CN103735552B - Pharmaceutical composition of ticagrelor and cilostazol and its preparation method and application - Google Patents
Pharmaceutical composition of ticagrelor and cilostazol and its preparation method and application Download PDFInfo
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- CN103735552B CN103735552B CN201410011807.5A CN201410011807A CN103735552B CN 103735552 B CN103735552 B CN 103735552B CN 201410011807 A CN201410011807 A CN 201410011807A CN 103735552 B CN103735552 B CN 103735552B
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- Prior art keywords
- ticagrelor
- cilostazol
- preparation
- mannitol
- carboxymethyl starch
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- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 title claims abstract description 124
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Landscapes
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Abstract
The present invention relates to the pharmaceutical composition of ticagrelor and cilostazol, said composition has the effect suppressing or reverse arterial vascular medicated porridge sample Lipid Plaque, especially in the effect suppressing or reverse coronary artery or carotid medicated porridge sample Lipid Plaque, and the preparation method of described pharmaceutical composition, the invention still further relates to the application of aforementioned pharmaceutical compositions in medicine; Said composition effectively can solve and miss ticagrelor and the drug effect " vacuum phase " produced sporadicly, reduce contingent cardiocerebrovasculaevents events, in addition, significantly can also reduce the degree of gastrointestinal hemorrhage, be far smaller than combinationally using of ticagrelor and aspirin.
Description
Technical field
The invention belongs to medical art, relate to the pharmaceutical composition for the treatment of or preventing, it comprises ticagrelor and cilostazol, 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:
。
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, this point is different from clinical widely used chlorine pyrroles thunder, 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.The oral each 90mg of ticagrelor, every day 2 times, usually suggestion and aspirin combination medication.
The ticagrelor half-life is 7 hours only, must take medicine every day 2 times, and this patient not good to compliance is a kind of challenge.Patient is unlikely after all observes this administering mode completely, such as, according to estimates, accept in the patient of Effect of Clopidogrel in Treating, about 20% does not adhere to dosage regimen completely, and these patients also can not use in strict accordance with prescribed dose when using ticagrelor, for the ticagrelor that can reverse fast, missing medicine probably makes patient very soon myocardial infarction and apoplexy occur, even if ticagrelor and aspirin combination medication, but the half-life of aspirin only has 15-20 minute, the drug effect of aspirin cannot make up the anticoagulant effect caused because missing medicine and to decline the risk brought.When using ticagrelor medicine, for patient's occasionality to disobey dosage regimen and potential treatment danger be ticagrelor that maximum use is worried, in addition, long-time, single use ticagrelor, also may there is uncertainty in its curative effect.
Summary of the invention
The object of this invention is to provide a kind of pharmaceutical composition containing ticagrelor and cilostazol, described ticagrelor 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 cilostazol, 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 cilostazol 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 cilostazol 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 cilostazol, 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 cilostazol are independent preparations, both pharmaceutical dosage forms can be identical, also can be different, as ticagrelor sheet and cilostazol tablet medicament composition, ticagrelor capsule and cilostazol capsule pharmaceutical composition, ticagrelor sheet and cilostazol capsule pharmaceutical composition, ticagrelor capsule and cilostazol tablet medicament composition, 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.No matter simultaneously or administration in turn it is also understood that, ticagrelor and cilostazol can with independent or any combining form administrations, preferably by ticagrelor and cilostazol administration simultaneously 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 cilostazol 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 cilostazol to exist with the ratio of synergistic drug dose combines.
The ratio of the synergistic drug dose that ticagrelor and cilostazol combine, such as mass ratio is (0.2 ~ 5): 1, described ticagrelor also comprises its pharmaceutically acceptable salt or solvate, show when in compositions, ticagrelor generally can adopt it to be used alone with the consumption of cilostazol 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 cilostazol giving effective dose.
Preferably, the pharmaceutical composition of ticagrelor and cilostazol, wherein contain 80 ~ 200mg ticagrelor and 30 ~ 250mg cilostazol in preferred per unit preparation, such as, containing 80 ~ 100mg ticagrelor and 30 ~ 150mg cilostazol in per unit preparation, concrete, containing 90mg ticagrelor and 50mg cilostazol in per unit preparation, or containing 90mg ticagrelor and 60mg cilostazol in per unit preparation, or containing 90mg ticagrelor and 70mg cilostazol in per unit preparation, or containing 90mg ticagrelor and 80mg cilostazol in per unit preparation, or containing 90mg ticagrelor and 90mg cilostazol in per unit preparation, or containing 90mg ticagrelor and 100mg cilostazol in per unit preparation, or containing 90mg ticagrelor and 110mg cilostazol in per unit preparation, or containing 80mg ticagrelor and 80mg cilostazol in per unit preparation, or containing 80mg ticagrelor and 90mg cilostazol in per unit preparation, or containing 180mg ticagrelor and 180mg cilostazol in per unit preparation, or containing 180mg ticagrelor and 200mg cilostazol in per unit preparation, or containing 180mg ticagrelor and 120mg cilostazol 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 cilostazol, 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 cilostazol or the wherein drug regimen of each component of ticagrelor and cilostazol.
Preferably, the combination of ticagrelor and cilostazol is generally the Pharmaceutical composition with one or more pharmaceutically acceptable carriers of unit dosage form, the ticagrelor contained in conventional unit formulation and the dosage of cilostazol 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 cilostazol, ticagrelor can be different on medicament releasing pattern from the chemical composition of cilostazol, such as ticagrelor can the form of slow release or controlled release occur, and cilostazol also can the form of slow release or controlled release occur, to improve the not synergism of the blood drug level that ticagrelor and the time difference of cilostazol 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 cilostazol combinationally use, it demonstrates unexpected advantage, and especially this drug regimen demonstrates outstanding, the beyond thought effect suppressing or reverse arterial vascular medicated porridge sample Lipid Plaque.Preferably, the pharmaceutical composition of ticagrelor of the present invention and cilostazol, 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 cilostazol, wherein said ticagrelor also comprises its pharmaceutically acceptable salt or solvate, and described cilostazol 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 cilostazol, 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 cilostazol, it comprises ticagrelor and described cilostazol and pharmaceutically acceptable pharmaceutical carrier is mixed and made into acceptable any pharmaceutical preparation on pharmaceutics, such as ticagrelor and cilostazol 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 cilostazol, it comprises ticagrelor and described cilostazol 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 cilostazol, ticagrelor and cilostazol synergism, can observe in certain quality ratio range.
The pharmaceutical composition of ticagrelor of the present invention and cilostazol, 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 cilostazol combinationally use, it demonstrates unexpected advantage, and especially this drug regimen demonstrates outstanding, the beyond thought effect suppressing or reverse arterial vascular medicated porridge sample Lipid Plaque.Preferably, the pharmaceutical composition of ticagrelor of the present invention and cilostazol, 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 cilostazol is preparing the application in the medicine suppressing or reverse arterial vascular medicated porridge sample Lipid Plaque; The compositions of preferred ticagrelor and cilostazol is preparing the application in the medicine suppressing or reverse medicated porridge sample Lipid Plaque coronarius; Also preferably the compositions of ticagrelor and cilostazol 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.
The ticagrelor half-life is 7 hours only, must take medicine every day 2 times, and this patient not good to compliance is a kind of challenge.Patient is unlikely after all observes this administering mode completely, such as, according to estimates, accept in the patient of Effect of Clopidogrel in Treating, about 20% does not adhere to dosage regimen completely, and these patients also can not use in strict accordance with prescribed dose when using ticagrelor, for the ticagrelor that can reverse fast, drug effect " vacuum phase " can be formed, missing medicine probably makes patient very soon myocardial infarction and apoplexy occur, even if ticagrelor and aspirin combination medication, but the half-life of aspirin only has 15-20 minute, the drug effect of aspirin cannot make up the anticoagulant effect caused because missing medicine and to decline the risk brought.But, the composition of medicine of ticagrelor and cilostazol, the drug effect of cilostazol in vivo the persistent period longer, duration of efficacy is more than 30 times of aspirin, effectively can solve and miss ticagrelor and the drug effect " vacuum phase " produced sporadicly, reduce contingent cardiocerebrovasculaevents events.
In addition, inventor finds, combinationally using of ticagrelor and cilostazol, significantly can reduce the degree of gastrointestinal hemorrhage, is far smaller than combinationally using of ticagrelor and aspirin, demonstrates beyond thought creativeness.
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 cilostazol and preparation thereof
Prescription:
Ticagrelor 90g
Cilostazol 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, cilostazol, mannitol, calcium hydrogen phosphate, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.After taking by recipe quantity, first by ticagrelor and cilostazol mix homogeneously, 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 and granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add the magnesium stearate of recipe quantity, mixing, is pressed into 1000, every sheet contains 90mg ticagrelor and 50mg cilostazol, to obtain final product.
Preparation method two: ticagrelor, cilostazol, 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 cilostazol 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 cilostazol.The mass ratio of ticagrelor and cilostazol is 1.8:1.
The combined tablet-preparation of embodiment 2. ticagrelor and cilostazol and preparation thereof
Prescription:
Ticagrelor 90g
Cilostazol 60g
Hydroxypropyl emthylcellulose (K
4M) 380g
Mannitol 40g
Microcrystalline Cellulose 30g
80% ethanol water is appropriate
Carboxymethyl starch sodium 6g
Magnesium stearate 4g
8% aqueous povidone solution is appropriate
Preparation method: ticagrelor, cilostazol, hydroxypropyl emthylcellulose, mannitol, microcrystalline Cellulose, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.First by after ticagrelor, cilostazol, hydroxypropyl emthylcellulose, mannitol, microcrystalline Cellulose mix homogeneously, soft material is made with 80% ethanol water, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain granule, after adding carboxymethyl starch sodium mix homogeneously, add 8% aqueous povidone solution and make soft material, cross 24 mesh sieves to granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add magnesium stearate, mixing, be pressed into 1000, every sheet contains 90mg ticagrelor and 60mg cilostazol, to obtain final product.The mass ratio of ticagrelor and cilostazol is 1.5:1.
In the combined tablet-preparation of this ticagrelor and cilostazol, hydroxypropyl emthylcellulose is hydrophilic polymer, as framework material in said preparation, meet water or Digestive system expansion formation gel barrier, control ticagrelor, slow released cilostazol diffusion, to play the effect of slow release, this tablet can every day once oral, the dosage of each 2.
The combined tablet-preparation of embodiment 3. ticagrelor and cilostazol and preparation thereof
Prescription:
Ticagrelor 90g
Cilostazol 80g
Mannitol 160g
Calcium hydrogen phosphate 85g
Carboxymethyl starch sodium 18g
2.5% hydroxypropyl cellulose aqueous solution is appropriate
Magnesium stearate 5g
Preparation method: with embodiment 1.The mass ratio of ticagrelor and cilostazol is 1.125:1.
The combined tablet-preparation of embodiment 4. ticagrelor and cilostazol and preparation thereof
Prescription:
Ticagrelor 90g
Cilostazol 90g
Mannitol 160g
Calcium hydrogen phosphate 85g
Carboxymethyl starch sodium 18g
2.5% hydroxypropyl cellulose aqueous solution is appropriate
Magnesium stearate 5g
Preparation method: with embodiment 1.The mass ratio of ticagrelor and cilostazol is 1:1.
The combined tablet-preparation of embodiment 5. ticagrelor and cilostazol and preparation thereof
Prescription:
Ticagrelor 90g
Cilostazol 100g
Mannitol 160g
Calcium hydrogen phosphate 85g
Carboxymethyl starch sodium 18g
2.5% hydroxypropyl cellulose aqueous solution is appropriate
Magnesium stearate 5g
Preparation method: with embodiment 1.The mass ratio of ticagrelor and cilostazol is 0.9:1.
The combined tablet-preparation of embodiment 6. ticagrelor and cilostazol and preparation thereof
Prescription:
Ticagrelor 80g
Cilostazol 80g
Mannitol 160g
Calcium hydrogen phosphate 85g
Carboxymethyl starch sodium 18g
2.5% hydroxypropyl cellulose aqueous solution is appropriate
Magnesium stearate 5g
Preparation method: with embodiment 1.The mass ratio of ticagrelor and cilostazol is 1:1.
The combined tablet-preparation of embodiment 7. ticagrelor and cilostazol and preparation thereof
Prescription:
Ticagrelor 80g
Cilostazol 100g
Mannitol 160g
Calcium hydrogen phosphate 85g
Carboxymethyl starch sodium 18g
2.5% hydroxypropyl cellulose aqueous solution is appropriate
Magnesium stearate 5g
Preparation method: with embodiment 1.The mass ratio of ticagrelor and cilostazol is 0.8:1.
The assembly adhesive wafer of embodiment 8. ticagrelor and cilostazol and preparation thereof
Prescription:
Ticagrelor 80g
Cilostazol 50g
Mannitol 75g
Pregelatinized Starch 100g
Carboxymethyl starch sodium 10g
Magnesium stearate 3.5g
70% alcoholic solution of 3% polyvinylpyrrolidone is appropriate
Preparation method 1: ticagrelor, cilostazol, mannitol, pregelatinized Starch, carboxymethyl starch sodium are crossed 100 mesh sieves respectively.After taking by recipe quantity, first ticagrelor and cilostazol to be progressively increased method mix homogeneously by equivalent, obtain A mixed-powder, stand-by; Separately carboxymethyl starch sodium is mixed homogeneously with the mannitol equivalent method of progressively increasing, then mix homogeneously with pregelatinized Starch, obtain B mixed-powder, then A mixed-powder is mixed homogeneously with B mixed-powder, 70% alcoholic solution adding aqueous solution 3% polyvinylpyrrolidone makes soft material, cross 20 mesh sieves to granulate, 60 DEG C of oven dry, dry granule crosses 18 mesh sieve granulate, add magnesium stearate mix homogeneously, be filled to 1000 capsules, every capsules contains 80mg ticagrelor and 50mg cilostazol, to obtain final product.
Preparation method 2: adopt dry granulation, replaces its alcoholic solution in prescription with polyvinylpyrrolidone pressed powder.Ticagrelor, cilostazol, mannitol, pregelatinized Starch, carboxymethyl starch sodium, polyvinylpyrrolidone are crossed 100 mesh sieves respectively.After taking by recipe quantity, polyvinylpyrrolidone, carboxymethyl starch sodium are mixed homogeneously with the mannitol equivalent method of progressively increasing; then mix homogeneously with pregelatinized Starch; add the ticagrelor of mix homogeneously and the powder of cilostazol in advance again; mix homogeneously, adopts dry granulating machine to granulate, crosses 20 mesh sieve granulate; add magnesium stearate mix homogeneously; be filled to 1000 capsules, every capsules contains 80mg ticagrelor and 50mg cilostazol, to obtain final product.The mass ratio of ticagrelor and cilostazol is 1.6:1.
The compositions of embodiment 9. ticagrelor of the present invention and cilostazol 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)+cilostazol (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 cilostazol, in model of experimental atherosclerosis in rats is formed, can significantly reduce atherosclerotic plaques ratio, relative to ticagrelor administration group, has highly significant difference, p<0.01.Illustrate that the compositions of ticagrelor of the present invention and cilostazol 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 10. ticagrelor of the present invention and cilostazol 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)+cilostazol (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 cilostazol 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 11. embodiment 1 to 8 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 (2)
1. a combined tablet-preparation for ticagrelor and cilostazol, its prescription:
Ticagrelor 90g,
Cilostazol 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: by ticagrelor, cilostazol, mannitol, calcium hydrogen phosphate, after carboxymethyl starch sodium crosses 100 mesh sieves respectively, first by ticagrelor and cilostazol mix homogeneously, 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: ticagrelor, cilostazol, 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 cilostazol 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. a combined tablet-preparation for ticagrelor and cilostazol, its prescription:
Ticagrelor 90g,
Cilostazol 60g,
Hydroxypropyl emthylcellulose K
4M380g,
Mannitol 40g,
Microcrystalline Cellulose 30g,
80% ethanol water is appropriate,
Carboxymethyl starch sodium 6g,
Magnesium stearate 4g,
8% aqueous povidone solution is appropriate;
Its preparation method: by ticagrelor, cilostazol, hydroxypropyl emthylcellulose K
4M, mannitol, microcrystalline Cellulose, carboxymethyl starch sodium respectively cross 100 mesh sieves, first by ticagrelor, cilostazol, hydroxypropyl emthylcellulose K
4M, mannitol, after microcrystalline Cellulose mix homogeneously, make soft material with 80% ethanol water, cross 24 mesh sieves and granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, obtain granule, after adding carboxymethyl starch sodium mix homogeneously, add 8% aqueous povidone solution and make soft material, cross 24 mesh sieves and granulate, after 60 DEG C of dryings, 20 mesh sieve granulate, add magnesium stearate, mixing, is pressed into 1000.
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Non-Patent Citations (2)
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| Treatment options for patients with poor clopidogrel response;Roberts DI, et al;《Cardiol Rev.》;20131231;第21卷(第6期);309-317 * |
| Triple versus dual antiplatelet therapy in acute coronary syndromes: adding cilostazol to aspirin and clopidogrel?;Niazi AK, et al;《Cardiology》;20131231;第126卷(第4期);233-243 * |
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