CN105310991A - Vorapaxar sulfate tablet and its preparation method - Google Patents
Vorapaxar sulfate tablet and its preparation method Download PDFInfo
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- CN105310991A CN105310991A CN201510647497.0A CN201510647497A CN105310991A CN 105310991 A CN105310991 A CN 105310991A CN 201510647497 A CN201510647497 A CN 201510647497A CN 105310991 A CN105310991 A CN 105310991A
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- sulphuric acid
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- acid walla
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Abstract
The invention provides a preparation method of a vorapaxar sulfate tablet, belongs to the technical field of novel pharmaceutical techniques, and relates to a vorapaxar sulfate tablet and its preparation method. The tablet is made by directly tableting powder of vorapaxar sulfate as a main ingredient and contains a filler, a cracking agent, a flow aid and a lubricant. The production process of the vorapaxar sulfate tablet is simplified, production cost is reduced, and sample dissolution rate is increased so that a sample has better curative effect.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, specifically, relate to the preparation of the husky sheet of a kind of sulphuric acid Walla handkerchief.
Background technology
U.S. FDA approved in 2014 sulphuric acid Walla handkerchief husky sheet (trade name: Zontivity), listing is produced by MSDInternationalGmbH (SingaporeBranch), be a kind of proteinase-activated receptor-1 (PAR-1) antagonist, be suitable for as myocardial infarction (MI) or the attenuating having thrombotic cardiovascular event in peripheral arterial disease (PAD) patients with history; Zontivity once showed attenuating cardiovascular death, MI, and apoplexy and urgent coronary-artery revascularization (UCR) combine the incidence rate of terminal, and this medicine existing goes on the market in the U.S., domestic producer of also not going on the market.
Anticoagulin, also makes anti-coaguin, anticoagulant or anticoagulant, is commonly called as thin blood ball/thin blood medicine, is a kind of material being used for preventing blood coagulation.It comprises multiple different medicine, and main purposes avoids thrombosis; Secondly be exactly when client need connects more past Medical Instruments, again or need to accept blood transfusion, again or its blood needs sample presentation to chemically examine time, also can add anticoagulin, in order to avoid blood coagulation.
All the time, some needs of patients suffering from cardiovascular diseases are taken thin blood medicine (anticoagulation medicine) and are prevented blood vessel embolism, are called as the warfarin (Warfarin) of old-fashioned thin blood medicine, use till today over more than 50 year, the correct dose that pharmacy is carefully supervised and used, is very shown in drug effect.But warfarin is easy to " rush mutually " with medicine with the food in daily life, so that affects drug effect.Add that pill taker's such as general idea in a period of time forgets regular blood count, doctor is just difficult to according to blood situation, adjust comparatively suitable dose to maintain drug effect.Although this can bring worry and uneasiness for user and household, for guaranteeing that the dosage range that old-fashioned thin blood medicine is being applicable to provides effectiveness and safety, user also needs to defer to instruction.
Large-scale random, double blinding, a placebo-controlled trial including 26499 routine patients in, Walla handkerchief husky 2.5mg treatment group primary focus reduces by 13%; Get rid of urgent coronary-artery revascularization person, secondary emphasis (cardiovascular death, MI, apoplexy) also obviously reduces.Handkerchief husky uniquely main safety problem in Walla is hemorrhage.Add bleeding risk according to multiple definition Wallas handkerchief sand, but the difference that data show between the husky group of Walla handkerchief and placebo group is not remarkable.
Antithrombotic reagent, comprises anticoagulant, antiplatelet drug and direct thrombolytic drug, all can be used for the treatment of thrombotic prevention or acute stage.Estimate that the market of anticoagulation will increase greatly.The reason of market dilatation comprises the increase of aged tendency of population and cardiovascular disease incidence rate, but mainly due to the listing of new drug, this will improve present quality condition greatly.The present invention is oral anticoagulation, and the stroke prevention market will be correlated with on atrial fibrillation is brought and affected the most significantly.
Walla handkerchief sand is the proteinase activated receptors 1(PAR-1 of a kind of pioneering (First-in-class)) antagonist, be a kind of anti-platelet agent, be intended to reduce platelet aggregation tendency, suppress the formation of blood clotting grumeleuse.PAR-1 be a kind of can by the receptor of thrombin activation, and thrombin is a kind of effective platelet activating agent.Walla handkerchief sand can suppress PAR-1 receptor in platelet, thus the platelet aggregation of enzyme induction anticoagulant.By reducing the formation of blood clotting, Zontivity can reduce the risk of heart attack and apoplexy.
Antithrombotic reagent, comprises anticoagulant, antiplatelet drug and direct thrombolytic drug, all can be used for the treatment of thrombotic prevention or acute stage.Due to the increase of aged tendency of population and cardiovascular disease incidence rate, estimate that the market of anticoagulation will increase greatly.But the listing of new drug, will improve present quality condition greatly.The present invention is oral anticoagulation, and the stroke prevention market will be correlated with on atrial fibrillation is brought and affected the most significantly.
Within 2007, MSD Corp. of the U.S. has applied for patent, the patent No. is US7235567 and US7304078, compound [(1R, 3aR, 4aR is reported in patent, 6R, 8aR, 9S, 9aS)-9-{ (1E)-2-[5-(3fluorophenyl) pyridin-2-yl] ethen-1-yl}-1-methyl-3-oxododecahydronaphtho [2,3-c] furan-6-yl] carbamatesulfate, namely sulphuric acid Walla handkerchief is husky; And claimed a kind of crystal formation, a kind of disulfate receptor antagonist of thrombin, domestic at present not yet have patent to issue, and the chemical constitution of sulphuric acid Walla handkerchief sand is as follows:
Handkerchief sand in sulphuric acid Walla belongs to BCS II class, low dissolving, Thief zone types of drug, dissolves and has pH dependency, in the aqueous medium of pH4-7.5, have lower dissolubility, is 1 aqueous solution or has highest solubility at pH in simulated gastric fluid pH1.4, can reach 3.76mg/mL.It can discharge rapidly in vivo, within 1-2 hour, just can reach the highest blood drug level.
Summary of the invention
The husky sheet of sulphuric acid Walla handkerchief involved in the present invention, it is characterized in that adopting direct powder compression, simplify technique, time-saving energy-saving, reduce costs, improve the dissolution of sample simultaneously, sample has better curative effect.
The present invention realizes mainly through following technical scheme, after husky for sulphuric acid Walla handkerchief crude drug is mixed homogeneously with filler, disintegrating agent, fluidizer, lubricant etc., adopt the mode of direct powder compression, carry out the preparation of tablet, improve the disintegrate of sample, improve sample dissolution, make sample have better curative effect; And preparation technology is simple, time-saving energy-saving, greatly can reduce production cost.
The preparation of the husky sheet of sulphuric acid Walla handkerchief, its percentage by weight is composed as follows:
Sulphuric acid Walla handkerchief sand 2.5% ~ 5%
Filler 20% ~ 90%
Disintegrating agent 5% ~ 20%
Fluidizer 1% ~ 5%
Lubricant 0.5% ~ 3%
Wherein said filler is selected from one or more in mannitol, sorbitol, microcrystalline Cellulose pH102, spray-dried lactose, calcium hydrogen phosphate, starch, sucrose, one or more in preferably spray drying lactose, mannitol, microcrystalline Cellulose pH102, one or more more preferably in spray-dried lactose, microcrystalline Cellulose pH102.
Wherein said disintegrating agent is one or more in carboxymethylstach sodium, low-substituted hydroxypropyl methylcellulose, cross-linking sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, pregelatinized Starch, one or more in preferred polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, are more preferably one or more in polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose.
Wherein said fluidizer is one or more in silicon dioxide, micropowder silica gel, Pulvis Talci, is preferably one or more in silicon dioxide, Pulvis Talci.
Wherein said lubricant is one or more in sodium stearyl fumarate, Glyceryl Behenate, magnesium stearate, calcium stearate, hard paraffin, one or more in preferred magnesium stearate, hard paraffin, sodium stearyl fumarate.
Present invention also offers being prepared as follows of the husky sheet of above-mentioned sulphuric acid Walla handkerchief:
1) by sulphuric acid Walla handkerchief and each adjuvant, all 60 mesh sieves are crossed, for subsequent use;
2) and each adjuvant husky by recipe quantity weighting raw materials sulphuric acid Walla handkerchief, and crude drug is mixed homogeneously with each adjuvant, tabletting, packaging, obtains the husky sheet of sulphuric acid Walla handkerchief.
The preparation process that described technique is reduced to because of current clinical preparation is tediously long, and technique is loaded down with trivial details, time-consuming effort, and production cost is high; The present invention adopts powder vertical compression technique, and technique is simple, and time-saving energy-saving, is widely used, and requires low, greatly can reduce production cost to adjuvant.
Detailed description of the invention
By following object lesson, understanding the present invention that can be more concrete, but the present invention is not limited to following embodiment.
embodiment:
The existence form of this embodiment is tablet.(with every 1000 gauge)
Embodiment 1:
| Supplementary material title | Percentage (%) | 1000 supplementary materials consumption (g) |
| Sulphuric acid Walla handkerchief is husky | 2.50 | 2.50 |
| Spray-dried lactose | 57.50 | 57.50 |
| Microcrystalline Cellulose pH102 | 30.00 | 30.00 |
| Low-substituted hydroxypropyl cellulose | 8.00 | 8.00 |
| Silicon dioxide | 1.00 | 1.00 |
| Magnesium stearate | 1.00 | 1.00 |
| Amount to | 100.00 | 100.00 |
Embodiment 2:
| Supplementary material title | Percentage (%) | 1000 supplementary materials consumption (g) |
| Sulphuric acid Walla handkerchief is husky | 2.50 | 2.50 |
| Pregelatinized Starch | 55.50 | 55.50 |
| Microcrystalline Cellulose pH102 | 30.00 | 30.00 |
| Polyvinylpolypyrrolidone | 10.00 | 10.00 |
| Silicon dioxide | 1.00 | 1.00 |
| Magnesium stearate | 1.00 | 1.00 |
| Amount to | 100.00 | 100.00 |
Embodiment 3:
| Supplementary material title | Percentage (%) | 1000 supplementary materials consumption (g) |
| Sulphuric acid Walla handkerchief is husky | 2.50 | 2.50 |
| Spray-dried lactose | 55.50 | 55.50 |
| Microcrystalline Cellulose pH102 | 30.00 | 30.00 |
| Polyvinylpolypyrrolidone | 10.00 | 10.00 |
| Silicon dioxide | 1.00 | 1.00 |
| Magnesium stearate | 1.00 | 1.00 |
| Amount to | 100.00 | 100.00 |
Embodiment 4:
| Supplementary material title | Percentage (%) | 1000 supplementary materials consumption (g) |
| Sulphuric acid Walla handkerchief is husky | 2.50 | 2.50 |
| Spray-dried lactose | 30.00 | 30.00 |
| Microcrystalline Cellulose pH102 | 55.50 | 55.50 |
| Polyvinylpolypyrrolidone | 10.00 | 10.00 |
| Silicon dioxide | 1.00 | 1.00 |
| Magnesium stearate | 1.00 | 1.00 |
| Amount to | 100.00 | 100.00 |
Embodiment 5:
| Supplementary material title | Percentage (%) | 1000 supplementary materials consumption (g) |
| Sulphuric acid Walla handkerchief is husky | 2.50 | 2.50 |
| Spray-dried lactose | 42.50 | 42.50 |
| Microcrystalline Cellulose pH102 | 43.00 | 43.00 |
| Polyvinylpolypyrrolidone | 10.00 | 10.00 |
| Silicon dioxide | 1.00 | 1.00 |
| Magnesium stearate | 1.00 | 1.00 |
| Amount to | 100.00 | 100.00 |
Preparation method:
1) above-mentioned each prescription Raw medicine sulphuric acid Walla handkerchief is husky and adjuvant, namely spray-dried lactose, (pregelatinized Starch), microcrystalline Cellulose pH102, polyvinylpolypyrrolidone (low-substituted hydroxypropyl cellulose), silicon dioxide, magnesium stearate cross 60 mesh sieves respectively, for subsequent use;
2) three-dimensional mixer is placed in together, mix homogeneously by above-mentioned each recipe quantity weighting raw materials sulphuric acid Walla handkerchief sand, spray-dried lactose, (pregelatinized Starch), microcrystalline Cellulose pH102, polyvinylpolypyrrolidone (low-substituted hydroxypropyl cellulose), silicon dioxide, magnesium stearate;
3) get the material after mixing, with the flat stamping of rotary tablet machine φ 6, and pack.
By above-mentioned prescription obtained sample 1,2,3,4,5 respectively.
Stripping is tested
1-5 sample and listing product (MSDInternationalGmbH (SingaporeBranch)) are contrasted and carry out In Vitro Dissolution experiment, specific operation process is as follows:
Stripping investigation method: " Chinese Pharmacopoeia " version in 2010 two annex XD bis-method slurry processes
Dissolution medium: 0.04M sodium hydrogen phosphate and 1.0% (w/v) citric acid, pH is 3.00 ± 0.05
Stripping volume: 900mL
Rotating speed: 50 turns/min
Sampling time point: 10,15,30,45,60min
Assay method: HPLC
External contrast stripping experimental result:
As seen from the above table, the sample stripping of embodiment of the present invention 1-5 is all better than listing product preparation.
Therefore reach a conclusion, the husky sheet of sulphuric acid Walla handkerchief adopting direct powder compression to prepare husky for sulphuric acid Walla handkerchief principal agent and adjuvant, technique is simple, and time-saving energy-saving, tool is high-dissolution comparatively.
Claims (8)
1. the husky sheet of sulphuric acid Walla handkerchief, it is characterized in that, it contain a kind of can the dosage unit of oral release, each dosage unit is containing the husky crude drug of sulphuric acid Walla handkerchief of the 2.5mg that has an appointment, adopt the mode of direct powder compression, be equipped with filler, disintegrating agent, fluidizer, lubricant etc. and be prepared from, simplify technique, improve the dissolution of sample simultaneously, make sample have better therapeutic effect.
2. the husky sheet of sulphuric acid Walla as claimed in claim 1 handkerchief, is characterized in that, wherein:
1) consumption of filler accounts for 20% ~ 90% of recipe quantity;
2) consumption of disintegrating agent accounts for 5% ~ 20% of recipe quantity;
3) consumption of fluidizer accounts for 1% ~ 5% of recipe quantity;
4) consumption of lubricant accounts for 0.5% ~ 3% of recipe quantity.
3. the husky sheet of sulphuric acid Walla as claimed in claim 1 handkerchief, it is characterized in that, described filler is selected from one or more in mannitol, sorbitol, microcrystalline Cellulose pH102, spray-dried lactose, calcium hydrogen phosphate, starch, sucrose, one or more in preferred mannitol, microcrystalline Cellulose pH102, spray-dried lactose.
4. the husky sheet of sulphuric acid Walla as claimed in claim 1 handkerchief, it is characterized in that, described disintegrating agent is one or more in carboxymethylstach sodium, low-substituted hydroxypropyl methylcellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, pregelatinized Starch, one or more in preferred polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose.
5. the husky sheet of sulphuric acid Walla as claimed in claim 1 handkerchief, it is characterized in that, described fluidizer is one or more in silicon dioxide, micropowder silica gel, Pulvis Talci, is preferably one or more in silicon dioxide, Pulvis Talci.
6. the husky sheet of sulphuric acid Walla as claimed in claim 1 handkerchief, it is characterized in that, described lubricant is one or more in sodium stearyl fumarate, Glyceryl Behenate, magnesium stearate, calcium stearate, hard paraffin, one or more in preferred magnesium stearate, sodium stearyl fumarate.
7. the preparation method of the husky sheet of the sulphuric acid Walla handkerchief as described in claim arbitrary in claim 1 ~ 6, is characterized in that:
1) by sulphuric acid Walla handkerchief and each adjuvant, all 60 mesh sieves are crossed, for subsequent use;
2) and each adjuvant husky by recipe quantity weighting raw materials sulphuric acid Walla handkerchief, and crude drug is mixed homogeneously with each adjuvant, tabletting, packaging, obtains the husky sheet of sulphuric acid Walla handkerchief.
8. the husky sheet of sulphuric acid Walla as claimed in claim 1 handkerchief, it is characterized in that, the preparation process that described technique is reduced to because of current clinical preparation is tediously long, and technique is loaded down with trivial details, time-consuming effort, and production cost is high; The present invention adopts direct powder compression technology, and technique is simple, and time-saving energy-saving, is widely used, and greatly can reduce production cost.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510647497.0A CN105310991A (en) | 2015-10-09 | 2015-10-09 | Vorapaxar sulfate tablet and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510647497.0A CN105310991A (en) | 2015-10-09 | 2015-10-09 | Vorapaxar sulfate tablet and its preparation method |
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| Publication Number | Publication Date |
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| CN105310991A true CN105310991A (en) | 2016-02-10 |
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| CN201510647497.0A Pending CN105310991A (en) | 2015-10-09 | 2015-10-09 | Vorapaxar sulfate tablet and its preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105919966A (en) * | 2016-06-12 | 2016-09-07 | 佛山市腾瑞医药科技有限公司 | Vorapaxar sulfate preparation and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104523628A (en) * | 2014-12-24 | 2015-04-22 | 乐普药业股份有限公司 | Succinic acid solifenacin tablet capable of achieving direct powder compression and preparation method of succinic acid solifenacin tablet |
-
2015
- 2015-10-09 CN CN201510647497.0A patent/CN105310991A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104523628A (en) * | 2014-12-24 | 2015-04-22 | 乐普药业股份有限公司 | Succinic acid solifenacin tablet capable of achieving direct powder compression and preparation method of succinic acid solifenacin tablet |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105919966A (en) * | 2016-06-12 | 2016-09-07 | 佛山市腾瑞医药科技有限公司 | Vorapaxar sulfate preparation and application thereof |
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Application publication date: 20160210 |