CN1089248C - Medicine for curing diseases in nerve system and its preparing process - Google Patents
Medicine for curing diseases in nerve system and its preparing process Download PDFInfo
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Abstract
The present invention discloses a novel medicine for treating cranial nerve system diseases and a preparation method thereof. The medicine is prepared from main materials of cranial nerve nutrition factors and auxiliary materials of notoginseng, safflower and musk. The preparation method comprises the steps: after being homogenized, brain tissue is repeatedly frozen and dissolved; the brain tissue is processed by the acidolysis, the neutralization and the centrifugation so as to suck supernatant liquid; the separation and the purification are carried out, and biologic active components are combined; concentrated solution of the cranial nerve nutrition factors is prepared through double filtration and cold storage; then, the notoginseng, the safflower, the musk, etc., are pulverized, and are distilled in a dry way for extracting volatile components; water is used for decoction so as to extract water-soluble components; impurities are removed by concentration and alcoholysis, and sodium chloride and citrate buffer solution are used for medicine preparation and sterilization; the concentrated solution of the cranial nerve nutrition factors are added; the split charging operation and the sealing operation are carried out according to clinic requirements.
Description
The present invention relates to a kind of medicine for the treatment of nervous system disease, specifically a kind of is major ingredient with a kind of novel cranial nerve trophic factors, is the medicine of the treatment nervous system disease of adjuvant with Chinese medicine, the invention still further relates to manufacturing method for above mentioned medicine.
Nervous system disease is the disease that commander's maincenter of people breaks down, and is the common frdquently encountered disease of serious harm human health.According to the interrelated data report, China's cranial nerve diseases sickness rate accounts for 18.4 ‰ of population, and mentally retarded child's sickness rate accounts for 22.2 ‰, and the sickness rate of senile disease accounts for 10% of aging population, and the migraine sickness rate accounts for 3.5% of population.Add wound, tumor, apoplexy, the total number of persons of China's nervous system disease has more than one hundred million populations, and the trend that increases is year by year arranged.
At present, the clinical application of popular treatment nervous system disease is the cerebrolysin in the Western medicine, this is that grow up over nearly 10 years a kind of can trophic nerve, activate the medicine preferably of nerve growth, but this curative effect of medication is made slow progress, it costs an arm and a leg, and the source is difficult, can't satisfy the needs of present nervous system disease clinical treatment.
The inventor is engaged in the research of medicine for a long time, draws nutrition from motherland's medical treasure-house of vast vastness, in making every effort to bring into play, Western medicine strong point separately, accomplishes treating both the principal and secondary aspects of a disease.Medical experiment and clinical discovery for many years contain Radix Notoginseng, Flos Carthami in the Chinese patent medicine, the medicine of compositions such as Moschus is to trophic nerve, and the excitor nerve tool has certain effect.With the neurotrophic factor in they and the Western medicine, the special and bonded medicine of cranial nerve trophic factors.Can improve the therapeutic effect of the Western medicine of original treatment nervous system disease greatly,
The object of the present invention is to provide a kind of is core with the cranial nerve trophic factors, is aided with medicinal herb components, under the prerequisite of improving existing treatment nervous system disease, can reduce the cost of medicine again greatly.
The present invention also provides the method for preparing above-mentioned treatment nervous system disease medicine.
A kind of medicament for the treatment of nervous system disease of the present invention is characterized in that it is the medicament made by following raw material (below be weight ratio):
Dry cranial nerve trophic factors 0.5-3.5 Radix Notoginseng 0.1-8
Flos Carthami 0.35-20 Moschus 0.05-4
Citrate buffer agent 5-300 sodium chloride 0.045-4.
The pharmacy optimization composition of raw materials for preparing above-mentioned treatment nervous system disease is,
Dry cranial nerve trophic factors 0.5-2.5 Radix Notoginseng 0.1-5
Flos Carthami 0.35-17.5 Moschus 0.05-2.5
Citrate buffer agent 5-250 sodium chloride 0.045-2.25.
The medicament optimum feed stock prescription for preparing above-mentioned treatment nervous system disease is,
Dry cranial nerve trophic factors 2.5 Radix Notoginseng 5
Flos Carthami 17.5 Moschus 2.5
Citrate buffer agent 250 sodium chloride 2.25.
Described cranial nerve trophic factors is the cranial nerve trophic factors that is made by fresh Medulla caprae seuovis.
Described medicament is the above a dosage form of any pharmaceutics.
Described medicament is injection preferably.
The preparation method of the medicine of above-mentioned treatment nervous system disease, undertaken by following step successively:
(A) preparation of cranial nerve trophic factors
Get fresh Medulla caprae seuovis, freeze moltenly behind the homogenization repeatedly, acidolysis again, be neutralized to PH7.4, centrifugal absorption supernatant, separation and purification merges biological active component, filter membrane degerming, cold preservation;
The preparation of B Chinese patent medicine adjuvant
Get Radix Notoginseng, Flos Carthami, Moschus pulverize separately, packing, decompression dry distilling, obtain the dry distillation liquid of Radix Notoginseng, Flos Carthami, Moschus respectively after, mix, with its mixed liquor distillation, the rectification liquid cooling is hidden in rectification; Again with the medicine short, bristly hair or beard of above-mentioned dry distilling, add decocting secondary, filtration, merging filtrate, concentrate, add 2 times of amounts ethanol, stir evenly, reflux to the half an hour of boiling, be chilled to room temperature, put into refrigerator cold-storage more than 24 hours, incline get supernatant after, reclaim ethanol, after repeating above-mentioned separating out alcohol method, filter with qualitative filter paper, filtrate recycling ethanol gets the flowing soaking paste thing;
The preparation of C finished product
The Chinese medicine rectification liquid of above-mentioned cold preservation is added sodium chloride and citric acid buffer agent (PH=7), under constantly stirring, slowly add above-mentioned Chinese medicine adjuvant flowing soaking paste thing, regulate PH=7.4, add 0.3% active carbon sucking filtration, fine straining, 100 ℃ of high temperature sterilizes add the cranial nerve trophic factors of above-mentioned cold preservation after 30 minutes, mixing, and packing makes the medicine of treatment nerve systemic disease of the present invention.
Use 5 microns and the degerming of 2 microns secondary filter membranes in proper order in the concentrated solution that fresh Medulla caprae seuovis makes.
A key character of the present invention be contain abundant promotion nerve growth in the medicine of the present invention, stop blooding, invigorate blood circulation, the composition of pain relieving, short effect such as wake up: measure through the XXXXXXX of Beijing, each dosage group main component is as follows:
| Title | 5ml | 100ml | 250ml |
| Polypeptide | 0.075 | 1.5 | 3.75 |
| Aminoacid | 0.425 | 8.5 | 21.25 |
| Dencichine | 0.01 | 0.2 | 0.5 |
| Carthamus yellow II | 0.015 | 0.3 | 0.75 |
| Carthamus yellow III | 0.015 | 0.3 | 0.75 |
| Moschus | 0.005 | 0.1 | 0.25 |
| Sodium chloride | 0.045 | 0.9 | 2.25 |
The chemical characteristic of medicine of the present invention is that the biological active component by the thick product of supernatant component of the acidolysis of total homogenate process, the centrifugal acquisition of neutralization is responsive to trypsin, shows that the peptide class is a main component in this medicine.The biological active component that exists in the thick product of above-mentioned supernatant abstract elutes on the SephadexG-50 post, and elution time is similar to cytochrome C, shows that the isoelectric level of bioactive molecule is similar to cytochrome C, promptly about 10-10.5.Resulting biological active component is carried out the SDS-PAGE electrophoresis, and the situation of movement of the signal band of the bioactive substance that is obtained by the TSK-CM-3SW post is close with the standard lysozyme, thereby the macromolecule that has is about 10KD.
Medicine of the present invention is based on following drug effect principle:
1. promotion neurotrophy: the cranial nerve trophic factors is that a group belongs to the nature generation; has polypeptide to the cranial nerve specific action; it mainly acts on and is to promote neuronic differentiation (formation of aixs cylinder and dendron); keep the integrity (metabolism of specific Transmitter) of neurocyte and prevent the degeneration (protection that avoids damaging) of neurocyte.The cranial nerve trophic factors has the effect that promotes growth to the maincenter neurocyte different with peripheral nervous system, and this effect be along with many sons of this factor what and decide.Medicine of the present invention is a kind of have trophic nerve, regenerated medicine of stimulating neuronal; it can induce neuronic differentiation; keep neuronic survival, and the neuroprotective cell avoids ischemia and toxic injury, it is high degree of specificity that immunohistochemical method discloses its effect.Experiment shows, is injected by periphery, and medicine of the present invention can pass through blood brain barrier.Multinomially experiment showed, that it can reach following effect: (1) prevents that free radical from generating; (2) the vulnerable Hippocampus CA1 cone cell of protection; (3) prevent the generation of cellularity toxicity edema; (4) stablize the microcirculation of brain; (5) mortality rate of reduction acute cerebral ischemia.
2. regulate function of nervous system: electric physiology shows that medicine of the present invention has persistent electric physiological effect (secular current potential enhancement effect) to Hippocampus and cortex cell, and this electric physiological effect can be used as the foundation of judging learning process usually.Histological studies show that, medicine of the present invention can obviously promote the formation of Hippocampus taper nerve synapse.Zoopery shows that also medicine of the present invention can obviously improve the learning capacity of animal.
3. adjusting nerve metabolism: brain tissue slice and homogenate research experiment show that medicine of the present invention can improve the energy metabolism of aerobic; can improve protein synthesis in addition and improve the function of the exchanging pump in the cell plasma; these effects oppose that cerebral tissue has specificity; and do not influence the effectiveness of other organ; in addition; medicine of the present invention in vivo can obviously reduce the concentration of lactic acid in the brain; illustrate that medicine of the present invention has protective effect to ischemia or anoxybiotic accident; because the lactic acid concn in the brain reduces; oxygen-derived free radicals is reduced, and therefore neuronic mitochondrion is difficult for suffering damage.
We have carried out toxicity or dysgenic experiment to the medicine of the invention described above with animal, and the result is as follows:
1. acute toxicity testing: when using medicine of the present invention, the rat oral administration gavage is to 1200mg (pharmaceutical quantities)/Kg (Mus body weight), during mice oral administration gavage 3000mg/kg, observes in 3 days, all do not have any untoward reaction;
2. long term toxicity test: carry out vein and intramuscular injection medicine of the present invention respectively with rat, mice, rabbit and carry out long term toxicity test, dosage is 10,50,125mg/kg/ days, continuous 20 days, stopped after 1 week again continuous use 20 days, put to death animal after 60 days, get hemanalysis, biochemistry, urine sample are all normal as a result, and stomach is not seen pathological changes.Medication group body weight, brain heavy (medication 30 days, 60 days) increase fast than matched group, histopathological examination is not seen pathological changes.Rabbit 125mg/kg/ days groups find that liver transaminase (mainly being serum paddy third and glutamic oxaloacetic transaminase, GOT) raises and the pathological pathological changes of liver organization.And the rabbit of 10mg/kg/ days and 50mg/kg/ days groups is not found the toxic action to liver.And people's clinical application be 0.3-0.6mg/kg/ days (for the rabbit experimental group 1/1/417th), prove that clinical experiment is safe and reliable.
3 reproductive toxicity testings: rat in the time of conceived 6-17 days intravenous administration dosage be 5,15,45mg/kg, every day 1 time, except that 5mg/kg dosage group F1 neonatal rat body weight slightly descended, other did not have any harmful effect.In another experiment, rabbit is in the time of conceived 6-18 days, vein 5,15,45mg/kg, and medicine of the present invention does not as a result have any harmful effect to rabbit.Proof the present invention have no effect to animal and offspring, promptly do not have genotoxicity.
4. carcinogenic toxicity: medicine of the present invention has the effect that promotes neurocyte proliferation, but does not find that any one group has the carcinogenecity pathological changes to take place.
This medicine is inner preparation in nineteen ninety-five by Beijing XXXXX approval, the routine patient surplus 3 years on probation 1000 of XXXXXX and two hospitals of XXXXXX, do not wait in age 4-87 year,
Wherein: traumatic craniocerebral injury 421 examples
Other traumatic brain injury (as hemorrhage, operation) 213 examples
Cerebral infarction 197 examples
Facial paralysis 17 examples
Nerve deafness 5 examples
Senile dementia 50 examples
Migraine 98 examples
Other nervous system disease 21 examples
For curative effect of the present invention is described, elitely select following three groups, first group is experimental group, use traditional Therapeutic Method (citicoline, vitamin, hormone etc.) to add with treating in medicine 250ml/ people of the present invention/sky, second group is that the traditional Therapeutic Method of matched group 1 usefulness adds Western medicine cerebrolysin 20ml/ people/sky that is produced by XXXXX buied from Beijing XXXX pharmaceuticals with in December, 1994 (allow use by its medicine explanation maximal dose) and treats, intravenous drip, matched group 2 all use traditional Therapeutic Method to compare separately;
1. hemiplegic patient treatment contrast: this group patient is the acute injury that cerebral trauma or apoplexy cause, and the damage time, the age, the men and women half and half in 15-50 year all in 30 days, and its treatment front and back muscular strength is measured in each medication 20 days, is compared as follows:
Table 1 hemiplegic patient treatment contrast
| Group | Case | Average muscular strength before the medication | Average muscular strength after the medication | Balanced growth (level) | Treatment effective percentage % |
| Experimental group | 50 | 3.875 | 4.781 | 0.906 | 87 |
| Matched group 1 | 50 | 3.911 | 3.998 | 0.087 | 4 |
| Matched group 2 | 50 | 3.883 | 3.887 | 0.004 | 2 |
2. coma patient treatment recovery situation contrast: all select cerebral trauma or apoplexy for use and each 10 example of coma patient suddenly, age 20-60 year, the men and women all has, the begin treatment in 3 days of falling ill.Before and after 10 days, with international Glassgow stupor index scoring method, test and appraisal before and after treating:
Table 2 coma patient treatment contrast
| Group | Case | Glas (branch) before the medication | Glas after the medication (branch) | Average improve (branch) | Treatment effective percentage % |
| Experimental group | 10 | 7.8 | 14.2 | 6.4 | 90 |
| Matched group 1 | 10 | 8.1 | 11.3 | 3.2 | 40 |
| Matched group 2 | 10 | 7.6 | 8.2 | 0.6 | 10 |
3. migraine disease human therapy contrast: each organizes 20 examples, and medical history was more than 5 years, and age 30-50 year, the woman is more than the man, and the Shi Junyou that the is admitted to hospital outbreak of have a headache was treated 10 days, contrasted the transference cure number of having a headache.
The contrast of table 3 migraine disease human therapy
| Group | Case | Headache outbreak number before the medication | Transference cure number after the medication | Treatment effective percentage % |
| Experimental group | 20 | 20 | 17 | 85 |
| Matched group 1 | 20 | 20 | 7 | 35 |
| Matched group 2 | 20 | 20 | 1 | 5 |
Experiment statistics shows that medicine of the present invention has the obvious treatment effect to various nervous system disease.
Through long-term clinical observation, patient's obvious effective rate and clinical medicine dose have much relations, when dosage control at 500ml (injection)/when it is following, curative effect and dosage are directly proportional, and (consumption is DeGrain in the time of 5-20ml/ days, the effect that consumption can be observed when being 100ml/ days, when consumption during at 250-500ml/ days, effect is remarkable).When dosage surpassed 500ml/ days, curative effect was not seen and is significantly increased progressively enhancing.
Above-mentioned consumption is adult's consumption.
Embodiment
(1) preparation of cranial nerve trophic factors
1. freeze molten: with fresh Medulla caprae seuovis, about 300 grams of the every batch of goods break into homogenate with the phosphate buffer of 3 times of volumes ,-20 ℃ freezing after, under 20 ℃ of conditions, melt.More than repeat 5 times, to quicken protein cleavage.
2. acidolysis: freeze the homogenate after molten,, places 80 ℃ of water-baths heating, splash into the hydrochloric acid of 5N in the heating process simultaneously gradually, do not cutoff and give vibrations stirring 3-4 hour, acidolysis with 2 times of phosphate buffer dilutions;
3. neutralization: with the acidolysis diluent, splash into the coarse adjustment of 1N sodium hydroxide earlier, it is neutralized to PH7.35 near the sodium hydroxide of reuse 0.1N after the scope.Neutralizer is placed the natural cooling that spends the night.
4. centrifugal: that refrigerative neutralizer centrifugal (15000rpm, 10 minutes) is drawn supernatant;
5. separation and purification: the post gel with Sephadex G-100 filters the post ultrafiltration of reuse Sephadex G-50 earlier.In the monitoring of A280 place, merge biological active component with spectrophotometer;
6. degerming: in the degerming jar, successively use the filter membrane degerming 2 times of 0.5 micron and 0.2 micron, use 150ml (about 0.2 kilogram) the cranial nerve trophic factors concentrated solution that method obtains, be placed on 0 ℃ and preserve down.Necessity is it to be prepared into dry powder.
(2) preparation of Chinese medicine adjuvant
Get 0.4 kilogram of Radix Notoginseng; 1.4 kilograms on Flos Carthami; 0.2 kilogram in Moschus; 20 kilograms of citrate buffer agents; 0.20 kilogram in sodium chloride;
Preparation process is as follows:
1. volatile component is extracted in the steam dry distilling:
Get Radix Notoginseng, Flos Carthami, Moschus pulverize separately, packing, the decompression dry distilling, obtain the dry distillation liquid of Radix Notoginseng, Flos Carthami, Moschus respectively after, mix, with its mixed liquor distillation, rectification (rectification liquid be dry distillation liquid 1/3), cold preservation;
2. decocting extracts water soluble ingredient: with the medicinal residues of above-mentioned dry distilling, add decocting secondary, filtration, merging filtrate, be concentrated into and last equivalent.
3. precipitate with ethanol is removed impurity: in water drug-decocting concentrating liquid, add qdx ethanol, stir evenly, reflux to the half an hour of boiling, cool to room temperature, put into refrigerator cold-storage more than 24 hours, incline get supernatant after, reclaim ethanol to medicinal liquid and 2,3 equivalent, after repeating above-mentioned separating out alcohol method, filter with qualitative filter paper, filtrate recycling ethanol gets the flowing soaking paste thing;
(3) dosing
The rectification liquid of above-mentioned cold preservation is added sodium chloride and citric acid buffer agent, under constantly stirring, slowly add above-mentioned flowing soaking paste thing and regulate PH=7.4, add 0.3% active carbon sucking filtration, fine straining, after 100 ℃ of high temperature, the sterilization in 30 minutes, add the cranial nerve trophic factors that the Medulla caprae seuovis of above-mentioned cold preservation makes, packing, seal, make 1000 of every 20ml medicines of the present invention.
Claims (10)
1. medicine for the treatment of nervous system disease is characterized in that it is the medicament of being made by following raw material:
Dry cranial nerve trophic factors 0.5-3.5 Radix Notoginseng 0.1-8
Flos Carthami 0.35-2 0 Moschus 0.05-4
Citrate buffer agent 5-300 sodium chloride 0.045-4.
2. according to a kind of medicine for the treatment of nervous system disease of claim 1, it is characterized in that it is the medicament of being made by following raw material:
Dry cranial nerve trophic factors 0.5-2.5 Radix Notoginseng 0.1-5
Flos Carthami 0.35-17.5 Moschus 0.05-2.5
Citrate buffer agent 5-250 sodium chloride 0.045-2.25.
3. according to a kind of medicine for the treatment of nervous system disease of claim 1 or 2, it is characterized in that it is the medicament of being made by following raw material:
Dry cranial nerve trophic factors 2.5 Radix Notoginseng 5
Flos Carthami 17.5 Moschus 2.5
Citrate buffer agent 250 sodium chloride 2.25.
4. according to the medicine of claim 1,2 or 3 treatment nervous system disease, it is characterized in that described cranial nerve trophic factors is the cranial nerve trophic factors that is made by fresh Medulla caprae seuovis.
5. according to the medicine of claim 1,2 or 3 treatment nervous system disease, it is characterized in that described medicament is the above a dosage form of any pharmaceutics.
6. the medicine of treatment nervous system disease according to claim 5 is characterized in that described medicament is an injection.
7. the preparation method of the medicine of any treatment nervous system disease that requires according to aforesaid right, undertaken by following step successively:
The preparation of A cranial nerve trophic factors
Get fresh Medulla caprae seuovis, freeze moltenly behind the homogenization repeatedly, acidolysis again, be neutralized to PH7.4, centrifugal absorption supernatant, separation and purification merges biological active component, filter membrane degerming, cold preservation;
The preparation of B Chinese patent medicine adjuvant
Get Radix Notoginseng, Flos Carthami, Moschus pulverize separately, packing, decompression dry distilling, obtain the dry distillation liquid of Radix Notoginseng, Flos Carthami, Moschus respectively after, mix, with its mixed liquor distillation, the rectification liquid cooling is hidden in rectification; Again with the medicinal residues of above-mentioned dry distilling, add decocting secondary, filtration, merging filtrate, concentrate, add 2 times of amounts ethanol, stir evenly, reflux to the half an hour of boiling, cool to room temperature, put into refrigerator cold-storage more than 24 hours, incline get supernatant after, reclaim ethanol, after repeating above-mentioned separating out alcohol method, filter with qualitative filter paper, filtrate recycling ethanol gets the flowing soaking paste thing;
The preparation of C finished product
The Chinese medicine rectification liquid of above-mentioned cold preservation is added sodium chloride and citric acid buffer agent (PH=7), under constantly stirring, slowly add above-mentioned Chinese medicine adjuvant flowing soaking paste thing, regulate PH=7.4, add 0.3% active carbon sucking filtration, fine straining, 100 ℃ of high temperature sterilizes add the cranial nerve trophic factors of above-mentioned cold preservation after 30 minutes, mixing, and packing makes the medicine of treatment nerve systemic disease of the present invention.
8. according to the preparation method of the medicine of the treatment nervous system disease of claim 7, it is characterized in that the concentrated solution that fresh Medulla caprae seuovis makes uses 5 microns and the degerming of 2 microns filter membrane secondaries in proper order.
9. the method for preparing treatment nervous system disease medicine according to any of claim 7 or 8 is characterized in that described medicament is the above a dosage form of any pharmaceutics.
10. the method for the medicine of preparation treatment nervous system disease according to claim 9 is characterized in that described medicament is an injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN99125296A CN1089248C (en) | 1999-12-01 | 1999-12-01 | Medicine for curing diseases in nerve system and its preparing process |
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|---|---|---|---|
| CN99125296A CN1089248C (en) | 1999-12-01 | 1999-12-01 | Medicine for curing diseases in nerve system and its preparing process |
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| CN1089248C true CN1089248C (en) | 2002-08-21 |
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| Title |
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| 河南中医,1983,(4) 1983.1.1 孙会文，通窍活血汤治验举隅 * |
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