CN105943508A - Rivaroxaban-containing pharmaceutical composition and preparation method thereof - Google Patents
Rivaroxaban-containing pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN105943508A CN105943508A CN201610358812.2A CN201610358812A CN105943508A CN 105943508 A CN105943508 A CN 105943508A CN 201610358812 A CN201610358812 A CN 201610358812A CN 105943508 A CN105943508 A CN 105943508A
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- razaxaban
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- lactose monohydrate
- magnesium stearate
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- 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
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- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention aims at providing a rivaroxaban-containing composition, prepared from rivaroxaban, lactose monohydrate, lauryl sodium sulfate and other acceptable pharmaceutical excipients. The invention also provides a preparation method of the rivaroxaban-containing composition. The method can remarkably improve the dissolution rate of medicines, and the dissolution behaviors of the medicines are superior to those of original developed preparations.
Description
Technical field
The present invention relates to the compositions of a kind of razaxaban medicine, be specifically related to razaxaban sheet and preparation method thereof, belong to field of medicaments.
Background technology
Razaxaban sheet, is the oral drugs of a kind of high selectivity direct inhibitive factor Xa, can high selectivity, competitive inhibition be free and the Xa factor that combines and prothrombin activity, thus extend clotting time.Principal indication is clinically: 1. be used for select a time hip joint or replacement knee in arthroplasty adult patients, to prevent venous thrombosis (VTE).2. it is used for treating adult's venous thrombosis (DVT), reduces DVT recurrence and the risk of pulmonary infarction (PE) after acute DVT.3. it is used for the nonvalvular atrial fibrillation adult patients with one or more risk factors (such as: congestive heart failure, hypertension, age >=75 year old, diabetes, apoplexy or transient ischemic attack medical history), to reduce the risk of apoplexy and systemic embolism.First this medicine listed in Europe in 2008, within 2011, listed in the U.S., and 2010 in Chinese granted listing.
Razaxaban belongs to II class medicine (low dissolving in Biopharmaceutics Classification system (BCS), Thief zone), dissolubility becomes the biggest obstacle of its In Vitro Dissolution and body absorption, in Yuan Yan producer patent (CN1886120B), its hydrophiling is made by being suspended in binder solution by the razaxaban after micronization, fluid bed wet granulation, quickly discharged and significantly improved the razaxaban tablet of bioavailability, but the preparation technology in this patent is relatively cumbersome, and the time of processing of pelletizing is longer.
Using micronization principal agent in WO2010146179A2 and adjuvant is co-mulled and made into, hot-melt extruded, dry granulation technology prepare oral solid formulation, the pharmaceutical preparation dissolution rate obtained can reach 30min at least dissolution 70%, but this technique is complex.
Method disclosed in CN200680045548.1, is prepared the razaxaban of amorphous state and crystal formation II, then is applied in oral solid pharmaceutical formulation, can significantly improve its dissolution rate and bioavailability by dissolution method, fusion method, extrusion by melting.But the razaxaban due to its amorphous or metastable type used, can be affected by stability problem, and owing to razaxaban crude drug dissolubility is poor, use dissolution method to need to use substantial amounts of solvent, it is difficult to industrialized production, uses fusion method preparation then can produce disadvantageous degraded composition.
Preparation method disclosed in CN103550165A, by the wet granulation technology preparation blank granules without razaxaban, again blank granules is prepared by mixing into solid preparation with razaxaban and other adjuvants, the method can be effectively improved the dissolution rate of razaxaban, crude drug after single micronization is big with blank granules particle size differences, and mixing homogeneity is difficult to ensure that.
Preparation method disclosed in CN104055743A, uses dry powder vertical compression technology, and technique is simple, and single-prescription is complicated, need to use more than 10 kind adjuvants altogether.
Summary of the invention
It is an object of the invention to provide a kind of pharmaceutical composition comprising razaxaban, a kind of pharmaceutical composition comprising razaxaban, and preparation method thereof.The dissolution of medicine can be significantly improved, and drug-eluting behavior is better than former triturate.
The present invention provides a kind of razaxaban pharmaceutical composition, described composition component is based on following weight portion: razaxaban 8 ~ 12 parts, lactose monohydrate 29.5 ~ 38.25 parts, microcrystalline Cellulose 31.45 ~ 39.95 parts, sodium lauryl sulphate 0.85 ~ 4.25 part, hydroxypropyl methylcellulose 1.7 ~ 5.1 parts, cross-linking sodium carboxymethyl cellulose 2.55 ~ 5.1 parts, magnesium stearate 0.1～1 part.
The present invention also provides for a kind of method preparing above-mentioned razaxaban compositions, it comprises the steps of and razaxaban raw material is micronized to D90 is 5-25 μm, by the razaxaban after micronization, lactose monohydrate, microcrystalline Cellulose, sodium lauryl sulphate, hydroxypropyl methylcellulose, cross-linking sodium carboxymethyl cellulose pelletize, again this granules is mixed with magnesium stearate, and tabletting.
In above-mentioned composition, described lactose monohydrate weight portion is preferably 31.5 ~ 36.25 parts, more preferably 34 parts.
In above-mentioned composition, described microcrystalline Cellulose weight portion is preferably 33.45 ~ 37.95 parts, more preferably 35.7 parts.
In above-mentioned composition, described sodium lauryl sulphate weight portion is preferably 1.05 ~ 4 parts, more preferably 2.55 parts.
In above-mentioned composition, described hydroxypropyl methylcellulose weight portion is preferably 2 ~ 4.8 parts, more preferably 3.4 parts.
In above-mentioned composition, described cross-linking sodium carboxymethyl cellulose weight portion is preferably 3 ~ 4 parts, more preferably 2.55 parts.
In above-mentioned composition, described magnesium stearate weight portion is preferably 0.3 ~ 0.7 part, more preferably 0.55 part.
In the present invention, prilling process is had no particular limits, as long as medicine and excipient can be formed the form of pelletize.Described prilling process can be enumerated: such as, utilizes the various prilling process such as spray drying method, fluosolids comminution granulation, stirring-granulating method, rotation comminution granulation to be prepared.
The solid composite medicament of the razaxaban that the present invention provides, the preparation of preparation has higher dissolution, significantly improves bioavailability, has the biggest social benefit.
Detailed description of the invention
Embodiments of the invention are only used for illustrating that the present invention provides, and are not the restrictions for the present invention.So the simple modifications of the present invention all being belonged to the scope of protection of present invention under the method premise of the present invention.
Embodiment 1
Razaxaban crude drug 500g jet mill is pulverized 1 hour, obtains the micronization crude drug that granularity D90 is 10 μm.By micronized razaxaban 8g, lactose monohydrate 29.75g, microcrystalline Cellulose 35.7g, sodium lauryl sulphate 4.25g, hydroxypropyl methylcellulose 1.7g, cross-linking sodium carboxymethyl cellulose 3.825g, magnesium stearate 0.1g mixing granulation.Utilize tablet machine, use diameter 8.0mm, the drift of curvature 9.6R, beating under conditions of sheet pressure is 12kN, by this mixture forming be weight be the tablet of 85mg, the hardness of obtained tablet is 55N.
Embodiment 2
By the micronized razaxaban crude drug 9g of preparation, lactose monohydrate 38.25g, microcrystalline Cellulose 31.45g, sodium lauryl sulphate 0.85g, hydroxypropyl methylcellulose 1.7g, cross-linking sodium carboxymethyl cellulose 2.55g, the mixing pelletize of magnesium stearate 0.3g in embodiment 1.Utilize tablet machine, use diameter 8.0mm, the drift of curvature 9.6R, beating under conditions of sheet pressure is 12kN, by this mixture forming be weight be the tablet of 85mg, the hardness of obtained tablet is 50N.
Embodiment 3
By the micronized razaxaban crude drug 10g of preparation, lactose monohydrate 34g, microcrystalline Cellulose 31.45g, sodium lauryl sulphate 4.25g, hydroxypropyl methylcellulose 1.7g, cross-linking sodium carboxymethyl cellulose 2.55g, the mixing pelletize of magnesium stearate 0.5g in embodiment 1.Utilize tablet machine, use diameter 8.0mm, the drift of curvature 9.6R, beating under conditions of sheet pressure is 12kN, by this mixture forming be weight be the tablet of 85mg, the hardness of obtained tablet is 55N.
Embodiment 4
By the micronized razaxaban crude drug 11g of preparation, lactose monohydrate 29.75g, microcrystalline Cellulose 39.95g, sodium lauryl sulphate 0.85g, hydroxypropyl methylcellulose 1.7g, cross-linking sodium carboxymethyl cellulose 2.55g, the mixing pelletize of magnesium stearate 0.7g in embodiment 1.Utilize tablet machine, use diameter 8.0mm, the drift of curvature 9.6R, beating under conditions of sheet pressure is 12kN, by this mixture forming be weight be the tablet of 85mg, the hardness of obtained tablet is 50N.
Embodiment 5
By the micronized razaxaban crude drug 12g of preparation, lactose monohydrate 29.75g, microcrystalline Cellulose 34g, sodium lauryl sulphate 2.55g, hydroxypropyl methylcellulose 5.1g, cross-linking sodium carboxymethyl cellulose 2.55g, the mixing pelletize of magnesium stearate 0.9g in embodiment 1.Utilize tablet machine, use diameter 8.0mm, the drift of curvature 9.6R, beating under conditions of sheet pressure is 12kN, by this mixture forming be weight be the tablet of 85mg, the hardness of obtained tablet is 50N.
Embodiment 6
By the micronized razaxaban crude drug 10g of preparation, lactose monohydrate 29.75g, microcrystalline Cellulose 34g, sodium lauryl sulphate 2.55g, hydroxypropyl methylcellulose 3.4g, cross-linking sodium carboxymethyl cellulose 5.1g, the mixing pelletize of magnesium stearate 1.0g in embodiment 1.Utilize tablet machine, use diameter 8.0mm, the drift of curvature 9.6R, beating under conditions of sheet pressure is 12kN, by this mixture forming be weight be the tablet of 85mg, the hardness of obtained tablet is 55N.
Embodiment 7
By the micronized razaxaban crude drug 10g of preparation, lactose monohydrate 29.75g, microcrystalline Cellulose 32.3g, sodium lauryl sulphate 3.83g, hydroxypropyl methylcellulose 5.1g, cross-linking sodium carboxymethyl cellulose 3.4g, the mixing pelletize of magnesium stearate 0.55g in embodiment 1.Utilize tablet machine, use diameter 8.0mm, the drift of curvature 9.6R, beating under conditions of sheet pressure is 12kN, by this mixture forming be weight be the tablet of 85mg, the hardness of obtained tablet is 50N.
Embodiment 8
Using 2015 editions annex dissolution detection methods of Chinese Pharmacopoeia to detect above-described embodiment 1 ~ 7 gained tablet, and detect former triturate, result is as follows:
| 5min | 10min | 15min | 20min | 30min | 45min | 60min | |
| Embodiment 1 | 59.4% | 90.3% | 95.6% | 95.6% | 98.7% | 98.7% | 98.8% |
| Embodiment 2 | 57.1% | 85.2% | 95.3% | 95.2% | 99.1% | 99.1% | 99.1% |
| Embodiment 3 | 55.1% | 83.2% | 93.8% | 95.0% | 95.1% | 98.6% | 98.7% |
| Embodiment 4 | 59.1% | 87.3% | 95.3% | 95.3% | 98.9% | 98.9% | 98.9% |
| Embodiment 5 | 62.1% | 90.2% | 97.3% | 97.3% | 99.3% | 99.3% | 99.3% |
| Embodiment 6 | 58.1% | 86.2% | 94.2% | 94.2% | 97.3% | 97.3% | 98.9% |
| Embodiment 7 | 59.4% | 88.1% | 95.8% | 95.8% | 99.3% | 99.3% | 99.3% |
| Former triturate | 56.7% | 84.3% | 93.7% | 94.8% | 94.9% | 96.1% | 96.1% |
Testing result illustrates, the sample (embodiment 1 ~ 7) using the inventive method to prepare, and has Fast Stripping speed, and is better than former triturate dissolved corrosion, but the formulation and technology of the present invention is the simplest, and is prone to industrialized production.
Claims (3)
1. a razaxaban pharmaceutical composition, it is characterized in that: described composition component is based on following weight portion: razaxaban 8 ~ 12 parts, lactose monohydrate 29.5 ~ 38.25 parts, microcrystalline Cellulose 31.45 ~ 39.95 parts, sodium lauryl sulphate 0.85 ~ 4.25 part, hydroxypropyl methylcellulose 1.7 ~ 5.1 parts, cross-linking sodium carboxymethyl cellulose 2.55 ~ 5.1 parts, magnesium stearate 0.1～1 part.
2. razaxaban compositions as claimed in claim 1, it is characterized in that, described composition components is razaxaban 10 parts based on following weight portion, lactose monohydrate 34 parts, microcrystalline Cellulose 35.7 parts, sodium lauryl sulphate 2.55 parts, hypromellose 3.4 parts, cross-linked carboxymethyl cellulose receives 3.825 parts, magnesium stearate 0.55 part.
3. the preparation method preparing razaxaban compositions as claimed in claim 1 or 2, it comprises the steps of and razaxaban raw material is micronized to D90 is 5-25 μm, by the razaxaban after micronization, lactose monohydrate, microcrystalline Cellulose, sodium lauryl sulphate, hydroxypropyl methylcellulose, cross-linking sodium carboxymethyl cellulose pelletize, again this granules is mixed with magnesium stearate, and tabletting.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610358812.2A CN105943508A (en) | 2016-05-27 | 2016-05-27 | Rivaroxaban-containing pharmaceutical composition and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610358812.2A CN105943508A (en) | 2016-05-27 | 2016-05-27 | Rivaroxaban-containing pharmaceutical composition and preparation method thereof |
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| CN105943508A true CN105943508A (en) | 2016-09-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610358812.2A Pending CN105943508A (en) | 2016-05-27 | 2016-05-27 | Rivaroxaban-containing pharmaceutical composition and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| JP2020029455A (en) * | 2018-08-20 | 2020-02-27 | 大原薬品工業株式会社 | Solid preparation containing finely crushed rivaroxaban |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015097090A1 (en) * | 2013-12-23 | 2015-07-02 | Laboratorios Del Dr. Esteve, S.A. | Oral pharmaceutical composition |
| 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 |
-
2016
- 2016-05-27 CN CN201610358812.2A patent/CN105943508A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015097090A1 (en) * | 2013-12-23 | 2015-07-02 | Laboratorios Del Dr. Esteve, S.A. | Oral pharmaceutical composition |
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| JP2020029455A (en) * | 2018-08-20 | 2020-02-27 | 大原薬品工業株式会社 | Solid preparation containing finely crushed rivaroxaban |
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Application publication date: 20160921 |
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