CN100350914C - Medicinal composition for antipyretic, analgesic, anti-inflammatory and anti platelet aggregation - Google Patents
Medicinal composition for antipyretic, analgesic, anti-inflammatory and anti platelet aggregation Download PDFInfo
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Abstract
The present invention relates to a novel medical composition with the functions of relieving fever, easing pain, relieving inflammation and preventing platelet aggregation and a method for preparing the medical composition. More specifically, the medical medicine comprises aspirin or acceptable salt, acceptable ester and acceptable salt of ester of aspirin on pharmacology, and ligustrazine or acceptable salt thereof on pharmacology, wherein for 100 portions by weight of aspirin or acceptable salt, acceptable ester and acceptable salt of ester of aspirin on pharmacology, which contain aspirin of the equivalent weight, 27 to 432 portions by weight of ligustrazine or acceptable salt thereof on pharmacology, which comprises aspirin of the equivalent weight, are provided. Due to the use of the composition, aspirin and ligustrazine can perform synergistic action, and under the precondition of guaranteeing the curative effect, the side effects of aspirin, such as gastrointestinal tract irritation, are reduced.
Description
Technical field: the present invention relates to the pharmaceutical composition and the preparation thereof of new analgesic, analgesia, antiinflammatory, antiplatelet aggregation.
Particularly, the present invention relates to the pharmaceutical composition of a kind of new analgesic, analgesia, antiinflammatory, antiplatelet aggregation, contain 1) salt of aspirin or its pharmaceutically acceptable salt, ester, ester; With 2) ligustrazine or its pharmaceutically acceptable salt.
Exist as the aspirin of active component salt form with its free form or pharmaceutically acceptable salt, ester or ester; Ligustrazine exists with its free form or pharmaceutically acceptable salt form.By the use of said composition, aspirin and ligustrazine performance synergism under the prerequisite that guarantees curative effect, have reduced the side effect of aspirin, such as the side effect of GI irritation.
Technical background: medicine be used for the treatment of, prophylactic special material.Generally speaking, require drug safety, effective, stable and controllable.Exception is also arranged certainly, and such as anticarcinogen, the requirement of its safety is just low than other medicines.
It is effective in cure that the effectiveness of medicine refers to medicine.Medicine is also wanted safety in addition, and promptly toxicity or side effect are little.Especially some needs disease long-term or even that treat throughout one's life, more needs the medicine of high-efficiency low-toxicity.Mean that efficiently therapeutic effect is good.Low toxicity has just guaranteed under the situation of life-time service medicine, can not produce another kind of symptom or the disease that health is had ill effect because of medicine.Even some drugs is life-time service not, but, also can produce undesirable toxicity to health owing to need heavy dose of the use.Even some medicine once used amount is little, but life-time service or frequent drug administration, owing to store up, reason such as drug resistance, also have bad side effect.
Antipyretic-antalgic anti-inflammatory agent (antipyretic analgesic andanti-inflammatory drugs) is also referred to as NSAID (non-steroidal anti-inflammatory drug) (non-steroidalanti-inflammatory, NSAIDs) medicine analgesic, analgesic activity that is that a class has, such medicine overwhelming majority is with antiinflammatory and anti rheumatism action.(cycloxygenase COX), makes the synthetic minimizing of prostaglandin (PG) to epoxidase in the inhibition arachidonic acid metabolic process, is the common mechanism of action of such medicine.Referring to document:
The Li Duan chief editor, the pharmacology, the 4th edition, 150 pages, 1999.11, the People's Health Publisher
As everyone knows, aspirin (aspirin, formula I chemical compound) belongs to NSAID (non-steroidal anti-inflammatory drug).Its chemistry is called 2-acetoxy-benzoic acid (2-Acetoxy benzozic acid), claims aspirin again, aspirin.
Formula I chemical compound
Through the clinical practice over 100 years, prove that aspirin is an effective antiinflammatory, analgesic, analgesic.Because its antiinflammatory, analgesic, analgesic activity still are widely used in treatment cold, flu, headache, neuralgia, acute and chronic rheumatoid and rheumatoid pain etc. now.The discovered in recent years aspirin is irreversible arachidonic acid cox-2 inhibitors.Can also suppress thromboxane A in the platelet
2(TXA
2) synthetic, have potent anti-platelet aggregation effect, therefore, aspirin has been used for the prevention and the treatment of diseases of cardiovascular and cerebrovascular systems now.And its range of application is also constantly being expanded.Referring to document: 1)
The Zheng Hu chief editor, pharmaceutical chemistry, the 4th edition, In December, 2000, the People's Health Publisher2)
Geng Hongye, Wang Shaohua chief editor, practicality is controlled Treat materia medica, 344-354 page or leaf, in April, 1997, People's Health PublisherFor the present invention is described better, will quote from above-mentioned document comprehensively.
1) is used for the general oral 0.3-0.6g of antipyretic-antalgic and can reaches antipyretic effect.Dosage strengthens and can prolong action time, but its usefulness not necessarily increases, and increases side effect.It is reliable to be usually used in curative effects such as heating, flu, headache, neuralgia, arthralgia, myalgia, menstrual pain.
2) the normal and Propranolol of treatment migraine is united use
3) being used for the rheumatism aspirin and having stronger antiinflammatory, anti rheumatism action, is the important drugs for the treatment of rheumatic fever, rheumatic arthritis, rheumatoid arthritis at present.Aspirin is used for rheumatism treatment and need gives heavy dose and just can come into force each 0.5-1g that is grown up usually, every day 3-5 time; Children's 0.1g/kg every day divides and takes for three times.
Dosage when being particularly useful for rheumatism can cause serious gastrointestinal irritation side effect.
4), treatment gout oral 1-2g aspirin every day can pass through analgesic and anti-inflammatory effects, be used for the treatment of acute and chronic gout, but curative effect is limited.
5) develop by cerebral ischemia more than prevention transient cerebral ischemia and the apoplexy apoplexy, and cause because of cerebral arteriosclerosis more than the cerebral ischemia.Aspirin is relevant with its anticoagulant to preventing and treating transient cerebral ischemic attack and cerebral infarction is effective.Each 40-50mg, every day 1 time.
6), the treatment tunica intima cell injury of cerebral thrombosis under pathological state, prostacyclin is formed be obstructed, destroyed thromboxane A
2With the balance of prostacyclin, trigger thrombosis easily, now confirmed cerebral thrombus patient's thromboxane A
2Significantly increase and the prostacyclin minimizing.
7) control angina pectoris and myocardial infarction are when coronary flow is obstructed, and zymoplastin IV and plasma globulin level raise in the blood plasma, thromboxane B in the coronary sinus
2Raise, all promote thromboxane A
2Generation, aspirin suppresses adhesive attraction and anticoagulant proenzyme the formation liver in of platelet to blood vessel wall, thereby can be used for preventing and treating angina pectoris and myocardial infarction.
The application of aspirin is so extensive, but side effect is also arranged, and especially needs long-term or during than large dose oral administration.One of its main side effect is a gastrointestinal reaction.Oral aspirin has direct stimulation to gastric mucosa, causes epigastric discomfort, dyspepsia, anorexia, stomachache, feels sick, symptom such as vomiting, and individual patient can cause constipation.Can cause erosive gastritis, ulcer and hemorrhage and occult blood when heavy dose of.It is reported, take the 4-6g aspirin every day, hemorrhage 3-10ml 70% pill taker's every day is arranged approximately.For healthy people, bled profusely the 1st, 2 day that to betide idol clothes aspirin in.In addition, aspirin also can cause stomach-esophageal reflux esophagostenosis.In experiment of the present invention, also confirmed its gastrointestinal irritation side effect.
Therefore, hope can continue to use aspirin but wish and can reduce its toxic and side effects.
The use of compositions can make the identical pharmacologically active of generation between different compound component and offset some side effect, perhaps produces synergism between chemical compound and improves drug effect.So just can curative effect be constant so that the single dosage reduces and total dosage of the whole course of disease reduces even improve, and side effect reduces.
At present, developed many compound recipes and used clinically, following example has been arranged concretely:
1) be used for antipyretic-antalgic and form compound recipe with other medicines often, existing compound recipe has:
A, aspirin phenacetin caffeine, every contains aspirin 0.2268g, phenacetin 0.16g, caffeine 0.35g.One after each meal 1-2 sheet, every day 3 times.
B, aspirin calcium tablet, every contains aspirin 0.324g, citric acid 32.4mg, calcium carbonate 97.2mg, saccharin sodium 3.3mg.Each 1-3 sheet, every day 3 times.
C, Compound Chlorphenamine Maleate sheet, every contains aspirin 0.2688g, chlorphenamine 2mg, phenacetin 0.162g, caffeine 32.4mg.Each 1-2 sheet, every day 3 times.
D, compound recipe acetaminophen sheet, every contains aspirin 0.23g, acetaminophen 0.1265g, caffeine 30mg.Each 1-2 sheet, every day 2-3 time.
Above-mentioned compound recipe only is fit to antipyretic-antalgic, is not suitable for antiinflammatory and antiplatelet aggregation.
2) treatment migraine aspirin and Propranolol use in conjunction, the treatment migraine has good effect.Each oral aspirin 0.5-1g, Propranolol 20-30mg, every day 3 times.
3), treatment cerebral thrombosis
Can adopt based on the cerebral vasodilators compound preparation of aspirin the cerebral thrombus patient and to treat.The dust head has:
A, aspirin 0.1g, papaverine 30mg, nicotinic acid 50mg, stable 2.5mg, vitamin B
610mg, this is for once measuring every day 2-3 time.
B, aspirin 0.1-0.2g, rutin 20mg-40mg, vitamin B
610mg, vitamin C 0.1g, this is for once measuring every day 2-3 time.
C, dipyridamole (being persantin) 200mg, the compound preparation of aspirin 25mg goes on the market.
Above-mentioned compound preparation has therapeutic effect to existing cerebral thrombosis person, cerebral arteriosclerosis, cerebral vasospasm person is had the effect of the apoplexy of preventing.Also there is the scholar to think, should adopts heavy dose of aspirin and 5 usefulness dipyridamoles (persantin) to treat the patient of cerebral thrombosis is taken place.The each 1g of aspirin, takes during dining at every day 2-3 time; The each 50mg of dipyridamole, every day 3 times, clothes before the meal, decrement gradually after 7-10 days.
4) control angina pectoris and myocardial infarction has the compound recipe of 75mg/150mg aspirin and 60mg elanfan long can be for anginal use.
Though the above-described compound recipe that contains aspirin is a lot, be that the compound recipe of purpose does not but have with the gastrointestinal side-effect of reduction aspirin.The synergistic pharmaceutical combination that especially can guarantee to ease pain, reduce again antiinflammatory, antiplatelet aggregation each side drug effect even raising the time aspirin side effect (mainly being the gastrointestinal irritation side effect) does not but have.
In addition, the above-mentioned compound recipe that contains aspirin can only be used for some aspects of antipyretic-antalgic, antiinflammatory, antiplatelet aggregation.There is not versatility between each compound recipe.Be not suitable for the application of rheumatism and antiplatelet aggregation such as the compound recipe that is suitable for antipyretic-antalgic; The compound recipe that is suitable for antiplatelet aggregation is not suitable for the application of others again; Be suitable for anginal compound recipe and be not suitable for the rheumatism that eases pain again.
Therefore, wish to develop the new compound preparation of aspirin.It can keep even improve the treatment or the preventive effect of aspirin antipyretic-antalgic, antiinflammatory, antiplatelet aggregation, reduces its gastrointestinal side effect simultaneously again.
Existing aspirin and nitrate esters medicine use in conjunction reduce the report of gastrointestinal side effect.But nitrate wherein has its inherent shortcoming, i.e. drug resistance is especially when needs heavy dose, frequent drug administration, life-time service.See document:
Geng Hongye, Wang Shaohua chief editor, practical curative Thing is learned, and 636 pages, in April, 1997, People's Health Publisher
U.S. Pat 4287174 (1979) discloses aspirin and surfactant use in conjunction, and the effect of protection mucosa, minimizing gastroenteritic ulcer is arranged.But surfactant does not strengthen the effect of aspirin pharmacologically active.
Ligustrazine (Ligustrazine) claims tetramethylpyazine (tetramethylpyrazine) (formula II chemical compound) again, document (Ji Yubin chief editor, Chinese medicine blood circulation promoting and blood stasis dispelling effective ingredient pharmacology and application, the 71-85 page or leaf, in April, 1994, Heilungkiang science tech publishing house) ligustrazine there is detailed description, and has summarized clinical application and usage.For the present invention is described better, will quote from the document comprehensively.
Formula II chemical compound
The salt of ligustrazine commonly used such as ligustrazine monophosphate monohydrate, abbreviates ligustrazine phosphate as clinically.Also have ligustrazine hydrochloride also to use always.
Ligustrazine has multiple pharmacological effect, such as: to the protective effect of cerebral ischemia, to the protective effect of myocardial ischemia, antithrombotic forms anticoagulant, prevents and treats arteriosclerosis, blood pressure lowering, arrhythmia etc.Clinically, can be used for
1) treatment of slow, acute ischemic cerebrovascular disease, each 80-160mg, once a day;
2) the each 100mg of treatment benign paroxysmal vertigo, once a day;
3) treatment cerebrovascular each 80mg that has a headache, once a day;
4) treatment craniocerebral trauma;
5) treatment chronic nephritis is with renal failure etc.;
6) treatment hepatitis is 80-240mg/ time, 1 time/day.
Summary of the invention: the use of compositions can make the identical pharmacologically active of generation between different compound component and offset some side effect, perhaps produces synergism between chemical compound and improves drug effect.So just can curative effect to be constant so that the single dosage reduces and total dosage of the whole course of disease reduces even improve, side effect reduces.
Now, make us unexpectedly, the inventor finds through experiment: the salt of aspirin or its pharmaceutically acceptable salt, ester, ester and ligustrazine or its pharmaceutically acceptable salt have the synergism of increased activity, and the side reaction of gastrointestinal zest reduces greatly.The pharmaceutical composition that contains aspirin and ligustrazine is suitable for using aspect analgesic, analgesia, antiinflammatory, antiplatelet aggregation.
So main purpose of the present invention provides the pharmaceutical composition and the preparation thereof of a kind of new analgesia, antiinflammatory, antiplatelet aggregation.Concretely, said composition contains aspirin and ligustrazine, because both synergism make compositions to have reduced the potential side effect of aspirin guaranteeing even improving under the prerequisite of curative effect, has solved the gastrointestinal side effect of aspirin.
In pharmaceutical composition of the present invention, aspirin exists with the salt form of free or its officinal salt, ester or ester; Ligustrazine exists with the form of free or officinal salt.
Suitable aspirin salt has inorganic salt and organic salt.Inorganic salt is such as sodium, magnesium, zinc, potassium, aluminum salt etc.; Organic salt is such as amino acid salts such as lysinate, ligustrazine salt; Suitable aspirin ester is such as methyl aspirin, aspirin ethyl ester etc.; Also comprise aspirin amino ethyl ester hydrochlorate, maleate etc.
The salt of suitable ligustrazine comprises its inorganic salt and organic salt.The example of inorganic acid salt has: hydrochlorate, sulfate, disulfate, phosphate, hydrobromic acid etc.; The example of acylate has: maleate, fumarate, mesylate, tosilate, ferulate, aspirin salt etc.Other solvates such as hydrate that comprise these salt in addition are such as the ligustrazine phosphate monohydrate.
For better explanation the present invention, for example the present invention is described with aspirin and ligustrazine phosphate monohydrate (the formula III chemical compound claims ligustrazine phosphate again) in the present invention.Said herein ligustrazine phosphate monohydrate is the monohydrate of the monophosphate of ligustrazine.For convenience's sake, below we are called Asp with aspirin (aspirin), and (phosphoric acid Ligustrazine) is called Pal with the ligustrazine phosphate monohydrate.By structural formula as can be seen, the Pal of 1 weight portion is equivalent to the ligustrazine of 0.54 weight portion.
The formula III chemical compound
Many generally acknowledged methods have been used for the safety and the efficiency evaluation of medicine.Document 1)
The Xu Shuyun chief editor, pharmacological experimental methodology, People's Health Publisher, front pageWith 2)
In Ministry of Public Health bureau of drug administration of Chinese people republic, new drug (Western medicine) preclinical study guideline compilation, 1993.7,Many full and accurate documents are provided.
One embodiment of the present of invention provide the analgesic experiment of compositions.The evaluating drug effect of analgesic generally carries out on whole animal.White mice or rat writhing method are the assessment methods of using always.Referring to document:
Bureau of drug administration of Ministry of Health of the People's Republic of China grinds before new drug (Western medicine) is clinical Study carefully the guideline compilation, 1993.7, the 50-52 page or leafIn intraperitoneal mouse, inject chemical irritant can cause the deep, large tracts of land and more persistent pain stimulation causes white mice to produce " turning round body " reaction.Analgesic has inhibitory action to this, can obviously reduce generation " turn round body " reaction the white mice number.The chemical irritant that the present invention adopts is 0.7% acetum.Experiment of the present invention is found: blank group mouse writhing number of times is 30.88 ± 13.12; Asp (200mg/kg) group mouse writhing number of times is 8.00 ± 6.45; Asp+Pal (100+100mg/kg) group mouse writhing number of times is 5.43 ± 8.31.Illustrate that Asp+Pal (100+100mg/kg) analgesic effect that is reached and the analgesic effect of Asp200mg/kg are not bad.Illustrate collaborative analgesic activity is arranged between Asp and the Pal.Its synergism makes and improving under the prerequisite of curative effect, and the dosage of Asp has only normally 1/2 in the compositions, significantly reduces the dosage of Asp.
The present invention also provides the analgesic pharmacodynamic experiment of compositions.By study group's compound to beer dried yeast to the influence of rat fever experiment conclusive evidence: aspect analgesic, aspirin and ligustrazine have synergism.Asp+Pal (70+70mg/kg) is reached separate that thermal effect and Asp140mg/kg reach to separate thermal effect suitable, illustrating has collaborative refrigeration function between Asp and the Pal.Its synergism makes and improving under the prerequisite of curative effect, and the dosage of Asp has only normally 1/2 in the compositions, significantly reduces the dosage of Asp.
Embodiments of the invention also provide the antiinflammatory pharmacodynamic experiment of compositions.The present invention adopts mouse ear caused by dimethylbenzene xylene ophthalmia method to estimate antiphlogistic effects.Referring to document:
The People's Republic of China (PRC) defends Bureau of drug administration of life portion, new drug (Western medicine) preclinical study guideline compilation, 1993.7,50-52 Page or leafGet the male mice of body weight 26-30g, random packet, is established feminine gender and positive control by ten every group.Cause scorching preceding administration in 30-60 minute.Dimethylbenzene 0.03-0.05ml is dripped in the Mus auris dextra left ear contrast.Put to death mice after 30 minutes, beat the circle auricle, weigh, ask the poor of left and right sides auricle weight, as the swelling degree.The swelling degree is more little, illustrates that inflammation is light, and the antiphlogistic effects of medicine is good more.Experiment of the present invention is found: blank group mice swelling degree is 14.00 ± 3.22 (mg); Asp (200mg/kg) group mice swelling degree is 10.31 ± 4.73 (mg); Asp+Pal (50+50mg/kg) group mice swelling degree is 11.06 ± 4.97 (mg).Illustrate that Asp+Pal (50+50mg/kg) antiphlogistic effects that is reached is suitable with the antiphlogistic effects of Asp200mg/kg.Illustrate collaborative antiinflammatory action is arranged between Asp and the Pal.Its synergism makes and guaranteeing under the prerequisite of curative effect, and the dosage of Asp is only used normally 1/4 in the compositions, significantly reduces the dosage of Asp.
The present invention also provides the effect experiment of pharmaceutical composition antiplatelet aggregation.The effect experiment method of antiplatelet aggregation has multiple, in the present invention, provides compositions to the external clotting time influence of experiment, the mice of the pharmacophore model of the inductive platelet aggregation of ADP experiment, the influence in mouse tail bleeding time experiment.
The effect experiment result of the inductive platelet aggregation of anti-ADP shows: behind rabbit gastric infusion Asp+Pal (9.25+9.25mg/kg, 18.5+18.5mg/kg, the 37+37mg/kg) 1hr, middle and high dosage group and normal control group are relatively, inductive anticoagulant effect has significant differences to ADP, and tangible dose-effect relationship is arranged, with folk prescription Asp or Pal group ratio, effect obviously strengthens.The drug effect of Asp+Pal (18.5+18.5mg/kg) is better than the drug effect of Asp37mg/kg or Pal37mg/kg.Their platelet aggregation inhibition rate is respectively 37.0 ± 9.5%, and 23.0 ± 22.4%, 36.5 ± 18.5%.Be easy to reach a conclusion from numeral, Asp and Pal antiplatelet aggregation have synergism.The consumption of Asp is single during with half amount of Asp in the compositions, and compositions has better drug effect than Asp.And the Asp consumption reduces half.
Compositions shows the influence experiment of the external clotting time of mice: the drug effect of Asp+Pal (25+25mg/kg) is suitable with the drug effect of Asp100mg/kg or Pal100mg/kg.Be respectively 180.3 ± 70.0 (s) with the external clotting time of the mice of their administrations, 180.0 ± 46.4 (s), 186.1 ± 60.1 (s).And the clotting time of Asp+Pal (50+50mg/kg) group is 206.4 ± 54.9 (s).This experiment has also illustrated collaborative antiplatelet aggregative activity between Asp and the Pal.Its synergism makes and guaranteeing under the prerequisite of curative effect, and the dosage of Asp is only used normally 1/4 in the compositions, significantly reduces the using dosage of Asp.
Compositions shows the influence experiment in mouse tail bleeding time: the drug effect of Asp+Pal (50+50mg/kg) is suitable with the drug effect of Asp100mg/kg.The mouse tail bleeding time of their each self administration of medication groups is respectively 1489.3 ± 595.9 (s), 1406.1 ± 737.1 (s).The amount that is to say compositions Asp is amount one half of normal folk prescription Asp, and its drug effect is consistent.
The present invention also provides the experiment of pharmaceutical composition anti-thrombosis function.Rabbit is implemented the operation of common carotid artery thrombosis, and postoperative 2hr takes out and the thrombosed weight in wet base of weighing.Result of the test shows: rabbit gastric infusion Asp+Pal (9.25+9.25mg/kg, 18.5+18.5mg/kg, 37+37mg/kg), the thrombus weight that middle and high dosage treated animal forms behind the 2hr obviously reduces, compare with matched group, significant differences is arranged, and tangible dose-effect relationship is arranged, with folk prescription Asp (37mg/kg) or Pal (37mg/kg) group ratio, effect obviously strengthens.Each is organized wet weight of thrombus and is respectively 21.8 ± 3.2mg, 10.2 ± 1.9mg, 9.5 ± 0.8mg, 15.6 ± 2.5mg, 14.8 ± 3.2mg.Above data show that when with Asp+Pal (18.5+18.5mg/kg) administration, the drug effect of compositions is better than the antithrombotic formation effect of individually dosed Asp (37mg/kg) or Pal (37mg/kg).Illustrate and truly have antithrombotic synergism between Asp and the Pal.And the Asp using dosage can be half as large.
The present invention also provides an embodiment who investigates compatibility relationship between Asp and the Pal.In this experiment, be index to send out platelet aggregation inhibition rate in the collagen-induced rat halfbody, with Jin Shi probability additive process research various dose, different proportion Asp and Pal interaction relationship.Asp+Pal=70+70mg/kg, i.e. Asp: Pal=1: 1 (weight ratio) administration group q=1.2, synergism is best.
The present invention also provides the GI irritation experiment of pharmaceutical composition.In this experiment, measure and respectively to organize ulcer index or the corresponding ulcer inhibition rate that aspirin causes chmice acute ulcer and estimate compositions the gastrointestinal protective effect.Ulcer index is the smaller the better, and ulcer inhibition rate is the bigger the better.Experiment shows that mice continuous irrigation stomach gave Pal (5,10,20,40mg/kg) or Asp+Pal (25+25,50+50,100+100mg/kg) after 7 days; and compare between the normal control group; except that 5mg/kgPal, all the other each groups cause chmice acute ulcer to aspirin all to be had significantly or the protective effect of highly significant.The antiulcer action of compositions Asp+Pal has tangible dose-effect relationship, and dosage is big more, and antiulcer action is good more.This guaranteed heavy dose of medication when bringing into play maximum drug effect to the gastrointestinal protective effect.Solved gastrointestinal zest problem, especially the GI irritation problem when the heavy dose of use of aspirin.
The present invention also provides the acute toxicity testing of pharmaceutical composition.Observe disposable filling stomach of animal subject and lumbar injection and give the acute toxic reaction and the death condition that are produced behind the mice, to investigate its clinical application safety.This experiment is found: Asp+Pal (1: 2) irritates stomach and gives mice LD
50And the credible 2143.4 ± 171.0mg/kg that is limited to; Lumbar injection is given mice LD
50And the credible 731 ± 127.0mg/kg that is limited to; Asp irritates stomach and gives mice LD
50And the credible 1559.7 ± 288.0mg/kg that is limited to; Pal irritates stomach and gives mice LD
50And the credible 1135.0 ± 157.0mg/kg that is limited to.Its acute toxicity of the pharmaceutical composition of above data declaration Asp+Pal is less than Asp and Pal, and is also promptly safer.
In sum, use the cooperative compositions contain Asp and Pal, compare, have better analgesic, analgesia, antiinflammatory, antiplatelet aggregation and anti-thrombosis function with independent use Asp.Although its difference slightly on the result of dosage, persistent period and method of testing of different pharmacological actions.Both have synergism in analgesic, analgesia, antiinflammatory, antiplatelet aggregation each side; compositions by Asp and Pal is used; can keep or even improve under the prerequisite of curative effect; by to the gastrointestinal protective effect; side effect with Asp minimizes such as zest side effect such as gastrointestinal ulcerations.
It makes preparation analgesic, antiinflammatory of the present invention, analgesia, medicament for resisting platelet aggregation compositions, contains the Pal of 50-800 weight portion for the Asp of 100 weight portions, and the Asp that promptly is equivalent to 100 weight portions contains the ligustrazine of 27-432 weight portion.Or the ligustrazine or other officinal salt that are equivalent to salt, the ester of the aspirin of this tittle and are equivalent to this tittle accordingly.Wherein aspirin with every day 25-2000mg amount use, preferred every day, the amount of 25-1000mg was used, preferred again every day, the amount of 25-500mg was used.
Can be based on described pharmaceutical composition through enteral administration, such as oral, described pharmaceutical composition can be made into solid preparations such as tablet, capsule, granule.Certainly also can be made into oral administration solution.Compositions of the present invention can also be made the dosage form through parenterai administration.Such as injection.When making preparation, preparation comprises salt and ligustrazine or its salt of the aspirin of specified amount or its salt, ester, ester, and in preparation of pharmaceutical formulations diluent, carrier and auxiliary agent commonly used.Such as comprising diluent/excipient, absorbent, binding agent, wetting agent, disintegrating agent, lubricant, fluidizer, coating materials, coloring agent, desiccant, emulsifying agent, cosolvent, correctives, anti-caking agent, plasticizer, suspending agent and thickening agent etc.
The solid unit preparation that aforementioned pharmaceutical compositions is prepared into should contain the aspirin of 25-500mg, preferred 50-150mg, or be equivalent to salt, the ester of the aspirin of this tittle, the salt of ester.The unit dose of Pal should be 25-500mg, preferred 50-150mg, or be equivalent to ligustrazine or other officinal salt of this tittle.Consumption every day based on the pharmaceutical composition of described invention depends on medication or treatment condition, but under oral situation, adult's preferred administration every day 1-4 time.
The various method for preparing tablet thereof that contain the pharmaceutical composition of a certain amount of active component are known, for example see
Pharmaceutics, the 4th edition, Bi Dianzhou chief editor, People's Health Publisher, 1999.11One embodiment of the present of invention provide the method for preparing tablet thereof of compositions.
Description of drawings:
In Fig. 1, Ah represents Asp; Pal is represented in the river.Dosage is measurement unit with mg/kg.
The specific embodiment:
Embodiment based on following indefiniteness will explain the present invention in more detail.
Described in an embodiment aspirin is the commodity that buy.Equally, ligustrazine monophosphate monohydrate also is the commodity that buy.Both have a large amount of supplies of commodities on market.
The analgesia pharmacodynamic experiment of I, pharmaceutical composition
One. medicine and equipment:
(1) aspirin phenacetin caffeine
High dose: Asp200mg/kg+Pal200mg/kg
Middle dosage: Asp100mg/kg+Pal100mg/kg
Low dosage: Asp50mg/kg+Pal50mg/kg
(2) aspirin
(3) 0.7% acetic acid
Two. laboratory animal
Kunming mouse, male and female half and half, body weight 18-22g.
Three. experimental technique
Mice is divided into 7 groups at random, and every group of 10-20 only.In experiment fasting in evening the previous day, an experiment day filling stomach gives aspirin and the high, medium and low dosage of aspirin phenacetin caffeine.Behind the administration 1h, the mouse writhing number of times in lumbar injection 0.7% acetum, immediate record 15min.
Three. experimental result
Table 1. aspirin and aspirin phenacetin caffeine to Dichlorodiphenyl Acetate to the influence of mouse writhing reaction
| Group | Dosage (mg/kg) | Number of elements | Turn round the body number of times |
| Blank group Asp Asp Asp Asp+Pal Asp+Pal Asp+Pal | —— 200 100 50 200+200 100+100 50+50 | 16 15 13 15 14 14 14 | 30.88±13.12 8.00±6.45 ** 7.77±6.62 ** 13.00±11.84 ** 1.71±1.94 **## 5.43±8.31 ** 11.43±9.82 ** |
*Compare with the blank group P＜0.01
Compare with aspirin 140mg/kg ##P＜0.01
As shown in table 1, blank group mouse writhing number of times is 30.88 ± 13.12; Asp (200mg/kg) group mouse writhing number of times is 8.00 ± 6.45; Asp+Pal (100+100mg/kg) group mouse writhing number of times is 5.43 ± 8.31.Illustrate that Asp+Pal (100+100mg/kg) analgesic effect that is reached and the analgesic effect of Asp200mg/kg are not bad.Illustrate collaborative analgesic activity is arranged between Asp and the Pal.Its synergism makes and improving under the prerequisite of curative effect, and the dosage of Asp has only normally 1/2 in the compositions, significantly reduces the dosage of Asp.And along with the dosage of compositions increases, analgesic activity is strengthened.
The antiinflammatory pharmacodynamic experiment of II, pharmaceutical composition
One, medicine and equipment:
(1) aspirin phenacetin caffeine: Asp50mg/kg+Pal50mg/kg
(2) aspirin
(3) dimethylbenzene
(4) TN-100B type pellet type torsion balance
Two, laboratory animal
Kunming mouse, male and female half and half, body weight 18～22g.
Three, experimental technique
Be divided into group at random, 12～14 every group.Irritate stomach every day and give aspirin and aspirin phenacetin caffeine, continuous 6 days.In experiment fasting in evening the previous day, behind the experiment day administration 1h, dimethylbenzene totally 25 μ L are evenly smeared on the two sides before and after the mouse right ear exterior feature, put to death mice behind the 30min, cut left and right two auricles, lay left and right two auricles with the 8mm card punch, weigh, and calculate the swelling degree.
Swelling degree (mg)=auris dextra sheet heavy (mg)-left auricle heavy (mg)
Four, experimental result
Table 2 aspirin and aspirin phenacetin caffeine xylol to the influence of mice ear
| Group | Dosage (mg/kg) | Number of elements | Swelling degree (mg) |
| Blank group Asp Asp Asp+Pal | —— 200 100 50+50 | 13 14 13 12 | 14.00±3.22 10.31±4.73 * 13.07±3.60 11.06±4.97 |
*Compare with the blank group P＜0.05
As shown in table 2, experiment of the present invention is found: blank group mice swelling degree is 14.00 ± 3.22 (mg); Asp (200mg/kg) group mice swelling degree is 10.31 ± 4.73 (mg); Asp+Pal (50+50mg/kg) group mice swelling degree is 11.06 ± 4.97 (mg).Illustrate that Asp+Pal (50+50mg/kg) antiphlogistic effects that is reached is suitable with the antiphlogistic effects of Asp200mg/kg.Illustrate collaborative antiinflammatory action is arranged between Asp and the Pal.Its synergism makes and guaranteeing under the prerequisite of curative effect, and the dosage of Asp is only used normally 1/4 in the compositions, significantly reduces the dosage of Asp.
The analgesic pharmacodynamic experiment of III, pharmaceutical composition
One, medicine and equipment:
(1) aspirin phenacetin caffeine:
High dose: Asp 200mg/kg+Pal200mg/kg
Middle dosage: Asp 100mg/kg+Pal 100mg/kg
Low dosage: Asp 50mg/kg+Pal 50mg/kg
(2) aspirin:
(3) beer dried yeast: facing the time spent is configured to 20% beer yeast suspension.
(4) digital thermometer
Two. laboratory animal
The SD rat, male and female half and half, body weight 160-200g.
Three. experimental technique
Rat is divided into 7 groups at random, and every group of 10-20 only.Measure the anus temperature the previous day in experiment, make the stimulation of rat adaptive temperature meter.Experiment fasting in evening the previous day, experiment day is measured rat anus temperature once every 1h, and totally 2 times, anus using warming therapy difference is given it up above 0.3 ℃ rat.The anus temperature meansigma methods of getting 2 times is the rat basal body temperature.The 20% beer dried yeast suspension of rat skin lower injection 10ml/kg.Measure the anus temperature behind the 5h, the anus temperature rise is given it up less than 1.0 ℃ rat.Irritate stomach and give aspirin and the high, medium and low dosage of aspirin phenacetin caffeine.Behind administration 1h, 2h, 3h, 4h, 6h, measure the variation of anus temperature.
Experimental result as shown in Figure 1, Asp+Pal (70+70mg/kg) is reached separate that thermal effect and Asp140mg/kg reach to separate thermal effect suitable, illustrating has collaborative refrigeration function between Asp and the Pal.Its synergism makes and guaranteeing under the prerequisite of curative effect, and the dosage of Asp has only normally 1/2 in the compositions, significantly reduces the dosage of Asp.
The effect experiment of IV, pharmaceutical composition antiplatelet aggregation
Get 48 of rabbit, body weight 2.5-3.0kg, male and female dual-purpose.Be divided into 6 groups at random: normal control group, the basic, normal, high dosage group of Asp/Pal, Asp organize, Pal organizes,, 8 every group.The normal control group is irritated stomach 0.5%CMC-Na solution, the administration volume is the 5ml/kg body weight, all the other each groups are irritated stomach by equal volume and are given relative medicine, the 1hr auricular vein is got blood after the administration, with 3.8% sodium citrate (1: 9) anticoagulant, preparation PRP and PPP, determine that aggregating agent prepared therefrom ADP concentration is 2.2 μ M, measure platelet aggregation rate and obtain the gathering suppression ratio.
Assembling suppression ratio %=(matched group is assembled %-administration group and assembled %)/matched group gathering % * 100% is to compare significance test between index is organized with the aggregation rate.
Result of the test is as shown in table 1: behind rabbit gastric infusion Asp+Pal (9.25+9.25mg/kg, 18.5+18.5mg/kg, the 37+37mg/kg) 1hr, middle and high dosage group and normal control group are relatively, inductive anticoagulant effect has significant differences to ADP, and tangible dose-effect relationship is arranged, with folk prescription Asp or Pal group ratio, effect obviously strengthens.
Table 3 aspirin phenacetin caffeine is to the influence of the inductive platelet aggregation of ADP (n=8, x ± s)
| Group | Dosage (mg/kg) | Platelet aggregation rate (%) | Suppression ratio (%) |
| Control group A sp+Pal Asp Pal | - 37+37 37 37 | 52.4±10.0 22.0±11.1 **++- 41.8±11.6 33.2±9.7 ** | 58.0±21.2 23.0±22.4 36.5±18.5 |
Compare with matched group
*P＜0.01
Compare with the Asp group
++P＜0.01
Compare with the Pal group
-P＜0.05
As shown in table 3, the drug effect of Asp+Pal (18.5+18.5mg/kg) is better than the drug effect of Asp37mg/kg or Pal37mg/kg.Their platelet aggregation inhibition rate is respectively 37.0 ± 9.5%, and 23.0 ± 22.4%, 36.5 ± 18.5%.Can reach a conclusion on numeral, Asp and Pal antiplatelet aggregation have synergism.The consumption of Asp is single during with half amount of Asp in the compositions, and compositions has better drug effect than Asp.And the Asp consumption reduces half.
Embodiment 5, the external clotting time influence of mice experiment
Get 60 of mices, body weight 18-22g, male and female dual-purpose.Be divided into 6 groups at random: matched group, the basic, normal, high dosage group of Asp+Pal, Asp group, Pal group, 10 every group.Each treated animal is irritated stomach respectively and is given relative medicine, and the administration volume is the 0.2ml/10g body weight, and 1hr measures external clotting time after the administration.
Result of the test is as shown in table 4: mouse stomach gives Asp+Pal (25+25/kg, 50+50mg/kg, 100+100mg/kg) back 1hr, and compares between the normal control group, and the compound recipe high dose group has significant prolongation effect to the external clotting time of mice.
Table 4 aspirin phenacetin caffeine is to the influence of the external clotting time of mice (n=10, x ± s)
| Group | Dosage (mg/kg) | Clotting time (s) |
| Control group A sp/Pal Asp Pal | - 25+25 50+50 100+100 100 100 | 171.5±42.5 180.3±70.0 206.4±54.9 223.0±60.5 * 180.0±46.4 186.1±60.1 |
Compare with matched group
*P＜0.05
Compositions shows the influence experiment of the external clotting time of mice: the drug effect of Asp+Pal (25+25mg/kg) is suitable with the drug effect of Asp100mg/kg or Pal100mg/kg.Be respectively 180.3 ± 70.0 (s) with the external clotting time of the mice of their administrations, 180.0 ± 46.4 (s), 186.1 ± 60.1 (s).And the clotting time of Asp+Pal (50+50mg/kg) group is 206.4 ± 54.9 (s).This experiment has also illustrated collaborative antiplatelet aggregative activity between Asp and the Pal.Its synergism makes and guaranteeing under the prerequisite of curative effect, and the dosage of Asp is only used normally 1/4 in the compositions, significantly reduces the using dosage of Asp.
The influence experiment in embodiment 6, mouse tail bleeding time.
Get 60 of mices, body weight 18-22g, male and female half and half.Fasting 6hr before the experiment is divided into 6 groups at random: matched group, the basic, normal, high dosage group of Asp+Pal, Asp group, Pal group, 10 every group.When 1hr mensuration tail is hemorrhage after the administration.
Result of the test is as shown in table 5: after mouse stomach gives Asp+Pal (25+25/kg, 50+50mg/kg, 100+100mg/kg), and compare between the normal control group, the compound recipe high dose group has significant prolongation effect to the external clotting time of mice.
The influence when hemorrhage to mouse tail of table 5 aspirin phenacetin caffeine (n=10, x ± s)
| Group | Dosage (mg/kg) | When tail is hemorrhage (s) |
| Control group A sp/Pal Asp Pal | - 25+25 50+50 100+100 100 100 | 1016.7±565.6 1070.6±516.8 1489.3±595.9 1726.3±587.3 * 1406.1±737.1 1532.6±792.1 |
Compare with matched group
*P＜0.05
Compositions shows the influence experiment to the mouse tail bleeding time: the drug effect of Asp+Pal (50+50mg/kg) is suitable with the drug effect of Asp100mg/kg.The mouse tail bleeding time of their each self administration of medication groups is respectively 1489.3 ± 595.9 (s), 1406.1 ± 737.1 (s).The amount that is to say compositions Asp is amount one half of normal folk prescription Asp, and its drug effect is consistent.
Embodiment 7, the experiment of pharmaceutical composition anti-thrombosis function
Get 36 of rabbit, body weight 1.5-2.5kg, the male and female dual-purpose is divided into 6 groups at random: matched group, the basic, normal, high dosage group of Asp+Pal, Asp group, Pal group, 6 every group.Matched group is irritated stomach 0.5%CMC-Na, and the administration volume is the 5ml/kg body weight, and all the other each groups are irritated stomach by equal volume and given relative medicine.1hr after the administration implements the operation of common carotid artery thrombosis to rabbit, and postoperative 2hr takes out and the thrombosed weight in wet base of weighing.
Shown in the result of the test table 6: rabbit gastric infusion Asp+Pal (9.25+9.25mg/kg, 18.5+18.5mg/kg, 37+37mg/kg), the thrombus weight that middle and high dosage treated animal forms behind the 2hr obviously reduces, compare with matched group, significant differences is arranged, and tangible dose-effect relationship is arranged, with folk prescription Asp or Pal group ratio, effect obviously strengthens.
Table 6 aspirin phenacetin caffeine is to the thrombotic influence of rabbit common carotid artery (n=6, x ± s)
| The G group | Dosage (mg/kg) | Wet weight of thrombus (mg) |
| Control group A sp/Pal Asp Pal | - 9.25+9.25 18.5+18.5 37+37 37 37 | 21.8±2.8 21.8±3.2 10.2±1.9 ***+- 9.5±0.8 ***+++- 15.6±2.5 ** 14.8±3.2 ** |
Compare with matched group
*P＜0.01,
* *P＜0.001; Compare with the Asp group
+P＜0.05,
+++P＜0.001
Compare with the Pal group
-P＜0.05,
--P＜0.01
Above data show that when with Asp+Pal (18.5+18.5mg/kg) administration, the drug effect of compositions is better than the antithrombotic formation effect of individually dosed Asp (37mg/kg) or Pal (37mg/kg).Illustrate and truly have anti-antithrombotic synergism between Asp and the Pal.And the Asp using dosage can be half as large.
IV, the experiment of sieve side
Embodiment 8,
Test objective: the inhibitory action to collagen-induced rat half intracorporal method platelet aggregation behind discussion aspirin and the ligustrazine phosphate compatibility reaches compatibility relationship preferably.
Faced with preceding by reagent thing: Asp and be made into the desired concn suspension with 0.5%CMC-Na.
Pal faces with preceding and is made into the desired concn suspension with 0.5%CMC-Na.
Animal subject: the Wistar rat, male, body weight: 250 ± 20g, 160 (10 every group) of animal sum.
Test method:
1.Asp, Pal drug combination Research on effect
(12h illumination is fed mechanism material piece, the drink tap water to animal subject for 20 ± 3 ℃ of observation ward's temperature, relative humidity 30-70% in indoor one week of observation of breeding observing.) animal subject according to the form below random packet.1h is under waking state behind the gastric infusion, get blood from the socket of the eye vein, with 3.8% citric acid anticoagulant (9: 1), conventional preparation PRP, PPP, selection causes that the collagen quantity of matched group 50 ± 10% platelet aggregations is 20 μ l (by literature method self-control) and carries out statistical procedures with the mean that this collagen quantity is measured each administration group platelet aggregation rate mean and matched group aggregation rate, significance test, and obtain each administration group platelet aggregation inhibition rate, assemble and suppress %=(matched group is assembled %-administration group and assembled %)/matched group gathering %, with the suppression ratio is index, by formula q=E
AB/ (E
A+ E
B-E
AE
B), obtain and respectively organize Q-value, Asp/Pal=70/70mg/kg group q value maximum wherein, q=1.2 illustrates that two medicines are synergism (seeing table 7 for details) in this ratio compatibility to the inhibition of half collagen-induced intracorporal method platelet aggregation.
Table 7 aspirin, ligustrazine phosphate drug combination effect research grouping catalog
| Be subjected to the reagent thing | Dosage (mg/kg) | ||
| Asp Pal Asp/Pal Asp/Pal Asp/Pal | 17.5 35 17.5/35 35/35 70/35 | 35 70 17.5/70 35/70 70/700 | 70 140 17.5/140 35/140 70/140 |
2. aspirin, ligustrazine phosphate optimum organization result of the test
Test grouping and result of the test are as shown in table 8, press L
9(3
2) the row orthogonal table, be index with platelet aggregation inhibition rate (%), by the direct-vision method analysis, the result shows, Pal extreme difference value R=30.0, Asp extreme difference value R=19.5; The F check, the result shows: ligustrazine phosphate F=38.04 (p＜0.05), aspirin F=9.10 (p＞0.05).
Result of the test: in the compound recipe that aspirin, ligustrazine phosphate are formed, with aspirin 70mg/kg, ligustrazine phosphate 70mg/kg collagen-induced rat half intracorporal method platelet aggregation is obvious inhibitory action, prove with Jin Shi probability additive process, two medicines are in this ratio compatibility, drug effect strengthens, be synergism, q=1.20.
Table 8 aspirin, ligustrazine phosphate drug combination effect analysis (to the influence of collagen-induced rat half intracorporal method platelet aggregation) n=10
| Group | Dosage (mg/kg) | Platelet aggregation rate (%) | Suppression ratio (%) | Q-value | |
| | - 17.5 35 70 35 70 140 | 51.8±9.9 40.9±11.8 48.9±3.3 31.4±10.3 40.9±13.0 32.5±8.2 25.2±10.6 | - 21.1±23.4 5.6±6.4 39.0±20.0 20.7±25.1 36.9±16.0 51.1±20.6 | ||
| Asp/Pal(A/P) | |||||
| A 1/P 1 A 1/P 2 A 1/P 3 A 2/P 1 A 2/P 2 A 2/P 3 A 3/P 1 A 3/P 2 A 3/P 3 | 17.5/35 17.5/70 17.5/140 35/35 35/70 35/140 70/35 70/70 70/140 | 43.9±5.3 26.6±8.5 26.3±11.1 39.0±6.5 23.2±14.0 21.8±13.2 33.3±13.0 13.3±6.0 21.7±11.6 | 15.1±10.4 47.9±16.5 48.6±21.5 24.4±12.6 55.0±27.1 57.7±25.6 35.3±25.3 74.1±11.7 57.9±22.5 | 0.40 0.97 0.80 0.97 1.11 0.95 0.68 1.20 0.83 | |
L
9(3
2) table 9 different proportion aspirin, ligustrazine phosphate compound preparation be to the influence of collagen-induced rat half intracorporal method platelet aggregation
Table 10 different proportion aspirin, ligustrazine phosphate are to collagen-induced anticoagulant effect analysis of variance table
| Sum of sguares of deviation from mean | |||||
| Source of variation (1) | (l) (2) | Degree of freedom (n ') (3) | Mean square (MS) (4)=(2) ÷ (3) | F (5) | P (6) |
| Aspirin ligustrazine phosphate error amounts to | 500.36 2090.69 109.93 2700.98 | 2 2 4 | 250.18 1045.34 27.48 | 9.10 0 38.0 40 | ＞0.05 ＜0.05 |
More than experiment shows Asp: the compositions of the various different proportionings of Pal=100: 50-800 (weight ratio) is all effective in cure, but synergistic action effect the best during Asp+Pal (70+70mg/kg).Be that Asp and Pal weight ratio are 1: 1 o'clock administering effect the best.
V, acute toxicity testing
Embodiment 9, observe and to be tried the disposable filling stomach of thing and lumbar injection and give the acute toxic reaction and the death condition that are produced behind the mice, to investigate its clinical application safety.
Test material:
1. tried thing
1.1 title: Asp
Compound method: use the ware electronic balance and take by weighing a certain amount of medicine, add 0.5%CMC-Na and be mixed with required administration concentration solution.
1.2 title: Pal
Compound method is the same.
2. animal subject
Title: mice
Strain: Kunming kind
Sex: male and female dual-purpose
Body weight: 18-22g
Every treated animal number: 10
Test method and result:
1. gastric infusion acute toxicity test in mice
1.1 aspirin phenacetin caffeine (Asp+Pal, 1: 1)
With 40 mices, fasting is 16 hours before the test, is divided into four groups at random, and 10 every group, male and female half and half.Determine D according to trial test
mBe 2933mg/kg, D
nBe 1077mg/kg; Dosage is respectively 2933mg/kg, 2199.8mg/kg, 1649.8mg/kg, 1237.4mg/kg, and agent is apart from being 1: 0.75, and the administration volume is 0.2ml/10g.Observe the toxic reaction of animal subject behind the gastric infusion, a continuous week.Show as refusing to eat behind most mouse stomaches, refuse water, accelerated breathing, restless before dead, 30min occurs deadly after the administration, and the dead mouse overwhelming majority appeared at after the perfusion in 12 hours, and the activity in 48 hours after irritating stomach of not dead mice, diet recover normal gradually.Do not find under the postmortem naked eyes that being tried the mice main organs has obvious pathological changes.LD
50And 95% fiducial limit the results are shown in Table 11 with the calculating of Bliss method.
Table 11 aspirin phenacetin caffeine is irritated stomach and is given mice LD
50And 95% fiducial limit
| Group | Number of animals | Dosage (mg/kg) | Death toll (n) | Mortality rate (P) |
| 1 2 3 4 | 10 10 10 10 | 2933 2199.8 1649.8 1237.4 | 9 5 2 0 | 0.9 0.5 0.2 0.0 |
LD
50=2143.4mg/kg LD
50The 95% credible 1998.8-2340.8mg/kg that is limited to
1.2 aspirin
Test method is the same.Determine D according to trial test
mBe 3500mg/kg, D
nBe 1200mg/kg; Dosage is respectively 3500mg/kg, 2450mg/kg, 1715mg/kg, 1200.5mg/kg, and agent is apart from being 1: 0.7, and the administration volume is 0.2ml/10g.Observe the toxic reaction of animal subject behind the gastric infusion, a continuous week.Show as refusing to eat behind the part mouse stomach, refuse water, muscular tension descends, and balance is poor, rapid breathing, dead preceding restless, 17min occurs dead after the administration, the dead mouse overwhelming majority appears at after the administration in the 12h, and the 24h activity after irritating stomach of not dead mice, diet recover normal gradually.Do not find under the postmortem naked eyes that being tried mouse GI tract has obvious pathological changes.LD
50And 95% fiducial limit the results are shown in Table 12 with the calculating of B1iss method.
Table 12 aspirin is irritated stomach and is given mice LD
50And 95% fiducial limit
| Group | Number of animals | Dosage (mg/kg) | Death toll (n) | Mortality rate (P) |
| 1 2 3 4 | 10 10 10 10 | 3500 2450 1715 1200.5 | 10 9 5 3 | 1.0 0.9 0.5 0.3 |
LD
50=1559.7mg/kg LD
50The 95% credible 1271.7-1847.7mg/kg that is limited to
1.3 ligustrazine phosphate
Test method is the same.Determine D according to trial test
mBe 2600mg/kg, D
nBe 892mg/kg; Dosage is respectively 2600mg/kg, 1820mg/kg, 1274mg/kg, 891.8mg/kg, and agent is apart from being 1: 0.7, and the administration volume is 0.2ml/10g.Observe the toxic reaction of animal subject behind the gastric infusion, a continuous week.See refusing to eat behind most mouse stomaches, refuse water, be slow in action, it is inharmonious to move, rapid breathing, dead preceding restless, 30min occurs dead after the administration, the dead mouse overwhelming majority appears at after the administration in 5 hours h, and the 24h activity after irritating stomach of not dead mice, diet recover normal gradually.Do not find under the postmortem naked eyes that being tried the mice main organs has obvious pathological changes.LD
50And 95% fiducial limit the results are shown in Table 13 with the calculating of Bliss method.
Table 13 ligustrazine phosphate is irritated stomach and is given mice LD
50And 95% fiducial limit
| Group | Number of animals | Dosage (mg/kg) | Death toll (n) | Mortality rate (P) |
| 1 2 3 4 | 10 10 10 10 | 2600 1820 1274 891.8 | 10 9 7 2 | 1.0 0.9 0.4 0.2 |
LD
50=1135.0mg/kg LD
50The 95% credible 978.0-1292.0mg/kg that is limited to
2, aspirin phenacetin caffeine intraperitoneal injection acute toxicity test in mice
With 40 mices, be divided into four groups at random, 10 every group, male and female half and half.Determine D according to trial test
mBe 1238mg/kg, D
nBe 867mg/kg; Dosage is respectively 1238mg/kg, 928.5mg/kg, 696.4mg/kg, 522.3mg/kg, and agent is apart from being 1: 0.75, and the administration volume is 0.2ml/10g.Observe a week continuously behind the intraperitoneal injection, to refuse water, myasthenia of limbs, motion inharmonious, blunt to irritant reaction, indivedual restless before dead for most of mice appearance activity minimizing, refusing to eat after the administration, 10min occurs deadly after the administration, and the death time concentrates on after the administration in the 12h.The survivor is movable behind 24h, the recovery gradually of ingesting is normal.Do not find under the postmortem naked eyes that being tried the mice main organs has obvious pathological changes.LD
50And 95% fiducial limit sees Table 14 with Bliss method result of calculation.
Mice LD is given in table 14 aspirin phenacetin caffeine, ligustrazine phosphate intravenous injection
50And 95% fiducial limit
| Group | Number of animals | Dosage (mg/kg) | Death toll (n) | Mortality rate (P) |
| 1 2 3 4 | 10 10 10 10 | 1237.5 928.5 696.4 522.3 | 10 9 3 1 | 1 0.9 0.3 0.1 |
LD
50=731.7mg/kg LD
50The 95% credible 604.7-858.7mg/kg that is limited to
Conclusion: aspirin phenacetin caffeine is irritated the harmonization of the stomach lumbar injection and is given mice LD
50Add up LD with the Bliss method
50And 95% fiducial limit is respectively 2143.4 ± 171.0mg/kg, 731.7 ± 127.0mg/kg; Aspirin is irritated stomach and is given mice LD
50And the 95% credible 1559.7 ± 288.0mg/kg that is limited to; Ligustrazine phosphate is irritated stomach and is given mice LD
50And the 95% credible 1135.0 ± 157.0mg/kg that is limited to.Its acute toxicity of the pharmaceutical composition of above data declaration Asp+Pal is less than Asp and Pal, and is also promptly safer.
VI, pipe intestinal protection effect experiment
Embodiment 10, aspirin caused the influence of chmice acute gastric ulcer
Get 80 of male mices, body weight 18-22g.Be divided into 8 groups, be respectively model control group, four dosage groups of folk prescription Pal, three dosage groups of aspirin phenacetin caffeine.Administration in continuous seven days, water 24hr is can't help in fasting before the last administration, 30min irritates stomach and gives 72mg/kg Asp (0.2ml/10g) after the administration, measure behind the 4h and respectively organize ulcer index: contrafluxion is rubescent to be 1 minute, petechial hemorrhage or erosion respectively are 1 minute, rotten to the corn 1 of wire is 3 minutes, amounts to the back as index, carries out statistical analysis.
Result of the test is as shown in Table 15: mice continuous irrigation stomach gave Pal (5,10,20,40mg/kg) or Asp+Pal (25+25,50+50,100+100mg/kg) after 7 days; and compare between the normal control group; except that 5mg/kgPal, all the other each groups cause chmice acute ulcer to aspirin all to be had significantly or the protective effect of highly significant
Table 15 folk prescription ligustrazine phosphate and aspirin phenacetin caffeine cause influence (n=10, the x ± s) of chmice acute gastric ulcer to aspirin
| Group | Dosage (mg/kg) | Ulcer index | Suppression ratio (%) |
| Model group Pal Pal Pal Pal Asp+Pal Asp+Pal Asp+Pal | - 5 10 20 40 25+25 50+50 100+100 | 13.3±5.5 10.6±6.4 7.2±4.5 * 5.5±6.2 ** 3.3±4.0 *** 7.8±5.3 * 5.4±5.6 ** 4.4±4.7 ** | - 20.3 45.9 58.6 75.2 41.3 59.3 66.9 |
Compare with model group
*P＜0.05,
*P＜0.01,
* *P＜0.001
In this experiment, aspirin is the medicine for ulcer that causes of ulcer model.Pal and Asp+Pal show good antiulcer effect.Dose-effect relationship is significantly arranged.Composition dosage is big more, and the antiulcer effect is good more.So compositions of the present invention solves the GI irritation problem of aspirin well, the gastric ulcer problem when especially heavy dose of.
The preparation of V, preparation
The preparation of embodiment 11, ordinary tablet
According to composition shown in the table 16 and content, be prepared into independently sheet with the conventional method for preparing tablet.
Table 16
| Component | Consumption (mg) |
| Aspirin ligustrazine phosphat pregelatinized starch sodium carboxymethyl starch 95% ethanol talcum powder superfine silica gel powder | An amount of 5mg 2mg of 75mg 75mg 150mg 20mg |
Claims (11)
1, the pharmaceutical composition of a kind of analgesic, analgesia, antiinflammatory, antiplatelet aggregation is characterized in that: contain 1) salt of aspirin or its pharmaceutically acceptable salt, ester or ester; With 2) ligustrazine or its pharmaceutically acceptable salt, described pharmaceutical composition is mixed with the oral formulations through intestinal canal administration.
2, the pharmaceutical composition of analgesic, analgesia according to claim 1, antiinflammatory, antiplatelet aggregation, wherein for the aspirin of 100 weight portions or contain its pharmaceutically acceptable salt, the ester of a great deal of, the salt of ester, described ligustrazine is 27-432 weight portion or its pharmaceutically acceptable salt that contains a great deal of.
3, the pharmaceutical composition of analgesic, analgesia according to claim 2, antiinflammatory, antiplatelet aggregation, it is mixed with solid preparation.
4, the pharmaceutical composition of analgesic, analgesia according to claim 3, antiinflammatory, antiplatelet aggregation, it is mixed with the unit formulation of tablet form.
5, according to the pharmaceutical composition of described analgesic, the analgesia of any one claim among the claim 1-4, antiinflammatory, antiplatelet aggregation, its unit formulation that is mixed with contains 1) aspirin of 25-600mg or be equivalent to aspirin officinal salt, the ester of this tittle, the salt of ester; With 2) ligustrazine of 13.5-324mg or be equivalent to the ligustrazine officinal salt of this tittle; With 3) pharmaceutically suitable carrier.
6, the pharmaceutical composition of analgesic, analgesia according to claim 5, antiinflammatory, antiplatelet aggregation, its unit formulation that is mixed with contains 1) aspirin of 25-150mg or be equivalent to aspirin officinal salt, the ester of this tittle, the salt of ester; With 2) ligustrazine of 13.5-81mg or be equivalent to the ligustrazine officinal salt of this tittle; With 3) pharmaceutically suitable carrier.
7, the pharmaceutical composition of analgesic, analgesia according to claim 6, antiinflammatory, antiplatelet aggregation, its unit formulation that is mixed with contains 1) aspirin of 75mg; With 2) the ligustrazine phosphate monohydrate of 75mg; With 3) pharmaceutically suitable carrier.
8, the application of the described pharmaceutical composition of any one claim in the preparation antipyretic analgesics among the claim 1-7.
9, the application of the described pharmaceutical composition of any one claim in the preparation analgesic among the claim 1-7.
10, the application of the described pharmaceutical composition of any one claim in the preparation anti-inflammatory drug among the claim 1-7.
11, the application of the described pharmaceutical composition of any one claim in the preparation medicament for resisting platelet aggregation among the claim 1-7.
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| CN1329035C (en) * | 2005-09-06 | 2007-08-01 | 北京思普润安医药科技有限公司 | Method for preparing medicine composition contg. aspirin |
| CN101919890A (en) * | 2010-08-18 | 2010-12-22 | 徐震 | Tablet containing clopidogrel hydrogen sulfate and preparation method thereof |
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| CN104127416A (en) * | 2014-07-17 | 2014-11-05 | 沈阳华泰药物研究有限公司 | Novel use of ligustrazine and its medicinal salt |
| CA3121235A1 (en) | 2018-11-30 | 2020-06-04 | Beth Israel Deaconess Medical Center, Inc. | Compositions and methods for reducing major thrombotic events in cancer patients |
| CN111635315B (en) * | 2019-03-01 | 2024-03-12 | 华创合成制药股份有限公司 | Antipyretic analgesic medicine and preparation method and application thereof |
| CN113402390B (en) * | 2021-07-21 | 2022-12-06 | 河北农业大学 | Aspirin medicine eutectic and preparation method and application thereof |
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| US5037815A (en) * | 1986-03-04 | 1991-08-06 | Bristol-Myers Squibb Co. | Non-steroidal anti-inflammatory compositions protected against gastrointestinal injury with a combination of certain H1 - and H2 -receptor blockers |
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| US5037815A (en) * | 1986-03-04 | 1991-08-06 | Bristol-Myers Squibb Co. | Non-steroidal anti-inflammatory compositions protected against gastrointestinal injury with a combination of certain H1 - and H2 -receptor blockers |
| US5043358A (en) * | 1986-03-04 | 1991-08-27 | Bristol-Myers Squibb Company | Gastroprotective process |
| JPH0826990A (en) * | 1990-03-19 | 1996-01-30 | E R Squibb & Sons Inc | Composition for prophylaxis and/or therapy for ulcer and/or inflammation |
| CN1262103A (en) * | 1999-01-26 | 2000-08-09 | 山东绿叶制药股份有限公司 | Chinese-medicinal compound extract for curing cerebrovascular diseases |
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| CN1507870A (en) | 2004-06-30 |
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