CN114073679A - Celecoxib composition and preparation method and application thereof - Google Patents
Celecoxib composition and preparation method and application thereof Download PDFInfo
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- CN114073679A CN114073679A CN202111194497.1A CN202111194497A CN114073679A CN 114073679 A CN114073679 A CN 114073679A CN 202111194497 A CN202111194497 A CN 202111194497A CN 114073679 A CN114073679 A CN 114073679A
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- celecoxib
- mixing
- celecoxib composition
- polyethylene glycol
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- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 title claims abstract description 126
- 229960000590 celecoxib Drugs 0.000 title claims abstract description 126
- 239000000203 mixture Substances 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000002156 mixing Methods 0.000 claims description 69
- 239000002775 capsule Substances 0.000 claims description 29
- 238000005303 weighing Methods 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 238000002844 melting Methods 0.000 claims description 15
- 230000008018 melting Effects 0.000 claims description 15
- 229920002554 vinyl polymer Polymers 0.000 claims description 15
- 239000000945 filler Substances 0.000 claims description 14
- 229920001577 copolymer Polymers 0.000 claims description 13
- 239000002245 particle Substances 0.000 claims description 13
- 239000002202 Polyethylene glycol Substances 0.000 claims description 11
- 229920001223 polyethylene glycol Polymers 0.000 claims description 11
- 238000001125 extrusion Methods 0.000 claims description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 239000011812 mixed powder Substances 0.000 claims description 9
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 8
- -1 acetate-polyethylene Chemical group 0.000 claims description 8
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 8
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 7
- 229920001993 poloxamer 188 Polymers 0.000 claims description 7
- 229940044519 poloxamer 188 Drugs 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 239000011802 pulverized particle Substances 0.000 claims description 7
- 229920000578 graft copolymer Polymers 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 239000004014 plasticizer Substances 0.000 claims description 6
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 5
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229960003943 hypromellose Drugs 0.000 claims description 5
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 239000004359 castor oil Substances 0.000 claims description 4
- 235000019438 castor oil Nutrition 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 229940093471 ethyl oleate Drugs 0.000 claims description 4
- 239000010408 film Substances 0.000 claims description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 4
- 229940051841 polyoxyethylene ether Drugs 0.000 claims description 4
- 229920000056 polyoxyethylene ether Polymers 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 239000000829 suppository Substances 0.000 claims description 4
- 239000003826 tablet Substances 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 3
- 208000005298 acute pain Diseases 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 239000001069 triethyl citrate Substances 0.000 claims description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 3
- 235000013769 triethyl citrate Nutrition 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000004090 dissolution Methods 0.000 abstract description 34
- 239000012535 impurity Substances 0.000 abstract description 5
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 24
- 239000013558 reference substance Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- 239000003814 drug Substances 0.000 description 16
- 238000007865 diluting Methods 0.000 description 15
- 238000011049 filling Methods 0.000 description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000000463 material Substances 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- 239000003085 diluting agent Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000007873 sieving Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 229920003081 Povidone K 30 Polymers 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000009474 hot melt extrusion Methods 0.000 description 8
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 8
- 235000019796 monopotassium phosphate Nutrition 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 239000012738 dissolution medium Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 6
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 239000007903 gelatin capsule Substances 0.000 description 6
- 239000012088 reference solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000013022 formulation composition Substances 0.000 description 5
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 4
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 238000009210 therapy by ultrasound Methods 0.000 description 4
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 3
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012490 blank solution Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000000053 physical method Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000007962 solid dispersion Substances 0.000 description 3
- 239000013589 supplement Substances 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- 238000009736 wetting Methods 0.000 description 3
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 2
- LGIMTMFJBCXYRP-UHFFFAOYSA-N 4-[3-(4-methylphenyl)-5-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide Chemical compound C1=CC(C)=CC=C1C1=NN(C=2C=CC(=CC=2)S(N)(=O)=O)C(C(F)(F)F)=C1 LGIMTMFJBCXYRP-UHFFFAOYSA-N 0.000 description 2
- MPVPOTMPKLOUHZ-UHFFFAOYSA-N 4-[5-(3-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide Chemical compound CC1=CC=CC(C=2N(N=C(C=2)C(F)(F)F)C=2C=CC(=CC=2)S(N)(=O)=O)=C1 MPVPOTMPKLOUHZ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229940114079 arachidonic acid Drugs 0.000 description 2
- 235000021342 arachidonic acid Nutrition 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 235000012438 extruded product Nutrition 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 239000002699 waste material Substances 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a celecoxib composition and a preparation method and application thereof, and relates to the technical field of pharmaceutical preparations. The preparation method provided by the invention is simple to operate, does not need to carry out airflow crushing on the celecoxib, is green and environment-friendly, and the prepared celecoxib composition has high dissolution rate, good stability and low moisture and impurity content, so that the safety of clinical application is improved.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a celecoxib composition and a preparation method and application thereof.
Background
Celecoxib is a non-steroidal anti-inflammatory drug, and has the anti-inflammatory and analgesic effects of NSAIDs. Due to the characteristics of the chemical structure, the compound can be combined with COX-2 and has selective inhibition effect on the COX-2. The phenyl group of celecoxib binds to the hydrophobic channel of COX-2, and the hydrophilic sulfonamido group forms a hydrogen chain with arginine 513 and histidine 90 in the "side pocket" of COX-2. Celecoxib can be closely combined with arginine at COX-2120 position to play a role in inhibiting the conversion of arachidonic acid into prostaglandin which is harmful to human body by COX-2, and due to slight difference of structures of COX-1 and COX-2, the medicine cannot enter molecules of COX-1 and cannot inhibit the effect of COX-1 in converting arachidonic acid into prostaglandin. It is suitable for relieving symptoms and physical signs of osteoarthritis, adult rheumatoid arthritis and ankylosing spondylitis, and can also be used for treating acute pain of adult.
Celecoxib is white to off-white crystal, is easy to dissolve in methanol, ethanol, acetone and metformin, is almost insoluble in water, is almost insoluble in 0.1mol/L hydrochloric acid solution and 0.1mol/L sodium hydroxide, and has a melting point of 160.0-164.0 ℃. The bulk density of the celecoxib raw material medicine is low, and the raw material is easy to be bonded into blocks in the crushing process.
Most of the products on the market at present are celecoxib capsules. The preparation process is wet granulation, and the celecoxib bulk drug subjected to wet granulation needs to be subjected to air flow grinding to reduce the particle size of the bulk drug so as to improve the dissolution rate of the drug. But the airflow crushing dust in the preparation process is large, so that the environmental pollution is easily caused, and the yield is low after crushing, so that the waste is caused; therefore, wet granulation has the defects of complex process and high energy consumption.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a celecoxib composition and a preparation method and application thereof, the preparation method is simple to operate and environment-friendly, and the obtained preparation has high dissolution rate, good stability and low moisture and impurity content, so that the safety of clinical application is improved.
In order to solve the technical problems, the invention provides the following technical scheme:
in a first aspect, a method for preparing a celecoxib composition is provided, comprising the steps of:
(1) weighing: respectively weighing the following components in percentage by mass: 40-70% of celecoxib, 20-50% of a filler, 1-6% of a plasticizer and 0-4% of a lubricant; wherein the filler is selected from at least one of hypromellose, polyvidone K30, crospovidone, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl alcohol-polyethylene glycol copolymer, methacrylic acid/ethyl acrylate copolymer, and polyethylene glycol 6000;
(2) mixing: adding celecoxib and a filler into a mixer, adding a plasticizer, and uniformly mixing to obtain mixed powder;
(3) hot melting and extruding: setting the extrusion temperature of the screw extruder to be 100-;
(4) crushing: adding the extrudate into a pulverizer to be pulverized, and collecting pulverized particles;
(5) mixing: and adding the crushed particles and the lubricant into a mixer, and uniformly mixing to obtain the celecoxib composition.
Further, the plasticizer is at least one of polyethylene glycol 400, triethyl citrate, hydrogenated castor oil polyoxyethylene ether, ethyl oleate and poloxamer 188.
Further, the lubricant is magnesium stearate.
Further, in the step (2), the mixing speed of the mixer is 10-20 rpm, and the mixing time is 10-15 minutes.
Further, in the step (3), the screw extruder is a twin-screw extruder.
Further, in the step (4), the mixing speed of the mixer is 10-20 rpm, and the mixing time is 5-10 minutes.
In a preferable embodiment, in the steps (2) and (4), the mixer is a three-dimensional mixer.
The preparation method related in the invention is a hot-melt extrusion technology. In the hot melting extrusion process, unit operations such as solid conveying, material melting, shearing mixing, air exhausting, melt conveying, consignment forming and the like are performed, under the action of strong shearing force and heat energy provided by the sleeve, the grain size of the multi-component material is continuously reduced, the mixing is more uniform, the molecular level mixing is finally achieved, and the medicine is changed from a multi-phase state at an inlet to a single-phase state at an outlet.
Extruders are tools that implement hot melt extrusion techniques. The extruder consists of four parts: (1) feeding systems, often comprising a material funnel, one or more feeders; (2) a drive system comprising a barrel and a screw; (3) a machine head mouth mold system, which enables the material to be molded when leaving the extruder, and granules, pellets, tablets, suppositories, films, implant transdermal or transmucosal administration preparations or ocular implants and the like can be prepared by selecting mouth molds with different shapes or only one-step cutting; (4) downstream secondary processing systems, including cooling, cutting and/or collecting the finished product. The extruder can be divided into a plunger type extruder and a screw type extruder, the plunger type extruder is gradually eliminated due to poor mixing capability, and the screw type extruder mainly comprises a single screw extruder and a double screw extruder.
In a preferable embodiment, in the step (3), the screw extruder is a twin-screw extruder. Compared with a single-screw extruder, the process adjustment of the double-screw extruder is more refined, the mixing effect is better, and the double-screw extruder is more suitable for preparing pharmaceutical preparations.
To improve the solubility of insoluble drugs, pretreatment of the drugs is required, and two common methods are chemical and physical methods. In pharmacological studies, physical methods are most commonly used. The usual physical methods are most commonly micronization and solid dispersion techniques. After the drug is micronized, the surface free energy is large, and the tendency of spontaneous aggregation is existed, so that the micronization effect is reduced. Therefore, the solid dispersion technique is the first technique to improve the solubility of the drug. However, in the traditional solid dispersion technology, a solvent method pollutes the environment and the used organic solvent is difficult to remove; the spray (freeze) drying process is time consuming and costly.
Aiming at the problems, the proper filler is further screened by adopting a hot-melt extrusion technology, the extrusion temperature of the filler adopted by the invention is proper, the filler has better fluidity in the temperature section and can be uniformly mixed with the celecoxib, and the stability of the celecoxib can be ensured because the temperature is lower than the degradation temperature of the celecoxib. The selected fillers are hydrophilic materials, which are beneficial to wetting the main drugs by water and achieving the purpose of quick dissolution; meanwhile, the hot-melt extrusion technology can lead the drug to be dispersed in the carrier in an amorphous state or dissolved in the carrier in a molecular state, thus leading the drug and the carrier to achieve the mixing of the molecular level and obviously improving the solubility of the drug.
In a second aspect, a celecoxib composition is provided, wherein the celecoxib composition is prepared by the preparation method of the first aspect.
In a third aspect, there is provided a celecoxib composition according to the second aspect for use in the treatment of osteoarthritis, rheumatoid arthritis and acute pain.
Further, the celecoxib composition is in the form of capsules, granules, pills, tablets, suppositories, films or powder.
Specifically, when the celecoxib composition is in a capsule form, the celecoxib capsule is prepared by filling the celecoxib composition into a gelatin capsule.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention further screens the filler with proper extrusion temperature and hydrophilicity by adopting a hot-melt extrusion technology, the filler has better fluidity in the temperature section and can be uniformly mixed with the celecoxib, and the temperature is lower than the degradation temperature of the celecoxib, so that the stability of the celecoxib can be ensured. The selected filling agents are hydrophilic materials, so that celecoxib can be better dispersed, and the speed of wetting the surface of the celecoxib is higher during dissolution, so that the final dissolution rate of the celecoxib capsule is increased, the dissolution rate is higher, and the aim of quick dissolution is fulfilled.
2. The preparation method disclosed by the invention is simple to operate, does not need to carry out jet milling on the celecoxib, is green and environment-friendly, and the prepared celecoxib composition is high in dissolution rate, good in stability and low in moisture and impurity content, so that the safety of clinical application is improved.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The present invention will be further described and illustrated with reference to specific embodiments in order to more fully understand the technical content of the present invention; it is to be understood that the embodiments described below are only a few embodiments of the present invention, and not all embodiments; all other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The features, benefits and advantages of the present invention will become apparent to those skilled in the art from a reading of the present disclosure.
All percentages, parts and ratios are based on the total weight of the composition of the present invention, unless otherwise specified. The term "weight content" herein may be represented by the symbol "%".
The use of "including," "comprising," "containing," "having," or other variations thereof herein, is meant to encompass the non-exclusive inclusion, as such terms are not to be construed. The term "comprising" means that other steps and ingredients can be added that do not affect the end result. The term "comprising" also includes the terms "consisting of and" consisting essentially of. The compositions and methods/processes of the present invention can comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as any of the additional or optional ingredients, components, steps, or limitations described herein.
In the following examples, the screw extruders were all twin screw extruders.
Example 1
The present embodiment provides a celecoxib composition, specifically, the celecoxib composition is in the form of capsule, and the formulation composition (in weight percentage) thereof is shown in table 1.
Table 1:
| celecoxib | 50％ |
| Povidone K30 | 45％ |
| Oleic acid ethyl ester | 3％ |
| Magnesium stearate | 2％ |
The preparation method of the celecoxib capsule comprises the following steps:
(1) treating raw materials and auxiliary materials: sieving celecoxib with a 40-mesh sieve, and sieving povidone K30 with a 80-mesh sieve;
(2) weighing: weighing according to the prescription;
(3) mixing: adding celecoxib and povidone K30 into a three-dimensional mixer, setting the mixing speed to be 15 r/m, mixing for 10 minutes, dropwise adding ethyl oleate, and uniformly mixing to obtain mixed powder;
(4) hot melting and extruding: setting the extrusion temperature of a screw extruder to be 130 ℃, starting the screw when the temperature of the screw extruder reaches 130 ℃ and is stable, adding the mixed powder into the extruder, melting and extruding, and collecting the obtained strip-shaped extrudate;
(5) crushing: adding the extrudate into a pulverizer to be pulverized, and collecting pulverized particles;
(6) mixing: adding the crushed particles and magnesium stearate into a three-dimensional mixer, setting the mixing speed to be 15 rpm, mixing for 5 minutes, and uniformly mixing to obtain a celecoxib composition;
(7) filling: and (3) filling the celecoxib composition (particles) obtained in the step (6) into a No. 2 gelatin capsule to obtain the celecoxib capsule in the embodiment 1.
In example 1, the povidone K30 can also be hypromellose, methacrylic acid/ethyl acrylate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol-polyethylene glycol copolymer, or polyethylene glycol 6000; or a mixture of any of the above components in any ratio.
The ethyl oleate can also adopt polyethylene glycol 400, triethyl citrate, hydrogenated castor oil polyoxyethylene ether or poloxamer 188; or a mixture of any of the above components in any ratio.
Example 2
The present embodiment provides a celecoxib composition, specifically, the celecoxib composition is in the form of capsule, and the formulation composition (in weight percentage) thereof is shown in table 2.
Table 2:
the preparation method of the celecoxib capsule comprises the following steps:
(1) treating raw materials and auxiliary materials: sieving celecoxib with a 40-mesh sieve, and sieving the polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer with a 80-mesh sieve;
(2) weighing: weighing according to the prescription;
(3) mixing: adding celecoxib and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer into a three-dimensional mixer, setting the mixing speed to be 15 r/m, mixing for 10 minutes, then dropwise adding hydrogenated castor oil polyoxyethylene ether, and uniformly mixing to obtain mixed powder; uniformly mixing to obtain powder;
(4) hot melting and extruding: setting the extrusion temperature of a screw extruder to be 130 ℃, starting the screw when the temperature of the screw extruder reaches 130 ℃ and is stable, adding the mixed powder into the extruder, melting and extruding, and collecting the obtained strip-shaped extrudate;
(5) crushing: adding the extrudate into a pulverizer to be pulverized, and collecting pulverized particles;
(6) mixing: adding the crushed particles and magnesium stearate into a three-dimensional mixer, setting the mixing speed to be 15 rpm, mixing for 5 minutes, and uniformly mixing to obtain a celecoxib composition;
(7) filling: and (3) filling the celecoxib composition (particles) obtained in the step (6) into a No. 2 gelatin capsule to obtain the celecoxib capsule in the embodiment 2.
In example 2, the graft copolymer of polycaprolactone-polyvinyl acetate-polyethylene glycol can also be povidone K30, hypromellose, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol-polyethylene glycol copolymer or polyethylene glycol 6000; or a mixture of any of the above components in any ratio.
Example 3
The present embodiment provides a celecoxib composition, specifically, the celecoxib composition is in the form of capsule, and the formulation composition (in weight percentage) thereof is shown in table 3.
Table 3:
the preparation method of the celecoxib capsule comprises the following steps:
(1) treating raw materials and auxiliary materials: sieving celecoxib with a 40-mesh sieve, and sieving the methacrylic acid/ethyl acrylate copolymer with a 80-mesh sieve;
(2) weighing: weighing according to the prescription;
(3) mixing: adding celecoxib and methacrylic acid/ethyl acrylate copolymer into a three-dimensional mixer, setting the mixing speed to be 15 revolutions per minute, mixing for 10 minutes, then dropwise adding poloxamer 188, and uniformly mixing to obtain powder;
(4) hot melting and extruding: setting the extrusion temperature of a screw extruder to be 150 ℃, starting the screw when the temperature of the screw extruder reaches 150 ℃ and is stable, adding the mixed powder into the extruder, melting and extruding, and collecting the obtained strip-shaped extrudate;
(5) crushing: adding the extrudate into a pulverizer to be pulverized, and collecting pulverized particles;
(6) mixing: adding the crushed particles and magnesium stearate into a three-dimensional mixer, setting the mixing speed to be 15 rpm, mixing for 5 minutes, and uniformly mixing to obtain a celecoxib composition;
(7) filling: and (3) filling the celecoxib composition (particles) obtained in the step (6) into a No. 2 gelatin capsule to obtain the celecoxib capsule in the embodiment 3.
In example 3, the methacrylic acid/ethyl acrylate copolymer can also be povidone K30, hypromellose, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol-polyethylene glycol copolymer or polyethylene glycol 6000; or a mixture of any of the above components in any ratio.
Example 4
The present embodiment provides a celecoxib composition, specifically, the celecoxib composition is in the form of capsule, and the formulation composition (in weight percent) is shown in table 4.
Table 4:
the preparation method of the celecoxib capsule comprises the following steps:
(1) treating raw materials and auxiliary materials: sieving celecoxib with a 40-mesh sieve, and sieving the methacrylic acid/ethyl acrylate copolymer and the crospovidone with a 80-mesh sieve;
(2) weighing: weighing according to the prescription;
(3) mixing: adding celecoxib, methacrylic acid/ethyl acrylate copolymer and crospovidone into a three-dimensional mixer, setting the mixing speed to be 15 revolutions per minute, mixing for 10 minutes, then dropwise adding poloxamer 188, and mixing uniformly to obtain powder;
(4) hot melting and extruding: setting the extrusion temperature of a screw extruder to be 150 ℃, starting the screw when the temperature of the screw extruder reaches 150 ℃ and is stable, adding the mixed powder into the extruder, melting and extruding, and collecting the obtained strip-shaped extrudate;
(5) crushing: adding the extrudate into a pulverizer to be pulverized, and collecting pulverized particles;
(6) mixing: adding the crushed particles and magnesium stearate into a three-dimensional mixer, setting the mixing speed to be 15 rpm, mixing for 5 minutes, and uniformly mixing to obtain a celecoxib composition;
(7) filling: and (3) filling the celecoxib composition (particles) obtained in the step (6) into a No. 2 gelatin capsule to obtain the celecoxib capsule in the embodiment 4.
Comparative example 1
Comparative example 1 provides a celecoxib composition, specifically, the celecoxib composition is in the form of a capsule, and the formulation composition (in weight percent) is shown in table 5.
Table 5:
| celecoxib | 80％ |
| Povidone K30 | 18％ |
| Poloxamer 188 | 2％ |
| Magnesium stearate | 1％ |
The preparation method of the celecoxib capsule comprises the following steps:
(1) treating raw materials and auxiliary materials: sieving celecoxib with a 40-mesh sieve, and sieving povidone K30 with a 80-mesh sieve;
(2) weighing: weighing according to the prescription;
(3) mixing: adding celecoxib and povidone K30 into a three-dimensional mixer, setting the mixing speed to be 15 r/m, mixing for 10 minutes, then dropwise adding poloxamer 188, and mixing uniformly to obtain powder;
(4) hot melting and extruding: setting the extrusion temperature of a screw extruder to be 150 ℃, starting the screw when the temperature of the screw extruder reaches 150 ℃ and is stable, adding the mixed powder into the extruder, melting and extruding, and collecting the obtained strip-shaped extrudate;
(5) crushing: adding the extrudate into a pulverizer for pulverizing, and collecting pulverized particles.
(6) Mixing: adding the crushed particles and magnesium stearate into a three-dimensional mixer, setting the mixing speed to be 15 rpm, mixing for 5 minutes, and uniformly mixing to obtain a celecoxib composition;
(7) filling: and (3) filling the celecoxib composition (particles) obtained in the step (6) into a No. 2 gelatin capsule to obtain the celecoxib capsule in the comparative example 1.
The quality of celecoxib capsules prepared in examples 1-3 and celecoxib from the pfumbo pharmaceutical factory were tested.
The specific test items include:
1. determining the content of celecoxib:
(1) solution preparation
Mobile phase: weighing 2.7g of monopotassium phosphate, adding water to dissolve and dilute the monopotassium phosphate to 1000ml, adjusting the pH to 3.0 +/-0.05 by using phosphoric acid, carrying out suction filtration, discarding about 50ml of primary filtrate, weighing 600ml of subsequent filtrate, adding 300ml of methanol and 100ml of acetonitrile, and uniformly mixing to obtain the potassium dihydrogen phosphate.
Diluting the solution: methanol-water (75: 25).
(2) Sample preparation
Control solution: precisely weighing about 25mg of celecoxib reference substance, placing into a 50mL measuring flask, adding about 40mL of diluent solution, performing ultrasonic treatment for 5min, cooling, dissolving with diluent, diluting to scale, and shaking. Preparing 2 parts of reference solution 1 and reference solution 2 (containing celecoxib about 0.5mg/mL)
System applicability solution: weighing about 3mg of each of the reference substance of the celecoxib impurity A and the reference substance of the celecoxib impurity B, placing the reference substances and the reference substances into a same 50ml measuring flask, dissolving and diluting the reference substances to a scale by using a diluent, and shaking up; precisely measuring 1ml, adding into a 25ml measuring flask, diluting with reference solution to scale, and shaking; and (5) obtaining the product. (containing about 2.4. mu.g/ml of impurity A, about 2.4. mu.g/ml of impurity B, and about 0.5mg/ml of celecoxib)
Test solution: taking 20 granules of the product, pouring out the contents, calculating the average filling amount, uniformly mixing, taking about 67.5mg (equivalent to 50mg of celecoxib) of the contents, precisely weighing, placing in a 100mL measuring flask, adding about 80mL of a diluting solution, carrying out ultrasonic treatment for 15min, cooling to room temperature, diluting to a scale with the diluting solution, shaking uniformly, filtering, discarding 2mL of primary filtrate, and taking a proper amount of filtrate to obtain the celecoxib-containing oral liquid. Preparing 2 parts of sample solution-1 and sample solution-2 (containing celecoxib about 0.5mg/mL)
Blank solution: taking a proper amount of the diluent to obtain the product.
(3) Chromatographic conditions
The instrument comprises the following steps: agilent 1260 II + VWD (DAD) or other similar instruments with equivalent configuration;
mobile phase: 0.1M potassium dihydrogen phosphate solution (pH adjusted to 3.0. + -. 0.05 with phosphoric acid) -methanol-acetonitrile (60:30: 10);
a chromatographic column: supelcosil LC-DP phenyl column (4.6 mm. times.25 cm, 5 μm) or a comparable performance column;
column temperature: 60 ℃;
detection wavelength: 215 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 25 mul;
operating time: 1.5 times the main peak retention time.
2. Determination of related substances
(1) Solution preparation
Mobile phase: weighing 2.7g of monopotassium phosphate, adding water to dissolve and dilute the monopotassium phosphate to 1000ml, adjusting the pH to 3.0 +/-0.05 by using phosphoric acid, filtering, discarding about 50ml of primary filtrate, weighing 600ml of subsequent filtrate, adding 300ml of methanol and 100ml of acetonitrile, and uniformly mixing to obtain the potassium dihydrogen phosphate.
Diluting liquid: methanol-water (75: 25).
(2) Sample preparation
Control solution: precisely weighing about 25mg of celecoxib reference substance, placing into a 50ml measuring flask, adding about 40ml of diluent, performing ultrasonic treatment for 5min, cooling, diluting with diluent to scale, and shaking up to obtain the final product. 2 parts of reference solution 1 and reference solution 2 are prepared in parallel. (containing celecoxib about 0.5mg/ml)
System applicability solution: weighing about 3mg of each of the reference substance of the celecoxib impurity A and the reference substance of the celecoxib impurity B, placing the reference substances and the reference substances into a same 50ml measuring flask, dissolving and diluting the reference substances to a scale by using a diluent, and shaking up; precisely measuring 1ml, adding into a 25ml measuring flask, diluting with reference solution to scale, and shaking; and (5) obtaining the product. (containing about 2.4. mu.g/ml of impurity A, about 2.4. mu.g/ml of impurity B, and about 0.5mg/ml of celecoxib)
Test solution: taking 20 granules of the product, pouring out contents, calculating the average filling amount, uniformly mixing, taking about 67.5mg (equivalent to 50mg of celecoxib) of the contents, precisely weighing, placing in a 100ml measuring flask, adding about 80ml of diluent, carrying out ultrasonic treatment for 15min, cooling to room temperature, diluting to a scale with the diluent, shaking uniformly, filtering, discarding 2ml of primary filtrate, and taking a proper amount of filtrate to obtain the celecoxib-containing oral liquid. 2 parts of a test solution-1 and a test solution-2 are prepared in parallel. (containing celecoxib about 0.5mg/ml)
Self-control solution: precisely measuring 1ml of the sample solution-1, placing in a 100ml measuring flask, diluting with the diluted solution to scale, and shaking; precisely measuring 1ml of diluted sample solution-1 again, placing in a 10ml measuring flask, diluting to scale with the diluted solution, and shaking; and (5) obtaining the product. (containing celecoxib about 0.5. mu.g/ml)
Blank solution: taking a proper amount of the diluent to obtain the product.
(3) Chromatographic conditions
The instrument comprises the following steps: agilent 1260 II + VWD (DAD) or other similar instruments with equivalent configuration;
mobile phase: 0.1M potassium dihydrogen phosphate solution (pH adjusted to 3.0. + -. 0.05 with phosphoric acid) -methanol-acetonitrile (60:30: 10);
a chromatographic column: supelcosil LC-DP phenyl column (4.6 mm. times.25 cm, 5 μm) or a comparable performance column;
column temperature: 60 ℃;
detection wavelength: 215 nm;
flow rate: 1.5 ml/min;
sample introduction amount: 25 mul;
operating time: 2 times main peak retention time
3. Dissolution Curve detection
(1) The dissolution conditions are shown in table 6;
table 6:
| dissolution media | 1.0% SDS-aqueous Medium |
| Dissolution volume | 1000ml |
| Device for measuring the position of a moving object | II (paddle method) + settling basket |
| Rotational speed | 50rpm |
| Temperature of the medium | 37.0℃±0.5℃ |
| Sample volume | 10ml |
| Whether to supplement liquid or not | Fluid infusion |
| Sampling time point | 7min、12min、20min、45min |
(2) Solution preparation
Mobile phase: measuring 1.0ml of phosphoric acid, adding water to dilute the phosphoric acid to 1000ml, and adjusting the pH value to 6.0 +/-0.05 by using triethylamine; and weighing 300ml and 700ml of methanol, and mixing uniformly to obtain the methanol-methanol composite material.
Dissolution medium: weighing 10.00g of sodium dodecyl sulfate, adding 1000ml of degassed purified water, stirring for dissolving, and uniformly mixing to obtain the sodium dodecyl sulfate. (or prepared in equal proportion)
(3) Sample preparation
Control solution: taking about 20mg of celecoxib reference substance, precisely weighing, placing into a 100mL measuring flask, adding 10mL of methanol, shaking to dissolve, diluting with dissolution medium to scale, and shaking up to obtain the celecoxib reference substance. Two parts are prepared in parallel, namely a reference substance solution 1 and a reference substance solution 2. (containing celecoxib about 0.2mg/ml)
Test solution: preparing the instrument according to the standard operation rules of the dissolution instrument, and setting the parameters of the dissolution instrument. Respectively measuring 1000ml of dissolution medium, placing the dissolution medium in each dissolution cup, taking 12 samples of the samples after the temperature of the dissolution medium in each dissolution cup is constant at 37 +/-0.5 ℃, placing the samples into a dry sedimentation basket, respectively putting the samples into 12 dissolution cups until the specified sampling time point, filtering and sucking 10ml of dissolution liquid by using a sampler provided with a polytetrafluoroethylene microporous filter membrane (10 mu m), and taking liquid supplement (timely supplementing the medium until the total volume is unchanged) or liquid supplement operation as required. The filtrate is the solution of the sample to be tested at each sampling time.
Program control solution: taking a proper amount of the reference substance solution 1 to obtain the composition.
Blank solution: taking a proper amount of dissolution medium to obtain the product.
(4) Chromatographic conditions
The instrument comprises the following steps: agilent 1260 II + VWD (DAD) or other similar instruments with equivalent configuration;
mobile phase: 0.1% phosphate buffer (pH adjusted to 6.0. + -. 0.05 with triethylamine) -methanol (30: 70);
a chromatographic column: ultimate AQ-C18, 4.6mm x 15cm, 3 μm or equivalent performance column;
flow rate: 1.5 ml/min;
column temperature: 30 ℃;
sample introduction amount: 10 mu l of the mixture;
detection wavelength: 250 nm;
operating time: the peak-off time of the main peak is 1.5 times.
The test results are shown in tables 7 and 8.
Table 7: examples 1-3 and content of celecoxib
| Batches of | Content (%) | Related substance (%) |
| Example 1 | 99.5 | 0.05 |
| Example 2 | 99.6 | 0.06 |
| Example 3 | 99.6 | 0.05 |
| Xile Bao | 99.5 | 0.06 |
Table 8: examples 1-3 and cumulative dissolution of celecoxib
From the test data in tables 7 and 8, the celecoxib capsules prepared in examples 1-3 were comparable in content and levels of related substances to celecoxib, demonstrating that the hot melt extrusion process did not cause celecoxib degradation. Compared with celecoxib, the dissolution curves of examples 1-3 have higher dissolution rate and higher dissolution rate, and prove that the capsule prepared by hot-melt extrusion has higher dissolution rate and can exert the drug effect faster.
Celecoxib capsules of examples 1 and 2 and celecoxib (from the pfeiffer pharmaceutical factory) were placed at 40 ℃ and 75% ± 5% relative humidity for 6 months and tested in accelerated tests, the results of which are shown in table 9.
Table 9: accelerated test investigation results
From the results of accelerated testing in table 9, celecoxib showed reduced dissolution at months 3 and 6, while the dissolution rates of examples 1 and 2 were not significantly changed. The hot melt extrusion technology is proved to be capable of effectively reducing the aging phenomenon of the capsule and ensuring the dissolution rate of the medicine to be unchanged. The content and related substances are not obviously changed, which shows that the physical and chemical stability of the hot-melt extruded product is good.
The invention also further compares the dissolution curve tests of the celecoxib capsules of the example 1 and the comparative example 1; the test method was the same as the test method for the dissolution curve of celecoxib capsules of examples 1-3.
The results are shown in Table 10.
Table 10: cumulative dissolution of example 1 and comparative example 1
Comparing the dissolution results of example 1 and comparative example 1, it was found that when the celecoxib proportion of comparative example 1 is higher (greater than 70%), the dissolution rate is significantly lower than that of example 1. The reason is that the proportion of the hydrophilic filling agent is low, and the celecoxib is difficult to disperse well, so that the speed of wetting the surface of the celecoxib is slow during dissolution, and the final dissolution rate of the celecoxib capsule is slow and the dissolution rate is low.
Tests prove that the celecoxib composition can be prepared into other dosage forms of medicines, such as granules, pills, tablets, suppositories, films or powder, and the celecoxib composition in other dosage forms has the same effect as the celecoxib composition in the embodiment within the range of the mixture ratio disclosed by the invention.
The technical solutions provided by the embodiments of the present invention are described in detail above, and the principles and embodiments of the present invention are explained herein by using specific examples, and the descriptions of the embodiments are only used to help understanding the principles of the embodiments of the present invention; meanwhile, for a person skilled in the art, according to the embodiments of the present invention, there may be variations in the specific implementation manners and application ranges, and in summary, the content of the present description should not be construed as a limitation to the present invention.
Claims (9)
1. A method for preparing a celecoxib composition, comprising the steps of:
(1) weighing: respectively weighing the following components in percentage by mass: 40-70% of celecoxib, 20-50% of a filler, 1-6% of a plasticizer and 0-4% of a lubricant; wherein the filler is selected from at least one of hypromellose, polyvidone K30, crospovidone, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl alcohol-polyethylene glycol copolymer, methacrylic acid/ethyl acrylate copolymer, and polyethylene glycol 6000;
(2) mixing: adding celecoxib and a filler into a mixer, adding a plasticizer, and uniformly mixing to obtain mixed powder;
(3) hot melting and extruding: setting the extrusion temperature of the screw extruder to be 100-;
(4) crushing: adding the extrudate into a pulverizer to be pulverized, and collecting pulverized particles;
(5) mixing: and adding the crushed particles and the lubricant into a mixer, and uniformly mixing to obtain the celecoxib composition.
2. A method of preparing a celecoxib composition according to claim 1, wherein the plasticizer is at least one of polyethylene glycol 400, triethyl citrate, hydrogenated castor oil polyoxyethylene ether, ethyl oleate, poloxamer 188.
3. A process for preparing a celecoxib composition according to claim 1 wherein the lubricant is magnesium stearate.
4. The method of claim 1, wherein in step (2), the mixing speed of the mixer is 10-20 rpm and the mixing time is 10-15 minutes.
5. The method of preparing a celecoxib composition according to claim 1, wherein in step (3), the screw extruder is a twin screw extruder.
6. The process for preparing a celecoxib composition according to claim 1 wherein in step (4), the mixing speed of the mixer is from 10 to 20 rpm and the mixing time is from 5 to 10 minutes.
7. A celecoxib composition prepared by the preparation method of any one of claims 1-6.
8. Celecoxib composition according to claim 7 for use in the treatment of osteoarthritis, rheumatoid arthritis and acute pain.
9. The use according to claim 8, wherein the celecoxib composition is in the form of a capsule, granule, pill, tablet, suppository, film or powder.
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| US20160193151A1 (en) * | 2015-01-06 | 2016-07-07 | Maria Del Pilar Noriega Escobar | Dosage form incorporating an amorphous drug solid solution |
| CN104721169A (en) * | 2015-03-28 | 2015-06-24 | 河北仁合益康药业有限公司 | Composition for celecoxib capsule |
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