CN106620707B - A kind of pharmaceutical composition and its preparation method and application preventing and treating myocardial ischemia - Google Patents
A kind of pharmaceutical composition and its preparation method and application preventing and treating myocardial ischemia Download PDFInfo
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- CN106620707B CN106620707B CN201710151839.9A CN201710151839A CN106620707B CN 106620707 B CN106620707 B CN 106620707B CN 201710151839 A CN201710151839 A CN 201710151839A CN 106620707 B CN106620707 B CN 106620707B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
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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
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a kind of pharmaceutical compositions and its preparation method and application for preventing and treating myocardial ischemia, described pharmaceutical composition is using sphingosine 1-phosphate, naproxen and anticoagulation as active pharmaceutical ingredient, wherein anticoagulant is selected from heparin, bicoumarin, neodicoumarin, aspirin etc., preferably bicoumarin.Synergistic multi-path plays the effect for preventing and treating myocardial ischemia between the active pharmaceutical ingredient of pharmaceutical composition of the present invention, can improve myocardial ischemia ECG Change and anticoagulation.Described pharmaceutical composition can be effectively prevented and treated myocardial ischemia, prevention and allevating angina pectoris, myocardial infarction or ischemic cardiomyopathy etc. by oral administration or parenteral administration.
Description
Technical field
The invention belongs to drug fields, and in particular, to it is a kind of prevent and treat myocardial ischemia pharmaceutical composition and its
Preparation method and purposes.
Background technique
Modern society is due to the accelerating rhythm of life, excessive consumption of alcohol, nutrition intake surplus, the necessary movement of shortage and environment
Pollution etc., result in cardiovascular and cerebrovascular disease become threaten human health one of common disease, have high illness rate, high disability rate and
The characteristics of high mortality, according to statistics, cardiovascular and cerebrovascular disease has become the first cause of whole world human death at present.Myocardial ischemia
For one of the common disease of cardiovascular and cerebrovascular disease, the reduction due to the hemoperfusion of heart is generally referred to, the confession of heart is resulted in
Oxygen is reduced, and energy metabolism of myocardial is not normal, so that the pathological state of normal heart action cannot be supported, clinical symptoms mainly include labor
There is uncomfortable in chest, palpitaition, shortness of breath etc. when tired or nervous, has and angina pectoris, the risk of myocardial infarction and sudden death occurs.Due to life
Horizontal raising, myocardial ischemia has no longer been only the threat of the elderly's health, starts the trend for showing rejuvenation,
The related symptoms for myocardial ischemia occur also are started in 30 years old crowds below, to seriously threaten the health of the mankind.
Myocardial ischemia be since the reduction of the hemoperfusion of heart is induced, currently, being directed to controlling for myocardial ischemia
Treatment focuses primarily upon drug therapy and surgical operation therapy, and drug treatment is concentrated on to be preced with using expansions such as nitrate esters medicines
Shape artery increases myocardial blood supply oxygen supply；Inhibit the receipts of cardiac muscle using beta-blockers reducing heart rate or using calcium ion antagonist
Contracting etc., to reduce the oxygen demand of cardiac muscle；Using antiplatelet drug, statins, thrombolytic drug etc., prevention or dissolution blood
Bolt etc..Said medicine treatment is often only capable of playing the effect for alleviating symptom, and side effect is larger, or even can also aggravate corresponding disease
Shape, therefore, therapeutic effect are unsatisfactory.
Sphingosine 1-phosphate (Sphingosine-1-phosphate, abbreviation S1P) be sphingomyelins metabolism intermediate product it
One, there is important physiological function, receptor wide expression in endothelial cell, vascular smooth muscle cells and cardiac muscle cell etc., because
This, S1P can play extensively blood vessel endothelium protection, Ischemic/reperfusion protection the effects of, can also reduce ventricular muscles movement
Current potential amplitude, increases myocardial contractive power at over reach potential duration, so as to play Ischemic/reperfusion protection work
With while, be conducive to correct myocardial ischemia when cardiac muscle abnormal operating state.
The present invention is to study for sphingosine 1-phosphate, is dedicated to developing a kind of myocardial ischemia prevention and treatment
The better pharmaceutical composition of effect.
Summary of the invention
The drug for the prevention and treatment myocardial ischemia that it is an object of the present invention to provide a kind of comprising sphingosine 1-phosphate
Composition, described pharmaceutical composition is using sphingosine 1-phosphate, naproxen and anticoagulation as active constituent.
Wherein the mass ratio of sphingosine 1-phosphate, naproxen and anticoagulation is 5-10: 5-10: 1- in described pharmaceutical composition
5, preferably 6-8: 6-8: 2-4, more preferably 6: 6: 2,7: 7: 2,8: 8: 2,6: 6: 3,7: 7: 3,8:8: 3,6: 6: 4,7: 7:
4、8∶8∶4。
The anticoagulation is selected from: heparin, neodicoumarin, bicoumarin etc..
The preferred anticoagulation is bicoumarin.
The pharmaceutical composition that the present invention prevents and treats myocardial ischemia can add pharmaceutically acceptable auxiliary material and be prepared into
Convenient for the pharmaceutical dosage form of clinical use, the pharmaceutical dosage form includes combination of oral medication or gastrointestinal drug composition, described
Combination of oral medication is preferably tablet or capsule, and the parenteral pharmaceutical composition is preferably injection or freeze-dried powder
Agent.
Sphingosine 1-phosphate, naproxen in the pharmaceutical composition of the present invention of preparation, as active pharmaceutical ingredient
Content with anticoagulation is the 0.1-10% (weight) of pharmaceutical composition total weight.
In further preferred technical solution, the pharmaceutical composition that the present invention prevents and treats myocardial ischemia is capsule
Agent, the capsule include: sphingosine 1-phosphate, naproxen and anticoagulation and pharmaceutically acceptable auxiliary material, it is described pharmaceutically
Acceptable auxiliary material includes: filler, lubricant and gelatine capsule shell, and the filler is selected from starch, dextrin, lactose or crystallite
Cellulose, the lubricant are selected from: talcum powder, magnesium stearate or superfine silica gel powder.
In preferred technical solution, the capsule that the present invention prevents and treats myocardial ischemia has consisting of:
4 parts of sphingosine 1-phosphate；
4 parts of naproxen；
2 parts of bicoumarin；
89 parts of microcrystalline cellulose；
1 part of magnesium stearate.
Another object of the present invention is to provide a kind of preparation method of capsule for preventing and treating myocardial ischemia, the systems
Preparation Method includes the following steps:
A) sphingosine 1-phosphate, naproxen and anticoagulation and the filling other than lubricant, gelatine capsule shell are weighed according to the ratio
Agent crushes after mixing, crosses 50-100 mesh, obtains mixed powder, spare；
B) filling powder is stirred evenly to obtain after adding lubricant in the mixed powder prepared in step a, it is spare；
C) will made from step b filling powder filling and gelatine capsule shell to get.
It is also another object of the present invention to provide sphingosine 1-phosphate, naproxen and anticoagulations to prevent and treat the heart in preparation
Purposes in the pharmaceutical composition of myocardial ischemia, the myocardial ischemia are selected from angina pectoris, myocardial infarction or ischemic cardiomyopathy.
Naproxen: also known as naproxen, Naproxen have the effect of antipyretic, analgesia, anti-inflammatory, for rheumatoid
The treatment of arthritis, ankylosing spondylitis, dysmenorrhea etc., analgesic effect duration are long, highly-safe.
Anticoagulation: referring to the drug for preventing coagulation process effect, can be used for preventing or treating thrombus, it is pre- anti-stroke or
Other thrombus related diseases, comprising: heparin, Coumarins anticoagulation, antiplatelet drug etc..
Beneficial effect
The present invention prevents and treats active constituent sphingosine 1-phosphate in the pharmaceutical composition of myocardial ischemia, naproxen and resists
Solidifying medicine synergistic effect, the performance of multi-path prevent and treat the effect of myocardial ischemia, and therapeutic effect is clear, and highly-safe.
Naproxen with antipyretic, analgesia, anti-inflammatory effect is used for the prevention and treatment of myocardial ischemia, naphthalene for the first time by the present invention
General life and sphingosine 1-phosphate and anticoagulation, the prevention and treatment as multi-path plays myocardial ischemia after bicoumarin combination are made
With, and synergistic, the prevention and treatment definite effect of myocardial ischemia, and it is highly-safe, it can be widely used for all kinds of myocardial ischemias
And its prevention and treatment of related disease.
Specific embodiment
The present invention is described below in more detail to facilitate the understanding of the present invention.
It should be understood that the term or word used in the specification and in the claims is not construed as having
The meaning limited in dictionary, and be interpreted as having on the basis of following principle and its meaning one in the context of the present invention
The meaning of cause: the concept of term can suitably limit best illustration of the invention by inventor.
Effect example 1: influence of the pharmaceutical composition of the present invention to rat
(1) rat myocardial cell primary culture method: SD suckling mouse 25 in life for 24 hours are taken out and are picked after heart all takes out
Except the blood clotting and fibr tissue on heart periphery, cell is collected in digestive juice (0.125% pancreatin+0.05%II Collagenase Type) digestion,
It is filtered to remove and does not digest tissue, be inoculated in culture bottle, culture in cell incubator (37 DEG C, 95%O2+5%CO2) is set, with difference
Fast adherent method removes fibrocyte, purifies cardiac muscle cell.After 2h, not yet adherent cell suspension is sucked out and blows even, adjustment density to 1
× 10-6 is implanted into 24 orifice plates (every 500 μ l of hole), is uniformly distributed cell, and Brdu to 0.1mmol/L is added, changes the liquid once for 24 hours,
Later every 3-4d is changed the liquid once.Periodically under inverted microscope observe cell growth the case where, cultivate 48h after, be grouped at random into
Row experiment.
By cell with 1 × 106The density of a/ml is inoculated in 24 orifice plates, every 500 μ l of hole.37 DEG C, 5%CO2 saturated humidity
Under the conditions of cultivate.After primary myocardial cell culture 72h, Normal group and model group are normally trained with 500 μ l DMEM culture solutions
It supports, the DMEM culture solution for containing 10% medical fluid is added in each administration group, after being incubated for 6h, is rinsed 2 times with ice-cold PBS, model group and administration
500 μ l are added through 95%N in the every hole of group2- 5%O2Culture plate, is then put into a closed container by the Tyrode liquid of saturation, continues
Pass to mixed gas (95%N2- 5%O2) closed container after 30min, it is put into incubator anoxic 12h, is simulated in body ischemia model.Just
Normal group cleans Tyrode liquid 500 the μ l, CO of addition glucose containing 10g/L after old culture medium212h is cultivated in incubator.
Every hole is added final concentration of 500 μ l of 0.5mg/ml MTT serum-free DMEM culture solution and cultivates 4h, and then incline supernatant
The DMSO of 500 μ l is added in liquid, shakes 10min, with the absorbance value (OD570nm) at full-automatic microplate reader measurement 570nm, uses
In quantitative cell survival rate.
By treated, 200 μ l culture supernatants are drawn in the every hole of culture plate, are illustrated according to LDH detection kit, are detected LDH
Activity.
(2) concrete outcome is as follows:
Salvia root P.E is to propose Radix Salviae Miltiorrhizae alcohol extracting and water by influence of each simple to the rat myocardial cell of Anoxia
Medicinal extract mixes to obtain the final product, and wilsonii and Radix Notoginseng extract the extract up to two taste medicines respectively, and the preparation method of each extract is the same as implementation
Example 1.
Cell survival rate (MTT) and LDH activity result are as follows:
| Grouping | LDH(U/L) | Cell activity (%) |
| Control group | 16.3±3.7 | 100 |
| Model group | 136.8±11.9## | 50.6±2.7## |
| Administration group 1 | 83.6±8.4** | 66.9±3.6** |
| Administration group 2 | 97.5±7.3** | 61.3±3.4** |
| Administration group 3 | 112.1±10.6 | 52.2±2.9 |
| Administration group 4 | 91.5±9.4** | 64.7±4.1** |
| Administration group 5 | 104.7±8.8* | 58.1±3.7* |
| Administration group 6 | 57.4±6.3**$$ | 84.6±3.9**$$ |
| Administration group 7 | 73.6±6.9** | 73.7±4.3** |
| Administration group 8 | 68.7±5.8** | 75.2±3.8** |
| Administration group 9 | 88.4±6.1** | 65.8±3.3** |
| Administration group 10 | 93.8±7.4** | 61.2±3.7** |
* indicates to examine the P < 0.01 compared with model group through Oneway-ANOVA；$$Expression is examined through Oneway-ANOVA
It tests compared with other administration groups, P < 0.01.
Each administration group composition are as follows:
Effect example 2: pharmaceutical composition of the present invention causes the influence of Acute Myocardial Ischemia Rats electrocardiogram to pituitrin
1.1 experimental drug
(1) pharmaceutical composition of the present invention: weighing sphingosine 1-phosphate, naproxen and bicoumarin according to 8: 8: 4 ratio,
Pure water is added after mixing is configured to high dose, middle dosage and low dose group suspension that content is 20%, 10%, 5%；
(2) sphingosine 1-phosphate group: addition pure water is configured to the suspension that content is 20% after weighing sphingosine 1-phosphate
Liquid；
(3) naproxen group: addition pure water is configured to the suspension that content is 20% after weighing naproxen；
(4) bicoumarin group: addition pure water is configured to the suspension that content is 20% after weighing bicoumarin.
1.2 experimental method
Screen SD rat 70 of normal ECG, half male and half female is randomly divided into 7 groups, and every group 10, specifically: blank
Group, high dose group of the present invention, middle dose group of the present invention, low dose group of the present invention, sphingosine 1-phosphate group, naproxen group and double perfume (or spice)
Legumin group, every group is administered once a day, stomach-filling relative medicine 3mL, wherein the isometric pure water of blank group stomach-filling.Gastric infusion 10
It, sublingual vein injection of pituitrin 1U/Kg after last dose 1 hour records Rat Ecg, measurement injection posterior pituitary
ST sections of rat, the variation of T wave in element 30 seconds, calculate ST sections of variation inhibiting rates and T wave change inhibiting rate, measure blood coagulation using slide method
Time, Coagulative inhibitors rate is calculated, specific experiment the results are shown in Table 1, table 2.Wherein
ST sections of variation inhibiting rates=(blank group-experimental group)/blank group；
T wave changes inhibiting rate=(blank group-experimental group)/blank group；
Coagulative inhibitors rate=(experimental group-blank group)/blank group.
1.3 test result
1 experimental result of table show blank group rat ST sections after injection of pituitrin, T wave obviously raised, from
And shows this experimental model and construct successfully.The experimental result of each administration group, which is then shown, individually gives sphingosine 1-phosphate, Nabumetone
Raw only sphingosine 1-phosphate, which is shown, improves the effect that pituitrin causes ECG Change with after bicoumarin, injects naphthalene
Not showing after general life and bicoumarin improves the effect that pituitrin causes ECG Change, to show exclusive use
Naproxen and when bicoumarin itself and do not have the effect for improving acute myocardial ischemia ECG Change.And drug of the invention
The high, medium and low dosage group of composition then all shows the significant effect for improving acute myocardial ischemia ECG Change, wherein low
The corresponding effect and sphingosine 1-phosphate group of dosage group are roughly the same, and the dosage of pharmaceutical composition low dose group of the present invention is only
For 1/4 with sphingosine 1-phosphate group, so that showing pharmaceutical composition of the present invention improves acute myocardial ischemia electrocardiogram
The effect of variation not only relies upon sphingosine 1-phosphate, and drug of the present invention identical with sphingosine 1-phosphate group dosage
ST section variation inhibiting rate, the T wave variation inhibiting rate of high dose group are twice of sphingosine 1-phosphate group, and the experimental result is more
It adequately shows after sphingosine 1-phosphate, naproxen are combined with bicoumarin in pharmaceutical composition of the present invention that collaboration has played to change
The effect of kind acute myocardial ischemia Rat Ecg variation.
Experimental drug causes the influence of Acute Myocardial Ischemia Rats electrocardiogram to pituitrin
Note: compared with blank group: * P < 0.05, * * P < 0.01, * * * P < 0.001.
Influence of the experimental drug to the rat clotting time
Note: compared with blank group: * P < 0.05, * * P < 0.01, * * * P < 0.001.
2 experimental result of table shows that bicoumarin has blood coagulation resisting function, and sphingosine 1-phosphate is not shown with naproxen
Anticoagulant effect is shown, but the present invention is then shown comprising the pharmaceutical composition of sphingosine 1-phosphate, naproxen and bicoumarin
Clearly more powerful blood coagulation resisting function, wherein there is pharmaceutical composition low dose group of the present invention the anticoagulation similar with bicoumarin to make
With, but its dosage is only the 1/4 of bicoumarin group, and the Coagulative inhibitors rate of pharmaceutical composition high dose group of the present invention is obviously high
In bicoumarin group, so that pharmaceutical composition of the present invention, which is also illustrated, in table also has the anticoagulant effect of collaboration.
Embodiment 1, the capsule for preventing and treating myocardial ischemia
The capsule has consisting of:
4 parts of sphingosine 1-phosphate；
4 parts of naproxen；
2 parts of bicoumarin；
89 parts of microcrystalline cellulose；
1 part of magnesium stearate.
It prepares in accordance with the following steps:
A) sphingosine 1-phosphate, naproxen and anticoagulation and the filling other than lubricant, gelatine capsule shell are weighed according to the ratio
Agent crushes after mixing, sieves with 100 mesh sieve, and obtains mixed powder, spare；
B) filling powder is stirred evenly to obtain after adding lubricant in the mixed powder prepared in step a, it is spare；
C) will made from step b filling powder filling and gelatine capsule shell to get.
Claims (8)
1. a kind of for preventing and treating the pharmaceutical composition of myocardial ischemia, it is characterised in that with sphingosine 1-phosphate, naproxen
With anticoagulation as active pharmaceutical ingredient, the anticoagulation is bicoumarin, the sphingosine 1-phosphate, naproxen and double tonka-beans
The mass ratio of element is 8: 8: 4.
2. the pharmaceutical composition according to claim 1 for preventing and treating myocardial ischemia, which is characterized in that the 1- phosphoric acid
The content of sphingol, naproxen and anticoagulation accounts for the 0.1-10% of described pharmaceutical composition total weight.
3. -2 described in any item pharmaceutical compositions for preventing and treating myocardial ischemia according to claim 1, which is characterized in that institute
Stating pharmaceutical composition is combination of oral medication or parenteral pharmaceutical composition.
4. the pharmaceutical composition according to claim 3 for preventing and treating myocardial ischemia, which is characterized in that the oral medicine
Compositions are tablet or capsule, and the parenteral pharmaceutical composition is injection or freeze drying powder injection.
5. the pharmaceutical composition according to claim 4 for preventing and treating myocardial ischemia, which is characterized in that the capsule
Composition include: sphingosine 1-phosphate, naproxen and anticoagulation and pharmaceutically acceptable auxiliary material, it is described pharmaceutically acceptable
Auxiliary material includes: filler, lubricant and gelatine capsule shell, and the filler is selected from starch, dextrin, lactose or microcrystalline cellulose,
The lubricant is selected from: talcum powder, magnesium stearate or superfine silica gel powder.
6. a kind of prepare the method for preventing and treating the pharmaceutical composition of myocardial ischemia described in claim 5, it is characterised in that
The preparation method following steps:
A) sphingosine 1-phosphate, naproxen and anticoagulation and filler other than lubricant, gelatine capsule shell is weighed according to the ratio to mix
It is crushed after closing uniformly, crosses 50-100 mesh, obtain mixed powder, it is spare；
B) filling powder is stirred evenly to obtain after adding lubricant in the mixed powder prepared in step a, it is spare；
C) will made from step b filling powder filling and gelatine capsule shell to get.
The use of 7.1- phosphoric acid sphingol, naproxen and bicoumarin in the pharmaceutical composition of preparation prevention or treatment myocardial ischemia
On the way, which is characterized in that the mass ratio of the sphingosine 1-phosphate, naproxen and bicoumarin is 8: 8: 4.
8. purposes according to claim 7, which is characterized in that the myocardial ischemia is selected from angina pectoris, myocardial infarction or lacks
Hemorrhagic cardiomyopathy.
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| CN201710151839.9A CN106620707B (en) | 2017-03-14 | 2017-03-14 | A kind of pharmaceutical composition and its preparation method and application preventing and treating myocardial ischemia |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011060944A2 (en) * | 2009-11-20 | 2011-05-26 | Gp Pharm, S.A. | Active pharmaceutical ingredient capsules and polyunsaturated fatty acid esters |
| CN105726576A (en) * | 2016-02-04 | 2016-07-06 | 刘玉财 | Tablet used for treating angina in slow-release stage and preparation method thereof |
-
2017
- 2017-03-14 CN CN201710151839.9A patent/CN106620707B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011060944A2 (en) * | 2009-11-20 | 2011-05-26 | Gp Pharm, S.A. | Active pharmaceutical ingredient capsules and polyunsaturated fatty acid esters |
| CN105726576A (en) * | 2016-02-04 | 2016-07-06 | 刘玉财 | Tablet used for treating angina in slow-release stage and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 1-磷酸鞘氨醇在心血管系统中作用的研究进展;景小东，等;《医学综述》;20130831;第19卷(第15期);第2720页第3节 |
| S1P/S1PR2的心血管调节作用及其信号通路;鲁艳菊，等;《中国心血管杂志》;20150430;第20卷(第2期);第158-160页 |
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