A liver-protecting bio-pharmaceutical manufacturing process and compound formula based on corn oligopeptide and active components of traditional Chinese medicine

Abstract

The application discloses a kind of based on corn oligopeptide and traditional Chinese medicine active component's liver-protecting biological medicine manufacturing process and compound formula. Including: preparation or obtain corn oligopeptide raw material, obtain first corn oligopeptide component and second corn oligopeptide component by weak hydrophobic separation;Respectively prepare puerariae radix water-soluble active component and schisandra chinensis fat-soluble active component;Second corn oligopeptide component, medicinal phospholipid and schisandra chinensis fat-soluble active component are carried out controlled alcohol-water mixing and phase separation compound, and the obtained dispersion is sprayed on pellet core, and is prepared into phase separation protection granule by low-temperature drying and enteric coating;First corn oligopeptide component, puerariae radix water-soluble active component and fast-release auxiliary material are granulated, and the whole particle is prepared into fast-release peptide segment granule;Two kinds of granules are low-shear final mixing, capsule filling and packaging. First corn oligopeptide component keeps free state, and two kinds of granules constitute same dose unit in independent state. The process avoids two kinds of granules to be wet mixed together, and is beneficial to keep the state of each material.

Description

Technical Field

[0001] This invention relates to oral solid dosage forms and their preparation techniques, specifically to a manufacturing process and compound formulation for a liver-protecting biopharmaceutical based on corn oligopeptides and active components of traditional Chinese medicine. Background Technology Corn oligopeptides, kudzu root extract, and schisandra chinensis extract can be used in oral formulations. Some of the active components in kudzu root are water-soluble, while some of the active components in schisandra chinensis are fat-soluble. When materials of different polarities are directly mixed, it is often necessary to simultaneously consider the dispersion of water-soluble components, the stability of fat-soluble components, and the shaping of the final formulation.

[0002] In existing preparation methods, all corn oligopeptides are often mixed with various extracts, or two types of traditional Chinese medicine extracts are concentrated together before granulation. In this process, some corn oligopeptides need to maintain rapid dispersion while also contributing to the stability of the fat-soluble components, making the interactions between materials prone to interference. The fat-soluble components may also precipitate, agglomerate, or become unevenly dispersed. If different particles are wet-mixed together in the subsequent granulation stage, the integrity of the enteric-coated granules may be affected. Therefore, a manufacturing process is needed that allows different components in the same corn oligopeptide raw material to perform different functions, and ensures that the two types of particles remain independent in the finished product. Summary of the Invention

[0003] The technical problem solved by this invention is: how to keep a portion of the corn oligopeptide component free and form fast-release particles together with the water-soluble active component of kudzu root in the same dosage unit, while allowing another portion of the corn oligopeptide component to participate in the phase separation and compounding of the fat-soluble active component of schisandra chinensis and form phase separation protective particles with an enteric outer layer; and how to avoid the two types of particles from being wet-mixed and pulverized twice in the final mixing stage.

[0004] The above-mentioned technical objective of the present invention is achieved through the following technical solution: a manufacturing process for a liver-protecting composition based on corn oligopeptides and active components of traditional Chinese medicine, comprising the following steps: S1. Prepare or obtain corn oligopeptide raw materials; S2. The same corn oligopeptide raw material obtained in S1 is subjected to weak hydrophobic separation to obtain the first corn oligopeptide component and the second corn oligopeptide component respectively. S3. Extract, concentrate and dry the kudzu root slices with water to prepare the water-soluble active components of kudzu root; S4. The Schisandra chinensis slices were subjected to alcohol extraction and concentration to prepare the lipophilic active components of Schisandra chinensis. S5. Dissolve the second corn oligopeptide component in the aqueous phase, dissolve the schisandra chinensis fat-soluble active component and medicinal phospholipid in the alcohol phase, add the alcohol phase to the aqueous phase at a controlled rate, and perform controlled alcohol-water mixing and phase separation compounding to obtain a phase separation compound dispersion. S6. Spray the phase-separated composite dispersion onto the pellet core, and then dry it at low temperature and coat it with enteric coating to obtain phase-separated protective particles; S7. The first corn oligopeptide component, the kudzu water-soluble active component and the fast-release excipient are granulated and sized by dry method or low moisture method to obtain fast-release peptide particles. S8. The fast-release peptide particles and the phase-separated protective particles are mixed with low shear, and then capsules are filled and packaged to obtain a liver-protecting composition. The first corn oligopeptide component remains in a free state in the fast-release peptide particles and does not participate in the phase separation and compounding of the schisandra chinensis fat-soluble active component. The fast-release peptide particles and the phase separation protection particles are not subjected to co-wet mixing and secondary pulverization.

[0005] Furthermore, in S1, the corn oligopeptide raw material is commercially available corn oligopeptide powder, or it is prepared from corn protein powder through slurry preparation, enzymatic hydrolysis, solid-liquid separation, membrane separation, concentration and drying.

[0006] Furthermore, in S2, the corn oligopeptide raw material is dissolved in purified water and filtered to clarify. The resulting liquid is then passed through a weakly hydrophobic macroporous adsorption resin. The liquid is first eluted with purified water and the effluent is collected. After concentration and drying, the first corn oligopeptide component is obtained. Then, the liquid is eluted with an ethanol aqueous solution and the eluent is collected. After ethanol recovery, concentration and drying, the second corn oligopeptide component is obtained.

[0007] Furthermore, in S3, the kudzu root slices are pulverized and extracted twice with purified water. The resulting extract is filtered, concentrated under low temperature and reduced pressure, and spray-dried or vacuum-dried to obtain the water-soluble active components of kudzu root. In S4, the schisandra fruit slices are pulverized and extracted with an ethanol-water solution. The resulting extract is filtered, the ethanol is recovered under reduced pressure, and the extract is concentrated to obtain the fat-soluble active components of schisandra fruit.

[0008] Furthermore, in S5, the concentration of the second corn oligopeptide component in the aqueous phase is 1% to 5%, the system temperature during phase separation and recombination is not higher than 35°C, and the system pH is 6.0 to 6.8; after phase separation and recombination, the ethanol content in the system is reduced by low temperature and reduced pressure.

[0009] Furthermore, in S6, the pellet core is a microcrystalline cellulose pellet core, a sucrose pellet core, or a pharmaceutically acceptable porous pellet core; the enteric coating is made of hydroxypropyl methylcellulose acetate succinate, methacrylic acid copolymer, or a pharmaceutically acceptable equivalent enteric material.

[0010] Furthermore, in S7, the fast-release excipient includes one or more of mannitol, microcrystalline cellulose, and crospovidone.

[0011] The present invention also provides a liver-protecting composition based on corn oligopeptides and active components of traditional Chinese medicine, comprising fast-release peptide particles and phase-separated protective particles; The fast-release peptide particles include a first corn oligopeptide component, a kudzu root water-soluble active component, and fast-release excipients, wherein the first corn oligopeptide component remains in a free state in the fast-release peptide particles. The phase-separated protective particles include a pellet core, a phase-separated composite drug-carrying layer disposed on the surface of the pellet core, and an enteric coating outer layer disposed on the outside of the phase-separated composite drug-carrying layer. The phase-separated composite drug-carrying layer includes a second corn oligopeptide component, pharmaceutical phospholipids, and schisandra chinensis fat-soluble active components. The first and second corn oligopeptide components are different components obtained from the same corn oligopeptide raw material after weak hydrophobic separation. The fast-release peptide particles and the phase-separated protective particles coexist in the same dosing unit as independent particles that can be identified from each other.

[0012] Furthermore, based on the dry basis mass parts of the liver-protecting composition, the first corn oligopeptide component is 25-45 parts, the second corn oligopeptide component is 8-18 parts, the kudzu root water-soluble active component is 8-16 parts, the schisandra fruit fat-soluble active component is 2-8 parts, the medicinal phospholipid is 2-6 parts, and the enteric material is 3-8 parts.

[0013] Furthermore, the same dosage unit is a hard capsule, the particle size of the fast-release peptide particles is 20-60 mesh, and the particle size of the pellet core is 0.45-0.85 mm.

[0014] Compared with the prior art, the present invention has at least the following beneficial effects: This invention separates the same corn oligopeptide raw material into a first corn oligopeptide component and a second corn oligopeptide component. The first corn oligopeptide component is used for fast-release peptide particles and remains in a free state. The second corn oligopeptide component is combined with pharmaceutical phospholipids and schisandra chinensis fat-soluble active components in a phase-separated compound, and then sprayed and enteric coated to form phase-separated protective particles. The kudzu root water-soluble active components and the schisandra chinensis fat-soluble active components are sent to different preparation branches. The two types of particles coexist independently during final mixing, without co-wetting or secondary pulverization. This process reduces the mutual influence of different materials during the preparation stage and helps maintain the respective material states of the fast-release particles and the phase-separated protective particles. Attached Figure Description

[0015] Figure 1 This is a flowchart of the manufacturing process for the liver-protecting biological drug of the present invention. Detailed Implementation

[0016] The following combination Figure 1 The specific embodiments of the present invention will be further described below. Figure 1S1 to S8 are interconnected steps within the same manufacturing process. The corn oligopeptide raw material is first separated into two components of the same origin but different material states through weak hydrophobic separation. The first corn oligopeptide component is used for fast-release peptide particles; the second corn oligopeptide component is used for phase separation protection particles. The two types of particles are prepared separately and remain independent before final mixing and capsule filling, without undergoing co-wet mixing or secondary pulverization.

[0017] The compound formulation, on a dry basis, comprises: 25–45 parts of the first corn oligopeptide component; 8–18 parts of the second corn oligopeptide component; 8–16 parts of the water-soluble active component of kudzu root; 2–8 parts of the fat-soluble active component of schisandra fruit; 2–6 parts of pharmaceutical phospholipids; and 3–8 parts of enteric coating material. The remaining components are pellet cores, fillers, disintegrants, glidants, and other pharmaceutically acceptable excipients. The water-soluble active component of kudzu root can use total isoflavones and puerarin as quality control indicators; the fat-soluble active component of schisandra fruit can use one or more of total lignans, schisandrin A, and schisandrin B as quality control indicators.

[0018] In S1, commercially available, qualified corn oligopeptide powder can be used directly as raw material. Alternatively, corn oligopeptide raw material can be obtained from corn gluten powder through slurry preparation, enzymatic hydrolysis, solid-liquid separation, membrane separation, concentration, and drying. When preparing raw materials in-house, food-grade or pharmaceutical-grade proteases can be used, and basic control should be exercised over peptide content, ash content, moisture content, relative molecular mass distribution, and free amino acid composition. Retaining short peptides with hydrophobic side chains in the raw material helps to subsequently obtain a second corn oligopeptide component that can participate in interfacial stabilization.

[0019] In step S2, corn oligopeptide raw materials are prepared into a solution with a solid content of 3%–10%. After dissolving in purified water and filtering to clarify, the solution is passed through a weakly hydrophobic macroporous adsorption resin. First, 2–4 column volumes are eluted with purified water. The eluent is collected, concentrated at low temperature, and dried to obtain the first corn oligopeptide component. Then, 2–5 column volumes are eluted with an ethanol-water solution. The eluent is collected, the ethanol is recovered, concentrated, and dried to obtain the second corn oligopeptide component. During scale-up, the resin type, loading concentration, elution volume, and elution order are kept consistent, and chromatographic fingerprints of both components can be established. The first component exhibits weaker retention on the resin, making it suitable for remaining free in fast-release particles; the second component exhibits relatively stronger retention on the weakly hydrophobic resin, making it suitable for entering interfacial systems containing phospholipids and lipid-soluble active components. This step is not aimed at obtaining a fixed molecular weight range, but rather at enabling different peptide components from the same raw material to perform different material functions.

[0020] In step S3, kudzu root slices were pulverized and extracted twice with 8–12 times the volume of purified water at 60–75°C. The extracts were combined, filtered, concentrated under low-temperature reduced pressure, and then spray-dried or vacuum-dried to obtain the water-soluble active components of kudzu root. The extraction and concentration conditions were adjusted according to the retention of puerarin and total isoflavones. The kudzu root extract was not co-concentrated with the fat-soluble active components of Schisandra chinensis to reduce the chance of different polar materials forming a viscous system in a high-solids state and to maintain its wetting and dispersion conditions in the fast-release granules.

[0021] In step S4, Schisandra chinensis slices are pulverized and extracted with a 50%–75% (v / v) ethanol aqueous solution at 40–60°C. The extract is filtered, the ethanol is recovered under reduced pressure, and the extract is concentrated to obtain the lipophilic active component of Schisandra chinensis. The concentration process is carried out at a low temperature to reduce the loss of lignans during prolonged heating. The obtained lipophilic active component of Schisandra chinensis is not wet-mixed with the first corn oligopeptide component, but forms a phase-separated complex system with the second corn oligopeptide component and medicinal phospholipids in subsequent steps.

[0022] In step S5, the second corn oligopeptide component is dissolved in purified water to prepare an aqueous phase with a concentration of 1%–5%. The lipophilic active component of Schisandra chinensis and medicinal phospholipids are dissolved in an ethanol-water solution to form an alcohol phase. The temperature of the aqueous phase is controlled not higher than 35°C, and the pH is controlled between 6.0 and 6.8. Under light-protected conditions, the alcohol phase is slowly added to the aqueous phase at a constant flow rate. After the addition is complete, gentle stirring continues to form a phase-separated composite dispersion, and then the ethanol content is reduced by low-temperature depressurization. The hydrophobic side chains in the second corn oligopeptide component can be adjacent to the lipophilic active phase of Schisandra chinensis, with the polar groups facing the external aqueous phase; the medicinal phospholipids provide an amphiphilic interface. In this way, the lipophilic active component of Schisandra chinensis is less likely to precipitate as large oil droplets or crystalline particles. This step does not use transglutaminase cross-linking, nor does it use the loading rate of a single component as a criterion.

[0023] The phase-separated composite dispersion can be used as a key intermediate for testing S5. After standing, there should be no obvious oil droplets or coarse flocs; the sedimentation volume should not increase abnormally after low-speed centrifugation; it should regain a uniform appearance after a limited number of inversions; and the recovery rate of the lignan marker component after spraying should be within a stable range. If visible oil droplets or obvious precipitation occur, the alcohol phase addition rate, local ethanol concentration, the concentration of the second corn oligopeptide component in the aqueous phase, and the system temperature should be checked first. Simply increasing the stirring speed is not advisable. Excessive shear may temporarily improve the appearance, but it is detrimental to maintaining the dispersion during subsequent spraying.

[0024] In S6, the phase-separated composite dispersion is sprayed onto the surface of microcrystalline cellulose pellet cores, sucrose pellet cores, or pharmaceutically acceptable porous pellet cores. The pellet core particle size can be selected from 0.45 to 0.85 mm. Fluidized bed low-temperature drying is used during spraying, with the product temperature controlled not exceeding 38°C, and the moisture content after drying is preferably 2.5% to 5.0%. The resulting drug-loaded pellet cores are then coated with an enteric coating. The enteric material can be hydroxypropyl methylcellulose acetate succinate, methacrylic acid copolymer, or a pharmaceutically acceptable equivalent enteric material. The coating weight gain is adjusted according to the tolerance to acidic media. The enteric outer layer maintains the particle integrity in the stomach; upon entering the intestinal tract, the enteric layer opens, and the internal second corn oligopeptide component, phospholipids, and schisandra chinensis fat-soluble active components re-disperse. After coating, no high-intensity pulverization or wet granulation with fast-release granules is used.

[0025] If the pellet cores stick together during spraying, the spray volume per unit time can be reduced, the drying interval extended, or the dehumidification capacity of the air intake increased. If the release of lignans in the acidic medium after coating is too high, adjustments can be made in three aspects: coating weight gain, coating liquid solids content, and particle surface smoothness. The spraying pressure, atomization method, and bed temperature are judged based on whether the particles stick together, whether the drug-loaded layer is uniform, and whether the enteric coating is continuous.

[0026] In step S7, the first corn oligopeptide component, the water-soluble active component of kudzu root, and one or more fast-release excipients selected from mannitol, microcrystalline cellulose, and crospovidone are mixed. Dry granulation, low-moisture granulation, or direct compression followed by granulation can be used. The fast-release particles should ideally be controlled to a mesh size of 20–60 mesh. In this branch, the first corn oligopeptide component does not come into contact with the lipophilic active component of Schisandra chinensis, the phase-separated composite dispersion, or the enteric coating solution, thus remaining in a free state. Mannitol and microcrystalline cellulose aid in particle formation and wetting, while crospovidone facilitates particle disintegration in the medium. The purpose of this branch is to enable rapid dispersion of the first corn oligopeptide component and the water-soluble active component of kudzu root after the capsule shell dissolves.

[0027] In S8, after inspecting the appearance, moisture content, and particle size of the rapid-release peptide granules and phase-separation protection granules, they are subjected to low-shear, short-time final mixing according to a set ratio. The median particle size of the two types of granules should not differ too much to reduce stratification before filling. If fluctuations in fill weight or granule stratification occur, the granulation screen size of the rapid-release granules and the core size of the phase-separation protection granules can be adjusted separately. High-speed mixing, secondary grinding, co-wet granulation, or secondary coating are not used as routine treatment measures. The final mixture is filled into hard capsules, with a small amount of glidant added if necessary. The finished product can be packaged in aluminum-plastic blister packs or light-proof high-barrier bottles, using desiccants or low-moisture packaging conditions to reduce the impact of moisture migration on the enteric coating during storage.

[0028] After the hard capsule shell dissolves in the stomach, the fast-release peptide particles first come into contact with the medium, and the first corn oligopeptide component and the water-soluble active component of kudzu root disperse as the particles are wetted. In an acidic medium, the phase-separation protection particles maintain an enteric outer layer, limiting the release of the lipophilic active component of Schisandra chinensis. Upon entering the intestine, the enteric outer layer opens, and the second corn oligopeptide component, along with medicinal phospholipids, helps the lipophilic active component of Schisandra chinensis to form a dispersed state. Both types of particles coexist in the same dosage unit but do not need to be made into the same homogeneous powder during manufacturing.

[0029] Example 1: Based on a total dry basis of 100 parts for the composite formulation, the following components were included: 30 parts for the first corn oligopeptide component, 12 parts for the second corn oligopeptide component, 12 parts for the water-soluble active component of kudzu root, 5 parts for the fat-soluble active component of schisandra fruit, and 4 parts for pharmaceutical phospholipids; for the rapid-release granules, 5 parts for mannitol, 2 parts for microcrystalline cellulose, 2 parts for crospovidone, and 1 part for silica; for the phase-separation protective granules, 17 parts for the microcrystalline cellulose core, 5 parts for the enteric coating material solids, 2 parts for the coating agent, and 1 part for the flow aid; the remaining 2 parts were pharmaceutically acceptable filler excipients. The first and second corn oligopeptide components were prepared according to the above S2. After mixing the first corn oligopeptide component with the water-soluble active component of kudzu root and the rapid-release excipients, the mixture was dry-granulated and sized to obtain rapid-release peptide fragment granules. The second corn oligopeptide component, the schisandra chinensis fat-soluble active component, and the medicinal phospholipids are formed into a phase-separated composite dispersion according to S5. This dispersion is sprayed onto the pellet core, dried, and then enteric-coated to obtain phase-separated protective granules. The two types of granules are then mixed under low shear and filled into hard capsules.

[0030] In Example 1, when scaled up to a total dry weight of 10 kg, the first corn oligopeptide component was 3.0 kg, the second corn oligopeptide component was 1.2 kg, the water-soluble active component of kudzu root was 1.2 kg, the fat-soluble active component of schisandra fruit was 0.5 kg, and the pharmaceutical phospholipid was 0.4 kg; the remainder consisted of fast-release granulation excipients, pellet cores, enteric coating materials, coating agents, flow aids, and filler excipients. First, the first corn oligopeptide component, the water-soluble active component of kudzu root, mannitol, microcrystalline cellulose, crospovidone, and silica were premixed, then dry-granulated and sized, removing excessively coarse and fine particles. The second corn oligopeptide component was dissolved in purified water. The fat-soluble active component of schisandra fruit and the pharmaceutical phospholipid were prepared into an alcohol phase. After maintaining a stable temperature in the aqueous phase, the alcohol phase was added at a constant rate. After addition, the mixture was gently stirred. The resulting dispersion showed no obvious oil droplets visible to the naked eye and no obvious stratification after standing. The drug-loaded material was sprayed onto the core of the capsule, and after the drug-loaded layer dried, it was enteric-coated. After both types of granules passed inspection, they were finally mixed, and the uniformity of the filling weight was verified by the mass ratio of the two types of granules and the content of lignan marker components in each capsule.

[0031] Example 2: Based on Example 1, pharmaceutical phospholipids were used as the main amphiphilic component, without the addition of Tween-type small molecule emulsifiers. By adjusting the feeding ratio of the second corn oligopeptide component to the schisandra chinensis fat-soluble active component, the alcohol-water phase volume ratio, and the alcohol phase addition rate, a stable phase-separated composite dispersion was formed. During process screening, the particle size of the dispersion, the stratification after standing, and the lignan retention rate after spraying were examined. Without the addition of small molecule emulsifiers, the phospholipids and the second corn oligopeptide component jointly assume the interfacial stabilizing effect, which can reduce the impact of added emulsifiers on enteric coating and the taste of the finished product.

[0032] Example 3: While maintaining the independent existence of the two types of particles, the fast-release peptide particles and phase-separation protection particles can be formulated into a dual-particle mixed bag formulation. The bagged formulation can be taken with warm water and should not be pre-dissolved in hot beverages for an extended period, as this may affect the enteric coating of the phase-separation protection particles. In this embodiment, the two types of particles are not co-pulverized into a uniform powder.

[0033] To confirm that the two peptide components obtained from S2 have different material states, the same batch of corn oligopeptide raw materials, the first corn oligopeptide component, and the second corn oligopeptide component were analyzed. Peptide content was determined using the OPA method, moisture content using the loss on drying method, relative hydrophobic retention index using reversed-phase HPLC, and dispersion release at 15 min was evaluated using the amino nitrogen release method. Three independent samples were taken for each item, and results are expressed as mean ± standard deviation. The results are shown in Table 1.

[0034] Table 1. Grading and material state data of corn oligopeptides

[0035] In Table 1, the peptide contents of the first and second corn oligopeptide components are at similar levels. The first corn oligopeptide component has a lower relative hydrophobic retention index and a higher dispersion release at 15 min; the second corn oligopeptide component has a higher relative hydrophobic retention index. This indicates that the difference in S2 formation is mainly reflected in the hydrophilic-hydrophobic interface and dispersion behavior, rather than simply distinguishing the two components by total peptide content.

[0036] To evaluate the stability of the phase-separated protective particles, the phase-separated composite dispersion obtained in Example 1 was taken and allowed to stand at 25°C in the dark for 2 hours. The layer thickness was then observed. The sedimentation volume ratio was determined by low-speed centrifugation, and the re-dispersion state after 10 manual inversions was recorded. After spraying, the recovery rate of the lignan marker component was determined by HPLC, and the content retention rate was examined after standing at 25°C for 7 days. F1 is the sample from Example 1; C1 is the group where all materials are directly mixed; C2 is the group without the addition of the second corn oligopeptide component; C3 is the group where all corn oligopeptides are used in the phase-separated composite. The results are shown in Table 2.

[0037] Table 2. Stability data of the phase-separated composite system.

[0038] In Table 2, F1 showed lower sedimentation volume ratio and stratification than the direct mixing group and the group without the second corn oligopeptide, but also higher lignan recovery rate after spraying. The stability of the total peptide complex group was improved, but its overall performance was still lower than that of F1. This indicates that simply increasing the total amount of peptides cannot replace the division of labor between the first and second corn oligopeptide components.

[0039] To evaluate the two-stage release behavior, 900 mL of dissolution medium was used. The mixture was run at 37±0.5℃ and 100 r / min, first in pH 1.2 medium for 2 h, then transferred to pH 6.8 medium for 60 min. The first corn oligopeptide component was determined using the amino nitrogen release method or the characteristic peptide method; puerarin and schisandrin were determined by HPLC. Six replicates were taken from each group. F1 was the capsule from Example 1; C1 was the capsule containing the full amount of direct mixing; C2 was the capsule containing the full amount of corn oligopeptides in a phase-separated compound; and C3 was the granular capsule without an enteric coating. The results are shown in Table 3.

[0040] Table 3. Data on two-stage release behavior

[0041] In Table 3, F1 maintained a high early release of the first corn oligopeptide component and puerarin in acidic medium, while lignan release was low in acidic medium, increasing after transitioning to pH 6.8. C2 showed lignan release similar to F1 in the intestinal fluid stage, but lower early release of the first corn oligopeptide component and puerarin. These results indicate that the function of free peptides in the rapid-release particles is affected when the full amount of corn oligopeptides participates in the phase-separation complex.

[0042] For accelerated stability evaluation of the finished product, the samples were placed at 40±2℃ and 75±5% relative humidity for 3 months. Appearance, moisture content, retention rates of puerarin and lignans, and lignan release in acidic media were compared at 0 and 3 months. F1 is the capsule from Example 1; C1 is the directly mixed capsule; C2 is the full peptide complex capsule; and C3 is the granular capsule without an enteric coating. Room temperature stability can be tested at 0, 1, 2, 3 months, or longer intervals under the same testing conditions. Results under accelerated conditions are shown in Table 4.

[0043] Table 4 Accelerated stability data

[0044] In Table 4, F1 showed high retention rates of puerarin and lignans, low lignan release in acidic media, and no significant adhesion of enteric-coated particles. C2 exhibited similar gastric protection to F1, but differences remained in lignan retention rate and particle appearance; C3 showed higher release in acidic media. These results correspond to the preparation sequence of phase separation and compounding in S5, low-temperature spraying and enteric coating in S6, and avoiding co-wetting in S8.

[0045] To investigate the adjunctive protective effect against alcohol-related liver injury, a routine acute alcohol exposure model was used in a facility with animal ethics compliance. The total amount of corn oligopeptides and the total amount of active components of the traditional Chinese medicine were kept comparable across all treatment groups, with eight animals in each group. Animals were randomly divided into a normal group, a model group, a direct mixing group, a group with full corn oligopeptide drug loading, and the Example 1 group. Blood samples were collected after the last alcohol exposure to measure blood ethanol, acetaldehyde, ALT, and AST; liver tissue was collected to measure MDA and SOD, and routine HE staining was performed for observation. The experimental procedures were conducted according to approved animal ethics protocols. Results are shown in Table 5.

[0046] Table 5. Data from the adjuvant protective trial against alcohol-related liver injury.

[0047] In Table 5, the blood ethanol, acetaldehyde, ALT, AST, and MDA levels in the Example 1 group were lower than those in the model group, while SOD levels were higher. Compared with the direct mixing group and the full peptide complex group, most of the detection indicators in the Example 1 group were in the optimal range. These experimental results are consistent with the aforementioned physicochemical results regarding phase-separated composite stability, two-stage release, and the retention of the first corn oligopeptide component in a free state. This animal experiment was used to evaluate the auxiliary protective indicators of the formulation under this model and cannot be directly extrapolated to humans.

[0048] In the above experiments, the phase-separated composite system exhibited lower sedimentation and stratification; the phase-separated protective particles showed lower lignan release in acidic media; while the rapid-release particles maintained faster peptide and puerarin release. These results are consistent with... Figure 1 The process sequence shown corresponds to S2 separation, S5 phase separation and compounding, S6 spraying and enteric coating, S7 rapid release granulation, and S8 independent final mixing. The first corn oligopeptide component remains in a free state, while the second corn oligopeptide component participates in the interfacial stabilization of the lipophilic active phase. The two types of particles play their respective roles in the same dosage unit.

Claims

1. A manufacturing process for a liver-protecting composition based on corn oligopeptides and active components of traditional Chinese medicine, characterized in that, Includes the following steps: S1. Prepare or obtain corn oligopeptide raw materials; S2. The same corn oligopeptide raw material obtained in S1 is subjected to weak hydrophobic separation to obtain the first corn oligopeptide component and the second corn oligopeptide component respectively. S3. Extract, concentrate and dry the kudzu root slices with water to prepare the water-soluble active components of kudzu root; S4. The Schisandra chinensis slices were subjected to alcohol extraction and concentration to prepare the lipophilic active components of Schisandra chinensis. S5. Dissolve the second corn oligopeptide component in the aqueous phase, dissolve the schisandra chinensis fat-soluble active component and medicinal phospholipid in the alcohol phase, add the alcohol phase to the aqueous phase at a controlled rate, and perform controlled alcohol-water mixing and phase separation compounding to obtain a phase separation compound dispersion. S6. Spray the phase-separated composite dispersion onto the pellet core, and then dry it at low temperature and coat it with enteric coating to obtain phase-separated protective particles; S7. The first corn oligopeptide component, the kudzu water-soluble active component and the fast-release excipient are granulated and sized by dry method or low moisture method to obtain fast-release peptide particles. S8. The fast-release peptide particles and the phase-separated protective particles are mixed with low shear, and then capsules are filled and packaged to obtain a liver-protecting composition. The first corn oligopeptide component remains in a free state in the fast-release peptide particles and does not participate in the phase separation and compounding of the schisandra chinensis fat-soluble active component. The fast-release peptide particles and the phase separation protection particles are not subjected to co-wet mixing and secondary pulverization.

2. The manufacturing process of the liver-protecting composition according to claim 1, characterized in that, In S1, the corn oligopeptide raw material is commercially available corn oligopeptide powder, or it is prepared from corn protein powder through slurry preparation, enzymatic hydrolysis, solid-liquid separation, membrane separation, concentration and drying.

3. The manufacturing process of the liver-protecting composition according to claim 1, characterized in that, In S2, the corn oligopeptide raw material is dissolved in purified water and filtered to clarify. The resulting liquid is then passed through a weakly hydrophobic macroporous adsorption resin. The liquid is first eluted with purified water and the effluent is collected. After concentration and drying, the first corn oligopeptide component is obtained. The mixture was then eluted with an aqueous ethanol solution and the eluent was collected. After ethanol recovery, concentration and drying, the second corn oligopeptide component was obtained.

4. The manufacturing process of the liver-protecting composition according to claim 1, characterized in that, In S3, the kudzu root slices were pulverized and extracted twice with purified water. The resulting extract was filtered, concentrated under low temperature and reduced pressure, and spray-dried or vacuum-dried to obtain the water-soluble active components of kudzu root. In S4, Schisandra chinensis slices were pulverized and extracted with an ethanol-water solution. The resulting extract was filtered, the ethanol was recovered under reduced pressure, and the extract was concentrated to obtain the fat-soluble active components of Schisandra chinensis.

5. The manufacturing process of the liver-protecting composition according to claim 1, characterized in that, In S5, the concentration of the second corn oligopeptide component in the aqueous phase is 1% to 5%, the system temperature during phase separation and recombination is not higher than 35°C, and the system pH is 6.0 to 6.

8. After phase separation and recombination, the ethanol content in the system is reduced by low temperature and reduced pressure.

6. The manufacturing process of the liver-protecting composition according to claim 1, characterized in that, In S6, the pellet core is a microcrystalline cellulose pellet core, a sucrose pellet core, or a pharmaceutically acceptable porous pellet core; the enteric coating is hydroxypropyl methylcellulose acetate succinate, methacrylic acid copolymer, or a pharmaceutically acceptable equivalent enteric material.

7. The manufacturing process of the liver-protecting composition according to claim 1, characterized in that, In S7, the fast-release excipient includes one or more of mannitol, microcrystalline cellulose, and crospovidone.

8. A liver-protective composition based on corn oligopeptides and active components of traditional Chinese medicine, characterized in that, Includes fast-release peptide particles and phase-separation protection particles; The fast-release peptide particles include a first corn oligopeptide component, a kudzu root water-soluble active component, and fast-release excipients, wherein the first corn oligopeptide component remains in a free state in the fast-release peptide particles. The phase-separated protective particles include a pellet core, a phase-separated composite drug-carrying layer disposed on the surface of the pellet core, and an enteric coating outer layer disposed on the outside of the phase-separated composite drug-carrying layer. The phase-separated composite drug-carrying layer includes a second corn oligopeptide component, pharmaceutical phospholipids, and schisandra chinensis fat-soluble active components. The first and second corn oligopeptide components are different components obtained from the same corn oligopeptide raw material after weak hydrophobic separation. The fast-release peptide particles and the phase-separated protective particles coexist in the same dosing unit as independent particles that can be identified from each other.

9. The liver-protecting composition according to claim 8, characterized in that, Based on the dry basis mass parts of the liver-protecting composition, the first corn oligopeptide component is 25-45 parts, the second corn oligopeptide component is 8-18 parts, the kudzu root water-soluble active component is 8-16 parts, the schisandra fruit fat-soluble active component is 2-8 parts, the medicinal phospholipid is 2-6 parts, and the enteric material is 3-8 parts.

10. The liver-protecting composition according to claim 8, characterized in that, The same dosage unit is a hard capsule, the particle size of the fast-release peptide particles is 20-60 mesh, and the particle size of the pellet core is 0.45-0.85 mm.

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