Summary modifed release oral dosage forms

Modified release oral dosage forms

Control over the release of drugs offers the possibility to release the drug
- At the desired site
- At the right moment in time
- With the desired rate
- In the appropriate dose

This may result in:
- Improved therapeutic efficacy
- Reduction in side-effects
- Increased ease of use

Oral controlled release
(combinations/relationships/variations)

Slow release (extended release, prolonged release)
- The release of the drug from the dosage form in the dissolved state is prolonged over
a longer period of time. (>45 minutes)
- Objectives:
 Reduction of the dosing frequency (beta-blockers: metoprolol, oxprenolol,
pindolol), so the patient compliance will be improved.
 Flattening of peaks of plasma-profile to reduce the side-effects (lower peak
levels) and the troughs in blood concentration. Therapy-free periods are
reduced. (anti-epileptics: carbamazepine)
 Protection of the gastro-intestinal tract wall against irritating substances
(valproic acid)

Delayed release
- Dosage form will not immediately start to release the drug when the drug is taken,
but after a specified time frame: lag-time.
- The lag-time is more or less precisely predetermined by the technical properties of
the product.
- Objectives:
 Protection of the drug against the environment in the gastro-intestinal tract
 Protection of the stomach against irritating drug effects

Targeted release
- The release of drug will occur at a predetermined site in the gastro-intestinal tract.
- Often a lag-time too
- Objectives:
 Maximization of a local effect in the gastro-intestinal tract
 Specific side of absorption in the intestinal tract  target the release of that
drug to that specific part  maximization of bioavailability

, Objectives optimization of therapy and effect
- optimization of the therapeutic effect
 Time at which drug release occurs
 Bioavailability
 Release targeted drug to the site of action
- Improved convenience for the patient
 Dosing frequency
 Reduction of side-effects

The effect of prolongation, delay or targeting of the drug release may often be strongly
optimized by the combination of different forms of controlled release
- Mesalazine: locally acting drug which works against inflammations in your lower
gastro-intestinal tract.
- Delay the release to the colon  reduced systemic absorption  reduced the
systemic side effects  increased therapeutic effect

Verelan: verapamil used against myocardial infarcts
In the early morning there’s a larger chance of myocardial infarcts than in the afternoon and
early evening. The plasma-levels in the early morning are higher than in the afternoon.
Prevention of these infarcts is done by producing of a specific capsule containing slow
release beats, which give a peak plasma-level of verapamil in the early morning.

USP dissolution test
- Determines in vitro drug release
- The medium simulates stomach (HCL), intestinal conditions (Phosphate buffer) and
the bile salts (if the solubility is insufficient, surfactants are added)
- By measuring the drug release, it can be controlled whether a drug needs release
requirements.
- This test is useful to find out whether there is a so-called ivivc: in vitro in vivo
correlation between the release of the drug in the vitro situation (vessel) and the
absorption rate (pharmacokinetic parameters AUC/Cmax/Tmax) of the drug in vivo,
in the human being.

The plasma profiles in vitro have different plasma concentrations than the released profiles
in vivo, because we also have to deal with the elimination phase, besides the drug release.
Slow released doesn’t reach the MTC: no side effects
The dose frequency can be reduced.

Slow release is
interesting: beneath
the MTC, therapeutic
effects lasts longer