CN109745295B - Rivaroxaban oral solid preparation and preparation method thereof - Google Patents
Rivaroxaban oral solid preparation and preparation method thereof Download PDFInfo
- Publication number
- CN109745295B CN109745295B CN201910211402.9A CN201910211402A CN109745295B CN 109745295 B CN109745295 B CN 109745295B CN 201910211402 A CN201910211402 A CN 201910211402A CN 109745295 B CN109745295 B CN 109745295B
- Authority
- CN
- China
- Prior art keywords
- rivaroxaban
- tablet
- coating
- prescription amount
- preparation
- 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.)
- Active
Links
Abstract
The invention discloses a rivaroxaban oral solid preparation which comprises the following components in percentage by weight: 2 to 30 percent of rivaroxaban, 0.5 to 5 percent of wetting agent, 60 to 90 percent of filling agent, 3 to 10 percent of disintegrating agent and 0.1 to 1.5 percent of lubricating agent. In addition, a preparation method is also disclosed. The oral solid preparation avoids using a hydrophilic adhesive and solves the problem of poor dissolution rate of the rivaroxaban oral solid preparation.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a rivaroxaban oral solid preparation and a preparation method thereof.
Background
Rivaroxaban, an oral anticoagulant with high selectivity for direct inhibition of factor Xa, is chemically named 5-chloro-N- ({ (5S) -2-oxo-3- [ -4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolin-5-yl } methyl) -2-thiophenecarboxamide, is soluble in N, N-dimethylformamide or dimethylsulfoxide, slightly soluble in dichloromethane and almost insoluble in water, and belongs to the BCS II class of compounds.
The rivaroxaban has the characteristic of almost insoluble dissolution in water, so that the key problem to be solved by the rivaroxaban oral solid preparation is to improve the dissolution rate of rivaroxaban in vivo and in vitro and ensure the oral bioavailability of the rivaroxaban oral solid preparation, and therefore, the prior art discloses various methods and preparations for improving the external dissolution rate of rivaroxaban.
Bayer corporation discloses a rivaroxaban oral solid preparation and a preparation method thereof in Chinese patent ZL200480035106. X: the product is granulated by a fluidized bed wet method, and the in-vitro dissolution behavior of the product is improved by adding active substances into a hydrophilic solvent containing hydroxypropyl methylcellulose and lauryl sodium sulfate. "
The Jiangsu Haosen pharmaceutical industry Co., Ltd discloses a method for solving the problem of poor dissolution rate of an insoluble drug rivaroxaban by increasing the dosage of a disintegrant in Chinese patent CN 104337787A.
Disclosure of Invention
The inventor develops a rivaroxaban oral solid preparation, avoids using a hydrophilic adhesive, and overcomes the problem of poor dissolution rate of the rivaroxaban oral solid preparation.
The invention aims to provide a rivaroxaban oral solid preparation.
Another object of the present invention is to provide a method for preparing the above oral solid preparation.
Specifically, the invention provides a rivaroxaban oral solid preparation which comprises the following components in percentage by weight: 2 to 30 percent of rivaroxaban, 0.5 to 5 percent of wetting agent, 60 to 90 percent of filling agent, 3 to 10 percent of disintegrating agent and 0.1 to 1.5 percent of lubricating agent.
In an embodiment of the invention, the rivaroxaban oral solid preparation provided by the invention, wherein the wetting agent is sodium lauryl sulfate.
In an embodiment of the present invention, the rivaroxaban oral solid preparation provided by the present invention, wherein the filler may be selected from one or more of lactose, microcrystalline cellulose, pregelatinized starch, mannitol, xylitol, and calcium hydrogen phosphate, preferably lactose and microcrystalline cellulose.
In an embodiment of the invention, the rivaroxaban oral solid preparation provided by the invention is characterized in that the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and crospovidone, and is preferably croscarmellose sodium or low-substituted hydroxypropyl cellulose.
In an embodiment of the invention, the rivaroxaban oral solid preparation provided by the invention is characterized in that the lubricant is selected from magnesium stearate, calcium stearate, sodium fumarate stearate or stearic acid, preferably magnesium stearate or sodium fumarate stearate.
In an embodiment of the invention, the rivaroxaban oral solid formulation provided by the invention, wherein rivaroxaban is formulated with a wetting agent and water as a suspension, and then the suspension is added to a pre-mix of a filler and a disintegrant.
In an embodiment of the rivaroxaban oral solid preparation provided by the invention, the weight ratio of the wetting agent to water in the suspension is 1: 4-1: 150; preferably 1: 7 to 1: 50.
In some embodiments, the rivaroxaban oral solid preparation provided by the invention consists of the following components in percentage by weight: 2% -30% of rivaroxaban, 0.5% -5% of sodium dodecyl sulfate, 60% -90% of a filler, 3% -10% of croscarmellose sodium and 0.1% -1.5% of magnesium stearate, wherein the filler is microcrystalline cellulose and lactose; optionally, wherein the weight ratio of microcrystalline cellulose to lactose is from 1: 0.1 to 1: 10.
In some embodiments of the invention, the lactose may be lactose monohydrate.
On the other hand, the invention provides a preparation method of the rivaroxaban oral solid preparation, which comprises the following steps:
(1) preparing a suspension
Dissolving a wetting agent in water, suspending rivaroxaban therein, heating and stirring at 30-50 ℃, and carrying out ultrasonic treatment;
(2) premixing
Uniformly mixing the filler and the disintegrant to obtain a premix;
(3) granulating and straightening
Adding the suspension obtained in the step (1) into the premix obtained in the step (2) to prepare a soft material, and sieving the soft material to granulate; drying and granulating to obtain dry granules;
(4) total mixing
And (4) adding a lubricant into the dry particles obtained in the step (3), and uniformly mixing.
In an embodiment of the present invention, the present invention provides a method for preparing, further comprising the steps of tableting and coating.
The rivaroxaban oral solid preparation provided by the invention has the advantage that the rivaroxaban oral solid preparation with high dissolution rate is obtained under the condition that a water-soluble polymer is not used.
Detailed Description
The invention is further described below by way of examples. It will be apparent to those skilled in the art that equivalent modifications of the following examples using prior art teachings are within the scope of the present invention.
Dissolution apparatus: paddle method
Rotating speed: 75rpm
Dissolution medium: 0.2% sodium dodecyl sulfate in pH4.5 acetate buffer
Volume of dissolution medium: 900ml
Sampling time points are as follows: 5. 10, 15, 20, 30, 45 and 60min
Sampling volume: 7ml (Filter membrane filtration, discarding the initial filtrate, taking the subsequent filtrate as the test solution)
UV method, measurement wavelength: 247nm
Example 1
Rivaroxaban tablets
(1) Suspension prescription and preparation method (API + SDS)
Dissolving the prescription amount of sodium dodecyl sulfate in the prescription amount of purified water, adding the prescription amount of rivaroxaban to suspend in the solution after complete dissolution, stirring for 1h at 40 ℃, and then carrying out ultrasonic treatment on the suspension for 1 h.
(2) Premixing
Uniformly mixing the microcrystalline cellulose, the lactose monohydrate and the croscarmellose sodium according to the prescription amount to obtain the premix.
(3) Granulating, drying and grading
Slowly and uniformly adding the suspension obtained in the step (1) into the premix to prepare a soft material, and granulating through a 40-mesh screen. Drying in a forced air drying oven at 55 +/-5 ℃ until the moisture is within the range of 2-3 percent. Taking out the granules, and sieving with 80 mesh sieve to obtain dry granules.
(4) Total mixing
Adding additional adjuvant magnesium stearate 0.6 mg/tablet, and mixing.
(5) Tabletting
The tablet hardness is 5-9 kg.
(6) Coating film
Dispersing Opadry (Y-1-7000) in water, stirring, and sieving with 80 mesh sieve to obtain coating solution. Putting the tablet core into a coating pan, controlling the rotation speed of the coating pan at 3-14rpm, the temperature of the tablet bed at 35-55 deg.C, the air intake temperature at 50-85 deg.C, the spray rotation speed at 20-60rpm, increasing the weight of the coating by about 4%, cooling the temperature in the coating pan to below 40 deg.C after coating, and taking out the tablet.
Example 2
Rivaroxaban tablets
(1) Suspension prescription and preparation method (API + SDS)
The prescribed amount of sodium dodecyl sulfate is dissolved in the prescribed amount of purified water, after complete dissolution, the prescribed amount of rivaroxaban is added and suspended in the solution, stirred at 40 ℃ for 1h, and the suspension is again sonicated for 1.5 h.
(2) Premixing
Uniformly mixing the microcrystalline cellulose, the lactose monohydrate and the croscarmellose sodium according to the prescription amount to obtain the premix.
(3) Granulating, drying and grading
Slowly and uniformly adding the suspension obtained in the step (1) into the premix to prepare a soft material, and granulating through a 40-mesh screen. Drying the mixture in a fluidized bed at 50-70 ℃ until the water content is within the range of 2% -3%. Taking out the granules, and sieving with 80 mesh sieve to obtain dry granules.
(4) Total mixing
Adding additional auxiliary material magnesium stearate 1.0 mg/tablet, and mixing uniformly.
(5) Tabletting
The tablet hardness is 5-9 kg.
(6) Coating film
Dispersing Opadry (14F1200) in water, stirring uniformly, and sieving with 80 mesh sieve to obtain coating solution. Putting the tablet core into a coating pan, controlling the rotation speed of the coating pan at 3-14rpm, the temperature of the tablet bed at 35-55 deg.C, the air intake temperature at 50-85 deg.C, the spray rotation speed at 20-60rpm, increasing the weight of the coating by about 4%, cooling the temperature in the coating pan to below 40 deg.C after coating, and taking out the tablet.
Comparative example 1
Rivaroxaban oral solid preparation disclosed in Chinese patent ZL200480035106.X and preparation method thereof
(1) Prescription
Hydroxypropyl methylcellulose (5cp) and sodium lauryl sulfate were dissolved in water and micronized rivaroxaban was suspended into this solution. The suspension thus prepared is sprayed as granulation liquid onto the mass consisting of microcrystalline cellulose, lactose monohydrate and croscarmellose sodium in the fluid bed granulation stage. Magnesium stearate was added and mixed after drying and sieving (mesh width of 0.8 mm) the resulting granules. The compressible blend thus obtained is compressed into tablets of 6mm diameter and 50-100N hardness. The tablets were then coated with titanium dioxide suspended in an aqueous solution consisting of hydroxypropyl methylcellulose (15cp) and polyethylene glycol.
Comparison of dissolution results
The invention does not need to carry out special micronization treatment on the raw material medicines, does not need to adopt a complicated process of preparing hydrophilic medicine-containing particles by using a hydrophilic adhesive, prepares suspension of API + SDS by heating and stirring the wetting agent/cosolvent SDS and the API and an ultrasonic dispersion method, adds the suspension into a mixture of other auxiliary materials, carries out wet granulation and drying, carries out size stabilization by a sieve with 80 meshes, carries out tabletting and carries out coating. The preparation method is simple, convenient and stable, and the prepared tablet can greatly improve the dissolution speed of the tablet, and achieve the technical effects that the dissolution is more than 85% in 5min and more than 90% in 10min, thereby realizing the development requirements of BCSII low-dissolution and high-permeability pharmaceutical preparations.
Claims (2)
1. The rivaroxaban tablet comprises the following components in percentage by weight: 10mg of rivaroxaban, 2mg of sodium lauryl sulfate, 40mg of microcrystalline cellulose, 30mg of lactose monohydrate, 6mg of croscarmellose sodium, 0.6mg of magnesium stearate and 30mg of purified water, wherein the particle size of rivaroxaban D90 is 82 μm; the rivaroxaban tablet is prepared by the following preparation method, and the preparation method comprises the following steps:
(1) preparing a suspension
Dissolving the prescription amount of sodium dodecyl sulfate in the prescription amount of purified water, adding the prescription amount of rivaroxaban to suspend in the solution after the sodium dodecyl sulfate is completely dissolved, stirring for 1h at 40 ℃, and then carrying out ultrasonic treatment on the suspension for 1 h;
(2) premixing
Uniformly mixing the microcrystalline cellulose, lactose monohydrate and croscarmellose sodium according to the prescription amount to obtain a premix;
(3) granulating and straightening
Slowly and uniformly adding the suspension obtained in the step (1) into the premix obtained in the step (2) to prepare a soft material, and granulating through a 40-mesh screen; drying in a forced air drying oven at 55 +/-5 ℃ until the moisture is within the range of 2-3%; taking out the granules, and sieving with a 80-mesh sieve to obtain dry granules;
(4) total mixing
Adding 0.6 mg/tablet of magnesium stearate as an additional auxiliary material, and uniformly mixing;
(5) tabletting
The tabletting hardness range is 5-9 kg;
(6) coating film
Dispersing Opadry Y-1-7000 in water, stirring, and sieving with 80 mesh sieve to obtain coating solution; putting the tablet core into a coating pan, controlling the rotation speed of the coating pan at 3-14rpm, the temperature of the tablet bed at 35-55 deg.C, the air intake temperature at 50-85 deg.C, the spray rotation speed at 20-60rpm, increasing the weight of the coating by about 4%, cooling the temperature in the coating pan to below 40 deg.C after coating, and taking out the tablet.
2. The rivaroxaban tablet comprises the following components in percentage by weight: 15mg of rivaroxaban, 5mg of sodium lauryl sulfate, 60mg of microcrystalline cellulose, 40mg of lactose monohydrate, 9mg of croscarmellose sodium, 1.0mg of magnesium stearate and 40mg of purified water, wherein the particle size of the rivaroxaban D90 is 38 μm; the rivaroxaban tablet is prepared by the following preparation method, and the preparation method comprises the following steps:
(1) preparing a suspension
Dissolving the prescription amount of sodium dodecyl sulfate in the prescription amount of purified water, adding the prescription amount of rivaroxaban to suspend in the solution after the sodium dodecyl sulfate is completely dissolved, stirring for 1h at 40 ℃, and then carrying out ultrasonic treatment on the suspension for 1.5 h;
(2) premixing
Uniformly mixing the microcrystalline cellulose, lactose monohydrate and croscarmellose sodium according to the prescription amount to obtain a premix;
(3) granulating and straightening
Slowly and uniformly adding the suspension obtained in the step (1) into the premix obtained in the step (2) to prepare a soft material, and granulating through a 40-mesh screen; drying the mixture by a fluidized bed at 50-70 ℃ until the water content is within the range of 2-3%; taking out the granules, and sieving with a 80-mesh sieve to obtain dry granules;
(4) total mixing
Adding additional auxiliary material magnesium stearate 1.0 mg/tablet, and mixing uniformly;
(5) tabletting
The tabletting hardness range is 5-9 kg;
(6) coating film
Dispersing Opadry 14F1200 in water, stirring uniformly, and sieving with a 80-mesh sieve to obtain a coating solution; putting the tablet core into a coating pan, controlling the rotation speed of the coating pan at 3-14rpm, the temperature of the tablet bed at 35-55 deg.C, the air intake temperature at 50-85 deg.C, the spray rotation speed at 20-60rpm, increasing the weight of the coating by about 4%, cooling the temperature in the coating pan to below 40 deg.C after coating, and taking out the tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910211402.9A CN109745295B (en) | 2019-03-15 | 2019-03-15 | Rivaroxaban oral solid preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910211402.9A CN109745295B (en) | 2019-03-15 | 2019-03-15 | Rivaroxaban oral solid preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109745295A CN109745295A (en) | 2019-05-14 |
| CN109745295B true CN109745295B (en) | 2021-11-12 |
Family
ID=66408942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910211402.9A Active CN109745295B (en) | 2019-03-15 | 2019-03-15 | Rivaroxaban oral solid preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109745295B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111346064B (en) * | 2020-03-10 | 2022-03-29 | 南京嘉晨医药科技有限公司 | Rivaroxaban tablet and preparation method thereof |
| CN115590856A (en) * | 2022-10-31 | 2023-01-13 | 南京海纳医药科技股份有限公司（Cn） | Rivaroxaban-containing pharmaceutical composition and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2266541A1 (en) * | 2009-06-18 | 2010-12-29 | Krka Tovarna Zdravil, D.D., Novo Mesto | Solid pharmaceutical composition comprising rivaroxaban |
| CN104337787A (en) * | 2013-08-06 | 2015-02-11 | 江苏豪森药业股份有限公司 | Rivaroxaban-containing pharmaceutical preparation |
| CN104721156A (en) * | 2013-12-18 | 2015-06-24 | 山东新时代药业有限公司 | Rivaroxaban-containing tablets |
-
2019
- 2019-03-15 CN CN201910211402.9A patent/CN109745295B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2266541A1 (en) * | 2009-06-18 | 2010-12-29 | Krka Tovarna Zdravil, D.D., Novo Mesto | Solid pharmaceutical composition comprising rivaroxaban |
| CN104337787A (en) * | 2013-08-06 | 2015-02-11 | 江苏豪森药业股份有限公司 | Rivaroxaban-containing pharmaceutical preparation |
| CN104721156A (en) * | 2013-12-18 | 2015-06-24 | 山东新时代药业有限公司 | Rivaroxaban-containing tablets |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109745295A (en) | 2019-05-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5714492B2 (en) | Granules, methods for their preparation, and pharmaceuticals containing them | |
| KR101151117B1 (en) | Method for the production of a solid, orally applicable pharmaceutical composition | |
| RU2466717C2 (en) | Pharmaceutical solid preparation containing benzazepin and method for preparing it | |
| MX2007008162A (en) | Sustained release pharmaeutical formulations. | |
| KR20100121483A (en) | Tablet having improved elution properties | |
| KR20180125574A (en) | Oral preparation with excellent elution property | |
| CN109745295B (en) | Rivaroxaban oral solid preparation and preparation method thereof | |
| WO2011079609A1 (en) | Preparation method of solid formulations and solid formulations prepared thereby | |
| JP6639024B2 (en) | Amorphous solifenacin-containing formulation with improved chemical stability | |
| CN110755392A (en) | Rivaroxaban tablet pharmaceutical composition and preparation method thereof | |
| CN111888477B (en) | Bedaquinoline pharmaceutical preparation | |
| CN106913537B (en) | Abiraterone acetate sublingual tablet and preparation method thereof | |
| CN111467317B (en) | Pharmaceutical composition containing atorvastatin calcium and preparation method thereof | |
| JPH04159222A (en) | Production of solid preparation for oral administration | |
| CN109925293B (en) | Eplerenone oral solid preparation and preparation method thereof | |
| CN107744509B (en) | Mosapride citrate tablet and preparation method thereof | |
| JP3007387B2 (en) | Base powder for sustained release formulation | |
| WO2020122244A1 (en) | Tablet and method for producing same | |
| CN105853367B (en) | The preparation method and its pharmaceutical preparation of Deferasirox solid dispersions | |
| CN117045610B (en) | High-stability dissolution labetalol hydrochloride composition and preparation method thereof | |
| JP6199922B2 (en) | Irbesartan-containing tablets with improved chemical stability | |
| CN112999176B (en) | Acertinib tablet | |
| CN115590833B (en) | Lercanidipine hydrochloride tablet composition with high dissolution stability and preparation method thereof | |
| WO2022100641A1 (en) | Pharmaceutical composition containing egfr inhibitor, and preparation method therefor | |
| CN102805745B (en) | Iloperidone composition and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |