A combination consisting of resveratrol, curcumin, quercetin and NAD precursor, a composition comprising the combination and uses thereof

Abstract

The subject of the invention is a combination consisting of resveratrol, curcumin, quercetin and an NAD precursor. The subject of the invention is also a composition comprising the combination according to the invention. The invention also relates to the use of the combination and the composition according to the invention.

Description

[0001] A COMBINATION CONSISTING OF RESVERATROL, CURCUMIN, QUERCETIN AND NAD PRECURSOR, A COMPOSITION COMPRISING THE COMBINATION AND USES THEREOF The subject of the invention is a combination of resveratrol, curcumin, quercetin and a NAD precursor. The subject of the invention is also a composition comprising the combination according to the invention. The subject of the invention is also the use of the combination according to the invention or the composition according to the invention. The invention will find application in broadly understood nutritional support, and in particular in supporting diet and / or in supporting healthy aging.

[0002] SIRTuin diets (hereinafter also referred to as SIRT diets) are gaining increasing interest among both patients and scientists. SIRT diets, by design, utilize foods rich in so- called sirtuin activators (also referred to in the literature as sirtuin modulators and / or regulators). Importantly, however, SIRT diets emphasize the inclusion of appropriate foods in the diet, not the elimination of others. Furthermore, SIRT diets move away from severe restriction of calories or meal frequency (so-called fasting). Thanks to this approach, SIRT diets are expected to be easier to implement and have long-term acceptance compared to most currently available restrictive diets.

[0003] Despite their advantages, SIRT diets also have their limitations. Firstly, there is a wide range of foods rich in sirtuin activators. These include grapes rich in resveratrol, citrus fruits rich in naringin, cucumbers, and fisetin- rich blueberries. Selecting the most beneficial substances and their quantities from a large catalog of foods from different climates presents a significant challenge in standardizing SIRT diets and maximizing their effectiveness. Secondly, foods available and inexpensive in certain climates (such as citrus fruits and grapes in the Mediterranean) may be beyond the reach of the daily diet in other latitudes. Furthermore, each sirtuin activator — regardless of its advantages — has its own individual limitations and drawbacks. For example, resveratrol — despite its high potential for sirtuin activation — presents formulation challenges, such as low solubility and bioavailability. Therefore, intensive research and implementation work is currently underway on standardized SIRT dietary supplements containing ingredients that are more optimal in terms of active substances, quantity, and acceptability (including economic). These products must be easily digestible and have favorable storage life (e.g., powders, tablets, and capsules). At the same time, their optimization cannot come at the expense of the solubility, digestibility, and bioavailability of the active substances and nutrients they contain.

[0004] An example of a commercially available Sirt diet supplement is the Italian product Yes, Sirt. The supplement is sold in capsule form, containing many ingredients, but in small quantities. These include mate, garcinia, green tea, cocoa, olive (fruit), fenugreek, resveratrol, grape extract, matcha (powder), and nucleotides.

[0005] In addition to weight loss, an emerging health and cultural need is healthy aging. It's worth emphasizing that, contrary to popular belief, aging affects everyone. This is because everyone, regardless of age, is exposed to adverse external factors (e.g., UV radiation on the skin) and internal factors (e.g., oxidative stress). Healthy aging, unlike anti - aging, does not involve the currently popular drastic prevention, treatment, or reversal of aging. Instead, healthy aging focuses on accepting this natural phenomenon and supporting health maintenance and optimizing, among other things, appearance, weight, and fitness as we age.

[0006] Furthermore, sirtuins modulate gene expression. It turns out that sirtuin -regulated genes are responsible for, among other things, aging processes (DNA repair, tissue regeneration, signaling between neurons) and metabolic processes (control of metabolism, processes related to glucose metabolism - gluconeogenesis, glycolysis, maintaining optimal glucose and insulin levels).

[0007] The SIRT diet is also rich in antioxidants and promotes the production of antioxidant substances in the body. Therefore, its use in healthy aging would be very beneficial. As with the weight-loss effects of the SIRT diet, selecting the most beneficial antioxidants and their quantities from a large catalog of foods presents a significant challenge in standardizing SIRT diets, maximizing their effectiveness and economic availability. Furthermore, the catalog of foods and antioxidant substances does not necessarily overlap with the catalog of foods and substances that support weight loss, further complicating the selection of a universal composition combining weight-loss and anti-aging benefits.

[0008] On the other hand, recent research indicates that excessive antioxidant use can lead to the unfavorable phenomenon of reductive stress. Therefore, drastic antioxidant intervention can lead to the counterproductive effect of accelerated aging.

[0009] Therefore, the main technical problem solved by the present invention is to provide an alternative - preferably improved - SIRT diet composition within the financial reach of patients. Furthermore, this preparation should be a universal, single-dose weight-loss composition that simultaneously slows down aging in a healthy way. Another technical challenge addressed by the invention is optimizing the composition to maximize antioxidant potential while simultaneously reducing the risk of reductive stress. Synergy between ingredients is also expected, along with avoiding potential incompatibilities.

[0010] The subject of the invention is a combination consisting of resveratrol, curcumin, quercetin and NAD precursor.

[0011] Preferably, the combination according to the invention is characterized in that the resveratrol is in the form of trans-resveratrol.

[0012] Preferably, the combination according to the invention is characterized in that the NAD precursor is selected from nicotinamide (NAD), reduced nicotinamide dinucleotide (NADH), nicotinic acid (NA), nicotinamide riboside (NR), tryptophan (Trp), nicotinamide (N) and nicotinamide mononucleotide (NMN) or a combination thereof.

[0013] Preferably, the combination according to the invention is characterized in that it comprises from 10 mg to 200 mg of NAD+ precursor, from 100 mg to 1000 mg of resveratrol, from 10 mg to 200 mg of quercetin and from 10 mg to 200 mg of curcumin.

[0014] The subject of the invention is a composition characterized in that it comprises the combination according to the invention.

[0015] Preferably, the composition according to the invention is characterized in that it further comprises an active substance selected from epigallocatechin gallate (EGCG), piperine, trimethylglycine (TMG) and leucine or a combination thereof. Preferably, the composition according to the invention is characterized in that it comprises from 10 mg to 200 mg of epigallocatechin gallate (EGCG) and / or from 0.1 mg to 2 mg piperine and / or from 100 mg to 800 mg trimethylglycine (TMG) and / or from 100 mg to 2000 mg leucine or a combination thereof.

[0016] Preferably, the composition according to the invention is characterized in that it further comprises at least one food and / or pharmaceutically acceptable excipient.

[0017] Preferably, the composition according to the invention is characterized in that it is in the form of a powder, granulate, micropellet, microtablet, capsule, tablet, solution, food, dietary supplement and / or food additive.

[0018] The subject of the invention is the use of the combination according to the invention in nutritional support.

[0019] Preferably, the use according to the invention is characterized in that the nutritional support is a dietary support.

[0020] Preferably the use according to the invention is characterized in that the nutritional support is support of healthy aging.

[0021] The subject of the invention is the use of the composition according to the invention in nutritional support.

[0022] Preferably, the use according to the invention is characterized in that the nutritional support is a dietary support.

[0023] Preferably, the method used according to the invention is characterized in that the nutritional support is support for healthy aging.

[0024] Resveratrol in the present application is understood as mixture of trans and cisresveratrol, and particularly preferably pure trans-resveratrol.

[0025] NAD precursor is understood as the NAD precursors known in the art and NAD and NADH itself, in particular the nicotinamide dinucleotide (NAD), reduced nicotinamide dinucleotide (NADH), nicotinic acid (NA), nicotinamide riboside (NR), tryptophan (Trp), nicotinamide (N) and nicotinamide mononucleotide (NMN) or combinations thereof.

[0026] Curcuminoids are understood as a group of alkaloids extracted from Turmeric, in particular curcumin, demethoxycurcumin and bisdemethoxycurcumin.

[0027] Healthy aging is understood as activities aimed at optimizing aging-related processes, such as slowing down the metabolic rate and changing body composition in favor of fat tissue through dietary modifications — from energy requirements and protein content to the use of biologically active substances, in proportions that achieve specific physiological effects. Healthy aging focuses on accepting this natural phenomenon and supporting health maintenance and optimizing, among other things, appearance, weight, and fitness as we age.

[0028] The combination according to the invention and the composition according to the invention will be used to support nutrition, e.g. by health-conscious people, including: wanting proper body weight and composition, especially the appropriate percentage of fat and lean body mass wanting to optimize the aging process and stay fit and healthy for as long as possible wanting to ensure that, in addition to a balanced diet, they consume sufficient amounts of antioxidants, which is of great importance during a season of limited availability of fresh vegetables and fruits as support of lifestyle changes for the better (increased physical activity, diet therapy )

[0029] In particular, it can be used to support a diet, for example, in the process of implementing a weight-loss diet, healthy eating habits, and physical activity. Alternatively, it can be used to support healthy aging. It is particularly beneficial when used simultaneously to support both diet and healthy aging, as the qualitative and quantitative composition is optimized for both of these indications.

[0030] Example 1

[0031] In one embodiment, a combination consisting of resveratrol, curcumin, quercetin, and an NAD precursor is prepared. Such a combination can be prepared by methods known in the art. These methods include mixing the ingredients to obtain a visually homogeneous mixture, or dissolving the mixture of ingredients to obtain a visually homogeneous mixture. In this case, the ingredients are weighed, mixed to obtain a visually homogeneous mixture, and encapsulated. One skilled in the art will understand that, without departing from the scope of the invention, the combination according to the invention can be further processed by methods known in the art, e.g., granulated, encapsulated, tableted, micropelletized, added to a food to obtain an even more pharmaceutically and / or nutritionally acceptable form. In one preferred embodiment, the resveratrol was in the form of trans-resveratrol. Various NAD precursors have been tested with substantially comparable levels of effectiveness. In one embodiment, the NAD precursor used in the micropellet according to the invention was nicotinamide dinucleotide (NAD), in another reduced nicotinamide dinucleotide (NADH), in another nicotinic acid (NA), in another nicotinamide riboside (NR), in another tryptophan (Trp), in another nicotinamide (N) in yet another nicotinamide mononucleotide (NMN). A person skilled in the art understands that it is also possible to use a combination of the above-mentioned substances. In another preferred embodiment, the weight ratio of curcumin to resveratrol is 8:2. This ratio of the components gives the highest synergistic benefits and the protective effect of curcumin and resveratrol against H2O2 - induced changes in cell survival, caspase-3 activity and ROS production. In yet another preferred embodiment, the combination according to the invention comprises from 10 mg to 200 mg of NAD+ precursor, from 100 mg to 1000 mg of resveratrol, from 10 mg to 200 mg of quercetin and from 10 mg to 200 mg of curcumin. A positive effect on the absorption of resveratrol and curcumin induced by quercetin was observed (without a simultaneous effect on the absorption of quercetin). Table I below presents variants of the tested amounts of the invention's ingredients. The ingredients produced a homogeneous, well-flowing mixture, regardless of the weight ratio. No negative effects (e.g., gastrointestinal) were observed at higher doses.

[0032] Table I. Tests of various weight ratios of the ingredients used according to the invention.

[0033] Example 2

[0034] In another example, the possibility of enriching the developed combination with additional beneficial ingredients was investigated. Therefore, the previously described combination according to the invention was used with the addition of various beneficial active ingredients as additional ingredients of the composition according to the invention. Such a composition can be prepared by methods known in the art. These methods include mixing the ingredients to obtain a visually homogeneous mixture or dissolving the mixture of ingredients to obtain a visually homogeneous mixture. In this case, the ingredients were weighed, mixed to obtain a visually homogeneous mixture, and encapsulated. One skilled in the art will understand that, without departing from the scope of the invention, the composition according to the invention can be further processed by methods known in the art, e.g., granulated, encapsulated, tableted, micropelletized, added to a food product to obtain an even more pharmaceutically and / or nutritionally acceptable form. In one preferred embodiment, the additional active ingredient was epigallocatechin gallate (EGCG). In one preferred embodiment, the composition comprises 10 mg of EGCG. In another preferred embodiment, the composition comprises 200 mg of EGCG. In another preferred embodiment, the additional active ingredient was piperine. In one preferred embodiment, the composition comprises 0.1 mg of piperine. In another preferred embodiment, the composition comprises 2 mg of piperine. In another preferred embodiment, the additional active ingredient was trimethylglycine (TMG). In one preferred embodiment, the composition comprises 100 mg of TMG. In another preferred embodiment, the composition comprises 800 mg of TMG. In another preferred embodiment, the additional active ingredient was leucine. In one preferred embodiment, the composition comprises 100 mg of leucine. In another preferred embodiment, the composition comprises 2000 mg of leucine. One skilled in the art will understand that it is also possible to use combinations of the aforementioned substances in the required amounts. In another preferred embodiment, the composition comprises at least one food and / or pharmaceutically acceptable excipient, in particular to obtain an acceptable pharmaceutical and / or food form. Particularly preferred pharmaceutically and / or food acceptable forms prepared within departing from the scope according to the invention were: powder, granulate, micropellet, microtablet, capsule, tablet, solution, food, dietary supplement and food additive.

[0035] Example 3

[0036] In one embodiment, the combination according to the invention described above is used in nutritional support. In a preferred embodiment, the combination according to the invention is used in dietary support. In another preferred embodiment, the combination according to the invention is used in healthy aging support. In yet another embodiment, the combination according to the invention is used both for dietary support and for healthy aging support.

[0037] In another embodiment, the described composition according to the invention is used in nutritional support. In a preferred embodiment, the composition according to the invention is used in dietary support. In another preferred embodiment, the composition according to the invention is used in healthy aging support. In yet another embodiment, the composition according to the invention is used both for dietary support and healthy aging support.

[0038] The combination of ingredients according to the invention is particularly advantageous, as it appears to combine polyphenols acting at the cellular level (requiring direct contact with cells for the antioxidant effect) and polyphenols having an antioxidant effect through action on enzymes (indirect action). For example, NAD promoters (e.g. nicotinamide mononucleotide (NMN) and nicotinic acid (NA)) have a different mechanism of action as sirtuin activators than, for example, resveratrol. This, in turn, increased the effectiveness of the combination and allowed for a reduction in the doses of individual components and the total dose of the combination. The combination according to the invention and the composition comprising the combination according to the invention require the administration of the aforementioned components simultaneously. In the prior art, for example, there are diets that consider, as part of extensive and multi-component dietary programs, the administration of some of the components discussed herein. However, administering them separately does not achieve the above-mentioned synergy effect and excludes the achievement of the further discussed effect of increasing the absorption of some of the components of the combination according to the invention and the composition containing this combination. Therefore, dividing the ingredients into two separate formulations is excluded, regardless of the time of administration.

[0039] The combination according to the invention and the composition comprising the combination according to the invention have been found to contain an appropriate combination of active ingredients and specific beneficial proportions allowing for increasing the solubility and bioavailability of these ingredients, in particular the typically poorly soluble resveratrol, achieving synergy of the selected ingredients and maximizing the antioxidant potential of these ingredients, while reducing the risk of unfavorable reduction potential, reducing the dose of individual active ingredients and the total amount of these substances.

[0040] In particular, substances with strong antioxidant effects include resveratrol, quercetin, and EGCG, which have been selected to minimize the risk of reductive stress (e.g., NAD precursors, particularly NMN and NA). Despite being part of the combination according to the invention, resveratrol and quercetin are present together with ingredients that reduce the amount of resveratrol and quercetin (e.g., NAD precursors, particularly NMN and NA). Interestingly, resveratrol also has a positive effect on quercetin. Thus, surprisingly, the main active ingredients (resveratrol and the NAD precursor) act on the additional active ingredients (quercetin and EGCG). Meanwhile, a composition comprising the combination according to the invention supplemented with EGCG contains these ingredients in their optimal amounts to achieve an antioxidant effect while avoiding the risk of reductive stress.

[0041] Administration of the combination according to the invention enriched with additional active ingredients in the form of a composition according to the invention further increased the solubility of poorly soluble substances. For example, in one preferred embodiment, the addition of leucine - which, as an active substance, increases SIRT1 expression in liver, brown adipose tissue, and skeletal muscle - increased the solubility (and thus the bioavailability) of resveratrol. In another preferred embodiment, the addition of TMG increased the solubility (and thus the bioavailability) of resveratrol. Resveratrol has a solubility of 35 pg / ml. The use of leucine and / or TMG in the use according to the invention increased the solubility of resveratrol twofold, and in some preferred embodiments (as a complex with leucine) almost threefold. At the same time, the use of quercetin increased the bioavailability of resveratrol and curcumin. Regardless of this, a curcumin to resveratrol weight ratio of 8:2 proved particularly beneficial for increasing the bioavailability of resveratrol. Curcumin also acts synergistically with resveratrol, and for this reason, the combination and composition according to the invention are standardized for the curcumin content from the curcuminoid group (at least 79% of the target amounts indicated in the invention). Therefore, the presence of other curcuminids is not excluded if a turmeric extract is used instead of pure curcumin. However, such an extract must be standardized for curcumin content to achieve the curcumin content according to the invention. These benefits are independent of the use of the indicated ingredients of the combination according to the invention and the composition containing this combination due to their beneficial role as sirtuin activators (i.e. as the active substances of the invention).

[0042] Meanwhile, the use of piperine in the composition according to the invention, in addition to its properties as an active substance, increases the bioavailability of sirtuin activators in another way than described above - piperine belongs to the inhibitors of enzymes metabolizing these compounds, thus helping to maintain them in an active, unmetabolized form after absorption.

[0043] Finally, it is worth mentioning that despite its beneficial role as a sirutuin activator and antioxidant, epigallocatechin gallate (EGCG) should preferably be contained in the composition according to the invention in an amount of no more than 1000 mg due to the possibility of adverse hepatological effects. Due to the high solubility of resveratrol, the synergistic effect of other ingredients and thus high antioxidant potential, the amount of the epigallocatechin gallate (EGCG) content in the composition according to the invention has been limited to approximately 200 mg. This also has the beneficial effect of reducing excessive reduction potential.

[0044] Example 4

[0045] The diet was tested on a group of 15 women divided into 3 equal groups:

[0046] Group A: with a defined BMI of 22 to 25 Group B: with a defined BMI > 25

[0047] Group C: with a defined BMI > 30

[0048] The inclusion criterion was BMI from the above groups. The exclusion criteria were:

[0049] - BMI <18.5,

[0050] - pregnant and breastfeeding women,

[0051] - surgeries performed in the last 3 months,

[0052] - chemotherapy in the last 6 months,

[0053] - organ failure, including kidney disease

[0054] - eating disorders, i.e. bulimia, anorexia,

[0055] - type I, II diabetes

[0056] - allergies to dietary ingredients

[0057] The invention was used in all groups. The dietary regimen was divided into three stages. In each stage, resveratrol, curcumin, quercetin, and NAD precursor were administered in accordance with the invention or preferred embodiments thereof. These ingredients were administered in the form of shakes prepared, in one preferred embodiment, from micropellets comprising the aforementioned ingredients according to the invention, and in the second preferred embodiment, from a powder comprising the aforementioned ingredients according to the invention. The shakes and solid meals were administered in amounts depending on the stage and the associated caloric restrictions.

[0058] In a preferred embodiment, the daily energy value of the meals was reduced gradually in stages from higher to lower. In a particularly preferred embodiment, in stage I the daily energy value of the meals was reduced by 30% - 40% of the TMR, in stage II the daily energy value of the meals was reduced by 20% - 30% of the TMR, and in stage III the daily energy value of the meals was reduced by 10% - 20% of the TMR. In another particularly preferred embodiment, stage I took 3 days, stage II took 7 days, and stage III took 14 days.

[0059] In a preferred embodiment, nutritional support was provided according to the scheme in Table II. Caloric restriction was calculated relative to the current total energy requirement (total metabolic rate, TMR). The goal of Stage I was to facilitate the initiation of the diet, rapid activation of sirtuins using the ingredients according to the invention, caloric deficits for natural sirtuin activation, and a shift in metabolism toward ketosis. The goal of Stage II was to maintain sirtuin activity through continued use of the ingredients according to the invention and to exit ketosis (increasing the energy content of the diet, protecting muscle mass). The goal of Stage III was to maintain sirtuin activity through the use of the ingredients according to the invention in the form of a ready-made composition and / or meal, protecting muscle mass, and exiting a weight-loss diet.

[0060] Table II. Preferred scheme for the use of nutritional support according to the invention.

[0061] In another preferred embodiment, nutritional support was provided according to the scheme in Table III.

[0062] Table III. Nutrition support scheme (*caloric groups were calculated based on TMR for the current body weight. The restriction is calculated from this value)

[0063] Even such short-term (3-week) caloric restriction resulted in a significant increase in SIRT1-4 and SIRT7 mRNA expression compared to an ad libitum diet. The use of the ingredients according to the invention to support nutrition further enhances and accelerates this effect.

[0064] The effects of the combination and composition according to the invention were also confirmed by tests of blood glucose and fat levels, which were maintained at normal levels in individuals using the combination and the composition according to the invention. Normal blood glucose and fat levels are also a determinant of achieving (or maintaining) a healthy body composition (fat and fat-free mass). Maintaining such a state also positively influences the aging process.

[0065] The determinations were performed by chromatography on a Hitachi Chromaster HPLC apparatus with a DAD detector and autosampler.

Claims

Claims:

1. A combination consisting of resveratrol, curcumin, quercetin and NAD precursor.

2. The combination according to the preceding claim, characterized in that the resveratrol is in the form of trans-resveratrol.

3. The combination according to any of the preceding claims, characterized in that the NAD precursor is selected from a nicotinamide dinucleotide (NAD), reduced nicotinamide dinucleotide (NADH), nicotinic acid (NA), nicotinamide riboside (NR), tryptophan (Trp), nicotinamide (N) and nicotinamide mononucleotide (NMN) or a combination thereof.

4. The combination according to any of the preceding claims, characterized in that, it comprises from 10 mg to 200 mg of NAD+ precursor, from 100 mg to 1000 mg of resveratrol, from 10 mg to 200 mg of quercetin, and from 10 mg to 200 mg of curcumin.

5. A composition characterized in that it comprises the combination according to any preceding claim.

6. The composition according to the preceding claim, characterized in that it further comprises an active substance selected from epigallocatechin gallate (EGCG), piperine, trimethylglycine (TMG) and leucine or a combination thereof.

7. The composition according to any of claims 5-6, characterized in that it comprises from 10 mg to 200 mg of epigallocatechin gallate (EGCG) and / or from 0.1 mg to 2 mg piperine and / or from 100 mg to 800 mg trimethylglycine (TMG) and / or from 100 mg to 2000 mg leucine or a combination thereof.

8. The composition according to any of claims 5-7, characterized in that it further comprises at least one food and / or pharmaceutically acceptable excipient.

9. The composition according to any of claims 5-8, characterized in that it is in the form of a powder, granulate, micropellet, microtablet, capsule, tablet, solution, food, dietary supplement and / or food additive.

10. Use of the combination according to any of claims 1-4 in nutritional support.

11. The use according to claim 10, characterized in that the nutritional support is a dietary support.

12. The use according to any of claims 10-11 , characterized in that the nutritional support is support of healthy aging.

13. Use of the composition according to any of claims 5-9 in nutritional support.

14. The use according to claim 13, characterized in that the nutritional support is a dietary support.

15. Use according to any of claims 13-14, characterized in that the nutritional support is support of healthy aging.

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