CN102349931B - Cockroach extract preparation method - Google Patents
Cockroach extract preparation method Download PDFInfo
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- CN102349931B CN102349931B CN2011102301067A CN201110230106A CN102349931B CN 102349931 B CN102349931 B CN 102349931B CN 2011102301067 A CN2011102301067 A CN 2011102301067A CN 201110230106 A CN201110230106 A CN 201110230106A CN 102349931 B CN102349931 B CN 102349931B
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Abstract
The invention provides a cockroach extract, a preparation method thereof, and application of a cockroach extract preparation in treatment of cardiovascular disease. The cockroach extract comprises the following components (based on dry weight): 20-40% of composite nucleoside base, 30-60% of associated amino acid, 2-4% of uracil, 3-6% of hypoxanthine and 5-10% of inosine. The preparation method comprises the following steps of: pulverizing dried cockroach into coarse powder, carrying out percolation or reflux extraction with 90-95% ethanol to obtain dense paste, carrying out oil-water separation, and removing precipitate and oil to obtain water-layer drug liquid; and adsorbing with activated carbon, carrying out secondary alcohol extraction and water extraction, decolorizing, carrying out ultrafiltration and concentrating to obtain the cockroach extract dense paste. Combined with proper pharmaceutical auxiliary materials, the cockroach extract can be prepared into aqueous injection, freeze-dried powder injection, capsules, granules, tablets, oral liquid, dropping pills and other various dosage forms, and the obtained preparation can be used for treating cardiovascular disease, particularly heart failure caused by pulmonary heart disease, cardiomyopathy, rheumatism, coronary disease, high-altitude heart disease and the like.
Description
Technical field
The invention belongs to biological extraction pharmaceutical technology field, further belong to cockroach and extract the pharmaceutical technology field, be specifically related to a kind of cockroach extractive and preparation method thereof and its application on the treatment cardiovascular diseases.
Background technology
Cockroach, having another name called periplaneta americana (being commonly called as Blatta seu periplaneta) is volume maximum in the Blattidae, becomes long 29-35 millimeters of polypide.The cockroach epidermis contains sclerotin and chitin, the elements such as bromine, zinc, nickel, manganese, potassium, calcium, titanium, chlorine, sulfur, silicon, aluminum, magnesium, the muscle hydrolysis can get 13 seed amino acids, the also in store plain B1 of little life, B2, nicotinic acid and ascorbic acid etc. in the health contain trehalose, trehalase, glycoprotein, inositol, protocatechuic acid Fructus Vitis viniferae glycoside etc. in the lymph; All contain ergothioneine, 1-methyl-2-pyridinium carboxylate, trigonelline, glycine, betanin, anus alkali, trimethylamine, adenine etc.Modern scientific research shows, cockroach extractive has very strong biological activity, but also there is significant limitation in prior art for the application of cockroach extractive, and the cockroach extractive application potential awaits further development and utilization.
Summary of the invention
The first purpose of the present invention is for the deficiencies in the prior art, a kind of cockroach extractive is provided, the second purpose is to provide the preparation method of this cockroach extractive, the 3rd purpose is to provide the pharmaceutical preparation that contains this cockroach extractive, and the 4th purpose is to provide this to contain the application of the pharmaceutical preparation of cockroach extractive.
The first purpose of the present invention be achieved in that described cockroach extractive its contain the compound nucleoside base 20～40% of weight ratio, in conjunction with aminoacid 30～60%, uracil 2～4%, hypoxanthine 3～6% and inosine 5～10%.
As preferred version: described cockroach extractive contains the compound nucleoside base of weight ratio 25～40%, and 35～60% in conjunction with aminoacid, 2.5～4% uracil, the inosine of 3.5～6% hypoxanthine and 6～10 %.
Described cockroach extractive contains the compound nucleoside base of weight ratio 22～36%, and 35～48% in conjunction with aminoacid, 2.5～3.5% uracil, 3.5～5% hypoxanthine and 6～8% inosine.
Described cockroach extractive contains the compound nucleoside base of weight ratio 24～38%, and 32～48% in conjunction with aminoacid, 2.0～3.2% uracil, 3.4～5% hypoxanthine and 7～10% inosine.
The present invention's the second purpose is to realize like this, the preparation method of described cockroach extractive may further comprise the steps: the dried polypide of cockroach is ground into coarse powder, make thick paste through 90～95% ethanol with percolation or reflux extraction, adding purified water in the thick paste fully stirs, precipitate and oils and fats are removed in oil-water separation, collect the water layer medicinal liquid, activated carbon adsorption, upper prop separates, and n-butyl alcohol eluting or phenol solution eluting carry out the secondary ethanol extraction after eluent is concentrated, filter after the cold preservation, carry out water extraction after filtrate is concentrated, centrifugal filtration gets water extraction liquid after cold preservation again, and water extraction liquid is through decolouring, concentrate to get the cockroach extractive thick paste after the ultrafiltration.
Described No. 4 yellow color solutions are according to " appendix an XI of Chinese pharmacopoeia first method.
The present invention's the 3rd purpose is achieved in that water needle injection, lyophilized injectable powder, capsule, granule, tablet, oral liquid, the drop pill of serving as reasons described pharmaceutical preparation this cockroach extractive and suitable pharmaceutic adjuvant making.
The present invention's the 4th purpose is achieved in that the application of pharmaceutical preparation on Cardiovarscular of any one prepared dosage form, is applied in the heart failure that especially pulmonary heart disease, cardiomyopathy, rheumatism, coronary heart disease and hypertensive cardiopathy etc. is caused.
Cockroach extractive of the present invention and preparation thereof can promote myocardial cell Ca
2+Interior stream, gentleness increase myocardial contraction enduringly, and blood vessel dilating reduces pulmonary artery pressure, pulmonary capillary wedge; Coronary artery dilating, increase coronary flow, the myocardial damage of inhibition Mediated by Free Radicals; Nephrectasia blood vessel, increase renal blood flow, diuresis; Improve microcirculation; The correction neuroendocrine is unbalance.
Description of drawings
Accompanying drawing is the standard finger-print of cockroach extractive extractum of the present invention.
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment, but never in any form the present invention is limited, and any change or improvement based on training centre of the present invention is done all belong to protection scope of the present invention.
Cockroach extractive of the present invention can be obtained by following methods:
The dried polypide of cockroach is ground into coarse powder, make thick paste through 90～95% ethanol with percolation or reflux extraction, adding purified water in the thick paste fully stirs, precipitate and oils and fats are removed in oil-water separation, collect the water layer medicinal liquid, activated carbon adsorption, upper prop separates, n-butyl alcohol eluting or phenol solution eluting, carry out the secondary ethanol extraction after eluent is concentrated, filter after the cold preservation, carry out again water extraction after filtrate is concentrated, centrifugal filtration gets water extraction liquid after cold preservation, and water extraction liquid concentrates to get the cockroach extractive thick paste after decolouring, ultrafiltration.
Described percolation adds 90～95% alcohol dipping 48～60 hours of 5～10 times of weight ratios in the dried worm coarse powder of cockroach, make the slow percolation of solvent with 90～95% ethanol again and be little yellow to filtrate, and filtrate gets thick paste through concentrating under reduced pressure, simultaneously Recycled ethanol.
Described reflux extraction, 90～95% alcohol heat reflux that add 5～10 times of weight ratios at the dried worm coarse powder of cockroach extracted 8～12 hours, and filtrate gets thick paste through concentrating under reduced pressure, simultaneously Recycled ethanol.
The preparation method of described cockroach extractive further comprises:
With behind the alcohol extraction thick paste importing oil water separator, the purified water that adds 4～6 times of weight portions fully stirs, and leaves standstill to layering obviously, removes bottom precipitate and upper strata oils and fats, collects the brown medicinal liquid in middle level in A, the oil-water separation step;
B, upper prop separating step herb liquid add the medical injection active carbon of particle diameter 200～325 orders, fully stirred rear static 1～2 hour, be adsorbed as colourless rear dress post to medicinal liquid, liquid is drained, adding water-saturated n-butanol or concentration are 5～10% phenol solution eluting, collect the eluting medicinal liquid, be eluted to the medicinal liquid color and be not deeper than yellow color solution No. 4; The eluting medicinal liquid gets thick paste at 60～80 ℃ of lower concentrating under reduced pressure, and reclaims n-butyl alcohol or reclaim phenol solution;
With stirring behind 65～85% ethanol of B step gained thick paste with 8～10 times of weight portions, 4～8 ℃ of lower cold preservations 12～24 hours, filter to get supernatant in C, the secondary alcohol extraction step, the supernatant concentrating under reduced pressure gets thick paste, simultaneously Recycled ethanol;
After in D, the water extraction step C step gained thick paste fully being stirred with the purified water of 8～10 times of weight portions, filter after 12～24 hours 4～8 ℃ of lower cold preservations, filtering residue is at 2～6 ℃ of lower low-temperature centrifugations, merging filtrate and centrate obtain clear liquid, the medical injection active carbon of particle diameter 200～325 orders that adds liquid measure 0.1～0.5% weight ratio in the clear liquid, the limit edged stirs, and after being heated to 60～80 ℃ static 0.5～1 hour; Then decarbonization filtering, filtered solution again after ultrafiltration concentrating under reduced pressure get the cockroach extractive thick paste; The relative density of described thick paste is 1.2～1.3.
The pharmaceutic adjuvant that can adopt during useful in preparing drug formulations of the present invention comprises: PEG400, sodium chloride, sodium hydroxide, starch, dextrin, Icing Sugar, Pulvis Talci, magnesium stearate, silicon dioxide, polyethylene glycol 6000, methyl-silicone oil, glycerol, sodium benzoate.
Cockroach extractive is the transparent dope of brown color, the tool hygroscopicity.Differentiate by the following method, check and measure:
1, differentiates
⑴ get this product 0.05g, and thin up is to 5ml, as need testing solution.Other gets cockroach medical material 1g, adds n-butyl alcohol-glacial acetic acid (4:1) mixed liquor 50ml, and supersound process 30min filters, and filtrate evaporate to dryness, residue add water 1ml and dissolve in contrast medical material solution.According to thin layer chromatography (" an appendix VI of Chinese pharmacopoeia B) test, draw each 5 μ l of above-mentioned two kinds of solution, put respectively on same silica GF254 lamellae, launch with n-butyl alcohol-glacial acetic acid-water (4:1:1), take out, dry, put under the uviol lamp (254nm) and inspect, in the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, should show the speckle of 3 same colors.Spray with 2% ninhydrin solution, 105 ℃ to be heated to speckle colour developing clear again, with the corresponding position of control medicinal material chromatograph on, should show the speckle of 1 same color.
⑵ get this product 0.05g, thin up is to 5ml, by strong alkalinity anion exchange glucosan chromatographic column (QAE-Sephadex A-25 type, internal diameter 1.5cm, the high 5cm of post), water 20ml eluting, discard water elution liquid, use again 0.02mol/L hydrochloric acid eluting, discard just eluent 8ml, collect continuous eluent 20ml, as need testing solution.Detect according to high performance liquid chromatography (" an appendix VI of Chinese pharmacopoeia D), take octadecylsilane chemically bonded silica as filler, chromatographic column (column length 150mm, column internal diameter are 4.6mm); Take 0.05mol/L sodium-acetate buffer (pH 5.0)-methanol (90:10) as mobile phase, detect with diode array detector (DAD) detector, the detection wavelength is 246nm, and flow velocity is per minute 0.5ml, and column temperature is 30 ℃.The accurate need testing solution 5 μ l that draw, the injection liquid chromatography is measured, and records the chromatogram in 12 minutes.The DAD ultraviolet detection spectrogram of main peak in the test sample chromatogram (maximum peak area) has absorption maximum at the wavelength place of 246nm and 286nm.
2, check
Color and luster: get this product 0.05 and restrain, add water 10ml dissolving and make the solution that every 1ml contains 5mg, press (" an appendix XI of Chinese pharmacopoeia first method) check, compare with yellow No. 7 standard color solutions, must not be darker. in accordance with the law
N-butyl alcohol: the preparation essence of inner mark solution claims that the isoamyl alcohol reference substance is an amount of, adds without organic water to be mixed with the solution that every 1ml contains 10 μ g, as inner mark solution.
The preparation essence of reference substance solution claims that the n-butyl alcohol reference substance is an amount of, adds inner mark solution and makes the solution that 1ml contains 10 μ g, in contrast product solution.
Algoscopy: precision takes by weighing this product 0.5g, and the accurate inner mark solution 5ml that adds dissolves, and shakes up, and is need testing solution.Get each 2 μ l of reference substance solution and need testing solution, inject gas chromatograph, measure according to organic solvent residual method (" two appendix VIII of Chinese pharmacopoeia P method), with 401 organic carrier chromatographic columns (column length 2m), 170 ℃ of mensuration of column temperature, press internal standard method with peak area and calculate the n-butyl alcohol residual quantity, must not surpass 0.1%.
Tannin: get this product 0.05g, add water 1ml dissolving after, add 1 of spirit of vinegar, add again 4～5 of gelatin sodium chloride solutions (contain gelatin 1%, the aqueous solution of sodium chloride 10% must fresh preparation), muddiness and precipitation must not appear.
Resin: get this product 0.25g, add water 5ml dissolving after, add 1 of hydrochloric acid, placed 30 minutes, should separate out without the resin-like thing.
Oxalates: get this product 0.10g, add water 2ml dissolving after, add 2～3 of 3% calcium chloride test solutions, placed 10 minutes, muddiness or precipitation must not appear.
Potassium ion: get this product 0.10g, burn to carbonization with little heated first, 500～600 ℃ of blazing extremely fully ashing, add 6% acetic acid and make dissolving again.Put in the 25ml measuring bottle, thin up is to scale, mixing, measuring 1ml puts in the 10ml nessler colorimetric tube, add 12 of alkaline formaldehyde solution (get formalin, transfer pH to 8.0～9.0 with the 0.1mol/L sodium hydroxide solution), 2 of 3% editic acid sodium solutions, 3% tetraphenyl borate sodium solution 0.5ml adds water to 10ml as the test sample pipe.The accurate potassium ion solution of label taking (100 μ g/ml) 0.8ml puts in the 10ml nessler colorimetric tube in addition, and the same operation is QC in contrast, gets the test sample pipe and contrasts QC and estimate than turbid, and the test sample pipe must not be more turbid.
Standard potassium ion solution preparation: get an amount of porphyrize of potassium sulfate, be dried to constant weight in 110 ℃, precision takes by weighing 2.330g, adds water and makes in right amount and be dissolved into 1000ml, and the accurate 10ml thin up of drawing becomes 100ml, and get final product, and every 1ml is equivalent to 100 μ g potassium ions.
Protein: get this product 0.1g, add water 2ml dissolving, add freshly prepared 30% sulfosalicylic acid solution 2ml, mixing was placed 5 minutes, muddiness must not occur.
Loss on drying: 105 ℃ of dryings 3 hours, less loss weight must not cross 15.0%.By (" an appendix IX of Chinese pharmacopoeia G) check.
Residue on ignition: get this product 1.0g, press (" an appendix IX of Chinese pharmacopoeia J) check, leave over residue and must not cross 1.0%. in accordance with the law
Heavy metal: get residue under the residue on ignition item, press (" an appendix IX of Chinese pharmacopoeia E the second method) check, contain heavy metal and must not cross 20/1000000ths. in accordance with the law
Arsenic salt: get this product 1.0g, slowly heat carbonization, incomplete such as carbonization, add a small amount of sulphuric acid moistening after, slowly heating makes complete carbonization, in 500～600 ℃ of blazing ashing, let cool again, add hydrochloric acid 5ml, make its dissolving in the water-bath, add water 23ml, press (" an appendix IX of Chinese pharmacopoeia F first method) check, contain arsenic salt and must not cross 2/1000000ths. in accordance with the law
Finger printing: get this product 0.05g, thin up is to 5ml, by strong-base anion-exchange resin chromatographic column (Dowex2, Cl-type, 200 orders, internal diameter 1.5cm, high 2.5cm, wet method dress post, 0.5 mol/L sodium hydroxide solution 10ml eluting, again water 10ml eluting adopted in the chromatographic column pretreatment, for subsequent use), water 10ml eluting discards water elution liquid, use again 0.25mol/L acetum eluting, discard just eluent 5ml, collect continuous eluent 25ml, shake up, as need testing solution.Get the inosine reference substance an amount of, accurately weighed, add water and be mixed with the solution that every 1ml contains inosine 50 μ g, in contrast product solution.Measure according to high performance liquid chromatography (" an appendix VI of Chinese pharmacopoeia D), take octadecylsilane chemically bonded silica as filler, chromatographic column (column length 150mm, column internal diameter are 4.6mm); Gradient elution, take 0.05 mol/L sodium-acetate buffer (pH 5.0) as mobile phase A, take methanol as Mobile phase B, the detection wavelength is 254nm, and flow velocity is per minute 0.6ml, and column temperature is 30 ℃.Number of theoretical plate calculates by the inosine peak should be not less than 5000.
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0～5 | 90 | 10 |
| 5～15 | 90→74 | 10→26 |
| 15～18 | 74 | 26 |
Precision is drawn reference substance solution and each 5 μ l of need testing solution respectively, and the injection liquid chromatography records the chromatogram in 25 minutes.The test sample chromatogram should be basically identical with standard finger-print.The test sample chromatogram is imported similarity evaluation (2004,1.0B version), compare with standard finger-print, calculate similarity.Similarity should be not less than 0.90.
3, assay
4, effective component content is measured in the cockroach extractive
The mensuration of compound nucleoside base: precision measures cockroach extractive 1ml, puts in the 50ml measuring bottle, with the dissolving of glycine-hydrochloride buffer and be diluted to scale, shake up, precision measures 5ml and puts in the 100ml measuring bottle, adds above-mentioned buffer to scale, shake up, namely get need testing solution.According to ultraviolet visible spectrophotometry (" appendix VA of Chinese pharmacopoeia), measure trap at 254nm wavelength place, be calculated as follows the compound nucleoside base contents C(mg of every ml cockroach extractive injection)
?
In the formula: A is the need testing solution trap
490 when being 1% for compound nucleoside base class concentration in the cockroach extractive at the average absorption degree at 254nm wavelength place.
N is extension rate
Measurement result is to contain compound nucleoside base among the every 1ml of cockroach extractive to should be 10.0mg～18.0mg.
In conjunction with amino acid whose mensuration:
The preparation standard curve.Precision takes by weighing glutamic acid reference substance 10mg, adds approximately 160ml water temperature heat of solution, puts in the 200ml volumetric flask, adds water to scale, shakes up, and namely gets the reference substance solution that contains 0.05mg among every 1ml.Get 6 in tool plug test tube, accurate reference substance solution 0.2,0.4,0.6,0.8, the 1.0ml of adding adds water to respectively 1.0ml respectively, respectively adds 0.2mol/L citrate buffer solution (pH5.0) 1.0ml take 1.0ml water as blank.Ninhydrin reagent 1.0ml shakes up, and heating is 15 minutes in 100 ℃ of water-baths, take out, use water cooling, placed 5～10 minutes, each adds 60% ethanol 3.0ml, shakes up, and measures trap at 570nm wavelength place according to ultraviolet visible spectrophotometry (" an appendix V of Chinese pharmacopoeia A).Take aminoglutaric acid concentration as abscissa, trap is vertical coordinate drawing standard curve.
The preparation need testing solution.Precision measures cockroach extractive 1.0ml, in the 50ml measuring bottle, adds water to scale, shakes up, and is the test sample diluent.Precision measures 1.0ml test sample diluent, put in the sky ampoule, add 1.0ml hydrochloric acid, sealing was in 110 ℃ of hydrolysis 8 hours, taking-up lets cool, all forward content to evaporating dish mid-boiling water bath evaporate to dryness, add water and make in right amount in dissolving and the immigration 10ml measuring bottle, add water to scale, shake up, be the test sample hydrolyzed solution.
Measure.Precision measures test sample hydrolyzed solution 0.1ml, adds water to 1.0ml, places test tube A, is test sample hydrolyzed solution not; Getting test sample hydrolyzed solution 1.0ml places test tube B many.Take 1.0ml water as blank, according to the method under the above-mentioned standard curve preparation from " respectively adding 0.2mol/L citrate buffer solution (pH5.0) 1.0ml ", measure respectively the trap of not hydrolysis and hydrolyzed solution, find its amino acid concentration from standard curve, calculate, namely get every gram cockroach extractive Determination of Free Amino Acids (A) and total amino acids content (B), by (B-A) namely get in every gram cockroach extractive in conjunction with amino acid content.
The every 1ml of this product contains in conjunction with aminoacid with glutamic acid (C
5H
9NO
4) meter, should be 15.0 mg～25.0mg.
The mensuration of uracil, hypoxanthine and inosine:
According to " the high effective liquid chromatography for measuring of an appendix VI of Chinese pharmacopoeia D.
Chromatographic condition and system suitability.Take octadecylsilane chemically bonded silica as filler.Mobile phase A is 0.05mol/L sodium-acetate buffer (pH5.0); Mobile phase B is methanol-mobile phase A (80:20).According to the form below carries out gradient elution; The detection wavelength is 254nm, and flow velocity is 0.5ml/min, and number of theoretical plate calculates by uracil, hypoxanthine and inosine peak respectively all should be not less than 3000.Separating degree between uracil, hypoxanthine and the inosine should meet the requirements.
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0～5 | 90 | 10 |
| 5～15 | 90→70 | 10→30 |
| 15～18 | 70 | 30 |
The preparation of reference substance solution.It is an amount of that precision takes by weighing uracil, hypoxanthine and inosine reference substance, adds mobile phase A and make and contain the solution that uracil, hypoxanthine and inosine are respectively 30 μ g, 40 μ g, 70 μ g among every 1ml, shakes up, and get final product.
The preparation of need testing solution.Precision measures cockroach extractive 1ml, puts in the 50ml measuring bottle, is diluted to scale with mobile phase A, shakes up, and get final product.
Measure.Precision is drawn reference substance solution and each 10 μ l of need testing solution respectively, and the injection liquid chromatography is measured, and be get final product.
Contain uracil (C among the every ml of cockroach extractive
4H
4N
2O
2) should be 1.0mg～1.8mg, hypoxanthine (C
5H
5N
4O) should be 1.5mg～2.5mg, inosine (C
10H
12N
4O
5) should be 3.5mg～5.0mg.
Embodiment 1
Get the dried polypide coarse powder of cockroach 1000g, added 90% ethanol 5L dipping 48 hours, make the slow percolation of solvent with 90%% ethanol again and be little yellow to filtrate, filtrate gets thick paste through concentrating under reduced pressure, simultaneously Recycled ethanol; Behind alcohol extraction thick paste importing oil water separator, the purified water that adds 4 times of weight portions fully stirs, and leaves standstill to layering obviously, removes bottom precipitate and upper strata oils and fats, collects the brown medicinal liquid in middle level; Medicinal liquid adds the medical injection active carbon of particle diameter 200～325 orders, the last fully stirring static 1 hour, is adsorbed as colourless rear dress post to medicinal liquid, liquid is drained, add the water-saturated n-butanol eluting, collect the eluting medicinal liquid, be eluted to the medicinal liquid color and be not deeper than yellow color solution No. 4; The eluting medicinal liquid gets thick paste at 60 ℃ of lower concentrating under reduced pressure, and reclaims n-butyl alcohol or reclaim phenol solution; Stir behind 65% ethanol of gained thick paste with 8 times of weight portions, 4 ℃ of lower cold preservations 12 hours, filter to get supernatant, the supernatant concentrating under reduced pressure gets thick paste, simultaneously Recycled ethanol; After the gained thick paste fully stirs with the purified water of 8 times of weight portions, filter after 12 hours 4 ℃ of lower cold preservations, filtering residue is at 2 ℃ of lower low-temperature centrifugations, merging filtrate and centrate obtain clear liquid, the medical injection active carbon of particle diameter 200 orders that adds liquid measure 0.1% weight ratio in the clear liquid, the limit edged stirs, and after being heated to 60 ℃ static 0.5 hour; Then decarbonization filtering, filtered solution filters by the film filter of aperture 0.22 μ m, and concentrating under reduced pressure gets approximately 5.8g of cockroach extractive thick paste to filtered solution under 60 ℃ of temperature through not being higher than after the ultrafiltration apparatus ultrafiltration again; The relative density of described thick paste is 1.2～1.3.
The present embodiment cockroach extractive consists of after testing: compound nucleoside base 36.3%, in conjunction with aminoacid 40.2%, uracil (C
4H
4N
2O
2) 2.5%, hypoxanthine (C
5H
5N
4O) 3.3%, inosine (C
10H
12N
4O
5) 6.5%.
Embodiment 2
Get the dried polypide coarse powder of cockroach 1000g, added 95% ethanol 10L dipping 60 hours, make the slow percolation of solvent with 95% ethanol again and be little yellow to filtrate, filtrate gets thick paste through concentrating under reduced pressure, simultaneously Recycled ethanol; Behind alcohol extraction thick paste importing oil water separator, the purified water that adds 6 times of weight portions fully stirs, and leaves standstill to layering obviously, removes bottom precipitate and upper strata oils and fats, collects the brown medicinal liquid in middle level; Medicinal liquid adds the medical injection active carbon of particle diameter 325 orders, the last fully stirring static 2 hours, is adsorbed as colourless rear dress post to medicinal liquid, liquid is drained, adding concentration is 5% phenol solution eluting, collects the eluting medicinal liquid, is eluted to the medicinal liquid color and is not deeper than yellow color solution No. 4; The eluting medicinal liquid gets thick paste at 80 ℃ of lower concentrating under reduced pressure, and reclaims n-butyl alcohol or reclaim phenol solution; Stir behind 85% ethanol of gained thick paste with 10 times of weight portions, 8 ℃ of lower cold preservations 24 hours, filter to get supernatant, the supernatant concentrating under reduced pressure gets thick paste, simultaneously Recycled ethanol; After the gained thick paste fully stirs with the purified water of 10 times of weight portions, filter after 24 hours 8 ℃ of lower cold preservations, filtering residue is at 6 ℃ of lower low-temperature centrifugations, merging filtrate and centrate obtain clear liquid, the medical injection active carbon of particle diameter 325 orders that adds liquid measure 0.5% weight ratio in the clear liquid, the limit edged stirs, and after being heated to 80 ℃ static 1 hour; Then decarbonization filtering, filtered solution again after ultrafiltration concentrating under reduced pressure get cockroach extractive thick paste 6g; The relative density of described thick paste is 1.2～1.3.
The present embodiment cockroach extractive consists of after testing: compound nucleoside base 20.8%, in conjunction with aminoacid 49.1%, uracil (C
4H
4N
2O
2) 2.3%, hypoxanthine (C
5H
5N
4O) 4.6%, inosine (C
10H
12N
4O
5) 9.1%.
Embodiment 3
Get the dried polypide coarse powder of cockroach 1000g, added 95% ethanol 8L dipping 50 hours, make the slow percolation of solvent with 95% ethanol again and be little yellow to filtrate, filtrate gets thick paste through concentrating under reduced pressure, simultaneously Recycled ethanol; Behind alcohol extraction thick paste importing oil water separator, the purified water that adds 5 times of weight portions fully stirs, and leaves standstill to layering obviously, removes bottom precipitate and upper strata oils and fats, collects the brown medicinal liquid in middle level; Medicinal liquid adds the medical injection active carbon of particle diameter 250 orders, fully stirred rear static 1.5 hours, be adsorbed as colourless rear dress post to medicinal liquid, liquid is drained, adding water-saturated n-butanol or concentration are 8% phenol solution eluting, collect the eluting medicinal liquid, be eluted to the medicinal liquid color and be not deeper than yellow color solution No. 4; The eluting medicinal liquid gets thick paste at 70 ℃ of lower concentrating under reduced pressure, and reclaims n-butyl alcohol or reclaim phenol solution; Stir behind 75% ethanol of gained thick paste with 9 times of weight portions, 6 ℃ of lower cold preservations 18 hours, filter to get supernatant, the supernatant concentrating under reduced pressure gets thick paste, simultaneously Recycled ethanol; After the gained thick paste fully stirs with the purified water of 9 times of weight portions, filter after 18 hours 6 ℃ of lower cold preservations, filtering residue is at 4 ℃ of lower low-temperature centrifugations, merging filtrate and centrate obtain clear liquid, the medical injection active carbon of particle diameter 250 orders that adds liquid measure 0.3% weight ratio in the clear liquid, the limit edged stirs, and after being heated to 70 ℃ static 0.8 hour; Then decarbonization filtering, filtered solution filters by the film filter of aperture 0.22 μ m, and concentrating under reduced pressure gets approximately 5.6g of cockroach extractive thick paste to filtered solution under 70 ℃ of temperature through not being higher than after the ultrafiltration apparatus ultrafiltration again; The relative density of described thick paste is 1.2～1.3.
The present embodiment cockroach extractive consists of after testing: compound nucleoside base 39.3%, in conjunction with aminoacid 31.2%, uracil (C
4H
4N
2O
2) 3.6%, hypoxanthine (C
5H
5N
4O) 3.3%, inosine (C
10H
12N
4O
5) 5.5%.
Embodiment 4
Get the dried polypide coarse powder of cockroach 1000g, add 90% ethanol 5L hot reflux and extracted 8 hours, filtrate gets thick paste through concentrating under reduced pressure, simultaneously Recycled ethanol; Behind alcohol extraction thick paste importing oil water separator, the purified water that adds 4 times of weight portions fully stirs, and leaves standstill to layering obviously, removes bottom precipitate and upper strata oils and fats, collects the brown medicinal liquid in middle level; Medicinal liquid adds the medical injection active carbon of particle diameter 200 orders, and the last fully stirring static 1 hour, be adsorbed as colourless rear dress post to medicinal liquid, liquid is drained, add the water-saturated n-butanol eluting, collect the eluting medicinal liquid, be eluted to the medicinal liquid color and be not deeper than yellow color solution No. 4; The eluting medicinal liquid gets thick paste at 60 ℃ of lower concentrating under reduced pressure, and reclaims n-butyl alcohol or reclaim phenol solution; Stir behind 65% ethanol of gained thick paste with 8 times of weight portions, 4 ℃ of lower cold preservations 12 hours, filter to get supernatant, the supernatant concentrating under reduced pressure gets thick paste, simultaneously Recycled ethanol; After the gained thick paste fully stirs with the purified water of 8 times of weight portions, filter after 12 hours 4 ℃ of lower cold preservations, filtering residue is at 2 ℃ of lower low-temperature centrifugations, merging filtrate and centrate obtain clear liquid, the medical injection active carbon of particle diameter 200 orders that adds liquid measure 0.1% weight ratio in the clear liquid, the limit edged stirs, and after being heated to 60 ℃ static 0.5 hour; Then decarbonization filtering, filtered solution filters by the film filter of aperture 0.22 μ m, and concentrating under reduced pressure gets approximately 5.2g of cockroach extractive thick paste to filtered solution under 70 ℃ of temperature through not being higher than after the ultrafiltration apparatus ultrafiltration again; The relative density of described thick paste is 1.2～1.3.
The present embodiment cockroach extractive consists of after testing: compound nucleoside base 35%, in conjunction with aminoacid 43%, uracil (C
4H
4N
2O
2) 3.01%, hypoxanthine (C
5H
5N
4O) 4.2%, inosine (C
10H
12N
4O
5) 8.0%.
Embodiment 5
Get the dried polypide coarse powder of cockroach 1000g, add 95% ethanol 10L hot reflux and extracted 12 hours, filtrate gets thick paste through concentrating under reduced pressure, simultaneously Recycled ethanol; Behind alcohol extraction thick paste importing oil water separator, the purified water that adds 6 times of weight portions fully stirs, and leaves standstill to layering obviously, removes bottom precipitate and upper strata oils and fats, collects the brown medicinal liquid in middle level; Medicinal liquid adds the medical injection active carbon of particle diameter 325 orders, the last fully stirring static 2 hours, is adsorbed as colourless rear dress post to medicinal liquid, liquid is drained, adding concentration is 5% phenol solution eluting, collects the eluting medicinal liquid, is eluted to the medicinal liquid color and is not deeper than yellow color solution No. 4; The eluting medicinal liquid gets thick paste at 80 ℃ of lower concentrating under reduced pressure, and reclaims n-butyl alcohol or reclaim phenol solution; Stir behind 85% ethanol of gained thick paste with 10 times of weight portions, 8 ℃ of lower cold preservations 24 hours, filter to get supernatant, the supernatant concentrating under reduced pressure gets thick paste, simultaneously Recycled ethanol; After the gained thick paste fully stirs with the purified water of 10 times of weight portions, filter after 24 hours 8 ℃ of lower cold preservations, filtering residue is at 6 ℃ of lower low-temperature centrifugations, merging filtrate and centrate obtain clear liquid, the medical injection active carbon of particle diameter 325 orders that adds liquid measure 0.5% weight ratio in the clear liquid, the limit edged stirs, and after being heated to 80 ℃ static 1 hour; Then decarbonization filtering, filtered solution filters by the film filter of aperture 0.22 μ m, and concentrating under reduced pressure gets approximately 5.4g of cockroach extractive thick paste to filtered solution under 70 ℃ of temperature through not being higher than after the ultrafiltration apparatus ultrafiltration again; The relative density of described thick paste is 1.2～1.3.
The present embodiment cockroach extractive consists of after testing: compound nucleoside base 32%, in conjunction with aminoacid 45.2%, uracil (C
4H
4N
2O
2) 3.6%, hypoxanthine (C
5H
5N
4O) 4.0%, inosine (C
10H
12N
4O
5) 7.02%.
Embodiment 6
Get the dried polypide coarse powder of cockroach 1000g, get the dried polypide coarse powder of cockroach 1000g, add 90% ethanol 8L hot reflux and extracted 10 hours, filtrate gets thick paste through concentrating under reduced pressure, simultaneously Recycled ethanol; Behind alcohol extraction thick paste importing oil water separator, the purified water that adds 5 times of weight portions fully stirs, and leaves standstill to layering obviously, removes bottom precipitate and upper strata oils and fats, collects the brown medicinal liquid in middle level; Medicinal liquid adds the medical injection active carbon of particle diameter 250 orders, fully stirred rear static 1.5 hours, be adsorbed as colourless rear dress post to medicinal liquid, liquid is drained, adding water-saturated n-butanol or concentration are 8% phenol solution eluting, collect the eluting medicinal liquid, be eluted to the medicinal liquid color and be not deeper than yellow color solution No. 4; The eluting medicinal liquid gets thick paste at 70 ℃ of lower concentrating under reduced pressure, and reclaims n-butyl alcohol or reclaim phenol solution; Stir behind 75% ethanol of gained thick paste with 9 times of weight portions, 6 ℃ of lower cold preservations 18 hours, filter to get supernatant, the supernatant concentrating under reduced pressure gets thick paste, simultaneously Recycled ethanol; After the gained thick paste fully stirs with the purified water of 9 times of weight portions, filter after 18 hours 6 ℃ of lower cold preservations, filtering residue is at 4 ℃ of lower low-temperature centrifugations, merging filtrate and centrate obtain clear liquid, the medical injection active carbon of particle diameter 250 orders that adds liquid measure 0.3% weight ratio in the clear liquid, the limit edged stirs, and after being heated to 70 ℃ static 0.8 hour; Then decarbonization filtering, filtered solution filters by the film filter of aperture 0.22 μ m, and concentrating under reduced pressure gets approximately 5.8g of cockroach extractive thick paste to filtered solution under 70 ℃ of temperature through not being higher than after the ultrafiltration apparatus ultrafiltration again; The relative density of described thick paste is 1.2～1.3.
The present embodiment cockroach extractive consists of after testing: compound nucleoside base 26%, in conjunction with aminoacid 39.1%, uracil (C
4H
4N
2O
2) 2.2%, hypoxanthine (C
5H
5N
4O) 3.8%, inosine (C
10H
12N
4O
5) 6.7%.
Embodiment 7
Get embodiment 1 gained cockroach extractive extractum 50g(in dry product), dissolve in right amount with water for injection, add 200g PEG-4000,9g sodium chloride, mixing, inject water to 1000ml, transfer pH value 5.4～6.4, mixing, filter, canned, sterilization gets final product injection.
Embodiment 8
Get embodiment 2 gained cockroach extractive extractum 50g(in dry product), dissolve in right amount with water for injection, add sodium chloride 9g, mixing, inject water to 1000ml, transfer pH value 5.4～6.4, mixing, aseptic filtration, fill, lyophilization namely obtains lyophilized injectable powder.
Embodiment 9
Get embodiment 3 gained cockroach extractive extractum 50g(in dry product), add starch 50g, mixing, 120 mesh sieves are crossed in 80 ℃ of dryings, pulverizing, get mixed powder, add appropriate amount of ethanol, mixing, granulation, add again 1% Pulvis Talci and 0.3% magnesium stearate mix homogeneously after, incapsulate, namely obtain capsule.
Embodiment 10
Get embodiment 4 gained cockroach extractive extractum 50g(in dry product), add an amount of purified water dissolving, add cockroach extractive, the sucrose of 2 times of amounts and the dextrin of 2 times of amounts, mixing adds an amount of ethanol and granulates as wetting agent, dry, granulate, mix the agent of packing granulation.
Embodiment 11
Get embodiment 5 gained cockroach extractive extractum 50g(in dry product), add starch 50g, mixing, 120 mesh sieves are crossed in 80 ℃ of dryings, pulverizing, get mixed powder, add appropriate amount of ethanol, mixing, granulation, add again 0.3% magnesium stearate and 1% silicon dioxide and mix rear tabletting, coating, packing, and get final product.
Embodiment 12
Get embodiment 6 gained cockroach extractive extractum 50g(in dry product), add an amount of purified water dissolving, add 10% glycerol, 0.3% sodium benzoate, mixing adds purified water to 500ml, transfers pH value 6.4～7.4, mixing, fill, sterilization namely gets oral solutions.
Embodiment 13
Get embodiment 2 gained cockroach extractive extractum 50g(in dry product), with after the polyethylene glycol 6000 melting of substrate 120g with cockroach extractive extractum mix homogeneously, 80 ℃ of lower insulations, be 3.3mm with internal diameter, external diameter is 5.1 mm, dropper, dripping speed with 60-70/minutes splashes in the methyl-silicone oil, collect drop pill, except liquid coolant, and get final product.
The test of pesticide effectiveness result of pharmaceutical preparation of the present invention
Gained preparation of the present invention has benefiting QI for activating blood circulation, activating YANG for promoting diuresis.Be used for gas sun two void, cardiopalmus, tachypnea, edema, dim complexion, lip cyanosis due to the blood-stasis internal-depression; Above-mentioned patient is seen in chronic heart failure.
The random sample of selecting carries out controlled trial, injection of the present invention and dobutamine matched group, each 100 example; Other has open trial 208 examples, total 408 examples.
Result of the test shows: injection treatment group obvious effective rate 37% of the present invention, effective percentage 89%; Open trial group obvious effective rate 55.29%, effective percentage 87.5%.Preparation for treating group of the present invention and matched group (dobutamine) compare, statistics has significant difference P ﹤ 0.01.
Preparation of the present invention declines whole-heartedly to right heart failure, cardiac function II level, and III level curative effect is obvious, all is better than the dobutamine matched group.Two groups of cardiac function onset time no difference of science of statistics P＞0.05. treatment group cardiac function onset time is 3.31 days.
Preparation for treating group of the present invention is respectively 93.35% and 88.46% to Qi deficiency blood stasis type and motive YIN-deficiency type curative effect, with matched group there were significant differences P ﹤ 0.01 and P ﹤ 0.05.
Preparation for treating group of the present invention has obvious curative effects to breathing, heart rate and edema.Heart rate onset time comparison is inhaled in two group callings, and significant difference P ﹤ 0.01 and P ﹤ 0.05 are all arranged.
Traditional Chinese medical science disease integral contrast, preparation for treating group of the present invention is improved significantly better than matched group P ﹤ 0.01 cardiopalmus, tachypnea, weak and fear of cold integration.Electrocardiogram, rabat, blood pressure, two groups of no difference of science of statistics, security inspection has no obvious adverse reaction.
In sum, preparation of the present invention can improve cardiac function, alleviates the diseases such as cardiopalmus, tachypnea, edema, and is obvious to Qi deficiency blood stasis type and motive YIN-deficiency type curative effect.Treatment congestive heart failure curative effect is reliable, uses safety.
Claims (1)
1. the preparation method of a cockroach extractive, it is characterized in that being may further comprise the steps: the dried polypide of cockroach is ground into coarse powder, make thick paste through 90 ~ 95% ethanol with percolation or reflux extraction, adding purified water in the thick paste fully stirs, precipitate and oils and fats are removed in oil-water separation, collect the water layer medicinal liquid, activated carbon adsorption, upper prop separates, and n-butyl alcohol eluting or phenol solution eluting carry out the secondary ethanol extraction after eluent is concentrated, filter after the cold preservation, carry out water extraction after filtrate is concentrated, centrifugal filtration gets water extraction liquid after cold preservation again, and water extraction liquid is through decolouring, concentrate to get the cockroach extractive thick paste after the ultrafiltration; Described percolation is, adds 90 ~ 95% alcohol dipping 48 ~ 60 hours of 5 ~ 10 times of weight ratios in the dried worm coarse powder of cockroach, uses 90 ~ 95% ethanol to make the slow percolation of solvent again and is little yellow to filtrate, and filtrate gets thick paste through concentrating under reduced pressure, simultaneously Recycled ethanol; Described reflux extraction is, 90 ~ 95% alcohol heat reflux that add 5 ~ 10 times of weight ratios at the dried worm coarse powder of cockroach extracted 8 ~ 12 hours, and filtrate gets thick paste through concentrating under reduced pressure, simultaneously Recycled ethanol;
Described oil-water separation step is that behind alcohol extraction thick paste importing oil water separator, the purified water that adds 4 ~ 6 times of weight portions fully stirs, and leaves standstill to layering obviously, removes bottom precipitate and upper strata oils and fats, collects the brown medicinal liquid in middle level;
Described upper prop separating step is, medicinal liquid adds the medical injection active carbon of particle diameter 200 ~ 325 orders, fully stirred rear static 1 ~ 2 hour, be adsorbed as colourless rear dress post to medicinal liquid, liquid is drained, adding water-saturated n-butanol or concentration are 5～10% phenol solution eluting, collect the eluting medicinal liquid, are eluted to the medicinal liquid color and are not deeper than yellow color solution No. 4; The eluting medicinal liquid gets thick paste at 60～80 ℃ of lower concentrating under reduced pressure, and reclaims n-butyl alcohol or reclaim phenol solution;
Described secondary alcohol extraction step is, with stirring behind 65 ~ 85% ethanol of upper prop separating step gained thick paste with 8 ~ 10 times of weight portions, 4 ~ 8 ℃ of lower cold preservations 12 ~ 24 hours, filters to get supernatant, and the supernatant concentrating under reduced pressure gets thick paste, simultaneously Recycled ethanol;
Described water extraction step is, after secondary alcohol extraction step gained thick paste fully stirred with the purified water of 8 ~ 10 times of weight portions, filter after 12 ~ 24 hours 4 ~ 8 ℃ of lower cold preservations, filtering residue is at 2 ~ 6 ℃ of lower low-temperature centrifugations, merging filtrate and centrate obtain clear liquid, the medical injection active carbon of particle diameter 200 ~ 325 orders that adds liquid measure 0.1 ~ 0.5% weight ratio in the clear liquid, the limit edged stirs, and after being heated to 60 ~ 80 ℃ static 0.5 ~ 1 hour; Then decarbonization filtering, filtered solution again after ultrafiltration concentrating under reduced pressure get the cockroach extractive thick paste; The relative density of described thick paste is 1.2 ~ 1.3.
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| CN102885856B (en) * | 2012-11-10 | 2014-02-26 | 昆明赛诺制药有限公司 | Production method for producing medicine for treating hepatitis B by periplaneta americana extract |
| CN104337843A (en) * | 2013-08-02 | 2015-02-11 | 成都百草和济科技有限公司 | Decolourized periplaneta americana extract as well as preparation method and application thereof |
| CN109820873B (en) * | 2019-04-17 | 2023-05-02 | 云南京新生物科技有限公司 | Defatted periplaneta americana and preparation method and application thereof |
| CN111925408B (en) * | 2020-08-14 | 2023-06-06 | 云南中医药大学 | Preparation method of periplaneta americana polypeptide extract taking water as medium |
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