Preparation method and application of Qiandang pulse-activating quick-acting preparation

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation method and application of a Qiandang pulse-activating quick-acting preparation. The invention relates to a Qiandang pulse-activating quick-acting preparation, which is prepared from the following raw materials: medicinal components and auxiliary materials, the traditional Chinese medicine composition is prepared from the following medicinal components in parts by weight: 200 to 250 parts of radix astragali seu hedysari, 200 to 250 parts of radix salviae miltiorrhizae, 100 to 150 parts of radix angelicae sinensis, 200 to 250 parts of flos carthami and 50 to 100 parts of ramulus cinnamomi. The auxiliary materials comprise 30 to 40 parts of polyethylene glycol and 80 to 100 parts of povidone. The radix astragali and radix salviae miltiorrhizae pulse-activating composition is prepared into a sublingual powder dosage form, the first-pass effect of the liver can be avoided, the bioavailability of the medicine is improved, rapid absorption is achieved through blood capillaries, and timely and effective treatment support can be provided during acute attack of angina pectoris. According to the technical scheme, the technical problems of slow effect taking, low bioavailability, poor patient compliance and the like of a Qiandang meridian-dredging pharmaceutical composition preparation in the prior art can be solved, and the Qiandang meridian-dredging pharmaceutical composition preparation has ideal popularization and application prospects.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a preparation method of a Qidan Tongmai fast-acting preparation and application thereof. BACKGROUND

[0002] In the long-term practice of treating cardiovascular diseases with traditional Chinese medicine, Qidan Tongmai tablets, as a classic Chinese patent medicine preparation, have played an important role in the treatment of stable exertional angina pectoris. The drug is composed of multiple traditional Chinese medicinal materials such as Radix Astragali (prepared), Salvia miltiorrhiza, Angelica sinensis (prepared), safflower and Ramulus Cinnamomi, and has the effects of tonifying qi, promoting blood circulation, unblocking collaterals and relieving pain, and is suitable for patients with angina pectoris of qi deficiency and blood stasis. Its indications include chest pain, stabbing pain or angina, fixed pain site, shortness of breath, fatigue, palpitation, sweating and other symptoms, tongue appearance of pale, purple or with petechiae and ecchymosis, and pulse appearance of sinking and weakness or sinking and astringency, which are typical symptoms of qi deficiency and blood stasis. From the composition, Radix Astragali tonifies qi, raises yang, removes water and reduces swelling; Salvia miltiorrhiza promotes blood circulation, removes blood stasis and calms the mind; Angelica sinensis nourishes blood, promotes blood circulation and stops pain; safflower promotes blood circulation, removes blood stasis and relieves pain; and Ramulus Cinnamomi warms meridians, assists yang and transforms qi. The five ingredients together have the effects of tonifying qi, promoting blood circulation, unblocking collaterals and relieving pain, which embodies the theoretical essence of traditional Chinese medicine that "qi is the commander of blood and blood is the mother of qi", and has good clinical effects on improving myocardial blood supply and relieving angina pectoris symptoms.

[0003] The Qidan Tongmai tablets widely used in the clinic at present are in the form of oral tablets, each weighing 0.3 g, and the recommended dosage is 4 tablets at a time, 3 times a day, taken with warm water after meals. This traditional dosage form is convenient to carry and take, and has certain advantages in the control of chronic disease and long-term conditioning. However, with the increasing requirements of modern medicine for the treatment of cardiovascular diseases, especially the strict requirements for the speed of drug effect and the strength of action in the acute stage, the limitations of Qidan Tongmai tablets as oral tablets have become increasingly apparent. First, Qidan Tongmai tablets are not a fast-acting preparation. As a solid oral dosage form, it needs to go through the processes of disintegration, dissolution and absorption in the gastrointestinal tract, resulting in a long onset time and difficulty in quickly exerting therapeutic effects in the acute stage of angina pectoris, thus limiting its application in emergency situations. Second, the tablet has certain bioavailability problems. Some active ingredients may be metabolized in the liver due to the first-pass effect, resulting in a decrease in the amount of effective drug entering the systemic circulation and affecting the overall efficacy of the drug. In addition, the solubility of some active ingredients in the gastrointestinal tract is poor, which may further reduce their absorption rate and degree and delay the exertion of drug effects. Third, the administration mode of the tablet is not friendly to certain groups of people. For example, the elderly or those with difficulty swallowing may have difficulty in taking the medicine, affecting medication compliance. Especially in the acute stage of chest pain, patients are often in a state of anxiety, discomfort or even weakness, and oral administration not only is inconvenient to operate, but also may delay the treatment opportunity.

[0004] In summary, although Qidan Tongmai tablets have certain effects in the adjuvant treatment of chronic coronary heart disease angina pectoris, they have obvious limitations in dealing with acute attacks as traditional oral tablets, including slow onset, low bioavailability, poor patient compliance and other problems. Therefore, it is urgent to develop a new type of high-efficiency Qidan Tongmai immediate-release preparation to meet the clinical demand for rapid relief of symptoms. SUMMARY

[0005] The present application aims to provide a Qidan Tongmai fast-acting preparation to solve the technical problems of slow onset, low bioavailability, poor patient compliance and the like of the Qidan Tongmai pharmaceutical composition preparation in the prior art.

[0006] To achieve the above-mentioned purposes, the present application adopts the following technical solutions: A Qidan Tongmai fast-acting preparation, which comprises raw materials including pharmaceutical ingredients and excipients; the pharmaceutical ingredients include 200-250 parts of Huangqi, 200-250 parts of Danshen, 100-150 parts of Dangui, 200-250 parts of Honghua and 50-100 parts of Guizhi by weight; and the excipients include 30-40 parts of polyethylene glycol and 80-100 parts of povidone.

[0007] Further, the polyethylene glycol includes any one of polyethylene glycol 3350-4000; and the povidone includes any one of povidone K15-K17.

[0008] Further, the excipients further include a flavoring agent and a sweetening agent. Preferably, the flavoring agent includes at least one of peppermint essence, strawberry essence, banana essence and raspberry essence; and the sweetening agent includes at least one of steviol glycoside, sodium saccharin, sucralose and aspartame.

[0009] The present application also provides a preparation method of the Qidan Tongmai fast-acting preparation, which comprises the following steps performed in sequence: S1: Huangqi, Danshen, Dangui, Honghua and Guizhi are co-mixed and crushed, and then subjected to carbon dioxide supercritical extraction to obtain an extraction liquid and a residue; the extraction liquid is concentrated, dried and crushed to obtain an extract I powder; S2: the residue is subjected to percolation extraction to obtain a percolation liquid, which is then concentrated, dried and crushed to obtain an extract II powder; S3: the extract I powder, the extract II powder, polyethylene glycol and povidone are mixed and heated to melt to obtain a melt; S4: the melt is subjected to spray drying, sieved and mixed with a flavoring agent and a sweetening agent to obtain a total mixture; and the total mixture is filled into capsules.

[0010] Further, in S1, the Astragalus, Salvia miltiorrhiza, Angelica sinensis, safflower, cassia twig are coarsely mixed, crushed and sieved through a 20-60 mesh sieve, and then subjected to carbon dioxide supercritical extraction; the extract is concentrated, dried and crushed, and then sieved through an 80-120 mesh sieve to obtain the extract I medicinal powder.

[0011] Further, in S1, the parameters of the carbon dioxide supercritical extraction are as follows: temperature 25-35℃, pressure not less than 7.4 MPa, time 2-3 h, and carbon dioxide flow rate 20-25 L / h.

[0012] Further, in S2, the drug residues are soaked in 70-80% ethanol for 2-4 hours before percolation extraction.

[0013] Further, in S2, the percolation extraction is performed as follows: 55-75% ethanol is used as the percolation solvent, the percolation rate is 1-3 mL / min / kg, and the percolation time is 22-26 hours, and the percolation liquid is collected; the percolation liquid is concentrated, dried and crushed, and then sieved through a 40-60 mesh sieve to obtain the extract II medicinal powder.

[0014] Further, in S3, the extract I medicinal powder, the extract II medicinal powder, polyethylene glycol and povidone are mixed, and heated to 70-75℃ to make the materials into a molten state, and then stirred and mixed uniformly for 2-3 hours to obtain a molten material.

[0015] Further, in S4, the molten material is subjected to spray drying, sieved through an 80 mesh sieve, and then mixed with a flavoring agent and a sweetening agent to obtain a total mixture; the total mixture is filled into capsules to obtain the finished product. The weight fraction of the flavoring agent is 0.5-0.8 parts, and the weight fraction of the sweetening agent is 0.5-0.8 parts.

[0016] The technical solution also provides a use of the Qidan Tongmai rapid preparation in the preparation of a drug for treating migraine.

[0017] The technical principle of the technical solution is that: The present application provides a Qidan Tongmai rapid preparation, and the technical principle is that efficient extraction and rapid release of effective components of traditional Chinese medicines are achieved by optimizing the extraction process and preparation technology. Specifically, the active components are fully extracted from medicinal materials such as Astragalus, Salvia miltiorrhiza, Angelica sinensis, safflower and cassia twig by using the method of supercritical carbon dioxide extraction combined with ethanol percolation extraction, and a medicinal powder with high content of marker components (such as astragaloside A and salvianolic acid B) is obtained; then the extract is mixed with povidone, polyethylene glycol and other auxiliary materials at a specific temperature, and the total mixture material with good fluidity and low hygroscopicity is formed after spray drying, and finally a sublingual dispersible capsule is prepared.

[0018] In the technical solution, supercritical carbon dioxide extraction can efficiently obtain fat-soluble ingredients, and percolation extraction is beneficial to the sufficient dissolution of water-soluble active ingredients, so that the utilization rate of medicinal materials and the content of active ingredients are significantly improved. Povidone and polyethylene glycol form a synergistic effect in the state of heating and melting, and construct a hydrophobic protective layer on the surface of the drug powder particles, which significantly reduces the hygroscopicity, while maintaining good wettability and flowability, thereby ensuring the stability and processing performance of the preparation. The product produced by the scheme can be administered sublingually, avoiding the liver first-pass effect, so that the drug is rapidly absorbed into the blood circulation through the oral mucosa, significantly shortening the onset time, and being suitable for rapid relief in the acute attack of angina pectoris. At the same time, the sublingual powder is convenient to carry and use, especially suitable for the elderly and patients with swallowing difficulties, thereby improving the convenience and compliance of drug use. Therefore, the research and development of the sublingual powder of Qidan Tongmai can not only fill the gap of existing tablets in the field of acute treatment, but also provide a safer, more efficient and convenient treatment option for patients with stable exertional coronary heart disease and angina pectoris.

[0019] In addition, the rapid-acting preparation of Qidan Tongmai developed by the scheme can be used not only for the treatment of stable exertional coronary heart disease and angina pectoris, but also for the treatment of migraine. As a sublingual powder, the rapid-acting preparation of Qidan Tongmai can rapidly absorb drug ingredients through the sublingual mucosa, thereby rapidly exerting the drug effect and improving the bioavailability and onset speed of the drug. Therefore, for cases requiring rapid relief of symptoms, such as acute attack of migraine, sublingual administration may be more effective than oral administration and other dosage forms.

[0020] The beneficial effects of the technical solution are as follows: (1) High content of active ingredients, and more stable drug effect By adopting the method of combining supercritical carbon dioxide extraction with ethanol percolation extraction, the marker active ingredients in Huangqi, such as astragaloside A and danshenshuan B in Danshen, are fully extracted, so that the content of key ingredients in the final preparation reaches the ideal level, thereby providing a solid foundation for the stable efficacy of the drug.

[0021] (2) Sublingual administration mode has rapid onset, and meets the needs of acute treatment Compared with traditional oral tablets, the present application prepares the drug into a sublingual powder, which is rapidly absorbed by utilizing the rich capillary network of the oral mucosa, avoids the liver first-pass effect, and makes the drug enter the systemic circulation more quickly, thereby significantly shortening the onset time, and being particularly suitable for emergency relief in the acute attack of angina pectoris, thereby filling the gap of existing dosage forms in the field of acute treatment.

[0022] (3) Excellent physical properties of the preparation, and improved production and storage stability Through the synergistic effect of povidone and polyethylene glycol in a molten state, the total mixture exhibits good fluidity, extremely low hygroscopicity, and excellent wetting performance. These characteristics not only benefit the dose uniformity and process stability during the capsule filling process, but also greatly improve the physical stability of the finished product during transportation and storage, prolonging the shelf life.

[0023] (4) Wide application to people, improving medication compliance The sublingual powder does not need to be taken with water, and is especially suitable for the elderly, dysphagia patients, and patients with acute chest pain who are inconvenient to move, greatly improving the convenience and compliance of medication, and helping to improve the overall treatment effect.

[0024] (5) New indications are expanded, and migraine is quickly relieved The Qidan Tongmai quick-acting sublingual powder developed in this scheme can be used for the treatment of migraine in addition to the treatment of stable exertional coronary heart disease angina. The preparation is rapidly absorbed through the sublingual mucosa, has rapid onset and high bioavailability, and is especially suitable for acute migraine episodes that require rapid symptom relief.

[0025] In summary, the present application not only exhibits outstanding advantages in extraction efficiency, preparation performance, bioavailability, and clinical application, but also has clear technical innovation and practicality, providing a feasible new scheme for the upgrading of Qidan Tongmai traditional Chinese medicine preparations, and has a broad application prospect. DETAILED DESCRIPTION

[0026] The following examples are only used to more clearly illustrate the technical solutions of the present application, and therefore only serve as examples, but cannot limit the protection scope of the present application. The specific examples listed in the present application are only as examples of the present application, and the present application is not limited to the specific examples described below. Any equivalent modifications and substitutions to the examples described below by those skilled in the art are also within the scope of the present application. Therefore, equivalent transformations and modifications made without departing from the spirit and scope of the present application should be included in the scope of the present application. In order to better illustrate the present application, numerous specific details are given in the following specific embodiments. Those skilled in the art should understand that the present application can also be implemented without certain specific details. In some embodiments, methods, means, apparatus and steps that are well known to those skilled in the art are not described in detail, in order to highlight the main idea of the present application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art. Unless otherwise specified, the units used in this specification are international standard units, and the numerical values and numerical ranges appearing in this application should be understood to include the systematic errors that are unavoidable in industrial production.

[0027] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; the materials, reagents or instruments used are commercially available reagents and materials, and the specific conditions not mentioned in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. Meanwhile, the source of the raw materials used in the present application is not limited, and the raw materials used in the present application are ordinary commercially available products in the technical field unless otherwise specified. Unless otherwise specified, the "ratio" referred to in the following examples is the ratio of the mass parts.

[0028] The composition of the Qidantongmai composition is as follows: The pharmaceutical ingredients are 200-250 parts of Radix Astragali (processed), 200-250 parts of Salvia miltiorrhiza, 100-150 parts of Angelica sinensis (processed), 200-250 parts of Carthamus tinctorius, and 50-100 parts of Ramulus Cinnamomi.

[0029] The excipients are 30-40 parts of polyethylene glycol 3350-4000, 80-100 parts of povidone K15-K17, 0.5-0.8 parts of flavoring agent, and 0.5-0.8 parts of sweetener. The flavoring agent includes at least one of peppermint essence, strawberry essence, banana essence, and raspberry essence; and the sweetener includes at least one of steviol glycoside, sodium saccharin, sucralose, and aspartame.

[0030] The Qidantongmai fast-acting preparation is prepared by the following method: (1) The Radix Astragali (processed), Salvia miltiorrhiza, Angelica sinensis (processed), Carthamus tinctorius, and Ramulus Cinnamomi are co-mixed, crushed, and passed through a 20-60 mesh sieve (preferably a 40 mesh sieve) to obtain a medicinal material powder. The Radix Astragali (processed), Salvia miltiorrhiza, Angelica sinensis (processed), Carthamus tinctorius, and Ramulus Cinnamomi are all in accordance with the quality requirements of the 2020 edition of Chinese Pharmacopoeia. The medicinal material powder is subjected to carbon dioxide supercritical extraction. The temperature of the supercritical extraction is 25-35°C (preferably 30°C), the pressure is not less than 7.4 MPa (preferably 7.4-10.5 MPa, and further preferably 8.5 MPa), the time is 2-3 hours (preferably 2.5 hours), and the carbon dioxide flow rate is 20-25 L / h (preferably 22.5 L / h).

[0031] After the extraction is completed, the extract is filtered from the extraction kettle, the filtered extract is concentrated by conventional reduced pressure distillation and CO2 is removed, and then dried at 55-65°C until the moisture content is less than 3% to obtain a concentrated block-shaped solid of the supercritical extraction extract. The medicinal residue after supercritical extraction is also retained for the next step. The concentrated block-shaped solid is crushed and passed through an 80-120 mesh sieve (preferably a 100 mesh sieve) to obtain an extract Ι medicinal powder.

[0032] (2) The drug residue after supercritical extraction is extracted by percolation, ethanol is recovered, dried, and crushed to obtain drug powder of extract II. More specifically, the drug residue after supercritical extraction is loaded into a percolation tank, 70% to 80% ethanol (preferably 75% ethanol) is added to immerse the drug residue, and the drug residue is soaked for 2 to 4 hours (preferably 3 hours). After the soaking operation is completed, 70% to 80% ethanol solution (preferably 75% ethanol) is used as the percolation solvent, the percolation speed is 1 to 3 mL / min / kg (preferably 2 mL / min / kg), and the percolation is performed for 22 to 26 hours (preferably 24 hours). The percolation liquid is collected (the ethanol solution is always kept immersed in the drug during the percolation process). Then, the percolation liquid is concentrated by conventional reduced pressure to recover ethanol and concentrate the material to obtain a flow extract (60°C relative density is 1.2 to 1.3), which is dried at 55°C to 65°C until the moisture content is less than 3%. The obtained dry extract is crushed and sieved through a 80 to 120 mesh sieve (preferably a 100 mesh sieve) to obtain drug powder of extract II.

[0033] (3) The drug powder of extract I, the drug powder of extract II, polyethylene glycol, and povidone are mixed and heated to 70 to 75°C (preferably 73°C) to make the material into a molten state. After melting, the mixture is stirred uniformly for 2 to 3 hours (preferably 2.5 hours) to obtain a melt.

[0034] (4) Spray agglomeration: turn on the spray drying tower fan and let in natural wind. The melt is sprayed into the spray tower, the flow is adjusted to make the spray into a fine mist state. After all the spraying is completed, turn on the spray drying tower fan and heat until the inlet air temperature is 40°C. Then, turn off the heating and continue to blow for 20 to 30 minutes (preferably 30 minutes). Stop the machine and discharge the material.

[0035] (5) Sieving: the material after spray drying is added to a vibrating sieve and sieved through a 80 mesh sieve for standby use.

[0036] (6) Total mixing: the sieved material is taken and mixed with flavoring agents and sweetening agents in a three-dimensional motion mixer for 10 to 20 minutes (preferably 20 minutes) to obtain a total mixture.

[0037] (7) Sub-packing: the total mixture (Qidan Tongmai Quick-acting Preparation, specifically: sublingual powder) is sub-packed into capsules, 0.2 g per capsule. When used, open the capsule shell cap, pour the powder in the capsule body into the mouth, and absorb it under the tongue for 2 to 3 minutes before swallowing.

[0038] The technical solutions of the present application will be described below in combination with specific examples, which specifically include: Example 1 The formula of this example is: Drug ingredients: 230 parts of Huangqi (fried), 230 parts of Danshen, 130 parts of Dangui (fried), 230 parts of Honghua, and 80 parts of Guizhi.

[0039] Auxiliary materials: 35 parts of polyethylene glycol 4000, 80 parts of povidone K15, 0.65 parts of flavoring agent, 0.65 parts of sweetening agent. The flavoring agent is specifically strawberry essence, and the sweetening agent is specifically sucralose.

[0040] The preparation process is carried out according to the optimal parameters of the foregoing process, and the obtained capsule product is capsule 1. The specific process is as follows: The astragalus root (fried), salvia miltiorrhiza, angelica (fried), safflower, and cassia twig are coarsely mixed and then pulverized through a 40-mesh sieve to obtain medicinal material powder. The supercritical extraction is carried out at a temperature of 30°C, a pressure of 8.5 MPa (preferably 8.5 MPa), and a time of 2.5 hours (preferably 2.5 hours), and the carbon dioxide flow rate is 22.5 L / h. After the extraction is completed, the extract is filtered, concentrated, dried, and pulverized, and then sieved through a 100-mesh sieve to obtain extract I medicinal powder.

[0041] The residue after supercritical extraction is loaded into a percolation tank, and 75% ethanol is added to cover the residue, and the residue is soaked for 3 hours. Then, 75% ethanol solution is used as the percolation solvent, and the percolation speed is 2 mL / min / kg, and the percolation is carried out for 24 hours, and the percolation liquid is collected. The percolation liquid is concentrated, dried, and pulverized, and then sieved through a 100-mesh sieve to obtain extract II medicinal powder.

[0042] The extract I medicinal powder, extract II medicinal powder, polyethylene glycol, and povidone are mixed and heated to 73°C to make the materials into a molten state. After melting, the mixture is stirred uniformly for 2.5 hours to obtain a molten material.

[0043] After the molten material is subjected to spray drying, sieving, total mixing, and sub-packaging, the capsule product is obtained.

[0044] Example 2 The formula of this example is as follows: 230 parts of astragalus root (fried), 230 parts of salvia miltiorrhiza, 130 parts of angelica (fried), 230 parts of safflower, and 80 parts of cassia twig.

[0045] Auxiliary materials: 30 parts of polyethylene glycol 3350, 90 parts of povidone K17, 0.65 parts of flavoring agent, and 0.65 parts of sweetening agent. The flavoring agent is specifically strawberry essence, and the sweetening agent is specifically steviol glycoside.

[0046] The preparation process is carried out according to Example 1, and the obtained capsule product is called capsule 2.

[0047] Example 3 The formula of this example is as follows: 230 parts of astragalus root (fried), 230 parts of salvia miltiorrhiza, 130 parts of angelica (fried), 230 parts of safflower, and 80 parts of cassia twig.

[0048] Auxiliary materials: 40 parts of polyethylene glycol 4000, 100 parts of povidone K15, 0.7 parts of flavoring agent, 0.7 parts of sweetening agent. The flavoring agent is specifically banana essence, and the sweetening agent is specifically sodium saccharin.

[0049] The preparation process is carried out according to Example 1, and the obtained capsule product is called Capsule 3.

[0050] Comparative Example 1 The formula of the present comparative example is consistent with Example 1, and the preparation method is specifically as follows: Take Astragalus (fried), Salvia miltiorrhiza, Angelica (fried), safflower, cassia twig, coarse mix, and crush through a 40-mesh sieve to obtain a mixed powder of medicinal materials. The supercritical extraction temperature is 30°C, the pressure is 8.5 MPa (preferably 8.5 MPa), the time is 2.5 hours (preferably 2.5 hours), and the carbon dioxide flow rate is 22.5 L / h. After extraction is complete, the extract is filtered, concentrated, dried, and crushed, and then sieved through a 100-mesh sieve to obtain a powder of the extract.

[0051] The powder of the extract, polyethylene glycol, and povidone are mixed and heated to 73°C to form a molten state. After melting, the mixture is stirred uniformly for 2.5 hours to obtain a molten material. The subsequent operations are the same as steps (3)-(7) of Example 1 (optimal parameters are selected), and a total mixture is obtained. After spray drying, sieving, total mixing, and packaging, a capsule product (Comparative Capsule 1) is obtained.

[0052] Comparative Example 2 The formula of the present comparative example is consistent with Example 1, and the preparation method is specifically as follows: Take Astragalus (fried), Salvia miltiorrhiza, Angelica (fried), safflower, cassia twig, coarse mix, and crush through a 40-mesh sieve to obtain a mixed powder of medicinal materials. Then, the mixed powder of medicinal materials is extracted by percolation, ethanol is recovered, and after drying, the powder is crushed to obtain a powder of the extract. More specifically, the mixed powder of medicinal materials is loaded into a percolation tank, and 75% ethanol is added to cover the mixed powder of medicinal materials, and soaked for 4 days. After the soaking operation is complete, 75% ethanol is used as the percolation solvent, and the percolation speed is 2 mL / min / kg, and the percolation is carried out for 24 hours, and the percolation liquid is collected. Then, the percolation liquid is subjected to conventional vacuum concentration, and ethanol is recovered to obtain a flow extract with a relative density of about 1.25-1.30 (60°C), and the flow extract is dried at 55°C-65°C to a dry block with a water content of less than 3%, and then crushed and sieved through a 100-mesh sieve to obtain a powder of the extract.

[0053] The powder of the extract, polyethylene glycol, and povidone are mixed and heated to form a molten material. The subsequent operations are the same as steps (3)-(7) of Example 1 (optimal parameters are selected), and a total mixture is obtained. The total mixture is prepared into a capsule (Comparative Capsule 2).

[0054] The comparative example adopts the method of percolation extraction to extract medicinal materials, without supercritical extraction before percolation extraction, resulting in low content of astragaloside A in the product.

[0055] Comparative Example 3 The formulation of the comparative example is consistent with Example 1, and the preparation method is specifically as follows: The preparation method of the extract I medicinal powder is completely consistent with Example 1 (supercritical extraction), and the preparation of the extract II medicinal powder is carried out in the following manner (decoction extraction): The supercritically extracted medicinal residues are subjected to decoction extraction, 10 times the mass of water is added, and decoction extraction is carried out for 2 hours. Decoction extraction is carried out twice, the extract is combined, and conventional reduced pressure concentration is carried out to obtain a flow extract with a relative density of about 1.25-1.30 (60°C). The flow extract is dried at 55°C-65°C to obtain a dry block with a water content of less than 3%, which is then pulverized into a fine powder and passed through a 100-mesh sieve to obtain the extract II medicinal powder.

[0056] The subsequent operations are consistent with the steps (3)-(7) of Example 1 (optimal parameters are selected), and the total mixture is obtained, which is prepared into capsules (Comparative Capsule 3).

[0057] The comparative example adopts supercritical extraction and water decoction extraction, resulting in low content of astragaloside A and very low content of salvianolic acid B in the product.

[0058] Comparative Example 4 The formulation and preparation method of the comparative example are basically consistent with Example 1, except that only polyethylene glycol 4000 is not added (polyvidone K15 is used instead of the combination of polyvidone K15 and polyethylene glycol 4000 in Example 1), and capsules (Comparative Capsule 4) are prepared. The experimental results show that the total mixture obtained in this comparative example has strong hygroscopicity and very poor flowability, which will lead to unstable capsule loading and reduced chemical stability of the active ingredients.

[0059] Comparative Example 5 The formulation and preparation method of the comparative example are basically consistent with Example 1, except that only polyvidone K15 is not added (polyethylene glycol 4000 is used instead of the combination of polyvidone K15 and polyethylene glycol 4000 in Example 1), and capsules (Comparative Capsule 5) are prepared. The experimental results show that the total mixture obtained in this comparative example has strong hygroscopicity, which will lead to unstable capsule loading and reduced chemical stability of the active ingredients.

[0060] Comparative Example 6 The formulation and preparation method of the comparative example are basically consistent with Example 1, except that the polyethylene glycol 4000 is replaced by an equal amount of polyethylene glycol 2000, and capsules (Comparative Capsule 6) are prepared.

[0061] Comparative Example 7 The formulation and preparation method of this comparative example are basically the same as those of Example 1, except that the added polyethylene glycol 4000 is replaced with an equal amount of polyethylene glycol 5000 to prepare capsules (comparative capsule 7).

[0062] Comparative Example 8 The formulation and preparation method of this comparative example are basically the same as those of Example 1, except that the added povidone K15 is replaced with an equal amount of K12 to prepare capsules (comparative capsule 8).

[0063] Comparative Example 9 The formulation and preparation method of this comparative example are basically the same as those of Example 1, except that the added povidone K15 is replaced with an equal amount of K30 to prepare capsules (comparative capsule 9).

[0064] Comparative Example 10 The formulation and preparation method of this comparative example are basically the same as those of Example 1. The difference is that: after mixing the extract I powder, extract II powder, polyethylene glycol and povidone, no heating and melting treatment was performed. After mixing evenly at room temperature, the operation of Example 1 (4)-(7) was carried out (using the optimal parameters) to prepare capsules (comparative capsule 10).

[0065] Experimental Example 1: Identification and Content Determination The sublingual powders prepared in the examples and comparative examples were tested in accordance with the drug quality standards of Qidan Tongmai Tablets.

[0066] [Identification] Take 20 capsules, collect the total mixture from the capsules, add 30 ml of ether, heat under reflux in a water bath for 30 minutes, filter, evaporate the filtrate to dryness at low temperature, dissolve the residue in 1 ml of ethyl acetate, and use this as the test solution. Separately, take 1 g of *Salvia miltiorrhiza* reference material and prepare a reference material solution using the same method. Perform thin-layer chromatography (Chinese Pharmacopoeia 2020 edition), applying 6 μl of each of the above two solutions separately to the same silica gel G thin-layer plate. Use benzene-ethyl acetate (19:1) as the developing solvent, develop, remove, air dry, spray with 10% sulfuric acid ethanol solution, and bake at 100℃ until the spots are clearly visible. In the chromatogram of the test sample, spots of the same color appear at the corresponding positions as in the chromatogram of the reference material.

[0067] Take 40 capsules, take the total mixture in the capsule, add water 40 ml, heat in boiling water bath for 10 minutes to dissolve, adjust pH to 2 with hydrochloric acid, extract with diethyl ether 2 times, 30 ml each time, combine the diethyl ether liquid, low temperature dry, add ethanol 1 ml to dissolve the residue as the test solution. Another take protocatechuic aldehyde control, add ethanol to make a solution containing 2 mg per 1 ml, as the control solution. According to the thin layer chromatography (2020 edition of Chinese Pharmacopoeia) take the above two solutions 6 μl respectively, point on the same silica gel G thin layer plate, with benzene-ethyl acetate-formic acid (80:50:8) as developing agent, develop, take out, dry, spray with 1% ferric trichloride ethanol solution. The test chromatogram shows the same color spots at the corresponding positions of the control chromatogram.

[0068]

Content Determination

[0069] Each capsule contains Radix Astragali, preferably ≥0.02 mg calculated as astragaloside.

[0070] Salvia miltiorrhiza Determined by high performance liquid chromatography (2020 edition of Chinese Pharmacopoeia).

[0071] Chromatographic conditions and system suitability test: octadecylsilane-bonded silica gel as the filler; methanol-acetonitrile-formic acid-water (30:10:1:59) as the mobile phase; the detection wavelength was 286 nm, and the theoretical plate number calculated according to the salvianolic acid B peak should be no less than 2000.

[0072] Preparation of the reference solution: an appropriate amount of salvianolic acid B reference substance was accurately weighed, water was added to prepare a solution containing 75 μg per 1 ml, and the solution was obtained.

[0073] Preparation of the test crystal solution: 10 capsules were taken, the total mixture in the capsules was accurately weighed, finely ground, 0.2 g was accurately weighed, placed in a conical flask with a stopper, 25 ml of water was accurately added, the weight was determined, ultrasonic treatment (power 250 W, frequency 50 kHz) was performed for 30 minutes, taken out, cooled, and the weight was determined again. The lost weight was made up with water, shaken well, filtered, and the filtrate was obtained. The determination method was as follows: 10 μl of the reference solution and the test solution were accurately taken and injected into the liquid chromatograph for determination.

[0074] Each capsule of the product contains ≥2.4 mg of Danshen calculated as salvianolic acid B.

[0075] The detection results are shown in Table 1.

[0076] Table 1: Identification and content detection results (n = 10)

[0077] Note: The data of astragaloside A and salvianolic acid B in Table 1 are the average values of 10 repeated experiments; * indicates a significant difference compared with Example 1, p < 0.05.

[0078] The technical solution adopts the following extraction method: first, all the medicinal material raw materials are extracted by supercritical carbon dioxide, and then the extracted residues are extracted by percolation with 70%-80% ethanol as the solvent. The content of the active ingredients in the sublingual powder capsules obtained is ideal. Through the combination of the above two extraction methods, the effective components in the medicinal materials are fully extracted, thereby effectively guaranteeing the curative effect of the medicine. According to the experimental data of Examples 1-3, the content of astragaloside A in the sublingual powder capsules prepared by the method can reach more than 0.045 mg per particle, and the content of salvianolic acid B can reach more than 3.5 mg per particle.

[0079] In Comparative Example 1, only supercritical carbon dioxide extraction was performed on the medicinal materials, and the contents of astragaloside A and salvianolic acid B in the obtained product were relatively low. It can be seen that the single supercritical extraction is not suitable for the preparation of the product.

[0080] Comparative Example 2 did not use the supercritical carbon dioxide extraction step, but all medicinal materials were uniformly subjected to percolation extraction. Due to the lack of combination with other extraction methods, the content of astragaloside A in the final product was low, indicating that a single extraction method cannot fully extract various active ingredients from medicinal materials.

[0081] Comparative Example 3 used supercritical extraction first, and then water decoction extraction. However, this combination method was not ideal for extracting active ingredients from medicinal materials, as the content of salvianolic acid B decreased significantly, and the content of astragaloside A was low. The inventors analyzed the reasons, which may be due to the fact that water decoction extraction has a large outflow and low efficiency, and the marker components may have compatibility reactions or degradation, or be absorbed by the medicinal materials during the decoction process, failing to achieve full extraction.

[0082] In summary, the present technical solution combines supercritical carbon dioxide extraction and percolation extraction processes to achieve efficient extraction of key active ingredients from various medicinal materials, significantly improving the content of marker components in the preparation, and has good application prospects and development value.

[0083] Experimental Example 2: Flowability, hygroscopicity, and wettability

Total mixture flowability test

[0084] Generally, if the material has a repose angle of more than 40°, its flowability is poor, which can easily lead to various problems in the production process, such as blockage, uneven filling, etc. The flowability of the powder prepared directly from the material extracted by the present scheme is not ideal, and the present scheme controls the repose angle of the material to about 35° by adding appropriate excipients, ensuring the flowability of the total mixture, reducing the loading difference, and improving the smoothness of the continuous production process.

[0085]

Hygroscopicity detection

[0086] The hygroscopicity of the total mixture refers to the ability of the mixture to absorb moisture in the air. In the pharmaceutical industry, for the total mixture used for filling capsules (usually containing active pharmaceutical ingredients and excipients), its hygroscopicity is a very important consideration factor. This is because the hygroscopicity not only affects the physical properties of the material, such as flowability, repose angle, etc., but also may bring challenges to the stability, shelf life of the final product and the handling in the production process. Materials with high hygroscopicity are prone to absorb moisture in the air, causing liquid bridges or solid bridges between particles, increasing the viscosity of the material, and thus reducing its flowability. This will directly affect the repose angle of the material and may cause uneven filling problems in the capsule filling process. Some pharmaceutical ingredients may undergo hydrolysis or other chemical reactions after absorbing moisture, resulting in reduced drug efficacy or the production of adverse byproducts. Therefore, controlling the hygroscopicity of the total mixture is crucial to maintaining the effectiveness and safety of pharmaceutical products. Materials with high hygroscopicity may form clumps or adhere to the surface of the production equipment, causing production difficulties, and even requiring equipment cleaning, reducing production efficiency.

[0087]

Wetting time detection

[0088] Hygroscopicity and wettability of a mixture are two distinct concepts, each describing a different aspect of the interaction between the substance and water. Hygroscopicity refers to a substance's ability to absorb moisture from its surrounding environment. This property is particularly important for pharmaceuticals as it can affect drug stability, shelf life, and handling during manufacturing. Highly hygroscopic materials readily absorb moisture from the air, potentially leading to changes in physical and chemical properties, such as reduced flowability or degradation of the active ingredient. Wetting (wetting time) refers to the time required for a solid dosage form's surface to be completely covered by a liquid from initial contact with it. This characteristic is especially important for sublingual delivery systems, as it relates to the rapid wetting and dissolution of the drug by saliva, enabling absorption by the body. Hygroscopicity primarily focuses on a material's ability to absorb moisture from the air, while wettability focuses on the speed at which a solid material is covered by a liquid upon contact. Both are important parameters for evaluating the performance of pharmaceutical formulations. Hygroscopicity is more related to product stability and storage conditions, while wettability is more directly linked to drug bioavailability and patient experience.

[0089] The experimental results are detailed in Table 2.

[0090] Table 2: Results of relevant characteristic detection (n=10)

[0091] Note: The data in Table 2 are the average of 10 repeated experiments; * indicates a significant difference compared to Example 1, p < 0.05.

[0092] Based on the experimental data in Table 2, the results are analyzed as follows: (1) Advantages of the sublingual powder capsules prepared according to this technical solution As shown in Table 1, the angle of repose of the sublingual powder mixtures prepared in Examples 1-3 is between 33° and 35°, which meets the basic requirements for powder flowability of pharmaceutical excipients (generally, an angle of repose of less than 40° is considered acceptable flowability). Good flowability not only helps to improve the uniformity and operability of the formulation process, but also effectively reduces the problem of filler volume variation caused by poor material flowability during capsule filling, thereby improving the overall stability and controllability of the process.

[0093] Further research shows that the total mixture prepared by the scheme has a moisture absorption rate of 1.3% to 1.4% within 24 hours, showing low moisture absorption performance. For oral solid preparations, moisture absorption is one of the important factors affecting the stability and processing performance of the material. High moisture absorption material is easy to absorb water from the air, forming a liquid bridge on the surface of the particles or even a solid bridge after drying, which leads to caking, decreased flowability, tabletting sticking and other problems, thereby affecting product quality and production efficiency. The total mixture prepared by the technical scheme has good moisture resistance, which can to some extent avoid the above problems, ensure the smooth progress of the preparation process and the stability of the finished product quality. In addition, the total mixture prepared by the scheme has a short wetting time of about 15 to 16 seconds, indicating that it can be quickly wetted and dissolved by artificial or natural saliva in the sublingual environment. The sublingual administration route relies on the rapid disintegration and dissolution of drugs in the oral environment, followed by rapid absorption through the rich capillary network of the sublingual mucosa, bypassing the liver first-pass effect and improving bioavailability. Shortening the wetting time helps to speed up this process, thereby improving the speed of onset and clinical application value. In summary, the technical scheme has significant advantages in prescription design and process optimization, not only improving the physical properties of the material, but also enhancing the in vitro behavior characteristics of the preparation, providing a strong guarantee for the efficient, stable and controllable production of sublingual powders.

[0094] (2) Synergistic effect of povidone and polyethylene glycol In Comparative Example 4, only povidone K15 was added to the total blend without polyethylene glycol 4000. Due to the lack of one of the key excipients, polyethylene glycol 4000, the total blend exhibited poor flowability (resting angle > 40°) and high hygroscopicity (moisture uptake > 5%). The flowability of the total blend was further reduced when it was exposed to air for a prolonged period of time due to the absorption of moisture from the air. Poor flowability not only causes the inconsistency of capsule fill weight, but also affects the smoothness of the production process. In Comparative Example 5, only polyethylene glycol 4000 was added to the total blend without povidone K15. Due to the lack of another key excipient, povidone K15, the total blend also exhibited high hygroscopicity. The material absorbed moisture when exposed to air for a prolonged period of time, resulting in a decrease in flowability. This flowability problem also adversely affects the consistency of the capsule fill weight and the smoothness of the process flow. In addition to Comparative Examples 4 and 5, the inventors also tried not to add polyethylene glycol 4000 and povidone K15 to the formulation of Example 1 (otherwise identical to Example 1). The hygroscopicity of the total blend obtained was not ideal, about 6%. It should be noted that for a powder or any solid formulation in the pharmaceutical industry, a hygroscopicity of more than 5% is a relatively high value (too high hygroscopicity). A material with high hygroscopicity is prone to absorbing moisture from the air, causing particles to stick or clump together, which affects the flowability of the material and in turn affects the dose uniformity and operational efficiency during the production process. Some drug ingredients are very sensitive to humidity, and hygroscopicity can cause the drug to degrade or become inactive, affecting the effectiveness and safety of the drug. In general, the ideal moisture uptake of a powder should be as low as possible to maintain its physical and chemical stability, and it is generally considered that a resting angle of less than 40° and a moisture uptake of less than 2% is a relatively ideal range.

[0095] From the experimental data of Example 1, Comparative Example 4 and Comparative Example 5, it can be seen that the use of povidone K15 and polyethylene glycol 4000 alone will bring the problem of unsatisfactory hygroscopicity of the total mixture, while the combination of the two can greatly reduce the hygroscopicity of the total mixture from the level of 5-6% to below 1.5%. And the combination of the two is through the melting treatment of the four materials of extract I drug powder, extract II drug powder, polyethylene glycol and povidone heated to 70-75°C. The inventors also analyzed the possible reasons for the above phenomenon: in the molten state, polyethylene glycol 4000 and povidone K15 can better cover the surface of the drug powder particles to form a continuous protective layer, reducing the direct contact of particles with moisture in the air. This protective layer has a good barrier effect on moisture in the air, but cannot resist the case of being soaked by a large amount of liquid, so the sublingual powder (total mixture) can be quickly soaked under the tongue in the case of having anti-hygroscopicity, ensuring the bioavailability of the drug. Under the condition of heating and melting, polyethylene glycol 4000 and povidone K15 may have a certain degree of intermolecular interaction, enhancing the stability of the overall structure. Melting treatment helps to improve the microstructure of the particles inside and on the surface, making the final powder more loose and not easy to cake, thereby further improving the flowability and anti-hygroscopicity. Povidone K15 and polyethylene glycol 4000 show significant synergistic effect in reducing the hygroscopicity of the total mixture. Through a specific melting treatment process, these two excipients not only can exert their own advantages, but also can form a more effective moisture-proof system through complex intermolecular interactions. This method not only can significantly reduce the hygroscopicity of the total mixture, but also can improve its flowability and stability, providing strong technical support for the preparation of high-quality solid preparations.

[0096] (3) Role of melting treatment In Comparative Example 10, the extract I drug powder, extract II drug powder, polyethylene glycol and povidone were mixed without heating and melting treatment, resulting in the total mixture having unsatisfactory flowability, hygroscopicity and soakability. The inventors analyzed the possible reasons as follows: Regarding the overall performance of the total mixture: using the method of Comparative Example 10, the excipients and drug powder lack effective fusion. During the physical mixing at room temperature, polyethylene glycol and povidone as functional excipients are difficult to uniformly distribute on the surface of drug powder particles and form a continuous coating layer. When heated to 70-75°C, the materials enter the molten state, have good flowability and spreadability, and better play the roles of adhesion and film formation, which helps to form a uniform hydrophobic protective film on the surface of drug powder particles. The lack of this melting process makes the excipients unable to fully exert their functional properties, thereby affecting the overall performance of the total mixture.

[0097] Regarding the hygroscopicity of the total mixture: Comparative Example 10 failed to build an effective anti-hygroscopic barrier. The polyethylene glycol can form a relatively dense hydrophobic film on the surface of the drug powder particles in a molten state, effectively preventing moisture in the air from entering. At the same time, the addition of povidone K15 can further enhance the stability of the film, and the synergistic effect of the two significantly reduces the hygroscopicity of the material. If the auxiliary materials are not heated and melted, they cannot form an effective coating structure, resulting in a sensitivity to external humidity and a significant increase in hygroscopicity.

[0098] Regarding the flowability of the total mixture: melting processing helps to improve the interfacial contact state between particles, reducing electrostatic adsorption and frictional resistance, thereby improving the flowability of the powder. Without heating treatment, the particle surface is rough and the auxiliary materials are unevenly distributed, increasing the adhesion between particles and internal friction, resulting in an increased angle of repose and poor flowability.

[0099] Regarding the wetting properties of the total mixture: the total mixture that has not been subjected to melting treatment may have a decreased drug dissolution rate due to surface caking or wetting hysteresis in the sublingual environment. Due to the synergistic effect of polyethylene glycol and povidone produced by melting treatment, the wetting time of the total mixture that has not been subjected to melting treatment is prolonged, affecting the release and bioavailability of the drug.

[0100] In summary, heating and melting treatment plays a key role in this technical solution. It not only promotes uniform compounding between auxiliary materials and drug powder, but also significantly improves the flowability of the total mixture, reduces hygroscopicity, and accelerates the wetting rate through the construction of a hydrophobic coating layer and optimization of particle microstructure. Therefore, the absence of this step will directly affect the key quality attributes of the preparation, resulting in unsatisfactory processing performance and use effect of the product.

[0101] (4) Effect of polyethylene glycol type In Comparative Example 6, the polyethylene glycol used has a low molecular weight. During capsule filling, the heat generated by the equipment operation causes the viscosity of polyethylene glycol 2000 to increase significantly, which in turn causes the total mixture to stick to the screw and other phenomena. This problem directly causes a decrease in the flowability of the material, and the hygroscopicity is also enhanced, affecting the overall process performance of the preparation. In Comparative Example 7, a high molecular weight polyethylene glycol is used, and the results show that its dispersing performance is not ideal, significantly prolonging the wetting time of the drug, even more than three times that of Example 1, severely affecting the in vitro release behavior of the drug and the clinical application effect. The above experimental results show that the molecular weight of polyethylene glycol has a significant effect on the key properties of the total mixture. To balance the flowability, hygroscopicity, and wetting properties, an appropriate molecular weight of polyethylene glycol must be selected. Considering the performance requirements, a polyethylene glycol with a molecular weight range of 3350-4000 is preferred to ensure that the total mixture has good processing performance and use characteristics.

[0102] (5) The influence of povidone type In Comparative Example 8, using povidone K12 as an excipient significantly increased the hygroscopicity of the mixture, affecting its stability and processing performance. In Comparative Example 9, the use of high molecular weight povidone K30 resulted in decreased solubility of the powder and a significantly prolonged wetting time, hindering rapid drug release under the tongue. These experimental results demonstrate that the molecular weight of povidone significantly impacts its performance in formulations. Different molecular weights of povidone exhibit significant differences in improving flowability, controlling hygroscopicity, and promoting wetting. Therefore, to achieve a good balance among key indicators, it is essential to select a povidone variety with an appropriate molecular weight. Based on comprehensive performance evaluation results, povidones with a molecular weight range of K15-K17 are preferred. This range effectively controls hygroscopicity while ensuring good flowability, and also considers the wetting and dissolution properties of the formulation, thereby ensuring the overall mixture possesses excellent processing adaptability and application characteristics.

[0103] Experimental Example 3: Efficacy of Astragalus and Danshen Fast-Acting Preparation in Treating Migraine Sixty SD rats weighing 180-220g were randomly divided into six groups: a normal control group (n=10), a model control group (n=10), a treatment group treated with the drug in Example 1 (low dose) (n=10), a treatment group treated with the drug in Example 1 (medium dose) (n=10), a treatment group treated with the drug in Example 1 (high dose) (n=10), and a positive control group (n=10, Sibelium capsules).

[0104] Except for the normal control group, all other groups received intraperitoneal injections of nitroglycerin 10 mg / kg for 3 consecutive days to complete the modeling process. During modeling, except for the normal control group which received saline injections, all other groups received intraperitoneal injections of nitroglycerin 10 mg / kg for 3 consecutive days as described above. In Example 1, the drug treatment group received medication concurrently during the modeling phase (sublingual powder from the capsules was used for the experiment and measured). The low, medium, and high doses were administered at 0.75 g / kg, 1.5 g / kg, and 3.0 g / kg daily, respectively, via gavage. The positive control group received oral (oral) Sibelium capsules (1 mg / kg).

[0105] Behavioral indicators were observed 30–150 minutes after the last modeling. Starting from the last modeling, every 30 minutes was considered a time period, and the rats' head-scratching behavior was observed in each time period using a segmented counting method. Serum NO, SOD, and MDA levels were measured at the end of the experiment.

[0106] The experimental data are detailed in Tables 3 and 4.

[0107] Table 3: Effect of Qidan Tongmai Sublingual Powder on the number of times a rat with migraine scratches its head (x±s, n=10)

[0108] Note: * indicates p < 0.05 compared with the model control group; ** indicates p < 0.01 compared with the model control group; △△ indicates p < 0.01 compared with the normal control group.

[0109] Experimental results showed that the normal control group only occasionally scratched their heads once or twice during a few time periods, while the model control group showed obvious head-scratching from 30 to 150 minutes. P <0.01); compared with the model control group, the high-dose Qidan Tongmai group significantly reduced the number of times the model rats scratched their heads ( P <0.05, P <0.01).

[0110] Table 4: Results of serum NO, SOD, and MDA levels in rats (x±s, n=10)

[0111] Note: * indicates p < 0.05 compared with the model control group; ** indicates p < 0.01 compared with the model control group; △△ indicates p < 0.01 compared with the normal control group.

[0112] The experimental results showed that compared with the normal control group, the serum NO and MDA levels in the model control group were significantly increased (P<0.01), and the SOD level was significantly decreased (P<0.05). Compared with the model control group, the medium dose group of Qidan Tongmai significantly reduced the serum MDA content and increased the SOD content in the model animals (P<0.05), while the high dose group significantly reduced the serum NO and MDA levels in the model animals (P<0.05).

[0113] In summary, in the head-scratching frequency experiment in model rats, the normal control group showed mild and infrequent head-scratching behavior. The model control group showed a significantly increased number of head-scratching occurrences, indicating the successful establishment of a migraine model. The high-dose Qidan Tongmai fast-acting preparation significantly reduced the number of head-scratching occurrences in the model rats, particularly at the 90, 120, and 150 min timeframes. Regarding serum NO, SOD, and MDA levels, compared to the normal control group, the model control group showed significantly increased NO and MDA levels and significantly decreased SOD levels. The medium- and high-dose Qidan Tongmai fast-acting preparation significantly improved serum parameters in the model rats, specifically reducing NO and MDA levels and increasing SOD levels. The Qidan Tongmai fast-acting preparation, especially the medium and high-dose groups, effectively alleviated the symptoms of nitroglycerin-induced migraine model rats, manifested in a reduction in head-scratching frequency, and also had a positive regulatory effect on serum biochemical parameters. These findings suggest that Qidan Tongmai fast-acting preparation may have potential value as a drug for treating migraines.

[0114] The above description is merely an embodiment of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solution of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A fast-acting preparation for promoting blood circulation using Astragalus and Licorice, characterized in that, Its raw materials include medicinal ingredients and excipients; by weight, the medicinal ingredients include 200-250 parts of Astragalus membranaceus, 200-250 parts of Salvia miltiorrhiza, 100-150 parts of Angelica sinensis, 200-250 parts of Carthamus tinctorius, and 50-100 parts of Cinnamomum cassia; the excipients include 30-40 parts of polyethylene glycol and 80-100 parts of povidone.

2. The fast-acting Qi-Dan-tonifying and meridian-clearing preparation according to claim 1, characterized in that, The polyethylene glycol includes any one of polyethylene glycol 3350 to 4000; the povidone includes any one of povidone K15 to K17.

3. The Qidan meridian-clearing and fast-acting preparation according to claim 2, characterized in that, The excipients also include flavoring agents and sweeteners; Preferably, the flavoring agent includes at least one of peppermint flavoring, strawberry flavoring, banana flavoring, and raspberry flavoring; the sweetener includes at least one of steviol glycosides, sodium saccharin, sucralose, and aspartame.

4. A method for preparing a fast-acting Qi-Dan meridian-clearing preparation according to any one of claims 1-3, characterized in that, The following steps are performed sequentially: S1: Astragalus membranaceus, Salvia miltiorrhiza, Angelica sinensis, Carthamus tinctorius, and Cinnamomum cassia are coarsely mixed and pulverized, and then subjected to supercritical carbon dioxide extraction to obtain extract and residue; the extract is concentrated, dried and pulverized to obtain extract I powder. S2: The residue is percolated to obtain percolate, which is then concentrated, dried and pulverized to obtain extract II powder. S3: Mix extract I powder, extract II powder, polyethylene glycol and povidone, and heat to melt to obtain a melt; S4: Spray dry the melt, sieve it, and mix it with flavoring and sweetener to obtain a total mixture; fill the total mixture into capsules to obtain the final product.

5. The preparation method of the Qidan meridian-clearing and fast-acting preparation according to claim 4, characterized in that, In S1, Astragalus membranaceus, Salvia miltiorrhiza, Angelica sinensis, Carthamus tinctorius, and Cinnamomum cassia are coarsely mixed, pulverized, and passed through a 20-60 mesh sieve, followed by supercritical carbon dioxide extraction. The extract is concentrated, dried, and pulverized before being passed through an 80-120 mesh sieve to obtain extract I powder.

6. The preparation method of the Qidan Tongmai fast-acting preparation according to claim 5, characterized in that, In S1, the parameters for supercritical carbon dioxide extraction are: temperature 25~35℃, pressure not less than 7.4MPa, time 2~3 h, and carbon dioxide flow rate 20~25L / h.

7. The preparation method of the Qidan meridian-clearing and fast-acting preparation according to claim 4, characterized in that, In S2, the residue is soaked in 70%~80% ethanol for 2~4 hours before percolation extraction.

8. The preparation method of the Qidan meridian-clearing and fast-acting preparation according to claim 7, characterized in that, In S2, the percolation extraction method is as follows: using 55%~75% ethanol as the percolation solvent, percolating at a rate of 1~3 mL / min / kg for 22~26 hours, and collecting the percolate; after concentration, drying and pulverization, the percolate is passed through a 40~60 mesh sieve to obtain extract II powder.

9. The preparation method of the Qidan meridian-clearing and fast-acting preparation according to claim 4, characterized in that: In S3, extract I powder, extract II powder, polyethylene glycol and povidone are mixed and heated to 70-75°C to make the materials melt. After melting, the mixture is stirred and mixed evenly for 2-3 hours to obtain the melt. In step S4, the melt is spray-dried, passed through an 80-mesh sieve, and then mixed with flavoring and sweeteners to obtain a total mixture; the total mixture is then filled into capsules to obtain the finished product. The flavoring agent is 0.5 to 0.8 parts by weight, and the sweetener is 0.5 to 0.8 parts by weight.

10. The use of any one of the Qidan Tongmai fast-acting preparations according to claims 1 to 3 in the preparation of a drug for treating migraine.

Images