Introduction

Drugs are commonly applied in animal or human beings to correct, prevent or modify physiological functions and can be administered to the body by various routes. The route of administration is the path by which a drug or another substance is taken into the body and is generally classified by the location at which the drug substance is applied. Common routes of administration include orally, intravenously, intramuscularly, subcutaneously, transdermal and vaginal administration. Routes of administration can also be classified whether the effect is local or systemic. In case of a local treatment the drug substance is applied directly where its action is desired. In other cases the drug is administered systematically like in case of an oral administration. Once absorbed, the drug will subsequently be distributed over the body and finally eliminated from the body by renal and/or hepatic clearing. Depending on the physicochemical properties of the drug (solubility, lipophilicity, molecular weight etc.) and the design of the formulation the concentration of drug in blood will initially increase, reach a maximum and eventually decrease in time until the drug is totally removed from the body. The figure below illustrates drug plasma levels after administration of a formulation of a drug with different pharmacokinetic properties. Differences in physicochemical properties of the drug may lead to significant differences in drug plasma profiles.

In some cases it is desired to maintain drug plasma levels at a certain concentration. Repetitive administration of equal doses at a fixed interval of time ensures the maintenance of an effective therapeutic effect. Here, it is important that the concentration is kept between respectively the maximum safe plasma concentration and the minimum effective plasma concentration. When the plasma half-life of a drug is short, the formulation should be taken several times a day. In this situation, a formulation with a sustained release may offer the possibility to reduce the dose frequency to once a day. A sustained release formulation which is able to release the drug over a longer period of time offers advantages like increased efficacy, safety, compliance and convenience. Therefore such a drug delivery system is often preferred above daily administration of drugs. Furthermore sustained release formulations can be designed to deliver one or more drugs at a specified rate, for a specific period of time and even at a desired location.
In order to adapt or control the drug plasma profile, the design of the drug formulation is of importance. Here, knowledge of the drug and its physical interaction with the excipients within the formulation is essential. In order to design an optimal formulation and reduce development times computational modeling offers significant advantages. A computational model contains relevant parameters that define the drug delivery process being studied. Simulation is done by adjusting these parameters and observing how the changes affect the results predicted by the drug delivery model. The simulation helps in a better understanding of the drug delivery process and allows for a more efficient development of an optimal controlled delivery system.

In literature many types of sustained release formulations have been described like injectable suspension depots, in situ forming depots, polymeric implants (either biodegradable or non-biodegradable), injectable hydrogels, biodegradable microspheres etc. These formulations can be classified into three major groups:

Suspension depot formulations
A suspension depot is usually administered subcutaneously or intramuscularly and allows slow release of drug and gradual absorption to the body. The release rate and duration of the depot is controlled by the dissolution rate in the interstitial fluid and diffusivity over the lipid membranes. The release rate and corresponding plasma levels can tuned by varying the injection volume, particle size and drug concentration.

Matrix formulations
In case the physicochemical properties of the drug are not suitable for development of a suspension formulation, the drug can also be incorporated in a carrier matrix. In the carrier matrix the drug is dispersed, either molecularly or as solid drug particles. The release rate is controlled by the dissolution rate of drug in the carrier matrix. In case the carrier matrix is also biodegradable the release rate is also controlled by the degradation rate of the matrix.

Reservoir formulations
In a reservoir device the drug is incorporated in a core that is surrounded by a rate limiting membrane. In the core the drug is dispersed, either molecularly or as solid drug particles. The presence of a release rate controlling membrane normally provides a better release profile. The release rate is controlled by the solubility and diffusivity in both core and membrane and by the thickness of the membrane.