Granules for clearing away heart-fire and removing blood stasis and preparation method thereof

Abstract

The invention provides granules for clearing away heart-fire and removing blood stasis and a preparation method thereof, coptis chinensis, pogostemon cablin, ligusticum wallichii, astragalus membranaceus and salvia miltiorrhiza are used as raw materials, and the granules for clearing away the heart-fire and removing blood stasis are prepared through volatile oil extraction and inclusion, water-soluble substance extraction, concentration, drying and granulation in sequence. The preparation process comprises volatile oil extraction and inclusion processes, in the volatile oil extraction process, oil-water mixed liquid collected by a steam distillation method is enriched by an oily carrier, so that the oil yield of mixed oil of ligusticum wallichii and pogostemon cablin is increased, the emulsification phenomenon is reduced, and the prepared granules for clearing away the heart-fire and removing the blood stasis are convenient to take, carry and store, and have a good application prospect. And the process route is simple, parameters are reasonable, the process is stable, and industrial production can be realized.

Description

Technical Field

[0001] The invention belongs to the field of traditional Chinese medicine and relates to Qingxin Jieyu granules and a preparation method thereof. Background Art

[0002] Coronary heart disease is one of the diseases with high morbidity and mortality among cardiovascular diseases. Percutaneous coronary intervention (PCI) is one of the main means of clinical treatment of coronary heart disease. It has obvious advantages in improving patient symptoms, reducing short-term mortality and improving prognosis. However, at the same time, restenosis after coronary heart disease surgery and the recurrence of major adverse cardiac events (MACE) have gradually become prominent. MACE is an important complication after PCI, which greatly affects the quality of life and long-term prognosis of patients. MACE is a composite cardiovascular event, mainly including sudden cardiac death, non-fatal re-myocardial infarction, recurrent unstable angina, subacute stent thrombosis, and target vessel revascularization. Such patients often need revascularization, which also increases the economic burden of patients to a certain extent. The incidence of MACE events is 5%-10%. How to reduce the incidence of complications or adverse events after PCI for coronary heart disease is a key issue that needs to be solved urgently.

[0003] Traditional Chinese medicine believes that restenosis after PCI surgery falls into the category of "chest pain", and its etiology and pathogenesis are similar to those of coronary heart disease. Coronary heart disease belongs to the category of "chest pain" and "true heart pain" in traditional Chinese medicine. The pathogenesis is obstruction of the heart meridians, and blood stasis runs through the whole process. The treatment mainly focuses on promoting blood circulation and removing blood stasis. At the same time, it targets the pathogenesis of qi stagnation, phlegm turbidity, qi deficiency, yin deficiency, etc., supplemented by therapies such as promoting qi, resolving phlegm, invigorating qi, and nourishing yin.

[0004] Qingxin Jieyu Formula is composed of 5 medicinal materials, including Coptis chinensis, Astragalus membranaceus, Chuanxiong, Salvia miltiorrhiza and Patchouli. It can treat cardiovascular diseases such as ischemic heart disease, arrhythmia, hypertension, heart failure, etc. It is also a representative formula for the treatment of stable coronary heart disease based on the etiology and pathogenesis of coronary heart disease "stasis and toxicity". Previous studies have found that Qingxin Jieyu Formula has a good effect in inhibiting inflammatory response, which is mainly reflected in: (1) reducing the serum hs-CRP level and IL-6, MMP-9, sCD40L and other inflammatory factors in patients with stable coronary heart disease; (2) inhibiting the therapeutic inflammatory factors of patients with stable coronary heart disease, inhibiting keratin KRT6B, KRT16, KRTA, improving blood lipid levels, improving efficacy, and reducing the occurrence of adverse cardiovascular events. The Qingxin Jieyu recipe can also reduce the incidence of endpoint events in patients (including major composite endpoint events such as cardiac death, non-fatal myocardial infarction, and revascularization, and secondary composite endpoint events such as stroke, unstable angina, heart failure, and malignant arrhythmias); stabilize AS plaques; improve the resting electrocardiogram and TCM symptoms (chest tightness, shortness of breath, spontaneous sweating, insomnia, and dry mouth) of patients with stable angina pectoris, and improve the quality of life of patients; improve the level of CXC chemokines, promote cardiac function recovery, and has significant clinical efficacy.

[0005] Chinese herbal volatile oils play a significant role in preventing cardiovascular diseases, regulating and improving cardiovascular function. Chuanxiong volatile oil can improve the electrocardiogram of rats with acute myocardial ischemia, reduce the level of myocardial injury enzyme spectrum, resist oxidation, inhibit the expression of apoptosis-related protein Bax, and promote the expression of Bcl-2. The main component of patchouli volatile oil is terpenoids, which have obvious vasodilatory activity.

[0006] At present, Qingxin Jieyu Formula is mainly taken in the form of decoction in clinical practice, and it is effective in the clinical treatment of angina pectoris in unstable coronary heart disease. Summary of the invention

[0007] Problem that the invention aims to solve

[0008] Qingxin Jieyu Granules are mainly used in the form of decoction in clinical practice. It has the characteristics of simple preparation, rapid absorption, and rapid efficacy, but it is inconvenient to take, carry, and store.

[0009] In addition, both Chuanxiong and Patchouli in Qingxin Jieyu Granules contain volatile oils. The temperature is high during the decoction process, and the local heating of the liquid medicine causes most of the volatile oils to volatilize, leaving only a small amount of volatile oils in the decoction. More volatile oils can be retained in the decoction by extraction, but aromatic Chinese medicines contain a variety of volatile oil components, and the specific gravity of volatile oils of different medicinal flavors varies greatly. The specific gravity of volatile oils in Chuanxiong will change with temperature; at the same time, when volatile oils are mixed with Patchouli to extract, emulsification is prone to occur. Therefore, it is difficult to use a single light oil or heavy oil extraction method for extraction during the production process, resulting in low volatile oil extraction efficiency.

[0010] Based on the above problems, it is of great significance to provide a Qingxin Jieyu granule with high oil extraction rate and easy to take, carry and store and a preparation method thereof.

[0011] Solutions for solving problems

[0012] During the extraction of volatile oil, the volatile oil exists in the form of an oil-water mixture and is difficult to aggregate to form an oil layer. The present invention adds a pharmaceutically acceptable and edible oily carrier, such as corn oil, soybean oil, etc., into the volatile oil collector, so that the collected oil-water mixture passes through the oily carrier. According to the principle of like dissolves like, the volatile oil and the oily carrier are mutually soluble, and the oil-water mixture is separated, thereby better solving the problem of the difficulty in agglomerating the oil layer and improving the collection of volatile oil.

[0013] The present invention believes that the above technical problems can be solved by implementing the following technical solutions:

[0014] [1]. The present invention provides a method for preparing Qingxin Jieyu granules, which comprises the following steps:

[0015] 1) Extraction and inclusion of volatile oil: Patchouli and Ligusticum chuanxiong are added with 4-12 times by weight, preferably 4-10 times by weight, of water, and extracted by steam distillation for 1h-9h. The oil-water mixture is enriched with an oily carrier to obtain a mixed volatile oil containing an oily carrier, and an inclusion carrier material with a mass ratio of 6-12 times by weight, preferably 6-10 times by weight, of the mixed volatile oil is added for inclusion to obtain inclusion compound A;

[0016] 2) Extraction of water-soluble substances: separating the remaining medicinal liquid and the medicinal residue obtained after the volatile oil extraction, mixing the medicinal residue with Astragalus, Salvia miltiorrhiza, and Coptis chinensis, adding 6-14 times by weight, preferably 8-12 times by weight of water, decocting for 1-3.5 hours, filtering, combining the filtrate with the remaining medicinal liquid to obtain a Chinese medicine mixed medicinal liquid;

[0017] 3) Concentration: The mixed Chinese medicine solution in step 2) is concentrated under reduced pressure at 50-80° C., preferably 55-75° C., to a specific gravity of 1.03 to 1.10 to obtain a Chinese medicine extract;

[0018] 4) Drying: Drying the Chinese medicine extract in step 3) to obtain Chinese medicine extract B;

[0019] 5) Granulation: The inclusion compound A in step 1) and the Chinese herbal extract B in step 4) are mixed and granulated to obtain the product.

[0020] [2] The preparation method according to [1], wherein the mass ratio of coptis root, patchouli, ligusticum chuanxiong, astragalus and salvia miltiorrhiza is 1:2:2:3:3.

[0021] [3]. The preparation method according to [1] or [2], wherein the oily carrier in step 1) is a vegetable oil, preferably one of peanut oil, soybean oil, corn oil, linseed oil, castor oil, rapeseed oil, rapeseed salad oil, sesame oil, olive oil and sunflower oil, more preferably corn oil or soybean oil.

[0022] [4] The preparation method according to any one of [1] to [3], wherein the relative amount of the oily carrier in step 1) is 0.25% to 0.75%, preferably 0.45% to 0.55%, based on the total mass of the patchouli and ligusticum chuanxiong.

[0023] [5]. The preparation method according to any one of [1] to [4], wherein the inclusion complex carrier material in step 1) is a polysaccharide, preferably one of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, starch, methyl cellulose and cellulose, more preferably β-cyclodextrin or hydroxypropyl-β-cyclodextrin.

[0024] [6] The preparation method according to any one of [1] to [5], wherein the inclusion method in step 1) is a grinding method or an ultrasonic method, preferably a grinding method;

[0025] Preferably, the inclusion comprises a drying step;

[0026] More preferably, the drying method is low temperature drying or spray drying.

[0027] [7]. The preparation method according to [6], wherein the grinding method comprises the following steps: mixing the inclusion complex carrier material and water, grinding for 10 minutes, adding the mixed volatile oil and ethanol, and grinding for 30 to 120 minutes, preferably 30 minutes;

[0028] Preferably, the volume ratio of the mixed volatile oil to ethanol is 1:1 to 1:2, preferably 1:1;

[0029] Preferably, the mass ratio of the inclusion complex carrier material to water is 1:2-1:12, preferably 1:2-1:8.

[0030] [8] The preparation method according to any one of [1] to [7], wherein the decoction in step 2) is performed at least twice, preferably for 0.5-2 h for the first decoction and for 0.5-1.5 h for the second decoction.

[0031] [9]. The preparation method according to any one of [1] to [8], wherein the vacuum degree of the reduced pressure concentration in step 3) is -0.06 to -0.10 MPa.

[0032]

[10] The preparation method according to any one of [1] to [9], wherein the drying method in step 4) is reduced pressure drying or spray drying;

[0033] Preferably, the drying method is reduced pressure drying;

[0034] More preferably, the pressure of the reduced pressure drying is -0.05 to -0.095 MPa;

[0035] Preferably, the drying method is spray drying;

[0036] More preferably, the spray drying comprises the following steps: adding auxiliary materials to the Chinese medicine extract, and spray drying under the conditions of an inlet air temperature of 165 to 195° C. and an outlet air temperature of 85 to 105° C.;

[0037] Further preferably, the auxiliary material is a polysaccharide, preferably maltodextrin, and / or, based on the total mass of the coptis root, patchouli, ligusticum chuanxiong, astragalus and salvia miltiorrhiza, the amount of the auxiliary material is 3% to 5%.

[0038]

[11] The preparation method according to any one of [1] to

[10] , wherein the auxiliary materials used in the granulation in step 5) include a lubricant and a molding agent;

[0039] Preferably, the lubricant is one or more of silicon dioxide and magnesium stearate;

[0040] and / or,

[0041] Preferably, the shaping agent is maltodextrin or lactose.

[0042]

[12] . The preparation method according to any one of [1] to

[11] , wherein the granulation method in step 5) is dry granulation or fluidized bed granulation.

[0043]

[13] . A Qingxin Jieyu granule, which is prepared by the preparation method according to any one of [1] to

[12] .

[0044]

[14] . The present invention provides a method for extracting volatile oil, which comprises the following steps: taking patchouli and chuanxiong, adding 4-12 times by weight, preferably 4-10 times by weight, water, extracting by steam distillation for 1h-9h, enriching the oil-water mixture with an oily carrier, and obtaining a mixed volatile oil containing an oily carrier;

[0045] Preferably, the mass ratio of patchouli to ligusticum chuanxiong is 1:1;

[0046] and / or,

[0047] Preferably, the oily carrier is a vegetable oil, preferably one of peanut oil, soybean oil, corn oil, linseed oil, castor oil, rapeseed oil, rapeseed salad oil, sesame oil, olive oil and sunflower oil, more preferably corn oil or soybean oil;

[0048] and / or,

[0049] Preferably, based on the total weight of the patchouli and ligusticum chuanxiong, the content of the oily carrier is 0.25% to 0.75%, preferably 0.45% to 0.55%.

[0050] Effects of the Invention

[0051] The process of the invention comprises the extraction and inclusion process of volatile oil. In the volatile oil extraction process, the oil-water mixed liquid collected by the steam distillation method is enriched by the oily carrier, so that the oil yield of the mixed oil of chuanxiong and patchouli is improved and the emulsification phenomenon is reduced. The prepared Qingxin Jieyu granules are easy to take, carry and store, and the process route is simple, the parameters are reasonable, the process is stable, and industrial production can be realized. DETAILED DESCRIPTION

[0052] Various exemplary embodiments, features and aspects of the present invention will be described in detail below. The word "exemplary" used here means "used as an example, embodiment or illustrative". Any embodiment described here as "exemplary" is not necessarily interpreted as being superior or better than other embodiments.

[0053] In addition, in order to better illustrate the present invention, numerous specific details are provided in the following specific embodiments. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In other examples, methods, means, equipment and steps well known to those skilled in the art are not described in detail in order to highlight the subject matter of the present invention.

[0054] Unless otherwise stated, the units used in this specification are all international standard units, and the numerical values ​​and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0055] In this specification, the word "may" means both performing a certain process and not performing a certain process.

[0056] In this specification, the references to "some specific / preferred embodiments", "other specific / preferred embodiments", "embodiments", etc., mean that the specific elements (e.g., features, structures, properties and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not exist in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any suitable manner.

[0057] In this specification, the numerical range expressed using "a numerical value A to a numerical value B" means a range including the endpoints numerical values ​​A and B.

[0058] In this specification, when "normal temperature" or "room temperature" is used, the temperature may be 10-40°C.

[0059] In this specification, unless otherwise specified, the term "Huangqi" refers to the dried root of the perennial herb Astragalus membranaceus (Fisch.) Bge. and A.membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao of the Leguminosae family. It is slightly warm in nature, sweet in taste, and enters the spleen and lung meridians. It has the effects of invigorating qi and raising yang, strengthening the body's defense system, expelling toxins and promoting tissue regeneration, and promoting diuresis and reducing swelling.

[0060] In this specification, unless otherwise specified, the term "patchouli" refers to the dried aerial parts of the perennial herbaceous plant Pogostemon cablin (Blanco) Benth. of the Lamiaceae family. It is slightly warm in nature, pungent in taste, and enters the spleen, stomach, and lung meridians, and has the effects of removing dampness, relieving heat, and stopping vomiting.

[0061] In this specification, unless otherwise specified, the term "Coptis chinensis" refers to the rhizome, root hair and leaves of the perennial herb Coptis chinensis Franch., C.deltoidea CYCheng et Hsiao or C.teetoidesC.Y.Cheng of the Ranunculaceae family. It is cold in nature, bitter in taste, and enters the heart, liver, stomach and large intestine meridians, and has the effects of clearing away heat and dampness, purging fire and detoxifying.

[0062] In this specification, unless otherwise specified, the term "Chuanxiong" refers to the rhizome of the perennial herbaceous plant Ligusticum chuanxiong Hort. of the Apiaceae family. It is warm in nature, pungent in taste, and enters the liver, gallbladder, and pericardium meridians, and has the effects of promoting blood circulation and qi, dispelling wind and relieving pain.

[0063] In this specification, unless otherwise specified, the term "Danshen" refers to the root of the perennial herb Salviamiltiorrhiza Bge. of the Labiatae family. It is slightly cold in nature, bitter in taste, and enters the heart, pericardium, and liver meridians. It has the effects of promoting blood circulation and removing blood stasis, cooling blood and eliminating carbuncle, nourishing blood and calming the mind.

[0064] <Preparation method of Qingxin Jieyu granules>

[0065] In the first aspect of the present invention, a method for preparing Qingxin Jieyu Granules is provided, which mainly comprises the following steps:

[0066] 1) Extraction and inclusion of volatile oil: Patchouli and Ligusticum chuanxiong are added with 4-12 times by weight, preferably 4-10 times by weight, of water, and extracted by steam distillation for 1h-9h. The oil-water mixture is enriched with an oily carrier to obtain a mixed volatile oil containing an oily carrier, and an inclusion carrier material with a mass ratio of 6-12 times by weight, preferably 6-10 times by weight, of the mixed volatile oil is added for inclusion to obtain inclusion compound A;

[0067] 2) Extraction of water-soluble substances: separating the remaining medicinal liquid and the medicinal residue obtained after the volatile oil extraction, mixing the medicinal residue with Astragalus, Salvia miltiorrhiza, and Coptis chinensis, adding 6-14 times by weight, preferably 8-12 times by weight of water, decocting for 1-3.5 hours, filtering, combining the filtrate with the remaining medicinal liquid to obtain a Chinese medicine mixed medicinal liquid;

[0068] 3) Concentration: Concentrate the mixed Chinese medicine solution in step 2) under reduced pressure at 50°C-80°C, preferably 55°C-75°C to a specific gravity of 1.03-1.10 to obtain a Chinese medicine extract;

[0069] 4) Drying: Drying the Chinese medicine extract in step 3) to obtain Chinese medicine extract B;

[0070] 5) Granulation: The inclusion compound A in step 1) and the Chinese herbal extract B in step 4) are mixed and granulated to obtain the product.

[0071] Volatile oil extraction and inclusion

[0072] In the preparation method of the present invention, the steps of volatile oil extraction and inclusion are mainly to enrich and extract the volatile oil in patchouli and chuanxiong containing volatile oil through an oily carrier, and then use cyclodextrin for inclusion.

[0073] Specifically, the volatile oil is extracted by steam distillation. In the steam distillation, the amount of water used, in some specific embodiments, can be 4-12 times the mass of patchouli and Chuanxiong, for example, 4 times, 6 times, 8 times, 10 times, etc., preferably 4-10 times, and further preferably 6-8 times. When the amount of water added is within the above range, the oil extraction amount is optimal. The time for the volatile oil extraction, in some specific embodiments, can be 1h-9h. Within the above time range, the oil extraction amount increases, and the oil extraction amount hardly increases after 7h. However, considering that ferulic acid in Chuanxiong is unstable under high temperature conditions, the longer the high-temperature decoction time, the faster the ferulic acid degrades. Therefore, the volatile oil extraction time is selected to be 2h.

[0074] In some specific embodiments, the amount of the oily carrier can be 0.25% to 0.75%, such as 0.25%, 0.45%, 0.55%, 0.75%, etc., preferably 0.45% to 0.55%. Within the above range, the oil yield is relatively high. In the process of extracting volatile oil, the volatile oil exists in the form of an oil-water mixture, which is difficult to aggregate to form an oil layer. The present invention adds a pharmaceutically acceptable and edible oily carrier, such as vegetable oil, preferably one of peanut oil, soybean oil, corn oil, linseed oil, castor oil, rapeseed oil, rapeseed salad oil, sesame oil, olive oil and sunflower oil, more preferably corn oil or soybean oil, to the volatile oil collector, so that the collected oil-water mixture passes through the oily carrier. According to the principle of similar compatibility, the volatile oil and the oily carrier are mutually soluble, and the oil-water mixture is separated, which better solves the problem of difficult aggregation of the oil layer and improves the collection of volatile oil.

[0075] Furthermore, in the inclusion step, the volatile oil is included with an inclusion carrier material. Specifically, the mixed volatile oil and ethanol are mixed for later use, the inclusion carrier material is mixed with water, and after mixing evenly, the mixture is ground for 10 minutes, and a mixed solution of the mixed volatile oil and ethanol is added, and ground for 30 minutes to 120 minutes, preferably 30 minutes. The inclusion solution is dried to obtain the inclusion compound.

[0076] In some specific embodiments, the mass ratio of the mixed volatile oil to the inclusion complex carrier material can be 1:6-10. Within the above range, the total inclusion rate of patchouli ketone and ligustilide in the inclusion complex is relatively high, and the inclusion effect is better.

[0077] In some specific embodiments, the volume ratio of the mixed volatile oil to ethanol can be 1:1 to 1:2, preferably 1:1. The mass ratio of the inclusion complex carrier material to water can be 1:2-1:12, for example, 1:2, 1:4, 1:6, 1:8, preferably 1:2-1:8. Considering the particularity of the equipment in the spray drying described below, the higher the specific gravity of the inclusion complex, the easier it is to clog the nozzle during the spray drying process. Therefore, the mass ratio of the inclusion complex carrier material to water is preferably 1:8.

[0078] In some specific embodiments, the inclusion complex carrier material can be a polysaccharide substance, such as one of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, starch, methylcellulose and cellulose, preferably β-cyclodextrin or hydroxypropyl-β-cyclodextrin.

[0079] In some specific embodiments, the drying method can be low-temperature drying or spray drying, wherein the inlet air temperature of the spray drying is 165-175°C, the outlet air temperature is 80-90°C, and the inclusion rate obtained by spray drying is relatively high, so spray drying is preferred as the drying method.

[0080] The calculation formula of inclusion rate is as follows:

[0081] Inclusion rate % = total content of patchouli ketone and ligustilide in inclusion complex / total content of patchouli ketone and ligustilide in volatile oil × 100

[0082] Wherein, the total content of patchouli ketone and ligustilide in the inclusion compound = the measured content of patchouli ketone and ligustilide in the inclusion compound × (volatile oil content × specific gravity + beta-cyclodextrin amount),

[0083] The total content of patchouli ketone and ligustilide in volatile oil = measured content of patchouli ketone and ligustilide in volatile oil × amount of volatile oil × specific gravity.

[0084] Among them, the detection method of patchouli ketone and ligustilide content is as follows:

[0085] (1) Determination of patchouli ketone content

[0086] Chromatographic conditions and system suitability: octadecylsilane bonded silica gel as filler; methanol as mobile phase A, 0.1% phosphoric acid as mobile phase B, gradient elution (0-5min, 55% A; 5-10min, 55%→80% A; 10-11min, 80%→55% A); column temperature 40°C; flow rate 0.3ml / min; detection wavelength 310nm;

[0087] Preparation of reference solution: Take an appropriate amount of patchouli ketone reference solution, weigh it accurately, and add methanol to make the patchouli ketone concentration 250 μg ml -1 The solution is obtained.

[0088] Preparation of test solution: Take an appropriate amount of inclusion compound, take about 0.5g, weigh accurately, put it in a stoppered conical flask, add 10ml of methanol accurately, stopper it tightly, weigh it, extract it ultrasonically (power 250W, frequency 40kHz) for 60min, take it out, weigh it after cooling, make up the lost weight, shake it well, filter it, take the filtrate, and get it. Cool, filter it, take the filtrate, and get it.

[0089] (2) Determination of ligustilide content

[0090] Chromatographic conditions and system suitability: Octadecylsilane bonded silica gel as filler; methanol-water (60:40) as mobile phase; column temperature 35°C; flow rate 0.3 ml / min; detection wavelength 280 nm;

[0091] Preparation of reference solution: Take an appropriate amount of ligustilide reference substance, weigh it accurately, and add methanol to make the concentration of ligustilide 100 μg ml -1 The solution is obtained.

[0092] Preparation of test solution: the same as that of patchouli ketone.

[0093] Water-soluble substance extraction

[0094] The step of extracting water-soluble substances refers to the process of decocting the patchouli and chuanxiong residues after volatile oil extraction with other astragalus, salvia miltiorrhiza and coptis root without volatile oil to extract the water-soluble substances therein, and mixing them with the remaining liquid medicine after volatile oil extraction to obtain a mixed Chinese medicine liquid medicine.

[0095] Specifically, the amount of water added during decoction in some specific embodiments can be 6-14 times the total mass of the crude drug, such as 8 times, 10 times, 12 times, etc., preferably 8-12 times, the extraction time in some specific embodiments can be 1-3.5h, the number of extractions is at least 2 times, in some specific embodiments, the first decoction can be 0.5-2h, and the second decoction can be 0.5-1.5h. Within the above range, the content of each active ingredient in the extract, the transfer rate and the paste yield are all high.

[0096] The active ingredients are respectively salvianolic acid B, ferulic acid, berberine hydrochloride and astragaloside IV. The content detection method is as follows:

[0097] (1) Determination of salvianolic acid B and ferulic acid content

[0098] Chromatographic conditions and system suitability: Octadecylsilane bonded silica gel as filler; acetonitrile as mobile phase A, 0.1% phosphoric acid as mobile phase B, gradient elution (0-4 min, 85%-81% B; 4-10 min, 81%-65% B; 10-11 min, 65% B; 11-12 min, 65%-85%); detection wavelength: 286 nm (salvianolic acid B), 321 nm (ferulic acid). Flow rate: 0.3 L min -1 ; The column temperature is 30℃; The theoretical plate number calculated based on the salvianolic acid B peak should not be less than 100,000.

[0099] Preparation of reference solution: Take appropriate amount of salvianolic acid B reference substance and ferulic acid reference substance, weigh accurately, place in a 25 ml volumetric flask, add 80% methanol to make salvianolic acid B concentration of 70 μg ml -1 , ferulic acid concentration is 15μg ml -1 The mixed solution is obtained.

[0100] Preparation of test solution: Take an appropriate amount of water extract (concentrate), accurately transfer 5 ml (weigh 1.0 g), dilute with 80% methanol and make up to volume in a 10 ml volumetric flask, shake well, filter, and take the filtrate to obtain.

[0101] Spray-dried powder: Take an appropriate amount of spray-dried powder, accurately weigh 0.3g, put it in a stoppered conical flask, accurately add 25ml of 80% methanol, shake well, weigh the weight, ultrasonic extraction (power 250W, frequency 40kHz) for 30min, take out, weigh after cooling, make up the lost weight, shake well, filter, and take the filtrate to obtain.

[0102] (2) Determination method of berberine hydrochloride content

[0103] Chromatographic conditions and system suitability: Octadecylsilane bonded silica gel as filler; acetonitrile-25mmol / L potassium dihydrogen phosphate solution (0.4g sodium dodecyl sulfate was added to every 100ml, and the pH value was adjusted to 4.0 with phosphoric acid) (47:53) as mobile phase; detection wavelength was 345nm; flow rate was 0.4ml·min -1 ; The column temperature is 30℃; The theoretical plate number calculated based on the berberine hydrochloride peak should not be less than 5000.

[0104] Preparation of reference solution: Take 1 mg of berberine hydrochloride reference substance, accurately weigh it, and add methanol to make a solution with a concentration of 50 μg / ml.

[0105] Preparation of test solution: Take an appropriate amount of water extract (concentrate), accurately transfer 2 ml (weigh 1.0 g), dilute with methanol: hydrochloric acid (100:1) and make up to volume in a 5 ml volumetric flask, shake well, filter, and take the filtrate to obtain.

[0106] Spray-dried powder: Take an appropriate amount of spray-dried powder, accurately weigh 0.3g, put it in a stoppered conical flask, accurately add 25ml of methanol: hydrochloric acid (100:1), shake well, weigh the weight, ultrasonic extraction (power 250W, frequency 40kHz) for 30min, take out, weigh after cooling, make up the lost weight, shake well, filter, and take the filtrate to obtain.

[0107] (3) Astragaloside IV content determination method

[0108] Chromatographic conditions and system suitability: Octadecylsilane bonded silica gel as filler; acetonitrile-water (33:67) as mobile phase; flow rate 0.4 ml min -1 ; Column temperature is 30℃, ELSD detector. The theoretical plate number calculated based on the astragaloside IV peak should not be less than 4000.

[0109] Preparation of reference solution: Take an appropriate amount of Astragaloside IV reference substance, weigh it accurately, place it in a 25 ml volumetric flask, add methanol to dissolve and dilute to a constant volume to make a concentration of 200 μg ml -1 The solution is shaken well and you have it.

[0110] Preparation of test solution: Accurately pipette 25 ml of water extract (weigh 10.0 g of concentrate) into a separating funnel, extract 4 times with water-saturated n-butanol, 40 ml each time, combine the n-butanol solutions, wash 3 times with ammonia test solution, 40 ml each time, discard the ammonia test solution, evaporate the n-butanol solution, dissolve the residue in methanol, make up to volume in a 5 ml volumetric flask, filter, and obtain the filtrate.

[0111] Spray-dried powder: Take an appropriate amount of spray-dried powder, accurately weigh 1.5g, add 25ml of pure water to dissolve, transfer to a separatory funnel, extract 4 times with water-saturated n-butanol, 40ml each time, combine the n-butanol liquid, wash 3 times with ammonia test solution, 40ml each time, discard the ammonia test solution, evaporate the n-butanol liquid, dissolve the residue in methanol, make up to volume in a 5ml volumetric flask, filter, and take the filtrate to obtain.

[0112] The water extract paste yield is determined by referring to the "hot immersion method" in the 2020 edition of the Chinese Pharmacopoeia, General Rules 2201 of the Fourth Volume, Extract Determination Method. Accurately draw 25 ml of the extract, place it in a constant-weight evaporating dish, evaporate it on a water bath, dry it at 105°C for 5 hours, cool it in a desiccator for 30 minutes, and quickly and accurately weigh it. The calculation formula is:

[0113] The calculation formula for the extract paste yield is: paste yield (%) = extract volume * extract solid content / slice volume * 100%.

[0114] The filtering method is to use a filter to filter while hot, wherein the mesh number of the filter, in some specific embodiments, can be 200 mesh or 350 mesh. After the extract is filtered through 200 mesh and 350 mesh, the medicinal solution is clear and there is no obvious insoluble impurities observed by naked eye. 350 mesh filtration is slower, and 200 mesh sieve is preferably used for filtration.

[0115] concentrate

[0116] After obtaining the Chinese medicine mixed liquid, the extract is concentrated into a Chinese medicine extract by using a reduced pressure concentration method.

[0117] Specifically, under the conditions of pressure P and temperature T, the mixed Chinese medicine liquid is concentrated to an extract with a specific gravity of 1.03 to 1.10, wherein the vacuum degree of the reduced pressure concentration is -0.06 to -0.10 MPa, and the temperature T, in some specific embodiments, can be 50 to 80°C, for example, 55°C, 65°C, 75°C, etc., preferably 55 to 75°C.

[0118] dry

[0119] After obtaining the extract, the Chinese medicine extract is dried and powdered to obtain Chinese medicine extract B.

[0120] The drying method, in some specific embodiments, can be spray drying or reduced pressure drying. Reduced pressure drying and spray drying have little effect on the content and transfer rate of the index components, but the reduced pressure drying time is long and the drying efficiency is low. Spray drying has high drying efficiency and the obtained powder is uniform and loose. Combined with the actual production situation of large-scale production, spray drying is preferred.

[0121] In some specific embodiments, the pressure of the reduced pressure drying is -0.05 to -0.095 MPa.

[0122] The spray drying step includes adding auxiliary materials, and spray drying is performed at an inlet air temperature of 165-195°C and an outlet air temperature of 85-105°C. The auxiliary materials, in some specific embodiments, may be polysaccharides, such as maltodextrin. The amount of the auxiliary materials, based on the amount of the decoction pieces fed, may be 3% to 5% in some embodiments. Adding auxiliary materials to the concentrate can improve the powder recovery rate to a certain extent.

[0123] The calculation formula of powder recovery rate is as follows:

[0124] Powder recovery rate % = dry powder weight / (auxiliary material addition amount + liquid solid content * test solution volume) * 100%

[0125] Granulation

[0126] After obtaining the inclusion compound A and the traditional Chinese medicine extract B, they can be granulated to obtain Qingxin Jieyu granules.

[0127] Specifically, the inclusion compound A and the Chinese medicine extract B are mixed, auxiliary materials are added, mixed evenly, sieved, and the feed speed of the dry granulator is adjusted to 90.0 r / min, the pressure wheel speed is 10.0 r / min, and the final granulation speed is 95 r / min, and granulation is performed to obtain.

[0128] The auxiliary materials include lubricants and molding agents. The lubricants are one or more of silicon dioxide and magnesium stearate. The amount of silicon dioxide, based on the mass of the Chinese medicine extract B, can be 0.3% to 0.5% in some specific embodiments. Adding silicon dioxide can improve the fluidity of the extract. The more silicon dioxide is added, the better the improvement effect. Considering the actual dosage, etc., 0.3% is preferred. The amount of magnesium stearate, based on the mass of the Chinese medicine extract B, can be 0.1% to 0.3%, preferably 0.1% in some specific embodiments. Magnesium stearate has the function of a lubricant and is helpful for granulation.

[0129] The molding agent, in some specific embodiments, can be maltodextrin or lactose, which can be added in an amount of 36-40% in some specific embodiments. When it is within the above range, the particle molding rate is high.

[0130] The fluidity is investigated by using the angle of repose, which refers to the maximum angle formed by the free slope of the powder accumulation layer and the horizontal plane. The measurement method is: take an appropriate amount of extract, carefully pour the extract into the upper port of the powder measuring instrument, measure according to the powder measuring method, until the lower disk forms a conical pile, measure the angle of repose of the pile at this angle, and then rotate the disk 120° and 240° in turn, measure the angles of repose at different angles, measure each sample 3 times, and take the average value.

[0131] Table 1 Reference results of powder fluidity evaluation

[0132]

[0133] <Qingxin Jieyu Granules>

[0134] In the second aspect of the present invention, a Qingxin Jieyu granule is provided. The Qingxin Jieyu granule is prepared by the preparation method of the first aspect.

[0135] The Qingxin Jieyu Granules use an oily carrier in the preparation method to enrich the volatile oil components in the prescription, thereby improving the oil yield. Compared with traditional prescriptions, the Qingxin Jieyu Granules of the present invention retain more volatile oil and have higher medicinal value.

[0136] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0137] Example 1: Study on the extraction process of mixed volatile oil

[0138] (1) Investigation of soaking time and oil extraction time

[0139] Weigh about 50g of patchouli slices and 4 portions of chuanxiong slices respectively, add 6 times water and soak for 0, 0.5, 1, and 1.5h respectively, add volatile oil extraction device (light oil device) to reflux extraction for 9h, and record the amount of volatile oil collected at different times. The results are shown in Table 2.

[0140] Table 2 Soaking time and oil extraction time Volatile oil determination results

[0141]

[0142] The results showed that the amount of volatile oil was the highest when soaking for 0h and 0.5h, so it was chosen not to soak for oil extraction. According to the oil amount measured at different times, the amount of oil hardly increased after 7h of oil extraction, and most of the oil had been extracted, indicating that the volatile oils of Chuanxiong and Patchouli were basically extracted completely after 7h of extraction.

[0143] (2) Investigation of water addition amount

[0144] Weigh about 50g of patchouli slices and chuanxiong slices respectively, make 4 portions in total, add 4 times, 6 times, 8 times and 10 times water respectively, add volatile oil extraction device (light oil device) to reflux extraction for 7h, record the amount of volatile oil collected at different time, and the investigation results are shown in Table 3.

[0145] Table 3 Results of oil quantity measurement at different times for each water addition amount

[0146]

[0147] The results showed that the volatile oil content at each time point was higher when the water addition was 6 times, that is, the optimal water addition for oil extraction was 6 times. Considering that the ferulic acid in Chuanxiong was unstable under high temperature conditions, the longer the high temperature decoction time, the faster the ferulic acid degradation, so the volatile oil extraction time was selected as 2h.

[0148] (3) Investigation of the amount of oily carrier used

[0149] Take 100g each of Patchouli and Chuanxiong slices, add 6 times water, add volatile oil extraction device, add corn oil at the total feed amount of 0%, 0.15%, 0.25%, 0.45%, 0.55%, and 0.75%, respectively, extract the oil for 2h, collect the mixed volatile oil containing corn oil, and determine the total volatile oil content. The investigation results are shown in Table 4.

[0150] Table 4 Collection results of mixed oil with different corn oil dosages

[0151]

[0152] The results showed that the oil yield reached a maximum when the corn oil addition amount was 0.45%-0.55%. Therefore, the amount of corn oil added in the pilot volatile oil collection of Qingxin Jieyu Recipe was 0.25%-0.75% of the total amount of patchouli and Chuanxiong, preferably 0.45%-0.55%.

[0153] From the above experiments, it can be seen that the optimal process scheme for the extraction of mixed volatile oil is: take patchouli and chuanxiong slices in a mass ratio of 1:1, add 6 times water, add volatile oil extraction device, add corn oil at a total feed amount of 0.45%, extract the oil for 2 hours, and collect the mixed volatile oil containing corn oil.

[0154] Example 2: Inclusion process study

[0155] (1) Investigation of β-cyclodextrin dosage

[0156] The extraction method of the mixed volatile oil refers to the preferred process of Example 1.

[0157] Take 2g of mixed volatile oil, add 2g of 95% ethanol and mix for use, a total of 3 portions, take 12g, 16g, 20g of β-cyclodextrin respectively, keep the ratio of β-cyclodextrin to water at 1:2, mix evenly and grind for 10min, slowly add the mixture of oil and ethanol, grind for 30min, filter the inclusion liquid, wash the inclusion compound with 95% ethanol in appropriate amounts, dry the inclusion compound at low temperature, and obtain. Determine the content of patchouli ketone and ligustilide in the inclusion compound, calculate the inclusion rate, and the results are shown in Table 5.

[0158] Table 5 Results of investigation on the ratio of mixed oil and β-cyclodextrin

[0159]

[0160] The results showed that when the ratio of mixed oil to β-cyclodextrin was 1:6, the total inclusion rate of patchouli and ligustilide in the inclusion complex was higher, and the inclusion effect was better.

[0161] (2) Investigation of the effect of elution on inclusion rate

[0162] The extraction method of the mixed volatile oil refers to the preferred process of Example 1.

[0163] Take 2g of mixed volatile oil, add 2g of 95% ethanol and mix for later use, a total of 2 parts, take 12g of β-cyclodextrin respectively, add 24g of water in turn, mix evenly and grind for 10min, slowly add the mixture of oil and ethanol, grind for 30min, filter the inclusion liquid, wash one part of the inclusion complex with 20mL of 95% ethanol in batches, do not elute one part, dry the inclusion complex at low temperature, and obtain. Determine the content of patchouli ketone and ligustilide in the inclusion complex, calculate the inclusion rate, and the results are shown in Table 6.

[0164] Table 6 Ethanol elution investigation results

[0165]

[0166] The results showed that the total inclusion rate of ligustilide and patchouli ketone after filtration and elution with 95% ethanol was much lower than that of the uneluted inclusion complex. The possible reason was that the 95% ethanol elution destroyed the inclusion liquid system and the inclusion was insufficient.

[0167] (2) Investigation of drying methods

[0168] The extraction method of the mixed volatile oil refers to the preferred process of Example 1.

[0169] Take 20g of mixed volatile oil, add 20g of 95% ethanol and mix for use, a total of 5 parts, take 120g of β-cyclodextrin respectively, add 960g of water in turn, mix evenly, place in a colloid mill and grind for 10min, slowly add the mixture of oil and ethanol, grind for 30min, and the obtained inclusion liquid is dried by different drying methods (suction drying, direct drying, spray drying (process parameters: inlet air temperature: 165-175℃ outlet air temperature: 80-90℃)). Determine the content of patchouli ketone and ligustilide in the inclusion complex, calculate the inclusion rate, and the results are shown in Table 7.

[0170] Table 7 Results of investigation on different drying methods

[0171]

[0172] The results showed that the total inclusion rate of patchouli ketone and ligustilide in the inclusion complex obtained by spray drying was the highest, and spray drying was the selected method for drying the inclusion complex.

[0173] From the above experiments, it can be seen that the preferred scheme of the inclusion process is: adding volatile oil: 95% ethanol: β-cyclodextrin: water in a ratio of 1:1:6:48 (volatile oil and 95% ethanol are first mixed in a ratio of 1:1, and then mixed with β-cyclodextrin and water in proportion), colloid mill grinding time is 30 minutes, spray drying (process parameters: inlet air temperature: 165-175°C, outlet air temperature: 80-90°C, continuous stirring during the spraying process to avoid precipitation), and collecting powder in a timely manner.

[0174] Example 3: Investigation of influencing factors in the extraction process of water-soluble substances

[0175] Decoction time, decoction times and water addition amount were selected as influencing factors. A four-factor three-level orthogonal experimental scheme was adopted. Water was used as the solvent. A heating reflux extraction process was adopted. The total transfer rate of tannic acid B, ferulic acid, alkaloids and astragaloside IV and the paste yield were used as evaluation indicators. The extraction process was optimized according to the results of each indicator. The levels of each experimental factor are shown in Table 8. The experiment was carried out according to the orthogonal design in Table 9.

[0176] Table 8 Orthogonal test factor level table

[0177]

[0178] Table 9 Orthogonal test table

[0179]

[0180] According to the prescription, a total of 100 g of the decoction pieces were weighed and prepared in 9 parallel portions. The amount of water added for the first decoction and the decoction time were extracted according to the levels of each factor in the table. The amount of water added for the second and third decoctions were both 6 times, and the decoction time was 30 min. The extract was filtered while hot (200 mesh), cooled, and mixed evenly. Samples were prepared according to the test sample preparation method, and tested and analyzed. The results are shown in Table 10.

[0181] Table 10 Orthogonal test results

[0182]

[0183] The results in Table 10 were subjected to variance analysis, and the results are shown in Table 11.

[0184] Table 11 Variance analysis table

[0185]

[0186] According to the range analysis and variance analysis, the influence of the three factors on the paste yield is: C>A>B, that is, the number of extractions>extraction time>water addition, and the number of decoctions has a significant effect on the paste yield; the influence of the three factors on the total transfer rate of the four index components is: C>B>A, that is, the number of extractions>water addition>extraction time, and the number of decoctions has a significant effect on the total transfer rate of the four index components. Taking the absolute value of the paste yield as the evaluation index, A3B2C3 is preferred; taking the absolute value of the total transfer rate of the four index components, A2B3C3 is preferred. A and B factors have no significant effect on the paste yield and the total transfer rate of the four indicators. The number of decoctions is a significant influencing factor. Under normal circumstances, the extraction rate of each index can exceed 90% after 2 extractions, and the contribution rate of 3 decoctions in the entire extraction is relatively small. Considering the actual production, the preferred extraction process is: A2B2C2, that is, adding 10 / 6 times of water, extracting twice, and the extraction time is 1.0 / 0.5h.

[0187] Example 4: Drying process study

[0188] (1) Investigation of drying methods

[0189] Weigh 40.9 g of Astragalus slices, 40.9 g of Salvia miltiorrhiza slices, 27.2 g of Chuanxiong slices, 27.2 g of Patchouli slices, and 13.6 g of Coptis chinensis slices respectively, and make three parallel portions. First, place patchouli and Chuanxiong slices in a round-bottom flask, add 6 times water, add a volatile oil extraction device to extract volatile oil for 2 hours, read the amount of volatile oil, collect the volatile oil, and set aside the liquid medicine. Add 10 times water to the residues and Astragalus, Salvia miltiorrhiza and Coptis chinensis slices, reflux extraction, extract for 1.0h for the first time, filter through a 200-mesh standard sieve, add 6 times water for the second time, extract for 0.5h, filter through a 200-mesh standard sieve, combine the aromatic water and the extracted liquid medicine to obtain a mixed Chinese medicine liquid medicine, and concentrate the mixed Chinese medicine liquid medicine at 65°C under reduced pressure to a specific gravity of 1.03-1.06. Take different concentration temperatures to investigate the obtained concentrated solution, combine and mix, take an appropriate amount, and dry according to different drying methods. The moisture content, index component content, and drying efficiency of the dry paste powder are used as evaluation indicators to select the best drying method. The results are shown in Tables 12 and 13.

[0190] The specific drying method is as follows:

[0191] ①Spray drying: air inlet temperature: 165~175℃, air outlet temperature: 85~95℃

[0192] ②Spray drying: Inlet air temperature: 175~185℃, outlet air temperature: 95~100℃

[0193] ③Spray drying: Inlet air temperature: 185~195℃, outlet air temperature: 100~105℃

[0194] ④Decompression vacuum drying: vacuum degree: -0.095Mpa, temperature: 60~70℃

[0195] Table 12 Comparison of moisture content and drying efficiency of dry paste powder under different drying methods and spray drying temperatures

[0196]

[0197] Table 13 Comparison of content and transfer rate of various indicators in different drying methods

[0198]

[0199] The results show that vacuum drying and spray drying have little effect on the content and transfer rate of index components, but vacuum drying takes a long time and has low drying efficiency. Spray drying has high drying efficiency and the obtained powder is uniform and loose. Combined with the actual production situation of large-scale production, spray drying is the best choice.

[0200] (2) Investigation of maltodextrin dosage

[0201] Weigh 40.9 g of Astragalus slices, 40.9 g of Salvia miltiorrhiza slices, 27.2 g of Chuanxiong slices, 27.2 g of Patchouli slices, and 13.6 g of Coptis chinensis slices respectively, and make three parallel portions. First, place patchouli and chuanxiong slices in a round-bottom flask, add 6 times water, add volatile oil extraction device to extract volatile oil for 2 hours, read the amount of volatile oil, collect the volatile oil, and set aside the liquid medicine. Add 10 times water to the residues and astragalus, salvia miltiorrhiza and coptis slices, reflux extraction, the first extraction is 1.0h, filtered through a 200-mesh standard sieve, add 6 times water for the second time, extract for 0.5h, filter through a 200-mesh standard sieve, combine the aromatic water and the extracted liquid medicine to obtain a mixed Chinese medicine liquid medicine, and concentrate the mixed Chinese medicine liquid medicine under reduced pressure at 65°C to a specific gravity of 1.03-1.06. Take an appropriate amount of concentrated liquid, and investigate the effect of maltodextrin dosage on spray drying powder recovery rate. The spray drying powder recovery rate is used as the evaluation index. The inlet air temperature during spray drying is 175-185°C, and the outlet air temperature is 95-100°C. The investigation results are shown in Table 14.

[0202] Table 14 Results of spray drying maltodextrin dosage

[0203]

[0204] Note: Powder recovery rate (%) = dry paste powder weight / (auxiliary material added amount + liquid solid content * test solution volume) * 100%. The results show that adding maltodextrin to the concentrate can improve the powder recovery rate to a certain extent. Therefore, it is advisable to add 3% to 5% auxiliary materials to the concentrate before spray drying, preferably 5%.

[0205] Example 5: Granulation process study

[0206] (1) Investigation of silica dosage

[0207] The method for preparing the Chinese herbal medicine extract is shown in Example 4 (2), and the amount of maltodextrin is selected to be 5%.

[0208] Take an appropriate amount of Chinese herbal medicine extract and add 0.1%, 0.2%, 0.3%, 0.4% and 0.5% silicon dioxide in proportion respectively. The effect of the amount of silicon dioxide on the improvement of the fluidity of the extract is investigated. The results are shown in Table 15.

[0209] Table 15 Results of investigation on silicon dioxide dosage

[0210]

[0211] The results showed that adding silicon dioxide can improve the fluidity of the extract. The more silicon dioxide is added, the better the improvement effect. According to the evaluation criteria in Table 1, when the silicon dioxide dosage is 0.3%, it meets the standard of good fluidity. Therefore, the silicon dioxide dosage is selected to be 0.3% and above. After comprehensive consideration, 0.3% is selected.

[0212] (2) Investigation of the dosage of magnesium stearate

[0213] The method for preparing the Chinese herbal medicine extract is shown in Example 4 (2), and the amount of maltodextrin is selected to be 5%.

[0214] Take an appropriate amount of Chinese herbal medicine extract, compare the difference with or without adding magnesium stearate, and investigate the improvement of the fluidity of the extract by adding magnesium stearate. The results are shown in Table 16.

[0215] Table 16 Magnesium stearate dosage investigation results

[0216]

[0217] The results showed that the fluidity of the extract could be improved after adding magnesium stearate.

[0218] (3) Investigation of the types of molding agents

[0219] The preparation method of the Chinese medicine extract is shown in Example 4 (2), and the dosage of maltodextrin is 5%. The preparation method of the inclusion compound is shown in Example 2 (2), and the drying method is spray drying.

[0220] Take an appropriate amount of Chinese herbal medicine extract, add inclusion compound, 0.3% silicon dioxide and 0.1% magnesium stearate and molding agent in proportion, adjust the feeding speed of dry granulator to 90.0r / min, the speed of pressing wheel to 10.0r / min, and the final granulation speed to 95r / min for granulation. Among them, the types of auxiliary materials are selected as maltodextrin MD15, maltodextrin MD20 and lactose, and each auxiliary material is added according to the amount of 40%. The difficulty of granulation process, molding rate, granule moisture absorption rate and solubility are used as evaluation indicators to investigate the improvement of granulation process by different auxiliary materials. The results are shown in Table 17.

[0221] Table 17 Results of investigation on different excipients

[0222]

[0223] The results showed that the addition of maltodextrin MD20 and lactose could significantly improve the particle forming rate. After comprehensive consideration, maltodextrin MD20 was selected as an auxiliary material for subsequent research.

[0224] (4) Investigation of the amount of molding agent

[0225] The preparation method of the Chinese medicine extract is shown in Example 4 (2), and the dosage of maltodextrin is 5%. The preparation method of the inclusion compound is shown in Example 2 (2), and the drying method is spray drying.

[0226] Take an appropriate amount of Chinese herbal medicine extract, add 0.3% silicon dioxide and 0.1% magnesium stearate in proportion, add maltodextrin MD20 according to the amount of preparation, respectively 36%, 40%, 44%, adjust the feed speed of the dry granulator to 90.0r / min, the speed of the pressing wheel to 10.0r / min, and the final granulation speed to 95r / min, and conduct granulation. The difficulty of the granulation process, the forming rate, the granule moisture absorption rate, and the solubility are used as evaluation indicators to investigate the improvement of the granulation process by the amount of maltodextrin. The results are shown in Table 18.

[0227] Table 18 Results of investigation on the dosage of molding agent

[0228]

[0229] The results showed that when the pellet production amount was 40%, the pellet forming rate was higher, pelletizing was easier and the pelletizing did not stick to the wheel.

[0230] (5) Investigation of granulation method

[0231] The preparation method of the Chinese medicine extract is shown in Example 4 (2), and the dosage of maltodextrin is 5%. The preparation method of the inclusion compound is shown in Example 2 (2), and the drying method is spray drying.

[0232] Take an appropriate amount of Chinese medicine extract, add inclusion compound, 0.3% silicon dioxide and 0.1% magnesium stearate and auxiliary materials in proportion, set granulation process parameters of each granulator (fluidized bed granulator parameters: inlet temperature: 90°C, induced draft fan frequency and feeding peristaltic pump frequency are adjusted in time), and granulate. The granule texture, hygroscopicity and solubility are used as evaluation indicators to compare the granulation effects of dry granulation and fluidized bed boiling granulation. The results are shown in Table 19.

[0233] Table 19 Results of investigation on different granulation methods

[0234]

[0235] The results showed that the granules prepared by the two granulation methods had good solubility, and the dry granulation method had strong operability. After comprehensive consideration, the dry granulation method was selected as the granulation method of Qingxin Jieyu Recipe.

[0236] It should be noted that, although the technical solution of the present invention is introduced with specific examples, those skilled in the art will appreciate that the present invention should not be limited thereto.

[0237] The embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles of the embodiments, practical applications, or technical improvements in the market, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein.

Claims

1. A method for preparing Qingxin Jieyu granules, comprising the following steps: 1) Extraction and inclusion of volatile oil: Patchouli and Ligusticum chuanxiong are taken, 4-12 times by weight, preferably 4-10 times by weight of water are added, and the mixture is extracted by steam distillation for 1-9 hours. The oil-water mixture is enriched by an oily carrier to obtain a mixed volatile oil containing an oily carrier, and an inclusion carrier material is added at a weight of 6-12 times by weight, preferably 6-10 times by weight of the mixed volatile oil for inclusion to obtain inclusion compound A; 2) Extraction of water-soluble substances: separating the remaining medicinal liquid and the medicinal residue obtained after the volatile oil extraction, mixing the medicinal residue with Astragalus, Salvia miltiorrhiza, and Coptis chinensis, adding 6-14 times by weight, preferably 8-12 times by weight of water, decocting for 1-3.5 hours, filtering, combining the filtrate with the remaining medicinal liquid to obtain a Chinese medicine mixed medicinal liquid; 3) Concentration: The mixed Chinese medicine solution in step 2) is concentrated under reduced pressure at 50-80° C., preferably 55-75° C., to a specific gravity of 1.03 to 1.10 to obtain a Chinese medicine extract; 4) Drying: Drying the Chinese medicine extract in step 3) to obtain Chinese medicine extract B; 5) Granulation: The inclusion compound A in step 1) and the Chinese herbal extract B in step 4) are mixed and granulated to obtain the product.

2. The preparation method according to claim 1, characterized in that: The mass ratio of coptis root, patchouli, ligusticum chuanxiong, astragalus and salvia miltiorrhiza is 1:2:2:3:

3.

3. The preparation method according to claim 1 or 2, characterized in that: The oily carrier in step 1) is a vegetable oil, preferably one of peanut oil, soybean oil, corn oil, linseed oil, castor oil, rapeseed oil, rapeseed salad oil, sesame oil, olive oil and sunflower oil, more preferably corn oil or soybean oil.

4. The preparation method according to any one of claims 1 to 3, characterized in that: Based on the total weight of the patchouli and ligusticum chuanxiong, the relative amount of the oily carrier in step 1) is 0.25% to 0.75%, preferably 0.45% to 0.55%.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The inclusion complex carrier material in step 1) is a polysaccharide, preferably one of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, starch, methylcellulose and cellulose, more preferably β-cyclodextrin or hydroxypropyl-β-cyclodextrin.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The inclusion method in step 1) is grinding or ultrasonic method, preferably grinding; Preferably, the inclusion comprises a drying step; More preferably, the drying method is low temperature drying or spray drying.

7. The preparation method according to claim 6, characterized in that: The grinding method comprises the following steps: mixing the inclusion complex carrier material and water, grinding for 10 minutes, adding mixed volatile oil and ethanol, and grinding for 30 to 120 minutes, preferably 30 minutes; Preferably, the volume ratio of the mixed volatile oil to ethanol is 1:1 to 1:2, preferably 1:1; Preferably, the mass ratio of the inclusion complex carrier material to water is 1:2-1:12, preferably 1:2-1:

8.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The decoction in step 2) is performed at least twice, preferably for 0.5-2 hours for the first decoction and for 0.5-1.5 hours for the second decoction.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The vacuum degree of the reduced pressure concentration in step 3) is -0.06 to -0.10 MPa.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The drying method in step 4) is reduced pressure drying or spray drying; Preferably, the drying method is reduced pressure drying; More preferably, the pressure of the reduced pressure drying is -0.05 to -0.095 MPa; Preferably, the drying method is spray drying; More preferably, the spray drying comprises the following steps: adding auxiliary materials to the Chinese medicine extract, and spray drying under the conditions of an inlet air temperature of 165 to 195° C. and an outlet air temperature of 85 to 105° C.; Further preferably, the auxiliary material is a polysaccharide, preferably maltodextrin, and / or, based on the total mass of the coptis root, patchouli, ligusticum chuanxiong, astragalus and salvia miltiorrhiza, the amount of the auxiliary material is 3% to 5%.

11. The preparation method according to any one of claims 1 to 10, characterized in that: The auxiliary materials used in the granulation in step 5) include lubricants and molding agents; Preferably, the lubricant is one or more of silicon dioxide and magnesium stearate; and / or, Preferably, the shaping agent is maltodextrin or lactose.

12. The preparation method according to any one of claims 1 to 11, characterized in that: The granulation method in step 5) is dry granulation or fluidized bed granulation.

13. Qingxin Jieyu granules, prepared by the preparation method according to any one of claims 1 to 12.

14. A method for extracting volatile oil, characterized in that: It includes the following steps: Take patchouli and chuanxiong, add 4-12 times by weight, preferably 4-10 times by weight, of water, extract by steam distillation for 1-9 hours, and enrich the oil-water mixture with an oily carrier to obtain a mixed volatile oil containing an oily carrier; Preferably, the mass ratio of patchouli to ligusticum chuanxiong is 1:1; and / or, Preferably, the oily carrier is a vegetable oil, preferably one of peanut oil, soybean oil, corn oil, linseed oil, castor oil, rapeseed oil, rapeseed salad oil, sesame oil, olive oil and sunflower oil, more preferably corn oil or soybean oil; and / or, Preferably, based on the total weight of the patchouli and ligusticum chuanxiong, the content of the oily carrier is 0.25% to 0.75%, preferably 0.45% to 0.55%.

Images