CN1494902A - Application of high-solubility berberine in preparation of medicine. - Google Patents

Abstract

The present invention relates to the application of high-solubility berberine in the preparation of medicine for curing and preventing diabetes and its complicating diseases. The described berberine includes other berberine except for berberine hydrochloride, high-solubility berberine which can be dissolved in the water and animal berberine. They are easily dissolved in water, can make the medicine be easily absorbed by human body so as to greatly raise therapeutic effect. The medicine also can be used for curing and preventing tumor or cancer and other various infective diseases.

Description

The application of high-dissolvability berberine in pharmacy

Technical field

The present invention relates to the new purposes of berberine (except the berberine hydrochloride), relate in particular to the application of high-dissolvability berberine in preparation treatment or prevent diabetes and medicines such as complication, tumor and cancer and human antimicrobial drug thereof.

Background technology

Along with the continuous prolongation with human average life of improving constantly of people's living standard, the healthy primary symbol that has been regarded as life happiness, but the patient of some commonly encountered diseases, frequently-occurring disease, difficult disease is on the increase.Classified as the third-largest disease---the global rapid spread of diabetes of harm humans health by The World Health Organization (WHO) and IDF (IDF).Diabetics surpasses 100,015,000 people in the world, and China has reached 40,000,000, and the trend that increases is year by year arranged.Relevant expert's prophesy, diabetes will be popular in China's burst.

The oral medicine of treatment diabetes mainly is sulphanylureas, biguanides and alpha-glucosidase inhibitor at present.Digestive system reaction such as sulfaurea drugs regular meeting serious hypoglycemic reaction and loss of appetite take place, feels sick, vomiting, stomachache, diarrhoea and liver function infringement etc.; Side effect such as feeling sick also can appear in biguanide drug, vomiting, stomachache, diarrhoea, and hepatic and renal function had infringement, lactic acidosis also can take place in severe patient; Symptoms such as abdominal distention, diarrhoea, flatulence often appear in alpha-glucosidase inhibitor, occur serious hepatic injury (Chinese diabetes magazine, 1999 individually; 2:125).

Calendar year 2001 China's a kind of " euglycemic agent of new generation "---thiazolidinedione kind new medicine that Britain GlaxoSmithKline PLC drugmaker has spent two ten years and multi-billion dollar to succeed in developing---Avandia (rosiglitazone) that gone on the market.This medicine can make body that the sensitivity of insulin is increased, and can " attack insulin resistant directly, the long-term control type 2 diabetes mellitus ", " with other hypoglycemic drug use in conjunction, has strengthened the glycemic control to type 2 diabetes mellitus." (Avandia advertising slogan)

These unique curative effects of Avandia have solved a great difficult problem medically, have promoted treatment diabetes Progress in technique.For this reason, doctor Steve of invention Avandia has obtained to represent " prize of medical research association " of medical circle top level in calendar year 2001.This medicine is proposed as the " line basis medication of diabetics in the 5th IDF's Asia-Pacific conference in west holding in Beijing in May, 2002." several medical experts of China commendation of publishing an article in succession after this: " appearance of Avandia can be rated as a new monument undoubtedly, a milestone that is with historically new significance " is " historical breakthrough ", " revolutionary medicine ".Because Avandia is that first significantly reduces the medicine of insulin resistant in the world, obtains this many special honours, and is undisputed.

Blemish in an otherwise perfect thing be that Avandia remains some unsatisfactory part:

1, neither big nor small " anemia and the edema of untoward reaction---light, moderate.The danger that increases the weight of congestive heart failure is arranged." (in the quotation marks is this medicine description original text).Other has how tame research report and report, uses Avandia and " weight increase, upper respiratory tract infection, damage, side effect such as headache also occur." (the practical diabetes magazine in Liaoning, 2002; 1:15,55.2002；3：55。Chinese Medicine, 2002.9.21,8 editions.)

2, take effect slow, the course of treatment is long---it is documented, take 26 weeks of Avandia, the fasting glucose 2.1～2.8mmoI/L that on average descends; China-item to 442 type 2 diabetes mellitus patients add with Avandia 24 week the back results of study show the fasting glucose 1.5mmoI/L that on average descends.(the practical diabetes magazine in Liaoning, 2002; 1:54.) therefore, patient must take medicine and could obtain this curative effect nearly half a year.

3, cost an arm and a leg--every up to 17.09 yuan.(friend of diabetes, 2002; 2:38.) 1～2 of diabetes patient's consumption every day (it was reported that if the effective blood sugar control of this dosage, but dosage is to 3 of every days), even singly obey this medicine, also wanted 500～1000 yuan of expenses in every month.Low income patient has quite a few and can heave a sigh by the prestige valency, can not benefit from.

From the eighties in last century, some scholars have carried out a large amount of research and report and have proposed berberine hydrochloride treating diseases (seeing Table 1) such as diabetes and cancer to berberine hydrochloride commonly used clinically, but because of the dissolubility of berberine hydrochloride very low, cause curative effect too poor, some medical experts are not to " clinical research reaches therapeutic effect " of this work.For this reason, above saying fails to obtain the affirmation and the enforcement of hygiene department so far.

Berberine another name berberine is an isoquinoline alkaloid, is the active ingredient of plant such as Rhizoma Coptidis.The Rhizoma Coptidis total alkaloids that obtains from Chinese medicine extraction such as Rhizoma Coptidis mainly contains berberine hydrochloride (berberine hydrochloride), citric acid berberine (citric acid berberine), hydrogen sulfate berberine (hydrogen sulfate berberine), berberine sulfate (berberine sulphate) and phosphoric acid berberine (phosphoric acid berberine) through further isolated monomer berberine.

The dissolubility difference of various berberine very big (seeing Table 2).One one, two ones of the Pharmacopoeias of the People's Republic of China are all pointed out in " note on the use ": " dissolubility is a kind of physical property of medicine, can reflect the purity of medicine to a certain extent." send according to Deng and to write articles: " active ingredient of some medical material is insoluble in water or water insoluble, also may dissolve a bit because of the phenomenon of dissolving each other, but some active ingredient confession has been wasted after all." (Chinese medicine system is recorded with experience, China Traditional Chinese Medicine Publishing House, 1992,64～65.) international new drug research person pays much attention to the important function of biopharmaceutics categorizing system (BCS) in the medicament research and development process in recent years.BCS is divided into four classes to medicine according to the height of the membrane permeability of its dissolubility and intestinal, high-dissolvability is classified as the primary standard of first kind medicine.The most dissolubility of Chinese medicine is lower, and membrane permeability is higher, belongs to the second class medicine among the BCS.Former chairman of American Pharmaceutical Association points out that the discovery of medicine and research worker will be paid close attention to the situations such as dissolubility of medicine from the beginning, thereby before can avoiding the later stage clinical and the failure of clinical research, improves the success rate of new drug development.(Chinese Medicine, 2002.8.10,8 editions.) therefore, the height of berberine dissolubility too can be directly has very important influence to the size of its bioavailability and range of application and clinical efficacy.

The part berberine was once produced injection as the human antimicrobial drug, because of meeting generation serious adverse reaction, even the causing death.For this reason, the berberine injection is disabled before more than ten years.So far after this, people still take berberine hydrochloride (seeing Fig. 1 of Figure of description) for a long time, but its dissolubility is very little, and oral absorption is very poor, and blood drug level is very low, only is used for antibiotic.Though the higher berberine of other several dissolubility is soluble in water, oral absorption is good, but the drug effect of giving full play to, but only make antimicrobial drug for animals (the berberine sulphate injection is seen Fig. 2) or make chemical reagent.Country expressly provides: people's medicine, veterinary drug must strictly separate, forbid using with; Chemical reagent does not belong to medicine, is not useable for medical treatment.Up to now, oral " berberine " in clinical use and pharmacy's sale all is single berberine hydrochloride.Therefore, human " berberine " taken for a long time be berberine hydrochloride in fact still, does not comprise other berberine as veterinary drug and reagent." berberine " that it has often been said only is the abbreviation to berberine hydrochloride, then indicates its full name on medical books and periodicals and this drug package thing.For a long time, medicinal berberine signs at state-promulgated pharmacopoeia or Arzneibucs or veterinary drug standard or this medicine bottle that all only to state clearly be that " antimicrobial drug is used for intestinal infection." even the pharmacy corporation of producing various berberine in the operation instruction of its product (crude drug or people, animal medicine etc.) and the scope of application except antibiotic the purposes of all not mentioned human treatment's of can be used for diabetes and other disease.

According to above-mentioned situation and in conjunction with each figure, table relative analysis, can find several rules:

1. present, no matter be that human or berberine for animals all belong to the anti-microbial type medicine, all be not used for the treatment of diabetes and other medical application.

2. what be used for human body has only the very low berberine hydrochloride of dissolubility, illustrates that what use in clinical practice and experimentation also is berberine hydrochloride.

3. to berberine, patient's suitable for oral administration is forbidden injection; Animal is then opposite: unsuitable oral, be suitable for injection.

4. the dissolubility of berberine is high more, and bioavailability is big more, and pharmacological action is strong more, and therapeutic effect is good more.

5. the human berberine of only taking low solubility, beasts are used the berberine of high-dissolvability entirely.

Article 5, in In the view of today the very inequitable phenomenon and the mankind can not take the formed technology prejudice of veterinary drug and continued decades so far, cause people not go to consider that animal drugs is used for the treatment of the probability of human body diseases, hinder the research and development of people for a long time this technical field.If high-dissolvability berberine such as berberine sulphate for animals are improved dosage form, be prepared as the human oral drug, greatly change the route of administration of this material, the bioavailability of its active substance is improved, toxicity reduces, stability increases, the dissolubility that adds them has improved manyfold than the berberine hydrochloride of human, can promote drug absorption, give full play to drug effect, impel curative effect to increase substantially, can enlarge medical application thus, be widely used in treatment and multiple diseases such as prevention people's diabetes or its complication.

Summary of the invention

The object of the present invention is to provide the new purposes of other berberine in the medicine of preparation treatment or prevent diabetes and some other disease except berberine hydrochloride.Described berberine also comprises the berberine of high-dissolvability and the above-mentioned berberine of citric acid berberine, hydrogen sulfate berberine, berberine sulfate and phosphoric acid berberine and extraction from plant, chemosynthesis or the acquisition of other method.

The berberine of described high-dissolvability be meant can be in less than 500 parts of (weight) water dissolved berberine, preferred berberine is that the dissolubility in water is 1: 100 (weight), preferably 1: 30 (weight), 1: 15 even (weight).

In fact, the present invention relates to the application of high-dissolvability berberine in the medicine of preparation treatment or prevent diabetes or its complication.

Relate to the application of high-dissolvability berberine in the medicine of preparation treatment or prophylaxis of tumours or cancer.

Relate to the application of high-dissolvability berberine in preparation human antimicrobial drug.

Described diabetic complication comprises hypertension, hyperlipidemia, arrhythmia, cholecystitis, stomach or duodenal ulcer.Because the infection of diabetes each section of easy concurrent whole body and multisystem is infected and can be brought out or increase the weight of diabetes again, the two influences each other, reciprocal causation.Therefore, high-dissolvability berberine of the present invention also can be used to treat digestive system or respiratory infectious disease and surgery or gynecological or the department of eye infectious disease (as: gastritis concurrent with prevent diabetes, biliary tract infection, respiratory tract infection, lobar pneumonia, infantile pneumonia, lung abscess, pulmonary tuberculosis, acute/chronic bronchitis, candida albicans infection, renal pelvis, nephritis, hepatitis, the cutization pyogenic infection, carbuncle, furuncle, painful abdominal mass, abscess, lymphadenitis, panaris, mastitis, impetigo, refer to osteomyelitis, refer to or the toe pyogenic infection, vaginitis, adnexitis, cervical erosion, trachoma, conjunctivitis, the eyes-affinity blepharitis, hordeolum, keratitis, otitis media, otitis externa, rhinitis, maxillary sinusitis, the acute and chronic tonsillitis, oro-maxillo-facial inflammation, herpetic stomatitis, recurrent stomatitis, various actute infection such as stomatocace, severe infection, bacterial infection, viral infection disease and multiple different pathogens, different parts is not even with the infectious disease of lesion nature) medicine in application.

The specific embodiment:

In one embodiment of the invention, described berberine also can obtain through chemosynthesis and other method except extracting from plant.

According to " the reagent handbook (compile by China Drug Co.'s Shanghai chemical reagent purchasing and supply station; Shanghai science tech publishing house publishes; in November, 1985 second edition) the 178th, 179 page of record, the hydrogen sulfate berberine of chemosynthesis, berberine sulfate also can be used for checking the chemical reagent of nitrate etc.Fig. 3, Fig. 4 are seen in its structural formula and relevant explanation.

In another embodiment of the invention, select any or two or more other berberine except berberine hydrochloride for use or adopt high-dissolvability (can be dissolved in less than 500 parts of water) berberine (comprising citric acid berberine, hydrogen sulfate berberine, berberine sulfate and phosphoric acid berberine) crude drug powder to be prepared into medicine according to a conventional method; The medicine that also can use any or two or more above-mentioned berberine crude drug or its preparation and other any material (medicine or pharmaceutics acceptable auxiliary component) to make up according to a conventional method or prepare is used for the treatment of or prevent diabetes or its complication, tumor and cancer and preparation human antibacterials etc.Its preparation is that the described any dosage form except injection of pharmaceutics---oral formulations comprises capsule and tablet, and the each clothes of adult berberine 0.3～1.2g took at whenever 2 hours before the meal every day 3 times, added once in case of necessity.General 1～3 month of the course of treatment.Because diabetes are the lifelong participation disease, after blood glucose is normal, need takes medicine on a small quantity and keep.In comprise suitable preparations such as powder, membrane, ointment with, external preparation, medicine is directly applied to the affected part.Said medicine and preparation not only can be used for treatment and prevent diabetes, tumor or cancer, the various infection of human body, also can be respectively applied for treatment and common hypertension, hyperlipidemia, the arrhythmia of prevent diabetes complication.Cholecystitis, stomach or duodenal ulcer and respiratory system or digestive system infection disease, surgery or gynecological or department of eye infectious disease.In above-mentioned berberine, preferred at present as the berberine sulfate of veterinary injection, other berberine also can use.These berberine also can produce a series of new product in pharmacy with in using, and main new product name sees Table 3.

In order to understand essence of the present invention better, the result with treatment diabetes such as using sulfated berberine illustrates its new purposes in pharmaceutical field below.

Embodiment 1

Zoopery

A1 (hydrogen sulfate berberine) and A2 (berberine sulphate) hyperglycemia test report

1, experiment purpose:, observe A1 and A2 hypoglycemic activity to hyperglycemia animal by animal experiment.

2, being subjected to reagent product: A1 and A2 all is yellow powder, irritates stomach (i.g.) to desired concn for animal with the eliminating cold for resuscitation water dissolution before the test.

3, experimental animal: the km mice cleans level, licence scxk Shanghai 2002-002 number available from the department of the Chinese Academy of Sciences of Fudan University in Shanghai laboratory animal section.

4, main agents: chain assistant rhzomorph (streptozotocin) is the Sigma product, and analytical pure is made into 1.5% solution with the 0.05mol/L citric acid.

5, test method:

Get 24 hours Km mices of fasting, male, body weight 18.0～22.5g, tail vein injection chain assistant rhzomorph 150mg/kg got the fasting blood sugar of blood by each Mus of determination of glucose oxidase from the eyeball posterior vein after two days.Choose the mice that fasting glucose surpasses 9.5mmol/L and be used for this experiment.Get 40 of hyperglycemia Km mices, be divided into 4 groups at random by blood glucose value, i.gA1 2.4g/kg respectively, A2 2.4g/kg, glyburide 50mg/kg (positive controls) and water 0.3ml/10g, in addition, 10 blood glucose value normal mouses are i.g water 0.3ml/10g also.Below all once a day, continuous seven days, and after the last administration 24 hours, all mices are got blood once more and survey fasting blood sugar, are calculated as follows the blood sugar increasing suppression ratio.Experimental result is carried out the t check.

Blood sugar increasing suppression ratio (%)=[1-(administration group blood glucose value-normal group blood glucose value)/(model group blood glucose value-normal

The group blood glucose value)] * 100%

6, result of the test: see Table 1

Table 1 A1 and A2 are to the hypoglycemic activity (n=10) of hyperglycemia mice

Blood glucose (mmol/L) blood sugar increasing

Suppression ratio (%) P value behind the medicine medicine prodrug

(normal group) water 0.3ml/10g 6.06 ± 0.59 6.11 ± 0.49＜0.001

(model group) water 0.3ml/10g 13.56 ± 1.96 15.21 ± 1.34

Glyburide 50mg/kg 13.41 ± 2.05 11.52 ± 1.33 40.55＜0.001

A1 2.4g/kg 13.56±2.02 13.43±1.74 19.56 ＜0.05

A2 2.4g/kg 13.56±1.94 13.31±1.59 20.88 ＜0.05

7, conclusion (of pressure testing)

A1, A2 serve on seven at dosage 2.4g/kg, and the mice hyperglycemia that chain assistant rhzomorph is brought out has certain hypoglycemic activity, points out two medicines that type 2 diabetes mellitus is had certain curative effect.

Embodiment 2

Clinical trial

Selection is through being diagnosed as type 2 diabetes mellitus patient totally 35 examples, male's 20 examples wherein, women's 15 examples; Just send out person's 25 examples, do not control person's 10 examples again; Fasting glucose＜8.33mmol/L6 example, 8.33～13.9mmol/L24 example,＞13.9mmol/L5 example.The patient all has polydipsia, polyphagia, polyuria, easy hungry symptom in various degree.On the basis that strictness is kept on a diet, single berberine treatment with high-dissolvability is made capsule, every 0.3g with berberine sulfate etc.According to each one state of an illness weight, course of disease length and situation such as fasting blood glucose level before the meal recently, everyone obeys 1～4 (increasing gradually from minimum dose) at every turn, every day 3 times.Indivedual original dawn phenomenons (morning 4～8 o'clock blood sugar increasing) can add 1 time 2 o'clock mornings.General 1～3 month of the course of treatment.All cases except that 2 examples because of older and with the severe complication unsatisfactory curative effect, the fasting glucose of all the other 33 examples is all reduced to normal or near normal level, clinical symptom disappearance, non-evident effect hypoglycemic reaction all do not occur after blood glucose is normal.Wherein the hypertension that occurs together of 12 examples is reduced to normal range, and 9 routine hyperlipemias significantly reduce.As patient Wu * *, be diagnosed as type 2 diabetes mellitus on November 15th, 1998 by hospital, at that time fasting glucose 12.7mmol/L.Through taking the berberine sulfate capsule, each 3～4, every day 3 times.Blood glucose begins to descend after 4 weeks, glucostasis after 8 weeks, and fasting glucose more than 4 years remains on 4.87～6.12mmol/L scope so far, rises for a long time again.Original hypertension is reduced to normal level, and the blood T-CHOL significantly reduces, transference cure such as arrhythmia, uncomfortable in chest and numb pain of brothers.Now obey 1～2 at every turn, every day 3 times, keep blood glucose and keep normal.Above-mentioned 35 routine patients are according to the criterion of therapeutical effect statistics of " technological guidance's principle of new drug (Chinese medicine) treatment diabetes (diabetes) clinical research " regulation of Ministry of Public Health issue, and total effective rate reaches 94.28%.Show the determined curative effect of using high-dissolvability berberine treatment diabetes, and can repeat to realize.

Embodiment 3

Adopt high-dissolvability berberine (preferably sulfuric acid berberine) and houttuynine sodium bisulfite to unite the medicine of making and have the Synergistic antimicrobial antivirus action and do not have antagonism and can reduce their Drug resistance significantly, can obtain better therapeutic aspect the disease of control pathogenic bacteria viral infection body.

The prescription for preparing its combination formulations for the preferred weight percent scope is: berberine sulfate 50～80%, houttuynine sodium bisulfite 20～50%.

The optimum weight percentage ratio for preparing the prescription of its combination formulations is: berberine sulfate 20%.Houttuynine sodium bisulfite 30%.

More than two medicines be mixed with into oral formulations (preferred capsule or tablet) routinely according to amount.The each oral 0.3～1.2g of adult (measuring increase gradually) from minimizing agent, three times on the one, servicing once after meal at every turn, the state of an illness heavier person add once before sleeping evening.

Houttuynine sodium bisulfite in the above-mentioned prescription also can use other antimicrobial drug instead and the high-dissolvability berberine is mixed with, but adopts the effect of houttuynine sodium bisulfite preferable and cheap.

In the past few years use said medicine and treat the tonsillitis of 40 many cases, influenza, severe cold, urethritis etc. and all obtain satisfactory effect, particularly, have effect preferably human body immunity improving power and treatment or prevention respiratory tract infectious disease.Now trying out atypical pneumonia in current popular.

The medicine of the high-dissolvability jamaicin preparation that the present invention uses also has following beneficial effect:

1, safety of medicine is efficient: these jamaicins are soluble in water, can be absorbed fully by body, so blood concentration increases biological profit Expenditure improves thereupon, can give full play to drug effect, surpasses significantly Berberine hydrochloride commonly used on curative effect, particularly with the sulfuric acid Huang Lian Su is improved to oral formulations, and the serious adverse reaction that can avoid administrated by injection to bring is taken very safe.

2, can fall postprandial blood sugar: diabetes patient's ubiquity postprandial blood sugar rising phenomenon will add α-grape mostly in treatment Glycosidase inhibitor (only having at present " Glucobay " of Germany and " Voglibose " two kinds of Western medicine of Japan). Use of the present invention The jamaicin preparation also has stronger control action to postprandial hyperglycemia in reducing the fasting blood-glucose process. If before the meal about 2 little In time, take, and can obtain optimum efficiency, can control to a certain extent postprandial blood sugar and raise, and can refuse to obey or take less other and fall postprandial blood sugar Medicine. If can strictly keep on a diet and sweet food simultaneously, 2 hours blood glucoses also can equally with fasting blood-glucose can remain on normally substantially after the meal Or near normal range (NR), this prevents having of diabetic vascular and Microvascular Complication more important for the diabetes B people Meaning.

3, recover islet function: they have repair to the pancreas islet of pathology, can impel beta Cell of islet regeneration and functional rehabilitation, Correct metabolic disorder, activate the β cell and normally secrete pancreas islet, to IGT (IGT) and light, middle disease diabetic's treatment Imitate very obvious; The patient heavier to the state of an illness by delaying and block destruction and the depletion of β cell, no longer is the state of an illness and carries out Sexual development reaches the purpose of long-term control diabetes.

4, regulate acid-base balance: cause that diet structure changes because people's living standard improves, take in a large number high protein, higher fatty acid, High-carbohydrate food often makes body fluid be faintly acid. Interrelated data shows that 70% disease occurs on the person of acidic constitution. Acid Physique causes tissue organ function to descend, immunity degradation, and insulin sensitivity descends, and causes easily and increase the weight of diabetes, height A series of diseases such as blood pressure. Jamaicin belongs to the quaternary ammonium type alkaloid, also is a kind of organic base, and is adjustable in the treatment diabetes Joint body fluid acid-base balance is improved vivo environment, forms benign cycle, is conducive to treatment and the prevention of diabetes and complication thereof.

5, have the effect of contracting urine: the classical symptom of diabetes is " three-many-one-littles ", and blood sugar is more high, and the urine amount is more many. Use this After bright, the urine amount obviously reduces, and the state of an illness alleviates gradually. If before sleeping evening, add once, can reduce the enuresis nocturna number of times.

6, reduce insulin resistance (IR): they have the effect that increases insulin sensitivity, can alleviate insulin resistance, also Can resist blood sugar that exogenous glucose causes and raise and do not increase insulin secretion, its hypoglycemic mechanism is irrelevant with insulin, β Cell obtains owing to burden reduces having a rest and recovering.

The berberine that the present invention uses and the mechanism of action of Avandia are basic identical, all can increase the sensitivity of body to insulin, reduce insulin resistant, avoid the depletion of β cell function.The two all has and reduces fasting glucose and post-prandial glycemia, does not singly cause hypoglycemia with only reducing hyperglycemia, and bring high blood pressure down, effect such as blood fat.The former also can directly repair the pancreatic tissue that disease is decreased, strengthening vital QI to eliminate pathogenic factors from the source, impel beta Cell of islet to recover normal excreting insulin function, fundamentally remove source of disease, its hypoglycemic effect also is not less than Avandia, also can prevent and treat various infection and some diabetic complication simultaneously, and not have those three shortcomings of the latter.

7, meet quality standard: they are definite to curative effect of disease such as diabetes, steady quality, and side effect is slight, no hypoglycemia danger.Get owing to its raw material adopts single medicinal material to extract, effective ingredient is clear, and effect clearly has controlled quality standard, meets the international quality standards of " safe, effective, controlled, stable " that medicine should possess, also is the unitary basis of the modernization of Chinese medicine.

8, desirable hypoglycemic medicine: the berberine that the present invention adopts meets the following ideal conditions of selecting that treatment diabetes oral drugs should possess: 1. improve carbohydrate tolerance and insulin resistant; 2. reduce hyperglycemia and do not cause hypoglycemia; 3. do not stimulate beta Cell of islet, do not increase its burden, protection or recovery β cell function; 4. can improve blood pressure, dyslipidemia; 5. weight increase not; 6. there is not serious toxic and side effects.

9, be beneficial to anti-curing oncoma: berberine has active anticancer, to ehrlich carcinoma and lymphoma NK/LY cell etc. have inhibitory action, its mechanism be to suppress glucose utilization and with the interaction of nucleic acid.The high-dissolvability berberine can further improve body and presses down cancer, anti-cancer ability, and bacteriotoxin and cancerous cell are had more obvious antidotal effect, and short cancer material capable of blocking changes or real cancerous cell having potential short cancerous cell, can play a great role to anti-cancer.

10, medical application is extensive: the diabetics hypoimmunity, bring out multiple acute and chronic complication and various infection easily, the berberine that the present invention adopts is very wide to the purposes of human body, but except blood sugar lowering, treatment tumor or cancer, also cardiovascular disease such as the hypertension that diabetes are merged, hyperlipidemia, heart disease and multiple complications such as multisystem and each section's infectious disease have and treat preferably and preventive effect, for alleviating the state of an illness, promote that rehabilitation has positive effect.

The invention has the advantages that:

1, the present invention has excavated new medical usage to high-dissolvability berberine such as antibacterials for animals and chemical reagent, has opened up many-sided application prospect.

2, the present invention medicine material source of using is abundant, preparation technology is simple, low production cost, pharmacological action is very strong, range of application is wide.There are the various berberine of production in high-new plant material pharmaceutical factory, Chengdu, Sichuan Province.

3, the present invention to diabetes light in the disease patient can use separately, the person of being in a bad way can be used with medicine such as insulin, has reduced the consumption of other antidiabetic drug, effect obviously increases.

Description of drawings:

Fig. 1 is a human drugs berberine hydrochloride tablet label;

Fig. 2 is a medicine berberine sulphate injection label for animals;

Fig. 3 is hydrogen sulfate berberine structural formula and relevant explanation;

Fig. 4 is berberine sulphate structural formula and relevant explanation.

Table 1. research Berberine hydrochloride is used for the part information of hypoglycemic etc.

The researcher	Zoopery and clinical research	Document and sequence number
			Old its bright wisdom of thanking of institute of Materia Medica,Chinese Academy of Medical Sciences	Jamaicin has the characteristics of sulfonylureas and biguanide compound concurrently. To normally little Mouse, Spontaneous Diabetic mouse and alloxan diabetes mouse have hypoglycemic work With. Can resist the blood sugar rising that Exogenous Glucose causes. Can be to antiadrenergic drug The blood glucose increasing effect. Hypoglycemic activity is stronger. Reach 5～6 hours action time. Can improve disturbance of blood coagulation, antiatherosclerosis.	Acta Pharmaceutica Sinica 1986; 21 (6): 401～406 [1]
Jamaicin does not increase the insulin secretion of normal mouse, does not increase to grape yet Insulin behind the glucose load discharges, to normal mouse liver cell film insulin receptor number Order and affinity all do not have impact, thereby may be to reduce mouse by the acceptor aftereffect Blood sugar also may be gluconeogenesis and/or the promotion periphery group by suppressing liver The glucose glycolysis of knitting produces hypoglycemic activity.	Acta Pharmaceutica Sinica 1987; 22 (3): 161～165 [2]
		PLA's the 208th Ni Yan of hospital rosy clouds etc.		Berberine in treating diabetes B (together lower) 60 examples, 1～3 month course for the treatment of, The fasting blood-glucose 5.1mmol/L that on average descends, total effective rate 90%. Animal by experiment The observation of pathologic finding beta Cell of islet shows that the coptis have the promotion beta Cell of islet The effect of regeneration and functional rehabilitation. Liver, renal function and blood during all patients treatment Resemble and all do not have unusual variation, non-evident effect.	Combination of Chinese tradiational and Western medicine magazine 1988; 8 (12): 711～713 [3]
Jiujiang city Pengze institute of traditional Chinese medicine Liu state should	Treat 30 examples, efficient 90%. To light, moderate diabetic's curative effect Significantly. Have simultaneously hypotensive, reducing blood lipid, anti-infective, prevent the effects such as complication. Japanese scholars experiment showed, that berberine short cancer material capable of blocking is to having potential short cancer Cell is transformed into real cancer cell, can play a great role to anti-cancer.		Old medicine is newly used 1992; (1): 3～4 [4]
		Beijing builder hospital is in cotton honor etc.		Treat 75 examples, efficient 69.33%, all cases " more than three " symptom exists Taking medicine disappeared in two weeks, consistent fall time with blood sugar. Observe sugar with Berberine in treating Urine patient 4 years, no matter the dosage size does not have 1 example and side effect or hypoglycemia occur Disease. Wherein 11 examples subtract dosage keep 3 years surplus, blood sugar is normal.	Beijing medical science 1994; 16 (2): 117 [5]
Shan County, Henan Hu Faguang of the People's Hospital etc.	Treat 60 examples, total effective rate 90%, this medicine blood sugar reducing function is gentle and lasting, About two weeks beginning hypoglycemic reaches greatest treatment efficacy in 8 weeks, all cases diabetic symptom All disappear or alleviate, its common complication is had good result. The super body severe one of 4 examples Become normal. There is not serious toxic and side effect. Angiocardiopathy there is important curative effect.		Practical combination of Chinese tradiational and Western medicine magazine 1995; 8 (6): 358～259 [6]

Continued

The researcher	Zoopery and clinical research	Document and sequence number
			Xing of the People's Hospital, Huantai County, Shandong Province Sinology	Berberine tablet is treated 33 examples, after 3 weeks of medication, and 30 examples, 2 type patients " three Many " transference cure. 3 examples, 1 type patient blood sugar descends, the injection of insulin number of times Be kept to the dosage minimizing 2 times by 3 times. Observing more than 3 months does not have obviously not Good reaction.	The traditional Chinese medical science is taught by correspondence communication 1997; 16 (2): 22 [7]
Deng Wenlong	Jamaicin can reduce blood sugar, and mechanism and the insulin of its blood sugar reducing function do not have Close. Can treat and prevent diabetes and complication thereof, hypertension, high fat of blood, Arrhythmia cordis, angina pectoris, heart failure, VPB, atrial premature beats, Atherosclerotic, the multiple angiocardiopathy such as platelet aggregation and hepatitis, Tumour, cancer, septicaemia have maincenter calmness, local anaesthesia, resist the effect of putting, Irradiation causes dead mouse to Co 60 protective effect. In due to the industrial poison The toxicity hepatic injury has certain protection effect. Remarkable anti-inflammatory activity is arranged, low concentration The time antibacterial, sterilization during high concentration. Can prevent and treat gastritis, gastroduodenal ulcer, Cholera, ileotyphus, balantidium Coli disease, cholecystitis, infection of biliary tract, Respiratory tract infection, lobar pneumonia, infantile pneumonia, lung abscess, pulmonary tuberculosis; Acute/chronic bronchitis, pleurisy, diphtheria, influenza, pertussis, A Er The infection of bar bacterium, candida albicans infection, renal plevis, ephritis, the cutization purulence Infect, carbuncle, furuncle, ruffian, abscess, adenolymphitis, the pyogenic infection of the pad of a finger, mastitis, Impetigo, refer to osteomyelitis, refer to the pyogenic infection of (toe) section, infection of burn, Vaginitis, adnexitis, cervical erosion, trachoma, conjunctivitis, eyes-affinity blepharitis, Sty, keratitis, tympanitis, otitis externa, rhinitis, jaw sinusitis, Acute and chronic tonsillitis, oro-maxillo-facial inflammation, herpetic stomatitis, recurrence The property stomatitis, oral mucosa ulcer, put forth energy Sen Shi stomatitis, uncommon Shandong Salmonella disease, Leptospirosis, leprosy, scarlet fever, Hemorrhagic fever, various Acute infection, severe infection, bacterial infection, viral infection disease, The multiple differences such as digestive system, respiratory system, surgery, gynaecology, ENT dept. Pathogen, different parts be not even with the infectious diseases of lesion nature.	Herbal pharmacology with use the king and bathe the chief editor People's Health Publisher such as Sheng Dengwenlong December in 1998 the 1st edition 1004～1019 [8]
			The Zhang Jiaqing of Changhai hospital of The 2nd Army Medical College	The coptis have certain increase insulin sensitivity effect, Sensitivity Index Near melbine, alleviate insulin resistance.	The practical diabetes magazine in Liaoning 1999; 1 (4): 56～57 [9]
Linchuan city of Jiangxi province first hospital of traditional Chinese medicine Deng chess is defended	The berberine blood sugar reducing function certainly, but consumption should 25 slices/day or more than.	The friend of diabetes 2002; (1): 42～43 [10]

Continued

The researcher	Zoopery and clinical research	Document and sequence number
			The new medical college in Jiangsu	The coptis or jamaicin are to hemolytic streptococcus, meningococcus, the two balls of pneumonia Bacterium, comma bacillus, bacillus anthracis, staphylococcus aureus, shigella dysenteriae, white Larynx bacillus, hay bacillus, viridans streptococci, pneumobacillus, Bordetella pertussis, Yersinia pestis, Brucella, clostridium tetani, Bacillus perfringens, tuberculosis bar Bacterium, proteus, Escherichia coli, typhoid bacillus have inhibitory action. Low concentration presses down Bacterium, the high concentration sterilization, effect extensively can be used as anticorrisive agent. Oral barberry once Alkali 2 grams or coptis powder 100 grams have no any side effect. (purposes slightly)	Chinese medicine voluminous dictionary Shanghai science tech publishing house June in 1986 the 1st edition (volume two) 2022～2030 [11]
Lee of Academy of Traditional Chinese Medicine, Xinjiang is with justice	Coptis nature and flavor bitter cold, bitter can hot-temperedly wetting, the heat-clearing of cold energy, its main component jamaicin Energy is hemangiectasis directly, loose vascular smooth muscle, and antiadrenergic drug promotes that blood is suitable Sharp circulation, the drying damp and strengthening spleen effect of similar motherland medical science goes phlegm also to change so wet. Clinical The product of used clearing heat and nourishing yin all are to bring into play therapeutic action by the hypoglycemic that reduces phlegm.	All kinds of diseases and ailments all are born in phlegm Xueyuan Press March in 1991 the 1st edition 41,124 [12]
			302 Wang Yong of hospital of Beijing PLA are happy etc.	Berberine is at first manually synthesized successfully in the world by China. Maximum characteristics are Side effect is little, is side effect reckling in the antidysenteric thing, and liver, kidney, bone are reached The main organs such as nervous centralis have no adverse effects.	Golden Shield publishing house October in 1991 the 1st edition 36～37 [13] is asked in the sick control 320 of common transmittable
Dong three Bai Zhoulin are female	The coptis have extensive bacteriostasis, loose smooth muscle and buck functionality is arranged, energy Increase bile and form, make bile thinning, thus the performance choleretic effect. Also has anti-arrow Poison, adrenolytic. When low dose, can strengthen the effect of acetylcholine, Heavy dose is then resisted it. Therefore, has again the atropine-like effect.	Food restriction or checking relation in five elements and diet compatibility and incompatibility of drugs China Light Industry Press November in 1991 the 1st edition 298～299 [14]
			The huge state of Beijing Chinese Traditional and Western Medicine New Technology Inst. bright mansion army etc.	Jamaicin can treat esophagitis, ischemic heart disease, popular myelencephalon, Around film inflammation, ulcerative colitis, Halophiles food poisoning, anal fissure, the hedrosyrinx Scorching, newborn subcutaneous gangrene, skin ulcer, stubborn dermatitis etc. (all the other are with document 8)	The clinical complete works of China Traditional Chinese Medicine Publishing House of the new purposes of common drug January in 1994 the 1st edition 34～35,446～450 [15]
King's equality	Jamaicin and some derivatives thereof have active anticancer. Have antimicrobial and antigen Worm effect can also increase coronary flow by excited cat isolated heart, can reduce Mouse Liver, The oxygen consumption of brain homogenate can make the excitement of animal organ's smooth muscle, strengthens cholinergic nerve.	Integrative Chinese-Western guide China Traditional Chinese Medicine Publishing House October in 1994 the 1st edition 23～25 [16]

The main jamaicin overview table of table 2.

The bulk drug title	Solubility in water		Purposes
				Berberine hydrochloride (Halomine)	1∶500	Low	1. human or antimicrobial for animals, Be used for enteric infection. 2. chemical reagent.
Citric acid jamaicin (citric acid berberine)	1∶125	High
			Berberine bisulfate (Berberine bisulfate)	1∶100
Berberine sulfate (berberine sulphate)	1∶30
			Phosphoric acid jamaicin (phosphoric acid berberine)	1∶15

Annotate: (1) dissolubility data draws from " Chemistry for Chinese Traditional Medicine) ", the Wu Lijun chief editor, and Yan Liu's literary composition is write articles, and Chinese Medicine science and technology is published

Society, 2001,48.

(2) standard of Berberine solubility height of the present invention is with the dissolubility data of human drugs Berberine hydrochloride in water

Be the line of demarcation.

(3) high-dissolvability jamaicin of the present invention refers to the various jamaicins that can dissolve in less than 500 parts of water.

Table 3. is used the producible main new product of high-dissolvability jamaicin

The bulk drug title	Formulation	New product name
			Citric acid jamaicin (citric acid berberine)	Capsule	Citric acid jamaicin capsule (citric acid berberine capsule)
Tablet	Citric acid jamaicin sheet (citric acid berberine tablet)
		Ointment		Citric acid jamaicin ointment (citric acid berberine ointment)
Berberine bisulfate (Berberine bisulfate)	Capsule				Berberine bisulfate capsule (Berberine bisulfate capsule)
		Tablet	Berberine bisulfate sheet (Berberine bisulfate sheet)
	Ointment			Berberine bisulfate ointment (Berberine bisulfate ointment)
		Berberine sulfate (berberine sulphate)	Capsule		Berberine sulfate capsule (berberine sulfate cellulose capsule)
Tablet	Berberine sulfate sheet (berberine sulphate sheet)
			Ointment	Berberine sulfate ointment (berberine sulphate ointment)
Phosphoric acid jamaicin (phosphoric acid berberine)	Capsule				Phosphoric acid jamaicin capsule (phosphoric acid berberine capsule)
		Tablet	Phosphoric acid jamaicin sheet (phosphoric acid berberine tablet)
	Ointment			Phosphoric acid jamaicin ointment (phosphoric acid berberine ointment)

Annotate: other interior usefulness, external preparation can produce different according to different purposes with formulation (such as powder, film etc.)

New product and corresponding newname thereof.

The main jamaicin overview table of table 2.

The bulk drug title	Solubility in water		Purposes
				Berberine hydrochloride (Halomine)	1∶500	Low	1. human or antimicrobial for animals, Be used for enteric infection. 2. chemical reagent.
Citric acid jamaicin (citric acid berberine)	1∶125	High
			Berberine bisulfate (Berberine bisulfate)	1∶100
Berberine sulfate (berberine sulphate)	1∶30
			Phosphoric acid jamaicin (phosphoric acid berberine)	1∶15

Annotate: (1) dissolubility data draws from " Chemistry for Chinese Traditional Medicine ", the Wu Lijun chief editor, and Yan Liu's literary composition is write articles, and Chinese Medicine science and technology is published

Society, 2001,48.

(2) standard of Berberine solubility height of the present invention is with the dissolubility data of human drugs Berberine hydrochloride in water

Be the line of demarcation.

(3) high-dissolvability jamaicin of the present invention refers to the various jamaicins that can dissolve in less than 500 parts of water.

Table 3. is used the producible main new product of high-dissolvability jamaicin

The bulk drug title	Formulation	New product name
			Citric acid jamaicin (citric acid berberine)	Capsule	Citric acid jamaicin capsule (citric acid berberine capsule)
Tablet	Citric acid jamaicin sheet (citric acid berberine tablet)
		Ointment		Citric acid jamaicin ointment (citric acid berberine ointment)
Berberine bisulfate (Berberine bisulfate)	Capsule				Berberine bisulfate capsule (Berberine bisulfate capsule)
		Tablet	Berberine bisulfate sheet (Berberine bisulfate sheet)
	Ointment			Berberine bisulfate ointment (Berberine bisulfate ointment)
		Berberine sulfate (berberine sulphate)	Capsule		Berberine sulfate capsule (berberine sulfate cellulose capsule)
Tablet	Berberine sulfate sheet (berberine sulphate sheet)
			Ointment	Berberine sulfate ointment (berberine sulphate ointment)
Phosphoric acid jamaicin (phosphoric acid berberine)	Capsule				Phosphoric acid jamaicin capsule (phosphoric acid berberine capsule)
		Tablet	Phosphoric acid jamaicin sheet (phosphoric acid berberine tablet)
	Ointment			Phosphoric acid jamaicin ointment (phosphoric acid berberine ointment)

Annotate: other interior usefulness, external preparation can produce different according to different purposes with formulation (such as powder, film etc.)

New product and corresponding newname thereof.

Claims (10)

1. the application of high-dissolvability berberine in the medicine of preparation treatment or prevent diabetes and complication thereof.

2. the application of high-dissolvability berberine in the medicine of preparation treatment or prophylaxis of tumours and cancer.

3. the application of high-dissolvability berberine in the medicine that the disease for preparing treatment or the viral infection of prevention pathogenic bacteria---comprises atypical pneumonia---.

4. according to the described application of claim 1～3, it is characterized in that: described berberine is other berberine except berberine hydrochloride.

5. application according to claim 4 is characterized in that: described berberine be can be in less than 500 parts of water dissolved berberine---comprising citric acid berberine, hydrogen sulfate berberine, phosphoric acid berberine with now be the berberine sulfate of veterinary drug.

6. application according to claim 5 is characterized in that: described berberine comprises from plant and to extract or berberine that chemosynthesis obtains.

7. application according to claim 6 is characterized in that: described berberine is the medicine that the combination of single berberine or two or more berberine or any berberine and other medicine are mixed with.

8. application according to claim 7 is characterized in that: described medicine is any dosage form except injection.

9. application according to claim 8 is characterized in that: described dosage form comprises capsule, tablet, powder, membrane and ointment.

10. application according to claim 9, it is characterized in that: described medicine name comprises citric acid berberine capsule, citric acid berberine sheet, citric acid berberine ointment, hydrogen sulfate berberine capsule, hydrogen sulfate berberine sheet, hydrogen sulfate berberine ointment, berberine sulfate capsule, berberine sulfate sheet, berberine sulfate ointment, phosphoric acid berberine capsule, phosphoric acid berberine sheet, phosphoric acid berberine ointment.

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