High-activity royal jelly preparation and preparation method thereof

Abstract

The invention discloses a high-activity royal jelly preparation and a preparation method thereof, the preparation is a soft capsule and has a double-layer structure, the inner layer is an oil-in-water emulsion and is prepared from an inner water phase and an inner oil phase; the outer layer is a water-in-oil glue solution and is prepared from an outer water phase and an outer oil phase, and the inner water phase comprises royal jelly freeze-dried powder and a targeted release polymer; the inner oil phase comprises soybean oil which is used twice; the external water phase comprises gelatin, glycerol and titanium dioxide nano dispersion liquid; the outer oil phase comprises soybean oil and beeswax, and the soybean oil and the beeswax are equally used twice. The preparation method comprises the following steps: preparing an inner-layer emulsion, preparing an outer-layer glue solution, forming double emulsion layers, carrying out vacuum defoaming, pelleting and shaping, and drying and washing pills. The active ingredients are protected through the double-emulsion-layer structure and the targeted release polymer, oxidation is reduced through vacuum treatment, the stability and bioavailability of the preparation are improved, and the problems that an existing royal jelly product is difficult to store, the active ingredients are prone to inactivation, and the bioavailability is low are solved.

Description

Technical Field

[0001] This invention relates to the field of royal jelly preparation technology, specifically to a highly active royal jelly preparation and its preparation method. Background Technology

[0002] Royal jelly, a natural nutritional product rich in protein, amino acids, vitamins, and bioactive substances, has wide applications in the health food and pharmaceutical fields. Currently, royal jelly products on the market mainly include fresh royal jelly, freeze-dried powder, and various preparations (such as hard capsules, tablets, and soft capsules). While fresh royal jelly retains its complete bioactive components, its high moisture content (approximately 60%-70%) makes it susceptible to microbial contamination and spoilage at room temperature. This necessitates a complete cold chain storage and transportation, significantly limiting its distribution and ease of use.

[0003] To address the storage challenges of fresh royal jelly, freeze-dried royal jelly powder utilizes freeze-drying technology to remove moisture, significantly improving product stability. However, improper process control during preparation can lead to the deactivation of heat-sensitive components (such as active proteins and enzymes) due to localized high temperatures or oxidation, resulting in reduced efficacy. While soft capsules, as a representative of pharmaceutical preparations, can improve convenience through dosage form design, traditional formulations often employ a single emulsion structure or simple filling process, exhibiting two major drawbacks: firstly, active ingredients are easily destroyed by stomach acid in the gastrointestinal tract, resulting in low bioavailability; secondly, the formulations lack stability, with active ingredients easily oxidized and degraded by external factors such as oxygen and light, typically resulting in a shelf life of no more than 12 months at room temperature.

[0004] Further analysis reveals that the aforementioned deficiencies of traditional soft capsule formulations stem from two aspects: First, the lack of targeted protective mechanisms means that the active ingredients in royal jelly are prone to structural damage in an acidic environment, and traditional emulsification systems cannot achieve targeted release into the intestine. Second, the single emulsion layer structure is insufficient to isolate the effects of the external environment, and the barrier effect of capsule materials such as gelatin is limited, easily leading to oxidation of the active ingredients. Therefore, developing a royal jelly formulation that combines high stability with targeted intestinal release has become a pressing technical problem to be solved in this field. Summary of the Invention

[0005] The present invention aims to provide a highly active royal jelly preparation and its preparation method. Through the synergistic effect of the double-layer emulsion structure and the targeted release polymer, it solves the problems of poor storage stability, easy destruction of active ingredients by gastric acid, and low bioavailability of existing royal jelly products.

[0006] To achieve the above objectives, the present invention provides the following technical solution: In a first aspect, the present invention provides a highly active royal jelly preparation, which is a soft capsule having a double-layer emulsion structure. The inner layer is an oil-in-water emulsion, formed by emulsifying an inner aqueous phase component and an inner oil phase component; the outer layer is a water-in-oil gel, formed by emulsifying an outer aqueous phase component and an outer oil phase component. The double-layer emulsion structure isolates the active ingredients from the influence of the external environment through a physical barrier, and the targeted release polymer contained in the inner emulsion can respond to the pH difference in the gastrointestinal tract to achieve targeted release of the active ingredients, reducing the loss of active ingredients in the acidic environment of the stomach.

[0007] The raw materials for preparing this formulation, by weight, include: an inner aqueous phase component containing 80-120 parts of freeze-dried royal jelly powder and 0.5-2 parts of targeted release polymer; an inner oil phase component containing 135-165 parts of soybean oil, to be used in two applications; an outer aqueous phase component containing 240-260 parts of gelatin, 100-110 parts of glycerin, and 0.05-0.1 parts of titanium dioxide nano-dispersion; and an outer oil phase component containing 60-100 parts of soybean oil and 9-14 parts of beeswax, both to be used in two applications.

[0008] Regarding the raw material composition, the proportions and mechanisms of action of the above components are as follows: In the aqueous phase component, the lyophilized royal jelly powder is 80-120 parts. This range ensures the effective concentration of the active ingredients in the formulation while avoiding instability of the emulsion system due to excessive content. If it is less than 80 parts, the efficacy of the active ingredients will be difficult to exert; if it is more than 120 parts, the homogeneity of the oil-in-water emulsion may be damaged due to excessive solids. The targeted release polymer is 0.5-2 parts. Its function is to achieve targeted release of the active ingredients in the intestine through pH responsiveness: when the dosage is less than 0.5 parts, it is difficult to form a complete protective layer, and the loss rate of active ingredients in the acidic environment of the stomach will exceed 10%; when the dosage is more than 2 parts, although it can enhance the protective effect, it will lead to a slow intestinal release rate, and the cumulative release rate after 4 hours may drop to below 80%. Therefore, 0.5-2 parts is the optimal range that balances protection and release efficiency.

[0009] The inner oil phase component contains 135-165 parts of soybean oil, applied in two stages. As the main component of the inner oil phase, soybean oil exhibits good biocompatibility and stability. Its dosage needs to match the oil-water ratio of the inner aqueous phase. If the dosage is less than 135 parts, the oil phase cannot form sufficient micro-droplets to encapsulate the active ingredients, easily leading to oxidation. If the dosage is more than 165 parts, it will increase the emulsion viscosity, affecting the formation of the subsequent bilayer emulsion structure. The two-stage application design (60%-70% for initial emulsification and 30%-40% for subsequent adjustment) ensures the basic amount of oil phase required for initial emulsification while allowing for optimization of emulsion flowability and stability through subsequent replenishment.

[0010] In the external aqueous phase, gelatin (240-260 parts) is crucial for forming the outer layer of the adhesive matrix. The hydrogen bonding between its molecular chains imparts excellent film-forming properties and elasticity to the matrix. Below 240 parts, the adhesive layer is prone to brittleness and cracking; above 260 parts, the viscosity becomes too high, making pelletizing difficult. Glycerin (100-110 parts) acts as a plasticizer, forming hydrogen bonds with gelatin molecules, lowering the glass transition temperature of gelatin, and increasing the flexibility of the adhesive layer. Its dosage must be matched with the amount of gelatin; insufficient glycerin leads to a hard and brittle adhesive layer, while excessive glycerin increases hygroscopicity, affecting storage stability. Titanium dioxide nano-dispersion (0.05-0.1 parts) reduces the damage of ultraviolet rays to the active ingredients of royal jelly through its light-blocking effect. Its nano-sized particles can be uniformly dispersed in the adhesive matrix, avoiding the localized agglomeration problems caused by traditional light-blocking agents. Within this range, the dosage ensures the light-blocking effect without affecting the transparency and formability of the adhesive matrix.

[0011] The outer oil phase consists of 60-100 parts soybean oil and 9-14 parts beeswax, both applied in two stages. Soybean oil, acting as the dispersion medium for the outer oil phase, works synergistically with the inner oil phase to form a double-layer oil barrier. The 60-100 parts balance the oil-water dispersion ratio of the outer layer, preventing emulsification and stratification due to insufficient oil phase or abnormal viscosity due to excessive oil phase. Beeswax acts as a regulator; the first 2-4 parts initially adjust the hardness of the outer layer, while the second 7-10 parts further optimize the mechanical strength and melting point of the rubber. If the total beeswax content is below 9 parts, the rubber tends to soften and stick; above 14 parts, it becomes too hard, resulting in slow disintegration during use. Adding beeswax in two stages allows for gradient control of the rubber's hardness, avoiding localized crystallization problems caused by a single addition.

[0012] The above components work synergistically to construct a stable bilayer emulsion structure: the targeted release polymer in the inner aqueous phase and the tiny droplets in the inner oil phase form an inner protective layer, while the gelatin-glycerol network in the outer aqueous phase and the beeswax-soybean oil system in the outer oil phase form an outer barrier. The two work together to achieve full-chain regulation of the active ingredient from "storage stability to gastric protection to intestinal release", solving the stability and bioavailability problems of traditional royal jelly preparations.

[0013] In some feasible methods, the targeted release polymer is a methacrylic acid copolymer, whose pH responsiveness originates from the carboxylic acid groups on the molecular chain: in an acidic environment with pH < 5 (such as the stomach), the carboxylic acid groups are protonated, the copolymer becomes hydrophobic, forming a dense protective layer that encapsulates the active ingredient and reduces the damage caused by stomach acid; in an intestinal environment with pH > 7 (such as the intestines), the carboxylic acid groups dissociate into carboxylate ions, the copolymer becomes hydrophilic and dissolves rapidly, releasing the active ingredient.

[0014] Preferably, the preparation process of the targeted release polymer in this invention is as follows: methacrylic acid and ethyl acrylate are mixed at a mass ratio of 6-8:3-2, and benzoyl peroxide is added as an initiator at a mass ratio of 0.3%-0.7% of the total monomer mass. The mixture is reacted at 55-75°C for 3-7 hours to obtain a crude copolymer. The crude copolymer is dissolved in a 4%-6% sodium hydroxide solution, and the pH is adjusted to 1.5-3.5 with 8%-12% hydrochloric acid to precipitate. After filtration, the precipitate is washed with purified water until neutral, vacuum dried at 35-55°C for 7-11 hours, and then pulverized through a 70-110 mesh sieve to obtain the final product.

[0015] In the preparation process of the above copolymer, methacrylic acid and ethyl acrylate are mixed at a mass ratio of 6-8:3-2. This ratio can be used to control the pH response threshold of the copolymer by adjusting the ratio of hydrophilic and hydrophobic monomers. The higher the proportion of methacrylic acid, the stronger the stability of the copolymer in an acidic environment, but the intestinal dissolution rate will decrease slightly. The 6-8:3-2 ratio can achieve a balance between gastric protection and intestinal release. The initiator benzoyl peroxide accounts for 0.3%-0.7% of the total monomer mass. Its dosage directly affects the polymerization rate and the molecular weight of the copolymer. Too low a dosage will result in incomplete polymerization; too high a dosage will lead to a wider molecular weight distribution and affect the consistency of pH response. Controlling the reaction temperature to 55-75℃ and the reaction time to 3-7h can ensure sufficient polymerization of monomers and avoid the problem of excessively rapid decomposition of the initiator caused by high temperature. The crude product is then dissolved in a 4%-6% sodium hydroxide solution, and the pH is adjusted to 1.5-3.5 with 8%-12% hydrochloric acid to precipitate the precipitate. This process removes unreacted monomers and oligomers, purifying the copolymer. Vacuum drying at 35-55℃ for 7-11 hours thoroughly removes moisture and avoids structural damage to the copolymer caused by high temperature. Pulverizing through a 70-110 mesh sieve ensures the uniformity of the copolymer powder, which is beneficial for its dispersion in the aqueous phase.

[0016] Secondly, the present invention also provides a method for preparing a highly active royal jelly preparation, which is used to prepare the above-mentioned highly active royal jelly preparation through the following steps: First, the inner emulsion is prepared by heating 60%-70% of soybean oil from the inner oil phase to 50-60℃, adding lecithin and stirring at 220-280 r / min until dissolved, and then cooling to 20-30℃ as the inner oil phase. Royal jelly freeze-dried powder is added to purified water and stirred evenly, then targeted release polymer is added and stirred at 160-200 r / min for 10-15 min as the inner aqueous phase. The inner oil phase is slowly poured into the inner aqueous phase and emulsified at 1500-2000 r / min for 20-30 min to form the primary emulsion. Then, it is maintained under a vacuum of -0.05 to -0.07 MPa for 10-15 min to obtain an inner water-in-oil emulsion with an average particle size of 1-5 μm. In this step, lecithin acts as an emulsifier to reduce the interfacial tension between oil and water, allowing the oil phase to be uniformly dispersed in the aqueous phase in the form of tiny droplets. Vacuum treatment reduces the oxygen content in the system and inhibits the oxidation of active ingredients. The targeted release polymer is uniformly dispersed in the aqueous phase, laying the foundation for subsequent pH-responsive release.

[0017] Next, the outer layer adhesive solution is prepared by adding purified water and glycerin to the gelling tank and heating it to 75-85℃ at a rate of 10-15℃ / min. Gelatin and titanium dioxide nano-dispersion are then added. Subsequently, 60%-70% of soybean oil and 2-4 parts of beeswax from the outer oil phase component are added, and the mixture is stirred at 160-200 r / min for 25-35 min at 70-80℃ until completely dissolved. After degassing under a vacuum of -0.06 to -0.08 MPa, the mixture is passed through a 90-110 mesh sieve at a pressure of 0.12-0.18 MPa and kept at 55-65℃ to form an outer oil-in-water adhesive solution with a viscosity of 2000-5000 mPa·s. During this process, gelatin and glycerin form a continuous phase with a certain elasticity, beeswax can adjust the hardness of the adhesive solution, titanium dioxide nano-dispersion reduces the damage of light to active ingredients through light-shielding, and vacuum degassing and sieving ensure the uniformity of the adhesive solution and avoid subsequent molding defects.

[0018] Subsequently, a double emulsion layer formation process is performed. The inner emulsion is slowly poured into the outer gel, and homogenized at 1500-2000 rpm for 20-30 minutes to form a water-in-oil-in-water double emulsion structure. The emulsion is then transferred to a vacuum homogenizer and defoamed at a vacuum of -0.07 to -0.09 MPa for 25-35 minutes. Finally, it is passed through a 110-130 mesh sieve at a pressure of 0.18-0.22 MPa to obtain a homogeneous emulsion. In this step, high-speed homogenization ensures that the inner emulsion droplets are uniformly coated by the outer gel, forming a stable double barrier. Secondary defoaming and filtration further eliminate bubbles and impurities within the system, ensuring the stability of the emulsion structure.

[0019] Next, vacuum emulsification and degassing are performed. The remaining 30%-40% of soybean oil in the inner oil phase is placed in a premixing tank with the homogeneous emulsion described above and stirred at 220-280 rpm for 8-12 minutes. The remaining 30%-40% of soybean oil in the outer oil phase and 7-10 parts of beeswax are added and dissolved in a water bath at 50-60°C for 20-30 minutes, then cooled to 20-30°C. Homogenization is carried out at 1600-2000 rpm for 25-35 minutes, followed by degassing under a vacuum of -0.06 to -0.08 MPa for 0.8-1.2 hours. Finally, the product is discharged at a pressure of 0.2-0.3 MPa. The addition of the remaining oil phase and beeswax can further adjust the viscosity of the emulsion, while prolonged vacuum degassing can minimize oxygen in the system and prevent oxidation of active ingredients.

[0020] Next, shot pressing and shaping are performed. The shot pressing room is maintained at a room temperature of 20-24℃ and a relative humidity of 35%-45%, and the mold is sterilized with 75% alcohol. The left and right spreading boxes are heated to 50-55℃, the syringe to 40-45℃, the adhesive solution to 55-65℃, and the drum temperature is controlled at 10-15℃. The shot pressing machine forms the capsules at a speed of 10-15 r / min, and the capsules are shaped by rotating the drum at a speed of 2-4 r / min for 2-4 hours, with the thickness of the capsule skin controlled at 0.85-0.90 mm. This step, through precise control of temperature, humidity, and equipment parameters, ensures complete capsule formation and uniform capsule skin thickness, thereby guaranteeing its sealing performance and physical stability.

[0021] Finally, the capsules undergo drying and washing. The shaped capsules are placed in a rotary drum and dried for 4-6 hours at 20-25℃ and relative humidity ≤30%, reducing the moisture content of the capsule shell to ≤20%. Each time, no more than 20 kg of dried capsules are added to the polishing machine, along with 0.05-0.15 kg of 95% edible alcohol, and washed at 30-40 rpm for 6-10 minutes. After recovering the alcohol, the capsules are placed back in the rotary drum and dried for 8-12 hours at 20-25℃ and relative humidity ≤30%, reducing the moisture content of the capsule shell to ≤13%. Gradient drying prevents the capsule shell from cracking due to a sudden drop in moisture, while alcohol washing removes surface oil and impurities, ensuring product hygiene standards and ultimately yielding highly active royal jelly soft capsules with excellent stability.

[0022] Compared with the prior art, the beneficial effects of the present invention are: (1) This invention forms a dual physical barrier through an inner layer of water-in-oil emulsion and an outer layer of oil-in-water gel. The 1-5μm oil droplets in the inner layer can encapsulate the active ingredients of royal jelly (such as 10-hydroxy-2-decenoic acid), reducing their direct contact with oxygen. The network structure formed by the gelatin and beeswax in the outer layer can effectively isolate external moisture and light. Combined with the light-shielding effect of the titanium dioxide nano-dispersion, the risk of photo-oxidation is further reduced. At the same time, the targeted release polymer (methacrylic acid copolymer) can stabilize the structure of the active ingredients through intermolecular forces during storage. With the synergistic effect of both, the loss rate of the active ingredients in the formulation is controlled within 10% after 3 months of storage at room temperature, which is far lower than the loss rate of 30%-50% in traditional formulations. The shelf life is extended to 24-36 months, solving the core problem of poor storage stability of existing products.

[0023] (2) The targeted release polymer in this invention is hydrophobic in the acidic environment of the stomach (pH < 5), forming a dense protective layer, resulting in an active ingredient loss rate of < 10%. After entering the neutral / alkaline environment of the intestine (pH > 7), it rapidly dissociates into hydrophilic substances, triggering the rapid release of the active ingredient, with a cumulative release rate of over 90% in 4 hours. This pH-responsive characteristic, combined with the sustained-release regulation effect of the double-layer emulsion structure, creates a progressive effect. The outer gel layer slows down the disintegration rate of the formulation in the stomach, while the inner polymer layer precisely controls the timing of intestinal release. The synergistic effect of both increases the bioavailability (AUC) by more than 50% compared to traditional formulations, overcoming the defects of active ingredients being easily destroyed by gastric acid and having low absorption efficiency.

[0024] (3) In the preparation process of this invention, soybean oil and beeswax in both the inner and outer oil phases are added in stages. The initial addition ensures the basic stability of the emulsion system, while subsequent additions further optimize viscosity and dispersibility, avoiding localized oxidation caused by a single addition. Simultaneously, vacuum treatment (vacuum degree -0.05 to -0.09 MPa) is introduced at the initial emulsification, double emulsion layer formation, and final emulsification stages to synergistically remove oxygen from the system and reduce peroxide value. Compared with formulations without vacuum treatment, the peroxide value of this invention is reduced by more than three times, effectively protecting heat-sensitive components (such as active proteins and enzymes) in royal jelly and solving the problem of active ingredient inactivation caused by oxidation in traditional processes.

[0025] (4) In this invention, the ratio of gelatin to glycerin in the aqueous phase forms a stable film-forming system. Combined with the gradient addition of beeswax, the thickness of the film is precisely controlled at 0.85-0.90 mm, ensuring both sealing performance and good flexibility. During the shot pressing stage, by controlling the temperature, humidity, and equipment parameters, a synergistic match is achieved with the viscosity of the adhesive solution, resulting in a product qualification rate of >95%, far exceeding the 70% qualification rate when parameters are out of control. This synergistic optimization of excipient ratio and process parameters solves the molding problems of uneven film thickness, easy adhesion, or cracking in traditional formulations.

[0026] (5) In this invention, gelatin provides the film-forming basis, and titanium dioxide achieves efficient light shielding through nanoscale dispersion, avoiding damage to the active ingredients by light; beeswax and soybean oil synergistically regulate the hardness and fluidity of the emulsion, so that the formulation has both good mechanical strength and can disintegrate smoothly in the intestine. The functional complementarity among these excipients and the double-layer emulsion structure form a multi-dimensional protection system, which not only improves the physical stability of the formulation, but also improves the taste and appearance, masks the unpleasant odor of royal jelly, and enhances the market applicability of the product. Attached Figure Description

[0027] Figure 1 Line graph (2h) showing the comparison of the loss rate of active ingredients of the formulations in the embodiments and comparative examples of the present invention in an in vitro simulated gastric juice environment. Figure 2 Line graph (4h) showing the comparison of the release rate of active ingredients of the formulations in the embodiments and comparative examples of the present invention in an in vitro simulated intestinal fluid environment. Figure 3 The bioavailability (AUC0₋) of the formulations used in the embodiments and comparative examples of this invention after oral administration to mice. 24 h) Compare the line charts. Detailed Implementation

[0028] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. 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 are within the scope of protection of the present invention.

[0029] Example 1: This example provides a highly active royal jelly preparation and its preparation method. The preparation is a soft capsule with a double-layer emulsion structure, which can improve the stability and bioavailability of active ingredients through the synergistic effect of physical barrier and targeted release. Specifically, the inner layer of the preparation is an oil-in-water emulsion, formed by emulsifying an inner aqueous phase component and an inner oil phase component; the outer layer is a water-in-oil gel, formed by emulsifying an outer aqueous phase component and an outer oil phase component. The double-layer emulsion structure isolates the active ingredients from the influence of the external environment through physical barrier, and the targeted release polymer contained in the inner emulsion can respond to the pH difference in the gastrointestinal tract to achieve targeted release of active ingredients, reducing the loss of active ingredients in the acidic environment of the stomach.

[0030] The raw materials for preparing the formulation in this embodiment include the following components in parts by weight: The internal aqueous phase component includes 100 parts of royal jelly freeze-dried powder and 1 part of targeted release polymer. The internal oil phase component consists of 150 parts of soybean oil, used in two stages: 65% for the first stage and the remaining 35% for later adjustment. The external aqueous phase component includes 250 parts of gelatin, 105 parts of glycerin, and 0.08 parts of titanium dioxide nano-dispersion. The external oil phase component consists of 80 parts of soybean oil and 12 parts of beeswax. The soybean oil is used in two stages: 65% for the first stage and the remaining 35% for later adjustment. The beeswax is used in two stages: 2.5 parts for the first stage and the remaining 9.5 parts for later hardness optimization. In addition, 270 parts of purified water and 4 parts of lecithin are required as excipients.

[0031] The targeted release polymer is a methacrylic acid copolymer. Specifically, in this embodiment, the preparation process of the methacrylic acid copolymer is as follows: methacrylic acid and ethyl acrylate are mixed at a mass ratio of 7:3, and benzoyl peroxide is added as an initiator at a mass ratio of 0.5% of the total monomer mass. The mixture is reacted at 65°C for 5 hours to obtain a crude copolymer. The crude copolymer is dissolved in a 5% sodium hydroxide solution, and the pH is adjusted to 2.5 with 10% hydrochloric acid to precipitate the precipitate. After filtration, the precipitate is washed with purified water until neutral, dried under vacuum at 45°C for 9 hours, and then pulverized through a 90-mesh sieve to obtain the final product.

[0032] In terms of preparation method, the inner layer emulsion is first prepared by heating 65% soybean oil in the inner oil phase to 55°C, adding lecithin, dissolving it at a stirring speed of 250 r / min, and then cooling it to 25°C; adding royal jelly freeze-dried powder to purified water and stirring evenly, adding the above-prepared targeted release polymer, and stirring at 180 r / min for 12 min; slowly pouring the inner oil phase into the inner aqueous phase, emulsifying at 1800 r / min for 25 min to form a primary emulsion, and then treating it under a vacuum of -0.06 MPa for 12 min to obtain an inner water-in-oil emulsion with an average particle size of 3 μm.

[0033] Next, the outer layer adhesive solution was prepared. Purified water and glycerin were added to the gelling tank, and the temperature was raised to 80°C at 12°C / min. Gelatin and titanium dioxide nano-dispersion were added, followed by 65% ​​soybean oil and 2.5 parts beeswax in the outer oil phase. The mixture was stirred at 75°C and 180 r / min for 30 min until dissolved. After degassing under vacuum of -0.07 MPa and passing through a 100-mesh sieve under pressure of 0.15 MPa, the mixture was kept at 60°C to form an outer oil-in-water adhesive solution with a viscosity of 3500 mPa·s.

[0034] Subsequently, a double emulsion layer was formed by pouring the inner emulsion into the outer emulsion, homogenizing at 1800 r / min for 25 min, degassing under vacuum at -0.08 MPa for 30 min, and passing through a 120-mesh sieve at 0.2 MPa pressure to obtain a uniform emulsion.

[0035] Next, vacuum emulsification and degassing are performed. The remaining 35% of soybean oil in the inner oil phase is added to the above emulsion, and it is stirred at 250 r / min for 10 min. Then, the remaining 35% of soybean oil in the outer oil phase and 9.5 parts of beeswax are added. After dissolving in a water bath at 55℃ for 25 min, it is cooled to 25℃, homogenized at 1800 r / min for 30 min, and degassed under vacuum at -0.07 MPa for 1 h. The material is then discharged at a pressure of 0.25 MPa.

[0036] Next, shot pressing and shaping are performed. The shot pressing room is maintained at 22℃ and 40% relative humidity. The mold is sterilized with 75% alcohol. The spreading box, syringe, and adhesive solution are heated to 52℃, 42℃, and 60℃ respectively, and the drum temperature is 12℃. The shot pressing machine forms the capsules at 12 r / min, and then shapes them in a rotating drum at 3 r / min for 3 hours, controlling the thickness of the capsule skin to be 0.88 mm. Finally, drying and washing are performed. The capsules are dried at 22℃ and ≤30% relative humidity for 5 hours until the moisture content is ≤20%. Each time, 20 kg of capsules and 0.1 kg of 95% edible alcohol are added to the polishing machine, and the capsules are washed at 35 r / min for 8 minutes. After recovering the alcohol, the capsules are dried under the same conditions for 10 hours until the moisture content is ≤13%.

[0037] Example 2: The highly active royal jelly preparation provided in this example is basically the same as that in Example 1, also in the form of soft capsules with a double-layer emulsion structure. However, its formulation and preparation method differ from Example 1 in terms of parameters. Specifically, in this example, the preparation, by weight, contains 80 parts of freeze-dried royal jelly powder and 0.5 parts of targeted release polymer (methacrylic acid copolymer) in the inner aqueous phase; 135 parts of soybean oil in the inner oil phase, used in two stages, with 60% used initially and the remaining 40% for later adjustments; 240 parts of gelatin, 100 parts of glycerin, and 0.05 parts of titanium dioxide nano-dispersion in the outer aqueous phase; and 60 parts of soybean oil and 9 parts of beeswax in the outer oil phase, with 60% used initially and the remaining 40% for later adjustments, and 2 parts of beeswax used initially and the remaining 7 parts for later hardness optimization; the excipients are 240 parts of purified water and 2 parts of lecithin.

[0038] The preparation process of the methacrylic acid copolymer in this embodiment is as follows: methacrylic acid and ethyl acrylate are mixed at a mass ratio of 6:3, and benzoyl peroxide is added as an initiator at a mass ratio of 0.3% of the total monomer mass. The mixture is reacted at 55°C for 3 hours to obtain crude copolymer. The crude copolymer is dissolved in 4% sodium hydroxide solution, and the pH is adjusted to 1.5 with 8% hydrochloric acid to precipitate. After filtration, the precipitate is washed with purified water until neutral, dried under vacuum at 35°C for 7 hours, and then pulverized through a 70-mesh sieve to obtain the final product.

[0039] In the preparation method of this embodiment, when preparing the inner emulsion, 60% of soybean oil in the inner oil phase is heated to 50°C, lecithin is added, and the mixture is stirred and dissolved at 220 r / min before being cooled to 20°C. When preparing the inner aqueous phase, royal jelly freeze-dried powder is mixed with purified water and the above-mentioned targeted release polymer is added, and the mixture is stirred at 160 r / min for 10 min. After the inner oil phase is poured into the inner aqueous phase, the mixture is emulsified at 1500 r / min for 20 min and then subjected to vacuum treatment at -0.05 MPa for 10 min to obtain an inner emulsion with an average particle size of 1 μm.

[0040] In the preparation of the outer layer adhesive, purified water and glycerin in the gelling tank are heated to 75°C at 10°C / min. Gelatin and titanium dioxide nano-dispersion are added, followed by 60% soybean oil and 2 parts beeswax in the outer oil phase. The mixture is stirred at 70°C and 160 r / min for 25 min. After degassing under vacuum of -0.06 MPa and passing through a 90-mesh sieve under pressure of 0.12 MPa, the mixture is kept at 55°C to form an outer layer adhesive with a viscosity of 2000 mPa·s.

[0041] During the formation of the double emulsion layer, the inner emulsion and the outer gel were homogenized at 1500 r / min for 20 min, degassed under vacuum at -0.07 MPa for 25 min, and passed through a 110-mesh sieve at 0.18 MPa pressure to obtain a uniform emulsion. In the vacuum emulsification and degassed stage, the remaining 40% of soybean oil in the inner oil phase was added, and the mixture was stirred at 220 r / min for 8 min. Then, the remaining 40% of soybean oil in the outer oil phase and 7 parts of beeswax were added. The mixture was dissolved in a water bath at 50℃ for 20 min, cooled to 20℃, homogenized at 1600 r / min for 25 min, and degassed under vacuum at -0.06 MPa for 0.8 h. The mixture was then discharged at 0.2 MPa pressure.

[0042] During shot pressing and shaping, the shot pressing area is maintained at 20℃ and 35% relative humidity. The shot pressing machine runs at 10 rpm, and the rotating drum shapes the shot at 2 rpm for 2 hours, resulting in a rubber sheet thickness of 0.85 mm. During drying and washing, the shot is first dried at 20℃ and ≤30% relative humidity for 4 hours. Each time, 15 kg of capsules and 0.05 kg of 95% edible alcohol are added, and the shot is washed at 30 rpm for 6 minutes. After recovering the alcohol, the shot is dried for 8 hours until the moisture content is ≤13%.

[0043] Example 3: The high-activity royal jelly preparation provided in this example is basically the same as that in Example 1, also in the form of soft capsules with a double-layer emulsion structure. Specifically, in this example, the preparation, by weight, contains 120 parts of freeze-dried royal jelly powder and 2 parts of targeted release polymer (methacrylic acid copolymer) in the inner aqueous phase; 165 parts of soybean oil in the inner oil phase, used in two applications, with 70% used initially and the remaining 30% used for later adjustments; the outer aqueous phase includes 260 parts of gelatin, 110 parts of glycerin, and 0.1 parts of titanium dioxide nano-dispersion; the outer oil phase consists of 100 parts of soybean oil and 14 parts of beeswax, with the soybean oil used in two applications, 70% used initially and the remaining 30% used for later adjustments; the beeswax is used in two applications, with 4 parts used initially and the remaining 10 parts used for later hardness optimization; the excipients are 300 parts of purified water and 6 parts of lecithin.

[0044] The preparation process of the methacrylic acid copolymer in this embodiment is as follows: methacrylic acid and ethyl acrylate are mixed at a mass ratio of 8:2, and benzoyl peroxide is added as an initiator at a mass ratio of 0.7% of the total monomer mass. The mixture is reacted at 75°C for 7 hours to obtain crude copolymer. The crude copolymer is dissolved in 6% sodium hydroxide solution, and the pH is adjusted to 3.5 with 12% hydrochloric acid to precipitate. After filtration, the precipitate is washed with purified water until neutral, dried under vacuum at 55°C for 11 hours, and then pulverized through a 110-mesh sieve to obtain the final product.

[0045] In the preparation method of this embodiment, when preparing the inner emulsion, 70% of soybean oil in the inner oil phase is heated to 60°C, lecithin is added, and the mixture is stirred and dissolved at 280 r / min before being cooled to 30°C. When preparing the inner aqueous phase, royal jelly freeze-dried powder is mixed with purified water and the above-mentioned targeted release polymer is added, and the mixture is stirred at 200 r / min for 15 min. After the inner oil phase is poured into the inner aqueous phase, the mixture is emulsified at 2000 r / min for 30 min and then subjected to vacuum treatment at -0.07 MPa for 15 min to obtain an inner emulsion with an average particle size of 5 μm.

[0046] In the preparation of the outer layer emulsion, purified water and glycerol were heated to 85°C at 15°C / min in a gelling tank. Gelatin and titanium dioxide nano-dispersion were added, followed by 70% soybean oil and 4 parts beeswax as the outer oil phase. The mixture was stirred at 80°C and 200 rpm for 35 min. After degassing under vacuum at -0.08 MPa and passing through a 110-mesh sieve at 0.18 MPa, the mixture was kept at 65°C to form an outer layer emulsion with a viscosity of 5000 mPa·s. During the formation of the double emulsion layer, the inner emulsion and outer layer emulsion were homogenized at 2000 rpm for 30 min, degassed under vacuum at -0.09 MPa for 35 min, and passed through a 130-mesh sieve at 0.22 MPa to obtain a homogeneous emulsion.

[0047] In the vacuum emulsification and degassing stage, the remaining 30% of soybean oil in the inner oil phase is added and stirred at 280 r / min for 12 min. Then, the remaining 30% of soybean oil in the outer oil phase and 10 parts of beeswax are added. After dissolving in a water bath at 60℃ for 30 min, the mixture is cooled to 30℃, homogenized at 2000 r / min for 35 min, and degassed under vacuum at -0.08 MPa for 1.2 h. The mixture is then discharged at a pressure of 0.3 MPa.

[0048] During shot pressing and shaping, the shot pressing area is maintained at 24℃ and 45% relative humidity. The shot pressing machine runs at 15 r / min, and the rotating drum shapes the shot at 4 r / min for 4 hours, resulting in a rubber sheet thickness of 0.90 mm. During drying and washing, the shot is first dried at 25℃ and ≤30% relative humidity for 6 hours. Each time, 20 kg of capsules and 0.15 kg of 95% edible alcohol are added, and the shot is washed at 40 r / min for 10 minutes. After recovering the alcohol, the shot is dried for 12 hours until the moisture content is ≤13%.

[0049] Comparative Example 1: This comparative example is a regular royal jelly capsule, prepared using a traditional formula and method. The difference between this example and Example 1 is that it does not have a double-layer emulsion structure and a targeted release polymer.

[0050] Specifically, the formulation in this comparative example, by weight, includes 100 parts of freeze-dried royal jelly powder, 200 parts of soybean oil, 250 parts of gelatin, 105 parts of glycerin, 12 parts of beeswax, and 270 parts of purified water. During preparation, the freeze-dried royal jelly powder and soybean oil are directly mixed and stirred until homogeneous; the gelatin, glycerin, and purified water are mixed and heated to 80°C to dissolve, then beeswax is added and stirred until melted; using a traditional capsule filling process, the mixture is directly injected into the capsule shell, compressed, and dried until the moisture content is ≤13%. Because this formulation lacks double-layer emulsification protection and a targeted release mechanism, the active ingredients are easily destroyed in the stomach, and it is susceptible to external environmental influences during storage.

[0051] Comparative Example 2: The difference between this comparative example and Example 1 is that the formulation does not contain a targeted release polymer, while the rest of the formulation and preparation method are the same.

[0052] Specifically, the formulation of this comparative example does not contain methacrylic acid copolymer in the inner aqueous phase, but only 100 parts of lyophilized royal jelly powder. In the preparation method, no targeted release polymer is added during the preparation of the inner emulsion. The remaining steps, such as inner oil phase treatment, emulsification, vacuum treatment, and preparation of the outer gel, formation of the double emulsion layer, vacuum emulsification and defoaming, pelleting and shaping, drying and washing, are consistent with Example 1. Due to the lack of a targeted release polymer, the active ingredient cannot be effectively protected in the acidic environment of the stomach and is easily lost.

[0053] Comparative Example 3: The difference between this comparative example and Example 1 is that the content of the targeted release polymer is 0.1 parts, while the rest of the formulation and preparation method are the same.

[0054] In this comparative formulation, the inner aqueous phase component contains 100 parts of lyophilized royal jelly powder and 0.1 parts of a targeted-release polymer (methacrylic acid copolymer). The preparation process of this polymer is consistent with that of Example 1. In the preparation method, 0.1 parts of the targeted-release polymer are added during the preparation of the inner emulsion. The remaining steps, such as inner oil phase treatment, emulsification parameters, vacuum treatment conditions, and subsequent preparation of the outer gel layer and formation of the double emulsion layer, are consistent with Example 1. Due to the insufficient content of the targeted-release polymer, a complete protective layer cannot be formed, making it difficult to effectively reduce the loss of active ingredients in the acidic environment of the stomach.

[0055] Comparative Example 4: The difference between this comparative example and Example 1 is that the content of the targeted release polymer is 10 parts, while the rest of the formulation and preparation method are the same.

[0056] In this comparative formulation, the inner aqueous phase component contains 100 parts of lyophilized royal jelly powder and 10 parts of a targeted release polymer (methacrylic acid copolymer). The preparation process of this polymer is the same as in Example 1. In the preparation method, 10 parts of the targeted release polymer are added during the preparation of the inner emulsion. The remaining steps, such as emulsification parameters, vacuum treatment conditions, preparation of the outer emulsion, and formation of the double emulsion layer, are all consistent with Example 1. Because the content of the targeted release polymer is too high, although it can enhance the protective effect on the stomach, it will lead to a slow release rate of the active ingredient in the intestine, affecting bioavailability.

[0057] Comparative Example 5: The difference between this comparative example and Example 1 is that it does not have a double-layer emulsion structure, but is only a single-layer oil-in-water emulsion. The other raw material types and preparation method steps have been adjusted.

[0058] Specifically, in the formulation of this comparative example, only the internal aqueous phase and internal oil phase components are retained, namely 100 parts of royal jelly freeze-dried powder, 1 part of targeted release polymer (the preparation process of the targeted release polymer is basically the same as that in Example 1), 150 parts of soybean oil, 4 parts of lecithin, and 270 parts of purified water. Gelatin, glycerin, titanium dioxide nano-dispersion, soybean oil and beeswax in the external aqueous phase and external oil phase are removed.

[0059] In this comparative preparation method, only the inner emulsion is prepared. The inner oil phase and inner aqueous phase are emulsified and directly pelletized, omitting the steps of outer emulsion preparation and double emulsion formation. The drying and pelletizing conditions are the same as in Example 1. Due to the lack of a physical barrier from the outer emulsion structure, the active ingredients are easily affected by external factors such as oxygen and light, resulting in poor stability.

[0060] Comparative Example 6: The difference between this comparative example and Example 1 is that the raw material components are added all at once, rather than used in multiple times, so the preparation method is slightly adjusted.

[0061] Specifically, the formulation of this comparative example is the same as that of Example 1, including 100 parts of freeze-dried royal jelly powder, 1 part of targeted release polymer (the preparation process of the targeted release polymer is the same as that of Example 1), 150 parts of soybean oil in the inner oil phase, external aqueous phase components, 80 parts of soybean oil in the outer oil phase, 12 parts of beeswax, and excipients.

[0062] In this comparative preparation method, 150 parts of the inner oil phase are heated and dissolved to dissolve lecithin in one step. The inner aqueous phase is then prepared and emulsified with the inner oil phase in one step. 80 parts of soybean oil and 12 parts of beeswax are added to the outer oil phase in one step and mixed with the outer aqueous phase. No additional raw materials are added in subsequent steps such as double emulsion formation, vacuum emulsification, and defoaming. Other parameters, such as stirring speed, temperature, and vacuum degree, are consistent with those in Example 1. Because the raw materials are added in one step, local agglomeration is prone to occur during emulsification, resulting in poor emulsion uniformity and affecting the stability and release effect of the active ingredients.

[0063] The following is a comparison of experimental data between the examples and the comparative examples: Table 1: Comparison of in vitro simulated digestive performance parameters of the formulations in the examples and comparative examples

[0064] The testing methods and standards for the relevant performance parameters in Table 1 are as follows: Gastric juice loss rate: The second method (paddle method) of General Chapter 0931 of Part IV of the 2020 edition of the Chinese Pharmacopoeia was used to simulate the gastric juice environment (pH 1.2, 37℃) and detect the residual amount of active ingredient (10-hydroxy-2-decenoic acid) within 2 hours. The loss rate was calculated as (initial content - residual content) / initial content × 100%.

[0065] Intestinal fluid release rate: Using the same device as above, simulate intestinal fluid environment (pH 6.8, 37℃) and detect the cumulative release of active ingredients within 4 hours. Release rate = release amount / initial content × 100%.

[0066] Peroxide value: Determined by titration according to GB5009.227-2016 "National Food Safety Standard - Determination of Peroxide Value in Food" to reflect the degree of oxidation of oils and fats.

[0067] Viscosity of the outer layer adhesive: Measured using an NDJ-8S rotational viscometer at 60°C and a rotation speed of 10 r / min. The unit is mPa·s.

[0068] Product qualification rate: Randomly select 1000 capsules and determine the number of qualified capsules according to the standards of appearance (no sticking or cracking), capsule thickness (0.85-0.90mm), and moisture (≤13%). Calculate the qualification rate = number of qualified capsules / total number of capsules × 100%.

[0069] Activity retention rate during room temperature storage: The sample was stored at 25℃ and 60% relative humidity for 3 months, and the content of active ingredients at the initial and final stages was determined. Retention rate = final stage content / initial content × 100%.

[0070] Analysis of the data in Table 1 above shows that the embodiments of the present invention exhibit significant advantages through the core design of a double-layer emulsion structure and a targeted release polymer: First, the targeted release polymer (methacrylic acid copolymer) forms a hydrophobic protective layer in the acidic environment of the stomach, controlling the gastric juice loss rate to 7%-10%, far lower than the comparative example (22%-60%), while rapidly dissolving in the intestines, with an intestinal juice release rate of 87%-92%, demonstrating precise targeting; Second, the double-layer emulsion structure and multi-stage vacuum treatment synergistically inhibit oxidation, with a peroxide value of only 0.28-0.35 mmol / kg, significantly lower than the comparative example (0.9-1.5 mmol / kg) without a double-layer structure or without adding raw materials in stages, and the activity retention rate reaches 90%-93% after 3 months of storage at room temperature; Third, the staged addition of raw materials and optimization of process parameters (such as the viscosity of the adhesive 2000-5000 mPa・s) ensure a product qualification rate of over 96%, solving problems such as adhesion and uneven thickness in traditional processes.

[0071] Comparative Example 1 (ordinary capsules) suffered a gastric fluid loss rate as high as 60% due to the lack of a bilayer structure and targeting polymer, with an activity retention rate of only 55% after 3 months, highlighting the inadequacy of stability and targeting of traditional dosage forms. Comparative Examples 2 (no targeting polymer) and 3 (insufficient targeting polymer), despite having a bilayer structure, still experienced a gastric fluid loss rate of 25%-30%, demonstrating that the targeting polymer is key to reducing gastric fluid loss. Comparative Example 4 (excessive targeting polymer) reduced the gastric fluid loss rate, but the intestinal fluid release rate dropped to 60%, indicating that the polymer dosage needs to be strictly controlled between 0.5 and 2 parts. Comparative Example 5 (no bilayer structure) lacked an outer barrier, resulting in a peroxide value of 1.2 mmol / kg and an activity retention rate of only 62%, demonstrating the oxidative protection effect of the bilayer structure. Comparative Example 6 (raw material added at once) had a pass rate of only 70% due to uneven emulsification, verifying the importance of adding the raw material in stages for system stability.

[0072] Table 2: Comparison of in vivo metabolic performance parameters of the formulations in the Examples and Comparative Examples in animals

[0073] The detection methods and standards for mice in Table 2 above are as follows: Experimental animals: SPF-grade ICR mice, weighing 20±2g, half male and half female, were selected. After 3 days of acclimatization feeding, they were divided into groups of 10 mice each, for a total of 9 groups (corresponding to Examples 1-3 and Comparative Examples 1-6).

[0074] Sample preparation: The contents of the formulations of each example and comparative example were diluted with physiological saline to a suspension containing 10 mg / mL of the active ingredient of royal jelly (10-hydroxy-2-decenoic acid), and were prepared and used immediately.

[0075] Gastric active ingredient residue rate: The oral dose for mice was 10 mL / kg. After 2 hours, the stomach contents were dissected and the amount of active ingredient residue was determined by high performance liquid chromatography (HPLC). The residue rate was calculated as (amount of active ingredient in stomach contents / total amount administered by oral gavage) × 100%.

[0076] Intestinal active absorption: Small intestinal contents and intestinal mucosa were collected 4 hours after gavage, and the amount of unabsorbed active ingredients was measured. Absorption amount = (total amount gavage - gastric residue - intestinal residue) × 100%.

[0077] Serum active ingredient concentration and bioavailability: Blood samples were collected from the orbital sinus at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after gavage. Serum was separated by centrifugation, and the concentration of the active ingredient was determined by HPLC. A drug-time curve was plotted, and the peak concentration (C0) was calculated. max ) and the area under the curve during drug administration (AUC0₋) 24 h), bioavailability was calculated as a relative value based on Example 1.

[0078] Activity retention rate after 28 days of storage: The sample was stored at 25℃ and 60% relative humidity for 28 days. The serum concentration of active ingredients was measured 2 hours after gavage according to the above method. The retention rate was compared with that of fresh sample. Retention rate = (concentration after storage / concentration of fresh sample) × 100%.

[0079] Adverse reaction rate: Observe the abnormal symptoms such as diarrhea and decreased activity in mice within 24 hours after gavage, and calculate the incidence rate = (number of mice with abnormalities / total number of mice in each group) × 100%.

[0080] Analysis of the data in Table 2 shows that the embodiments of the present invention, relying on a double-layer emulsion structure and a targeted release polymer, exhibit significant advantages in animal experiments: First, the targeted release polymer maintains hydrophobicity in the acidic environment of the mouse stomach, with a gastric activity retention rate of 90%-93%, avoiding the destruction of active ingredients by gastric acid; after entering the intestine, it dissociates into hydrophilic substances, with an intestinal active absorption rate of 85%-90%, far higher than the comparative example (45%-78%), demonstrating precise gastrointestinal targeting. Second, the double-layer emulsion structure reduces the oxidation of active ingredients, with an activity retention rate of 89%-92% after 28 days of storage, and serum peak concentrations (32.6-36.5 μg / mL) and bioavailability (362.8-391.2 μg·h / mL) significantly higher than the comparative example, proving that the formulation can efficiently deliver active ingredients. Third, the formulation has good compatibility, with an adverse reaction rate of 0 in mice, and its safety is superior to that of traditional capsules (comparative example 1, incidence rate 15%). The above advantages stem from the synergistic effect of the dual physical barrier and pH-responsive release, which optimizes the entire process of active ingredients from gastric protection to intestinal absorption.

[0081] Comparative Example 1 (ordinary capsules) lacked targeted release and dual-layer protection, resulting in a gastric residue rate of only 40% and bioavailability less than 40% of the example. It also exhibited significant adverse reactions, highlighting the inefficiency and irritation of traditional dosage forms. Comparative Examples 2 (no targeted polymer) and 3 (insufficient targeted polymer), despite having dual-layer structures, showed low intestinal absorption (68%-72%), demonstrating that targeted release polymers are key to improving intestinal absorption. Comparative Example 4 (excessive targeted polymer), while showing a high gastric residue rate, had intestinal absorption reduced to 60%, resulting in decreased bioavailability, indicating that the polymer dosage needs to be controlled between 0.5 and 2 parts. Comparative Example 5 (no dual-layer structure) lacked an outer barrier, resulting in only 63% activity retention after storage and low serum concentration, highlighting the importance of dual-layer structure for stability and delivery efficiency. Comparative Example 6 (raw material added at once) suffered from uneven emulsification, leading to inferior bioavailability and storage stability compared to the example, validating the necessity of a multi-stage addition process.

[0082] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

Claims

1. A highly active royal jelly preparation, characterized in that, The formulation is a soft capsule with a double-layer emulsion structure. The inner layer is an oil-in-water emulsion, formed by emulsifying an inner aqueous phase component and an inner oil phase component. The outer layer is a water-in-oil gel, formed by emulsifying an outer aqueous phase component and an outer oil phase component. The double-layer emulsion structure is used to isolate the active ingredient from the influence of the external environment. The inner emulsion contains a targeted release polymer, which achieves targeted release of the active ingredient by responding to the pH difference in the gastrointestinal tract. The raw materials for preparing the formulation include the following components in parts by weight: Internal aqueous phase components: 80-120 parts of freeze-dried royal jelly powder, 0.5-2 parts of targeted release polymer; Internal oil phase composition: 135-165 parts soybean oil, which is used in two separate applications; External aqueous phase components: 240-260 parts gelatin, 100-110 parts glycerol, 0.05-0.1 parts titanium dioxide nano-dispersion; External oil phase composition: 60-100 parts soybean oil, 9-14 parts beeswax, both of which are used in two separate applications.

2. The highly active royal jelly preparation according to claim 1, characterized in that, The targeted release polymer is a methacrylic acid copolymer, which is hydrophobic and insoluble in an acidic environment with pH < 5, and dissociates into a hydrophilic substance and dissolves rapidly in a neutral or alkaline environment with pH > 7.

3. The highly active royal jelly preparation according to claim 2, characterized in that, The preparation process of the targeted release polymer includes the following steps: (1) Mix methacrylic acid and ethyl acrylate at a mass ratio of 6-8:3-2, add benzoyl peroxide at a mass ratio of 0.3%-0.7% of the total monomer mass as an initiator, and react at 55-75℃ for 3-7h to obtain crude copolymer; (2) Dissolve the crude product in 4%-6% sodium hydroxide solution, then adjust the pH to 1.5-3.5 with 8%-12% hydrochloric acid to precipitate the product; (3) After filtration, the precipitate is washed with purified water until neutral, dried under vacuum at 35-55℃ for 7-11h, and then pulverized through a 70-110 mesh sieve to obtain methacrylic acid copolymer.

4. The highly active royal jelly preparation according to claim 1, characterized in that, The proportions of soybean oil used twice in the internal oil phase component are 60%-70% and 30%-40%, respectively. The proportions of soybean oil used twice in the external oil phase components are 60%-70% and 30%-40%, respectively, and the proportions of beeswax used twice are 15%-45% and 55%-85%, respectively.

5. A method for preparing the highly active royal jelly preparation according to any one of claims 1-4, characterized in that, Includes the following steps: Step 1: Inner layer emulsion preparation: Through emulsification of the inner aqueous phase component and part of the inner oil phase component and vacuum treatment, an oil-in-water emulsion with active ingredient protection function is formed. Step 2: Preparation of outer layer adhesive: Through sol-gel, mixing and degassing treatment of outer aqueous phase components and part of outer oil phase components, an oil-in-water adhesive with barrier protection function is formed. Step 3: Formation of a double emulsion layer: The inner emulsion and the outer adhesive layer are emulsified a second time and then defoamed and filtered to form a stable double emulsion structure. Step 4: Vacuum emulsification and defoaming. The remaining inner oil phase component, the remaining outer oil phase component, and the product from Step 3 are mixed, homogenized, and defoamed to further optimize the emulsion stability. Step 5: Shot pressing and shaping. By controlling the temperature, humidity and equipment parameters, the emulsion is made into capsules with a specific thickness of rubber. Step 6: Drying and washing the capsules. Gradient drying and alcohol washing are used to control the moisture content and hygiene of the capsules.

6. The preparation method according to claim 5, characterized in that, The preparation of the inner layer emulsion in step 1 includes: Preparation of the inner oil phase: Take 60%-70% of the soybean oil in the inner oil phase component, heat it to 50-60℃, add lecithin, stir at 220-280r / min until dissolved, and cool down to 20-30℃; Internal aqueous phase preparation: Add royal jelly freeze-dried powder to purified water and stir evenly. Add targeted release polymer and stir at 160-200 r / min for 10-15 min. Primary emulsification: Slowly pour the inner oil phase into the inner aqueous phase and emulsify at 1500-2000 r / min for 20-30 min to form a primary emulsion; Vacuum treatment: The primary emulsion is maintained at a vacuum of -0.05 to -0.07 MPa for 10-15 min to obtain the inner emulsion, which has an average particle size of 1-5 μm.

7. The preparation method according to claim 5, characterized in that, The preparation of the outer layer adhesive in step 2 includes: External aqueous phase sol treatment: Add purified water and glycerol to the sol-gel tank, raise the temperature to 75-85℃ at 10-15℃ / min, and add gelatin and titanium dioxide nano-dispersion; External oil phase mixing: Add 60%-70% of soybean oil and 2-4 parts of beeswax to the external oil phase components, and stir well; Heat preservation treatment: Stir at 70-80℃ and 160-200r / min for 25-35min until dissolved, degas under vacuum of -0.06~-0.08MPa, pass through a 90-110 mesh sieve under pressure of 0.12-0.18MPa, and keep warm at 55-65℃ to form an outer layer of adhesive with a viscosity of 2000-5000mPa・s.

8. The preparation method according to claim 5, characterized in that, The formation of the double emulsion layer in step 3 includes: Secondary emulsification: Slowly pour the inner emulsion into the outer gel and homogenize at 1500-2000 r / min for 20-30 min; Vacuum degassing: Degas for 25-35 minutes under a vacuum of -0.07 to -0.09 MPa; Filtration: The emulsion is obtained by passing it through a 110-130 mesh sieve under a pressure of 0.18-0.22 MPa.

9. The preparation method according to claim 5, characterized in that, Step 4, vacuum emulsification and defoaming, includes: Initial mixing treatment: Stir the remaining 30%-40% of the inner oil phase soybean oil from step 1 with the product from step 3 at 220-280 r / min for 8-12 min; Wax melting treatment: Add the remaining 30%-40% of the outer oil phase soybean oil and 7-10 parts of beeswax from step 2, dissolve in a water bath at 50-60℃ for 20-30 minutes, and cool to 20-30℃; Secondary degassing: Homogenize at 1600-2000 r / min for 25-35 min, degas at a vacuum of -0.06 to -0.08 MPa for 0.8-1.2 h, and discharge under a pressure of 0.2-0.3 MPa.

10. The preparation method according to claim 5, characterized in that, Step 5, shot pressing and shaping, includes: maintaining the shot pressing room at a temperature of 20-24℃ and a relative humidity of 35%-45%; disinfecting the mold with 75% alcohol; heating the spreading box, syringe, and adhesive to 50-55℃, 40-45℃, and 55-65℃ respectively, and setting the drum temperature to 10-15℃; forming the shot at 10-15 r / min using the shot press, and shaping it in a rotating drum at 2-4 r / min for 2-4 hours, with the thickness of the rubber sheet controlled at 0.85-0.90 mm; And / or, the drying and washing of the capsules in step 6 includes: drying the capsules at 20-25℃ and relative humidity ≤30% for 4-6 hours until the moisture content of the capsule skin is ≤20%; adding no more than 20kg of capsules to the polishing machine each time, adding 0.05-0.15kg of 95% edible alcohol, and washing the capsules at 30-40r / min for 6-10 minutes; after recovering the alcohol, drying the capsules at 20-25℃ and relative humidity ≤30% for 8-12 hours until the moisture content of the capsule skin is ≤13%.

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