Multi-layer multi-release metagen composition and application thereof

Abstract

The invention discloses a multi-layer multi-release metagen composition and application thereof in quickly promoting defecation, lubricating intestinal tracts, relieving intestinal problems such as flatulence, stomachache, diarrhea, constipation, irritable bowel syndrome and inflammatory bowel disease, maintaining intestinal flora balance, repairing intestinal tracts, repairing intestinal mucosa health, relieving dyspepsia and improving gastrointestinal functions.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of dietary nutritional supplements, and particularly relates to a multi-layer multi-release postbiotic composition and its use in rapidly promoting defecation, lubricating the intestinal tract, relieving intestinal gas, abdominal pain, diarrhea, constipation, irritable bowel syndrome, inflammatory bowel disease, and other intestinal problems, maintaining intestinal flora balance, repairing the intestinal tract, repairing intestinal mucosal health, relieving indigestion, and improving gastrointestinal function. BACKGROUND

[0002] Constipation is a common and stubborn disease. Constipation can cause physical discomfort, cause pain, and confusion. Long-term constipation can lead to complications such as hemorrhoids, anal fissures, and rectal prolapse. The treatment of constipation is mainly drug treatment. However, such treatment cannot be used for a long time, cannot fundamentally solve the problem, and also causes side effects such as intestinal damage, further exacerbating intestinal flora imbalance.

[0003] Intestinal flora is the core part of intestinal microecology. Probiotics play an important role in maintaining intestinal homeostasis and treating intestinal diseases. Postbiotics are active products or cell components produced by probiotics during metabolism, including short-chain fatty acids, cell wall components, and exopolysaccharides, which have the effects of regulating the intestinal environment and enhancing the intestinal barrier function. It has the advantages of high safety, good stability, wide application range, not limited by antibiotics, clear chemical structure, convenient storage and transportation, etc.

[0004] Plant extracts can regulate the structure and composition of intestinal flora, thereby improving or inhibiting its dysfunction and pathological state. In addition, plant extracts contain active substances such as fiber, lubricants, polysaccharides, volatile oils, and organic acids, which have the effects of sterilization, improving digestion, enhancing antioxidant capacity, anti-inflammatory, improving gastrointestinal health, and promoting intestinal peristalsis.

[0005] The combination of plant extracts and postbiotics can quickly promote defecation, relieve intestinal gas, promote immune function and digestive function, and at the same time can synergistically eliminate harmful bacteria in the intestinal tract, regulate intestinal flora, improve intestinal health, further relieve constipation, and promote defecation.

[0006] However, the current conventional composition of plant extracts and postbiotics is a single release mode, which cannot meet the needs of plant extracts and postbiotics to be released in different areas of the gastrointestinal tract, and is not conducive to the targeted delivery of postbiotics to the gastrointestinal tract and colonization in the intestinal tract. SUMMARY

[0007] The present application provides a multi-layer multi-release probiotic composition which can quickly promote defecation, increase the amount of defecation, increase the volume of defecation, soften the stool and reduce the time required for defecation, repair and lubricate the intestinal tract, relieve intestinal problems such as intestinal gas, abdominal pain, diarrhea, constipation, irritable bowel syndrome, inflammatory bowel disease, repair the intestinal barrier, repair the intestinal mucosa, increase beneficial bacteria, regulate the balance of intestinal flora, regulate intestinal health, relieve indigestion, and improve gastrointestinal function. At the same time, the multi-layer multi-release has different release rates, which can target the delivery and release of probiotics in the intestinal tract, improve bioavailability and stability, achieve optimal absorption and utilization, further regulate the balance of intestinal flora, and enable patients to maintain regular defecation for a long time. Moreover, it is safe and does not contain laxative ingredients, avoiding irritation of the intestinal tract.

[0008] The present application provides a multi-layer composition comprising at least a first layer and a second layer, wherein the first layer comprises a plant extract; and the second layer comprises a probiotic and / or a prebiotic.

[0009] In one embodiment, the multi-layer composition of the present application, the first layer is characterized by a first release rate, and the second layer is characterized by a second release rate; further, the first release rate is immediate release, and the second release rate is extended release.

[0010] In one embodiment, the multi-layer composition of the present application, the first release rate is complete disintegration within 60 minutes in artificial gastric juice.

[0011] In a preferred embodiment, the multi-layer composition of the present application, the first release rate is complete disintegration within 40 minutes in artificial gastric juice.

[0012] In a more preferred embodiment, the multi-layer composition of the present application, the first release rate is complete disintegration within 30 minutes in artificial gastric juice.

[0013] In a particularly preferred embodiment, the multi-layer composition of the present application, the first release rate is complete disintegration within 25 minutes in artificial gastric juice.

[0014] In one embodiment, the multi-layer composition of the present application, the second release rate is complete disintegration within 180 minutes in artificial gastric juice.

[0015] In a preferred embodiment, the multi-layer composition of the present application, the second release rate is complete disintegration within 150 minutes in artificial gastric juice.

[0016] In a more preferred embodiment, the multi-layer composition of the present application, the second release rate is complete disintegration within 120 minutes in artificial gastric juice.

[0017] In a particularly preferred embodiment, the multilayer composition according to the present application, the second release rate is complete disintegration within 110 min in artificial gastric juice.

[0018] In one embodiment, the multilayer composition according to the present application, the time interval between the extended release and the immediate release is > 15 min in artificial gastric juice. Such as 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 66, 67, 68, 69, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150 min.

[0019] In a preferred embodiment, the multilayer composition according to the present application, the time interval between the extended release and the immediate release is > 20 min in artificial gastric juice.

[0020] In a more preferred embodiment, the multilayer composition according to the present application, the time interval between the extended release and the immediate release is > 30 min in artificial gastric juice.

[0021] In a more preferred embodiment, the multilayer composition according to the present application, the time interval between the extended release and the immediate release is > 40 min in artificial gastric juice.

[0022] In a particularly preferred embodiment, the multilayer composition according to the present application, the time interval between the extended release and the immediate release is > 60 min in artificial gastric juice.

[0023] In a particularly preferred embodiment, the multilayer composition according to the present application, the time interval between the extended release and the immediate release is 30-120 min in artificial gastric juice.

[0024] In a particularly preferred embodiment, the multilayer composition according to the present application, the time interval between the extended release and the immediate release is 40-100 min in artificial gastric juice.

[0025] In a particularly preferred embodiment, the multilayer composition according to the present application, the time interval between the extended release and the immediate release is 40-80 min in artificial gastric juice.

[0026] In a particularly preferred embodiment, the multilayer composition according to the present application, the time interval between the extended release and the immediate release is 50-70 min in artificial gastric juice.

[0027] In one embodiment, the multilayer composition according to the present application, the number of probiotic cells is 1-100 billion per part.

[0028] In one embodiment, the multi-layer composition of the present application has a probiotic cell count of 1-500 billion per serving.

[0029] In one preferred embodiment, the multi-layer composition of the present application has a probiotic cell count of 10-100 billion per serving.

[0030] In one more preferred embodiment, the multi-layer composition of the present application has a probiotic cell count of 20-80 billion per serving.

[0031] In one particularly preferred embodiment, the multi-layer composition of the present application has a probiotic cell count of 30-80 billion per serving.

[0032] In one embodiment, the multi-layer composition of the present application has a plant extract that is one or more of okra extract, orange peel extract, fennel extract, clove extract, konjac extract, licorice extract, white kidney bean extract, citrus extract, flaxseed extract, gotu kola extract, mulberry leaf extract, rosehip extract, yerba mate extract, fermented black bean powder, bergamot extract, kiwi extract, dragon fruit extract, hibiscus sabdariffa extract, hollyhock extract, winter melon seed extract, dandelion extract, scullcap extract, chrysanthemum extract, maitake mushroom extract, quinoa extract, jujube extract, apple extract, wood ear mushroom extract, ginseng extract, purple sweet potato extract, rhizoma bamboo extract, enoki mushroom extract, goji berry extract, cordyceps extract, cocoa bean hull extract, corn extract, witch hazel leaf extract, jujube extract, gynostemma extract, horse chestnut seed extract, hesperidin extract, pueraria extract, prune extract, buckwheat extract, pumpkin extract, banana extract, spinach extract, white cardamom extract, psyllium hull extract, white atractylodes extract, almond extract, cashew extract, brazil nut extract, avocado extract, grape seed extract, green tea extract, amla extract, cranberry extract, gamboge fruit extract, white kidney bean extract, oolong tea extract, chia seed extract, apricot extract, sugar cane extract, peach, plum, fig extract, mushroom extract, pineapple extract, olive extract, sweet potato, carrot, asparagus extract, giant knotweed extract, semen cassiae extract, rhubarb extract, radix falcaliae extract, ginger extract, garlic extract, inulin, chicory extract, onion extract, legume extract, canola oil extract, plantain, oat, brown rice, pear, banana, orange, grape, spinach, beet.

[0033] In one preferred embodiment, the multi-layer composition of the present application has a plant extract that is at least one or more of okra extract, orange peel extract, fennel extract, clove extract, licorice extract.

[0034] In a preferred embodiment, the multilayer composition according to the present application, the plant extract is a combination of okra extract, orange peel extract, fennel extract, clove extract, liquorice extract.

[0035] In one embodiment, the multilayer composition according to the present application, the plant extract is present in an amount of > 1 mg per serving. Such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150 mg per serving.

[0036] In a preferred embodiment, the multilayer composition according to the present application, the plant extract is present in an amount of > 5 mg per serving.

[0037] In a more preferred embodiment, the multilayer composition according to the present application, the plant extract is present in an amount of > 10 mg per serving.

[0038] In a more preferred embodiment, the multilayer composition according to the present application, the plant extract is present in an amount of > 20 mg per serving.

[0039] In a particularly preferred embodiment, the multilayer composition according to the present application, the plant extract is present in an amount of 5-20 mg per serving.

[0040] In a particularly preferred embodiment, the multilayer composition according to the present application, the plant extract is present in an amount of 5-100 mg per serving.

[0041] In one embodiment, the multilayer composition according to the present application, the liquorice extract is present in an amount of > 0.5 mg per serving. Such as 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3 mg per serving.

[0042] In a preferred embodiment, the multilayer composition according to the present application, the liquorice extract is present in an amount of > 1 mg per serving.

[0043] In a more preferred embodiment, the multilayer composition according to the present application, the liquorice extract is present in an amount of 1-5 mg per serving.

[0044] In a particularly preferred embodiment, the multilayer composition according to the present application, the liquorice extract is present in an amount of 1-2 mg per serving.

[0045] Dietary fiber can promote the growth of probiotics and regulate the number of harmful bacteria, while dietary fiber has the effect of increasing stool volume, softening stool, promoting intestinal peristalsis, helping to adjust the balance of intestinal flora, promoting defecation, and maintaining gastrointestinal health.

[0046] In one embodiment, the multi-layer composition of the present application, the first layer and / or the second layer further comprises a dietary fiber.

[0047] In one embodiment, the multi-layer composition of the present application, the dietary fiber is one or more of polydextrose, white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract, glucosan, wheat fiber, apple dietary fiber, carob, lemon dietary fiber, aloe dietary fiber, guar gum, gum arabic, pectin, inulin, fructooligosaccharide, xylooligosaccharide, galactooligosaccharide.

[0048] In one preferred embodiment, the multi-layer composition of the present application, the dietary fiber is one or more of white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract.

[0049] In one more preferred embodiment, the multi-layer composition of the present application, the dietary fiber is a combination of white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract.

[0050] In one preferred embodiment, the multi-layer composition of the present application, the dietary fiber is in the second layer.

[0051] In one embodiment, the multi-layer composition of the present application, the total content of the dietary fiber is ≥1 mg / serving. Such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 mg / serving.

[0052] In one preferred embodiment, the multi-layer composition of the present application, the total content of the dietary fiber is ≥10 mg / serving.

[0053] In one more preferred embodiment, the multi-layer composition of the present application, the total content of the dietary fiber is ≥50 mg / serving.

[0054] In one preferred embodiment, the multi-layer composition of the present application, the total content of the dietary fiber is 10-200 mg / serving.

[0055] In one more preferred embodiment, the multi-layer composition of the present application, the total content of the dietary fiber is 20-150 mg / serving.

[0056] Osmotic agents promote a large amount of water into the large intestine, making the stool soft and loose. Excessive liquid makes the large intestine wall stretch, stimulating contraction. Some salts, including those containing magnesium ions, phosphate ions, such as magnesium hydroxide, magnesium sulfate, magnesium phosphate, etc., by promoting osmosis, stimulating intestinal movement, thereby having the effect of clearing the intestine and removing intestinal toxins.

[0057] In one embodiment, the multilayer composition of the present application, the first layer and / or the second layer further comprises a magnesium salt; further, the magnesium salt is one or a combination of magnesium hydroxide, magnesium sulfate, magnesium phosphate, magnesium oxide, magnesium citrate, magnesium carbonate, magnesium chloride, magnesium threonate, magnesium gluconate.

[0058] In one embodiment, the multilayer composition of the present application, the probiotic- derived strain is one or more of Lactobacillus casei, Lactobacillus plantarum, Bifidobacterium longum subsp. longum, Bifidobacterium longum subsp. infantis, Akkermansia muciniphila, Bifidobacterium breve, Streptococcus thermophilus, Bifidobacterium bifidum, Lactobacillus rhamnosus, Bifidobacterium lactis, Bacillus coagulans, Lactobacillus acidophilus, Bifidobacterium animalis, Bifidobacterium infantis, Lactobacillus casei, Bifidobacterium thermophilum, Lactobacillus reuteri, Pediococcus pentosaceus, Pediococcus acidilactici.

[0059] In one preferred embodiment, the multilayer composition of the present application, the probiotic-derived strain is Lactobacillus casei.

[0060] In one embodiment, the multilayer composition of the present application, the probiotic- derived strain is a yeast, further, the yeast cell count is 10 million to 10 billion per serving.

[0061] In one embodiment, the multilayer composition of the present application, the probiotic- derived strain is one or more of Lactobacillus casei, Akkermansia muciniphila.

[0062] In one embodiment, the multilayer composition of the present application, the Akkermansia muciniphila cell count is 10 to 200 billion per serving.

[0063] In one preferred embodiment, the multilayer composition of the present application, the Akkermansia muciniphila cell count is 50 to 150 billion per serving.

[0064] In one more preferred embodiment, the multilayer composition of the present application, the Akkermansia muciniphila cell count is 80 to 150 billion per serving.

[0065] In one particularly preferred embodiment, the multilayer composition of the present application, the Akkermansia muciniphila cell count is 80 to 100 billion per serving.

[0066] In one embodiment, the multilayer composition of the present application, the first layer further comprises a sugar alcohol, preferably one or a combination of sorbitol, maltitol, mannitol, lactitol, erythritol, xylitol, further the sugar alcohol is sorbitol.

[0067] In one embodiment, the multilayer composition of the present application has a total magnesium salt content of > 100 mg / portion. For example, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg / portion.

[0068] In a preferred embodiment, the multilayer composition of the present application has a total magnesium salt content of 100-500 mg / portion.

[0069] In one embodiment, the multilayer composition of the present application has a magnesium salt content in the first layer of 100-500 mg / portion.

[0070] In one embodiment, the multilayer composition of the present application has a second layer further comprising probiotic bacteria.

[0071] In a preferred embodiment, the multilayer composition of the present application has probiotic bacteria that are one or more of Lactobacillus plantarum, Bifidobacterium longum subsp. longum, Lactobacillus casei, Akkermansia muciniphila, Bifidobacterium breve, Streptococcus thermophilus, Bifidobacterium bifidum, Lactobacillus rhamnosus, Bifidobacterium lactis, Bacillus coagulans, Lactobacillus acidophilus, Bifidobacterium animalis, Bifidobacterium infantis, Lactobacillus casei, Bifidobacterium thermophilum, Lactobacillus reuteri, Pediococcus pentosaceus, Pediococcus acidilactici.

[0072] In one embodiment, the multilayer composition of the present application has a postbiotic that includes, but is not limited to, inactivated bacteria, lysed bacteria, and / or culture broth containing dead bacterial bodies.

[0073] In one embodiment, the multilayer composition of the present application has inactivated bacteria that are inactivated by methods including, but not limited to, pasteurization, ultraviolet irradiation, chemical treatment.

[0074] In one embodiment, the method of preparing the plant extract specifically includes: (1) selecting and processing plant raw materials, such as washing, cutting, or pulverizing;

[0075] (2) extracting active ingredients using enzymatic hydrolysis, water extraction, alcohol extraction, ultrasonic extraction, supercritical fluid extraction, etc.

[0076] (3) isolating and purifying the extract by filtration, centrifugation, chromatography, membrane separation, and crystallization, etc.

[0077] (4) concentrating and drying the extract by evaporation, freeze-drying, or spray-drying, etc.

[0078] In another aspect, the present application provides a product prepared by adding the above-mentioned multilayer composition to food-acceptable excipients to form a bilayer tablet, a sustained-release microsphere, a capsule, or a soft capsule.

[0079] In one embodiment, the product of the present application, the capsule includes but is not limited to micro-tablets in capsules, sustained-release granules in capsules, sustained-release tablets in capsules; the soft capsule includes but is not limited to micro-tablets in capsules, sustained-release granules in capsules, sustained-release tablets in capsules.

[0080] In a preferred embodiment, the present application provides a product, a multi-layer tablet prepared from the above-mentioned multi-layer composition and food acceptable adjuvants.

[0081] In one embodiment, the multi-layer tablet of the present application is prepared by wet granulation compression, powder direct compression or 3D printing technology.

[0082] In another aspect, the present application provides the use of the above-mentioned multi-layer composition and product in rapidly promoting defecation, lubricating the intestinal tract, relieving intestinal problems such as bloating, abdominal pain, diarrhea, constipation, irritable bowel syndrome, inflammatory bowel disease, maintaining the balance of intestinal flora, repairing the intestinal tract, repairing the health of intestinal mucosa, relieving indigestion, and improving gastrointestinal function.

[0083] The present application provides the use of the above-mentioned multi-layer composition and product in rapidly promoting defecation, lubricating the intestinal tract, maintaining the balance of intestinal flora, repairing the intestinal tract, repairing the health of intestinal mucosa, relieving indigestion, and improving gastrointestinal function.

[0084] The multi-layer multi-release probiotic composition provided by the present application has the following advantages:

[0085] 1. It can increase intestinal mucus, lubricate the intestinal tract, increase the thickness of the intestinal muscle layer, enhance the peristaltic force of the intestinal tract, repair the intestinal barrier and intestinal mucosa, increase beneficial bacteria, regulate intestinal health, balance intestinal flora, support intestinal mucosa health, promote intestinal health, and maintain the balance of intestinal flora;

[0086] 2. It can increase the amount and volume of defecation, soften the stool, reduce the time required for defecation, effectively help smooth and regular defecation, and relieve intestinal problems such as constipation, bloating, abdominal pain, diarrhea, etc.

[0087] 3. It has the effects of immunity, anti-inflammation, and promoting metabolism, enabling patients to maintain long-term regular defecation, has high safety, does not contain laxative ingredients, and avoids irritating the intestinal tract.

[0088] 4. The multi-layer tablet is beneficial to improving the stability of plant extracts, is convenient to store and transport, has good stability, is convenient to take, and is easy to carry.

[0089] 5. Multi-layer multi-release, the first layer releases immediately, the effective ingredients are quickly decomposed in gastric acid, and the effect is immediate; the second layer of probiotics is released slowly, so that it can be released targetedly and colonize the intestinal tract; it improves the bioavailability, and realizes the best absorption and utilization rate.

[0090] The composition provided by the application can realize first defecation within 8 hours.

[0091] Term explanation

[0092] The "postbiotic" is a general term for metabolite components of probiotics after processing, including bacterial cells and metabolites. The components mainly include inactivated bacterial cells, bacterial lysates, cell wall components and metabolites, etc. The metabolites include gamma-aminobutyric acid, short-chain fatty acids, tryptophan, etc.

[0093] The "dietary fiber" is a compound composed of polysaccharides, lignin and hemicellulose, etc., including soluble dietary fiber and insoluble dietary fiber.

[0094] The "per serving" refers to each serving of composition or product, such as each tablet, each capsule, each oral liquid, etc. The "postbiotic cell number is 1-100 billion per serving" refers to that the number of postbiotic cells contained in each tablet / capsule / oral liquid / powder, etc. is 1-100 billion.

[0095] The "multi-layer" refers to different layers containing different drugs or excipients, and the release time of different layers is different. It can be double-layer, triple-layer, four-layer, five-layer, six-layer, etc. BRIEF DESCRIPTION OF DRAWINGS

[0096] Figure 1 The first defecation time detection result is shown in Table 1.

[0097] Figure 2 The total number of fecal particles in 6h is shown in Table 2.

[0098] Figure 3 The weight detection result of 6h feces is shown in Table 3.

[0099] Figure 4 The rectal feces water content detection result is shown in Table 4.

[0100] Figure 5 The small intestine propulsion rate detection result is shown in Table 5.

[0101] Figure 6 The colon tissue HE staining result is shown in Table 6.

[0102] Figure 7 The colon tissue muscle layer thickness detection result is shown in Table 7.

[0103] Figure 8 The total amount of beneficial bacteria and harmful bacteria at genus level in the intestinal microorganisms of mice is shown in Table 8.

[0104] Figure 9 The beneficial bacteria content detection result of intestinal microorganisms of mice is shown in Table 9.

[0105] Figure 10The results of detecting the harmful bacteria content of the intestinal microorganisms of mice. DETAILED DESCRIPTION

[0106] For the convenience of those skilled in the art, the present application will be further described below in conjunction with examples, and the content mentioned in the embodiments is not a limitation on the present application.

[0107] Example 1

[0108] A multilayer composition comprising a first layer and a second layer, wherein the first layer comprises a plant extract; the second layer comprises a probiotic. The plant extract is a combination of okra extract, orange peel extract, fennel extract, clove extract, liquorice extract; the probiotic is Lactobacillus casei inactivated bacteria.

[0109] Example 2

[0110] A multilayer composition comprising a first layer and a second layer, the first layer comprises a plant extract; the second layer comprises a probiotic, dietary fiber. The plant extract comprises okra extract, orange peel extract, fennel extract, clove extract, liquorice extract; the dietary fiber comprises a combination of white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract, and the probiotic is Lactobacillus casei inactivated bacteria.

[0111] Example 3

[0112] A multilayer composition comprising a first layer and a second layer, the first layer comprises a plant extract, magnesium oxide; the second layer comprises a probiotic, dietary fiber. The plant extract comprises okra extract, orange peel extract, fennel extract, clove extract, liquorice extract; the dietary fiber comprises a combination of white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract, and the probiotic is Lactobacillus casei inactivated bacteria.

[0113] Example 4

[0114] A multilayer composition comprising a first layer and a second layer, the first layer comprises a plant extract, magnesium oxide; the second layer comprises a probiotic, dietary fiber, magnesium oxide. The plant extract comprises okra extract, orange peel extract, fennel extract, clove extract, liquorice extract; the dietary fiber comprises a combination of white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract, and the probiotic is Lactobacillus casei inactivated bacteria.

[0115] Example 5

[0116] A multi-layer composition comprising a first layer and a second layer, the first layer comprising a plant extract, magnesium oxide; the second layer comprising a probiotic, dietary fiber, magnesium oxide. Wherein the plant extract comprises okra extract, orange peel extract, fennel extract, clove extract, liquorice extract; the dietary fiber comprises a combination of white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract, and the probiotic is Lactobacillus casei inactivated bacteria. The plant extract is 15mg, the dietary fiber is 135mg, the probiotic cell number is 5 billion, and the total content of magnesium oxide is 450mg.

[0117] Example 6

[0118] A multi-layer composition comprising a first layer and a second layer, the first layer comprising a plant extract, magnesium oxide; the second layer comprising a probiotic, dietary fiber, magnesium oxide. Wherein the plant extract comprises okra extract, orange peel extract, fennel extract, clove extract, liquorice extract; the dietary fiber comprises a combination of white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract, and the probiotic is Lactobacillus casei inactivated bacteria. The plant extract is 15mg, the dietary fiber is 135mg, the probiotic cell number is 5 billion, and the total content of magnesium oxide is 450mg.

[0119] Example 7

[0120] A multi-layer composition comprising a first layer and a second layer, the first layer comprising a plant extract, magnesium oxide; the second layer comprising a probiotic, dietary fiber. Wherein the plant extract comprises okra extract, orange peel extract, fennel extract, clove extract, liquorice extract; the dietary fiber comprises a combination of white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract, and the probiotic is Lactobacillus casei inactivated bacteria. The plant extract is 15mg, the dietary fiber is 135mg, the probiotic cell number is 5 billion, and the magnesium oxide is 450mg.

[0121] Example 8

[0122] A multi-layer composition comprising a first layer and a second layer, the first layer comprising a plant extract, magnesium oxide; the second layer comprising a probiotic, dietary fiber. Wherein the plant extract comprises okra extract, orange peel extract, fennel extract, clove extract, liquorice extract, and the dietary fiber comprises a combination of white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract; the probiotic is Lactobacillus casei inactivated bacteria. The okra extract is 5mg, the orange peel extract is 3.7mg, the fennel extract is 3.2mg, the liquorice extract is 1.8mg, the clove extract is 0.8mg, the dietary fiber is 134mg, the probiotic cell number is 5 billion, and the magnesium oxide is 450mg.

[0123] Example 9

[0124] A multi-layer composition comprising a first layer and a second layer, the first layer comprising a plant extract, magnesium oxide; the second layer comprising a probiotic, dietary fiber, magnesium oxide. Wherein the plant extract comprises okra extract, orange peel extract, fennel extract, clove extract, liquorice extract; the dietary fiber comprises a combination of white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract, and the probiotic is Lactobacillus casei inactivated bacteria. The okra extract is 5 mg, the orange peel extract is 3.7 mg, the fennel extract is 3.2 mg, the liquorice extract is 1.8 mg, the clove extract is 0.8 mg, the dietary fiber is 134 mg, the probiotic cell number is 50 billion, and the total content of magnesium oxide is 450 mg.

[0125] Example 10

[0126] A multi-layer composition comprising a first layer and a second layer, the first layer comprising a plant extract, magnesium oxide; the second layer comprising a probiotic, dietary fiber, magnesium oxide. Wherein the plant extract comprises okra extract, orange peel extract, fennel extract, clove extract, liquorice extract; the dietary fiber comprises a combination of white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract, and the probiotic is Lactobacillus casei inactivated bacteria. The okra extract is 5 mg, the orange peel extract is 3.7 mg, the fennel extract is 3.2 mg, the liquorice extract is 1.8 mg, the clove extract is 0.8 mg, the dietary fiber is 134 mg, the probiotic cell number is 50 billion, and the total content of magnesium oxide is 450 mg. The preparation method comprises: adding the first layer (plant extract, magnesium oxide) and the second layer (probiotic, dietary fiber, magnesium oxide) to excipients respectively, crushing, sieving, and mixing uniformly, then compressing the two-layer composition into tablets, and coating to obtain double-layer tablets.

[0127] Example 11

[0128] A multi-layer composition comprising a first layer and a second layer, the first layer comprising a plant extract, magnesium oxide; the second layer comprising a probiotic, dietary fiber, magnesium oxide. Wherein the first layer further comprises excipients such as hydroxypropyl cellulose, silicon dioxide, sodium bicarbonate, polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, polyethylene glycol, hydroxypropyl methyl cellulose, fatty acid, magnesium salt of fatty acid, etc., and the second layer further comprises excipients such as hydroxypropyl cellulose, sodium bicarbonate, microcrystalline cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, polyethylene glycol, hydroxypropyl methyl cellulose, etc. The preparation method comprises: adding the first layer (plant extract, magnesium oxide) and the second layer (probiotic, dietary fiber, magnesium oxide) to excipients respectively, crushing, sieving, and mixing uniformly, then compressing the two-layer composition into tablets, and coating to obtain double-layer tablets.

[0129] Test Example

[0130] Test Example 1

[0131] The disintegration time of the composition (Example 10) of the present application was detected according to the Chinese Pharmacopoeia 2020 edition four general rules 0921 (artificial gastric juice). The detection results are that the first layer is completely disintegrated in 22 min, and the second layer is completely disintegrated in 107 min.

[0132] Test Example 2

[0133] 2.1. Experimental materials

[0134] Sample preparation: After preparation with normal saline to the specified concentration, it is given intragastrically, and it is prepared and used every day.

[0135] Experimental animals: SPF level balb / c male mice, 6-8 weeks old, weighing 18-22 g, a total of 90. Raising in a clean level animal experiment room, the environmental conditions are kept at 12 h day-night cycle, constant temperature (21℃-23℃), humidity of 55%-58%. After 1 week of adaptive feeding, the formal experiment is started.

[0136] Instruments, consumables and reagents: loperamide hydrochloride, Indian ink, intragastric needle, disposable syringe, electronic balance, dissecting instruments, etc.

[0137] 2.2. Evaluation method

[0138] 2.2.1 Experimental steps: After 1 week of adaptive feeding of all mice, 90 balb / c mice were randomly divided into 5 groups, 18 in each group. The experimental drug administration period is 14 days, sample intragastric administration is carried out 7 days before the experiment, and 7 days after the experiment, except for the normal group, the rest of the groups are modeled, loperamide hydrochloride (10 mg / kg) is given intragastrically in the morning, and each sample group is given intragastrically according to the specified dose in the afternoon, and the normal group and the model group are given distilled water with the same volume. After the sample intragastric administration is completed, 18 mice in each group are divided into group A and group B, 10 mice in group A are used for fecal property observation, and 8 mice in group B are used for intestinal propulsion experiment, (HE) staining, intestinal flora sequencing experiment and intestinal fecal water content detection. The specific drug administration dose is shown in Table 1.

[0139] Table 1

[0140]

[0141] 2.2.2 Experimental data collection

[0142] 2.2.2.1 General observation of mice: observe the changes of hair, activity, mental state, etc. of mice during the whole experiment. The body weight and food intake of all mice are recorded during the experiment, and the measurement is carried out twice a week.

[0143] 2.2.2.2 Mouse fecal parameters - Group A mice: On the evening of the 13th day of the experiment, group A mice in each group were fasted and deprived of water for 12-16 h, and on the morning of the 14th day of the experiment, loperamide hydrochloride was administered by gavage, and the control group was given an equal amount of 5% CMC-Na, 1 h later, the sample group was given the sample by gavage, and the normal group and the model group were given an equal amount of normal saline by gavage. 30 min after gavage of the sample, each mouse in each group was given 0.2 mL of ink by gavage, and the mice were placed in clean cages, which were separated by partitions, and each cage contained one mouse. The surrounding environment was kept quiet, and the time was started. Collect 6 h feces, record the first defecation time, 6 h fecal particle count and 6 h fecal weight.

[0144] 2.2.2.3 Small intestine propulsion rate and rectal fecal water content - Group B mice: Group B mice were treated the same as group A mice, 30 min after gavage of the sample, each mouse in each group was given 0.2 mL of ink by gavage, and 20 min later, the mice were sacrificed by cervical dislocation, the small intestine was taken out and placed on a scale board, the distance from the pylorus to the front of the ink (L1) and the distance from the pylorus to the cecum (L2) were measured, and the small intestine propulsion rate was calculated. Small intestine propulsion rate = L1 / L2 x 100%.

[0145] The fecal particles in the rectum were collected and weighed, then the feces were placed in an electric hot air drying oven for drying until a constant weight was obtained, the weight was taken, and the rectal fecal water content was calculated. Fecal water content (%) = [(wet weight - dry weight) / wet weight] x 100%.

[0146] 2.2.2.4 Colonic histopathology detection

[0147] 2.2.2.4 Colonic histopathology detection

[0148] Table 2

[0149]

[0150]

[0151] 2.2.2.5 Effect of sample on mouse intestinal flora

[0152] The ileocecal feces of group B mice were collected in sterile cryopreservation tubes, the operation was rapid, and contamination was avoided as much as possible during the process. All samples were immediately placed in liquid nitrogen after collection, and dry ice was stored after sampling and subjected to 16S rRNA sequencing to analyze the fecal flora abundance of each group of mice.

[0153] 2.2.3 Data processing

[0154] The experimental data obtained are expressed as mean ± standard error (Mean ± SEM), and all data are processed and statistically analyzed using GraphPad Prism 8.0. The t test is used for comparison between the means of two sample groups, and the ANOVA test is used for comparison between the means of multiple sample groups. A p value of less than 0.05 indicates that the difference is statistically significant.

[0155] 2.3. Evaluation results

[0156] 2.3.1 Time of first defecation

[0157] The results of the time of first defecation show that, compared with the control group, the time of first defecation of the model group significantly increased, indicating that the model was successfully constructed. After taking the composition of the application, the first defecation was achieved within 5 hours. The specific results are shown in Table 2.3.1. Figure 1 .

[0158] 2.3.26h fecal particle count

[0159] The total number of fecal particles within 6 hours was collected from the mice at the end point and recorded. The results show that, compared with the control group, the total number of fecal particles of the model group significantly decreased, indicating that the model was successfully constructed. After taking the composition of the application, the total number of fecal particles within 6 hours of the mice significantly increased. The specific results are shown in Table 2.3.2. Figure 2 .

[0160] 2.3.36h fecal weight

[0161] The total amount of feces within 6 hours was collected from the mice at the end point and weighed, and the results show that, compared with the control group, the fecal weight of the mice within 6 hours of the model group significantly decreased. After taking the composition of the application, the fecal weight of the mice within 6 hours significantly increased, i.e., the composition of the application can increase the amount of defecation. The specific results are shown in Table 2.3.3. Figure 3 .

[0162] 2.3.4 Water content of rectal feces

[0163] After the mice were sacrificed, the rectal feces were taken, photographed, and then the water content of the feces was determined. The results show that, compared with the control group, the water content of the feces of the mice of the model group significantly decreased, and the state of the feces was dry and hard, indicating that the model was successfully constructed. After taking the composition of the application, the water content of the rectal feces increased. The specific results are shown in Table 2.3.4. Figure 4 .

[0164] 2.3.5 Small intestine propulsion rate

[0165] By intragastrically administering ink to the mice, the small intestine propulsion distance was measured after 20 minutes, and the small intestine propulsion rate was calculated to determine the speed of intestinal peristalsis. The results show that, compared with the control group, the small intestine propulsion rate of the mice of the model group significantly decreased, indicating that the model was successfully constructed. After taking the composition of the application, the small intestine propulsion rate significantly increased. The specific results are shown in Table 2.3.5. Figure 5 .

[0166] 2.3.6 Intestinal pathology

[0167] The colon tissue of 2 cm of the mice was placed in a fixing solution for preservation, paraffin-embedded overnight, and colon tissue paraffin sections were prepared for subsequent HE staining. The pathological changes of the colon tissue were observed under an optical microscope, and photographs were taken and saved. The colon tissue of the control group of mice had complete mucosa, submucosa, muscle layer and adventitia structures, the mucosa was covered by a single layer of columnar epithelial cells, and there were a large number of intestinal glands in the lamina propria. Some areas of the colon tissue of the model group of mice showed mucosal necrosis, crypt damage and thinning of the intestinal wall muscle layer, while the thinning of the muscle layer could interfere with the normal peristalsis of the intestine, leading to a slowing of the transport of intestinal contents, and thus affecting the digestive and absorptive functions. After taking the composition of the application, the colon muscle layer thickness of the mouse group increased significantly. The specific results are shown in Table 2.3.6-1. Figure 6 、 Figure 7 .

[0168] 2.3.7 Intestinal flora abundance

[0169] The abundance of beneficial bacteria (AKK bacteria, Bifidobacterium, Lactobacillus, Bacteroides, Lactobacillus) and harmful bacteria (Streptococcus) in the intestines of mice in each group was analyzed. The results showed that after taking the composition of the application, the beneficial bacteria in the intestines of mice increased significantly, and the abundance of Streptococcus flora decreased. According to the analysis of the sequencing results, taking the composition of the application can significantly increase the abundance of beneficial bacteria in the intestines and reduce the abundance of harmful bacteria in the intestines. The specific results are shown in Table 2.3.7-1. Figure 8 、 Figure 9 、 Figure 10 .

[0170] In summary, taking the composition of the application can achieve first defecation within 5 hours, i.e., effectively helping to promote defecation; increasing the amount and volume of defecation; increasing the water content of feces; and compared to single-layer release, multi-layer multiple release is beneficial to improving the utilization rate and promoting the colonization of postbiotics in the intestines, thereby effectively repairing the intestinal barrier and intestinal mucosa, increasing the abundance of beneficial bacteria in the intestines, reducing the abundance of harmful bacteria in the intestines, balancing the intestinal flora, and maintaining the balance of the intestinal flora.

[0171] It should be understood that the above detailed description of the technical solutions of the application by means of preferred embodiments is illustrative rather than limiting. Based on the description of the application, those of ordinary skill in the art can modify the technical solutions described in the embodiments, or make equivalent substitutions for some of the technical features; and these modifications or substitutions do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the application.

Claims

1. A multilayer composition comprising at least a first layer and a second layer, wherein: The first layer includes plant extracts; the second layer includes postbiotics and / or probiotics.

2. The composition according to claim 1, characterized in that The first layer is characterized by a first release rate, and the second layer is characterized by a second release rate; further, the first release rate is immediate release, and the second release rate is extended release.

3. The composition according to claim 2, characterized in that The time interval between the extended release and the immediate release in artificial gastric juice is ≥15 min.

4. The composition according to claim 1, characterized in that The plant extracts are okra extract, orange peel extract, fennel extract, clove extract, konjac extract, licorice extract, white kidney bean extract, citrus extract, flax seed extract, salacia extract, mulberry leaf extract, rose hip extract, yerba mate extract, fermented black bean powder, bergamot extract, kiwi fruit extract, pitaya extract, mallow extract, hollyhock extract, winter mallow seed extract, dandelion extract, scutellaria baicalensis extract, chrysanthemum extract, Agaricus blazei extract, quinoa extract, jujube extract, apple extract, wood ear extract, ginseng extract, purple sweet potato extract, long skirt bamboo fungus extract, enoki mushroom extract, wolfberry extract, cordyceps militaris extract, cocoa pod shell extract, corn extract, witch hazel leaf extract, gynostemma pentaphyllum extract, horse chestnut seed extract, hesperidin extract, kudzu root extract, prune extract One or more of: buckwheat extract, pumpkin extract, banana extract, spinach extract, white cardamom extract, psyllium husk extract, atractylodes extract, almond extract, cashew extract, Brazil nut extract, avocado extract, grape seed extract, green tea extract, amla extract, cranberry extract, garcinia cambogia extract, white kidney bean extract, oolong tea extract, chia seed extract, apricot extract, sugarcane extract, peach, plum, fig extract, mushroom extract, pineapple extract, olive extract, sweet potato, carrot, asparagus extract, knotweed extract, cassia seed extract, rhubarb extract, polygonum multiflorum extract, ginger extract, garlic extract, inulin, chicory extract, onion extract, bean extract, rapeseed oil extract, plantain, oats, brown rice, pear, banana, orange, grape, green grape, beet.

5. The composition according to claim 1, characterized in that The first layer and / or the second layer also include dietary fiber. Further, the dietary fiber is one or more of polydextrose, white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, resistant dextrin, konjac extract, glucomannan, wheat fiber, apple dietary fiber, carob, lemon dietary fiber, aloe dietary fiber, guar gum, gum arabic, pectin, inulin, fructooligosaccharides, xylo-oligosaccharides, and galacto-oligosaccharides.

6. The composition according to claim 1, characterized in that The first layer and / or the second layer further comprises a magnesium salt; further, the magnesium salt is one or a combination of magnesium hydroxide, magnesium sulfate, magnesium phosphate, magnesium oxide, magnesium citrate, magnesium carbonate, magnesium chloride, magnesium threonate, and magnesium gluconate.

7. The composition according to claim 5, characterized in that The dietary fiber is a composition of white kidney bean fiber, citrus fiber, tremella powder, flaxseed powder, konjac extract and resistant dextrin.

8. The composition according to claim 5, characterized in that The dietary fiber is in the second layer.

9. The composition according to claim 1, characterized in that The postbiotic source strain is one or more of Lactobacillus casei, Lactobacillus plantarum, Bifidobacterium longum subsp. longum, Bifidobacterium longum infantis subsp. infantis, Akkermansia muciniphila, Bifidobacterium breve, Streptococcus thermophilus, Bifidobacterium bifidum, Lactobacillus rhamnosus, Bifidobacterium lactis, Bacillus coagulans, Lactobacillus acidophilus, Bifidobacterium animalis, Bifidobacterium infantis, Lactobacillus casei, Bifidobacterium thermophilus, Lactobacillus reuteri, Pediococcus pentosaceus, and Pediococcus acidilactici.

10. The composition according to claim 9, characterized in that The postbiotic source strain is Lactobacillus casei.

11. A product, characterized in that The composition according to any one of claims 1 to 10 is added with food-acceptable excipients to prepare multilayer tablets, sustained-release microspheres, capsules and soft capsules.

12. The product according to claim 11, characterized in that The dosage form of the product is a multi-layer tablet.

13. Use of the composition according to any one of claims 1 to 10 and the product according to any one of claims 11 to 12 for rapidly promoting defecation, lubricating the intestines, relieving intestinal problems such as flatulence, abdominal pain, diarrhea, constipation, irritable bowel syndrome, inflammatory bowel disease, maintaining intestinal flora balance, repairing the intestines, repairing intestinal mucosal health, relieving indigestion, and improving gastrointestinal function.

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