CN100509005C - Compound medicine contg. musk - Google Patents
Compound medicine contg. musk Download PDFInfo
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- CN100509005C CN100509005C CNB2006100657926A CN200610065792A CN100509005C CN 100509005 C CN100509005 C CN 100509005C CN B2006100657926 A CNB2006100657926 A CN B2006100657926A CN 200610065792 A CN200610065792 A CN 200610065792A CN 100509005 C CN100509005 C CN 100509005C
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Abstract
A Chinese medicine for treating coma, cardiovascular and cerebrovascular diseases, senile dementia, diametes, etc is prepared from peony root and musk.
Description
Technical field
The present invention relates to pharmaceutical composition, specifically, is to contain Moschus and natural plant extracts or monomeric Pharmaceutical composition and application thereof according to modern medical theory development.
Background technology
Moschus is the representative medicine commonly used of aromatic and inducing resuscitation Chinese medicine, and Moschus has stronger central nervous system's excitement and suppresses pharmacologically actives such as amphicheirality's effect, resisting oxygen lack, cardiac vascular activity, antiinflammatory action.At present, Moschus application (especially cardiovascular and cerebrovascular disease) clinically is very extensive, and for example compound Salviae Miltiorrhizae class, storax pill for treating coronary heart disease, cow-bezoar bolus for resurrection, HUATUO ZAIZAO WAN, refreshment wait all containing Moschus quietly.At this quasi-tradition Cheng Fangzhong, utilized the effect of Moschus " fragrance is walked to scurry, inducing resuscitation (seeing through blood brain barrier) " more, produce " returning " effect (Shandong medical industry 2002,21 (1): 26-27 through going into brain; Hour hands traditional Chinese medical science traditional Chinese medicines 2004,15 (4) 4248-249; New Chinese medicine and clinical pharmacology 2000,11 (4): 208-255).
For many years, many scholars have done extensive work based on modern medical theory to the aspects such as pharmacodynamics, pharmacokinetics and safety of Moschus, have obtained many new developments.For example, discover: Moschus is returned the experimental study (Chen Wen high and dry land etc., combination of Chinese and Western medicine journal the 2nd the 4th phase of volume of July in 2004) through going into brain; With Moschus Borneolum Syntheticum combination cerebral protection (Shen Qiang etc., Moschus and Borneolum Syntheticum pour into the influence that the interleukin-1 ' beta ' mRNA of rat cerebral tissue expresses again to global brain ischemia, the time precious traditional Chinese medical science traditional Chinese medicines rolled up for the 7th phase in 2003 the 14th).
Rely on these progress, scholars are attempting with Moschus and the combination of other active component, in the hope of obtaining better curative effect.For example, ZL03110967.5, ZL200310105455.1, (Jilin University's journal medicine such as Zhao Hongmei, 30 (3): 393-395)), (2004 26 volumes of Chinese patent medicine supplementary issue: 13-16) such as Lin Jiayi, (1998 17 volumes (9) of Shandong journal of Chinese medicine: 404-405) such as Nie Youzhi, Li Xiangxin (2004 13 19 phases of volume of modern combination of Chinese and Western medicine magazine: 2541-2542), (2002 19 1 phases of volume of Shenyang Pharmaceutical University's journal: 41-42) such as Zhang Li, (2004 21 volumes of Traditional Chinese Medicine University Of Guangzhou's journal, 5 phases: 382-384 such as Yu Shangzhen, (Jilin Chinese medicine 6 phases of calendar year 2001: 34) such as Xue Yafeng, (1999 30 5 phases of volume of Jiangxi Chinese medicine: 9-10) such as Chen Su, and the side's of one-tenth Moschus is rather felt at ease, XINGNAOJING ZHUSHEYE etc., be widely used in the treatment of cardiovascular and cerebrovascular disease, all obtained certain achievement.
Yet above-mentioned compound recipe can not satisfy demand clinically far away.On the one hand, existing compound recipe is normally formed by the principle of " determination of treatment based on pathogenesis obtained through differentiation of symptoms and signs ", and this is for the pathogenesis complexity, with the disease of different classes of complication, and these Moschus compound preparations are difficult to multi-faceted proving effective.More crucial is, these big compound medicine compositions are too complicated, and the interaction between each composition is not clear, does not meet the trend of modern medicines, the homogeneity that is difficult to ensure the quality of products.
In previous work, we had once carried out careful research to " Borneolum Syntheticum+Radix Paeoniae ", found useful effect: when Borneolum Syntheticum or Radix Paeoniae are 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 " does 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: promptly the material base of compound preparation is not only the summation of every kind of effective ingredient, and comprise the interaction of each composition in the compound preparation process, this interaction had both comprised that simple physics changed the chemical change that also comprises complexity, the interaction of various compositions can change the stripping character and the coherent condition of various compositions, even might take place to produce new material behind the chemical reaction.In other words, compound recipe effectiveness is the general performance of mutual relation between the compound chemical component under the specific effect condition, and some so-called active component leave the compound recipe condition then may not have obvious effect.
Consider that Borneolum Syntheticum and Moschus have a lot of something in common on effect, such as, be all " having one's ideas straightened out " class Chinese medicine.Therefore, be easy to associate: the combination of " Moschus+Radix Paeoniae " may have " Borneolum Syntheticum+Radix Paeoniae " similarly beneficial effect.
The application attempts the combination that contains Moschus and Radix Paeoniae is studied, and in the hope of reducing dosage by adduction between them even synergism, thereby further reduces untoward reaction when guaranteeing (even raising) curative effect.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.
One object of the present invention is to provide the combination of Moschus 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 Moschus+Radix Paeoniae.When attempt from prior art, to seek this bonded according to the time, we find: at Moschus 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 Moschus can obviously strengthen the inherent pharmacological action of Moschus, such as anti-cerebral ischemia reperfusion injury and protect, anti-inflammatory response effect etc.
Therefore, one object of the present invention is to provide " Moschus+Radix Paeoniae " with synergistic function combination.
In pharmaceutical composition of the present invention, can select flavour of a drug (for example Radix Paeoniae, Moschus) directly to be ground into powder and be used as medicine, extract or other forms that also can be equivalent to above-mentioned natural drug material crude drug amount are used as medicine.Therefore, the active component of pharmaceutical composition of the present invention comprises the former powder of medical material, fat or water solubility extract (or effective site) or effective ingredient or monomer, perhaps adopts existing other goods forms in the prior art.For example, described active component comprises:
A. Moschus: be meant natural or the artificial Moschus, or contain the Moschus extract of glycoprotein, cholesterol etc. such as muscone, androsterone, Moschus-1, or the muscone monomer.
B. Radix Paeoniae: be meant the dry root powder of Radix Paeoniae (Radix Paeoniae Alba, Radix Paeoniae Rubra, river Radix Paeoniae Rubra), contain the extract of Radix Paeoniae Alba total glycosides compounds (being preferably peoniflorin and lactone glucoside of Radix Paeoniae), or the peoniflorin monomer.In addition, studies show that the effective site that contains peoniflorin, lactone glucoside of Radix Paeoniae, Hydroxy peoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, lacdtlorin, paeonol, the former glycosides of paeonol, Cortex Moutan phenolic glycoside, Radix Paeoniae aglycon etc. simultaneously also is useful.The source that it will be appreciated by persons skilled in the art that Radix Paeoniae glycoside of the present invention is not limited to Radix Paeoniae, and the other plant (for example Cortex Moutan) that contains the Radix Paeoniae glycoside also can be realized the present invention, and it extracts and preparation method is a known technology, does not give unnecessary details at this.
Owing to compare with some existing plant amedica, Moschus lacks the active function of (or weak) blood vessel aspect, so based on above-mentioned achievement, we study " Moschus+Radix Paeoniae " and the probability of other active component combinations.
Therefore, except that above-mentioned two kinds of active component a, b, the present composition can also comprise Herba Erigerontis, can make the present composition have more comprehensive therapeutic effect by Herba Erigerontis.
In the test of carrying out subsequently, found very interesting phenomenon: " Moschus+Herba Erigerontis " or " Radix Paeoniae+oil lamp " do not have the present invention " Moschus+Radix Paeoniae+Herba Erigerontis " effect of Combination.This shows that the present invention's beneficial effect is not only to derive from Moschus, but derives from " Moschus+Radix Paeoniae " this basis combination.
Therefore, another object of the present invention is to provide " Moschus+Radix Paeoniae+Herba Erigerontis " with synergistic function combination.
Wherein, described Herba Erigerontis is meant: the scutellarin monomer of the lower alcohol extraction thing of the herb powder of Herba Erigerontis (having another name called Herba Erigerontis), the water extract of Herba Erigerontis, Herba Erigerontis (containing scutellarin (being scutellarin), single and or the effective site of dicaffeoylquinic acid etc.), breviscapine (containing scutellarin, breviscapine and other flavones ingredients) 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, the other plant (for example Radix Scutellariae, Herba Scutellariae Barbatae etc.) that contains scutellarin also can be realized the present invention, equally, single and or the source of dicaffeoylquinic acid also be 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.
Advantageously, on the basis of the above-mentioned useful combination of the present invention, other active component that can also add 15-200, preferred 30-120 weight portion in the present composition, for example extract of Radix Salviae Miltiorrhizae (active component salvianolic acid and/or TANSHINONES), Flos Carthami (active component Flos Carthami total flavochromes), Radix Puerariae (active component Radix Puerariae total flavones and/or puerarin), Semen Ginkgo (active component bilobalide and/or ginkgetin), Rhizoma Chuanxiong (active component ligustrazine and/or ferulic acid) or Radix Ginseng (active component Radix Ginseng total saponins).It is pointed out that adopting these plant extract active component or corresponding monomeric technology is known technology, does not give unnecessary details at this.
In context, the related term " active component " of pharmaceutical composition of the present invention has above-mentioned definition.
In pharmaceutical composition of the present invention, each components contents is:
Component a, 5-65, preferred 10-50, more preferably 15-45 weight portion; With
Components b is counted 5-100 with peoniflorin, preferred 10-80, more preferably 20-60 weight portion; With
Amount of component b is counted 5-100 with scutellarin, preferred 10-80, more preferably 20-60 weight portion.
In addition, in context, " Moschus+Radix Paeoniae 5/15 " or " Moschus+Radix Paeoniae+oil lamp 5:2:15 ", represent this two, the weight proportion of three kind of active component is 5:15 and 5:2:15.
Below test will confirm: the combination of the Moschus with above-mentioned definition, " Radix Paeoniae " and the Herba Erigerontis of describing according to the present invention 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), phospholipid preparations (ZL001278126, ZL031320627, ZL01139971, ZL03128337), 2005 30 volumes of CHINA JOURNAL OF CHINESE MATERIA MEDICA, 4 phases: 260-263 etc.
Pharmaceutical composition of the present invention; form by the active component of 10-90wt.% and the pharmaceutic adjuvant of 90-10wt.%; can be used for treating stupor, 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 Moschus and Radix Paeoniae combination
Collaborative antiinflammatory action
The influence of 1 pair of acute exudative inflammation (dimethylbenzene induced mice ear swelling)
1.1 material
Pharmaceutical composition of the present invention (Radix Paeoniae Alba extract+Moschus 5:1) is divided into 10,30, the 50mg/kg group;
Blank group: normal saline;
Positive control drug: the Radix Paeoniae Alba extract that is equivalent to same dosage; 10% Moschus group; Aspirin 0.2g/kg group.
1.1.2 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 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 with the Radix Paeoniae group: △ P＜0.05, △ △ P＜0.01; Compare with the Moschus group: #P＜0.05.
2 xylol cause the influence of mouse skin capillary permeability
2.1 material
Pharmaceutical composition of the present invention (Radix Paeoniae Alba extract+Moschus 2:1) is divided into 10,30, the 50mg/kg group;
Positive control drug: the Radix Paeoniae Alba extract that is equivalent to same dose; 10% Moschus group; Aspirin 0.2g/kg group.
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 with Radix Paeoniae Alba extract: △ P＜0.05, △ △ P＜0.01;
Compare with Moschus: #P＜0.05, ##P＜0.01.
The result shows: present composition xylol induced mice ear swelling and xylol induced mice capillary of skin permeability have the obvious suppression effect, has the effect that the early stage capillary permeability of inflammation-inhibiting increases, compare with matched group and to have significant difference, compare with the one pack system extract group of Isodose, also has significant difference (P＜0.05), senior middle school's dosage group and blank group be P＜0.05-0.01 relatively, other antiinflammatory experiments have also been done simultaneously, the result shows, the present composition has also shown significant effect in rat foot due to suppressing Ovum Gallus domesticus album is wasted time swelling, and effect obviously is better than Radix Paeoniae Alba extract and Moschus group, prompting Moschus and Radix Paeoniae are single with having on the basis of antiinflammatory action separately at it, a certain proportion of compatibility more can promote the antiinflammatory action of Radix Paeoniae/Moschus single medicinal material, plays collaborative antiinflammatory action.
Two. the pharmacological action for the treatment of cardiac and cerebral vascular diseases
1. global brain ischemia is poured into again the influence of rat cerebral tissue's amino acid neurotransmitter
1.1 material
Pharmaceutical composition A of the present invention (peoniflorin+Moschus 1:3,40mg/kg irritates stomach);
Pharmaceutical composition B of the present invention (peoniflorin+Moschus 1:8,40mg/kg irritates stomach);
Positive control drug: peoniflorin 40mg/kg, muscone 12mg/kg;
1.2 method
The every day of administration at twice before the modeling for three days on end, undergos surgery after 30 minutes in administration in the morning in the 4th day.According to the standard method modeling, separate bilateral common carotid arteries, pour into 6h again, sacrificed by decapitation, get brain and place rapidly and get the right side brain on the ice pan and be divided into A, B, C, D five equilibrium, get C, D brain sheet is weighed, and adds methanol homogenate according to 1ml/50mg from antinion to occipital lobe, centrifugal collection supernatant, boil off methanol, add 80% ethanol again, ultrasonic Treatment, centrifugal, collect supernatant and be used to detect the cerebral tissue amino acid neurotransmitter.
Most of neurotransmitter is an amino acids among the central nervous system, comprise γ-An Jidingsuan (GABA), glutamic acid (Glu), aspartic acid (Asp) and glycine (Gly), under the physiological conditions, Glu, Asp have extremely strong excitation to neuron, GABA, Gly neuron enforcement effect are important inhibitory aminoacid.
Analytical method: reversed-phase HPLC, peak area external standard method, statistical analysis then.
1.3 result
See the following form 3.
Table 3. is respectively organized global brain ischemia and is poured into the content of rat cerebral tissue's amino acid neurotransmitter (μ mol/g) again
Compare with sham-operation,
*P＜0.05
*P＜0.01; Compare with model group,
△P＜0.05,
△ △P＜0.01; Compare #P＜0.05 with the muscone group.
1.4 conclusion
Pharmaceutical composition of the present invention, peoniflorin injection and muscone injection rat cerebral tissue's ischemia 45 minutes, pour into (Glu, Asp obviously raise) after 6 hours again, and to the Asp decrease to some degree, present composition group is the most obvious; And peoniflorin injection and muscone injection are not obvious to the Glu reduction, and pharmaceutical composition of the present invention can reduce Glu, 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; compare with peoniflorin and muscone group; has significant difference between group; may be peoniflorin and the beneficial effect that jointly bring different with the mechanism of action of Moschus extract (muscone); the combination that the present composition is described is by reducing the Asp in the ischemic region cerebral tissue; improved the toxicity of the content of GABA and Gly with the antagonism excitatory amino acid; thereby the damage of the follow-up unit of going crazy of protection cerebral ischemia; though these are one of medical mechanisms of drugs of causing resuscitation by administering aromatic drugs; but share of muscone of the present invention and peoniflorin; improve drug effect undoubtedly, 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 3:1,4,8mg/kg injection);
Pharmaceutical composition B of the present invention (peoniflorin+Moschus 10:1,4,8mg/kg injection);
Blank group: normal saline;
Positive control drug: peoniflorin injection, each 8mg/kg of muscone 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).
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 1uCi'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%.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 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).
Three. the short effect of waking up
1. material
Mice: Kunming kind, body weight 18-22g, male and female half and half.
Reagent: oil lamp+Radix Paeoniae injection (self-control); Oil lamp injection (the biological paddy in Yunnan pharmaceutical factory); Muscone injection (self-control); Caffeine and sodium benzoate injection raw material (Shanghai the 14 pharmaceutical factory); The present composition 1 (Radix Paeoniae+Moschus, weight ratio 1:2) senior middle school's low dose group; The present composition 2 (Radix Paeoniae+Moschus+caffeoylquinic acids 2/1/2) 40mg/kg;
The present composition 3 (Radix Paeoniae+Moschus+Herba Erigerontis extract 8/5/2) 40mg/kg.
2. method and result
The mice random packet, difference tail vein injection sodium chloride injection, caffeine and sodium benzoate normal saline solution, oil lamp+reagents such as Radix Paeoniae 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 to the time of recovering, calculate each class mean and standard deviation, carry out the t check, the results are shown in Table 4.
The short effect of waking up of table 4 pair mice (X ± SD, n=10)
Compare with the blank group:
*P＜0.05,
*P＜0.01; Compare with the oil lamp group: △ P＜0.05, △ △ P＜0.01;
Compare with oil lamp+Radix Paeoniae: #P＜0.05, ##P＜0.01.
3. conclusion
Compare with matched group, the present composition, contrast medicine 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 Moschus, has greatly strengthened the pharmacologically active of the short aspect of waking up of medicine.
Four. the pharmacological action of diabetes aspect
1. material
Pharmaceutical composition A of the present invention: Radix Paeoniae+Moschus (weight ratio 2:1) group, 80mg/kg irritates stomach;
Pharmaceutical composition B of the present invention: Radix Paeoniae+Moschus+Herba Erigerontis group (weight ratio 2:1:1), 80mg/kg irritates stomach;
Normal control group: normal saline;
Diabetic groups: normal saline;
Positive control drug: peoniflorin 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 the influence of serum I ns
Compare with diabetic groups:
*P＜0.05
*P＜0.01; Compare with peoniflorin: △ P＜0.05, △ △ P＜0.01.
Above-mentioned experiment shows that the effect that the present composition is two groups is obvious.The present composition has obviously reduced the blood glucose of alloxan diabetes, and it is not obvious to serum I ns level affects, this shows that Radix Paeoniae, Moschus drug combination have produced stronger hypoglycemic activity to alloxan diabetes rats, and hypoglycemic activity is not realized by improving insulin level.
Five. to the antioxidation of hyperlipidemia rat
1. material
Pharmaceutical composition A of the present invention: Radix Paeoniae+Moschus 10:1,50mg/kg irritates stomach;
Pharmaceutical composition B of the present invention: Radix Paeoniae+Moschus+oil lamp 1:5:2,50mg/kg irritates stomach;
Normal control group: normal saline;
Hyperlipidemia group: normal saline;
Positive control drug: peoniflorin (50mg/kg); VE (50mg/kg); Moschus+oil lamp.
2 methods 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:
The influence (nmol/L) of table 6 pair hyperlipemia rat serum and liver LPO and SOD
Compare with the hyperlipidemia group:
*P＜0.05,
*P＜0.01; Compare with Radix Paeoniae: △ P＜0.05, △ △ P＜0.01.
3 conclusions
Experiment shows, the antioxidant activity of the present composition significantly is better than peoniflorin, the Moschus+oil lamp used separately.
The above results also proves: being combined in of Radix Paeoniae+Moschus promoted antioxidant activity to a certain extent more, but contains Radix Paeoniae and Moschus simultaneously, is compositions obtains outstanding effect aspect antioxidation essential condition.
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 share, antioxidant activity significantly is better than single Radix Paeoniae of using, the composition explanation is aspect the hyperlipidemia antioxidation, and there is the enhancing synergism in the two.
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.
Six. the brain cell protective effect
1 material
Laboratory animal: healthy Wistar rat;
Medicine: present composition A: peoniflorin+Moschus 2:1; Compositions B: peoniflorin+Moschus+scutellarin 1/2/1; Each 30mg/kg;
Positive control drug: peoniflorin+scutellarin injection, 30mg/kg; Moschus+scutellarin injection, 30mg/kg; The Edaravone Injection injection, 10mg/kg; The muscone injection, 10mg/kg;
2 methods
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.Two groups of the present compositions 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.Positive control drug group neuronal structure except Edaravone Injection owes 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 two groups of the present compositions 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.Positive control drug group neuronal kernel except Edaravone Injection 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 two groups of the present compositions and Edaravone group astrocyte is light than model group, and organelle is compared obviously more with model group.Positive control drug group astrocyte except Edaravone Injection is then similar substantially to model group.
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); Two groups of rising and increased SOD activity (P＜0.01) that all can suppress perfusion back cerebral tissue mda content of the present composition, improve brain water content (P＜0.01), effect and Edaravone are suitable, obviously are better than the Chinese medicine positive control drug group except Edaravone Injection.
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 other matched groups (peoniflorin+scutellarin injection; Moschus+scutellarin injection, muscone injection).
The clinical observation of cardiovascular and cerebrovascular disease aspect
1. medicine
The present invention's combination: muscone (15mg/ days) with Radix Paeoniae Alba extract+Herba Erigerontis extract (100mg/ days), merges oral.
Contrast: muscone 15mg/ days, Radix Paeoniae Alba extract (containing peoniflorin) 60mg/ days, oral at times.
2. method 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 45.15%, total effective rate 90.17% are organized in treatment; Matched group 100 examples, cure-remarkable-effectiveness rate 28.96%, 70.16%, 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 160 examples altogether, wherein 80 examples are organized in treatment, curative effect cure-remarkable-effectiveness rate 35.43%, total effective rate 84.53%; Matched group 80 examples, cure-remarkable-effectiveness rate 27.64%, total effective rate 73.97%.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;
Get the 6g extract I,, add adjuvant (gross weight 5%) low-substituted hydroxypropyl cellulose, magnesium stearate, starch, microcrystalline Cellulose, granulate and tablet forming technique prepares according to standard with 1g Moschus mixing.
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;
Get 10g extract I, 20g extract II,, add low-substituted hydroxypropyl cellulose, magnesium stearate, starch, microcrystalline Cellulose, prepare 1000 according to standard granulation and tablet forming technique with 3g Moschus mixing.
Embodiment 3 soft capsules
Get the CO of peoniflorin 8g, Moschus
2Supercritical extract 24g, 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 I is standby;
Get 15g extract II I, 20g breviscapine,, get IV with Moschus water vapour extract 10g 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 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 Moschus 5g), aspartame, Fructus Citri Limoniae essence and the magnesium stearate of Radix Paeoniae Alba extract 20g, Herba Erigerontis extract (scutellarin content is not less than 60%) 10g 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 20g (Moschus 5g) of peoniflorin 12g, Herba Erigerontis extract (total coffee acid ester content is not less than 50%) 20g, 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 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 artificial Moschus's supercritical carbon dioxide extraction thing (containing macrocyclic ketone of Moschus more than 30%) 20g, add polyoxyethylene sorbitan monoleate, uniform mixing adds HP-again, and the ultrasonic agitation enclose got HP-beta-CD inclusion VI after 2 hours.
Get V10g, VI, add lyophilizing figuration mannitol, add to the full amount of water for injection, add active carbon, absorption, decarbonization filtering; Gained filtrate is continued with 0.22 μ m filtering with microporous membrane, packing, lyophilization.
Embodiment 8 injectable emulsions
With macrocyclic ketone of Moschus 5g, oleic acid 0.6g, join behind the mix homogeneously in the triglyceride, add behind the thermally homogenising standby; Get in refined lecithin 2.0g, poloxamer 1880.5g, glycerol 2.0g, the peoniflorin 40g adding distilled water, fully mix.With oil, the biphase mixing of water, regulate pH value, make 100ml, detect with laser particle analyzer, after particle diameter meets the requirements, pass through filtering with microporous membrane again, then fill, inflated with nitrogen, seal, sterilize.
Claims (8)
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. Moschus, or contain the Moschus extract of muscone, androsterone and Moschus-1, or the muscone monomer, the 5-65 weight portion; With
Components b. Radix Paeoniae dry root powder, or contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, Hydroxy peoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, lacdtlorin, or the peoniflorin monomer, the 5-100 weight portion.
2. pharmaceutical composition as claimed in claim 1, wherein component a is that 10-50 weight portion and components b are the 10-80 weight portion.
3. 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. Moschus, or contain the Moschus extract of muscone, androsterone and Moschus-1, or the muscone monomer, the 5-65 weight portion; With
Components b. Radix Paeoniae dry root powder, or contain peoniflorin, Radix Paeoniae Alba extract, or peoniflorin monomer, 5-100 weight portion; With
Amount of component b. Herba Erigerontis herb powder, or the alcohol extract of Herba Erigerontis, or breviscapine, or the scutellarin monomer of free or sodium-salt form, 5-100 weight portion.
4. pharmaceutical composition as claimed in claim 3, described active component is:
Component a. contains the Moschus extract of muscone, androsterone and Moschus-1,10-50 weight portion; With
Components b. contain the Radix Paeoniae Alba extract of peoniflorin, lactone glucoside of Radix Paeoniae, the 10-80 weight portion; With
Amount of component b. contain the Herba Erigerontis alcohol extract of scutellarin, list and/or dicaffeoylquinic acid, the 10-80 weight portion.
5. pharmaceutical composition as claimed in claim 3, wherein component a is the 15-45 weight portion, components b is that 20-60 weight portion and amount of component b are the 20-60 weight portion.
6. as the pharmaceutical composition of one of claim 3-5, also contain Hydroxy peoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, lacdtlorin in the described Radix Paeoniae Alba extract.
7. as the pharmaceutical composition of one of claim 3-5, wherein said active component is: component a. muscone monomer; And components b. the peoniflorin monomer; And amount of component b. list and/or dicaffeoylquinic acid.
8. as the pharmaceutical composition of one of claim 3-5, wherein said active component is: component a. muscone monomer; And components b. the peoniflorin monomer; And amount of component b. breviscapine, scutellarin monomer or scutellarin sodium salt.
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| CNB2006100657926A CN100509005C (en) | 2006-01-26 | 2006-03-16 | Compound medicine contg. musk |
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| CN200610002632.7 | 2006-01-26 | ||
| CN200610002632 | 2006-01-26 | ||
| CNB2006100657926A CN100509005C (en) | 2006-01-26 | 2006-03-16 | Compound medicine contg. musk |
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Non-Patent Citations (2)
| Title |
|---|
| 治疗冠心病心绞痛的中医常用方药. 贾林娜等.中国临床医生，第28卷第10期. 2000 |
| 治疗冠心病心绞痛的中医常用方药. 贾林娜等.中国临床医生，第28卷第10期. 2000 * |
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