A three-layer seamless softgel capsule composition

Abstract

Provided is a three-layer seamless soft capsule including a core, an intermediate protective layer, and an outer layer of a film, the intermediate protective layer including an oily substance that completely dissolves and recovers to form a fatty layer including solid oily substance particles and a liquid fat form of an intermediate layer, the solid oily substance particles being directly connected or connected via the intermediate layer, wherein the average maximum diameter of the solid oily substance particles is 100 μm-500 μm and the ratio of the average maximum diameter to the average thickness of the intermediate layer is 5-100:1. The three-layer seamless soft capsule of the present application forms a unique solid fat form in the intermediate protective layer, reduces the problem of easy rupture and oil leakage of the capsule and inability to form due to the fact that the oil droplets in the film during the manufacturing process of the seamless soft capsule are too large, and improves the accelerated stability of the product.

Description

TECHNICAL FIELD

[0001] The present invention relates to the field of soft capsules, in particular to a three-layer seamless soft capsule. BACKGROUND

[0002] Seamless soft capsules are formed using the drop method, under different liquid flow rates and specific frequency of conduction, forming stable dose spherical-shaped pellets. However, the skin film of the seamless capsule has the disadvantage of "oil droplets", and the solid or semi-solid seamless has the defect of poor protection effect of the middle layer, affecting the stability of the inner layer nutrients.

[0003] To reduce the "oil droplet" problem of the skin film of the seamless capsule, the existing solutions are to add components such as interfacial tension modifiers and gel promoters in the film composition or capsule content. JP2015199698A provides a two-layer seamless capsule containing phospholipids, as the seamless capsule with a single layer film containing phospholipid oil cannot be formed, the capsule content is further compounded with an emulsifier with HLB 3 or lower. JP2022026425A provides a two-layer seamless soft capsule, which contains 85% phosphatidylcholine in the capsule content, which can reduce the thickness unevenness and oil droplets in the seamless capsule. CN202211685460.3 provides a three-layer seamless soft capsule and its preparation method and use, wherein the same uses an intermediate protective layer containing phospholipids to overcome the above problems.

[0004] Therefore, the prior art has solved the problem of oil droplets in the seamless soft capsule by adding phospholipids containing 85% phosphatidylcholine in the content, or forming a complex of phospholipids and HLB <3 emulsifier.

[0005] There is still a need in the art for improved three-layer seamless soft capsule compositions with improved formulations. SUMMARY

[0006] The inventors found that when adding phospholipids to the prior art multi-layer seamless soft capsule products to solve the technical problem of soft capsule oil droplets, there is a risk of discoloration, and some phospholipids are of soybean origin, which has the risk of introducing allergens. Therefore, the inventors tried to avoid the addition of phospholipids by combining different oily materials. Surprisingly, in a three-layer seamless soft capsule, the inventors avoided the "oil droplet" problem of the skin film by combining different oily materials to produce an intermediate protective layer without adding phospholipids.

[0007] In one aspect, there is provided a three-layer seamless soft capsule comprising a core, an intermediate protective layer and a film outer layer, the intermediate protective layer comprising an oily substance, the oily substance completely melting and reconstituting to form an intermediate layer comprising solid oily substance particles and a liquid fat form of a fatty layer (e.g. a solid fatty layer) at 25-35°C. The solid oily substance particles can be directly connected or connected via an intermediate layer, wherein the average maximum diameter of the solid oily substance particles is 100-500 μιη and the ratio of the average maximum diameter to the average thickness of the intermediate layer is 5-100:1.

[0008] In one embodiment, the average maximum diameter of the solid oily substance particles is 200-500 μιη or 300-440 μιη or 300-350 μιη and / or the ratio of the average maximum diameter to the average thickness of the intermediate layer is 10-50:1 or 20-30:1.

[0009] In one embodiment, the intermediate protective layer of the three-layer seamless soft capsule comprises 170-230 or 180-225 parts by weight of a first oily substance and 70-120 or 75-110 parts by weight of a second oily substance, the first oily substance being a hardened oil or a compounded hardened oil composition in a solid state at room temperature and having a melting point of 30-60°C, the second oily substance being a hardened oil or a compounded hardened oil composition in a solid state at room temperature and having a melting point of 35-65°C, the melting point of the second oily substance being 2-20°C higher than the melting point of the first oily substance when used in combination.

[0010] In one embodiment, the first oily substance is selected from one or more of cocoa butter, cocoa butter alternatives, cocoa butter equivalents, shea oil, palm oil and palm kernel oil and / or the second oily substance is selected from one or more of shortening, filling oil, margarine, margarine-like spread, hydrogenated soybean oil and hydrogenated oil. In one embodiment, the intermediate protective layer does not comprise a phospholipid.

[0011] In one embodiment, the core, the intermediate protective layer and the film outer layer are in direct contact, the intermediate protective layer encloses the core and the film outer layer encloses the intermediate protective layer.

[0012] In one embodiment, the weight ratio of the core layer: intermediate protective layer: film layer is 4-7:2-4:1-3. In one embodiment, the weight ratio of the core layer: intermediate protective layer: film layer is 5:3:2.

[0013] In one embodiment, the melting point of the intermediate protective layer is 0-10°C higher than the melting point of the core and / or the water content of the film outer layer is 2-10 wt%.

[0014] In one embodiment, the core comprises 0.5-100 parts by weight of the active substance and 300-500 parts by weight of the third oily substance, the third oily substance being a hardened oil or a compounded hardened oil which is in a solid state at room temperature and has a melting point of 24-64°C.

[0015] In one embodiment, the outer layer of the film comprises 80-320 parts by weight of the water-soluble gelling agent and 10-125 parts by weight of the plasticizer.

[0016] In one embodiment, the third oily substance is selected from one or more of palm oil, ghee, coconut oil, hydrogenated soybean oil, hydrogenated palm oil, extremely hydrogenated palm oil, hydrogenated coconut oil, finished fractionated palm stearin, palm olein, palm super olein, palm kernel oil, palm dual olein, palm mid fraction, palm oil interesterified, palm separated oil interesterified, cocoa butter, cocoa butter substitute, cocoa butter equivalent, and shea oil.

[0017] In one embodiment, the active substance is a substance unstable to water and / or acid.

[0018] In one embodiment, the substance unstable to water and / or acid is a powder. In one embodiment, the powder is a powder having an average particle size of 1-250 micrometers.

[0019] In one embodiment, the substance unstable to water and / or acid comprises one or more of probiotic bacteria, vitamins, lactoferrin, cells, and enzymes. In one embodiment, the cells are active stem cells.

[0020] In one embodiment, the probiotic bacteria comprise Bifidobacterium and / or lactic acid bacteria.

[0021] In one embodiment, the vitamins comprise one or more of vitamin B, vitamin B1, vitamin B2, vitamin B12, and vitamin C.

[0022] In one embodiment, the water-soluble gelling agent is selected from one or more of gelatin, carrageenan, agar, gellan gum, pectin, and starch.

[0023] In one embodiment, the water-soluble gelling agent comprises gelatin and pectin. In one embodiment, the weight ratio of pectin to gelatin is 1:10-3:10.

[0024] In one embodiment, the pectin is selected from low-ester pectin and / or amidated pectin. In one embodiment, the pectin has a degree of esterification DE < 50%. In one embodiment, the pectin has a degree of amidation DA of 0-25%. In one embodiment, the plasticizer is selected from one or more of glycerol, sorbitol, erythritol, and maltitol.

[0025] In one embodiment, the outer layer of the film comprises a water-soluble gelling agent and soft capsule additives such as a pigment and / or a sweetener.

[0026] In one embodiment, the pigment is selected from one or more of titanium dioxide, allura red, brilliant blue, lemon yellow, sunset yellow, cochineal red, turmeric, bixin, gardenia yellow, gardenia blue, safflower yellow, vegetable carbon black, carotenes, sodium copper chlorophyllin. In one embodiment, the sweetener is selected from one or more of sucralose, aspartame, advantame, sodium saccharin, acesulfame potassium, allulose, advantame, cyclamate, thaumatin, steviol glycosides, mogrosides, isomaltulose, ammonium glycyrrhizinate, mono- and tri-potassium glycyrrhizinate, D-mannitol, xylitol, erythritol, maltitol, lactitol.

[0027] In one embodiment, the weight ratio of the pigment to the water-soluble gelling agent is 0-0.25: 100.

[0028] In one embodiment, the weight ratio of the sweetener to the water-soluble gelling agent is 0-50: 100.

[0029] In another aspect, there is provided a composition for preparing the three-layer seamless soft capsule described herein, comprising a composition for forming an intermediate protective layer, the composition for forming an intermediate protective layer comprising an oily substance which completely melts and recovers to form an intermediate layer comprising solid oily substance particles and a liquid fat form at 25-35 °C, the solid oily substance particles being directly connected or connected via the intermediate layer, wherein the average maximum diameter of the solid oily substance particles is 100-500 μm and the ratio of the average maximum diameter to the average thickness of the intermediate layer is 5-100: 1. In one embodiment, the average maximum diameter of the solid oily substance particles is 200-500 μm or 300-440 μm or 300-350 μm. In one embodiment, the ratio of the average maximum diameter to the average thickness of the intermediate layer is 10-50: 1 or 20-30: 1. In one embodiment, the composition for forming an intermediate protective layer comprises 170-230 or 180-225 parts by weight of a first oily substance and 70-120 or 75-110 parts by weight of a second oily substance, the first oily substance being a hardened oil or a compounded hardened oil composition which is in a solid state at room temperature and has a melting point of 30-60 °C, the second oily substance being a hardened oil or a compounded hardened oil composition which is in a solid state at room temperature and has a melting point of 35-65 °C, the melting point of the second oily substance being 2-20 °C higher than the melting point of the first oily substance when used in combination.

[0030] In one embodiment, the first oily substance is selected from one or more of cocoa butter, cocoa butter equivalents, cocoa butter-like fats, shea oil, palm oil and palm kernel oil.

[0031] In one embodiment, the second oily material is selected from one or more of shortening, filling oil, margarine, artificial butter, hydrogenated soybean oil, and hydrogenated oil.

[0032] In one embodiment, the composition forming the intermediate protective layer does not comprise a phospholipid.

[0033] In one embodiment, the composition comprises a composition forming a core, the composition forming a core comprising 0.5-100 parts by weight of the active material and 300-500 parts by weight of a third oily material, the third oily material being a hardened oil or a compounded hardened oil which is in a solid state at room temperature and has a melting point of 24-64°C.

[0034] In one embodiment, the composition comprises a composition forming an outer layer of the film, the composition forming an outer layer of the film comprising 80-320 parts by weight of a water-soluble gelling agent and 10-125 parts by weight of a plasticizer.

[0035] In one embodiment, the composition forming an outer layer of the film further comprises water, for example 400-700 or 500-650 or 550-600 parts by weight of water.

[0036] In one embodiment, the third oily material is selected from one or more of palm oil, shortening, coconut oil, hydrogenated soybean oil, hydrogenated palm oil, extremely hydrogenated palm oil, hydrogenated coconut oil, fractionated palm stearin, palm olein, palm super olein, palm kernel oil, palm dual olein, palm mid fraction, palm oil interesterified, palm separated oil interesterified, cocoa butter, cocoa butter substitute, cocoa butter equivalent, and shea oil.

[0037] In one embodiment, the active material is a material which is unstable in the presence of water and / or an acid.

[0038] In one embodiment, the material which is unstable in the presence of water and / or an acid is a powder, preferably a powder having an average particle size of 1-250 microns.

[0039] In one embodiment, the material which is unstable in the presence of water and / or an acid comprises one or more of probiotic bacteria, vitamins, lactoferrin, cells, and enzymes. In one embodiment, the cells are active stem cells.

[0040] In one embodiment, the probiotic bacteria comprise Bifidobacterium and / or Lactobacillus.

[0041] In one embodiment, the vitamins comprise one or more of vitamin B, vitamin B1, vitamin B2, vitamin B12, and vitamin C.

[0042] In one embodiment, the water-soluble gelling agent is selected from one or more of gelatin, carrageenan, agar, gellan gum, pectin, and starch.

[0043] In one embodiment, the water-soluble gelling agent comprises gelatin and pectin, wherein the weight ratio of pectin to gelatin is 1 : 10 - 3: 10.

[0044] In one embodiment, the pectin is selected from low-ester pectin and / or amidated pectin.

[0045] In one embodiment, the degree of esterification DE of the pectin is < 50%.

[0046] In one embodiment, the degree of amidation DA of the pectin is 0 - 25%.

[0047] In one embodiment, the plasticizer is selected from one or more of glycerol, sorbitol, erythritol and maltitol.

[0048] In one embodiment, the composition forming the outer film layer of the soft capsule comprises a water-soluble gelling agent and a soft capsule additive, such as a pigment and / or a sweetener.

[0049] In one embodiment, the pigment is selected from one or more of titanium dioxide, Allura Red, Brilliant Blue, Lemon Yellow, Sunset Yellow, Carmine, Curcuma, Bixin, Gardenia Yellow, Gardenia Blue, Safflower Yellow, Vegetable Carbon Black, Carotene, Sodium Copper Chlorophyll.

[0050] In one embodiment, the sweetener is selected from one or more of sucralose, aspartame, alitame, sodium saccharin, acesulfame, allulose, advantame, cyclamate, thaumatin, steviol glycosides, mogroside, isomaltulose, ammonium glycyrrhizinate, mono- and tri-potassium glycyrrhizinate, D-mannitol, xylitol, erythritol, maltitol, lactitol.

[0051] In one embodiment, the weight ratio of pigment to water-soluble gelling agent is 0 - 0.25: 100.

[0052] In one embodiment, the weight ratio of sweetener to water-soluble gelling agent is 0 - 50: 100.

[0053] In another aspect, there is provided a method of making a three-layer seamless soft capsule according to the present disclosure, comprising: melting an oily substance at 60-85 °C, after complete stirring to homogeneity, cooling to 40-60 °C to obtain an intermediate protective layer solution; wherein the oily substance completely melts and upon return to 25-35 °C forms a fat layer comprising a solid oily substance particle and a liquid fat form of an intermediate layer, the solid oily substance particle being directly connected or connected via the intermediate layer, wherein the average maximum diameter of the solid oily substance particle is 100-500 μιη and the ratio of the average maximum diameter to the average thickness of the intermediate layer is 5-100: 1. In one embodiment, the average maximum diameter of the solid oily substance particle is 200-500 μιη or 300-440 μιη or 300-350 μιη. In one embodiment, the ratio of the average maximum diameter to the average thickness of the intermediate layer is 10-50: 1 or 20-30: 1.

[0054] In one embodiment, the first oily substance and the second oily substance are melted at 60-85 °C, after complete stirring to homogeneity, cooled to 40-60 °C to obtain an intermediate protective layer solution.

[0055] In one embodiment, the method comprises one or more of:

[0056] (1) Sol: premixing a water-soluble gelling agent and a plasticizer, dispersing uniformly, adding to water under stirring, optionally adding a colorant and a sweetener, heating and stirring at 55-85 °C until the colloid dissolves and removes air bubbles to obtain a skin outer layer;

[0057] (2) Core formulation: melting a third oily substance completely at 60-85 °C, cooling to 35-50 °C, adding an active ingredient, such as a water / acid-labile substance, stirring to homogeneity, removing air bubbles to obtain a core solution;

[0058] (3) Dropping: using a seamless soft capsule dropping device, selecting a 3-layer dropping head for dropping;

[0059] (4) Drying: using a rotating cage for drying until the moisture of the capsule skin is 2-10%, for example 3%, 4%, 5%, 6%, 7%, 8% or 9%.

[0060] In yet another aspect, there is provided a use of the three-layer seamless soft capsule according to the present disclosure in a food, health product, cosmetic or pharmaceutical product.

[0061] Advantages of the present disclosure include:

[0062] 1. The three-layer seamless soft capsule of the present disclosure does not add phospholipids in the intermediate protective layer. The problem of "oil droplets" in the skin film is avoided without adding phospholipids.

[0063] 2. The formulation of this invention avoids the risk of discoloration or allergens caused by phospholipids.

[0064] 3. The middle layer of the three-layer seamless soft capsule of this invention forms a unique solid fat morphology, reducing the problem of capsule rupture and oil leakage caused by excessively large oil droplets in the membrane during the manufacturing process of seamless soft capsules, and ensuring that the product is not prone to rupture or oil leakage during production, storage, and transportation. At the same time, the optimized three-layer seamless soft capsule structure of this invention improves the protection of the core substance by the middle protective layer, ensuring the stability of its active ingredients. Attached Figure Description

[0065] Figure 1 Images showing the morphological characteristics of the solid fat in the intermediate protective layer of Example 3 are displayed. Figure 1 As shown, the average diameter of the maximum diameter of multiple solid fat morphologies under the field of view is 100μm to 500μm, and the ratio of the average maximum diameter of multiple selected solid fat morphologies to the average thickness of the intermediate layer is 5 to 100:1.

[0066] Figure 2 Images showing the morphological characteristics of the solid fat in the intermediate protective layer of Comparative Example 3 are displayed. Figure 2 As shown, the average diameter of the maximum diameter of multiple solid fat morphologies under the field of view is less than 100 μm, and the ratio of the average maximum diameter of multiple selected solid fat morphologies to the average thickness of the intermediate layer under the field of view is less than 5:1. Detailed Implementation

[0067] As used herein, the term "comprising" is synonymous with "including" or "containing" and is inclusive of endpoints or open-ended concepts, and does not exclude additional unstated elements or method steps. "Comprising" is a technical term used in the language of claims, meaning that the stated element is present, but other elements may be added and still form a construction or method within the scope of the claims. Unless otherwise indicated, "%" as used herein refers to weight percentage.

[0068] In the manufacturing process of three-layer seamless soft capsules, because the nozzles are concentric, air bubbles and oil components from the core and intermediate layers inevitably remain in the outer membrane layer (outer membrane layer), forming small oil droplets. When the diameter of these droplets exceeds one-third of the cross-sectional area of ​​the capsule, the product is prone to rupture, oil leakage, or even failure to form. While the intermediate layer of the three-layer seamless soft capsule protects the inner layer, the protective effect of the solid fat precipitated from different formulations varies significantly. The purpose of this invention is to provide a three-layer seamless soft capsule that forms a dense intermediate layer to effectively protect the inner layer, solving the problem of excessive oil droplets in the membrane layer during the manufacturing process, which leads to rupture, oil leakage, or even failure to form.

[0069] The present application provides a three-layer seamless soft capsule, comprising a core, an intermediate protective layer wrapping the core, and a film layer containing a water-soluble gelling agent wrapping the intermediate protective layer. Through in-depth research, the present inventors have found that the three-layer seamless soft capsule forms a unique solid fat morphology in the intermediate protective layer, reduces the problem of capsule easy to break and oil leakage caused by oil droplets too large in the film during the manufacturing process of the seamless soft capsule, and improves the accelerated stability of the product.

[0070] Provided herein are three-layer seamless soft capsules comprising a core, an intermediate protective layer, and a film outer layer. The core, the intermediate protective layer, and the film outer layer can be in direct contact, the intermediate protective layer wraps the core, and the film outer layer wraps the intermediate protective layer. Preferably, the weight ratio of the core layer: intermediate protective layer: film layer is 4-7: 2-4: 1-3; preferably 5:3:2. Preferably, the intermediate protective layer has a melting point that is 0-10°C higher than the melting point of the core and / or the film outer layer has a water content of 2-10 wt%. The intermediate protective layer can be a fat layer (e.g., a solid fat layer) comprising an oily substance that completely dissolves and reverts to an intermediate layer comprising solid oily substance particles and a liquid fat form at 25-35°C, the solid oily substance particles being directly connected or connected via the intermediate layer. The oily substance is preferably two or more (e.g., 3-10, e.g., 3, 4, 5, 6, 7, 8, 9, or 10) different oily substances, e.g., oily substances having different melting points. The average maximum diameter of the solid oily substance particles can be 100 pm-500 pm, e.g., 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, or 490 pm. The ratio of the average maximum diameter of the solid oily substance particles to the average thickness of the intermediate layer is 5-100: 1, e.g., 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 15: 1, 20: 1, 25: 1, 30: 1, 35: 1, 40: 1, 45: 1, 50: 1, 55: 1, 60: 1, 65: 1, 70: 1, 75: 1, 80: 1, 85: 1, 90: 1, or 95: 1. The method of determining the average maximum diameter of the solid oily substance particles is known to one of skill in the art. For example, the method of determining can comprise completely dissolving the fat (e.g., at 60-85°C) and reverting to 25-35°C, smearing on a glass slide for 30 s, observing under 4*10 fold using an optical microscope, and measuring using LISSCAPTURE software, recording the maximum diameter of multiple visible solid fat forms in the field of view, and taking the arithmetic mean, which is the average maximum diameter. The method of determining the ratio of the average maximum diameter of the solid oily substance particles to the thickness of the intermediate layer is known to one of skill in the art. For example, the method of determining can comprise completely dissolving the fat and reverting to 25-35°C, smearing on a glass slide for 30 s, observing under 4*10 fold using an optical microscope, and measuring using LISSCAPTURE software, recording the thickness of the intermediate layer in the field of view, and taking the arithmetic mean, which is the average thickness of the intermediate layer. The ratio of the average maximum diameter of the solid fat forms to the average thickness of the intermediate layer is the average maximum diameter of the solid fat forms divided by the average thickness of the intermediate layer.

[0071] The intermediate protective layer of the three-layer seamless soft capsules of the present application can comprise 170-230 or 180-225 parts by weight (e.g. 180, 190, 200, 210 or 220 parts by weight) of a first oily substance and 70-120 or 75-110 parts by weight (e.g. 70, 80, 90, 100 or 110 parts by weight) of a second oily substance. The first oily substance can be a hardened oil or a compounded hardened oil composition which is in a solid state at room temperature and has a melting point of 30-60°C. The second oily substance can be a hardened oil or a compounded hardened oil composition which is in a solid state at room temperature and has a melting point of 35-65°C, and when used in combination, the melting point of the second oily substance is 2-20°C (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20°C) higher than the melting point of the first oily substance. For example, the first oily substance can be selected from one or more of cocoa butter, cocoa butter substitute, cocoa butter equivalent, shea oil, palm oil and palm kernel oil, and / or the second oily substance can be selected from one or more of shortening, margarine, artificial butter, artificial margarine, hydrogenated soybean oil and hydrogenated oil. Preferably, the intermediate protective layer of the three-layer seamless soft capsules of the present application does not comprise a phospholipid.

[0072] The core of the three-layer seamless soft capsule of the present application can comprise 0.5-100 parts by weight (e.g., 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 parts by weight) of an active substance and 300-500 parts by weight (e.g., 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 parts by weight) of a third oily substance, which is a hardened oil or a compounded hardened oil that is in a solid state at room temperature and has a melting point of 24-64°C. The film outer layer can comprise 80-320 parts by weight (e.g., 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, or 310) of a water-soluble gelling agent and 10-125 parts by weight (e.g., 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, or 120 parts by weight) of a plasticizer. The third oily substance can be selected from one or more of palm oil, shortening, coconut oil, hydrogenated soybean oil, hydrogenated palm oil, extremely hydrogenated palm oil, hydrogenated coconut oil, finished fractionated palm stearin, palm olein, palm super olein, palm kernel oil, palm dual olein, palm mid fraction, palm oil interesterified oil, palm separated oil interesterified oil, cocoa butter, cocoa butter substitute, cocoa butter equivalent, and shea oil. The active substance can be a substance that is unstable in the presence of water and / or acid, and can include one or more of probiotics (e.g., bifidobacteria and / or lactic acid bacteria), vitamins (e.g., one or more of vitamin B, vitamin B1, vitamin B2, vitamin B12, and vitamin C), lactoferrin, active stem cells, and enzymes. The water-soluble gelling agent can be selected from one or more of gelatin, carrageenan, agar, gellan gum, pectin, and starch. For example, the water-soluble gelling agent can comprise gelatin and pectin, wherein the weight ratio of pectin to gelatin is 1:10-3:10 (e.g., 1:10, 2:10, 3:10). The pectin is selected from low-ester pectin and / or amidated pectin; for example, the degree of esterification DE of the pectin is <50% and / or the degree of amidation DA of the pectin is 0-25%. The plasticizer can be selected from one or more of glycerol, sorbitol, erythritol, and maltitol.

[0073] The outer shell layer of the three-layer seamless softgel can comprise a water-soluble gelling agent and softgel additives, such as a colorant and / or a sweetener. It will be understood by one skilled in the art that the amount of softgel additives added is routinely determinable by one skilled in the art. Preferably, the colorant is selected from one or more of titanium dioxide, allura red, brilliant blue, lemon yellow, sunset yellow, cochineal red, turmeric, bixin, gardenia yellow, gardenia blue, safflower yellow, vegetable carbon black, carotenes, sodium copper chlorophyllin. Preferably, the sweetener is selected from one or more of sucralose, aspartame, advantame, sodium saccharin, acesulfame potassium, allulose, advantame, cyclamate, thaumatin, steviol glycosides, mogroside, isomaltulose, ammonium glycyrrhizinate, mono- and tri-potassium glycyrrhizinate, D-mannitol, xylitol, erythritol, maltitol, lactitol. The weight ratio of colorant to water-soluble gelling agent can be 0-0.25: 100 (e.g., 0.01: 100, 0.02: 100, 0.03: 100, 0.04: 100, 0.05: 100, 0.06: 100, 0.07: 100, 0.08: 100, 0.09: 100, 0.1: 100, 0.12: 100, 0.14: 100, 0.16: 100, 0.18: 100, 0.2: 100, 0.22: 100, 0.24: 100), and / or the weight ratio of sweetener to water-soluble gelling agent is 0-50: 100 (e.g., 1: 100, 2: 100, 3: 100, 4: 100, 5: 100, 6: 100, 7: 100, 8: 100, 9: 100, 10: 100, 20: 100, 30: 100, 40: 100, 50: 100).

[0074] The present application also provides a material composition for making a three-layer seamless softgel, comprising compositions for forming the core, the intermediate protective layer, and the outer shell layer. It will be understood by one skilled in the art that the description of the three-layer seamless softgel above applies equally to the material composition for making a three-layer seamless softgel.

[0075] The three-layer seamless soft capsules of the present application can be prepared by conventional three-layer seamless soft capsule preparation, which generally uses a seamless soft capsule dropping device, and a 3-layer dropping head is selected for dropping. For example, the method can include: melting the first oily substance and the second oily substance at 60-85°C, after complete stirring and uniformity, cooling to 40-60°C to obtain an intermediate protective layer solution. Preferably, the method includes one or more of the following: (1) sol: uniformly pre-mixing the water-soluble gelling agent and the plasticizer, adding to water under stirring, optionally adding pigments and sweeteners, heating and stirring at 55-85°C until the colloid dissolves and the bubbles are removed to obtain the outer skin film layer; (2) core preparation: melt the third oily substance completely at 60-85°C, cool to 35-50°C, add active ingredients such as water / acids-unstable substances, stir well and evenly, and remove bubbles to obtain the core solution; (3) dropping: use a seamless soft capsule dropping device, and a 3-layer dropping head is selected for dropping; (4) drying: drying is performed using a rotating cage until the moisture content of the capsule skin is 2-10%, for example, 3%, 4%, 5%, 6%, 7%, 8%, or 9%.

[0076] Examples

[0077] The embodiments of the present application will be described in detail below with reference to the examples, and those skilled in the art will understand that the following examples are only used to illustrate the present application and should not be regarded as limiting the scope of the present application. If no specific conditions are specified in the examples, the conventional conditions or the conditions recommended by the manufacturer are used. If no manufacturer of the reagent or instrument is specified, it is a conventional product that can be obtained by purchase. If no special indication is given, the amount listed is based on the total weight and described in parts by weight. The present application should not be interpreted as being limited to the specific examples described.

[0078] Method

[0079] For the solid fat morphology structure characteristics, the following characterization methods are used:

[0080] 1. Average maximum diameter of solid fat morphology: completely dissolve the oil (e.g. 85°C) and restore to 25-35°C, spread on a glass slide and stabilize for 30s, use an optical microscope to observe under 4*10 times, and use LISSCAPTURE software to measure, record the maximum diameter of multiple visible solid fat morphologies in the field of view, and take the arithmetic mean value, which is the average maximum diameter.

[0081] 2. The ratio of the average maximum diameter of solid fat morphology to the thickness of the intermediate layer (also referred to as the average spacing ratio in the table): completely dissolve the oil and fat and restore to 25-35°C, spread on the glass slide and stabilize for 30s, use optical microscope to observe under 4*10 times, and use LISSCAPTURE software to measure, record the thickness of the intermediate layer under the field of view, and take the arithmetic mean, which is the average thickness of the intermediate layer. The ratio of the average maximum diameter of solid fat morphology to the average thickness of the intermediate layer is the ratio of the two.

[0082] In order to better illustrate the effect of the present application, the following seamless soft capsule performance indicators are used for evaluation and illustration:

[0083] 1. Oil droplet diameter ratio: use optical microscope to observe under 4*10 times, and use LISSCAPTURE software to measure, record the oil droplet diameter and the thickness of the rubber at the position of the oil droplet. The calculation formula of the oil droplet diameter ratio is as follows:

[0084] Oil droplet diameter ratio (X) = oil droplet diameter (A) / thickness of rubber at the position of oil droplet (B)

[0085] 2. Oil droplet number: use optical microscope to observe under 4*10 times, and use LISSCAPTURE software to measure, record the number of oil droplets at the rubber of the gel pill.

[0086] 3. Appearance deformation determination:

[0087] Randomly sample 1000 particles, observe the appearance of obvious non-spherical gel pills such as long strips, filaments, irregular polygons, etc., record the number of unqualified products, and the appearance deformation unqualified rate (P1) = unqualified product number / total number*100%.

[0088] Table 1 Oil droplet ratio, oil droplet number, and appearance qualified rate of seamless soft capsule

[0089]

[0090] Note: If the seamless soft capsule cannot be formed, the comprehensive score is directly defined as 0

[0091] When the oil droplet diameter ratio is large and the oil droplet number is large, it is difficult to form a gel pill. If a gel pill is formed, the overall pressure resistance will be low because the place where the oil droplet exists is a weak point when testing the breaking force, which is manifested as extremely low gel pill breaking force. Breaking force is significantly related to these two indicators. Generally, for the evaluation of seamless soft capsules, the oil droplet ratio and the oil droplet number are the standard of the forming stability of soft capsules, and the appearance deformation rate represents the yield or the qualified rate of finished products.

[0092] When the oil droplet proportion score, oil droplet number score, and appearance deformation score are high, i.e., the comprehensive score is generally 4 points and above, at this time, the roundness is good, and the product parts can be uniformly stressed, so the product breaking force is high, and the accelerated oil leakage phenomenon rarely occurs. When any one of the oil droplet proportion, oil droplet number, and appearance deformation scores is less than 3 points, the prepared seamless soft capsules have a high oil leakage rate.

[0093] 4. Product accelerated stability

[0094] The product is accelerated at 35±2°C and 75±5% RH, and the survival rate / yield of water / acid unstable substances in the core of the product is observed. The present application takes lactic acid bacteria as an example, and the number of living bacteria is measured by using the national standard 4789.35-2016, and the survival rate is calculated as follows:

[0095] Survival rate (P2) = number of living bacteria in the month / 0 month * 100%.

[0096] The following components are expressed in parts, and 1 part of the example is 1 g in weight.

[0097] Examples 1-4

[0098] The ingredients and contents in the following table are prepared by the following preparation method to form the intermediate protective layer structure within the scope of the present application, form the seamless soft capsule, and perform testing and scoring. The determination results are shown as follows.

[0099] Preparation method:

[0100] (1) Sol: A) First, mix and disperse pectin, gelatin and plasticizer (glycerol) uniformly, and add to an appropriate amount of water under stirring, heat and stir at 70°C until the colloid is dissolved; B) remove the bubbles to obtain the gel solution of the skin layer.

[0101] (2) Ingredients: A) intermediate protective layer solution preparation method: melt the shortening and cocoa butter completely at 85°C, stir uniformly, and remove the bubbles to obtain the intermediate protective layer solution; B) core layer solution preparation method: melt the shortening at 85°C (the related oils involved in this paper can eliminate their original crystallization memory at this temperature, which can effectively avoid the influence of the original crystal form on the structure generation at a specific temperature, thereby affecting the structure observation), cool to 35-45°C, add the bacterial powder, stir uniformly, and remove the bubbles to obtain the core layer solution.

[0102] (3) Drop: use seamless soft capsule drop device, and select 3-layer drop head for drop.

[0103] (4) Drying: use a rotating cage for drying until the moisture content of the gel skin is less than 10%. That is, after drying, the core layer: intermediate protective layer: skin layer = 5:3:2

[0104] Table 2: Film layer formulation of Examples 1-4

[0105] Coating layer formulation composition Parts Gelatin 160 Glycerin 24 Pectin 24 Water 592

[0106] Table 3: Core formulation of Examples 1-4

[0107] Core formulation composition Parts Probiotic powder 100 Shortening 400

[0108] Table 4: Intermediate protective layer formulation and index score of Examples 1-4

[0109] Example 1 Example 2 Example 3 Example 4 Cocoa butter substitute 180 195 210 225 Shortening 120 105 90 75 Average maximum diameter / pm 208 300 350 440 Average spacing ratio 10：1 21：1 30：1 42：1 Oil droplet diameter ratio (X) 4 4 5 5 Oil droplet number (Y) * 5 5 5 4 Appearance deformation measurement (P1) 5 5 5 4 Overall evaluation 4.55 4.55 5 4.45

[0110] As shown in the above examples, the average maximum diameter of the solid fat morphology, the ratio of the average maximum diameter of the solid fat morphology to the average thickness of the intermediate layer in Examples 1-4 is in a suitable range (10:1 to 42:1), at this time, the mutual influence of crystallization between the oils and fats makes part of the oils and fats coagulate and form larger solid fat regions, and the oils and fats also have a special spacing ratio, the spacing between the oils and fats is small, and a tight solid fat morphology distribution is formed. Under the influence of these two factors, the comprehensive evaluation of the product comes to a higher level. If the solid fat region of the oils and fats is small and the spacing ratio is too large, more large oil droplets are likely to appear; if the solid fat region of the oils and fats is large and the spacing ratio is too small, more dispersed small oil droplets are likely to appear, and even because the solid fat region is too large to be squeezed, a good structure cannot be formed, resulting in the product being unable to be shaped. Within the protection scope of the present application, as the average maximum diameter of the solid fat morphology gradually increases to the upper limit diameter size, the number of oil droplets increases, and the oil droplet number score decreases, but is within an acceptable range; the solid fat morphology is too small to have poor support effect, and is too large to be difficult to shape, which both affect the appearance deformation score, and the appearance deformation score first increases and then decreases.

[0111] Table 5: Accelerated stability of products of Examples 1-4

[0112] Product accelerated stability Example 1 Example 2 Example 3 Example 4 Accelerated 1 month 91.3％ 90.3％ 95.2％ 88.3％ Accelerated 2 months 80.4％ 79.5％ 84.1％ 76.9％ Accelerated 3 months 60.6％ 62.1％ 78.3％ 59.9％

[0113] When the average maximum diameter of the solid fat morphology and the ratio of the average maximum diameter of the solid fat morphology to the average thickness of the intermediate layer are in the best proportion, the product has a better structure and the best accelerated stability, and when the product is in other formulation proportions, the product structure score decreases and the product stability is affected and decreases.

[0114] Examples 5-12

[0115] The ingredients and contents in the following table are prepared by the following preparation method to form the intermediate protective layer structure within the scope of the present application, form a seamless soft capsule, and are tested and scored. The determination results are shown as follows.

[0116] Preparation method:

[0117] (1) A) First, mix pectin, gelatin and plasticizer (glycerol) uniformly, add to water under stirring, heat and stir at 70°C until the colloid dissolves; B) remove bubbles to obtain the gel solution of the skin layer.

[0118] (2) Ingredients: A) Preparation of the intermediate protective layer solution: melt the first and second oily substances (specific classes are shown in Table 8) completely at 85°C, stir until uniform, remove bubbles to obtain the intermediate protective layer solution; B) Preparation of the core layer solution: melt the shortening completely at 85°C, cool to 35-45°C, add the bacteria powder, stir until uniform, remove bubbles to obtain the core layer solution.

[0119] (3) Dropping: use a seamless soft capsule dropping device, select a 3-layer dropping head for dropping.

[0120] (4) Drying: use a rotating cage for drying until the moisture content of the gel skin is less than 10%. That is, after drying, the core layer: intermediate protective layer: skin layer = 5:3:2

[0121] Table 6: Skin layer formulations for Examples 5-12

[0122] Coating layer formulation composition Parts Gelatin 160 Glycerin 24 Pectin 24 Water 592

[0123] Table 7: Core formulations for Examples 5-12

[0124] Core formulation composition Parts Probiotic powder 100 Shortening 400

[0125] Table 8: Intermediate protective layer formulations and scores for Examples 5-12

[0126]

[0127]

[0128] As shown in the above examples, the average maximum diameter of the solid fat morphology, the ratio of the average maximum diameter of the solid fat morphology to the average thickness of the intermediate layer in examples 5-12 is in a suitable range, at this time, the mutual influence of crystallization between the oils and fats makes part of the oils and fats coagulate and precipitate to form larger solid fat regions, and at the same time, the oils and fats also appear a special spacing ratio, the spacing between the oils and fats is small, and a tight solid fat morphology distribution is formed. If the solid fat region of the oils and fats is small and the spacing ratio is too large, more large oil droplets are prone to appear, and if the solid fat region of the oils and fats is large and the spacing ratio is too small, more small oil droplets are prone to appear, and even because the solid fat region is too large to be squeezed, a good structure cannot be formed, resulting in that the product cannot be formed. Within the protection scope of the present application, as the average maximum diameter of the solid fat morphology gradually increases to the upper limit diameter size, the number of oil droplets increases, and the oil droplet number score decreases, but is within an acceptable range; the solid fat particles are too small to have a poor supporting effect, and are too large to be difficult to form, which all affect the appearance deformation score, and the appearance deformation score first increases and then decreases.

[0129] Table 9: Accelerated stability of products of examples 5-12

[0130]

[0131] Examples 5-12 list some combination cases of the first oily substance and the second oily substance, and as can be known from the above table, when the average maximum diameter of the solid fat morphology and the ratio of the average maximum diameter of the solid fat morphology to the average thickness of the intermediate layer are in an optimal ratio, the intermediate protective layer has a good structure, the product accelerated survival rate is greater than or equal to 50%, and the stability is good, which can effectively protect the sensitive substances in the core layer.

[0132] Comparative example 1

[0133] The ingredients and contents in the following table are prepared by the following preparation method to form the intermediate protective layer structure within the protection scope of the present application, to form a seamless soft capsule, and to be tested and scored. The determination results are shown as follows.

[0134] Preparation method:

[0135] (1) Sol: A) First, uniformly disperse the pectin, gelatin and plasticizer (glycerol) by premixing, and add to a proper amount of water under stirring, heat and stir at 70℃ until the colloid is dissolved; B) remove the bubbles to obtain the gel solution of the skin layer.

[0136] (2) Ingredients: A) core layer solution preparation method: melt the shortening completely at 85℃, cool to 35-45℃, add the bacteria powder, and stir uniformly to remove the bubbles to obtain the core layer solution; B) intermediate protective layer solution preparation method: melt the cocoa butter substitute completely at 85℃, stir uniformly, and remove the bubbles to obtain the intermediate protective layer solution.

[0137] (3) Dripping: Using the seamless soft capsule dripping equipment, 3-layer dripping head is selected for dripping.

[0138] (4) Drying: Drying is performed using a rotating cage until the moisture of the skin layer is less than 10%. That is, after drying, the core layer: intermediate protective layer: skin layer = 5:3:2

[0139] Table 10: Skin layer formula of Control Example 1

[0140] Coating layer formulation composition Parts Gelatin 160 Glycerin 24 Pectin 24 Water 592

[0141] Table 11: Core formula of Control Example 1

[0142] Core formulation composition Parts Probiotic powder 100 Shortening 400

[0143] Table 12: Intermediate protective layer formula of Control Example 1 and its index evaluation score

[0144]

[0145]

[0146] As shown in Control Example 1, the average maximum diameter of the solid fat form precipitated at this time is 723 μm (> upper limit of average maximum diameter 500 μm), and because the solid fat form is too large, the plasticity of the gel pellets is reduced during the dripping process, and regular spherical gel pellets cannot be formed, so the comprehensive evaluation is 0 points.

[0147] Control Example 2

[0148] The ingredients and contents in the following table are prepared according to the following preparation method to form an intermediate protective layer structure within the scope of the present application, form a seamless soft capsule, and are tested and scored. The test results are shown below.

[0149] Preparation method:

[0150] (1) Sol: A) First, mix and disperse pectin, gelatin and plasticizer (glycerol) uniformly, add to an appropriate amount of water under stirring, heat and stir at 70°C until the colloid is dissolved; B) remove the bubbles to obtain the skin layer glue solution.

[0151] (2) Ingredients: A) Core layer solution preparation method: melt the shortening completely at 85°C, cool to 35-45°C, add the bacteria powder, stir well, and remove the bubbles to obtain the core layer solution; B) Intermediate protective layer solution preparation method: melt the cocoa butter and shortening completely at 85°C, stir well, and remove the bubbles to obtain the intermediate protective layer solution.

[0152] (3) Dripping: Using the seamless soft capsule dripping equipment, 3-layer dripping head is selected for dripping.

[0153] (4) Drying: drying in a rotating cage until the moisture content of the coating is less than 10%. That is, after drying, the core layer: intermediate protective layer: film layer = 5:3:2

[0154] Table 13: Film layer formulation of Comparative Example 2

[0155] Coating layer formulation composition Parts Gelatin 160 Glycerin 24 Pectin 24 Water 592

[0156] Table 14: Core formulation of Comparative Example 2

[0157]

[0158]

[0159] Table 15: Intermediate protective layer formulation of Comparative Example 2 and its respective index score

[0160] Core formulation composition Parts Cocoa butter substitute 50 Shortening 250 Oil droplet diameter ratio (X) 2 Oil droplet number (Y) * 3 Appearance deformation measurement (P1) 4 Overall evaluation 2.8

[0161] As shown in Comparative Example 2, the average maximum diameter of the solid fat form precipitated at this time was 96 μm, but the ratio of the average maximum diameter of the solid fat form to the average thickness of the intermediate layer was 3.2:1 (< lower limit of the ratio of the average maximum diameter to the average thickness of the intermediate layer 5:1), and the solid fat was relatively sparse, the oil droplet content was large, and there were many large oil droplets, and the gelatin pill was prone to deformation during the molding process. During the acceleration process, the product was easily affected by environmental factors, resulting in a decrease in stability of more than 3 orders of magnitude after 3 months of acceleration.

[0162] Table 16: Accelerated stability of the product of Comparative Example 2

[0163] Product accelerated stability Comparative Example 2 Accelerated 1 month 10.6％ Accelerated 2 months 1.3％ Accelerated 3 months 0.08％

[0164] Comparative Example 3

[0165] The ingredients and contents in the following table were prepared according to the following preparation method to form an intermediate protective layer structure within the scope of the present application, to form a seamless soft capsule, and to test and score. The results of the determination are shown as follows.

[0166] Preparation method:

[0167] (1) Sol: A) First, the pectin, gelatin and plasticizer (glycerol) were pre-mixed and uniformly dispersed, and were added to an appropriate amount of water under stirring, and were heated and stirred at 70°C until the colloid was dissolved; B) the bubbles were removed to obtain the film layer glue solution.

[0168] (2) Formulation: A) Core layer solution preparation method: melt the shortening completely at 85°C, cool to 35-45°C, add the yeast powder, stir well, remove the bubbles, and obtain the core layer solution; B) Intermediate protective layer solution preparation method: melt the shortening completely at 85°C, stir well, remove the bubbles, and obtain the intermediate protective layer solution.

[0169] (3) Dropping: use a seamless soft capsule dropping device, and select a 3-layer dropping head for dropping.

[0170] (4) Drying: use a rotating cage for drying until the moisture content of the capsule skin is less than 10%. That is, after drying, the core layer: intermediate protective layer: skin layer = 5:3:2

[0171] Table 17: Skin layer formulation of Comparative Example 3

[0172] Coating layer formulation composition Parts Gelatin 160 Glycerin 24 Pectin 24 Water 592

[0173] Table 18: Core formulation of Comparative Example 3

[0174] Core formulation composition Parts Probiotic powder 100 Shortening 400

[0175] Table 19: Intermediate protective layer formulation of Comparative Example 3 and its index score

[0176] Core formulation composition Parts Shortening 300 Oil droplet diameter ratio (X) 0 Oil droplet number (Y) * 2 Appearance deformation measurement (P1) 2 Overall evaluation 1.1

[0177] As shown in Comparative Example 3, the average maximum diameter of the solid fat form precipitated at this time is 18 μm, and the ratio of the average maximum diameter of the solid fat form to the average thickness of the intermediate layer is 0.1:1, which is much smaller than the lower limit of the ratio of the average maximum diameter to the average thickness of the intermediate layer, 5:1. At this time, the solid fat is small and very sparse from each other. Under this structure, the oil droplet content is large, and the gel pill is prone to deformation during the molding process. During the acceleration process, the product is easily affected by environmental factors, resulting in a decrease in stability. The stability decreases by more than 5 orders of magnitude after 3 months of acceleration.

[0178] Table 20: Accelerated stability of the product of Comparative Example 3

[0179] Product accelerated stability Comparative Example 3 Accelerated 1 month 2.9％ Accelerated 2 months 0.05％ Accelerated 3 months 0.0003％

[0180] Comparative Example 4

[0181] The ingredients and contents in the following table were prepared according to the following preparation method to form an intermediate protective layer structure within the scope of the present application, form a seamless soft capsule, and be tested and scored. The test results are shown as follows.

[0182] Preparation method:

[0183] (1) Sol: A) First, mix pectin, gelatin and plasticizer (glycerol) uniformly, add to water under stirring, heat to 70°C and stir until the colloid dissolves; B) remove bubbles to obtain the gel solution of the skin layer.

[0184] (2) Ingredients: A) core layer solution preparation method: melt the shortening completely at 85°C, cool to 35-45°C, add the bacteria powder, stir well and remove bubbles to obtain the core layer solution; B) intermediate protective layer solution preparation method: melt the cocoa butter and shortening completely at 85°C, stir well and remove bubbles to obtain the intermediate protective layer solution.

[0185] (3) Dropping: use a seamless soft capsule dropping device, select a 3-layer nozzle for dropping.

[0186] (4) Drying: use a rotating cage for drying until the moisture content of the gel skin is less than 10%. That is, after drying, the core layer: intermediate protective layer: skin layer = 5:3:2

[0187] Table 21: Skin layer formula of Comparative Example 4

[0188] Coating layer formulation composition Parts Gelatin 160 Glycerin 24 Pectin 24 Water 592

[0189] Table 22: Core formula of Comparative Example 4

[0190] Core formulation composition Parts Probiotic powder 100 Shortening 400

[0191] Table 23: Intermediate protective layer formula of Comparative Example 4 and its index score

[0192] Core formulation composition Parts Cocoa butter substitute 280 Shortening 20 Oil droplet diameter ratio (X) 4 Oil droplet number (Y) * 1 Appearance deformation measurement (P1) 1 Overall evaluation 2.35

[0193] As shown in the comparative example, the average maximum diameter of the solid fat form at this time is 621 μm (greater than the upper limit of the average maximum diameter of the solid fat form 500 μm), but the ratio of the average maximum diameter of the solid fat form to the average thickness of the intermediate layer is 52:1. Compared with Comparative Example 1, although the average maximum diameter of the solid fat form and the relative reduction of the density of Comparative Example 4, the solid fat at this time is larger, the gap is smaller, and it is easy to form small and dispersed multiple oil droplets. At this time, the plasticity of the gel pill is reduced, the appearance is changed, the stability during the acceleration process is also greatly reduced, and the acceleration for 3 months is reduced by more than 4 orders of magnitude.

[0194] Table 24: Accelerated stability of the product of Comparative Example 4

[0195] Product accelerated stability Comparative Example 4 Accelerated 1 month 7.5％ Accelerated 2 months 0.03％ Accelerated 3 months 0.001％

[0196] Comparative Example 5

[0197] The ingredients and amounts in the following table were prepared according to the following method to form an intermediate protective layer structure within the scope of the present application, to form a seamless soft capsule, and to be tested and scored. The results of the testing are shown below.

[0198] Preparation Method:

[0199] (1) Sol: A) First, the pectin, gelatin and plasticizer (glycerol) were mixed and dispersed uniformly, and then added to an appropriate amount of water under stirring, heated and stirred at 70°C until the colloid was dissolved; B) The bubble was removed to obtain the glue solution of the skin layer.

[0200] (2) Ingredients: A) Core layer solution preparation method: melt the shortening completely at 85°C, cool to 35-45°C, add the bacteria powder, stir well, and remove the bubbles to obtain the core layer solution; B) Intermediate protective layer solution preparation method: melt the cocoa butter and soybean oil completely at 85°C, stir well, and remove the bubbles to obtain the intermediate protective layer solution.

[0201] (3) Dropping: Use the seamless soft capsule dropping equipment, and select 3-layer nozzles for dropping.

[0202] (4) Drying: Use a rotating cage to dry until the moisture content of the capsule skin is less than 10%. That is, after drying, the core layer: intermediate protective layer: skin layer = 5:3:2

[0203] Table 25: Skin layer formula of Control Example 5

[0204] Coating layer formulation composition Parts Gelatin 160 Glycerin 24 Pectin 24 Water 592

[0205] Table 26: Core formula of Control Example 5

[0206] Core formulation composition Parts Probiotic powder 100 Shortening 400

[0207] Table 27: Intermediate protective layer formula of Control Example 5 and its index score

[0208]

[0209]

[0210] As shown in Comparative Example 5, the average maximum diameter of the precipitated solid fat morphology was 87 μm (less than the lower limit of 100 μm for average maximum diameter). However, the ratio of the average maximum diameter of the solid fat morphology to the average thickness of the intermediate layer was 0.5:1 (less than the lower limit of 5:1 for the ratio of average maximum diameter to average thickness of the intermediate layer). Compared with Comparative Example 3, although the average maximum diameter of the solid fat morphology in Comparative Example 5 reached 87 μm and the average spacing ratio was 0.5:1 after changing to oil, it was still outside the scope of this patent. The solid fat was still relatively small and sparse, easily forming multiple large-diameter oil droplets. Under this structure, the increased proportion and number of oil droplets led to a lower overall appearance deformation measurement score, and the stability decreased significantly during acceleration, dropping by more than four orders of magnitude after three months of acceleration.

[0211] Table 28: Accelerated stability of products compared to Example 5

[0212] Product accelerated stability Comparative Example 5 Accelerated 1 month 5.6％ Accelerated 2 months 0.03％ Accelerated 3 months 0.008％

[0213] In summary, when the average maximum diameter of the solid grease morphology in the intermediate protective layer is 100μm to 500μm, and the ratio of the average maximum diameter of the solid grease morphology to the average distance between it and other surrounding solid grease morphologies is 5 to 100:1, the resulting product has a smaller proportion of oil droplet diameter, a smaller number of grease morphologies, a round and non-irregular appearance, better acceleration and stability, improved barrier function of the intermediate protective layer, and improved overall product performance.

Claims

1. A three-layer seamless soft capsule comprising a core, an intermediate protective layer, and an outer membrane layer, wherein the intermediate protective layer comprises an oily substance, which, upon complete melting and restoration to 25-35°C, forms a fat layer comprising solid oily substance particles and liquid fat in the intermediate layer, wherein the solid oily substance particles are directly connected or connected via the intermediate layer, wherein the average maximum diameter of the solid oily substance particles is 100μm-500μm and the ratio of the average maximum diameter to the average thickness of the intermediate layer is 5-100:

1. The intermediate protective layer comprises 170-230 or 180-225 parts by weight of a first oily substance and 70-120 or 75-110 parts by weight of a second oily substance, wherein the first oily substance is selected from one or more of cocoa butter, cocoa butter substitute, cocoa butter-like substances, shea butter, palm oil, and palm kernel oil, and the second oily substance is selected from one or more of shortening, filling oil, margarine, artificial butter, hydrogenated soybean oil, and hydrogenated oil, and the intermediate protective layer does not contain phospholipids.

2. The three-layer seamless soft capsule according to claim 1, wherein the average maximum diameter of the solid oily substance particles is 200μm-500μm or 300μm-440μm or 300μm-350μm, and / or the ratio of the average maximum diameter to the average thickness of the intermediate layer is 10-50:1 or 20-30:

1.

3. The three-layer seamless soft capsule according to claim 1 or 2, wherein the first oily substance is a hardened oil or a compound hardened oil composition that is solidified at room temperature and has a melting point of 30-60°C, and the second oily substance is a hardened oil or a compound hardened oil composition that is solidified at room temperature and has a melting point of 35-65°C; when used in combination, the melting point of the second oily substance is 2-20°C higher than the melting point of the first oily substance.

4. The three-layer seamless soft capsule according to any one of claims 1-3, wherein the core, the intermediate protective layer and the outer membrane are in direct contact, the intermediate protective layer wraps around the core, and the outer membrane wraps around the intermediate protective layer.

5. The three-layer seamless soft capsule according to any one of claims 1-4, wherein the weight ratio of the core layer: intermediate protective layer: outer membrane layer is 4-7:2-4:1-3.

6. The three-layer seamless soft capsule according to any one of claims 1-5, wherein the weight ratio of the core layer: intermediate protective layer: outer membrane layer is 5:3:

2.

7. The three-layer seamless soft capsule according to any one of claims 1-6, wherein the melting point of the intermediate protective layer is 0-10°C higher than that of the core and / or the water content of the outer membrane layer is 2-10 wt%.

8. The three-layer seamless soft capsule according to any one of claims 1-7, wherein the core comprises 0.5-100 parts by weight of active substance and 300-500 parts by weight of a third oily substance, wherein the third oily substance is a hardened oil or a compound hardened oil that is solidified at room temperature and has a melting point of 24-64°C; and / or The outer layer of the film contains 80-320 parts by weight of water-soluble gelling agent and 10-125 parts by weight of plasticizer.

9. The three-layer seamless soft capsule according to claim 8, wherein the third oily substance is selected from one or more of palm oil, shortening, coconut oil, hydrogenated soybean oil, hydrogenated palm oil, highly hydrogenated palm oil, hydrogenated coconut oil, finished fractionated palm stearate, palm oil extract, palm super oil extract, palm kernel oil, palm double oil extract, palm middle fraction, palm oil transesterified fat, palm oil transesterified fat, cocoa butter, cocoa butter substitute, cocoa butter-like substance, and shea butter.

10. The three-layer seamless soft capsule according to claim 8 or 9, wherein the active substance is a substance that is unstable in water and / or acid.

11. The three-layer seamless soft capsule of claim 10, wherein the substance that is unstable in water and / or acid is a powder.

12. The three-layer seamless soft capsule of claim 11, wherein the powder is a powder with an average particle size of 1-250 micrometers.

13. The three-layer seamless soft capsule according to any one of claims 10-12, wherein the substance unstable in water and / or acid includes one or more of probiotics, vitamins, lactoferrin, cells, and enzymes.

14. The three-layer seamless soft capsule of claim 13, wherein the cells are active stem cells.

15. The three-layer seamless soft capsule of claim 13, wherein the probiotics include Bifidobacteria and / or Lactobacillus.

16. The three-layer seamless soft capsule of claim 13, wherein the vitamins include one or more of vitamin B, vitamin B1, vitamin B2, vitamin B12, and vitamin C.

17. The three-layer seamless soft capsule according to any one of claims 8-16, wherein the water-soluble gelling agent is selected from one or more of gelatin, carrageenan, agar, gellan gum, pectin and starch.

18. The three-layer seamless soft capsule of claim 17, wherein the water-soluble gelling agent comprises gelatin and pectin, wherein the weight ratio of pectin to gelatin is 1:10 to 3:

10.

19. The three-layer seamless soft capsule according to claim 17 or 18, wherein the pectin is selected from low-ester pectin and / or amide pectin.

20. The three-layer seamless soft capsule according to any one of claims 17-19, wherein the degree of esterification of pectin (DE) is less than 50%.

21. The three-layer seamless soft capsule according to any one of claims 17-20, wherein the degree of amidation (DA) of the pectin is 0-25%.

22. The three-layer seamless soft capsule according to any one of claims 8-21, wherein the plasticizer is selected from one or more of glycerin, sorbitol, erythritol and maltitol.

23. The three-layer seamless soft capsule according to any one of claims 1-22, wherein the outer layer of the membrane comprises a water-soluble gelling agent and a soft capsule additive.

24. The three-layer seamless soft capsule of claim 23, wherein the soft capsule additive is a coloring and / or a sweetener.

25. The three-layer seamless soft capsule according to claim 24, wherein the pigment is selected from one or more of titanium dioxide, Allura Red, Brilliant Blue, Tartrazine, Sunset Yellow, Cochineal, Turmeric, Natura Orange, Gardenia Yellow, Gardenia Blue, Safflower Yellow, Vegetable Carbon Black, Carotene, and Sodium Copper Chloride.

26. The three-layer seamless soft capsule according to claim 24, wherein the sweetener is selected from one or more of sucralose, aspartame, alitame, sodium saccharin, acesulfame potassium, allulose, adventitia, cyclamate, sematrandezidine, steviol glycosides, mogrosides, isomaltulose, ammonium glycyrrhizate, monopotassium and tripotassium glycyrrhizate, D-mannitol, xylitol, erythritol, maltitol, and lactitol.

27. The three-layer seamless soft capsule according to any one of claims 24-26, wherein the weight ratio of pigment to water-soluble gelling agent is 0-0.25:100, and / or the weight ratio of sweetener to water-soluble gelling agent is 0-50:

100.

28. A composition for preparing a three-layer seamless soft capsule according to any one of claims 1-27, comprising a composition forming an intermediate protective layer, the composition forming the intermediate protective layer comprising an oily substance, the oily substance being completely melted and restored to 25-35°C to form a fat layer comprising solid oily substance particles and a liquid fat layer in the form of an intermediate layer, the solid oily substance particles being directly connected or connected via the intermediate layer, wherein the average maximum diameter of the solid oily substance particles is 100 μm-500 μm and the ratio of the average maximum diameter to the average thickness of the intermediate layer is 5-100:1; the composition forming the intermediate protective layer comprises 170-230 or 180-225 parts by weight of a first oily substance and 70-120 or 75-110 parts by weight of a second oily substance; The first oily substance is selected from one or more of cocoa butter, cocoa butter substitute, cocoa butter-like substances, shea butter, palm oil, and palm kernel oil, and / or the second oily substance is selected from one or more of shortening, filling oil, margarine, artificial butter, hydrogenated soybean oil, and hydrogenated oil; the composition forming the intermediate protective layer does not contain phospholipids.

29. The composition according to claim 28, wherein the average maximum diameter of the solid oily substance particles is 200 μm-500 μm or 300 μm-440 μm or 300 μm-350 μm, and / or the ratio of the average maximum diameter to the average thickness of the intermediate layer is 10-50:1 or 20-30:

1.

30. The composition according to claim 28 or 29, wherein the first oily substance is a hardened oil or a compound hardened oil composition that is solidified at room temperature and has a melting point of 30-60°C, and the second oily substance is a hardened oil or a compound hardened oil composition that is solidified at room temperature and has a melting point of 35-65°C; when used in combination, the melting point of the second oily substance is 2-20°C higher than the melting point of the first oily substance.

31. The composition according to any one of claims 28-30, comprising a core-forming composition, said core-forming composition comprising 0.5-100 parts by weight of an active substance and 300-500 parts by weight of a third oily substance, said third oily substance being a hardened oil or a compound hardened oil that is solidified at room temperature and has a melting point of 24-64°C; and / or The composition comprises a composition forming an outer layer of a film, the composition forming the outer layer of the film comprising 80-320 parts by weight of a water-soluble gelling agent and 10-125 parts by weight of a plasticizer.

32. The composition of claim 31, wherein the composition forming the outer layer of the membrane further comprises water.

33. The composition according to claim 31 or 32, wherein the third oily substance is selected from one or more of palm oil, shortening, coconut oil, hydrogenated soybean oil, hydrogenated palm oil, highly hydrogenated palm oil, hydrogenated coconut oil, finished fractionated palm stearate, palm oil extract, palm super oil extract, palm kernel oil, palm double oil extract, palm middle fraction, palm oil transesterified fat, palm oil transesterified fat, cocoa butter, cocoa butter substitute, cocoa butter-like fat, and shea butter.

34. The composition according to any one of claims 31-33, wherein the active substance is a substance that is unstable in water and / or acid.

35. The composition according to claim 34, wherein the substance that is unstable in water and / or acid is a powder.

36. The composition of claim 35, wherein the powder is a powder with an average particle size of 1-250 micrometers.

37. The composition according to any one of claims 34-36, wherein the substance unstable in water and / or acid includes one or more of probiotics, vitamins, lactoferrin, cells, and enzymes.

38. The composition of claim 37, wherein the cell is a live stem cell.

39. The composition of claim 37, wherein the probiotics comprise Bifidobacteria and / or Lactobacilli.

40. The composition of claim 37, wherein the vitamins include one or more of vitamin B, vitamin B1, vitamin B2, vitamin B12, and vitamin C.

41. The composition according to any one of claims 31-40, wherein the water-soluble gelling agent is selected from one or more of gelatin, carrageenan, agar, gellan gum, pectin and starch.

42. The composition according to any one of claims 31-41, wherein the water-soluble gelling agent comprises gelatin and pectin, wherein the weight ratio of pectin to gelatin is 1:10 to 3:

10.

43. The composition according to claim 41 or 42, wherein the pectin is selected from low-ester pectin and / or amide pectin.

44. The composition according to any one of claims 41-43, wherein the degree of esterification of the pectin is DE < 50%.

45. The composition according to any one of claims 41-44, wherein the degree of amidation (DA) of the pectin is 0-25%.

46. ​​The composition according to any one of claims 31-45, wherein the plasticizer is selected from one or more of glycerol, sorbitol, erythritol and maltitol.

47. The composition according to any one of claims 31-46, wherein the composition forming the outer layer of the membrane comprises a water-soluble gelling agent and a soft capsule additive.

48. The composition of claim 47, wherein the soft capsule additive is a coloring and / or a sweetener.

49. The composition according to claim 48, wherein the pigment is selected from one or more of titanium dioxide, Allura Red, Brilliant Blue, Tartrazine, Sunset Yellow, Cochineal, Turmeric, Natura Orange, Gardenia Yellow, Gardenia Blue, Safflower Yellow, Vegetable Carbon Black, Carotene, and Sodium Copper Chloride.

50. The composition of claim 48, wherein the sweetener is selected from one or more of sucralose, aspartame, alitame, sodium saccharin, acesulfame potassium, allulose, adventitia, cyclamate, sematrandezine, steviol glycosides, mogrosides, isomaltulose, ammonium glycyrrhizate, monopotassium and tripotassium glycyrrhizate, D-mannitol, xylitol, erythritol, maltitol, and lactitol.

51. The composition according to any one of claims 48-50, wherein the weight ratio of pigment to water-soluble gelling agent is 0-0.25:100, and / or the weight ratio of sweetener to water-soluble gelling agent is 0-50:

100.

52. A method for preparing a three-layer seamless soft capsule according to any one of claims 1-27, comprising: (1) A sol-gel process is performed to obtain the outer layer of the film; (2) Melt 170-230 or 180-225 parts by weight of the first oily substance and 70-120 or 75-110 parts by weight of the second oily substance at 60-85°C, stir them thoroughly and then cool them down to 40-60°C to obtain the intermediate protective layer solution. When the oily substance is completely melted and restored to 25-35°C, a fat layer is formed comprising solid oily substance particles and a liquid fat layer. The solid oily substance particles are directly connected or connected through the intermediate layer. The average maximum diameter of the solid oily substance particles is 100μm-500μm and the ratio of the average maximum diameter to the average thickness of the intermediate layer is 5-100:

1. The first oily substance is selected from one or more of cocoa butter, cocoa butter substitute, cocoa butter-like substances, shea butter, palm oil, and palm kernel oil. The second oily substance is selected from one or more of shortening, filling oil, margarine, artificial butter, hydrogenated soybean oil, and hydrogenated oil. (3) Prepare the core solution; (4) Perform dripping to obtain the three-layer seamless soft capsule; (5) Dry the three-layer seamless soft capsule.

53. The method of claim 52, wherein the average maximum diameter of the solid oily substance particles is 200 μm-500 μm or 300 μm-440 μm or 300 μm-350 μm, and / or the ratio of the average maximum diameter to the average thickness of the intermediate layer is 10-50:1 or 20-30:

1.

54. The method according to claim 52 or 53, wherein the sol comprises premixing and dispersing a water-soluble gelling agent and a plasticizer evenly, adding them to water under stirring, optionally adding a pigment and a sweetener, heating and stirring at 55-85°C until the colloid dissolves and bubbles are removed to obtain an outer layer of film.

55. The method according to any one of claims 52-54, wherein the core preparation comprises completely melting the third oily substance at 60-85°C, cooling it to 35-50°C, adding the active ingredient, stirring thoroughly to remove air bubbles, and thus obtaining the core solution.

56. The method according to any one of claims 52-55, wherein the dripping includes using a seamless soft capsule dripping device and selecting a 3-layer dripper for dripping.

57. The method according to any one of claims 52-56, wherein the drying comprises drying using a rotary drum until the rubber moisture content is reduced to 2-10%.

58. Use of the three-layer seamless soft capsule according to any one of claims 1-27 in food, health products or cosmetics.

59. Use of the three-layer seamless soft capsule according to any one of claims 1-27 in the preparation of a pharmaceutical product.

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