Drug Absorption from a Parenteral Oil Depot

[Michael Scally MD]

Highlights
· A study was initiated to determine in vivo nandrolone absorbance release out of an oil depot
· Oil depot was administrated subcutaneously to elderly women
· The pharmacokinetic profile of nandrolone is related to that of benzyl alcohol
· Small molecules are directly absorbed, while larger, more lipophilic molecules exhibit an incomplete and slow absorption

Kalicharan RW, Schot P, Vromans H. Fundamental understanding of drug absorption from a parenteral oil depot. Eur J Pharm Sci. 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.

 

[Michael Scally MD]

Fundamental Understanding of Drug Absorption from a Parenteral Oil Depot

Oily solutions of lipophilic compounds are widely used as a sustained release formulation. Although this pharmaceutical approach has been applied for several decades already, relatively little research has been published on the fundamental parameters that determine the absorption characteristics.

Generally, the formulation of an oil depot contains arachis or sesame oil as well as an amount of benzyl alcohol (BOH) which increases the solubility of the (pro)drug in the oil. In addition to these excipients, the formulation contains the active compound, most often as the esterified substance. Theoretically, there are a number of factors that determine drug absorption from a parenteral oil depot:

1) The drug dissolved in the oil is released as a result of the concentration gradient. Relevant parameters are

a) the concentration in the oil,
b) the thickness of the diffusion layer as well as the diffusion coefficient in the oil,
c) the surface area of the depot,
d) the partition coefficient (P) between oil and tissue fluid and finally
e) the thickness of the diffusion layer in the aqueous phase as well as the diffusivity in this compartment.

Basically, this represents the rate at which the drug is transported through the tissue. The oil liquid is not injected directly in the blood stream, while yet the absorption is normally measured in this central compartment (Cserum). Therefore, a membrane should be included in this model representing the tissue which is situated in between the oil and the central circulation.

2) BOH exhibits not only a significant solubility in the oil phase, but does also dissolve in the aqueous phase. Consequently, it will also be released out of the depot. Because of the different physicochemical properties, it can be expected that BOH shows a completely different release profile than the prodrug. BOH in turn has a significant influence on the solubility of the active compound in both the oil and the aqueous phase. Therefore, it is obvious that the partition coefficient is not a constant value during the release from the depot.

3) In most cases a lipophilic ester is used as a prodrug. After release out of the oil, this ester has to be hydrolysed to the parent drug. The prodrug exhibits a significantly higher logP than the parent compound. As a consequence, the transport through tissue can be considerably different; highly lipophilic drugs show both retardation by tissue absorption effects and lymphatic transport whereas less lipophilic compounds diffuse directly to the central circulation. Hence, the speed and the place at which (enzymatic) hydrolysis occurs may have impact on the rate of absorption.

Other factors that may also contribute to the absorption rate are:
· injection depth,
· site of injection,
· lymphatic absorption,
· massage before injection and
· muscle activity.

Although these suggested and obvious factors could lead to a complete understanding of drug absorption from oil depots, no studies have been published on this topic so far. This article makes a distinction between release and absorption kinetics: substance release from the depot can be translated from the mass flux from oil towards the aqueous phase, while absorption represents the entire process in which the substance enters in de central compartment. Hence, absorption includes the release out of the oil and the subsequent transfer through the tissue to the blood stream.

 

[Michael Scally MD]

[OA] Kalicharan RW, Oussoren C, Schot P, de Rijk E, Vromans H. The contribution of the in-vivo fate of an oil depot to drug absorption. International Journal of Pharmaceutics 2017;528:595-601. The contribution of the in-vivo fate of an oil depot to drug absorption - ScienceDirect

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 1.0 mL 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 31 days of injection. All rats were injected with a 0.1 mL 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 31 days. 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.