CN101766699B - Medicinal combination containing musk - Google Patents
Medicinal combination containing musk Download PDFInfo
- Publication number
- CN101766699B CN101766699B CN2009102107515A CN200910210751A CN101766699B CN 101766699 B CN101766699 B CN 101766699B CN 2009102107515 A CN2009102107515 A CN 2009102107515A CN 200910210751 A CN200910210751 A CN 200910210751A CN 101766699 B CN101766699 B CN 101766699B
- Authority
- CN
- China
- Prior art keywords
- moschus
- extract
- radix paeoniae
- peoniflorin
- monomer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000000178 monomer Substances 0.000 claims abstract description 26
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- FINHMKGKINIASC-UHFFFAOYSA-N Tetramethylpyrazine Chemical compound CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 claims description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims description 29
- ALHUZKCOMYUFRB-OAHLLOKOSA-N Muscone Chemical compound C[C@@H]1CCCCCCCCCCCCC(=O)C1 ALHUZKCOMYUFRB-OAHLLOKOSA-N 0.000 claims description 20
- ALHUZKCOMYUFRB-UHFFFAOYSA-N muskone Natural products CC1CCCCCCCCCCCCC(=O)C1 ALHUZKCOMYUFRB-UHFFFAOYSA-N 0.000 claims description 20
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- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
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- 230000002792 vascular Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000002550 vasoactive agent Substances 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000008918 xingnaojing Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Abstract
The invention relates to drug combinations, in particular to a medicinal combination which is developed according to modern medical theories and contains natural plant extracts or monomers, and a preparation method and application thereof. The drug mainly comprises peony and musk and is applicable in treating coma, cardiovascular and cerebrovascular diseases, senile dementia, cerebral cytoprotection, diabetes and other diseases.
Description
Technical field
The present invention relates to pharmaceutical composition, specifically, is to contain Moschus and natural plant extracts or monomeric Pharmaceutical composition and application thereof according to modern medical theory development.
Background technology
Moschus is the representative medicine commonly used of aromatic and inducing resuscitation Chinese medicine, and Moschus has stronger central nervous system's excitement and suppresses pharmacologically actives such as amphicheirality's effect, resisting oxygen lack, cardiac vascular activity, antiinflammatory action.At present, Moschus application (especially cardiovascular and cerebrovascular disease) clinically is very extensive, and for example compound Salviae Miltiorrhizae class, storax pill for treating coronary heart disease, cow-bezoar bolus for resurrection, HUATUO ZAIZAO WAN, refreshment wait all containing Moschus quietly.At this quasi-tradition Cheng Fangzhong, utilized the effect of Moschus " fragrance is walked to scurry, inducing resuscitation (seeing through blood brain barrier) " more, produce " returning " effect (Shandong medical industry 2002,21 (1): 26-27 through going into brain; Hour hands traditional Chinese medical science traditional Chinese medicines 2004,15 (4) 4248-249; New Chinese medicine and clinical pharmacology 2000,11 (4): 208-255).
For many years, many scholars have done extensive work based on modern medical theory to the aspects such as pharmacodynamics, pharmacokinetics and safety of Moschus, have obtained many new developments.For example, discover: Moschus is returned the experimental study (Chen Wen high and dry land etc., combination of Chinese and Western medicine journal the 2nd the 4th phase of volume of July in 2004) through going into brain; With Moschus Borneolum Syntheticum combination cerebral protection (Shen Qiang etc., Moschus and Borneolum Syntheticum pour into the influence that the interleukin-1 ' beta ' mRNA of rat cerebral tissue expresses again to global brain ischemia, the time precious traditional Chinese medical science traditional Chinese medicines rolled up for the 7th phase in 2003 the 14th).
Rely on these progress, scholars are attempting with Moschus and the combination of other active component, in the hope of obtaining better curative effect.For example, ZL03110967.5, ZL200310105455.1, (Jilin University's journal medicine such as Zhao Hongmei, 30 (3): 393-395)), (2004 26 volumes of Chinese patent medicine supplementary issue: 13-16) such as Lin Jiayi, (1998 17 volumes (9) of Shandong journal of Chinese medicine: 404-405) such as Nie Youzhi, Li Xiangxin (2004 13 19 phases of volume of modern combination of Chinese and Western medicine magazine: 2541-2542), (2002 19 1 phases of volume of Shenyang Pharmaceutical University's journal: 41-42) such as Zhang Li, (2004 21 volumes of Traditional Chinese Medicine University Of Guangzhou's journal, 5 phases: 382-384 such as Yu Shangzhen, (Jilin Chinese medicine 6 phases of calendar year 2001: 34) such as Xue Yafeng, (1999 30 5 phases of volume of Jiangxi Chinese medicine: 9-10) such as Chen Su, and the side's of one-tenth Moschus is rather felt at ease, XINGNAOJING ZHUSHEYE etc., be widely used in the treatment of cardiovascular and cerebrovascular disease, all obtained certain achievement.
Yet above-mentioned compound recipe can not satisfy demand clinically far away.On the one hand, existing compound recipe is normally formed by the principle of " determination of treatment based on pathogenesis obtained through differentiation of symptoms and signs ", and this is for the pathogenesis complexity, with the disease of different classes of complication, and these Moschus compound preparations are difficult to multi-faceted proving effective.More crucial is, these big compound medicine compositions are too complicated, and the interaction between each composition is not clear, does not meet the trend of modern medicines, the homogeneity that is difficult to ensure the quality of products.
In previous work, we had once carried out careful research to " Moschus+Radix Paeoniae ", found useful effect, also verified such inference to a certain extent: promptly the material base of compound preparation is not only the summation of every kind of effective ingredient, and comprise the interaction of each composition in the compound preparation process, this interaction had both comprised that simple physics changed the chemical change that also comprises complexity, the interaction of various compositions can change the stripping character and the coherent condition of various compositions, even might take place to produce new material behind the chemical reaction.In other words, compound recipe effectiveness is the general performance of mutual relation between the compound chemical component under the specific effect condition, and some so-called active component leave the compound recipe condition then may not have obvious effect.
Consider above-mentioned inference, the result of study of relevant " Moschus+Radix Paeoniae " may represented certain research tendency.Simultaneously, this result of study also is tempting, and it is reminding scholars very likely also to exist similarly other combinations.
The application attempts the combination that contains Moschus, Radix Paeoniae and " blood circulation promoting and blood stasis dispelling " class medicine is studied, in the hope of reducing dosage, thereby when guaranteeing (even raising) curative effect, further reduce untoward reaction by adduction between them even synergism.Can be contemplated that there is urgent demand this area to this natural drug safely and effectively (combination).
Summary of the invention
The inventor has carried out deep exploration in this respect, and has obtained many gratifying results.
In the previous test of the inventor, show that the combination of Radix Paeoniae and Moschus can obviously strengthen the inherent pharmacological action of Moschus, such as anti-cerebral ischemia reperfusion injury and protect, anti-inflammatory response effect etc.
Simultaneously, when adding has vasoactive Herba Erigerontis in above-mentioned Radix Paeoniae and Moschus combination, can possess more comprehensive therapeutic effect.
So we have further carried out the experimental study of Radix Paeoniae, Moschus and the combination of other vasoactive agents, found that compositions possesses better effect equally.
Therefore, the object of the present invention is to provide " Moschus+Radix Paeoniae+amount of component b " combination, be used for the treatment of and/or prevent diseases such as cardio-cerebrovascular diseases, senile dementia, brain cell protection, diabetes with synergistic function.
In pharmaceutical composition of the present invention, can select flavour of a drug (for example Radix Paeoniae, Moschus) directly to be ground into powder and be used as medicine, extract or other forms that also can be equivalent to above-mentioned natural drug material crude drug amount are used as medicine.Therefore, the active component of pharmaceutical composition of the present invention comprises the former powder of medical material, fat or water solubility extract (or effective site) or effective ingredient or monomer, perhaps adopts existing other goods forms in the prior art.For example, described active component comprises:
A.
Moschus: be meant natural or the artificial Moschus, or contain the Moschus extract of glycoprotein, cholesterol etc. such as muscone, androsterone, Moschus-1, or the muscone monomer.
B.
Radix Paeoniae: be meant the dry root powder of Radix Paeoniae (Radix Paeoniae Alba, Radix Paeoniae Rubra, river Radix Paeoniae Rubra), contain the extract of Radix Paeoniae Alba total glycosides compounds (being preferably peoniflorin and lactone glucoside of Radix Paeoniae), or the peoniflorin monomer.In addition, studies show that the effective site that contains peoniflorin, lactone glucoside of Radix Paeoniae, Hydroxy peoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, lacdtlorin, paeonol, the former glycosides of paeonol, Cortex Moutan phenolic glycoside, Radix Paeoniae aglycon 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 the 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.
Described active component c is selected from a kind of among the following c1-c6:
C1.
Radix Salviae Miltiorrhizae: be meant and mainly contain salvianolic acid
*And/or TANSHINONES
*Radix Salviae Miltiorrhizae extract; Or water-soluble extract of red sage root, mainly contain with salvianolic acid A, salvianolic acid B, protocatechualdehyde, danshensu is the liposoluble ingredient (total phenolic content 40%, preferred more than 60%) of representative, or salvianolic acid monomer or its pharmaceutical salts (for example magnesium salt), or the monomeric mixture of salvianolic acid; Or the Radix Salviae Miltiorrhizae liposoluble extract, mainly contain TANSHINONES (TANSHINONES content 50%, preferred more than 80%, for example Tanshinone I, Tanshinone I I
A, Tanshinone I I
B, cryptotanshinone, dihydrotanshinone I etc.), or TANSHINONES monomer or its pharmaceutical salts (for example sulfonate sodium), or the monomeric mixture of TANSHINONES; Or
C2.
Semen Ginkgo: be meant Semen Ginkgo extrac (for example Folium Ginkgo extract of lower alcohol, acetone, ethyl acetate), mainly contain bilobalide
*And/or ginkgetin
*As the Semen Ginkgo extrac (for example standard extract Egb) of active component, or ginkgetin monomer and ginkgolide monomer, or ginkgolide monomer, or the ginkgetin monomer.Wherein, described bilobalide 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; Or
C3.
Flos Carthami: be meant and contain Flos Carthami total flavochromes (safflower yellow A for example
*, B, content is more than 50%) Flos Carthami extract, (hydroxyl) Carthamus yellow monomer, perhaps these monomeric mixture; Or
C4.
Radix Puerariae: be meant and contain daidzein, daidzein glycosides, puerarin
*, multiple osajin such as glucosulfone daiazi, methoxy puerarin, 7-xylose-puerarin, diacetyl-puerarin, formononetin Radix Puerariae extract, or Radix Puerariae total flavones, or puerarin monomer and derivant thereof, or daidzein or soybean isoflavone monomer, perhaps these monomeric mixture; Or
C5.
Rhizoma Chuanxiong: be meant and contain ligustrazine
*, chuanxingol, ferulic acid
*, the volatilization wet goods Rhizoma Chuanxiong extract, or ligustrazine monomer or ligustrazine derivant (for example ligustrazine hydrochloride), or ferulic acid/sodium and derivant (for example ferulic acid ligustrazine), perhaps these monomeric mixture; Or
C6.
Radix Ginseng: be meant and mainly contain Radix Ginseng total saponins
*Radix Ginseng extract, or ginsenoside monomer; The other plant (for example Radix Notoginseng etc.) that contains the ginsenoside also can be realized the present invention.
On the surface, said components c1-c6 is seemingly different, but analyzes from the chemistry formation, and known main pharmacological component can classify as two big constituents with " blood circulation promoting and blood stasis dispelling " effect in these plants: flavone, phenolic acid.From the angle of modern medical theory, the flavones ingredient in the above-mentioned plant substantially all has blood vessel dilating, improves tissue ischemia, antioxidation, improve pharmacological effects such as hemorheology; Phenolic acids then has more multifarious effect, as pharmacological effects such as anti-inflammatory response, endotheliocyte protections.For example, with puerarin, Radix Salviae Miltiorrhizae, Folium Ginkgo, arasaponin, ligustrazine or Flos Carthami be used as medicine and patent medicine, be principal indication all also clinically with coronary heart disease, apoplexy, diabetes and/or senile dementia.This fully proves, these plant extracts " similarity " of tool height on the chemistry of pharmacological effect and main active constitutes, and this is well known to those skilled in the art.Similarly, obtain said extracted thing or monomer and also belong to routine techniques.
When we attempt from prior art, to seek this " Moschus+Radix Paeoniae+amount of component b " for the medicine on basis bonded according to the time, we find that prior art does not up to now provide scientific basis, even similar hint not.
In context, the related term " active component " of pharmaceutical composition of the present invention has above-mentioned definition.
In pharmaceutical composition of the present invention, each components contents is:
Component a, 5-65, preferred 10-50, more preferably 15-45 weight portion; With
Components b is counted 5-100 with peoniflorin, preferred 10-80, more preferably 20-60 weight portion; With
Amount of component b is to indicate symbol
*Composition count 5-100, preferred 10-80, more preferably 20-60 weight portion.
In addition, in context, " peoniflorin+muscone+danshensu 5: 2: 1 ", the weight proportion of representing these three kinds of active components is 5: 2: 1.
Below test will confirm: the combination according to the Moschus with above-mentioned definition, Radix Paeoniae and the amount of component b of the present invention description has beneficial effect of the present invention.In view of the technology that had existed suitable maturation and the effective above-mentioned definition component of preparation/purification in the prior art already, do not make emphasis at this and describe.For example, can adopt modern the extraction and isolation technics, to improve the purity of active substance, remove unwanted impurity, for example: Chinese patent application ZL200410096958 as far as possible, ZL200410041752, ZL011103787, ZL021109737, ZL021332983, ZL031131263, ZL02156681X, ZL011301309, ZL2004100413049, ZL00120986, ZL2003101134541, ZL021179239, ZL02149694, ZL92108623, ZL00113019, ZL02153750X, ZL03117754, ZL03141616, JP2000247890A, GB2317613A, Chinese crude drug 2000 23 (6): 316-6, prolong limit medical college journal nineteen ninety-fives 18 volume (1): 73-78) etc.。
Can be at absorption characteristics in the physicochemical property of said components and the body, adopt the standard preparation technology, add pharmaceutic adjuvant and make suitable for oral administration or parenterai administration dosage form, similar techniques is also quite effectively ripe, for example: oral cavity disintegration tablet (ZL2003101133322, ZL200310123852, ZL03102405, ZL200410016510, ZL200410041256), drop pill (ZL200310107292, ZL03136485, ZL01133515, ZL03135325, ZL200310119222), dispersible tablet (ZL03125462, ZL03112974, ZL02153445), slow controlling agent (ZL011333332, ZL011387106, ZL02116223, ZL200310110709, ZL01117620, ZL02109758, ZL02116795, ZL02129313, ZL02134118, ZL03100021, ZL03133897), cyclodextrin clathrate (ZL01141436, ZL02108778, ZL200310125175,2002 37 volumes (9) of Chinese Pharmaceutical Journal: 673-75), solid dispersion (ZL001194313), injection (ZL001215329, ZL031399428, ZL031573150, ZL2003101241702, ZL021337241, ZL95104038, ZL97101107, ZL02155001, ZL021332983, ZL031279953, ZL03141614, ZL03113037, ZL2003101210259, ZL200410013845), powder pin (ZL200410037717, ZL031323820, ZL021446008, ZL200410002103, ZL03131959.9, ZL200410013937, ZL2003101210259, ZL200410000912), little or nanometer formulation (ZL021378630, ZL00119579), contain phospholipid preparation (ZL001278126, ZL031320627, ZL01139971, ZL03128337), 2005 30 volumes of CHINA JOURNAL OF CHINESE MATERIA MEDICA, 4 phases: 260-263 etc.
Pharmaceutical composition of the present invention; form by the active component of 10-90wt.% and the pharmaceutic adjuvant of 90-10wt.%; can be used for treating stupor, cardiovascular and cerebrovascular disease, senile dementia, brain cell protection, and be used for the treatment of the recurrence with prevent diabetes and complication thereof, prevention cardiovascular and cerebrovascular disease.Aforementioned pharmaceutical compositions has overcome shortcomings such as the effect that existing medicine exists is single, dosage is big, has represented the natural drug treatment and has prevented the new trend of above-mentioned disease.
The pharmacology pharmacodynamic experimental study
One. basic research
Collaborative antiinflammatory action
The influence of 1 pair of acute exudative inflammation (dimethylbenzene induced mice ear swelling)
1.1 material
The present invention makes up A (Radix Paeoniae Alba extract+Moschus+Radix Salviae Miltiorrhizae extract 5: 1: 2), divides 10,20, the 40mg/kg group;
The present invention makes up B (peoniflorin+muscone+danshensu 5: 2: 1), divides 10,15, the 30mg/kg group;
The present invention makes up C (Radix Paeoniae Alba extract+Moschus+Semen Ginkgo extrac 2: 5: 10), divides 15,30, the 50mg/kg group;
The present invention makes up D (peoniflorin+Moschus+ginkgetin 3: 1: 2), divides 10,20, the 40mg/kg group;
Blank group: normal saline;
Positive control drug: the Radix Paeoniae Alba extract that is equivalent to same dosage; 10% Moschus group; Radix Paeoniae Alba extract+Moschus 5: 1, the 30mg/kg group; Aspirin 0.2g/kg group; Danshensu 2mg/kg group; Ginkgetin group 20mg/kg.
1.2 method and result
The ICR mice, body weight 21-23g, by body weight all groupings at random, 10 every group, continuous gastric infusion 4 days (0.4ml/20g), the blank group is given the distilled water of equal volume.Behind last administration 1h, 60 μ l dimethylbenzene evenly are applied to every Mus auris dextra two sides, behind the 40min dislocation of mice cervical vertebra is put to death, taking off left and right sides auricle with diameter 8mm scleral perforation device weighs, obtain two ear weight differences, calculate the swelling rate, t check comparable group differences the results are shown in Table 1.
The influence of table 1 xylol induced mice ear swelling (X ± SD, n=10)
Annotate: swelling rate=[(auris dextra heavy-left ear is heavy)/left ear is heavy] * 100%;
Compare with the blank group:
*P＜0.05,
*P＜0.01;
Compare △ P＜0.05, △ △ P＜0.01 with the Radix Paeoniae group; Compare #P＜0.05 with the Moschus group.
Compare with danshensu or ginkgetin
∧P＜0.01
2 xylol cause the influence of mouse skin capillary permeability
2.1 material
Pharmaceutical composition A of the present invention (Radix Paeoniae Alba extract+Moschus+60% (Carthamus yellow) Flos Carthami extract 12: 2: 20), branch 10,20,40mg/kg group;
Pharmaceutical composition B of the present invention (Radix Paeoniae Alba extract+Moschus+60% (puerarin) Radix Puerariae extract 2: 2: 12), branch 10,30,50mg/kg group
Positive control drug: the Radix Paeoniae Alba extract that is equivalent to same dose; 10% Moschus group; Radix Paeoniae Alba extract+Moschus 10: 1, the 30mg/kg group; Aspirin 0.2g/kg group; 60% (Carthamus yellow) Flos Carthami extract group 15mg/kg; 60% (puerarin) Radix Puerariae extract 15mg/kg.
2.2 method and result
Make the animal inflammatory model with reference to " herbal pharmacology research methodology ", the results are shown in following table 2:
The influence of table 2 xylol induced mice capillary of skin permeability (X ± SD, n=10)
Compare with matched group: * P＜0.05, * * P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with Radix Paeoniae Alba extract;
Compare #P＜0.05, ##P＜0.01 with Moschus.
Compare with Flos Carthami extract or Radix Puerariae extract
∧P＜0.01
The result shows: present composition xylol induced mice ear swelling and xylol induced mice capillary of skin permeability have the obvious suppression effect, 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, also has significant difference (P＜0.05), senior middle school's dosage group and blank group be P＜0.05-0.01 relatively, other antiinflammatory experiments have also been done simultaneously, the result shows, the present composition has also shown significant effect in rat foot due to suppressing Ovum Gallus domesticus album is wasted time swelling, and effect obviously is better than Radix Paeoniae Alba extract, Moschus group and one pack system extract group, the prompting present composition is single with having on the basis of antiinflammatory action separately at it, a certain proportion of compatibility more can promote the antiinflammatory action of Radix Paeoniae/Moschus or other single medicinal materials, plays collaborative antiinflammatory action.
Two. the pharmacological action for the treatment of cardiac and cerebral vascular diseases
1. global brain ischemia is poured into again the influence of rat cerebral tissue's amino acid neurotransmitter
1.1 material
Pharmaceutical composition A of the present invention (peoniflorin+Moschus+ligustrazine 1: 2: 6,30mg/kg irritates stomach);
Pharmaceutical composition B of the present invention (peoniflorin+Moschus+ligustrazine 5: 3: 1: 1,30mg/kg irritates stomach);
Positive control drug: peoniflorin 10mg/kg, muscone suspension 12mg/kg, ligustrazine 20mg/kg;
1.2 method
The every day of administration at twice before the modeling for three days on end, undergos surgery after 30 minutes in administration in the morning in the 4th day.According to the standard method modeling, separate bilateral common carotid arteries, pour into 6h again, sacrificed by decapitation, get brain and place rapidly and get the right side brain on the ice pan and be divided into A, B, C, D five equilibrium, get C, D brain sheet is weighed, and adds methanol homogenate according to 1ml/50mg from antinion to occipital lobe, centrifugal collection supernatant, boil off methanol, add 80% ethanol again, ultrasonic Treatment, centrifugal, collect supernatant and be used to detect the cerebral tissue amino acid neurotransmitter.
Most of neurotransmitter is an amino acids among the central nervous system, comprise γ-An Jidingsuan (GABA), glutamic acid (Glu), aspartic acid (Asp) and glycine (Gly), under the physiological conditions, Glu, Asp have extremely strong excitation to neuron, GABA, Gly neuron enforcement effect are important inhibitory aminoacid.
Analytical method: reversed-phase HPLC, peak area external standard method, statistical analysis then.
1.3 result
See the following form 3.
Table 3 is respectively organized global brain ischemia and is poured into the content of rat cerebral tissue's amino acid neurotransmitter (μ mol/g) again
Compare with sham-operation,
*P＜0.05
*P＜0.01; Compare with model group,
△P＜0.05,
△ △P＜0.01; Compare #P＜0.05 with the Moschus group; Compare with ligustrazine
∧P＜0.05
1.4 conclusion
Each group of pharmaceutical composition of the present invention, peoniflorin injection, muscone and ligustrazine rat cerebral tissue's ischemia 45 minutes, pour into (Glu, Asp obviously raise) after 6 hours again, and to the Asp decrease to some degree, present composition group is the most obvious; And peoniflorin injection, muscone and ligustrazine are not obvious to the Glu reduction, and pharmaceutical composition of the present invention all can reduce Glu for two groups, compare with contrast medicine group to have significant difference; The rising of GABA and Gly also is that present composition group is the most obvious; with peoniflorin; muscone and ligustrazine are relatively; has significant difference between group; may be peoniflorin and the beneficial effect that jointly bring different with the mechanism of action of Moschus extract (muscone); the combination that the present composition is described is by reducing the Asp in the ischemic region cerebral tissue; improved the toxicity of the content of GABA and Gly with the antagonism excitatory amino acid; thereby the damage of the follow-up unit of going crazy of protection cerebral ischemia; though these are one of medical mechanisms of muscone; but the present composition has improved drug effect undoubtedly, has brought into play collaborative effect.
2. to preventing postangioplasty restenosis
Postangioplasty restenosis (RS), belong to the syndrome of blood stasis category, its sickness rate height, the abnormality proliferation of vascular smooth muscle cell (VSMCs), be the Chinese medicine pathological characters of RS, therefore suppress the important means that the VSMCs abnormality proliferation becomes worldwide cardiovascular research prevention RS.
2.1 material
Pharmaceutical composition A of the present invention (peoniflorin+Moschus+Radix Ginseng total saponins 3: 2: 6,6,12mg/kg injection);
Pharmaceutical composition B of the present invention (peoniflorin+Moschus+bilobalide 1: 6: 1,4,8mg/kg injection);
Pharmaceutical composition C of the present invention (peoniflorin+Moschus+TANSHINONES 10: 1: 1,5,10mg/kg injection);
Pharmaceutical composition D of the present invention (peoniflorin+Moschus+puerarin 1: 2: 10,6,12mg/kg injection);
Blank group: normal saline;
Positive control drug: peoniflorin injection, muscone injection, bilobalide 1mg/kg; TANSHINONES 1mg/kg; Puerarin 6mg/kg; Each 8mg/kg of Radix Ginseng total saponins;
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).
Cultivate attached cell, change DMEM (containing penicillin 100U/ml, streptomycin 100 μ g/ml) continuation cultivation again into and make the cell growth synchronously, add medicine at last 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.
Cell survival rate=attached cell/total cell number (attached cell+not attached cell)
2.3 result
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%.Each group of pharmaceutical composition of the present invention, peoniflorin injection and muscone injection are all inhibited to the abnormality proliferation of vascular smooth muscle cell (VSMCs), but each group of pharmaceutical composition of the present invention is the strongest, compare with peoniflorin and muscone, having significant difference between group, may be peoniflorin and the beneficial effect that jointly bring different with Moschus extract (muscone) mechanism of action.
Three. the short effect of waking up
1. material
Mice: Kunming kind, body weight 18-20g, male and female half and half.
Reagent: TANSHINONES+Radix Paeoniae injection (self-control); Flos Carthami extract injection (self-control); Radix Puerariae extract (self-control); Muscone injection (self-control); Caffeine and sodium benzoate injection raw material (Shanghai the 14 pharmaceutical factory); Present composition A (Radix Paeoniae+Moschus+Rhizoma Chuanxiong extract, weight ratio 1: 2: 8) group; Present composition B (Radix Paeoniae+Moschus+Radix Ginseng extract 8: 2: 1).
2. method and result
Mice random packet, tail vein injection sodium chloride injection, caffeine and sodium benzoate normal saline solution, TANSHINONES+musk injection, Flos Carthami extract injection, Radix Puerariae extract respectively; Reagents such as muscone injection, once a day, successive administration 2 days, 15min after the last administration, lumbar injection pentobarbital sodium normal saline solution (3mg/ml) 0.3ml/20g, record mice righting reflex loss is calculated each class mean and standard deviation to the time of recovering, carry out the t check, the results are shown in Table 4.
The short effect of waking up of table 4 pair mice (X ± SD, n=10)
Compare with the blank group:
*P＜0.05,
*P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with Flos Carthami and Radix Puerariae extract; Compare with TANSHINONES+Radix Paeoniae: #P＜0.05, ##P＜0.01.
3. conclusion
Compare with matched group, two groups of present composition A, B, contrast medicine caffeine and sodium benzoate group all show short effect of waking up, and Flos Carthami and Radix Puerariae extract group then do not have obviously thick property effect.Compare with TANSHINONES+Radix Paeoniae, this compositions presents significant difference for two groups, and it is active to show that the present composition has good agrypnotic reason.
Four. the pharmacological action of diabetes aspect
1. material
Pharmaceutical composition A of the present invention: Radix Paeoniae+Moschus+Radix Salviae Miltiorrhizae extract group (weight ratio 5: 1: 10)
Pharmaceutical composition B of the present invention: Radix Paeoniae+Moschus+TANSHINONES group (weight ratio 3: 5: 2)
Normal control group: normal saline;
Diabetic groups: normal saline;
Positive control drug: peoniflorin group; The Radix Salviae Miltiorrhizae extract group; JIANGZHILING PIAN;
2. method and result
The foundation of diabetes experimental model: secondary SD rat is according to 150mg/kg body weight tail vein injection alloxan liquid, under the effect of alloxan liquid, the beta Cell of islet of rat sustains damage, cause insulin generation obstacle, tail vein blood is surveyed fasting glucose after 3 days, and blood glucose value is a diabetes rat greater than 11.0mmol/L's.
Once a day, in continuous 4 weeks, afterwards, tail vein blood is surveyed fasting glucose (FBG) and serum I ns.
The FBG of table 5 pair diabetes rat and serum I ns influence n=15
Compare with diabetic groups:
*P＜0.05
*P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with peoniflorin.
Above-mentioned experiment shows, the present composition has obviously reduced the blood glucose of alloxan diabetes, and it is not obvious to serum I ns level affects, this shows that Radix Paeoniae, Moschus drug combination and the present composition have produced stronger hypoglycemic activity to alloxan diabetes rats, and hypoglycemic activity is not realized by improving insulin level.
Five. to the antioxidation of hyperlipidemia rat
1. material
Pharmaceutical composition of the present invention: Radix Paeoniae+Moschus+Semen Ginkgo extrac 10: 1: 2: 8,50mg/kg irritates stomach;
Normal control group: normal saline;
Hyperlipidemia group: normal saline;
Positive control drug: peoniflorin (50mg/kg); VE (50mg/kg); Moschus+Semen Ginkgo (30mg/kg); Semen Ginkgo extrac (20mg/kg).
2. method and result
Set up high blood lipid model, 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, according to the operation of test kit description, surveys LPO and SOD, the results are shown in Table 6:
Influence (nmol/L) n=10 of table 6 pair hyperlipemia rat serum and liver LPO and SOD
Compare with the hyperlipidemia group:
*P＜0.05,
*P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with Radix Paeoniae.
Conclusion
Experiment shows, the antioxidant activity of the present composition significantly is better than Radix Paeoniae, the Moschus used separately.
The above results also proves: Moschus is through experimental results show that ability and the effect with enhancing maincenter anoxia enduring, and it is verified, the ability of the enhancing maincenter anoxia enduring of Moschus is to the direct effect of cental system but not remote-effects, therefore claim its causing resuscitation with aromatic drugs on the traditional Chinese medical science, not only control apoplectic coma but also control infantile convulsion with Moschus, but do not prove that it has tangible antioxidation, the application experimental results show that itself and Radix Paeoniae and Semen Ginkgo share, antioxidant activity significantly is better than single Radix Paeoniae of using, explanation is aspect the hyperlipidemia antioxidation, and there is the enhancing synergism in the three.
5 usefulness of the present composition are not then found toxic and side effects, the adverse side effect that does not bring.
In addition; also from aspects such as neuroprotective cell, minimizing cerebral tissue malonaldehyde (MDA) and NO generations; investigated the antioxidation of the present composition; the result proves that the present composition has the obvious suppression effect to cerebral tissue MDA; reduced the NO that raises in the cerebral tissue, neurocyte has also been shown protective effect.
Example of formulations
Embodiment 1 tablet
Get Radix Paeoniae Rubra, be ground into coarse powder, add the 80-90% alcohol reflux three times, merge extractive liquid,, use n-butanol extraction three times behind the concentrating under reduced pressure, each 600ml merges n-butanol extracting liquid, be evaporated to no n-butyl alcohol flavor, add water 400ml, heating for dissolving filters, the filtrate spray drying, it is standby to get extract I;
Get the 6g extract I, with the CO of 1g Moschus and Radix Salviae Miltiorrhizae
2Supercritical extract 15g (ethanol is entrainer) mixing adds adjuvant (gross weight 5%) low-substituted hydroxypropyl cellulose, magnesium stearate, starch, microcrystalline Cellulose, granulates and tablet forming technique prepares according to standard.
Embodiment 2 tablets
Get extract product of general flavone of kudzuvine root 3g, 10g extract I and 15g Moschus mixing, add low-substituted hydroxypropyl cellulose, magnesium stearate, starch, microcrystalline Cellulose, prepare 1000 according to standard granulation and tablet forming technique.
Embodiment 3 soft capsules
Get the CO of peoniflorin 2g, Moschus
2Supercritical extract 4g, bilobalide 1g, with the glycerol mixing, 1000 of pills promptly get soft capsule.
Embodiment 4 drop pill
Get Radix Paeoniae Rubra, use water extraction after being ground into coarse powder, with macroporous adsorptive resins on the water extract, water, 70% ethanol elution are collected ethanol elution, concentrate back elimination precipitate, the filtrate spray drying, extract II is standby;
Get 15g extract II, 30g ligustrazine hydrochloride, Moschus water vapour extract 20g mixing, get III;
It is evenly mixed to get xylitol and Furcellaran, adds the III of method for preparing, fully mixes, the mixture heated fusion stirs and is incubated, and splashes under about 60 ℃ in 0 ℃ the methyl-silicone oil, make 10000 drop pill, the most and most liquid coolant of wiping with the drop pill drop, back packing to be dried.
Embodiment 5 oral cavity disintegration tablets
Get cyclodextrin clathrate 20g (Moschus 4g), aspartame, Fructus Citri Limoniae essence and the magnesium stearate of Radix Paeoniae Alba extract 10g, ginsenoside extract (total saponin content is not less than 60%) 50g, Moschus water vapour extract, mixed 100 mesh sieves.Add cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose, cross 100 mesh sieves behind the mix homogeneously, tabletting is made 1000 altogether.
Embodiment 6 slow releasing tablets
Get the cyclodextrin clathrate 30g (Moschus contains 8g) of peoniflorin 18g, Carthamus yellow extract (total uranidin content is not less than 50%) 100g, Moschus water vapour extract, uniform mixing, add lactose, microcrystalline Cellulose, hydroxypropyl methyl base cellulose, polyethylene pyrroles, hard magnesium, prepare 1000 according to standard granulation and tablet forming technique.
Embodiment 7 lyophilized injections
Get Ginkgo total flavones 25g, an amount of organic base, add the injection water approximately to 900ml, stir and make dissolving, behind the adjusting pH value, add peoniflorin 15g to dissolving, mix homogeneously filters, and it is standby to get IV;
Get artificial Moschus's supercritical carbon dioxide extraction thing (containing macrocyclic ketone of Moschus more than 30%) 16g, add polyoxyethylene sorbitan monoleate, uniform mixing adds HP-again, and the ultrasonic agitation enclose got HP-beta-CD inclusion V after 2 hours.
Get IV 3g, V, add lyophilizing figuration mannitol, add to the full amount of water for injection, add active carbon, absorption, decarbonization filtering; Gained filtrate is continued with 0.22 μ m filtering with microporous membrane, packing, lyophilization.
Embodiment 8 injectable emulsions
With macrocyclic ketone of Moschus 5g, oleic acid 0.6g, join behind the mix homogeneously in the triglyceride, add behind the thermally homogenising standby; Get in refined lecithin 2.0g, poloxamer 188 0.5g, glycerol 2.0g, danshensu 1g, the peoniflorin 40g adding distilled water, fully mix.With oil, the biphase mixing of water, regulate pH value, make 1000ml, detect with laser particle analyzer, after particle diameter meets the requirements, pass through filtering with microporous membrane again, then fill, inflated with nitrogen, seal, sterilize.
Claims (5)
1. a pharmaceutical composition is made up of the active component of 10-90wt.% and the pharmaceutic adjuvant of 90-10wt.%, and described active component is:
A. Moschus, or contain the Moschus extract of muscone, androsterone and Moschus-1, or the muscone monomer, the 5-65 weight portion: and
B. Radix Paeoniae dry root powder, or contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, or peoniflorin monomer, the 5-100 weight portion and
Have vasoactive c.5-100 weight portion, it is:
The Rhizoma Chuanxiong extract that contains ligustrazine, chuanxingol, ferulic acid, volatile oil, or ligustrazine monomer, or sodium ferulate.
2. pharmaceutical composition as claimed in claim 1 also contains Hydroxy peoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, lacdtlorin in the described Radix Paeoniae Alba extract.
3. pharmaceutical composition, described active component is:
A. the Moschus extract that contains muscone, androsterone and Moschus-1, the 10-50 weight portion; With
B. the Radix Paeoniae Alba extract that contains peoniflorin, lactone glucoside of Radix Paeoniae, the 10-80 weight portion; With
C.10-80 weight portion, it is the Rhizoma Chuanxiong extract that contains ligustrazine, ferulic acid.
4. pharmaceutical composition as claimed in claim 1, wherein component a is the 15-45 weight portion, components b is that 20-60 weight portion and c are the 20-60 weight portion.
5. pharmaceutical composition as claimed in claim 1, wherein said active component is:
A. muscone monomer; With
B. peoniflorin monomer; With
C. ligustrazine monomer.
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| CN102988398A (en) * | 2012-12-20 | 2013-03-27 | 济南杏林生物技术有限公司 | Traditional Chinese medicine composition mixture for treating ischemic cerebrovascular disease and preparation method thereof |
| CN103720765B (en) * | 2014-01-16 | 2017-01-11 | 珠海海滨医药生物科技有限公司 | Traditional Chinese medicine composition for treating diabetes and preparation method thereof |
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| Title |
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| 刘晛，贾琳娜.治疗冠心病心绞痛的中医常用方药.《中国临床医生》.2000,第28卷(第10期),16-18. * |
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