Drug Release Patterns of Controlled Delivery Dosage Forms

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Chapter: Biopharmaceutics and Pharmacokinetics : Controlled Release Medication

1. Slow zero-order release 2. Slow first-order release 3. Initial rapid release of loading dose followed by slow zero-order release 4. Initial rapid release of loading dose followed by slow first-order release.

Drug Release Patterns of Controlled Delivery Dosage Forms


If one assumes that —

1.        Drug disposition follows first-order kinetics

2.        Rate-limiting step in the absorption is rate of drug release from the controlled-release formulation (i.e. Kr < Ka), and

3.        Released drug is rapidly and completely absorbed,

then, the four models for drug input based on the drug release pattern can be defined:

1. Slow zero-order release

2. Slow first-order release

3. Initial rapid release of loading dose followed by slow zero-order release

4. Initial rapid release of loading dose followed by slow first-order release.

The resulting profiles are depicted in Fig. 14.3.

Fig. 14.3 Schematic representation of four major types of drug release characteristics from controlled-release formulations

1. Slow Zero-Order Release Systems

If the drug released from controlled-release formulations is stable in fluids at the absorption site, has similar absorption efficiency from all absorption sites and is absorbed rapidly and completely after its release, then, its rate of appearance in plasma will be governed by its rate of release from the controlled-release formulation. Thus, when the drug release follows zero-order kinetics, absorption will also be a zero-order process and concentration of drug in plasma at any given time can be given by equation:

where K0 = zero-order release rate constant, also written as R0, the zero-order release rate.

The above equation is similar to the one that expresses the concentration-time course of a drug that shows one-compartment kinetics following constant rate i.v. infusion. The time to reach steady-state depends upon the elimination half-life of the drug. It is usually not possible with a single oral controlled-release dose to attain the plateau even with a drug having short half-life such as 3 hours since the mean GI residence time is around 12 hours. It takes 4.3 half-lives for attainment of 95% steady-state values. Thus, if t½ is 3 hours, about 13 hours will be required for the drug to reach plateau. Slower the elimination, (longer the t½), more the time required to reach steady-state. Once the desired steady-state is reached with repeated dosing of zero-order controlled-release formulation, minimal fluctuations will be observed. Zero-order release systems are thus ideal controlled delivery formulations.

2. Slow First-Order Release Systems

Such systems are easier to design but are inferior to zero-order systems especially when they are meant for oral use. This is because with first-order release characteristics, smaller and smaller amounts of drug are released as time passes and secondly, as the formulation advances along the GIT, the absorption efficiency generally decreases due to a number of reasons like decreased intestinal surface area, increased viscosity and decreased mixing. Thus, larger amounts of drug are needed to be released at a later stage when in fact the opposite happens with first-order systems.

The concentration of drug in plasma following administration of a controlled-release formulation with slow first-order release is given by equation:

When Kr < KE, flip-flop phenomena is observed which is a common feature for such controlled-release formulations. With repeated dosing of slow first-order release formulations, one generally observes a lower Cmax, higher Cmin and longer tmax in comparison to conventional release formulations.

3. Slow Zero-Order Release Systems with a Rapid Release Component

With such formulations, an initial dose is rapidly released (burst-effect) for immediate first-order availability while the remaining amount is released and absorbed at a slow zero-order rate. The equation for concentration-time course of such a formulation contains two portions, one each to denote rapid first-order release and slow zero-order release.

Such a formulation is ideally suited for drugs with long t½ in which cases attainment of plateau would otherwise take a long time. The slow release component should ideally begin releasing the drug when the drug levels from the fast component are at a peak. However, the approach suffers from a big disadvantage when the formulation is meant for repetitive dosing — the blood level profile shows a peak-trough pattern (which normally does not result when all of the drug is released at a slow zero-order rate); this may cause a momentous rise in peak concentration immediately after each dose triggering toxic reactions (see Fig. 14.4). It is for this reason that such a design is unpopular.

The transient fluctuations in the peak concentration with these formulations can however be overcome by:

1. Decreasing the loading dose in the subsequent dosage forms (which appears to be impractical),

2. Increasing the dosing interval (this also seems to be tedious), or

3. Administering an immediate-release conventional dosage form prior to repetitive dosing of zero-order controlled-release formulation instead of incorporating it in the latter.

Fig. 14.4 Plasma concentration-time profile which results from repeated dosing of a controlled-release formulation with zero-order release and an initial fast release component.

4. Slow First-Order Release Systems with a Rapid Release Component

The equation describing the time course of plasma drug concentration with this type of formulation will also contain two portions—one to describe rapid first-order absorption and the other for slow first-order absorption from controlled-release portion.

As in the previous case, to obtain the desired plateau, the slow release component, DM should start releasing the drug:

1. When the peak has been attained with rapid release dose, DI; this requires DM >> DI which results in wastage of drug since the absorption efficiency reduces as time passes and dosage form descends down the GIT, or

2. When all of the DI has been released; this requires relatively small DM and therefore less drug wastage and better sustained levels despite fluctuations in drug levels (Fig. 14.5).

The problems that result from repeated dosing of this type of formulation are similar to that described for the third type of release pattern and can be handled in a similar manner.

Fig. 14.5 Plasma concentration-time profile which results after a single oral dose of controlled-release drug delivery system containing a rapid release dose and a slow first-order release component

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