CN108542891A - A kind of solid composite medicament containing ticagrelor - Google Patents
A kind of solid composite medicament containing ticagrelor Download PDFInfo
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- ticagrelor
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- butylated hydroxyanisole
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K9/282—Organic compounds, e.g. fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The present invention relates to a kind of solid composite medicament containing ticagrelor, inventor has found in the research process to ticagrelor, and there are two kinds of degradation pathways of oxidative degradation and light degradation for ticagrelor, and will produce corresponding oxidation and light degradation impurity.The preparation of preparation and storage stability can be had an impact, inventor is by research, it was found that antioxidant Butylated Hydroxyanisole is added in preparation prescription, with metal ion chelation agent sodium carboxymethylcellulose, the degradation of ticagrelor raw material in preparation can be significantly inhibited, surprisingly the light degradation of ticagrelor is equally also suppressed in preparation, i.e., Butylated Hydroxyanisole equally plays the role of light stabilizer.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of solid composite medicament and its system containing ticagrelor
Preparation Method and purposes.
Background technology
The heart, brain and vascular diseases are the disease that incidence is high, harmfulness is big, lethal, disability rate is high, cardiovascular and cerebrovascular disease sheet
All it is vascular lesion in matter, the main reason for vascular lesion is arterial vascular athero- Lipid Plaque and due to athero- lipid
Aberrant angiogenesis caused by patch, this is the main reason for forming heart and cerebral ischemia, infarct illness；About atherosclerosis
Mechanism has the theories such as lipid infiltration, proliferation of smooth muscle, thrombosis, platelet aggregation and arterial intimal injury, this explanation
Therefore cardiovascular and cerebrovascular disease, is prevented happens is that caused by many factors and is inhibited or reversed lipid spot from many aspects
Block is the basic method solved the problems, such as and thinking and particularly significant and significant.
Ticagrelor piece is the anti-platelet aggregation class antithrombotic of Astrazeneca AB of Britain exploitation, trade name
" Brilique ", specification are every 90mg containing ticagrelor and 60mg.Astrazeneca AB developed auspicious for lattice since 1999
Lip river, the heart of Europe disease association III phase test result for announcing ticagrelor for the first time in 2009, in detail narration compare it to acute
The effect of coronary syndrome patient.In November, 2009, Astrazeneca AB have submitted to European Union and U.S. FDA for lattice respectively
The new drug application of auspicious Lip river, in December, 2010, ticagrelor obtained European Union's approval, sick or unstable for preventing Adult cardiac
Property patient with angina pectoris thrombotic episodes generation, in January, 2011 ticagrelor formally in the sale of all member states of European Union, 2011 years
July 20, AstraZeneca announce FDA approveds ticagrelor for reducing acute coronary syndrome patient's thrombotic cardiovascular thing
The incidence of part.FDA approval times Linda (ticagrelor piece) the 60mg new dosages of in September, 2015 are used for patient of the heart infarction after 1 year.
Highlighting times Linda can simultaneously be used in acute stage and the chronic phase patient and can be to the cardiovascular event of reduction duration
Risk plays a role.
PLATO (The Study of Platelet Inhibition and Patient Outcomes, PLATO) is ground
Study carefully the effect of also showing ticagrelor and be substantially better than clopidogrel, ticagrelor treats 12 months in the feelings for not increasing main bleeding
Under condition, cardiovascular death/myocardial infarction/palsy composite end points event wind of ACS patient is further significantly reduced compared with clopidogrel
Danger significantly reduces cardiovascular death up to 21% up to 16%.Recommend so being listed in a line by domestic and international multiple guides, and Europe
Guide is even more before the recommendation rank of ticagrelor is listed in clopidogrel by nearly 2 years, in the non-serviceable patient of ticagrelor
It is middle to use clopidogrel.
Ticagrelor (Ticagrelor, also referred to as Ticagrelor), belongs to cyclopenta triazolopyrimidines, chemistry
Entitled (1S, 2S, 3R, 5s) -3- [7- [(1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamino] -5- (thiopropyl) -3H- [1,2,
3]-triazole [4,5-d] pyrimidin-3-yl] -5- (2- hydroxyl-oxethyls) pentamethylene -1,2- glycol, molecular formula：C23H28F2N6O4S,
Molecular weight 522.57, No. CAS：274693-27-5, structural formula are as follows：
Point out that ticagrelor exists for the assessing drug actions report of times Linda (Brilique) according to European Bureau of Drugs Supervision (EMA)
Belong to Section IV class drug (low dissolving, hyposmosis) in Biopharmaceutics Classification system (BCS), not only it is external molten to become it for solubility
Go out the obstacle with body absorption, and the effect due to cell membrane to drug hyposmosis, take orally absolute bioavailability down to
36%.
The study found that ticagrelor bulk pharmaceutical chemicals have good thermal stability, but it is more sensitive to illumination and oxidation, it presses
It is degraded to corresponding impurity according to following reaction, to influence the stability and validity of drug.
In the prior art, there is no disclosing any reduction illumination and aoxidizing the influence to bulk pharmaceutical chemicals and preparation, to improve
The technical solution of preparation stability, although the import ticagrelor tablet of existing Astrazeneca AB, using the opaque clothing of cladding
The scheme of film has completely cut off influence of the oxygen in illumination and air to ticagrelor bulk pharmaceutical chemicals in tablet.But in formulation process
In, for example, bulk pharmaceutical chemicals and auxiliary material mixing, granulation, tabletting, in coating process, the oxygen and indoor illumination in air are apparent
The ticagrelor bulk pharmaceutical chemicals for participating in preparation can be had an impact.Meanwhile in production process, material is inevitably mixing,
In tableting processes, contacting metal.A part in metal can exist in the form of ion, so metal ion can to oxidation and
Catalytic action is played in the further reaction of the peroxy radical generated in During Illumination.It is well known that minimal amount of catalyst is
The influence of highly significant can be generated to reaction.It shows as being obviously promoted here and replaces lattice in production process and preparation storing process
Degradation of the auspicious Lip river bulk pharmaceutical chemicals to the peroxy radical generated due to illumination and dioxygen oxidation in formulation process.Final performance
It is reduced for the storage stability of preparation.
A statement is done to existing published technical solution as follows, but in following scheme, does not provide solution and as above asks
Any technical solution of topic and the technique effect obtained by corresponding technical solution.
Chinese patent 201510136454.6 discloses a kind of ticagrelor solid pharmaceutical preparation and preparation method thereof.It is described solid
Body preparation includes active constituents of medicine ticagrelor and diluent, and wherein diluent is the combination of mannitol and microcrystalline cellulose,
And the weight ratio of mannitol and microcrystalline cellulose is 0.2:1 to 3:1.Solid pharmaceutical preparation provided by the invention is molten in quickening drug
Drug is promoted to dissolve out completely while going out, bioavilability is high, and storage stability is good.On the other hand, the present invention also provides one
The preparation method of ticagrelor solid pharmaceutical preparation described in kind, this method is simple and practicable, and production cost is low, is suitable for industrialized production.
Chinese patent 201410801996.6 discloses a kind of ticagrelor piece and preparation method thereof, belongs to medical science neck
Domain.Ticagrelor piece of the present invention selects mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose
Sodium, magnesium stearate are auxiliary material, and the use for forming ticagrelor piece, each auxiliary material and bulk pharmaceutical chemicals in restriction is compounded with bulk pharmaceutical chemicals ticagrelor
It mutually acts synergistically in amount range, so that the dissolution rate of the ticagrelor piece of preparation is higher than existing marketed tablet, and show
Dissolved corrosion identical with street drug ensure that ticagrelor piece has preferable assimilation effect, and improve ticagrelor
The bioavilability of piece.Ticagrelor piece impurity content of the present invention is few, and performance is stablized under high temperature, illumination condition.The present invention replaces
The preparation method of Ge Ruiluo pieces, technical process is simple, easily operated realization, is suitable for industrial application.
Chinese patent 201380050404.5 discloses a kind of solid oral pharmaceutical preparation, and it includes with chemical name
(1S, 2S, 3R, 5S) -3- [7- [[(1R, 2S) -2- (3,4- difluorophenyls) cyclopropyl] amino] -5- (rosickyite base) -3H-1,2,
3- triazols [4,5-d] pyrimidin-3-yl] -5- (2- hydroxyl-oxethyls) -1,2- ring pentanediols ticagrelor, it includes at least
A kind of non-hygroscopic bulking agent and/or at least one non-hygroscopic adhesive, wherein filler and adhesive do not have any
It is disintegrated effect.The preparation of said preparation can compress progress by wet granulation or dry granulation or directly.
Chinese patent 201310748653.3 discloses Ticagrelor dry suspension and preparation method thereof, specifically discloses one
Kind treats drug dry suspensoid agent of acute coronary syndrome and preparation method thereof, and the drug dry suspensoid agent is by replacing lattice auspicious
Solid orally ingestible prepared by Lip river, filler, suspending agent, disintegrant, lubricant or other pharmaceutically acceptable auxiliary materials.This hair
The dry suspensoid agent of bright offer is met water and is disintegrated rapidly, and drug-eluting is fast, and bioavilability is high.Simultaneously relative to old man and dysphagia
Patient be more easy to take, and it is easy to carry, make patient be easy to receive.
Chinese patent 201310593355.1 discloses ticagrelor times semihydrate capsule and preparation method thereof, the present invention
Obtained ticagrelor times semihydrate capsule, has the advantage that：Simple process, of low cost, bioavilability is high；It is small to blood
The inhibiting effect of plate aggregation, ticagrelor times semihydrate capsule improve nearly 10%.It is controlled the invention further relates to this capsule is used
Treat the application of diseases of cardiovascular and cerebrovascular systems.
Chinese patent 201310432438.2 discloses a kind of ticagrelor solid dispersions and preparation method thereof.Specifically
Ground, the present invention provide a kind of solid dispersions containing ticagrelor, and the ticagrelor is scattered in carrier material, the load
Body material contains one or more of polyvinylpyrrolidone, copolyvidone, crospovidone, preferably also contains ethyl cellulose
Element.The present invention is made drug be in high degree of dispersion state, is solved and replaced using solid dispersion technology using specific pharmaceutical carrier
The indissoluble sex chromosome mosaicism of Ge Ruiluo, while in preferred embodiments, solid dispersions provided by the invention can reduce drug
Burst release improves drug safety, reduces the risk that myocardial infarction and apoplexy occur during medication for patient.
201310408327.8 disclosing a kind of tablet composition and preparation method thereof of anticoagulation medicine ticagrelor.It should
Composition includes ticagrelor, filler, disintegrant, lubricant and/or adhesive, it is characterised in that：The tablet is by directly pressing
Prepared by piece method or prepared by dry granulation tabletting method.The preparation method operating procedure is simple, and technological parameter controllability is good, technique
Reproducibility is good；Meanwhile it avoiding ticagrelor transformation of crystal and impurity caused by damp and hot possibility in the process and increasing；It is prepared
Ticagrelor piece have similar dissolved corrosion in vitro with former triturate.Therefore, ticagrelor tablet quality provided by the invention
Stably and controllable, efficacy and saferry is good.
Invention content
As described above, ticagrelor bulk pharmaceutical chemicals can be influenced in production process by illumination and oxidation, to reduce it
It is preparing and the stability in storing process.
Inventor has obtained a kind of solid composite medicament containing ticagrelor by further investigation, and the composition is passed through
Certain technique is prepared into film coating tablet.
The study found that common antioxidant Butylated Hydroxyanisole (BHA) not only has good antioxidant effect in preparation, but also
Unexpectedly there is good smooth stablizing effect to ticagrelor bulk pharmaceutical chemicals, ticagrelor bulk pharmaceutical chemicals can be played
The absorption and masking action of light.
The metal ion generated in production process makees the catalysis of radical reaction in preparation preparation and storing process
With equally need avoid, by research be added to metal ion chelation agent in the composition, for avoid this metal from
The catalytic action of son.
The solid composite medicament containing ticagrelor further includes filler using ticagrelor as main ingredient, metal from
Sub- chelating agent, light stabilizer, antioxidant, disintegrant, lubricant and coating agent；It is further prepared into as follows thin
Film-coated tablet：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, it is spare to cross 200 mesh sieve；
2) it takes metal ion chelation agent, light stabilizer, antioxidant to be dissolved as aqueous solution, obtains adhesive；
3) filler, disintegrant is taken to crush, it is spare；
4) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and filler and disintegrant that step 3) obtains are taken, is uniformly mixed, adds
Enter the adhesive that step 2) obtains, softwood processed；
5) softwood for taking step 4) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
6) lubricant is added in the midbody particle for taking step 5) to obtain, and is uniformly mixed, tabletting obtains plain piece；
7) it takes plain piece obtained by step 6), coating agent to be coated, obtains ticagrelor thin membrane coated tablet.
It is characterized in that, the light stabilizer and antioxidant are Butylated Hydroxyanisole, i.e. BHA, the metal ion chelation agent
For sodium carboxymethylcellulose.
Further, the coating agent is the common stomach dissolution type film coating agent of shading, and is added to mass fraction wherein
For 0.01% Butylated Hydroxyanisole, for avoiding primary contributions of the oxygen in air to tablet.Coating agent weightening is plain piece piece weight
3%-5%.
The filler is calcium dihydrogen phosphate and mannitol, and the disintegrant is croscarmellose sodium, the profit
Lubrication prescription is magnesium stearate.
The solid composite medicament containing ticagrelor, unit formulation composition are as follows：
The solid composite medicament containing ticagrelor, unit formulation composition are as follows：
The solid composite medicament containing ticagrelor, is further prepared into thin membrane coated tablet as follows
Agent：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, the sieve of 200 mesh excessively is spare, spare；
2) it takes Butylated Hydroxyanisole to be dissolved in appropriate 95% ethyl alcohol, and this ethanol solution is dissolved in appropriate 50 DEG C or more purified waters,
The aqueous solution containing 0.01% Butylated Hydroxyanisole is obtained, it is spare；
3) aqueous solution containing 0.01% Butylated Hydroxyanisole obtained by step 2) is taken, sodium carboxymethylcellulose is added, it is stirring while adding, it obtains
Carboxymethyl cellulose aqueous solution is adhesive；
4) it takes mannitol, calcium monohydrogen phosphate, croscarmellose sodium to crush, crosses 80 mesh sieve, it is spare；
5) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and the mannitol that step 3) obtains, calcium monohydrogen phosphate, cross-linked carboxymethyl are taken
Sodium cellulosate is uniformly mixed, and the adhesive that step 3) obtains, softwood processed is added；
6) softwood for taking step 5) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
7) magnesium stearate lubricant is added in the midbody particle for taking step 6) to obtain, and is uniformly mixed, tabletting obtains plain piece；
8) the common stomach dissolution type film coating agent of shading is taken, the suspension of solid content about 10% is configured to purified water, and add
Enter the Butylated Hydroxyanisole ethanol solution obtained by step 2), obtains the coating solution containing 0.001% Butylated Hydroxyanisole, i.e. coating constituents solid content
Middle Butylated Hydroxyanisole content is 0.01%, spare；
9) plain piece obtained by step 7) is taken, is coated with coating agent obtained by step 8), obtains ticagrelor thin membrane coated tablet；
10) thin membrane coated tablet obtained by step 9) is taken, is packed with PVC aluminium foils, obtains finished product.
Patent application is further illustrated the present invention through the following experiment.
Experiment one：The study on light stability of Butylated Hydroxyanisole (BHA),
Draw 1mL ticagrelors standard solution four parts of (0.1M ethanol solutions) respectively, label A, B, C, D as a contrast, in A, B, C
It is separately added into 0.01M BHA ethanol solutions 0.05mL, 0.1mL, 0.2mL in three parts of solution, 10mL is settled to ethyl alcohol, is then set
It is irradiated 1 hour under 20W ultraviolet lamps, measures the content (%) of ticagrelor light degradation impurity I-VI in solution, as shown in the table：
From upper table data it is found that after BHA ethanol solutions are added, the light degradation impurity in ticagrelor sample obviously becomes
Few, after addition 0.1mL, 0.01M BHA ethanol solutions, the light degradation impurity of ticagrelor disappears substantially in sample.
Experiment two：Compatibility experiments
By ticagrelor bulk pharmaceutical chemicals；Respectively with filler microcrystalline cellulose, mannitol, calcium monohydrogen phosphate collapses ticagrelor bulk pharmaceutical chemicals
Agent croscarmellose sodium is solved, according to weight ratio 1:5, it is uniformly mixed, ticagrelor bulk pharmaceutical chemicals distinguish lubricant stearic acid
Magnesium, the common stomach dissolution type film coating agent of shading, light stabilizer Butylated Hydroxyanisole BHA, metal ion chelation agent sodium carboxymethylcellulose,
By weight 20:1, be uniformly mixed, set respectively in culture dish booth at<The thin layer of 5mm thickness.Sample number into spectrum is respectively A, B, C, D, E,
F, G, H, I.
Above-mentioned sample is set 60 DEG C respectively, RH20% ± 5%；10 are placed under the conditions of 25 DEG C of high humidity, RH92.5% ± 5%
It, sampled in the 5th day and the 10th day, detected ticagrelor content and related substance.Detection data is as shown in the table.
1 ticagrelor bulk pharmaceutical chemicals of table and auxiliary material compatibility experiments result (60 DEG C, RH20% ± 5%) to be selected
2 ticagrelor bulk pharmaceutical chemicals of table and auxiliary material compatibility experiments result to be selected (25 DEG C of high humidity, RH92.5% ± 5%)
Selected auxiliary material is can be seen that from the above experimental result to store under high temperature, super-humid conditions with bulk pharmaceutical chemicals ticagrelor,
Compared with ticagrelor bulk pharmaceutical chemicals, no significant change.That is ticagrelor and filler microcrystalline cellulose, mannitol, calcium monohydrogen phosphate,
Disintegrant croscarmellose sodium, magnesium stearate lubricant, the common stomach dissolution type film coating agent of shading, light stabilizer fourth hydroxyl
Fennel ether BHA, metal ion chelation agent sodium carboxymethylcellulose compatibility is good, can be formed under solid states with above-mentioned auxiliary material
Composition, and it is further prepared into solid pharmaceutical preparation, but equally find out from experimental result, microcrystalline cellulose data are poor, therefore excellent
Select mannitol and calcium monohydrogen phosphate as filler.
Experiment three：Prescription screening
Rule of thumb design 90mg tablet plain piece weights are 300mg, coating weight gain 3%-5%.Other specification tablets change proportionally
Respective components dosage.
Coating agent used is the common stomach dissolution type film coating agent of shading, the dosage containing Butylated Hydroxyanisole in coating agent solid content
For 0.01%-0.04%.
Preparation process：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, the sieve of 200 mesh excessively is spare, spare；
2) it takes Butylated Hydroxyanisole to be dissolved in appropriate 95% ethyl alcohol, and this ethanol solution is dissolved in appropriate 50 DEG C or more purified waters,
The aqueous solution containing 0.01%-0.04% Butylated Hydroxyanisoles is obtained, it is spare；
3) aqueous solution containing 0.01%-0.04% Butylated Hydroxyanisoles obtained by step 2) is taken, sodium carboxymethylcellulose, side edged is added
Stirring is obtained containing 2%-4% carboxymethyl cellulose aqueous solutions, is adhesive；
4) it takes mannitol, calcium monohydrogen phosphate, croscarmellose sodium to crush, crosses 80 mesh sieve, it is spare；
5) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and the mannitol that step 3) obtains, calcium monohydrogen phosphate, cross-linked carboxymethyl are taken
Sodium cellulosate is uniformly mixed, and the adhesive that step 3) obtains, softwood processed is added；
6) softwood for taking step 5) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
7) magnesium stearate lubricant is added in the midbody particle for taking step 6) to obtain, and is uniformly mixed, tabletting obtains plain piece；
8) the common stomach dissolution type film coating agent of shading is taken, the suspension of solid content about 10% is configured to purified water, and add
Enter step
2) the Butylated Hydroxyanisole ethanol solution obtained by, obtains the coating solution containing 0.001%-0.004% Butylated Hydroxyanisoles, i.e. coating constituents
Butylated Hydroxyanisole content is 0.01%-0.04% in solid content, spare；
9) plain piece obtained by step 7) is taken, is coated with coating agent obtained by step 8), obtains ticagrelor thin membrane coated tablet.
Ticagrelor thin membrane coated tablet is prepared with prescription as above and technique, conclusion is as follows：
1) under above-mentioned prescription, plain piece molding is preferable, can be coated operation；
2) when carboxymethylcellulose sodium solution it is a concentration of 2.0% when, adhesive flow is preferable, to the wetability of solid material compared with
Good, granulating process operation is smooth.As concentration increases, adhesive flow is deteriorated, and granulating process becomes slightly difficult.Therefore according to this
Smooth degree is operated, selects binder concn for 2.0% and 3.0%；
3) when Butylated Hydroxyanisole content is 0.01% in adhesive, adhesive is clear shape, even when a concentration of 0.02%
The microscopic grains for seeing Butylated Hydroxyanisole, when a concentration of 0.04%, crystalline condition becomes apparent, stablizes in conjunction with Butylated Hydroxyanisole light and tests
It is found that Butylated Hydroxyanisole concentration is about that 0.01% both can effectively inhibit the light degradation of ticagrelor in the solution.Therefore selection adhesive
A concentration of the 0.01% of middle Butylated Hydroxyanisole；
In conclusion selection granulating process is smooth, compression molding is good, and adhesive prepares the prescription one that nodeless mesh is precipitated, place
The optimal prescriptions of Fang Siwei, the side of clicking here reduce corresponding component ratio and prepare 60mg ticagrelor film coating tablets.
Experiment four：Dissolution experiment
Ticagrelor thin membrane coated tablet is prepared respectively by embodiment 1-8, and tablet format is respectively 30mg, 60mg, 90mg, 120mg.
Using 900mL0.2% polyoxyethylene sorbitan monoleates aqueous solution as dissolution medium, 37 DEG C, paddle method, 75rpm, in 10min, 20min, 30min,
45min, 60min, 75min sample detection compare Dissolution behaviours, sample number into spectrum A-I with Imported Tablet times Linda.Dissolve out data
Comparison is as follows.
Table 375min dissolution rates investigate experiment (n=5)
From above-mentioned data it is found that with the ticagrelor tablet technique of patent disclosure of the present invention, that is, press prepared by embodiment 1-8
Four specification tablets, compared with import ticagrelor tablet, Dissolution behaviours no significant difference.
Experiment five：Accelerated stability experiment in 12 months
Take nine groups of aforementioned four specification film coating tablet (embodiment 1-8) and 90mg specification import ticagrelor tablets times Linda
Number A-I sets 40 DEG C ± 2 DEG C to sample respectively respectively, is stored 12 months under the conditions of 75% ± 5%RH, respectively at 0 month, January, and March,
June, December are measured by sampling relevant nature, obtain corresponding data, as shown in the table：
4 embodiment 1-8 of table is compared with commercially available Imported Tablet sample stability
According to auspicious for lattice prepared by prescription described in embodiment 1-8 of the present invention and technique it can be seen from upper table data
Lip river film coating tablet, at 40 DEG C ± 2 DEG C, under 75% ± 5%RH acceleration environments, after storage in 12 months, content, related substance
Be varied from, but content is more than 98.5%, maximum list impurity is less than 0.3%, and total impurities are below 1.8%, oxidation and
Light degradation total impurities are below 0.08%, 75min dissolution rates and are more than 85%；It corresponds, commercially available ticagrelor tablet warp
It crosses after accelerating storage in 12 months, content falls to approximately 96.75%, and maximum list impurity rises to about 0.548%, and oxidation and light drop
Total impurities are solved respectively more than 0.15%, twice of sample described in about embodiment 1-8, total impurities reach 2.175%,
75min dissolution rates are down to 82.23%.
Based on analysis as above, according to prescription described in embodiment 1-8 of the present invention and the ticagrelor film prepared by technique
Under acceleration conditions, the data after storing 12 months are shown coated tablet, and stability is significantly better than marketed tablet, and 75min is molten
Out-degree is slightly above commercially available import product.Prescription and technique i.e. through the invention makes the stability of ticagrelor tablet obtain obviously
Enhancing so that the present invention has substantive distinguishing features outstanding and marked improvement, and has practicability.
Specific implementation mode
The advantageous effect further illustrated the present invention is tested by following.But it is not limited to following embodiments, this field
Technical staff on the basis of the present invention made by, do not depart from equivalent substitute or the transformation of substantive content of the present invention, also this
Within the protection domain of invention.
1 30mg specification ticagrelor thin membrane coated tablets of embodiment prepare (unit：g)
The solid composite medicament containing ticagrelor, is further prepared into thin membrane coated tablet as follows
Agent：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, the sieve of 200 mesh excessively is spare, spare；
2) it takes Butylated Hydroxyanisole to be dissolved in appropriate 95% ethyl alcohol, and this ethanol solution is dissolved in appropriate 50 DEG C or more purified waters,
The aqueous solution containing 0.01% Butylated Hydroxyanisole is obtained, it is spare；
3) aqueous solution containing 0.01% Butylated Hydroxyanisole obtained by step 2) is taken, sodium carboxymethylcellulose is added, it is stirring while adding, it obtains
Carboxymethyl cellulose aqueous solution is adhesive；
4) it takes mannitol, calcium monohydrogen phosphate, croscarmellose sodium to crush, crosses 80 mesh sieve, it is spare；
5) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and the mannitol that step 3) obtains, calcium monohydrogen phosphate, cross-linked carboxymethyl are taken
Sodium cellulosate is uniformly mixed, and the adhesive that step 3) obtains, softwood processed is added；
6) softwood for taking step 5) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
7) magnesium stearate lubricant is added in the midbody particle for taking step 6) to obtain, and is uniformly mixed, tabletting obtains plain piece；
8) the common stomach dissolution type film coating agent of shading is taken, the suspension of solid content about 10% is configured to purified water, and add
Enter the Butylated Hydroxyanisole ethanol solution obtained by step 2), obtains the coating solution containing 0.001% Butylated Hydroxyanisole, i.e. coating constituents solid content
Middle Butylated Hydroxyanisole content is 0.01%, spare；
9) plain piece obtained by step 7) is taken, is coated with coating agent obtained by step 8), obtains ticagrelor thin membrane coated tablet；
10) thin membrane coated tablet obtained by step 9) is taken, is packed with PVC aluminium foils, obtains finished product.
2 30mg specification ticagrelor thin membrane coated tablets of embodiment prepare (unit：g)
The solid composite medicament containing ticagrelor, is further prepared into thin membrane coated tablet as follows
Agent：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, the sieve of 200 mesh excessively is spare, spare；
2) it takes Butylated Hydroxyanisole to be dissolved in appropriate 95% ethyl alcohol, and this ethanol solution is dissolved in appropriate 50 DEG C or more purified waters,
The aqueous solution containing 0.01% Butylated Hydroxyanisole is obtained, it is spare；
3) aqueous solution containing 0.01% Butylated Hydroxyanisole obtained by step 2) is taken, sodium carboxymethylcellulose is added, it is stirring while adding, it obtains
Carboxymethyl cellulose aqueous solution is adhesive；
4) it takes mannitol, calcium monohydrogen phosphate, croscarmellose sodium to crush, crosses 80 mesh sieve, it is spare；
5) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and the mannitol that step 3) obtains, calcium monohydrogen phosphate, cross-linked carboxymethyl are taken
Sodium cellulosate is uniformly mixed, and the adhesive that step 3) obtains, softwood processed is added；
6) softwood for taking step 5) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
7) magnesium stearate lubricant is added in the midbody particle for taking step 6) to obtain, and is uniformly mixed, tabletting obtains plain piece；
8) the common stomach dissolution type film coating agent of shading is taken, the suspension of solid content about 10% is configured to purified water, and add
Enter the Butylated Hydroxyanisole ethanol solution obtained by step 2), obtains the coating solution containing 0.001% Butylated Hydroxyanisole, i.e. coating constituents solid content
Middle Butylated Hydroxyanisole content is 0.01%, spare；
9) plain piece obtained by step 7) is taken, is coated with coating agent obtained by step 8), obtains ticagrelor thin membrane coated tablet；
10) thin membrane coated tablet obtained by step 9) is taken, is packed with PVC aluminium foils, obtains finished product.
Embodiment 360mg specification ticagrelor thin membrane coated tablets prepare (unit：g)
The solid composite medicament containing ticagrelor, is further prepared into thin membrane coated tablet as follows
Agent：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, the sieve of 200 mesh excessively is spare, spare；
2) it takes Butylated Hydroxyanisole to be dissolved in appropriate 95% ethyl alcohol, and this ethanol solution is dissolved in appropriate 50 DEG C or more purified waters,
The aqueous solution containing 0.01% Butylated Hydroxyanisole is obtained, it is spare；
3) aqueous solution containing 0.01% Butylated Hydroxyanisole obtained by step 2) is taken, sodium carboxymethylcellulose is added, it is stirring while adding, it obtains
It is adhesive containing 2% carboxymethyl cellulose aqueous solution；
4) it takes mannitol, calcium monohydrogen phosphate, croscarmellose sodium to crush, crosses 80 mesh sieve, it is spare；
5) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and the mannitol that step 3) obtains, calcium monohydrogen phosphate, cross-linked carboxymethyl are taken
Sodium cellulosate is uniformly mixed, and the adhesive that step 3) obtains, softwood processed is added；
6) softwood for taking step 5) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
7) magnesium stearate lubricant is added in the midbody particle for taking step 6) to obtain, and is uniformly mixed, tabletting obtains plain piece；
8) the common stomach dissolution type film coating agent of shading is taken, the suspension of solid content about 10% is configured to purified water, and add
Enter the Butylated Hydroxyanisole ethanol solution obtained by step 2), obtains the coating solution containing 0.001% Butylated Hydroxyanisole, i.e. coating constituents solid content
Middle Butylated Hydroxyanisole content is 0.01%, spare；
9) plain piece obtained by step 7) is taken, is coated with coating agent obtained by step 8), obtains ticagrelor thin membrane coated tablet；
10) thin membrane coated tablet obtained by step 9) is taken, is packed with PVC aluminium foils, obtains finished product.
Embodiment 460mg specification ticagrelor thin membrane coated tablets prepare (unit：g)
The solid composite medicament containing ticagrelor, is further prepared into thin membrane coated tablet as follows
Agent：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, the sieve of 200 mesh excessively is spare, spare；
2) it takes Butylated Hydroxyanisole to be dissolved in appropriate 95% ethyl alcohol, and this ethanol solution is dissolved in appropriate 50 DEG C or more purified waters,
The aqueous solution containing 0.01% Butylated Hydroxyanisole is obtained, it is spare；
3) aqueous solution containing 0.01% Butylated Hydroxyanisole obtained by step 2) is taken, sodium carboxymethylcellulose is added, it is stirring while adding, it obtains
It is adhesive containing 3% carboxymethyl cellulose aqueous solution；
4) it takes mannitol, calcium monohydrogen phosphate, croscarmellose sodium to crush, crosses 80 mesh sieve, it is spare；
5) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and the mannitol that step 3) obtains, calcium monohydrogen phosphate, cross-linked carboxymethyl are taken
Sodium cellulosate is uniformly mixed, and the adhesive that step 3) obtains, softwood processed is added；
6) softwood for taking step 5) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
7) magnesium stearate lubricant is added in the midbody particle for taking step 6) to obtain, and is uniformly mixed, tabletting obtains plain piece；
8) the common stomach dissolution type film coating agent of shading is taken, the suspension of solid content about 10% is configured to purified water, and add
Enter the Butylated Hydroxyanisole ethanol solution obtained by step 2), obtains the coating solution containing 0.001% Butylated Hydroxyanisole, i.e. coating constituents solid content
Middle Butylated Hydroxyanisole content is 0.01%, spare；
9) plain piece obtained by step 7) is taken, is coated with coating agent obtained by step 8), obtains ticagrelor thin membrane coated tablet；
10) thin membrane coated tablet obtained by step 9) is taken, is packed with PVC aluminium foils, obtains finished product.
5 90mg specification ticagrelor thin membrane coated tablets of embodiment prepare (unit：g)
The solid composite medicament containing ticagrelor, is further prepared into thin membrane coated tablet as follows
Agent：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, the sieve of 200 mesh excessively is spare, spare；
2) it takes Butylated Hydroxyanisole to be dissolved in appropriate 95% ethyl alcohol, and this ethanol solution is dissolved in appropriate 50 DEG C or more purified waters,
The aqueous solution containing 0.01% Butylated Hydroxyanisole is obtained, it is spare；
3) aqueous solution containing 0.01% Butylated Hydroxyanisole obtained by step 2) is taken, sodium carboxymethylcellulose is added, it is stirring while adding, it obtains
It is adhesive containing 2% carboxymethyl cellulose aqueous solution；
4) it takes mannitol, calcium monohydrogen phosphate, croscarmellose sodium to crush, crosses 80 mesh sieve, it is spare；
5) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and the mannitol that step 3) obtains, calcium monohydrogen phosphate, cross-linked carboxymethyl are taken
Sodium cellulosate is uniformly mixed, and the adhesive that step 3) obtains, softwood processed is added；
6) softwood for taking step 5) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
7) magnesium stearate lubricant is added in the midbody particle for taking step 6) to obtain, and is uniformly mixed, tabletting obtains plain piece；
8) the common stomach dissolution type film coating agent of shading is taken, the suspension of solid content about 10% is configured to purified water, and add
Enter the Butylated Hydroxyanisole ethanol solution obtained by step 2), obtains the coating solution containing 0.001% Butylated Hydroxyanisole, i.e. coating constituents solid content
Middle Butylated Hydroxyanisole content is 0.01%, spare；
9) plain piece obtained by step 7) is taken, is coated with coating agent obtained by step 8), obtains ticagrelor thin membrane coated tablet；
10) thin membrane coated tablet obtained by step 9) is taken, is packed with PVC aluminium foils, obtains finished product.
6 90mg specification ticagrelor thin membrane coated tablets of embodiment prepare (unit：g)
The solid composite medicament containing ticagrelor, is further prepared into thin membrane coated tablet as follows
Agent：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, the sieve of 200 mesh excessively is spare, spare；
2) it takes Butylated Hydroxyanisole to be dissolved in appropriate 95% ethyl alcohol, and this ethanol solution is dissolved in appropriate 50 DEG C or more purified waters,
The aqueous solution containing 0.01% Butylated Hydroxyanisole is obtained, it is spare；
3) aqueous solution containing 0.01% Butylated Hydroxyanisole obtained by step 2) is taken, sodium carboxymethylcellulose is added, it is stirring while adding, it obtains
It is adhesive containing 3% carboxymethyl cellulose aqueous solution；
4) it takes mannitol, calcium monohydrogen phosphate, croscarmellose sodium to crush, crosses 80 mesh sieve, it is spare；
5) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and the mannitol that step 3) obtains, calcium monohydrogen phosphate, cross-linked carboxymethyl are taken
Sodium cellulosate is uniformly mixed, and the adhesive that step 3) obtains, softwood processed is added；
6) softwood for taking step 5) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
7) magnesium stearate lubricant is added in the midbody particle for taking step 6) to obtain, and is uniformly mixed, tabletting obtains plain piece；
8) the common stomach dissolution type film coating agent of shading is taken, the suspension of solid content about 10% is configured to purified water, and add
Enter the Butylated Hydroxyanisole ethanol solution obtained by step 2), obtains the coating solution containing 0.001% Butylated Hydroxyanisole, i.e. coating constituents solid content
Middle Butylated Hydroxyanisole content is 0.01%, spare；
9) plain piece obtained by step 7) is taken, is coated with coating agent obtained by step 8), obtains ticagrelor thin membrane coated tablet；
10) thin membrane coated tablet obtained by step 9) is taken, is packed with PVC aluminium foils, obtains finished product.
7 120mg specification ticagrelor thin membrane coated tablets of embodiment prepare (unit：g)
The solid composite medicament containing ticagrelor, is further prepared into thin membrane coated tablet as follows
Agent：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, the sieve of 200 mesh excessively is spare, spare；
2) it takes Butylated Hydroxyanisole to be dissolved in appropriate 95% ethyl alcohol, and this ethanol solution is dissolved in appropriate 50 DEG C or more purified waters,
The aqueous solution containing 0.01% Butylated Hydroxyanisole is obtained, it is spare；
3) aqueous solution containing 0.01% Butylated Hydroxyanisole obtained by step 2) is taken, sodium carboxymethylcellulose is added, it is stirring while adding, it obtains
Carboxymethyl cellulose aqueous solution is adhesive；
4) it takes mannitol, calcium monohydrogen phosphate, croscarmellose sodium to crush, crosses 80 mesh sieve, it is spare；
5) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and the mannitol that step 3) obtains, calcium monohydrogen phosphate, cross-linked carboxymethyl are taken
Sodium cellulosate is uniformly mixed, and the adhesive that step 3) obtains, softwood processed is added；
6) softwood for taking step 5) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
7) magnesium stearate lubricant is added in the midbody particle for taking step 6) to obtain, and is uniformly mixed, tabletting obtains plain piece；
8) the common stomach dissolution type film coating agent of shading is taken, the suspension of solid content about 10% is configured to purified water, and add
Enter the Butylated Hydroxyanisole ethanol solution obtained by step 2), obtains the coating solution containing 0.001% Butylated Hydroxyanisole, i.e. coating constituents solid content
Middle Butylated Hydroxyanisole content is 0.01%, spare；
9) plain piece obtained by step 7) is taken, is coated with coating agent obtained by step 8), obtains ticagrelor thin membrane coated tablet；
10) thin membrane coated tablet obtained by step 9) is taken, is packed with PVC aluminium foils, obtains finished product.
8 120mg specification ticagrelor thin membrane coated tablets of embodiment prepare (unit：g)
The solid composite medicament containing ticagrelor, is further prepared into thin membrane coated tablet as follows
Agent：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, the sieve of 200 mesh excessively is spare, spare；
2) it takes Butylated Hydroxyanisole to be dissolved in appropriate 95% ethyl alcohol, and this ethanol solution is dissolved in appropriate 50 DEG C or more purified waters,
The aqueous solution containing 0.01% Butylated Hydroxyanisole is obtained, it is spare；
3) aqueous solution containing 0.01% Butylated Hydroxyanisole obtained by step 2) is taken, sodium carboxymethylcellulose is added, it is stirring while adding, it obtains
Carboxymethyl cellulose aqueous solution is adhesive；
4) it takes mannitol, calcium monohydrogen phosphate, croscarmellose sodium to crush, crosses 80 mesh sieve, it is spare；
5) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and the mannitol that step 3) obtains, calcium monohydrogen phosphate, cross-linked carboxymethyl are taken
Sodium cellulosate is uniformly mixed, and the adhesive that step 3) obtains, softwood processed is added；
6) softwood for taking step 5) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
7) magnesium stearate lubricant is added in the midbody particle for taking step 6) to obtain, and is uniformly mixed, tabletting obtains plain piece；
8) the common stomach dissolution type film coating agent of shading is taken, the suspension of solid content about 10% is configured to purified water, and add
Enter the Butylated Hydroxyanisole ethanol solution obtained by step 2), obtains the coating solution containing 0.001% Butylated Hydroxyanisole, i.e. coating constituents solid content
Middle Butylated Hydroxyanisole content is 0.01%, spare；
9) plain piece obtained by step 7) is taken, is coated with coating agent obtained by step 8), obtains ticagrelor thin membrane coated tablet；
10) thin membrane coated tablet obtained by step 9) is taken, is packed with PVC aluminium foils, obtains finished product.
Claims (9)
1. a kind of solid composite medicament containing ticagrelor further includes filler, metal ion using ticagrelor as main ingredient
Chelating agent, light stabilizer, antioxidant, disintegrant, lubricant and coating agent；It is further prepared into film as follows
Coated tablet：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, it is spare to cross 200 mesh sieve；
2) metal ion chelation agent, light stabilizer, antioxidant dissolving is taken to obtain adhesive；
3) filler, disintegrant is taken to crush, it is spare；
4) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and filler and disintegrant that step 3) obtains are taken, is uniformly mixed, adds
Enter the adhesive that step 2) obtains, softwood processed；
5) softwood for taking step 4) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
6) lubricant is added in the midbody particle for taking step 5) to obtain, and is uniformly mixed, tabletting obtains plain piece；
7) plain piece obtained by step 6) is taken, is coated with coating agent, obtains ticagrelor thin membrane coated tablet.
2. the solid composite medicament containing ticagrelor as described in claim 1, which is characterized in that the coating agent is shading
Common stomach dissolution type film coating agent, and it is added to the Butylated Hydroxyanisole of mass percent 0.01% wherein, coating agent weightening is
The 3%-5% of plain piece piece weight.
3. the solid composite medicament containing ticagrelor as claimed in claim 2, which is characterized in that the filler is phosphoric acid
Calcium dihydrogen and mannitol, the disintegrant are croscarmellose sodium, and the lubricant is magnesium stearate.
4. the solid composite medicament containing ticagrelor as claimed in claim 3, which is characterized in that the composition unit formulation
Composition is as follows：
5. the solid composite medicament containing ticagrelor as claimed in claim 3, which is characterized in that the composition unit formulation
Composition is as follows
6. the solid composite medicament containing ticagrelor as claimed in claim 3, which is characterized in that the composition unit formulation
Composition is as follows：
7. the solid composite medicament containing ticagrelor as claimed in claim 3, which is characterized in that the composition unit formulation
Composition is as follows：
8. the solid composite medicament containing ticagrelor as claimed in claim 3, which is characterized in that the composition unit formulation
Composition is as follows：
9. any solid composite medicament containing ticagrelor as described in claim 1-8, which is characterized in that the composition is logical
It crosses following steps and is further prepared into film coating tablet：
1) ticagrelor bulk pharmaceutical chemicals are taken, are crushed, the sieve of 200 mesh excessively is spare, spare；
2) it takes Butylated Hydroxyanisole to be dissolved in appropriate 95% ethyl alcohol, and this ethanol solution is dissolved in appropriate 50 DEG C or more purified waters,
The aqueous solution containing 0.01% Butylated Hydroxyanisole is obtained, it is spare；
3) aqueous solution containing 0.01% Butylated Hydroxyanisole obtained by step 2) is taken, sodium carboxymethylcellulose is added, it is stirring while adding, it obtains
It is adhesive containing 2%-3% carboxymethyl cellulose aqueous solutions；
4) it takes mannitol, calcium monohydrogen phosphate, croscarmellose sodium to crush, crosses 80 mesh sieve, it is spare；
5) the ticagrelor bulk pharmaceutical chemicals that step 1) obtains and the mannitol that step 3) obtains, calcium monohydrogen phosphate, cross-linked carboxymethyl are taken
Sodium cellulosate is uniformly mixed, and the adhesive that step 3) obtains, softwood processed is added；
6) softwood for taking step 5) to obtain, dry successively through wet granular processed, whole grain obtains the midbody particle containing ticagrelor；
7) magnesium stearate lubricant is added in the midbody particle for taking step 6) to obtain, and is uniformly mixed, tabletting obtains plain piece；
8) the common stomach dissolution type film coating agent of shading is taken, the suspension of solid content about 10% is configured to purified water, and add
Enter the Butylated Hydroxyanisole ethanol solution obtained by step 2), obtains the coating solution containing 0.001% Butylated Hydroxyanisole, i.e. coating constituents solid content
Middle Butylated Hydroxyanisole content is 0.01%, spare；
9) plain piece obtained by step 7) is taken, is coated with coating agent obtained by step 8), obtains ticagrelor thin membrane coated tablet；
10) thin membrane coated tablet obtained by step 9) is taken, is packed with PVC aluminium foils, obtains finished product.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810582828.0A CN108542891A (en) | 2018-06-07 | 2018-06-07 | A kind of solid composite medicament containing ticagrelor |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810582828.0A CN108542891A (en) | 2018-06-07 | 2018-06-07 | A kind of solid composite medicament containing ticagrelor |
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| CN201810582828.0A Withdrawn CN108542891A (en) | 2018-06-07 | 2018-06-07 | A kind of solid composite medicament containing ticagrelor |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109806261A (en) * | 2019-03-11 | 2019-05-28 | 梁江丽 | A kind of ticagrelor sustained release preparation and its preparation and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237540A (en) * | 2015-09-21 | 2016-01-13 | 南京正大天晴制药有限公司 | Preparation method, detection method and application for ticagrelor-related substances |
| CN105998017A (en) * | 2009-01-23 | 2016-10-12 | 韩美科学株式会社 | Solid pharmaceutical composition comprising amlodipine and losartan with improved stability |
| CN108078944A (en) * | 2016-11-22 | 2018-05-29 | 重庆植恩药业有限公司 | Solid composite containing ticagrelor and preparation method thereof |
-
2018
- 2018-06-07 CN CN201810582828.0A patent/CN108542891A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105998017A (en) * | 2009-01-23 | 2016-10-12 | 韩美科学株式会社 | Solid pharmaceutical composition comprising amlodipine and losartan with improved stability |
| CN105237540A (en) * | 2015-09-21 | 2016-01-13 | 南京正大天晴制药有限公司 | Preparation method, detection method and application for ticagrelor-related substances |
| CN108078944A (en) * | 2016-11-22 | 2018-05-29 | 重庆植恩药业有限公司 | Solid composite containing ticagrelor and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109806261A (en) * | 2019-03-11 | 2019-05-28 | 梁江丽 | A kind of ticagrelor sustained release preparation and its preparation and application |
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