CN106727506B - A kind of composition and preparation method thereof, purposes - Google Patents
A kind of composition and preparation method thereof, purposes Download PDFInfo
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- CN106727506B CN106727506B CN201611107818.9A CN201611107818A CN106727506B CN 106727506 B CN106727506 B CN 106727506B CN 201611107818 A CN201611107818 A CN 201611107818A CN 106727506 B CN106727506 B CN 106727506B
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- composition
- warfarin sodium
- pharmaceutically acceptable
- dry granulation
- warfarin
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- 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)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of compositions and preparation method thereof, purposes, one of composition, include pharmaceutically acceptable excipient and warfarin sodium, and the composition is prepared by dry granulation, the present invention can ensure that the stability of crystal form in production process using dry granulation to avoid solid-state unstability of the warfarin sodium isopropanol solvate under wet granulation production technology；It avoids thermal sensitivity degradation impurity from generating, has ensured product in the stability of shelf life and the validity of clinical application and safety.
Description
Technical field
The present invention relates to drug fields more particularly to a kind of composition and preparation method thereof, purposes.
Background technique
Warfarin sodium bulk pharmaceutical chemicals are warfarin sodium isopropanol solvate, and isopropanol is easy in conventional wet-granulation process
In losing, lead to the change of warfarin sodium crystal form, and influences Clinical efficacy and safety.It is thus impossible to using conventional wet lay
Granulating process prepares warfarin sodium pharmaceutical composition.
Summary of the invention
The present invention provides a kind of composition and preparation method thereof, purposes, and wherein composition includes pharmaceutically acceptable tax
Shape agent and warfarin sodium and the composition are prepared by dry granulation, can be to avoid warfarin sodium using dry granulation
Solid-state unstability of the isopropanol solvate under wet granulation production technology；It avoids thermal sensitivity degradation impurity from generating, ensures
Product is in the stability of shelf life and validity, the safety of clinical application, and uses dry granulation, ensure that preparation mistake
The stability of crystal form in journey, it is ensured that the validity and safety that preparation is clinically applied.
Of the invention adopts the following technical scheme that
A kind of composition, the composition include pharmaceutically acceptable excipient and warfarin sodium, wherein warfarin sodium
Amount be greater than dry particl weight 0.45%, the amount of further preferably warfarin sodium is the 1~1.25% of dry particl weight.
As the preferred technical solution of the present invention, the warfarin sodium is warfarin sodium isopropanol solvate, wherein doing
The water content of particle is 1~5% weight, and water content is measured by Karl Fischer method.
As the preferred technical solution of the present invention, the pharmaceutically acceptable excipient is pharmaceutically acceptable disintegration
Agent, pharmaceutically acceptable filler, pharmaceutically acceptable adhesive, at least one in pharmaceutically acceptable lubricant
Kind.
As the preferred technical solution of the present invention, the raw material composition including following mass parts: warfarin sodium 10-100g, medicine
Acceptable filler 1200-2000g, pharmaceutically acceptable disintegrating agent 50-600g, pharmaceutically acceptable lubricant on
5-50g。
As the preferred technical solution of the present invention, the pharmaceutically acceptable disintegrating agent be starch or pregelatinized starch or
Microcrystalline cellulose.
As the preferred technical solution of the present invention, the pharmaceutically acceptable filler is lactose or Lactis Anhydrous.
As the preferred technical solution of the present invention, the pharmaceutically acceptable excipient is magnesium stearate or stearic acid.
Another side of the invention, a kind of preparation method of composition, comprising the following steps:
It carries out smashed warfarin sodium, excipient to be mixed to get mixture；
Mixture obtained above is carried out to dry granulation in dry granulating machine and obtains particle；
Tabletting is carried out after particle obtained above is mixed with magnesium stearate obtains the composition.
As the preferred technical solution of the present invention, it is described smashed warfarin sodium, excipient be mixed to get it is mixed
Close object the step of include:
Smashed warfarin sodium, pharmaceutically acceptable filler, pharmaceutically acceptable disintegrating agent are passed with measuring again
Increasing method carries out being mixed to get mixture；
Detection obtains the intermediates content of mixture, qualified then carry out next step.
One side again of the invention, a kind of purposes of composition in medicine preparation, the composition are used for anticoagulant therapy.
The invention has the following advantages: 1, warfarin sodium pharmaceutical composition is prepared using dry granulation, to keep away
Exempted from influence of the damp and hot factor to warfarin stable sodium in wet-granulation process, make dry-pressing granulation front and back warfarin sodium crystal form and
Related substance is substantially unchanged；2, using dry granulation, it ensure that the stability of crystal form in production process, ensure that preparation
The validity and safety clinically applied；It 3, can be to avoid warfarin sodium isopropanol solvate at it using dry granulation
Solid-state unstability under his wet process technique；It avoids thermal sensitivity degradation impurity from generating, ensures product in the stabilization of shelf life
Validity, the safety of property and clinical application.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical scheme in the embodiment of the invention is clearly and completely described,
Obviously, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based in the present invention
Embodiment, every other embodiment obtained by those of ordinary skill in the art without making creative efforts, all
Belong to the scope of protection of the invention.
Embodiment 1: a kind of composition, includes pharmaceutically acceptable excipient and warfarin sodium, wherein warfarin sodium
Amount is greater than the 0.45% of dry particl weight, and the amount of further preferred warfarin sodium is the 1~1.25% of dry particl weight, the combination
Object is prepared by dry granulation, and wherein the loss on drying of dry particl is within 5%, preferably 5%, 3%, 2%.
Embodiment 2: a kind of composition, composition include pharmaceutically acceptable excipient and warfarin sodium, Chinese method
Woods sodium is warfarin sodium isopropanol solvate, the isopropanol comprising being no less than 0.085% weight.
Embodiment 3: a kind of composition includes pharmaceutically acceptable excipient and warfarin sodium, wherein can pharmaceutically connect
The excipient received is pharmaceutically acceptable disintegrating agent, pharmaceutically acceptable filler, pharmaceutically acceptable adhesive, medicine
At least one of acceptable lubricant on.
Embodiment 4: a kind of composition includes pharmaceutically acceptable excipient and warfarin sodium, wherein can pharmaceutically connect
The excipient received is pharmaceutically acceptable disintegrating agent, and further pharmaceutically acceptable disintegrating agent is starch or pregelatinized starch
Or microcrystalline cellulose.
Embodiment 5: a kind of composition includes pharmaceutically acceptable excipient and warfarin sodium, wherein can pharmaceutically connect
The excipient received is pharmaceutically acceptable filler, and further pharmaceutically acceptable filler is lactose or Lactis Anhydrous.
Embodiment 6: a kind of composition includes pharmaceutically acceptable excipient and warfarin sodium, wherein can pharmaceutically connect
The excipient received is pharmaceutically acceptable adhesive.
Embodiment 7: a kind of composition includes pharmaceutically acceptable excipient and warfarin sodium, wherein can pharmaceutically connect
The excipient received is pharmaceutically acceptable lubricant, and further, lubricant is the alkali metal salt of C8-C18 fatty acid, specifically may be used
Think magnesium stearate or stearic acid.
Embodiment 8: a kind of composition includes pharmaceutically acceptable excipient and warfarin sodium, wherein can pharmaceutically connect
The excipient received is magnesium stearate.
Embodiment 9: the raw material composition including following mass parts: warfarin sodium 10-100g, a kind of composition pharmaceutically may be used
The filler 1200-2000g of receiving, pharmaceutically acceptable disintegrating agent 50-600g, pharmaceutically acceptable lubricant 5-50g.
Wherein warfarin sodium has the tablet of multiple and different specifications, and different warfarin sodium contents is selected according to different specifications.
Embodiment 10: a kind of composition, the raw material composition including following mass parts: warfarin sodium 25g, lactose 1800g form sediment
Powder 200g, magnesium stearate 15g.
Embodiment 11: a kind of composition, the raw material composition including following mass parts: warfarin sodium 10g, lactose 1200g form sediment
Powder 85g, magnesium stearate 15g.
Embodiment 12: a kind of composition, the raw material composition including following mass parts: warfarin sodium 25g, Lactis Anhydrous
2000g, starch 200g, magnesium stearate 15g.
Embodiment 13: a kind of composition, the raw material composition including following mass parts: warfarin sodium 35g, lactose 1400g, in advance
Gelling starch 260g, magnesium stearate 15g.
Embodiment 14: a kind of composition, the raw material composition including following mass parts: warfarin sodium 25g, lactose 1600g, in advance
Gelling starch 150g, microcrystalline cellulose 300g, stearic acid 20g.
Embodiment 15: a kind of composition, the raw material composition including following mass parts: warfarin sodium 35g, lactose 2000g, in advance
Gelling starch 480g, magnesium stearate 20g.
Embodiment 16: a kind of composition, the raw material composition including following mass parts: warfarin sodium 100g, lactose 2000g,
Pregelatinized starch 460g, magnesium stearate 20g
Another side of the invention, a kind of preparation method of composition, comprising the following steps:
Step S1: by smashed warfarin sodium, pharmaceutically acceptable filler, pharmaceutically acceptable disintegrating agent into
Row be mixed to get mixture, including, warfarin sodium is crushed through pulverizer, cross 80 meshes；By lactose, starch mistake respectively
100 sieves, discard agglomeration, specifically, warfarin sodium raw material, lactose, starch are carried out after tentatively mixing to measure incremental method again, set height
It is mixed in effect mixing machine, detects intermediates content, carry out next step operation after qualified.
Step S2: mixture obtained above is carried out to dry granulation in dry granulating machine and obtains particle, wherein dry method
The parameter of granulation are as follows: dry granulation parameter area are as follows: 10~40rpm of straight feeding speed；3~18rpm of idler wheel revolving speed；Idler wheel pressure
1~15MPa of power, further preferably are as follows: straight feeding speed 20rpm；Idler wheel revolving speed 12rpm；Roller pressure 3MPa.Granulating system
Middle sieve selects 16 mesh standard sieves.
Step S3: tabletting is carried out after particle obtained above is mixed with magnesium stearate and obtains the composition, is had
Body is that conforming particle is placed in three-dimensional mixer, and magnesium stearate is added and carries out total mix 15 minutes；Material obtained as above is carried out
Tabletting.
Embodiment 17, a kind of composition, the raw material composition including following mass parts: warfarin sodium 25g, lactose 1800g form sediment
Powder 200g, magnesium stearate 15g, preparation process are as follows: warfarin sodium is crushed through pulverizer, crosses 80 meshes；Lactose, starch are distinguished
100 sieves are crossed, agglomeration is discarded, specifically, warfarin sodium raw material, lactose, starch are carried out after tentatively mixing with measuring incremental method again, are set
It is mixed in high efficient mixer, detects intermediates content, next step operation is carried out after qualified, by the mixture after qualification in dry method system
Dry granulation is carried out in grain machine and obtains particle, wherein the parameter of dry granulation are as follows: straight feeding speed 20rpm；Idler wheel revolving speed
12rpm；Roller pressure 3MPa.Sieve selects 16 mesh standard sieves in granulating system, by particle obtained above and magnesium stearate into
Tabletting is carried out after row mixing and obtains the composition, specially conforming particle is placed in three-dimensional mixer, and magnesium stearate is added
It carries out total mix 15 minutes；Material obtained as above is subjected to tabletting.To illustrate that dry granulation through the invention, can make
To warfarin sodium composition have the advantage that 1, prepare warfarin sodium pharmaceutical composition using dry granulation, to keep away
Exempted from influence of the damp and hot factor to warfarin stable sodium in wet-granulation process, make dry-pressing granulation front and back warfarin sodium crystal form and
Related substance is substantially unchanged；2, using dry granulation, it ensure that the stability of crystal form in production process, it is ensured that preparation is facing
The validity and safety applied on bed；It 3, can be wet at other to avoid warfarin sodium isopropanol solvate using dry granulation
Solid-state unstability under method production technology；Avoid thermal sensitivity degradation impurity generate, ensure product shelf life stability and
The validity and safety of clinical application.
One side, composition of the invention again of the invention can be used for anticoagulant therapy, and in particular to dry granulation, by dry
Method is pelletized after obtained particle, Tabules can be made according to clinical requirement.
Isopropanol measures in the composition prepared in the present invention by dry granulation, as shown in table 1.
Instrument and equipment: Agilent 6890 (autosampler, fid detector, head-space sampler)；Carrier gas is high pure nitrogen；
Capillary column: the 101 white carriers for being coated with 10% polyethylene glycol 1500 are stationary phase, column flow rate: 1.8ml/min；Split ratio:
20:1.
Temperature programming: then 50 DEG C of holding 3.5min are warming up to 120 DEG C of holding 6min with 40 DEG C/min speed.
Sample injector temperature: 220 DEG C；Detector temperature: 240 DEG C；Sample volume: 1 μ l；
Prepared by reference substance solution and test solution: precision weighs isopropanol about 10mg, sets in 100mL measuring bottle, dilute with water
It releases to scale, shakes up, precision measures 5mL, and accurate plus inner mark solution (1% propanol solution) 5ml, mixes, molten as reference substance
Liquid.
Composition 4 of the another preparation of Example 17, are divided into two parts, split in two 10ml measuring bottles, in a measuring bottle
Precision plus inner mark solution 5ml, are dissolved in water respectively and are diluted to scale, shake up, and as containing the internal standard substance and are free of internal standard substance
Test solution.Above-mentioned solution is taken, is tested according to gas chromatography, the amount containing isopropanol in test sample is calculated；And by same
The method of sample measures the content of isopropanol in the warfarin sodium composition prepared by wet granulation, wherein the group prepared
At identical, that is to say, that formula is identical, and mode of only pelletizing is different, and the results are shown in Table 1.
Warfarin sodium content measures in the composition prepared in the present invention by dry granulation.
Instrument and equipment: Waters2695 high performance liquid chromatograph, Waters2998 diode array detector；Sai Duolisi
Electronic analytical balance (ten a ten thousandths), liquid-transfering gun, volumetric flask.
Chromatographic condition and system suitability: being filler with octadecylsilane chemically bonded silica；With acetonitrile-water-ice
Acetic acid (55:45:1) is mobile phase；Detection wavelength is 282nm.Warfarin sodium, BENZYLIDENE ACETONE and 4 hydroxy coumarin are taken, is added
It flows phased soln and dilutes and the respectively solution containing about 50mg is made in every lml, 20 μ l is taken to inject liquid chromatograph, record chromatogram,
Number of theoretical plate is calculated by warfarin sodium peak is not less than 2000, and 4 hydroxy coumarin peak and the separating degree at BENZYLIDENE ACETONE peak should be greater than
10.0, BENZYLIDENE ACETONE peak and the separating degree at warfarin sodium peak should be greater than 5.0.
Measuring method takes warfarin sodium reference substance, accurately weighed, add flowing phased soln and quantify dilution be made in every lml containing about
The solution of 50 μ g, as reference substance solution.
Composition 20 of the preparation of Example 17, accurately weighed, finely ground, precision, which weighs, (is approximately equivalent to warfarin in right amount
Sodium 5mg), it sets in 100ml measuring bottle, adds mobile phase appropriate, shaking dissolves warfarin sodium, and it is diluted to scale with mobile phase, is shaken up,
Filtration takes subsequent filtrate as test solution, and precision measures 20 μ l, measures according to the method under warfarin sodium content determination item.It presses
External standard method is with calculated by peak area；And measure the warfarin sodium composition prepared by wet granulation by the same method
The content of middle warfarin sodium, wherein the composition prepared is identical, that is to say, that formula is identical, and mode of only pelletizing is different (to be labeled as
Control sample a), the results are shown in Table 1.
Related content of material measures in the composition prepared in the present invention by dry granulation.
This product fine powder prepared by Example 17, adds mobile phase appropriate, and shaking dissolves warfarin sodium and dilute to be made often
Solution in lml containing about lmg, filtration, takes subsequent filtrate as test solution；Precision measures 1ml, sets in 200ml measuring bottle, with stream
Phase dilution is moved to scale, is shaken up, as contrast solution.According to the chromatographic condition under content determination item, accurate measurement test solution,
Each 20 μ l of contrast solution, is injected separately into liquid chromatograph, and 5 times of record chromatogram to principal component peak retention time.Test sample is molten
If any impurity peaks in the chromatogram of liquid, in addition to auxiliary material peak, the sum of each impurity peak area is not greater than the 2 of contrast solution main peak area
Again (1.0%)；And measure in the warfarin sodium composition prepared by wet granulation related object by the same method
The content of matter, wherein the composition prepared is identical, that is to say, that formula is identical, and mode of only pelletizing is different, and the results are shown in Table 1.
Table 1
Available from table 1, in the composition prepared by dry granulation, the content of isopropanol is bright 0.094% or more
The aobvious isopropanol content higher than in wet process preparation, so as to avoid factor damp and hot in wet-granulation process to warfarin stable sodium
Influence, that is to say, that improve the stability of warfarin sodium isopropanol solvate；Content in relation to substance is significantly lower than wet
Content in method preparation, avoids thermal sensitivity degradation impurity from generating, and ensures product in the stability of shelf life and having for clinical application
Effect property, safety；And effective warfarin sodium content is apparently higher than wet process in warfarin sodium composition by dry granulation
Effective warfarin sodium content in granulation.
The above description is merely a specific embodiment, but scope of protection of the present invention is not limited thereto, any
Those skilled in the art is in technical scope disclosed by the invention, and any changes or substitutions that can be easily thought of, all answers
It is included within the scope of the present invention.Therefore, protection scope of the present invention should be with the scope of protection of the claims
It is quasi-.
Claims (2)
1. a kind of composition is made of the raw material of following mass parts: warfarin sodium isopropanol solvent compound 25g, lactose
1800g, starch 200g, magnesium stearate 15g, preparation process are as follows: warfarin sodium isopropanol solvent compound is crushed through pulverizer,
Cross 80 meshes；Lactose, starch are crossed to 100 sieves respectively, agglomeration is discarded, next step operation is carried out after qualified, by the mixing after qualification
Object carries out dry granulation in dry granulating machine and obtains particle, wherein the parameter of dry granulation are as follows: straight feeding speed 20rpm；
Idler wheel revolving speed 12rpm；Roller pressure 3MPa；Tabletting is carried out after particle obtained above is mixed with magnesium stearate to obtain
The composition.
2. the purposes of composition in medicine preparation according to claim 1, which is characterized in that the composition is for anticoagulant
Blood treatment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611107818.9A CN106727506B (en) | 2016-12-06 | 2016-12-06 | A kind of composition and preparation method thereof, purposes |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611107818.9A CN106727506B (en) | 2016-12-06 | 2016-12-06 | A kind of composition and preparation method thereof, purposes |
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| Publication Number | Publication Date |
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| CN106727506A CN106727506A (en) | 2017-05-31 |
| CN106727506B true CN106727506B (en) | 2019-09-10 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CZ20032854A3 (en) * | 2003-10-17 | 2005-05-18 | Pliva - Lachema A.S. | Process for preparing dosage units of solid medicamentous form containing warfarin sodium salt as active |
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2016
- 2016-12-06 CN CN201611107818.9A patent/CN106727506B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| Physical Chemical Stability of Warfarin Sodium;Danchen Gao等;《AAPS Pharmsci》;20010116;第3卷(第1期);第1-8页，尤其是第1页摘要 |
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