Chinese herbal medicine component for relieving neurodegenerative diseases and preparation method thereof

Abstract

The invention relates to the technical field of medicines, in particular to a Chinese herbal medicine component for relieving neurodegenerative diseases and a preparation method thereof.The Chinese herbal medicine component is prepared from Chinese herbal medicine powder, modified chitosan, modified sodium alginate, gluconic acid-delta-lactone powder, hydrophobic fumed silica and magnesium stearate; modified chitosan and modified sodium alginate form orthoester bonds, a three-dimensional network structure is constructed to wrap chicoric acid molecules, and moisture and polyvinylpyrrolidone molecules are prevented from damaging the activity of chicoric acid during storage; under the sublingual condition, saliva permeates to trigger hydrolysis of gluconic acid-delta-lactone, create a local subacid environment and catalyze hydrolysis of acid-sensitive orthoester bonds, so that a network structure is rapidly dissociated, chicoric acid is released, and the bioavailability of the chicoric acid is effectively improved; hydrophobic fumed silica and magnesium stearate are responsible for protecting gluconic acid-delta-lactone and preventing gluconic acid-delta-lactone from absorbing moisture during storage.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical technology, in particular to a Chinese herbal medicine component for relieving neurodegenerative diseases and a preparation method thereof. BACKGROUND

[0002] Chicoric acid, as a natural active ingredient extracted from chicory, dandelion and other plants, has been considered as a potential drug candidate for intervening neurodegenerative diseases in recent years due to its significant anti-inflammatory, antioxidant and neuroprotective effects. However, the chemical instability of chicoric acid ester bond makes it easy to hydrolyze and inactivate during oral administration, and it also faces a serious liver first-pass effect, resulting in extremely low bioavailability and difficulty in achieving effective clinical treatment. To avoid the first-pass effect and achieve rapid onset, sublingual administration is considered as an ideal solution. Sublingual tablets can rapidly disintegrate in saliva, allowing the drug to be directly absorbed through the rich blood vessels of the sublingual mucosa, greatly improving the bioavailability and onset speed of the drug.

[0003] Polyvinylpyrrolidone is one of the most commonly used high-quality excipients for preparing sublingual tablets due to its excellent performance. However, the strong hygroscopicity of polyvinylpyrrolidone and the polar groups in its molecular structure can catalyze the hydrolysis of chicoric acid ester bond, accelerating the degradation of active ingredients during the preparation and storage of the preparation, resulting in loss of drug efficacy. Therefore, the core of current research is how to isolate the destructive effect of polyvinylpyrrolidone on chicoric acid ester bond in an efficient sublingual delivery system and improve the bioavailability of chicoric acid. SUMMARY

[0004] (1) Technical problem to be solved The purpose of the present application is to provide a Chinese herbal medicine component for relieving neurodegenerative diseases and a preparation method thereof, and to improve the bioavailability of chicoric acid.

[0005] (2) Technical solution To achieve the above-mentioned purpose, on the one hand, the present application provides a Chinese herbal medicine component for relieving neurodegenerative diseases, which comprises the following components in parts by weight: 80-85 parts of Chinese herbal medicine powder, 15-20 parts of modified chitosan, 15-20 parts of modified sodium alginate, 8-10 parts of gluconic acid-delta-lactone powder, 0.3-0.6 parts of hydrophobic fumed silica, and 0.2-0.3 parts of magnesium stearate. Among them, the Chinese herbal medicine powder comprises chicory root powder and dandelion powder, and the mass ratio of the chicory root powder to the dandelion powder is 5:3; the modified chitosan and the modified sodium alginate form an orthoester bond.

[0006] Further, the components further include the following components in the weight parts: 40-45 parts of microcrystalline cellulose, 25-30 parts of mannitol, 15-20 parts of a binder, 15-20 parts of a super disintegrant, 1.0-2.0 parts of a lubricant, 1.0-1.5 parts of a sweetener, and 0.2-0.5 parts of a flavoring agent.

[0007] Further, the binder includes polyvinylpyrrolidone K-30; the super disintegrant includes cross-linked polyplasdone; the lubricant includes fumaric acid; the sweetener includes sucralose; and the flavoring agent includes menthol.

[0008] Further, the preparation method of the modified chitosan includes the following steps: S11. Disperse chitosan in anhydrous dimethyl sulfoxide, stir vigorously under nitrogen protection, add catalyst p-toluenesulfonic acid, place in an ice water bath, and drop trifluoroacetaldehyde ethyl hemiacetal. Remove the ice bath, warm to room temperature, and continue stirring under nitrogen protection. After the reaction is completed, pour into an ice-ethanol / acetone mixed solvent, centrifuge to collect the precipitate, wash the precipitate with fresh ethanol, and dry in a vacuum drying oven until the weight is constant to obtain a first compound; S12. Dissolve the first compound in anhydrous methanol containing 2% triethylamine, drop lauric anhydride methanol solution under stirring, react at room temperature under nitrogen protection, pour into a large amount of ice acetone to precipitate after the reaction is completed, centrifuge to collect the precipitate, and wash the precipitate with acetone and ethanol in sequence. Dry in a vacuum drying oven until the weight is constant, and pass through a 100-mesh sieve to obtain the modified chitosan.

[0009] Further, the volume ratio of ice ethanol to acetone in the ice ethanol / acetone mixed solvent is 1:1.

[0010] Further, the preparation method of the modified sodium alginate includes the following steps: S21. Disperse sodium alginate in isopropyl alcohol, add 50% NaOH solution, alkalize, and then drop a mixture obtained by uniformly mixing epichlorohydrin and glycerol. Stir vigorously to react, neutralize to pH = 7.0 with dilute hydrochloric acid after the reaction is completed, dialyze with deionized water, and freeze-dry to obtain a second compound; S22. Dissolve the second compound in 0.1 mol / L NaOH solution, add methoxy polyethylene glycol propylene oxide, stir until completely dissolved, and react at 60°C. Neutralize to pH = 7.0 with dilute hydrochloric acid after the reaction is completed, dialyze with deionized water, freeze-dry, and pass through a 100-mesh sieve to obtain the modified sodium alginate.

[0011] Based on the same inventive concept, in a second aspect, the present application also provides a preparation method of a Chinese herbal medicine component for relieving neurodegenerative diseases, which is applied to the preparation of the Chinese herbal medicine component for relieving neurodegenerative diseases, and the preparation method includes: S31. Put gluconic acid-delta-lactone powder into a high-speed shearing mixer, slowly add hydrophobic fumed silica under low-speed stirring, mix, keep stirring, slowly add magnesium stearate, continue mixing, to obtain a complex; S32. Disperse modified chitosan and modified sodium alginate in anhydrous ethanol, add Chinese herbal medicine powder, uniformly mix, dropwise add dilute hydrochloric acid to catalyze, initiate the cross-linking reaction of the original acid ester bond, freeze-dry, and then ultrafine grind and pass through a 100-mesh sieve to obtain hydrogel particles; S33. Dissolve polyvinylpyrrolidone K-30 in anhydrous ethanol to prepare a 15% w / w adhesive solution, mix the hydrogel particles, microcrystalline cellulose and mannitol in a dry granulator, spray the adhesive solution, granulate, and then after low-temperature drying of the obtained wet granules, size the dry granules to obtain dry granules; S34. Transfer the dry granules to a three-dimensional motion mixer, add the complex and cross-linked povidone, mix, sieve fumaric acid, sucralose and menthol, mix, and press to obtain a Chinese herbal medicine for relieving neurodegenerative diseases.

[0012] During storage, the original acid ester bond formed by the condensation reaction between the original acid ester precursor groups introduced by the modified chitosan and the terminal primary hydroxyl groups of the glycerol groups grafted by the modified sodium alginate cross-links the two modified substances to construct a stable three-dimensional network structure, and the chicoric acid molecules are embedded therein. This network effectively isolates the contact between the environment and the polyvinylpyrrolidone molecules and the chicoric acid ester bond, and provides excellent protection for chicoric acid. When the sublingual tablet is placed in the oral environment, saliva penetration triggers the coexisting gluconic acid-delta-lactone hydrolysis, creating a slightly acidic environment locally, catalyzing the specific hydrolysis of the acid-sensitive original acid ester bond, causing the entire protection network to rapidly dissociate, releasing chicoric acid, and effectively improving the bioavailability of chicoric acid. The lauryl group of the modified chitosan acts as a penetration enhancer, which can temporarily and reversibly interact with the mucosal cell membrane, increase the permeability between cells; at the same time, the polyethylene glycol long chain of the modified sodium alginate binds to the mucin of the mucosa through hydrogen bonds, prolonging the residence time of the drug in the absorption site, preventing the sublingual drug from being swallowed, and both of them synergistically promote the sublingual mucosal absorption of chicoric acid, further improving the bioavailability of chicoric acid.

[0013] Glucaric acid-delta-lactone powder is extremely sensitive to moisture during storage, even with moisture-proof packaging, trace amounts of environmental moisture can penetrate into the film, leading to glucaric acid-delta-lactone to occur slow hydrolysis in advance. This not only consumes glucaric acid-delta-lactone, but more seriously, the glucaric acid generated in advance attacks and hydrolyzes the original acid ester bond during storage, resulting in the entire intelligent delivery system to be invalid before reaching the patient's sublingual, and the drug stability is destroyed. Hydrophobic fumed silica has a large specific surface area and strong adsorption properties, which is tightly adsorbed on the surface of glucaric acid-delta-lactone particles by van der Waals force, forming a primary porous and hydrophobic coating layer, effectively isolating the water molecules in the environment from contacting with glucaric acid-delta-lactone, thereby inhibiting its moisture absorption and pre-hydrolysis. Magnesium stearate can effectively fill the micro voids between the hydrophobic fumed silica nanoparticles, block the water vapor penetration channel, and further strengthen the hydrophobic properties of the entire barrier layer through the hydrophobic effect of its long alkyl chain. The two cooperate to form a dense and stable physical barrier on the surface of glucaric acid-delta-lactone particles, which reliably protects the chemical integrity of glucaric acid-delta-lactone during storage, and when the sublingual tablet is placed in saliva, a large amount of liquid can quickly destroy this barrier, so that glucaric acid-delta-lactone can be dissolved and released to exert its acidification function.

[0014] (3) Beneficial effects Compared with the prior art, the beneficial effects of the present application are: 1. The present application forms an original acid ester bond by modifying chitosan and modified sodium alginate, constructs a stable three-dimensional network structure, and embeds chrysanthemic acid molecules in it, which effectively isolates the water in the environment and the contact between polyvinylpyrrolidone molecules and chrysanthemic acid ester bonds during storage, providing excellent protection for chrysanthemic acid. When the sublingual tablet is placed in the oral environment, the saliva penetration triggers the hydrolysis of coexisting glucaric acid-delta-lactone, creating a slightly acidic environment locally, catalyzing the specific hydrolysis of the acid-sensitive original acid ester bond, causing the entire protection network to rapidly dissociate, releasing chrysanthemic acid, and effectively improving the bioavailability of chrysanthemic acid.

[0015] 2. In the present application, hydrophobic fumed silica is tightly adsorbed on the surface of glucaric acid-delta-lactone particles by van der Waals force, forming a primary porous and hydrophobic coating layer, effectively isolating the water molecules in the environment from contacting with glucaric acid-delta-lactone, thereby inhibiting its moisture absorption and pre-hydrolysis.

[0016] 3. In the present application, magnesium stearate can effectively fill the micro voids between the hydrophobic fumed silica nanoparticles, block the water vapor penetration channel, and further strengthen the hydrophobic properties of the entire barrier layer through the hydrophobic effect of its long alkyl chain, further enhancing the protection of hydrophobic fumed silica on glucaric acid-delta-lactone. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 A preparation flow chart of a Chinese herbal medicine component for relieving neurodegenerative diseases. DETAILED DESCRIPTION

[0018] In order to make the objectives, technical solutions and advantages of the present application clearer, the present application will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and should not be used to limit the present application, that is, the described embodiments are only a part of the embodiments of the present application, but not all the embodiments. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without creative work fall within the scope of the present application.

[0019] Embodiment 1: The present embodiment discloses a Chinese herbal medicine component for relieving neurodegenerative diseases, comprising the following components in parts by weight: 80 parts of Chinese herbal medicine powder, 15 parts of modified chitosan, 15 parts of modified sodium alginate, 8 parts of gluconic acid-delta-lactone powder, 0.4 parts of hydrophobic fumed silica, and 0.24 parts of magnesium stearate. The Chinese herbal medicine powder comprises chicory root powder and dandelion powder, and the mass ratio of the chicory root powder to the dandelion powder is 5:3; the modified chitosan and the modified sodium alginate form an orthoester bond.

[0020] It further comprises the following components in parts by weight: 45 parts of microcrystalline cellulose, 30 parts of mannitol, 18 parts of a binder, 16 parts of a super-disintegrant, 1.5 parts of a lubricant, 1.2 parts of a sweetener, and 0.4 parts of a flavoring agent.

[0021] The binder comprises polyvinylpyrrolidone K-30; the super-disintegrant comprises cross-linked povidone; the lubricant comprises fumaric acid; the sweetener comprises sucralose; and the flavoring agent comprises menthol.

[0022] The preparation method of the modified chitosan comprises the following steps: S11. Disperse 1 g of chitosan in 100 mL of anhydrous dimethyl sulfoxide, stir vigorously under nitrogen protection, add 50 mg of a catalyst p-toluenesulfonic acid, cool to 0-4℃ in an ice water bath, slowly drop 5 mL of trifluoroacetaldehyde ethyl hemiacetal using a constant pressure dropping funnel, remove the ice bath, slowly warm to room temperature, and continue to stir for 48 h under nitrogen protection. After the reaction is completed, slowly pour the mixture into a large amount of a mixed solvent of ethyl acetate / acetone to precipitate the product, centrifuge to collect the precipitate, and wash the precipitate with fresh ethyl acetate three times. Dry in a vacuum drying oven at 40℃ until the weight is constant to obtain a first compound; S12. Dissolve 1 g of the first compound in 50 mL of anhydrous methanol containing 2% (v / v) triethylamine, slowly add a methanolic solution of lauric anhydride dropwise under stirring, react at room temperature for 24 h under nitrogen protection, after the reaction is completed, pour the reaction solution into a large amount of ice acetone to precipitate, centrifuge to collect the precipitate, and wash the precipitate with acetone and ethyl ether successively three times, dry in a vacuum drying box at 40°C until the weight is constant, pass through a 100-mesh sieve, and obtain modified chitosan.

[0023] The volume ratio of ethyl ether to acetone in the ice ethyl ether / acetone mixed solvent is 1:1.

[0024] The preparation method of the modified sodium alginate comprises the following steps: S21. Disperse 2 g of sodium alginate in 50 mL of isopropanol, slowly add 10 mL of a 50% (w / v) NaOH solution, alkalinize at 60°C for 1 h, slowly add a mixture of 5 mL of epichlorohydrin and 2 mL of glycerol, and react at 65°C for 6-8 h under vigorous stirring, after the reaction is completed, neutralize to pH = 7.0 with dilute hydrochloric acid, dialyze with deionized water for 3 days, and freeze-dry to obtain a second compound; S22. Dissolve 1 g of the second compound in 50 mL of a 0.1 mol / L NaOH solution, add 2 g of methoxypolyethylene glycol propylene oxide, stir until completely dissolved, and react at 60°C for 24 h under stirring, after the reaction is completed, neutralize to pH = 7.0 with dilute hydrochloric acid, dialyze with deionized water for 4-5 days, and freeze-dry to pass through a 100-mesh sieve to obtain modified sodium alginate.

[0025] The preparation method of the Chinese herbal medicine component for relieving neurodegenerative diseases comprises the following steps: S31. Place gluconic acid-delta-lactone powder in a high-speed shearing mixer, slowly add hydrophobic fumed silica under low-speed stirring, mix for 5 min, keep stirring, slowly add magnesium stearate, and continue to mix for 10 min to obtain a compound; S32. Preliminarily disperse the modified chitosan and the modified sodium alginate in anhydrous ethanol, add Chinese herbal medicine powder, uniformly mix by using a high-speed shearing homogenizer, add dilute hydrochloric acid dropwise to catalyze, initiate crosslinking reaction of the ortho ester bond, freeze-dry, and super-micro powderize to pass through a 100-mesh sieve to obtain hydrogel particles; S33. Dissolve polyvinylpyrrolidone K-30 in anhydrous ethanol to prepare a 15% w / w adhesive solution, mix the hydrogel particles, microcrystalline cellulose, and mannitol in a dry granulation machine, spray the adhesive solution, granulate, and after low-temperature drying of the obtained wet particles at 40°C, size the dry particles (20-mesh sieve) to obtain dry particles. S34. The dry granules are transferred to a three-dimensional motion mixer, the complexing agent and the cross-linked povidone are added and mixed for 10 minutes, the fumaric acid, sucralose and menthol are sieved through a 60-mesh sieve and added, mixed for 5 minutes, and tableted to obtain a Chinese herbal medicine for relieving neurodegenerative diseases. The preparation process is shown in Figure 1 .

[0026] Example 2: This example discloses a Chinese herbal medicine component for relieving neurodegenerative diseases, which comprises the following components in parts by weight: 80 parts of Chinese herbal medicine powder, 15 parts of modified chitosan, 15 parts of modified sodium alginate, 8 parts of glucono-delta-lactone powder, 0.3 parts of hydrophobic fumed silica, and 0.2 parts of magnesium stearate; wherein the Chinese herbal medicine powder comprises chicory root powder and dandelion powder, and the mass ratio of the chicory root powder to the dandelion powder is 5:3; the modified chitosan and the modified sodium alginate form an ortho ester bond.

[0027] It further comprises the following components in parts by weight: 40 parts of microcrystalline cellulose, 25 parts of mannitol, 15 parts of a binder, 15 parts of a super-disintegrating agent, 1.0 part of a lubricant, 1.0 part of a sweetening agent, and 0.2 part of a flavoring agent.

[0028] The other components and the preparation method are the same as those in Example 1.

[0029] Example 3: This example discloses a Chinese herbal medicine component for relieving neurodegenerative diseases, which comprises the following components in parts by weight: 85 parts of Chinese herbal medicine powder, 20 parts of modified chitosan, 20 parts of modified sodium alginate, 10 parts of glucono-delta-lactone powder, 0.6 parts of hydrophobic fumed silica, and 0.3 parts of magnesium stearate; wherein the Chinese herbal medicine powder comprises chicory root powder and dandelion powder, and the mass ratio of the chicory root powder to the dandelion powder is 5:3; the modified chitosan and the modified sodium alginate form an ortho ester bond.

[0030] It further comprises the following components in parts by weight: 45 parts of microcrystalline cellulose, 30 parts of mannitol, 20 parts of a binder, 20 parts of a super-disintegrating agent, 2.0 parts of a lubricant, 1.5 parts of a sweetening agent, and 0.5 part of a flavoring agent.

[0031] The other components and the preparation method are the same as those in Example 1.

[0032] Example 4: This example discloses a Chinese herbal medicine component for relieving neurodegenerative diseases, which comprises the following components in parts by weight: 82.5 parts of Chinese herbal medicine powder, 17.5 parts of modified chitosan, 17.5 parts of modified sodium alginate, 9 parts of glucono-delta-lactone powder, 0.45 parts of hydrophobic fumed silica, and 0.25 parts of magnesium stearate; wherein the Chinese herbal medicine powder comprises chicory root powder and dandelion powder, and the mass ratio of the chicory root powder to the dandelion powder is 5:3; the modified chitosan and the modified sodium alginate form an ortho ester bond.

[0033] Also included are the following components in parts by weight: 42.5 parts microcrystalline cellulose, 27.5 parts mannitol, 17.5 parts binder, 17.5 parts superdisintegrant, 1.5 parts lubricant, 1.25 parts sweetener, 0.35 parts flavoring agent.

[0034] The other components and the preparation method are the same as in Example 1.

[0035] Comparative Example 1: Based on Example 1, the difference between Example 1 and this comparative example is that the modified chitosan in this comparative example does not introduce an orthoester precursor.

[0036] The preparation method of the modified chitosan includes the following steps: S11. 1 g of chitosan is dissolved in 50 mL of anhydrous methanol containing 2% (v / v) triethylamine, and a methanol solution of lauric anhydride is slowly added dropwise under stirring, and the reaction is carried out at room temperature for 24 h under nitrogen protection. After the reaction is completed, the reaction solution is poured into a large amount of ice acetone to precipitate, the precipitate is collected by centrifugation, and the precipitate is washed with acetone and ethyl ether three times in turn, and dried to constant weight in a vacuum drying box at 40°C, and sieved through a 100-mesh sieve to obtain the modified chitosan.

[0037] The other components and the preparation method are the same as in Example 1.

[0038] Comparative Example 2: Based on Example 1, the difference between Example 1 and this comparative example is that the modified chitosan in this comparative example does not graft lauroyl groups.

[0039] The preparation method of the modified chitosan includes the following steps: S11. 1 g of chitosan is dispersed in 100 mL of anhydrous dimethyl sulfoxide, and 50 mg of the catalyst p-toluenesulfonic acid is added under vigorous stirring and nitrogen protection, and the mixture is cooled to 0-4°C in an ice water bath, and 5 mL of trifluoroacetaldehyde ethyl hemiacetal is slowly added dropwise using a constant-pressure dropping funnel, the ice bath is removed, the temperature is slowly raised to room temperature, and the reaction is continuously stirred for 48 h under nitrogen protection. After the reaction is completed, the mixture is slowly poured into a large amount of ice ethyl ether / acetone mixed solvent to precipitate the product, the precipitate is collected by centrifugation, and the precipitate is washed with fresh ethyl ether three times, and dried to constant weight in a vacuum drying box at 40°C, and sieved through a 100-mesh sieve to obtain the modified chitosan.

[0040] The other components and the preparation method are the same as in Example 1.

[0041] Comparative Example 3: Based on Example 1, the difference between Example 1 and this comparative example is that the modified sodium alginate in this comparative example does not graft glycerol groups.

[0042] The preparation method of the modified sodium alginate includes the following steps: S21. 1 g of sodium alginate was dissolved in 50 mL of 0.1 mol / L NaOH solution, 2 g of methoxypolyethylene glycol propylene oxide was added, stirred until completely dissolved, and stirred at 60°C for 24 h. After the reaction was completed, it was neutralized to pH = 7.0 with dilute hydrochloric acid, dialyzed with deionized water for 4-5 days, freeze-dried, and passed through a 100 mesh sieve to obtain modified sodium alginate.

[0043] The other components and the preparation method were the same as in Example 1.

[0044] Comparative Example 4: Based on Example 1, the difference from Example 1 is that the modified sodium alginate in this comparative example is not grafted with polyethylene glycol.

[0045] The preparation method of the modified sodium alginate includes the following steps: S21. 2 g of sodium alginate was dispersed in 50 mL of isopropanol, 10 mL of 50% (w / v) NaOH solution was slowly added, and the alkalization reaction was carried out at 60°C for 1 h. Then a mixture obtained by uniformly mixing 5 mL of epoxy chloropropane and 2 mL of glycerol was slowly added dropwise, and the reaction was carried out at 65°C with vigorous stirring for 6-8 h. After the reaction was completed, it was neutralized to pH = 7.0 with dilute hydrochloric acid, dialyzed with deionized water for 3 days, freeze-dried, and passed through a 100 mesh sieve to obtain modified sodium alginate.

[0046] Comparative Example 5: Based on Example 1, the difference from Example 1 is that this comparative example does not include modified chitosan.

[0047] Comparative Example 6: Based on Example 1, the difference from Example 1 is that this comparative example does not include modified sodium alginate.

[0048] Comparative Example 7: Based on Example 1, the difference from Example 1 is that this comparative example does not include modified chitosan and modified sodium alginate.

[0049] Comparative Example 8: Based on Example 1, the difference from Example 1 is that this comparative example does not include hydrophobic fumed silica.

[0050] Comparative Example 9: Based on Example 1, the difference from Example 1 is that this comparative example does not include magnesium stearate.

[0051] Comparative Example 10: Based on Example 1, the difference from Example 1 is that this comparative example does not include hydrophobic fumed silica and magnesium stearate.

[0052] Comparative Example 11: Based on Example 1, the difference from Example 1 is that this comparative example does not include glucono-delta-lactone powder.

[0053] Comparative Example 12: Based on Example 1, different from Example 1 is that the comparative example does not include modified chitosan, modified sodium alginate, gluconic acid-delta-lactone powder, hydrophobic fumed silica and magnesium stearate.

[0054] Test Example 1: The Chinese herbal medicine sublingual tablets obtained in Examples 1-4 and Comparative Examples 1-7, 12 were taken, about 2 mg of solid sample was mixed with 100 mg of dry potassium bromide (KBr) powder in a corundum mortar, and was ground uniformly, and was pressed into a transparent wafer under a pressure of about 10 MPa using a tablet press; a Fourier transform infrared spectrometer was used to scan and detect the stretching vibration peak of the ester bond (C-O-C); the results are shown in Table 1.

[0055] Table 1: Detection of ester bond

[0056] Test Example 2: Each Chinese herbal medicine sublingual tablet obtained in Examples 1-4 and Comparative Examples 1-12 was accurately placed under the tongue of a rat (healthy adult SD rat, male, body weight 200±20 g), and swallowing was prevented, and about 0.3 mL of blood was collected from the orbital plexus at 0 h before administration and 5, 15, 30, 60, 120, 240, 360, 480 min after administration, and was placed in a heparin sodium anticoagulant tube, and was centrifuged to separate the plasma, and was stored at -80℃ for testing, and a blood concentration-time curve was obtained by high performance liquid chromatography-tandem mass spectrometry; the results are shown in Table 2.

[0057] Table 2: Detection of chicoric acid blood concentration

[0058] In combination with the results of Table 1, Table 2, it can be concluded that, compared with Comparative Examples 1, 3, 5, 6, 7, no original ester bond forms a protective network, and the chicoric acid has been destroyed by polyvinylpyrrolidone and moisture during preparation and storage, and no drug can be released; compared with Comparative Example 2, it can be concluded that the modified chitosan has no lauroyl group, the network can trigger release, but lacks a penetration enhancer, the drug permeation efficiency is reduced, resulting in reduced absorption speed and total amount; compared with Comparative Example 4, it can be concluded that the modified sodium alginate has no polyethylene glycol, can quickly release and efficiently absorb, but lacks a retention effect, the drug is easily removed by saliva or swallowed, resulting in shortened in vivo action time and reduced total absorption amount; compared with Comparative Example 8, it can be concluded that there is no hydrophobic fumed silica, the gluconic acid-δ-lactone may be partially pre-hydrolyzed, the stability is reduced, resulting in incomplete and untimely triggering, slow and insufficient drug release; compared with Comparative Example 9, it can be concluded that there is no magnesium stearate, the physical barrier is incomplete, and the effect is similar to that of Comparative Example 8; compared with Comparative Example 10, it can be concluded that there is no hydrophobic fumed silica and magnesium stearate, the gluconic acid-δ-lactone has poorer stability, and the triggering mechanism is severely ineffective; compared with Comparative Example 11, it can be concluded that there is no gluconic acid-δ-lactone powder, the core triggering mechanism is missing, the protective network cannot be opened in the sublingual environment, the drug is “locked” in the network, and cannot be released; compared with Comparative Example 12, it can be concluded that the ordinary sublingual tablet has no protection for chicoric acid, and the chicoric acid has been destroyed by polyvinylpyrrolidone and moisture during preparation and storage, and no drug can be released.

[0059] Test Example 3: The sublingual tablets of each Chinese herbal component obtained in Examples 1-4 were detected for appearance, content uniformity, disintegration time, and hardness according to the method of the Chinese Pharmacopoeia; the results are shown in Table 3.

[0060] Table 3: Basic performance detection of sublingual tablets

[0061] Test Example 4: The sublingual tablets of each Chinese herbal component obtained in Examples 1-4 were subjected to functional verification for relieving neurodegenerative diseases: male C57BL / 6 mice (sensitive to MPTP) aged 8-10 weeks were selected. A chronic MPTP-Probenecid model was used: intraperitoneal injection of MPTP (25 mg / kg) and Probencid (250 mg / kg) was performed twice a week for 5 weeks (Probencid can prolong the action time of MPTP in the central nervous system, simulating a more gradual human pathological process), and sublingual tablet treatment was performed synchronously from the start of modeling and lasted for 5 weeks; a blank group of mice was not given sublingual tablet treatment, and only physiological saline was given synchronously as a comparison; the mice were observed, and the levels of inflammatory factors (TNF-α, IL-1β) and oxidative stress markers in the substantia nigra and striatal tissues were detected; the results are shown in Table 4.

[0062] Table 4 Neurodegenerative disease alleviating performance test

[0063] Finally, it should be noted that although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still make modifications to the technical solutions recorded in the foregoing embodiments, or make equivalent replacements to part of the technical features, and any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A traditional Chinese medicine ingredient for alleviating neurodegenerative diseases, characterized in that, The product comprises the following components in parts by weight: 80-85 parts of traditional Chinese medicine powder, 15-20 parts of modified chitosan, 15-20 parts of modified sodium alginate, 8-10 parts of gluconate-δ-lactone powder, 0.3-0.6 parts of hydrophobic fumed silica, and 0.2-0.3 parts of magnesium stearate. The herbal powder includes chicory root powder and dandelion powder, with a mass ratio of 5:3; the modified chitosan forms an orthoester bond with the modified sodium alginate.

2. The herbal medicine component for alleviating neurodegenerative diseases according to claim 1, characterized in that, It also includes the following components in parts by weight: 40-45 parts microcrystalline cellulose, 25-30 parts mannitol, 15-20 parts binder, 15-20 parts super disintegrant, 1.0-2.0 parts lubricant, 1.0-1.5 parts sweetener, and 0.2-0.5 parts flavoring agent.

3. The herbal medicine component for alleviating neurodegenerative diseases according to claim 2, characterized in that, The adhesive comprises polyvinylpyrrolidone K-30; the super-disintegrant comprises crospovidone; the lubricant comprises fumaric acid; the sweetener comprises sucralose; and the flavoring agent comprises menthol.

4. The herbal medicine component for alleviating neurodegenerative diseases according to claim 1, characterized in that, The preparation method of the modified chitosan includes the following steps: S11. Chitosan was dispersed in anhydrous dimethyl sulfoxide and stirred vigorously under nitrogen protection. The catalyst p-toluenesulfonic acid was added, and the mixture was placed in an ice-water bath. Trifluoroacetaldehyde ethyl hemiacetal was added dropwise. The ice bath was removed, the temperature was raised to room temperature, and the reaction was continuously stirred under nitrogen protection. After the reaction was completed, the mixture was poured into an ice-cold diethyl ether / acetone mixed solvent, the precipitate was collected by centrifugation, and the precipitate was washed with fresh diethyl ether. The precipitate was dried to constant weight in a vacuum drying oven to obtain the first compound. S12. The first compound was dissolved in anhydrous methanol containing 2% triethylamine. A methanol solution of lauric anhydride was added dropwise with stirring. The reaction was carried out at room temperature under nitrogen protection. After the reaction was completed, the precipitate was poured into a large amount of ice-cold acetone, centrifuged to collect the precipitate, and washed with acetone and diethyl ether in sequence. The precipitate was dried to constant weight in a vacuum drying oven and passed through a 100-mesh sieve to obtain modified chitosan.

5. The herbal medicine component for alleviating neurodegenerative diseases according to claim 4, characterized in that, The volume ratio of icy ether to acetone in the icy ether / acetone mixed solvent is 1:

1.

6. The herbal medicine component for alleviating neurodegenerative diseases according to claim 1, characterized in that, The preparation method of the modified sodium alginate includes the following steps: S21. Disperse sodium alginate in isopropanol, add 50% NaOH solution, alkalize the reaction, then add dropwise a mixture obtained by uniformly mixing epichlorohydrin and glycerol, stir vigorously to react, after the reaction is completed, neutralize with dilute hydrochloric acid to pH = 7.0, dialyze with deionized water, freeze dry to obtain the second compound; S22. Dissolve the second compound in 0.1 mol / L NaOH solution, add methoxy polyethylene glycol propylene oxide, stir until completely dissolved, and react at 60°C. After the reaction is complete, neutralize with dilute hydrochloric acid to pH = 7.0, dialyze with deionized water, freeze dry, and pass through a 100-mesh sieve to obtain modified sodium alginate.

7. A method for preparing a traditional Chinese medicine component for alleviating neurodegenerative diseases, applied to the preparation of the traditional Chinese medicine component for alleviating neurodegenerative diseases as described in any one of claims 1 to 6, characterized in that, The preparation method includes: S31. Place gluconate-δ-lactone powder in a high-speed shear mixer, slowly add hydrophobic fumed silica while stirring at low speed, mix, keep stirring, slowly add magnesium stearate, continue mixing, and obtain the complex. S32. Modified chitosan and modified sodium alginate were dispersed in anhydrous ethanol, and traditional Chinese medicine powder was added. The mixture was mixed evenly, and dilute hydrochloric acid was added dropwise to catalyze the cross-linking reaction of orthoester bonds. After freeze-drying, the mixture was ultra-finely pulverized and passed through a 100-mesh sieve to obtain hydrogel particles. S33. Dissolve polyvinylpyrrolidone K-30 in anhydrous ethanol to prepare a 15% w / w adhesive solution. Add hydrogel particles, microcrystalline cellulose, and mannitol into a dry granulator and mix evenly. Spray the adhesive solution into the mixture and granulate. After drying the wet particles at low temperature, granulate them to obtain dry particles. S34. Transfer the dry granules to a three-dimensional motion mixer, add the complex and cross-linked povidone, mix, add fumaric acid, sucralose and menthol after sieving, mix, compress into tablets, and obtain a traditional Chinese medicine for relieving neurodegenerative diseases.

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