Summary of the invention
The objective of the invention is to propose a kind of compound capsule that is used for the treatment of the resistance of the apoplexy apoplex involving the channels and collaterals wind-phlegm stasis of blood and preparation method thereof, to satisfy the clinical needs of stroke patient for overcoming the weak point that the existing apoplexy apoplex involving the channels and collaterals wind-phlegm stasis of blood hinders compound pattern of syndrome medicine.
A kind of compound capsule that is used for the treatment of the resistance of the apoplexy apoplex involving the channels and collaterals wind-phlegm stasis of blood that the present invention proposes is characterized in that, by capsule and wherein the pulverulent mixture of being made up of Chinese medicine and adjuvant of packing into; The composition of described Chinese medicine and 1000 s' consumption is:
Rhizoma Gastrodiae 192-288g Radix Paeoniae Rubra 256-384g Ramulus Uncariae Cum Uncis 192-288g Pheretima 256-384g
Herba Siegesbeckiae 256-384g Rhizoma Chuanxiong 256-384g Radix Salviae Miltiorrhizae 256-384g Zaocys 192-288g
Cortex et Radix Polygalae (processed) 64-96g Radix Cyathulae 256-384g.
The preparation that the present invention proposes is used for the treatment of the method for the compound capsule of apoplexy apoplex involving the channels and collaterals wind-phlegm stasis of blood resistance, it is characterized in that, may further comprise the steps:
1) chooses Rhizoma Gastrodiae, Radix Paeoniae Rubra, Ramulus Uncariae Cum Uncis, Pheretima, Herba Siegesbeckiae, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Zaocys, Cortex et Radix Polygalae (processed) and Radix Cyathulae ten flavor Chinese crude drugs by 1000 recipe quantities and concoct into decoction pieces respectively on request;
2) hook taking rattan adds 4-6 and doubly measures 60-80% alcohol reflux secondary, and each 1-2 hour, merge extractive liquid, filtered, and filtrate is concentrated into the thick paste that relative density is 1.25~1.28 (60 ℃ of surveys), and is standby;
3) get Radix Salviae Miltiorrhizae, add 4-6 and doubly measure 60-90% alcohol reflux secondary, each 1-2 hour, merge extractive liquid, filtered, and medicinal residues are standby, and filtrate is concentrated into the thick paste that relative density is about 1.25~1.28 (60 ℃ of surveys), and is standby;
4) get medicinal residues and eight flavors such as remaining Rhizoma Gastrodiae, Radix Paeoniae Rubra, Pheretima, Herba Siegesbeckiae, Rhizoma Chuanxiong, Zaocys, Cortex et Radix Polygalae (processed) and Radix Cyathulae after the Radix Salviae Miltiorrhizae alcohol extraction, add 6-10 times of water gaging, decoct secondary, each 1-2 hour, collecting decoction filtered, filtrate is concentrated into relative density and is about 1.09~1.11 (60 ℃ of surveys), puts coldly, adds ethanol and makes the alcohol amount of containing be 50-70%, stir evenly, leave standstill more than 24 hours, filter filtrate recycling ethanol, it is standby to be condensed into thick paste shape (relative density is 1.25 ~ 1.28,60 ℃ of surveys);
5) above-mentioned standby thick paste is merged, drying under reduced pressure (control vacuum: 0.08MPa, temperature: 80 ℃) is ground into fine powder, adds starch or the about 40g of dextrin adjuvant, and mixing incapsulates, and makes.
Every of this product contains peoniflorin (C
23H
28O
11) be no less than 3.2mg.
Characteristics of the present invention and effect:
The present invention is capsule preparations (is called for short Gekko Swinhonis and goes on foot capsule again), and its content is tan powder; Feeble QI, the little acid and puckery of distinguishing the flavor of, little hardship.Have endogenous wind stopping and reduce phlegm, promoting blood circulation to remove obstruction in the collateral.Be used for the acute stage of wind-phlegm stasis of blood resistance card cerebral thrombosis (apoplexy apoplex involving the channels and collaterals) and recover early stage, disease is seen numb limbs and tense tendons, weak or hemiplegia, distortion of commissure, language sialorrhea person.
The used medical material of the present invention is recorded by version pharmacopeia in 2000.Crude drug source is extensive, and is cheap.Technical study has been determined best selection process (water decoction-alcohol sedimentation, alcohol extraction) by comparing the influence of Different Extraction Method to the curative effect of medication and the quality of the pharmaceutical preparations, with after pilot scale is amplified three batches, confirms that institute's selection process is reasonable, stable, but suitability for industrialized production.
Expermental research on main pharmacodynamics shows, this product is to cerebral thrombosis (apoplexy apoplex involving the channels and collaterals) acute stage and recover early stage, and disease sees that numb limbs and tense tendons, weak or hemiplegia, distortion of commissure, language sialorrhea person have obvious therapeutic action.
Acute toxicity test, long term toxicity test result show that the safety of this capsule is good, meet the drug safety principle.
According to situations such as the characteristics of physicochemical property, the clinical indication of the main effective ingredient of each flavour of a drug in the prescription and dosages, selecting the said preparation most preferred dosage form is capsule, and it had both kept the characteristics of original decoction, had characteristics such as rapid-action, taking convenience again.
The specific embodiment
Embodiment 1 is a capsule, and content is tan powder; Feeble QI, the little acid and puckery of distinguishing the flavor of, little hardship.By capsule and wherein the pulverulent mixture of forming by Chinese medicine and adjuvant of packing into; The composition of described Chinese medicine and 1000 s' consumption is:
Rhizoma Gastrodiae 288g Radix Paeoniae Rubra 384g Ramulus Uncariae Cum Uncis 288g Pheretima 384g
Herba Siegesbeckiae 384g Rhizoma Chuanxiong 384g Radix Salviae Miltiorrhizae 384g Zaocys 288g
Cortex et Radix Polygalae (processed) 96g Radix Cyathulae 384g.
Every of present embodiment contains peoniflorin (C
23H
28O
11) be no less than 3.2mg.
Every 4 of dress 0.4g one time is oral, 3 times on the one.
The preparation method of present embodiment may further comprise the steps:
1) chooses Rhizoma Gastrodiae, Radix Paeoniae Rubra, Ramulus Uncariae Cum Uncis, Pheretima, Herba Siegesbeckiae, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Zaocys, Cortex et Radix Polygalae (processed) and Radix Cyathulae ten flavor Chinese crude drugs by recipe quantity and concoct into decoction pieces respectively on request;
2) hook taking rattan adds 5 times of amount 70% alcohol reflux secondaries, and each 1 hour, merge extractive liquid, filtered, and filtrate is concentrated into the thick paste that relative density is about 1.25~1.28 (60 ℃ of surveys), and is standby;
3) get Radix Salviae Miltiorrhizae, add 5 times of amount 80% alcohol reflux secondaries, each 1 hour, merge extractive liquid, filtered, and medicinal residues are standby, and filtrate is concentrated into the thick paste that relative density is about 1.25~1.28 (60 ℃ of surveys), and is standby;
4) get eight flavors such as medicinal residues and residue Rhizoma Gastrodiae after the Radix Salviae Miltiorrhizae alcohol extraction, add 6 times of water gagings, decoct secondary, each 1 hour, collecting decoction filtered, filtrate is concentrated into relative density and is about 1.09~1.11 (60 ℃ of surveys), puts coldly, adds ethanol and makes that to contain alcohol amount be 70%, stir evenly, leave standstill more than 24 hours, filter filtrate recycling ethanol, it is standby to be condensed into thick paste shape (relative density is 1.25-1.28,60 ℃ of surveys);
5) above-mentioned standby thick paste is merged, drying under reduced pressure (control vacuum: 0.08MPa, temperature: 80 ℃) is ground into fine powder, adds the about 40g of starch, and mixing incapsulates, and makes 1000, promptly.
Embodiment 2 is a capsule, and content is tan powder; Feeble QI, the little acid and puckery of distinguishing the flavor of, little hardship.By capsule and wherein the pulverulent mixture of forming by Chinese medicine and adjuvant of packing into; The composition of described Chinese medicine and 1000 s' consumption is:
Rhizoma Gastrodiae 192g Radix Paeoniae Rubra 256g Ramulus Uncariae Cum Uncis 192g Pheretima 256g
Herba Siegesbeckiae 256g Rhizoma Chuanxiong 256g Radix Salviae Miltiorrhizae 256g Zaocys 192g
Cortex et Radix Polygalae (processed) 64g Radix Cyathulae 256g.
Every of present embodiment contains peoniflorin (C
23H
28O
11) be no less than 3.2mg.
Every 4 of dress 0.4g one time is oral, 3 times on the one.
The preparation method of present embodiment may further comprise the steps:
1) chooses Rhizoma Gastrodiae, Radix Paeoniae Rubra, Ramulus Uncariae Cum Uncis, Pheretima, Herba Siegesbeckiae, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Zaocys, Cortex et Radix Polygalae (processed) and Radix Cyathulae ten flavor Chinese crude drugs by recipe quantity and concoct into decoction pieces respectively on request;
2) hook taking rattan adds 6 times of amount 80% alcohol reflux secondaries, and each 2 hours, merge extractive liquid, filtered, and filtrate is concentrated into the thick paste that relative density is about 1.25~1.28 (60 ℃ of surveys), and is standby;
3) get Radix Salviae Miltiorrhizae, add 6 times of amount 90% alcohol reflux secondaries, each 2 hours, merge extractive liquid, filtered, and medicinal residues are standby, and filtrate is concentrated into the thick paste that relative density is about 1.25~1.28 (60 ℃ of surveys), and is standby;
4) get eight flavors such as medicinal residues and residue Rhizoma Gastrodiae after the Radix Salviae Miltiorrhizae alcohol extraction, add 10 times of water gagings, decoct secondary, each 2 hours, collecting decoction filtered, filtrate is concentrated into relative density and is about 1.09~1.11 (60 ℃ of surveys), puts coldly, adds ethanol and makes that to contain alcohol amount be 50%, stir evenly, leave standstill more than 24 hours, filter filtrate recycling ethanol, it is standby to be condensed into thick paste shape (relative density is 1.25-1.28,60 ℃ of surveys);
5) above-mentioned standby thick paste is merged, drying under reduced pressure (control vacuum: 0.08M Pa, temperature: 80 ℃) is ground into fine powder, adds the about 40g of dextrin, and mixing incapsulates, and makes 1000, promptly.
It is as follows that the present invention carries out the preliminarily stabilised test:
According to the specification requirement of Chinese medicine research, the method that adopts room temperature to keep sample is carried out study on the stability to three batches of these capsule samples.Promptly under the condition of " bottled ", with three batch samples, lot number is followed successively by: 040201,040202,040203, at room temperature placed 3 months, carry out every index examination respectively at 0 month, January, February, March, and with detected the result in 0 month and compare, the result shows that every index has no significant change, and shows that this capsule preliminarily stabilised is good.
The present invention is as follows to the result of the test of rat long term toxicity:
With content 6.88g/kg of the present invention, 3.44g/kg, 1.72g/kg (be equivalent to 47.04,23.52 respectively, the 11.76g crude drug/kg) three dosage are given rat oral gavage (ig), continuous 6 months, observe the general state situation of animal behind the medicine: outward appearance sign, behavioral activity, breathing, reach periodic logging body weight, food-intake, after administration 3 months, administration 6 months and drug withdrawal 15 days, respectively put to death 1/3 animal respectively, and carry out hematology, blood biochemical and cardinal principle, organ coefficient and histopathologic examination.The result, during the administration, each treated animal is not seen untoward reaction, body weight increment, food-intake, hematology and blood biochemical learn every index and matched group compares, difference that there are no significant, animal viscera reaches main organs histopathologic examination substantially except that the minority animal lung has blood stasis, chronic matter inflammation, and all the other also find that obviously unusual histopathology changes.
The capsular effect experiment of the present invention is as follows:
By three kinds of animals, the Multitest method has been carried out the pharmacology evaluation of cerebral ischemia aspect to this capsule, the result shows, this capsule can obviously reduce cerebral edema and cerebral tissue lactic acid content due to the acute cerebral ischemia in rats, compare with perfusion group again, the medication group has the effect of increasing the cerebral tissue creatine phosphokinase, and pathological examination proves, the ischemia-reperfusion neuronal damage obviously increases the weight of and administration group and positive drug group, has the effect that alleviates brain injury.Same this medicine is cerebral blood flow increasing amount and reduction cerebral vascular resistance and total peripheral resistance obviously, but blood pressure, heart rate there is not obvious influence, this product also can reduce whole blood contrast viscosity, plasma viscosity, packed cell volume and the platelet aggregation intensity of blood stasis model animal simultaneously, and suppressing thrombosis length and weight, this product also can prolong blood coagulation time and cerebral ischemia mice time-to-live in addition.
One, this capsule is to the influence of anesthetized dog cerebral blood flow and cerebral vascular resistance
The result shows: each group of this capsule administration and matched group all do not have obvious influence to the dog heart rate.Each group of administration and matched group all do not have obvious influence to dog systolic pressure, dog diastolic pressure, dog mean blood pressure.
Each group of this capsule administration and matched group all do not have obvious influence to dog left indoor pressure, left chamber end diastolic pressure.Each group of this capsule administration and matched group to the dog left indoor pressure maximum rise, fall off rate (± dp/dtmax) does not all have obviously and influences.
Change percentage rate after this capsule 0.65g powder/kg, 0.26g powder/kg and the administration of three dosage groups of 0.13g powder/kg at 45~180 minutes, compare, all can obviously increase the dog cerebral blood flow, have obvious statistical significance (p<0.05, p<0.01) with matched group.Change percentage rate after the positive drug BUCHANG NAOXINTONG JIAONANG 0.65g/kg administration at 45~180 minutes, have obvious cerebral blood flow increasing amount equally, (p<0.05, p<0.01).Each group of medication compares no significant difference with the positive drug group, and statistical procedures is meaningless.
Change percentage rate after this capsule 0.65g powder/kg group administration and can obviously reduce cerebral vascular resistance, relatively have obvious statistical significance (p<0.01, p<0.05) with matched group at 45~180 minutes.Changed percentage rate 45~120 minutes after this capsule 0.26g powder/kg group administration, can obviously reduce cerebral vascular resistance (p<0.05), measured value was at 45~150 minutes, same obviously reduction cerebral vascular resistance (p<0.05), change percentage rate at 45~120 minutes after this capsule 0.13g powder/kg group administration, obviously reduce cerebral vascular resistance (p<0.05), change percentage rate after the NAOXINTONG JIAONANG 0.65g/kg administration, also can obviously reduce cerebral vascular resistance (p<0.01, p<0.05) at 45~180 minutes.
Two, this capsule is to the protective effect of cerebral ischemia
1) variation of brain water content
Ischemia group Mus brain water content is apparently higher than sham-operation line (P<0.01); Perfusion group does not more relatively have significant difference (P>0.05) with simple ischemia group.The large, medium and small dosage group of this capsule all significantly reduces (P<0.05, P<0.001, P<0.01) than filling group again.Positive control drug group brain water content relatively has reduction trend, but statistics meaningless (P>0.05) with perfusion again.
2) variation of cerebral tissue lactic acid content
Ischemia group murine brain lactic acid content increases (P<0.001) than sham operated rats is remarkable, lactic acid further raises in the murine brain of filling group again, apparently higher than ischemia group (P<0.001).This capsule for treating group murine brain lactic acid content all is starkly lower than ischemia group and perfusion group again (P<0.001, P<0.001, P<0.001).Increase with this capsular dosage, lactic acid content reduces obviously in the cerebral tissue.The lactic acid content of positive control drug group also is starkly lower than perfusion group again (P<0.001).
3) variation of cerebral tissue creatine phosphokinase (CPK)
In the sham operated rats rat cerebral tissue CPK content be 1410,2 ± 106.5u/g, CPK content obviously reduces in the simple ischemia group cerebral tissue, with sham operated rats comparing difference significantly (P<0.001); Compare with ischemia group, CPK content further reduces (P<0.001) in the cerebral tissue of filling group again.From this capsule for treating group as seen: the CPK content of large, medium and small three dosage groups all obviously raises, with the comparing difference of filling group more remarkable (P<0.001).The CPK content of positive drug group also obviously raises, and relatively there were significant differences (P<0.001) with perfusion group again.
4) brain CA1 and cortical areas's neure damage degree
Under optical microscope, each is organized tissue morphology and observes as follows:
A, simple cerebral ischemia group: the one-sided or obvious neuronal damage in bilateral Hippocampus CA1 district, the animal that has has neuronal necrosis widely from CA1 to CA4, and cortex mostly is neuronal necrosis.
B, sham operated rats: brain neuron injury is light, and individual animal visible Hippocampus CA1 district and cortical neuron have the sporadoneure damage.
C, cerebral ischemia re-pouring group: damage location is with simple cerebral ischemia group, but degree of injury is than obviously increasing the weight of.
D, positive control drug group: most of animal brain neuronal damages are lighter, the visible sporadoneure damage of individual animal Hippocampus CA1 and cortical areas.
E, low dose of investigational agent group: the half animal does not detect Hippocampus CA1 district neuron obvious necrosis, and the most of neurons of cortex are normal, and neuronal damage is arranged individually.
F, middle dosetest medicine group: most animals hippocampal neuron visible damage, the also visible more neuronal necrosis of cortex.
G, heavy dose of investigational agent group: the anatomical lesion degree is with middle dosetest medicine group.
Conclusion:
The success of operation cerebral ischemic model, brain neuron injury obviously increases the weight of behind the ischemia-reperfusion, positive controls has better prevention effect to the ischemic neuronal damage, little, in, heavy dose of investigational agent group all has preventive and therapeutic effect to the ischemic neuronal damage, and is but more obvious with the small dose group effect.
The histopathology brain tissue impairment, in this capsule of semiquantitative determination, relatively there were significant differences for low dose group and filling group again, illustrates that this capsule has the certain protection effect to cerebral tissue and neuron, but low dose of show more obvious.
Annotate: owing to adopt four duct ligation hypodesmus, it is downright bad that neuronal damage forms the zone, and necrocytosis is decentralized, so can't measure infarct size.Represent with semiquantitative determination.
Three, this capsule is to the influence of rat plasma platelet aggregation
The high, medium and low three kinds of dosage of this capsule all have in various degree inhibitory action to the rat plasma platelet aggregation, wherein the effect of 1.72g/kg group is the most obvious, effect is better than the positive reference substance BUCHANG NAOXINTONG, the maximum suppression ratio of assembling of medication group is respectively 24.82,15.03,13.28%, and BUCHANG NAOXINTONG is 16.96%.
Four, this capsule is to the influence of hemorheology of rat
This capsule in high dose group to the height of animal's whole blood specific viscosity cut, in cut, low cut, packed cell volume and plasma viscosity all have tangible reduction effect, illustrate that this product can obviously improve " viscosity " of body blood, " concentration ", thereby play the effect of invigorating blood circulation.
Five, this capsule is to the thrombotic influence of rats in vitro
This capsule in high dose group forms rats in vitro blood shape has the obvious suppression effect, though middle dosage group has inhibition trend to external thrombus, statistical procedures is meaningless, and positive drug NAOXINTONG inhibitory action is similar to high dose.
Six, this capsule is to the influence of clotting time of mice
This capsule height, middle dosage group have tangible prolongation effect to clotting time of mice.
Seven, this capsule is to the influence of mouse brain ischemia time-to-live
[3]
Adopt straightforward procedure to cause the death of mouse brain ischemia, this capsule in high dose group can prolong the mice time-to-live, compares P<0.05 with matched group.
Every cerebral ischemia result of the test shows: three kinds of various dose of this capsule, can obviously reduce (four duct ligation hypodesmus) cerebral edema and cerebral tissue lactic acid content due to the acute cerebral ischemia in rats, have the effect of increasing the cerebral tissue creatine phosphokinase with the comparison of perfusion group again medication group, illustrate that this product can alleviate brain tissue impairment and the Physiology and biochemistry environment that improves brain.Histopathologic examination confirms; ischemia-reperfusion and simple ischemia group cerebral cortex district and Hippocampus CA1 district neuronal damage obviously increase the weight of; and administration group and positive reference substance neuronal damage are lighter; the necrosis region area reduces, and the effect that medicine has the excellent protection cerebral tissue and alleviates degree of injury is described.Same this medicine is obviously cerebral blood flow increasing amount, reduction cerebral vascular resistance and total peripheral resistance also, but blood pressure, heart rate are not had obvious influence, and the variation of these indexs is useful for anti-cerebral ischemia.Experiment has also been measured the platelet aggregation response curve by rat plasma, and the result shows that this medicine has the obvious suppression effect to platelet aggregation, the maximum suppression ratio of assembling, and the medication group is respectively 39.08,22.24,14.68%.The inside and outside thrombotest of body has illustrated that equally this medicine can obviously suppress thrombosis, points out it can obviously reduce thrombosis.Hemorheology index is measured and to be shown, to whole blood contrast viscosity, plasma viscosity, packed cell volume and significant reduction effect is all arranged.In addition, this product also can prolong blood clotting time and chmice acute cerebral ischemia time-to-live.These pharmacologically actives have confirmed the therapeutical effect of this capsule to cerebral ischemia.
In sum; various dose shown in this capsule has the certain protection effect to the brain tissue impairment that is caused by cerebral ischemia; but also cerebral blood flow increasing amount and reduction cerebral vascular resistance simultaneously; reduce platelet aggregation, reduce blood viscosity, the concentration of blood stasis model animal; restrain pharmacological actions such as thrombosis and prolongation clotting time; consistent with the clinical practice curative effect, illustrate that the present invention is the active drug of treatment apoplexy.