CN110507624A - A kind of controlled release composition of ticagrelor or its salt - Google Patents
A kind of controlled release composition of ticagrelor or its salt Download PDFInfo
- Publication number
- CN110507624A CN110507624A CN201910422501.1A CN201910422501A CN110507624A CN 110507624 A CN110507624 A CN 110507624A CN 201910422501 A CN201910422501 A CN 201910422501A CN 110507624 A CN110507624 A CN 110507624A
- Authority
- CN
- China
- Prior art keywords
- ticagrelor
- release
- component
- composition according
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 title claims abstract description 89
- 229960002528 ticagrelor Drugs 0.000 title claims abstract description 88
- 239000000203 mixture Substances 0.000 title claims abstract description 68
- 150000003839 salts Chemical class 0.000 title claims abstract description 39
- 238000013270 controlled release Methods 0.000 title claims abstract description 29
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 20
- 239000003085 diluting agent Substances 0.000 claims abstract description 13
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000007962 solid dispersion Substances 0.000 claims abstract description 11
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 10
- 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 10
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- 239000000463 material Substances 0.000 claims description 21
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- 238000000034 method Methods 0.000 claims description 18
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 17
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- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 12
- 239000002775 capsule Substances 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
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- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 claims description 7
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 6
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- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 claims description 5
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- 239000004925 Acrylic resin Substances 0.000 claims description 4
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 4
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 4
- 235000013539 calcium stearate Nutrition 0.000 claims description 4
- 239000008116 calcium stearate Substances 0.000 claims description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 4
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- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 3
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- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 3
- 238000009702 powder compression Methods 0.000 claims description 3
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 2
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- DKMROQRQHGEIOW-UHFFFAOYSA-N Diethyl succinate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 claims description 2
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- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
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- BGNXCDMCOKJUMV-UHFFFAOYSA-N Tert-Butylhydroquinone Chemical compound CC(C)(C)C1=CC(O)=CC=C1O BGNXCDMCOKJUMV-UHFFFAOYSA-N 0.000 claims description 2
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- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000004703 cross-linked polyethylene Substances 0.000 description 1
- 229920003020 cross-linked polyethylene Polymers 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-N n-Decanedioic acid Natural products OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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Abstract
The present invention relates to a kind of ticagrelor or the controlled release compositions of its salt.Specifically, the present invention provides a kind of ticagrelor or the controlled release composition containing immediate release component and release sustaining component of its salt, wherein ticagrelor or its salt exist in the form of solid dispersions in the core of release sustaining component, separately containing croscarmellose sodium and at least one diluent.The controlled release composition of ticagrelor provided by the invention is in 0.2% tween pH1.0 hydrochloric acid solution and 0.2% tween pH6.8 phosphate buffer, and drug release rate is greater than 90% in 12h prescription.
Description
Technical field
The present invention is ticagrelor or the slow releasing composition of its officinal salt, is suitable for by daily single.
Background technique
Ticagrelor is a kind of platelet aggregation inhibitor, is that a kind of novel cyclopenta triazolo pyrimidine class (CPTP) is oral
Antiplatelet drug.Chemical name are as follows: 1S, 2S, 3R, 5S) -3- [7- { [(1R, 2S) -2- (3,4- difluorobenzene) cyclopropyl] amino } -
5- (rosickyite base) -3H- [1,2,3]-triazol [4,5-d] pyrimidin-3-yl] -5- (2- hydroxyl-oxethyl) pentamethylene -1,2- two
Alcohol, molecular formula C23H28F2N6O4S, structural formula are as follows:
Ticagrelor is a member of chemical classification cyclopenta triazolo pyrimidine (CPTP), and CPTP is a kind of selective Adenosine diphosphate
Glycosides (ADP) receptor antagonist, acts on P2Y12ADP receptor, the platelet activation to inhibit ADP to mediate and aggregation, with thieno
The mechanism of action of pyridines drug (such as clopidogrel) is similar.Unlike but, ticagrelor and blood platelet P2Y12ADP receptor
Between interaction there is invertibity, transmitted without conformational change and signal, and the blood platelet function after drug withdrawal in blood
It can also fast quick-recovery therewith.
In the patients with stable coronary artery disease for receiving aspirin for treatment in ONSET/OFFSET research, ticagrelor is shown
The pharmacological action of quick acting,
Average platelet aggregation inhibits (IPA) up to 41% after ticagrelor 180mg loading dose administration 0.5 hour, is administered
Reach maximum IPA effect 89% after 2-4 hours, this effect can be kept 2-8 hours.The pharmacokinetics of ticagrelor is in line
Property, until 1260mg, ticagrelor and active metabolite (AR-C124910XX) exposed amount are substantially proportional to dosage.
It is absorbed rapidly after ticagrelor is oral, middle position tmaxAbout 1.5 hours.Since ticagrelor is non-precursor drug, directly
It connects and acts on P2Y12 receptor, activated without liver metabolism, its main loop metabolite AR- can be quickly generated
C124910XX.Drug itself and its metabolite are active, therefore the blood that can not only inhibit ADP to mediate quick and potently
Platelet aggregation, and validity is not influenced by liver CYP 2C19 gene pleiomorphism.Ticagrelor is mainly eliminated by hepatic metabolism.It is logical
The ticagrelor for taking radio-labeled is crossed, the average recovery rate for measuring radiation, which is about 84%, (contains 58%, in urine in excrement
Contain 26%).The average t of ticagrelor1/2About 7 hours, active metabolite was 9 hours.
Number is taken to reduce, improves the compliance of patient's medication, is reduced since patient misses caused by ticagrelor
Ticagrelor is prepared into suitable sustained release preparation and is necessary by the risk of heart infarction or apoplexy caused by Acute thrombosis,
Such as it can be prepared into only taking primary pharmaceutical composition daily.
Patent CN102657629A is related to a kind of ticagrelor sustained release tablets system and preparation method, which uses hydroxypropyl
Methylcellulose or hydroxypropyl cellulose carry out the preparation of ticagrelor release sustaining component as slow-release material, and inventor attempts using special
Cellulosic polymer hypromellose polymer involved in sharp CN102657629A uses the preparation of common tabletting
Means prepare sustained-release matrix tablets, and as a result the later period has the incomplete situation of release and pushes away since ticagrelor is almost insoluble in water
It is related with the dissolubility of ticagrelor to survey this.
Existing numerous patents, which are disclosed using the combination of quick-release and sustained release, at present achievees the effect that ticagrelor controlled release drug administration,
Wherein patent application CN105998026A discloses a kind of ticagrelor composition containing two or three medicine-releasing systems, this is specially
There is no the pharmacokinetic parameters of related preparations in benefit, therefore the effect of preparation in vivo is unknown；Patent application CN106074357A is public
The composition of a kind of microplate containing quick-release, enteric-coated quick releasing microplate and enteric slow release microplate has been opened, but the composition is found through experiments that
Exist in amplification and dissolves out incomplete problem.
Summary of the invention
The present invention provides a kind of ticagrelor or the controlled release composition of its salt, thus blood concentration when reducing patient's medication
Peak valley phenomenon, improve curative effect of medication and drug safety, reduce medicining times.
The present invention provides a kind of ticagrelor or the controlled release composition of its salt, it is characterised in that the composition includes quick-release
Component and release sustaining component, release sustaining component include core and coating agent, and ticagrelor or its salt in the core are dispersed with solid
The form of body exists, and also containing croscarmellose sodium and at least one diluent in release sustaining component core.
The controlled release composition of ticagrelor or its salt provided by the invention, it is characterised in that the dilution in the release sustaining component
Agent is selected from microcrystalline cellulose, maltodextrin, sorbierite, maltose, dextrin, partially pregelatinized starch, mannitol, two hydration phosphorus
Sour hydrogen calcium, calcium phosphate dibasic anhydrous etc., the combination of preferably microcrystalline cellulose and mannitol.
The controlled release composition of ticagrelor or its salt provided by the invention, it is characterised in that the dilution in the release sustaining component
The content of agent be core weight 15%-50%, preferably 20%-40%, most preferably 25%-35% (w/w), the present invention in it is all
It is related to material proportion, solid material is quality and mass ratio, and solid-liquid material ratio is also quality and mass ratio.
The controlled release composition of ticagrelor or its salt provided by the invention, it is characterised in that the microcrystalline cellulose and sweet dew
The ratio of alcohol is 0.1:1-10:1, preferably 1:1-8:1, most preferably 1:1-3:1.
The controlled release composition of ticagrelor or its salt provided by the invention, it is characterised in that the friendship carboxymethyl cellulose
The content of sodium is the 3%-30%, preferably 5%-15%, most preferably 8%-12% of core weight.
The controlled release composition of ticagrelor or its salt provided by the invention, it is characterised in that the quick-release include diluent,
Adhesive, lubricant, disintegrating agent, the diluent are selected from one of lactose, microcrystalline cellulose, mannitol, calcium monohydrogen phosphate
Or several, preferably mannitol and calcium monohydrogen phosphate；The adhesive be selected from polyvinylpyrrolidone, starch, carboxymethyl cellulose,
One or more of hydroxypropyl cellulose, hypromellose, preferably hydroxypropyl cellulose；The disintegrating agent, which is selected from, to be handed over
Join sodium carboxymethylcellulose, dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, pre-
The one or several kinds of gelling starch, preferably sodium carboxymethyl starch；The lubricant be selected from magnesium stearate, Compritol 888 ATO,
One or more of hydrogenated vegetable oil, calcium stearate, superfine silica gel powder, fumaric acid odium stearate, preferably magnesium stearate.
The controlled release composition of ticagrelor or its salt provided by the invention, the solid dispersions of the release sustaining component contain load
Body, the carrier are selected from one or more of povidone, copolyvidone, polyethylene glycol, poloxamer, Utech class, preferably
Copolyvidone；The immediate release component contains following component:
Ticagrelor 20%-45%
Mannitol 20%-50%
Calcium monohydrogen phosphate 10%-30%
Sodium carboxymethyl starch 2%-6%
Hydroxypropyl cellulose 2%-6%.
The controlled release composition of ticagrelor or its salt provided by the invention, carrier and ticagrelor in the release sustaining component
Or the weight ratio of its salt is 1:0.1-1:10, preferably 1:5-5:1, more preferable 1:2-3:1, most preferably 1:1-2:1.
In some embodiments of the invention, in the solid dispersions optionally comprising antioxidant dibutyl hydroxy toluene,
Butylated hydroxy anisole, propylgallate, tert-butylhydroquinone, vitamin C, preferably dibutyl hydroxy toluene, antioxidant
Content range be selected from 0.001%-0.3%, preferably 0.01%-0.2%.
In the preferred embodiment of the invention, the immediate release component contains:
Ticagrelor 20%-45%
Mannitol 20%-50%
Calcium monohydrogen phosphate 10%-30%
Sodium carboxymethyl starch 2%-6%
Hydroxypropyl cellulose 2%-6% (with immediate release component total weight)；
Release sustaining component contains:
Ticagrelor 20%-45%
Copolyvidone 20%-45%
Mannitol and microcrystalline cellulose 25%-35%
Croscarmellose sodium 8%-12% (be sustained core total weight).
The controlled release composition of ticagrelor or its salt provided by the invention, the release sustaining component further contain glidant,
Lubricant, the glidant are selected from one or more of superfine silica gel powder, stearic acid, and preferably superfine silica gel powder, glidant contains
Amount is the 0.1%-5%, preferably 0.5%-2% of sustained release core gross weight；The lubricant is selected from magnesium stearate, behenyl acid glycerol
One or more of ester, hydrogenated vegetable oil, preferably magnesium stearate；The content of lubricant is the 0.01%- for being sustained core gross weight
10%, preferably 0.5%-5%, most preferably 1.0%-2%.
The coating agent of release sustaining component described in the controlled release composition of ticagrelor or its salt provided by the invention contains at least one
Kind enteric material, at least one plasticizer and at least one antiplastering aid, the enteric material are selected from acrylic resin, HPMC-AS,
It is preferred that Utech L100, Utech S100, Utech L30D-55, most preferably Utech L30D-55；The plasticizer is selected from lemon
Lemon triethylenetetraminehexaacetic acid ester tributyl citrate, polyethylene glycol, triethyl phthalate, tributyl phthalate, two fourth of decanedioic acid
Ester, diethyl sebacate, tristerin, diethyl succinate, propylene glycol, castor oil or glyceryl triacetate, preferably lemon
Lemon triethylenetetraminehexaacetic acid ester；The antiplastering aid is selected from magnesium stearate, Compritol 888 ATO, hydrogenated vegetable oil, talcum powder, calcium stearate, micro-
Powder silica gel, fumaric acid odium stearate, preferably talc powder.
Release sustaining component is coated by enteric material in the controlled release composition of ticagrelor or its salt provided by the invention, to provide
In the sustained release that the pH more than or equal to 5.5 dissolves.
It is total that the coating agent of release sustaining component described in the controlled release composition of ticagrelor or its salt provided by the invention accounts for core
The 5%-15%, preferably 8%-12%, most preferably 10% of weight.
In the controlled release composition of ticagrelor or its salt provided by the invention ticagrelor or in terms of ticagrelor replace lattice
The content of auspicious Lip river officinal salt is 45mg-220mg, optional 60m, 70mg, 90mg, 120mg, 150mg, 180mg.
Lattice are replaced in immediate release component described in the controlled release composition of ticagrelor or its salt provided by the invention and release sustaining component
Auspicious Lip river or and salt weight ratio be 1:0.5 to 1:10, preferably 1:1 to 1:5, most preferably 1:2 to 1:5.
It is provided in one embodiment in the present invention, immediate release component and release sustaining component are tablet in composition.
The immediate release component of heretofore described controlled release composition, optional wet granule compression tablet, dry granulation tabletting or
Prepared by the method for direct powder compression, preferably the method for wet granule compression tablet, the solvent used in wet granulation be selected from purified water,
One of the ethyl alcohol of various concentration, isopropanol, acetone are a variety of, preferably the ethyl alcohol of purified water or various concentration.
The optional wet granule compression tablet of the release sustaining component of controlled release composition of the present invention, dry granulation tabletting or powder
Prepared by the method for direct tablet compressing, the method preparation of preferably dry granulation tabletting.
As needed, coating material appropriate may be selected to be coated immediate release component, specifically, coating material can be selected from
One of hydroxypropyl methyl cellulose, polyethylene glycol, Arabic gum, Opadry etc. are a variety of, preferably Opadry.Above-mentioned coating
Material can also be used in combination with other medicinal antiplastering aid, plasticizer, thickener, colorant, defoaming agent, opacifiers etc..
In the controlled release composition of ticagrelor or its salt provided by the invention, the content of the coating material of immediate release component is speed
Release the 3%-20% of component ticagrelor or the quality of its salt, preferably 5-15%.
Since ticagrelor is practically insoluble in water, ideal effect, drug can not be obtained according to common process preparation
It often dissolved out slow or incomplete.In one embodiment of the invention, in the immediate release component, the partial size model of ticagrelor
It encloses for D (90) less than 50 microns, further preferential D (90) is less than 30 microns.
Common process preparation, such as solvent method, melting can be used in the solid dispersions of ticagrelor of the invention or its salt
Method, solid precipitation evaporation, spray drying process, ball mill grinding etc..Present invention preferably employs spray drying processes to prepare solid point
Drug, carrier are dissolved in suitable solvent by granular media, then spray-dried obtained solid dispersions.It is molten described in wherein
Agent is selected from dehydrated alcohol, acetone, ethyl acetate, methylene chloride etc., and the further preferred solvent of the present invention is dehydrated alcohol.
In the controlled release composition of ticagrelor or its salt provided by the invention, it can be prepared into the form of multilayer tablet together；
The piller or pellet that multi-dose can also be prepared select different pellets filling in capsule as needed；It can also be prepared into
The form of microplate containing unit dose selects different the piece numbers filling in capsule as needed.
Preferred embodiment is the mode of the filling capsule of microplate in the present invention.In one embodiment of the present of invention, individually
Quick-release microplate number is 1-4 piece in capsule, and sustained release microplate number is selected from 1-8 piece.
The controlled release composition of ticagrelor provided by the invention, the optionally also delay quick-release group containing ticagrelor or its salt
Point, the immediate release component is coated by enteric material, starts to discharge in the pH more than or equal to 5.5, the enteric material is selected from
One of acrylic resin, HPMC-AS, preferably Utech L100, Utech S100, Utech L30D-55 are a variety of.
The controlled release composition of ticagrelor provided by the invention, also containing being subjected on preparation in the delay immediate release component
Excipient, wherein the excipient includes one of diluent, adhesive, disintegrating agent, lubricant or their any group
It closes；Diluent is selected from one or more of lactose, microcrystalline cellulose, mannitol, calcium monohydrogen phosphate in the delay immediate release component,
Adhesive is selected from one or more of polyvinylpyrrolidone, starch, carboxymethyl cellulose, hypromellose, disintegration
Agent is selected from croscarmellose sodium, dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinked polyethylene pyrrole
The one or several kinds of pyrrolidone, pregelatinized starch, lubricant is in magnesium stearate, Compritol 888 ATO, hydrogenated vegetable oil
One or more.
Ticagrelor slow releasing composition provided by the invention is in 0.2% tween pH1.0 hydrochloric acid solution and 0.2% tween
In in pH6.8 phosphate buffer, drug release rate is greater than 90%, preferably greater than 93% in 12h prescription.
The controlled release composition of ticagrelor or its salt provided by the invention is combined compared to disclosed in CN106074357A
Object, technique are more stable.
Detailed description of the invention
Fig. 1 is the release profiles of different prescriptions in embodiment 1；
Fig. 2 is the release profiles of different prescriptions in embodiment 2；
Fig. 3 is the release profiles of different batch prescriptions in comparative example 1.
Specific embodiment
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is merely to illustrate skill of the invention
Art scheme, the spirit and scope of the invention are not limited thereto.
Embodiment 1. prepares the preparation of 180mg specification
It prepares to have respectively according to 1000 batches according to prescription 1,2,3,4,5 and releases immediately ticagrelor microplate and delay is released
The composition for putting ticagrelor microplate, the two-phase pulse including the composition of quick-release microplate and enteric slow release microplate composition.In intestines
In molten sustained release microplate, ticagrelor by be dispersed in copolyvidone as be prepared into carrier material solid dispersions then with its
The mixing of its auxiliary material, cladding enteric coating are formed.
1. composition (unit mg) of table
Preparation method: quick-release and sustained release microplate are prepared respectively using tablet forming technique, and by matching enteric coated film accordingly
After load capsule, spansule obtained is measured in 0.2% tween pH1.0 hydrochloric acid solution using UV-VIS spectrophotometry
Release in 0.2% tween pH6.8 phosphate buffer, the results are shown in Table 2.
Capsule release result in different media in 2. embodiment 1 of table
The experimental results showed that the prescription drug release containing croscarmellose sodium is greater than in enteric slow release microplate
90%, in addition, the drug release effect of the prescription in enteric slow release microplate simultaneously containing croscarmellose sodium and mannitol is more
It is good, reach 95.6% and 97.6%.
Embodiment 2 prepares the preparation of 120mg specification
Have according to prescription 6 according to 1000 batch preparations and releases immediately ticagrelor microplate and sustained release ticagrelor is micro-
The composition of piece, the two-phase pulse including the composition of quick-release microplate and enteric slow release microplate composition.In enteric slow release microplate,
Ticagrelor is added dibutyl hydroxy toluene and is prepared into as antioxidant by being dispersed in copolyvidone as in carrier material
Solid dispersions are then mixed with other auxiliary materials, and cladding enteric coating is formed.
Table 3. (unit mg)
Preparation method: quick-release and sustained release microplate are prepared respectively using tablet forming technique, and by matching enteric coated film accordingly
After load capsule, spansule obtained is measured in 0.2% tween pH1.0 hydrochloric acid solution using UV-VIS spectrophotometry
Release in 0.2% tween pH6.8 phosphate buffer, the results are shown in Table 4.
Capsule release result in different media in 4. embodiment 2 of table
Embodiment 3
Prescription in above-described embodiment is selectively carried out to human pharmacokinetics (blood concentration) and pharmacodynamics, and (blood is small
Plate inhibiting rate) it tests, the relationship between comprehensive analysis release in vitro and pharmacokinetics (PK) and pharmacodynamics (PD) is probed into for lattice
The In vitro-in vivo correlation of auspicious Lip river.
Different prescriptions are carried out random, intersection, single centre, check experiment research using healthy volunteer by the present invention,
The pharmacokinetics and pharmacodynamics of ticagrelor in research evaluation health volunteer.In the research, prescription of the present invention
It is once a day administered for 180mg dosage, commercially available quick releasing formulation is that 90mg dosage is two times a day administered.Acquisition plasma sample is used for
The blood concentration and blood platelet for determining ticagrelor inhibit situation.Sample is analyzed by HPLC/MS/MS.
5. ticagrelor pharmacokinetic parameters of table
Have one it is found that preparation is dissolved out in preliminary in vitro in conjunction with internal pharmacokinetics and release in vitro the data analysis of drug
Fixed drug release facilitates with certain blood concentration (C2h), and then guarantee drug effect of the drug at 2 and 4 hours, thus
It ensure that drug rapid-onset；Guarantee drug blood concentration after 12h in certain level, such as at least 0.2 μ g/mL with
On, 24 hours drug effects can be maintained；Maximum plasma concentration (the C of drug of the inventionmax) suitable or slightly above commercially available quick-release system
Agent, in order to avoid cause that 8h and 12h drug effect is excessively high and generates side effect.
Specifically, the time in subject in 2 hours can reach the blood plasma of the greater than about ticagrelor of 0.2 μ g/mL
Concentration；It still can reach the plasma concentration of the greater than about ticagrelor of 0.2 μ g/mL after 12h with taking medicine in subject；With
In subject generate about 0.2 μ g/mL between about 0.8 μ g/mL ticagrelor or its pharmaceutically acceptable salt most
Big plasma concentration (Cmax)。
Comparative example 1
According to prescription 7 according to different batches (100 and 1000) prepare respectively a batch have release immediately ticagrelor
The composition of the microplate of microplate and sustained release ticagrelor, including quick-release microplate, enteric-coated quick releasing microplate and enteric slow release are micro-
The three-phase pulse of the composition composition of piece, it is finally that three is common filling in capsule.Wherein, enteric-coated quick releasing microplate be by
Obtained from quick-release microplate outer cladding enteric material, in enteric slow release microplate, ticagrelor is made by being dispersed in copolyvidone
It is then mixed with other auxiliary materials to be prepared into solid dispersions in carrier material, cladding enteric coating is formed.
Table 6. (unit mg)
| Prescription 7 | Prescription 7 | |
| In batches | 100 | 1000 |
| Quick-release microplate | ||
| Ticagrelor | 30 | 30 |
| Mannitol | 34.8 | 34.8 |
| Calcium monohydrogen phosphate | 18.9 | 18.9 |
| Sodium carboxymethyl starch | 2.7 | 2.7 |
| Hydroxypropylcellulose E5 | 2.7 | 2.7 |
| Magnesium stearate | 0.9 | 0.9 |
| Total slice weight | 90 | 90 |
| The piece number | 2 | 2 |
| Enteric-coated quick releasing microplate | ||
| Quick-release microplate | 90 | 90 |
| Utech L100 | 2.5 | 2.5 |
| Utech S100 | 7.5 | 7.5 |
| Total slice weight | 100 | 100 |
| The piece number | 1 | 1 |
| Enteric slow release microplate | ||
| Ticagrelor | 30 | 30 |
| Copolyvidone | 30 | 30 |
| Microcrystalline cellulose | 29 | 29 |
| Crospovidone | 10 | 10 |
| Magnesium stearate | 1 | 1 |
| Utech L100 | 2.5 | 2.5 |
| Utech S100 | 7.5 | 7.5 |
| Total slice weight | 110 | 110 |
| The piece number | 3 | 3 |
Preparation method: quick-release and sustained release microplate are prepared respectively using tablet forming technique, and by matching enteric coated film accordingly
After load capsule, spansule obtained is measured in 0.2% tween pH1.0 hydrochloric acid solution using UV-VIS spectrophotometry
Release in 0.2% tween pH6.8 phosphate buffer, the results are shown in Table 1.
Capsule release result in different media in 7. comparative example 1 of table
The results showed that prescription 7, after amplifying batch, drug can not discharge completely in dissolution medium.
Due to describing the present invention according to its specific embodiment, certain modifications and equivalent variations are for being proficient in this neck
The technical staff in domain is obvious and is included within the scope of the invention.
Claims (21)
1. the controlled release composition of a kind of ticagrelor or its salt, the composition includes immediate release component and release sustaining component, sustained release group
Subpackage contains core and coating agent, and ticagrelor or its salt are deposited in the form of solid dispersions in the core, and release sustaining component core
Also containing croscarmellose sodium and at least one diluent in core.
2. composition according to claim 1, the diluent is selected from microcrystalline cellulose, maltodextrin, sorbierite, wheat
Bud sugar, dextrin, partially pregelatinized starch, mannitol, calcium phosphate dibasic dihydrate, calcium phosphate dibasic anhydrous etc., preferably microcrystalline cellulose
With the combination of mannitol.
3. composition according to claim 2, the content of the diluent is the 15%-50% of core weight, preferably
20%-40%, most preferably 25%-35%.
4. the ratio of composition according to claim 2, the microcrystalline cellulose and mannitol is 0.1:1-10:1, preferably
1:1-8:1, most preferably 1:1-3:1.
5. the content of composition according to claim 1, the friendship sodium carboxymethylcellulose is the 3%- of core weight
30%, preferably 5%-15%, most preferably 8%-12%.
6. a kind of composition described in claim 1, the quick-release includes diluent, adhesive, lubricant, disintegrating agent, described
Diluent be selected from one or more of lactose, microcrystalline cellulose, mannitol, calcium monohydrogen phosphate, preferably mannitol and phosphoric acid hydrogen
Calcium；The adhesive is selected from polyvinylpyrrolidone, starch, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose
One or more of element, preferably hydroxypropyl cellulose；The disintegrating agent be selected from croscarmellose sodium, dried starch,
Sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, the one or several kinds of pregelatinized starch,
It is preferred that sodium carboxymethyl starch；The lubricant is selected from magnesium stearate, Compritol 888 ATO, hydrogenated vegetable oil, calcium stearate, micro mist
One or more of silica gel, fumaric acid odium stearate, preferably magnesium stearate.
7. composition according to claim 6, the solid dispersions of the release sustaining component contain carrier, and the carrier is selected from
One or more of povidone, copolyvidone, polyethylene glycol, poloxamer, Utech class, preferably copolyvidone；The speed
Component is released containing following component:
Ticagrelor 20%-45%
Mannitol 20%-50%
Calcium monohydrogen phosphate 10%-30%
Sodium carboxymethyl starch 2%-6%
Hydroxypropyl cellulose 2%-6%.
Carrier and ticagrelor or its salt 8. composition according to claim 1-7, in the release sustaining component
Weight ratio be 1:0.1-1:10, preferably 1:5-5:1, more preferable 1:2-3:1, most preferably 1:1-2:1.
9. composition according to claim 8, in the solid dispersions optionally comprising antioxidant dibutyl hydroxy toluene,
Butylated hydroxy anisole, propylgallate, tert-butylhydroquinone, vitamin C, preferably dibutyl hydroxy toluene, antioxidant
Content range be selected from 0.001%-0.3%, preferably 0.01%-0.2%.
10. composition according to claim 8, it is characterised in that
Immediate release component contains:
Ticagrelor 20%-45%
Mannitol 20%-50%
Calcium monohydrogen phosphate 10%-30%
Sodium carboxymethyl starch 2%-6%
Hydroxypropyl cellulose 2%-6% (with immediate release component total weight)；
Release sustaining component contains:
Ticagrelor 20%-45%
Copolyvidone 20%-45%
Mannitol and microcrystalline cellulose 25%-35%
Croscarmellose sodium 8%-12% (be sustained core total weight).
11. -10 described in any item compositions according to claim 1, the release sustaining component further contains glidant, lubrication
Agent, the glidant are selected from one or more of superfine silica gel powder, stearic acid, and preferably superfine silica gel powder, the content of glidant is
It is sustained the 0.1%-5%, preferably 0.5%-2% of core gross weight；The lubricant be selected from magnesium stearate, Compritol 888 ATO,
One or more of hydrogenated vegetable oil, preferably magnesium stearate；The content of lubricant is the 0.01-10% for being sustained core gross weight,
It is preferred that 0.5%-5%, most preferably 1.0%-2%.
12. composition according to claim 11, the coating agent of the release sustaining component contains at least one enteric material, at least
A kind of plasticizer and at least one antiplastering aid, the enteric material are selected from acrylic resin, HPMC-AS, preferably Utech L100,
Utech S100, Utech L30D-55, most preferably Utech L30D-55；The plasticizer is selected from triethyl citrate, citron
Sour tributyl, polyethylene glycol, triethyl phthalate, tributyl phthalate, dibutyl sebacate, decanedioic acid diethyl
Ester, tristerin, diethyl succinate, propylene glycol, castor oil or glyceryl triacetate, optimization citric acid triethyl；Institute
It states antiplastering aid and is selected from magnesium stearate, Compritol 888 ATO, hydrogenated vegetable oil, talcum powder, calcium stearate, superfine silica gel powder, fumaric acid
Odium stearate, preferably talc powder.
13. composition according to claim 12, the coating agent accounts for the 5%-15% of core gross weight, preferably 8%-
12%, most preferably 10%.
14. composition described in -13 according to claim 1, the ticagrelor or ticagrelor in terms of ticagrelor can medicines
It is 45mg-220mg with the content of salt.
15. composition according to claim 14, the weight of ticagrelor or its salt in the immediate release component and release sustaining component
Amount is than being 1:0.5 to 1:10, preferably 1:1 to 1:8, most preferably 1:2- to 1:5.
16. -15 described in any item compositions according to claim 1, the immediate release component and release sustaining component are tablet.
17. composition according to claim 16, the quick-release group contains coating, and coating material can be selected from hydroxypropyl methyl
One of cellulose, polyethylene glycol, Arabic gum, Opadry are a variety of, preferably Opadry, and the content of coating material is quick-release
The 3%-20% of the quality of component ticagrelor or its salt, preferably 5-15%.
18. composition according to claim 16, the optional wet granule compression tablet of the immediate release component, dry granulation tabletting or
Prepared by the method for person's direct powder compression, preferably wet granule compression tablet；The optional wet granule compression tablet of the release sustaining component, dry method system
The preparation of the method for grain tabletting or direct powder compression, preferably dry granulation tabletting.
19. the described in any item compositions of 6-18 according to claim 1, the composition is capsule, the release sustaining component and speed
Releasing component is microplate.
20. -19 described in any item combinations according to claim 1, the composition is optionally containing ticagrelor or its salt
Postpone immediate release component, the immediate release component is coated by enteric material, and the enteric material is selected from acrylic resin, HPMC-AS；It is excellent
Select one of Utech L100, Utech S100, Utech L30D-55 or a variety of.
21. composition according to claim 20, also containing acceptable figuration on preparation in the delay immediate release component
Agent, wherein the excipient includes one of diluent, adhesive, disintegrating agent, lubricant or their any combination, it is described
Postpone diluent in immediate release component and is selected from one or more of lactose, microcrystalline cellulose, mannitol, calcium monohydrogen phosphate, adhesive
Selected from one of polyvinylpyrrolidone, starch, carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose or several
Kind, disintegrating agent is selected from croscarmellose sodium, dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, is crosslinked and gathers
The one or several kinds of vinylpyrrolidone, pregelatinized starch, lubricant are selected from magnesium stearate, Compritol 888 ATO, hydrogenation plant
One or more of object oil.
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| CN115212171A (en) * | 2022-06-01 | 2022-10-21 | 浙江东亚药业股份有限公司 | Ticagrelor sustained-release pellet and pharmaceutical preparation containing same |
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