CN104337884A

CN104337884A - Medicine composition for preventing and/or treating diabetes and complication of diabetes

Info

Publication number: CN104337884A
Application number: CN201410380545.XA
Authority: CN
Inventors: 颜明; 刘畅; 周毅; 曹林; 陆洋
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-08-06
Filing date: 2014-08-05
Publication date: 2015-02-11

Abstract

The invention discloses a medicine composition for preventing and/or treating diabetes and complication of diabetes. The medicine composition is prepared from Chinese herbaceous peony and cassia bark in a weight ratio of (10-1) to 1. The medicine composition comprises the following effective components in parts by weight: 50-150 parts of a pinane monoterpene glycoside compound in Chinese herbaceous peony, and 1-5 parts of a cinnamic acid/aldehyde compound. The medicine composition not only has a good and stable blood sugar reduction and weight loss function, but also can effectively prevent and treat multiple diabetes complications, such as fatty liver, diabetic cardiomyopathy, diabetes peripheral neuritis, diabetes eye diseases and diabetic nephropathy. The composition is low in toxicity, small in side effect, low in cost and safe to use.

Description

A kind of pharmaceutical composition preventing and/or treating diabetes and complication thereof

Technical field

The present invention relates to natural medicine field, particularly a kind of pharmaceutical composition preventing and/or treating diabetes and complication thereof.

Background technology

Modern medicine is thought, diabetes be one group due to insulin definitely or relative deficiency and the target cell systemic disease that the sensitivity of insulin reduced and causes.Clinical in early days can be asymptomatic, typical person has polydipsia, polyphagia, polyuria, tired, the syndrome such as to become thin, and within 50 ~ 70 years old, is ill peak.Diabetes are generally divided into insulin-dependent (I type, IDDM) and non-insulin-depending type (II type, NIDDM) two classes, and its type ii diabetes accounts for more than 80%.Along with the raising day by day of living standards of the people, diabetes prevalence just sharply increases, and has become one of principal disease affecting human body health.1997 annual reports, nineteen ninety-five the whole world have diabetics 1.25 hundred million, predict and within 2025, will surge to 2.29 hundred million, in the diabetics that quantity sharply increases, type ii diabetes accounts for patient populations's more than 95%.If diabetes are not diagnosed in time, regular treatment can cause multiple chronic complicating diseases.Common complication has microangiopathies, the neuropathy etc. such as actute infection, pulmonary tuberculosis, atherosclerosis, kidney and retina.According to statistics, the concurrent neuropathy of diabetics over half; About have the concurrent proliferative retinopathy of the diabetics of 30%, wherein have every year 1.2% may develop into blind; The type i diabetes patient of 30% ~ 40% and the type ii diabetes patients complicated with diabetes mellitus nephropathy (DN) of 15% ~ 20%, can by occurring that albuminuria develops into hypertension, nephrotic syndrome at first, finally cause renal failure and death, 3 years survival rates of DN are only 53%.Diabetes about 50% merging fatty liver.When blood glucose control is unsatisfied with, easily suffer from fatty liver.This is because insufficient insulin, in body glucose utilization reduce, steatolysis accelerate, fatty acid in blood is increased, so in liver synthctic fat; Again because liver glycogen reserves reduces, fat is easily caused to form fatty liver in the accumulation of liver.Diabetes become the third-largest disease that M & M is the highest after cardiovascular disease, cancer.In view of the significant damage of diabetes, finding screening treatment diabetes and the active drug of complication thereof has become the focus that current medicine sector competitively studies.

Along with the research that deepens continuously to pathogenesis of diabetes mellitus, find numerous AD-targeted drugs, develop the medicine of many treatment diabetes and complication thereof.Antidiabetic medicine generally can be divided into 3 classes: reducing hyperglycaemia medicine, anti-hypoglycemic medicament and Chinese medicine.

Reducing hyperglycaemia medicine can reduce hyperglycemia, but also also can have reducing effect to the normal person of blood glucose by this type of medicine, should note hypoglycemia during application.This type of drug main will comprise: insulin, Insulin secretagogues (sulfonylurea, benzoic acid derivative and amino acid derivativges) etc.Indication: first-selected be used for non-obese type ii diabetes, or with hyperglycemia medicine use in conjunction type ii diabetes; Insulin can also be applied to type i diabetes.

Hyperglycemia medicine only reduces hyperglycemia, is used alone and does not generally cause hypoglycemia, to the normal person of blood glucose without obvious hypoglycemic activity.This type of drug main will comprise: TZD, biguanides and alpha-glucosidase inhibitor etc.Indication: alone in fat or overweight type 2 diabetes mellitus, or with hypoglycemic drug therapeutic alliance II type or type i diabetes.

Much Chinese medicine has certain hypoglycemic activity, and its main advantage is to prevent and treat chronic complicating diseases of diabetes.Pure Chinese medicinal preparation single application generally can not cause hypoglycemia, but apply Chinese medicine separately, general blood sugar reducing function is quick and durable not as Western medicine, also needing to combine has Western medicine just can reach ideal hypoglycemic effect, as diabetes pill (10 diabetes pilles about containing glyburide 2.5mg) and be large compound recipe many blood-sugar lowering tcm drugs, manufacturing cost is higher, and not easily, effective ingredient is indefinite for quality control.These all limit the development of Chinese medicine antidiabetic drug, make it treat mainly as the auxiliary hyperglycemic of senile diabetes with some diabeticss.

In addition, utilize the technological means of Natural Medicine Chemistry, from single medicinal material, screening and separating has active site and the activated monomer of hypoglycemic activity, also have made great progress, the composition with hypoglycemic activity of current discovery mainly contains the number of chemical structure types such as polysaccharide, saponin, terpenoid, flavone, alkaloid, and wherein polysaccharide proportion in sugar-lowering components is maximum.But compared with current Western medicine hypoglycemic medicine, the active site of these natural plants and the hypoglycemic activity of activated monomer, still have larger gap, can not directly as clinical medicine.In order to improve the blood sugar reducing function of these natural products, the at present main method adopting chemical modification, and carry out secondary development in conjunction with high flux screening, but such method cost is higher, and due to the complexity of natural product, the difficulty of research and development is also larger.

In face of above-mentioned research and development predicament, many developers have also carried out a large amount of screenings and trial to drug combination or polypharmacy, but majority is based on the existing medicine of one or two existing treatment diabetes, or select the compound that blood sugar reducing function is higher, natural drug or natural drug extract combine, attempt to improve blood sugar reducing function further by drug combination or reduce side effect, but such screening remains random, there is certain Unpredictability in effect, a lot of drug combination is had finally to be found to produce a desired effect, screen and there is good blood sugar lowering synergism and toxic and side effects is low, drug combination probability diabetic complication to better retarding action is still very low, and such drug combination can not provide new mechanism or the new approaches for the treatment of diabetes.

Radix Paeoniae comprises Radix Paeoniae Rubra and the Radix Paeoniae Alba, and Radix Paeoniae Rubra is the dry root of ranunculaceae plant Radix Paeoniae or river Radix Paeoniae Rubra.The Radix Paeoniae Alba is that the root of ranunculaceae plant Radix Paeoniae dries and obtains after decocting in water.Modern study shows, the Radix Paeoniae Alba is containing peoniflorin, lactone glucoside of Radix Paeoniae, oxypaeoniflorin, benzoylpaeoniflorin, benzoic acid, tannin, volatile oil, cupreol, fatty wet goods composition, and wherein benzoic acid is its harmful components.

Pinane monoterpene glycosides compound in Radix Paeoniae is the principle active component (chemical constitution study of Radix Paeoniae of conventional Chinese medicine Radix Paeoniae, Zhang Xiaoyan, Shenyang Pharmaceutical University's master thesis, calendar year 2001,18-30 page), comprise: peoniflorin, Radix Paeoniae Alba glycosides, lacdtlorin Ⅲ, lactone glucoside of Radix Paeoniae A, lactone glucoside of Radix Paeoniae B, lactone glucoside of Radix Paeoniae C, oxypaeoniflorin, benzoylpaeoniflorin, etc. compound, wherein peoniflorin (Paeoniflorin, PF) be that wherein content is the highest, pinane monoterpene glucoside compound in the representational Radix Paeoniae of most.

In recent years, Chinese scholars (peoniflorin New research progress in pharmacological activities, Zheng Shicun; Deng, " Chinese pharmacovigilance ", 2012,9 (2): 100-103 pages) comparatively deep research is expanded to the pharmacological action of paeoniflorin compound, find that peoniflorin has free radical resisting damage, calcium overload and against neurotoxicity isoreactivity in T suppression cell, experiment in vivo proves that it all has the pharmacological action of affirmative to aspects such as cardiovascular, central nervous system, immunomodulating and smooth muscle; There is reduction blood viscosity, antiplatelet aggregation, blood vessel dilating, improve the various biological effects such as microcirculation, antioxidation, convulsion.

Radix Paeoniae Alba extract and peoniflorin monomer have certain for anti-diabetic or hypoglycemic relevant report in the prior art.CN101856399A has disclosed and has been pulverized by the Radix Paeoniae Alba, carries out supersound extraction after soaking with ethanol-water solution; After being extracted with ethyl acetate, except desolventizing obtains Radix Paeoniae Alba extract.Prove through zoopery: above-mentioned Radix Paeoniae Alba extract to glucose there is certain inhibitory action to hyperglycemia.Y.-C.Juan, Deng (The novel anti-hyperglycemic effect of Paeoniae radix via the transcriptional suppression of phosphoenopyruvate carboxykinase (PEPCK), Phytomedicine, 17 (2010), the mRNA of the PEPCK of the diabetic model rats that ethanol extraction 626-634) disclosing Peony Root can dose-dependently suppress STZ to manufacture and db/db mice transcribes, and reaches certain and falls hypoglycemic effect.And in H4IIE cell, this extract can suppress the PEPCK caused by various condition mrna expression and without any cytotoxicity, and after 24 hours again administration time, still have inhibition.But peoniflorin monomer can not reduce the expression of PEPCK in 5-40 μ g/ml concentration.Peoniflorin intravenous injection obviously can reduce the blood glucose of STZ diabetic mice, but returns to normal level after administration 3h, and its blood sugar lowering mechanism and insulin irrelevant (Planta Med, 1997,63 (4): 323).Tang L M, Deng (Stimulatory effect of paeoniflorin on adenosine release to increase the glucose up take into white adipocytes of Wistar rat, Planta Med, 2003,69 (4): 332) disclose peoniflorin monomer and can stimulate the adipose cell release adenosine thus promotion cellular uptake periphery glucose cultivated.(peoniflorin is to the protection of the INS-1 cell that STZ damages and repair for Ren Wenhui etc., Aged in China magazine, in January, 2011,31st volume, 230-232 page) disclose, in islet cell culture experiment, peoniflorin monomer has stronger protective effect to the islet cells that STZ damages, and the cell viability caused by STZ, amount of insulin secretion can be made to reduce degree and be greatly improved; But not obvious to islet cells repair, prompting peoniflorin can effectively prevent diabetes.

Although disclosed Radix Paeoniae Alba extract in prior art or peoniflorin monomer has certain hypoglycemic activity, disclosed hypoglycemic effect is unsatisfactory, the research more mainly in mechanism.Also some researcheres are had to attempt improving Radix Paeoniae Alba extract or the undesirable problem of peoniflorin monomer hypoglycemic activity by the method for combination, as disclosed the Pharmaceutical composition of a kind of scutellarin and peoniflorin in CN1857293A, said composition can be treated and prevent diabetes coronary heart disease, but said composition must drug administration by injection could onset, and whether said composition does not have the proof of experimental data to the direct control action of blood glucose.The compositions disclosing the Radix Paeoniae Alba and Radix Glycyrrhizae in CN101780155A can play potentiation to the blood sugar reducing function of acarbose, but said composition is used alone the proof whether direct control action of blood glucose not being had to experimental data.Therefore the independent blood sugar reducing function of these compositionss is still undesirable.

Radix Paeoniae monoterpene glycosides compound toxic and side effects little (toxicity research of Radix Paeoniae Alba total glucosides, Chinese Pharmacological Bulletin, Li Jun; Deng, 1991,7 (1): 53), mouse vein administration ID50 is 150mg/kg, and intraperitoneal administration ID50 is 230mg/kg, and gavage 2500mg/kg observes one week, has no obvious poisoning symptom also without dead.Rat (every day ig500,1000,2000mg/kg, successive administration 30 and 90d) and Canis familiaris L. (every day ig280 560mg/kg, successive administration 90d), long term administration latter two animal is except number of platelets increases, diet, body weight, hematuria are conventional, hepatic and renal function all without obvious change, to 18 important organs such as the heart, brain, liver, kidney of two kinds of animals and the pathologic examination of tissue also without overt toxicity.

Cortex cinnamomi japonici (Ramulus Cinnamomi), also known as Cortex Cinnamomi, is the dry bark of canella Cortex Cinnamomi Cinnamomum cassia Presl, and record the earliest and come from Shennong's Herbal, its nature and flavor are pungent, sweet, hot greatly, return kidney, spleen, the heart, Liver Channel.Have the medicinal history of 2000 at least in China, have effects such as mending fire is supporing yang, let the fire back to its origin, dispersing cold for relieving pain, fecund is in provinces such as Yunnan Province of China, Guangxi, Guangdong, Fujian.Cortex Cinnamomi is the vegetable material of the dietotherapeutic that China's Ministry of Public Health is announced, and both widely uses as flavorant among the people, and uses again on tcm clinical practice as medicine.Chemical composition contained by Cortex Cinnamomi has Oleum Cinnamomi, polyphenol, organic acid, tannin, polysaccharide, cinnamoside, Cortex cinnamomi japonici (Ramulus Cinnamomi) glycosides, steroidal, lignin etc.

Ramulus Cinnamomi derives from the dry twig of canella Cortex Cinnamomi, acrid-sweet flavor warm in nature, GUIXIN, lung, urinary bladder channel.There is relieving the exterior syndrome by diaphoresis, effect of warming the meridian for promoting the flow of YANG QI.

Cortex Cinnamomi finds the Be very effective of Cortex Cinnamomi extract treatment diabetes through a large amount of experiments and research the more external scientists of clinical practice, all achieve successfully with it mice and human body, and abroad the multiplex Cortex Cinnamomi powder of patient or Cortex Cinnamomi extract, as assistant hypoglycemic drug administration, obtain good effect.Multitest result shows that Chinese medicine cinnamon can also reduce blood fat hypoglycemic while, the prompting control tool of Cortex Cinnamomi to diabetes and complication thereof has certain effect, and its pharmacological Mechanism mainly contains following several form: 1. by protection, stimulate B cell and increase the content of serum insulin; 2. increase the sensitivity of insulin, improve insulin resistant; 3. scavenging free radicals, anti peroxidation of lipid; 4. promote insulin secretion, increase the content of serum insulin.

Although have separately in prior art and mention Radix Paeoniae and Cortex Cinnamomi has certain hypoglycemic activity respectively, but their respective hypoglycemic activities are not strong, and can not to diabetic complication---diabetic cardiomyopathy, diabetic peripheral neuritis, diabetic ophthalmopathy, diabetic nephropathy etc. play therapeutical effect, therefore still need research blood sugar reducing function definite, and the medicine of therapeutical effect can be played multiple diabetic complication.

Cinnamic acid (cinnamic acid, cinnamic acid, β-cinnamic acid, cinnamic acid, cinnamic acid, β-phenylacrylic acid) and cinnamic aldehyde compounds be one of important organic synthesis intermediate, be widely used in the aspects such as medicine, agricultural, chemical industry, daily use chemicals.Cinnamic acid is a kind of spice inherently, has and well protect fragrant effect, for food such as beverage, cold drink, confection, drinks; And cinnamic acid has sterilization, antisepsis, excitation very by force, can extensively directly make an addition in all food.Cinnamic acid is used to synthesize multiple important cardiovascular drugs in medical industry.CN1303671A has disclosed the purposes of cinnamic acid on the medicine of preparation treatment diabetes, CN1313085A has disclosed the purposes of cinnamic acid on the medicine of the incidence rate of preparation control type 1 diabetes, CN1303672A has disclosed potassium salt or the purposes of sodium salt on the medicine of preparation treatment diabetes of cinnamic acid, but the hypoglycemic effect of cinnamic acid is unsatisfactory.Cinnamic acid (the resource metabolism of cinnamic acid and allied compound thereof and toxicity, " foreign medical science. pharmacy fascicle ", Chen Han is fragrant, 01 phase in 1986, 58 pages) be that the enzymolysis of phenylalanine and derivant thereof deaminizes product, by the beta-oxidation of side chain, reduction is converted into benzenpropanoic acid, metabolite after human oral's cinnamic acid is single Cortex Cinnamomi phenol glucuronic acid and hippuric acid, allied compound comprises cinnamic acid, cinnamic aldehyde, cinnamyl alcohol, cinnamic esters etc. make drug and food additive, various cinnamate and cinnamyl alcohol analog are used as medicine, clean and food flavor and flavoring agent, all side reaction is not found through long-term eating.The toxicity of cinnamic acid is very low, and total property ID50 of rat, mice and Cavia porcellus is all greater than 5000mg/kg.But because the chemical constitution of cinnamic acid is similar with the structure of coumarin with toxic compounds styrene, there is styrene group, therefore, European countries and U.S. FDA and the United Nations's health, food and agricultural organization etc. all make stipulations to the remaining addition in the human body maximum intake every day (ADI) of this compounds and food, medicine.Such as the ADI of regulation cinnamic acid, cinnamate and Cortex Cinnamomi dialdehyde is 1.25mg/kg.

At present, prior art is current, also the compositions of Radix Paeoniae and Cortex Cinnamomi is not used for the bibliographical information for the treatment of diabetes, also the compositions of the pinane monoterpene glycosides compound in Radix Paeoniae and cinnamic acid/aldehyde compound is not used for the bibliographical information for the treatment of diabetes.

Summary of the invention

In view of the deficiencies in the prior art, the object of the present invention is to provide a kind of with Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) concertedness treatment diabetes, and make all improved pharmaceutical composition of complication such as diabetic cardiomyopathy, diabetic peripheral neuritis, diabetic ophthalmopathy, diabetic nephropathy of diabetics.

And on this basis; although find that paeoniflorin compound, cinnamic acid compound do not have act on or act on very weak separately or with certain consumption proportion on blood sugar lowering; but when combining with specific consumption proportion, there is on blood sugar lowering beyond thought synergism; serve good blood sugar reducing function; and this drug regimen toxic and side effects is extremely low; and there is the functions such as excellent the liver protecting; research and development for Glucovance provide new approaches and new research direction, and the mechanism of action of said composition needs further to be studied.

The invention provides a kind of pharmaceutical composition treating and/or preventing diabetes and how its multiple complications, it is characterized in that by weight ratio be 10-1: 1 Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) make.

Radix Paeoniae described in said composition can be the Radix Paeoniae Alba or Radix Paeoniae Rubra, and described Cortex cinnamomi japonici (Ramulus Cinnamomi) can be Cortex Cinnamomi or Ramulus Cinnamomi.

In said composition, the weight ratio of Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) can also be 8-2: 1, or is 6-4: 1, or is 5: 1.

Present invention also offers a kind of preparation method treating and/or preventing diabetes and the how pharmaceutical composition of its multiple complications, comprise the Radix Paeoniae of pharmaceutical composition weight proportion of the present invention and Cortex cinnamomi japonici (Ramulus Cinnamomi) is with the alcohol of water or 30-90% respectively or after united extraction, through 40-80 DEG C of vacuum concentration, cold drying, to obtain final product.Described alcohol can be ethanol, n-butyl alcohol etc.

Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) also directly can be pulverized use by pharmaceutical composition of the present invention.

The preparation method of pharmaceutical composition of the present invention, comprise the Radix Paeoniae of pharmaceutical composition weight proportion of the present invention and Cortex cinnamomi japonici (Ramulus Cinnamomi) be with the ethanol of water or 30-90% respectively or after united extraction, be separated through macroporous resin, through 40-80 DEG C of vacuum concentration, cold drying, to obtain final product.

Present invention also offers a kind of pharmaceutical preparation, is that pharmaceutical composition of the present invention and pharmaceutically acceptable adjuvant are made pharmaceutically acceptable any dosage form.Described dosage form can be ordinary tablet, slow releasing tablet, granule, hard or soft capsule, solution, Emulsion, injection, injectable powder, patch, suppository, cream, unguentum, gel, solution or suspension etc.

Purposes in the medicine that pharmaceutical composition of the present invention treats and/or prevents diabetes and how its multiple complications in preparation.Wherein said diabetes are type ii diabetes, and described diabetic complication is diabetic nephropathy, diabetic ophthalmopathy, diabetic peripheral neuritis, diabetic cardiomyopathy.

Pharmaceutical composition of the present invention is lost weight in preparation, is reduced blood fat or treat and/or prevent the purposes in the medicine of fatty liver.

Pharmaceutical composition of the present invention can also widely use in medicine, health product, health food, cosmetics.

The present invention also provides a kind of new pharmaceutical composition, wherein contains by the pinane monoterpene glycosides compound in Radix Paeoniae and cinnamic acid/aldehyde compound.

In aforementioned pharmaceutical compositions, the pinane monoterpene glycoside compound in described Radix Paeoniae is one or more of following compositions: the aglycon of peoniflorin, Radix Paeoniae Alba glycosides, lacdtlorin Ⅲ, lactone glucoside of Radix Paeoniae A, lactone glucoside of Radix Paeoniae B, lactone glucoside of Radix Paeoniae C, oxypaeoniflorin, benzoylpaeoniflorin or above-mentioned glycoside; Described cinnamic acid/aldehyde compound is one or more of following compositions: cinnamic acid, 4-hydroxycinnamic acid, 3,4-dihydroxycinnamic acid, 3,4-dihydroxy hydrocinnamic acid, cinnamic aldehyde, hydroxyl replace cinnamic aldehyde.

Preferably, in aforementioned pharmaceutical compositions, the pinane monoterpene glycosides compound in described Radix Paeoniae is peoniflorin, and described cinnamic acid/aldehyde compound is cinnamic acid.

Another object of the present invention is to provide the aforementioned pharmaceutical compositions of specified weight proportioning, and its weight proportion can be: the pinane monoterpene glycosides compound in the Radix Paeoniae of 50-150 weight portion, the cinnamic acid/aldehyde compound of 1-5 weight portion; Preferably, the weight proportion of described pharmaceutical composition is: the pinane monoterpene glycosides compound in the Radix Paeoniae of 75-125 weight portion, the cinnamic acid/aldehyde compound of 2-4 weight portion; More preferably, the weight proportion of described pharmaceutical composition is: the pinane monoterpene glycosides compound in the Radix Paeoniae of 100 weight portions, the cinnamic acid/aldehyde compound of 3 weight portions.

A third aspect of the present invention, provides a kind of pharmaceutical preparation, is to be prepared from by any one above-mentioned pharmaceutical composition and pharmaceutically acceptable adjuvant.

Above-mentioned pharmaceutical composition adds customary adjuvant or excipient, can make clinical acceptable peroral dosage form or parenteral dosage form.

A fourth aspect of the present invention, discloses any one pharmaceutical composition above-mentioned and is preparing the purposes prevented and/or treated in the medicine of diabetes and complication thereof.Wherein said diabetes are type i diabetes or type ii diabetes; Described diabetic complication comprises diabetic nephropathy, diabetic ophthalmopathy, diabetic gastroparesis, diabetic peripheral neuritis, diabetes hepatopathy; And described diabetic complication is fatty liver.

A fifth aspect of the present invention, discloses any one pharmaceutical composition above-mentioned and is preparing the purposes prevented and/or treated in the medicine of fatty liver and complication thereof.

Medicine/health composition of the present invention can make the dosage form of any routine by conventional method.

The dosage form of medicine/health composition of the present invention can be diversified, as long as the dosage form that active component can be made effectively to arrive in mammalian body is all fine.Compositions can make the various forms being applicable to required administering mode.Such as, the peroral dosage form that pharmaceutical composition can be made is tablet, capsule, pill, lozenge, granule, drop pill, and described parenteral dosage form is lyophilized injectable powder, propellant (in solid matrix), ointment, suppository.Pharmaceutical composition of the present invention is preferably and is present in suitable solid.

Pharmaceutical composition thing preferred oral of the present invention administration, oral form includes but not limited to: tablet, capsule, dispersible powder, or carries out parenteral routes with sterile injectable solution or form of suspension (containing 0.05-0.5% suspending agent of having an appointment in isotonic medium).These medicines can be applied to animal; Especially people.Containing the pharmaceutical composition of active substance of the present invention, can the mode such as oral administration, subcutaneous, Intradermal, intravenous injection apply.Therapeutic dose scheme can be single dose regimen or multiple doses.

Pharmaceutical composition of the present invention and compositions thereof also through parenteral or intraperitoneal administration, also can prepare solution or the suspension of these active substances in the water being suitably mixed with surfactant (as hydroxypropyl cellulose).Also can prepare dispersion liquid in glycerol, liquid, Polyethylene Glycol and the mixture in oil thereof.Under conventional storage and service condition, contain antiseptic in these preparations to prevent microbial growth.

The effective dose of active component used can change with the order of severity of the pattern of administration and disease to be treated.But, usually when extract of the present invention gives with the dosage of about 1-300mg/kg the weight of animals every day, gratifying effect can be obtained, preferably give with the dosage that 1-3 time is separated every day, or with sustained release forms administration.For most of large mammal, the accumulated dose of every day is about 5-1000mg, is preferably about the dosage form that 10-500mg is applicable to take orally, comprises the active component with the intimately mixed about 1-200mg of solid-state or liquid pharmaceutically acceptable carrier.This dosage of scalable is replied to provide optimal treatment.Such as, by an urgent demand for the treatment of situation, the dosage separated for thousand times if can give every day, or dosage is reduced pari passu.

Compositions of the present invention also can with other anti-diabetic or lipotropic active constituents of medicine administering drug combinations.Antidiabetic medicine can be such as (but being not limited to): insulin sensitivity enhancer, glucose absorption inhibitor, biguanide, insulin secretion enhancers, SGLT2 inhibitor, insulin or insulin analog, glucagon receptor antagonist, insulin receptor kinase agonist etc.Described anti-fatty liver medicine can be such as (but being not limited to): statins (atorvastatin, simvastatin, lovastatin, pravastatin and fluvastatin), Colestid, olbetam etc.

When two or more administered in combination, generally there is the effect due to the individually administration of two kinds of medicines.Preferably, conbined usage medicine or other preparation do not disturb the therapeutic activity of pharmaceutical composition of the present invention.

The suitable dosage of pharmaceutical composition of the present invention can with such as compound method, administration fashion, the age, the sex of body weight and patient, pathological condition, diet, administration time, administering mode, and excretion rate and the many factors to the sensitivity of reaction change.Described pharmaceutical composition contains the present composition of the effective dose as effective ingredient.By clinical administration that is oral or parenteral route, administration is carried out to the described present composition, and its can common form pharmaceutical preparation use.In other words, by multiple oral and parenteral administration, the clinical administration through reality carries out administration to compositions as described in the present invention.When preparing, traditional filler can be used, supplement, binding agent, wetting agent, disintegrating agent, the diluent of such as surfactant, or excipient carries out described preparation.Solid preparation for oral administration comprises, such as tablet, pill, powder, granule and capsule, and by with such as starch, calcium carbonate, sucrose, one or more excipient of lactose and gelatin and the present composition mixing be prepared.Except simple excipient, the lubricant of such as magnesium stearate and Talcum can also be used.As the liquid preparation of oral administration, it might also be mentioned suspension, solution for oral administration, emulsion and syrup.Except the simple diluent of normally used such as water and liquid paraffin, above-mentioned preparation also can comprise multiple excipient, such as wetting agent, sweeting agent, aromatic and antiseptic.Preparation for parenteral comprises aseptic aqueous solution, water-insoluble solvent, suspension, Emulsion, the preparation of lyophilizing and suppository.As water-insoluble solvent and suspension, can also propylene glycol be used, Polyethylene Glycol, vegetable oil, such as olive oil, injectable ester, such as ethyl oleate (ethylolate), etc.As the stock of suppository, Witepsol can be used, Polyethylene Glycol (macrogol), Tween61, cacao butter, laurin butter, glycerol and gelatin.

According to a further aspect in the invention, provide containing as the health of the prevention and therapy diabetes of the present composition of effective ingredient and complication thereof, obesity, hyperlipidemia, fatty liver and functional food composite.

The term that uses in whole description of the present invention " healthy and functional food " refers to and with the addition of the present composition to improve the food of its function in bread and cheese.The present composition can be added in bread and cheese, maybe can be prepared and claim capsule, powder, the forms such as suspension.Take in this health containing the present composition and functional food is that health provides useful effect, and its advantage is the side effect that do not show caused by the life-time service of medicine, because food material is used as raw material, instead of the medicine of routine.

The present composition can also as food additive, and these compositionss can be added individually, or together can use with other foods or food component, or suitably can use based on the method for other routines.The effective ingredient of combined amount suitably can be determined according to the object used (prevention, healthy or therapeutic treatment).Usually, when using the present composition of mixing to produce food or beverage, relative to raw-material gross weight, can the amount of 0.0001-10% weight ratio, and be preferably the amount that 1-5% measures ratio and add these derivants.But, when in order to health purpose and health or when controlling to take in for a long time in order to health, the amount of the described present composition can be adjusted to lower than described scope.In addition, when used as pharmaceutical composition, health food of the present invention is preferably containing the present composition within the toxicity range measured.

To the not specific restriction of above-mentioned food species, can be noodles, chewing gum, skimmed milk, Yoghourt, ice cream, various beverage, tea, beverage, alcoholic beverage and multivitamin goods.Especially, as the example of the health food containing the present composition, it might also be mentioned the goods of health food using the present composition as main component and special flavour, such as fruit juice, tea, fruit jelly and beverage.

When the present composition of the present invention uses as cosmetic raw materials by needs, these derivants available itself carry out adding or can using together with other components of cosmetics, or suitably can use according to other existing methods.The object that can use according to it suitably determines the combined amount of effective ingredient.Usually, in the process using present composition production cosmetic, relative to raw-material gross weight, can the amount of 0.0001-10% by weight, and the amount being preferably 0.1-5% adds these derivants.Cosmetics include, but are not limited to facial cream, cosmetic water, emulsion, and color make-up.

Beneficial effect

Applicant is found by animal experiment, pharmaceutical composition oral administration of the present invention administration can treat diabetes, and compared with the medicine of existing treatment diabetes, the pharmaceutical composition tool containing Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) that the present invention relates to has the following advantages and progress significantly:

(1) we find through experiment, though Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) drug combination are after chronic oral administration, reduce the blood glucose of diabetes rat very significantly, and in whole dosage period, blood sugar lowering is steady, not bounce-back.On the contrary, the second filial generation sulfonylurea hypoglycemic agent thing of the promoted insulin releasing used clinically is now (as glipizide, gliclazide, pioglitazone, gliquidone etc.) although the blood glucose of rat temporarily can be reduced after medication, but but after long term administration, not only can not reduce blood glucose, there is the trend raising rat blood sugar on the contrary, this disease progression of present diabetics clinically that also exactly coincide, a lot of diabeticss is after long-term taking sulfonylurea hypoglycemic agent, the difficulty of glycemic control is increasing, finally insulinize must be answered.

(2) found by cell pharmacological testing, although Radix Paeoniae and the independent medication of Cortex cinnamomi japonici (Ramulus Cinnamomi) do not promote the division growth of islet cells, increase the effect of the vigor of islet cells; But Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) drug combination can promote to increase the division growth of islet cells the vigor of islet cells, prevent the exhaustion of islet cell function in pole significantly.These all show, said composition has good prospect in diabetes long-term treatment.

(3) animal pharmacological experiment also shows that said composition can also treat diabetes and multiple complications, as: diabetic cardiomyopathy, diabetic peripheral neuropathy, diabetic retinopathy, diabetic nephropathy etc.

(4) said composition effectively can improve insulin resistant falling hypoglycemic while, there is no the shortcoming that Western medicine antidiabetic drug easily rebounds simultaneously, do not have to waste greatly when current most of Chinese medicine hypoglycemic medicine prescriptions complexity, extraction yet, the indefinite shortcoming of composition, has the advantages such as raw material is simple, cheap, quality control is easy.

(5) the component Radix Paeoniae of said composition and Cortex cinnamomi japonici (Ramulus Cinnamomi) all have very high safety, and through animal acute toxicity and long term toxicity test checking, said composition itself to laboratory animal also without overt toxicity.

(6) said composition has significant fat-reducing, reduces the effect of blood fat, is suitable for the diabetes patient that blood fat is high simultaneously.

Although once there was the correlation technique content that document is disclosed peoniflorin, cinnamic acid has hypoglycemic activity in prior art, these two kinds of compounds were not carried out the research combining and be used for diabetes and fatty liver by people.Find through the further investigation of applicant and contrast test repeatedly, the independent blood sugar lowering of these two kinds of compounds, suppress the effect of fatty liver and not obvious, blood sugar reducing function differs greatly compared with the medicine of existing treatment diabetes, do not have the value studied further as treatment Glucovance standby, this does not all have to obtain the authorization smoothly from existing Patents or the defending party to the application abandons being proven.And the pharmaceutical composition of the application and these two kinds independent compounds are essentially different, and are embodied in following several aspect:

(1) hypoglycemic activity is strong.

Applicant finds the blood sugar lowering of pharmaceutical composition of the present invention in an experiment, the activity of suppression fatty liver does not present conventional dose-effect relationship, but present beyond thought synergism, and now pharmacologically active greatly exceed compound independent time activity, wherein hypoglycemic activity reaches the close effect of the rosiglitazone of one of the marketed drug strong with existing hypoglycemic activity; Even also greatly be better than the hypoglycemic effect of rosiglitazone when specified weight ratio range, meet or exceed the GTT level of high fat diet group mice, close to the different blood glucose levels of normal mouse; Possesses the value studied further as the standby for the treatment of Glucovance.

(2) effect of diabetes-alleviating complication is strong.

In the treatment of diabetes, a very important aspect to the control of diabetic complication while blood sugar lowering, directly affect the life quality of patient and the selection of medicine, therefore screen and at blood sugar lowering, there is the good medicine controlling diabetic complication simultaneously and paid much attention to always.Applicant finds that pharmaceutical composition of the present invention can in the symptom improving multiple diabetic complication in an experiment, particularly improve the fatty liver aspect of model mouse, be better than rosiglitazone, show at the mouse liver hierarchical model of aforementioned pharmaceutical compositions experimental group, the cell of hepatocyte tissue is complete, edge clear, arrangement are tight, bright-colored, do not have lipochondrion to precipitate in cell tissue, and the form of hepatocyte tissue reaches the level of healthy mice.

(3) toxicity is little, side effect is little, safety of taking medicine.

The toxic and side effects of medicine is the large problem in medicament research and development, many new drugs had good prospects research and develop failure owing to finding serious toxic and side effects in clinical course, even in the medicine gone on the market, there is also day by day increasing in recent years of serious toxic and side effects Er Beiche city, therefore, while guarantee curative effect, also toxic and side effects to be reduced as much as possible.According to prior art, the toxic and side effects of peoniflorin, cinnamic acid is all very little, Radix Paeoniae Alba total glycosides is the domestic a kind of medicine gone on the market for many years, Clinical practice is safe and reliable, cinnamic acid is a kind of additive of conventional use in food service industry, its toxicity is also very little, China adds consumption to it to it and does not limit in food, it is also little that European Union and the U.S. add consumption restriction to it to it in food, and, through animal acute toxicity and long term toxicity test checking, the compositions of these two kinds of compounds to laboratory animal also without overt toxicity.

(4) supply of goods is sufficient, and follow-up research and development are easy.

Peoniflorin, the cinnamic acid content in medical material is high, and their extraction process is all very ripe, and on market, the supply of goods is sufficient, stable, and raw materials for production can be secure.Said composition definite ingredients, both studies of pharmacy have a lot of previous work, and when carrying out follow-up research and development, clinical, pharmaceutics etc. is studied all can than being easier to.

(5) there is a strong possibility exists hypoglycemic new role mechanism.

In a series of pharmacological evaluation said composition done as can be seen from applicant, blood sugar lowering mode and the present clinical hypoglycemic drug of said composition have diverse mode, present blood glucose first slight rising, then dropping to close to normal mouse blood sugar level; And be different from existing medicine and descend blood sugar lowering always, be then stabilized in the mode of certain level (still more higher than normal mouse blood sugar level); And do not rebound after the blood sugar reducing function drug withdrawal of said composition, the situation that after this is different from the drug withdrawal of existing orally-taken blood sugar reducing medicine, blood glucose easily rebounds; Especially the composition of said composition divides other hypoglycemic activity and not obvious, and has occurred significant hypoglycemic activity after combining; These all show the said composition feature different from present clinical hypoglycemic drug, and current blood sugar lowering mechanism cannot explain above-mentioned phenomenon, needs further to further investigate its mechanism.And new hypoglycemic mechanism or target spot, bring new direction by for the treatment of diabetes and research, have great meaning.

Accompanying drawing explanation

Fig. 1 loses weight when being each group of mice administration 28 days of experimental example 10 comparison diagram of %.

The abbreviation of each experimental group wherein in Fig. 1 refers to table 1, in following each figure, these abbreviation representated by implication identical.

GTT comparison diagram when Fig. 2 is each group of mice administration 14 days of experimental example 10.

GTT comparison diagram when Fig. 3 is each group of mice administration 28 days of experimental example 10.

Fig. 4 is the slice map of CTL group mice at 28 days liver organizations of experimental example 11.

Fig. 5 is the slice map of HFD group mice at 28 days liver organizations of experimental example 11.

Fig. 6 is the slice map of HFD+STZ group mice at 28 days liver organizations of experimental example 11.

Fig. 7 is the slice map of Rg group mice at 28 days liver organizations of experimental example 11.

Fig. 8 is the slice map of Rg+CA3 group mice at 28 days liver organizations of experimental example 11.

Fig. 9 is the slice map of PF+CA group mice at 28 days liver organizations of experimental example 11.

Figure 10 is the slice map of PF+CA3 group mice at 28 days liver organizations of experimental example 11.

Detailed description of the invention:

Experiment material and instrument

1) materials such as the reagent in following examples and experimental example and originate as follows.

Peoniflorin (95%, HPLC, reagent abbreviation PF), Radix Paeoniae Alba extract (containing peoniflorin 60%, reagent abbreviation PE) to come biological engineering company limited purchased from Xi'an.Cinnamic acid (analytical pure, reagent abbreviation Cinna) is purchased from Bo Di chemical inc, Tianjin.Rosiglitazone maleate (reagent abbreviation Rg) is purchased from GlaxoSmithKline PLC company.Glucose (analytical pure, reagent abbreviation Glu) is purchased from Beijing chemical reagents corporation.The Radix Paeoniae Alba, Radix Paeoniae Rubra, Cortex Cinnamomi, Ramulus Cinnamomi are purchased from Nanjing first sign pharmacy.

2) instrument used in following experimental example is as follows:

Blood glucose meter (Roche) and blood sugar test paper (Roche).

3) animal in following experimental example and source as follows:

Cleaning grade C57BL6 mice, body weight 18-22g, is divided into 9 groups, often organizes 10, is provided by southern large model Institute of Botany.Raise with normal diet for 1 group.1 group with fed with high.All the other 7 groups with fed with high, and continuous 5 days lumbar injection streptozotocin (STZ) induce modeling, result shows, raise after 3 months, model group mice increases significantly than the body weight of the mice of normal diet raising group, and there is obvious insulin resistant, may be used for simulating the obesity that causes of high fat diet and type 2 diabetes mellitus.

* animal feeding condition SPF cleaning grade.

4), after experimental data single factor test variance is analyzed, add up with SPSS software.* P < 0.05 is regarded as having significant difference.

Embodiment 1:

Take Radix Paeoniae Alba 100g, Ramulus Cinnamomi 10g by quality proportioning, the Radix Paeoniae Alba is mixed with Ramulus Cinnamomi, add 60% ethanol (solid-liquid ratio is 1: 15), soak 24 hours under room temperature; Circumfluence method extracts (temperature 65 DEG C is extracted 2 times, each 4 hours); Decompress filter; Merging filtrate, Rotary Evaporators transpiring moisture, concentrates and makes extractum.

Embodiment 2:

Radix Paeoniae Alba 100g, Cortex Cinnamomi 30g is taken by quality proportioning.

Radix Paeoniae Rubra extract is prepared from as follows: get totally and the Radix Paeoniae Rubra of drying, pulverize, add in 60%-80% (v/v) ethanol of 8-12 times of weight, 65-75 DEG C of insulation is extracted 1-3 time, each 2-4h, merge extractive liquid, filters, filtrate is through decompression and solvent recovery, and vacuum concentration becomes Radix Paeoniae Rubra crude extract; Gained Radix Paeoniae Rubra crude extract is added in 60%-80% (v/v) ethanol of 18-25 times of weight and dissolve, pH=5.5-6.5 is regulated with sodium hydroxide solution, the HPD-300 macroporous adsorbent resin of polystyrene backbone is adopted to adsorb solution, be adsorbed to saturated after, first use water suck up impurity to Molish reaction negative, again with 60%-80% (v/v) ethanol of 8-13 times of amount of resin, with 1-5 times of amount of resin/hour flow velocity eluting, reclaim eluent, concentrated, drying, obtains Radix Paeoniae Rubra extract, for subsequent use.

Cortex Cinnamomi extract is made as follows: add 30% ethanol (solid-liquid ratio is 1: 8), and circumfluence method extracts (temperature 70 C extracts 3 times, each 2 hours); Decompress filter; Merging filtrate, Rotary Evaporators transpiring moisture, concentrates and makes extractum, obtain Cortex Cinnamomi extract, for subsequent use.

The Radix Paeoniae Rubra extract prepared and Cortex Cinnamomi extract are mixed, obtains the extract of pharmaceutical composition of the present invention.

Embodiment 3:

The Radix Paeoniae Alba 100 grams, Ramulus Cinnamomi 50 grams,

Get the Radix Paeoniae Alba and be ground into coarse powder, add 75% alcohol reflux three times, first and second time each 2 hours, 1 hour third time, merge extractive liquid, 50 DEG C are evaporated to about 400ml, with n-butanol extraction three times, each 300ml, merges n-butanol extracting liquid, be evaporated to without n-butyl alcohol taste, add water 200ml, heating for dissolving, filter, filtrate spraying dry, obtains Radix Paeoniae Alba extract, for subsequent use:

Get Ramulus Cinnamomi and be ground into coarse powder, then use 5 times to the heavy water boil of raw material 3 hours, boiling liquid is leached; Add 4 times again to the water that raw material is heavy, filtering residue to be continued to boil 2 hours; Boiling liquid is leached, then adds 3 times and to the water that raw material is heavy, filtering residue is continued to boil 2 hours, filter, obtain filtrate.Three gained filtrates merged, 70 DEG C concentrate, obtain concentrated solution, merge three concentrated solutions, Rotary Evaporators transpiring moisture, concentrate and make extractum, obtain Ramulus Cinnamomi extract, for subsequent use.

The Radix Paeoniae Alba extract prepared and Ramulus Cinnamomi extract are mixed, obtains the extract of pharmaceutical composition of the present invention.

Pharmaceutics is tested

Embodiment 4: produce the tablet containing following component in a conventional manner

Embodiment 5: produce the capsule containing following component in a conventional manner

Embodiment 6: produce the watered pill containing following component in a conventional manner

Embodiment 7: extract of the present invention is applied to cosmetic emulsion

Embodiment 8: extract of the present invention is applied in orange juice

Embodiment 9 makes capsule

Get Radix Paeoniae Alba extract (containing peoniflorin 60%) 75g, cinnamic acid 4g, starch 150g respectively, make 1000 hard capsules with hard capsule routine fashion.

Embodiment 10 makes tablet

Get peoniflorin 100g, cinnamic acid 3g, starch 150g, 10% starch slurry 12g, dried starch 12g, magnesium stearate 1.5g respectively, make 1000 with tablet customary preparation methods.

Embodiment 11 makes granule

Get peoniflorin 120g, cinnamic acid 1.5g, starch 180g, 10% starch slurry 20g respectively, make granule with granule customary preparation methods.

Embodiment 12 makes soft capsule

Technique: get cinnamic acid and peoniflorin, add cod-liver oil or refining of edible vegetable oil (sloughing hard fat at about 0 DEG C), dissolve, and adjust concentration to every ball containing cinnamic acid be 90% ~ 120% of labelled amount, more than 90% ~ 120% of labelled amount is should be containing peoniflorin, stand-by as medicinal liquid; Separately get glycerol and water is heated to 70 DEG C ~ 80 DEG C, add gelatin, stirring is dissolved, and is incubated 1 ~ 2 hour, the foam that removing is floated, filter, adding pill dripping machine dripping, take liquid paraffin as liquid coolant, collect the soft gelatin capsule of condensation, wipe the liquid coolant of sticking with gauze away, at room temperature blow a cold wind over 4 hours, dry 4 hours at being put in 25 ~ 35 DEG C, again through petroleum ether twice (each 3 ~ 5min), removing soft gelatin capsule outer layer liquid paraffin, then use 95% washing with alcohol once, finally dry about 2 hours at 30 ~ 35 DEG C, screening, quality inspection, packaging, to obtain final product.

Pharmacological experiment

Embodiment 1: pharmaceutical composition of the present invention is on the impact of islet cells vigor

Take out raw 1 ~ 3d SD rat, routine disinfection, cuts open the belly and exposes visual area, aseptic taking-up pancreas, through 4 DEG C of Hanks liquid rinsing 2 ~ 3 times after the outer nethike embrane of removing pancreas, fatty tissue.With eye scissors, pancreas is cut into 0.5mm3 size tissue pieces, after Hanks liquid rinsing 3 times, add 5 times of volume 3g/LV Collagenase Types (pH7.4) mixings, vibrate in 37 DEG C of water-baths digestion 6 ~ 8min.Time muddy to Digestive system, draw upper strata after natural sedimentation and digest turbid liquid, stop digestion with 4 DEG C of Hanks liquid.Residue does not digest tissue and adds Digestive system continuation digestion.Repeat 4-5 time, until pancreatic tissue digests complete substantially by aforesaid operations.Collect each the centrifugal 5-7min of the turbid liquid 1000r/min of digestion, sedimentation cell is inoculated in the T75 bottle of the PRMI1640 culture fluid including 15% hyclone, and cell moves to 37 DEG C, 5%CO ₂cultivate in the CO2 incubator of the complete humidifying of 95% air.Observation of cell growth conditions during cell culture 18 h.When cell is bright, refractivity is strong, culture fluid lighter time, indicator cells well-grown.

The cell of 96 well culture plates is divided into vehicle group, Radix Paeoniae group, Cortex cinnamomi japonici (Ramulus Cinnamomi) group, drug combination group.According to cell attachment speed difference, cell is blown down gently at the bottom of bottle, low-speed centrifugal, sedimentation cell adds new culture fluid, be inoculated in 96 well culture plates (every hole 200 μ L) with 2 × 104/ml, add after 2d not containing the culture medium culturing 24h of hyclone, then change culture fluid, often group is except the PRMI1640 culture fluid containing 16.7mmol/L glucose, 15% hyclone, as follows respectively containing other medicines in addition:

(1) vehicle group: do not add any medicine;

(2) Radix Paeoniae group: the Radix Paeoniae Rubra extract of 50mg/L embodiment 2;

(3) Cortex cinnamomi japonici (Ramulus Cinnamomi) group: the Cortex Cinnamomi extract of 15mg/L embodiment 3;

(4) drug combination group low dose group: the Cortex Cinnamomi extract of the Radix Paeoniae Rubra extract+7.5mg/L embodiment 2 of 25mg/L embodiment 2;

(5) dosage group in drug combination group: the Cortex Cinnamomi extract of the Radix Paeoniae Rubra extract+15mg/L embodiment 2 of 50mg/L embodiment 2;

(6) drug combination group high dose group: the Cortex Cinnamomi extract of the Radix Paeoniae Rubra extract+30mg/L embodiment 2 of 100mg/L embodiment 2.

Every 2d changes liquid 1 time (culture fluid is prepared respectively by above-mentioned each component), detects level of insulin secretion in original fluid when changing liquid with radioimmunology at every turn.

Result of the test shows, and in the whole incubation of islet cells, drug combination group is compared with vehicle group, and at first 2 days of islet cell culture, the vigor of cell uelralante was as broad as long.But along with the prolongation of time, drug combination group has significant difference (P < 0.05 or P < 0.01) compared with vehicle group; Behind 6 days of islet cell culture, the middle and high dosage group of drug combination also has significant difference (P < 0.05 or P < 0.01) compared with Cortex cinnamomi japonici (Ramulus Cinnamomi) group or Radix Paeoniae group.This illustrates, As time goes on the islet cells vigor of vehicle group and single medicine group and the function of uelralante in decline, may be that the exhaustion of function has appearred in islet cells; Along with the decline of cell viability appears in the prolongation of incubation time the cell that the cell of drug combination group does not resemble vehicle group or single medicine group, but remain good cell viability at 10 days in incubation always.This result points out us, and Cortex cinnamomi japonici (Ramulus Cinnamomi) and Radix Paeoniae drug combination are clinically after life-time service, and for the exhaustion preventing patient's islet cell function, function and the vigor of effective protection patient islet cells will have good effect.This result also imply that simultaneously, and long-term taking contains the medicine of Cortex cinnamomi japonici (Ramulus Cinnamomi) and Radix Paeoniae, and diabetics can be made well to be fully recovered.

Embodiment 2: pharmaceutical composition of the present invention is on the impact of diabetes rat model

Healthy SD rat 80,8 rats are normally raised in contrast in random taking-up, all the other 72 rats can't help water 12 hours in test fasting evening before that day, lumbar injection 1%STZ the next morning (30mg/kg), lumbar injection STZ (30mg/kg) again after 3 days, after 72h, fasting 5h surveys blood glucose, picks out the unsuccessful person of modeling.

Modeling success rat is divided into model group according to blood sugar level, metformin group, Radix Paeoniae group, Cortex cinnamomi japonici (Ramulus Cinnamomi) group, drug combination group low dose group, dosage group in drug combination group, drug combination group high dose group at random, often organizes 8.The body weight of weighed each group of rat.Often organize and give corresponding medicine respectively, continuous gavage 4 weeks, the body weight of weighed each group of rat after fasting 12h the morning, and measure blood glucose.Each group gastric infusion is as follows respectively:

(1) matched group: healthy rat, the normal saline of same volume;

(2) model group: the normal saline of same volume;

(3) metformin group: 200mg/kg/d metformin;

(4) Radix Paeoniae group: the Radix Paeoniae Alba extract of 200mg/kg/d embodiment 3;

(5) Cortex cinnamomi japonici (Ramulus Cinnamomi) group: the Ramulus Cinnamomi extract of 100mg/kg/d embodiment 3;

(6) drug combination low dose group: the Ramulus Cinnamomi extract of Radix Paeoniae Alba extract+25mg/ (kg.d) embodiment 3 of 50mg/kg/d embodiment 3;

(7) dosage group in drug combination: the Ramulus Cinnamomi extract of Radix Paeoniae Alba extract+50mg/ (kg.d) embodiment 3 of 100mg/kg/d embodiment 3;

(8) drug combination high dose group: the Ramulus Cinnamomi extract of Radix Paeoniae Alba extract+100mg/ (kg.d) embodiment 3 of 200mg/kg/d embodiment 3.

After modeling success rat random packet, according to dosage gastric infusion, continuous 4 weeks, normally raises.All rats were got tail vein respectively at after administration 1 week, 2 weeks, 3 weeks, 4 weeks and detect fasting glucose (FBG), the results are shown in Table 1.

Table 1 respectively organizes medicine to the impact (mmol/L) of diabetes rat fasting glucose

Compare with model group, ^*p < 0.05; Compare with model group, ^*p < 0.01

Experimental result: as can be seen from Table 1, the blood sugar level impact of Radix Paeoniae group on diabetes rat is not obvious.Cortex cinnamomi japonici (Ramulus Cinnamomi) group effectively improves carbohydrate tolerance after short-term administration, but but after long term administration, does not only reduce blood glucose significantly, has the trend of raise blood sugar on the contrary.And drug combination group is compared with model group, Radix Paeoniae group, Cortex cinnamomi japonici (Ramulus Cinnamomi) group, administration showed pole significant difference after 4 weeks.This shows that Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) drug combination are after chronic oral administration, reduce the blood glucose of diabetes rat very significantly, and in whole dosage period, blood sugar lowering is steady, not bounce-back.Cure prospect from the long term of diabetics, pharmaceutical composition of the present invention steadily can reduce blood sugar level, is better than the Western medicine such as euglycemic agent.The Pharmacodynamics research of Pharmaceutical composition of the present invention confirms that it has blood sugar reducing function.

Experimental example 3: pharmaceutical composition of the present invention is on the impact of hyperlipemia rat

SD rat, male, 80, body weight 120 ~ 160g (Nanjing University's animal center).First be divided into blank group (10) and high lipid food group (70), blank group normal diet, high lipid food group is to high lipid food (high lipid food formula: 2.0% cholesterol, 0.2% propylthiouracil, 0.3% sodium cholate, 7.5% Adeps Sus domestica, 2..0% egg yolk, 88.0% normal feedstuff), continuous nursing 21d, get blood, separation of serum, measures the content (before getting blood, water 14h is can't help in fasting) of cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, LDL and free fatty in high lipid food group rat blood serum.Choose the rat that blood fat is higher, according to blood lipid level, 7 groups are divided into again to high lipid food group, that is: model group, lovastatin group, Radix Paeoniae group, Cortex cinnamomi japonici (Ramulus Cinnamomi) group, drug combination (pharmaceutical composition of the present invention of embodiment 1) basic, normal, high dosage group, often organize 10, gastric infusion, once a day, continuous 28d.

Each group gastric infusion is as follows respectively:

(1) matched group: healthy rat, the normal saline of same volume;

(2) model group: the normal saline of same volume;

(3) lovastatin group: 30mg/kg/d lovastatin, 0.5% sodium carboxymethyl cellulose is made into suspension;

(4) Radix Paeoniae group: the Radix Paeoniae Alba extract of 200mg/kg/d embodiment 1;

(5) Cortex cinnamomi japonici (Ramulus Cinnamomi) group: the Ramulus Cinnamomi extract of 100mg/kg/d embodiment 1;

(6) drug combination low dose group: the Ramulus Cinnamomi extract of Radix Paeoniae Alba extract+25mg/ (kg.d) embodiment 3 of 50mg/kg/d embodiment 1;

(7) dosage group in drug combination: the Ramulus Cinnamomi extract of Radix Paeoniae Alba extract+50mg/ (kg.d) embodiment 3 of 100mg/kg/d embodiment 1;

(8) drug combination high dose group: the Ramulus Cinnamomi extract of Radix Paeoniae Alba extract+100mg/ (kg.d) embodiment 1 of 200mg/kg/d embodiment 1.

After modeling success rat random packet, according to dosage gastric infusion, continuous 4 weeks, normally raises.All rats were weighed respectively at after administration 1 week, 2 weeks, 3 weeks, 4 weeks, and got tail vein detection TC, TG, HDL-c, LDL-c, FFA, the results are shown in Table 2,3.

Table 2 respectively organizes medicine to the impact (g) of hyperlipemia rat body weight

Compare with model group, ^*p < 0.05, ^*p < 0.01.

Table 3 respectively organizes medicine to the impact (mmol/L) of hyperlipemia rat blood fat

Compare with blank group, ^△p < 0.05, ^{△ △}p < 0.01; Compare with model group, ^*p < 0.05, ^*p < 0.01.

Compare with blank group, model group TC and LDL-c significantly raises, p < 0.01, illustrates that blood lipid metabolism is disorderly, hyperlipemia model modeling success; Compare with model group, positive drug can reduce hyperlipemia rat serum TC, TG, LDL-c level, p < 0.05 or p < 0.01, the middle and high dosage group of pharmaceutical composition of the present invention can reduce hyperlipemia rat serum TC, TG, LDL-c and FFA level, p < 0.05 or p < 0.01.

The Pharmacodynamics research of Pharmaceutical composition of the present invention confirms that it has the effect of fat-reducing, blood fat reducing.

In addition, inventor is investigated the effect of pharmaceutical composition of the present invention to diabetic cardiomyopathy, diabetic peripheral neuropathy, diabetic ophthalmopathy, diabetic nephropathy, finds that pharmaceutical composition of the present invention has these diabetic complications and has obvious preventive and therapeutic effect.

Experimental example 4: heighten sugar under pharmaceutical composition of the present invention and cultivate Cardiac Fibroblasts transforming growth factor-beta 1 (TGF-β 1) expression

Be separated 1 ~ 3d SD Neonatal myocardial fibroblast also to cultivate, for experiment when being passaged to the second filial generation.All cells is divided into 5 groups, with normal glucose DMEM culture medium for contrast, all the other organize in DMEM culture medium, add normal dose and high dose respectively glucose, Radix Paeoniae Alba extract, Cortex Cinnamomi extract or compositions, and consumption is in table 2.Each group of cell all stimulates 24h, and with trypsinization, extracted total RNA, reverse transcription cDNA, with reverse transcription cDNA for template amplification respectively organizes cell I type, type III collagen mrna.

I type, the type III collagen mrna expression ratio I group of the experimental result display II group of table 4 significantly raise, the decline more remarkable in high sugar group of III group, and than IV group or the effect of V group more obviously, namely Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) extract conbined usage more effective.

Heighten sugar under the compositions of table 4 Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) extract and cultivate Cardiac Fibroblasts transforming growth factor-beta 1 (TGF-β 1) expression

Experimental example 5: pharmaceutical composition of the present invention reduces Ca2+ overload effect in Leonurus heterophyllus sweet rat myocardial cell

The myocardial cell Ca2+ overload of diabetic cardiomyopathy is the impaired immediate cause of myocardial function.

Copy diabetic cardiomyopathy rat model: healthy SD rat, random selecting 10 is only as Normal group (I), and all the other are model group.Model group adopts lumbar injection streptozotocin (STZ, use citric acid-sodium citrate buffer, pH4.2) method brings out rat diabetes, and injection formed type 2 diabetes mellitus model after 5 weeks continuously, feeds after 10 weeks and forms Leonurus heterophyllus sweet model.Normal group is lumbar injection citric acid-sodium citrate buffer only.

Successful for modeling rat is divided into 4 groups at random, be respectively diabetic cardiomyopathy model group (II), medicine composite for curing group (III) of the present invention, Radix Paeoniae Alba extract treatment group (IV), Cortex cinnamomi japonici (Ramulus Cinnamomi) extract treatment group (V).

After treating 4 weeks, adopt Ca2+ fluorescence indicator Fura-2, measure the fluorescent value of excitation wavelength 340/380nm, with calcium concentration in F340/F380 ratio reflection rat myocardial cell.

Table 5 experimental result shows, and pharmaceutical composition of the present invention can reduce Ca2+ overload effect in Leonurus heterophyllus sweet rat myocardial cell, than both alone better effects if.

Table 5 pharmaceutical composition of the present invention reduces Ca2+ overload effect in type 2 diabetes mellitus cardiomyopathy rat myocardial cell

Experimental example 6: pharmaceutical composition of the present invention is to the therapeutical effect of rat diabetes peripheral neuropathy

It is a reliable index of diabetic peripheral neuropathy that peripheral ner ve conduction velocity (NVC) slows down.The detection of motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV) has important value to early diagnosis, and the therapeutic effect of diabetic peripheral neuropathy depends on early diagnosis.

Set up Diabetic Peripheral Neuropathy In Rats model: healthy SD rat, random selecting 10 is only as Normal group (I), and all the other are model group.Model group adopts lumbar injection streptozotocin (STZ, use citric acid-sodium citrate buffer, pH4.2) method brings out rat diabetes, and injection formed type 2 diabetes mellitus model after 5 weeks continuously, feeds after 8 weeks and forms diabetic peripheral neuropathy model.Normal group is lumbar injection citric acid-sodium citrate buffer only.

Successful for modeling rat is divided into 4 groups at random, is respectively diabetic peripheral neuropathy model group (II), medicine composite for curing group of the present invention (III), Radix Paeoniae Alba extract treatment group (IV) and Cortex cinnamomi japonici (Ramulus Cinnamomi) extract treatment group (V).After treating 4 weeks, electrode method of thrusting is adopted to measure Electroneuromyography.

Table 6 experimental result shows, and pharmaceutical composition of the present invention can accelerate the nerve conduction velocity of diabetic neuropathy rat, than both alone better effects if.

Table 6 pharmaceutical composition of the present invention is on the impact of diabetic neuropathy rat conduction velocity

Experimental example 7. pharmaceutical composition of the present invention is to the protective effect of rat diabetes oculopathy

Set up diabetic eye disease model: healthy SD rat, random selecting 10 is only as Normal group (I), and all the other are model group.Model group adopts the method for lumbar injection streptozotocin (STZ uses citric acid-sodium citrate buffer, pH4.2) to bring out rat diabetes, and injection formed type 2 diabetes mellitus model after 5 weeks continuously, feeds after 12 weeks and forms diabetic eye disease model.Normal group is lumbar injection citric acid-sodium citrate buffer only.

Successful for modeling rat is divided into 4 groups at random, is respectively diabetic ophthalmopathy model group (II), medicine composite for curing group of the present invention (III), Radix Paeoniae Alba extract treatment group (IV) and Cortex cinnamomi japonici (Ramulus Cinnamomi) extract treatment group (V).After treating 4 weeks, detect the expression of rat microvessel density and VEGF and TPA.

Table 7 experimental result shows that pharmaceutical composition of the present invention has good protective effect to type 2 diabetes mellitus rat oculopathy, more effective than being used alone.

Table 7 pharmaceutical composition of the present invention is to the protective effect of type 2 diabetes mellitus rat oculopathy

Experimental example 8. pharmaceutical composition of the present invention is to the therapeutical effect of pharmaceutical composition to Diabetic Nephropathy

Set up diabetic nephropathy model: healthy SD rat, random selecting 10 is only as Normal group (I), and all the other are model group.Model group adopts lumbar injection streptozotocin (STZ, use citric acid-sodium citrate buffer, pH4.2) method brings out rat diabetes, and injection formed type 2 diabetes mellitus model after 5 weeks continuously, feeds after 12 weeks and forms diabetic nephropathy varying model.Normal group is lumbar injection citric acid-sodium citrate buffer only.

Successful for modeling rat is divided into 4 groups at random, is respectively diabetic nephropathy model group (II), medicine composite for curing group of the present invention (III), Radix Paeoniae Alba extract treatment group (IV) and Cortex cinnamomi japonici (Ramulus Cinnamomi) extract treatment group (V).After treating 4 weeks, get 24h urine specimen and measure urine protein, retroorbital venous clump gets hematometry serum creatinine, blood urea nitrogen (water 12h is can't help in fasting) simultaneously.

The renal function of table 8 experimental result pharmaceutical composition of the present invention to type 2 diabetes mellitus rat has a better role, better than independent effect.

Table 8 pharmaceutical composition of the present invention is to the therapeutical effect of type 2 diabetes mellitus adriamycin-induced nephropathy in Wistar rats

The preparation of experimental example 9 gavage solution

The administration solution composition that in the carbohydrate tolerance experiment of mice, each group gavage is used is specifically as shown in table 9, and 4-7 group all uses distilled water as solvent, and solution concentration is according to the standard preparation of mouse stomach amount 0.2ml/10g.

Table 9 divides into groups and administration condition

Group	Abbreviation	Mice	Every day gastric infusion
				1	CTL	Healthy Mus	Distilled water
2	HFD	High fat diet Mus	Distilled water
				3	HFD+STZ	Model mouse	Distilled water
4	PF	Model mouse	Peoniflorin 100mg/kg
				5	CA	Model mouse	Cinnamic acid 6mg/kg
6	Rg	Model mouse	Rosiglitazone 5mg/kg
				7	Rg+CA3	Model mouse	Rosiglitazone 5mg/kg+ cinnamic acid 3mg/kg
8	PF+CA	Model mouse	Peoniflorin 100mg/kg+ cinnamic acid 6mg/kg

9

PF+CA3

Model mouse

Peoniflorin 100mg/kg+ cinnamic acid 3mg/kg

Carbohydrate tolerance test (GTT) experiment of experimental example 10 mice

Mice overnight starvation carries out carbohydrate tolerance test experiment after (16 hours).Every mouse peritoneal injectable dextrose monohydrate (1g/kg), 0min after injection, 15min, 30min, 60min, 90min, 120min measure the blood glucose value of each group of mice.By blood glucose meter and the blood sugar test paper mensuration of Roche.

Above-mentioned 9 groups of mouse stomaches are given according to the dosage of experimental example 9, determine the change of diabetic mice body weight, blood glucose and the carbohydrate tolerance of after pharmaceutical intervention the 14th day, the 28th day, concrete data are in table 10, table 11 and table 12, and the chart of related data is shown in Fig. 1, Fig. 2 and Fig. 3.

After table 10 pharmaceutical intervention, the diabetic mice body weight of the 14th day, 28 days changes (body weight unit: g)

Group	Grouping	0 day body weight	28 days body weight	28 days body weight range of decrease %
					1	CTL	25.93±0.33	26.83±0.32	-3.47％
2	HFD	29.38±3.26	28.08±4.2	4.42％
					3	HFD+STZ	30.76±2.44	29.5±4.48	4.10％
4	PF	28.31±1.36	26.82±2.75	5.25％
					5	CA	26.8±3.07	24.81±1.67	7.41％
6	Rg	28.2±1.19	26.67±1.21	5.43％
					7	Rg+CA3	29.175±1.93	26.425±2.45	9.43％
8	PF+CA	27.6±1.36	28.5±0.95	-3.26％
					9	PF+CA3	29.18±2.09	28.14±1.29	3.56％

Except healthy mice group and peoniflorin+cinnamic acid (PF+CA) group, other 7 groups of mices are 28 days time, alleviating in various degree has all been there is than body weight during on-test, wherein rosiglitazone+cinnamic acid group (Rg+CA3) loses weight at most, is then cinnamic acid group (CA), rosiglitazone group (Rg), peoniflorin group (PF), peoniflorin+cinnamic acid 3 groups (PF+CA3), high fat diet group (HFD), placebo group (HFD+STZ) successively.As can be seen from above-mentioned data, rosiglitazone and cinnamic acid have synergism on losing weight, and peoniflorin and cinnamic acid are not having synergism on losing weight.

The change (blood glucose unit: mmol/L) of diabetic mice carbohydrate tolerance (GTT) of the 14th day after table 11 pharmaceutical intervention

Grouping

0min

15min

30min

60min

90min

120min

CTL

4.68±0.46

11.6±1.35

9.46±1.60

8.24±1.71

7.98±1.57

6.72±1.36

HFD

4.6±0.89

17.33±2.49

13.85±2.21

10.18±1.73

7.68±1.65

6.8±1.61

HFD+STZ

5.7±0.59

26.47±3.12

27.13±3.87

25.9±2.41

20.47±2.89

17.1±2.27

PF

5.68±0.43

25.15±2.82

24.43±1.44

22.95±1.03

19.77±1.64

18.13±1.92

CA

6.12±0.78

24.23±1.67

25.2±2.26

22.6±2.33

18.32±0.88

16.3±1.17

Rg

4.83±0.60

23.63±12.38

22.67±3.06

22.3±1.75

15.2±0.94

11.9±1.27

Rg+CA3

6.82±0.81

23.48±1.45

29.12±2.04

27.1±2.81

21.5±1.57

17.95±2.75

PF+CA

9.77±1.23

27.23±3.98

31.73±2.15

30.33±4.33

25.23±2.41

23.33±1.93

PF+CA3

5.84±0.93

29.08±2.47

31.14±3.57

27.54±3.06

22.44±1.63

19.56±1.97

The change (blood glucose unit: mmol/L) of diabetic mice carbohydrate tolerance (GTT) of the 28th day after table 12 pharmaceutical intervention

Grouping

omin

15min

30min

60min

90min

120min

CTL

3.93±0.79

10.45±0.33

10.60±1.41

8.88±1.89

8.32±1.45

7.06±0.67

HFD

3.75±0.47

20.42±3.72

16.38±3.42

11.23±2.54

8.42±0.97

7.88±11.04

HFD+STZ

8.03±1.23

27.93±11.59

27.57±2.62

26.43±2.59

21.7±11.98

19.32±2.33

PF

6.03±0.67

26.03±1.68

25.87±2.44

24.18±3.17

20.84±11.53

20.14±2.71

CA

6.72±0.59

23.12±2.77

24.05±1.54

211.83±3.29

18.37±11.53

17.4±0.86

Rg

5.37±0.78

18.83±2.74

18.73±1.55

15.07±1.59

12.6±0.96

110.23±0.75

Rg+CA3

6.50±1.14

20.70±2.05

21.17±2.36

16.83±2.34

113.47±11.84

110.83±11.27

PF+CA

4.75±0.55

15.71±1.95

17.85±1.83

116.25±1.39

13.78±0.67

111.68±1.33

PF+CA3

4.47±0.63

14.90±1.69

15.93±2.27

11.63±1.33

9.08±0.92

8.37±0.75

From above-mentioned data, known healthy mice (CTL), high fat diet group (HFD), this GTT of three groups of placebo group (HFD+STZ) do not have significant change when 14 days and 28 days.Slightly reduction when peoniflorin group (PF) and the GTT of cinnamic acid group (CA) these two groups 28 days time were than 14 days, change is little, this GTT of two groups is just lower than placebo group (HFD+STZ), and gap is still very large compared with the GTT of rosiglitazone group (Rg).14 days time, by the comparison of GTT, rosiglitazone group (Rg) be 6 give best with effect in medicine group, be better than placebo group (HFD+STZ), only higher than healthy mice (CTL), high fat diet group (HFD).14 days time, data after rosiglitazone+cinnamic acid group (Rg+CA3) 30min are not as good as placebo group (HFD+STZ), 28 days time, although the GTT of this group is greatly improved, but still less than rosiglitazone group (Rg), this illustrates between rosiglitazone, cinnamic acid on blood sugar lowering, not synergistic effect, cooperative effect.

By analyzing above-mentioned 9 groups of mices GTT data of 14 days, 28 days, applicant has found that beyond thought phenomenon has appearred in the GTT data of peoniflorin+cinnamic acid group (PF+CA) and peoniflorin+cinnamic acid 3 groups (PF+CA3).Although these two groups 14 days time GTT level even also higher than placebo group (HFD+STZ), but there occurs 28 days time and significantly decline, the GTT level of PF+CA group is close to Rg group, it is minimum that PF+CA3 group to become in all groups overall blood sugar level except healthy mice, not only be better than rosiglitazone, also lower than HFD group before 60min, according to blood sugar level during trend 60-120min should also with HFD group closely, and integrated curved trend is consistent with healthy mice; And they are also far superior to both superpositions separately to the GTT improvement level of model mouse to the GTT improvement level of model mouse.This all illustrates, peoniflorin, cinnamic acid two kinds of compounds between there is beyond thought strong cooperative effect on blood sugar lowering.

The liver section of experimental example 11 experiment mice

The mice of experimental example 10 was put to death 28 days time, and get liver organization and cut into slices, the experimental result wherein organizing 1,2,3,6,7,8,9 is shown in Fig. 4-10.Hepatocyte section result display: the hepatocyte tissue of healthy mice group, HFD group and PF+CA3 group in the best state: cell is complete, edge clear, arrangement are tight, bright-colored, do not have lipochondrion to precipitate in cell tissue; Next be Rg group, PF+CA group hepatocyte structural state secondly: cell is complete, edge is more clear, and sporadically appear a small amount of fat vacuole; Third, cell is complete, edge is more clear for the hepatocyte structural state of Rg+CA3 group, the lipochondrion precipitation sporadically appearing a small amount of; HFD+STZ group is the poorest: iuntercellular has a large amount of lipochondrion precipitations.These all illustrate that PF+CA3 group improves the state of the fatty liver of model mice, and effect is better than rosiglitazone.

Claims

1. treat and/or prevent a pharmaceutical composition for diabetes and how its multiple complications, it is characterized in that by weight ratio be 10-1: 1 Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) make.

2. pharmaceutical composition according to claim 1, it is characterized in that described Radix Paeoniae is the Radix Paeoniae Alba or Radix Paeoniae Rubra, described Cortex cinnamomi japonici (Ramulus Cinnamomi) is Cortex Cinnamomi or Ramulus Cinnamomi; The weight ratio of Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) is 8-2: 1, or is 6-4: 1, or is 5: 1.

3. the preparation method of pharmaceutical composition according to claim 1, is characterized in that: the method comprise Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) be with the ethanol of water or 30-90% respectively or after united extraction, through 40-80 DEG C of vacuum concentration, cold drying, to obtain final product; The method comprise Radix Paeoniae and Cortex cinnamomi japonici (Ramulus Cinnamomi) be with the alcohol of water or 30-90% respectively or after united extraction, be separated through macroporous resin, through 40-80 DEG C of vacuum concentration, cold drying, to obtain final product.Described alcohol can be ethanol, n-butyl alcohol etc.

4. pharmaceutical composition according to claim 1 treats and/or prevents diabetes and the how medicine of its multiple complications, fat-reducing, reduction blood fat or the purposes that treats and/or prevents in fatty liver in preparation.

5. purposes according to claim 4, wherein said diabetes are type ii diabetes, and described diabetic complication is diabetic nephropathy, diabetic ophthalmopathy, diabetic peripheral neuritis, diabetic cardiomyopathy.

6. a pharmaceutical composition, is characterized in that: contain by the pinane monoterpene glycosides compound in Radix Paeoniae and cinnamic acid/aldehyde compound.

7. pharmaceutical composition according to claim 6, is characterized in that: the pinane monoterpene glycoside compound in described Radix Paeoniae is one or more of following compositions: the aglycon of peoniflorin, Radix Paeoniae Alba glycosides, lacdtlorin Ⅲ, lactone glucoside of Radix Paeoniae A, lactone glucoside of Radix Paeoniae B, lactone glucoside of Radix Paeoniae C, oxypaeoniflorin, benzoylpaeoniflorin or above-mentioned glycoside; Described cinnamic acid/aldehyde compound is one or more of following compositions: cinnamic acid, 4-hydroxycinnamic acid, 3,4-dihydroxycinnamic acid, 3,4-dihydroxy hydrocinnamic acid, cinnamic aldehyde, hydroxyl replace cinnamic aldehyde.

8. the pharmaceutical composition according to any one of claim 6, is characterized in that: the weight proportion of described pharmaceutical composition is: the pinane monoterpene glycosides compound in the Radix Paeoniae of 50-150 weight portion, the cinnamic acid/aldehyde compound of 1-5 weight portion; The preferred weight proportioning of described pharmaceutical composition is: the pinane monoterpene glycosides compound in the Radix Paeoniae of 75-125 weight portion, the cinnamic acid/aldehyde compound of 2-4 weight portion; More preferably the weight proportion of described pharmaceutical composition is: the pinane monoterpene glycosides compound in the Radix Paeoniae of 100 weight portions, the cinnamic acid/aldehyde compound of 3 weight portions.

9. the pharmaceutical composition according to any one of claim 6-8 prevents and/or treats diabetes and complication thereof in preparation, and the purposes in the medicine of fatty liver and complication thereof.

10. purposes according to claim 9, wherein said diabetes are type i diabetes or type ii diabetes, and described diabetic complication comprises diabetic nephropathy, diabetic ophthalmopathy, diabetic gastroparesis, diabetes hepatopathy.