Enteric probiotic soft capsule as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicine manufacturing, and relates to an enteric probiotic soft capsule and a preparation method and application thereof.The enteric probiotic soft capsule is composed of soft capsule content and soft capsule skin, and the content comprises probiotic powder and oleogel; the oil gel is prepared from 52 type palm oil and an oil phase gel agent according to a mass part ratio of (20-80): (0-20) or 24 type palm oil, 30 type palm oil and 52 type palm oil according to a mass part ratio of (0-20): (0-60): (30-90), the capsule skin raw materials comprise a film-forming agent, a gel agent, a coagulant, a plasticizer and water, and good capsule skin wrapping performance is obtained through a specific raw material composition ratio and a preparation technology. The soft capsule provided by the invention has the excellent characteristics of targeted release in intestinal tracts, short disintegration time, stable viable count in the storage process and the like, and has a wide application prospect in probiotic utilization.

Description

Technical Field

[0001] The invention belongs to the technical field of biopharmaceutical manufacturing, and specifically relates to an enteric-coated probiotic soft capsule and a preparation method and application thereof. Background Art

[0002] Probiotics are a class of active microorganisms that are beneficial to the host. They colonize the intestines and play a role in maintaining healthy intestinal flora, inhibiting the growth of pathogens, and relieving allergic reactions. However, only if you take enough (≥10 7 CFU / mL or 10 7 CFU / g) has health benefits to the human body. However, most probiotics are sensitive to temperature, moisture, pH, and bile salts, which causes their viable counts to greatly decrease during processing, transportation, storage, and the human gastrointestinal tract. In addition, the current method of taking probiotics is mainly oral, and probiotics will be destroyed in large quantities in the acidic environment of gastric acid, causing the number of probiotics reaching the intestine to be insufficient to exert its beneficial biological activity. Therefore, adopting a suitable probiotic delivery system to protect probiotics from the destruction of gastric acid so that there are enough viable counts to colonize the intestine is of great significance for exerting the function of probiotics.

[0003] Enteric-coated capsules have the characteristics of not disintegrating in the stomach but quickly releasing drugs in the intestinal tract, which can protect probiotics from being destroyed by gastric juice and release and colonize in the intestine. However, the base material of soft capsules on the market is generally gelatin, which has certain defects due to its strong hygroscopicity, causing the drug to absorb moisture and deteriorate, and can undergo cross-linking reactions with aldehyde drugs or excipients, resulting in prolonged capsule disintegration time. In addition, the water absorption and air permeability of the soft capsule skin will make the environmental water activity in the soft capsule higher, and the oil phase environment of the soft capsule content will make the probiotics unstable, poorly uniform, and easy to stratify and precipitate. Some studies have made the contents of probiotic soft capsules into emulsion gels. The emulsion gels show good gastrointestinal survival rate when used to deliver probiotics. However, in this type of delivery system, whether the probiotics are added to the oil phase or the water phase to make the emulsion gel, the probiotics are ultimately distributed in the water phase, which is not conducive to the long-term storage of the probiotics. At present, some studies have been conducted to ensure the activity of the probiotics during storage by dissolving the probiotics in an oil-soluble matrix. For example, a probiotic soft capsule and a preparation method thereof disclosed in application number CN102613458A uses a compound of vegetable oil, animal oil, mineral oil and a stabilizer to play a role in maintaining The system is stable and the probiotics are kept uniformly dispersed. However, the bacterial activity of the soft capsule is only maintained at 60-80% after being stored for 1 month. It is obvious that the protective effect on the probiotic activity is not strong enough, and the activity decline is still quite obvious. For example, a probiotic enteric soft capsule and its preparation method and application disclosed in application No. CN116672322A adopt edible oil and beeswax suspending agent to prepare a capsule (dry) with a bacterial survival rate of less than 84% after being stored for 1 month, and a capsule (wet) with a bacterial survival rate of only 10-15% after being stored for 1 month. Therefore, this technical solution is still difficult to meet the storage of probiotic activity of plant soft capsules. Summary of the invention

[0004] In order to overcome the deficiencies in the above-mentioned prior art, the present invention provides an enteric-coated probiotic soft capsule and a preparation method and application thereof. The soft capsule product uses plant-derived materials as the main component of the capsule shell, uses oil gel as the content, has a simple process, has excellent storage stability, resistance to gastric juice erosion, and the property of dissolving under neutral to alkaline conditions, that is, has good enteric solubility.

[0005] The first aspect of the present invention provides an enteric-coated probiotic soft capsule, comprising a soft capsule content and a soft capsule shell, wherein the soft capsule content comprises probiotic powder and an oil gel, wherein the oil gel comprises 80-100 parts by weight of a base oil and 0-20 parts by weight of an oil phase gelling agent, wherein the base oil is 52 type palm oil, and the oil phase gelling agent is glyceryl monostearate.

[0006] The second aspect of the present invention provides another enteric-coated probiotic soft capsule, which comprises a soft capsule content and a soft capsule shell, wherein the soft capsule content comprises probiotic powder and oil gel, and the oil gel is a mixture of type 24 palm oil, type 30 palm oil and type 52 palm oil in a mass ratio of (0-20): (0-60): (30-90).

[0007] Preferably, the capsule shell of the enteric probiotic soft capsule comprises a film-forming agent, a gelling agent, a coagulant, a plasticizer and water, the film-forming agent is selected from pullulan and / or hydroxypropyl methylcellulose, the gelling agent is selected from one or more of κ-carrageenan, sodium alginate and gellan gum, the coagulant is selected from potassium chloride and / or sodium chloride, and the plasticizer is glycerol and / or polyethylene glycol-4000.

[0008] Preferably, the raw materials for preparing the soft capsule shell include, by weight, 2-6 parts of film-forming agent, 2-2.5 parts of gelling agent, 0.05-0.25 parts of coagulant, 0.5-2.5 parts of plasticizer and 100 parts of water.

[0009] Preferably, the gelling agent is made of κ-carrageenan, sodium alginate and gellan gum in a mass ratio of (0.2-1.2):(0.5-2.5):(0.5-1.5); the coagulant is made of potassium chloride and sodium chloride in a mass ratio of (0.05-0.15):(0-0.1); and the plasticizer is made of glycerol and polyethylene glycol-4000 in a mass ratio of (0.5-1.5):(0-1.5).

[0010] The third aspect of the present invention is to provide a method for preparing the above-mentioned enteric-coated probiotic soft capsule, comprising the following steps:

[0011] S1. Weigh the plasticizer in proportion and dissolve it in water at 55-70 ° C, stir until completely dissolved, keep the temperature at 55-70 ° C, slowly add the uniformly mixed gelling agent, film-forming agent, and coagulant and stir until completely dissolved, and let the resulting liquid stand at 45-60 ° C and keep warm for 5-12h to obtain a soft capsule capsule gel;

[0012] S2. Weigh the base oil and / or oil phase gel at 60-80°C and stir until melted, keep stirring and cool the temperature to 35-45°C to obtain an oil gel, weigh the probiotic powder and disperse it in the oil gel and stir for 0.5-1h to obtain the oil gel content of the dispersed bacterial powder;

[0013] S3. The gel solution prepared in step S1 and the oil gel content of the dispersed bacterial powder prepared in step S2 are placed in the gel solution tank and the feed tank of the pill machine for pill making;

[0014] S4. The pellets prepared in step S3 are transferred to a calcium chloride solution with a mass concentration of 1%-10% for calcification for 5-15 minutes. After being taken out, they are placed in an environment with a temperature of 25-35°C and a relative humidity of 50-65% for drying for 24-48 hours to obtain enteric-coated probiotic soft capsules.

[0015] Preferably, in step S3, the temperature of the glue tank is 55-65°C, the temperature of the material tank is 50-60°C, the temperature of the coolant is 10-20°C, and the temperature of the dripper is 50-60°C.

[0016] Preferably, in step S3, the mass ratio of the glue solution to the oil gel content of the dispersed bacterial powder is 100-500:50-200.

[0017] The fourth aspect of the present invention is to provide the use of the enteric-coated probiotic soft capsule in the preparation of food, health care products or medicines.

[0018] The strains in the probiotic powder can be selected from commercially available or homemade probiotics, and can be selected from one or more of Lactobacillus acidophilus, Lactobacillus plantarum, Bifidobacterium, Lactobacillus rhamnosus and the like.

[0019] The present invention is an enteric probiotic soft capsule prepared based on an oil gel system, and the oil gel is used as a new saturated fat replacement form, and a crystal particle network, a fiber network or a polymer network are formed by intermolecular interaction, and the liquid oil is wrapped, and the characteristics of plastic fat are obtained. The oil gel system of the present invention is prepared by 80-100 parts by mass of base oil and 0-20 parts by mass of oil phase gel, wherein the base oil is palm oil, and the oil phase gel is selected from glyceryl monostearate, and glyceryl monostearate is mutually aggregated in liquid oil (palm oil) by non-covalent interactions (such as van der Waals forces and hydrogen bonds) to form a three-dimensional network structure, and this network can wrap liquid oil, thereby limiting the fluidity of oil, so that it exhibits characteristics similar to plastic fat, and forms a gel network with a specific crystal phase, such as α-type, β′-type and β-type crystals, and the formed gel network can evenly distribute probiotic powder in the oil matrix, avoid agglomeration between powders, and improve the stability and uniformity of the product. At the same time, the gel network further physically isolates the probiotic powder through the encapsulation effect of oil-in-water. This oil-in-water packaging structure can effectively prevent the influence of external environmental factors (such as humidity and oxygen) on the activity of probiotics, thereby improving their stability and storage life.

[0020] In addition, the present invention uses compound palm oil (type 24 palm oil, type 30 palm oil, type 52 palm oil) to achieve excellent moisture and air isolation performance without adding oil phase gelling agent, while it is difficult to achieve better moisture and air isolation performance when compounded with type 24 palm oil and type 30 palm oil. This may be related to the interaction and configuration between different types of palm oil molecular chains.

[0021] The soft capsule shell of the present invention is made of a film-forming agent, a gelling agent, a coagulant, a plasticizer and water, wherein a composite gelling agent of kappa-carrageenan, sodium alginate and gellan gum is used in a mass ratio of (0.2-1.2):(0.5-2.5):(0.5-1.5), and a plasticizer of glycerol and polyethylene glycol-4000 is used in a mass ratio of (0.5-1.5):(0-1.5), and a film-forming agent of pullulan and / or hydroxypropyl methylcellulose is used. After calcification, an enteric-coated plant soft capsule shell with good wrapping performance is obtained, which effectively improves the stable delivery and intestinal targeted release of the content (probiotic powder dispersed in oil gel), and can significantly improve the storage stability of the content, and ensure the biological activity of the probiotics.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. Compared with the soft capsules prepared from traditional gelatin, the soft capsules of the present invention are safer and more stable. Sodium alginate is used as the main enteric material. The soft capsule skin formed after calcification has the characteristics of intestinal targeted release. The present invention first achieves a stable oil gel system by compounding 52-type palm oil with oil phase gelling agent monostearate glyceryl or compounding 24-type palm oil, 30-type palm oil and 52-type palm oil. The formed gel network can evenly distribute the probiotic powder in the oil matrix, avoid agglomeration between the powders, and better Isolate moisture and air to improve the stability and uniformity of the product; secondly, use a suitable mass ratio of κ-carrageenan, sodium alginate and gellan gum compound gelling agent, and suitable glycerin and polyethylene glycol-4000 plasticizers in combination with pullulan and / or hydroxypropyl methylcellulose film-forming agents, and after calcification, obtain an enteric-coated plant soft capsule skin with good wrapping performance, effectively improve the stable delivery of the contents (oil gel-dispersed probiotic powder) and intestinal targeted release, while significantly improving the storage stability of the contents and ensuring the biological activity of the probiotics.

[0024] 2. Probiotics have the ability to promote digestion and improve immunity. The present invention improves the delivery efficiency of probiotics in the human body and achieves stable delivery and targeted release of probiotics;

[0025] 3. The oil gel system used can effectively isolate moisture and air. The prepared soft capsule can significantly reduce the influence of humidity and air on probiotics during storage, thereby improving the survival rate of probiotics. At the same time, the oil gel system has the advantages of thermal reversibility, good stability, oral and rectal administration, no need for redispersion, and adjustable physical properties. It can significantly improve the delivery efficiency of probiotics in the human body and achieve stable delivery and intestinal targeted release of probiotics.

[0026] 4. The preparation method of the present invention is simple, the process is simple, and it is suitable for industrial production. DETAILED DESCRIPTION

[0027] In order to better understand the present invention, the present invention is further described in detail below in conjunction with the embodiments. However, those skilled in the art understand that the following embodiments are not limitations on the scope of protection of the present invention, and any changes and modifications made on the basis of the present invention are within the scope of protection of the present invention.

[0028] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0029] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0030] Example 1 Preparation of enteric-coated probiotic soft capsules based on oil gel system

[0031] The raw material formula of the soft capsule of this embodiment is shown in Table 1:

[0032] Table 1: Raw material formula of an enteric probiotic soft capsule based on an oil gel system 1

[0033]

[0034]

[0035] The probiotic powder is selected from the Yibishi probiotic powder product produced by By-Health Co., Ltd. (containing 1.0×10 8 CFU / g and Lactobacillus rhamnosus 5.0×10 7 CFU / g).

[0036] According to the raw material formula in Table 1, the preparation steps of the soft capsules in this embodiment are as follows:

[0037] S1. Weigh plasticizers (glycerol and polyethylene glycol-4000) in proportion and dissolve them in deionized water at 60°C, stir until completely dissolved, keep the temperature at 60°C, slowly add the uniformly mixed gelling agent (gellan gum and carrageenan) and stir at 60°C for 1.5h, then slowly add the uniformly mixed film-forming agent (pululan), gelling agent (sodium alginate), and coagulant (potassium chloride and sodium chloride) and stir for 1.5h until completely dissolved, let the resulting liquid stand at 60°C and keep warm for 5h to obtain the gelatin solution of the plant soft capsule skin;

[0038] S2. Weigh the base oil (type 24 palm oil, type 30 palm oil and type 52 palm oil) and the oil phase gel (glyceryl monostearate) and stir at 80°C for 2h until completely melted, keep stirring and cool the temperature to 40°C to obtain an oil gel, weigh the probiotic freeze-dried powder and disperse it in the oil gel and stir for 0.5h to obtain the oil gel content of the dispersed bacterial powder;

[0039] S3. The obtained 300 parts by mass of the glue and 100 parts by mass of the oil gel content of the dispersed bacterial powder were placed in the glue tank and the feed tank of the pill dropping machine for pill dropping, wherein the glue tank temperature is 60 ° C, the feed tank temperature is 50 ° C, the coolant temperature is 15 ° C, and the dripper temperature is 50 ° C;

[0040] S4. The prepared pellets were transferred to a calcium chloride solution with a mass concentration of 5% for calcification for 10 minutes. After being taken out, they were placed in an environment with a temperature of 25° C. and a relative humidity of 65% for drying for 48 hours to obtain enteric-coated probiotic soft capsules.

[0041] Example 2 Preparation of enteric probiotic soft capsules based on oil gel system

[0042] The raw material formula of the soft capsule of this embodiment is shown in Table 2:

[0043] Table 2: Raw material formula of an enteric probiotic soft capsule based on an oil gel system 2

[0044]

[0045] The probiotic powder is selected from the Yibishi probiotic powder product produced by By-Health Co., Ltd. (containing 1.0×10 8 CFU / g and Lactobacillus rhamnosus 5.0×10 7 CFU / g).

[0046] According to the raw material formula in Table 2, the preparation steps of the soft capsule of this embodiment are as follows:

[0047] S1. Weigh the plasticizer (glycerol) in proportion and dissolve it in deionized water at 60°C, stir until completely dissolved, keep the temperature at 60°C, slowly add the uniformly mixed gelling agent (gellan gum and carrageenan) and stir at 60°C for 1.5h, then slowly add the uniformly mixed film-forming agent (pululan), gelling agent (sodium alginate), and coagulant (potassium chloride) and stir for 1.5h until completely dissolved, let the resulting liquid stand at 60°C and keep warm for 5h to obtain the gelatin solution of the plant soft capsule skin;

[0048] S2. Weigh the base oil (type 24 palm oil, type 30 palm oil and type 52 palm oil) and stir at 80°C until completely melted, keep stirring and cool the temperature to 40°C to obtain an oil gel, weigh the probiotic freeze-dried powder and disperse it in the oil gel and stir for 0.5h to obtain the oil gel content of the dispersed bacterial powder;

[0049] S3. The obtained 300 parts by mass of the glue and 100 parts by mass of the oil gel content of the dispersed bacterial powder were placed in the glue tank and the feed tank of the pill dropping machine for pill dropping, wherein the glue tank temperature is 60 ° C, the feed tank temperature is 50 ° C, the coolant temperature is 15 ° C, and the dripper temperature is 50 ° C;

[0050] S4. The prepared pellets were transferred to a calcium chloride solution with a mass concentration of 5% for calcification for 10 minutes. After being taken out, they were placed in an environment with a temperature of 25° C. and a relative humidity of 65% for drying for 48 hours to obtain enteric-coated probiotic soft capsules.

[0051] Example 3 Preparation of enteric probiotic soft capsules based on oil gel system

[0052] The raw material formula of the soft capsule of this embodiment is shown in Table 3:

[0053] Table 3: Raw material formula of an enteric probiotic soft capsule based on an oil gel system

[0054]

[0055] The probiotic powder is selected from the Yibishi probiotic powder product produced by By-Health Co., Ltd. (containing 1.0×10 8 CFU / g and Lactobacillus rhamnosus 5.0×10 7 CFU / g).

[0056] According to the raw material formula in Table 3, the preparation steps of the soft capsule of this embodiment are as follows:

[0057] S1. Weigh plasticizers (glycerol and polyethylene glycol-4000) in proportion and dissolve them in deionized water at 60°C, stir until completely dissolved, keep the temperature at 60°C, slowly add the uniformly mixed gelling agent (gellan gum and carrageenan) and stir at 60°C for 1.5h, then slowly add the uniformly mixed film-forming agent (pululan), gelling agent (sodium alginate), and coagulant (potassium chloride) and stir for 1.5h until completely dissolved, let the resulting liquid stand at 60°C and keep warm for 5h to obtain the gelatin solution of the plant soft capsule skin;

[0058] S2. Weigh the base oil (type 24 palm oil, type 30 palm oil and type 52 palm oil) and stir at 80°C until completely melted, keep stirring and cool the temperature to 40°C to obtain an oil gel, weigh the probiotic freeze-dried powder and disperse it in the oil gel and stir for 0.5h to obtain the oil gel content of the dispersed bacterial powder;

[0059] S3. The obtained 300 parts by mass of the glue and 100 parts by mass of the oil gel content of the dispersed bacterial powder were placed in the glue tank and the feed tank of the pill dropping machine for pill dropping, wherein the glue tank temperature is 60 ° C, the feed tank temperature is 50 ° C, the coolant temperature is 15 ° C, and the dripper temperature is 50 ° C;

[0060] S4. The prepared pellets were transferred to a calcium chloride solution with a mass concentration of 5% for calcification for 10 minutes. After being taken out, they were placed in an environment with a temperature of 25° C. and a relative humidity of 65% for drying for 48 hours to obtain enteric-coated probiotic soft capsules.

[0061] Example 4 Preparation of enteric probiotic soft capsules based on oil gel system

[0062] The raw material formula of the soft capsule of this embodiment is shown in Table 4:

[0063] Table 4: Raw material formula of an enteric probiotic soft capsule based on an oil gel system

[0064]

[0065]

[0066] The probiotic powder is selected from the Yibishi probiotic powder product produced by By-Health Co., Ltd. (containing 1.0×10 8 CFU / g and Lactobacillus rhamnosus 5.0×10 7 CFU / g).

[0067] According to the raw material formula in Table 4, the preparation steps of the soft capsule of this embodiment are as follows:

[0068] S1. Weigh plasticizers (glycerol and polyethylene glycol-4000) in proportion and dissolve them in deionized water at 60°C, stir until completely dissolved, keep the temperature at 60°C, slowly add the uniformly mixed gelling agent (gellan gum and carrageenan) and stir at 60°C for 1.5h, then slowly add the uniformly mixed film-forming agent (pululan), gelling agent (sodium alginate), and coagulant (potassium chloride) and stir for 1.5h until completely dissolved, let the resulting liquid stand at 60°C and keep warm for 5h to obtain the gelatin solution of the plant soft capsule skin;

[0069] S2. Weigh the base oil (52 type palm oil) and the oil phase gelling agent (glyceryl monostearate) and stir them at 80°C until they are completely melted. Keep stirring and cool the temperature to 40°C to obtain an oil gel. Weigh the probiotic freeze-dried powder and disperse it in the oil gel and stir for 0.5h to obtain the oil gel content of the dispersed bacterial powder.

[0070] S3. The obtained 300 parts by mass of the glue and 100 parts by mass of the oil gel content of the dispersed bacterial powder were placed in the glue tank and the feed tank of the pill dropping machine for pill dropping, wherein the glue tank temperature is 60 ° C, the feed tank temperature is 50 ° C, the coolant temperature is 15 ° C, and the dripper temperature is 50 ° C;

[0071] S4. The prepared pellets were transferred to a calcium chloride solution with a mass concentration of 5% for calcification for 10 minutes. After being taken out, they were placed in an environment with a temperature of 25° C. and a relative humidity of 65% for drying for 48 hours to obtain enteric-coated probiotic soft capsules.

[0072] Test Example 1: Performance test of enteric-coated probiotic plant soft capsules

[0073] The enteric probiotic soft capsules based on the oil gel system prepared in Examples 1-4 were subjected to performance tests. The test indicators included appearance, filling volume difference, disintegration time, storage stability, etc. The test standards were in accordance with the performance indicators of capsules in the 2020 edition of the Chinese Pharmacopoeia. The test indicators and test results are shown in Tables 5 and 6, respectively:

[0074] Table 5: Performance test standards for enteric probiotic soft capsules based on oil gel system

[0075]

[0076] The calculation method of bacterial survival rate is as follows: take 1g of the content of the soft capsule of Examples 1-4 respectively, add it to 9mL of physiological saline containing 5% Tween 80, shake it at 37°C for 10min to form a uniform emulsion, dilute it with physiological saline containing 5% Tween 80, and count the viable bacteria by plate method. The calculation method of survival rate is calculated by formula (1);

[0077]

[0078] Wherein, W1 represents the number of viable bacteria in the soft capsule sample after being stored for a specific period of time; W2 represents the number of viable bacteria in the soft capsule sample before the storage stability test.

[0079] Table 6: Performance test results of enteric probiotic soft capsules based on oil gel system

[0080]

[0081] As shown in Table 6, the enteric probiotic soft capsules based on the oil gel system prepared in Examples 1-4 of the present invention are neat in appearance, without adhesion, deformation, leakage, shell rupture, or odor, and the difference in loading meets the detection standard of the Chinese Pharmacopoeia. At the same time, the enteric probiotic soft capsules based on the oil gel system prepared by the present invention meet the disintegration time limit standard of the enteric capsules in the Chinese Pharmacopoeia, and there are no cracks, disintegration or softening in pH = 1.2 hydrochloric acid solution and pH = 6.8 phosphate hydrochloric acid solution, and completely disintegrate in pH = 7.8 phosphate hydrochloric acid solution, and the disintegration time limit does not exceed 5min, which can achieve rapid release of the contents. In addition, the enteric-coated probiotic soft capsules based on the oil gel system prepared by the present invention have good storage stability. When the capsules are stored for 1 month, the survival rate of the probiotics in the contents remains above 95%, and the survival rate of the probiotics in the contents is still maintained above 85% after storage for 2 months. The bacterial survival rate only decreases by 10.8-13.7% in 2 months, and has excellent storage performance.

[0082] Comparative Example 1

[0083] The formula of this comparative example is different from that of Example 1 in that the oil gel is composed of 90 parts by mass of soybean oil and 10 parts by mass of oil phase gelling agent (glyceryl monostearate), and the other raw materials, their contents and preparation method are the same as those of Example 1.

[0084] Comparative Example 2

[0085] The formula of this comparative example differs from that of Example 1 in that the oil gel composition is: 90 parts by mass of type 8 palm oil and 10 parts by mass of oil phase gelling agent (glyceryl monostearate), and the other raw materials, their contents and preparation method are the same as those of Example 1.

[0086] Comparative Example 3

[0087] The formula of this comparative example differs from that of Example 1 in that the oil phase gelling agent in the oil gel does not contain type 52 palm oil. The oil phase gelling agent of this comparative example is composed of 50 parts by mass of type 24 palm oil and 50 parts by mass of type 30 palm oil. Other raw materials, their contents and preparation methods are the same as those in Example 1.

[0088] Comparative Example 4

[0089] The formula of this comparative example differs from that of Example 1 in that the oil gel composition is: 10 parts by mass of type 24 palm oil, 40 parts by mass of type 30 palm oil, 20 parts by mass of type 52 palm oil and 30 parts by mass of oil phase gelling agent (glyceryl monostearate), and the other raw materials, their contents and preparation method are the same as those in Example 1.

[0090] Comparative Example 5

[0091] The formula of this comparative example is different from that of Example 1 in that monostearate glyceryl is replaced by soybean lecithin, and other raw materials, their contents and preparation methods are the same as those of Example 1.

[0092] Comparative Example 6

[0093] The formula of this comparative example differs from that of Example 1 in that the composition of the gelling agent in the plant soft capsule skin is different. The composition of the gelling agent used in this comparative example is: 1.0 parts by mass of gellan gum, 0.1 parts by mass of κ-carrageenan, and 1.2 parts by mass of sodium alginate. Other raw materials, their contents, and preparation methods are the same as those in Example 1.

[0094] Comparative Example 7

[0095] The formula of this comparative example differs from that of Example 1 in that the composition of the gelling agent in the plant soft capsule skin is different. The gelling agent used in this comparative example is composed of: 0.3 parts by mass of gellan gum, 1.5 parts by mass of κ-carrageenan, and 0.5 parts by mass of sodium alginate. Other raw materials, their contents, and preparation methods are the same as those in Example 1.

[0096] Comparative Example 8

[0097] The formula of this comparative example differs from that of Example 1 in that the composition of the gelling agent in the plant soft capsule skin is different. The gelling agent used in this comparative example is composed of 1.8 parts by mass of gellan gum, 0.5 parts by mass of κ-carrageenan, and 1.5 parts by mass of sodium alginate. Other raw materials, their contents, and preparation methods are the same as those in Example 1.

[0098] Comparative Example 9

[0099] The formula of this comparative example differs from that of Example 1 in that the plasticizer composition in the plant soft capsule skin is different. The plasticizer composition used in this comparative example is: 0.75 parts by mass of glycerol and 0.75 parts by mass of polyethylene glycol-2000. Other raw materials, their contents and preparation methods are the same as those in Example 1.

[0100] Comparative Example 10

[0101] The formula of this comparative example differs from that of Example 1 in that the plasticizer composition in the plant soft capsule skin is different. The plasticizer composition used in this comparative example is: 0.3 parts by mass of glycerol and 1.2 parts by mass of polyethylene glycol-4000. Other raw materials, their contents and preparation methods are the same as those in Example 1.

[0102] Comparative Example 11

[0103] The formula of this comparative example differs from that of Example 1 in that the content of plasticizer in the plant soft capsule skin is different. The plasticizer used in this comparative example is composed of: 1.0 parts by mass of glycerol and 2.0 parts by mass of polyethylene glycol-4000. Other raw materials, their contents and preparation methods are the same as those in Example 1.

[0104] Comparative Example 12

[0105] The formula of this comparative example is different from that of the best embodiment 1 in that the probiotic freeze-dried powder in the plant soft capsule content is increased to 1.3 parts by mass, the oil gel content and composition are the same, and the other raw materials and their contents and preparation methods are the same as those in embodiment 1.

[0106] Comparative Example 13

[0107] The difference between this comparative example and Example 1 is that the dripping process parameters are different. In the process of dripping soft capsules in this comparative example, the temperature of the glue tank is 70°C, the temperature of the material tank is 65°C, the temperature of the coolant is 25°C, and the temperature of the dripper is 65°C. Other raw materials, their contents, and preparation methods are the same as those in Example 1.

[0108] Comparative Example 14

[0109] The difference between this comparative example and Example 1 is that the calcification process is different. The mass concentration of calcium chloride used in the calcification process of this comparative example is 0.5%, the calcification time is 10 minutes, and other raw materials and their contents, and the preparation method are the same as those in Example 1.

[0110] Test Example 2: Performance test of enteric-coated probiotic plant soft capsules

[0111] The probiotic enteric-coated plant soft capsules prepared in Comparative Examples 1-14 were subjected to performance tests, and the test indicators were the same as those in Test Example 1. The test results are shown in Table 7:

[0112] Table 7: Performance test results of probiotic enteric-coated plant soft capsules

[0113]

[0114]

[0115] From the results in Table 7, it can be seen that the comprehensive performance of the probiotic enteric-coated plant soft capsules prepared in Comparative Examples 1-14 is lower than that in Examples 1-4:

[0116] In Comparative Example 1, soybean oil was used as the base oil of the oil gel instead of the palm oil in Example 1. The survival rate of the probiotics in the prepared soft capsules during storage was significantly lower than that in Examples 1-4. Therefore, under the same storage conditions, the probiotic soft capsules prepared by selecting palm oil as the base oil of the oil gel had better performance.

[0117] In Comparative Example 2, type 8 palm oil was used as the base oil of the oil gel instead of type 24, type 30, and type 52 palm oil in Example 1. The prepared soft capsules had problems such as content leakage and unqualified filling amount difference. The survival rate of the probiotics was significantly lower than that of Examples 1-4 during storage. Therefore, under the same storage conditions, the probiotic soft capsules prepared by selecting palm oil as the base oil of the oil gel had better performance.

[0118] The base oil of the oil gel in Comparative Example 3 does not contain type 52 palm oil. Compared with the base oil containing type 52 palm oil in Comparative Examples 1-4, the prepared soft capsules have problems such as content leakage and unqualified filling amount difference. The survival rate of probiotics during storage is significantly lower than that of Examples 1-4. Therefore, the performance of the probiotic soft capsules prepared by selecting type 52 palm oil as the base oil of the oil gel is better.

[0119] In Comparative Example 4, the base oil and the oil phase gelling agent of the oil gel are beyond the range of 80-100:0-20, while in Comparative Examples 1-4, the base oil and the oil phase gelling agent are between 80-100:0-20. The disintegration time of the prepared soft capsule is significantly prolonged, and the survival rate of the probiotics during storage is significantly lower than that of Examples 1-4. Therefore, the performance of the probiotic soft capsule prepared when the base oil and the oil phase gelling agent are between 80-100:0-20 is better.

[0120] In Comparative Example 5, the oil phase gelling agent of the oil gel is soybean lecithin, and the prepared soft capsules have problems such as content leakage and unqualified filling amount difference. In Comparative Example 1, the oil phase gelling agent of the oil gel is glyceryl monostearate, so that the liquid oil is aggregated with each other through non-covalent interactions, and the formed three-dimensional network structure can wrap the liquid oil and control the fluidity of the oil. Comparative Example 5 does not use glyceryl monostearate, so that the survival rate of probiotics during storage is significantly lower than that of Examples 1-4. Therefore, the probiotic soft capsules prepared by selecting glyceryl monostearate as the oil phase gel have better performance.

[0121] In Comparative Examples 6-7, the gel content of the capsule skin glue solution is outside the range of κ-carrageenan, sodium alginate and gellan gum (0.2-1.2): (0.5-2.5): (0.5-1.5), while in Comparative Examples 1-4, the gel content of κ-carrageenan, sodium alginate and gellan gum in the capsule skin glue solution is between (0.2-1.2): (0.5-2.5): (0.5-1.5). The prepared soft capsules have problems such as deformation and prolonged disintegration time. The survival rate of probiotics during storage is significantly lower than that of Examples 1-4. Therefore, the probiotic soft capsules prepared by having a gel content of κ-carrageenan, sodium alginate and gellan gum in the range of (0.2-1.2): (0.5-2.5): (0.5-1.5) have better performance.

[0122] In Comparative Example 8, the gel content of the capsule skin glue solution exceeds 2.5%, while the gel content of the capsule skin glue solution in Comparative Examples 1-4 is between 2-2.5%. The prepared soft capsules have problems such as partial leakage and unqualified filling amount difference. The survival rate of probiotics is significantly lower than that of Examples 1-4 during storage. Therefore, the probiotic soft capsules prepared with a gel content of the capsule skin glue solution between 2-2.5% have better performance.

[0123] In comparative example 9, polyethylene glycol-2000 is used instead of polyethylene glycol-4000. In comparative example 10, the ratio of plasticizer glycerol and polyethylene glycol-4000 in the capsule skin glue solution is (0.5-1.5): (0-1.5). In comparative examples 1-4, the ratio of plasticizer glycerol and polyethylene glycol-4000 in the capsule skin glue solution is between (0.5-1.5): (0-1.5). The prepared soft capsules have a sticking problem, and the survival rate of probiotics is significantly lower than that of examples 1-4 during storage. Therefore, the probiotic soft capsules prepared by the ratio of plasticizer glycerol and polyethylene glycol-4000 in the capsule skin glue solution is between (0.5-1.5): (0-1.5) have better performance.

[0124] In Comparative Example 11, the ratio of plasticizer glycerol and polyethylene glycol-4000 in the capsule skin glue solution is (0.5-1.5): (0-1.5). In Comparative Examples 1-4, the ratio of plasticizer glycerol and polyethylene glycol-4000 in the capsule skin glue solution is between (0.5-1.5): (0-1.5). The survival rate of probiotics in the prepared soft capsules during storage is significantly lower than that in Examples 1-4. Therefore, the performance of the probiotic soft capsules prepared by the ratio of plasticizer glycerol and polyethylene glycol-4000 in the capsule skin glue solution is better.

[0125] In Comparative Example 12, the mass ratio of probiotic powder to oil gel is (0.01-1): (80-120). In Comparative Examples 1-4, the mass ratio of probiotic powder to oil gel is between (0.01-1): (80-120). The survival rate of probiotics in the prepared soft capsules during storage is significantly lower than that in Examples 1-4. Therefore, the probiotic soft capsules prepared by the mass ratio of probiotic lyophilized powder to oil gel between (0.01-1): (80-120) have better performance.

[0126] In comparative example 13, during the dripping process, the temperature of the glue tank is 70°C, the temperature of the feed tank is 65°C, the temperature of the coolant is 25°C, and the temperature of the dripper is 65°C. In comparative examples 1-4, during the dripping process, the temperature of the glue tank is 55-65°C, the temperature of the feed tank is 50-60°C, the temperature of the coolant is 10-20°C, and the temperature of the dripper is 50-60°C. The survival rate of the probiotics in the prepared soft capsules is significantly lower than that in examples 1-4 during storage. Therefore, the performance of the probiotic soft capsules prepared by controlling the glue tank temperature to 55-65°C, the feed tank temperature to 50-60°C, the coolant temperature to 10-20°C, and the dripper temperature to 50-60°C during the dripping process is better.

[0127] In Comparative Example 14, during the calcification process, the mass concentration of the calcium chloride solution was 0.5%, and the calcification time was 10 min. In Comparative Example 1-4, during the calcification process, the mass concentration of the calcium chloride solution was 1%-10%, and the calcification time was 5-15 min. The disintegration time of the prepared soft capsule was significantly prolonged, and the survival rate of the probiotics during storage was significantly lower than that of Examples 1-4. Therefore, during the calcification process, the concentration of the calcium chloride solution was 1%-10%, and the calcification time was 5-15 min, and the performance of the prepared probiotic soft capsule was better.

[0128] In summary, the present invention adopts an oil gel system and a suitable ratio of raw materials to prepare soft capsules with greater safety and stability. Sodium alginate is used as the main enteric material, and the soft capsule skin formed after calcification has the characteristics of intestinal targeted release; the delivery efficiency of probiotics in the human body is improved, and the rapid and targeted release of probiotics is achieved; the oil gel system adopted can effectively isolate moisture and air, and the prepared soft capsules can significantly reduce the influence of humidity and air on the probiotics during storage, thereby improving the survival rate of the probiotics; at the same time, the oil gel system has the advantages of thermal reversibility, good stability, oral and rectal administration, no need for re-dispersion, and adjustable physical properties, etc., which can significantly improve the delivery efficiency of probiotics in the human body and achieve rapid and targeted release of probiotics; the preparation method is simple, the process is simple, and it is suitable for industrial production.

[0129] Although the specific implementation modes of the present invention are described above, those skilled in the art should understand that the specific implementation modes described are only illustrative and are not intended to limit the scope of the present invention. Equivalent modifications and changes made by those skilled in the art in accordance with the spirit of the present invention should be included in the scope of protection of the claims of the present invention.

Claims

1. An enteric-coated probiotic soft capsule, characterized in that: The enteric-coated probiotic soft capsule comprises soft capsule contents and a soft capsule shell, wherein the soft capsule contents comprise probiotic powder and oil gel, wherein the oil gel comprises 80-100 parts by weight of a base oil and 0-20 parts by weight of an oil phase gelling agent, wherein the base oil is 52 type palm oil, and the oil phase gelling agent is glyceryl monostearate.

2. An enteric-coated probiotic soft capsule, characterized in that: The enteric-coated probiotic soft capsule comprises soft capsule contents and a soft capsule shell. The soft capsule contents comprise probiotic powder and oil gel. The oil gel is made of 24-type palm oil, 30-type palm oil and 52-type palm oil in a mass ratio of (0-20):(0-60):(30-90).

3. The enteric-coated probiotic soft capsule according to claim 1 or claim 2, characterized in that: The soft capsule shell comprises a film former, a gelling agent, a coagulant, a plasticizer and water, wherein the film former is selected from pullulan and / or hydroxypropyl methylcellulose, the gelling agent is selected from one or more of κ-carrageenan, sodium alginate and gellan gum, the coagulant is selected from potassium chloride and / or sodium chloride, and the plasticizer is glycerol and / or polyethylene glycol-4000.

4. The enteric-coated probiotic soft capsule according to claim 3, characterized in that: Calculated by weight, the raw materials for preparing the soft capsule shell include 2-6 parts of a film former, 2-2.5 parts of a gelling agent, 0.05-0.25 parts of a coagulant, 0.5-2.5 parts of a plasticizer and 100 parts of water.

5. The enteric-coated probiotic soft capsule according to claim 4, characterized in that: The gelling agent is prepared from kappa-carrageenan, sodium alginate and gellan gum in a mass ratio of (0.2-1.2):(0.5-2.5):(0.5-1.5); the coagulant is prepared from potassium chloride and sodium chloride in a mass ratio of (0.05-0.15):(0-0.1); and the plasticizer is prepared from glycerol and polyethylene glycol-4000 in a mass ratio of (0.5-1.5):(0-1.5).

6. A method for preparing the enteric-coated probiotic soft capsule according to any one of claims 1 to 5, comprising the following steps: S1. Weigh the plasticizer in proportion and dissolve it in water at 55-70 ° C, stir until completely dissolved, keep the temperature at 55-70 ° C, slowly add the uniformly mixed gelling agent, film-forming agent, and coagulant and stir until completely dissolved, and let the resulting liquid stand at 45-60 ° C and keep warm for 5-12h to obtain a soft capsule capsule gel; S2. Weigh the base oil and / or oil phase gel at 60-80°C and stir until melted, keep stirring and cool the temperature to 35-45°C to obtain an oil gel, weigh the probiotic powder and disperse it in the oil gel and stir for 0.5-1h to obtain the oil gel content of the dispersed bacterial powder; S3. The gel solution prepared in step S1 and the oil gel content of the dispersed bacterial powder prepared in step S2 are placed in the gel solution tank and the feed tank of the pill machine for pill making; S4. The pellets prepared in step S3 are transferred to a calcium chloride solution with a mass concentration of 1%-10% for calcification for 5-15 minutes. After being taken out, they are placed in an environment with a temperature of 25-35°C and a relative humidity of 50-65% for drying for 24-48 hours to obtain enteric-coated probiotic soft capsules.

7. The method for preparing the enteric-coated probiotic soft capsule according to claim 6, characterized in that: In step S3, the temperature of the glue tank is 55-65°C, the temperature of the material tank is 50-60°C, the temperature of the coolant is 10-20°C, and the temperature of the dripper is 50-60°C.

8. The method for preparing the enteric-coated probiotic soft capsule according to claim 6, characterized in that: In step S3, the mass ratio of the glue solution to the oil gel content of the dispersed bacterial powder is 100-500:50-200.

9. Use of the enteric-coated probiotic soft capsule according to any one of claims 1 to 5 in the preparation of food, health products or medicines.

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