CN102178697A - Compound leech capsule and preparation method thereof - Google Patents
Compound leech capsule and preparation method thereof Download PDFInfo
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- CN102178697A CN102178697A CN2011101042192A CN201110104219A CN102178697A CN 102178697 A CN102178697 A CN 102178697A CN 2011101042192 A CN2011101042192 A CN 2011101042192A CN 201110104219 A CN201110104219 A CN 201110104219A CN 102178697 A CN102178697 A CN 102178697A
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Abstract
The invention relates to a compound leech capsule and a preparation method thereof. The compound leech capsule is characterized in that content of the capsule is prepared by mixing leech extract, fructose diphosphate sodium and starch. The preparation method comprises the following steps: firstly extracting the leech extract from leech at room temperature and mixing the extract with the fructose diphosphate sodium; and then adding a proper amount of excipient starch to finally obtain the finished product of compound leech capsule. The compound leech capsule is suitable for treating and preventing thrombotic cardio-cerebrovascular diseases and has the efficacies of benefiting heart and brain, strengthening body and protecting liver and can also prevent symptoms such as coronary heart disease, cerebral thrombosis, stroke and the like if taken for a long term.
Description
Technical field:
The invention belongs to field of medicaments, relate generally to a kind of compound recipe Leech capsule and preparation method thereof, particularly relate to a kind of compound recipe Leech capsule that is used to prevent and treats the thrombosis cardiovascular and cerebrovascular disease with and preparation method thereof.
Background technology:
Cardiovascular and cerebrovascular disease is a kind of serious threat human health, the commonly encountered diseases of middle-aged and elderly people more than 50 years old particularly, even use most advanced, perfect at present treatment means, the cerebrovascular accident survivor life that still has more than 50% can not be taken care of oneself fully, every year is died from the number of cardiovascular and cerebrovascular disease up to 1,500 ten thousand people in the whole world, occupy various causes of the death first place, cardiovascular and cerebrovascular disease has become the highest No.1 killer of the human dead cause of disease, also is " the noiseless demon " of health of people.
Cardiovascular and cerebrovascular disease has " sickness rate height, disability rate height, mortality rate height, relapse rate height, complication are many " i.e. characteristics of " four is high by more than ", and at present, China cardiovascular and cerebrovascular disease patient has surpassed 2.7 hundred million people.China dies from cardiovascular and cerebrovascular disease every year nearly 3,000,000 people, accounts for 51% of the annual total dead cause of disease of China, and 75% disability in various degree among the patient of survive, 40% weight is residual.
Behind China's apoplexy patient discharge the relapse rate in 1 year be the relapse rate in 30%, the five year up to 59%, and secondary prevention do preferably the U.S. only be 10; Because China's medical care insurance covers a people group of mean people, apoplexy patient's relapse rate is compared with the international average level and will be exceeded more than 1 times.
The treatment cardiovascular and cerebrovascular disease is the medicine of thrombosis cardiovascular and cerebrovascular disease particularly, ubiquity uses medical material too much, therefore shortcomings such as side effect is big, curative effect is general, are developed and are a kind ofly used that medical material is few, good effect and the little medicine of toxic and side effects become problem demanding prompt solution.
Summary of the invention:
1, goal of the invention:
The present invention is directed to the defective that above-mentioned prior art Chinese medicine compatibility exists, a kind of compound recipe Leech capsule and preparation method thereof is provided, have stimulate the menstrual flow, invigorate blood circulation, effect such as pain relieving, can improve cardio and vascular function, treating both the principal and secondary aspects of a disease, particularly splendid to thrombosis cardiovascular and cerebrovascular disease curative effect, and various hepatitis such as hepatitis A, hepatitis B are had auxiliary treatment effect preferably.
2, technical scheme:
The present invention is achieved through the following technical solutions:
A kind of compound recipe Leech capsule, it is characterized in that: this capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, each component proportionate relationship by weight is: 80～120 parts of Hirudo extracts, 80～360 parts of Fructose Diphosphate sodium, 20～50 parts of starch.
This capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, and each component proportionate relationship by weight is: 90～110 parts of Hirudo extracts, 180～240 parts of Fructose Diphosphate sodium, 30～40 parts of starch.
This capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, and each component proportionate relationship by weight is: 100 parts of Hirudo extracts, 200 parts of Fructose Diphosphate sodium, 35 parts of starch.
A kind of preparation method of compound recipe Leech capsule is characterized in that: this method is carried out according to the following steps:
(1) slightly carries: fresh and alive all or dry all with Hirudo, putting into homogenizer after cleaning smashes, get 5～15kg, the normal saline that at room temperature adds 2500～7500ml, stirred 20～50 minutes, and froze molten 4～8 times, 2～8 ℃ left standstill 18～24 hours, 4000～6000 rev/mins of centrifuging and taking supernatant, and the adjusting pH value is that 4～5 backs are standby.
(2) mass concentration that adds 4～6 times of precipitate quality get supernatant in step (1) after in the remaining precipitate is 40～70% ethanol, stirs 20～50 minutes, and the centrifuging and taking precipitate is standby.
(3) refining: as in step (2), to add the physiological saline solution precipitate in the standby precipitate, the addition of normal saline is 4～6 times of precipitate quality, through anion-exchange column high efficiency chromatography gradient elution, behind the efficient reversed phase chromatographic column stepwise of the phenyl post eluting, again through anion-exchange column concentrate, degerming, filter to get filtrate standby.
(4) filtrate standby in supernatant standby in the step (1) and the step (3) is merged, after concentrating, it is stand-by promptly to get Hirudo extract (liquid).
(5) get each raw material for standby in the described ratio of claim 1, the Hirudo extract and the starch that obtain in the step (4) is even by the mixed of mass ratio 1:0.2～0.5, make wet granular, mix with Fructose Diphosphate sodium after the oven dry, the mass ratio of Hirudo extract and Fructose Diphosphate sodium is 1:1～3 again.
(6) mixture that obtains in the step (5) is pulverized and crossed 10～15 mesh sieves, dry under 40～65 ℃ of conditions, granulate, sterilization back are encapsulated, promptly get compound recipe Leech capsule finished product of the present invention after packing.
Fresh and alive all or dry all with Hirudo in the above-mentioned steps (1), putting into homogenizer smashes, get 10kg, at room temperature add the 5000ml normal saline, the reason that limits this concentration is to destroy the activity of extract in the Hirudo, stirred 30 minutes, freeze molten 6 times, 4 ℃ left standstill 20 hours, 5000 rev/mins of centrifuging and taking supernatant, regulating pH value is that 4.8 backs are standby, and the activity of Hirudo extract reaches best when pH value is 4.8.
In the above-mentioned steps (2), the mass concentration that adds 5 times of precipitate quality get supernatant in step (1) after in the remaining precipitate is 55% ethanol.
In the above-mentioned steps (3), in step (2), add the physiological saline solution precipitate in the standby precipitate, the addition of normal saline is 4～6 times of precipitate quality, through anion-exchange column (ISN-5 Φ 40 * 300mm) high efficiency chromatography gradient elutions, the phenyl post (behind ISB-10 Φ 40 * 500mm) the efficient reversed phase chromatographic column stepwise eluting, again through anion-exchange column (ISN-20 Φ 40 * 250mm) concentrates, degerming, filter to get filtrate standby.
In the above-mentioned steps (5), the mass ratio of Hirudo extract and starch is 1:0.35, the mass ratio of Hirudo extract and Fructose Diphosphate sodium is 1:2, adopts this proportional arrangement can promote the synergism of Hirudo and Fructose Diphosphate sodium, makes clinical effectiveness reach best.
In the above-mentioned steps (6), the mixture that obtains in the step (5) is pulverized and crossed 12 mesh sieves, dry under 50 ℃ of conditions, during granulate, after 8～10 mesh sieves, the sterilization back is encapsulated, promptly gets compound recipe Leech capsule finished product of the present invention after packing.
Above-mentioned Hirudo extract is a liquid, and its active component is a hirudin.
Above-mentioned normal saline is the sodium-chloride water solution of mass fraction 0.9%.
3, advantage and effect:
A kind of compound recipe Leech capsule that the present invention proposes and preparation method thereof has following advantage:
Hirudo is cold in nature, salty in the mouth, poisonous, the function of have removing blood stasis, leading to the stasis of blood, stimulating the menstrual flow, clinical lump in the abdomen, mass in the abdomen, blood stasis amenorrhea, the traumatic injury of being used for the treatment of; Prove through looking into lot of documents report and clinical trial, contain hirudin in the Hirudo saliva, have powerful Trombin inhibiting effect, belong to the efficient anticoagulant of a kind of brute force.Experiment shows, hirudin has very high selectivity and specificity to the inhibitory action of thrombin, a kind of factor that it only suppresses in the hemostasis system is a thrombin, does not disturb other body fluid or cytokine, and its inhibitory action does not need other coagulation factorss or plasma fraction to participate in yet; Hirudin acts on the incipient stage of blood coagulation, prevents that Fibrinogen from fragmenting into fibrin, stops thrombin to fibrinous polymerization, prevents that fibrin-grumeleuse from forming, thereby prevents blood coagulation.
Effective active composition in the Hirudo extract is a hirudin, the effect of hirudin anticoagulant blood is very strong, very the Hirudo extract of low dosage can produce the blood coagulation resisting function that can measure, and can suppress venous thrombosis and also make Fibrinogen and platelet count recover normal rapidly.Continuous drip 0.6mg Hirudo extract/h again behind the once quiet notes of the people 0.9mg Hirudo extract calculates by 75 ㎏ body weight, and whole body constant anticoagulant of enzyme concentration can reach promptly about 0.5 antithrombin unit of 50ng/ml((AT-U)/ml).A kind of like this inhibition concentration has proved and can enough prevent animal model experiment.Fructose Diphosphate sodium (FDP) is a kind of bioactive substance, and its production process need consume ATP, plays an important role in energy metabolism.A large amount of in recent years pharmacology and clinical trials prove that FDP is activating brain cell effectively, (brain cell activator).Strengthen the keeping ability of brain cell, (myocardial cell reinforcing agent).And can be used as hepatocellular immunomodulator, (hepatocyte activator).Its clinical efficacy is as follows:
1.1:FDP in its metabolic process, can produce a large amount of ATP(Energy mixtures) provide energy to tissue metabolism.
1.2:FDP generation effect in multiple biochemical reaction has certain biological activity, particularly has the effect (detoxifcation, protein synthesis etc.) of keeping the liver normal function.
1.3:FDP can strengthen brain cell activity, improve big brain energy metabolism.Can alleviate the nervous symptoms of ischemic brain infarction; Energy expenditure behind reduction infarct size and the ischemia, the protection cerebral tissue.
1.4:FDP be of value to energy metabolism, physical strength reinforcing and the endurance of cardiac muscle.Can increase the myocardial oxygen delivery amount; Reduce myocardial oxygen consumption; Reduce the area of acute myocardial infarction, and antiplatelet aggregative activity is arranged, comparatively ideal effect is arranged for the prevention and the treatment of some cardiovascular and cerebrovascular disease.
1.5:FDP to multiple metabolic disease, especially disease such as diabetes has the auxiliary treatment effect.
1.6:FDP also have Antishock function simultaneously.
The leaching process of Hirudo extract of the present invention does not need complicated condition, at room temperature can carry out, and has simplified preparation technology, has reduced preparation cost; Hirudo extract is applicable to the treatment and the prevention of thrombosis cardiovascular and cerebrovascular disease, and Fructose Diphosphate sodium has the effect that heart-nourishing brain-nourishing, strong body protect the liver, and the two is in conjunction with playing complementary effect just; Use Hirudo or Fructose Diphosphate sodium complex operation separately, the cost height, very inconvenient, do not reduce the biological activity of Hirudo and Fructose Diphosphate sodium and to have on the technology basis of stablizing Hirudo and Fructose Diphosphate sodium physiological action guaranteeing, it is made compound recipe, both to have made things convenient for the patient, also help bringing into play the synergism of the two physiologically active, improve clinical efficacy, not only avoided the issuable side effect of independent use Hirudo, can also play the effect that protects the liver; This compound recipe Leech capsule of the present invention is applicable to coronary heart disease, angina pectoris, myocardial infarction, and various hepatitis such as hepatitis A, hepatitis B are had auxiliary treatment effect preferably; Take diseases such as to prevent coronary heart disease, cerebral thrombosis, apoplexy for a long time.
Description of drawings:
Fig. 1 is a process chart of the present invention.
The specific embodiment:
Below in conjunction with specific embodiment the present invention is elaborated, but protection scope of the present invention is not limited only to following embodiment.
Embodiment 1:
A kind of compound recipe Leech capsule is characterized in that: this capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, and each component proportionate relationship by weight is: 100 parts of Hirudo extracts, 200 parts of Fructose Diphosphate sodium, 35 parts of starch.
A kind of preparation method of aforesaid compound recipe Leech capsule is characterized in that: this method is carried out according to the following steps:
(1) slightly carry: fresh and alive all or dry all with Hirudo, put into homogenizer after cleaning and smash, get 10kg, at room temperature add the 5000ml normal saline, stirred 30 minutes, freeze molten 6 times, 4 ℃ left standstill 20 hours, 5000 rev/mins of centrifuging and taking supernatant, and the adjusting pH value is that 4.8 backs are standby;
(2) mass concentration that adds 5 times of precipitate quality get supernatant in step (1) after in the remaining precipitate is 55% ethanol, stirs 30 minutes, and the centrifuging and taking precipitate is standby;
(3) refining: as in step (2), to add the physiological saline solution precipitate in the standby precipitate, the addition of normal saline is 5 times of precipitate quality, through anion-exchange column (ISN-5 Φ 40 * 300mm) high efficiency chromatography gradient elutions, the phenyl post (behind ISB-10 Φ 40 * 500mm) the efficient reversed phase chromatographic column stepwise eluting, again through anion-exchange column (ISN-20 Φ 40 * 250mm) concentrates, degerming, filter to get filtrate standby;
(4) filtrate standby in supernatant standby in the step (1) and the step (3) is merged, after concentrating, it is stand-by promptly to get Hirudo extract;
(5) get each raw material for standby in the described ratio of claim 1, the Hirudo extract and the starch that obtain in the step (4) is even by the mixed of mass ratio 1:0.35, make wet granular, mix with Fructose Diphosphate sodium after the oven dry, the mass ratio of Hirudo extract and Fructose Diphosphate sodium is 1:2 again;
(6) mixture that obtains in the step (5) is pulverized and crossed 12 mesh sieves, dry under 50 ℃ of conditions, after 10 mesh sieves, the sterilization back is encapsulated during granulate, promptly gets compound recipe Leech capsule finished product of the present invention after packing.
Embodiment 2:
A kind of compound recipe Leech capsule is characterized in that: this capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, and each component proportionate relationship by weight is: 80 parts of Hirudo extracts, 80 parts of Fructose Diphosphate sodium, 20 parts of starch.
A kind of preparation method of aforesaid compound recipe Leech capsule is characterized in that: this method is carried out according to the following steps:
(1) slightly carry: fresh and alive all or dry all with Hirudo, put into homogenizer after cleaning and smash, get 5kg, at room temperature add the 2500ml normal saline, stirred 20 minutes, freeze molten 4 times, 2 ℃ left standstill 18 hours, 4000 rev/mins of centrifuging and taking supernatant, and the adjusting pH value is that 4.0 backs are standby;
(2) mass concentration that adds 4 times of precipitate quality get supernatant in step (1) after in the remaining precipitate is 40% ethanol, stirs 20 minutes, and the centrifuging and taking precipitate is standby;
(3) refining: as in step (2), to add the physiological saline solution precipitate in the standby precipitate, the addition of normal saline is 4 times of precipitate quality, through anion-exchange column (ISN-5 Φ 40 * 300mm) high efficiency chromatography gradient elutions, the phenyl post (behind ISB-10 Φ 40 * 500mm) the efficient reversed phase chromatographic column stepwise eluting, again through anion-exchange column (ISN-20 Φ 40 * 250mm) concentrates, degerming, filter to get filtrate standby;
(4) filtrate standby in supernatant standby in the step (1) and the step (3) is merged, after concentrating, it is stand-by promptly to get Hirudo extract;
(5) get each raw material for standby in the described ratio of claim 1, the Hirudo extract and the starch that obtain in the step (4) is even by the mixed of mass ratio 1:0.25, make wet granular, mix with Fructose Diphosphate sodium after the oven dry, the mass ratio of Hirudo extract and Fructose Diphosphate sodium is 1:1 again;
(6) mixture that obtains in the step (5) is pulverized and crossed 10 mesh sieves, dry under 40 ℃ of conditions, after 8 mesh sieves, the sterilization back is encapsulated during granulate, promptly gets compound recipe Leech capsule finished product of the present invention after packing.
Embodiment 3:
A kind of compound recipe Leech capsule is characterized in that: this capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, and each component proportionate relationship by weight is: 90 parts of Hirudo extracts, 180 parts of Fructose Diphosphate sodium, 30 parts of starch.
A kind of preparation method of aforesaid compound recipe Leech capsule is characterized in that: this method is carried out according to the following steps:
(1) slightly carry: fresh and alive all or dry all with Hirudo, put into homogenizer after cleaning and smash, get 8kg, at room temperature add the 4000ml normal saline, stirred 25 minutes, freeze molten 5 times, 3 ℃ left standstill 19 hours, 4500 rev/mins of centrifuging and taking supernatant, and the adjusting pH value is that 4.2 backs are standby;
(2) add the ethanol of the mass concentration 70% of 6 times of precipitate quality get supernatant in step (1) after in the remaining precipitate, stirred 20 minutes, the centrifuging and taking precipitate is standby;
(3) refining: as in step (2), to add the physiological saline solution precipitate in the standby precipitate, the addition of normal saline is 6 times of precipitate quality, through anion-exchange column (ISN-5 Φ 40 * 300mm) high efficiency chromatography gradient elutions, the phenyl post (behind ISB-10 Φ 40 * 500mm) the efficient reversed phase chromatographic column stepwise eluting, again through anion-exchange column (ISN-20 Φ 40 * 250mm) concentrates, degerming, filter to get filtrate standby;
(4) filtrate standby in supernatant standby in the step (1) and the step (3) is merged, after concentrating, it is stand-by promptly to get Hirudo extract;
(5) get each raw material for standby in the described ratio of claim 1, the Hirudo extract and the starch that obtain in the step (4) is even by the mixed of mass ratio 1:1/3, make wet granular, mix with Fructose Diphosphate sodium after the oven dry again, the mass ratio of Hirudo extract and Fructose Diphosphate sodium is 1:2;
(6) mixture that obtains in the step (5) is pulverized and crossed 15 mesh sieves, dry under 45 ℃ of conditions, after 10 mesh sieves, the sterilization back is encapsulated during granulate, promptly gets compound recipe Leech capsule finished product of the present invention after packing.
Embodiment 4:
A kind of compound recipe Leech capsule is characterized in that: this capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, and each component proportionate relationship by weight is: 120 parts of Hirudo extracts, 240 parts of Fructose Diphosphate sodium, 48 parts of starch.
A kind of preparation method of aforesaid compound recipe Leech capsule is characterized in that: this method is carried out according to the following steps:
(1) slightly carry: fresh and alive all or dry all with Hirudo, put into homogenizer after cleaning and smash, get 13kg, at room temperature add the 6500ml normal saline, stirred 45 minutes, freeze molten 7 times, 7 ℃ left standstill 23 hours, 5800 rev/mins of centrifuging and taking supernatant, and the adjusting pH value is that 4.6 backs are standby;
(2) add the ethanol of the mass concentration 50% of 5 times of precipitate quality get supernatant in step (1) after in the remaining precipitate, stirred 40 minutes, the centrifuging and taking precipitate is standby;
(3) refining: as in step (2), to add the physiological saline solution precipitate in the standby precipitate, the addition of normal saline is 5 times of precipitate quality, through anion-exchange column (ISN-5 Φ 40 * 300mm) high efficiency chromatography gradient elutions, the phenyl post (behind ISB-10 Φ 40 * 500mm) the efficient reversed phase chromatographic column stepwise eluting, again through anion-exchange column (ISN-20 Φ 40 * 250mm) concentrates, degerming, filter to get filtrate standby;
(4) filtrate standby in supernatant standby in the step (1) and the step (3) is merged, after concentrating, it is stand-by promptly to get Hirudo extract;
(5) get each raw material for standby in the described ratio of claim 1, the Hirudo extract and the starch that obtain in the step (4) is even by the mixed of mass ratio 1:0.4, make wet granular, mix with Fructose Diphosphate sodium after the oven dry again, the mass ratio of Hirudo extract and Fructose Diphosphate sodium is 1:2;
(6) mixture that obtains in the step (5) is pulverized and crossed 12 mesh sieves, dry under 55 ℃ of conditions, after 8 mesh sieves, the sterilization back is encapsulated during granulate, promptly gets compound recipe Leech capsule finished product of the present invention after packing.
Embodiment 5:
A kind of compound recipe Leech capsule is characterized in that: this capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, and each component proportionate relationship by weight is: 100 parts of Hirudo extracts, 100 parts of Fructose Diphosphate sodium, 50 parts of starch.
A kind of preparation method of aforesaid compound recipe Leech capsule is characterized in that: this method is carried out according to the following steps:
(1) slightly carry: fresh and alive all or dry all with Hirudo, put into homogenizer after cleaning and smash, get 6kg, at room temperature add the 3000ml normal saline, stirred 35 minutes, freeze molten 8 times, 5 ℃ left standstill 21 hours, 4800 rev/mins of centrifuging and taking supernatant, and the adjusting pH value is that 4.5 backs are standby;
(2) add the ethanol of the mass concentration 65% of 6 times of precipitate quality get supernatant in step (1) after in the remaining precipitate, stirred 35 minutes, the centrifuging and taking precipitate is standby;
(3) refining: as in step (2), to add the physiological saline solution precipitate in the standby precipitate, the addition of normal saline is 4 times of precipitate quality, through anion-exchange column (ISN-5 Φ 40 * 300mm) high efficiency chromatography gradient elutions, the phenyl post (behind ISB-10 Φ 40 * 500mm) the efficient reversed phase chromatographic column stepwise eluting, again through anion-exchange column (ISN-20 Φ 40 * 250mm) concentrates, degerming, filter to get filtrate standby;
(4) filtrate standby in supernatant standby in the step (1) and the step (3) is merged, after concentrating, it is stand-by promptly to get Hirudo extract;
(5) get each raw material for standby in the described ratio of claim 1, the Hirudo extract and the starch that obtain in the step (4) is even by the mixed of mass ratio 1:0.5, make wet granular, mix with Fructose Diphosphate sodium after the oven dry again, the mass ratio of Hirudo extract and Fructose Diphosphate sodium is 1:1;
(6) mixture that obtains in the step (5) is pulverized and crossed 14 mesh sieves, dry under 60 ℃ of conditions, after 10 mesh sieves, the sterilization back is encapsulated during granulate, promptly gets compound recipe Leech capsule finished product of the present invention after packing.
Embodiment 6:
A kind of compound recipe Leech capsule is characterized in that: this capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, and each component proportionate relationship by weight is: 110 parts of Hirudo extracts, 330 parts of Fructose Diphosphate sodium, 22 parts of starch.
A kind of preparation method of aforesaid compound recipe Leech capsule is characterized in that: this method is carried out according to the following steps:
(1) slightly carry: fresh and alive all or dry all with Hirudo, put into homogenizer after cleaning and smash, get 12kg, at room temperature add the 6000ml normal saline, stirred 40 minutes, freeze molten 6 times, 6 ℃ left standstill 22 hours, 5500 rev/mins of centrifuging and taking supernatant, and the adjusting pH value is that 4.9 backs are standby;
(2) add the ethanol of the mass concentration 60% of 4 times of precipitate quality get supernatant in step (1) after in the remaining precipitate, stirred 45 minutes, the centrifuging and taking precipitate is standby;
(3) refining: as in step (2), to add the physiological saline solution precipitate in the standby precipitate, the addition of normal saline is 6 times of precipitate quality, through anion-exchange column (ISN-5 Φ 40 * 300mm) high efficiency chromatography gradient elutions, the phenyl post (behind ISB-10 Φ 40 * 500mm) the efficient reversed phase chromatographic column stepwise eluting, again through anion-exchange column (ISN-20 Φ 40 * 250mm) concentrates, degerming, filter to get filtrate standby;
(4) merging of filtrate standby in supernatant standby in the step (1) and the step (3) is concentrated after, it is stand-by promptly to get Hirudo extract;
(5) get each raw material for standby in the described ratio of claim 1, the Hirudo extract and the starch that obtain in the step (4) is even by the mixed of mass ratio 1:0.2, make wet granular, mix with Fructose Diphosphate sodium after the oven dry again, the mass ratio of Hirudo extract and Fructose Diphosphate sodium is 1:3;
(6) mixture that obtains in the step (5) is pulverized and crossed 11 mesh sieves, dry under 65 ℃ of conditions, after 9 mesh sieves, the sterilization back is encapsulated during granulate, promptly gets compound recipe Leech capsule finished product of the present invention after packing.
Embodiment 7:
A kind of compound recipe Leech capsule is characterized in that: this capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, and each component proportionate relationship by weight is: 120 parts of Hirudo extracts, 360 parts of Fructose Diphosphate sodium, 40 parts of starch.
A kind of preparation method of aforesaid compound recipe Leech capsule is characterized in that: this method is carried out according to the following steps:
(1) slightly carry: fresh and alive all or dry all with Hirudo, put into homogenizer after cleaning and smash, get 15kg, at room temperature add the 7500ml normal saline, stirred 50 minutes, freeze molten 8 times, 8 ℃ left standstill 24 hours, 6000 rev/mins of centrifuging and taking supernatant, and the adjusting pH value is that 5.0 backs are standby;
(2) add the ethanol of the mass concentration 45% of 5 times of precipitate quality get supernatant in step (1) after in the remaining precipitate, stirred 50 minutes, the centrifuging and taking precipitate is standby;
(3) refining: as in step (2), to add the physiological saline solution precipitate in the standby precipitate, the addition of normal saline is 6 times of precipitate quality, through anion-exchange column (ISN-5 Φ 40 * 300mm) high efficiency chromatography gradient elutions, the phenyl post (behind ISB-10 Φ 40 * 500mm) the efficient reversed phase chromatographic column stepwise eluting, again through anion-exchange column (ISN-20 Φ 40 * 250mm) concentrates, degerming, filter to get filtrate standby;
(4) filtrate standby in supernatant standby in the step (1) and the step (3) is merged, after concentrating, it is stand-by promptly to get Hirudo extract;
(5) get each raw material for standby in the described ratio of claim 1, the Hirudo extract and the starch that obtain in the step (4) is even by the mixed of mass ratio 1:1/3, make wet granular, mix with Fructose Diphosphate sodium after the oven dry again, the mass ratio of Hirudo extract and Fructose Diphosphate sodium is 1:3;
(6) mixture that obtains in the step (5) is pulverized and crossed 13 mesh sieves, dry under 50 ℃ of conditions, after 9 mesh sieves, the sterilization back is encapsulated during granulate, promptly gets compound recipe Leech capsule finished product of the present invention after packing.
In order to ensure safety of clinical administration, before clinical use, the present invention has been carried out acute toxicity test in mice:
(1) material and method
Animal subject is a Kunming kind white mice, supplies with by my laboratory animal room of company, and health, body weight 20+1.0g, male and female half and half are divided into three groups at random, tail vein injection group, subcutaneous injection group and matched group, 10 every group.
A) tail vein injection medicine-feeding test:
Animal and grouping as above, the contents mixed of getting compound recipe Leech capsule of the present invention is even, precision takes by weighing 0.25g(and is equivalent to 20u) add sodium chloride water for injection 80ml and fully dissolve, get supernatant, medication adopts tail vein injection method, administration after the fasting overnight.Administration volume 0.5ml/20g body weight, dosage is pressed the maximum dosage conversion of human body: (40u * 9.01 * 20g) ÷ (60kg * 1000)=0.12u, in the formula: u is an active unit, 9.01 is conversion coefficient, 20g is a white mice weight, and 60kg is an average human weight; 0.12u be the dosage of every of the heavy mice of 20g, every mice administration should be 0.5ml, promptly the medicinal liquid of 0.5ml is equivalent to 0.12u.Reaction and the mortality rate in 2 days after the observation administration.
B) mouse subcutaneous injection acute toxicity test:
Animal and divide into groups the same; the contents mixed of getting compound recipe Leech capsule of the present invention is even; precision takes by weighing 0.25g(and is equivalent to 20u) adding sodium chloride water for injection 80ml fully dissolves; get supernatant; medication adopts subcutaneous method; administration after the fasting overnight, and injection in 1 hour is once injected 4 times continuously at interval.Administration volume 0.5ml/20g body weight, dosage is pressed the maximum dosage conversion of human body: (40u * 9.01 * 20g) ÷ (60kg * 1000)=0.12u, in the formula: u is an active unit, 9.01 is conversion coefficient, 20g is a white mice weight, and 60kg is an average human weight; 0.12u be the dosage of every of the heavy mice of 20g, every mice administration should be 0.5ml, promptly the medicinal liquid of 0.5ml is equivalent to 0.12u.Reaction and the mortality rate in 2 days after the observation administration.
C) matched group: tail vein and subcutaneous injection all compare experiment, press the normal saline that tail vein and subcutaneous injection dosage are given injected in mice equivalent.
(2) result and discussion:
The water-soluble back of compound recipe Leech capsule is a suspendible liquid, has carried out the test of tail intravenously administrable and two kinds of methods of mouse subcutaneous injection, and mouse tail vein injection and subcutaneous injection administration group were all survived in 48 hours, and weightening finish is normal, the no abnormality seen Signs.
Tail vein injection does not have all uncomfortable phenomenons, gun-ho, and weight increase in 2 days, none is only dead; To be tried Mus and put to death and to carry out system and analyse, each internal organs is not seen obvious pathological change.
Mouse subcutaneous injection four times, gun-ho, weight increase in 2 days, none is only dead; To be tried Mus and put to death and to carry out system and analyse, stimulation is not seen in the administration part, and each internal organs is not seen obvious pathological change.
The normal saline of matched group injection equivalent was observed 2 days, the no discomfort and the phenomena of mortality, and weight average increases about 1g.
Comprehensive The above results as seen, the compound recipe Leech capsule of continuous three batches of trial-productions, through acute toxicity test checking (maximum dosage method), tail vein injection people consumption or subcutaneous injection people consumption are very safe for healthy mice, compare with matched group, weightening finish significantly, none has only uncomfortable phenomenon or death, will be tried Mus and put to death and to carry out system and analyse, and each internal organs is not seen obvious pathological change, prove that thus the present invention is very safe and reliable.
Adopt the present invention to carry out clinical application, wherein male 50 examples, woman's 30 examples are used for the treatment of 65 examples, are used for rehabilitation and prevention 15 examples, the oldest 75 years old, at minimum 16 years old of age, after the patient used, symptoms such as coronary heart disease, angina pectoris, myocardial infarction, cerebral thrombosis all had alleviation in various degree, the state of an illness is effectively controlled, and symptoms such as the dizziness that caused by above-mentioned disease, tinnitus, headache, hypomnesis, insomnia are had good rehabilitation and preventive effect.Usage: during treatment, oral adult: 2～3 times on the one, one time 2～4; Rehabilitation and when prevention, 2 times on the one, one time 1～2, every 0.25g.
This compound recipe Leech capsule of the present invention content is white or off-white color granule or powder.This compound recipe Leech capsule is applicable to the treatment and the prevention of thrombosis cardiovascular and cerebrovascular disease; Heart-nourishing brain-nourishing, strong body protect the liver, and are applicable to coronary heart disease, angina pectoris, myocardial infarction; Brain atrophy, alzheimer disease, cerebral arteriosclerosis, apoplexy sequela, cerebral trauma, diseases such as the dizziness that diseases such as neurosis cause, tinnitus, headache, hypomnesis, insomnia, take diseases such as can preventing coronary heart disease, cerebral thrombosis, apoplexy for a long time, more remarkable for the severe patient curative effect.
The discriminating of Hirudo: contain in the Hirudo saliva and be dissolved in alcoholic acid Hirudo extract, get this product powder 1g, add ethanol 5ml, supersound process 15 minutes filters, and filtrate is as need testing solution.Other trematodiasis control medicinal material 1g that fetches water shines medical material solution in pairs with legal system.According to the thin layer chromatography test, draw each 5 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, with normal hexane one ethyl acetate (4:1) is developing solvent, launches, and takes out, dry, spray is with 10% ethanol solution of sulfuric acid, and it is clear to be heated to speckle colour developing at 105 ℃.In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show identical aubergine speckle; Ultra-violet lamp (365nm) shows identical fluorescent red-orange speckle down.
Check moisture, measure, be no more than 18.0% according to aquametry.
Total ash is no more than 10.0%.
Acid-insoluble ash is no more than 2.0%.
Extractum is measured according to the hot dipping under the ethanol-soluble extractives algoscopy item, makes solvent with Diluted Alcohol, is no less than 15.0%
Assay: get the about 1g of this product powder (crossing sieve No. three), the accurate title, decide, the accurate 0.9% sodium chloride solution 5ml that adds, fully stir, lixiviate 30 minutes, and jolting constantly, centrifugal, precision is measured supernatant 100 μ l, (among the 10mm * 100mm), (0.2mol/L tris solution 25ml and the about 40ml of 0.1mol/L hydrochloric acid solution add water to 100ml to add the Tris hydrochloride buffer that contains 0.5% (cattle) Fibrinogen (in coagulum) to put test tube, regulate pH value to 7.4) 200 μ l, shake up, put slowly drip in the water-bath (37 ℃ ± 0.5 ℃) contain 40 units among every 1ml thrombin solution (per minute 5 μ l shake up gently while dripping) to solidifying, record consumes the volume of thrombin solution, is calculated as follows:
In the formula: the every 1g of U--contains thrombin activity unit, U/g;
C
1--the concentration of thrombin solution, μ/ml;
C
2--the concentration of need testing solution, g/m1;
V
1--consume the volume of thrombin solution, μ l;
V
2--the addition of need testing solution, μ l;
The W--sampling amount.
The amount of the thrombin of a unit of neutralization is an antithrombin activity unit.
The every 1g of this product contains antithrombin activity and is not less than 16.0U.
Fructose Diphosphate sodium is with reference to the Fructose Diphosphate sodium (C of Ministry of Public Health ministry standard (trying)
6H
11Na
3O
128H
2O) quality standard inspection.
Differentiate: it is an amount of to get this product, adds water and makes the solution that every ml contains 50mgFDP, as test sample.It is an amount of that other gets the fructose diphosphate reference substance, and water is made the solution that every ml contains 50mg, product in contrast.With two of little smart cellulose thin-layer plates (the high 20cm of bed thickness 0.5mm), the difference point sample, according to the operation down of 2005 editions two appendix thin layer chromatography items of Chinese Pharmacopoeia, developing solvent is a n-butyl alcohol: acetone: glacial acetic acid: 10% ammonia: water (35:15:20:7.5:22.5), exhibition is apart from being 18cm, the heating evaporation solvent, and spray is with 12.5% ammonium molybdate: concentrated hydrochloric acid: perchloric acid: the solution of acetone (8:3:3:86), irradiation is 10 minutes under the 365nm ultraviolet light, should show blue (to show PO
4 -3Existence); Another piece sprays with 2% aniline solution: 2% diphenylamines ethanol liquid: phosphoric acid (4:4:1) solution through 105 ℃ of heating 10 minutes, should show rufous (differentiating the existence of sugar).
The Fructose Diphosphate sodium assay:
1, reference substance solution: precision takes by weighing FDP reference substance 30mg in the 100ml measuring bottle, is dissolved in water and is diluted to scale, shakes up, and is standby.
2, need testing solution: precision takes by weighing the content an amount of (being equivalent to 30mgFDP) under the content uniformity item, puts in the 100ml measuring bottle, is dissolved in water, and is diluted to scale, filters filtrate for later use.
3, assay method: essence is got test sample liquid and each 1ml of reference substance solution, put respectively in the 10ml measuring bottle, add 8mol/L hydrochloric acid solution 5ml and 2.5% diphenylamines glacial acetic acid liquid 2ml, shake up, put on the steady rest 96 ℃ ± 1 ℃ water bath with thermostatic control heating 30 minutes, and jolting constantly, be cooled to room temperature after the taking-up rapidly, to scale, measure trap in 640nm wavelength place with 70% ethanol dilution, trap according to reference substance and test sample is calculated content, is 90.0%～110.0% of labelled amount.
On inspection, this product meets the pertinent regulations under 2005 editions two appendix capsule items of Chinese Pharmacopoeia.
This compound recipe Leech capsule of the present invention has wide range of applications, and is all applicable to following clinical symptoms through test:
(1) coronary heart disease, angina pectoris, myocardial infarction; Hyperlipemia; Pulmonary infarction; Behind artificial cardiac valve prosthesis's replacement.
(2) cerebral thrombosis, cerebral embolism, cerebral atherosclerosis; Transient ischemic attack (TIA); Vertebra-basilar artery insufficiency.
(3) thromboangiitis obliterans, thrombophlebitis, prevention of postoperative thrombosis.
(4) acute and chronic glomerulonephritis, the nephrotic syndrome, renal veins thrombosis.
(5) retinal vessel occlusion ocular fundus arteriosclerosis; Sudden deafness; Diabetes merge the treatment of various vascular lesions; Hyperglycemia, hyperlipidemia, hemorheology reach platelet activation unusually and easily cause high sticking, high poly-, the hypercoagulability of blood, cause tissue ischemia, anoxia, oxygen-derived free radicals generate to increase, then generates lipid peroxide, activates anticoagulant factor and brings out thrombosis and microangiopathies.
Claims (9)
1. compound recipe Leech capsule, it is characterized in that: this capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, each component proportionate relationship by weight is: 80～120 parts of Hirudo extracts, 80～360 parts of Fructose Diphosphate sodium, 20～50 parts of starch.
2. a kind of compound recipe Leech capsule according to claim 1, it is characterized in that: this capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, each component proportionate relationship by weight is: 90～110 parts of Hirudo extracts, 180～240 parts of Fructose Diphosphate sodium, 30～40 parts of starch.
3. a kind of compound recipe Leech capsule according to claim 1, it is characterized in that: this capsule 's content is mixed with by Hirudo extract, Fructose Diphosphate sodium and starch and forms, each component proportionate relationship by weight is: 100 parts of Hirudo extracts, 200 parts of Fructose Diphosphate sodium, 35 parts of starch.
4. the preparation method of a compound recipe Leech capsule as claimed in claim 1, it is characterized in that: this method is carried out according to the following steps:
(1) slightly carries: fresh and alive all or dry all with Hirudo, putting into homogenizer after cleaning smashes, get 5～15kg, the normal saline that at room temperature adds 2500～7500ml, stirred 20～50 minutes, and froze molten 4～8 times, 2～8 ℃ left standstill 18～24 hours, 4000～6000 rev/mins of centrifuging and taking supernatant, and the adjusting pH value is that 4～5 backs are standby;
(2) mass concentration that adds 4～6 times of precipitate quality get supernatant in step (1) after in the remaining precipitate is 40～70% ethanol, stirs 20～50 minutes, and the centrifuging and taking precipitate is standby;
(3) refining: in step (2), add the physiological saline solution precipitate in the standby precipitate, through the high efficiency chromatography gradient elution, behind the efficient reversed phase chromatographic column stepwise eluting, concentrate, degerming, filter to get filtrate standby;
(4) filtrate standby in supernatant standby in the step (1) and the step (3) is merged, after concentrating, it is stand-by promptly to get Hirudo extract;
(5) get each raw material for standby in the described ratio of claim 1, the Hirudo extract and the starch that obtain in the step (4) is even by the mixed of mass ratio 1:0.2～0.5, make wet granular, mix with Fructose Diphosphate sodium after the oven dry, the mass ratio of Hirudo extract and Fructose Diphosphate sodium is 1:1～3 again;
(6) mixture that obtains in the step (5) is pulverized and crossed 10～15 mesh sieves, dry under 40～65 ℃ of conditions, granulate, sterilization back are encapsulated, promptly get compound recipe Leech capsule finished product of the present invention after packing.
5. the preparation method of a kind of compound recipe Leech capsule according to claim 4, it is characterized in that: fresh and alive all or dry all with Hirudo in the step (1), putting into homogenizer smashes, get 10kg, at room temperature add the 5000ml normal saline, stirred 30 minutes, freeze molten 6 times, 4 ℃ left standstill 20 hours, 5000 rev/mins of centrifuging and taking supernatant, and regulating pH value is that 4.8 backs are standby.
6. the preparation method of a kind of compound recipe Leech capsule according to claim 4 is characterized in that: in the step (2), the mass concentration that adds 5 times of precipitate quality get supernatant in step (1) after in the remaining precipitate is 55% ethanol.
7. the preparation method of a kind of compound recipe Leech capsule according to claim 4, it is characterized in that: in the step (3), in step (2), add normal saline in the standby precipitate, the addition of normal saline is 4～6 times of precipitate quality, the dissolution precipitation thing, through anion-exchange column high efficiency chromatography gradient elution, behind the efficient reversed phase chromatographic column stepwise of the phenyl post eluting, again through anion-exchange column concentrate, degerming, filter to get filtrate standby.
8. the preparation method of a kind of compound recipe Leech capsule according to claim 4 is characterized in that: in the step (5), the mass ratio of Hirudo extract and starch is 1:0.35, and the mass ratio of Hirudo extract and Fructose Diphosphate sodium is 1:2.
9. the preparation method of a kind of compound recipe Leech capsule according to claim 4, it is characterized in that: in the step (6), 12 mesh sieves are pulverized and crossed to the mixture that obtains in the step (5), dry under 50 ℃ of conditions, during granulate, after 8～10 mesh sieves, the sterilization back is encapsulated, promptly gets compound recipe Leech capsule finished product of the present invention after packing.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103405501A (en) * | 2013-08-12 | 2013-11-27 | 赵磊石 | Preparation method of three-component blood-activating and stasis-dissolving capsules |
| CN104706645A (en) * | 2013-12-11 | 2015-06-17 | 武汉威立得生物医药有限公司 | Application of fructose bisphosphate in preparation of drugs for treating hepatitis C virus (HCV) |
| CN108414667A (en) * | 2018-01-19 | 2018-08-17 | 广西中医药大学附属瑞康医院 | The detection method of one seed ginseng osmanthus Yixin granule quality standard |
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| CN103405501A (en) * | 2013-08-12 | 2013-11-27 | 赵磊石 | Preparation method of three-component blood-activating and stasis-dissolving capsules |
| CN104706645A (en) * | 2013-12-11 | 2015-06-17 | 武汉威立得生物医药有限公司 | Application of fructose bisphosphate in preparation of drugs for treating hepatitis C virus (HCV) |
| CN104706645B (en) * | 2013-12-11 | 2017-08-01 | 武汉威立得生物医药有限公司 | Application of the fructose diphosphate in preventing and treating infection with hepatitis C virus medicine is prepared |
| CN108414667A (en) * | 2018-01-19 | 2018-08-17 | 广西中医药大学附属瑞康医院 | The detection method of one seed ginseng osmanthus Yixin granule quality standard |
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