A compound preparation containing new dried citrus peels and a preparation method thereof

Abstract

The present disclosure relates to the field of biological agents, and provides a compound preparation containing Xinhui Chenpi and a preparation method thereof. The method comprises: adding Xinhui Chenpi powder into an aqueous ethanol solution for extraction to obtain an Xinhui Chenpi alcohol extract, and then adding water-soluble plant components and Xinhui Chenpi filter residue into water for extraction to obtain a water extract concentrate; dissolving a degradable carrier modified by cholic acid and the Xinhui Chenpi alcohol extract in an organic solvent to obtain an oil phase solution, and then adding the oil phase solution dropwise into a weakly alkaline aqueous phase to obtain a cholic acid modified Xinhui Chenpi suspension; performing wall breaking treatment on oil and fat plant components to obtain an oil phase slurry, and then adding the oil phase slurry into a gum component and the water extract concentrate to obtain a compound gel paste matrix; and adding the cholic acid modified Xinhui Chenpi suspension into the compound gel paste matrix for mixing to obtain the compound preparation containing Xinhui Chenpi. The technical solution solves the problems of poor dispersion stability of active ingredients of Xinhui Chenpi in the compound preparation and insufficient gastrointestinal release and utilization.

Description

Technical Field

[0001] This disclosure relates to the field of biopharmaceuticals, and more specifically, to a compound preparation containing Xinhui tangerine peel and its preparation method. Background Technology

[0002] In the gastrointestinal field, dried tangerine peel (Chenpi) is primarily used as a raw material for spleen and stomach regulation and digestive support. It is derived from the aged peel of the tangerine peel and is both a food and a medicine. It possesses an aromatic fragrance and traditionally has the characteristics of regulating qi, strengthening the spleen, and dispelling dampness, making it suitable for gastrointestinal regulation scenarios such as postprandial fullness, decreased appetite, stomach bloating, and nausea. In terms of its effects, the volatile oil components in dried tangerine peel help improve the aroma and taste of products and can assist in promoting the secretion of digestive juices and gastrointestinal motility. Its flavonoids, polysaccharides, polyphenols, and dietary fiber can participate in the regulation of the gastrointestinal environment, anti-oxidation, and nutritional support for intestinal flora. Therefore, dried tangerine peel is more suitable for use in the development of products such as compound plant extracts, fermented beverages, gastrointestinal conditioning granules, and prebiotic compound foods to enhance the digestive support and intestinal health conditioning value of these products.

[0003] However, the extracted tangerine peel contains a large number of fat-soluble or poorly soluble active ingredients. When these are directly added to a complex system containing aqueous extract, colloidal components, and plant components, they are prone to aggregation, precipitation, or uneven distribution due to insufficient compatibility. After entering the gastrointestinal environment, these poorly soluble components have limited contact with digestive juices, affecting their release and dispersion, making it difficult to fully utilize the active ingredients of tangerine peel.

[0004] It should be noted that the information disclosed in the background section above is only used to enhance the understanding of the background of this disclosure. Summary of the Invention

[0005] The purpose of this disclosure is to provide a compound preparation containing Xinhui tangerine peel and its preparation method, which solves the problems of poor dispersion and instability of the effective components of tangerine peel, as well as insufficient gastrointestinal release and utilization.

[0006] Other features and advantages of this disclosure will become apparent from the following detailed description, or may be learned in part from practice of this disclosure.

[0007] According to one aspect of this disclosure, a method for preparing a compound preparation containing Xinhui tangerine peel is provided, comprising the following steps: S1. Add Xinhui tangerine peel powder to an ethanol aqueous solution for extraction to obtain Xinhui tangerine peel alcohol extract. Then, add water to extract the water-soluble plant components and Xinhui tangerine peel filter residue to obtain a concentrated water extract. S2. The bile acid-modified biodegradable carrier and the alcohol extract of Xinhui tangerine peel are dissolved together in an organic solvent to obtain an oil phase solution. Then, a stabilizer is added to water and the pH value is adjusted to a preset range to obtain a weakly alkaline aqueous phase. The oil phase solution is added dropwise to the weakly alkaline aqueous phase for emulsification, solvent removal, centrifugation and washing to obtain a bile acid-modified Xinhui tangerine peel suspension. S3. The oily plant components are subjected to cell wall breaking treatment to obtain an oil phase slurry. The oil phase slurry is then added to the colloidal components and water extract concentrate for shear emulsification to obtain a composite gel paste matrix. S4. The bile acid-modified Xinhui tangerine peel suspension was added to the composite gel paste matrix for mixing, and then concentrated, homogenized, defoamed, filled and sealed at low temperature to obtain a composite preparation containing Xinhui tangerine peel.

[0008] According to one aspect of this disclosure, a compound preparation containing Xinhui tangerine peel is provided, which is prepared by the method described above for preparing a compound preparation containing Xinhui tangerine peel.

[0009] As can be seen from the above technical solutions, the exemplary embodiments disclosed herein possess at least the following advantages and positive effects: In some embodiments of this disclosure, the technical solutions provided include, on the one hand, the extraction of Xinhui tangerine peel powder by adding it to an ethanol-water solution, and the dissolution of the bile acid-modified biodegradable carrier and the Xinhui tangerine peel alcohol extract in an organic solvent, followed by emulsification, solvent removal, centrifugation, and washing in a weakly alkaline aqueous phase. This allows the insoluble active ingredients in the Xinhui tangerine peel alcohol extract to enter the bile acid-modified biodegradable carrier and form a bile acid-modified Xinhui tangerine peel suspension. This solves the problems of easy aggregation, precipitation, and uneven distribution of the active ingredients in the Xinhui tangerine peel alcohol extract when directly added to the composite system in the prior art, thereby achieving the technical effect of improving the dispersion stability and system uniformity of the active ingredients in Xinhui tangerine peel. On the other hand, by adding the bile acid-modified Xinhui tangerine peel suspension to a composite gel paste matrix formed by shearing and emulsifying an oil phase slurry, a colloidal component, and a concentrated water extract, and then subjecting it to low-temperature vacuum concentration, homogenization, and defoaming treatment, the bile acid-modified Xinhui tangerine peel suspension can be evenly distributed in the composite gel paste matrix. This further overcomes the problem of limited contact area and insufficient release and dispersion of poorly soluble active ingredients with aqueous digestive juices in the gastrointestinal environment. After the composite preparation enters the gastrointestinal environment, the composite gel paste matrix can be gradually dispersed, and the bile acid-modified degradable carrier can gradually release the alcohol-extracted active ingredients of Xinhui tangerine peel during the matrix dispersion process, thus achieving continuous release and full dispersion of the active ingredients of Xinhui tangerine peel in the gastrointestinal environment.

[0010] In summary, this technical solution utilizes alcohol extraction, water extraction, bile acid-modified carrier emulsification and encapsulation, cell wall disruption oil phase shear emulsification, and gel matrix composite to allow active ingredients of different polarities in Xinhui tangerine peel to enter suitable dispersion systems. These active ingredients then gradually exert their effects in the gastrointestinal environment through dispersion of the composite gel paste matrix and release of the biodegradable carrier. This solution comprehensively addresses the problems of poor dispersion stability and insufficient gastrointestinal release and utilization of active ingredients in Xinhui tangerine peel in composite preparations.

[0011] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only, and are not intended to limit this disclosure. Attached Figure Description

[0012] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with this disclosure and, together with the description, serve to explain the principles of this disclosure. It is obvious that the drawings described below are merely some embodiments of this disclosure, and those skilled in the art can obtain other drawings based on these drawings without any inventive effort. In the drawings: Figure 1 This is a schematic flowchart illustrating a method for preparing a compound preparation containing Xinhui tangerine peel in one embodiment; Figure 2 This is a schematic flowchart of step S1 in a method for preparing a compound preparation containing Xinhui tangerine peel in one embodiment; Figure 3 This is a schematic flowchart of step S2 in a method for preparing a compound preparation containing Xinhui tangerine peel in one embodiment; Figure 4 This is a schematic flowchart of step S3 in a method for preparing a compound preparation containing Xinhui tangerine peel in one embodiment. Detailed Implementation

[0013] Exemplary embodiments will now be described more fully with reference to the accompanying drawings. However, these exemplary embodiments can be implemented in many forms and should not be construed as limited to the examples set forth herein; rather, these embodiments are provided so that this disclosure will be more thorough and complete, and will fully convey the concept of the exemplary embodiments to those skilled in the art.

[0014] Furthermore, the described features or characteristics may be combined in any suitable manner in one or more embodiments. Numerous specific details are provided in the following description to give a thorough understanding of embodiments of this disclosure. However, those skilled in the art will recognize that the technical solutions of this disclosure may be practiced without one or more of the specific details, or other methods, steps, etc. may be employed. In other instances, well-known methods, implementations, or operations are not shown or described in detail to avoid obscuring various aspects of this disclosure.

[0015] The flowcharts shown in the accompanying drawings are merely illustrative and do not necessarily include all content and operations / steps, nor do they necessarily need to be performed in the described order. For example, some operations / steps can be broken down, while others can be combined or partially combined; therefore, the actual execution order may change depending on the specific circumstances.

[0016] like Figure 1 and Figure 2 As shown, this invention proposes a method for preparing a compound preparation containing Xinhui tangerine peel, the steps of which include: S1. Add Xinhui tangerine peel powder to an ethanol aqueous solution for extraction to obtain Xinhui tangerine peel alcohol extract. Then, add water to extract the water-soluble plant components and Xinhui tangerine peel filter residue to obtain a concentrated water extract.

[0017] Step S1 includes: S1.1. Add 35%–50% (v / v) ethanol aqueous solution to Xinhui tangerine peel powder for pre-wetting, stir and wet for 15–40 min at 25–35℃, then add 60%–80% (v / v) ethanol aqueous solution for extraction. Control the mass-volume ratio of Xinhui tangerine peel powder to total ethanol aqueous solution to be 1g:8mL–1g:18mL, the extraction temperature to be 40–60℃, the extraction time to be 60–150 min, and the stirring speed to be 80–250 r / min to obtain the primary extract. S1.2. The primary extract is subjected to solid-liquid separation, and the filtrate and residue are collected. The filtrate is subjected to low-temperature settling, centrifugation and microfiltration to obtain a clear alcohol extract. The low-temperature settling temperature is 4-10℃, the settling time is 2-8h, the centrifugation speed is 4000-8000r / min, the centrifugation time is 5-15min, and the microfiltration membrane pore size is 0.45-1.0μm. Subsequently, the clear alcohol extract is concentrated under low-temperature reduced pressure at a temperature of 35-50℃ and a vacuum degree of -0.06--0.09MPa until the solid content is 8%-25% to obtain Xinhui tangerine peel alcohol extract. S1.3. First, treat the Xinhui tangerine peel filter residue at 35-45℃ and a vacuum of -0.04--0.08MPa for 10-30 minutes. Then, add purified water to the de-alcoholized Xinhui tangerine peel filter residue for rehydration and swelling. Control the mass ratio of Xinhui tangerine peel filter residue to purified water to be 1:4-1:8, the rehydration temperature to be 35-45℃, the stirring time to be 20-60 minutes, and the stirring speed to be 60-180 r / min. S1.4 Add the pulverized water-soluble plant components and Xinhui tangerine peel filter residue to purified water, and control the total mass ratio of water-soluble plant components, rehydrated tangerine peel filter residue and purified water to 1:8 to 1:18 to obtain a primary mixture. The water-soluble plant components include Poria cocos, Cassia seed, Coix seed, red adzuki bean, hawthorn and lotus leaf. S1.5. First, heat the primary mixture to 60-70℃ and hold for 30-60 min, then heat to 80-95℃ and hold for 60-120 min, controlling the stirring speed at 50-150 r / min to obtain a composite water extract. Perform solid-liquid separation and clarification on the composite water extract. Concentrate the clarified composite water extract at low temperature under conditions of 45-60℃ and a vacuum degree of -0.06 to -0.09 MPa until the solid content is 15%-40% to obtain a concentrated water extract.

[0018] In one embodiment, between step S1.4 and step S1.5, step S1 further includes: A compound enzyme is added to the primary mixture for enzymatic hydrolysis, and the pH is adjusted to 5.0–6.2. The amount of compound enzyme added is 0.05%–0.5% of the mass of the primary mixture. The hydrolysis temperature is 40–55℃, the hydrolysis time is 30–90 min, and the stirring speed is 60–180 r / min. The compound enzyme includes at least two of cellulase, pectinase, and hemicellulase.

[0019] Separating the fat-soluble active ingredients and water-soluble matrix components in Xinhui tangerine peel ensures a clear source for different functional components in subsequent formulations. Xinhui tangerine peel powder is first pre-wetted with a 35%–50% (v / v) ethanol aqueous solution, followed by extraction with a 60%–80% (v / v) ethanol aqueous solution. The low-concentration ethanol aqueous solution can penetrate the pores and interfiber spaces of the Xinhui tangerine peel powder, ensuring thorough wetting of the powder interior; subsequently, the higher-concentration ethanol aqueous solution further extracts norihesperidin, tangeretin, and other polymethoxyflavonoids, making these fat-soluble or weakly polar components more readily available in the ethanol extract.

[0020] After solid-liquid separation, the filtrate is subjected to low-temperature settling, centrifugation, and microfiltration to remove coarse particles, suspended impurities, and some colloidal impurities, making the alcohol extract clearer. Subsequent low-temperature vacuum concentration is performed at a lower temperature, which helps reduce the heat loss of hesperidin, tangeretin, and volatile components of tangerine peel, while ensuring that the Xinhui tangerine peel alcohol extract reaches a suitable solids content for subsequent encapsulation, emulsification, and nucleation.

[0021] After de-alcoholization and rehydration, the residual ethanol in the filter residue of Xinhui tangerine peel is removed, and the cell walls, pectin layer, and fiber network from the alcohol extraction process reabsorb water and swell. At this point, the residual tangerine peel pectin, tangerine peel polysaccharides, water-soluble flavonoid glycosides, and hydrophilic organic acids in the filter residue are more easily released during the subsequent water extraction process. This treatment avoids the waste of components caused by directly discarding the alcohol extraction filter residue and also allows the water-soluble components in Xinhui tangerine peel to continue to participate in the construction of the composite gel paste matrix.

[0022] Water-soluble plant components are extracted together with rehydrated Xinhui tangerine peel residue. This allows polysaccharides from Poria cocos, gums from Cassia tora, starches and dietary fiber from Coix lacryma-jobi and red adzuki beans, pectin and organic acids from hawthorn, water-soluble plant active ingredients from lotus leaves, and tangerine peel pectin and polysaccharides from the tangerine peel residue to enter the extraction system. The resulting concentrated water extract can form a complex gel matrix with the gum components in subsequent steps, improving the paste's water retention, adhesion, and dispersion stability.

[0023] The water extraction process employs a segmented approach, first maintaining a temperature of 60–70℃, then 80–95℃. The relatively mild temperature in the first stage is suitable for the slow release of pectin, gums, and some polysaccharides, reducing rapid gum precipitation and polysaccharide aggregation. The increased temperature in the second stage facilitates the further dissolution of water-soluble components from Poria cocos, Coix seed, red adzuki bean, and lotus leaf. Compared to single-stage high-temperature water extraction, segmented water extraction is more effective in preserving the structure of large gum-forming molecules while simultaneously releasing water-soluble active ingredients.

[0024] In an optional embodiment, a compound enzyme treatment is performed between steps S1.4 and S1.5. Cellulase, pectinase, and hemicellulase can moderately loosen plant cell walls, making it easier to release polysaccharides, pectin, and gums. By controlling the enzymatic hydrolysis pH, hydrolysis temperature, enzyme dosage, and hydrolysis time within a defined range, excessive degradation of pectin and polysaccharides can be avoided, thereby improving water extraction efficiency while preserving the viscoelasticity required for subsequent gelation, water retention, and stable dispersion of the water extract concentrate.

[0025] Therefore, step S1 ultimately yields two functionally distinct intermediates: the ethanol extract of Xinhui tangerine peel primarily provides hesperidin, terpenein, and other polymethoxylated flavonoids, which are fat-soluble active ingredients; the concentrated water extract primarily provides tangerine peel pectin, poria cocos polysaccharide, cassia seed gum, hawthorn pectin, and other water-soluble plant active ingredients. The former is suitable for subsequent preparation of bile acid-modified Xinhui tangerine peel suspension, while the latter is suitable for constructing a composite gel matrix. Together, they provide the raw material basis for the dispersion stability, water retention, gelation, and fractional release of subsequent formulations.

[0026] S2. The bile acid-modified biodegradable carrier and the alcohol extract of Xinhui tangerine peel are dissolved together in an organic solvent to obtain an oil phase solution. Then, a stabilizer is added to water and the pH value is adjusted to a preset range to obtain a weakly alkaline aqueous phase. The oil phase solution is added dropwise to the weakly alkaline aqueous phase for emulsification, solvent removal, centrifugation and washing to obtain a bile acid-modified Xinhui tangerine peel suspension.

[0027] Please refer to Figure 3 Step S2 includes: S2.1 Add the bile acid-modified biodegradable carrier and the ethanol extract of Xinhui tangerine peel to an organic solvent and stir to dissolve under light-protected conditions. The mass concentration of the bile acid-modified biodegradable carrier in the oil phase solution is 5-25 mg / mL, the mass ratio of solids to bile acid-modified biodegradable carrier in the ethanol extract of Xinhui tangerine peel is 1:3-1:15, the dissolution temperature is 25-40℃, the stirring speed is 100-400 r / min, and the dissolution time is 20-60 min. During the stirring process, lecithin is added, and the amount of lecithin is 2%-15% of the mass of the bile acid-modified biodegradable carrier, to obtain the oil phase solution. S2.2 Dissolve the stabilizer in purified water. The mass-volume concentration of the stabilizer in the aqueous phase is 0.3% to 2.5%, the temperature is 20 to 35°C, the stirring speed is 100 to 500 r / min, and the stirring time is 20 to 60 min. Then adjust the pH value to 8.0 to 9.2 with sodium bicarbonate or sodium hydroxide to obtain a weakly alkaline aqueous phase. S2.3. The oil phase solution is added dropwise to the weakly alkaline aqueous phase under ice bath conditions, and the volume ratio of the oil phase solution to the weakly alkaline aqueous phase is controlled at 1:5 to 1:15. The dropping rate of the oil phase solution is 0.3 to 1.5 mL / min. During the dropping process, a high-speed shear emulsifier is used for emulsification, with a shearing speed of 8000 to 15000 r / min, a shearing time of 3 to 10 min, and an emulsification temperature of 10 to 25℃ to obtain a primary emulsion. S2.4. The primary emulsion is subjected to desolventizing treatment under reduced pressure. The desolventizing equipment is a rotary evaporator with a temperature of 30-40℃, a vacuum degree of -0.06 to -0.09 MPa, and a treatment time of 20-60 min. During the process, the stirring speed is controlled at 80-200 r / min. After evaporation, centrifugation and washing are performed. The centrifugation temperature is 4-10℃, the centrifugation force is 8000-20000 g, and the centrifugation time is 10-30 min. The precipitate is collected and washed 2-3 times with purified water. It is then dispersed in a pectin aqueous solution with a concentration of 1-3 mg / mL, and the solid content is controlled at 2%-12%. Low-pressure homogenization is performed at 20-35℃ with a homogenization pressure of 5-30 MPa and a cycle of 1-3 times to obtain a bile acid-modified Xinhui tangerine peel suspension.

[0028] The biodegradable carrier includes at least one of zein, lecithin complex carrier, and sodium alginate-pectin complex carrier; the organic solvent includes ethanol or ethyl acetate; and the stabilizer includes at least one of pectin, gum arabic, and sodium carboxymethyl cellulose.

[0029] The ethanol extract of Xinhui tangerine peel contains hesperidin, citrinin, and other polymethoxyflavonoids. These components are lipophilic or weakly polar. If directly added to the aqueous extract concentrate or paste matrix, uneven dispersion, localized precipitation, and unstable release can easily occur. By co-dissolving or dispersing the ethanol extract of Xinhui tangerine peel with a bile acid-modified biodegradable carrier in ethanol, ethyl acetate, or a mixture thereof, the lipophilic active ingredients first enter the hydrophobic region or oil phase environment of the carrier. Then, through emulsification, solvent removal, and resuspension, a suspension is formed, thereby improving its dispersion in the subsequent composite gel paste.

[0030] Cholic acid-modified biodegradable carriers are preferably cholic acid-modified zein or cholic acid-lecithin composite carriers. Zein has a hydrophobic structure, which can provide an encapsulation environment for polymethoxylated flavonoids such as hesperidin and citric acid; the lecithin composite carrier is amphiphilic and can improve the interfacial dispersion between the oil phase and the aqueous phase. Sodium alginate-pectin composite carriers are more suitable for aqueous phase protection, particle resuspension, or outer layer stabilization, but are not suitable as oil phase carriers that are completely soluble in organic solvents.

[0031] Adding lecithin to the oil phase solution helps reduce the interfacial tension between the oil and aqueous phases, making it easier for the oil phase to form fine droplets during emulsification. Lecithin also enables the fat-soluble active ingredients in the Xinhui tangerine peel alcohol extract to distribute in the hydrophobic region of the carrier and near the oil-water interface, providing a basis for subsequent interfacial migration and release under bile salt conditions.

[0032] The weakly alkaline aqueous phase is prepared with a stabilizer, purified water, and sodium bicarbonate or sodium hydroxide. The stabilizer is selected from pectin, gum arabic, or sodium carboxymethyl cellulose. Pectin and gum arabic can form a hydrophilic protective layer on the outside of the particles, while sodium carboxymethyl cellulose can increase the viscosity of the aqueous phase and reduce particle collision and aggregation. Controlling the pH of the aqueous phase at 8.0–9.2 can ionize the carboxyl groups in the bile acid structure, making the bile acid groups more easily exposed to the aqueous phase, thereby improving the hydrophilicity and dispersion stability of the particle surface.

[0033] Adding the oil phase solution dropwise to a weakly alkaline aqueous phase under ice bath conditions, followed by high-speed shear emulsification, allows the oil phase to be rapidly dispersed into smaller droplets. The ice bath condition reduces the temperature rise during the shearing process, minimizing the thermal impact on the polymethoxyflavonoids and carrier structure of Xinhui tangerine peel. High-speed shearing increases the contact area between the oil and aqueous phases, allowing the bile acid-modified carrier, the alcohol-extracted active ingredients of Xinhui tangerine peel, and lecithin to rearrange at the oil-water interface, forming a more homogeneous primary emulsion.

[0034] After desolventizing the primary emulsion under low temperature and reduced pressure, the organic solvent is gradually removed, and the bile acid-modified biodegradable carrier changes from a dissolved or dispersed state to a particulate state. Norihesperidin, tangeretin, and other polymethoxylated flavonoids in the Xinhui tangerine peel alcohol extract are immobilized in the hydrophobic or interfacial regions of the particles. Subsequent centrifugation and washing remove free stabilizers, unencapsulated small molecules, and residual solvents, resulting in a more stable suspension composition.

[0035] After washing, the particles are dispersed in a pectin aqueous solution of 1–3 mg / mL and then homogenized under low pressure to reduce particle aggregation. The pectin aqueous solution can form a hydration protective layer on the outside of the particles, improving the compatibility of the particles with the subsequent composite gel matrix; low-pressure homogenization can break up loose aggregates while avoiding excessive homogenization that could damage the bile acid structure and hydration protective layer on the particle surface.

[0036] In one embodiment, the preparation of the cholic acid-modified zein carrier includes: dissolving cholic acid in an aqueous ethanol solution, activating it by adding 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide, wherein the molar ratio of cholic acid, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide is 1:1-2:0.5-1.5, the activation temperature is 20-35°C, and the activation time is 30-120 min, to obtain activated cholic acid. Solution; separately, zein is dissolved in an aqueous ethanol solution with a volume fraction of 70%–90% to obtain a zein mass concentration of 5–30 mg / mL. Then, an activated bile acid solution is added to the zein solution. The mixture is stirred at 25–40°C in the dark for 4–12 h at a stirring speed of 100–400 r / min. After the reaction is completed, free bile acid and activator residue are removed by dialysis, ultrafiltration, or precipitation washing. Finally, the mixture is dried under low temperature and vacuum to obtain the bile acid modified zein carrier.

[0037] In one embodiment, the preparation of the cholic acid-lecithin composite carrier includes: dissolving cholic acid and lecithin together in ethanol or an ethanol-ethyl acetate mixed solvent, with a cholic acid to lecithin mass ratio of 1:2 to 1:10, a dissolution temperature of 30 to 50°C, a stirring speed of 100 to 500 r / min, and a dissolution time of 20 to 60 min, to obtain a cholic acid-lecithin mixed solution; placing the mixed solution in a rotary evaporator, removing the solvent under conditions of 35 to 45°C and a vacuum degree of -0.06 to -0.09 MPa, so that cholic acid and lecithin form a composite film on the container wall; then adding purified water or sodium bicarbonate aqueous solution with a pH of 7.5 to 8.8 for hydration, with a hydration temperature of 35 to 55°C and a hydration time of 20 to 60 min, and then using ultrasonic dispersion or low-pressure homogenization treatment, with an ultrasonic power of 100 to 300 W and a treatment time of 3 to 10 min, to obtain a cholic acid-lecithin composite carrier dispersion.

[0038] In one embodiment, the preparation of the cholic acid-modified sodium alginate-pectin composite carrier includes: dissolving sodium alginate and pectin in purified water, wherein the mass-volume concentration of sodium alginate is 0.2%–1.5%, the mass-volume concentration of pectin is 0.1%–1.0%, the dissolution temperature is 25–45°C, the stirring speed is 100–500 r / min, and the stirring time is 30–90 min, to obtain a sodium alginate-pectin aqueous phase; separately, dissolving sodium cholate in purified water, wherein the mass-volume concentration of sodium cholate is 0.02%. Add sodium cholate solution to the sodium alginate-pectin aqueous phase at 0.3%–25°C and stir for 20–60 min at 25–40°C to distribute sodium cholate between the sodium alginate-pectin molecular chains and in the aqueous phase interface region. Then, slowly add calcium lactate or calcium gluconate aqueous solution for mild cross-linking. The calcium ion concentration is 0.005–0.05 mol / L, the addition time is 10–40 min, and the stirring speed is 50–200 r / min to obtain a cholic acid modified sodium alginate-pectin composite carrier dispersion.

[0039] S3. The oily plant components are subjected to cell wall disruption to obtain an oil phase slurry. The oil phase slurry is then added to the colloidal components and water extract concentrate for shear emulsification to obtain a composite gel paste matrix.

[0040] Please refer to Figure 4 Step S3 includes: S3.1. Heat the oily plant components to 70–95℃ for 10–40 min, controlling the moisture content to 15%–35% during the process. Then, perform low-temperature drying at 40–55℃ until the moisture content is 6%–12%. Place the dried components in a cell wall blender for cell wall breaking, adding purified water as the dispersion medium. Control the mass ratio of oily plant components to dispersion medium to be 1:1–1:4, the cell wall breaking temperature to be 20–45℃, the cell wall breaking time to be 5–30 min, and the colloid mill gap to be 20–100 μm to obtain an oil phase slurry. The oily plant components include almonds, peach kernels, apricot kernels, and hemp kernels. S3.2 The gelatinous component includes donkey-hide gelatin and honey. First, donkey-hide gelatin is added to purified water for swelling, with the mass ratio of donkey-hide gelatin to purified water controlled at 1:3 to 1:8, the swelling temperature at 20 to 35℃, and the swelling time at 30 to 120 min. Then, it is heated to 55 to 75℃ for dissolution, with a stirring speed of 50 to 200 r / min and a dissolution time of 20 to 60 min. Subsequently, honey is added, with the mass ratio of honey to donkey-hide gelatin controlled at 2:1 to 8:1. Stirring is continued for 10 to 40 min to obtain a premixed solution of the gelatinous component. S3.3 Add the concentrated water extract to the premixed gel component and mix them. Control the mass ratio of the concentrated water extract to the premixed gel component to be 1:1 to 5:1, the feeding temperature to be 45 to 65℃, the feeding time to be 10 to 40 min, the stirring speed to be 80 to 300 r / min, and continue to keep warm and stir for 20 to 60 min to obtain the hydrophilic gel matrix. S3.4. The oil phase slurry is added to the hydrophilic gel matrix for shear emulsification. The mass ratio of the oil phase slurry to the hydrophilic gel matrix is ​​controlled at 1:2 to 1:8. The feeding temperature is 40 to 55℃ and the feeding time is 10 to 45 min. First, it is premixed at a low speed of 100 to 300 r / min for 10 to 30 min, then shear emulsified at 3000 to 8000 r / min for 3 to 15 min. Then, it is matured at a low shear temperature of 35 to 50℃ with a stirring speed of 50 to 150 r / min and a maturation time of 20 to 90 min. Subsequently, it is degassed under vacuum conditions at a temperature of 35 to 50℃, a vacuum degree of -0.04 to -0.08 MPa, and a degassed time of 10 to 40 min to obtain a composite gel paste matrix.

[0041] In one embodiment, between steps S3.1 and S3.2, step S3 further includes: Bile salts are added to purified water. The bile salts include at least one of sodium taurocholate, sodium glycocholate, or sodium cholate, and the mass-volume concentration of the bile salts is 0.02% to 0.20%, to obtain a bile salt phase. Add the bile saline phase to the oil phase slurry, controlling the mass ratio of the bile saline phase to the oil phase slurry to be 1:5 to 1:20, and stir at 35 to 40°C with a stirring speed of 80 to 300 r / min for 10 to 45 min. Then add a stabilizer, which includes at least one of pectin, gum arabic, and sodium carboxymethyl cellulose, at a mass of 0.05% to 0.6% of the oil phase slurry. Continue stirring at 35 to 45°C for 10 to 40 min with a stirring speed of 80 to 250 r / min.

[0042] Almonds, peach kernels, apricot kernels, and hemp seeds are transformed from ordinary powders into an oil-phase slurry that can be stably coated by a hydrophilic gel system. After moist heat softening, low-temperature drying, and cell wall disruption, the oily plant components, including plant oils, fine powders, proteins, and dietary fiber, can be dispersed together in the aqueous phase, reducing the problems of clumping, oil separation, and uneven distribution that easily occur when directly pulverized and added to the paste.

[0043] The donkey-hide gelatin is first swollen and dissolved by heating, then mixed with honey to form a premixed solution of the gelatinous component, which can improve the adhesiveness, water retention, and shaping stability of the paste. After the water extract concentrate is added to the premixed solution of the gelatinous component, water-soluble components such as tangerine peel pectin, poria cocos polysaccharide, cassia seed gum, and hawthorn pectin can form a hydrophilic gel matrix with the donkey-hide gelatin and honey, providing a coating environment for the oil phase slurry.

[0044] After the oil phase slurry is added to the hydrophilic gel matrix, it undergoes low-speed premixing, high-speed shear emulsification, low-shear maturation, and vacuum degassing. This allows the oily plant components to form dispersed oil droplets, which are then coated with polysaccharides, pectin, and gum components. This improves the uniformity, water retention, and oil phase stability of the composite gel paste matrix.

[0045] In one embodiment, the oil phase slurry is pretreated with bile saline solution and stabilized with pectin, gum arabic, or sodium carboxymethyl cellulose, which can form an oil-water interface with bile salt responsive characteristics on the outside of the oil droplets. This structure facilitates subsequent interfacial linkage with bile acid-modified Xinhui tangerine peel suspension, giving the compound preparation a basis for oil phase interface migration and release in a bile salt environment.

[0046] S4. The bile acid-modified Xinhui tangerine peel suspension was added to the composite gel paste matrix for mixing, and then concentrated, homogenized, defoamed, filled and sealed at low temperature to obtain a composite preparation containing Xinhui tangerine peel.

[0047] Step S4 includes: S4.1 Add the bile acid-modified Xinhui tangerine peel suspension to the composite gel paste matrix in 2 to 5 portions, controlling the mass ratio of bile acid-modified Xinhui tangerine peel suspension to composite gel paste matrix to be 1:3 to 1:15. After each addition, stir at 35 to 45°C for 5 to 20 minutes at a stirring speed of 50 to 200 r / min to obtain the mixed matrix. S4.2. The mixed matrix is ​​concentrated under vacuum at a temperature of 45-60℃, a vacuum degree of -0.06--0.09MPa, a stirring speed of 20-100r / min, and a concentration time of 20-90min until the solid content of the system is 55%-75%, thus obtaining a concentrated composite paste. S4.3. Homogenize the concentrated compound paste under a pressure of 3–15 MPa for 1–2 cycles. Perform vacuum degassing at a temperature of 35–50°C and a vacuum of -0.04–-0.08 MPa for 10–40 min. Stir at 20–80 r / min during degassing. After degassing, fill and seal the product at a temperature of 35–50°C. Immediately after filling, seal and cool to room temperature to obtain a compound preparation containing Xinhui tangerine peel.

[0048] In one embodiment, between steps S4.1 and S4.2, step S4 further includes: The interface conditioning solution, consisting of glyceryl monostearate, L-arginine, and resistant dextrin, is added to the mixed matrix in 2–4 portions. The mass-volume concentration of glyceryl monostearate is 0.03%–0.30%, that of L-arginine is 0.02%–0.15%, and that of resistant dextrin is 0.10%–1.00%. After each addition, the mixture is stirred at 38–45°C at a speed of 60–180 r / min for 5–12 min, followed by standing for 3–8 min. This process is repeated 2–5 times.

[0049] The bile acid-modified Xinhui tangerine peel suspension is uniformly embedded in the composite gel matrix, allowing the active dispersed phase of Xinhui tangerine peel, the oil phase slurry, the water extract concentrate, and the gelatinous components to form a stable composite paste structure. The bile acid-modified Xinhui tangerine peel suspension is added in 2-5 stages, which reduces localized dilution, particle aggregation, and uneven distribution caused by a single addition, allowing the suspended particles to gradually enter the paste network formed by donkey-hide gelatin, honey, and water-extracted polysaccharides.

[0050] The mixed matrix is ​​concentrated under low-temperature vacuum at 45–60℃, which removes some moisture at a lower temperature, resulting in a solids content of 55%–75% in the system. This also reduces the adverse effects of high temperatures on polymethoxylated flavonoids, oily plant components, and gum components of Xinhui tangerine peel. Subsequent low-pressure homogenization at 3–15 MPa breaks up localized agglomerates formed during concentration, resulting in a more uniform distribution of the bile acid-modified Xinhui tangerine peel suspension and the composite gel paste matrix. Vacuum degassing reduces internal air bubbles in the paste, improving filling and storage stability.

[0051] In one embodiment, an interface conditioning solution is added between steps S4.1 and S4.2. Glyceryl monostearate in the interface conditioning solution can distribute between the oil droplet interface and the hydrophilic phase of the paste, improving the interfacial compatibility between the oil phase and the hydrophilic gel matrix; L-arginine can form weak interactions with bile acid-modified particles, pectin, polysaccharides, or protein components, reducing particle aggregation; resistant dextrin can distribute in the aqueous phase channels, improving the water retention and viscoelastic stability of the paste. Adding the interface conditioning solution in stages, combined with stirring and static circulation, can prevent local enrichment of the interface conditioning components, allowing them to gradually distribute around the oil droplets, on the outer side of the particles, and within the gel network.

[0052] This invention proposes a compound preparation containing Xinhui tangerine peel, which is prepared by a method for preparing a compound preparation containing Xinhui tangerine peel.

[0053] Example 1: Take 100 parts of Xinhui tangerine peel, 30 parts of Poria cocos, 30 parts of Cassia seed, 40 parts of Coix seed, 40 parts of red adzuki bean, 25 parts of hawthorn, 20 parts of lotus leaf, 20 parts of apricot kernel, 20 parts of peach kernel, 15 parts of Prunus japonica seed, 30 parts of hemp seed, 20 parts of donkey-hide gelatin, and 80 parts of honey. Add a 45% (v / v) ethanol aqueous solution to the Xinhui tangerine peel powder for pre-wetting, and stir at 30℃ for 30 min. Then add a 70% (v / v) ethanol aqueous solution for extraction. Control the mass-to-volume ratio of Xinhui tangerine peel powder to total ethanol aqueous solution to be 1 g: 12 mL, the extraction temperature to be 50℃, the extraction time to be 100 min, and the stirring speed to be 150 r / min to obtain the primary extract. The primary extract was subjected to solid-liquid separation, and the filtrate and residue were collected. The filtrate was allowed to stand at 6℃ for 4 hours, then centrifuged at 6000 r / min for 10 min, and treated through a 0.45 μm microfiltration membrane to obtain a clear alcohol extract. Subsequently, it was concentrated under low temperature and reduced pressure at 40℃ and a vacuum degree of -0.08 MPa until the solid content was 15%, obtaining the Xinhui tangerine peel alcohol extract. The Xinhui tangerine peel residue was treated at 40℃ and a vacuum degree of -0.06 MPa for 20 min, and then rehydrated with purified water. The mass ratio of Xinhui tangerine peel residue to purified water was controlled at 1:6, the rehydration temperature was 40℃, the stirring time was 40 min, and the stirring speed was 120 r / min. The pulverized Poria cocos, Cassia seed, Coix seed, red adzuki bean, hawthorn, lotus leaf, and rehydrated tangerine peel residue were added to purified water. The total mass ratio of water-soluble plant components, rehydrated tangerine peel residue, and purified water was controlled at 1:12 to obtain a primary mixture. The primary mixture was first heated to 65℃ and kept at that temperature for 45 min, then heated to 90℃ and kept at that temperature for 90 min, with a stirring speed of 100 r / min, to obtain a composite water extract. The composite water extract was subjected to solid-liquid separation and clarification, and then concentrated at 55℃ and a vacuum of -0.08 MPa to a solid content of 25% to obtain a concentrated water extract.

[0054] The bile acid-modified biodegradable carrier uses bile acid-modified zein, with ethanol as the organic solvent and pectin as the stabilizer. Bile acid-modified zein and Xinhui tangerine peel extract were added to ethanol and dissolved under light-protected conditions. The mass concentration of bile acid-modified zein in the oil phase solution was 15 mg / mL, and the mass ratio of solids to bile acid-modified zein in the Xinhui tangerine peel extract was 1:8. The dissolution temperature was 30℃, the stirring speed was 250 rpm, and the dissolution time was 40 min. Lecithin was added during stirring, with the amount of lecithin being 8% of the mass of bile acid-modified zein, resulting in the oil phase solution. Pectin was dissolved in purified water, with a pectin mass-volume concentration of 1.2% in the aqueous phase. The temperature was 25℃, the stirring speed was 300 rpm, and the stirring time was 40 min. The pH was then adjusted to 8.6 using sodium bicarbonate to obtain a weakly alkaline aqueous phase. The oil phase solution was added dropwise to a weakly alkaline aqueous phase under ice bath conditions, with a volume ratio of 1:10 and a dropping rate of 0.8 mL / min. Emulsification was performed using a high-speed shear emulsifier at 12000 r / min for 6 min at an emulsification temperature of 18℃ to obtain a primary emulsion. The primary emulsion was then subjected to reduced pressure solvent removal in a rotary evaporator at 35℃, a vacuum of -0.08 MPa, for 40 min at a stirring speed of 120 r / min. After evaporation, the emulsion was centrifuged at 12000 g for 20 min at 6℃, and the precipitate was collected. The precipitate was washed three times with purified water and then dispersed in a 2 mg / mL pectin aqueous solution, maintaining a solids content of 8%. Low-pressure homogenization was performed at 25℃ at 15 MPa for two cycles to obtain a bile acid-modified Xinhui tangerine peel suspension.

[0055] Almonds, peach kernels, apricot kernels, and hemp seeds were used as oily plant components. They were heated to 85℃ for 25 minutes, with the moisture content controlled at 25%. Subsequently, they were dried at low temperature (50℃) to a moisture content of 9%. The dried components were then subjected to cell wall disruption in a high-speed blender, with purified water added as the dispersion medium. The mass ratio of oily plant components to dispersion medium was controlled at 1:2, the disruption temperature at 35℃, and the disruption time at 20 minutes. The colloid mill gap was 60 μm, resulting in an oil phase slurry. First, donkey-hide gelatin was added to purified water for swelling, with a mass ratio of donkey-hide gelatin to purified water controlled at 1:5. The swelling temperature was 25℃, and the swelling time was 80 minutes. Then, it was heated to 65℃ for dissolution, with a stirring speed of 120 r / min and a dissolution time of 40 minutes. Honey was then added, with a mass ratio of honey to donkey-hide gelatin controlled at 4:1, and stirring continued for 25 minutes to obtain a premixed solution of the gelatinous component. The concentrated aqueous extract was added to the premixed gel component, with a mass ratio of 3:1. The addition temperature was 55℃, the addition time was 25 min, and the stirring speed was 180 r / min. After mixing, the mixture was kept warm and stirred for another 40 min to obtain a hydrophilic gel matrix. The oil phase slurry was added to the hydrophilic gel matrix for shear emulsification, with a mass ratio of 1:5. The addition temperature was 45℃, the addition time was 25 min, the mixture was first premixed at a low speed of 200 r / min for 20 min, then sheared and emulsified at 5000 r / min for 8 min, and then low-shear maturation was carried out at 42℃ for 50 min with a stirring speed of 100 r / min. Subsequently, degassing was performed under vacuum conditions at a temperature of 42℃, a vacuum degree of -0.06 MPa, and a degassing time of 25 min to obtain a composite gel paste matrix.

[0056] A bile acid-modified Xinhui tangerine peel suspension was added to the composite gel paste matrix in three portions, maintaining a mass ratio of 1:8 between the bile acid-modified Xinhui tangerine peel suspension and the composite gel paste matrix. After each addition, the mixture was stirred at 40°C for 12 minutes at a stirring speed of 120 r / min to obtain a mixed matrix. The mixed matrix was then vacuum concentrated at 52°C, a vacuum degree of -0.08 MPa, a stirring speed of 60 r / min, and a concentration time of 60 minutes, until the solid content of the system reached 65%, resulting in a concentrated composite paste. The concentrated composite paste was homogenized at a homogenization pressure of 8 MPa for two cycles. Subsequently, vacuum degassing was performed at 42°C, a vacuum degree of -0.06 MPa, and a degassing time of 25 minutes, with a stirring speed of 50 r / min during the degassing process. After degassing, the mixture was filled and sealed at 42°C and cooled to room temperature to obtain a composite preparation containing Xinhui tangerine peel.

[0057] Example 2: Example 2 adds a compound enzyme hydrolysis step to Example 1, while the remaining raw material amounts and process conditions are the same as in Example 1. Specifically, in Example 2, between steps S1.4 and S1.5, a compound enzyme is added to the primary mixture for enzymatic hydrolysis, and the pH is adjusted to 5.6. The amount of compound enzyme added is 0.20% of the mass of the primary mixture, the hydrolysis temperature is 48℃, the hydrolysis time is 60 min, and the stirring speed is 120 r / min. The compound enzyme consists of cellulase, pectinase, and hemicellulase in a mass ratio of 1:1:1.

[0058] Example 3: Example 3 adds a bile saline pretreatment step to Example 2, while the remaining raw material amounts and process conditions are the same as in Example 2. Specifically, in Example 3, between steps S3.1 and S3.2, sodium taurocholate is added to purified water to prepare a bile saline phase with a mass-volume concentration of 0.10%. The bile saline phase is then added to the oil phase slurry, controlling the mass ratio of the bile saline phase to the oil phase slurry to be 1:10, and stirred at 37°C at a stirring speed of 180 r / min for 25 min. Subsequently, pectin is added as a stabilizer, with the amount of pectin added being 0.30% of the mass of the oil phase slurry. Stirring continues at 40°C for 25 min at a stirring speed of 150 r / min.

[0059] Example 4: Example 4 adds an interface conditioning liquid step to Example 3, while the remaining raw material amounts and process conditions are the same as in Example 3. The specific difference is that in Example 4, the interface conditioning liquid is added to the mixed matrix in three separate additions between steps S4.1 and S4.2. The interface conditioning liquid comprises glyceryl monostearate, L-arginine, and resistant dextrin, wherein the mass-volume concentration of glyceryl monostearate is 0.15%, the mass-volume concentration of L-arginine is 0.08%, and the mass-volume concentration of resistant dextrin is 0.50%. The total amount of interface conditioning liquid added is 2.0% of the mass of the mixed matrix. After each addition, the mixture is stirred at 42°C at a stirring speed of 120 r / min for 8 min, followed by standing for 5 min, and this process is repeated three times.

[0060] Comparative Example 1: The difference between Comparative Example 1 and Example 1 is that Xinhui tangerine peel is not subjected to fractional extraction with ethanol and aqueous solution. Instead, Xinhui tangerine peel powder and water-soluble plant components are added together to purified water, extracted at 90°C for 120 min, and then concentrated. The resulting water extract concentrate is directly used for subsequent ointment preparation. Comparative Example 1 does not prepare Xinhui tangerine peel ethanol extract or bile acid modified Xinhui tangerine peel suspension. The amount of other raw materials and subsequent ointment preparation conditions are the same as in Example 1.

[0061] Comparative Example 2: The difference between Comparative Example 2 and Example 1 is that in step S2, no bile acid-modified biodegradable carrier is added, and no emulsification, solvent removal, centrifugation, and pectin aqueous solution resuspension are performed. Instead, the Xinhui tangerine peel alcohol extract obtained in Example 1 is directly added to the composite gel paste matrix, and the remaining steps are the same as in Example 1.

[0062] Comparative Example 3: The difference between Comparative Example 3 and Example 1 is that the oily plant components are not subjected to wet heat softening, low temperature drying and cell wall breaking treatment, but are directly pulverized to pass through a 60-mesh sieve and then added to the hydrophilic gel matrix for mixing. The remaining steps are the same as in Example 1.

[0063] Comparative Example 4: The difference between Comparative Example 4 and Example 1 is that the bile acid modified Xinhui tangerine peel suspension was added to the composite gel paste matrix at one time, and the mixed matrix was concentrated to the same solid content at 80°C and normal pressure, without low-temperature vacuum concentration treatment. The remaining steps were the same as in Example 1.

[0064] The experimental procedure is as follows.

[0065] Particle size and dispersibility testing: The bile acid-modified Xinhui tangerine peel suspensions prepared in step S2 of Examples 1 to 4 were diluted 100 times with purified water, and the average particle size and polydispersity index were measured using a dynamic light scattering particle size analyzer at 25°C. Each sample was tested in triplicate, and the average value was taken. Comparative Examples 1 and 2 did not prepare bile acid-modified Xinhui tangerine peel suspensions, so this test was not performed.

[0066] Active ingredient content and uniformity testing: Samples of the upper, middle, and lower layers of the final formulations obtained in the examples and comparative examples were taken, with 1.0 g of each layer. Extraction was performed using 70% ethanol aqueous solution, followed by ultrasonic treatment for 30 min and centrifugation. The supernatant was then analyzed using high-performance liquid chromatography (HPLC) to determine the total content of nonotrimonin and hesperidin. The relative standard deviation was calculated based on the results of the upper, middle, and lower layers to evaluate the uniformity of the active ingredient distribution in the ointment.

[0067] Oil separation stability test: 20g of the final formulations obtained in the examples and comparative examples were taken and placed in sealed transparent containers, and placed at 40℃ for 14 days. After the placement period, it was observed whether there was oil phase precipitation on the surface of the paste, and the oil phase precipitated on the surface was collected. The oil separation rate was calculated based on the ratio of the mass of the precipitated oil phase to the initial mass of the sample. The lower the oil separation rate, the better the stability of the oily plant components in the composite gel paste.

[0068] Water retention test: 10g of the final formulations obtained in the examples and comparative examples were placed in an open environment at 37°C for 24 hours. The mass change before and after placement was recorded, and the water retention rate was calculated based on the ratio of the mass after placement to the mass before placement. The higher the water retention rate, the better the water extract concentrate, colloidal components, and composite gel network can retain water.

[0069] Simulated intestinal fluid migration and release assay: 1.0 g of the final formulation obtained in the examples and comparative examples was added to simulated intestinal fluid with a pH of 6.8. The simulated intestinal fluid was prepared using a phosphate buffer system. The sample was placed in a 37°C constant-temperature shaker and shaken at 100 rpm for 120 min. After treatment, centrifugation was performed, and the supernatant was used as the aqueous release solution. The precipitate was extracted again with an ethanol-water solution to calculate the total amount of norepinephrine and hesperidin in the sample. The total amount of norepinephrine and hesperidin in the aqueous release solution was detected by high-performance liquid chromatography (HPLC). The simulated intestinal fluid migration and release ratio was calculated based on the ratio of the total amount of norepinephrine and hesperidin in the aqueous release solution to the total amount of norepinephrine and hesperidin in the sample.

[0070] The experimental data from the above experiment are shown in Table 1.

[0071] Table 1: The experimental data above show that Example 1 exhibited a good migration and release effect in simulated intestinal fluid, indicating that after fractional extraction, preparation of bile acid-modified Xinhui tangerine peel suspension, and construction of composite gel paste, the fat-soluble active ingredients of Xinhui tangerine peel could be released from the paste system under conditions close to the small intestinal environment. Example 2, by adding a compound enzyme hydrolysis step based on Example 1, further improved the migration and release effect in simulated intestinal fluid, indicating that the polysaccharides, pectin, and gums in the water extract concentrate were released more fully, which is beneficial to improving the wettability and swelling properties of the paste. Example 3, by further adding a bile saline pretreatment step, further improved the migration and release effect in simulated intestinal fluid. Example 4, by further adding an interface conditioning solution, further improved the migration and release effect in simulated intestinal fluid, paste uniformity, water retention, and oil separation stability, indicating that glyceryl monostearate, L-arginine, and resistant dextrin can improve the interfacial compatibility between bile acid-modified particles, oil droplets, and the hydrophilic gel network, making it easier for active ingredients to migrate and be released in simulated intestinal fluid.

[0072] Comparative Example 1, without the preparation of an alcoholic extract and bile acid-modified suspension of Xinhui tangerine peel, showed poor simulated intestinal fluid migration and release, indicating that simple water extraction is insufficient to fully obtain and release the fat-soluble polymethoxyflavonoids in Xinhui tangerine peel. Comparative Example 2, although using an alcoholic extract of Xinhui tangerine peel, did not prepare a bile acid-modified suspension, and the simulated intestinal fluid migration and release effect was still unsatisfactory, indicating that the alcoholic extract, when directly added to the paste, tends to accumulate locally, hindering release in an aqueous environment. Comparative Example 3, without undergoing moist heat softening, low-temperature drying, and cell wall disruption treatment of the oily plant components, suffered from insufficient oil phase stability, resulting in a lower simulated intestinal fluid migration and release effect compared to the examples. Comparative Example 4, employing a one-time addition of the suspension and high-temperature, atmospheric-pressure concentration, easily caused loss of active ingredients and decreased paste structural stability, thus correspondingly reducing the simulated intestinal fluid migration and release effect.

[0073] Other embodiments of this disclosure will readily occur to those skilled in the art upon consideration of the specification and practice of the invention disclosed herein. This application is intended to cover any variations, uses, or adaptations of this disclosure that follow the general principles of this disclosure and include common knowledge or customary techniques in the art not disclosed herein. The specification and examples are to be considered exemplary only, and the true scope and spirit of this disclosure are indicated by the following claims.

[0074] It should be understood that this disclosure is not limited to the precise structures described above and shown in the accompanying drawings, and various modifications and changes can be made without departing from its scope. The scope of this disclosure is limited only by the appended claims.

Claims

1. A method for preparing a compound preparation containing Xinhui tangerine peel, characterized in that the steps include... include: S1. Add Xinhui tangerine peel powder to an ethanol aqueous solution for extraction to obtain Xinhui tangerine peel alcohol extract. Then, add water to extract the water-soluble plant components and Xinhui tangerine peel filter residue to obtain a concentrated water extract. S2. The bile acid-modified biodegradable carrier and the alcohol extract of Xinhui tangerine peel are dissolved together in an organic solvent to obtain an oil phase solution. Then, a stabilizer is added to water and the pH value is adjusted to a preset range to obtain a weakly alkaline aqueous phase. The oil phase solution is added dropwise to the weakly alkaline aqueous phase for emulsification, solvent removal, centrifugation and washing to obtain a bile acid-modified Xinhui tangerine peel suspension. S3. The oily plant components are subjected to cell wall breaking treatment to obtain an oil phase slurry. The oil phase slurry is then added to the colloidal components and water extract concentrate for shear emulsification to obtain a composite gel paste matrix. S4. The bile acid-modified Xinhui tangerine peel suspension was added to the composite gel paste matrix for mixing, and then concentrated, homogenized, defoamed, filled and sealed at low temperature to obtain a composite preparation containing Xinhui tangerine peel.

2. The method for preparing a compound preparation containing Xinhui tangerine peel according to claim 1, characterized in that, Step S1 includes: S1.

1. Add 35%–50% (v / v) ethanol aqueous solution to Xinhui tangerine peel powder for pre-wetting, stir and wet for 15–40 min at 25–35℃, then add 60%–80% (v / v) ethanol aqueous solution for extraction. Control the mass-volume ratio of Xinhui tangerine peel powder to total ethanol aqueous solution to be 1g:8mL–1g:18mL, the extraction temperature to be 40–60℃, the extraction time to be 60–150 min, and the stirring speed to be 80–250 r / min to obtain the primary extract. S1.

2. The primary extract is subjected to solid-liquid separation, and the filtrate and residue are collected. The filtrate is subjected to low-temperature settling, centrifugation and microfiltration to obtain a clear alcohol extract. The low-temperature settling temperature is 4-10℃, the settling time is 2-8h, the centrifugation speed is 4000-8000r / min, the centrifugation time is 5-15min, and the microfiltration membrane pore size is 0.45-1.0μm. Subsequently, the clear alcohol extract is concentrated under low-temperature reduced pressure at a temperature of 35-50℃ and a vacuum degree of -0.06--0.09MPa until the solid content is 8%-25% to obtain Xinhui tangerine peel alcohol extract. S1.

3. First, treat the Xinhui tangerine peel filter residue at 35-45℃ and a vacuum of -0.04--0.08MPa for 10-30 minutes. Then, add purified water to the de-alcoholized Xinhui tangerine peel filter residue for rehydration and swelling. Control the mass ratio of Xinhui tangerine peel filter residue to purified water to be 1:4-1:8, the rehydration temperature to be 35-45℃, the stirring time to be 20-60 minutes, and the stirring speed to be 60-180 r / min. S1.4 Add the pulverized water-soluble plant components and Xinhui tangerine peel filter residue to purified water, and control the total mass ratio of water-soluble plant components, rehydrated tangerine peel filter residue and purified water to 1:8 to 1:18 to obtain a primary mixture. The water-soluble plant components include Poria cocos, Cassia seed, Coix seed, red adzuki bean, hawthorn and lotus leaf. S1.

5. First, heat the primary mixture to 60-70℃ and hold for 30-60 min, then heat to 80-95℃ and hold for 60-120 min, controlling the stirring speed at 50-150 r / min to obtain a composite water extract. Perform solid-liquid separation and clarification on the composite water extract. Concentrate the clarified composite water extract at low temperature under conditions of 45-60℃ and a vacuum degree of -0.06 to -0.09 MPa until the solid content is 15%-40% to obtain a concentrated water extract.

3. The method for preparing a compound preparation containing Xinhui tangerine peel according to claim 2, characterized in that, Between steps S1.4 and S1.5, step S1 further includes: A compound enzyme is added to the primary mixture for enzymatic hydrolysis, and the pH is adjusted to 5.0–6.

2. The amount of compound enzyme added is 0.05%–0.5% of the mass of the primary mixture. The hydrolysis temperature is 40–55℃, the hydrolysis time is 30–90 min, and the stirring speed is 60–180 r / min. The compound enzyme includes at least two of cellulase, pectinase, and hemicellulase.

4. The method for preparing a compound preparation containing Xinhui tangerine peel according to claim 1, characterized in that, Step S2 includes: S2.1 Add the bile acid-modified biodegradable carrier and the ethanol extract of Xinhui tangerine peel to an organic solvent and stir to dissolve under light-protected conditions. The mass concentration of the bile acid-modified biodegradable carrier in the oil phase solution is 5-25 mg / mL, the mass ratio of solids to bile acid-modified biodegradable carrier in the ethanol extract of Xinhui tangerine peel is 1:3-1:15, the dissolution temperature is 25-40℃, the stirring speed is 100-400 r / min, and the dissolution time is 20-60 min. During the stirring process, lecithin is added, and the amount of lecithin is 2%-15% of the mass of the bile acid-modified biodegradable carrier, to obtain the oil phase solution. S2.2 Dissolve the stabilizer in purified water. The mass-volume concentration of the stabilizer in the aqueous phase is 0.3% to 2.5%, the temperature is 20 to 35°C, the stirring speed is 100 to 500 r / min, and the stirring time is 20 to 60 min. Then adjust the pH value to 8.0 to 9.2 with sodium bicarbonate or sodium hydroxide to obtain a weakly alkaline aqueous phase. S2.

3. The oil phase solution is added dropwise to the weakly alkaline aqueous phase under ice bath conditions, and the volume ratio of the oil phase solution to the weakly alkaline aqueous phase is controlled at 1:5 to 1:

15. The dropping rate of the oil phase solution is 0.3 to 1.5 mL / min. During the dropping process, a high-speed shear emulsifier is used for emulsification, with a shearing speed of 8000 to 15000 r / min, a shearing time of 3 to 10 min, and an emulsification temperature of 10 to 25℃ to obtain a primary emulsion. S2.

4. The primary emulsion is subjected to desolventizing treatment under reduced pressure. The desolventizing equipment is a rotary evaporator with a temperature of 30-40℃, a vacuum degree of -0.06 to -0.09 MPa, and a treatment time of 20-60 min. During the process, the stirring speed is controlled at 80-200 r / min. After evaporation, centrifugation and washing are performed. The centrifugation temperature is 4-10℃, the centrifugation force is 8000-20000 g, and the centrifugation time is 10-30 min. The precipitate is collected and washed 2-3 times with purified water. It is then dispersed in a pectin aqueous solution with a concentration of 1-3 mg / mL, and the solid content is controlled at 2%-12%. Low-pressure homogenization is performed at 20-35℃ with a homogenization pressure of 5-30 MPa and a cycle of 1-3 times to obtain a bile acid-modified Xinhui tangerine peel suspension.

5. The method for preparing a compound preparation containing Xinhui tangerine peel according to claim 4, characterized in that, In step S2, the degradable carrier includes at least one of zein, lecithin complex carrier, and sodium alginate-pectin complex carrier; the organic solvent includes ethanol or ethyl acetate; and the stabilizer includes at least one of pectin, gum arabic, and sodium carboxymethyl cellulose.

6. The method for preparing a compound preparation containing Xinhui tangerine peel according to claim 1, characterized in that, Step S3 includes: S3.

1. Heat the oily plant components to 70–95℃ for 10–40 min, controlling the moisture content to 15%–35% during the process. Then, perform low-temperature drying at 40–55℃ until the moisture content is 6%–12%. Place the dried components in a cell wall blender for cell wall breaking, adding purified water as the dispersion medium. Control the mass ratio of oily plant components to dispersion medium to be 1:1–1:4, the cell wall breaking temperature to be 20–45℃, the cell wall breaking time to be 5–30 min, and the colloid mill gap to be 20–100 μm to obtain an oil phase slurry. The oily plant components include almonds, peach kernels, apricot kernels, and hemp kernels. S3.2 The gelatinous component includes donkey-hide gelatin and honey. First, donkey-hide gelatin is added to purified water for swelling, with the mass ratio of donkey-hide gelatin to purified water controlled at 1:3 to 1:8, the swelling temperature at 20 to 35℃, and the swelling time at 30 to 120 min. Then, it is heated to 55 to 75℃ for dissolution, with a stirring speed of 50 to 200 r / min and a dissolution time of 20 to 60 min. Subsequently, honey is added, with the mass ratio of honey to donkey-hide gelatin controlled at 2:1 to 8:

1. Stirring is continued for 10 to 40 min to obtain a premixed solution of the gelatinous component. S3.3 Add the concentrated water extract to the premixed gel component and mix them. Control the mass ratio of the concentrated water extract to the premixed gel component to be 1:1 to 5:1, the feeding temperature to be 45 to 65℃, the feeding time to be 10 to 40 min, the stirring speed to be 80 to 300 r / min, and continue to keep warm and stir for 20 to 60 min to obtain the hydrophilic gel matrix. S3.

4. The oil phase slurry is added to the hydrophilic gel matrix for shear emulsification. The mass ratio of the oil phase slurry to the hydrophilic gel matrix is ​​controlled at 1:2 to 1:

8. The feeding temperature is 40 to 55℃ and the feeding time is 10 to 45 min. First, it is premixed at a low speed of 100 to 300 r / min for 10 to 30 min, then shear emulsified at 3000 to 8000 r / min for 3 to 15 min. Then, it is matured at a low shear temperature of 35 to 50℃ with a stirring speed of 50 to 150 r / min and a maturation time of 20 to 90 min. Subsequently, it is degassed under vacuum conditions at a temperature of 35 to 50℃, a vacuum degree of -0.04 to -0.08 MPa, and a degassed time of 10 to 40 min to obtain a composite gel paste matrix.

7. The method for preparing a compound preparation containing Xinhui tangerine peel according to claim 6, characterized in that, Between step S3.1 and step S3.2, step S3 further includes: Bile salts are added to purified water. The bile salts include at least one of sodium taurocholate, sodium glycocholate, or sodium cholate, and the mass-volume concentration of the bile salts is 0.02% to 0.20%, to obtain a bile salt phase. Add the bile saline phase to the oil phase slurry, controlling the mass ratio of the bile saline phase to the oil phase slurry to be 1:5 to 1:20, and stir at 35 to 40°C with a stirring speed of 80 to 300 r / min for 10 to 45 min. Then add a stabilizer, which includes at least one of pectin, gum arabic, and sodium carboxymethyl cellulose, at a mass of 0.05% to 0.6% of the oil phase slurry. Continue stirring at 35 to 45°C for 10 to 40 min with a stirring speed of 80 to 250 r / min.

8. The method for preparing a compound preparation containing Xinhui tangerine peel according to claim 1, characterized in that, Step S4 includes: S4.1 Add the bile acid-modified Xinhui tangerine peel suspension to the composite gel paste matrix in 2 to 5 portions, controlling the mass ratio of bile acid-modified Xinhui tangerine peel suspension to composite gel paste matrix to be 1:3 to 1:

15. After each addition, stir at 35 to 45°C for 5 to 20 minutes at a stirring speed of 50 to 200 r / min to obtain the mixed matrix. S4.

2. Vacuum concentration of the mixed matrix is ​​carried out at a temperature of 45-60℃, a vacuum degree of -0.06--0.09MPa, a stirring speed of 20-100r / min, and a concentration time of 20-90min until the solid content of the system is 55%-75%, to obtain a concentrated composite paste. S4.

3. Homogenize the concentrated compound paste under a pressure of 3–15 MPa for 1–2 cycles. Perform vacuum degassing at a temperature of 35–50°C and a vacuum of -0.04–-0.08 MPa for 10–40 min. Stir at 20–80 r / min during degassing. After degassing, fill and seal the product at a temperature of 35–50°C. Immediately after filling, seal and cool to room temperature to obtain a compound preparation containing Xinhui tangerine peel.

9. A method for preparing a compound preparation containing Xinhui tangerine peel according to claim 8, characterized in that, Between step S4.1 and step S4.2, step S4 further includes: The interface conditioning solution, consisting of glyceryl monostearate, L-arginine, and resistant dextrin, is added to the mixed matrix in 2–4 portions. The mass-volume concentration of glyceryl monostearate is 0.03%–0.30%, that of L-arginine is 0.02%–0.15%, and that of resistant dextrin is 0.10%–1.00%. After each addition, the mixture is stirred at 38–45°C at a speed of 60–180 r / min for 5–12 min, followed by standing for 3–8 min. This process is repeated 2–5 times.

10. A compound preparation containing Xinhui tangerine peel, characterized in that, It is prepared by the method of any one of claims 1-9 for a compound preparation containing Xinhui tangerine peel.

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