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WO2024222408A1 - Composition de sel de vitamine c de berbérine, son procédé de préparation et son utilisation - Google Patents

Composition de sel de vitamine c de berbérine, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2024222408A1
WO2024222408A1 PCT/CN2024/085762 CN2024085762W WO2024222408A1 WO 2024222408 A1 WO2024222408 A1 WO 2024222408A1 CN 2024085762 W CN2024085762 W CN 2024085762W WO 2024222408 A1 WO2024222408 A1 WO 2024222408A1
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Prior art keywords
berberine
salt
vitamin
fat
acid
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Chinese (zh)
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张洪涛
许瑶
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Hangzhou Juweiye Biomedical Co Ltd
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Hangzhou Juweiye Biomedical Co Ltd
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/62—Three oxygen atoms, e.g. ascorbic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine

Definitions

  • the invention belongs to the technical field of drug research, and specifically relates to a berberine vitamin C salt composition, a preparation method and application thereof.
  • Berberine also known as berberine, is a quaternary ammonium alkaloid isolated from the Chinese herbal medicine Coptis chinensis and is the main active ingredient in the antibacterial effect of Coptis chinensis. It was first obtained by M.-E. Chavalier and G. Pertain from the bark of Xanthoxylonclava in 1826.
  • berberine hydrochloride has multiple pharmacological activities, such as improving cardiovascular diseases and lowering blood sugar and blood lipids, in addition to its antibacterial and anti-inflammatory effects.
  • berberine is a highly polar quaternary ammonium base, which makes it difficult to penetrate the lipophilic barrier of the intestine.
  • its hydrochloride has very low water solubility, resulting in poor absorption in the human body after oral administration [Yu Chen, Zhang Hui, Pan Junfang, et al., Detection and preliminary study of metabolites in urine of healthy volunteers after oral administration of berberine hydrochloride, Chinese Journal of Clinical Pharmacology, 2000: (16) 36-39.].
  • Patent document CN 101323613 A discloses a berberine adduct, which acts as a prodrug to increase the blood concentration of berberine in the body, thereby improving the bioavailability of berberine.
  • Patent document US20220185807A1 discloses a berberine ascorbate (name: 9,10-dimethoxy-5,6-dihydro-[1,3]dioxane[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium.(R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-ol ester, molecular weight: 367.14), the structure of which is as follows:
  • the invention provides a berberine vitamin C salt composition, a preparation, a preparation method and an application.
  • a berberine vitamin C salt composition comprises berberine vitamin C salt and one or more of a gel base component, a pH regulator, a moisturizer, a chelating agent, an emulsifier, a penetration enhancer, a solvent and other additives.
  • a berberine vitamin C salt composition comprises berberine vitamin C salt, a moisturizer, an emulsifier and other additives.
  • the berberine vitamin C salt composition comprises, by weight percentage:
  • the above composition can be prepared into a gel.
  • berberine vitamin C salt composition which comprises, by weight percentage:
  • the above composition can be used to prepare emulsion preparations and the like.
  • Another feasible solution is a berberine vitamin C salt composition, according to weight percent Percentage:
  • the above composition can be used to prepare a patch and the like.
  • the berberine vitamin C salt is an effective ingredient of the composition.
  • the weight percentage of the berberine vitamin C salt is 5 to 20%. Further, the weight percentage of the berberine vitamin C salt is 10 to 20%.
  • the gel base component has multiple physiological functions such as biodegradability, biocompatibility, non-toxicity, antibacterial, anti-cancer, lipid-lowering, and immune enhancement.
  • the gel base component is selected from one or more of other high molecular natural active polysaccharides such as chitosan, chitin, chitosan derivatives, chitosan, pullulan, gum arabic, etc.
  • the gel is chitosan.
  • the weight percentage content of the gel base component is 0.5-5%; further 1-5%. Further 2-5%.
  • the pH regulator is selected from one or more of other organic acid regulators such as lactic acid, citric acid, sodium citrate, succinic acid, disodium succinate, propionic acid, butyric acid, and azelaic acid.
  • the weight percentage content of the pH regulator is 0.1 to 8%; further, the weight percentage content of the pH regulator is 0.5 to 8%; further, the weight percentage content of the pH regulator is 1 to 8%; further, the weight percentage content of the pH regulator is 2 to 8%.
  • the moisturizer is selected from one or more of lactic acid, glycerin, hyaluronic acid, urea, emu oil, manuka oil, olive oil, glycine, isopropyl palmitate and other common moisturizers.
  • the weight percentage of the moisturizer is 0.1-5%; further, the weight percentage of the moisturizer is 0.5-5%; further, the weight percentage of the moisturizer is 1-5%; further, the weight percentage of the moisturizer is 2-5%.
  • the moisturizer when preparing a gel, is selected from lactic acid, and one or more of glycerol, hyaluronic acid, and urea.
  • the moisturizer is selected from one or more of emu oil, manuka oil, olive oil, isopropyl palmitate, and glycine.
  • the pH regulator and the moisturizing agent can be selected from the same substance, that is, this substance can not only adjust the pH of the composition, but also have a moisturizing effect.
  • the total amount of the pH regulator and the moisturizing agent added is 0.1-8% (wt); further 1-8%.
  • the chelating agent plays a stabilizing role and has a synergistic antiseptic and antioxidative effect.
  • the chelating agent is selected from one or more of other common chelating agents such as ethylenediaminetetraacetic acid, sodium triphosphate, sodium hexametaphosphate, citric acid, sodium citrate, triethanolamine, diethanolamine, polyacrylic acid sodium salt, etc.
  • the weight percentage content of the chelating agent is 0.5-5%; more preferably, the weight percentage content of the chelating agent is 0.5-4%; further, the weight percentage content of the chelating agent is 0.5-3%.
  • the emulsifier is selected from one or more of the common emulsifiers such as Tween 80, steareth-6, glyceryl stearate, behenyl alcohol, ceteareth-20, arachidyl alcohol, hydroxyethyl acrylate, glycerin, sorbic acid, polysorbate 20, etc.
  • the weight percentage content of the emulsifier is 0.1-5%; further 1-5%.
  • the preferred emulsifier when preparing a gel, is selected from one or more of Tween 80, steareth-6, glyceryl stearate, behenyl alcohol, ceteareth-20, arachidyl alcohol, hydroxyethyl acrylate, and glycerin; when preparing an emulsion, the preferred emulsifier is selected from one or more of sorbic acid and polysorbate 20 or a mixture of two.
  • the penetration enhancer is selected from one or more of common penetration enhancers such as laurocapram, cyclohexane hexol, dimethyl isosorbide, tetrahydropiperine, N-n-alkylbenzisothiazolone, propylene glycol, urea, ethanol, benzalkonium chloride, polysorbate 80, etc.
  • the weight percentage of the penetration enhancer is 0.1-5%.
  • some components of the emulsifier or penetration enhancer can play both an emulsifying role and a penetration enhancing role, and have multiple comprehensive effects.
  • the solvent is one or more of water, ethanol, and glycerol.
  • some solvents, while serving as solvents, can also perform functions such as moisturizing, promoting penetration, emulsifying, and pH adjustment.
  • the other additives include one or more of preservatives, antioxidants, solubilizers, thickeners, colorants, and adhesives.
  • the preservatives include propylene glycol, benzoic acid, sorbic acid, parabens, dehydroacetic acid, and their corresponding salts.
  • the antioxidants include one or more of phospholipid complex flavonoids (lecithin), flavonoid extracts (peony leaf extract or calendula extract) or vitamin C, methyl hydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and sodium benzoate.
  • the solubilizer is selected from inulin lauryl carbamate, etc.; the thickener includes glycerol, etc.
  • the other additives include preservatives, antioxidants, solubilizers, and thickeners. Further, the weight percentage of the preservative is 0.3-5%; further, 0.5-5%; and further, 0.8-4%. Further, the weight percentage of the antioxidant is 1-15%. The weight percentage of the solubilizer or thickener is 1-8%.
  • a preparation is prepared from the composition described in any one of the above technical solutions.
  • the preparation is an external ointment.
  • it can be applied as gel, emulsion, or cream, etc. Furthermore, it can be applied as cream, gel, or emulsion to human skin, such as the abdomen, waist, back, buttocks, limbs, etc. where fat accumulation is obvious.
  • the preparation is an oral aqueous solution, ointment, tablet, powder, capsule, etc.
  • a preparation method of the gel comprises: dissolving the gel base component in a solvent, adding a chelating agent, an emulsifier or a penetration enhancer, and then adding berberine vitamin C salt, a pH regulator or a moisturizer to the remaining solvent, stirring, and obtaining the preparation.
  • composition described in any of the above technical solutions in the preparation of drugs for treating or improving cardiovascular diseases and reducing blood sugar, blood lipids, body weight, and body fat.
  • composition described in any of the above technical solutions in the preparation of drugs for treating or improving cardiovascular diseases, blood sugar lowering drugs, blood lipid lowering drugs, weight reducing drugs, and body fat reducing drugs.
  • composition described in any one of the above technical solutions in treating or improving cardiovascular diseases, lowering blood sugar, reducing body weight, and reducing body fat.
  • composition can be used by external application, external patch or internal administration.
  • the dosage for external use can be 100 mg/kg or more, and further, the dosage is 10 mg/kg to 1000 mg/kg.
  • the dosage is The oral dosage is 50 mg/kg/day or more, and the further oral dosage is 50 mg/kg to 500 mg/kg/day.
  • the dosage for external use can be 3 mg/kg or more, and further, the dosage is 1 mg/kg to 30 mg/kg.
  • the dosage is 3 mg/kg/day or more, and further, the oral dosage is 1 mg/kg to 30 mg/kg/day.
  • composition of the present invention has the effects of lowering blood sugar, blood lipids and blood pressure, and when used for in vitro coating, it is effectively enriched in fat and reduces fat volume.
  • the composition of the present invention has the effects of lowering blood sugar, blood lipids, blood pressure, as well as reducing body weight and body fat.
  • it When used for in vitro coating, it can effectively reduce body weight, while effectively enriching in fat, and can directly act on abdominal fat cells, reducing the volume of fat cells and causing white fat to change to brown; when used orally, it can also effectively reduce body weight, body fat and blood lipids.
  • the invention discloses an application of berberine vitamin C salt, which is used for preparing drugs for improving cardiovascular diseases of humans or animals, lowering blood sugar, lowering blood lipids, lowering body weight and lowering body fat.
  • the experimental results show that when high-fat model mice are orally administered with the new berberine salt, the new berberine salt can help the mice resist the weight gain induced by a high-fat diet, effectively reduce body weight, and reduce body fat at the same time.
  • the new berberine salt directly participates in the energy metabolism of obesity at the fat cell level, causing the volume of white fat cells to decrease.
  • Fig. 1 is a graph showing the average plasma concentration-time curve after abdominal administration of 200 mg/kg berberine new salt to SD rats.
  • Fig. 2 Bar graph of average tissue drug concentrations after administration of berberine new salt.
  • FIG. 3 Schematic diagram of abdominal fat in mice after drug administration.
  • Figure 4 Schematic diagram of pathological staining of abdominal adipocytes in mice after drug administration (scale size is 50 ⁇ m).
  • Figure 5 is a graph showing changes in body weight of high-fat model mice after abdominal administration.
  • Figure 6 is a graph showing changes in body weight of high-fat model mice after oral administration.
  • Figure 7 Body fat data of high-fat model mice detected by nuclear magnetic resonance imaging after oral administration.
  • Figure 8 is a graph showing the body weight changes in the oral drug-discontinuation group and the drug-continuation group of high-fat model mice.
  • Figure 10 eWAT tissue staining images of high-fat model mice after oral administration (scale size is 50 ⁇ m).
  • Figure 11 iWAT tissue staining images of high-fat model mice after oral administration (scale size is 50 ⁇ m).
  • Figure 12 is a graph showing weight changes in cats in the control group.
  • Figure 13 is a graph showing changes in body weight of cats in the high-dose medication group.
  • Figure 14 is a graph showing changes in body weight of cats in the low-dose medication group.
  • Fig. 15 is a curve diagram of changes in TG triglycerides of cats.
  • Figure 16 is an ellipsoid diagram of the three-dimensional structure of the new salt molecule of berberine.
  • Figure 17 Molecular stacking diagram of the crystal cell of the new berberine salt (projected along the a-axis and b-axis).
  • berberine vitamin C salt can be obtained according to the preparation method of US20220185807A1.
  • Embodiment 3 (gel)
  • a gel was prepared in a similar manner to that of Example 1.
  • Example 2 After obtaining the gel of Example 1, add an appropriate amount of sodium polyacrylate, stir evenly, dry, and then apply with the aid of patch to obtain a patch preparation of the salt.
  • the test article was prepared to a final concentration of 109 mg/mL for abdominal administration.
  • test sample is prepared in CMC-Na (sodium carboxymethyl cellulose) solvent and appears as a uniform yellow suspension after preparation.
  • Planned age at dosing 6-8 weeks at the start of dosing.
  • Planned body weight at dosing 180-250 g at the start of dosing.
  • the animals were housed in transparent resin plastic cages (530 mm x 400 mm x 200 mm).
  • Fluorescent lighting 12 hours of lighting (08:00-20:00) and 12 hours of no lighting per day.
  • the ambient temperature and relative humidity of the animal room should be controlled within the range of 20-26°C and 40-70%, respectively.
  • the animal body weight was measured before administration, and healthy animals with similar body weight were selected for inclusion in the experiment.
  • Dosing frequency Single dose.
  • liver and abdominal fat were collected and then stored in a -80°C refrigerator.
  • the centrifugation conditions are:
  • Preparation of berberine standard curve and quality control samples Prepare standard curve working solutions (concentrations of 4 ng/mL, 10 ng/mL, 20 ng/mL, 50 ng/mL, 100 ng/mL, 200 ng/mL, 500 ng/mL, 1000 ng/mL) and quality control working solutions (concentrations of 8 ng/mL, 80 ng/mL, 800 ng/mL) using 50% methanol water as the diluent. Take 5 ⁇ L of each working solution and mix with 45 ⁇ L of blank plasma to prepare plasma standard curve and quality control samples.
  • Pretreatment of berberine new salt plasma samples After the plasma samples were thawed at room temperature, 30 ⁇ L were taken, 180 ⁇ L of internal standard (200 ng/mL, methanol, methyldopa) was added, vortexed for about 1 min, centrifuged at 4 ° C, 15400g for 10 min, and the supernatant was taken for sampling and analysis.
  • internal standard 200 ng/mL, methanol, methyldopa
  • NCA WinNonlin software non-compartmental method
  • the experiment selected 4 SD rats of similar weight and divided them into 2 groups. Berberine new salt was smeared on the abdominal epidermis of rats 1-3, and the dosage was 200 mg/kg, a single dose. Blood was collected at 0min before administration, and 15min, 30min, 45min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, and 36h after administration. After 36h, liver tissue and abdominal fat were collected. The remaining rats were assigned to Group 2 as a spare group for backup and taking blank matrix.
  • the samples were placed in labeled centrifuge tubes and centrifuged quickly (centrifugation conditions: 3000 rpm, 15 minutes, 4°C) to separate the plasma, and the plasma was stored at -40°C for testing.
  • the berberine content in plasma was detected by LC-MS/MS analysis, and the lower limit of quantification of the method was 4ng/mL.
  • the plasma concentration data were statistically analyzed using the metabolic kinetic data analysis software WinNonlin 7.0, and the pharmacokinetic parameters were calculated using the non-compartmental model method (NCA).
  • internal standard working solution 200ng/mL, methanol, methyldopa
  • vortex mix for 1min
  • centrifuge 4°C, 15400g for 10min.
  • the plasma concentration data were statistically analyzed using the metabolic kinetic data analysis software WinNonlin7.0, and the pharmacokinetic parameters were calculated using the non-compartmental model method (NCA).
  • Temperature and relative humidity were controlled (22 ⁇ 2°C, 55 ⁇ 5%) with 12-h light-dark cycle and free access to food and water.
  • the control group was fed normally, and the experimental group was treated with the patch (dose of about 22 mg/mouse)
  • FIG 3 is a schematic diagram of abdominal fat after patch administration in mice, where samples No. 1 and No. 2 are administered for 5 consecutive days, and samples No. 3 and No. 4 are administered for 1 day. From the color of the visceral fat, it can be seen that the fat of mice that have been applied with the new salt of berberine for 5 days is darker than the fat that has been applied for only 1 day, indicating that the fat "browns" as the berberine is applied. Therefore, the experimental results show that berberine can be absorbed by fat cells through the skin and directly acts on fat cells. The abdominal fat cells show brown changes of white fat cells, and the color deepens with the increase of administration time.
  • Figure 4 is a schematic diagram of pathological staining of abdominal fat cells after administration in mice. After pathological staining, we observed the changes in fat cells before and after the use of berberine. It can be found that after the use of berberine, the abdominal fat cells of mice became significantly smaller, which is consistent with the expectation of browning of white fat cells
  • a total of 10 DIO model mice fed with HFD (high fat diet) were divided into a control group and a drug group, with 5 mice in each group.
  • Temperature and relative humidity were controlled (22 ⁇ 2°C, 55 ⁇ 5%) with 12-h light-dark cycle and free access to food and water.
  • mice in the control group were fed normally, and the mice in the medication group were treated with berberine new salt gel (dose of about 22 mg/mouse)
  • Temperature and relative humidity were controlled (22 ⁇ 2°C, 55 ⁇ 5%) with 12-h light-dark cycle and free access to food and water.
  • the experimental group DIO mice were orally administered berberine new salt 100mg/kg/day (the drug was dissolved in the mouse drinking water), and after 50 days of continuous administration, the dose was adjusted to 500mg/kg/day. After 77 days of continuous administration, the experimental group was divided into two groups, the drug withdrawal group stopped drinking water administration, and the continued drug administration group continued normal administration.
  • the experimental group was equally divided into two groups, the drug withdrawal group (WATER) and the continued drug administration group (BBR).
  • WATER drug withdrawal group
  • BBR continued drug administration group
  • FIG. 9 is an electron micrograph of iWAT tissue.
  • the control group (WT) and the experimental group (BBR) each showed two electron micrographs of different regions, and it can be seen that the number and size of mitochondria in the abdominal white fat iWAT of high-fat model mice increased under the condition of oral administration of berberine new salt.
  • FIG. 10 is the eWAT tissue staining diagram.
  • the control group and the experimental group each show 2 pictures of different areas of vision. It can be seen that the inguinal white fat eWAT in the experimental group
  • Figure 11 is a staining diagram of iWAT tissue. The control group and the experimental group each show 2 diagrams of different field of view. It can be seen that the cell size of abdominal white fat iWAT tissue in the experimental group is also significantly reduced.
  • the results of Figures 10 and 11 both indicate that oral administration of the new berberine salt may affect the energy metabolism of fat cells and cause the volume of white fat cells to decrease.
  • the experimental cats were divided into a healthy control group, an obese control group, a high-dose medication group, and a low-dose medication group.
  • the experimental groups are shown in Table 5:
  • the berberine new salt powder is directly packaged in capsules for oral administration.
  • the new salt of berberine was orally administered to the obese cats, with the high-dose group receiving 100 mg/day and the low-dose group receiving 50 mg/day.
  • the cats in the healthy control group and the obese control group were raised normally.
  • the triglyceride index of the obese control cat increased over time, and the triglyceride of the healthy control cat was stable at 0.33mmol/L. Under the condition of oral administration of the new berberine salt, the triglyceride index of the obese cat decreased. This result shows that oral administration of the new berberine salt can reduce the blood lipids of obese cats.
  • microcrystal electron diffraction MicroED
  • MicroED data were collected using a Talos F200C cryo-EM coupled with a CetaD detector. After checking the quality of the microcrystals, 19 crystals were selected and data were collected under liquid nitrogen freezing conditions. During data analysis, the 8 best sets of data were used to determine the unit cell parameters and merge the data.
  • the atomic scattering factor of electrons (waves) was used to calculate the theoretical structure factor, and the structural analysis was completed using the SHELXT software to obtain the initial structure. Subsequent refinements were completed using the SHELXL program based on the least squares refinement method. Combined with the molecular formula information of the compound, all non-hydrogen atoms were identified and anisotropically refined, and all hydrogen atoms were obtained by computational hydrogenation.
  • FIG. 16 is the three-dimensional structure ellipsoid diagram of the berberine new salt molecule
  • Figure 17 is the molecular stacking diagram of the berberine new salt unit cell (projected along the a-axis and b-axis).

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  • Pharmacology & Pharmacy (AREA)
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  • Epidemiology (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dispersion Chemistry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition de sel de vitamine C de berbérine, qui comprend un sel de vitamine C de berbérine, et un ou plusieurs éléments parmi un composant de base de gel, un régulateur de pH, un humectant, un agent chélatant, un émulsifiant, un activateur de perméation et un solvant. L'invention concerne en outre l'utilisation de la composition. La composition a pour effet de réduire le sucre sanguin, la graisse sanguine et la pression artérielle, de réduire le poids corporel et de réduire la graisse corporelle. La composition peut être utilisée en application externe, ce qui permet de réduire efficacement le poids corporel et de stimuler les adipocytes ; de plus, la composition peut agir directement sur les cellules adipeuses abdominales, réduisant ainsi leur volume et induisant le brunissement de l'adipocyte blanc. Lors d'une utilisation par voie orale, la composition peut également être utilisée pour réduire efficacement le poids corporel, la graisse corporelle et la graisse sanguine.
PCT/CN2024/085762 2023-04-28 2024-04-03 Composition de sel de vitamine c de berbérine, son procédé de préparation et son utilisation Pending WO2024222408A1 (fr)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
CN102258517A (zh) * 2011-08-30 2011-11-30 缪刚刚 一种外用型高血压西药制剂及其制备方法
CN103919774A (zh) * 2013-12-20 2014-07-16 中国药科大学 去亚甲基小檗碱在制备降血脂药物中的应用
CN106687460A (zh) * 2014-07-29 2017-05-17 深圳君圣泰生物技术有限公司 小檗碱盐、熊去氧胆酸盐、相关复方及其制备方法和应用
US20180235870A1 (en) * 2015-08-17 2018-08-23 Delivra Inc. Transdermal formulations for delivery of berberine compounds, and their use in the treatment of berberine-responsive diseases and conditions
US11345697B1 (en) * 2020-12-10 2022-05-31 Beiture LLC Crystalline berberine ascorbate salt, methods of preparation and applications thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102258517A (zh) * 2011-08-30 2011-11-30 缪刚刚 一种外用型高血压西药制剂及其制备方法
CN103919774A (zh) * 2013-12-20 2014-07-16 中国药科大学 去亚甲基小檗碱在制备降血脂药物中的应用
CN106687460A (zh) * 2014-07-29 2017-05-17 深圳君圣泰生物技术有限公司 小檗碱盐、熊去氧胆酸盐、相关复方及其制备方法和应用
US20180235870A1 (en) * 2015-08-17 2018-08-23 Delivra Inc. Transdermal formulations for delivery of berberine compounds, and their use in the treatment of berberine-responsive diseases and conditions
US11345697B1 (en) * 2020-12-10 2022-05-31 Beiture LLC Crystalline berberine ascorbate salt, methods of preparation and applications thereof

Non-Patent Citations (1)

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Title
LIU, ZEWEI: "Emulsion Formulation Optimization of Berberine Hydrochloride", JOURNAL OF TIANJIN AGRICULTURAL UNIVERSITY, vol. 27, no. 3, 1 September 2020 (2020-09-01), pages 70 - 78, XP093229171, ISSN: 1008-5394, DOI: 10.19640/j.cnki.jtau.2020.03.016 *

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