Collagen composite soft capsule with three-layer structure as well as preparation method and application of collagen composite soft capsule

Abstract

The invention discloses a collagen composite soft capsule with a three-layer structure as well as a preparation method and application of the collagen composite soft capsule, and belongs to the technical field of composite sustained-release capsules. The capsule contains an outer collagen peptide-gelatin composite rubber layer, a middle Pickering emulsion layer and an inner sustained-release pellet. A compact network is formed on the outer layer under the action of molecules, so that the mechanical strength and the biocompatibility are improved; the middle layer stably loads active ingredients; and the inner-layer sustained-release pellet fixes collagen peptide and integrates various components, so that controlled release is realized. During preparation, a three-layer structure is constructed step by step, physical mixing avoids damage to activity, step-by-step injection keeps each layer independent, and sealing does not need an additional adhesive. The process enhances the strength of the capsule skin, ensures the structural stability, accurately controls the sustained-release structure of the pellet, and improves the gastric acid tolerance and active ingredient stability of the capsule.

Description

Technical Field

[0001] This invention belongs to the field of composite sustained-release capsule technology, specifically relating to a three-layer collagen composite soft capsule, its preparation method, and its application. Background Technology

[0002] In recent years, with the increasing demand for functional foods and health products, capsules have become an important carrier for delivering active ingredients due to their convenience, precise dosage, and ingredient protection. However, current capsule products on the market reveal many pain points that urgently need to be addressed in practical applications. These problems severely limit their application effects and the full realization of their market potential, specifically manifested as follows: Single dosage form: Traditional capsules mostly adopt a single-layer structure design, which cannot adapt to complex physiological environments (such as gastric acid erosion and differences in intestinal absorption), leading to premature release or insufficient utilization of active ingredients. For example, water-soluble components such as collagen peptides are easily degraded rapidly in the stomach, making it difficult to effectively reach intestinal absorption sites. Simple ingredients: Existing technologies use a single loading method for active ingredients, lacking the ability to synergistically encapsulate multiple types of components (such as hydrophilic and hydrophobic substances). At the same time, the stability of the ingredients is insufficient, and long-term storage can easily lead to a decline in efficacy due to oxidation, moisture absorption, and other problems. Simple structure: Traditional capsules rely on a single material (such as gelatin) or a simple coating process, making it difficult to balance mechanical strength, sustained-release function, and environmental tolerance. Taking collagen peptides as an example, as a water-soluble active ingredient, they are easily degraded rapidly in the stomach, making it difficult to effectively reach the intestinal absorption sites. Furthermore, in existing technologies, the maximum dosage of commercially available collagen peptide soft capsules is not high, failing to meet consumers' demands for high-efficiency dosages. Simultaneously, the gelatinous outer shell of traditional soft capsules is susceptible to leakage or deformation due to temperature and humidity fluctuations, and is prone to rapid disintegration in the acidic environment of the stomach, leading to premature release and inactivation of the active ingredients.

[0003] The aforementioned problems not only directly reduce the bioavailability of capsule products and affect the consumer experience, but also severely restrict the application expansion of capsules in the high-end functional product market. For example, in the high-end functional product market for anti-aging and joint health, consumers have higher requirements for product efficacy and quality. However, traditional capsules, due to the aforementioned defects, are unable to meet these demands, thus limiting their market share in these areas. To address these issues, some improvement solutions have been developed, such as using compound plasticizers to improve gelatin toughness and enhance the mechanical strength of the capsules; and using multi-layer coating processes to improve stability and reduce the release loss of active ingredients. However, these methods still have many shortcomings in practical application. On the one hand, the use of compound plasticizers and multi-layer coating processes may adversely affect the bioavailability of capsules, altering the release rate and absorption pathway of active ingredients; on the other hand, these improved capsules are still prone to moisture absorption, adhesion, and disintegration during their shelf life, affecting product quality and stability. Therefore, there is an urgent need to develop a new capsule structure design to effectively solve the technical problems of poor stability of active ingredients, low loading capacity, and easy leakage in existing technologies, so as to meet consumers' urgent demand for efficient and long-lasting functional products. Capsule structure design has become a key issue that the functional food and health product industry urgently needs to solve. Summary of the Invention

[0004] Existing technologies suffer from problems such as simple capsule structure, low active ingredient loading, easy leakage, and poor stability in gastric acid. This invention aims to provide a three-layer collagen composite soft capsule, its preparation method, and its applications.

[0005] To achieve the above objectives, the present invention employs the following technical solution: This invention provides a three-layer collagen composite soft capsule, comprising, from the outside to the inside, a 20%–26% collagen peptide-gelatin composite gelatin layer, a 50%–65% Pickering emulsion layer, and a 10%–30% sustained-release microcapsules; the Pickering emulsion layer is tightly bonded to the collagen peptide-gelatin composite gelatin layer through intermolecular forces; the sustained-release microcapsules are bonded to the Pickering emulsion layer through physical adsorption and intermolecular forces; The collagen peptide-gelatin composite adhesive layer is composed of gelatin, collagen peptides, glycerin and water; The Pickering emulsion layer consists of an oil phase and an aqueous phase. The oil phase consists of a stabilizer and a vegetable oil, and the aqueous phase is a collagen peptide solution. The sustained-release microcapsules contain collagen peptides, hydroxypropyl methylcellulose, and maltodextrin.

[0006] Preferably, the hydroxypropyl methylcellulose and maltodextrin form a three-dimensional network structure framework through hydrogen bonding and intermolecular entanglement, and the collagen peptides are fixed inside the sustained-release microspheres with the hydroxypropyl methylcellulose and maltodextrin through hydrogen bonding and electrostatic interactions.

[0007] Preferably, the stabilizer is any one or a combination of lecithin, β-cyclodextrin and soy protein isolate, and the vegetable oil is high-oleic sunflower seed oil or flaxseed oil.

[0008] The Pickering emulsion, by weight, comprises 80-95 parts of high-oleic sunflower seed oil; 1-3 parts of β-cyclodextrin; 0.1-0.5 parts of lecithin or soy protein isolate; and 5-10 parts of collagen peptide solution, wherein the collagen peptide solution has a mass concentration of 5% and a molecular weight of 2000 Da.

[0009] Based on parts by weight, the sustained-release microspheres contain 8-10 parts of collagen peptides, 5-10 parts of hydroxypropyl methylcellulose, and 22-35 parts of maltodextrin.

[0010] The sustained-release microcapsules also include functional ingredients, which are any one or a combination of fermented red ginseng powder, amla powder, and salmon extract powder.

[0011] The above-mentioned method for preparing a three-layer collagen composite soft capsule involves mixing Pickering emulsion and sustained-release microspheres, injecting the mixture into a molded collagen peptide-gelatin composite film, and sealing it to obtain a three-layer collagen composite soft capsule.

[0012] The collagen peptide-gelatin composite rubber sheet is prepared using the following steps: gelatin is swollen in a water bath, then collagen peptides and glycerin are added sequentially and stirred until homogeneous to obtain a mixture. The mixture is then injected into a mold for shaping and subjected to gradient drying to obtain the collagen peptide-gelatin composite rubber sheet.

[0013] The mass ratio of the gelatin, collagen peptides and glycerin is 100:(5~15):8.

[0014] Preferably, the swelling temperature is 50~70℃ and the time is 20~40min.

[0015] Preferably, the gradient drying is performed at 40°C for 1 hour, at 50°C for 1 hour, and at 60°C for 1 hour.

[0016] The sustained-release microspheres are prepared using the following steps: collagen peptides, hydroxypropyl methylcellulose, maltodextrin and deionized water are mixed, extruded and dried to obtain sustained-release microspheres; the mass ratio of collagen peptides, hydroxypropyl methylcellulose and maltodextrin to deionized water is (8-10):(5-10):(22-35):(65-35).

[0017] Preferably, the extrusion pressure is 2-5 MPa, the screw speed is 30-60 rpm, and the cutting frequency is 200-400 times / minute.

[0018] This invention provides the application of the above-mentioned three-layer collagen composite soft capsule in the preparation of beauty products.

[0019] Compared with the prior art, the present invention has the following beneficial effects: This invention provides a three-layer collagen composite soft capsule, employing a three-layer structure design to synergistically address the shortcomings of traditional capsules. The outer collagen peptide-gelatin composite layer utilizes hydrogen bonds and hydrophobic interactions between gelatin and collagen peptides to form a dense network, enhancing mechanical strength to resist temperature and humidity changes and improving biocompatibility through the introduction of collagen peptides. The middle Pickering emulsion layer uses a specific oil phase (high-oleic vegetable oil) and stabilizers (such as β-cyclodextrin, lecithin, and soy protein isolate) to form a stable interface, binding with the aqueous collagen peptide solution and achieving physical isolation and synergistic loading of the active ingredients through intermolecular forces. The inner sustained-release microcapsules immobilize collagen peptides through a three-dimensional network framework of hydroxypropyl methylcellulose and maltodextrin, delaying release through hydrogen bonds and electrostatic interactions to prevent rapid degradation in the acidic environment of the stomach. This three-layer structure design achieves multi-level synergistic protection and release control, effectively solving the problem of premature release or insufficient utilization of active ingredients caused by the single structure of traditional capsules, thus improving the product's functionality and stability.

[0020] Furthermore, the three-dimensional network framework of the sustained-release microcapsules, while immobilizing collagen peptides through hydrogen bonds and electrostatic interactions, integrates components with different physicochemical properties, such as fermented red ginseng powder, amla powder, and salmon extract powder, into the same carrier. Fermented red ginseng powder, as a fat-soluble active substance, can form a complex with the oil phase components; the polyphenols of amla powder protect collagen peptides through antioxidant effects; and the protein components of salmon extract powder enhance structural stability through intermolecular interactions with hydroxypropyl methylcellulose. The arbitrary combination of these three functional components not only meets the customized needs of different application scenarios for effective ingredients but also avoids mutual interference between multiple components through the controlled-release mechanism of the sustained-release microcapsules.

[0021] This invention provides a three-layer collagen composite soft capsule and its preparation method, achieving synergistic effects through stepwise construction of the three-layer structure. By mixing Pickering emulsion with sustained-release microspheres, the interfacial stabilizing effect of the Pickering emulsion encapsulates the sustained-release microspheres, forming a combination of the middle and inner layers, preventing microsphere aggregation during processing. The mixture is then injected into a pre-formed collagen peptide-gelatin composite gelatin layer, where the high mechanical strength of the gelatin layer maintains the overall structure, and finally, the capsule is sealed to form a complete capsule. The physical mixing method avoids the destruction of active ingredients by high temperatures or chemical cross-linking, preserving the bioactivity of the collagen peptides. The stepwise injection rather than co-molding method ensures that each functional layer maintains an independent structure: the outer gelatin layer provides a physical barrier, the middle emulsion layer delivers lipid-soluble components, and the inner microsphere layer controls the sustained release of water-soluble components. The sealing process is completed through the self-adhesiveness of the gelatin layer material, eliminating the need for additional adhesives and preventing the introduction of foreign matter that could affect product purity.

[0022] Furthermore, the gelatin molecules are fully expanded through water bath swelling, providing space for the subsequent embedding of collagen peptides. Collagen peptides and glycerol are added sequentially, utilizing the hydrogen bonds and hydrophobic interactions between the collagen peptides and gelatin, and the glycerol acting as a plasticizer to adjust the viscosity of the mixture. The three work synergistically to form a homogeneous mixture system. The mixture is then injected into a mold for shaping, and the molding conditions are controlled to ensure consistency in the thickness and shape of the capsule. The gradient drying process employs staged temperature and humidity control to avoid cracking or structural loosening of the capsule caused by rapid dehydration, ultimately forming a dense and elastic composite capsule layer. This process strengthens the mechanical strength of the capsule layer through intermolecular interactions, and the gradient drying technology ensures structural stability, thereby improving the capsule's tolerance to the acidic environment of the stomach.

[0023] This process utilizes the viscoelasticity of hydroxypropyl methylcellulose and the filling properties of maltodextrin to form a uniform dispersion system, ensuring molecular-level dispersion of the active ingredients. Secondly, the extrusion process uses mechanical shear force to induce hydrogen bonding and molecular entanglement between the hydroxypropyl methylcellulose molecular chains and maltodextrin particles, forming a three-dimensional network framework structure with a continuous phase. Finally, the drying process removes moisture and solidifies the three-dimensional network, anchoring collagen peptides within the framework pores through hydrogen bonding and electrostatic interactions, forming a stable sustained-release carrier. This step-by-step process of physical mixing, mechanical shaping, and solidification achieves precise control of the sustained-release structure within the microcapsules, overcoming the impact of solvent residue on the stability of active ingredients in traditional wet granulation.

[0024] The application provided by this invention is that the inner layer of the three-layer soft capsule has excellent encapsulation capabilities, capable of not only encapsulating collagen but also simultaneously loading various active ingredients with different properties, such as vitamins, minerals, and plant extracts, including both hydrophilic and hydrophobic ones. These active ingredients with different properties can coexist stably within the soft capsule without reacting or degrading, thus achieving a synergistic effect of multiple functional components. For example, when vitamin C and collagen are co-encapsulated in the inner layer, vitamin C promotes collagen synthesis, and their synergistic effect more effectively improves skin condition, enhancing skin elasticity and radiance. The special design of the middle and inner layers effectively prevents interactions between active ingredients and contact with the external environment, reducing factors such as oxidation and moisture absorption that lead to ingredient inactivation. During long-term storage, the various active ingredients within the soft capsule maintain high stability and activity, ensuring the functional food maintains stable efficacy throughout its shelf life. Attached Figure Description

[0025] Figure 1 This is a scanning electron microscope image of the collagen composite soft capsule skin of the present invention, wherein A is the pure gelatin capsule skin and B is the collagen peptide-gelatin composite skin layer. Figure 2 The images show the adhesion and breakage of the gelatin-collagen peptide composite capsule (100:4-100:15) of the present invention and ordinary gelatin capsules, wherein A is the gelatin-collagen peptide composite capsule of the present invention and B is an ordinary gelatin capsule. Figure 3 This is a comparison diagram of emulsification of different groups of the intermediate layer Pickering emulsion of the present invention; Figure 4 Micrograph of Pickering emulsion in experimental group A of the invention; Figure 5 This is a picture of the food after digestion in the stomach. Figure 6 Comparison photos showing the improvement in crow's feet wrinkles after different groups tried the product; Figure 7 Before and after photos showing improvement in under-eye wrinkles in different groups. Detailed Implementation

[0026] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0027] Unless otherwise specified, the raw materials or chemical reagents used in the embodiments of this invention are obtained through conventional commercial channels.

[0028] Example 1 This embodiment provides a three-layer collagen composite soft capsule. The soft capsule consists of, from the outside in, a collagen peptide-gelatin composite gelatin layer, a Pickering emulsion layer, and protective microspheres. The collagen peptide-gelatin composite gelatin layer has high mechanical strength; the Pickering emulsion layer stabilizes the oil-water interface through nanoparticles, achieving efficient loading of water-soluble active ingredients; the protective microspheres have low solubility in gastric acid, ensuring targeted release of active ingredients in the intestine. This maximizes the collagen peptide content loaded in each soft capsule while protecting the stability of the collagen peptides in gastric acid. The specific preparation process of this collagen composite soft capsule includes the following steps: (1) Preparation of outer collagen peptide-gelatin composite skin layer By weight, the collagen peptide-gelatin composite rubber layer consists of 110 parts gelatin (food grade, Bloom value ≥200), 10 parts collagen peptide (molecular weight 2000 Da), 8 parts glycerol (plasticizer) and 100 parts deionized water.

[0029] Soak 220g of gelatin in 200mL of deionized water in a water bath at 60±2℃ for 30 minutes. After swelling, add 20g of collagen peptides and stir until completely dissolved (200 r / min, 20 minutes). Add 16g of glycerin and continue stirring for 10 minutes to form a homogeneous gel. Pour the gel into capsule molds and cool to 25℃ for initial shaping. Perform gradient drying: first place the molds at 40℃ (1 hour) → 50℃ (1 hour) → 60℃ (1 hour), until the final moisture content is ≤8%.

[0030] (2) Preparation of intermediate Pickering emulsion By weight, the Pickering emulsion layer consists of an aqueous phase and an oil phase. The oil phase consists of 90 parts high-oleic sunflower seed oil, 2 parts β-cyclodextrin, and 0.3 parts lecithin. The aqueous phase consists of 8 parts collagen peptide solution (5%, molecular weight 2000 Da).

[0031] 900 mL of oil phase and 80 mL of water phase were mixed and pre-dispersed using a stirrer (handheld small stirrer, speed 2000 r / min, 5-8 min). Then, the mixture was passed through a three-stage microfluidic homogenizer (pressure 150 MPa, 3 cycles). After homogenization, a stable Pickering emulsion with a particle size ≤200 nm was obtained.

[0032] (3) Preparation of core layer sustained-release microspheres Based on weight, the sustained-release microcapsules were prepared by mixing 9 parts collagen peptides, 8 parts hydroxypropyl methylcellulose, 30 parts maltodextrin, and 53 parts deionized water using a pelletizing machine. The equipment type was a twin-screw extruder pelletizing machine (length-to-diameter ratio 8:1); extrusion pressure was 2-5 MPa (adjusted according to pellet diameter, pressure is positively correlated with pellet diameter); screw speed was 30-60 rpm (speed is negatively correlated with pellet density); cutting frequency was 200-400 times / minute (synchronized with extrusion speed); drying was performed (gradient drying, first at 50℃ and then at 55℃ for 3-4 hours) to obtain microcapsules with a diameter of 0.5-1.2 mm.

[0033] Alternatively, 2%–5% fermented red ginseng powder, 1%–4% amla powder, and 3%–8% salmon extract powder can be added to the micro-pill base formula for blending and pressing into pellets.

[0034] (4) Three-layer capsule assembly Filling: Mix 115g of sustained-release microcapsules (core layer) with 490mL of Pickering emulsion (intermediate layer); using a capsule filling machine, inject the mixture into 150g of pre-formed collagen peptide-gelatin composite outer layer, with a total weight of 750±20g; seal the interface with a rotary capsule sealing machine (temperature 70℃, pressure 0.2 MPa); quality inspection indicators: moisture permeability ≤5% (detected by dynamic moisture adsorption method), appearance: no cracks or dents, content uniformity: RSD≤5%, to obtain a three-layer collagen composite soft capsule.

[0035] Example 2 This embodiment provides a three-layer collagen composite soft capsule. The soft capsule consists of, from the outside in, a collagen peptide-gelatin composite gelatin layer, a Pickering emulsion layer, and protective microspheres. The collagen peptide-gelatin composite gelatin layer has high mechanical strength; the Pickering emulsion layer stabilizes the oil-water interface through nanoparticles, achieving efficient loading of water-soluble active ingredients; the protective microspheres have low solubility in gastric acid, ensuring targeted release of active ingredients in the intestine. This maximizes the collagen peptide content loaded in each soft capsule while protecting the stability of the collagen peptides in gastric acid. The specific preparation process of this collagen composite soft capsule includes the following steps: (1) Preparation of outer collagen peptide-gelatin composite skin layer By weight, the product consists of 100 parts gelatin (food grade, ≥200 Bloom) of collagen peptide-gelatin composite gelatin layer, 5 parts collagen peptide (molecular weight 2000 Da), 8 parts glycerol (plasticizer), and 100 parts deionized water.

[0036] Soak 200g of gelatin in 200mL of deionized water in a water bath at 60±2℃ for 30 minutes. After swelling, add 10g of collagen peptides and stir until completely dissolved (200 r / min, 20 minutes). Add 16g of glycerin and continue stirring for 10 minutes to form a homogeneous gel. Pour the gel into capsule molds and cool to 25℃ for initial shaping. Perform gradient drying: first place the molds at 40℃ (1 hour) → 50℃ (1 hour) → 60℃ (1 hour), until the final moisture content is ≤8%.

[0037] (2) Preparation of intermediate Pickering emulsion By weight, the Pickering emulsion layer consists of an aqueous phase and an oil phase. The oil phase consists of 80 parts of high-oleic sunflower seed oil (or flaxseed oil), 1 part of β-cyclodextrin, and 0.1 parts of lecithin. The aqueous phase consists of 5 parts of collagen peptide solution (5%, molecular weight 2000 Da).

[0038] 800 mL of oil phase and 50 mL of water phase were mixed and pre-dispersed using a stirrer (handheld small stirrer, speed 2000 r / min, 5-8 min). Then, the mixture was passed through a three-stage microfluidic homogenizer (pressure 150 MPa, 3 cycles). After homogenization, a stable Pickering emulsion with a particle size ≤200 nm was obtained.

[0039] (3) Preparation of core layer sustained-release microspheres Based on weight, the sustained-release microcapsules were prepared by mixing 8 parts collagen peptides, 5 parts hydroxypropyl methylcellulose, 22 parts maltodextrin, and 65 parts deionized water using a pelletizing machine. The equipment type was a twin-screw extruder pelletizing machine (length-to-diameter ratio 8:1); extrusion pressure was 2-5 MPa (adjusted according to pellet diameter, pressure is positively correlated with pellet diameter); screw speed was 30-60 rpm (speed is negatively correlated with pellet density); cutting frequency was 200-400 times / minute (synchronized with extrusion speed); drying was performed (gradient drying, first at 50℃ and then at 55℃ for 3-4 hours) to obtain microcapsules with a diameter of 0.5-1.2 mm.

[0040] Alternatively, 2%–5% fermented red ginseng powder, 1%–4% amla powder, and 3%–8% salmon extract powder can be added to the micro-pill base formula for blending and pressing into pellets.

[0041] (4) Three-layer capsule assembly Filling: 120 g of sustained-release microcapsules (core layer) were mixed with 500 mL of Pickering emulsion (intermediate layer). Using a capsule filling machine, the mixture was injected into 160 g of pre-formed collagen peptide-gelatin composite outer layer, with a total weight of 780±20 g. The interface was sealed using a rotary capsule sealing machine (temperature 70℃, pressure 0.2 MPa). Quality control indicators: moisture permeability ≤5% (detected by dynamic moisture adsorption method), appearance: no cracks or dents, content uniformity: RSD≤5%, to obtain a three-layer collagen composite soft capsule.

[0042] Example 3 This embodiment provides a three-layer collagen composite soft capsule. The soft capsule consists of, from the outside in, a collagen peptide-gelatin composite gelatin layer, a Pickering emulsion layer, and protective microspheres. The collagen peptide-gelatin composite gelatin layer has high mechanical strength; the Pickering emulsion layer stabilizes the oil-water interface through nanoparticles, achieving efficient loading of water-soluble active ingredients; the protective microspheres have low solubility in gastric acid, ensuring targeted release of active ingredients in the intestine. This maximizes the collagen peptide content loaded in each soft capsule while protecting the stability of the collagen peptides in gastric acid. The specific preparation process of this collagen composite soft capsule includes the following steps: (1) Preparation of outer collagen peptide-gelatin composite skin layer By weight, the collagen peptide-gelatin composite rubber layer consists of 120 parts gelatin (food grade, ≥200 Bloom); 10 parts collagen peptide (molecular weight 2000 Da); 8 parts glycerin (plasticizer); and 100 parts deionized water.

[0043] Soak 240g of gelatin in 200mL of deionized water in a water bath at 60±2℃ for 30 minutes. After swelling, add 20g of collagen peptides and stir until completely dissolved (200 r / min, 20 minutes). Add 16g of glycerin and continue stirring for 10 minutes to form a homogeneous gel. Pour the gel into capsule molds and cool to 25℃ for initial shaping. Perform gradient drying: first place the molds at 40℃ (1 hour) → 50℃ (1 hour) → 60℃ (1 hour), until the final moisture content is ≤8%.

[0044] (2) Preparation of intermediate Pickering emulsion By weight, the Pickering emulsion layer consists of an aqueous phase and an oil phase. The oil phase consists of 95 parts of high-oleic sunflower seed oil (or flaxseed oil), 3 parts of β-cyclodextrin, and 0.5 parts of lecithin. The aqueous phase consists of 10 parts of collagen peptide solution (5%, molecular weight 2000 Da).

[0045] 950 mL of oil phase and 100 mL of water phase were mixed and pre-dispersed using a stirrer (handheld small stirrer, speed 2000 r / min, 5-8 min). Then, the mixture was passed through a three-stage microfluidic homogenizer (pressure 150 MPa, 3 cycles). After homogenization, a stable Pickering emulsion with a particle size ≤200 nm was obtained.

[0046] (3) Preparation of core layer sustained-release microspheres Based on weight, the sustained-release microcapsules were prepared by mixing 10 parts collagen peptides, 10 parts hydroxypropyl methylcellulose, and 35 parts maltodextrin (base formulation) using a pelletizing machine. The equipment type was a twin-screw extruder pelletizing machine (length-to-diameter ratio 8:1); extrusion pressure was 2-5 MPa (adjusted according to pellet diameter, pressure is positively correlated with pellet diameter); screw speed was 30-60 rpm (speed is negatively correlated with pellet density); cutting frequency was 200-400 times / minute (synchronized with extrusion speed); drying was performed (gradient drying, first at 50℃ and then at 55℃ for 3-4 hours) to obtain microcapsules with a diameter of 0.5-1.2 mm.

[0047] Alternatively, 2%–5% fermented red ginseng powder, 1%–4% amla powder, and 3%–8% salmon extract powder can be added to the micro-pill base formula for blending and pressing into pellets.

[0048] (4) Three-layer capsule assembly Filling: Mix 110g of sustained-release microcapsules (core layer) with 480mL of Pickering emulsion (intermediate layer); using a capsule filling machine, inject the mixture into 145mL of pre-formed collagen peptide-gelatin composite outer layer, with a total weight of 735±20g; seal the interface with a rotary capsule sealing machine (temperature 70℃, pressure 0.2 MPa); quality inspection indicators: moisture permeability ≤5% (detected by dynamic moisture adsorption method), appearance: no cracks or dents, content uniformity: RSD≤5%, to obtain a three-layer collagen composite soft capsule.

[0049] II. Product Performance Testing 1. Scanning electron microscope See appendix Figure 1As can be observed from the comparison images, the structure of a pure gelatin capsule shell is relatively rough, with numerous fine pores and an uneven overall distribution; some areas are smooth, while others are rough and layered. In contrast, the collagen peptide-gelatin composite capsule shell of this invention, compared to pure gelatin capsule shells, has a smoother surface after the collagen peptide composite, exhibiting uniform wrinkles resembling satin. This indicates that the addition of collagen peptides makes the arrangement of gelatin molecules more orderly and compact. The uniform wrinkles help improve the mechanical and barrier properties of the capsule shell; the pore size is significantly smaller than that of pure gelatin capsule shells, which can better prevent the penetration of external substances (such as moisture and oxygen), thereby improving the shelf life and quality stability of the contents of the capsule. Collagen peptides are products of collagen hydrolysis, with small molecular weights, allowing them to penetrate into the intermolecular spaces of gelatin. This small-molecule penetration alters the intermolecular interactions of gelatin molecules, such as hydrogen bonds and hydrophobic interactions, thus affecting the texture of the gelatin matrix. Amino acids such as glycine, proline, and hydroxyproline in collagen peptides can form new hydrogen bonds and hydrophobic interactions with their corresponding amino acids in gelatin, enhancing the binding force between gelatin molecules. Furthermore, nonpolar amino acids in collagen peptides (such as proline) interact hydrophobically with nonpolar regions in gelatin, further making the gelatin structure more compact.

[0050] Overall, the scanning electron microscopy images visually demonstrate the positive impact of adding collagen peptides on the microstructure of gelatin capsule shells, providing microscopic evidence for understanding the role of collagen peptides in improving the performance of gelatin capsule shells.

[0051] 2. Tensile strength test Experimental groups 1-5 prepared gelatin-collagen peptide capsule shells with gelatin to collagen peptide ratios of 100:3 (experimental group 1), 100:4 (experimental group 2), 100:10 (experimental group 3), 100:15 (experimental group 4), and 100:20 (experimental group 5), respectively, and pure gelatin capsule shells (control group).

[0052] Cut the prepared capsule shells into dumbbell-shaped specimens according to ASTM D882 standard, with an effective test area size of 30 mm long × 5 mm wide. Set the tensile speed to 10 mm / min and the initial gauge length to 20 mm; prepare 10 specimens per group and number them randomly. Accurately measure the thickness of each specimen using vernier calipers, and calculate the cross-sectional area based on the measured thickness and known width. Mount the specimens on a tensile testing machine and perform tensile tests according to the set parameters, recording the maximum tensile force (N) and elongation at break (%) for each specimen. Tensile strength (MPa) = maximum tensile force (N) / cross-sectional area (mm²) is calculated using the formula: Tensile strength (MPa) = maximum tensile force (N) / cross-sectional area (mm²) 2The tensile strength of each specimen was calculated. The average tensile strength and standard deviation of the experimental group and the control group were calculated, and the increase in tensile strength of the experimental group relative to the control group was further calculated. The specific data are shown in Table 1.

[0053] Table 1: Test Results of Tensile Strength Test

[0054] As shown in Table 1, compared with the control group, the tensile strength of most experimental groups was improved, indicating that the addition of collagen peptides enhanced the mechanical properties of gelatin capsule shells. The tensile strength of experimental group 1 was 25.5 MPa, with an increase of only 0.7%, indicating that when the amount of collagen peptides added was low, it was insufficient to form enough hydrogen bonds or other non-covalent bonds with gelatin, resulting in a negligible enhancement of the mechanical properties of the gelatin capsule shells. Experimental group 2 (100:4) achieved a tensile strength of 27.9 MPa, an increase of 10.3%; experimental group 3 (100:10) achieved a tensile strength of 28.9 MPa, an increase of 14.2%, the largest increase among all groups; and experimental group 4 (100:15) achieved a tensile strength of 28.2 MPa, an increase of 11.5%. Collagen peptides can fully interact with gelatin to form sufficient hydrogen bonds and other non-covalent bonds, thereby effectively enhancing the mechanical properties of gelatin capsule shells. The tensile strength of experimental group 5 was 26.2 MPa, an increase of 3.6%. When the collagen peptide content was too high, it affected the overall film-forming properties of the gelatin, resulting in a decrease in tensile strength.

[0055] This tensile strength test clarified that the enhancing effect of collagen peptides on the mechanical properties of gelatin capsule shells is closely related to the addition ratio. A good positive enhancing effect is achieved when the gelatin:collagen peptide addition ratio is between 100:4 and 100:15, providing experimental basis for optimizing the formulation of gelatin-collagen peptide capsule shells.

[0056] 3. Shelf life storage experiment Experimental groups 1-5 consisted of soft capsules prepared from gelatin-collagen peptides in different ratios: gelatin:collagen peptide = 100:3 (experimental group 1), gelatin:collagen peptide = 100:4 (experimental group 2), gelatin:collagen peptide = 100:10 (experimental group 3), gelatin:collagen peptide = 100:15 (experimental group 4), gelatin:collagen peptide = 100:20 (experimental group 5), and soft capsules prepared from pure gelatin capsule shells (control group).

[0057] All soft capsules were placed in a constant temperature and humidity chamber, with temperatures set at 37℃ and 55℃ respectively, and a constant humidity of 45%, for 30 days of continuous observation. During the observation period, the soft capsules were regularly checked for adhesion and breakage, and the time and specific details of adhesion and breakage were recorded. See Table 2 and Appendix for specific results. Figure 2 As shown.

[0058] Table 2: Test Results of Anti-adhesion / Breakage Performance of Soft Capsules

[0059] From Table 2 and Appendix Figure 2 Data shows that at 37℃, the soft capsules prepared from the pure gelatin capsule shells in the control group showed severe adhesion on day 5, and the capsule shells tore upon separation, indicating that the pure gelatin capsule shells had poor anti-adhesion and mechanical properties under simulated accelerated conditions at room temperature. Experimental group 1 showed moderate adhesion on day 6, with cracks after separation, showing slightly better performance than the control group. Experimental groups 2-4 performed excellently; experimental groups 2 and 3 showed no adhesion and separated completely within 30 days; experimental group 4 showed slight adhesion on day 28, but separation was undamaged. This indicates that when the gelatin-collagen peptide ratio is within the range of 100:4-100:15, the capsules have good anti-adhesion and mechanical stability. Experimental group 5 showed moderate adhesion on day 12, with local detachment and breakage after separation, indicating that excessive collagen peptide addition can affect capsule performance.

[0060] Storage at 55℃: The control group showed severe adhesion on day 3, with the capsule shells breaking upon separation, indicating that pure gelatin capsule shells are more prone to problems at higher temperatures. Experimental group 1 showed moderate adhesion on day 4, with micro-cracks after separation. Experimental group 2 showed slight adhesion on day 25, with no damage upon separation; experimental group 3 showed slight adhesion on day 28, with no damage upon separation; experimental group 4 showed trace adhesion on day 20, with no damage upon separation. Although the performance at 55℃ was slightly lower than at 37℃, it was still significantly better than the control group. Experimental group 5 showed moderate adhesion on day 8, with edge breakage upon separation, causing leakage of contents.

[0061] Improved tear resistance: Gelatin contains a large number of hydroxyl, amino, and carboxyl groups, which easily bind with water molecules, leading to swelling and adhesion. The short-chain structure of collagen peptides can insert into the gelatin molecular chains, forming a denser three-dimensional network through additional hydrogen bonds. This increases the cross-linking density, reduces the free movement of molecular chains, and inhibits thermal motion at high temperatures, thereby reducing adhesion tendency and enhancing tear resistance. Enhanced anti-adhesion: Collagen peptides contain hydrophobic amino acid residues, which can partially shield the hydrophilic groups of gelatin, reducing the surface polarity of the composite film. Simultaneously, the cross-linked network prolongs the diffusion path of water molecules, and the hydrophobic regions hinder water penetration, resulting in a decrease in water vapor permeability and delaying the softening and moisture absorption of the capsule.

[0062] 4. Intermediate layer Pickering emulsion test Multiple experimental and control groups were set up, with different oil and water phase formulations for each group.

[0063] Experimental Group A: Oil phase: sunflower seed oil 85% + β-CD2 + lecithin 0.3%, aqueous phase: collagen peptide solution (5%) 5%. Experimental Group B: Oil phase: sunflower seed oil 90% + β-CD1.5% + lecithin 0.2%, aqueous phase: collagen peptide solution (5%) 8%. Experimental Group C: Oil phase: sunflower seed oil 80% + β-CD3% + lecithin 0.5%, aqueous phase: collagen peptide solution (5%) 12%. Control Group A: Oil phase: sunflower seed oil 95% + β-CD1 + lecithin 0.1%, aqueous phase: collagen peptide solution (5%) 3%. Control Group B: Oil phase: sunflower seed oil 75% + β-CD3.5% + lecithin 0.6%, aqueous phase: collagen peptide solution (5%) 18%. Control group C: The oil phase consisted of sunflower seed oil 95% + β-CD 0.5% + lecithin 0.05%, and the aqueous phase consisted of collagen peptide solution (5%) 16%. The emulsion state was observed after 24 hours and graded according to stability (1-5 grade), as detailed in Table 3 and Appendix. Figures 3-4 As shown.

[0064] Table 3: Performance Test Results of the Intermediate Layer Pickering Emulsion

[0065] From Table 3 and Appendix Figures 3-4 Data shows that the emulsions in experimental groups A, B, and C were in good condition, all exhibiting a microemulsion or milky white color without stratification, and a stability grade of 5, indicating good stability of the Pickering emulsion at these formulation ratios. Control group A had a certain amount of collagen peptide droplets loaded in the oil layer, which remained stable, was basically transparent, showed no signs of loading, and had a stability grade of 2, indicating low emulsification and insufficient aqueous phase. Control group B showed obvious stratification, with the aqueous phase separating at the bottom, and a stability grade of 1, indicating demulsification. Control group C had a blurred oil-water interface, with partial aggregation, and a stability grade of 3, indicating partial instability.

[0066] Based on the experimental results, the recommended proportions for Pickering emulsion are: high oleic sunflower oil: 80-95 parts (flaxseed oil can also be used); β-cyclodextrin: 1-3 parts; lecithin: 0.1-0.5 parts; collagen peptide solution (5%, molecular weight 2000 Da): 5-10 parts. This proportion can achieve a larger collagen peptide loading (80 parts oil loading 0.5 parts pure collagen peptide).

[0067] Through shelf-life storage experiments and Pickering emulsion tests, the influence of the gelatin-collagen peptide ratio on the shelf-life performance of soft capsules and the optimal formulation ratio of Pickering emulsion were clarified, providing an important basis for the optimized production of three-layer functional capsules.

[0068] 5. Disintegration Experiment There are five groups in total: three sample groups (samples of the three-layer collagen composite soft capsules of this invention). The first group is the energy type of the three-layer capsules of Example 1 (microcapsules with 3% fermented red ginseng powder added), the second group is the four-antibiotic type of the three-layer capsules of Example 1 (microcapsules with 3% amla powder and 1% white kidney bean extract added), the third group is the repair type of the three-layer capsules of Example 1 (microcapsules with 5% salmon extract powder added), the fourth group is commercially available competitor 1, and the fifth group is commercially available competitor 2.

[0069] Simulated gastric digestive tract enzyme digestion: Weigh 3g of each sample and dissolve it in deionized water to prepare a 3% (w / w) solution; adjust the pH of the system to 2.0 with 1.0 mol / L hydrochloric acid, add pepsin (4% of the sample weight), stir moderately, and incubate at 37 ℃ for 2 hours in a shaker; after incubation, quickly adjust the pH to 7.5 and centrifuge at 4℃ (6000 r / min, 15 min); the insoluble precipitate is dried to constant weight below 65 ℃ and then weighed.

[0070] Simulated intestinal digestive tract enzyme digestion: 3g of sample was taken from each group and digested by gastric digestive tract enzymes for 2 hours. The pH of the system was then adjusted to 7.5 with 1.0mol / L sodium hydroxide. Trypsin (4% of the sample weight) was added and stirred moderately, then incubated at 37℃ for 2 hours in a shaker. After incubation, the sample was centrifuged at low temperature (6000r / min, 15min), and the supernatant was collected and placed in a boiling water bath for 10min to inactivate the enzyme. The insoluble precipitate was dried to constant weight below 65℃ and weighed. The digestibility DT (%) was calculated using the formula: DT = (w0 - w1) / w0 × 100%, where DT is the digestibility, w0 is the total sample weight before digestion, and w1 is the weight of the dried insoluble precipitate after digestion. The digestibility of each sample at different time points in the stomach and intestines was calculated. Specific data are shown in Table 4 and Appendix. Figure 5 As shown.

[0071] Table 4: Gastrointestinal digestibility of each sample

[0072] From Table 4 and Appendix Figure 5Data shows that, regarding gastric digestion: within 2 hours of gastric digestion, the digestibility of the energy capsules, repair capsules, and four-antibody capsules showed little change compared to the two competing products. At 120 minutes, the gastric digestibility of the energy capsules was 45%, the four-antibody capsules 41%, and the repair capsules 45%, while competing product 1 was 55% and competing product 2 was 58%. This indicates that the three self-developed capsules are digested more slowly in the stomach, with less change in quality, mainly manifested in capsule shell rupture and oil dissolution, while the microcapsules remain stable. This suggests that the three-layer capsule structure provides some resistance to the gastric digestive environment, effectively protecting the active ingredients in the microcapsules from premature digestion in the stomach. Regarding intestinal digestion: within 2 hours of intestinal digestion, the digestibility of the energy capsules, repair capsules, and four-antibody capsules all reached over 90%. At 120 minutes, the intestinal digestibility of the energy capsules reached 91%, the four-antibody capsules reached 96%, and the repair capsules reached 95%. Compared to competing products (competitor 1 had an intestinal digestibility of 91% at 120 minutes, and competitor 2 had 95%), the three three-layer collagen composite soft capsules based on Example 1 of this invention exhibit faster digestion in the intestine and a more significant rate of mass change, mainly manifested in the rupture and rapid dissolution of the microcapsules. This is beneficial for increasing product digestion and absorption, and improving bioavailability. Comparison of collagen peptide content: Commercially available collagen peptide soft capsules of the same type contain 800mg to 4000mg of collagen peptide per bottle (45g, 60 capsules, 0.75g per capsule), while the three-layer capsules of Example 1 of this invention can reach a maximum collagen peptide content of 6000 to 7000mg per bottle (45g, 60 capsules, 0.75g per capsule), significantly higher than similar competing products on the market. This demonstrates the advantage of the three-layer collagen composite soft capsules of this invention in terms of ingredient content, potentially leading to better efficacy.

[0073] Disintegration experiments show that the three-layer collagen composite soft capsules of this invention can effectively protect the active ingredients in the gastric digestive environment and disintegrate rapidly in the intestinal digestive environment, which is conducive to the absorption of the active ingredients. Moreover, the amount of collagen peptides added is higher than that of commercially available competing products, which has good application prospects and market competitiveness.

[0074] 6. Human trials of three-layer capsules (repair type) Experimental design: Adopting the principle of pre- and post-control, the experimental group (three-layer capsules (repair type), collagen peptide added amount 6600mg, 2 capsules), blank group (ordinary fish oil capsules 2 capsules), and control group (commercially available collagen peptide soft capsules, collagen peptide added amount 800mg, 2 capsules).

[0075] Subjects: A total of 33 volunteers aged 25 to 45 who met the subject voluntary inclusion criteria were recruited and divided into three groups, namely the experimental group, the blank group, and the control group.

[0076] Prepare a VISIA7-Antera3D skin image analysis system (HC10230, Delfn), an Ultrascan UC22 skin ultrasound diagnostic instrument, and a balance (accuracy 0.01g). The test environment temperature was controlled at 20.0℃ - 22.0℃, and the humidity at 40% - 60%, with dynamic monitoring performed.

[0077] Experimental Procedure: Upon initial visit, participants were informed of the trial details, obtained informed consent, and were screened according to the trial requirements to finalize the participants. On the day of the test, participants cleansed their faces and equilibrated in the test environment for 20 minutes. Then, images were taken using the Antera 3D imaging system and measurements were taken on the observed areas using the Ultrascan UC22 skin ultrasound diagnostic instrument. After measurement, the sample usage method was explained to the participants, and samples were distributed. At designated follow-up times (0W, 2W, and 4W), measurements were taken again using the Antera 3D imaging system and the Ultrascan UC22 skin ultrasound diagnostic instrument. Specific results are detailed in the appendix. Figures 6-7 .

[0078] From the appendix Figures 6-7 The results show the following improvements in crow's feet: Experimental Group: After 28 days of use, volunteers experienced a significant reduction of 45.20% in the average number of wrinkles in the assessed area at the outer corner of the eyes, and a significant reduction of 62.96% in the total wrinkle area. This indicates that the three-layer capsules (repair type) in the experimental group have a significant improvement effect on crow's feet. Control Group: After 28 days of use, volunteers experienced a significant reduction of 25.50% in the average number of wrinkles in the assessed area at the outer corner of the eyes, and a significant reduction of 32.17% in the total wrinkle area. This indicates that commercially available collagen peptide soft capsules have some improvement effect on crow's feet, but the effect is not as good as the experimental group. Blank Group: After 28 days of use, volunteers experienced a significant reduction of 5.20% in the average number of wrinkles in the assessed area at the outer corner of the eyes, and a reduction of 8.06% in the total wrinkle area. This indicates that ordinary fish oil capsules have no significant improvement effect on crow's feet.

[0079] Improvement of under-eye wrinkles: Experimental group: After 28 days of use, volunteers showed a significant reduction of 34.20% in the average number of wrinkles in the under-eye assessment area and a significant reduction of 35.46% in the total wrinkle area. This indicates that the product in the experimental group has a better improvement effect on under-eye wrinkles. Control group: After 28 days of use, volunteers showed a significant reduction of 19.10% in the average number of wrinkles in the under-eye assessment area and a significant reduction of 22.30% in the total wrinkle area. This indicates that commercially available collagen peptide soft capsules have some improvement effect on under-eye wrinkles, but the effect is weaker than that of the experimental group. Blank group: After 28 days of use, volunteers showed a decrease of -6.08% in the average number of wrinkles in the under-eye assessment area and a decrease of -7.56% in the total wrinkle area. This means that ordinary fish oil capsules not only do not improve under-eye wrinkles, but may even slightly worsen them.

[0080] This human trial demonstrates that the three-layer capsule (repair type) of this invention effectively increases the maximum amount of collagen peptides added, exhibiting significant effects in improving facial wrinkles (crow's feet and under-eye wrinkles), and its effects are superior to commercially available collagen peptide soft capsules and ordinary fish oil capsules. Consistent use of this three-layer capsule (repair type) product can effectively improve facial wrinkles, providing beauty and anti-aging benefits.

[0081] The above content is only for illustrating the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. Any modifications made to the technical solution based on the technical concept proposed in this invention shall fall within the scope of protection of the claims of this invention.

Claims

1. A three-layer collagen complex soft capsule, characterized in that, From the outside in, the composition consists of a 20%–26% collagen peptide-gelatin composite gelatin layer, a 50%–65% Pickering emulsion layer, and a 10%–30% sustained-release microcapsules. The Pickering emulsion layer adheres tightly to the collagen peptide-gelatin composite gelatin layer through intermolecular forces. The sustained-release microcapsules are combined with the Pickering emulsion layer through physical adsorption and intermolecular forces. The collagen peptide-gelatin composite adhesive layer is composed of gelatin, collagen peptides, glycerin and water; The Pickering emulsion layer consists of an oil phase and an aqueous phase. The oil phase consists of a stabilizer and a vegetable oil, and the aqueous phase is a collagen peptide solution. The sustained-release microcapsules contain collagen peptides, hydroxypropyl methylcellulose, and maltodextrin.

2. The three-layer collagen composite soft capsule according to claim 1, characterized in that, By weight, the collagen peptide-gelatin composite gelatin layer is composed of 100-120 parts gelatin, 5-15 parts collagen peptide, 8 parts glycerol, and 100 parts deionized water, wherein the molecular weight of the collagen peptide is 2000 Da.

3. The three-layer collagen composite soft capsule according to claim 1, characterized in that, The Pickering emulsion, by weight, comprises 80-95 parts of high-oleic sunflower seed oil; 1-3 parts of β-cyclodextrin; 0.1-0.5 parts of lecithin or soy protein isolate; and 5-10 parts of collagen peptide solution, wherein the collagen peptide solution has a mass concentration of 5% and a molecular weight of 2000 Da.

4. The three-layer collagen composite soft capsule according to claim 1, characterized in that, Based on parts by weight, the sustained-release microspheres contain 8-10 parts of collagen peptides, 5-10 parts of hydroxypropyl methylcellulose, and 22-35 parts of maltodextrin.

5. A three-layer collagen composite soft capsule according to claim 4, characterized in that, The sustained-release microcapsules also include functional ingredients, which are any one or a combination of fermented red ginseng powder, amla powder, and salmon extract powder.

6. A method for preparing a three-layer collagen composite soft capsule according to any one of claims 1 to 5, characterized in that, Pickering emulsion and sustained-release microcapsules are mixed, injected into a molded collagen peptide-gelatin composite capsule, and sealed to obtain a three-layer collagen composite soft capsule.

7. The method for preparing a three-layer collagen composite soft capsule according to claim 6, characterized in that, The collagen peptide-gelatin composite rubber sheet is prepared using the following steps: gelatin is swollen in a water bath, then collagen peptides and glycerin are added sequentially and stirred until homogeneous to obtain a mixture. The mixture is then injected into a mold for shaping and subjected to gradient drying to obtain the collagen peptide-gelatin composite rubber sheet.

8. The method for preparing a three-layer collagen composite soft capsule according to claim 7, characterized in that, The mass ratio of gelatin, collagen peptides, and glycerin is 100:5~15:

8.

9. The method for preparing a three-layer collagen composite soft capsule according to claim 6, characterized in that, The sustained-release microspheres are prepared using the following steps: collagen peptides, hydroxypropyl methylcellulose, maltodextrin, and deionized water are mixed, extruded, and dried to obtain sustained-release microspheres; the mass ratio of collagen peptides, hydroxypropyl methylcellulose, maltodextrin, and deionized water is (8-10):(5-10):(22-35):(65-35).

10. The application of the three-layer collagen complex soft capsule according to any one of claims 1 to 5 in the preparation of beauty products.

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