WO2022062518A1 - 氧化小檗碱在制备代谢性疾病药物中的应用及包含氧化小檗碱的药物组合物 - Google Patents

氧化小檗碱在制备代谢性疾病药物中的应用及包含氧化小檗碱的药物组合物 Download PDF

Info

Publication number
WO2022062518A1
WO2022062518A1 PCT/CN2021/102587 CN2021102587W WO2022062518A1 WO 2022062518 A1 WO2022062518 A1 WO 2022062518A1 CN 2021102587 W CN2021102587 W CN 2021102587W WO 2022062518 A1 WO2022062518 A1 WO 2022062518A1
Authority
WO
WIPO (PCT)
Prior art keywords
berberine
oxide
group
uric acid
lowering
Prior art date
Application number
PCT/CN2021/102587
Other languages
English (en)
French (fr)
Inventor
苏子仁
陈建南
黎玉翠
谢建辉
刘煜洪
谢友良
黄晓其
Original Assignee
广州中医药大学(广州中医药研究院)
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广州中医药大学(广州中医药研究院) filed Critical 广州中医药大学(广州中医药研究院)
Publication of WO2022062518A1 publication Critical patent/WO2022062518A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention belongs to the technical field of biomedicine, and particularly relates to the application of berberine oxide in the preparation of drugs for metabolic diseases and a pharmaceutical composition comprising the berberine oxide.
  • hypoglycemic, lipid-lowering and uric acid-lowering are the primary tasks of clinical treatment of various metabolic diseases.
  • metabolism of carbohydrates, lipids, proteins, and nucleic acids involves the coordinated operation of multiple organs and multiple pathways, and the current clinical drug targets are single, combination drugs are often required. This will not only increase the patient's medication burden, but also requires physicians to fully consider the possible side effects of the drug combination. Therefore, a new candidate drug with comprehensive curative effect and less toxic and side effects is urgently needed.
  • the primary purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art, and to provide the application of berberine oxide in the preparation of drugs for metabolic diseases.
  • Another object of the present invention is to provide the application of berberine oxide in the preparation of a pharmaceutical composition with hypoglycemic, hypolipidemic and uric acid-lowering effects.
  • Another object of the present invention is to provide a pharmaceutical composition with the effects of lowering blood sugar, blood lipid and uric acid and its application.
  • the metabolic disease drugs include drugs for the treatment and/or prevention of metabolic diseases.
  • the drug for treating and/or preventing metabolic diseases comprises berberine oxide, and/or a salt formed by combining berberine oxide with a pharmaceutically acceptable acid.
  • the pharmaceutically acceptable acid includes at least one of organic acid, inorganic acid and amino acid.
  • the metabolic disease includes at least one of hyperglycemia, hyperlipidemia, hyperuricemia, uric acid nephropathy, obesity, diabetes, fatty liver and gout.
  • Said diabetes preferably includes at least one of type 1 diabetes and type 2 diabetes.
  • Said fatty liver preferably includes non-alcoholic fatty liver.
  • Said hyperuricemia preferably includes hyperuricemia caused by one or more of the uric acid poor excretion type, the hypersynthetic type, the mixed type and post-tumor chemotherapy.
  • a pharmaceutical composition with hypoglycemic, hypolipidemic and uric acid-lowering effects comprises berberine oxide and/or a salt formed by combining berberine oxide with a pharmaceutically acceptable acid.
  • the molecular formula of the berberine oxide is: C 20 H 17 NO 5 ; the molecular weight is: 351.4; the molecular structural formula is shown in formula I
  • the purity of the berberine oxide is preferably not less than 90%; more preferably more than 95%.
  • the pharmaceutical composition also includes a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier preferably includes at least one of fillers, binders, lubricants, disintegrants, cosolvents, adsorbent carriers, solvents, antioxidants, adsorbents, osmotic pressure regulators and pH regulators. A sort of.
  • the lubricant preferably includes but is not limited to magnesium stearate and paraffin.
  • the disintegrant preferably includes, but is not limited to, at least one of sodium starch glycolate, microcrystalline cellulose, crospovidone and pregelatinized starch.
  • Said co-solvent preferably includes, but is not limited to, polyvinyl pyrrolidone.
  • the filler preferably includes, but is not limited to, at least one of polyethylene glycol 4000 and starch.
  • the binder preferably includes, but is not limited to, at least one of crospovidone, dextrin, starch slurry and starch.
  • the dextrin preferably includes but is not limited to cyclodextrin alfa.
  • the pharmaceutical composition also includes a substance containing at least one effective active ingredient in lowering blood sugar, lowering blood lipids and lowering uric acid.
  • the substances containing at least one effective active ingredient for lowering blood sugar, lowering blood lipids and lowering uric acid include but are not limited to gliclazide, glibenclamide, repaglinide, febuxostat, benzbromarone, At least one of suvastatin, probucol, fenofibrate, dapagliflozin, sitagliptin, and metformin.
  • the metabolic disease includes at least one of hyperglycemia, hyperlipidemia, hyperuricemia, uric acid nephropathy, obesity, diabetes, fatty liver and gout.
  • a pharmaceutical composition formulation prepared from the above-mentioned pharmaceutical composition includes, but are not limited to, solid dosage forms, semi-solid dosage forms, liquid dosage forms, syrups, dropping pills, sustained-release preparations, sustained-release preparations, injections, injections, emulsions and suspensions. a dosage form.
  • the solid dosage form preferably includes, but is not limited to, at least one of tablets, capsules, granules, orally disintegrating tablets, sustained-release tablets, patches, pellets, dropping pills, microcapsules and microspheres.
  • the liquid dosage form preferably includes, but is not limited to, at least one of oral liquid and liposome.
  • the injection preferably includes, but is not limited to, at least one of water injection, freeze-dried powder injection and sterile powder injection.
  • the administration form of the pharmaceutical composition preparation preferably includes at least one of oral administration, subcutaneous injection, intramuscular injection and parenteral administration.
  • the present invention has the following advantages and effects:
  • the inventors conducted research on the metabolites of berberine in vivo and found that one of the metabolites, berberine oxide, has better hypoglycemic, lipid-lowering and uric acid-lowering effects; The product has high safety to human body and has certain development potential.
  • Berberine oxide has good hypoglycemic, lipid-lowering and uric acid-lowering effects in models of diabetes, fatty liver and hyperuricemia, and the effect of some indicators is stronger than or close to that of positive drug and prodrug berberine, The toxic and side effects are small, and it can improve the pathological damage of related organs.
  • Berberine oxide is expected to be developed into a class of innovative drugs with hypoglycemic, lipid-lowering, and uric acid-lowering effects for clinical treatment of metabolic diseases such as obesity, diabetes, fatty liver, and gout.
  • Figure 1 is the experimental flow chart.
  • FIG. 2 is a graph showing the results of body weight changes of mice at different times in Example 1.
  • Fig. 3 is the body weight and fasting blood glucose (FBG) change result graph of each group of rats in Example 2 within 4 weeks; wherein, Fig. A is the result graph of body weight change of each group of rats within 4 weeks; Fig. B is the result graph of each group's large Results of changes in fasting blood glucose (FBG) in mice within 4 weeks.
  • FBG fasting blood glucose
  • Fig. 4 is the result graph of fasting insulin (FINS) and ⁇ -cell function changes of the rats in each group in Example 2; wherein, Fig. A is the result graph of the fasting insulin (FINS) content of the rats in each group; Fig. ⁇ -cell function results in mice.
  • Fig. 5 is the comparison result graph of each group's oral glucose tolerance test blood glucose level and the oral glucose tolerance test glucose area under the curve AUC in Example 2; Wherein, Fig. A is the oral glucose tolerance test blood glucose level result graph of each group of rats; Fig. B is the comparison result of the area under the curve of glucose in the oral glucose tolerance test of rats in each group.
  • FIG. 6 is a graph showing the effect of each group of drugs on rat pancreatic tissue (HE staining) in Example 2.
  • FIG. 6 is a graph showing the effect of each group of drugs on rat pancreatic tissue (HE staining) in Example 2.
  • Fig. 7 is a graph showing the results of changes in body weight and fasting blood glucose (FBG) of rats in each group within 10 weeks in Example 3; wherein, Fig. A is a graph showing the results of changes in body weight of rats in each group within 10 weeks; Fig. Results of changes in fasting blood glucose (FBG) in mice within 10 weeks.
  • FBG body weight and fasting blood glucose
  • Figure 8 is a graph of the results of fasting insulin and insulin resistance index of rats in each group in Example 3; wherein, Figure A is a graph of the results of fasting insulin content of rats in each group; Figure B is a graph of results of insulin resistance index of rats in each group.
  • Fig. 9 is the comparison result diagram of the blood glucose level of each group of oral glucose tolerance test and the area under the curve of oral glucose tolerance test glucose AUC in Example 3; Wherein, Fig. A is the result diagram of the blood glucose level of oral glucose tolerance test of each group of rats; Fig. B is the comparison result of the area under the curve of glucose in the oral glucose tolerance test of rats in each group.
  • Figure 10 is a graph showing the results of changes in blood lipid indexes of each group of rats in Example 3; wherein, Figure A is a graph of the changes in serum glycated serum protein (GSP) content of each group of rats; Figure B is a graph of serum free serum levels of each group of rats; Figure C is the change result of serum triglyceride (TG) content of each group of rats; Figure D is the change result of serum total cholesterol (TC) content of each group of rats; Figure E are the results of changes in serum high-density lipoprotein cholesterol (HDL-c) content of rats in each group; Figure F is a graph of changes in serum low-density lipoprotein (LDL-c) content of rats in each group.
  • GSP serum glycated serum protein
  • TG serum triglyceride
  • TC total cholesterol
  • Figure E are the results of changes in serum high-density lipoprotein cholesterol (HDL-c) content of rats in each group
  • Figure F is a graph of changes in
  • Figure 11 is a graph showing the effect of each group of drugs on rat liver tissue in Example 3 (Oil Red O staining).
  • FIG. 12 is a graph showing the effect of each group of drugs on rat pancreatic tissue (HE staining) in Example 3.
  • FIG. 12 is a graph showing the effect of each group of drugs on rat pancreatic tissue (HE staining) in Example 3.
  • Figure 13 is a graph showing the results of the intervention of different drugs on the non-alcoholic fatty liver model of L02 cells in Example 4; wherein, Figure A is the result of cell survival in each group; Figure B is intracellular triglyceride (TG) in each group Content result chart; Figure C is the result chart of intracellular alanine aminotransferase (ALT) content of each group; Figure D is the result chart of intracellular aspartate aminotransferase (AST) content of each group.
  • Figure A is the result of cell survival in each group
  • Figure B is intracellular triglyceride (TG) in each group Content result chart
  • Figure C is the result chart of intracellular alanine aminotransferase (ALT) content of each group
  • Figure D is the result chart of intracellular aspartate aminotransferase (AST) content of each group.
  • FIG. 14 is a graph showing the results of the fat content (Oil Red O staining) of the L02 cells after the intervention of different drugs in Example 4.
  • FIG. 14 is a graph showing the results of the fat content (Oil Red O staining) of the L02 cells after the intervention of different drugs in Example 4.
  • FIG. 15 is a graph showing the results of changes in body weight of rats in each group in Example 5.
  • FIG. 16 is a graph showing the tissue weight results of rats in each group in Example 5.
  • FIG. 17 is a graph showing the tissue index results of each group of rats in Example 5.
  • Figure 18 is a graph showing the results of changes in blood lipid indexes of the rats in each group in Example 5; wherein, Figure A is a graph of the serum triglyceride (TG) concentration results of the rats in each group; Figure B is the total serum cholesterol of the rats in each group (TC) Concentration result chart; Figure C is the result chart of serum high-density lipoprotein cholesterol (HDL-c) concentration of rats in each group; Figure D is the serum low-density lipoprotein cholesterol (LDL-c) concentration of rats in each group Result chart; Figure E is the result chart of serum free fatty acid (FFA) concentration of rats in each group.
  • TG serum triglyceride
  • TC Total serum cholesterol of the rats in each group
  • Figure C is the result chart of serum high-density lipoprotein cholesterol (HDL-c) concentration of rats in each group
  • Figure D is the serum low-density lipoprotein cholesterol (LDL-c) concentration of rats in each group
  • Figure E is the result chart of
  • Figure 19 is a graph showing the results of changes in fasting blood glucose, serum insulin and insulin resistance index indexes of each group of rats in Example 5; wherein, Figure A is a graph of the results of the fasting blood glucose (FBG) concentration of each group of rats in Example 5; Figure B is the result graph of serum insulin (FINS) concentration of the rats in each group in Example 5; Figure C is the result graph of the insulin resistance index (HOMA-IR) of the rats in each group in Example 5.
  • FBG fasting blood glucose
  • FTS serum insulin
  • Figure C is the result graph of the insulin resistance index (HOMA-IR) of the rats in each group in Example 5.
  • Figure 20 is a graph showing the results of changes in the relevant indicators of liver function in each group of rats in Example 5;
  • Figure A is a graph of the results of serum alanine aminotransferase (ALT) in each group of rats in Example 5;
  • Figure B is an example The results of serum aspartate aminotransferase (AST) in each group of rats in 5.
  • FIG. 21 is a graph of the liver results of rats in each group after drug treatment in Example 5.
  • FIG. 21 is a graph of the liver results of rats in each group after drug treatment in Example 5.
  • FIG. 22 is a graph showing the results of HE staining of the livers of rats in each group after drug treatment in Example 5.
  • FIG. 22 is a graph showing the results of HE staining of the livers of rats in each group after drug treatment in Example 5.
  • FIG. 23 is a graph showing the results of oil red O staining of liver tissue of rats in each group after drug treatment in Example 5.
  • FIG. 23 is a graph showing the results of oil red O staining of liver tissue of rats in each group after drug treatment in Example 5.
  • FIG. 24 is a graph showing the results of changes in body weight of mice in each group within 10 days in Example 6.
  • FIG. 25 is a graph showing the results of liver weight and liver index of mice in each group in Example 6.
  • FIG. 26 is a graph showing the results of kidney weight and kidney index of each group of mice in Example 6.
  • FIG. 27 is a graph showing the results of spleen weight and spleen index of each group of mice in Example 6.
  • Figure 28 is a graph showing the representative therapeutic effect of different drugs in Example 6 on renal hyperuricemia in mice.
  • FIG. 29 is a diagram showing the overall effect of kidney treatment after the nine groups of mice in Example 6 were treated with corresponding drugs.
  • Figure 30 is a graph showing the results of HE staining of the kidneys of mice in each group after drug treatment in Example 6.
  • Figure 31 is a graph showing the results of serum uric acid, blood urea nitrogen, creatinine content and XO enzyme inhibition in the in vitro experiments of each group of mice in Example 6; wherein, Figure A is a graph of the results of serum uric acid content of each group of mice; Figure B is a graph showing the results of each group of small The results of serum urea nitrogen content in mice; Figure C is the results of creatinine content of mice in each group; Figure D is the results of XO enzyme inhibition in vitro experiments.
  • 32 is a graph showing the results of body weight, blood uric acid, creatinine and blood urea nitrogen content of mice in each group within 10 days in Example 7.
  • GSP is determined by using a glycosylated serum protein assay kit
  • NEFA is determined by using a free fatty acid assay kit
  • FBG is determined by using a blood glucose assay kit
  • FINS is determined by an insulin assay kit (purchased from Shanghai Enzyme Link).
  • TG is determined by triglyceride determination kit
  • TC is determined by total cholesterol determination kit
  • HDL-c is determined by high-density lipoprotein cholesterol determination kit
  • LDL-c is determined by low-density lipoprotein cholesterol determination kit
  • Protein cholesterol determination kit is determined by ALT is determined by alanine aminotransferase determination kit
  • AST is determined by aspartate aminotransferase determination kit
  • UA is determined by uric acid determination kit
  • CRE is determined by creatinine determination kit
  • BUN is determined by urea determination kit
  • the nitrogen determination kit was used for determination; the above kits were purchased from Nanjing Jiancheng Bioengineering Institute unless otherwise specified, and the specific operation steps were carried out according to the kit instructions.
  • FFA was measured using a free fatty acid assay kit (purchased from Shanghai Enzyme Link Biotechnology Co., Ltd.) according to the kit instructions.
  • HOMA- ⁇ and HOMA-IR were calculated using the data of FBG and FINS, respectively, according to the following formulas:
  • Berberine was purchased from Chengdu Refensi Biotechnology Co., Ltd.
  • Berberine oxide was prepared and identified according to the method in the literature (Dostal J, Man S, Seckarova P, et al. Berberine and coptisine free bases [J]. Journal of Molecular Structure. 2004(687): 135-142. The purity of berberine oxide is greater than 95%.
  • Allopurinol was purchased from Beijing Bailingwei Technology Co., Ltd.; Febuxostat and Benzbromarone were purchased from Shanghai Yuanye Biotechnology Co., Ltd.; Xanthine was purchased from Meilun Biotechnology Co., Ltd.
  • Example 1 Acute oral toxicity test of berberine oxide
  • mice The median lethal dose (LD 50 ) of berberine oxide (OBB) was determined according to the National Standard of the People's Republic of China "Chemicals: Test Methods for Acute Oral Toxicity of Chemicals (GB/T21603-2008)".
  • OLB berberine oxide
  • SPF grade SPF grade
  • OBB-1 ⁇ 5 groups of mice were given 0.1mL/10g body weight by one-time intragastric administration, and the daily doses were: 50.2mg/kg, 162.0mg/kg, 512.2mg/kg, 1638.0mg/kg, 5243.6mg/kg kg; the blank group was given an equal volume of 0.5% Tween 80.
  • mice After administration, the mice had free access to food and water, and were continuously observed for 14 days. The changes in body weight, food intake and other daily life and death status of the mice were recorded every two days. In addition, within 12 hours after administration, the toxicity, number of deaths and death time of mice in each group were observed and recorded every 3 hours, and the above indicators were observed and recorded every 6 hours after 12 hours of administration. The results are shown in Tables 1-1 and 1-2 and Figure 2 below.
  • streptozocin streptozocin, STZ; purchased from Shanghai Yisheng Biotechnology Co., Ltd.
  • type 1 diabetes model was explored to explore the effect of berberine oxide on type 1 diabetes in rats.
  • Rats with successful modeling were randomly divided into model group (T1DM group), positive control group (Metformin Met group, 300mg/kg), Berberine BBR group (100mg/kg), OBB low-dose group (50mg/kg) and OBB High-dose group (100mg/kg) group, 10 in each group.
  • Rats in Met group, BBR group and OBB group were given the corresponding drugs and doses by gavage every day, and the normal control group (Con group) and T1DM were gavaged with the same amount of normal saline, and all rats were measured weekly fasting blood glucose and body weight.
  • the rats in each group were sacrificed after continuous intervention for 4 weeks, and the related indicators of type 1 diabetes were determined.
  • the experimental results are shown in the following table and Figures 3-6, with significant statistical differences.
  • Table 2-1 Changes in body weight of rats in each group within 4 weeks (unit: g)
  • Table 2-2 Changes in fasting blood glucose of rats in each group within 4 weeks (unit: mmol/L)
  • Table 2-4 Comparison of blood glucose levels (unit: mmol/L) and area under the glucose curve (AUC) of oral glucose tolerance test of rats in each group
  • the blood glucose level and the area under the blood glucose concentration-time AUC curve at 30 min, 60 min and 120 min were all smaller than those in the T1DM group, and there was a very significant difference (p ⁇ 0.01), suggesting that the oxidation of berberine Alkali can improve the hyperglycemia and impaired glucose tolerance caused by high-dose streptozotocin.
  • the pathological section of the rat pancreas tissue was performed by HE staining. The results of the pathological section (as shown in Figure 6) showed that after the OBB treatment of the diabetic rats, the islet structure was significantly improved, the cells were arranged neatly, and the acinar lobule structure was relatively complete.
  • high-dose berberine oxide and metformin were equally effective in controlling fasting blood glucose levels, reducing weight loss, increasing insulin secretion levels, and improving glucose tolerance, and both were stronger than berberine at the same dose.
  • a classic type 2 diabetes model was used to explore the effect of berberine oxide on type 2 diabetes in rats.
  • Rats with successful modeling were randomly divided into: model group (T2DM), positive control group (Metformin Met group, 300 mg/kg), berberine BBR group (100 mg/kg), and OBB low-dose group (50 mg/kg). And OBB high-dose group (100mg/kg) group, 10 in each group. Except for the Con group and the T2DM model group, the Met group, the BBR group and the OBB group were given the corresponding doses of drugs, once a day. Fasting blood glucose and body weight were measured weekly in all rats. The rats in each group were sacrificed after continuous intervention for 6 weeks, and the related indicators of type 2 diabetes were determined. The experimental results are shown in the following table and Figures 7-12, with significant statistical differences.
  • Table 3-1 Changes in body weight of rats in each group within 10 weeks (unit: g)
  • Table 3-2 Changes in fasting blood glucose (mmol/L) of rats in each group within 10 weeks
  • Table 3-3 Changes in fasting blood glucose, fasting insulin and insulin resistance index of rats in each group
  • Table 3-4 Comparison of blood glucose levels (unit: mmol/L) and area under the glucose curve (AUC) of oral glucose tolerance test of rats in each group
  • the rats in the normal control group had good mental state, quick response, bright and lustrous hair color, normal diet, drinking water and urine volume during the experiment, and their weight gradually increased. After 4 weeks of high-fat feeding, the rats in the model group increased significantly in body weight, their mental state was acceptable, and there was no significant change in the amount of water and urine. After the model was established, the diabetic rats were significantly reduced in body weight, lethargic, unresponsive, decreased in activity, withered and dull coat color, and accompanied by symptoms of polydipsia, polyphagia and obvious polyuria. After 6 weeks of berberine oxide intervention, the rats' weight loss, polydipsia, polyphagia, polyuria, and listlessness were significantly improved.
  • the fasting insulin level ( Figure 8, Table 3-3) in the berberine oxide intervention group was significantly recovered, and both the fasting blood glucose and insulin resistance index (HOMA-IR) were significantly decreased.
  • the results of the OGTT experiment showed that the blood glucose and AUC of the berberine oxide intervention group were significantly lower than those of the diabetes model group after oral administration of glucose for 30 min, 60 min and 120 min.
  • serum free fatty acids (NEFA), total triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL-C), and glycated serum protein (GSP) were significantly decreased. HDL-C levels rose significantly.
  • the oil red O fat staining method was used to stain the liver tissue of the rats.
  • the cells are mostly round or oval, with normal size, full shape, even distribution, and compact and regular arrangement.
  • the islets of the diabetic control group showed obvious atrophy, no clear boundary of the cells in the islet, irregular cell morphology and structure, disordered arrangement, partial pyknosis and hyperchromatic nuclei, and islet interstitium.
  • Massive fibrosis was mostly loose reticular and accompanied by a large number of vacuoles.
  • Example 4 Interventional effect of berberine oxide on L02 cell non-alcoholic fatty liver model
  • the normal human L02 cell line (purchased from ATCC) was cultured, and after starvation for 6 hours, normal RPMI-1640 medium (purchased from ThermoFisher), high-fat medium, containing 0.2% (v/v) DMSO (purchased from Sigma- Aldrich), berberine oxide (10 ⁇ M, 20 ⁇ M, 40 ⁇ M), berberine (BBR, 40 ⁇ M) and metformin (Met, 5 mM) high-fat medium, and incubated for 24 h.
  • normal RPMI-1640 medium purchased from ThermoFisher
  • high-fat medium containing 0.2% (v/v) DMSO (purchased from Sigma- Aldrich)
  • berberine oxide (10 ⁇ M, 20 ⁇ M, 40 ⁇ M
  • BBR, 40 ⁇ M berberine
  • metformin Metal, 5 mM
  • the observed indicators are as follows:
  • Table 4-3 Contents of intracellular alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in each group (unit: IU/L)
  • Example 5 Treatment of Hyperlipidemia and Non-Alcoholic Fatty Liver with Berberine Oxide
  • mice Male SD rats, SPF grade, weighing 200 ⁇ 10g, were randomly divided into four groups (8 rats in each group): normal group (Con), model group (HFD), metformin group (HFD+Met-300), berberine oxide Low-dose group (HFD+OBB-50), high-dose berberine oxide group (HFD+OBB-100), berberine group (HFD+BBR-100). Except the normal group was given normal feed (purchased from Guangdong Provincial Medical Laboratory Animal Center), the other groups were given high-fat feed (purchased from Guangdong Provincial Medical Laboratory Animal Center), and were given intragastric administration at the same time for 8 weeks.
  • normal group was given normal feed (purchased from Guangdong Provincial Medical Laboratory Animal Center)
  • the other groups were given high-fat feed (purchased from Guangdong Provincial Medical Laboratory Animal Center)
  • intragastric administration at the same time for 8 weeks.
  • the metformin group was given a high-fat diet at the same time as 300 mg/kg metformin, the berberine group was given 100 mg/kg berberine, and the low-dose and high-dose berberine oxide groups were given 50 mg/kg and 100 mg/kg berberine oxide, respectively. .
  • Insulin resistance related indicators FINS, HOMA-IR;
  • liver HE staining Oil red O staining.
  • Table 5-2 Weight of liver and adipose tissue of rats in each group
  • Table 5-4 Changes in fasting blood glucose, serum insulin and insulin resistance index of rats in each group
  • berberine oxide can slow down body weight gain, reduce liver and adipose tissue weight, significantly reduce serum total triglyceride (TG), total cholesterol (TC) and free fatty acid (FFA), and increase high-density lipoprotein (HDL-c), lowering low-density lipoprotein (LDL-c); lowering fasting blood glucose (FBG), raising insulin (FINS), lowering insulin resistance index (HOMA-IR); lowering serum alanine aminotransferase (ALT) ) and aspartate aminotransferase (AST); Figure 21-23
  • TG total triglyceride
  • TC total cholesterol
  • FFA free fatty acid
  • HDL-c high-density lipoprotein
  • LDL-c low-density lipoprotein
  • FBG fasting blood glucose
  • FINS raising insulin
  • HOMA-IR lowering insulin resistance index
  • ALT serum alanine aminotransferase
  • AST aspartate aminotransferase
  • berberine oxide was significantly better than berberine in lowering body fat mass index, lowering serum free fatty acids (FFA), raising insulin and lowering transaminases.
  • FFA serum free fatty acids
  • berberine oxide was slightly weaker, most of the index levels were also close to berberine (100mg/kg).
  • metformin 300mg/kg was three times that of berberine oxide (100mg/kg), but there was no significant difference in efficacy between the two.
  • mice Male KM mice, SPF grade, weighing 20 ⁇ 2g, were randomly divided into nine groups (10 mice in each group): blank control group (Con group), model group (HUA), allopurinol group (AP, 5mg/kg), Febuxostat group (FEB, 5mg/kg), benzbromarone group (BEN, 5mg/kg), OBB low-dose group (5mg/kg), OBB medium-dose group (10mg/kg), OBB high-dose group (20mg/kg), BBR group (100mg/kg). After the mice were purchased, they were adaptively fed for one week.
  • Blank control group Con group
  • model group SUV
  • AP allopurinol group
  • FEB Febuxostat group
  • BEN benzbromarone group
  • OBB low-dose group OBB low-dose group
  • OBB medium-dose group 10mg/kg
  • OBB high-dose group (20mg/kg
  • BBR group 100mg/kg
  • mice in each group were given intraperitoneal injection of potassium oxonate (300 mg/kg) and hypoxanthine (300 mg/kg) to establish hyperuricemia except for the blank control group.
  • Model blank control group was injected subcutaneously with equal volume of normal saline and gavage with equal volume of normal saline. After 1 hour of modeling, the test substance of corresponding concentration was given by gavage. The blank control group was given an equal volume of normal saline, the positive control group was given the positive drugs allopurinol, febuxostat and benzbromarone at 5 mg/kg body weight, and the other drug groups were given the corresponding concentration of drugs. The experiment was carried out for a total of 10 days.
  • Inhibition rate (%) (1- As /A 0 ) ⁇ 100%
  • a 0 is the absorbance value of xanthine oxidase activity without sample added
  • a s is the absorbance value of xanthine oxidase activity added sample.
  • Table 6-1 Changes in body weight of mice in each group within 10 days (unit: g)
  • Table 6-3 Blood uric acid ( ⁇ mol/L), blood urea nitrogen (mmol/L), and creatinine content ( ⁇ mol/L) of mice in each group
  • the positive drugs allopurinol, febuxostat and benzbromarone can significantly reduce the level of blood uric acid
  • the tested drugs berberine and berberine oxide can also significantly reduce the level of blood uric acid
  • the effect of berberine oxide is strong.
  • the effect of 10mg/kg berberine oxide is better than that of the positive drugs 5mg/kg benzbromarone and 100mg/kg berberine, and it has the same effect as 5mg/kg allopurinol and 5mg/kg febuxostat. The effect is comparable.
  • the model group increased uric acid, increased kidney and spleen index, increased blood urea nitrogen and creatinine, and had obvious renal damage.
  • the positive drugs allopurinol, febuxostat and benzbromarone significantly reduced serum uric acid (UA) levels, but at the same time, they could reduce the weight gain rate of mice, increase kidney and spleen index, and further increase blood urea nitrogen ( BUN), aggravating kidney damage.
  • Both berberine oxide and berberine can significantly reduce serum uric acid (UA) and urea nitrogen (BUN) levels, but have no effect on body weight gain, kidney and spleen index of mice, suggesting that they have renal protection.
  • berberine oxide can significantly reduce the level of blood uric acid, the effect is better than that of the existing drugs, or the effect is equivalent to the existing drugs; and it has a renal protective effect. It can be seen that, compared with the existing uric acid-lowering drugs, the effect of berberine oxide is better than that of the existing drugs, and there is no side effect such as liver and kidney damage of the existing drugs.
  • Example 7 Treatment of 5-FU-induced hyperuricemia with berberine oxide
  • mice Male KM mice, SPF grade, weighing 22 ⁇ 2g, were randomly divided into six groups (10 mice in each group): blank control group (Con group), model group (HUA), BBR group (50mg/kg), OBB low-dose group (12.5mg/kg), OBB middle dose group (25mg/kg), OBB high dose group (50mg/kg). After the mice were purchased, they were adaptively fed for one week. After that, the mice in each group were given intraperitoneal injection of pentafluorouracil (5-FU, 60 mg/kg) to establish a hyperuricemia model, except for the blank control group, and the blank control group was injected subcutaneously with an equal volume saline.
  • pentafluorouracil 5-FU, 60 mg/kg
  • test substance of corresponding concentration was given by gavage.
  • the blank control group was given an equal volume of normal saline, and the BBR control group and the OBB drug group were given the corresponding concentrations of drugs.
  • the experiment was carried out for a total of 7 days.
  • Table 7-1 Changes in body weight of mice in each group within 7 days (unit: g)
  • Example 1 Take 500 g of berberine oxide, add 500 g of crospovidone, 754 g of starch, 250 g of microcrystalline cellulose, mix well, and use 300 g of 5% (w/v) starch slurry as a binder , wet granulation, drying, adding 16g of magnesium stearate and mixing, and pressing into 10,000 tablets each containing 50mg of berberine oxide according to conventional methods, and each tablet has a net weight of 0.2g. Oral, 2 times a day, 3 capsules each time; for 30 days, it is used to treat metabolic diseases represented by diabetes, fatty liver and gout. As a result, it was found that the above-mentioned tablet has a good effect of lowering blood sugar, blood lipid and uric acid.
  • Example 2 Weigh 200 g of berberine oxide, add 1000 g of cyclodextrin alfa, and formulate 10,000 tablets each containing 20 mg of berberine oxide according to conventional methods. Oral, 2 times a day, 3 capsules each time; continuous for 30 days, for metabolic diseases represented by diabetes, fatty liver, and gout. As a result, it was found that the above-mentioned tablet has a good effect of lowering blood sugar, blood lipid and uric acid.
  • Example 3 (tablet) Weigh 1000 g of berberine oxide, add an appropriate amount of pharmaceutical excipients such as hypromellose acetate succinate, micropowder silica gel, polyvinyl pyrrolidone, etc., and prepare each tablet containing berberine oxide according to conventional methods. 10,000 controlled-release tablets of alkali 100mg. Oral, 2 times a day, 3 capsules each time; for 30 days, it is used to treat metabolic diseases represented by diabetes, fatty liver and gout. As a result, it was found that the above-mentioned sustained and controlled release tablet has a good effect of lowering blood sugar, blood lipid and uric acid.
  • pharmaceutical excipients such as hypromellose acetate succinate, micropowder silica gel, polyvinyl pyrrolidone, etc.
  • Example 4 (tablets) 500 g of berberine oxide and 500 g of metformin were weighed, and appropriate pharmaceutical excipients were added to prepare 10,000 tablets according to conventional methods. Oral, 2 times a day, 3 capsules each time; for 30 days, it is used to treat metabolic diseases represented by diabetes, fatty liver and gout. As a result, it was found that the above-mentioned tablet has good hypoglycemic, hypolipidemic and uric acid-lowering effects.
  • Example 5 (capsule) 500 g of berberine oxide was weighed, and appropriate pharmaceutical excipients were added, and 10,000 capsules each containing 50 mg of berberine oxide were prepared according to conventional methods. Oral, 2 times a day, 3 capsules each time; for 30 days, it is used to treat metabolic diseases represented by diabetes, fatty liver and gout. As a result, it was found that the above-mentioned capsules have good hypoglycemic, hypolipidemic and uric acid-lowering effects.
  • Example 6 (capsule) 200 g of berberine oxide was weighed, and appropriate pharmaceutical excipients were added, and 10,000 capsules each containing 20 mg of berberine oxide were prepared according to conventional methods. Oral, 2 times a day, 3 capsules each time; for 30 days, it is used to treat metabolic diseases represented by diabetes, fatty liver and gout. As a result, it was found that the above-mentioned capsules have good hypoglycemic, hypolipidemic and uric acid-lowering effects.
  • Example 7 (capsule) 1000 g of berberine oxide was weighed, appropriate pharmaceutical excipients were added, and 10,000 sustained-release capsules containing 100 mg of berberine oxide per capsule were prepared according to conventional methods. Oral, 2 times a day, 3 capsules each time; for 30 days, it is used to treat metabolic diseases represented by diabetes, fatty liver and gout. The results showed that the above-mentioned sustained-release capsules had good hypoglycemic, hypolipidemic and uric acid-lowering effects.
  • Example 8 (capsules) 500 g of berberine oxide and 500 g of metformin were weighed, added with appropriate pharmaceutical excipients, and prepared into 10,000 capsules according to conventional methods, each containing 50 mg of berberine oxide. Oral, 2 times a day, 3 capsules each time; for 30 days, it is used to treat metabolic diseases represented by diabetes, fatty liver and gout. As a result, it was found that the above-mentioned capsules have good hypoglycemic, hypolipidemic and uric acid-lowering effects.
  • Example 9 (Dropping Pills) Take 300g of berberine oxide, add 900g of PEG4000 as a matrix, and liquid paraffin as a cooling agent; make dropping pills containing 10mg of berberine oxide in each pill, and each pill has a net weight of 30mg. Oral, 2 times a day, 10 capsules each time; for 30 days, it is used to treat metabolic diseases represented by diabetes, fatty liver and gout. The results showed that the above dropping pills had good hypoglycemic, hypolipidemic and uric acid-lowering effects.
  • Example 10 (Dropping Pills) Weigh 1000 g of berberine oxide, add appropriate pharmaceutical excipients, and prepare dropping pills containing 30 mg of berberine oxide per pill according to conventional methods. Oral, 2 times a day, 6 capsules each time; for 30 days, it is used to treat metabolic diseases represented by diabetes, fatty liver and gout. The results showed that the above dropping pills had good hypoglycemic, hypolipidemic and uric acid-lowering effects.
  • Example 11 (Injection) Take 150 mg of berberine oxide, add appropriate pharmaceutical excipients, and dissolve in 1000 mL to prepare 0.15% (m/v) berberine oxide injection. Intramuscular injection, once a day, 10 mL each time; for 30 consecutive days, for the treatment of metabolic diseases represented by diabetes, fatty liver, and gout. As a result, it was found that the above-mentioned injections have good hypoglycemic, hypolipidemic and uric acid-lowering effects.
  • Example 12 (Injection) Weigh 200 mg of berberine oxide, add appropriate pharmaceutical excipients, and prepare powder injection according to conventional methods. Intramuscular injection, once a day, 10 mL each time; for 30 consecutive days, for the treatment of metabolic diseases represented by diabetes, fatty liver, and gout. As a result, it was found that the above-mentioned injections have good hypoglycemic, hypolipidemic and uric acid-lowering effects.
  • Example 13 Take 400 g of berberine oxide, add 500 g of crospovidone, 480 g of lactose, 500 g of starch and mix well, use starch slurry as a binder, wet granulation, dry, add magnesium stearate 16g was mixed and pressed into 10,000 tablets each containing 40mg of berberine oxide according to the conventional method, and the net weight of each tablet was 0.2g. Oral, once a day, 1 capsule each time; for 30 days, it is used to treat hyperuricemia, gout, and uric acid nephropathy. As a result, it was found that the above-mentioned tablet has a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 14 (tablets) Weigh 500 g of berberine oxide, add appropriate pharmaceutical excipients, and prepare 10,000 tablets containing 50 mg, each with a net weight of 0.2 g. Oral, 1 time a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperuricemia, gout, uric acid nephropathy. As a result, it was found that the above-mentioned tablet has a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 15 (tablets) Weigh 1000 g of berberine oxide, add appropriate pharmaceutical excipients, and prepare 10,000 tablets each containing 100 mg of berberine oxide, each with a net weight of 0.25 g. Oral, once a day, 1 capsule each time; for 30 days, it is used to treat hyperuricemia, gout, and uric acid nephropathy. As a result, it was found that the above-mentioned tablet has a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 16 Weigh 500 g of berberine oxide and 500 g of benzbromarone, add appropriate pharmaceutical excipients, and prepare 10,000 tablets according to conventional methods, each containing 50 mg of berberine oxide. Oral, 1 time a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperuricemia, gout, uric acid nephropathy. As a result, it was found that the above-mentioned tablet has a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 17 Weigh 500 g of berberine oxide and 500 g of allopurinol, add appropriate pharmaceutical excipients, and prepare 10,000 tablets according to conventional methods, each containing 50 mg of berberine oxide. Oral, 1 time a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperuricemia, gout, uric acid nephropathy. As a result, it was found that the above-mentioned tablet has a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 18 Weigh 500 g of berberine oxide and 500 g of febuxostat, add appropriate pharmaceutical excipients, and prepare 10,000 sustained-release tablets according to conventional methods, each containing 50 mg of berberine oxide. Oral, once a day, 1 capsule each time; for 30 days, it is used to treat hyperuricemia, gout, and uric acid nephropathy. As a result, it was found that the above-mentioned tablet has a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 19 (capsules) 250 g of berberine oxide were weighed, and appropriate pharmaceutical excipients were added to prepare 10,000 capsules containing 25 mg of berberine oxide per capsule according to conventional methods. Oral, once a day, 1 capsule each time; for 30 days, it is used to treat hyperuricemia, gout, and uric acid nephropathy. As a result, it was found that the above-mentioned capsules have good effects of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 20 (capsule) 500 g of berberine oxide was weighed, and appropriate pharmaceutical excipients were added, and 10,000 capsules each containing 50 mg of berberine oxide were prepared according to conventional methods. Oral, once a day, 1 capsule each time; for 30 days, it is used to treat hyperuricemia, gout, and uric acid nephropathy. As a result, it was found that the above-mentioned capsules have good effects of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 21 (capsule) 1000 g of berberine oxide was weighed, appropriate pharmaceutical excipients were added, and each capsule containing 100 mg of berberine oxide was prepared according to conventional methods. Oral, once a day, 1 capsule each time; for 30 days, it is used to treat hyperuricemia, gout, and uric acid nephropathy. As a result, it was found that the above-mentioned capsules have good effects of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 22 (Dropping Pills) Take 300g of berberine oxide, add 1500g of PEG4000 as a matrix, and liquid paraffin as a coolant; make dropping pills containing 6mg of berberine oxide in each pill, and each pill has a net weight of 30mg. Oral, once a day, 8 capsules each time; for 30 days, it is used to treat hyperuricemia, gout, and uric acid nephropathy. As a result, it was found that the above-mentioned dropping pills had a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 23 (Dropping Pills) Weigh 1000 g of berberine oxide, add appropriate pharmaceutical excipients, and prepare dropping pills containing 30 mg of berberine oxide per pill according to conventional methods. Oral, once a day, 2 capsules each time; for 30 days, it is used to treat hyperuricemia, gout, and uric acid nephropathy. As a result, it was found that the above-mentioned dropping pills had a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 24 (Injection) Take 150 mg of berberine oxide, add appropriate pharmaceutical excipients, and dissolve in 1000 mL of propylene glycol to prepare 0.15% (m/v) berberine oxide injection. Intramuscular injection, once a day, 10 mL each time; for 30 consecutive days, for the treatment of hyperuricemia, gout, and uric acid nephropathy. As a result, it was found that the above-mentioned injection had a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 25 (soft capsule) Weigh 100g of berberine oxide, add appropriate pharmaceutical excipients, fully stir to obtain the contents of the berberine oxide soft capsule, weigh gelatin, glycerin, water (mass ratio is 2:1: 2) Prepare the capsule material glue according to the conventional method; adopt the rotary molding method, put the contents and the capsule material glue into the automatic rotary capsule making machine, and press out the soft capsule with the specification of 100 mg of berberine oxide per capsule according to the conventional method. There are 1000 capsules, each with a net weight of 800 mg, and liquid paraffin as a lubricant. Oral, once a day, 1 capsule each time; for 30 days, it is used to treat hyperuricemia, gout, and uric acid nephropathy. As a result, it was found that the above-mentioned soft capsules have good effects of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 26 (Suspension) Weigh 50 g of berberine oxide, add 1000 g of stachyose and appropriate auxiliary materials, and prepare a suspension containing 1 mg of berberine oxide per mL. Oral, once a day, 10 mL each time; continuous for 30 days, for the treatment of hyperuricemia, gout, uric acid nephropathy. As a result, it was found that the above-mentioned syrup has a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 27 (Suspension) Weigh 50 g of berberine oxide, add appropriate auxiliary materials, and prepare a suspension containing 5 mg of berberine oxide per mL. Oral, shake well before use, once a day, 10 mL each time; take it continuously for 30 days for the treatment of hyperuricemia, gout, and uric acid nephropathy. As a result, it was found that the above suspension has a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 28 (Injection) Weigh 200 mg of berberine oxide, add appropriate excipients, and prepare 0.20% (w/v) berberine oxide injection. Subcutaneous injection, once a day, 1 mL each time; for 30 consecutive days, for the treatment of hyperuricemia, gout, and uric acid nephropathy. The results showed that the above-mentioned injection had a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 29 (External emulsion) Take 1 g of berberine oxide, add appropriate pharmaceutical excipients, and prepare a 20% (w/v) emulsion according to conventional methods. Usage: 0.1-0.5mL for external use, smear on the joint or painful body surface area, 3-5 times a day, an appropriate amount each time; take it continuously for 15 days for the treatment of gout. As a result, it was found that the above topical emulsion has good effects of reducing uric acid, reducing inflammation and swelling.
  • Example 30 (tablet) take 400g of berberine oxide, add 480g of lactose, 754g of starch and mix well, use 350g of 7% (w/v) starch slurry as a binder, wet granulation, dry, add stearin Mix 16 g of magnesium acid, and press into 10,000 tablets each containing 40 mg of berberine oxide, each with a net weight of 0.2 g. Oral, 3 times a day, 4 capsules each time; continuous service for 30 days, for the treatment of hyperlipidemia, obesity, fatty liver. As a result, it was found that the above-mentioned tablet has good effects of lowering blood cholesterol, lowering triglyceride or lowering density lipoprotein, reducing body weight and lowering transaminase.
  • Example 31 (tablets) Weigh 500 g of berberine oxide, add appropriate excipients, and prepare tablets each containing 50 mg of berberine oxide according to conventional methods. Oral, 3 times a day, 4 capsules each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. As a result, it was found that the above-mentioned tablet has good effects of lowering blood cholesterol, lowering triglyceride or lowering density lipoprotein, reducing body weight and lowering transaminase.
  • Example 32 Weigh 1000 g of berberine oxide, add appropriate auxiliary materials, and prepare a tablet containing 100 mg of berberine oxide according to conventional methods. Oral, 3 times a day, 4 capsules each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. As a result, it was found that the above-mentioned tablet has good effects of lowering blood cholesterol, lowering triglyceride or lowering density lipoprotein, reducing body weight and lowering transaminase.
  • Example 33 Weigh 500 g of berberine oxide and 100 g of fenofibrate, add appropriate pharmaceutical excipients, and prepare 10,000 tablets according to conventional methods. Oral, 1 time a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. As a result, it was found that the above-mentioned tablet has good effects of lowering blood cholesterol, lowering triglyceride or lowering density lipoprotein, reducing body weight and lowering transaminase.
  • Example 34 Weigh 500 g of berberine oxide and 100 g of lovastatin, add appropriate pharmaceutical excipients, and prepare 10,000 tablets according to conventional methods. Oral, oral, 1 time a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. As a result, it was found that the above-mentioned tablet has good effects of lowering blood cholesterol, lowering triglyceride or lowering density lipoprotein, reducing body weight and lowering transaminase.
  • Example 35 Weigh 500 g of berberine oxide and 500 g of probucol, add appropriate pharmaceutical excipients, and prepare 10,000 tablets according to conventional methods. Oral, orally, 2 times a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. As a result, it was found that the above-mentioned tablet has good effects of lowering blood cholesterol, lowering density lipoprotein, reducing body weight and lowering transaminase.
  • Example 36 (capsule) 1000 g of berberine oxide was weighed, added with appropriate pharmaceutical excipients, and prepared into capsules containing 100 mg of berberine oxide per capsule according to conventional methods. Oral, 3 times a day, 4 capsules each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. As a result, it was found that the above capsules have good effects of lowering blood cholesterol, triglyceride or density lipoprotein, weight loss and transaminase.
  • Example 37 (capsule) 500 g of berberine oxide was weighed, and appropriate pharmaceutical excipients were added, and each capsule was prepared into a capsule containing 50 mg of berberine oxide according to conventional methods. Oral, 3 times a day, 4 capsules each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. As a result, it was found that the above capsules have good effects of lowering blood cholesterol, triglyceride or density lipoprotein, weight loss and transaminase.
  • Example 38 (capsule) 1000 g of berberine oxide and 500 g of niacin were weighed, and appropriate pharmaceutical excipients were added, and each capsule containing 100 mg of berberine oxide was prepared according to conventional methods. Oral, 3 times a day, 4 capsules each time; continuous service for 30 days. 3 times a day, 4 capsules each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. As a result, it was found that the above capsules have good effects of lowering blood cholesterol, triglyceride or density lipoprotein, weight loss and transaminase.
  • Example 39 (Dropping Pills) Take 300g of Berberine Oxide, add 1500g PEG4000 as a matrix, and liquid paraffin as a coolant; the dripping method is used to make dripping pills containing 6mg of Berberine Oxide per pill, and each pill has a net weight of 30mg. Oral, 3 times a day, 10 capsules each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. The results showed that the above dropping pills have good effects of lowering blood cholesterol, lowering triglyceride or lowering density lipoprotein, reducing body weight and lowering transaminase.
  • Example 40 (Dropping Pills) Weigh 1000 g of berberine oxide, add appropriate pharmaceutical excipients, and prepare dropping pills containing 30 mg of berberine oxide per pill according to conventional methods. Oral, 3 times a day, 5 capsules each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. The results showed that the above dropping pills have good effects of lowering blood cholesterol, lowering triglyceride or lowering density lipoprotein, reducing body weight and lowering transaminase.
  • Example 41 (soft capsule) Weigh 100g of berberine oxide, add appropriate pharmaceutical excipients, fully stir to obtain the contents of the berberine oxide soft capsule, weigh gelatin, glycerin, water (mass ratio is 2:1: 2) Prepare the capsule material glue according to the conventional method; adopt the rotary molding method, put the contents and the capsule material glue into the automatic rotary capsule making machine, and press out the soft capsule with a specification of 200 mg of berberine oxide per capsule according to the conventional method. There are 500 capsules, each with a net weight of 1000 mg, and liquid paraffin as a lubricant. Oral, 3 times a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. As a result, it was found that the above-mentioned soft capsules have good effects of lowering blood cholesterol, lowering triglyceride or lowering density lipoprotein, reducing body weight and lowering transaminase.
  • Example 42 (soft capsule) Weigh 1000 g of berberine oxide, add appropriate pharmaceutical excipients, and prepare a soft capsule containing 500 mg of berberine oxide according to conventional methods. Oral, 3 times a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. As a result, it was found that the above-mentioned soft capsules have good effects of lowering blood cholesterol, lowering triglyceride or lowering density lipoprotein, reducing body weight and lowering transaminase.
  • Example 43 (soft capsule) Weigh 25 g of berberine oxide, add appropriate pharmaceutical excipients, and prepare soft capsules each containing 50 mg of berberine oxide according to conventional methods. Oral, 3 times a day, 6 capsules each time; continuous service for 30 days. For the treatment of hyperlipidemia, obesity, fatty liver. As a result, it was found that the above-mentioned soft capsules have good effects of lowering blood cholesterol, lowering triglyceride or lowering density lipoprotein, reducing body weight and lowering transaminase.
  • Example 44 (tablets) Weigh 800 g of berberine oxide, add appropriate pharmaceutical excipients, and press into 10,000 tablets each containing 80 mg of berberine oxide according to conventional methods, each with a net weight of 0.2 g. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of type 1 diabetes and type 2 diabetes. As a result, it was found that the above-mentioned tablet has a good hypoglycemic effect.
  • Example 45 (Tablet) 500 g of berberine oxide was weighed, added with appropriate pharmaceutical excipients, and prepared into a tablet containing 50 mg according to conventional methods. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. Combined with human insulin (20-40U daily insulin dose, subcutaneous injection) for the treatment of type 1 diabetes. The results showed that the combination of the above tablet and insulin can increase the hypoglycemic effect of insulin and reduce the dosage of insulin.
  • Example 46 (Tablet) Weigh 1000 g of berberine oxide, add appropriate pharmaceutical excipients, and prepare a tablet containing 100 mg of berberine oxide according to conventional methods. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. Combined with bovine insulin (40U daily insulin dose, subcutaneous injection) for the treatment of type 1 diabetes. It was found that the combination of the above tablet and insulin can increase the hypoglycemic effect of insulin and reduce the dosage and frequency of insulin.
  • bovine insulin 40U daily insulin dose, subcutaneous injection
  • Example 47 Weigh 500 g of berberine oxide and 500 g of metformin, add appropriate pharmaceutical excipients, and prepare 10,000 tablets according to conventional methods, each containing 50 mg of berberine oxide and 50 mg of metformin orally, 3 times a day, each 3 capsules at a time for 30 days. It is used in combination with long-acting insulin analogues Nuopin (40U daily insulin dose, subcutaneous injection) for the treatment of type 1 diabetes and type 2 diabetes. The results showed that the combination of the above tablet and insulin can increase the hypoglycemic effect of insulin and reduce the dosage and frequency of insulin.
  • Example 48 Weigh 500 g of berberine oxide and 500 g of glyburide, add appropriate pharmaceutical excipients, and prepare 10,000 tablets according to conventional methods, each containing 50 mg of berberine oxide and 50 mg of glyburide respectively. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of type 2 diabetes. As a result, it was found that the above-mentioned tablet has a highly effective hypoglycemic effect.
  • Example 49 Weigh 500 g of berberine oxide and 500 g of repaglinide, add appropriate pharmaceutical excipients, and prepare 10,000 tablets according to conventional methods, each containing 50 mg of berberine oxide and 50 mg of repaglinide, respectively. Oral, used to treat type 2 diabetes. As a result, it was found that the above-mentioned tablet has a highly effective hypoglycemic effect.
  • Example 50 (capsule) 100 g of berberine oxide was weighed, and appropriate pharmaceutical excipients were added, and each capsule was prepared into a capsule containing 25 mg of berberine oxide according to conventional methods. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of type 2 diabetes. As a result, it was found that the above-mentioned capsules have a hypoglycemic effect.
  • Example 51 (capsule) 200 g of berberine oxide was weighed, appropriate pharmaceutical excipients were added, and each capsule containing 50 mg of berberine oxide was prepared according to conventional methods. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of type 2 diabetes. As a result, it was found that the above-mentioned capsules have a hypoglycemic effect.
  • Example 52 (Capsule) 1000 g of berberine oxide and 500 g of acarbose were weighed, and appropriate pharmaceutical excipients were added, and each capsule was prepared according to conventional methods to prepare a capsule containing 100 mg of berberine oxide and 50 mg of acarbose. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of type 2 diabetes. As a result, it was found that the above-mentioned capsules have good hypoglycemic effect.
  • Example 53 (Dropping Pills) Take 300g of Berberine Oxide, add 1500g PEG4000 as a matrix, and liquid paraffin as a coolant; the dripping method is used to make dripping pills containing 6mg of Berberine Oxide per pill, and each pill has a net weight of 30mg. Oral, 3 times a day, 10 capsules each time; continuous service for 30 days. For the treatment of type 2 diabetes. As a result, it was found that the above-mentioned dropping pills have the effect of lowering blood sugar.
  • Example 54 (Dropping Pills) Weigh 1000 g of berberine oxide, add appropriate pharmaceutical excipients, and prepare dropping pills containing 30 mg of berberine oxide according to conventional methods. Oral, 3 times a day, 10 capsules each time; continuous service for 30 days. For the treatment of type 2 diabetes, it was found that the above-mentioned dripping pills have the effect of lowering blood sugar.
  • Example 55 (soft capsule) Weigh 125 g of berberine oxide, and press out 500 soft capsules each containing 250 mg of berberine oxide, each with a net mass of 800 mg, and liquid paraffin as a lubricant. Oral, 3 times a day, 1 capsule each time; continuous service for 30 days. For the treatment of type 2 diabetes, it was found that the above-mentioned soft capsules have hypoglycemic effect.
  • Example 56 (soft capsule) Weigh 200 g of berberine oxide, add appropriate excipients, and prepare soft capsules each containing 200 mg of berberine oxide according to conventional methods. Oral, 3 times a day, 1 capsule each time; continuous service for 30 days. For the treatment of type 2 diabetes, it was found that the above-mentioned soft capsules have hypoglycemic effect.
  • Example 57 (soft capsule) Weigh 100 g of berberine oxide, add appropriate excipients, and prepare soft capsules each containing 100 mg of berberine oxide according to conventional methods. Oral, 3 times a day, 2 capsules each time; continuous service for 30 days. For the treatment of type 2 diabetes. As a result, it was found that the above-mentioned soft capsules have a hypoglycemic effect.
  • Example 58 (tablet) Take 400 g of berberine oxide, add appropriate pharmaceutical excipients, and press into 10,000 tablets according to conventional methods, each tablet has a net weight of 0.2 g and each tablet contains 40 mg of berberine oxide. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of type 2 diabetes and gout. Results The tablet had the effect of lowering blood sugar and uric acid.
  • Example 59 Take 400 g of berberine oxide and 500 g of gliclazide, add appropriate pharmaceutical excipients, and press into 10,000 tablets according to conventional methods, each with a net weight of 0.25 g. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of type 2 diabetes and gout. Each capsule contains 40mg of berberine oxide. Results The tablet had the effect of lowering blood sugar and uric acid.
  • Example 60 (tablets) Weigh 500 g of berberine oxide and 500 g of metformin, add appropriate pharmaceutical excipients, and prepare 10,000 tablets according to conventional methods. Each tablet contains 50 mg of berberine oxide and 50 mg of metformin, respectively. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of diabetes and gout. As a result, it was found that the above-mentioned tablet has a good effect of lowering blood sugar and uric acid.
  • Example 61 (capsule) 500 g of berberine oxide was weighed, and appropriate pharmaceutical excipients were added, and 10,000 capsules were prepared according to conventional methods, each containing 50 mg of berberine oxide. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of diabetes and gout. As a result, it was found that the above capsules have hypoglycemic and uric acid-lowering effects.
  • Example 62 (tablets) Weigh 1000 g of berberine oxide, add appropriate pharmaceutical excipients, and prepare 10,000 tablets according to conventional methods, each containing 100 mg of berberine oxide. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of diabetes and gout. As a result, it was found that the above-mentioned tablet has a good effect of lowering blood sugar and uric acid.
  • Example 63 (Dropping Pills) Take 300 g of berberine oxide, add 1500 g of PEG4000 as a matrix, and an appropriate amount of liquid paraffin as a coolant; make dropping pills containing 6 mg of berberine oxide in each pill, with a net weight of 30 mg per pill. Oral, 3 times a day, 10 capsules each time; continuous service for 30 days. For the treatment of diabetes and gout. As a result, it was found that the above dropping pills have good hypoglycemic and uric acid-lowering effects.
  • Example 64 (Dropping Pills) Weigh 1000 g of berberine oxide, add appropriate pharmaceutical excipients, and prepare dropping pills containing 30 mg of berberine oxide according to conventional methods. Oral, 3 times a day, 5 capsules each time; continuous service for 30 days. For the treatment of diabetes and gout. As a result, it was found that the above dropping pills have a good effect of lowering blood sugar and uric acid.
  • Example 65 Take 1000 g of berberine oxide, add an appropriate amount of medicinal excipients such as hypromellose acetate succinate, micropowder silica gel, lactose, starch, etc., mix well, wet granulate, dry, and add stearin Mix 16 g of magnesium acid, and press into 10,000 tablets, each containing 100 mg of berberine oxide, and each tablet has a net weight of 0.3 g. Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of diabetes and hyperlipidemia. As a result, it was found that the above-mentioned sustained and controlled release tablets had good hypoglycemic and hypolipidemic effects.
  • medicinal excipients such as hypromellose acetate succinate, micropowder silica gel, lactose, starch, etc.
  • Example 66 (capsule) Take 1000 g of berberine oxide and 100 g of gliclazide, add an appropriate amount of pharmaceutical excipients such as lactose, hypromellose acetate succinate, micropowder silica gel, polyvinyl pyrrolidone, etc. granules, drying, adding 16 g of magnesium stearate and mixing to make 10,000 capsules (each capsule contains 100 mg of berberine oxide and 10 mg of gliclazide). Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of diabetes and hyperlipidemia, it was found that the capsules have good hypoglycemic and hypolipidemic effects.
  • pharmaceutical excipients such as lactose, hypromellose acetate succinate, micropowder silica gel, polyvinyl pyrrolidone, etc. granules, drying, adding 16 g of magnesium stearate and mixing to make 10,000 capsules (each capsule
  • Example 67 (capsule) Take 1000 g of berberine oxide and 100 g of sitagliptin, add an appropriate amount of medicinal excipients such as lactose starch, mix well, granulate, dry, add 16 g of magnesium stearate and mix well to make 10000 Capsules (each capsule contains 100 mg of berberine oxide and 10 mg of sitagliptin). Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of diabetes and hyperlipidemia. As a result, it was found that the above capsules have good hypoglycemic and hypolipidemic effects.
  • Example 68 (capsule) Take 1000 g of berberine oxide and 300 g of dapagliflozin, add an appropriate amount of pharmaceutical excipients such as lactose, starch, micropowder silica gel, polyvinyl pyrrolidone, mix well, granulate, dry, and add stearin Mix 16 g of magnesium acid to make 10,000 capsules (each capsule contains 100 mg of berberine oxide and 30 mg of dapagliflozin). Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of diabetes and hyperlipidemia. As a result, it was found that the above capsules have good hypoglycemic and hypolipidemic effects.
  • pharmaceutical excipients such as lactose, starch, micropowder silica gel, polyvinyl pyrrolidone, mix well, granulate, dry, and add stearin Mix 16 g of magnesium acid to make 10,000 capsules (each capsule contains 100 mg of ber
  • Example 69 (Capsules) Take 500 g of berberine oxide and 100 g of fenofibrate, add appropriate amount of appropriate pharmaceutical excipients, and make 10,000 capsules according to conventional methods (each capsule contains 50 mg of berberine oxide and fenofibrate). 10 mg). Oral, 3 times a day, 2 capsules each time; continuous service for 30 days. For the treatment of hyperglycemia and hyperlipidemia. As a result, it was found that the above capsules have good hypoglycemic and hypolipidemic effects.
  • Example 70 (Capsule) Take 500g of berberine oxide and 100g of probucol, add appropriate amount of appropriate pharmaceutical excipients, and make 10,000 capsules according to conventional methods (each capsule contains 50mg of berberine oxide and 10mg of probucol) . Oral, 3 times a day, 2 capsules each time; continuous service for 30 days. For the treatment of hyperglycemia and hyperlipidemia. As a result, it was found that the above capsules have good hypoglycemic and hypolipidemic effects.
  • Example 71 (Capsules) Take 500 g of berberine oxide and 100 g of rosuvastatin, add appropriate amount of pharmaceutical excipients, and make 10,000 capsules according to conventional methods (each capsule contains 50 mg of berberine oxide and rosuvastatin) 10 mg). Oral, 3 times a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperglycemia and hyperlipidemia. As a result, it was found that the above capsules have good hypoglycemic and hypolipidemic effects.
  • Example 72 (tablets) Take 400 g of berberine oxide, add appropriate amount of appropriate pharmaceutical excipients, and press into 10,000 tablets each containing 40 mg of berberine oxide according to conventional methods, each with a net weight of 0.2 g. Oral, 3 times a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperuricemia, hyperlipidemia. As a result, it was found that the above-mentioned tablet has good hypoglycemic and hypolipidemic effects.
  • Example 73 (Tablet) Weigh 500 g of berberine oxide and 100 g of rosuvastatin, add appropriate excipients, and prepare 10,000 tablets according to conventional methods (each tablet contains 50 mg of berberine oxide and 10 mg of rosuvastatin). Oral, 3 times a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperuricemia, hyperlipidemia. As a result, it was found that the above-mentioned tablet has good hypoglycemic and hypolipidemic effects.
  • Example 74 (tablets) Weigh 500 g of berberine oxide and 100 g of benzbromarone, add appropriate auxiliary materials, and prepare 10,000 tablets according to conventional methods (each tablet contains 50 mg of berberine oxide and 10 mg of benzbromarone). Oral, 3 times a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperuricemia and hyperlipidemia, it was found that the above-mentioned tablets have good uric acid and blood lipid-lowering effects.
  • Example 75 (tablets) Weigh 500 g of berberine oxide and 100 g of febuxostat, add appropriate excipients, and prepare 10,000 tablets according to conventional methods (each tablet contains 50 mg of berberine oxide and 10 mg of febuxostat). Oral, 1 time a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperuricemia and hyperlipidemia, it was found that the above-mentioned tablets have good uric acid and blood lipid-lowering effects. .
  • Example 76 (Capsules) Take 1000 g of berberine oxide and 400 g of gliclazide, add appropriate excipients, and make 10,000 capsules according to conventional methods (each capsule contains 100 mg of berberine oxide and 40 mg of gliclazide). Oral, 1 time a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperuricemia and hyperlipidemia, it was found that the above capsules have good effects of lowering uric acid and blood lipids.
  • Example 77 (tablets) Take 400 g of berberine oxide, add appropriate excipients, and press into 10,000 tablets each containing 40 mg of berberine oxide according to conventional methods, each with a net weight of 0.2 g. Oral, 3 times a day, 1 capsule each time; continuous service for 30 days. For the treatment of hyperuricemia after tumor chemotherapy. As a result, it was found that the above-mentioned tablet had a good effect of lowering uric acid, blood urea nitrogen and creatinine.
  • Example 78 (tablets) Weigh 500 g of berberine oxide, add an appropriate amount of pharmaceutical excipients such as microcrystalline cellulose, micropowder silica gel, polyvinyl pyrrolidone, etc., and prepare according to conventional methods to prepare 10,000 tablets (each tablet contains berberine oxide). 50mg). Oral, 3 times a day, 3 capsules each time; continuous service for 30 days. For the treatment of metabolic syndrome. As a result, it was found that the above-mentioned tablet has good effects of reducing body weight, reducing transaminase, reducing blood sugar, reducing blood lipid, reducing uric acid, blood urea nitrogen and creatinine.
  • pharmaceutical excipients such as microcrystalline cellulose, micropowder silica gel, polyvinyl pyrrolidone, etc.

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了氧化小檗碱在制备代谢性疾病药物中的应用及包含氧化小檗碱的药物组合物，属于生物医药技术领域。本发明所述的氧化小檗碱可用于制备代谢性疾病药物，也可用于制备具有降血糖、降血脂和降尿酸作用的药物组合物。氧化小檗碱在糖尿病、脂肪肝、高尿酸血症模型中具有良好的降糖、降脂和降尿酸作用，某些指标作用强度优于或接近阳性药和小檗碱，毒副作用小，并能改善相关器官病理损伤。氧化小檗碱有望开发成为一类具有降糖、降脂、降尿酸作用的创新药物，用于临床治疗肥胖、糖尿病、脂肪肝、痛风等代谢性疾病。

Description

氧化小檗碱在制备代谢性疾病药物中的应用及包含氧化小檗碱的药物组合物 技术领域
本发明属于生物医药技术领域，特别涉及氧化小檗碱在制备代谢性疾病药物中的应用及包含氧化小檗碱的药物组合物。
背景技术
随着生活水平提高，以糖尿病、脂肪肝、痛风为代表的代谢性疾病患病人数持续增加，且有年轻化的趋势。它们是现代社会所派生出来的“富贵病”，可能单独存在，也可能相互关联。高血糖、高血脂、高尿酸分别是糖尿病、脂肪肝和痛风的病理基础。机体中超量的糖、脂和尿酸，通过血液遍布全身，影响着各个组织器官，增加其他代谢器官的压力(如肾脏)，提高了心脑血管疾病的发生风险。因此，降糖、降脂、降尿酸是目前临床对各种代谢性疾病治疗的首要任务。然而，由于糖、脂、蛋白、核酸代谢涉及多器官、多通路协调运转，而目前临床用药靶标单一，常需要联合用药。这不仅会增加患者用药负担，还需要医师充分考虑药物组合有可能产生的副作用，故急需一种疗效全面，毒副作用小的新候选药物。
传统中药经过几千年临床应用实践，具有疗效确切、毒副作用小的优势。故从中药中寻找降糖、降脂的新药是目前研究热点之一。黄连具有清热燥湿，泻火解毒的功效，主治湿热痞满，消渴等症，其治疗的适应症与现代医学糖尿病、脂肪肝和痛风等代谢性疾病相似。小檗碱是黄连的主要化学成分，是一个经典的抗炎药物，现代多个基础和临床研究均证明该化合物具有显著的降低血糖、血脂和血尿酸，改善糖尿病、脂肪肝和痛风症状的作用。然而，小檗碱极低的口服生物利用度(＜1％)，制约着该药物的研究、开发与应用。
前体药物理论认为，某些药物经过生物体内代谢后，能转变为高活性、高生物利用度的结构。但目前未见有关氧化小檗碱预防和/或治疗代谢性疾病的报道。
发明内容
本发明的首要目的在于克服现有技术的缺点与不足，提供氧化小檗碱在制备代谢性疾病药物中的应用。
本发明的另一目的在于提供氧化小檗碱在制备具有降血糖、降血脂和降尿酸作用的药物组合物中的应用。
本发明的再一目的在于提供一种具有降血糖、降血脂和降尿酸作用的药物组合物及其应用。
本发明的上述目的通过以下技术方案予以实现：
氧化小檗碱在制备代谢性疾病药物中的应用。
所述的代谢性疾病药物包括治疗和/或预防代谢性疾病的药物。
所述的治疗和/或预防代谢性疾病的药物包含氧化小檗碱，和/或氧化小檗碱与药学上可接受的酸结合所形成的盐。
所述的药学上可接受的酸包括有机酸、无机酸和氨基酸中的至少一种。
所述的代谢性疾病包括高血糖、高血脂、高尿酸血症、尿酸性肾病、肥胖症、糖尿病、脂肪肝和痛风中的至少一种。
所述的糖尿病优选包括1型糖尿病和2型糖尿病中的至少一种。
所述的脂肪肝优选包括非酒精性脂肪肝。
所述的高尿酸血症优选包括由尿酸排泄不良型、合成过多型、混合型和肿瘤后化疗中的一种或几种引起的高尿酸血症。
氧化小檗碱在制备具有降血糖、降血脂和降尿酸作用的药物组合物中的应用。
一种具有降血糖、降血脂和降尿酸作用的药物组合物，包括氧化小檗碱，和/或氧化小檗碱与药学上可接受的酸结合所形成的盐。
所述的氧化小檗碱的分子式为：C 20H 17NO 5；分子量为：351.4；分子结构式如式I所示
Figure PCTCN2021102587-appb-000001
所述的氧化小檗碱的纯度优选为不低于90％；更优选为大于95％。
所述的药物组合物，还包括药学上可接受的载体。
所述的药学上可接受的载体优选包括填充剂、粘合剂、润滑剂、崩解剂、助溶剂、吸附载体、溶剂、抗氧化剂、吸附剂、渗透压调节剂和pH调节剂中的至少一种。
所述的润滑剂优选包括但不限于硬脂酸镁、石蜡。
所述的崩解剂优选包括但不限于羧甲淀粉钠、微晶纤维素、交联聚维酮和预胶化淀粉中的至少一种。
所述的助溶剂优选包括但不限于聚乙烯醇吡咯烷酮。
所述的填充剂优选包括但不限于聚乙二醇4000和淀粉中的至少一种。
所述的粘合剂优选包括但不限于交联聚维酮、糊精、淀粉浆和淀粉中的至少一种。
所述的糊精优选包括但不限于阿法环糊精。
所述的药物组合物，还包括含有降血糖、降血脂和降尿酸中的至少一种有效活性成分的物质。
所述的含有降血糖、降血脂和降尿酸至少一种有效活性成分的物质包括但不限于格列齐特、格列本脲、瑞格列奈、非布司他、苯溴马隆、瑞舒伐他汀、普罗布考、非诺贝特、达格列净、西格列汀和二甲双胍中的至少一种。
所述的药物组合物在制备用于治疗和/或预防代谢性疾病药物中的应用。
所述的代谢性疾病包括高血糖、高血脂、高尿酸血症、尿酸性肾病、肥胖症、糖尿病、脂肪肝和痛风中的至少一种。
由上述药物组合物制备的药物组合物制剂。所述的药物组合物制剂的剂型包括但不限于固体剂型、半固体剂型、液体剂型、糖浆剂、滴丸剂、缓控释制剂、缓释制剂、针剂、注射剂、乳剂和混悬剂中的至少一种剂型。
所述的固体剂型优选包括但不限于片剂、胶囊、颗粒、口崩片、缓释片、贴剂、微丸、滴丸、微囊和微球中的至少一种。
所述的液体剂型优选包括但不限于口服液和脂质体中的至少一种。
所述的针剂优选包括但不限于水针、冻干粉针和无菌粉针中的至少一种。
所述的药物组合物制剂的给药形式优选包括口服给药、皮下注射、肌肉注射和胃肠外给药形式中的至少一种。
本发明相对于现有技术具有如下的优点及效果：
(1)发明人通过对小檗碱体内代谢产物进行研究，发现其中一个代谢产物氧化小檗碱具有更好的降糖、降脂和降尿酸疗效；而且氧化小檗碱是小檗碱体内代谢产物，对人体安全性高，具有一定的开发潜能。
(2)氧化小檗碱在糖尿病、脂肪肝、高尿酸血症模型中具有良好的降糖、降脂和降尿酸作用，某些指标作用强度优于或接近阳性药和前药小檗碱，毒副作用小，并能改善相关器官病理损伤。氧化小檗碱有望开发成为一类具有降糖、降脂、降尿酸作用的创新药物，用于临床治疗肥胖、糖尿病、脂肪肝、痛风等代谢性疾病。
附图说明
图1为实验流程图。
图2为实施例1中不同时间小鼠的体重变化结果图。
图3为实施例2中各组大鼠4周内的体重和空腹血糖(FBG)变化结果图；其中，图A为各组大鼠4周内的体重变化结果图；图B为各组大鼠4周内的空腹血糖(FBG)变化结果图。
图4为实施例2中各组大鼠的空腹胰岛素(FINS)和β细胞功能变化结果图；其中，图A为各组大鼠的空腹胰岛素(FINS)含量结果图；图B为各组大鼠的β细胞功能结果图。
图5为实施例2中各组口服糖耐量试验血糖水平和口服糖耐量试验葡萄糖曲线下面积AUC的比较结果图；其中，图A为各组大鼠的口服糖耐量试验血糖水平结果图；图B为各组大鼠口服糖耐量试验葡萄糖曲线下面积AUC的比较结果图。
图6为实施例2中各组药物对大鼠胰腺组织的影响(HE染色)结果图。
图7为实施例3中各组大鼠10周内的体重和空腹血糖(FBG)变化结果图；其中，图A为各组大鼠10周内的体重变化结果图；图B为各组大鼠10周内的空腹血糖(FBG)变化结果图。
图8为实施例3中各组大鼠的空腹胰岛素和胰岛素抵抗指数结果图；其中，图A为各组大鼠的空腹胰岛素含量结果图；图B为各组大鼠胰岛素抵抗指数结果图。
图9为实施例3中各组口服糖耐量试验血糖水平和口服糖耐量试验葡萄糖曲线下面积AUC的比较结果图；其中，图A为各组大鼠的口服糖耐量试验血糖水平结果图；图B为各组大鼠口服糖耐量试验葡萄糖曲线下面积AUC的比较结果图。
图10为实施例3中各组大鼠血脂指标的变化结果图；其中，图A为各组大鼠的血清糖化血清蛋白(GSP)含量变化结果图；图B为各组大鼠的血清游离脂肪酸(NEFA)含量变化结果图；图C为各组大鼠的血清甘油三酯(TG)含量变化结果图；图D为各组大鼠的血清总胆固醇(TC)含量变化结果图；图E为各组大鼠的血清高密度脂蛋白胆固醇(HDL-c)含量变化结果图；图F为各组大鼠的血清血清低密度脂蛋白(LDL-c)含量变化结果图。
图11为实施例3中各组药物对大鼠肝组织的影响(油红O染色)结果图。
图12为实施例3中各组药物对大鼠胰腺组织的影响(HE染色)结果图。
图13为实施例4中不同药物对L02细胞非酒精性脂肪肝模型的干预作用结果图；其中，图A为各组细胞存活率结果图；图B为各组细胞内甘油三酯(TG)含量结果图；图C为各组细胞内谷丙转氨酶(ALT)含量结果图；图D为各组细胞内天冬氨酸转氨酶(AST)含量结果图。
图14为实施例4中不同药物对L02细胞干预后细胞的脂肪含量(油红O染色)结果图。
图15为实施例5中各组大鼠的体重变化结果图。
图16为实施例5中各组大鼠的组织重量结果图。
图17为实施例5中各组大鼠的组织指数结果图。
图18为实施例5中各组大鼠血脂指标的变化结果图；其中，图A为各组大鼠的血清甘油三酯(TG)浓度结果图；图B为各组大鼠的血清总胆固醇(TC)浓度结果图；图C为各组大鼠的血清高密度脂蛋白胆固醇(HDL-c)浓度结果图；图D为各组大鼠的血清低密度脂蛋白胆固醇(LDL-c)浓度结果图；图E为各组大鼠的血清游离脂肪酸(FFA)浓度结果图。
图19为实施例5中各组大鼠空腹血糖、血清胰岛素和胰岛素抵抗指数指标的变化结果图；其中，图A为实施例5中各组大鼠的空腹血糖(FBG)浓度结果图；图B为实施例5中各组大鼠的血清胰岛素(FINS)浓度结果图；图C为实施例5中各组大鼠的胰岛素抵抗指数(HOMA-IR)结果图。
图20为实施例5中各组大鼠肝功能相关指标的变化结果图；图A为实施例5中各组大鼠的血清丙氨酸氨基转移酶(ALT)结果图；图B为实施例5中各组大鼠的血清谷草转氨酶(AST)结果图。
图21为实施例5中各组大鼠经药物处理后的肝结果图。
图22为实施例5中各组大鼠经药物处理后的肝脏HE染色结果图。
图23为实施例5中各组大鼠经药物处理后的肝组织油红O染色结果图。
图24为实施例6中各组小鼠10天内的体重变化结果图。
图25为实施例6中各组小鼠的肝重和肝指数结果图。
图26为实施例6中各组小鼠的肾重和肾指数结果图。
图27为实施例6中各组小鼠的脾脏重和脾脏指数结果图。
图28为实施例6中不同药物对小鼠肾脏高尿酸血症的代表性治疗效果图。
图29为实施例6的九组小鼠分别经相应药物处理后的肾脏治疗整体效果图。
图30为实施例6中各组小鼠分别经药物处理后肾脏HE染色结果图。
图31为实施例6中各组小鼠血尿酸、尿素氮、肌酐含量和体外实验中XO酶抑制结果图；其中，图A为各组小鼠血清尿酸含量结果图；图B为各组小鼠血清尿素氮含量结果图；图C为各组小鼠肌酐含量结果图；图D为体外实验中XO酶抑制结果图。
图32为实施例7中各组小鼠10天内的体重、血尿酸、肌酐和尿素氮含量结果图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
本申请实施例中：GSP是利用糖化血清蛋白测定试剂盒测定；NEFA是利用游离脂肪酸测定试剂盒测定；FBG是利用血糖测定试剂盒测定；FINS是利用胰岛素测定试剂盒测定(购于上海酶联生物科技有限公司)；TG是利用甘油三酯测定试剂盒测定；TC是利用总胆固醇测定试剂盒测定；HDL-c是利用高密度脂蛋白胆固醇测定试剂盒测定；LDL-c是利用低密度脂蛋白胆固醇测定试剂盒测定；ALT是利用谷丙转氨酶测定试剂盒测定；AST是利用谷草转氨酶测定试剂盒测定；UA是利用尿酸测定试剂盒测定；CRE是利用肌酐测定试剂盒测定；BUN是利用尿素氮测定试剂盒测定；上述试剂盒若非特别说明均购于南京建成生物工程研究所，具体操作步骤按照试剂盒说明书进行。
FFA是利用游离脂肪酸测定试剂盒(购于上海酶联生物科技有限公司)按照试剂盒说明书进行测定。
HOMA-β和HOMA-IR利用FBG和FINS的数据分别按以下公式计算：
Figure PCTCN2021102587-appb-000002
Figure PCTCN2021102587-appb-000003
小檗碱购于成都瑞芬思生物科技有限公司。
氧化小檗碱根据文献(Dostal J,Man S,Seckarova P,et al.Berberine and coptisine free bases[J].Journal of Molecular Structure.2004(687):135-142.中的方法进行制备和鉴定。氧化小檗碱的纯度大于95％。
别嘌呤醇购买于北京百灵威科技有限公司；非布司他和苯溴马隆购买于上海源叶生物科技有限公司；次黄嘌呤、氧嗪酸钾及XO酶购买于Sigma-Aldrich公司；二甲双胍、黄嘌呤购买于美仑生物技术有限公司。
本申请的实验流程如图1所示。
实施例1：氧化小檗碱急性经口毒性试验
试验动物及方法：
根据中华人民共和国国家标准的《化学品：化学品急性经口毒性试验方法(GB/T21603–2008)》测定氧化小檗碱(OBB)的半数致死量(LD 50)。KM小鼠(由广东省实验动物中心提供；下同)，SPF级，体重20±2g，随机分成六组(每组10只，雌雄各半)。OBB-1～5组小鼠按0.1mL/10g体重一次性灌胃，每日给药剂量依次为：50.2mg/kg、162.0mg/kg、512.2mg/kg、1638.0mg/kg、5243.6mg/kg；空白组给予等体积的0.5％Tween 80。
给药后，小鼠自由获取食物和水，并连续观察14天，每两天记录小鼠的体重变化、摄食量等日常生活状况及死亡状况。此外，在给药后12小时内，每隔3小时观察记录各组小鼠的毒性反应，死亡数和死亡时间，给药12小时之后每隔6小时观察记录以上指标。结果如下表1-1和1-2和图2所示。
表1-1：氧化小檗碱小鼠急性毒性试验结果
Figure PCTCN2021102587-appb-000004
表1-2：急性毒性试验小鼠体重变化
Figure PCTCN2021102587-appb-000005
如表1-1和1-2所示，氧化小檗碱各剂量组在14天内未见明显异常和死亡，结果表明：氧化小檗碱LD 50值大于5243.6mg/kg，属于低毒化学品。
实施例2：氧化小檗碱对1型糖尿病的治疗
1、实验动物及方法
本实验采用链脲佐菌素(streptozocin，STZ；购自上海翊圣生物科技有限公司)诱导1型糖尿病模型探究氧化小檗碱对大鼠1型糖尿病的作用。60只SPF级雄性SD大鼠(由广东省实验动物中心提供，下同；)，体重220±10g，随机分为正常对照组(Con组，n＝10)以及造模组(50只)。造模组大鼠空腹12h一次性腹腔注射STZ的柠檬酸缓冲液(STZ的柠檬酸缓冲液中STZ的给药剂量为60mg/kg，STZ的柠檬酸缓冲液由0.1mol/L、pH＝4.5柠檬酸缓冲液配制)构建大鼠1型糖尿病模型(正常组注射等量缓冲液)。一周后测定大鼠空腹血糖，空腹血糖大于13.8mmol/L者视为造模成功。造模成功大鼠随机分为模型组(T1DM组)，阳性对照组(二甲双胍Met组，300mg/kg)，小檗碱BBR组(100mg/kg)，OBB低剂量组(50mg/kg)与OBB高剂量组(100mg/kg)组，每组10只。Met组、BBR组与OBB组大鼠均每日灌胃给予对应药物和剂量，正常对照组(Con组)和T1DM灌胃等量生理盐水， 所有大鼠每周测定空腹血糖和体重。各组连续干预4周后处死大鼠，测定1型糖尿病相关指标。实验结果如下表和图3-6所示，具有显著的统计学差异。
2、实验结果
表2-1：各组大鼠4周内的体重变化(单位：g)
Figure PCTCN2021102587-appb-000006
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与T1DM组比较； &p＜0.05， &&p＜0.01，与T1DM+BBR-100组比较
表2-2：各组大鼠4周内的空腹血糖变化(单位：mmol/L)
Figure PCTCN2021102587-appb-000007
注： #p＜0.05， ##p与Con组比较； *p＜0.05， **p＜0.01，与T1DM组比较； &p＜0.05， &&p＜0.01，与T1DM+BBR-100组＜0.01比较
表2-3：各组大鼠空腹血糖、空腹胰岛素和β细胞功能指标的变化
Figure PCTCN2021102587-appb-000008
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与T1DM组比较； &p＜0.05， &&p＜0.01，与T1DM+BBR-100组比较
表2-4：各组大鼠口服糖耐量试验血糖水平(单位：mmol/L)及葡萄糖曲线下面积AUC的比较
Figure PCTCN2021102587-appb-000009
Figure PCTCN2021102587-appb-000010
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与T1DM组比较； &p＜0.05， &&p＜0.01，与T1DM+BBR-100组比较
结果表明：给药结束后，正常对照组大鼠毛色正常，精神状态良好，未见行为异常；糖尿病大鼠毛色杂乱，饮水、尿量增多，行动迟缓，氧化小檗碱治疗后，以上症状有所改善。与T1DM组相比，口服氧化小檗碱显著减缓了体重减轻和空腹血糖水平。此外，氧化小檗碱给药可显著提高空腹胰岛素水平和胰岛素β细胞功能水平(HOMA-β)。糖尿病大鼠在经过氧化小檗碱处理后，30min、60min、120min的血糖水平及血糖浓度-时间AUC曲线下面积均小于T1DM组，且有极显著性差异(p<0.01)，提示氧化小檗碱能够改善高剂量链脲佐菌素所引起的血糖升高及糖耐量受损情况。经HE染色法对大鼠胰腺组织进行病理切片，病理切片结果(如图6)显示，糖尿病大鼠经过OBB处理后，胰岛结构明显改善，细胞排列较为整齐，腺泡小叶结构较为完整。此外，在控制空腹血糖水平，减轻体重下降，提高胰岛素分泌水平和改善糖耐量等方面，高剂量氧化小檗碱和二甲双胍效果相当，均较其相同剂量下的小檗碱强。
实施例3：氧化小檗碱对2型糖尿病的治疗
1、实验动物及方法：
本实验采用经典的2型糖尿病模型探究氧化小檗碱对大鼠2型糖尿病的作用。将60只雄性SD大鼠(体重220±10g)适应性喂养7d后被随机分为2组，分别为正常对照组(Con组，n＝10)，造模组(n＝50)。造模组D12492高脂饲料(购于广东省医学实验动物中心)喂养4周后，一次性腹腔注射STZ的柠檬酸缓冲液(STZ的柠檬酸缓冲液中STZ的给药剂量为40mg/kg，STZ的柠檬酸缓冲液由0.1mol/L、pH＝4.5柠檬酸缓冲液配制)用于诱发Ⅱ型糖尿病，正常对照组腹腔注射等体积柠檬酸钠缓冲液。STZ注射72h后，使用血糖仪检测大鼠空腹血糖，以空腹血糖>13.8mmol/L为模型造模成功标准。将造模成功的大鼠随机分为：模型组(T2DM)，阳性对照组(二甲双胍Met组，300mg/kg)，小檗碱BBR组(100mg/kg)，OBB低剂量组(50mg/kg)与OBB高剂量组(100mg/kg)组，每组10只。除Con组和T2DM模型组灌胃生理盐水外，Met组、BBR组与OBB组均灌胃对应剂量的药物，每日一次。所有大鼠每周测定空腹血糖和体重。各组连续干预6周后处死大鼠，测定2型糖尿病相关指标。实验结果如下表和图7-12所示，具有显著的统计学差异。
2、实验结果
表3-1：各组大鼠10周内的体重变化(单位：g)
Figure PCTCN2021102587-appb-000011
Figure PCTCN2021102587-appb-000012
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与T2DM组比较； &p＜0.05， &&p＜0.01，与T2DM+BBR-100组比较
表3-2：各组大鼠10周内的空腹血糖变化(mmol/L)
Figure PCTCN2021102587-appb-000013
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与T2DM组比较； &p＜0.05， &&p＜0.01，与T2DM+BBR-100组比较
表3-3：各组大鼠空腹血糖、空腹胰岛素和胰岛素抵抗指数指标的变化
Figure PCTCN2021102587-appb-000014
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与T2DM组比较； &p＜0.05， &&p＜0.01，与T2DM+BBR-100组比较
表3-4：各组大鼠口服糖耐量试验血糖水平(单位：mmol/L)及葡萄糖曲线下面积AUC的比较
Figure PCTCN2021102587-appb-000015
Figure PCTCN2021102587-appb-000016
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与T2DM组比较； &p＜0.05， &&p＜0.01，与T2DM+BBR-100组比较
表3-5：各组大鼠血脂指标的变化
Figure PCTCN2021102587-appb-000017
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与T2DM组比较； &p＜0.05， &&p＜0.01，与T2DM+BBR-100组比较
正常对照组大鼠精神状态良好、反应敏捷、毛色鲜亮有光泽，实验过程中饮食、饮水和尿量正常，体重逐渐增加。经过4周高脂喂养的造模组大鼠体重明显增加，精神状态尚可，饮水和尿量无明显变化。成模后的糖尿病大鼠体重明显减轻，精神萎靡、反应迟钝、活动减少、毛色枯黄无光泽，并且伴有多饮、多食和明显的多尿症状。给予氧化小檗碱干预6周后，大鼠体重降低、多饮、多食、多尿、精神萎靡等症状明显改善。与模型组相比，氧化小檗碱干预组空腹胰岛素水平(图8，表3-3)显著恢复，空腹血糖与胰岛素抵抗指数(HOMA-IR)均显著下降。OGTT实验结果显示，在口服葡萄糖30min、60min和120min后，氧化小檗碱干预组血糖及AUC均显著低于糖尿病模型组。给予氧化小檗碱干预后，血清中游离脂肪酸(NEFA)、总甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL-C)、糖化血清蛋白(GSP)均显著下降，HDL-C水平则显著回升。利用油红O脂肪染色法对大鼠肝组织进行染色，油红O染色结果(图11)显示，与正常对照组相比较，糖尿病对照组大鼠肝脏脂肪堆积上升明显，肝细胞界限不清，脂肪滴形状不规则，面积较大。给予氧化小檗碱干预后肝脏脂肪堆积显著减少，肝细胞界限相对清晰，部分肝细胞内偶见红色脂滴，面积较小。经HE染色法对大鼠胰腺组织进行病理切片，病理切片结果(如图12)显示，在光学显微镜下观察，正常对照组大鼠的胰岛结构完整，呈团索状，岛内细胞界限清晰可见，细胞多呈圆形或椭圆形，大小正常，形态饱满，分布均匀，排列紧密规整。与正常对照组相比，糖尿病对照组大鼠的胰岛出现明显的萎缩现象，未见到清晰的岛内细胞界限，细胞形态结构不规整，排列紊乱，细胞核出现部分固缩深染，胰岛间质大量纤维化多呈松网状并伴有大量空泡。与糖尿病对照组相比，氧化小檗碱干预后能见到胰岛形态结构不同程度的改善，胰岛萎缩明显好转，结构趋于完整，岛内细胞数量增多，形态较好，空泡样变减少，增生和炎性浸润。此外，高剂量氧化小檗碱作用效果略逊于其3倍剂量的二甲双胍，但在降低血糖、改善胰岛素抵抗、减轻体重下降、降低血清游离脂肪酸和总胆固醇等方面显著优于相同剂量下的小檗碱。
实施例4：氧化小檗碱对L02细胞非酒精性脂肪肝模型的干预作用
1、实验细胞及方法
培养正常人L02细胞株(购于ATCC)，饥饿6h后，分别给予正常RPMI-1640培养基(购于ThermoFisher公司)、高脂培养基、含0.2％(v/v)DMSO(购于Sigma-Aldrich公司)、氧化小檗碱(10μM、20μM、40μM)、小檗碱(BBR，40μM)和二甲双胍(Met，5mM)高脂培养基，孵育24h。其中，高脂培养基指含1mM游离脂肪酸(FFA)混合物(油酸∶软脂酸按摩尔比＝2:1)的RPMI-1640培养基；氧化小檗碱和小檗碱使用DMSO (Sigma-Aldrich公司)分别配制成含20mM氧化小檗碱的母液和含20mM小檗碱的母液，二甲双胍使用PBS缓冲液(购于ThermoFisher公司；pH＝7.4)配制成含1M的二甲双胍母液；药物母液用高脂培养基稀释至上述浓度。观察指标如下：
1)细胞存活率(利用CCK-8试剂盒，450nm波长处测定其光吸收值间接反映活细胞数量；CCK-8试剂盒购自于大连美仑生物技术有限公司)；
2)细胞内TG；
3)细胞内ALT和AST；
4)油红染色(利用油红染色法)。
2、实验结果
给药结束后测定上述指标水平，实验数据以
Figure PCTCN2021102587-appb-000018
表示并进行方差分析。
结果如下表和图13-14所示。
表4-1：各组细胞存活率(单位：％)
Figure PCTCN2021102587-appb-000019
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与FFA组比较； &p＜0.05， &&p＜0.01，与FFA+BBR-40组比较
表4-2：各组细胞内甘油三酯(TG)含量(μM/g Prot)
Figure PCTCN2021102587-appb-000020
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与FFA组比较； &p＜0.05， &&p＜0.01，与FFA+BBR-40组比较
表4-3：各组细胞内谷丙转氨酶(ALT)、天冬氨酸转氨酶(AST)含量(单位：IU/L)
Figure PCTCN2021102587-appb-000021
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与FFA组比较； &p＜0.05， &&p＜0.01，与FFA+BBR-40组比较
结果表明，氧化小檗碱和小檗碱均能减少脂肪在肝细胞内累积，显著降低细胞中TG、ALT和AST含量，保护肝细胞。其中，在降低ALT和AST含量方面同等剂量(40μM)下OBB优于BBR。
实施例5：氧化小檗碱对高脂血症和非酒精性脂肪肝的治疗
1、实验动物及方法
雄性SD大鼠，SPF级，体重200±10g，随机分成四组(每组8只)：正常组(Con)、模型组(HFD)、二甲双胍组(HFD+Met-300)、氧化小檗碱低剂量组(HFD+OBB-50)、氧化小檗碱高剂量组(HFD+OBB-100)、小檗碱组(HFD+BBR-100)。除正常组给予正常饲料(购于广东省医学实验动物中心)外，其余组给予高脂饲料(购于广东省医学实验动物中心)，并同时灌胃给药8周。二甲双胍组在高脂饮食同时灌胃300mg/kg二甲双 胍，小檗碱组灌胃100mg/kg小檗碱，氧化小檗碱低、高剂量组分别灌胃50mg/kg和100mg/kg氧化小檗碱。
观察指标：
1)8周体重变化；
2)肝脏和脂肪组织重；
3)血脂相关指标：TG、TC、FFA、HDL-c、LDL-c；
4)血糖相关指标：FBG；
5)胰岛素抵抗相关指标：FINS、HOMA-IR；
6)肝功能相关指标：ALT、AST；
7)病理学检查：肝脏HE染色、油红O染色。
2、实验结果
给药结束后测定上述指标水平，实验数据以
Figure PCTCN2021102587-appb-000022
表示并进行方差分析。
结果如下表和图15-23所示。
表5-1：各组大鼠体重变化(单位：g)
Figure PCTCN2021102587-appb-000023
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与HFD组比较； &p＜0.05， &&p＜0.01，与HFD+BBR-100组比较
表5-2：各组大鼠肝脏和脂肪组织重量
Figure PCTCN2021102587-appb-000024
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与HFD组比较； &p＜0.05， &&p＜0.01，与HFD+BBR-100组比较
表5-3：各组大鼠血脂指标的变化
Figure PCTCN2021102587-appb-000025
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与HFD组比较； &p＜0.05， &&p＜0.01，与HFD+BBR-100组比较
表5-4：各组大鼠空腹血糖、血清胰岛素和胰岛素抵抗指数指标的变化
Figure PCTCN2021102587-appb-000026
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与HFD组比较； &p＜0.05， &&p＜0.01，与HFD+BBR-100组比较
表5-5：各组大鼠肝功能相关指标的变化
Figure PCTCN2021102587-appb-000027
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与HFD组比较； &p＜0.05， &&p＜0.01，与HFD+BBR-100组比较
结果表明：氧化小檗碱可减慢体重增长，减少肝脏和脂肪组织重量，显著降低血清中总甘油三酯(TG)、总胆固醇(TC)和游离脂肪酸(FFA)，升高高密度脂蛋白(HDL-c)，降低低密度脂蛋白(LDL-c)；降低空腹血糖(FBG)，升高胰岛素(FINS)，降低胰岛素抵抗指数(HOMA-IR)；降低血清中丙氨酸转氨酶(ALT)和天门冬氨酸转氨酶(AST)；图21-23经药物处理后的肝及其病理切片结果显示氧化小檗碱能够有效减少肝脏脂肪堆积，保护肝细胞形态，改善因脂肪变性导致的肝功能损害。
其中，相同剂量(100mg/kg)氧化小檗碱和小檗碱疗效相似。在降低体内脂肪重量指数、降低血清游离脂肪酸(FFA)、升高胰岛素和降低转氨酶方面，氧化小檗碱明显优于小檗碱。低剂量(50mg/kg)氧化小檗碱虽然效果稍弱，但大部分指标水平也接近小檗碱(100mg/kg)。二甲双胍剂量(300mg/kg)是氧化小檗碱(100mg/kg)的3倍，但两者疗效并无显著性差异。
实施例6：氧化小檗碱对高尿酸血症的治疗
1、实验动物及方法：
雄性KM小鼠，SPF级，体重20±2g，随机分成九组(每组10只)：空白对照组(Con组)，模型组(HUA)，别嘌呤醇组(AP，5mg/kg)，非布司他组(FEB，5mg/kg)，苯溴马隆组(BEN，5mg/kg)，OBB低剂量组 (5mg/kg)，OBB中剂量组(10mg/kg)，OBB高剂量组(20mg/kg)，BBR组(100mg/kg)。小鼠购买回来后，适应性喂养一周。之后每天上午9点开始给药造模，除空白对照组外，其余各组小鼠均腹腔注射氧嗪酸钾(300mg/kg)和灌胃次黄嘌呤(300mg/kg)构建高尿酸血症模型，空白对照组皮下注射等体积生理盐水和灌胃等体积生理盐水。造模1h后，灌胃相应浓度的受试物。空白对照组灌胃等体积生理盐水，三组阳性对照组分别按5mg/kg体重灌胃阳性药别嘌呤醇、非布司他和苯溴马隆，其他药物组灌胃相应浓度的药物。实验共进行10天。
观察指标：
1)10天体重变化；
2)脏器重量及脏器指数；
3)肾脏外观；
4)肾脏HE染色；
5)血尿酸UA含量；
6)肾功能相关指标：CRE、BUN；
7)对XO酶的体外抑制作用；
XO酶体外抑制实验方法：
分别精密吸取各种浓度的样品溶液50μL，黄嘌呤氧化酶(XO酶)7μL(0.4unit/mL)及10mM PBS溶液(pH＝7.2，购买于ThermoFisher公司)77μL，于37℃共孵育15min后，加入黄嘌呤储备液(400μM)66μL启动反应，37℃反应30min后，在反应液中加入1％(v/v)盐酸50μL终止反应，以空白组(以PBS溶液代替XO酶溶液，其余不变)调零，在290nm处测定样品组A，即为A s，再以阴性对照组(134μL PBS+66μL黄嘌呤)调零，在290nm处测定空白对照组(以PBS溶液代替测试样品，其余不变)A，即为A 0，每个样品平行测定3次。XO抑制率的计算如下：
抑制率(％)＝(1-A s/A 0)×100％；
式中：A 0为未加样品的黄嘌呤氧化酶活力的吸光度值；A s为加入样品的黄嘌呤氧化酶活力的吸光度值。
2、实验结果
给药结束后测定上述指标水平，实验数据以
Figure PCTCN2021102587-appb-000028
表示并进行方差分析。
结果如下表和图24-31所示。
表6-1：各组小鼠10天内的体重变化(单位：g)
Figure PCTCN2021102587-appb-000029
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与HUA组比较
表6-2：各组小鼠器官重量(g)及器官指数(％)
Figure PCTCN2021102587-appb-000030
Figure PCTCN2021102587-appb-000031
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与HUA组比较
表6-3：各组小鼠血尿酸(μmol/L)、尿素氮(mmol/L)、肌酐含量(μmol/L)
Figure PCTCN2021102587-appb-000032
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与HUA组比较
结果表明：阳性药别嘌呤醇、非布司他、苯溴马隆均可明显降低血尿酸水平，受试药小檗碱和氧化小檗碱也均可明显降低血尿酸水平，氧化小檗碱作用强度呈剂量依赖关系，10mg/kg氧化小檗碱作用效果优于阳性药5mg/kg苯溴马隆、100mg/kg小檗碱，并与5mg/kg别嘌醇、5mg/kg非布司他作用效果相当。
在体外实验中，阳性药别嘌醇表现出明显的XO酶抑制作用，但氧化小檗碱和小檗碱对XO酶的抑制作用均不明显。
模型组在升高尿酸的同时，并可增加肾脏及脾脏指数，并可升高尿素氮和肌酐，具有明显的肾损害。阳性药别嘌醇、非布司他和苯溴马隆显著降低血清中尿酸(UA)水平的同时，却可降低小鼠体重增长速率、增加肾脏及脾脏指数，并可进一步升高尿素氮(BUN)，加重肾脏损伤。而氧化小檗碱和小檗碱均可显著降低血清中尿酸(UA)、尿素氮(BUN)水平的同时，对小鼠体重增长、肾脏及脾脏指数无影响，提示具有肾脏保护作用。
结果显示，氧化小檗碱具有明显的降低血尿酸水平，作用效果优于现有药物，或与现有药物作用相当；并且具有肾脏保护作用。由此可见，与现有降尿酸药物相比，氧化小檗碱作用效果优于现有药物，且没有现有药物的肝肾损害等副作用。
实施例7：氧化小檗碱对5-FU引起的高尿酸血症的治疗
1、实验动物及方法：
雄性KM小鼠，SPF级，体重22±2g，随机分成六组(每组10只)：空白对照组(Con组)，模型组(HUA)，BBR组(50mg/kg)，OBB低剂量组(12.5mg/kg)，OBB中剂量组(25mg/kg)，OBB高剂量组(50mg/kg)。小鼠购买回来后，适应性喂养一周。之后每天上午9点开始给药造模，除空白对照组外，其余各组小鼠均腹腔注射五氟尿嘧啶(5-FU，60mg/kg)构建高尿酸血症模型，空白对照组皮下注射等体积生理盐水。造模0.5h后，灌胃相应浓度的受试物。空白对照组灌胃等体积生理盐水，BBR对照组和OBB药物组灌胃相应浓度的药物。实验共进行7天。
观察指标：
1)7天体重变化；
2)血尿酸UA含量；
3)肾功能相关指标：CRE、BUN；
2、实验结果
给药结束后测定上述指标水平，实验数据以
Figure PCTCN2021102587-appb-000033
表示并进行方差分析。
结果如下表和图32所示。
表7-1：各组小鼠7天内的体重变化(单位：g)
Figure PCTCN2021102587-appb-000034
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与5-FU组比较
表7-2：各组小鼠血尿酸(μmol/L)、尿素氮(mmol/L)、肌酐含量(μmol/L)
Figure PCTCN2021102587-appb-000035
注： #p＜0.05， ##p＜0.01，与Con组比较； *p＜0.05， **p＜0.01，与5-FU组比较
结果表明：5-FU在升高尿酸的同时，可升高尿素氮和肌酐，且小鼠体重降低，具有肾损害。对照药小檗碱和受试药氧化小檗碱均可明显降低血尿酸、尿素氮(BUN)和肌酐(CRE)水平，且对小鼠体重增长无影响；氧化小檗碱降低血尿酸、尿素氮(BUN)和肌酐(CRE)作用强度，均呈剂量依赖关系，25mg/kg氧化小檗碱作用效果优于小檗碱50mg/kg。结果显示，氧化小檗碱具有明显的降低血尿酸水平，并且具有肾脏保护作用；氧化小檗碱作用效果优于小檗碱。
实施例8：药物组合物的制备
例1：(片剂)取氧化小檗碱500g，加入交联聚维酮500g、淀粉754g、微晶纤维素250g，混合均匀，用5％(w/v)的淀粉浆300g作为粘合剂，湿法制粒，烘干，加入硬脂酸镁16g混匀，按照常规方法压制成每片含氧化小檗碱50mg的片剂10000片，每片净重0.2g。口服，每日2次，每次3粒；连服30天，用于治疗糖尿病、脂肪肝、痛风为代表的代谢性疾病。结果发现上述片剂具有良好的降血糖、血脂和尿酸的效果。
例2：(片剂)称取氧化小檗碱200g，加入阿法环糊精1000g，药用辅料适当按照常规方法配制成每片含氧化小檗碱20mg的片剂10000片。口服，每日2次，每次3粒；连服30天，用于糖尿病、脂肪肝、痛风为代表的代谢性疾病。结果发现上述片剂具有良好的降血糖、血脂和尿酸的效果。
例3：(片剂)称取氧化小檗碱1000g，加入醋酸羟丙甲纤维素琥珀酸酯、微粉硅胶、聚乙烯醇吡咯烷酮等药用辅料适量，按照常规方法配制成每片含氧化小檗碱100mg的缓控释片剂10000片。口服，每日2次，每次3粒；连服30天，用于治疗糖尿病、脂肪肝、痛风为代表的代谢性疾病。结果发现上述缓控释片剂具有良好的降血糖、血脂和尿酸的效果。
例4：(片剂)称取氧化小檗碱500g和二甲双胍500g，加入适当药用辅料，按照常规方法配制成10000粒片剂。口服，每日2次，每次3粒；连服30天，用于治疗糖尿病、脂肪肝、痛风为代表的代谢性疾病。结果发现上述片剂具有良好的降血糖、降血脂和降尿酸的效果。
例5：(胶囊剂)称取500g氧化小檗碱，加入适当药用辅料，按照常规方法配制成每粒含氧化小檗碱50mg的胶囊剂10000粒。口服，每日2次，每次3粒；连服30天，用于治疗糖尿病、脂肪肝、痛风为代表的代谢性疾病。结果发现上述胶囊剂具有良好的降血糖、降血脂和降尿酸的效果。
例6：(胶囊剂)称取氧化小檗碱200g，加入适当药用辅料，按照常规方法配制成含每粒含氧化小檗碱20mg的胶囊剂10000粒。口服，每日2次，每次3粒；连服30天，用于治疗糖尿病、脂肪肝、痛风为代表的代谢性疾病。结果发现上述胶囊剂具有良好的降血糖、降血脂和降尿酸的效果。
例7：(胶囊剂)称取氧化小檗碱1000g，加入适当药用辅料，按照常规方法配制成含每粒含氧化小檗碱100mg的缓释胶囊剂10000粒。口服，每日2次，每次3粒；连服30天，用于治疗糖尿病、脂肪肝、痛风为代表的代谢性疾病。结果发现上述缓释胶囊剂具有良好的降血糖、降血脂和降尿酸的效果。
例8：(胶囊剂)称取氧化小檗碱500g和二甲双胍500g，加入适当药用辅料，按照常规方法配制成10000粒胶囊剂，每粒含氧化小檗碱50mg。口服，每日2次，每次3粒；连服30天，用于治疗糖尿病、脂肪肝、痛风为代表的代谢性疾病。结果发现上述胶囊剂具有良好的降血糖、降血脂和降尿酸的效果。
例9：(滴丸)取氧化小檗碱300g，加入900g PEG4000作为基质，液体石蜡为冷却剂；制成每丸含氧化小檗碱10mg的滴丸，每丸净重30mg。口服，每日2次，每次10粒；连服30天，用于治疗糖尿病、脂肪肝、痛风为代表的代谢性疾病。结果发现上述滴丸具有良好的降血糖、降血脂和降尿酸的效果。
例10：(滴丸)称取氧化小檗碱1000g，加入适当药用辅料，按照常规方法配制成每丸含氧化小檗碱30mg的滴丸。口服，每日2次，每次6粒；连服30天，用于治疗糖尿病、脂肪肝、痛风为代表的代谢性疾病。结果发现上述滴丸具有良好的降血糖、降血脂和降尿酸的效果。
例11：(注射剂)取氧化小檗碱150mg，加入适当药用辅料，溶入1000mL，制成0.15％(m/v)氧化小檗碱注射液。肌肉注射，每日1次，每次10mL；连续30天，用于治疗糖尿病、脂肪肝、痛风为代表的代谢性疾病。结果发现上述注射剂具有良好的降血糖、降血脂和降尿酸的效果。
例12：(注射剂)称取氧化小檗碱200mg，加入适当药用辅料，按照常规方法配制成粉针剂。肌肉注射，每日1次，每次10mL；连续30天，用于治疗糖尿病、脂肪肝、痛风为代表的代谢性疾病。结果发现上述注射剂具有良好的降血糖、降血脂和降尿酸的效果。
例13：(片剂)取氧化小檗碱400g，加入交联聚维酮500g、乳糖480g、淀粉500g混合均匀，用淀粉浆作为粘合剂，湿法制粒，烘干，加入硬脂酸镁16g混匀，按照常规方法压制成每片含氧化小檗碱40mg的片剂10000片，每片净重0.2g。口服，每日1次，每次1粒；连服30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述片剂具有良好的降尿酸、降尿素氮和降肌酐的效果。
例14：(片剂)称取氧化小檗碱500g，加入适当药用辅料，配制成含50mg的片剂10000片，每片净重0.2g。口服，每日1次，每次1粒；连服30天。用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述片剂具有良好的降尿酸、降尿素氮和降肌酐的效果。
例15：(片剂)称取氧化小檗碱1000g，加入适当药用辅料，配制成每片含氧化小檗碱100mg的片剂10000片，每片净重0.25g。口服，每日1次，每次1粒；连服30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述片剂具有良好的降尿酸、降尿素氮和降肌酐的效果。
例16：称取氧化小檗碱500g和苯溴马隆500g，加入适当药用辅料，按照常规方法配制成10000粒片剂，每粒含氧化小檗碱50mg。口服，每日1次，每次1粒；连服30天。用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述片剂具有良好的降尿酸、降尿素氮和降肌酐的效果。
例17：称取氧化小檗碱500g和别嘌呤醇500g，加入适当药用辅料，按照常规方法配制成10000粒片剂，每粒含氧化小檗碱50mg。口服，每日1次，每次1粒；连服30天。用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述片剂具有良好的降尿酸、降尿素氮和降肌酐的效果。
例18：称取氧化小檗碱500g和非布司他500g，加入适当药用辅料，按照常规方法配制成10000粒缓释片剂，每粒含氧化小檗碱50mg。口服，每日1次，每次1粒；连服30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述片剂具有良好的降尿酸、降尿素氮和降肌酐的效果。
例19：(胶囊剂)称取250g氧化小檗碱，加入适当药用辅料，按照常规方法配制成含每粒含氧化小檗碱25mg的胶囊剂10000粒。口服，每日1次，每次1粒；连服30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述胶囊剂具有良好的降尿酸、降尿素氮和降肌酐的效果。
例20：(胶囊剂)称取氧化小檗碱500g，加入适当药用辅料，按照常规方法配制成含每粒含氧化小檗碱50mg 的胶囊剂10000粒。口服，每日1次，每次1粒；连服30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述胶囊剂具有良好的降尿酸、降尿素氮和降肌酐的效果。
例21：(胶囊剂)称取氧化小檗碱1000g，加入适当药用辅料，按照常规方法配制成每粒含氧化小檗碱100mg的胶囊剂。口服，每日1次，每次1粒；连服30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述胶囊剂具有良好的降尿酸、降尿素氮和降肌酐的效果。
例22：(滴丸)取氧化小檗碱300g，加入1500g PEG4000作为基质，液体石蜡为冷却剂；制成每丸含氧化小檗碱6mg的滴丸，每丸净重30mg。口服，每日1次，每次8粒；连服30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述滴丸具有良好的降尿酸、降尿素氮和降肌酐的效果。
例23：(滴丸)称取氧化小檗碱1000g，加入适当药用辅料，按照常规方法配制成每丸含氧化小檗碱30mg的滴丸。口服，每日1次，每次2粒；连服30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述滴丸具有良好的降尿酸、降尿素氮和降肌酐的效果。
例24：(注射剂)取氧化小檗碱150mg，加入适当药用辅料，溶入1000mL丙二醇，制成0.15％(m/v)氧化小檗碱注射液。肌肉注射，每日1次，每次10mL；连续30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述注射剂具有良好的降尿酸、降尿素氮和降肌酐的效果。
例25：(软胶囊)称取100g氧化小檗碱，加入适当药用辅料，充分搅匀制得氧化小檗碱软胶囊内容物，称取明胶、甘油、水(质量比为2:1:2)按照常规方法制备囊材胶液；采用旋转模压法，将内容物和囊材胶液装入自动旋转制囊机中，按照常规方法压制出规格为每粒含氧化小檗碱100mg的软胶囊1000粒，每粒净质量800mg，液状石蜡作为润滑剂。口服，每日1次，每次1粒；连服30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述软胶囊具有良好的降尿酸、降尿素氮和降肌酐的效果。
例26：(混悬液)称取氧化小檗碱50g，加入水苏糖1000g及适当辅料，配制成每mL含氧化小檗碱1mg的混悬液。口服，每日1次，每次10mL；连服30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述糖浆剂具有良好的降尿酸、降尿素氮和降肌酐的效果。
例27：(混悬液)称取氧化小檗碱50g，加入适当辅料，配制成每mL含氧化小檗碱5mg的混悬液。口服，用前摇匀，每日1次，每次10mL；连服30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述混悬液具有良好的降尿酸、降尿素氮和降肌酐的效果。
例28：(注射剂)称取氧化小檗碱200mg，加入适当辅料，配制成0.20％(w/v)氧化小檗碱注射液。皮下注射，每日1次，每次1mL；连续30天，用于治疗高尿酸血症、痛风、尿酸性肾病。结果发现上述注射液具有良好的降尿酸、降尿素氮和降肌酐的效果。
例29：(外用乳液)取氧化小檗碱1g，加入适当药用辅料，按照常规方法配制成20％(w/v)的乳液。用法：外用0.1～0.5mL，涂抹于关节或疼痛体表区域，每日3～5次，每次适量；连服15天，用于治疗痛风。结果发现上述外用乳液具有良好的降尿酸、消炎、消肿的效果。
例30：(片剂)取氧化小檗碱400g，加入乳糖480g、淀粉754g混合均匀，用7％(w/v)的淀粉浆350g作为粘合剂，湿法制粒，烘干，加入硬脂酸镁16g混匀，压制成每片含氧化小檗碱40mg的片剂10000片，每片净重0.2g。口服，每日3次，每次4粒；连服30天，用于治疗高脂血症、肥胖、脂肪肝。结果发现上述片剂具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例31：(片剂)称取氧化小檗碱500g，加入适当辅料，按照常规方法配制成每片含50mg氧化小檗碱的片剂。口服，每日3次，每次4粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述片剂具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例32：(片剂)称取氧化小檗碱1000g，加入适当辅料，按照常规方法配制成含氧化小檗碱100mg的片剂。口服，每日3次，每次4粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述片剂具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例33：称取氧化小檗碱500g和非诺贝特100g，加入适当药用辅料，按照常规方法配制成10000粒片剂。口服，每日1次，每次1粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述片剂具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例34：称取氧化小檗碱500g和洛伐他汀100g，加入适当药用辅料，按照常规方法配制成10000粒片剂。口服，口服，每日1次，每次1粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述片剂具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例35：称取氧化小檗碱500g和普罗布考500g，加入适当药用辅料，按照常规方法配制成10000粒片剂。口服，口服，每日2次，每次1粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述片剂具有良好的降血胆固醇、降低密度脂蛋白脂、减体重、降转氨酶的效果。
例36：(胶囊剂)称取1000g氧化小檗碱，加入适当药用辅料，按照常规方法配制成含每粒含氧化小檗碱100mg的胶囊剂。口服，每日3次，每次4粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述胶囊剂具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例37：(胶囊剂)称取氧化小檗碱500g，加入适当药用辅料，按照常规方法配制成每粒含氧化小檗碱50mg的胶囊剂。口服，每日3次，每次4粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述胶囊剂具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例38：(胶囊剂)称取氧化小檗碱1000g和烟酸500g，加入适当药用辅料，按照常规方法配制成每粒含氧化小檗碱100mg的胶囊剂。口服，每日3次，每次4粒；连服30天。每日3次，每次4粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述胶囊剂具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例39：(滴丸)取氧化小檗碱300g，加入1500g PEG4000作为基质，液体石蜡为冷却剂；滴制法制成每丸含氧化小檗碱6mg的滴丸，每丸净重30mg。口服，每日3次，每次10粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述滴丸具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例40：(滴丸)称取氧化小檗碱1000g，加入适当药用辅料，按照常规方法配制成每丸含氧化小檗碱30mg的滴丸。口服，每日3次，每次5粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述滴丸具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例41：(软胶囊)称取100g氧化小檗碱，加入适当药用辅料，充分搅匀制得氧化小檗碱软胶囊内容物，称取明胶、甘油、水(质量比为2:1:2)按照常规方法制备囊材胶液；采用旋转模压法，将内容物和囊材胶液装入自动旋转制囊机中，按照常规方法压制出规格为每粒含氧化小檗碱200mg的软胶囊500粒，每粒净质量1000mg，液状石蜡作为润滑剂。口服，每日3次，每次1粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述软胶囊具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例42：(软胶囊)称取氧化小檗碱1000g，加入适当药用辅料，按照常规方法配制成含氧化小檗碱500mg的软胶囊。口服，每日3次，每次1粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述软胶囊具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例43：(软胶囊)称取氧化小檗碱25g，加入适当药用辅料，按照常规方法配制成每粒含氧化小檗碱50mg的软胶囊。口服，每日3次，每次6粒；连服30天。用于治疗高脂血症、肥胖、脂肪肝。结果发现上述软胶囊具有良好的降血胆固醇、降甘油三酯或降低密度脂蛋白脂、减体重、降转氨酶的效果。
例44：(片剂)称氧化小檗碱800g，加入适当药用辅料，按照常规方法压制成每片含氧化小檗碱80mg的片剂10000片，每片净重0.2g。口服，每日3次，每次3粒；连服30天。用于治疗1型糖尿病和2型糖尿病。结果发现上述片剂具有良好的降血糖的效果。
例45：(片剂)称取氧化小檗碱500g，加入适当药用辅料，按照常规方法配制成含50mg的片剂。口服，每日3次，每次3粒；连服30天。与人胰岛素(每日胰岛素用量20-40U，皮下注射)合用，用于治疗1型糖尿病。结果发现上述片剂与胰岛素合用，可增加胰岛素的降血糖作用，减少胰岛素用量。
例46：(片剂)称取氧化小檗碱1000g，加入适当药用辅料，按照常规方法配制成含氧化小檗碱含100mg的片剂。口服，每日3次，每次3粒；连服30天。与牛胰岛素(每日胰岛素用量40U，皮下注射)合用，用于治疗1型糖尿病。结果发现上述片剂与胰岛素合用可增加胰岛素的降血糖作用，减少胰岛素用量和次数。
例47：称取氧化小檗碱500g和二甲双胍500g，加入适当药用辅料，按照常规方法配制成10000粒片剂，每粒分别含氧化小檗碱50mg和二甲双胍50mg口服，每日3次，每次3粒，连服30天。与长效胰岛素类似物诺和平(每日胰岛素用量40U，皮下注射)合用，用于治疗1型糖尿病和2型糖尿病。结果发现上述片剂与胰岛素合用，可增加胰岛素的降血糖作用，减少胰岛素用量和次数。
例48：称取氧化小檗碱500g和格列本脲500g，加入适当药用辅料，按照常规方法配制成10000粒片剂，每粒分别含氧化小檗碱50mg和格列本脲50mg。口服，每日3次，每次3粒；连服30天。用于治疗2型糖尿病。结果发现上述片剂具有高效降血糖的效果。
例49：称取氧化小檗碱500g和瑞格列奈500g，加入适当药用辅料，按照常规方法配制成10000粒片剂，每粒分别含氧化小檗碱50mg和瑞格列奈50mg。口服，用于治疗2型糖尿病。结果发现上述片剂具有高效降血糖的效果。
例50：(胶囊剂)称取100g氧化小檗碱，加入适当药用辅料，按照常规方法配制成每粒含氧化小檗碱25mg的胶囊剂。口服，每日3次，每次3粒；连服30天。用于治疗2型糖尿病。结果发现上述胶囊剂具有降血糖的效果。
例51：(胶囊剂)称取氧化小檗碱200g，加入适当药用辅料，按照常规方法配制成每粒含氧化小檗碱50mg的胶囊剂。口服，每日3次，每次3粒；连服30天。用于治疗2型糖尿病。结果发现上述胶囊剂具有降血糖的效果。
例52：(胶囊剂)称取氧化小檗碱1000g和阿卡波糖500g，加入适当药用辅料，按照常规方法配制成每粒含氧化小檗碱100mg和阿卡波糖50mg的胶囊剂。口服，每日3次，每次3粒；连服30天。用于治疗2型糖尿病。结果发现上述胶囊剂具有良好的降血糖的效果。
例53：(滴丸)取氧化小檗碱300g，加入1500g PEG4000作为基质，液体石蜡为冷却剂；滴制法制成每丸含氧化小檗碱6mg的滴丸，每丸净重30mg。口服，每日3次，每次10粒；连服30天。用于治疗2型糖尿病。结果发现上述滴丸具有降血糖的效果。
例54：(滴丸)称取氧化小檗碱1000g，加入适当药用辅料，按照常规方法配制成含氧化小檗碱30mg的滴丸。口服，每日3次，每次10粒；连服30天。用于治疗2型糖尿病，结果发现上述滴丸具有降血糖的效果。
例55：(软胶囊)称取125g氧化小檗碱，压制出规格为每粒含氧化小檗碱250mg的软胶囊500粒，每粒净质量800mg，液状石蜡作为润滑剂。口服，每日3次，每次1粒；连服30天。用于治疗2型糖尿病，结果发现上述软胶囊具有降血糖的效果。
例56：(软胶囊)称取氧化小檗碱200g，加入适当辅料，按照常规方法配制成每粒含氧化小檗碱200mg的软胶囊。口服，每日3次，每次1粒；连服30天。用于治疗2型糖尿病，结果结果发现上述软胶囊具有降血糖的效果。
例57：(软胶囊)称取氧化小檗碱100g，加入适当辅料，按照常规方法配制成每粒含氧化小檗碱100mg的软胶囊。口服，每日3次，每次2粒；连服30天。用于治疗2型糖尿病。结果发现上述软胶囊具有降血糖的效果。
例58：(片剂)取氧化小檗碱400g，加入适当药用辅料，按照常规方法压制成片剂10000片，每片净重0.2g每片含氧化小檗碱40mg。口服，每日3次，每次3粒；连服30天。用于治疗2型糖尿病兼痛风。结果片剂具有降血糖、降尿酸的效果。
例59：(片剂)取氧化小檗碱400g和格列齐特500g，加入适当药用辅料，按照常规方法压制成片剂10000片，每片净重0.25g。口服，每日3次，每次3粒；连服30天。用于治疗2型糖尿病兼痛风。每粒含氧化小檗碱40mg。结果片剂具有降血糖、降尿酸的效果。
例60：(片剂)称取氧化小檗碱500g和二甲双胍500g，加入适当药用辅料，按照常规方法配制成10000片每片分别含氧化小檗碱50mg和二甲双胍50mg。口服，每日3次，每次3粒；连服30天。用于治疗糖尿病兼痛风。结果发现上述片剂具有良好的降血糖、降尿酸的效果。
例61：(胶囊剂)称取氧化小檗碱500g，加入适当药用辅料，按照常规方法配制成10000粒胶囊剂每粒含氧化小檗碱50mg。口服，每日3次，每次3粒；连服30天。用于治疗糖尿病兼痛风。结果发现上述胶囊剂具有降血糖、降尿酸的效果。
例62：(片剂)称取氧化小檗碱1000g，加入适当药用辅料，按照常规方法配制成10000片每粒含氧化小檗碱100mg。口服，每日3次，每次3粒；连服30天。用于治疗糖尿病兼痛风。结果发现上述片剂具有良好的降血糖、降尿酸的效果。
例63：(滴丸)取氧化小檗碱300g，加入1500g PEG4000作为基质，适量液体石蜡为冷却剂；制成每丸含氧化小檗碱6mg的滴丸，每丸净重30mg。口服，每日3次，每次10粒；连服30天。用于治疗糖尿病兼痛风。结果发现上述滴丸具有良好的降血糖、降尿酸的效果。
例64：(滴丸)称取氧化小檗碱1000g，加入适当药用辅料，按照常规方法配制成含氧化小檗碱30mg的滴丸。口服，每日3次，每次5粒；连服30天。用于治疗糖尿病兼痛风。结果发现上述滴丸具有良好的具有降血糖、降尿酸的效果。
例65：(片剂)取氧化小檗碱1000g，加入醋酸羟丙甲纤维素琥珀酸酯、微粉硅胶、乳糖、淀粉等药用辅料适量，混合均匀，湿法制粒，烘干，加入硬脂酸镁16g混匀，压制成片剂10000片每片含氧化小檗碱100mg，每片净重0.3g。口服，每日3次，每次3粒；连服30天。用于治疗糖尿病兼高血脂症。结果发现上述缓控释片剂具有良好的降血糖、降血脂的效果。
例66：(胶囊剂)取氧化小檗碱1000g和格列齐特100g，加入乳糖、醋酸羟丙甲纤维素琥珀酸酯、微粉硅胶、聚乙烯醇吡咯烷酮等药用辅料适量，混合均匀，制粒，烘干，加入硬脂酸镁16g混匀，制成10000粒胶囊剂(每粒含氧化小檗碱100mg和格列齐特10mg)。口服，每日3次，每次3粒；连服30天。用于治疗糖尿病兼高血脂症，结果发现上述胶囊剂具有良好的降血糖、降血脂的效果。
例67：(胶囊剂)取氧化小檗碱1000g和西格列汀100g，加入乳糖淀粉等药用辅料适量，混合均匀，制粒，烘干，加入硬脂酸镁16g混匀，制成10000粒胶囊剂(每粒含氧化小檗碱100mg和西格列汀10mg)。口服，每日3次，每次3粒；连服30天。用于治疗糖尿病兼高血脂症。结果发现上述胶囊剂具有良好的降血糖、降血脂的效果。
例68：(胶囊剂)取氧化小檗碱1000g和达格列净300g，加入乳糖、淀粉、微粉硅胶、聚乙烯醇吡咯烷酮等药用辅料适量，混合均匀，制粒，烘干，加入硬脂酸镁16g混匀，制成10000粒胶囊剂(每粒含氧化小檗碱100mg和达格列净分别30mg)。口服，每日3次，每次3粒；连服30天。用于治疗糖尿病兼高血脂症。结果发现上述胶囊剂具有良好的降血糖、降血脂的效果。
例69：(胶囊剂)取氧化小檗碱500g和非诺贝特100g，加入适当药用辅料适量，按照常规方法制成10000粒胶囊剂(每粒含氧化小檗碱50mg和非诺贝特10mg)。口服，每日3次，每次2粒；连服30天。用于治疗高血糖、高血脂症。结果发现上述胶囊剂具有良好的降血糖、降血脂的效果。
例70：(胶囊剂)取氧化小檗碱500g和普罗布考100g，加入适当药用辅料适量，按照常规方法制成10000粒胶囊剂(每粒含氧化小檗碱50mg和普罗布考10mg)。口服，每日3次，每次2粒；连服30天。用于治疗高血糖、高血脂症。结果发现上述胶囊剂具有良好的降血糖、降血脂的效果。
例71：(胶囊剂)取氧化小檗碱500g和瑞舒伐他汀100g，加入适当药用辅料适量，按照常规方法制成10000粒胶囊剂(每粒含氧化小檗碱50mg和瑞舒伐他汀10mg)。口服，每日3次，每次1粒；连服30天。用于治疗高血糖、高血脂症。结果发现上述胶囊剂具有良好的降血糖、降血脂的效果。
例72：(片剂)取氧化小檗碱400g，加入适当药用辅料适量，按照常规方法压制成每片含氧化小檗碱40mg的片剂10000片，每片净重0.2g。口服，每日3次，每次1粒；连服30天。用于治疗高尿酸血症、高血脂症。结果发现上述片剂具有良好的降血糖、降血脂的效果。
例73：(片剂)称取氧化小檗碱500g和瑞舒伐他汀100g，加入适当辅料，按照常规方法配制成含10000片(每粒含氧化小檗碱50mg和瑞舒伐他汀10mg)。口服，每日3次，每次1粒；连服30天。用于治疗高尿酸血症、高血脂症。结果发现上述片剂具有良好的降血糖、降血脂的效果。
例74：(片剂)称取氧化小檗碱500g和苯溴马隆100g，加入适当辅料，按照常规方法配制成10000片(每粒含氧化小檗碱50mg和苯溴马隆10mg)。口服，每日3次，每次1粒；连服30天。用于治疗高尿酸血症、高血脂症，结果发现上述片剂具有良好的降尿酸、降血脂的效果。
例75：(片剂)称取氧化小檗碱500g和非布司他100g，加入适当辅料，按照常规方法配制成10000片(每粒含氧化小檗碱50mg和非布司他10mg)。口服，每日1次，每次1粒；连服30天。用于治疗高尿酸血症、高血脂症，结果发现上述片剂具有良好的降尿酸、降血脂的效果。。
例76：(胶囊剂)取氧化小檗碱1000g和格列齐特400g，加入适当辅料，按照常规方法制成10000粒胶囊剂(每粒含氧化小檗碱100mg和格列齐特40mg)。口服，每日1次，每次1粒；连服30天。用于治疗高尿酸血症、高血脂症，结果发现上述胶囊剂具有良好的降尿酸、降血脂的效果。
例77：(片剂)取氧化小檗碱400g，加入适当辅料，按照常规方法压制成每片含氧化小檗碱40mg的片剂10000片，每片净重0.2g。口服，每日3次，每次1粒；连服30天。用于治疗肿瘤化疗后高尿酸血症。结果发现上述片剂具有良好的降尿酸、尿素氮和肌酐的效果。
例78：(片剂)称取氧化小檗碱500g，加入微晶纤维素、微粉硅胶、聚乙烯醇吡咯烷酮等药用辅料适量，按照常规方法配制成含10000片(每粒含氧化小檗碱50mg)。口服，每日3次，每次3粒；连服30天。用于治疗代谢综合征。结果发现上述片剂具有良好的减体重、降转氨酶、降血糖、降血脂、降尿酸、尿素氮和肌酐的效果。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 氧化小檗碱在制备代谢性疾病药物中的应用。
  2. 根据权利要求1所述的应用，其特征在于，所述的代谢性疾病药物包括治疗和/或预防代谢性疾病的药物。
  3. 根据权利要求2所述的应用，其特征在于，所述的治疗和/或预防代谢性疾病的药物包含氧化小檗碱，和/或氧化小檗碱与药学上可接受的酸结合所形成的盐。
  4. 根据权利要求3所述的应用，其特征在于，所述的药学上可接受的酸包括有机酸、无机酸和氨基酸中的至少一种。
  5. 根据权利要求1所述的应用，其特征在于，所述的代谢性疾病包括高血糖、高血脂、高尿酸血症、尿酸性肾病、肥胖症、糖尿病、脂肪肝和痛风中的至少一种。
  6. 根据权利要求5所述的应用，其特征在于，所述的糖尿病包括1型糖尿病和2型糖尿病中的至少一种；
    所述的脂肪肝包括非酒精性脂肪肝；
    所述的高尿酸血症包括由尿酸排泄不良型、合成过多型、混合型和肿瘤后化疗中的一种或几种引起的高尿酸血症。
  7. 氧化小檗碱在制备具有降血糖、降血脂和降尿酸作用的药物组合物中的应用。
  8. 一种具有降血糖、降血脂和降尿酸作用的药物组合物，其特征在于，包括氧化小檗碱，和/或氧化小檗碱与药学上可接受的酸结合所形成的盐。
  9. 根据权利要求8所述的药物组合物，其特征在于，所述的氧化小檗碱的分子式为：C 20H 17NO 5；分子量为：351.4；分子结构式如式I所示
    Figure PCTCN2021102587-appb-100001
  10. 权利要求8～9任一所述的药物组合物在制备用于治疗和/或预防代谢性疾病药物中的应用。
PCT/CN2021/102587 2020-09-23 2021-06-27 氧化小檗碱在制备代谢性疾病药物中的应用及包含氧化小檗碱的药物组合物 WO2022062518A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011006419.X 2020-09-23
CN202011006419.XA CN112138007B (zh) 2020-09-23 2020-09-23 氧化小檗碱在制备代谢性疾病药物中的应用及包含氧化小檗碱的药物组合物

Publications (1)

Publication Number Publication Date
WO2022062518A1 true WO2022062518A1 (zh) 2022-03-31

Family

ID=73897730

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/102587 WO2022062518A1 (zh) 2020-09-23 2021-06-27 氧化小檗碱在制备代谢性疾病药物中的应用及包含氧化小檗碱的药物组合物

Country Status (2)

Country Link
CN (1) CN112138007B (zh)
WO (1) WO2022062518A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112138007B (zh) * 2020-09-23 2021-12-28 广州中医药大学(广州中医药研究院) 氧化小檗碱在制备代谢性疾病药物中的应用及包含氧化小檗碱的药物组合物
CN115444847A (zh) * 2021-06-08 2022-12-09 广州中医药大学(广州中医药研究院) 原小檗碱类生物碱8-氧化产物在制备降尿酸药物增效剂中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060223838A1 (en) * 2004-09-17 2006-10-05 Jian-Dong Jiang Methods and compositions for the treatment of hyperlipidemia
WO2010104595A1 (en) * 2009-03-11 2010-09-16 Xintria Pharmaceutical Corporation, Inc. Methods and compositions for the treatment of metabolic and cardiovascular disorders
CN112138007A (zh) * 2020-09-23 2020-12-29 广州中医药大学(广州中医药研究院) 氧化小檗碱在制备代谢性疾病药物中的应用及包含氧化小檗碱的药物组合物

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101153039B (zh) * 2006-09-30 2010-12-01 中国科学院上海药物研究所 13，13a-二氢小檗碱衍生物及其药物组合物和用途
CN101870694B (zh) * 2009-04-21 2012-08-22 中国科学院上海药物研究所 8,8-二取代-13,13a-二氢小檗碱衍生物及其药物组合物和用途
JP6106603B2 (ja) * 2011-01-11 2017-04-05 スノビオン プハルマセウトイカルス インコーポレイテッド ヘテロアリール化合物及びその使用方法
US20130237556A1 (en) * 2012-03-12 2013-09-12 Hong Kong Baptist University Berberine alkaloid as a medicament for prevention and treatment of neural disease
CN110227077A (zh) * 2019-06-06 2019-09-13 广州中医药大学(广州中医药研究院) 氧化小檗碱在制备治疗溃疡性结肠炎的药物中的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060223838A1 (en) * 2004-09-17 2006-10-05 Jian-Dong Jiang Methods and compositions for the treatment of hyperlipidemia
WO2010104595A1 (en) * 2009-03-11 2010-09-16 Xintria Pharmaceutical Corporation, Inc. Methods and compositions for the treatment of metabolic and cardiovascular disorders
CN112138007A (zh) * 2020-09-23 2020-12-29 广州中医药大学(广州中医药研究院) 氧化小檗碱在制备代谢性疾病药物中的应用及包含氧化小檗碱的药物组合物

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HONG-YING CHEN; XIAO-LI YE; XUE-LONG CUI; KAI HE; YA-NAN JIN; ZHU CHEN; XUE-GANG LI;: "Cytotoxicity and antihyperglycemic effect of minor constituents fromin HepG2 cells", FITOTERAPIA, IDB HOLDING, MILAN., IT, vol. 83, no. 1, 13 September 2011 (2011-09-13), IT , pages 67 - 73, XP028391883, ISSN: 0367-326X, DOI: 10.1016/j.fitote.2011.09.014 *
JIALAL ISHWARLAL, KAUR HARMEET, DEVARAJ SRIDEVI: "Toll-like Receptor Status in Obesity and Metabolic Syndrome: A Translational Perspective", JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, THE ENDOCRINE SOCIETY, US, vol. 99, no. 1, 1 January 2014 (2014-01-01), US , pages 39 - 48, XP055914527, ISSN: 0021-972X, DOI: 10.1210/jc.2013-3092 *
LI CAILAN, AI GAOXIANG, WANG YONGFU, LU QIANG, LUO CHAODAN, TAN LIHUA, LIN GUOSHENG, LIU YUHONG, LI YUCUI, ZENG HUIFANG, CHEN JIAN: "Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-κB pathway", PHARMACOLOGICAL RESEARCH, ELSEVIER, AMSTERDAM, NL, vol. 152, 1 February 2020 (2020-02-01), AMSTERDAM, NL, pages 104603, XP055914508, ISSN: 1043-6618, DOI: 10.1016/j.phrs.2019.104603 *
RU LIU-BRYAN, PETER SCOTT, ANYA SYDLASKE, DAVID M. ROSE, AND ROBERT TERKELTAUB: "Innate Immunity Conferred by Toll-like Receptors 2 and 4 and Myeloid Differentiation Factor 88 Expression is Pivotal to Monosodium Urate Monohydrate Crystal– induced Inflammation", ARTHRITIS & RHEUMATISM, vol. 52, no. 9, 1 September 2005 (2005-09-01), pages 2936 - 2946, XP055914519, DOI: 10.1002/art.21238 *
WANG, YONGLING: "Application of High-Speed Countercurrent Chromatography to the Rapid Screening of Bioactive Components from Chinese Materia Medica (CMM) and Natural Products", SHI JIE KE XUE JI SHU ZA ZHI, CN, vol. 19, no. 2, 1 January 2017 (2017-01-01), CN , pages 265 - 275, XP055914535, ISSN: 1674-3849, DOI: 10.11842/wst.2017.02.013 *

Also Published As

Publication number Publication date
CN112138007B (zh) 2021-12-28
CN112138007A (zh) 2020-12-29

Similar Documents

Publication Publication Date Title
TWI706947B (zh) 含有葡萄糖激酶啟動劑和k-atp通道阻斷劑的藥物組合及其製備方法和用途
AU2006295440B2 (en) Capsule formulation of pirfenidone and pharmaceutically acceptable excipients
WO2022062518A1 (zh) 氧化小檗碱在制备代谢性疾病药物中的应用及包含氧化小檗碱的药物组合物
CN101590007A (zh) 一种盐酸二甲双胍/伏格列波糖降糖口服制剂组合物及其制备
CN115887460A (zh) 川芎嗪硝酮衍生物在预防和治疗糖尿病并发症疾病中的应用
KR101567660B1 (ko) 진성 당뇨병을 치료하기 위한 병용제
CN115518066A (zh) 一种用于治疗抗凝血的药物组合物及应用
CA2563325C (en) Oral modified-release lozenges and their preparation method
CN102727894A (zh) 一种治疗糖尿病及其并发症的药物组合物及其应用
CA3104916C (en) Pharmaceutical composition for preventing diabetes and use thereof
CN110859843A (zh) 一种治疗动脉硬化合并心绞痛的药物组合物及制备方法
CN100531729C (zh) 含有苯氧芳酸类药物和牛磺酸的组合物
KR101441355B1 (ko) 레파글리니드 및 메트포르민을 함유하는 이층정 및 그의 제조방법
CN102552143A (zh) 含普伐他汀钠非诺贝特脂质体的药物组合物及其制备方法
AU2013201986B2 (en) Capsule Formulation Of Pirfenidone And Pharmaceutically Acceptable Excipients
CN114401724B (zh) 一种降糖药物组合物
CN107510696A (zh) 用于治疗非酒精性脂肪肝的药物组合物
CN101396560B (zh) 治疗多囊肾病的药物组合物及其应用
CN101428012B (zh) 一种治疗心脑血管疾病的药物组合物
AU2014240300B2 (en) Capsule Formulation of Pirfenidone and Pharmaceutically Acceptable Excipients
TWI393562B (zh) 左旋丁基苯酞在製備預防和治療腦梗塞的藥物中的應用
CN100455279C (zh) 口服延迟释放锭剂组成物及其制法
CN101897708A (zh) 一种治疗血脂代谢障碍的缓释组合物
CN118045129A (zh) 一种预防和治疗糖尿病肾病的药物组合物
CN105079794A (zh) 一种可用于口服的利拉鲁肽与磺脲类复方制剂

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21870898

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21870898

Country of ref document: EP

Kind code of ref document: A1