High-utilization-rate ginseng active ingredient medicinal preparation and preparation method thereof

Abstract

The invention discloses a high-utilization-rate ginseng active ingredient medicinal preparation and a preparation method thereof, and relates to the technical field of medicines. The high-utilization-rate ginseng active ingredient pharmaceutical preparation is prepared from chitosan coated drug-loaded porous silicon dioxide composite nanoparticles and a drug-loaded MIL-101 metal organic framework matrix material, chitosan-coated drug-loading porous silicon dioxide composite nanoparticles are loaded on the surface of a drug-loading MIL-101 metal organic framework base material, and sodium alginate and a chitosan gel material are subjected to cross-linking connection, so that independent coating is formed, the framework base material and the composite nanoparticles are connected into a whole, the encapsulation performance and the drug loading capacity are improved, and the drug-loading capacity of the drug-loading MIL-101 metal organic framework composite nanoparticles is improved. Furthermore, the loading and the loading stability of the ginsenoside are improved, the adverse effects of gastric juice and gastrointestinal peristalsis on the activity of the ginsenoside are effectively reduced, the release and the absorption of the ginsenoside in intestinal tracts are remarkably enhanced, and the bioavailability is relatively high.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically refers to a pharmaceutical preparation of ginseng active ingredients with high utilization rate and its preparation method. Background Art

[0002] Ginseng is a herbaceous plant of the Araliaceae family, known as the "king of all herbs" and has the effect of greatly tonifying primordial qi. Ginseng has many active ingredients, such as ginsenosides, polysaccharides, volatile oils, flavonoids, etc. Among them, ginsenosides, as the main active ingredients, have a wide range of pharmacological effects, including anti-tumor, anti-inflammatory, protecting the myocardium, protecting the kidneys and spleen, and enhancing immunity. As an implant extract, ginsenosides have relatively high safety and are suitable as health products or adjuvant therapeutic drugs.

[0003] Ginsenosides are divided into oleanolic acid-type pentacyclic triterpenoid saponins and dammarane-type tetracyclic triterpenoid saponins according to their sapogenin structures. Among them, dammarane-type ginsenosides include diol-type ginsenosides (Rb1, Rd, Rg3, Rh2, etc.) and triol-type ginsenosides (Re, Rg1, Rg2, Rh1, etc.). Multiple ginsenosides regulate the body's functions through multiple mechanisms and have the "adaptogen" property to help the body cope with stress and restore balance.

[0004] Currently, the following main problems exist in the prior art:

[0005] Due to the strong hydrophobicity and poor solubility of ginsenosides, they often face the problem of low loading. At the same time, their activity is affected by the gastric environment, resulting in low bioavailability and limiting the effective exertion of pharmacological effects. Summary of the Invention

[0006] In view of the above situation, in order to overcome the defects of the prior art, the present invention proposes a pharmaceutical preparation of ginseng active ingredients with high utilization rate, which is a freeze-dried powder of nanoparticles and comprises the following components in parts by weight: 50 - 60 parts of chitosan-coated drug-loaded porous silica composite nanoparticles, and 20 - 30 parts of drug-loaded MIL-101 metal-organic framework matrix material.

[0007] The chitosan-coated drug-loaded porous silica composite nanoparticles comprise the following components in parts by weight: 30 - 40 parts of silica, 30 - 50 parts of trichlorohexylsilane, 10 - 20 parts of ginsenoside I, and 10 - 20 parts of chitosan.

[0008] The drug-loaded MIL-101 metal-organic framework matrix material comprises the following components in parts by weight: 30 - 40 parts of chromium(III) nitrate nonahydrate, 1 - 3 parts of L-glutamic acid, 10 - 20 parts of ginsenoside II, 10 - 15 parts of sodium alginate, and 20 - 30 parts of calcium chloride.

[0009] The preparation method of the chitosan-coated drug-loaded porous silica composite nanoparticles specifically comprises the following steps:

[0010] (1) Mix 45 mL of absolute ethanol, 1 mL of ammonia water, 0.15 g of cetyltrimethylammonium bromide, and 0.02 mL of β-mercaptoethanol evenly. Under stirring, slowly add 3 mL of tetraethyl orthosilicate dropwise to the mixture. Stir and react at a constant temperature of 25 °C for 3 - 4 h, then centrifuge, collect the precipitate for freeze-drying. Weigh 0.3 - 0.4 g of the obtained silica and add it to a beaker containing 20 mL of n-hexane. Stir to disperse, then add trichlorohexylsilane liquid, seal the beaker to reduce the volatilization of the reagent, and magnetically stir at 25 °C for 3 - 4 h. Keep the operation in the dark during the stirring process. After the reaction, centrifuge, wash the precipitate with n-hexane 2 - 3 times to remove the excess unreacted trichlorohexylsilane, and then freeze-dry. The pores of the silica can be loaded with ginsenosides through physical adsorption or chemical bonding and can act as a carrier for delivering active substances. The rigid structure of the silica can shield ginsenosides from gastric acid, enzymatic hydrolysis, or oxidative degradation, improving the bioavailability. The silica modified with trichlorohexylsilane not only forms a more optimized pore structure, but also the hexyl long chain of trichlorohexylsilane can increase the hydrophobicity of the silica surface, making it more suitable for loading lipophilic active ingredients, enhancing the loading efficiency of ginsenosides. The hydrophobic modification can also reduce the hydrolysis or degradation of ginsenosides during storage and delivery, improving the stability of ginsenoside activity during storage and in gastric juice. At the same time, the hydrophobic interaction can also promote the targeted release of lipophilic components under the action of lipase or bile salts, obtaining modified porous silica;

[0011] (2) Dissolve 0.1 - 0.2 g of ginsenoside I in 80 mL of ethanol with a mass fraction of 70 - 80%, then add the modified porous silica described in step (1), stir for 20 - 30 min, let it stand at 4 °C for 1 - 2 h, centrifuge, wash the product with deionized water 2 - 3 times, and then freeze-dry. By loading ginsenosides onto the modified porous silica, the loading amount and stability of ginsenosides are improved. The modified porous silica can also improve the activity and targeting of ginsenosides after oral administration through its own delivery function, which is beneficial to improving the bioavailability and better exerting the pharmacological activity, obtaining drug-loaded modified porous silica nanoparticles;

[0012] (3) Dissolve 0.1 - 0.2 g of chitosan in 40 mL of 1% acetic acid solution to obtain a chitosan solution. Then mix the drug-loaded modified porous silica nanoparticles described in step (2) with the chitosan solution and stir for 20 - 30 min to obtain Component I. Add 80 mL of Tween 80 and 40 mL of absolute ethanol to 500 mL of n-hexane and stir magnetically until completely dissolved to obtain Component II. Then add Component I to Component II and stir for 2 min to obtain an emulsion. Next, add 10 - 15 mL of 0.8% sodium tripolyphosphate aqueous solution and stir at room temperature for 20 - 30 min at a stirring speed of 600 - 800 rpm. Let it stand for 30 min. After the emulsion layers, remove the supernatant. Continue to add 100 - 200 mL of ethanol and stir magnetically for 20 - 30 min. Place it at 4 °C overnight. Finally, centrifuge. Wash the precipitate 3 - 5 times with 75% ethanol by mass fraction and then perform freeze-drying. Coating the drug-loaded modified porous silica nanoparticles with chitosan densely and uniformly through the reverse microemulsion method not only improves the encapsulation of ginsenosides, but also enhances the loading capacity and loading stability of modified porous silica for ginsenosides through the hydrogen bond or electrostatic interaction of chitosan, effectively improving the loading rate of ginsenosides. The chitosan gel coating layer provides a mechanical protection effect, reducing the burst release or leakage of components. And the gel film formed by the cross-linking of chitosan and sodium tripolyphosphate can reduce the decomposition of the composite nanoparticles in gastric juice, enabling them to release ginsenosides in the neutral environment of the intestine and improving the bioavailability, thus obtaining chitosan-coated drug-loaded porous silica composite nanoparticles;

[0013] Preferably, in step (1), the addition amount of trichlorohexylsilane is 0.3 - 0.5 mL. As an organosilane compound, trichlorohexylsilane has high reactivity and can react with the silica surface through silanol groups (Si-OH) to form stable Si-O-Si bonds, thereby endowing the silica surface with hydrophobicity and organic compatibility and reducing the aggregation of silica;

[0014] Preferably, in step (2), ginsenoside I includes ginsenoside Re and ginsenoside Rb1, and the weight ratio of ginsenoside Re to ginsenoside Rb1 is 1:(1 - 2). The two show a significant synergistic effect, which can enhance each other's pharmacological activities and reduce side effects.

[0015] The present invention also provides a preparation method of a high-utilization-rate ginseng active ingredient pharmaceutical preparation, which specifically includes the following steps:

[0016] S1. Add 3.0 - 4.0 g of chromium(III) nitrate nonahydrate, 1.6 g of terephthalic acid, 0.5 g of hydrofluoric acid, 50.0 g of deionized water, and 1.0 - 2.0 g of ginsenoside II into the inner liner of a 100 mL reactor. In the composition of ginsenoside II, the weight ratio of ginsenoside Re to ginsenoside Rb1 is (1 - 2):1. Stir at room temperature for 20 - 30 min, then add L-glutamic acid and stir for 10 - 20 min. Then place it in an oven and react at 200 - 210 °C for 8 - 10 h. Cool to room temperature, then centrifuge. Wash the product successively with N,N-dimethylformamide and ethanol, and perform supercritical drying. Through the porous structure of the MIL-101 metal-organic framework material, the hydrophilic and hydrophobic components of ginsenoside are completely and efficiently encapsulated in the framework, improving the loading rate of the active ingredient. The addition of L-glutamic acid modifies and modifies the MIL-101 metal-organic framework material on the premise of maintaining the stability of the MIL-101 structure, enhancing the interaction between the MIL-101 metal-organic framework material and the biological membrane, and promoting the targeted delivery of ginsenoside in the intestinal or immune microenvironment. The good water solubility and stability of L-glutamic acid not only increase the drug loading capacity of the poorly soluble component but also ensure the stable activity of ginsenoside in the gastric juice environment. Moreover, L-glutamic acid itself is an important neurotransmitter in the central nervous system and participates in immune regulation, capable of producing a synergistic effect with ginsenoside, enhancing the immune regulation or intestinal protection effect, and obtaining a drug-loaded modified MIL-101 metal-organic framework material;

[0017] S2. Add sodium alginate into 100 mL of deionized water and stir in a water bath at 40 - 50 °C for 2 - 3 h to obtain a sodium alginate solution for use. Then add the drug-loaded modified MIL-101 metal-organic framework material described in step S1 into the sodium alginate solution, then add 1 mL of Tween 80 and stir for 20 - 30 min. Then slowly add it into 100 mL of a calcium chloride solution with a mass fraction of 2 - 3% and crosslink at room temperature for 30 min. Then filter, wash, and dry. The surface of the drug-loaded modified MIL-101 metal-organic framework material is encapsulated with a gel film formed by crosslinking sodium alginate and calcium chloride, which not only enhances the protection effect on ginsenoside, reduces the adverse effects of gastric juice, improves the utilization rate in the intestine, but also increases the mechanical strength, reduces the physical damage of the framework material caused by gastrointestinal peristalsis, thereby avoiding the burst release phenomenon of the active ingredient and ensuring the effective release of ginsenoside, obtaining a drug-loaded MIL-101 metal-organic framework matrix material;

[0018] S3. Disperse the drug-loaded MIL-101 metal-organic framework matrix material described in step S2 in 100 mL of deionized water, and at the same time disperse the chitosan-coated drug-loaded porous silica composite nanoparticles in 100 mL of deionized water. Then mix the two and stir, and carry out a crosslinking reaction at room temperature for 1 - 2 h. Filter and freeze-dry. Through the connection of sodium alginate and chitosan gel materials, the crosslinking loading of chitosan-coated drug-loaded porous silica composite nanoparticles on the surface of the drug-loaded MIL-101 metal-organic framework matrix material is realized. The gel material at the connection provides support for the composite nanoparticles and the framework matrix material with a flexible three-dimensional network, reducing the structural damage caused by gastrointestinal peristalsis and improving the drug-loading stability. Even if a single nanoparticle is damaged, the ginsenoside it loads can enter the gel connection material, effectively protecting the stability of ginsenoside in gastric juice. At the same time, the gel material connects each component to act synergistically at the intestine for effective release, thereby improving the bioavailability of ginsenoside and the therapeutic effectiveness of ginsenoside, and obtaining a high-utilization-rate ginseng active ingredient pharmaceutical preparation;

[0019] Preferably, in step S1, the addition amount of L-glutamic acid is 0.1 - 0.3 g. L-glutamic acid can be actively absorbed through amino acid transporters in the intestine, promoting the intestinal penetration of the carrier and its loaded substances. The carboxyl group of L-glutamic acid can also interact with mucin in the mucosal layer, prolonging the residence time at the absorption site, thus enhancing the absorption of ginsenoside in the intestine;

[0020] Preferably, in step S2, the addition amount of sodium alginate is 1.0 - 1.5 g. In gastric juice, the carboxylic acid groups of sodium alginate are protonated to form -COOH, and the intermolecular hydrogen bonds are enhanced, forming a dense gel layer, effectively blocking the degradation or erosion of gastric acid. After entering the intestine, the carboxylic acid groups are deprotonated, and the gel swells and gradually degrades, thereby releasing the active ingredient.

[0021] The beneficial effects obtained by the present invention are as follows:

[0022] In the present invention, the chitosan-coated drug-loaded porous silica composite nanoparticles are loaded on the surface of the drug-loaded MIL-101 metal-organic framework matrix material, and cross-linked and connected with the sodium alginate and chitosan gel materials, forming both separate encapsulations and connecting the framework matrix material and the composite nanoparticles into a whole, improving the encapsulation efficiency and drug loading capacity, thereby increasing the loading and loading stability of ginsenosides, effectively reducing the adverse effects of gastric juice and gastrointestinal peristalsis on the activity of ginsenosides, significantly enhancing the release and absorption of ginsenosides in the intestine, having a high bioavailability, and being conducive to the full exertion of pharmacological effects; in the chitosan-coated drug-loaded porous silica composite nanoparticles, trichloromethylsilane is first used to modify the silica, optimizing the pore structure of the silica, improving the hydrophobicity of the silica surface, making it more conducive to loading lipophilic active ingredients, thereby enhancing the drug loading capacity of ginsenosides, reducing the acidolysis of ginsenosides during the delivery process, improving the stability of ginsenosides in gastric juice, and promoting the targeted release of lipophilic components under the action of lipase or bile salts. Then, chitosan is densely and uniformly coated on the surface of the drug-loaded modified porous silica nanoparticles, enhancing the loading amount and loading stability of the modified porous silica for ginsenosides. Among them, the gel film formed by the cross-linking of chitosan and sodium tripolyphosphate can reduce the decomposition of the composite nanoparticles in gastric juice, enabling the release of ginsenosides in the neutral environment of the intestine, improving the bioavailability. The chitosan gel coating layer also provides a mechanical protection effect, reducing the burst release or leakage of components. The physiological activity of chitosan can also produce a synergistic effect with ginsenosides, enhancing the therapeutic and health care effects; in the drug-loaded MIL-101 metal-organic framework matrix material, L-glutamic acid is first used to modify the MIL-101 metal-organic framework material, enhancing the interaction between the MIL-101 metal-organic framework material and the biological membrane, effectively promoting the targeted delivery of ginsenosides in the intestinal or immune microenvironment, improving the bioavailability of ginsenosides, and the good water solubility and gastric acid stability of L-glutamic acid not only increase the drug loading capacity of poorly soluble components but also ensure the high activity of ginsenosides in the gastric juice environment. Moreover, the sodium alginate gel film encapsulates the drug-loaded modified MIL-101 metal-organic framework material, further enhancing the protective effect on ginsenosides, reducing the damage of gastric juice and gastrointestinal peristalsis to the active substance of ginsenosides and the framework material, and improving the effective release of ginsenosides in the intestine; the present invention uses chitosan-coated drug-loaded porous silica composite nanoparticles and drug-loaded MIL-101 metal-organic framework matrix materials to prepare a high-utilization-rate pharmaceutical preparation of ginseng active ingredients, not only improving the encapsulation efficiency and loading amount of ginsenosides, but also effectively reducing the adverse effects of gastric juice, significantly enhancing the effective release and absorption in the intestine, and improving the bioavailability of ginsenosides. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1Scanning electron micrograph of the chitosan-coated drug-loaded porous silica composite nanoparticles prepared in Example 1 of the present invention;

[0024] Figure 2 Scanning electron micrograph of the cross-linking site on the surface of the drug-loaded MIL-101 metal-organic framework matrix material of the chitosan-coated drug-loaded porous silica composite nanoparticles prepared in Example 1 of the present invention;

[0025] Figure 3 Drug loading results graph of Examples 1-4 and Comparative Examples 1-3 of the present invention;

[0026] Figure 4 Results graph of ginsenoside content of Examples 1-4 and Comparative Examples 1-3 of the present invention. Detailed implementation manners

[0027] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments; based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0028] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the present invention. The preferred implementation methods and materials described in the text are only for demonstration purposes, but cannot limit the content of this application.

[0029] The experimental methods in the following embodiments are all conventional methods unless otherwise specified; the test materials used in the following embodiments are all obtained from commercial channels unless otherwise specified.

[0030] Example 1

[0031] This example presents a drug preparation of ginseng active ingredients with high utilization rate, which is a freeze-dried powder of nanoparticles and includes the following components in parts by weight: 60 parts of chitosan-coated drug-loaded porous silica composite nanoparticles and 30 parts of drug-loaded MIL-101 metal-organic framework matrix material.

[0032] The chitosan-coated drug-loaded porous silica composite nanoparticles include the following components in parts by weight: 40 parts of silica, 50 parts of trichlorohexylsilane, 20 parts of ginsenoside I, and 20 parts of chitosan.

[0033] The drug-loaded MIL-101 metal-organic framework matrix material includes the following components in parts by weight: 40 parts of chromium(III) nitrate nonahydrate, 3 parts of L-glutamic acid, 20 parts of ginsenoside II, 15 parts of sodium alginate, and 30 parts of calcium chloride.

[0034] Preparation method of chitosan-coated drug-loaded porous silica composite nanoparticles, which specifically comprises the following steps:

[0035] (1) Mix 45 mL of absolute ethanol, 1 mL of ammonia water, 0.15 g of cetyltrimethylammonium bromide, and 0.02 mL of β-mercaptoethanol evenly. Under stirring, slowly drop 3 mL of tetraethyl orthosilicate into the mixture, and carry out a constant-temperature stirring reaction at 25°C for 4 h. Then, centrifuge and collect the precipitate for freeze-drying. Weigh 0.4 g of the obtained silica and add it to a beaker containing 20 mL of n-hexane, stir to disperse it, and then add trichlorohexylsilane liquid. The addition amount of trichlorohexylsilane is 0.5 mL. As an organosilane compound, trichlorohexylsilane has high reactivity and can react with the silica surface through silanol groups (Si-OH) to form stable Si-O-Si bonds, thereby endowing the silica surface with hydrophobicity and organic compatibility, reducing the aggregation of silica, sealing the beaker to reduce the volatilization of reagents, and carrying out magnetic stirring at 25°C for 4 h, keeping the operation away from light during the stirring process. After the reaction, centrifuge, wash the precipitate with n-hexane three times to remove the excess unreacted trichlorohexylsilane, and then carry out freeze-drying. The pores of silica can be loaded with ginsenosides through physical adsorption or chemical bonding and can act as a carrier for delivering active substances. The rigid structure of silica can shield ginsenosides from gastric acid, enzymatic hydrolysis, or oxidative degradation, improving the bioavailability. The silica modified with trichlorohexylsilane not only forms a more optimized pore structure, but also the hexyl long chain of trichlorohexylsilane can increase the hydrophobicity of the silica surface, making it more suitable for loading lipophilic active ingredients and enhancing the loading efficiency of ginsenosides. The hydrophobic modification can also reduce the hydrolysis or degradation of ginsenosides during storage and delivery, improving the stability of ginsenoside activity in storage and gastric juice. At the same time, the hydrophobic effect can also promote the targeted release of lipophilic components under the action of lipase or bile salts, obtaining modified porous silica;

[0036] (2) Dissolve 0.2 g of ginsenoside I in 80 mL of ethanol with a mass fraction of 80%. Ginsenoside I includes ginsenoside Re and ginsenoside Rb1, and the weight ratio of ginsenoside Re to ginsenoside Rb1 is 1:2. The two show a significant synergistic effect, which can enhance each other's pharmacological activities and reduce side effects. Then add the modified porous silica described in step (1), stir for 30 min, let it stand at 4°C for 2 h, centrifuge, wash the product with deionized water three times, and then carry out freeze-drying. By loading ginsenosides on the modified porous silica, the loading amount and stability of ginsenosides are improved. The modified porous silica can also improve the activity and targeting of ginsenosides after oral administration through its own delivery function, which is beneficial to improving the bioavailability and better exerting the pharmacological activity, obtaining drug-loaded modified porous silica nanoparticles;

[0037] (3) Dissolve 0.2 g of chitosan in 40 mL of 1% acetic acid solution to obtain a chitosan solution. Then mix the drug-loaded modified porous silica nanoparticles described in step (2) with the chitosan solution and stir for 30 min to obtain Component I. Add 80 mL of Tween 80 and 40 mL of absolute ethanol to 500 mL of n-hexane and stir magnetically until fully dissolved to obtain Component II. Then add Component I to Component II, stir for 2 min to obtain an emulsion. Next, add 15 mL of 0.8% sodium tripolyphosphate aqueous solution, stir at room temperature for 30 min at a stirring speed of 800 rpm, let it stand for 30 min. After the emulsion layers, remove the supernatant. Continue to add 200 mL of ethanol, stir magnetically for 30 min, place it at 4 °C overnight, and finally centrifuge. The precipitate is washed 5 times with 75% ethanol by mass and then freeze-dried. The chitosan is densely and uniformly coated on the surface of the drug-loaded modified porous silica nanoparticles by the inverse microemulsion method, which not only improves the encapsulation of ginsenosides, but also enhances the loading amount and loading stability of modified porous silica for ginsenosides through hydrogen bonding or electrostatic interaction of chitosan, effectively improving the loading rate of ginsenosides. The chitosan gel coating layer provides mechanical protection, reducing the burst release or leakage of components. And the gel film formed by the cross-linking of chitosan and sodium tripolyphosphate can reduce the decomposition of the composite nanoparticles in gastric juice, enabling them to release ginsenosides in the neutral environment of the intestine and improving the bioavailability, thus obtaining chitosan-coated drug-loaded porous silica composite nanoparticles.

[0038] This example provides a preparation method of a pharmaceutical preparation of ginseng active ingredients with high utilization rate, specifically including the following steps:

[0039] S1. Add 4.0 g of chromium(III) nitrate nonahydrate, 1.6 g of terephthalic acid, 0.5 g of hydrofluoric acid, 50.0 g of deionized water, and 2.0 g of ginsenoside II into the inner liner of a 100 mL autoclave. In the composition of ginsenoside II, the weight ratio of ginsenoside Re to ginsenoside Rb1 is 2:1. Stir at room temperature for 30 min, then add L-glutamic acid with an addition amount of 0.3 g. L-glutamic acid can be actively absorbed through amino acid transporters in the intestine, promoting the intestinal permeability of the carrier and its loaded substances. The carboxyl group of L-glutamic acid can also interact with mucin in the mucosal layer, prolonging the residence time at the absorption site, thus enhancing the absorption of ginsenosides in the intestine. Stir for 20 min, then place it in an oven and react at 210 °C for 10 h. Cool to room temperature, then centrifuge. The product is washed successively with N,N-dimethylformamide and ethanol, and then supercritically dried. The hydrophilic and hydrophobic components of ginsenosides are completely and efficiently encapsulated in the framework through the porous structure of MIL-101 metal-organic framework material, improving the loading rate of the active ingredient. The addition of L-glutamic acid modifies and modifies the MIL-101 metal-organic framework material on the premise of maintaining the stability of the MIL-101 structure, enhancing the interaction between the MIL-101 metal-organic framework material and the biological membrane, and promoting the targeted delivery of ginsenosides in the intestine or immune microenvironment. The good water solubility and stability of L-glutamic acid not only increase the drug loading of poorly soluble components but also ensure the stable activity of ginsenosides in the gastric juice environment. Moreover, L-glutamic acid itself is an important neurotransmitter in the central nervous system and participates in immune regulation, capable of producing a synergistic effect with ginsenosides, enhancing the immune regulation or intestinal protection effect, and obtaining a drug-loaded and modified MIL-101 metal-organic framework material;

[0040] S2. Add sodium alginate into 100 mL of deionized water. The addition amount of sodium alginate is 1.5 g. In gastric juice, the carboxylic acid groups of sodium alginate are protonated to form -COOH, the intermolecular hydrogen bonds are enhanced, and a dense gel layer is formed, effectively blocking the degradation or erosion of gastric acid. After entering the intestine, the carboxylic acid groups are deprotonated, the gel swells and gradually degrades, thereby releasing the active ingredient. Stir in a water bath at 50 °C for 3 h to obtain a sodium alginate solution for use. Then add the drug-loaded modified MIL-101 metal-organic framework material described in step S1 into the sodium alginate solution, then add 1 mL of Tween 80, stir for 30 min, and then slowly add it into 100 mL of a calcium chloride solution with a mass fraction of 3%. Crosslink at room temperature for 30 min, then filter, wash, and dry. The surface of the drug-loaded modified MIL-101 metal-organic framework material is encapsulated with a gel film formed by crosslinking sodium alginate and calcium chloride, which not only enhances the protection effect on ginsenosides, reduces the adverse effects of gastric juice, improves the utilization rate in the intestine, but also improves the mechanical strength, reduces the physical damage of the framework material caused by gastrointestinal peristalsis, thereby avoiding the burst release phenomenon of the active ingredient and ensuring the effective release of ginsenosides, and obtaining a drug-loaded MIL-101 metal-organic framework matrix material;

[0041] S3. Disperse the drug-loaded MIL-101 metal-organic framework matrix material described in step S2 in 100 mL of deionized water, and at the same time disperse the chitosan-coated drug-loaded porous silica composite nanoparticles in 100 mL of deionized water. Then mix and stir the two, and carry out a crosslinking reaction at room temperature for 2 h. Filter and freeze-dry. Through the connection of sodium alginate and chitosan gel materials, the crosslinking and loading of chitosan-coated drug-loaded porous silica composite nanoparticles on the surface of the drug-loaded MIL-101 metal-organic framework matrix material are realized. The gel material at the connection provides support for the composite nanoparticles and the framework matrix material with a flexible three-dimensional network, reducing the structural damage caused by gastrointestinal peristalsis and improving the drug-loading stability. Even if a single nanoparticle is damaged, the ginsenosides loaded on it can enter the gel connection material, effectively protecting the stability of ginsenosides in gastric juice. At the same time, the gel material connects the components to act synergistically at the intestine for effective release, thereby improving the bioavailability of ginsenosides and the therapeutic effectiveness of ginsenosides, and obtaining a high-utilization-rate ginseng active ingredient pharmaceutical preparation.

[0042] In this example, scanning electron microscopy was performed on the prepared drug-loaded MIL-101 metal-organic framework matrix material and the crosslinking site of chitosan-coated drug-loaded porous silica composite nanoparticles on the surface of the drug-loaded MIL-101 metal-organic framework matrix material to observe its microscopic morphology. Figure 1 Figure 8 is an SEM image of the drug-loaded MIL-101 metal-organic framework matrix material prepared in Example 1 magnified 10,000 times. Figure 2SEM image at 500× magnification of the cross-linking site of chitosan-coated drug-loaded porous silica composite nanoparticles prepared in Example 1 on the surface of the drug-loaded MIL-101 metal-organic framework matrix material, as Figure 1 , the drug-loaded MIL-101 metal-organic framework matrix material prepared in this example presents a coated spherical shape with surface wrinkles and depressions, as Figure 2 , the cross-linking site of the chitosan-coated drug-loaded porous silica composite nanoparticles prepared in this example on the surface of the drug-loaded MIL-101 metal-organic framework matrix material is a gel-tight porous structure.

[0043] Example 2

[0044] This example proposes a drug preparation of ginseng active ingredients with high utilization rate, which is a freeze-dried powder of nanoparticles and comprises the following components in parts by weight: 50 parts of chitosan-coated drug-loaded porous silica composite nanoparticles and 20 parts of drug-loaded MIL-101 metal-organic framework matrix material.

[0045] The chitosan-coated drug-loaded porous silica composite nanoparticles comprise the following components in parts by weight: 30 parts of silica, 30 parts of trichlorohexylsilane, 10 parts of ginsenoside I, and 10 parts of chitosan.

[0046] The drug-loaded MIL-101 metal-organic framework matrix material comprises the following components in parts by weight: 30 parts of chromium(III) nitrate nonahydrate, 1 part of L-glutamic acid, 10 parts of ginsenoside II, 10 parts of sodium alginate, and 20 parts of calcium chloride.

[0047] The preparation method of the chitosan-coated drug-loaded porous silica composite nanoparticles specifically comprises the following steps:

[0048] (1) Mix 45 mL of absolute ethanol, 1 mL of ammonia water, 0.15 g of cetyltrimethylammonium bromide, and 0.02 mL of β-mercaptoethanol uniformly. Under stirring, slowly add 3 mL of tetraethyl orthosilicate dropwise to the mixture. Stir and react at a constant temperature of 25 °C for 3 h, then centrifuge and collect the precipitate for freeze-drying. Weigh 0.3 g of the obtained silica and add it to a beaker containing 20 mL of n-hexane, stir to disperse it, and then add trichlorohexylsilane liquid. The addition amount of trichlorohexylsilane is 0.3 mL. As an organosilane compound, trichlorohexylsilane has high reactivity and can react with the silica surface through silanol groups (Si-OH) to form stable Si-O-Si bonds, thereby endowing the silica surface with hydrophobicity and organic compatibility, reducing the aggregation of silica, sealing the beaker to reduce the volatilization of reagents, and magnetically stirring at 25 °C for 3 h while keeping the operation light-shielded during the stirring process. After the reaction, centrifuge, wash the precipitate twice with n-hexane to remove the excess unreacted trichlorohexylsilane, and then freeze-dry. The pores of the silica can be loaded with ginsenosides through physical adsorption or chemical bonding and can act as a carrier for delivering active substances. The rigid structure of the silica can shield ginsenosides from gastric acid, enzymatic hydrolysis, or oxidative degradation, improving the bioavailability. The silica modified with trichlorohexylsilane not only forms a more optimized pore structure, but also the hexyl long chain of trichlorohexylsilane can increase the hydrophobicity of the silica surface, making it more suitable for loading lipophilic active ingredients and enhancing the loading efficiency of ginsenosides. The hydrophobic modification can also reduce the hydrolysis or degradation of ginsenosides during storage and delivery, improve the stability of ginsenoside activity in storage and gastric juice, and at the same time, the hydrophobic interaction can also promote the targeted release of lipophilic components under the action of lipase or bile salts, obtaining modified porous silica;

[0049] (2) Dissolve 0.1 g of ginsenoside I in 80 mL of ethanol with a mass fraction of 70%. Ginsenoside I includes ginsenoside Re and ginsenoside Rb1, and the weight ratio of ginsenoside Re to ginsenoside Rb1 is 1:1. The two show a significant synergistic effect, which can enhance each other's pharmacological activities and reduce side effects. Then add the modified porous silica described in step (1), stir for 20 min, let it stand at 4 °C for 1 h, centrifuge, wash the product twice with deionized water, and then freeze-dry. By loading ginsenosides on the modified porous silica, the loading amount and stability of ginsenosides are improved. The modified porous silica can also improve the activity and targeting of ginsenosides after oral administration through its own delivery function, which is beneficial to improving the bioavailability and better exerting the pharmacological activity, obtaining drug-loaded modified porous silica nanoparticles;

[0050] (3) Dissolve 0.1 g of chitosan in 40 mL of 1% acetic acid solution to obtain a chitosan solution. Then mix the drug-loaded modified porous silica nanoparticles described in step (2) with the chitosan solution and stir for 20 min to obtain Component I. Add 80 mL of Tween 80 and 40 mL of absolute ethanol to 500 mL of n-hexane and stir magnetically until fully dissolved to obtain Component II. Then add Component I to Component II and stir for 2 min to obtain an emulsion. Next, add 10 mL of 0.8% sodium tripolyphosphate aqueous solution and stir at room temperature for 20 min at a stirring speed of 600 rpm. Let it stand for 30 min. After the emulsion layers, remove the supernatant. Continue to add 100 mL of ethanol and stir magnetically for 20 min. Place it at 4 °C overnight. Finally, centrifuge. Wash the precipitate 3 times with 75% ethanol by mass and then perform freeze-drying. Coat the drug-loaded modified porous silica nanoparticles uniformly and densely with chitosan by the inverse microemulsion method, which not only improves the encapsulation of ginsenosides but also enhances the loading amount and loading stability of modified porous silica for ginsenosides through hydrogen bonding or electrostatic interaction of chitosan, effectively improving the loading rate of ginsenosides. The chitosan gel coating layer provides a mechanical protection effect, reducing the burst release or leakage of components. And the gel film formed by the cross-linking of chitosan and sodium tripolyphosphate can reduce the decomposition of the composite nanoparticles in gastric juice, enabling them to release ginsenosides in the neutral environment of the intestine and improving the bioavailability, thus obtaining chitosan-coated drug-loaded porous silica composite nanoparticles.

[0051] This example provides a preparation method for a pharmaceutical preparation of ginseng active ingredients with high utilization rate, specifically including the following steps:

[0052] S1. Add 3.0 g of chromium(III) nitrate nonahydrate, 1.6 g of terephthalic acid, 0.5 g of hydrofluoric acid, 50.0 g of deionized water, and 1.0 g of ginsenoside II into the inner liner of a 100 mL autoclave. In the composition of ginsenoside II, the weight ratio of ginsenoside Re to ginsenoside Rb1 is 1:1. Stir at room temperature for 20 min, then add L-glutamic acid with an addition amount of 0.1 g. L-glutamic acid can be actively absorbed through amino acid transporters in the intestine, promoting the intestinal penetration of the carrier and its loaded substances. The carboxyl group of L-glutamic acid can also interact with mucin glycoproteins in the mucosal layer, prolonging the residence time at the absorption site, thus enhancing the absorption of ginsenosides in the intestine. Stir for 10 min, then place it in an oven and react at 200 °C for 8 h. Cool to room temperature, then centrifuge. The product is washed successively with N,N-dimethylformamide and ethanol, and then supercritically dried. Through the porous structure of the MIL-101 metal-organic framework material, the hydrophilic and hydrophobic components of ginsenosides are completely and efficiently encapsulated in the framework, improving the loading rate of the active ingredients. The addition of L-glutamic acid modifies and modifies the MIL-101 metal-organic framework material on the premise of maintaining the stability of the MIL-101 structure, enhancing the interaction between the MIL-101 metal-organic framework material and the biological membrane, and promoting the targeted delivery of ginsenosides in the intestine or immune microenvironment. The good water solubility and stability of L-glutamic acid not only increase the drug loading of poorly soluble components but also ensure the stable activity of ginsenosides in the gastric juice environment. Moreover, L-glutamic acid itself is an important neurotransmitter in the central nervous system and participates in immune regulation, capable of producing a synergistic effect with ginsenosides, enhancing the immune regulation or intestinal protection effect, and obtaining a drug-loaded and modified MIL-101 metal-organic framework material;

[0053] S2. Add sodium alginate to 100 mL of deionized water. The addition amount of sodium alginate is 1.0 g. In gastric juice, the carboxylic acid groups of sodium alginate are protonated to form -COOH, the intermolecular hydrogen bonds are enhanced, and a dense gel layer is formed, effectively blocking the degradation or erosion of gastric acid. After entering the intestine, the carboxylic acid groups are deprotonated, the gel swells and gradually degrades, thereby releasing the active ingredient. Stir in a water bath at 40 °C for 2 h to obtain a sodium alginate solution for use. Then add the drug-loaded modified MIL-101 metal-organic framework material described in step S1 to the sodium alginate solution, then add 1 mL of Tween 80, stir for 20 min, and then slowly add it to 100 mL of a 2% calcium chloride solution. Crosslink at room temperature for 30 min, then filter, wash, and dry. The surface of the drug-loaded modified MIL-101 metal-organic framework material is encapsulated with a gel film formed by crosslinking sodium alginate and calcium chloride, which not only enhances the protection of ginsenosides, reduces the adverse effects of gastric juice, improves the utilization rate in the intestine, but also improves the mechanical strength, reduces the physical damage of the framework material caused by gastrointestinal peristalsis, thereby avoiding the burst release phenomenon of the active ingredient and ensuring the effective release of ginsenosides, obtaining a drug-loaded MIL-101 metal-organic framework matrix material;

[0054] S3. Disperse the drug-loaded MIL-101 metal-organic framework matrix material described in step S2 in 100 mL of deionized water, and at the same time disperse the chitosan-coated drug-loaded porous silica composite nanoparticles in 100 mL of deionized water. Then mix and stir the two, and carry out a crosslinking reaction at room temperature for 1 h, filter, and freeze-dry. Through the connection of sodium alginate and chitosan gel materials, the crosslinking and loading of chitosan-coated drug-loaded porous silica composite nanoparticles on the surface of the drug-loaded MIL-101 metal-organic framework matrix material are realized. The gel material at the connection provides support for the composite nanoparticles and the framework matrix material with a flexible three-dimensional network, reduces the structural damage caused by gastrointestinal peristalsis, and improves the drug-loading stability. Even if a single nanoparticle is damaged, the ginsenosides loaded on it can enter the gel connection material, effectively protecting the stability of ginsenosides in gastric juice. At the same time, the gel material connects each component to act synergistically at the intestine for effective release, thereby improving the bioavailability of ginsenosides and the therapeutic effectiveness of ginsenosides, obtaining a high-utilization-rate ginseng active ingredient pharmaceutical preparation.

[0055] Example 3

[0056] This example presents a high-utilization-rate ginseng active ingredient pharmaceutical preparation, which is a freeze-dried powder of nanoparticles and includes the following components in parts by weight: 55 parts of chitosan-coated drug-loaded porous silica composite nanoparticles and 25 parts of drug-loaded MIL-101 metal-organic framework matrix material.

[0057] Chitosan-coated drug-loaded porous silica composite nanoparticles, comprising the following components in parts by weight: 35 parts of silica, 40 parts of trichlorohexylsilane, 15 parts of ginsenoside I, and 15 parts of chitosan.

[0058] Drug-loaded MIL-101 metal-organic framework matrix material, comprising the following components in parts by weight: 35 parts of chromium(III) nitrate nonahydrate, 2 parts of L-glutamic acid, 15 parts of ginsenoside II, 12.5 parts of sodium alginate, and 25 parts of calcium chloride.

[0059] Preparation method of chitosan-coated drug-loaded porous silica composite nanoparticles, specifically comprising the following steps:

[0060] (1) Mix 45 mL of absolute ethanol, 1 mL of ammonia water, 0.15 g of cetyltrimethylammonium bromide, and 0.02 mL of β-mercaptoethanol evenly. Under stirring, slowly drop 3 mL of tetraethyl orthosilicate into the mixture, and stir at a constant temperature of 25 °C for 3.5 h. Centrifuge and collect the precipitate for freeze-drying. Weigh 0.35 g of the obtained silica and add it to a beaker containing 20 mL of n-hexane, stir to disperse, and then add trichlorohexylsilane liquid. The addition amount of trichlorohexylsilane is 0.4 mL. As an organosilane compound, trichlorohexylsilane has high reactivity and can react with the silica surface through silanol groups (Si-OH) to form stable Si-O-Si bonds, thereby imparting hydrophobicity and organic compatibility to the silica surface, reducing the aggregation of silica, sealing the beaker to reduce the volatilization of reagents, and magnetically stirring at 25 °C for 3.5 h. Keep the operation in the dark during the stirring process. After the reaction, centrifuge, wash the precipitate with n-hexane 3 times to remove the excess unreacted trichlorohexylsilane, and then freeze-dry. The pores of silica can load ginsenoside through physical adsorption or chemical bonding and can act as a carrier for delivering active substances. The rigid structure of silica can shield ginsenoside from gastric acid, enzymatic hydrolysis, or oxidative degradation, improving the bioavailability. The silica modified with trichlorohexylsilane not only forms a more optimized pore structure, but also the hexyl long chain of trichlorohexylsilane can increase the hydrophobicity of the silica surface, making it more suitable for loading lipophilic active ingredients and enhancing the loading efficiency of ginsenoside. The hydrophobic modification can also reduce the hydrolysis or degradation of ginsenoside during storage and delivery, improving the stability of ginsenoside activity during storage and in gastric juice. At the same time, the hydrophobic interaction can also promote the targeted release of lipophilic components under the action of lipase or bile salts to obtain modified porous silica;

[0061] (2) Dissolve 0.15 g of ginsenoside I in 80 mL of ethanol with a mass fraction of 75%. Ginsenoside I includes ginsenoside Re and ginsenoside Rb1, and the weight ratio of ginsenoside Re to ginsenoside Rb1 is 1:1.5. The two show a significant synergistic effect, which can enhance each other's pharmacological activities and reduce side effects. Then add the modified porous silica described in step (1), stir for 25 min, let it stand at 4 °C for 1.5 h, centrifuge, wash the product 3 times with deionized water, and then freeze-dry. By loading ginsenoside on the modified porous silica, the loading amount and stability of ginsenoside are improved. The modified porous silica can also improve the activity and targeting of ginsenoside after oral administration through its own delivery effect, which is beneficial to improving the bioavailability and better exerting the pharmacological activity, and obtain drug-loaded modified porous silica nanoparticles;

[0062] (3) Dissolve 0.15 g of chitosan in 40 mL of acetic acid solution with a mass fraction of 1% to obtain a chitosan solution. Then mix the drug-loaded modified porous silica nanoparticles described in step (2) and the chitosan solution, stir for 25 min as component I. Add 80 mL of Tween 80 and 40 mL of absolute ethanol to 500 mL of n-hexane, and stir magnetically to make it fully dissolve as component II. Then add component I to component II, stir for 2 min to obtain an emulsion, then add 12.5 mL of an aqueous solution of sodium tripolyphosphate with a mass fraction of 0.8%, stir at room temperature for 25 min with a stirring speed of 700 rpm, let it stand for 30 min. After the emulsion is layered, remove the supernatant, continue to add 150 mL of ethanol, stir magnetically for 25 min, place it at 4 °C overnight, and finally centrifuge. The precipitate is washed 4 times with ethanol with a mass fraction of 75% and then freeze-dried. By the inverse microemulsion method, chitosan is densely and evenly coated on the surface of the drug-loaded modified porous silica nanoparticles, which not only improves the encapsulation of ginsenoside, but also can enhance the loading amount and loading stability of ginsenoside on the modified porous silica through the hydrogen bond or electrostatic interaction of chitosan, effectively improving the loading rate of ginsenoside. The chitosan gel coating layer provides a mechanical protection effect, reducing the sudden release or leakage of components, and the gel film formed by the cross-linking of chitosan and sodium tripolyphosphate can reduce the decomposition of the composite nanoparticles in gastric juice, making it release ginsenoside in the neutral environment of the intestine and improving the bioavailability, and obtain chitosan-coated drug-loaded porous silica composite nanoparticles.

[0063] This example provides a preparation method of a high-utilization-rate ginseng active ingredient pharmaceutical preparation, which specifically includes the following steps:

[0064] S1. Add 3.5 g of chromium(III) nitrate nonahydrate, 1.6 g of terephthalic acid, 0.5 g of hydrofluoric acid, 50.0 g of deionized water, and 1.5 g of ginsenoside II into the inner liner of a 100 mL reaction kettle. In the composition of ginsenoside II, the weight ratio of ginsenoside Re to ginsenoside Rb1 is 1.5:1. Stir at room temperature for 25 min, then add L-glutamic acid. The addition amount of L-glutamic acid is 0.2 g. L-glutamic acid can be actively absorbed through amino acid transporters in the intestine, promoting the intestinal permeability of the carrier and its loaded substances. The carboxyl group of L-glutamic acid can also interact with the glycoprotein in the mucosal layer, prolonging the residence time at the absorption site, thus enhancing the absorption of ginsenosides in the intestine. Stir for 15 min, then place it in an oven and react at 205 °C for 9 h. Cool to room temperature, then centrifuge. The product is washed successively with N,N-dimethylformamide and ethanol, and then supercritically dried. Through the porous structure of the MIL-101 metal-organic framework material, the hydrophilic and hydrophobic components of ginsenosides are completely and efficiently encapsulated in the framework, improving the loading rate of the active ingredients. The addition of L-glutamic acid modifies and modifies the MIL-101 metal-organic framework material on the premise of maintaining the stability of the MIL-101 structure, enhancing the interaction between the MIL-101 metal-organic framework material and the biological membrane, and promoting the targeted delivery of ginsenosides in the intestine or immune microenvironment. The good water solubility and stability of L-glutamic acid not only improve the drug loading of poorly soluble components but also ensure the stable activity of ginsenosides in the gastric juice environment. Moreover, L-glutamic acid itself is an important neurotransmitter in the central nervous system and participates in immune regulation, capable of producing a synergistic effect with ginsenosides, enhancing the immune regulation or intestinal protection effect, and obtaining a drug-loaded and modified MIL-101 metal-organic framework material;

[0065] S2. Add sodium alginate to 100 mL of deionized water. The addition amount of sodium alginate is 1.25 g. In gastric juice, the carboxylic acid groups of sodium alginate are protonated to form -COOH, and the intermolecular hydrogen bonds are enhanced to form a dense gel layer, effectively blocking the degradation or erosion of gastric acid. After entering the intestine, the carboxylic acid groups are deprotonated, and the gel swells and gradually degrades, thereby releasing the active ingredient. Stir in a water bath at 45 °C for 2.5 h to obtain a sodium alginate solution for later use. Then add the drug-loaded modified MIL-101 metal-organic framework material described in step S1 to the sodium alginate solution, then add 1 mL of Tween 80, stir for 25 min, and then slowly add it to 100 mL of a 2.5% calcium chloride solution. Crosslink at room temperature for 30 min, then filter, wash, and dry. The surface of the drug-loaded modified MIL-101 metal-organic framework material is encapsulated with a gel film formed by crosslinking sodium alginate and calcium chloride, which not only enhances the protection of ginsenosides, reduces the adverse effects of gastric juice, improves the utilization rate in the intestine, but also improves the mechanical strength, reduces the physical damage of the framework material caused by gastrointestinal peristalsis, thereby avoiding the sudden release phenomenon of active ingredients and ensuring the effective release of ginsenosides, and obtaining a drug-loaded MIL-101 metal-organic framework matrix material;

[0066] S3. Disperse the drug-loaded MIL-101 metal-organic framework matrix material described in step S2 in 100 mL of deionized water, and at the same time disperse the chitosan-coated drug-loaded porous silica composite nanoparticles in 100 mL of deionized water. Then mix and stir the two, and carry out a crosslinking reaction at room temperature for 1.5 h, filter, and freeze-dry. Through the connection of sodium alginate and chitosan gel materials, the crosslinking and loading of chitosan-coated drug-loaded porous silica composite nanoparticles on the surface of the drug-loaded MIL-101 metal-organic framework matrix material are realized. The gel material at the connection provides support for the composite nanoparticles and the framework matrix material with a flexible three-dimensional network, reducing the structural damage caused by gastrointestinal peristalsis and improving the drug-loading stability. Even if a single nanoparticle is damaged, the ginsenosides it loads can enter the gel connection material, effectively protecting the stability of ginsenosides in gastric juice. At the same time, the gel material connects each component to act synergistically at the intestine for effective release, thereby improving the bioavailability of ginsenosides and the therapeutic effectiveness of ginsenosides, and obtaining a high-utilization-rate ginseng active ingredient pharmaceutical preparation.

[0067] Example 4

[0068] This example presents a high-utilization-rate ginseng active ingredient pharmaceutical preparation, which is a freeze-dried powder of nanoparticles and includes the following components in parts by weight: 60 parts of chitosan-coated drug-loaded porous silica composite nanoparticles and 20 parts of drug-loaded MIL-101 metal-organic framework matrix material.

[0069] Chitosan-coated drug-loaded porous silica composite nanoparticles, comprising the following components in parts by weight: 40 parts of silica, 30 parts of trichlorohexylsilane, 20 parts of ginsenoside I, and 10 parts of chitosan.

[0070] Drug-loaded MIL-101 metal-organic framework matrix material, comprising the following components in parts by weight: 40 parts of chromium(III) nitrate nonahydrate, 1 part of L-glutamic acid, 20 parts of ginsenoside II, 15 parts of sodium alginate, and 30 parts of calcium chloride.

[0071] Preparation method of chitosan-coated drug-loaded porous silica composite nanoparticles, specifically comprising the following steps:

[0072] (1) Mix 45 mL of absolute ethanol, 1 mL of ammonia water, 0.15 g of cetyltrimethylammonium bromide, and 0.02 mL of β-mercaptoethanol evenly. Under stirring, slowly drop 3 mL of tetraethyl orthosilicate into the mixture, and stir and react at a constant temperature of 25 °C for 3 h. Centrifuge, collect the precipitate for freeze-drying. Weigh 0.4 g of the obtained silica and add it to a beaker containing 20 mL of n-hexane, stir and disperse, then add trichlorohexylsilane liquid. The addition amount of trichlorohexylsilane is 0.3 mL. As an organosilane compound, trichlorohexylsilane has high reactivity and can react with the silica surface through silanol groups (Si-OH) to form stable Si-O-Si bonds, thereby endowing the silica surface with hydrophobicity and organic compatibility, reducing the aggregation of silica, sealing the beaker to reduce the volatilization of reagents, and magnetically stirring at 25 °C for 3 h, keeping the operation in the dark during the stirring process. After the reaction, centrifuge, wash the precipitate with n-hexane twice to remove the excess unreacted trichlorohexylsilane, and then freeze-dry. The pores of silica can load ginsenoside through physical adsorption or chemical bonding and can act as a carrier for delivering active substances. The rigid structure of silica can shield ginsenoside from gastric acid, enzymatic hydrolysis, or oxidative degradation, improving the bioavailability. The silica modified with trichlorohexylsilane not only forms a more optimized pore structure, but also the hexyl long chain of trichlorohexylsilane can increase the hydrophobicity of the silica surface, making it more suitable for loading lipophilic active ingredients, enhancing the loading efficiency of ginsenoside. The hydrophobic modification can also reduce the hydrolysis or degradation of ginsenoside during storage and delivery, improving the stability of ginsenoside activity during storage and in gastric juice. At the same time, the hydrophobic interaction can also promote the targeted release of lipophilic components under the action of lipase or bile salts, obtaining modified porous silica;

[0073] (2) Dissolve 0.2 g of ginsenoside I in 80 mL of ethanol with a mass fraction of 80%. Ginsenoside I includes ginsenoside Re and ginsenoside Rb1, and the weight ratio of ginsenoside Re to ginsenoside Rb1 is 1:1. The two show a significant synergistic effect, which can enhance each other's pharmacological activities and reduce side effects. Then add the modified porous silica described in step (1), stir for 20 min, let it stand at 4 °C for 1 h, centrifuge, wash the product twice with deionized water, and then freeze-dry. By loading ginsenoside on the modified porous silica, the loading amount and stability of ginsenoside are improved. The modified porous silica can also improve the activity and targeting of ginsenoside after oral administration through its own delivery effect, which is beneficial to improving the bioavailability and better exerting the pharmacological activity, and obtain the drug-loaded modified porous silica nanoparticles;

[0074] (3) Dissolve 0.1 g of chitosan in 40 mL of acetic acid solution with a mass fraction of 1% to obtain a chitosan solution. Then mix the drug-loaded modified porous silica nanoparticles described in step (2) and the chitosan solution, stir for 20 min as component I. Add 80 mL of Tween 80 and 40 mL of absolute ethanol to 500 mL of n-hexane, and magnetically stir to dissolve them fully as component II. Then add component I to component II, stir for 2 min to obtain an emulsion. Then add 10 mL of an aqueous solution of sodium tripolyphosphate with a mass fraction of 0.8%, stir at room temperature for 20 min at a stirring speed of 800 rpm, let it stand for 30 min. After the emulsion is layered, remove the supernatant. Continue to add 200 mL of ethanol, magnetically stir for 20 min, place it at 4 °C overnight, and finally centrifuge. Wash the precipitate three times with ethanol with a mass fraction of 75% and then freeze-dry. By the inverse microemulsion method, chitosan is densely and evenly coated on the surface of the drug-loaded modified porous silica nanoparticles, which not only improves the encapsulation of ginsenoside, but also can enhance the loading amount and loading stability of ginsenoside on the modified porous silica through the hydrogen bond or electrostatic interaction of chitosan, effectively improving the loading rate of ginsenoside. The chitosan gel coating layer provides a mechanical protection effect, reducing the sudden release or leakage of components. And the gel film formed by the cross-linking of chitosan and sodium tripolyphosphate can reduce the decomposition of the composite nanoparticles in gastric juice, making them release ginsenoside in the neutral environment of the intestine and improving the bioavailability, and obtain the chitosan-coated drug-loaded porous silica composite nanoparticles.

[0075] This example provides a preparation method of a high-utilization-rate ginseng active ingredient pharmaceutical preparation, which specifically includes the following steps:

[0076] S1. Add 4.0 g of chromium(III) nitrate nonahydrate, 1.6 g of terephthalic acid, 0.5 g of hydrofluoric acid, 50.0 g of deionized water, and 2.0 g of ginsenoside II into the inner liner of a 100 mL autoclave. In the composition of ginsenoside II, the weight ratio of ginsenoside Re to ginsenoside Rb1 is 2:1. Stir at room temperature for 20 min, then add L-glutamic acid with an addition amount of 0.1 g. L-glutamic acid can be actively absorbed through amino acid transporters in the intestine, promoting the intestinal permeability of the carrier and its loaded substances. The carboxyl group of L-glutamic acid can also interact with mucin in the mucosal layer, prolonging the residence time at the absorption site, thus enhancing the absorption of ginsenosides in the intestine. Stir for 10 min, then place it in an oven and react at 210 °C for 8 h. Cool to room temperature, then centrifuge. The product is washed successively with N,N-dimethylformamide and ethanol, and then supercritically dried. Through the porous structure of the MIL-101 metal-organic framework material, the hydrophilic and hydrophobic components of ginsenosides are completely and efficiently encapsulated in the framework, improving the loading rate of the active ingredients. The addition of L-glutamic acid modifies and modifies the MIL-101 metal-organic framework material on the premise of maintaining the stability of the MIL-101 structure, enhancing the interaction between the MIL-101 metal-organic framework material and the biological membrane, and promoting the targeted delivery of ginsenosides in the intestine or immune microenvironment. The good water solubility and stability of L-glutamic acid not only increase the drug loading of poorly soluble components but also ensure the stable activity of ginsenosides in the gastric juice environment. Moreover, L-glutamic acid itself is an important neurotransmitter in the central nervous system and participates in immune regulation, capable of producing a synergistic effect with ginsenosides, enhancing the immune regulation or intestinal protection effect, and obtaining a drug-loaded and modified MIL-101 metal-organic framework material;

[0077] S2. Add sodium alginate to 100 mL of deionized water. The addition amount of sodium alginate is 1.5 g. In gastric juice, the carboxylic acid groups of sodium alginate are protonated to form -COOH, the intermolecular hydrogen bonds are enhanced, and a dense gel layer is formed, effectively blocking the degradation or erosion of gastric acid. After entering the intestine, the carboxylic acid groups are deprotonated, the gel swells and gradually degrades, thereby releasing the active ingredient. Stir in a water bath at 50 °C for 2 h to obtain a sodium alginate solution for later use. Then add the drug-loaded modified MIL-101 metal-organic framework material described in step S1 to the sodium alginate solution, then add 1 mL of Tween 80, stir for 20 min, and then slowly add it to 100 mL of a 3% calcium chloride solution. Crosslink at room temperature for 30 min, then filter, wash, and dry. The surface of the drug-loaded modified MIL-101 metal-organic framework material is encapsulated with a gel film formed by crosslinking sodium alginate and calcium chloride, which not only enhances the protection of ginsenosides, reduces the adverse effects of gastric juice, improves the utilization rate in the intestine, but also improves the mechanical strength, reduces the physical damage of the framework material caused by gastrointestinal peristalsis, thereby avoiding the sudden release phenomenon of the active ingredient and ensuring the effective release of ginsenosides, and obtaining a drug-loaded MIL-101 metal-organic framework matrix material;

[0078] S3. Disperse the drug-loaded MIL-101 metal-organic framework matrix material described in step S2 in 100 mL of deionized water, and at the same time disperse the chitosan-coated drug-loaded porous silica composite nanoparticles in 100 mL of deionized water. Then mix and stir the two, and carry out a crosslinking reaction at room temperature for 1 h. Filter and freeze-dry. Through the connection of sodium alginate and chitosan gel materials, the crosslinking load of chitosan-coated drug-loaded porous silica composite nanoparticles on the surface of the drug-loaded MIL-101 metal-organic framework matrix material is realized. The gel material at the connection provides support for the composite nanoparticles and the framework matrix material with a flexible three-dimensional network, reducing the structural damage caused by gastrointestinal peristalsis and improving the drug-loading stability. Even if a single nanoparticle is damaged, the ginsenosides loaded on it can enter the gel connection material, effectively protecting the stability of ginsenosides in gastric juice. At the same time, the gel material connects the components to act synergistically at the intestine for effective release, thereby improving the bioavailability of ginsenosides and the therapeutic effectiveness of ginsenosides, and obtaining a high-utilization-rate ginseng active ingredient pharmaceutical preparation.

[0079] Comparative Example 1

[0080] This comparative example provides a high-utilization-rate ginseng active ingredient pharmaceutical preparation, which is different from Example 1 in that the chitosan-coated drug-loaded porous silica composite nanoparticles do not contain trichlorohexylsilane; trichlorohexylsilane is not added in step (1) of the preparation method of the chitosan-coated drug-loaded porous silica composite nanoparticles; the preparation method of the high-utilization-rate ginseng active ingredient pharmaceutical preparation is the same as that of Example 1.

[0081] Comparative Example 2

[0082] This comparative example provides a pharmaceutical preparation of ginseng active ingredients with high utilization rate, which is different from Example 1 in that the drug-loaded MIL-101 metal-organic framework matrix material does not contain L-glutamic acid; the preparation method of chitosan-coated drug-loaded porous silica composite nanoparticles is the same as that in Example 1; L-glutamic acid is not added in step S1 of the preparation method of the pharmaceutical preparation of ginseng active ingredients with high utilization rate.

[0083] Comparative Example 3

[0084] This comparative example provides a pharmaceutical preparation of ginseng active ingredients with high utilization rate, which is different from Example 1 in that the pharmaceutical preparation of ginseng active ingredients with high utilization rate does not contain chitosan, sodium alginate and calcium chloride; the preparation method of chitosan-coated drug-loaded porous silica composite nanoparticles does not include step (3); the preparation method of the pharmaceutical preparation of ginseng active ingredients with high utilization rate does not include step S2.

[0085] Experimental Example 1

[0086] Drug loading experiment

[0087] Test samples: Pharmaceutical preparations of ginseng active ingredients with high utilization rate prepared in Examples 1-4 and Comparative Examples 1-3.

[0088] Test method: Weigh ginsenoside Re and Rb1 accurately and place them in 5 mL volumetric flasks respectively. Dissolve them with methanol and make up the volume, dilute to 5 mg / mL and 3.9 mg / mL respectively, and then dilute them into drug solutions of 0.2 - 1.0 mg / mL respectively. Analyze them according to the following chromatographic conditions:

[0089] Use a NanoChromCore-300 C18 chromatographic column (4.6 mm × 250 mm, 5 μm), mobile phase acetonitrile (A) - water (B), gradient elution: 0 - 26 min, 19% → 22% A; 26 - 56 min, 22% → 31% A; 56 - 80 min, 31% → 34% A, column temperature 30 °C, volume flow rate 1.3 mL·min -1 , detection wavelength 203 nm, injection volume 10 μL, the regression equation of ginsenoside Re is Y = 31.374X + 0.0223, r = 0.9999, the best linear range is 0.0156 - 0.0390 mg / mL, the regression equation of ginsenoside Rb1 is Y = 22.861X - 0.0096, r = 1.000, the best linear range is 0.0458 - 1.144 mg / mL;

[0090] Weigh 2 g of the test sample and dissolve it in 10 mL of methanol solution. Sonicate for 1 h, let it stand until room temperature, weigh it, and then make up the lost weight with methanol. Filter it through a 0.22-μm microporous filter membrane. Take 1 mL of the supernatant and dilute it to 50 mL in a volumetric flask. Analyze it according to the above chromatographic conditions. Obtain the mass concentrations of ginsenoside Re and Rb1 according to the regression equation, and then calculate the total drug loading amount (%).

[0091] Figure 3 It is the graph of the drug loading results of Examples 1-4 and Comparative Examples 1-3; as shown in the figure, the drug loading amounts of Examples 1-4 are 45-52%, indicating a relatively large drug loading amount; the drug loading amounts of Comparative Examples 1-3 are 27-36%, indicating a relatively small drug loading amount; the chitosan-coated drug-loaded porous silica composite nanoparticles in Comparative Example 1 do not contain trichlorohexylsilane, which cannot optimize the pore structure of silica and cannot improve the hydrophobicity of the silica surface by modification, which is not conducive to loading lipophilic active ingredients, thus reducing the loading of ginsenosides and resulting in a relatively small drug loading amount; the drug-loaded MIL-101 metal-organic framework matrix material in Comparative Example 2 does not contain L-glutamic acid, which cannot improve the encapsulation of poorly soluble components by the modification of L-glutamic acid on MIL-101 metal-organic framework, and is not conducive to the loading of the lipophilic part of ginsenosides, resulting in a relatively small drug loading amount; the high-utilization-rate ginseng active ingredient pharmaceutical preparation in Comparative Example 3 does not contain chitosan, sodium alginate and calcium chloride, which can neither form separate encapsulation of the drug-loaded porous silica composite nanoparticles and the drug-loaded MIL-101 metal-organic framework matrix material, nor connect the two by cross-linking of the gel material, which is not conducive to the encapsulation and loading of ginsenosides as a whole and individually, resulting in a relatively small drug loading amount.

[0092] Experimental Example 2

[0093] Stability experiment

[0094] Test samples: The high-utilization-rate ginseng active ingredient pharmaceutical preparations prepared in Examples 1-4 and Comparative Examples 1-3.

[0095] Test method: Preparation of simulated gastric digestive fluid: Add pepsin at 3.2 mg / mL to a mixed solution containing 2 mg / mL NaCl and 7 mL / L HCl, and adjust its pH to 2.0 for later use; Add 5 g of the test sample to 9.9 mL of the simulated gastric digestive fluid, and place it in a water bath at 37 °C and 100 r / min for shaking and stirring for 2 h. After gastric digestion, adjust the pH value of the mixed solution to 7.0 with 0.25 mol / L NaOH, and place the mixed solution on ice to reduce the enzyme activity. Then centrifuge at 3000 rpm for 10 min, collect the supernatant, wash the precipitate with methanol solution and centrifuge 2 times, combine the supernatants, concentrate with a rotary evaporator, dissolve with methanol solution, make up the volume to 2 mL, filter through a 0.22 μm filter membrane, and finally perform detection according to the operation in Experimental Example 1 to obtain the contents (%) of ginsenoside Re and ginsenoside Rb1.

[0096] Figure 4 It is a graph of the ginsenoside content results of Examples 1-4 and Comparative Examples 1-3; As shown in the figure, the contents of ginsenoside Re and ginsenoside Rb1 in Examples 1-4 are 22-25% and 20-23% respectively, indicating that reducing degradation in the stomach helps to improve the utilization rate; The contents of ginsenoside Re and ginsenoside Rb1 in Comparative Examples 1-3 are 14-18% and 11-15% respectively, indicating that they cannot effectively resist degradation in the stomach and the utilization rate is average; The chitosan-coated drug-loaded porous silica composite nanoparticles in Comparative Example 1 do not contain trichloromethylsilane, and cannot improve the protection of porous silica on ginsenosides through hydrophobic modification, increasing the hydrolysis and decomposition of ginsenosides in the stomach and also reducing the delivery to the intestine, resulting in the inability to effectively resist degradation in the stomach and an average utilization rate; The drug-loaded MIL-101 metal-organic framework matrix material in Comparative Example 2 does not contain L-glutamic acid, and cannot play the modification of the MIL-101 metal-organic framework material by L-glutamic acid, reducing the stability of ginsenosides in the gastric acid environment and being unfavorable for maintaining the activity and content of ginsenosides in the stomach, resulting in the inability to effectively resist degradation in the stomach and an average utilization rate; The high-utilization-rate ginseng active ingredient pharmaceutical preparation in Comparative Example 3 does not contain chitosan, sodium alginate and calcium chloride, and can neither form a separate encapsulation of the drug-loaded porous silica composite nanoparticles and the drug-loaded MIL-101 metal-organic framework matrix material, nor connect the two through the cross-linking of the gel material, increasing the degradation and damage of the whole and individuals by gastric digestive fluid and gastrointestinal peristalsis, causing the loaded ginsenosides to be released in the stomach and being unfavorable for delivering them to the intestinal part, resulting in the inability to effectively resist degradation in the stomach and an average utilization rate.

[0097] The above experimental results show that the drug loading capacity and the effect of resisting gastric degradation of Examples 1-4 of the present invention are significantly better than those of the samples of Comparative Examples 1-3. Among them, Example 1 using the drug-loaded nanoparticles with both magnetic and reactive oxygen dual responsiveness and the modified carbon nanotube hydrogel carrier has a higher drug loading capacity and a better effect of resisting gastric degradation. The chitosan-coated drug-loaded porous silica composite nanoparticles are loaded on the surface of the drug-loaded MIL-101 metal-organic framework matrix material, and crosslinked and connected with the sodium alginate and chitosan gel materials, forming both a separate package and connecting the framework matrix material and the composite nanoparticles as a whole, improving the encapsulation and drug loading capacity, thereby increasing the loading and loading stability of ginsenosides, effectively reducing the adverse effects of gastric juice and gastrointestinal peristalsis on the activity of ginsenosides, and significantly enhancing the release and absorption of ginsenosides in the intestine.

[0098] Although the embodiments of the present invention have been shown and described, those of ordinary skill in the art can understand that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention.

[0099] The present invention and its embodiments have been described above. Such description is not restrictive. What is shown in the drawings is only one of the embodiments of the present invention, and the actual application is not limited thereto. Generally speaking, if those of ordinary skill in the art are inspired by it and design similar ways and embodiments to this technical solution without creative work without departing from the purpose of the present invention, they should all belong to the protection scope of the present invention.

Claims

1. A pharmaceutical preparation of ginseng active ingredients with high utilization rate, characterized in that: The high-utilization ginseng active ingredient pharmaceutical preparation is a freeze-dried powder of nanoparticles, comprising the following components in parts by weight: 50-60 parts of chitosan-coated drug-loaded porous silica composite nanoparticles, and 20-30 parts of drug-loaded MIL-101 metal-organic framework matrix material; the chitosan-coated drug-loaded porous silica composite nanoparticles comprise the following components in parts by weight: 30-40 parts of silica, 30-50 parts of trichlorohexylsilane, 10-20 parts of ginsenoside I, and 10-20 parts of chitosan; the drug-loaded MIL-101 metal-organic framework matrix material comprises the following components in parts by weight: 30-40 parts of chromium(III) nitrate nonahydrate, 1-3 parts of L-glutamic acid, 10-20 parts of ginsenoside II, 10-15 parts of sodium alginate, and 20-30 parts of calcium chloride.

2. A preparation method of the high-utilization-rate ginseng active ingredient pharmaceutical preparation according to claim 1, characterized in that: Specifically, it includes the following steps: S1. Add 3.0-4.0 g of chromium(III) nitrate nonahydrate, 1.6 g of terephthalic acid, 0.5 g of hydrofluoric acid, 50.0 g of deionized water, and 1.0-2.0 g of ginsenoside II into the inner liner of a 100 mL autoclave. In the composition of ginsenoside II, the weight ratio of ginsenoside Re to ginsenoside Rb1 is 1-2:

1. Stir at room temperature for 20-30 min, then add L-glutamic acid and stir for 10-20 min. Then place it in an oven and react at 200-210 °C for 8-10 h. Cool to room temperature, then centrifuge. Wash the product successively with N,N-dimethylformamide and ethanol, and perform supercritical drying to obtain the drug-loaded modified MIL-101 metal-organic framework material. S2. Add sodium alginate into 100 mL of deionized water and stir in a water bath at 40-50 °C for 2-3 h to obtain a sodium alginate solution for use. Then add the drug-loaded modified MIL-101 metal-organic framework material obtained in step S1 into the sodium alginate solution. Then add 1 mL of Tween 80 and stir for 20-30 min. Then slowly add it into 100 mL of a calcium chloride solution with a mass fraction of 2-3%, crosslink at room temperature for 30 min, then filter, wash, and dry to obtain the drug-loaded MIL-101 metal-organic framework matrix material. S3. Disperse the drug-loaded MIL-101 metal-organic framework matrix material obtained in step S2 in 100 mL of deionized water, and at the same time disperse the chitosan-coated drug-loaded porous silica composite nanoparticles in 100 mL of deionized water. Then mix and stir the two, perform a crosslinking reaction at room temperature for 1-2 h, filter, and perform freeze-drying to obtain the high-utilization ginseng active ingredient pharmaceutical preparation.

3. The preparation method of the pharmaceutical preparation of ginseng active ingredients with high utilization rate according to claim 2, characterized in that: In step S1, the addition amount of L-glutamic acid is 0.1-0.3 g.

4. The preparation method of the pharmaceutical preparation of ginseng active ingredients with high utilization rate according to claim 3, characterized in that: In step S2, the addition amount of sodium alginate is 1.0-1.5 g.

5. The preparation method of the highly utilized pharmaceutical preparation of ginseng active ingredients according to claim 4, characterized in that: The preparation method of the chitosan-coated drug-loaded porous silica composite nanoparticles specifically includes the following steps: (1) Mix 45 mL of absolute ethanol, 1 mL of ammonia water, 0.15 g of cetyltrimethylammonium bromide, and 0.02 mL of β-mercaptoethanol evenly. While stirring, slowly drop 3 mL of tetraethyl orthosilicate into the mixture. Carry out constant-temperature stirring reaction at 25 °C for 3 - 4 h, centrifuge, collect the precipitate for freeze-drying. Weigh 0.3 - 0.4 g of the obtained silica and add it to a beaker containing 20 mL of n-hexane, stir to disperse, then add trichlorohexylsilane liquid, seal the beaker, carry out magnetic stirring at 25 °C for 3 - 4 h, and keep the operation in the dark during the stirring process. After the reaction, centrifuge, wash the precipitate with n-hexane for 2 - 3 times, and then carry out freeze-drying to obtain modified porous silica; (2) Dissolve 0.1 - 0.2 g of ginsenoside I in 80 mL of ethanol with a mass fraction of 70 - 80%, then add the modified porous silica described in step (1), stir for 20 - 30 min, let it stand at 4 °C for 1 - 2 h, centrifuge, wash the product with deionized water for 2 - 3 times, and then carry out freeze-drying to obtain drug-loaded modified porous silica nanoparticles; (3) Dissolve 0.1 - 0.2 g of chitosan in 40 mL of acetic acid solution with a mass fraction of 1% to obtain a chitosan solution. Then mix the drug-loaded modified porous silica nanoparticles described in step (2) and the chitosan solution, stir for 20 - 30 min as component I. Add 80 mL of Tween 80 and 40 mL of absolute ethanol to 500 mL of n-hexane, and carry out magnetic stirring to dissolve them fully as component II. Then add component I to component II, stir for 2 min to obtain an emulsion. Then add 10 - 15 mL of aqueous sodium tripolyphosphate solution with a mass fraction of 0.8%, stir at room temperature for 20 - 30 min, with a stirring speed of 600 - 800 rpm, let it stand for 30 min. After the emulsion is layered, remove the supernatant, continue to add 100 - 200 mL of ethanol, carry out magnetic stirring for 20 - 30 min, place it at 4 °C overnight, finally centrifuge, wash the precipitate with ethanol with a mass fraction of 75% for 3 - 5 times and then carry out freeze-drying to obtain chitosan-coated drug-loaded porous silica composite nanoparticles.

6. The preparation method of the highly utilized ginseng active ingredient pharmaceutical preparation according to claim 5, characterized in that: In step (1), the addition amount of trichlorohexylsilane is 0.3 - 0.5 mL.

7. The preparation method of the high-utilization-rate ginseng active ingredient pharmaceutical preparation according to claim 6, characterized in that: In step (2), ginsenoside I includes ginsenoside Re and ginsenoside Rb1, and the weight ratio of ginsenoside Re to ginsenoside Rb1 is 1:1 - 2.

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