New Insights into Drug Absorption from Oil Depots

Abstract

Sustained delivery formulations are used in order to prolong the pharmacological activity of a drug. A commonly used parenteral sustained delivery formulation is an oil depot which consists of a solution of lipophilic molecules in a vegetable oil. These are normally administered either intramuscularly (i.m.) or subcutaneously (s.c.). The idea of the formulation approach is that a substance that is far better soluble in oil than in water tends to stay in the oil phase. The exact mechanism of drug absorption from these formulations is not fully understood however. The aim of this dissertation was to obtain more understanding about the way a drug is absorbed from an oil depot into the human body. It is generally assumed that the drug release from the oil is mainly determined by the substance’s partition coefficient, i.e. the ratio between lipid and aqueous solubilities of the drug. In the human body, the aqueous phase is represented by the interstitial fluid, which is located between cell tissue at the site of injection. Logically, the higher the affinity for oil, the lower the tendency a drug will have to leave the oil phase. Consequently, a more pronounced sustained drug release is obtained by an increase of the drugs lipophilicity (i.e. higher partition coefficient). A drug can be made more lipophilic through esterification of the molecule with a fatty acid. This esterified compound is inactive as such and is therefore referred to as prodrug. After release from the oil it is activated by hydrolysis, resulting in the so-called parent compound or active substance, which is responsible for the pharmacological effect. The papers that have been published until now can be distinguished into two different focus points: On the one hand, in vitro models examined the prodrug release from the oil depot, which is basically nothing else than a diffusion process through an interface. On the other hand, other studies focused mainly on the pharmacokinetic profiles, i.e. the plasma concentrations of the parent compound. Clearly, the appearance of the parent compound in the blood stream must be considered as a result of a sequence of steps including release out of the oil, hydrolysis of the prodrug and transport to the central circulation. These steps, i.e. the exact fate of the prodrug once released from the oil depot has remained relatively uninvestigated. Therefore, the specific aim of this dissertation is to assess what happens with the prodrug once it is released out of the oil depot. In my dissertation, it is presented what the new insights are of drug absorption from oil depots. It has been examined what the role of the excipient benzyl alcohol was on the absorption of nandrolone and how the oil is distributed over the injection site. Finally, I have studied where activation of the inactive drugs takes place in the body. These fundamental aspects on drug absorption from oil depots are relevant for the therapeutic efficacy in patients.