Soft capsule for regulating blood fat and preventing atherosclerosis as well as preparation method and application of soft capsule

Abstract

The invention relates to a preparation method of a soft capsule for regulating blood fat and preventing atherosclerosis, the soft capsule comprises a soft capsule content and a soft capsule shell, and the mass ratio of the soft capsule content to the soft capsule shell is (0.9-1.7): 1; wherein the soft capsule content comprises a traditional Chinese medicine composition, a diluent and a suspending aid, and the mass ratio of the traditional Chinese medicine composition to the sum of the diluent and the suspending aid is 1: (1.30-1.60); the traditional Chinese medicine composition comprises red yeast rice, a grape seed extract and a ginkgo leaf extract according to a mass ratio of (170-200): (70-100): (15-35). The soft capsule skin is prepared from water, gelatin and glycerol in a mass ratio of (0.7-1.2): 1: (0.3-0.7); the soft capsule content and the capsule skin glue solution are pressed into pills by a pill pressing machine. The soft capsule has the effects of regulating blood fat and preventing atherosclerosis, also has economical efficiency and stability, and solves the technical problems of long disintegration time limit, adhesion, oil leakage, bubbles and aging of the soft capsule.

Description

Technical Field

[0001] The invention relates to the field of preparations, and in particular to a preparation method and application of a soft capsule for regulating blood lipids and preventing atherosclerosis. Background Art

[0002] The consensus of the international medical community is that when any one or more of the total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), or the total cholesterol / high-density lipoprotein cholesterol ratio TC / HDL-C is high, or when high-density lipoprotein cholesterol is low, it is called abnormal blood lipid metabolism or hyperlipidemia. Hyperlipidemia has many complications, especially atherosclerosis caused by hyperlipidemia. If atherosclerosis occurs, the blood circulation inside the body will be obviously abnormal, causing organ ischemia and even more serious complications such as coronary heart disease, myocardial infarction or thrombosis. Therefore, when preventing or treating hyperlipidemia, it is necessary not only to consider the changes in blood lipids, but also to consider whether there is a preventive effect on hyperlipidemia complications such as atherosclerosis. High-density lipoprotein cholesterol is a lipoprotein that resists atherosclerosis and can promote the elimination of cholesterol in peripheral tissues, thereby preventing the risk of atherosclerosis. CN100336517C discloses a red yeast rice and ginkgo leaf composition for regulating blood lipids, which can reduce total cholesterol and triglycerides, but cannot increase high-density lipoprotein cholesterol.

[0003] Soft capsules are fully enclosed dosage forms that are formed in one step by compression or dripping. They are commonly used dosage forms in the field of traditional Chinese medicine and have the characteristics of high bioavailability. However, during the preparation or storage process, soft capsules may suffer from unqualified disintegration, adhesion, oil leakage, bubbles, and aging and hardening of the soft capsule shell, which affects product quality and bioavailability.

[0004] Therefore, there is an urgent need for a soft capsule that can increase high-density lipoprotein cholesterol, regulate blood lipids and prevent atherosclerosis and has excellent disintegration time, stability and intact properties. Summary of the invention

[0005] In order to solve the above technical problems, the present application provides a soft capsule for increasing high-density lipoprotein cholesterol, regulating blood lipids and preventing atherosclerosis and a preparation method thereof. The soft capsule has the functions of regulating blood lipids and preventing atherosclerosis, and is also economical and stable, solving the technical problems of long disintegration time, adhesion, oil leakage, bubbles and aging.

[0006] This application is achieved through the following technical solutions:

[0007] In a first aspect of the present application, a method for preparing a soft capsule for regulating blood lipids and preventing atherosclerosis is provided.

[0008] The method for preparing a soft capsule for regulating blood lipids and preventing atherosclerosis described in the present application comprises the following steps: (1) preparing the contents of the soft capsule:

[0009] Red yeast rice, grape seed extract, and ginkgo leaf extract are mixed in a mass ratio of (170-200):(70-100):(15-35), and passed through a 100-120 mesh sieve to obtain a Chinese medicine composition; wherein the grape seed extract is prepared according to the following method: grape seeds are extracted with 60-75% ethanol at a slight boiling temperature of 83-88°C, filtered, subjected to macroporous resin column chromatography, gradient eluted with 35-95% ethanol, the eluate is collected, concentrated, and dried to obtain the composition; the ginkgo leaf extract is prepared according to the following method: ginkgo leaves are extracted with 65-85% ethanol at an extraction temperature of 80-85°C, filtered, subjected to macroporous resin column chromatography, eluted with 65-75% ethanol, the eluate is collected, concentrated, and dried to obtain the composition;

[0010] Heat and melt the diluent and suspending agent, stir, and cool to obtain a molten liquid;

[0011] The Chinese medicine composition is mixed with the melt, ground, passed through a 100-120 mesh sieve, and vacuum-degassed to obtain the contents, and the mixture is kept warm; the mass ratio of the Chinese medicine composition to the sum of the diluent and the suspending agent is 1:1.20-1.60;

[0012] (2) Preparation of soft capsule coating solution:

[0013] Water, gelatin and glycerin are heated to swell, and any one or more of a colorant, a sunscreen and a preservative are added, mixed evenly, passed through an 80-100 mesh sieve, and vacuum-debubbled to obtain a glue solution, which is kept warm; the mass ratio of water, gelatin and glycerin is (0.7-1.2):1:(0.3-0.7);

[0014] (3) Soft capsule compression:

[0015] The above contents and capsule skin glue liquid are pressed into pills in a mass ratio of 0.9-1.7:1 using a pill press, the air supply temperature of the pill press head is 8-12°C, the glue box temperature is 50-55°C, the spray body or nozzle temperature is 37-50°C, and the soft capsule skin thickness is 0.7-0.9mm; the shaping is performed for 8-12 hours and the drying is performed for 12-16 hours.

[0016] In a second aspect of the present application, a soft capsule is provided for regulating blood lipids and preventing atherosclerosis.

[0017] The soft capsule for regulating blood lipids and preventing atherosclerosis described in the present application comprises soft capsule contents and soft capsule shell; wherein the soft capsule contents comprise a Chinese medicine composition, a diluent, and a suspending agent, and the mass ratio of the Chinese medicine composition to the sum of the diluent and the suspending agent is 1:1.20-1.60; the Chinese medicine composition comprises red yeast rice, grape seed extract, and ginkgo leaf extract, which are composed according to the mass ratio of (170-200):(70-100):(15-35); The grape seed extract is obtained by the following method: extracting grape seeds with 60-75% ethanol at a micro-boiling temperature of 83-88°C, filtering, macroporous resin column chromatography, gradient elution with 35-95% ethanol, collecting the eluate, concentrating, and drying; the ginkgo leaf extract is obtained by the following method: extracting ginkgo leaves with 65-85% ethanol at an extraction temperature of 80-85°C, filtering, macroporous resin column chromatography, eluting with 65-75% ethanol, collecting the eluate, concentrating, and drying;

[0018] The soft capsule shell comprises water, gelatin and glycerin in a mass ratio of (0.7-1.2):1:(0.3-0.7);

[0019] The mass of the content of the soft capsule is 0.5-1.0 g / capsule, and the thickness of the soft capsule skin is 0.7-0.9 mm.

[0020] Preferably, the soft capsule shell further comprises any one or more of a colorant, a sunscreen, and a preservative.

[0021] Preferably, the mass ratio of the soft capsule content to the soft capsule shell in the unit dose of the soft capsule is 1-1.7:1.

[0022] In one embodiment of the present application, the soft capsule preparation method of the first aspect and the soft capsule of the second aspect of the present application, wherein the Chinese medicine composition comprises red yeast rice, grape seed extract and ginkgo leaf extract in a mass ratio of 180:80:25.

[0023] There is no separate record of "hyperlipidemia" in classical Chinese medicine. The earliest documented record is the discussion of "body fluid", "oil" and "fat" in the Yellow Emperor's Classic of Internal Medicine. "Lingshu·Defense Qi Disorder" says: "People are fat, fat, and meat", "fat people have less blood serum and less qi". Modern Chinese medicine classifies it into the categories of "phlegm dampness", "fat turbidity", "dizziness", "blood turbidity", "blood stasis", "chest obstruction", "stroke" and so on according to its clinical manifestations, so it is often treated by removing dampness and expectoration, promoting blood circulation and removing blood stasis. The soft capsule of this application is made of red yeast rice, grape seed extract and ginkgo leaf extract as raw materials through modern processing. The ginkgo leaf extract in the formula contains total flavonoids and terpenoid lactones, and the grape seed extract contains a large amount of proanthocyanidins and monomer polyphenols such as catechins and epicatechins. The present application uses red yeast rice and ginkgo biloba together to "remove dampness and eliminate phlegm, promote blood circulation and remove blood stasis", improve symptoms such as "blood stasis" and "chest pain", reduce total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels, and have the effect of assisting in lowering blood lipids. The addition of grape seed extract can increase the content of high-density lipoprotein cholesterol, which not only synergizes the blood lipid-lowering effect of red yeast rice and ginkgo biloba extracts, but also has the effect of preventing atherosclerosis.

[0024] The dosage of red yeast rice, ginkgo leaf extract and grape seed extract selected in the present application is not only based on the above-mentioned compatibility principles, but also fully considers the safety limit of the dosage of each component to demonstrate and arrive at a scientific dosage ratio.

[0025] The red yeast rice described in this application is a red yeast rice made from rice as raw material and fermented by Monascus purpurogenous, which contains the bioactive substance molaclin K naturally produced by fermentation. Its quality should comply with the provisions of QB / T2847 "Functional Red Yeast Rice (Powder)".

[0026] One embodiment of the present application is the soft capsule preparation method of the first aspect of the present application and the soft capsule of the second aspect, wherein the soft capsule contains one or more of the following effective active ingredients: lovastatin, proanthocyanidins, catechins, epicatechin, quercetin, kaempferol, isorhamnetin, bilobalide, ginkgolide A, ginkgolide B and ginkgolide C.

[0027] One embodiment of the present application is the soft capsule preparation method of the first aspect of the present application and the soft capsule of the second aspect, wherein the active ingredient lovastatin content of the soft capsule is ≤237mg / 100g, preferably the lovastatin content is 103-237mg / 100g; more preferably, the lovastatin content is 210-220mg / 100g, wherein 100g is the mass of the soft capsule content. The red yeast rice dosage is approximately 1.08g / day according to the daily dosage, which does not exceed 2g per day, which not only ensures the efficacy but also avoids the side effects caused by the red yeast rice active ingredient lovastatin, such as indigestion, abdominal distension, stomach pain and other gastrointestinal reactions, and has good safety for long-term use.

[0028] One embodiment of the present application is the soft capsule preparation method of the first aspect of the present application and the soft capsule of the second aspect, wherein the content of active ingredient proanthocyanidins in the soft capsule is ≥9g / 100g, preferably, the content of proanthocyanidins is ≥10g / 100g, wherein 100g is the mass of the content of the soft capsule.

[0029] In one embodiment of the present application, the soft capsule preparation method of the first aspect and the soft capsule of the second aspect of the present application, the total content of the active ingredients catechin and epicatechin in the soft capsule is ≥0.2g / 100g, wherein 100g is the total mass of the contents of the soft capsule.

[0030] One embodiment of the present application is the soft capsule preparation method of the first aspect of the present application and the soft capsule of the second aspect, wherein the content of quercetin, kaempferol and isorhamnetin as active ingredients of the soft capsule, with the total flavonol glycosides totaling 0.5-1.5g / 100g, wherein 100g is the mass of the soft capsule contents.

[0031] In one embodiment of the present application, the soft capsule preparation method of the first aspect and the soft capsule of the second aspect of the present application, wherein the soft capsule active ingredient bilobalide (C 15 H 18 O8), Ginkgolide A (C 20 H 24 O9), Ginkgolide B (C 20 H 24 O 10 ) and Ginkgolide C(C 20 H 24 O 11 ) has a total mass of terpenoid lactones of 0.1-0.5 g / 100 g, wherein 100 g is the mass of the soft capsule contents.

[0032] One embodiment of the present application is the soft capsule preparation method of the first aspect of the present application and the soft capsule of the second aspect, wherein the soft capsule contains 150-237 mg / 100 g of lovastatin as the active ingredient, ≥10 g / 100 g of proanthocyanidins, and 0.5-1.5 g / 100 g of total flavonol glycosides, wherein 100 g is the mass of the contents of the soft capsule.

[0033] Further preferably, the soft capsule contains 150-237 mg / 100 g of active ingredient lovastatin, ≥10 g / 100 g of proanthocyanidins, 0.5-1.5 g / 100 g of total flavonol glycosides, ≥0.2 g / 100 g of the sum of catechin + epicatechin contents, and 0.1-0.5 g / 100 g of terpenoid lactones, wherein 100 g is the mass of the contents of the soft capsule.

[0034] One embodiment of the present application is the method for preparing the soft capsule of the first aspect and the soft capsule of the second aspect of the present application, wherein the grape seed extract is obtained by the following method: the grape seeds are extracted with 4-6 times the amount of 60-75% ethanol, the extraction is performed at a temperature of 83-88°C with slight boiling, the extraction is performed 1-3 times, each time for 1-3 hours, filtering, macroporous resin column chromatography, 35-95% ethanol gradient elution, the eluate is collected, concentrated to 60-75°C with a relative density of 1.05-1.15, and spray dried to obtain the extract.

[0035] Preferably, the grape seeds are extracted with 5 times the amount of 70% ethanol, the extraction temperature is 83-88° C., and the extraction is performed twice, each time for 2 hours.

[0036] The above-mentioned macroporous resin models of the present application include but are not limited to AB-8, D101, DM21, HPD-600, HPD-700, LX-60, LX-69, LX-3020, preferably DM21 macroporous resin. It is found that DM21 macroporous resin shows good adsorption rate and desorption rate in the adsorption process in the macroporous resin models. For example, the static adsorption experiment of HPD-700 and DM21 shows that the adsorption rate of proanthocyanidins by HPD-700 and DM21 macroporous resins is not much different. However, in the desorption test, the desorption rate of proanthocyanidins by DM21 macroporous resin is the highest, which shows that DM21 macroporous resin performs better in separating proanthocyanidins, and the purity of proanthocyanidins in the prepared extract is the highest. At the same time, the use of DM21 macroporous resin can effectively remove mucus, pigments, etc., avoids the bonding phenomenon of the soft capsule contents during the preparation of soft capsules, thereby reducing the generation of bubbles or particles in the soft capsule contents.

[0037] In the present application, the upper column flow rate of the above macroporous resin column is 3-5BV, the impurities are washed with water until the washing liquid is clear, and 35-95% ethanol is used for gradient elution, and the elution flow rate is controlled to 150L / h.

[0038] The 35-95% ethanol gradient elution described in the present application includes first eluting with 35-45% ethanol, collecting the eluate, then eluting with 85-95% ethanol, collecting the eluate, and combining the two eluates. The present application adopts two-stage elution to elute proanthocyanidins and monomeric polyphenol components such as catechins and epicatechin, so that the proanthocyanidin content reaches more than 95%.

[0039] Further preferably, the grape seed extract is prepared by the following method: extract twice with 5 times the amount of 70% ethanol at a slight boiling temperature, each time for 2 hours, at an extraction temperature of 83-88°C, filter, chromatograph on a DM21 macroporous resin column, first elute with 35-45% ethanol, collect the eluate, then elute with 85-95% ethanol, collect the eluate, combine the two eluates, concentrate, and spray dry to obtain the extract.

[0040] The concentration described in this application is to a relative density of 1.05-1.15 at 60-75°C, preferably 1.05-1.15 at 60°C. 70% ethanol can completely extract the proanthocyanidins in grape seeds, but during the concentration process, as the ethanol concentration decreases, the proanthocyanidins are at risk of precipitation and will adhere to the rotary evaporator, causing changes in the effective ingredients in the extract. After exploration, the present application found that the proanthocyanidin component can be retained to the greatest extent when concentrated to a relative density of 1.05-1.15 at 60-75°C.

[0041] The spray drying described in the present application has an air inlet temperature of 185-195°C and an air outlet temperature of 95-105°C.

[0042] In the present application, proanthocyanidins are highly oxidizing and sensitive to high temperatures. In order to avoid high-temperature extraction from destroying the structure of proanthocyanidins, a micro-boiling extraction at 83-88°C is used. At the same time, it is also found in the present application that by controlling the inlet and outlet temperatures of spray drying, not only the high-temperature decomposition of proanthocyanidins in grape seed extract is avoided, but also a crisp powder can be obtained. Because, during the spray drying process, when the inlet temperature is 185-195°C and the outlet temperature is 95-105°C, it is found that the residual steam has enough pressure to blow the surface of the powder into holes to obtain a crisp powder. The grape seed extract crisp powder is easier to mix evenly when mixed with the molten liquid of the diluent and the suspending agent. The molten liquid enters the cavities of the powder, reducing the agglomeration of the powder, thereby reducing the generation of bubbles or particles in the contents of the soft capsule. According to the relative density of the present application, only when the inlet air temperature is 185-195°C and the outlet air temperature is 95-105°C, the dust in the spray tower is dense and uniform, and the falling dust does not stick to the wall or agglomerate, which is conducive to the collection of dry powder, with a high yield, and also reduces the workload of the later cleaning equipment.

[0043] The grape seed extract is obtained by the grape seed extraction method of the present application, wherein the proanthocyanidin content is ≥95%, the yield is as high as 3.5% or more, the ash content is ≤2.0%, the particle size passing through a 100-mesh sieve is ≥98%, and the bulk density is 0.45-0.65 g / ml.

[0044] One embodiment of the present application is the method for preparing the soft capsule of the first aspect and the soft capsule of the second aspect of the present application, wherein the ginkgo leaf extract is prepared by the following method: extracting the ginkgo leaf with 5-7 times the amount of 65-85% ethanol, extracting 2-4 times, each time for 0.5-2 hours, extracting at 80-85°C with a slight boiling point, filtering to obtain an extract, applying D101 macroporous resin column chromatography, eluting with 65-75% ethanol, collecting the eluate, concentrating until there is no alcohol taste, concentrating to a relative density of 1.15-1.18 at 80°C, and spray drying to obtain the extract.

[0045] The upper column flow rate of the macroporous resin column is 800-1000kg / h, the impurities are washed with water until the washing liquid is clear, and eluted with 70% ethanol, and the elution flow rate is controlled to 600-800kg / h.

[0046] Further preferably, the ginkgo leaf extract is prepared by the following method: extracting with 70% ethanol three times, the first time the liquid input volume is 6 times the amount of the raw material, the second and third times are 5 times the amount of the raw material, each extraction is 1 hour, the extraction temperature is controlled to 80-85°C, D101 macroporous resin column chromatography, first washing impurities with water, discarding them, then eluting with 70% ethanol, collecting the eluate, concentrating the eluate until there is no alcohol taste, the relative density at 80°C is 1.15-1.18, and spray drying to obtain.

[0047] The D101 macroporous resin described in the present application has good comprehensive adsorption performance for flavonoid glycosides and terpenoid lactones in Ginkgo biloba leaves, and can effectively separate and purify active ingredients.

[0048] The spray drying described in the present application has an air inlet temperature of 110-160°C and an air outlet temperature of 70-85°C.

[0049] The active ingredients of the ginkgo leaf extract of the present application, flavonoids or terpenes, are heat-sensitive substances. If the temperature is too high, the active ingredients will be oxidized and deteriorated. In order to ensure the extraction efficiency, yield, purity and stability of the active ingredients, it is preferred to use 70% ethanol at a slightly boiling state of 80-85°C for extraction. The present application also found that the looseness and density of the ginkgo leaf extract powder was guaranteed by controlling the inlet and outlet temperatures of spray drying. During the spray drying process, the inlet temperature is 110-160°C and the outlet temperature is 70-85°C. The residual steam has enough pressure to blow the surface of the powder into cavities. When mixed with the molten liquid of the diluent and the suspending agent, it is easier to mix evenly. The molten liquid enters the cavities of the powder, reducing the agglomeration of the powder into lumps, thereby reducing the generation of bubbles or particles in the contents of the soft capsule. At the same time, the relative density at 80°C specified in the present application is 1.15-1.18, and the clear paste does not stick to the wall and is easy to transfer. When the relative density is greater than 1.18, the texture of the clear paste is relatively viscous and the fluidity is poor. When transferring the clear paste, phenomena such as wall hanging will occur, resulting in large losses and low yields. Therefore, according to the relative density range of the ginkgo leaf extract of the present application, spraying is performed at an inlet air temperature of 110-160°C, and the outlet temperature is between 70-85°C. The dust in the spray tower is dense and uniform, and the falling dust does not stick to the wall. When the inlet air temperature is lower than 110°C, the dust begins to stick to the wall, the yield is reduced, and the powder particles are prone to agglomeration, which leads to bubbles or larger particles when the powder is mixed with the molten liquid to prepare the contents of the soft capsule. According to the concentrated relative density of the present application, the inlet and outlet temperatures of the spray drying can not only ensure the smooth drying, but also the high drying efficiency, while the powder can be loose and not easy to agglomerate.

[0050] The ginkgo leaf extract obtained by the method of the present application has a total flavonoid glycoside content of 24-32%, a terpene lactone content of 6-12%, a yield of more than 2%, an ash content of ≤0.80%, a moisture content of ≤5%, a particle size of ≥98% through a 100-mesh sieve, and a bulk density of 0.45-0.65 g / ml.

[0051] The ginkgo leaf extract and grape seed extract of the present application are both extracted with 70% ethanol for effective active ingredients, but alcohol-soluble viscous substances such as colloid, resin, chlorophyll are extracted at the same time. If these impurities are not removed, it will affect the subsequent processes such as drying, crushing, pilling, etc., and will be easy to stick together, especially when grinding on the colloid mill, as the temperature rises, the above-mentioned viscous substances will cause the extract to stick and aggregate, which is easy to cause the colloid mill to get stuck and burn, thereby causing the soft capsule content to agglomerate. Therefore, the present application adopts macroporous resin to remove impurities, which not only ensures the content or purity of effective active ingredients, but also ensures the smoothness of the soft capsule process, reducing the risk of unqualified soft capsules.

[0052] In one embodiment of the present application, the method for preparing the soft capsule of the first aspect and the soft capsule of the second aspect of the present application, wherein the mass ratio of the diluent to the suspending agent is 10-18:1, which can be selected from 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, and 18:1. Preferably, the mass ratio of the diluent to the suspending agent is 11-14:1.

[0053] The diluent described in the present application is a vegetable oil, which includes one or more of olive oil, soybean oil, prickle oil, linseed oil, sunflower seed oil, jojoba oil, peanut oil, tea oil, tea tree oil, rosehip oil, nut oil, avocado oil, castor oil, cottonseed oil, peppermint oil, sesame oil, salad oil, palm oil, rapeseed oil, corn germ oil and corn oil.

[0054] The suspending agent described in the present application includes beeswax, polyethylene glycol, soybean lecithin, etc. The suspending agent and the diluent have good fluidity and sedimentation ratio. In order to prevent the capsule shell from hardening during long-term storage of soft capsules, the preferred suspending agent is beeswax.

[0055] In one embodiment of the present application, the method for preparing the soft capsule of the first aspect and the soft capsule of the second aspect of the present application, the Chinese medicine composition and the melt (i.e., the sum of the diluent and the suspending agent) are mixed in a mass ratio of 1:1.20-1.60. For example, the mass ratio of the Chinese medicine composition to the melt can be 1:1.20, 1:1.30, 1:1.40, 1:1.50, or 1:1.60.

[0056] One embodiment of the present application is a method for preparing a soft capsule of the first aspect of the present application and a soft capsule of the second aspect, wherein the content of the soft capsule comprises a Chinese medicine composition: vegetable oil: beeswax in a mass ratio of (3.0-4.0): (4.5-5.5): (0.3-0.5). Preferably, the mass ratio of the Chinese medicine composition: vegetable oil: beeswax is (3.4-3.6): (4.8-5.1): (0.35-0.45). Experiments have shown that the content of the soft capsule prepared by this ratio has an optimal sedimentation ratio and fluidity, stable quality, and is not easy to stratify.

[0057] One embodiment of the present application is a method for preparing soft capsules in the first aspect of the present application, wherein the grinding described in step (1) is performed by a colloid mill for 1-3 times, preferably 2 times, to achieve a mixture of at least 98% or more that can pass through a 100-120 mesh sieve (preferably a 120 mesh sieve). The present application can extend the shelf life of the soft capsules by grinding with a colloid mill, and the soft capsule contents will not stratify even if the soft capsules are placed for more than one year. The grinding step also increases the mixing uniformity of the contents. It has been verified through experiments that the RSD% of the active ingredient content measured at any position of the soft capsule is <2.0%. After the soft capsule contents of the present application are ground with a colloid mill, the suspended powder particle size is stable and does not aggregate, and the particle size is small enough to pass through a 100-120 mesh sieve, thereby avoiding the generation of a large number of bubbles when the contents are mixed with the molten liquid.

[0058] One embodiment of the present application is the method for preparing soft capsules according to the first aspect of the present application, wherein the cooling temperature in step (1) is 35-40°C. The inventors of the present application have found that the molten liquid after the diluent and the suspending agent are melted is sensitive to temperature. When the temperature is low, the molten liquid will thicken and even become semi-solid; when the temperature is high, the molten liquid and the Chinese medicine composition will be pressed into the contents of the soft capsule and obvious stratification will occur.

[0059] One embodiment of the present application is a method for preparing soft capsules according to the first aspect of the present application, wherein the insulation temperature in step (1) is 35-40°C, and after the Chinese medicine composition of the present application and the molten liquid are evenly mixed, the contents have good fluidity, and the contents of the soft capsules obtained by pelleting are stable and not stratified.

[0060] One embodiment of the present application, the soft capsule preparation method of the first aspect of the present application and the soft capsule of the second aspect, wherein the soft capsule skin comprises water, gelatin, and glycerol. The ratio of water, gelatin, and glycerol affects the encapsulation efficiency and disintegration time of the soft capsule. When the ratio of glycerol to gelatin is less than 0.3:1.0, the soft capsule skin is too hard and the disintegration time is extended; when it reaches 0.8:1.0, the prepared gelatin is too soft, there is adhesion, which affects the encapsulation efficiency and oil leakage. Therefore, the ratio of glycerol to gelatin is 0.3-0.7:1.0, more preferably 0.4-0.5:1. The mass ratio of water to gelatin is 0.7-1.2:1.0, but it is found that water and gelatin exceed 1.2:1. Due to excessive water in the rubber skin, the soft capsule encapsulation efficiency is low, and there are oil leakage and rotten pills. If it is less than 0.7:1, the capsule skin is too thick, the glue discharge speed is slow, the viscosity decreases, the seam is not good, and it is easy to leak oil. Preferably, the ratio of water to gelatin is 0.9-1.1:1, more preferably 1:1. The water to gelatin ratio range can ensure that after the gelatin is dissolved, when vacuuming to remove bubbles, the bubbles can be removed as much as possible when the gelatin liquid is vacuumed and drawn into a boiling state, saving vacuuming time and improving production efficiency. The water content in the soft capsule skin also satisfies that even if the contents absorb water, they will not stick together.

[0061] More preferably, gelatin: glycerol: water = 1: 0.4-0.5: 1, or gelatin: glycerol: water = 1: 0.5: 0.9.

[0062] One embodiment of the present application is the method for preparing the soft capsule of the first aspect of the present application and the soft capsule of the second aspect, wherein the soft capsule skin of the present application contains a colorant, and the colorant comprises one or more of red iron oxide, yellow iron oxide, black iron oxide, sunset yellow, anthocyanin, titanium dioxide, and cocoa shell color, more preferably one or more of red iron oxide, yellow iron oxide, and black iron oxide. Preferably, the amount of the colorant is 0.16-0.18%. Adding a colorant has a light-shielding effect, inhibits the aging of the rubber skin, and avoids the extension of the disintegration time limit.

[0063] One embodiment of the present application is a method for preparing soft capsules in the first aspect of the present application, wherein the soft capsule pressing method in step (3) is used. The soft capsule pressing process is greatly affected by the ambient temperature. If the ambient temperature is too high, the soft capsule is not easy to cool and set quickly. If the ambient temperature is too low, the capsule skin will cool too early, resulting in a loose sealing of the soft capsule seam and leakage. Therefore, it is preferred to perform the pill pressing process under an environment of 18°C-25°C. In the pressing process, if the temperature of the glue box is too high, the destructiveness of the glue liquid will increase. If the temperature is too low, the fluidity of the glue liquid will be poor. In order to ensure the quality and good fluidity of the glue liquid, the temperature of the glue box is selected to be 50°C-60°C. In the pressing process, if the temperature of the spray body or the spray head is too high, the soft capsule will become soft and sticky. If the temperature of the spray body or the spray head is too low, the soft capsule seam will not be easy to seal and oil leakage will occur. Therefore, it is preferred that the temperature of the spray body or the spray head is 37-50°C in the pressing process.

[0064] Further preferably, the indoor temperature is 20°C-24°C, the relative humidity is 30%-40%, the head air supply temperature is 8°C-12°C, the glue box temperature is 50°C-55°C, and the nozzle or nozzle temperature is 40°C-47°C.

[0065] The inventor of the present application found that the oil leakage at the seam of the soft capsule or the extension of the disintegration time limit is not only caused by the improper composition or ratio of the soft capsule skin glue liquid and the improper parameter selection during the soft capsule pressing process, but also may be caused by the reaction between the soft capsule content and the soft capsule skin material. The content dissolves the gelatin in the skin, causing oil leakage or extension of the disintegration time limit. The surface area of ​​the soft capsule seam in contact with the content is larger, so the capsule shell at the seam becomes thinner and the oil leakage becomes more serious. The active ingredient ginkgo flavonoids of the ginkgo leaf extract in the present application belong to aldehyde substances. If there are a large number of aldehyde substances in the soft capsule content, it is easy to cross-link with the gelatin in the skin, resulting in an extension of the disintegration time limit. The amount of the ginkgo leaf extract in the present application is only 3.6% of the content, and it is evenly mixed in the content after grinding with a colloid mill, reducing the possibility of cross-linking reaction with the gelatin in the skin. After investigation, the present application found that if polyethylene glycol PEG is used as a diluent in the soft capsule content, leakage and extended disintegration time will occur. First, PEG absorbs moisture in the capsule skin, causing the rubber skin to harden, cracking the seams and leaking oil. Second, PEG is easily oxidized during storage to generate low molecular weight aldehydes. Aldehydes are easy to cross-link with gelatin to cause aging, changing the dissolution properties of the capsule shell, and thus slowing down the disintegration time.

[0066] We also found that in addition to the above reasons causing oil leakage at the side seams of the soft capsule, oil leakage often occurs at the bottom of the soft capsule. The bottom oil leakage is often related to the thickness of the capsule skin. If the capsule skin is too thin, the capsule has poor hardness resistance and is prone to leakage during net drying or transportation. However, if the capsule skin is too thick, the disintegration time limit will be extended. For example, when the capsule skin thickness is less than 0.5mm, the soft capsule is very likely to rupture. When the capsule skin thickness is higher than 1.0mm, the disintegration time limit is close to the upper limit of the specified value (60min). Therefore, the thickness of the capsule skin of this application is 0.7mm-1.1mm, which can be 0.8mm, 0.9mm, 1.0mm, 1.1mm. Preferably, 0.7-0.9mm, the thickness of the soft capsule capsule skin is moderate, which can not only tightly encapsulate the contents without rupture, but also effectively shorten the disintegration time limit, and the disintegration time limit is less than 30min.

[0067] One embodiment of the present application is a method for preparing soft capsules in the first aspect of the present application, wherein the shaping temperature, relative humidity and shaping time described in step (3) are the main factors affecting the shaping process, and the shaping process preferably sets the temperature at 22-25°, the relative humidity at 30%-40%, and the shaping time at 8-12 hours, and the soft capsules are moderately soft and hard. The drying process of the soft capsules is affected by the ambient temperature, relative humidity and drying time. The preferred environment requires a temperature of 25-28° and a relative humidity of 20%-30%. The drying time is 12-24 hours, the capsule skin is moderately soft and hard, there is no adhesion phenomenon, and the disintegration time limit is less than 20 minutes. If the drying time is less than 12 hours, the capsule skin may adhere, and if the drying time is greater than 24 hours, the capsule skin is relatively hard.

[0068] In one embodiment of the present application, the method for preparing soft capsules according to the first aspect of the present application, step (3) further comprises one or more of pill washing, pill rubbing, pill selection, inner packaging, and outer packaging.

[0069] The pill washing is performed between the shaping and drying steps, and the pill washing solvent includes 75-95% ethanol.

[0070] In one embodiment of the present application, a method for preparing a soft capsule for regulating blood lipids and preventing atherosclerosis comprises the following steps:

[0071] (1) Preparation of soft capsule contents:

[0072] Weigh soybean oil and beeswax and heat them to 70°C, wait for the beeswax to melt, stir evenly, add the Chinese medicine composition when the temperature drops to 35-40°C, stir and mix for 20 minutes, grind twice through a colloid mill, filter with a 120-mesh sieve, evacuate the filtrate (-0.07 to -0.08Mpa) to remove all bubbles, keep warm at 35-40°C for later use; the Chinese medicine composition comprises red yeast rice, grape seed extract, and ginkgo leaf extract in a mass ratio of 180:80:25;

[0073] (2) Preparation of soft capsule coating solution

[0074] Weigh gelatin, glycerin and water in a mass ratio of 1:0.4:1, heat to 65-75°C, stir evenly after gelatin is completely swollen, add red iron oxide, continue to stir evenly, filter with a 100-mesh nylon sieve, vacuum the filtrate (-0.07~-0.08Mpa) to degas, keep warm at 50-55°C, and set aside;

[0075] (3) Preparation of soft capsules

[0076] The above contents and the glue liquid are pressed into pellets, the room temperature is 20-24°C, the relative humidity is 30%-40%, the air supply temperature of the machine head is 8°C, the temperature of the glue box is 50°C-55°C, the temperature of the nozzle is 40°C-47°C, the capsule skin thickness is 0.7-0.9mm, and the weight of each pellet is 0.7g;

[0077] The formed soft capsules are shaped in a rolling cage for 8-12 hours at a temperature of 22-25°C and a relative humidity of 30%-40%. After shaping, the pills are washed with 95% ethanol and dried in a drying room for 12-16 hours at a temperature of 25-28°C and a relative humidity of 20%-30%. After pill selection, packaging and inspection, the finished product is obtained.

[0078] In a third aspect, the present application provides a soft capsule for regulating blood lipids and preventing atherosclerosis, which is prepared by the preparation method described in the first aspect.

[0079] The fourth aspect of the present application provides the use of the soft capsules described in the second and third aspects in the preparation of lipid-regulating drugs and / or health products.

[0080] The soft capsules described in the second and third aspects of the present application are used in the preparation of drugs and / or health products for lowering triglycerides, lowering cholesterol, lowering low-density lipoprotein cholesterol and / or increasing high-density lipoprotein cholesterol.

[0081] The use of the soft capsules described in the second and third aspects of the present application in the preparation of drugs or health products for preventing atherosclerosis.

[0082] The daily dosage of the soft capsules of the present application is 3-6 g.

[0083] Beneficial Effects

[0084] 1. The soft capsule of the present application is made of red yeast rice, grape seed extract and ginkgo leaf extract as raw materials through modern processing. The ginkgo leaf extract in the formula contains total flavonoids and terpenoid lactones, and the grape seed extract contains a large amount of proanthocyanidins, monomer polyphenols such as catechins and epicatechins. The present application uses red yeast rice and ginkgo leaf together to "remove dampness and eliminate phlegm, promote blood circulation and remove blood stasis", improve "blood stasis" and "chest obstruction", reduce total cholesterol, triglycerides, and low-density lipoprotein cholesterol content, and have the effect of assisting in lowering blood lipids. In addition, grape seed extract can increase high-density lipoprotein cholesterol content, which not only cooperates with the blood lipid-lowering effect of red yeast rice and ginkgo leaf extract, but also has the effect of preventing atherosclerosis. Because high-density lipoprotein is a lipoprotein that resists atherosclerosis, it can promote the elimination of cholesterol in peripheral tissues and prevent the risk of atherosclerosis.

[0085] 2. This application only selects soybean oil and beeswax as dispersion medium according to the soft capsule content, and does not use PEG, water, etc. as dispersion medium, so the prescription is simpler and the drug loading of the preparation is higher. During the screening process, it was found that if the soft capsule content contains PEG and the Chinese medicine composition of this application is made into the content, it will absorb the moisture in the rubber skin and accelerate the aging of the soft capsule skin. When the stability test is about 1 year, problems will occur in disintegration, such as the extension of the disintegration time limit.

[0086] 3. The capsule skin formula, content formula and compression parameters selected in this application, the extraction temperature of ginkgo leaf extract and grape seed extract in the traditional Chinese medicine composition, macroporous resin column chromatography, spray drying parameter settings, and content preparation parameters such as the use of colloid mills, etc., the prepared soft capsules have no bubbles, no oil leakage, good stability, and a disintegration time of less than 30 minutes.

[0087] 4. The prescription of the present application is effective, simple and inexpensive. After grape seed extract replaces most of the ginkgo leaf extract, the blood lipid regulating effect of the Chinese medicine composition is not reduced, but it has the effect of increasing high-density lipoprotein cholesterol and preventing atherosclerosis. The price of grape seed extract is much lower than that of ginkgo leaf extract, and the production cost is greatly reduced, thereby reducing the cost of daily treatment or health care for patients, and the patient's compliance is better and the popularity is better.

[0088] 5. After replacing a large amount of ginkgo leaf extract with a large amount of grape seed extract in the present application, since the amount of ginkgo leaf extract in the soft capsule is small, its flavonoid component is low, which avoids the cross-linking reaction between aldehyde components and capsule gelatin, and has better stability. DETAILED DESCRIPTION

[0089] The following examples will help to understand the present invention, but they are not intended to limit the scope of the present invention. The following discloses some embodiments of the present invention, and those skilled in the art can appropriately improve the process parameters according to the content of this article. It is particularly important to point out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0090] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0091] Example 1

[0092] (1) Preparation of soft capsule contents:

[0093] Weigh 387g soybean oil and 28g beeswax and heat to 70°C, wait for the beeswax to melt, stir evenly, add the Chinese medicine composition when the temperature drops to 35°C-40°C, stir and mix for 20min with a stirring paddle, grind twice with a colloid mill, filter with a 120-mesh sieve, vacuum the filtrate (-0.07 to -0.08Mpa) to remove all bubbles, keep warm at 35°C-40°C for later use; the Chinese medicine composition comprises 180g red yeast rice, 80g grape seed extract, and 25g ginkgo leaf extract;

[0094] (2) Preparation of soft capsule coating solution:

[0095] Weigh 300g of gelatin, 120g of glycerin, and 300g of water, heat to 65-75°C, stir evenly after the gelatin is completely swollen, add 1.25g of red iron oxide, continue to stir evenly, filter through a 100-mesh nylon sieve, vacuum the filtrate (-0.07 to -0.08Mpa) to degas, keep warm at 50-55°C, and set aside;

[0096] (3) Preparation of soft capsules:

[0097] The above contents and the glue liquid are pressed into pellets, the room temperature is 20°C-24°C, the relative humidity is 30%-40%, the head air supply temperature is 8°C-12°C, the glue box temperature is 50°C-55°C, the nozzle temperature is 40°C-47°C, the capsule skin thickness is 0.7mm, and 1000 pellets are made, each pellet has a content of 0.7g;

[0098] The formed soft capsules are shaped in a tumbling cage for 8-12 hours at a temperature of 22°C-25°C and a relative humidity of 30%-40%. After shaping, the capsules are washed with 95% ethanol and dried in a drying room for 12-16 hours at a temperature of 25°C-28°C and a relative humidity of 20%-30%. After pill selection, packaging and inspection, the finished product is obtained.

[0099] Example 2

[0100] (1) Preparation of soft capsule contents:

[0101] Weigh 387g corn oil and 28g beeswax and heat to 70°C, wait for the beeswax to melt, stir evenly, add the Chinese medicine composition when the temperature drops to 35-40°C, stir and mix with a stirring paddle for 20min, stir evenly, grind twice with a colloid mill, filter with a 120-mesh sieve, vacuum the filtrate (-0.07 to -0.08Mpa) to remove all bubbles, keep warm at 35-40°C for later use; the Chinese medicine composition comprises 180g red yeast rice, 80g grape seed extract, and 25g ginkgo leaf extract;

[0102] (2) Preparation of soft capsule coating solution

[0103] Weigh 300g of gelatin, 120g of glycerin, and 300g of water, heat to 65-75°C, stir evenly after the gelatin is completely swollen, then add 1.25g of red iron oxide, continue to stir evenly, filter through a 100-mesh nylon sieve, vacuum the filtrate (-0.07 to -0.08Mpa) to degas, keep warm at 50-55°C, and set aside;

[0104] (3) Preparation of soft capsules

[0105] The above contents and the glue liquid are pressed into pellets, the room temperature is 20-24°C, the relative humidity is 30%-40%, the head air supply temperature is 8-12°C, the glue box temperature is 50-55°C, the nozzle temperature is 40-47°C, the capsule skin thickness is 0.8mm, and 1000 pellets are made, each pellet has a content of 0.7g;

[0106] The formed soft capsules are shaped in a tumbling cage for 8-12 hours at a temperature of 22-25°C and a relative humidity of 30%-40%. After shaping, the pills are washed with 95% ethanol and dried in a drying room for 12-16 hours at a temperature of 25-28°C and a relative humidity of 20%-30%. After pill selection, packaging and inspection, the finished product is obtained.

[0107] Example 3

[0108] (1) Preparation of soft capsule contents:

[0109] Weigh 387g soybean oil and 28g beeswax and heat to 70°C, wait for the beeswax to melt, stir evenly, add the Chinese medicine composition when the temperature drops to 35°C-40°C, mix for 20min, stir evenly, grind twice with a colloid mill, filter with a 120-mesh sieve, evacuate the filtrate (-0.07 to -0.08Mpa) to remove all bubbles, keep warm at 35°C-40°C for later use; the Chinese medicine composition comprises 170g red yeast rice, 25g ginkgo leaf extract, and 70g grape seed extract;

[0110] (2) Preparation of soft capsule coating solution:

[0111] Weigh 300g of gelatin, 120g of glycerin, and 300g of water, heat to 65-70°C, stir evenly after the gelatin is completely swollen, add 1.25g of red iron oxide, continue to stir evenly, filter through a 100-mesh nylon sieve, vacuum the filtrate (-0.07 to -0.08Mpa) to degas, keep warm at 50-55°C, and set aside;

[0112] (3) Preparation of soft capsules:

[0113] The above contents and the glue liquid are pressed into pellets, the room temperature is 20°C-24°C, the relative humidity is 30%-40%, the head air supply temperature is 8°C-12°C, the glue box temperature is 50°C-55°C, the nozzle temperature is 40°C-47°C, the capsule skin thickness is 0.9mm, and 1000 pellets are made, each pellet has a content of 0.7g;

[0114] The formed soft capsules are shaped in a tumbling cage for 8-12 hours at a temperature of 22°C-25°C and a relative humidity of 30%-40%. After shaping, the capsules are washed with 95% ethanol and dried in a drying room for 12-16 hours at a temperature of 25°C-28°C and a relative humidity of 20%-30%. After pill selection, packaging and inspection, the finished product is obtained.

[0115] Example 4

[0116] (1) Preparation of soft capsule contents:

[0117] Weigh 387g soybean oil and 28g beeswax and heat them to 70°C. When the beeswax is melted, stir evenly. When the temperature drops to 35°C-40°C, add the Chinese medicine composition, mix for 20min, stir evenly, grind twice with a colloid mill, filter with a 120-mesh sieve, evacuate the filtrate (-0.07 to -0.08Mpa) to remove all bubbles, keep warm at 35°C-40°C for later use; the Chinese medicine composition comprises 200g red yeast rice, 35g ginkgo leaf extract, and 100g grape seed extract;

[0118] (2) Preparation of soft capsule coating solution:

[0119] Weigh 300g of gelatin, 120g of glycerin, and 300g of water, heat to 70-75°C, stir until the gelatin is completely swollen, add 1.25g of red iron oxide, continue to stir, filter through a 100-mesh nylon mesh, vacuum the filtrate (-0.07 to -0.08Mpa) to degas, keep warm at 50-55°C, and set aside;

[0120] (3) Preparation of soft capsules:

[0121] The above contents and the glue liquid are pressed into pellets, the room temperature is 20°C-24°C, the relative humidity is 30%-40%, the head air supply temperature is 8°C-12°C, the glue box temperature is 50°C-55°C, the nozzle temperature is 40°C-47°C, the capsule skin thickness is 0.7-0.9mm, and 1000 pellets are made, each pellet has a content of 0.7g;

[0122] The formed soft capsules are shaped in a tumbling cage for 8-12 hours at a temperature of 22°C-25°C and a relative humidity of 30%-40%. After shaping, the capsules are washed with 95% ethanol and dried in a drying room for 12-16 hours at a temperature of 25°C-28°C and a relative humidity of 20%-30%. After pill selection, packaging and inspection, the finished product is obtained.

[0123] Example 5

[0124] (1) Preparation of soft capsule contents:

[0125] Weigh 193.5 g soybean oil and 12 g beeswax and heat to 70° C., wait for the beeswax to melt, stir evenly, add 142.5 g of the Chinese medicine composition when the temperature drops to 35° C.-40° C., mix for 20 min, stir evenly, grind twice with a colloid mill, filter with a 120-mesh sieve, evacuate the filtrate (-0.07 to -0.08 MPa) to remove all bubbles, keep warm at 35° C.-40° C. for later use; the Chinese medicine composition comprises 90 g red yeast rice, 40 g grape seed extract and ginkgo leaf extract, and 12.5 g ginkgo leaf extract;

[0126] (2) Preparation of soft capsule coating solution

[0127] Weigh 150g of gelatin, 60g of glycerin and 150g of water, heat to 65-75℃, stir evenly after the gelatin is completely swollen, add 0.6g of red iron oxide, continue to stir evenly, filter with a 100-mesh nylon mesh, vacuum the filtrate (-0.07~-0.08Mpa) to degas, keep warm at 50-55℃, and set aside;

[0128] (3) Preparation of soft capsules

[0129] The above contents and the glue liquid are pressed into pellets, the room temperature is 20°C-24°C, the relative humidity is 30%-40%, the head air supply temperature is 8°C-12°C, the glue box temperature is 50°C-55°C, the nozzle temperature is 40°C-47°C, the capsule skin thickness is 0.7-0.9mm, and 440 pellets are made, each pellet has a content of 0.8g;

[0130] The formed soft capsules are shaped in a tumbling cage for 8-12 hours at a temperature of 22°C-25°C and a relative humidity of 30%-40%. After shaping, the capsules are washed with 95% ethanol and dried in a drying room for 12-16 hours at a temperature of 25°C-28°C and a relative humidity of 20%-30%. After pill selection, packaging and inspection, the finished product is obtained.

[0131] Example 6

[0132] (1) Preparation of soft capsule contents:

[0133] Weigh 193.5 g soybean oil and 14 g beeswax and heat to 70° C., wait for the beeswax to melt, stir evenly, add 142.5 g of the Chinese medicine composition when the temperature drops to 35° C.-40° C., mix for 20 min, stir evenly, grind twice with a colloid mill, filter with a 120-mesh sieve, evacuate the filtrate (-0.07 to -0.08 MPa) to remove all bubbles, keep warm at 35° C.-40° C. for later use; the Chinese medicine composition comprises 90 g red yeast rice, 40 g grape seed extract ginkgo leaf extract, and 12.5 g ginkgo leaf extract;

[0134] (2) Preparation of soft capsule coating solution:

[0135] Weigh 150g of gelatin, 60g of glycerin and 150g of water, heat to 65-75°C, stir until the gelatin is completely swollen, add 0.6g of red iron oxide, continue to stir, filter with a 100-mesh nylon mesh, vacuum the filtrate (-0.07 to -0.08Mpa) for degassing, keep warm at 50-55°C, and set aside;

[0136] (3) Preparation of soft capsules:

[0137] The above contents and the glue liquid are pressed into pellets, the room temperature is 20℃-24℃, the relative humidity is 30%-40%, the head air supply temperature is 8℃-12℃, the glue box temperature is 50℃-55℃, the nozzle temperature is 40℃-47℃, the capsule skin thickness is 0.7-0.9mm, and 400 pellets are made, each pellet has a content of about 0.8g;

[0138] The formed soft capsules are shaped in a tumbling cage for 8-12 hours at a temperature of 22°C-25°C and a relative humidity of 30%-40%. After shaping, the capsules are washed with 95% ethanol and dried in a drying room for 12-16 hours at a temperature of 25°C-28°C and a relative humidity of 20%-30%. The finished product is then obtained after pill selection, packaging and inspection.

[0139] Example 7

[0140] (1) Preparation of soft capsule contents:

[0141] Weigh 203.5 g soybean oil and 18 g beeswax and heat to 70° C., stir evenly when the beeswax is melted, add 142.5 g of the Chinese medicine composition when the temperature drops to 35° C.-40° C., mix for 20 min, stir evenly, grind twice with a colloid mill, filter with a 120-mesh sieve, evacuate the filtrate (-0.07 to -0.08 MPa) to remove all bubbles, keep warm at 35° C.-40° C. for later use; the Chinese medicine composition consists of 90 g red yeast rice, 40 g grape seed extract and ginkgo leaf extract, and 12.5 g ginkgo leaf extract;

[0142] (2) Preparation of soft capsule coating solution:

[0143] Weigh 150g of gelatin, 60g of glycerin and 150g of water, heat to 65-75℃, stir evenly after the gelatin is completely swollen, add 0.5g of red iron oxide, continue to stir evenly, filter with a 100-mesh nylon mesh, vacuum the filtrate (-0.07~-0.08Mpa) to degas, keep warm at 50-55℃, and set aside;

[0144] (3) Preparation of soft capsules:

[0145] The above contents and the glue liquid are pressed into pellets, the room temperature is 20℃-24℃, the relative humidity is 30%-40%, the head air supply temperature is 8℃-12℃, the glue box temperature is 50℃-55℃, the nozzle temperature is 40℃-47℃, the capsule skin thickness is 0.7-0.9mm, and 500 pellets are made, each pellet has a content of about 0.8g;

[0146] The formed soft capsules are shaped in a tumbling cage for 8-12 hours at a temperature of 22°C-25°C and a relative humidity of 30%-40%. After shaping, the capsules are washed with 95% ethanol and dried in a drying room for 12-16 hours at a temperature of 25°C-28°C and a relative humidity of 20%-30%. After pill selection, packaging and inspection, the finished product is obtained.

[0147] Example 8

[0148] (1) Preparation of soft capsule contents:

[0149] Weigh 213.5 g soybean oil and 20 g beeswax and heat to 70° C., stir evenly when the beeswax is melted, add 142.5 g of the Chinese medicine composition when the temperature drops to 35° C., mix for 20 min, stir evenly, grind twice with a colloid mill, filter with a 120-mesh sieve, evacuate the filtrate (-0.07 to -0.08 MPa) to remove all bubbles, keep warm at 35° C.-40° C. for later use; the Chinese medicine composition comprises 90 g red yeast rice, 40 g grape seed extract and ginkgo leaf extract, and 12.5 g ginkgo leaf extract;

[0150] (2) Preparation of soft capsule coating solution:

[0151] Weigh 150g of gelatin, 60g of glycerin and 150g of water, heat to 65-75°C, stir until the gelatin is completely swollen, add 0.5g of red iron oxide, continue to stir, filter through a 100-mesh nylon mesh, vacuum the filtrate (-0.07 to -0.08Mpa) to degas, keep warm at 50-55°C, and set aside;

[0152] (3) Preparation of soft capsules:

[0153] The above contents and the glue liquid are pressed into pellets, the room temperature is 20℃-24℃, the relative humidity is 30%-40%, the head air supply temperature is 8℃-12℃, the glue box temperature is 50℃-55℃, the nozzle temperature is 40℃-47℃, the capsule skin thickness is 0.7-0.9mm, and 500 pellets are made, each pellet has a content of about 0.8g;

[0154] The formed soft capsules are shaped in a tumbling cage for 8-12 hours at a temperature of 22°C-25°C and a relative humidity of 30%-40%. After shaping, the capsules are washed with 95% ethanol and dried in a drying room for 12-16 hours at a temperature of 25°C-28°C and a relative humidity of 20%-30%. The finished product is then obtained after pill selection, packaging and inspection.

[0155] Example 9

[0156] (1) Preparation of soft capsule contents:

[0157] Weigh 387g soybean oil and 28g beeswax and heat to 70°C, wait for the beeswax to melt, stir evenly, add the Chinese medicine composition when the temperature drops to 35°C, mix for 30min, stir evenly, grind twice with a colloid mill, filter with a 120-mesh sieve, evacuate the filtrate (-0.07 to -0.08Mpa) to remove all bubbles, keep warm at 35°C-40°C for later use; the Chinese medicine composition comprises 180g red yeast rice, 80g grape seed extract and 25g ginkgo leaf extract;

[0158] (2) Preparation of soft capsule coating solution

[0159] Weigh 300g of gelatin, 120g of glycerin, and 300g of water, heat to 65-75°C, stir evenly after the gelatin is completely swollen, add 1.25g of red iron oxide, continue to stir evenly, filter through a 100-mesh nylon sieve, vacuum the filtrate (-0.07 to -0.08Mpa) to degas, keep warm at 50-55°C, and set aside;

[0160] (3) Preparation of soft capsules

[0161] The above contents and the glue liquid are pressed into pellets, the room temperature is 20℃-24℃, the relative humidity is 30%-40%, the head air supply temperature is 8℃-12℃, the glue box temperature is 50℃-55℃, the nozzle temperature is 40℃-47℃, the capsule skin thickness is 0.7-0.9mm, and 1000 pellets are made, each pellet has a content of about 0.7g;

[0162] The formed soft capsules are shaped in a tumbling cage for 8-12 hours at a temperature of 22°C-25°C and a relative humidity of 30%-40%. After shaping, the capsules are washed with 95% ethanol and dried in a drying room for 12-16 hours at a temperature of 25°C-28°C and a relative humidity of 20%-30%. The finished product is then obtained after pill selection, packaging and inspection.

[0163] Example 10

[0164] (1) Preparation of soft capsule contents:

[0165] Weigh 387g soybean oil and 28g beeswax and heat to 70°C, wait for the beeswax to melt, stir evenly, add the Chinese medicine composition when the temperature drops to 35°C-40°C, mix for 30min, stir evenly, grind twice with a colloid mill, filter with a 120-mesh sieve, vacuum the filtrate (-0.07 to -0.08Mpa) to remove all bubbles, keep warm at 35°C-40°C for later use; the Chinese medicine composition comprises 180g red yeast rice, 80g grape seed extract and 25g ginkgo leaf extract;

[0166] (2) Preparation of soft capsule coating solution

[0167] Weigh 300g of gelatin, 150g of glycerin, and 300g of water, heat to 65-75°C, stir until the gelatin is completely swollen, add 1.25g of red iron oxide, continue to stir, filter through a 100-mesh nylon sieve, vacuum the filtrate (-0.07 to -0.08Mpa) to degas, keep warm at 50-55°C, and set aside;

[0168] (3) Preparation of soft capsules

[0169] The above contents and the glue liquid are pressed into pellets, the room temperature is 20℃-24℃, the relative humidity is 30%-40%, the head air supply temperature is 8℃-12℃, the glue box temperature is 50℃-55℃, the nozzle temperature is 40℃-47℃, the capsule skin thickness is 0.7-0.9mm, and 1000 pellets are made, each pellet has a content of about 0.7g;

[0170] The formed soft capsules are shaped in a tumbling cage for 8-12 hours at a temperature of 22°C-25°C and a relative humidity of 30%-40%. After shaping, the capsules are washed with 95% ethanol and dried in a drying room for 12-16 hours at a temperature of 25°C-28°C and a relative humidity of 20%-30%. The finished product is then obtained after pill selection, packaging and inspection.

[0171] Embodiment 11

[0172] Polyethylene glycol 600 was used to replace the beeswax in Example 5. Other ingredients and operating steps were the same as those in Example 5.

[0173] Example 12

[0174] Soybean lecithin was used to replace the beeswax in Example 5. Other ingredients and operating steps were the same as those in Example 5.

[0175] Embodiment 13

[0176] Take 170g of red yeast rice, 70g of grape seed extract, and 15g of ginkgo leaf extract; other ingredients and operating steps are the same as those in Example 1.

[0177] Embodiment 14

[0178] Take 200g of red yeast rice, 100g of grape seed extract, 35g of ginkgo leaf extract, and 387g of olive oil; other ingredients and operating steps are the same as those in Example 1.

[0179] Test example

[0180] Test Example 1 Soft Capsule Stability Test Method: The sample of Example 1 was placed at a temperature of 37±1°C and a relative humidity of 75% for 3 months to detect properties, active ingredient content, disintegration time, etc.

[0181] (I) Determination of Lovastatin Content

[0182] 1. Principle: Lovastatin in the sample is extracted with water at pH=3, then extracted with chloroform, separated by a C18 column in a high performance liquid chromatograph, and detected by 238nm ultraviolet absorption. The retention time is compared with that of the standard for qualitative analysis, and the peak area external standard method is used for quantitative analysis.

[0183] 2. Reagents: Lovastatin standard, chloroform, phosphoric acid, methanol

[0184] 3. Instruments

[0185] Chromatographic system: ThermoU3000 high performance liquid chromatograph.

[0186] Chromatographic conditions:

[0187] Chromatographic column: Shim-pack VO-ODS (C18) column, 4.6 mm × 250 mm, 5 μm; mobile phase: methanol: water: phosphoric acid

[0188] =385:115:0.14; detection wavelength: 238nm; column temperature: 30°0; flow rate: 1.0mL / min.

[0189] Preparation of test solution: Take 20 soft capsules, mix them, accurately weigh about 2.0g, put them in a 50mL centrifuge tube, add 10.0mL of pH=3 phosphoric acid aqueous solution, ultrasonically extract for 10min, then add 10.0mL of chloroform, put them in a vortex mixer and mix them for 3min, remove the upper aqueous phase after standing, centrifuge the chloroform layer at 300Orpm / min for 3min. Accurately pipette 1mL to 5mL of supernatant into a test tube, place the test tube in a water bath at about 50°, use a vacuum pump to reduce pressure and dry until all solvents are evaporated, add 80% methanol-water to the test tube and make it up to 5mL, mix thoroughly, and filter through a 0.45μm filter membrane to obtain the test solution.

[0190] Preparation of reference solution: Accurately weigh 10.09 mg of lovastatin reference substance, place it in a 50 mL volumetric flask, add 80% methanol-water to dissolve it, dilute to the scale, shake well, and obtain a lovastatin standard solution with a concentration of 200.59 μg / mL.

[0191] Determination method: Pipette 10 μl of the test solution and the reference solution and inject them into the liquid chromatograph, and perform the determination according to the above instrument conditions. Determine the content of lovastatin in the sample by the external standard method.

[0192] Result calculation: X = (C × V × 100) / (m × 1000)

[0193] Wherein: X-Lovastatin content in sample (mg / 100g);

[0194] m-sample mass (g);

[0195] V-sample fixed volume (mL);

[0196] C--The concentration of lovastatin in the test solution was determined by external standard method (μg / mL).

[0197] (II) Determination method of proanthocyanidin content

[0198] Preparation of test solution: squeeze out the contents of 20 capsules and stir evenly. Accurately weigh about 50 mg, place in a small beaker, stir with 20 mL of methanol several times, place in a 50 mL volumetric flask until the methanol extract is colorless, add methanol to the scale, and shake well.

[0199] Preparation of standard solution: Weigh 10.02 mg of proanthocyanidin reference substance and dissolve it in 10 mL of methanol to prepare a proanthocyanidin standard solution with a concentration of 0.990 mg / mL.

[0200] b. Standard curve: pipette 0, 0.1, 0.25, 0.5, 1.0, and 1.5 mL of proanthocyanidin standard solution into 6 10 mL volumetric flasks, add methanol to the scale, and shake well.

[0201] Color development and drawing of standard curve: After mixing n-butanol and hydrochloric acid in a volume ratio of 95:5, take out 6mL and place it in a 10mL stoppered colorimetric tube, then add 0.2mL ammonium ferric sulfate solution and 1mL standard solution, mix well, heat in a boiling water bath for 40 minutes, and immediately cool in ice water. After 15 minutes, measure the absorbance at a wavelength of 546nm. Use methanol color development reaction solution as a blank and record the absorbance of different concentrations of proanthocyanidin standard solutions. Use proanthocyanidin concentration (μg / mL) as the horizontal axis (X) and absorbance value (A) as the vertical axis (Y) to draw a standard working curve and obtain the standard curve equation.

[0202] (3) Determination: After mixing n-butanol and hydrochloric acid in a volume ratio of 95:5, take out 6 mL and place it in a 10 mL stoppered colorimetric tube, then add 0.2 mL of ammonium ferric sulfate solution and 1 mL of sample solution, mix well, heat in a boiling water bath for 40 minutes, immediately cool in ice water, and measure the absorbance at a wavelength of 546 nm after 15 minutes. Calculate the content of proanthocyanidins in the sample from the standard curve.

[0203] (4) Calculation of results:

[0204]

[0205] Where: C = content calculated according to the standard curve equation (ug / mL);

[0206] V-total volume of sample solution (mL);

[0207] W-sample mass (g).

[0208] (3) Determination method of total flavonol glycosides content: refer to the total flavonol glycosides method under the "Ginkgo Leaf Extract" in the 2020 edition of the "Chinese Pharmacopoeia".

[0209] Test items and results: see Table 1

[0210] Table 1 Stability test data

[0211]

[0212]

[0213] Test Example 2 Screening of diluent

[0214] Test method: The excipients in Table 2 were screened as diluents. Except for the different diluents, other excipients and process preparation were the same as those in Example 1. The soft capsules were placed at a temperature of 25°C-28°C and a relative humidity of 20%-30% for 3 months to examine the process, appearance, oil leakage and hardness of the soft capsules prepared with different diluents.

[0215] Test results: See Table 2. It can be seen from Table 2 that the Chinese medicine composition is well dispersed in both soybean oil and corn oil, which can ensure smooth compression, low cost, good stability, and moderate hardness and no oil leakage when placed at a temperature of 25℃-28℃ and a relative humidity of 20%-30% for 3 months. The disintegration time does not change in 3 months. Using polyethylene glycol 400 as a diluent, the hardness is hard at 25-28℃ and a relative humidity of 20%-30% for 3 months, and there is leakage in the gap. The disintegration time is greater than 30min in 3 months, and the disintegration time is extended. Guessed reasons: First, PEG easily absorbs moisture in the capsule skin, causing the rubber skin to harden, the seams to crack and leak oil. Second, PEG is easily oxidized during storage to generate low molecular weight aldehydes. Aldehydes easily undergo cross-linking reactions with gelatin to cause aging, which changes the dissolution properties of the capsule shell, thereby slowing down the disintegration time.

[0216] Table 2 Screening test of diluent

[0217]

[0218]

[0219] Test Example 3 Selection of suspending agent type and diluent dosage

[0220] Purpose of the experiment: When compressing soft capsules, the fluidity of the liquid directly affects the preparation and filling accuracy of the soft capsules. The mixing state of the contents affects the uniformity of the distribution of the active ingredients. Therefore, the types and proportions of raw materials, soybean oil and suspending agents in the contents are screened.

[0221] Test method: Heat to 70°C according to the formula in Table 3 to melt the suspending agent and stir evenly. When the temperature drops to 35°C-40°C, add about 142.5g of the Chinese medicine composition, stir evenly, and let it stand for 48 hours to examine its sedimentation ratio (take 50mL of the mixed solution and place it in a stoppered measuring cylinder with the same diameter. After shaking for 1 minute, measure the original height Ho and the sedimentation height Hu after standing, sedimentation ratio F=Hu / Ho) and fluidity (take an appropriate amount of the mixed solution with a medicine spoon, the medicine spoon is at 45° to the horizontal plane, and observe the dripping of the mixed solution from the medicine spoon).

[0222] Test results: See Table 3. As can be seen from Table 3, the formulas of Examples 5-8 and 11-12 have good fluidity, are easier to drip from a medicine spoon, are convenient for filling, and thus the soft capsule is accurately filled. The 48-hour sedimentation ratio of the formulas of Examples 5-8 and 11-12 is greater than 0.9, indicating that the fluidity and stability of the formulas of Examples 5-8 and 11-12 are both good, which is conducive to the manufacture of soft capsule contents. However, the Chinese medicine composition of the present application contains flavonoid components. In order to avoid cross-linking reaction between aldehyde groups and gelatin, the preferred suspending agents are beeswax and soybean lecithin, and the more preferred suspending agent is beeswax according to the sedimentation ratio.

[0223] The amount of beeswax has an effect on fluidity and sedimentation ratio. Preferably, the mass ratio of Chinese medicine composition: vegetable oil: beeswax is (3.0-4.0): (4.5-5.5): (0.3-0.5). According to the principle of minimizing the number of auxiliary materials, preferably, the mass ratio of Chinese medicine composition: vegetable oil: beeswax is (3.4-3.6): (4.8-5.1): (0.35-0.45).

[0224] Table 3 Selection of suspending agents and dosage

[0225]

[0226]

[0227] Note: ++Good fluidity, easy to flow down from the medicine spoon; +Good fluidity, easy to drip from the medicine spoon: -

[0228] Viscous and poor fluidity.

[0229] Experimental Example 4 Investigation of the stirring and mixing time of the soft capsule contents

[0230] Test sample: Take 387g soybean oil and 28g beeswax and heat them to 70℃ to melt the beeswax and stir evenly. When the temperature drops to 35℃-40℃, add 180g red yeast rice, 80g grape seed extract and 25g ginkgo leaf extract. Mix three times with a stirring paddle for 10min, 20min and 30min. Take samples at 5 different positions at different times and measure the amount of proanthocyanidins to further investigate the effect of stirring time on mixing uniformity.

[0231] Test results: See Table 4. The above results show that after mixing for 20 minutes or 30 minutes, the samples taken from different parts of the mixer have uniform color and similar proanthocyanidin content, indicating that they have been mixed evenly. However, considering saving working hours and reducing energy consumption, the mixing time of 20 minutes was selected.

[0232] Table 4 Mixing process investigation results

[0233]

[0234] Test Example 5 Verification experiment of mixing the contents of soft capsules uniformly

[0235] Test sample: Take 387g soybean oil and 28g beeswax and heat them to 70℃ to melt the beeswax and stir evenly. When the temperature drops to 35℃-40℃, add 180g red yeast rice, 80g grape seed extract and 25g ginkgo leaf extract, stir and mix for 20 minutes, take 5 samples at different positions, and measure the amount of proanthocyanidins.

[0236] Test results: see Table 5. After mixing for 20 minutes, the samples taken from different parts of the mixer had uniform color and similar proanthocyanidin content, with RSD (%) less than 2.0%, indicating that the mixing process was uniform.

[0237] Table 5 Mixing process verification results

[0238] Serial number 1 2 3 4 5 RSD(%) Proanthocyanidins (g / 100g) 12.6 12.3 12.5 12.1 12.4 1.55

[0239] Test Example 6 Screening of Soft Capsule Shell Formula

[0240] Test method: The soft capsule shell formula is according to Table 6, heated to 65-70℃ and mixed, and the gelatin is completely swollen after absorbing water, stirred evenly, and then placed in an ultrasonic oscillator to eliminate bubbles, and evenly spread on a glass plate in a liquid state to make the thickness uniform, about 0.7-0.9mm, and dried into a soft film, cut into small pieces of 2cm×2cm, and examine its softness and hardness.

[0241] Test results: As can be seen from Table 6, when the ratio of glycerol to gelatin is less than 0.3:1.0, the glue produced is too hard; if it reaches 0.7-0.8:1.0, the glue produced is too soft; in the formulas of Example 1 and Example 10, the ratio of gelatin, glycerol and purified water is 1:0.4-0.5:1, and the hardness of the rubber is moderate, so the formula with less glycerol is selected, that is, the ratio of gelatin: glycerol: purified water is 1:0.4:1, which is the best.

[0242] Table 6 Screening of soft capsule skin formula

[0243] Components Comparative Example 6 Example 1 Example 10 Comparative Example 7 Comparative Example 8 Comparative Example 9 Gelatin(g) 300 300 300 300 300 300 glycerin 90 120 150 180 210 240 Purified water 300 300 300 300 300 300 The proportion of the three 1:0.3:1 1:0.4:1 1:0.5:1 1:0.6:1 1:0.7:1 1:0.8:1 hardness hard Moderate Moderate soft Too soft Too soft

[0244] Test Example 7 Screening Test for Capsule Thickness

[0245] Test method: The compression test was carried out according to the capsule skin thickness set in Table 7. The compression method was the same as in Example 1. The disintegration time and appearance were used as indicators for investigation.

[0246] Disintegration time: Based on the disintegration time inspection method in Part IV General Rules 0921 of the Pharmacopoeia of the People's Republic of China (2015 edition).

[0247] Test results: see Table 7. As can be seen from Table 7, 0.7-0.9 mm as the capsule skin thickness can not only encapsulate the contents tightly, but also effectively shorten the disintegration time.

[0248] Table 7 Results of investigation on capsule skin thickness

[0249] Thickness of capsule(mm) Disintegration time (min) Appearance 0.3 2 The cyst is thin and easily ruptured 0.5 6 The cyst skin is thin and has a few ruptures 0.7 9 The cyst skin is moderately thick and has no ruptures. 0.9 20 The cyst skin is moderately thick and has no ruptures. 1.1 55 After encapsulation, the disintegration time is close to the upper limit of the specified value

[0250] Test Example 8 Screening of Styling Parameters

[0251] Test method: The temperature of the product setting process is set at 22-25°C and the relative humidity is 30%-40%. The appearance of the soft capsule is used as an indicator to examine the effect of the setting time on the product quality.

[0252] Test results: As shown in Table 8, the soft capsules of this product can meet the setting requirements in an environment with a temperature of 22°C to 25°C and a relative humidity of 30% to 40% for 8 to 12 hours.

[0253] Table 8 Results of investigation on molding process parameters

[0254]

[0255]

[0256] Test Example 9 Screening of Drying Process Parameters

[0257] Test method: The drying process temperature is set at 25℃~28℃ and the relative humidity is 20%~30%. The disintegration time and appearance are used as indicators to examine the effect of drying time on product quality.

[0258] Test results: When the drying time is 12-24 hours, the capsule skin is moderately hard and soft, and there is no adhesion. When the drying time is less than 12 hours, the capsule skin may be adhered. When the drying time is more than 20 hours, the capsule skin is relatively hard, and the disintegration time is also extended. According to the appearance and disintegration time, the preferred drying time is 12 to 16 hours. The capsule is moderately hard and soft, not easy to deform, and the disintegration time meets the regulations.

[0259] Table 9 Drying process parameter investigation results

[0260] Drying temperature(℃) Relative humidity (%) Setting time (h) Disintegration time (min) Appearance 25-28 20-30 8 43 Capsules are soft and easily deformed 25-28 20-30 12 15 The capsule is moderately hard and not easily deformed 25-28 20-30 16 10 The capsule is moderately hard and not easily deformed 25-28 20-30 20 25 Hard capsule 25-28 20-30 24 ＞30 Hard capsule

[0261] Experimental Example 10 Process Screening of Ginkgo Biloba Extract

[0262] 1. Sample preparation:

[0263] Ginkgo leaf water extract: Take appropriate amount of ginkgo leaf, add water and boil for 3 times, with the solid-liquid ratio of 1:6, 1:5, 1:5 respectively, each time for 1.0h, extraction temperature 80-85℃, filter, concentrate to 80℃ with relative density of 1.15-1.18, spray dry, crush and sieve for later use.

[0264] 30% ethanol extract of Ginkgo biloba leaves: Take an appropriate amount of Ginkgo biloba leaves, add 30% ethanol and reflux extract for 3 times, with the solid-liquid ratio of 1:6, 1:5, 1:5 respectively, each time for 1.0h, extraction temperature 80-85℃, filter, concentrate to 80℃ with a relative density of 1.15-1.18, spray dry, crush and sieve for later use.

[0265] Preparation of extract from ginkgo leaves by 70% ethanol and column chromatography: Take appropriate amount of ginkgo leaves, add 70% ethanol and reflux for 3 times, with the solid-liquid ratio of 1:6, 1:5, 1:5, each time for 1.0h, extraction temperature 80-85℃, filter, concentrate, pass through D101 macroporous resin column, elute with 70% ethanol, collect the eluate, concentrate the eluate to 80℃ with a relative density of 1.15-1.18, spray dry, crush and sieve for later use.

[0266] 2. Content Determination

[0267] (1) Determination method of total flavonol glycosides and terpenoid lactones: refer to the method for total flavonol glycosides and terpenoid lactones under the item "Ginkgo Leaf Extract" in the 2020 edition of the "Chinese Pharmacopoeia".

[0268] (II) Determination method of crude polysaccharide content:

[0269] Preparation of standard solution: Accurately weigh 5 mg of D-anhydrous glucose standard in a 50 mL volumetric flask, add appropriate amount of water to dissolve by ultrasonication and dilute to the scale, shake well to prepare a D-anhydrous glucose standard solution with a concentration of 0.1 mg / mL.

[0270] Standard curve: Pipette 0, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0mL of D-anhydrous glucose standard solution into a 25mL colorimetric tube, add water to 2.0mL, add 1.0mL of 5% phenol solution, mix well on a vortex mixer, carefully add 10mL of concentrated sulfuric acid, carefully mix well on a vortex mixer, place in a boiling water bath for 2min, cool to room temperature, and use a spectrophotometer at a wavelength of 485nm with the reagent blank as the reference to measure the absorbance value. Draw a standard curve with the mass of glucose as the horizontal axis and the absorbance value (A as the vertical axis.

[0271] Sample extraction: Weigh 1.0g of Ginkgo biloba leaf extract, place it in a 100mL volumetric flask, add about 80mL of water, heat in boiling water for 1 hour, cool to room temperature and add water to the scale (V1), mix well and filter, discard the initial filtrate, and collect the remaining filtrate for precipitation of crude polysaccharides.

[0272] Precipitate crude polysaccharide: Accurately pipette 5.0 mL (V2) of the above filtrate into a 50 mL centrifuge tube, add 20 mL of anhydrous ethanol, mix well, place in a 4°C refrigerator for more than 4 hours, centrifuge at 4000 r / min for 5 min, discard the supernatant, wash the residue with a few milliliters of 80% (V / V) ethanol solution, discard the supernatant after centrifugation, repeat the operation 3 times. Dissolve the residue with water and make up to 10 mL (V3).

[0273] Sample determination: Accurately pipette 0.4 mL (V4) of the upper liquid into a 25 mL colorimetric tube, add water to 2.0 mL, add 1.0 mL of 5% phenol solution, mix on a vortex mixer, carefully add 10 mL of concentrated sulfuric acid, mix carefully on a vortex mixer, place in a boiling water bath for 2 min, cool to room temperature, and measure the absorbance using a spectrophotometer at a wavelength of 485 nm with the reagent blank as a reference.

[0274] Result calculation

[0275] Where: X-crude polysaccharide content in the sample, g / 100g;

[0276] m1-mass of glucose in the sample test solution, μg;

[0277] m2-sample mass, g;

[0278] V1-total volume of sample extract, mL;

[0279] V2-volume of sample extract used to precipitate crude polysaccharides, mL;

[0280] V3-volume of crude polysaccharide solution, mL;

[0281] V4-volume of sample solution for determination, mL;

[0282] 0.9- Coefficient for conversion of glucose to crude polysaccharides.

[0283] Results: See Table 10. As shown in Table 10, the total flavonol glycosides and terpenoid lactones in the Ginkgo biloba extract obtained by 70% ethanol extraction and column chromatography, which are active components related to lowering blood lipids, have the highest content, while the crude polysaccharide has the lowest content.

[0284] Table 10 Ginkgo biloba extract investigation results

[0285]

[0286] Test Example 11 Screening process for preparing grape seed extract

[0287] 1. Sample preparation:

[0288] Grape seed water extract: Take an appropriate amount of grape seeds, add water and boil twice, with the solid-liquid ratio being 1:5 and 1:5 respectively, each time for 2 hours, extract at a slight boiling temperature of 83-88℃, filter, concentrate, spray dry, crush and sieve for later use.

[0289] 30% ethanol extract of grape seeds: Take appropriate amount of grape seeds, add 30% ethanol and reflux extraction twice, the solid-liquid ratio is 1:5 and 1:5 respectively, each time for 2 hours, the temperature is 83-88℃ for slight boiling extraction, filter, concentrate, spray dry, crush and sieve for later use.

[0290] Extraction of grape seeds with 70% ethanol and preparation of extract by column chromatography: Take an appropriate amount of grape seeds, add 70% ethanol and reflux extraction twice, with the solid-liquid ratio being 1:5 and 1:5 respectively, each time for 2 hours, and extract at a slight boiling temperature of 83-88°C, filter, concentrate, spray dry, crush and sieve for later use.

[0291] 2. Content Determination

[0292] (I) Determination of proanthocyanidin content is the same as in Experiment 1.

[0293] (II) Determination of catechin and epicatechin content: refer to "RP-HPLC method for simultaneous determination of gallic acid, catechin and epicatechin in grape seed extract" "Journal of Pharmaceutical Analysis", Issue 4, 2015, pp. 723-727.

[0294] (III) Polysaccharide content determination method: The same method as the crude polysaccharide content determination method of Experimental Example 10 was used, except that the ginkgo leaf extract was replaced with grape seed extract.

[0295] Results: As shown in Table 11, 70% ethanol extraction and column chromatography obtained the highest effective active ingredient and the lowest crude polysaccharide content.

[0296] Table 11 Grape seed extract investigation results

[0297]

[0298] Test Example 12: Animal Experiment on Lowering Blood Lipids

[0299] 1. Materials and Methods:

[0300] 1.1 Sample: The soft capsule of Example 1 was tested at a dosage of 0.07 gkg.Bw.

[0301] 1.2 Experimental animals: 50 SD male rats, weighing 140-170 g, certificate number: 1100111911005381, provided by Beijing Weitonglihua Experimental Animal Technology Co., Ltd., production license number: SCXK (Beijing) 2016-0006, SPF grade. Experimental animal room license number: SYXK (Shaanxi) 2018-009, temperature 20-25 ° C, humidity 45%-65%.

[0302] 1.3 Model feed: The maintenance feed contains 20% sucrose, 15% lard, 1.2% cholesterol, 0.2% sodium cholate, and appropriate amounts of casein, calcium hydrogen phosphate, stone powder, etc. All indicators meet the national standards for maintenance feed. It is provided by Jiangsu Collaborative Pharmaceutical Bioengineering Co., Ltd., with a production license number of Su Feed Certificate (2014) 01008, Class A.

[0303] 1.4 Instruments and reagents: Shenzhen Mindray BS-420 fully automatic biochemical analyzer and TC, TG, and LDL-C test kits produced by Shenzhen Mindray Bio-Medical Electronics Co., Ltd.

[0304] 1.5 Dosage design: 1.40g / kg.Bw, 0.70g / kg.Bw, 0.35g / kg.Bw were set as high, medium and low dose groups, which were equivalent to 20 times, 10 times and 5 times of the recommended dosage, respectively. A high-fat model control group and a blank control group (soybean oil) were also set up. Sample preparation: After removing the capsule, 14.0g, 7.0g and 3.5g of the contents were weighed and added to 20mL of soybean oil as samples of the high, medium and low dose groups. The high-fat model control group and the blank control group were given solvent soybean oil. The samples were given orally, and gavage was performed at 2mL / kg.Bw.

[0305] 1.6 Experimental method: Rats were fed with maintenance feed. After 7 days of adaptation, they were randomly divided into two groups according to body weight, namely 40 model control groups and 10 blank control groups. The model control group rats were fed with model feed, and the blank control group rats were fed with maintenance feed. After 14 days of feeding, blood was collected from the fundus vein to measure TC, TG, and LDL-C. According to the TC level, the model control group was divided into 4 groups, three dose groups, and one high-fat model control group. During the experiment, the three dose groups were given model feed and different doses of samples, the high-fat model control group was given model feed, and the blank control group was given maintenance feed. At the same time, the same volume of soybean oil was infused. At the end of the experiment, the rats were weighed, blood was collected without fasting, and TC, TG, and LDL-C indicators were measured.

[0306] 1.7 Experimental data statistics: The experimental data were subjected to variance homogeneity test, and variance analysis was performed if the variance was homogeneous. If the P value was less than 0.05, Dunnett's T3 method was used for pairwise comparison. The above statistics were processed using SPSS17.0 for Windows software.

[0307] 2. Test results

[0308] As can be seen from Tables 12-14, after the experiment, the TC value in the serum of rats in the high-dose group was significantly different from that in the high-fat model control group (P<0.05); the TG values ​​in the serum of rats in the high- and medium-dose groups were significantly lower than those in the high-fat model control group, and the differences were significant (P<0.01, P<0.05); the LDL-C value in the serum of rats in each dose group was significantly lower than that in the high-fat model control group, and the differences were significant (P<0.05, P<0.01, P<0.05); at the same time, it can be seen that the TC, TG, and LDL-C values ​​of the high-fat model control group were significantly higher than those of the blank control group, and the differences were extremely significant (P<0.01), indicating that the high-fat model was successfully established.

[0309] Table 12 Effect of the soft capsule of this application on rat serum TC (X±s)

[0310]

[0311] Note: Compared with the high-fat model control group, each dose group * Indicates P<0.05; compared with the blank control group and the high-fat model control group, ## Indicates P<0.01.

[0312] Table 13 Effect of the soft capsule of the present application on serum TG in rats (X±s)

[0313]

[0314] Note: Compared with the high-fat model control group, each dose group * indicates P < 0.05, **Indicates P<0.01; compared with the blank control group and the high-fat model control group, ## Indicates P<0.01.

[0315] Table 14 Effect of the soft capsule of the present application on serum LDL-C in rats (X±s)

[0316]

[0317] Note: Compared with the high-fat model control group, each dose group * indicates P<0.05, ** Indicates P < 0.01; compared with the blank control group and the high-fat model control group, ## Indicates P<0.01.

[0318] 4. Summary:

[0319] 4.1 The TC, TG, and LDL-C values ​​in the high-fat model control group were significantly higher than those in the blank control group, and the differences were extremely significant (P<0.01), indicating that the high-fat model was successfully established.

[0320] 4.2 Determination of total cholesterol (TC) in rat serum: The total cholesterol (TC) value in the high-dose group was significantly lower than that in the high-lipid model control group, and the difference was statistically significant (P<0.05).

[0321] 4.3 Determination of serum triglyceride (TG) in rats: The serum triglyceride (TG) values ​​of rats in the high- and medium-dose groups were significantly lower than those in the hyperlipidemia model control group, and the differences were statistically significant (P<0.01, P<0.05).

[0322] 4.4 Determination of serum low-density lipoprotein cholesterol (LDL-C) in rats: The serum low-density lipoprotein cholesterol (LDL-C) values ​​of rats in each dose group were significantly lower than those in the high-fat model control group, and the differences were statistically significant (P<0.05, P<0.01, P<0.05).

[0323] 5. Conclusion: The soft capsules of the present application have the effect of lowering blood lipids.

[0324] Test Example 13 Clinical Trial

[0325] 1 Sample: The soft capsules and placebos in Example 1 (the color, smell and other shapes are basically the same as the test samples) are produced by Xi'an Royal Healthcare Products Co., Ltd. and submitted for inspection by Yangtze River Pharmaceutical Group Co., Ltd. The samples are soft capsules, 0.7g / capsule, 60 capsules / bottle, batch number 20180601, and the recommended dose for humans is 2 times a day, 3 capsules each time.

[0326] 2 Subjects

[0327] 2.1 Inclusion criteria of the subjects

[0328] 2.1.1 Under normal diet conditions, blood lipid levels are tested after fasting for 12-14 hours. If serum total cholesterol is 5.18-6.21mmol / L and serum triglycerides are 1.70-2.25mmolL, they can be used as candidates for the auxiliary function of lowering blood lipids; serum triglycerides are 1.70-2.25mmolL, and serum total cholesterol ≤6.21mmolL, they can be used as candidates for the auxiliary function of lowering triglycerides; serum total cholesterol is 5.18-6.21mmol / L, and serum triglycerides ≤2.25mmolL, they can be used as candidates for the auxiliary function of lowering cholesterol. Based on the reference animal experimental results, those with corresponding indicators are selected as subjects. 2.1.2 Primary hyperlipidemia.

[0329] 2.1.3 Obtain informed consent from participants who voluntarily participate in the trial.

[0330] 2.2 Exclusion criteria for the study population

[0331] 2.2.1 Those aged under 18 or over 65.

[0332] 2.2.2 Pregnant or lactating women, people with allergic constitution or those who are allergic to the test sample.

[0333] 2.2.3 Patients with serious diseases of the heart, liver, kidney and hematopoietic system, and mental illness.

[0334] 2.2.4 Those who have taken lipid-lowering drugs in the past two weeks, which may affect their judgment of the results.

[0335] 2.2.5 Hospitalized patients with hyperlipidemia.

[0336] 2.2.6 Failure to consume the test samples in accordance with regulations, or incomplete information, which affects the judgment of efficacy or safety.

[0337] 1.3 Experimental design and grouping

[0338] The self-control and inter-group control test design was adopted, that is, a test group and a control group were divided into two groups randomly according to the blood lipid level, with 60 subjects in each group.

[0339] 1.4 Dosage and method of consumption

[0340] Take 3 capsules twice a day for 60 consecutive days. The test group takes the test sample, and the control group takes a placebo.

[0341] 1.5 Main instruments

[0342] Fully automatic biochemical analyzer (AU-5800, Beckman Coulter, USA); biochemical reagent kit (AU5800, Beckman Coulter, USA); fully automatic blood cell analyzer (XS-900i, Sysmex, Japan); urine chemistry analyzer (UF-10001, Sysmex, Japan); B-ultrasound machine (Ww-99000326, Shenzhen Mindray); X-ray fluoroscopy machine (DEr-800mA, Philips, Germany); electrocardiograph: ZQ-1206 (Wuhan Zhongqi).

[0343] 1.6 Observation indicators

[0344] 1.6.1 Safety indicators

[0345] 1.6.1.1 General condition: including mental state, sleep, diet, urination, defecation, blood pressure, etc.

[0346] 1.6.1.2 Routine examination of blood, urine and stool.

[0347] 1.6.1.3 Liver and kidney function tests.

[0348] 1.6.1.4 Chest X-ray, electrocardiogram, and abdominal B-ultrasound examination (only once before the food tasting).

[0349] 1.7 Efficacy indicators

[0350] 1.7.1 Serum total cholesterol (TC) level and reduction percentage, triglyceride (TG) level and reduction percentage, high-density lipoprotein cholesterol (HDL-C) level and increase, low-density lipoprotein cholesterol (LDL-C) level.

[0351] 1.7.2 Efficacy criteria

[0352] Effective: TC decreased by >10%; TG decreased by >15%; HDL-C increased by >0.104mmol / L. Ineffective: Those who did not meet the effective criteria.

[0353] 1.7.3 Data Processing

[0354] The paired t test was used for self-control data, and the group t test was used for comparison of means between two groups. The X2 test was used for comparison of count data between groups.

[0355] 2. Results

[0356] A total of 120 subjects were included in this trial, with 60 subjects in the trial group and 60 subjects in the control group. After the trial, 1 subject in the trial group and 2 subjects in the control group dropped out of the trial. The effective numbers of the two groups were 59 and 58, respectively. The dropout rate was 2.50%.

[0357] 2.1 Comparison of general information before tasting

[0358] The subjects were questioned and examined before the tasting. There was no significant difference in the general information between the tasting group and the control group (P>0.05), see table.

[0359] Table 15 Comparison of general data between the two groups before the trial (x±s)

[0360] project Food tasting group Control group P-value Number of examples (examples) 59 58 men and women 33 / 26 39 / 19 0.209 Age (years) 50.05±6.40 50.07±6.24 0.988 Total cholesterol (mmol / L) 5.77±0.24 5.76±0.23 0.755 Triglyceride (mmol / L) 1.90±0.12 1.92±0.13 0.442 Low-density lipoprotein cholesterol (mmol / L) 3.16±0.27 3.17±0.20 0.698 High-density lipoprotein cholesterol (mmol / L) 1.76±0.33 1.73±0.34 0.604

[0361] 2.3.1 Total cholesterol

[0362] The total cholesterol of the trial group decreased after the trial, and the differences before and after the trial and after the trial with the control group were significant (P<0.01). After the trial, the total cholesterol of the trial group decreased by an average of 13.58%, which was significantly different from the control group (P<0.01), see table.

[0363] Table 16 Changes in total cholesterol before and after the test (mmol / L, )

[0364] Group Number of examples (examples) Before tasting After tasting Total cholesterol reduction % P value (self) Food tasting group 59 5.77±0.2 4 4.99±0.57 13.58±9.08 0.000 Control group 58 5.76±0.23 5.69±0.39 1.08±6.01 0.167 P value (between groups) 0.755 0.000 0.000

[0365] 2.3.2 Triglycerides

[0366] The triglyceride level of the trial group decreased after the trial, and the difference between the trial group before and after the trial and the control group after the trial was significant (P<0.01). After the trial, the triglyceride level of the trial group decreased by an average of 16.53%, which was significantly different from that of the control group (P<0.01), see table.

[0367] Table 17 Changes in triglycerides before and after the test meal (mmol / L, )

[0368] Group Number of examples (examples) Before tasting After tasting Triglyceride reduction percentage (%) P value (self) Food tasting group 59 1.90±0.12 1.59±0.22 16.53±9.54 0.000 Control group 58 1.92±0.13 1.94±0.18 -0.93±6.04 0.247 P value (between groups) 0.442 0.000 0.000 -

[0369] 2.3.3 High-density lipoprotein cholesterol

[0370] The high-density lipoprotein cholesterol level in the trial group increased after the trial, and the difference before and after the trial was significant (P<0.01). There was no significant difference in the control group before and after the trial (P>0.05). There was a significant difference in the increase in high-density lipoprotein cholesterol between the trial group and the control group (P<0.01), see table.

[0371] Table 18 Changes in high-density lipoprotein cholesterol before and after the trial (mmol / L, )

[0372]

[0373] 2.3.4 Low-density lipoprotein cholesterol

[0374] The low-density lipoprotein cholesterol level in the trial group decreased after the trial. There were significant differences in the comparison between the trial group and the control group (P<0.01). There was a significant difference in the reduction of low-density lipoprotein cholesterol between the trial group and the control group (P<0.01), as shown in Table 19.

[0375] Table 19 Changes of low-density lipoprotein cholesterol before and after the trial (mmol / L, )

[0376]

[0377] 2.3.5 Atherosclerosis Index (AI)

[0378] The calculation method of arteriosclerosis index is:

[0379] Arteriosclerosis index (AI) = [total cholesterol (TC) - high-density lipoprotein cholesterol (HDL)] ÷ high-density lipoprotein cholesterol (HDL)

[0380] The smaller the AI ​​value, the milder the degree of arteriosclerosis and the lower the risk of cardiovascular and cerebrovascular diseases.

[0381] Results: As shown in Table 20, the atherosclerosis index (AI) of the trial group after the trial was significantly lower than that before the trial, indicating that the soft capsule of the present application has the effect of preventing arteriosclerosis.

[0382] Table 20 Atherosclerosis Index (AI)

[0383]

[0384] 3. Summary

[0385] (1) After the trial diet, the serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol in the trial group decreased, while the high-density lipoprotein cholesterol increased. There were significant differences in the comparison between before and after the trial diet (P<0.01).

[0386] (2) There were significant differences in the difference in low-density lipoprotein cholesterol and high-density lipoprotein cholesterol before and after the trial, as well as in the reduction rate of triglycerides and total cholesterol between the two groups (P<0.05), indicating that the trial group can significantly improve the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol in the subjects, and has the effect of assisting in regulating blood lipids. At the same time, the level of high-density lipoprotein cholesterol is increased. High-density lipoprotein cholesterol is an anti-atherosclerotic lipoprotein that can promote the elimination of cholesterol in peripheral tissues and prevent the risk of atherosclerosis.

[0387] (3) The atherosclerosis index (AI) before and after the diet trial was significantly lower in the two groups than that before the diet trial. The lower the AI, the lower the risk of atherosclerosis.

[0388] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a soft capsule for regulating blood lipids and preventing atherosclerosis, characterized in that: The steps include: (1) Preparation of soft capsule contents: Red yeast rice, grape seed extract, and ginkgo leaf extract are mixed in a mass ratio of (170-200):(70-100):(15-35), and passed through a 100-120 mesh sieve to obtain a Chinese medicine composition; wherein the grape seed extract is prepared by the following method: grape seeds are extracted with 60-75% ethanol at a slight boiling temperature of 83-88°C, filtered, subjected to macroporous resin column chromatography, gradient eluted with 35-95% ethanol, the eluate is collected, concentrated, and dried to obtain the composition; the ginkgo leaf extract is prepared by the following method: ginkgo leaves are extracted with 65-85% ethanol at an extraction temperature of 80-85°C, filtered, subjected to macroporous resin column chromatography, eluted with 65-75% ethanol, the eluate is collected, concentrated, and dried to obtain the composition; Heat and melt the diluent and suspending agent, stir, and cool to obtain a molten liquid; The Chinese medicine composition is mixed with the melt, ground, passed through a 100-120 mesh sieve, vacuum-degassed to obtain the contents, and kept warm; the mass ratio of the Chinese medicine composition to the sum of the diluent and the suspending agent is 1:1.20-1.60; (2) Preparation of soft capsule coating solution: Water, gelatin and glycerin are heated to swell, and any one or more of a colorant, a sunscreen or a preservative are added, mixed evenly, passed through an 80-100 mesh sieve, and vacuum-debubbled to obtain a glue solution, which is kept warm; the mass ratio of water, gelatin and glycerin is (0.7-1.2):1:(0.3-0.7); (3) Preparation of soft capsules: The soft capsule contents and the capsule skin glue liquid are pressed into pills using a pill press according to a mass ratio of 0.9-1.7:1, the air supply temperature of the pill press head is 8-12°C, the glue box temperature is 50-55°C, the spray body or nozzle temperature is 37-50°C, and the soft capsule skin thickness is 0.7-0.9mm; shaping for 8-12 hours and drying for 12-16 hours; Preferably, the red yeast rice, grape seed extract and ginkgo leaf extract are mixed in a mass ratio of 180:80:

25.

2. The preparation method according to claim 1, characterized in that: The grape seed extract is prepared by the following method: extracting grape seeds with 4-6 times the amount of 60-75% ethanol, extracting at a temperature of 83-88°C with slight boiling, extracting 1-3 times, each time for 1-3 hours, filtering, macroporous resin column chromatography, 35-95% ethanol gradient elution, collecting the eluate, concentrating until there is no alcohol taste, the relative density is 1.05-1.15 at 60-75°C, and spray drying to obtain the extract; Preferably, the grape seeds are extracted with 5 times the amount of 70% ethanol, the extraction temperature is 83-88° C., and the extraction is performed twice, each time for 2 hours; Also preferably, the macroporous resin model is DM21; More preferably, the 35-95% ethanol gradient elution comprises first eluting with 35-45% ethanol, collecting the eluate, then eluting with 85-95% ethanol, collecting the eluate, and combining the two eluates; Further preferably, the spray drying air inlet temperature is 185-195°C, and the air outlet temperature is 95-105°C.

3. The preparation method according to claim 1 or 2, characterized in that: The ginkgo leaf extract is prepared by the following method: extracting the ginkgo leaf with 5-7 times the amount of 65-85% ethanol, extracting 2-4 times, each time for 0.5-2 hours, extracting at 80-85°C with a slight boiling point, filtering to obtain an extract, applying D101 macroporous resin column chromatography, eluting with 65-75% ethanol, collecting the eluate, concentrating until there is no alcohol taste, and the relative density at 80°C is 1.15-1.18, spray drying, and obtaining the extract; Preferably, the ginkgo leaf extract is prepared by the following method: extracting with 70% ethanol three times, the first time the liquid volume is 6 times the amount of the raw material, the second and third times are 5 times the amount of the raw material, each extraction is 1 hour, the extraction temperature is 80-85°C, D101 macroporous resin column chromatography, first washing impurities with water, discarding them, then eluting with 70% ethanol, collecting the eluate, concentrating the eluate until there is no alcohol taste, the relative density at 80°C is 1.15-1.18, spray drying, and obtaining; Also preferably, the spray drying air inlet temperature is 110-160°C, and the air outlet temperature is 70-85°C.

4. The preparation method according to any one of claims 1 to 3, characterized in that The mass ratio of the diluent to the suspending agent is 10-18:1, preferably 11-14:1; More preferably, the diluent is a vegetable oil, and the vegetable oil is selected from one, two or more of olive oil, soybean oil, prune oil, linseed oil, sunflower oil, jojoba oil, peanut oil, tea oil, tea tree oil, rosehip oil, nut oil, avocado oil, castor oil, cottonseed oil, peppermint oil, sesame oil, salad oil, palm oil, rapeseed oil, corn germ oil and corn oil; Also preferably, the suspending agent is selected from one or more of beeswax, polyethylene glycol and soybean lecithin.

5. The preparation method according to claim 4, characterized in that: The mass ratio of the traditional Chinese medicine composition: vegetable oil: beeswax is (3.0-4.0):(4.5-5.5):(0.3-0.5); preferably (3.4-3.6):(4.8-5.1):(0.35-0.45).

6. The preparation method according to any one of claims 1 to 5, characterized in that: The mass ratio of water, gelatin and glycerin is (0.9-1.1):1:(0.4-0.5), preferably 1:0.4-0.5:1 or 0.9:0.5:

1.

7. The preparation method according to claim 1, characterized in that: The steps include: (1) Preparation of soft capsule contents: Weigh soybean oil and beeswax and heat them to 70°C, wait for the beeswax to melt, stir evenly, add the Chinese medicine composition when the temperature drops to 35-40°C, stir and mix for 20 minutes, grind twice through a colloid mill, filter with a 120-mesh sieve, evacuate the filtrate (-0.07 to -0.08Mpa) to remove all bubbles, keep warm at 35-40°C for later use; the Chinese medicine composition comprises red yeast rice, grape seed extract, and ginkgo leaf extract in a mass ratio of 180:80:25; (2) Preparation of soft capsule coating solution Weigh gelatin, glycerin and water in a mass ratio of 1:0.4:1, heat to 65-75°C, stir evenly after gelatin is completely swollen, add red iron oxide, continue to stir evenly, filter with a 100-mesh nylon sieve, vacuum the filtrate (-0.07~-0.08Mpa) to degas, keep warm at 50-55°C, and set aside; (3) Preparation of soft capsules The soft capsule contents and capsule skin glue liquid are pressed into pills using a pill press machine, the room temperature is 20-24°C, the relative humidity is 30%-40%, the head air supply temperature is 8°C, the glue box temperature is 50°C-55°C, the spray body or spray head temperature is 40°C-47°C, the capsule skin thickness is 0.7-0.9mm, and each pellet weighs 0.7g; The formed soft capsules are shaped in a rolling cage for 8-12 hours at a temperature of 22-25°C and a relative humidity of 30%-40%. After shaping, the capsules are washed with 95% ethanol and dried for 12-16 hours at a temperature of 25-28°C and a relative humidity of 20%-30%. The finished product is then obtained after pill selection, packaging and inspection.

8. The soft capsule obtained according to the preparation method described in any one of claims 1 to 7.

9. A soft capsule for regulating blood lipids and preventing atherosclerosis, comprising soft capsule contents and soft capsule skin, wherein the mass ratio of the soft capsule contents to the soft capsule skin is 0.9-1.7:1; wherein the soft capsule contents comprise a Chinese medicine composition, soybean oil, and beeswax, and the mass ratio of the Chinese medicine composition: soybean oil: beeswax is (3.0-4.0):(4.5-5.5):(0.3-0.5); the Chinese medicine composition comprises red yeast rice, grape seed extract, and ginkgo leaf extract, which are in a mass ratio of 18:

1. 0:80:25; wherein the grape seed extract is prepared according to the following method: grape seeds are extracted with 60-75% ethanol at a micro-boiling temperature of 83-88°C, filtered, chromatographed on a macroporous resin column, gradient eluted with 35-95% ethanol, the eluate is collected, concentrated, and dried to obtain the extract; the ginkgo leaf extract is prepared according to the following method: ginkgo leaves are extracted with 65-85% ethanol at an extraction temperature of 80-85°C, filtered, chromatographed on a macroporous resin column, eluted with 65-75% ethanol, the eluate is collected, concentrated, and dried to obtain the extract; The soft capsule shell is prepared from water, gelatin and glycerin in a mass ratio of (0.9-1.1):1:(0.4-0.5); The mass of the soft capsule content is 0.5-1.0 g / capsule, and the thickness of the soft capsule skin is 0.7-0.9 mm; Preferably, the ginkgo leaf extract is prepared by the following method: extracting the ginkgo leaf with 5-7 times the amount of 65-85% ethanol, extracting 2-4 times, each time for 0.5-2 hours, extracting at 80-85°C with a slight boiling temperature, filtering to obtain an extract, applying D101 macroporous resin column chromatography, eluting with 70% ethanol, collecting the eluate, concentrating until there is no alcohol taste, and the relative density at 80°C is 1.15-1.18, spray drying, and obtaining the extract; More preferably, the grape seed extract is prepared according to the following method: grape seeds are extracted with 4-6 times the amount of 70% ethanol, the extraction temperature is 83-88°C with slight boiling, the extraction is performed 1-3 times, each time for 1-3 hours, filtering, macroporous resin column chromatography, 35-95% ethanol gradient elution, collecting the eluate, concentrating until there is no alcohol taste, the relative density is 1.05-1.15 at 60-75°C, and spray drying to obtain the extract.

10. Use of the soft capsule according to claim 8 or 9 in the preparation of medicines or health products for regulating blood lipids and / or preventing atherosclerosis; Preferably, the soft capsule is used in the preparation of drugs and / or health products for lowering triglycerides, lowering cholesterol, lowering low-density lipoprotein cholesterol and / or increasing high-density lipoprotein cholesterol.

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