A feed additive for regulating intestinal microecology to eliminate antibiotic residues

Abstract

The present application relates to the technical field of feed additive composition and its preparation, and discloses a feed additive for regulating intestinal microecology to eliminate antibiotic residues, which comprises schisandra chinensis extract and dandelion extract, and is obtained through a co-preparation process, wherein the process forms a stable synergistic inner core microstructure by in-situ encapsulating lignan components of the schisandra chinensis extract in a water-soluble polysaccharide matrix of the dandelion extract through high-speed shearing emulsification and a synergistic alcohol precipitation step, the present application innovates from the source of the preparation process, avoids pharmacological function antagonism among components caused by conventional physical mixing by using the formed specific microstructure, and provides a material basis for realizing synergistic enhancement of host and flora elimination pathways.

Description

Technical Field

[0001] This invention relates to a feed additive that regulates the intestinal microecology to eliminate antibiotic residues, belonging to the technical field of feed additive compositions and their preparation. Background Technology

[0002] Currently, eliminating antibiotic residues in aquatic animals is a key technical challenge for ensuring product safety in aquaculture. These residues exist in two forms within the animal body: localized residues residing in the digestive system and systemic residues absorbed by the host and distributed in tissues and organs such as muscles and liver. To achieve complete elimination of both forms of residues, existing technologies typically rely on a combination of two different pharmacological pathways: one is by introducing host drug-metabolizing enzyme inducers, such as specific plant extracts, to activate the hepatic cytochrome P450 enzyme system, accelerating systemic elimination. The first approach involves addressing residual metabolism and excretion. The second approach involves adding prebiotics or probiotics to activate specific gut microbiota, such as Bifidobacteria, enabling them to highly express functional enzymes like nitroreductase, thus achieving in-situ biotransformation of local gut residues. Both of these approaches have inherent performance limitations in terms of pharmacological mechanisms. Active ingredients that can be effectively absorbed by the host and activate liver metabolism often have broad-spectrum antibacterial properties, inhibiting the gut microbiota that performs biotransformation functions before reaching the hindgut. Conversely, prebiotics specifically designed to regulate gut microbiota do not possess the pharmacological activity to be absorbed by the host and induce liver metabolic enzymes.

[0003] To circumvent this inherent limitation, the most common technical practice in this field is to use a compounding process of single-component extraction and physical mixing. Extracts of active component A and component B are prepared separately and then simply dry-mixed using equipment such as a V-type mixer. The underlying design of this process assumes that the functions of the two components can be linearly superimposed. However, this simple physical mixing leads to the aforementioned performance limitation in animals, causing direct pharmacodynamic antagonism between the two active ingredients in the intestinal microenvironment, making it difficult for both elimination pathways to function effectively. This technical approach of simply compounding different functional components is currently ineffective. This is not uncommon. For example, Chinese invention patent CN105360613A discloses a novel green feed additive that can replace antibiotics. This scheme simply mixes a microecological preparation with a variety of traditional Chinese medicine ingredients such as Platycladus orientalis leaf extract, Magnolia officinalis powder, and Eucommia ulmoides leaf powder. This design ignores the potential antagonism between the components. The broad-spectrum antibacterial properties of the added traditional Chinese medicine ingredients, such as Platycladus orientalis leaf extract and Magnolia officinalis powder, may directly inhibit the activity of the microecological preparations added to the formula, such as Enterococcus lactis and Bacillus tarda, in the animal intestine, making it difficult for the two claimed technical paths to work synergistically.

[0004] Therefore, the technical problem to be solved by this invention is to innovate from the source of the preparation process and devise a specific co-preparation method so that two intrinsically antagonistic active components can form a material basis with a specific microscopic synergistic structure in advance during the preparation process; and to fundamentally regulate the pharmacokinetics and pharmacodynamics of the two components in the animal body by using this material basis, transforming functional antagonism into synergistic enhancement, and realizing the synchronous activation of host metabolic pathways and microbial transformation pathways. Summary of the Invention

[0005] To address the problems mentioned in the background art, the technical solution of the present invention is as follows: a feed additive for regulating intestinal microecology to eliminate antibiotic residues, the feed additive comprising:

[0006] A synergistic core microstructure; wherein the synergistic core microstructure comprises: Schisandra chinensis extract and Taraxacum mongolicum extract; wherein the weight ratio of Schisandra chinensis extract to Taraxacum mongolicum extract is 1:3 to 1:5; the synergistic core microstructure is a structure formed by in-situ encapsulating fat-soluble lignans from Schisandra chinensis extract in the form of a solid dispersion in the water-soluble polysaccharide matrix, using water-soluble polysaccharides from Taraxacum mongolicum extract as the matrix.

[0007] The product obtained through a co-preparation process involving the following steps, resulting in a co-core microstructure:

[0008] Step 101: Provide an alcohol phase of Schisandra chinensis extract rich in lignans, the alcohol phase containing lignans and an aqueous phase of dandelion extract rich in polysaccharides, the aqueous phase containing water-soluble polysaccharides.

[0009] Step 102: Take the alcohol phase of Schisandra chinensis extract and the aqueous phase of Taraxacum mongolicum extract in a weight ratio of 1:3 to 1:5.

[0010] Step 103: Under high-speed shearing conditions, the alcohol phase of Schisandra chinensis extract is injected into the aqueous phase of Taraxacum mongolicum extract, so that water-soluble polysaccharides act as emulsifiers to coat lignan components and form an emulsion.

[0011] Step 104: Add ethanol to the emulsion and adjust the final ethanol concentration of the system to 60% to 75% to cause the water-soluble polysaccharides that have been coated with lignans to undergo synergistic precipitation and form a precipitate with a synergistic core microstructure.

[0012] Step 105: Dry the precipitate.

[0013] Preferably, the weight ratio of Schisandra chinensis extract to dandelion extract is 1:4; in step 101, the alcohol phase of Schisandra chinensis extract is prepared by reflux extraction of Schisandra chinensis medicinal material using an ethanol solution with a concentration of 70% to 80%; the aqueous phase of dandelion extract is prepared by decocting dandelion medicinal material in water and then concentrating it.

[0014] Preferably, the composition is used to induce the activity of drug-metabolizing enzymes in the host liver and functional enzymes in the gut microbiota, defining the synergistic enhancement index of the composition. for: ,in, The enzyme activity induced after feeding the composition. The enzyme activity induced after feeding the individual component of Schisandra chinensis extract at the same dosage as that contained in the composition. The enzyme activity induced after feeding the same dosage of the dandelion extract component as contained in the composition was measured. The value is greater than 1.

[0015] Preferably, the high-speed shearing condition in step 103 is achieved by a high-speed homogenizer with a rotation speed of 5000 rpm to 10000 rpm.

[0016] Preferably, in step 101, the ethanol phase of Schisandra chinensis extract is prepared by reflux extraction with 6 to 10 times the amount of ethanol solution 1 to 2 times, and the aqueous phase of dandelion extract is prepared by decoction with 8 to 12 times the amount of water 1 to 2 times.

[0017] 6. The feed additive for regulating intestinal microecology to eliminate antibiotic residues according to claim 1, characterized in that the synergistic core microstructure is a matrix-dispersion system, wherein the fat-soluble lignan components are dispersed in amorphous or microcrystalline form in a water-soluble polysaccharide matrix.

[0018] Preferably, the composition further comprises pharmaceutically or feed-acceptable excipients.

[0019] Preferably, the composition or formulation comprising the composition is externally coated with a pH-responsive enteric coating.

[0020] Preferably, the pH-responsive enteric coating uses acrylic resin No. II material, and the pH-responsive enteric coating is limited to dissolving in the pH environment of the animal's hindgut to release the synergistic core microstructure.

[0021] Preferably, the antibiotic residue is florfenicol residue or enrofloxacin residue. Feed additives that regulate the intestinal microecology to eliminate antibiotic residues are used for aquatic animals, specifically Litopenaeus vannamei.

[0022] Compared with the prior art, the beneficial effects of the present invention are:

[0023] 1. A specific co-preparation process is provided, which constructs a physically stable synergistic core microstructure between the fat-soluble lignans of Schisandra chinensis extract (component A) and the water-soluble polysaccharides of Taraxacum mongolicum extract (component B) through forced emulsification under high-speed shearing and subsequent synergistic alcohol precipitation steps. The lignans are in situ encapsulated by the polysaccharide matrix in the form of a solid dispersion. This process solves the limitation of the two components being difficult to form an effective material basis under conventional single extraction and physical mixing processes due to differences in physicochemical properties from the preparation source. It provides a uniform and reproducible material guarantee for the two components to exert synergistic pharmacological effects in animals, which is not available in the current technology.

[0024] 2. The resulting synergistic core material structure constitutes a drug delivery system. The dandelion polysaccharide matrix (component B) acts as a pharmacokinetic regulator for schisandrin lignans (component A). This structure physically alters the release characteristics of component A, preventing its inactivation or degradation by gut microbiota due to rapid and uncontrolled release in the upper intestine. It transforms component A into a controlled and sustained-release mode, ensuring that it can cross the intestinal barrier and be effectively absorbed by the host, efficiently reaching target organs such as the liver. This allows it to induce the activity of drug-metabolizing enzymes, solving the problem in existing technologies where such active ingredients have low bioavailability and are difficult to effectively act on systemic residues.

[0025] 3. The controlled sustained-release properties achieved by the synergistic core structure simultaneously regulate the pharmacokinetic behavior of component A (schisandrin) in the animal hindgut. This structure precisely controls the local concentration within a specific selective inhibition window. At this concentration, the broad-spectrum inhibition of component A on the target bacterial population (such as Bifidobacterium) to be proliferated by dandelion extract (component B) is avoided; the inhibitory effect on opportunistic pathogens is preserved, freeing up ecological niches for the target bacterial population, and allowing component B to fully exert its efficacy in inducing the activity of bacterial functional enzymes (such as nitroreductase), avoiding the problem of antagonistic functions between the two components in conventional mixing methods. Attached Figure Description

[0026] Figure 1 This is a flowchart illustrating the co-preparation process and dual-pathway synergistic mechanism of the present invention;

[0027] Figure 2 This is a comparison chart showing the effect of different preparation methods on the synergistic improvement index S of the present invention;

[0028] Figure 3 This diagram illustrates the release mechanism of the enteric-coated particles of the present invention under different pH conditions. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below. However, those skilled in the art will understand that modifications or equivalent substitutions can be made to the technical solutions of this invention without departing from the spirit and scope of this invention, and such modifications and equivalent substitutions should all be covered within the scope of protection claimed by this invention.

[0030] This invention provides a feed additive for regulating intestinal microecology to eliminate antibiotic residues. The core of this feed additive is a synergistic core microstructure comprising Schisandra chinensis extract and Taraxacum mongolicum extract. Obtained through a specific co-preparation process, it fundamentally solves the functional antagonism problem between active components of different pharmacological pathways in existing technologies. The technical solution of this invention is primarily applied in aquaculture, particularly in the farming of Litopenaeus vannamei, as a feed additive to eliminate antibiotic residues such as florfenicol or enrofloxacin. In aquaculture, eliminating antibiotic residues faces long-standing technical challenges, requiring simultaneous activation of host metabolic pathways to eliminate absorbed systemic residues and activation of intestinal flora transformation pathways to eliminate localized intestinal residues. Existing technologies, such as those activating host liver drug-metabolizing enzymes (e.g., lignans in Schisandra chinensis extract), often possess broad-spectrum antibacterial properties and easily inhibit bacteria that exert biotransformation functions before reaching the hindgut; conversely, those aiming to activate intestinal functional enzymes (e.g., water-soluble polysaccharides in Taraxacum mongolicum extract), cannot be absorbed by the host to induce liver metabolism. Conventional single-component extraction and physical mixing processes... The process allows these two antagonistic components to come into direct contact in the animal body, making it difficult for both elimination pathways to function effectively. The technical solution of this invention lies in constructing a specific synergistic core microstructure between Schisandra chinensis extract rich in fat-soluble lignans and Taraxacum mongolicum extract rich in water-soluble polysaccharides through a specific co-preparation process. The fat-soluble lignans are in situ encapsulated in a water-soluble polysaccharide matrix in a solid dispersion form, preferably amorphous or microcrystalline, forming a matrix-dispersion system. This specific material form enables Taraxacum mongolicum... The polysaccharide matrix acts as a pharmacokinetic regulator for Schisandra lignans, physically altering their release characteristics and preventing rapid, uncontrolled release in the upper intestine. This ensures that lignans cross the intestinal barrier and are effectively absorbed by the host, efficiently reaching the liver target and activating host metabolic pathways. The sustained-release properties of this structure in the hindgut precisely control the local concentration of lignans within a specific selective inhibition window, creating ecological niches for the target bacterial community to proliferate, allowing the activity of bacterial functional enzymes to be fully utilized, activating the bacterial transformation pathway, and thus synergistically initiating two elimination pathways in both the host and the bacterial community.

[0031] To provide a quantitative quality control procedure for the selective inhibition window of synergistic kernel microstructure products, an in vitro co-culture model was established, including a target beneficial strain such as *Bifidobacterium adolescentis* and a common opportunistic pathogen in aquaculture such as *Vibrio parahaemolyticus*. Synergistic kernel microstructure products were added to this co-culture system at concentration gradients from 0.01 mg / mL to 10 mg / mL, and their minimum inhibitory concentrations (MICs) against both strains were determined. When the MIC value of the product against *Vibrio parahaemolyticus* was orders of magnitude lower than its MIC value against *Bifidobacterium adolescentis*, the batch of product was considered to meet the technical requirements for the selective inhibition window. To obtain the aforementioned synergistic... The weight ratio of Schisandra chinensis extract to Taraxacum mongolicum extract is a key parameter in the microstructure of the core, and this weight ratio is limited to 1:3 to 1:5. This range is the technical window for forming a synergistic effect. If the ratio is lower than 1:5, such as 1:10, the concentration of Schisandra chinensis extract is too low and cannot effectively induce the activity of host metabolic enzymes, and its effect on optimizing the ecological niche of the bacterial community is also insufficient. If the ratio is higher than 1:3, such as 1:1, the concentration of Schisandra chinensis lignans is too high, and the broad-spectrum antibacterial properties will completely inhibit the activity of the target bacterial community, leading to the collapse of the bacterial community transformation pathway. In the preferred embodiment of the present invention, the weight ratio of Schisandra chinensis extract to Taraxacum mongolicum extract is 1:4. Under this ratio, the two synergistic mechanisms, namely the protection of the bioavailability of lignans by polysaccharides and the optimization of the ecological niche of the target bacterial community by lignans, can achieve a better balance.

[0032] The co-preparation process for the synergistic kernel microstructure is a product obtained through the following steps: Step 101, providing an alcoholic phase of Schisandra chinensis extract rich in lignans and an aqueous phase of Taraxacum mongolicum extract rich in polysaccharides; in a specific embodiment, the preparation method of the alcoholic phase of Schisandra chinensis extract is as follows: take Schisandra chinensis medicinal material, use 6 to 10 times, preferably 8 times, of a 70% to 80%, preferably 75% ethanol solution, and reflux extract 1 to 2 times, preferably 2 times, each time for 1 to 2 hours; combine the extracts and concentrate under reduced pressure to obtain the alcoholic phase, which is rich in lignans. Lipid components; In the same embodiment, the preparation method of the aqueous phase of dandelion extract is as follows: Take dandelion medicinal material, use 8 to 12 times, preferably 10 times, of water, decoct 1 to 2 times, preferably 2 times, each time for 1 to 2 hours; combine the extracts, filter, and concentrate the filtrate to obtain the aqueous phase, which is rich in water-soluble polysaccharides; Step 102, according to the dry weight of the raw medicinal material in step 101, make the weight ratio of Schisandra chinensis extract to dandelion extract 1:3 to 1:5, preferably 1:4, and take the alcoholic phase of Schisandra chinensis extract prepared in step 101. Step 103: Under high-speed shearing conditions, the alcohol phase of Schisandra chinensis extract is injected into the aqueous phase of dandelion extract to form an emulsion; the water-soluble polysaccharides in the aqueous phase act as emulsifiers and protective colloids, shearing, dispersing, and coating the water-insoluble lignan components in the alcohol phase; the high-speed shearing conditions are preferably achieved by a high-speed homogenizer, the speed of which can be set to 5000 rpm to 10000 rpm, and in a specific embodiment, the speed is 8000 rpm; Step 104: Slowly add the ethanol phase of Schisandra chinensis extract to the emulsion formed in step 103. Ethanol is added and stirred to adjust the final ethanol concentration of the system to 60% to 75%, preferably 70%. At this ethanol concentration, the water-soluble polysaccharides that have been fully coated with lignans precipitate out, promoting the synergistic precipitation of lignans and polysaccharides to form a precipitate with a synergistic core microstructure. Step 105: Drying the precipitate; using conventional drying methods in the art, such as vacuum drying or spray drying, to obtain the feed additive composition powder. To characterize the synergistic effect produced by the composition of the present invention, a synergistic enhancement index of the composition is defined. The calculation method is as follows: ,in, The enzyme activity induced after feeding the composition. The corresponding enzyme activity induced after feeding the individual component of Schisandra chinensis extract at the same dosage as that contained in the composition. The corresponding enzyme activity induced by feeding the same dosage of the dandelion extract component as contained in the composition; the composition obtained through the above co-preparation process and specific ratio, its A value greater than 1 indicates that its effect is not a simple superposition of component functions, but rather a non-linear synergistic enhancement. When preparing feed formulations, the composition may further include pharmaceutically or feed-acceptable excipients, such as diluents, binders, lubricants, etc., to enable the synergistic core microstructure to accurately reach the animal's hindgut and exert its effect. The composition or formulation containing the composition may be coated with a pH-responsive enteric coating. The pH-responsive enteric coating uses acrylic resin II material. This pH-responsive enteric coating is limited to dissolving in a specific pH environment in the hindgut of an animal, taking Litopenaeus vannamei as an example, and releasing the synergistic core microstructure in the target intestinal segment.

[0033] Example 1: In the high-density Litopenaeus vannamei farming cycle, florfenicol was administered to control disease. During the withdrawal period, the farming system faced a key technical challenge: simultaneously eliminating systemic residues absorbed into the hepatopancreas and localized residues remaining in the hindgut. Conventional compound formulations used in the field, which physically mix Schisandra chinensis extract powder and Taraxacum mongolicum extract powder in a 1:4 ratio before addition, exhibit unstable effects. This is because the lignans in Schisandra chinensis extract are absorbed to activate host metabolism. When released prematurely in the upper digestive tract, their broad-spectrum antibacterial properties severely inhibit the activity of the target bacterial population upon which Taraxacum mongolicum extract depends, resulting in the inability to effectively establish either elimination pathway. In this example, a synergistic core microstructure obtained through a specific co-preparation process was used. This feed additive, composed of Schisandra chinensis extract and Taraxacum mongolicum extract in a 1:4 weight ratio, undergoes a high-speed shear emulsification process at 8000 rpm in step 103 and a synergistic alcohol precipitation process in step 104, adjusting the final ethanol concentration to 70%. When ingested by Litopenaeus vannamei, the synergistic core microstructure undergoes predetermined physicochemical behavior in the digestive tract. The water-soluble polysaccharide matrix of Taraxacum mongolicum extract provides physical protection for the in-situ encapsulated fat-soluble lignans, enabling them to effectively penetrate the complex enzymatic and microbial environment of the upper intestine. This ensures the absorption rate across the intestinal barrier, allowing sufficient amounts to reach target organs such as the hepatopancreas, activating the cytochrome P450 enzyme system for efficient metabolism of systemic florfenicol residues absorbed into the bloodstream.

[0034] Meanwhile, the controlled sustained-release properties of the synergistic core microstructure regulate the release rate of lignans in the hindgut, keeping the local concentration within a selective inhibition window. This concentration is insufficient to inhibit the target bacterial populations such as Bifidobacteria that the dandelion extract aims to proliferate, but it can inhibit the growth of some opportunistic pathogens. This objectively frees up ecological niches for the target bacterial populations, allowing the dandelion extract to fully induce the high expression of nitroreductase in the bacterial population, thus enabling efficient biotransformation of florfenicol residues in the hindgut. The host metabolic pathway and the bacterial transformation pathway transform from a functional antagonistic relationship under conventional physical mixing to a synergistic relationship, with both elimination pathways being activated simultaneously.

[0035] Example 2: The purpose of this example is to objectively verify the synergistic effect of the co-preparation process of the present invention compared with the conventional physical mixing process by setting up a multi-dimensional control system, and to empirically verify the rationality and boundary of the weight ratio of Schisandra chinensis extract to dandelion extract in the range of 1:3 to 1:5; Experimental materials and animals: Schisandra chinensis extract (component A, prepared by ethanol extraction in step 101 and then dried) and dandelion extract (component B, prepared by water decoction in step 101 of the specific embodiment and then dried); healthy and uniformly sized Litopenaeus vannamei shrimp with an average weight of 8.0±0.5g; basal feed; florfenicol; Initial treatment of experimental animals: All Litopenaeus vannamei shrimp were uniformly fed a basal feed containing florfenicol (0.1% addition) under standard culture conditions for 7 days to establish a detectable baseline of florfenicol residue in their bodies.

[0036] Experimental group design: The treated Litopenaeus vannamei were randomly divided into 9 groups, with 3 replicates in each group. Each group was fed experimental feeds with different additives for 10 days. The preparation and addition methods of the additives for each group were as follows: Control group 1: Only basic feed was fed, without any extract additives; Control group 2 (component B acting alone): Component B was added to the basic feed at a rate of 0.4% of the total feed weight; Control group 3 (component A acting alone): Component A was added to the basic feed at a rate of 0.1% of the total feed weight; Control group 4 (physical mixing control): Dry powder of component A and dry powder of component B were mixed in a V-type mixer at a weight ratio of 1:4 using conventional physical dry mixing; this physical mixture was then added to the basic feed at a rate of 0.5% of the total feed weight (i.e., A accounts for 0.1%, B accounts for 0.4%); Experimental group 1 (1:3 sample group of this invention): Schisandra chinensis extract and... A synergistic kernel microstructure composition with a dandelion extract weight ratio of 1:3 was prepared. This composition was added to the basal feed at 0.4% of the total feed weight. Experimental Group 2 (1:4 sample group of this invention): The same preparation process as Experimental Group 1 was used to prepare a synergistic kernel microstructure composition with a weight ratio of 1:4. This composition was added to the basal feed at 0.5% of the total feed weight. Experimental Group 3 (1:5 sample group of this invention): The same preparation process as Experimental Group 1 was used to prepare a synergistic kernel microstructure composition with a weight ratio of 1:5. The composition was added to the basal feed at a weight ratio of 0.6% of the total feed weight. Control group 5 (out-of-range 1:20 sample group): A synergistic core microstructure composition with a weight ratio of 1:20 was prepared using the same co-preparation process as experimental group 1. This composition was added to the basal feed at a weight ratio of 2.1% of the total feed weight. Control group 6 (out-of-range 1:1 sample group): A synergistic core microstructure composition with a weight ratio of 1:1 was prepared using the same co-preparation process as experimental group 1. This composition was added to the basal feed at a weight ratio of 0.2% of the total feed weight. Added to the basal feed; Detection indicators and methods: At the end of day 10 of the experiment, samples were randomly taken from each group; Hepatopancreatic tissue was taken, and the activity of cytochrome P450 enzyme system (CYP3A4) was determined using conventional methods in the field, in nmol / mgprot / min; Hippogusal contents were taken, and the nitroreductase activity of Bifidobacterium was determined, in U / g; Muscle tissue was taken, and the florfenicol residue rate was determined using high performance liquid chromatography (HPLC), in %; The experimental data are shown in Table 1 below.

[0037] Table 1: Comparison of enzyme activity and residual rate between experimental groups and control groups.

[0038]

[0039] Referring to Table 1, control group 1 showed a high residual baseline under no-intervention conditions; data from control groups 2 (group B only) and 3 (group A only) confirmed the functional limitations of single components. Component A alone, while increasing CYP3A4 activity (0.48), exhibited strong inhibition of nitroreductase activity (1.9); data from control group 4 (physical mixing) (CYP3A4 activity 0.29, nitroreductase activity 3.1) were similar to those of control group 3, objectively confirming that the conventional physical mixing process directly antagonized the broad-spectrum antibacterial activity of component A and the probacterial function of component B, inhibiting the function of both pathways; conversely, the CYP3A4 activity (0.6) in experimental groups 1, 2, and 3 (1:3 to 1:5, co-preparation process) was significantly lower. Both 4-0.73) and nitroreductase activity (21.2-25.1) showed high levels, which were superior to the sum of the activities of control groups 2 and 3. This proves that the synergistic core microstructure formed by the co-preparation process of the present invention overcomes component antagonism and produces nonlinear synergistic effects. Furthermore, the data of control group 5 (1:20) and control group 6 (1:1) empirically verified the boundary of the ratio range. When the ratio deviates from the range of 1:3 to 1:5, the dual activation effect also drops sharply when the same co-preparation process is used. In control group 5, the CYP3A4 activity was insufficient (0.22) due to the low proportion of component A. In control group 6, the lignan concentration exceeded the selective inhibition window due to the high proportion of component A, resulting in the inhibition of nitroreductase activity (3.9).

[0040] Example 3: This example combines Figures 1 to 3 This describes a feed additive that regulates the gut microbiota to eliminate antibiotic residues, such as... Figure 1 As shown, the alcoholic component A of Schisandra chinensis extract rich in lignans is mixed with the aqueous component B of Taraxacum mongolicum extract rich in polysaccharides. Through a high-speed shear emulsification step, the polysaccharides are used as emulsifiers to coat the lignans, forming an emulsion. Co-precipitation with alcohol is then performed, with ethanol added to a concentration range of 60% to 75% to form a co-precipitate. After drying, the precipitate yields a feed additive product with a co-core microstructure. When ingested by animals, this microstructure provides physical protection and controlled sustained release during intestinal delivery. This characteristic protects lignan A and improves its bioavailability, allowing it to be absorbed by the host to activate drug-metabolizing enzymes such as the hepatic CYP450 enzyme system, thereby eliminating systemic residues. The controlled release of this structure in the hindgut places lignan A within a selective inhibition window, freeing up a microbial niche. This allows polysaccharide B to activate target bacteria such as Bifidobacteria and nitroreductase, eliminating local residues. The combined action of host metabolic pathways and microbial transformation pathways achieves a synergistic effect, systematically eliminating antibiotic residues.

[0041] like Figure 2As shown, the synergistic indices of the CYP3A4 pathway and the nitroreductase pathway in the physically mixed control group 4 were both much less than 1.0, exhibiting an antagonistic effect. Although control group 6 (1:1 co-prepared) used a co-preparation process, the ratio exceeded the acceptable range, resulting in both synergistic indices being less than 1.0. In contrast, the CYP3A4 pathway synergistic index of experimental group 2 (1:4 co-prepared) reached 1.20, and its nitroreductase pathway synergistic index reached 1.83, both values ​​being greater than 1.0. This empirically demonstrates the synergistic effect brought about by the specific process and ratio of this invention. Figure 3 As shown, after the enteric-coated particles enter the gastric fluid environment at pH 1.5, the coating material, acrylic resin II, remains intact in the acidic environment, with a cumulative release rate of only 7.8% within 2 hours, protecting the internal synergistic core structure from being released. When the particles pass through the pylorus and enter the small intestinal fluid environment at pH 6-7, the coating material continues to remain intact, continuing to protect the core structure until the particles reach the target area of ​​the hindgut fluid at pH 7.4. This pH value triggers the dissolution threshold of acrylic resin II, causing the polymer chains to break, the coating to dissolve rapidly, and the synergistic core structure to be released. A total release rate of 91.3% can be achieved within 45 minutes.

[0042] Example 4: This example is used to determine the synergistic improvement index. The calculation method is used to calculate some key data obtained in Example 2 to quantitatively verify the synergistic effect produced by the co-preparation process and specific ratio range of the present invention; synergistic improvement index The calculation formula is ,in This represents the measured enzyme activity value of the experimental or control group (mixture). The measured enzyme activity values ​​are those of the corresponding dose of component A added alone (i.e., the data of control group 3). The measured enzyme activity values ​​when component B is added alone at the corresponding dose (i.e., data from control group 2); based on the data in Table 1 of Example 2, targeting CYP3A4 activity (host metabolic pathway). , , ;Targeting nitroreductase activity (microbial community transformation pathway). , , The synergistic enhancement index of control group 4 (1:4, physical mixture) was calculated: its CYP3A4 activity , (This value is less than 1); its nitroreductase activity , (This value is less than 1); conventional physical mixing processes exhibit antagonistic effects in both pathways.

[0043] Calculate the synergistic enhancement index of experimental group 2 (1:4, co-prepared, preferred sample group of this invention): its CYP3A4 activity , (This value is greater than 1); Nitroreductase activity , (This value is greater than 1); The co-preparation process and specific ratio of the present invention produce synergistic enhancement effects on both host metabolic pathways and microbial community transformation pathways. The synergistic enhancement index of control group 6 (1:1, co-prepared, out of range) was calculated: its CYP3A4 activity , (This value is less than 1); Nitroreductase activity , (This value is less than 1); even if a co-preparation process is used, if the ratio deviates from the specific window of 1:3 to 1:5, the synergistic effect cannot be generated, or even antagonistic.

[0044] Example 5: This example clarifies the key process parameters in the co-preparation process of the present invention, specifically the effects of the high-speed shearing rotation speed in step 103 and the final ethanol concentration in step 104 on the morphology and key indicators of the synergistic core microstructure. It provides morphological evidence of the microstructure, determines the preferred range of the high-speed shearing rotation speed in step 103, fixes the weight ratio of Schisandra chinensis extract to Taraxacum mongolicum extract at 1:4, and fixes the final ethanol concentration in step 104 at 70%. Synergistic core microstructure compositions are prepared using different shearing rotation speeds; a control group is also included. Group A was homogenized at 0 rpm using conventional mechanical stirring. Groups A1, A2, A3, and A4 were homogenized at high speeds of 1000 rpm, 5000 rpm, 8000 rpm, and 15000 rpm, respectively. The encapsulation efficiency of lignans in the resulting powder compositions was measured. The encapsulation efficiency of control group A was only 15.3%, while that of experimental group A1 at 1000 rpm was 45.2%. Experimental groups A2 and A3 achieved encapsulation efficiencies of 88.6% and 91% at 5000 rpm and 8000 rpm, respectively. The encapsulation rate of group A4 at 15000 rpm was 90.8%, which was no improvement compared to group A3, but the energy consumption increased significantly. This data indicates that high-speed shearing of 5000 rpm to 10000 rpm is a necessary process condition for forming effective encapsulation. To determine the optimal range of the final ethanol concentration for synergistic alcohol precipitation in step 104, the weight ratio of Schisandra chinensis extract to Taraxacum mongolicum extract was fixed at 1:4, and the high-speed shearing speed in step 103 was fixed at 8000 rpm. Experimental groups B1, B2, B3, B4, and B5 were set up. The final ethanol concentrations of the adjustment system were 40%, 60%, 70%, 75%, and 90%, respectively; the encapsulation efficiency and precipitation yield of the lignan components were determined; at a concentration of 40% ethanol, B1 showed incomplete polysaccharide precipitation and a low yield, with an encapsulation efficiency of only 30.5%; B2 to B4, within the concentration range of 60% to 75%, all achieved encapsulation efficiencies of over 90%, namely 90.8%, 91.5%, and 90.2%, respectively; when the ethanol concentration was increased to 90% for B5, some other fat-soluble impurities in the alcohol phase also precipitated, causing the encapsulation efficiency to decrease to 85.5%.

[0045] To further confirm the synergistic core microstructure, the powders from experimental group 2 (1:4, co-prepared) in Example 2 and the powders from control group 4 (1:4, physically mixed) in Example 2 were subjected to scanning electron microscopy (SEM) morphology observation. The powders from control group 4 showed two morphologically different particles at the micrometer scale: one was crystalline particles of component A, and the other was amorphous particles of component B, which were simply stacked. The powders from experimental group 2, on the other hand, showed nearly spherical composite particles. Energy dispersive spectroscopy (EDS) analysis or further transmission electron microscopy (TEM) observation of the cross-section of the composite particles showed a typical matrix-dispersion structure, that is, the core region rich in lignans was covered by a polysaccharide-rich matrix. This morphological evidence provides direct physical evidence for the synergistic core microstructure formed by the co-preparation process of the present invention, confirming that this structure is the material basis for achieving pharmacokinetic regulation and functional synergy.

[0046] Example 6: This example provides a quality control procedure for standardizing raw materials. Before step 101 of the co-preparation process, the active ingredients of the purchased Schisandra chinensis and Taraxacum mongolicum batches need to be identified. High-performance liquid chromatography (HPLC) is used to determine the total content of lignans in Schisandra chinensis, and the phenol-sulfuric acid method is used to determine the total content of water-soluble polysaccharides in Taraxacum mongolicum. Based on the measured actual content data, the amount of solvent used in step 101 is adjusted, or the ratio of the alcohol phase to the aqueous phase extract is adjusted in step 102. This ensures that during high-speed shear emulsification in step 103, the actual weight ratio of lignans to water-soluble polysaccharides is consistently controlled within the range of 1:3 to 1:5, eliminating the impact of fluctuations in active ingredient content between different raw material batches on the synergistic microstructure of the final product. The impact of homogeneity; this embodiment provides an adaptive calibration procedure for pH-responsive enteric coating for different aquatic animals; when the application target is changed from Litopenaeus vannamei to other farmed species, taking grass carp as an example, the physiological pH range of the grass carp hindgut is determined, and the measured range is pH 7.2 to 7.8; given this target pH environment, when performing optional formulation steps, the originally selected acrylic resin II, with a pH dissolution threshold of 6.0, is no longer applicable, and acrylic resin III, with a pH dissolution threshold of 7.0, should be selected as the coating material; the selected acrylic resin III material is used to coat the synergistic core microstructure composition powder, so that it remains intact in the acidic and neutral environments of the grass carp stomach and small intestine until it reaches the hindgut environment of pH 7.2 to 7.8 before dissolving.

[0047] Example 7: This example provides a specific process for preparing a pH-responsive enteric-coated formulation from a synergistic core microstructure composition; 1.0 kg of the synergistic core microstructure composition powder prepared in Experimental Group 2 of Example 2 was mixed with 0.5 kg of excipient microcrystalline cellulose and 0.1 kg of pregelatinized starch in a V-type mixer for 15 minutes to obtain granulation powder; the granulation powder was placed in a fluidized bed granulator and coated with 85% ethanol solution as a wetting agent, dried, and blank granules were obtained; 150 g of acrylic resin II was weighed and dissolved in 1500 mL of 85% ethanol solution to prepare a coating solution; the blank granules were placed in a fluidized bed coating pan, and the inlet air temperature was set to 55°C. Up to 65 The material temperature is maintained at 40°C. ±2 The atomization pressure was set to 0.15 to 0.25 MPa, and the spraying rate was controlled at 12 to 18 g / min. The coating process was continued until the coating weight gain reached 9% to 11% of the total particle weight. Spraying was then stopped, and the particles were dried to obtain pH-responsive enteric-coated granules. The target weight gain for pH-responsive enteric coating, taking 9% to 11% as an example, was determined using a release curve calibration procedure. Parallel batches of granules with weight gains of 5%, 7%, 9%, 11%, and 13% were prepared, and the dissolution test was performed at pH 1.5 according to the method in the Chinese Veterinary Pharmacopoeia. After running in acidic medium for 2 hours, the mixture was switched to a hindgut-simulated medium at pH 7.4. A 9% lower limit of weight gain was defined as the cumulative release rate at pH 1.5 being just below the critical coating amount of 10%, while an 11% upper limit of weight gain was defined as above this level. The release rate did not decrease further in the acidic phase, but the release rate began to slow down at pH 7.4, failing to reach 90% release within 45 minutes. The obtained enteric-coated granules were then subjected to dissolution testing according to the Chinese Veterinary Pharmacopoeia, Method 1 (rotary basket method), at 100 rpm and 37°C. The sample was placed in 900 mL of simulated gastric fluid (pH 1.5 hydrochloric acid solution) and sampled after 2 hours to determine the cumulative release rate of lignans. The basket was then transferred to 900 mL of simulated hindgut environment (pH 7.4 phosphate buffer) and the experiment continued. Samples were taken at 45 minutes to determine the cumulative release rate of lignans. The results showed that the cumulative release rate of lignans was 7.8% after 2 hours in simulated gastric fluid and reached 91.3% after 45 minutes in the simulated hindgut environment. This indicates that the coating process can effectively protect the synergistic core microstructure as it passes through the stomach and achieves rapid release in the target intestinal segment.

[0048] 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 present invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the present invention.

[0049] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. A feed additive that regulates the intestinal microecology to eliminate antibiotic residues, characterized in that, Feed additives include: A synergistic core microstructure; wherein the synergistic core microstructure comprises: Schisandra chinensis extract and Taraxacum mongolicum extract; wherein the weight ratio of Schisandra chinensis extract to Taraxacum mongolicum extract is 1:3 to 1:5; the synergistic core microstructure is a structure formed by in-situ encapsulating fat-soluble lignans from Schisandra chinensis extract in the form of a solid dispersion in the water-soluble polysaccharide matrix, using water-soluble polysaccharides from Taraxacum mongolicum extract as the matrix. The product obtained through a co-preparation process involving the following steps, resulting in a co-core microstructure: Step 101: Provide an alcohol phase of Schisandra chinensis extract rich in lignans and an aqueous phase of Taraxacum mongolicum extract rich in polysaccharides, wherein the alcohol phase contains lignans and the aqueous phase contains water-soluble polysaccharides. Step 102: Take the alcohol phase of Schisandra chinensis extract and the aqueous phase of Taraxacum mongolicum extract in a weight ratio of 1:3 to 1:

5. Step 103: Under high-speed shearing conditions, the alcohol phase of Schisandra chinensis extract is injected into the aqueous phase of dandelion extract, so that water-soluble polysaccharides act as emulsifiers to coat lignan components and form an emulsion. Step 104: Add ethanol to the emulsion and adjust the final ethanol concentration of the system to 60% to 75% to cause the water-soluble polysaccharides that have been coated with lignans to undergo synergistic precipitation and form a precipitate with a synergistic core microstructure. Step 105: Dry the precipitate; Furthermore, the synergistic core microstructure is a matrix-dispersion system, in which fat-soluble lignans are dispersed in amorphous or microcrystalline form in a water-soluble polysaccharide matrix; The antibiotic residues are either florfenicol residues or enrofloxacin residues. Feed additives that regulate the intestinal microecology to eliminate antibiotic residues are used in aquatic animals, specifically Litopenaeus vannamei.

2. The feed additive for regulating intestinal microecology to eliminate antibiotic residues according to claim 1, characterized in that, The weight ratio of Schisandra chinensis extract to dandelion extract is 1:4; in step 101, the alcohol phase of Schisandra chinensis extract is prepared by reflux extraction of Schisandra chinensis medicinal material using an ethanol solution with a concentration of 70% to 80%; the aqueous phase of dandelion extract is prepared by decocting dandelion medicinal material in water and then concentrating it.

3. The feed additive for regulating intestinal microecology to eliminate antibiotic residues according to claim 1, characterized in that, The composition is used to induce the activity of drug-metabolizing enzymes in the host liver and functional enzymes in the gut microbiota, and the synergistic enhancement index of the composition is defined. for: ,in, The enzyme activity induced after feeding the composition. The enzyme activity induced after feeding the individual component of Schisandra chinensis extract at the same dosage as that contained in the composition. The enzyme activity induced after feeding the same dosage of the dandelion extract component as contained in the composition was measured. The value is greater than 1.

4. A feed additive for regulating intestinal microecology to eliminate antibiotic residues according to claim 1, characterized in that, The high-speed shearing condition in step 103 is achieved by a high-speed homogenizer with a rotation speed of 5000 rpm to 10000 rpm.

5. A feed additive for regulating intestinal microecology to eliminate antibiotic residues according to claim 1, characterized in that, In step 101, the ethanol phase of Schisandra chinensis extract is prepared by reflux extraction with 6 to 10 times the amount of ethanol solution 1 to 2 times, and the aqueous phase of dandelion extract is prepared by decoction with 8 to 12 times the amount of water 1 to 2 times.

6. A feed additive for regulating intestinal microecology to eliminate antibiotic residues according to claim 1, characterized in that, The composition contains pharmaceutically or feed-acceptable excipients.

7. A feed additive for regulating intestinal microecology to eliminate antibiotic residues according to claim 1, characterized in that, The composition or formulation comprising the composition is externally coated with a pH-responsive enteric coating.

8. A feed additive for regulating intestinal microecology to eliminate antibiotic residues according to claim 7, characterized in that, The pH-responsive enteric coating uses acrylic resin II material. The pH-responsive enteric coating is limited to dissolving in the pH environment of the animal's hindgut to release the synergistic core microstructure.

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