Pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to an application of a pharmaceutical composition in preparation of medicines for preventing and / or treating type II diabetes mellitus. The invention provides an application of a pharmaceutical composition in preparation of a medicine for preventing and / or treating type II diabetes mellitus. The pharmaceutical composition comprises the following components: ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rg3, ginsenoside Rh4, ginsenoside Rk3, a ginseng ethanol-water extract and a pharmaceutically acceptable carrier. The pharmaceutical composition component provided by the invention can effectively reduce blood sugar and / or reduce the glycosylated hemoglobin level, and prevent and / or treat type II diabetes mellitus.

Description

[0001] This invention is a divisional application based on the application filed on December 14, 2023, with application number 202311727772.0 and entitled "Use of a pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of type II diabetes". Technical Field

[0002] This invention belongs to the field of pharmaceutical technology, specifically relating to the use of a pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of type II diabetes. Background Technology

[0003] Diabetes mellitus is a group of endocrine disorders characterized by hyperglycemia, primarily caused by an absolute or relative deficiency of insulin secretion, leading to disturbances in the metabolism of carbohydrates, fats, and proteins. The main cause of type 2 diabetes is peripheral insulin resistance and relative insulin deficiency, manifested as reduced glucose uptake by peripheral tissues such as fat and skeletal muscle, and a weakened ability of insulin to stimulate hepatic gluconeogenesis. This results in increased glucose output, leading to abnormal glucose and lipid metabolism, ultimately causing elevated blood glucose levels.

[0004] Diabetes is a chronic disease requiring long-term treatment. It necessitates not only medication but also changes in unhealthy lifestyle habits, along with the use of functional anti-diabetic foods with fewer side effects. Currently, many scholars both domestically and internationally are searching for diabetes treatment agents in natural medicines, hoping to reduce the side effects of diabetes medications, improve symptoms, and enhance quality of life. Summary of the Invention

[0005] The purpose of this invention is to provide the use of a pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of type 2 diabetes. The pharmaceutical composition of this invention has extremely high safety and can lower blood glucose and / or glycated hemoglobin levels, thereby achieving the prevention and / or treatment of type 2 diabetes.

[0006] This invention provides the use of a pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of type II diabetes, the pharmaceutical composition comprising the following components: ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rg3, ginsenoside Rh4, ginsenoside Rk3, ginseng ethanol-water extract, and a pharmaceutically acceptable carrier.

[0007] The present invention also provides the use of a pharmaceutical composition in the preparation of a drug for lowering blood glucose and / or lowering glycosylated hemoglobin levels, the pharmaceutical composition comprising the following components: ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rg3, ginsenoside Rh4, ginsenoside Rk3, ginseng ethanol-water extract, and a pharmaceutically acceptable carrier.

[0008] Preferably, in the pharmaceutical composition, the mass percentage of ginsenoside Rk1 is 5-12%, the mass percentage of ginsenoside Rg5 is 5-12%, the mass percentage of ginsenoside Rg3 is 5-12%, the mass percentage of ginsenoside Rh4 is 3-8%, the mass percentage of ginsenoside Rk3 is 2-6%, and the mass percentage of ginsenoside ethanol-water extract is 50-80%.

[0009] Preferably, the ginseng ethanol-water extract comprises the following components in weight percentage: 5-11.3% ginsenosides, 20-30% ginseng polysaccharides, 22-32.7% ginseng polypeptides, 1.0-2.0% ginseng polyphenols, and 2.0-4.0% ginseng flavonoids.

[0010] Preferably, the ginsenoside components include Rg1, Re, Rf, Rb1, Rc, Rd, and Rb2; the mass percentage of Rg1 in the ginseng ethanol-water extract is 2-3%, the mass percentage of Re in the ginseng ethanol-water extract is 1.0-2.5%, the mass percentage of Rf in the ginseng ethanol-water extract is 0.2-1.5%, the mass percentage of Rb1 in the ginseng ethanol-water extract is 0.5-1.5%, the mass percentage of Rc in the ginseng ethanol-water extract is 0.5-1.2%, the mass percentage of Rd in the ginseng ethanol-water extract is 0.5-0.8%, and the mass percentage of Rb2 in the ginseng ethanol-water extract is 0.3-0.8%.

[0011] Preferably, the ginseng ethanol-water extract is extracted from white ginseng, fresh ginseng, or red ginseng.

[0012] Preferably, the extraction method of the ginseng ethanol-water extract includes the following steps: drying and pulverizing ginseng to obtain pulverized ginseng; mixing the pulverized ginseng with an ethanol aqueous solution with a volume percentage of 75%, heating at 55°C for 3 hours, and filtering to obtain a first filtrate and a first filter residue; mixing the first filter residue with an ethanol aqueous solution with a volume percentage of 45%, heating at 55°C for 3 hours, and filtering to obtain a second filtrate and a second filter residue; mixing the second filter residue with water, heating at 80°C for 3 hours, and filtering to obtain a third filtrate; combining the first filtrate, the second filtrate, and the third filtrate, evaporating the solvent, and freeze-drying to obtain the ginseng ethanol-water extract.

[0013] Preferably, the sources of ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rg3, ginsenoside Rh4 and ginsenoside Rk3 include natural extraction.

[0014] Preferably, the ginsenosides Rk1, Rg5, Rh4, Rg3, and Rk3 are extracted from wild ginseng, cultivated ginseng, American ginseng, Panax notoginseng, red ginseng, or white ginseng.

[0015] Preferably, the method for preparing the pharmaceutical composition includes the following steps: Ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rg3, ginsenoside Rh4, ginsenoside Rk3, ginseng ethanol-water extract, and a pharmaceutically acceptable carrier are mixed to obtain a pharmaceutical composition.

[0016] This invention provides the application of a pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of type 2 diabetes. The composition of this invention is more stable and easier to store, showing significant application potential. The components of the pharmaceutical composition of this invention have extremely high safety and can lower blood glucose and / or glycated hemoglobin levels, achieving the prevention and / or treatment of type 2 diabetes. Experimental results show that the pharmaceutical composition of this invention can effectively reduce blood glucose and glycated hemoglobin levels in a Wistar rat hyperglycemia animal model, exhibiting treatment time-dependent effects and maintaining blood glucose levels within the normal concentration range, which is statistically significant. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0018] Figure 1 The figure shows the effect of this invention on blood glucose levels in a hyperglycemic model rat. Detailed Implementation

[0019] This invention provides the use of a pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of type II diabetes. The pharmaceutical composition comprises the following components: ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rg3, ginsenoside Rh4, ginsenoside Rk3, ginseng ethanol-water extract, and a pharmaceutically acceptable carrier. The composition of this invention exhibits extremely high safety; no LD50 was detected in acute toxicity tests. 50 The pharmaceutical composition of this invention can effectively reduce blood glucose and glycated hemoglobin levels in a Wistar rat hyperglycemia animal model, thereby achieving the treatment of type II diabetes.

[0020] The pharmaceutical composition of the present invention can only achieve the effect of lowering blood glucose and / or lowering glycosylated hemoglobin levels, and preventing and / or treating type II diabetes, when all components are combined.

[0021] In this invention, the preferred mass percentage of ginsenoside Rk1 in the pharmaceutical composition is 5-12%, the preferred mass percentage of ginsenoside Rg5 is 5-12%, the preferred mass percentage of ginsenoside Rg3 is 5-12%, the preferred mass percentage of ginsenoside Rh4 is 3-8%, the preferred mass percentage of ginsenoside Rk3 is 2-6%, and the preferred mass percentage of ginseng ethanol-water extract is 50-80%.

[0022] In this invention, the mass percentage of ginsenoside Rk1 in the pharmaceutical composition is 5-12%, preferably 5.3-10.8%. In this invention, ginsenoside Rk1, chemical name: 3β,6α,12β-trihydroxydammar-20(21),24-diene-6-O-β-D-glucopyranoside, molecular formula C 42 H 70 O 12 It has a molecular weight of 767.0, is odorless, and is a white powder. It is soluble in methanol and ethanol, slightly soluble in ethyl acetate, poorly soluble in water, and insoluble in chloroform and diethyl ether. CAS No.: 494753-69-4. Its structural formula is shown in Formula I.

[0023] , Formula I.

[0024] In this invention, the ginsenoside Rg5 in the pharmaceutical composition has a mass percentage content of 5-12%, preferably 6.1-10.5%. In this invention, ginsenoside Rg5, chemical name: beta-D-Glucopyranoside,(3beta,12beta,20E)-12-hydroxydammara-20(22),24-dien-3-yl2-O-beta-D-glucopyranosyl, molecular formula C 42 H 70 O 12 Molecular weight: 767.0, odorless, white powder. Soluble in methanol and ethanol, slightly soluble in ethyl acetate, poorly soluble in water, insoluble in chloroform and diethyl ether. CAS number: 74964-14-0, structural formula as shown in Formula II.

[0025] Formula II.

[0026] In this invention, the ginsenoside Rg3 in the pharmaceutical composition has a mass percentage of 5% to 12%, preferably 5.5% to 8.9%. In this invention, ginsenoside Rg3, chemically named 3-O-[β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl]-20(S)-protopanaxadiol, has the molecular formula: C 42 H 72 O 13 Molecular weight: 784.5, odorless, white powder. Soluble in methanol and ethanol, slightly soluble in ethyl acetate, poorly soluble in water, insoluble in chloroform and diethyl ether. CAS number: 14197-60-5. Structural formula as shown in Formula III.

[0027] Formula III.

[0028] In this invention, the ginsenoside Rh4 in the pharmaceutical composition has a mass percentage of 3-8%, preferably 3.0-6.2%. In this invention, ginsenoside Rh4, scientifically known as 6-O-β-D-glucopyranosyl-20(-H2O)-trans-protopanaxatriol, has the molecular formula C2. 36 H 60 O8; Molecular weight: 620.4. Odorless, white powder. Soluble in methanol and ethanol, slightly soluble in ethyl acetate, poorly soluble in water, insoluble in chloroform and ether; CAS number: 174721-08-5, structural formula as shown in Formula IV.

[0029] Formula IV.

[0030] In this invention, the ginsenoside Rk3 in the pharmaceutical composition has a mass percentage of 2-6%, preferably 2.5-4.3%. In this invention, ginsenoside Rk3, scientifically known as Trihydroxydammar-20(21),24-diene-6-O-β-D-glucopyranoside, has the molecular formula C2. 36 H 60 O8; Molecular weight: 620.87, odorless, white powder. Soluble in methanol and ethanol, slightly soluble in ethyl acetate, poorly soluble in water, insoluble in chloroform and diethyl ether; CAS number: 364779-15-7, structural formula as shown in Formula V.

[0031] , formula V.

[0032] In this invention, the ginseng ethanol-water extract in the pharmaceutical composition has a mass percentage content of 50-80%, preferably 63-75%. In this invention, the ginseng ethanol-water extract preferably comprises the following components in mass percentage: 5-11.3% ginsenosides, 20-30% ginseng polysaccharides, 22-32.7% ginseng polypeptides, 1.0-2.0% ginseng polyphenols, and 2.0-4.0% ginseng flavonoids.

[0033] In this invention, the ginseng ethanol-water extract preferably comprises 5-11.3% ginsenosides, more preferably 7-9.3%, and more preferably 9%. In this invention, the ginsenosides preferably include Rg1, Re, Rf, Rb1, Rc, Rd, and Rb2; the mass percentage of Rg1 in the ginseng ethanol-water extract is 2-3%, preferably 2.4-2.7%, and more preferably 2.6%; the mass percentage of Re in the ginseng ethanol-water extract is 1.0-2.5%, preferably 1.4-2.0%, and more preferably 1.5%; the mass percentage of Rf in the ginseng ethanol-water extract is 0.2-1.5%, preferably 0.5-1.4%, and more preferably 1.4%; the mass percentage of Rb1 in the ginseng ethanol-water extract is... The ginseng ethanol-water extract contains 0.5-1.5% by mass, preferably 0.8-1.2%, more preferably 0.9% by mass; Rc contains 0.5-1.2% by mass, preferably 0.8-1.1%, more preferably 1.1% by mass; Rd contains 0.5-0.8% by mass, preferably 0.6-0.7%, more preferably 0.7% by mass; and Rb2 contains 0.3-0.8% by mass, preferably 0.5-0.8%, more preferably 0.8% by mass.

[0034] In this invention, the ginseng ethanol-water extract comprises 20-30% ginseng polysaccharides, preferably 29.3%. In this invention, the ginseng ethanol-water extract comprises 22-32.7% ginseng polypeptides, preferably 32.3%. In this invention, the ginseng ethanol-water extract comprises 1.0-2.0% ginseng polyphenols, preferably 1.3%. In this invention, the ginseng ethanol-water extract comprises 2.0-4.0% ginseng flavonoids, preferably 3.1%.

[0035] In this invention, the ginseng ethanol-water extract is preferably extracted from white ginseng, fresh ginseng, or red ginseng.

[0036] In this invention, the extraction method of the ginseng ethanol-water extract preferably includes the following steps: drying and pulverizing ginseng to obtain pulverized ginseng; mixing the pulverized ginseng with an ethanol aqueous solution with a volume percentage of 75%, heating at 55°C for 3 hours, and filtering to obtain a first filtrate and a first filter residue; mixing the first filter residue with an ethanol aqueous solution with a volume percentage of 45%, heating at 55°C for 3 hours, and filtering to obtain a second filtrate and a second filter residue; mixing the second filter residue with water, heating at 80°C for 3 hours, and filtering to obtain a third filtrate; combining the first filtrate, the second filtrate, and the third filtrate, evaporating the solvent, and freeze-drying to obtain the ginseng ethanol-water extract.

[0037] This invention involves drying and pulverizing ginseng to obtain pulverized ginseng. The invention does not specify any particular method for drying and pulverizing; conventional drying and pulverizing methods well-known to those skilled in the art can be used.

[0038] After obtaining the pulverized ginseng, the present invention mixes the pulverized ginseng with an ethanol aqueous solution containing 75% by volume, heats at 55°C for 3 hours, and filters to obtain a first filtrate and a first filter residue. In the present invention, the volume ratio of the pulverized ginseng to the ethanol aqueous solution containing 75% by volume is preferably 1:(8-12), more preferably 1:10. In the present invention, the heating method is preferably a water bath heating method. In the present invention, the first filtrate is preferably stored in a refrigerator at 4°C.

[0039] After obtaining the first filter residue, the present invention mixes the first filter residue with an aqueous ethanol solution with a volume percentage of 45%, heats at 55°C for 3 hours, and filters to obtain a second filtrate and a second filter residue. In the present invention, the volume ratio of the first filter residue to the aqueous ethanol solution with a volume percentage of 45% is preferably 1:(8-12), more preferably 1:10. In the present invention, the heating method is preferably a water bath heating method. In the present invention, the second filtrate is preferably stored in a refrigerator at 4°C.

[0040] After obtaining the second filter residue, the present invention mixes the second filter residue with water, heats it at 80°C for 3 hours, and filters it to obtain the third filtrate. In the present invention, the volume ratio of the second filter residue to water is preferably 1:(8-12), more preferably 1:10. In the present invention, the heating method is preferably a water bath heating method. In the present invention, the second filtrate is preferably stored in a refrigerator at 4°C.

[0041] After obtaining the first, second, and third filtrates, this invention combines the three filtrates, evaporates the solvent, and freeze-dries them to obtain ginseng ethanol-water extract. This invention does not have a specific limitation on the solvent evaporation method; conventional methods are acceptable, such as using a rotary evaporator to remove the solvent. After evaporating the solvent, this invention preferably freeze-dries the concentrate. This invention does not have a specific limitation on the freeze-drying method; conventional freeze-drying methods are acceptable. After freeze-drying, this invention preferably grinds the freeze-dried solid into powder.

[0042] In this invention, the sources of ginsenosides Rk1, Rg5, Rg3, Rh4, and Rk3 are preferably natural extractions. In this invention, the ginsenosides Rk1, Rg5, Rh4, Rg3, and Rk3 are preferably extracted from wild ginseng, cultivated ginseng, American ginseng, Panax notoginseng, red ginseng, or white ginseng. In this invention, the extraction methods for ginsenosides Rk1, Rg5, Rg3, Rh4, and Rk3 preferably include one or more of the following: water extraction, organic solvent extraction, permeation, distillation, ultrasonic impregnation, extraction, and macroporous adsorption resin separation. In this invention, the ginsenosides Rk1, Rg5, and Rg3 are preferably obtained through the conversion of other diol-type ginsenosides. For example, ginsenosides Rk1 and Rg5 can be obtained by conversion of diol-type ginsenosides such as Rb1. In this invention, ginsenosides Rh4 and Rk3 are preferably obtained by conversion of other triol-type ginsenosides. For example, ginsenosides Rh4 and Rk3 can be obtained by conversion of triol-type ginsenoside Rg1. In this invention, the conversion method preferably includes enzymatic degradation. The sources of ginsenosides Rk1, Rg5, Rg3, Rh4, and Rk3 in this invention preferably also include direct purchase.

[0043] In this invention, the pharmaceutically acceptable carrier in the pharmaceutical composition preferably comprises 1-10% by mass. In this invention, the pharmaceutically acceptable carrier preferably includes one or more of the following: solvent, buffer, coating, isotonist, wetting agent, emulsifier, preservative, and antibacterial agent. In this invention, the dosage form of the pharmaceutical composition preferably includes: tablets, powder, suspension, emulsion, capsules, granules, sugar-coated tablets, pills, liquid, medicated solution, or syrup.

[0044] In this invention, the method for preparing the pharmaceutical composition preferably includes the following steps: Ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rg3, ginsenoside Rh4, ginsenoside Rk3, ginseng ethanol-water extract, and a pharmaceutically acceptable carrier are mixed to obtain a pharmaceutical composition.

[0045] This invention also provides the use of a pharmaceutical composition in the preparation of a drug for lowering blood glucose and / or lowering glycated hemoglobin levels, the pharmaceutical composition comprising the following components: ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rg3, ginsenoside Rh4, ginsenoside Rk3, ginseng ethanol-water extract, and a pharmaceutically acceptable carrier. In this invention, the pharmaceutical composition and its preparation method are preferably the same as described above and will not be repeated here. The pharmaceutical composition of this invention can achieve the prevention and / or treatment of hyperglycemia. The pharmaceutical composition of this invention can also achieve the reduction of high glycated hemoglobin. In this invention, diseases leading to elevated blood glucose and elevated glycated hemoglobin preferably include metabolic diseases, autoimmune diseases, and type II diabetes. Diseases that the pharmaceutical composition of this invention can prevent and / or treat include, but are not limited to, diabetes.

[0046] To further illustrate the present invention, the application of a pharmaceutical composition provided by the present invention in the preparation of a medicament for the prevention and / or treatment of type II diabetes is described in detail below with reference to the accompanying drawings and embodiments, but these descriptions should not be construed as limiting the scope of protection of the present invention.

[0047] Example 1 Ginsenoside Rk1 was purchased from Shanghai Yuanye Biotechnology Co., Ltd. Ginsenoside Rg5 was purchased from Shanghai Yuanye Biotechnology Co., Ltd. Ginsenoside Rh4 was purchased from Shanghai Yuanye Biotechnology Co., Ltd. Ginsenoside Rg3 was purchased from Shanghai Yuanye Biotechnology Co., Ltd. Ginsenoside Rh4 was purchased from Shanghai Yuanye Biotechnology Co., Ltd. Ginsenoside Rk3 was purchased from Shanghai Yuanye Biotechnology Co., Ltd.

[0048] Their purity all meets pharmaceutical standards. They are prepared according to the proportions shown in Tables 1-1 to 1-3.

[0049] Preparation method of ethanol-water extract: 1. Dry the ginseng and grind it into powder; 2. Heat ginseng powder with 10 times its volume of 75% ethanol in a water bath at 55°C for 3 hours. Store the filtrate at 4°C. 3. Heat the filter residue from the previous step with 10 times its volume of 45% ethanol in a 55°C water bath for 3 hours, and store the filtrate in a 4°C refrigerator. 4. Heat the filter residue from the previous step with 10 times its volume of pure water in an 80°C water bath for 3 hours. Store the filtrate in a 4°C refrigerator and discard the filter residue. 5. Combine the filtrates obtained in steps 2, 3 and 4, and use a rotary evaporator to evaporate most of the solvent; 6. Freeze-dry the concentrated liquid, and grind the freeze-dried solid into powder.

[0050] Ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rg3, ginsenoside Rh4, ginsenoside Rk3, ginseng ethanol-water extract and dextrin (Shanghai Yuanye Biotechnology Co., Ltd.) were mixed to obtain a pharmaceutical composition.

[0051] Table 1-1 Composition of the Pharmaceutical Composition

[0052] Table 1-2 Composition of Pharmaceutical Compositions

[0053] Table 1-3 Composition of Pharmaceutical Compositions

[0054] The composition of ginseng ethanol-water extract is shown in Table 2.

[0055] Table 2 Composition of Ginseng Ethanol-Water Extract

[0056] Example 2 Safety evaluation of the compositions of the present invention The non-clinical safety evaluation of the compositions of the present invention is as follows: 1. Acute oral toxicity test in mice Mice were orally administered composition 1 of the present invention by gavage under the conditions of maximum dosing concentration and maximum dosing volume, and observed continuously for 14 days to obtain the maximum tolerated dose of the composition of the present invention >10.0 g / kg BW.

[0057] 2. Acute oral toxicity test in Beagle dogs The composition of the present invention was administered orally by gavage to Beagle dogs at the maximum dosing concentration and maximum dosing volume conditions, thereby obtaining a maximum tolerated dose of the composition of the present invention >2.0 g / kg BW.

[0058] 3. Long-term toxicity of oral administration to rats A long-term toxicity test was conducted on SD rats using composition 1 of the present invention via oral gavage for three consecutive months, followed by a four-week recovery period after drug withdrawal. The results showed: ① General condition: During the administration and recovery periods, the animals' food and water intake were normal, their weight increased, their fur was smooth, and their behavior was normal; ② Hematological and blood biochemical indicators: After the administration and recovery periods, all hematological and blood biochemical indicators fluctuated within the normal range, with no obvious abnormalities observed; ③ Bone marrow and urinalysis indicators: After the administration and recovery periods, no obvious abnormalities were observed in the bone marrow and urinalysis indicators; ④ Histopathological indicators: After the administration and recovery periods, no obvious abnormalities were observed in the organs of the animals, and there were no significant differences in organ weight and organ coefficients compared to the control group. No obvious pathological changes were observed in any organ. The results indicate that no significant toxic reactions were observed with long-term administration to SD rats.

[0059] 4. Long-term toxicity test of oral administration in Beagle dogs A long-term toxicity test was conducted on Beagle dogs using the composition 1 of the present invention via oral gavage for three months, followed by a four-week recovery period after drug withdrawal. The results showed: ① General condition: During the administration and recovery periods, food and water intake and body temperature were normal, weight increased, fur was smooth, and behavior was normal; ② Hematological and blood biochemical indicators: After the administration and recovery periods, all hematological and blood biochemical indicators fluctuated within the normal range, with no obvious abnormalities observed; ③ Electrocardiogram indicators: After the administration and recovery periods, all electrocardiogram indicators fluctuated within the normal range, with no obvious abnormalities observed; ④ Bone marrow and ophthalmological examination: After the administration and recovery periods, bone marrow cells... No abnormalities were observed in cells and their taxa; ophthalmic examination revealed clear vascular patterns without hemorrhage or exudation in the fundus of all groups of animals, no edema in the optic disc, and normal arteriovenous ratios; ⑤ Immunological and urinary / fecal indicators: After the end of administration and during the recovery period, all immunological and urinary / fecal indicators fluctuated within the normal range, with no significant abnormalities observed; ⑥ Histopathological indicators: After the end of administration and during the recovery period, no significant abnormalities were observed in any of the animals' organs grossly, and there were no significant differences in organ weight and organ coefficients compared to the control group. No significant pathological changes were observed in any organ. The results indicate that long-term administration to Beagle dogs did not result in significant toxic reactions.

[0060] 5. General pharmacological tests Oral administration of composition 1 of the present invention to anesthetized Beagle dogs via gavage had no significant effect on their blood pressure (diastolic and systolic), heart rate, P wave, T wave, R wave, QRS interval, PR interval, QT interval, respiratory rate, or respiratory amplitude. The composition of the present invention also had no significant effect on the Irwin's behavioral test score and pole climbing test score in mice. This indicates that the composition of the present invention does not affect the central nervous system, cardiovascular system, or respiratory system of animals.

[0061] 6. Mutagenicity test Chromosomal aberration assays in cultured mammalian cells (CHL), Ames assays, and mouse micronucleus assays showed that composition 1 of the present invention had no mutagenic effect.

[0062] Example 3 Pharmacodynamics The composition of the present invention can reduce blood glucose and glycated hemoglobin levels in Wistar rat hyperglycemia model animals.

[0063] Materials: Wistar rats, compositions 1-3 and compositions 4-9 obtained in Example 1 of this invention.

[0064] Methods: An experimental hyperglycemic model was established in Wistar rats (50% male, 50% female) with blood glucose levels within the normal range. Blood glucose was measured several days later, with a blood glucose level greater than 10 mmol / L indicating a successful model. The blood glucose levels were compared with the normal control group (P < 0.001). The successfully modeled hyperglycemic Wistar rats were divided into a model group and groups 1-3 and 4-9 of the drug compositions described in Example 1 of this invention. They were administered the drugs by gavage once daily for 4 weeks at a dose of 150 mg / kg, with blood glucose measured weekly. After 4 weeks of gavage, blood glucose and glycated hemoglobin levels were measured in the experimental animals. A control group was included in the experiment; both the model group and the control group were administered an equal volume of physiological saline by gavage.

[0065] The experimental results are shown in Table 3-1 (corresponding to...) Figure 1 As shown in Tables 3-3 and 4-1 to 4-3.

[0066] Table 3-1 Effects of the effect on blood glucose levels in hyperglycemic model rats (mmol / L, x±s)

[0067] Table 3-2 Effects of the effect on blood glucose levels in hyperglycemic model rats (mmol / L, x±s)

[0068] Table 3-3 Effects of the effect on blood glucose levels in hyperglycemic model rats (mmol / L, x±s)

[0069] Table 4-1 Effects on glycated hemoglobin in hyperglycemic model rats (%, x±s)

[0070] Table 4-2 Effects on glycated hemoglobin in hyperglycemic model rats (%, x±s)

[0071] Table 4-3 Effects on glycated hemoglobin in hyperglycemic model rats (%, x±s)

[0072] The results showed that compositions 1, 2, and 3 of the present invention effectively reduced blood glucose and glycated hemoglobin levels in the Wistar rat hyperglycemia animal model, exhibiting treatment time-dependent effects and maintaining blood glucose levels within the normal range, which was statistically significant. Other drug compositions, compositions 4, 5, 6, 7, 8, and 9, did not achieve the same therapeutic effects as compositions 1, 2, and 3 of the present invention. This indicates that the absence of any one of the rare ginsenoside group components (ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rk3, ginsenoside Rg3, and ginsenoside Rh4) in compositions 1-3 of the present invention is necessary to achieve the desired effect.

[0073] Example 4 Ms. Yang, 67 years old, has had type II diabetes for 15 years. She has been taking composition 1 in Example 1 of this invention since 2018, taking 2.4g daily. Her current fasting blood glucose level is 5.9-6.1.

[0074] Mr. Fan, male, 45 years old, has had type II diabetes for 3 years. He started taking composition 1 in Example 1 of this invention in 2021, taking 2.4g daily. His fasting blood glucose is currently 6.0-6.5.

[0075] Mr. Zheng, male, 65 years old, has had type II diabetes for 30 years. He started taking composition 5 in Example 1 in 2021. After 3 months, his fasting blood glucose did not improve. He then switched to taking composition 2 in Example 1 of this invention, taking 2.4g every day. His current fasting blood glucose is 5.1-6.3.

[0076] Mr. Li, male, 58 years old, has had type II diabetes for 10 years. He started taking composition 7 in Example 1 of this invention in 2020. After 2 months, his fasting blood glucose did not improve, so he switched to taking composition 2 in Example 1 of this invention, taking 2.4g every day. His current fasting blood glucose is 4.9-5.8.

[0077] Ms. Zhang, 60 years old, had been suffering from type II diabetes for 8 years. She started taking the drug of composition 6 in Example 1 in 2020. After one month, her fasting blood glucose did not improve. She then switched to taking composition 2 in Example 1 of this invention, taking 2.4g every day. After one month, her fasting blood glucose tended to be within the normal concentration range.

[0078] Fan X, female, born on June 14, 1959, ID number 1101xxxxxxxxx4562, postprandial blood glucose >10, has been taking composition 3 in Example 1 of this invention for a long time, taking 2.4g daily, and currently has a postprandial blood glucose of 6.0-7.1.

[0079] Fan X, male, born on February 16, 1962, ID number 1101xxxxxxxxx4551, postprandial blood glucose 20, has been taking composition 3 in Example 1 of this invention for a long time, taking 2.4g daily, and currently his postprandial blood glucose is 6.3-8.0.

[0080] The results showed that compositions 1, 2, and 3 of the present invention effectively reduced blood glucose and glycated hemoglobin levels in diabetic patients, exhibiting time-dependent therapeutic effects and maintaining blood glucose levels within the normal range, which was statistically significant. Other drug compositions, including compositions 4, 5, 6, 7, 8, and 9, did not achieve the same therapeutic effects as compositions 1, 2, and 3 of the present invention. This indicates that the absence of any one of the rare ginsenoside group components (ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rk3, ginsenoside Rg3, and ginsenoside Rh4) in compositions 1–3 of the present invention is necessary to achieve the desired therapeutic effect.

[0081] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, Based on mass percentage, it consists of 5-12% ginsenoside Rk1, 5-12% ginsenoside Rg5, 5-12% ginsenoside Rg3, 3-8% ginsenoside Rh4, 2-6% ginsenoside Rk3, 50-80% ginseng ethanol-water extract, and 1-10% pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1, characterized in that, The ginseng ethanol-water extract comprises the following components in weight percentage: 5-11.3% ginsenosides, 20-30% ginseng polysaccharides, 22-32.7% ginseng polypeptides, 1.0-2.0% ginseng polyphenols, and 2.0-4.0% ginseng flavonoids.

3. The pharmaceutical composition according to claim 2, characterized in that, The ginsenosides include Rg1, Re, Rf, Rb1, Rc, Rd, and Rb2; Among them, Rg1 has a mass percentage of 2-3% in the ginseng ethanol-water extract, Re has a mass percentage of 1.0-2.5% in the ginseng ethanol-water extract, Rf has a mass percentage of 0.2-1.5% in the ginseng ethanol-water extract, Rb1 has a mass percentage of 0.5-1.5% in the ginseng ethanol-water extract, Rc has a mass percentage of 0.5-1.2% in the ginseng ethanol-water extract, Rd has a mass percentage of 0.5-0.8% in the ginseng ethanol-water extract, and Rb2 has a mass percentage of 0.3-0.8% in the ginseng ethanol-water extract.

4. The pharmaceutical composition according to claim 1, characterized in that, The ginseng ethanol-water extract is extracted from white ginseng, fresh ginseng, or red ginseng.

5. The pharmaceutical composition according to claim 4, characterized in that, The extraction method of the ginseng ethanol-water extract includes the following steps: (1) Dry the ginseng, pulverize it, and obtain pulverized ginseng; (2) Mix the crushed human ginseng with an ethanol aqueous solution with a volume percentage of 75%, heat at 55°C for 3 hours, and filter to obtain the first filtrate and the first filter residue; (3) Mix the first filter residue with an ethanol aqueous solution with a volume percentage of 45%, heat at 55°C for 3 hours, and filter to obtain the second filtrate and the second filter residue; (4) Mix the second filter residue with water, heat at 80°C for 3 hours, and filter to obtain the third filtrate; (5) Combine the first filtrate, the second filtrate and the third filtrate, evaporate the solvent, freeze dry, and obtain ginseng ethanol-water extract.

6. The pharmaceutical composition according to claim 5, characterized in that, The volume ratio of the pulverized ginseng to the ethanol aqueous solution in step (2) is 1:(8-12). In step (3), the volume ratio of the first filter residue to the ethanol aqueous solution is 1:(8-12). In step (4), the volume ratio of the second filter residue to water is 1:(8-12).

7. The pharmaceutical composition according to claim 1, characterized in that, The ginsenosides Rk1, Rg5, Rg3, Rh4, and Rk3 are derived from natural extraction. Alternatively, the ginsenosides Rk1, Rg5, Rh4, Rg3, and Rk3 mentioned above are extracted from wild ginseng, cultivated ginseng, American ginseng, Panax notoginseng, red ginseng, or white ginseng.

8. The pharmaceutical composition according to any one of claims 1-7, characterized in that, The pharmaceutically acceptable carriers include one or more of the following: solvents, buffers, coatings, isotonics, wetting agents, emulsifiers, preservatives, and antibacterial agents.

9. A method for preparing a pharmaceutical composition according to any one of claims 1-8, characterized in that, Includes the following steps: Ginsenoside Rk1, ginsenoside Rg5, ginsenoside Rg3, ginsenoside Rh4, ginsenoside Rk3, ginseng ethanol-water extract, and a pharmaceutically acceptable carrier were mixed to obtain a pharmaceutical composition.

10. Use of a pharmaceutical composition according to any one of claims 1-8 or a pharmaceutical composition prepared by the method of claim 9 in the preparation of a medicament for the prevention and / or treatment of type II diabetes.

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