The contribution of the in-vivo fate of an oil depot to drug absorption.

Sustained release of lipophilic compounds can be achieved with oil depots. These parenteral formulations are generally injected in the vastus lateralis and deltoid muscle. It is known that the absorption rate differs between these two muscles. The reason for this is not fully understood. The aim of the current study was to investigate the fate of an oil depot in different tissues to elucidate whether the disappearance rate of oil is the cause of observed differences in absorption rate. A study with healthy volunteers was conducted to determine 1.0mL oil depots in the vastus lateralis and deltoid muscle for two weeks. The spatial distribution of the oil depots was determined using MRI. Additionally, a study in rats was conducted to microscopically examine the oil immediately and after 31days of injection. All rats were injected with a 0.1mL oil depot with and without benzyl alcohol (BOH), a commonly used excipient in oil depots. In humans, it was shown that all oil depots were equal in volume and surface area directly after injection. Moreover, the disappearance rate for all oil depots was similar; within one week there was no depot visible anymore by MRI. This in contrast to the depots in rats, which were still microscopically visible after 31days. It is concluded from these observations that the oil is dispersed to small droplets in the course of time. The resulting increase in surface area does not lead to an increase in absorption rate however. The results of this paper show that the variation in drug absorption as found for the two muscles is not caused by a distinction in surface areas or disappearance rates of the oil depots. Therefore, it is argued that the local tissue drainage (e.g. lymph flow) plays a considerable role in drug absorption from oil depots, whereby the lymph flow differs between the muscles.

Spatial distribution of oil depots monitored in human muscle using MRI.

Oil depots are parenteral drug formulations meant for sustained release of lipophilic compounds. According to mass transport models, the drug-release rate from these injections is determined by the surface area of the oil depot. Until now, the size of the surface area of injected depots has not been assessed, however. MRI provides an excellent possibility to distinguish between water and adipose tissue. The aim of this study was to investigate whether MRI can be used to determine the shape and hence the surface area of oil depots in muscle tissue. The developed MRI-scan protocol is demonstrated to be suitable for visualising oil depots. It was applied to determine the surface area of 0.5mL oil, i.m. injected in healthy volunteers. The mean (±RSD) surface area and volume of the depots recovered after injection was 755.4mm(2) (±26.5) and 520.1mm(3) (±24.6). It is shown that the depot disappearance from the injection site is very variable between volunteers. It is suggested that the oil is first solubilized and subsequently distributed. In all cases, the oil was not detectable after 14days. These factors are relevant for the understanding of the mechanism by which compounds are released out of oil depots.

Fundamental understanding of drug absorption from a parenteral oil depot.

Oil depots are parenteral drug formulations meant for sustained release of lipophilic compounds. Until now, a comprehensive understanding of the mechanism of drug absorption from oil depots is lacking. The aim of this paper was to fill this gap. A clinical study with healthy volunteers was conducted. An oil depot with nandrolone decanoate and benzyl alcohol was subcutaneously administered in the upper arm of female volunteers. Pharmacokinetic profiles of both substances were related to each other and to literature data. Benzyl alcohol absorbs much more rapidly than nandrolone. In detail, it appears that benzyl alcohol enters the central compartment directly, while nandrolone decanoate is recovered in serum after a lag time. This lag time is also seen in literature data, although not reported explicitly. The absorption of nandrolone is enhanced by the presence of benzyl alcohol. This is most likely an effect of altered oil viscosity and partition coefficient between the oil and aqueous phase. The absorption rate constant of compounds is found to be related to the logP of the solubilized prodrug. The absorption rate is however not only determined by the physico-chemical properties of the formulation but also by the tissue properties. Here, it is argued that lymphatic flow must be considered as a relevant parameter.

Elimination of Elyzol 25% Dentalgel matrix from periodontal pockets.

Elyzo 25% Dentalgel (EDG) which is developed for use in the treatment of periodontitis is a suspension of metronidazole benzoate (40%) in a mixture of glyceryl mono-oleate (GMO) and triglyceride (sesame oil). Metronidazole can be detected in the periodontal pockets 24-36 h after application. The aim of the present study was to estimate the period of time that the gel matrix persists on periodontal pockets after 1 application of EDG. 12 patients were included in the study. From each patient, 1 sample was taken before and immediately after, and 1, 2, 3, 4, 5, 6, 8, 12 and 24 h after application. Subgingival scaling followed by absorption of gingival crevicular fluid with filter paper was used for sampling. The sampling unit was 1 tooth. Each sample was assayed for the amount of GMO and oleic acid (a degradation product of GMO) by means of high-performance liquid chromatography (HPLC) with UV detection. To allow determination of the GMO dose applied into the pockets and to estimate the recovery rate of the sampling method, 1 tooth in each patient was selected for sampling as soon as the gel had set, i.e., about 10 min after application. Only in 1 patient was a detectable amount of GMO within the pocket revealed 24 h after application. This amount was approximately 0.5% of the mean GMO dose applied around 1 tooth. GMO was found no longer than 12 h in the remaining patients.