Transfer of Lipophilic Drugs from Nanoemulsions into Lipid-Containing Alginate Microspheres

Abstract

Knowledge about the release behavior and drug retention properties of colloidal carriers is of essential importance for quality control as well as to predict in vivo performance. When conducting release studies from such systems, the release media should preferentially contain lipophilic acceptor components in order to mimic physiological conditions. In this study, transfer from a trimyristin nanoemulsion into lipid-containing hydrogel beads was investigated for fenofibrate, cannabidiol, retinyl acetate, orlistat, and lumefantrine. To generate the acceptor system, a trimyristin nanoemulsion was incorporated into Ca-alginate microspheres (mean diameter ~40 µm) with a spraying method. Using this approach, the advantages of small lipophilic acceptor particles with a large interfacial area were combined with a single separation process from the donor via a filtration step. The method was applicable to distinguish between fast (fenofibrate) and slow drug transfer (lumefantrine) with good time resolution. Lipophilicity, estimated according to the calculated logP value of the respective drug, was a major factor influencing the transfer performance: the higher the logP value, the slower the transfer. This experimental setup is a promising technique to investigate the release of poorly water-soluble drugs from various types of nanocarriers under closer to physiological conditions than with many other methods currently applied.

Transfer Investigations of Lipophilic Drugs from Lipid Nanoemulsions to Lipophilic Acceptors: Contributing Effects of Cholesteryl Esters and Albumin as Acceptor Structures

“…The D10 diameter was not below 8 µm so that the acceptor gel particles could be separated from the nanosized donor via filtration. The particle diameters, as well as the particle size distributions, were reproducible and very similar to those of the particles obtained in an earlier study [ 29 ].…”

“…The cryo-SEM images illustrate that the nanoparticles were associated with the hydrogel network and that their individuality seemed to be preserved in most cases (Figure 4). This is in accordance with the results obtained in earlier studies, in which the melting pattern of incorporated trimyristin particles was analyzed, and which indicated the presence of small nanoparticles inside the hydrogel beads [29].…”

“…After mixing of donor and acceptor, fenofibrate (logP 4.86) transfer was completed within a few minutes, whereas retinyl acetate (logP 6.56) transferred more slowly and reached equilibrium at >40 h. Orlistat (logP 7.61) transfer seemed to be completed after about 70 h (Figure 5). The transfer course of all drugs was very similar to that obtained in earlier studies using trimyristin-nanodropletcontaining hydrogel microbeads as acceptor; however, the extent of drug transfer was distinctly smaller in the present case [29]. Assuming an equal distribution between the donor and acceptor lipids, a maximum fraction of 90% transferred drug would have been expected based on the adjusted lipid-mass ratio of 1 + 9 (d + a).…”

“…In general, the lipid content of the hydrogel bead dispersions was adjusted to ~4.4% by adding water (corresponding to approximately 44 mg/mL). A certain fraction of water surrounding the hydrogel particles was required to ensure thorough mixing of the donor and acceptor on the one hand, and to be able to draw a sufficient volume of sample out of the transfer vial for drug quantification on the other hand [ 29 , 33 ]. The lipid concentration of the hydrogel particle dispersions used for the transfer studies, as determined via DSC, are indicated in Figure 1 .…”

“…In a recent study, the transfer of lipophilic drugs from drug-loaded trimyristin emulsions was investigated using an unloaded trimyristin nanoemulsion incorporated into small calcium alginate hydrogel microbeads as a lipophilic acceptor [ 29 ]. This setup combined the advantages of small acceptor particles (with a large corresponding interfacial area) with a simple, filtration-based separation procedure from the donor particles.…”