CN116370423A - Ticagrelor orally disintegrating tablet and preparation method thereof - Google Patents
Ticagrelor orally disintegrating tablet and preparation method thereof Download PDFInfo
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- CN116370423A CN116370423A CN202310173481.5A CN202310173481A CN116370423A CN 116370423 A CN116370423 A CN 116370423A CN 202310173481 A CN202310173481 A CN 202310173481A CN 116370423 A CN116370423 A CN 116370423A
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- China
- Prior art keywords
- orally disintegrating
- ticagrelor
- tablet
- particles
- preparation
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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 64
- 229960002528 ticagrelor Drugs 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 35
- 239000002245 particle Substances 0.000 claims abstract description 36
- 239000003826 tablet Substances 0.000 claims abstract description 28
- 239000004480 active ingredient Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 22
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims abstract description 19
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000000811 xylitol Substances 0.000 claims abstract description 19
- 235000010447 xylitol Nutrition 0.000 claims abstract description 19
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims abstract description 19
- 229960002675 xylitol Drugs 0.000 claims abstract description 19
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 15
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 15
- 229940069328 povidone Drugs 0.000 claims abstract description 15
- 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 abstract description 14
- 229930195725 Mannitol Natural products 0.000 claims abstract description 14
- 239000000594 mannitol Substances 0.000 claims abstract description 14
- 235000010355 mannitol Nutrition 0.000 claims abstract description 14
- 239000000314 lubricant Substances 0.000 claims abstract description 13
- 229960001855 mannitol Drugs 0.000 claims abstract description 13
- 229920002472 Starch Polymers 0.000 claims abstract description 10
- 239000011734 sodium Substances 0.000 claims abstract description 10
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 10
- 239000008107 starch Substances 0.000 claims abstract description 10
- 235000019698 starch Nutrition 0.000 claims abstract description 10
- 229940032147 starch Drugs 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 15
- 238000007873 sieving Methods 0.000 claims description 10
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 9
- 235000015424 sodium Nutrition 0.000 claims description 9
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 9
- 238000010298 pulverizing process Methods 0.000 claims description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 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 5
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 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 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 2
- 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 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 229940057948 magnesium stearate Drugs 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229960004274 stearic acid Drugs 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 10
- 230000008569 process Effects 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000000546 pharmaceutical excipient Substances 0.000 abstract description 6
- 239000004615 ingredient Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 abstract 1
- 239000008187 granular material Substances 0.000 description 28
- 239000003814 drug Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 13
- 238000004090 dissolution Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 241000282472 Canis lupus familiaris Species 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000007919 dispersible tablet Substances 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- 238000005507 spraying Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 229920003081 Povidone K 30 Polymers 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000007689 inspection Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 229960000913 crospovidone Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000009747 swallowing Effects 0.000 description 3
- -1 3, 4-difluorophenyl Chemical group 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 238000013146 percutaneous coronary intervention Methods 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- NJDNDJPFOPBMTJ-UHFFFAOYSA-N 5-cyclopentyl-2h-triazolo[4,5-d]pyrimidine Chemical class C1CCCC1C1=NC=C(NN=N2)C2=N1 NJDNDJPFOPBMTJ-UHFFFAOYSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 208000000770 Non-ST Elevated Myocardial Infarction Diseases 0.000 description 1
- 208000006117 ST-elevation myocardial infarction Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 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 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940086777 brilinta Drugs 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- UYDJAHJCGZTTHB-UHFFFAOYSA-N cyclopentane-1,1-diol Chemical compound OC1(O)CCCC1 UYDJAHJCGZTTHB-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000000079 presaturation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 230000000152 swallowing effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- 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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K9/2095—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
- 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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a ticagrelor orally disintegrating tablet and a preparation method thereof; the orally disintegrating tablet is prepared from active ingredients and other pharmaceutical excipients by a proper process, namely, the active ingredients, orally disintegrating particles and lubricants are pressed into tablets with rapid disintegrating effect. The preferable ingredients in the orally disintegrating particles comprise crosslinked sodium carboxymethyl starch, povidone, mannitol and xylitol, and the parts ratio is 56:2:139:10. the preparation method provided by the invention is easy for industrial production and greatly reduces the production cost; the orally disintegrating tablet has excellent disintegrating effect and higher bioavailability than that of a commercially available preparation.
Description
Technical Field
The invention relates to the technical field of oral solid preparations, in particular to a preparation method of a ticagrelor orally disintegrating tablet.
Background
Oral tablet administration forms a concern as the average life span of humans increases and swallowing capacity decreases with age. It is estimated that about 50% of the population has difficulty swallowing tablets and capsules, affecting compliance with medication. In the fields of pediatric and geriatric medicine, there is a great need for a solid preparation which can be dissolved or suspended in water, chewed or dissolved rapidly in the mouth, and an oral rapidly dispersing preparation (orally rapidly disintegrating tablet Orally disintegrating tablets, abbreviated as ODT) which can be rapidly dispersed or dissolved without water and swallowing actions can solve this problem. The preparation can be rapidly dispersed or dissolved in saliva after being put into mouth, and the medicine can be absorbed by mucous membrane in oral cavity or esophagus, has higher bioavailability than common preparation, and can reduce side effect caused by first pass metabolism.
The invention relates to a preparation method of Ticagrelor orally disintegrating tablets, which comprises the active ingredient of Ticagrelor, the English name of the Ticagrelor is Ticagrenor, and the chemical name of the Ticagrenor is (1S, 2S,3R, 5S) to 3 to [7 to [ (1R, 2S) to 2 to (3, 4-difluorophenyl) cyclopropyl ]]Amino group]5-propylthiotriazolo [4, 5-d ]]Pyrimidine-3-yl]5 to (2 to hydroxyethoxy) to 1,2 to cyclopentanediol, the molecular formula of which is C 23 H 28 F 2 N 6 O 4 S, the molecular weight is 522.568, and the chemical structural formula is:
ticagrelor belongs to cyclopentyl triazolopyrimidine compounds, is the first reversible P2Y12 platelet inhibitor and is a novel anti-platelet aggregation drug; for patients with acute coronary syndrome (unstable angina, non-ST elevation myocardial infarction or ST elevation myocardial infarction), including patients receiving drug therapy and Percutaneous Coronary Intervention (PCI) therapy, reducing the incidence of thrombotic cardiovascular events.
Ticagrelor tablet is developed by Astrazeneca AB company, EMA approved for market in 2010, and has the trade name Brillique, the dosage form is a tablet with the specification of 60mg and 90mg; the U.S. FDA approved market for 7 months and 20 days 2011, with the trade name BRILINTA, the dosage form being a tablet and the specification being 90mg. The European Committee approved an Aos Li Kangti Gerilo orally disintegrating tablet (trade name: brillique, specification: 90 mg) on the market at 25 th 5.2017. Subsequently, ticagrelor orally disintegrating tablets were marketed in 28 member countries of the european union, irish, norway and column Zhi Duishi.
Ticagrelor orally disintegrating tablets are very popular after being marketed, helping to address the need of patients who cannot swallow tablets, and they can be administered rapidly when they are needed. The new preparation provides greater flexibility for medical staff, can provide required treatment for patients, and meets the requirements of the patients. The ticagrelor orally disintegrating tablet is used by placing the tablet under the tongue at the time of administration so that it can be rapidly dissolved in saliva. Then, the medicine is swallowed, and water is not used. The tablet can also be dissolved in water and used through nasogastric tube. If the patient is intubated or has difficulty swallowing the film coated tablet, they will be able to replace the equivalent gauge of the ticagrelor film coated tablet with a ticagrelor orally disintegrating tablet. However, ticagrelor is rapidly absorbed after oral administration, with an average T max About 1.5 hours; the average absolute bioavailability is low, only about 36%. Ticagrelor belongs to class IV (i.e. low solubility and low permeability) according to BCS classification, and the solubility in physiological pH environment between pH1.0 and pH7.4 is about 10 mug/ml, and the permeability is about 51%. Because ticagrelor belongs to a low-solubility low-permeability drug, the dissolution and permeability of the preparation of the ticagrelor affect the key speed limiting process of the absorption of the ticagrelor in vivo, and the preparation of the ticagrelor brings great challenges to pharmaceutical companies.
Patent CN109700773A and patent CN109718218A are respectively prepared into ticagrelor tablets by a spray drying technology and a solid dispersion technology, and the problem of indissolvable of the ticagrelor is solved; however, the preparation method is complex in process and is not suitable for large-scale industrial production.
Patent CN111450067A discloses a ticagrelor dispersible tablet and a preparation method thereof, wherein the dispersible tablet is prepared by taking ticagrelor as a main drug, co-powdering the ticagrelor and hydrophilic auxiliary materials until the particle size is 30-60 mu m, and adopting a direct tabletting method. Although the dispersible tablet disintegrates rapidly and has dissolution rate of more than 85% in 30min, the direct tabletting process has high requirement on auxiliary materials, and direct compression auxiliary materials with good adhesiveness and fluidity are required to be selected, so that the dispersible tablet is high in price.
Patent CN107530288A discloses an orally disintegrating tablet prepared by granulating an active ingredient with an excipient, and then mixing with a pre-blend of disintegrating excipients to form tablets, wherein the tablet has a disintegration time of less than about 60 seconds. However, the disintegrating excipient premix used in the patent is prepared by adopting a co-spray drying method, the process is complex, the time is long, the market price of the disintegrating excipient premix is several times that of common auxiliary materials, and the cost of pharmaceutical companies is greatly increased if the disintegrating excipient is purchased in industrial mass production.
Disclosure of Invention
The invention aims to overcome the defects and the shortcomings of the prior art and provides a novel orally disintegrating tablet and a preparation method thereof. The invention adopts a simple mixed direct tabletting process to mix and tablet the active ingredients with the orally disintegrating particles and the lubricant, thereby simplifying the production operation of medicines; through a great deal of test and comparison, the orally disintegrating particles with good uniformity, strong disintegration property and good fluidity can be prepared by only adopting four cheap common auxiliary materials of the crosslinked sodium carboxymethyl starch, the povidone, the mannitol and the xylitol, thereby greatly reducing the production cost of medicines and effectively ensuring the in vivo bioavailability of active ingredients. The orally disintegrating tablet prepared by the invention can be rapidly disintegrated within 1 minute, has excellent dissolution effect, and the dissolution rate of 5 minutes can reach more than 90 percent; the method also satisfies acceleration condition and long-term condition, and related substances have no obvious change in the 6-month standing process.
In order to achieve the above purpose, the present invention provides the following technical solutions:
the ticagrelor orally disintegrating tablet is characterized in that the ticagrelor orally disintegrating tablet is prepared by mixing and tabletting active ingredients, orally disintegrating particles and lubricants, wherein each 1000 tablets consist of the following components in parts by weight: 60-90 g of active ingredient, 207-290 g of orally disintegrating particles and 2-8 g of lubricant; the active ingredient refers to ticagrelor;
the orally disintegrating particles comprise four components selected from crosslinked sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, povidone, lactose, microcrystalline cellulose, crosslinked povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, mannitol, xylitol, sucrose and anhydrous calcium hydrophosphate, wherein the parts ratio is 30-80: 1 to 8: 100-150: 4-20; one of the preferred components comprises croscarmellose sodium, povidone, mannitol and xylitol; another preferred composition of ingredients is low substituted hydroxypropyl cellulose, povidone, anhydrous dibasic calcium phosphate, and xylitol; another preferred composition of ingredients is crospovidone, hypromellose, microcrystalline cellulose and xylitol; another preferred ingredient composition is a crospovidone, povidone, mannitol, and xylitol composition;
the lubricant is selected from one of talcum powder, colloidal silicon dioxide, magnesium stearate, stearic acid and sodium stearyl fumarate.
The preparation method of the orally disintegrating tablet comprises the following steps:
step one: crushing the active ingredients and sieving the crushed active ingredients with a 100-200-mesh sieve;
step two: mixing the active ingredient treated in the first step, the orally disintegrating particles and the lubricant together for 5-30 minutes;
step three: tabletting, wherein the hardness of the tablet is controlled to be 4-10 kg.
Through a large number of experimental screening, the composition of the components in the orally disintegrating particles, including crosslinked sodium carboxymethyl starch, povidone, mannitol and xylitol, is more preferably 56:2:139:10.
the preparation method of the orally disintegrating tablet comprises the following steps:
step one: pulverizing the active ingredients, and sieving with 200 mesh sieve;
step two: mixing the components in the orally disintegrating particles, granulating by a wet method, drying the prepared wet particles at 60 ℃, and finishing the particles by a 30-mesh screen after drying to prepare the orally disintegrating particles;
step three: mixing the active ingredient treated in the first step and the orally disintegrating particles prepared in the second step with a lubricant for 10 minutes;
step four: tabletting, wherein the hardness of the tablet is controlled to be 5-7 kg.
The invention further discloses application of the ticagrelor orally disintegrating tablet in improving bioavailability. Experimental results show that the ticagrelor orally disintegrating tablet is rapidly disintegrated within 1 minute, has excellent dissolution effect, and the dissolution rate of 5 minutes can reach more than 90 percent; the relevant substances during 6 months of standing under accelerated conditions and long-term conditions were not significantly changed.
Typical examples of the ticagrelor orally disintegrating tablets disclosed by the invention are as follows:
the ticagrelor orally disintegrating tablet is prepared by mixing and tabletting ticagrelor, orally disintegrating particles and a lubricant, wherein each 1000 tablets consist of the following components in parts by weight: 90g of ticagrelor, 207g of orally disintegrating particles, 3g of sodium stearyl fumarate; the orally disintegrating particles comprise the following components in parts by weight: 2:139:10.
the preparation method of the ticagrelor orally disintegrating tablet comprises the following steps:
1. pulverizing ticagrelor, and sieving with 200 mesh sieve;
2. adding crosslinked sodium carboxymethyl starch, povidone K30, mannitol and xylitol into a wet granulator, setting stirring speed to 400rpm, and mixing for 10 minutes at cutter speed of 1500 rpm; spraying purified water to granulate for 1 minute; drying the obtained wet granules in a fluidized bed at 60 ℃ for 15 minutes, and finishing the granules with a 30-mesh screen after drying to obtain orally disintegrating granules;
3. mixing the orally disintegrating particles, the crushed ticagrelor and the sodium stearyl fumarate in a three-dimensional mixer for 10 minutes;
4. tabletting by adopting a shallow concave round punch with the diameter of 9.0mm, and controlling the hardness of the tablet to be 5-7 kg.
Compared with the prior art, the preparation method of the orally disintegrating tablet has the advantages of rapid disintegration, stable quality and high in vivo bioavailability (compared with the bioavailability of the preparation produced by the example 1 given to the Beagle dog and the preparation sold on the market, the preparation method shows that the dispersing tablet of the ticagrelor of the example 1 is adopted, the absorption speed is high, and the dispersing tablet is expressed as T) max 45 minutes, and commercially available formulation T max 55 minutes; the relative bioavailability of the ticagrelor dispersible tablets produced in example 1 is improved (107.2-90.4)/90.4=18.6% compared with the commercial formulation; in addition, the preparation method provided by the invention is easy for industrial production and greatly reduces the production cost.
The orally disintegrating tablet obtained by adopting the technical scheme can ideally achieve the aim and the technical effects, and particularly, the orally disintegrating tablet and the preparation method thereof can produce:
(1) Rapid disintegration, excellent dissolution effect and high bioavailability;
(2) Stable technological process, high quality reproducibility, low production cost and high economic benefit.
It should be noted that, in order to enable those skilled in the art to understand the invention content and technical meaning of the present invention more clearly, the inventor of the present invention describes the related technical terms, symbols, reagent consumables and apparatus used as follows:
"day 0": refers to the time when sample preparation is complete;
"long term conditions": refers to a temperature of 30+/-2 ℃ and a relative humidity of 65+/-5%;
"acceleration condition": refers to a temperature of 40+/-2 ℃ and a relative humidity of 75+/-5%;
“T max ": refers to the time when the drug reaches the maximum blood concentration after administration;
“C max ": refers to the maximum blood concentration detected in the body after administration;
“AUC 0～∞ ": refers to the area under the blood concentration-time curve, and the same administration dose is used in the bioavailability research process, the high value indicates high bioavailability, and the low value indicates low bioavailability.
Detailed Description
The invention is described below by means of specific embodiments. The technical means used in the present invention are methods well known to those skilled in the art unless specifically stated. Further, the embodiments should be construed as illustrative, and not limiting the scope of the invention, which is defined solely by the claims. Various changes or modifications to the materials ingredients and amounts used in these embodiments will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The raw materials and reagents used in the invention are all commercially available. In order to facilitate understanding of the present invention by those skilled in the art, the present invention provides the following specific embodiments for further explanation of the orally disintegrating tablet and the preparation method thereof:
example 1
Prescription (1000 pieces)
The preparation method comprises the following steps:
1. pulverizing ticagrelor, and sieving with 200 mesh sieve;
2. adding crosslinked sodium carboxymethyl starch, povidone K30, mannitol and xylitol into a wet granulator, setting stirring speed to 400rpm, and mixing for 10 minutes at cutter speed of 1500 rpm; spraying purified water to granulate for 1 minute; drying the obtained wet granules in a fluidized bed at 60 ℃ for 15 minutes, and finishing the granules with a 30-mesh screen after drying to obtain orally disintegrating granules;
3. mixing the orally disintegrating particles, the crushed ticagrelor and the sodium stearyl fumarate in a three-dimensional mixer for 10 minutes;
4. tabletting by adopting a shallow concave round punch with the diameter of 9.0mm, and controlling the hardness of the tablet to be 5-7 kg.
Example 2
Prescription (1000 pieces)
The preparation method comprises the following steps:
1. pulverizing ticagrelor, and sieving with 150 mesh sieve;
2. adding low-substituted hydroxypropyl cellulose LH-21, povidone K30, anhydrous calcium hydrophosphate and xylitol into a wet granulator, setting stirring speed to 400rpm, and mixing for 10 minutes at cutter speed of 1500 rpm; spraying purified water to granulate for 1 minute; drying the obtained wet granules in a fluidized bed at 60 ℃ for 15 minutes, and finishing the granules with a 30-mesh screen after drying to obtain orally disintegrating granules;
3. mixing the orally disintegrating particles, the crushed ticagrelor and the sodium stearyl fumarate in a three-dimensional mixer for 10 minutes;
4. tabletting by adopting a shallow concave round punch with the diameter of 9.0mm, and controlling the hardness of the tablet to be 5-7 kg.
Example 3
Prescription (1000 pieces)
The preparation method comprises the following steps:
1. pulverizing ticagrelor, and sieving with 200 mesh sieve;
2. adding crospovidone XL-10, hydroxypropyl methylcellulose E5LV, microcrystalline cellulose PH101 and xylitol into a wet granulator, setting stirring speed to 400rpm, and mixing at cutter speed of 1500rpm for 10 minutes; spraying purified water to granulate for 1 minute; drying the obtained wet granules in a fluidized bed at 60 ℃ for 15 minutes, and finishing the granules with a 30-mesh screen after drying to obtain orally disintegrating granules;
3. mixing the orally disintegrating particles, the crushed ticagrelor and the sodium stearyl fumarate in a three-dimensional mixer for 15 minutes;
4. tabletting by adopting a shallow concave round punch with the diameter of 9.0mm, and controlling the hardness of the tablet to be 6-8 kg.
Example 4
Prescription (1000 pieces)
The preparation method comprises the following steps:
1. pulverizing ticagrelor, and sieving with 200 mesh sieve;
2. adding the crosslinked povidone XL-10, povidone K30, mannitol and xylitol into a wet granulator, setting stirring speed to 400rpm, and mixing for 10 minutes at cutter speed of 1500 rpm; spraying purified water to granulate for 1 minute; drying the obtained wet granules in a fluidized bed at 60 ℃ for 15 minutes, and finishing the granules with a 24-mesh screen after drying to obtain orally disintegrating granules;
3. mixing the orally disintegrating particles, the crushed ticagrelor and the sodium stearyl fumarate in a three-dimensional mixer for 10 minutes;
4. tabletting by adopting a shallow concave round punch with the diameter of 9.0mm, and controlling the hardness of the tablet to be 5-7 kg.
Comparative example 1
Prescription (1000 pieces)
The preparation method comprises the following steps:
1. pulverizing ticagrelor, and sieving with 200 mesh sieve;
2. adding crushed ticagrelor, crosslinked sodium carboxymethyl starch, hydroxypropyl methylcellulose E5LV and mannitol into a wet granulator, setting stirring speed to 400rpm, and mixing for 10 minutes at cutter speed of 1500 rpm; spraying purified water to granulate for 1 minute; drying the obtained wet granules in a fluidized bed at 60 ℃ for 15 minutes, and finishing the granules with a 30-mesh screen after drying to obtain medicine-containing granules;
3. adding crosslinked sodium carboxymethyl starch, povidone K30, mannitol and xylitol into a wet granulator, setting stirring speed to 400rpm, and mixing for 10 minutes at cutter speed of 1500 rpm; spraying purified water to granulate for 1 minute; drying the obtained wet granules in a fluidized bed at 60 ℃ for 15 minutes, and finishing the granules with a 30-mesh screen after drying to obtain orally disintegrating granules;
4. mixing the orally disintegrating particles, the drug-containing particles and the sodium stearyl fumarate in a three-dimensional mixer for 10 minutes;
5. tabletting by adopting a shallow concave round punch with the diameter of 10.0mm, and controlling the hardness of the tablet to be 5-7 kg.
Test example 1
Content uniformity inspection:
according to the content uniformity checking method under the related item in the current Chinese pharmacopoeia, the content uniformity of the preparation in examples 1-4, comparative example 1 and the commercial preparation is checked, and the result is as follows:
the content uniformity of the related items in the current Chinese pharmacopoeia prescribes that A+2.2S should be less than or equal to 15.0; the sample content uniformity A+2.2S of examples 1-4 is less than 15.0, and has more excellent content uniformity.
Test example 2
Disintegration time determination:
according to the disintegration time limit checking method under the related item in the current Chinese pharmacopoeia, the disintegration time of the examples 1-4, the comparative example 1 and the commercial preparation is detected, and the results are as follows:
the disintegration time limit under the related item in the current Chinese pharmacopoeia prescribes that the Chinese pharmacopoeia disintegrates completely within 1 minute; the sample of example 1 disintegrated completely within 40 seconds, the disintegration rate was the fastest, and the disintegration time of examples 1-4 was significantly faster than that of comparative example 1 and the commercial formulation, with excellent fast-disintegrating effect.
Test example 3
Dissolution test:
according to the dissolution rate inspection method under the related item in the current Chinese pharmacopoeia, the detection is carried out, and the result is as follows:
the dissolution rate of the traditional Chinese pharmacopoeia under the relevant item is specified that the dissolution rate of 15 minutes is not lower than 75 percent; the dissolution rate of the sample of example 1 in 15 minutes in the invention is higher than 90 percent, which is obviously higher than that of the sample of comparative example 1 and the commercial preparation, and has excellent dissolution effect.
Test example 4
Inspection of substances:
packaging the product of example 1 in a commercial manner, respectively placing the product and a commercial preparation under a long-term condition and an accelerating condition, taking out the product after 6 months, and detecting related substances; according to the related substance inspection method in the related item in the current "Chinese pharmacopoeia", the related substances of example 1 and the commercially available preparation were inspected, and the results are as follows:
the examination results of the related substances show that: the sample of example 1 has significantly less maximum mono-impurity and total impurity content in the relevant substances after 6 months under long-term and accelerated conditions than the commercially available preparation, and the fluctuation of the impurity content is smaller; the preparation method in the patent can be used for obtaining the sample with good level of related substances and high stability.
Test example 5
The bioavailability of example 1 and the commercially available formulations of the present invention were studied using Beagle dogs as the test animals, and it was noted that the following test protocol was performed on the same standardized diet throughout the entire period of Beagle dog feeding to exclude the possible adverse effects of food on the results.
Test animals were selected and grouped: female, healthy and age-matched Beagle dogs are selected, the weight of the Beagle dogs is within the range of 12+/-1.0 kg, and the total of 12 dogs are randomly divided into 2 groups of 6 dogs each.
Test protocol: 1) No drug was administered 21 days prior to the trial; 2) 7 days before the test, 1mg of ticagrelor/kg of body weight of the drug is given every day to perform background presaturation on each tested animal, so that the background ticagrelor concentration of each tested animal reaches a steady-state level; 3) Day 1 before the test 20: animals in groups 00 began fasted, day 7 of the trial: 00 fasting administration of 2.4mg ticagrelor/kg body weight and drawing 2mL blood sample from the median forelimb vein at each sampling time point (0 point, 15 minutes, 30 minutes, 45 minutes, 1.0 hour, 1.5 hours, 2.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, 12.0 hours, 24.0 hours, 48.0 hours); 4) The method comprises the steps of detecting the ticagrelor content of samples of each sampling time point of animals of each tested group by adopting a Beagle dog ticagrelor ELISA kit, calculating the average value of each evaluation item of 3 Beagle dogs of each tested group, and carrying out systematic methodological verification on the precision, the recovery rate, the specificity, the detection limit and the like of the method before sample analysis and detection by the inventor.
The results of Beagle dogs bioavailability studies using the test examples of the present invention are shown in the following table:
from the analysis of the results of the table, it can be seen that: the ticagrelor solid preparation of the invention and the preparation method thereof obtain the ticagrelor dispersible tablet of example 1, which has high absorption speed and is expressed as T max 45 minutes, and commercially available formulation T max 55 minutes; the relative bioavailability of the ticagrelor in the ticagrelor dispersible tablet of the invention is improved by (107.2-90.4)/90.4=18.6% compared with the commercial preparation, and the bioavailability is higher in vivo.
The above description of the embodiments is only intended to assist in understanding the method and core idea of the invention. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.
Claims (4)
1. The ticagrelor orally disintegrating tablet is characterized in that the ticagrelor orally disintegrating tablet is prepared by mixing and tabletting active ingredients, orally disintegrating particles and lubricants, wherein each 1000 tablets consist of the following components in parts by weight: 60-90 g of active ingredient, 207-290 g of orally disintegrating particles and 2-8 g of lubricant; the active ingredient refers to ticagrelor;
the components in the orally disintegrating particles are four selected from crosslinked sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, povidone, lactose, microcrystalline cellulose, crosslinked povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, mannitol, xylitol, sucrose and anhydrous calcium hydrophosphate; the components in the orally disintegrating particles comprise crosslinked sodium carboxymethyl starch, povidone, mannitol and xylitol composition, or low-substituted hydroxypropyl cellulose, povidone, anhydrous calcium hydrophosphate and xylitol composition, or crosslinked povidone, hydroxypropyl methylcellulose, microcrystalline cellulose and xylitol composition, or crosslinked povidone, mannitol and xylitol composition; the part ratio is 30-80: 1 to 8: 100-150: 4-20;
the lubricant is selected from one of talcum powder, colloidal silicon dioxide, magnesium stearate, stearic acid and sodium stearyl fumarate; the preparation method of the orally disintegrating tablet comprises the following steps:
step one: crushing the active ingredients and sieving the crushed active ingredients with a 100-200-mesh sieve;
step two: mixing the active ingredient treated in the first step, the orally disintegrating particles and the lubricant together for 5-30 minutes;
step three: tabletting, wherein the hardness of the tablet is controlled to be 4-10 kg.
2. The orally disintegrating tablet according to claim 1, wherein the orally disintegrating particles comprise the following components in parts by weight: 2:139:10.
3. the orally disintegrating tablet according to claim 1, wherein the preparation method comprises the steps of:
step one: pulverizing the active ingredients, and sieving with 200 mesh sieve;
step two: mixing the components in the orally disintegrating particles, granulating by a wet method, drying the prepared wet particles at 60 ℃, and finishing the particles by a 30-mesh screen after drying to prepare the orally disintegrating particles;
step three: mixing the active ingredient treated in the first step, the orally disintegrating particles prepared in the second step and the lubricant for 10 minutes;
step four: tabletting, wherein the hardness of the tablet is controlled to be 5-7 kg.
4. Use of the ticagrelor orally disintegrating tablet of claim 1 for improving bioavailability.
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| CN114712317A (en) * | 2021-01-04 | 2022-07-08 | 弘和制药有限公司 | Ticagrelor pharmaceutical composition, and preparation method and application thereof |
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| CN101732725A (en) * | 2010-01-25 | 2010-06-16 | 江西本草天工科技有限责任公司 | Composition for speeding up disintegration of tablet and application thereof |
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