CN1785283A - Medicinal composition for treating cardiorascular disease and its preparation method - Google Patents
Medicinal composition for treating cardiorascular disease and its preparation method Download PDFInfo
- Publication number
- CN1785283A CN1785283A CN 200410093839 CN200410093839A CN1785283A CN 1785283 A CN1785283 A CN 1785283A CN 200410093839 CN200410093839 CN 200410093839 CN 200410093839 A CN200410093839 A CN 200410093839A CN 1785283 A CN1785283 A CN 1785283A
- Authority
- CN
- China
- Prior art keywords
- fructus crataegi
- cyclodextrin
- water
- crataegi extract
- medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
A compound medicine for treating cardiovascular and cerebrovascular diseases is prepared from cyclodextrin and haw flavone. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to treat the medicinal preparation of cardiovascular disease, more particularly, relating to Chinese medicine is pharmaceutical composition of the treatment cardiovascular disease made of raw material and preparation method thereof.
Background technology
Cardiovascular and cerebrovascular disease is listed as first of each big disease, serious harm human body health, and the sequela that is caused is also brought very big misery to patient and family members, becomes the social problem of a worth extensive concern.Coronary flow is an important indicator of estimating the control myocardial ischemia drug, and external coronary flow is measured can observe the influence of medicine to coronary resistance.Anoxia enduring is that medicine improves body tissue (particularly cerebral tissue and heart tissue) hypoxia-bearing capability, improves one of important mechanisms of energy metabolism.Countries in the world medicine worker constantly studies, develops the medicine of cardiovascular and cerebrovascular disease, and the cardiovascular and cerebrovascular disease patient can effectively be treated.The medicine that is used for the treatment of cardiovascular disease at present is more, and it is real that the Fructus Crataegi Tang materia medica is called red pawl, and ancient prescription is seldom used, from the beginning merit of Fructus Crataegi of Zhu Dan small stream, satisfies and is key medicine.The acid of Fructus Crataegi property, sweet, tepor are returned spleen, stomach, Liver Channel, have promoting digestion and removing stagnation, promoting blood circulation to remove blood stasis.The at present clinical food stagnation that is mainly used in is stagnated, normal and compatibility application such as Fructus Hordei Germinatus, six songs; Also be used for postpartum stagnation stomachache, lochiorrhea, compatibilities such as normal and Radix Angelicae Sinensis, Rhizoma Chuanxiong, Herba Leonuri; Also be used for the treatment of hypertension, coronary heart disease, hyperlipidemia in recent years.Modern pharmacology evidence, Fructus Crataegi have the increase myocardial contraction, increase cardiac output, decreased heart rate, and the coronary artery dilator blood vessel reduces myocardial oxygen consumption, and can bring high blood pressure down and blood fat.What play a major role in the Fructus Crataegi is Fructus Crataegi total flavones.Fructus Crataegi total flavones be used for the treatment of cardiovascular and cerebrovascular disease many with the use of drug for invigorating blood circulation and eliminating stasis compatibility, use separately less, Fructus Crataegi total flavones and which kind of adjuvant is used and Fructus Crataegi total flavones and adjuvant between the proportioning of the best be the key that influences curative effect of medication.
Summary of the invention
Purpose of the present invention just provides a kind of medicine for the treatment of cardiovascular and cerebrovascular disease.
Another object of the present invention provides this treatment cardiovascular and cerebrovascular diseases medicament preparation method.
The May Rosaceae Crataegus is the conventional Chinese medicine material, and the sweet tepor of its nature and flavor acid can appetite-stimulating indigestion-relieving, removing food stagnancyization stagnates, activating blood circulation to dissipate blood stasis, convergence dysentery relieving.Be widely used in common disease such as treatment dyspepsia, hyperlipidemia and coronary heart disease etc., its contained flavones ingredient of bibliographical information has the effect of blood pressure lowering, blood fat reducing, antioxidation, dilating coronary blood vessel, coronary blood flow increasing.
Fructus Crataegi total flavones extracts from Rosaceae Crataegus plant Folium Crataegi.Be sundown or pale brown toner end, special aroma is arranged, odorless, bitter in the mouth, soluble in water and ethanol.Main active is vitexin rhamnopyranoside and vitexin glycoside etc.Has anticoagulant, coronary artery dilator; Improve blood supply of cardiac muscle, reduce myocardial oxygen consumption, ischemic heart desease is produced significant protective effect, have blood fat reducing, the effect of blood pressure lowering.Be applicable to coronary heart disease, coronary insufficiency, angina pectoris and treatment cardiovascular disease etc.The present invention utilizes this effect of the Radix Astragali just, by a large amount of tests, makes pharmaceutical composition of the present invention.
Amount of drug component of the present invention also gropes to sum up to draw through the inventor in a large number, and each amounts of components proportioning all has curative effect preferably in following ranges:
Cyclodextrin 1.0～4.0g, Fructus Crataegi extract 0.3～1.2g, water 300～1500ml.
The preferable amount proportioning is:
Cyclodextrin 1.5～3.0g, Fructus Crataegi extract 0.5～0.8g, water 600～850ml.
The optimum amount proportioning is:
Cyclodextrin 2.0g, Fructus Crataegi extract 0.6g, water 750ml.
Fructus Crataegi extract can adopt present common extracting method to extract its effective ingredient in the bright medicine of this law, but in order to make Fructus Crataegi bring into play better drug effect, preferably adopt following technology to extract to raw material, but this can not limit protection scope of the present invention.
Get Fructus Crataegi, add ethanol extraction 3 times, merge extractive liquid,, standing over night is filtered, filtrate concentrates, and reclaims ethanol, and concentrated solution is crossed macroporous adsorbent resin, adds the suitable quantity of water eluting, the reuse ethanol elution, merge concentrated solution, cross poly-fine amine, washing, reuse ethanol is washed, and concentrates to obtain Fructus Crataegi extract.
The extracting method of Fructus Crataegi extract is in the preferred medicine of the present invention: get Fructus Crataegi, extract altogether 3 times, 70% the ethanol extraction 0.5 hour that adds for the first time 7 times of amounts, 70% the ethanol extraction 0.5 hour that adds for the second time 6 times of amounts, 70% the ethanol extraction 0.5 hour that adds 6 times of amounts for the third time, standing over night is filtered, and filtrate concentrates, reclaim ethanol, concentrated solution is crossed macroporous adsorbent resin, add the suitable quantity of water eluting, reuse 30% ethanol elution, merge concentrated solution, cross poly-fine amine, washing, reuse 50% ethanol is washed, and concentrates to obtain Fructus Crataegi extract.
Medicine of the present invention can adopt the Chinese medicine preparation conventional method to be prepared into any conventional formulation.For example these crude drug pulverize mix homogeneously can be made powder takes after mixing it with water; Also can be with these medicines decocting together, the condensed water decocting liquid is made oral liquid then; But, preferably adopt following technology to extract, but this can not limit protection scope of the present invention to raw material in order to make each crude drug of this medicine better bring into play drug effect.
Preparation of drug combination method of the present invention:
(a) by proportioning raw materials take by weighing cyclodextrin 1.0～4.0g, Fructus Crataegi extract 0.3～1.2g, water 300～1500ml is standby;
(b) take by weighing cyclodextrin, be dissolved in the water standby; Other gets the ultrasonic one-tenth suspension of Fructus Crataegi extract water; With the cyclodextrin aqueous solution heating, stir, add the suspension of Fructus Crataegi extract; Stir concentrating under reduced pressure, filtering with microporous membrane postlyophilization;
(c) the gained active component is mixed with appropriate amount of auxiliary materials, make any medicament on the pharmaceutics.
Preferred preparation of drug combination method of the present invention:
(a) by proportioning raw materials take by weighing cyclodextrin 1.5～3.0g, Fructus Crataegi extract 0.5～0.8g, water 600～850ml is standby;
(b) take by weighing cyclodextrin, be dissolved in the water standby; Other gets the ultrasonic one-tenth suspension of Fructus Crataegi extract water; Cyclodextrin aqueous solution is warming up to 30-90 ℃, stirs, add the suspension of Fructus Crataegi extract, application of sample speed is 1.0-10ml/min; 25～70 ℃ are continued to stir 4-20 hour, are evaporated to 20-100ml, the filtering with microporous membrane postlyophilization in 50-100 ℃;
(c) the gained active component is mixed with appropriate amount of auxiliary materials, make any medicament on the pharmaceutics.
Best preparation of drug combination method of the present invention is:
(a) by proportioning raw materials take by weighing cyclodextrin 2.0g, Fructus Crataegi extract 0.6g, water 750ml is standby;
(b) take by weighing cyclodextrin 2.0 grams, be dissolved in the 700ml water standby; Other gets the 0.6g Fructus Crataegi extract and became suspension in ultrasonic 3 minutes with 50ml water; Cyclodextrin aqueous solution is warming up to 60-70 ℃, and 300 rev/mins of stirrings slowly add the suspension of Fructus Crataegi extract, and application of sample speed is 3.0-4.0ml/min; 40 ℃ are continued to stir 8-10 hour, are evaporated to 40-50ml, 0.45 μ m filtering with microporous membrane postlyophilization in 70-80 ℃;
(c) the gained active component is mixed with appropriate amount of auxiliary materials, make any medicament on the pharmaceutics.
Cyclodextrin in the medicine of the present invention can be alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin; Preferred cyclodextrin is a HP-, methyl-beta-schardinger dextrin-, and carboxymethyl-beta-cyclodextrin, sulphur are stung ether-beta-schardinger dextrin-; Best cyclodextrin is a HP-.
The dosage form of pharmaceutical composition of the present invention can be: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, solution, injection, suppository, ointment, plaster, spray, drop pill, freeze-dried powder, effervescent tablet, micropill, soft capsule etc.
The dosage form of preferred pharmaceutical composition of the present invention can be granule, capsule, tablet, oral liquid, drop pill, pill, freeze-dried powder, effervescent tablet, micropill, soft capsule etc.
After effective ingredient Fructus Crataegi extract of the present invention adopted the inclusion technique preparation, the dissolubility of this effective ingredient Fructus Crataegi extract significantly increased, and dissolubility is stable, suitability for industrialized production.
More than form when producing and to increase or to reduce according to corresponding ratio, as large-scale production can be unit with kilogram or with the ton, small-scale production can be unit with the gram also, and weight can increase or reduce, but the crude drug material weight proportion constant rate between each composition.
Medicine of the present invention can be determined usage and dosage according to patient's situation in use, but every day 1-3 time, and every day, each crude drug consumption was as the criterion with the state-promulgated pharmacopoeia dosage, was no more than the pharmacopeia ormal weight.
After effective ingredient Fructus Crataegi extract of the present invention adopted the inclusion technique preparation, the dissolubility of this effective ingredient Fructus Crataegi extract significantly increased, and dissolubility is stable, suitability for industrialized production.
The present invention is through a large amount of preparation technology's test and pharmacology, the resulting preparation of pharmacodynamics test.For a better understanding of the present invention, below by experiment example further set forth the beneficial effect of invention medicine, experimental example comprises the Fructus Crataegi extract dissolubility behind pharmacodynamics animal experiment, Fructus Crataegi extract and the enclose of medicine of the present invention.Test is intended to further specify effect of the present invention below, but not limitation of the present invention.The invention medicine that this experimental example adopts is to be prepared from by embodiment 1.For the ease of narration, below pharmaceutical composition of the present invention is called the Fructus Crataegi total flavones injection.
Experimental example 1 Fructus Crataegi total flavones injection is to the protective effect of local cerebral ischemia damage due to the intraluminal middle cerebral artery occlusion in rats thrombosis
Purpose: observe of the protective effect of Fructus Crataegi total flavones injection to local cerebral ischemia damage due to the intraluminal middle cerebral artery occlusion in rats thrombosis.
Materials and methods
Animal SD rat, body weight 180-220g, all male, Beijing dimension tonneau China animal company provides.
Medicine and instrument Fructus Crataegi total flavones injection and salvianolic acid injection provide by our company's Chinese medicine.
Operating microscope is the Japanese OLYMPUS production LG-PS2 of company type, and constant water bath box is the German MEMMERT production WB14 of company type.
Experiment grouping and administration laboratory animal are weighed, and are divided into five groups at random by body weight: model group, and salvianolic acid group dosage is 48mg/kg, Fructus Crataegi total flavones small dose group dosage is 12mgkg
-1, dosage group dosage is 24mgkg in the Fructus Crataegi total flavones
-1, the heavy dose of group of Fructus Crataegi total flavones dosage is 48mgkg
-1
Tail vein injection administration at once after administering mode: the MCAO operation was performed the operation after 2 hours, and intraperitoneal injection is adopted in administration for the second time.
Dosage: twice administration is 4mlkg
-1
The preparation SD rats by intraperitoneal injection 10% chloral hydrate (35mgkg of middle cerebral artery thrombus model
-1) anesthesia, get lateral position, make a kerf by literature method at outer canthus and external auditory meatus line mid point, be about 1.5cm, separation, pinch off temporalis and excision expose temporal bone, under stero microscope, remake the bone window of a diameter 2.5mm in temporo squamosum junction near oral-lateral 1mm place with dental burr, cleaning residue, exposure middle cerebral artery (between tractus olfactorius and inferior cerebral vein).Put small pieces plastic sheeting protection blood vessel surrounding tissue, suction is had 50% ferric chloride solution (1molL
-1Hydrochloric acid) the small pieces quantitative filter paper of 10 μ l applies on this section middle cerebral artery (subsides filter paper method), causes thrombosis, takes off filter paper behind the 30min, uses the normal saline flushing local organization, and layer-by-layer suture steams again and raises.
Observation index
(1) mensuration of cerebral infarction scope: operation back 24h broken end is got brain, removes olfactory bulb, cerebellum and low brain stem, putting into 4 ℃ of normal saline rapidly cleans, cut four blade at ice face upper edge sagittal axis and become five, put into the TTC dye liquor (1%) of 5ml, in 37 ℃ of water-baths water-bath 8-10 minute.Normal cerebral tissue takes on a red color, and blocking tissue is white in color, and the cerebral tissue after the dyeing is fixed 24 hours in 4% formalin.White organized carefully to dig down weigh, account for the percentage ratio of brain weight as infarction size with blocking tissue's weight.
(2) mensuration of brain water content: operation back 24h, put to death animal, broken end is got brain, weighs rapidly, puts into 105 ℃ of baking ovens, 48 hours, dries to constant weight.Take out, cool off in drying baker, taking-up is weighed, and calculates brain water content.
The result
(1) Fructus Crataegi total flavones is to the influence of cerebral infarction scope
The result shows that salvianolic acid and the big or middle dosage of Fructus Crataegi total flavones can obviously reduce focal cerebral ischemia in rats hindbrain infarction size, and the reduction effect is relevant with dosage.The Fructus Crataegi total flavones small dose group is compared no significant difference (table 1) with matched group.
Table 1: Fructus Crataegi total flavones is to the result that influences of focal cerebral ischemia in rats damage hindbrain infarction size
| Group | n | Dosage (mgkg -1) | Cerebral infarction scope (%) |
| | 10 | 5.04±1.82 | |
| The | 10 | 48 | 3.02±1.27 * |
| The Fructus Crataegi total flavones | 10 | 12 | 3.92±1.50 |
| Dosage group in the Fructus Crataegi | 10 | 24 | 2.89±1.05 * |
| The heavy dose of group of Fructus Crataegi | 10 | 48 | 1.71±0.87 ** |
Annotate:
*P＜0.05,
*P＜0.01, compared with model group.
Fructus Crataegi total flavones is seen (Fig. 1) to the result that influences of focal cerebral ischemia in rats damage hindbrain infarction size
(2) Fructus Crataegi total flavones is to the influence of brain water content
The result shows the brain water content after salvianolic acid and the large, medium and small dosage of Fructus Crataegi total flavones all can obviously reduce focal cerebral ischemia in rats, and comparing with matched group all has notable difference, and the reduction effect is relevant with dosage.Result statistics sees Table 2, Fig. 2:
Table 2: Fructus Crataegi total flavones to the focal cerebral ischemia in rats damage after brain water content influence the result
| Group | n | Dosage (mgkg -1) | Full brain water content (%) |
| | 10 | 80.48±0.59 | |
| The | 10 | 48 | 79.81±0.32 ** |
| The Fructus Crataegi total flavones | 10 | 12 | 80.10±0.21 * |
| Dosage group in the Fructus Crataegi | 10 | 24 | 79.97±0.35 * |
| The heavy dose of group of Fructus Crataegi | 10 | 48 | 79.60±0.47 ** |
Annotate:
*P＜0.05,
*P＜0.01, compared with model group.
Fructus Crataegi total flavones to the focal cerebral ischemia in rats damage after brain water content influence the result, see (Fig. 2)
Fructus Crataegi total flavones can reduce the cerebral infarction scope due to the middle cerebral artery thrombosis, reduces brain water content, alleviates cerebral edema.Show that Fructus Crataegi total flavones has protective effect to cerebral ischemic injury.
Experimental example 2 Fructus Crataegi total flavones injection are to the influence of rat coronary flow
Purpose: observe of the influence of Fructus Crataegi total flavones injection to the rat coronary flow.
Materials and methods
30 of animal health Wistar rats, male, body weight 350g ± 30g, Beijing dimension tonneau China company provides.
Medicine and instrument Fructus Crataegi total flavones injection and salvianolic acid injection provide by our company's Chinese medicine.
Krebs-Henseleit liquid, Powerlab/8sp Langendorff isolated heart perfusion system, ADInstrument Pty Ltd (Australia).
Experimental technique is chosen 30 of healthy rats, is divided into 3 groups at random, 10 every group, the rat sacrificed by decapitation is opened breast rapidly and is exposed heart, breaks pericardium, cut off superior and inferior vena cava, pulmonary artery, aorta (keeping about 1cm) and heart surrounding tissue, win heart, place to contain 4 ℃ of K-H liquid of oxygen, push heart gently, discharge remained blood, heart is connected to perfusion device and fixes the beginning perfusion with silk thread, perfusate is kept 37 ℃, and feeds 95% oxygen.Connect electrocardioelectrode, after treating that electrocardio steadily, perfusion pressure is adjusted in carries out the voltage stabilizing perfusion about 45mmHg, coronary flow and heart rate before the record administration of stable back, slowly inject the medicinal liquid that 0.2ml prepares through dosing holes, be Fructus Crataegi total flavones injection 1.2mg/ heart and positive control salvianolic acid injection 1.2mg/ heart, the above-mentioned every index of immediate record after administration finishes continues to observe 20 minutes.
The result
(1) Fructus Crataegi total flavones is to the influence of isolated rat heart coronary flow
As Fig. 3, shown in Figure 1, the Fructus Crataegi total flavones injection can significantly increase coronary flow, administration in the time of 1 minute drug effect reach maximum, with compare coronary flow before the administration and increased by 18%, and its effect is similar to the salvianolic acid injection, effect fades away after 5 minutes, and coronary flow returns to the preceding level of administration.
(2) Fructus Crataegi total flavones is to the influence of isolated rat heart heart rate
As Fig. 4, shown in Figure 2, each medicine is little to heart rate influence, and the rat heart rate remains in 140-180 time/minute the scope substantially, no difference of science of statistics between each medicine group.
Fig. 4: Fructus Crataegi total flavones is to the influence of isolated rat heart heart rate
Table 1: Fructus Crataegi total flavones influences result (n=10) to the isolated rat heart coronary flow
| Group | Dosage (the mg/ heart) | Before the administration | 1min | 2min | 3min | 4min | 5min | 10min | 15min | 20min |
| | 0 | 8.02±1.63 | 8.04±1.01 | 7.95±1.37 | 8.10±1.45 | 8.06±1.26 | 7.93±1.84 | 7.98±1.82 | 8.06±1.42 | 7.92±1.65 |
| Salvianolic acid | 1.2 | 7.99±1.82 | 9.44±1.15 | 9.61±1.11 | 8.75±1.41 | 8.25±1.51 | 8.05±1.73 | 8.16±1.62 | 7.95±1.16 | 7.89±1.64 |
| The Fructus Crataegi group | 1.2 | 8.13±1.93 | 9.59±1.46 | 9.34±1.23 | 8.67±1.81 | 8.24±1.65 | 8.11±1.52 | 7.98±1.85 | 7.77±1.54 | 7.82±2.07 |
Table 2: Fructus Crataegi total flavones influences result (n=10) to the isolated rat heart heart rate
| Group | Dosage (the mj/ heart) | Before the administration | 1min | 2min | 3min | 4min | 5min | 10min | 15min | 20min |
| | 0 | 157±50 | 149±36 | 164±46 | 159±45 | 161±46 | 155±49 | 158±42 | 153±42 | 160±45 |
| Salvianolic acid | 1.2 | 168±32 | 169±45 | 159±44 | 175±41 | 165±51 | 162±43 | 158±42 | 155±36 | 164±44 |
| The Fructus Crataegi group | 1.2 | 173±33 | 167±46 | 172±43 | 161±45 | 157±55 | 169±52 | 168±45 | 177±54 | 162±47 |
This result of experiment proves that Fructus Crataegi total flavones does not have remarkable influence to heart rate simultaneously in the external effect that good increase coronary flow is arranged.Can under the situation that does not increase the heart burden, (not accelerate heart rate), increase the amount of blood supply of heart, thereby obviously alleviate the hypoxic-ischemic of cardiac muscle.Can think that its effect that increases coronary flow is a mechanism of action of its antagonism heart ischemia.
The dissolubility of 3: three batches of Fructus Crataegi total flavones clathrates of experimental example and Fructus Crataegi total flavones crude drug
Purpose: the mensuration of Fructus Crataegi total flavones clathrate and Fructus Crataegi total flavones dissolubility
The preparation of flavone content of hawthorn bioassay standard curve: precision takes by weighing the about 10mg of rutin standard substance, places the 25ml volumetric flask, with being diluted to scale, shakes up; Precision takes by weighing above-mentioned solution 0.5,0.8,1.5,2.0,3.0 in the 25ml volumetric flask respectively, adds 30% ethanol to 10ml, adds 10%NaNO respectively
20.3ml, left standstill 6 minutes, add 10%Al (NO respectively
3)
30.3ml, leave standstill after 6 minutes and add 4ml 4%NaOH,, leave standstill after 15 minutes and survey absorbance to scale with distilled water diluting, the standard curve (see figure 5).
The clathrate preparation:
20041010 take by weighing HP-2 grams, are dissolved in the 700ml60-70 ℃ of water for injection.The 0.6g Fructus Crataegi extract was become suspension in ultrasonic 10 minutes with 50ml water, stir the suspension that slowly adds Fructus Crataegi extract down, continue to stir 8-10 hour, be evaporated to 40-50ml, 0.45 μ m filtering with microporous membrane postlyophilization in 70-80 ℃.
20041011 take by weighing HP-3 grams, are dissolved in the 900ml60-70 ℃ of water for injection.The 0.9g Fructus Crataegi extract was become suspension in ultrasonic 10 minutes with 100ml water, stir the suspension that slowly adds Fructus Crataegi extract down, continue to stir 8-10 hour, be evaporated to 50-60ml, 0.45 μ m filtering with microporous membrane postlyophilization in 70-80 ℃.
20041012 take by weighing HP-4 grams, are dissolved in the 1000ml60-70 ℃ of water for injection.The 1.2g Fructus Crataegi extract was become suspension in ultrasonic 10 minutes with 100ml water, stir the suspension that slowly adds Fructus Crataegi extract down, continue to stir 8-10 hour, be evaporated to 100ml, 0.45 μ m filtering with microporous membrane postlyophilization in 70-80 ℃.
The clathrate flavone content of hawthorn is measured: precision takes by weighing the about 20mg of clathrate, places the 25ml volumetric flask, with 30% ethanol dilution to scale, get 1ml in the 25ml volumetric flask, press standard curve method and handle, measure absorbance, try to achieve the content of Fructus Crataegi total flavones in the clathrate by regression equation.
Result of the test sees Table 1
The dissolubility of table 1 Fructus Crataegi total flavones and HP-beta-CD inclusion thereof (mg/ml) data
| Lot number | Clathrate | Fructus Crataegi total flavones |
| 20041011 | 46.1563 | 16.3124 |
| 20041010 | 45.8795 | 15.4678 |
| 20041012 | 43.1254 | 15.3916 |
The dissolution determination of Fructus Crataegi total flavones clathrate and Fructus Crataegi total flavones crude drug: take by weighing 50mg Fructus Crataegi total flavones crude drug and three parts of Fructus Crataegi total flavones clathrates, put into the 50ml small beaker respectively, each adds 20ml water, magnetic agitation is taken a sample at the appointed time, by the proper proportion dilution, use the determined by ultraviolet spectrophotometry solution concentration, absorbance is the reading of instrument.
The results are shown in Table 2
Table 2 dissolution determination result (absorbance)
| Time | Fructus Crataegi total flavones | Clathrate I | Clathrate II | Clathrate III |
| min | 50mg | 31.4mg | 28.7mg | 16.9 |
| 1 | 0.035 | 0.098 | 0.091 | 0.067 |
| 3 | 0.047 | 0.121 | 0.114 | 0.095 |
| 5 | 0.066 | 0.166 | 0.157 | 0.114 |
| 10 | 0.087 | 0.214 | 0.196 | 0.143 |
| 30 | 0.113 | 0.287 | 0.264 | 0.232 |
Above-mentioned result of the test explanation is faster than Fructus Crataegi total flavones crude drug through the Fructus Crataegi total flavones dissolution rate of enclose.Illustrate and adopt inclusion technique can solve Fructus Crataegi total flavones shortcoming not soluble in water.
Description of drawings
Fig. 1: Fructus Crataegi total flavones is to the result that influences of focal cerebral ischemia in rats damage hindbrain infarction size
Fig. 2: Fructus Crataegi total flavones to the focal cerebral ischemia in rats damage after brain water content influence the result
Fig. 3: Fructus Crataegi total flavones is to the result that influences of isolated rat heart coronary flow
Fig. 4: Fructus Crataegi total flavones is to the influence of isolated rat heart heart rate
Fig. 5: flavone content of hawthorn bioassay standard curve
The specific embodiment
Embodiment 1: the preparation method of Fructus Crataegi extract
Get Fructus Crataegi, extract altogether 3 times, add for the first time 70% the ethanol extraction 0.5 hour of 7 times of amounts, 70% the ethanol extraction 0.5 hour that adds for the second time 6 times of amounts adds 70% the ethanol extraction 0.5 hour of 6 times of amounts, standing over night for the third time, filter, filtrate concentrates, and reclaims ethanol, concentrated solution is crossed macroporous adsorbent resin, add the suitable quantity of water eluting, reuse 30% ethanol elution, merge concentrated solution, cross poly-fine amine, washing, reuse 50% ethanol is washed, and concentrates to obtain Fructus Crataegi extract.
(a) by proportioning raw materials take by weighing HP-2.0g, to get the Fructus Crataegi extract 0.6g, the water 750ml that obtain according to embodiment 1 method standby;
(b) take by weighing HP-2.0 grams, be dissolved in the 700ml water standby; Other gets the 0.6g Fructus Crataegi extract and became suspension in ultrasonic 3 minutes with 50ml water; Cyclodextrin aqueous solution is warming up to 60-70 ℃, and 300 rev/mins of stirrings slowly add the suspension of Fructus Crataegi extract, and application of sample speed is 3.0-4.0ml/min; 40 ℃ are continued to stir 8-10 hour, are evaporated to 40-50ml, 0.45 μ m filtering with microporous membrane postlyophilization in 70-80 ℃;
(c) the gained active component is mixed the system injection with an amount of distilled water.
(a) by proportioning raw materials take by weighing HP-4.0g, to get the Fructus Crataegi extract 1.0g, the water 1000ml that obtain according to embodiment 1 method standby;
(b) take by weighing HP-4.0 grams, be dissolved in the 900ml water standby; Other gets the 0.6g Fructus Crataegi extract and became suspension in ultrasonic 2 minutes with 100ml water; Cyclodextrin aqueous solution is warming up to 40-80 ℃, and 200 rev/mins of stirrings slowly add the suspension of Fructus Crataegi extract, and application of sample speed is 2.0-8.0ml/min; 30 ℃ continue to be stirred 1-8 hour, were evaporated to 10-100ml in 20-70 ℃, and 0.40 μ m filtering with microporous membrane postlyophilization is made lyophilized injectable powder.
(b) take by weighing by proportioning raw materials that sulphur is stung ether-beta-schardinger dextrin-1.5g, to get the Fructus Crataegi extract 0.5g, the water 600ml that obtain according to embodiment 1 method standby;
(b) take by weighing sulphur and sting ether-beta-schardinger dextrin-, be dissolved in the water standby; Other gets the ultrasonic one-tenth suspension of Fructus Crataegi extract water; Cyclodextrin aqueous solution is warming up to 30-90 ℃, stirs, add the suspension of Fructus Crataegi extract, application of sample speed is 1.0-10ml/min; 25～70 ℃ are continued to stir 4-20 hour, are evaporated to 20-100ml, the filtering with microporous membrane postlyophilization in 50-100 ℃;
(c) the gained active component is mixed with appropriate amount of auxiliary materials, make capsule, promptly.
(c) by proportioning raw materials take by weighing methyl-beta-schardinger dextrin-3.0g, to get the Fructus Crataegi extract 0.8g, the water 850ml that obtain according to embodiment 1 method standby;
(b) take by weighing methyl-beta-schardinger dextrin-, be dissolved in the water standby; Other gets the ultrasonic one-tenth suspension of Fructus Crataegi extract water; Cyclodextrin aqueous solution is warming up to 40-60 ℃, stirs, add the suspension of Fructus Crataegi extract, application of sample speed is 1.0-10ml/min; 65～70 ℃ are continued to stir 4-8 hour, are evaporated to 20-100ml, the filtering with microporous membrane postlyophilization in 50-100 ℃;
(c) the gained active component is mixed with appropriate amount of auxiliary materials, make tablet, promptly.
(d) by proportioning raw materials take by weighing cyclodextrin 2.5g, to get the Fructus Crataegi extract 0.6g, the water 700ml that obtain according to embodiment 1 method standby;
(b) take by weighing cyclodextrin, be dissolved in the water standby; Other gets the ultrasonic one-tenth suspension of Fructus Crataegi extract water; Cyclodextrin aqueous solution is warming up to 30-60 ℃, stirs, add the suspension of Fructus Crataegi extract, application of sample speed is 2.0-5.0ml/min; 60～70 ℃ are continued to stir 10-12 hour, are evaporated to 50-60ml, the filtering with microporous membrane postlyophilization in 70-90 ℃;
(c) the gained active component is mixed with an amount of Macrogol 4000, make drop pill by the conventional preparation method of drop pill, promptly.
(e) by proportioning raw materials take by weighing beta-schardinger dextrin-4.0g, to get the Fructus Crataegi extract 1.0g, the water 600ml that obtain according to embodiment 1 method standby;
(b) take by weighing beta-schardinger dextrin-, be dissolved in the water standby; Other gets the ultrasonic one-tenth suspension of Fructus Crataegi extract water; Cyclodextrin aqueous solution is warming up to 30-60 ℃, stirs, add the suspension of Fructus Crataegi extract, application of sample speed is 4.0-6.0ml/min; 30～40 ℃ are continued to stir 4-8 hour, are evaporated to 30-40ml, the filtering with microporous membrane postlyophilization in 70-80 ℃;
(c) the gained active component is mixed with appropriate amount of auxiliary materials, make soft capsule according to the conventional preparation method of soft capsule, promptly.
(a) by proportioning raw materials take by weighing gamma-cyclodextrin 4.0g, to get the Fructus Crataegi extract 0.3g, the water 1500ml that obtain according to embodiment 1 method standby;
(b) take by weighing gamma-cyclodextrin, be dissolved in the water standby; Other gets the ultrasonic one-tenth suspension of Fructus Crataegi extract water; With the cyclodextrin aqueous solution heating, stir, add the suspension of Fructus Crataegi extract; Stir concentrating under reduced pressure, filtering with microporous membrane postlyophilization;
(c) the gained active component is mixed with appropriate amount of auxiliary materials, make micropill according to the conventional preparation method of micropill, promptly.
Embodiment 9
(a) by proportioning raw materials take by weighing cyclodextrin 1.0g, to get the Fructus Crataegi extract 1.2g, the water 300ml that obtain according to embodiment 1 method standby:
(b) take by weighing cyclodextrin, be dissolved in the water standby; Other gets the ultrasonic one-tenth suspension of Fructus Crataegi extract water; With the cyclodextrin aqueous solution heating, stir, add the suspension of Fructus Crataegi extract; Stir concentrating under reduced pressure, filtering with microporous membrane postlyophilization;
(c) the gained active component is mixed with appropriate amount of auxiliary materials, make disintegrating tablet according to the conventional preparation method of disintegrating tablet, promptly.
(a) by proportioning raw materials take by weighing alpha-cyclodextrin 2.8g, to get the Fructus Crataegi extract 1.2g, the water 750ml that obtain according to embodiment 1 method standby;
(b) take by weighing alpha-cyclodextrin 2.8 grams, be dissolved in the 700ml water standby; Other gets the 1.2g Fructus Crataegi extract and became suspension in ultrasonic 3 minutes with 50ml water; Cyclodextrin aqueous solution is warming up to 60-70 ℃, and 300 rev/mins of stirrings slowly add the suspension of Fructus Crataegi extract, and application of sample speed is 3.0-4.0ml/min; 40 ℃ are continued to stir 8-10 hour, are evaporated to 40-50ml, 0.45 μ m filtering with microporous membrane postlyophilization in 70-80 ℃;
(c) the gained active component is mixed with appropriate amount of auxiliary materials, make effervescent tablet according to the conventional preparation method of effervescent tablet, promptly.
Embodiment 11
Take by weighing HP-2 grams, be dissolved in the 700ml60-70 ℃ of water for injection; To become suspension in ultrasonic 10 minutes with 50ml water according to the 0.6g Fructus Crataegi extract that embodiment 1 method obtains, stir the suspension that slowly adds Fructus Crataegi extract down, continue to stir 8-10 hour, be evaporated to 40-50ml in 70-80 ℃, 0.45 μ m filtering with microporous membrane postlyophilization is made freeze-dried powder.
Get HP-3 grams, be dissolved in the 900ml60-70 ℃ of water for injection; To become suspension in ultrasonic 10 minutes with 100ml water according to the 0.9g Fructus Crataegi extract that embodiment 1 method obtains, stir the suspension that slowly adds Fructus Crataegi extract down, continue to stir 8-10 hour, be evaporated to 50-60ml in 70-80 ℃, 0.45 μ m filtering with microporous membrane postlyophilization is made injection.
Embodiment 13
Get HP-4 grams, be dissolved in the 1000ml60-70 ℃ of water for injection; To become suspension in ultrasonic 10 minutes with 100ml water according to the 1.2g Fructus Crataegi extract that embodiment 1 method obtains, stir the suspension that slowly adds Fructus Crataegi extract down, continue to stir 8-10 hour, be evaporated to 100ml in 70-80 ℃, 0.45 μ m filtering with microporous membrane postlyophilization is made freeze-dried powder.
Claims (11)
1, a kind of medicine for the treatment of cardiovascular and cerebrovascular disease is characterized in that it mainly is to be made by following raw materials in weight portion medicine: cyclodextrin 1.0～4.0g, Fructus Crataegi extract 0.3～1.2g, water 300～1500ml.
2, the medicine of treatment cardiovascular and cerebrovascular disease according to claim 1 is characterized in that wherein the amount of each crude drug is: cyclodextrin 1.5～3.0g, Fructus Crataegi extract 0.5～0.8g, water 600～850ml.
3, the medicine of treatment cardiovascular and cerebrovascular disease according to claim 1 is characterized in that wherein the amount of each crude drug is: cyclodextrin 2.0g, Fructus Crataegi extract 0.6g, water 750ml.
4, the preparation method of treatment cardiovascular and cerebrovascular diseases medicament according to claim 1 comprises the steps:
(a) by proportioning raw materials take by weighing cyclodextrin 1.0～4.0g, Fructus Crataegi extract 0.3～1.2g, water 300～1500ml is standby;
(b) take by weighing cyclodextrin, be dissolved in the water standby; Other gets the ultrasonic one-tenth suspension of Fructus Crataegi extract water; With the cyclodextrin aqueous solution heating, stir, add the suspension of Fructus Crataegi extract; Stir concentrating under reduced pressure, filtering with microporous membrane postlyophilization;
(c) the gained active component is mixed with appropriate amount of auxiliary materials, make any medicament on the pharmaceutics.
5, the preparation method of treatment cardiovascular and cerebrovascular diseases medicament according to claim 4 comprises the steps:
(a) by proportioning raw materials take by weighing cyclodextrin 1.5～3.0g, Fructus Crataegi extract 0.5～0.8g, water 600～850ml is standby;
(b) take by weighing cyclodextrin, be dissolved in the water standby; Other gets the ultrasonic one-tenth suspension of Fructus Crataegi extract water; Cyclodextrin aqueous solution is warming up to 30-90 ℃, stirs, add the suspension of Fructus Crataegi extract, application of sample speed is 1.0-10ml/min; 25～70 ℃ are continued to stir 4-20 hour, are evaporated to 20-100ml, the filtering with microporous membrane postlyophilization in 50-100 ℃;
(c) the gained active component is mixed with appropriate amount of auxiliary materials, make any medicament on the pharmaceutics.
6, the preparation method of treatment cardiovascular and cerebrovascular diseases medicament according to claim 5 comprises the steps:
(a) by proportioning raw materials take by weighing cyclodextrin 2.0g, Fructus Crataegi extract 0.6g, water 750ml is standby;
(b) take by weighing cyclodextrin 2.0 grams, be dissolved in the 700ml water standby; Other gets the 0.6g Fructus Crataegi extract and became suspension in ultrasonic 3 minutes with 50ml water; Cyclodextrin aqueous solution is warming up to 60-70 ℃, 300 rev/mins of stirrings slowly add the suspension of Fructus Crataegi extract, and application of sample speed is that 3.0-4.0ml/min continues for 40 ℃ to stir 8-10 hour, be evaporated to 40-50ml, 0.45 μ m filtering with microporous membrane postlyophilization in 70-80 ℃;
(c) the gained active component is mixed with appropriate amount of auxiliary materials, make any medicament on the pharmaceutics.
7,, it is characterized in that cyclodextrin wherein is: alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin according to the medicine of the treatment cardiovascular and cerebrovascular disease described in arbitrary in the claim 1～6.
8, the medicine of treatment cardiovascular and cerebrovascular disease according to claim 7 is characterized in that cyclodextrin wherein is: HP-, and methyl-beta-schardinger dextrin-, carboxymethyl-beta-cyclodextrin, sulphur are stung ether-beta-schardinger dextrin-.
9, the medicine of treatment cardiovascular and cerebrovascular disease according to claim 8 is characterized in that cyclodextrin wherein is: HP-.
10, the medicine of treatment cardiovascular and cerebrovascular disease according to claim 4, it is characterized in that this medicament be on the pharmaceutics tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, solution, injection, suppository, ointment, plaster, spray, drop pill, freeze-dried powder, effervescent tablet, micropill, soft capsule.
11, the medicine of treatment cardiovascular and cerebrovascular disease according to claim 10 is characterized in that this medicament is granule, injection, capsule, tablet, oral liquid, drop pill, pill, freeze-dried powder, effervescent tablet, micropill, the soft capsule on the pharmaceutics.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410093839 CN1785283B (en) | 2004-12-06 | 2004-12-06 | Medicinal composition for treating cardiorascular disease and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200410093839 CN1785283B (en) | 2004-12-06 | 2004-12-06 | Medicinal composition for treating cardiorascular disease and its preparation method |
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| CN1785283A true CN1785283A (en) | 2006-06-14 |
| CN1785283B CN1785283B (en) | 2011-03-23 |
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| CN 200410093839 Expired - Fee Related CN1785283B (en) | 2004-12-06 | 2004-12-06 | Medicinal composition for treating cardiorascular disease and its preparation method |
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Address after: 300402 Tianjin Beichen Xinyi white road Liaohe Road No. 1 Patentee after: Tasly Pharmaceutical Group Co., Ltd. Address before: 300402 Tianjin Beichen Xinyi white road Liaohe Road No. 1 Patentee before: Tianjin Tianshili Pharmaceutical Co., Ltd. |
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