Composition containing ethyl eicosapentaenoate, soft capsule type preparation, preparation process and application

Abstract

The invention relates to the technical field of eicosapentaenoic acid ethyl ester soft capsules, and discloses a composition containing eicosapentaenoic acid ethyl ester, a soft capsule type preparation, a preparation process and application, eicosapentaenoic acid ethyl ester compounded with various antioxidant auxiliary material components is used as a content, gelatin and Arabic gum are used as wall materials, and the soft capsule type preparation is prepared by compounding the eicosapentaenoic acid ethyl ester and the soft capsule type preparation. A safe and non-toxic polyhedral oligomeric silsesquioxane (POSS) framework compound which is independently researched and synthesized and has a salicylaldehyde group functional group is used as a curing agent, and safe and non-toxic titanium dioxide which is independently researched and synthesized and has the surface modified with the salicylaldehyde group functional group is used as an opacifying agent; and preparing the ethyl eicosapentaenoate soft capsule preparation by adopting a complex coacervation method. The eicosapentaenoic acid ethyl ester soft capsule type preparation prepared by the invention not only has excellent stability under high-temperature and high-humidity conditions, but also has the peroxide value of eicosapentaenoic acid ethyl ester as low as 1.02 meq / kg and the content of eicosapentaenoic acid ethyl ester as high as 98.79%.

Description

Technical Field

[0001] The present invention relates to the technical field of research and development of eicosapentaenoic acid ethyl soft capsules, and in particular to a composition comprising eicosapentaenoic acid ethyl, a soft capsule preparation, a preparation process and applications. Background Art

[0002] Eicosapentaenoic acid ethyl ester (EPA-EE) is an omega-3 fatty acid derivative derived from eicosapentaenoic acid (EPA). EPA-EE has demonstrated widespread application in anti-inflammatory, cardiovascular and cerebrovascular health, and mental health through multiple mechanisms, including inhibiting the production of inflammatory mediators, improving lipid profiles, and stabilizing plaques.

[0003] Because icosapentaenoic acid ethyl contains multiple double bonds, it is extremely sensitive to oxygen, light, and heat, and is prone to oxidation. Once oxidized, it not only loses its physiological functions but also causes great harm to the human body. Microencapsulating icosapentaenoic acid ethyl can effectively prevent icosapentaenoic acid ethyl from oxidative deterioration caused by oxygen and light, thereby maintaining its physiological functions.

[0004] The commonly used microcapsule preparation method is spray drying. However, under high temperature conditions, the glassy microcapsule wall material collapses, releasing the core material. Under high humidity conditions, the hydrophilic wall material absorbs water and swells, also causing the core material to be released. This release of the core material exposes ethyl eicosapentaenoate to direct contact with the high temperature and humidity, causing it to oxidize rapidly and thus failing to provide effective protection.

[0005] Microcapsules prepared by the composite gel method form a cross-linked network structure after curing, which has good stability in high-temperature and high-humidity environments and can protect the core material in high-temperature and high-humidity environments. Currently, the wall materials of the composite coacervation method are basically gelatin and gum arabic. The process of gelatin-gum arabic composite coacervation to generate a coacervate phase from a colloidal aqueous solution system through phase separation is a reversible change process between sol and gel. If the equilibrium is destroyed, the coacervate phase will disappear. In order to prevent the gel coagulated around the capsule core from dissolving, a curing treatment is required. The most commonly used curing agents are formaldehyde or glutaraldehyde, but the residual chemical cross-linking agent and the biodegradation of chemical cross-linked macromolecules in the body are toxic, and cannot be applied to the curing of composite coacervate eicosapentaenoic acid ethyl microcapsules.

[0006] In addition, the composite gel method is relatively complex and the temperature is high. Eicosapentaenoic acid ethyl ester will undergo a certain degree of oxidation during the emulsification and microencapsulation process. There are many ways to prevent the oxidation of eicosapentaenoic acid ethyl ester. Adding antioxidants and using nitrogen protection are two of the more commonly used methods.

[0007] Polyhedral Oligomeric Silsesquioxane (POSS) is a new type of material that combines organic and inorganic materials. It has a cage-shaped core composed of an inorganic silicon-oxygen-silicon structure and organic side chains. It is currently the only molecular-level nanohybrid material and has good surface and interfacial compatibility with polymers. Its non-toxicity, odorlessness, low volatility and excellent biocompatibility have earned it the reputation of a "new generation of biomedical material." Summary of the Invention

[0008] In order to solve the problem of oxidation of icosapentaenoic acid ethyl during the emulsification and microencapsulation process, a composition containing icosapentaenoic acid ethyl was developed by optimizing the auxiliary material components and dosages. In addition, a safe and non-toxic POSS framework compound with salicylaldehyde functional groups was independently developed and synthesized. It was applied to the solidification of composite coacervation icosapentaenoic acid ethyl microcapsules to prepare an icosapentaenoic acid ethyl soft capsule preparation for reducing triglyceride (TG) levels in adult patients with severe hypertriglyceridemia (≥500 mg / dL).

[0009] An eicosapentaenoic acid ethyl ester soft capsule preparation, consisting of contents and a capsule shell, wherein the mass ratio of the contents to the capsule shell is 1:(1.5-3);

[0010] The content is a composition containing eicosapentaenoic acid ethyl ester, which comprises eicosapentaenoic acid ethyl ester and an antioxidant, wherein the amount of the antioxidant is (0.1-1) wt% of the amount of eicosapentaenoic acid ethyl ester;

[0011] The capsule shell is composed of gelatin, gum arabic, an opacifying agent, and a curing agent;

[0012] The mass ratio of gelatin to gum arabic is 1:(0.5-2);

[0013] The curing agent is octasalicylaldehyde cage-type polysilsesquioxane, and its usage is (0.15-0.45) wt% of the amount of gelatin;

[0014] The sunscreen is titanium dioxide with salicylaldehyde functional groups modified on the surface, and the amount of the titanium dioxide is (0.3-0.7) wt% of the amount of gelatin.

[0015] Preferably, the antioxidant is one or a combination of vitamin E, tert-butylhydroquinone and quercetin.

[0016] Preferably, the titanium dioxide powder with a surface modified with salicylaldehyde functional groups is obtained by organically modifying the surface of pharmaceutical-grade titanium dioxide powder with monosalicylaldehyde trimethoxysilane.

[0017] A preparation process of an icosapentaenoic acid ethyl ester soft capsule preparation comprises the following steps:

[0018] Fully dissolve gelatin and gum arabic, dilute with distilled water, add the composition containing eicosapentaenoic acid ethyl ester under nitrogen protection, and continuously emulsify with a high-speed disperser to form a uniform emulsion;

[0019] Distilled water is added to dilute the emulsion, the pH value of the system is adjusted to cause gelatin and gum arabic to coagulate, and octa-salicylaldehyde-based cage-type polysilsesquioxane and titanium dioxide with surface modification of salicylaldehyde functional groups are added to solidify the microcapsules to obtain a microcapsule dispersion.

[0020] The microcapsule dispersion is allowed to stand and separate to obtain wet icosapentaenoic acid ethyl ester microcapsules, which are shaped and freeze-dried to obtain icosapentaenoic acid ethyl ester soft capsule preparations.

[0021] Preferably, the process conditions for curing the microcapsules are: pH value of 4.5-6, temperature of (10-20)° C., and stirring speed of (500-800) r / min.

[0022] Preferably, the process conditions for the coagulation of gelatin and gum arabic are: pH value of 3.5-4.5, temperature of (37-45)°C, and stirring speed of (300-400) r / min.

[0023] Compared with the prior art, the present invention has the following beneficial technical effects:

[0024] The invention uses ethyl eicosapentaenoate compounded with a plurality of antioxidant auxiliary ingredients as the content, gelatin and gum arabic as the wall materials, a independently developed and synthesized safe and non-toxic cage-type polysilsesquioxane POSS framework compound with salicylaldehyde functional groups as a curing agent, and a independently developed and synthesized safe and non-toxic titanium dioxide surface-modified with salicylaldehyde functional groups as a sunscreen, and adopts a complex coacervation method to prepare the ethyl eicosapentaenoate soft capsule preparation.

[0025] The experimental results show that the eicosapentaenoic acid ethyl ester soft capsule preparation of the present invention not only has excellent stability under high temperature and high humidity conditions, but also has a peroxide value of eicosapentaenoic acid ethyl ester as low as 1.02 meq / kg and an eicosapentaenoic acid ethyl ester content as high as 98.79%. DETAILED DESCRIPTION

[0026] Example 1:

[0027] Synthesis Experiment 1-1: Synthesis of octahydrogen cage-type polysilsesquioxane: 500 mL of petroleum ether, 25 mL of concentrated hydrochloric acid, 25 g of anhydrous ferric chloride, and 1 g of sodium lauryl sulfate were added to a reaction flask and stirred for 0.5 h. 24 mL of trichlorosilane dissolved in 250 mL of petroleum ether was added to the reaction flask using a constant pressure funnel at a rate of 1 drop / 10 s. After the addition was complete, the mixture was stirred for 0.5 h, and the organic layer was allowed to stand and recrystallized from cyclohexane to obtain octahydrogen cage-type polysilsesquioxane, whose chemical structure is as follows:

[0028]

[0029] Synthesis Experiment 1-2: Synthesis of Octaacyl Chloride Cage Polysilsesquioxane: In the presence of a Karstedt catalyst, the silyl-hydrogen functional groups of the octahydrogen cage polysilsesquioxane and the alkenyl functional groups of methacryloyl chloride undergo an addition reaction. The molar ratio of the octahydrogen cage polysilsesquioxane to methacryloyl chloride is controlled to be 1:(8.05-8.3), yielding an octaacyl chloride cage polysilsesquioxane.

[0030] The experimental steps for the preparation of octaacyl chloride cage-type polysilsesquioxane are as follows: 4.24 g of octahydrogen cage-type polysilsesquioxane and 80 mL of anhydrous toluene are added to a three-necked flask, which is evacuated, filled with nitrogen for protection, and stirred. 8 mL of methacryloyl chloride dissolved in 40 mL of anhydrous toluene is added dropwise to the reaction flask using a constant pressure funnel. The temperature is raised to 80°C, 1 mL of anhydrous toluene solution containing 0.1 mL of platinum (0)-1,3-diethylene-1,1,3,3-tetramethyldisiloxane is added, and the mixture is reacted at 80°C for 8 h. 4 mL of anhydrous toluene solution containing 3 mg of triphenylphosphine is added dropwise to the reaction flask, the mixture is reacted for 2 h, and the mixture is filtered to obtain octaacyl chloride cage-type polysilsesquioxane.

[0031] The chemical structure of octaacyl chloride cage-type polysilsesquioxane is:

[0032]

[0033] Synthesis Experiment 1-3: Synthesis of Octasalicylicaldehyde-Based Cage-Type Polysilsesquioxane: In the presence of an acid-binding agent, the acyl chloride functional groups of the octaacyl chloride-based cage-type polysilsesquioxane react with the phenolic hydroxyl functional groups of salicylaldehyde through a nucleophilic addition reaction. The molar ratio of the octaacyl chloride-based cage-type polysilsesquioxane to salicylaldehyde is controlled to be 1:(8.01-8.5), yielding the octasalicylicaldehyde-based cage-type polysilsesquioxane.

[0034] The experimental steps for preparing octasalicylaldehyde-based cage-type polysilsesquioxane are as follows: 6.28 g of octaacyl chloride-based cage-type polysilsesquioxane, 0.5 mL of pyridine, and 100 mL of chloroform are added to a three-necked round-bottom flask, stirring is started, and 50 mL of chloroform dissolved with 4.5 mL of salicylaldehyde is added dropwise to the three-necked round-bottom flask using a constant pressure funnel. After the addition is complete, the mixture is refluxed at 60°C for 2 h, deionized water is added, the mixture is extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation to obtain octasalicylaldehyde-based cage-type polysilsesquioxane;

[0035] The chemical structure of octasalicyl cage-type polysilsesquioxane is:

[0036]

[0037] The hydrogen spectrum characterization results of octasalicylaldehyde cage-type polysilsesquioxane are as follows: 1 H NMR (400MHz, DMSO-d6, δ, ppm): 1.12-1.14 (d, 24H), 1.16-1.29 (m, 16H), 2.62-2.70 (m, 8H), 7.30-7.88 (m, 32H), 10.26 (s, 8H).

[0038] Example 2:

[0039] Synthesis Experiment 2-1: Synthesis of monoacyl chloride trimethoxysilane: Under the action of Karstedt's catalyst, the silyl functional group of trichlorosilane and the alkenyl functional group of methacryloyl chloride undergo an addition reaction to obtain monoacyl chloride trimethoxysilane;

[0040] The experimental steps for the preparation of monoacyl chloride trimethoxysilane are as follows: 10 mL of trichlorosilane and 80 mL of chloroform are added to a three-necked flask, the flask is vacuumed, nitrogen is filled for protection, stirring is started, 6 drops of platinum (0)-1,3-diethylene-1,1,3,3-tetramethyldisiloxane and 10 mg of triphenylphosphine are added, 30 mL of chloroform dissolved with 5 mL of methacryloyl chloride is added dropwise to the reaction flask using a constant pressure funnel, the reaction is carried out at 60°C for 4 h, the reaction is completed, the solvent is dried, and the product is purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1, V / V) to obtain monoacyl chloride trimethoxysilane;

[0041] The chemical structure of monoacyl chloride trimethoxysilane is:

[0042]

[0043] Synthesis Experiment 2-2: Synthesis of Monosalicylaldehyde Trimethoxysilane: Under the action of an acid-binding agent, the acyl chloride functional group of monoacyl chloride trimethoxysilane undergoes a nucleophilic addition reaction with the phenolic hydroxyl functional group of salicylaldehyde to generate monosalicylaldehyde trimethoxysilane.

[0044] The experimental steps for the preparation of monosalicylaldehyde trimethoxysilane are as follows: 2.26 g of monoacyl chloride trimethoxysilane, 1 mL of pyridine, and 40 mL of dichloromethane are added to a three-necked round-bottom flask, stirring is started, and 20 mL of dichloromethane dissolved with 1.2 mL of salicylaldehyde is added dropwise to the three-necked round-bottom flask using a constant pressure funnel. After the addition is complete, the mixture is refluxed at 38° C. for 2 h. After the reaction is completed, the solvent is dried, and the crude product is washed with deionized water and saturated NaHCO 3 , and the organic phase is extracted with ethyl acetate, dried with anhydrous magnesium sulfate, filtered, and the filtrate is evaporated to dryness, diluted with tetrahydrofuran, and precipitated in n-hexane, filtered, to obtain monosalicylaldehyde trimethoxysilane;

[0045] The chemical structure of monosalicylicaldehyde trimethoxysilane is:

[0046]

[0047] The hydrogen spectrum characterization results of monosalicylicaldehyde trimethoxysilane are: 1 H NMR (400MHz, DMSO-d6, δ, ppm): 1.13-1.14 (d, 3H), 1.16-1.28 (m, 2H), 2.60-2.69 (m, 1H), 3.55 (s, 9H), 7.31-7.90 (m, 4H), 10.03 (s, 1H).

[0048] Example 3:

[0049] A composition containing eicosapentaenoic acid ethyl ester comprises the following raw materials in parts by weight: 100 parts by weight of eicosapentaenoic acid ethyl ester (EPA-EE), 0.10 parts by weight of vitamin E, 0.05 parts by weight of tert-butylhydroquinone and 0.3 parts by weight of quercetin.

[0050] Example 4:

[0051] An eicosapentaenoic acid ethyl ester soft capsule preparation, consisting of contents and a capsule shell, wherein the mass ratio of the contents to the capsule shell is 1:2;

[0052] The content is the composition containing eicosapentaenoic acid ethyl ester in Example 3;

[0053] The capsule shell is composed of gelatin, gum arabic, an opacifying agent, and a curing agent;

[0054] The mass ratio of gelatin to gum arabic is 1:1;

[0055] The curing agent is octasalicyl cage-type polysilsesquioxane, and its amount is 0.25wt% of the gelatin amount;

[0056] The amount of sunscreen is 0.5 wt% of the amount of gelatin;

[0057] The sunscreen is titanium dioxide with a surface modified with salicylaldehyde functional groups, and its preparation method is as follows:

[0058] Anhydrous ethanol and water are prepared into 50 mL of a mixed solution in a volume ratio of 1:1, and ammonia water is added dropwise to adjust the pH value of the mixed solution to 9; 10 g of dry pharmaceutical-grade titanium dioxide powder (purchased from Xi'an Hongyao Pharmaceutical Excipients Co., Ltd.) is weighed and added to a beaker containing the mixed solution. After ultrasonic dispersion for 10 minutes, the mixture is transferred to a 250 mL three-necked flask and stirred in a constant temperature water bath at 80°C for 20 minutes. 10 mL of anhydrous ethanol solution containing 0.25 g of monosalicylicaldehyde trimethoxysilane is added dropwise to the three-necked flask, and the mixture is reacted in a water bath at a constant temperature for 2 hours under rapid stirring conditions. The mixture is aged at room temperature, filtered, washed, and dried in a constant temperature drying oven at 80°C for 12 hours to obtain titanium dioxide with a surface modified with a salicylaldehyde functional group.

[0059] Embodiment 5:

[0060] A preparation process of an icosapentaenoic acid ethyl ester soft capsule preparation comprises the following steps:

[0061] Step 1: prepare the ingredients according to the formula of the eicosapentaenoic acid ethyl soft capsule preparation described in Example 4;

[0062] Step 2: Gelatin (purchased from Sinopharm Chemical Reagent Co., Ltd.) and gum arabic (purchased from Shanghai Runchuang Food Co., Ltd.) were placed in a 60°C water bath and stirred to fully dissolve, and then diluted with distilled water to a concentration of 5wt%. Under nitrogen protection, a composition containing eicosapentaenoic acid ethyl ester was added, and emulsification was continued for 5 minutes using a high-speed disperser at 10,000 rpm to form a uniform emulsion;

[0063] Step 3: dilute the emulsion to a concentration of 1 wt% with distilled water, place it in a 40°C water bath, stir at 350 rpm, and add 10% acetic acid solution to adjust the pH value of the system to 4.0 to cause gelatin and gum arabic to coagulate. Maintain the temperature for 10 minutes, cool the system to 15°C, adjust the pH value of the system to 5.0 with 10% sodium oxide solution, add octa-salicylaldehyde cage-type polysilsesquioxane and titanium dioxide modified with salicylaldehyde functional groups on the surface, and stir at 600 rpm for 3 hours to solidify the microcapsules to obtain a microcapsule dispersion.

[0064] Step 4: standing the microcapsule dispersion to separate layers, removing the supernatant, filtering, and washing with distilled water to obtain wet eicosapentaenoic acid ethyl ester microcapsules, shaping, and freeze-drying to obtain eicosapentaenoic acid ethyl ester soft capsule preparation;

[0065] A stability test was conducted on wet ethyl eicosapentaenoic acid ester microcapsules. The specific method was as follows: the wet ethyl eicosapentaenoic acid ester microcapsules were stored in an 80°C water bath for 2 hours, and the morphology of the ethyl eicosapentaenoic acid ester microcapsules was observed using a polarizing microscope (XP-201 model). The experimental results showed that the spherical structure of the capsules remained intact without disintegration, and the capsule wall was clearly visible.

[0066] Example 6:

[0067] The ethyl eicosapentaenoic acid sample in the ethyl eicosapentaenoic acid soft capsule preparation prepared in Example 5 was extracted. On the one hand, the peroxide value of the ethyl eicosapentaenoic acid was determined by iodine titration, and on the other hand, the content of the ethyl eicosapentaenoic acid was determined by gas chromatography-mass spectrometry (GC-MS). The specific process is as follows:

[0068] Extracting an eicosapentaenoic acid ethyl ester sample from an eicosapentaenoic acid ethyl ester soft capsule preparation, the specific method is as follows: adding 15 g of the eicosapentaenoic acid ethyl ester soft capsule preparation, 0.5 g of neutral protease and 100 mL of deionized water to a stoppered conical flask, vortexing to mix, standing for 15 minutes, adding 100 mL of ethanol, 100 mL of petroleum ether and 100 mL of ether, shaking for 2 minutes, transferring to a separatory funnel, standing for stratification, taking the lower layer liquid, extracting with 80 mL of petroleum ether and 50 mL of ether in sequence, combining the supernatants, adding anhydrous sodium sulfate to dry, rotary evaporation at 45° C. to leave 25 mL, blowing dry with nitrogen to constant weight, and obtaining an eicosapentaenoic acid ethyl ester sample;

[0069] The peroxide value of the ethyl eicosapentaenoic acid sample obtained by the above extraction was determined by the following specific method: 2 g of the ethyl eicosapentaenoic acid sample was weighed and placed in a 250 mL conical flask, 50 mL of a mixed solution of acetic acid and isooctane (acetic acid / isooctane=3 / 2, V / V) was added, the lid was closed and shaken until the sample was dissolved; 0.5 mL of saturated potassium iodide solution was added, the stopper was closed and the reaction was allowed to proceed for 1 min, during which the conical flask was shaken at least 3 times, 30 mL of distilled water was added, and the solution was titrated with 0.1 mol of Na2S2O3 solution. Stirring was started during the titration process. When the yellow color almost disappeared, 0.5 mL of a 0.5 wt% starch solution was added, and the titration was continued until the blue color disappeared, which was the end point; at the same time, a blank solution was prepared using the same solvent and reagent for titration;

[0070] The calculation formula for the peroxide value of icosapentaenoic acid ethyl ester sample is:

[0071] Peroxide value POV (meq / kg) = [1000 × (V-V0) × c] / m;

[0072] Where: V represents the volume of Na2S2O3 solution consumed when titrating the sample, mL;

[0073] V0 represents the volume of Na2S2O3 solution consumed in the titration of blank, mL;

[0074] c represents the concentration of Na2S2O3 solution, mol / L;

[0075] m represents the sample mass, g;

[0076] The eicosapentaenoic acid ethyl ester sample obtained by the above extraction was tested for content using gas chromatography-mass spectrometry (GC-MS);

[0077] The chromatographic conditions are:

[0078] Chromatographic column: HP-5 capillary mass spectrometry column (30m×0.32mm×0.25μm);

[0079] Carrier gas: high-purity helium, carrier gas flow rate 1 mL / min;

[0080] Inlet temperature: 250°C;

[0081] Temperature program: initial temperature 50℃, maintain for 2 min, increase the temperature to 100℃ at 20℃ / min, then increase the temperature to 260℃ at 5℃ / min, maintain for 1 min;

[0082] Split ratio: 100:1;

[0083] Injection volume: 0.2 μL;

[0084] Mass spectrometry conditions:

[0085] Interface temperature: 250℃;

[0086] Ionization mode: EI source; ionization voltage: 70 eV;

[0087] Ion source temperature: 220°C;

[0088] Scan mode: full scan state, scanning range: m / z 60~500;

[0089] The above test results are shown in Table 1 below;

[0090] Table 1 Performance test results of eicosapentaenoic acid ethyl ester soft capsule preparation

[0091] Performance indicators Eicosapentaenoic acid ethyl ester soft capsule preparation Peroxide value POV (meq / kg) 1.02 Content of eicosapentaenoic acid ethyl ester (%) 98.79

[0092] The experimental results show that the peroxide value and content of icosapentaenoic acid ethyl ester in the icosapentaenoic acid ethyl ester soft capsule preparation are in compliance with the Chinese drug registration standards (peroxide value ≤ 2 meq / kg, icosapentaenoic acid ethyl ester content ≥ 96.5%).

Claims

1. A soft capsule preparation of eicosapentaenoic acid ethyl ester, characterized in that: It consists of contents and capsule shell, and the mass ratio of contents to capsule shell is 1:(1.5-3); The content is a composition containing eicosapentaenoic acid ethyl, which includes eicosapentaenoic acid ethyl and an antioxidant, and the amount of the antioxidant is (0.1-1) wt% of the amount of eicosapentaenoic acid ethyl; The capsule shell is composed of gelatin, gum arabic, an opacifying agent, and a curing agent; The mass ratio of gelatin to gum arabic is 1:(0.5-2); The curing agent is octa-salicylaldehyde cage-type polysilsesquioxane, and the amount thereof is (0.15-0.45) wt% of the amount of gelatin; The sunscreen agent is titanium dioxide with salicylaldehyde functional groups modified on the surface, and the amount of the titanium dioxide used is (0.3-0.7) wt% of the amount of gelatin.

2. The eicosapentaenoic acid ethyl ester soft capsule preparation according to claim 1, characterized in that: The antioxidant is one of vitamin E, tertiary butylhydroquinone and quercetin, or a combination of the above.

3. The eicosapentaenoic acid ethyl ester soft capsule preparation according to claim 1, characterized in that: The chemical structural formula of the octasalicyl cage-type polysilsesquioxane is:

4. The eicosapentaenoic acid ethyl ester soft capsule preparation according to claim 3, characterized in that: The preparation method of the octasalicyl cage-type polysilsesquioxane is as follows: Under the action of Karstedt catalyst, the silyl functional group of the octahydrogen cage-type polysilsesquioxane and the alkenyl functional group of methacryloyl chloride undergo addition reaction, and the molar ratio of the octahydrogen cage-type polysilsesquioxane to the methacryloyl chloride involved in the reaction is controlled to be 1:(8.05-8.3), thereby obtaining the octaacyl chloride cage-type polysilsesquioxane; Under the action of the acid-binding agent, the acyl chloride functional group of the octaacyl chloride cage-type polysilsesquioxane undergoes a nucleophilic addition reaction with the phenolic hydroxyl functional group of salicylaldehyde, and the molar ratio of the octaacyl chloride cage-type polysilsesquioxane to salicylaldehyde participating in the reaction is controlled to be 1:(8.01-8.5) to generate octasalicylaldehyde cage-type polysilsesquioxane.

5. The eicosapentaenoic acid ethyl ester soft capsule preparation according to claim 1, characterized in that: The titanium dioxide powder with salicylaldehyde functional groups on the surface is obtained by organically modifying the surface of medical grade titanium dioxide powder with monosalicylicaldehyde trimethoxysilane; The chemical structure of monosalicylicaldehyde trimethoxysilane is:

6. The eicosapentaenoic acid ethyl ester soft capsule preparation according to claim 5, characterized in that: The preparation method of the monosalicylicaldehyde trimethoxysilane is: Under the action of Karstedt's catalyst, the silyl functional group of trichlorosilane reacts with the alkenyl functional group of methacryloyl chloride to obtain monoacyl chloride trimethoxysilane; Under the action of the acid-binding agent, the acyl chloride functional group of monoacyl chloride trimethoxysilane undergoes a nucleophilic addition reaction with the phenolic hydroxyl functional group of salicylaldehyde to generate monosalicylaldehyde trimethoxysilane.

7. The preparation process of an eicosapentaenoic acid ethyl ester soft capsule preparation according to any one of claims 1 to 6, characterized in that: The following steps are involved: Fully dissolve gelatin and gum arabic, dilute with distilled water, add a composition containing eicosapentaenoic acid ethyl ester under nitrogen protection, and continuously emulsify with a high-speed disperser to form a uniform emulsion; Distilled water is added to dilute the emulsion, the pH value of the system is adjusted to cause gelatin and gum arabic to coagulate, octa-salicylaldehyde cage-type polysilsesquioxane and titanium dioxide with salicylaldehyde functional groups on the surface are added to solidify the microcapsules to obtain a microcapsule dispersion; The microcapsule dispersion is allowed to stand and separate to obtain wet eicosapentaenoic acid ethyl ester microcapsules, which are shaped and freeze-dried to obtain eicosapentaenoic acid ethyl ester soft capsule preparations.

8. The preparation process of the eicosapentaenoic acid ethyl ester soft capsule preparation according to claim 7, characterized in that: The process conditions for microcapsule curing are: pH value of 4.5-6, temperature of (10-20)°C, and stirring speed of (500-800) r / min.

9. The preparation process of the eicosapentaenoic acid ethyl ester soft capsule preparation according to claim 7, characterized in that: The process conditions for gelatin and gum arabic coagulation are: pH value of 3.5-4.5, temperature of (37-45)°C, and stirring speed of (300-400) r / min.

10. The use of an eicosapentaenoic acid ethyl ester soft capsule preparation according to any one of claims 1 to 6, characterized in that: Eicosapentaenoic acid ethyl soft capsule preparation is used to reduce triglyceride levels in adult patients with severe hypertriglyceridemia.

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