WO2021142815A1 - Berbérine et coptisine, ou métabolites actifs associés et application de sels associés dans un médicament destiné à la prévention et/ou au traitement d'une néphropathie à l'acide urique - Google Patents

Berbérine et coptisine, ou métabolites actifs associés et application de sels associés dans un médicament destiné à la prévention et/ou au traitement d'une néphropathie à l'acide urique Download PDF

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WO2021142815A1
WO2021142815A1 PCT/CN2020/072901 CN2020072901W WO2021142815A1 WO 2021142815 A1 WO2021142815 A1 WO 2021142815A1 CN 2020072901 W CN2020072901 W CN 2020072901W WO 2021142815 A1 WO2021142815 A1 WO 2021142815A1
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uric acid
berberine
model
blood
nephropathy
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PCT/CN2020/072901
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Chinese (zh)
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蒋建东
王琰
潘利斌
赵朕雄
丛林
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中国医学科学院药物研究所
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    • 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
    • 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

Definitions

  • the invention relates to the application of berberine, berberine or their active metabolites, and pharmaceutically acceptable salts thereof in the preparation of drugs for the prevention and/or treatment of uric acid nephropathy; it belongs to the technical field of medicine.
  • Uric acid nephropathy is kidney damage caused by hyperuricemia due to excessive blood uric acid production or decreased excretion. It is also called gout nephropathy, which may have elevated uric acid, uric acid stones, proteinuria, edema, nocturia, and high blood pressure. , Hematuria and renal tubular function damage. The disease has no obvious seasonality. The incidence of obesity, carnivorous and alcoholics is high. The incidence of men is higher than that of women, and 85% of the affected population are middle-aged and elderly people. In patients with uric acid nephropathy, the concentration of urate in the blood increases to a supersaturated state, and urate crystals deposit in the kidneys and cause lesions.
  • the histological features are the appearance of urate crystals in the renal interstitium and renal tubules, resulting in damage to the nephron , And easily lead to secondary bacterial infections. If the disease can be diagnosed early and given appropriate treatment (control hyperuricemia and protect renal function), the development of kidney disease can be reduced or stopped. If treatment is delayed or improperly treated, the condition can worsen and develop into end-stage renal failure. Need dialysis treatment.
  • the current treatment methods are mainly low-purine diet, drinking more water, maintaining urine output, alkalizing urine, and applying drugs that inhibit uric acid production and promote uric acid excretion. However, clinical medications often have significant adverse reactions and deserve our in-depth study.
  • Berberine is a natural compound isolated from many different plants, such as Coptis, Eryngium, Ranunculus, Phellodendron, etc. For decades, berberine has been used as an over-the-counter drug to treat diarrhea without obvious adverse reactions. Since 2004, we have discovered that berberine can be used as a new drug to treat hyperlipidemia and type I diabetes. Its clinical efficacy has been confirmed by many domestic and foreign research groups. At the same time, in the experiments of rodent models, we proved that berberine has a good effect on reducing blood uric acid content and treating uric acid nephropathy.
  • berberine oral and intraperitoneal injection of berberine can reduce the blood uric acid content of SD rats with uric acid nephropathy induced by yeast powder and adenine and significantly improve the renal function of SD rats.
  • the berberine analogues jatrorrhizine, palmatine and berberine and the mixture of berberine total alkalis can also reduce hyperuricemia after oral administration The content of uric acid in the blood of ICR mice.
  • Oral or intraperitoneal injection of berberine reduced the blood uric acid content of SD rats with uric acid nephropathy and significantly improved renal function.
  • Berberine reduces the deposition of uric acid crystals in the kidney by reducing the content of uric acid, and significantly improves renal function. Therefore, it is described in this patent that oral or intraperitoneal injection of berberine, berberine or its active metabolites, and pharmaceutically acceptable salts thereof can reduce the content of uric acid in the blood of SD rats or ICR mice, thereby improving the kidneys.
  • the function suggests that berberine, berberine or its active metabolites, and pharmaceutically acceptable salts thereof have applications in the prevention and/or treatment of uric acid nephropathy.
  • the technical problem to be solved by the present invention is to provide a new class of drugs for preventing and/or treating uric acid nephropathy.
  • the present invention provides the following technical solutions:
  • the present invention provides berberine represented by structural formula (I), berberine represented by structural formula (II) or active metabolites of both or both, and pharmaceutically acceptable salts thereof in the preparation of prevention and/or treatment of uric acid
  • berberine represented by structural formula (I) berberine represented by structural formula (II) or active metabolites of both or both, and pharmaceutically acceptable salts thereof in the preparation of prevention and/or treatment of uric acid
  • the pharmaceutically acceptable salt includes hydrochloride, sulfate, hydrobromide, hydroiodide, formate, acetate, and oxalate.
  • the uric acid nephropathy is caused by the increase in blood uric acid content and the deposition of uric acid crystals in the kidney.
  • the SD rat model of uric acid nephropathy induced by yeast powder and adenine is one of the important experiments to evaluate uric acid nephropathy.
  • Example 1 The therapeutic effect of berberine in SD rats with uric acid nephropathy induced by yeast powder and adenine.
  • the blood uric acid content, creatinine content, urea nitrogen content, left kidney weight index and the pathological comparison of rat kidney HE are important indicators to evaluate the therapeutic effect of uric acid nephropathy in rats.
  • SD rats (6 weeks old) were purchased from Beijing Weitong Lihua Animal Technology Co., Ltd., and the animals were kept in an SPF environment (21 ⁇ 2°C, 12-hour photoperiod), and they were free to eat and drink during the experiment.
  • Berberine was purchased from Bailingwei Company. Creatinine, uric acid, febuxostat, adenine, 4% tissue cell fixative and yeast powder were purchased from Beijing Soleibao Technology Company.
  • the urea nitrogen test kit (urease method) was purchased from Nanjing Jiancheng Institute of Biological Engineering. Pathological section technical support is provided by the pathological section research group of the Institute of Materia Medica, Chinese Academy of Medical Sciences.
  • High performance liquid chromatography-triple quadrupole tandem mass spectrometry (LC-MS/MS 8050, Shimadzu Corporation) was used to quantitatively determine the content of blood uric acid and creatinine.
  • the experiment uses a Waters HSS T3 (3.5 ⁇ m, 2.1x100mm) chromatographic column, and the column temperature is kept at 30°C.
  • the mobile phases for the determination of uric acid and creatinine are water and acetonitrile.
  • gradient elution A:B, 0min, 95:5; 2.0min, 80:20; 2.01min, 5:95; 5min, 5:95; 5.01min, 95:5; 9min 95:5)
  • the flow rate is 0.2mL/min.
  • the quantification adopts multiple reaction monitoring (MRM) mode, the quantitative ion pair of uric acid is 167.00 ⁇ 96.05 (m/z), and the quantitative ion pair of creatinine is 114.35 ⁇ 86.15.
  • MRM multiple reaction monitoring
  • urea nitrogen (BUN) test kit (urease method) is used for the determination of urea nitrogen, and the specific method is detailed in the instructions.
  • the kidneys were removed, the left kidney capsule was removed, washed with physiological saline, and the remaining water was absorbed by the filter paper.
  • the weight was accurately weighed on an electronic balance to calculate the left kidney weight index, which is the weight of the left kidney (mg)/body weight (g).
  • the right kidney was fixed in 4% tissue cell fixative (4% paraformaldehyde) for 24 hours, dehydrated by an automatic dehydrator for 16 hours, embedded in a paraffin embedding machine, and then stained with HE and observed under a microscope.
  • tissue cell fixative 4% paraformaldehyde
  • the experimental animals were divided into 6 groups, including a control group, a model group, a positive drug oral treatment group, a model intraperitoneal administration treatment group, a model low-dose oral treatment group, and a model high-dose oral treatment group.
  • the establishment of the model started from 6-week-old SD rats. After one week of adaptive feeding with the modeled feed, the model was administered at the same time for 6 weeks.
  • the model feed is a normal feed containing 10% yeast and 0.15% adenine.
  • Control group normal feed feeding + oral normal saline 1mL;
  • Model group Modeling feed feeding + oral normal saline 1mL;
  • Model low-dose treatment group model feed + oral berberine (100mg/kg/day);
  • Model high-dose treatment group model feed + oral berberine (200mg/kg/day);
  • Model intraperitoneal administration treatment group modeling feed + intraperitoneal injection of berberine (10mg/kg/day).
  • the blood creatinine content of the model group was significantly higher than that of the normal control group, indicating that the model was successfully established.
  • creatinine in the blood of SD rats treated with berberine for 6 weeks at the same time as the model was significantly reduced and was dose-dependent.
  • the blood creatinine in the intraperitoneal injection treatment group decreased significantly, indicating that the intraperitoneal injection treatment is effective.
  • the blood urea nitrogen content of the model group was significantly higher than that of the normal control group, indicating that the model was successfully established.
  • the blood urea nitrogen in SD rats after 6 weeks of oral berberine treatment at the same time as the model was significantly reduced and was dose-dependent.
  • the blood urea nitrogen in the intraperitoneal injection treatment group decreased significantly, indicating that the intraperitoneal injection treatment is effective.
  • the left kidney index of the model group was significantly higher than that of the normal control group, indicating that the model was successfully established.
  • SD rats treated with berberine for 6 weeks at the same time as the model the left kidney index decreased significantly, and was dose-dependent.
  • the left kidney index decreased significantly in the intraperitoneal injection treatment group, indicating that the intraperitoneal injection treatment is effective.
  • kidneys of the normal group are light brown, while the kidneys of the rats in the model group are pale, significantly enlarged, with white spots scattered on the surface; while the kidneys of the rats in the berberine group were taken orally at the same time as the model Significant improvement, light brown, and only a few white spots; the kidney in the intraperitoneal injection treatment group also improved significantly, indicating that the intraperitoneal injection treatment is effective.
  • the results of HE staining showed that the structure of the kidney tissue in the normal group was normal without urate crystals; while in the renal cortex and medulla tubules and interstitium of the model group, there were obvious urate crystals. Needle-like arrangement, vacuolar degeneration of renal tubules, markedly widened interstitium.
  • the kidneys of the rats in the model-making and oral berberine group were significantly improved, with a small amount of urate crystals, and the vacuolar degeneration was lighter; the kidneys in the intraperitoneal injection treatment group also improved significantly, indicating that the intraperitoneal injection treatment is effective.
  • the content of uric acid in blood is an important index to evaluate the therapeutic effect of uric acid nephropathy in rats.
  • ICR mice male, 20 ⁇ 2g were purchased from Beijing Weitonglihua Animal Technology Co., Ltd., and the animals were kept in an SPF environment (21 ⁇ 2°C, 12-hour photoperiod), and they were free to eat and drink during the experiment.
  • Uric acid and yeast powder were purchased from Beijing Soleibao Technology Co., Ltd., and palmatine was purchased from Chengdu Mansite Biotechnology Co., Ltd.
  • Experimental design The experimental animals were divided into 3 groups, including the control group, the model group, and the oral palmatine 200mg/kg group.
  • the model was fed with model feed. After one month of feeding, the model was successful. After 14 days of continuous administration, the blood uric acid content was measured.
  • the model feed is 10% yeast powder added to the normal feed.
  • Control group normal feed feeding + 0.2mL oral normal saline
  • Model group Modeling feed feeding + oral normal saline 0.2mL;
  • Oral palmatine 200 mg/kg group model feed feeding + oral palmatine 200 mg/kg.
  • the content of uric acid in blood is an important index to evaluate the therapeutic effect of uric acid nephropathy in rats.
  • ICR mice male, 20 ⁇ 2g were purchased from Beijing Weitonglihua Animal Technology Co., Ltd., and the animals were kept in an SPF environment (21 ⁇ 2°C, 12-hour photoperiod), and they were free to eat and drink during the experiment.
  • Uric acid and yeast powder were purchased from Beijing Soleibao Technology Co., Ltd., and jatrorrhizine was purchased from Chengdu Mansite Biotechnology Co., Ltd.
  • the experimental animals were divided into 3 groups, including the control group, the model group, and the oral jatrorrhizine 200 mg/kg group.
  • the model was fed with model feed. After one month of feeding, the model was successful. After 14 days of continuous administration, the blood uric acid content was measured.
  • the model feed is 10% yeast powder added to the normal feed.
  • Control group normal feed feeding + 0.2mL oral normal saline
  • Model group Modeling feed feeding + oral normal saline 0.2mL;
  • Oral rhizoline 200mg/kg group model-fed feed + oral rhizoline 200mg/kg.
  • the blood uric acid content of the model group was significantly higher than that of the normal control group, indicating that the model was successfully established.
  • the blood uric acid decreased significantly, indicating that jatrorrhizine can improve the metabolism of uric acid and has the effect of treating uric acid nephropathy.
  • Example 4 The effect of berberine on reducing uric acid in ICR mice.
  • the content of uric acid in blood is an important index to evaluate the therapeutic effect of uric acid nephropathy in rats.
  • ICR mice male, 20 ⁇ 2g were purchased from Beijing Weitonglihua Animal Technology Co., Ltd., and the animals were kept in an SPF environment (21 ⁇ 2°C, 12-hour photoperiod), and they were free to eat and drink during the experiment.
  • Uric acid and yeast powder were purchased from Beijing Soleibao Technology Co., Ltd., and Coptis was purchased from Chengdu Mansite Biotechnology Co., Ltd.
  • Experimental design The experimental animals were divided into 3 groups, including the control group, the model group, and the oral berberine 200 mg/kg group.
  • the model was fed with model feed. After one month of feeding, the model was successful. After 14 days of continuous administration, the blood uric acid content was measured.
  • the model feed is 10% yeast powder added to the normal feed.
  • Control group normal feed feeding + 0.2mL oral normal saline
  • Model group Modeling feed feeding + oral normal saline 0.2mL;
  • Oral berberine 200mg/kg group model-fed feed + oral berberine 200mg/kg.
  • the blood uric acid content of the model group was significantly higher than that of the normal control group, indicating that the model was successfully established.
  • uric acid in the blood decreased significantly, indicating that berberine can improve the metabolism of uric acid and has the effect of treating uric acid nephropathy.
  • Example 5 The effect of total alkalis of Coptis in reducing uric acid in ICR mice.
  • the content of uric acid in blood is an important index to evaluate the therapeutic effect of uric acid nephropathy in rats.
  • ICR mice male, 20 ⁇ 2g were purchased from Beijing Weitonglihua Animal Technology Co., Ltd., and the animals were kept in an SPF environment (21 ⁇ 2°C, 12-hour photoperiod), and they were free to eat and drink during the experiment.
  • Uric acid and yeast powder were purchased from Beijing Soleibao Technology Company.
  • Coptis total alkali was purchased from Suzhou Siyuan Natural Products Research and Development Co., Ltd. It is a Chinese medicine Coptis extract, which mainly contains natural products such as berberine, berberine, and jatrorrhizine.
  • Experimental design The experimental animals were divided into 3 groups, including a control group and a model group, a group of 100 mg/kg of total alkaloids of berberine or 200 mg/kg of total alkaloids of berberine.
  • the model was fed with model feed. After one month of feeding, the model was successful. After 14 days of continuous administration, the blood uric acid content was measured.
  • the model feed is 10% yeast powder added to the normal feed.
  • Control group normal feed feeding + 0.2mL oral normal saline
  • Model group Modeling feed feeding + oral normal saline 0.2mL;

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Abstract

La présente invention concerne la berbérine représentée par la formule développée (I), la coptisine représentée par la formule développée (II), les métabolites actifs de la berbérine représentés par les formules développées (III) (IV) (V) (VI) (VII) (VIII) et (IX), comprenant de la jatrorrhizine, de la dihydroberbérine, de la taliféndine, de la berbérrubine, de la déméthylèneberbérine, de la palmatine et de la columbamine et l'application de sels pharmaceutiquement acceptables associés dans la préparation d'un médicament destiné à prévenir et/ou à traiter la néphropathie à l'acide urique (néphropathie goutteuse).
PCT/CN2020/072901 2020-01-18 2020-01-18 Berbérine et coptisine, ou métabolites actifs associés et application de sels associés dans un médicament destiné à la prévention et/ou au traitement d'une néphropathie à l'acide urique WO2021142815A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
CN101102768A (zh) * 2004-09-17 2008-01-09 中国医学科学院医药生物技术研究所 治疗高脂血症的方法和组合物
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WO2010104595A1 (fr) * 2009-03-11 2010-09-16 Xintria Pharmaceutical Corporation, Inc. Méthodes et compositions utilisées pour le traitement de maladies métaboliques et cardiovasculaires
CN110731962A (zh) * 2018-07-18 2020-01-31 中国医学科学院药物研究所 小檗碱、黄连碱或其活性代谢产物、及其盐在预防和/或治疗尿酸性肾病药物中的应用
CN108653284A (zh) * 2018-08-07 2018-10-16 陶军 黄连素在制备防治血管内皮功能障碍药物中的应用

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CHEN HAI-FANG, ZHANG CHEN, YAO YUN, LI JUN-MAO, DU WEN-DI, LI MU-LAN, WU BEI, YANG SHI-LIN, FENG YU-LIN, ZHANG WU-GANG: "Study on anti-hyperuricemia effects and active ingredients of traditional Tibetan medicine TongFengTangSan (TFTS) by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 165, 20 February 2019 (2019-02-20), pages 213 - 223, XP055828471, ISSN: 0731-7085, DOI: 10.1016/j.jpba.2018.11.038 *
HASSANEIN EMAD H.M.; SHALKAMI ABDEL-GAWAD S.; KHALAF MARWA M.; MOHAMED WAFAA R.; HEMEIDA RAMADAN A.M.: "The impact of Keap1/Nrf2, P38MAPK/NF-κB and Bax/Bcl2/caspase-3 signaling pathways in the protective effects of berberine against methotrexate-induced nephrotoxicity", BIOMEDICINE & PHARMACOTHERAPY, vol. 109, 2 November 2018 (2018-11-02), pages 47 - 56, XP085552189, ISSN: 0753-3322, DOI: 10.1016/j.biopha.2018.10.088 *
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