CN1123663A - Composition for curing angicardiopathy and its production and usage - Google Patents
Composition for curing angicardiopathy and its production and usage Download PDFInfo
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Abstract
The medicinal composition for prevention and cure of cardiovascular disease is industrially prepared from capejasmine fruit instead of saffron to extract saffron glycoside (I), saffron glycoside 1 and its aglycone saffron acid with low cost.
Description
The present invention relates to a kind of pharmaceutical composition and preparation method thereof and purposes of anti-angiocardiopathy, specifically, this pharmaceutical composition can be used for preventing and treating the various cardiovascular and cerebrovascular diseases that cause because of ischemia, anoxia.
Stigma Croci is an irides, is a kind of ancient famous and precious plant amedica, in China medicine masterpiece Compendium of Material Medica, record and narrate Stigma Croci " sweet flat nontoxic, cure mainly to worry and smoulder, unhappyly do not loose; Food makes us heart happiness for a long time, controls palpitation with fear again." quantity research explanation Stigma Croci Main Ingredients and Appearance is a water soluble carotenoid greatly both at home and abroad, also claims Stigma Croci general glycoside, Crocin, Stigma Croci general glycoside, crocin or gardenin, a large amount of animal experiment studies prove, as United States Patent (USP): U.S.4,176,179; U.S.4,070,460, crocin and glycoside thereof unit can cholesterol reducing, triglyceride, prevent and treat atherosclerosis, coronary heart disease, treatment cerebral edema, bone marrow injury, papillary tumor, arthritis and hypertension etc.
Before the eighties, the main dependence on import of Stigma Croci that China is used, its international market price becomes ascendant trend always, by 200 dollars before 15 years, breaks through to 2000 dollars of high pointes, so the medicine source is in great shortage, still can not utilize this material in commercial production at present.
Although contain crocin (1980 pages of Chinese medicine voluminous dictionary volume two) in the cape jasmine fruit, but recent decades, never the someone expects utilizing cape jasmine fruit to replace Stigma Croci to extract crocin or crocin is used for clinical, pharmacy circle is just being done a lot of work aspect the introducing a fine variety of Stigma Croci, the cultivation, even to this day, still have the people to suspect and really contain crocin in the Fructus Gardeniae, this may be relevant with the method for extracting crocin from Fructus Gardeniae.
Common water of food manufacturing those skilled in the art or alcohol water blend extraction separation crocin from cape jasmine fruit in the past, after filtering, carry out concentrate drying, make sale as gardenin, be widely used in food color, but adopt the crocin content of this class methods extraction separation low, impurity is many, usually cause variable color, usually content is: 5～10% (Japan's special permission discloses clear and 52-1397, special permission discloses clear and 58-27537) in order to remove the impurity in the gardenin, as polyphenol and cyclenes terpene glycosides etc., the Japan relevant expert develops again and uses styrene adding preservative agent (the open 56-27753 of special permission) and two kinds of adsorbents of polyamide and use semi-rigid polyethylene kind colloid (special permission discloses clear and 61-50981), yet preceding kind of method is loaded down with trivial details, consuming time; Latter's cost height.In order further to overcome above-mentioned deficiency, the somebody adopts Emathlite or active hargil, it is added the flavochrome solution that extracts, after isolating hargil, water and alcoholic solution eluting are collected eluent, spray drying (special permission discloses clear and 52-129921), but the content of this method crocin is still not high enough, generally 10～15%, and also time-consuming taking a lot of work.All can not obtain crocin with above-mentioned all extractions, separation, process for purification
1Monomer.
The objective of the invention is to avoid above-mentioned weak point of the prior art and provide a kind of prevention, therapeutical effect remarkable, the pharmaceutical composition that toxicity is low cardiovascular system diseases; The glycosides composition that extracts from crude drug still can be used for health product, medicine pigment or food coloring except that can preparing various preparations.
The present invention also aims to utilize domestic mass production, low-cost medical material to replace dependence on import, expensive medical material as the raw material for preparing described pharmaceutical composition.
Purpose of the present invention still is to utilize cost preparation method, production purity low, simple to operate, that be suitable for suitability for industrialized production higher thereby be suitable for preparing crocin, the crocin of medicine
1The bayer acid composition.
Purpose of the present invention can reach by following measure: a kind of pharmaceutical composition of anti-angiocardiopathy is characterized in that: comprising the crocin that from cape jasmine fruit, extracts, and general formula (I), bayer acid and salt thereof are as active component.
Crocin
1: R
1=R
2=D-gentiobiose
Crocin
2: R
1=D-gentiobiose, R
2=D-glucose
Crocin
3: R
1=D-gentiobiose, R
2=H
Crocin
4: R
1=D-glucose, R
2=-CH
3
Bayer acid: R
1=R
2=H
Also comprise the available carrier of described active component simultaneously.
The present invention also provides preparation to contain crocin, crocin
1Or the method for the pharmaceutical composition of its glycoside unit bayer acid, it comprises the steps:
1. after sophisticated cape jasmine fruit commercially available or that adopt certainly being pulverized, defat according to a conventional method; Take off
Fatsolvent adopts petroleum ether, ether, gasoline or other mixed liquor.
2. the medical material after the defat is that 30～80% water-alcohol solutions extract with containing the alcohol amount, and pure liquid can be selected from
Methanol, ethanol, propanol or n-butyl alcohol.
3. extracting solution is condensed into extractum through normal pressure, decompression or thin film evaporation, adopts decompression dense usually
Contract.
4. the ethanol that adds 2～5 times of amounts in the extractum is precipitated.
5. behind the pure precipitate in the filtering extractum, keep filtrate, it is condensed into concentrated solution.Dense
Contract and under decompression or normal pressure, to carry out routinely.
6. concentrated solution can take two kinds of methods of A, B to handle.
A method, concentrated solution resin column chromatography, first water is washed impurity off towards post, and reuse contains
Alcohol amount 30～95% water alcohol liquid gradient elution.Used resin is the big of commercially available synthetic
The pass resin, porous type resin or weak-acid cation-exchange resin.Used alcohol is first
Alcohol or ethanol merge the elution fraction contain crocin, concentrate or spray drying after,
The mixture of crocin, i.e. crocin, yield is 0.4～1% by weight.
Crocin is the burgundy solid, is Powdered, mildly bitter flavor.This product is soluble in
0.1mol/L NaOH solution is dissolved in water and methanol, slightly is dissolved in dehydrated alcohol, the utmost point
Be slightly soluble in chloroform.This product can make sulfuric acid solution show blue color, demonstrate crocin and
The reaction of glycoside unit; The maximum absorption wavelength of this product solution respectively 458 ± 1nm and
432 ± 1nm, absorbance ratio are 0.893; This product with the KBr method measure infrared spectrum with
The collection of illustrative plates of Stigma Croci extract is in full accord, column chromatography band of this extract and efficient liquid
The phase collection of illustrative plates is consistent with the Stigma Croci extract, mainly contains four kinds of glycosides: crocin
1,
Crocin
2, crocin
3And crocin
4, but glycoside in the Stigma Croci extract
2High
In the Fructus Gardeniae extract glycoside
2, and glycoside
3Then be lower than Fructus Gardeniae extract.According to said method system
The crocin that is equipped with can further separate each glycoside of Stigma Croci.With silica gel on the crocin
Column chromatography, use methanol: ethyl acetate: water is as eluant, by polarity from small to large than
Example, conventional gradient elution merges same composition, and is concentrated, dry, recrystallization,
Trace.Resultant crocin
1Purity is good, measures through high performance liquid chromatograph, contains
Amount is 75～98%; Crocin
1Being peony acicular crystal, fusing point is 176～
178 ℃, dissolubility is consistent with the Stigma Croci extract with chromogenic reaction.Two kinds of extracts
The glycoside of separation and purification
1Thin layer chromatography and high performance liquid chroma-tography collection of illustrative plates consistent.This product
As seen in full accord with infrared spectrum and Stigma Croci Sa Dela standard spectrum.According to nuclear-magnetism
Resonance hydrogen analysis of spectrum, elementary analysis and quantitative chemical analysis infer structure be last shown in,
Molecular formula is: C
44H
64O
24, molecular weight is 977.
The B method also can directly be used silica gel column chromatography with concentrated solution, uses methanol: ethyl acetate: water is done
Be eluant, be made into the eluent of different proportion from small to large by polarity, as routine
Gradient elution merges same composition, and concentrated respectively, dry, recrystallization get sarranine
The flower glycoside
110～50%, crocin
24～6%, crocin
3And glycoside
4Trace.
Crocin is water-soluble 7., carry out conventional acid hydrolysis or basic hydrolysis, obtain Stigma Croci
Acid is measured through high performance liquid chromatograph, and bayer acid content is 75～98%, yield
Be 10.0～30.0%.With bayer acid and pharmaceutically acceptable alkali effect, promptly
The Stigma Croci hydrochlorate.Alkali commonly used is the sodium hydroxide of 1.0mol/L, potassium hydroxide or
Calcium hydroxide.Bayer acid is a brown powder, mildly bitter flavor, and abnormal smells from the patient is special, and fusing point is
284～286 ℃; Be dissolved in dilute alkaline soln, be slightly soluble in water and organic solvent; Chromogenic reaction
Extract the consistent of preparation with Stigma Croci; This product visible and infrared spectrum and its Sa Dela
Standard spectrum is consistent.Quantitatively divide according to nuclear-magnetism carbon analysis of spectrum, elementary analysis and chemistry
Analyse, push away the card its structure be last shown in, molecular formula is: C
20H
24O
4, molecular weight is 368.
8. crocin, crocin
1, bayer acid and salt thereof can use conventional formulation method system
Become tablet, electuary, capsule, pill, injection, controlled release agent or slow releasing agent.Often
With pharmaceutical carrier have: (a) filler and solubilizing agent, as starch, lactose, glucose,
Mannitol and silicon dioxide; (b) binding agent, for example carboxymethyl cellulose, alginic acid
Salt, gelatin and polyvinylpyrrolidone; (c) Humectant is as glycerol; (d) disintegrate
Agent, agar, calcium bicarbonate, sodium bicarbonate; (e) dissolving delayer; (f) absorb again
Accelerator is as quaternary ammonium compound; (g) wetting agent, as hexadecanol, the stearic acid list is sweet
Grease; (h) adsorbent is as Kaolin and bentonite; (i) lubricant.
The manufacture method of pill: get crocin 1.25～20.09 grams, add refined honey 100
Gram, glutinous rice flour 200 gram, with the method for knowing make small honey pill 100 grams or big honeyed pills every
Ball 3 grams.
Capsular manufacture method: get crocin 1.25～20 grams, starch 5.0 grams,
Lactose 5.0 grams are crossed sieve respectively No. four, add 1% sodium carboxymethyl cellulose and make in right amount
Soft material, through No. two sieve series grains, the granule oven dry, control moisture content adds 1.0 below 2%
Gram starch is crossed the sieve granulate No. two, adds Pulvis Talci, measures granule content, calculates
Loading amount is sub-packed in 100 of No. 2 capsules.
The manufacture method of intravenous injection: it is an amount of to get water for injection, with propylene glycol 10 gram,
Sodium thiosulfate 0.1 gram adds stirring and dissolving, regulates pH7.0, adds crocin
1
0.1～2.5 grams, stirring and dissolving, filtering solution is added an amount of injection from filter
Water makes the filtrate total amount reach 100ml, and above-mentioned clear filtrate stirs, and embedding is in 2ml
In the ampoule, per ampoule 2ml.Sterilization promptly, adds 5% Glucose Liquid and annotates for vein
Penetrate or instil.
The manufacture method of slow releasing tablet: get crocin 3.75～24.00 grams, lactose
3.0 gram, stearic acid 2.5 grams, octadecanol 2.5 grams, microcrystalline Cellulose 2.0 grams, hydroxyl
Base propyl methocel 5.0 grams, mix homogeneously is with 1% hydroxypropyl methyl fibre
The plain alcoholic solution of dimension is granulated, and after drying, adds an amount of Pulvis Talci, presses then and dashes 100
Sheet, reuse water-insoluble acrylic resin bag film-coat.
Pharmaceutical composition provided by the invention can be used for treatment or prevention hyperlipidemia. atherosclerosis. and coronary heart disease, anoxia cerebrovascular disease and various thromboembolism sexually transmitted disease (STD).Crocin. crocin
1Can be used as health product, medicine pigment or food coloring with glycoside unit and salt thereof.
Pharmaceutical composition provided by the invention is evident in efficacy to cardiovascular system diseases, and the crocin that it is contained is with crocin
1Reach bayer acid or salt and have similar pharmacological action.It mainly acts on and comprises the accent blood fat; Anticoagulant and thrombosis; Change hemorheology, reduce blood viscosity; Increase blood oxygen saturation, function of resisting myocardial ischemia.In a word, every disease that causes by anoxia, all available this product treatment.
One, transfer blood fat, not only to cholesterol. triglyceride. low density lipoprotein, LDL, very low density lipoprotein (VLDL) have significant reduction effect; And high density lipoprotein increasing very significantly.Crocin and chemical compound thereof can be used for treating hyperlipidemia, atherosclerotic cardiovascular disease.
1, rat disorders of lipid metabolism prevention administration
Select healthy male Wistar rat, body weight is 180 ± 20g.Random packet is matched group and administration group, 10 every group.The equal feed high lipid food of each treated animal (prescription is egg yolk 10%, Adeps Sus domestica 15%, cholesterol 3%, methylthiouracil 0.1%, normal diet 72.9%).Experiment beginning gastric infusion, every day 1 time, matched group is given same water gaging, and fasting is 12 hours after the 10th day, abdominal aortic blood. separation of serum.With enzymatic assays serum total cholesterol (TC). the content of triglyceride (TG) and high density lipoprotein.Calculate low density lipoprotein, LDL (LDL-c) by technical staff's well-known formula. very low density lipoprotein (VLDL) (VLDL-c) and atherogenic index.Experimental result sees Table 1.The result has disclosed between matched group and the administration group, and every index all has the difference (P＜0.01) of highly significant.
2, rabbit disorders of lipid metabolism treatment administration
Select healthy male livid purple blue rabbit, add feed cholesterol after, select the rabbit that forms disorders of lipid metabolism, random packet, 10 every group, continue the feeding cholesterol, add again and feed ripe egg yolk, one finishes until experiment.Treatment experiment beginning, administration group gastric infusion, once a day, matched group is irritated stomach and is given same water gaging, and per 2 weeks are surveyed a blood fat, try to achieve TC, TG, HDL-c, LDL-c, VLDL-c by the known method of pharmacology worker.The experimental result for the treatment of after six weeks is seen Fig. 1.Experimental result shows: crocin and chemical compound thereof have significant therapeutic effect to the rabbit of disorders of lipid metabolism.
Two, anticoagulant and thrombosis effect
1, the outer anticoagulant experiment of external and halfbody
Select male SD rat, body weight is 300 ± 20g, from abdominal aortic blood 4.5ml, adds the test tube of putting into 0.5ml 3.8% sodium citrate in advance with the silication syringe, and its centrifugal 3min (1000 rev/mins) is drawn upper strata PRP; Remaining blood plasma recentrifuge (3000 rev/mins) 10min, supernatant is PPP.Getting 20 μ l PRP puts in the opacity tube, 37 ℃ of incubation 5min, assemble on the instrument in the PPP autobalance, measure the maximum of derivant ADP and thrombin and assemble percent, the experimental result explanation: crocin and chemical compound thereof have significant inhibitory effect to the rat platelet aggregation of ADP and thrombin induction, the results are shown in Table 2 and 3.
Get male SD rat, body weight 250 ± 20g is divided into matched group and administration group at random.Gastric infusion, after 2 hours, abdominal aortic blood is operated the same in vitro method, and derivant is ADP, and experimental result sees Table 4.Experimental result shows: vivo medicine-feeding, crocin and chemical compound thereof have the obvious suppression effect to the inductive rat platelet aggregation of ADP.
2, to the influence of intravenous injection ADP mouse death rate
Select male mice in kunming, body weight is 20g, is divided into matched group and administration group at random.Behind the gastric infusion 2 hours, tail vein injection ADP 480mg/12ml/kg, mortality of mice in the record 3min.Experimental result sees Table 5.Experimental result shows: crocin and chemical compound thereof have the obvious suppression effect to the microvascular platelet thrombus of lung that mouse tail vein injection ADP causes.
3, to the thrombotic effect of rat arteriovenous shut
Get healthy male SD rat, body weight 300 ± 20g, lumbar injection pentobarbital sodium 35mg/kg, after the anesthesia, it is fixing to lie on the back, and separates trachea, inserts the vinyl tube of a long 5cm.Separate right common carotid artery and left external jugular vein.Put into No. 4 surgical threads of a long 6cm in polyethylene tube, heparin-saline solution is full of polyethylene tube.After polyethylene tube one end inserts vein, accurately inject anticoagulant heparin from the other end of this pipe, again this end is inserted right common carotid artery.After opening blood flow, blood flow flow in the polyethylene tube from right common carotid artery, returns left external jugular vein, and the matsurface of the platelet contact silk thread in the blood flow can adhere on it, forms platelet thrombus.After the administration 2 hours, to perform a surgical operation, postoperative is decontroled blood flow immediately, and 15 minutes hemostasis stream takes out silk thread and weighs, and it heavily is wet weight of thrombus that this weight deducts line.Experimental result sees Table 6.Table 6 shows that crocin and chemical compound thereof have significant inhibitory effect to rat arteriovenous shut thrombosis.
Method is the same, crocin, and 50mg/kg, gastric infusion, respectively at undergoing surgery in 1,2,4,8,16 hour after the administration, each time point is 6 rats, asks the average weight in wet base of its each time point thrombosis, the results are shown in Figure 2.Experimental result shows: crocin reaches more than 16 hours rat arteriovenous shut thrombosis inhibitory action.
4, the influence that the rabbit external thrombus is formed
Select healthy male rabbit (big ear is white), body weight 2.5 ± 0.5kg/ only, be divided into matched group and administration group at random, before administration and administration after 3.5 hours,, inject immediately in the rotating ring from heart extracting blood 1.8ml with the silication syringe, observe fibrinous thrombus formation time (TFT), go out thrombosis in the filter paper updip after 15 minutes, measure its length and weight in wet base.64 ℃ of dryings 2 hours, survey its dry weight, experimental result sees Table 7.The experimental result explanation: crocin and chemical compound thereof all have tangible reduction effect to length, weight in wet base and the dry weight of rabbit external thrombus, and the fibrinous thrombus formation time is had the prolongation effect.
Three, to hemorheological influence
1, to the effect of hemorheology of rat
Select healthy male SD rat, body weight is 200 ± 20g, is divided into matched group and administration group at random.Gastric infusion, after 2 hours, abdominal aortic blood, anticoagulant heparin is pressed the Liao Shi method and is measured whole blood contrast viscosity and plasma viscosity, erythrocyte sedimentation rate, packed cell volume and erythrocyte electrophoretic time.Whole blood contrast viscosity is with 20
S-1With 100
S-1Two kinds of shearings are measured.Experimental result sees Table 8.The experimental result explanation: crocin and chemical compound thereof can reduce whole blood contrast viscosity, erythrocyte sedimentation rate and hematocrit very significantly, but erythrocyte electrophoretic time is not had obvious influence.
2, to the influence of the blood viscosity of rabbit
Select healthy male white big ear rabbit, body weight 2.5 ± 0.5kg/ only is divided into matched group and administration group at random, and behind the gastric infusion 3.5 hours, get blood 2.0ml from Cor Leporis respectively, add the test tube mixing that fills the 0.2ml3.8% sodium citrate, for measuring.Experimental result sees Table 9.Experimental result shows: crocin has tangible reduction effect to rabbit whole blood contrast viscosity and plasma viscosity.
Four, function of resisting myocardial ischemia
1, to the effect of rat coronary artery ligation myocardial infarction
Select healthy male SD rat, body weight 220 ± 20g is divided into matched group and administration group at random.Every group 10, preceding 1 hour gastric infusion of art, rat is used etherization, it is fixing to lie on the back, and opens the thoracic cavity, cuts off pericardium, the light thorax of pressing is extruded heart outside the thoracic cavity, wears the not damaged line with No. 6 little garden loopers, behind ligation coronary artery between pulmonary artery garden awl and the left auricle, put back to the thoracic cavity, take out tight thoracic wall suture rapidly, tie at this and respectively stitch a pin down, close the thoracic cavity fully, make animal recover autonomous respiration.Whether successful with the operation of electrocardiogram machine testing, postoperative injection gentamycin 0.2ml.
Postoperative 24 hours, reuse etherization rat is measured electrocardiogram.Begin to speak to take out heart, after rinsing well, cut off the atrium, N-BT liquid is immersed in section (about 8～9), and vibration dyeing is 15 minutes in 37 ℃ of aqueous solutions, will dye and non-dyeing myocardial infarction separate tissue is weighed; Get blood by rat aorta, survey CPK and LDH activity behind the separation of serum.Experimental result sees Table 10.Experimental result shows: crocin and chemical compound thereof cause that to coronary artery ligation the rat myocardium block area dwindles, and reduce serum CPK and LDH activity.
2, to the influence of guinea pig isolated heart perfusion
Select healthy guinea pig, male and female half and half, body weight is 400 ± 20g gram, be divided into matched group and administration group at random, every group 6, according to Langedorf rat heart device, adopt improvement Song Shi method, after heart is fixed on the perfusion device, promptly carry out the arbitrary Rockwell liquid of oxygen containing physiology perfusion 20～30 member record coronary flows (CBF), index such as heart rate and myocardial contraction, after treating that these indexs are stable, change to pastille perfusate record 5,10,15,20, every index of 25 and 30 minutes the results are shown in Figure 3, compare with matched group, coronary flow increases significantly, and heart rate is had more weak effect, but the myocardial contraction amplitude is not had obvious influence.
3, to the influence of guinea-pig heart myocardial ischemia due to the pituitrin
Method is the same, all contains pituitrin 40 μ/L in matched group and the administration group perfusate, writes down every index of 5,10,15,20,25 and 30 minutes; According to creatine phosphokinase (CPK) test kit operating procedure, measure CPK activity in the perfusate at wavelength 340nm place.Pituitrin can make the matched group coronary flow obviously reduce, and CPK is active obviously to be increased; Add crocin and chemical compound thereof and can obviously resist the coronary spasm that pituitrin brings out, increase coronary flow, suppress the activity of CPK significantly.The results are shown in Table 11, Fig. 4.
The present invention adopts Fructus Gardeniae to make raw material replacement Stigma Croci, extraction separation crocin.Raw material is easy to get, low price.All there is cultivation in most of area to Fructus Gardeniae in the whole nation, and tens yuan of mature fruit per kilograms are 0.6% with the cubage of glycoside, extract one kilogram of crocin and only need 2000 yuan of RMB.Stigma Croci price in recent years once rose to 2000 dollars, even calculate by 30% extraction ratio, extracts one kilogram of crocin and want 6600 dollars Stigma Croci from Stigma Croci.Replace Stigma Croci can save a large amount of foreign exchanges with Fructus Gardeniae, one of raw material only simultaneously is surplus cost can reduce by 20 times.
The present invention adopts the column chromatography for separation glycosides composition, especially adopts the resin column chromatography, and separation method is easy, and cost is low, and decontamination is effective, is suitable for suitability for industrialized production, and the glycoside purity that obtains is higher.The crocin that obtains behind the resin column chromatography, through high effective liquid chromatography for measuring, glycoside wherein
1Content is 10～50%, glycoside
2Content is about 6%; Through ultraviolet---visible spectrophotometer is measured, and crocin and acid content thereof are more than 50%.
Because purity is higher, so the crocin hygroscopicity is little.
Fig. 1 is the therapeutical effect sketch map of crocin of the present invention after to the rabbit disorders of lipid metabolism.
Fig. 2 is the timeliness figure of crocin of the present invention to the influence of rat arteriovenous shut thrombosis.
Fig. 3 influences sketch map for crocin of the present invention to the dirty arteria coronaria perfusion flow of normal guinea-pig heart.
Fig. 4 is the hat flow effect sketch map of crocin of the present invention to the dirty coronary spasm of guinea-pig heart.
Crocin extracts embodiment
1kg cape jasmine fruit, pulverizing defat, the ethanol 4L with 60% is under 50～60 ℃ of temperature, stir and extract merge extractive liquid,, concentrating under reduced pressure 2 times, concentrated solution discards precipitation with the ethanol repeated precipitation of 2 times of volumes, macroporous resin column on the concentrated solution behind the recovery ethanol, after the absorption, water flushing 10 hours, reuse 75～85% ethanol gradient elutions merge eluent, concentrating under reduced pressure, drying are re-refined to such an extent that crocin 8.7 restrains.
Through high effective liquid chromatography for measuring, crocin in the general glycoside
1Content is 45.7%, crocin
2Be 6.4%.
Crocin
1Extract embodiment:
100 gram crocins, last silicagel column carries out gradient elution with ethyl acetate/methanol mixed liquor, collects crocin
1The eluent of band, concentrating under reduced pressure, the reuse recrystallizing methanol is filtered after drying and is got 26.7 grams.
Through high effective liquid chromatography for measuring, crocin
1Content be 86.4%.
Bayer acid prepares embodiment:
In the 100g crocin dissolving suitable quantity of water, add 0.5N sulphuric acid, carry out the boiling water bath hydrolysis, behind the solution decolourization, separate out red precipitate, filter the water flushing to being neutral, drying.Get bayer acid 24.8 grams.
Through high effective liquid chromatography for measuring, bayer acid content is 85.4%.
Embodiment one, injection
Prescription 1:
Crocin
12.50 gram
Vitamin C 5.00 grams
Propylene glycol 10.00 grams
Sodium thiosulfate 0.10 gram
Preparation: it is an amount of to get water for injection, propylene glycol, sodium thiosulfate, vitamin C added, and stirring and dissolving, regulating pH is 6.5～7.5, adds crocin
1Stirring and dissolving, filtering solution is added an amount of water for injection from filter, makes the filtrate total amount reach 100.0 milliliters.
Above-mentioned clear filtrate stirs, and embedding is in 2 milliliters of ampoules, and 2 milliliters of per ampoules are sterilized promptly.
Annotate: add in 5% Glucose Liquid and splash into for vein.
Prescription 2:
Crocin
12.50 gram
Vitamin C 5.00 grams
Lactose 3.00 grams
Water for injection is added to 100.0 milliliters
Preparation: an amount of with water for injection, add vitamin C, lactose stirring and dissolving, regulating pH is 6.5～7.5, adds crocin again
1Dissolving, aseptic filtration makes the filtrate total amount reach 100 milliliters of embeddings in 2 milliliters of ampoules, 2 milliliters of per ampoules are removed moisture in the medicinal liquid through lyophilization, the lyophilization powder, become injectable lyophilised powder in sealed under aseptic conditions.
Using method:
1, the powder pin one normal saline 2ml dissolving back injection of drawing is got in intramuscular injection, once-a-day or secondary.
2, intravenous injection is got the powder pin one 50% Fructus Vitis viniferae powder injection 20ml dissolving back of drawing and is used, once-a-day or secondary.
3, intravenous drip is got powder pin two to three 50% Fructus Vitis viniferae powder injection, 100～500ml dissolving back of drawing and is used.
Embodiment two, capsule
Prescription 1:
Crocin (50～100%) 5.0g
Vitamin C 10.0g
Dextrin 1.0g
Lactose 1.0g
Starch 3.0g
Low substituted hydroxy propyl cellulose 0.5g
In will writing out a prescription after each medicine weighing, mix homogeneously is granulated with the aqueous solution of 0.5%HPMC (HYDROXY PROPYL METHYLCELLULOSE), cross No. two sieves after, wet granular, will adorn 100 capsules behind the particle drying.
Using method: once-a-day or secondary, one time one.
Prescription 2:
Crocin (50～100%) 5.0g
Vitamin C 10.0g
Starch 3.0g
Lactose 1.0g
Dextrin 1.0g
Ethyl cellulose 0.5g
After each medicine weighing in the prescription, mix homogeneously is made piller with 10% tragakanta liquid, and 100 capsules are adorned with water-insoluble acrylic resin bag film-coat in dry back after the drying.
Using method: once-a-day or secondary, one time one.
Embodiment three, pill
Prescription:
Crocin 5g
Refined honey 100g
Glutinous rice flour 200g
Take by weighing each medicine by prescription, make small honey pill or big honeyed pills (the heavy 3g of every ball).
Oral, once-a-day, once take small honey pill 3g or big honeyed pills 1 ball.
Embodiment four, slow releasing preparation
Prescription 1 (tablet)
Crocin (50～100%) 15.0g
Vitamin C 15.0g
Lactose 3.0g
Stearic acid 2.5g
Octadecanol 2.5g
Microcrystalline Cellulose 2.0g
HYDROXY PROPYL METHYLCELLULOSE 5.0g
After each medicine weighing in the prescription, mix homogeneously is granulated with the alcoholic solution of 1% HYDROXY PROPYL METHYLCELLULOSE, after drying, adds an amount of Pulvis Talci, presses 100 then, reuse water-insoluble acrylic resin bag film-coat.
Using method: weekly, each two.
Prescription 2 (capsules)
Crocin 15.0g
Vitamin C 15.0g
Lactose 3.0g
HYDROXY PROPYL METHYLCELLULOSE 5.0g
Ethyl cellulose 2.5g
Dextrin 1.0g
After each medicine weighing in the prescription, mix homogeneously is made piller with 10% Arabic glue, and reuse water-insoluble acrylic resin bag film-coat is adorned 100 capsules after drying.
Using method: weekly, each two.
Table 1 crocin is to effect (N=10) the group dosage TC TG HDL LDL VLDL of prevention rat fat disorder
(mg/kg) (mg/dl) (mg/dl) (mg/dl) (mg/dl) (mg/dl) high fat contrast 218.24 233.00 44.90 126.74 46.60
± 28.69 ± 52.74 ± 5.50 ± 27.89 ± 10.55 crocins 50 106.19 130.69 56.86 23.19 26.14
±12.96
*** ±41.09
*** ±4.71
*** ±10.81
*** ±12.22
*** *P＞0.05，
**P＜0.05，
***P＜0.01，
****P＜0.001, the high fat control group of VS
The rat platelet aggregation inhibitory action group final concentration number of animals inhibiting rate that table 2, crocin are induced ADP
(ug/ml) (%) control group N.S 12 0 crocins 12.5 6 23.3
25.0 6 38.8
50.0 6 52.7
Table 3, crocin suppress group final concentration number of animals inhibiting rate to the rat platelet aggregation of thrombin induction
(ug/ml) (%) control group 12 0 crocins 75.0 6 53.4
100.0 6 80.8
The effect group dosage number of animals inhibiting rate of the rat platelet aggregation that table 4, crocin are induced ADP
(mg/kg) (%) control group N.S 60 crocins 50.0 6 64.4
Table 5, crocin affect the group dosage number of animals death toll death rate to intravenous injection ADP mouse death rate
(mg/kg) (%) control group N.S 46 39 84.78 crocins 25.0 18 11 61.11
50.0 26 7 26.92
100.0 22 3 13.44
Table 6, crocin are to the thrombotic effect group of rat arteriovenous shut dosage number of animals inhibiting rate
(mg/kg) (%) control group 60 crocins 50 6 25.03
100 6 54.21
Table 7, crocin are to the thrombotic impact of rabbit (N=6) group dosage TFT thrombus
Mg/kg length (mm) weight in wet base (mg) dry weight (mg) control group 6.72 ± 1.95 11.63 ± 2.73 406.4 ± 109.0 108.0 ± 84.9 crocins 25.0 8.80 ± 1.47 8.14 ± 1.05*** 231.4±66.6
*** 89.3±36.6
50.0 9.52±2.16
** 5.70±2.24
**** 202.6±91.2
**** 78.5±65.6
Table 8, crocin are to effect (N=8) the group dosage whole blood contrast viscosity plasma viscosity red blood cell red blood cell red blood cell of hemorheology of rat
(mg/kg) 20s-1 100s-1 rate of settling hematocrit electrophoresis time control group 4.82 3.24 1.51 0.63 49.88 20.50
± 0.45 ± 0.39 ± 0.13 ± 0.23 ± 3.25 ± 1.5 crocins 50.0 4.43 2.91 1.27 0.81 47.43 19.21
±0.29 ±0.36 ±0.26 ±0.53 ±2.46 ±1.4
100.0 4.28 2.85 1.20 1.39 44.60 18.51
±0.25
**±0.51
** ±0.20
*** ±0.79
**±4.57
* ±1.9
* *P＞0.05，
**P＜0.06，
***P＜0.01，
****P＜0.001, the VS control group
Table 9, kind crocins are to impact (n=6) the group dosage whole blood contrast viscosity plasma viscosity of rabbit blood viscosity
(mg/kg) control group 3.30 ± 0.29 3.30 ± 0.23 1.98 ± 0.23 1.96 ± 0.20 crocin 50.0 3.49 ± 0.37 2.24 ± 0.20 after the administration before the administration after the administration before the administration*** 1.94±0.09 1.34±0.04
**
100.0 3.36±0.30 2.09±0.26
*** 1.80±0.20 1.09±0.10
*** *P＞0.05，
**P＜0.05，
***P＜0.01，
****P＜0.001, the VS control group
Table 10, crocin improve group dosage myocardial infarction area CPK LDH to rat coronary artery ligation miocardial infarction
(mg/kg) (%) (μ/L control group 50.80 ± 3.31 1684.4 ± 469.5 3540.0 ± 583.6 crocins 100.0 36.30 ± 3.95 of μ/L)**** 953.3±304.8
** 2612.8±660.4
**
Table 11, crocin discharge inhibiting rate to affecting before the group dosage ischemic of discharging of phosphocreatinase behind the ischemic
(mg/kg) (μ/L) ((%) control group 209 ± 23 309 ± 21 0.0 Verapamils of μ/L) you 0.125 205 ± 21 251 ± 21**54.4 crocin 6.3 212 ± 28 296 ± 28* 16.6
12.5 193±29 243±28
** 50.9
25.0 230±38 223±40
*** 107.3
Claims (11)
1. the pharmaceutical composition of an anti-angiocardiopathy is characterized in that: comprising extracting crocin, general formula (I), crocin from cape jasmine fruit
1, bayer acid and salt thereof is as active component,
Crocin
1: R
1=R
2=D-gentiobiose
Crocin
2: R
1=D-gentiobiose, R
2=D-glucose
Crocin
3: R
1=D-gentiobiose, R
2=H
Crocin
4: R
1=D-glucose, R
2=-CH
3
Bayer acid: R
1=R
2=H
Also comprise the pharmaceutically useful carrier of described active component simultaneously.
2. pharmaceutical composition according to claim 1 is characterized in that it can being tablet.
3. pharmaceutical composition according to claim 1 is characterized in that it can being injection.
4. pharmaceutical composition according to claim 1 is characterized in that it can being capsule.
5. pharmaceutical composition according to claim 1 is characterized in that it can being pill.
6. pharmaceutical composition according to claim 1 is characterized in that it can being electuary.
7. pharmaceutical composition according to claim 1 is characterized in that it can being slow releasing agent.
8. pharmaceutical composition according to claim 1 is characterized in that it can being controlled release agent.
9. a method for preparing the described pharmaceutical composition of claim 1 is characterized in that comprising the steps:
＜1〉with after the cape jasmine fruit pulverizing, defat according to a conventional method;
＜2〉medical material after the defat with the alcohol amount of containing be 30～80% water and methanol, ethanol, propanol or
The water alcohol liquid that n-butyl alcohol is made into extracts;
＜3〉extracting solution is condensed into extractum through normal pressure, decompression or thin film evaporation;
＜4〉ethanol that adds 2～5 times of amounts in the extractum is precipitated;
＜5〉behind the pure precipitate in the filtering extractum, filtrate is condensed into concentrated solution;
＜6〉A method, concentrated solution resin column chromatography, first water is washed impurity off towards post, and reuse contains
The water alcohol liquid gradient elution of alcohol amount 30～95% merges the elution fraction that contains crocin,
Concentrate or spray drying after, crocin, yield is 0.4～1% by weight; Again
With the crocin silica gel column chromatography, use methanol: alcohol, acetic acid: water is pressed as eluant
Polarity is ratio from small to large, and conventional gradient elution merges same composition, and is concentrated, dry,
Get crocin
110～50%, crocin
24～6%, crocin
3And glycoside
4Little
Amount,
The B method also can directly be used silica gel column chromatography with concentrated solution, uses methanol: ethyl acetate: water is done
Be eluant, be made into the eluent of different proportion from small to large, as conventional ladder by polarity
The degree eluting merges same composition, and concentrated, dry, recrystallization get crocin
1
10～50%, crocin
24～6%, crocin
3And glycoside
4Trace,
＜7〉crocin is water-soluble, carry out conventional acid hydrolysis or basic hydrolysis, obtain bayer acid;
With bayer acid and pharmaceutically acceptable alkali effect, promptly get the Stigma Croci hydrochlorate,
＜8〉crocin, crocin
1, bayer acid and salt thereof can make with the conventional formulation method
Tablet, electuary, capsule, pill, injection, controlled release agent or slow releasing agent.
10. according to the described preparation of drug combination method of claim 9, it is characterized in that＜6〉A methods described in the resin used resin be macroporous ion-exchange resin, porous type resin, weak-acid cation-exchange resin.
11. the described pharmaceutical composition of claim 1 is characterized in that the crocin, the crocin that extract in the contained cape jasmine fruit in the compositions
1With bayer acid and salt thereof, still can be used as health product, medicine pigment or food coloring.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94111504A CN1059444C (en) | 1994-11-29 | 1994-11-29 | Composition for curing angicardiopathy and its production and usage |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94111504A CN1059444C (en) | 1994-11-29 | 1994-11-29 | Composition for curing angicardiopathy and its production and usage |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1123663A true CN1123663A (en) | 1996-06-05 |
| CN1059444C CN1059444C (en) | 2000-12-13 |
Family
ID=5035369
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94111504A Expired - Fee Related CN1059444C (en) | 1994-11-29 | 1994-11-29 | Composition for curing angicardiopathy and its production and usage |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1059444C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012025229A1 (en) | 2010-08-27 | 2012-03-01 | Persavita Ltd. | Composition and method of manufacture |
| CN105503968A (en) * | 2015-12-02 | 2016-04-20 | 武汉绿孚生物工程有限责任公司 | Method for separation and purification of crocin and crocetion from gardenia yellow pigment |
| WO2017185900A1 (en) * | 2016-04-29 | 2017-11-02 | 暨南大学 | Crocins compounds and uses thereof |
| WO2019077621A1 (en) * | 2017-10-16 | 2019-04-25 | Council Of Scientific And Industrial Research | Sustained release formulations of crocus sativus |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9211298B2 (en) | 2012-11-16 | 2015-12-15 | Song Gao | Compositions containing enriched natural crocin and/or crocetin, and their therapeutic or nutraceutical uses |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4070460A (en) * | 1975-11-10 | 1978-01-24 | University Of Virginia Patents Foundation | Method for treating cerebral edema |
| US4176179A (en) * | 1978-04-17 | 1979-11-27 | The University Of Virginia Alumni Patents Foundation | Method for treating arthritis |
-
1994
- 1994-11-29 CN CN94111504A patent/CN1059444C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012025229A1 (en) | 2010-08-27 | 2012-03-01 | Persavita Ltd. | Composition and method of manufacture |
| CN105503968A (en) * | 2015-12-02 | 2016-04-20 | 武汉绿孚生物工程有限责任公司 | Method for separation and purification of crocin and crocetion from gardenia yellow pigment |
| CN105503968B (en) * | 2015-12-02 | 2017-10-31 | 武汉绿孚生物工程有限责任公司 | A kind of method of separating-purifying crocin and crocetin from Gardenia Yellow |
| WO2017185900A1 (en) * | 2016-04-29 | 2017-11-02 | 暨南大学 | Crocins compounds and uses thereof |
| AU2017255363B2 (en) * | 2016-04-29 | 2019-10-17 | Jinan University | Crocins compounds and uses thereof |
| US11440931B2 (en) | 2016-04-29 | 2022-09-13 | Jinan University | Crocins compounds and uses thereof |
| WO2019077621A1 (en) * | 2017-10-16 | 2019-04-25 | Council Of Scientific And Industrial Research | Sustained release formulations of crocus sativus |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1059444C (en) | 2000-12-13 |
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