CN105769882B - A kind of medical composition and its use of inhibition thrombosis - Google Patents
A kind of medical composition and its use of inhibition thrombosis Download PDFInfo
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- CN105769882B CN105769882B CN201610143655.3A CN201610143655A CN105769882B CN 105769882 B CN105769882 B CN 105769882B CN 201610143655 A CN201610143655 A CN 201610143655A CN 105769882 B CN105769882 B CN 105769882B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
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- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of pharmaceutical composition of inhibition thrombosis, it includes a effective amount of aspirin of a) 1 compound of a effective amount of at least one formula, b)；The mass ratio of 1 compound of formula and aspirin is 1157:1~7:1.The pharmaceutical composition can be used for preparing the drug of antiplatelet drug and/or inhibition thrombosis.Research is found, choline and its derivative and aspirin have synergistic effect in terms of preventing or treating thrombus, cholinergic reduces the effective antithrombotic dosage of aspirin, aspirin dose only needs the 1/4 of former dosage, greatly reduce aspirin and prevents or treating the adverse reaction that may occur in thrombotic diseases, the compliance for improving patient's medication improves clinical application safety and curative effect, has good clinical use value and great Development volue.
Description
Technical field
The present invention relates to a kind of medical composition and its uses of inhibition thrombosis, belong to pharmaceutical technology field.
Background technique
Thrombus refers to blood constituent in flow process, forms a kind of half solidifying block in blood vessel or cardiac intima surface
Matter.In variable fluid dependent form, thrombus by insoluble fibrin, the blood platelet of deposition, accumulation leucocyte and fall into
Red blood cell composition.Promote the factor of thrombosis mainly have vascular endothelial cell damage, blood flow velocity slowly and blood at
Physicochemical property is divided to change.In addition to above three factor, fibrinolytic, kassinin kinin and complement system, hyperlipidemia, malignant tumour
Etc. the formation for also assisting in thrombus.
Thrombotic diseases are a kind of common cardiovascular and cerebrovascular diseases, are that the lumen of vessels as caused by thrombus is narrow with occlusion, make to lead
It wants internal organs that ischemic and infarct occurs and causes the various diseases of dysfunction.Thrombotic diseases include that myocardial infarction, brain bolt be dead, lung
Thrombus, deep vein thrombosis and peripheral vessels embolism etc. are the diseases for seriously endangering human health and life.According to world health group
Statistics is knitted, the world about 26,000,000 dies of various forms of thrombotic diseases every year.China dies of cardiovascular and cerebrovascular disease every year
Number reach 3,000,000 people or more, the patient 75% of survival is disabled, wherein 40% or more weight it is residual.
The Western medicine of clinical treatment thrombotic diseases is broadly divided into anti-platelet drug, thrombolytic and anticoagulation at present
Drug three categories, but these medicines are while playing antithrombotic, it may appear that the side effects such as drug resistance, bleeding, serious limitation
Their clinical application.Aspirin is used as ntipyretic analgesic medicine and antirheumatic to be clinically widely applied earliest, small
Dose aspirin is also unique cardiovascular primary prevention antiplatelet medication that domestic and international associated guideline is recommended, and is commonly used to blood
Platelet increases or the primary and secondary prevention of thrombus disease and treatment, and is that other antiplatelet drugs are incomparable.Although Ah Si
Woods is commonly used to the prevention and treatment of these diseases, but clinically for treating or preventing the optimal dose of these diseases extremely
The present does not all standardize, some serious adverse reactions happen occasionally, when a large amount of Aspirins of especially weak the elderly,
It may cause the elderly's Cerebral microbleeds.
Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical compositions of inhibition thrombosis, and can reduce aspirin takes agent
Amount, reduces the side effect of aspirin.
It is a further object of the present invention to provide aforementioned pharmaceutical compositions to prepare antiplatelet drug and/or inhibit thrombus shape
At the purposes in drug.
To achieve the goals above, the pharmaceutical composition of a kind of inhibition thrombosis of the invention, it includes: a) effective quantity
1 compound of at least one formula；B) a effective amount of aspirin；
In formula: R1Selected from hydroxyl, the acid group of pharmaceutically acceptable inorganic acid or pharmaceutically acceptable organic acid
Acid group；R2Selected from hydrogen, C1-C6Alkanoyl or sulfonyl.
In the active constituent of described pharmaceutical composition, the mass ratio of 1 compound of formula and aspirin be 1157:1~
7:1, preferred mass ratio are 289:1~10:1, and preferred mass ratio is 250:1~120:1.
The pharmaceutically acceptable inorganic acid of 1 compound of formula is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or phosphoric acid,
They can be respectively formed salt acid group (Cl-), hydrobromic acid root (Br-), hydroiodic acid root (I-), sulfate radical (SO4 2-Or HSO4 -) or phosphorus
Acid group (PO4 3-、HPO4 2-、H2PO4 -) it is used as R1Group.
The pharmaceutically acceptable organic acid of 1 compound of formula is selected from C1-C6Be saturated unary fatty acid (formic acid, acetic acid,
Propionic acid, butyric acid, valeric acid, caproic acid), C1-C6It is saturated binary of fatty acids (oxalic acid, malonic acid, succinic acid), C1-C6Unsaturated fatty acid
(maleic acid, fumaric acid, benzoic acid) or C1-C6Hydroxycarboxylic acid (lactic acid, tartaric acid, citric acid, malic acid).
The C of 1 compound of formula1-C6Alkanoyl is selected from acetyl group or propiono.
Preferably, 1 compound of formula is selected from choline (i.e. (beta-hydroxyethyl) trimethylammonium hydroxide), choline chloride, second
Sour choline, propionic acid choline, dihydrogen citrate choline, choline bitartrate.It is furthermore preferred that 1 compound of formula is selected from chlorination gallbladder
Alkali.
Described pharmaceutical composition also includes selective pharmaceutically acceptable carrier as auxiliary material, and the auxiliary material can be selected from
Sodium carboxymethyl starch, starch, lactose, microcrystalline cellulose, dextrin, sucrose, superfine silica gel powder, magnesium stearate etc..
Described pharmaceutical composition can be made into the dosage forms such as injection, tablet, granule, capsule, pill, oral solutions,
The preferably oral preparations such as tablet, granule, capsule or pill.
Described pharmaceutical composition can be used for treating thrombotic diseases, and the thrombotic diseases are concretely due to thrombosis
Caused thrombotic diseases.
Described pharmaceutical composition can be used for preparing the drug of antiplatelet drug and/or inhibition thrombosis.
The study found that the pharmaceutical composition of the choline chloride containing aforementioned proportion and aspirin is administered orally, pitched at angle
On the model for the mouse tail thrombosis that dish glue induces, it can obviously inhibit the generation of mouse thrombus, and it is long to can be reduced thrombus
Degree, and the side reaction without GI irritation and bleeding.
Research cooperates with effect it has furthermore been found that choline and its derivative have in terms of preventing or treating thrombus with aspirin
It answers, choline and aspirin oral combination application, cholinergic reduces the effective antithrombotic dosage of aspirin, aspirin dose
The 1/4 of former dosage is only needed, greatly reduces aspirin and is preventing or treating the adverse reaction that may occur in thrombotic diseases, change
The compliance of patient's medication has been apt to it, has improved clinical application safety and curative effect, with good clinical use value and greatly
Development volue.
Detailed description of the invention
Fig. 1 shows that the aspirin Carrageenan of 0.625mg/kg, 1.25mg/kg, 2.5mg/kg dosage causes mouse
The influence of tail portion thrombosis.
Fig. 2 shows that the aspirin Carrageenan of 2.5mg/kg, 5mg/kg, 10mg/kg dosage causes mouse tail blood
The influence that bolt is formed.
It is small that Fig. 3 shows that the choline chloride Carrageenan of 10mg/kg, 20mg/kg, 40mg/kg and 80mg/kg dosage causes
The influence of rat-tail portion thrombosis.
Fig. 4 shows that the choline chloride Carrageenan of 100mg/kg, 200mg/kg and 400mg/kg dosage causes mouse tail
The influence of portion's thrombosis.
Fig. 5 shows that choline chloride and aspirin combination Carrageenan cause the influence of mouse tail thrombosis.
Specific embodiment
With reference to the accompanying drawing and specific embodiment present invention is further described in detail.
Experimental animal: healthy kunming mice, male, weight 18-22g, SPF grade are dynamic purchased from Military Medical Science Institute's experiment
Object center, quality certification number: SCXK- (army) 2007-2004.22-24 DEG C of raising temperature, relative humidity 52%-58%, 12:12h is bright
Dark alternating.Experimental animal is grouped at random, every group 10, animal free water and intake food.
Experimental drug: carrageenan and choline chloride are purchased from SIGMA company of the U.S., and aspirin is purchased from Shandong Xinhua system
Medicine limited liability company.
Embodiment 1: the influence of aspirin Carrageenan cause mouse tail thrombosis
Test mice is randomly divided into four groups, and every group 15, administrations are as follows: first group: blank control: giving physiology salt
Water；Second group: giving aspirin 0.625mg/kg；Third group: aspirin 1.25mg/kg is given；4th group: giving Ah Si
Woods 2.5mg/kg.
Experimental method: the quality physiological saline such as intragastric administration on mice gives aspirin, and blank control is given, 12h is primary, and the 5th
Carrageenan is injected intraperitoneally in 1h after secondary administration, continues stomach-filling and gives aspirin, mouse thrombosis length, knot are detected after 48h
Fruit with mean ± SD as shown in Figure 1, indicated, compared with giving salt water group with stomach-filling, p < 0.01 * p < 0.05, * *.
As shown in Figure 1: compared with blank control group, aspirin 1.25mg/kg and 2.5mg/kg dosage group can significantly contract
Short mouse tail thrombus length, shows the effect of inhibition thrombosis.
Test mice is randomly divided into four groups, and every group 15, administrations are as follows: first group: blank control: giving physiology salt
Water；Second group: giving aspirin 2.5mg/kg；Third group: aspirin 5mg/kg is given；4th group: giving aspirin
10mg/kg。
Experimental method: the quality physiological saline such as intragastric administration on mice gives aspirin, and blank control is given, 12h is primary, and the 5th
Carrageenan is injected intraperitoneally in 1h after secondary administration, continues stomach-filling and gives aspirin, mouse thrombosis length, knot are detected after 48h
Fruit with mean ± SD as shown in Fig. 2, indicated, compared with giving salt water group with stomach-filling, p < 0.01 * p < 0.05, * *.
As shown in Figure 2: compared with blank control group, the equal energy of aspirin 2.5mg/kg, 5mg/kg and 10mg/kg dosage group
It is significant to shorten mouse tail thrombus length, show the effect of inhibition thrombosis.
Embodiment 2: the influence of choline chloride Carrageenan cause mouse tail thrombosis
Test mice is randomly divided into five groups, and every group 15, administrations are as follows: first group: blank control: giving physiology salt
Water；Second group: giving choline chloride 10mg/kg；Third group: choline chloride 20mg/kg is given；4th group: giving choline chloride
40mg/kg；5th group: giving choline chloride 80mg/kg.
Experimental method: mouse peritoneal injects choline chloride, and blank control such as gives at the quality physiological saline, once a day, the
Carrageenan is injected intraperitoneally in 1h after administration in two days, continues that choline chloride is injected intraperitoneally, detects mouse thrombosis length after 48h,
As a result as shown in figure 3, being indicated with mean ± SD, compared with salt water group is injected intraperitoneally, p < 0.01 * p < 0.05, * *.
As shown in Figure 3: compared with blank control group, choline chloride 10mg/kg, 20mg/kg, 40mg/kg and 80mg/kg agent
Amount group cannot significantly shorten mouse tail thrombus length, not show the effect of inhibition thrombosis.
Test mice is randomly divided into four groups, and every group 15, administrations are as follows: first group: blank control: giving physiology salt
Water；Second group: giving choline chloride 100mg/kg；Third group: choline chloride 200mg/kg is given；4th group: giving chlorination gallbladder
Alkali 400mg/kg；
Experimental method: the quality physiological saline such as intragastric administration on mice gives choline chloride, and blank control is given, 12h is primary, and the 5th
Carrageenan is injected intraperitoneally in 1h after secondary administration, continues stomach-filling and gives choline chloride, mouse thrombosis length, knot are detected after 48h
Fruit with mean ± SD as shown in figure 4, indicated, compared with giving salt water group with stomach-filling, p < 0.01 * p < 0.05, * *.
As shown in Figure 4: compared with blank control group, only choline chloride 400mg/kg dosage group can significantly shorten mouse tail
Thrombus length shows the effect of inhibition thrombosis.
Embodiment 3: the influence of choline chloride and aspirin combination Carrageenan cause mouse tail thrombosis
Test mice is randomly divided into five groups, and every group 15, administrations are as follows: first group: blank control: giving physiology salt
Water；Second group: giving drug: choline chloride 50mg/kg+ aspirin 0.15mg/kg；Third group: drug is given: choline chloride
100mg/kg+ aspirin 0.30mg/kg；Third group: drug is given: choline chloride 200mg/kg+ aspirin 0.625mg/
kg；Third group: drug is given: choline chloride 400mg/kg+ aspirin 1.25mg/kg.
Experimental method: the quality physiological saline such as intragastric administration on mice gives choline chloride and aspirin, and blank control is given,
12h is primary, and carrageenan is injected intraperitoneally in 1h after the 5th administration, continues stomach-filling and gives choline chloride and aspirin, pitches to angle
Mouse thrombus length is detected after dish glue 48h, as a result as shown in figure 5, being indicated with mean ± SD, compared with giving salt water group with stomach-filling, *
P < 0.01 p < 0.05, * *.
By as shown in Figure 5: compared with blank control group, choline chloride 100mg/kg+ aspirin 0.30mg/kg group, chlorine
Change choline 200mg/kg+ aspirin 0.625mg/kg group and the equal energy of choline chloride 400mg/kg+ aspirin 1.25mg/kg group
It is significant to shorten mouse tail thrombus length, show the effect of inhibition thrombosis.It is indicated above choline chloride and aspirin
Use in conjunction, which has the function of significantly cooperateing with, prevents and treats thrombosis.
Claims (9)
1. a kind of pharmaceutical composition of inhibition thrombosis is, characterized by comprising: a) a effective amount of at least one 1 chemical combination of formula
Object, b) a effective amount of aspirin；Wherein, the mass ratio as 1 compound of the formula of active constituent and aspirin is
1000:3 or 320:1；
Formula 1
In formula: R1Acid group selected from hydroxyl, the acid group of pharmaceutically acceptable inorganic acid or pharmaceutically acceptable organic acid；
R2Selected from hydrogen, C1-C6Alkanoyl or sulfonyl.
2. the pharmaceutical composition of inhibition thrombosis as described in claim 1, which is characterized in that the drug of unit dose
In composition, contain the formula 1 compound 100mg and aspirin 0.3mg as active constituent；Or containing as activity
The formula 1 compound 200mg and aspirin 0.625mg of ingredient；Or contain 1 compound of the formula as active constituent
400mg and aspirin 1.25mg.
3. the pharmaceutical composition of inhibition thrombosis as claimed in claim 1 or 2, which is characterized in that 1 compound of formula
Pharmaceutically acceptable inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or phosphoric acid；1 compound of formula pharmaceutically may be used
The organic acid of receiving is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, malonic acid, succinic acid, maleic acid, rich horse
Acid, benzoic acid, lactic acid, tartaric acid, citric acid, malic acid.
4. the pharmaceutical composition of inhibition thrombosis as claimed in claim 1 or 2, which is characterized in that 1 compound of formula
C1-C6Alkanoyl is selected from acetyl group or propiono.
5. the pharmaceutical composition of inhibition thrombosis as claimed in claim 1 or 2, which is characterized in that 1 compound of the formula choosing
From choline, choline chloride, acetic acid choline, propionic acid choline, dihydrogen citrate choline, choline bitartrate.
6. the pharmaceutical composition of inhibition thrombosis as claimed in claim 5, which is characterized in that 1 compound of formula is selected from
Choline chloride.
7. the pharmaceutical composition of inhibition thrombosis as claimed in claim 1 or 2, which is characterized in that described pharmaceutical composition
Pharmaceutically acceptable carrier also comprising selectivity.
8. the pharmaceutical composition of inhibition thrombosis as claimed in claim 1 or 2, which is characterized in that described pharmaceutical composition
For the dosage form of oral preparation.
9. pharmaceutical composition as claimed in claim 1 or 2 is in the drug for preparing antiplatelet drug and/or inhibition thrombosis
Purposes.
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| CN105769882A CN105769882A (en) | 2016-07-20 |
| CN105769882B true CN105769882B (en) | 2019-02-22 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996027380A1 (en) * | 1995-03-06 | 1996-09-12 | Interneuron Pharmaceuticals, Inc. | Reduction of infarct volume using citicoline |
| CN1260981A (en) * | 1999-01-18 | 2000-07-26 | 王至国 | Antisanility mixture |
| CN101204396A (en) * | 2006-12-20 | 2008-06-25 | 上海太平洋制药厂 | Citicoline sodium dispersible tablets and preparation method thereof |
| CN101237868A (en) * | 2005-06-13 | 2008-08-06 | 伊兰制药国际有限公司 | Nanoparticulate clopidogrel and aspirin combination formulations |
| CN101801368A (en) * | 2007-08-02 | 2010-08-11 | 布达生物制药有限公司 | Pharmaceutical compositions for intranasal administration comprising choline salts of succinic acid |
| CN102138892A (en) * | 2010-02-03 | 2011-08-03 | 广州汉光医药进出口有限公司 | Choline alfoscerate injection preparation as well as preparation method and detection method thereof |
-
2016
- 2016-03-14 CN CN201610143655.3A patent/CN105769882B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996027380A1 (en) * | 1995-03-06 | 1996-09-12 | Interneuron Pharmaceuticals, Inc. | Reduction of infarct volume using citicoline |
| CN1260981A (en) * | 1999-01-18 | 2000-07-26 | 王至国 | Antisanility mixture |
| CN101237868A (en) * | 2005-06-13 | 2008-08-06 | 伊兰制药国际有限公司 | Nanoparticulate clopidogrel and aspirin combination formulations |
| CN101204396A (en) * | 2006-12-20 | 2008-06-25 | 上海太平洋制药厂 | Citicoline sodium dispersible tablets and preparation method thereof |
| CN101801368A (en) * | 2007-08-02 | 2010-08-11 | 布达生物制药有限公司 | Pharmaceutical compositions for intranasal administration comprising choline salts of succinic acid |
| CN102138892A (en) * | 2010-02-03 | 2011-08-03 | 广州汉光医药进出口有限公司 | Choline alfoscerate injection preparation as well as preparation method and detection method thereof |
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