CN1264522C - Medicinal composition, its preparation method and its use - Google Patents
Medicinal composition, its preparation method and its use Download PDFInfo
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- CN1264522C CN1264522C CNB200410070499XA CN200410070499A CN1264522C CN 1264522 C CN1264522 C CN 1264522C CN B200410070499X A CNB200410070499X A CN B200410070499XA CN 200410070499 A CN200410070499 A CN 200410070499A CN 1264522 C CN1264522 C CN 1264522C
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Abstract
The invention discloses a medicinal composition containing weinaolutong (7, 3', 4'-troxerutin) obtained by hydroxyethylating eldrin and brain extract which is extracted form brain tissue of mammalian except human. The medicinal composition contains 1 to 1000 parts of weinaolutong, by weight, and the weight of the weinaolutong in the medicinal composition is 0.1 to 200 times bigger than total nitrogen content in the brain extract. The invention also discloses preparation method and use of the medicinal composition. The medicinal composition can restrain platelet agglutination thereby preventing thrombosis, and can regulate and improve brain supersession, and is used for treating acute and chronic cerebrovascular disease and sequela such as brain dysfunctional caused by craniocerebral trauma and cerebrovascular disease; and can also be used for treating occlusive syndrome, arteriosclerosis, thrombosis phlebitis, capillary bleeding and dropsy caused by elevation of vascular permeability.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, Its Preparation Method And Use, specifically, relate to a kind of pharmaceutical composition, its preparation method and in the purposes of sequela medicines such as preparation treatment acute and chronic cerebrovascular disease and caused disordered brain function thereof by brain extract that extracts in the mammal cerebral tissue except that the people and troxerutin.
Background technology
Troxerutin (having another name called troxerutin) is rutin and the water-soluble flavone compounds that obtains semi-synthetic through hydroxyethylation, for with troxerutin (7,3 ', 4 '-troxerutin) being the mixture of master's hydroxyethyl rutin, the general medicinal anhydride of pressing calculates, and contains troxerutin (C
33H
42O
19) must not be less than 80.0% (injection) and 60.0% (pro ore).Troxerutin can suppress hematoblastic gathering, prevents thrombotic effect.The blood vessel injury that can cause medmain, Kallidin I simultaneously increases the resistance of blood capillary, reduces the permeability of blood capillary, can prevent the edema that vascular permeability raises and causes.
The clinical medical value of troxerutin has: be applicable to syndrome before hemiplegia that obliterated cerebral vascular disease causes, aphasia, the coronary heart disease infarction, central retinitis, thrombophlebitis, vascular permeability the raise edema, lymphedema, burn and the traumatic edema that cause, arteriosclerosis etc.
As one of component, constitute compound recipe with troxerutin, relevant patent also has open.Such as, application number 93107252.2 discloses a kind of compound henbane seed injection to artery or vein and preparation method thereof, and this injection of every 10ml contains hydrochloric acid mountain gelsemium henbane alkali 30-80mg, scopolamine hydrobromide 0.3-1.5mg, troxerutin 0.1-0.4g, glucose 200-400mg.Its preparation method is that to mix, bottle, seal, sterilize, inspect by random samples qualified back successively by the order of troxerutin-hydrochloric acid mountain gelsemium henbane alkali-scopolamine hydrobromide-glucose standby.
Application number 95109431.9 discloses a kind of compound recipe Naomaitong injection for cerebral angiopathy water formulation that is mixed, be characterized in: Radix Salviae Miltiorrhizae 100-300 part, troxerutin 5-15 part, citicoline 5-10 part, coenzyme A 1-2 part, 0.4 part of adenosine triphosphate, water 240-770 part, this medicine has the effect that suppresses erythrocyte and platelet aggregation, can prevent and treat thrombosis, can prevent and treat cerebral edema, promote neovascularity to generate, can prevent and treat senile dementia, can treat brain arteries and veins angiopathy.
Above-mentioned patent does not all relate to troxerutin and the assembly of animal brain extract, prepares new medicine.
Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical composition, this pharmaceutical composition is formed by brain extract that extracts in the mammal cerebral tissue except that the people and troxerutin assembly.
Another object of the present invention is to provide this preparation of drug combination method.
A further object of the present invention provides above-mentioned composition at preparation treatment acute and chronic cerebrovascular disease and by the purposes of sequela medicines such as cerebrovascular disease, the caused disordered brain function of cerebral trauma.
The invention still further relates to the purposes of pharmaceutical composition in the inaccessible syndrome of preparation treatment, arteriosclerosis, thrombophlebitis, capillary hemorrhage and vascular permeability raise the medicines such as edema that cause.
A kind of pharmaceutical composition of the present invention, wherein contain animal brain's extracting solution, contain a large amount of active polypeptide, several amino acids etc. in the brain tissue extract, the active polypeptide that contains, aminoacid are controlled when the ultrafiltration by the ultrafilter membrane of molecular cut off 5000-10000.
Pharmaceutical composition of the present invention, it is characterized in that containing the troxerutin (7 that rutin obtains through hydroxyethylation, 3 ', 4 '-troxerutin) with by the brain extract that extracts in the mammal cerebral tissue except that the people, containing troxerutin in the pharmaceutical composition is the 1-1000 weight portion, described weight portion can be the known content of field of medicaments such as μ g, mg, g, and wherein the weight ratio of total nitrogen content is 0.1～200 in troxerutin and the brain extract.
Wherein in the preferred pharmaceutical compositions in troxerutin and the brain extract weight ratio of total nitrogen content be 10-100; This weight ratio is 70-90 more preferably; Most preferably be 80.
Mammal cerebral tissue except that the people of the present invention is preferably the cerebral tissue of pig, Canis familiaris L., cattle, sheep, deer, horse or rabbit.
Consider the preferred pig brain tissue of above-mentioned mammal cerebral tissue from factors such as production cost, production technology, constant product quality, clinical efficacies.
Preparation of drug combination method of the present invention comprises that the preparation of brain extract and brain extract and troxerutin are mixed in proportion, and wherein the weight ratio of total nitrogen content is 0.1～200 in troxerutin and the brain extract, makes finished product preparation through post processing then.Wherein the preparation process of brain extract is: the animal brain of getting fresh and healthy, add the homogenate of 0.5-2.5 times of weight water for injection, be heated to 80-95 ℃, kept 15-30 minute, be cooled to hydrolysis temperature, be adjusted to the enzymolysis pH value, the proteolytic enzyme that adds brain weight 0.1-1.5%, carry out primary enzymolysis or secondary enzymolysis, primary enzymolysis liquid or secondary enzymolysis liquid, are handled through centrifugal filtration after 8-24 hour 4-8 ℃ of placement, and filtrate is the ultrafilter membrane ultrafiltration of 5000-10000 with molecular cut off, ultrafiltrate is a brain extract, and its total nitrogen content is 0.1～10mg/ml.
Described primary enzymolysis is behind the proteolytic enzyme that adds brain weight 0.1-1.5%, keeps 2-20 hour at this proteolytic enzyme hydrolysis temperature, keeps the enzymolysis pH value, is heated to 80-95 ℃ and kept 15-30 minute then, primary enzymolysis liquid.
Described proteolytic enzyme preferably uses trypsin, and it is 35-50 ℃ that enzymolysis is fit to temperature, and it is 7.5-8.5 that enzymolysis is fit to pH value, and the enzymolysis pH value is preferably 7.8～8.2, and hydrolysis temperature is preferably 37～42 ℃; For keeping temperature stabilization, can take the method for interlayer water bath heat preservation.
Described secondary enzymolysis process is adjusted to the enzymolysis pH value for primary enzymolysis liquid is cooled to hydrolysis temperature, adds the proteolytic enzyme of brain weight 0.1-1.5%, enzymolysis 2-20 hour, keep the enzymolysis pH value, be heated to 80-95 ℃ then and kept 15-30 minute, get secondary enzymolysis liquid.
Described proteolytic enzyme preferably uses pepsin, and hydrolysis temperature is 35-50 ℃, and hydrolysis temperature is preferably 37～42 ℃, and the enzymolysis pH value is 2.5-3.5, and the enzymolysis pH value is preferably 2.5-3.2.
Described hydrolysis temperature is the operating temperature of biologically active of the protease correspondence of above-mentioned use, and under this temperature, the protease of use has normal biological activity.
Described enzymolysis pH value is the environment pH value that is fit to employed protease, and under this pH value, the protease of use has normal biological activity.
Centrifugal filtration after the described primary enzymolysis is treated to: centrifugal back separation of supernatant, and with supernatant liquid filtering, the filtrate adjust pH is 3.5-4.5, be heated to 80-95 ℃, kept 15-30 minute, placed 8-24 hour at 4-8 ℃, centrifugal back separation of supernatant, with supernatant liquid filtering, the filtrate adjust pH is 6.5-7.5, is heated to 80-95 ℃, kept 15-30 minute, placed 8-24 hour at 4-8 ℃, centrifugal then, supernatant gets filtrate after filtration.
Centrifugal filtration after the described secondary enzymolysis is treated to: centrifugal back separation of supernatant, and with supernatant liquid filtering, the filtrate adjust pH is 8.0-10.0, be heated to 80-95 ℃, kept 15-30 minute, placed 8-24 hour at 4-8 ℃, centrifugal back separation of supernatant, with supernatant liquid filtering, the filtrate adjust pH is 6.5-7.5, is heated to 80-95 ℃, kept 15-30 minute, placed 8-24 hour at 4-8 ℃, centrifugal then, supernatant gets filtrate after filtration.
Described centrifugal condition is 4000 rev/mins, and centrifugation time is 15-30 minute.
Describedly be filtered into paper pulp filtering general in the prior art or the clarification plate filters.
The said process adjust pH uses hydrochloric acid and/or sodium hydroxide.
Described proteolytic enzyme is the proteolytic enzyme that uses in the prior aries such as trypsin, pepsin, papain, bromelain, neutral protease, and occupation mode can be single use, also can be successively to use different enzymes; Preferred trypsin or the pepsin of using.The pepsin regular size is 1: 3000-10000, trypsin regular size are 1: 250, and for making production technology of the present invention, constant product quality, the enzyme of use should be as far as possible provided by fixing manufacturer.
Above-mentioned ultrafilter membrane is preferably the ultrafilter membrane that molecular cut off is 6000-10000, and more preferably molecular cut off is 8000 ultrafilter membrane.The ultrafilter membrane that uses is the commercially available prod, and its manufacturer should be the production unit of industry approval, and the filter membrane model of use and size can be determined according to concrete volume of production, the ultrafilter size selected for use.
The dosage form of above-mentioned finished product preparation is an acceptable forms on the pharmaceutics, such as tablet, capsule, granule, oral liquid, small-volume injection, bulk capacity injection or lyophilized injectable powder etc., be preferably small-volume injection, bulk capacity injection or lyophilized injectable powder, most preferably be small-volume injection.Therefore, described post processing can be to carry out according to the conventional method of acceptable forms on the preparation pharmaceutics.
Brain extract after the secondary enzymolysis of the present invention contains polypeptide and free amino acid, meets national drug standards Cerebrolysin Vial quality standard.The every gram of Cerebrolysin Vial (for oral use) contains total nitrogen and should be 80-100mg behind the brain extract concentrate drying after the secondary enzymolysis of the present invention, meets Cerebrolysin Vial (for oral use) national drug standards; Brain extract after the secondary enzymolysis of the present invention (injection, aqueous solution) dilution or concentrate after can be used for preparing brain protein hydrolysate injection, and meet the national drug standards.Cerebrolysin Vial is the peculiar peptidergic nerve nutrient of a kind of brain; can act on nervus centralis in many ways, regulate and improve neuronic metabolism, promote the formation of synapse; induce neuronic differentiation, and further neuroprotective cell is avoided the infringement of various ischemias and neurotoxin.Can pass through blood brain barrier, promote the synthetic of brain internal protein, influence respiratory chain, have the protective capability of anti-hypoxia, improve the metabolism of brain self-energy, but other hormone systems of activated adenyl cyclase and catalysis provide neurotransmitter, peptide hormone and coenzyme precursors.Can be used for craniocerebral trauma, apoplexy sequela is concentrated the doing well,improving of obstacle with hypomnesis and attention.Brain insufficiency there is the auxiliary improvement effect, also is used for potein deficiency, patient neurasthenia and the case of general protein digestibility malabsorption.
Pharmaceutical composition of the present invention can be applicable to prepare the purposes of acute and chronic cerebrovascular disease medicament aspects such as treatment cerebral thrombosis, cerebral embolism, brain spasm, can be used for treating craniocerebral trauma and cerebrovascular disease (incomplete brain blood supply, cerebral infarction) and cause sequela such as disordered brain function, and as raise the application in the medicines such as edema that cause of treatment inaccessible syndrome, arteriosclerosis, thrombophlebitis, capillary hemorrhage and vascular permeability.
Research worker of the present invention is tested discovery in a large number, and when troxerutin weight in this pharmaceutical composition is in the brain extract during 80 times of total nitrogen content, the synergism of the two is best, is more conducive to absorption by human body and utilization.
The present invention most preferably specification of medicine composition injection is:
2ml:80mg (troxerutin): 1mg (total nitrogen);
5ml:200mg (troxerutin): 2.5mg (total nitrogen);
10ml:400mg (troxerutin): 5mg (total nitrogen);
Intramuscular injection: a 2～4ml, 2 times on the one
Intravenous drip: a 10ml, once-a-day, use with 250～500ml normal saline or 5% glucose injection dilution back.20 is a course of treatment, available 1～3 course of treatment, 3～7 days at interval per course of treatment.
Pharmaceutical composition of the present invention contains the active substance of the disordered brain function sequela for the treatment of cerebrovascular disease and causing, this active matter mass-energy is regulated and is improved the brain metabolism, adopt the synergism of troxerutin and brain extract active substance, reached best clinical effectiveness.
This pharmaceutical composition has been brought into play the synergism of the two by the organic assembling of brain extract and troxerutin, is more conducive to effective treatment of cerebrovascular disease and the improvement of the sequela that caused by cerebrovascular disease.
Pharmaceutical composition of the present invention contains the active substance of the disordered brain function sequela for the treatment of cerebrovascular disease and causing, comprises a large amount of active polypeptide and the several amino acids that contain in troxerutin, the brain extract.Troxerutin can suppress hematoblastic gathering, prevents thrombotic effect.The blood vessel injury that can cause medmain, Kallidin I simultaneously increases the resistance of blood capillary, reduces the permeability of blood capillary, can prevent the edema that vascular permeability raises and causes.The contained a large amount of active polypeptide of brain extract, several amino acids etc. can see through blood brain barrier; act on nervus centralis in a variety of forms; adjust and improve the neuron metabolism; and influence its respiratory chain; have activation, improve the activity of neurotransmitter and enzyme in the brain, the neuroprotective cell is avoided the infringement of various ischemias and neurotoxin.Can increase the utilization of cerebral tissue, improve the brain cell anaerobic condition, to the protective effect of anoxybiotic cerebral tissue tool glucose.Can be applicable to prepare the purposes of acute and chronic cerebrovascular disease medicament aspects such as treatment cerebral thrombosis, cerebral embolism, brain spasm, can be used for treating craniocerebral trauma and cerebrovascular disease (incomplete brain blood supply, cerebral infarction) and cause sequela such as disordered brain function, and as raise the application in the medicines such as edema that cause of treatment inaccessible syndrome, arteriosclerosis, thrombophlebitis, capillary hemorrhage and vascular permeability.
Description of drawings
Fig. 1 is treatment group and the comparison of matched group clinical efficacy in the comparative example 3
Fig. 2 is treatment group and matched group neurologic impairment integration (X ± S) relatively in the comparative example 3
The specific embodiment
Embodiment 1
Get fresh and healthy Medulla sus domestica 10kg, remove impurity such as fascia, wash with water for injection, add 10L water for injection, homogenate is heated 80 ℃, kept 15 minutes, and be cooled to 42 ℃, regulate pH value 7.5, add 45g trypsin U.S. DIFCO company, specification: 500g) 42 ℃ of enzymolysis 3 hours, control pH value 8.5 in the enzymolysis process, take out, be heated to 80 ℃, kept 20 minutes, get primary enzymolysis liquid;
4 ℃ of placements are centrifugal after 24 hours, and centrifugal condition is 4000 rev/mins, and centrifugation time is 15 minutes, paper pulp filtering, supernatant adjust pH 3.5 heats 95 ℃, kept 20 minutes, 4 ℃ of placements are centrifugal after 12 hours, and centrifugal condition is 4000 rev/mins, centrifugation time is 20 minutes, paper pulp filtering, filtrate adjust pH 6.5, be heated to 90 ℃, kept 15 minutes, place after 8 hours centrifugal for 8 ℃, centrifugal condition is 4000 commentaries on classics parts, and centrifugation time is 20 minutes, gets filtrate; Filtrate is 6000 ultrafilter membrane (U.S. millipore company, standard ultrafiltration system) ultrafiltration with molecular cut off, and ultrafiltrate is brain extract, and wherein total nitrogen content is 4mg/ml.
Take by weighing the pure product 80g of injection troxerutin, can be made into the 2000ml medicinal liquid, finally make 1000 of little molten amount injections (specification is 2ml:80mg troxerutin and 1mg total nitrogen) with the 250ml brain extract.The water for injection of getting dosing amount about 40% is in dense preparing tank, add troxerutin and be stirred well to dissolving fully, the activity that adds total dose volume 0.05% stirs boiled 15 minutes, and fluid temperature is reduced to 40～50 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, in dilute preparing tank, drop into brain extract, add water to the dosing amount, regulate pH value 6.8～7.0, medicinal liquid after filtration behind the system filtration embedding in the 2ml ampoule, sterilization promptly gets small-volume injection.
Embodiment 2
Get fresh and healthy Medulla sus domestica 10kg, remove impurity such as fascia, wash with water for injection, add 10L water for injection, pH value 8.2 is regulated in homogenate, heat 80 ℃, kept 15 minutes, be cooled to 42 ℃, add 80g trypsin U.S. DIFCO company, specification: 500g) 42 ℃ of enzymolysis 10 hours, control pH value 8.2 in the enzymolysis process, take out, be heated to 80 ℃, kept 20 minutes, get primary enzymolysis liquid;
Primary enzymolysis liquid is cooled to 44 ℃, and regulating pH value is 2.5, adds 50g pepsin (the grand chemical reagent company limited that reaches of Xiamen star; 1: 10000; Specification: 100g), enzymolysis 10 hours, process pH value is controlled to be 2.5, is heated to 90 ℃ then and keeps 20 minutes, obtains secondary enzymolysis liquid;
With 4000 rev/mins speed centrifugal 30 minutes, supernatant to be clarified plate filter, the filtrate adjust pH is for g.0, be heated to 95 ℃, kept 15 minutes, and placed 20 hours at 6 ℃, identical centrifugation is separated supernatant, filter, the filtrate adjust pH is 7.3, is heated to 85 ℃, keeps 25 minutes, placed 15 hours at 6 ℃ then, same way as is centrifugal, filter to get filtrate; Filtrate is 10000 ultrafilter membrane (U.S. millipore company, standard ultrafiltration system) ultrafiltration with molecular cut off, and ultrafiltrate is brain extract, and wherein total nitrogen content is 6mg/ml.
Take by weighing the pure product 60g of injection troxerutin, can be made into the 2000ml medicinal liquid, finally make 1000 of little molten amount injections (specification is 2ml:60g troxerutin and 1.5mg total nitrogen) with the 250ml brain extract.The water for injection of getting dosing amount about 40% is in dense preparing tank, add troxerutin and be stirred well to dissolving fully, the activity that adds total dose volume 0.05% stirs boiled 15 minutes, and fluid temperature is reduced to 40～50 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, in dilute preparing tank, drop into brain extract, add water to the dosing amount, regulate pH value 7.1～7.3, medicinal liquid after filtration behind the system filtration embedding in the 2ml ampoule, sterilization promptly gets small-volume injection.
Embodiment 3
Get fresh and healthy Medulla Bovis seu Bubali 10kg, remove impurity such as fascia, wash with water for injection, add 25L water for injection, pH value 9.0 is regulated in homogenate, heat 95 ℃, kept 30 minutes, be cooled to 38 ℃, add the 150g trypsin, be incubated 4 hours, control pH value 8.0 is heated to 85 ℃ then in the enzymolysis process, kept 30 minutes, and got primary enzymolysis liquid;
Placed 8 hours for 8 ℃, centrifugal, centrifugal condition is 4000 rev/mins, and centrifugation time is 20 minutes, the supernatant paper pulp filtering, filtrate adjust pH 4.0 heats 80 ℃, keeps 30 minutes, placed 12 hours for 5 ℃, centrifugal, centrifugal condition is 4000 rev/mins, and centrifugation time is 30 minutes, supernatant liquid filtering, filtrate adjust pH 7.0 is heated to 95 ℃, kept 30 minutes, 7 ℃ of placements are centrifugal after 18 hours, and centrifugal condition is 4000 rev/mins, centrifugation time is 30 minutes, and supernatant liquid filtering gets filtrate; Filtrate is 8000 ultrafilter membrane ultrafiltration with molecular cut off, and ultrafiltrate is brain extract, and its total nitrogen content is 1.4mg/mL.
Take by weighing the pure product 100g of injection troxerutin, can be made into the 2000ml medicinal liquid, finally make 1000 of little molten amount injections (specification is 2ml:100mg troxerutin and 0.7mg total nitrogen) with the 500ml brain extract.The water for injection of getting dosing amount about 40% is in dense preparing tank, add troxerutin and be stirred well to dissolving fully, the activity that adds total dose volume 0.05% stirs boiled 15 minutes, and fluid temperature is reduced to 40～50 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, in dilute preparing tank, drop into brain extract, add water to the dosing amount, regulate pH value 7.0～7.2, medicinal liquid after filtration behind the system filtration embedding in the 2ml ampoule, sterilization promptly gets small-volume injection.
Embodiment 4
According to the operation of embodiment 3, obtain primary enzymolysis liquid.
Primary enzymolysis liquid is cooled to 45 ℃, and regulating pH value is 3.5, adds 100g pepsin (the grand chemical reagent company limited that reaches of Xiamen star; 1: 10000; Specification: 100g), enzymolysis 2 hours, process pH value is controlled to be 3.2, is heated to 95 ℃ then and keeps 15 minutes, obtains secondary enzymolysis liquid;
With centrifugal 30 minutes of 4000 speed of changeing part, supernatant to be clarified plate filter, the filtrate adjust pH is 10.0, be heated to 80 ℃, kept 30 minutes, and placed 8 hours at 4 ℃, identical centrifugation is separated supernatant, filter, the filtrate adjust pH is 7.0, is heated to 90 ℃, keeps 30 minutes, placed 15 hours at 6 ℃ then, same way as is centrifugal, filter to get filtrate; Filtrate is 8000 ultrafilter membrane (U.S. millipore company, standard ultrafiltration system) ultrafiltration with molecular cut off, and ultrafiltrate is brain extract, and wherein total nitrogen content is 2.5mg/ml.
Operation according to embodiment 3 makes injection.
Get fresh and healthy brain of Cervus nippon Temminck (C. elaphus L.) 10kg, remove impurity such as fascia, with the water for injection washing, add 5L water for injection, pH value to 8.5 is regulated in homogenate, heats 85 ℃, keeps 20 minutes, is cooled to 45 ℃, adds 40g pepsin (the grand chemical reagent company limited that reaches of Xiamen star; 1:10000; Specification: 100g), 45 ℃ of enzymolysis 20 hours, control pH value 2.5 was heated to 95 ℃ then in the enzymolysis process, keeps 15 minutes, obtains primary enzymolysis liquid;
Place after 10 hours centrifugal for 7 ℃, centrifugal condition is 4000 rev/mins, centrifugation time is 30 minutes, and supernatant clarification plate filters filtrate adjust pH 3.5, be heated to 80 ℃, kept 30 minutes, 8 ℃ of placements are centrifugal after 8 hours, centrifugal, the filtration of same way as, filtrate adjust pH 7.3, be heated to 85 ℃, kept 15 minutes, place after 24 hours for 4 ℃, centrifugal, the filtration of same way as, get filtrate, filtrate is 8000 ultrafilter membrane (U.S. millipore company, standard ultrafiltration system) ultrafiltration with molecular cut off, ultrafiltrate is brain extract, and wherein total nitrogen content is 7mg/ml.
Take by weighing the pure product 100g of injection troxerutin, can be made into the 2000ml medicinal liquid, finally make 1000 of little molten amount injections (specification is 2ml:100mg troxerutin and 3.5mg total nitrogen) with the 500ml brain extract.The water for injection of getting dosing amount about 40% is in dense preparing tank, add troxerutin and be stirred well to dissolving fully, the activity that adds total dose volume 0.05% stirs boiled 15 minutes, and fluid temperature is reduced to 40～50 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, in dilute preparing tank, drop into brain extract, add water to the dosing amount, regulate pH value 7.0～7.2, medicinal liquid after filtration behind the system filtration embedding in the 2ml ampoule, sterilization promptly gets small-volume injection.
Embodiment 6
According to the operation of embodiment 5, obtain primary enzymolysis liquid.
Primary enzymolysis liquid is cooled to 50 ℃, and regulating pH value is 7.8, adds 80g trypsin U.S. DIFCO company, specification: 500g), enzymolysis 10 hours, process pH value is controlled to be 7.8, is heated to 90 ℃ then and keeps 20 minutes, obtains secondary enzymolysis liquid;
With centrifugal 30 minutes of 4000 speed of changeing part, supernatant to be clarified plate filter, the filtrate adjust pH is 9.0, be heated to 85 ℃, kept 25 minutes, and placed 10 hours at 8 ℃, identical centrifugation is separated supernatant, filter, the filtrate adjust pH is 7.2, is heated to 80 ℃, keeps 20 minutes, placed 25 hours at 6 ℃ then, same way as is centrifugal, filter to get filtrate; Filtrate is 6000 ultrafilter membrane (U.S. millipore company, standard ultrafiltration system) ultrafiltration with molecular cut off, and ultrafiltrate is brain extract, and wherein total nitrogen content is 8.0mg/ml.
Operation according to embodiment 5 makes injection.
Get fresh and healthy Medulla sus domestica 10kg, add the homogenate of 15I water for injection, standby with reference to embodiment 1 preparation brain extract, wherein total nitrogen content is 2.4mg/ml.
Take by weighing the pure product 80g of injection troxerutin, can be made into the 2000ml medicinal liquid, finally make 400 of little molten amount injections (specification is 5ml:200mg troxerutin and 1.5mg total nitrogen) with the 250ml brain extract.The water for injection of getting dosing amount about 40% is in dense preparing tank, add troxerutin and be stirred well to dissolving fully, the activity that adds total dose volume 0.05% stirs boiled 15 minutes, and fluid temperature is reduced to 40～50 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, in dilute preparing tank, drop into brain extract, add water to the dosing amount, regulate pH value 6.8～7.0, medicinal liquid after filtration behind the system filtration embedding in the 2ml ampoule, sterilization promptly gets small-volume injection.
Embodiment 8
According to the operation among the embodiment 1, the preparation brain extract.
Take by weighing the pure product 80g of injection troxerutin, can be made into the 2000ml medicinal liquid, finally make 200 of little molten amount injections (specification is 10ml:400mg troxerutin and 20mg total nitrogen) with the 1000ml brain extract.The water for injection of getting dosing amount about 30% is in dense preparing tank, add troxerutin and be stirred well to dissolving fully, the activity that adds total dose volume 0.05% stirs boiled 15 minutes, and fluid temperature is reduced to 40～50 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, in dilute preparing tank, drop into brain extract, add water to the dosing amount, regulate pH value 6.8～7.0, medicinal liquid after filtration behind the system filtration embedding in the 2ml ampoule, sterilization promptly gets small-volume injection.
Embodiment 9～14
With reference to embodiment 1～6, brain extract and troxerutin carry out proportioning, by known method, make granule, and dry back tabletting gets tablet.
With reference to embodiment 1～5, brain extract and troxerutin carry out proportioning, add suitable excipient (as Dextran 40, mannitol etc.), carry out the degerming fill, and by known method, the freeze-dried powder product is made in lyophilization.
Embodiment 21～26
With reference to embodiment 1～5, brain extract is put in the dilute preparing tank; In dense preparing tank, drop into the sodium chloride of troxerutin and 0.85% final preparation cumulative volume, add 0.4 ‰ active carbons and boil decarbonization filtering, after the cooling, with medical filtration to dilute preparing tank, add water for injection to the dosing amount in dilute preparing tank, transferring PH is 6.8～7.0, filters.Embedding is in infusion bottle, and 100 ℃ of flowing steam sterilizations 45 minutes promptly get infusion products.
Experimental example 1
This experimental example is the most preferably detection of the injection inspection item of pharmaceutical composition small-volume injection (every ml contains 40mg troxerutin and 0.5g total nitrogen) appearance character, pH value, protein, pyrogen, undue toxicity and other regulation of the present invention.
√ this product is yellow or sundown clear liquid.
√ measures according to two appendix VI of Chinese Pharmacopoeia version in 2000 H, and this product pH value should be 5.5-7.5.
√ gets this product 2ml, adds 20% sulfosalicylic acid solution 2ml, and solution should be clarified.
√ pyrogen test: get this product, be diluted to the solution that contains troxerutin 20mg among every ml, check (two appendix XI of Chinese Pharmacopoeia version in 2000 D) in accordance with the law with sodium chloride injection.Dosage should be up to specification by the every kg injection of rabbit body weight this product 2ml.
The √ undue toxicity measures: get this product, be diluted to the solution that contains troxerutin 20mg among every ml with sodium chloride injection, check (two appendix XIC of Chinese Pharmacopoeia version in 2000) in accordance with the law.Press intravenous administration, should be up to specification.
√ other: should meet under the injection item relevant every regulation (2000 editions two appendix I B of Chinese Pharmacopoeia).
Experimental example 2
This experimental example is the most preferably qualitative determination of the middle key component of pharmaceutical composition small-volume injection (every ml contains 40mg troxerutin and 0.5mg total nitrogen) of the present invention.
√ gets this product 0.5ml, and thin up is to 20ml, and it is a small amount of to add hydrochloric acid 1ml and zinc powder, puts in the water-bath and heats, and shows the redness that continues.
√ gets this product 0.5ml, and thin up is to 20ml, and it is a small amount of to add aluminum chloride, and solution shows glassy yellow.
√ gets this product 2ml, adds ninhydrin solution number droplet, and heating should show bluish violet.
In the chromatogram that √ writes down under troxerutin assay item, the main peak retention time of need testing solution should be consistent with the retention time at troxerutin reference substance peak.
More than three kinds of experiments be the qualitative reactions of the contained component of pharmaceutical composition of the present invention, illustrate and contain definite component in the drug regimen of the present invention.
Experimental example 3
This experimental example is the most preferably troxerutin quantitative assay in the pharmaceutical composition small-volume injection (every ml contains 40mg troxerutin and 0.5mg total nitrogen) of the present invention.
This experimental example is measured by high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
√ chromatographic condition and system suitability test; With octadecylsilane chemically bonded silica is filler; With 0.1% citric acid soln-second eyeball-oxolane (85: 9: 6) is mobile phase: the detection wavelength is 254nm.Number of theoretical plate calculates by the troxerutin peak should be not less than 2000.Troxerutin peak and the peak-to-peak separating degree of other materials should meet the requirements.
The √ algoscopy: it is an amount of to get this product, quantitatively is diluted to the solution that contains troxerutin 0.20mg among every 1ml with mobile phase, as need testing solution, gets 10 μ l and injects chromatograph of liquid, the record chromatogram; It is an amount of that precision takes by weighing the troxerutin reference substance in addition, makes the solution that contains troxerutin 0.20mg among every 1ml with mobile phase dissolving and dilution, and product solution is measured with method in contrast, presses external standard method with calculated by peak area.
√ troxerutin content should be 90～110% of labelled amount.
√ the results are shown in following table by three batches of mensuration:
| Lot number | Account for labelled amount % |
| 20020603 | 103.7 |
| 20020604 | 104.7 |
| 20020605 | 100.6 |
Experimental example 4
This experimental example is the most preferably quantitative assay of the middle total nitrogen of pharmaceutical composition small-volume injection (every ml contains 40mg troxerutin and 0.5mg total nitrogen) of the present invention.
Get this product and measure (two appendix VII of Chinese Pharmacopoeia version in 2000 D) in accordance with the law.
By the result of three batches of mensuration, total nitrogen content should be 85～115% of labelled amount in this product, sees table:
| Lot number | Account for labelled amount % |
| 20020603 | 92.3 |
| 20020604 | 99.6 |
| 20020605 | 104.6 |
Experimental example 5
This experimental example detects for the main project that embodiment 2 prepared brain extracts are undertaken by the brain protein hydrolysate injection standard.
The √ amino acid content is measured: get this product, carry out separation determination with suitable amino-acid analyzer or high performance liquid chromatograph; Other gets the reference substance solution of the respective concentration that corresponding aminoacid reference substance makes, and measures with method.Press external standard method with each amino acid whose content of calculated by peak area.
Measurement result is as follows:
It is 34.70mg/ml that every 1ml contains free amino acid, wherein:
Aspartic Acid 3.05mg/ml glutamic acid 3.89mg/ml serine 0.25mg/ml
Histidine 1.22mg/ml glycine 1.49mg/ml threonine 0.24mg/ml
Alanine 2.99mg/ml arginine 0.55mg/ml valine 1.94mg/ml
Methionine 0.43mg/ml isoleucine 1.90mg/ml phenylalanine 1.80mg/ml
Leucine 6.18mg/ml lysine 6.55mg/ml proline 2.22mg/ml
The √ total nitrogen content is measured: get this product, measure (two appendix VII of Chinese Pharmacopoeia version in 2000 D) in accordance with the law, total nitrogen is 6.10mg/ml.
√ differentiates (1): get this product 2ml, add two gland reagent that contract (get copper sulfate 0.75g and sodium potassium tartrate tetrahydrate 0.3g, add water 250ml and make dissolving,
Under agitation add 10% sodium hydroxide solution 150ml, add water to 500ml) 4ml, displaing amaranth, up to specification.
√ differentiates (2): get this product, according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D) test.
Chromatographic condition: use gel chromatographic columns: with phosphate buffer (get dipotassium hydrogen phosphate 10.63g and potassium dihydrogen phosphate 5.31g, add isopropyl alcohol 50ml, add water to 1000ml, with phosphoric acid regulating ph value to 7.0) is mobile phase; Flow velocity is per minute 1ml.
Algoscopy: get each 10 υ l of contrast solution and need testing solution and inject chromatograph of liquid, the record chromatogram, the chromatogram of need testing solution should with the chromatogram basically identical of contrast solution, up to specification.
The √ index of refraction: the index of refraction of this product (two appendix VI of Chinese Pharmacopoeia version in 2000 H) is 1.342, and is up to specification.
PH value: pH value is 7.2 (two appendix VI of Chinese Pharmacopoeia version in 2000 H), and is up to specification.
√ protein: get this product 5ml, add 20% sulfosalicylic acid 2ml, solution should be clarified, and is up to specification.
Comparative example 1
This example is most preferably a pharmaceutical composition small-volume injection (every ml contains 40mg troxerutin and 0.5mg total nitrogen) and the clinical comparison of troxerutin injection at the treatment cerebral thrombosis of the present invention, the good efficacy of injection of the present invention is described, promptly the coordinating effect of troxerutin and brain extract is better than using separately troxerutin injection.
Clinical settings:
The cerebral thrombus patient is divided into 2 groups at random.
58 examples are organized in treatment, and wherein the male is 48 examples, and the women is 10 examples.Age 41-79 year, average 61.3 years old.
Matched group 51 examples, wherein the male is 42 examples, the women is 9 examples.Age 43-82 year, average 60.5 years old.All cases are the first patient of cerebral thrombosis, meet the academic diagnostic criteria that can work out of cerebrovascular, all do not see intracranial hemorrhage through CT scan.
Therapeutic Method:
The equal intravenous drip troxerutin injection of treatment group patient, a 400mg, 1 time on the one: instil with 5～10% glucose injections or low molecular dextran injection dilution back, 20 is a course of treatment, treats 3 courses of treatment, as the treatment group.
Matched group patient intravenous drip injection of the present invention, a 10ml once-a-day, uses with 250～500ml normal saline or 5% glucose injection dilution back.20 is a course of treatment, treats 3 courses of treatment, in contrast group.
Efficacy determination:
√ cures: transference cure, and language is fluent, and the energy independent ambulation is taken care of oneself, and the affected limb Myodynamia recovery is to more than the IV level;
√ takes a turn for the better; Main physical signs is obviously recovered, and symptom has improvement in various degree, more than the affected limb Myodynamia recovery II level;
√ is invalid: symptom, sign no change or sb.'s illness took a turn for the worse.
Therapeutic outcome:
The total effective rate and the curative effect of treatment group and matched group are compared, be significant difference, the results are shown in following table.
Treatment group and matched group curative effect are relatively
| Matched group (n=58) | Treatment group (n=58) | |||
| It is invalid effectively total to cure improvement | Example several 7 49 2 56 | (％) (12.1) (84.5) (3.4) (96.6) | Example several 3 39 9 42 | (％) (5.9) (76.5) (17.6) (82.4) |
Annotate: two groups of curative effects compare p＜0.01
Comparative example 2
This example is most preferably a pharmaceutical composition small-volume injection (every ml contains 40mg troxerutin and 0.5mg total nitrogen) and the clinical comparison of troxerutin injection at the treatment cerebral infarction of the present invention, illustrate that injection of the present invention has good efficacy, curative effect is better than the multiple plain injection of brain.
Clinical settings:
33 routine cases are divided into 2 groups according to the medication difference:
The multiple plain injection group of √ brain: male's 12 examples, women's 5 examples:
Of the present invention group of √: male's 11 examples, women's 5 examples.
Therapeutic Method:
√ uses injection group of the present invention: intravenous drip, and a 10ml, once-a-day, with instiling at a slow speed in 250ml normal saline or the 5% glucose injection dilution back.Treat 2 courses of treatment.
√ makes the multiple plain injection group of requiring mental skill: intravenous drip, and a 10ml-20ml, 1 time on the one, with instiling at a slow speed in 250ml normal saline or the 5% glucose injection dilution back.Treat 2 courses of treatment.
Efficacy determination:
Judge that curative effect is as the criterion to leave hospital, be in hospital 15 days with interior person's 3 examples; 16-30 days person's 30 examples.
√ cures: symptom and sign complete obiteration, take care of oneself, as usual work.
√ cures substantially: the paralysis human body, and Myodynamia recovery is left over part pathology sign to the 4-5 level, and life is taken care of oneself substantially.
√ takes a turn for the better: symptom and sign improves, and muscular strength improves the 1-2 level, and language function partly recovers, and life can not be taken care of oneself fully.
√ is invalid or dead: the sings and symptoms no change, or increase the weight of to death.
The √ responding time: cardinal symptom begins to take a turn for the better, and is the shortest 1 day, the longest 28 days, general 7-14 days.
The result compares:
Two groups of curative effects compare (example)
| The medication group | Significant figure | Cure | The basic healing | Take a turn for the better | No change | Sum | Effective percentage % |
| The multiple plain group of | 15 | 3 | 4 | 8 | 2 | 17 | 88.2％ |
| Of the present invention group | 16 | 3 | 12 | 1 | 0 | 16 | 100％ |
Comparative example 3
This example is most preferably pharmaceutical composition small-volume injection (every ml contains 40mg troxerutin and 0.5mg total nitrogen) and the clinical comparison of troxerutin injection aspect the treatment cerebral infarction of the present invention, the good efficacy of injection of the present invention is described, promptly the coordinating effect of troxerutin and brain extract is better than using separately troxerutin injection.
Clinical settings:
Patients with Cerebral Infarction totally 120 examples is divided into two groups at random.120 examples are falls ill 72 hours with interior internal carotid artery system Patients with Cerebral Infarction, meets the diagnostic criteria of the 4th the cerebrovascular academic conference in the whole nation, and makes a definite diagnosis through cranium brain CT or MR1 inspection.120 examples are divided into two groups at random, injection for treating group 60 examples of the present invention, troxerutin injection matched group 60 examples.Two groups of ages, sex, courses of disease, fall ill, comparability is arranged to administration time, history of past illness, complication there was no significant difference.
Therapeutic Method:
Two groups of patients all take the circumstances into consideration to use dehydrant and other symptomatic treatments, but all without medicines such as other blood vessel dilating, anticoagulants.Injection for treating group of the present invention, one time 10ml adds, and instils with 250ml normal saline dilution back every day 1 time, and 14 days is a course of treatment.The troxerutin injection matched group, a 400mg, every day 1 time, quiet of glucose injection with 5%～10% or low molecular dextran injection dilution back, 14 days is a course of treatment.
Efficacy determination:
Observe the variation of two groups of patient function of nervous system, blood flow index before and after the treatment.Efficacy assessment standard is the marked improvement that is almost recovered, 5 grades of progress, no change, deterioration, and the result adopts statistical procedures, and measurement data adopts μ check and X
2Check.
Therapeutic outcome:
Curative effect has significant difference (P＜0.01) between treatment group and the matched group, sees Fig. 1; The neurologic impairment integration relatively before and after the treatment, compare no significant difference (P＜0.005) before and after the treatment between two groups, treatment back treatment group neurologic impairment obviously alleviates (P＜0.01) than matched group, sees Fig. 2: do not find apparent side effect during whole blood viscosity reaches before and after two groups of treatments.
Interpretation of result:
Injection of the present invention can combine with the adenosine carrier protein on the platelet membrane; the content of cycli phosphate glycosides (cAMP) in the platelet increasing; thereby suppress erythrocyte and platelet aggregation; prevent thrombosis; and endotheliocyte there is protective effect; the blood vessel injury that can cause medmain, Kallidin I, antibacterial mycin, oxygen-derived free radicals keeps capillary permeability.Can increase oxygen content and oxygen saturation in the blood, activity, the microcirculation improvement of enzyme under the protection anaerobic condition promote neovascularity to generate to promote collateral circulation; thereby cerebral blood flow increasing amount; improve the blood supply in half blanking bar zone, alleviate the edema of neighboring area, reduce brain infarction area.
Use injection for treating 60 routine acute cerebral infarction patients of the present invention in this example, total effective rate is 93%, obvious effective rate is 70%, with matched group significant difference is arranged relatively, and the neurologic impairment integration reduces obviously after the treatment, whole blood viscosity, plasma viscosity obviously improve in the hemorheology, show that injection of the present invention can improve cerebral blood flow and blood viscosity, obviously alleviating the nervous function damage of cerebral infarction, and do not have obvious adverse reaction, is the active drug of treatment cerebral infarction.
Claims (8)
1, a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease, it is characterized in that described pharmaceutical composition is formed by Cerebrolysin Vial that extracts in the mammal cerebral tissue except that the people and troxerutin assembly, containing troxerutin in the pharmaceutical composition is the 1-1000 weight portion, and wherein the weight ratio of total nitrogen content is 70～90 in troxerutin and the Cerebrolysin Vial.
2, according to the described pharmaceutical composition of claim 1, the weight ratio that it is characterized in that total nitrogen content in troxerutin and the Cerebrolysin Vial is 80.
3, according to claim 1 or 2 described preparation of drug combination methods, it is characterized in that this preparation method comprises that the preparation of Cerebrolysin Vial and Cerebrolysin Vial and troxerutin are mixed in proportion, containing troxerutin in the pharmaceutical composition is the 1-1000 weight portion, wherein the weight ratio of total nitrogen content is 70～90 in troxerutin and the Cerebrolysin Vial, makes finished product preparation through post processing then.
4, preparation method according to claim 3, it is characterized in that, the preparation process of described Cerebrolysin Vial is: the animal brain of getting fresh and healthy, add the homogenate of 0.5-2.5 times of weight water for injection, be heated to 80-95 ℃, kept 15-30 minute, be cooled to hydrolysis temperature, be adjusted to the enzymolysis pH value, add the proteolytic enzyme of brain weight 0.1-1.5%, carry out primary enzymolysis or secondary enzymolysis, primary enzymolysis liquid or secondary enzymolysis liquid, are handled through centrifugal filtration after 8-24 hour 4-8 ℃ of placement, and filtrate is the ultrafilter membrane ultrafiltration of 6000-10000 with molecular cut off, ultrafiltrate is a Cerebrolysin Vial, and its total nitrogen content is 0.1～10mg/ml.
5, preparation method according to claim 4, it is characterized in that, described primary enzymolysis is behind the proteolytic enzyme that adds brain weight 0.1-1.5%, kept 2-20 hour at this proteolytic enzyme hydrolysis temperature, keep the enzymolysis pH value, be heated to 80-95 ℃ and kept 15-30 minute then, primary enzymolysis liquid; Described proteolytic enzyme is a trypsin, and hydrolysis temperature is 37-42 ℃, and the enzymolysis pH value is 7.8-8.2; Centrifugal filtration after the described primary enzymolysis is treated to: centrifugal back separation of supernatant, and with supernatant liquid filtering, the filtrate adjust pH is 3.5-4.5, be heated to 80-95 ℃, kept 15-30 minute, placed 8-24 hour at 4-8 ℃, centrifugal back separation of supernatant, with supernatant liquid filtering, the filtrate adjust pH is 6.5-7.5, is heated to 80-95 ℃, kept 15-30 minute, placed 8-24 hour at 4-8 ℃, centrifugal then, supernatant gets filtrate after filtration.
6, preparation method according to claim 4, it is characterized in that, described secondary enzymolysis process is for to be cooled to hydrolysis temperature with primary enzymolysis liquid, be adjusted to the enzymolysis pH value, the proteolytic enzyme that adds brain weight 0.1-1.5% enzymolysis 2-20 hour, keeps the enzymolysis pH value, be heated to 80-95 ℃ then and kept 15-30 minute, get secondary enzymolysis liquid; Described proteolytic enzyme is a pepsin, and it is 37-42 ℃ that enzymolysis is fit to temperature, and it is 2.5-3.2 that enzymolysis is fit to pH value; Centrifugal filtration after the described secondary enzymolysis is treated to: centrifugal back separation of supernatant, and with supernatant liquid filtering, the filtrate adjust pH is 8.0-10.0, be heated to 80-95 ℃, kept 15-30 minute, placed 8-24 hour at 4-8 ℃, centrifugal back separation of supernatant, with supernatant liquid filtering, the filtrate adjust pH is 6.5-7.5, is heated to 80-95 ℃, kept 15-30 minute, placed 8-24 hour at 4-8 ℃, centrifugal then, supernatant gets filtrate after filtration.
According to each described preparation method of claim 3-6, it is characterized in that 7, described centrifugal condition is 4000 rev/mins, centrifugation time is 15-30 minute.
According to each described preparation method of claim 3-6, it is characterized in that 8, the dosage form of described finished product preparation is tablet, capsule, granule, oral liquid, small-volume injection, bulk capacity injection or lyophilized injectable powder.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB200410070499XA CN1264522C (en) | 2003-08-07 | 2004-08-05 | Medicinal composition, its preparation method and its use |
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| CN102718857B (en) * | 2012-07-09 | 2013-05-22 | 河北智同医药控股集团有限公司 | Denatured protein powder and brain protein hydrolyzate prepared from same |
| CN104511007B (en) * | 2013-09-26 | 2018-03-06 | 西藏易明西雅医药科技股份有限公司 | A kind of preparation method of Cerebrolysin Vial |
| CN104511008B (en) * | 2013-09-26 | 2018-03-06 | 西藏易明西雅医药科技股份有限公司 | A kind of Cerebrolysin Vial preparation method |
| CN104497102B (en) * | 2014-12-10 | 2017-08-04 | 内蒙古天奇生物科技有限公司 | A kind of pig brain polypeptide for preventing and treating the nervous system disease and preparation method thereof |
| CN113908174B (en) * | 2021-10-29 | 2022-06-24 | 北京四环制药有限公司 | Efficient and safe preparation method and application of cerebroprotein hydrolysate |
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