Double-layer capsule shell controlled release type fish oil soft capsule and preparation method thereof

Abstract

The invention discloses a double-layer capsule shell controlled release type fish oil soft capsule and a preparation method thereof, and relates to the technical field of fish oil soft capsules. The double-layer capsule shell controlled release type fish oil soft capsule comprises an outer-layer large capsule shell, an inner-layer small capsule shell and a fish oil content wrapped in the inner-layer small capsule shell. Multiple technical breakthroughs are realized through the design of a double-layer structure and a whole polysaccharide system: the outer layer capsule shell constructs an environment barrier, the inner layer realizes targeted controlled release of intestinal tracts, intragastric stimulation of fish oil is avoided from the source, and requirements of special crowds such as infants, postoperative patients and the like are met; the whole polysaccharide raw material replaces gelatin, so that the problem of cross-linking aging is avoided, and long-term disintegration stability and bioavailability of the capsule shell are guaranteed; meanwhile, the auxiliary materials synergistically improve the storage performance, the pain points of gastrointestinal discomfort, storage failure and the like of a traditional single-layer capsule shell and an open capsule shell are effectively solved, the comprehensive performance is remarkably superior to that of a traditional fish oil soft capsule, and the fish oil soft capsule has safety, stability and adaptability to special crowds.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of fish oil soft capsules, in particular to a double-layer capsule shell controlled-release fish oil soft capsule and a preparation method thereof. BACKGROUND

[0002] As a mainstream dosage form for supplementing Omega-3 polyunsaturated fatty acids (mainly including EPA and DHA), fish oil soft capsules are favored because they can effectively mask the fishy smell of fish oil and precisely control the dosage. However, the existing conventional single-layer structure fish oil soft capsules still have technical bottlenecks that have not been overcome in terms of long-term storage stability and applicability to specific groups of people.

[0003] Firstly, the chemical stability of the core components of fish oil is relatively poor. The molecular structure of EPA and DHA contains multiple unsaturated double bonds, which are easily affected by oxygen, light and temperature in the environment and oxidize and rancid, leading to degradation of effective components, increase of peroxide value and generation of unpleasant halitosis. The barrier ability of conventional single-layer capsule shell, whether traditional gelatin capsules or other polysaccharide matrix capsules, to oxygen and ultraviolet light is limited, which makes it difficult to ensure the quality stability of the product during the shelf life.

[0004] Secondly, the gastrointestinal disintegration behavior of the existing soft capsules is single, which cannot meet the needs of special groups of people. For infants and young children whose gastrointestinal function has not yet developed perfectly, or for patients who are in the postoperative recovery period and have fragile intestinal mucosa, traditional soft capsules disintegrate rapidly in the stomach acid environment, which can instantly release high concentrations of fish oil. This sudden stimulation can easily cause gastrointestinal discomfort such as diarrhea, abdominal distension or nausea, thereby limiting the safe application of fish oil in these groups of people who urgently need nutritional support.

[0005] In addition, the core raw material of traditional gelatin capsules is mainly gelatin, which is made by hydrolysis of collagen. The amino acids in its molecules are prone to Maillard cross-linking reaction with aldehyde substances released from fish oil during storage, which causes the capsule shell to harden and age over time, thereby causing delayed disintegration and affecting bioavailability.

[0006] Therefore, there is an urgent need in the art for an innovative fish oil soft capsule technical solution; this solution must systematically solve the above problems: on the one hand, it must have excellent barrier properties to provide all-round protection for fish oil to maintain long-term storage stability; on the other hand, it should be able to intelligently control the release behavior of the contents to achieve intestinal targeted release, thereby completely eliminating the gastrointestinal irritation to sensitive groups of people. This has become a clear and urgent topic to be tackled in this technical field.

[0007] The information disclosed in this BACKGROUND section is only for the purpose of increasing the understanding of the background of the present application and should not be regarded as an acknowledgment or any form of suggestion that this information forms prior art that is publicly known. SUMMARY

[0008] To solve the above problems, the present application provides a double-layer capsule shell controlled-release fish oil soft capsule and a preparation method thereof.

[0009] Firstly, the design principle of the double-layer capsule shell controlled-release fish oil soft capsule and the preparation method thereof is as follows: (I) Abandoning the defects of gelatin to ensure the long-term stability and bioavailability of the capsule shell In view of the inherent problems of traditional gelatin capsule shell, the present application fundamentally solves the problems by replacing gelatin with polysaccharide composite glue: the outer large capsule shell uses "konjac glucomannan-trehalose composite glue", and the inner small capsule shell uses "pullulan-low acyl gellan gum composite glue". Both types of composite glue do not contain the amino acid side chain in gelatin, which completely eliminates the Maillard crosslinking reaction.

[0010] At the same time, the polysaccharide molecules form a stable network through glycosidic bonds, and the process of low-temperature dissolution, dynamic defoaming (avoiding micropores), and gradient drying ensures that the capsule shell does not harden or crack during long-term storage, and the disintegration performance is always stable, completely solving the pain points of the aging failure of traditional gelatin capsule shell.

[0011] It is explained that the preparation of konjac glucomannan-trehalose composite glue and pullulan-low acyl gellan gum composite glue is a conventional physical mixing technology. The core process is: taking two raw materials according to their respective specific mass ratio, dissolving and uniformly mixing them under heating conditions through mechanical stirring, and then obtaining the product.

[0012] (II) Key scene adaptation: precise solution for controlled-release fish oil for infants and postoperative patients Scene pain points: the thickness of the gastrointestinal mucosa of infants is only 1 / 3 of that of adults, and direct gastric release of fish oil can easily cause diarrhea; postoperative patients need to slowly intake Omega-3 to reduce inflammatory response, and single capsule shell rapid release cannot meet the needs; Adaptation logic: first, when the soft capsule enters the stomach (acidic environment, pH 1.2-3.0), the konjac glucomannan in the outer large capsule shell will form a dense gel barrier under acidic conditions - this gel structure can firmly lock the outer shape, preventing the large capsule shell from disintegrating in the stomach, and thus preventing the inner small capsule shell from being exposed to the stomach cavity in advance, thereby blocking the release of fish oil in the stomach from the root and avoiding direct stimulation of high-concentration fish oil on the gastric mucosa (especially the fragile mucosa of infants and postoperative patients); Subsequently, with the gastric emptying process, the soft capsule enters the intestine (neutral / weakly alkaline environment, pH 6.8-7.4), and the specific flora in the intestine can gradually decompose the konjac glucomannan in the outer large capsule shell (the glycosidase secreted by the flora can break the β-(1→4) glycosidic bond of konjac glucomannan), allowing the outer large capsule shell to slowly degrade and break, and thus releasing the inner small capsule shell containing fish oil; Finally, when the inner small capsule shell contacts with intestinal fluid, the cross-linked propylene glycol alginate ester contained therein will swell and disintegrate rapidly in the neutral environment of the intestine (the network structure of the cross-linked structure will expand when it contacts with the intestinal fluid), but due to the slow-release effect of the pullulan-low acyl gellan gum composite glue on fish oil, the disintegrated capsule shell will gradually release fish oil, achieving slow release within 12 hours, which not only avoids the instantaneous high concentration of fish oil in the intestine, further reducing gastrointestinal discomfort, but also continuously supplies Omega-3 to the patient after surgery, meeting the needs of suppressing inflammatory response through slow intake.

[0013] It is explained that the role of low acyl gellan gum in the inner small capsule shell is to serve as a structure reinforcing agent and a stomach stabilizer, providing strength to prevent oil leakage; ensuring that the inner layer does not disintegrate in the stomach to achieve intestinal targeting. In addition, the role of trehalose in the outer small capsule shell is to serve as a moisture stabilizer and an aging agent, maintaining the toughness of the outer capsule shell, preventing dry cracking or adhesion, and ensuring long-term storage stability of the product.

[0014] II. A double-layer capsule shell controlled-release fish oil soft capsule, comprising an outer large capsule shell, an inner small capsule shell, and fish oil content wrapped in the inner small capsule shell, in mass parts: The raw materials of the inner small capsule shell include: pullulan-low acyl gellan gum composite glue 8-15 parts, cross-linked propylene glycol alginate ester 1-3 parts, glycerol 2-5 parts, and deionized water 30-50 parts; The raw materials of the outer large capsule shell include: konjac glucomannan-trehalose composite glue 12-20 parts, polyglycerol-6 caprylate 3-7 parts, titanium dioxide 0.1-0.2 parts, calcium disodium ethylenediaminetetraacetate 0.1-0.5 parts, and deionized water 35-60 parts; The mass ratio of the large capsule shell to the small capsule shell is 1:0.8-1.2; the fish oil content includes fish oil 50-70 parts and trisodium citrate 0.2-0.8 parts.

[0015] Preferably, in the pullulan-low acyl gellan gum composite glue, the mass ratio of pullulan to low acyl gellan gum is 1:0.2-0.4.

[0016] Preferably, in the konjac glucomannan-trehalose composite glue, the mass ratio of konjac glucomannan to trehalose is 1:0.3-0.5.

[0017] Preferably, the preparation method of the cross-linked propylene glycol alginate ester includes the following steps: (1) Disperse alginate acid in 1,2-propylene glycol, and perform esterification reaction at 90-110°C for 3-6 hours in the presence of a catalyst, then purify and dry to obtain propylene glycol alginate ester; (2) dissolving the alginate propylene glycol ester obtained in step (1) in water to form a colloidal solution, adding a crosslinking agent under alkaline conditions, and performing crosslinking reaction at 45-65°C for 4-8 hours; (3) after the reaction is completed, neutralizing, washing, drying and crushing to obtain the crosslinked alginate propylene glycol ester.

[0018] Preferably, the mass ratio of the alginate to 1,2-propylene glycol is 1:4-8; and the crosslinking agent is added in an amount of 10%-30% of the mass of the alginate propylene glycol ester.

[0019] Preferably, the catalyst is citric acid, and the amount of the catalyst is 5%-15% of the mass of the alginate.

[0020] Preferably, the crosslinking agent is glycerophosphate.

[0021] A preparation method of the double-layered capsule controlled-release fish oil soft capsule as described above, comprising the following steps: (1) preparation of the inner-layer small capsule latex: heating deionized water to 50-55°C, adding pullulan-low acyl gellan gum composite glue, and treating under ultrasonic action at a power of 200-300W for 15-20 minutes; then adding crosslinked alginate propylene glycol ester and glycerol, and stirring at a rotation speed of 1000-1200r / min for 10-15 minutes; finally, dynamic defoaming under the conditions of a vacuum degree of -0.09 to -0.1MPa and a stirring rotation speed of 300-400r / min for 25-35 minutes to obtain the inner-layer small capsule latex; (2) forming of the inner-layer small capsule: pressing and forming the inner-layer small capsule latex obtained in step (1) and fish oil content under the conditions of a temperature of 22-25°C and a relative humidity of 35-40%, and drying to a water content of 5.0-7.0wt% to obtain the inner-layer small capsule; (3) preparation of the outer-layer large capsule latex: heating deionized water to 45-50°C, adding konjac glucomannan-trehalose composite glue, and treating under the synergistic action of microwave radiation at a power of 150-200W and mechanical stirring at a rotation speed of 800-1000r / min for 20-25 minutes; then adding polyglycerol-6 caprylate, titanium dioxide and calcium disodium EDTA, and stirring for 15-20 minutes before gradient cooling to 40°C; finally, defoaming under a vacuum degree of -0.095MPa for 30-40 minutes to obtain the outer-layer large capsule latex; (4) Forming and drying of the double-layer soft capsule: the inner small capsule shell prepared in step (2) is taken as the content, and the outer large capsule shell latex prepared in step (3) is sent into a rotary soft capsule machine to be pressed and formed under the conditions of a temperature of 24-26℃ and a relative humidity of 32-35%; the formed soft capsule is pre-cooled at -18 to -15℃ for 1-1.5 hours, and then hot air dried at 28-30℃ for 5-6 hours until the water content of the outer large capsule shell is 4.0-6.0 wt%, and the double-layer soft capsule is obtained.

[0022] The double-layer capsule shell controlled-release type fish oil soft capsule and the preparation method thereof provided by the embodiment of the present application have the following beneficial effects: the present application realizes multiple technical breakthroughs through the design of a double-layer structure and a full polysaccharide system: the outer capsule shell constructs an environmental barrier, and the inner layer realizes intestinal targeting controlled release, thus avoiding fish oil stimulation in the stomach from the root, and adapting to the needs of special groups such as infants, postoperative patients and the like; the full polysaccharide raw material replaces gelatin, thus eliminating the cross-linking aging problem and guaranteeing the long-term disintegration stability of the capsule shell and the bioavailability; at the same time, the storage performance is improved by the synergistic effect of the excipients, thus effectively solving the problems of gastrointestinal discomfort and storage failure of traditional single-layer capsule shells and gelatin capsule shells, and the comprehensive performance is significantly better than that of traditional fish oil soft capsules, and the safety, stability and special group adaptability are all possessed. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the protection scope of the present application.

[0024] In view of the above technical problems, the embodiment of the present application provides a double-layer capsule shell controlled-release type fish oil soft capsule and a preparation method thereof to solve the problems in the background art. I. Specific embodiments Embodiment 1 1. Raw material ratio (in mass parts) Inner small capsule shell: pullulan-low acyl gellan gum composite glue 12 parts (mass ratio 1:0.3), cross-linked propylene glycol alginate 2 parts, glycerol 3 parts, deionized water 40 parts; Outer large capsule shell: konjac glucomannan-trehalose composite glue 16 parts (mass ratio 1:0.4), polyglycerol-6 caprylate 5 parts, titanium dioxide 0.1 part, calcium disodium ethylenediaminetetraacetate 0.3 part, deionized water 50 parts; Fish oil content: fish oil 60 parts, trisodium citrate 0.5 part; mass ratio of large capsule shell to small capsule shell: 1:1.

[0026] 2. Preparation of key excipients (cross-linked propylene glycol alginate) (1) Take 10 parts of alginic acid, 60 parts of 1,2-propanediol (mass ratio 1:6), add 1 part of citric acid (10% of the mass of alginic acid), esterify at 105°C for 4 hours, dry at 80°C for 3 hours after purification, and obtain propylene glycol alginate; (2) Dissolve the propylene glycol alginate in deionized water, adjust the pH to 9.0, add 2.5 parts of glycerophosphate, and crosslink at 55°C for 6 hours; (3) Neutralize to pH 7.0 with 1 mol / L hydrochloric acid, wash 3 times, dry at 100°C for 2 hours, and crush to 80 mesh to obtain crosslinked propylene glycol alginate.

[0027] 3. Preparation steps (1) Inner layer small capsule shell latex preparation: heat 40 parts of deionized water to 55°C, add 12 parts of pullulan-low acyl gellan gum composite glue, and treat with 250W ultrasonic for 20 minutes; add 2 parts of crosslinked propylene glycol alginate and 3 parts of glycerol, and stir at 1100r / min for 12 minutes; dynamic defoaming at -0.095MPa vacuum degree and 350r / min for 30 minutes to obtain the inner layer latex; (2) Inner layer small capsule shell forming: the inner layer latex and fish oil content are sent into a soft capsule machine, and are pressed and formed at 23°C and 38% relative humidity, and dried to a water content of 6.0wt% to obtain the inner layer small capsule shell; (3) Outer layer large capsule shell latex preparation: heat 50 parts of deionized water to 48°C, add 16 parts of konjac glucomannan-trehalose composite glue, and treat with 180W microwave+900r / min stirring for 22 minutes; add 5 parts of polyglycerol-6 caprylate, 0.1 parts of titanium dioxide, and 0.3 parts of calcium disodium edetate, stir for 20 minutes, and then gradient cooling to 40°C; defoaming at -0.095MPa vacuum for 35 minutes to obtain the outer layer latex; (4) Double-layer forming and drying: the inner layer small capsule shell is taken as the content, and the outer layer latex is sent into a rotary soft capsule machine, and is pressed and formed at 25°C and 34% relative humidity; pre-cooling at -18°C for 1.2 hours, and hot air drying at 30°C for 5.5 hours until the water content of the outer layer is 5.0wt% to obtain the finished product.

[0028] Example 2 (adjusting the proportion of inner layer composite glue) 1. Raw material ratio (by mass parts) Inner layer small capsule shell: pullulan-low acyl gellan gum composite glue 8 parts (mass ratio 1:0.2), crosslinked propylene glycol alginate 1 part, glycerol 2 parts, deionized water 30 parts; Outer layer large capsule shell: same as example 1; Fish oil content: same as example 1; Mass ratio of large capsule shell to small capsule shell: 1:0.8.

[0029] 2. Preparation steps The procedure is the same as in Example 1, and the final outer layer moisture content is 4.3 wt%.

[0030] Example 3 (adjusting the proportion of the outer layer composite glue) 1. Raw material ratio (by mass) Inner layer small capsule shell: same as in Example 1; Outer layer large capsule shell: konjac glucomannan-trehalose composite glue 20 parts (mass ratio 1:0.5), polyglycerol-6 octanoate 7 parts, titanium dioxide 0.1 part, calcium disodium ethylenediaminetetraacetate 0.5 part, deionized water 60 parts; Fish oil content: same as in Example 1; Mass ratio of large capsule shell to small capsule shell: 1:1.2.

[0031] 2. Preparation steps The procedure is the same as in Example 1, and the final outer layer moisture content is 6.0 wt%.

[0032] Comparative Example 1 (single-layer capsule shell, no double-layer structure) Capsule shell: using the outer layer large capsule shell raw material of Example 1 (without an inner layer small capsule shell), directly wrapping the fish oil content; Preparation steps: preparing the latex according to the outer layer latex preparation method of Example 1, and single-layer pressing and molding with the fish oil content, drying to a moisture content of 5.0 wt%; Core difference: no double-layer structure, no inner layer controlled release design.

[0033] Comparative Example 2 (inner layer does not use cross-linked propylene glycol alginate) Inner layer small capsule shell: using ordinary propylene glycol alginate (not cross-linked) instead of cross-linked propylene glycol alginate, and the rest is the same as in Example 1; Outer layer and content: same as in Example 1; Preparation steps: same as in Example 1; Core difference: no cross-linking structure in the inner layer, no intestinal targeting disintegration ability.

[0034] Comparative Example 3 (outer layer without trehalose) Outer layer large capsule shell: using an equal amount of konjac glucomannan instead of trehalose (i.e. pure konjac glucomannan 16 parts), and the rest is the same as in Example 1; Inner layer and content: same as in Example 1; Preparation steps: same as in Example 1; Core difference: no trehalose in the outer layer, which cannot stabilize moisture.

[0035] Comparative Example 4 (traditional gelatin capsule shell, single layer) Capsule shell: gelatin 15 parts, glycerol 5 parts, sorbitol 3 parts, water 45 parts; Content: same as in Example 1; Preparation step: dissolve gelatin and excipients in hot water at 70℃, static defoaming for 2 hours, single-layer compression molding, dry at 30℃ for 8 hours; Core difference: traditional gelatin single-layer capsule shell, no double-layer and controlled release design.

[0036] II. Performance test and effect data 1. Test items and standards Disintegration performance: disintegration time limit test method in Chinese Pharmacopoeia 2020 edition, respectively measure the disintegration time in stomach (pH 1.2) and intestinal tract (pH 6.8); Storage stability: High temperature stability: 60℃ sealed storage for 30 days, HPLC measurement of DHA preservation rate (GB5009.82-2016); Light stability: 3000lux light for 28 days, measure DHA preservation rate; Accelerated stability: 40℃, 75%RH storage for 30 days, measure the oil leakage rate; Gastrointestinal irritation: 20 SD rats (simulating infant gastrointestinal tract) were gavaged, and the incidence of diarrhea within 24 hours was counted.

[0037] The specific test results are shown in Table 1: Table 1

[0038] The double-layer capsule shell controlled release fish oil soft capsule prepared by the present application has the technical effect of being significantly better than the traditional fish oil soft capsule through scientific component design and process optimization, and the specific effects are as follows: 1. Double-layer structure and controlled release design: solve the pain point of gastrointestinal irritation Example 1-3 does not disintegrate in stomach (>120min), intestinal tract disintegration time is 180-255 seconds, and the incidence of diarrhea in rats is only 0.8-1.2%, which is significantly better than Comparative Example 1 (single-layer capsule shell, disintegration time in stomach is 280min, and the incidence of diarrhea in rats is 18%) and Comparative Example 4 (gelatin single-layer, the incidence of diarrhea in rats is 22%).

[0039] Comparative Example 1 (single-layer capsule shell), because there is no acidic gel barrier of konjac glucomannan outer layer, although it completely disintegrates in stomach for 280min, but the capsule shell will be slowly softened by gastric acid during the process, and small cracks will appear, fish oil will continue to leak and contact gastric mucosa, and stimulate the fragile mucosa to cause diarrhea; Comparative Example 4 (gelatin single-layer capsule shell), because gelatin is easy to absorb water and swell when it meets gastric acid, and cracks are formed, and the stability of gelatin is poor, the amount of fish oil leakage is more than that of Comparative Example 1, and the stimulation to gastric mucosa is more severe, so the incidence of diarrhea is higher.

[0040] 2. Cross-linked alginate propylene glycol ester: guarantee controlled release and intestinal tract adaptation Comparative Example 2 (ordinary propylene glycol alginate) showed an intestinal disintegration time of only 150 seconds, with fish oil release being too rapid and the irritation rate rising to 5.5%. In contrast, Examples 1-3, due to the extended release caused by the cross-linked structure, showed a fish oil release rate of ≥90% within 12 hours, which not only met the anti-inflammatory needs of postoperative patients but also reduced intestinal irritation, thus verifying the controlled-release value of cross-linked excipients.

[0041] 3. Trehalose: Stabilizes moisture and improves storage performance. Comparative Example 3 (without trehalose) showed a high-temperature DHA retention rate of only 78.3% and an oil leakage rate of 1.2%, far lower than Example 1 (89.5% / 0.2%). Trehalose stabilizes the outer layer's moisture content at 4.0-6.0 wt%, preventing the konjac glucomannan oxygen barrier network from loosening due to moisture fluctuations, while also preventing the shell from cracking, thus ensuring long-term storage stability.

[0042] 4. Full polysaccharide system: Avoiding the defects of gelatin Comparative Example 4 (gelatin capsule shell) had a DHA retention rate of only 71.9% and a disintegration time of 380 seconds after 30 days due to gelatin cross-linking and aging; while Examples 1-3 used a full polysaccharide composite adhesive without amino acid side chains, avoiding Maillard reaction, and significantly improved disintegration performance and storage stability.

[0043] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications to the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the invention. All variations and improvements should fall within the protection scope defined by the claims of this invention.

Claims

1. A double-layered capsule controlled-release fish oil soft capsule, characterized in that, The outer large capsule shell, the inner small capsule shell, and the fish oil content wrapped in the inner small capsule shell, in mass parts, comprise: The inner small capsule shell raw material comprises: pullulan-low acyl kollagen complex glue 8-15 parts, cross-linked propylene glycol alginate 1-3 parts, glycerol 2-5 parts, and deionized water 30-50 parts; The outer large capsule shell raw material comprises: konjac glucomannan-trehalose complex glue 12-20 parts, polyglycerol-6 caprylate 3-7 parts, titanium dioxide 0.1-0.2 parts, calcium disodium ethylenediaminetetraacetate 0.1-0.5 parts, and deionized water 35-60 parts; The mass ratio of the large capsule shell to the small capsule shell is 1:0.8-1.2; and the fish oil content comprises fish oil 50-70 parts and trisodium citrate 0.2-0.8 parts.

2. The double-layered capsule controlled-release fish oil soft capsule according to claim 1, wherein, In the pullulan-low acyl kollagen complex glue, the mass ratio of pullulan to low acyl kollagen is 1:0.2-0.

4.

3. The double-layered capsule controlled-release fish oil soft capsule according to claim 1, wherein, In the konjac glucomannan-trehalose complex glue, the mass ratio of konjac glucomannan to trehalose is 1:0.3-0.

5.

4. The double-layered capsule controlled-release fish oil soft capsule according to claim 1, wherein, The preparation method of the cross-linked propylene glycol alginate comprises the following steps: (1) dispersing alginate in 1,2-propylene glycol, performing esterification reaction at 90-110°C for 3-6 hours in the presence of a catalyst, purifying and drying after the reaction is completed to obtain propylene glycol alginate; (2) dissolving the obtained propylene glycol alginate in step (1) in water to form a colloidal solution, adding a cross-linking agent under alkaline conditions, and performing cross-linking reaction at 45-65°C for 4-8 hours; (3) after the reaction is completed, neutralizing, washing, drying, and crushing to obtain the cross-linked propylene glycol alginate.

5. The double-layered soft capsule of claim 4, wherein the fish oil is a fish oil having a DHA content of 30% or more. The mass ratio of the alginate to 1,2-propylene glycol is 1:4-8; and the addition amount of the cross-linking agent is 10%-30% of the mass of the propylene glycol alginate.

6. The double-layered soft capsule of claim 4, wherein the capsule is prepared by using a material selected from the group consisting of gelatin, starch, cellulose, and derivatives thereof. The catalyst is citric acid, and the amount of the catalyst is 5%-15% of the mass of the alginate.

7. The double-layered soft capsule of claim 4, wherein the capsule is prepared by using a material selected from the group consisting of gelatin, starch, cellulose, and derivatives thereof. The cross-linking agent is glycerophosphate.

8. A method of preparing the double-layered capsule controlled release fish oil soft capsule according to claim 1, characterized in that, The method comprises the following steps: (1) preparation of the inner small capsule shell latex: heating deionized water to 50-55°C, adding pullulan-low acyl kollagen complex glue, treating under the action of ultrasonic waves with a power of 200-300W for 15-20 minutes; then adding cross-linked propylene glycol alginate and glycerol, stirring at a rotation speed of 1000-1200r / min for 10-15 minutes; finally, dynamically defoaming under the conditions of a vacuum degree of-0.09 to-0.1MPa and a stirring rotation speed of 300-400r / min for 25-35 minutes to obtain the inner small capsule shell latex; (2) forming of the inner small capsule shell: pressing and forming the inner small capsule shell latex obtained in step (1) and the fish oil content under the conditions of a temperature of 22-25°C and a relative humidity of 35-40%, and drying to a water content of 5.0-7.0wt% to obtain the inner small capsule shell; (3) Preparation of outer large capsule shell latex: deionized water was heated to 45-50℃, konjac glucomannan-fucoidan composite glue was added, and treated under the synergistic action of microwave radiation with power of 150-200 W and mechanical stirring at 800-1000 r / min for 20-25 min; then polyglycerol-6 caprylate, titanium dioxide and calcium disodium EDTA were added, and stirred for 15-20 min, and then gradient cooling to 40℃; finally, defoaming under vacuum degree of-0.095 MPa for 30-40 min to obtain outer large capsule shell latex; (4) Forming and drying of double-layer soft capsules: the inner small capsule shell prepared in step (2) was taken as content, and the outer large capsule shell latex prepared in step (3) was sent into a rotary soft capsule machine together, and then formed and pressed under the conditions of temperature of 24-26℃ and relative humidity of 32-35%; the formed soft capsules were pre-cooled at-18 to-15℃ for 1-1.5 h, and then hot air dried at 28-30℃ for 5-6 h, until the water content of outer large capsule shell was 4.0-6.0 wt%, and then the double-layer soft capsules were obtained.

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