Artificial Neural Networks to Predict the Apparent Degree of Supersaturation in Supersaturated Lipid-Based Formulations: A Pilot Study.
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ABSTRACT:
SUBMITTER: Bennett-Lenane H
PROVIDER: S-EPMC8466847 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this study we investigated lipolysis-triggered supersaturation and precipitation of a set of model compounds formulated in lipid-based formulations (LBFs). The purpose was to explore the relationship between precipitated solid form and inherent physicochemical properties of the drug. Eight drugs were studied after formulation in three LBFs, representing lipid-rich (extensively digestible) to surfactant-rich (less digestible) formulations. In vitro lipolysis of drug-loaded LBFs were conducted, and the amount of dissolved and precipitated drug was quantified. Solid form of the precipitated drug was characterized with polarized light microscopy (PLM) and Raman spectroscopy. A significant solubility increase for the weak bases in the presence of digestion products was observed, in contrast to the neutral and acidic compounds for which the solubility decreased. The fold-increase in solubility was linked to the degree of ionization of the weak bases and thus their attraction to free fatty acids. A high level of supersaturation was needed to cause precipitation. For the weak bases, the dose number indicated that precipitation would not occur during lipolysis; hence, these compounds were not included in further studies. The solid state analysis proved that danazol and griseofulvin precipitated in a crystalline form, while niclosamide precipitated as a hydrate. Felodipine and indomethacin crystals were visible in the PLM, whereas the Raman spectra showed presence of amorphous drug, indicating amorphous precipitation that quickly crystallized. The solid state analysis was combined with literature data to allow analysis of the relationship between solid form and the physicochemical properties of the drug. It was found that low molecular weight and high melting temperature increases the probability of crystalline precipitation, whereas precipitation in an amorphous form was favored by high molecular weight, low melting temperature, and positive charge.
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Project description:Lipid-based formulations (LBF) enhance oral drug absorption by promoting drug solubilization and supersaturation. The aim of the study was to determine the effect of the lipid carrier type, drop size and surfactant concentration on the rate of fenofibrate release in a bicarbonate-based in vitro digestion model. The effect of the lipid carrier was studied by preparing type I LBF with drop size ≈ 2 µm, based on medium-chain triglycerides (MCT), sunflower oil (SFO), coconut oil (CNO) and cocoa butter (CB). The drop size and surfactant concentration effects were assessed by studying MCT and SFO-based formulations with a drop size between 400 nm and 14 µm and surfactant concentrations of 1 or 10%. A filtration through a 200 nm filter followed by HPLC analysis was used to determine the aqueous fenofibrate, whereas lipid digestion was followed by gas chromatography. Shorter-chain triglycerides were key in promoting a faster drug release. The fenofibrate release from long-chain triglyceride formulations (SFO, CNO and CB) was governed by solubilization and was enhanced at a smaller droplet size and higher surfactant concentration. In contrast, supersaturation was observed after the digestion of MCT emulsions. In this case, a smaller drop size and higher surfactant had negative effects: lower peak fenofibrate concentrations and a faster onset of precipitation were observed. The study provides new mechanistic insights on drug solubilization and supersaturation after LBF digestion, and may support the development of new in silico prediction models.
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Project description:PURPOSE:To evaluate the performance of artificial membranes in in vitro lipolysis-permeation assays useful for absorption studies of drugs loaded in lipid-based formulations (LBFs). METHODS:Polycarbonate as well as PVDF filters were treated with hexadecane, or lecithin in n-dodecane solution (LiDo) to form artificial membranes. They were thereafter used as absorption membranes separating two compartments mimicking the luminal and serosal side of the intestine in vitro. Membranes were subjected to dispersions of an LBF that had been digested by porcine pancreatin and spiked with the membrane integrity marker Lucifer Yellow (LY). Three fenofibrate-loaded LBFs were used to explore the in vivo relevance of the assay. RESULTS:Of the explored artificial membranes, only LiDo applied to PVDF was compatible with lipolysis by porcine pancreatin. Formulation ranking based on mass transfer in the LiDo model exposed was the same as drug release in single-compartment lipolysis. Ranking based on observed apparent permeability coefficients of fenofibrate with different LBFs were the same as those obtained in a cell-based model. CONCLUSIONS:The LiDo membrane was able to withstand lipolysis for a sufficient assay period. However, the assay with porcine pancreatin as digestive agent did not predict the in vivo ranking of the assayed formulations better than existing methods. Comparison with a Caco-2 based assay method nonetheless indicates that the in vitro in vivo relationship of this cell-free model could be improved with alternative digestive agents.
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