CN113967197A - Trifluridine and tipepidine hydrochloride compound tablet and preparation method thereof - Google Patents
Trifluridine and tipepidine hydrochloride compound tablet and preparation method thereof Download PDFInfo
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- CN113967197A CN113967197A CN202010726009.6A CN202010726009A CN113967197A CN 113967197 A CN113967197 A CN 113967197A CN 202010726009 A CN202010726009 A CN 202010726009A CN 113967197 A CN113967197 A CN 113967197A
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- Prior art keywords
- trifluridine
- tipepidine
- hydrochloride
- compound tablet
- tablet
- Prior art date
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- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 title claims abstract description 80
- 229960003962 trifluridine Drugs 0.000 title claims abstract description 79
- 229960000896 tipepidine Drugs 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 50
- -1 tipepidine hydrochloride compound Chemical class 0.000 title claims abstract description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 45
- JWIXXNLOKOAAQT-UHFFFAOYSA-N tipepidine Chemical compound C1N(C)CCCC1=C(C=1SC=CC=1)C1=CC=CS1 JWIXXNLOKOAAQT-UHFFFAOYSA-N 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000000463 material Substances 0.000 claims abstract description 15
- 239000011248 coating agent Substances 0.000 claims description 20
- 238000000576 coating method Methods 0.000 claims description 20
- 239000000314 lubricant Substances 0.000 claims description 14
- 235000021355 Stearic acid Nutrition 0.000 claims description 13
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 13
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 13
- 239000008117 stearic acid Substances 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 235000012239 silicon dioxide Nutrition 0.000 claims description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 8
- 238000004090 dissolution Methods 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 62
- 239000000243 solution Substances 0.000 description 28
- 230000000052 comparative effect Effects 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 6
- 239000007884 disintegrant Substances 0.000 description 6
- 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 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 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 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- VPXSYLFGBHFLCF-VWZUFWLJSA-N 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(trifluoromethyl)pyrimidine-2,4-dione hydrochloride Chemical compound C1[C@@H]([C@H](O[C@H]1N2C=C(C(=O)NC2=O)C(F)(F)F)CO)O.Cl VPXSYLFGBHFLCF-VWZUFWLJSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical group [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- JYNGWFMXEJIJEE-UHFFFAOYSA-N (2-formyloxy-3-hydroxypropyl) formate Chemical compound O=COC(CO)COC=O JYNGWFMXEJIJEE-UHFFFAOYSA-N 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229940122294 Phosphorylase inhibitor Drugs 0.000 description 1
- 101710132082 Pyrimidine/purine nucleoside phosphorylase Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 102000013537 Thymidine Phosphorylase Human genes 0.000 description 1
- 229940122020 Thymidine phosphorylase inhibitor Drugs 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940126587 biotherapeutics Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000005699 fluoropyrimidines Chemical class 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- LJSOLTRJEQZSHV-UHFFFAOYSA-L potassium;sodium;hydron;hydroxide;phosphate Chemical compound [OH-].[Na+].[K+].OP(O)([O-])=O LJSOLTRJEQZSHV-UHFFFAOYSA-L 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 229960001740 tipiracil hydrochloride Drugs 0.000 description 1
- KGHYQYACJRXCAT-UHFFFAOYSA-N tipiracil hydrochloride Chemical compound Cl.N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1 KGHYQYACJRXCAT-UHFFFAOYSA-N 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000003643 water by type Substances 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
- A61K9/205—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
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicinal preparations, and particularly relates to a trifluridine and tipepidine hydrochloride compound tablet which is prepared by the following method: the trifluridine and the tipepidine hydrochloride are mixed with the starlac, then the pharmaceutically common auxiliary materials are added, the mixture is mixed, tableted and coated, and the compound tablet of the trifluridine and the tipepidine hydrochloride prepared by the method has the advantages of small using amount of the auxiliary materials, simple preparation process, good stability of the product and high dissolution speed, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to a trifluridine and tipepidine hydrochloride compound tablet and a preparation method thereof.
Background
Trifloxuridine (Trifluridine and Tipiracil Hydrochloride, TAS-102, also known as Trifluridine pridine) consists of Trifluridine and a thymine phosphorylase inhibitor, i.e., pirimidine, in a weight ratio of 2:1, and is an oral fluorouracil drug. The mechanism of action of trifluridine tipyrimidine is that after it is taken into cancer cells, trifluridine is incorporated into the DNA of cancer cells, interfering with the synthesis of the DNA of cancer cells and inhibiting the proliferation of cancer cells, while tipyrimidine inhibits the metabolism of trifluridine by thymidine phosphorylase to increase the exposure of trifluridine, and pharmacological experiments prove that trifluridine/tipyrimidine shows antitumor activity against KRAS wild-type and mutant human colorectal cancers in xenografted mice. Trifluridine tipyrimidine, approved by the U.S. FDA at 22/9/2015 for treatment of refractory metastatic colorectal cancer (mCRC) patients who no longer respond to other therapies (chemotherapeutics and biotherapeutics) and approved by european EMA at 2016 at 4, is currently approved in 21 countries and regions of japan, the united states, the uk, canada, the european union, etc. for treatment of metastatic colorectal cancer (mCRC), and is in the registration reporting phase in china, and is also recommended for metastatic colorectal cancer patients (mCRC) who have previously received fluoropyrimidines, oxaliplatin and irinotecan chemotherapy and targeted therapy, based on high-level evidence of evidence and good clinical use experience.
CN101107001A discloses an anticancer agent containing α, α, α -trifluorothymidine and a thymidine phosphorylase inhibitor, and many kinds of excipients are used in the formulation, and the stability of the obtained preparation has not been studied.
CN104105491B discloses a pharmaceutical composition for oral administration containing FTD and TPI, which uses excipient containing saccharide with critical relative humidity above 85% at 25 deg.C to promote tablet stability, but the obtained product has great difference in stability data of one week, two weeks and one month in stability test of 40 deg.C and 75% humidity, the content of total analogues, i.e. total impurities, is increased from 0.00% to 0.40%, which indicates that the self stability of the obtained pharmaceutical composition or tablet is still to be improved.
CN 104105490 a discloses a pharmaceutical composition for oral administration, which is prepared by adding an additive comprising a metal salt to a formulation in such a small amount that the stability of FTD and TPI is not impaired, and an excipient selected from the group consisting of sugar alcohols and disaccharides, and adding 2 to 16% of a disintegrant to improve the disintegratability in oral administration.
CN 105963271A discloses a pharmaceutical adjuvant composition and a trifluridine and hydrochloric acid-substituted pyrimidine film-coated tablet, wherein stearic acid is used for replacing magnesium stearate, so as to solve the problems that tablet cores cannot be formed, split, loose, cannot be coated and the like when the magnesium stearate is used as a lubricant for preparing the trifluridine and hydrochloric acid-substituted pyrimidine film-coated tablets, the hardness of the obtained tablet is 5-11N, and the problem that the formability of the obtained tablet is poor is reflected basically under the critical value (10-200N) of the qualified hardness standard of the tablet.
CN 106913580A discloses a pharmaceutical composition containing trifluridine hydrochloride tepa inhaul and application thereof, the pharmaceutical composition specifically comprises FTD, TPI, lactose, pregelatinized starch and glyceryl behenate, the stability of the pharmaceutical composition is improved under high temperature and high humidity conditions, but after raw materials of FTD and TPI are mixed, the raw materials are crushed to the diameter D90 of less than or equal to 100 mu m, after mixed API is obtained, more auxiliary materials are used for preparation, and the preparation is not favorable for improving the safety of medicine taking, in the content of the invention, the total impurity content of the tablet obtained in example 3 in 17 days is increased by nearly 1 time compared with the total impurity content in 7 days, the impurity TPI-B content of the coated tablet obtained in example 3 in 10 days is increased by 1.6 times compared with the content in 7 days, namely, the total impurity content of the pharmaceutical composition obtained in the invention is increased by 1.6 times compared with the impurity content of the tablet sold in markets
Decreases, but the stability thereof still remains to be improved.
The trifluridine and tipepidine hydrochloride compound preparation is mainly a common oral compressed tablet, in the preparation of the tablet, in order to ensure that the tablet is easy to take orally, auxiliary materials except main components such as excipient, adhesive, disintegrant, lubricant, flavoring agent and the like are usually added, and the auxiliary materials influence the stability and the weight of the tablet and need to be carefully selected; in addition, when the tablet of the product obtained by the preparation is heavy, the compliance of patients is poor, and when the stability of the obtained product is poor, an independent packaging bag is needed to increase the production cost, which is more unfavorable for environmental protection. In the prior art, the compound preparation of trifluridine and tipepidine hydrochloride has the problems of complex preparation prescription, poor stability, poor formability, poor dissolution performance and the like. Therefore, the development of a novel trifluridine hydrochloride and tipepidine compound tablet is an urgent requirement for the technical personnel in the field.
Disclosure of Invention
In view of the technical problems of the preparation of the compound preparation of trifluridine and tipepidine hydrochloride in the prior art, the invention provides a compound tablet of trifluridine and tipepidine hydrochloride, and the effects of good formability, high dissolution performance and good stability of the obtained tablet are achieved by screening appropriate auxiliary materials, formula proportion and preparation process. The compound preparation of trifluridine and tipepidine hydrochloride and the preparation method thereof provided by the invention have the advantages of fewer types of preparation auxiliary materials, simple preparation process and suitability for industrial production.
A compound tablet of trifluridine and tipepidine hydrochloride comprises trifluridine, tipepidine hydrochloride, starlac and pharmaceutically common adjuvants.
The preparation method of the trifluridine and tipepidine hydrochloride compound tablet comprises the following steps: mixing trifluridine, tipepidine hydrochloride and starlac, adding pharmaceutically-used adjuvants, mixing, tabletting, and coating.
Preferably, in the trifluridine and tipepidine hydrochloride compound tablet, the weight ratio (g/g) of the trifluridine to the tarlac is 1: 2-6.
Further preferably, in the trifluridine and tipepidine hydrochloride compound tablet, the weight ratio (g/g) of the trifluridine to the starlac is 1: 2-4.
More preferably, in the trifluridine and tipepidine hydrochloride compound tablet, the weight ratio (g/g) of the trifluridine to the tarlac is 1: 2-3.
Preferably, in the trifluridine and tipepidine hydrochloride compound tablet, the pharmaceutically commonly used auxiliary material is a lubricant, and the dosage of the auxiliary material is 1-2% of the weight (g/g) of the plain tablet of the compound tablet.
Further preferably, in the trifluridine and tipepidine hydrochloride compound tablet, the lubricant is stearic acid, glycerol diformate, talcum powder and silicon dioxide.
More preferably, in the trifluridine and tipepidine hydrochloride compound tablet, the lubricant is stearic acid.
Preferably, in the compound tablet of trifluridine and tipepidine hydrochloride, the molar ratio of trifluridine to tipepidine hydrochloride is 2:1, and the total weight (g/g) of trifluridine and tipepidine hydrochloride accounts for 19-42% of the compound tablet, the total weight (g/g) of starlac accounts for 57-79% of the compound tablet, and the weight (g/g) of the lubricant accounts for 1-2% of the compound tablet.
Further preferably, in the compound tablet of trifluridine and tipepidine hydrochloride, the molar ratio of trifluridine to tipepidine hydrochloride is 2:1, and the total amount of trifluridine and tipepidine hydrochloride accounts for 32-42%, the total amount of stallac accounts for 57-66% and the amount of lubricant accounts for 1-2% of the weight (g/g) of the compound tablet.
The type and amount of the coating material and the operation of the compound tablet of trifluridine and tipepidine hydrochloride are not particularly limited, and the coating material may be appropriately selected, and the coating layer may contain a small amount of additives such as a colorant, a flavoring agent, a lubricant, and the like, to such an extent that the stability of trifluridine and tipepidine hydrochloride is not substantially affected.
The trifluridine and tipepidine hydrochloride compound tablet and the preparation method thereof have the following advantages:
(1) the prescription of the trifluridine and tipepidine hydrochloride compound tablet has fewer types of auxiliary materials;
(2) the prescription of the trifluridine and tipepidine hydrochloride compound tablet does not need to be additionally added with a disintegrant;
(3) the preparation process of the trifluridine and tipepidine hydrochloride compound tablet is simple;
(4) the trifluridine and tipepidine hydrochloride compound tablet prepared by the invention has good formability, rapid dissolution and better stability.
Detailed Description
The advantages of the present invention are further described below by way of examples, it being properly understood that: the examples of the present invention are given solely for the purpose of illustration and not as limitations of the present invention, and therefore, simple modifications of the present invention in the context of the methods of the present invention are intended to fall within the scope of the claims.
Example 1
(I) prescription
(II) the preparation process comprises the following steps:
respectively crushing trifluridine and tipepidine hydrochloride, sieving by a 100-mesh sieve, weighing according to a prescription amount, mixing with a starlac according to the prescription amount, adding stearic acid, mixing, tabletting, and coating the obtained plain tablets with an opadry solution with the solid content of about 7% (weighing 27g of opadry, adding 360g of purified water, magnetically stirring for 2h, filtering by a 120-mesh sieve, and taking the filtrate, namely the 7% opadry solution).
Example 2
(I) prescription
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through a 120 mesh sieve, weighed according to the prescription, then mixed with tarlac according to the prescription, added with stearic acid, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation method of example 1, i.e. a 7% opadry solution.
Example 3
(I) prescription
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through 100 mesh sieve, weighed according to the prescription, mixed with tarlac according to the prescription, added with stearic acid, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation method of example 1, i.e. 7% opadry solution.
Example 4
(I) prescription
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through 100 mesh sieve, weighed according to the prescription, then mixed with tarlac according to the prescription, added with silicon dioxide, mixed and tabletted, and the obtained plain tablets were coated with the same coating solution as the preparation method of example 1, i.e. 7% opadry solution.
Example 5
(I) prescription
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through 100 mesh sieve, weighed according to the prescription, then mixed with tarlac according to the prescription, added with talc powder, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation method of example 1, i.e. 7% opadry solution.
Example 6
(I) prescription
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through a 100 mesh sieve, weighed according to the prescription, mixed with tarlac according to the prescription, added with glycerol dicarboxylate, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation of example 1, i.e. a 7% opadry solution.
Example 7
(I) prescription
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through 100 mesh sieve, weighed according to the prescription, then mixed with tarlac according to the prescription, added with talc powder, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation method of example 1, i.e. 7% opadry solution.
Example 8
(I) prescription
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through a 100 mesh sieve, weighed according to the prescription, then mixed with tarlac according to the prescription, magnesium stearate was added, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation method of example 1, i.e. a 7% opadry solution.
Comparative example 1
(I) prescription
(II) the preparation process comprises the following steps:
1) respectively crushing trifluridine and tipepidine hydrochloride, and sieving by a 80-mesh sieve for later use; 2) mixing the trifluridine obtained in the step 1 and the tipepidine hydrochloride, and then uniformly mixing the mixture with the lactose, the pregelatinized starch and the stearic acid in the prescribed amount to obtain an intermediate; 3) calculating the weight of the tabletting sheets according to the FTD content in the intermediate, and tabletting; 4) detecting the quality of the tablet core after tabletting, and coating according with the coating conditions, wherein the coating specifically comprises the following steps: adding water into Opadry gastric-soluble film coating premix to obtain solution, and coating.
Comparative example 2:
50g of trifluridine, 23.55g of tipepidine hydrochloride, 196.45g of lactose hydrate, 30g of corn starch as a disintegrant and 3g of stearic acid were mixed in a polyethylene bag, and the mixture was formed into a general tablet having a mass of 121.2mg by a rotary tablet machine, and the obtained plain tablet was coated with a 7% opadry solution which was the same coating solution as the preparation method of example 1.
Comparative example 3:
50g of trifluridine, 23.55g of tipepidine hydrochloride, 196.45g of lactose hydrate, 30g of partially gelatinized starch as a disintegrant, and 3g of stearic acid were mixed in a polyethylene bag, and the mixture was formed into a general tablet having a mass of 121.2mg by a rotary tablet machine, and the obtained plain tablet was coated with a 7% opadry solution which was the same coating solution as the preparation method of example 1.
Comparative example 4:
50g of trifluridine, 23.55g of tipepidine hydrochloride, 196.45g of lactose hydrate, 30g of low-substituted hydroxypropylcellulose as a disintegrant, and 3g of stearic acid were mixed in a polyethylene bag, and the mixture was formed into a general tablet having a mass of 121.2mg by a rotary tablet machine, and the obtained plain tablet was coated with a 7% opadry solution which was the same coating solution as that of the preparation method of example 1. Comparative example 5:
(I) prescription
(II) the preparation process comprises the following steps:
weighing trifluridine and tipepidine hydrochloride according to the prescription amount, mixing with lactose, corn starch and hydroxypropyl cellulose according to the prescription amount, and preparing granules.
Comparative example 6:
(I) prescription
(II) the preparation process comprises the following steps:
weighing trifluridine and tipepidine hydrochloride according to the prescription amount, mixing with lactose and crystalline cellulose according to the prescription amount, adding magnesium stearate, and preparing capsules.
Comparative example 7:
(I) prescription
(II) the preparation process comprises the following steps:
trifluridine and tipepidine hydrochloride were separately crushed, sieved through a 100 mesh sieve, weighed according to the prescription, then mixed with lactose and corn starch according to the prescription, and then stearic acid was added, mixed and tabletted, and the obtained plain tablets were coated with a coating solution identical to the preparation method of example 1, i.e. 7% opadry solution.
Verification examples
Measurement of hardness: measured using a tablet hardness tester.
Determination of dissolution: according to the determination method of dissolution rate and release rate of the four parts (0931) of the Chinese pharmacopoeia 2015 edition, the dissolution conditions are that potassium dihydrogen phosphate-sodium hydroxide solution with pH6.8 is used as dissolution medium, the volume is 900mL, the rotating speed is 50 r/min, 5mL is sampled in 5 minutes, and then filtered, and the subsequent filtrate is taken and determined according to the following method: the mobile phase is disodium hydrogen phosphate solution (8.92 g of disodium hydrogen phosphate is taken, water is added to 1000mL, the pH value is adjusted to 7.3 by phosphoric acid) -methanol (76:24), an ultraviolet detector is used for detecting the wavelength of 275nm, octadecylsilane chemically bonded silica is used as a filler for a chromatographic column, Waters Xbridge is used, the particle size of the filler is 5 mu m, and the length is 150 cm; flow rate: 1.0mL/min, sample size: 10 mu; preparation of a reference solution: taking a trifluridine reference substance and a tipepidine hydrochloride reference substance, precisely weighing, dissolving with water, and quantitatively diluting to prepare a mixed solution containing about 22 mu g of trifluridine and 10 mu g of tipepidine hydrochloride in 1mL, wherein the mixed solution is used as a reference substance solution; the determination method comprises the following steps: the elution amount of trifluridine and tipepidine hydrochloride in each tablet is calculated by an external standard method.
And (3) determination of the total impurity content in related substances: the tablets obtained in examples 1 to 8 and comparative examples 1 to 7 were stored open at 40 ℃/75% r.h. for 3 months, and the total analog content (i.e., total impurities) was measured, and the total analog mass was calculated by taking peaks other than the peaks of trifluridine, tipirimidine hydrochloride and additives as analog mass peaks and calculating the total of the similar substance amounts based on the effective component area from the areas.
Measurement results of examples and comparative examples
Claims (10)
1. The compound tablet of trifluridine and tipepidine hydrochloride is characterized by comprising trifluridine, tipepidine hydrochloride, starlac and pharmaceutically commonly used auxiliary materials.
2. The compound tablet of claim 1, wherein the weight ratio of trifluridine to starlac is 1: 2-6.
3. The compound tablet according to claim 1 or 2, wherein the weight ratio of trifluridine to starlac is 1: 2-4.
4. The compound tablet according to claim 1 or 2, wherein the weight ratio of trifluridine to starlac is 1: 2-3.
5. The compound tablet according to claim 1, wherein the pharmaceutically common auxiliary material is a lubricant, and the dosage of the lubricant is 1-2% of the weight of the tablet of the compound tablet.
6. The compound tablet of claim 5, wherein the lubricant is stearic acid, a glycol ester, talc, and silicon dioxide.
7. The compound tablet of claim 5 or 6, wherein the lubricant is stearic acid.
8. The compound tablet according to claim 1, wherein the molar ratio of trifluridine to tipepidine hydrochloride is 2:1, and the total amount of trifluridine and tipepidine hydrochloride is 19-42%, the amount of stallac is 57-79% and the amount of lubricant is 1-2% of the weight of the compound tablet.
9. The compound tablet according to claim 1, wherein the molar ratio of trifluridine to tipepidine hydrochloride in the compound tablet of trifluridine and tipepidine hydrochloride is 2:1, and the total amount of trifluridine and tipepidine hydrochloride is 32-42%, the total amount of stalllac is 57-66% and the amount of lubricant is 1-2% of the weight of the compound tablet.
10. The preparation method of the compound tablet as claimed in claim 1, wherein the preparation method comprises the steps of fully mixing trifluridine, tipepidine hydrochloride and starlac, adding pharmaceutically common auxiliary materials, mixing, tabletting and coating.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102885787A (en) * | 2011-07-22 | 2013-01-23 | 重庆华邦制药股份有限公司 | Moxifloxacin hydrochloride tablets for preventing color change and cracking and preparation method thereof |
| CN105963271A (en) * | 2016-06-01 | 2016-09-28 | 国药心制药有限公司 | Pharmaceutical adjuvant composition and floxuridine and hydrochloric acid substituted pyrimidine film-coated tablets |
| CN106551946A (en) * | 2015-09-24 | 2017-04-05 | 江苏奥赛康药业股份有限公司 | It is a kind of containing trifluorothymidine and hydrochloric acid for the pharmaceutical composition and preparation method than pyrimidine |
| CN109999053A (en) * | 2019-04-26 | 2019-07-12 | 周德旺 | Trifluridine or Trifluridine replace the medical usage of a pyrimidine compositions |
| WO2019171394A1 (en) * | 2018-03-03 | 2019-09-12 | Natco Pharma Limited | Stable pharmaceutical compositions comprising trifluridine and tipiracil hydrochloride |
-
2020
- 2020-07-24 CN CN202010726009.6A patent/CN113967197B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102885787A (en) * | 2011-07-22 | 2013-01-23 | 重庆华邦制药股份有限公司 | Moxifloxacin hydrochloride tablets for preventing color change and cracking and preparation method thereof |
| CN106551946A (en) * | 2015-09-24 | 2017-04-05 | 江苏奥赛康药业股份有限公司 | It is a kind of containing trifluorothymidine and hydrochloric acid for the pharmaceutical composition and preparation method than pyrimidine |
| CN105963271A (en) * | 2016-06-01 | 2016-09-28 | 国药心制药有限公司 | Pharmaceutical adjuvant composition and floxuridine and hydrochloric acid substituted pyrimidine film-coated tablets |
| WO2019171394A1 (en) * | 2018-03-03 | 2019-09-12 | Natco Pharma Limited | Stable pharmaceutical compositions comprising trifluridine and tipiracil hydrochloride |
| CN109999053A (en) * | 2019-04-26 | 2019-07-12 | 周德旺 | Trifluridine or Trifluridine replace the medical usage of a pyrimidine compositions |
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