A pharmaceutical composition of shendan tongnao drop pill and a preparation method thereof

Abstract

The application provides a medicine composition and a preparation method of Shendan Tongnao drop pills. The medicine composition of the Shendan Tongnao drop pills comprises the following components in parts by weight: 1-20 parts of Chuanxiong, 1-8 parts of Danshen, 0.1-5 parts of Renshen and 1-15 parts of Chuangen Teng. The clear paste is prepared by an alcohol extraction method, is crushed, is uniformly mixed with excipients, and is prepared into brown drop pills with a fragrance and a slightly bitter taste. The Shendan Tongnao drop pills have the effects of activating blood and benefiting qi, removing blood stasis and dredging collaterals, and regulating the spleen and stomach, can improve the swelling and numbness of limbs, fatigue and poor appetite of a patient in a recovery period of meridians after stroke, promote the repair of nerve cells, and promote the recovery of motor function, language function and cognitive function.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine compositions, specifically relating to a pharmaceutical composition and preparation method of Shendan Tongnao Dripping Pills. Background Technology

[0002] Stroke is an acute cerebrovascular disease, mainly caused by the sudden rupture of blood vessels in the brain or by vascular obstruction, preventing blood from flowing to the brain and causing brain tissue damage. Its pathogenesis is related to factors such as arteriosclerosis, vascular stenosis, thrombosis, and abnormal blood rheology. It is characterized by high incidence, high disability rate, high mortality rate, and high recurrence rate, seriously endangering human health. Stroke patients with impaired consciousness often present with typical symptoms such as hemiplegia, limb numbness, slurred speech, pale tongue or ecchymosis, and a thready, hesitant pulse. During the recovery period, as the pathogenic factors such as wind, fire, phlegm, and blood stasis gradually recede, the pathological characteristics of prolonged illness damaging the body's vital energy become more apparent. Qi deficiency and blood stasis become the most common combination of syndromes in Traditional Chinese Medicine (TCM). TCM combinations have significant clinical significance and practical value in improving the rehabilitation effect and quality of life of stroke patients.

[0003] Patent CN110680845B discloses a pharmaceutical composition for treating stroke, its preparation method and application. The pharmaceutical composition includes ginseng, salvia miltiorrhiza and chuanxiong, which can invigorate qi and promote blood circulation. However, it cannot solve the problems of limb swelling, weakness and poor appetite in stroke patients during the meridian recovery period. It may affect the drug adaptability of elderly patients with concurrent metabolic disorders. Summary of the Invention

[0004] This invention provides a pharmaceutical composition and preparation method for Shendan Tongnao Dripping Pills. One objective is to leverage the synergistic effects of Chuanxiong, Danshen, Ginseng, and Chuangen Teng to invigorate blood circulation, replenish qi, and remove blood stasis, thus addressing the complex pathogenesis of qi deficiency and blood stasis combined with spleen deficiency and dampness in the recovery period after stroke, thereby improving limb swelling, fatigue, and poor appetite. A further objective of this invention is to add Coix seed to the synergistic effects of Chuanxiong, Danshen, Ginseng, and Chuangen Teng to further improve limb numbness and regulate gastrointestinal function, targeting dampness obstructing the meridians and spleen deficiency. A further objective of this invention is to add Sea Buckthorn and Licorice to assist in invigorating blood circulation and regulating the spleen and stomach, improving medication adherence and making it more suitable for long-term users and elderly patients with metabolic disorders. Another objective of this invention is to eliminate the need for prolonged high-temperature processing, thus preserving heat-sensitive components more completely, reducing differences in effective components between pills, making them easier to take sublingually, and reducing irritation.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] On one hand, the present invention provides a pharmaceutical composition for Shendan Tongnao Dripping Pills, comprising the following components in parts by weight: 1-20 parts of Ligusticum chuanxiong, 1-8 parts of Salvia miltiorrhiza, 0.1-5 parts of Panax ginseng, and 1-15 parts of Tremella fuciformis.

[0007] In this invention, Ligusticum chuanxiong invigorates blood circulation, dispels wind, and relieves pain. Ferulic acid dilates cerebral blood vessels and inhibits vascular smooth muscle spasm, while ligustrazine promotes collateral circulation and cerebral blood perfusion. Salvia miltiorrhiza invigorates blood circulation, removes blood stasis, reduces thrombus formation, improves circulation, and relieves limb numbness. Tanshinone inhibits platelet aggregation and reduces blood viscosity. Tanshinone B has antioxidant free radical damage, inhibits inflammatory responses, resists nerve cell apoptosis, and protects brain nerve cells. Ginseng greatly replenishes vital energy, promotes cerebral blood circulation, and improves fatigue and shortness of breath caused by qi deficiency. Ginsenosides dilate cerebral blood vessels, promote blood oxygen supply to ischemic areas, and promote the secretion of brain-derived neurotrophic factor (BDNF), accelerating nerve cell / functional repair and enhancing cognitive function improvement after cerebral ischemia. Andrographis paniculata dispels wind and dampness, relaxes muscles and tendons, reduces swelling, and relieves pain. Its alkaloid components inhibit the release of inflammatory factors, improve limb numbness / edema, and promote the recovery of motor function.

[0008] This invention aims to improve the qi deficiency and blood stasis caused by blood stasis during the recovery period of stroke patients. Through the synergistic effects of Chuanxiong, Danshen, Ginseng, and Chuangenteng, it replenishes qi and generates fluids, invigorates blood and removes blood stasis, dispels wind and dampness, and reduces swelling and inflammation. By dilating cerebral blood vessels and promoting blood circulation, it inhibits platelet aggregation, reduces blood viscosity, enhances the rate of cerebral blood flow perfusion, inhibits the production of inflammatory factors, promotes the release of brain-derived neurotrophic factors, reduces secondary damage, enhances the repair capacity of nerve cells / functions, promotes the smooth flow of meridians, and improves the recovery capacity of motor function.

[0009] Preferably, the composition includes the following components in parts by weight: 5-18 parts Ligusticum chuanxiong, 1-5 parts Salvia miltiorrhiza, 0.5-4 parts Panax ginseng, and 3-14 parts...

[0010] A vine that runs through the roots.

[0011] Preferably, the composition includes the following components in parts by weight: 7-15 parts Ligusticum chuanxiong, 1.5-3 parts Salvia miltiorrhiza, 1-2 parts Panax ginseng, and 5-12 parts...

[0012] Root vine, 1-10 parts of Job's tears.

[0013] In this invention, coix seed strengthens the spleen and promotes diuresis, relaxes muscles and relieves numbness. Its polysaccharide components regulate intestinal flora, improve metabolism, and improve appetite. At the same time, its triglyceride components can also regulate metabolism, regulate blood lipids, inhibit tissue fibrosis, reduce joint stiffness, and relieve edema. Moreover, coix seed is sweet, bland, and cool in taste, which can relieve the warming and drying effects of ginseng and chuanxiong, prevent internal heat, and work synergistically with chuangen teng to remove dampness and remove blood stasis, and improve swelling and heaviness of limbs.

[0014] Preferably, the product also includes the following components in parts by weight: 0.1-4 parts sea buckthorn and 0.1-2 parts licorice.

[0015] In this invention, sea buckthorn promotes blood circulation, removes blood stasis, resolves phlegm and eliminates stagnation, strengthens the spleen and aids digestion. It also helps to invigorate blood circulation and regulate the spleen and stomach. Its organic acids promote gastric juice secretion, relieve stomach discomfort, and improve the gastrointestinal experience of people who take medication for a long time. In addition, it is rich in flavonoids that can scavenge oxygen free radicals, reduce blood viscosity, lower blood lipids, and work synergistically with chuanxiong and danshen to fight arteriosclerosis, prevent thrombosis, and prevent stroke recurrence.

[0016] In this invention, licorice tonifies the spleen and replenishes qi, clears heat and detoxifies, and harmonizes the effects of other herbs. Glycyrrhizic acid can effectively protect the liver, inhibit the activity of liver drug-metabolizing enzymes, delay the metabolism of active ingredients in the drug, extend the duration of drug action, alleviate the irritation of the gastrointestinal tract by *Chuan Gen Teng* and *Chuan Xiong*, and work synergistically with *Yi Yi Ren* and *Hippophae rhamnoides* to protect the spleen and stomach, promote the safety of long-term medication, harmonize the properties and bitterness of the herbs, and improve patient compliance with medication.

[0017] On the other hand, based on the above-mentioned pharmaceutical composition of Shendan Tongnao Dripping Pills, the present invention provides a method for preparing Shendan Tongnao Dripping Pills, comprising the following steps:

[0018] S1: Extract Ligusticum chuanxiong and Salvia miltiorrhiza by ethanol refluxing to obtain extract I;

[0019] S2: Ginseng, *Gynostemma pentaphyllum*, sea buckthorn, and licorice were extracted by ethanol reflux to obtain extract II;

[0020] S3: Extract and concentrate the coix seed water to obtain clear extract III;

[0021] S4: Combine and mix the clear paste I, clear paste II, and clear paste III, dry under reduced pressure, and pulverize to obtain fine powder;

[0022] S5: After mixing the fine powder with the excipients, melt and mix them evenly, keep them at a certain temperature and then condense them to obtain droplets.

[0023] Both Salvia miltiorrhiza and Ligusticum chuanxiong contain fat-soluble active ingredients, namely tanshinone and tetramethylpyrazine, which can be extracted simultaneously with ethanol reflux, avoiding repeated heating in step-by-step extraction and saving energy and time. Ginseng, Dioscorea opposita, Hippophae rhamnoides, and Glycyrrhiza uralensis contain ginsenosides, flavonoids, and glycyrrhizic acid, all of which are alcohol-soluble and highly compatible. Simultaneous ethanol extraction can retain heat-sensitive components to a greater extent and avoid excessive loss of effective ingredients. Coix seed can better retain its polysaccharide components by water extraction alone, which is more conducive to its ability to regulate intestinal flora and assist in regulating blood lipids and spleen and stomach.

[0024] Preferably, in step S1, the extract is refluxed twice with 8 times the volume of 75% ethanol, 1 hour each time. The extract is filtered, the filtrates are combined, the ethanol is recovered and concentrated to a relative density of 1.05-1.08 (50℃). The concentrated extract is extracted twice with ethyl acetate, the ethyl acetate extracts are combined, the ethyl acetate is recovered under reduced pressure and concentrated to a clear extract with a relative density of 1.05-1.08 (40℃). The aqueous extract is concentrated under reduced pressure until there is no ethyl acetate odor. The extract is centrifuged under a filter cloth with a pore size of 3 μm, and the centrifuged liquid is adsorbed through a D101 macroporous adsorption resin column. After adsorption for 12 hours, the extract is first washed with 1 column volume (1 BV) of water, the wash liquid is discarded, and then eluted with 1 BV of 70% ethanol and concentrated to obtain a clear extract I with a relative density of 1.1-1.15 (50℃).

[0025] Preferably, in step S2, the extract is refluxed three times with 10 times the volume of 80% ethanol, each time for 2 hours. After concentration, the extract is filtered, the filtrates are combined, the ethanol is recovered and concentrated to a relative density of 1.04-1.06 (50℃). The extract is centrifuged under a filter cloth pore size of 3μm, and the centrifuged liquid is adsorbed through a D101 type macroporous adsorption resin column. After adsorption for 12 hours, the extract is first washed with 2BV of water, the washing liquid is discarded, and then eluted with 2BV of 75% ethanol and concentrated to obtain a clear extract II with a relative density of 1.1-1.15 (50℃).

[0026] Preferably, in step S3, the decoction is prepared twice with 8 times the amount of water, each time for 1 hour, filtered and concentrated to obtain a clear extract III with a relative density of 1.1-1.15 (50℃).

[0027] Preferably, in step S5, the excipients include: glyceryl mono / distearate, polyethylene glycol 4000, and polyethylene glycol 6000; wherein the ratio of glyceryl mono / distearate to polyethylene glycol 4000 is 1:20-25; the ratio of polyethylene glycol 4000 to polyethylene glycol 6000 is 1-3:1; and the ratio of fine powder to excipients is 1:1-4.

[0028] Preferably, in step S5, the melting temperature is 75-80℃ and the viscosity of the dimethicone oil in the condensate is 100cs.

[0029] In this invention, the concentrated extract has good fluidity and can be easily dispersed when mixed with mono / distearate glyceryl stearate, polyethylene glycol 4000, and polyethylene glycol 6000. It does not require prolonged high-temperature treatment and can form a homogeneous melt, reducing the loss of active ingredients, improving the retention of heat-sensitive ingredients, and having moderate viscosity during dripping. It also has high sphericity of pellets, small weight difference, and small difference in active ingredients between pellets.

[0030] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0031] This invention can effectively improve metabolic disorders commonly associated with stroke patients and reduce the burden on the liver and kidneys from long-term medication. The pharmaceutical composition of this invention can inhibit the release of inflammatory factors, protect brain nerve cells, promote nerve cell repair, promote the recovery of motor function, and improve cognitive function after cerebral ischemia. The pharmaceutical composition of this invention is rich in components that scavenge oxygen free radicals, and can regulate blood lipids, reduce blood viscosity, prevent thrombosis, and inhibit stroke recurrence. Detailed Implementation

[0032] Example 1

[0033] A method for preparing Shendan Tongnao Dripping Pills includes the following steps:

[0034] S1: Weigh 14.9 parts by weight of Ligusticum chuanxiong and 1.49 parts by weight of Salvia miltiorrhiza. Extract the Salvia miltiorrhiza and Ligusticum chuanxiong twice with 8 times the amount of 75% ethanol, 1 hour each time. Filter the extract, combine the filtrates, recover the ethanol and concentrate to a relative density of 1.05-1.08 (50℃). Extract the concentrate twice with ethyl acetate, combine the ethyl acetate extracts, recover the ethyl acetate under reduced pressure and concentrate to a clear extract with a relative density of 1.05-1.08 (40℃). Concentrate the aqueous solution under reduced pressure until the recovered solution has no ethyl acetate odor. Centrifuge under a filter cloth with a pore size of 3μm. Take the centrifuged liquid and adsorb it through a D101 macroporous adsorption resin column. After adsorption for 12 hours, wash with 1 column volume (1 BV) of water, discard the water wash, and then elute with 1 BV of 70% ethanol and concentrate to obtain a clear extract I with a relative density of 1.1-1.15 (50℃).

[0035] S2: Weigh 1 part by weight of ginseng, 7 parts by weight of *Cynanchum paniculatum*, 2 parts by weight of sea buckthorn, and 1.5 parts by weight of licorice. Extract the ginseng, *Cynanchum paniculatum*, sea buckthorn, and licorice three times by reflux with 10 times the volume of 80% ethanol, each time for 2 hours. After concentration, filter the extract, combine the filtrates, recover the ethanol, and concentrate to a relative density of 1.04-1.06 (50℃). Centrifuge under a filter cloth pore size of 3μm. Take the centrifuged liquid and adsorb it through a D101 type macroporous adsorption resin column. After adsorption for 12 hours, wash with 2BV of water, discard the water wash, and then elute with 2BV of 75% ethanol and concentrate to obtain clear extract II with a relative density of 1.1-1.15 (50℃).

[0036] S3: Weigh 5 parts by weight of coix seed, decoct the coix seed twice with 8 times the amount of water, 1 hour each time, filter and concentrate to obtain clear extract III with a relative density of 1.1-1.15 (50℃);

[0037] S4: Combine and mix the clear paste I, clear paste II, and clear paste III, dry under reduced pressure, and pulverize to obtain fine powder;

[0038] S5: Mix fine powder with excipients mono / distearate glyceryl stearate, polyethylene glycol 4000, and polyethylene glycol 6000, wherein the ratio of mono / distearate glyceryl stearate to polyethylene glycol 4000 is 1:22.5, the ratio of polyethylene glycol 4000 to polyethylene glycol 6000 is 1.5:1, and the ratio of fine powder to excipients is 1:2.5. Melt and mix at 75°C, keep warm, and then drop into cooled dimethicone oil (viscosity 100cs) to obtain brownish-brown pellets with a fragrant aroma and slightly bitter taste.

[0039] Example 2

[0040] A method for preparing Shendan Tongnao Dripping Pills includes the following steps:

[0041] S1: Weigh 18 parts by weight of Ligusticum chuanxiong and 2 parts by weight of Salvia miltiorrhiza. Extract the Salvia miltiorrhiza and Ligusticum chuanxiong twice with 8 times the amount of 75% ethanol, 1 hour each time. Filter the extract, combine the filtrates, recover the ethanol and concentrate to a relative density of 1.05-1.08 (50℃). Extract the concentrate twice with ethyl acetate, combine the ethyl acetate extracts, recover the ethyl acetate under reduced pressure and concentrate to a clear extract with a relative density of 1.05-1.08 (40℃). Concentrate the aqueous solution under reduced pressure until the recovered solution has no ethyl acetate odor. Centrifuge under a filter cloth with a pore size of 3μm. Take the centrifuged liquid and pass it through a D101 macroporous adsorption resin column for adsorption. After adsorption for 12 hours, wash with 1 column volume (1 BV) of water, discard the water wash, and then elute with 1 BV of 70% ethanol and concentrate to obtain a clear extract I with a relative density of 1.1-1.15 (50℃).

[0042] S2: Weigh 2 parts ginseng, 10 parts *Cynanchum paniculatum*, 4 parts *Hippophae rhamnoides*, and 2 parts licorice. Extract the ginseng, *Cynanchum paniculatum*, *Hippophae rhamnoides*, and licorice three times with 10 times the volume of 80% ethanol, each time for 2 hours. After concentration, filter the extract, combine the filtrates, recover the ethanol, and concentrate to a relative density of 1.04-1.06 (50℃). Centrifuge at a filter cloth pore size of 3μm. Take the centrifuged liquid and pass it through a D101 macroporous adsorption resin column for adsorption. After adsorption for 12 hours, wash with 2BV water, discard the water wash, and then elute with 2BV 75% ethanol and concentrate to obtain a clear extract II with a relative density of 1.1-1.15 (50℃).

[0043] S3: Weigh 8 parts by weight of coix seed, decoct the coix seed twice with 8 times the amount of water, 1 hour each time, filter and concentrate to obtain clear extract III with a relative density of 1.1-1.15 (50℃);

[0044] S4: Combine and mix the clear paste I, clear paste II, and clear paste III, dry under reduced pressure, and pulverize to obtain fine powder;

[0045] S5: Mix fine powder with excipients mono / distearate glyceryl monostearate, polyethylene glycol 4000, and polyethylene glycol 6000, wherein the ratio of mono / distearate glyceryl monostearate to polyethylene glycol 4000 is 1:25, the ratio of polyethylene glycol 4000 to polyethylene glycol 6000 is 2:1, and the ratio of fine powder to excipients is 1:3. Melt and mix at 75°C, keep warm, and then drop into cooled dimethicone oil (viscosity 100cs) to obtain brownish-brown pellets with a fragrant odor and slightly bitter taste.

[0046] Comparative Example 1

[0047] A method for preparing Shendan Tongnao Dripping Pills includes the following steps:

[0048] S1: Weigh 14.9 parts by weight of Ligusticum chuanxiong and 1.49 parts by weight of Salvia miltiorrhiza. Extract the Salvia miltiorrhiza and Ligusticum chuanxiong twice with 8 times the amount of 75% ethanol, 1 hour each time. Filter the extract, combine the filtrates, recover the ethanol and concentrate to a relative density of 1.05-1.08 (50℃). Extract the concentrate twice with ethyl acetate, combine the ethyl acetate extracts, recover the ethyl acetate under reduced pressure and concentrate to a clear extract with a relative density of 1.05-1.08 (40℃). Concentrate the aqueous solution under reduced pressure until the recovered solution has no ethyl acetate odor. Centrifuge under a filter cloth with a pore size of 3μm. Take the centrifuged liquid and adsorb it through a D101 macroporous adsorption resin column. After adsorption for 12 hours, wash with 1 column volume (1 BV) of water, discard the water wash, and then elute with 1 BV of 70% ethanol and concentrate to obtain a clear extract I with a relative density of 1.1-1.15 (50℃).

[0049] S2: Weigh 1 part by weight of ginseng, 20 parts by weight of *Cynanchum paniculatum*, 2 parts by weight of sea buckthorn, and 1.5 parts by weight of licorice. Extract the ginseng, *Cynanchum paniculatum*, sea buckthorn, and licorice three times by reflux with 10 times the volume of 80% ethanol, each time for 2 hours. After concentration, filter the extract, combine the filtrates, recover the ethanol, and concentrate to a relative density of 1.04-1.06 (50℃). Centrifuge under a filter cloth pore size of 3μm. Take the centrifuged liquid and pass it through a D101 type macroporous adsorption resin column for adsorption. After adsorption for 12 hours, wash with 2BV of water, discard the water wash, and then elute with 2BV of 75% ethanol and concentrate to obtain clear extract II with a relative density of 1.1-1.15 (50℃).

[0050] S3: Weigh 5 parts by weight of coix seed, decoct the coix seed twice with 8 times the amount of water, 1 hour each time, filter and concentrate to obtain clear extract III with a relative density of 1.1-1.15 (50℃);

[0051] S4: Combine and mix the clear paste I, clear paste II, and clear paste III, dry under reduced pressure, and pulverize to obtain fine powder;

[0052] S5: Mix fine powder with excipients mono / distearate glyceryl stearate, polyethylene glycol 4000, and polyethylene glycol 6000, wherein the ratio of mono / distearate glyceryl stearate to polyethylene glycol 4000 is 1:22.5, the ratio of polyethylene glycol 4000 to polyethylene glycol 6000 is 1.5:1, and the ratio of fine powder to excipients is 1:2.5. Melt and mix at 75°C, keep warm, and then drop into cooled dimethicone oil (viscosity 100cs) to obtain brownish-brown pellets with a fragrant aroma and slightly bitter taste.

[0053] Comparative Example 2

[0054] A method for preparing Shendan Tongnao Dripping Pills includes the following steps:

[0055] S1: Weigh 22 parts by weight of Ligusticum chuanxiong and 1.49 parts by weight of Salvia miltiorrhiza. Extract the Salvia miltiorrhiza and Ligusticum chuanxiong twice with 8 times the amount of 75% ethanol, 1 hour each time. Filter the extract, combine the filtrates, recover the ethanol and concentrate to a relative density of 1.05-1.08 (50℃). Extract the concentrate twice with ethyl acetate, combine the ethyl acetate extracts, recover the ethyl acetate under reduced pressure and concentrate to a clear extract with a relative density of 1.05-1.08 (40℃). Concentrate the aqueous solution under reduced pressure until the recovered solution has no ethyl acetate odor. Centrifuge under a filter cloth with a pore size of 3μm. Take the centrifuged liquid and adsorb it through a D101 macroporous adsorption resin column. After adsorption for 12 hours, wash with 1 column volume (1 BV) of water, discard the water wash, and then elute with 1 BV of 70% ethanol and concentrate to obtain a clear extract I with a relative density of 1.1-1.15 (50℃).

[0056] S2: Weigh 1 part by weight of ginseng, 7 parts by weight of *Cynanchum paniculatum*, 2 parts by weight of sea buckthorn, and 1.5 parts by weight of licorice. Extract the ginseng, *Cynanchum paniculatum*, sea buckthorn, and licorice three times by reflux with 10 times the volume of 80% ethanol, each time for 2 hours. After concentration, filter the extract, combine the filtrates, recover the ethanol, and concentrate to a relative density of 1.04-1.06 (50℃). Centrifuge under a filter cloth pore size of 3μm. Take the centrifuged liquid and adsorb it through a D101 type macroporous adsorption resin column. After adsorption for 12 hours, wash with 2BV of water, discard the water wash, and then elute with 2BV of 75% ethanol and concentrate to obtain clear extract II with a relative density of 1.1-1.15 (50℃).

[0057] S3: Weigh 5 parts by weight of coix seed, decoct the coix seed twice with 8 times the amount of water, 1 hour each time, filter and concentrate to obtain clear extract III with a relative density of 1.1-1.15 (50℃);

[0058] S4: Combine and mix the clear paste I, clear paste II, and clear paste III, dry under reduced pressure, and pulverize to obtain fine powder;

[0059] S5: Mix fine powder with excipients mono / distearate glyceryl stearate, polyethylene glycol 4000, and polyethylene glycol 6000, wherein the ratio of mono / distearate glyceryl stearate to polyethylene glycol 4000 is 1:22.5, the ratio of polyethylene glycol 4000 to polyethylene glycol 6000 is 1.5:1, and the ratio of fine powder to excipients is 1:2.5. Melt and mix at 75°C, keep warm, and then drop into cooled dimethicone oil (viscosity 100cs) to obtain brownish-brown pellets with a fragrant aroma and slightly bitter taste.

[0060] Weight difference test

[0061] Twenty pills of the test samples from Examples 1 and 2 were taken and tested according to the drop pill method under the Pills section of the Chinese Pharmacopoeia 2020 General Chapter 0108. The weight difference limit was ±12%, and no more than two pills exceeded the weight difference limit, and no single pill exceeded the limit by more than 100%. The weight difference test results of the three batches of samples from Examples 1 and 2 are shown in Table 1 below:

[0062] The results showed that the weight differences of the three batches of samples in Example 1 and Example 2 all met the requirements.

[0063] Filling volume variation test

[0064] The product of this invention is a single-dose packaged pill, and the content variation test was conducted according to the method for checking the content variation of single-dose packaged pills under General Chapter 0108 of the Chinese Pharmacopoeia 2020. The content variation test results of three batches of samples from Examples 1 and 2 are shown in Table 2 below:

[0065]

[0066] The results showed that the differences in the loading of the three batches of samples in Example 1 and Example 2 all met the requirements.

[0067] Dissolution time limit test

[0068] Six pills of the test samples from Examples 1 and 2 were taken and tested without a baffle according to the method for dispersibility test (General Chapter 0108 of the Chinese Pharmacopoeia 2020) for pills. The pills should dissolve completely within 30 minutes. The results of the dispersibility test for the three batches of samples from Examples 1 and 2 are shown in Table 3 below:

[0069]

[0070] The results showed that the dissolution time of the three batches of samples in Examples 1 and 2 all met the requirements.

[0071] Solvent Residue Test

[0072] (1) Residues of toluene, xylene, styrene, diethylbenzene, and divinylbenzene shall be determined according to the residual solvent determination method (General Chapter 0861, Chinese Pharmacopoeia 2020 Edition):

[0073] Chromatographic conditions and system suitability test: A capillary column with polyethylene glycol as the stationary phase was used (30 m column length, 0.32 mm inner diameter, 0.25 μm film thickness); the column temperature was programmed, starting at 40 °C, held for 5 minutes, and then increased to 150 °C at 3 °C per minute; a flame ionization detector was used at 300 °C; the injection port temperature was 240 °C; and nitrogen was used as the carrier gas. Headspace injection was performed, with the headspace vial equilibrating at 90 °C for 30 minutes. The theoretical plate number, calculated based on the toluene peak, should be no less than 40,000, and the resolution between each analyte peak and adjacent peaks should meet the specified requirements.

[0074] Preparation of the reference solution: Accurately weigh appropriate amounts of toluene, xylene, styrene, diethylbenzene, and divinylbenzene. Add N,N-dimethylformamide to prepare a mixed solution containing 80 μg of each per mL. Shake well. Accurately measure 1 mL of this solution into a 100 mL volumetric flask, add water to the mark, and shake well to obtain the reference solution (containing 0.8 μg of each per mL). Accurately measure 5 mL of this solution into a 20 mL headspace vial, seal, and obtain the reference solution.

[0075] Preparation of the test solution: Take three batches of samples from Example 1 and Example 2, grind them finely, take 0.2g, weigh accurately, place in a 20mL headspace vial, accurately add 5mL of 1% N,N-dimethylformamide, seal, shake well, and the solution is obtained;

[0076] Determination: Accurately measure 1 mL of headspace gas from both the reference solution and the test solution and inject them into the gas chromatograph.

[0077] The test results showed that toluene, xylene, styrene, diethylbenzene, and divinylbenzene residues were not detected in the three batches of samples in Examples 1 and 2, which met the requirement of being less than 0.002%.

[0078] (2) Benzene, n-hexane, and ethyl acetate residues shall be determined according to the residual solvent determination method (General Chapter 0861, Chinese Pharmacopoeia 2020 Edition):

[0079] Chromatographic conditions and system suitability: A capillary column (30 m length, 0.53 mm inner diameter, 3 μm film thickness) with 6% cyanopropylbenzene and 94% dimethylsiloxane as stationary phase; programmable column temperature, starting at 40 °C, holding for 5 min, then ramping to 120 °C at 3 °C / min; flame ionization detector, detector temperature 300 °C; injection port temperature 240 °C; nitrogen as carrier gas. Headspace injection, headspace equilibration temperature 90 °C, equilibration time 30 min; theoretical plate number based on benzene peak should be no less than 20,000; the resolution between each analyte peak and adjacent peaks should meet the requirements.

[0080] Preparation of the reference solution: Accurately weigh appropriate amounts of benzene, n-hexane, and ethyl acetate, add N,N-dimethylacetamide to prepare a mixed solution containing 8 μg, 80 μg, and 4 mg per 1 mL, respectively. Shake well. Accurately pipette 1 mL into a 100 mL volumetric flask, add water to the mark, and shake well. Alternatively, accurately measure 5 mL into a 20 mL headspace vial, seal, and obtain the reference solution.

[0081] Preparation of the test solution: Take three batches of samples from Example 1 and Example 2, grind them finely, take 0.2g, weigh accurately, place in a 20ml headspace vial, accurately add 5mL of 1% N,N-dimethylacetamide, seal, shake well, and the solution is obtained;

[0082] Determination: Accurately measure 1 mL of headspace gas from both the reference solution and the test solution and inject them into the gas chromatograph.

[0083] The test results showed that in Example 1, benzene and n-hexane residues were not detected in the three batches of samples, meeting the requirements of not exceeding 0.0002% and 0.002% respectively; the ethyl acetate residues were 0.05%, 0.05%, and 0.08%, all below 0.1%, and met the requirements. In Example 2, benzene and n-hexane residues were not detected in the three batches of samples, meeting the requirements of not exceeding 0.0002% and 0.002% respectively; the ethyl acetate residues were 0.09%, 0.06%, and 0.08%, all below 0.1%, and met the requirements.

[0084] Sample content testing

[0085] (1) Ferulic acid content

[0086] Chromatographic conditions and system suitability: Octadecylsilane-bonded silica gel was used as the stationary phase; methanol-1% acetic acid solution (30:70) was used as the mobile phase; the detection wavelength was 321 nm; and the theoretical plate number calculated based on the ferulic acid peak should be no less than 4000.

[0087] Preparation of reference solution: Take an appropriate amount of ferulic acid reference standard, place it in a brown volumetric flask, and add methanol to prepare a solution containing 20 μg per 1 mL;

[0088] Preparation of test solution: Take 200 pills from each of Examples 1-2 and Comparative Examples 1-2, grind them into a fine powder, take 0.5g, place them in a stoppered conical flask, add 50mL of methanol, weigh, sonicate (power 250W, frequency 40KHz) for 30min, cool, weigh again, replenish the lost weight with methanol, shake well, filter, and take the filtrate.

[0089] Determination: Inject 10 μL of the reference solution and the test solution into the liquid chromatograph.

[0090] (2) Danshensu B content

[0091] Chromatographic conditions and system suitability: Octadecylsilane-bonded silica gel was used as the stationary phase; acetonitrile-methanol-1% formic acid (8:31:61) was used as the mobile phase; the detection wavelength was 286 nm; and the theoretical plate number, calculated based on the B peak of salvianolic acid, should not be less than 6000.

[0092] Preparation of reference solution: Take an appropriate amount of salvianolic acid B reference standard, accurately weigh it, and add 50% methanol to prepare a solution containing 0.1 mg per 1 mL;

[0093] Preparation of test solution: Take the products of Examples 1-2 and Comparative Examples 1-2, grind them into fine powder, take 0.2g, place them in a stoppered conical flask, add 50mL of 50% methanol, weigh, sonicate (power 480W, frequency 40kHz) for 30min, take out, cool, weigh again, make up the lost weight with 50% methanol, shake well, filter, take 5mL of the filtrate, place it in a 10mL volumetric flask, dilute to the mark with 50% methanol, shake well, filter;

[0094] Determination: Accurately pipette 10 μL each of the reference solution and the test solution and inject them into the liquid chromatograph.

[0095] (3) Content of ginsenoside Re and ginsenoside Rb1

[0096] Chromatographic conditions and system suitability: Octadecylsilane-bonded silica gel was used as the stationary phase; acetonitrile was used as mobile phase A and water was used as mobile phase B, and gradient elution was performed according to the specifications in the table below; the detection wavelength was 203 nm, and the theoretical plate number calculated based on ginsenoside Rg1 should not be less than 6000;

[0097] Preparation of reference solution: Take appropriate amounts of ginsenoside Rg1, ginsenoside Re, and ginsenoside Rb1 reference standards, add methanol to prepare a mixed reference solution containing 0.1 mg, 0.1 mg, and 0.2 mg of each per 1 mL;

[0098] Preparation of test solution: Grind the products of Examples 1-2 and Comparative Examples 1-2 into a fine powder. Take 1 g of each powder and place it in a stoppered conical flask. Accurately add 50 mL of water-saturated n-butanol, shake well, weigh, and sonicate (power 480 W, frequency 40 kHz) for 60 min. Remove, cool, and replenish the lost weight with water-saturated n-butanol. Shake well, filter, and accurately measure 25 mL of the filtrate. Transfer to a separatory funnel and wash three times with 20 mL of 1% sodium hydroxide solution saturated with n-butanol. Take a portion of the solution. Wash twice with 30 mL of water-saturated n-butanol solution and alkali solution, respectively. Discard the alkali solution. Combine the n-butanol solutions and wash twice more with 30 mL of water-saturated n-butanol solution, respectively. Extract the washing solution with 20 mL of water-saturated n-butanol solution by shaking. Discard the aqueous solution. Combine the n-butanol solutions and evaporate to dryness. Dissolve the residue in methanol and transfer it to a 10 mL volumetric flask. Add methanol to the mark, shake well, filter, and collect the filtrate. For determination: inject 10 μL each of the reference solution and the test solution into the liquid chromatograph.

[0099] The test results are shown in Table 4 below:

[0100] ferulic acid mg / g Tanshinone B mg / g <![CDATA[ginsenoside Rb1 mg / g]]> <![CDATA[Sum of ginsenoside Re and ginsenoside Rb1 mg / g]]> Example 1 2.15 69.09 6.32 7.62 Example 2 2.73 75.60 6.58 8.23 Comparative Example 1 2.11 68.82 6.03 7.22 Comparative Example 2 3.28 64.71 6.26 7.53

[0101] In this invention, ferulic acid in Ligusticum chuanxiong has antioxidant and antithrombotic effects, but excessive amounts may lead to excessive vasodilation or affect coagulation function. Therefore, it is necessary to control the amount of Ligusticum chuanxiong added. Appropriate dosage can effectively promote blood circulation. Excessive amounts of Dioscorea opposita may reduce the bioavailability of Salvia miltiorrhiza and may also cause gastrointestinal discomfort. Therefore, controlling the amount of Dioscorea opposita added can reduce inflammation and pain, relax muscles and tendons, and avoid nausea and diarrhea induced by medication.

[0102] Antibacterial activity test

[0103] After culturing Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae, the bacterial solutions were centrifuged, the solutions were discarded, and the precipitates were reconstituted with physiological saline. 1 mL of each bacterial solution was then taken to achieve a bacterial concentration of 1×10⁻⁶. 8 CFU; Take the products from Examples 1-2 and Comparative Examples 1-2, grind them finely, take 25g, add 300mL of water, soak for 1h, heat in a water bath at 100℃ for 90min, filter with a 200-mesh filter cloth, add 250mL of water to the residue, heat in a water bath at 100℃ for 1h, filter, combine the filtrates and concentrate to 1g / mL; use a 96-well culture plate, add 0.2mL of concentrate and 10μL of test bacterial solution to each well, and set up positive and negative controls. After incubation at 37℃ for 24h, add chromogenic reagent and observe color change, with bacterial growth and red color.

[0104] The test results showed no color change, indicating no bacterial growth. This suggests that the product of this invention has a good inhibitory effect on Streptococcus pneumoniae, Escherichia coli, and Staphylococcus aureus, effectively reducing inflammation and preventing damage to the infected site. It acts on brain tissue through blood circulation, thereby damaging brain nerves, aggravating cerebral ischemia / hypoxia, and hindering the repair and regeneration of damaged nerves. It can also reduce the level of systemic inflammatory factors, reduce secondary damage to brain tissue, and promote the recovery of motor function, language function, and cognitive function.

Claims

1. A pharmaceutical composition for Shendan Tongnao Dripping Pills, characterized in that, It includes the following components by weight: 1-20 parts of Ligusticum chuanxiong, 1-8 parts of Salvia miltiorrhiza, 0.1-5 parts of Panax ginseng, 1-15 parts of Dioscorea opposita, 1-10 parts of Coix lacryma-jobi, 0.1-4 parts of Hippophae rhamnoides, and 0.1-2 parts of Glycyrrhiza uralensis.

2. The pharmaceutical composition of Shendan Tongnao Dripping Pills according to claim 1, characterized in that, It includes the following components by weight: 5-18 parts of Ligusticum chuanxiong, 1-5 parts of Salvia miltiorrhiza, 0.5-4 parts of Panax ginseng, 3-14 parts of Dioscorea opposita, 1-10 parts of Coix lacryma-jobi, 0.1-4 parts of Hippophae rhamnoides, and 0.1-2 parts of Glycyrrhiza uralensis.

3. The pharmaceutical composition of Shendan Tongnao Dripping Pills according to claim 1 or 2, characterized in that, It includes the following components by weight: 7-15 parts Ligusticum chuanxiong, 1.5-3 parts Salvia miltiorrhiza, 1-2 parts Panax ginseng, 5-12 parts Dioscorea opposita, 1-10 parts Coix lacryma-jobi, 0.1-4 parts Hippophae rhamnoides, and 0.1-2 parts Glycyrrhiza uralensis.

4. A method for preparing a Shendan Tongnao Dripping Pill, characterized in that, A pharmaceutical composition based on any one of claims 1-3, namely, a Shendan Tongnao Dripping Pill, comprises the following steps: S1: Extract Ligusticum chuanxiong and Salvia miltiorrhiza by ethanol refluxing to obtain extract I; S2: Ginseng, *Gynostemma pentaphyllum*, sea buckthorn, and licorice were extracted by ethanol reflux to obtain extract II; S3: Extract and concentrate the coix seed water to obtain clear extract III; S4: Combine and mix the clear paste I, clear paste II, and clear paste III, dry under reduced pressure, and pulverize to obtain fine powder; S5: After mixing the fine powder with the excipients, melt and mix them evenly, keep them warm and then cool them to obtain droplets.

5. A method for preparing a Shendan Tongnao Dripping Pill according to claim 4, characterized in that, In step S1, the extract was refluxed twice with 8 times the volume of 75% ethanol, each time for 1 hour. The resulting concentrate was extracted twice with ethyl acetate and then adsorbed through a D101 macroporous adsorption resin column. After elution with 1 BV of 70% ethanol and concentration, a clear extract I with a relative density of 1.1-1.15 at 50℃ was obtained.

6. A method for preparing a Shendan Tongnao Dripping Pill according to claim 4, characterized in that, In step S2, the extract was refluxed three times with 10 times the volume of 80% ethanol, each time for 2 hours. After concentration, it was adsorbed through a D101 macroporous adsorption resin column, eluted with 2 BV of 75% ethanol and concentrated to obtain a clear extract II with a relative density of 1.1-1.15 at 50℃.

7. A method for preparing a Shendan Tongnao Dripping Pill according to claim 4, characterized in that, In step S3, the mixture is decocted twice with 8 times the amount of water, each time for 1 hour, filtered and concentrated to obtain a clear extract III with a relative density of 1.1-1.15 at 50℃.

8. The preparation method of the Shendan Tongnao Dripping Pill according to claim 4, characterized in that, In step S5, the excipients include: glyceryl mono / distearate, polyethylene glycol 4000, and polyethylene glycol 6000; The ratio of mono / distearate glyceryl stearate to polyethylene glycol 4000 is 1:20-25; the ratio of polyethylene glycol 4000 to polyethylene glycol 6000 is 1-3:

1. The ratio of fine powder to excipients is 1:1-4.

9. A method for preparing a Shendan Tongnao Dripping Pill according to claim 4 or 8, characterized in that, In step S5, the melting temperature is 75-80℃ and the viscosity of the dimethicone oil in the condensate is 100cs.

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