibility of dose dumping
2) Reduced potential for dose adjustment
3) Cost of single unit higher than conventional dosage forms
4) Increased potential for first-pass metabolism
5) Decreased systemic availability in comparison to immediate release conventional dosage forms
6) Poor in vitro and in vivo correlations
discuss what information we need to know in order to select a drug for modified release?
requires knowledge on the absorption mechanism of the drug from the gastrointestinal (GI) tract, the general absorbability, the drug’s molecular weight, pKa, solubility at different pH, and apparent partition coefficient
outline the characteristic that makes a drug unsuitable for modified release formulation
1) Short elimination half-life, i.e t1/2 <2 hrs
2) Long elimination half-life, i.e t1/2 >8 hrs
3) Narrow therapeutic index
4) Large doses
5) poor absorption
6) Low or slow solubility
7) Extensive first-pass clearance
define sustained-release (SR)
These are drug delivery systems (DDS) that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of single-dose of drug
what is meant by a Controlled-release dosage form?
planned, predictable, and slower-than-normal manner for a longer period of time
what is meant by Extended release?
especially selected to release the drug over longer periods, typical drugs short t1/2 such as Phyllocontin Continus
what is meant by Delayed release?
The drug is released at a specific site such as in the colon, PENTASA® (mesalamine)
what is a Repeat action DDS?
If granules are partly coated, some will dissolve in stomach (uncoated) and some in the intestine to achieve repeated or controlled release
explain what is meant by a Prolonged release system?
designed to release the drug slowly and to provide a continuous supply of drug over an extended period. They prevent very rapid absorption of the drug, which could result in extremely high peak plasma drug concentration
outline the physiochemical factors that affect the release rate of a drug
1) Aqueous solubility: low solubility→ drug loss
2) Partition coefficient: High Log P→ low permeability
3) Drug pKa and ionization at physiological pH→ ionization vs permeability
4) Drug stability→ hydrolysis, e.g. penicillin
5) Molecular weight and diffusivity: Large MW→ low permeability
discuss the desirable physicochemical parameters for drug selection
1) molecular weight: <1000 daltons
2) solubility: >0.1mg/ml
3) partition coefficient: high
4) absorption mechanism: diffusion
5) absorbability : from all GI segments
6) release: not influenced by enzymes or pH
discuss the biological factors that affect the release rate of a drug
1) It is essential that the rate of release is much slower than the rate of absorption.
2) Drugs with high apparent volume of distribution, which influence the rate of elimination of the drug are poor candidate for oral SR drug delivery system.
3) A drug which extensively metabolizes is not suitable for SR drug delivery system. A drug capable of inducing metabolism, inhibiting metabolism, metabolized at the site of absorption or first-pass effect is poor candidate for SR delivery, as it could be difficult to maintain constant blood level.
If we assume the transit time of dosage forms in the absorptive areas of GI tract is about 8-12 hours, what should the maximum half-life for absorption be?
the maximum half-life for absorption should be approximately 3-4 hours. Otherwise the dosage form will pass out of absorptive regions before drug release is complete.
summarise the USP requirements and FDA guidance for Drug release of modified-release dosage forms
1) The USP test for drug release for extended-release and delayed-release articles is based on drug dissolution from the dosage unit against elapsed test time
- 1.0(hr) - Amount dissolved between 15% and 40%
- 2.0- between 25% and 60%
- 4.0- between 35% and 75%
- 8.0- not less than 70%
summarise the USP requirements and FDA guidance for modified-release dosage forms with regards to Uniformity of dosage units
Uniformity of dosage units may be demonstrated by either of two methods, weight variation or content uniformity
In vitro/in vivo correlations (IVIVCs) are part of the requirements for USP and FDA guidance. why are IVIVCs important?
IVIVCs is critical to the development of oral extended-release products. Assessing IVIVCs is important throughout the periods of product development, clinical evaluation, submission of an application for FDA-approval for marketing, and during post approval for any formulation or manufacturing changes which are proposed.