COMPOSITION COMPRISING CURCUMINOIDS, MODIFIED STARCH AND/OR ACACIA GUM AND SAPONINS FOR USE AS A MEDICAMENT

Abstract

The present invention relates to the use of an improved curcuminoids composition for reducing LPS levels in blood, reducing endotoxemia, protecting the integrity of the intestinal barrier, treating, decreasing and/or preventing leaky gut syndrome, reducing intestinal lipids absorption, reducing ApoB48 levels in blood and/or for in treating, decreasing and/or preventing dyslipidemia in a subject.

Claims

1. (canceled)

2. (canceled)

3. (canceled)

4. (canceled)

5. A method for maintaining liver health, cardiovascular health, reducing LPS levels in blood, in reducing endotoxemia, in protecting the integrity of the intestinal barrier, in treating, decreasing and/or preventing leaky gut syndrome, in reducing intestinal lipids absorption, in reducing ApoB48 levels in blood, and/or in treating, decreasing and/or preventing dyslipidemia: comprising administering an effective amount of a composition comprising i) curcuminoids; ii) modified starch and/or acacia gum; and iii) one or more saponins to a subject in need thereof.

6. The method according to claim 5, wherein the composition comprising curcuminoids is administered to provide curcuminoids in an amount selected from the group consisting of from about 50 mg/dose to about 300 mg/dose, about 60 mg/dose, 70 mg/dose, 80 mg/dose, 90 mg/dose, 100 mg/dose, 150 mg/dose, 200 mg/dose and 300 mg/dose.

7. The method according to claim 5, wherein the curcuminoids are curcumin and its phase I or phase II metabolites, demethoxycurcumin and its phase I or phase II metabolites, bisdemethoxycurcumin and its phase I or phase II metabolites and mixtures thereof.

8. Composition for use, use, of The method according to claim 7, wherein curcuminoids are selected from curcumin, demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), and mixtures thereof.

9. The method according to claim 5, wherein the composition comprises an amount of curcuminoids selected from the group consisting of 30 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, or from about 90 mg to about 1500 mg, 1400 mg, 1200 mg, 1110 mg, 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 400 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg or 95 mg, from about 70 mg to about 300 mg, from about 70 mg to about 200 mg, from about 70 mg to about 100 mg, such as and 90 mg.

10. The method according to claim 5, wherein the acacia gum is in an amount from about 30%, 35%, 40%, 45%, 50%, 55%, to about 85%, 80%, 75%, 70%, 65%, 60% by weight of the composition, based on the total weight on the composition.

11. The method according to claim 5, wherein the one or more saponins is selected from Quillaja saponins, yucca saponins, tea saponins, peanut saponins, spinach saponins, sugar beet saponins, yam saponins, blackberry saponins, liquorice root saponins, primula root saponins, ginseng saponins, and mixtures thereof.

12. The method according to claim 5, wherein the at least one saponin(s) is present in an amount selected from the group consisting of about 0.1% to about 5% by weight of the composition, from about 0.5% to about 3% by weight of the composition, and from about 0.5% to about 1.3% by weight of the composition, based on the total weight on the composition.

13. The method according to claim 5, wherein the composition comprises particles having an average diameter selected from the group consisting of from about 100 nm to about 10,000, nm from about 100 nm to about 700 nm, and from about 1,000 nm to about 6,000 nm measured using laser diffraction.

14. The method according to claim 5, wherein the composition is administered to provide curcuminoids in an amount selected from the group consisting of from about 50 mg/day, about 60 mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, about 100 mg/day, about 150 mg/day, about 200 mg/day, about 300 mg/day, to about 1400 mg/day, about 1,300 mg/day, about 1,200 mg/day, about 1,100 mg/day, about 1,000 mg/day, about 900 mg/day, about 800 mg/day, about 700 mg/day, about 600 mg/day, about 500 mg/day, and about 400 mg/day.

15. The method according to claim 5, wherein the composition is administered or dosed in a dosage of from about 100 mg to about 500 mg, and wherein the daily dose of curcuminoids is from about 50 mg/day to about 500 mg/day.

16. The method according to claim 15 wherein the composition is administered to provide curcuminoids in an amount of about 70 mg/day to about 90 mg/day of curcuminoids, with from about 54 mg/day to about 69 mg/day curcumin and from 16 mg/day to about 21 mg/day of DMC and BDMC.

17. The method according to claim 5, wherein the composition is administered as a single daily dose.

18. The method according to claim 5, wherein the composition is administered to before a fat containing food is eaten by the subject.

19. The method according to claim 5, wherein the composition is administered at least 2 days before a fat containing food is eaten by the subject, optionally is also administrated one day after the fat containing food has been eaten by the subject.

20. The method according to claim 5, wherein the composition comprises a pharmaceutical, a nutraceutical or a food composition.

21. The method according to claim 5, wherein the subject is a human.

22. The method according to claim 5, wherein the subject suffers from IBS.

23. The method according to claim 10, wherein the acacia gum is in an amount from about 50% to about 60% by weight of the composition, based on the total weight on the composition.

24. The method according to claim 14, wherein the composition is administered to provide curcuminoids in an amount of from about 70 mg/day to about 100 mg/day.

25. The method according to claim 5, wherein the composition is administered or dosed in a dosage of about 300 mg, and wherein the daily dose of curcuminoids is from about 70 mg/day to about 90 mg/day.

Description

FIGURES

[0140] FIG. 1. LPS blood translocation. Blood levels of LPS before and 5 hours after fat challenge (time 0). While no main treatment effect on post-prandial response was observed for LPS, a trend for a baseline effect of the Test Formulation according to the invention (Supplement A) on LPS levels (p=0.06) was found if compared with the control (Supplement B).

[0141] FIG. 2. Chylomicron production. ApoB48 is a chylomicron-specific biomarker of chylomicron, which incorporate LPS and lipids for their blood translocation, A significant effect of the Test Formulation according to the invention (Supplement A) was found on postprandial ApoB48 levels (p<0.001) and ApoB48 AUC (p=0.04) compared with the control (Supplement B).

[0142] FIG. 3. Study design.

EXAMPLES

1. Test Formulation

[0143] A Test Formulation (TPG) was composed of: natural powdered extract obtained from turmeric (Curcuma longa) root, acacia gum, sunflower oil and Quillaja extract. It was developed and was intended for use as a food supplement. It has already been tested for safety in pre-clinical and human studies.

[0144] The Test Formulation comprised: 30-40% of Curcuma longa rhizome ethanol extract, 55-65% acacia gum, 3-7%, sunflower oil, 1-3% Quillaja extract. The Quillaja component was an extract powder containing approximately 65% saponins by dry weight. The curcuminoids content was 30% w/w (23% (w/w) curcumin and 7% (w/w) DMC and BDMC (% w/w in respect to total weight of the Test Formulation). The Test Formulation was prepared in the form of capsules.

[0145] The Test Formulation was selected for in vivo study on fat-induced intestinal barrier disruption as measured with LPS translocation in IBS patients with a diarrhea-predominant subtype (IBS-D). The primary objective of this study was to determine the effect of short-term Test Formulation (Turmipure GOLD) supplementation on LPS translocation in IBS-D patients after a high-fat challenge. The secondary objective of this study was to determine the effect of short term Test Formulation (Turmipure GOLD) supplementation on gastrointestinal complaints and LPS-related biomarkers in IBS-D patients after a high-fat challenge.

[0146] In this double-blind, randomized, placebo-controlled cross-over trial 20 adult (18-70 yrs) IBS-D patients were included.

[0147] The participants ingested three times a single dose (300 mg) of turmeric or placebo.

[0148] The primary study parameter is blood LPS levels. The secondary study parameters are blood levels of LPS-related biomarkers.

[0149] Blood sampling was performed via a cannula.

2. Study Design

[0150] To study the effect of the Test Formulation on postprandial LPS translocation. LPS-related biomarkers, and gastrointestinal complaints in IBS-D patients, a double-blind, randomized, placebo-controlled cross-over trial was conducted (FIG. 3).

[0151] Before the start of supplementation (day 3), participants filled out a questionnaire on the severity of their IBS-related gastrointestinal complaints (IBS-SSS). Next, participants consumed the Test Formulation capsules (300 mg) or placebo (Dyed Acacia Gum) at three occasions: day 2 and 1, and on the morning of the high-fat challenge test days. They furthermore consumed a standardized meal the evening before the test day with a high-fat challenge test. The two test days were separated by at least 14 days wash-out. On the test day, participants consumed a high-fat shake followed by 5 hourly blood collections and they filled out short questionnaires on gastrointestinal complaints.

2.1 Population (Base)

[0152] The study included 20 adult IBS-D patients. This subgroup of IBS patients was chosen as it had been shown that they had in general increased plasma LPS levels, indicating reduced intestinal barrier function and low grade inflammation. They furthermore indicated more often to have gastrointestinal complaints following consumption of high-fat foods. The intervention could therefore be especially beneficial for this subgroup. As increased BMI is also known to have an effect on intestinal barrier function and low grade inflammation it was chosen to apply a somewhat higher upper limit in BMI range for the inclusion criteria.

2.2 Inclusion Criteria

[0153] In order to be eligible to participate in this study, a subject had to meet all of the following criteria: [0154] IBS patients that meet the Rome IV criteria+additional criteria specific for the diarrhea-predominant subtype, based on the most frequent self-reported stool types using the Bristol stool chart (BSC). [0155] Male and female adults, aged 18-70 years; [0156] Having a Body Mass Index (BMI) between 18.5 and 30 kg/m2; [0157] Willing to keep a stable dietary pattern throughout the study.

3. Investigational Product/Treatment

[0158] Participants were supplemented with 1 capsule per day of Test Formulation and placebo during 3 days: 48 hour before the high-fat challenge test, 24 hour before the high-fat challenge test and on the day of the high-fat challenge test. Capsules containing 300 mg were consumed with water before breakfast (between 7.00-8.00 hr).

4. Main Study Parameter/Endpoint

[0159] The main study parameter was LPS translocation measured as levels of LPS in venous blood samples collected at baseline and 5 hourly after high-fat shake consumption. [0160] LPS was determined by Pyrochrome-LAL kit (Associates of Cape Cod Inc).

4.1. Secondary Study Parameters/Endpoints

[0161] The secondary parameters were gastrointestinal complaints and LPS-related biomarkers in venous blood samples collected at baseline and 5 hourly after high-fat shake consumption. [0162] Gastrointestinal complaints were measured via repeated short questionnaires (at T=1, 2, 3, 4, and 5 hour) [0163] abdominal pain, bloating, flatulence, nausea, heartburn [0164] LPS-related biomarkers: [0165] ApoB48 concentration was assessed using a commercial sandwich ELISA method (Fujifilm Wako Shibayagi Corp). [0166] LBP was measured by commercially available ELISA assays (Sanbio BV) [0167] sCD14 was measured by commercially available ELISA assays (Sanbio BV)

[0168] All laboratory analyses were conducted in the laboratory facilities of Wageningen Food & Biobased Research.

4.2. Randomisation, Blinding and Treatment Allocation

[0169] Study participants were randomized over the two cross-over arms (Test Formulation.fwdarw.Placebo and Placebo.fwdarw.Test Formulation). Blocked randomization for BMI and age was applied. To ensure similar BMI and age in both treatment groups, participants were sorted by BMI and age, and for each block of two participants the two possible treatment orders (1.fwdarw.2 and 2.fwdarw.1) were randomly assigned.

[0170] Any other clinically relevant differences in baseline characteristics were accounted for in the statistical analysis (covariance analysis).

[0171] Both capsules were uniformly packaged, but with a coded label that specifically corresponded to the intervention, to ensure double-blinding. After analyses of all data, product coding was unblinded for the investigators.

[0172] Baseline IBS complaints and daily questionnaire

[0173] At day 3, subjects filled out the online IBS-SSS questionnaire.

[0174] At day 3 to day +2, subjects filled out a short daily questionnaire via an app (LifeData, LLC), asking amongst others for GI complaints and when applicable supplement compliance.

Supplement Intake

[0175] Subjects ingested one capsule (with water) in the morning before breakfast, between 7:00 h and 8:00 h (supplement or placebo), of day 2, day 1 and at the research unit in the morning of the test day. After at least 14 days washout and cross-over, subjects ingested again one capsule (with water) in the morning before breakfast, between 7:00 h and 8:00 h (supplement or placebo), of day 2, day 1 and at the research unit in the morning of the second test day.

Test Day (Day 0)

[0176] Subjects consumed a standardised low fat evening meal prior to the test days and were asked to refrain from alcohol and strenuous exercise. After an overnight fast, all subjects came to the research facility by own transport. The subjects consumed the third and last supplement capsule (at T=1 hour). A study nurse inserted a cannula to allow blood collection throughout the day. Thereafter, a baseline (t=0) blood sample was collected. After the baseline measurements, the participant consumed the high-fat shake within 10 minutes (T=0). Postprandial blood samples were collected hourly for 5 hours from the cannula after consumption of the shake. At each collection it was sampled 11 mL of blood through the cannula (4 mL EDTA plasma, 4 mL serum, 3 mL dummy to flush cannula) resulting in a total blood volume collection of 66 mL per test day.

[0177] Statistical analyses were done using SPSS statistics. A p-value of p<0.05 is considered as statistically significant. In general, the continuous data is presented as meanstandard deviation (SD). Data may be log-transformed to normalize data distribution before parametric statistical analyses.

Results.

[0178] As it can be seen on FIG. 1, a trend for a baseline effect of the Test Formulation (Supplement A) on LPS levels (p=0.06) was found.

[0179] As it can be seen on FIG. 2. A significant effect of Test Formulation (Supplement A) was found on postprandial ApoB48 levels (p<0.001) with lower concentrations of ApoB48 observed 2 hours, 3 hours, 4 hours and 5 hours after the high-fat challenge test. A significantly lower Area under the concentration-time curve (ApoB48 AUC) was also observed (p=0.04).