Double-layer soft gelatin capsule and its preparation method and application to large-volume capsules

Abstract

The present application relates to soft capsule preparation material field, disclose a kind of double-layer soft gelatin film and its preparation method and application and big loading capsule.The double-layer soft gelatin film includes gelatin-based glue layer and inner barrier layer;The gelatin-based glue layer includes gelatin, composite plasticizing system, shading system, soluble calcium salt;The inner barrier layer composition includes hydroxypropyl methyl cellulose.The present application significantly improves the compactness of film body and adhesion, peel strength can reach 0.85 N / cm, oil permeation rate is less than 1%, the retention rate of fat-soluble content reaches more than 96%.The glue film is suitable for preparing big loading high content fat-soluble soft capsule, with high strength, low migration and excellent humidity and heat stability.

Description

Technical Field

[0001] This invention relates to the field of soft capsule formulation materials, and more specifically, to a double-layer soft capsule film, its preparation method, and its application in large-volume capsules. Background Technology

[0002] Vitamin D is a typical fat-soluble active ingredient with poor chemical stability. It is sensitive to light, heat, and oxygen, and is prone to oxidative degradation when stored in the oil phase for a long time, leading to decreased purity and insufficient stability. In high-content vitamin D systems, the local saturation of the oil phase increases, making it easier to induce microcrystal precipitation and sedimentation, resulting in uneven content distribution and reduced dosage accuracy.

[0003] As the single-capsule content increases, the contact area and time between the lipid contents and the capsule shell increase significantly, leading to a greater risk of moisture and plasticizer migration. Under humid and hot conditions, this can easily cause the capsule shell to soften, deform, stick, and leak oil, affecting the appearance and encapsulation stability. For reagent-grade applications or those requiring high purity, low-molecular-weight extractables, trace metals, and biodegradation products in the capsule shell may migrate into the contents, interfering with purity determination and quantitative analysis, and affecting the purity retention and quantifiable liquid extraction performance during long-term storage. Therefore, high-content vitamin D soft capsules still present challenges in terms of uniformity, oxidative accumulation control, interfacial stability, and maintaining low-migration purity.

[0004] Most existing vitamin D soft capsules are designed for whole-capsule consumption, and their shells must balance ingestion safety, gastrointestinal disintegration, and sensory acceptability. For example, CN113546062A improves oral stability through an oil and solid lipid system, while CN118557542A utilizes an oil-phase antioxidant system to enhance oral stability and absorption; both are primarily geared towards routine nutritional supplementation. These technologies focus on oral absorption, suspension, and photo-oxidation stability, but do not address the potential for microcrystal precipitation, content uniformity fluctuations, and the impact of shell-content interface migration on purity detection and quantification in high-content vitamin D systems during long-term storage. Summary of the Invention

[0005] To overcome the defects of the prior art, such as easy crystal precipitation and sedimentation, unstable oxidation, oil seepage and softening caused by shell-core migration, and insufficient sealing of soft capsules containing large amounts of fat-soluble contents, the present invention provides a double-layer soft film. Another object of the present invention is to provide a method for preparing a double-layer soft adhesive film; Another object of the present invention is to provide an application of a double-layer soft adhesive film; Another object of the present invention is to provide a high-volume capsule.

[0006] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows: A double-layer soft adhesive film includes a gelatin-based adhesive layer and an inner barrier layer; the gelatin-based adhesive layer comprises gelatin, a composite plasticizing system, and a light-shielding system, and the composition of the gelatin-based adhesive layer includes the following components based on the dry basis weight of the adhesive film: 50-63 parts gelatin, 35-42 parts composite plasticizing system, 0.25-1.0 parts light-shielding system, and 0.1-0.3 parts soluble calcium salt; the inner barrier layer comprises hydroxypropyl methylcellulose (HPMC), accounting for 1.0-5.0 parts of the dry basis weight of the adhesive film.

[0007] Preferably, the HPMC has a substitution degree of 28-30%.

[0008] Preferably, the soluble calcium salt includes calcium chloride or calcium lactate.

[0009] Furthermore, the thickness of the inner barrier layer is 20~50 µm, and the total thickness of the double-layer soft film is 0.5~1.0 mm.

[0010] Furthermore, the gel strength of the gelatin is 180~220 Bloom and the viscosity is 17000~25000 mPa·s.

[0011] Furthermore, the composite plasticizing system includes sorbitol and glycerol, with a mass ratio of sorbitol to glycerol of 1:1.2~1.5.

[0012] Furthermore, the light-blocking system comprises calcium carbonate and iron oxide pigment in a mass ratio of 2~6:0.5~2.

[0013] A method for preparing the aforementioned double-layer soft adhesive film includes the following steps: S1. Add gelatin to water in sequence and heat to swell and dissolve. Add the composite plasticizing system, the light-blocking system and the soluble calcium salt. Stir evenly and adjust the pH to obtain gelatin-based solution. S2. Hydroxypropyl methylcellulose is dissolved in water to obtain an inner barrier layer adhesive solution; S3. Degas the gelatin-based adhesive and the inner barrier layer adhesive. S4. The gelatin-based adhesive and the inner barrier layer adhesive are simultaneously spread and bonded through a dual-channel system to obtain a double-layer rubber sheet, and finally the double-layer soft adhesive film is obtained.

[0014] Preferably, in S1, the pH is adjusted to 4.8~5.6.

[0015] Preferably, the liquid solids content of the inner barrier layer is 8-12 wt%.

[0016] Preferably, in step S3, degassing is performed at -0.08 to -0.095 MPa for 3 to 8 minutes.

[0017] Furthermore, during the dual-channel synchronous spreading and laminating process described in S4, the temperature of the gelatin-based adhesive solution is 55~65℃, and the temperature of the inner barrier layer adhesive solution is 35~55℃.

[0018] Preferably, the temperature difference between the gelatin-based adhesive and the inner barrier layer adhesive is no greater than 15°C.

[0019] Preferably, in S4, when the gelatin-based adhesive solution forms a film, the wet film thickness is 0.8~1.5 mm.

[0020] Preferably, a double-layer wet tape is obtained by simultaneously spreading and bonding gelatin-based adhesive and inner barrier layer adhesive through a dual-channel system. The tape is then cooled and set at 15-25°C for 4-8 seconds to obtain a double-layer rubber sheet. After drying, a double-layer soft adhesive film is obtained.

[0021] Preferably, the rubber is dried until the moisture content is between 9% and 13%.

[0022] An application of the aforementioned double-layer soft film for the preparation of soft capsules.

[0023] Furthermore, the soft capsule can be used to load contents containing fat-soluble components.

[0024] Preferably, the contents containing fat-soluble components include vitamin D, vitamin A, vitamin E, vitamin K, and coenzyme Q10.

[0025] Preferably, it is suitable for capsule shells of pharmaceuticals, health products, and dietary supplements.

[0026] A high-volume capsule is prepared from the double-layer soft gel film, wherein the volume of the high-volume soft capsule ranges from 1.0 to 5.0 mL.

[0027] Preferably, the volume of the large-volume soft capsules ranges from 1.0 to 3.0 mL.

[0028] Preferably, the IU dose of the soft capsule is 10,000 to 100,000 IU.

[0029] Unlike existing technologies that simply increase film thickness or adjust the plasticizer ratio, this invention introduces a low-content HPMC barrier layer into a gelatin-based system for the first time. Through polarity regulation and molecular orientation structure, a dynamic diffusion barrier is formed at the shell-core interface, fundamentally blocking the migration channels of lipid-soluble solvents and plasticizers. This bilayer system breaks through the traditional approach of increasing thickness, significantly improving encapsulation stability while maintaining flexibility.

[0030] The composite plasticizing system is designed with an equal ratio of glycerol and sorbitol, utilizing their complementary effects in hydrophilicity and glass transition temperature to achieve dual regulation of moisture migration and mechanical strength, maintaining a balance between film moisture content and mechanical properties under high-volume encapsulation conditions. The light-shielding system abandons the commonly used titanium dioxide, employing a composite structure of calcium carbonate and iron oxide. Through the synergistic effect of light scattering and absorption, it achieves equivalent or even better light-shielding effects without the need for photosensitive inorganic catalysts. This invention establishes a synergistic mechanism of ion water-locking and interfacial coordination by introducing trace amounts of soluble calcium salts. 2+ Reversible coordination crosslinking is formed between gelatin chains and bridged with HPMC hydroxyl groups, which significantly improves the film density and interlayer adhesion, thereby improving humid heat stability and reducing the risk of oil seepage and crystallization.

[0031] In summary, this invention has formed an innovative synergistic system in terms of material composition, interface structure control, and drying and curing path. It not only overcomes the technical defects of traditional large-volume soft capsules, such as easy oil seepage, easy crystallization, and poor light stability, but also achieves high strength, low migration, and long-term stable encapsulation performance under titanium-free system conditions.

[0032] Compared with the prior art, the beneficial effects of the technical solution of the present invention are: This invention can significantly inhibit the migration of plasticizers and oil phases. Compared with the film without a barrier layer, the oil penetration rate is reduced from over 4% to less than 1%, the crystallization and sedimentation index is reduced from 3.8% to 0.3%, and the vitamin D retention rate is increased by about 7 percentage points. During the curing process, the HPMC layer can form hydrogen bond entanglements with the outer gelatin segments, which increases the peel strength to 0.85 N / cm and makes the sealing more stable.

[0033] The composite plasticizer system of this invention effectively balances flexibility and hygroscopicity, maintaining the final moisture content of the film at 9-13 wt%, thus preserving the film's elasticity over a long period without moisture regain or softening. Compared to single plasticizer groups, oil seepage is reduced by approximately 80%, and adhesion on the capsule surface is significantly reduced.

[0034] This invention maintains good antibacterial properties without the addition of preservatives. It exhibits significant antibacterial activity against three types of bacteria at 14 days, with a total colony count reduction of over 99.9%, and no significant rebound in colony count at 28 days. Against fungi such as Candida albicans and Aspergillus niger, the colony count also decreased after 28 days, demonstrating a sustained inhibitory effect. Attached Figure Description

[0035] Figure 1 This is a picture of the prepared vitamin D3 soft capsules. Detailed Implementation

[0036] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0037] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0038] Example 1 1. Preparation of double-layer soft adhesive film Take 200 parts of purified water, heat and stir at 60℃, and slowly add 60 parts of gelatin (gel strength 180~220 Bloom, viscosity 17000~25000 mPa·s), allowing it to swell and dissolve fully to form a homogeneous solution. After the gelatin is completely dissolved, add 17 parts of sorbitol and 21 parts of glycerol and continue stirring to mix the system evenly. Then add 0.4 parts of calcium carbonate and 0.2 parts of iron oxide yellow as a light-shielding system, and add 0.2 parts of calcium lactate as an ion synergist to enhance hydrothermal stability. Continue stirring until homogeneous, adjust the pH of the system to 5.0, and obtain the outer gelatin-based solution. Degas the solution at -0.085 MPa for 5 min to remove air bubbles and improve film density.

[0039] Take 3 parts of HPMC (substitution degree 28%~30%) and add them to 22 parts of purified water. Stir to form a homogeneous and transparent solution. Let it stand to remove bubbles and obtain the inner barrier gel.

[0040] The outer gelatin-based adhesive is continuously spread into a strip using a spreading roller at 55-65°C to form a wet gelatin tape with a wet thickness of 0.8-1.5 mm. Simultaneously, an inner barrier layer adhesive, maintained at 35-55°C, is bonded to the outer gelatin-based adhesive through a second adhesive supply channel during the spreading process, forming a continuous inner barrier layer in situ on the side in contact with the contents, resulting in a double-layer wet tape. The double-layer wet tape is then cooled and set at 20±5°C for 4-8 seconds, achieving a semi-solid state where the surface is non-sticky but still retains heat-sealing adhesive properties.

[0041] 2. Preparation of soft capsules Measure out 80% oleoyl polyoxyethylene glycerol ester, keep it in a water bath at 50℃, add 3.8 g sorbic acid and 1.0 g saccharin and stir to dissolve, cool to 25℃, add 1.0 g lemon essential oil and 2.5 g vitamin D3 and stir to dissolve, then bring the volume to 2000 mL and set aside.

[0042] Turn on the soft capsule pelleting machine, fill the vitamin D3 solution into the shell formed by the above-mentioned double-layer wet adhesive tape, and press and seal it under the pressure of the mold to obtain soft capsules, with a filling volume of 2 mL per capsule. Shape and dry the prepared soft capsules in a rotating drum until the moisture content of the outer shell is 9%~13%, the thickness of the inner barrier layer is 20~50 µm, and the total thickness of the double-layer soft film is 0.5~1.0 mm.

[0043] Example 2

[0044] The technical solution of Embodiment 2 is similar to that of Embodiment 1, with the following specific differences: The gelatin-based adhesive solution consists of the following components: 63 parts gelatin, 14 parts sorbitol, 21 parts glycerol, 0.3 parts calcium carbonate, 0.05 parts iron oxide yellow, and 0.1 parts calcium lactate. 180 parts purified water are added, and the solution is dissolved by heating at 60°C. The pH is adjusted to 5.5, and the solution is degassed at -0.08 MPa for 3 minutes to obtain the outer gelatin-based adhesive solution. Separately, 1 part HPMC is dissolved in 9 parts purified water to prepare the inner barrier adhesive solution.

[0045] Example 3 The technical solution of Example 3 is similar to that of Example 1, with the following specific differences: The gelatin-based adhesive solution consists of the following components: 50 parts gelatin, 16 parts sorbitol, 25 parts glycerol, 0.6 parts calcium carbonate, 0.2 parts iron oxide yellow, and 0.3 parts calcium lactate. 220 parts purified water are added, and the solution is dissolved by heating at 60°C. The pH is adjusted to 4.8, and the solution is degassed at -0.095 MPa for 8 minutes to obtain the outer gelatin-based adhesive solution. Separately, 5 parts of HPMC are dissolved in 45 parts purified water to prepare the inner barrier adhesive solution.

[0046] Comparative Example 1 The technical solution of Comparative Example 1 is similar to that of Example 1, except that: Take 200 parts of purified water, heat and stir at 60℃, and slowly add 60 parts of gelatin (gel strength 180~220 Bloom, viscosity 17000~25000 mPa·s), allowing it to swell and dissolve fully to form a homogeneous solution. After the gelatin is completely dissolved, add 17 parts of sorbitol and 21 parts of glycerol and continue stirring to mix the system evenly. Then add 0.4 parts of calcium carbonate and 0.2 parts of iron oxide yellow as a light-shielding system, and add 0.2 parts of calcium lactate as an ion synergist to enhance hydrothermal stability. Continue stirring until homogeneous, adjust the pH of the system to 5.0, and obtain the outer gelatin-based solution. Degas the solution at -0.085 MPa for 5 min to remove air bubbles and improve film density.

[0047] Comparative Example 2 The technical solution of Comparative Example 2 is similar to that of Example 1, except that: 1. Preparation of double-layer soft adhesive film Take 200 parts of purified water, heat and stir at 60℃, slowly add 60 parts of gelatin (gel strength 180~220 Bloom), allowing it to swell and dissolve fully to form a homogeneous solution. After the gelatin is completely dissolved, add 17 parts of sorbitol and 21 parts of glycerol and continue stirring to mix the system evenly. Then add 0.4 parts of calcium carbonate and 0.2 parts of iron oxide yellow as a light-shielding system, and add 0.2 parts of calcium lactate as an ion synergist to enhance hydrothermal stability. Continue stirring until homogeneous, adjust the pH of the system to 5.0, and obtain the outer gelatin-based solution. Degas the solution at -0.085 MPa for 5 min to remove air bubbles and improve film density.

[0048] Take another 3 parts of HPC and add them to 22 parts of purified water. Stir to form a homogeneous and transparent solution. Let it stand to remove bubbles and obtain the inner barrier adhesive solution.

[0049] Comparative Example 3 The technical solution of Comparative Example 3 is similar to that of Example 1, except that: 1. Preparation of double-layer soft adhesive film Take 200 parts of purified water, heat and stir at 60℃, and slowly add 60 parts of gelatin (gel strength 180~220 Bloom, viscosity 17000~25000 mPa·s), allowing it to swell and dissolve fully to form a homogeneous solution. After the gelatin is completely dissolved, add 21 parts of glycerol and continue stirring to mix the system evenly. Then add 0.4 parts of calcium carbonate and 0.2 parts of iron oxide yellow as a light-shielding system, and add 0.2 parts of calcium lactate as an ion synergist to enhance hydrothermal stability. Continue stirring until homogeneous, adjust the pH of the system to 5.0, and obtain the outer gelatin-based solution. Degas the solution at -0.085 MPa for 5 min to remove air bubbles and improve film density.

[0050] Take another 3 parts of HPMC and add them to 22 parts of purified water. Stir to form a homogeneous and transparent solution. Let it stand to remove bubbles and obtain the inner barrier gel.

[0051] Comparative Example 4 The technical solution of Comparative Example 4 is similar to that of Example 1, except that: 1. Preparation of double-layer soft adhesive film Take 200 parts of purified water, heat and stir at 60℃, and slowly add 60 parts of gelatin (gel strength 180~220 Bloom, viscosity 17000~25000 mPa·s), allowing it to swell and dissolve fully to form a homogeneous solution. After the gelatin is completely dissolved, add 17 parts of sorbitol and continue stirring to mix the system evenly. Then add 0.4 parts of calcium carbonate and 0.2 parts of iron oxide yellow as a light-shielding system, and add 0.2 parts of calcium lactate as an ion synergist to enhance hydrothermal stability. Continue stirring until homogeneous, adjust the pH of the system to 5.0, and obtain the outer gelatin-based solution. Degas the solution at -0.085 MPa for 5 min to remove air bubbles and improve film density.

[0052] Take another 3 parts of HPMC and add them to 22 parts of purified water. Stir to form a homogeneous and transparent solution. Let it stand to remove bubbles and obtain the inner barrier gel.

[0053] Comparative Example 5 The technical solution of Comparative Example 4 is similar to that of Example 1, except that: 1. Preparation of double-layer soft adhesive film Take 200 parts of purified water, heat and stir at 60℃, and slowly add 60 parts of gelatin (gel strength 180~220 Bloom, viscosity 17000~25000 mPa·s), allowing it to swell and dissolve fully to form a homogeneous solution. After the gelatin is completely dissolved, add 25 parts of sorbitol and 13 parts of glycerol and continue stirring to mix the system evenly. Then add 0.4 parts of calcium carbonate and 0.2 parts of iron oxide yellow as a light-shielding system, and add 0.2 parts of calcium lactate as an ion synergist to enhance hydrothermal stability. Continue stirring until homogeneous, adjust the pH of the system to 5.0, and obtain the outer gelatin-based solution. Degas the solution at -0.085 MPa for 5 min to remove air bubbles and improve film density.

[0054] Take another 3 parts of HPMC and add them to 22 parts of purified water. Stir to form a homogeneous and transparent solution. Let it stand to remove bubbles and obtain the inner barrier gel.

[0055] Comparative Example 6 The technical solution of Comparative Example 6 is similar to that of Example 1, except that: 1. Preparation of double-layer soft adhesive film Take 200 parts of purified water, heat and stir at 60℃, and slowly add 60 parts of gelatin (gel strength 180~220 Bloom, viscosity 17000~25000 mPa·s), allowing it to swell and dissolve fully to form a homogeneous gel solution. After the gelatin is completely dissolved, add 17 parts of sorbitol and 21 parts of glycerol and continue stirring to mix the system evenly. Then add 0.4 parts of calcium carbonate as a light-shielding agent and 0.2 parts of calcium lactate as an ion synergist to enhance hydrothermal stability. Continue stirring until homogeneous, adjust the pH of the system to 5.0, and obtain the outer gelatin-based gel solution. Degas the gel solution at -0.085 MPa for 5 min to remove air bubbles and improve film density.

[0056] Take another 3 parts of HPMC and add them to 22 parts of purified water. Stir to form a homogeneous and transparent solution. Let it stand to remove bubbles and obtain the inner barrier gel.

[0057] Comparative Example 7 The technical solution of Comparative Example 7 is similar to that of Example 1, except that: 1. Preparation of double-layer soft adhesive film Take 200 parts of purified water, heat and stir at 60℃, and slowly add 60 parts of gelatin (gel strength 180~220 Bloom, viscosity 17000~25000 mPa·s), allowing it to swell and dissolve fully to form a homogeneous gel solution. After the gelatin is completely dissolved, add 17 parts of sorbitol and 21 parts of glycerol and continue stirring to mix the system evenly. Then add 0.2 parts of iron oxide yellow as a light-shielding agent and 0.2 parts of calcium lactate as an ion synergist to enhance hydrothermal stability. Continue stirring until homogeneous, adjust the pH of the system to 5.0, and obtain the outer gelatin-based gel solution. Degas the gel solution at -0.085 MPa for 5 min to remove air bubbles and improve film density.

[0058] Take another 3 parts of HPMC and add them to 22 parts of purified water. Stir to form a homogeneous and transparent solution. Let it stand to remove bubbles and obtain the inner barrier gel.

[0059] Comparative Example 8 The technical solution of Comparative Example 8 is similar to that of Example 1, except that: 1. Preparation of double-layer soft adhesive film Take 200 parts of purified water, heat and stir at 60℃, and slowly add 60 parts of gelatin (gel strength 180~220 Bloom, viscosity 17000~25000 mPa·s), allowing it to swell and dissolve fully to form a homogeneous solution. After the gelatin is completely dissolved, add 17 parts of sorbitol and 21 parts of glycerol and continue stirring to mix the system evenly. Then add 0.56 parts of calcium carbonate and 0.035 parts of iron oxide yellow as a light-shielding system, and add 0.2 parts of calcium lactate as an ion synergist to enhance hydrothermal stability. Continue stirring until homogeneous, adjust the pH of the system to 5.0, and obtain the outer gelatin-based solution. Degas the solution at -0.085 MPa for 5 min to remove air bubbles and improve film density.

[0060] Take another 3 parts of HPMC and add them to 22 parts of purified water. Stir to form a homogeneous and transparent solution. Let it stand to remove bubbles and obtain the inner barrier gel.

[0061] Comparative Example 9 The technical solution of Comparative Example 9 is similar to that of Example 1, except that: 1. Preparation of double-layer soft adhesive film Take 200 parts of purified water, heat and stir at 60℃, and slowly add 60 parts of gelatin (gel strength 180~220 Bloom, viscosity 17000~25000 mPa·s), allowing it to swell and dissolve fully to form a homogeneous gel solution. After the gelatin is completely dissolved, add 17 parts of sorbitol and 21 parts of glycerol and continue stirring to mix the system evenly. Then add 0.6 parts of titanium dioxide as a light-shielding system and 0.2 parts of calcium lactate as an ion synergist to enhance hydrothermal stability. Continue stirring until homogeneous, adjust the pH of the system to 5.0, and obtain the outer gelatin-based gel solution. Degas the gel solution at -0.085 MPa for 5 min to remove air bubbles and improve film density.

[0062] Take another 3 parts of HPMC and add them to 22 parts of purified water. Stir to form a homogeneous and transparent solution. Let it stand to remove bubbles and obtain the inner barrier gel.

[0063] Comparative Example 10 The technical solution of Comparative Example 10 is similar to that of Example 1, except that: 1. Preparation of double-layer soft adhesive film The outer gelatin-based adhesive is continuously spread into a strip using a spreading roller at 65°C to form a wet gelatin tape with a wet thickness of 0.6~0.8 mm. Simultaneously, the inner barrier layer adhesive, maintained at 30°C, is compounded with the outer gelatin-based adhesive during the spreading process through a second adhesive supply channel, forming a continuous inner barrier layer in situ on the side in contact with the contents, resulting in a double-layer wet tape. The double-layer wet tape is then cooled and set at 20±5°C for 4~8 s, achieving a semi-solid state where the surface is non-sticky but still retains heat-sealing adhesive properties.

[0064] Comparative Example 11 The technical solution of Comparative Example 11 is similar to that of Example 1, except that: 1. Preparation of double-layer soft adhesive film The outer gelatin-based adhesive is continuously spread into a strip using a spreading roller at 50°C to form a wet gelatin tape with a wet thickness of 0.6~0.8 mm. Simultaneously, the inner barrier layer adhesive, maintained at 65°C, is compounded with the outer gelatin-based adhesive during the spreading process through a second adhesive supply channel, forming a continuous inner barrier layer in situ on the side in contact with the contents, resulting in a double-layer wet tape. The double-layer wet tape is then cooled and set at 20±5°C for 4~8 s, achieving a semi-solid state where the surface is non-sticky but still retains heat-sealing adhesive properties.

[0065] Comparative Example 12 The technical solution of Comparative Example 12 is similar to that of Example 1, except that: 1. Preparation of double-layer soft adhesive film Take 200 parts of purified water, heat and stir at 60℃, and slowly add 60 parts of gelatin (gel strength 180~220 Bloom, viscosity 17000~25000 mPa·s), allowing it to swell and dissolve fully to form a homogeneous gel solution. After the gelatin is completely dissolved, add 17 parts of sorbitol and 21 parts of glycerol and continue stirring to mix the system evenly. Then add 0.4 parts of calcium carbonate and 0.2 parts of iron oxide yellow as a light-shielding system. Continue stirring until homogeneous, and adjust the pH of the system to 5.0 to obtain the outer gelatin-based gel solution. Degas the gel solution at -0.085 MPa for 5 min to remove air bubbles and improve film density.

[0066] Take another 3 parts of HPMC and add them to 22 parts of purified water. Stir to form a homogeneous and transparent solution. Let it stand to remove bubbles and obtain the inner barrier gel.

[0067] Comparative Example 13 The technical solution of Comparative Example 12 is similar to that of Example 1, except that: 1. Preparation of double-layer soft adhesive film Take 200 parts of purified water, heat and stir at 60℃, and slowly add 60 parts of gelatin (gel strength 180~220 Bloom, viscosity 15000 mPa·s), allowing it to swell and dissolve fully to form a homogeneous solution. After the gelatin is completely dissolved, add 17 parts of sorbitol and 21 parts of glycerol and continue stirring to mix the system evenly. Then add 0.4 parts of calcium carbonate and 0.2 parts of iron oxide yellow as a light-shielding system, and add 0.2 parts of calcium lactate as an ion synergist to enhance hydrothermal stability. Continue stirring until homogeneous, adjust the pH of the system to 5.0, and obtain the outer gelatin-based solution. Degas the solution at -0.085 MPa for 5 min to remove air bubbles and improve film density.

[0068] Detection methods 1. Crystallization / Sedimentation Test The sample was placed in a constant temperature oven at 40℃ and 75%RH for 90 days and then centrifuged (3000 g × 10 min). The crystallization sedimentation index was calculated as the sedimentation layer height / total height × 100%.

[0069] 2. Vitamin D retention rate Vitamin D content was determined by HPLC, and the retention rate was calculated as (accelerated 90-day content / initial content) × 100%. The accelerated test conditions were: 40℃ ± 2℃, RH 25% ± 5%.

[0070] 3. Oil seepage rate determination The oil absorption paper wiping and weighing method was used to determine the oil penetration rate after 7 days of sealed storage at 30℃. The result was calculated as (weight gain of oil absorption paper / initial mass of capsule) × 100%.

[0071] 4. Seal peel strength Using an electronic tensile tester, at a peeling rate of 100 mm·min -1 Determine the maximum force required to separate the two sides of the seal.

[0072] 5. Light transmittance Take a dry film sample (100 µm) and measure the average transmittance at 400~450 nm using UV-Vis.

[0073] 6. Antibacterial properties Measure 80% oleoyl polyoxyethylene glycerol ester, add 6.25g vitamin D3 and stir to dissolve, then bring the volume to 5000 mL. Set aside. Turn on the soft capsule pelletizing machine and fill the vitamin D3 solution into the soft capsules prepared by the double-layer soft film in Example 1, 2 mL per capsule. Shape and dry the prepared soft capsules in a rotary drum to the appropriate softness and hardness.

[0074] Analysis and Explanation like Figure 1As shown, the soft capsules prepared in Example 1 had a volume of 2.1 mL, and the volume variation was controlled to be ≤±5%.

[0075] As can be seen from the data in Table 1, the performance indicators of the embodiments show significant advantages: crystallization sedimentation index ≤0.4%, oil penetration rate ≤0.9%, seal peel strength ≥0.82 N / cm, and vitamin D retention rate ≥96%, all of which are significantly better than those of the comparative examples. This indicates that the synergistic structure of the double-layer soft film constructed in this invention has a significant effect on improving the stability and packaging integrity of large-volume fat-soluble soft capsules.

[0076] Table 1. Performance test results of soft capsules

[0077] 1. Inhibition of HPMC inner barrier layer migration In Comparative Example 1, which did not employ an HPMC inner barrier layer, the crystallization sedimentation index increased to 3.8%, the oil permeation rate reached 4.2%, and the vitamin D retention rate decreased to 89.9%. This indicates that the inner barrier layer plays a decisive role in inhibiting oil phase migration, which is closely related to physical isolation and the polarity matching and molecular orientation structure of HPMC. HPMC molecules contain methoxy and hydroxypropyl side chains, which can form a hydrophilic-lipophilic gradient interface between the gelatin shell and the oil phase. This reduces the diffusion rate of plasticizers and water through a hydrogen bond network, thereby significantly inhibiting the migration of oily contents into the gelatin layer. In contrast, the HPC in Comparative Example 2 has a higher degree of methoxy substitution and weaker polarity, lacking the flexibility and interfacial adsorption force provided by hydroxypropyl groups. This results in insufficient bonding between membrane layers and a higher microporosity, allowing the oil phase to still permeate.

[0078] 2. Water migration control of composite plasticizing system The plasticizer system plays a crucial role in the moisture retention, flexibility, and migration stability of the film. Glycerin provides interchain lubrication and flexibility, while sorbitol reduces the freeness of the plasticizer through polyhydroxy complexation, forming a "bound water" network that inhibits moisture migration.

[0079] When Comparative Example 3 used only glycerin or when the sorbitol ratio in Comparative Example 5 was unbalanced, the moisture absorption and rehydration capacity of the gelatin film increased significantly, leading to excessive accumulation of free water in the gelatin, forming localized softening zones, and increasing the oil seepage rate to 6.4%, while also raising the crystallization sedimentation index. Conversely, when Comparative Example 4 used only sorbitol, the gelatin film lacked flexibility, became more brittle, and exhibited poor sealing. These results indicate that the combination of glycerin and sorbitol has a synergistic effect in controlling moisture content and preventing cross-migration.

[0080] 3. Light-blocking knee lift and photothermal stability After removing iron oxide or calcium carbonate from Comparative Examples 6 and 7, respectively, the transmittance increased to 13.5% and 15.3%, while the vitamin D retention rate decreased to about 93%. This indicates that iron oxide and calcium carbonate have a significant optical complementary effect: CaCO3 provides light scattering, while Fe2O3 absorbs short-wave blue light and some UV-A, achieving a balance between high reflectivity and low transmittance.

[0081] In Comparative Example 8, increasing the proportion of CaCO3 increased the light transmittance to 6.8%, indicating an intensified oxidation reaction. This demonstrates that the shading system needs to maintain a specific ratio to ensure a balance between light absorption and scattering. If the ratio is unbalanced, insufficient Fe2O3 absorption or excessive CaCO3 reflection will lead to increased local light transmission and heat focusing effects, thereby causing a rise in the temperature of the coating and accelerated oxidation.

[0082] In addition, although replacing the light-shielding system with TiO2 in Comparative Example 9 can reduce the light transmittance to 3.0%, TiO2 has photocatalytic activity and is prone to inducing oil phase peroxidation during long-term storage, which poses migration and safety risks.

[0083] 4. The curing process densifies the membrane structure. The temperature deviation of the adhesive solutions in Comparative Examples 10 and 11 caused the viscosity and gelation process of the barrier layer at the moment of lamination to deviate from the window of continuous layering and strong interfacial adhesion. Discontinuities and micro-defects appeared between the layers, which initially manifested as a significant increase in oil seepage rate and a decrease in seal peel strength. Under the cumulative effect of oxygen exposure caused by oil seepage and micro-defects, the vitamin D retention rate further decreased and the crystallization sedimentation index increased. Since the light-shielding system remained unchanged, the overall light transmittance remained at a low level, with only a slight increase due to membrane structure defects.

[0084] Comparative Example 13: Due to the apparent viscosity of the outer gelatin-based adhesive being less than 17,000 mPa·s, the tape lacked structural support during shot pressing and sealing, making it difficult to withstand the shearing and internal pressure of the mold. It was prone to bursting or sealing failure during pressing, resulting in a significant decrease in shot yield and failing to meet the requirements of continuous industrial production. Therefore, no test results were obtained.

[0085] 5. Ion synergy and hydrothermal stability Soluble calcium salts play a dual role in interfacial ionic cross-linking and structural homeostasis regulation. In the examples, the carboxyl groups and Ca in the gelatin molecules... 2+ Reversible coordination crosslinking is formed, causing the micropores inside the film to shrink and the density to increase; at the same time, Ca 2+ During the drying process, it can form ion bridges with the HPMC layer, enhancing the bonding strength between the two layers.

[0086] Comparative Example 12, without the addition of soluble calcium salts, exhibited uneven moisture migration within the film, leading to localized microcracks due to drying shrinkage. This resulted in a decrease in peel strength to 0.73 N / cm and an increase in oil penetration to approximately 1.9%. Furthermore, the loss of Ca...2+ After the ion-locking water effect, the membrane is prone to absorbing moisture and softening under humid and hot conditions, and the oil seepage and oxidation reaction intensify during long-term storage.

[0087] 6. Antibacterial properties As shown in Table 2, the sample of Example 1 without added preservatives exhibited significant antibacterial activity against all three bacteria at 14 days, with corresponding lg values ​​exceeding 3.0 and a total colony count reduction of over 99.9%. No significant rebound in colony count was observed at 28 days. For fungi such as Candida albicans and Aspergillus niger, the colony count also decreased at 28 days compared to the initial count, demonstrating a sustained inhibitory effect.

[0088] Table 2. Results of antibacterial performance in Example 1

[0089] Note: NI not increased means that the increase in the number of test bacteria at the previous measurement time did not exceed 0.5 lg.

[0090] The weakly acidic ionic microenvironment formed by the soluble calcium salts within the double-layered soft gel membrane of this invention can significantly inhibit the proliferation of Gram-negative bacteria. The double-layered membrane structure also significantly reduces the permeation rate of external water vapor and oxygen, decreasing the water activity requirements for microbial growth. The gelatin-HPMC composite interface structure exhibits low migration and high density, effectively blocking nutrient leakage and exogenous bacterial invasion, forming a stable physical and chemical barrier.

[0091] Therefore, the double-layer soft film of the present invention not only has good sealing properties and low migration, but also has significant advantages in inhibiting microbial contamination and extending product shelf life.

[0092] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A high-volume capsule for loading large quantities of fat-soluble contents, characterized in that, The film is prepared from a double-layer soft adhesive film. The double-layer soft adhesive film consists of a gelatin-based adhesive layer and an inner barrier layer. The gelatin-based adhesive layer contains gelatin, a composite plasticizer system, and a light-shielding system. The composition of the gelatin-based adhesive layer is as follows, based on the dry weight of the adhesive film: 50-63 parts gelatin, 35-42 parts composite plasticizer system, 0.25-1.0 parts light-shielding system, and 0.1-0.30 parts soluble calcium salt. The inner barrier layer is composed of hydroxypropyl methylcellulose, accounting for 1.0 to 5.0 parts by dry basis weight of the film; the degree of substitution of the hydroxypropyl methylcellulose is 28 to 30%; the composite plasticizing system is glycerol and sorbitol, with a mass ratio of glycerol to sorbitol of 1:1.2 to 1.5; the light-shielding system is calcium carbonate and iron oxide pigment in a mass ratio of 2 to 6:0.5 to 2; the thickness of the inner barrier layer is 20 to 50 µm, and the total thickness of the double-layer soft film is 0.5 to 1.0 mm; the gel strength of the gelatin is 180 to 220 Bloom, and the viscosity is 17,000 to 25,000 mPa·s; The method for preparing the double-layer soft adhesive film includes the following steps: S1. Add gelatin to water and heat to swell and dissolve. Then add the composite plasticizing system, the light-blocking system, and the soluble calcium salt in sequence. Stir evenly and adjust the pH to obtain a gelatin-based solution. S2. Hydroxypropyl methylcellulose is dissolved in water to obtain an inner barrier layer adhesive solution; S3. Degas the gelatin-based adhesive and the inner barrier layer adhesive. S4. The gelatin-based adhesive and the inner barrier layer adhesive are simultaneously spread and bonded through a dual-channel system to obtain a double-layer adhesive film, and finally the double-layer soft adhesive film is obtained. In S2, the liquid solids content of the inner barrier layer is 8-12 wt%; In S3, degassing is performed at -0.08 to -0.095 MPa for 3 to 8 minutes; When the dual-channel synchronous gelling and lamination is carried out as described in S4, the temperature of the gelatin-based adhesive solution is 55~65℃, and the temperature of the inner barrier layer adhesive solution is 35~55℃; the temperature difference between the gelatin-based adhesive solution and the inner barrier layer adhesive solution is no more than 15℃. In S4, when the gelatin-based adhesive solution forms a film, the wet film thickness is 0.8~1.5 mm; In S4, gelatin-based adhesive and inner barrier layer adhesive are simultaneously spread and bonded through a dual-channel system to obtain a double-layer wet tape. Then, it is cooled and shaped at 15~25℃ for 4~8 s to obtain a double-layer rubber sheet. After drying, a double-layer soft film is obtained. The volume range of the high-volume capsules is 1.0 to 5.0 mL.

2. A method for preparing a large-volume capsule for loading large amounts of fat-soluble contents as described in claim 1, characterized in that, The method for preparing the double-layer soft adhesive film includes the following steps: S1. Add gelatin to water and heat to swell and dissolve. Then add the composite plasticizing system, the light-blocking system, and the soluble calcium salt in sequence. Stir evenly and adjust the pH to obtain a gelatin-based solution. S2. Hydroxypropyl methylcellulose is dissolved in water to obtain an inner barrier layer adhesive solution; S3. Degas the gelatin-based adhesive and the inner barrier layer adhesive. S4. The gelatin-based adhesive and the inner barrier layer adhesive are simultaneously spread and bonded through a dual-channel system to obtain a double-layer adhesive film, and finally the double-layer soft adhesive film is obtained. In S2, the liquid solids content of the inner barrier layer is 8-12 wt%; In S3, degassing is performed at -0.08 to -0.095 MPa for 3 to 8 minutes; When the dual-channel synchronous gelling and lamination is carried out as described in S4, the temperature of the gelatin-based adhesive solution is 55~65℃, and the temperature of the inner barrier layer adhesive solution is 35~55℃; the temperature difference between the gelatin-based adhesive solution and the inner barrier layer adhesive solution is no more than 15℃. In S4, when the gelatin-based adhesive solution forms a film, the wet film thickness is 0.8~1.5 mm; In S4, gelatin-based adhesive and inner barrier layer adhesive are simultaneously spread and bonded through a dual-channel system to obtain a double-layer wet tape. Then, it is cooled and shaped at 15~25℃ for 4~8 s to obtain a double-layer rubber sheet. After drying, a double-layer soft film is obtained.

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