CN101766702B - Medicinal combination containing borneol and musk - Google Patents
Medicinal combination containing borneol and musk Download PDFInfo
- Publication number
- CN101766702B CN101766702B CN2009102107549A CN200910210754A CN101766702B CN 101766702 B CN101766702 B CN 101766702B CN 2009102107549 A CN2009102107549 A CN 2009102107549A CN 200910210754 A CN200910210754 A CN 200910210754A CN 101766702 B CN101766702 B CN 101766702B
- Authority
- CN
- China
- Prior art keywords
- moschus
- borneolum syntheticum
- extract
- radix paeoniae
- peoniflorin
- 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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- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 title claims abstract description 102
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 title abstract description 9
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 title abstract description 9
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 title abstract description 7
- 229940116229 borneol Drugs 0.000 title abstract description 7
- 241000402754 Erythranthe moschata Species 0.000 title abstract 2
- 239000000178 monomer Substances 0.000 claims abstract description 26
- 239000000284 extract Substances 0.000 claims description 67
- YKRGDOXKVOZESV-WRJNSLSBSA-N Paeoniflorin Chemical compound C([C@]12[C@H]3O[C@]4(O)C[C@](O3)([C@]1(C[C@@H]42)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)C)OC(=O)C1=CC=CC=C1 YKRGDOXKVOZESV-WRJNSLSBSA-N 0.000 claims description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims description 28
- ALHUZKCOMYUFRB-OAHLLOKOSA-N Muscone Chemical compound C[C@@H]1CCCCCCCCCCCCC(=O)C1 ALHUZKCOMYUFRB-OAHLLOKOSA-N 0.000 claims description 27
- ALHUZKCOMYUFRB-UHFFFAOYSA-N muskone Natural products CC1CCCCCCCCCCCCC(=O)C1 ALHUZKCOMYUFRB-UHFFFAOYSA-N 0.000 claims description 26
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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 borneol, musk and peony 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 Borneolum Syntheticum and Moschus and natural plant extracts or monomeric Pharmaceutical composition and application thereof according to modern medical theory development.
Background technology
Borneolum Syntheticum, Moschus are all the representative medicine commonly used of aromatic and inducing resuscitation Chinese medicine.
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.Moschus also is divided into natural and synthetic two classes, owing to the restriction of rules, that most uses is the artificial Moschus in the medicine at present, and main component is (Liu Yangfeng such as glycoprotein, cholesterol such as muscone, androsterone, Moschus-1, Chinese medicine journal 2003,31 (6): 55-58; He Xiaojing, West China pharmaceutical journal 2005,20 (4): 323-325; Shandong medical industry 2002,21 (1): 26-27; 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).
Different with Borneolum Syntheticum is that Moschus also 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, the application (especially cardiovascular and cerebrovascular disease) clinically of Borneolum Syntheticum and/or Moschus 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 Borneolum Syntheticum and/or Moschus quietly.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 drug as " guiding drug ", utilized simultaneously the effect of Moschus " fragrance is walked to scurry, inducing resuscitation (seeing through blood brain barrier) " again, produced " returning " effect through going into brain.
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 and Moschus, have obtained many new developments.Rely on these progress, scholars are attempting with Borneolum Syntheticum and/or 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) 2004 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.This be because: 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, existingly contains Borneolum Syntheticum and the Moschus compound preparation is 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 " Borneolum Syntheticum+Radix Paeoniae ", had found useful effect: for example, the combination of Radix Paeoniae and Borneolum Syntheticum can obviously strengthen the inherent pharmacological action of Borneolum Syntheticum, has also reduced the toxicity of Borneolum Syntheticum simultaneously.Making us beat all is, when Borneolum Syntheticum or Radix Paeoniae were made up with other active component (for example Radix Salviae Miltiorrhizae) respectively, the combination of " Borneolum Syntheticum+Radix Salviae Miltiorrhizae " or " Radix Paeoniae+Radix Salviae Miltiorrhizae " did not all have " Borneolum Syntheticum+Radix Paeoniae+Radix Salviae Miltiorrhizae " effect of Combination.This shows, above-mentioned beneficial effect is not only to derive from Borneolum Syntheticum, promptly be not the effect of merely having utilized Borneolum Syntheticum in traditional compound recipe " fragrance is walked to scurry, priming up ", " gesture then of walking alone is weak, assistant make then meritorious ", but derive from " Borneolum Syntheticum+Radix Paeoniae " this basis combination.This discovery, also verified such inference to a certain extent, that is: 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 both may comprise that simple physics changed the chemical change that also may comprise complexity, the interaction of various compositions can change the stripping character and the coherent condition of various compositions, even may take place to produce new material behind the chemical reaction.In other words, compound recipe effectiveness is the general performance of compound chemical component mutual relation 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 " Borneolum Syntheticum+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 Borneolum Syntheticum, 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 Borneolum Syntheticum, Moschus can obviously strengthen Borneolum Syntheticum and the inherent pharmacological action of Moschus, such as anti-cerebral ischemia reperfusion injury and protect, anti-inflammatory response effect etc.And three's combination has also reduced the toxicity of Borneolum Syntheticum, and this extensive use for further promotion Borneolum Syntheticum has realistic meaning.
Simultaneously, when in above-mentioned Radix Paeoniae and Borneolum Syntheticum, Moschus combination, adding when having vasoactive Herba Erigerontis, can possess more comprehensive therapeutic effect.
So we have further carried out the experimental study of Radix Paeoniae, Borneolum Syntheticum, 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 " Borneolum Syntheticum+Moschus+Radix Paeoniae+component d " combination, be used for the treatment of and/or prevent diseases such as cardiovascular and cerebrovascular vessel, senile dementia, brain cell protection, diabetes with Synergistic and/or Attenuation.
In pharmaceutical composition of the present invention, can select Radix Paeoniae, Moschus, Borneolum Syntheticum flavour of a drug 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.
Borneolum Syntheticum: be meant the crystallization that the processed goods of Borneolum Syntheticum resin or feverfew Herba Blumeae Balsamiferae leaf extract, 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.
Moschus: be meant natural or the artificial Moschus, or contain the Moschus extract of glycoprotein, cholesterol etc. such as muscone, androsterone and/or Moschus-1, or the muscone monomer.
C.
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.
In combinations thereof, the content of Borneolum Syntheticum is not less than 1wt%.
Described active component d is selected from a kind of among the following d1-d6:
D1.
Radix Salviae Miltiorrhizae: be meant the Radix Salviae Miltiorrhizae extract that mainly contains salvianolic acid * and/or TANSHINONES *; 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
D2.
Semen Ginkgo: be meant Semen Ginkgo extrac (for example Folium Ginkgo extract of lower alcohol, acetone, ethyl acetate), mainly contain bilobalide * and/or ginkgetin * Semen Ginkgo extrac (for example standard extract Egb) as active component, or ginkgetin monomer and ginkgolide monomer, or ginkgolide monomer, or ginkgetin monomer.Wherein, described bilobalide 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
D3.
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
D4.
Radix Puerariae: the Radix Puerariae extract that is meant multiple osajins such as containing daidzein, daidzein glycosides, puerarin *, glucosulfone daiazi, methoxy puerarin, 7-xylose-puerarin, diacetyl-puerarin, formononetin, or Radix Puerariae total flavones, or puerarin monomer and derivant thereof, or daidzein or soybean isoflavone monomer, perhaps these monomeric mixture; Or
D5.
Rhizoma Chuanxiong: be meant the Rhizoma Chuanxiong extract that contains ligustrazine *, chuanxingol, ferulic acid *, volatilization wet goods, 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
D6.
Radix Ginseng: be meant the Radix Ginseng extract that mainly contains Radix Ginseng total saponins *, 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 d1-d6 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 " Borneolum Syntheticum+Moschus+Radix Paeoniae+component d " 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 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, 5-65, preferred 10-50, more preferably 15-45 weight portion; With
Amount of component b in peoniflorin, is 5-100, preferred 10-80, more preferably 20-60 weight portion; With
Component d indicating the composition of symbol *, is 5-100, preferred 10-80, more preferably 20-60 weight portion.
In addition, in context, " peoniflorin+muscone+Borneolum Syntheticum+danshensu 5: 2: 3: 1 ", the weight proportion of representing these four kinds of active components is 5: 2: 3: 1.
Following test will confirm: the combination with above-mentioned definition it " Borneolum Syntheticum ", Moschus, " Radix Paeoniae " and component d 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, 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), 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), drop pill (ZL200310107292, ZL03136485, ZL01133515, ZL03135325, ZL200310119222), dispersible tablet (ZL03125462, ZL03112974, ZL02153445), little or nanometer formulation (ZL021378630, ZL00119579), contain phospholipid preparation (ZL001278126, ZL031320627, ZL01139971, ZL03128337,2005 30 4 phases of volume of CHINA JOURNAL OF CHINESE MATERIA MEDICA: 260-263).
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, 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
1. collaborative antiinflammatory action
1.1 influence to acute exudative inflammation (dimethylbenzene induced mice ear swelling)
1.1.1 material
Drug regimen A of the present invention (Radix Paeoniae Alba extract+Moschus+Borneolum Syntheticum+Radix Salviae Miltiorrhizae extract 5: 1: 1: 2), be divided into 15,30, the 50mg/kg group;
Drug regimen B of the present invention (peoniflorin+muscone+Borneolum Syntheticum+danshensu 5: 2: 3: 1), be divided into 10,15, the 30mg/kg group;
Drug regimen C of the present invention (Radix Paeoniae Alba extract+Moschus+Borneolum Syntheticum+Semen Ginkgo extrac 2: 5: 3: 10), be divided into 15,30, the 50mg/kg group;
Drug regimen D of the present invention (peoniflorin+Moschus+Borneolum Syntheticum+ginkgetin 3: 1: 8: 2), be divided into 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.
1.1.2 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 ^P＜0.01 with danshensu or ginkgetin
1.2 xylol causes the influence of mouse skin capillary permeability
1.2.1 material
Pharmaceutical composition A of the present invention (Radix Paeoniae Alba extract+Moschus+Borneolum Syntheticum+60% (Carthamus yellow) Flos Carthami extract 12: 2: 3: 20), be divided into 10,20, the 40mg/kg group;
Pharmaceutical composition B of the present invention (Radix Paeoniae Alba extract+Moschus+Borneolum Syntheticum+60% (puerarin) Radix Puerariae extract 2: 2: 3: 12), be divided into 10,30, the 50mg/kg group
Positive control drug: the Radix Paeoniae Alba extract that is equivalent to same dose; 10% Moschus group; Radix Paeoniae Alba extract+Borneolum Syntheticum 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.
1.2.2 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 ^P＜0.01 with Flos Carthami extract or Radix Puerariae extract
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＜0.01), 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 share the antiinflammatory action that more can promote Radix Paeoniae/Borneolum Syntheticum/Moschus or other single medicinal materials, plays collaborative antiphlogistic effect.
2 improve the active constituents of medicine absorption in vivo
2.1 material
Pharmaceutical composition of the present invention: peoniflorin+muscone+Borneolum Syntheticum+puerarin 6: 4: 3: 1;
Blank group: normal saline;
Positive control drug: the peoniflorin, muscone, Borneolum Syntheticum and the puerarin that are equivalent to the one pack system of same dosage.
2.2 method and result
Rat is divided into single with peoniflorin, muscone group, Borneolum Syntheticum puerarin group and pharmaceutical composition group of the present invention, (respectively with oral and intravenous injection dual mode administration) different time points after the administration, use gas chromatography determination blood drug level, experiment shows, muscone and Borneolum Syntheticum can be absorbed soon, thereby improve its blood drug level, oral administration can see through blood brain barrier at 5-6 minute and enter the central nervous system, and intravenously administrable can see through blood brain barrier about 2 minutes; Same method (gas chromatography), the blood drug level of mensuration peoniflorin and puerarin has proved that also muscone and Borneolum Syntheticum can promote medicine (peoniflorin and puerarin) to absorb; Simultaneously the three is repeated above-mentioned experiment in the proportion of 1-5: 1-5: 1-5, the result has confirmed that all muscone and peoniflorin and Borneolum Syntheticum share the effect that improves drug absorption.
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+Borneolum Syntheticum+ligustrazine 1: 2: 3: 6,40mg/kg irritates stomach);
Pharmaceutical composition B of the present invention (peoniflorin+Moschus+Borneolum Syntheticum+ligustrazine 5: 3: 1: 1,40mg/kg irritates stomach);
Positive control drug: peoniflorin 10mg/kg, muscone+Borneolum Syntheticum 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 Moschus+Borneolum Syntheticum group; Compare ^P＜0.05 with ligustrazine
1.4 conclusion
Each group of pharmaceutical composition of the present invention, peoniflorin injection, muscone+Borneolum Syntheticum injection and ligustrazine, rat cerebral tissue's ischemia 45 minutes, pour into (Glu, Asp obviously raise) after 6 hours, to the Asp decrease to some degree, present composition group is the most obvious again; And peoniflorin injection, muscone+Borneolum Syntheticum injection 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+Borneolum Syntheticum group 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) and Borneolum Syntheticum; 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 drugs of causing resuscitation by administering aromatic drugs (muscone and Borneolum Syntheticum); 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+Borneolum Syntheticum+Radix Ginseng total saponins 3: 2: 6: 2,6,12mg/kg injection);
Pharmaceutical composition B of the present invention (peoniflorin+Moschus+Borneolum Syntheticum+bilobalide 1: 6: 2: 1,4,8mg/kg injection);
Pharmaceutical composition C of the present invention (peoniflorin+Moschus+Borneolum Syntheticum+TANSHINONES 10: 1: 2: 1,5,10mg/kg injection);
Pharmaceutical composition D of the present invention (peoniflorin+Moschus+Borneolum Syntheticum+puerarin 1: 2: 1: 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 the mechanism of action of Moschus extract (muscone) and Borneolum Syntheticum.
Three. the short effect of waking up
1. material
Mice: Kunming kind, body weight 19-21g, 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+Borneolum Syntheticum+Rhizoma Chuanxiong extract, weight ratio 2: 1: 1: 5) group; Present composition B (Radix Paeoniae+Moschus+Borneolum Syntheticum+Radix Ginseng extract 5: 1: 3: 1).
2. method and result
Mice random packet, tail vein injection sodium chloride injection, caffeine and sodium benzoate normal saline solution, TANSHINONES+Radix Paeoniae 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; With Flos Carthami and Radix Puerariae extract △ P＜0.05, △ △ P＜0.01; 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+Borneolum Syntheticum+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 of the present invention: Radix Paeoniae+Moschus+Borneolum Syntheticum+Radix Salviae Miltiorrhizae extract group (weight ratio 5: 1: 2: 4)
Normal control group: normal saline;
Diabetic groups: normal saline;
Positive control drug: peoniflorin group; Radix Paeoniae+Moschus (weight ratio 2: 1) group, 80mg/kg irritates stomach; Radix Paeoniae+Moschus+Borneolum Syntheticum (weight ratio 2: 1: 2) group, 80mg/kg irritates stomach; 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, Borneolum Syntheticum drug combination and the present composition have produced stronger hypoglycemic activity to alloxan diabetes rats, the strongest with present composition effect, and hypoglycemic activity is not realized by improving insulin level.
Five. to the antioxidation of hyperlipidemia rat
1. material
The present composition: Radix Paeoniae+Moschus+Borneolum Syntheticum+Semen Ginkgo extrac 1: 2: 3: 5,50mg/kg irritates stomach;
Normal control group: normal saline;
Hyperlipidemia group: normal saline;
Positive control drug: peoniflorin (50mg/kg); VE (50mg/kg); 10% Borneolum Syntheticum; 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 peoniflorin.
Conclusion
Experiment shows, the antioxidant activity of the present composition significantly is better than peoniflorin, the Borneolum Syntheticum 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 Borneolum Syntheticum 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;
Natural Broneolum Syntheticum 0.5g is ground into fine powder, with the CO of 6g extract I, 3g 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 13g, natural Broneolum Syntheticum 2g is ground into fine powder, with 10g extract I and 15g Moschus mixing, adds low-substituted hydroxypropyl cellulose, magnesium stearate, starch, microcrystalline Cellulose, granulate and tablet forming technique prepares 1000 according to standard.
Embodiment 3 soft capsules
Get the CO of peoniflorin 2g, Borneolum Syntheticum cyclodextrin clathrate 25g (containing Borneolum Syntheticum 2.5g), Moschus
2Supercritical extract 4g, bilobalide 0.5g, 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 natural Broneolum Syntheticum 3.5g and be ground into fine powder,, get III with 15g extract II, 20g ligustrazine hydrochloride, Moschus water vapour extract 20g mixing;
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 (containing Borneolum Syntheticum 2g, Moschus 2g), 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, Borneolum Syntheticum and 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 (containing Borneolum Syntheticum 3g, Moschus 5g) of peoniflorin 18g, Carthamus yellow extract (total uranidin content is not less than 50%) 100g, Borneolum Syntheticum and 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%) 12g, Borneolum Syntheticum 4g, 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
Get the about 6g of water vapour extract of Moschus, add 1,2-propylene glycol, glycerol, heating makes clarification, other gets peoniflorin 10g, danshensu 1g and adds, and continues to be heated with stirring to 60 ℃ and keep constant, water.Get Borneolum Syntheticum 12g, emulsifying agent phospholipid, add an amount of dehydrated alcohol and make dissolving, add refining Oleum Glycines, VE, cholic acid then, be heated with stirring to 60 ℃ and keep constant, oil phase.Constant temperature stirs down water slowly is added drop-wise in the oil phase, adds the distilled water standardize solution of equality of temperature after dropwising, and continues stir about 15min and gets colostrum.After crossing 0.80 μ m filter membrane, 0.22 μ m filter membrane is crossed in homogenize, 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. Borneolum Syntheticum, the 1-15 weight portion; With
B. Moschus, or contain the Moschus extract of muscone, androsterone and Moschus-1, or the muscone monomer, the 5-65 weight portion; With
C. Radix Paeoniae dry root powder, or contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, or the peoniflorin monomer, the 5-100 weight portion; With
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.
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 as claimed in claim 1, described active component is:
A. Borneolum Syntheticum, the 2-10 weight portion; With
B. the Moschus extract that contains muscone, androsterone and Moschus-1, the 10-50 weight portion; With
C. the Radix Paeoniae Alba extract that contains peoniflorin, lactone glucoside of Radix Paeoniae, the 10-80 weight portion; With
D.10-80 weight portion, it is the Radix Puerariae extract that contains puerarin.
4. pharmaceutical composition as claimed in claim 1, wherein component a is the 5-10 weight portion, and components b is the 15-45 components by weight percent, and c is that 20-60 weight portion and component d are the 20-60 weight portion.
5. pharmaceutical composition as claimed in claim 1, wherein said active component is:
A. Borneolum Syntheticum
B. muscone monomer; With
C. peoniflorin monomer; With
D. puerarin monomer and derivant thereof.
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| CN1698835A (en) * | 2005-06-23 | 2005-11-23 | 张文芳 | Compound Chinese medicinal injection for treating cardiovascular and cerebrovascular diseases |
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| CN1698835A (en) * | 2005-06-23 | 2005-11-23 | 张文芳 | Compound Chinese medicinal injection for treating cardiovascular and cerebrovascular diseases |
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| .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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| 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. * |
| 贾琳娜 |
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