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We investigated the pharmacokinetic pathway of berberine and its metabolites in vitro, in Caco-2 cells, and in human participants following the administration of dihydroberberine (DHB) and micellar berberine (LipoMicel®, LMB) formulations. A pilot trial involving nine healthy volunteers was conducted over a 24 h period; blood samples were collected and subjected to Ultra High-Performance Liquid Chromatography–High Resolution Mass Spectrometry (UHPLC-HRMS) analyses to quantify the concentrations of berberine and its metabolites. Pharmacokinetic correlations indicated that berberrubine and thalifendine follow distinct metabolic pathways. Additionally, jatrorrhizine sulfate appeared to undergo metabolism differently compared to the other sulfated metabolites. Moreover, berberrubine glucuronide likely has a unique metabolic pathway distinct from other glucuronides. The human trial revealed significantly higher blood concentrations of berberine metabolites in participants of the DHB treatment group compared to the LMB treatment group—except for berberrubine glucuronide, which was only detected in the LMB treatment group. Similarly, results from in vitro investigations showed significant differences in berberine metabolite profiles between DHB and LMB. Dihydroberberine, dihydroxy-berberrubine/thalifendine and jatrorrhizine sulfate were detected in LMB-treated cells, but not in DHB-treated cells; thalifendine and jatrorrhizine-glucuronide were detected in DHB-treated cells only. While DHB treatment provided higher blood concentrations of berberine and most berberine metabolites, both in vitro (Caco-2 cells) and in vivo human studies showed that treatment with LMB resulted in a higher proportion of unmetabolized berberine compared to DHB. These findings suggest potential clinical implications that merit further investigation in future large-scale trials.

The aim of this pilot study was to evaluate and compare bioavailability and safety of two Vitamin D3 formulations (softgels) in healthy adults, at single daily doses of 1000 and 2500 IU, over a 60-day period. A total of 69 participants were initially screened for eligibility in a double-blind randomized study with a four-arm parallel design; 35 participants were randomized to treatment groups: (1) standard Vitamin D3 1000 IU (STD1000), (2) micellar Vitamin D3 1000 IU (LMD1000), (3) standard Vitamin D3 2500 IU (STD2500), and (4) micellar Vitamin D3 2500 IU (LMD2500). Serum Vitamin D concentrations were determined through calcifediol [25(OH)D] at baseline (=before treatment), at day 5, 10, and 15 (=during treatment), at day 30 (=end of treatment), and at day 45 and 60 (=during follow-up/post treatment). Safety markers and minerals were evaluated at baseline and at day 30 and day 60. The pharmacokinetic parameters with respect to iAUC were found to be significantly different between LMD1000 vs. STD1000: iAUC(5–60): 992 ± 260 vs. 177 ± 140 nmol day/L; p < 0.05, suggesting up to 6 times higher Vitamin D3 absorption of LMD when measured incrementally. During follow-up, participants in the LMD1000 treatment group showed approx. 7 times higher Vitamin D3 concentrations than the STD1000 group (iAUC(30–60): 680 ± 190 vs. 104 ± 91 nmol day/L; p < 0.05). However, no significant differences were found between the pharmacokinetics of the higher dosing groups STD2500 and LMD2500. No significant changes in serum 1,25(OH)2D concentrations or other biochemical safety markers were detected at day 60; no excess risks of hypercalcemia (i.e., total serum calcium > 2.63 mmol/L) or other adverse events were identified. LMD, a micellar delivery vehicle for microencapsulating Vitamin D3 (LipoMicel®), proved to be safe and only showed superior bioavailability when compared to standard Vitamin D at the lower dose of 1000 IU. This study has clinical trial registration: NCT05209425.

This study evaluated the differences in the metabolite profile of three n-3 FA fish oil formulations in 12 healthy participants: (1) standard softgels (STD) providing 600 mg n-3 FA; (2) enteric-coated softgels (ENT) providing 600 mg n-3 FA; (3) a new micellar formulation (LMF) providing 374 mg n-3 FA. The pharmacokinetics (PKs), such as the area under the plot of plasma concentration (AUC), and the peak blood concentration (Cmax) of the different FA metabolites including HDHAs, HETEs, HEPEs, RvD1, RvD5, RvE1, and RvE2, were determined over a total period of 24 h. Blood concentrations of EPA (26,920.0 ± 10,021.0 ng/mL·h) were significantly higher with respect to AUC0-24 following LMF treatment vs STD and ENT; when measured incrementally, blood concentrations of total n-3 FAs (EPA/DHA/DPA3) up to 11 times higher were observed for LMF vs STD (iAUC 0-24: 16,150.0 ± 5454.0 vs 1498.9 ± 443.0; p ≤ 0.0001). Significant differences in n-3 metabolites including oxylipins were found between STD and LMF with respect to 12-HEPE, 9-HEPE, 12-HETE, and RvD1; 9-HEPE levels were significantly higher following the STD vs. ENT treatment. Furthermore, within the scope of this study, changes in blood lipid levels (i.e., cholesterol, triglycerides, LDL, and HDL) were monitored in participants for up to 120 h post-treatment; a significant decrease in serum triglycerides was detected in participants (~20%) following the LMF treatment; no significant deviations from the baseline were detected for all the other lipid biomarkers in any of the treatment groups. Despite a lower administered dose, LMF provided higher blood concentrations of n-3 FAs and certain anti-inflammatory n-3 metabolites in human participants—potentially leading to better health outcomes.

Vitamin D is an essential nutrient with important immunomodulatory properties. As a fat-soluble compound, Vitamin D (and its D3 form) is immiscible with water, which presents challenges to absorption. In an in vitro setting, the current study characterizes novel micellar formulations of Vitamin D3 designed to improve absorption. Techniques used to evaluate and compare the micellar formulations against a non-micellar formula include the following: cryo-SEM to determine morphology; laser diffraction to determine particle size and distribution; zeta potential to determine stability of the particles; solubility assays to determine solubility in water and gastrointestinal media; and Caco-2 cell monolayers to determine intestinal permeability. Results show advantageous features (particle size range in the low micrometres with an average zeta potential of −51.56 ± 2.76 mV), as well as significant improvements in intestinal permeability, in one optimized micellar formula (LipoMicel®). When introduced to Caco-2 cells, LipoMicel’s permeability was significantly better than the control (p < 0.01; ANOVA). Findings of this study suggest that the novel micellar form of Vitamin D3 (LipoMicel) has the potential to promote absorption of Vitamin D3. Thus, it can serve as a promising candidate for follow-up in vivo studies in humans.

Berberine is a plant-origin quaternary isoquinoline alkaloid with a vast array of biological activities, including antioxidant and blood-glucose- and blood-lipid-lowering effects. However, its therapeutic potential is largely limited by its poor oral bioavailability. The aim of this study was to investigate the in vitro solubility and Caco-2 cell permeability followed by pharmacokinetic profiling in healthy volunteers of a new food-grade berberine delivery system (i.e., Berberine LipoMicel®). X-ray diffractometry (XRD), in vitro solubility, and Caco-2 cell permeability indicated higher bioavailability of LipoMicel Berberine (LMB) compared to the standard formulation. Increased aqueous solubility (up to 1.4-fold), as well as improved Caco-2 cell permeability of LMB (7.18 × 10−5 ± 7.89 × 10−6 cm/s), were observed when compared to standard/unformulated berberine (4.93 × 10−6 ± 4.28 × 10−7 cm/s). Demonstrating better uptake, LMB achieved significant increases in AUC0–24 and Cmax compared to the standard formulation (AUC: 78.2 ± 14.4 ng h/mL vs. 13.4 ± 1.97 ng h/mL, respectively; p < 0.05; Cmax: 15.8 ± 2.6 ng/mL vs. 1.67 ± 0.41 ng/mL) in a pilot study of healthy volunteers (n = 10). No adverse reactions were reported during the study period. In conclusion, LMB presents a highly bioavailable formula with superior absorption (up to six-fold) compared to standard berberine formulation and may, therefore, have the potential to improve the therapeutic efficacy of berberine. The study has been registered on ClinicalTrials.gov with Identifier NCT05370261.

Randomized clinical trials (RCT) and observational studies have highlighted the importance of flavonoid consumption for human health. Several studies have associated a high intake of dietary flavonoids with (a) enhanced metabolic and cardiovascular health, (b) enhanced cognitive and vascular endothelial functions, (c) an improved glycemic response in type 2 diabetes mellitus, and (d) a reduced risk of breast cancer in postmenopausal women. Since flavonoids belong to a broad and diverse family of polyphenolic plant molecules—with more than 6000 compounds interspersed in the human diet—researchers are still uncertain whether the intake of single, individual polyphenols or a large combination of them (i.e., synergistic action) can produce the greatest health benefits for humans. Furthermore, studies have reported a poor bioavailability of flavonoid compounds in humans, which presents a major challenge for determining their optimal dosage, recommended intake, and, consequently, their therapeutic value. Especially because of their scarce bioavailability from foods—along with the overall declining food quality and nutrient density in foods—the role of flavonoid supplementation may become increasingly important for human health. Although research shows that dietary supplements can be a highly useful tool to complement diets that lack sufficient amounts of important nutrients, some caution is warranted regarding possible interactions with prescription and non-prescription drugs, especially when taken concurrently. Herein, we discuss the current scientific basis for using flavonoid supplementation to improve health as well as the limitations related to high intakes of dietary flavonoids.

Commonly used to treat mood disorders, St. John’s Wort (Hypericum perforatum) is a popular herb in the natural health products industry. The potency of its active ingredients can be determined using a number of different analytical methods, but it is more widely determined using high performance liquid chromatography (HPLC). While monographs in the United States Pharmacopeia (USP) can often be relied upon for suitable analytical methods, the method proposed for determining hypericin content in St. John’s Wort products is inefficient in carrying out this purpose. This paper presents a modified new HPLC method for determining the hypericin content that can also be used for St. John’s Worts capsules and tablets by making use of purified hypericin as a chemical standard instead of oxybenzone, applying a wavelength of 588 nm during analysis and utilizing a binary instead of ternary mobile phase gradient. The resulting method and sample chromatograms provide better resolved, more easily identifiable peaks, shorter run time, and increased sustainability compared to the original USP method. This proposed method was developed using the more refined ultra-high performance liquid chromatography (UHPLC) and serves as a more accurate and reliable method for determining hypericin content in St. John’s Wort.

The most prominent horsetail species, Equisetum arvense, has an array of different medicinal properties, thus the proper authentication and differentiation of the plant from the more toxic Equisetum palustre is important. This study sought to identify different samples of E. arvense and E. palustre using three analytical methods. The first method involved the use of HPTLC analysis, as proposed by the European Pharmacopoeia. The second, HPLC-ESI-MS/MS, is capable of both identification and quantification and was used to determine the Equisetum alkaloid content in each sample. A third method was DNA barcoding, which identifies the samples based on their genetic make-up. Both HPTLC and HPLC-ESI-MS/MS proved to be suitable methods of identification, with HPLC-ESI-MS/MS proving the more sophisticated method for the quantification of alkaloids in the Equisetum samples and for determining the adulteration of E. arvense. For DNA barcoding, optimal primer pairs were elucidated to allow for the combined use of the rbcL and ITS markers to accurately identify each species. As new DNA marker sequences were added to GenBank, the reference library has been enriched for future work with these horsetail species.