Synbiotic micronutrient combination product in a two-component drinking system

Abstract

Synbiotic micronutrient combination product in a two-component drinking system, comprising 1.1 a drinking ampoule (Phase A) with an aqueous suspension containing - at least one prebiotic, - at least one postbiotic and - at least one micronutrient, - as well as bioactive substances, peptides and secondary plant substances 1.2 a closure cap (phase B) attached to the drinking ampoule with a closed reservoir, which - at least one spore-forming probiotic strain in an amount of at least 1 × 10 9 CFU per serving and - contains at least one digestive enzyme, 1.3 a predetermined breaking membrane arranged between phase A and phase B, which can be destroyed by axial pressure or torque, whereby the reservoir is opened immediately before consumption, its contents are completely transferred into phase A and dispersed there, thus producing a ready-to-drink synbiotic beverage.

Description

[0001] The present invention relates to a synbiotic micronutrient combination product in a two-component drinking system consisting of pre-, pro- and postbiotics, digestive enzymes, peptides, bioactive substances and micronutrients, in particular with Bacillus subtillis var. natto and enzymes from Aspergillus oryzae, as well as its use as a dietary food for oral intestinal microbiome modulation.

[0002] The inventive synbiotic micronutrient combination product in a two-component drinking system with prebiotics, probiotics, and postbiotics is suitable for the dietary treatment of disorders of the intestinal flora and the gut-associated immune system, e.g., allergies, liver and lipid metabolism disorders, after chemotherapy and radiotherapy, after taking antibiotics, and psychological stress such as depression, ADHD, and fatigue. The inventive synbiotic micronutrient combination product in a two-component drinking system with prebiotics, probiotics, and postbiotics enables holistic, multi-layered stimulation of the intestinal microbiome and metabolic intestinal function, as well as all associated physiological processes, through the simultaneous intake of prebiotics, probiotics, and postbiotics, digestive enzymes, peptides, bioactive substances, secondary plant substances, and micronutrients.

[0003] Over the past two centuries, technological advances in agriculture, food production, and medicine have fundamentally transformed human nutrition. While these developments have helped overcome hunger and malnutrition, they have also led to profound changes in our lifestyles and environmental conditions. As a result, a silent epidemic has emerged: the disruption of the human microbiome.

[0004] A particular focus is on the intestinal microbiome, whose functional and structural balance is essential for human health. It is becoming increasingly clear that dysbiosis—that is, a qualitative or functional imbalance of the intestinal microbiota—is causal or partly responsible for the development of numerous multifactorial diseases. These include chronic inflammatory, autoimmune, metabolic, neoplastic, and neurodegenerative diseases such as type 2 diabetes mellitus, obesity, bronchial asthma, multiple sclerosis, Crohn's disease, ulcerative colitis, as well as Alzheimer's and Parkinson's diseases.

[0005] The rapid increase in these diseases in a comparatively short period of time suggests that genetic factors alone cannot explain the increase. Rather, environmental and lifestyle factors are at the center of causal research. These include, among others, changing dietary habits, physical inactivity, extended lifespans, excessive hygiene, the increased use of xenobiotics, and artificial light and temperature control – all changes that are almost universal in post-industrial society.

[0006] As these connections were clarified, it became increasingly clear that, in addition to the human genome, the so-called metagenome—the totality of microbial genes in and on our bodies—must also be considered. This microbiome, which has co-evolved with its human host over millennia, exhibits a significantly faster adaptability to environmental changes due to shorter generation times. This places the microbiome at the center of research into the effects of modern environmental conditions on human health.

[0007] Recent studies demonstrate that many of these diseases are associated with an altered microbial signature. This shows that not only the bacterial composition but also the metabolic functions of the microbiota are disrupted. In particular, the intestinal bacterial flora has a direct influence on immune homeostasis and thus on the development of immune-associated diseases.

[0008] Against this background, the development of innovative synbiotic technologies specifically aimed at restoring a healthy microbial balance is necessary. The present invention addresses this medical and societal need.

[0009] Certain normally harmless bacteria, such as Enterobacteriaceae, can proliferate excessively when the microbial balance is disrupted. Such overgrowths of pathogenic bacteria occur consistently in inflammatory bowel disease, both in humans and in mouse models. They are considered less a cause than a consequence of the inflammation-induced restructuring of the intestinal environment.

[0010] At the same time, beneficial intestinal bacteria can decline or be completely lost—for example, due to impaired proliferation or deadly environmental factors. This loss is functionally relevant, as the targeted reintroduction of these ("probiotic") bacteria (e.g., Lactobacillus reuteri or Bacteroides fragilis) has already led to the attenuation of pathological symptoms in animal models, such as autism or Clostridium difficile infections. Specific microbial metabolites ("postbiotics") also show potential for restoring intestinal homeostasis, e.g., by influencing microglia, cytokine production, or neurodegenerative processes.

[0011] A common hallmark of dysbiosis is reduced microbial diversity ("alpha diversity"). A diverse microbiota, which develops primarily in early childhood and can be positively influenced by diet ("prebiotics"), is closely linked to metabolic health. Conversely, reduced diversity is found in irritable bowel syndrome, AIDS, type 1 diabetes, and other diseases, as well as in an unbalanced diet.

[0012] A disturbed microbiome (dysbiosis) is caused by several external influences. Particularly significant are modern dietary habits, exposure to foreign substances (xenobiotics), and the early childhood imprinting of the microbiome, especially through birth and breastfeeding.

[0013] Our modern diet is often low in fiber and high in fat. However, fiber ("prebiotics") is the primary food source for many beneficial gut bacteria. If it is lacking, they starve, die out, or are displaced. Studies show that a low-fiber diet over several generations dramatically reduces microbial diversity, sometimes with irreversible consequences. High-fat diets also promote pro-inflammatory bacterial profiles. Not only antibiotics, but also artificial sweeteners, emulsifiers, and other xenobiotics negatively impact the microbiome. They inhibit the growth of beneficial bacteria or promote disease-causing bacteria. Thus, in the long term, they can contribute to the development of immune and metabolic disorders.

[0014] The child's microbiome is decisively shaped during birth and the first months of life. Breastfeeding is a key factor in this: Breast milk not only directly transmits beneficial bacteria (“probiotics”), but also contains bioactive substances such as human milk oligosaccharides (“prebiotics”), secretory IgA, and antimicrobial peptides. These specifically promote the growth of health-promoting bacteria in the infant's gut and contribute to the maturation of the immune system. The IgA contained in breast milk, in particular, plays an important role: It binds microbes in the infant's gut and helps build a protective immune barrier. The IgA contained in breast milk reflects the mother's gut-associated immune system, which is influenced by the maternal microbiome. Breastfeeding can therefore have a long-term impact on the risk of allergies, infections, and chronic diseases.

[0015] Our Western lifestyle disrupts the symbiosis with our microbiome from birth onward. Therefore, it seems inevitable that innovative dietary supplements should be developed to support the restoration of microbiome symbiosis.

[0016] Synbiotic micronutrient supplements are already known. These contain prebiotics, probiotics, and occasionally postbiotics, as well as micronutrients, which, for stability reasons, are offered in separate dosage forms—powder, granules, capsules, tablets, or solutions—that must be taken at different times. Conventional synbiotics often offer a partial mix of prebiotics and probiotics, but omit postbiotics, digestive enzymes, or essential micronutrients. A disadvantage of existing products is that the separate form and intake of the individual components, as well as the fragmented formulation, often means that holistic intestinal stimulation is not achieved.

[0017] For manufacturing reasons, the entire daily dose is often compressed into a single tablet or capsule. Taking tablets or film-coated tablets can result in the ingredients being released at different times in the stomach and intestines, which can lead to delayed and impaired absorption. Tablets are often tasteless or unpleasant in the mouth. Furthermore, because they lack any visual, gustatory, or tactile-interactive components, fatigue and reduced compliance quickly develop. A further disadvantage of these products is that the ingredients are rehydrated and dissolved in the stomach only after ingestion under the negative influence of gastric acid, thereby reducing their bioavailability.A further disadvantage is that in many products, stomach acid leads to extensive decomposition of probiotic cultures, such as lactic acid bacteria, especially if they were previously in an inactive form. The amount of probiotic cultures that ultimately reach the intestine is therefore negligible. Furthermore, the number of living probiotic cultures reaching the intestine is further reduced due to the poor growth and living conditions at the site of action and the previously inactive form of the probiotics, resulting in a significant loss of activity within a short period of time. Two-component drinking systems are also known, in which a delicate micronutrient granulate is pressed into a drinking ampoule and suspended immediately before consumption.

[0018] Capsule-in-chamber drinking systems are also already known. In these designs, a capsule containing sensitive active ingredients is contained in a special lid-like reservoir. The chamber is opened, and the capsule is taken separately from the contents of the drinking ampoule.

[0019] However, to date, no product exists that (i) provides a complete synbiotic formula of pre-, pro-, and postbiotics, as well as digestive enzymes, peptides, bioactive substances, and micronutrients, and (ii) separates these sensitive components in a two-component drinking system in such a way that the sensitive probiotics and digestive enzymes, in particular, are freshly transferred into pre- and postbiotic suspension with micronutrients immediately before consumption, suspended, rehydrated, and activated there, or taken separately from the suspension as an enteric-coated oral dosage form (capsule, tablet, etc.). Due to this gap, holistic synbiotic intestinal stimulation does not occur in current products.

[0020] The aim of the present invention is to provide a synbiotic micronutrient combination product in a two-component drinking system that overcomes the deficiencies of conventional preparations and enables comprehensive, multi-layered stimulation of the intestinal microbiome. The invention aims at a formulation in which prebiotics, probiotics, and postbiotics are combined with digestive enzymes, peptides, bioactive substances, and essential micro- and trace elements in a two-component drinking system. The sensitive probiotics and digestive enzymes are protected from moisture and biodegradation until immediately before consumption. They are transferred into a prebiotic and postbiotic suspension only at the moment of use, where they are rehydrated and activated, or they can be taken separately as an enteric-coated oral dosage form (capsule, tablet, etc.), thus ensuring optimal viability and being introduced into the digestive tract.

[0021] Spatial separation and real-time activation ensure the stability of all ingredients during storage and gastric transit, while simultaneously ensuring the simultaneous availability of all active components in the intestine. The synchronized delivery of substrate (prebiotics), live microorganisms (probiotics), and their metabolites (postbiotics), supplemented by specific enzymes, bioactive substances, peptides, and micronutrients, has been proven to produce synergistic effects, increase microbial diversity, and promote the metabolic activity of the intestinal ecosystem. Since all components are already present in solution or fine suspension before swallowing, bioavailability is also improved compared to solid dosage forms, where active ingredients are often only partially absorbed due to delayed dissolution or acid degradation.

[0022] Ultimately, the product is intended to offer an interactive, sensorially appealing user experience: The visual and motor interaction upon activation, as well as the gustatory enhancement of the liquid, increase acceptance and support daily compliance, especially among younger, health-conscious users. The invention thus creates a stable, user-friendly, and scientifically sound basis for effective, reproducible microbiome modulation.

[0023] The task is solved by a synbiotic micronutrient combination product in a two-component drinking system.

[0024] It comprises a drinking ampoule (first component) with an aqueous suspension – Phase A – containing at least one prebiotic, at least one postbiotic (preferably as a fermentation concentrate), water-soluble micronutrients, as well as bioactive substances, peptides, and / or secondary plant substances. It also comprises a cap with a reservoir (second component) containing a solid Phase B consisting of at least one probiotic strain and at least one digestive enzyme. By axially pressing or screwing the cap, a predetermined breaking membrane is opened; Phase B trickles into Phase A, dissolves within a few seconds, and creates a ready-to-drink, holistic synbiotic product. In a second embodiment, Phase B is available as an enteric-coated oral dosage form (capsule, tablet, etc.) in a reservoir, which is taken separately from Phase A.

[0025] The probiotic cultures of the probiotic-containing synbiotic micronutrient multi-combination product in the two-component drinking system are selected from the group comprising Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus crispatus, Lactobacillus gallinarum, Lactobacillus gasseri, Lactobacillus johnsonii, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus reuten, Lactobacillus rhamnosus, Lactobacillus salivarius, Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium lactis, Bifidobacterium longum, Enterococcus faecalis, Enterococcus faecium, Lactococcus lactis, Leuc. mesenteroides, Ped.acidilactici, Sporolactobacillus inulinus, Strep, thermophilus, Bacillus cereus, Bacillus subtillis, Bacillus coagulans, Bacillus, clausii, Escherichia coli, Propionibacterium freudenreichii and Saccharomyces cerevisiae, preferably Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium animalis, Lactobacillus plantarum, Lactobacillus brevis, Lactobacillus acidophilus, Lactobacillus gasseri, Lactobacillus reuteri, Lactobacillus casei Shirota, Bacillus subtilis var. Natto, Enterococcus faecium, Eschericha Coli and / or Sacharomyces cerevisiae.

[0026] A key advantage of the product according to the invention stems from the added lactic acid bacteria: The lactic acid they produce lowers the pH value in the intestinal lumen, allowing trace elements, especially iron and zinc, to dissolve more easily and thus be absorbed much more efficiently. At the same time, the probiotic cultures increase the absorptive surface of the intestinal mucosa, which further promotes the absorption of these micronutrients.

[0027] In the two-component drinking system according to the invention, Bacillus subtilis var. natto is preferably combined with selected lactic acid bacteria. This spore-forming Bacillus forms stable biofilms in the intestine, protecting the sensitive lactic acid bacteria from stomach acid, bile salts, and lysozyme, thereby significantly improving their survival. At the same time, B. subtilis var. natto possesses pronounced amylase activity: It breaks down starch into simple sugars and provides the lactic acid bacteria with immediately available energy. Other hydrolytic enzymes (proteases, lipases, and polysaccharidases) support the breakdown of complex food components, provide additional nutrient substrates for the microbiome, and promote the formation of health-relevant metabolites such as polyunsaturated fatty acids.The strain is extremely robust – it tolerates high temperatures and salinity, survives the entire gastrointestinal transit, and exhibits pronounced antimicrobial activity against pathogens such as Salmonella enterica and Staphylococcus aureus. Animal and human studies have also described improvements in lipid homeostasis (lowering LDL, increasing HDL), beneficial effects on serum proteins, and positive effects in type 2 diabetes and obesity. Overall, B. subtilis var. natto thus potentiates the growth, vitality, and functional performance of the added lactic acid bacteria and makes a decisive contribution to the overall efficacy of the synbiotic micronutrient product.

[0028] In this two-component drinking system, Enterococcus faecium is preferably combined with lactic acid bacteria, as this strain surprisingly significantly enhances their effectiveness. E. faecium lowers the pH already in the upper small intestine, rapidly acidifying the environment and creating optimal growth conditions for the accompanying lactic acid bacteria. The resulting accelerated proliferation leads to a further reduction in pH, which further potentiates the probiotic effect. Studies also show that the intake of this bacterial mixture, particularly the E. faecium strain, significantly increases the production of gut-associated immunoglobulins (sIgA) and the activity of natural killer cells, thus sustainably strengthening the mucosal immune system.

[0029] The use of digestive enzymes from the Japanese rice fungus Aspergillus oryzae has proven particularly advantageous in the two-component drinking system according to the invention. These enzymes operate within a wide pH (3-8) and temperature range (25-55 °C) and retain at least 80% of their activity; they are therefore effective in both the stomach and the small intestine. Their comprehensive substrate spectrum – amylase, protease, lipase, and lactase – covers the breakdown of carbohydrates, proteins, fats, and lactose and can reduce postprandial symptoms such as bloating and a feeling of fullness. Furthermore, the enzymes develop synergies with the added probiotics: The partial hydrolysis of complex food components produces oligo- and peptide substrates that promote the growth of lactic acid bacteria. Since A. oryzae is obtained through koji fermentation, the enzyme preparation is purely plant-based, halal / kosher and vegan-friendly, and classified as GRAS by the US FDA.In the dry reservoir, a residual activity of over 95% is maintained even after 24 months of storage at 25°C and 60% relative humidity. According to the invention, the synbiotic micronutrient multi-combination product in the two-component drinking system comprises prebiotics selected from the group comprising inulin, fructooligosaccharides, galactooligosaccharides, and β-glucan. It has been shown that the micronutrient combination product according to the invention contributes to the survival of probiotic cultures in the intestine through the addition of these prebiotics.

[0030] The synbiotic two-component drinking system contains selected inactivated probiotics or microbial fermentation products as postbiotics. A kombucha fermentation concentrate alone and / or other ferments are preferably used. The addition of this postbiotic has been proven to improve the survival of the added probiotics in the gut, promote the activity of the overall microbiome, and support the modulation of the gut-associated immune system.

[0031] The vitamins comprised in the probiotic-containing micronutrient combination product are selected according to the invention from the group comprising vitamin A, vitamin C, natural vitamin E, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folic acid), vitamin B12 (cobalamin), vitamin K1 / K2 and / or vitamin D3. The secondary plant substances of the probiotic-containing micronutrient combination product are selected according to the invention from the group comprising carotenoids and bioflavonoids.

[0032] The trace elements comprised in the probiotic-containing micronutrient combination product are selected from the group comprising calcium, selenium, iron, zinc, manganese, copper, chromium, molybdenum, iodine, phosphorus, magnesium, potassium and / or chloride, preferably selenium, iron, zinc, manganese, copper, chromium, molybdenum and / or iodine.

[0033] The synbiotic micronutrient combination product may comprise additives that improve bioavailability, solubility, and / or dissolution rate and / or additives selected from the group consisting of disintegrants, shelf-life-enhancing substances, taste-masking and / or taste-enhancing substances, and substances that increase or decrease viscosity. The synbiotic micronutrient multi-combination product may comprise additives selected from the group consisting of dextrose, maltodextrin, corn starch, natural orange flavor, citric acid acidifier, sodium bicarbonate, gum arabic, sodium saccharin, and / or enzymes.

[0034] The phases of the synbiotic micronutrient multi-combination product can be solid, liquid, or semi-solid and are preferably stored separately in a two-component drinking system. The first component – ​​usually in a reservoir in the cap – contains the sensitive substances, namely probiotic cultures and digestive enzymes. The second component is contained as an aqueous suspension in the drinking bottle and provides prebiotics, postbiotics, micronutrients, and optionally bioactive substances, peptides, and secondary plant compounds.

[0035] The system can be implemented in two practical versions: Push-cap variant

[0036] The lid contains granules of probiotics and enzymes. By applying axial pressure or unscrewing, a membrane breaks, the granules fall into the liquid phase, dissolve within seconds, and the ready-mixed synbiotic is ready to drink. Reservoir oral dosage form variant

[0037] The cap contains an enteric-coated oral dosage form (capsule, tablet, etc.) with probiotics and enzymes. The user opens the cap, takes the oral dosage form (capsule, tablet, etc.) separately, and then drinks the contents of the bottle containing the liquid prebiotics, postbiotics, and micronutrients. Example A:

[0038] Cap (granules): probiotics, digestive enzymes, peptides, bioactive substances. Bottle (suspension): pre- and postbiotics, micronutrients, excipients. Example B:

[0039] Cap (oral dosage form): probiotics, digestive enzymes, peptides, bioactive substances. Bottle (suspension): pre- and postbiotics, micronutrients, excipients.

[0040] This arrangement ensures maximum stability during storage, fresh activation immediately before consumption and simultaneous delivery of all functional components in the digestive tract.

Claims

[1] Synbiotic micronutrient combination product in a two-component drinking system, comprising 1.1 a drinking ampoule (Phase A) with an aqueous suspension containing - at least one prebiotic, - at least one postbiotic and - at least one micronutrient, - as well as bioactive substances, peptides and secondary plant substances 1.2 a closure cap (phase B) attached to the drinking ampoule with a closed reservoir, which - at least one spore-forming probiotic strain in an amount of at least 1 × 10 9 CFU per serving and - contains at least one digestive enzyme, 1.3 a predetermined breaking membrane arranged between phase A and phase B, which can be destroyed by axial pressure or torque, whereby the reservoir is opened immediately before consumption, its contents are completely transferred into phase A and dispersed there, thus producing a ready-to-drink synbiotic beverage. [2] Synbiotic micronutrient combination product in a two-component drinking system according to claim 1, characterized by that the spore-forming strain is Bacillus subtilis var. natto. [3] Synbiotic micronutrient combination product in a two-component drinking system according to one of claims 1 or 2, characterized by that Phase B additionally comprises at least one lactic acid or bifidobacteria strain. [4] Synbiotic micronutrient combination product in a two-component drinking system according to one of claims 1, 2 or 3, characterized by that Phase B contains Enterococcus faecium or Sacharomyces Cerevisia as an additional probiotic strain. [5] Synbiotic micronutrient combination product in a two-component drinking system according to one of the preceding claims, characterized by that the digestive enzyme mixture contains amylase, protease, lipase and lactase derived from Aspergillus oryzae. [6] Synbiotic micronutrient combination product in a two-component drinking system according to one of the preceding claims, characterized by that Phase A contains 3 - 6 g of soluble fiber per serving, selected from inulin, fructooligosaccharides, galactooligosaccharides and β-glucan. [7] Synbiotic micronutrient combination product in a two-component drinking system according to one of the preceding claims, characterized by that Phase A contains 5 - 100 ml of an inactivated (kombucha) ferment concentrate as a postbiotic. [8] Synbiotic micronutrient combination product in a two-component drinking system according to one of the preceding claims, characterized bythat the enzyme component per serving includes: - Lactase: 1,000 - 10,000 ALU, - Amylase: 5 000 - 50 000 DU, - Protease: 2 000 - 20 000 HUT and - Lipase: 300 - 3 000 FIP. [9] Synbiotic micronutrient combination product in a two-component drinking system according to one of the preceding claims, characterized by that phase A and / or phase B are solid, liquid or semi-solid. [10] Synbiotic micronutrient combination product in a two-component drinking system in alternative design, comprising 10.1 a drinking ampoule according to claim 1.1, and 10.2 a lid arranged on the drinking ampoule with a removable reservoir containing a gastro-resistant oral dosage form (Phase B) according to claim 1.2, wherein the oral dosage form is taken separately from the contents of the drinking ampoule. [11] Synbiotic micronutrient combination product in a two-component drinking system according to one of claims 1 to 10, characterized by that Phase A contains at least one water-soluble vitamin selected from B1, B2, B3, B6, B7, B9, B 12 or C in an amount of 15% - 100% of the respective reference value according to Regulation (EU) 1169 / 2011 per portion. [12] Synbiotic micronutrient combination product in a two-component drinking system according to one of claims 1 to 11, characterized by that Phase A contains at least one fat-soluble vitamin selected from vitamin A, vitamin D3, vitamin E, vitamin K1 or vitamin K2 in an amount of 15% - 100% of the respective reference value according to Regulation (EU) 1169 / 2011 per serving. [13] Synbiotic micronutrient combination product in a two-component drinking system according to one of claims 1 to 12, characterized bythat Phase A contains at least one trace element selected from calcium, magnesium, iron, zinc, selenium, manganese, copper, chromium, molybdenum or iodine in an amount of 10% - 100% of the respective reference value according to Regulation (EU) 1169 / 2011 per serving. [14] Synbiotic micronutrient combination product in a two-component drinking system according to one of claims 1 to 13, characterized by that phase A or phase B comprises secondary plant substances, wherein the secondary plant substance is at least one carotenoid or bioflavonoid. [15] Synbiotic micronutrient combination product in a two-component drinking system according to one of claims 1 to 14, characterized by that Phase A contains peptides with an average molecular mass of 0.5 - 3 kDa in an amount of 10 - 100 mg per serving. [16] Synbiotic micronutrient combination product in a two-component drinking system according to one of claims 1 to 15, characterized bythat Phase A contains at least one bioactive substance selected from creatine, creatinine or L-carnitine in an amount of 50 - 500 mg per serving. [17] Synbiotic micronutrient combination product in a two-component drinking system according to one of claims 1 to 16, characterized by that Phase A and / or Phase B contains technological excipients to improve the bioavailability, solubility or dissolution rate in an amount of up to 10% by weight of the respective phase, wherein the excipient is selected from dextrose, maltodextrin, sodium bicarbonate, citric acid, gum arabic or natural flavorings.