A method for processing traditional Chinese medicine

Abstract

This invention relates to the field of modern pharmaceutical formulation technology and discloses a processed traditional Chinese medicine, made from the following raw materials in parts by weight: 100 parts of crude Corydalis rhizome powder; 5-15 parts of solid organic acid; and 1-5 parts of inorganic powder excipients. The solid organic acid is selected from at least one of citric acid monohydrate or L-malic acid; the inorganic powder excipients are selected from at least one of hydrophilic fumed silica, hydrophobic fumed silica, or talc. Microwave vacuum dehydration breaks down the cell walls of the medicinal material, forming a microporous structure within the powder. Combined with a co-grinding process, the insoluble free alkaloids and solid organic acid undergo an in-situ salt-forming reaction in a dry phase environment. This combination of physical structural modification and chemical salt-forming phase transition eliminates the physical barrier of plant cell walls, improves the solubility of the active ingredients, shortens the in vitro dissolution time after oral administration, and accelerates the analgesic onset rate in live animal models.

Description

Technical Field

[0001] This invention relates to the field of modern pharmaceutical preparation technology, specifically a method for processing traditional Chinese medicine. Background Technology

[0002] The main active pharmaceutical substances in Corydalis rhizome are alkaloids such as corydaline, which are mainly encapsulated within dense cell walls in the form of free alkaloids in natural plant tissues. Free alkaloids have poor water solubility, resulting in slow in vitro dissolution after oral administration. To improve the solubility of the active ingredients, current technologies typically employ acid treatment processes to convert free alkaloids into easily soluble organic acid salts.

[0003] Current conventional acid treatment processes mainly rely on liquid-phase acid hydrolysis, such as soaking in rice vinegar or spraying in liquid acetic acid. This process introduces a continuous liquid medium, requiring a high-temperature drying step after the reaction to obtain the dry powder needed for subsequent formulations. However, the active ingredients in Corydalis yanhusuo are heat-sensitive substances, undergoing degradation and oxidation reactions under the combined conditions of liquid phase and high temperature, leading to a decrease in the retention rate of active ingredients and an increase in impurities. Furthermore, conventional liquid-phase soaking is insufficient to physically destroy the cell walls of the medicinal material, and the physical barriers preventing the diffusion of already formed salts from the interior remain. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a method for processing traditional Chinese medicine, solving the problem of decreased retention rate of effective components in existing extraction processes.

[0005] To achieve the above objectives, the present invention provides the following technical solution: a processed traditional Chinese medicine, made from raw materials comprising the following parts by weight: 100 parts of coarsely ground Corydalis rhizome; 5-15 parts of solid organic acids; 1-5 parts of inorganic powder excipients.

[0006] Preferably, the solid organic acid is selected from at least one of citric acid monohydrate or L-malic acid; The inorganic powder additive is selected from at least one of hydrophilic fumed silica, hydrophobic fumed silica, or talc.

[0007] Preferably, the inorganic powder excipient is hydrophobic fumed silica, and the hydrophobic fumed silica is prepared by the following method: Hydrophilic fumed silica powder was placed in a fluidized bed reactor, and dry nitrogen gas was introduced as a fluidizing medium and the temperature was raised for pre-drying and dehydration. Subsequently, hexamethyldisilazane vapor was injected into the fluidized bed, and the reaction was carried out under closed conditions. After the reaction was completed, nitrogen gas was introduced to purge and the mixture was cooled to room temperature to obtain hydrophobic fumed silica.

[0008] Preferably, in the method for preparing the hydrophobic fumed silica, the pre-drying temperature is 120℃~150℃ and the time is 2 hours; the amount of hexamethyldisilazane vapor injected is 5.0%~10.0% of the weight of the hydrophilic fumed silica; and the temperature of the heat preservation reaction is 120℃~150℃ and the time is 3.0~4.0 hours.

[0009] A method for preparing processed traditional Chinese medicine includes the following steps: S1. Take the cleaned dried Corydalis tubers, soften and slice them, then place them in a microwave vacuum device for dehydration and cell wall breaking treatment, then cool, crush and sieve to obtain porous Corydalis coarse powder. S2. Add the coarse powder of Corydalis yanhusuo obtained in step S1, inorganic powder excipients and solid organic acid into a mixer and dry mix them evenly so that the inorganic powder excipients adhere to the powder surface to form a barrier layer. S3. The mixed powder after dry mixing in step S2 is put into a high-energy ball mill. The grinding chamber is kept at a low temperature to carry out a continuous solid-phase co-grinding reaction. The final product is obtained after discharge sieving.

[0010] Preferably, in step S1, the dried Corydalis tubers are pre-treated by softening and slicing as follows: the surface is evenly sprayed with purified water to soften, and the overall moisture increase is controlled to be 1.0% to 2.0% of the dry weight of the medicinal material, and then sliced ​​into thin slices with a thickness of 2.0 to 3.0 mm.

[0011] Preferably, in step S1, the specific implementation method of the dehydration and cell wall breaking treatment is as follows: Corydalis flakes are spread flat in a polytetrafluoroethylene material tray with a thickness of 2.0 to 4.0 cm; a sealed drying chamber is used, the vacuum degree inside the chamber is controlled at -0.08 MPa to -0.095 MPa, the microwave power density is set at 1.5 to 2.5 W / g, the surface temperature of the material is controlled not to exceed 45°C to 55°C, and the treatment is continued for 10 to 20 minutes until the residual absolute moisture content of the discharged material is controlled at 1.0% to 3.0%.

[0012] Preferably, in step S2, the parameters for dry mixing are as follows: a three-dimensional motion mixer is used, the container rotation speed is set to 15-25 rpm, and dry mixing is carried out continuously for 15-30 minutes.

[0013] Preferably, in step S3, the specific process parameters are as follows: the high-energy ball mill is a planetary high-energy ball mill, with zirconia beads or stainless steel balls added as grinding media, and the ball-to-material weight ratio controlled at 5:1 to 15:1; the cooling water jacket is turned on to control the internal temperature of the grinding chamber at 15℃ to 30℃; the spindle rotation speed is set to 300 to 500 rpm, and the time is 30 to 60 minutes. Furthermore, the entire solid-phase co-milling reaction is controlled to be carried out in a completely dry phase powder state without the addition of any liquid solvent; after the reaction product is discharged and sieved, it is stored by vacuum sealing or by filling high-purity nitrogen gas into sealed packaging.

[0014] The application of processed Chinese medicinal materials in the preparation of analgesic drugs, wherein the analgesic drugs are immediate-release oral solid preparations used to inhibit pain responses induced by chemical stimuli.

[0015] This invention provides a method for processing traditional Chinese medicine. It has the following beneficial effects: 1. This invention utilizes microwave vacuum dehydration to disrupt the cell walls of medicinal materials, forming a microporous structure within the powder. Combined with a co-milling process, this allows for in-situ salt formation reactions between sparingly soluble free alkaloids and solid organic acids in a dry phase environment. This combination of physical structural modification and chemical salt formation phase transition eliminates the physical barrier of plant cell walls, improves the solubility of active ingredients, shortens the in vitro dissolution time after oral administration, and accelerates the analgesic onset rate in live animal models.

[0016] 2. The preparation process of this invention introduces inorganic powder excipients in the dry phase premixing and ball milling stages. Fine inorganic powders adhere to the surface of the coarse Corydalis powder, forming an isolation layer that blocks direct contact between starch particles in the medicinal material and high-energy mechanical impact. This structural feature eliminates mechanical gelatinization and agglomeration caused by localized frictional heating, ensuring continuous operation of the co-milling process and giving the final processed powder the flowability required for industrial formulations. Attached Figure Description

[0017] Figure 1 This is a schematic diagram of the process steps of the present invention. Detailed Implementation

[0018] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. 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.

[0019] The main raw materials and reagents used in the following examples and comparative examples have the following sources and specifications. Reagents not specifically mentioned are all commercially available analytical grade or higher grade products.

[0020] The dried tuber of Corydalis Rhizome, the origin of which is the dried tuber of Corydalis Rhizome, a plant of the Papaveraceae family, has quality and moisture limits that comply with the provisions of the current edition of the Chinese Pharmacopoeia. Citric acid monohydrate, CAS number 5949-29-1, pharmaceutical grade; L-malic acid, CAS number 97-67-6, pharmaceutical grade; Hydrophilic fumed silica, CAS No. 112945-52-5, with a specific surface area of ​​180 to 220 square meters per gram as determined by the BET method, pharmaceutical grade; Hexamethyldisilazane, CAS No. 999-97-3, analytical grade; Talc powder, whose main component is hydrated magnesium silicate, has a CAS number of 14807-96-6, a central particle size D50 of less than or equal to 10 micrometers, and is of pharmaceutical grade.

[0021] Preparation Example 1: This preparation example provides a method for preparing hydrophobic fumed silica, comprising the following steps: placing hydrophilic fumed silica powder with a specific surface area of ​​200 square meters per gram in a fluidized bed reactor; introducing dry nitrogen as a fluidizing medium and raising the bed temperature to 135°C for pre-drying and dehydration for 2 hours; injecting hexamethyldisilazane vapor into the fluidized bed through an atomizing nozzle at 7.5% of the weight of the hydrophilic fumed silica; maintaining the reaction at 135°C in a sealed environment for 3.5 hours; after the reaction is completed, purging with pure nitrogen for 1 hour to remove residual gas, and cooling to room temperature to obtain hydrophobic fumed silica.

[0022] Preparation Example 2: This preparation example provides a method for preparing hydrophobic fumed silica, comprising the following steps: placing hydrophilic fumed silica powder with a specific surface area of ​​180 square meters per gram in a fluidized bed reactor; introducing dry nitrogen as a fluidizing medium and raising the bed temperature to 120°C for pre-drying and dehydration for 2 hours; injecting hexamethyldisilazane vapor into the fluidized bed through an atomizing nozzle at 5.0% of the weight of the hydrophilic fumed silica; maintaining the reaction at 120°C in a sealed environment for 3.0 hours; after the reaction is completed, purging with pure nitrogen for 1 hour to remove residual gas, and cooling to room temperature to obtain hydrophobic fumed silica.

[0023] Preparation Example 3: This preparation example provides a method for preparing hydrophobic fumed silica, comprising the following steps: placing hydrophilic fumed silica powder with a specific surface area of ​​220 square meters per gram in a fluidized bed reactor; introducing dry nitrogen as a fluidizing medium and raising the bed temperature to 150°C for pre-drying and dehydration for 2 hours; injecting hexamethyldisilazane vapor into the fluidized bed at 10.0% of the weight of the hydrophilic fumed silica through an atomizing nozzle; maintaining the reaction at 150°C in a sealed environment for 4.0 hours; after the reaction is completed, purging with pure nitrogen for 1 hour to remove residual gas, and cooling to room temperature to obtain hydrophobic fumed silica.

[0024] Example 1: This example provides a method for preparing a processed Corydalis rhizome with significantly enhanced analgesic activity. (See attached document.) Figure 1 This includes the following steps: Take 100 parts by weight of cleaned and dried Corydalis rhizome, spray the surface evenly with purified water to soften it, and control the overall moisture increase to 1.5% of the dry weight of the herb. Use a slicer to cut it into thin slices with a thickness of 2.5 mm. Spread the Corydalis rhizome slices evenly in the polytetrafluoroethylene material tray of a vacuum microwave dryer, with a material thickness of 3.0 cm. Seal the drying chamber, extract the vacuum degree in the chamber and maintain it at -0.09 MPa, set the microwave power density to 2.0 W / g, control the material surface temperature to not exceed 50°C, and continue processing for 15 minutes until the residual absolute moisture content of the material is 2.0%. Stop the microwave and break the vacuum to discharge the material. Cool the dehydrated and cell wall-breaking material to 25°C, put it into a stainless steel universal mill for pulverization, pass it through an 80-mesh sieve, and collect the Corydalis rhizome coarse powder. Take 100 parts by weight of the above-mentioned corydalis corydalis coarse powder, 10 parts by weight of citric acid monohydrate and 3 parts by weight of hydrophilic fumed silica, put them into a three-dimensional motion mixer, set the container speed to 20 revolutions per minute, and continue to dry mix for 20 minutes. The mixed powder is fed into the grinding jar of a planetary high-energy ball mill, and zirconia beads are added as grinding media. The ball-to-powder weight ratio is controlled at 10:1. The cooling water jacket is turned on to control the internal temperature of the grinding chamber at 25°C. The spindle rotation speed is set to 400 rpm, and the co-grinding reaction is carried out continuously for 45 minutes. The material is discharged, passed through a 100-mesh vibrating screen, and the undersize material is collected and vacuum-sealed in an aluminum-plastic composite packaging bag to obtain the final product.

[0025] Example 2: This embodiment provides a method for preparing Corydalis rhizome with significantly enhanced analgesic activity, including the following steps: take 100 parts by weight of cleaned dried Corydalis rhizome tubers, spray the surface evenly with purified water to soften it, control the overall moisture increase to 1.0% of the dry weight of the medicinal material, and cut it into thin slices with a thickness of 2.0 mm. Spread the Corydalis slices evenly on the PTFE material tray of the vacuum microwave dryer, with a thickness of 2.0 cm; seal the drying chamber, extract and maintain the vacuum degree in the chamber at -0.08 MPa, set the microwave power density to 1.5 W / g, control the surface temperature of the material to not exceed 45°C, and continue processing for 10 minutes until the residual absolute moisture content of the material is 3.0%, then discharge the material. Cool the dehydrated and cell-wall-breaking material to 25°C, pulverize it, pass it through a 60-mesh sieve, and collect the coarse powder of Corydalis yanhusuo. Take 100 parts by weight of the above coarse powder of Corydalis yanhusuo, 5 parts by weight of L-malic acid, and 1 part by weight of hydrophilic fumed silica, and put them into a three-dimensional motion mixer. Set the container speed to 15 revolutions per minute and continue dry mixing for 15 minutes. Put the mixed powder into the grinding jar of a planetary high-energy ball mill, add zirconia beads, control the ball-to-material weight ratio to 5:1, turn on the cooling water jacket to control the internal temperature of the grinding chamber to 15°C, set the spindle rotation speed to 300 revolutions per minute, and continuously co-grind for 30 minutes. Discharge the material, pass it through a 100-mesh vibrating screen, collect the undersize material, fill it with high-purity nitrogen, and seal it in a package to obtain the final product.

[0026] Example 3: This example provides a method for preparing Corydalis rhizome processed product with significantly enhanced analgesic activity, including the following steps: Take 100 parts by weight of cleaned dried Corydalis tubers, spray the surface evenly with purified water to soften it, and control the overall moisture increase to 2.0% of the dry weight of the medicinal material. Cut it into thin slices with a thickness of 3.0 mm. Spread the Corydalis slices flat in the material tray of the vacuum microwave dryer with a thickness of 4.0 cm. In a sealed drying chamber, the vacuum level inside the chamber is extracted and maintained at -0.095 MPa. The microwave power density is set to 2.5 W / g, and the surface temperature of the material is controlled to not exceed 55°C. The process is continued for 20 minutes until the residual absolute moisture content of the material is 1.0%. The material is then discharged. After cooling to 25°C, it is pulverized and passed through a 100-mesh sieve to collect the coarse powder of Corydalis yanhusuo. 100 parts by weight of the above coarse powder of Corydalis yanhusuo, 15 parts by weight of citric acid monohydrate, and 5 parts by weight of talc are added to a three-dimensional motion mixer. The container speed is set to 25 rpm, and the mixture is continuously dry-mixed for 30 minutes. The mixed powder is fed into a planetary high-energy ball mill, stainless steel balls are added, the ball-to-powder weight ratio is controlled at 15:1, the cooling water jacket is turned on to control the internal temperature of the grinding chamber at 30℃, the spindle rotation speed is set to 500 rpm, and the co-grind reaction is carried out continuously for 60 minutes; the material is discharged, passed through a 120-mesh vibrating screen, the undersize material is collected and vacuum-sealed for packaging, and the product is obtained.

[0027] Example 4: This example provides a method for preparing Corydalis rhizome processed product with significantly enhanced analgesic activity, including the following steps: Take 100 parts by weight of cleaned and dried Corydalis rhizome, spray the surface evenly with purified water to soften it, and control the overall moisture increase to 1.5% of the dry weight of the herb. Cut it into thin slices with a thickness of 2.5 mm. Spread the Corydalis rhizome slices flat in the material tray of a vacuum microwave dryer with a thickness of 3.0 cm. Seal the drying chamber, extract the vacuum degree in the chamber and maintain it at -0.09 MPa, set the microwave power density to 2.0 W / g, control the surface temperature of the material to not exceed 50°C, and continue processing for 15 minutes until the residual absolute moisture content of the material is 2.0%. Discharge the material. Cool to 25°C, pulverize, pass through an 80-mesh sieve, and collect the coarse powder of Corydalis yanhusuo; take 100 parts by weight of the above coarse powder of Corydalis yanhusuo, 10 parts by weight of citric acid monohydrate and 3 parts by weight of hydrophobic fumed silica prepared in Preparation Example 1, put them into a three-dimensional motion mixer, set the container speed to 20 revolutions per minute, and continue to dry mix for 20 minutes. The mixed powder is fed into a planetary high-energy ball mill, zirconia beads are added, the ball-to-powder weight ratio is controlled at 10:1, the internal temperature of the grinding chamber is controlled at 25℃, the spindle rotation speed is set at 400 rpm, and the continuous co-grinding reaction is carried out for 45 minutes; the material is discharged, passed through a 100-mesh vibrating screen, the undersize material is collected and vacuum-sealed for packaging, and the product is obtained.

[0028] The difference between this embodiment and Example 1 is that in the multi-component dry phase premixing and ball milling steps, hydrophilic fumed silica is replaced with an equal amount of hydrophobic fumed silica, while the remaining process steps and parameters are the same.

[0029] Comparative Example 1: Compared with Example 1, the difference is that microwave dehydration and cell wall breaking and solid phase salt formation process were not used. Instead, the Corydalis vinegar processing process in the current edition of the Chinese Pharmacopoeia was used. The Corydalis was mixed with liquid rice vinegar and thoroughly moistened before being stir-fried at high temperature. All other aspects were the same.

[0030] Comparative Example 2: Compared with Example 1, the difference is that the microwave vacuum dehydration and cell wall breaking steps are omitted. Conventional dried slices are directly crushed and ball-milled. All other aspects are the same.

[0031] Comparative Example 3: Compared with Example 1, the difference is that citric acid monohydrate was not added in the multi-component dry phase premixing and ball milling steps, but instead an equimolar amount of liquid glacial acetic acid was sprayed in during ball milling, and an 80°C drying step was added after ball milling, and the rest were the same.

[0032] Comparative Example 4: Compared with Example 1, the difference is that hydrophilic fumed silica was not added in the multi-component dry phase premixing and ball milling steps, while the rest are the same.

[0033] Test Example 1: Engineering Feasibility and Powder Rheology Test This test case aims to verify the effectiveness of adding specific micro-powder excipients in counteracting the mechanochemical gelatinization of natural medicinal material matrices under prolonged mechanical work, and to examine the engineering feasibility of the solid-phase in-situ salt formation process of this invention in actual continuous production.

[0034] Record the total mass of materials fed into the grinding jar of the ball mill in Examples 1 to 4 and Comparative Example 4. Complete the dry mixing and high-energy ball milling operations according to the programs and parameters set for each group. After the program is completed, open the grinding jar and observe and record the material adhesion and agglomeration state on the inner wall, bottom and surface of the grinding media.

[0035] The material in the tank is sieved through a vibrating screen, and the undersize powder is collected and accurately weighed. The actual process yield of each group is calculated as the ratio of the actual collected undersize mass to the total feed mass.

[0036] The angle of repose of the collected powder was determined using the fixed funnel method. The funnel was fixed to a lifting bracket on a horizontal table, and the vertical height of the lower end of the funnel from the table was adjusted to 3.0 cm. Graph paper was placed below the funnel. The sieved powder was slowly poured into the funnel, allowing it to fall naturally and accumulate into a cone. Feeding was stopped when the tip of the cone touched the lower end of the funnel. The diameter of the cone's base was measured, and the radius was calculated. The arctangent value was calculated using the ratio of the cone's height to its base radius, yielding the angle of repose. Each sample was measured in triplicate, and the average value was taken. If the powder had extremely poor flowability and could not flow naturally out of the funnel or form a regular cone, it was recorded as unmeasurable.

[0037] Table 1. Process yield and rheological test results for each group of samples.

[0038] According to the data in Table 1, the process yields of Examples 1 to 4 ranged from 94.8% to 97.1%, and the powder angle of repose ranged from 30.5° to 33.7°. In conventional formulation processes, an angle of repose of less than 40° meets the requirements for powder flowability in industrial automated capsule filling or tableting. Comparative Example 4, due to the absence of excipients such as fumed silica, had an actual process yield of only 14.2%, and discharge was difficult. Most of the material formed a high-viscosity, hard, gel-like layer on the inner wall of the ball mill grinding chamber and the surface of the grinding media. The small amount of residual material collected was in irregular clumps, making it impossible to determine the angle of repose using a funnel.

[0039] Corydalis contains a large amount of starch. When ground for a long time without the addition of excipients, the starch granules will generate heat due to continuous friction and compression, and then gelatinize, causing the originally dry powder to lose its fluidity and clump together.

[0040] In this embodiment, extremely fine fumed silica or talc powder is added. During the initial mixing and grinding stages, these fine excipients are evenly distributed and adhere to the surface of the Corydalis powder, forming a physical barrier. This barrier prevents direct contact between starch particles during mechanical extrusion, effectively reducing the accumulation of heat generated by friction.

[0041] Comparative Example 4, lacking the addition of such physical barrier additives, completely agglomerated into lumps during grinding. This test verifies that the proposed method of using fine inorganic powders to prevent the gelatinization and agglomeration of high-starch materials during grinding is feasible, and this is a prerequisite for ensuring the continuous operation of this solid-state processing technology.

[0042] Test Example 2: Solid-phase salt formation conversion rate test This test case aims to verify the authenticity and conversion efficiency of the solid-phase in-situ salt formation reaction between solid organic acids and free alkaloids of Corydalis yanhusuo induced by high-energy mechanical shearing under conditions of room temperature and absence of macroscopic liquid solvent.

[0043] Accurately weigh 2.0 g each of the sample powders prepared in Examples 1 to 4, Comparative Examples 2 and 3, and place them in stoppered conical flasks. Add 50 mL of chloroform, sonicate for 30 minutes, filter, and collect the filtrate. Wash the residue twice with 10 mL of chloroform each time. Combine the filtrate and washings, evaporate to dryness on a water bath, dissolve the residue in methanol, transfer to a 10 mL volumetric flask, shake well, filter through a 0.45 μm microporous membrane, and use the filtrate as the test solution for free alkaloids.

[0044] Take 2.0 g of each of the corresponding batches of sample powder mentioned above, accurately weigh them, and place them in a stoppered conical flask. Add 50 mL of 70% methanol aqueous solution, sonicate for 45 minutes, filter, and wash the residue twice with 10 mL of 70% methanol aqueous solution each time. Combine the extracts and evaporate them on a water bath until no alcohol odor remains. Dissolve the residue in methanol and transfer it to a 10 mL volumetric flask, shake well, filter through a 0.45 μm microporous membrane, and use the filtrate as the total alkaloid test solution.

[0045] Weigh an appropriate amount of corydaline reference standard, dissolve and dilute it in methanol to prepare a solution containing 1.0 mg per 1 ml, which is used as the reference solution.

[0046] The determination was performed using high performance liquid chromatography (HPLC). The chromatographic column was an octadecylsilane-bonded silica column. The mobile phase was methanol-0.1% phosphoric acid aqueous solution with gradient elution. The detection wavelength was set to 280 nm. The flow rate was 1.0 mL per minute. The column temperature was controlled at 30 °C.

[0047] Accurately pipette 10 μL each of the reference solution and each test solution into the liquid chromatograph and record the chromatograms. Calculate the absolute content of free corydaline and the absolute content of total corydaline in each group of samples using the external standard method. The formula for calculating the solid-phase salt formation conversion rate is: (Total corydaline content - Free corydaline content) divided by total corydaline content, and the result multiplied by 100%; each group of samples was measured in parallel 3 times, and the average value was taken.

[0048] Table 2. Results of Corydaline content and solid-phase salt conversion rate determination in each group of samples.

[0049] According to the data in Table 2, the solid-phase salt formation conversion rates of Examples 1 to 4 ranged from 88.9% to 94.4%. In the absence of a macroscopic liquid-phase reaction medium, free fumarate was converted to an organic acid salt form. The total alkaloid content of Comparative Example 2 was similar to that of the Examples, but its free fumarate content was measured at 3.82 mg / g, and its solid-phase salt formation conversion rate was only 42.8%. The total fumarate content of Comparative Example 3 decreased to 5.42 mg / g, and its solid-phase salt formation conversion rate was 75.3%.

[0050] Chemical reactions between solid materials are generally difficult to occur because it is hard for reactant molecules to come into sufficient contact. The active ingredients of Corydalis are encapsulated inside plant cells, and the dense cell walls form a natural physical barrier.

[0051] This embodiment employs a microwave vacuum pretreatment process. Under negative pressure, the water inside the cells is rapidly heated, turning into gas and expanding in volume, thus disrupting the rigid cell wall structure and creating numerous microchannels. This process directly opens up space for the subsequent entry of reactants. In the subsequent mixing and grinding stage, mechanical impact causes the solid organic acids to release a very small amount of water. This water creates a localized micro-humid environment at the powder contact surface, which helps the organic acids and alkaloids combine, thus successfully completing the salt formation transformation in the dry powder state.

[0052] In contrast, in Comparative Example 2, the cell walls remained intact due to the lack of a microwave-induced cell disruption step. Relying solely on conventional surface grinding, solid acids struggle to penetrate this barrier and react inside the cells, resulting in a lower proportion of cells ultimately converted into salts.

[0053] Although Comparative Example 3 replaced the solid organic acid with liquid glacial acetic acid, the liquid was difficult to mix evenly in the dry powder and was prone to evaporation. Due to the addition of liquid, a drying step at 80°C had to be added later. This not only accelerated the volatilization and loss of the acid, but the high temperature also destroyed some heat-sensitive active ingredients, resulting in a significantly lower total content of active substances compared to other groups.

[0054] These test data confirm that the proposed method first uses microwaves to disrupt cell walls, and then utilizes the trace amounts of water released during grinding by solid acid to assist the reaction. This combined technology is feasible and has successfully transformed the originally insoluble components in traditional Chinese medicine into easily absorbed salts under conditions of room temperature and almost no water.

[0055] Test Example 3: Comparison Test of Retention Rate of Active Ingredients and Thermal Degradation Impurities This test case aims to investigate the effect of microwave vacuum dehydration combined with room temperature solid-phase co-grinding process on inhibiting the degradation of heat-sensitive alkaloids and controlling the formation of related substances, and to compare and analyze the effects of traditional high-temperature processing and liquid-phase heating processes on the stability of the chemical composition of Corydalis yanhusuo.

[0056] Take 1.0 g each of untreated Corydalis rhizome powder, sample powder prepared in Example 1, Comparative Example 1, and Comparative Example 3, accurately weigh them, and place them in a stoppered conical flask. Add 50 mL of a methanol-concentrated ammonia solution mixture (volume ratio 50:1), weigh it, and sonicate for 45 minutes.

[0057] After cooling, weigh the solution again, replenish the lost weight with the above mixed solution, shake well, and filter. Accurately measure 25 mL of the filtrate, place it in an evaporating dish, and evaporate to dryness on a water bath. Dissolve the residue in methanol and transfer it to a 10 mL volumetric flask, shake well, filter through a 0.22 μm microporous membrane, and use the filtrate as the test solution.

[0058] Accurately weigh appropriate amounts of corydaline B reference standard and corydaline A reference standard, dissolve and dilute them in methanol to prepare a mixed solution containing 0.5 mg of corydaline B and 0.2 mg of corydaline A per 1 ml, which is used as the reference solution.

[0059] The determination was performed using high-performance liquid chromatography (HPLC). The chromatographic column was an octadecylsilane-bonded silica column. Mobile phase A was acetonitrile, and mobile phase B was 0.1% aqueous phosphoric acid solution. A gradient elution program was used, specifically: 0 to 20 minutes, 15% to 25% A; 20 to 40 minutes, 25% to 45% A; 40 to 60 minutes, 45% to 60% A. The detection wavelength was set to 280 nm. The flow rate was 1.0 mL per minute, and the column temperature was controlled at 30 °C.

[0060] Accurately pipette 10 μL each of the reference solution and each test solution and inject them into the liquid chromatograph. Record the chromatograms within 60 minutes and calculate the absolute contents of corydaline and corydaline in each group of samples using the external standard method.

[0061] Using the sum of the contents of corydaline and corydaline in the original medicinal material as the theoretical baseline, the retention rate of the effective components in each group of samples was calculated. After subtracting the solvent peak and the known main peaks of corydaline and corydaline, the peak areas of all remaining elution peaks in the chromatogram were integrated and summed to obtain the total peak area of ​​thermally degraded impurities. Each group of samples was measured in triplicate, and the average value was taken.

[0062] Table 3. Results of retention rate of effective components and peak area of ​​thermally degraded impurities for each group of samples.

[0063] According to the data in Table 3, the contents of corydaline B and corydaline A in Example 1 were close to those of the original medicinal material, with an effective component retention rate of 97.2% and a total impurity peak area of ​​1362.8 mAUs, showing a limited increase compared to the original medicinal material. In Comparative Example 1, the effective component retention rate decreased to 68.4%, and the total impurity peak area increased to 8634.2 mAUs. In Comparative Example 3, the effective component retention rate was 74.9%, and the total impurity peak area was 6917.5 mAUs.

[0064] The main alkaloid components in Corydalis are relatively sensitive to heat. When exposed to heat or oxygen, their molecular structure is easily destroyed or oxidized, degrading into impurities with no pharmacological activity.

[0065] Comparative Example 1 employed a traditional vinegar-roasting process, where the materials, after being soaked in rice vinegar, needed to be dried at high temperatures. The liquid environment itself accelerates side reactions, and the high-temperature roasting directly damages these heat-sensitive components, ultimately leading to a decrease in the content of active ingredients and the accumulation of impurities. Although Comparative Example 3 added liquid glacial acetic acid during grinding, the introduction of liquid necessitated an additional drying step at 80°C. Continuous high-temperature heating also exacerbated the degradation and loss of active ingredients, which was visually reflected in the test data as a reduction in active ingredients and an increase in impurities.

[0066] This embodiment employs negative pressure microwaves, which lower the temperature required for moisture evaporation by using negative pressure, allowing the material to be dehydrated while its surface temperature does not exceed 50°C. In the subsequent grinding stage, a cooling water jacket is used to strictly control the internal temperature of the equipment at around 25°C. The entire processing is maintained at a low temperature and in a dry powder state.

[0067] Because of the absence of a large amount of liquid and minimal overall heating, this environment is insufficient to trigger destructive reactions in the active ingredients. This mechanism ensures the smooth progress of solid-state salt formation while maximally maintaining the stability of the original alkaloid structure and reducing degradation side reactions. Test results confirm that strict temperature control and a liquid-free dry-phase processing environment are the key technological foundations for protecting heat-sensitive active ingredients in traditional Chinese medicine from degradation.

[0068] Test Example 4: Comparative Test of In Vitro Biopharmaceutical Dissolution Prepare the experimental equipment according to Method II (paddle method) of the Dissolution and Release Determination Method in the Chinese Pharmacopoeia. Prepare a hydrochloric acid solution with pH 1.2 as the artificial gastric juice dissolution medium. Measure 900 ml of this dissolution medium and inject it into each dissolution vessel. Turn on the water bath circulation system and set and maintain the temperature of the dissolution medium at a constant 37 ± 0.5℃.

[0069] Set the stirring paddle speed to 50 revolutions per minute. Take the powder samples prepared in Examples 1 to 4, Comparative Examples 1 and 2 respectively. Calculate the total alkaloid content in the previous test and accurately weigh the powder equivalent to 5.0 mg of corydaline in each group of samples. Add the powder evenly to the surface of the medium in each dissolution vessel and start timing.

[0070] At sampling times of 5, 10, 15, 30, 45 and 60 minutes, 5 ml of dissolution solution was taken from a fixed position in each dissolution vessel, and blank dissolution medium of the same volume and temperature was immediately added to the dissolution vessel.

[0071] The obtained dissolution solutions at each time point were filtered through a 0.45-micrometer microporous membrane, and the filtrate was used as the test solution. Separately, corydaline reference standard was accurately weighed, dissolved in methanol, and diluted with dissolution medium to prepare a solution containing 5.5 micrograms per milliliter, which was used as the reference solution.

[0072] High-performance liquid chromatography (HPLC) was used for determination. Chromatographic conditions were the same as in Test Example 2. The dissolution rate of corydaline in each group of samples at different time points was calculated using the external standard method, and the cumulative dissolution percentage was calculated. Six samples were measured in parallel for each group, and the arithmetic mean was taken.

[0073] Table 4. Results of cumulative dissolution of corydaline in each group of samples at different time points (%)

[0074] According to the data in Table 4, the cumulative dissolution rates of Examples 1 to 3 all reached over 87% within 15 minutes, exhibiting typical immediate-release characteristics and maintaining a supersaturated dissolution plateau in the subsequent time period. The initial dissolution rate of Example 4 was slightly lower than the first three groups, but the dissolution rate reached 94.2% at 60 minutes. Comparative Example 1 had a cumulative dissolution rate of only 61.2% at 60 minutes, indicating extremely slow initial drug release. Comparative Example 2 had a higher dissolution rate than Comparative Example 1, but its cumulative dissolution rate at 15 minutes was only 52.1%, significantly lower than all the other example groups.

[0075] The rate at which plant medicinal powder dissolves in a liquid depends primarily on whether the liquid can quickly penetrate the powder and dissolve and bring out the active ingredients.

[0076] Comparative Example 1 used the traditional vinegar-processing method, which preserved the plant cell structure of Corydalis yanhusuo. This resulted in the insoluble active ingredients remaining encapsulated within the cell tissue. External liquids required a long time to slowly penetrate the cell wall, a natural barrier, thus leading to a very slow drug release.

[0077] Although Comparative Example 2 employed conventional pulverization and salt conversion processes to make some active ingredients more soluble in water, the lack of prior cell wall disruption meant that intact cell walls remained blocked. Water penetration was difficult, and the dissolved salts also struggled to diffuse outwards, resulting in a limited dissolution rate in the initial stages and hindering rapid release.

[0078] In Example 4, the addition of hydrophobic fumed silica excipients resulted in these water-repellent fine particles coating the surface of the medicinal powder. This made it difficult for the liquid to quickly wet the powder initially, slowing down the water penetration process. This directly explains why the solubility data at the 5th and 10th minutes were relatively low. However, with continuous stirring and the ongoing penetration of the liquid, the active ingredients that had already formed salts were eventually able to completely dissolve and be released, so the overall final solubility was not substantially affected.

[0079] Test Example 5: In vivo pharmacodynamic analgesic onset time comparison test This test case aims to investigate the in vivo drug release conversion behavior of high in vitro dissolution in animal models and to verify the effects of microwave pretreatment and solid-phase in-situ salt formation technology on the analgesic onset time and overall pain inhibition efficacy of Corydalis extract.

[0080] Forty healthy male Kunming mice, weighing 20 to 25 grams, were randomly divided into four groups of 10 mice each after 3 days of acclimatization. The groups included a blank control group, Example 1 group, Comparative Example 1 group, and Comparative Example 2 group.

[0081] Before use, each group of test sample powders was suspended in a 0.5% sodium carboxymethyl cellulose aqueous solution to prepare suspensions with equal amounts of crude drug. An equal volume of 0.5% sodium carboxymethyl cellulose aqueous solution was prepared for the blank control group.

[0082] Mice were fasted for 12 hours before the experiment, but had free access to water. Each 10 grams of mouse body weight was administered 0.10 ml of the corresponding suspension or blank solvent via gavage.

[0083] Fifteen minutes after oral administration, 0.10 ml of 0.6% glacial acetic acid saline solution was injected intraperitoneally per 10 g of mouse body weight to induce a pain response in chemical peritonitis.

[0084] The time span during which mice first exhibited a writhing response (abdominal retraction, trunk extension, and hind limb extension) after intraperitoneal injection of glacial acetic acid was recorded and denoted as the writhing latency. Simultaneously, the total number of writhing episodes in each group of mice within 15 minutes after injection was observed and recorded.

[0085] The formula for calculating the torsional inhibition rate is as follows: (The average number of writhing movements in the blank control group minus the average number of writhing movements in the drug treatment group) divided by the average number of writhing movements in the blank control group, and then multiplied by 100%.

[0086] Table 5. Results of writhing latency and analgesic inhibition rate in mice of each group.

[0087] According to the data in Table 5, mice in the blank control group showed a rapid pain response after injection of glacial acetic acid, with an average writhing latency of 3.15 minutes and 46.8 writhing movements within 15 minutes. In Example 1 group, the writhing latency was prolonged to 11.42 minutes, and the number of writhing movements decreased to 12.6, with an analgesic inhibition rate of 73.07%. In Comparative Example 1 group, the latency was 4.83 minutes, the number of writhing movements was 34.5, and the inhibition rate was 26.28%. In Comparative Example 2 group, the latency was 7.36 minutes, the number of writhing movements was 23.2, and the inhibition rate was 50.42%.

[0088] The in vivo onset time of oral solid dosage forms of traditional Chinese medicine is limited by the rate of wetting, disintegration, dissolution, and subsequent transmembrane absorption in gastrointestinal fluids. Comparative Example 1, processed with vinegar, preserved the intact tissue structure of Corydalis rhizome, with the active ingredient primarily existing in the form of free alkali. This form exhibits low equilibrium solubility under the physiological pH environment of the gastrointestinal tract, and the diffusion of solutes from within the tissue requires overcoming mass transfer resistance from the plant cell wall, resulting in slow in vitro dissolution. Within the 15-minute onset window after administration, the total amount of active substance entering the bloodstream was limited, failing to form a high peak blood concentration, exhibiting a short latency period and low inhibition rate.

[0089] In Comparative Example 2, the powder underwent a solid-phase salt formation reaction after high-energy mechanical co-milling, converting the alkaloids into highly water-soluble organic acid salts. The increased hydration energy of the salt molecules improved the system's solubility. However, since the raw material was not pretreated with microwave cell disruption, the intact cellulose and pectin networks created steric hindrance. The penetration of gastrointestinal fluids into the powder and the outward diffusion of dissolved salt molecules were still limited by physical barriers. Due to the release rate, its in vivo absorption was delayed, and the overall analgesic onset time and inhibitory efficacy were inferior to those of Example 1.

[0090] Example 1 combines negative pressure microwave-induced cell wall disruption with mechanochemical salt formation. Microwave treatment lowers the boiling point of water, and the expansion stress generated by the vaporization of residual water inside cells disrupts the dense structure of the cell wall, forming mesoporous channels within the powder. High-energy ball milling disrupts the original crystal lattice of the drug and completes in-situ amorphous salt formation. After oral administration, the porous powder topology reduces gastric juice wetting resistance, allowing fluid to rapidly penetrate into the tissue along microscopic fissures. Amorphous alkaloid organic acid salts in a high thermodynamic energy state undergo instantaneous dissolution under conditions of lack of physical steric hindrance. This superimposed mechanism of physical structural modification and chemical phase transition shortens the mass transfer time of the active ingredient from the solid matrix to the body fluid, increasing the drug absorption per unit time. Data confirms that this mechanism can rapidly increase blood drug concentration in the early stages of administration, manifested in animal models as a significant prolongation of the latency period of the first pain response and effective inhibition of pain behavior.

[0091] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A processed traditional Chinese medicine product, characterized in that, Made from the following ingredients in parts by weight: 100 parts of coarsely ground Corydalis rhizome; 5-15 parts of solid organic acids; 1-5 parts of inorganic powder excipients.

2. The processed traditional Chinese medicine product according to claim 1, characterized in that: The solid organic acid is selected from at least one of citric acid monohydrate or L-malic acid; The inorganic powder additive is selected from at least one of hydrophilic fumed silica, hydrophobic fumed silica, or talc.

3. The processed traditional Chinese medicine product according to claim 2, characterized in that: The inorganic powder additive is hydrophobic fumed silica, and the hydrophobic fumed silica is prepared by the following method: Hydrophilic fumed silica powder was placed in a fluidized bed reactor, and dry nitrogen gas was introduced as a fluidizing medium and the temperature was raised for pre-drying and dehydration. Subsequently, hexamethyldisilazane vapor was injected into the fluidized bed, and the reaction was carried out under closed conditions. After the reaction was completed, nitrogen gas was introduced to purge and the mixture was cooled to room temperature to obtain hydrophobic fumed silica.

4. The processed traditional Chinese medicine product according to claim 3, characterized in that: In the method for preparing hydrophobic fumed silica, the pre-drying temperature is 120℃~150℃ and the time is 2 hours; the amount of hexamethyldisilazane vapor injected is 5.0%~10.0% of the weight of hydrophilic fumed silica; the temperature of the heat preservation reaction is 120℃~150℃ and the time is 3.0~4.0 hours.

5. A method for preparing a processed traditional Chinese medicine, as described in any one of claims 1-4, characterized in that, Includes the following steps: S1. Take the cleaned dried Corydalis tubers, soften and slice them, then place them in a microwave vacuum device for dehydration and cell wall breaking treatment, then cool, crush and sieve to obtain porous Corydalis coarse powder. S2. Add the coarse powder of Corydalis yanhusuo obtained in step S1, inorganic powder excipients and solid organic acid into a mixer and dry mix them evenly so that the inorganic powder excipients adhere to the powder surface to form a barrier layer. S3. The mixed powder after dry mixing in step S2 is put into a high-energy ball mill. The grinding chamber is kept at a low temperature to carry out a continuous solid-phase co-grinding reaction. The final product is obtained after discharge sieving.

6. The method for preparing a processed traditional Chinese medicine according to claim 5, characterized in that: In step S1, the dried Corydalis tubers are pre-treated by softening and slicing as follows: the surface is evenly sprayed with purified water to soften, and the overall moisture increase is controlled to be 1.0% to 2.0% of the dry weight of the medicinal material. Then, they are sliced ​​into thin slices with a thickness of 2.0 to 3.0 mm.

7. The method for preparing a processed traditional Chinese medicine according to claim 5, characterized in that: In step S1, the specific implementation method of the dehydration and cell wall breaking treatment is as follows: Corydalis flakes are spread flat in a polytetrafluoroethylene material tray with a thickness of 2.0 to 4.0 cm; a sealed drying chamber is used, with the vacuum degree inside the chamber controlled at -0.08 MPa to -0.095 MPa, the microwave power density set at 1.5 to 2.5 W / g, and the surface temperature of the material controlled at no more than 45°C to 55°C. The treatment is continued for 10 to 20 minutes until the residual absolute moisture content of the discharged material is controlled at 1.0% to 3.0%.

8. The method for preparing a processed traditional Chinese medicine according to claim 5, characterized in that: In step S2, the parameters for dry mixing are as follows: a three-dimensional motion mixer is used, the container speed is set to 15-25 rpm, and dry mixing is continued for 15-30 minutes.

9. The method for preparing a processed traditional Chinese medicine according to claim 5, characterized in that: In step S3, the specific process parameters are as follows: the high-energy ball mill is a planetary high-energy ball mill, with zirconia beads or stainless steel balls added as grinding media, and the ball-to-material weight ratio controlled at 5:1 to 15:1; the cooling water jacket is turned on to control the internal temperature of the grinding chamber at 15℃ to 30℃; the spindle rotation speed is set to 300 to 500 rpm, and the time is 30 to 60 minutes. Furthermore, the entire solid-phase co-milling reaction is controlled to be carried out in a completely dry phase powder state without the addition of any liquid solvent; after the reaction product is discharged and sieved, it is stored by vacuum sealing or by filling high-purity nitrogen gas into sealed packaging.

10. The application of the processed traditional Chinese medicine as described in any one of claims 1-4 in the preparation of analgesic drugs, characterized in that: The analgesic drug is an immediate-release oral solid dosage form used to suppress pain responses induced by chemical stimuli.

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