CN101152246B - Pharmaceutical composition for cardiovascular and cerebrovascular diseases and method for preparing the same - Google Patents
Pharmaceutical composition for cardiovascular and cerebrovascular diseases and method for preparing the same Download PDFInfo
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- CN101152246B CN101152246B CN2006101594835A CN200610159483A CN101152246B CN 101152246 B CN101152246 B CN 101152246B CN 2006101594835 A CN2006101594835 A CN 2006101594835A CN 200610159483 A CN200610159483 A CN 200610159483A CN 101152246 B CN101152246 B CN 101152246B
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- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000012109 statistical procedure Methods 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- WCTAGTRAWPDFQO-UHFFFAOYSA-K trisodium;hydrogen carbonate;carbonate Chemical compound [Na+].[Na+].[Na+].OC([O-])=O.[O-]C([O-])=O WCTAGTRAWPDFQO-UHFFFAOYSA-K 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
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- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the medical technical field and discloses a drug combination, which is made from a danshen root and a snakegourd fruit according to certain proportion and is used for remedying the cardio-cerebrovascular disease and the preparation, which contains the drug combination and the preparation method. The drug combination can be made into any preparation, which is acceptable in the clinic or the pharmacy, and the injection preparation and the oral preparation are preferential. The danshen root in the drug combination can be replaced by danshen root extract; the snakegourd fruit can be replaced by snakegourd fruit extract, and the danshen root extract and the snakegourd fruit extract can be directly put as the raw materials. The drug combination has the synergistic interaction effect with the good stability, and the effect is improved greatly than singly using the danshen root extract or the snakegourd fruit extract.
Description
[technical field]
The invention belongs to medical technical field, relate to a kind of Radix Salviae Miltiorrhizae of cardiovascular and cerebrovascular disease or pharmaceutical composition of its extract and Fructus Trichosanthis or its extract of being used for, and preparation method thereof and contain the preparation of this pharmaceutical composition.
[background technology]
Cardiovascular and cerebrovascular disease all is the formidable enemy who threatens human health all the time, raising year by year in China along with living standard, the change of life style, and China progresses into aged society, the threat of cardiovascular and cerebrovascular disease is serious day by day, and present epidemiological survey result shows that cardiovascular and cerebrovascular disease has been the primary disease that threatens Chinese population health, particularly its morbidity and dead age are rejuvenation trend day by day, and how effectively control also just causes people's great attention.
Cardiovascular and cerebrovascular disease comprises coronary heart disease, angina pectoris, myocardial infarction, blood stasis type pulmonary heart disease, ischemic encephalopathy, cerebral thrombosis, hypertension, hyperlipidemia etc.The main pathogenic factor of these diseases is that arteriosclerosis causes luminal stenosis or pipeline obstruction, thereby causes cerebral ischemia, causes that head is heavy, dizziness, headache, symptom such as uncomfortable in chest, and severe patient can cause the generation of apoplexy and myocardial infarction.Influence energy metabolism behind the cardiac-cerebral ischemia, multiple variations such as the accumulation of secondary lactic acid, calcium overload, radical damage.Many target spots reverse or improve these and change, and improving comprehensive therapeutic effect is the important goal of Drug therapy.
Radix Salviae Miltiorrhizae is the dry root and rhizome of labiate Radix Salviae Miltiorrhizae Salvia miltiorrhiza Bge.Bitter in the mouth, cold nature, GUIXIN, Liver Channel.Stasis-dispelling and pain-killing is arranged, promoting blood circulation to restore menstrual flow, the effect of the relieving restlessness that clears away heart-fire.Be used for menoxenia, amenorrhea dysmenorrhea ， lumps in the chest and abdomen, breast ventral spine pain, pyretic arthralgia pain, skin infection swell and ache dysphoria and insomnia, hepatosplenomegaly, angina pectoris.
Radix Salviae Miltiorrhizae has many-sided pharmacological action: can increase coronary flow to cardiovascular system; reduce myocardial excitability and conductivity; microcirculation improvement; the formation of antiplatelet gathering and thrombosis makes blood viscosity descend antioxidation; increase oxygen-resistant ability; anti-inflammation improves renal function, to the cerebral tissue ischemia with in the effects such as protection of perfusion injury.The effective ingredient of Radix Salviae Miltiorrhizae can be divided into fat-soluble and water miscible, and wherein, liposoluble constituent has: Tanshinone I, tanshinone, Tanshinone II B, cryptotanshinone etc.; Water soluble ingredient has: danshensu sodium, protocatechuic acid, protocatechualdehyde, salvianolic acid A, salvianolic acid B, salvianolic acid C etc., and Radix Salviae Miltiorrhizae total phenolic acids is the effective ingredient of Radix Salviae Miltiorrhizae blood circulation promoting and blood stasis dispelling, wherein the effect of salvianolic acid B is the strongest.
Fructus Trichosanthis is the dry mature fruit of cucurbitaceous plant Fructus Trichosanthis Trichosanthes kirilowii Maxim. or trichosanthes rosthornii Harms Trichosanthes rosthorniiHarms.Sweet in the mouth, little hardship, cold in nature, return lung, stomach, large intestine channel.The effect that clearing away heat and eliminating phlegm, relieving stuffiness of the chest by dispersing aggregation of pathogens is arranged, moisturize laxation.Be used for the cough due to lung-heat, the turbid Huang of expectorant is thick, obstruction of qi in the chest and cardialgia, and the blocked-up chest feeling of fullness, acute mastitis, lung abscess, acute appendicitis swells and ache, constipation.
Fructus Trichosanthis mainly contains oils and fats and organic acid, with trichosanic acid (Trichosanic acid C
18H
33O
2) be main, secondly be triterpene, a small amount of flavone and several amino acids.Pharmacological research shows that Fructus Trichosanthis and active component thereof have arrhythmia, protection myocardial ischemic injury, anticoagulant, blood fat reducing and blood vessel dilating etc. aspect cardiovascular.
At present, utilize the interaction of Radix Salviae Miltiorrhizae or Radix Salviae Miltiorrhizae extract and Fructus Trichosanthis or Fructus Trichosanthis extract, composition of prescription, the medicine of aspects such as preparation treatment cardiovascular and cerebrovascular disease does not appear in the newspapers as yet.
[summary of the invention]
One of purpose of the present invention provides a kind of being used to and prepares the compositions for the treatment of cardiovascular and cerebrovascular diseases medicament, makes the contained raw materials of effective components medicine of this pharmaceutical composition and is: Radix Salviae Miltiorrhizae or its extract and Fructus Trichosanthis or its extract.
Make the consisting of of crude drug of the contained active ingredient of this pharmaceutical composition: Radix Salviae Miltiorrhizae 50-2000 part, Fructus Trichosanthis 200-4000 part prove that through a large amount of screening experiment of the inventor pharmaceutical composition of the present invention all has synergism in above-mentioned weight portion scope; Be preferably: Radix Salviae Miltiorrhizae 100-1000 part, Fructus Trichosanthis 500-2000 part; More preferably: Radix Salviae Miltiorrhizae 200-400 part, Fructus Trichosanthis 1000-1500 part.
Radix Salviae Miltiorrhizae in the aforementioned pharmaceutical compositions and Fructus Trichosanthis can with appropriate solvent and method be independent or mixed extraction processing obtains its extract, and total extract is made clinically any or pharmaceutically acceptable preparation with the pharmaceutic adjuvant hybrid process again.The main effective ingredient of gained total extract is mainly phenolic acids and steroid compound.
Radix Salviae Miltiorrhizae in the aforementioned pharmaceutical compositions can be carried acid precipitation, alcohol extraction, water extract-alcohol precipitation or water by water and put forward multiple modes such as post and prepare, and the present invention has carried out preferably the extraction process of Radix Salviae Miltiorrhizae, and step is as follows:
Get red rooted salvia, be ground into coarse powder, decoct with water twice, add for the first time 12 times of amounts of water, add 10 times of amounts of water, each 2 hours for the second time, collecting decoction filters, and filtrate decompression is concentrated into the concentrated solution of relative density 1.10～1.15 (60 ℃), add ethanol and reach 85% to containing the alcohol amount, cold preservation 24 hours filters, filtrate recycling ethanol adds hydrochloric acid and transfers pH value to 2 to there not being the alcohol flavor, extracts 3 times with the ethyl acetate jolting, merge ethyl acetate liquid, evaporate to dryness.Residue adds the sour water dissolving of pH value 2, is added on the polyamide column of having handled well, with the water elution of 2 times of column volumes, discards water lotion earlier, and 95% ethanol elution of 4 times of column volumes of reuse is collected eluent, reclaims ethanol, and vacuum drying, promptly.
By the Radix Salviae Miltiorrhizae extract of above-mentioned prepared, yield is 1.5～2%, and Radix Salviae Miltiorrhizae total phenolic acids content is not less than 70% content of danshinolic acid B and is not less than 30%.
Fructus Trichosanthis in the aforementioned pharmaceutical compositions can extract preparation by following selection process, but is not limited only to following technology:
Get the Fructus Trichosanthis medical material, oven dry is ground into coarse powder, add entry reflux, extract, twice, add 10 times of water gagings at every turn, reflux, extract, 2 hours, filter, merging filtrate, being concentrated into relative density is the concentrated solution of 1.10～1.15 (60 ℃), add ethanol to content and reach 80%, placement is spent the night, and gets supernatant, reclaim ethanol to there not being the alcohol flavor, be evaporated to the thick paste shape, vacuum drying, promptly.
By the Fructus Trichosanthis extract of above-mentioned prepared, yield is 6～7%, and steroid compound content is not less than 20%.
In order to make pharmaceutical composition of the present invention reach better therapeutic, also above-mentioned Fructus Trichosanthis extract further can be made with extra care: after above-mentioned Fructus Trichosanthis extract is dissolved with suitable quantity of water, extract 2 times with the jolting of equivalent petroleum ether, water liquid extracts 3 times with the jolting of equivalent water-saturated n-butanol, merge n-butanol extracting liquid, be concentrated into dried, residue adds low amounts of water makes dissolving, last macroporous resin column, water, 15% ethanol, 70% ethanol elution are collected 70% ethanol elution respectively, decompression recycling ethanol, be concentrated into the thick paste shape, spray drying promptly gets the Fructus Trichosanthis essence extract.
By the Fructus Trichosanthis extract of above-mentioned prepared, yield is 3～4%, and steroid compound content is not less than 30%.
Pharmaceutical composition of the present invention can also be made up of Radix Salviae Miltiorrhizae extract and Fructus Trichosanthis extract, calculating (yield of Radix Salviae Miltiorrhizae extract is 1.5%～2.0%, and the yield of Fructus Trichosanthis extract is 3%～7%) its weight proportion according to extract with respect to the yield of medical material is: Radix Salviae Miltiorrhizae extract 1-40 part, Fructus Trichosanthis extract 5-280 part; Be preferably: Radix Salviae Miltiorrhizae extract 2-20 part, Fructus Trichosanthis extract 15-140 part; More preferably: Radix Salviae Miltiorrhizae extract 4-8 part, Fructus Trichosanthis extract 30-100 part.
The main effective ingredient of the Radix Salviae Miltiorrhizae extract in the aforementioned pharmaceutical compositions is a Radix Salviae Miltiorrhizae total phenolic acids, and content is not less than 50%, and wherein salvianolic acid B is not less than 30%; The main effective ingredient of Fructus Trichosanthis extract is a steroid compound, and content is not less than 20%, preferably is not less than 30%.
Each drug component gets consumption and gropes in a large number to sum up to draw through the inventor in the pharmaceutical composition of the present invention, and the consumption of each component all has better curative effect in above-mentioned weight range.Above-mentioned composition as if being unit with the gram, can be made the preparation of 10～1000 consumptions, as making 10～1000 as injection, 1～10 of each consumption.As tablet, can make 10～1000,1～10 of each consumption.More than form when producing and according to the corresponding proportion increase or to reduce, as large-scale production can be raw material with the kilogram, or is unit with the ton, and small-scale production can be unit with the gram also, weight can increase or reduce, but the constant rate of weight proportion between each composition.Above ratio obtains through science screening, and for especial patient, the ratio of can corresponding adjustment forming increases or reduce being no more than 100%.
Another object of the present invention is to provide a kind of compositions for the treatment of cardiovascular and cerebrovascular diseases medicament that is used to prepare.Pharmaceutical composition of the present invention can coronary artery dilator, and the alleviating vascular spasm increases coronary flow, improves coronary circulation; Reduce myocardial oxygen consumption, improve the ischemic myocardium contractile function; Can anticoagulant, blood viscosity lowering improves hemorheology and microcirculation; Improve the heart blood supply function, reduce cerebral vascular resistance, increase cerebrovascular flow, improve brain microcirculation; Decreased heart rate brings high blood pressure down, arrhythmia; Suppress renin-angiotensin system, reduce changes of Catecholamine Content, antiadrenergic drug is risen the sugar effect; Promote the hemopoietic system function, regulate body's immunity, improve bone metabolism, defying age, antitumor etc.Be mainly used in coronary heart disease, angina pectoris, myocardial infarction, blood-deficiency type cardiac insufficiency, ischemic cerebrovascular, and apoplexy and apoplexy sequela, hyperlipidemia etc.
The present composition can be made clinically any or pharmaceutically acceptable dosage form with acceptable accessories, can parenteral or mode such as oral administration be applied to the patient who needs this treatment, optimizing injection or oral formulations.
When being used for parenteral, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or concentrated solution that injection can be divided into injection, injectable sterile powder and concentrated solution for injection.Injection means that the confession that medicine is made is injected into sterile solution type injection, emulsion-type injection or the suspension type injection of using in the body, can be used for intramuscular injection, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2m, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection of using for intravenous drip also claims venous transfusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available venous transfusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray drying method or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic concentrated solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the conventional method production in the existing pharmaceutical field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solutions; Non-aqueous solvent commonly used is a vegetable oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, Polyethylene Glycol etc.During the preparation injection, can add suitable additives according to the character of medicine, as osmotic pressure regulator, pH value regulator, solubilizing agent, filler, antioxidant, antibacterial, emulsifying agent, suspending agent etc.Osmotic pressure regulator commonly used comprises sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol etc., preferred sodium chloride or glucose; PH value regulator commonly used comprises acetic acid-sodium acetate, lactic acid, citric acid-sodium citrate, sodium bicarbonate-sodium carbonate etc.; Solubilizing agent commonly used comprises polyoxyethylene sorbitan monoleate, propylene glycol, lecithin, polyoxyethylene castor oil etc.; Filler commonly used comprises lactose, mannitol, sorbitol, dextran etc.; Antioxidant commonly used has sodium sulfite, sodium sulfite, sodium pyrosulfite etc.; Antibacterial commonly used is phenol, cresol, chlorobutanol etc.Injection container commonly used has glass ampule, vial, plastic ampoule, plastic bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has buccal tablet, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coatel tablets etc.Capsule means medicine or is added with the adjuvant filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (soft gelatin capsule), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable adjuvant uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises drop pill, sugar pill, piller etc.Granule means that medicine and suitable adjuvant make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as granule), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral supernatant liquid preparation in suitable solvent.Oral suspensions means the slightly solubility solid drugs, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspension or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral formulations, can add suitable filler, binding agent, disintegrating agent, lubricant etc.Filler commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol etc.; Typical binders comprises sodium carboxymethyl cellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methylcellulose, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dried starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises magnesium stearate, Pulvis Talci, sodium lauryl sulphate, micropowder silica gel etc.
In sum, pharmaceutical composition of the present invention has the following advantages:
(1) adopts Radix Salviae Miltiorrhizae or its extract and Fructus Trichosanthis or its extract reasonable compatibility first, be used to prepare the medicine for the treatment of cardiovascular and cerebrovascular disease, and confirm that by experiment the two has synergistic function, be better than the two independent medication.
(2) pharmaceutical composition of the present invention proves through pharmaceutical research and drug effect animal experiment study result, by Radix Salviae Miltiorrhizae or its extract and Fructus Trichosanthis or its extract is the pharmaceutical composition that main component is made, can coronary blood flow increasing, increase blood supply of cardiac muscle, reduce left chamber EDP, reduce cardiac preload etc., obviously improve dog blood flow mechanics; Remarkable antiplatelet aggregation; Significantly reduce myocardial infarct size; The rabbit cerebral ischemia reperfusion injury had significant protective effect; Remove too much free radical in the body; Protective tissue.
Prove through pharmacological experiment that (3) drug effect of pharmaceutical composition of the present invention is better than using separately the drug effect of Radix Salviae Miltiorrhizae or its extract and Fructus Trichosanthis or its extract, has synergistic function, dosage reduces relatively, is with a wide range of applications.
(4) pharmaceutical composition effective ingredient of the present invention is clear and definite, the content height, and better stability of preparation, preparation technology is simple and easy to do, is convenient to control of quality, can guarantee clinical drug safety.
Below routine by experiment beneficial effect of further setting forth pharmaceutical composition of the present invention, these experimental examples comprise the pharmacodynamic experiment of pharmaceutical composition of the present invention, the compositions of Radix Salviae Miltiorrhizae or its extract and Fructus Trichosanthis or its extract is hereinafter to be referred as red melon compositions.Radix Salviae Miltiorrhizae extract in the experimental example comes from embodiment 1, and Fructus Trichosanthis extract comes from embodiment 2.
Experimental example 1: the research of red melon compositions drug combination drug effect
Animal subject: the Wistar rat, male, body weight 200～220g, 160.
Test sample: DANSHEN KELI agent: self-control is equivalent to crude drug 2.5g;
The Fructus Trichosanthis granule: self-control is equivalent to crude drug 10g;
Red melon granule, 12 groups, self-control, the crude drug proportioning sees Table 1.
Experimental technique: rat is divided into 16 groups at random.Every group 10.Be respectively matched group; Model group; DANSHEN KELI agent group; Fructus Trichosanthis granule group; Red melon granule: pellet+melon (50+1500,100+2000,200+4000,400+1000,200+1500,400+1500,200+1000,400+500,1000+1000,1000+1500,1000+500,2000+1000).Gastric infusion, once a day, continuous 7 days.
The rat experiment myocardial infarction model: it is fixing that animal pentobarbital intraperitoneal injection of anesthesia (45mg/kg) is faced upward the position.Tracheal intubation is made the longitudinal incision of 2cm in breastbone left side, nearly breastbone side is cut off the 3rd, the 4th costicartilage, open the thoracic cavity after, connect artificial respirator (ventilation 2ml/100g, 50 times/min).Cut off pericardium, expose heart, left anterior descending coronary artery root threading is in order to ligation, and record standard II lead electrocardiogram was stablized 10 minutes, and the ligation left anterior descending coronary artery is closed the thoracic cavity.With syringe sucking-off animal throat secretions, make animal recover autonomous respiration.Behind the ligation coronary artery 15min, intravenously administrable.Behind the ligation coronary artery 4 hours, win heart, 5 of the following crosscuts of ligature, carry out chlorination nitro blue tetrazolium (N-BT) dyeing, calculating myocardium infarcted region area accounts for the percentage ratio of ventricle and heart area, and carries out statistical procedures (t check).
The red melon compositions of table 1 to the influence of rat experiment myocardial inyaretion scope (x ± s, n=10)
Annotate:
﹠amp;P＜0.05 is compared with matched group;
*P＜0.05,
*P＜0.01 is compared with model group;
aP＜0.05 is compared with the Radix Salviae Miltiorrhizae group;
bP＜0.05 is compared with the Fructus Trichosanthis group.
Result and conclusion: the results are shown in Table 1.Model group compares with matched group that there were significant differences, and modeling success (p＜0.05) is described.Each administration group all has significant function of resisting myocardial ischemia (p＜0.05, p＜0.01), the effect of wherein red each weight portion array of melon composition granule is better than single with DANSHEN KELI agent or Fructus Trichosanthis granule (p＜0.05), points out two medicine compatibilities that synergistic function is arranged.
Experimental example 2 pharmaceutical compositions of the present invention are to the protective effect of dog Ischemic Heart function
Animal subject: 66 of hybrid dogs, body weight 12.97kg ± 1.98kg, male and female half and half.
Test sample: Radix Salviae Miltiorrhizae Injection, self-control is equivalent to crude drug 2.5g;
The Fructus Trichosanthis injection, self-control is equivalent to crude drug 10g;
Red melon injection, self-control.
Experimental technique: dog is divided into 11 groups at random, 6 every group.Be respectively false ligation group, model group, the Radix Salviae Miltiorrhizae Injection group, Fructus Trichosanthis injection group, (pellet+melon=50+200 is called for short A to red melon composite injection; Pellet+melon=400+1000 is called for short B; Pellet+melon=400+1500 is called for short C; Pellet+melon=100+500 is called for short D; Pellet+melon=200+500 is called for short E; Pellet+melon=1000+2000 is called for short F; Pellet+melon=1000+4000 is called for short G) group, medicine all is diluted to desired concn with normal saline, intravenous administration, continuous 7 days.
Dog myocardial infarction and ischemia model preparation: the administration expiration respectively organize dog intravenous injection pentobarbital sodium (30mgkg
-1) anaesthetize and fix, monitoring limbs II lead electrocardiogram; Set up the femoral vein passage, anticoagulant in the 0.5% heparin sodium body; Separate femoral artery, femoral arteriography continuous monitoring BP after the heparinization; Separate left carotid,, retouch and survey left ventricular systolic pressure, left ventricular end diastolic presssure, the maximum rate of change curve in left chamber the cardiac catheterization left ventricle; Separate trachea and intubate, and the positive pressure respiration of pedestrian worker's respirator (16～18 times/min of frequency, air-breathing: as to exhale than 1: 1.5 tidal volume 350～550ml); Open breast and expose heart, separate the left coronary artery LC, connect blood flowmeter, measure coronary flow; Separate the below 2mm of left coronary artery anterior descending branch first branch, except that the not ligation of threading of false ligation group, all the other each groups all penetrate two No. 1 silk threads, 5min before the first phase ligation, and by per kilogram of body weight 2mg, vein splashes into lignocaine.Article one, handling diameter with one during the silk thread ligation is that No. 9 syringe needles of 1mm place between ligature and the blood vessel, after the ligation syringe needle is extracted out, carry out the first phase ligation of angiostenosis, behind the 30mi, again with the ligation of second silk thread, carry out the second stage of ligation of bloodstream blocking, finish the preparation of myocardial infarction and ischemia model.
Detect index: before ligation, first phase ligation 10min, the second stage of ligation at once, 15min, 30min, 60min, 120min measure and record: left ventricular systolic pressure (LVSP), left ventricular end diastolic presssure (LVEDP), the maximum rate of change in left chamber (± index such as dP/dt).
The red melon compositions of table 2 to the influence of dog heart rate, mean arterial pressure and arteria coronaria blood flow (x ± s, n=6)
Annotate:
##P＜0.01 is with false ligation group ratio;
*P＜0.01 is with the model ratio;
aP＜0.05 is with Radix Salviae Miltiorrhizae group ratio;
bP＜0.05 is with Fructus Trichosanthis group ratio.
The red melon compositions of table 3 is pressed by dog left ventricular systolic pressure, diastole end and the influence of maximum rate of change (x ± s, n=6)
Annotate:
##P＜0.01 is with false ligation group ratio;
*P＜0.01 is with the model ratio;
aP0.05 is with Radix Salviae Miltiorrhizae group ratio;
bP＜0.05 is with Fructus Trichosanthis group ratio.
Experimental result: to the influence of dog heart rate, mean arterial pressure and arteria coronaria blood flow: behind the coronary ligation 120min, model group is compared with false ligation group, and heart rate, mean arterial pressure all extremely significantly raise (p＜0.01), and coronary flow extremely significantly reduces (p＜0.01).Compare with model group, the heart rate of the red melon A of Radix Salviae Miltiorrhizae group, Fructus Trichosanthis group and pharmaceutical composition of the present invention, B, C, D, E, F, G group, mean arterial pressure all extremely significantly reduce (p＜0.01), coronary flow extremely significantly raise (p＜0.01), compare with Radix Salviae Miltiorrhizae group, Fructus Trichosanthis group, the red melon A of pharmaceutical composition of the present invention, B, C, D, E, each group of F, G all have significant difference (p＜0.05), see Table 2.
Influence to dog left ventricular systolic pressure, diastole end pressure and maximum rate of change: behind the coronary ligation 120min, compare with false ligation group, press at the left ventricular systolic pressure of model group, diastole end and maximum rate of change all extremely significantly reduces (p＜0.01).Compare with model group, the left ventricular systolic pressure of each administration group, diastole end are pressed and maximum rate of change all extremely significantly raises (p＜0.01), compare with Radix Salviae Miltiorrhizae, Fructus Trichosanthis group, and red melon A, B, C, D, E, each group of F, G all have significant difference (p＜0.05) to see Table 3.
Conclusion: compare with model group; the red melon A of Radix Salviae Miltiorrhizae group, Fructus Trichosanthis group and pharmaceutical composition of the present invention, B, C, D, E, F, G organize behind arteria coronaria left anterior descending branch ligation blocking blood flow; all can significantly reduce heart rate; keep the stable of mean arterial pressure, coronary flow, left ventricular systolic pressure, left ventricular end diastolic presssure and maximum rate of change; Ischemic Heart had remarkable protective effect; wherein the effect of each ratio of weight and number of Radix Salviae Miltiorrhizae extract and Fructus Trichosanthis extract compatibility is better than list with Radix Salviae Miltiorrhizae extract or Fructus Trichosanthis extract (p＜0.05), points out two medicine compatibilities that synergistic function is arranged.
Experimental example 3: red melon compositions is to the influence of blood stasis type rat platelet aggregation
Laboratory animal: the Wistar rat, male, body weight 250～300g, 120.
Test sample: Radix Salviae Miltiorrhizae Injection, self-control is equivalent to crude drug 2.5g;
The Fructus Trichosanthis injection, self-control is equivalent to crude drug 10g;
Red melon composite injection (Different Weight proportioning) group, 8 groups, self-control.
Experimental technique: rat is divided into 12 groups at random, 10 every group, is respectively the normal saline matched group; Model group; The Radix Salviae Miltiorrhizae extract group; The Fructus Trichosanthis extract group; (pellet+melon=50+500 is called for short A to red melon composite injection; Pellet+melon=200+1000 is called for short B; Pellet+melon=200+1500 is called for short C; Pellet+melon=100+4000 is called for short D; Pellet+melon=50+1000 is called for short E; Pellet+melon=200+200 is called for short F; Pellet+melon=400+2000 is called for short G; Pellet+melon=1000+2000 is called for short H; ) group.Each medicine all is diluted to desired concn with normal saline, the tail vein injection administration.Once a day, successive administration is 7 days.
The preparation of rat blood stasis model: except that the normal saline group, all the other are respectively organized respectively at behind the administration last day 1h, subcutaneous injection 0.1% adrenalin hydrochloride 0.08ml100g
-1, totally 2 times, two minor ticks 4 hours, (front and back each 2 hours at interval) immersed frozen water 5 minutes with rat between the administration, stopped eating after the disposal.Stop eating time morning, each group is used 20% urethane (1gkg respectively
-1) anesthesia, (1: 9, V/V), from abdominal aortic blood, 1000 changeed min in 3.8% liquor sodii citratis anticoagulant
-1, centrifugal 10min gets supernatant, and platelet blood plasma (PRP) is rich in preparation; Surplus 4000 commentaries on classics/min, centrifugal 10min, getting supernatant is platelet poor plasma (PPP).With ADP (1mg/1ml adds 16 μ l), Thro (5U/ml adds 16 μ l), COL (1mg/ml adds 16 μ l) is derivant, measures the platelet maximum agglutination rate with turbidimetry at LBY-NJ blood pool instrument.By formula calculate platelet aggregation inhibition rate.Platelet aggregation inhibition rate (%)=(model control group platelet maximum agglutination rate-administration group platelet maximum agglutination rate)/model control group platelet maximum agglutination rate.
The red melon compositions of table 4 to the influence of blood stasis rat platelet aggregation effect (x ± s, n=10)
Annotate:
##P＜0.01 is with the matched group ratio;
*P＜0.01 is with the model ratio;
aP＜0.05 is with Radix Salviae Miltiorrhizae group ratio;
bP＜0.05 is with Fructus Trichosanthis group ratio.
Conclusion: each administration group makes the platelet maximum agglutination rate of COL, ADP, the inductive blood stasis rat of Thro extremely significantly reduce (p＜0.01), the results are shown in Table 4, the effect of wherein red melon composite injection is better than single with Radix Salviae Miltiorrhizae Injection or Fructus Trichosanthis injection (p＜0.05), the compositions of prompting Radix Salviae Miltiorrhizae and Fructus Trichosanthis compatibility has good antiplatelet aggregative activity, and two medicine compatibilities have synergistic function.
Experimental example 4: red melon compositions is to the protective effect of rat cerebral ischemia perfusion injury
Laboratory animal: 70 of Wistar rats, male, body weight 250g ± 10g.
Test sample: Radix Salviae Miltiorrhizae extract injection, self-control;
The Fructus Trichosanthis extract injection, self-control;
Red melon composite injection group, 3 groups, self-control.
Experimental technique: rat is divided into 7 groups at random, 10 every group.(1) sham-operation (SAM) group: 5d puts to death after the sham-operation.(2) ischemia-reperfusion (IR) group: pour into 5d behind the ischemia 30min again and put to death.(3) Radix Salviae Miltiorrhizae extract group: continuous intravenous injection gave Radix Salviae Miltiorrhizae Injection 5d (dosage is 20mg/kg) after ischemia 30min poured into 30min again, put to death behind the last administration 1h.(4) Fructus Trichosanthis extract group: continuous intravenous injection gave Fructus Trichosanthis injection 5d (dosage is 20mg/kg) after ischemia 30min poured into 30min again, put to death behind the last administration 1h.(5) red melon extract injection group, 9 groups, continuous intravenous injection gave red melon composite injection 5d (dosage is 15mg/kg) after ischemia 30min poured into 30min again, put to death behind the last administration 1h.Get brain on ice rapidly, put in the liquid nitrogen frozen to be measured.
Animal model: the Wistar rat anesthesia, the 4VO legal system is equipped with the global brain ischemia animal model of reperfusion injury, by close the infusion time again of bilateral carotid control rat cerebral ischemia with the bulldog clamp folder.
Index detects: the Ach variation is represented with choline acetylase (ChAT) activity in acetylcholine (Ach) the mensuration cerebral tissue, and the active radiochemical method that adopts of ChAT carries out, and protein content is undertaken by the Lowry method in the tissue, and unit is μ mol/ (h.mgPr).
Nitric oxide (NO) is measured: big rat brain tissue homogenate, the centrifugal 5min of 4000 commentaries on classics/min gets supernatant 2ml and adds 1ml sodium acetate and 1ml P-aminobenzene-sulfonamide.Detect the pH scope 6.25～6.35, add zinc powder 10～15mg, the whirlpool 15min that shakes filters, get supernatant 4ml, add the 2.0ml developer, transfer pH to 1.75～1.85, add NaCl2.0g, n-butyl alcohol 3.0ml, the whirlpool shakes, and the centrifugal 5min of 3000 commentaries on classics/min gets supernatant, 540nm place test sample product absorbance.Biuret method test sample product protein content, NO content in the calculation sample, unit are nmol/mgPr.
The mensuration of Endothelin (ET): press ET content in ET medicine box (PLA General Hospital) the description ria-determination brain tissue homogenate, unit is pg/mgPr.
The influence that the red melon compositions of table 5 is damaged Ischemia and Reperfusion in vivo in Rats (x ± s, n=10)
Annotate:
*P＜0.05,
*P＜0.01 is compared with sham operated rats;
#P＜0.05,
##P＜0.01 is compared with ischemia-reperfusion group;
aP＜0.05 is compared with the Radix Salviae Miltiorrhizae extract group;
bP＜0.05 is compared with the Fructus Trichosanthis extract group.
Experimental result and conclusion: cerebral tissue NO, Ach, ET changes of contents after the Ischemia and Reperfusion in vivo in Rats see Table 5.Ischemia-reperfusion group is compared with sham operated rats, and NO content raises in the rat cerebral tissue, and ChAT content reduces, and ET content raises, and difference extremely significantly (p＜0.01).Fructus Trichosanthis extract group and Radix Salviae Miltiorrhizae extract group and sham operated rats compare NO content rising in the rat cerebral tissue, and ChAT content reduces, and ET content raises, significant difference (p＜0.05); Compare NO content reduction in the rat cerebral tissue with ischemia-reperfusion group, ChAT content raises, and ET content reduces, significant difference (p＜0.05).Red melon each dosage group of compositions and ischemia-reperfusion group compare NO content reduction in the rat cerebral tissue, and ChAT content raises, and ET content reduces, and difference is (p＜0.01) extremely significantly; Compare NO content reduction in the rat cerebral tissue with the Radix Salviae Miltiorrhizae extract group with the Fructus Trichosanthis extract group, ChAT content raises, and ET content reduces, significant difference (p＜0.05).The result shows, red each dosage group of melon compositions can both make NO content reduction in the ischemical reperfusion injury rat cerebral tissue, and ChAT content raises, and ET content reduces, therefore showing that Fructus Trichosanthis extract and Radix Salviae Miltiorrhizae extract compatible combination have treats the cerebral ischemia ability preferably, can Synergistic.
Experimental example 5: Radix Salviae Miltiorrhizae and Fructus Trichosanthis compositions drug combination influence microcirculation of mouse auricle
Animal subject: male mice, 260, body weight 20～25g is divided into 13 groups at random, 20 every group.
Test sample: matched group: normal saline, commercial.
Radix Salviae Miltiorrhizae tablet group: self-control;
Fructus Trichosanthis tablet group: self-control;
Red melon composition tablet group: self-control.
Experimental technique: mice is pressed the dosage gastric infusion of table 6, and matched group filling stomach gives the normal saline with volume, uses urethane 1g/kg intraperitoneal injection of anesthesia then.Postanesthetic mice places on the supporting plate that is covered with Cotton Gossypii, keeps 20 ± 2 ℃ of room temperatures.Mouse right ear is placed on the ear carriage, on auris dextra, drips a little liquid paraffin, supporting plate is placed on the microscope carrier, regulate cold light source, make illuminating ray and auricle plane at 45～60 ° of angles, and parallel with the direction of growth of hair.Under low power lens, observe the auricle overall picture earlier, select suitable position, use high power lens instead and fix a point to observe continuously.The microcirculating state of 20min after the observation administration, the diameter and the blood flow rate of measurement arteriole, venule.
Experimental result and conclusion: experimental result sees Table 6.Compare with matched group, the Radix Salviae Miltiorrhizae group can make mouse ear arteriole, venule caliber enlarge markedly (p＜0.05), and blood flow rate is significantly accelerated (p＜0.05); The Fructus Trichosanthis group can make mouse ear arteriole, venule caliber enlarge markedly (p＜0.05), and blood flow rate is significantly accelerated (p＜0.05); Red each weight proportion group of melon compositions all can make mouse ear arteriole, the venule caliber utmost point enlarge markedly (p＜0.01), and blood flow rate is extremely significantly accelerated (p＜0.01).Red each weight proportion group of melon compositions is compared with Radix Salviae Miltiorrhizae group or Fructus Trichosanthis group, and mouse ear arteriole, venule caliber are enlarged markedly, and blood flow rate is significantly accelerated, and has significant difference (p＜0.05, p＜0.01).By The above results as can be seen, the effect of red each umber proportioning of melon compositions all is better than Radix Salviae Miltiorrhizae or the individually dosed effect of Fructus Trichosanthis, points out red melon compositions drug combination that synergistic function is arranged.
The red melon compositions of table 6 drug combination to microcirculation of mouse auricle influence (x ± s, n=20)
Annotate:
*P＜0.05,
*P＜0.01 is compared with matched group;
aP＜0.05 is compared with the Radix Salviae Miltiorrhizae group;
bP＜0.01 is compared with the Fructus Trichosanthis group.
Experimental example 6: red melon composite injection stability experiment
Sample: red melon extract composite injection, self-control.
Investigation project: character, pH value, clarity
Long-time stability experimental technique and result: this product is put under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% and placed 6 months, 12 months, every index has no significant change, experimental result show composite injection long-term place basicly stable.
[specific embodiment]
Come further to set forth preparation of drug combination method of the present invention by the following examples.Following embodiment can make those skilled in the art more fully understand the present invention, but does not limit the present invention in any way.The used Radix Salviae Miltiorrhizae extract of embodiment 4-12 comes from embodiment 1, and Fructus Trichosanthis extract comes from embodiment 2.
Embodiment 1 Radix Salviae Miltiorrhizae extract extraction process and preparation
The preparation of Radix Salviae Miltiorrhizae extract:
Get red rooted salvia, be ground into coarse powder, decoct with water twice, add for the first time 12 times of amounts of water, add 10 times of amounts of water, each 2 hours for the first time, collecting decoction filters, and filtrate decompression is concentrated into the concentrated solution of relative density 1.10～1.15 (60 ℃), add ethanol to containing the alcohol amount to 85%, cold preservation 24 hours filters, filtrate recycling ethanol adds hydrochloric acid and transfers pH value to 2 to there not being the alcohol flavor, extracts 3 times with the ethyl acetate jolting, merge ethyl acetate liquid, evaporate to dryness.Residue adds the sour water dissolving of pH value 2, is added on the polyamide column of having handled well, with the water elution of 2 times of column volumes, discards water lotion earlier, and 95% ethanol elution of 4 times of column volumes of reuse is collected eluent, reclaims ethanol, and vacuum drying, gets Radix Salviae Miltiorrhizae extract.
The assay of Radix Salviae Miltiorrhizae extract:
Total phenolic content is measured
The preparation precision of reference substance solution takes by weighing the protocatechualdehyde reference substance 1mg that is dried to constant weight in 105 ℃, is dissolved in water, and is settled to 100ml.
The preparation precision of need testing solution takes by weighing sample 50mg, put in the 50ml volumetric flask, thin up to scale precision is measured 0.1ml and is put and add ethanol 5ml in the 25ml volumetric flask, adds 0.3% sodium lauryl sulphate 2ml, 0.6% potassium ferricyanide-0.9% ferric oxide (face and use preceding mixed in equal amounts) 1ml, so 5min is placed in the dark place, add the 0.1mol/L hydrochloric acid solution to scale, shake up, after 20min is placed in the dark place, put in the lena colorimetric pool, the 720nm place measures.
The assay high performance liquid chromatography of salvianolic acid B
Chromatographic condition and system suitability experiment are filler with the octadecylsilane chemically bonded silica; With methanol-acetonitrile-formic acid-water (30: 10: 1: 59) be mobile phase; The detection wavelength is 286nm.Theoretical cam curve is calculated by the danshensu peak should be not less than 1500.
It is an amount of that the preparation precision of reference substance solution takes by weighing the salvianolic acid B reference substance, adds 75% methanol and make the solution that every 1ml contains 0.14mg, promptly.
The about 0.2g of this product is got in the preparation of need testing solution, and accurate the title decides, and puts in the tool plug conical flask, and the accurate 75% methanol 50ml that adds claims to decide weight, reflux 1h takes out, and puts coldly, claims to decide weight again, supplies with 75% methanol to subtract weight loss, shake up, filter, get subsequent filtrate, promptly.
Accurate respectively reference substance solution and each the 20 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly.
3 batches of water-soluble extract of red sage root that make according to the method described above, wherein total phenolic acid and content of danshinolic acid B measurement result see Table 7.As can be seen from the results, the yield of the Radix Salviae Miltiorrhizae extract that makes by this technology is 1.5～2%, and Radix Salviae Miltiorrhizae total phenolic acids content is not less than 50%, and content of danshinolic acid B is not less than 30%.
The assay result and the yield of table 7 Radix Salviae Miltiorrhizae extract
Embodiment 2 Fructus Trichosanthis extract extraction process and preparations
The preparation of Fructus Trichosanthis extract:
Get the Fructus Trichosanthis medical material, oven dry is ground into coarse powder, add entry reflux, extract, twice, add 10 times of water gagings at every turn, reflux, extract, 2 hours, filter, merging filtrate, being concentrated into relative density is the concentrated solution of 1.10～1.15 (60 ℃), add ethanol to content and reach 80%, placement is spent the night, and gets supernatant, reclaim ethanol to there not being the alcohol flavor, be evaporated to the thick paste shape, vacuum drying promptly gets the Fructus Trichosanthis crude extract.
Above-mentioned Fructus Trichosanthis extract with after the suitable quantity of water dissolving, is extracted 2 times with the jolting of equivalent petroleum ether, and water liquid extracts 3 times with the jolting of equivalent water-saturated n-butanol, merge n-butanol extracting liquid, be concentrated into driedly, residue adds low amounts of water makes dissolving, last macroporous resin column, difference water, 15% ethanol, 70% ethanol elution, collect 70% ethanol elution, decompression recycling ethanol is concentrated into the thick paste shape, spray drying promptly gets the Fructus Trichosanthis extract.
The Fructus Trichosanthis extract assay:
The preparation of standard curve accurately pipettes ginsenoside's standard substance Rg1 (concentration is 2.2mg/ml) 5 respectively, 10,30,50,70,90,110 make series standard solution in 10ml tool plug test tube, water-bath volatilizes methanol, the vanillin glacial acetic acid solution that adds 0.7ml8%, add people 5ml perchloric acid again, shake up, in 60 ℃ of water-bath 15min, take out at once and dash to room temperature with tap water, do blank with the parallel sample that does not add sample, measure absorbance in 560nm, with absorbance (A) to content of ginsenoside (M, unit: μ g) make regression curve, get regression equation: M=213.13A+4.7576, R=0.997.
The preparation of vanillin-glacial acetic acid test solution: accurately take by weighing the 4g vanillin, add the 50ml glacial acetic acid, place brown bottle, mix shaking up, place refrigerator (now with the current) to dissolving fully.
The assay of Fructus Trichosanthis extracting solution: accurately pipette sample solution 30 μ l, place 10ml tool plug test tube, water-bath volatilizes methanol, the vanillin glacial acetic acid solution that adds 0.5mL 8% adds people 5ml perchloric acid again, shakes up, in 60 ℃ of water-bath 15min, take out and be chilled to room temperature rapidly with mobile tap water at once, make blank, measure absorbance A in 560nm with the parallel sample that does not add sample.
The Fructus Trichosanthis extract that makes according to the method described above, wherein the steroid compound assay the results are shown in Table 8.As can be seen from the results, the yield of the Fructus Trichosanthis crude extract that makes by this technology is 6～7%, and steroid compound content is not less than 20%; The yield of Fructus Trichosanthis crude extract is 3～4%, and steroid compound content is not less than 30%.
The assay result and the yield of table 8 Fructus Trichosanthis extract
Embodiment 3: the preparation of red melon composition powder injection
Prescription 1:
Radix Salviae Miltiorrhizae extract 40g (being equivalent to crude drug 2kg)
Fructus Trichosanthis extract 1000g (being equivalent to crude drug 15kg)
Mannitol 300g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
Prescription 2:
Radix Salviae Miltiorrhizae extract 80g (being equivalent to crude drug 4kg)
Fructus Trichosanthis extract 300g (being equivalent to crude drug 10kg)
Mannitol 300g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
Prescription 3:
Radix Salviae Miltiorrhizae extract 200g (being equivalent to crude drug 10kg)
Fructus Trichosanthis extract 150g (being equivalent to crude drug 5kg)
Mannitol 300g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
Prescription 4:
Radix Salviae Miltiorrhizae extract 400g (being equivalent to crude drug 20kg)
Fructus Trichosanthis extract 300g (being equivalent to crude drug 10kg)
Mannitol 300g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
Preparation technology:
1) vessel and the antibiotic glass bottle of earlier dosing being used, plug etc. carry out aseptic process.
2) take by weighing supplementary material according to recipe quantity.
3) heating for dissolving in Fructus Trichosanthis extract and Radix Salviae Miltiorrhizae extract adding dosing amount 50% sterile water for injection is complete.It is complete that mannitol adds the sterile water for injection heated and stirred dissolving of dosing amount 30%, merges above-mentioned solution, adds sterile water for injection to full dose.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.22 μ m.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) be sub-packed in the antibiotic glass bottle half tamponade.Sample is put into the freeze dryer lyophilization.Pre-freeze-45 ℃ 5 hours, low-temperature vacuum drying-45 ℃～0 ℃ 20 hours was warming up to 25 ℃ of vacuum dryings 3 hours then.
9) lyophilizing finishes, and lid is rolled in tamponade.
10) finished product is examined entirely, the packing warehouse-in.
Embodiment 4: the preparation of red melon compositions aqueous injection
Prescription 1:
Radix Salviae Miltiorrhizae extract 20g (being equivalent to crude drug 0.5kg)
Fructus Trichosanthis extract 1000g (being equivalent to crude drug 20kg)
Water for injection adds to 1000ml
Prepare 1000 altogether
Prescription 2:
Radix Salviae Miltiorrhizae extract 40g (being equivalent to crude drug 2kg)
Fructus Trichosanthis extract 150g (being equivalent to crude drug 5kg)
Water for injection adds to 1000ml
Prepare 1000 altogether
Prescription 3:
Radix Salviae Miltiorrhizae extract 40g (being equivalent to crude drug 2kg)
Fructus Trichosanthis extract 1400g (being equivalent to crude drug 20kg)
Water for injection adds to 1000ml
Prepare 1000 altogether
Prescription 4:
Radix Salviae Miltiorrhizae extract 200g (being equivalent to crude drug 10kg)
Fructus Trichosanthis extract 50g (being equivalent to crude drug 2kg)
Water for injection adds to 1000ml
Prepare 1000 altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) with heated and stirred dissolving in the water for injection of Radix Salviae Miltiorrhizae extract and Fructus Trichosanthis extract adding dosing amount 80% fully.
3) benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45 μ m.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) with the solution sealing by fusing in glass ampule.
9) 100 ℃ of flowing steam sterilizations are 30 minutes.
10) while hot sample being put into 0.01% methylene blue solution hunts leak.
11) lamp inspection, finished product is examined entirely, the packing warehouse-in.
Embodiment 5: the preparation of red melon compositions sodium chloride injection
Prescription 1:
Radix Salviae Miltiorrhizae extract 200g (being equivalent to crude drug 2kg)
Fructus Trichosanthis extract 300g (being equivalent to crude drug 2kg)
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 2:
Radix Salviae Miltiorrhizae extract 400g (being equivalent to crude drug 20kg)
Fructus Trichosanthis extract 150g (being equivalent to crude drug 5kg)
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 3:
Radix Salviae Miltiorrhizae extract 10g (being equivalent to crude drug 0.5kg)
Fructus Trichosanthis extract 300g (being equivalent to crude drug 10kg)
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 4:
Radix Salviae Miltiorrhizae extract 80g (being equivalent to crude drug 4kg)
Fructus Trichosanthis extract 50g (being equivalent to crude drug 2kg)
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Preparation technology:
1) handles the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) Fructus Trichosanthis extract, Radix Salviae Miltiorrhizae extract are added the dissolving of dosing amount 40% water for injection heated and stirred fully, sodium chloride is complete with the water for injection dissolving of dosing amount 20%.
3) merge above-mentioned solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45 μ m.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) fill is in the infusion bottle of 100ml.
9) 115 ℃ of pressure sterilizings are 30 minutes.
10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
Embodiment 6: the preparation of red melon compositions glucose injection
Prescription 1
Radix Salviae Miltiorrhizae extract 80g (being equivalent to crude drug 4kg)
Fructus Trichosanthis extract 150g (being equivalent to crude drug 5kg)
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 2:
Radix Salviae Miltiorrhizae extract 200g (being equivalent to crude drug 10kg)
Fructus Trichosanthis extract 2800g (being equivalent to crude drug 40kg)
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 3:
Radix Salviae Miltiorrhizae extract 40g (being equivalent to crude drug 2kg)
Fructus Trichosanthis extract 300g (being equivalent to crude drug 10kg)
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 4:
Radix Salviae Miltiorrhizae extract 80g (being equivalent to crude drug 4kg)
Fructus Trichosanthis extract 1000g (being equivalent to crude drug 15kg)
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) with heated and stirred dissolving in Fructus Trichosanthis extract, Radix Salviae Miltiorrhizae extract adding dosing amount 20% water for injection fully, that glucose is complete with the water for injection dissolving of dosing amount 20%, heated and boiled 15 minutes.
3) merge above-mentioned solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) fill is in the infusion bottle of 100ml.
9) 115 ℃ of pressure sterilizings are 30 minutes.
10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
Embodiment 7: the preparation of red melon composition tablet
Prescription 1:
Radix Salviae Miltiorrhizae extract 20g (being equivalent to crude drug 1kg)
Fructus Trichosanthis extract 150g (being equivalent to crude drug 5kg)
Starch 40.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 6.0g
Carboxymethylstach sodium 12.0g
Prepare 1000 altogether
Prescription 2:
Radix Salviae Miltiorrhizae extract 40g (being equivalent to crude drug 2kg)
Fructus Trichosanthis extract 300g (being equivalent to crude drug 10kg)
Starch 40.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 6.0g
Carboxymethylstach sodium 12.0g
Prepare 1000 altogether
Prescription 3:
Radix Salviae Miltiorrhizae extract 10g (being equivalent to crude drug 0.5kg)
Fructus Trichosanthis extract 1400g (being equivalent to crude drug 20kg)
Starch 40.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 6.0g
Carboxymethylstach sodium 12.0g
Prepare 1000 altogether
Prescription 4:
Radix Salviae Miltiorrhizae extract 400g (being equivalent to crude drug 20kg)
Fructus Trichosanthis crude extract 1000g (being equivalent to crude drug 15kg)
Starch 40.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 6.0g
Carboxymethylstach sodium 12.0g
Prepare 1000 altogether
Preparation technology:
1) it is standby Fructus Trichosanthis crude extract and Radix Salviae Miltiorrhizae extract to be pulverized 100 mesh sieves.
2) take by weighing supplementary material according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with Fructus Trichosanthis crude extract, Radix Salviae Miltiorrhizae extract, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
5) cross 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) dry good granule adds magnesium stearate and carboxymethylstach sodium, crosses 18 mesh sieve granulate, mix homogeneously.
8) sampling, the semi-finished product chemical examination.
9) the sheet weight sheet of determining according to chemical examination.
10) finished product is examined entirely, the packing warehouse-in.
Embodiment 8: the preparation of red melon composition capsule
Prescription 1:
Radix Salviae Miltiorrhizae extract 80g (being equivalent to crude drug 4kg)
Fructus Trichosanthis crude extract 2.8kg (being equivalent to crude drug 40kg)
Starch 20.0g
Microcrystalline Cellulose 60.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 6.0g
Prepare 1000 altogether
Prescription 2:
Red melon extract 200g (being equivalent to crude drug 10kg)
Starch 1000g (being equivalent to crude drug 15kg)
Microcrystalline Cellulose 60.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 6.0g
Prepare 1000 altogether
Prescription 3:
Radix Salviae Miltiorrhizae extract 40g (being equivalent to crude drug 0.5kg)
Fructus Trichosanthis crude extract 50g (being equivalent to crude drug 2kg)
Starch 20.0g
Microcrystalline Cellulose 60.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 6.0g
Prepare 1000 altogether
Prescription 4:
Radix Salviae Miltiorrhizae extract 80g (being equivalent to crude drug 4kg)
Fructus Trichosanthis crude extract 300g (being equivalent to crude drug 10kg)
Starch 20.0g
Microcrystalline Cellulose 60.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 6.0g
Prepare 1000 altogether
Preparation technology:
1) it is standby Fructus Trichosanthis crude extract and Radix Salviae Miltiorrhizae extract to be pulverized 100 mesh sieves.
2) take by weighing supplementary material according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) with Fructus Trichosanthis extract, Radix Salviae Miltiorrhizae extract, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
5) cross 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) dry good granule adds magnesium stearate, crosses 18 mesh sieve granulate, mix homogeneously.
8) sampling, the semi-finished product chemical examination.
9) loading amount of determining according to chemical examination incapsulates.
10) finished product is examined entirely, the packing warehouse-in.
Embodiment 9: the preparation of red melon composition granule
Prescription 1:
Radix Salviae Miltiorrhizae extract 200g (being equivalent to crude drug 10kg)
Fructus Trichosanthis crude extract 150g (being equivalent to crude drug 5kg)
Icing Sugar 2000.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
Prescription 2:
Radix Salviae Miltiorrhizae extract 80g (being equivalent to crude drug 4kg)
Fructus Trichosanthis extract 1000g (being equivalent to crude drug 15kg)
Icing Sugar 2000.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
Preparation technology:
1) it is standby sucrose to be pulverized 100 mesh sieves.It is standby that Fructus Trichosanthis extract and Radix Salviae Miltiorrhizae extract (or red melon extract) were pulverized 100 mesh sieves.
2) take by weighing supplementary material according to recipe quantity.
3) the method mix homogeneously that Fructus Trichosanthis crude extract, Radix Salviae Miltiorrhizae extract and Icing Sugar are progressively increased with equivalent, adding 2%HPMC50% alcoholic solution is an amount of, stirs, and makes suitable soft material,
4) cross 20 mesh sieve system granules.
5) granule is dried under 60 ℃ condition.
6) dried granule is crossed 18 mesh sieve granulate.
7) sampling, the content of principal agent is determined loading amount in the semi-finished product chemical examination granule.
8) packing, finished product is examined entirely, the packing warehouse-in.
Embodiment 10: the preparation of red melon composition oral liquid
Prescription:
Radix Salviae Miltiorrhizae extract 200g (being equivalent to crude drug 10kg)
Fructus Trichosanthis crude extract 1000g (being equivalent to crude drug 15kg)
Sodium benzoate 15g
Stevioside 10g
Purified water adds to 10000ml
Prepare 1000 altogether
Preparation technology:
1) with heated and stirred dissolving in the purified water of Fructus Trichosanthis crude extract, Radix Salviae Miltiorrhizae extract (or red melon extract) adding dosing amount 50% fully.
2) sodium benzoate and stevioside is complete with the water dissolution of dosing amount 20%.
3) merge above-mentioned solution, add purified water to full dose.
4) filtering with microporous membrane of mistake 0.8 μ m.
5) semi-finished product chemical examination.
6) fill.Finished product is examined entirely, the packing warehouse-in.
Claims (4)
1. a pharmaceutical composition that is used for cardiovascular and cerebrovascular disease is characterized in that, makes the consisting of of crude drug of the contained active ingredient of this pharmaceutical composition: Radix Salviae Miltiorrhizae extract 1-40 part, Fructus Trichosanthis extract 5-280 part,
The preparation method of described Radix Salviae Miltiorrhizae extract is: get red rooted salvia, be ground into coarse powder, decoct with water twice, add for the first time 12 times of amounts of water, add 10 times of amounts of water, each 2 hours for the second time, collecting decoction, filter, filtrate decompression is concentrated into the concentrated solution of relative density 1.10～1.15 under 60 ℃ of conditions, adds ethanol and reaches 85% to containing the alcohol amount, cold preservation 24 hours, filter, filtrate recycling ethanol adds hydrochloric acid and transfers pH value to 2 to there not being the alcohol flavor, extract 3 times with the ethyl acetate jolting, merge ethyl acetate liquid, evaporate to dryness, residue add the sour water dissolving of pH value 2, be added on the polyamide column of having handled well, with the water elution of 2 times of column volumes, discard water lotion, 95% ethanol elution of 4 times of column volumes of reuse earlier, collect eluent, reclaim ethanol, and vacuum drying, promptly;
The preparation method of described Fructus Trichosanthis extract is: get the Fructus Trichosanthis medical material, oven dry is ground into coarse powder, add entry reflux, extract, twice, add 10 times of water gagings at every turn, reflux, extract, 2 hours, filter, merging filtrate is concentrated into relative density and is 1.10～1.15 concentrated solution under 60 ℃ of conditions, add ethanol to content and reach 80%, placement is spent the night, and gets supernatant, reclaim ethanol to there not being the alcohol flavor, be evaporated to the thick paste shape, vacuum drying, promptly.
2. pharmaceutical composition according to claim 1 is characterized in that, makes the consisting of of crude drug of the contained active ingredient of this pharmaceutical composition: Radix Salviae Miltiorrhizae extract 2-20 part, Fructus Trichosanthis extract 15-140 part.
3. pharmaceutical composition according to claim 1 and 2 is characterized in that, this pharmaceutical composition is made clinically any or pharmaceutically acceptable preparation.
4. pharmaceutical composition according to claim 3 is characterized in that this pharmaceutical composition is made injection or oral formulations.
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| CN2006101594835A CN101152246B (en) | 2006-09-25 | 2006-09-25 | Pharmaceutical composition for cardiovascular and cerebrovascular diseases and method for preparing the same |
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| CN113262262B (en) * | 2021-07-07 | 2022-11-08 | 天津中医药大学第一附属医院 | Traditional Chinese medicine preparation for treating phlegm-heat stasis type stable coronary heart disease and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1254577A (en) * | 1998-11-19 | 2000-05-31 | 王鸿翔 | Exterior-applied Chinese-medicinal bag for treating cardiopathy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1254577A (en) * | 1998-11-19 | 2000-05-31 | 王鸿翔 | Exterior-applied Chinese-medicinal bag for treating cardiopathy |
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| 吴德康.丹参和丹参注射液.上海医药23 2.2002,23(2),80. |
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