WO2016110250A1 - 芒果苷 -6-o- 小檗碱盐及其制备方法与用途 - Google Patents
芒果苷 -6-o- 小檗碱盐及其制备方法与用途 Download PDFInfo
- Publication number
- WO2016110250A1 WO2016110250A1 PCT/CN2016/070229 CN2016070229W WO2016110250A1 WO 2016110250 A1 WO2016110250 A1 WO 2016110250A1 CN 2016070229 W CN2016070229 W CN 2016070229W WO 2016110250 A1 WO2016110250 A1 WO 2016110250A1
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- WO
- WIPO (PCT)
- Prior art keywords
- mangiferin
- salt
- berberine
- solution
- berberine salt
- Prior art date
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Definitions
- the present invention relates to mangiferin-6-0-berberine salt, a process for the preparation thereof and use as an AMPK activator or the like.
- Mangiferin is a natural polyphenolic compound having the formula: C 19 H 18 0 consult, molecular weight: 422.
- Berberine is an isoquinoline alkaloid. Molecular formula: [ C 2 . H 18 NO .
- the mangiferin berberine salt should be mangiferin-3-0-berberine salt and mangiferin-7- A composition of 0-berberine salt.
- the specific conditions of mangiferin-3-0-berberine salt and mangiferin-7-0-berberine salt, such as the ratio of the two, WO2010/145192A1 is not described.
- ATP-activated protein kinase is a protein kinase that regulates energy metabolism in cells.
- a MPK plays a vital role in the pathogenesis of metabolic diseases, cardiovascular diseases, nervous system diseases, inflammatory diseases, tumors, and systemic diseases.
- AMPK is becoming a new target for disease treatment.
- AMPK activator listed, so the study of AMPK activators has important clinical significance [ ⁇ .AMPK: a new target for the treatment of diabetes and cardiovascular disease. China Medical Tribune, 2009,
- the structure of the drug substance provided by the listed drug must be clear, if the raw material The drug is a composition, and the proportion must also be determined in order to meet the controllable requirements of the drug quality. Therefore, the mangiferin berberine salt which obtains a single salt-forming site is a technical problem that must be solved for the compound as a drug substance.
- reaction solvent and mangiferin are suspended to obtain a suspension, and an aqueous solution of an alkaline sodium (potassium) salt is added to the suspension, and the reaction is clarified, and filtered to obtain a solution A.
- the reaction solvent is one or a mixture of two or more of water and a water-miscible organic solvent such as ethanol, methanol or acetone, wherein the volume ratio of water is 10 to 90% (v/v) o.
- the present invention provides a mangiferin-6-0-berberine salt, characterized in that the mangiferin-6-0-berberine salt has a structure of the following formula (I).
- the present invention provides a method for preparing the mangiferin-6-0-berberine salt, which is characterized in that: [0020] 1 alkaline sodium salt or alkaline potassium salt is added to water to prepare an alkaline sodium salt solution or an alkaline potassium salt solution, concentration
- [0021] 2 is added mangiferin dissolved in dimethyl sulfoxide, to prepare a mangiferin solution;
- the preparation method of the mangiferin-6-0-berberine salt according to the present invention is characterized in that the ratio of the mangiferin to dimethyl sulfoxide is 1:0.2-5 (w/v) ).
- the method for preparing mangiferin-6-0-berberine salt according to the present invention is characterized in that the molar ratio of the mangiferin to the basic sodium salt or the basic potassium salt is 1:0.5- 1.
- the method for preparing mangiferin-6-0-berberine salt according to the present invention is characterized in that: the mangiferin-6-0
- the preparation method of the mangiferin-6-0-berberine salt according to the present invention is characterized in that the basic sodium salt or the basic potassium salt is selected from the group consisting of sodium carbonate, sodium hydrogencarbonate and potassium carbonate.
- the basic sodium salt or the basic potassium salt is selected from the group consisting of sodium carbonate, sodium hydrogencarbonate and potassium carbonate.
- the present invention provides a medicament, characterized in that: the medicament consists of the above-mentioned mangiferin-6-0-berberine salt and a pharmaceutically acceptable adjuvant, and can be clinically applied according to a corresponding pharmaceutical method.
- Oral preparations such as tablets, capsules, granules, oral solutions, oral suspensions, syrups, pills, etc.; gels
- the present invention provides the use of the mangiferin-6-0-berberine salt in the preparation of an AMPK activator.
- the present invention provides the use of a medicament prepared by using the mangiferin-6-0-berberine salt as an active ingredient in the preparation of an AMPK activator.
- AMPK activators can be used to prevent or treat any one or more of the following diseases: diabetes, diabetes, various Chronic complications (including coronary heart disease, atherosclerosis, cerebrovascular disease, diabetic nephropathy, diabetic retinopathy, neuropathy, diabetic foot, maculopathy, cataract, glaucoma, refractive changes, iridocyclitis, etc.), Obesity, hyperlipidemia, insulin resistance, hyperinsulinemia, metabolic syndrome, hypertension, atherosclerosis, ischemic heart disease, cardiac hypertrophy, arrhythmia, heart failure, upper respiratory tract infection, chronic bronchitis, Chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, hepatitis, simple fatty liver, nonalcoholic fatty liver disease, non
- the present invention also provides a manganoside-6-0-berberine salt for use in the preparation of a medicament for the treatment of breast hyperplasia, uterine polyps, prostatic hyperplasia, sexual dysfunction, infertility, eczema and fatigue.
- the effective dosage range of the mangiferin-6-0-berberine salt provided by the present invention for the treatment of the above diseases is 37.5-
- 600 mg / day / person preferably 75 - 300 mg / day / person, administered 1-3 times a day, preferably 2 times a day.
- the usage can be selected according to the specific disease, and oral administration is preferred.
- mangiferin-6-0-berberine salt is formed.
- mangiferin-6-0-berberine salt not only solves the problem that the mangiferin berberine salt has a well-defined structure as a drug substance, but also, compared with the mangiferin berberine salt disclosed in WO2010/145192A1, The mangiferin-6-0-berberine salt of the compound of the present invention achieves the following unexpected technical effects:
- the maximum solubility of mangiferin-6-0-berberine salt is 12 mg/ml, while the mangiferin berberine salt of W 02010/145192A1 is 4 mg/ml, mangiferin-
- the solubility of 6-0-berberine salt in hydrochloric acid solution of pH 1 is 3 times that of mangiferin berberine salt disclosed in WO2010/145192A1, and the solution of mangiferin-6-0-berberine salt The stability is much better than the mangiferin berberine salt disclosed in WO2010/145192A1.
- the mangiferin-6-0-berberine salt of the present invention has a hygroscopic weight gain ratio which is much smaller than the mangiferin berberine salt disclosed in WO2010/1 45192A1 in a high-humidity environment. This stability in a high-humidity environment is conducive to the storage of the drug, reduces the absorption of water during the preparation process, and improves the quality of the drug.
- the mangiferin-6-0-berberine salt of the present invention has a therapeutic effect on mammary gland hyperplasia, uterine polyps, sexual dysfunction, benign prostatic hyperplasia, infertility, fatigue, and eczema. These therapeutic effects are not predicted and known from the activity of the mangiferin berberine salt disclosed by W O2010/145192A1.
- Test Example 1 Comparison of acid and water dissolution of two mangiferin berberine salts at pH 1
- Sample B Mangiferin berberine salt prepared by the method for preparing mangiferin berberine salt disclosed in WO2010/145192A1.
- Sample B was soluble in 1 minute, but the solution quickly became cloudy, indicating precipitation of precipitates.
- Another 50 ml of the solution was placed in a triangular flask, and the mango saponin berberine salt sample A which was ground into a fine powder was accurately weighed.
- sample A 400 mg was rapidly dissolved in 50 ml of an aqueous acid solution, and the solution was clear. After 24 hours of storage, no precipitate was precipitated.
- sample A 600 mg was completely dissolved in 50 ml of an aqueous acid solution, and the solution was clear. A small amount of precipitation occurred in about 30 minutes, and the solution was slightly turbid.
- Test Example 2 Comparison of the stability of two mangiferin berberine salts in high humidity environment
- Sample B Mangiferin berberine salt prepared by the preparation method of mangiferin berberine salt disclosed in WO2010/145192A1
- sample A and sample B are placed in a flat dish, accurately weighed, the test sample is placed in a constant humidity sealed container, placed at 25 ° C, RH90% ⁇ 5% for 10 days , accurately weighed on the 5th and 10th days respectively, and recorded the results. Calculate the moisture absorption gain ratio.
- Test Example 3 Activation of AMPK by Mangiferin-6-0-berberine salt
- Mangiferin-6-0-berberine salt 2 hydrate was prepared according to the above examples, and dissolved in DMSO. Dilute with medium or HBS buffer before use. The final concentration of DMSO is ⁇ 0.2 ⁇ 3 ⁇ 4.
- L6 cells were purchased from ATCC.
- High glucose DMEM medium was purchased from GIBCO; fetal calf serum was purchased from Hyclon e.
- L6 cells before differentiation are treated with high glucose DMEM medium containing 10% fetal bovine serum, 100
- L6 cells U/ml penicillin, 100 U/ml streptomycin, was placed in an incubator containing 5% C02 at 37 °C.
- the differentiation of L6 cells is about 60% of the cells, and replaced with high-sugar DMEM medium containing 2% fetal bovine serum. The medium is changed every two days until the L6 cells differentiate to about 90%.
- Cells in a 6-well plate were first starved in serum-free high glucose DMEM medium.
- the test substance was added to serum-free high glucose DMEM medium at a different concentration gradient with a DMSO content of 0.2%.
- the test substance was incubated with the cells for 3 h, then washed twice with ice-cold lxPBS, and added to 200 ⁇ l of lxSDS running buffer (50 mM Tris HCL, 100 mM).
- the lysate was analyzed by 10% SDS polyacrylamide gel electrophoresis, and then transferred to a PVDF membrane at 100 V, l-2 h in a film transfer apparatus.
- the protein in the gel was semi-dried onto a nitrocellulose membrane and Ponce au S determined the band.
- Block 1 small in blocking solution (3% skim milk powder, 0.1 ⁇ 3 ⁇ 4Tween, TBS dissolved) ⁇ , add 1: 1000 diluted primary antibody at 4 ° C overnight, TBS wash 3xl5min, add 1: 1000 diluted secondary antibody, incubate for 1 hour at room temperature, TBS wash 3xl5min, rinse in ECL for 5-10 min, use X-ray film Tablet display
- Test Example 4 Improvement of various indicators of metabolic disorders by mangiferin-6-0-berberine salt
- a patient who meets the diagnostic criteria for type 2 diabetes mellitus other than alcoholic fatty liver disease is administered 75 mg of mangiferin-6-0-berberine salt tablets (see Example 7 for the preparation method), twice daily, orally. After 6 months, the patient's liver enzyme (ALT).
- AST liver color hyperlipidemia
- APRI index reflecting liver fibrosis
- mangiferin-6-0-berberine salt has liver-lowering enzymes, improves hepatic steatosis, improves liver fibrosis, hypoglycemic, insulin-lowering, increases insulin sensitivity, lowers blood fat, lowers blood pressure, lowers Urinary protein, the role of weight loss.
- Test Example 5 Various therapeutic effects of mangiferin-6-0-berberine salt on human body
- Mangiferin-6-0-berberine salt tablet (abbreviated as A, the preparation method is shown in Example 7) is administered orally.
- Mangiferin-6-0-berberine salt is found in humans to improve rheumatoid arthritis, breast hyperplasia, uterine polyps, benign prostatic hyperplasia, dementia, sexual dysfunction, infertility, arrhythmia, heart failure, fatigue .
- the mangiferin-6-0-berberine salt gel (abbreviated as B, the preparation method is shown in Example 10) is applied, and the affected area is applied to treat eczema. details as follows:
- Test Example 6 Comparison of the pharmacokinetics of mangiferin-6-0-berberine salt with mangiferin berberine salt
- Sample B Mangiferin berberine salt prepared by the method for preparing mangiferin berberine salt disclosed in WO2010/145192A1
- Mangiferin reference solution Accurately weigh the mangiferin reference substance, put it into a 25ml volumetric flask, add methanol to dissolve and dilute to the mark, and prepare the reference mother liquor for use. Precisely dilute the reference mother solution to a reference solution containing mangiferin 2, 5, 10, 50, 100, 200 ng/ml.
- Preparation of berberine hydrochloride reference solution accurately weigh berberine hydrochloride reference substance, placed in a 25ml volumetric flask Add methanol to dissolve and dilute to the mark to prepare the reference mother liquor for use. Precisely dilute the reference mother solution to a reference solution containing berberine 0.2, 0.5, 2, 10, 20, 50 ng/ml.
- Blood sample processing method taking the blood of the rat in a heparin anticoagulation centrifuge tube, centrifuging at 6000 rpm for 10 min, taking plasma
- Treatment of blank plasma Take 100 ul of plasma, add 500 ul of acetonitrile-acetic acid (9:1) solution for 5 min, centrifuge at 6000 rpm for 10 min, take the supernatant, vacuum dry at 50 ° C, and add 100 ul of the mobile phase solution to the residue. Vortex for 3 min, centrifuge at 6000 rpm for 10 min to obtain a blank plasma sample, and take 10 ul of the supernatant.
- Pretreatment of the administered plasma sample 100 ul of plasma was collected from each blood collection point, acetonitrile-acetic acid (9:1) solution was added to vortex 500 ul for 5 min, centrifuged at 6000 rpm for 10 min, the supernatant was taken, and vacuum dried at 50 ° C for residue. Add 100 ⁇ l of the mobile phase solution, squish for 3 min, centrifuge at 6000 rpm for 10 min to obtain a blank plasma sample, and take 10 ul of the supernatant.
- Mass spectrometry conditions Ion detection method: Multi-ion detection (MRM); Ion polarity: Positive ion; Mangiferin: m/z 422.9/327.1, Berberine: m/z 337.3/321.3, Internal standard: m/ z 494.2/369.1.
- MRM Multi-ion detection
- Ion polarity Positive ion
- Mangiferin m/z 422.9/327.1
- Berberine m/z 337.3/321.3
- Internal standard m/ z 494.2/369.1.
- the ratio of mangiferin to DMSO is l:0.5 (w/v)) Dissolved by heating to prepare mangiferin solution; slowly add mangiferin solution to potassium bicarbonate solution, stir well, keep the reaction at 70 °C, filter After, get the mangiferin-6-0-potassium salt solution, keep warm at 60 °C; take berberine hydrochloride O.lmol and dissolve in 3700ml of 70 °C water, get berberine hydrochloride solution, keep warm at 80 °C.
- the mangiferin-6-0-potassium salt solution was slowly added to the berberine hydrochloride solution, stirred well, the reaction was completed, and the precipitate was allowed to stand still, filtered, and the solid was dried under vacuum at 45 ° C to obtain an orange-yellow solid mangiferin-6- 0 - Berberine salt 2 hydrate 65.7 g, yield 82.8%.
- the sample purity was determined by HPLC to be 97.6 ⁇ 3 ⁇ 4.
- the mangiferin of the present invention is commercially available (Xi'an Yangling Dongke Pharmaceutical Co., Ltd., and the manufacturer having the corresponding extraction equipment can produce 98%).
- Berberine hydrochloride, berberine sulfate, etc. are all commercially available (Xi'an Xiaocao Plant Technology Co., Ltd.).
- Commercially available products such as sodium hydrogencarbonate, sodium carbonate, potassium hydrogencarbonate, potassium carbonate, and dimethyl sulfoxide (DMSO) are commercially available.
- the reaction solution was cooled to 40 ° C, and acetone was added in an amount of 2 times the volume of the reaction solution, and the mixture was thoroughly stirred to precipitate a large amount of precipitate.
- the mixture was filtered, and the precipitate was washed with absolute ethanol.
- the precipitate was vacuum dried at 50 ° C, and pulverized to obtain a light yellow powdered mango.
- the glycoside-6-0-potassium salt was 25.3 g, the yield was 60.2%, and the sample purity was 98.3% as determined by HPLC.
- the mangiferin-6-0-sodium salt solution is slowly added to the berberine hydrochloride solution, stirred well, the reaction is completed, the precipitate is allowed to stand still, filtered, and the solid is dried under vacuum at 60 ° C, and the obtained dried product is added to an appropriate amount of DM SO.
- Dissolve slowly add DMSO solution to an appropriate amount of acetone, stir well, stand, precipitate, precipitate, filter, and wash the precipitate with an appropriate amount of absolute ethanol, solid 55.
- the sample purity was determined by HPLC to be 95.6 ⁇ 3 ⁇ 4.
- the berberine hydrochloride solution is slowly added to the medium mangiferin-6-0-sodium salt solution, stirred well, the reaction is completed, the precipitate is allowed to stand still, filtered, and the solid is dried to obtain an orange-yellow solid mangiferin-6-0-small
- the alkali salt 2 hydrate was 57.0 g, and the yield was 71.8%.
- the sample purity was determined by HPLC to be 94.5%.
- the berberine sulfate solution is slowly added to the mangiferin-6-0-potassium salt solution, stirred well, the reaction is completed, the precipitate is allowed to stand still, filtered, and the solid is dried under vacuum at 50 ° C to obtain an orange-yellow solid mangiferin-6- 0-berberine salt 2 hydrate 48.2 g, yield 57.6%.
- the sample purity was determined by HPLC to be 95.5%.
- the rate was 70.8%; the obtained dried product was recrystallized from an appropriate amount of methanol to obtain orange-yellow mangiferin-6-0-
- the berberine salt 4 hydrate was 35.9 g, and the yield was 44.3%.
- the sample purity was determined by HPLC to be 97.5 ⁇ 3 ⁇ 4.
- the berberine hydrochloride solution was slowly added to the medium mangiferin-6-0-sodium salt solution, stirred well, the reaction was completed, the temperature was lowered, the precipitate was allowed to stand still, filtered, and the precipitate was thoroughly washed with pure water, and the solid was vacuum dried at 55 ° C. , an orange-yellow solid mangiferin-6-0-berberine salt 2 hydrate 64.9 g was obtained, and the yield was 81.8%.
- the sample purity was determined by HPLC to be 96.5%.
- the mangiferin-6-0-berberine salt 2 hydrate prepared by the method of the example was pulverized through a 160 mesh sieve, and 37.5 g of the powder was weighed, and 50 g of microcrystalline cellulose and 45 g of pregelatinized starch were added as a dilution.
- the agent, mixed, compressed, made into 1000 tablets, coated with a film, that is, the drug content is 37.5 mg / tablet.
- the mangiferin-6-0-berberine salt prepared by the method of the example was pulverized through a 160 mesh sieve, 103 g of the powder was weighed, 150 g of pregelatinized starch was added as a diluent, and 100 g of xylose was added as a flavoring agent.
- the preparation formula is prepared, mixed, and the soft material is made by using 1% sodium carboxymethyl cellulose solution as a binder, and the granules are sieved by 24 mesh, dried, granulated, and packaged, that is, the drug content is 42 mg/g.
- the mangiferin-6-0-berberine salt 2 hydrate prepared by the method of the example was pulverized through a 160 mesh sieve, and 75 g of the powder was weighed, and 20 g of microcrystalline cellulose and 25 g of medicinal starch were added as a diluent.
- Preparation formula, mix, use 10 ⁇ 3 ⁇ 4 povidone K30 ethanol solution as binder, soft material, 24 mesh sieve granules, dry and granulate, capsules, 1000 capsules, that is, the drug content It is 75 mg/grain.
- Example 9 Preparation of mangiferin-6-0-berberine salt gel
- the sulfoxide is dissolved and uniformly mixed with the matrix to prepare a 1000 ml homogeneous liquid, that is, a mangiferin-6-0-berberine salt gel.
- the preparation method of the compound of the present invention solves the environmental pressure and cost problem caused by the use of a large amount of organic solvents, and is thus more suitable for industrial production.
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CA2970561A CA2970561C (en) | 2015-01-07 | 2016-01-06 | Mangiferin-6-o-berberine salt and preparation method and use thereof |
JP2017536871A JP6460498B2 (ja) | 2015-01-07 | 2016-01-06 | マンギフェリン−6−o−ベルベリン塩、その製造方法および用途 |
BR112017014416A BR112017014416A2 (pt) | 2015-01-07 | 2016-01-06 | sal de mangiferina-6-o-berberina e método de preparação e uso do mesmo |
AU2016206179A AU2016206179B2 (en) | 2015-01-07 | 2016-01-06 | Mangiferin-6-O-berberine salt and preparation method and use thereof |
EP16734910.9A EP3243823B1 (en) | 2015-01-07 | 2016-01-06 | Mangiferin-6-o-berberine salt and preparation method and use thereof |
RU2017123522A RU2670088C1 (ru) | 2015-01-07 | 2016-01-06 | Соль мангиферин-6-о-берберина, способ ее получения и применение |
CN201680003926.3A CN107108603B (zh) | 2015-01-07 | 2016-01-06 | 芒果苷-6-o-小檗碱盐及其制备方法与用途 |
KR1020177018073A KR101986983B1 (ko) | 2015-01-07 | 2016-01-06 | 망기페린-6-o-베르베린염 수화물 및 그 제조방법과 용도 |
US15/619,936 US10285969B2 (en) | 2015-01-07 | 2017-06-12 | Mangiferin-6-O-berberine salt and preparation method and use thereof |
ZA2017/04743A ZA201704743B (en) | 2015-01-07 | 2017-07-13 | Mangiferin-6-o-berberine salt and preparation method and use thereof |
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CN108570046A (zh) * | 2018-05-31 | 2018-09-25 | 闽江学院 | 一种黄连素-白杨素药物共晶及其制备方法 |
EP3479829A4 (en) * | 2016-07-04 | 2020-01-08 | Changzhou Deze Medical Science Co., Ltd. | MANGIFERIN-6-O-CALCIUM SALTS AND PRODUCTION METHOD AND USE THEREOF |
CN115414350A (zh) * | 2022-09-22 | 2022-12-02 | 湖北省农业科学院畜牧兽医研究所 | 芒果苷在制备抑制副猪嗜血杆菌药物中的应用 |
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JP2019178070A (ja) * | 2018-03-30 | 2019-10-17 | 大正製薬株式会社 | Mitol産生促進剤 |
JP7185226B2 (ja) * | 2018-11-22 | 2022-12-07 | 国立大学法人 鹿児島大学 | 1,5-アンヒドロフルクトース誘導体を含むampk活性化剤 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3479829A4 (en) * | 2016-07-04 | 2020-01-08 | Changzhou Deze Medical Science Co., Ltd. | MANGIFERIN-6-O-CALCIUM SALTS AND PRODUCTION METHOD AND USE THEREOF |
CN108570046A (zh) * | 2018-05-31 | 2018-09-25 | 闽江学院 | 一种黄连素-白杨素药物共晶及其制备方法 |
CN115414350A (zh) * | 2022-09-22 | 2022-12-02 | 湖北省农业科学院畜牧兽医研究所 | 芒果苷在制备抑制副猪嗜血杆菌药物中的应用 |
CN115414350B (zh) * | 2022-09-22 | 2023-08-04 | 湖北省农业科学院畜牧兽医研究所 | 芒果苷在制备抑制副猪嗜血杆菌药物中的应用 |
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US10285969B2 (en) | 2019-05-14 |
JP2018501293A (ja) | 2018-01-18 |
CN107108603A (zh) | 2017-08-29 |
ZA201704743B (en) | 2018-12-19 |
KR101986983B1 (ko) | 2019-06-07 |
EP3243823B1 (en) | 2020-12-16 |
RU2670088C1 (ru) | 2018-10-18 |
EP3243823A4 (en) | 2018-07-18 |
JP6460498B2 (ja) | 2019-01-30 |
EP3243823A1 (en) | 2017-11-15 |
CA2970561A1 (en) | 2016-07-14 |
KR20170092628A (ko) | 2017-08-11 |
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CA2970561C (en) | 2019-07-23 |
US20170273940A1 (en) | 2017-09-28 |
BR112017014416A2 (pt) | 2018-03-20 |
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