EPA phospholipid soft capsule composition and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to an EPA phospholipid soft capsule composition and a preparation method thereof.The composition comprises EPA phospholipid and an enteric soft capsule shell, the EPA phospholipid is prepared from EPA ethyl ester and a reaction substrate under the action of immobilized phospholipase, and the enteric soft capsule shell comprises an enteric material, a plasticizer and purified water. According to the EPA phospholipid enteric-coated soft capsule provided by the invention, EPA ethyl ester is phosphatidylated, and EPA phospholipid is prepared into the enteric-coated soft capsule, so that stable retention of a medicine in the stomach can be reduced, accurate dissolution of the medicine in the small intestine is realized, the problems of peculiar smell and degradation caused by release of EPA ethyl ester in the stomach are effectively avoided, and the EPA phospholipid enteric-coated soft capsule has the characteristic of pH-enzyme dual response.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to an EPA phospholipid soft capsule composition and its preparation method. Background Technology

[0002] Cardiovascular and cerebrovascular diseases are among the leading causes of death and disability worldwide. Numerous epidemiological and clinical studies have confirmed that omega-3 polyunsaturated fatty acids, especially eicosapentaenoic acid (EPA), have significant physiological activities and therapeutic potential in lowering blood lipids, reducing inflammation, inhibiting platelet aggregation, and stabilizing atherosclerotic plaques.

[0003] EPA contains multiple double bonds and is extremely sensitive to light, heat, and oxygen. It typically requires low-temperature, airtight, and light-protected storage. Most EPA products on the market use EPA ethyl ester, which is encapsulated in softgels to mask odor and improve product stability. Traditional softgels are stomach-soluble; after oral administration, they rupture in the stomach, releasing the EPA ethyl ester, causing upper gastrointestinal symptoms such as stomach discomfort, nausea, and belching, affecting consumer compliance. Furthermore, the acidic environment of the stomach can cause EPA ethyl ester to degrade, resulting in the loss of the effective active ingredient. To avoid the above situation, Chinese patent CN106822027A discloses an enteric-coated soft capsule of omega-3 acid and its derivatives and its preparation method. Although the enteric-coated soft capsule of omega-3 acid and its derivatives in this method does not release in artificial gastric juice for 3-4 hours, but releases rapidly in artificial intestinal juice, avoiding the odor and degradation problems caused by the release of omega-3 acid and its derivatives in the stomach and improving bioavailability, the preparation process is cumbersome and complex, and the uniformity and stability of the content are challenging. In addition, since the human intestine cannot directly absorb EPA ethyl ester, it needs to rely on food to promote absorption. Under the action of pancreatic enzymes and bile, it is re-esterified into triglyceride form in the intestine before it can be effectively absorbed. This process is not efficient and is greatly affected by individual digestive function. When EPA ethyl ester stays in the gastrointestinal tract for a long time, the EPA ethyl ester that is not digested and absorbed in time will still rise with the gas in the stomach, causing fishy odor and belching.

[0004] Currently, most enteric-coated soft capsules use gelatin as the capsule shell, which has excellent formability and biocompatibility. However, its inherent acid solubility dictates that it must rely on additional and complex enteric coating, which not only increases costs and process complexity but also introduces new risks related to the compatibility between the coating layer and the contents. In addition, while using single-material enteric coating materials such as HPMCAS, sodium alginate, and pectin for direct molding eliminates the coating step, single materials have disadvantages such as poor biodegradability, weak intestinal targeting, and insufficient mechanical strength, which directly affect drug bioavailability and formulation stability.

[0005] In summary, there is an urgent need for an EPA derivative soft capsule composition that is stable, has high absorption and utilization rates, does not rely on food to promote absorption, and has intestinal targeting. Summary of the Invention

[0006] The purpose of this invention is to provide a new EPA phospholipid soft capsule composition to solve the technical problems of traditional EPA ethyl ester, such as instability, low absorption and utilization rate, large gastrointestinal side effects, and dependence on food to promote absorption.

[0007] To address the aforementioned problems, one objective of this invention is to provide a pH-enzyme-responsive EPA phospholipid enteric-coated soft capsule composition, comprising EPA phospholipids and an enteric-coated soft capsule shell; wherein, The EPA phospholipids are prepared by reacting EPA ethyl ester with a reaction substrate under the action of an immobilized phospholipase. The immobilized phospholipase in the EPA phospholipids is selected from one or more of phospholipase A1, phospholipase A2, phospholipase C and phospholipase D, with immobilized phospholipase A1 being preferred.

[0008] The reaction substrate is selected from one or more of soybean phosphatidylcholine, lysophosphatidylcholine, soybean lecithin, and egg yolk phosphatidylcholine, with soybean lecithin or egg yolk phosphatidylcholine being preferred.

[0009] The enteric-coated soft capsule shell comprises an enteric material, a plasticizer, and purified water, wherein the weight ratio of the enteric material, plasticizer, and purified water is (0.75~1.2):(0.3~0.5):(0.5~1.5), preferably 1:0.45:0.85. As a preferred embodiment, the enteric material is a composition of hydroxypropyl methylcellulose acetate succinate, sodium alginate, and carboxymethyl chitosan. Furthermore, the mass ratio of hydroxypropyl methylcellulose acetate succinate, sodium alginate, and carboxymethyl chitosan is (1.5:1):(0.01:0.5):(0.1~0.8), preferably 1:0.35:0.28.

[0010] As a preferred embodiment, the hydroxypropyl methylcellulose acetate succinate is one or more of the MF, LF, and HF types, with the LF type being preferred. The LF type hydroxypropyl methylcellulose acetate succinate has an acetyl substitution degree of 5% to 9% and a succinyl substitution degree of 14% to 18%.

[0011] As a preferred embodiment, the degree of substitution of the carboxymethyl chitosan is 0.7~1.0, and the purity is ≥98%. This degree of substitution can balance the hydrophilic-hydrophobic properties of carboxymethyl chitosan: it can synergistically enhance acid resistance with HPMCAS, and form a stable three-dimensional network structure with sodium alginate, avoiding defects such as pores and cracks in the capsule shell due to poor solubility; at the same time, sufficient carboxyl groups can form hydrogen bonds with the hydroxyl groups of sodium alginate, and produce a hydrophobic-hydrophilic synergistic effect with the ester groups of HPMCAS, improving the film-forming uniformity of the ternary system.

[0012] The carboxyl group (-COOH) of carboxymethyl chitosan is protonated in the acidic environment of the stomach, which reduces its water solubility and can help HPMCAS enhance the acid resistance of the capsule. In the alkaline environment of the intestine (pH 6.0~7.5), the carboxyl group dissociates into -COO⁻, and the molecule swells and dissolves, ensuring that the capsule disintegrates and releases the drug in time in the intestine.

[0013] As a preferred embodiment, the plasticizer is one or more of glycerin, sorbitol, maltitol, sorbitol-sorbitan solution, mannitol, erythritol, and xylitol. Furthermore, the plasticizer is glycerol and sorbitol, wherein the ratio of glycerol to sorbitol is 1:(0.8~2.0), preferably 1:1.

[0014] Another object of the present invention is to provide a method for preparing an EPA phospholipid enteric-coated soft capsule composition, comprising the following steps: (1) Preparation of EPA phospholipids: ① First, mix the reaction substrate and EPA ethyl ester in a certain proportion until homogeneous. The mass ratio of the reaction substrate to EPA ethyl ester is 1:(1~10).

[0015] ②Then immobilized phospholipase A1 (5%~30% w / w, relative to the total mass of the substrate) and distilled water (0.2%~2.5 w / w, relative to the total mass of the substrate) were added to ①, and after purging with nitrogen, the reaction was carried out at a set temperature for 3~48 h with a stirring speed of 100~800 rpm, preferably 200 rpm.

[0016] ③ After filtering the mixture from reactions ① and ② to remove the immobilized enzyme, add 5 times the volume of cold acetone, centrifuge for 5-30 minutes, and separate the precipitate. The supernatant is a mixture of acetone and EPA ethyl ester. Evaporate the acetone under reduced pressure to recover the EPA ethyl ester. Wash the precipitate repeatedly with acetone until the washing liquid is dropped onto a clean glass slide and evaporated quickly without any oil residue. Dry with nitrogen to obtain EPA phospholipids.

[0017] As a preferred embodiment, the reaction substrate in step ① is soybean lecithin, and the mass ratio of soybean lecithin to EPA ethyl ester is 1:6. As a preferred option, the amount of immobilized phospholipase A1 added in step ② is 20% (w / w) of the total substrate mass.

[0018] As a preferred option, the amount of distilled water added in step ② is 0.75% (w / w) of the total mass of the substrate.

[0019] As a preferred option, the reaction temperature in step ② is 30℃~65℃, and the transesterification reaction lasts for 3h~60h.

[0020] As a preferred option, in step ③, after filtering the mixture to remove the immobilized enzyme, add 3 to 10 times the volume of cold acetone, centrifuge for 10 minutes, and then separate the precipitate.

[0021] (2) Preparation of enteric-coated soft capsule materials: ① Pretreatment and water preparation: Pass HPMCAS, sodium alginate, and carboxymethyl chitosan through an 80-100 mesh sieve. Add the prescribed amount of purified water to a mixing tank, heat to 50-55℃, and maintain the temperature.

[0022] ② Dissolving the hydrophilic matrix: Under low-speed stirring at 200 rpm, add the plasticizer, sodium alginate and carboxymethyl chitosan to the warm water in ① and stir for 15 minutes until completely dissolved to form a uniform and viscous polysaccharide matrix.

[0023] ③ Dispersing and swelling HPMCAS: Increase the stirring speed to 500 rpm, slowly add HPMCAS powder to the above polysaccharide matrix in multiple portions, with an interval of at least 6 minutes between each addition, and continue stirring for 30 minutes until a semi-transparent swelling system without obvious particles is formed.

[0024] ④ Vacuuming and degassing: Place the liquid under a vacuum of ≤-0.08MPa, vacuum, degas, let stand for at least 2 hours, then sieve for later use.

[0025] As a preferred option, the stirring speed in step ② above is 100~300 rpm.

[0026] As a preferred option, the stirring time in step ② above is 10 min to 60 min.

[0027] As a preferred option, the stirring speed in step ③ above is 400 rpm to 600 rpm.

[0028] As a preferred option, in step ③ above, HPMCAS powder is slowly added to the polysaccharide matrix in 3-6 portions, with an interval of 6-15 minutes between each addition.

[0029] (3) Preparation of EPA phospholipid enteric-coated soft capsules EPA phospholipids are poured into the hopper of a fully automatic soft capsule machine. The contents are maintained at a constant temperature in the filling system. The enteric-coated soft capsule material prepared above is used to press the contents into soft capsules. These capsules are then dried in a gradient from 18°C ​​to 33°C and set at 20°C to 27°C to obtain EPA phospholipid enteric-coated soft capsules. Each soft capsule contains 1.0g of EPA phospholipids. As a preferred option, the temperature of the contents in the constant temperature filling system is 30-35℃.

[0030] This invention addresses the problems of instability, low absorption and utilization, significant gastrointestinal side effects, and reliance on food to promote absorption in existing EPA ethyl ester soft capsules. By phospholipidifying EPA ethyl ester, the instability and low absorption and utilization of EPA ethyl ester are improved. Furthermore, by incorporating a compound enteric coating material of hydroxypropyl methylcellulose acetate succinate, sodium alginate, and carboxymethyl chitosan into the capsule shell, the polyelectrolyte complex of sodium alginate and carboxymethyl chitosan synergistically enhances enteric coating performance and biocompatibility, overcoming the shortcomings of poor enteric coating and insufficient stability in traditional single / binary systems. This improves the intestinal targeting of the drug, solves the problems of odor and degradation caused by release in the stomach, and enhances bioavailability.

[0031] Furthermore, the EPA phospholipids prepared by the specific enzymatic catalysis process described above are chemically stable, not easily oxidized or degraded, more easily absorbed by the human body, and have superior bioavailability. Simultaneously, the enteric-coated soft capsule shell of this invention protects the EPA phospholipids as they safely pass through gastric juice, dissolving and releasing them in the alkaline environment of the intestine, significantly improving bioavailability. Specifically, the pH response mechanism is as follows: In the gastric environment (pH 1.2), the amino group of carboxymethyl chitosan is protonated, forming a tight polyelectrolyte complex structure with the carboxyl group of sodium alginate. The HPMCAS molecular chains contract, jointly preventing the capsule shell from swelling. Upon entering the small intestine (pH 5.5~6.0), the succinyl group of HPMCAS dissociates, the molecular chains unfold, and the sodium alginate-carboxymethyl chitosan polyelectrolyte complex swells due to charge repulsion caused by the increased pH, and the capsule shell begins to disintegrate, creating conditions for enzyme response. This pH threshold precisely matches the small intestinal absorption window, avoiding the problem of decreased absorption efficiency caused by the lag in pH response of traditional materials.

[0032] The enzyme response mechanism is as follows: Complete enzymatic degradation by the intestine exposes the sodium alginate skeleton after swelling, which can be specifically hydrolyzed by alginate lyases in the intestinal flora. Simultaneously, the glycosidic bonds of carboxymethyl chitosan are gradually broken by intestinal glycosidases, leading to the complete disintegration of the sodium alginate-carboxymethyl chitosan polyelectrolyte complex network. The synergistic mechanism of pH-enzyme response is as follows: the "pre-swelling" of pH response provides sufficient sites for enzyme degradation, avoiding slow degradation caused by enzymes acting only on the shell surface; while enzymatic degradation accelerates shell disintegration, solving the problem of incomplete dissolution of single pH-responsive materials. Detailed Implementation

[0033] The following embodiments are used to illustrate the present invention, but are not intended to limit the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they should be performed in accordance with the techniques or conditions described in the literature in the field, or in accordance with the product manual.

[0034] In the following embodiments, all instruments and equipment used, unless otherwise specified, are conventional products that can be purchased through legitimate channels. Unless otherwise stated, all methods described are conventional methods, and all raw materials are available from publicly available commercial sources.

[0035] Hydroxypropyl methylcellulose acetate succinate (AQOAT) ® HPMCAS-LF was purchased from Shin-Etsu Chemical Co., Ltd., Japan; sodium alginate was purchased from Qingdao Mingyue Algae Group Co., Ltd.; carboxymethyl chitosan was purchased from Jiangsu Kangting Biotechnology Co., Ltd.; glycerol was purchased from Nanchang Baiyun Pharmaceutical Co., Ltd.; sorbitol was purchased from Roquette Freres; immobilized phospholipase A1 was prepared in-house; soybean lecithin was purchased from Avanti Polar-Lipids, USA; ethyl EPA was purchased from Chemport Inc., South Korea; high-purity nitrogen (purity ≥99.999%) was purchased from Xuzhou Xinchang Gas Co., Ltd.; acetone, potassium dihydrogen phosphate, sodium hydroxide, hydrochloric acid, etc. were all analytical grade, and trypsin and pepsin were biochemical reagents, all of which were purchased from Sinopharm Chemical Reagent Co., Ltd.

[0036] YWJ100-Ⅱ Fully Automatic Soft Capsule Machine, Beijing Xinhangcheng Shangjie (Langfang) Technology Development Co., Ltd.; RV10 DS96 Rotary Evaporator, IKA, Germany; BSD-YX2200 Constant Temperature Shaker, Shanghai Boxun Medical Biological Instrument Co., Ltd.; HPLC High Performance Liquid Chromatograph, Agilent Technologies, USA; ZB-1D Intelligent Disintegrator, Tianjin University Precision Instrument Factory; 8890 Gas Chromatograph, Agilent Technologies, USA.

[0037] Example 1 (1) Preparation of EPA phospholipids ① Mix soybean lecithin and EPA ethyl ester at a mass ratio of 1:6 until homogeneous.

[0038] ②Immobilized phospholipase A1 (20.3% w / w, relative to the total substrate mass) and distilled water (0.75% w / w, relative to the total substrate mass) were added to ①, and after purging with nitrogen, the mixture was reacted at 40℃ for 48 h with a stirring speed of 200 rpm.

[0039] ③ After filtering the mixture of reactions ① and ② to remove the immobilized enzyme, add 3 times the volume of cold acetone, centrifuge for 10 min and separate the precipitate. The supernatant is a mixture of acetone and EPA ethyl ester. Evaporate the acetone under reduced pressure to recover the EPA ethyl ester. Wash the precipitate repeatedly with acetone until the washing liquid is dropped onto a clean glass slide and evaporated quickly without any oil residue. Dry with nitrogen to obtain EPA phospholipids.

[0040] (2) Preparation of enteric-coated soft capsule material: Element Prescription dosage Hydroxypropyl methylcellulose acetate succinate LF type (acetyl substitution degree 8%, succinyl substitution degree 16%) 15kg Sodium alginate 5.25kg Carboxymethyl chitosan (degree of substitution 0.8, purity 99.2%) 4.2kg glycerin 5.5kg Sorbitol 5.5kg Purified water 20.78kg ① Pretreatment and water preparation: First, pass HPMCAS-LF, sodium alginate, and carboxymethyl chitosan through an 80-100 mesh sieve. Add the prescribed amount of purified water to a mixing tank, heat to 50-55℃, and maintain the temperature.

[0041] ② Dissolving the hydrophilic matrix: Under low-speed stirring at 200 rpm, add glycerol, sorbitol, sodium alginate and carboxymethyl chitosan to the warm water in ① and stir for 35 min until completely dissolved to form a uniform and viscous polysaccharide matrix.

[0042] ③ Dispersing and swelling HPMCAS-LF: Increase the stirring speed to 500 rpm, slowly add HPMCAS-LF powder to the above polysaccharide matrix in multiple batches, with an 8-minute interval between each addition, and continue stirring for 30 minutes until a semi-transparent swelling system without obvious particles is formed.

[0043] ④ Vacuuming and degassing: Place the liquid under a vacuum of ≤-0.08MPa, vacuum, degas, let stand for at least 2 hours, then sieve for later use.

[0044] (3) Preparation of EPA phospholipid enteric-coated soft capsules EPA phospholipids are poured into the hopper of a fully automatic soft capsule machine. The contents are kept at a constant temperature of 30-35℃ in the filling system. The enteric-coated soft capsule material obtained in step (2) is used to compress the contents into soft capsules. These capsules are then dried in a gradient of 18℃ to 33℃ and shaped at 20-27℃ to obtain EPA phospholipid enteric-coated soft capsules. Each soft capsule contains 1.0g of EPA phospholipids.

[0045] Example 2 (1) Preparation of EPA phospholipids ① Mix soybean lecithin and EPA ethyl ester at a mass ratio of 1:8.

[0046] ②Immobilized phospholipase A1 (21.8% w / w, relative to the total substrate mass) and distilled water (0.75% w / w, relative to the total substrate mass) were added to ①, and after purging with nitrogen, the mixture was reacted at 40℃ for 24 h with a stirring speed of 250 rpm.

[0047] ③ After filtering the mixture of reactions ① and ② to remove the immobilized enzyme, add 3 times the volume of cold acetone, centrifuge for 10 min and separate the precipitate. The supernatant is a mixture of acetone and EPA ethyl ester. Evaporate the acetone under reduced pressure to recover the EPA ethyl ester. Wash the precipitate repeatedly with acetone until the washing liquid is dropped onto a clean glass slide and evaporated quickly without any oil residue. Dry with nitrogen to obtain EPA phospholipids.

[0048] (2) Preparation of EPA phospholipid enteric-coated soft capsules: Element Prescription dosage Hydroxypropyl methylcellulose succinate LF type (acetyl substitution degree 5%, succinyl substitution degree 14%) 15kg Sodium alginate 5.0kg Carboxymethyl chitosan (degree of substitution 0.7, purity 99.8%) 4.5kg glycerin 8.6kg Purified water 19.6kg ① Pretreatment and water preparation: First, pass HPMCAS-LF, sodium alginate, and carboxymethyl chitosan through an 80-100 mesh sieve. Add the prescribed amount of purified water to a mixing tank, heat to 50-55℃, and maintain the temperature.

[0049] ② Dissolving the hydrophilic matrix: Under low-speed stirring at 200 rpm, add glycerol, sodium alginate and carboxymethyl chitosan to the warm water in ① and stir for 25 minutes until completely dissolved to form a uniform and viscous polysaccharide matrix.

[0050] ③ Dispersing and swelling HPMCAS-LF: Increase the stirring speed to 450 rpm, slowly add HPMCAS-LF powder to the above polysaccharide matrix in multiple batches, with a 10-minute interval between each addition, and continue stirring for 40 minutes until a semi-transparent swelling system without obvious particles is formed.

[0051] ④ Vacuuming and degassing: Place the liquid under a vacuum of ≤-0.08MPa, vacuum, degas, let stand for at least 2 hours, then sieve for later use.

[0052] ⑤ Pour EPA phospholipids into the hopper of a fully automatic soft capsule machine. Maintain the contents temperature at 30-35℃ in a constant-temperature filling system. Compress the contents into soft capsules using enteric-coated soft capsule material. Dry the soft capsules in a gradient of 18℃~33℃ and set them at 20~27℃ to obtain EPA phospholipid enteric-coated soft capsules. Each soft capsule contains 1.0g of EPA phospholipids.

[0053] Example 3 (1) Preparation of EPA phospholipids ① Mix soybean lecithin and EPA ethyl ester at a mass ratio of 1:5 until homogeneous.

[0054] ② Add immobilized phospholipase A1 (15% w / w, relative to the total substrate mass) and distilled water (0.5% w / w, relative to the total substrate mass) to ①, purge with nitrogen, and react at 40°C for 60 h with stirring speed of 250 rpm.

[0055] ③ After filtering the mixture of reactions ① and ② to remove the immobilized enzyme, add 3 times the volume of cold acetone, centrifuge for 20 min and separate the precipitate. The supernatant is a mixture of acetone and EPA ethyl ester. Evaporate the acetone under reduced pressure to recover the EPA ethyl ester. Wash the precipitate repeatedly with acetone until the washing liquid is dropped onto a clean glass slide and evaporated quickly without any oil residue. Dry with nitrogen to obtain EPA phospholipids.

[0056] (2) Preparation of EPA phospholipid enteric-coated soft capsules: Element Prescription dosage Hydroxypropyl methylcellulose succinate LF type (acetyl substitution degree of 9%, succinyl substitution degree of 18%) 15kg Sodium alginate 5.6kg Carboxymethyl chitosan (degree of substitution 1.0, purity 98.9%) 4.8kg Sorbitol 11.2kg Purified water 21.5kg ① Pretreatment and water preparation: First, pass HPMCAS-LF, sodium alginate, and carboxymethyl chitosan through an 80-100 mesh sieve. Add the prescribed amount of purified water to a mixing tank, heat to 50-55℃, and maintain the temperature.

[0057] ② Dissolving the hydrophilic matrix: Under low-speed stirring at 250 rpm, add sorbitol, sodium alginate and carboxymethyl chitosan to ① warm water, stir for 30 min until completely dissolved to form a uniform and viscous polysaccharide matrix.

[0058] ③ Dispersing and swelling HPMCAS-LF: Increase the stirring speed to 450 rpm, slowly add HPMCAS-LF powder to the above polysaccharide matrix in multiple batches, with an interval of 12 min between each addition, and continue stirring for 35 min until a semi-transparent swelling system without obvious particles is formed.

[0059] ④ Vacuuming and degassing: Place the liquid under a vacuum of ≤-0.08MPa, vacuum, degas, let stand for at least 2 hours, then sieve for later use.

[0060] ⑤ Pour EPA phospholipids into the hopper of a fully automatic soft capsule machine. Maintain the contents temperature at 30-35℃ in a constant-temperature filling system. Compress the contents into soft capsules using enteric-coated soft capsule material. Dry the soft capsules in a gradient of 18℃~33℃ and set them at 20~27℃ to obtain EPA phospholipid enteric-coated soft capsules. Each soft capsule contains 1.0g of EPA phospholipids.

[0061] Comparative Example Commercially available eicosapentaenoic acid ethyl capsules were used as a comparative example.

[0062] The EPA phospholipid raw material prepared in Example 1 and the commercially available EPA ethyl ester raw material were respectively placed in sealed stoppered glass bottles and stored for 10 days and 30 days under high temperature (50°C) and high humidity (92.5%RH, 25°C), respectively; and under light (total illuminance not less than 1.2 × 10⁻⁶ ppm). 6 Lux•hr, near-ultraviolet energy not less than 200w•hr / m 2 Under the conditions of ), the samples were placed in sealed glass bottles with stoppers for 6 days and 12 days respectively. The properties and contents were measured and compared with the samples from day 0. The results of stability are summarized in Table 1 below.

[0063] Table 1 Summary of Chemical Stability Study Results of EPA Phospholipid and EPA Ethyl Ester Raw Materials in Example 1 As can be seen from Table 1, compared with commercially available EPA ethyl ester raw materials, the EPA phospholipids prepared in this application have higher stability under high temperature, high humidity and light conditions.

[0064] Table 2 shows a comparison of the disintegration time and accelerated stability of Examples 1-3 and Comparative Example 1 in artificial gastric and intestinal fluids. Enteric coagulation test: In vitro digestion simulation was performed. Ten capsules with intact appearance were randomly selected from each set of examples and comparative examples and placed in artificial gastric fluid. After 2 hours of treatment, they were removed and checked for cracks or disintegration. The number was counted and recorded. Then, capsules without cracks or disintegration were selected, washed with a small amount of water, and placed in artificial intestinal fluid for examination. The average disintegration time was calculated and recorded.

[0065] Artificial gastric fluid and artificial intestinal fluid were prepared according to the methods for preparing artificial gastric fluid and artificial intestinal fluid in the 2025 edition of the Chinese Pharmacopoeia. The preparation method for artificial gastric fluid was as follows: 16.4 ml of dilute hydrochloric acid and 10 g of pepsin were measured, 800 ml of water was added, mixed well, and the volume was adjusted to 1000 ml.

[0066] The artificial intestinal fluid is prepared as follows: Weigh 6.8g of potassium dihydrogen phosphate, dissolve it in 500ml of water, add 0.1mol / L sodium hydroxide to adjust the pH to 6.8, take 10g of pancreatic enzyme, dissolve it in water, mix it with the above potassium dihydrogen phosphate solution, and dilute it with water to 1000ml to obtain the final product.

[0067] Table 2 Comparison of Acceleration Stability between Examples 1-3 and Comparative Example 1 As shown in Table 2, compared with commercially available soft capsules, the EPA phospholipid-type enteric-coated soft capsules prepared in this application were relatively stable during the accelerated stability study for 6 months, with essentially no change in content, while the content of commercially available soft capsules showed significant differences. The EPA phospholipid-type enteric-coated soft capsules prepared in this application did not disintegrate within 2 hours in simulated gastric fluid, with no content dissolution or capsule shell damage, and completely disintegrated within 20 minutes in simulated intestinal fluid. This indicates that the EPA phospholipid enteric-coated soft capsules prepared in this invention have the property of not dissolving in the stomach but being released in a concentrated manner in the intestine, thereby improving the bioavailability of EPA.

[0068] This embodiment, by phospholipidifying EPA ethyl ester and formulating EPA phospholipids into enteric-coated soft capsules, effectively avoids the odor and degradation problems caused by the release of EPA ethyl ester in the stomach, thus improving bioavailability. Furthermore, phospholipid-type EPA is more stable, more easily absorbed by the human body, more effectively crosses the blood-brain barrier, and has superior bioavailability. The pH-enzyme-responsive enteric-coated soft capsules overcome the technical shortcomings of existing enteric-coated soft capsule materials, such as poor acid stability, insufficient precision in intestinal targeted release, and imbalance between biocompatibility and mechanical properties. They achieve dual pH-enzyme response characteristics, reducing stable drug retention in the stomach and facilitating precise dissolution in the small intestine.

[0069] In addition to the above embodiments, the immobilized phospholipase in this scheme is also selected from one or more of phospholipase A2, phospholipase C and phospholipase D; In this scheme, the reaction substrate can also be selected from one or more of soybean phosphatidylcholine, lysophosphatidylcholine, and egg yolk phosphatidyl lipoprotein; In this scheme, the plasticizer may also be selected from one or more of maltitol, sorbitol-sorbitan solution, mannitol, erythritol and xylitol.

[0070] In this scheme, the hydroxypropyl methylcellulose acetate succinate type can also be selected from one or more of the MF, LF, and HF types.

[0071] Other reagents with similar properties and the selection of similar reaction parameters can be determined by those skilled in the art based on common knowledge. The above descriptions are merely embodiments of the present invention, and the specific structures, properties, and reactant ratios known in the schemes are not described in detail here. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention, such as simply adjusting the selection of parameters within or near a specified parameter range. These should also be considered within the scope of protection of the present invention, and will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application shall be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. An EPA phospholipid enteric-coated soft capsule composition, characterized in that: It includes EPA phospholipids and enteric-coated soft capsule shells, among which, The EPA phospholipids are prepared by reacting EPA ethyl ester with a reaction substrate under the action of an immobilized phospholipase. The immobilized phospholipase in the EPA phospholipids is selected from one or more of phospholipase A1, phospholipase A2, phospholipase C, and phospholipase D. The reaction substrate is selected from one or more of soybean phosphatidylcholine, lysophosphatidylcholine, soybean lecithin, and egg yolk phospholipid. The enteric-coated soft capsule shell comprises enteric material, plasticizer, and purified water, wherein the weight ratio of enteric material, plasticizer, and purified water is 0.75~1.2:0.3~0.5:0.5~1.

5.

2. The EPA phospholipid enteric-coated soft capsule composition as described in claim 1, characterized in that: The enteric material is a composition of hydroxypropyl methylcellulose acetate succinate, sodium alginate, and carboxymethyl chitosan, wherein the weight ratio of hydroxypropyl methylcellulose acetate succinate, sodium alginate, and carboxymethyl chitosan is 1.5~1:0.01~0.5:0.1~0.

8.

3. The EPA phospholipid enteric-coated soft capsule composition as described in claim 1, characterized in that: The plasticizer is one or more of glycerol, sorbitol, maltitol, sorbitol-sorbitan solution, mannitol, erythritol and xylitol.

4. The EPA phospholipid enteric-coated soft capsule composition as described in claim 2, characterized in that: The hydroxypropyl methylcellulose acetate succinate is one or more of the MF, LF and HF types, and the degree of acetyl substitution in the hydroxypropyl methylcellulose acetate succinate is 5%~11% and the degree of succinyl substitution is 8%~18%.

5. The EPA phospholipid enteric-coated soft capsule composition as described in claim 2, characterized in that: The degree of substitution of the carboxymethyl chitosan is 0.7~1.0, and the purity is ≥98%.

6. The EPA phospholipid enteric-coated soft capsule composition as described in claim 1, characterized in that: The plasticizers are glycerin and sorbitol, with a ratio of glycerin to sorbitol of 1:0.8~2.

0.

7. A method for preparing the EPA phospholipid enteric-coated soft capsule composition as described in claim 1, characterized in that... It includes the following steps: (1) Preparation of EPA phospholipids: First, the reaction substrate and EPA ethyl ester are mixed evenly in a set ratio of 1:1 to 10. Then, 5% to 30% w / w immobilized phospholipase and 0.2% to 2.5% w / w distilled water are added, and the mixture is purged with nitrogen and reacted at 30 to 65°C for 3 to 48 hours. Finally, the mixture is filtered to remove the immobilized phospholipase, and 5 times the volume of cold acetone is added. The precipitate is separated by centrifugation, and the supernatant is a mixture of acetone and EPA ethyl ester. The acetone is removed by vacuum distillation to recover the EPA ethyl ester. The precipitate is repeatedly washed with acetone and dried with nitrogen to obtain EPA phospholipids. Preparation of enteric-coated soft capsule material: First, prepare the prescribed amount of purified water and heat it to 50-55℃ and maintain the temperature. Then, add plasticizer, sodium alginate, and carboxymethyl chitosan according to the prescription ratio, and stir until completely dissolved to form a uniform and viscous polysaccharide matrix. After that, accelerate the stirring and add the corresponding hydroxypropyl methylcellulose succinate powder in batches, and continue stirring until a semi-transparent swelling system without obvious particles is formed. Finally, vacuum and degas the system for later use to obtain the enteric-coated soft capsule material. EPA phospholipid enteric-coated soft capsules EPA phospholipids are poured into the hopper of a fully automatic soft capsule machine. The contents are kept in a constant temperature filling system at a set temperature. The soft capsules are then pressed using enteric-coated soft capsule material and dried in a gradient of 18°C ​​to 33°C. The soft capsules are then set at 20°C to 27°C to obtain EPA phospholipid enteric-coated soft capsules.

8. The method for preparing an EPA phospholipid enteric-coated soft capsule composition as described in claim 7, characterized in that: In step (1), the immobilized phospholipase added is immobilized phospholipase A1, the amount added is 20% w / w, the amount of distilled water added is 0.75% w / w, and the reaction substrate is soybean lecithin, the mass ratio of which to EPA ethyl ester is 1:

6.

9. The method for preparing an EPA phospholipid enteric-coated soft capsule composition as described in claim 7, characterized in that: In step (2), hydroxypropyl methylcellulose succinate powder is slowly added to the polysaccharide matrix in 3-6 portions, with an interval of 6-15 minutes between each addition.

10. The method for preparing an EPA phospholipid enteric-coated soft capsule composition as described in claim 7, characterized in that: In step (3), the temperature of the contents in the constant temperature filling system is 30-35℃.

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