CN103735551B - Pharmaceutical composition of cardiovascular and cerebrovascular vessel and its preparation method and application - Google Patents

Abstract

The present invention relates to the pharmaceutical composition of ticagrelor and Equations of The Second Kind therapeutic agent, described Equations of The Second Kind therapeutic agent be selected from troxerutin, cinnarizine, flunarizine hydrochloride, ligustrazine hydrochloride, ligustrazine phosphate, sodium ferulate or piperazine ferulate one or more, and the preparation method of described pharmaceutical composition, the invention still further relates to the application of aforementioned pharmaceutical compositions in medicine, especially in the application suppressed or reverse in arterial vascular medicated porridge sample Lipid Plaque.

Description

Pharmaceutical composition of cardiovascular and cerebrovascular vessel and its preparation method and application

Technical field

The invention belongs to medical art, relate to the pharmaceutical composition for the treatment of or preventing, it comprises ticagrelor and an other class therapeutic agent, for the control of the heart, brain and angiopathy, and its preparation method and its application in medicine.

Background technology

The heart, brain and angiopathy are the diseases that sickness rate is high, hazardness is large, lethal, disability rate is high, cardiovascular and cerebrovascular disease is inherently vascular lesion, the aberrant angiogenesis that the main cause of vascular lesion is arterial vascular medicated porridge sample Lipid Plaque and causes due to medicated porridge sample Lipid Plaque, this is the main cause forming heart and cerebral ischemia, infarction disease; About atherosclerotic mechanism, there are the theories such as lipid infiltration, proliferation of smooth muscle, thrombosis, platelet aggregation and Artery injury, what this illustrated cardiovascular and cerebrovascular disease generation is caused by many factors, therefore, carry out from many aspects preventing and treating and suppressing or reverse Lipid Plaque, being the basic method and thinking of dealing with problems, is also very important and significant.

Ticagrelor (Ticagrelor, also known as making ADZ6140), belongs to cyclopenta triazolopyrimidines, chemistry (1S, 2S, 3R by name, 5s)-3-[7-[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3]-triazole [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-glycol, molecular formula: C23H28F2N6O4S, molecular weight 522.57, No. CAS: 274693-27-5, structure formula is as follows:

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The international publication WO00/34283 of PCT patent application and China Patent No. 99815926.3 disclose ticagrelor compound and preparation method and medicinal usage; The international publication WO2001/092262 of PCT patent application and China Patent No. 01810582.3 disclose multiple compound crystal form of ticagrelor and armorphous.

Ticagrelor is a kind of Novel anti-platelet agent, ticagrelor and main metabolites thereof can reversibly with platelet P2Y12ADP acceptor interaction, disabling signal conduction and platelet activation.Different with prasugrel from thiophene pyridines anticoagulant medicine clopidogrel, it is the antiplatelet drug of the first adenosine diphosphate (ADP) receptor subtype P2Y12 that can reversibly act in platelet, obvious inhibitory action is had to the platelet aggregation that ADP causes, effectively can improve the symptom of Acute Coronary Syndrome Patients, reduce mortality rate.

But ticagrelor anticoagulant effect active side overweights cardiovascular aspect, and cardiovascular and cerebrovascular disease are accompanied often, often there is cerebral arteriosclerosis in the patient of most coronary atherosclerosis; And cardiovascular and cerebrovascular disease are all critical, that hazardness is very large disease usually, the patient caused by cardiovascular and cerebrovascular vessel thunder bolt is lethal, disability rate is very high.

Summary of the invention

The object of this invention is to provide the pharmaceutical composition of ticagrelor and Equations of The Second Kind therapeutic agent, described Equations of The Second Kind therapeutic agent be selected from troxerutin, cinnarizine, flunarizine hydrochloride, ligustrazine hydrochloride, ligustrazine phosphate, sodium ferulate or piperazine ferulate one or more, described ticagrelor also comprises its pharmaceutically acceptable salt or solvate, and described Equations of The Second Kind therapeutic agent also comprises its pharmaceutically acceptable salt or solvate.

Another object of the present invention is to provide the preparation method of aforementioned pharmaceutical compositions;

The invention still further relates to the application of aforementioned pharmaceutical compositions in medicine, medical usage.

The present composition comprises two kinds of compound modes:

A kind of compound mode is existed with the form of compound preparation ticagrelor and Equations of The Second Kind therapeutic agent, and the dosage form of described medicine is any pharmaceutical dosage form of acceptable on pharmaceutics.Use corresponding pharmaceutical carrier or adjuvant, adopt different preparation technologies to can be made into different compound medicinal formulations.Be to be understood that, compound preparation refers to makes independent preparation using ticagrelor and Equations of The Second Kind therapeutic agent as medicament active composition, it can be any pharmaceutical dosage form that pharmaceutics can accept, preferred oral preparation, such as tablet (comprises dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, effervescent tablet, Deng), hard capsule (comprising enteric coated capsule), soft capsule, granule, pill, pellet (comprising enteric coated micropill), drop pill, dry suspension, oral solution, dry syrup, powder, oral administration mixed suspension, and oral rapid release or the dosage form such as slow release or controlled release, or injection or cutaneous permeable agent, powder ampoule agent for injection (comprises Injectable sterile fill injectable powder, lyophilized injectable powder), aqueous solution injection, injection can also be with glucose, sodium chloride, fructose, Nulomoline, xylitol or maltose etc. use the aqueous solution of (comprising intravenous injection and intravenous drip) as the intravenous injection of osmotic pressure regulator, also comprise the ointment of external preparation for skin, gel, emulsion agent, emulsion agent, patch, etc., also can be the dosage form such as rapid release, slow release, controlled release of above various dosage form, such as oral dispersible tablet, slow releasing tablet, slow releasing capsule, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets, born of the same parents rise granule, etc.Especially, by means known in the art preparation, be preferred for preparing tablet (comprising dispersible tablet, slow-release tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets), capsule (comprising gastric solubleness, enteric, slow releasing capsule), oral solution, injection (comprising powder ampoule agent for injection and injection) that pharmaceutics uses;

Another kind of compound mode is that ticagrelor and Equations of The Second Kind therapeutic agent are made independent preparation respectively, in use, patient can successively medication successively, also medication simultaneously after the preparation of the ticagrelor separated can being mixed with the preparation of Equations of The Second Kind therapeutic agent, finally to reach the object using composition of medicine of the present invention, necessary, two kinds of independent preparations should be packaged in same medicine box by conveniently patient medication and represent the feature of drug regimen, further, when ticagrelor and Equations of The Second Kind therapeutic agent are independent preparations, both pharmaceutical dosage forms can be identical, also can be different, as ticagrelor sheet and Equations of The Second Kind therapeutic agent tablet medicament composition, ticagrelor capsule and Equations of The Second Kind therapeutic agent pharmaceutical capsules compositions, ticagrelor sheet and Equations of The Second Kind therapeutic agent pharmaceutical capsules compositions, ticagrelor capsule and Equations of The Second Kind therapeutic agent tablet medicament composition, such as, concrete, the composite reagent thing of ticagrelor tablet and troxerutin tablet, the composite reagent thing of ticagrelor capsule and cinnarizine tablet, the composite reagent thing of ticagrelor capsule and Flunarizine hydrochloride tablet, etc., also can be the rapid release of above various dosage form, slow release, the dosage forms such as controlled release, such as oral dispersible tablet, slow releasing tablet, slow releasing capsule, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets, born of the same parents rise granule, etc..Especially, by means known in the art preparation, be preferred for preparing tablet (comprising dispersible tablet, slow-release tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets), capsule (comprising gastric solubleness, enteric, slow releasing capsule), oral solution, injection (comprising powder ampoule agent for injection and injection) etc. that pharmaceutics uses.

Should be appreciated that or can give the present invention's compound of combination in turn simultaneously, these combination of compounds can be same or different pharmaceutical compositions.If administration in turn, the delay administration of the second active component should not reduce the effect of synergistic therapeutic action between this active ingredient combinations or collaborative drug mechanism.It should also be understood that, no matter simultaneously or administration in turn, ticagrelor and Equations of The Second Kind therapeutic agent can with independent or any combining form administrations, preferably by ticagrelor and the administration simultaneously of Equations of The Second Kind therapeutic agent or with the administration in turn of independent medicine type, and most preferably administration simultaneously.

Preferably give drug regimen of the present invention with single combination preparation form.

The present invention also provides the while of applying ticagrelor preparation and Equations of The Second Kind therapeutic agent or is administered for the medicine for the treatment of or preventing cardiovascular and cerebrovascular disease in turn, and reducing the application that the risk that myocardial infarction, apoplexy or cardiovascular disease cause occurs, especially, for suppressing or reversing arterial vascular medicated porridge sample Lipid Plaque.

The present invention that another aspect of the present invention provides ticagrelor and Equations of The Second Kind therapeutic agent to exist with the ratio of synergistic drug dose combines.

The ratio of the synergistic drug dose of ticagrelor and Equations of The Second Kind therapeutic combination, such as mass ratio is 0.2:1 ~ 5:1, show when in compositions, ticagrelor generally can adopt it to be used alone with the consumption of Equations of The Second Kind therapeutic agent treat or the amount of preventive effect effect more favourable.

The oral applicable dosage of ticagrelor is generally adult's 50 ~ 200mg level every day and gives this compound, preferred every day 180mg single or give this compound at twice, such as 80mg, 90mg, 100mg, 120mg, 150mg, 180mg, 200mg, and the Equations of The Second Kind therapeutic agent containing effective dose, such as, the pharmaceutical composition of ticagrelor described below and Equations of The Second Kind therapeutic agent, the wherein dosage of Equations of The Second Kind therapeutic agent:

The pharmaceutical composition of ticagrelor and troxerutin, wherein the oral applicable dosage of troxerutin is generally adult's 80 ~ 600mg level every day and gives this compound, preferred every day, 100 ~ 500mg gave troxerutin, such as 120mg, 150mg, 180mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg or 500mg gives troxerutin, special, containing 80 ~ 200mg ticagrelor and 100 ~ 500mg troxerutin in preferred per unit preparation, such as, containing 80 ~ 100mg ticagrelor and 100 ~ 500mg troxerutin in per unit preparation, concrete, containing 90mg ticagrelor and 100mg troxerutin in per unit preparation, or containing 90mg ticagrelor and 110mg troxerutin in per unit preparation, or containing 90mg ticagrelor and 120mg troxerutin in per unit preparation, or containing 80mg ticagrelor and 150mg troxerutin in per unit preparation, or containing 80mg ticagrelor and 120mg troxerutin in per unit preparation, or containing 180mg ticagrelor and 150mg troxerutin in per unit preparation, or containing 180mg ticagrelor and 250mg troxerutin in per unit preparation, or containing 180mg ticagrelor and 350mg troxerutin in per unit preparation,

The pharmaceutical composition of ticagrelor and cinnarizine, wherein the oral applicable dosage of cinnarizine is generally adult's 30 ~ 150mg level every day and gives this compound, preferred every day, 50 ~ 100mg gave cinnarizine, such as 50mg, 60mg, 80mg, 90mg, 100mg gives cinnarizine, special, containing 80 ~ 200mg ticagrelor and 30 ~ 150mg cinnarizine in preferred per unit preparation, such as, containing 80 ~ 100mg ticagrelor and 20 ~ 150mg cinnarizine in per unit preparation, concrete, containing 90mg ticagrelor and 25mg cinnarizine in per unit preparation, or containing 90mg ticagrelor and 30mg cinnarizine in per unit preparation, or containing 90mg ticagrelor and 40mg cinnarizine in per unit preparation, or containing 80mg ticagrelor and 50mg cinnarizine in per unit preparation, or containing 80mg ticagrelor and 60mg cinnarizine in per unit preparation, or containing 180mg ticagrelor and 70mg cinnarizine in per unit preparation, or containing 180mg ticagrelor and 80mg cinnarizine in per unit preparation, or containing 180mg ticagrelor and 100mg cinnarizine in per unit preparation,

The pharmaceutical composition of ticagrelor and flunarizine hydrochloride, wherein the oral applicable dosage of flunarizine hydrochloride is generally adult's 5 ~ 30mg level every day and gives this compound, preferred every day, 5 ~ 20mg gave flunarizine hydrochloride, such as 5mg, 8mg, 10mg, 15mg or 20mg gives flunarizine hydrochloride, special, containing 80 ~ 200mg ticagrelor and 5 ~ 30mg flunarizine hydrochloride in preferred per unit preparation, such as, containing 80 ~ 100mg ticagrelor and 50 ~ 30mg flunarizine hydrochloride in per unit preparation, concrete, containing 90mg ticagrelor and 5mg flunarizine hydrochloride in per unit preparation, or containing 90mg ticagrelor and 10mg flunarizine hydrochloride in per unit preparation, or containing 90mg ticagrelor and 15mg flunarizine hydrochloride in per unit preparation, or containing 90mg ticagrelor and 20mg flunarizine hydrochloride in per unit preparation, or containing 90mg ticagrelor and 25mg flunarizine hydrochloride in per unit preparation, or containing 80mg ticagrelor and 8mg flunarizine hydrochloride in per unit preparation, or containing 80mg ticagrelor and 10mg flunarizine hydrochloride in per unit preparation, or containing 180mg ticagrelor and 10mg flunarizine hydrochloride in per unit preparation, or containing 180mg ticagrelor and 20mg flunarizine hydrochloride in per unit preparation, or containing 180mg ticagrelor and 25mg flunarizine hydrochloride in per unit preparation,

The pharmaceutical composition of ticagrelor and ligustrazine hydrochloride, wherein the oral applicable dosage of ligustrazine hydrochloride is generally adult's 50 ~ 300mg level every day and gives this compound, preferred every day, 100 ~ 300mg gave ligustrazine hydrochloride, such as 125mg, 150mg, 180mg, 200mg1, 250mg or 300mg gives ligustrazine hydrochloride, special, containing 80 ~ 200mg ticagrelor and 50 ~ 300mg ligustrazine hydrochloride in preferred per unit preparation, such as, containing 80 ~ 100mg ticagrelor and 80 ~ 300mg ligustrazine hydrochloride in per unit preparation, concrete, containing 90mg ticagrelor and 100mg ligustrazine hydrochloride in per unit preparation, or containing 90mg ticagrelor and 130mg ligustrazine hydrochloride in per unit preparation, or containing 90mg ticagrelor and 150mg ligustrazine hydrochloride in per unit preparation, or containing 90mg ticagrelor and 110mg ligustrazine hydrochloride in per unit preparation, or containing 90mg ticagrelor and 200mg ligustrazine hydrochloride in per unit preparation, or containing 80mg ticagrelor and 150mg ligustrazine hydrochloride in per unit preparation, or containing 80mg ticagrelor and 120mg ligustrazine hydrochloride in per unit preparation, or containing 180mg ticagrelor and 200mg ligustrazine hydrochloride in per unit preparation, or containing 180mg ticagrelor and 300mg ligustrazine hydrochloride in per unit preparation, or containing 180mg ticagrelor and 150mg ligustrazine hydrochloride in per unit preparation,

The pharmaceutical composition of ticagrelor and ligustrazine phosphate, wherein the oral applicable dosage of ligustrazine phosphate is generally adult's 50 ~ 300mg level every day and gives this compound, preferred every day, 100 ~ 300mg gave ligustrazine phosphate, such as 125mg, 150mg, 180mg, 200mg1, 250mg or 300mg gives ligustrazine phosphate, special, containing 80 ~ 200mg ticagrelor and 50 ~ 300mg ligustrazine phosphate in preferred per unit preparation, such as, containing 80 ~ 100mg ticagrelor and 80 ~ 300mg ligustrazine phosphate in per unit preparation, concrete, containing 90mg ticagrelor and 100mg ligustrazine phosphate in per unit preparation, or containing 90mg ticagrelor and 130mg ligustrazine phosphate in per unit preparation, or containing 90mg ticagrelor and 150mg ligustrazine phosphate in per unit preparation, or containing 90mg ticagrelor and 110mg ligustrazine phosphate in per unit preparation, or containing 90mg ticagrelor and 200mg ligustrazine phosphate in per unit preparation, or containing 80mg ticagrelor and 150mg ligustrazine phosphate in per unit preparation, or containing 80mg ticagrelor and 120mg ligustrazine phosphate in per unit preparation, or containing 180mg ticagrelor and 200mg ligustrazine phosphate in per unit preparation, or containing 180mg ticagrelor and 300mg ligustrazine phosphate in per unit preparation, or containing 180mg ticagrelor and 150mg ligustrazine phosphate in per unit preparation,

The pharmaceutical composition of ticagrelor and sodium ferulate, wherein the oral applicable dosage of sodium ferulate is generally adult's 50 ~ 300mg level every day and gives this compound, preferred every day, 100 ~ 300mg gave sodium ferulate, such as 125mg, 150mg, 180mg, 200mg1, 250mg or 300mg gives sodium ferulate, special, containing 80 ~ 200mg ticagrelor and 50 ~ 300mg sodium ferulate in preferred per unit preparation, such as, containing 80 ~ 100mg ticagrelor and 80 ~ 300mg sodium ferulate in per unit preparation, concrete, containing 90mg ticagrelor and 100mg sodium ferulate in per unit preparation, or containing 90mg ticagrelor and 130mg sodium ferulate in per unit preparation, or containing 90mg ticagrelor and 150mg sodium ferulate in per unit preparation, or containing 90mg ticagrelor and 110mg sodium ferulate in per unit preparation, or containing 90mg ticagrelor and 200mg sodium ferulate in per unit preparation, or containing 80mg ticagrelor and 150mg sodium ferulate in per unit preparation, or containing 80mg ticagrelor and 120mg sodium ferulate in per unit preparation, or containing 180mg ticagrelor and 200mg sodium ferulate in per unit preparation, or containing 180mg ticagrelor and 300mg sodium ferulate in per unit preparation, or containing 180mg ticagrelor and 150mg sodium ferulate in per unit preparation,

The pharmaceutical composition of ticagrelor and piperazine ferulate, wherein the oral applicable dosage of piperazine ferulate is generally adult's 100 ~ 600mg level every day and gives this compound, preferred every day, 150 ~ 500mg gave piperazine ferulate, such as 110mg, 130mg, 140mg, 180mg, 190mg, 210mg, 250mg, 300mg, 350mg, 400mg, 410mg, 450mg, 490mg or 550mg gives piperazine ferulate, special, containing 80 ~ 200mg ticagrelor and 100 ~ 600mg piperazine ferulate in preferred per unit preparation, such as, containing 80 ~ 100mg ticagrelor and 150 ~ 500mg piperazine ferulate in per unit preparation, concrete, containing 90mg ticagrelor and 150mg piperazine ferulate in per unit preparation, or containing 90mg ticagrelor and 200mg piperazine ferulate in per unit preparation, or containing 90mg ticagrelor and 250mg piperazine ferulate in per unit preparation, or containing 90mg ticagrelor and 300mg piperazine ferulate in per unit preparation, or containing 80mg ticagrelor and 250mg piperazine ferulate in per unit preparation, or containing 80mg ticagrelor and 300mg piperazine ferulate in per unit preparation, or containing 180mg ticagrelor and 400mg piperazine ferulate in per unit preparation, or containing 180mg ticagrelor and 500mg piperazine ferulate in per unit preparation.

Although the active component of drug regimen can be given with chemical raw material form, preferably give with Pharmaceutical composition form.Pharmaceutical composition of the present invention comprises ticagrelor and described Equations of The Second Kind therapeutic agent, and the drug regimen of the present invention of one or more pharmaceutically acceptable carriers or excipient.These carriers must be acceptable, can with other component compatibility of formula, and nontoxic to its receiver.When giving separately each component of said composition, they are each form of Pharmaceutical composition naturally generally.Unless otherwise indicated, the compositions of indication of the present invention refers to the compositions of drug regimen containing ticagrelor and Equations of The Second Kind therapeutic agent or the wherein drug regimen of each component of ticagrelor and Equations of The Second Kind therapeutic agent.

Preferably, the combination of ticagrelor and Equations of The Second Kind therapeutic agent is generally the Pharmaceutical composition with one or more pharmaceutically acceptable carriers of unit dosage form, and the dosage of the ticagrelor contained in conventional unit formulation and Equations of The Second Kind therapeutic agent is clear and definite in the foregoing.

Use corresponding, different pharmaceutical carriers and preparation technology, pharmaceutical composition of the present invention can be made different pharmaceutical dosage forms.What those skilled in the art were appreciated that is, these pharmaceutical carriers be become various dosage form for the ease of production and processing, guarantee medicine safe, effectively with the factor such as to stablize, and to select according to the physicochemical property of different pharmaceutical dosage forms and medicine self.The choice for use of pharmaceutical carrier is that those of skill in the art of the present invention know with apparent.

Be to be understood that, for oral or injection, according to method well known in the art, usually select according to different medicaments or combinationally use pharmaceutical carrier, optionally comprise excipient or diluent, such as microcrystalline Cellulose, mannitol, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, calcium hydrogen phosphate, hydroxypropyl emthylcellulose, sucrose, dextran, poloxamer, sodium chloride, sorbitol, glucose, fructose, water, Polyethylene Glycol, propylene glycol, glycerol, cyclodextrin and derivant thereof, etc.; For oral solid formulation, optionally can also comprise binding agent, such as polyvidone (polyvinylpyrrolidone), methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, etc.; Also comprise lubricant, such as magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate, sodium lauryl sulphate, etc.; Also optionally comprise disintegrating agent, such as carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula sodium, pregelatinized Starch, etc.; Also optionally comprise surfactant or cosolvent, such as sodium lauryl sulphate, Tween-80, etc.; Also can comprise pH value regulator or buffer agent or cosolvent, such as phosphate buffer, citric acid, sodium citrate, acetate buffer, dilute hydrochloric acid, lactic acid, sodium carbonate, sodium hydroxide, alkaline organic compound, as arginine, lysine, meglumine, trometamol, etc.; Also optionally comprise antiseptic, such as sodium benzoate, potassium sorbate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, etc.; Also optionally comprise stabilizing agent and antioxidant, such as metal chelating agent selects ethylenediaminetetraacetic acid and salt (calcium disodium edetate, disodium edetate) etc. thereof, sodium sulfite, sodium pyrosulfite, vitamin C, vitamin E, etc.; Also optionally comprise taste regulator, such as maltose alcohol, fructose, sucrose, saccharin sodium, flavoring orange essence, strawberry essence, etc.; That also can comprise other routine in addition, appropriate additive.It is also understood that agent type be tablet or capsule time, can be film coating.For the material of film coating, comprise applicable coating materials, such as hydroxypropyl methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate (enteric-coating material), etc.; Also can comprise plasticizer, such as Polyethylene Glycol, triethyl citrate, etc.; Also optionally comprise suitable solubilizing agent, as Polyoxyethylene Sorbitan Monooleate; Also can comprise suitable pigment, as titanium dioxide, various ferrum oxide, pink pigment, etc.Should be appreciated that above-mentioned " optionally comprising " refers to namely can optionally choice for use, also can not use.

Especially, the pharmaceutical composition of ticagrelor of the present invention and described Equations of The Second Kind therapeutic agent, ticagrelor can be different on medicament releasing pattern from the chemical composition of Equations of The Second Kind therapeutic agent, such as ticagrelor can the form of slow release or controlled release occur, and Equations of The Second Kind therapeutic agent occurs with the medicament releasing pattern of the medicament releasing pattern of routine or rapid release, to improve the not synergism of the blood drug level that ticagrelor and the time difference of described Equations of The Second Kind therapeutic agent in onset or metabolism cause.

In the present patent application, " pharmaceutical composition " refer on one or more described compounds or its physiology/pharmaceutically acceptable salt or prodrug, with other chemical composition, such as, on physiology/and the mixture that formed of pharmaceutically acceptable carrier or excipient, the object of pharmaceutical composition is conducive to the using of medicine, carries, preserves; " administration " mentioned here refers to prevent or disease therapy and to compound, its pharmaceutically useful salt or its solvate described in organism (comprising patient or healthy population) delivery formula; Described " per unit preparation " refers to the preparation unit of minimum package or minimum form of medication, as each capsules, each tablet or pill, each bottle of oral administration solution, each bag of granule or powder, each injection or injection, each bottle of injection or injection, each piece of suppository, each bottle of eye drop, each pipe ointment, etc.

On the other hand, have now found that, when ticagrelor and Equations of The Second Kind therapeutic combination use, it demonstrates unexpected advantage, and especially this drug regimen demonstrates outstanding, beyond thought in the effect suppressed or reverse in arterial vascular medicated porridge sample Lipid Plaque.Preferably, the pharmaceutical composition of ticagrelor of the present invention and Equations of The Second Kind therapeutic agent, such as, for suppressing or reversing arterial vascular medicated porridge sample Lipid Plaque, coronary artery, or carotid artery, or peripheral arterial, etc.Therefore, on the other hand, the invention provides a kind of pharmaceutical composition suppressing or reverse arterial vascular medicated porridge sample Lipid Plaque, it contains ticagrelor and Equations of The Second Kind therapeutic agent, described Equations of The Second Kind therapeutic agent be selected from troxerutin, cinnarizine, flunarizine hydrochloride, ligustrazine hydrochloride, ligustrazine phosphate, sodium ferulate or piperazine ferulate one or more, wherein said ticagrelor also comprises its pharmaceutically acceptable salt or solvate, and described Equations of The Second Kind therapeutic agent also comprises its pharmaceutically acceptable salt or solvate.It will be appreciated by those skilled in the art that, this suppression or reverse in the pharmaceutical composition of arterial vascular medicated porridge sample Lipid Plaque, dosage ratio in the compound mode of ticagrelor and Equations of The Second Kind therapeutic agent, per unit preparation and content, just the same with the aforesaid content of the present invention.

Further, present invention also offers the preparation method of the pharmaceutical composition of ticagrelor and described Equations of The Second Kind therapeutic agent, it comprises ticagrelor and described Equations of The Second Kind therapeutic agent and pharmaceutically acceptable pharmaceutical carrier is mixed and made into acceptable any pharmaceutical preparation on pharmaceutics, such as ticagrelor and troxerutin and pharmaceutical carrier dry powder blend, dry granulation mixing (dry granulating machine process), wet granulation mixing (with water or alcoholic solution wet granulation), liquid or semisolid mixes (as the content of soft capsule, drop pill dropping liquid mixes) etc., preferred pharmaceutical dosage form is that tablet (comprises dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, effervescent tablet etc.), hard capsule (comprising enteric coated capsule), soft capsule, granule, pill, pellet (comprising enteric coated micropill), drop pill, dry suspension, oral solution, dry syrup, powder, oral administration mixed suspension, and oral rapid release or the dosage form such as slow release or controlled release, powder ampoule agent for injection (comprises Injectable sterile fill powder, lyophilized injectable powder), aqueous solution injection, injection can also be with glucose, sodium chloride, fructose, Nulomoline, xylitol or maltose etc. use the aqueous solution of (comprising intravenous injection and intravenous drip) as the intravenous injection of osmotic pressure regulator, also can be the rapid releases of above various dosage form, slow release, the dosage forms such as controlled release, such as oral dispersible tablet, slow releasing tablet, slow releasing capsule, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets, born of the same parents rise granule, etc.Especially, by means known in the art preparation, be preferred for preparing tablet (comprising dispersible tablet, slow-release tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets), capsule (comprising gastric solubleness, enteric, slow releasing capsule), oral solution, injection (comprising powder ampoule agent for injection and injection) etc. that pharmaceutics uses; Or

The preparation method of the pharmaceutical composition of the ticagrelor that the present invention also provides and described Equations of The Second Kind therapeutic agent, it comprises ticagrelor and described Equations of The Second Kind therapeutic agent is mixed and made into independent pharmaceutical preparation with pharmaceutically acceptable pharmaceutical carrier respectively, and by two kinds of independent pharmaceutical preparation packages in same medicine box, preferred pharmaceutical dosage form is that tablet (comprises dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, effervescent tablet etc.), hard capsule (comprising enteric coated capsule), soft capsule, granule, pill, pellet (comprising enteric coated micropill), drop pill, dry suspension, oral solution, dry syrup, powder, oral administration mixed suspension, and oral rapid release or the dosage form such as slow release or controlled release, powder ampoule agent for injection (comprises Injectable sterile fill powder, lyophilized injectable powder), aqueous solution injection, injection can also be with glucose, sodium chloride, fructose, Nulomoline, xylitol or maltose etc. use the aqueous solution of (comprising intravenous injection and intravenous drip) as the intravenous injection of osmotic pressure regulator.Also can be the dosage form such as rapid release, slow release, controlled release of above various dosage form, such as oral dispersible tablet, slow releasing tablet, slow releasing capsule, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets, effervescent granule, etc.Especially, by means known in the art preparation, be preferred for preparing tablet (comprising dispersible tablet, slow-release tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets), capsule (comprising gastric solubleness, enteric, slow releasing capsule), oral solution, injection (comprising powder ampoule agent for injection and injection) etc. that pharmaceutics uses.

On the other hand, present invention also offers the medicinal application of ticagrelor and Equations of The Second Kind therapeutic agent, ticagrelor and Equations of The Second Kind therapeutic agent synergism, can observe in certain quality ratio range.

The pharmaceutical composition of ticagrelor of the present invention and Equations of The Second Kind therapeutic agent, be used for the treatment of or prevent cardiovascular and cerebrovascular disease, and reducing the application that the risk that myocardial infarction, apoplexy or cardiovascular disease cause occurs, especially, for suppressing or reversing arterial vascular medicated porridge sample Lipid Plaque.

In addition, said composition has antiplatelet aggregative activity, also may be used for the application prepared prevention or treat in the disease relevant with platelet aggregation and atherosclerotic medicine; And for prevention or treatment platelet aggregation disorder; For prevention or treatment acute coronary syndrome (unstable angina pectoris, non-ST elevation acute myocardial infraction or ST section Elevation Myocardial Infarction) patient, comprise and accept Drug therapy and percutaneous coronary and get involved the patient that (PCI) treat, reduce the incidence rate of thrombotic cardiovascular event; For prevention or treatment myocardial infarction, thrombosis apoplexy, transient ischemic attack and/or peripheral blood vessel; For preventing or treating unstable or Stable angina pectorsis; For prevention and therapy artery thrombosis complication.

Have now found that, when ticagrelor and Equations of The Second Kind therapeutic combination use, it demonstrates unexpected advantage, and especially this drug regimen demonstrates outstanding, beyond thought in the effect suppressed or reverse in arterial vascular medicated porridge sample Lipid Plaque.Preferably, the pharmaceutical composition of ticagrelor of the present invention and Equations of The Second Kind therapeutic agent, such as, for suppressing or reversing arterial vascular medicated porridge sample Lipid Plaque, coronary artery, or carotid artery, or peripheral arterial, etc.

The compositions of ticagrelor of the present invention and Equations of The Second Kind therapeutic agent is preparing the application in the medicine suppressing or reverse arterial vascular medicated porridge sample Lipid Plaque; The compositions of preferred ticagrelor and Equations of The Second Kind therapeutic agent is preparing the application in the medicine suppressing or reverse medicated porridge sample Lipid Plaque coronarius; Also preferably the compositions of ticagrelor and Equations of The Second Kind therapeutic agent is preparing the application in the medicine suppressing or reverse carotid medicated porridge sample Lipid Plaque.

Atherosclerosis is the basis causing a series of heart, cerebrovascular, medicated porridge sample Lipid Plaque coronarius is that the damage of coronary blood tube wall, the visible component in blood vessel caused due to multiple risk factors occurs to assemble the medicated porridge sample formed, the calm structure of crumby lipid, medicated porridge sample Lipid Plaque coronarius is the main cause causing myocardial infarction, angina pectoris, myocardial ischemia, and hazardness is very big; Carotid medicated porridge sample Lipid Plaque is that the damage of carotid artery vascular wall, the visible component in blood vessel caused due to multiple risk factors occurs to assemble the medicated porridge sample formed, the calm structure of crumby lipid, carotid medicated porridge sample Lipid Plaque is the main cause causing cerebral embolism event and cerebrum ischemia, and hazardness is huge equally.In addition, especially, the compositions of ticagrelor and troxerutin, not only has pharmacology synergism, and troxerutin has reduction capillary permeability, can prevent the bleeding that ticagrelor may cause.

detailed description of the inventionshould be appreciated that in implementation process of the present invention, those of ordinary skill in the art are not departing from the scope of the present invention various embodiment that the basis with spirit produces and are modifying apparent and be easily carry out.By the following examples the present composition done and illustrate further, but do not represent embodiment limitation of the present invention.

The combined tablet-preparation of embodiment 1. ticagrelor and troxerutin and preparation thereof

Prescription:

Ticagrelor 90g

Troxerutin 150g

Mannitol 180g

Calcium hydrogen phosphate 85g

Carboxymethyl starch sodium 18g

2.5% hydroxypropyl cellulose aqueous solution is appropriate

Magnesium stearate 5g

Preparation method one: ticagrelor, troxerutin, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.After taking by recipe quantity, first ticagrelor and troxerutin to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then mix homogeneously with mannitol, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 150mg troxerutin, obtain.

Preparation method two: ticagrelor, troxerutin, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.First 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with 90g mannitol, add ticagrelor mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 8g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with 90g mannitol, add troxerutin mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 150mg troxerutin.The mass ratio of ticagrelor and troxerutin is 0.6:1.

The combined tablet-preparation of embodiment 2. ticagrelor and cinnarizine and preparation thereof

Prescription:

Ticagrelor 90g

Cinnarizine 50g

Mannitol 160g

Calcium hydrogen phosphate 85g

Carboxymethyl starch sodium 18g

2.5% hydroxypropyl cellulose aqueous solution is appropriate

Magnesium stearate 5g

Preparation method one: ticagrelor, cinnarizine, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.After taking by recipe quantity, first ticagrelor and cinnarizine to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then mix homogeneously with mannitol, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 50mg cinnarizine, obtain.

Preparation method two: ticagrelor, cinnarizine, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.First 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, add ticagrelor mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 8g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, add cinnarizine mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 50mg cinnarizine, to obtain final product.The mass ratio of ticagrelor and cinnarizine is 1.8:1.

The combined tablet-preparation of embodiment 3. ticagrelor and flunarizine hydrochloride and preparation thereof

Prescription:

Ticagrelor 90g

Flunarizine hydrochloride 10g

Mannitol 110g

Calcium hydrogen phosphate 85g

Carboxymethyl starch sodium 15g

2.5% hydroxypropyl cellulose aqueous solution is appropriate

Magnesium stearate 5g

Preparation method one: ticagrelor, flunarizine hydrochloride, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.After taking by recipe quantity, first ticagrelor and flunarizine hydrochloride to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then mix homogeneously with mannitol, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 50mg flunarizine hydrochloride, obtain.

Preparation method two: ticagrelor, flunarizine hydrochloride, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.First 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, add ticagrelor mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 5g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with 30g mannitol, add flunarizine hydrochloride mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 50mg flunarizine hydrochloride, to obtain final product.The mass ratio of ticagrelor and flunarizine hydrochloride is 9:1.

The combined tablet-preparation of embodiment 4. ticagrelor and ligustrazine hydrochloride and preparation thereof

Prescription:

Ticagrelor 90g

Ligustrazine hydrochloride 100g

Mannitol 80g

Microcrystalline Cellulose 80g

Calcium hydrogen phosphate 85g

Carboxymethyl starch sodium 18g

2.5% hydroxypropyl cellulose aqueous solution is appropriate

Magnesium stearate 5g

Preparation method one: ticagrelor, ligustrazine hydrochloride, mannitol, microcrystalline Cellulose, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.After taking by recipe quantity, first ticagrelor and ligustrazine hydrochloride to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then with mannitol, microcrystalline Cellulose mix homogeneously, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 100mg ligustrazine hydrochloride, obtain.

Preparation method two: ticagrelor, ligustrazine hydrochloride, mannitol, microcrystalline Cellulose, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.First 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with mannitol, then add ticagrelor mix homogeneously, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves and granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 8g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with microcrystalline Cellulose, add ligustrazine hydrochloride mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 100mg ligustrazine hydrochloride, to obtain final product.The mass ratio of ticagrelor and ligustrazine hydrochloride is 0.9:1.

The combined tablet-preparation of embodiment 5. ticagrelor and ligustrazine phosphate and preparation thereof

Prescription:

Ticagrelor 90g

Ligustrazine phosphate 80g

Mannitol 80g

Microcrystalline Cellulose 80g

Calcium hydrogen phosphate 85g

Carboxymethyl starch sodium 18g

2.5% hydroxypropyl cellulose aqueous solution is appropriate

Magnesium stearate 5g

Preparation method one: ticagrelor, ligustrazine phosphate, mannitol, microcrystalline Cellulose, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.After taking by recipe quantity, first ticagrelor and ligustrazine phosphate to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then with mannitol, microcrystalline Cellulose mix homogeneously, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 80mg ligustrazine phosphate, obtain.

Preparation method two: ticagrelor, ligustrazine phosphate, mannitol, microcrystalline Cellulose, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.First 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with mannitol, then add ticagrelor mix homogeneously, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves and granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 8g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with microcrystalline Cellulose, add ligustrazine phosphate mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 80mg ligustrazine phosphate, to obtain final product.The mass ratio of ticagrelor and ligustrazine phosphate is 1.12:1.

The combined tablet-preparation of embodiment 6. ticagrelor and sodium ferulate and preparation thereof

Prescription:

Ticagrelor 90g

Sodium ferulate 100g

Mannitol 160g

Calcium hydrogen phosphate 85g

Carboxymethyl starch sodium 18g

2.5% hydroxypropyl cellulose aqueous solution is appropriate

Magnesium stearate 5g

Preparation method one: ticagrelor, sodium ferulate, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.After taking by recipe quantity, first ticagrelor and sodium ferulate to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then mix homogeneously with mannitol, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 100mg sodium ferulate, obtain.

Preparation method two: ticagrelor, sodium ferulate, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.First 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, add ticagrelor mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 8g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, add sodium ferulate mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 100mg sodium ferulate, to obtain final product.The mass ratio of ticagrelor and sodium ferulate is 0.9:1.

The combined tablet-preparation of embodiment 7. ticagrelor and piperazine ferulate and preparation thereof

Prescription:

Ticagrelor 90g

Piperazine ferulate 150g

Mannitol 160g

Calcium hydrogen phosphate 85g

Carboxymethyl starch sodium 18g

2.5% hydroxypropyl cellulose aqueous solution is appropriate

Magnesium stearate 5g

Preparation method one: ticagrelor, piperazine ferulate, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.After taking by recipe quantity, first ticagrelor and piperazine ferulate to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then mix homogeneously with mannitol, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 150mg piperazine ferulate, obtain.

Preparation method two: ticagrelor, piperazine ferulate, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.First 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, add ticagrelor mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 8g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, add piperazine ferulate mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 150mg piperazine ferulate, to obtain final product.The mass ratio of ticagrelor and piperazine ferulate is 0.6:1.

The compositions of embodiment 8. ticagrelor of the present invention and Equations of The Second Kind therapeutic agent is in the effect suppressing or reverse aortal medicated porridge sample Lipid Plaque

The atherosis model of application rat aorta compares research.

Method: the method adopting feed high lipid food and vitamin D3 associating modeling, builds the atherosis model of rat aorta, modeling rat is divided at random blank group, model group, ticagrelor administration group, compositions administration group, often organize 8.

Experiment grouping:

(1) blank group: base particle feedstuff feed;

(2) model group: modeling feedstuff (base particle feedstuff+2% Adeps Sus domestica+1% cholesterol);

(3) ticagrelor administration group: modeling feedstuff feed+ticagrelor (20mg/kg);

(4) compositions administration group: modeling feedstuff feed+ticagrelor (20mg/kg)+Equations of The Second Kind therapeutic agent (dosage is determined according to ticagrelor proportioning).

Modeling method: every day 1 time, successive administration 10 weeks, administration group and model group continue feed high lipid food during administration, and gavage gives modeling medicine propylthiouracil to accelerate model formation; Blank group feed normal feedstuff.

The histopathologic examination of Lipid Plaque: after the modeling phase terminates, gets each group of rat aorta vascular specimen, longitudinally cuts open, normal saline flushing, is placed in 10% neutral formalin and fixes.Specimen is application image analysis-e/or determining aortic tunica intima Lipid Plaque area percentage (ratio of Lipid Plaque area and the blood vessel gross area) after Sudan IV dyeing.Result is as following table 1.

Table 1

Conclusion: the compositions of ticagrelor of the present invention and Equations of The Second Kind therapeutic agent is in model of experimental atherosclerosis in rats is formed, can significantly reduce atherosclerotic plaques ratio, relative to ticagrelor administration group, there is highly significant difference, p<0.01.Illustrate that the compositions of ticagrelor of the present invention and Equations of The Second Kind therapeutic agent has the good action significantly suppressing or reverse arterial vascular medicated porridge sample Lipid Plaque; The significant of the risk that causes of myocardial infarction, apoplexy or cardiovascular disease is there is in this for reducing.

The compositions of embodiment 9. ticagrelor of the present invention and Equations of The Second Kind therapeutic agent is in the effect suppressing or reverse carotid medicated porridge sample Lipid Plaque

Build White Rabbit carotid arterial atherosclerosis animal model and compare research.

Method: White Rabbit row rabbit carotid artery stenosis model after high fat high cholesterol diet feeds 1 week makes: 25% urethane presses the anesthesia of 1g/kg auricular vein, aseptically, in center, rabbit throat incision of skin 3 ~ 4cm longitudinal incision, abundant separation appears right common carotid artery and is about 3 ~ 4cm, right common carotid artery be fixed in self-control lucite blood vessel groove, tremulous pulse two ends give rubber band tension blocking blood flow.The in-built normal saline of 10ml syringe, connects 4.5 number sword-shaped needles, is parallel to the puncture of blood vessel y direction and blocks in one end intravasation of blood vessel, blood vessel filling function.The other end No. 4.5 scalp needle puncture intravasations, after normal saline flushing displaces the blood of Endovascular, air displacement goes out Ink vessel transfusing normal saline.Connect the medical stream of nitrogen gas of adjusted good flow 100ml/min, last 5min and cause endothelium dry, inner film injury.Then normal saline displaces the gas of Endovascular, and the rubber band decontroling tremulous pulse two ends blocking blood flow recovers blood flow.Compressing point of puncture 4 ~ 5min hemostasis.Skin suture is also wrapped up.Own control left common carotid artery is left intact, preoperative, postoperative all without antibiotic.The high fat of postoperative continuation is fed 6 weeks, and row pathological examination shows that the right carotid tube wall of damage is all-round and obviously thickens, and luminal stenosis is comparatively obvious, in right carotid atheromatous plaque phase state of progress, is modeling success.Successful for modeling White Rabbit is divided at random model blank group, ticagrelor administration group, compositions administration group, often organizes 8.

Experiment grouping:

(1) the blank group of model: base particle feedstuff feed;

(2) ticagrelor administration group: base particle feedstuff feed+ticagrelor (20mg/kg);

(4) compositions administration group: base particle feedstuff feed+ticagrelor (20mg/kg)+Equations of The Second Kind therapeutic agent (dosage is determined according to ticagrelor proportioning).

Administration group daily 1 time, the continuous feed/administration of each group 12 weeks.

The histopathologic examination of Lipid Plaque: after feed/administration phase terminates, anesthesia is fixing the same, in center, rabbit throat incision of skin 3 ~ 4cm otch, abundant separation appears left and right common carotid artery and is about 3 ~ 4cm, and confirm that right common carotid artery is pathological changes tremulous pulse, cut the total pathological changes tremulous pulse of right neck and be about 2cm, and cut the corresponding left common carotid artery of equal length, rinse vessel inner blood, be placed in 10% formaldehyde and fix.Specimen is application image analysis-e/or determining tunica intima Lipid Plaque area percentage (ratio of Lipid Plaque area and the blood vessel gross area) after Sudan IV dyeing.Result is as following table 2.

Table 2

Conclusion: the compositions of ticagrelor of the present invention and Equations of The Second Kind therapeutic agent is in the animal model of White Rabbit carotid arterial atherosclerosis, significantly can reduce carotid artery Lipid Plaque area ratio, in the left common carotid artery reversing light moderate lipid pathological changes, relative to ticagrelor administration group, there is highly significant difference, p<0.01; In the right common carotid artery reversing severe lipid pathological changes, relative to ticagrelor administration group, also have highly significant difference, p<0.01, both are relative to the blank group of model, p<0.005.Demonstrate pharmaceutical composition of the present invention and reverse the outstanding effect in carotid medicated porridge sample Lipid Plaque.

Pharmaceutical composition application in the following areas in embodiment 10. embodiment 1 to 15 described in any one:

(1) in the application that preparation suppresses or reverses in the medicine of arterial vascular medicated porridge sample Lipid Plaque;

(2) in the application that preparation suppresses or reverses in the medicine of medicated porridge sample Lipid Plaque coronarius;

(3) in the application that preparation suppresses or reverses in the medicine of carotid medicated porridge sample Lipid Plaque;

(4) application in the medicine of the disease that preparation prevents or treatment is relevant with platelet aggregation;

(5) prevent in preparation or treat the application in the medicine of acute coronary syndrome;

(6) application in the medicine of preparation prevention or treatment myocardial infarction, thrombosis apoplexy, transient ischemic attack and/or peripheral blood vessel.

Claims (7)

1. the combined tablet-preparation of ticagrelor and troxerutin, its prescription is:

Ticagrelor 90g,

Troxerutin 150g,

Mannitol 180g,

Calcium hydrogen phosphate 85g,

Carboxymethyl starch sodium 18g,

2.5% hydroxypropyl cellulose aqueous solution is appropriate,

Magnesium stearate 5g;

Its preparation method is: by ticagrelor, troxerutin, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium crosses 100 mesh sieves respectively, after taking by recipe quantity, first ticagrelor and troxerutin to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then mix homogeneously with mannitol, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000,

Or, its preparation method is: ticagrelor, troxerutin, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively, first 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with 90g mannitol, then add ticagrelor mix homogeneously, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 8g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with 90g mannitol, add troxerutin mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, is pressed into 1000.

2. the combined tablet-preparation of ticagrelor and cinnarizine, its prescription is:

Ticagrelor 90g,

Cinnarizine 50g,

Mannitol 160g,

Calcium hydrogen phosphate 85g,

Carboxymethyl starch sodium 18g,

2.5% hydroxypropyl cellulose aqueous solution is appropriate,

Magnesium stearate 5g;

Its preparation method is: by ticagrelor, cinnarizine, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium crosses 100 mesh sieves respectively, after taking by recipe quantity, first ticagrelor and cinnarizine to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then mix homogeneously with mannitol, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000,

Or, its preparation method is: ticagrelor, cinnarizine, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively, first 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, then add ticagrelor mix homogeneously, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 8g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, add cinnarizine mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, is pressed into 1000.

3. the combined tablet-preparation of ticagrelor and flunarizine hydrochloride, its prescription is:

Ticagrelor 90g,

Flunarizine hydrochloride 10g,

Mannitol 110g,

Calcium hydrogen phosphate 85g,

Carboxymethyl starch sodium 15g,

2.5% hydroxypropyl cellulose aqueous solution is appropriate,

Magnesium stearate 5g;

Its preparation method is: by ticagrelor, flunarizine hydrochloride, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium crosses 100 mesh sieves respectively, after taking by recipe quantity, first ticagrelor and flunarizine hydrochloride to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then mix homogeneously with mannitol, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000,

Or, its preparation method is: ticagrelor, flunarizine hydrochloride, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively, first 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, then add ticagrelor mix homogeneously, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 5g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with 30g mannitol, add flunarizine hydrochloride mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, is pressed into 1000.

4. the combined tablet-preparation of ticagrelor and ligustrazine hydrochloride, its prescription is:

Ticagrelor 90g,

Ligustrazine hydrochloride 100g,

Mannitol 80g,

Microcrystalline Cellulose 80g,

Calcium hydrogen phosphate 85g,

Carboxymethyl starch sodium 18g,

2.5% hydroxypropyl cellulose aqueous solution is appropriate,

Magnesium stearate 5g;

Its preparation method is: by ticagrelor, ligustrazine hydrochloride, mannitol, microcrystalline Cellulose, calcium hydrogen phosphate, carboxymethyl starch sodium crosses 100 mesh sieves respectively, after taking by recipe quantity, first ticagrelor and ligustrazine hydrochloride to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then with mannitol, microcrystalline Cellulose mix homogeneously, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000,

Or, its preparation method is: ticagrelor, ligustrazine hydrochloride, mannitol, microcrystalline Cellulose, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively, first 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with mannitol, then add ticagrelor mix homogeneously, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 8g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with microcrystalline Cellulose, add ligustrazine hydrochloride mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, is pressed into 1000.

5. the combined tablet-preparation of ticagrelor and ligustrazine phosphate, its prescription is:

Ticagrelor 90g,

Ligustrazine phosphate 80g,

Mannitol 80g,

Microcrystalline Cellulose 80g,

Calcium hydrogen phosphate 85g,

Carboxymethyl starch sodium 18g,

2.5% hydroxypropyl cellulose aqueous solution is appropriate,

Magnesium stearate 5g;

Its preparation method is: by ticagrelor, ligustrazine phosphate, mannitol, microcrystalline Cellulose, calcium hydrogen phosphate, carboxymethyl starch sodium crosses 100 mesh sieves respectively, after taking by recipe quantity, first ticagrelor and ligustrazine phosphate to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then with mannitol, microcrystalline Cellulose mix homogeneously, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000,

Or, its preparation method is: ticagrelor, ligustrazine phosphate, mannitol, microcrystalline Cellulose, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively, first 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with mannitol, then add ticagrelor mix homogeneously, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 8g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with microcrystalline Cellulose, add ligustrazine phosphate mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, is pressed into 1000.

6. the combined tablet-preparation of ticagrelor and sodium ferulate, its prescription is:

Ticagrelor 90g,

Sodium ferulate 100g,

Mannitol 160g,

Calcium hydrogen phosphate 85g,

Carboxymethyl starch sodium 18g,

2.5% hydroxypropyl cellulose aqueous solution is appropriate,

Magnesium stearate 5g;

Its preparation method is: by ticagrelor, sodium ferulate, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium crosses 100 mesh sieves respectively, after taking by recipe quantity, first ticagrelor and sodium ferulate to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then mix homogeneously with mannitol, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000,

Or, its preparation method is: ticagrelor, sodium ferulate, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively, first 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, then add ticagrelor mix homogeneously, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 8g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, add sodium ferulate mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, is pressed into 1000.

7. the combined tablet-preparation of ticagrelor and piperazine ferulate, its prescription is:

Ticagrelor 90g,

Piperazine ferulate 150g,

Mannitol 160g,

Calcium hydrogen phosphate 85g,

Carboxymethyl starch sodium 18g,

2.5% hydroxypropyl cellulose aqueous solution is appropriate,

Magnesium stearate 5g;

Its preparation method is: by ticagrelor, piperazine ferulate, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium crosses 100 mesh sieves respectively, after taking by recipe quantity, first ticagrelor and piperazine ferulate to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by, separately carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with calcium hydrogen phosphate, then mix homogeneously with mannitol, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, be pressed into 1000,

Or, its preparation method is: ticagrelor, piperazine ferulate, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively, first 10g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 55g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, then add ticagrelor mix homogeneously, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain A granule; In addition 8g carboxymethyl starch sodium is mixed homogeneously by the equivalent method of progressively increasing with 30g calcium hydrogen phosphate, then mix homogeneously with 80g mannitol, add piperazine ferulate mix homogeneously again, add 2.5% hydroxypropyl cellulose aqueous solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain B granule; Then by A granule and B granule mix homogeneously, add magnesium stearate, mixing, is pressed into 1000.