CN100391489C - Medicinal composition containing borneol - Google Patents

Medicinal composition containing borneol Download PDF

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CN100391489C
CN100391489C CNB2005101325637A CN200510132563A CN100391489C CN 100391489 C CN100391489 C CN 100391489C CN B2005101325637 A CNB2005101325637 A CN B2005101325637A CN 200510132563 A CN200510132563 A CN 200510132563A CN 100391489 C CN100391489 C CN 100391489C
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radix paeoniae
component
extract
borneolum syntheticum
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CN1823922A (en
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林艳和
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YUNNAN BIOVALLEY PHARMACEUTICAL CO., LTD.
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SHENGWUGU SCIENCE AND TECHNOLOGY Co Ltd SHENZHEN CITY
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Abstract

The present invention relates to a medicinal composition, in particular to a medicinal composition which is developed according to the modern medicine theory and contains natural plant extracts or monomers, and a preparation method and the application of the medicinal composition. The medicinal composition of the present invention mainly contains peony and borneol, and is used for treating diseases, such as coma, cardiovascular diseases, cerebrovascular diseases, diabetes, etc.

Description

The pharmaceutical composition that contains Borneolum Syntheticum
Technical field
The present invention relates to pharmaceutical composition, specifically, is to contain Borneolum Syntheticum and natural plant extracts or monomeric Pharmaceutical composition and application thereof according to modern medical theory development.
Background technology
Borneolum Syntheticum is divided into natural Broneolum Syntheticum and synthetic borneol two big classes.Wherein, borneol is mainly dextro Borneolum Syntheticum, is the certified products in the Borneolum Syntheticum, and Blumeae preparatum Tabellae is mainly left-handed Borneolum Syntheticum, and synthetic borneol also contains the epimer isoborneol of a large amount of Borneolum Syntheticum except that containing Borneolum Syntheticum.At present, Borneolum Syntheticum 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 etc. all contain Borneolum Syntheticum.At this quasi-tradition Cheng Fangzhong, utilized the effect of Borneolum Syntheticum " fragrance is walked to scurry, priming up ", " gesture then of walking alone is weak, assistant make then meritorious " more, increase the therapeutic effect of other medicines as " guiding drug ".
For many years, many scholars have done extensive work based on modern medical theory to the aspects such as pharmacodynamics, pharmacokinetics and safety of Borneolum Syntheticum, have obtained many new developments.For example, discover: Borneolum Syntheticum is not only " priming ", it can not only urge the penetrating blood brain barrier of some drugs (BBB), improve the bioavailability and the blood drug level of some drugs, and the open pathologic opening with encephalitis, cerebral trauma of the inductive BBB of Borneolum Syntheticum has the difference of matter, it has certain protection effect (Zhao Baosheng, new Chinese medicine and clinical pharmacology 2002,13 (5): 287-288) to brain and BBB; With Borneolum Syntheticum to making CBSF rise, decreased heart rate, reduction myocardial oxygen consumption (Jiang Wende, Acta Pharmaceutica Sinica 1979,14 (11): 655-660); With Borneolum Syntheticum may be by improving the blood oxygen supply of ischemic tissue of brain, and then improve this regional energy metabolism impairment, damage play a protective role (He Xiaojing, West China pharmaceutical journal 2005,20 (4): 323-325) to ischemic tissue of brain; With the expression of Borneolum Syntheticum,, in the treatment of cerebral ischemia reperfusion injury, brings into play the inhibition polymorphonuclear leukocyte cerebral protection (Shen Qiang, combination of Chinese and Western medicine cardiovascular and cerebrovascular disease magazine 2003,1 (3): 136-138) thereby sticking by inhibition ICAM-1.
Above-mentioned progress has caused more scholars' interest, and they are attempting with Borneolum Syntheticum and the combination of other active component, in the hope of obtaining better curative effect.For example, to disclose be that monarch drug and Rhizoma Acori Graminei, Rhizoma Chuanxiong, the Radix Angelicae Dahuricae three flavors are the glacier Dimetothiazine of ministerial drug altogether with the Borneolum Syntheticum to ZL2003101172399; The compound preparation of being made up of Rhizoma Chuanxiong, Rhizoma Cyperi, Borneolum Syntheticum, Cortex Moutan is disclosed with 200410020426X; Fang Yongqi (Chinese Chinese medicine science and technology 2004,11 (6): 353-354) disclose the compound preparation of beta-Asarone and Borneolum Syntheticum.These compound recipes are normally formed by the principle of " determination of treatment based on pathogenesis obtained through differentiation of symptoms and signs ", are widely used in the treatment of cardiovascular and cerebrovascular disease, have all obtained certain achievement.
Yet above-mentioned compound recipe can not satisfy the growing clinically demand to Borneolum Syntheticum far away.On the one hand, for the pathogenesis complexity, with the disease of different classes of complication, the existing Borneolum Syntheticum compound preparation that contains is difficult to multi-faceted proving effective.More crucial is, though disclosed Borneolum Syntheticum is not only " priming ", but as there being the scholar to point out, at present the research on the modern medicine meaning of being carried out at Borneolum Syntheticum itself still can not be satisfactory, be fruitful to the also rather limited (Liu Yangfeng of perspective directive significance of descendant's research, Chinese medicine journal 2003,31 (6): 55-58).For example, Borneolum Syntheticum itself to cardiovascular and neural drug effect how, it whether only by the bioavailability that improves other medicines where bring into play drug effect, its concrete action target spot, relation between its drug effect and the dosage how, it has or not time effect etc. in clinical practice, regrettably, prior art to this unclear, proper explanations.
In this case, attempt to adopt the mode of multiple natural drug coupling as people, in the hope of reducing dosage by adduction between them even synergism, thereby when when guaranteeing (even raising) curative effect, further reducing untoward reaction, but can not find reliable scientific basis in the prior art.As everyone knows, the composition of natural drug, the mechanism of action are very complicated, compare with the interaction between the chemical drugs, more are difficult to predict its interaction.
Therefore, there is urgent demand this area to the natural drug safely and effectively (combination) that contains Borneolum Syntheticum.
Summary of the invention
The inventor has carried out deep exploration in this respect, and has obtained many gratifying results.
One object of the present invention is to provide the combination of Borneolum Syntheticum and other active component, is used for the treatment of and/or prevents cardio-cerebrovascular diseases.
By a large amount of guiding tests, we tentatively determine to have such potential quality based on the medicine of Borneolum Syntheticum and Radix Paeoniae.When attempt from prior art, to seek this bonded according to the time, we find: at Borneolum Syntheticum can with the Radix Paeoniae use in conjunction, the mechanism of action of the two is underlying issues such as adduction, collaborative or antagonism, prior art does not up to now provide scientific basis.Whether can unite with other active component as for the two, prior art does not similarly hint again.
In traditional medicine, extremely extensive to the clinical practice of ranunculaceae plant Radix Paeoniae, for example in " typhoid fever is sunk " pandect 112 sides, count 33 head with the Radix Paeoniae person, account for 1/3rd (Li Zhongnan, Anhui Chinese Medicine College journal 1992,11 (2): 52-53) of total number formulary.The modern plants chemistry is thought, Radix Paeoniae Rubra, Radix Paeoniae Alba chemical constituent basically identical, Radix Paeoniae Alba total glycosides wherein is a main active, has pharmacologically active widely, cardiovascular disease, senile dementia, diabetes, inflammation, tumor, hepatopathy etc. there is certain curative effect (Fourier sea, Anhui medicine 2002,6 (2): 62-63; Ruan Jinlan, Acta Pharmacologica Sinica 2003,19 (9): 695-670).
That has carried out studies show that, the combination of Radix Paeoniae and Borneolum Syntheticum can obviously strengthen the inherent pharmacological action of Borneolum Syntheticum, such as anti-cerebral ischemia reperfusion injury and protect, anti-inflammatory response effect etc.Surprisingly, the combination of the two has also reduced the toxicity of Borneolum Syntheticum, and this extensive use for further promotion Borneolum Syntheticum has realistic meaning.
Therefore, one object of the present invention is to provide " Borneolum Syntheticum+Radix Paeoniae " with Synergistic and/or Attenuation combination.
In pharmaceutical composition of the present invention, can select flavour of a drug (for example Radix Paeoniae) directly to be ground into powder and be used as medicine, extract or other form 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 form in the prior art.For example, described active component comprises:
A. Borneolum Syntheticum: be meant the processed goods of Borneolum Syntheticum resin or the crystallization that feverfew Herba Blumeae Balsamiferae leaf extracts, or be raw material, through the synthetic highly finished product of chemical method with Camphora, Lignum Pini Nodi wet goods.Comprise borneol (dextro Borneolum Syntheticum), Blumeae preparatum Tabellae (left-handed Borneolum Syntheticum), synthetic borneol (containing Borneolum Syntheticum and isoborneol).
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 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 combinations thereof, the content of Borneolum Syntheticum is not less than 1wt%.
Then, based on above-mentioned achievement, we study " Borneolum Syntheticum+Radix Paeoniae " and the probability of other active component combinations.According in the prior art to the understanding of Borneolum Syntheticum, we infer: the medicine in the serum not necessarily all can see through intravital various barriers, and the adding of Borneolum Syntheticum has promoted the penetrating blood brain barrier of other active components, and promptly Borneolum Syntheticum might increase the curative effect of other medicines by the mode with " guiding drug ".
Preliminary test shows, except that above-mentioned two kinds of active component a and b, the present composition can comprise other active component, if its do not conflict with described indication and not to " Borneolum Syntheticum+Radix Paeoniae " combination Synergistic and/or Attenuation have a negative impact.Through a large amount of screening operations, the active component that is selected from following c1-c7 satisfies above-mentioned requirements.
In the test of carrying out subsequently, found very interesting phenomenon: the combination of " Radix Paeoniae+amount of component b " or " Borneolum Syntheticum+amount of component b " does not all have the present invention " Borneolum Syntheticum+Radix Paeoniae+amount of component b " effect of Combination.This shows that the present invention's beneficial effect is not only to derive from Borneolum Syntheticum, but derives from " Borneolum Syntheticum+Radix Paeoniae " this basis combination.This discovery is favourable for the unexpected effect of understanding the present invention.The experiment of carrying out already shows under the situation that departs from this prescription condition, when promptly independent Radix Paeoniae or independent Borneolum Syntheticum make up with amount of component b respectively, then not possess the present invention's Synergistic treatment/preventive effect and/or Attenuation.
Therefore, another object of the present invention is to provide " Borneolum Syntheticum+Radix Paeoniae+amount of component b " with Synergistic and/or Attenuation combination.
Wherein, described active component c is selected from one or both among the following c1-c7:
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. Herba Erigerontis: be meant that the herb powder of Herba Erigerontis (having another name called Herba Erigerontis), the water extract of Herba Erigerontis, the lower alcohol extraction thing of Herba Erigerontis (contain scutellarin *(being scutellarin), list/pair caffeoylquinic acids (ester) *Deng effective site), the scutellarin monomer of breviscapine (containing scutellarin, breviscapine and other flavones ingredient) or free or sodium-salt form.It will be understood by those skilled in the art that, the source of scutellarin of the present invention is not limited to Herba Erigerontis, other plant (for example Radix Scutellariae, Herba Scutellariae Barbatae etc.) that contains scutellarin also can be realized the present invention, equally, the source of list/pair caffeoylquinic acids (ester) also is not limited to Herba Erigerontis, such as coffee bean, these extract and preparation method is a known technology, do not give unnecessary details at this.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. 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
C6. 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
C7. Radix Ginseng: be meant and mainly contain Radix Ginseng total saponins *Radix Ginseng extract, or ginsenoside monomer; Other plant (for example Radix Notoginseng etc.) that contains the ginsenoside also can be realized the present invention.
In context, the related term " active component " of pharmaceutical composition of the present invention has above-mentioned definition.
As for amount of component b 1-c7, in view of prior art has been carried out a large amount of research to the collaborative/gain prescription that contains said components, therefore on the basis of Borneolum Syntheticum of the present invention and the useful combination of Radix Paeoniae, can select one or both components and Borneolum Syntheticum, Radix Paeoniae among the c1-c7 to make up.
For example, relate to The useful combination of one of Radix Paeoniae and c1-c7Prior art comprise: ZL200410037717X has disclosed the combination of Radix Paeoniae and Flos Carthami, ZL2003101173090 has disclosed the combination of Radix Paeoniae and Radix Puerariae, 2003101107099 have disclosed the combination of Radix Paeoniae and Radix Ginseng, ZL200410040776 has disclosed the combination of Radix Paeoniae and Herba Erigerontis, ZL981107567 has disclosed the combination of Radix Paeoniae and Folium Ginkgo and Radix Ginseng, Xu Fengqin (Chinese combination of Chinese and Western medicine magazine 2004,24 (4): 331-335) disclosed the combination of Radix Paeoniae and Rhizoma Chuanxiong, Zhou Ming (Chinese Chinese medicine science and technology 2004,11 (1): 46) disclosed the useful combination etc. of Radix Paeoniae and Radix Notoginseng total arasaponins.
For example, relate to Useful combination between the c1-c7Prior art comprise: ZL031046657 has disclosed the combination of Radix Notoginseng total arasaponins and breviscapine, ZL2003101110655 has disclosed the combination of Semen Ginkgo and Radix Ginseng, ZL018208754 has disclosed the combination of Radix Salviae Miltiorrhizae and Radix Notoginseng and Borneolum Syntheticum, ZLCN200310125148.X 021533121 has disclosed the combination of Radix Salviae Miltiorrhizae and Flos Carthami, ZL20041002252 has disclosed the combination that the people participates in Radix Notoginseng, ZL200410040458 has disclosed the combination of Flos Carthami and Herba Erigerontis, ZL2004100340508 has disclosed the combination of Semen Ginkgo and Radix Ginseng, ZL2004100581025 has disclosed the combination of Radix Ginseng total saponins and Carthamus yellow, ZL2004100581010 has disclosed the combination of Radix Salviae Miltiorrhizae and Radix Ginseng, ZL971118795 has disclosed the combination of Rhizoma Chuanxiong and Radix Ginseng, ZL021394172 has disclosed the combination of Radix Puerariae and Semen Ginkgo, ZL2005100049273 has disclosed the combination of Radix Puerariae and Radix Notoginseng.
On the surface, above-mentioned c1-c7 component 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 Herba Erigerontis, 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 should be well known to those skilled in the art.Similarly, obtain said extracted thing or monomer and also belong to routine techniques.
In pharmaceutical composition of the present invention, each components contents is:
Component a, 1-15, preferred 2-10, more preferably 5-10 weight portion; With
Components b in peoniflorin, is 5-85, preferred 10-60, more preferably 20-50 weight portion; With
Amount of component b is to indicate symbol *The composition meter, be 15-200, preferred 20-120, more preferably 40-80 weight portion.
And when c was the combination of two kinds of components among the c1-c7, above-mentioned numerical value was the total amount of the two.For example, when c is " Herba Erigerontis+Flos Carthami ", then, be the 15-200 weight portion in " safflower yellow A+scutellarin " or " safflower yellow A+list/pair caffeoylquinic acids or its ester ".
In addition, in context, " Radix Paeoniae+Borneolum Syntheticum+Radix Salviae Miltiorrhizae 5/1/15 " or " Radix Paeoniae+Borneolum Syntheticum+Radix Salviae Miltiorrhizae 5: 1: 15 ", the weight proportion of representing these three kinds of active components is 5: 1: 15.
Following test will confirm: the combination with above-mentioned definition it " Borneolum Syntheticum ", " Radix Paeoniae " and " amount of component b " according to the present invention describes 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 as far as possible, for example: Chinese patent application ZL011103787, ZL021109737, ZL021332983, ZL031131263, ZL02156681X, ZL011301309, ZL2004100413049, ZL00120986, ZL2003101134541, ZL021179239, ZL02149694, ZL92108623, ZL00113019, ZL02153750X, ZL03117754, ZL03141616, JP2000247890A, GB2317613A, Chinese patent medicine (2004,26 (10): 855-6) 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), slow controlling agent (ZL011333332, ZL011387106, ZL02116223, ZL200310110709, ZL01117620, ZL02109758, ZL02116795, ZL02129313, ZL02134118, ZL03100021, ZL03133897), cyclodextrin clathrate (ZL01141436, ZL02108778, ZL200310125175), 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), drop pill (ZL200310107292, ZL03136485, ZL01133515, ZL03135325, ZL200310119222), dispersible tablet (ZL03125462, ZL03112974, ZL02153445), little or nanometer formulation (ZL021378630, ZL00119579), phospholipid preparations (ZL001278126, ZL031320627, ZL01139971, ZL03128337) etc.
That carries out subsequently studies show that, (for example make up with existing " greatly " prescription, ZL2003101060209, ZL02129269, ZL02123498, ZL001039695, ZL02149694, ZL98100232.3, ZL001327631, ZL011139919 etc.) compare, under the situation that has reduced one or more active component, it is identical that pharmaceutical composition of the present invention has still kept, even more favourable pharmacological action with regard to some aspect (for example having avoided some to become the unwanted pharmacological action or the untoward reaction of branch), many index significantly is better than Radix Paeoniae or the amount of component b used separately, and this is that those skilled in the art can't infer according to prior art.
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, hyperpyrexia, cardiovascular and cerebrovascular disease, senile dementia, brain cell protection, central retinal vein occlusion, hyperlipemia, fatty liver, 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. the basic research of Borneolum Syntheticum and Radix Paeoniae combination
1. to animal LD 50Influence
1.1 medicine
Pharmaceutical composition A group of the present invention (peoniflorin+natural Broneolum Syntheticum 4: 1); Pharmaceutical composition B group of the present invention (peoniflorin+synthetic borneol 5: 1); (get Borneolum Syntheticum crystalline solid mortar porphyrize and cross 140 mesh sieves, content and purity are the natural Broneolum Syntheticum group: dextro Borneolum Syntheticum content 97%); And synthetic borneol group.
1.2 animal
Purebred ICR mice, weight average 18-22g, male and female half and half.
1.3 method and result
LD50 measures (preliminary experiment): natural Broneolum Syntheticum mouse stomach administration LD in the preliminary experiment 50Be 4.486g/kg bw synthetic borneol mouse stomach administration LD 50Be 4.711g/kg bw.
The medicine of each group of A, B, synthetic borneol and natural Broneolum Syntheticum is diluted to 0.2g Borneolum Syntheticum/ml with distilled water solution.Determine the agent distance according to the trial test result, two kinds of Borneolum Syntheticums (four groups) are all got its 2 times of LD respectively according to two kinds of Borneolum Syntheticums (natural and synthetic) 50Be maximum dose level, with 1,1/2,1/4LD 50Be middle dosage and 1/8LD 50Be the principle of low dosage, that is, the mice of natural Broneolum Syntheticum group and A group respectively is divided into 5 groups (I-V) at random, and 10 every group, dosage is 8.972,4.486,2.243,1.1215 respectively, 0.561g/kg bw, gastric infusion; The mice of synthetic borneol group and B group respectively is divided into 5 groups (I-V) at random, and 10 every group, dosage is 9.422,4.711,2.3555,1.1778 respectively, 0.5889g/kgbw, gastric infusion.
With the NDST new drug statistical procedure software of establishments such as Sun Ruiyuan, calculate LD with the Bliss method 50, the results are shown in Table 1.
The result shows, the present composition LD of Borneolum Syntheticum to mice that can raise 50, reduce since certain density Borneolum Syntheticum to the toxicity due to the body, combination group respectively with single with Borneolum Syntheticum relatively, ☆ P＜0.1.
The LD of table 1 different dosing group 50
Figure C20051013256300131
2. collaborative antiinflammatory action
2.1 influence to acute exudative inflammation (dimethylbenzene induced mice ear swelling)
2.1.1 material
Pharmaceutical composition of the present invention (Radix Paeoniae Alba extract+Borneolum Syntheticum 5: 1) is divided into 10,30, the 50mg/kg group;
Blank: normal saline;
Positive control: the Radix Paeoniae Alba extract that is equivalent to same dosage; 10% Borneolum Syntheticum group; Aspirin 0.2g/kg group.
2.1.2 method and result
The ICR mice, body weight 19-21g, 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 2a.
The influence of table 2a xylol induced mice ear swelling (X ± SD, n=10)
Figure C20051013256300132
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 Borneolum Syntheticum.
2.2 xylol causes the influence of mouse skin capillary permeability
2.2.1 material
Pharmaceutical composition of the present invention (Radix Paeoniae Alba extract+Borneolum Syntheticum 8: 1) is divided into 10,30, the 50mg/kg group;
Positive control drug: the Radix Paeoniae Alba extract that is equivalent to same dose; 10% Borneolum Syntheticum group; Aspirin 0.2g/kg group.
2.2.2 method and result
" herbal pharmacology research methodology " with reference to the Qi Chen chief editor makes the animal inflammatory model, the results are shown in following table 2b:
The influence of table 2b xylol induced mice capillary of skin permeability (X ± SD)
Figure C20051013256300141
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 Borneolum Syntheticum.
The result shows: present composition xylol induced mice ear swelling and xylol induced mice capillary of skin permeability have the obvious suppression effect, can obviously suppress dimethylbenzene induced mice ear swelling, can alleviate mice caused by dimethylbenzene xylene capillary of skin permeability, has the effect that the early stage capillary permeability of inflammation-inhibiting increases, compare with matched group and to have significant difference, compare with the one pack system extract group of Isodose, high dose composition group of the present invention also has significant difference (P＜0.05) senior middle school's dosage group and the blank group compares P＜0.05-0.01, show that this medicine has the effect of obvious inhibition acute inflammation infiltration, two medicines share, effect obviously strengthens, and demonstrates significant synergism.
Also have experiment to show, 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 and 10% Borneolum Syntheticum concentration group, the compatibility of prompting Borneolum Syntheticum and Radix Paeoniae can promote the antiinflammatory action of Radix Paeoniae/Borneolum Syntheticum single medicinal material, and its two compatibility plays collaborative antiphlogistic effect.
3. the influence that the other drug active component is absorbed
3.1. improve active constituents of medicine blood drug level in vivo
3.1.1 material
Pharmaceutical composition of the present invention: peoniflorin+Borneolum Syntheticum+TANSHINONES 5/1/5;
Blank group: normal saline;
Positive control drug: the peoniflorin+TANSHINONES that is equivalent to the one pack system of same dosage.
3.1.2 method and result
Rat is divided into single peoniflorin+TANSHINONES group, pharmaceutical composition group of the present invention used, and different time points is obtained pharmacokinetic parameters with the blood drug level of gas chromatography determination TANSHINONES with the NONLIN routine processes after the administration.
Two groups relatively: C MaxBe 587 and 896ng/ml, p＜0.01, AUC is 36476:63885, p＜0.05 is indicated that Borneolum Syntheticum can promote the absorption of TANSHINONES, thereby is improved its blood drug level; Same method (gas chromatography), the blood drug level of mensuration peoniflorin has proved that also Borneolum Syntheticum can promote the absorption of peoniflorin.
3.2. improve the interior bioavailability of the body of active constituents of medicine
3.2.1 material
Pharmaceutical composition of the present invention: peoniflorin+Borneolum Syntheticum+TANSHINONES 10/1/5;
Blank group: normal saline;
Positive control drug: the peoniflorin+TANSHINONES that is equivalent to the one pack system of same dosage.
3.2.2 method and result
Rat is divided into single with Radix Paeoniae+Radix Salviae Miltiorrhizae extract group, pharmaceutical composition group of the present invention.After irritating stomach, adopt the high effective liquid chromatography for measuring rat intravital through the time process and calculate pharmacokinetic parameter.The T of present composition group and extract group 1/2kaBe respectively 17.35min and 21.96min, T 1/2keBe respectively 557.41min and 429.64min, T MaxBe respectively 17.35min and 21.96min, T MaxBe 93.12min and 101.56min, C MaxBe 12.68 and 8.67ng/ml, AUC (curve during medicine) is 11876.46 microgram min/ml and 6385.11 microgram min/ml.
Experimental result is indicated, because the adding of Borneolum Syntheticum, obviously improved the blood drug level of Radix Paeoniae and effective component in red sage, significantly increase area under the drug-time curve, analyzing this is because Borneolum Syntheticum has promoted Radix Paeoniae and effective component in red sage (peoniflorin and TANSHINONES) in the absorption of small intestinal, has significantly improved Radix Paeoniae and effective component in red sage in the intravital bioavailability of rat.
In addition, to Radix Paeoniae+Borneolum Syntheticum+Herba Erigerontis, Radix Paeoniae+Borneolum Syntheticum+Radix Puerariae, Radix Paeoniae+Borneolum Syntheticum+Herba Erigerontis+Flos Carthami, also carried out same experiment, trend is consistent with the result of aforementioned pharmaceutical compositions as a result.
Two. the pharmacological action for the treatment of cardiac and cerebral vascular diseases
1. to the influence of different derivant induced platelet aggregations
1.1 material
Pharmaceutical composition of the present invention (peoniflorin+Borneolum Syntheticum+scutellarin 6/1/10 is called for short compositions A, the 8mg/kg injection), and Radix Paeoniae Alba extract+Borneolum Syntheticum+Herba Erigerontis extract (10/1/20, be called for short compositions B, 20,30,60mg/kg irritates stomach);
Blank group: normal saline;
Positive control drug: aspirin tablet (100mg/kg); Radix Paeoniae+oil lamp (1: 1) group 60mg/kg; Radix Paeoniae+oil lamp (1: 1) group; And aspirin.
1.2 method and result
The Cavia porcellus grouping was irritated stomach 5 days, the blank normal saline.Last administration rear neck artery blood sampling in 1 hour, with the sodium citrate anticoagulant, mixing, centrifugal, merge supernatant as PRP (platelet rich plasma), platelet count; Remaining blood plasma is centrifugal, gets supernatant as PPP (platelet poor plasma); With the PPP zeroing, to get PRP300 μ L and add opacity tube, 37 ℃ of incubations add derivant PAF (platelet activating factor), assemble different time, record data.The results are shown in Table 3.
The accumulative influence of the inductive guinea pig blood platelet of table 3 pair platelet activating factor
Figure C20051013256300161
Compare with the blank group: *P＜0.05 *P＜0.01; Compare #P＜0.05 with oil lamp+Radix Paeoniae.
Derivant is the experimental result of adenosine diphosphate (ADP), is similar to the effect that table shows.
By The above results as can be known, aspirin tablet, compositions A group, combination object height/middle dosage B group all can suppress the inductive platelet aggregation of different derivants (coagulation), reduce maximum agglutination rate, wherein best with aspirin tablet, compositions A group, B group high dose effect, middle dosage group also shows the anticoagulant effect, be better than Radix Paeoniae+oil lamp group, the effect that Borneolum Syntheticum has played increases curative effect is described; Compositions A group also is better than the aspirin group.
Aspirin tablet, compositions A group, high dose B group have significant difference (P＜0.01) than matched group, and compare between Radix Paeoniae Alba extract of using separately and Radix Salviae Miltiorrhizae extract group, and significant difference (P＜0.05) is arranged.
1.3 discuss
The prevention transient ischemic attack is exactly in order to postpone or prevent the generation of cerebral infarction, the first-selected anti-platelet aggregation agent of treatment measure.Aspirin is a medicine commonly used, but that aspirin is proved the mechanism of action of antiplatelet aggregation is single, only blocks synthetic this approach of TXA2.In addition, aspirin occurs digestive tract reaction, side effect such as hemorrhage in treatment aspect this, causes compliance poor, and this just causes the failure of part patient when taking aspirin prevention cardio-cerebral apoplexy.Simultaneously, aspirin is to arteriosclerotic prevention curative effect instability, its reason is that also this medicine can not suppress the two or more poly-inductive platelet aggregations of agent that cause, promptly can not suppress platelet accumulative whole approach takes place, the present composition then can improve cAMP content and suppress different derivant induced platelet aggregations, clinically verify that also compositions of the present invention is equal to or is better than aspirin in effect aspect the effect of anticoagulant, and there is not the side effect (in clinical treatment stage, the patient of aspirin group drops by the wayside because of intensive side effect has nearly half) of aspirin.Processing is learned in two groups of side effect by statistics, and the result relatively has significant difference (P＜0.05).
Also to the thrombotic influence of rat neck artery-vein blood flow coronary artery bypass grafting, the thrombotic influence of rats in vitro etc. is tested, the result shows that the present composition forms thrombus in vivo and has obvious antagonism.
2. to preventing postangioplasty restenosis
Postangioplasty restenosis (RS), its sickness rate is up to 30-50%, the verified syndrome of blood stasis category that belongs to of its case, because 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 of the present invention (peoniflorin+breviscapine+Borneolum Syntheticum 8/15/1,4,8mg/kg injection);
Blank group: normal saline;
Positive control drug: peoniflorin injection, each 8mg/kg of Breviscapini injection; Radix Paeoniae+oil lamp (1: 3) injection;
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).
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
Table 4 pair smooth muscle cell 3The influence of H-TdR incorporation (X ± s)
Figure C20051013256300171
Figure C20051013256300181
With compare, *P＜0.05 *P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with Radix Paeoniae;
Compare #P＜0.05 with oil lamp; Compare ◇ p＜0.05, ◇ ◇ p＜0.01 with Radix Paeoniae+oil lamp
The influence of table 5 pair smooth muscle cell counting (X ± s)
Figure C20051013256300182
Compare with blank, *P＜0.05, *P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with Radix Paeoniae;
Compare #P＜0.05, ##P＜0.01 with oil lamp; Compare ◇ p＜0.05, ◇ ◇ p＜0.01 with Radix Paeoniae+oil lamp.
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%.
2.4 conclusion
Pharmaceutical composition of the present invention, peoniflorin+oil lamp injection, oil lamp injection are inhibited to the abnormality proliferation of vascular smooth muscle cell (VSMCs).Pharmaceutical composition of the present invention is the strongest, compare with peoniflorin+oil lamp, have significant difference between group, analysis may be peoniflorin and the beneficial effect that jointly brings different with the mechanism of action of oil lamp extract (breviscapine) and Borneolum Syntheticum, significant difference between group (P＜0.05).Proof Radix Paeoniae and oil lamp and Borneolum Syntheticum share the blood circulation invigorating efficacies that can strengthen Radix Paeoniae and oil lamp, and the three plays synergism.
In addition, to Radix Paeoniae+Borneolum Syntheticum+Herba Erigerontis, Radix Paeoniae+Borneolum Syntheticum+Radix Puerariae, Radix Paeoniae+Borneolum Syntheticum+Herba Erigerontis+Radix Puerariae), carried out same experiment, the result is close with the result of aforementioned pharmaceutical compositions, and the blood circulation invigorating efficacies of Radix Paeoniae+Borneolum Syntheticum group slightly is inferior to other compositions group of the present invention.
Three. the short effect of waking up
1. material
Mice: Kunming kind, body weight 18-22g, male and female half and half.
Reagent: XINGNAOJING ZHUSHEYE (Dali pharmaceutcal corporation, Ltd, 10ml/ props up); Fleabane injection (the biological paddy in Yunnan pharmaceutical factory); Oil lamp+Radix Paeoniae injection (self-control); Caffeine and sodium benzoate injection raw material (Shanghai the 14 pharmaceutical factory); The present composition (Radix Paeoniae+Borneolum Syntheticum+oil lamp 10/1/20) senior middle school's low dose group; The present composition 2 (Radix Paeoniae+Borneolum Syntheticum+oil lamp+Flos Carthami 4/1/2/3) group 40mg/kg; The present composition 3 (Radix Paeoniae+Borneolum Syntheticum+Radix Puerariae 4/1/5) group 40mg/kg.
2. method and result
The mice random packet, reagents such as tail vein injection sodium chloride injection, caffeine and sodium benzoate normal saline solution, XINGNAOJING ZHUSHEYE respectively, 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 to the time of recovering, calculate each class mean and standard deviation, carry out the t check, the results are shown in Table 6.
The short effect of waking up of table 6 pair mice (X ± SD, n=10)
Figure C20051013256300191
Compare with the blank group: *P＜0.05, *P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with the oil lamp group;
Compare #P＜0.05, ##P＜0.01 with oil lamp+Radix Paeoniae.
3. conclusion
Compare with matched group, the present composition, contrast medicine XINGNAOJING, caffeine and sodium benzoate group all show short effect of waking up.Compare with oil lamp+Radix Paeoniae, this compositions presents significant difference, shows share of Radix Paeoniae oil lamp and Borneolum Syntheticum, has strengthened the pharmacologically active of the short aspect of waking up of Borneolum Syntheticum (potential).
Four. the pharmacological action of diabetes aspect
1. hypoglycemic activity
1.1 material
Pharmaceutical composition of the present invention: Radix Paeoniae Alba extract+Borneolum Syntheticum+Herba Erigerontis extract+Folium Ginkgo extract 20/1/30/10, the A group is irritated stomach for 10mg/kg injection, B group for 80mg/kg;
Normal control group: normal saline;
Diabetic groups: normal saline;
Positive control drug: bilobalide; Scutellarin; Borneolum Syntheticum+oil lamp+compositions extracted from gingko biloba leaves; JIANGZHILING PIAN;
1.2. 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 7 pair diabetes rat and the influence of serum I ns
Figure C20051013256300201
Compare with diabetic groups: *P＜0.05 *P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with scutellarin/bilobalide; Compare #P＜0.05, ##P＜0.01 with Borneolum Syntheticum+oil lamp+compositions extracted from gingko biloba leaves.
Above-mentioned experiment shows, and is the most obvious with the effect of pharmaceutical composition injection group of the present invention and oral group.Oral scutellarin/bilobalide all can produce the effect of certain blood sugar lowering, but obvious not as Borneolum Syntheticum+oil lamp+Folium Ginkgo combination, more the effect not as the present composition (Radix Paeoniae+Borneolum Syntheticum+oil lamp+compositions extracted from gingko biloba leaves) is obvious.JIANGZHILING PIAN only shows the effect of blood sugar lowering.Present composition injection group has obviously reduced the blood glucose of alloxan diabetes, and it is not obvious to serum I ns level affects, this drug combination that shows Radix Paeoniae, Borneolum Syntheticum, oil lamp and Folium Ginkgo has produced stronger hypoglycemic activity to alloxan diabetes rats, and hypoglycemic activity is not realized by improving insulin level.
Simultaneously, the present invention has studied the influence of the present composition to lipid peroxidation product malonaldehyde (MDA) in the serum of the rat of diabetes model, liver, the brain.Compare with the normal control group, lipid peroxidation product malonaldehyde (MDA) content significantly improves in the serum of the rat of diabetes model, liver, brain, the pancreas, and use through behind the medicine of the present invention, MDA in the above-mentioned tissue obviously descends, illustrate that Semen Ginkgo (lactone) and Radix Paeoniae (glycosides) and Semen Ginkgo (lactone) are the active drugs that improves and treat diabetes, especially use the effect of its 5 usefulness adduction best (obviously being better than single each component of using) with three's combination and auxiliary a certain proportion of Borneolum Syntheticum compatibility.
2. to the diabetic retinal tissue in rat protective effect
2.1 materials and methods
Laboratory animal is selected 50 of male SD rats for use, and adaptability was raised 7 days, surveys fasting glucose and all is lower than 7mmol/L, is divided into 10 of normal control groups (E group) at random, 40 of experimental grouies.(STZ) brings out diabetes with streptozotocin.All blood glucose 〉=16.7mmol/L are divided into 3 groups more at random as diabetic groups, and each 10, the DM group is not treatment group of diabetes, and every day, normal saline 100mg/kg irritated stomach; The A group is Borneolum Syntheticum+Flos Carthami extract (5: 2) group, and 40mg/kg irritates stomach; The B group is Radix Paeoniae Alba extract+Flos Carthami extract (1: 2) group, and 20mg/kg irritates stomach; The C group is present composition group: Borneolum Syntheticum+Radix Paeoniae Alba extract+Flos Carthami extract (4: 1: 6), 40mg/kg irritates stomach.Each component 2 cage is fed, ad lib and drinking-water.
2.2 result
Test shows that the present composition has the effect that promotes weight increase, blood sugar lowering for the DM rat, sees Table 8.
Compare with normal group: each activity, the active of AR (aldose reductase) of organizing retinal tissue of rats with diabetic mellitus NOS significantly strengthens, and NO content significantly increases.Compare with the DM group: C group rat retina organizes the activity of NOS, the activity of AR obviously to be suppressed, and the content of NO also significantly reduces, and the inhibitory action of A, B group is not obvious, sees Table 9.
2.3 discuss
1. rising of hyperglycemia level and glycolated hemoglobin ratio and retinopathy have confidential relation between taking place, developing.Above-mentioned experiment shows, the effect of present composition blood sugar lowering can obviously suppress the activity of AR and NOS, reduces the synthetic of NO, and diabetic renal papillary necrosis is had obvious preventive and therapeutic effect.
Find that simultaneously the present composition can significantly reduce NO content, this may to improve the activity of retinal tissue of rats with diabetic mellitus SOD relevant with the present composition, and the SOD increased activity is in time removed the NO of excessive generation, and radical damage is played certain protective role.
2. in another test, investigated the influence of the present composition, studies show that the effect that the present composition has obvious functions of blood sugar and alleviates insulin resistant diabetes type piglets retinal vessel endothelial growth factor expression.
3. in addition, Chinese scholars is thought and can be stoped and postpone the formation of proliferative diabetic retinopathy (PDR) by the expression that suppresses VEGF.What the applicant had carried out studies show that, compare with matched group (high fat high-sucrose feedstuff+Borneolum Syntheticum+Flos Carthami extract or+Radix Paeoniae Alba extract+Flos Carthami extract), the vegf protein in the animal retinal tissue of treatment group (high fat high-sucrose feedstuff+present composition) is expressed has significant difference (P＜0.01).
The inventor wishes to borrow above-mentioned statement indefiniteness ground to explain that present composition effect obviously is better than using the mechanism of Borneolum Syntheticum+Flos Carthami extract combination or Radix Paeoniae+Flos Carthami extract combination.
Rat body weight respectively organized by table 8 and blood glucose compares (n=10)
Figure C20051013256300221
Compare with the E group: *P＜0.01; Compare with the DM group: #P＜0.01
Table 9 is respectively organized rat retina and is organized the activity of the content of NO, NOS, the activity of AR (n=10)
Figure C20051013256300222
Compare with the E group: *P＜0.01; Compare with the DM group: #P＜0.01
Five. to the antioxidation of hyperlipidemia rat
1. material
Pharmaceutical composition of the present invention: Radix Paeoniae+Borneolum Syntheticum+Flos Carthami 4/1/5,50mg/kg irritates stomach;
Normal control group: normal saline;
Hyperlipidemia group: normal saline;
Positive control drug: Flos Carthami extract 50mg/kg (containing total Carthamus yellow); Peoniflorin (50mg/kg); VE (50mg/kg); Flos Carthami extract; Flos Carthami+Borneolum Syntheticum group.
2 methods and result
The foundation of high blood lipid model: the Wistar rat gives high lipid food; Normal control group feeding normal diet.Compare with normal group: the LPO of hyperlipidemia model serum and liver obviously raises, and obviously reduces and SOD is active.
Medicine is irritated stomach, handles animal, surveys LPO and SOD, according to the operation of test kit description, gets 1/2 liver LPO to be measured and SOD, the results are shown in Table 10:
The influence (nmol/L) of table 10 pair hyperlipemia rat serum and liver LPO and SOD
Figure C20051013256300223
Figure C20051013256300231
Compare with the hyperlipidemia group: *P＜0.05, *P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with Radix Paeoniae;
Compare #P＜0.05, ##P＜0.01 with Flos Carthami+Borneolum Syntheticum.
3 conclusions
Experiment shows, the antioxidant activity of the present composition significantly is better than Radix Paeoniae, Flos Carthami and the Flos Carthami used separately and the combination of Borneolum Syntheticum.Infer that this is because contain peoniflorin, Borneolum Syntheticum and total Carthamus yellow in the present composition, these three kinds of chemical constituents can suppress the release of lactic acid dehydrogenase from different aspects, with different mechanisms, have the effect of significant antioxidation and resistant activity oxygen, have certain lipoid peroxidization resistant.
The above results also proves: though the combination of Flos Carthami and Borneolum Syntheticum can promote antioxidant activity to a certain extent, containing Radix Paeoniae and Borneolum Syntheticum simultaneously, is compositions obtains outstanding effect aspect antioxidation essential condition.
5 usefulness of the present composition are not then found toxic and side effects, therefore adopt Radix Paeoniae and Flos Carthami and Borneolum Syntheticum 5 usefulness, and both having played synergism has increased curative effect, the adverse side effect that does not bring again.
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.
Six. the brain cell protective effect
1 material
Laboratory animal: 72 of healthy Wistar rats, body weight 250 ± 10g;
Medicine: the present composition (Borneolum Syntheticum+peoniflorin+puerarin 2/1/3,30mg/kg);
Positive control drug: Radix Paeoniae group: peoniflorin+puerarin injection, 30mg/kg; Borneolum Syntheticum group: Borneolum Syntheticum+puerarin injection, 30mg/kg; Edaravone group: Edaravone Injection injection, 10mg/kg.
2. method
Rat is divided into 6 groups at random, 12 every group.The normal control group: by left external jugular vein intubate, quiet notes 1% heparin (2ml/kg) is given 0.9% sodium chloride liquid 3ml/kg respectively at reaching 1.5h at once through left external jugular vein intubate, gets brain detection or fixing behind the 3h.Model group: set up the cerebral ischemia re-pouring animal model with reference to Kaizumis bolt collimation method.The equal ischemia 1.5h of experimental animal model gets brain detection or fixing, takes out the bolt line then and pours into 1.5h again, gets brain detection or fixing.Specimen: rat broken end is got brain, peel off cerebral tissue, get and get brain cortex and tail shell nuclear light, electron microscope specimen between two coronal sections of optic chiasma and interpeduncular fossa respectively.
The mensuration of cerebral edema and brain calcium content: get right front brain 50-100mg, dry, be dry weight to constant weight.
Brain water content is measured: use formula: (weight in wet base-dry weight)/weight in wet base, calculate brain water content.
3. result
1. rat cerebral tissue's infarct is observed:
Under the light microscopic: model group neuron soft edge, cell space is painted to deepen, and karyon is little, the kytoplasm boundary is unclear.The cell peripheral clear zone broadens and there were significant differences (P＜0.01) for the normal control group.Present composition group and Edaravone group neuronal structure are still clear, and karyon and kytoplasm boundary still can be distinguished, and cell peripheral clear zone broad dwindles there was no significant difference though compare with model group.Peoniflorin group and Borneolum Syntheticum group neuronal structure owe clear, and karyon and kytoplasm boundary can be distinguished, and cell peripheral clear zone broad is compared with model group and not seen obviously and dwindle.
Under the Electronic Speculum: the distortion of model group neuron, the light and shade neuron is not easily distinguishable, karyon distortion, surperficial indentation, in the nuclear heterochromatin increase, nuclear membrane and perinuclear space is smudgy, the caryoplasm boundary is unclear, network structure disappears, organelle minimizing or distortion, structure are unclear.Mitochondrion is the swelling of balloon sample, plasma structure is unclear or disappearance is ruptured, cell peripheral has a large amount of edematous fluid to be the low electron density clear zone.The all nuclear membranes of present composition group and Edaravone group neuronal kernel are clear, the interior heterochromatin of nuclear increases slightly, the perinuclear space is narrower, the kytoplasm inner cell organ is obvious but mitochondrion all has the change of edema sample, cell peripheral that a small amount of edematous fluid is arranged.Peoniflorin group and Borneolum Syntheticum group neuronal kernel week nuclear membrane owe in clear, the nuclear heterochromatin slightly showed increased, the perinuclear space is narrower, the kytoplasm inner cell organ is not obvious, mitochondrion has the edema sample to change.Model group astrocyte edema, kytoplasm electron density reduce, organelle reduces, the local cells membrane structure is unclear.The edema performance of present composition group and Edaravone group astrocyte is light than model group, and organelle is compared obviously more with model group.The peoniflorin group is then similar substantially to model group with Borneolum Syntheticum group astrocyte.
2. the experimental result of cerebral tissue calcium, malonaldehyde, superoxide dismutase, brain moisture: model group cerebral tissue mda content, calcium content, brain moisture all obviously raise (P＜0.01) than normal matched group, and the SOD activity then is starkly lower than normal control group (P＜0.01); The present composition can suppress the rising and the increased SOD activity (P＜0.01) of perfusion back cerebral tissue mda content, improves brain water content (P＜0.01), and effect and Edaravone are suitable, obviously are better than Borneolum Syntheticum+puerarin group, peoniflorin+puerarin group.
5.3 conclusion
The present composition can significantly suppress the rising and the SOD activity improving of the MDA of cerebral ischemia re-pouring rat cerebral tissue content, improves brain water content, and confirms that from ultrastructure membranous structure is still had certain protective role.The present composition is removed oxygen-derived free radicals, thereby brain cell is shielded mainly by SOD activity improving, and its effect is suitable with Edaravone, obviously is better than Borneolum Syntheticum+Radix Puerariae group, peoniflorin+puerarin group.
Seven. the pharmacological action of others
1. treat the observation of curative effect of rat fat liver
1.1 materials and methods
Medicine: present composition group (Borneolum Syntheticum+peoniflorin+ginsenoside 1: 5: 3,40mg/kg, 10mg/kg); Borneolum Syntheticum group (Borneolum Syntheticum+ginsenoside 20mg/kg); The peoniflorin group (peoniflorin+ginsenoside, 20mg/kg).
50 of male SD rats, body weight 150g ± 10g.After normal 1 week of nursing, be divided into 2 groups at random: experimental group (40), raise with high fat high cholesterol diet (10.0% Adeps Sus domestica, 2.0% cholesterol, 0.5% sodium cholate, 87.5% normal feedstuff); With normal control group (10), give normal feedstuff, two groups of rats are all freely intake.
After 12 weeks, randomly draw 8 from experimental group, the normal control group is randomly drawed 2, and the execution animal is got liver and does pathological section, checking fatty liver modeling success.Remaining experimental group rat is divided into compositions high-dose therapy group, compositions low dose therapy group, Borneolum Syntheticum treatment group and peoniflorin treatment group more at random by the body weight level.The normal control group is to irritate stomach with the isometric(al) distilled water, and each group is all given normal feedstuff and raised, and blood and hepatic tissue are got in administration after 4 weeks, detect every index.
1.2 observation index
When (1) experiment finishes to put to death animal, weigh and the liver weight;
(2) biochemical index: content, the empty stomach serum insulin (FINS) of measuring fasting glucose (FBG) T-CHOL (TC), triglyceride (TG) and highdensity lipoprotein-cholesterol (HDL-C);
(3) insulin resistance index: insulin resistance index HOMA-IR=(FBG * FINS)/22.5; With
(4) histopathological examination: the content of spectrophotometry TG.
1.3 result
Each group did not all have animal dead during experiment was carried out.
When experiment finished, body weight, the liver index (liver weight in wet base/body weight * 100%) of Borneolum Syntheticum, peoniflorin treatment treated animal significantly increased (P＜0.05 than normal control group; P＜0.01); Compare with Borneolum Syntheticum, peoniflorin treatment group: body weight, the liver index of high and low dose combination treatment group significantly reduce (P＜0.01); Compare with the normal control group, high and low dose combination treatment group body weight, liver index differential not statistically significant see the following form 11.
The variation of serum and liver tissue homogenate's lipid: Borneolum Syntheticum, peoniflorin treatment group serum TG, TC and hepatic tissue TG are normal, and matched group raises; Compare with Borneolum Syntheticum, peoniflorin treatment group: These parameters is all obviously improved in the high and low dose combination treatment group, sees the following form 12.
Variation such as FBG and FINS: Borneolum Syntheticum treatment group FBG and FINS and HOMA-IR are and increase trend; Peoniflorin treatment group FBG and FINS and HOMA-IR are on a declining curve; Compare with Borneolum Syntheticum treatment group: the FINS and the HOMA-IR of high and low dose combination treatment group significantly descend, and the equal not statistically significant of all the other comparing differences sees the following form 12.
Pathological change: (1) perusal: Borneolum Syntheticum, Radix Paeoniae treatment group rats'liver outward appearance are butter yellow, and volume obviously increases, the edge rust, and the quality deliquescing, tangent plane is greasy feeling slightly; High and low dose combination treatment group liver outward appearance is near the normal control group; (2) om observation: the fat drop that occurs differing in size in Borneolum Syntheticum, the peoniflorin treatment group lobules of liver center band hepatocyte, part of hepatocytes nuclear is then pushed by fat drop and obvious off normal, reach the focal inflammatory cell infiltration in portal area in the lobule, with some lamellar necrosis to a certain degree; High and low dose combination treatment group lobules of liver and hepatic sinusoid clear in structure are seen a little vesicle fat drop, accidental hepatic necrosis in the cell.
1.4 conclusion
Above-mentioned experiment prompting, the present composition can significantly improve the fatty live lesions degree, improves lipid metabolism, significantly is better than Borneolum Syntheticum+ginsenoside, peoniflorin+ginsenoside.
Because the generation and the insulin resistant of non-alcoholic fatty liver disease are closely related, and the patient often merges obesity, hyperglycemia, hyperinsulinemia.We think that the present composition is by reducing patients with insulin resistance, improve lipid metabolism, the effect of aspects such as anti-cell inflammatory generation improvement fatty live lesions, worth further discussion of its synergism mechanism.
Table 11 rat body weight, liver index variation (X ± S, n=8)
Figure C20051013256300261
Compare with the normal control group: *P＜0.05; #P＜0.01;
Compare with the normal control group: P＞0.05; Compare with Borneolum Syntheticum, Radix Paeoniae treatment group: ▲ P＜0.01
The variation of table 12 rat blood serum and liver homogenate lipid (X ± S)
Figure C20051013256300262
Compare with the normal control group: *P＜0.05; #p＜0.01;
Compare with model control group: P＞0.05; Compare with Radix Salviae Miltiorrhizae, Radix Paeoniae treatment group: ▲ p＜0.05
The variation of table 13 rat fasting blood-glucose, serum insulin and insulin resistance index level (X ± S)
Figure C20051013256300271
Compare with Borneolum Syntheticum treatment group: *P＜0.05
2. treat the experimentation of the rabbit retinal vein occlusion
2.1 material and method
36 of purebred male New Zealand rabbits, body weight 2.2-2.5kg causes retinal vein occlusion model.
Divide 6 groups, 6 every group, that is: blank group, present composition treatment group (Borneolum Syntheticum+peoniflorin+ligustrazine 2/2/10 divides high, medium and low three dosage groups), Borneolum Syntheticum treatment group (Borneolum Syntheticum+ligustrazine), peoniflorin treatment group (peoniflorin+ligustrazine).The 3rd day began successive administration 10 days after the modeling, and the blank group waits the capacity drinking water.
2.2 result
The optical fundus situation: the 2nd day visible retinal hemorrhage of modeling, the 6th day present composition high dose group retinal hemorrhage obviously begins to absorb, and blank group retinal hemorrhage just obviously begins after 20 days to absorb, difference that there was a significant difference.Borneolum Syntheticum treatment group and peoniflorin treatment group obviously begin to absorb with the 11st, 18 day beginning retinal hemorrhage respectively, and this compares there was no significant difference with the blank group.After blood absorbs fully, the optical fundus blood vessel of blank group and peoniflorin treatment group is thin and tortuous, and the optical fundus blood vessel of 3 dosage groups of the present composition is all near normal condition, and the optical fundus blood vessel of Borneolum Syntheticum treatment group changes between blank group and present composition low dose group.The results are shown in Table 14.
Fundus photography and fundus fluorescein angiography inspection: 3 dosage groups of the present composition, Borneolum Syntheticum treatment group optical fundus blood vessel form are near normal, do not see the fluorescein seepage, also do not see new vessels, though and blank group, peoniflorin group retinal hemorrhage have absorbed, but still the plain seepage of visible fluorescence, and visible new vessels.6 hemorrhage all absorptions fully of group are seen in fundus photography, but the vascular morphology difference, situation is consistent with the inspection of direct ophthalmoscope.
2.3 conclusion
Experiment shows that the present composition has the therapeutical effect of highly significant to the experimental central retinal vein occlusion of rabbit.Especially it should be noted that the therapeutic effect that Borneolum Syntheticum+ligustrazine of using or peoniflorin+ligustrazine all can't reach the present composition.We think, this with compositions in Borneolum Syntheticum and peoniflorin+ligustrazine to produce obvious synergism in following mechanism of action relevant: promote drug absorption, strengthen drug effect, blood vessel dilating, reduce vascular resistance; Microcirculation improvement improves hypoxia-bearing capability; It is synthetic to suppress fibrin, anticoagulation and hamartoplasia; Suppressed the release of sensitive media, antianaphylaxis.
The influence of hemorrhage complete soak time at the bottom of the table 14 pair lagophthalmos (x ± s, n=6)
Figure C20051013256300281
Compare with the normal saline group: *P＜0.05, *P＜0.01
Clinical observation
The clinical trial of cardiovascular and cerebrovascular disease aspect
1 medicine
The present invention's combination: Borneolum Syntheticum+breviscapine, 150mg/ days; With Radix Paeoniae Alba extract, 15mg/ days, merge oral.
Contrast: breviscapine 120mg/ days, Radix Paeoniae Radix Paeoniae Alba extract (containing peoniflorin) 15mg/ days, oral.
2 methods and result
Adopt the method for randomized controlled to investigate its curative effect and untoward reaction, observe coronary heart disease patient 200 examples altogether, wherein 100 examples (oral combination of the present invention), curative effect cure-remarkable-effectiveness rate 43.87%, total effective rate 90.33% are organized in treatment; Matched group 100 examples, cure-remarkable-effectiveness rate 24.46%, 73.23%, two group of coronary heart disease curative effect of total effective rate is learned processing by statistics, and there is significant difference P＜0.01, and the treatment group is better than matched group.The treatment group is not seen tangible untoward reaction.
Adopt the method for randomized controlled to investigate its curative effect and untoward reaction, observe acute ischemic patient 150 examples altogether, wherein 80 examples are organized in treatment, curative effect cure-remarkable-effectiveness rate 38.34%, total effective rate 86.653%; Matched group 70 examples, cure-remarkable-effectiveness rate 26.46%, total effective rate 74.93%.Two groups of coronary heart disease curative effects are learned processing by statistics, and there is significant difference P＜0.05, and the treatment group is better than matched group.The treatment group is not seen tangible untoward reaction.
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;
Natural Broneolum Syntheticum 0.5g is ground into fine powder, with 6g extract I 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 Herba Erigerontis and 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,, concentrating under reduced pressure, with n-butanol extraction three times, each 300ml merges n-butanol extracting liquid, be evaporated to no n-butyl alcohol flavor, add the water heating for dissolving, add dilute sodium hydroxide again and regulate pH value to 7, filter, the filtrate spray drying, it is standby to get extract II;
Natural Broneolum Syntheticum 2g is ground into fine powder, with 10g extract I, 20g extract II mixing, adds low-substituted hydroxypropyl cellulose, magnesium stearate, starch, microcrystalline Cellulose, prepares 1000 according to standard granulation and tablet forming technique.
Embodiment 3 soft capsules
Get the CO of peoniflorin 8g, Borneolum Syntheticum cyclodextrin clathrate 25g (containing Borneolum Syntheticum 2.5g), Radix Salviae Miltiorrhizae 2Supercritical extract 15g (ethanol is entrainer), ligustrazine hydrochloride 5g with glycerol mixing, pill, 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 I is standby;
Get natural Broneolum Syntheticum 3.5g and be ground into fine powder,, get IV with 15g extract II I, 20g breviscapine mixing;
It is evenly mixed to get xylitol and Furcellaran, adds the IV 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 1000 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 Radix Paeoniae Alba extract 10g, Radix Salviae Miltiorrhizae extract 25g, Borneolum Syntheticum cyclodextrin clathrate 25g (containing Borneolum Syntheticum 4g), aspartame, Fructus Citri Limoniae essence and magnesium stearate, 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 extract product of general flavone of kudzuvine root 12g, peoniflorin 18g, Borneolum Syntheticum cyclodextrin clathrate 20g (containing Borneolum Syntheticum 3g), 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 scutellarin 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 V;
Get HP-, add water and make dissolving, stir on agitator, 60 ℃ of insulations are standby; Borneolum Syntheticum solution is slowly dropped in the cyclodextrin aqueous solution, and 70 ℃ were stirred 2-3 hour, continued to stir 3-5 hour (or ultrasonic) under the room temperature with abundant enclose, filtered and obtained Borneolum Syntheticum HP-beta-CD inclusion VI (containing Borneolum Syntheticum 2g);
V and VI are mixed, add lyophilizing figuration mannitol, add to the full amount of water for injection, adjust pH adds active carbon, and coarse filtration is taken off charcoal, and gained filtrate is continued with 0.22 μ m filtering with microporous membrane, packing, lyophilization.

Claims (14)

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:
Component a. Borneolum Syntheticum, the 1-15 weight portion; With
Components b. Radix Paeoniae dry root powder, or contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, or the peoniflorin monomer, the 5-85 weight portion.
2. pharmaceutical composition as claimed in claim 1, wherein component a is that 2-10 weight portion and components b are the 10-60 weight portion.
3. as the pharmaceutical composition of claim 1 or 2, also contain Hydroxy peoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, lacdtlorin in the described Radix Paeoniae Alba extract.
4. 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:
Component a. Borneolum Syntheticum, the 1-15 weight portion; With
Components b. Radix Paeoniae dry root powder, or contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, or the peoniflorin monomer, be the 5-85 weight portion; With
Amount of component b .15-200 weight portion, it is selected from one of following c2-c7 or two kinds:
The alcohol extract of c2. Herba Erigerontis herb powder, or Herba Erigerontis, or breviscapine, or the scutellarin monomer of free or sodium-salt form;
C3. the Flos Carthami extract that contains Flos Carthami total flavochromes, or safflower yellow A, B monomer, perhaps these monomeric mixture;
C4. the osajin extract that contains the Radix Puerariae of daidzein, daidzein glycosides, puerarin, glucosulfone daiazi, methoxy puerarin, 7-xylose-puerarin, diacetyl-puerarin, formononetin, or Radix Puerariae total flavones, or puerarin monomer;
C5. contain bilobalide and/or ginkgetin Semen Ginkgo extrac as active component, or ginkgetin monomer and ginkgolide monomer, or ginkgolide monomer, or the ginkgetin monomer;
C6. the Rhizoma Chuanxiong extract that contains ligustrazine, chuanxingol, ferulic acid, volatile oil, or ligustrazine monomer, or sodium ferulate, perhaps these monomeric mixture;
C7. the Radix Ginseng extract that contains Radix Ginseng total saponins, Radix Ginseng total saponins, or ginsenoside monomer.
5. pharmaceutical composition as claimed in claim 4 also contains Hydroxy peoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, lacdtlorin in the described Radix Paeoniae Alba extract.
6. pharmaceutical composition as claimed in claim 4, described active component is:
Component a. Borneolum Syntheticum, the 2-10 weight portion; With
Components b. contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, the 10-60 weight portion and
Amount of component b .20-120 weight portion, it is selected from one of following c2-c7 or two kinds:
C2. the Herba Erigerontis alcohol extract that contains scutellarin, list/pair caffeoylquinic acids;
C3. the Flos Carthami extract that contains Flos Carthami total flavochromes;
C4. the Radix Puerariae extract that contains puerarin;
C5. contain bilobalide and/or ginkgetin Semen Ginkgo extrac as active component;
C6. the Rhizoma Chuanxiong extract that contains ligustrazine, ferulic acid;
C7. the Radix Ginseng extract that contains Radix Ginseng total saponins.
7. pharmaceutical composition as claimed in claim 4, wherein component a is the 5-10 weight portion, components b is that 20-50 weight portion and amount of component b are the 40-80 weight portion.
8. as the pharmaceutical composition of one of claim 4-7, wherein said active component is:
Component a. Borneolum Syntheticum; With
Components b. the peoniflorin monomer; With
Amount of component b. be selected from one of following c2-c7 or two kinds:
C2. list/pair caffeoylquinic acids;
C3. safflower yellow A, B monomer, perhaps these monomeric mixture;
C4. puerarin monomer;
C5. ginkgolide monomer;
C6. ligustrazine monomer;
C7. ginsenoside monomer.
9. as the pharmaceutical composition of one of claim 4-7, wherein said active component is:
Component a. Borneolum Syntheticum; With
Components b. the peoniflorin monomer; With
Amount of component b. be selected from one of following c2-c7 or two kinds:
C2. breviscapine, scutellarin monomer or its sodium salt;
C3. safflower yellow A, B monomer, perhaps these monomeric mixture;
C4. Radix Puerariae total flavones;
C5. ginkgetin monomer;
C6. ligustrazine monomer and sodium ferulate;
C7. the Radix Ginseng extract that contains Radix Ginseng total saponins.
10. as the pharmaceutical composition of one of claim 4-7, wherein said active component is:
Component a. Borneolum Syntheticum; With
Components b. contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, or the peoniflorin monomer; With
Amount of component b. be selected from one of following c2-c5 or two kinds:
C2. breviscapine, or the scutellarin monomer of free or sodium-salt form;
C3. the Flos Carthami extract that contains Flos Carthami total flavochromes, or safflower yellow A, B monomer, perhaps these monomeric mixture;
C4. the osajin extract that contains the Radix Puerariae of daidzein, daidzein glycosides, puerarin, glucosulfone daiazi, methoxy puerarin, 7-xylose-puerarin, diacetyl-puerarin, formononetin, or Radix Puerariae total flavones, or puerarin monomer;
C5. contain bilobalide and/or ginkgetin Semen Ginkgo extrac as active component, or ginkgetin monomer and ginkgolide monomer, or ginkgolide monomer, or the ginkgetin monomer.
11. as the pharmaceutical composition of one of claim 4-7, wherein said active component is:
Component a. Borneolum Syntheticum; With
Components b. contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, or the peoniflorin monomer; With
Amount of component b. be selected from one of following c2, c5 or two kinds:
C2. the alcohol extract of Herba Erigerontis, or breviscapine, or the scutellarin monomer of free or sodium-salt form;
C5. contain bilobalide and/or ginkgetin Semen Ginkgo extrac as active component, or ginkgetin monomer and ginkgolide monomer or ginkgolide monomer or ginkgetin monomer.
12. as the pharmaceutical composition of one of claim 4-7, wherein said active component is:
Component a. Borneolum Syntheticum; With
Components b. contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, or the peoniflorin monomer; With
Amount of component b. be selected from one of c2, c3 or two kinds:
C2. list/pair caffeoylquinic acids, or breviscapine, or the scutellarin monomer of free or sodium-salt form;
C3. the Flos Carthami extract that contains Flos Carthami total flavochromes.
13. as the pharmaceutical composition of one of claim 4-7, wherein said active component is:
Component a. Borneolum Syntheticum; With
Components b. contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, or the peoniflorin monomer; With
Amount of component b. be selected from one of c3, c4 or two kinds:
C3. the Flos Carthami extract that contains Flos Carthami total flavochromes;
C4. Radix Puerariae total flavones, or puerarin monomer.
14. as the pharmaceutical composition of one of claim 4-7, wherein said active component is:
Component a. Borneolum Syntheticum; With
Components b. contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, or the peoniflorin monomer; With
Amount of component b. be selected from one of c2, c4 or two kinds:
C2. list/pair caffeoylquinic acids, or breviscapine, or the scutellarin monomer of free or sodium-salt form;
C4. Radix Puerariae total flavones, or puerarin monomer.
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CN102940694B (en) * 2012-10-31 2014-06-25 成都医路康医学技术服务有限公司 Medicine composition for treating cardia-cerebrovascular diseases
CN114404405A (en) * 2022-01-07 2022-04-29 江西普正制药股份有限公司 Application of formononetin and natural borneol composition in preparation of medicine for preventing or treating central nervous system diseases
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CN1038585A (en) * 1988-05-16 1990-01-10 金荣 Clear away heart-fire liquid and preparation method thereof
CN1565601A (en) * 2003-07-04 2005-01-19 成都永泽药物研究开发有限责任公司 Application of sichuan lovage rhizome oil by supercritical CO2 extraction method in pharmacy
CN1778335A (en) * 2004-11-26 2006-05-31 天津天士力制药股份有限公司 Chinese medicine for treating coronary heart disease and angina cordis

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Publication number Priority date Publication date Assignee Title
CN1038585A (en) * 1988-05-16 1990-01-10 金荣 Clear away heart-fire liquid and preparation method thereof
CN1565601A (en) * 2003-07-04 2005-01-19 成都永泽药物研究开发有限责任公司 Application of sichuan lovage rhizome oil by supercritical CO2 extraction method in pharmacy
CN1778335A (en) * 2004-11-26 2006-05-31 天津天士力制药股份有限公司 Chinese medicine for treating coronary heart disease and angina cordis

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