Browsing by Subject "In vitro digestion"

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Increasing post-digestive solubility of curcumin is the most successful strategy to improve its oral bioavailability: A randomized cross-over trial in healthy adults and in vitro bioaccessibility experiments
(2021) Flory, Sandra; Sus, Nadine; Haas, Kathrin; Jehle, Sina; Kienhöfer, Eva; Waehler, Reinhard; Adler, Günther; Venturelli, Sascha; Frank, Jan
Scope: Different mechanistic approaches to improve the low oral bioavailability of curcumin have been developed, but not yet directly compared in humans. Methods and Results: In a randomized, double-blind, cross-over trial with 12 healthy adults, the 24 h pharmacokinetics of a single dose of 207 mg curcumin is compared from the following formulations: native, liposomes, with turmeric oils, with adjuvants (including piperine), submicron-particles, phytosomes, γ-cyclodextrin complexes, and micelles. No free, but only conjugated curcumin is detected in all subjects. Compared to native curcumin, a significant increase in the area under the plasma concentration–time curve is observed for micellar curcumin (57-fold) and the curcumin-γ-cyclodextrin complex (30-fold) only. In vitro digestive stability, solubility, and micellization efficiency of micellar curcumin (100%, 80%, and 55%) and curcumin-γ-cyclodextrin complex (73%, 33%, and 23%) are higher compared to all other formulations (<72%, <8%, and <4%). The transport efficiencies through Caco-2 cell monolayers of curcumin from the digested mixed-micellar fractions did not differ significantly. Conclusion: The improved oral bioavailability of micellar curcumin, and to a lesser extent of γ-cyclodextrin curcumin complexes, appears to be facilitated by increased post-digestive stability and solubility, whereas strategies targeting post-absorptive processes, including inhibition of biotransformation, appear ineffective.
Prumnopitys andina fruit extract activates liver X receptors after in vitro digestion
(2022) Jiménez‐Aspee, Felipe; Pospiech, Jonas; Bauer, Sarah; Sus, Nadine; Kufer, Thomas A.; Frank, Jan
Scope: 20-Hydroxyecdysone (20E) is the main phytochemical present in the fresh arils of Prumnopitys andina. 20E is reported to have anabolic effects by modulation of gene transcription by interaction with nuclear receptors. Our aim is to evaluate the in vitro bioaccessibility, transepithelial transport of 20E, and the capacity of P. andina fruit extract and 20E to activate selected mammalian nuclear receptors in transiently transfected human cells after simulated gastrointestinal digestion. Results: 20E shows good stability, solubility, and micellization after in vitro digestion. 20E is taken up by Caco-2 cells, but poorly transported through the epithelial cell membrane, possibly due to P-glycoprotein-mediated efflux. In transiently transfected HepG2 cells, the fruit extract significantly induces the signal intensity for the liver X receptor (LXR)-α and -β by 1.6 and 1.4-fold, respectively. In contrast, the treatment with 20E, irrespective of its concentration, did not change the activity of both LXR receptors. No effects are observed for the pregnane X receptor or the constitutive androstane receptor. Conclusion: Our findings show that components of the digested P. andina extract other than 20E are responsible for the effects on LXR-α and -β. Our findings open new perspectives on the potential role of P. andina fruits in cholesterol metabolism and inflammatory diseases.
Recovery of polyphenols using pressurized hot water extraction (PHWE) from black rosehip followed by encapsulation for increased bioaccessibility and antioxidant activity
(2022) Kasapoğlu, Kadriye Nur; Demircan, Evren; Gültekin-Özgüven, Mine; Kruger, Johanita; Frank, Jan; Arslaner, Ayla; Özçelik, Beraat
In this work, pressurized hot water extraction (PHWE) of hydrophilic polyphenols from black rosehip fruit was maximized using response surface methodology for simultaneous optimization in terms of extraction yield, total antioxidant capacity, total (poly)phenols, catechin, total monomeric anthocyanins, and cyanidin-3-O-glucoside. Extraction parameters, including temperature (X1: 40–80 °C) and the solvent-to-solid ratio (X2: 10–40 mL/g), were investigated as independent variables. Experimentally obtained values were fitted to a second-order polynomial model, and optimal conditions were determined using multiple regression analysis and analysis of variance. The black rosehip extract (BRE) obtained at optimized PHWE conditions was further encapsulated in biopolymer-coated liposomes and spray dried to enhance its processing and digestive stability. After reconstitution, the fabricated particles had an average size of 247–380 nm and a zeta-potential of 15–45 mV. Moreover, encapsulation provided remarkable protection of the phenolics under in vitro gastrointestinal digestion conditions, resulting in up to a 5.6-fold more phenolics in the bioaccessible fraction, which also had 2.9–8.6-fold higher antioxidant activity compared to the nonencapsulated BRE. In conclusion, PHWE in combination with a biopolymer coating is a potent method for the production of stable and safe edible natural extracts for the delivery of (poly)phenolic compounds in food and dietary supplements.
Relative bioavailability of curcumin as affected by formulation strategies
from in vitro digestion and cell culture experiments to human clinical trials
(2022) Flory, Sandra; Frank, Jan
Curcumin, the bioactive component of turmeric (Curcuma longa L.), has been used for thousands of years in traditional medicine for the prevention or treatment of several diseases and symptoms. Nowadays, curcumin is investigated worldwide as a nutritional supplement. To overcome the central limitation of its naturally low oral bioavailability, several formulation strategies have been developed, such as its co-administration with turmeric oils or piperine to inhibit its metabolism and efflux or its incorporation into micelles, cyclodextrin complexes or phospholipid bilayers to improve its stability and solubility. So far, the different formulations have not been compared directly, in one cohort of participants and at equal doses. The present doctoral thesis aimed, for the first time, at a direct comparison of the bioavailability of curcumin in form of a native curcuma extract or seven formulations, namely polysorbate 80 micelles, g-cyclodextrin complexes, liposomes, phytosomes, submicron-particle curcumin or curcumin administered with turmeric oils or piperine, in healthy adults. The project further aimed to investigate several critical factors for curcumin bioavailability in vitro and to explain thereby the observations made in vivo. In a randomized, double-blind crossover trial with 12 healthy participants (6 females, 6 males), curcumin pharmacokinetics, namely AUC (area under the plasma concentration-time curve), Cmax (maximum plasma concentration) and tmax (time to reach Cmax) were compared after administration of a single oral dose of 207 mg curcumin in form of a native curcuma extract or one of the seven formulations. Curcumin incorporated into polysorbate 80 micelles or g-cyclodextrin complexes showed 57-fold and 30-fold improved bioavailability compared to the native extract, whereas all other formulations showed no or minor effects. tmax of the better bioavailable formulations was smaller (1 to 2 hours) compared to all others (up to 7 hours). To compare the formulations regarding their digestion characteristics and transepithelial transport, in vitro digestion experiments followed by Caco-2 cell transport assays were conducted with the formulations normalized to their curcumin content. In parallel to the effects in vivo, curcumin showed higher stability, solubility and micellization efficiency when it was incorporated into polysorbate 80 micelles (100%, 80%, 55%) or g-cyclodextrin complexes (73%, 33%, 23%), whereas curcumin permeability through Caco-2 cell monolayers was not affected by its formulation. In the next study, curcumin efflux, partially mediated by P-glycoprotein (P-gp), was investigated, because the inhibition of curcumin efflux from the intestinal cells back to the intestinal lumen is targeted by the co-administration of curcumin with turmeric oils or piperine. In LS180 (colon adenocarcinoma) cells, native curcuma extract and the seven formulations were studied regarding cellular curcumin uptake within 1 hour and efflux within further 8 hours, as well as their effects on P-gp activity. Independently from its formulation, curcumin inhibited the activity of P-gp. Cellular curcumin uptake and efflux showed significant variability between formulations but no consistent effects. Cellular uptake and efflux may thus not be important for curcumin bioavailability in vivo. Another potential factor influencing bioavailability, that was investigated for native and micellar curcumin, was the time-dependent intracellular distribution in intestinal cells. Uptake and intracellular distribution in Caco-2 cells mainly did not differ between native and micellar curcumin. After 30 minutes, both were localized in lysosomes and mitochondria, after 180 minutes in peroxisomes and native curcumin also in mitochondria. The temporary localization in lysosomes is in line with the involvement of endocytosis in cellular uptake of curcumin. Nevertheless, the intracellular localization of curcumin was not affected by its incorporation into polysorbate 80 micelles. The data generated in this doctoral project thus demonstrate that the incorporation of curcumin into polysorbate 80 micelles or g-cyclodextrin complexes successfully improve its bioavailability. The improved bioavailability of both formulations can be explained by enhanced digestive stability, solubility and micellization efficiency and appears to be independent from post-digestive processes, such as intestinal permeability, cellular uptake, cellular efflux or intracellular distribution. Consequently, the present doctoral thesis delivers relevant information for the therapeutical application of curcumin, for the development of highly bioavailable formulations, as well as the basis for further clinical research on the health beneficial effects of curcumin.