CN1839815A - Pharmaceutical composition containing caffeoylquinic acids - Google Patents
Pharmaceutical composition containing caffeoylquinic acids Download PDFInfo
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- CN1839815A CN1839815A CN 200610001806 CN200610001806A CN1839815A CN 1839815 A CN1839815 A CN 1839815A CN 200610001806 CN200610001806 CN 200610001806 CN 200610001806 A CN200610001806 A CN 200610001806A CN 1839815 A CN1839815 A CN 1839815A
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Abstract
The invention relates to a medicinal functional compound for health products or cosmetics, its preparing process and use thereof, wherein the compound comprises natural plants extract or monomer as the active constituents. The pharmaceutical composition can be used for treating and/or preventing diabetes and complications, cardiovascular and cerebrovascular diseases, senile dementia and hyperlipemia.
Description
Technical field
The present invention relates to the combination of medicinal, functional health product or used for cosmetic, specifically, is a kind of contain natural plant extracts or monomer combination and application aspect medicine, functional health product or cosmetics thereof.
Background technology
Along with the high speed development of modern science, people more and more pay attention to " natural " medicine.In recent years, the world of medicine has strengthened analysis and research to bioactive substance, in the hope of further clear and definite its effect having done many work aspect the medicinal plants study such as treatment cardiovascular and cerebrovascular disease, blood sugar lowering.Yet the effect that obtains is limited.This mainly is the pathogenesis complexity owing to cardiovascular and cerebrovascular disease, diabetes, and normal with one or more different classes of complication, existing single active skull cap components is difficult to comprehensive proving effective.
Radical damage is one of important pathogenic factors of type ii diabetes, and hyperglycemia can cause free radical to generate.It is reported that caffeic acid, chlorogenic acid can antioxidation, and peoniflorin can blood sugar lowering, but mechanism of action is not fully aware of separately (Chinese discipline inspection newspaper 2000/6/21; Guo Ting etc., foreign medical science physiology, pathology science and clinical fascicle 1999,19 (4); Clinical endocrinology and metabolism 2005,8; Planta Med 1997,63 (4): 323), this further improves treatment of diabetes for the pluses and minuses of scientifically utilizing the two is disadvantageous.In addition, diabetes and complication thereof all need to take medicine for a long time, so improving on the basis of curative effect, reducing dosage/number of times, reducing the treatment cost is the urgent task that medical worker must solve.
The coupling of different pharmaceutical, as if always a kind of good solution.Yet, up to now, at list/dicaffeoylquinic acid can with the Radix Paeoniae use in conjunction, the mechanism of action of the two is underlying issues such as adduction, collaborative or antagonism, prior art does not provide scientific basis.Whether can unite as for the two and to be used for other disease (for example brain cell protection, senile dementia), prior art even similar hint or attempt not.
Summary of the invention
The inventor has carried out a large amount of benefiting our pursuits in this respect, and has obtained many gratifying results.
One object of the present invention is to provide being combined in of list and/or dicaffeoylquinic acid and Radix Paeoniae to treat and/or prevent application in the diseases such as diabetes and complication thereof, cardiovascular and cerebrovascular disease, brain cell protection, senile dementia, hyperlipemia.
Below the present invention is further elaborated.
Diabetes and complication thereof
As for the beneficial effect of drug regimen of the present invention, at first be in the process of treatment compressibility disease " diabetic silent myocardial ischemia ", to find.Studies confirm that drug regimen of the present invention has the excellent treatment effect to diabetes and related complication thereof.
Studies show that, diabetic coronary heart disease than non-diabetic evidence of coronary heart diseases and all high 3-4 of mortality rate doubly, especially diabetes can cause heart microvascular pathological changes, macroangiopathy, cardiomyopathy, diabetes autonomic nervous dysfunction etc., make the diabetic silent ischemia just more serious (
Beijing medical science2003,25 (2): 84-85).In view of the mechanism of diabetes and complication thereof very complicated, academia and clinical dispute (J Am Coll Cardiol2003,41 (1): 1-7 that this is also existed; Intern Med 2003,42 (7): 554-9; Exp Clin Endocrinol Diabetes 2002,110 (5): 212-8; Biol Pharm Bull 2003,26 (12): 1668-73;
Shandong medicine2003,43 (1): 14-15), still do not have practicable therapeutic scheme (especially adopting the therapy of natural drug), and the coupling between some hypoglycemic medicine increases the weight of the generation of its cardiovascular pathological changes on the contrary.Regrettably, the known technology deficiency thinks that coupling scheme of the present invention provides enough technology even theoretic supports.
We according to following Mechanism Design drug combination of the present invention: 1. the blood sugar lowering of peoniflorin mechanism is irrelevant with insulin, it is to play a role by the availability that improves glucose, and this has positive effect to hyperglycemia and the Developmental and Metabolic Disorder of improving in the diabetic cardiomyopathy evolution thereof; 2. peoniflorin has the aldose reductase inhibitory action, can suppress the abnormal metabolism of polyhydric alcohol in the diabetes, can keep diabetes lower NADH/NAD in the myocardial cell in the I/R process
+, keep higher ATP in the cell, promote K
+-Na
+Exchange, thus the interior calcium overload of myocardial cell suppressed to the diabetic induced myocardial injury; 3. list/dicaffeoylquinic acid, caffeic acid have antioxidation, reduce effects such as blood viscosity, anticoagulant, microcirculation improvement; 4. peoniflorin is to the influence of vascular endothelial cell.
Ensuingly experimental results show that this beneficial effect: each 100 example of patient of selecting to meet WHO coronary heart disease and WHO diabetes (II type) diagnostic criteria, respectively write down 24h ambulatory electrocardiogram and blood glucose before and after the treatment, result: present composition group produce effects 45 examples, effective 31 examples, invalid 14 examples, effective percentage 86%; Effective 26 examples of peoniflorin group, invalid 74 examples, effective percentage 26%; Effective 30 examples of list/dicaffeoylquinic acid group, invalid 70 examples, effective percentage 30%; Effective 20 examples of nitroglycerin group, invalid 80 examples, effective percentage 80%.This shows that drug regimen of the present invention has the excellent treatment effect to the relevant symptom of diabetes and coronary heart disease, and this is that those skilled in the art are unpredictable.
The present invention combination also is suitable for treating diabetes (especially type ii diabetes) and complication thereof for example diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic neuropathy, Diabetes with Hypertension, hyperlipidemia etc.
Expectation is not limit by any theory or prescription, on the basis of a large amount of experiments, the inventor infers that this is because peoniflorin acts on different target spots with list/dicaffeoylquinic acid, especially at different pathological stages performance therapeutical effect, has brought into play the wholistic therapy advantage of drug combination.Especially it should be noted that with the list/dicaffeoylquinic acid or the Radix Paeoniae of independent use and compare that the present composition has significantly reduced animal subject insulin resistant and the anti-inflammatory reaction of organizing.
Cardiovascular and cerebrovascular disease, senile dementia
The beneficial effect of the two coupling also not only is confined in diabetes and the complication thereof.In further research, we are surprised to find, and drug regimen of the present invention also shows the excellent treatment effect in the treating and/or preventing of cardiovascular and cerebrovascular disease (especially ischemic diseases), senile dementia.
Described cardiovascular and cerebrovascular disease for example comprises that coronary heart disease, apoplexy (also claiming apoplexy), myocardial infarction and described senile dementia comprise Alzheimer (being called for short AD) or vascular dementia (being called for short VD).
Hyperlipemia
In research, find that also the present invention makes up the effect with blood lipid regulation at above-mentioned disease.
The cardiovascular and cerebrovascular disease recurrence
Another important discovery of the present invention is that the present invention is combined in the beneficial effect that prevents cardiovascular and cerebrovascular disease recurrence aspect.
Cardiovascular and cerebrovascular disease is the commonly encountered diseases and the frequently-occurring disease of harm modern health, and its sickness rate, case fatality rate and disability rate are all very high.Current, the treatment result of study after the cardiovascular and cerebrovascular disease morbidity still can't be satisfactory, but generally acknowledged that this class disease is disease (Sacco RL etc., Cerebrovasc Dis 1999, (supplementary issue 3): 37-44) that can prevent.According to the time that intervening measure gets involved, prevention can be divided into two stages usually: " primary prevention ", and promptly to healthy population or have the cardiovascular and cerebrovascular disease risk factor but the crowd that still do not have a cardiovascular and cerebrovascular disease symptom carries out prevention." primary prevention " emphasizes mainly that usually life (behavior) mode intervenes, and do not advocate the use pharmaceutical intervention; " secondary prevention " promptly to occurring the cardiovascular and cerebrovascular disease symptom, carries out prevention as the patient of dementia onset history after transient ischemic attack (TIA) or the existing Ischemic Stroke, prevents that it from disease of the same race taking place once more and the measure taked.At this, term of the present invention " prevention of recurrence " is meant " secondary prevention ".
Though conventional chemical medicine for example aspirin etc. can be realized effective prevention to a certain extent, but suitable limitation is arranged, in addition Failure cases also a lot (referring to Wang Shaohua etc., railway medical science 1999,27 (2): 136), be commonly called as clinically and be " aspirin resistance ".Simultaneously, aspirin increases the danger of body hemorrhage (especially upper gastrointestinal hemorrhage), and quite a few patient uses limited.And, report is arranged recently, the comprehensive existing data of U.S. food Drug Administration (FDA) thinks that there is the probability that increases the cardiovascular adverse events in NSAID (non-steroidal anti-inflammatory drug).At present, in clinical practice, also can have following pharmacological action (particularly synergism) simultaneously without any a kind of medicine, the clinician is forced to select multiple medicine to use simultaneously.And use miscellaneous medicine simultaneously, bring the stack (although report is seldom, be difficult to decision-making during clinician's practical application medicine, take drug side effect often into account) of drug side effect probably.Particularly disadvantageously, in numerous risk factors of recurrence, any actually risk factor plays main effect to recurrence, does not also have clear and definite conclusion, does not therefore still have a kind of medicine at present and goes on the market as main activity/indication with " primary prevention " or " secondary prevention ".
The inventor has done good try and exploration in this regard, and has obtained tempting achievement.Zoopery shows, being combined in of list/dicaffeoylquinic acid and Radix Paeoniae controlled a plurality of main risk factors of recurrence aspects simultaneously and shown beat all synergism.In view of time and medical science logic factor, we have only carried out cerebral infarction " secondary prevention " the clinical observation test of limited quantity, but can therefrom dope the present invention is combined in cardiovascular and cerebrovascular disease " primary prevention ", especially " secondary prevention " potential application foreground clinically.
According to result of the test, and in conjunction with present internationally recognized cardiovascular and cerebrovascular disease " primary prevention ", " secondary prevention " evidence-based medicine EBM evidence, we infer, why pharmaceutical composition of the present invention can prevent the recurrence of cardiovascular and cerebrovascular disease effectively, very likely is the synergism that shows on following:
1. antiplatelet aggregative activity (suppress hematoblastic gathering and secretion, change the prostaglandin metabolism approach of platelet and endothelial cell, make the environment trend prevents platelet aggregation, prevents thrombosis and blood vessel endothelium breakage in the blood vessel);
2. blood lipid regulation effect (triglyceride and T-CHOL are reduced, and high density lipoprotein increases slightly, and the synthetic very low density lipoprotein (VLDL) of liver reduces, and these three kinds of variations can both actively prevent arteriosclerotic generation);
3. regulate carbohydrate metabolism (blood sugar level of diabetics is controlled in the ideal range, improves lipodystrophy, control the synthetic of cholesterol);
4. antioxidation (SOD in the human activin suppresses the effect of free radical, suppresses the destruction of lipid peroxide to biomembrane normal function in the body, reduces tremulous pulse, especially arteriolar hardener meeting);
5. blood pressure regulation effect (reduces the passive expansion of blood vessel, reduces the suffered tension force of blood vessel wall, permeability increase, prevent that plasma fraction from exosmosing; Reduce the blood vessel wall thickness, improving its robustness increases, and prevents smooth muscle hyaline degeneration and necrosis);
6. vascular endothelial cell protective effect reduces the thrombosis chance.
Simultaneously, in view of the complexity of cardiovascular and cerebrovascular disease secondary prevention, inventor's expectation is not subjected to the restriction of any theory, and obtained beneficial effect all be experimental results show that by pharmacological effect.Advantageously, zoopery shows, drug regimen of the present invention also shows significant anti-inflammatory response effect: after using medicine of the present invention, the atheromatous plaque of animal subject forms is subjected to the inhibition degree, parallel with the reduction level of Inflammatory Mediators CRP in its body (perhaps MCP-1), this obviously points out pharmaceutical composition of the present invention by suppressing blood vessel generation inflammatory reaction, cause arteriosclerotic chance thereby suppressed the lipid calmness, reduced apoplexy recurrence or dead important risk factor.Above-mentioned discovery has verified further that in conjunction with clinical test results the present invention is combined in the application potential of cerebral infarction " secondary prevention " aspect.
Therefore, another object of the present invention is to be provided in list and/or dicaffeoylquinic acid and Radix Paeoniae are used for preventing the medicine of cardiovascular and cerebrovascular disease recurrence in preparation application.When clinical practice, the doctor can formulate individual dosage regimen according to factors such as patient's age, system, the orders of severity, for example gives 1/5-1 and doubly treat/prevent the pharmaceutical composition of the present invention of effective dose.As everyone knows, long-term oral administration relatively is suitable for prevention of recurrence.
Prevent postangioplasty restenosis
In the current clinical medicine practice, the interventional therapy that Wicresoft hinders is used widely.Wherein, it is one of important means in the interventional therapy that endovascular stent is inserted plasty, and these means are applied in the treatment of diseases such as heart infarction, cerebral infarction, large vein thrombosis and have obtained the short term efficacy that attracts people's attention.But regrettably, it is high that the vascular restenosis after the endovascular stent plasty reaches occlusion rate again, and the restenosis rate in a year can reach 50% up to 20%, three year.Though coating stent of medicine can reduce the incidence rate of postangioplasty restenosis (RS), its effective percentage still can not be satisfactory.Also there is report to use some drugs (as antibiotic, immunosuppressant) can reduce the incidence rate of RS, but it is evident that the side effect of antibiotic or immunosuppressant makes it and is not suitable for life-time service.
The abnormality proliferation of vascular smooth muscle cell (VSMCs) is the pathological characters of RS, suppresses the important means that the VSMCs abnormality proliferation is prevention RS.We studies show that; drug regimen of the present invention has the effect of remarkable inhibition VSMCs; infer that its mechanism is because the present composition has stronger antiinflammatory and endotheliocyte protective effect; can effectively suppress the inflammatory reaction that produces after the vascular endothelial cell damaged, thereby reach the effect that suppresses VSMCs.Simultaneously,, be more suitable for long term administration, in preventing RS, have the not available advantage of prior art because the present composition has the low good characteristic of side effect.
Functional health product
The 3rd purpose of the present invention is that the present invention is combined in the application in the preparation functional health product.
Because the present composition possesses above-mentioned effect, also meets the requirement of functional health product safety.Therefore, combinations thereof of the present invention also can be used as the major function composition of preparation functional health-care food or is spiked in food, the beverage as accelerant, for adaptation population's life-time service.And, on the basis of the present invention's test, it will be appreciated by persons skilled in the art that the functional health product that contains combinations thereof of the present invention has following health care at least: auxiliary lipid-lowering function, auxiliary hyperglycemic function, auxiliary adjustment blood pressure, anti-oxidation function, auxiliary improving memory function, function.
Equally, the functional health product technology of preparing also belongs to known technology.But for medicine, the present composition is used for source, the condition of functional health product can be more extensive and loose.For example, can use the extract and the Radix Paeoniae Alba extract combination that contain list and/or dicaffeoylquinic acid, also can directly select the combination of list and/or dicaffeoylquinic acid and peoniflorin, also can select to contain other plant extract of caffeic acid ester or use complete synthesis, the semisynthetic of its chemistry.In the functional component of functional health product constitutes, can only contain the present invention's combination, also can be that the present invention makes up and adds that other is auxiliary or strengthen the composition of effect, as: add vitamin E in order to strengthen anti-oxidation efficacy, do not repeat them here.
Cosmetics
The 4th purpose of the present invention is that the present invention is combined in the application in the preparation external antioxidative cosmetics.
At cosmetics, especially during the cosmetics (be cosmeceutical, also claim therapeutic cosmetic, medicine to make up product, medicine woman's persona etc.) that contain medicine prepare, can reach specific treating/health effect by adding a certain amount of material with specific pharmacological effect.Because the present composition has stronger anti-oxidation efficacy, can be very easily make up in the product as the functional additive use, thereby the effect by external antioxidation, antioxidant radical reaches corresponding effect, as delaying decrepitude of skin etc. at cosmetics, medicine.And similar techniques belongs to equally known, mature technology.
Combination of the present invention and corresponding preparations
The present invention's combination is meant: co-administered with the independent dosage form confession that contains list and/or dicaffeoylquinic acid, Radix Paeoniae separately, perhaps provide with the compositions/products form that contains the two simultaneously.
Therefore, another object of the present invention is to be provided for containing the Pharmaceutical composition of Radix Paeoniae and list and/or dicaffeoylquinic acid, wherein in the peoniflorin in list/dicaffeoylquinic acid and the Radix Paeoniae, the part by weight of the two is 0.02-50: 1, preferred 0.05-20: 1, more preferably 0.1-15: 1 and more preferably 0.5-10: 1.
In the present composition, Radix Paeoniae can be selected flavour of a drug directly to be ground into powder to be used as medicine, and extract or other form that also can be equivalent to above-mentioned Chinese crude drug crude drug amount are used as medicine.Therefore, the Radix Paeoniae of pharmaceutical composition of the present invention comprises the former powder of medical material, fat or water solubility extract, effective site or effective ingredient active the composition, perhaps adopts existing goods form in the prior art.For example, comprise described active the composition:
A). with peoniflorin (Paeoniflorin) is the material of main active: the dry root powder of Radix Paeoniae (Radix Paeoniae Alba, Radix Paeoniae Rubra, river Radix Paeoniae Rubra), contain the extract or the peoniflorin monomer of glycosides compound (being preferably peoniflorin and lactone glucoside of Radix Paeoniae).In addition, studies show that the effective site that contains peoniflorin, lactone glucoside of Radix Paeoniae, Hydroxy peoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, lacdtlorin etc. simultaneously also is useful.The source that it will be appreciated by persons skilled in the art that Radix Paeoniae glycoside of the present invention is not limited to Radix Paeoniae, and other plant (for example Cortex Moutan) that contains the Radix Paeoniae glycoside also can be realized the present invention, and it extracts and preparation method is a known technology, does not give unnecessary details at this.
B). with list and/or dicaffeoylquinic acid is the material of main active: the list/dicaffeoylquinic acid that can extract from various plants, as: contain the plant extract of list and/or dicaffeoylquinic acid, for example the Herba Erigerontis water extract; Contain the coffee-extract of caffeic acid, tannin (tannic acid), caffeoylquinic acid (as chlorogenic acid), preferably wherein decaffeinated; The Flos Lonicerae, the Cortex Eucommiae extract that contain chlorogenic acid and/or isochlorogenic acid; Or directly get chlorogenic acid, isochlorogenic acid or other caffeoylquinic acid or dicaffeoylquinic acid.
List/dicaffeoylquinic acid, caffeic acid are then originated very for extensive.The source that it will be appreciated by persons skilled in the art that the used list/dicaffeoylquinic acid of the present invention is not limited to above-mentioned plant.Test shows, as long as contain list and/or dicaffeoylquinic acid, other plant or plant parts (extract) also can realize the present invention, for example: Rubiaceae Coffea coffee bean or feverfew, Fructus Xanthii, Helianthi, Folium Artemisiae Argyi, Caulis et Folium Chrysanthemi segeti, Herba Erigerontis, Herba Artemisiae Scopariae, Flos Inulae, Radix Asteris, Cynara scolymus L (Cyhara cardunculus.), Herba Lactucae Indicae, the shady Herba Senecionis Scandentis of woods, and propolis, the Cortex Eucommiae, Flos Lonicerae and other caprifoliaceae plant, wood continues, coffee, cocoa tree, siphonostegia chinensis, Echinacea angustifolia, Folium Ilicis and other Holly, Rhizoma Dioscoreae esculentae leaf, Rhizoma Dioscoreae esculentae, Fructus Gardeniae, Rhizoma Solani tuber osi, the Hedera plant, or Dichrocephala plant.Simultaneously, it is to be noted, adopting these plant extract lists and/or dicaffeoylquinic acid or corresponding monomeric extraction and preparation method is known technology, for example: pharmaceutical analysis magazine 2005,25 (7): 751-755, Luzhou Medical College journal 1999,22 (6): 469-470, medical science summary 2004,10 (4): 249-250, EP0299107, US5401858, ZL01115358X, ZL031287298, ZL99105113, ZL200310113536, ZL94102414, ZL97109109, ZL01144170, ZL02133448, ZL02811814, ZL02824704, ZL03110999, ZL03134575, ZL200310111180, ZL200510000484, ZL03117754 does not give unnecessary details at this.
Because caffeoylquinic acid and dicaffeoylquinic acid, its pharmacological effect has great homogeny, and, the caffeoylquinic acids that extracts in plant is single often, the mixture of dicaffeoylquinic acid, even also contain a small amount of three caffeoylquinic acids, and list, dicaffeoylquinic acid also often are the compounding substances (also being total coffee acid ester) of various isomerss.Therefore, the present invention both can adopt plant extract or the monomer that contains caffeoylquinic acid or contain dicaffeoylquinic acid, also can adopt caffeoylquinic acid monomer, the monomeric mixture of dicaffeoylquinic acid, also can adopt the extract that contains list, two, three caffeoylquinic acids.
Caffeoylquinic acid can be taken from 3-caffeoylquinic acids (chlorogenic acid), 5-caffeoylquinic acids (isochlorogenic acid), perhaps their mixture.
According to coffee acyl the position of substitution difference; dicaffeoylquinic acid is divided into 1; 5-two-O-caffeoylquinic acids, 1; 3-two-O-caffeoylquinic acids, 1; 4-two-O-caffeoylquinic acids, 3; 5-two-O-caffeoylquinic acids, 3,4-two-O-caffeoylquinic acids, 4,5-two-O-caffeoylquinic acids.
Can be separately or adopt the mixture of above-mentioned single, dicaffeoylquinic acid, for example chlorogenic acid, isochlorogenic acid, 3,4-position, 3,5-position, 1, the mixture of 5-position dicaffeoylquinic acid, perhaps for example contain 1, the extract of 5-position dicaffeoylquinic acid, the perhaps mixture of chlorogenic acid monomer, isochlorogenic acid monomer or chlorogenic acid and isochlorogenic acid for example, perhaps 3,5-two-O-caffeoylquinic acids monomer and/or 1,5-position dicaffeoylquinic acid monomer.Above-mentioned single, dicaffeoylquinic acid derivant or pharmaceutical salts also are suitable for the present invention.
Advantageously, above-mentioned active component is when being used as medicine with form of extract, the purity of peoniflorin in described extract is 2-98wt%, preferred 25%, 50%, 75% or 92%, and the purity of list/dicaffeoylquinic acid in described extract is 5-98wt%, preferred 40%, 75% or 96%.
In context, " the medicinal combination of the present invention " related term " list/dicaffeoylquinic acid ", " Radix Paeoniae " have above-mentioned definition.
Following test will confirm: the combination with above-mentioned definition it " list/dicaffeoylquinic acid " and " Radix Paeoniae " according to the present invention describes has beneficial effect of the present invention.In view of having existed the effectively technology of the above-mentioned definition component of preparation of suitable maturation in the prior art already, do not make emphasis at this and describe.For example, can adopt modern extraction and isolation technics to improve the purity of active substance, remove unwanted impurity as far as possible, similar techniques is quite effectively ripe in the prior art, for example: EP0299107, US5401858, Chinese patent application ZL200310113536, ZL01115358, ZL021109737, ZL021332983, ZL031131263, Chinese herbal medicine (1998,29 (10): 664-9), Chinese patent medicine (1999,21 (12): 644-5), Traditional Chinese Medicinal College of Liaoning's journal (2002,4 (1): 24), the time precious traditional Chinese medical science traditional Chinese medicines (2003,12 (7): 392-3); With ZL92108623, ZL00113019, ZL02110973, ZL02153750X, ZL03117754, ZL03141616, JP2000247890A, GB2317613A, Chinese patent medicine (2004,26 (10): 855-6).
Can be at absorption characteristics (China Medicine University's journal 2003,34 (01): 65-9 in the dissolution characteristics of Radix Paeoniae glycoside, list/dicaffeoylquinic acid and the body; Shenyang Pharmaceutical University's journal 1999,16 (4): 250-3; Chinese Pharmacological circular 1992,8 (4): 278-80), adopt the standard preparation technology, make suitable oral or parenterai administration dosage form with pharmaceutic adjuvant, similar techniques is also quite effectively ripe in the prior art, for example: tablet (ZL01115358, ZL03112999); Dispersible tablet (ZL03112974, ZL02153445); Oral cavity quick disintegrating slice (ZL03102405, ZL200410016510, ZL200410041256); Suspensoid (ZL200410080266), Emulsion (ZL200410080265), sustained-release preparation (ZL01117620, ZL02109758, ZL02116795, ZL02129313, ZL02134118, ZL03100021, ZL03133897), drop pill (ZL01133515, ZL03135325, ZL200310119222); Soft capsule (ZL01117620); Injection or infusion solution (ZL03129007, ZL200410008734, ZL200410022438, ZL200410080023, ZL93106319, ZL95104038, ZL97101107, ZL02155001, ZL021332983, ZL031279953, ZL03141614, ZL03113037, ZL2003101210259, ZL200410013845); Or contain phospholipid preparation (ZL03111469, ZL01138902, ZL03153496); And cosmetics (EP577516; US5445816).
In the clinical use of the present composition, exemplary every day, oral recommended dose was: list/dicaffeoylquinic acid 40-1000mg (preferred 80-200mg), peoniflorin 10-120mg (preferred 30-80mg).
Shortcomings such as the effect that said medicine combination of the present invention has overcome existing medicine existence is single, dosage is big; represented natural drug treatment and prevent diabetes and complication thereof, senile dementia, cardiovascular and cerebrovascular disease, hyperlipemia, brain cell protection, and the prevention cardiovascular and cerebrovascular disease recurs and prevents the new trend of postangioplasty restenosis.
The pharmacology pharmacodynamic experimental study
One. the pharmacological action of diabetes aspect
1. to the influence of diabetic nephropathy
Diabetic nephropathy patient 40 examples, wherein male 25 examples, women 15 examples, 64.34 ± 6.1 years old mean age, average fasting glucose (9.68 ± 1.1) mmol/L.The dicaffeoylquinic acid group (is called for short 1 group, administration 50mg) 12 examples, peoniflorin group (are called for short 2 groups, administration 50mg) 12 examples, the present composition (1: 1 dicaffeoylquinic acid and peoniflorin, administration 50mg) 16 examples, oral, every day three times, totally 28 days, observe medication front and back hemorheological indexes respectively and change.Specimen is taken from venous blood, and anticoagulant heparin, instrument are LG-R-20 type hemorheology instrument.
The comparison of hemorheology index before and after table 1. treatment (X ± S)
| 1 group | 2 groups | The present invention's combination | ||||
| Before group is handled | After the processing | Before the processing | After the processing | Before the processing | After the processing | |
| Low value of cutting 1 (Cp) plasma viscosity erythrocyte sedimentation rate (mm/h) red blood cell of the value of cutting H (Cp) whole blood is pressed the low reduced viscosity Rigidity of red cells index erythrocyte aggregation index ESR equation K value of cutting of grain (%) reduction viscosity of blood whole blood in whole blood high value of cutting (Cp) whole blood | 4.88±0.52 6.79±1.02 10.28±1.11 1.83±0.09 49.22±12.98 40.59±5.99 9.13±1.1 29.11±3.2 4.62±0.29 4.55±0.68 88.06±59.42 | 4.40±0.55 * 6.09±1.01 9.88±1.21 1.69±0.12 *** 48.75±13.75 35.99±4.31 * 8.66±1.0 26.53±2.8 * 3.98±0.24 *** 4.31±0.65 67.37±46.78 | 4.85±0.50 6.88±0.63 10.32±1.11 1.81±0.06 48.97±13.49 40.41±5.53 9.21±1.3 28.88±3.2 4.72±0.51 4.59±0.58 88.26±61.01 | 4.42±0.51 * 6.13±0.97 * 9.49±0.92 * 1.62±0.08 *** 46.82±11.03 35.12±4.67 ** 7.99±1.1 ** 24.36±2.8 *** 3.79±0.35 *** 4.01±0.51 ** 66.32±48.83 | 4.78±0.42 6.83±0.95 10.27±1.09 1.86±0.07 49.13±15.21 40.53±5.92 9.12±1.2 29.31±3.7 4.59±0.71 4.58±0.73 89.35±40.45 | 4.32±0.53 * 5.92±0.73 ** 8.94±1.10 ** 1.63±0.09 *** 41.11±12.14 * 29.94±4.07 *** 7.61±1.2 ** 23.88±3.2 *** 3.34±0.31 *** 3.83±0.59 ** 58.09±35.97 * |
Compare before and after the treatment,
*P＜0.1,
*P＜0.05,
* *P＜0.01
1 group, 2 groups of the conclusions and the present composition all can improve blood viscosity, and can effectively improve nephropathy, reduce the quantity of urine protein, can delay the generation evolution of nephropathy, 2 groups and the present invention combination also has the blood sugar control effect, but the effect of the present composition obviously is better than 1 or 2 group of the same dose that uses separately.
In addition, in view of VEGF (VEGF) may become the special target spot of preventing and treating diabetic nephropathy (DN), blocking VEGF is synthetic or biological action is significant.Also investigated expression and the regulating action of the present invention's combination to type ii diabetes rat kidney VEGF.At this test preparation T
2(the kidney hypertrophy has appearred in blood glucose 〉=16.7mmol/L), possess the insulin resistant feature, albuminuria, kidney VEGF and TGF-β 1 high expressed in the rat model of DM.Experiment shows, the present invention's combination (Radix Paeoniae Alba extract+dicaffeoylquinic acid extract 2: 1) can reduce T
2DM rat model urine protein reduces renal hypertrophy, alleviates the kidney vegf expression; the mechanism of its renal function protecting may be relevant with inhibition VEGF; its effect obviously is better than using separately dicaffeoylquinic acid or Radix Paeoniae, two groups of high and low dose, and (60mg/kg, 20mg/kg irritate stomach) curative effect does not have significant difference.
Simultaneously; the present invention also tests blood glucose, body weight, kidney weight/body weight and the twenty-four-hour urine albumin excretion rate (AER) etc. of the rat of diabetes model; and the variation of kidney of rats bead pathomorphology index is respectively organized in observation; the result shows; 2 groups and the present composition all have the effect of protection kidney; 2 groups (peoniflorin 50mg) also are the medicines that can improve and treat diabetes, but with the effect of the present composition (dicaffeoylquinic acid 25mg, peoniflorin 25mg) best (obviously being better than the single component of using of Radix Paeoniae).
In addition, further experiment proves, it is unusual that the present composition can be corrected diabetes blood capillary kinetics, and its effect is better than the dicaffeoylquinic acid, the peoniflorin that use separately.
Two. the pharmacological action for the treatment of cardiac and cerebral vascular diseases
1. to the protective effect of rat test cerebral ischemia
1.1 influence to brain water content
With body weight 160-180g rat random packet, tested preceding 9 days and art before 1hr oral administration every day once.The ligation bilateral carotid arteries causes the incomplete ischemia model of acute experiment.
Compositions: chlorogenic acid+Radix Paeoniae Alba extract 1: 2
Influence (X ± S) (n=10) of table 2 pair experimental cerebral ischemia rat brain water content
| Group and dosage | Brain water content (%) |
| Dosage 40mg/kg composition group low dosage 20mg/kg chlorogenic acid group 20mg/kg peony extract group 40mg/kg in the Normal group cerebral ischemic model huatuo zaizao pill 2g/kg composition group high dose 80mg/kg composition group | 74.2±2.87 75.1±2.45 73.9±3.06 62.2±2.69 *** 65.7±2.62 *** 71.0±3.29 ** 70.9±3.42 ** 70.6±3.12 ** |
Compare with matched group,
*P＜0.1,
*P＜0.05,
* *P＜0.01
As seen from the above table; the chlorogenic acid and the Radix Paeoniae Alba extract group cerebral edema that cerebral ischemia causes to imperfection of each group of the present invention and single prescription all demonstrate protective effect; but compare with the cerebral ischemic model group; the above dosage group of compositions group 40mg/kg makes brain water content reduce more significantly (P＜0.01), shows that its cerebral edema that cerebral ischemia causes to imperfection has significant protective effect.
2. to the influence of ischemic brain injury
Influence to rat cerebral infarction tissue weight
Get 70 rats, male and female half and half, be divided into 7 groups (sham operated rats, normal saline group (NS), 3 dosage groups of the present composition (list/dicaffeoylquinic acid mixture+peoniflorin 2: 1: 1), positive drug groups (list/dicaffeoylquinic acid mixture group 2: 1, peoniflorin group)) at random, 10 every group.Make intraluminal middle cerebral artery occlusion in rats ligation (MCAO) model according to known pharmacological method.The results are shown in following table.
The influence (n=10) of rat cerebral infarction tissue weight due to the table 3 couple MCAO
| Group and dosage | Infraction brain weight percentage ratio |
| Dosage 20mg/kg present composition low dosage 10mg/kg list/dicaffeoylquinic acid mixture group 15mg/kg Paeoniflorin group 5mg/kg in the control group NS present composition high dose 30mg/kg present composition | 4.0±5.1 30.7±6.3 21.4±3.8 *** 22.2±4.4 *** 25.1±5.2 * 24.9±6.7 * 25.2±6.3 * |
Compare with NS,
*P＜0.1,
*P＜0.05,
* *P＜0.01
The result shows, obviously there is cerebral infarction to take place behind the rat MCAO, the present invention makes up each dosage and (iv) organizes and can obviously reduce cerebral infarction tissue weight percentage ratio (P＜0.01, P＜0.05), and list/dicaffeoylquinic acid mixture, the peoniflorin group of same 10mg/kg also have and more significantly reduce effect (P＜0.05), but compare with the big or middle dosage of compositions, the positive controls effect is obviously not as the present invention's combination.
Equally, adopting and last epiphase medicine and dosage thereof together, in the experiment to the influence of rat ischemia derogatory behaviour index due to the MCAO, the result has shown and can draw and above-mentioned similar conclusion, be that compositions, list/dicaffeoylquinic acid mixture have all shown relevant effect with the peoniflorin group, but the effect that makes up big or middle dosage group with the present invention is best, obviously is better than simple list/dicaffeoylquinic acid mixture and peoniflorin group.
In addition, each (iv) administration of dosage group of the evidence present composition, the mouse brain circulatory disturbance time-to-live can obviously be prolonged, high, middle dosage group has prolonged about 2-3 doubly than matched group respectively, show that this medicine can increase the blood flow of mouse brain circulatory disturbance, thereby improved cerebral hypoxia ischemia animal tolerance effect.
3 prevent postangioplasty restenosis
Postangioplasty restenosis (RS), its sickness rate is up to 30-50%.Because the abnormality proliferation of vascular smooth muscle cell (VSMCs) is the pathological characters of RS, therefore suppress the important means that the VSMCs abnormality proliferation becomes worldwide cardiovascular research prevention RS.
3.1 material
Drug regimen of the present invention: peoniflorin+total coffee acid ester (containing chlorogenic acid, isochlorogenic acid, dicaffeoylquinic acid and caffeic acid) 1: 4, with 20,40, the 60mg/kg injection;
Blank group: normal saline;
Positive control drug: be equivalent to the one pack system peoniflorin injection of same dosage, 8mg/kg; Total coffee acid ester injection (containing chlorogenic acid, isochlorogenic acid, dicaffeoylquinic acid and caffeic acid), 10mg/kg; The arasaponin injection;
3.2 method
Vascular smooth muscle cell is separated, cultivates, is identified, reference literature (Piper HM edits, Cell CultureTechinques in Heart and Vessel Research.Springer-Verlag:Germany.1990:280) operation.
After treating that 90%VSMCs converges, through planting behind the trypsinization in culture dish, add the 10%FBS+SMWM incubated overnight, make cell attachment, cell converges about 80%, change serum-free DMEM again into and (contain penicillin 100U/ml, streptomycin 100 μ g/ml) continue to cultivate 24h, make the cell growth synchronously, change 10%FBS+DMEM at last into, and adding medicine at random, each concentration is diluted to 10 μ l/ holes with DMEM.
3H-TdR mixes experiment: replace the DMEM of every hole 1ml, add luCi's
3H-TdR measures the CPM value in each hole with liquid scintillation counter (1900CA).
Cell survival rate=attached cell/total cell number (attached cell+not attached cell)
3.3 result
The results are shown in down two tables.
To smooth muscle cell
3The influence of H-TdR incorporation (X ± s)
| Cultivated 28 hours 3H-TdR mixes | Cultivated 48 hours 3H-TdR mixes | |
| The matched group peoniflorin total coffee acid ester injection arasaponin present composition, (greatly) present composition, (in) present composition, (little) | 9027±451 8477±508 *6788±532 **5349±479 **3827±222 **ΔΔ##4068±418 **ΔΔ##7049±4891 **Δ | 18790±1816 14214±1257 **10237±1167 **11588±2437 **Δ3518±299 **ΔΔ##4239±316 **ΔΔ##14035±1823 ** |
Compare with blank,
*P＜0.05
*P＜0.01; Compare Δ P＜0.05, Δ Δ P＜0.01 with Radix Paeoniae; Compare #P＜0.05 with total coffee acid ester.
To the influence of smooth muscle cell counting (X ± s)
| Cultivate 24 hour cell quantity 1 * 10 4Attached cell | Cultivate 48 hour cell quantity 1 * 10 4Attached cell | |
| Matched group | 40.27±2.11 | 76.11±3.03 |
| The peoniflorin total coffee acid ester injection arasaponin present composition (greatly) present composition (in) present composition (little) | 39.41±2.23 38.20±2.15 * 37.81±2.32 *Δ 27.48±1.40 **ΔΔ## 33.33±1.36 **ΔΔ## 38.32±1.89 ** | 60.11±3.32 ** 58.97±2.99 ** 58.51±3.12 ** 34.59±3.01 **ΔΔ## 43.70±3.01 **ΔΔ## 47.98±2.99 **ΔΔ## |
Compare with blank,
*P＜0.05
*P＜0.01; Compare Δ P＜0.05, Δ Δ P＜0.01 with Radix Paeoniae; Compare #P＜0.05, ##P＜0.01 with total coffee acid ester
This experiment cell counting analysis, each organize the influence of medicine on cell proliferation with to smooth muscle cell
3H-TdR mixes basically identical, and records not obviously influence of cell survival rate, all more than 90%.
3.4 conclusion
Pharmaceutical composition of the present invention, peoniflorin, total coffee acid ester injection are inhibited to the abnormality proliferation of vascular smooth muscle cell (VSMCs), pharmaceutical composition wherein of the present invention is the strongest, total coffee acid ester, arasaponin and peoniflorin take second place respectively, drug regimen of the present invention and peoniflorin and total coffee ester relatively have significant difference between group.
4 brain cell protective effects
Material and method
Laboratory animal: 72 of healthy Wistar rats, body weight 260 ± 15g;
Medicine: the present composition: peoniflorin+total coffee acid ester (containing list, two, three caffeoylquinic acids and caffeic acid) 5: 1,24mg/kg;
Positive control drug: peoniflorin injection, 20mg/kg; Total coffee acid ester (containing list, two, three caffeoylquinic acids and caffeic acid) injection, 24mg/kg; The Edaravone Injection injection, 10mg/kg;
Experimental technique: rat is divided into 6 groups at random, 12 every group.The normal control group: by left external jugular vein intubate, quiet notes 1% heparin is given 0.9% sodium chloride liquid 3ml/kg respectively at reaching 1.5h at once through left external jugular vein intubate, gets brain detection or fixing behind the 3h.Model group: set up the cerebral ischemia re-pouring animal model with reference to Kaizumis bolt collimation method.The equal ischemia 1.5h of experimental animal model gets brain detection or fixing, takes out the bolt line then and pours into 1.5h again, gets brain detection or fixing.Specimen: rat broken end is got brain, peel off cerebral tissue, get and get brain cortex and tail shell nuclear light, electron microscope specimen between two coronal sections of optic chiasma and interpeduncular fossa respectively.
The mensuration of cerebral edema and brain calcium content: get right front brain 50～100mg, dry, be dry weight to constant weight.
Brain water content is measured: use formula: (weight in wet base-dry weight)/weight in wet base, calculate brain water content.
The result
(1) rat cerebral tissue's infarct is observed:
Under the light microscopic: model group neuron soft edge, cell space is painted to deepen, and the kytoplasm boundary is unclear.The cell peripheral clear zone broadens and there were significant differences (P＜0.01) for the normal control group.Present composition group and Edaravone group neuronal structure are still clear, and karyon and kytoplasm boundary still can be distinguished, and cell peripheral clear zone broad dwindles there was no significant difference though compare with model group.Peoniflorin group and total coffee acid ester group neuronal structure owe clear, and karyon and kytoplasm boundary can be distinguished, and cell peripheral clear zone broad is compared with model group and not seen obviously and dwindle.
Under the Electronic Speculum: model group neuron distortion, the light and shade neuron is not easily distinguishable, the karyon distortion, in the nuclear heterochromatin increase, nuclear membrane and perinuclear space is smudgy, the caryoplasm boundary is unclear, network structure disappears, organelle minimizing or distortion, structure are unclear.Mitochondrion is the swelling of balloon sample, plasma structure is unclear or disappearance is ruptured, cell peripheral has a large amount of edematous fluid to be the low electron density clear zone.The all nuclear membranes of present composition group and Edaravone group neuronal kernel are clear, the interior heterochromatin of nuclear increases slightly, the perinuclear space is narrower, the kytoplasm inner cell organ is obvious but mitochondrion all has the change of edema sample, cell peripheral that a small amount of edematous fluid is arranged.Peoniflorin group and total coffee acid ester group neuronal kernel week nuclear membrane owe in clear, the nuclear heterochromatin slightly showed increased, the perinuclear space is narrower, the kytoplasm inner cell organ is not obvious, mitochondrion has the edema sample to change.Model group astrocyte edema, kytoplasm electron density reduce, organelle reduces, the local cells membrane structure is unclear.The edema performance of present composition group and Edaravone group astrocyte is light than model group, and organelle is compared obviously more with model group.The peoniflorin group is then similar substantially to model group with total coffee acid ester group astrocyte.
(2) experimental result of cerebral tissue calcium, malonaldehyde, superoxide dismutase, brain moisture: model group cerebral tissue mda content, calcium content, brain moisture all obviously raise (P＜0.01) than normal matched group, and the SOD activity then is starkly lower than normal control group (P＜0.01); The present composition can suppress the rising and the increased SOD activity (P＜0.01) of perfusion back cerebral tissue mda content, improves brain water content (P＜0.01), and effect and Edaravone are suitable, obviously are better than total coffee acid ester and peoniflorin group.
Conclusion
The present composition can significantly suppress the rising and the SOD activity improving of the MDA of cerebral ischemia re-pouring rat cerebral tissue content, improves brain water content, and confirms that from ultrastructure membranous structure is still had certain protective role.The present composition is removed oxygen-derived free radicals, thereby brain cell is shielded mainly by SOD activity improving, and its effect is suitable with Edaravone, obviously is better than peoniflorin and total coffee acid ester group.
Three. the pharmacological action of senile dementia aspect
Effect to the VD model of ischemia-reperfusion preparation
Rat is divided into sham operated rats, model group, DANGGUI SHAOYAO SAN group (oral), caffeoylquinic acid group (containing chlorogenic acid, isochlorogenic acid), peoniflorin group and present composition group (caffeoylquinic acid (containing chlorogenic acid, isochlorogenic acid)+peoniflorin 10: 1, the A group of injecting drug use, B group with oral administration), successive administration before the preparation model, prepare the VD rat model with ischemia-reperfusion repeatedly then, measure the content of MDA in the hippocampal tissue.
The table 4. pair influence comparison (n=10) of pouring into MDA content in the VD rat hippocampus tissue for preparing again
| Group and dosage | MDA(nmol/mg) |
| The present invention of sham-operation group model group makes up A high dose 10mg/kg the present invention and makes up among the A dosage 5mg/kg the present invention and make up A low dosage 2mg/kg the present invention and make up B 50mg/kg caffeoylquinic acid group 10mg/kg Paeoniflorin group 10mg/kg DANGGUI SHAOYAO SAN group 3.8g/kg | 6.521±2.51 6.071±0.483 3.879±0.558 *** 4.187±0.682 ** 5.006±0.609 4.097±0.523 ** 6.088±0.421 4.875±0.637 * 4.271±0.413 ** |
Compare with sham operated rats,
*P＜0.1,
*P＜0.05,
* *P＜0.01
Last table shows, the present composition and Radix Angelicae Sinensis peoniflorin group all can reduce rat hippocampus MDA content, Wheat Protein, but the effect with the present composition (the A group of middle and high dosage and B group) is the most remarkable, the peoniflorin group has also reduced MDA content, the caffeoylquinic acid group of one pack system then a little less than.
Four. the pharmacological action of antioxidation aspect
Antioxidation to the hyperlipidemia rat
Material
Pharmaceutical composition of the present invention: peoniflorin+1,5-two-O-caffeoylquinic acids 1: 5,50mg/kg irritates stomach;
Normal control group: normal saline;
Hyperlipidemia group: normal saline;
Positive control drug: 1,5-two-O-dicaffeoylquinic acid (50mg/kg); Radix Paeoniae Alba extract (50mg/kg); VE (50mg/kg); DANSHAO KELI (50mg/kg contains 9 flavor medicines such as Cornu Bubali, the Radix Rehmanniae, Radix Salviae Miltiorrhizae, Radix Paeoniae Rubra);
Experimental technique
The foundation of high blood lipid model: the Wistar rat gives high lipid food; Normal control group feeding normal diet.Compare with normal group, the LPO of hyperlipidemia model serum and liver obviously raises, and obviously reduces and SOD is active.
Medicine is irritated stomach, handles animal, surveys LPO and SOD, according to the operation of test kit description, gets 1/2 liver LPO to be measured and SOD, the results are shown in following table:
The influence (nmol/L) of table 5. pair hyperlipemia rat serum and liver LPO and SOD
| Group | Serum LPO | SOD in serum | Liver L PO | Liver SOD |
| Hyperlipidemia group VE group 1,5-two-O-dicaffeoylquinic acid Radix Paeoniae Alba extract DANSHAO KELI present composition | 8.99±2.00 6.54±1.23 ** 8.24±1.18 7.89±1.17 6.96±1.07 *Δ 6.27±1.11 **ΔΔ## | 400.9±56.7 440.1±28.9 438.1±30.7 * 451.6±40.1 * 451.8±35.6 * 456.8±28.9 * | 6.91±1.18 5.61±1.13 * 6.02±1.43 5.89±1.37 5.87±1.59 5.19±1.31 ** | 7.59±1.19 8.87±1.27 * 8.73±1.35 * 8.73±1.18 * 9.01±1.28 * 9.25±1.19 ** |
Compare with the hyperlipidemia group
*P＜0.05
*P＜0.01; Compare with Radix Paeoniae,
ΔP＜0.05,
The Δ ΔP＜0.01; With 1,5-two-O-dicaffeoylquinic acid compares,
#P＜0.05,
##P＜0.01
Conclusion
Above-mentioned experiment shows, use separately 1,5-two-O-dicaffeoylquinic acid and Radix Paeoniae Alba extract (50mg/kg) show certain antioxidant activity, low dosage is then not obvious.The present composition has obvious antioxidation activity, the Radix Paeoniae that effect is better than using separately, 1,5-two-O-dicaffeoylquinic acid and other contrast medicine (P＜0.01), may be because not only contain dicaffeoylquinic acid in the present composition, also contain peoniflorin, the two synergism has strengthened the antioxidation of dicaffeoylquinic acid.Therefore the present invention's combination obviously is better than peoniflorin, 1,5-two-O-dicaffeoylquinic acid and other contrast medicine (P＜0.01) used separately to the antioxidation of hyperlipidemia.
5 usefulness of the present composition are not then found toxic and side effects; therefore in order to ensure invigorate blood circulation, effects such as antioxidation, antiinflammatory; adopt Radix Paeoniae and dicaffeoylquinic acid 5 usefulness, both having played synergism has increased curative effect, has overcome the adverse side effect that Radix Paeoniae may bring again.
Five. antiatherogenic pharmacological action
Influence to rabbit experimental atherosclerosis (AS) vascular remodeling
Material
Pharmaceutical composition of the present invention: peoniflorin+list/dicaffeoylquinic acid 3: 5,50mg/kg irritates stomach;
Normal control group: normal saline;
Model group: normal saline;
Positive control drug: list/dicaffeoylquinic acid (50mg/kg), Radix Paeoniae Alba extract (50mg/kg), probucol (25mg/kg).
Experimental technique
With purebred male new zealand rabbit, random packet, raised for 1 week after, adopt the continue method of feeding high lipid food of balloon injured endothelium to duplicate rabbit experiment AS model.Observed for 12 weeks.
Mensuration project and result
Histopathology: under the optical microscope, the complete no abnormality seen of normal control group endotheliocyte changes; The model group arterial endothelial cell is damaged, neointimal hyperplasia, and neointimal hyperplasia is serious during 6 weeks, tube chamber obvious stenosis and size are irregular, and the cell cytoplasm acidophilia is not obvious, a large amount of big or small irregular foam cells occur, the visible fat necrosis center that has, the visible a large amount of fusiformis proliferative cells of subintima; Damaged minimizing of each administration group endothelium thickens obviously and alleviates, and foam cell reduces, and is optimum with present composition group especially.
Tectology: maximum inner film thickness (MIT), minimum lumen diameter (MLD), tube chamber area (LA), interior elastic force film center on area (EELa) around area (IELa), outer elastic force film, and draw inner membrance area (IA), media area (MA), luminal stenosis percentage ratio (LS), wherein, IA=IELa-LA; MA=EELa-IELa; LS=LA/IELa.See the following form:
| Project | Normal control | Model group | Probucol | Radix Paeoniae | List/dicaffeoylquinic acid | Compositions |
| MIT(mm) IA(mm 2) MLD(mm) LA(mm 2) IELa(mm2) EELa(mm 2) MA(mm 2) LS(％) | 0 0 1.32±0.16 2.08±0.29 2.08±0.31 2.58±0.41 0.50±0.07 0 | 0.37±0.13 1.30±0.66 1.09±0.20 1.69±0.50 2.99±0.89 4.26±1.99 1.27±1.10 43.33±12.8 | 0.11±0.10 ** 0.45±0.27 ** 1.55±0.31 ** 3.14±1.22 ** 3.59±1.21 5.00±1.72 1.41±0.98 12.5±7.31 ** | 0.18±0.07 ** 0.33±0.30 ** 1.55±0.32 ** 3.05±1.10 ** 3.38±1.12 4.45±1.31 1.07±0.33 9.86±7.63 ** | 0.22±0.11 * 1.08±0.54 1.49±0.51 ** 3.10±0.93 ** 4.18±1.18 * 5.36±1.02 1.20±0.33 25.89±10.9 ** | 0.09±0.08 **Δ## 0.31±0.21 **## 1.50±0.39 ** 3.09±0.77 ** 3.40±1.15 4.11±1.05 0.76±0.4 **Δ## 8.87±7.19 **## |
Compare with model group
*P＜0.05,
*P＜0.01; Compare Δ P＜0.05, Δ Δ P＜0.01 with Radix Paeoniae; Compare #P＜0.05, ##P＜0.01 with list/dicaffeoylquinic acid.
Inner film thickness has been proved and has can be used as early stage arteriosclerotic useful indication.As seen from the above table, reducing aspect MIT, IA and LS, the increase LA, each administration group shows effect in various degree.Aspect the inhibition intimal proliferation, particularly evident with the present composition and the effect of probucol group, significantly be better than Radix Paeoniae group (P＜0.05).
Discuss
Known Radix Paeoniae and caffeoylquinic acids all have certain therapeutical effect to AS, but the emphasis difference of its anti-AS, share of Radix Paeoniae and caffeoylquinic acids, compatibility is relatively stable, can not produce chemical reaction and lost efficacy or the drug effect that detracts, on the contrary since treatment mechanism stress the direction difference, can produce more significant synergism, be better than the effect that Radix Paeoniae and other active component (for example Rhizoma Chuanxiong) share.
Six. the pharmacological action of anti-inflammatory aspect
Xylol causes the influence of mouse skin capillary permeability
Material
Pharmaceutical composition of the present invention: peoniflorin+chlorogenic acid 8: 1,30mg/kg, 50mg/kg irritate stomach;
Normal control group: normal saline;
Positive control drug: chlorogenic acid (50mg/kg); Radix Paeoniae Alba extract (50mg/kg); SHUANGHUANLIAN extract (50mg/kg);
Experimental technique
" herbal pharmacology research methodology " with reference to the Qi Chen chief editor makes the animal inflammatory model, the results are shown in following table:
| Group | The OD value |
| The normal control group SHUANGHUANLIAN Radix Paeoniae Alba extract chlorogenic acid present composition (low) present composition (height) | 0.067±0.022 0.031±0.023 ** 0.039±0.016 ** 0.033±0.015 ** 0.029±0.018 ** 0.023±0.011 **□# |
Compare with matched group,
*P＜0.05,
*P＜0.01; Compare with Radix Paeoniae Alba extract,
ΔP＜0.05,
The Δ ΔP＜0.01; Compare with chlorogenic acid,
#P＜0.05,
##P＜0.01
The result
No matter be Radix Paeoniae, chlorogenic acid, still generally acknowledged antipyretic and anti-inflammatory medicine SHUANGHUANLIAN, and the present composition, can alleviate mice caused by dimethylbenzene xylene capillary of skin permeability, has the effect that the early stage capillary permeability of inflammation-inhibiting increases, compare with matched group and to have significant difference, compare with the one pack system extract group of Isodose, high dose composition group of the present invention also has significant difference (P＜0.05).
And, the applicant further finds: the present invention combination both can suppress early stage inflammation owing to the hyperfunction swelling that causes of telangiectasis permeability, ooze out increase, but inflammation-inhibiting leukoplania in mid-term again, promptly to all presenting obvious suppression effect and effect in early stage, mid-term of inflammation and late period, infer that its mechanism may be that chlorogenic acid can suppress the synthetic of the interior inflammatory mediator PGE2 of body, peoniflorin then lays particular emphasis on the inflammation-inhibiting granulation tissue hyperplasia in late period.Therefore, the present invention finds that breakthroughly Radix Paeoniae and chlorogenic acid are under the prerequisite that all has antiinflammatory action, and two medicines share, and effect obviously strengthens, and demonstrates significant synergism.
Clinical observation
1. the clinical observation of treatment hyperlipemia
1.1 material and method
Case selected condition: (1) fasting plasma TC 〉=5.8mmol/L, TG 〉=1.8mmol/L; (2) no liver, kidney, abnormal thyroid function; (3) non-diabetic medical history can be with hypertension.
The first people of curing the disease that blood lipid level reaches inclusion criteria is totally 99 examples, wherein: hypercholesterolemia 63 examples (male 21 examples, women 42 examples, 55.9 ± 10.4 years old), hypertriglyceridemia 84 examples (male 36 examples, women 48 examples, 54.8 ± 9.3 years old), patient is equally divided into three groups more at random.The Xuezhikang treatment same period is matched group totally 37 examples (male 21 examples, women 16 examples, 52 ± 9 years old age), and four groups of case ages and sex are learned by statistics and handled no marked difference.
Medicine: (1) positive control drug: XUEZHIKANG JIAONANG (oral, 1.2g/ day); (2) the present invention combination (contained peoniflorin+total caffeoylquinic acids 1: 3, oral, 100mg/ day); (3) total caffeoylquinic acids (oral, 80mg/ day); (4) Radix Paeoniae Alba extract (oral, as to be equivalent to peoniflorin 40mg/ day).
1.2 observation index and result
Serum TC, TG and GDL-C measure with Enzymology method.Serum LDL-C calculates acquisition by Friedwald formula: LDL-C=TC-HDL-C-TG/2.2, the results are shown in Table 9.
The result shows, after 8 weeks of taking medicine, significantly reduces before combination of the present invention and Xuezhikang group patient's serum TC, TG level are all taken medicine, and total caffeoylquinic acids and Radix Paeoniae group be index there are no significant difference before and after the treatment then.This shows that behind combined therapy of the present invention, hyperlipemia serum TC, TG all can reduce, and effect is with to obey the 1.2g XUEZHIKANG JIAONANG every day identical, and obviously is better than using separately the therapeutic scheme of total caffeoylquinic acids and Radix Paeoniae.
Table 9 clinical observation result x ± s (n), mmol/L
| Group | TC | TG | LDL-C |
| Before taking medicine | |||
| The present invention makes up total caffeoylquinic acids Radix Paeoniae Xuezhikang | 7.11±1.22(21) 6.95±1.23(21) 7.13±1.32(21) 6.63±1.12(37) | 2.96±1.41(28) 2.67±1.36(28) 2.48±0.93(28) 1.69±0.54(37) | 3.62±1.17(33) 3.25±1.15(33) 3.73±1.08(33) 3.98±0.64(37) |
| Take medicine after 8 weeks | |||
| The present invention makes up total caffeoylquinic acids Radix Paeoniae Xuezhikang | 5.68±0.61(21) * 6.63±0.99(21) 6.71±1.23(21) 5.19±0.45(37) * | 2.29±1.37(28) * 2.58±1.28(28) 2.31±0.86(28) 1.35±0.19(37) * | 3.1 8±0.88(33) 3.06±1.05(33) 3.55±1.01(33) 2.59±0.34(37) * |
| Difference (%) before and after the administration | |||
| The present invention makes up total caffeoylquinic acids Radix Paeoniae Xuezhikang | -20.1 -4.6 -5.9 -21.7 | -22.6 -3.4 -6.8 -20.1 | -12.2 -5.9 -4.8 -34.9 |
*P＜0.01 with take medicine before compare on the same group
2. the clinical observation of cerebral infarction secondary prevention
2.1 object
Inclusion criteria: age＜75 year old; Cerebral infarction; Run initially or the secondary recurrent cases; After March acute stage; The CT/MRI diagnosis is arranged, and be consistent with clinical manifestation.
Exclusion standard: various hemorrhagic apoplexies; Three times and above cerebral seizure; Imaging examination is a cerebral infarction, and does not have the patient of clinical symptoms or sign; The patients with cerebral apoplexy that no CT/MRI makes a definite diagnosis; Cerebral infarction is in 3 months acute stages; The tumor apoplexy; Hematopathy; Serious hepatic and renal function damage; The tranquillization apoplexy.
2.2 method and result
The present invention combination: total caffeoylquinic acids extract (in dicaffeoylquinic acid), oral 120mg/ days, and Radix Paeoniae Alba extract (in peoniflorin) oral 20mg/ days, 420 examples;
Medicine contrast: aspirin, oral 75mg/ days, 480 examples;
Blank: do not provide aspirin or the present invention combination, 470 examples.
In the 30th, 60,90,180 day of the experiment beginning, observe whether the apoplexy recurrence is arranged, side effect symptoms such as (gastrointestinal upset, melena occur, feel sick) belch and serious side effects be (melena to occur, fecal occult blood is checked positive, melena, occult blood disappear for judging upper gastrointestinal hemorrhage side reaction foundation after the antiacid treatment of drug withdrawal), the evaluation recurrence must have CT/MRI to make a definite diagnosis.The results are shown in Table 10.
2.3 conclusion
Combination of the present invention and aspirin all can reduce the relapse rate of cerebral infarction, and both effects are suitable.Compare with the blank group, combination of the present invention and medicine matched group all have significant difference.
Take in 480 examples of aspirin, 37 routine side effect and 11 routine serious side effects occur; And take in 400 examples of the present invention's combination, have only 6 routine side effect, no serious side effects produces, and two groups of contrasts have significant difference.
The clinical observation result of table 10 secondary prevention
| 30 days | 60 days | 90 days | 180 days | The accumulation recurrence | |
| Composition of medicine contrast blank of the present invention composition of medicine contrast of the present invention blank | 11 11 16 1 11 2 | The 15 15 25 alimentary canal side reactions 3 21 2 of Stroke Recurrence rate | 17 21 42 5 28 5 | 26 28 53 6 37 8 | 6.2％ 5.8％ 11.3％ 1.42％ 7.71％ 1.70％ |
| Composition of medicine contrast blank of the present invention | 0 3 0 | Upper gastrointestinal hemorrhage side reaction 050 | 0 6 1 | 0 11 2 | 0.00％ 2.29％ 0.43％ |
Embodiment
Embodiment 1 capsule
Get Radix Paeoniae Rubra 5g, be ground into coarse powder, add 75% alcohol reflux three times, first and second time each 2 hours, 1 hour for the third time, merge extractive liquid,, be evaporated to about 400ml, use n-butanol extraction three times, each 300ml, merge n-butanol extracting liquid, be evaporated to no n-butyl alcohol flavor, add water 200ml, heating for dissolving, filter, the filtrate spray drying, it is standby to get extract I;
Get extract I portion, extracting honeysuckle extract (chlorogenic acid content is not less than 50%) 1g, add starch, magnesium stearate, mixing is in the hard capsule of packing into.After testing, contain chlorogenic acid 500mg and peoniflorin 100mg in every capsule.
Embodiment 2 tablets
Get coffee bean 5kg, the ethanol extraction with 95% gets petroleum ether part, ethyl acetate part and n-butyl alcohol part with petroleum ether, ethyl acetate and n-butanol extraction respectively after extract is water-soluble.The ethyl acetate part gets di-caffee acyl-oxy-quininic acid 8g and quininic acid 4g respectively through silica gel column chromatography and MCI column chromatography.Two coffees acyloxy-quininic acid 100mg, be dissolved in the aqueous solution heating for dissolving of making 0.1% concentration in the 1000ml water then, behind the mix homogeneously, seal in the medicine bottle of packing into, product is made in sterilization, and it is standby to get extract II.
Get two parts of extract I, the extract II portion of embodiment 1, add low-substituted hydroxypropyl cellulose, magnesium stearate, starch, microcrystalline Cellulose, granulate and the tablet forming technique granulation according to standard.After testing, contain dicaffeoylquinic acid 100mg/ sheet, peoniflorin 200mg/ sheet.
Embodiment 3 soft capsules
Get five parts of extract I moiety, the extract II of embodiment 1, add starch, magnesium stearate, mixing is made soft capsule according to standard technology.After testing, contain dicaffeoylquinic acid 500mg, peoniflorin 50mg in every capsule.
Embodiment 4 aqueous injection
Get Herba Erigerontis whole plant 30kg, the ethanol extraction with 95% gets petroleum ether part, ethyl acetate part and n-butyl alcohol part with petroleum ether, ethyl acetate and n-butanol extraction respectively after extract is water-soluble.The ethyl acetate part gets extract II I through silica gel column chromatography and MCI column chromatography.
Other gets peoniflorin 5g, and it is an amount of to add injection water and sodium chloride, adds said extracted thing III after the dissolving again, adds the injection water to 2000ml, filter, and embedding (10ml/ props up), sterilization, promptly.After testing, contain that total caffeic acid fat 150mg/ props up and peoniflorin 25mg/ props up.
Embodiment 5 lyophilized injections
Get list/dicaffeoylquinic acid mixture 25g, an amount of medicinal basic under the aseptic condition, add the injection water, stir and make dissolving approximately to 900ml, regulate pH value to 6.5-7.5, add peoniflorin 75g to dissolving, mix homogeneously, filtering with microporous membrane add the injection water to 1000ml.Then, 0.02% active carbon that adds amount of preparation stirs 5-10min, filter with aseptic suction funnel, and reuse sterilization sintered filter funnel fine straining or ultrafiltration, filtrate is sub-packed in 1000 5ml ampoules after the assay was approved, frozen drying, aseptic sealing by fusing is promptly.After testing, contain that caffeoylquinic acid 8mg/ props up, dicaffeoylquinic acid 15mg/ props up and peoniflorin 75mg/ props up.
Embodiment 6 functional health-care foods
It is an amount of to get propolis extract 100g (contain caffeic acid, caffeoylquinic acid is not less than 70%), Radix Paeoniae Alba extract (paeoniflorin content is not less than 50%) 100g, vitamin E 50g, sweetening agent, adjuvants such as adding starch are to gross mass 300g, mixing, become 1000 by the standard technology tabletting, promptly get the functional health-care food tablet.
Embodiment 7 functional health-care foods
Get coffee bean extract (total coffee acid ester content is not less than 50%, and is decaffeinated) 400g, peoniflorin 5g, sweetening agent, starch is an amount of, is prepared into granule by standard technology.
Embodiment 8 cosmetics
Herba Erigerontis extract (total coffee acid ester content is not less than 50%) 10g, vitamin E, poloxamer P188 and propylene glycol, heating for dissolving slowly splashes in the aqueous solution that contains Radix Paeoniae Rubra total glycosides 200g that is stirring, and obtains thick breast, through the dispersing emulsification machine circulating emulsion, the emulsion droplet particle diameter is less than 2.5 microns again.Embedding, 100 ℃ were heated 30 minutes, and promptly made the cosmetic breast.
Claims (12)
1. medicinal, functional health product or cosmetic composition comprise following active component:
A. the plant or the plant parts extract that contain list and/or dicaffeoylquinic acid, or list and/or dicaffeoylquinic acid monomer; With
B. the dry root powder of Radix Paeoniae, or contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae or peoniflorin monomer;
Wherein among the component a in list or dicaffeoylquinic acid and the components b part by weight of peoniflorin be 0.02-50: 1.
2. compositions as claimed in claim 1, described dicaffeoylquinic acid is selected from 1,5-two-O-caffeoylquinic acids, 1,3-two-O-caffeoylquinic acids, 1,4-two-O-caffeoylquinic acids, 3,5-two-O-caffeoylquinic acids, 3,4-two-O-caffeoylquinic acids, 4,5-two-O-caffeoylquinic acids, perhaps their mixture.
3. compositions as claimed in claim 1, described caffeoylquinic acid are selected from 3-caffeoylquinic acids, 5-caffeoylquinic acids, perhaps their mixture.
4. compositions as claimed in claim 1, described plant or plant parts are selected from: Fructus Xanthii, Helianthi, Folium Artemisiae Argyi, Caulis et Folium Chrysanthemi segeti, Herba Erigerontis, Herba Artemisiae Scopariae, Flos Inulae, Radix Asteris, Cynara scolymus L (Cyhara cardunculus.), Herba Lactucae Indicae, the shady Herba Senecionis Scandentis of woods, and propolis, the Cortex Eucommiae, Flos Lonicerae and other caprifoliaceae plant, the wood that continues, coffee, cocoa tree, siphonostegia chinensis, Echinacea angustifolia, Folium Ilicis and other Holly, Rhizoma Dioscoreae esculentae leaf, Rhizoma Dioscoreae esculentae, Fructus Gardeniae, Rhizoma Solani tuber osi, Hedera plant or Dichrocephala plant.
5. compositions as claimed in claim 1, described component a is the coffee-extract that contains list and/or dicaffeoylquinic acid.
6. compositions as claimed in claim 5 also contains caffeic acid in the described coffee-extract.
7. as the compositions of claim 5 or 6, described coffee-extract is decaffeinated.
8. compositions as claimed in claim 1, described active component a is the Flos Lonicerae extract that contains list and/or dicaffeoylquinic acid.
9. compositions as claimed in claim 1, described active component a is the Herba Erigerontis extract that contains list and/or dicaffeoylquinic acid.
10. compositions as claimed in claim 1, described active component a is the Cortex Eucommiae extract that contains list and/or dicaffeoylquinic acid.
11. compositions as one of claim 1-10, the part by weight that also contains peoniflorin in list among Hydroxy peoniflorin, oxypaeoniflorin, benzoylpaeoniflorin and/or lacdtlorin and the component a or dicaffeoylquinic acid and the components b in the described Radix Paeoniae Alba extract is 0.05-20: 1.
12., be the product that oral administration or non-intestinal are used as the compositions of one of claim 1-11.
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