CN1686166A - Medicinal composition for treating blood vessel kind disease, its preparation process and its use - Google Patents
Medicinal composition for treating blood vessel kind disease, its preparation process and its use Download PDFInfo
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- CN1686166A CN1686166A CNA2005100564503A CN200510056450A CN1686166A CN 1686166 A CN1686166 A CN 1686166A CN A2005100564503 A CNA2005100564503 A CN A2005100564503A CN 200510056450 A CN200510056450 A CN 200510056450A CN 1686166 A CN1686166 A CN 1686166A
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Abstract
A medicinal composition for treating cerebrovascular diseases, craniocerebral trauma, cerebral disfunction, arteriosclerosis, thrombophlebitis, etc is prepared from 7,3',4'-trihydroxyethyl rutin and the liquid extract of the brain of mammal except man.
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 for the treatment of blood vessel kind disease, 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 provides 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.
The pharmaceutical composition of treatment blood vessel kind disease of the present invention, wherein contain animal brain's extracting solution, contain a large amount of active polypeptide, several amino acids, nucleic acid etc. in the brain tissue extract, the active polypeptide that contains, aminoacid, nucleic acid 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, wherein troxerutin weight is 0.1～150 times of total nitrogen content, troxerutin weight is 0.5～50 times of content of peptides, and troxerutin weight is 1～80 times of nucleic acid content.The reaction of pharmaceutical composition ninhydrin solution is positive, and has uv absorption at 265～275nm.
Brain extract wherein, its total nitrogen content is 0.5～8mg/ml, and content of peptides is 2.0～20mg/ml, and nucleic acid content is 0.3～15mg/ml.
Wherein in the preferred pharmaceutical compositions troxerutin weight be total nitrogen content 10-100 doubly, troxerutin weight is 10～40 times of content of peptides, troxerutin weight is 1～80 times of nucleic acid content; More preferably troxerutin weight be total nitrogen content 50-90 doubly, troxerutin weight is 15～30 times of content of peptides, troxerutin weight is 15～55 times of nucleic acid content; Most preferably be troxerutin weight and be 80 times of total nitrogen content, troxerutin weight is 400/19 times of content of peptides, and troxerutin weight is 20～40 times of nucleic acid content.
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, wherein the weight ratio of total nitrogen content is 0.1～150 times in troxerutin and the brain extract, troxerutin weight is 0.5～50 times of content of peptides in the brain extract, and troxerutin weight is 1～80 times of brain extract amplifying nucleic acid content in the pharmaceutical composition.Make 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 adjusted to pH value to 3.0～4.0, freeze thawing 1～3 time is heated to 80-95 ℃, keeps 15-30 minute, handle through centrifugal filtration, filtrate is adjusted to pH value to 6.5～7.5, is heated to 80-95 ℃, keeps 15-30 minute, handle through centrifugal filtration, melt freezing back, handles after filtration again, and filtrate is the ultrafiltration of 5000-10000 ultrafilter membrane with molecular cut off, ultrafiltrate is a brain extract, its total nitrogen content is 0.5～8mg/ml, and content of peptides is 2.0～20mg/ml, and nucleic acid content is 0.3～15mg/ml.
The preparation process of preferred brain extract is: the animal brain of getting fresh and healthy, add the homogenate of 1.0-2.0 times of weight water for injection, be adjusted to pH value to 3.0～3.5, freeze thawing 1 time is heated to 80-85 ℃, kept 15-20 minute, handle through centrifugal filtration, filtrate is adjusted to pH value to 6.8～7.2, is heated to 80-85 ℃, kept 15-20 minute, handle through centrifugal filtration, freezing below-15 ℃, 10～30 ℃ melt down, handle after filtration again, filtrate is the ultrafiltration of 5000-10000 ultrafilter membrane with molecular cut off, and ultrafiltrate is a brain extract, and its total nitrogen content is 0.5～8mg/ml, content of peptides is 2.0～20mg/ml, and nucleic acid content is 0.3～15mg/ml.
Centrifugal filtration after the described heating is treated to: centrifugal back separation of supernatant under the 2-8 ℃ of condition, and with supernatant liquid filtering.
Described centrifugal condition is 3500～4000 rev/mins, and centrifugation time is 15-30 minute, and preferred centrifugal condition is 4000 rev/mins, and centrifugation time is 20-25 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.
Above-mentioned ultrafilter membrane is preferably the ultrafilter membrane that molecular cut off is 6000-10000, and more preferably molecular cut off is 10000 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.
Adopt freezing-thawing method in the preparation method of the present invention, extract polypeptide, aminoacid, nucleic acid quickly and easily from cerebral tissue, this method has the yield height, and the operating time is short, the characteristics that cost is low.
Brain extract of the present invention contains polypeptide and free amino acid and nucleic acid; be 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; activate substance metabolism and energy metabolism in the brain; promote the synthetic of brain internal protein; influence respiratory chain; protective capability with anti-hypoxia is improved 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, when troxerutin weight in this pharmaceutical composition is 0.1～150 times of total nitrogen content in the brain extract, troxerutin weight is 0.5～50 times of content of peptides in the brain extract, when troxerutin weight is 1～80 times of brain extract amplifying nucleic acid content in the pharmaceutical composition, the synergism of the two is good, is beneficial to absorption by human body and utilization.
The specification of preferred pharmaceutical compositions injection of the present invention is:
2ml:80mg (troxerutin): 1.0mg (total nitrogen): 3.8mg (polypeptide): 2～4mg (nucleic acid);
5ml:200mg (troxerutin): 2.5mg (total nitrogen): 4.75mg (polypeptide): 5～10mg (nucleic acid);
10ml:400mg (troxerutin): 5mg (total nitrogen): 19mg (polypeptide): 10～20mg (nucleic acid);
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 several amino acids and the nucleic acid 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.Contained a large amount of active polypeptide, several amino acids and the nucleic acid etc. of brain extract 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.
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 adjusted to pH value to 3.2, freeze thawing 1 time is heated to 80 ℃, keeps 20 minutes, centrifugal under 6 ℃ of conditions, centrifugal condition is 4000 rev/mins, and centrifugation time is 20 minutes, with supernatant liquid filtering, filtrate is adjusted to pH value to 7.0, is heated to 80 ℃, kept 20 minutes, centrifugal under 2 ℃ of conditions, centrifugal condition is 4000 rev/mins, and centrifugation time is 20 minutes, with supernatant liquid filtering, filtrate-18 is ℃ freezing, and 10 ℃ melt down, handle after filtration, filtrate is 10000 ultrafilter membrane ultrafiltration (U.S. millipore companies with molecular cut off, the standard ultrafiltration system), ultrafiltrate is a brain extract, and wherein total nitrogen content is 3mg/ml, content of peptides is 11mg/ml, and nucleic acid content is 7.5/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, 1mg total nitrogen, 3.7mg polypeptide, 2.5mg nucleic acid) with the 333ml 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 active carbon that adds total dose volume 0.05% stirs and to boil 15 minutes, and fluid temperature is reduced to 40 ℃, 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, 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, homogenate is adjusted to pH value to 3.8, freeze thawing 2 times is heated to 90 ℃, keeps 15 minutes, centrifugal under 4 ℃ of conditions, centrifugal condition is 4000 rev/mins, and centrifugation time is 25 minutes, with supernatant liquid filtering, filtrate is adjusted to pH value to 6.8, is heated to 90 ℃, kept 25 minutes, centrifugal under 4 ℃ of conditions, centrifugal condition is 4000 rev/mins, and centrifugation time is 25 minutes, with supernatant liquid filtering, freezing below the filtrate-20 ℃, 15 ℃ melt down, handle after filtration, filtrate is 8000 ultrafilter membrane ultrafiltration (U.S. millipore companies with molecular cut off, the standard ultrafiltration system), ultrafiltrate is a brain extract, and wherein total nitrogen content is 3.5mg/ml, content of peptides is 13mg/ml, and nucleic acid content is 8.5/ml.
Take by weighing the pure product 30g of injection troxerutin, can be made into the 2000ml medicinal liquid, finally make 1000 of little molten amount injections (specification is 2ml:30mg troxerutin, 0.88mg total nitrogen, 3.3mg polypeptide, 2.1mg nucleic acid) 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 active carbon that adds total dose volume 0.05% stirs and to boil 15 minutes, and fluid temperature is reduced to 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, 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, homogenate is adjusted to pH value to 3.3, freeze thawing 3 times is heated to 85 ℃, keeps 15 minutes, centrifugal under 5 ℃ of conditions, centrifugal condition is 4000 rev/mins, and centrifugation time is 30 minutes, with supernatant liquid filtering, filtrate is adjusted to pH value to 7.2, is heated to 85 ℃, keeps 15 minutes, centrifugal under 6 ℃ of conditions, centrifugal condition is 4000 rev/mins, and centrifugation time is 30 minutes, with supernatant liquid filtering, freezing below the filtrate-20 ℃, 25 ℃ melt down, handle after filtration again, and filtrate is 10000 ultrafilter membrane ultrafiltration (U.S. millipore companies with molecular cut off, the standard ultrafiltration system), ultrafiltrate is a brain extract, and wherein total nitrogen content is 1.6mg/ml, and content of peptides is 11mg/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, 0.8mg total nitrogen, 5.5mg polypeptide, 3.2mg nucleic acid) 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 active carbon that adds total dose volume 0.05% stirs and to boil 15 minutes, and fluid temperature is reduced to 45 ℃, 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 7.2, medicinal liquid after filtration behind the system filtration embedding in the 2ml ampoule, sterilization promptly gets small-volume injection.
Embodiment 4
Get fresh and healthy brain of Cervus nippon Temminck (C. elaphus L.) 10kg, remove impurity such as fascia, wash with water for injection, add 5L water for injection, homogenate is adjusted to pH value to 3.0, freeze thawing 2 times is heated to 80 ℃, keeps 15 minutes, centrifugal under 4 ℃ of conditions, centrifugal condition is 4000 rev/mins, and centrifugation time is 30 minutes, with supernatant liquid filtering, filtrate is adjusted to pH value to 7.5, is heated to 90 ℃, kept 15 minutes, centrifugal under 4 ℃ of conditions, centrifugal condition is 4000 rev/mins, and centrifugation time is 30 minutes, with supernatant liquid filtering, freezing below the filtrate-20 ℃, 28 ℃ melt down, handle after filtration, filtrate is 6000 ultrafilter membrane ultrafiltration (U.S. millipore companies with molecular cut off, the standard ultrafiltration system), ultrafiltrate is a brain extract, and wherein total nitrogen content is 6mg/ml, content of peptides is 16mg/ml, and nucleic acid content is 12.5/ml.
Take by weighing the pure product 100g of injection troxerutin, can be made into the 2000ml medicinal liquid, finally make 400 of little molten amount injections (specification is 5ml:250mg troxerutin, 7.5mg total nitrogen, 20.0mg polypeptide, 15.6mg nucleic acid) 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 active carbon that adds total dose volume 0.05% stirs and to boil 15 minutes, and fluid temperature is reduced to 40 ℃, 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, medicinal liquid after filtration behind the system filtration embedding in the 2ml ampoule, sterilization promptly gets small-volume injection.
Embodiment 5～8
With reference to embodiment 1～4, brain extract and troxerutin carry out proportioning, by known method, make granule, and dry back tabletting gets tablet.
Embodiment 8～12
With reference to embodiment 1～4, 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 12～16
With reference to embodiment 1～4, brain extract is put in the dilute preparing tank; Drop into the sodium chloride of troxerutin and 0.85% final preparation cumulative volume in dense preparing tank, add 0.4 ‰ active carbons and boil decarbonization filtering, after the cooling, medical filtration to dilute preparing tank, is added water for injection to the dosing amount in dilute preparing tank, transferring PH is 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 detection of injection inspection item of appearance character, pH value, protein, pyrogen, undue toxicity and other regulation of the pharmaceutical composition small-volume injection that obtained of the embodiment of the invention 1.
√ this product is yellow or sundown clear liquid.
√ measures according to two appendix VIH of Chinese Pharmacopoeia version in 2000, 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 XID of Chinese Pharmacopoeia version in 2000) 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 IB of Chinese Pharmacopoeia).
Experimental example 2
This experimental example is the qualitative determination of key component in the pharmaceutical composition small-volume injection that obtained of the embodiment of the invention 2.
√ 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 blue.
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 troxerutin quantitative assay of the pharmaceutical composition small-volume injection that obtained of the embodiment of the invention 1.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.
The every ml of this product contains troxerutin (C
33H
42O
19) be 40mg.
Experimental example 4
This experimental example is the quantitative assay of total nitrogen in the pharmaceutical composition small-volume injection that obtained of the embodiment of the invention 2.
Get this product and measure (two appendix VIID of Chinese Pharmacopoeia version in 2000) in accordance with the law.
It is 0.44mg that the every ml of this product contains total nitrogen.
Experimental example 5
This experimental example is the quantitative assay of the pharmaceutical composition small-volume injection polypeptide that obtained of the embodiment of the invention 3.
Precision is measured this product 2ml, put in the test tube, the accurate biuret test solution that adds (is got copper sulfate 1.50g and sodium potassium tartrate tetrahydrate 6.0g, is added water 500ml and make dissolving, add 10% sodium hydroxide solution 300ml while stirring, be diluted with water to 1000ml, mixing) 4ml, mixing, room temperature was placed 30 minutes, according to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2000), measure trap at the wavelength place of 540nm.It is an amount of that precision takes by weighing the casein reference substance in addition, adds the 0.05mol/L sodium hydroxide test solution and make the solution that contains 7mg among every 1ml approximately, and precision is measured 2ml, rises from " putting in the test tube ... ", with the method operation, measures trap, calculates I as a result; It is an amount of that precision takes by weighing the troxerutin reference substance, adds water and make the solution that every 1ml contains 40mg, measures with method, calculates the result, and this result * troxerutin actual content/troxerutin indicates content, gets II as a result; Deduct II as a result with I as a result, promptly get this product content of peptides.
It is 2.25mg that the every ml of this product contains polypeptide.
Experimental example 6
This experimental example is that the nucleic acid quantification in the pharmaceutical composition small-volume injection that obtained of the embodiment of the invention 1 is measured.
Get this product 2ml thin up to 50ml, get the 1ml thin up again, shake up,, measure absorption value down, press E according to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2000) fourth 260nm wavelength as need testing solution to 100ml
1cm 1%200 calculate nucleic acid content gets I as a result.It is an amount of that precision takes by weighing the troxerutin reference substance, adds water and make the solution that every 1ml contains 40mg, measures with method, calculates the result, and this result * troxerutin actual content/troxerutin indicates content, gets II as a result; Deduct II as a result with I as a result, promptly get this product nucleic acid content.
Comparative example 1
Pharmaceutical composition injection with small volume (every ml contains 40mg troxerutin, 0.5mg total nitrogen, 1.85mg polypeptide, 1.25mg nucleic acid) that this example is obtained for the embodiment of the invention 1 of the present invention and the clinical comparison of troxerutin injection at the treatment cerebral thrombosis, 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.
70 examples are organized in treatment, and wherein the male is 48 examples, and the women is 22 examples.Age 40-75 year, average 60.3 years old.
Matched group 68 examples, wherein the male is 45 examples, the women is 25 examples.Age 42-78 year, average 61.0 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 5.
Table 5: treatment group and matched group curative effect are relatively
| Treatment group (n=70) | Matched group (n=68) | |||
| The example number | ??(％) | The example number | ????(％) | |
| Cure | 9 | ??(12.8) | 4 | ????(5.9) |
| Take a turn for the better | 60 | ??(85.7) | 51 | ????(75.0) |
| Invalid | 1 | ??(1.4) | 13 | ????(19.1) |
| Effectively total | 69 | ??(98.8) | 55 | ????(80.9) |
Annotate: two groups of curative effects compare p＜0.01
Comparative example 2
Pharmaceutical composition small-volume injection (every ml contains 40mg troxerutin, 0.5mg total nitrogen, 1.85mg polypeptide, 1.25mg nucleic acid) that this example is obtained for the embodiment of the invention 1 of the present invention and the clinical comparison of the multiple plain injection of brain at the treatment cerebral infarction, illustrate that injection of the present invention has good efficacy, curative effect is better than the multiple plain injection of brain.
Clinical settings:
46 routine cases are divided into 2 groups according to the medication difference:
The multiple plain injection group of √ brain: male's 17 examples, women's 6 examples;
Of the present invention group of √: male's 15 examples, women's 8 examples.
Therapeutic Method:
√ uses injection group of the present invention: intravenous drip, a 10ml once-a-day, with instiling at a slow speed in 250ml normal saline or the 5% glucose injection dilution back, treats 2 courses of treatment.
√ makes the multiple plain injection group of requiring mental skill: intravenous drip, 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, treats 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 6 examples; 16-30 days person's 40 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 26 days, general 6-13 days.
The result compares:
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 6.
| 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 brain | ??19 | ????4 | ????6 | ????9 | ????3 | ????23 | ????82.6％ |
| Of the present invention group | ??23 | ????6 | ????15 | ????2 | ????0 | ????23 | ????100％ |
Annotate: two groups of curative effects compare p＜0.01
Claims (10)
1, a kind of pharmaceutical composition for the treatment of blood vessel kind disease, it is characterized in that described pharmaceutical composition is formed by brain extract that extracts in the mammal cerebral tissue except that the people and troxerutin assembly, wherein troxerutin weight is 0.1～150 times of total nitrogen content, troxerutin weight is 0.5～40 times of content of peptides, and troxerutin weight is 1～80 times of nucleic acid content.
2, pharmaceutical composition according to claim 1, the 10-100 that it is characterized in that troxerutin weight total nitrogen content in the described pharmaceutical composition doubly, troxerutin weight is 10～40 times of content of peptides, troxerutin weight is 1～80 times of nucleic acid content.
3, pharmaceutical composition according to claim 2, it is characterized in that troxerutin weight in the described pharmaceutical composition be total nitrogen content 50-90 doubly, troxerutin weight is 15～30 times of content of peptides, and troxerutin weight is 15～55 times of nucleic acid content.
4,, it is characterized in that the mammal brain except that the people in the described pharmaceutical composition is organized as the cerebral tissue of pig, Canis familiaris L., cattle, sheep, deer, horse or rabbit according to the described pharmaceutical composition of claim 1-3.
5, a kind of according to the described preparation of drug combination method of claim 1-3, it is characterized in that this preparation method comprises that the preparation of brain extract and brain extract and troxerutin are mixed in proportion, wherein the weight ratio of total nitrogen content is 0.1～150 in troxerutin and the brain extract, troxerutin weight is 0.5～40 times of content of peptides in the brain extract, troxerutin weight is 1～80 times of brain extract amplifying nucleic acid content in the pharmaceutical composition, makes finished product preparation through post processing then.
6, preparation method according to claim 5, it is characterized in that, the preparation process of described 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 adjusted to pH value to 3.0～4.0, freeze thawing 1～3 time is heated to 80-95 ℃, keeps 15-30 minute, handle through centrifugal filtration, filtrate is adjusted to pH value to 6.5～7.5, is heated to 80-95 ℃, keeps 15-30 minute, handle through centrifugal filtration, melt freezing back, handles after filtration again, and filtrate is the ultrafiltration of 5000-10000 ultrafilter membrane with molecular cut off, ultrafiltrate is a brain extract, its total nitrogen content is 0.5～8mg/ml, and content of peptides is 2.0～20mg/ml, and nucleic acid content is 0.3～15mg/ml.
7, according to claim 5 or 6 described preparation methoies, it is characterized in that the centrifugal filtration after the described heating is treated to: centrifugal back separation of supernatant under the 2-8 ℃ of condition, with supernatant liquid filtering.
According to claim 5 or 6 described preparation methoies, it is characterized in that 8, described centrifugal condition is 3500～4000 rev/mins, centrifugation time is 15-30 minute; It is the 6000-10000 ultrafilter membrane that described ultrafilter membrane is preferably molecular cut off.
9, according to claim 5 or 6 described preparation methoies, it is characterized in that, the dosage form of described 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.; Described post processing is to carry out according to the conventional method of acceptable forms on the preparation pharmaceutics.
10, pharmaceutical composition according to claim 1 and 2 is at acute and chronic cerebrovascular disease such as preparation treatment cerebral thrombosis, cerebral embolism, brain spasm, craniocerebral trauma and cerebrovascular disease, incomplete brain blood supply, the caused disordered brain function of cerebral infarction and sequela, the application in the medicines such as edema that inaccessible syndrome, arteriosclerosis, thrombophlebitis, capillary hemorrhage and vascular permeability rising cause.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113908174A (en) * | 2021-10-29 | 2022-01-11 | 北京四环制药有限公司 | Efficient and safe preparation method and application of cerebroprotein hydrolysate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113908174A (en) * | 2021-10-29 | 2022-01-11 | 北京四环制药有限公司 | Efficient and safe preparation method and application of cerebroprotein hydrolysate |
| 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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