Ethyl eicosapentaenoate soft capsule as well as preparation method and application thereof

Abstract

The invention provides an ethyl eicosapentaenoate soft capsule as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The ethyl eicosapentaenoate soft capsule comprises a content and a capsule shell, the content is prepared from the following components in parts by mass: 10 to 30 parts of ethyl eicosapentaenoate, 40 to 70 parts of oil phase matrix, 5 to 15 parts of emulsifier, 2 to 8 parts of antioxidant composition and 0 to 5 parts of cosolvent; the capsule shell comprises the following components in parts by mass: 40-60 parts of gelatin, 25-40 parts of a plasticizer, 20-35 parts of water, 0.5-3 parts of an opacifying agent and 0.1-1 part of an antioxidant. The invention provides the ethyl eicosapentaenoate soft capsule with excellent stability and safety and the preparation method thereof, and the technical problem that EPA-E is easy to oxidize is successfully solved by matching with an optimized anti-oxidation system and process parameters.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to an ethyl eicosapentaenoic acid soft capsule, its preparation method, and its application. Background Technology

[0002] Eicosapentaenoic acid (EPA) is an ω-3 polyunsaturated fatty acid with a carbon chain structure of five double bonds and 20 carbon atoms in length. Ethyl eicosapentaenoate (EPA-E) is an ethyl esterified derivative of EPA, which has better chemical stability than its free fatty acid form.

[0003] EPA-E exerts its pharmacological effects through multiple mechanisms, including inhibiting the synthesis and / or secretion of very low-density lipoprotein triglycerides (VLDL-TG) in the liver, enhancing the clearance of TG from circulating VLDL particles, increasing β-oxidation, inhibiting acyl-CoA: 1,2-diacylglycerol acyltransferase (DGAT), reducing hepatic lipogenesis, and increasing plasma lipoprotein lipase activity. Numerous clinical studies have confirmed the important role of EPA-E in the prevention and treatment of cardiovascular diseases. The REDUCE-IT study showed that in high-risk cardiovascular patients with persistent hypertriglyceridemia after statin therapy, EPA-E significantly reduced the relative risk of major adverse cardiovascular events by up to 25%. The MARINE study showed that EPA-E reduced the median triglyceride level by 33.1% in patients with severe hypertriglyceridemia (triglyceride levels 500-2000 mg / dL). However, EPA-E contains multiple unsaturated double bonds and is extremely sensitive to oxygen, light, and heat, making it prone to oxidative degradation. Oxidation not only causes EPA-E to lose its physiological activity, but may also produce harmful oxidation products. Therefore, improving the stability of EPA-E has become a key focus and challenge in formulation research.

[0004] Currently, the commonly used method for preparing soft capsules is compression. However, the capsule shell becomes brittle under high temperatures and tends to absorb moisture and stick together under high humidity, leading to its disintegration. This shell breakage exposes ethyl eicosapentaenoate to direct contact with the high-temperature, high-humidity environment, causing it to oxidize rapidly and failing to provide adequate protection.

[0005] In addition, existing EPA-E formulations have the following drawbacks: insufficient stability: EPA-E contains five unsaturated double bonds, making it susceptible to oxidative rancidity due to light, heat, and oxygen, leading to degradation of the active ingredient and affecting efficacy and safety; low bioavailability: EPA-E is a fat-soluble component. When traditional soft capsules use vegetable oils (such as soybean oil and rapeseed oil) as the oil phase matrix, its dispersibility in the gastrointestinal tract is poor and its dissolution is slow, resulting in low absorption efficiency; limited shell performance: ordinary soft capsule shells are easily softened or hardened by humidity and have insufficient barrier capacity against light and oxygen, further aggravating the oxidation of the contents; poor user experience: some formulations have high oil phase viscosity, leading to difficulty in swallowing the soft capsules, or the contents may stick to the mouth after the shell breaks, affecting patient compliance.

[0006] Therefore, there is an urgent need to develop an EPA-E soft capsule formulation that is highly stable, has good bioavailability, excellent shell properties, and is convenient to take. Summary of the Invention

[0007] The purpose of this invention is to provide an ethyl eicosapentaenoic acid (EPA-E) soft capsule, its preparation method, and its application. By optimizing the oil phase matrix, emulsifier system, antioxidant composition, and capsule shell formulation, and combining it with a specific preparation process, the problems of easy oxidation of EPA-E, low bioavailability, and insufficient capsule shell performance are solved.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides an ethyl eicosapentaenoate soft capsule, comprising contents and a capsule shell; The contents comprise the following components in parts by weight: 10-30 parts eicosapentaenoic acid ethyl ester, 40-70 parts oil phase matrix, 5-15 parts emulsifier, 2-8 parts antioxidant composition, and 0-5 parts cosolvent; wherein the oil phase matrix is ​​a medium-chain triglyceride and / or caprylate-caprylate triglyceride. The shell comprises the following components in parts by weight: 40-60 parts gelatin, 25-40 parts plasticizer, 20-35 parts water, 0.5-3 parts light-blocking agent, and 0.1-1 parts antioxidant.

[0009] Preferably, the emulsifier includes at least one of poloxamer 188, polyoxyethylene castor oil, and lecithin; the antioxidant composition includes vitamin E and rosemary extract, wherein the mass ratio of vitamin E to rosemary extract is 1~2:0.8~1.2; and the cosolvent is ethanol or propylene glycol.

[0010] Preferably, when the emulsifier is poloxamer 188 and lecithin, the mass ratio of poloxamer 188 to lecithin is 1.5~2.5:0.8~1.2; the content of rosmarinic acid in the rosemary extract is ≥5%; and the volume fraction of ethanol is ≥95%.

[0011] Preferably, the plasticizer includes at least one of glycerol and sorbitol; the light-blocking agent is titanium dioxide; and the antioxidant is propyl gallate.

[0012] Preferably, when the plasticizer is glycerol and sorbitol, the mass ratio of glycerol to sorbitol is 2.5~3.5:0.8~1.2; and the particle size of the titanium dioxide is ≤50nm.

[0013] This invention provides a method for preparing the ethyl eicosapentaenoic acid soft capsule, comprising the following steps: (1) Ethyl eicosapentaenoic acid was heated and stirred to dissolve the oil phase matrix, and an emulsifier was added for shearing to form a primary emulsion; an antioxidant composition and a cosolvent were added for further shearing to obtain a uniform emulsion; after sterilization, the contents were obtained. (2) After heating gelatin, plasticizer and water, stir to dissolve, add light-blocking agent and antioxidant and continue stirring. After vacuum degassing, the capsule shell solution is obtained. (3) The contents obtained in step (1) and the capsule shell liquid obtained in step (2) are pressed into pills by a soft capsule press, shaped and dried to obtain the ethyl eicosapentaenoic acid soft capsules.

[0014] Preferably, the heating temperature in step (1) is 50~60℃; the stirring rate is 20~40rpm; the shearing rate is 10000~15000rpm; the shearing time after adding the emulsifier is 5~10min; the shearing time after continuing is 3~5min; and the sterilization method is sterilization through a 0.45μm microporous filter membrane.

[0015] Preferably, the heating temperature in step (2) is 60~70℃; the stirring rate is 20~40rpm; the stirring time is 15~20min; the vacuum degassing pressure is -0.07~-0.09MPa and the time is 10~30min.

[0016] Preferably, the temperature during the shaping process in step (3) is 18~26℃, the humidity is 30~40%, and the time is 60~180min; the drying temperature is 23~27℃, the humidity is 20~25%, and the drying is carried out until the moisture content is 8~12%.

[0017] This invention provides the application of the ethyl eicosapentaenoic acid soft capsules described above or prepared by the method in the preparation of products for lowering triglyceride levels and protecting the cardiovascular system.

[0018] Compared with the prior art, the present invention has the following beneficial effects: 1. Significantly improved stability: This invention uses medium-chain triglycerides (MCT) as the oil phase matrix. Its small molecular weight and rapid metabolism can promote the absorption of EPA-E by the lymphatic system. Combined with the complex antioxidant system of vitamin E (fat-soluble antioxidant) and rosemary extract (water-soluble antioxidant), it effectively inhibits the auto-oxidation of EPA-E. Accelerated tests show that the EPA-E retention rate is ≥95% and the acid value is ≤0.1mg KOH / g.

[0019] 2. Improved bioavailability: This invention utilizes the synergistic effect of emulsifiers (poloxamer 188 + lecithin) to reduce the particle size of contents to the submicron level (≤1μm), increasing the dispersibility of gastrointestinal fluid; MCT can be rapidly hydrolyzed by intestinal mucosal lipases, releasing free EPA. Compared with long-chain triglycerides (such as soybean oil), the serum peak concentration (Cmax) of EPA is increased by about 30%, and the time to peak concentration (Tmax) is shortened to 1~2h (3~4h for traditional formulations).

[0020] 3. Optimization of capsule shell performance: The addition of titanium dioxide (nanoscale) to the capsule shell enhances light blocking, and propyl gallate (PG) forms covalent bonds with the amino groups in gelatin to inhibit oxidative degradation; glycerol and sorbitol are combined as plasticizers to improve the flexibility of the capsule shell (elongation at break ≥200%), avoiding softening or cracking under high temperature and high humidity conditions.

[0021] 4. Improved user experience: The viscosity of the contents of the soft capsules of this invention is controlled at 500~1500mPa·s (25℃), the capsule shell thickness is uniform (0.7~1.0mm), there is no odor, and the contents are prevented from sticking to the mouth.

[0022] In summary, this invention provides an ethyl eicosapentaenoic acid (EPA) soft capsule with excellent stability and safety, and its preparation method. By combining an optimized antioxidant system and process parameters, the technical challenge of easy oxidation of EPA-E is successfully solved. The soft capsule comprises a modified shell formulation and a stable content combination. By optimizing the oil phase matrix (MCT / COD), emulsifier (poloxamer 188 + lecithin), composite antioxidant system (vitamin E + rosemary extract), and shell formulation (nano-titanium dioxide for light shielding, propyl gallate for antioxidant properties), it exhibits excellent mechanical strength and stability. The content contains the active ingredient ethyl eicosapentaenoic acid (such as EPA extracted from fish oil or extracted from plant oils) and stabilizers, ensuring uniform dispersion and long-term storage stability, thus solving the problems of easy oxidation of EPA-E, low bioavailability, and insufficient shell performance. The soft capsules prepared by this invention have good stability and high bioavailability, significantly improving the product's antioxidant and drug release performance. Furthermore, the shell is flexible and easy to swallow, making it suitable for cardiovascular disease prevention and functional food applications. Attached Figure Description

[0023] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0024] Figure 1 The chemical structural formula of ethyl eicosapride is shown. Figure 2 This is a flowchart of the preparation method of ethyl eicosapentaenoic acid soft capsules. The D-level area refers to the general production area, which has a low cleanliness level. Detailed Implementation

[0025] This invention provides an ethyl eicosapentaenoate soft capsule, comprising contents and a capsule shell; The contents comprise the following components in parts by weight: 10-30 parts eicosapentaenoic acid ethyl ester, 40-70 parts oil phase matrix, 5-15 parts emulsifier, 2-8 parts antioxidant composition, and 0-5 parts cosolvent; wherein the oil phase matrix is ​​a medium-chain triglyceride and / or caprylate-caprylate triglyceride. The shell comprises the following components in parts by weight: 40-60 parts gelatin, 25-40 parts plasticizer, 20-35 parts water, 0.5-3 parts light-blocking agent, and 0.1-1 parts antioxidant.

[0026] In this invention, the contents preferably comprise the following components in parts by weight: 15-25 parts eicosapentaenoic acid ester, 50-60 parts oil phase matrix, 8-12 parts emulsifier, 3-6 parts antioxidant composition, and 1-3 parts cosolvent; more preferably, the contents comprise the following components in parts by weight: 20 parts eicosapentaenoic acid ester, 55 parts oil phase matrix, 10 parts emulsifier, 4 parts antioxidant composition, and 2 parts cosolvent.

[0027] In this invention, the oil phase matrix is ​​preferably a medium-chain triglyceride and caprylic / capric triglyceride, and the mass ratio of the medium-chain triglyceride to the caprylic / capric triglyceride is 1~3:0.8~1.2, preferably 1.5~2.5:0.9~1.1, and more preferably 2:1.

[0028] In this invention, the shell preferably comprises the following components in parts by weight: 45-55 parts gelatin, 30-35 parts plasticizer, 25-30 parts water, 1-2 parts light-blocking agent, and 0.2-0.5 parts antioxidant; more preferably, it comprises the following components in parts by weight: 50 parts gelatin, 33 parts plasticizer, 28 parts water, 1.5 parts light-blocking agent, and 0.3 parts antioxidant.

[0029] In this invention, the emulsifier includes at least one of poloxamer 188, polyoxyethylene castor oil, and lecithin; the antioxidant composition includes vitamin E and rosemary extract, wherein the mass ratio of vitamin E to rosemary extract is 1~2:0.8~1.2, preferably 1.2~1.8:0.9~1.1, and more preferably 1.5:1; the cosolvent is ethanol or propylene glycol.

[0030] In this invention, when the emulsifier is poloxamer 188 and lecithin, the mass ratio of poloxamer 188 to lecithin is 1.5~2.5:0.8~1.2, preferably 1.8~2.2:0.9~1.1, and more preferably 2:1; the content of rosmarinic acid in the rosemary extract is ≥5%; and the volume fraction of ethanol is ≥95%.

[0031] In this invention, the plasticizer includes at least one of glycerol and sorbitol; the light-blocking agent is titanium dioxide; and the antioxidant is propyl gallate.

[0032] In this invention, when the plasticizer is glycerol and sorbitol, the mass ratio of glycerol to sorbitol is 2.5~3.5:0.8~1.2, preferably 2.8~3.2:0.9~1.1, and more preferably 3:1; the particle size of the titanium dioxide is ≤50nm.

[0033] This invention provides a method for preparing the ethyl eicosapentaenoic acid soft capsule, comprising the following steps: (1) Ethyl eicosapentaenoic acid was heated and stirred to dissolve the oil phase matrix, and an emulsifier was added for shearing to form a primary emulsion; an antioxidant composition and a cosolvent were added for further shearing to obtain a uniform emulsion; after sterilization, the contents were obtained. (2) After heating gelatin, plasticizer and water, stir to dissolve, add light-blocking agent and antioxidant and continue stirring. After vacuum degassing, the capsule shell solution is obtained. (3) The contents obtained in step (1) and the capsule shell liquid obtained in step (2) are pressed into pills by a soft capsule press, shaped and dried to obtain the ethyl eicosapentaenoic acid soft capsules.

[0034] In this invention, the heating temperature in step (1) is 50~60℃, preferably 52~58℃, and more preferably 55℃; the stirring rate is 20~40rpm, preferably 25~35rpm, and more preferably 30rpm; the shearing rate is 10000~15000rpm, preferably 11000~14000rpm, more preferably 12000~13000rpm, and more preferably 12500rpm; the shearing time after adding the emulsifier is 5~10min, preferably 8min, and the shearing time after continuing is 3~5min, preferably 4min; the sterilization method is sterilization through a 0.45μm microporous filter membrane.

[0035] In this invention, the heating temperature in step (2) is 60~70℃, preferably 62~68℃, and more preferably 65℃; the stirring speed is 20~40rpm, preferably 25~35rpm, and more preferably 30rpm; the stirring time is 15~20min, preferably 18min; the vacuum degassing pressure is -0.07~-0.09MPa, preferably -0.08MPa, and the time is 10~30min, preferably 15~25min, and more preferably 20min.

[0036] In this invention, the parameters for pressing into pellets in step (3) are: wedge temperature 35~44℃, spreading box temperature 55~65℃, cold air temperature 15~25℃, cold water temperature 15~25℃, and equipment speed 2.0~3.0 rpm. During the pellet pressing process, the thickness of the rubber plate is controlled at 0.70mm~0.80mm, and the difference in the amount of rubber pellets is controlled at ±3%.

[0037] In this invention, the temperature during the shaping process in step (3) is 18~26℃, preferably 20~24℃, more preferably 22℃, the humidity is 30~40%, preferably 32~38%, more preferably 35%, the time is 60~180min, preferably 90~150min, more preferably 110~130min, more preferably 120min; the drying temperature is 23~27℃, preferably 24~26℃, more preferably 25℃, the humidity is 20~25%, preferably 22%, and the drying is carried out until the moisture content is 8~12%, preferably 9~11%, more preferably 10%.

[0038] This invention provides the application of the ethyl eicosapentaenoic acid soft capsules described above or prepared by the method in the preparation of products for lowering triglyceride levels and protecting the cardiovascular system.

[0039] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0040] Example 1

[0041] An ethyl eicosapentaenoic acid soft capsule, consisting of contents and a shell.

[0042] The contents consist of the following components in parts by weight: ethyl eicosapentaenoate (EPA-E) 20 parts, medium-chain triglycerides (MCT) 35 parts, caprylic / capric triglycerides (COD) 15 parts, poloxamer 188 8 parts, lecithin (soybean-derived) 4 parts, vitamin E 3 parts, rosemary extract (6% rosmarinic acid content) 3 parts, and 95% ethanol 2 parts. The capsule shell consists of the following components in parts by weight: gelatin 50 parts, glycerin 30 parts, sorbitol 10 parts, purified water 25 parts, titanium dioxide 1 part, and propyl gallate 0.5 parts.

[0043] The preparation method of the contents is as follows: EPA-E, MCT and COD are added to the reaction vessel, stirred at 60℃ and 30 rpm until dissolved; poloxamer 188 and lecithin are added, and sheared at 10000 rpm for 5 min until homogeneous; vitamin E, rosemary extract and ethanol are added, and shearing is continued for 3 min; the mixture is filtered through a 0.45 μm filter membrane; and cooled to room temperature to obtain the contents.

[0044] The preparation method of the capsule shell gel is as follows: Set the empty tank of the water bath gelling vessel to a heating temperature of 65°C, start heating, mix glycerin with about half the amount of purified water and add it to the water bath gelling vessel, start stirring at 30 rpm, wash the container holding the glycerin with the remaining purified water and add it all to the water bath gelling vessel; when the liquid temperature in the vessel rises to 65°C, add sorbitol and stir to dissolve; continue to add gelatin and stir to dissolve until completely melted, then add the opacifier titanium dioxide and antioxidant. Add propyl gallate and continue stirring for 15 minutes until homogeneous. Then turn off the stirring and let it stand for 30 minutes. Turn on the vacuum pump (vacuum degree -0.08±0.01MPa). Start timing when no more gas is released from the vent valve in the tank. Stir and degas for 15 minutes. After degassing, measure the viscosity of the glue solution when the temperature is 55±3℃. When it reaches 10000~30000mPa.s, dispense the glue solution. Filter the glue solution through a 100-mesh sieve into a warm glue tank. The temperature of the warm glue tank is 55℃. Let it stand and keep warm until use.

[0045] The preparation method of soft capsules is as follows: Shot Compression: The contents and capsule shell solution are compressed into pellets using a soft capsule compression machine. The compression process uses medium-chain triglycerides to lubricate the compression equipment. The thickness of the capsule sheet and the temperatures of the accompanying cold air, cold water, wedge, spreading box, and stroke are adjusted. Key parameter settings are: wedge temperature 41.2℃, spreading box temperature 56.1℃, cold air temperature 20.1℃, cold water temperature 19.8℃, and machine speed 2.5 rpm. During the compression process, the capsule sheet thickness is controlled to 0.78 mm, and the pellet weight variation is controlled to ±3%. Every 30 minutes, the appearance, capsule sheet thickness, and weight of two rows of pellets (12 in total) are checked. The compressed soft capsules are simultaneously transferred to a rotating drum for shaping (20~25℃, humidity 30%~40%), where they are dried for at least 2 hours after oil absorption and shaping. After shaping, the pellets are transferred from the rotating drum to a drying tray. The liquid in the feed hopper must be protected with nitrogen during the compression process.

[0046] Drying: The shaped soft capsules are laid flat in a single layer on a drying tray for drying. The relative humidity in the drying room is 30%~40%, and the temperature range is 18~26℃. After drying for 20 hours, samples are taken to test the moisture content using a rapid moisture analyzer (150℃, automatic mode). The moisture content of the capsule shell is less than 12.0%. The hardness of the capsule shell is tested using a texture analyzer (TPA mode, probe diameter 5mm, test speed 1mm / s, trigger force 5g). The hardness of the EPA-E capsule shell is 12N. After drying, the capsules are sent to the intermediate station, weighed, and then selected.

[0047] Shot selection: Use an illuminance meter to check the illuminance of the inspection table, with an illuminance range of 1500~3000Lx. Lay the capsules flat on the inspection table and select out defective products such as irregularly shaped capsules, bubble capsules, small capsules, and capsules with skin.

[0048] Bottle Packaging: 24 capsules / bottle. Each bottle contains the specified number of capsules, plus a pharmaceutical solid paper bag containing silica gel desiccant (one 1g desiccant bag per bottle, placed on top). Set appropriate packaging parameters: filling speed 10-30 bottles / min, sealing voltage 20-150V. Adjust the electromagnetic sealing voltage to ensure a tight seal, avoiding any incomplete sealing or scorching. At the start of production; every 60 minutes during production; and at the end of production, randomly sample 3 bottles to check the accuracy of the filling, tight capping, proper sealing, correct three-phase label printing, clear printing, and proper positioning. Regularly check the number of capsules inside the bottle during the packaging process.

[0049] Experimental Example 1

[0050] The purpose of this experiment is to determine the properties of the soft capsules prepared in Example 1. The specific method is as follows: 1. Stability determination The stability of soft capsules was determined by accelerated testing. The soft capsules were placed at 40 °C and 75% RH for 6 months, and the EPA-E retention rate, acid value, and peroxide value were detected. The EPA-E retention rate was determined by HPLC, and the remaining amount / initial amount × 100% was calculated; the acid value was determined according to the method specified in GB 5009.229-2016, and ≤ 2 mg KOH / g was considered qualified. The peroxide value was determined according to the method specified in GB 5009.227-2016, and ≤ 0.25 mg / 100 g was considered qualified.

[0051] The results are shown in Table 1. After 6 months of storage, the EPA-E retention rate was ≥ 95%, the acid value was ≤ 0.1 mg KOH / g (far lower than the pharmacopoeia-specified 2 mg KOH / g), and the peroxide value was ≤ 0.2 mg / 100 g (far lower than the pharmacopoeia-specified 0.25 mg / 100 g).

[0052] Table 1 Results of stability experiment

[0053] 2. Determination of bioavailability

[0054] A total of 120 SPF-grade male SD rats (body weight 200 ± 20 g) were selected and randomly divided into 6 groups. Administration protocol: Group 1 was intragastrically administered EPA free acid (EPA-FAs), Group 2 was intragastrically administered docosahexaenoic acid ethyl ester (DHA-E), Group 3 was intragastrically administered EPA triglyceride, Group 4 was intragastrically administered low-dose EPA-E (prepared in Example 1), Group 5 was intragastrically administered high-dose EPA-E (prepared in Example 1). Among them, the intragastric administration doses of Groups 1-3 were all 1000 mg / kg, the intragastric administration dose of Group 4 was 500 mg / kg, and the intragastric administration dose of Group 5 was 1000 mg / kg. The blank control group was given an equal amount of normal saline. Blood drug concentration detection: The rats were fasted for 12 h before administration. Blood was collected from the orbital cavity at 0.5, 1, 2, 4, 6, 8, 12, and 24 h after administration. Plasma was separated by centrifugation (rotation speed 3000 rpm, time 10 min, temperature 4 °C), and the EPA concentration was detected by HPLC-MS / MS to calculate the pharmacokinetic parameters (Cmax, Tmax, AU h).

[0055] Cmax = max{C1, C2,..., C n}; where C i is the blood drug concentration at each time point; Tmax = the time point corresponding to Cmax;

[0056] Table 2 Results of bioavailability experiment

[0057] 3. Determination of shell hardness

[0058] The force (N) required for the capsule shell to fracture was measured using a texture analyzer (TPA mode, probe diameter 5mm, test speed 1mm / s, trigger force 5g). The higher the value, the higher the hardness. After the sample prepared in Example 1 was placed for 6 months, the hardness (N) of the EPA-E capsule shell increased significantly from the initial 12N to 28N. Although it did not break, it was relatively hard, which can prevent softening or cracking under high temperature and high humidity conditions.

[0059] 4. Measurement of the viscosity of the contents

[0060] The viscosity of the contents (mPa·s) was measured using a rotational viscometer (NDJ-8S, 25℃, rotor #2, rotation speed 60rpm). The results showed that the viscosity of the contents was 980 mPa·s (25℃).

[0061] 5. User experience evaluation

[0062] Ten healthy volunteers (aged 20-30) were recruited. After a blind test, they rated the "smoothness of swallowing" and "oral adhesion" on a scale of 1 to 5 (1 being the worst and 5 being the best). The average results are shown in Table 3.

[0063] Table 3. User Experience Rating Results

[0064] Comparative Example 1

[0065] The difference between this comparative example and Example 1 is that the oil phase matrix used is different. In this comparative example, 60 parts of soybean oil are used to replace the medium-chain triglycerides (MCT) and caprylic / capric triglycerides (COD) used in Example 1. The other components and methods are the same as in Example 1.

[0066] The bioavailability and stability of the soft capsules prepared in Example 1 and Comparative Example 1 were determined using the same methods as in Example 1, and the results are shown in Table 4.

[0067] Table 4 Comparison results between Example 1 and Comparative Example 1

[0068] Results: Because soybean oil contains long-chain fatty acids, it may reduce the dispersibility of EPA-E, leading to a decrease in bioavailability; at the same time, soybean oil has more unsaturated double bonds, which may accelerate oxidation and result in higher acid value and peroxide value.

[0069] Comparative Example 2

[0070] The difference between this comparative example and Example 1 is that the antioxidant composition used is different. In this comparative example, the rosemary extract used in Example 1 is replaced with an equal amount of vitamin E. The other components and methods are the same as in Example 1.

[0071] The stability of the soft capsules prepared in Example 1 and Comparative Example 2 was determined using the same method as in Example 1, and the results are shown in Table 5.

[0072] Table 5 Comparison results between Example 1 and Comparative Example 2

[0073] Results: The antioxidant capacity of the soft capsules prepared in Comparative Example 2 was weakened, the EPA-E retention rate decreased after accelerated testing, and the acid value and peroxide value increased.

[0074] Comparative Example 3

[0075] The difference between this comparative example and Example 1 is that the emulsifier used is different. In this comparative example, an equal amount of glyceryl monostearate is used to replace poloxamer 188 and lecithin used in Example 1. The other components and methods are the same as in Example 1.

[0076] The bioavailability of the soft capsules prepared in Example 1 and Comparative Example 3 was determined using the same method as in Example 1, and the results are shown in Table 6.

[0077] Table 6 Comparison results between Example 1 and Comparative Example 3

[0078] Results: Comparative Example 3 showed poor emulsification, increased particle size of contents, and decreased bioavailability.

[0079] Comparative Example 4

[0080] The difference between this comparative example and Example 1 is that the shell of this comparative example does not contain titanium dioxide, while the other components and methods are the same as in Example 1.

[0081] The bioavailability of the soft capsules prepared in Example 1 and Comparative Example 4 was determined using the same method as in Example 1, and the results are shown in Table 7.

[0082] Table 7 Comparison results between Example 1 and Comparative Example 4

[0083] Results: In Comparative Example 4, the oxidation of the soft capsule contents was accelerated, the capsule shell had high light transmittance, the EPA-E retention rate was reduced, and the acid value and peroxide value were increased.

[0084] Comparative Example 5

[0085] The difference between this comparative example and Example 1 is that the capsule plasticizer used is different. In this comparative example, an equal amount of glycerol is used to replace the sorbitol used in Example 1. The other components and methods are the same as in Example 1.

[0086] The hardness of the capsule shells of the soft capsules prepared in Example 1 and Comparative Example 4 was measured using the same method as in Example 1. The results are shown in Table 8.

[0087] Table 8 Comparison results between Example 1 and Comparative Example 5

[0088] Results: The soft capsules in Comparative Example 5 showed decreased shell flexibility, were more prone to hardening and rupture, had higher hardness test values ​​but lower elongation at break.

[0089] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. An ethyl eicosapentaenoate softgel capsule, characterized in that, The content and the capsule shell are included; The content includes components in mass fractions as follows: 10-30 parts of eicosapentaenoic acid ethyl ester, 40-70 parts of oil phase matrix, 5-15 parts of emulsifier, 2-8 parts of antioxidant composition, and 0-5 parts of cosolvent; wherein the oil phase matrix is medium-chain triglyceride and / or caprylic capric triglyceride; The capsule shell includes components in mass fractions as follows: 40-60 parts of gelatin, 25-40 parts of plasticizer, 20-35 parts of water, 0.5-3 parts of light shielding agent, and 0.1-1 part of antioxidant.

2. The ethyl eicosapentaenoate softgel capsule according to claim 1, wherein The emulsifier includes at least one of poloxamer 188, polyoxyethylene castor oil, and lecithin; the antioxidant composition includes vitamin E and rosemary extract, and the mass ratio of the vitamin E to the rosemary extract is 1-2:0.8-1.2; and the cosolvent is ethanol or propylene glycol.

3. The ethyl eicosapentaenoate softgel capsule according to claim 2, wherein When the emulsifier is poloxamer 188 and lecithin, the mass ratio of the poloxamer 188 to the lecithin is 1.5-2.5:0.8-1.2; the content of rosemary acid in the rosemary extract is ≥5%; and the volume fraction of the ethanol is ≥95%.

4. The ethyl eicosapentaenoate softgel capsule according to claim 1, wherein The plasticizer includes at least one of glycerol and sorbitol; the light shielding agent is titanium dioxide; and the antioxidant is propyl gallate.

5. The ethyl eicosapentaenoate softgel capsule according to claim 4, wherein When the plasticizer is glycerol and sorbitol, the mass ratio of the glycerol to the sorbitol is 2.5-3.5:0.8-1.2; and the particle size of the titanium dioxide is ≤50 nm.

6. A method of preparing the ethyl eicosapentaenoate soft capsule according to any one of claims 1 to 5, characterized by, The method includes the following steps: (1) heating and stirring to dissolve eicosapentaenoic acid ethyl ester and oil phase matrix, adding emulsifier for shearing to form a primary emulsion, adding antioxidant composition and cosolvent for continuous shearing to obtain a uniform emulsion, sterilizing to obtain the content; (2) heating and stirring to dissolve gelatin, plasticizer, and water, adding light shielding agent and antioxidant for continuous stirring, vacuum defoaming to obtain capsule shell glue solution; (3) compressing the content obtained in step (1) and the capsule shell glue solution obtained in step (2) into pills through a soft capsule compression machine, shaping and drying to obtain the eicosapentaenoic acid ethyl ester soft capsules.

7. The method of claim 6, wherein, In step (1), the heating temperature is 50-60℃, the stirring rate is 20-40 rpm, the shearing rate is 10,000-15,000 rpm, the shearing time after adding the emulsifier is 5-10 min, the continuous shearing time is 3-5 min, and the sterilization method is sterilization through a 0.45 μm microporous filter membrane.

8. The method of claim 6, wherein, In step (2), the heating temperature is 60-70℃, the stirring rate is 20-40 rpm, the continuous stirring time is 15-20 min, the vacuum defoaming pressure is -0.07--0.09 MPa, and the vacuum defoaming time is 10-30 min.

9. The method of claim 6, wherein, In step (3), the shaping temperature is 18-26℃, the humidity is 30-40%, the shaping time is 60-180 min, the drying temperature is 23-27℃, the humidity is 20-25%, and the drying is performed until the water content is 8-12%.

10. Use of the ethyl eicosapentaenoate soft capsules according to any one of claims 1 to 5 or of the ethyl eicosapentaenoate soft capsules prepared according to the process of any one of claims 6 to 9 for the manufacture of a product for lowering triglyceride levels and for protecting the cardiovascular system.

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