Extraction method of ginkgo biflavone as well as product and application of ginkgo biflavone

Abstract

The invention discloses an extraction method of ginkgo biflavone as well as a product and application thereof, belongs to the technical field of small molecule extraction, and aims to solve the technical problem that the purity and the processability of ginkgo biflavone need to be further improved in the prior art. Phenylboronic acid cured silica gel selective adsorption, L-arginine molecular compounding and double-layer solubilizing auxiliary material construction are used as a core technical path, efficient conversion of the whole process from extraction and purification of ginkgetin to tablet forming is achieved, impurities are removed through specific adsorption, dispersity is improved through molecular compounding, and the bioavailability of ginkgetin is improved. The drug release and the structure stability are jointly regulated and controlled by a quick disintegration solubilizing system and a stable solubilizing system, the obtained tablet is high in purity, quick in disintegration, sufficient in dissolution and excellent in long-term storage performance, and the processability and the bioavailability of the ginkgetin in a solid preparation are comprehensively improved.

Description

Technical Field

[0001] This invention relates to the field of small molecule extraction technology, specifically to an extraction method for ginkgo biflavonoids, its products, and applications. Background Technology

[0002] Ginkgo biflavonoids are derived from the flavonoid glycosides active ingredients in ginkgo leaves. They are usually extracted using a water-alcohol system or with the aid of ionic liquids or deep eutectic solvents to obtain a dispersion. The purity is then improved by combining membrane separation and resin adsorption. The methods are mostly aimed at improving the recovery rate and impurity removal efficiency of flavonoid components. The resulting products are mainly used in health products, functional foods and solid dosage forms of traditional Chinese medicine. The market demand for high-purity and high-stability raw materials is gradually increasing.

[0003] In terms of pharmaceutical applications, Ginkgo biloba flavonoids often exhibit poor flowability, clumping, and difficulty in disintegration during tableting, granulation, and spray drying due to their tendency to aggregate between molecules and their strong hydrophobicity. To improve their processability, sugar alcohols, cyclodextrins, or polysaccharides are often introduced to improve their dispersion and dissolution properties, enabling them to be adapted to various dosage forms such as tablets, granules, and instant powders. Gradually, an application development direction centered on solubilization, shaping, and stabilization has been formed.

[0004] Currently, in the extraction and purification process of Ginkgo biloba flavonoids, non-selective adsorption or solvent extraction methods are mostly used, which makes it difficult to effectively distinguish the target flavonoids from structurally similar impurities such as polyphenols and sugars. This results in insufficient product purity and component stability. Some methods rely on strong acids, strong bases or organic solvents to adjust the system, which can easily cause partial degradation or transformation of the flavonoid structure, affecting its antioxidant activity and subsequent processing performance. At the same time, the impurities and solvents remaining in the extraction product may also have adverse effects on taste, color and safety. During formulation preparation, ginkgo biflavonoid molecules easily form hydrophobic aggregates, resulting in poor powder flowability and easy clumping after drying. Traditional excipient systems are difficult to balance disintegration rate and structural stability. Tablets often exhibit problems such as hardening, delayed dissolution, or decreased content during storage. In addition, the lack of carrier systems that can combine solubilization and shaping functions limits the dissolution efficiency of poorly soluble flavonoids in solid dosage forms, which also restricts their application potential in high-efficiency oral formulations. Summary of the Invention

[0005] The purpose of this invention is to provide a method for extracting ginkgo biloba flavonoids, as well as the product and application thereof, to solve the technical problem that the purity and processability of ginkgo biloba flavonoids need to be further improved in the prior art.

[0006] The objective of this invention can be achieved through the following technical solution: a method for extracting ginkgo biflavonoids, comprising the following steps: S1, take D 50=100μm Ginkgo leaf powder and deep eutectic solvent were placed in an ultrasonic instrument, and deionized water, pectinase and cellulase were added. The ultrasonic instrument was heated to 40-50℃ and ultrasonically extracted for 30 min. The post-processing yielded a Ginkgo biflavonoid dispersion. S2. Ginkgo biloba flavonoid dispersion was added to the reaction vessel, and the pH of the reaction system was adjusted to 8.5 using saturated sodium bicarbonate aqueous solution. Then, phenylboronic acid-cured silica gel adsorbent was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, carbon dioxide gas was introduced, and the ginkgo biloba flavonoid was obtained after post-treatment.

[0007] The reaction principle for preparing L-arginine-based ginkgo biflavonoids is as follows: First, under the action of the eutectic solvent and the complex enzyme system, the cell wall structure of Ginkgo biloba leaves is destroyed. Pectinase and cellulase work together to cleave the plant polysaccharide matrix. Combined with the strong hydrogen bond network of the eutectic solvent, the bound flavonoid active ingredients in Ginkgo biloba leaves are fully released and form a stable dispersion system. This stage is essentially achieved by the synergistic effect of solvation and biocatalysis to achieve efficient dissociation and transfer of flavonoid glycosides. Subsequently, by adjusting the pH of the system and introducing phenylboronic acid-cured silica gel adsorbent, the reversible borate ester bond between the phenylboronic acid group and the ortho-diphenol structure in the flavonoid molecule was used to achieve specific selective adsorption of flavonoid compounds. At the same time, by introducing carbon dioxide to adjust the pH to neutral, the borate ester bond was destroyed to achieve gentle desorption, thereby obtaining a high-purity Ginkgo biflavonoid purified solution. Overall, this process, through multi-level regulation of physicochemical interactions, achieves a green transformation of the entire process from plant tissue disruption and targeted enrichment to molecular complex stabilization, providing a feasible chemical basis for the efficient extraction and functional utilization of flavonoids.

[0008] Furthermore, in step S1, the ratio of the amount of ginkgo leaf powder, deep eutectic solvent, deionized water, pectinase and cellulase is 10g:15-20g:2-3mL:0.05g:0.03g. The deep eutectic solvent is obtained by mixing choline chloride and lactic acid in a ratio of 1g:2g. The post-treatment includes: after ultrasonication, waiting for the ultrasonic instrument temperature to drop to room temperature, filtering the reaction solution and collecting the filtrate to obtain ginkgo biflavonoid dispersion. Furthermore, in step S2, the ratio of the amount of the ginkgo biflavonoid dispersion to the phenylboronic acid-cured silica gel adsorbent is 25-30g:1g. The post-treatment includes: after standing for 10 minutes, filtering the reaction solution and collecting the filtrate, transferring the filtrate to a rotary evaporator at a temperature of 80°C, and distilling under reduced pressure until no liquid is collected to obtain ginkgo biflavonoids. Further, in step S2, the preparation method of the phenylboronic acid-cured silica gel adsorbent is as follows: anhydrous ethanol, 3-aminophenylboronic acid, triethylamine and propyltriethoxysilane isocyanate are added to a reaction vessel, stirred at room temperature for 30-40 minutes, and then silica gel, deionized water and glacial acetic acid are added to the reaction vessel. The temperature of the reaction vessel is raised to reflux, and the reflux is maintained for 3-4 hours. The phenylboronic acid-cured silica gel adsorbent is then obtained through post-treatment.

[0009] The reaction principle for preparing phenylboronic acid-cured silica gel adsorbent is as follows: First, the amino group in the 3-aminophenylboronic acid molecule undergoes a nucleophilic addition reaction with the isocyanate group (-NCO) in the propyltriethoxysilane molecule to generate a structurally stable urea bond linker, which allows the phenylboronic acid group to form an organic intermediate with an organosilane coupling agent containing a hydrolyzable silane end group. Subsequently, this intermediate undergoes hydrolysis in an ethanol-water system under acidic conditions, and the triethoxysilyl group hydrolyzes to generate silanol (-Si-OH), which further undergoes a dehydration condensation reaction with the hydroxyl group (≡Si-OH) present on the silica gel surface to generate a strong Si-O-Si covalent bond, thereby achieving covalent fixation of the phenylboronic acid functional group on the silica gel surface. Throughout the process, the organic end of the silane (the phenylboronic acid group linked by a urea bond) endows the material with specific chemical recognition functions, while the inorganic end (Si-O-Si) ensures stable binding with the silica matrix. The resulting adsorbent surface contains a fully preserved -B(OH)2 group, which can form a specific complex with compounds with ortho- and oxalic acid or similar structures (such as flavonoids and polyphenols) through reversible borate ester bonds, thereby achieving selective adsorption and mild desorption of target molecules.

[0010] Furthermore, the ratio of anhydrous ethanol, 3-aminophenylboronic acid, triethylamine, propyltriethoxysilane isocyanate, silica gel, deionized water, and glacial acetic acid is 50-60 mL: 1 g: 0.2 mL: 3-4 g: 10 g: 0.1 mL: 0.02 mL. The silica gel has a pore size of 60-80 Å and a particle size of 40-60 μm. The post-treatment includes: after reflux, waiting for the reaction solution temperature to drop to room temperature, filtering the reaction solution to collect the filter cake, washing the filter cake 3-5 times with anhydrous ethanol and deionized water, and then transferring the filter cake to a drying oven at 80°C for vacuum drying to room temperature to obtain phenylboronic acid-cured silica gel adsorbent.

[0011] The present invention also discloses a ginkgo biflavonoid product, which is obtained by combining ginkgo biflavonoid with L-arginine. The preparation method is as follows: L-arginine, ginkgo biflavonoid and 50wt% ethanol aqueous solution are added to a reaction vessel and stirred at room temperature for 15-20 min. After post-treatment, L-arginine composite ginkgo biflavonoid is obtained. The ratio of ginkgo biflavonoid purified solution to L-arginine is 3-4g:0.1g:30mL.

[0012] The principle for preparing L-arginine-based ginkgo biflavonoids is as follows: By introducing L-arginine into a neutral to slightly alkaline environment, the cationic properties of the guanidinium and amino groups in its molecule are utilized to form a stable non-covalent complex system through electrostatic interactions, hydrogen bonding, and π-π stacking effects with the phenolic hydroxyl or carbonyl groups of flavonoid molecules. This composite structure not only improves the water solubility and thermal stability of flavonoid molecules, but also enhances their dispersibility and bioavailability in subsequent drying and formulation.

[0013] Furthermore, the ratio of the purified ginkgo biloba flavonoid solution to L-arginine is 20-25g:0.1g. The post-treatment includes: after stirring, concentrating the reaction solution to 6-8wt%, and then spray drying under the conditions of 145℃ inlet air, 80℃ outlet air, 3-5mL / min feed rate, and 0.5-0.7MPa atomization pressure to obtain L-arginine compound ginkgo biloba flavonoids.

[0014] The present invention also discloses an application of a ginkgo biflavonoid product, which is used in the preparation of ginkgo biflavonoid tablets.

[0015] Furthermore, the Ginkgo biloba tablets are made from the following raw materials in parts by weight: 20 parts L-arginine compound Ginkgo biloba tablets, 25-30 parts rapid-disintegrating solubilizing excipients, 40-50 parts stable solubilizing excipients, 2-4 parts croscarmellose sodium and 1 part magnesium stearate.

[0016] Furthermore, the preparation method of the rapid-disintegration solubilizing excipient includes the following steps: A1. Mannitol, hydroxypropyl cellulose, arginine bicarbonate and deionized water are added to a reaction vessel and stirred. After stirring evenly, the mixture is spray-dried under the conditions of inlet air temperature of 150℃, outlet air temperature of 75℃, feed rate of 3-5mL / min and atomization pressure of 0.5-0.7MPa to obtain porous skeleton particles. A2. Tartaric acid, ethyl cellulose and anhydrous ethanol are added to a reaction vessel and stirred evenly to obtain a spraying solution. The spraying solution is then uniformly sprayed onto the surface of porous skeleton particles using a fluidized bed to increase the membrane weight by 8-10%. After post-processing, a rapid disintegration solubilizing agent is obtained.

[0017] The reaction principle for preparing rapid-disintegration solubilizing excipients is as follows: In the system, mannitol, as a hydrophilic framework, forms a hydrogen-bonded association structure with hydroxypropyl cellulose. Through the rapid solvent evaporation and phase separation effect during the spray drying process, a porous particle structure with regular channels and a large specific surface area is generated, providing a physical basis for subsequent rapid disintegration and solubilization. Arginine bicarbonate decomposes thermally during the drying process, releasing trace amounts of CO2 and water molecules, while introducing cationic groups. This not only forms micropores and increases porosity inside the particles, but also endows the particle surface with certain alkalinity and hydrophilicity, which helps to improve the wetting and dissolution rate of subsequent drugs. Hydroxypropyl cellulose, as a binding and film-forming aid, enables mannitol and L-arginine salt to form a stable dispersion system, preventing particle aggregation and improving structural strength. In the subsequent coating stage, ethyl cellulose, as a hydrophobic film-forming material, forms a weak acid-hydrophobic polymer composite film together with tartaric acid: tartaric acid interacts with the molecular chains of ethyl cellulose through hydrogen bonds, regulating the hydrophilicity and disintegration of the film layer, so that the coating can quickly swell and decompose after contact with water, promoting the penetration of water into the skeleton. This composite film can maintain the stability of the particle structure during storage at room temperature, and can quickly disintegrate when it comes into contact with water, achieving rapid drug release and efficient dissolution. Overall, the formation process of this excipient is a structural self-organization process driven by hydrogen bonding assembly, gas pore formation, phase separation pore formation, and surface functionalization coating. Through this multi-dimensional synergistic mechanism, the resulting rapid disintegration solubilizing excipient simultaneously possesses high porosity, good disintegration properties, and excellent water-wetting solubilizing performance, providing a physicochemical basis for the rapid release of poorly soluble active ingredients in solid dosage forms.

[0018] Furthermore, in step A1, the ratio of mannitol, hydroxypropyl cellulose, arginine bicarbonate, and deionized water is 7-8g:1g:1g:20mL. Furthermore, in step A2, the ratio of tartaric acid, ethyl cellulose, and anhydrous ethanol is 8-10g:3g:200mL, and the post-treatment includes: transferring the material to a drying oven at 40°C and vacuum drying it to constant weight to obtain a rapid-disintegration solubilizing excipient.

[0019] Furthermore, the preparation method of the stabilizing solubilizing excipient includes the following steps: B1. Add corn starch and deionized water to the reaction vessel and stir. Raise the temperature of the reaction vessel to 70-80℃, keep it warm and stir for 5-10 minutes, and then process it to obtain pregelatinized starch. B2. After adding β-cyclodextrin, microcrystalline cellulose, and pregelatinized starch to a reaction vessel and stirring evenly, anhydrous ethanol and deionized water are added for wet granulation. After granulation, D is obtained. 50 Particles with a diameter of 300µm were post-processed to obtain a solubilizing excipient precursor. B3. At 45℃, a 0.5wt% citric acid aqueous solution is uniformly sprayed onto the surface of the solubilizing excipient precursor using a fluidized bed. After the film weight increases by 4-5%, post-treatment is performed to obtain a stable solubilizing excipient.

[0020] The reaction principle for preparing stable solubilizing excipients is as follows: First, after heat treatment, corn starch undergoes partial gelatinization and molecular rearrangement, which destroys its crystalline structure. The amylopectin molecular chains unfold in the aqueous phase to form an amorphous three-dimensional gel network, giving the system good adhesion and formability, and serving as the subsequent structural framework and bonding matrix. Subsequently, in the wet granulation system, β-cyclodextrin, microcrystalline cellulose, and pregelatinized starch form a stable multiphase composite network through intermolecular interactions of hydrogen bonds and van der Waals forces: β-cyclodextrin provides a hydrophobic inclusion cavity, which can encapsulate hydrophobic or poorly soluble components through host-guest interactions, thereby significantly improving the solubility of the system; microcrystalline cellulose, as an inert framework material, provides mechanical support and controls the pore structure of the particles, giving the system both certain fluidity and compressive stability; and pregelatinized starch crosslinks after drying to form a continuous phase structure, allowing cyclodextrin and cellulose to be uniformly dispersed in the particle matrix, preventing component migration and phase separation, thereby constructing porous precursor particles that combine strength and solubility; In the final surface modification stage, the citric acid spray solution forms a weakly acidic film containing carboxyl groups on the particle surface. Citric acid molecules can undergo partial esterification or hydrogen bonding complexation with the hydroxyl groups in the particles, thereby forming a dense protective layer with polarity regulation function on the surface. This film layer can stabilize the internal structure of the particles through weak acid-hydroxyl interaction, prevent moisture absorption and collapse, and can also rapidly swell and disintegrate during use, promote water penetration and activate the inclusion effect of cyclodextrin, achieving a dynamic balance between structural stability and rapid solubility. Overall, the formation of stable solubilizing excipients relies on a multi-level synergistic mechanism of starch thermal denaturation, cyclodextrin molecular inclusion, cellulose skeleton support, and citric acid surface regulation. This system achieves a balance between structural stability and functional optimization through intermolecular interactions and interfacial energy regulation, thereby endowing the excipients with excellent physicochemical stability, solubilizing ability, and molding adaptability, providing an efficient solubilization and carrier basis for the formulation of poorly soluble active substances.

[0021] Furthermore, in step B1, the ratio of corn starch to deionized water is 1g:3-4g. The post-treatment includes: spreading the reaction system on a stainless steel tray, drying it with hot air at 60℃ until the moisture content is ≤5%, and then passing it through an 80-mesh sieve to obtain pregelatinized starch. Furthermore, in step B2, the ratio of β-cyclodextrin, microcrystalline cellulose, pregelatinized starch, anhydrous ethanol and deionized water is 5g:12-15g:1g:10mL:30mL. The post-treatment includes: transferring the particles to a drying oven at a temperature of 40-45℃ and vacuum drying them until the moisture content is ≤4% to obtain the solubilizing excipient precursor. Furthermore, in step B3, the post-processing includes: transferring the material to a drying oven at 80°C and vacuum drying it to constant weight to obtain a stable solubilizing excipient.

[0022] The present invention has the following beneficial effects: 1. In the extraction process of Ginkgo biloba flavonoids, the deep eutectic solvent used in this invention forms a dense hydrogen bond network, which can effectively destroy the cell structure of Ginkgo biloba leaves, promote the full release of flavonoids, and inhibit the co-solubility of impurities. The surface of the phenylboronic acid-cured silica gel adsorbent contains active boron hydroxyl functional groups, which can selectively bind to the ortho-diphenol structure in the flavonoid molecule. Specific recognition and adsorption separation are achieved through reversible borate ester bond interactions. The organic integration of the two systems in the extraction and purification stages enables highly selective enrichment of flavonoid components and effective removal of impurities. The entire process is mild and controllable, avoiding thermal degradation and structural damage of active ingredients. Through the synergistic regulation of intermolecular interactions, this invention achieves a benign synergistic effect in terms of extraction efficiency, purity control, and system stability, significantly improving the purification quality and process stability of Ginkgo biloba flavonoids.

[0023] 2. This invention utilizes the guanidinyl and amino groups in L-arginine molecules to form hydrogen bonds and electrostatic complexes with biflavonoid molecules, significantly improving their water solubility and dispersion stability, laying the foundation for uniform distribution and rapid dissolution of the drug in a solid system. The rapid disintegration solubilizing excipient, through the synergistic effect of a porous framework and hydrophilic groups, rapidly absorbs water and swells upon contact with liquid, forming liquid channels to accelerate tablet disintegration. The stabilizing solubilizing excipient, through the inclusion effect of cyclodextrin and the support of a cellulose framework, maintains the mechanical strength of the tablet while preventing component migration and structural collapse. The three form a multi-level network of synergistic solubilization, rapid disintegration, and structural stability at the microscopic level, enabling the tablet to achieve rapid disintegration and efficient dissolution while maintaining appropriate hardness, significantly improving the dissolution behavior and stability of ginkgo biflavonoids.

[0024] 3. The guanidino group and amino group in the L-arginine molecule of this invention can form hydrogen bonds and electrostatic complexes with ginkgo biflavonoid molecules, significantly improving its hydrophilicity and dispersion stability, and inhibiting molecular aggregation and oxidative degradation at high temperatures, thereby enhancing the thermal stability of the system; the rapid disintegrating solubilizing excipient expands rapidly after absorbing water, forming porous channels and accelerating the disintegration and release of the tablet; the cyclodextrin and microcrystalline cellulose in the stabilizing solubilizing excipient synergistically construct a support network, enabling the tablet to maintain uniform distribution and structural integrity of components while maintaining mechanical strength. The three form a complementary and synergistic effect at the molecular and microscopic levels, achieving both efficient dissolution and rapid disintegration, and giving the tablet excellent storage temperature stability. Even under high temperature and humidity conditions, it can still maintain structural stability, stable disintegration performance, and no reduction in the content of active ingredients, ensuring the consistency and long-term controllability of the formulation quality. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0026] Figure 1 The image shows the infrared absorption spectrum of the phenylboronic acid-cured silica gel adsorbent prepared in Example 3. Figure 2 The image shows the infrared absorption spectrum of the L-arginine-based ginkgo biflavonoids prepared in Example 3. Figure 3 The infrared absorption spectrum image of the rapid-disintegration solubilizing excipient prepared in Example 6; Figure 4 The image shows the infrared absorption spectrum of the stable solubilizing excipient prepared in Example 6. Detailed Implementation

[0027] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0028] In this application, the silica gel used was purchased from Beyotime Biotechnology Co., Ltd., item number Y187016; the croscarmellose sodium used was purchased from Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.; the cellulase used was purchased from Shanghai Maclean Biotechnology Co., Ltd., item number C758963; the pectinase used was purchased from Shanghai Maclean Biotechnology Co., Ltd., item number M6346; the hydroxypropyl cellulose used was purchased from Shanghai Maclean Biotechnology Co., Ltd., item number L823212; the ethyl cellulose used was purchased from Shanghai Maclean Biotechnology Co., Ltd., item number E809014; the corn starch used was purchased from Shanghai Maclean Biotechnology Co., Ltd., item number 768498; the microcrystalline cellulose used was purchased from Shanghai Maclean Biotechnology Co., Ltd., item number M909921; the croscarmellose sodium used was purchased from Shanghai Yuanye Biotechnology Co., Ltd., item number S25102; and the magnesium stearate used was purchased from Shanghai Yuanye Biotechnology Co., Ltd., item number S52902.

[0029] Example 1 This embodiment provides a method for preparing a ginkgo biflavonoid product, including the following steps: Step 1: Preparation of phenylboronic acid-cured silica gel adsorbent Weigh out 500.0 mL of anhydrous ethanol, 10.0 g of 3-aminophenylboronic acid, 2.0 mL of triethylamine, and 30.0 g of propyltriethoxysilane isocyanate and add them to the reaction vessel. After stirring at room temperature for 30 min, add 100.0 g of silica gel with a pore size of 60 Å and a particle size of 40 μm, 1.0 mL of deionized water, and 0.2 mL of glacial acetic acid to the reaction vessel. Raise the temperature of the reaction vessel to reflux and maintain the reflux for 3 h. After the reflux is completed, wait for the temperature of the reaction solution to drop to room temperature, filter the reaction solution and collect the filter cake. Wash the filter cake three times with anhydrous ethanol and deionized water, and then transfer the filter cake to a drying oven at 80 °C and vacuum dry it to room temperature to obtain phenylboronic acid-cured silica gel adsorbent.

[0030] Step 2: Prepare Ginkgo biloba flavonoid dispersion Weigh out 100.0g of choline chloride and 200.0g of lactic acid and mix them to obtain a deep eutectic solvent; Weigh out: 100.0gD 50 Ginkgo biloba leaf powder with a particle size of 100 μm and 150.0 g of deep eutectic solvent were placed in an ultrasonic instrument, and 20.0 mL of deionized water, 0.5 g of pectinase and 0.3 g of cellulase were added. The ultrasonic instrument was heated to 40 °C and ultrasonically extracted for 30 min. After ultrasonic extraction, the ultrasonic instrument temperature was allowed to drop to room temperature, and the reaction solution was filtered to collect the filtrate, thus obtaining a ginkgo biflavonoid dispersion.

[0031] Step 3: Prepare Ginkgo biloba flavonoid purified solution Weigh 250.0g of Ginkgo biloba flavonoid dispersion and add it to the reaction vessel. After adjusting the pH of the reaction system to 8.5 with saturated sodium bicarbonate aqueous solution, add 10.0g of phenylboronic acid-cured silica gel adsorbent. Stir at room temperature for 30min, then introduce carbon dioxide gas to adjust the pH of the reaction system to 6.0. After standing for 10min, filter the reaction solution and collect the filtrate. Transfer the filtrate to a rotary evaporator at 80℃ and distill under reduced pressure until no liquid is collected to obtain Ginkgo biloba flavonoid.

[0032] Step 4: Preparation of L-arginine-based Ginkgo biloba flavonoids Weigh out 1.0 g L-arginine, 40.0 g ginkgo biflavonoids and 300 mL 50 wt% ethanol aqueous solution and add them to the reaction vessel. Stir at room temperature for 15 min. After stirring, concentrate the reaction solution to 6 wt% and then spray dry it under the conditions of 145 ℃ air inlet, 80 ℃ air outlet, 3 mL / min feed rate and 0.5 MPa atomization pressure to obtain L-arginine compound ginkgo biflavonoids.

[0033] Example 2 This embodiment provides a method for preparing a ginkgo biflavonoid product, including the following steps: Step 1: Preparation of phenylboronic acid-cured silica gel adsorbent Weigh out 600.0 mL of anhydrous ethanol, 10.0 g of 3-aminophenylboronic acid, 2.0 mL of triethylamine, and 40.0 g of propyltriethoxysilane isocyanate and add them to a reaction vessel. After stirring at room temperature for 40 min, add 100.0 g of silica gel with a pore size of 80 Å and a particle size of 60 μm, 1.0 mL of deionized water, and 0.2 mL of glacial acetic acid to the reaction vessel. Raise the temperature of the reaction vessel to reflux and maintain the reflux for 4 h. After the reflux is complete, wait for the temperature of the reaction solution to drop to room temperature, filter the reaction solution and collect the filter cake. Wash the filter cake 5 times with anhydrous ethanol and deionized water, and then transfer the filter cake to a drying oven at 80 °C and vacuum dry it to room temperature to obtain phenylboronic acid-cured silica gel adsorbent.

[0034] Step 2: Prepare Ginkgo biloba flavonoid dispersion Weigh out 100.0g of choline chloride and 200.0g of lactic acid and mix them to obtain a deep eutectic solvent; Weigh out: 100.0gD 50 Ginkgo biloba leaf powder with a particle size of 100 μm and 200.0 g of deep eutectic solvent were placed in an ultrasonic instrument, and 30.0 mL of deionized water, 0.5 g of pectinase and 0.3 g of cellulase were added. The ultrasonic instrument was heated to 50 °C and ultrasonically extracted for 30 min. After ultrasonic extraction, the ultrasonic instrument temperature was allowed to drop to room temperature, and the reaction solution was filtered to collect the filtrate, thus obtaining a ginkgo biflavonoid dispersion.

[0035] Step 3: Prepare Ginkgo biloba flavonoid purified solution Weigh 300.0g of Ginkgo biloba flavonoid dispersion and add it to the reaction vessel. After adjusting the pH of the reaction system to 8.5 with saturated sodium bicarbonate aqueous solution, add 10.0g of phenylboronic acid-cured silica gel adsorbent. Stir at room temperature for 30min, then introduce carbon dioxide gas to adjust the pH of the reaction system to 6.0. After standing for 10min, filter the reaction solution and collect the filtrate. Transfer the filtrate to a rotary evaporator at 80℃ and distill under reduced pressure until no liquid is collected to obtain Ginkgo biloba flavonoid.

[0036] Step 4: Preparation of L-arginine-based Ginkgo biloba flavonoids Weigh out 1.0 g L-arginine, 30.0 g ginkgo biflavonoids and 300 mL 50 wt% ethanol aqueous solution and add them to the reaction vessel. Stir at room temperature for 20 min. After stirring, concentrate the reaction solution to 8 wt% and then spray dry it under the conditions of 145 ℃ air inlet, 80 ℃ air outlet, 5 mL / min feed rate and 0.7 MPa atomization pressure to obtain L-arginine compound ginkgo biflavonoids.

[0037] Example 3 This embodiment provides a method for preparing a ginkgo biflavonoid product, including the following steps: Step 1: Preparation of phenylboronic acid-cured silica gel adsorbent Weigh out 550.0 mL of anhydrous ethanol, 10.0 g of 3-aminophenylboronic acid, 2.0 mL of triethylamine, and 36.0 g of propyltriethoxysilane isocyanate and add them to a reaction vessel. After stirring at room temperature for 36 min, add 100.0 g of silica gel with a pore size of 70 Å and a particle size of 50 μm, 1.0 mL of deionized water, and 0.2 mL of glacial acetic acid to the reaction vessel. Raise the temperature of the reaction vessel to reflux and maintain the reflux for 4 h. After the reflux is completed, wait for the temperature of the reaction solution to drop to room temperature, filter the reaction solution and collect the filter cake. Wash the filter cake 4 times with anhydrous ethanol and deionized water, and then transfer the filter cake to a drying oven at 80 °C and vacuum dry it to room temperature to obtain phenylboronic acid-cured silica gel adsorbent.

[0038] The ATR-FTIR spectrum of the obtained phenylboronic acid-cured silica gel adsorbent sample is as follows: Figure 1 As shown (4000-400cm) -1 The spectrum showed a clear and stable baseline, with slight high-frequency noise superimposed, and a good signal-to-noise ratio. The reaction sample was a solid silica adsorbent with a uniform network structure. 1080cm -1 The strong peak of Si-O-Si asymmetric stretching at 800 cm⁻¹ -1 The symmetrical stretching peaks together confirm the presence of the silicone skeleton at 950 cm⁻¹ -1 The Si-OH / Si-OH absorption suggests that residual hydroxyl groups remain on the surface; the high wavenumber region is 3450 / 3330 cm⁻¹. -1The presence of a broad OH / NH band and a shoulder peak, combined with a 1655 cm⁻¹ -1 The urea group C=O has significant absorption and 1250 cm⁻¹ -1 CN (urea) was used to verify that propyltriethoxysilane isocyanate and 3-aminophenylboronic acid form urea bonds on the surface after condensation. The aromatic ring portion is at 1600 / 1510 cm. -1 It exhibits a medium-strength C=C band, 30-30 cm. -1 It exhibits weak aromatic CH absorption, 770 / 700cm. -1 The presence of out-of-plane bending signals on the aromatic ring indicates successful introduction of the benzene ring end group; boric acid-related vibrations are observed at 1330 cm⁻¹. -1 (BO) and 1205cm -1 The simultaneous appearance of (BOC / aryl-B environment) indicates that the phenylboronic acid functional group is in a covalently fixed / silanized surrounding environment; In addition, 2930 / 2860cm -1 The aliphatic CH stretching characterized the presence of the propylsilane segment, and no free isocyanate was observed in the spectrum (~2270 cm⁻¹). -1 The presence of strong residual organic solvent peaks and the co-occurrence of the key peak system of "Si-O-Si backbone + urea bond C=O / C-N + benzene ring C=C / out-of-plane bending + BO / BOC" are consistent with the expected peak positions, verifying that the sample is the target adsorbent of phenylboronic acid solidified on the surface of silica gel via urea bond-silanization, and the structure construction is consistent with the process expectation.

[0039] Step 2: Prepare Ginkgo biloba flavonoid dispersion Weigh out 100.0g of choline chloride and 200.0g of lactic acid and mix them to obtain a deep eutectic solvent; Weigh out: 100.0gD 50 Ginkgo biloba leaf powder with a particle size of 100 μm and 180.0 g of deep eutectic solvent were placed in an ultrasonic instrument, and 25.0 mL of deionized water, 0.5 g of pectinase and 0.3 g of cellulase were added. The ultrasonic instrument was heated to 45 °C and ultrasonically extracted for 30 min. After ultrasonic extraction, the ultrasonic instrument temperature was allowed to drop to room temperature, and the reaction solution was filtered to collect the filtrate, thus obtaining a ginkgo biflavonoid dispersion.

[0040] Step 3: Prepare Ginkgo biloba flavonoid purified solution Weigh 270.0g of Ginkgo biloba flavonoid dispersion and add it to the reaction vessel. After adjusting the pH of the reaction system to 8.5 with saturated sodium bicarbonate aqueous solution, add 10.0g of phenylboronic acid-cured silica gel adsorbent. Stir at room temperature for 30min, then introduce carbon dioxide gas to adjust the pH of the reaction system to 6.0. After standing for 10min, filter the reaction solution and collect the filtrate. Transfer the filtrate to a rotary evaporator at 80℃ and distill under reduced pressure until no liquid is collected to obtain Ginkgo biloba flavonoid.

[0041] Step 4: Preparation of L-arginine-based Ginkgo biloba flavonoids Weigh out 1.0 g L-arginine, 36.0 g ginkgo biflavonoids and 300 mL 50 wt% ethanol aqueous solution and add them to the reaction vessel. Stir at room temperature for 18 min. After stirring, concentrate the reaction solution to 7 wt% and then spray dry it under the conditions of 145 ℃ air inlet, 80 ℃ air outlet, 4 mL / min feed rate and 0.6 MPa atomization pressure to obtain L-arginine compound ginkgo biflavonoids.

[0042] The L-arginine-ginkgo biflavonoid sample obtained by spray drying was tested by ATR-FTIR (4000-4000 cm⁻¹). -1 ),like Figure 2 As shown, the spectral baseline is stable, noise is low, and the signal-to-noise ratio is good; The spectrum is at 1605 cm⁻¹ -1 With 1415cm -1 A pair of characteristic absorption peaks of carboxylate are observed, with a peak spacing of approximately 190 cm⁻¹. -1 And 1710-1730cm -1 No C=O absorption of free carboxylic acid was observed in the region, indicating that the carboxylic acid groups in the sample have been ionized and formed a salt-type structure, which is direct evidence of the complexation of L-arginine and ginkgo biflavonoids. 3330cm -1 Broadband and 3205cm -1 The shoulder peak corresponds to the absorption of NH / OH through hydrogen bonding, bound to 1648 cm⁻¹. -1 C=N / C=O complex absorption at 1365 cm⁻¹ -1 The CN absorption of the compound system was used to verify that the guanidinium cation had been introduced into the complex system. 1648cm -1 The conjugated carbonyl absorption, 1605 and 1510 cm⁻¹ -1 The aromatic ring C=C vibration and 1275-1050 cm -1 The continuous absorption of CO and COC within the range indicates that the biflavonoid core structure is intact and that its phenolic hydroxyl group participates in ionic or hydrogen bonding. 835 and 765cm -1 The out-of-plane bending vibration signal of the aromatic ring CH further confirms the preservation of the aromatic structure; No -NCO absorption or strong free acid carbonyl peaks were observed in the spectrum, nor were there any significant solvent characteristic bands interfering. Based on the comprehensive spectral characteristics, it can be determined that the sample contains carboxylate characteristic peaks, guanidine absorption bands, and biflavonoid skeleton signals simultaneously, which fully verifies that the prepared sample is an L-arginine complex ginkgo biflavonoid (salt type complex), and its structure meets the characterization requirements of the target product.

[0043] Example 4 This embodiment provides a preparation of Ginkgo biloba flavonoid tablets, including the following steps: Step 1: Preparation of rapid disintegration solubilizing excipients Weigh out 7.0g mannitol, 1.0g hydroxypropyl cellulose, 1.0g arginine bicarbonate and 20.0mL deionized water and add them to the reaction vessel. Stir and mix well. Then spray dry under the conditions of inlet air temperature of 150℃, outlet air temperature of 75℃, feed rate of 3mL / min and atomization pressure of 0.5MPa to obtain porous skeleton particles. Weigh out 8.0g tartaric acid, 3.0g ethyl cellulose and 200.0mL anhydrous ethanol and add them to the reaction vessel. Stir well to prepare a spraying solution. Use a fluidized bed to spray the spraying solution evenly onto the surface of 6.0g porous framework particles. After the membrane weight increases by 8%, transfer the material to a drying oven at 40℃ and vacuum dry to constant weight to obtain a rapid disintegration solubilizing excipient.

[0044] Step 2: Preparation of stable solubilizing excipients Weigh out 10.0g of corn starch and 30.0g of deionized water and add them to the reaction vessel. Stir the mixture and raise the temperature of the reaction vessel to 70℃. After stirring for 5 minutes, spread the reaction system on a stainless steel plate and dry it with hot air at 60℃ until the moisture content is ≤5%. Then, pass it through an 80-mesh sieve to obtain pregelatinized starch. Weigh out 5.0 g β-cyclodextrin, 12.0 g microcrystalline cellulose, and 1.0 g pregelatinized starch, add them to a reaction vessel, stir well, then add 10.0 mL anhydrous ethanol and 30.0 mL deionized water for wet granulation. After granulation, obtain D. 50 Particles with a diameter of 300µm were transferred to a drying oven at 40℃ and vacuum dried until the moisture content was ≤4% to obtain a solubilizing excipient precursor. At 45℃, a 0.5wt% citric acid aqueous solution was uniformly sprayed onto the surface of 10.0g of solubilizing excipient precursor using a fluidized bed. After the film weight increased by 4%, the material was transferred to a drying oven at 80℃ and vacuum dried to constant weight to obtain a stable solubilizing excipient.

[0045] Step 3: Preparation of Ginkgo Biflavonoid Tablets By weight, 20 parts of L-arginine complex ginkgo biflavonoids prepared in Example 1, 25 parts of rapidly disintegrating solubilizing excipients, 40 parts of stabilizing solubilizing excipients, 2 parts of cross-linked sodium carboxymethyl cellulose and 1 part of magnesium stearate were weighed and pressed into tablets to obtain ginkgo biflavonoid tablets.

[0046] Example 5 This embodiment provides a preparation of Ginkgo biloba flavonoid tablets, including the following steps: Step 1: Preparation of rapid disintegration solubilizing excipients Weigh out 8.0g mannitol, 1.0g hydroxypropyl cellulose, 1.0g arginine bicarbonate and 20.0mL deionized water and add them to the reaction vessel. Stir and mix well. Then spray dry under the conditions of inlet air temperature of 150℃, outlet air temperature of 75℃, feed rate of 5mL / min and atomization pressure of 0.7MPa to obtain porous skeleton particles. Weigh out 10.0g tartaric acid, 3.0g ethyl cellulose and 200.0mL anhydrous ethanol and add them to the reaction vessel. Stir well to prepare a spraying solution. Use a fluidized bed to spray the spraying solution evenly onto the surface of 6.0g porous framework particles. After the membrane weight increases by 10%, transfer the material to a drying oven at 40℃ and vacuum dry to constant weight to obtain a rapid disintegration solubilizing excipient.

[0047] Step 2: Preparation of stable solubilizing excipients Weigh out 10.0g of corn starch and 40.0g of deionized water and add them to the reaction vessel. Stir the mixture and raise the temperature of the reaction vessel to 80℃. After stirring for 10 minutes, spread the reaction system on a stainless steel plate and dry it with hot air at 60℃ until the moisture content is ≤5%. Then, pass it through an 80-mesh sieve to obtain pregelatinized starch. Weigh out 5.0 g β-cyclodextrin, 15.0 g microcrystalline cellulose, and 1.0 g pregelatinized starch, add them to a reaction vessel, stir well, then add 10.0 mL anhydrous ethanol and 30.0 mL deionized water for wet granulation. After granulation, obtain D. 50 Particles with a diameter of 300µm were transferred to a drying oven at 45℃ and vacuum dried until the moisture content was ≤4% to obtain a solubilizing excipient precursor. At 45℃, a 0.5wt% citric acid aqueous solution was uniformly sprayed onto the surface of 10.0g of solubilizing excipient precursor using a fluidized bed. After the film weight increased by 5%, the material was transferred to a drying oven at 80℃ and vacuum dried to constant weight to obtain a stable solubilizing excipient.

[0048] Step 3: Preparation of Ginkgo Biflavonoid Tablets By weight, 20 parts of L-arginine complex ginkgo biflavonoids prepared in Example 2, 30 parts of rapidly disintegrating solubilizing excipients, 50 parts of stabilizing solubilizing excipients, 4 parts of cross-linked sodium carboxymethyl cellulose and 1 part of magnesium stearate were weighed and pressed into tablets to obtain ginkgo biflavonoid tablets.

[0049] Example 6 This embodiment provides a preparation of Ginkgo biloba flavonoid tablets, including the following steps: Step 1: Preparation of rapid disintegration solubilizing excipients Weigh out 8.0g mannitol, 1.0g hydroxypropyl cellulose, 1.0g arginine bicarbonate and 20.0mL deionized water and add them to the reaction vessel. Stir and mix well. Then spray dry under the conditions of inlet air temperature of 150℃, outlet air temperature of 75℃, feed rate of 4mL / min and atomization pressure of 0.6MPa to obtain porous skeleton particles. Weigh out 9.0g tartaric acid, 3.0g ethyl cellulose and 200.0mL anhydrous ethanol and add them to the reaction vessel. Stir well to prepare a spraying solution. Use a fluidized bed to spray the spraying solution evenly onto the surface of 6.0g porous framework particles. After the membrane weight increases by 9%, transfer the material to a drying oven at 40℃ and vacuum dry to constant weight to obtain a rapid disintegration solubilizing excipient.

[0050] The obtained rapid-disintegration solubilizing excipient samples were tested by ATR-FTIR (4000-400 cm⁻¹). -1 ),like Figure 3 As shown, the spectrum has a stable baseline with slight superimposed noise, and the signal is well resolved. Spectrum at 3380 cm⁻¹ -1 The broad and strong absorption at 2930 cm⁻¹ is a characteristic of the superposition of OH and NH stretching vibrations in mannitol, hydroxypropyl cellulose, and arginine bicarbonate, indicating the presence of multiple hydroxyl and amino groups in the system. -1 With 2880cm -1 The absorption peaks are attributed to the CH stretching vibration, which is a characteristic signal of ethyl cellulose and the organic skeleton. 1712cm -1 A distinct C=O absorption appears at 1600 cm⁻¹, indicating tartrate esterification or carboxylic acid carbonyl vibration, serving as a confirmatory marker for coating film formation. -1 The presence of a medium-intensity band nearby is attributed to the NH bending or C=N vibration of L-arginine residues, indicating that the aminated component has participated in the complex system; 1460cm -1 With 1385cm -1 Absorption corresponds to CH2 bending and CN / COO - Vibrations, reflecting the presence of organic salts and amino acid residues, 1265-1025 cm -1 The continuous COC and CO stretching absorption within the range is strong and stable, proving that the polysaccharide ether bonds and polyhydroxy skeleton in the material remain intact; 1080cm -1 With 1025cm -1 The signal is particularly prominent at 850 cm⁻¹, which is a characteristic peak of mannitol and hydroxypropyl cellulose. -1 and 760cm -1 The weak peaks are CH bending vibration signals, indicating the presence of a film layer on the surface of ethyl cellulose; The absence of obvious free acid carbonyl abnormal peaks and solvent residue peaks in the full spectrum indicates that the system was thoroughly dried and chemically stable. The presence of positional correspondences among the characteristic absorptions confirms that the obtained sample is a rapid-disintegration solubilizing excipient composed of a mannitol-hydroxypropyl cellulose backbone, arginine bicarbonate solubilizing component, and tartaric acid-ethyl cellulose coating membrane. Its infrared spectral characteristics are consistent with the expected structure, proving that the target excipient was successfully prepared.

[0051] Step 2: Preparation of stable solubilizing excipients Weigh out 10.0g of corn starch and 36.0g of deionized water and add them to the reaction vessel. Stir the mixture and raise the temperature of the reaction vessel to 75℃. After stirring for 8 minutes, spread the reaction system on a stainless steel plate and dry it with hot air at 60℃ until the moisture content is ≤5%. Then, pass it through an 80-mesh sieve to obtain pregelatinized starch. Weigh out 5.0 g β-cyclodextrin, 15.0 g microcrystalline cellulose, and 1.0 g pregelatinized starch, add them to a reaction vessel, stir well, then add 10.0 mL anhydrous ethanol and 30.0 mL deionized water for wet granulation. After granulation, obtain D. 50 Particles with a diameter of 300µm were transferred to a drying oven at 45℃ and vacuum dried until the moisture content was ≤4% to obtain a solubilizing excipient precursor. At 45℃, a 0.5wt% citric acid aqueous solution was uniformly sprayed onto the surface of 10.0g of solubilizing excipient precursor using a fluidized bed. After the film weight increased by 5%, the material was transferred to a drying oven at 80℃ and vacuum dried to constant weight to obtain a stable solubilizing excipient.

[0052] The prepared stable solubilizing excipient samples were tested by ATR-FTIR (4000-400 cm⁻¹). -1 ),like Figure 4 As shown, 3380cm -1 The broad and strong OH absorption is a general characteristic of the starch / β-cyclodextrin / microcrystalline cellulose hydrogen bond network, 2930 / 2890 cm⁻¹. -1 For the stretching of the organic framework CH; 1716cm -1 The presence of a medium-intensity carbonyl band confirms the presence of the citric acid coating / carbonyl component; 1645 cm⁻¹ -1 For the bending vibration of bound water; 1462, 1424, 1374, 1336 cm -1 CH2 bending and skeletal bands are typical fingerprints of cellulose / starch; 1160-995cm -1 Continuous strong absorption in the range (including 1160, 1112, 1055, 1030, and 995 cm⁻¹) -1 (Corresponding to the polysaccharide COC / CO stretching cluster, 897 cm⁻¹) -1The β-glycosidic bond indicator peak is clearly present, proving that the polysaccharide backbone maintains the cyclodextrin backbone; 760 cm⁻¹ -1 The weak bands represent thin film / lattice-related bending signals. No abnormal strong solvent peaks or free salt / amine characteristic peaks were observed interfering with the full spectrum. The above key features (co-occurrence of polysaccharide COC / CO fingerprint clusters + β-glycosidic bond peaks, superimposed at 1716 cm⁻¹) -1 carbonyl band and 3380cm -1 The results, verified by both wide OH groups, showed that the sample was composed of a polysaccharide matrix consisting of pregelatinized starch-β-cyclodextrin-microcrystalline cellulose and a citric acid thin-coating film. Infrared evidence confirmed that the target structure of the "stable solubilizing excipient" was consistent, proving that the target excipient had been successfully prepared.

[0053] Step 3: Preparation of Ginkgo Biflavonoid Tablets By weight, 20 parts of L-arginine complex ginkgo biflavonoids prepared in Example 3, 28 parts of rapidly disintegrating solubilizing excipients, 45 parts of stabilizing solubilizing excipients, 3 parts of cross-linked sodium carboxymethyl cellulose and 1 part of magnesium stearate were weighed and pressed into tablets to obtain ginkgo biflavonoid tablets.

[0054] Comparative Example 1 The difference between this comparative example and Example 6 is that the L-arginine-based ginkgo biflavonoids used in this example do not use phenylboronic acid-cured silica gel adsorbent during the preparation process.

[0055] Comparative Example 2 The difference between this comparative example and Example 6 is that step 4 is omitted in the preparation process of the L-arginine-based ginkgo biflavonoid complex.

[0056] Comparative Example 3 The difference between this comparative example and Example 6 is that the stabilizing solubilizing excipient is omitted in step three.

[0057] Comparative Example 4 The difference between this comparative example and Example 6 is that the rapid disintegration solubilizing excipient was omitted in step three.

[0058] Performance testing: Ginkgo biloba flavonoids prepared in Examples 1-3 and Comparative Example 1 were used, and their purity was determined by high performance liquid chromatography. The purified samples were accurately weighed, dissolved in methanol, filtered through a 0.22 μm filter membrane, and the filtrate was injected. A C18 column was used with a gradient elution of acetonitrile and 0.1% phosphoric acid aqueous solution as the mobile phase, a flow rate of 1.0 mL / min, a column temperature of 35 °C, and a detection wavelength of 360 nm. The column was calibrated with a ginkgo biloba flavonoid standard. The peak areas of the main biloba flavonoid components in the sample were determined by the external standard method and summed. The percentage of the peak area of ​​the main component to the total peak area was calculated as the sample purity. The purity of ginkgo biloba flavonoids was finally expressed as the obtained percentage content. The specific data are shown in Table 1. Six tablets of Ginkgo biloba flavonoid prepared in Examples 4-6 and Comparative Examples 1-4 were placed in the paddle device of a dissolution tester. 900 mL of pH 6.8 phosphate buffer (containing 0.10% sodium dodecyl sulfate) was added to each chamber as the dissolution medium. The water bath temperature was controlled at 37.0℃±0.5℃ and the paddle speed was 50 rpm. After running for 30 min, 10 mL of each tablet was taken, filtered through a 0.45 μm filter membrane, and the concentration of the active ingredient was determined by ultraviolet spectrophotometer at a wavelength of 360 nm. The dissolution rate of each tablet at 30 min was calculated and the average dissolution rate was obtained. Six tablets of Ginkgo biloba flavonoid prepared in Examples 4-6 and Comparative Examples 1-4 were placed in the basket of a disintegration time tester. The instrument was started at 37℃±0.5℃ with 900mL of pH6.8 phosphate buffer as the medium. The time required for each tablet to completely disintegrate was recorded and the average disintegration time was calculated. Six Ginkgo biflavonoid tablets prepared in Examples 4-6 and Comparative Examples 1-4 were placed in a tablet hardness tester to measure the force required for the tablets to break and the average hardness of 10 tablets was recorded as a molding performance index. Six Ginkgo biloba flavonoid tablets prepared in Examples 4-6 and Comparative Examples 1-4 were sealed and packaged and stored at 40℃±2℃ / 75%±5%RH for 6 months. After the storage period, the samples were taken out and tested for dissolution rate, disintegration time, content uniformity and hardness after equilibration at room temperature to evaluate the stability of Ginkgo biloba flavonoid tablets under high temperature and high humidity conditions. The specific time is shown in Table 2. Table 1 - Performance Test Data for Each Sample

[0059] Table 2 - Performance Test Data for Each Sample

[0060] Data Analysis: Comparative analysis of the data in Tables 1-2 revealed that the Ginkgo biloba flavonoids prepared in this invention had a purity of 98.5%, an average dissolution rate of 95.9% over 30 minutes, an average disintegration time of 75 seconds, and a tablet hardness of 86 N. Furthermore, after aging, the dissolution rate remained at 96.7%, the disintegration rate at 94.6%, and the tablet hardness at 98.2%. All these data are superior to the comparative example, indicating that… Comparative Example 1 lost the selective complexation effect of the -B(OH)2 group of the phenylboronic acid-cured silica gel adsorbent on the ortho-diphenol structure of ginkgo biloba flavonoids, resulting in the residue of impurities such as flavonoids, polyphenols and sugars in the extract. The hydroxyl and carboxyl groups of the impurities are prone to hydrogen bonding with ginkgo biloba flavonoids to form unstable multi-component complexes, which disrupt the molecular dispersion of flavonoids in the purified solution. Such impurities promote particle aggregation and hydrophobic shielding at the interface during drying and tableting, hindering the water penetration channels of the rapid disintegration solubilizing excipients, causing disintegration delay and limited dissolution, and exacerbating oxidative degradation when the storage temperature increases. Comparative Example 2 lost the hydrogen bonding, electrostatic, and π-π synergistic effects between the guanidinium and amino groups of L-arginine on the phenolic hydroxyl and carbonyl groups of Ginkgo biloba flavonoids. This resulted in the Ginkgo biloba flavonoids re-polymerizing in the purification solution and forming a local crystalline structure. During spray drying, this self-polymer was prone to forming dense particles due to intermolecular π-π stacking, reducing its specific surface area and hydrophilicity. This led to insufficient structural looseness after tableting and a significant decrease in water penetration rate. At the same time, the lack of L-arginine weakened the system's buffering and antioxidant capacity. During high-temperature storage, the flavonoids underwent oxidative polymerization and darkened in color, resulting in a decrease in overall dissolution performance and stability. Comparative Example 3 lost the multiphase support network jointly constructed by β-cyclodextrin, microcrystalline cellulose, and pregelatinized starch. As a result, the porous skeleton formed in the rapid disintegration solubilizing excipient lacked morphological constraints and carrier support. After the sprayed film layer ruptured, although the particles could rapidly disintegrate upon contact with liquid, the pore walls collapsed and the particles agglomerated, leading to unstable liquid passages. Without skeleton regulation, the drug migrated unevenly in the system, and the dissolution behavior exhibited rapid disintegration and rapid sedimentation characteristics. As the temperature increased, water migration and pore wall collapse intensified, and the mechanical strength and drug release reproducibility of the tablets were significantly reduced. Comparative Example 4 lost the porous rapid-disintegration framework formed by mannitol, hydroxypropyl cellulose, and arginine bicarbonate, as well as the ethyl cellulose-tartaric acid composite membrane structure. This resulted in the tablet system lacking a rapid water absorption and swelling mechanism and a liquid flow and pore-building mechanism. The stabilizing and solubilizing excipients only exhibited slow surface swelling upon contact with liquid, and the interior was difficult to wet quickly. The obstructed liquid penetration led to surface erosion disintegration. As the storage temperature increased, the microcrystalline cellulose and citric acid membrane layers became further densified, increasing the liquid flow resistance. Drug release was delayed due to diffusion control, and the overall dissolution rate was significantly reduced. Ultimately, this process demonstrates that it achieves an organic integration of structure and function in each stage of raw material extraction, purification, compounding, and formulation construction. The phenylboronic acid-cured silica gel adsorbent imparts selective recognition and mild desorption properties to the system during pretreatment, providing high-purity raw materials for subsequent compounding. The introduction of L-arginine enables Ginkgo biloba flavonoids to form a stable dispersion structure at the molecular level, significantly improving film uniformity and component stability during drying. The rapidly disintegrating solubilizing excipients establish rapid penetration channels through a porous framework and a cleavable membrane layer, while the stabilizing solubilizing excipients maintain tablet structure and thermal stability through cyclodextrin inclusion and cellulose support networks. The interconnected functions of each component form a comprehensive system that combines rapid drug release, good mechanical strength, and excellent storage stability, resulting in Ginkgo biloba flavonoid tablets that are significantly superior to those prepared via conventional methods in terms of purity, dissolution, and long-term retention.

[0061] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to specific implementations. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for extracting ginkgo biflavonoids, characterized in that, Includes the following steps: S1, take D 50 =100μm Ginkgo leaf powder and deep eutectic solvent were placed in an ultrasonic instrument, and deionized water, pectinase and cellulase were added. The ultrasonic instrument was heated to 40-50℃ and ultrasonically extracted for 30 min. The post-processing yielded a Ginkgo biflavonoid dispersion. S2. Ginkgo biloba flavonoid dispersion was added to the reaction vessel, and the pH of the reaction system was adjusted to 8.5 using saturated sodium bicarbonate aqueous solution. Then, phenylboronic acid-cured silica gel adsorbent was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, carbon dioxide gas was introduced, and the ginkgo biloba flavonoid was obtained after post-treatment.

2. The method for extracting ginkgo biflavonoids according to claim 1, characterized in that, In step S1, the ratio of the amount of ginkgo leaf powder, deep eutectic solvent, deionized water, pectinase and cellulase is 10g:15-20g:2-3mL:0.05g:0.03g, wherein the deep eutectic solvent is obtained by mixing choline chloride and lactic acid in a ratio of 1g:2g; in step S2, the ratio of the amount of ginkgo biflavonoid dispersion and phenylboronic acid-cured silica gel adsorbent is 25-30g:1g.

3. The method for extracting ginkgo biflavonoids according to claim 1, characterized in that, In step S2, the preparation method of the phenylboronic acid-cured silica gel adsorbent is as follows: anhydrous ethanol, 3-aminophenylboronic acid, triethylamine, and propyltriethoxysilane isocyanate are added to a reaction vessel, stirred at room temperature for 30-40 minutes, and then silica gel, deionized water, and glacial acetic acid are added to the reaction vessel. The temperature of the reaction vessel is raised to reflux and kept at reflux for 3-4 hours. The phenylboronic acid-cured silica gel adsorbent is obtained by post-treatment. The ratio of anhydrous ethanol, 3-aminophenylboronic acid, triethylamine, propyltriethoxysilane isocyanate, silica gel, deionized water, and glacial acetic acid is 50-60 mL:1 g:0.2 mL:3-4 g:10 g:0.1 mL:0.02 mL. The pore size of the silica gel is 60-80 Å, and the particle size is 40-60 μm.

4. A ginkgo biflavonoid product, characterized in that, The ginkgo biflavonoid product is obtained by combining ginkgo biflavonoid extracted by the extraction method of any one of claims 1-3 with L-arginine. The preparation method is as follows: L-arginine, ginkgo biflavonoid and 50wt% ethanol aqueous solution are added to a reaction vessel, stirred at room temperature for 15-20 min, and then post-treated to obtain L-arginine-complex ginkgo biflavonoid. The ratio of ginkgo biflavonoid purified solution to L-arginine is 3-4g:0.1g:30mL.

5. An application of a ginkgo biflavonoid product, characterized in that, The Ginkgo biloba flavonoid product according to claim 4 is applied to the preparation of Ginkgo biloba flavonoid tablets.

6. The application of the Ginkgo biflavonoid product according to claim 5, characterized in that, The Ginkgo biloba tablets are made from the following raw materials in parts by weight: 20 parts L-arginine compound Ginkgo biloba tablets, 25-30 parts rapid-disintegrating solubilizing excipients, 40-50 parts stable solubilizing excipients, 2-4 parts croscarmellose sodium and 1 part magnesium stearate.

7. The application of the Ginkgo biflavonoid product according to claim 6, characterized in that, The preparation method of the rapid-disintegration solubilizing excipient includes the following steps: A1. Mannitol, hydroxypropyl cellulose, arginine bicarbonate and deionized water are added to a reaction vessel and stirred. After stirring evenly, the mixture is spray-dried under the conditions of inlet air temperature of 150℃, outlet air temperature of 75℃, feed rate of 3-5mL / min and atomization pressure of 0.5-0.7MPa to obtain porous skeleton particles. A2. Tartaric acid, ethyl cellulose and anhydrous ethanol are added to a reaction vessel and stirred evenly to obtain a spraying solution. The spraying solution is then uniformly sprayed onto the surface of porous skeleton particles using a fluidized bed to increase the membrane weight by 8-10%. After post-processing, a rapid disintegration solubilizing agent is obtained.

8. The application of the Ginkgo biflavonoid product according to claim 7, characterized in that, In step A1, the ratio of mannitol, hydroxypropyl cellulose, arginine bicarbonate, and deionized water is 7-8g:1g:1g:20mL; in step A2, the ratio of tartaric acid, ethyl cellulose, and anhydrous ethanol is 8-10g:3g:200mL.

9. The application of the Ginkgo biflavonoid product according to claim 6, characterized in that, The preparation method of the stabilized solubilizing excipient includes the following steps: B1. Add corn starch and deionized water to the reaction vessel and stir. Raise the temperature of the reaction vessel to 70-80℃, keep it warm and stir for 5-10 minutes, and then process it to obtain pregelatinized starch. B2. After adding β-cyclodextrin, microcrystalline cellulose, and pregelatinized starch to a reaction vessel and stirring evenly, anhydrous ethanol and deionized water are added for wet granulation. After granulation, D is obtained. 50 Particles with a diameter of 300µm were post-processed to obtain a solubilizing excipient precursor. B3. At 45℃, a 0.5wt% citric acid aqueous solution is uniformly sprayed onto the surface of the solubilizing excipient precursor using a fluidized bed. After the film weight increases by 4-5%, post-treatment is performed to obtain a stable solubilizing excipient.

10. The application of a ginkgo biflavonoid product according to claim 9, characterized in that, In step B1, the ratio of corn starch to deionized water is 1g:3-4g; in step B2, the ratio of β-cyclodextrin, microcrystalline cellulose, pregelatinized starch, anhydrous ethanol, and deionized water is 5g:12-15g:1g:10mL:30mL.

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