CN1543975A - Powder injection of hawthorn leaf flavonid salt and its preparation - Google Patents
Powder injection of hawthorn leaf flavonid salt and its preparation Download PDFInfo
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- CN1543975A CN1543975A CNA2003101087165A CN200310108716A CN1543975A CN 1543975 A CN1543975 A CN 1543975A CN A2003101087165 A CNA2003101087165 A CN A2003101087165A CN 200310108716 A CN200310108716 A CN 200310108716A CN 1543975 A CN1543975 A CN 1543975A
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- salt
- total flavones
- folium crataegi
- crataegi total
- injection
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Abstract
The invention relates to a haw leaf total flavone salt powder injection and method for preparation, comprising the following constituents (by weight proportions), haw leaf total flavone salt 15-85%, water dissolving medicinal adjuvant for injection 15-85%. The invention also discloses the process for preparing the powder injection, which has better stability and high biological availability. The powder injection can be used for the treatment for cranial vascular diseases.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of Folium Crataegi total flavones salt injectable powder that is used for the treatment of cardiovascular and cerebrovascular disease and preparation method thereof.
Background technology
In Fructus Crataegi be Chinese medicine commonly used simply, have that removing food stagnancyization stagnates, spleen reinforcing is good for the stomach, the effect of blood circulation promoting and blood stasis dispelling.Its chemical constituent is divided into organic acid and flavonoid, and the reach a conclusion main component of Fructus Crataegi blood circulation promoting and blood stasis dispelling of research is a total flavonoid, and in the Folium Crataegi content of total flavone than higher.Folium Crataegi total flavones has obtained lot of experiment validation as the effective ingredient of blood circulation promoting and blood stasis dispelling.Folium Crataegi total flavones has pharmacologically active widely, is mainly: blood pressure lowering, increase coronary flow, heart tonifying etc., the clinical treatment that has been widely used in cardiovascular and cerebrovascular disease.
The preparation of Folium Crataegi is used for the clinical history that has had more than 20 year, mostly is oral formulations, and onset is slow, the needs of first aid in the time of can not adapting to the cardiovascular and cerebrovascular disease patient and fall ill.So consider Folium Crataegi total flavones is prepared into injection, owing to injectable powder steady quality, low, the convenient transportation of preparation cost, so Folium Crataegi total flavones is prepared into injectable powder.Existing patent documentation (Chinese patent CN03114173.0,2003 are open) report is prepared into injectable powder with Folium Crataegi total flavones adding water soluble pharmaceutic adjuvant, and transfer pH to 7.5～8.5 with citric acid, in fact because the water solublity of Folium Crataegi total flavones is very poor, and show acid, it is infeasible directly it being prepared into injectable powder.We consider Folium Crataegi total flavones is prepared into water solublity inorganic salt preferably, adopt suitable technology that its salt is prepared into injectable powder again.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, a kind of can be used for the treating steady quality of cardiovascular and cerebrovascular disease, the Folium Crataegi total flavones salt injectable powder of definite ingredients are provided.
Another object of the present invention is to provide the preparation method of this Folium Crataegi total flavones salt.
The injection Folium Crataegi total flavones salt injectable powder that the present invention proposes is made up of Folium Crataegi total flavones salt and water for injection dissolubility pharmaceutic adjuvant.The content of Folium Crataegi total flavones salt is 15～85% in the injectable powder, and all the other are pharmaceutic adjuvant, and total amount satisfies 100%.
Among the present invention, described pharmaceutic adjuvant is a lot, for example, can adopt one or more of common amino acids, glucose, lactose, mannitol, polyvinylpyrrolidone, low molecular dextran, sodium chloride, calcium gluconate or calcium phosphate.
We have done a large amount of basic research to the main component of Folium Crataegi total flavones, draw Folium Crataegi total flavones and be mainly vitexin rhamnoside (5,7,4 '-trihydroxyflavone-8-C-β-D-glucosyl group (1 → 2)-β-D-rhamnoside), vitexin glucoside (5,7,4 '-trihydroxyflavone-8-C-β-D-glucosyl group (1 → 4)-β-D-glucoside), caffeic acid, quininic acid and chlorogenic acid and possible derivant thereof, these compositions are owing to the existence of acidic-group shows acid, can with the alkaline matter salify, the salt that is become has good water-solubility, solve the Folium Crataegi total flavones poorly water-soluble effectively, be difficult to make the problem of injectable powder.Structure behind the main component salify is as follows:
Formula 1 vitexin rhamnoside salt
Formula 2 vitexin glucoside salt
Formula 3 caffeiate's formulas 4 quinine hydrochlorates
Formula 5 chlorogenic acid salt
Wherein R=Na, K, Ca, Mg or other possible metal ion
Folium Crataegi total flavones salt described in the present invention can be the salt that can receive on sodium salt, potassium salt, calcium salt, magnesium salt and some other physiology.
The preparation method of above-mentioned injection Folium Crataegi total flavones salt injectable powder is as follows:
(1) Folium Crataegi total flavones and an amount of inorganic or organic base fully react salify.
(2) take by weighing the salt of recipe quantity, add an amount of water dissolution, the pH of control solution adds the water soluble adjuvant of corresponding weight ratio again 6.0～7.5, dissolves under the room temperature, use filtering with microporous membrane, must clear and bright filtrate.Be filled in the cillin bottle filtrate branch, lyophilization, and packing is promptly.
The Folium Crataegi total flavones salt injectable powder that the present invention proposes, solved the total flavones poorly water-soluble effectively, make the shortcoming of difficulty of injection, good stability, storage period is long, transportation and easy to use, and can guarantee the curative effect of medicine, face with before being mixed with solution, directly in intramuscular injection or adding injection normal saline or the glucose, with the mode administration of intravenous drip.
We have carried out the pharmacodynamics test of Folium Crataegi total flavones salt, and the part test outcome record is as follows:
(1) influence of the acute imperfection cerebral ischemic model of injection Folium Crataegi total flavones salt pair rat cerebral infarction volume
70 of SD rats, ♀ ♂ half and half, body weight 250～325g is divided into 7 groups at random, 10 every group.The reference literature method, after weighing, animal fixes with diazepam and each 1ml/kg ip anesthesia back dorsal position of ketamine injection, row neck median incision after the cervical region cropping, isolate bilateral common carotid arteries and threading, stablize behind the 5min ligation in the lump it, cause acute imperfection cerebral ischemic model, animal only separates and not ligation common carotid artery sham operated rats.30min injects medicine or GS from sublingual vein after the ligation.Drug dose is:
Injection Folium Crataegi total flavones sodium salt dissolves with 5% glucose, and high, medium and low dosage group dosage is respectively 16.0,8.0 and 4.0mg/kg;
Matched group Radix Salviae Miltiorrhizae group injected dose is the Radix Salviae Miltiorrhizae Injection of 7.5g crude drug/kg;
The administration volume is 5ml/kg, and the glucose group injection is with 5% glucose injection of volume.
The above again method anesthetized animal of 6h after the ligation, the sacrificed by exsanguination animal opens cranium and gets brain, rejects rhinencephalon, cerebellum and brain stem, cuts forebrain open from median line, and the weighing cutaneous horn is heavily back respectively behind the filter paper wipe dry handles respectively by following program:
The mensuration of cerebral infarction weight: adopt NBT staining [2,3].With a side cerebral tissue about 15min of quick-freezing in the rearmounted refrigerator that weighs, be cut into essentially identical 5 of thickness along coronalplane, be placed on and face with preceding with incubation 10min in the mid-37 ℃ of water-baths of 0.3%NBT dyeing liquor of phosphate buffer preparation, normal cerebral tissue dyes brownish black, and infraction cerebral tissue color does not have obvious change.The infarct cerebral tissue is downcut and weigh, calculate the percentage ratio that blocking tissue's weight accounts for weight in wet base, reflect the size of blocking tissue's volume with this.
Histopathologic examination: with second half undyed cerebral tissue with the fixing 24h of 4% neutral formalin solution, the crown brain that cuts, conventional dehydration, paraffin embedding, slice thick 5 μ m, HE dyeing, om observation.
The result shows, no matter basic, normal, high dosage group all can reduce cerebral infarction weight to injection Folium Crataegi total flavones salt, its infraction weight reduces by 23.6%, 28.6% and 31.2% than glucose group respectively, the infraction percentage by weight then reduces by 22.5%, 26.9% and 29.7% than glucose group respectively, all has significant difference, Radix Salviae Miltiorrhizae group cerebral infarction weight and infraction percentage by weight also reduce by 26.1% and 24.6% than glucose group respectively, see table 1 for details.
The influence (%) of table 1 injection Folium Crataegi total flavones salt pair rats with cerebral ischemia cerebral infarct volume
Infraction weight
Dosage body weight cerebral tissue weight in wet base
Group
n
Infraction weight (g) percentage ratio
mg/kg
(g) (g)
(％)
Sham operated rats/10 283.5 ± 29.5 653.1 ± 60.3 00
Glucose group/10 285.5 ± 29.6 669.5 ± 65.5 108.8 ± 15.4 16.2 ± 1.3
4.0 10?283.5±30.6 664.0±57.4 83.1±12.5
**?12.6±2.1
**
The injection Folium Crataegi
8.0 10?286.0±30.4 659.9±57.1 77.7±10.7
**?11.9±1.9
**
The total flavones sodium salt
16.0 10?284.0±32.6 662.1±69.8 74.9±16.5
**?11.4±2.7
**
Radix Salviae Miltiorrhizae Injection 7,500 10 284.0 ± 32.0 658.1 ± 55.8 80.4 ± 13.4
*12.2 ± 1.8
*
Annotate: compare with glucose group:
*P＜0.01
(2) injection Folium Crataegi total flavones salt pair pituitrin causes the effect of rat heart muscle ischemia
SD rats by intraperitoneal injection 2% chloralose (60mg/kg) anesthesia.It is fixing to lie on the back, and it is subcutaneous that needle electrode is inserted extremity and the front place of beating.Regulate electrocardiogram (ECG-6851C, Shanghai Photoelectricity Medical electron Instrument Co., Ltd.) sensitivity to 1mv=10mm, chart speed is 50mm/ second.Record precordial leads electrocardiogram, if any ANOMALOUS VARIATIONS such as ST-T ripple or arrhythmia, then discarding need not.
Rat is assigned to the different disposal group behind the record normal ECG.
Matched group: 20, quiet notes 5% glucose injection 1ml/kg.
Positive controls: 20, quiet notes injection of danshen liquid measure 6 gram/kg.
Injection Folium Crataegi total flavones sodium salt dissolves small dose group with 5%: 20, and quiet notes 12.5mg/kg.
Injection Folium Crataegi total flavones sodium salt dissolves middle dosage group with 5%: 20, and quiet notes 25.0mg/kg.
Injection Folium Crataegi total flavones sodium salt dissolves with 5%, heavy dose of group: 20, and quiet notes 50.0mg/kg.
To treat that reagent thing, glucose injection or Radix Salviae Miltiorrhizae Injection give 1 milliliter capacity by per 100 gram body weight, slowly are expelled in the rat tail vein through small size scalp entry needle.Constant syringe pump (HL-2 type, Shanghai Hu Xi analytical tool factory) control infusion velocity makes in 30 minutes and has annotated, anthropomorphic dummy's vena systemica dropleting medicine-feeding mode.
Instil and finish back 5 minutes, through tail vein injection pituitrin (Shanghai Hefeng Pharmaceutical Co., Ltd., lot number 010501), dosage is 0.5U/kg, and injection speed is 5 seconds.Back 30 seconds, 1,2,3,5 minute precordial lead electrocardiogram of record injection.
Criterion: electrocardiogram rises (more than the 1mv) based on the ST section and low flat, two-way, the inversion of T ripple behind the injection pituitrin.With this index as myocardial ischemia, the person of appearance counts the positive, and person not up to standard counts feminine gender.
Statistical procedures
Do not organize likening to of total number of animals and be the myocardial ischemia negative rate myocardial ischemia number of animals and each to occur.Experimental group and matched group data are carried out χ
2Check, the significance that relatively differs.
The result
Behind the intravenous injection pituitrin, chest lead V
3Significant myocardial ischemia electrocardiogram occurs and change, show as on the ST section and move, low flat, the two-way or inversion of T ripple also has decreased heart rate, conduction block and arrhythmia.Change typical case and responsive the most with ST section and T ripple.Different disposal sees Table 2 to the effect of myocardial ischemia due to the pituitrin.
Behind control rats infusion 5% glucose injection, quiet notes pituitrin causes that typical myocardial ischemia changes.
Myocardial ischemia negative rate after the injection Folium Crataegi total flavones salt administration of various dose due to the antagonism pituitrin has remarkable rising than matched group.Small dose group improvement rate is higher relatively.
Radix Salviae Miltiorrhizae Injection is under design dosage, and the ischemic electrocardiogram of part rat changed the improvement effect, does not have marked difference with matched group.
Table 2 injection Folium Crataegi total flavones salt pair pituitrin causes the Electrocardiographic influence of Acute Myocardial Ischemia in Rats
Group dosage number of animals myocardial ischemia improves number negative rate (%)
Matched group 10ml/kg 20 1 5.0
Radix Salviae Miltiorrhizae Injection 6g/kg 20 4 20.0
Folium Crataegi total flavones salt 12.5mg/kg 20 8 40.0
*
Folium Crataegi total flavones salt 25mg/kg 20 6 30.0
*
Folium Crataegi total flavones salt 50mg/kg 20 6 30.0
*
*Compare with matched group p＜0.05
The The above results explanation, Folium Crataegi total flavones salt can alleviate the cerebral infarction weight that the imperfection cerebral ischemia is caused, and reduces the cerebral infarction percentage by weight.Cause on the acute myocardial ischemia model injection Folium Crataegi total flavones salt can significantly alleviate the ischemic ECG change at the rat injection of pituitrin, prompting has value for coronary heart disease such as control acute myocardial infarction and angina pectoriss.
The specific embodiment
Embodiment 1
Prescription:
Folium Crataegi total flavones sodium salt 160 grams
Mannitol 160 grams
Make 1000
Preparation method:
Get the Folium Crataegi total flavones sodium salt and the mannitol of recipe quantity, add 1500ml70 ℃ water for injection stirring and dissolving, the pH that records solution is 7.0.Add 2 gram activated carbon adsorption 10min, filter, the water for injection that adds 70 ℃ is settled to 2000ml, 0.22 μ m microporous filter membrane fine straining, and packing, every 2ml, lyophilization, packing is promptly.
Embodiment 2
Prescription:
Folium Crataegi total flavones potassium salt 80 grams
Mannitol 10 grams
Glucose 20 grams
Make 1000
Preparation method:
Take by weighing the Folium Crataegi total flavones potassium salt of recipe quantity, the water for injection stirring and dissolving that adds 1500ml70 ℃, the pH that records solution is 7.2, adds the manna alcohol and glucose again, stirs to make dissolving, the water for injection that adds 70 ℃ is settled to 2000ml, 0.22 μ m microporous filter membrane fine straining, packing, every 2ml, lyophilization, packing promptly.
Embodiment 3:
Prescription:
Folium Crataegi total flavones magnesium salt 80 grams
Glucose 40 grams
Lactose 20 grams
Mannitol 60 grams
Make 1000
Preparation method:
Take by weighing the Folium Crataegi total flavones magnesium salt of recipe quantity, the water for injection stirring and dissolving that adds 1500ml70 ℃, the pH that records solution is 6.8, adds glucose, lactose and mannitol again, stirs to make dissolving, the water for injection that adds 70 ℃ is settled to 2000ml, 0.22 μ m microporous filter membrane fine straining, packing, every 2ml, lyophilization, packing promptly.
Claims (4)
1, a kind of injection Folium Crataegi total flavones salt injectable powder is characterized in that being made up of Folium Crataegi total flavones salt and water for injection dissolubility pharmaceutic adjuvant, and the weight content of Folium Crataegi total flavones salt is 15～85% in the injectable powder.
2, Folium Crataegi total flavones salt injectable powder according to claim 1 is characterized in that said Folium Crataegi total flavones salt is the salt that can receive on the sodium salt of Folium Crataegi total flavones, potassium salt, calcium salt, magnesium salt and some other physiology.
3, Folium Crataegi total flavones salt injectable powder according to claim 1 is characterized in that pharmaceutic adjuvant is one or more of aminoacid, glucose, lactose, mannitol, polyvinylpyrrolidone, low molecular dextran, sodium chloride, calcium gluconate or calcium phosphate.
4, a kind of preparation method of Folium Crataegi total flavones salt injectable powder as claimed in claim 1, it is characterized in that concrete steps are as follows: Folium Crataegi total flavones is prepared salify, dissolving, regulate pH 6.0～7.5, the water soluble adjuvant that adds corresponding weight ratio again, dissolve under the room temperature, use filtering with microporous membrane, get clear and bright filtrate; Be filled in the cillin bottle filtrate branch, lyophilization, and packing is promptly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2003101087165A CN1543975A (en) | 2003-11-19 | 2003-11-19 | Powder injection of hawthorn leaf flavonid salt and its preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2003101087165A CN1543975A (en) | 2003-11-19 | 2003-11-19 | Powder injection of hawthorn leaf flavonid salt and its preparation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101181387B (en) * | 2007-12-10 | 2010-12-08 | 江西中医学院 | Whitethorn leaf total chromocor colloidal solution and preparation method thereof |
| CN103054849A (en) * | 2012-12-21 | 2013-04-24 | 合肥七星医药科技有限公司 | Composition for treating cardiovascnlar and cerebrovascular diseases and preparation method thereof and test method thereof |
| CN105308742A (en) * | 2013-11-28 | 2016-02-03 | 富士电机株式会社 | Method of manufacturing cooler for semiconductor module, cooler for semiconductor module, semiconductor module, and electrically driven vehicle |
-
2003
- 2003-11-19 CN CNA2003101087165A patent/CN1543975A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101181387B (en) * | 2007-12-10 | 2010-12-08 | 江西中医学院 | Whitethorn leaf total chromocor colloidal solution and preparation method thereof |
| CN103054849A (en) * | 2012-12-21 | 2013-04-24 | 合肥七星医药科技有限公司 | Composition for treating cardiovascnlar and cerebrovascular diseases and preparation method thereof and test method thereof |
| CN105308742A (en) * | 2013-11-28 | 2016-02-03 | 富士电机株式会社 | Method of manufacturing cooler for semiconductor module, cooler for semiconductor module, semiconductor module, and electrically driven vehicle |
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