CN102091146A - Composite containing gingko extract or monomer - Google Patents
Composite containing gingko extract or monomer Download PDFInfo
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- CN102091146A CN102091146A CN2009102505495A CN200910250549A CN102091146A CN 102091146 A CN102091146 A CN 102091146A CN 2009102505495 A CN2009102505495 A CN 2009102505495A CN 200910250549 A CN200910250549 A CN 200910250549A CN 102091146 A CN102091146 A CN 102091146A
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- radix paeoniae
- fructus gardeniae
- ginkgetin
- peoniflorin
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Abstract
The invention relates to a composite for a medical or functional health-care product as well as a preparation method and application thereof. The composite contains natural plant extracts or monomers as active components. The medical composite can be used for treating and/or preventing diabetes, cardiovascular and cerebrovascular diseases, senile dementia and hyperlipidaemia and preparing the functional health-care product which an auxiliary hypolipidemic function, an auxiliary hypoglycemic function, an antioxidant function and an auxiliary memory improving function.
Description
Technical field
The present invention relates to medicinal or the functional health product combination, specifically, is a kind of contain natural plant extracts or monomer combination and application aspect medicine, functional health product thereof.Compositions can be used for treating and/or preventing diabetes, cardiovascular and cerebrovascular disease, senile dementia, hyperlipemia, and be used for having auxiliary lipid-lowering function, the functional health product of auxiliary hyperglycemic function, anti-oxidation function, auxiliary improving memory function.
Background technology
Cardiovascular and cerebrovascular disease and diabetes are deadly diseases of serious threat human health, and the sickness rate of apoplexy, coronary heart disease, diabetes is more and more high at present, and becomes younger day by day, is the highest disease of mortality rate except that malignant tumor.At these three kinds of chronic diseases, the mankind still do not have the radical cure way at present.
Cardiovascular and cerebrovascular disease and diabetes are diseases of one group of height correlation, and same patient often suffers from the multiple disease in above-mentioned three kinds of diseases simultaneously, such as suffering from coronary heart disease and diabetes simultaneously.At present, modern medicine has realized that the generation of above-mentioned disease, development have numerous identical pathomechanisms, these pathological changes or reciprocal causation or addition each other, thus cause disease to take place.
At present, medical circle generally acknowledges that insulin resistant (IR) is cardiovascular and cerebrovascular disease and the total pathogenesis of diabetes.Body can cause a series of pathological change after producing insulin resistant because of a variety of causes, such as: obesity, hyperlipidemia, carbohydrate tolerance reduction etc.As time goes on, hypertension, atherosclerosis be will progressively produce, thereby coronary heart disease and apoplexy caused.Certainly, insulin resistant itself is exactly the early stage performance of diabetes, and its natural history must cause the generation of diabetes.Because these common paathogenic factors, people recognize gradually, and the high-risk group of above-mentioned disease often possesses symptoms such as obesity, hyperlipidemia, hypertension, impaired glucose tolerance, medically is referred to as metabolic syndrome (MS).The people who possesses the MS performance, its probability that cardiovascular and cerebrovascular disease and diabetes take place is higher than the normal person far away, we can say that MS is cardiovascular and cerebrovascular disease and diabetes " omen " disease, and control MS is actually the generation of prevention cardiovascular and cerebrovascular disease and diabetes.
Therefore, for there being insulin resistant but as yet the crowd of morbidity not treats intervention at insulin resistant, is that the above-mentioned disease of prevention takes place essential and effective means.
If coronary heart disease, apoplexy take place, no matter be that acute stage or convalescent care have common intervention target spot too, such as: antioxidation and antiinflammatory.For acute stages treated, antioxidation and anti-inflammatory drug can reduce the death of cell, reservation function to greatest extent.For convalescent care, antioxidation and antiinflammatory and blood fat reducing can delay atherosclerotic generation, reduce the probability that thrombosis (or hemorrhage) takes place once more.
As from the foregoing, glucagon opposing, antioxidation, anti-inflammatory response and blood fat reducing are common, the essential control target spots of MS, cardiovascular and cerebrovascular vessel and diabetes.
Regrettably, prior art still can't provide the single medicine that possesses above-mentioned four kinds of pharmacological actions simultaneously.Existing medicine often all is to intervene (treatment) at single pathomechanism (target spot).Only at hypertension, blood lipid-lowering medicine is only at hyperlipidemia such as, antihypertensive drug, and diabetes medicament is only at diabetes, or the like.Therefore, a patient often will use multiple medicine in treatment, and this not only causes patient's inconvenience of taking medicine, and even more serious is: numerous medicines tend to bring more side effect, brings difficulty also for simultaneously doctor's clinical treatment decision-making.
So there is intensive demand this area to many target drugs of cardiovascular and cerebrovascular disease and diabetes control.
The world of medicine's practice is for many years recognized people, and the unification compound is difficult to satisfy many target spots pharmacological action demand.Therefore, this area scientific research personnel begins to consider to fall multiple existing chemical compound and is combined into the compound medicine use, so that satisfy the demands.Simultaneously, also there are more and more many people to turn one's attention to " natural " medicinal plants, because natural drug has the irreplaceable advantage of chemical synthetic drug.And along with the high speed development of modern science, various compositions can be by sharp separation and evaluation in the plant amedica, and this lays a good foundation for the development of natural drug.
In recent years, many work is being done by the world of medicine aspect the medicinal plants study of this area, strengthened analysis and research to bioactive substance, in the hope of further clear and definite its effect.Yet the effect that obtains is limited.This mainly is the pathogenesis complexity owing to cardiovascular and cerebrovascular vessel and diabetes, and normal with one or more different classes of complication, existing single active skull cap components is difficult to comprehensive proving effective.
It is reported that jasminoidin and peoniflorin all can blood sugar lowering, but mechanism of action is not fully aware of separately (referring to: the experimentation new Chinese medicine of Fructus Gardeniae hypoglycemic activity and clinical pharmacology in January, 2006, the 17th rolled up for the 1st phase); New Chinese medicine and clinical pharmacology 2006,17 (1): 1-3; Planta Med 1997,63 (4): 323).Semen Ginkgo extrac (mainly containing ginkgetin and bilobalide) has effects such as antioxidation, antiinflammatory, blood fat reducing.
For plant amedica, maximum advantage is to have the pharmacological action of many target spots, but its inferior position also is that significantly that is exactly that single medicinal material activity (drug effect) is lower.Therefore, reasonably plant amedica exploitation direction is not to adopt the multi-flavor medicine to increase the pharmacological action target spot, but obtains synergism with the least possible flavor medicine, improves drug effect.
Yet, up to now, at Semen Ginkgo, Radix Paeoniae can with the Fructus Gardeniae use in conjunction, three's mechanism of action is underlying issues such as adduction, collaborative or antagonism, prior art does not provide scientific basis even similar hint or attempt not.
Summary of the invention
The inventor has carried out a large amount of benefiting our pursuits to the potentiality of Fructus Gardeniae and the coupling of other plant active component on the basis of series of studies in early stage, and has obtained many gratifying results.
One object of the present invention is to provide the application in the diseases such as treating and/or preventing metabolism syndrome, diabetes and complication thereof, cardiovascular and cerebrovascular disease, senile dementia, hyperlipemia of being combined in of Semen Ginkgo (mainly containing ginkgetin and bilobalide), ginkgetin, bilobalide, Radix Paeoniae, Fructus Gardeniae.
Below the present invention is further elaborated.
Metabolism syndrome, diabetes
In the research in inventor early stage, with regard to should be used as studying and proving good curative effect is arranged in the diseases such as diabetes and cardiovascular and cerebrovascular disease, senile dementia, hyperlipemia that be combined in of caffeoylquinic acids and Radix Paeoniae and caffeoylquinic acids and Radix Paeoniae, Fructus Gardeniae.But these two kinds are made up the former aspect arteriosclerosis.To this, we select for use Semen Ginkgo to substitute caffeoylquinic acids to add combinations thereof, when expectation produces beneficial effect to the pathogenic factors of MS most critical, simultaneously can also arteriosclerotic therapeutic effect, and the result is unexpected satisfactory.
In the prior art, the combination coupling scheme about Semen Ginkgo and Radix Paeoniae, Fructus Gardeniae does not provide enough technology even theoretic supports.
Proof drug regimen of the present invention has the excellent treatment effect to arteriosclerosis and metabolism syndrome in experiment described later, 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 jasminoidin acts on different target spots with Semen Ginkgo (mainly containing ginkgetin and bilobalide), Radix Paeoniae, especially at different pathological stages performance therapeutical effect, brought into play the wholistic therapy advantage of drug combination.Especially it should be noted that with Semen Ginkgo, Radix Paeoniae or the Fructus Gardeniae of independent use and compare that the present composition has significantly reduced the animal subject insulin resistant.
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 also find, 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).
This may be 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);
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.
Therefore, another object of the present invention is to be provided in Semen Ginkgo and (is used for preventing the application of the medicine of cardiovascular and cerebrovascular disease recurrence in preparation with Radix Paeoniae, Fructus Gardeniae.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.
Hyperlipemia
In research, find that also the present invention makes up the effect with blood lipid regulation at above-mentioned disease.
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 Fructus Gardeniae, Semen Ginkgo (mainly containing ginkgetin and bilobalide), Radix Paeoniae separately, perhaps provide with the compositions/products form that contains the three simultaneously.
Therefore, another object of the present invention is to be provided for containing the Pharmaceutical composition of Fructus Gardeniae, Radix Paeoniae, Semen Ginkgo, form by the active component of 2-98wt.% and the pharmaceutic adjuvant of 98-2wt.%, wherein in jasminoidin, ginkgetin or bilobalide, peoniflorin, three's weight portion is 10-200, preferred 15-150, more preferably 20-100.
In the present composition, comprise described active the composition:
A). with the material of Semen Ginkgo main active: Semen Ginkgo extrac (for example Folium Ginkgo extract of lower alcohol, acetone, ethyl acetate), mainly contain bilobalide and ginkgetin Semen Ginkgo extrac (for example standard extract Egb) as active component, or ginkgetin monomer and ginkgolide monomer, or ginkgolide monomer, or ginkgetin monomer.Wherein, described bilobalide (Ginkgolides) is meant the mixture that contains various Semen Ginkgo terpene lactone materials (diterpenoid-lactone A, B, C, M, J, sesquialter lactone etc.); " ginkgolide monomer " is meant the monomer of various lactone materials in the above-mentioned terpene lactone and/or its derivant or its chemical modification object, analog.Described ginkgetin is meant the mixture that contains various ginkgetin materials (ginkgetin and glycosides thereof, total flavones alcohol and glycosides thereof, bisflavone, catechin etc.); " ginkgetin monomer " is meant the monomer of various Flavonoid substances in the above-mentioned flavone and/or its derivant or its chemical modification object, analog.
B). (be geniposide, Geniposide) be the material of main active: contain the Fructus Gardeniae extract of Fructus Gardeniae total glycosides, for example water extract of Fructus Gardeniae, alcohol extract, or Fructus Gardeniae total glycosides, or jasminoidin monomer or derivatives thereof with jasminoidin.Fructus Gardeniae total glycosides is meant the mixture of iridoid glycoside, main active jasminoidin wherein, also can contain Gardenoside (gardenoside), shanzhiside (shazhiside), Fructus Gardeniae ketoside (gardoside) and genipic acid glycosides, wherein also can contain crocin (crocin), crocetin (crocetin).It will be understood by those skilled in the art that, the extraction of jasminoidin and preparation method are known technology (for example Chinese patent application CN200510026143.0, CN02124158.9, ZL03109126, ZL 03122071, ZL 03137512, ZL 03137512, ZL200310111038), do not give unnecessary details at this.
C). 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.
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.
Advantageously, above-mentioned active component is when being used as medicine with form of extract, the purity of jasminoidin in described extract is 20-98wt%, preferred 50%, 90wt% or 98wt%, and the purity of peoniflorin in described extract is 2-98wt%, preferred 25%, 50%, 80wt% or 98wt%; Ginkgetin and or the purity of bilobalide in described extract be 5-98wt%, preferred 40%, 85wt% or 98wt%.
In context, " the present invention's (medicinal) combination " related term " Fructus Gardeniae ", " Semen Ginkgo ", " Radix Paeoniae " has above-mentioned definition.
Following test will confirm: the combination with above-mentioned definition it " Fructus Gardeniae ", " Semen Ginkgo " 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: Dalian Medical Univ's journal (2005,2:91-92), the Gansu traditional Chinese medical science (2005,7:59-60), Jiamusi University's journal natural science edition (2004,1:87-89), Mountain Western Medicine S University's journal (2003,4:316-317), modern food and medicine magazine (2006,3:76-78), China pharmacist (2006,2:100-101), ZL98112256, ZL98112256, ZL200310114437.X, ZL01128909.0, ZL01128909, ZL99814365, ZL96115742.9, ZL200610065718, ZL200310104132, 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 (North China national defence medicine 2006,4:13-15 in the dissolution characteristics of Fructus Gardeniae, peoniflorin, Semen Ginkgo and the body; China Medicine University's journal 2003,34 (01): 65-9; 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, ZL200310104199, ZL200310103556, ZL200410155481); 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, ZL200410014270); Soft capsule (ZL01117620); Injection or infusion solution (ZL03129007, ZL200410008734, ZL200410022438, ZL200410080023, ZL93106319, ZL95104038, ZL97101107, ZL02155001, ZL021332983, ZL031279953, ZL03141614, ZL03113037, ZL2003101210259, ZL200410013845, ZL200410050868, ZL03133967, ZL01124953.6, ZL03117287.3, ZL03133967.0); Or contain phospholipid preparation (ZL03111469, ZL01138902, ZL03153496).
In the clinical use of the present composition, exemplary every day, oral recommended dose was: the preferred 4-16mg of bilobalide 2mg-30mg), the preferred 20-60mg of ginkgetin 10-100mg), peoniflorin 10-120mg (preferred 20-80mg), jasminoidin 20-400mg (preferred 40-200mg).
Said medicine of the present invention makes up shortcomings such as the effect that has overcome existing medicine existence is single, side reaction is serious, dosage is big, has represented the development trend of natural drug treatment and prevention of metabolic syndrome, diabetes and complication thereof, senile dementia, cardiovascular and cerebrovascular disease, hyperlipemia.
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, and described health product are made up of with adjuvant the active component of 2-98wt.% and the health product of 98-2wt.%.
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, anti-oxidation function, auxiliary improving memory 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 Semen Ginkgo extrac extract and Radix Paeoniae Alba extract, the Fructus Gardeniae extract that contain ginkgetin and bilobalide to make up, also can directly select the combination of ginkgetin and/or bilobalide and peoniflorin, jasminoidin, also can select to contain bilobalide and or other plant extract of ginkgetin 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.
The pharmacology pharmacodynamic experimental study
One. the pharmacological action of metabolism syndrome and diabetes aspect
1. to the influence of blood glucose in diabetic rats due to the chain assistant rhzomorph and serum insulin
Method:
Get male SD rat and prepare low dose of chain assistant rhzomorph by standard method and cause diabetes rat model, behind the 3d according to rat blood sugar value random packet, 8 every group.
Each organizes continuous gastric infusion 8d, and every day 1 time, blank group gives the equivalent distilled water.2 hours (metformin group 1 hour) plucked eyeball and got blood after the last administration, measures blood glucose and serum insulin.
Experiment medicine: positive drug metformin group: 300mg/kg;
Semen Ginkgo group (mg/kg): Semen Ginkgo extrac (flavonoid of ginkgo biloba 50%) 100;
Radix Paeoniae group (mg/kg): peoniflorin 80
Fructus Gardeniae group (mg/kg): Fructus Gardeniae extract (Fructus Gardeniae total glycosides content 60%) 120;
Cape jasmine Chinese herbaceous peony group (mg/kg): [jasminoidin: peoniflorin=1: 1] 160
Combination A group (mg/kg): [Semen Ginkgo extrac (flavonoid of ginkgo biloba 50%): Fructus Gardeniae extract (Fructus Gardeniae total glycosides content 60%): peoniflorin=10: 1: 10] 100,50;
Combination B group (mg/kg): [bilobalide: Fructus Gardeniae total glycosides: peoniflorin=1: 10: 10] 100,50;
Combination C group (mg/kg): [ginkgetin: Fructus Gardeniae total glycosides: peoniflorin=1: 5: 1] 100,50;
The result:
Rat diabetes blood glucose and serum insulin influence due to the table 1 pair chain assistant rhzomorph (X ± s)
*: with the contrast of blank group, front and back difference P＜0.5;
*: with the contrast of blank group, front and back difference P＜0.01
Experiment shows: the metformin group can effectively reduce this rat model blood glucose, and difference has significance, but does not improve the rat blood serum insulin level.The Fructus Gardeniae group raises to serum insulin the significance influence, but does not have obvious blood sugar reducing function.Semen Ginkgo group is to there are no significant the influence of blood glucose and serum insulin, and Radix Paeoniae group and Fructus Gardeniae group can blood sugar lowering, but the difference not statistically significant does not have influence to insulin level.
Each dosage group of the present composition all can reduce rat blood sugar, and its effect is better than metformin or suitable with it, and each heavy dose of group can be improved serum insulin.
2. the influence that rat insulin is resisted
2.1 material and method
Male Wistar rat, body weight (160 ± 20) g is divided into 7 groups at random with rat.
Matched group: continue to give normal diet (360 kilocalories/100g) nursing of heat;
High fat group: contain the feedstuff (475 kilocalories/100g) nursing of heat of higher unsaturated fatty acid;
Compositions A group: give to give when high fat is fed present composition A (ginkgetin 60mg, peoniflorin 40mg, jasminoidin 80mg)/d;
Compositions B group: give to give when high fat is fed present composition B (bilobalide 8mg, Radix Paeoniae Alba extract (peoniflorin 60%) 70mg, jasminoidin 5mg)/d;
Radix Paeoniae group: give to give when high fat is fed Radix Paeoniae 20mg/d;
Fructus Gardeniae group: give to give when high fat is fed jasminoidin 80mg/d;
Semen Ginkgo group: give to give when high fat is fed Semen Ginkgo extrac (being equivalent to ginkgetin 60mg, bilobalide) 8mg/d.
Below respectively organize feeding during 11 weeks, the glucose tolerance of going is respectively tested, and measures fasting glucose (FPG), fasting insulin (Fins) and homocysteine in plasma (Hcy).
Glucose tolerance test: irritate stomach (dosage 2g/kg body weight) with glucose, after irritating stomach 30min, 1,2h respectively the tail vein get blood, survey each time point blood glucose value, and calculate area (AUCglu) under the blood glucose curve.
2.2 result
Respectively organize during table 2 off-test metabolic index comparison (X ± S, n=8)
| FIns(mIU/L) | FPG (mmol/L) | AUCglu | Hcy (μmol/L) | Test back weight increase (g) | |
| Matched group | 0.21 0.17-0.32 | 4.67±0.32 | 678±23.1 | 682±26.2 | 248±20.4 |
| High fat group | 0.97 0.48-1.29 *# | 5.70±0.31* # | 758±26.5 *# | 749±23.5 *# | 297±23.4 *# |
| Compositions A group | 0.53 0.25-1.12 # | 4.72±0.22 | 699±17.5 | 706±24.3 | 250±23.8 |
| Compositions B group | 0.52 0.28-0.91 # | 4.75±0.25 | 692±18.2 | 711±25.3 | 253±22.9 |
| The Radix Paeoniae group | 0.71 0.31-103^ # | 5.28±0.24^ | 719±22.5 *^ | 726±25.6^ | 272±23.1^ |
| The Fructus Gardeniae group | 0.96 0.33-1.43 *# | 5.45±0.31* # | 760±24.5 *# | 745±23.2* # | 303±26.5 *# |
| The Semen Ginkgo group | 0.88 0.46-1.34 *# | 5.62±0.26* # | 755±21.2* # | 763±25.2* # | 294±24.9 *# |
Annotate: compare #P＜0.01 with matched group; Organize relatively * P＜0.01 with compositions A, B; Compare ^P＜0.05 with high fat group.
Discuss:
Insulin resistant (IR) and high Hcy are the key factors of metabolism syndrome, studies show that in a large number both are all relevant with cardiovascular and cerebrovascular disease and type 2 diabetes mellitus patient sickness rate and case fatality rate big, microvascular complication, gently the hyperhomocysteinemiainjury to moderate significantly increases the heart, cerebrovascular disease sickness rate and case fatality rate.Above-mentioned experimental result shows, two groups of the present compositions can significantly improve insulin resistant level, blood sugar lowering, Hcy and the body weight of rat after the high fat diet, relatively have significant difference (P＜0.01) with high fat group, Fructus Gardeniae group, Semen Ginkgo group, comparing effect with the Radix Paeoniae group also has raising.
Therefore, the present composition has obvious therapeutic effect for the principal element of MS, and is better than Radix Paeoniae, Semen Ginkgo and the jasminoidin of using separately, shows that compositions has synergism.
3. insulin resistant (IR) rat model is transferred the fat effect
3.1 material and method
The healthy SD rat, body weight (180 ± 15) g, 80, male and female half and half, completely random is divided into 7 groups: normal control group, model group, lovastatin (captopril, 1mg/kg) two groups of group, peoniflorin group (40mg/kg), Fructus Gardeniae group (20mg/kg), ginkgetin group (20mg/kg), the present compositions (Semen Ginkgo extrac+peoniflorin of the apricot yellow ketone 70% of argentiferous+Fructus Gardeniae total glycosides 15: 1: 20,30mg/kg), (Semen Ginkgo extrac+peoniflorin of bilobalide-containing 50%+Fructus Gardeniae extract (total glycosides 85%) 50: 15: 35,20mg/kg), every group of 10 animals.The normal control group is fed normal feedstuff, and all the other rats feed high fat, high sugar feed (normal feedstuff 42%, Adeps Sus domestica 23%, sucrose 24%, Sal 5%), and drink 1% saline solution.After high fat, high sugar and high salt raised for 8 weeks, the rat diet condition was constant, model group and rats in normal control group intramuscular injection 50% propylene glycol 0.8ml/kg, and all the other respectively organize the rat corresponding medicine of intramuscular injection respectively, every day 1 time, 4 weeks of successive administration.
3.2 result
Influence to IR rat model blood lipid level: at 4 weekends of successive administration, model group, Radix Paeoniae group, Semen Ginkgo group, Fructus Gardeniae group TC, TG, LDL-C level all are significantly higher than normal control group (P＜0.01), and HDL-C level and normal control group difference are not remarkable.Lovastatin group, the present composition respectively organize TC, LDL and TG level (P＜0.01 or P＜0.05) all significantly is lower than model group.
Discuss:
Insulin susceptibility descends during insulin resistant, and the biological effect that the insulin of normal concentration causes in the circulation of body inner blood is lower than normally.IR often with the opposing of the glucose uptake of insulin-mediated, carbohydrate tolerance go down, hyperinsulinemia, hypertension, coronary heart disease, lipid metabolic disorder etc.Interact between IR and the hyperlipidemia, cause the state of an illness constantly development and deterioration.
This experimental result shows that the present composition has the effect that reduces the IR rat fat, and effect obviously is better than corresponding one pack system and uses.
Two. the pharmacological action for the treatment of cardiac and cerebral vascular diseases
1. to the protective effect (to the influence of brain water content) of rat test cerebral ischemia
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: jasminoidin+Semen Ginkgo extrac (being equivalent to ginkgetin 30mg, bilobalide) 6mg)+Radix Paeoniae Alba extract (peoniflorin 65%) 20: 1: 20
Influence (X ± S) (n=10) of table 3 pair experimental cerebral ischemia rat brain water content
Compare with matched group,
*P＜0.05,
*P＜0.01
As seen from the above table, the Radix Paeoniae Alba extract group cerebral edema that cerebral ischemia causes to imperfection of each group of the present invention, Edaravone and single prescription all demonstrates protective effect, and Fructus Gardeniae and Semen Ginkgo extrac group do not have 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); show that its cerebral edema that cerebral ischemia causes to imperfection has significant protective effect, and be better than one pack system group and Edaravone group.
2. 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.
2.1 material
Drug regimen A of the present invention: Fructus Gardeniae total glycosides+peoniflorin+ginkgetin 6: 4: 2, with 10,20, the 40mg/kg injection;
Drug regimen B of the present invention: jasminoidin+Radix Paeoniae Alba extract (peoniflorin 80%)+bilobalide 10: 20: 2, with 10,20, the 40mg/kg injection;
Blank group: normal saline;
Positive control drug (injection): peoniflorin, 10mg/kg; Ginkgetin, 10mg/kg; Bilobalide, 2mg/kg; Jasminoidin, 10mg/kg;
2.2 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)
2.3 result
Conclusion
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%.
Pharmaceutical composition of the present invention is respectively organized, peoniflorin is inhibited to the abnormality proliferation of vascular smooth muscle cell (VSMCs), and pharmaceutical composition wherein of the present invention is the strongest, and peoniflorin takes second place, and Fructus Gardeniae does not have effect substantially.Drug regimen of the present invention and peoniflorin and ginkgetin and bilobalide relatively have significant difference between group.
Three. the pharmacological action of senile dementia aspect
1. to the effect of the VD model of ischemia-reperfusion preparation
Rat be divided into model group, jasminoidin group, Semen Ginkgo group (containing ginkgetin, bilobalide), peoniflorin group and;
Present composition A group (ginkgetin+peoniflorin+Fructus Gardeniae total glycosides 6: 20: 2);
Present composition B group (bilobalide+peoniflorin+jasminoidin 1: 20: 1);
Present composition C group [Semen Ginkgo extrac group (containing ginkgetin and bilobalide)+Radix Paeoniae Alba extract (60% paeoniflorin content)+Fructus Gardeniae extract (85% jasminoidin content) 20: 2: 1] with A, B group equivalent;
Continuous oral administration before the preparation model prepares the VD rat model with ischemia-reperfusion repeatedly then, the content of malonaldehyde (MDA) in the mensuration hippocampal tissue.
The table 4. pair influence comparison (n=10) of pouring into MDA content in the VD rat hippocampus tissue for preparing again
Compare with model group,
*P＜0.1,
*P＜0.05,
* *P＜0.01
Last table shows that each group of the present composition and peoniflorin group all can reduce rat hippocampus MDA content, but the most remarkable with the effect of each group of the present composition, ginkgetin, bilobalide and then several no effects of Fructus Gardeniae group.
Four. the pharmacological action of antioxidation aspect
Present composition A, B: jasminoidin+peoniflorin+(10% bilobalide+90% ginkgetin) 1.: 1: 1,50mg/kg, jasminoidin+peoniflorin+(10% bilobalide+90% ginkgetin) 1: 10: 1,50mg/kg irritates stomach;
Normal group: normal saline is irritated stomach;
The hyperlipidemia group: normal saline is irritated stomach;
The contrast medicine: Semen Ginkgo (10% bilobalide+90% ginkgetin) (20mg/kg); Radix Paeoniae Alba extract (50mg/kg); Jasminoidin (20mg/kg) is irritated stomach;
Positive control drug: rosiglitazone group: 3mg/kg irritates stomach
Experimental technique
The foundation of model: after SD rat adaptability raised for 1 week, random packet, 8 every group.Normal group is fed normal feedstuff, drinks the tap water of cleaning.All the other rats feed high fat, high sugar feed (normal feedstuff 42%, Adeps Sus domestica 23%, sucrose 24%, Sal 5%), and drink 1% saline solution.Once a day, medicine is irritated stomach, gets the hematometry observation index after continuous 4 weeks.
The result
The influence (nmol/L) of table 5. pair rat blood serum and liver LPO and SOD
Compare with the hyperlipidemia group
*P＜0.05
*P＜0.01; Compare with the contrast medicine,
ΔP＜0.05,
The Δ ΔP＜0.01;
Experiment shows that the Semen Ginkgo of using separately, Radix Paeoniae Alba extract and jasminoidin all show certain antioxidant activity but be and not obvious.The present composition has obvious antioxidation activity, and the Radix Paeoniae that effect is better than using separately, Semen Ginkgo and Fructus Gardeniae (P＜0.01) show that three's synergism in the present composition has strengthened the antioxidation of each single medicinal material, and playing synergism has increased curative effect.
Five. antiatherogenic pharmacological action
1. to the influence of rabbit experimental atherosclerosis (AS) vascular remodeling
1.1 material
The present composition: [Fructus Gardeniae extract (total glycosides 50%)+peoniflorin+(30% bilobalide+70% ginkgetin)]=(1: 1: 10,20: 1: 1), 50mg/kg irritates stomach respectively;
Normal control group: normal saline;
Model group: normal saline;
The contrast medicine: Semen Ginkgo (30% bilobalide+70% ginkgetin) (50mg/kg), Radix Paeoniae Alba extract (50mg/kg), Fructus Gardeniae total glycosides (50mg/kg), probucol (25mg/kg).
1.2 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.
1.3 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 each group of the present composition 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=IA/IELa.
Inner film thickness has been proved and has can be used as early stage arteriosclerotic useful indication, and this experiment reality is reducing aspect MIT, IA and LS, the increase LA, and each administration group shows in various degree and acts on.Aspect the inhibition intimal proliferation, particularly evident with the present composition and the effect of probucol group, significantly be better than Fructus Gardeniae, Radix Paeoniae and Semen Ginkgo group.
Discuss
Known Radix Paeoniae and Semen Ginkgo all have certain therapeutical effect to AS, but the emphasis difference of its anti-AS, share of Fructus Gardeniae, Radix Paeoniae and Semen Ginkgo, 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 of Radix Paeoniae, the single usefulness of Semen Ginkgo.
Six. the pharmacological action of anti-inflammatory aspect
1. xylol causes the influence of mouse skin capillary permeability
1.1 material
Pharmaceutical composition A of the present invention: jasminoidin+peoniflorin+(50% bilobalide+50% ginkgetin) 3: 15: 2,50mg/kg irritates stomach;
Pharmaceutical composition B of the present invention: Fructus Gardeniae extract (80% jasminoidin)+peoniflorin+(70% bilobalide+30% ginkgetin) 20: 5: 1,50mg/kg irritates stomach;
Matched group: normal saline;
Positive control drug: jasminoidin (50mg/kg); Semen Ginkgo (50% bilobalide+50% ginkgetin) (40mg/kg); Radix Paeoniae Alba extract (50mg/kg); SHUANGHUANLIAN extract (50mg/kg);
1.2 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:
Compare with matched group,
*P＜0.05,
*P＜0.01; Compare Δ P＜0.05 with Radix Paeoniae Alba extract; Compare #P＜0.05 with Semen Ginkgo and jasminoidin
1.3 result
No matter be Radix Paeoniae, Semen Ginkgo, jasminoidin or 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, the present composition also has significant difference (P＜0.05) for two groups.
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 Semen Ginkgo 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, and Fructus Gardeniae might possess the effect that reduces capillary permeability.Therefore, present composition effect obviously strengthens, and demonstrates significant synergism.
Example of formulations
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 Fructus Gardeniae 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 II;
Get extract I, each portion of II, get Semen Ginkgo extrac (flavonoid of ginkgo biloba is not less than 50%) 100mg, add starch, magnesium stearate, mixing is in the hard capsule of packing into.After testing, contain ginkgetin 50mg, peoniflorin 100mg and jasminoidin 100mg in every capsule.
Get five parts of extract I, (bilobalide content the is not less than 10%) 100mg that gets Semen Ginkgo extrac, get the extract II moiety, add starch, magnesium stearate, mixing is in the hard capsule of packing into.After testing, contain bilobalide 10mg, peoniflorin 500mg and jasminoidin 50mg in every capsule.
Embodiment 2 tablets
Get two parts of extract I, extract II portion, the ginkgetin 200mg 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 ginkgetin 100mg/ sheet, peoniflorin 100mg/ sheet and Fructus Gardeniae total glycosides 100mg.
Get four parts of extract I moiety, extract II, the bilobalide 4mg 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 bilobalide 40mg/ sheet, peoniflorin 50mg/ sheet and jasminoidin 20mg.
Embodiment 3 soft capsules
Get extract I moiety, extract II moiety, the Semen Ginkgo extrac 1g of embodiment 1, add starch, magnesium stearate, mixing is made soft capsule according to standard technology.After testing, contain ginkgetin 50mg, bilobalide 12mg, peoniflorin 50mg and jasminoidin 50mg in every capsule.
Embodiment 4 lyophilized injections
Get Semen Ginkgo extrac thing 20g, 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 and jasminoidin 10g 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 bilobalide 8mg/ props up, ginkgetin 40mg/ props up, peoniflorin 75mg/ props up and jasminoidin 10mg/ props up.
Embodiment 5 functional health-care foods
Get Semen Ginkgo extrac 50g (the apricot yellow ketone of argentiferous is not less than 50%), Radix Paeoniae Alba extract (paeoniflorin content is not less than 50%) 50g, Fructus Gardeniae extract (containing jasminoidin 90%) 200g, vitamin E 50g, sweetening agent is an amount of, adjuvants such as adding starch are to gross mass 500g, mixing, become 1000 by the standard technology tabletting, promptly get the functional health-care food tablet.
Get Semen Ginkgo extrac 400g (bilobalide-containing is not less than 10%), peoniflorin 5g, jasminoidin 20g, sweetening agent is an amount of, adds adjuvant such as starch to gross mass 500g, mixing becomes 1000 by the standard technology tabletting, promptly gets the functional health-care food tablet.
Claims (4)
1. a medicinal or health product compositions is made up of with adjuvant the active component of 2-98wt.% and the medicinal or health product of 98-2wt.%, and described active component is:
Component a. Semen Ginkgo extrac, or contain bilobalide and ginkgetin Semen Ginkgo extrac as active component, or ginkgetin monomer and ginkgolide monomer or ginkgolide monomer or ginkgetin monomer, the 10-200 weight portion; With
Components b. contain the Fructus Gardeniae extract of Fructus Gardeniae total glycosides, or Fructus Gardeniae total glycosides, or the jasminoidin monomer, the 10-200 weight portion; With
Amount of component b. the dry root powder of Radix Paeoniae, or contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, or the peoniflorin monomer, the 10-200 weight portion.
2. compositions as claimed in claim 1, the content of component a, b, the c 15-150 weight portion of respectively doing for oneself.
3. as the compositions of one of claim 1, the content of component a, b, the c 20-100 weight portion of respectively doing for oneself.
The pharmaceutical composition of one of claim 1-3 preparation be used for the treatment of and/or the medicine of prevention of metabolic syndrome, diabetes and complication thereof, cardiovascular and cerebrovascular disease, senile dementia, hyperlipemia in application.
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| CN2009102505495A CN102091146A (en) | 2009-12-15 | 2009-12-15 | Composite containing gingko extract or monomer |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104857009A (en) * | 2015-04-22 | 2015-08-26 | 张永胜 | Geniposide and paeoniflorin pharmaceutical composition |
| CN105213548A (en) * | 2015-11-05 | 2016-01-06 | 南京中医药大学 | A kind of have vegetable oil composition preventing and treating presenile dementia effect and preparation method thereof and application |
| CN111743936A (en) * | 2020-07-28 | 2020-10-09 | 云南玉麻生物科技有限公司 | Functional hemp chewing gum for improving memory and reducing pressure and preparation method thereof |
-
2009
- 2009-12-15 CN CN2009102505495A patent/CN102091146A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104857009A (en) * | 2015-04-22 | 2015-08-26 | 张永胜 | Geniposide and paeoniflorin pharmaceutical composition |
| CN105213548A (en) * | 2015-11-05 | 2016-01-06 | 南京中医药大学 | A kind of have vegetable oil composition preventing and treating presenile dementia effect and preparation method thereof and application |
| CN105213548B (en) * | 2015-11-05 | 2019-04-19 | 南京中医药大学 | A kind of vegetable oil composition and the preparation method and application thereof with prevention and treatment alzheimer's disease effect |
| CN111743936A (en) * | 2020-07-28 | 2020-10-09 | 云南玉麻生物科技有限公司 | Functional hemp chewing gum for improving memory and reducing pressure and preparation method thereof |
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