CN108420798A - A kind of immediate release drug formulations of anti-coagulants and preparation method thereof - Google Patents
A kind of immediate release drug formulations of anti-coagulants and preparation method thereof Download PDFInfo
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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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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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
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/2036—Silicones; Polysiloxanes
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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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
The present invention relates to a kind of immediate release drug formulations of anti-coagulants and preparation method thereof, belong to pharmaceutical technology field.The immediate release drug formulations of the anti-coagulants include Vicagrel compound or its pharmaceutically acceptable form, the wherein described preparation is the form of tablet, capsule, the Vicagrel or its pharmaceutically acceptable form are provided with appropriate grain size, 50 μm of D90 ＜.The medicine-containing particle that the present invention obtains, its pharmaceutical preparation formed dissolves out the feature that quick release is shown in test in vitro, and comparable advantage is shown in pharmacokinetics in vivo, shows as the extent of drug absorption (AUC) and rate (C of biggermax).The present invention also provides the immediate release drug formulations preparation methods of the anti-coagulants, and the capsule or tablet quick releasing formulation of excellent in stability can be obtained by the combination of optional preparation process according to medicine-containing particle prescription disclosed by the invention.
Description
Technical field
The present invention provides immediate release drug formulations, specifically includes containing anti-coagulants Vicagrel and its acceptable salt carrier
Quick-release tablet or capsule, invention also provides the preparation methods of the immediate release drug formulations, belong to pharmaceutical technology field.
Background technology
Vicagrel is a kind of novel medicament for resisting platelet aggregation, can be used to overcome the clinic of existing antiplatelet drug to answer
With defect, such as the High risk of bleeding of " clopidogrel Resistant " and prasugrel.Vicagrel has been enter into clinical investigation phase, has
Prestige is developed into safer effective antiplatelet new drug.
Patent CN103254211B has been disclosed for Vicagrel and its preparation method of derivative, patent
CN103720700A discloses the composition of Vicagrel and aspirin, for preventing or treating disease caused by thrombus, but
Currently, there has been no the reports to Vicagrel single active ingredient preparation prescription technique.As anticoagulant, need fast in vivo
Speed reaches effective blood drug concentration and plays curative effect, and oral preparation of quick releasing exploitation is particularly necessary.
Invention content
The object of the present invention is to provide a kind of quick releasing formulations of Vicagrel.Based on this, the present invention devises one kind and is used for
Quick-release, can be capsule or tablet or granular form oral pharmaceutical preparation, it includes with Vicagrel or its pharmaceutically
Acceptable form.
The technical solution adopted in the present invention is：
A kind of immediate release drug formulations of anti-coagulants, including Vicagrel compound or its can pharmaceutically receive form,
It is characterized in that, wherein the preparation is the form of tablet, capsule, the Vicagrel or its pharmaceutically acceptable salt are with appropriate
Grain size provides, 50 μm of D90 ＜.
It is the pharmaceutically acceptable form of heretofore described Vicagrel, the including but not limited to salt of Vicagrel, molten
Agent compound and other pharmaceutically acceptable carriers, they have the pharmaceutical active of Vicagrel.
Quick releasing formulation provided by the present invention, bulk pharmaceutical chemicals are by crushing, 50 μm of the preferred D90 ＜ of grain size, further preferably
30 μm of D90 ＜, it is still further preferred that 15 μm of D90 ＜.
In one embodiment of the invention, immediate release drug formulations are for being filled into capsule or being formed containing for tablet
Medicine particle form comprising：
A) Vicagrel active constituent：Vicagrel or its pharmaceutically acceptable form；
B) one or more fillers；
C) one or more disintegrants；
D) one or more adhesives；
E) one or more glidant/lubricants.
Preferably, composition ratio is as follows：
A) the Vicagrel active constituent accounts for tablet or 0.5%~30%wt of capsule filling；
B) filler within the scope of tablet or 1%~95%wt of capsule filling to exist；
C) adhesive within the scope of tablet or 0%~20%wt of capsule filling to exist；
D) disintegrant within the scope of tablet or 0%~20%wt of capsule filling to exist；
E) glidant/lubricant within the scope of tablet or 0%~5%wt of capsule filling to exist；
F) stabilizer within the scope of 0%~5%wt to exist；
The percentage sum total of all compositions is 100%.
In one embodiment, medicine-containing particle includes Vicagrel and one or more fillers.Suitable filler
Include one or more combinations or known in the art such as microcrystalline cellulose, lactose, pregelatinized starch/starch, mannitol
Other common fillers.In other embodiments, medicine-containing particle optionally includes the one or more of following auxiliary material：(1) a kind of
Or a variety of adhesives；(2) one or more disintegrants；(3) one or more to help stream/lubricant.Suitable adhesive includes such as
Hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone and other substances known in the art.Suitable disintegration
Agent includes such as low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyethylene pyrrolidines
Ketone and other substances known in the art.Suitable stream/the lubricant that helps includes such as silica, magnesium stearate, stearoyl-fumarate
Sodium and other substances known in the art.
The medicine-containing particle when its be filled in capsule or it is tabletted after, Vicagrel with per unit preparation containing 1~
30mg forms exist, and daily daily dose is 1~30mg, can be that single dose or multi-dose are given, daily 1~4 time.
The present invention provides immediate release drug formulations, including tablet and capsule preparations, contains anticoagulant Vicagrel or dimension
Block Gray's salt, solvate or other pharmaceutically acceptable carriers.
The quick releasing formulation of the present invention, can be capsule, piece, the quick releasing formulation is embodied as being filled into capsule or compacting
The medicine-containing particle of piece agent.
" medicine-containing particle " described herein is including but not limited to pelletized with such as high shear, rolling granulation, spray drying system
The particle that particle is mixed to form with rear additional auxiliary material is made in interior plus auxiliary material by grain, the methods of lamination granulation, further includes by appropriate
The mixed-powder that the selection of excipient is formed after directly being mixed with API.
The quick releasing formulation of the present invention, may include drug excipient shown in this article, to contribute to form particle, particle, powder
The form at end, for filling capsule or tabletting.
Accounting in medicine-containing particle of the present invention is not added surely before being equal to materials result or filling capsule in measurement
Determine the weight percent of agent (optionally).
In medicine-containing particle of the present invention, Vicagrel or its pharmaceutically acceptable form accounting in medicine-containing particle are
0.5%~30%wt, preferably accounting are 1%~20%.
Filler exists to account within the scope of 1%~95%wt of medicine-containing particle in medicine-containing particle, it is further preferable that filler with
It measures and exists within the scope of 10%~85%wt of medicine-containing particle.The filler include but not limited to microcrystalline cellulose, lactose, starch,
Pregelatinized starch, mannitol, sorbierite and known filler commonly used in the art.Preferably microcrystalline cellulose, lactose, pregelatinated form sediment
Powder and mannitol, wherein lactose to exist in 10%~75% range of medicine-containing particle, mannitol with the 10% of medicine-containing particle~
75% range exists, and pregelatinized starch exists with 5%~65% range of medicine-containing particle filler, and microcrystalline cellulose is with drug containing
Exist in 10%~60% range of grain；
Adhesive exists with the amount within the scope of 0%~20%wt of medicine-containing particle, preferably 1%~10%wt ranges.Applicable
Adhesive include but not limited to hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, ethyl cellulose and its
One or more mixing of its traditional binders.It is preferred that hydroxypropyl methyl cellulose, hydroxypropyl cellulose.
Disintegrant exists with the amount within the scope of 0%~20%wt of medicine-containing particle, preferably 1%~10%wt ranges.Applicable
Disintegrant includes but not limited to low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, the poly- second of crosslinking
Alkene pyrrolidone.It is preferred that sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose.
Stream/lubricant is helped to exist with the amount within the scope of 0%~5%wt of medicine-containing particle, preferably 0.2%~2% range.It is applicable in
The stream/lubricant that helps include hydrogenated vegetable oil, silica, magnesium stearate, sodium stearyl fumarate, preferably stearic acid, tristearin
Acyl fumaric acid sodium.
, according to the invention it is preferred to medicine-containing particle prescription constitute it is as follows：
Invention further provides the quick releasing formulation preparation methods comprising following steps：
A) the Vicagrel powdered active ingredient of micronizing, 50 μm of D90 ＜ are provided；Vicagrel reactive powder refers to dimension card
The Micronised form of Gray or its pharmaceutically acceptable form；
B) Vicagrel powdered active ingredient and auxiliary agent are mixed and made into medicine-containing particle；
C) by medicine-containing particle by filling, tabletting or filling method obtain Vicagrel capsule or piece.
In the method for the present invention step a), the breaking method of micronizing is carried out using this field routine crushing technology, the skill
Art include but not limited to grind, squeeze, collision, cutting, grinding device used include but not limited to ball mill, airslide disintegrating mill,
Beater grinder.More preferably use air flow crushing device.
In the method for the present invention step b), the preparation of medicine-containing particle can be used dry granulation, wet granulation or directly mix
Mode can be specifically：
B1) Vicagrel active constituent and one or more fillers are mixed together by arbitrary required sequence；At other
It, can be with random order by Vicagrel or its pharmaceutical acceptable carrier and one or more fillers and optionally in embodiment
One or more following compounds be mixed together：One or more adhesives；One or more disintegrants；It is one or more to help
Stream/lubricant；The mixed method uses this field conventional mixing apparatus, including but not limited to three-dimensional mixer, V-type mixing
Machine is stirred, fluidisation mixing.
B2) optionally, pelletized using the method for wet method or dry method.Using the method for wet granulation, by b1) in it is mixed
By wet granulation equipment, spray adhesive is allowed to coalescence and forms particle material, dries whole grain later；Using the side of dry granulation
Method, by b1) in mixed material be added after lubricant rolled by dry granulating machine after formation material strip band, band is crushed
Particle is obtained after screening.The wet granulation method includes with high shear mixing granulation, fluidized bed granulation, the granulation of non-porous pot lamination
Etc. conventional methods.The dry granulation refers to by being formed after rolling material by horizontally or vertically position roller bearing after pre-compacted material
It smashes to form particle after material band.
B3) optionally, according to the method for wet granulation, need dry particle, in drying process temperature of charge control exist
60 DEG C or less；The equipment that the drying process uses includes but not limited to blowing-type drying box, fluidized bed drying.
B4 b1) will be passed through) b2) or the b3) particle of step, and glidant/mix lubricant and/or need additional disintegration
Agent, filler mixing, obtain medicine-containing particle.
In the step c) of the method for the present invention, filled out after one or more stabilizers can also being added in medicine-containing particle
It fills, tabletting or filling；Stabilizer is 0~5 with medicine-containing particle weight ratio：100, preferably 0.2~1:100
The stabilizer is selected from fumaric acid, citric acid, citric acid, rilanit special, oil with hydrogenated soybean and behenyl acid glycerol
Ester, methyl-silicone oil, dimethicone.
Further, for the tablet obtained in c), coating steps can be taken, Vicagrel coating tablet is obtained, it is described
Polyethylene glycol and talcum powder are free of in coating constituents.Coating solution film forming component can be hydroxypropyl methyl cellulose, hydroxypropyl fibre
Dimension element or polyvinyl alcohol, it includes the coating color lake/color commonly used in the art such as iron oxide, titanium dioxide that color lake adjustment color, which can be added,
Element.For commercially available coating prescription, often contain plasticizer polyethylene glycol and antiplastering aid talcum powder, and the present invention without polyethylene glycol and
Talcum powder.
According to the medicine-containing particle that the present invention obtains, the pharmaceutical preparation formed, which is dissolved out in vitro in test, shows fast quick-release
The feature put, and comparable advantage is shown in pharmacokinetics in vivo, show as the extent of drug absorption (AUC) of bigger
With rate (Cmax)。
According to medicine-containing particle prescription provided by the invention and preparation method, can provide a kind of with the utilization of high vivo biodistribution
The quick releasing formulation of degree and blood concentration, also, according to medicine-containing particle prescription provided by the invention, pass through the group of optional preparation process
It closes, the capsule or tablet quick releasing formulation of excellent in stability can be obtained.
Description of the drawings
Fig. 1 is the Dissolution profiles of Vicagrel preparation under different-grain diameter
Fig. 2 is that dog gives M9-2 plasma concentration curves after Vicagrel preparation prepared by different-grain diameter.A：D90=23 μm；
B：D90=86 μm；C：D90=9 μm；D：D90=49 μm.
Fig. 3 is that dog gives M15-1 plasma concentration curves after Vicagrel preparation prepared by different-grain diameter.A：D90=23 μm；
B：D90=86 μm；C：D90=9 μm；D：D90=49 μm.
Fig. 4 is that dog gives M15-2 plasma concentration curves after Vicagrel preparation prepared by different-grain diameter.A：D90=23 μm；
B：D90=86 μm；C：D90=9 μm；D：D90=49 μm.
Specific implementation mode
The following specific implementation mode for providing the present invention, it should be understood that the present invention is not limited to these specific implementation modes,
Those skilled in the art can carry out the present invention various modifications and change under without departing substantially from the spirit and scope of the present invention
Become, but such improvement is considered being included in the application scope of the appended claims.Embodiment is to the content of present invention
Further explanation, to illustrate the present invention innovation at.
1 Vicagrel capsule of embodiment
Vicagrel beater grinder (Frewitt) 0.20mm sieves, 6000rpm rotating speeds, 1kg/min blanking rate powder
It is broken, measure D90=43 μm.Vicagrel after crushing is mixed into 15min with microcrystalline cellulose, lactose in three-dimensional mixer,
Rilanit special mixing is added, gained is particles filled in No. 3 capsules.
2 Vicagrel capsule of embodiment
| Supplementary material | Dosage mg/ |
| Vicagrel | 5.5 |
| Microcrystalline cellulose | 100 |
| Lactose | 80 |
| Sodium carboxymethyl starch | 20 |
| Hydroxypropyl methyl cellulose | 6.5 |
| Water | q.s |
| Magnesium stearate | 0.5 |
| It amounts to | 212.5 |
Using QL-100 type airslide disintegrating mills crush raw material, pressure 0.8MPa, 15 DEG C, grinding time 10min of operating temperature,
D90=9 μm.Hydrochloric acid Vicagrel after crushing and microcrystalline cellulose, lactose, sodium carboxymethyl starch, hydroxypropyl methyl cellulose
The 35rpm mixing 10min in three-dimensional mixer, taking-up are set in bulk drug of pretreatment adds with interior granulator, 500rpm stirrings, 1000rpm cuttings
The granulation of lower addition water, particle cross 16 mesh sieves, and 60 DEG C of dryings in air dry oven take out, cross 24 mesh sieves, are added stearic
Sour magnesium always mixes.Vicagrel quick-release capsules are obtained in No. 3 capsules by medicine-containing particle is filling.
3 Vicagrel capsule of embodiment
Vicagrel salt after crushing is placed in pregelatinized starch, lactose, sodium carboxymethyl starch in fluid bed, stream is opened
Change mixing 10min, 5% hydroxypropyl methyl cellulose is prepared, as adhesive.80 DEG C of inlet air temperature, maintenance bed temperature 40~
Spray adhesive in the case of 50 DEG C maintains the dry 30min of 50~60 DEG C of bed temperature, discharging that stearoyl is added after forming particle
Fumaric acid sodium mixing 5min, filling capsule.
Embodiment 4
Vicagrel is ground into the powder of different-grain diameter, prepare medicine-containing particle and is filled in capsule, according to USPII
Method, 50rpm measure dissolution rate, as a result such as following table and Fig. 1 institutes using the pH4.0 acetate buffers containing 0.2%SDS as medium
Show：
In processing 1,2,3, when API grain sizes are at 50 μm or less, the rate of release in 30min ＞ 85% can be met, it is special
Not, as 30 μm of grain size ＜, 15min release rates ＞ 85%.In processing 4 and processing 5,50 μm of API grain sizes ＞, release in vitro
Rate is slow, and 45min dissolution rates are less than 85%.
Vicagrel capsule is prepared according to the raw material of the method different-grain diameter under embodiment 2, is measured after giving Beagle dogs
Blood concentration and active metabolite pharmacokinetic parameters, implementation specific as follows：
Healthy beasle dog 8, male, age 7-8 month, 8~10kg of weight, using trial design.Prohibit before experiment
12h is eaten, 4h provides food after administration, and entire experiment process can't help water.7 days phases are cleaned during week.With 40ml water delivery services when administration.
10min, 20min, 40min, 1.0,1.5,2.0,4.0,6.0,8.0,12 and for 24 hours after (0h) and administration before administration；It is set in above
It fixes time a little through limb vein extracting vein blood 1ml, sample is handled by relevant criterion operating instruction, it is cold in -70 DEG C of refrigerators after processing
It is to be measured to freeze preservation.Vicagrel metabolin M9-2, active metabolite M15-1 and M15-2 in blood plasma are measured using LC-MS/MS methods
Concentration.Vicagrel metabolin after beasle dog is administered is calculated using the non-chamber method of 6.4 softwares of Phoenix WinNonlin
The main pharmacokinetic parameters result such as following table (n=8) of M9-2, active metabolite M15-1 and M15-2：
* P is indicated<0.05 compared with grain size 23,49,86 μm of groups.
* P is indicated<0.05 compared with 86 μm of groups of grain size
M9-2 structural formulas are：
M15-1 structural formulas are：
M15-2 structural formulas are：
M9-2, M15-1 and M15-2 plasma concentration curve is respectively such as after dog gives the Vicagrel preparation of different-grain diameter preparation
Fig. 2, Fig. 3 and Fig. 4.
When raw material particle size is less than 50 μm, it is seen that drug AUC is significantly improved compared with 86 μm of grain size groups, particularly, when drug grain
When diameter is less than 15 μm, lower area of blood concentration-time curve and the active metabolism production of active metabolite A, B, C are observed
The C of object B, Cmax15 μm of groups of more other grain size ＞ significantly improve.This plays anticoagulant drug effect highly beneficial.Embodiment 5
Vicagrel piece
By the Vicagrel and pregelatinized starch, mannitol, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl fibre after crushing
Dimension element is stirred 5min in high shear granulator, is stirred with 4m/s linear velocities, and water system is added in the cutting of 800rpm cutter
Grain, particle go to roll into a ball through 10 mesh screens, dry in fluid bed, keep bed temperature to be less than 60 DEG C in dry.Take out particle, 24 mesh
Whole grain is sieved, sodium stearyl fumarate mixing is added, tabletting on rotary pelleting machine (ZP-10A, traditional Chinese medicines dragon are vertical), 8mm scrobiculas are rushed in 10
Punching.
6 Vicagrel piece of embodiment
By the friendship of Vicagrel and pregelatinized starch, microcrystalline cellulose, polyvinylpyrrolidone and half amount after crushing
Join sodium carboxymethylcellulose, the magnesium stearate of half amount mixes 10min in V-Mixer, material is placed in dry granulating machine
In (LGJ-300) to feed 20Hz, roller rotation rate 15rpm, extruding force 6bar, 20 mesh of sieve, the parameter of cutting rotating speed 300rpm
Operation granulation, the disintegrant and mix lubricant 5min of particle and remainder obtain medicine-containing particle, and medicine-containing particle is into advancing one
The sheeting operation of step.
7 Vicagrel piece of embodiment
By the Vicagrel and pregelatinized starch, lactose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl fiber after crushing
Element is stirred in wet granulator, and water is added and pelletizes, particle 55 DEG C of dryings in air dry oven after 16 mesh sieves,
It takes out and grinds whole grain with bevel-type pelletizing machine, sodium stearyl fumarate mixing 3min is added, stabilizer Compritol 888 ATO is added, mix
3min is closed, is taken out, 7.5mm scrobicula stampings, hardness >=6kgf.
8 Vicagrel piece of embodiment
By the Vicagrel and pregelatinized starch, mannitol, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl fibre after crushing
Dimension element is stirred in wet granulator, is added water granulation, particle after 16 mesh sieves in air dry oven 55 DEG C it is dry
It is dry, it takes out and grinds whole grain with bevel-type pelletizing machine, sodium stearyl fumarate mixing 3min is added, stabilizer behenyl acid glycerol is added
Ester mixes 3min, takes out, 7.5mm scrobicula stampings, hardness >=6kgf.
9 Vicagrel coating tablet of embodiment
The coating of label BG-10 type seed-coating machines is made in embodiment 8, using Opadry II coating powders, wherein in coating powder
Without polyethylene glycol and talcum powder.Label 600g, 50 DEG C of inlet air temperature are coated flow velocity 4g/min, intake 60m3/ h, bed temperature
35~45 DEG C of degree.Obtain Vicagrel coating tablet
The effect of 10 stabilizer of embodiment is compared
Vicagrel piece is prepared according to embodiment 7, embodiment 8, difference lies in be added without stabilizer after obtaining medicine-containing particle.
Gained tablet is sealed in HDPE bottles, is placed 10 days at 60 DEG C, measures related substance and dissolution rate.
As it can be seen that medicine-containing particle mixed with stabilizer after tabletting, be reduced in relation to substance increase degree, dissolution rate is not yet
It is remarkably decreased.
Embodiment 11 is coated tablet stability and compares
Vicagrel piece preparation is carried out according to embodiment 8, and by the parameter coating in embodiment 9, difference is, in coating solution
Contain common plasticizers polyethylene glycol and antiplastering aid talcum powder.
Amazing discovery, Vicagrel piece remain to provide good when coating constituents are free of polyethylene glycol and talcum powder
Clothing film well is simultaneously easily prepared, but its stability is dramatically increased compared with the coating tablet that mentioned component is added.
Claims (10)
1. a kind of immediate release drug formulations of anti-coagulants, including Vicagrel compound or its pharmaceutically acceptable form,
It is characterized in that, wherein the preparation is the form of tablet, capsule, the Vicagrel or its pharmaceutically acceptable form are with appropriate
Grain size provides, 50 μm of D90 ＜.
2. immediate release drug formulations according to claim 1, which is characterized in that include：
A) Vicagrel active constituent：Vicagrel or its pharmaceutically acceptable form；
B) one or more fillers；
C) one or more disintegrants；
D) one or more adhesives；
E) one or more glidant/lubricants.
3. preparation according to claim 2, which is characterized in that be grouped as by following groups：
A) the Vicagrel active constituent accounts for tablet or 0.5%~30%wt of capsule filling；
B) filler within the scope of tablet or 1%~95%wt of capsule filling to exist；
C) adhesive within the scope of tablet or 0%~20%wt of capsule filling to exist；
D) disintegrant within the scope of tablet or 0%~20%wt of capsule filling to exist；
E) glidant/lubricant within the scope of tablet or 0%~5%wt of capsule filling to exist；
F) stabilizer within the scope of 0%~5%wt to exist；
The percentage sum total of all compositions is 100%.
4. preparation according to claim 1, which is characterized in that the grain of the Vicagrel or its pharmaceutically acceptable form
30 μm of diameter D90 ＜.
5. preparation according to claim 4, which is characterized in that the grain of the Vicagrel or its pharmaceutically acceptable form
15 μm of diameter D90 ＜.
6. a kind of preparation method of the immediate release drug formulations of anti-coagulants, it is characterised in that its step includes：
A) the Vicagrel powdered active ingredient of micronizing, 50 μm of D90 ＜ are provided；Vicagrel reactive powder refers to Vicagrel
Or the Micronised form of its pharmaceutically acceptable salt, solvate or other carriers；
B) Vicagrel powdered active ingredient and auxiliary agent are mixed and made into medicine-containing particle；
C) by medicine-containing particle by filling, tabletting or filling method obtain Vicagrel capsule or piece.
7. preparation method according to claim 6, it is characterised in that：In the step c), one is added in medicine-containing particle
It is filled after kind or plurality of stable agent, tabletting or filling；Stabilizer is 0~5 with medicine-containing particle weight ratio：100.
8. preparation method according to claim 7, it is characterised in that：The stabilizer is selected from fumaric acid, citric acid, lemon
Acid, rilanit special, oil with hydrogenated soybean and Compritol 888 ATO.
9. preparation method according to claim 7, which is characterized in that stabilizer is 0.2~1 with medicine-containing particle weight ratio:
100。
10. preparation method according to claim 6, which is characterized in that for the tablet obtained in c), further take packet
Clothing step obtains Vicagrel coating tablet, polyethylene glycol and talcum powder is free of in the coating constituents.
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| CN115317456A (en) * | 2022-08-17 | 2022-11-11 | 北京科源创欣科技有限公司 | Nicorandil tablet composition and preparation method thereof |
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Also Published As
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| CN108420798B (en) | 2021-03-02 |
| CN113116834A (en) | 2021-07-16 |
| CN113116834B (en) | 2022-06-07 |
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