CN100404534C - Derivative of berberine, and prepartion method, composition of medication, and application - Google Patents
Derivative of berberine, and prepartion method, composition of medication, and application Download PDFInfo
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- CN100404534C CN100404534C CNB2006100194924A CN200610019492A CN100404534C CN 100404534 C CN100404534 C CN 100404534C CN B2006100194924 A CNB2006100194924 A CN B2006100194924A CN 200610019492 A CN200610019492 A CN 200610019492A CN 100404534 C CN100404534 C CN 100404534C
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Abstract
The present invention synthesizes an original berberine derivative (BBR-H) by mending the structure of the existing berberine (BBR). The berberine derivative is a compound expressed by a general formula (I), wherein R in the general formula (I) represents hydrogen or sugar or sulfonic group, and experiment proves that the compound is the prodrug of berberine. The present invention relates to the preparation method of the compound, medical composition with the compound as an active ingredient, the application of the compound and the medical composition for treating 2 type diabetes and regulating blood sugar and blood fat.
Description
Technical field
The present invention relates to a kind of pharmaceutical use of berberinc derivate, be meant the application of this derivative in the medicine of treatment diabetes B, blood sugar regulation and blood fat especially.
Background technology
At present, the diabetes prevailing disease that become international, data shows according to statistics: domestic diabetes B morbidity 1976 was 1.0%, 1989 is 2.0%, 1996 is 3.2%, calendar year 2001 Shanghai and Guangzhou then surpassed 9%, be higher than the mean level (ML) of American-European developed country.Diabetes have become human " the third-largest killer ", and associated medical treatment and nursing expenses is very huge, even economically developed country also can't bear the heavy load.
Berberine (BBR) also claim berberine, and it is a kind of germ resistance alkaloid that proposes from raw materials such as the Chinese medicine coptis, cork tree, and its hydrochloride is a yellow powder, and bitter is slightly soluble in water.It is energy dysentery bacterium, tubercule bacillus and staphylococcus etc. in test tube, and the general antibiotic of tiring is low, and its oral post-absorption is very poor, and is effective to bacillary dysentery and some intestinal tract infections.There is certain restraining effect its injection back to circulation and breathing.Its external application can be treated pyogenic infection and eye conjunctivitis etc.
The scientific research personnel has carried out the research in nearly ten years to the problem of Berberine (BBR) treatment and prevent diabetes, and great deal of experiment data shows: Berberine can be treated diabetes B, and its topmost effect is exactly to regulate patient's blood sugar and blood fat.Blood sugar regulation comprises the promotion insulin secretion, improves insulin resistant (mainly being the amount of regulating insulin resistant correlation factor free fatty acids FFA); Regulating blood fat mainly is the amount of triglyceride reducing, and determined curative effect.Yet in actual applications, not only the animal experiment taking dose of Berberine is higher, and its effective dose is up to 185mgKg
-1D
-1, and the clinical oral administration dosage of Berberine is also higher, have up to 3gd
-1, and 1～3 month be a course of treatment.High dosage long period ground uses, and can destroy the flora balance in patient's enteron aisle undoubtedly, increases the side effect of Berberine.And on the other hand, the isolated test result of Berberine shows that its effective concentration demand is but very low, 1～10 μ molL
-1Berberine be dosage and promote HIT-T15 emiocytosis Regular Insulin, 0.1～100 μ molL according to patience ground
-1Berberine can significantly increase the glucose consumption and the transhipment of adipocyte, 5～100 μ molL
-1Berberine can make the glucose consumption amount of HepG2 cell increase by 33%～60%, curative effect and 1mmolL
-1N1,N1-Dimethylbiguanide suitable, this shows the hypoglycemic effect of low dosage Berberine isolated test brilliance.Reach the huge contrast of dosage that exsomatizes in the body, point out Berberine effect brilliance but the oral absorption extreme difference.The researchist once was absorbed as purpose to strengthen the Berberine stomach, carried out the experimental exploring on many pharmaceuticies, but when being applied to the animal oral administration, find that effect is unsatisfactory, this may be due to the intravital hydrochloric acid in gastric juice of animal, enzyme system or other factor affecting.The rat intestine perfusion experiment is shown also only have an appointment after 2.5 hours 5% Berberine of bowel lavage disappears from the rat enteron aisle, this pointed out in 2.5 hours, and the Berberine up to 95% is not absorbed and used.How to solve the absorption problem of Berberine, reduce its taking dose significantly, the effect of giving full play to its treatment diabetes B is the difficult problem that the scientific research personnel is badly in need of capturing.
A kind of berberinc derivate is disclosed in " JOURNAL OF MOLECULAR STRUCTURE " (the molecular structure magazine) the 687th of publication in 2004 rolled up the 135th～142 page, we claim that it is a pure formula Berberine (BBR-H), specifically see the 136th page of second width of cloth among Fig. 1, its chemical structural formula is as follows:
Introduced the preparation method of this berberinc derivate in the literary composition, this method is that 100mg is vulcanized Berberine (1a, X=HSO
4) be dissolved in the 20ml water, with the protective layer of ether, add sodium hydroxide as this aqueous solution, shake mixed solution gently, allow its evaporation under the temperature around being placed on then, after 2 days, can collect some jonquilleous crystal 2 a, promptly pure formula Berberine (BBR-H).But the amount of the berberinc derivate that obtains by this method is few, is not enough to support large-scale pharmacology experiment and application.Also this berberinc derivate has been carried out the research experiment of some aspect of performances in the literary composition, but its conclusion is to find that this berberinc derivate does not almost have biological activity.
Summary of the invention
Purpose of the present invention will be abandoned the mistaken ideas of people on above-mentioned pure formula Berberine (BBR-H) performance understanding exactly, studies the new purposes of a kind of pure formula Berberine (BBR-H) in pharmacy.
Specifically, the invention provides the application of a kind of pure formula Berberine (BBR-H) in the medicine of treatment diabetes B, blood sugar regulation and blood fat, to overcome the very poor deficiency of existing Berberine (BBR) drug absorption rate.
The present invention is a raw material with the hydrogen sulfate Berberine, by the structure of existing Berberine (BBR) is modified, synthesizes above-mentioned pure formula Berberine (BBR-H), and its preparation method may further comprise the steps:
1) hydrogen sulfate Berberine raw material is soluble in water, make hydrogen sulfate Berberine saturated solution;
2) in hydrogen sulfate Berberine saturated solution, drip alkaline solution, till sediment-free produces again, form turbid solution;
3) above-mentioned turbid solution is filtered, obtain throw out;
4) the gained throw out is dissolved in the organic solvent, by silica gel column chromatography, uses the organic solvent wash-out, described organic solvent can be one or more the arbitrary combination in methyl alcohol, ether, chloroform, methylene dichloride, ethyl acetate, the acetone;
5) to above-mentioned organic solvent elutriant concentrating under reduced pressure, vacuum dehydrating at lower temperature obtains crude product;
6) with the gained crude product with methyl alcohol or ethyl alcohol recrystallization, can obtain the pure product of pure formula Berberine (BBR-H).After testing as can be known: its molecular weight is 353, molecular formula is C
20H
19NO
5
The above-mentioned pure formula Berberine (BBR-H) that makes is carried out the experiment of pharmacology aspect and find that it has multiple valuable drug activity, particularly its performance that absorbs easily is that existing Berberine (BBR) is not available.Specifically:
The pure formula Berberine that the present invention studied has demonstrated the excellent adjusting diabetes B rat blood sugar and the effect of blood fat in animal experiment, it than generally acknowledge at present have the diabetes B rat blood sugar of adjusting and effect blood fat, the maximally related compound berberine hydrochloride of structure far better, and effective dose is much smaller.
The effect of the pure formula Berberine that the present invention studied on the treatment diabetes B is mainly reflected in blood sugar regulation and lipid aspects.Blood sugar regulation comprises and improves oral glucose tolerance, promotes insulin secretion, improves insulin resistant (mainly being the amount of regulating insulin resistant correlation factor free fatty acids FFA) that regulating blood fat mainly is the amount of triglyceride reducing.The curative effect of its oral administration diabetes B rat is outstanding and stable.
With the pure formula Berberine that the present invention was studied is active ingredient, can make various types of pharmaceutical compositions.Described pharmaceutical composition contains the pure formula Berberine for the treatment of significant quantity and contains one or more pharmaceutically acceptable carriers.
The pure formula Berberine that the present invention studied and its pharmaceutical composition can be used for preparing the medicine for the treatment of diabetes B, blood sugar regulation and blood fat.
Above-mentioned pharmaceutically acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field routine, for example: thinner, vehicle such as water etc.; Weighting agent such as starch, sucrose etc.; Tamanori such as derivatived cellulose, alginate, gelatin and polyvinylpyrrolidone etc.; Wetting agent such as glycerine etc.; Disintegrating agent such as agar, lime carbonate and sodium bicarbonate etc.; Tensio-active agent such as cetyl alcohol etc.; Lubricant such as talcum powder, calcium stearate, magnesium and polyoxyethylene glycol etc.In addition, can also in pharmaceutical composition, add other auxiliary such as flavouring agent, sweeting agent etc.
The pure formula Berberine that the present invention studied usually with the form of pharmaceutical composition by oral, snuffing is gone into or the mode of rectal administration is applied to the patient who needs this treatment.Be used for when oral, can be made into conventional solid preparation such as tablet, pulvis, granule, capsule etc.Be used for that snuffing is gone into or during rectal administration, can be made into solution or water or oiliness suspension agent etc.Preferred form is tablet, coated tablet, capsule, and best form is the preparation that discharges at the enteron aisle privileged site.
The various formulations of pharmaceutical composition of the present invention can be according to the production method preparation of pharmaceutical field routine.Active ingredient is mixed with one or more carriers, be made into required formulation then.
It is 0.1%～99.5% active ingredient that preferred pharmaceutical composition of the present invention contains weight ratio, and it is 0.5%～95% active ingredient that most preferred pharmaceutical composition of the present invention contains weight ratio.
The amount of application of pharmaceutical composition of the present invention can be according to the variations such as severity of route of administration, patient age, body weight and conditions of patients, it can be 0.2mg～16mg/Kg body weight that its daily dosage calculates by active ingredient, most preferred daily dosage is 2mg～6mg/Kg body weight, can use by one or many.
The present invention is according to the principle of design of prodrug, and it is synthetic to be with Berberine (BBR) that parent carries out chemically modified, therefrom filters out the better pure formula Berberine (BBR-H) of performance, and has found its new purposes aspect the treatment diabetes.The present invention is that foundation is screened berberinc derivate with the scientific experiment, and its method of screening lead compound from hundreds thousand of kinds of compounds than the formula of looking for a needle in a haystack in the world has clear superiority.Moreover Berberine is cheap and good-quality treatment diabetes B medicine, its mechanism of action clearly help the sure reasonableness of using clinically as the pure formula berberinc derivate of its precursor, thereby give full play to its social benefit and economic benefit.
Description of drawings
Fig. 1 is berberine hydrochloride+blank serum sample high performance liquid chromatograph ultraviolet absorpting spectrum;
Fig. 2 is berberine hydrochloride+pure formula Berberine+blank serum sample high performance liquid chromatograph ultraviolet absorpting spectrum;
Fig. 3 is for gavaging rat blood serum sample high performance liquid chromatograph ultraviolet absorpting spectrum behind berberine hydrochloride+pure formula Berberine 30min;
Fig. 4 is for gavaging rat blood serum sample high performance liquid chromatograph ultraviolet absorpting spectrum behind berberine hydrochloride+pure formula Berberine 60min.
Embodiment
The present invention is described in further detail below in conjunction with drawings and Examples, and the following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
Embodiment 1: the preparation of pure formula Berberine
5g hydrogen sulfate Berberine powder is dissolved in the distilled water, and preparation is into about the saturated solution of 120ml; Dropping concentration is 20% sodium hydroxide solution, till not having the precipitation generation again; Filter formed turbid solution, obtain throw out; This throw out is dissolved in the organic solvent ether, filters this lysate, gained filtrate drips in the 20g silica gel G, and normal temperature volatilization dry diethyl ether is gone into silica gel G post (silica gel G 500g) on the dry method, use the ether wash-out; The elutriant concentrating under reduced pressure is lower than under the condition that 150mbar, temperature be lower than 60 ℃ in vacuum tightness and carries out vacuum dehydrating at lower temperature, obtains crude product 2.21g; Again with this crude product with methyl alcohol or ethyl alcohol recrystallization, drying is a yellow powder, can obtain the pure product 1.78g of pure formula Berberine.
Embodiment 2: with the preparation that is the tablet of active ingredient of pure formula Berberine
Ratio in the prepared pure formula Berberine 10mg of embodiment 1, lactose 187mg, W-Gum 50mg, Magnesium Stearate 3mg takes by weighing raw material, earlier pure formula Berberine, lactose and W-Gum are mixed, and be that 70% ethanol is moistening with concentration, then the mixture after moistening sieve, granulate, drying, after sieve, adding Magnesium Stearate, with the mixture compressing tablet, every weighs 250mg at last, and active ingredient content is 10mg.
Test example 1:
Embodiment 1 prepared pure formula Berberine shows good curing diabetes B, blood sugar regulation and blood fat in animal experiment effect.Concrete process of the test is as follows:
Adopt cleaning level Wistar male rat, body weight 200 ± 10g, single cage is fed, and experimentizes in cleaning level rat experiment chamber, and controlled temperature is 20～22 ℃.The laboratory strictly observes the aseptic technique standard, routine disinfection air, water and feed.Behind the fasting 12h, rat tail vein injection STZ liquid, STZ liquid is prepared with 0.1M citric acid-sodium citrate buffer, filtration sterilization, injection volume is 30mgkg
-1After feeding for 2 weeks with normal diet, fasting 12～15h presses 2.2gkg with 40% glucose
-1Irritate stomach, get the about 0.5ml of blood in 0min, 30min, 60min, 120min tail vein, separation of serum is surveyed blood sugar, use rat with this rat of screening impaired glucose tolerance as experiment, be divided into the basic, normal, high dosage group of pure formula Berberine (representing with BBR-H.L group, BBR-H.M group and BBR-H.H group respectively) of model group, acetylsalicylic acid group, existing Berberine group (representing) and embodiment 1 at random with the BBR group.Wherein: BBR group dosage is 185mgkg
-1D
-1, BBR-H.L group dosage is 18.5mgkg
-1D
-1, BBR-H.M group dosage is 37.0mgkg
-1D
-1, BBR-H.H group dosage is 74.0mgkg
-1D
-1, acetylsalicylic acid group dosage is 120mgkg
-1D
-1, the auxiliary liquid of model group with volume.
Except that normal group, all the other group sucrose: lard: milk powder: egg: normal diet=30: 20: 4: 2: 63 high 8 weeks of fat high calorie forage feed, after 4 weeks of treatment, do the OGTT test, detect blood sugar, calculate sugar tolerance; After 8 weeks of treatment,, detect Regular Insulin (IN) content, free fatty acids (FFA) content and triglyceride level (TG) from abdominal aortic blood.Test-results is embodied in following four aspects:
One, embodiment 1 prepared pure formula Berberine has improved the tolerance of diabetes B rat oral glucose.As shown in table 1 below:
The sugar tolerance result (mmol/L) of table 1:BBR-H.L group, BBR-H.M group and BBR-H.H group
# and normal group be P＜0.01 relatively; ▲ compare P＜0.01 with model group; * compare P＜0.05 with model group.
According to the carbohydrate tolerance test result of table 1 as can be known: BBR-H.M organizes (37.0mgkg
-1D
-1) and BBR-H.H group (74.0mgkg
-1D
-1) can both improve diabetes B rat oral glucose tolerance, its effect and acetylsalicylic acid group (120mgkg
-1D
-1) and BBR group (185mgkg
-1D
-1) quite.
Its two, embodiment 1 prepared pure formula Berberine can promote the secretion of diabetes B rat insulin.As shown in table 2 below:
The insulin content (uIU/mol) of table 2:BBR-H.L group, BBR-H.M group and BBR-H.H group
# and normal group be P＜0.01 relatively; ▲ compare P＜0.01 with model group; * compare P＜0.05 with model group.
From the insulin content analysis of table 2 as can be known: BBR-H.H organizes (74.0mgkg
-1D
-1) have and promote diabetes B rat insulin excretory effect, its effect and acetylsalicylic acid group (120mgkg
-1D
-1) quite.
Its three, embodiment 1 prepared pure formula Berberine can significantly reduce the level of diabetes B rat insulin opposing correlation factor free fatty acids FFA.As shown in table 3 below:
The free fatty acid content (mmol/L) of table 3:BBR-H.L group, BBR-H.M group and BBR-H.H group
# and normal group be P＜0.01 relatively; ▲ compare P＜0.01 with model group; * compare P＜0.05 with model group.
The free fatty acid content of table 3 shows: BBR-H.L organizes (18.5mgkg
-1D
-1), BBR-H.M organizes (37.0mgkg
-1D
-1) and BBR-H.H group (74.0mgkg
-1D
-1) can both significantly reduce the level of diabetes B rat free fatty acids, its effect and acetylsalicylic acid group (120mgkg
-1D
-1) and BBR group (185mgkg
-1D
-1) quite.
Its four, embodiment 1 prepared pure formula Berberine can significantly reduce the triglyceride levels of diabetes B rat.As shown in table 4 below:
The content of triglyceride (mmol/L) of table 4:BBR-H.L group, BBR-H.M group and BBR-H.H group
# and normal group be P＜0.01 relatively; ▲ compare P＜0.01 with model group; * compare P＜0.05 with model group.
From the content of triglyceride result of table 4 as can be known: BBR-H.L organizes (18.5mgkg
-1D
-1), BBR-H.M organizes (37.0mgkg
-1D
-1) and BBR-H.H group (74.0mgkg
-1D
-1) can both significantly reduce the contents level of diabetes B rat triglyceride level, its effect and acetylsalicylic acid group (120mgkg
-1D
-1) and BBR group (185mgkg
-1D
-1) quite.
Test example 2
The pure formula Berberine pharmacokinetics situation analysis in animal body that embodiment 1 is prepared.Concrete process of the test is as follows:
Medicine is selected the prepared pure formula Berberine of existing berberine hydrochloride and embodiment 1 for use.Adopt 12 of cleaning level Wistar rats, male and female half and half, body weight 200 ± 20 grams, single cage is fed, and experimentizes in cleaning level rat experiment chamber, and controlled temperature is 20～22 ℃.The laboratory strictly observes the aseptic technique standard, routine disinfection air, water and feed.Behind the fasting 12h, be divided into two groups by body weight: first group is the berberine hydrochloride group; Second group is berberine hydrochloride+pure formula Berberine group, 6 every group.The berberine hydrochloride group once gavages berberine hydrochloride 124mgkg respectively
-1D
-1Berberine hydrochloride+pure formula Berberine group once gavages berberine hydrochloride respectively and pure formula Berberine is total to 186mgkg
-1D
-1(berberine hydrochloride: pure formula Berberine=124: 62).Respectively at 30min, 60min, 120min tail vein blood 0.8ml, separation of serum.
Precision is measured 0.25ml serum, the sodium hydroxide solution that adds 0.25ml, 0.2mol/L, shake up, add anhydrous diethyl ether 3ml, 3ml, 2ml respectively successively, centrifugal vortex 1 minute is drawn the anhydrous diethyl ether layer, in 40 ℃ of water bath methods, adding moving phase vortex again dissolved it in 1 minute fully, made sample.Prepare blank serum sample, blank serum sample+berberine hydrochloride sample+pure formula Berberine sample as stated above simultaneously.Adopt Waters600ec high performance liquid chromatograph separation, quantitative.The chromatographic condition of high performance liquid chromatograph is: chromatographic column is (4.00mm * 25cm), moving phase is second cyanogen-water-sodium lauryl sulphate-potassium primary phosphate (500ml-500ml-1.70g-3.40g), with hydrochloric acid adjust pH to 5.4, moving phase is used behind ultrasonic degas, flow velocity is 1ml/min, column temperature is 40 ℃, ultraviolet detection wavelength 346nm, and detected result is seen Fig. 1 to Fig. 4.
By Fig. 1 to atlas analysis shown in Figure 4 as can be known: the retention time of berberine hydrochloride is 11.08min, and the retention time of pure formula Berberine is 7.65min.During rats gavaged berberine hydrochloride+pure formula Berberine 30min, 60min, the high performance liquid chromatograph ultraviolet absorpting spectrum of serum sample shows that area reduces gradually under the absorption peak of pure formula Berberine, several nothings of its absorption peak during 120min, and area has increase under the absorption peak of berberine hydrochloride.Concrete data are as shown in table 5 below:
Table 5: gavage area (microvolt * second) under the ultraviolet absorption peak of berberine hydrochloride, pure formula Berberine in the rat blood serum sample of berberine hydrochloride+pure formula Berberine
| 30min | 60min | 120min | |
| Berberine hydrochloride | 38286 | 39541 | 21537 |
| Berberine hydrochloride+pure formula Berberine | 28957 35480 | 80771 2970 | 41772 4417 |
By table 5 as seen: the initial proportion that medicine that rat gavages is formed is a berberine hydrochloride: pure formula Berberine=2: 1, and the ratio of rat vivo medicine concentration is a berberine hydrochloride behind 30min: pure formula Berberine is about 0.45: 0.55, berberine hydrochloride behind 60min: pure formula Berberine is about 0.96: 0.04, prompting pure formula Berberine that the present invention studied is the prodrug of existing Berberine, may be converted into Berberine in vivo and brings into play its pharmacological action.
Claims (1)
1. the application of berberinc derivate in the medicine of preparation treatment diabetes B, blood sugar regulation and blood fat, described berberinc derivate is the compound shown in the following structural:
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| CNA200710186428XA Division CN101157692A (en) | 2006-06-29 | 2006-06-29 | Berberinc derivatives, preparation method and medicinal composition and usage thereof |
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| CN112694473A (en) * | 2020-11-18 | 2021-04-23 | 南京林业大学 | 7, 9-disubstituted berberine derivative and preparation method and application thereof |
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| EP2217067A4 (en) * | 2007-11-07 | 2011-01-19 | Burnham Inst Medical Research | Method and compounds for modulating insulin production |
| CN101323613B (en) * | 2008-06-16 | 2012-02-22 | 上海市徐汇区中心医院 | Berberine additive product, medicament containing the same and preparation thereof |
| CN102079765B (en) * | 2010-12-15 | 2013-03-20 | 西南大学 | 9-O-glucoside-berberine salt, and preparation method and application thereof |
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Non-Patent Citations (4)
| Title |
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| berberine and coptisine free bases. jiri dostal et al.J. molecular structure,Vol.687 . 2004 |
| berberine and coptisine free bases. jiri dostal et al.J. molecular structure,Vol.687 . 2004 * |
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| chemical constituents from the stemes of mahonia japonica. tian-jye hsieh et al.J. Chinesechem. soc.,Vol.51 . 2004 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112694473A (en) * | 2020-11-18 | 2021-04-23 | 南京林业大学 | 7, 9-disubstituted berberine derivative and preparation method and application thereof |
| CN112694473B (en) * | 2020-11-18 | 2022-09-20 | 南京林业大学 | 7, 9-disubstituted berberine structural analogue and preparation method and application thereof |
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