A traditional Chinese medicine composition for treating insomnia, a preparation method and application thereof

Abstract

The present application relates to a kind of preparation method and application of traditional Chinese medicine composition for treating insomnia, the composition is obtained by the extract of fried jujube seed, huanghua and licorice and the extract of sanqi leaf together, as the active ingredient of drug for treating insomnia, wherein the preparation method of the extract of fried jujube seed, huanghua and licorice includes: fried jujube seed, huanghua and licorice are added water reflux extraction together or separately, filter, alcohol precipitation, and concentrated into extract, it is obtained;When extracting separately, three kinds of extracts are mixed to obtain;The preparation method of the extract of sanqi leaf includes: taking sanqi leaf, decocting with water, filtering, and the filtrate is passed through macroporous adsorption resin column, macroporous adsorption resin column is washed with water again, and then eluted with 40-60% ethanol, collect eluent, concentrate, dry, and crush, it is obtained, the preparation obtained according to the present application is more in line with the requirement of environmental protection, and the saponin content percentage in sanqi leaf extract is improved.

Description

Technical Field

[0001] This invention relates to the field of medicine, and in particular to a traditional Chinese medicine composition for treating insomnia, its preparation method, and its application. Background Technology

[0002] Insomnia is a prolonged condition characterized by unsatisfactory sleep quality and / or quantity, often manifested as difficulty falling asleep, inability to fall asleep, difficulty maintaining sleep, and premature or intermittent awakenings leading to insufficient sleep. Insomnia is one of the most common sleep disorders, and almost everyone has experienced it at some point. With societal development and a faster pace of life, the incidence of insomnia is on the rise. Statistics show that approximately 10% to 49% of the population in the United States, Europe, and Australia suffers from insomnia, and 20% to 30% of the global population (including adults and children) are severely affected by insomnia, with 5% of these cases caused by sleep-disordered breathing. Severe cases can significantly impact daily life and behavior. Short-term sleep restriction can lead to impaired glucose tolerance, potentially an independent risk factor for symptomatic diabetes. Insufficient sleep can have detrimental effects on carbohydrate metabolism and endocrine function. In addition to eliminating fatigue, sufficient sleep is closely related to improving the body's immunity and enhancing its resistance to disease.

[0003] CN100553653C discloses a new traditional Chinese medicine developed by Tasly Pharmaceutical Group, namely Anshen Dripping Pills, which has the effects of nourishing blood and promoting blood circulation, invigorating qi and calming the mind. It is currently in the market review stage. This patent document does not specifically disclose the extraction method of the notoginseng saponins (i.e., notoginsenosides). During the development of Anshen Dripping Pills, the researchers noticed that: 1) in the existing technology, the extraction of notoginseng leaf saponins uses a large amount of ethanol extraction, which is both environmentally unfriendly and costly; 2) the preparation method of extracts from jujube seed, albizia flower and licorice uses three decoction extractions, which is time-consuming and energy-intensive, and the precipitate accounts for a large proportion in the first alcohol precipitation, and the filtration cycle is long. Therefore, there is an urgent need to develop a composition with a more environmentally friendly preparation process, higher production efficiency, lower cost and higher ginsenoside Rb3 content. Summary of the Invention

[0004] To address the aforementioned problems, this invention provides a composition for treating insomnia, a preparation method thereof, and its applications. The preparation method involves using an optimized approach to prepare roasted jujube seed, albizia flower, licorice extract, and Panax notoginseng leaf extract, which are then mixed with excipients to form drop pills or concentrated pills. The traditional Chinese medicine composition for treating insomnia prepared according to this invention is more environmentally friendly, increases the percentage of saponins in the Panax notoginseng leaf extract, and improves upon the defect of material agglomeration forming small particles during the original drop pill preparation process, resulting in a more stable preparation process.

[0005] This invention claims protection for the following technical solutions:

[0006] A traditional Chinese medicine composition for treating insomnia is prepared from the following raw materials in the indicated weight ratios: 690-2070 parts of stir-fried jujube seed, 414-1242 parts of Albizia flower, 207-621 parts of licorice root, and 170-508 parts of Panax notoginseng leaf. The composition is characterized by being obtained by combining extracts of stir-fried jujube seed, Albizia flower, and licorice root, as well as an extract of Panax notoginseng leaf, as the active pharmaceutical ingredients for treating insomnia. The stir-fried jujube seed, Albizia flower, and licorice root... The preparation method of the extract includes: frying jujube seed, mimosa flower and licorice, adding water together or separately for reflux extraction, filtering, precipitating with alcohol, and concentrating into an extract; or, when extracting separately, mixing the three extracts to obtain the extract; the preparation method of the extract of Panax notoginseng leaf includes: taking Panax notoginseng leaf, adding water for decoction, filtering, passing the filtrate through a macroporous adsorption resin column, rinsing the macroporous adsorption resin column with water, then eluting with 40-60% ethanol, collecting the eluent, concentrating, drying, and pulverizing to obtain the extract.

[0007] Furthermore, the preparation method of the stir-fried jujube seed, mimosa flower, and licorice extract includes,

[0008] 1) Extraction: Boil the stir-fried jujube seeds, mimosa flowers and licorice in water and reflux to extract the extract, then filter.

[0009] 2) Concentration: The filtrate is concentrated under reduced pressure to a relative density of 1.05~1.10;

[0010] 3) First alcohol precipitation: Add ethanol to the concentrate to make the alcohol content reach 50-70%, let it stand, and separate the liquid.

[0011] 4) First-time ethanol recovery: The drug solution is concentrated to a relative density of 1.10~1.15 to obtain a first-time diluted extract;

[0012] 5) Secondary alcohol precipitation: Add ethanol to the first diluted extract to make the alcohol content reach 75-85%, let it stand, and separate the liquid.

[0013] 6) Secondary recovery of ethanol and extraction of extract: The medicinal liquid is concentrated to an extract with a relative density of 1.27~1.35, which yields the stir-fried jujube seed, albizia flower and licorice extract.

[0014] In a further embodiment,

[0015] The preparation method of the stir-fried jujube seed, mimosa flower and licorice extract includes,

[0016] 1) Extraction: Stir-fry jujube seeds, mimosa flowers, and licorice root with 8-12 times the amount of water, decoct and reflux to extract, then filter;

[0017] 2) Concentration: The filtrate is concentrated under reduced pressure to a relative density of 1.05~1.10;

[0018] 3) First alcohol precipitation: Add 90-99% ethanol to the concentrate to make the alcohol content reach 59-61%, let it stand for more than 12 hours, and then separate the liquid.

[0019] 4) First-time ethanol recovery: The drug solution is concentrated to a relative density of 1.10~1.15 to obtain a first-time diluted extract;

[0020] 5) Secondary alcohol precipitation: Add 90-99% ethanol to the first diluted extract to make the alcohol content reach 79-81%, let it stand for more than 12 hours, and then separate the liquid.

[0021] 6) Secondary ethanol recovery and extract collection: The medicinal liquid is concentrated to an extract with a relative density of 1.27-1.35, which yields the roasted jujube seed, albizia flower, and licorice extract for later use; wherein, in the first alcohol precipitation step, the separation of the medicinal liquid is performed by centrifugation or filtration to separate the precipitate into solid and liquid components. In some embodiments, in the preparation method of the roasted jujube seed, albizia flower, and licorice extract, the roasted jujube seed, albizia flower, and licorice are extracted twice by reflux with 10 times the amount of water.

[0022] In some embodiments, in the preparation method of the Panax notoginseng leaf extract, the step of adding water for decoction is to add 10 to 14 times the amount of the medicinal material for decoction.

[0023] More preferably, in the method for preparing the Panax notoginseng leaf extract, the step of adding water for decoction is to add 12 times the amount of water as the medicinal material.

[0024] In the preparation method of the Panax notoginseng leaf extract, the filtrate is passed through a macroporous adsorption resin column, wherein the mass ratio of Panax notoginseng leaf to resin is 1:1 to 1:1.5. Preferably, the macroporous adsorption resin column is a D101 macroporous adsorption resin column.

[0025] In some embodiments, in the preparation method of the Panax notoginseng leaf extract, the diameter-to-height ratio of the D101 macroporous adsorption resin column ranges from 1:3 to 1:6, corresponding to a loading and water washing flow rate range of 1.5 to 3 times the volume of medicinal material per hour.

[0026] In some embodiments, in the preparation method of the Panax notoginseng leaf extract, a macroporous adsorption resin column is eluted with 40-60% ethanol at an elution flow rate of 1.5-2.5 times the amount of medicinal material per hour.

[0027] Preferably, in the preparation method of the Panax notoginseng leaf extract, the macroporous adsorption resin column is eluted with 49%-51% ethanol, and the eluent is collected in an amount of 8-11 times that of the medicinal material.

[0028] The total saponin content in the Panax notoginseng leaf extract is not less than 60%. Preferably, the total saponin content in the Panax notoginseng leaf extract is 70% to 75%.

[0029] In some embodiments, the traditional Chinese medicine composition is a drop pill preparation, the preparation method of which includes mixing the stir-fried jujube seed, albizia flower, and licorice extract, the Panax notoginseng leaf extract, and polyethylene glycol 6000 at a mass ratio of 1:0.08~0.12:2.0~3.9, and then obtaining drop pills by dripping. In the preparation method of the drop pill preparation, the feeding and processing method of the stir-fried jujube seed, albizia flower, and licorice extract, the Panax notoginseng leaf extract, and polyethylene glycol 6000 is as follows: the stir-fried jujube seed, albizia flower, and licorice extract and the Panax notoginseng leaf extract are mixed at 65~85℃ and then added to polyethylene glycol 6000.

[0030] In other embodiments, the traditional Chinese medicine composition is a concentrated pill preparation, wherein the roasted jujube seed, albizia flower, and licorice extract, and the Panax notoginseng leaf extract account for 60% to 70% of its mass percentage, with the remainder being pharmaceutically acceptable excipients. Preferably, the pharmaceutically acceptable excipients are microcrystalline cellulose and / or dextrin; more preferably, the excipients are microcrystalline cellulose and dextrin in a mass ratio of 1:1 to 7; more preferably, the ratio of microcrystalline cellulose to dextrin is 1:1 to 1.7. The traditional Chinese medicine composition is a concentrated pill preparation, which can be prepared by mixing the roasted jujube seed, albizia flower, and licorice extract with dextrin, drying, pulverizing, and then mixing with the Panax notoginseng leaf extract and microcrystalline cellulose to form a soft material, which is then formed into concentrated pills by a pill-making machine, dried, and coated. The mass ratio of the roasted jujube seed, albizia flower, and licorice extract to the Panax notoginseng leaf extract is 1:0.08 to 0.12. In the preparation method of the concentrated pills, the drying method of the concentrated pills is to air-dry the concentrated pills for 4 to 12 hours, and then vacuum-dry them at 60℃ to 90℃ until the moisture content is no more than 7%.

[0031] This invention claims protection for the use of the described traditional Chinese medicine composition in the preparation of a drug for treating insomnia. This invention also claims protection for the use of the described traditional Chinese medicine composition in the preparation of a drug for nourishing blood, soothing the liver, relieving irritability, invigorating qi, calming the mind, and soothing the nerves.

[0032] This invention also claims protection for a method of preparing a traditional Chinese medicine composition for treating insomnia, characterized in that the preparation method includes the following steps:

[0033] 1) Preparation of extracts from stir-fried jujube seeds, mimosa flowers, and licorice:

[0034] (1) Extraction: 690-2070 parts of stir-fried jujube seeds, 414-1242 parts of mimosa flowers and 207-621 parts of licorice were extracted by reflux with water and filtered.

[0035] (2) Concentration: The filtrate is concentrated under reduced pressure to a relative density of 1.05~1.10;

[0036] (3) First alcohol precipitation: Add ethanol to make the alcohol content reach 50-70%, let stand, and separate the liquid;

[0037] (4) First-time ethanol recovery: Concentrate to a relative density of 1.10~1.15 to obtain a first-time dilute extract;

[0038] (5) Secondary alcohol precipitation: Add ethanol to the first diluted extract to make the alcohol content reach 75-85%, let it stand, and separate the liquid.

[0039] (6) Secondary recovery of ethanol and extraction of extract: Concentrate to a relative density of 1.27~1.35 to obtain the stir-fried jujube seed, mimosa flower and licorice extract, for later use;

[0040] 2) Preparation of Panax notoginseng leaf extract: Take 170-508 parts of Panax notoginseng leaves, add water and decoct, filter, pass the filtrate through a macroporous adsorption resin column, rinse the macroporous adsorption resin column with water, then elute with 40-60% ethanol, collect the eluent, concentrate, dry, and pulverize to obtain the Panax notoginseng leaf extract for later use.

[0041] 3) Preparation of oral formulations: The stir-fried jujube seed, albizia flower and licorice extract and the Panax notoginseng leaf extract are prepared into oral formulations with pharmaceutically acceptable excipients.

[0042] Furthermore, the preparation method of the stir-fried jujube seed, mimosa flower, and licorice extract includes,

[0043] 1) Extraction: Stir-fry jujube seeds, mimosa flowers, and licorice root with 8-12 times the amount of water, decoct and reflux to extract, then filter;

[0044] 2) Concentration: The filtrate is concentrated under reduced pressure to a relative density of 1.05~1.10;

[0045] 3) First alcohol precipitation: Add 90-99% ethanol to the concentrate to make the alcohol content reach 59-61%, let it stand for more than 12 hours, and then separate the liquid.

[0046] 4) First-time ethanol recovery: The drug solution is concentrated to a relative density of 1.10~1.15 to obtain a first-time diluted extract;

[0047] 5) Secondary alcohol precipitation: Add 90-99% ethanol to the first diluted extract to make the alcohol content reach 79-81%, let it stand for more than 12 hours, and then separate the liquid.

[0048] 6) Secondary ethanol recovery and extract collection: The medicinal liquid is concentrated to an extract with a relative density of 1.27~1.35, which yields the stir-fried jujube seed, albizia flower and licorice extract, for later use; wherein, in the first alcohol precipitation step, the separation of medicinal liquid is performed by centrifugation or filtration equipment to separate the precipitate into solid and liquid.

[0049] Preferably, in the preparation method of the stir-fried jujube seed, albizia flower and licorice extract, the stir-fried jujube seed, albizia flower and licorice are refluxed and extracted twice with 10 times the amount of water.

[0050] In step 2), the preparation method of Panax notoginseng leaf extract, the step of adding water for decoction is to add 10 to 14 times the amount of medicinal material to the decoction, preferably 12 times the amount of medicinal material to the decoction.

[0051] In the preparation method of the Panax notoginseng leaf extract, the filtrate is passed through a macroporous adsorption resin column, wherein the mass ratio of Panax notoginseng leaf material to resin is 1:1 to 1:1.5, and the preferred macroporous adsorption resin column is a D101 macroporous adsorption resin column. In the preparation method of the Panax notoginseng leaf extract, the diameter-to-height ratio of the D101 macroporous adsorption resin column ranges from 1:3 to 1:6, corresponding to a loading and washing flow rate range of 1.5 to 3 times the volume of the medicinal material / h. In the preparation method of the Panax notoginseng leaf extract, the macroporous adsorption resin column is eluted with 40-60% ethanol at an elution flow rate of 1.5 to 2.5 times the volume of the medicinal material / h.

[0052] In some embodiments, in the preparation method of the Panax notoginseng leaf extract, a macroporous adsorption resin column is eluted with 50% ethanol, and 8 to 11 times the amount of medicinal material is received as eluent.

[0053] In this invention's composition, roasted jujube seed, neutral in nature and sour and sweet in taste, enters the heart and liver meridians, nourishing blood and tonifying the liver, calming the mind and soothing the nerves; it is the principal ingredient. Albizia flower, neutral in nature and sweet in taste, also enters the heart and liver meridians, regulating qi, relieving depression, and calming the mind; it is the assistant ingredient. Roasted jujube seed, with its sour and sweet properties, nourishes liver blood and has astringent effects. When yin is nourished and astringed, the blood of the heart and liver is nourished, and the mind is calmed. Albizia flower excels at regulating qi and soothing the liver; when liver qi is soothed, mental irritability is relieved. The two herbs combined nourish blood and regulate the liver, one promoting circulation and the other astringing, nourishing without stagnation, nourishing the blood of the heart and liver while softening the liver, regulating the qi mechanism of liver stagnation, relieving irritability and calming the mind. Panax notoginseng leaf, pungent in taste, enters the liver and stomach meridians, can dispel blood stasis and disperse blood stasis, and also has the effects of tonifying qi, nourishing the heart, and calming the mind; it is the assistant ingredient, and when combined with roasted jujube seed, it has the effect of simultaneously tonifying qi and blood. Licorice root tonifies qi, harmonizes the middle jiao, and relieves urgency; combined with jujube seed, it has the intention of transforming yin with its sour and sweet properties; combined with Panax notoginseng leaf, it tonifies qi, strengthens the spleen, and nourishes the earth and wood. The composition of this invention has the effects of nourishing blood, soothing the liver, relieving irritability, invigorating qi, calming the mind, and soothing the nerves, and can be used to treat insomnia.

[0054] The present invention has the following beneficial effects:

[0055] 1. The preparation method of the traditional Chinese medicine composition for treating insomnia disclosed in this invention optimizes the preparation method of Panax notoginseng leaf extract. It eliminates the need for concentration, alcohol precipitation, and settling. After water extraction, the extract is directly loaded onto a macroporous resin column, and elution is performed by first washing with water and then with a 40-60% ethanol aqueous solution. This simplifies the extraction steps and reduces the use of organic solvents. In addition, this process is simple, has a short production cycle, good reproducibility, and is environmentally friendly. The total saponins and ginsenoside Rb3 content of the Panax notoginseng leaf extract obtained are superior to those of existing technologies.

[0056] 2. The preparation method of the traditional Chinese medicine composition for treating insomnia disclosed in this invention discloses a method for preparing extracts of jujube seed, albizia flower and licorice. It optimizes the existing technology by using three decoctions for extraction, which is time-consuming, energy-intensive and has poor efficacy, to two extractions.

[0057] 3. The preparation method of the traditional Chinese medicine composition for treating insomnia disclosed in this invention discloses a method for preparing drop pills. By optimizing the feeding sequence, the technical problem of the mixed material being relatively viscous and the material being lost due to sticking to the wall during the transfer process is solved. Furthermore, by optimizing the feeding sequence, the defect of the original drop pill preparation process where the material easily agglomerates and forms small particles during the dissolving process is solved, thereby improving the uniformity of the preparation.

[0058] 4. The preparation method of the traditional Chinese medicine composition for treating insomnia disclosed in this invention discloses a method for preparing concentrated pills, which has the advantages of large drug loading, easy swallowing, easy production and transportation, and can effectively avoid problems such as large dosage, bitter taste and poor taste, thereby improving patient compliance. Attached Figure Description

[0059] Figure 1 Leakage curve of ginsenoside Rb3;

[0060] Figure 2 Contour plots of spatial flow velocity tolerance of macroporous resin columns with different aspect ratios;

[0061] Figure 3 Elution curve of 2 times the amount of medicinal material / h;

[0062] Figure 4 Solid-liquid separation effect of concentrates with different alcohol contents after standing;

[0063] Figure 5 Coating samples were taken when the different feeding sequences (1-6#) were completed.

[0064] Figure 6 Stability test results of different dosage forms Detailed Implementation

[0065] The present invention is further illustrated by the following examples, but these are not intended to limit the invention.

[0066] Unless otherwise specified, the reagents, methods and equipment used in this invention are conventional reagents, methods and equipment in this technical field.

[0067] Example 1: A traditional Chinese medicine composition for treating insomnia and its preparation method

[0068] 1. Preparation method of the extracts of stir-fried jujube seed, mimosa flower and licorice: 1380 parts of stir-fried jujube seed, 828 parts of mimosa flower and 414 parts of licorice were extracted twice by reflux with 8 times the amount of water, 2 hours each time. The extract was filtered, and the filtrate was concentrated under reduced pressure to a relative density of 1.05-1.10 (60±1℃). Ethanol was added to make the alcohol content reach 50 (±1)%. The extract was allowed to stand, and the liquid was separated and concentrated to a relative density of 1.10-1.15 (60±1℃). Ethanol was added to make the alcohol content reach 75 (±1)%. The extract was allowed to stand, and the liquid was separated and concentrated to a relative density of 1.27~1.35 (60±1℃) to obtain the extract of stir-fried jujube seed, mimosa flower and licorice, which was then prepared for use.

[0069] 2. Preparation method of Panax notoginseng leaf extract: Take 339 parts of Panax notoginseng leaves, add 12 times the amount of medicinal material to water and decoct twice, 1.5h each time, filter, cool to 10-30℃, and pass the filtrate through a macroporous adsorption resin column with a column diameter-to-height ratio of 1:3. The mass ratio of Panax notoginseng leaf material (i.e., raw material mass) to resin (wet resin) is 1:1. Wash the resin column with water, with a flow rate of 1.5 times the volume of medicinal material / h for loading and washing. Then elute with 50% ethanol at a flow rate of 1.5 times the amount of medicinal material / h. Collect 8 times the amount of medicinal material in 50% (±1) ethanol eluent, concentrate to a relative density of 1.06-1.12 (60±1℃), dry, and pulverize to obtain Panax notoginseng leaf extract for later use.

[0070] 3. Preparation method of drop pills: Take stir-fried jujube seed, mimosa flower and licorice extract and Panax notoginseng leaf extract, mix them evenly and add polyethylene glycol 6000 to make drop pills. The mass ratio of stir-fried jujube seed, mimosa flower and licorice extract, Panax notoginseng leaf extract and polyethylene glycol 6000 is 1:0.08:2.0.

[0071] Example 2: A traditional Chinese medicine composition for treating insomnia and its preparation method 2

[0072] 1. Preparation method of stir-fried jujube seed, albizia flower and licorice extract: 690 parts of stir-fried jujube seed, 414 parts of albizia flower and 207 parts of licorice were extracted twice by reflux with 10 times the amount of water, 2 hours each time. The extract was filtered, and the filtrate was concentrated under reduced pressure to a relative density of 1.05-1.10 (60±1℃). Ethanol was added to make the alcohol content reach 70% (±1). The extract was centrifuged and concentrated to a relative density of 1.10-1.15 (60±1℃). Ethanol was added to make the alcohol content reach 85% (±1)%. The extract was allowed to stand, and the extract was separated and concentrated to a relative density of 1.27~1.35 (60±1℃) to obtain the stir-fried jujube seed, albizia flower and licorice extract, which was then used for later use.

[0073] 2. Preparation method of Panax notoginseng leaf extract: Take 170 parts of Panax notoginseng leaves, add 14 times the amount of medicinal material to water and decoct twice, 1.5h each time, filter, cool to 10-30℃, and pass the filtrate through a D101 type macroporous adsorption resin column with a column diameter-to-height ratio of 1:5. The mass ratio of Panax notoginseng leaf material (i.e., crude drug mass) to resin (wet resin) is 1:1.3. Rinse the resin column with water, and the corresponding sample loading and water washing flow rate range is 3 times the volume of medicinal material / h. Then elute with 50 (±1)% ethanol at a flow rate of 2 times the volume of medicinal material / h. Collect 10 times the volume of medicinal material in 50% ethanol eluent, concentrate to a relative density of 1.06-1.12 (60±1℃), dry, and pulverize to obtain Panax notoginseng leaf extract for later use.

[0074] 3. Preparation method of the drop pills: Take the roasted jujube seed, albizia flower and licorice extract and Panax notoginseng leaf extract, mix them evenly and then add polyethylene glycol 6000 to make drop pills. The mass ratio of roasted jujube seed, albizia flower and licorice extract, Panax notoginseng leaf extract and polyethylene glycol 6000 is 1:0.12:3.9.

[0075] Example 3: A traditional Chinese medicine composition for treating insomnia and its preparation method 3

[0076] 1. Preparation method of the extracts of stir-fried jujube seed, mimosa flower and licorice: 2070 parts of stir-fried jujube seed, 1242 parts of mimosa flower and 621 parts of licorice were extracted twice by reflux with 12 times the amount of water, 2 hours each time. The extracts were filtered, and the filtrate was concentrated under reduced pressure to a relative density of 1.05-1.10 (60±1℃). Ethanol was added to make the alcohol content reach 70 (±1)%. The extracts were centrifuged and concentrated to a relative density of 1.10-1.15 (60±1℃). Ethanol was added to make the alcohol content reach 85 (±1)%. The extracts were allowed to stand, and the extracts were concentrated to a relative density of 1.27~1.35 (60±1℃) to obtain the extracts of stir-fried jujube seed, mimosa flower and licorice, which were then set aside.

[0077] 2. Preparation method of Panax notoginseng leaf extract: Take 508 parts of Panax notoginseng leaves, add 14 times the amount of medicinal material to water and decoct twice, 1.5h each time, filter, cool to 10-30℃, and pass the filtrate through a D101 type macroporous adsorption resin column with a column diameter-to-height ratio of 1:6. The mass ratio of Panax notoginseng leaf material (i.e., crude drug mass) to resin (wet resin) is 1:1.5. Wash the resin column with water, and the corresponding sample loading and water washing flow rate range is 3 times the volume of medicinal material / h. Then elute with 50 (±1)% ethanol at a flow rate of 2.5 times the amount of medicinal material / h. Collect 11 times the amount of medicinal material in 50% ethanol eluent, concentrate to a relative density of 1.06-1.12 (60±1℃), dry, and pulverize to obtain Panax notoginseng leaf extract for later use.

[0078] 3. Preparation method of drop pills: Take stir-fried jujube seed, mimosa flower and licorice extract and Panax notoginseng leaf extract, mix them evenly and add polyethylene glycol 6000 to obtain drop pills, wherein the mass ratio of stir-fried jujube seed, mimosa flower and licorice extract, Panax notoginseng leaf extract and polyethylene glycol 6000 is 1:0.1:3.

[0079] Example 4: A concentrated pill preparation of a traditional Chinese medicine composition for treating insomnia 1

[0080] 1. The preparation methods of stir-fried jujube seed, mimosa flower and licorice extract, and the preparation method of Panax notoginseng leaf extract are the same as in Example 1;

[0081] 2. The roasted jujube seed, mimosa flower, and licorice extracts are mixed with dextrin, dried, and pulverized. This mixture is then combined with Panax notoginseng leaf extract and microcrystalline cellulose to form a soft mass. This mass is then processed into concentrated pills using a pelleting machine, dried, and coated to obtain the final product. The roasted jujube seed, mimosa flower, and licorice extracts, along with the Panax notoginseng leaf extract, constitute 70% of the preparation by mass. The mass ratio of the jujube seed, mimosa flower, and licorice extracts to the Panax notoginseng leaf extract is 1:0.1, and the mass ratio of microcrystalline cellulose to dextrin is 1:1.

[0082] Example 5: A concentrated pill preparation of a traditional Chinese medicine composition for treating insomnia 2

[0083] 1. The preparation methods of stir-fried jujube seed, mimosa flower and licorice extract, and the preparation method of Panax notoginseng leaf extract are the same as in Example 1;

[0084] 2. The roasted jujube seed, mimosa flower, and licorice extracts are mixed with dextrin, dried, and pulverized. This mixture is then combined with Panax notoginseng leaf extract and microcrystalline cellulose to form a soft mass. This mass is then processed into concentrated pills using a pelleting machine, dried, and coated to obtain the final product. The roasted jujube seed, mimosa flower, and licorice extracts, along with the Panax notoginseng leaf extract, constitute 60% of the total mass of the preparation. The mass ratio of these extracts to the Panax notoginseng leaf extract is 1:0.12, and the mass ratio of microcrystalline cellulose to dextrin is 1:7.

[0085] Example 6: A concentrated pill preparation of a traditional Chinese medicine composition for treating insomnia 3

[0086] 1. The preparation methods of stir-fried jujube seed, mimosa flower and licorice extract, and the preparation method of Panax notoginseng leaf extract are the same as in Example 1;

[0087] 2. The roasted jujube seed, mimosa flower, and licorice extracts are mixed with dextrin, dried, and pulverized. This mixture is then combined with Panax notoginseng leaf extract and microcrystalline cellulose to form a soft mass. This mass is then processed into concentrated pills using a pelleting machine, dried, and coated to obtain the final product. The roasted jujube seed, mimosa flower, and licorice extracts, along with the Panax notoginseng leaf extract, constitute 65% of the total mass of the preparation. The mass ratio of these extracts to the Panax notoginseng leaf extract is 1:0.08, and the mass ratio of microcrystalline cellulose to dextrin is 1:1.7.

[0088] Experiment Example 1: Optimization Experiment of the Method for Extracting Panax notoginseng

[0089] 1. Investigation on the ratio of resin dosage to drug solution volume in the preparation method of Panax notoginseng leaf extract

[0090] Preparation method of test sample: Take 3000g of Panax notoginseng leaves, add 12 times the amount of water and decoct twice, 1.5h each time, filter, cool to 10-30℃, and obtain about 60000ml of Panax notoginseng leaf extract.

[0091] Take a chromatography column with a diameter of 2.5 cm and a length of 50 cm, and measure 100 ml of D101 macroporous adsorption resin (equivalent to approximately 70 g of wet resin, i.e., the swollen resin). Pack the column using the wet packing method with water. Add the extract to the chromatography column, control the flow rate at 10 ml / min, and collect one fraction every 100 ml. Select different fractions and quantitatively inject them into the HPLC chromatograph to determine the concentration of ginsenoside Rb3. Plot a leakage curve with the number of fractions (eluent volume) on the x-axis and the concentration of ginsenoside Rb3 in the eluent on the y-axis. See [reference needed]. Figure 1 .

[0092] Depend on Figure 1 It can be seen that when the outflow volume is 1200ml, ginsenoside Rb3 begins to leak. Therefore, 1200ml is the optimal loading volume, which is equivalent to the original amount of medicinal material: 1200ml (volume of sample loaded onto the column before the leakage point) × 3000g (total mass of Panax notoginseng) / 60000ml (volume of loading liquid) = 60g. That is, 70g of resin can adsorb the equivalent of 60g of extract from the original medicinal material. The ratio of medicinal material mass to resin mass (wet resin) is 60:70≈1:1.17. Considering the actual situation of large-scale production, the feeding mass ratio of Panax notoginseng leaf medicinal material to resin (wet resin) should be 1:1~1:1.5.

[0093] 2. Clarification of the diameter-to-height ratio range and sample loading and water washing flow rates in the production process of Panax notoginseng leaf extract.

[0094] The flow rate of the sample solution through the resin has a significant impact on both the working efficiency and the adsorption of its active ingredients. Too high a flow rate reduces the amount of resin adsorbed, while too slow an adsorption rate increases the adsorption time. Therefore, the tolerable flow rate range needs to be considered when studying the aspect ratio.

[0095] A glass column with an inner diameter of 4.5 cm was filled with pretreated D101 macroporous adsorption resin, with diameter-to-height ratios of 1:3, 1:4, 1:5, 1:6, and 1:7. The resin and raw drug mass was calculated based on the resin swelling ratio (raw drug: wet resin 1:1.2). The extraction volume was calculated based on the raw drug mass, and the corresponding extraction volume was added. The loading flow rate was 4 times the raw drug volume / h (the raw drug volume refers to the raw drug mass corresponding to the loading solution in this experiment, which needs to be calculated based on the resin volume). After loading, the sample was eluted with 15 times the raw drug volume of water at a flow rate of 4 times the raw drug volume / h. Three samples were collected: the final discharge (i.e., the loading endpoint), the loading eluent, and the water eluent. Leakage of ginsenoside Rb3 in the samples was tested separately. A detection value of "1" was assigned, and a non-detection value of "0" was assigned. As shown in Table 10, it can be seen that ginsenoside Rb3 was not detected in any of the three samples at a diameter-to-height ratio of 1:4 when the sample loading rate was 4 times the amount of medicinal material / h. Leakage occurred during the sample loading process at all other diameter-to-height ratios. The 1:4 diameter-to-height ratio was tested using a sample loading rate of 6 times the amount of medicinal material / h and a water elution rate. For other diameter-to-height ratios, the flow rate was reduced to examine leakage at a rate of 3 times the amount of medicinal material / h. The results are shown in Table 1. The results indicate that leakage occurred at a diameter-to-height ratio of 1:7 when the sample loading rate was 3 times the amount of medicinal material / h, while no leakage occurred at other diameter-to-height ratios.

[0096] Table 1 Results of flow velocity tolerance tests at different diameter-to-height ratios

[0097]

[0098] Note: Ginsenoside Rb3 leakage status: "1" indicates detected, "0" indicates not detected, and "-" indicates not detected.

[0099] Use the above results to draw a contour map, see Figure 2 As shown in the figure, controlling the flow rate to below 3 times the amount of medicinal material per hour and maintaining a diameter-to-height ratio within the range of 1:3-1:6 during sample loading and washing ensures that the indicator component ginsenoside Rb3 will not leak. Based on the actual needs of large-scale production, the diameter-to-height ratio range of the D101 resin column in the preparation process of Panax notoginseng leaf extract was determined to be 1:3-1:6, corresponding to a sample loading and washing flow rate range of 1.5-3 times the volume of medicinal material per hour.

[0100] 3. Selection of Ethanol Concentration as Eluent

[0101] When the aqueous extract of Panax notoginseng leaves flows through a D101 macroporous adsorption resin column, saponins are adsorbed onto the resin. Therefore, to obtain the saponins, it is necessary to desorb them from the macroporous adsorption resin. Desorption is usually performed using water-soluble organic solvents, such as aqueous solutions of methanol, ethanol, and acetone at different concentrations. Considering drug safety, industrial production costs, labor protection, and environmental protection, and taking into account the physicochemical properties of saponins in Panax notoginseng leaves, an ethanol-water system is considered the optimal eluent.

[0102] Weigh out 500g of Panax notoginseng leaves into three portions, place them in 10L round-bottom flasks, add 12 times the amount of water and decoct twice, combine the extracts, totaling 31000ml, and set aside.

[0103] Three chromatography columns with a diameter of 2.5 cm and a length of 50 cm were used. Three portions of D101 macroporous adsorption resin, each 75 g of dry resin, were weighed and packed into the columns using the wet packing method with water. 1200 ml of extract was added to the chromatography column. After adding the extract, the column was rinsed with 15 times its volume of water. The macroporous adsorption resin columns after water elution were eluted with 40%, 50%, and 60% ethanol of different concentrations to the endpoint, respectively. The elution was concentrated, dried, and the total saponin and ginsenoside Rb3 content in the extract was determined (see Table 2).

[0104] Elution endpoint determination: Spot 10 μL of ethanol eluent onto a silica gel G thin-layer plate, spray with 10% sulfuric acid ethanol solution, heat, and check for purple spots.

[0105] Table 2 Elution results of ethanol at different concentrations

[0106]

[0107] The results showed that when 40% to 60% ethanol solution was used as the eluent, 50% (±1) ethanol was the optimal eluent concentration.

[0108] 4. Investigation of the dosage and flow rate when using 50% (±1) ethanol as the eluent.

[0109] A 4.5 cm diameter resin column was packed with resin at a diameter-to-height ratio of 1:4. Samples were loaded at a flow rate of 3 times the amount of medicinal material per hour, followed by washing with water. Elution was then performed with 50% ethanol at a flow rate of 2 times the amount of medicinal material per hour. Elution was initiated from the point of exchange with 50% ethanol, and a total of 12 times the amount of medicinal material was collected as eluent. Elution curves were plotted for each of these 12 times the amount of medicinal material, based on the Rb3 concentration in the eluent for each unit of medicinal material. (See figure). Figure 3 The results showed that at a flow rate of 2 times the amount of medicinal material per h, the elution ratio of 9 times the amount of medicinal material was the inflection point of the elution curve. Since the first amount of medicinal material contained almost no saponin components, receiving the elution ratio of 9 times the amount of medicinal material could elute most of the ginsenoside Rb3.

[0110] The results showed that receiving 8 to 11 times the amount of medicinal material as eluent could elute most of the ginsenoside Rb3.

[0111] 5. Multiple batches of pilot-scale and production data

[0112] Table 3. Detection results of Panax notoginseng leaf extract

[0113]

[0114] Table 4. Comparison of process time before macroporous resin extraction between the process of the present invention and the comparative process.

[0115]

[0116] The results in Tables 3 and 4 show that the water extraction process of Panax notoginseng in this invention is simple, and no alcohol precipitation step is required before elution with macroporous resin, which greatly shortens the process time and improves production efficiency. Furthermore, the content of ginsenoside Rb3 in the obtained Panax notoginseng extract is significantly reduced, and the process is environmentally friendly (no organic solvents are used). The quality of the obtained Panax notoginseng leaf extract is superior to that of existing technologies.

[0117] Experimental Example 2: Optimization of the preparation method of stir-fried jujube seed, mimosa flower and licorice extract.

[0118] 1. Design of the extraction process optimization experiment

[0119] The water-soluble components of roasted jujube seeds, mimosa flowers, and licorice have strong pharmacological effects. Therefore, water extraction was adopted as the extraction process. Based on the process design, an orthogonal experiment was designed to investigate the three factors and three levels of extraction time, solvent dosage, and number of extractions. The experimental scheme is shown in Table 5.

[0120] Table 5. Orthogonal factor level table of extraction conditions for stir-fried jujube seed, mimosa flower, and licorice.

[0121]

[0122] 2. Indicator Selection and Methods

[0123] 2.1 Indicator Selection

[0124] Ziziphus jujuba seed is the principal ingredient in this formula, and jujuboside B is one of its main active components. Therefore, jujuboside B was used as an indicator to examine the results of the orthogonal experiment.

[0125] 2.2 Method for determining the content of jujube seed saponin B

[0126] L9(3) is designed according to orthogonal design principles. 4 An orthogonal array was used to arrange the experiment. For each experiment, an appropriate amount of medicinal material was taken, and different amounts of water were added according to the experiment number. Different extraction times and times were used. The extracts were combined and concentrated to about 1 ml, which is equivalent to 1 g of raw drug, to obtain the extract concentrate.

[0127] 2.3 Results of Orthogonal Experiments

[0128] The orthogonal experimental parameters are shown in Table 6.

[0129] Table 6. Orthogonal experimental table of extraction methods for stir-fried jujube seed, mimosa flower, and licorice.

[0130]

[0131] Table 7 Analysis of Variance Table

[0132]

[0133] Results Analysis: Table 7 shows the R-values, indicating the order of importance of the factors: C > A > B. Analysis of variance showed that the number of extractions (factor C) and the amount of extraction solvent added (factor A) had significant effects on the yield of jujube seed saponin B (P < 0.1), while the extraction time (factor B) had a relatively small impact. The optimal extraction process was A2B3C3, i.e., reflux extraction with 10 times the amount of water three times, each time for 2 hours. Considering that the extraction rate of jujube seed saponin B was not significantly different between three and two extractions, two extractions were used to save energy. Although the extraction time had the least impact on the extraction rate of jujube seeds, considering the actual situation of large-scale production, a relatively long decoction time of 2 hours was still adopted, i.e., A2B3C2, extraction with 10 times the amount of water twice, each time for 2 hours.

[0134] 3. Optimization of the primary alcohol precipitation solid-liquid separation process

[0135] 3.1 Methods for determining the content of indicator components

[0136] Analytical method: Liquid chromatography

[0137] 3.2 Optimization of Solid-Liquid Separation Method

[0138] In the prior patent CN100553653C, after the water extraction of three medicinal herbs, ethanol was added to the concentrated liquid to achieve an alcohol content of 50-70%, and the mixture was allowed to stand overnight and then filtered. However, due to the large proportion of precipitation and the long cycle, this experiment optimized and screened the solid-liquid separation method.

[0139] Take appropriate amounts of stir-fried jujube seeds, mimosa flowers, and licorice root. Extract twice with water according to the method in Example 1, concentrate the extract, divide it into three equal portions, and add ethanol to each portion to achieve alcohol contents of 50%, 60%, and 70%, respectively. Stir well, take 100 ml of each portion into a graduated cylinder, let it stand for 12 hours, and observe the solid-liquid separation effect (see figure). The results are as follows: Figure 5As shown, the precipitate percentages were 43%, 40%, and 37%, respectively, indicating a large precipitate content. Directly aspirating the supernatant would result in the loss of active ingredients. To ensure a stable yield and transfer rate of the target components, the precipitate needs to be filtered. Filter cloths of 100 mesh, 200 mesh, 300 mesh, and 600 mesh were used to filter the precipitate. The results showed that 100 and 200 mesh filtration speeds were faster, but the filtrate was turbid; 300 mesh filtration improved turbidity but had a slower flow rate; and 600 mesh filtration resulted in a clear filtrate but an extremely low flow rate. Therefore, 300 mesh is the preferred filtration mesh size.

[0140] Based on the existing problems mentioned above, a centrifuge (2000-2500 rpm) was used for solid-liquid separation of the drug solution. Compared with filtration, scaled-up production data showed that the yield of the clarified liquid, the yield of the extract, and the glycyrrhizic acid transfer rate were all guaranteed after centrifugation, slightly better than filtration. Considering the continuous improvement of large-scale production equipment and the anticipated upgrade to automated production, centrifugation or filtration can be used for solid-liquid separation of the alcohol-precipitated drug solution. See Table 8 below.

[0141] Table 8 Comparison of the single-stage alcohol precipitation process of the three-flavor water-extracted alcohol immersion paste

[0142]

[0143] Clear liquid yield (%) = (Volume of clear liquid in one step / (Volume of concentrate before alcohol precipitation + Volume of 95% ethanol added)) * 100%

[0144] Experiment Example 3: Optimization of the Feeding and Mixing Method for An Shen Dripping Pills

[0145] In existing technology, the preparation method of Anshen dripping pills is as follows: Add the above-mentioned Panax notoginseng leaf saponin powder, jujube seed, Albizia julibrissin flower, and licorice extract to an appropriate amount of excipients, mix thoroughly, heat the mixture to 45–115℃ to melt, stir evenly for 1–120 minutes, keep warm, and drip at 40–95℃ using a dripper with a diameter of 1.0–4.5 mm into liquid paraffin, methyl silicone oil, or vegetable oil at -20–25℃ to form dripping pills. This method has the drawback that the materials easily aggregate to form small particles during the mixing process.

[0146] 1. Optimization of the feeding and dissolving method for An Shen Di Wan (a traditional Chinese medicine).

[0147] Preliminary tests revealed that the mixture of Panax notoginseng leaf extract and sedative water-based alcohol immersion paste was quite viscous, and some material was lost during the transfer process due to the material sticking to the walls.

[0148] Therefore, the feeding sequence was adjusted to first add the Panax notoginseng leaf extract to the molten polyethylene glycol 6000, mix thoroughly, and then add the sedative water-extracted alcohol immersion paste. This minimizes material loss. Process sampling and testing showed that this feeding sequence ensures the uniformity of the indicator components in the solution and the uniformity of the finished product after processing. Comparison of the appearance of the processed materials revealed that this feeding sequence was more prone to small aggregates. Analysis showed that since the main component of Panax notoginseng leaf extract is saponins, which are both hydrophilic and lipophilic and insoluble in polyethylene glycol 6000, adding the molten polyethylene glycol 6000 first forms uniformly dispersed particles. The subsequently added sedative water-extracted alcohol immersion paste then coats the Panax notoginseng leaf extract particles, causing aggregation. While this aggregation does not affect the uniformity of the indicator components in the solution or the content uniformity of the finished pellets, there is still a risk that the aggregates may further increase and clog the drippers or cause pellet defects. Therefore, a systematic comparative study of the feeding methods in the processing was conducted.

[0149] 1.1 Small-scale study on optimization of material processing method and sequence

[0150]

[0151] A comparative study was conducted using 0.5 units of the prescription, employing six different order of ingredient addition and processing methods. The results are shown in Table 9 and [Table data would be inserted here]. Figure 5 The results showed that when polyethylene glycol 6000 was added first, followed by intermediates (1#-4#), small black agglomerates appeared in the solution after the initial mixing. However, when the intermediates were added first, mixed thoroughly, and then polyethylene glycol 6000 was added (5#), the solution properties were better than those of 1-4#, with uniform material and no agglomerates. To accelerate the mixing speed of the sedative water-extracted alcohol immersion paste and Panax notoginseng leaf extract, experiment 6# was used. This involved adding 10% of the prescribed amount of polyethylene glycol 6000 before adding the intermediates. The results showed that the solution properties were the same as in experiment 5#, with uniform material and no agglomerates.

[0152] Table 9. Results and Evaluation of Material Processing under Different Feeding Sequences

[0153]

[0154] 1.2 Pilot-scale study on optimization of material processing method and sequence

[0155] Pilot-scale verification tests were conducted on #5, with a production batch of 40 kg. The material was prepared according to the key processes and parameter ranges in Table 10, and a portion of the prepared solution was dripped. Samples were taken after preparation and during the heat preservation process to detect the content of ginsenoside Rb3 and glycyrrhizic acid, used to evaluate the uniformity of preparation and the stability of components during preparation.

[0156] Table 10 Key Process Parameter Identification and Parameter Range in Pilot-Scale Study of Optimization of Anshen Dripping Pills' Feeding Sequence

[0157]

[0158] The results showed that the material was uniform in color and free of aggregated small particles upon completion of the mixing process. Coating samples taken after 30, 60, 120, 180, 240, 300, and 360 minutes of heat treatment showed stable material properties and no aggregated small particles during the heat treatment process. Process sampling and testing results showed good uniformity of the two quality control indicators at the completion of the mixing process. Specifically, the RSD% of glycyrrhizic acid at 6 points was 3.25%, and the RSD% of ginsenoside Rb3 at 6 points was 1.71%, both less than 5%. Compared to 0 hours after 6 hours of heat treatment, the changes in glycyrrhizic acid and ginsenoside Rb3 content were 1.98% and 0.77%, respectively, indicating good stability of the two quality control indicators during the mixing process. The optimized process can solve the problem of aggregated small particles in production while ensuring stable and uniform components, meeting the requirements for pellet production. A comparison of the dropping processes is shown in Table 11.

[0159] Table 11 Comparison of parameters for droplet production with different processing methods and sequences

[0160]

[0161] The above results indicate that the optimization of the chemical processing has no impact on the pelleting process.

[0162] In summary, the chemical processing method has been optimized from "adding the above-mentioned Panax notoginseng leaf saponin powder, jujube seed, Albizia julibrissin flower and licorice extract to an appropriate amount of excipients and mixing them thoroughly" to "taking the sedative water-extracted alcohol immersion paste and Panax notoginseng leaf extract, mixing the two together, adding an appropriate amount of polyethylene glycol 6000, and heating to melt them".

[0163] Experimental Example 4: Study on Concentrated Pellet Process

[0164] 1. Comparative study of multiple dosage forms

[0165] An Shen Dripping Pills are a solid oral dosage form. Due to the limitations of the matrix selection, the drug loading is relatively low. In order to maintain the stability of its administration method and formulation, through literature review and market research, four common solid oral dosage forms, namely granules, capsules, concentrated pills and tablets, were selected for comparative study. Granules, capsules, concentrated pills and tablets with 70% drug loading were prepared, and each dosage form was uniformly packaged. Accelerated stability studies were conducted, and its properties, moisture content, disintegration time and content were determined.

[0166] 1.1 Preparation of various dosage forms

[0167] 1.1.1 Prescription Design

[0168] Based on the commonly used excipients for various dosage forms in the Chinese Pharmacopoeia, formulations with a 70% drug loading for four common solid oral dosage forms—granules, capsules, concentrated pills, and tablets—were designed. The specific formulations are shown in Table 12 below. Preliminary experiments revealed that the Anshen water-extract alcohol-immersion paste, when dried and powdered alone, easily absorbs moisture and re-agglomerates. Mixing the Anshen water-extract alcohol-immersion paste with excipients before drying effectively improves moisture absorption. Therefore, the Anshen water-extract alcohol-immersion paste was subsequently dried and powdered together with the excipients before preparation of the formulation.

[0169] Table 12 Formulation Design for Each Dosage Form

[0170]

[0171] 1.1.2 Preparation of Granules

[0172] According to the prescription, the sedative water-extracted alcohol-immersed extract is mixed with dextrin and placed in a vacuum drying oven to dry. After drying, it is pulverized using a pulverizer to obtain a dry extract fine powder (the powder can all pass through a No. 5 sieve and contains no less than 95% that can pass through a No. 6 sieve). After mixing with Panax notoginseng leaf extract, wet granulation is performed using 95% ethanol as a binder to obtain sedative granules.

[0173] 1.1.3 Preparation of Capsules

[0174] According to the prescription, the sedative water-extracted alcohol immersion paste is mixed with starch and dried in a vacuum drying oven. After drying, it is pulverized using a pulverizer to obtain a fine powder of dry extract. Magnesium stearate and Panax notoginseng leaf extract are added and mixed well. The mixture is then filled into capsule shells to obtain sedative capsules.

[0175] 1.1.4 Tablet Preparation

[0176] According to the prescription, the sedative water-extract alcohol-immersion paste is mixed with dextrin and dried in a vacuum drying oven. After drying, it is ground into powder using a pulverizer to obtain a fine powder of dry extract. Magnesium stearate and Panax notoginseng leaf extract are added and mixed well. The mixture is then passed through a single-punch tablet press to obtain sedative tablets.

[0177] 1.1.5 Preparation of concentrated pills

[0178] According to the prescription, the sedative water-extract alcohol-immersion paste is mixed with dextrin and dried in a vacuum drying oven. After drying, it is ground into powder using a pulverizer to obtain a fine powder of dry extract. Microcrystalline cellulose and Panax notoginseng leaf extract are added and mixed well. The mixture is then passed through a fully automatic high-speed control Chinese medicine pill-making machine to obtain concentrated sedative pills.

[0179] 1.2 Accelerated Stability Study

[0180] Based on the pharmacopoeia and actual conditions, Anshen granules, Anshen capsules, Anshen tablets, and Anshen concentrated pills were packaged with polyester / aluminum / polyethylene pharmaceutical composite film and subjected to a six-month accelerated stability study (relative humidity 75%±5%, 40 ℃±2 ℃). The test item was appearance.

[0181] 1.3 Results of Accelerated Stability Study

[0182] like Figure 6 As shown, after a six-month accelerated stability test, the granules changed from brown granules to black lumps, the capsules changed from yellow powder to black strips, the sedative tablets changed from yellow tablets to yellowish-brown tablets, and the sedative concentrated pills remained brown pills. It can be seen that the granules and capsules underwent obvious changes, the tablets underwent slight changes, and the concentrated pills did not show obvious changes, indicating that the concentrated pills have stable properties.

[0183] 2. Examination of the types of auxiliary materials

[0184] By compiling a list of commonly used excipients for concentrated pills in the pharmacopoeia, a single-factor design method was used to investigate four commonly used excipients in concentrated pills: microcrystalline cellulose, dextrin, starch, and maltodextrin. Based on the experimental results, the composition of the excipients in the formulation was further adjusted. The screening results are shown in Table 13. A total of four formulations were designed, all with a drug loading of 70% for pill preparation. Among them, the sedative water-extract alcohol-immersion paste (fried jujube seed, albizia flower, and licorice extract) contained 908.35 g, Panax notoginseng leaf extract contained 94.6 g, and the total excipients were 430 g. The formulation composition was determined by comprehensively considering the preparation process, yield, pill testing results, and production cost.

[0185] Table 13 Results of the Experiment on the Types of Auxiliary Materials

[0186]

[0187] The results showed that the formulation with maltodextrin as the main filler produced softer pellets with uneven size; the formulation with starch as the main filler produced slow pelleting, harder pellets, and pellets that were not round and uneven in size; the formulation with dextrin as the main filler produced pellets smoothly with moderate softness and hardness, good toughness, and good pellet shape; the formulation with microcrystalline cellulose as the main filler had poor viscosity and could not be pelleted smoothly, presumably because microcrystalline cellulose has good filling and support properties but poor viscosity.

[0188] 3. Examination of the proportion of auxiliary materials

[0189] A single-factor design method was used to investigate the proportions of excipients. By adjusting the ratio of microcrystalline cellulose to dextrin and increasing the amount of materials, five formulations were designed, all of which were made into pills in batches of 1600g. The formulations included 725g of sedative water-based alcohol-immersion extract, 75g of Panax notoginseng leaf extract, and a total of 800g of excipients. The screening results are shown in Table 14. The formulation composition was determined by considering the formulation process, yield, pill testing results, and production cost.

[0190] Table 14 Results of the Experiment on the Proportion of Auxiliary Materials

[0191]

[0192] The results showed that the formulation with a microcrystalline cellulose to dextrin ratio of 1:1 to 7 produced pills with moderate softness and good toughness and good pill shape; the formulation with a microcrystalline cellulose to dextrin ratio of 1:1 to 1.7 produced pills with smooth extrusion, moderate softness and good toughness, good pill shape, round and uniform size, and high yield.

[0193] 4. Drug loading capacity study

[0194] A single-factor design method was used to investigate the drug loading. By adjusting the ratio of the sedative water-extract alcohol-immersion paste to excipients, four formulations with drug loadings of 60%, 65%, 70%, and 75% were designed. All formulations were produced in batches of 1600g. The excipients used were microcrystalline cellulose and dextrin in a 1:1 ratio. The screening results are shown in Table 15. The formulation composition was determined by considering the formulation process, yield, pill testing results, and production cost.

[0195] Table 15 Results of the Drug Loading Investigation Experiment

[0196]

[0197] The results showed that the 60% drug loading formulation produced smooth pellets, which were relatively soft, round, and uniform in size; the 65% drug loading formulation produced smooth pellets with moderate hardness, good toughness, good shape, and round, uniform size, achieving the highest forming rate; the 70% drug loading formulation produced smooth pellets with moderate hardness, good toughness, and round, uniform size; and the 75% drug loading formulation produced smooth pellets, which were relatively hard, had poor toughness, and poor roundness and uniformity in size. The dissolution time of all three formulations with drug loading between 60% and 70% met the requirements; therefore, the final drug loading range was determined to be 60%–70%.

Claims

1. A preparation method of a traditional Chinese medicine composition for treating insomnia, which is prepared from the following traditional Chinese medicine raw materials in the following weight ratio: fried Suanzaoren 690-2070 parts, Hehuanhua 414-1242 parts, and Gancao 207-621 parts, and Sanqiy e 170-508 parts, characterized in that, The composition is obtained by combining extracts of roasted jujube seed, mimosa flower, and licorice, as well as an extract of Panax notoginseng leaf, as a pharmacologically active ingredient for treating insomnia. The preparation method of the extracts of roasted jujube seed, mimosa flower, and licorice includes: extracting roasted jujube seed, mimosa flower, and licorice together or separately with water under reflux, filtering, precipitating with alcohol, and concentrating into an extract; or, when extracting separately, mixing the three extracts. The preparation method of the extract of Panax notoginseng leaf includes: taking Panax notoginseng leaves, decocting with water, filtering, passing the filtrate through a macroporous adsorption resin column, and using water... The macroporous adsorption resin column is rinsed, then eluted with 40-60% ethanol. The eluent is collected, concentrated, dried, and pulverized to obtain the final product. The total saponin content of the Panax notoginseng leaf extract is 70%-75%. The traditional Chinese medicine composition is a drop pill. The preparation method of the drop pill includes feeding the roasted jujube seed, albizia flower and licorice extract, Panax notoginseng leaf extract and polyethylene glycol 6000. The feeding method is as follows: the roasted jujube seed, albizia flower and licorice extract and Panax notoginseng leaf extract are mixed at 65-85℃ and then added to polyethylene glycol 6000 and heated to melt.

2. A preparation method of a traditional Chinese medicine composition for treating insomnia, which is prepared from traditional Chinese medicine raw materials in the following weight ratio: fried Suanzaoren 690-2070 parts, Hehuanhua 414-1242 parts, and Gancao 207-621 parts, and Sanqiy e 170-508 parts, characterized in that, The composition is obtained by combining extracts of roasted jujube seed, mimosa flower, and licorice, as well as an extract of Panax notoginseng leaf, as a medicinal active ingredient for treating insomnia. The preparation method of the extracts of roasted jujube seed, mimosa flower, and licorice includes: extracting roasted jujube seed, mimosa flower, and licorice together or separately with water under reflux, filtering, precipitating with alcohol, and concentrating into an extract; or, when extracting separately, mixing the three extracts. The preparation method of the extract of Panax notoginseng leaf includes: taking Panax notoginseng leaves, decocting with water, filtering, and passing the filtrate through a macroporous adsorption resin column. The macroporous adsorption resin column is rinsed with water, then eluted with 40-60% ethanol. The eluent is collected, concentrated, dried, and pulverized to obtain the final product. The total saponin content of the Panax notoginseng leaf extract is 70%-75%. The traditional Chinese medicine composition is a concentrated pill, wherein the roasted jujube seed, Albizia julibrissin flower, and licorice extract, along with the Panax notoginseng leaf extract, account for 60%-70% of the concentrated pill preparation by mass, and the remainder consists of pharmaceutically acceptable excipients, including microcrystalline cellulose and dextrin, with a mass ratio of microcrystalline cellulose to dextrin of 1:1-7.

3. The preparation method of the traditional Chinese medicine composition according to claim 1 or 2, characterized in that, The preparation method of the stir-fried jujube seed, mimosa flower and licorice extract includes, 1) Extraction: Boil the stir-fried jujube seeds, mimosa flowers and licorice in water and reflux to extract the extract, then filter. 2) Concentration: The filtrate is concentrated under reduced pressure to a relative density of 1.05~1.10; 3) First alcohol precipitation: Add ethanol to the concentrate to make the alcohol content reach 50-70%, let it stand, and separate the liquid. 4) First-time ethanol recovery: The drug solution is concentrated to a relative density of 1.10~1.15 to obtain a first-time diluted extract; 5) Secondary alcohol precipitation: Add ethanol to the first diluted extract to make the alcohol content reach 75-85%, let it stand, and separate the liquid. 6) Secondary recovery of ethanol and extraction of extract: The medicinal liquid is concentrated to an extract with a relative density of 1.27~1.35, which yields the stir-fried jujube seed, albizia flower and licorice extract.

4. The preparation method of the traditional Chinese medicine composition according to claim 3, characterized in that, The preparation method of the stir-fried jujube seed, mimosa flower and licorice extract includes, 1) Extraction: Stir-fry jujube seeds, mimosa flowers, and licorice root with 8-12 times the amount of water, decoct and reflux to extract, then filter; 2) Concentration: The filtrate is concentrated under reduced pressure to a relative density of 1.05~1.10; 3) First alcohol precipitation: Add 90-99% ethanol to the concentrate to make the alcohol content reach 59-61%, let it stand for more than 12 hours, and then separate the liquid. 4) First-time ethanol recovery: The drug solution is concentrated to a relative density of 1.10~1.15 to obtain a first-time diluted extract; 5) Secondary alcohol precipitation: Add 90-99% ethanol to the first diluted extract to make the alcohol content reach 79-81%, let it stand for more than 12 hours, and then separate the liquid. 6) Secondary ethanol recovery and extract collection: The medicinal liquid is concentrated to an extract with a relative density of 1.27~1.35, which yields the stir-fried jujube seed, albizia flower and licorice extract, for later use; wherein, in the first alcohol precipitation step, the separation of medicinal liquid is performed by centrifugation or filtration equipment to separate the precipitate into solid and liquid.

5. The preparation method of the traditional Chinese medicine composition according to claim 4, characterized in that, In the preparation method of the stir-fried jujube seed, albizia flower and licorice extract, the stir-fried jujube seed, albizia flower and licorice are extracted twice by reflux with 10 times the amount of water of the medicinal materials.

6. The preparation method of the traditional Chinese medicine composition according to claim 1 or 2, characterized in that, In the preparation method of the Panax notoginseng leaf extract, the step of adding water for decoction is to add 10 to 14 times the amount of the medicinal material for decoction.

7. The preparation method of the traditional Chinese medicine composition according to claim 6, characterized in that, In the preparation method of the Panax notoginseng leaf extract, the step of adding water for decoction is to add 12 times the amount of water as the medicinal material.

8. The preparation method of the traditional Chinese medicine composition according to claim 1 or 2, characterized in that, In the preparation method of the Panax notoginseng leaf extract, the macroporous adsorption resin column diameter-to-height ratio ranges from 1:3 to 1:

6.

9. The preparation method of the traditional Chinese medicine composition according to claim 8, characterized in that, In the preparation method of the Panax notoginseng leaf extract, a macroporous adsorption resin column is eluted with 40-60% ethanol.

10. The method for preparing the traditional Chinese medicine composition according to claim 9, characterized in that, In the preparation method of the Panax notoginseng leaf extract, the macroporous adsorption resin column is eluted with 49%-51% ethanol, and the eluent is collected in an amount of 8-11 times that of the medicinal material.

11. The method for preparing the traditional Chinese medicine composition according to claim 8, wherein in the method for preparing the Panax notoginseng leaf extract, the filtrate is passed through a macroporous adsorption resin column, wherein the mass ratio of Panax notoginseng leaf to resin is 1:1 to 1:1.

5.

12. The droplet preparation obtained by the preparation method of the traditional Chinese medicine composition for treating insomnia according to claim 1.

13. The concentrated pill preparation obtained by the preparation method of the traditional Chinese medicine composition for treating insomnia according to claim 2.

14. The use of the preparation according to claim 12 or 13 in the preparation of a medicine that nourishes blood, soothes the liver, relieves irritability, invigorates qi, calms the mind, and soothes the nerves.

15. The use of the formulation according to claim 12 or 13 in the preparation of a medicament for treating insomnia.

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