Preparation method of Duliang prescription composition, preparation and dripping pill preparation method

Abstract

The invention relates to the technical field of medicine preparation, and discloses a Duliang prescription composition preparation method and a preparation and dripping pill preparation method, the Duliang prescription composition preparation method comprises the following steps: angelica dahurica extraction: adopting a continuous countercurrent method to extract crushed angelica dahurica to obtain an extracting solution; extracting ligusticum wallichii: extracting the crushed ligusticum wallichii by adopting a segmented continuous gradient countercurrent method; and merging: mixing the upper layer oily substance of the angelica dahurica thick paste, the upper layer oily substance of the ligusticum wallichii thick paste 1 and the thick paste 3 to prepare the Duliang prescription composition. According to the scheme, the solute diffusion efficiency is improved by adopting a continuous countercurrent extraction process, so that the extraction production efficiency is improved, and the volatile oil and the water-soluble components of the ligusticum wallichii are synchronously and efficiently extracted by adopting a mode of extracting the ligusticum wallichii in stages by adopting ethanol gradient concentration; the lower-layer solution of the radix angelicae and the ligusticum wallichii is mixed with the low-concentration ethanol thick paste of the ligusticum wallichii, the mixture is further subjected to alcohol precipitation to remove impurities, and finally oily substances are combined, so that the maximum retention of oil-water two-phase effective components is realized.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, in particular to a preparation method and preparation of a Duliangfang composition and a preparation method of a dripping pill. Background Art

[0002] The ancient Duliang formula originates from Wang Qiu's "Shi Zhai Bai Yi Xuan Fang" (A Selection of Prescriptions from a Chinese Studio) from the Song Dynasty. Duliang Pills are made from a single ingredient, Angelica dahurica, ground into powder and mixed with refined honey. They are effective for treating dizziness caused by various wind-related symptoms, including hemicranial headaches. Modern Duliang Pills, from the "Beijing Collection of Traditional Chinese Medicine Formulas," consist of Angelica dahurica and Ligusticum chuanxiong in a 4:1 ratio by weight. Duliang preparations currently included in the Pharmacopoeia of the People's Republic of China (2020 Edition, Volume 1) include pills, soft capsules, and drop pills. Angelica dahurica is the main ingredient in this formula, known for its pungent, warm, and aromatic properties. It effectively dispels wind and cold from the head, clears the orifices, and relieves pain. It is supplemented by the pungent and dispersing Ligusticum chuanxiong, which invigorates blood circulation, promotes qi circulation, and dispels wind. This combination of herbs dispels wind and cold, harmonizes qi and blood, dispels wind and cold, and activates blood circulation to relieve pain. The two herbs work together to dispel wind and cold, activate blood circulation, and unclog the meridians. This formula treats headaches caused by wind-cold invading the head, obstruction of clear yang qi, and stagnation of qi and blood. Modern pharmacological research has shown that "Duliang Pills" has a significant analgesic effect, which may be related to the content of neurotransmitters such as 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) that affect pain regulation; and is related to the inhibition of c-fos gene expression in peripheral tissues.

[0003] Continuous countercurrent extraction technology involves flowing liquid in the opposite direction of the solid material being extracted during the extraction process. This maintains a high concentration difference between the active ingredient in the raw material and the solvent, thereby increasing the driving force of the entire extraction process and avoiding the problem of a gradual decrease in concentration difference during intermittent extraction. This method not only improves the overall extraction rate and processing efficiency, but also reduces solvent usage. The continuous operation also increases equipment utilization.

[0004] Chinese patent CN107320454A discloses a method for preparing Duliang Dropping Pills. It involves percolating and extracting Angelica dahurica and Chuanxiong rhizome. The extracts are mixed with melted PEG4000 and PEG6000 in an emulsifier, followed by dripping, using liquid paraffin as a coolant. This method is consistent with the preparation method for Duliang Dropping Pills in Part I of the 2020 edition of the Chinese Pharmacopoeia.

[0005] The above method clarifies the percolation extraction method of Angelica dahurica and Ligusticum chuanxiong and the preparation process of the pellets. The percolation method is a method in which moderately crushed medicinal materials are placed in a percolation cylinder, and a solvent is continuously added from the top. The solvent seeps through the medicinal material layer and flows downward to leach the medicinal material components. Although percolation is a dynamic leaching method with high solvent utilization, complete leaching of effective ingredients, and the leachate can be directly collected, the percolation process, however, has a long production cycle, low production efficiency, and a low retention rate of effective ingredients. In addition, liquid paraffin has a low viscosity, and when used as a coolant, the pellets descend quickly, resulting in slightly poor roundness of the pellets. In response to the above problems, the present application is proposed. Summary of the Invention

[0006] The purpose of the present invention is to provide a preparation method of a Duliangfang composition, a preparation and a preparation method of a dropping pill, which adopts a continuous countercurrent extraction process to improve the extraction production efficiency, thereby overcoming the problems of long production cycle, low production efficiency and low effective ingredient retention rate in the traditional Duliang preparation process.

[0007] The present invention is achieved through the following technical solutions.

[0008] The preparation method of the Duliangfang composition of the present invention comprises grinding angelica dahurica and chuanxiong rhizome, continuous countercurrent extraction of angelica dahurica, segmented continuous countercurrent extraction of chuanxiong rhizome, low-temperature concentration of the extract, static stratification of the concentrate and alcohol precipitation, and the following steps: Angelica dahurica extraction: Grind the Angelica dahurica to a set particle size, soak it with the extraction solution at a ratio of 1:1-1.5 until it is thoroughly soaked, and then put the soaked Angelica dahurica powder into a continuous countercurrent extraction device. The crushed Angelica dahurica is extracted using a continuous countercurrent method to obtain an extract. During the extraction process, a medium at a certain temperature is passed through the interlayer of the device to stabilize the temperature of the extraction process. When the medicinal material is pushed to the middle and back section of the device, the liquid inlet is opened so that it flows in the opposite direction of the medicinal material advancement, and the extract is received at the same time. The extract is concentrated at low temperature into a thick paste of Angelica dahurica. After the thick paste of Angelica dahurica is allowed to stand and separate, the upper oil layer and the lower solution layer are collected separately; Extraction of Chuanxiong: Crush the Chuanxiong to a set particle size, soak it with the extraction solution at a ratio of 1:1 to 1.5 until it penetrates the core, put the soaked Chuanxiong powder into a continuous countercurrent extraction device, and extract the crushed Chuanxiong using a segmented continuous gradient countercurrent method. The extraction process is the same as the extraction step of Angelica dahurica, except that the extraction is carried out in two stages using solvents of different concentrations as solvents, preferably using high and low concentrations of ethanol for segmented extraction, and extracts are obtained by segmented extraction of the two ethanol concentrations. The extracts are concentrated separately, and the high-concentration ethanol extract is concentrated into Chuanxiong thick paste 1. After the Chuanxiong thick paste 1 is allowed to stand for stratification, the upper oil layer and the lower solution layer are collected respectively; the low-concentration ethanol extract is concentrated into Chuanxiong thick paste 2; Merge: Combine the lower layer solution of Angelica dahurica thick paste, the lower layer solution of Chuanxiong thick paste 1 and Chuanxiong thick paste 2, add ethanol and stir to precipitate, let stand, take the supernatant and concentrate at low temperature to form thick paste 3, the alcohol precipitation serves to remove impurities, and mix the upper layer oily matter of Angelica dahurica thick paste, the upper layer oily matter of Chuanxiong thick paste 1 and thick paste 3 to prepare the Duliangfang composition.

[0009] Furthermore, in the steps of extracting Angelica dahurica and extracting Ligusticum chuanxiong, Angelica dahurica and Ligusticum chuanxiong are crushed and then passed through a 6-10 mm sieve to obtain Angelica dahurica coarse powder and Ligusticum chuanxiong coarse powder.

[0010] Preferably, the Angelica dahurica and Ligusticum chuanxiong medicinal materials are crushed and passed through a 10 mm sieve or a 6 mm sieve.

[0011] Furthermore, in the Angelica dahurica extraction step, the extraction solvent is 70%~95% ethanol, the temperature during the extraction process is 20~40°C, the solid-liquid ratio is 1:4~12, and the extraction time is 2~16h.

[0012] Preferably, in the Angelica dahurica extraction step, the extraction solvent is 84% to 86% ethanol, the temperature during the extraction process is 25° C. to 30° C., the solid-liquid ratio is 1:5 to 7, and the extraction time is 6 to 8 hours.

[0013] Furthermore, in the step of segmented extraction of Chuanxiong, the first extraction solvent is 70%~95% ethanol, the second extraction solvent is 40%~70% ethanol, the temperature during the extraction process is 20~40°C, the solid-liquid ratio is 1:4~12, and the extraction time is 2~16h.

[0014] Preferably, in the step of segmented extraction of Chuanxiong, the first extraction solvent is 88% to 92% ethanol, the second extraction solvent is 50% to 55% ethanol, the temperature during the extraction process is 25°C to 35°C, the solid-liquid ratio is 1:6 to 9, and the extraction time is 6 to 10 hours.

[0015] Furthermore, the Angelica dahurica extract was concentrated to a relative density of 1.00-1.20 (t=45°C) to obtain Angelica dahurica thick paste, and the Chuanxiong first segment extract and the Chuanxiong second segment extract were concentrated to a relative density of 1.20-1.30 (t=45°C) to obtain Chuanxiong thick paste 1 and Chuanxiong thick paste 2.

[0016] Preferably, the relative density of the Angelica dahurica paste is 1.05-1.08 (t=45°C), and the relative density of the Chuanxiong thick paste 1 and Chuanxiong thick paste 2 is 1.25-1.28 (t=45°C).

[0017] Furthermore, the Angelica dahurica paste and the Chuanxiong thick paste 1 were respectively allowed to stand at 5-40° C. for 4-24 hours, and the upper oily substance was collected after standing.

[0018] Preferably, the Angelica dahurica paste and the Chuanxiong Rhizome paste 1 are respectively allowed to stand at 20-30° C. for 12-16 hours, and the upper oily substance is taken after standing.

[0019] Furthermore, in the combining step, the supernatant was concentrated at low temperature to a relative density of 1.20-1.30 (t=45°C) to obtain a thick paste 3.

[0020] Furthermore, the alcohol precipitation step of the combined solution of the lower layer solution of Angelica dahurica paste, the lower layer solution of Chuanxiong paste 1 and Chuanxiong paste 2 is: adding 95% ethanol under stirring until the alcohol content is 50% to 80%.

[0021] Preferably, in the alcohol precipitation step, 95% ethanol is added under stirring until the alcohol content is 60% to 65%.

[0022] A Duliangfang composition preparation comprises the Duliangfang composition prepared by the above-mentioned Duliangfang composition preparation method and conventional pharmaceutical excipients.

[0023] Optionally, the Duliangfang composition preparation is in the form of pills, tablets, granules or capsules.

[0024] Furthermore, conventional pharmaceutical excipients are selected from one or more of fillers, binders, disintegrants, lubricants, suspending agents, wetting agents, surfactants or flavoring agents.

[0025] Furthermore, the filler is selected from starch, microcrystalline cellulose, dextrin, lactose, calcium sulfate, mannitol and the like.

[0026] Furthermore, the adhesive is selected from povidone, cellulose derivatives, starch, gelatin and the like.

[0027] Furthermore, the disintegrant is selected from sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, carboxymethyl cellulose calcium, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and the like.

[0028] Furthermore, the lubricant is selected from magnesium stearate, colloidal silicon dioxide, stearic acid, talc and the like.

[0029] Furthermore, the suspending agent is selected from methylcellulose, sodium carboxymethylcellulose, sodium alginate, carbomer, etc.

[0030] Furthermore, the wetting agent is selected from polysorbates, poloxamer, polyoxyethylene castor oil, etc.

[0031] Furthermore, the surfactant is selected from lecithin, polysorbates, polyethylene glycol and the like.

[0032] Preferably, the preparation is in the form of drop pills.

[0033] The coolant for preparing the drop pills is liquid paraffin, dimethicone, etc. Dimethicone is preferred.

[0034] A method for preparing Duliangfang composition dropping pills comprises the following steps: uniformly mixing the Duliangfang composition prepared by the above-mentioned Duliangfang composition preparation method and a matrix in a weight ratio of 1:1-5; heating and melting the matrix in an amount 2-4 times the weight of the Duliangfang composition; adding the mixture of the Duliangfang composition and the matrix to the molten matrix, heating and melting the mixture, and dripping the mixture; using dimethyl silicone oil as a coolant to prepare the Duliangfang composition dropping pills.

[0035] Furthermore, the matrix is a mixture of one or two of polyethylene glycol 4000, polyethylene glycol 6000, poloxamer, etc.

[0036] Furthermore, before dripping, the raw materials are sheared, stirred and mixed, and dripping is performed after being mixed evenly.

[0037] A Duliang Fang composition is prepared using the above-mentioned Duliang Fang composition preparation method, which contains imperatorin, isoimperatorin, ferulic acid and ligustilide, with imperatorin ≥8.0 mg / g, isoimperatorin ≥2.0 mg / g, ferulic acid ≥0.5 mg / g and ligustilide ≥8.0 mg / g.

[0038] Preferably, imperatorin ≥ 15.0 mg / g, isoimperatorin ≥ 4.0 mg / g, ferulic acid ≥ 1.0 mg / g, and ligustilide ≥ 15.0 mg / g; Preferably, imperatorin ≥ 20.0 mg / g, isoimperatorin ≥ 6.0 mg / g, ferulic acid ≥ 1.5 mg / g, and ligustilide ≥ 25.0 mg / g.

[0039] The beneficial effects of the present invention are as follows: in this scheme, by adopting a continuous countercurrent extraction process, the solute diffusion efficiency is improved, thereby improving the extraction production efficiency, and by adopting a method of extracting Chuanxiong in a segmented manner with a gradient concentration of ethanol, the synchronous and efficient extraction of the volatile oil and water-soluble components of Chuanxiong is taken into account; in addition, by mixing the lower layer solution of Angelica dahurica and Chuanxiong with a low-concentration ethanol thick paste of Chuanxiong and further precipitating the mixture with alcohol to remove impurities, and finally combining the oily substances, the maximum retention of the effective components of the oil-water biphasic phase is achieved, thereby ensuring that the subsequent drug efficacy reaches a high level.

[0040] The Duliangfang composition prepared by this scheme can reduce the turbidity and stratification that occurs during the preparation process of the dropping pills due to the removal of impurities. Combined with the use of the coolant dimethicone, it not only improves the stability of the dropping process, but also improves the roundness of the dropping pills, which is conducive to the stability of the preparation quality. DETAILED DESCRIPTION

[0041] The present invention is further described below in conjunction with specific examples, which are only used to illustrate the present invention but are not intended to limit the scope of the present invention. Where specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature in this area or the product specifications are used. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased through regular channels.

[0042] The content of the active ingredients in the Duliang formula was determined by HPLC-UV (Reference: Xi Haiwei, Ma Qiang, Li Qiang, et al. Simultaneous determination of ferulic acid, 5-methoxypsoralen, imperatorin, and isoimperatorin in Duliang pills by HPLC [J]. Chinese Journal of Experimental Traditional Chinese Medicine, 2011, 17(16):81-85). The efficacy of the treatment of migraine was evaluated by comparing the behavioral symptoms of the rats after administration of nitroglycerin-induced experimental migraine in rats. Example 1

[0043] A Duliang Fang composition contains imperatorin ≥8.0 mg / g, isoimperatorin ≥2.0 mg / g, ferulic acid ≥0.5 mg / g, and ligustilide ≥8.0 mg / g.

[0044] The preparation method of the Duliangfang composition comprises the following steps: 1) Grind Angelica dahurica and Ligusticum chuanxiong separately and pass through a 10 mm sieve.

[0045] 2) 90 kg of Angelica dahurica was soaked in 85% ethanol solution at a 1:1 ratio until thoroughly soaked. The extract was then extracted with 85% ethanol in a countercurrent manner at 25°C, a solid-to-liquid ratio of 1:4, and a time of 4 h. The Angelica dahurica extract was collected.

[0046] 3) Soak 22.5 kg of Chuanxiong rhizome in 88% ethanol solution at a 1:1 ratio until the core is completely penetrated. Then, extract with 88% ethanol and 50% ethanol in countercurrent mode at 25°C, a solid-liquid ratio of 1:5, and an extraction time of 5 h. Collect the Chuanxiong rhizome extract.

[0047] 4) The Angelica dahurica extract was concentrated under reduced pressure at low temperature to a relative density of 1.02 (t = 45°C). After standing at 20°C for 8 hours, the upper oily layer and the lower solution were collected for later use. The high-concentration ethanol extract of Chuanxiong was concentrated under reduced pressure at low temperature to Chuanxiong Paste 1 with a relative density of 1.23 (t = 45°C). After standing at 20°C for 15 hours, the upper oily layer and the lower solution were collected for later use. The low-concentration ethanol extract of Chuanxiong was concentrated under reduced pressure at low temperature to Chuanxiong Paste 2 with a relative density of 1.25 (t = 45°C).

[0048] 5) Combine the lower layer of Angelica dahurica solution, the lower layer of Chuanxiong paste 1 solution, and Chuanxiong paste 2. Add 95% ethanol while stirring to bring the alcohol content to 55%. After standing, collect the supernatant and concentrate under low temperature and reduced pressure to a paste 3 with a relative density of 1.25 (t=45℃).

[0049] 6) Evenly mix the Angelica dahurica oil, the Ligusticum chuanxiong oil and the thick paste 3 to prepare the Duliang Fang composition.

[0050] The results of the determination of the content of this Duliangfang composition are shown in Table 1. Example 2

[0051] A Duliang Fang composition contains imperatorin ≥20.0 mg / g, isoimperatorin ≥6.0 mg / g, ferulic acid ≥1.5 mg / g, and ligustilide ≥25.0 mg / g.

[0052] The preparation method of the Duliangfang composition comprises the following steps: 1) Grind Angelica dahurica and Ligusticum chuanxiong separately and pass through a 6 mm sieve.

[0053] 2) 90 kg of Angelica dahurica was soaked in 84% ethanol solution at a 1:1 ratio until thoroughly soaked. The extract was then extracted with 84% ethanol in a countercurrent manner at 20°C, a solid-to-liquid ratio of 1:5, and a time of 5 h. The Angelica dahurica extract was collected.

[0054] 3) Soak 22.5 kg of Chuanxiong rhizome in 90% ethanol solution at a 1:1 ratio until the core is completely penetrated. Then, extract with 90% ethanol and 55% ethanol in countercurrent mode at 30°C, a solid-liquid ratio of 1:6, and an extraction time of 6 h. Collect the Chuanxiong rhizome extract.

[0055] 4) The Angelica dahurica extract was concentrated under reduced pressure at low temperature to a relative density of 1.05 (t = 45°C). After standing at 25°C for 10 hours, the upper oily layer and the lower solution were collected for later use. The high-concentration ethanol extract of Chuanxiong was concentrated under reduced pressure at low temperature to Chuanxiong Paste 1 with a relative density of 1.25 (t = 45°C). After standing at 25°C for 18 hours, the upper oily layer and the lower solution were collected for later use. The low-concentration ethanol extract of Chuanxiong was concentrated under reduced pressure at low temperature to Chuanxiong Paste 2 with a relative density of 1.25 (t = 45°C).

[0056] 5) Combine the lower layer of Angelica dahurica solution, the lower layer of Chuanxiong paste 1 solution, and Chuanxiong paste 2. Add 95% ethanol while stirring to bring the alcohol content to 55%. After standing, collect the supernatant and concentrate under low temperature and reduced pressure to a thick paste 3 with a relative density of 1.28 (t=45℃).

[0057] 6) Evenly mix the Angelica dahurica oil, the Ligusticum chuanxiong oil and the thick paste 3 to prepare the Duliang Fang composition.

[0058] The results of the determination of the content of this Duliangfang composition are shown in Table 1. Example 3

[0059] A Duliang Fang composition contains imperatorin ≥20.0 mg / g, isoimperatorin ≥6.0 mg / g, ferulic acid ≥1.5 mg / g, and ligustilide ≥25.0 mg / g.

[0060] The preparation method of the Duliangfang composition comprises the following steps: 1) Grind Angelica dahurica and Ligusticum chuanxiong separately and pass through a 10-mesh sieve.

[0061] 2) 90 kg of Angelica dahurica was soaked in 85% ethanol solution at a 1:1 ratio until thoroughly soaked. The extract was then extracted with 85% ethanol in a countercurrent manner at 25°C, a solid-to-liquid ratio of 1:6, and a time of 6 h. The Angelica dahurica extract was collected.

[0062] 3) Soak 22.5 kg of Chuanxiong rhizome in 90% ethanol solution at a 1:1 ratio until the core is completely penetrated. Then, extract with 90% ethanol and 50% ethanol in countercurrent flow at 25°C, a solid-liquid ratio of 1:7, and an extraction time of 8 h. Collect the Chuanxiong rhizome extract.

[0063] 4) The Angelica dahurica extract was concentrated under reduced pressure at low temperature to a relative density of 1.05 (t = 45°C). After standing at 25°C for 10 hours, the upper oily layer and the lower solution were collected for later use. The high-concentration ethanol extract of Chuanxiong was concentrated under reduced pressure at low temperature to Chuanxiong Paste 1 with a relative density of 1.26 (t = 45°C). After standing at 25°C for 20 hours, the upper oily layer and the lower solution were collected for later use. The low-concentration ethanol extract of Chuanxiong was concentrated under reduced pressure at low temperature to Chuanxiong Paste 2 with a relative density of 1.25 (t = 45°C).

[0064] 5) Combine the lower layer of Angelica dahurica solution, the lower layer of Chuanxiong paste 1 solution, and Chuanxiong paste 2. Add 95% ethanol while stirring to bring the alcohol content to 60%. After standing, collect the supernatant and concentrate under low temperature and reduced pressure to a thick paste 3 with a relative density of 1.28 (t = 45°C).

[0065] 6) Evenly mix the Angelica dahurica oil, the Ligusticum chuanxiong oil and the thick paste 3 to prepare the Duliang Fang composition.

[0066] The results of the determination of the content of this Duliangfang composition are shown in Table 1.

[0067] Comparison example: Duliang mixed extract: Angelica dahurica oil and Chuanxiong thick paste were prepared according to the preparation methods disclosed in patent CN107320454A.

[0068] Preparation method: Grind Angelica dahurica into coarse powder, soak it in 1.5 times the amount of 85% ethanol for 24 hours, then add 4.5 times the amount of 85% ethanol for percolation at a percolation rate of 3.7 ml / (kg·min), collect the percolation liquid, and recover the ethanol under reduced pressure at below 55°C. Recover the Angelica dahurica percolation liquid to 1 / 20 of the volume of ethanol used, refrigerate and let it stand for 12 hours, and collect the upper oily material for later use. Grind Chuanxiong rhizome into coarse powder, soak it in 1.5 times the amount of 90% ethanol for 24 hours, then add 2.5 times the amount of 90% ethanol for percolation at a percolation rate of 3.7 ml / (kg·min), collect the percolation liquid, and recover the ethanol under reduced pressure at below 55°C. Recover the Chuanxiong rhizome percolation liquid to a thick paste with a relative density of 1.20-1.30 (50°C), and set aside. The control Duliang mixed extract was prepared by mixing Angelica dahurica oil and Chuanxiong thick paste according to the prescribed amount of Angelica dahurica: Chuanxiong (4:1).

[0069] The results of the determination of the content of the Duliang mixed extract of this control example are shown in Table 1.

[0070] Table 1 Content determination results of Duliang Fang composition and Duliang mixed extract Experimental Example 1: Preparation of dripping pills and observation of intermediates The Duliang mixed extract (control example), the Duliang prescription composition (Example 1, Example 2 and Example 3) and PEG6000 were respectively prepared into dropping pill intermediates.

[0071] The preparation method is as follows: Comparative Example Dropping Pill Intermediate: Weigh 1 part Duliang mixed extract and 3 parts PEG6000. First, heat the PEG6000 to 75°C to melt. Then, slowly add the mixed extract while stirring (shear speed 2500 rpm, stirring speed 50 rpm) for 20 minutes to obtain the Duliang Dropping Pill Intermediate.

[0072] The preparation method of the Duliangfang composition dropping pill intermediate is the same as the above-mentioned Duliang dropping pill intermediate, and the Duliangfang composition dropping pill intermediates 1, 2 and 3 are prepared.

[0073] Appropriate amounts of the above intermediates were taken and stored in a 75°C water bath. The samples were observed for turbidity and stratification at 0 h, 1 h, 2 h, 3 h, 4 h, 5 h and 6 h, respectively. The results are shown in Table 2.

[0074] The above intermediates were made into pellets. Liquid paraffin was used as the coolant for the control pellets, while dimethyl silicone oil (viscosity 100 mm² / s) was used as the coolant for the Duliangfang composite pellets. The pellet preparation parameters were a cooling temperature of 18°C, an oil bath temperature of 80°C, a nozzle temperature of 30°C, a drop rate of 30 pellets / min, and a drop distance of 3 cm. The pellet weight variation and dissolution time were inspected according to the methods in Appendix IV of the 2020 edition of the Chinese Pharmacopoeia. Appearance quality was visually inspected for roundness and color. A score of 5 was assigned based on roundness and smoothness, uniform size, and consistent color, with quality decreasing from best to worst. The results are shown in Table 3.

[0075] Table 2. Storage property changes of Duliangfang drop pills and Duliang drop pill intermediates Experimental results show that, despite high-speed shear homogenization, the Angelica dahurica oil and Chuanxiong rhizome extract in the Duliang pill intermediates can be mixed uniformly within a certain period of time with the aqueous matrix polyethylene glycol. However, there is a tendency for stratification. The preparation method of the Duliang formula composite not only reduces the turbidity of the material but also increases its stability, which is beneficial for improving the quality stability and content uniformity of the pills.

[0076] Table 3 Results of roundness and disintegration time of pills The above experimental results show that the appearance quality of the pills made with dimethyl silicone oil as the coolant is significantly better than that of the pills made with liquid paraffin as the coolant; the pill weight difference of the pills made with the Duliang formula composition is smaller than that of the Duliang pills made with the existing process; there is no significant difference in the dissolution time of the two.

[0077] Experimental Example 2: Effects of Duliang composition on behavioral symptoms in rats with experimental migraine model induced by nitroglycerin The behavioral symptoms of the nitroglycerin-induced migraine rat model (red ears, head scratching, and cage climbing) are somewhat similar to the manifestations and changes during human migraine attacks. This conforms to the principles that should be followed in model design and is a common choice for inducing experimental migraine animal models.

[0078] Experimental methods: 1. Experimental Grouping and Drug Administration 50 rats were randomly divided into 5 groups, namely blank group, model group, positive group, control group and experimental group, with 10 rats in each group. Blank group: rats were injected subcutaneously with 2 ml·kg normal saline at the back of the neck. -1 ; Model group, positive group, control group and experimental group: rats were injected subcutaneously with nitroglycerin 10 mg·kg at the back of the neck -1 A migraine model was established (5 minutes after modeling, rats showed redness in both ears, frequent scratching of the head with their forelimbs, and increased circling, cage climbing, and tail biting, indicating successful modeling). The drugs were administered orally 10 minutes after modeling. The specific dosage design is shown in Table 4.

[0079] Table 4 Grouping and dosage of nitroglycerin in experimental migraine model rats 2. Behavioral Investigation Number of head scratching: starting from the time of model establishment, every 30 minutes was regarded as a time period, and the duration segmented counting method was used to observe the number of times the rats scratched their heads in each time period after model establishment. The time periods included 0-30 minutes, 30-60 minutes, 60-90 minutes, 90-120 minutes, 120-150 minutes, and 150-180 minutes after model establishment.

[0080] Statistical processing The above measured data were analyzed using SPSS 26.0 statistical software package. The mean and dispersion of each measurement index are expressed as (`x ± SD). Multiple sample means were compared using one-way analysis of variance. P < 0.05 was used as the standard for judging significant differences.

[0081] Experimental results Rats in the blank group occasionally scratched their heads throughout the observation period. Rats in the model group and all drug-treated groups frequently scratched their heads within 0-10 minutes of modeling. Compared with the blank group, the model group exhibited a significant increase in the number of head scratches throughout the observation period (0-180 minutes) (P < 0.01). Compared with the model group, the positive, control, and experimental groups showed no significant difference in the number of head scratches within 30 minutes of modeling (P > 0.05), but the number of head scratches was significantly reduced between 60 and 180 minutes of modeling. Although there was no significant difference in the number of head scratches between the experimental and control groups (P > 0.05), there was a slight decrease in the number of head scratches. The results are shown in Table 5.

[0082] Table 5 Effect of Duliangfang composition on the number of head scratching in migraine model rats (`x±SD, n=10) Note: Compared with the blank group, ##P<0.01; compared with the model group, **P<0.01, *P<0.05.

[0083] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand and implement the present invention. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be covered by the scope of protection of the present invention.

Claims

1. A method for preparing a Duliangfang composition, characterized in that: The following steps are involved: Angelica dahurica extraction: Grind the Angelica dahurica and extract the ground Angelica dahurica using a continuous countercurrent method to obtain an extract, which is then concentrated at low temperature to form a thick paste of Angelica dahurica. After the thick paste of Angelica dahurica is allowed to stand and separate into layers, the upper oily layer and the lower solution layer are collected separately; Extraction of Chuanxiong: The Chuanxiong is crushed and extracted using a segmented continuous gradient countercurrent method. The extraction is performed segmentedly using solvents of high and low concentrations. Extracts are obtained by segmented extraction with the solvents of high and low concentrations. The extracts are concentrated separately. The high-concentration solvent extract is concentrated into Chuanxiong thick paste 1. After the Chuanxiong thick paste 1 is allowed to stand for stratification, the upper oil layer and the lower solution layer are collected respectively; the low-concentration solvent extract is concentrated into Chuanxiong thick paste 2. Merge: Combine the lower layer solution of Angelica dahurica thick paste, the lower layer solution of Chuanxiong thick paste 1 and Chuanxiong thick paste 2, add ethanol and stir to precipitate, let stand, take the supernatant and concentrate at low temperature to form thick paste 3, mix the upper layer oil of Angelica dahurica thick paste, the upper layer oil of Chuanxiong thick paste 1 and thick paste 3 to prepare the Duliangfang composition.

2. The method for preparing the Duliangfang composition according to claim 1, wherein: In the steps of extracting angelica dahurica and extracting chuanxiong rhizome, angelica dahurica and chuanxiong rhizome are crushed and then passed through a 6-10 mm sieve to obtain angelica dahurica coarse powder and chuanxiong coarse powder.

3. The method for preparing the Duliangfang composition according to claim 1 or 2, wherein: In the Angelica dahurica extraction step, the extraction solvent is 70%~95% ethanol, the temperature during the extraction process is 20~40℃, the solid-liquid ratio is 1:4~12, and the extraction time is 2~16h.

4. The method for preparing the Duliangfang composition according to claim 3, wherein: In the step of segmented extraction of Chuanxiong, the first extraction solvent is 70%~95% ethanol, the second extraction solvent is 40%~70% ethanol, the temperature during the extraction process is 20~40℃, the solid-liquid ratio is 1:4~12, and the extraction time is 2~16h.

5. The method for preparing the Duliangfang composition according to claim 4, wherein: The Angelica dahurica extract was concentrated to a relative density of 1.00-1.20 (t=45°C) to obtain Angelica dahurica thick paste, and the first and second segment extracts of Chuanxiong were concentrated to a relative density of 1.20-1.30 (t=45°C) to obtain Chuanxiong thick paste 1 and Chuanxiong thick paste 2.

6. The method for preparing the Duliangfang composition according to claim 5, wherein: The Angelica dahurica paste and the Chuanxiong paste 1 were allowed to stand at 5-40°C for 4-24 hours, respectively, and the upper oily substance was collected after standing.

7. The method for preparing the Duliangfang composition according to claim 5, wherein: In the combining step, the supernatant was concentrated at low temperature to a relative density of 1.20-1.30 (t=45°C) to obtain a thick paste 3.

8. The method for preparing the Duliangfang composition according to claim 1, wherein: The alcohol precipitation step of the combined solution of the lower layer solution of Angelica dahurica paste, the lower layer solution of Chuanxiong paste 1 and Chuanxiong paste 2 is as follows: adding 95% ethanol under stirring until the alcohol content is 50%-80%.

9. A Duliangfang composition preparation, characterized in that: The invention relates to a Duliangfang composition prepared by the preparation method of the Duliangfang composition according to any one of claims 1 to 8, wherein the preparation of the Duliangfang composition is in the form of pills, tablets, granules or capsules.

10. A method for preparing Duliangfang composition pills, characterized in that: The following steps are involved: The Duliangfang composition prepared by the preparation method of the Duliangfang composition according to any one of claims 1 to 8 is mixed with a matrix and melted, and then dripped, and dimethyl silicone oil is used as a coolant to prepare Duliangfang composition dripping pills.