CN107281154A - Antithrombotic and pre- anti-stroke Tecarfarin pharmaceutical preparations and preparation method thereof - Google Patents
Antithrombotic and pre- anti-stroke Tecarfarin pharmaceutical preparations 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
- 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
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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
- A61K9/2009—Inorganic compounds
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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
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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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- 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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- 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
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Abstract
The invention provides Tecarfarin tablets and preparation method thereof, the Tecarfarin tablets include：Tecarfarin, and pharmaceutically acceptable auxiliary material.Tecarfarin Dissolution of Tablet height, short disintegration time, Small side effects, the steady quality of the present invention, and preparation technology is simple, cost is low.
Description
Technical field
The present invention relates to pharmaceutical field, it is related to antithrombotic and pre- anti-stroke Tecarfarin pharmaceutical preparations and its preparation side
Method.
Background technology
Vitamin K is material necessary to the formation of factor Xa II, VII, Ⅺ and Ⅹ, and the K that is deficient in vitamin can make blood coagulation
Time lengthening.New drug vitamin K antagon Tecarfarin is grinding in ARYx Therapeutics companies of the U.S., is warfarin
Analog, it is as oral anticoagulant of new generation, for potential oral medication thrombosis, including DVT shape
Into, and prevention atrial fibrillation patients and the apoplexy of false cardiac valves or chronic renal insufficiency patient.II announced
With III clinical trial phase data display, Tecarfarin curative effect and warfarin have comparativity, and are likely to reduced more medicines
Interaction between thing and food or medicine.
However, the research to Tecarfarin relevant pharmaceutical formulations at present, still has to be strengthened.
The content of the invention
It is contemplated that at least solving one of technical problem in correlation technique to a certain extent.Therefore, the present invention
One purpose is to propose that a kind of good effect, dissolution rate are high, bioavilability is high, the Tecarfarin solid drugs of steady quality
Preparation.
In one aspect of the invention, the invention provides a kind of Tecarfarin tablets.Embodiments in accordance with the present invention,
The Tecarfarin tablets include：Tecarfarin；And pharmaceutically acceptable auxiliary material.Inventor has found, of the invention
Tecarfarin Dissolution of Tablet height, short disintegration time, Small side effects, steady quality, can effectively play antithrombotic and pre-
Anti-stroke effect, and preparation technology is simple, cost is low, is adapted to industrialized production.
Embodiments in accordance with the present invention, the pharmaceutically acceptable auxiliary material be selected from filler, disintegrant, adhesive and
At least one of lubricant.
Embodiments in accordance with the present invention, the filler is in lactose, cornstarch, microcrystalline cellulose, mannitol
At least one, preferably lactose and microcrystalline cellulose combination.Thereby, it is possible to improve the compressibility of medicine, main component is reduced
Dose deviations, promote disintegration and dissolution.Particularly, inventor has found, when the combination conduct of selection microcrystalline cellulose and lactose
During filler, only drugs compressibility is not good, and disintegration rate is fast, and dissolution rate is high, and can improve the hardness of tablet and unilateral bright and clean
Degree.
Embodiments in accordance with the present invention, described adhesive is selected from PVP K30, hydroxypropyl methylcellulose, methylcellulose
At least one, preferred PVP K30.Thus, not only with preferable adhesive effect, and Tecarfarin tablets can be promoted
Disintegration and dissolution.
Embodiments in accordance with the present invention, the disintegrant is selected from Ac-Di-Sol, sodium carboxymethyl starch, gathered
Tie up at least one of ketone, preferably Ac-Di-Sol.Thus, Tecarfarin tablets can fater disintegration, be conducive to
Tecarfarin dissolution.Particularly, inventor has found, when using Ac-Di-Sol for disintegrant,
The disintegration rate of Tecarfarin tablets is very fast, and dissolution rate is higher.
Embodiments in accordance with the present invention, the glidant is selected from silica.Thus, it can improve what is prepared
The mobility of Tecarfarin particles, preventing material layering from causing, the uneven unilateral finish of content is good, and outward appearance meets the requirements.
Embodiments in accordance with the present invention, the lubricant is selected from magnesium stearate.Thus, Tecarfarin tablets is unilateral
Finish is good, and outward appearance meets the requirements.
Embodiments in accordance with the present invention, according to parts by weight, the Tecarfarin tablets can include：It is described
Tecarfarin2.5-10 parts by weight, the filler 120-210 parts by weight, described adhesive 5-30 parts by weight, the disintegration
Agent 5-20 parts by weight, the glidant 0.1-2 parts by weight, the lubricant 0.2-5 parts by weight.Thus, Tecarfarin tablets
Disintegration rate is fast, dissolution rate is high, bioavilability is high, and steady quality, and toxic side effect is small.In addition, inventor unexpectedly sends out
Existing, the Tecarfarin tablets comprising aforementioned proportion supplementary material have the pharmaceutical properties better than other ratios.
According to the specific example of the present invention, according to parts by weight, the Tecarfarin tablets include：
The parts by weight of Tecarfarin 2.5, the parts by weight of lactose 80, the parts by weight of microcrystalline cellulose 40, the parts by weight of PVP K30 5 are crosslinked carboxylic
The parts by weight of sodium carboxymethylcellulose pyce 5, the parts by weight of silica 0.1, the parts by weight of magnesium stearate 0.2.
According to the specific example of the present invention, according to parts by weight, the Tecarfarin tablets include：
The parts by weight of Tecarfarin 2.5, the parts by weight of lactose 100, the parts by weight of microcrystalline cellulose 50, the parts by weight of PVP K30 8, crosslinking
The parts by weight of sodium carboxymethylcellulose 10, the parts by weight of silica 0.5, the parts by weight of magnesium stearate 0.5.
According to the specific example of the present invention, according to parts by weight, the Tecarfarin tablets include：
The parts by weight of Tecarfarin 5, the parts by weight of lactose 120, the parts by weight of microcrystalline cellulose 60, the parts by weight of PVP K30 15 are crosslinked carboxylic
The parts by weight of sodium carboxymethylcellulose pyce 12, silica 1 parts by weight, the parts by weight of magnesium stearate 3.
According to the specific example of the present invention, according to parts by weight, the Tecarfarin tablets include：
The parts by weight of Tecarfarin 5, the parts by weight of lactose 100, the parts by weight of microcrystalline cellulose 50, the parts by weight of PVP K30 10 are crosslinked carboxylic
The parts by weight of sodium carboxymethylcellulose pyce 8, the parts by weight of silica 0.8, the parts by weight of magnesium stearate 2.4.
According to the specific example of the present invention, according to parts by weight, the Tecarfarin tablets include：
The parts by weight of Tecarfarin 10, the parts by weight of lactose 140, the parts by weight of hydroxypropyl methylcellulose 70, the parts by weight of PVP K30 20 are handed over
Join the parts by weight of sodium carboxymethylcellulose 20, the parts by weight of silica 2, the parts by weight of magnesium stearate 5.
According to the specific example of the present invention, according to parts by weight, the Tecarfarin tablets include：
The parts by weight of Tecarfarin 10, the parts by weight of lactose 120, the parts by weight of microcrystalline cellulose 60, the parts by weight of PVP K30 20, crosslinking
The parts by weight of sodium carboxymethylcellulose 15, silica 1 .5 parts by weight, the parts by weight of magnesium stearate 3.
The parts by weight of Tecarfarin 5, the parts by weight of lactose 90, the parts by weight of hydroxypropyl methylcellulose 90, the weight of PVP K30 15
Part, the parts by weight of Ac-Di-Sol 12, silica 1 parts by weight, the parts by weight of magnesium stearate 3.
The parts by weight of Tecarfarin 5, the parts by weight of lactose 125, the parts by weight of hydroxypropyl methylcellulose 50, the weight of PVP K30 15
Measure part, the parts by weight of Ac-Di-Sol 12, silica 1 parts by weight, the parts by weight of magnesium stearate 3.
The parts by weight of Tecarfarin 5, the parts by weight of lactose 125, the parts by weight of hydroxypropyl methylcellulose 50, the weight of PVP K30 10
Measure part, the parts by weight of Ac-Di-Sol 8, the parts by weight of silica 0.8, the parts by weight of magnesium stearate 2.4.
Inventor has found by substantial amounts of experiment, when individually using lactose as filler, and the big production of industry occurs that sliver shows
As so the present invention does not select lactose individually in the auxiliary material selection of diluent.But it is due to water-soluble as the lactose of filler
Property it is good, and microcrystalline cellulose not only serves as filler, and possesses the performance of disintegrant, chooses lactose and microcrystalline cellulose two
The combination of person is simultaneously as diluent (herein, " filler " and " diluent " can be with used interchangeably), and what be can reach is molten
Go out effect.When the combination using lactose and microcrystalline cellulose is as filler, Tecarfarin dissolving can be effectively improved
Property, lactose can also increase Tecarfarin tablet hardnesses and unilateral finish with combining for microcrystalline cellulose, accelerate
The disintegration of Tecarfarin tablets, so as to improve Tecarfarin dissolution rate.Embodiments in accordance with the present invention, selection lactose and
The mass ratio of microcrystalline cellulose is (0.75~2.5)：1, the most preferably optimum quality ratio of lactose and microcrystalline cellulose is 2：1.
In addition, embodiments in accordance with the present invention, use Ac-Di-Sol for disintegrant, can further speed up
The disintegration rate of Tecarfarin tablets, improves Tecarfarin dissolution rate.
In another aspect of this invention, the invention provides the method for preparing foregoing Tecarfarin tablets.Root
According to embodiments of the invention, this method comprises the following steps：Tecarfarin is subjected to micronization processes, and will be obtained
Tecarfarin micro powder granules and the mixing of pharmaceutically acceptable auxiliary material, to obtain the medicinal mixture；By the medicine
Mixture carries out tabletting, to obtain Tecarfarin labels, and Tecarfarin labels are coated into processing by described, so as to
Tecarfarin tablets are obtained, wherein, the particle diameter of the Tecarfarin micro powder granules is 10-100 microns.Inventor's discovery,
Using this method of the present invention, foregoing Tecarfarin tablets, preparation technology letter can be fast and effeciently prepared
It is single, it is easy to operate, it is easy to control, it is adapted to industrialized production, while the Tecarfarin disintegration of tablet speed prepared is fast,
Dissolution rate is high, and steady quality, Small side effects, can effectively play antithrombotic and pre- anti-stroke effect.In supplementary material
In pre-treatment, after first Tecarfarin and filler mixing are micronized, then obtained Tecarfarin tablets, relative to
Without Tecarfarin tablets made from the Tecarfarin of micronizing, its dissolution rate can significantly be improved.
Embodiments in accordance with the present invention, the method for preparing Tecarfarin tablets may further include：Using polychlorostyrene second
Alkene bubble-cap+two-sided composite aluminium film bag is packed to the Tecarfarin tablets.Thus, sealing preferably, can effectively prevent
Only the Tecarfarin tablets moisture absorption, is conducive to the long term storage of Tecarfarin tablets.
Embodiments in accordance with the present invention, the method for preparing Tecarfarin tablets may comprise steps of：
(1) Tecarfarin and filler are mixed, and resulting mixture is subjected to micronization processes, to obtain
Particle diameter is 10 microns to 100 microns of mixture micro powder granule, and 80 mesh are crossed after disintegrant, adhesive and lubricant are crushed respectively
Sieve, it is standby；
(2) described adhesive is mixed with purified water, with the binder aqueous solution I that obtained mass fraction is 6%~12%,
It is standby；
(3) the mixture micro powder granule is mixed with the disintegrant that Inner adds, obtains mixture II；
(4) the described adhesive aqueous solution I is added in the mixture II, and softwood is made in resulting mixture,
Gained softwood is crossed into 18 mesh stainless steel sieve series grains, to obtain wet granular；
(5) at 55 DEG C~65 DEG C, the wet granular is dried into 1~4h, 18 mesh stainless steels sieve whole grain is then crossed, to obtain
Obtain dry particl；
(6) dry particl is mixed with additional disintegrant, glidant, then by resulting mixture and magnesium stearate
Mixing, to obtain the medicinal mixture；
(7) content of dispersion of the medicinal mixture is determined, and is calculated the theoretical tablet weight, then the medicinal mixture is carried out
Tabletting, to obtain the Tecarfarin tablets.
(8) it is coated：Powder white stomach dissolution type Opadry 81W68907 will be coated to be added in purified water, solid content is configured to
For 20% Coating Solution, stirred 45 minutes with screw type agitating paddle.Label is carried out using common transformation coating pan
It is coated, obtains Tecarfarin Film coated tablets, the parameter of the Cotton seeds is as follows：40 DEG C of control sheet bed tempertaure, coating pan air intake
65 DEG C of temperature, coating weight gain 3.0-4.5%.
(9) pack：The Tecarfarin tablets are packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.
Thereby, it is possible to fast and effectively prepare foregoing Tecarfarin tablets.Wherein, by inciting somebody to action
Tecarfarin carries out micronization processes, enables to Tecarfarin to be dispersed in auxiliary material, effectively improves
Tecarfarin dissolution rate.
The invention will be in two times added in disintegrant point plus disintegrant and additional disintegrant both forms,
Additional disintegrant can promote the disintegration of particle, and interior plus disintegrant can then accelerate the scattered of particle, can greatly improve
The dissolution rate of Tecarfarin tablets.Result described in the embodiment of the present invention can be seen that using addition inside and outside disintegrant
Technique, relative to technique of the disintegrant only with interior addition, its dissolution rate is significantly improved, its dissolution rate can bring up to 80% with
On.Therefore the consumption and addition manner of determination disintegrant are：The interior dosage of disintegrant is the 1/2 of disintegrant recipe quantity, and outer dosage is
Another the 1/2 of disintegrant recipe quantity.Embodiments in accordance with the present invention, control piece in the range of theoretical piece weight ± 5% during tabletting again,
Hardness is controlled in 5~7kg.Thus, the Tecarfarin tablet appearances of acquisition, piece meet the requirements again etc., and disintegration rate is fast, molten
Out-degree is high.
According to the specific example of the present invention, the method for preparing Tecarfarin tablets comprises the following steps：
(1) Tecarfarin is mixed with lactose and microcrystalline cellulose, and resulting mixture is carried out at micronizing
Reason, to obtain the mixture micro powder granule that particle diameter is 10 microns to 100 microns, by Ac-Di-Sol, gathers
Dimension ketone K30 and magnesium stearate cross 80 mesh sieves after crushing respectively, standby；
(2) PVP K30 is mixed with purified water, with the PVP K30 aqueous solution that obtained mass fraction is 6%~12%
I, it is standby；
(3) the mixture micro powder granule is mixed with the Ac-Di-Sol that Inner adds, obtains the mixture II；
(4) the PVP K30 aqueous solution I is added in the mixture II, and resulting mixture is made soft
Material, crosses 18 mesh stainless steel sieve series grains by gained softwood, obtains the wet granular；
(5) at 55 DEG C~65 DEG C, the wet granular is dried into 1~4h, 18 mesh stainless steels sieve whole grain is then crossed, to obtain
Obtain the dry particl；
(6) dry particl is mixed with additional Ac-Di-Sol, glidant silica, and by gained
The mixture arrived is mixed with magnesium stearate, to obtain the medicinal mixture；
(7) content of dispersion of the medicinal mixture is determined, and is calculated the theoretical tablet weight, will be described based on the theoretical piece weight
Medicinal mixture carries out tabletting, to obtain the Tecarfarin tablets；
(8) it is coated：Powder white stomach dissolution type Opadry 81W68907 will be coated to be added in purified water, solid content is configured to
For 20% Coating Solution, stirred 45 minutes with screw type agitating paddle.Label is carried out using common transformation coating pan
It is coated, obtains Tecarfarin Film coated tablets, the parameter of the Cotton seeds is as follows：40 DEG C of control sheet bed tempertaure, coating pan air intake
65 DEG C of temperature, coating weight gain 3.0-4.5%.
(9) pack：The Tecarfarin tablets are packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.
Thereby, it is possible to fast and effeciently prepare foregoing Tecarfarin tablets, preparation technology is simple, operation
It is convenient, and the Tecarfarin tablet qualities prepared are stable, disintegration rate is fast, and dissolution rate is high.
In particular, Tecarfarin and lactose are micronized, enable to slightly solubility
Tecarfarin is sufficiently dispersed in hydrophilic lactose, is then mixed, is made in this way with other auxiliary materials again
Tecarfarin tablets, its dissolution rate can significantly be improved.In addition, by Ac-Di-Sol by adding twice
(addition and outer addition in i.e.), into medicinal mixture, additional disintegrant can promote the disintegration of particle, and interior plus disintegrant then can
Accelerate the scattered of particle, the method can reach the effect that preferable dissolution is kept using less disintegrant, can not only save
About cost, while can accelerate the disintegration of particle and disperse, is conducive to improving dissolution rate.
By preparation-obtained Tecarfarin pieces of the invention, its character, hardness, friability, tablet weight variation are conformed to
Ask, and dissolution rate is higher, and can reach more than 85%, meet the requirements.
Embodiments in accordance with the present invention, 10 days influence factor result of the tests of Tecarfarin tablets show：
Tecarfarin tablets are placed 10 days under high temperature, high humidity, illumination, and content, relevant material change without conspicuousness, and quality is substantially steady
It is fixed, show, prescription science is feasible, rational technology, favorable reproducibility.But 10 days tablet surfaces of high humidity have the slight moisture absorption, and dissolution rate has
Declined, it is noted that moistureproof when pointing out to select to pack.Therefore, product needs to store at hermetically drying.
Further, embodiments in accordance with the present invention, are selected the interior packaging material of Tecarfarin tablets of the present invention
Select, the Tecarfarin tablets are packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.Thus, sealing compared with
It is good, the Tecarfarin tablet moisture absorptions can be effectively prevented, the long-time stability of this product can be effectively ensured, are conducive to Tecarfarin
The long term storage of tablet.Embodiments in accordance with the present invention, the invention has the advantages that：
1st, embodiments in accordance with the present invention, by using the combination of microcrystalline cellulose and lactose as filler, not only medicine
Thing compressibility is good, and disintegration rate is fast, and dissolution rate is high, and can improve the hardness and unilateral finish of tablet, accelerates
The disintegration of Tecarfarin tablets, so that Tecarfarin dissolution rate is improved, and lactose hydrophily is preferably, can further have
Effect improves Tecarfarin dissolubility.
Tecarfarin and filler, in the preceding processing of supplementary material, are first mixed into by the 2, embodiments in accordance with the present invention
After row micronizing, the Tecarfarin of slightly solubility is enabled to sufficiently to be dispersed in hydrophilic filler such as lactose, then
Mixed again with other auxiliary materials, the Tecarfarin tablets being made in this way, its dissolution rate can significantly be improved.
3rd, embodiments in accordance with the present invention, add disintegrant by inside and outside addition, can not only reduce the use of disintegrant
Amount, it is cost-effective, meanwhile, additional disintegrant can promote the disintegration of Tecarfarin tablets, and interior plus disintegrant can promote to collapse
The scattered of particle is solved, the result of extraction of Tecarfarin tablets can be significantly improved.
4th, embodiments in accordance with the present invention, control piece in the range of theoretical piece weight ± 5% during tabletting again, and hardness control exists
5~7kg.Thus, the Tecarfarin tablet appearances of acquisition, piece meet the requirements again etc., and disintegration rate is fast, and dissolution rate is high.
5th, embodiments in accordance with the present invention, Tecarfarin tablets control bag weightening of the invention is 3.0%~4.5%
In the range of, can cause Tecarfarin tablets that there is most suitable dissolution rate, be conducive to the performance of drug effect, moreover it is possible to play compared with
Good medicine shaded effect.
6th, using this method of the present invention, foregoing Tecarfarin tablets can be fast and effeciently prepared,
Preparation technology is simple, easy to operate, it is easy to control, and is adapted to industrialized production, while the Tecarfarin tablets prepared
Disintegration rate is fast, and dissolution rate is high, and steady quality, Small side effects, can be effective for antithrombotic and pre- anti-stroke.
Embodiment
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining this hair
It is bright, and be not considered as limiting the invention.Unreceipted particular technique or condition in embodiment, according to text in the art
Offer described technology or condition or carried out according to product description.Agents useful for same or the unreceipted production firm person of instrument, remove
Tecarfarin raw materials are outer for self-control, and other auxiliary materials are can be by the conventional products of acquisition purchased in market.
Embodiment 1：Main ingredient interacts with auxiliary material and tested
In the present embodiment, in order to investigate in main ingredient and prescription between selected auxiliary material whether have interaction, and preparation
During crystal formation whether have change, using following high performance liquid chromatography to the interaction between selected auxiliary material and main ingredient
Studied.
Chromatographic condition：Take Tecarfarin fine powder appropriate, plus [acetonitrile-water (50:50)] dissolve and dilute and every 1ml is made
In the 0.3mg containing Tecarfarin solution, with 10000 turns per minute, centrifuge 5 minutes, take supernatant as need testing solution；
Precision is measured in right amount, with [acetonitrile-water (50:50)] solution of 3 micrograms in every 1ml is made in quantitative dilution, is used as contrast solution.According to
High performance liquid chromatography (two D of annex V of Chinese Pharmacopoeia version in 2010) is determined, and is filling with octadecylsilane chemically bonded silica
Agent；Mobile phase A is 20mmol/L ammonium perchlorate, 1% triethylamine, with phosphorus acid for adjusting pH value to 6.00- acetonitriles (50:50), flow
Phase B is acetonitrile；Linear gradient elution is carried out by table 1, column temperature is 30 DEG C；Detection wavelength is 254nm.Take Tecarfarin appropriate,
Plus [acetonitrile-water (50:50)] dissolve and dilute and solution of every 1ml containing about 0.1mg is made, take 20 microlitres of injection liquid chromatographs,
Chromatogram is recorded, separating degree should be greater than 2.0.20 microlitres of injection liquid chromatographs of contrast solution are taken, sensitivity is adjusted, makes principal component
The peak height of chromatographic peak is about the 25% of full scale, then precision measures need testing solution and each 20 microlitres of contrast solution, is injected separately into
Liquid chromatograph, 3 times of record chromatogram to principal component peak retention time.
Table 1：Linear gradient elution condition
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 15 | 100 | 0 |
| 35 | 30 | 70 |
| 50 | 30 | 70 |
| 51 | 100 | 0 |
| 60 | 100 | 0 |
Specifically, by the mixture of independent auxiliary material, main ingredient and each independent auxiliary material, the mixture of main ingredient and all auxiliary materials
Place 10 days, compare after 0 day and 10 days, the character of mixture, the change about material and content under the conditions of influence factor respectively
Change.
1st, the preparation of test sample
The lot number of bulk drug (Tecarfarin)：Wuhan Yi Yang biological medicines Co., Ltd makes by oneself, purity 99.7%, first will
Tecarfarin bulk drugs cross 60 mesh sieves, and each auxiliary material crosses 80 mesh sieves.
No. 1 sample：Main ingredient and microcrystalline cellulose (mass ratio 1:5) mixture；
0.1g Tecarfarin bulk drugs and 0.5g microcrystalline celluloses are weighed, 60 mesh sieves is crossed and mixes 3 times, numbering is 1.
No. 2 samples：Main ingredient and lactose (mass ratio 1:5) mixture；
0.1g Tecarfarin bulk drugs and 0.5g lactose are weighed, 60 mesh sieves is crossed and mixes 3 times, numbering is 2.
No. 3 samples：Main ingredient and PVP K30 (mass ratio 5:1) mixture
0.5g Tecarfarin bulk drugs and 0.1g PVP K30s are weighed, 60 mesh sieves is crossed and mixes 3 times, numbering is 3.
No. 4 samples：Main ingredient and Ac-Di-Sol (mass ratio 5:2) mixture
0.5g Tecarfarin bulk drugs and 0.2g Ac-Di-Sols are weighed, 60 mesh sieves is crossed and mixes 3 times, compile
Number 4.
No. 5 samples：Main ingredient and magnesium stearate (mass ratio 20:1) mixture
2g Tecarfarin bulk drugs and 0.1g magnesium stearates are weighed, 60 mesh sieves is crossed and mixes 3 times, numbering is 5.
No. 6 samples：Main ingredient and mixed accessories (mass ratio 1:5) mixture；
Weigh 0.1g Tecarfarin bulk drugs and 0.5g mixtures (wherein lactose 0.23g+ microcrystalline celluloses
0.23g+ Ac-Di-Sol 0.04g), cross 60 mesh sieves and mix 3 times, numbering is 6.
2nd, test method
Above-mentioned 1-6 samples are respectively placed in high temperature, high humidity and lower 10 days of illumination condition, compared after 0 day and 10 days, are mixed
The character of thing, the change about material and content, result of the test are shown in Table 2.
The main ingredient of table 2 and auxiliary material compatibility experiments result
3rd, conclusion
1~No. 6 sample placed 10 days under high temperature, high humidity and illumination condition after measurement result, compared with 0 day, property
Shape, content do not have significant change, as a result show, compatibility is good between each auxiliary material and main ingredient, Tecarfarin and each auxiliary material it
Between do not interact.
Embodiment 2：The Tecarfarin tablet recipes and technical study of 5mg specifications
Because previous experiments research shows：When individually using lactose as filler, sliver phenomenon occurs in the big production of industry, institute
Lactose is not selected individually in the auxiliary material selection of diluent with the present invention.But it is due to the lactose good water solubility as filler,
And microcrystalline cellulose not only serves as filler, and possess the performance of disintegrant, choose both lactose and microcrystalline cellulose
Combination is simultaneously as diluent (herein, " filler " and " diluent " can be with used interchangeably), the dissolution effect that can reach
Really.
This research is promulgated according to 2010 editions formulation requirements to tablet of Chinese Pharmacopoeia with reference to CDE《Chemicals medicine is ground
Study carefully basic fundamental guideline》, it is investigation with character, hardness, friability, disintegration time, dissolution rate etc. with reference to the characteristics of tablet
Index, to this product prescription further screened using the species and consumption of auxiliary material.
Therefore, in the present embodiment, the prescription to specification for the Tecarfarin tablets of 5mg/ pieces has been carried out further
Research.(1) screening of diluent
The ratio and consumption of lactose and microcrystalline cellulose are screened, diluent different proportion and consumption is investigated to tabletting formability
With the influence of dissolution rate.
The screening prescription and measurement result of the filler of table 3
By 7 prescriptions in table 3, using wet granulation technology, Tecarfarin labels are first prepared, dissolution is determined
Degree, preparation method is specific as follows：
(1) supplementary material pre-treatment：After main ingredient (Tecarfarin), each auxiliary material are crushed respectively, main ingredient crosses 60 mesh sieves, auxiliary material
80 mesh sieves are crossed, it is standby；
(2) adhesive is matched somebody with somebody：
When the adhesive in prescription selects PVP K30 (PVPK30), 8 grams of PVP K30s are weighed in beaker, plus it is pure
Change 92 grams of water, stir to clarify, obtain the 8% PVP K30 aqueous solution I, it is standby；
(3) mix：Weigh the main ingredient of recipe quantity, filler it is well mixed after, add disintegrant cross-linked carboxymethyl fiber
Plain sodium (PVPP), silica are well mixed, and obtain mixture II；
(4) softwood processed and granulation：The binder aqueous solution I of recipe quantity is added in mixture II, softwood is made, by gained
Softwood crosses 18 mesh stainless steel sieve series grains, obtains wet granular；
(5) dry：By medicine wet granular resulting in step (4) in dry about 2h at 60 DEG C ± 5 DEG C；
(6) whole grain：18 mesh stainless steels sieve whole grain will be crossed by dry drug particles, obtain dry particl；
(7) it is total mixed：Recipe quantity magnesium stearate is added in dry particl, is well mixed, obtains and always mixes particle；
(8) tabletting：The content of dispersion according to measured by total mixed particle, calculates the theoretical tablet weight, tablet press machine is adjusted into suitable fills out
Charge, control pressure makes tablet hardness within 5~7kg, and tabletting is produced.
According to prescription shown in table 4 and the preparation method described in embodiment 2, pelletized, pressed with the batch of 1000/batches
Piece, then determines hardness, friability, disintegration time and the dissolution rate of the Tecarfarin tablets prepared, screens filler.
It the results are shown in Table 4.
Dissolution determination：
By the assay method under Chinese Pharmacopoeia 2010 editions dissolution rates, above-mentioned 7 prescriptions are determined 45 points in dissolution medium
The dissolution rate of clock, wherein dissolution medium are that (adding water, it is molten to make by sodium hydroxide 2.30g, potassium dihydrogen phosphate 7.65g for phosphate buffer
Solve as 1000ml, adjust pH to 8.8) with phosphoric acid, dissolution determination the results are shown in Table 4.
The inspection targets such as the dissolution rate of each tablet formulation of table 4 are contrasted
In terms of dissolution result, designed 9 prescriptions dissolution rate of 45 minutes in dissolution medium is shown, in prescription 3 and 4
Because microcrystalline cellulose proportion is larger, lactose proportion is smaller, cause disintegrating property slightly worse, dissolution rate is slightly lower, and locate
The disintegration of side 1,2,5,6,7 and dissolution rate are preferable, and its dissolution rate can reach more than 80%, therefore select lactose and microcrystalline cellulose
The mass ratio of element is (0.75~2.5)：1, the dissolution rate of the wherein gained of prescription 1 and 2 is best and disintegration time is moderate, therefore it is preferred that
The optimum quality ratio of lactose and microcrystalline cellulose is 2：1.
Further, the present invention is further optimized to the addition manner of disintegrant to prescription and preparation process, as a result
Show, Ac-Di-Sol disintegrant of the present invention, using the technique of addition inside and outside disintegrant, relative to disintegration
Agent is only with the technique of interior addition, and its dissolution rate significantly improves, and its dissolution rate can bring up to more than 85%.Therefore determine disintegrant
Consumption and addition manner are：The interior dosage of disintegrant is the 1/2 of disintegrant recipe quantity, and outer dosage is another the 1/ of disintegrant recipe quantity
2。
Therefore, according to the specific example of the present invention, the method for preparing Tecarfarin tablets comprises the following steps：
(1) Tecarfarin is mixed with lactose and microcrystalline cellulose, and resulting mixture is carried out at micronizing
Reason, to obtain the mixture micro powder granule that particle diameter is 10 microns to 100 microns, by Ac-Di-Sol, gathers
Dimension ketone K30 and magnesium stearate cross 80 mesh sieves after crushing respectively, standby；
(2) PVP K30 is mixed with purified water, with the PVP K30 aqueous solution that obtained mass fraction is 6%~12%
I, it is standby；
(3) the mixture micro powder granule is mixed with the Ac-Di-Sol that Inner adds, obtains the mixture II；
(4) the PVP K30 aqueous solution I is added in the mixture II, and resulting mixture is made soft
Material, crosses 18 mesh stainless steel sieve series grains by gained softwood, obtains the wet granular；
(5) at 55 DEG C~65 DEG C, the wet granular is dried into 1~4h, 18 mesh stainless steels sieve whole grain is then crossed, to obtain
Obtain the dry particl；
(6) dry particl is mixed with additional Ac-Di-Sol, glidant silica, and by gained
The mixture arrived is mixed with magnesium stearate, to obtain the medicinal mixture；
(7) content of dispersion of the medicinal mixture is determined, and is calculated the theoretical tablet weight, will be described based on the theoretical piece weight
Medicinal mixture carries out tabletting, to obtain the Tecarfarin tablets；
(8) the Tecarfarin tablets are packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.
Embodiment 3：Influence of the coating weight gain to Tecarfarin tablet dissolved corrosions
Prescription 1 (is shown in Table 5)：
Table 5：
Preparation technology：
(1) Tecarfarin is mixed with lactose and microcrystalline cellulose, and resulting mixture is carried out at micronizing
Reason, is 50 microns of the mixture micro powder granule to obtain particle diameter, by Ac-Di-Sol, PVP K30 and
Magnesium stearate crosses 80 mesh sieves after crushing respectively, standby；
(2) PVP K30 is mixed with purified water, it is standby with the PVP K30 aqueous solution I that obtained mass fraction is 8%
With；
(3) the mixture micro powder granule is mixed with the Ac-Di-Sol that Inner adds, obtains the mixture II；
(4) the PVP K30 aqueous solution I is added in the mixture II, and resulting mixture is made soft
Material, crosses 18 mesh stainless steel sieve series grains by gained softwood, obtains the wet granular；
(5) at 60 DEG C, the wet granular is dried into 2h, 18 mesh stainless steels sieve whole grain is then crossed, it is described dry to obtain
Particle；
(6) dry particl is mixed with additional Ac-Di-Sol, glidant silica, and by gained
The mixture arrived is mixed with magnesium stearate, to obtain the medicinal mixture；
(7) content of dispersion of the medicinal mixture is determined, and is calculated the theoretical tablet weight, will be described based on the theoretical piece weight
Medicinal mixture carries out tabletting, to obtain the Tecarfarin tablets；
(8) it is coated：Powder white stomach dissolution type Opadry 81W68907 will be coated to be added in purified water, solid content is configured to
For 20% Coating Solution, stirred 45 minutes with screw type agitating paddle.Label is carried out using common transformation coating pan
It is coated, obtains Tecarfarin Film coated tablets, the parameter of the Cotton seeds is as follows：40 DEG C of control sheet bed tempertaure, coating pan air intake
65 DEG C of temperature, coating weight gain 3.0%.
(9) pack：The Tecarfarin tablets are packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.
Embodiment 4：
Prescription be the same as Example 3, but be 4.5% by coating weight gain the step of preparation method in (8).
Embodiment 5：
Prescription be the same as Example 3, but be 3.5% by coating weight gain the step of preparation method in (8).
Embodiment 6：
Prescription be the same as Example 3, but be 2.5% by coating weight gain the step of preparation method in (8).
Embodiment 7：
Prescription be the same as Example 3, but be 5% by coating weight gain the step of preparation method in (8).
Table:The screening of 6 coating powder consumptions
| Coating weight gain | Coating effect (amplification sem observation) | Disintegration time (s) |
| 2.5% | Label has wrapped up complete substantially, but edge is imperfect | 70 |
| 3.0% | Coating tablet is fully wrapped around, and color is uniform, and edge is complete | 92 |
| 3.5% | Coating tablet is fully wrapped around, and color is uniform, and edge is complete | 98 |
| 4.5% | Coating tablet is fully wrapped around, and color is uniform, and edge is complete | 106 |
| 5.0% | Coating tablet is fully wrapped around, and color is uniform, and edge is complete | 188 |
The result of table 6 shows, when coating powder consumption is more than the 3.0% of label weight, and coating tablet outward appearance can be met will
Ask, and with the increase of coating powder consumption, disintegration time accordingly extends, when coating powder consumption is 5.0%, disintegration time, which exists, to be added
The possibility of speed extension.Desired coating tablet progress basic performance is met to above-mentioned three kinds of outward appearances and evaluates as shown in table 7 below：
The coating tablet basic performance of table 7 is commented
Thus illustrate, control bag weightening can cause Tecarfarin tablets to have in the range of 3.0%~4.5%
Most suitable dissolution rate, is conducive to the performance of drug effect, moreover it is possible to play preferable medicine shaded effect.
Therefore, according to the specific example of the present invention, the method for preparing Tecarfarin tablets comprises the following steps：
(1) Tecarfarin is mixed with lactose and microcrystalline cellulose, and resulting mixture is carried out at micronizing
Reason, to obtain the mixture micro powder granule that particle diameter is 10 microns to 100 microns, by Ac-Di-Sol, gathers
Dimension ketone K30 and magnesium stearate cross 80 mesh sieves after crushing respectively, standby；
(2) PVP K30 is mixed with purified water, with the PVP K30 aqueous solution that obtained mass fraction is 6%~12%
I, it is standby；
(3) the mixture micro powder granule is mixed with the Ac-Di-Sol that Inner adds, obtains the mixture II；
(4) the PVP K30 aqueous solution I is added in the mixture II, and resulting mixture is made soft
Material, crosses 18 mesh stainless steel sieve series grains by gained softwood, obtains the wet granular；
(5) at 55 DEG C~65 DEG C, the wet granular is dried into 1~4h, 18 mesh stainless steels sieve whole grain is then crossed, to obtain
Obtain the dry particl；
(6) dry particl is mixed with additional Ac-Di-Sol, glidant silica, and by gained
The mixture arrived is mixed with magnesium stearate, to obtain the medicinal mixture；
(7) content of dispersion of the medicinal mixture is determined, and is calculated the theoretical tablet weight, will be described based on the theoretical piece weight
Medicinal mixture carries out tabletting, to obtain the Tecarfarin tablets；
(8) it is coated：Powder white stomach dissolution type Opadry 81W68907 will be coated to be added in purified water, solid content is configured to
For 20% Coating Solution, stirred 45 minutes with screw type agitating paddle.Label is carried out using common transformation coating pan
It is coated, obtains Tecarfarin Film coated tablets.40 DEG C of control sheet bed tempertaure, 65 DEG C of coating pan EAT, coating weight gain 3.0-
4.5%.
(9) pack：The Tecarfarin tablets are packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.
Embodiment 8：The preparation of Tecarfarin pieces
Tecarfarin 2.5g, lactose 80g, microcrystalline cellulose 40g, PVP K30 5g, Ac-Di-Sol
(interior to add) 2.5g, Ac-Di-Sol (additional) 2.5g, silica 0.1g, magnesium stearate 0.2g, is made 1000 altogether
Piece.
Preparation method：
(1) supplementary material pre-treatment：Main ingredient (Tecarfarin) and auxiliary material filler lactose, microcrystalline cellulose are mixed and carried out
Micronizing (particle diameter is at 10 microns to 100 microns), remaining each auxiliary material cross 80 mesh sieves after crushing respectively, standby；
(2) adhesive is matched somebody with somebody：8 grams of adhesive PVP K30s are weighed in beaker, plus 92 grams of purified water, stir to clarify, obtain
The binder aqueous solution I of 8% PVP K30, it is standby；
(3) mix：After Tecarfarin and filler are well mixed, the disintegrant cross-linked carboxymethyl for needing Inner to add is added fine
The plain sodium of dimension is well mixed, and obtains mixture II；
(4) softwood processed and granulation：The binder aqueous solution I of recipe quantity is added in mixture II, softwood is made, by gained
Softwood crosses 18 mesh stainless steel sieve series grains, obtains wet granular；
(5) dry：By medicine wet granular resulting in step (4) in dry 2h at 60 DEG C；
(6) whole grain：18 mesh stainless steels sieve whole grain will be crossed by dry drug particles, obtain dry particl；
(7) it is total mixed：The need of recipe quantity additional disintegrant Ac-Di-Sol and dioxy are added in dry particl
SiClx, adds recipe quantity magnesium stearate, is well mixed, and obtains and always mixes particle；
(8) tabletting：The content of dispersion according to measured by total mixed particle, calculates the theoretical tablet weight, tablet press machine is adjusted into suitable fills out
Charge, control pressure makes tablet hardness within 5~7kg, and tabletting is produced.
(9) it is coated：Powder white stomach dissolution type Opadry 81W68907 will be coated to be added in purified water, solid content is configured to
For 20% Coating Solution, stirred 45 minutes with screw type agitating paddle.Label is carried out using common transformation coating pan
It is coated, obtains Tecarfarin Film coated tablets.40 DEG C of control sheet bed tempertaure, 65 DEG C of coating pan EAT, coating weight gain 3.5%,
Obtain the Tecarfarin tablets.
(10) pack：The Tecarfarin tablets are packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.
Embodiment 9：The preparation of Tecarfarin pieces
Prescription：
Tecarfarin 5g, lactose 120g, microcrystalline cellulose 60g, PVP K30 15g, Ac-Di-Sol
(interior to add) 6g, Ac-Di-Sol (additional) 6g, silica 1 g, magnesium stearate 3g, is made 1000 altogether.
Preparation method：
(1) supplementary material pre-treatment：Main ingredient (Tecarfarin) and auxiliary material filler lactose, microcrystalline cellulose are mixed and carried out
Micronizing (particle diameter is at 10 microns to 100 microns), remaining each auxiliary material cross 80 mesh sieves after crushing respectively, standby；
(2) adhesive is matched somebody with somebody：8 grams of adhesive PVP K30s are weighed in beaker, plus 92 grams of purified water, stir to clarify, obtain
The binder aqueous solution I of 8% PVP K30, it is standby；
(3) mix：After Tecarfarin and filler are well mixed, the disintegrant cross-linked carboxymethyl for needing Inner to add is added fine
The plain sodium of dimension is well mixed, and obtains mixture II；
(4) softwood processed and granulation：The binder aqueous solution I of recipe quantity is added in mixture II, softwood is made, by gained
Softwood crosses 18 mesh stainless steel sieve series grains, obtains wet granular；
(5) dry：By medicine wet granular resulting in step (4) in dry 4h at 55 DEG C；
(6) whole grain：18 mesh stainless steels sieve whole grain will be crossed by dry drug particles, obtain dry particl；
(7) it is total mixed：The additional disintegrant Ac-Di-Sol of the need of recipe quantity is added in dry particl, place is added
Side's amount magnesium stearate, is well mixed, obtains and always mix particle；
(8) tabletting：The content of dispersion according to measured by total mixed particle, calculates the theoretical tablet weight, tablet press machine is adjusted into suitable fills out
Charge, control pressure makes tablet hardness within 5~7kg, and tabletting is produced.
(9) it is coated：Powder white stomach dissolution type Opadry 81W68907 will be coated to be added in purified water, solid content is configured to
For 20% Coating Solution, stirred 45 minutes with screw type agitating paddle.Label is carried out using common transformation coating pan
It is coated, obtains Tecarfarin Film coated tablets.40 DEG C of control sheet bed tempertaure, 65 DEG C of coating pan EAT, coating weight gain 4.5%,
Obtain the Tecarfarin tablets.
(10) pack：The Tecarfarin tablets are packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.
Embodiment 10：The preparation of Tecarfarin pieces
Prescription：
Tecarfarin 5g, lactose 100g, microcrystalline cellulose 50g, PVP K30 10g, Ac-Di-Sol
(interior to add) 4g, Ac-Di-Sol (additional) 4g, silica 0.8g, magnesium stearate 2.4g, is made 1000 altogether.
(1) supplementary material pre-treatment：Main ingredient (Tecarfarin) and auxiliary material filler lactose, microcrystalline cellulose are mixed and carried out
Micronizing (particle diameter is at 5 microns to 100 microns), remaining each auxiliary material cross 80 mesh sieves after crushing respectively, standby；
(2) adhesive is matched somebody with somebody：8 grams of adhesive PVP K30s are weighed in beaker, plus 92 grams of purified water, stir to clarify, obtain
The binder aqueous solution I of 8% PVP K30, it is standby；
(3) mix：After Tecarfarin and filler are well mixed, the disintegrant cross-linked carboxymethyl for needing Inner to add is added fine
The plain sodium of dimension is well mixed, and obtains mixture II；
(4) softwood processed and granulation：The binder aqueous solution I of recipe quantity is added in mixture II, softwood is made, by gained
Softwood crosses 18 mesh stainless steel sieve series grains, obtains wet granular；
(5) dry：By medicine wet granular resulting in step (4) in dry 1h at 65 DEG C；
(6) whole grain：18 mesh stainless steels sieve whole grain will be crossed by dry drug particles, obtain dry particl；
(7) it is total mixed：The additional disintegrant Ac-Di-Sol of the need of recipe quantity is added in dry particl, place is added
Side's amount magnesium stearate, is well mixed, obtains and always mix particle；
(8) tabletting：The content of dispersion according to measured by total mixed particle, calculates the theoretical tablet weight, tablet press machine is adjusted into suitable fills out
Charge, control pressure makes tablet hardness within 5~7kg, and tabletting is produced.
(9) it is coated：Powder white stomach dissolution type Opadry 81W68907 will be coated to be added in purified water, solid content is configured to
For 20% Coating Solution, stirred 45 minutes with screw type agitating paddle.Label is carried out using common transformation coating pan
It is coated, obtains Tecarfarin Film coated tablets.40 DEG C of control sheet bed tempertaure, 65 DEG C of coating pan EAT, coating weight gain 3.0%,
Obtain the Tecarfarin tablets.
(10) pack：The Tecarfarin tablets are packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.
Embodiment 11：The preparation of Tecarfarin pieces
Prescription：
Tecarfarin 2.5g, lactose 100g, microcrystalline cellulose 50g, PVP K30 8g, cross-linked carboxymethyl cellulose
Sodium (interior to add) 5g, Ac-Di-Sol (additional) 5g, silica 0.5g, magnesium stearate 0.5g, is made 1000 altogether.
Preparation method：Be the same as Example 8.
Embodiment 12：The preparation of Tecarfarin pieces
Tecarfarin 10g, lactose 120g, microcrystalline cellulose 60g, PVP K30 20g, cross-linked carboxymethyl cellulose
Sodium (interior to add) 7.5g, Ac-Di-Sol (additional) 7.5g, silica 1 .5g, magnesium stearate 3g, is made 1000 altogether
Piece.
Preparation method：Be the same as Example 8.
Embodiment 13：The preparation of Tecarfarin pieces
Tecarfarin 10g, lactose 140g, hydroxypropyl methylcellulose 70g, PVP K30 20g, cross-linked carboxymethyl fiber
Plain sodium (interior to add) 10g, Ac-Di-Sol (additional) 10g, silica 2g, magnesium stearate 5g, are made 1000 altogether.
Preparation method：Be the same as Example 8.
Embodiment 14：The preparation of Tecarfarin pieces
Tecarfarin 5g, lactose 90g, hydroxypropyl methylcellulose 90g, PVP K30 15g, cross-linked carboxymethyl cellulose
Sodium (interior to add) 6g, Ac-Di-Sol (additional) 6g, silica 1 g, magnesium stearate 3g, is made 1000 altogether.
Preparation method：Be the same as Example 8.
Embodiment 15：The preparation of Tecarfarin pieces
Tecarfarin 5g, lactose 125g, hydroxypropyl methylcellulose 50g, PVP K30 15g, cross-linked carboxymethyl cellulose
Sodium (interior to add) 6g, Ac-Di-Sol (additional) 6g, silica 1 g, magnesium stearate 3g, is made 1000 altogether.
Preparation method：Be the same as Example 8.
Embodiment 16：The preparation of Tecarfarin pieces
Tecarfarin 5g, lactose 125g, hydroxypropyl methylcellulose 50g, PVP K30 10g, cross-linked carboxymethyl cellulose
Sodium (interior to add) 4g, Ac-Di-Sol (additional) 4g, silica 0.8g, magnesium stearate 2.4g, is made 1000 altogether.
Preparation method：Be the same as Example 8.
Embodiment 18：Quality evaluation
1st, performance evaluation
To totally 9 samples described in 8- of embodiment of the present invention embodiments 16, character, hardness, friability, the piece method of double differences are carried out
Different, dissolution rate inspection, in order to carry out performance evaluation to preparation-obtained Tecarfarin of the invention, the results are shown in Table 8.
The Tecarfarin piece performances of table 8 are evaluated
The result of table 8 shows that the character of 9 batches of samples, hardness, friability, tablet weight variation meet the requirements, and dissolution rate compared with
Height, and can reach 85%, meet the requirements.
2nd, influence factor experiment in 10 days：
Next, Tecarfarin pieces (Film coated tablets) are prepared to above-described embodiment 9 carries out influence factor experiment, tool
Body is as follows：
The Tecarfarin Film coated tablets (lot number 161201) of 5mg specifications is uncovered in culture dish, high temperature (60 DEG C),
Placed 10 days under the conditions of high humidity (RH 92.5%, 25 DEG C), strong light (4500lx ± 500lx), in the 5th, sampling in 10 days, observation system
The project such as agent outward appearance, content, dissolution rate, relevant material, weight-loss ratio, and be compared with the inspection data of sample before investigation, examine
Survey the results are shown in Table 9.
The Tecarfarin Film coated tablets of table 9 (5mg/ pieces) (lot number 161201) influence factor result of the test
Influence factor result of the test shows：Film coated tablets is placed 10 days under high temperature, high humidity, illumination, content, relevant material
Without conspicuousness change, quality is basicly stable, shows, prescription science is feasible, rational technology, favorable reproducibility.But 10 days films of high humidity
There is the slight moisture absorption on garment piece surface, and dissolution rate has declined, it is noted that moistureproof when pointing out to select to pack.Therefore, product needs sealing
Stored at drying.
In the description of the invention, it is to be understood that term " first ", " second " are only used for describing purpose, and can not
It is interpreted as indicating or implies relative importance or the implicit quantity for indicating indicated technical characteristic.Thus, define " the
One ", one or more this feature can be expressed or be implicitly included to the feature of " second ".In the description of the invention,
" multiple " are meant that two or more, unless otherwise specifically defined.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means to combine specific features, structure, material or the spy that the embodiment or example are described
Point is contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not
Identical embodiment or example must be directed to.Moreover, specific features, structure, material or the feature of description can be with office
Combined in an appropriate manner in one or more embodiments or example.In addition, in the case of not conflicting, the skill of this area
Art personnel can be tied the not be the same as Example or the feature of example and non-be the same as Example or example described in this specification
Close and combine.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changed, replacing and modification.
Claims (10)
1. a kind of Tecarfarin tablets, it is characterised in that including：
Tecarfarin；And
Pharmaceutically acceptable auxiliary material.
2. Tecarfarin tablets according to claim 1, it is characterised in that the pharmaceutically acceptable auxiliary material is choosing
From at least one of filler, disintegrant, adhesive, glidant and lubricant,
Wherein,
The filler be selected from lactose, cornstarch, microcrystalline cellulose, mannitol at least one, preferably lactose and crystallite
The combination of cellulose；
Described adhesive be selected from PVP K30, hydroxypropyl methylcellulose, methylcellulose at least one, preferred PVP
K30；
The disintegrant be selected from Ac-Di-Sol, sodium carboxymethyl starch, Ac-Di-Sol at least
One kind, preferably Ac-Di-Sol；
The glidant is selected from silica；
The lubricant is selected from magnesium stearate.
3. Tecarfarin tablets according to claim 2, it is characterised in that described according to parts by weight
Tecarfarin tablets include：
The Tecarfarin 2.5-10 parts by weight, the filler 120-210 parts by weight, described adhesive 5-30 parts by weight,
The disintegrant 5-20 parts by weight, the glidant 0.1-2 parts by weight, the lubricant 0.2-5 parts by weight.
4. Tecarfarin tablets according to claim 3, it is characterised in that described according to parts by weight
Tecarfarin tablets include one of following：
The parts by weight of Tecarfarin 2.5, the parts by weight of lactose 80, the parts by weight of microcrystalline cellulose 40, the parts by weight of PVP K30 5 are handed over
Join the parts by weight of sodium carboxymethylcellulose 5, the parts by weight of silica 0.1, the parts by weight of magnesium stearate 0.2；
The parts by weight of Tecarfarin 2.5, the parts by weight of lactose 100, the parts by weight of microcrystalline cellulose 50, the parts by weight of PVP K30 8,
The parts by weight of Ac-Di-Sol 10, the parts by weight of silica 0.5, the parts by weight of magnesium stearate 0.5；
The parts by weight of Tecarfarin 5, the parts by weight of lactose 120, the parts by weight of microcrystalline cellulose 60, the parts by weight of PVP K30 15 are handed over
Join the parts by weight of sodium carboxymethylcellulose 12, silica 1 parts by weight, the parts by weight of magnesium stearate 3；
The parts by weight of Tecarfarin 5, the parts by weight of lactose 100, the parts by weight of microcrystalline cellulose 50, the parts by weight of PVP K30 10 are handed over
Join the parts by weight of sodium carboxymethylcellulose 8, the parts by weight of silica 0.8, the parts by weight of magnesium stearate 2.4；
The parts by weight of Tecarfarin 10, the parts by weight of lactose 140, the parts by weight of hydroxypropyl methylcellulose 70, the weight of PVP K30 20
Part, the parts by weight of Ac-Di-Sol 20, the parts by weight of silica 2, the parts by weight of magnesium stearate 5；
The parts by weight of Tecarfarin 10, the parts by weight of lactose 120, the parts by weight of microcrystalline cellulose 60, the parts by weight of PVP K30 20,
The parts by weight of Ac-Di-Sol 15, silica 1 .5 parts by weight, the parts by weight of magnesium stearate 3；
The parts by weight of Tecarfarin 5, the parts by weight of lactose 90, the parts by weight of hydroxypropyl methylcellulose 90, the parts by weight of PVP K30 15,
The parts by weight of Ac-Di-Sol 12, silica 1 parts by weight, the parts by weight of magnesium stearate 3；
The parts by weight of Tecarfarin 5, the parts by weight of lactose 125, the parts by weight of hydroxypropyl methylcellulose 50, the parts by weight of PVP K30 15,
The parts by weight of Ac-Di-Sol 12, silica 1 parts by weight, the parts by weight of magnesium stearate 3；
The parts by weight of Tecarfarin 5, the parts by weight of lactose 125, the parts by weight of hydroxypropyl methylcellulose 50, the parts by weight of PVP K30 10,
The parts by weight of Ac-Di-Sol 8, the parts by weight of silica 0.8, the parts by weight of magnesium stearate 2.4.
5. a kind of method for preparing the Tecarfarin tablets in claim 1-4 described in any one, it is characterised in that bag
Include：
Tecarfarin is subjected to micronization processes, and by Tecarfarin micro powder granules obtained and pharmaceutically acceptable
Auxiliary material is mixed, to obtain the medicinal mixture；
The medicinal mixture is subjected to tabletting, to obtain Tecarfarin labels,
Tecarfarin labels are coated processing by described, to obtain Tecarfarin tablets,
Wherein, the particle diameter of the Tecarfarin micro powder granules is 10-100 microns.
6. method according to claim 5, it is characterised in that further comprise：
The Tecarfarin tablets are packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.
7. method according to claim 5, it is characterised in that including：
(1) Tecarfarin and filler are mixed, and resulting mixture is subjected to micronization processes, to obtain particle diameter
For 10 microns to 100 microns of mixture micro powder granule, 80 mesh sieves are crossed after disintegrant, adhesive and lubricant are crushed respectively,
It is standby；
(2) described adhesive is mixed with purified water, it is standby with the binder aqueous solution I that obtained mass fraction is 6%~12%
With；
(3) the mixture micro powder granule is mixed with the disintegrant that Inner adds, obtains mixture II；
(4) the described adhesive aqueous solution I is added in the mixture II, and softwood is made in resulting mixture, by institute
Obtain softwood and cross 18 mesh stainless steel sieve series grains, to obtain wet granular；
(5) at 55 DEG C~65 DEG C, the wet granular is dried into 1~4h, 18 mesh stainless steels sieve whole grain is then crossed, it is dry to obtain
Particle；
(6) dry particl is mixed with additional disintegrant, then resulting mixture is mixed with magnesium stearate, to obtain
Obtain the medicinal mixture；
(7) content of dispersion of the medicinal mixture is determined, and is calculated the theoretical tablet weight, then the medicinal mixture is pressed
Piece, to obtain the Tecarfarin labels.
(8) powder will be coated to add in purified water, is configured to the Coating Solution that solid content is 20%, it is then molten using the coating
Liquid is coated processing to the Tecarfarin labels, to obtain the Tecarfarin tablets,
Optionally, further comprise：
(9) the Tecarfarin tablets are packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.
8. method according to claim 7, it is characterised in that control piece in theoretical piece ± 5% scope of weight again during tabletting
Interior, hardness is controlled in 5~7kg.
9. method according to claim 7, it is characterised in that using common transformation coating pan to the Tecarfarin pieces
Core carries out the Cotton seeds, wherein the gross mass based on the Tecarfarin labels, according to mass percent meter, is coated and increases
Weight is 3.0~4.5%.
10. method according to claim 7, it is characterised in that including：
(1) Tecarfarin is mixed with lactose and microcrystalline cellulose, and resulting mixture is subjected to micronization processes, with
Just the mixture micro powder granule that particle diameter is 10 microns to 100 microns is obtained, by Ac-Di-Sol, PVP
K30, silica and magnesium stearate cross 80 mesh sieves after crushing respectively, standby；
(2) PVP K30 is mixed with purified water, it is standby with the PVP K30 aqueous solution I that obtained mass fraction is 6%~12%
With；
(3) the mixture micro powder granule is mixed with the Ac-Di-Sol that Inner adds, obtains the mixture II；
(4) the PVP K30 aqueous solution I is added in the mixture II, and softwood is made in resulting mixture, will
Gained softwood crosses 18 mesh stainless steel sieve series grains, obtains the wet granular；
(5) at 55 DEG C~65 DEG C, the wet granular is dried into 1~4h, 18 mesh stainless steels sieve whole grain is then crossed, to obtain
State dry particl；
(6) dry particl is mixed with additional Ac-Di-Sol, and by resulting mixture and stearic acid
Magnesium is mixed, to obtain the medicinal mixture；
(7) content of dispersion of the medicinal mixture is determined, and is calculated the theoretical tablet weight, based on the theoretical piece weight, by the medicine
Mixture carries out tabletting, to obtain the Tecarfarin labels；
(8) powder white stomach dissolution type Opadry 81W68907 will be coated to be added in purified water, it is 20% to be configured to solid content
Coating Solution, is stirred 45 minutes with screw type agitating paddle, then label is carried out using common transformation coating pan described
Cotton seeds, to obtain the Tecarfarin tablets,
Wherein, the parameter of the Cotton seeds is as follows：40 DEG C of control sheet bed tempertaure, 65 DEG C of coating pan EAT, coating weight gain
3.0-4.5%,
(9) the Tecarfarin tablets are packed using polyvinyl chloride bubble-cap+two-sided composite aluminium film bag.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710392947.5A CN107281154A (en) | 2017-05-27 | 2017-05-27 | Antithrombotic and pre- anti-stroke Tecarfarin pharmaceutical preparations and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710392947.5A CN107281154A (en) | 2017-05-27 | 2017-05-27 | Antithrombotic and pre- anti-stroke Tecarfarin pharmaceutical preparations and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7253208B2 (en) * | 2004-04-08 | 2007-08-07 | Aryx Therapeutics | Materials and methods for treating coagulation disorders |
| CN104490832A (en) * | 2014-12-05 | 2015-04-08 | 海南卫康制药(潜山)有限公司 | Lyophilized tablet prepared from warfarin composition and preparation method thereof |
| CN105434377A (en) * | 2014-08-29 | 2016-03-30 | 武汉光谷人福生物医药有限公司 | Meisuoshuli tablet and preparation method thereof |
-
2017
- 2017-05-27 CN CN201710392947.5A patent/CN107281154A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7253208B2 (en) * | 2004-04-08 | 2007-08-07 | Aryx Therapeutics | Materials and methods for treating coagulation disorders |
| CN105434377A (en) * | 2014-08-29 | 2016-03-30 | 武汉光谷人福生物医药有限公司 | Meisuoshuli tablet and preparation method thereof |
| CN104490832A (en) * | 2014-12-05 | 2015-04-08 | 海南卫康制药(潜山)有限公司 | Lyophilized tablet prepared from warfarin composition and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| DAVID J. ELLIS ET AL: "The First Evaluation of a Novel Vitamin K Antagonist,Tecarfarin (ATI-5923), in Patients With Atrial Fibrillation", 《CIRCULATION》 * |
| 李向荣: "《药剂学》", 28 February 2010 * |
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