Blood-glucose-reducing compound granules and preparation method thereof

Abstract

The invention belongs to the technical field of traditional Chinese medicine preparation, and particularly relates to blood glucose reducing compound granules and a preparation method thereof. In the early stage of the method, a moistening and ultrasonic combined technology is adopted to lay a foundation for subsequent extraction; meanwhile, most traditional Chinese medicines are extracted in groups to improve the extraction efficiency. Especially, the cortex lycii radicis and the radix trichosanthis are matched and extracted, starch in the radix trichosanthis is acidified by acid cellulase, and the starch is mixed with the cortex lycii radicis extract, so that the prepared hypoglycemic compound granules are better to store. In addition, the radix puerariae and the schisandra chinensis are matched and subjected to ultrasonic moistening and alcohol extraction twice, the astragalus membranaceus, the rhizoma anemarrhenae, the Chinese yam and the endothelium corneum gigeriae galli are matched and subjected to ultrasonic moistening and water extraction twice, and the yield is increased. The preparation method disclosed by the invention is simple, efficient, high in quality and high in yield, and the obtained hypoglycemic compound granules are high in yield, rich in active ingredients and easy to store, have the effects of tonifying qi and yin, and promoting the production of body fluid to quench thirst, and can be used for patients with deficiency of both qi and yin in non-insulin dependent diabetes mellitus.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicine preparation, and particularly relates to a hypoglycemic compound granule and a preparation method thereof. Background Art

[0002] Diabetes is a common endocrine system disease. Its causes can be divided into congenital and acquired. Congenital factors are genetic factors, which determine the susceptibility to diabetes. Acquired factors are environmental factors after birth and immune mechanism disorders.

[0003] Diabetes is divided into type I and type II. Type I is caused by the destruction of pancreatic p cells, the reduction of β cell granules, and the dysfunction of pancreatic secretion, which leads to insulin-dependent diabetes. Type II diabetes is caused by insulin resistance and insufficient insulin action, and is non-insulin-dependent diabetes.

[0004] At present, there are two types of drugs for the treatment of diabetes at home and abroad: traditional Chinese medicine and western medicine. Western medicine has better blood sugar lowering effect and lowers blood sugar faster, but has serious side effects when used for a long time. For example, chlorsulfuronamide has serious toxic side effects and improper use can easily cause hypoglycemia. Pure traditional Chinese medicine treatment of diabetes adopts the principle of syndrome differentiation and treatment. Traditional Chinese medicine compound preparations can not only control symptoms, but also prevent and treat various complications. They have stable efficacy, few toxic side effects, and treat both the symptoms and the root cause, but they are slow to take effect.

[0005] The combination of Chinese and Western medicine can not only achieve rapid and precise effects, but also achieve sustained and stable blood sugar reduction, and has significant effects in treating diabetes and its various chronic complications. However, in the existing preparation process, the active ingredients and quality of the medicine are not easy to control, and the yield of the drug product is low.

[0006] In view of this, the present invention is proposed. Summary of the invention

[0007] In view of the deficiencies in the prior art, the present invention aims to provide a hypoglycemic compound granule and a preparation method thereof, so as to solve the problems that the effective ingredients and quality of the drug are difficult to control during the preparation process and the drug yield is low.

[0008] To achieve the above objectives, the technical solution provided by the present invention is as follows:

[0009] In a first aspect, a method for preparing hypoglycemic compound granules comprises the following steps:

[0010] S1, ultrasonically moistening Puerariae Radix and Schisandrae Chinensis Fructus in ethanol, gradually heating to boiling, firstly extracting with alcohol, filtering, and concentrating, removing impurities from the alcohol-extracted residue, mixing with the concentrated product, and ultrasonically moistening in ethanol again, gradually heating to boiling again, and then extracting with alcohol again, filtering, and concentrating to obtain an alcohol-extracted extract;

[0011] S2, ultrasonically moistening the Radix Astragali, Rhizoma Anemarrhenae, Rhizoma Dioscoreae and Endothelium Galli in water, and gradually heating the temperature to boiling, then water extracting, filtering and concentrating for the first time, removing impurities from the water-extracted residue, mixing with the concentrated product and ultrasonically moistening the residue in water again, and then gradually heating the temperature to boiling, then water extracting, filtering and concentrating again to obtain a water-extracted extract;

[0012] S3, ultrasonically moistening the root bark of Lycium bark and Radix Trichosanthis in water-ethanol, gradually heating to boiling, initially extracting, filtering, and concentrating, removing impurities from the initial extraction residue and mixing with the concentrated product and ultrasonically moistening again in water-ethanol, adding acid cellulase for enzymolysis, and gradually heating to boiling again, re-extracting, filtering, and concentrating to obtain a modified extract;

[0013] S4, mixing the alcohol extract, the water extract and the modified extract and continuing to concentrate to obtain a thick paste;

[0014] S5, crushing the ginseng into fine powder and mixing it with the thick paste, drying, and crushing to obtain a dry paste powder;

[0015] S6. Grind glibenclamide into fine powder, mix with dry paste powder, add appropriate amount of dextrin, mix well, wet granulate, and dry to obtain hypoglycemic compound granules.

[0016] Furthermore, in step S1 or S2, the amount of ethanol or water used is 8 to 10 times the mass of the raw material drug; and / or, the time for the initial alcohol extraction or the initial water extraction is 0.5 to 2 hours; and / or, the time for the secondary alcohol extraction or the secondary water extraction is 0.5 to 2 hours.

[0017] Furthermore, in step S2, the boiling temperature is 97-100°C.

[0018] Further, in step S1 or S2 or S3, the frequency of the ultrasound is 35 to 45 kHz; and / or the mesh size for filtration is 80 to 120 meshes; and / or the time for ultrasonic moistening or gradual heating is 60 to 90 minutes; and / or the time for ultrasonic moistening again or gradual heating again is 40 to 80 minutes.

[0019] In the above technical solution, in step S1 or S2, the time of two ultrasonic moistening and heating is controlled within the above range, which can ensure both the preparation efficiency and the preparation effect, especially the extraction amount of puerarin can reach more than 2.5%.

[0020] Further, in step S3, the mass proportion of ethanol in the water-ethanol is 15-25%;

[0021] And / or, the amount of water-ethanol is 9 to 12 times the mass of the raw material drug;

[0022] And / or, the time of the initial extraction or the re-extraction is 0.5 to 1.5 hours;

[0023] And / or, the acid cellulase is produced by fermentation of green trichoderma strains;

[0024] And / or, the amount of the acid cellulase is 0.1-1% of the mass of the raw material drug;

[0025] And / or, the temperature of the enzymatic hydrolysis is 50-55°C;

[0026] And / or, the enzymatic hydrolysis time is 15 to 30 minutes.

[0027] Further, in step S4, the concentrated pressure is 0.1-0.2 MPa, the temperature is 60-80°C, the vacuum degree is -0.06--0.08 MPa, and the relative density is 1.35-1.38 g / cm when concentrated to 60°C. 3 .

[0028] Further, in step S5, the drying is low-temperature reduced-pressure drying, the vacuum degree is -0.06 to -0.08 MPa, the temperature is 55 to 60°C, and the time is 18 to 24 hours;

[0029] And / or, the particle size of the crushed product is less than 100 mesh.

[0030] Further, the alcohol extract: 36%≤yield limit≤42%;

[0031] And / or, the water extract: 33%≤yield limit≤37%;

[0032] and / or, the modified extract: 44%≤yield limit≤52%;

[0033] And / or, the thick paste: 38%≤yield limit≤45%;

[0034] And / or, the dry paste powder: 65%≤yield limit≤73%;

[0035] And / or, the glucose-lowering compound granules: 98%≤yield limit≤100%.

[0036] Furthermore, the raw materials used in the hypoglycemic compound granules include the following in mass parts:

[0037]

[0038]

[0039] In a second aspect, a hypoglycemic compound granule prepared by the preparation method described in the first aspect.

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] In the preparation method of the present invention, the steaming technology in the traditional Chinese medicine processing method is combined with modern ultrasound, so that the solvent gradually penetrates into the inside of the medicinal material tissue to swell the cells and even break the cell wall without losing or less losing the effective ingredients of the medicine, thereby improving the quality of subsequent treatment. The temperature is gradually increased during the ultrasonic steaming process, which can not only reach the temperature required for alcohol extraction / water extraction, but also gradually heat the medicinal material cells. While the cells absorb liquid and swell, they are more likely to break the wall when heated and pressurized, greatly shortening the extraction time, while improving the extraction quality such as more thorough impurity removal and more sufficient effective ingredient extraction. In the present invention, each ultrasonic process starts from steaming to boiling, and under the condition of ultrasound assistance, it can not only improve the material exchange speed inside and outside the cell, such as the speed of liquid entering the cell and the speed of effective ingredients in the cell escaping the cell, but also improve the separation speed of the material, such as accelerating the transfer of effective ingredients and the removal of impurities.

[0042] The hypoglycemic compound granules of the present invention have more Chinese medicinal ingredients, including nine Chinese medicinal herbs, including kudzu root, schisandra chinensis, astragalus, rhizoma anemarrhenae, yam, endothelium chicken, radix trichosanthis, cortex lycii and ginseng. In the preparation process, by extracting most of the Chinese medicinal herbs in groups, the extraction efficiency can be greatly improved. In particular, the cortex lycii and cortex trichosanthis are extracted in groups, which not only improves the extraction efficiency, but also utilizes the starch rich in the cortex trichosanthis to acidify and mix the cortex lycii extract with acid cellulose, and the hypoglycemic compound granules prepared have better storage performance and are not easy to be oxidized and damp. In addition to promoting the acidification of starch, the use of acid cellulose also further promotes the extraction of effective ingredients in the cortex lycii, and the acid cellulose can be inactivated by heating to the boiling temperature in the later stage, and the whole process is simple without additional operating steps. Since the cortex lycii contains flavonoids, organic acids, alkaloids, etc., and the cortex trichosanthis contains a large amount of starch and saponins, etc., most of the components of the two are water-soluble, so a water-ethanol solvent with more water and less alcohol is used for extraction, and the presence of a small amount of ethanol can further cause a concentration difference to improve the extraction efficiency. In addition, the main components of Pueraria lobata include pueraria flavonoids and puerarin. Pueraria flavonoids have the effects of lowering blood sugar and blood lipids, and can significantly repair the damage of vascular endothelial cells caused by glycation end products; puerarin can improve insulin sensitivity, reduce insulin resistance and remove free radicals in the body, thereby playing a role in lowering blood sugar, and can also dilate peripheral blood vessels, thereby improving lesions such as retinopathy caused by diabetic microangiopathy. However, the extraction rate of puerarin by various extraction methods is not high at present, such as conventional water boiling method and solvent leaching method may not be higher than 1.5%. The main component of Schisandra chinensis, lignans such as Schisandrin A, is a fat-soluble compound, which has the effects of protecting the liver and lowering blood sugar. The method of the present invention classifies the two into one group, performs two ultrasonic moistening, alcohol extraction, filtration and concentration, so that the extraction amount of puerarin can reach more than 2.5%. Astragalus contains saponins, sucrose, polysaccharides, and various amino acids; Anemarrhena asphodeloides contains anemarrhena glycosides, flavonoids, a large amount of mucus, carbohydrates, etc.; Chinese yam contains protein, vitamins, amino acids, as well as various trace elements and a certain amount of starch, saponins, mucus and choline; the three are combined with chicken gizzard lining, ultrasonically moistened twice, extracted with water, filtered and concentrated to obtain the extract.

[0043] The preparation method of the invention is not only simple and efficient but also high in quality and quantity. The obtained hypoglycemic compound granules have high yield, are enriched in effective ingredients, are easy to store, have the effects of invigorating qi and nourishing yin, promoting body fluid and quenching thirst, and can be used for patients with qi and yin deficiency syndrome in non-insulin-dependent diabetes (manifested as fatigue, spontaneous sweating and night sweats, shortness of breath and laziness to speak, thirst and love of drinking, fever in the five parts of the body, palpitations and insomnia, red urine and constipation, red tongue with little body fluid, enlarged tongue, thin or peeled tongue coating, and stringy or fine pulse). BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 The present invention is a process flow chart of the method for preparing the hypoglycemic compound granules. DETAILED DESCRIPTION

[0045] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. The embodiments of the present invention are implemented on the premise of the technical solution of the present invention, and detailed implementation methods and processes are given, but the protection scope of the present invention is not limited to the following embodiments. Those skilled in the art should understand that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0046] The endpoints and any values ​​of the ranges disclosed in the present invention are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be regarded as specifically disclosed in the present invention.

[0047] In the present invention, unless otherwise specified and / or described, all values ​​involving content are "weight parts or weight percentages" from beginning to end. The process parameters of the following examples without specific conditions are usually based on conventional conditions. The raw materials described in the following examples can all be obtained from public commercial channels.

[0048] According to a first aspect of the present invention, a method for preparing hypoglycemic compound granules comprises the following steps:

[0049] S1, ultrasonically moistening Puerariae Radix and Schisandrae Chinensis Fructus in ethanol, gradually heating to boiling, firstly extracting with alcohol, filtering, and concentrating, removing impurities from the alcohol-extracted residue, mixing with the concentrated product, and ultrasonically moistening in ethanol again, gradually heating to boiling again, and then extracting with alcohol again, filtering, and concentrating to obtain an alcohol-extracted extract;

[0050] S2, ultrasonically moistening the Radix Astragali, Rhizoma Anemarrhenae, Rhizoma Dioscoreae and Endothelium Galli in water, and gradually heating the temperature to boiling, then water extracting, filtering and concentrating for the first time, removing impurities from the water-extracted residue, mixing with the concentrated product and ultrasonically moistening the residue in water again, and then gradually heating the temperature to boiling, then water extracting, filtering and concentrating again to obtain a water-extracted extract;

[0051] S3, ultrasonically moistening the root bark of Lycium bark and Radix Trichosanthis in water-ethanol, gradually heating to boiling, initially extracting, filtering, and concentrating, removing impurities from the initial extraction residue and mixing with the concentrated product and ultrasonically moistening again in water-ethanol, adding acid cellulase for enzymolysis, and gradually heating to boiling again, re-extracting, filtering, and concentrating to obtain a modified extract;

[0052] S4, mixing the alcohol extract, the water extract and the modified extract and continuing to concentrate to obtain a thick paste;

[0053] S5, crushing the ginseng into fine powder and mixing it with the thick paste, drying, and crushing to obtain a dry paste powder;

[0054] S6. Grind glibenclamide into fine powder, mix with dry paste powder, add appropriate amount of dextrin, mix well, wet granulate, and dry to obtain hypoglycemic compound granules.

[0055] The method of the present invention adopts a technology combining moistening and ultrasound in the early stage to lay the foundation for subsequent extraction; at the same time, most of the Chinese medicines are extracted in groups to improve the extraction efficiency. In particular, the root bark of Lycium bark and Radix Trichosanthis are extracted in groups, and the starch in the Radix Trichosanthis is acidified by acid cellulase and mixed with the root bark extract to prepare the hypoglycemic compound granules for better storage. In addition, Pueraria lobata and Schisandra chinensis are grouped and ultrasonic moistening and alcohol extraction are performed twice to increase the extraction amount of puerarin; Astragalus membranaceus, Rhizoma Anemarrhenae, Chinese Yam and Gallus gallus endothelium are grouped and ultrasonic moistening and water extraction are performed twice. The preparation method of the present invention is not only simple and efficient but also high in quality and quantity. The obtained hypoglycemic compound granules have a high yield, are enriched in effective ingredients, are easy to store, have the effects of invigorating qi and nourishing yin, promoting body fluid and quenching thirst, and can be used for patients with qi and yin deficiency in non-insulin-dependent diabetes.

[0056] In addition, the preparation method of the present invention can reduce product loss in the process and improve the product yield limit. Specifically, one or more quality controls can be performed according to the following table:

[0057]

[0058] As an optional embodiment of the preparation method of the present invention, in step S1 or S2, the amount of ethanol or water is 8 to 10 times (such as 8.1 times, 8.3 times, 8.5 times, 8.7 times, 8.9 times, 9.1 times, 9.3 times, 9.5 times, 9.7 times, 9.9 times) the mass of the raw material drug;

[0059] And / or, the time of the initial alcohol extraction or the initial water extraction is 0.5 to 2 h (e.g., 0.6 h, 0.8 h, 1.0 h, 1.2 h, 1.4 h, 1.6 h, 1.8 h);

[0060] And / or, the time for the second alcohol extraction or the second water extraction is 0.5 to 2 h (such as 0.6 h, 0.8 h, 1.0 h, 1.2 h, 1.4 h, 1.6 h, 1.8 h).

[0061] As an optional implementation of the preparation method of the present invention, in step S2, the boiling temperature is 97-100°C (such as 97.5°C, 98°C, 98.5°C, 99°C, 99.5°C).

[0062] As an optional embodiment of the preparation method of the present invention, in step S1 or S2 or S3, the frequency of the ultrasound is 35 to 45 kHz (such as 36 kHz, 38 kHz, 40 kHz, 42 kHz, 44 kHz);

[0063] And / or, the mesh number for filtering is 80-120 mesh (such as 85 mesh, 90 mesh, 95 mesh, 100 mesh, 105 mesh, 110 mesh, 115 mesh);

[0064] And / or, the ultrasonic moistening or gradual heating time is 60 to 90 minutes (such as 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes);

[0065] And / or, the time for the second ultrasonic moistening or the second gradual heating is 40 to 80 minutes (such as 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes).

[0066] In the preparation method of the present invention, the extraction quality and efficiency are ensured by controlling the ultrasonic moistening frequency, time and / or the solvent amount, time and number of times during reflux alcohol extraction / water extraction. The alcohol extract obtained in step S1: 36%≤yield limit≤42%, the water extract obtained in step S2: 33%≤yield limit≤37%, yield=extract output / input medicinal material amount×100%.

[0067] As an optional embodiment of the preparation method of the present invention, in step S3, the mass proportion of ethanol in the water-ethanol is 15-25% (such as 16%, 18%, 20%, 22%, 24%);

[0068] And / or, the amount of water-ethanol is 9 to 12 times (e.g., 9.3 times, 9.5 times, 9.7 times, 10 times, 10.3 times, 10.5 times, 10.7 times, 11 times, 11.3 times, 11.5 times, 11.7 times) the mass of the raw material drug;

[0069] And / or, the time of the initial extraction or the re-extraction is 0.5 to 1.5 h (e.g., 0.6 h, 0.8 h, 1.0 h, 1.2 h, 1.4 h);

[0070] And / or, the acid cellulase is produced by fermentation of green trichoderma strains;

[0071] And / or, the amount of the acid cellulase is 0.1-1% (such as 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%) of the mass of the raw material drug;

[0072] and / or, the temperature of the enzymatic hydrolysis is 50-55° C. (e.g., 51° C., 52° C., 53° C., 54° C.);

[0073] And / or, the enzymatic hydrolysis time is 15 to 30 min (e.g., 16 min, 18 min, 20 min, 22 min, 24 min, 26 min, 28 min).

[0074] In the preparation method of the present invention, on the basis of ultrasonic moistening and reflux extraction, the output of the extract is further increased by enzymatic hydrolysis and controlling the enzymatic hydrolysis time, temperature and enzyme addition amount, and the starch in Radix Trichosanthis is acidified by utilizing the acidity of cellulase to promote its conversion into cyclodextrin, and then other extracts, especially the Cortex Lycii Extract, are mixed for coating and modification to increase its antioxidant and deliquescence resistance. The final modified extract is: 44%≤yield limit≤52%, and yield=extract output / amount of medicinal materials input×100%.

[0075] As an optional embodiment of the preparation method of the present invention, in step S4, the concentrated pressure is 0.1-0.2 MPa, the temperature is 60-80°C, the vacuum degree is -0.06--0.08 MPa, and the relative density is 1.35-1.38 g / cm2 when concentrated to 60°C. 3 . The concentration pressure can be typically but not limitedly selected as 0.11MPa, 0.13MPa, 0.15MPa, 0.17MPa, 0.19MPa, the concentration temperature can be typically but not limitedly selected as 61°C, 63°C, 65°C, 67°C, 69°C, 71°C, 73°C, 75°C, 77°C, 79°C, and the vacuum degree can be typically but not limitedly selected as -0.065MPa, -0.07MPa, -0.075MPa.

[0076] In the preparation method of the present invention, by controlling the concentration pressure, and / or the concentration temperature, and / or the concentration vacuum degree, and / or the concentration density, the obtained thick paste is: 38%≤yield limit≤45%, and the yield=thick paste output / the amount of medicinal materials input×100%.

[0077] As an optional embodiment of the preparation method of the present invention, in step S5, the drying is low-temperature reduced-pressure drying, the vacuum degree is -0.06 to -0.08 MPa, the temperature is 55 to 60° C., and the time is 18 to 24 hours;

[0078] And / or, the particle size of the crushed product is less than 100 mesh.

[0079] In the above technical scheme, the drying vacuum degree can be typically but not limitedly selected as -0.065MPa, -0.07MPa, -0.075MPa, the drying temperature can be typically but not limitedly selected as 56°C, 57°C, 58°C, 59°C, and the drying time can be typically but not limitedly selected as 19h, 20h, 21h, 22h, 23h.

[0080] In the preparation method of the present invention, by controlling the drying vacuum degree, and / or the drying temperature, and / or the drying time, and / or the grinding fineness, the obtained dry paste powder is: 65%≤yield limit≤73%, and the dry paste powder yield=dry paste powder weight / (extract weight+powder weight)×100%.

[0081] As an optional implementation of the preparation method of the present invention, the raw materials used in the hypoglycemic compound granules include the following parts by weight:

[0082]

[0083] In the present invention, there is no particular limitation on the equipment used in the preparation process, and any equipment with relevant functions in the prior art can be used, such as: XG1.D pulsating vacuum sterilizer, ZZKF-3-600 pulverizer group, FZ-400B Shibata pulverizer, LF-3 pulverizer group, HDWN-5000 hot reflux extraction unit, ZWXJ-1500 single-effect vacuum concentrator, CH-400 single-paddle tank mixer, CH-400 tank mixer, ZD-20 low-temperature vacuum drying oven, FZD-30 vacuum dryer, FZD-20 low-temperature vacuum drying oven, WF-30B universal pulverizer, F-60B universal pulverizer, F-50B universal pulverizer, HR-2000 two-dimensional mixer; and so on, no longer exemplified one by one.

[0084] According to a second aspect of the present invention, a hypoglycemic compound granule is prepared by the preparation method described in the first aspect.

[0085] The present invention will be further described in detail below with reference to specific embodiments and comparative examples.

[0086] The Chinese medicinal raw materials used in the following examples and comparative examples all comply with the description of the corresponding medicinal materials in the 2020 edition of the "Chinese Pharmacopoeia", especially the medicinal parts and the content of the effective ingredients. At the same time, they are all collected and prepared in accordance with the 2020 edition of the "Chinese Pharmacopoeia".

[0087] Determination of puerarin content: Determine according to high performance liquid chromatography (General Rule 0512), where the chromatographic conditions use octadecylsilane bonded silica gel as filler; 0.1% citric acid solution-methanol (75:25) as mobile phase; detection wavelength is 250nm; injection volume is 10μl. Reference solution: Take an appropriate amount of puerarin reference, accurately weigh it, add mobile phase to dissolve and quantitatively dilute it to make a solution containing 50μg per 1ml. Test solution: Take an appropriate amount of alcohol extract, accurately weigh it, add mobile phase to dissolve and quantitatively dilute it to make a solution containing 50μg per 1ml. Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate by peak area according to the external standard method.

[0088] Example 1

[0089] A hypoglycemic compound granule, the raw materials used include the following by weight:

[0090]

[0091] The manufacturing process is as follows Figure 1 As shown, Figure 1 The area where the preparation process is located in the shaded part needs to be controlled as a Class D clean area, with an ambient temperature of 18-30°C and a relative humidity of 45-65%. All Chinese medicinal materials are sterilized in an XG1.D pulsating vacuum sterilizer before preparation. The sterilization temperature is 115°C and the sterilization time is 30 minutes. After sterilization, they are crushed to a particle size of less than 100 mesh, and then granules are prepared. The specific preparation includes the following steps:

[0092] S1. Ultrasonic moisten Puerariae Radix and Schisandrae Chinensis Fructus in 75% ethanol, 10 times the amount of the original medicinal materials, and gradually increase the temperature at an ultrasonic frequency of 40 kHz for 60 to 90 min. After heating to boiling, put them into the HDWN-5000 hot reflux extraction unit for primary alcohol extraction for 1.5 h. Filter the extract through a double filter (100 mesh), put it into a storage tank, and concentrate it. The alcohol-extracted residue is removed from impurities and mixed with the concentrated product and ultrasonically moistened again in 75% ethanol, which is 8 times the amount of the original medicinal material. The temperature is gradually increased again, the ultrasonic frequency is 40 kHz, the heating time is 40 to 80 minutes, and after the temperature is increased to boiling, the alcohol extraction is performed again for 1.5 hours. The extract is filtered through a double filter (100 mesh), poured into a storage tank, and concentrated to obtain an alcohol-extracted extract, with a yield limit of 36%≤≤42%, where the yield = extract output / amount of medicinal material input×100%; the extraction amount of puerarin can reach 3.2%.

[0093] S2, ultrasonically moisten Astragalus, Rhizoma Anemarrhenae, Rhizoma Dioscoreae and Endothelium Gallifoliae in 10 times the amount of water of the original medicinal materials, and gradually heat up, the ultrasonic frequency is 40kHz, and the heating time is 60-90min; after heating to boiling, put it into the HDWN-5000 hot reflux extraction unit for initial water extraction, the boiling temperature is 97-100°C, and the time is 1h. The extract is filtered through a double filter (100 mesh), poured into a storage tank, and concentrated. After the water-extracted slag is removed from impurities, it is mixed with the concentrated product and ultrasonically moistened again in 8 times the amount of water of the original medicinal materials, and gradually heated again, the ultrasonic frequency is 40kHz, and the heating time is 40-80min. After heating to boiling, it is extracted again, the time is 1h, and the extract is filtered through a double filter (100 mesh), poured into a storage tank, and concentrated to obtain a water-extracted extract, 33%≤yield limit≤37%, yield=extract output / input medicinal material amount×100%.

[0094] S3, ultrasonically moistening the Cortex Lycii and Radix Trichosanthis in 11 times the amount of water-ethanol (ethanol 17wt%) of the original medicinal materials, and gradually heating up, the ultrasonic frequency is 40kHz, and the heating time is 60-90min; after heating to boiling, put it into the HDWN-5000 hot reflux extraction unit for initial extraction, the time is 1h; the initial extraction residue is removed and mixed with the concentrated product and ultrasonically moistened again in 11 times the amount of water-ethanol (ethanol 17wt%) of the original medicinal materials, the ultrasonic frequency is 40kHz, and the raw material is added 0.5% acidic cellulase (made by fermentation of green wood enzyme strains, purchased from Xijie Youtel (Shandong) Biotechnology Co., Ltd.) was used for enzymolysis at a temperature of 52.4°C for 30 min; after enzymolysis, the temperature was gradually raised to boiling again for re-extraction for 0.5 h, the extract was filtered through a double filter (100 mesh), poured into a storage tank, and concentrated to obtain a modified extract, with a yield limit of 48%≤≤52%, and yield = extract output / amount of medicinal materials input×100%.

[0095] S4. The alcohol extract, water extract and modified extract are gradually pumped into the same concentrator for further concentration. The pressure is controlled at 0.1-0.2 MPa, the concentration temperature is controlled at 60-80°C, and the vacuum degree is controlled at -0.06--0.08 MPa to obtain a thick paste. The yield limit is 38%≤≤45%, and the yield = thick paste output / amount of medicinal materials input × 100%; the relative density is 1.35-1.38 g / cm 3 (60℃).

[0096] S5. Grind the ginseng into fine powder below 100 mesh and mix it with the thick paste in a CH-400 tank mixer. After mixing for 20 minutes, transfer it to a low-temperature vacuum drying oven or vacuum dryer with a vacuum degree of -0.06 to -0.08 MPa and a temperature of 55 to 60°C for low-temperature reduced-pressure drying for 18 to 24 hours. Dry until the material is dry and has no wet core. Cool the material to obtain a dry paste. Put the dry paste into a grinder for grinding, pass through a 100-mesh sieve, and obtain a dry paste powder. The yield limit is 65% ≤ ≤ 73%. The yield of dry paste powder = dry paste powder weight / (extract weight + powder weight) × 100%.

[0097] S6. Glyburide is crushed into fine powder and then mixed with dry paste powder for 10 minutes to fully mix the two powders until there are no small lumps and no white spots. Note that the powder cannot be scattered outside the mortar; a 100-mesh nylon screen is fixed on a stainless steel barrel, and the above powder is sieved in batches. If it cannot pass through the screen, it is transferred to the mortar with a stainless steel scoop. When the amount is small, a small mortar is used. Grind and sieve repeatedly until all pass through the screen. Collect all the powders in the mortar and put them into the HR-2000 two-dimensional mixer together with dextrin. Mix for 40 minutes to obtain powder. Finally, put the powder into the CH-400 tank mixer for stirring, and add ethanol solution while stirring for wet mixing for 20 minutes. The soft material should be well formed. Select a 14-mesh screen and install it on the swing granulator. After starting the swing granulator, pour the soft material into the granulator and start granulation. The wet granules are required to be well formed. Finally, the air inlet temperature is set at 70-80°C as required, and the prepared wet granules are promptly poured into the XF-30B boiling dryer for drying for 20-40 minutes, and passed through a 12-mesh sieve to obtain the hypoglycemic compound granules, with a yield limit of 98%≤≤100%, where yield = granule weight / powder weight×100%.

[0098] Example 2

[0099] The only difference from Example 1 is as follows:

[0100] The ultrasonic frequency in S1 is 44 kHz, and the other settings are the same as those in Example 1. The puerarin extraction amount of the obtained alcohol extract can reach 2.8%.

[0101] Example 3

[0102] The only difference from Example 1 is as follows:

[0103] The ultrasonic frequency in S1 is 35 kHz, and the other settings are the same as those in Example 1. The puerarin extraction amount of the obtained alcohol extract can reach 2.5%.

[0104] Example 4

[0105] The only difference from Example 1 is as follows:

[0106] S3. Add 0.1% of the mass of the raw material drug acid cellulase (made by fermentation of green trichoderma strains, purchased from Xijie Youtel (Shandong) Biotechnology Co., Ltd.) for enzymolysis to obtain a modified extract: 44%≤yield limit≤46%, yield=extract output / amount of medicinal materials input×100%.

[0107] Example 5

[0108] The only difference from Example 1 is as follows:

[0109] S3. Add 1% of the mass of the raw material drug, acid cellulase (made by fermentation of green trichoderma, purchased from Xijie Youtel (Shandong) Biotechnology Co., Ltd.) for enzymolysis to obtain a modified extract: 47% ≤ yield limit ≤ 50%, yield = extract output / amount of medicinal materials input × 100%.

[0110] Example 6

[0111] The only difference from Example 1 is as follows:

[0112] S3. The enzymatic hydrolysis temperature is 50°C, and the obtained modified extract is: 45%≤yield limit≤46%, yield=extract output / input medicinal material amount×100%.

[0113] Example 7

[0114] The only difference from Example 1 is as follows:

[0115] S3. The enzymatic hydrolysis temperature is 54°C, and the obtained modified extract is: 47%≤yield limit≤51%, yield=extract output / input medicinal material amount×100%.

[0116] Comparative Example 1

[0117] The only difference from Example 1 is as follows:

[0118] The ultrasonic frequency in S1 is 32 kHz, and the other settings are the same as those in Example 1. The puerarin extraction amount of the obtained alcohol extract can reach 2.1%.

[0119] Comparative Example 2

[0120] The only difference from Example 1 is as follows:

[0121] The ultrasonic frequency in S1 is 48 kHz, and the other settings are the same as those in Example 1. The puerarin extraction amount of the obtained alcohol extract can reach 2.3%.

[0122] Comparative Example 3

[0123] The only difference from Example 1 is as follows:

[0124] S3. Add 0.08% of the mass of the raw material drug acid cellulase (produced by fermentation of green trichoderma strains, purchased from Xijie Youtel (Shandong) Biotechnology Co., Ltd.) for enzymolysis to obtain a modified extract: the yield limit is ≤43%, and the yield = extract output / the amount of medicinal materials input × 100%.

[0125] Comparative Example 4

[0126] The only difference from Example 1 is as follows:

[0127] S3. Add 1.2% of the mass of the raw material drug acid cellulase (made by fermentation of green trichoderma strains, purchased from Xijie Youtel (Shandong) Biotechnology Co., Ltd.) for enzymolysis to obtain a modified extract: the yield limit is ≤45%, and the yield = extract output / the amount of medicinal materials input × 100%.

[0128] Comparative Example 5

[0129] The only difference from Example 1 is as follows:

[0130] S3. The enzymatic hydrolysis temperature is 48°C, and the obtained modified extract has a yield limit of ≤41%, and the yield = extract output / amount of medicinal materials input × 100%.

[0131] Comparative Example 6

[0132] The only difference from Example 1 is as follows:

[0133] S3. The enzymatic hydrolysis temperature is 57°C, and the obtained modified extract has a yield limit of ≤38%, and the yield = extract output / amount of medicinal materials input × 100%.

[0134] Comparative Example 7

[0135] The only difference from Example 1 is as follows:

[0136] S3, extracting the Cortex Lycii and Radix Trichosanthis separately, and the rest of the settings are the same as those in Example 1.

[0137] Test Example 1

[0138] The storage performance test of the hypoglycemic compound granules obtained in Examples 1-7 and Comparative Examples 1-7 was performed:

[0139] (1) Determination of the antioxidant activity of the hypoglycemic compound granules: The DPPH method was used to prepare a 0.1 mmol / L DPPH methanol solution; 0.01 g of hypoglycemic compound granules and 2 mL of DPPH methanol solution were allowed to react at 25°C in the dark for 30 min, and the supernatant was aspirated to obtain a test sample. An equal amount of methanol was used to replace the hypoglycemic compound granules as a blank sample, and the absorbance was measured at 515 nm for the test sample A1 and the blank sample A0. The DPPH clearance rate was calculated according to (A0-A1) / A0×100%. Three parallel samples were set up in parallel for each test, and the absorbance was averaged.

[0140] Determination of moisture-proof performance of hypoglycemic compound granules: 10 g of hypoglycemic compound granules were exposed to air with humidity of 25% and 75%. After 48 hours, the weight B was measured and the moisture absorption rate was calculated according to the formula (B-10) / 10×100%.

[0141] The test results are shown in Table 1:

[0142] project DPPH·Scavenging rate (%) 25% humidity moisture absorption rate (%) 75% humidity moisture absorption rate (%) Example 1 75.1 1.08 8.38 Example 2 71.8 1.03 7.86 Example 3 65.5 0.96 7.28 Example 4 67.8 0.96 7.60 Example 5 69.2 1.03 8.22 Example 6 70.2 0.98 7.67 Example 7 71.9 1.06 8.22 Comparative Example 1 60.6 1.07 8.09 Comparative Example 2 64.8 1.00 7.52 Comparative Example 3 64.2 0.91 7.26 Comparative Example 4 64.7 0.95 7.52 Comparative Example 5 61.4 0.88 6.86 Comparative Example 6 58.7 0.81 6.29 Comparative Example 7 46.8 1.74 12.50

[0143] It can be seen from the results in Table 1 that the hypoglycemic compound granules obtained by the preparation method of the present invention have good antioxidant and moisture resistance and are easy to store. This should be the result of two extractions, namely, group extraction and ultrasonic moisturizing, which increases the extraction amount of puerarin and the extraction amount of Lycium bark, and at the same time improves the antioxidant capacity and deliquescence resistance of the extracts, especially the Lycium bark extract.

[0144] Test Example 2

[0145] The hypoglycemic compound granules obtained in Examples 1-7 were subjected to the alloxan diabetic rat blood sugar lowering test:

[0146] Preparation of alloxan diabetic rat model: SD rats, 45 females and 45 males, weighing 240-250g, aged 6-8 weeks. After one week of adaptation, 10 rats were randomly divided into the blank group, and the remaining 80 rats were fasted for 24 hours and injected intraperitoneally with 200mg / kg of 2wt% alloxan saline. The blank group was injected with an equal amount of saline. After 72 hours of injection, the rats were fasted for 12 hours but could not be deprived of water. Blood was collected from the orbital venous plexus to measure fasting blood glucose. The rats with fasting blood glucose values ​​higher than 16.5mmol / L were selected as successful models for subsequent experiments.

[0147] The rats with successful modeling were divided into 8 groups, with 10 rats in each group, namely the model group and Examples 1-7, a total of 8 groups; the rats were gavaged with 100 mg / kg hypoglycemic compound granules once at the same time every day, and the model group was not gavaged with hypoglycemic compound granules. The drug was administered continuously for 28 days, and the rats were fasted but not watered for 12 hours on the 7th and 14th days. Blood was collected from the tail vein to measure fasting blood glucose. The results of each group were averaged, and the data among the groups were statistically different.

[0148] The test results are shown in Table 2:

[0149]

[0150] The results in Table 2 show that the hypoglycemic compound granules prepared by the preparation method of the present invention have a good hypoglycemic effect, compared with the blank group, p<0.05.

[0151] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention are within the scope of protection of the pending claims of the present invention.

Claims

1. A method for preparing hypoglycemic compound granules, characterized in that: The following steps are involved: S1, ultrasonically moistening Puerariae Radix and Schisandrae Chinensis Fructus in ethanol, gradually heating to boiling, firstly extracting with alcohol, filtering, and concentrating, removing impurities from the alcohol-extracted residue, mixing with the concentrated product, and ultrasonically moistening in ethanol again, gradually heating to boiling again, and then extracting with alcohol again, filtering, and concentrating to obtain an alcohol-extracted extract; S2, ultrasonically moistening the Radix Astragali, Rhizoma Anemarrhenae, Rhizoma Dioscoreae and Endothelium Galli in water, and gradually heating the temperature to boiling, then water extracting, filtering and concentrating for the first time, removing impurities from the water-extracted residue, mixing with the concentrated product and ultrasonically moistening the residue in water again, and then gradually heating the temperature to boiling, then water extracting, filtering and concentrating again to obtain a water-extracted extract; S3, ultrasonically moistening the root bark of Lycium bark and Radix Trichosanthis in water-ethanol, gradually heating to boiling, initially extracting, filtering, and concentrating, removing impurities from the initial extraction residue and mixing with the concentrated product and ultrasonically moistening again in water-ethanol, adding acid cellulase for enzymolysis, and gradually heating to boiling again, re-extracting, filtering, and concentrating to obtain a modified extract; S4, mixing the alcohol extract, the water extract and the modified extract and continuing to concentrate to obtain a thick paste; S5, crushing the ginseng into fine powder and mixing it with the thick paste, drying, and crushing to obtain a dry paste powder; S6. Grind glibenclamide into fine powder, mix with dry paste powder, add appropriate amount of dextrin, mix well, wet granulate, and dry to obtain hypoglycemic compound granules.

2. The preparation method according to claim 1, characterized in that In step S1 or S2, the amount of ethanol or water used is 8 to 10 times the mass of the raw material drug; and / or, the time for the initial alcohol extraction or the initial water extraction is 0.5 to 2 hours; and / or, the time for the secondary alcohol extraction or the secondary water extraction is 0.5 to 2 hours.

3. The preparation method according to claim 1, characterized in that: In step S2, the boiling temperature is 97-100°C.

4. The preparation method according to claim 1, characterized in that: In step S1 or S2 or S3, the frequency of the ultrasound is 35 to 45 kHz; and / or the mesh size for filtration is 80 to 120 meshes; and / or the time for ultrasonic moistening or gradual heating is 60 to 90 minutes; and / or the time for ultrasonic moistening again or gradual heating again is 40 to 80 minutes.

5. The preparation method according to claim 1, characterized in that: In step S3, the mass percentage of ethanol in the water-ethanol is 15-25%; And / or, the amount of water-ethanol is 9 to 12 times the mass of the raw material drug; And / or, the time of the initial extraction or the re-extraction is 0.5 to 1.5 hours; And / or, the acid cellulase is produced by fermentation of green trichoderma strains; And / or, the amount of the acid cellulase is 0.1-1% of the mass of the raw material drug; And / or, the temperature of the enzymatic hydrolysis is 50-55°C; And / or, the enzymatic hydrolysis time is 15 to 30 minutes.

6. The preparation method according to claim 1, characterized in that: In step S4, the concentration pressure is 0.1-0.2 MPa, the temperature is 60-80°C, the vacuum degree is -0.06--0.08 MPa, and the relative density is 1.35-1.38 g / cm when concentrated to 60°C. 3 .

7. The preparation method according to claim 1, characterized in that: In step S5, the drying is low-temperature reduced-pressure drying, the vacuum degree is -0.06 to -0.08 MPa, the temperature is 55 to 60°C, and the time is 18 to 24 hours; And / or, the particle size of the crushed product is less than 100 mesh.

8. The preparation method according to claim 1, characterized in that: The alcohol extract: 36%≤yield limit≤42%; And / or, the water extract: 33%≤yield limit≤37%; And / or, the modified extract: 44%≤yield limit≤52%; And / or, the thick paste: 38%≤yield limit≤45%; And / or, the dry paste powder: 65%≤yield limit≤73%; And / or, the glucose-lowering compound granules: 98%≤yield limit≤100%.

9. The preparation method according to claim 1, characterized in that: The raw materials used in the hypoglycemic compound granules include the following in parts by weight:

10. A hypoglycemic compound granule, characterized in that: Prepared according to any one of claims 1 to 9.

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