CN101948469A - Method for synthesizing berberine citrate - Google Patents
Method for synthesizing berberine citrate Download PDFInfo
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- CN101948469A CN101948469A CN 201010270423 CN201010270423A CN101948469A CN 101948469 A CN101948469 A CN 101948469A CN 201010270423 CN201010270423 CN 201010270423 CN 201010270423 A CN201010270423 A CN 201010270423A CN 101948469 A CN101948469 A CN 101948469A
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- citric acid
- berberine
- berberine sulfate
- aqueous solution
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Abstract
The invention relates to a method for synthesizing berberine citrate, which can effectively solve the problems of preparing medicament for treating diabetes with simple process, low cost, no environmental pollution and adaptability to industrial production. The method comprises the following steps: selecting berberine sulfate and citric acid as raw materials; preparing an aqueous solution of the berberine sulfate and the citric acid respectively; stirring while slowly adding the aqueous solution of citric acid into the aqueous solution of berberine sulfate; continuing stirring for reaction; standing the reactant, crystallizing, filtering and removing water to obtain a filter cake; and washing the filter cake with clean water and drying to obtain the berberine citrate. The method of the invention is advanced and unique, which can be effectively used for preparing the medicament-berberine citrate for treating diabetes, ensures good curative effect and no toxic or side effect, enables industrial production and has the advantages of low cost, easy operation and no environmental pollution, thus being a major innovation of the medicament for treating diabetes.
Description
One, technical field
The present invention relates to medicine, particularly a kind of citric acid Berberine synthetic method.
Two, background technology
Diabetes are a kind of common frdquently encountered diseases, and sickness rate has the trend of rising, at present, and the popular three big characteristics that present of diabetes: popular, lifelong tenure and complication.Many experts spell out both at home and abroad, also do not have to effect a radical cure the medicine of diabetes in the world at present, can think that basically the diabetic subject need take medicine throughout one's life or make insulinize.In other words, under real medical level and condition, in case suffered from diabetes, just will be all the life needs the companion everyday to take medicine month in and month out every year.Diabetes itself are not fearful, and fearful is the such-and-such complication of following its development process may or produce at last.The main purpose of controlling blood sugar is exactly prevention or the generation that postpones complication.Control of diabetes also will realize by taking necessary medicine for a long time except dietary control, appropriate exercise.Therefore, the validity of control of diabetes medicine and security just seem particularly important.Regrettably, antidiabetic medicine at present commonly used all exists such-and-such serious side effects, particularly hypoglycemia and liver kidney and cardiovascular injury etc., causes the patient not take or can not take for a long time.Therefore, seeking new can take for a long time and safe and effective medicine is numerous diabetic subjects' active demand, also is duty-bound, the instant task of medical worker.At present, though many people have recognized this problem, what have is also making great efforts to seek solution, does not see the ideal product that can satisfy the demand so far as yet and comes out.
In medical Chinese medicine coptis treatment diabetes, be of long duration.Berberine is that the row of the coptis is imitated composition, and China's tradition is used for the treatment of diarrhoea and inflammation, often is used as the plant constituent foodstuff additive that help the control heart failure and sells on some western market.Recently, a large amount of research report show ， Xiao ?alkali might become a kind of medicine that can satisfy numerous diabetic subjects' the demand.The experience of taking in person by a large amount of clinical research datas of Macro or mass analysis and numerous patients, we find Berberine as antidiabetic medicine, compare with common antidiabetic drug and Chinese medicine have at least that drug effect is steadily lasting, safe without toxic side effect, not only hypoglycemic but also prevent and treat complication, six big advantages such as good synergy, the single system easy to control the quality of composition, aboundresources be cheap arranged with other drug.
Xiao ?these advantages of alkali just in time remedy and overcome hypoglycemia that traditional antidiabetic medicine exists, infringement liver kidney and serious side effects such as cardiovascular, real belong to estimable.Regrettably, current, Berberine has only the little ?alkali of salt acid as people's medicinal product, and this is a kind of.And berberine hydrochloride is except the bitter of generally acknowledging with cause that easily the shortcoming such as constipation, subject matter is that solubleness is little, be difficult for being absorbed, so drug effect is low, and the heavier patient of the state of an illness need take heavy dose.In addition, also has an even more important problem that does not cause ' the hydrochloride medicine potential risk ' of people's extensive concern at present as yet.Studies show that in a large number chlorion too much is to cause hypertension and cause the acidosic arch-criminal of hyperchloremia in the body, takes the potential this risk of hydrochloride medicine for a long time in a large number.Many studies have shown that is with avoiding these potential hazards behind alternative its hydrochloride of the Citrate trianion of medicine.In relevant medicine and foodstuff additive standard, not only muriate is stipulated finite quantity, and also lower than limiting the quantity of of vitriol, oxalate, and this shows that people pay close attention to some extent to muriatic amount in medicine or the food already.
In history, the clinical report that once constantly had berberine hydrochloride to poison does not cause that only people enough pay attention to, and do not go into seriously itself thus.Past this respect report is less, be because Yan Suan Xiao ?alkali as antiphlogistic drug, take that object is limited, dosage is little, the time is short, chlorion is put aside less in the body.Along with numerous diabeticss take for a long time in a large number, this risk is reaction to some extent successively.Can expect, along with Xiao ?widespread use such as the popularization of alkali and diabetics, cardiovascular patient, hypertensive patient, much more more and more the problem of this respect may occur from now on.
If these problems that above-mentioned berberine hydrochloride exists are solved, can improve its practicality, security and medicinal efficient greatly.The research work of this respect was done the clinical trial except human Berberine vitriol is once arranged, and there be limited evidence currently of is seen the someone and set foot in.And Berberine vitriol is that the pharmacopeia regulation is only for the medicine that is used to do veterinary drug.
The height of solubleness has material impact to bioavailability of medicament, range of application and clinical efficacy.Infer in theory, the chlorion in the alternative berberine hydrochloride of the citrate that contains hydroxyl and a plurality of carboxyls in the molecule is combined the citric acid Berberine that forms to increase the water-soluble of product with Berberine.The solubility experiment that the Berberine Citrate trianion that makes with the present invention carries out shows that its solubleness has improved ten doubly than berberine hydrochloride really.
It is reported that citric acid is a kind of useful natural nutrient additive that can alleviate many healths and mood aspect problem.It all is helpful for wholesome many aspects, and it does not have persistent bad side effect, and it and all medicines all have good consistency.In Japan for many years always as a kind of healthcare products; be widely used in and be of illnesses and fitness, for example be applied to delay senility, prevent senile dementia, prevent and treat diabetes, prevent and treat gout, prevent and treat stomach ulcer and duodenal ulcer, the protection liver, to the health-care effect of hypertension, ypotension and cardiovascular and cerebrovascular, to health-care effect of surgical disease or the like.Except cooking healthcare products, citric acid can also be eliminated human-body fatigue etc.
The many useful functions of this of citric acid, make us have reason to think, chlorion in the berberine hydrochloride is substituted the Berberine Citrate trianion that the back generates with citrate, not only can not influence all advantage of above-mentioned Berberine itself as antidiabetic medicine, on the contrary, also can increase and improve its curative effect, reduce side effect, particularly avoid the potential risk of above-mentioned hydrochloride, improve the security of medicine greatly, make it become a kind of medicine that can satisfy numerous diabetic subjects' the demand.
Not seeing in the market has citric acid Berberine product to sell, and its study on the synthesis also rarely has report.In one's early years the human berberine hydrochloride being arranged once is that raw material prepares the citric acid Berberine, but because the water-soluble extreme difference of berberine hydrochloride, causing not only, preparation condition requirement height, needs consume soda acid and a large amount of more expensive organic solvent of price, cause environmental pollution easily, and troublesome poeration causes considerable trouble, the cost height is not suitable for industrial production.
Three, summary of the invention
At above-mentioned situation, for overcoming the defective of prior art, the present invention's purpose just provides a kind of citric acid Berberine synthetic method, can effectively solve the medicine of treatment diabetes, and technology simple, with low cost, do not have an environmental pollution, be fit to industrial problem.
The technical scheme that the present invention solves is, choose berberine sulfate and citric acid is made raw material, the two weight ratio is a berberine sulfate: citric acid=1: 1-3, then with berberine sulfate and citric acid difference obtained aqueous solution, method is, the weight ratio of berberine sulfate and water is 1: 20-50, and promptly every 1g berberine sulfate adds entry 20-50g, and stirring and dissolving becomes into the berberine sulfate aqueous solution; The weight ratio of citric acid and water is 1: 1-5, and promptly every 1g citric acid adds entry 1-5g, and stirring and dissolving becomes aqueous citric acid solution; Then at 10-70 ℃, stir on the limit, and the limit adds aqueous citric acid solution in the berberine sulfate aqueous solution lentamente, continues to stir, reacted 1-5 hour, reactant leaves standstill 1-5 hour crystallization under 0-5 ℃ low temperature, suction filtration is removed moisture, get filter cake, filter cake is dried under 60-80 ℃ of temperature after washing with clear water, promptly gets Berberine Citrate trianion (reaction product).
The inventive method advanced person, uniqueness can be effective to prepare the Citrate trianion of the medicine Berberine for the treatment of diabetes, this reaction product good effect, have no side effect, and can suitability for industrialized production, cost is low, easy to operate, non-environmental-pollution is the innovation greatly on the treatment diabetes medicament.
Four, embodiment
Below in conjunction with embodiment the specific embodiment of the present invention is elaborated.
Embodiment 1
The present invention is realized by following steps in concrete enforcement:
1, get berberine sulfate and citric acid is made raw material, the two weight ratio is a berberine sulfate: citric acid=1: 2;
2, the preparation berberine sulfate aqueous solution and aqueous citric acid solution, method be, the weight ratio of berberine sulfate and water is 1: 35, and promptly every 1g berberine sulfate adds entry 35g, and stirring and dissolving becomes the berberine sulfate aqueous solution;
The weight ratio of citric acid and water is 1: 3, and promptly every 1g citric acid adds entry 3g, and stirring and dissolving becomes aqueous citric acid solution;
3, the berberine sulfate aqueous solution is inserted in the reaction vessel that has whipping appts, turn on agitator, at 20-40 ℃, stir on the limit, and the limit adds aqueous citric acid solution in the berberine sulfate aqueous solution lentamente, continues to stir, and reacts 3 hours, gets reactant;
4, in the container that the reactant transfer in the step 3 is equipped with to other, under 2 ℃ low temperature, left standstill 3.5 hours, crystallization, suction filtration behind the crystallization is removed moisture, filter cake, filter cake with the clear water washing after, under 70 ℃ of temperature, dry, promptly get citric acid Berberine synthetics.
Embodiment 2
The present invention is realized by following method in preparation:
Take by weighing 1.5g Liu Suan Xiao ?alkali, insert in the flask, add 50g water, turn on agitator is stirred molten, the berberine sulfate aqueous solution; Take by weighing the 3.5g citric acid, water-soluble in beaker with 15g, get aqueous citric acid solution; Stir slowly citric acid solution to be added in 60 ℃ down and be equipped with in the flask of the berberine sulfate aqueous solution, keep 60 ℃ of temperature, behind the stirring reaction 3 hours, reactant transfer in Erlenmeyer flask, was left standstill 2 hours in 0 ℃, treat abundant crystallization after, suction filtration, get filter cake, filter cake washing back obtains the yellow product of 2.2g in 70 ℃ of oven dry.
Embodiment 3
The present invention also can be realized by following method in preparation:
Take by weighing 10g Liu Suan Xiao ?alkali, insert in the flask, add 350g water, turn on agitator is stirred molten, the berberine sulfate aqueous solution; Take by weighing the 22g citric acid, water-soluble in beaker with 80g, get aqueous citric acid solution; Stir slowly citric acid solution to be added in 70 ℃ down and be equipped with in the flask of the berberine sulfate aqueous solution, keep 70 ℃ of temperature, behind the stirring reaction 3.5 hours, reactant transfer in Erlenmeyer flask, was left standstill 3 hours in 1 ℃, treat abundant crystallization after, suction filtration, get filter cake, filter cake washing back obtains 15g gilvous product in 80 ℃ of oven dry.
The citric acid Berberine reaction synthetics that the present invention is prepared, be used for the treatment of diabetes, obtained very gratifying effect, through outpatient service to 38 routine diabetes B patient (male 20 examples, woman's 18 examples) keep on a diet and the exercise therapy basis on take the capsule (0.30g/ grain) of this product (citric acid Berberine), 9 for each person every day, divide 3 times 15 minutes before the meal warm water delivery services.Took 60 days, and observed the treatment front and back and reach 2h changes of blood glucose after the meal on an empty stomach.The result tried before and after the patient treatment fasting plasma glucose and after the meal 2h blood sugar notable difference is all arranged, common feature is that glycemic control is steady, big rise and big fall do not find no uncomfortable phenomenon.Male patient of 73 years old wherein, the diabetes history in existing 13 years, before, once took multiple conventional sugar urine medicine, glycemic control is all undesirable, take the little ?alkali of the citric acid (capsule of the present invention's preparation from October, 2008,0.30g/ grain, 3 * 2～3/day) nearly 2 years, except cooperating a small amount of (2 * 6～8 unit/skies) Regular Insulin, do not eat other medicine again, fasting plasma glucose maintains about 5mmol/L always, and generally all between 6～9, physical examination result shows postprandial blood sugar, gallbladdergallstonecholetithiasis has originally diminished, originally higher blood pressure, blood fat is also normal.
In addition through hospital to clinical type II diabetes patient 180 examples (man 68, woman 112), 59～78 years old age, the course of disease 5～21 years, long-term oral antidiabetic drug, the blood sugar instability, fluctuation ratio is bigger, generally speaking is to be in higher level (on an empty stomach about 9-16mmol/L).On former oral medicine agent amount and diet basis of invariable separately, take citric acid Berberine capsule of the present invention (0.3g/ grain) every day, 9 for each person every day, divide and used warm water delivery service in 3 times 15 minutes before the meal, take treatment 60 days, measure every day and reach 2h blood sugar after the meal on an empty stomach.135 routine patient's fasting plasma glucoses on average descend 20.6% before taking citric acid Berberine of the present invention as a result, and 2h blood sugar on average descends 19.3% after the meal.The patient of the original blood sugar of 45 examples lower (8-9mmol/L on an empty stomach), though that blood sugar descends is not obvious, with take citric acid Berberine capsule before compare, blood sugar has become steadily.Except that 1 people does not have the positive effect, all the other patients have all obtained doing well,improving in various degree.No patient reacts gastrointestinal upset or other problems during being tried, its effect good, very satisfactory.
Provable thus, to take citric acid Berberine of the present invention and can effectively treat diabetes, the citric acid Berberine that the present invention succeeds in developing is the active drug of treatment diabetes, and has no side effect, and easily produces, and cost is low, and economic and social benefit is huge.
Claims (4)
1. citric acid Berberine synthetic method, it is characterized in that, choose berberine sulfate and citric acid is made raw material, the two weight ratio is a berberine sulfate: citric acid=1: 1-3, with berberine sulfate and citric acid difference obtained aqueous solution, method is that the weight ratio of berberine sulfate and water is 1: 20-50 then, berberine sulfate is added in the entry, and stirring and dissolving becomes the berberine sulfate aqueous solution; The weight ratio of citric acid and water is 1: 1-5, citric acid is added in the entry, and stirring and dissolving becomes aqueous citric acid solution; At 10-70 ℃, stir on the limit then, and the limit adds aqueous citric acid solution in the berberine sulfate aqueous solution lentamente, continue to stir, reacted 1-5 hour, reactant left standstill under 0-5 ℃ low temperature 1-5 hour, crystallization, suction filtration, remove moisture, get filter cake, after filter cake washs with clear water, under 60-80 ℃ of temperature, dry, promptly get citric acid Berberine synthetics.
2. citric acid Berberine synthetic method according to claim 1 is characterized in that, is realized by following steps:
(1), get berberine sulfate and citric acid is made raw material, the two weight ratio is a berberine sulfate: citric acid=1: 2;
(2), preparation the berberine sulfate aqueous solution and aqueous citric acid solution, method is, the weight ratio of berberine sulfate and water is 1: 35, and berberine sulfate is added in the entry, stirring and dissolving becomes the berberine sulfate aqueous solution;
The weight ratio of citric acid and water is 1: 3, and citric acid is added in the entry, and stirring and dissolving becomes aqueous citric acid solution;
(3), the berberine sulfate aqueous solution is inserted in the reaction vessel that has whipping appts, turn on agitator, at 20-40 ℃, stir on the limit, and the limit adds aqueous citric acid solution in the berberine sulfate aqueous solution lentamente, continues to stir, and react 3 hours, must reactant;
(4), in the container that the reactant transfer in the step 3 is equipped with to other, under 2 ℃ low temperature, left standstill 3.5 hours, crystallization, suction filtration behind the crystallization is removed moisture, filter cake, filter cake with the clear water washing after, under 70 ℃ of temperature, dry.
3. citric acid Berberine synthetic method according to claim 1 is characterized in that, take by weighing 1.5g Liu Suan Xiao ?alkali, insert in the flask, add 50g water, turn on agitator is stirred molten, the berberine sulfate aqueous solution; Take by weighing the 3.5g citric acid, water-soluble in beaker with 15g, get aqueous citric acid solution; Stir slowly citric acid solution to be added in 60 ℃ down and be equipped with in the flask of the berberine sulfate aqueous solution, keep 60 ℃ of temperature, stirring reaction is after 3 hours, reactant transfer in Erlenmeyer flask, was left standstill 2 hours in 0 ℃, treat abundant crystallization after, suction filtration gets filter cake, and filter cake washing back is in 70 ℃ of oven dry.
4. citric acid Berberine synthetic method according to claim 1 is characterized in that, take by weighing 10g Liu Suan Xiao ?alkali, insert in the flask, add 350g water, turn on agitator is stirred molten, the berberine sulfate aqueous solution; Take by weighing the 22g citric acid, water-soluble in beaker with 80g, get aqueous citric acid solution; Stir slowly citric acid solution to be added in 70 ℃ down and be equipped with in the flask of the berberine sulfate aqueous solution, keep 70 ℃ of temperature, stirring reaction is after 3.5 hours, reactant transfer in Erlenmeyer flask, was left standstill 3 hours in 1 ℃, treat abundant crystallization after, suction filtration gets filter cake, and filter cake washing back is in 80 ℃ of oven dry.
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| CN2010102704237A CN101948469B (en) | 2010-09-02 | 2010-09-02 | Method for synthesizing berberine citrate |
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| CN2010102704237A CN101948469B (en) | 2010-09-02 | 2010-09-02 | Method for synthesizing berberine citrate |
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| CN101948469A true CN101948469A (en) | 2011-01-19 |
| CN101948469B CN101948469B (en) | 2012-07-18 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108498590A (en) * | 2018-06-27 | 2018-09-07 | 浙江农林大学暨阳学院 | A kind of natural hypoglycemic agent that can be improved bioavilability and avoid hyperchloremia |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1494902A (en) * | 2002-04-23 | 2004-05-12 | 吴开敏 | Application of high-solubility berberine in preparation of medicine. |
| CN1565447A (en) * | 2003-06-22 | 2005-01-19 | 吴开敏 | Drug for prevention and cure of bacterial and viral infection , atypical pneumonia |
| CN1771944A (en) * | 2005-01-25 | 2006-05-17 | 吴开敏 | Application of high-solubility berberine in preparing medicine |
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2010
- 2010-09-02 CN CN2010102704237A patent/CN101948469B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1494902A (en) * | 2002-04-23 | 2004-05-12 | 吴开敏 | Application of high-solubility berberine in preparation of medicine. |
| CN1565447A (en) * | 2003-06-22 | 2005-01-19 | 吴开敏 | Drug for prevention and cure of bacterial and viral infection , atypical pneumonia |
| CN1771944A (en) * | 2005-01-25 | 2006-05-17 | 吴开敏 | Application of high-solubility berberine in preparing medicine |
Non-Patent Citations (1)
| Title |
|---|
| 《药学通报》 19811231 李文运，李拥飞 《枸橼酸黄连素的化学合成》 15-16 1-4 第18卷, 第3期 2 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108498590A (en) * | 2018-06-27 | 2018-09-07 | 浙江农林大学暨阳学院 | A kind of natural hypoglycemic agent that can be improved bioavilability and avoid hyperchloremia |
| CN108498590B (en) * | 2018-06-27 | 2021-05-11 | 浙江农林大学暨阳学院 | A natural hypoglycemic agent for improving bioavailability and preventing hyperchloremia |
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| CN101948469B (en) | 2012-07-18 |
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