CN103877060A - Rivaroxaban composition and preparation method thereof - Google Patents
Rivaroxaban composition and preparation method thereof Download PDFInfo
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- CN103877060A CN103877060A CN201410113352.8A CN201410113352A CN103877060A CN 103877060 A CN103877060 A CN 103877060A CN 201410113352 A CN201410113352 A CN 201410113352A CN 103877060 A CN103877060 A CN 103877060A
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- razaxaban
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Abstract
The invention relates to a composition containing rivaroxaban and a preparation method of the composition. The composition takes the rivaroxaban as an active component, the particle size of the rivaroxaban is below 10 microns through pretreatment, and a wet granulation process is adopted after the rivaroxaban is uniformly mixed with a hydrophilic auxiliary material, a disintegrating agent and a surfactant, thus the dissolubility and the dissolution rate of the rivaroxaban are effectively increased.
Description
Technical field
The present invention relates to a kind of for select a time hip joint or replacement knee in arthroplasty adult patients with prevention venous thrombosis pharmaceutical composition, particularly relate to a kind of pharmaceutical composition that contains razaxaban and preparation method thereof.
Background technology
Razaxaban (Rivaroxaban, trade name Xarelto) is the oral anticoagulation of a direct inhibitive factor Xa of high selectivity.Can interrupt endogenous and the extrinsic pathway of blood coagulation waterfall by direct inhibitive factor Xa, the generation of Trombin inhibiting and thrombosis.Razaxaban is developed by Johnson & Johnson and Beyer Co., Ltd, for the anticoagulant of select a time hip joint or replacement knee in arthroplasty adult patients, to prevent venous thrombosis (VTE).Razaxaban gets the Green Light in more than 100 country in the whole world, and is successfully gone on the market exceeding 75 countries by Beyer Co., Ltd.
Summary of the invention
The physicochemical property of razaxaban crude drug shows, its water solublity is poor, is about 7mg/L, therefore causes being difficult to improve oral biological degree, and the dissolution of medicine is to need the primary problems that solve.In existing patent 200480035106.X, the preparation technology of razaxaban tablet adopts adhesive and surfactant wiring solution-forming, filler and disintegrating agent mix, use fluid bed wet granulation after raw material micronization, lubricant are additional, and finally tabletting, coating are made.
The present invention is to provide a kind of new preparation method, that is: razaxaban raw material micronization, raw material after treatment and hydrophilicity condiment, disintegrating agent, surfactant mixed pelletization; Additional surplus adjuvant; Finally, by mixture tabletting, tablet carries out coating.This preparation technology can make the dissolution of medicine conform with the regulations.
Prescription:
| Supplementary material title | Part by weight |
| Razaxaban | 1%-20% |
| Diluent | 70%-90% |
| Disintegrating agent | 2%-10% |
| Adhesive | 0.6%-8% |
| Surfactant | 0.4%-2% |
| Lubricant | 0.5%-2% |
| Coating weightening finish | 1%-3% |
Preparation technology:
Razaxaban raw material micronization, raw material after treatment is mixed homogeneously with the disintegrating agent of hydrophilic diluents, surfactant, recipe quantity half; With the adhesive soft material processed of 1%-5% concentration, soft material is crossed 24 mesh sieves and is granulated, and wet granular is the about 30min of forced air drying under 60 ℃ of conditions; Dry granule is crossed 30 mesh sieve granulate; The disintegrating agent of additional surplus, diluent, lubricant; The mixture obtaining is thus pressed into the tablet of 6mm diameter and 30-70N fracture strength.Use subsequently titanium dioxide-coated tablet, titanium dioxide suspending is in the coating solution being made up of hydroxypropyl methylcellulose and Polyethylene Glycol.
Tablet A: directly prepared by tabletting without pelletize; Tablet B: prepared by the method for being described by above-mentioned preparation technology.
Beneficial effect of the present invention:
1, the disintegration time (USP disintegrate tester, Erweka) of tablet in water
Tablet A: about 1.5min, tablet B: about 2.0min.
2, release in vitro
In following table, provide the active matter quality discharging of the tablet total content to be announced:
| ? | 15min | 30min | 45min | 60min |
| Tablet A | 82% | 85% | 87% | 88% |
| Tablet B | 91% | 95% | 96% | 96% |
(USP oar, 900ml acetate buffer, pH4.5 ± 0.1 sodium lauryl sulfate, 75 turn/min).
Form is described in further detail content of the present invention more by the following examples, but should not be interpreted as in the above-mentioned subject area of the present invention at this point and only limit to following examples.Do not departing under the above-mentioned technology prerequisite of the present invention, the corresponding replacement of making according to ordinary skill knowledge and customary means or the modification of change, include within the scope of the invention
.
Embodiment 1
Prescription:
| Supplementary material title | Unit recipe quantity |
| Razaxaban | 5mg |
| Lactose | 45.4mg |
| Microcrystalline Cellulose | 23mg |
| Cross-linking sodium carboxymethyl cellulose (inside adding) | 1.5mg |
| Cross-linking sodium carboxymethyl cellulose (additional) | 1.5mg |
| Hydroxypropyl methylcellulose | 2.0mg |
| Sodium lauryl sulphate | 1.0mg |
| Stearic acid | 0.6mg |
| Hydroxypropyl methylcellulose | 1.5mg |
| Polyethylene Glycol | 0.5mg |
| Titanium dioxide | 0.5mg |
| Gross weight | 82.5mg |
Preparation technology:
1) razaxaban flow of feed gas is crushed to 10 μ m following for subsequent use;
2) the hydroxypropyl methylcellulose aqueous solution of preparation 5% is for subsequent use;
3) take by recipe quantity that razaxaban, lactose, cross-linked carboxymethyl cellulose are received, sodium lauryl sulphate mix homogeneously;
4) add 5% hydroxypropyl methylcellulose aqueous solution soft material processed, soft material is crossed 24 mesh sieves and is granulated;
5) wet granular forced air drying 30min under 60 ℃ of conditions;
6) dry granule is crossed 30 mesh sieve granulate;
7) add microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and the stearic acid of recipe quantity, mix homogeneously;
8) mixture obtaining is thus pressed into the tablet of 6mm diameter and 30-70N fracture strength;
9) use subsequently titanium dioxide-coated tablet, titanium dioxide suspending is in the coating solution being made up of hydroxypropyl methylcellulose and Polyethylene Glycol.
Embodiment 2
Prescription:
| Supplementary material title | Unit recipe quantity |
| Razaxaban | 10mg |
| Lactose | 46mg |
| Microcrystalline Cellulose | 23mg |
| Cross-linking sodium carboxymethyl cellulose (inside adding) | 1.5mg |
| Cross-linking sodium carboxymethyl cellulose (additional) | 1.5mg |
| Polyvidone | 1.4mg |
| Sodium lauryl sulphate | 1.0mg |
| Magnesium stearate | 0.6mg |
| Hydroxypropyl methylcellulose | 1.5mg |
| Polyethylene Glycol | 0.5mg |
| Titanium dioxide | 0.5mg |
| Gross weight | 87.5mg |
Preparation technology:
1) razaxaban flow of feed gas is crushed to 10 μ m following for subsequent use;
2) povidone solution of preparation 3% is for subsequent use;
3) take by recipe quantity that razaxaban, lactose, cross-linked carboxymethyl cellulose are received, sodium lauryl sulphate mix homogeneously;
4) add 3% polyvidone aqueous solution soft material processed, soft material is crossed 24 mesh sieves and is granulated;
5) wet granular forced air drying 30min under 60 ℃ of conditions;
6) dry granule is crossed 30 mesh sieve granulate;
7) add microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and the magnesium stearate of recipe quantity, mix homogeneously;
8) mixture obtaining is thus pressed into the tablet of 6mm diameter and 30-70N fracture strength;
9) use subsequently titanium dioxide-coated tablet, titanium dioxide suspending is in the coating solution being made up of hydroxypropyl methylcellulose and Polyethylene Glycol.
Embodiment 3
Prescription:
| Supplementary material title | Unit recipe quantity |
| Razaxaban | 20mg |
| Lactose | 70mg |
| Microcrystalline Cellulose | 20.5mg |
| Polyvinylpolypyrrolidone (inside adding) | 2.5mg |
| Polyvinylpolypyrrolidone (additional) | 2.5mg |
| Hydroxypropyl methylcellulose | 2.0mg |
| Sodium lauryl sulphate | 1.5mg |
| Magnesium stearate | 0.5mg |
| Micropowder silica gel | 0.5mg |
| Gross weight | 120mg |
Preparation technology:
1) razaxaban flow of feed gas is crushed to 10 μ m following for subsequent use;
2) the hydroxypropyl methylcellulose solution for standby of preparation 3%;
3) take razaxaban, lactose, polyvinylpolypyrrolidone, sodium lauryl sulphate mix homogeneously by recipe quantity;
4) add 3% hydroxypropyl methylcellulose aqueous solution soft material processed, soft material is crossed 24 mesh sieves and is granulated;
5) wet granular forced air drying 30min under 60 ℃ of conditions;
6) dry granule is crossed 30 mesh sieve granulate;
7) add microcrystalline Cellulose, polyvinylpolypyrrolidone, magnesium stearate and the micropowder silica gel of recipe quantity, mix homogeneously;
8) be packed as granule.
Embodiment 4
Prescription:
| Supplementary material title | Unit recipe quantity |
| Razaxaban | 20mg |
| Lactose | 70mg |
| Microcrystalline Cellulose | 20.5mg |
| Crosslinked carboxymethyl fecula sodium (inside adding) | 2.5mg |
| Crosslinked carboxymethyl fecula sodium (additional) | 2.5mg |
| Hydroxypropyl methylcellulose | 2.0mg |
| Sodium lauryl sulphate | 1.5mg |
| Magnesium stearate | 0.5mg |
| Micropowder silica gel | 0.5mg |
| Gross weight | 120mg |
Preparation technology:
1) razaxaban flow of feed gas is crushed to 10 μ m following for subsequent use;
2) the hydroxypropyl methylcellulose solution for standby of preparation 3%;
3) take razaxaban, lactose, crosslinked carboxymethyl fecula sodium, sodium lauryl sulphate mix homogeneously by recipe quantity;
4) adding 3% hydroxypropyl methylcellulose aqueous solution soft material processed, soft material to cross 24 mesh sieves granulates;
5) wet granular forced air drying 30min under 60 ℃ of conditions;
6) dry granule is crossed 30 mesh sieve granulate;
7) add microcrystalline Cellulose, crosslinked carboxymethyl fecula sodium, magnesium stearate and the micropowder silica gel of recipe quantity, mix homogeneously;
8) gained particle filling packs the capsule of suitable size into.
Claims (10)
1. a razaxaban compositions, contains razaxaban, diluent, adhesive, disintegrating agent, surfactant and lubricant, it is characterized in that the particle diameter of razaxaban is less than 10 μ m.
2. razaxaban compositions according to claim 1, is characterized in that the particle diameter of the razaxaban of 90% above weight percentage is less than 5 μ m.
3. razaxaban compositions according to claim 1, is characterized in that being made up of the component of following weight percentage: 1%～20% razaxaban, 70%～90% diluent, 0.6%～8% adhesive, 2%～10% disintegrating agent, 0.4%～2% surfactant and 0.5%～2% lubricant.
4. razaxaban compositions according to claim 1, is characterized in that diluent is selected from lactose, microcrystalline Cellulose, mannitol, sorbitol, xylitol, starch and pregelatinized Starch, the preferred lactose of hydrophilic diluents.
5. razaxaban compositions according to claim 1, it is characterized in that adhesive is selected from hydroxypropyl methylcellulose, polyoxyethylene, sodium carboxymethyl cellulose, polyvidone, hydroxypropyl cellulose, methylcellulose and ethyl cellulose, preferably hydroxypropyl methylcellulose.
6. razaxaban compositions according to claim 1, is characterized in that disintegrating agent is selected from polyvinylpolypyrrolidone, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose and receives and low-substituted hydroxypropyl cellulose, preferably cross-linking sodium carboxymethyl cellulose.
7. razaxaban compositions according to claim 1, is characterized in that surfactant is selected from sodium lauryl sulphate, dioctyl sodium sulphosuccinate, glyceryl monostearate, sorbitan monolaurate, preferably sodium dodecyl sulfate.
8. razaxaban compositions according to claim 1, is characterized in that lubricant is selected from magnesium stearate, micropowder silica gel, stearic acid, Pulvis Talci and Polyethylene Glycol, also can mix use, preferably stearic acid.
9. according to the razaxaban compositions described in any one in claim 1～8, it is characterized in that existence form is tablet, capsule, granule.
10. according to the method for preparing razaxaban compositions described in any one in claim 1～2, it is characterized in that razaxaban that described particle diameter is less than 10 μ m is that method by mixing rear granulation with hydrophilicity condiment, disintegrating agent, surfactant obtains.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410113352.8A CN103877060A (en) | 2014-03-25 | 2014-03-25 | Rivaroxaban composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410113352.8A CN103877060A (en) | 2014-03-25 | 2014-03-25 | Rivaroxaban composition and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103877060A true CN103877060A (en) | 2014-06-25 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410113352.8A Pending CN103877060A (en) | 2014-03-25 | 2014-03-25 | Rivaroxaban composition and preparation method thereof |
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| Country | Link |
|---|---|
| CN (1) | CN103877060A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030703A (en) * | 2015-06-23 | 2015-11-11 | 孙号 | Rivaroxaban tablets for preventing and treating embolismic diseases and preparing method thereof |
| CN105078915A (en) * | 2015-08-27 | 2015-11-25 | 江苏中邦制药有限公司 | Rivaroxaban tablets and preparation method for same |
| CN105267169A (en) * | 2015-12-07 | 2016-01-27 | 石家庄康贺威药业有限公司 | Rivaroxaban tablet and preparation method thereof |
| CN106109434A (en) * | 2016-08-26 | 2016-11-16 | 乐普药业股份有限公司 | A kind of razaxaban tablet and preparation method thereof |
| CN107773548A (en) * | 2016-08-30 | 2018-03-09 | 重庆植恩药业有限公司 | Solid composite containing razaxaban and preparation method thereof |
| CN108371655A (en) * | 2018-03-29 | 2018-08-07 | 重庆华邦制药有限公司 | Include the solid drugs and preparation method thereof of razaxaban |
| CN108864069A (en) * | 2018-05-03 | 2018-11-23 | 华东理工大学 | A kind of razaxaban particle and the preparation method and application thereof |
| CN110755392A (en) * | 2019-11-18 | 2020-02-07 | 扬子江药业集团广州海瑞药业有限公司 | Rivaroxaban tablet pharmaceutical composition and preparation method thereof |
| CN111053753A (en) * | 2018-10-16 | 2020-04-24 | 深圳翰宇药业股份有限公司 | Rivaroxaban pharmaceutical composition and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2308472A1 (en) * | 2009-10-06 | 2011-04-13 | ratiopharm GmbH | Pharmaceutical compositions comprising rivaroxaban |
| WO2011042156A1 (en) * | 2009-10-06 | 2011-04-14 | Ratiopharm Gmbh | Pharmaceutical compositions comprising rivaroxaban |
| CN102058889A (en) * | 2010-11-05 | 2011-05-18 | 王定豪 | Dispersible tablet containing anticoagulants and application thereof |
| CN103550166A (en) * | 2013-10-31 | 2014-02-05 | 江苏阿尔法药业有限公司 | Rivaroxaban oral microsphere preparation |
| CN103550165A (en) * | 2013-10-19 | 2014-02-05 | 浙江华海药业股份有限公司 | Medicinal composition containing rivaroxaban and preparation method thereof |
-
2014
- 2014-03-25 CN CN201410113352.8A patent/CN103877060A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2308472A1 (en) * | 2009-10-06 | 2011-04-13 | ratiopharm GmbH | Pharmaceutical compositions comprising rivaroxaban |
| WO2011042156A1 (en) * | 2009-10-06 | 2011-04-14 | Ratiopharm Gmbh | Pharmaceutical compositions comprising rivaroxaban |
| CN102058889A (en) * | 2010-11-05 | 2011-05-18 | 王定豪 | Dispersible tablet containing anticoagulants and application thereof |
| CN103550165A (en) * | 2013-10-19 | 2014-02-05 | 浙江华海药业股份有限公司 | Medicinal composition containing rivaroxaban and preparation method thereof |
| CN103550166A (en) * | 2013-10-31 | 2014-02-05 | 江苏阿尔法药业有限公司 | Rivaroxaban oral microsphere preparation |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030703A (en) * | 2015-06-23 | 2015-11-11 | 孙号 | Rivaroxaban tablets for preventing and treating embolismic diseases and preparing method thereof |
| CN105078915A (en) * | 2015-08-27 | 2015-11-25 | 江苏中邦制药有限公司 | Rivaroxaban tablets and preparation method for same |
| CN105267169A (en) * | 2015-12-07 | 2016-01-27 | 石家庄康贺威药业有限公司 | Rivaroxaban tablet and preparation method thereof |
| CN105267169B (en) * | 2015-12-07 | 2018-03-30 | 石家庄康贺威药业有限公司 | A kind of razaxaban tablet and preparation method thereof |
| CN106109434B (en) * | 2016-08-26 | 2019-04-05 | 乐普药业股份有限公司 | A kind of razaxaban tablet and preparation method thereof |
| CN106109434A (en) * | 2016-08-26 | 2016-11-16 | 乐普药业股份有限公司 | A kind of razaxaban tablet and preparation method thereof |
| CN107773548A (en) * | 2016-08-30 | 2018-03-09 | 重庆植恩药业有限公司 | Solid composite containing razaxaban and preparation method thereof |
| CN108371655A (en) * | 2018-03-29 | 2018-08-07 | 重庆华邦制药有限公司 | Include the solid drugs and preparation method thereof of razaxaban |
| CN108864069A (en) * | 2018-05-03 | 2018-11-23 | 华东理工大学 | A kind of razaxaban particle and the preparation method and application thereof |
| CN108864069B (en) * | 2018-05-03 | 2021-04-20 | 华东理工大学 | Rivaroxaban particle and preparation method and application thereof |
| CN111053753A (en) * | 2018-10-16 | 2020-04-24 | 深圳翰宇药业股份有限公司 | Rivaroxaban pharmaceutical composition and preparation method thereof |
| CN110755392A (en) * | 2019-11-18 | 2020-02-07 | 扬子江药业集团广州海瑞药业有限公司 | Rivaroxaban tablet pharmaceutical composition and preparation method thereof |
| CN110755392B (en) * | 2019-11-18 | 2020-09-01 | 扬子江药业集团广州海瑞药业有限公司 | Rivaroxaban tablet pharmaceutical composition and preparation method thereof |
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Application publication date: 20140625 |