CN105919966A - Vorapaxar sulfate preparation and application thereof - Google Patents
Vorapaxar sulfate preparation and application thereof Download PDFInfo
- Publication number
- CN105919966A CN105919966A CN201610405899.4A CN201610405899A CN105919966A CN 105919966 A CN105919966 A CN 105919966A CN 201610405899 A CN201610405899 A CN 201610405899A CN 105919966 A CN105919966 A CN 105919966A
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- CN
- China
- Prior art keywords
- sulphuric acid
- purposes
- acid walla
- sand
- content
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
The invention discloses a vorapaxar sulfate preparation and an application thereof. The vorapaxar sulfate preparation is prepared from vorapaxar sulfate, lactose, microcrystalline cellulose and a pharmaceutically acceptable carrier. The obtained vorapaxar sulfate preparation is relatively high in flowability, stability and dissolubility, so as to be suitable for industrial production. The medicinal composition for antithrombosis is reasonable in proportion, and medicaments can be rapidly released to achieve good curative effects on symptoms.
Description
Technical field
The present invention relates to sulphuric acid Walla handkerchief husky for preparing the purposes of medicine, be suitable to tablet and the capsule being administered orally in particular for preparation.
Sulphuric acid Walla handkerchief is husky (vorapaxar sulfate), molecular formula: C29H35FN2O8S, molecular weight: 590.66
For anticoagulant, three kind new medicines, currently carry out preclinical study.
Background technology
May 8 in 2014 Mo Shadong anticoagulant Zontivity(vorapaxar) obtain FDA approval, the patient of blocking is had, to reduce further heart attack, apoplexy, cardiovascular death and the risk of needs operation for the patient being had a heart attack or leg arteries.Vorapaxar is the proteinase activated receptors 1(PAR-1 of a kind of pioneering (first-in-class)) antagonist is a kind of anti-platelet agent, it is intended to reduce platelet aggregation tendency, the formation of suppression blood clotting grumeleuse.
Vorapaxar is a kind of Novel protease activated receptor 1(PAR-1) antagonist, can anticoagulant process.PAR-1 be a kind of can be by the receptor of thrombin activation, and thrombin is a kind of effective platelet activating agent.Vorapaxar can suppress PAR-1 receptor in platelet, thus the platelet aggregation of enzyme induction anticoagulant.
Antithrombotic reagent, including anticoagulant, antiplatelet drug and direct thrombolytic drug, is used equally to the treatment of thrombotic prevention or acute stage.Anticoagulation market is anticipated will increase to 9,000,000,000 dollars of 2014 from about 6,000,000,000 dollars of 2008.The reason of market dilatation includes aging and the increase of cardiovascular disease incidence rate of population, but mainly due to the listing of new drug, this will be substantially improved present treatment situation.Significant impact will be brought in the stroke prevention market that atrial fibrillation is relevant by oral anticoagulation, and warfarin may be along with the listing of new drug be gradually by market.
Summary of the invention
The present invention relates to the pharmaceutical composition husky containing sulphuric acid Walla handkerchief and this based composition is antithrombotic reagent.
The invention still further relates to the pharmaceutical composition containing the husky oral administration with other drug active substance of sulphuric acid Walla handkerchief.Said composition is to be obtained by the surface making the granule of pharmaceutically active substance adhere to carrier matrix.It is minimum in order to make the gathering of active substance/carrier substrate particles be reduced to for making the calm method on carrier matrix of pharmaceutically active substance.
The present invention relates to the pharmaceutical composition husky containing about 0.1mg--30 mg sulphuric acid Walla handkerchief, said composition is given daily three times for antithrombotic reagent.Preferably pharmaceutical composition contains the sulphuric acid Walla handkerchief sand of about 0.1mg--20 mg, and the sulphuric acid Walla handkerchief that most preferred pharmaceutical composition contains about 1mg--10 mg is husky.Further, this kind of preferred and most preferred pharmaceutical composition is given daily three times for antithrombotic.
Above-mentioned sulphuric acid Walla handkerchief sand pharmaceutical composition for being given daily also can be the most regular some patient is administered.Such as, to by daily sulphuric acid Walla handkerchief sand pharmaceutical composition carry out antithrombotic obtain control patient can implement maintaining treatment scheme to protect it from further infecting.This maintaining treatment scheme include every day not enough once take sulphuric acid Walla handkerchief sand pharmaceutical composition.Such as, just within every three or four days, being administered once, it is enough.
The sulphuric acid Walla handkerchief sand pharmaceutical composition of the present invention can be configured to the form through any suitable administration, and such as preferably oral administration combination can be tablet, capsule, granule or powder type.According to method well known in the art, sulphuric acid Walla handkerchief sand pharmaceutical composition can be to be configured to the form that parenteral, rectum or via intranasal application are administered.This kind of preparation can include that pharmaceutically acceptable excipient, described excipient include in this based composition conventional filler, fluidizer, lubricant, disintegrating agent, binding agent etc..Present invention additionally comprises slow releasing preparation.
The tablet husky containing about 1mg 10mg sulphuric acid Walla handkerchief and capsule preparations can be prepared, by the following method to guarantee the efficient of product and good uniformity.First handkerchief sand calmness in sulphuric acid Walla is prepared compositions on the surface of carrier matrix.This step is completed by following operation: forms the husky solution with adhesive material of sulphuric acid Walla handkerchief, then applies this solution in the way of spraying while carrier substrate particles keeps motion.Control condition is so that the gathering of granule is preferably minimized.
Any other composition that will comprise in granule and compositions after drying, such as disintegrating agent/fluidizer/mix lubricant.Then the powder obtained it is pressed into sheet or is filled into capsule.
Preferred solvent in said method is the ethanol of water or variable concentrations.
Adhesive material preferably has the polymer of high-consistency.The material being suitable for includes that polyvidone, methylcellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvidone, hydroxymethyl cellulose are preferred.In whole compositions, the content of adhesive material is preferably the about 1%--about 10%(weight of compositions gross weight).
The disintegrant content that whole compositions includes is preferably the about 1%--7% of compositions gross weight.The disintegrating agent being suitable for includes polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose, low-substituted hydroxypropyl methylcellulose, Explotab, pregelatinized Starch and corn starch, and polyvinylpolypyrrolidone is preferred.
The lubricant content that whole compositions includes is preferably the about 1%--5% of compositions gross weight.The lubricant being suitable for includes that micropowder silica gel, magnesium stearate, stearic acid, stearyl fumarate and sodium lauryl sulfate, micropowder silica gel, magnesium stearate are preferred.
Detailed description of the invention
The sulphuric acid Walla handkerchief sand compositions of the following example explanation present invention
Embodiment
1
Said method is used to prepare 1 milligram of sulphuric acid Walla handkerchief sand capsule
Composition | Amount %(w/w) | Amount/grain |
Sulphuric acid Walla handkerchief is husky | 1.08 | 1.0mg |
Microcrystalline Cellulose | 21.51 | 20 mg |
Lactose | 64.52 | 60 mg |
Polyvidone | 5.38 | 5 mg |
Low-substituted hydroxypropyl methylcellulose | 4.30 | 4.0mg |
Magnesium stearate | 1.08 | 1.0mg |
Silicon dioxide | 2.16 | 2.0 mg |
Purified water/ethanol | In right amount | In right amount |
Amount to | 100.00 | 93.00 mg |
Embodiment
2
Said method is used to prepare 2 milligrams of sulphuric acid Walla handkerchief sand capsules
Composition | Amount %(w/w) | Amount/grain |
Sulphuric acid Walla handkerchief is husky | 2.16 | 2.0mg |
Microcrystalline Cellulose | 21.51 | 20 mg |
Lactose | 63.44 | 59 mg |
Polyvidone | 5.38 | 5 mg |
Polyvinylpolypyrrolidone | 4.30 | 4.0mg |
Magnesium stearate | 1.08 | 1.0mg |
Silicon dioxide | 2.16 | 2.0 mg |
Purified water/ethanol | In right amount | In right amount |
Amount to | 100.00 | 93.00 mg |
Embodiment
3
Said method is used to prepare 4 milligrams of sulphuric acid Walla handkerchief sand capsules
Composition | Amount %(w/w) | Amount/piece |
Sulphuric acid Walla handkerchief is husky | 4.30 | 4.0mg |
Microcrystalline Cellulose | 21.51 | 20 mg |
Lactose | 61.29 | 57 mg |
Polyvidone | 5.38 | 5 mg |
Polyvinylpolypyrrolidone | 4.30 | 4.0mg |
Low-substituted hydroxypropyl methylcellulose | 1.08 | 1.0mg |
Magnesium stearate | 2.16 | 2.0 mg |
Purified water | In right amount | In right amount |
Amount to | 100.00 | 93.00 mg |
Embodiment
4
Said method is used to prepare 1 milligram of sulphuric acid Walla handkerchief sand sheet
Composition | Amount %(w/w) | Amount/piece |
Sulphuric acid Walla handkerchief is husky | 1.08 | 1.0mg |
Microcrystalline Cellulose | 21.51 | 20 mg |
Lactose | 64.52 | 60 mg |
Polyvidone | 5.38 | 5 mg |
Low-substituted hydroxypropyl methylcellulose | 4.30 | 4.0mg |
Magnesium stearate | 1.08 | 1.0mg |
Silicon dioxide | 2.16 | 2.0 mg |
Purified water/ethanol | In right amount | In right amount |
Amount to | 100.00 | 93.00 mg |
Embodiment
5
Said method is used to prepare 2 milligrams of sulphuric acid Walla handkerchief sand sheets
Composition | Amount %(w/w) | Amount/piece |
Sulphuric acid Walla handkerchief is husky | 2.16 | 2.0mg |
Microcrystalline Cellulose | 21.51 | 20 mg |
Lactose | 63.44 | 59 mg |
Polyvidone | 5.38 | 5 mg |
Low-substituted hydroxypropyl methylcellulose | 4.30 | 4.0mg |
Magnesium stearate | 1.08 | 1.0mg |
Silicon dioxide | 2.16 | 2.0 mg |
Purified water/ethanol | In right amount | In right amount |
Amount to | 100.00 | 93.00 mg |
Embodiment
6
Said method is used to prepare 4 milligrams of sulphuric acid Walla handkerchief sand sheets
Composition | Amount %(w/w) | Amount/piece |
Sulphuric acid Walla handkerchief is husky | 4.30 | 4.0mg |
Microcrystalline Cellulose | 21.51 | 20 mg |
Lactose | 61.29 | 57 mg |
Polyvidone | 5.38 | 5 mg |
Low-substituted hydroxypropyl methylcellulose | 4.30 | 4.0mg |
Magnesium stearate | 1.08 | 1.0mg |
Silicon dioxide | 2.16 | 2.0 mg |
Purified water/ethanol | In right amount | In right amount |
Amount to | 100.00 | 93.00 mg |
Claims (10)
1. handkerchief sand in sulphuric acid Walla is for preparing oral administration three times a day for the purposes of antithrombotic pharmaceutical composition in the form of tablets or capsules, and the sulphuric acid Walla handkerchief that wherein said pharmaceutical composition contains 0.1mg 30mg is husky.
2. the purposes of claim 1, the content of wherein said sulphuric acid Walla handkerchief sand is 0.1mg 20mg.
3. the purposes of claim 1, the content of wherein said sulphuric acid Walla handkerchief sand is 1mg 10mg.
4. the purposes of claim 3, the content of wherein said sulphuric acid Walla handkerchief sand is 1mg.
5. the purposes of claim 3, the content of wherein said sulphuric acid Walla handkerchief sand is 2mg.
6. the purposes of claim 3, the content of wherein said sulphuric acid Walla handkerchief sand is 4mg.
7. the purposes of claim 3, the content of wherein said sulphuric acid Walla handkerchief sand is 8mg.
8. the purposes of claim 3, the content of wherein said sulphuric acid Walla handkerchief sand is 10mg.
9. the purposes of claim 1, described compositions therein contains one or more other drug active substances.
10. the purposes of claims 1, wherein said filler is selected from lactose, xylitol, microcrystalline Cellulose, dextrin, mannitol, sorbitol, sucrose, starch, pregelatinized Starch, glucose, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, and mixture, and described sulphuric acid Walla handkerchief sand be by have enough stickiness polymerization emplastic stick together on described filler.
Priority Applications (1)
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CN201610405899.4A CN105919966A (en) | 2016-06-12 | 2016-06-12 | Vorapaxar sulfate preparation and application thereof |
Applications Claiming Priority (1)
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CN201610405899.4A CN105919966A (en) | 2016-06-12 | 2016-06-12 | Vorapaxar sulfate preparation and application thereof |
Publications (1)
Publication Number | Publication Date |
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CN105919966A true CN105919966A (en) | 2016-09-07 |
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CN201610405899.4A Pending CN105919966A (en) | 2016-06-12 | 2016-06-12 | Vorapaxar sulfate preparation and application thereof |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021204883A1 (en) | 2020-04-08 | 2021-10-14 | Cvasthera | Pharmaceutical composition for treating inflammatory bowel diseases |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105218343A (en) * | 2015-10-26 | 2016-01-06 | 乐普药业股份有限公司 | A kind of synthetic method of 3-bromine hexamethylene-2-alkene-1-ketone |
CN105310991A (en) * | 2015-10-09 | 2016-02-10 | 北京万全德众医药生物技术有限公司 | Vorapaxar sulfate tablet and its preparation method |
CN105348241A (en) * | 2015-12-11 | 2016-02-24 | 南京华威医药科技开发有限公司 | Synthetic method of vorapaxar sulfate intermediate |
-
2016
- 2016-06-12 CN CN201610405899.4A patent/CN105919966A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105310991A (en) * | 2015-10-09 | 2016-02-10 | 北京万全德众医药生物技术有限公司 | Vorapaxar sulfate tablet and its preparation method |
CN105218343A (en) * | 2015-10-26 | 2016-01-06 | 乐普药业股份有限公司 | A kind of synthetic method of 3-bromine hexamethylene-2-alkene-1-ketone |
CN105348241A (en) * | 2015-12-11 | 2016-02-24 | 南京华威医药科技开发有限公司 | Synthetic method of vorapaxar sulfate intermediate |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021204883A1 (en) | 2020-04-08 | 2021-10-14 | Cvasthera | Pharmaceutical composition for treating inflammatory bowel diseases |
FR3109089A1 (en) * | 2020-04-08 | 2021-10-15 | Cvasthera | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF INFLAMMATORY INTESTINAL DISEASES |
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Application publication date: 20160907 |