CN116942630B - Celecoxib capsule and preparation method thereof - Google Patents
Celecoxib capsule and preparation method thereof Download PDFInfo
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- CN116942630B CN116942630B CN202311205698.6A CN202311205698A CN116942630B CN 116942630 B CN116942630 B CN 116942630B CN 202311205698 A CN202311205698 A CN 202311205698A CN 116942630 B CN116942630 B CN 116942630B
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- celecoxib
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- capsule
- diluent
- lubricant
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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 86
- 229960000590 celecoxib Drugs 0.000 title claims abstract description 86
- 239000002775 capsule Substances 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title abstract description 30
- 229960004494 calcium gluconate Drugs 0.000 claims abstract description 20
- 239000004227 calcium gluconate Substances 0.000 claims abstract description 20
- 235000013927 calcium gluconate Nutrition 0.000 claims abstract description 20
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 claims abstract description 20
- 239000013078 crystal Substances 0.000 claims abstract description 15
- 239000003112 inhibitor Substances 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims description 21
- 239000011812 mixed powder Substances 0.000 claims description 17
- 239000002245 particle Substances 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 239000000853 adhesive Substances 0.000 claims description 8
- 230000001070 adhesive effect Effects 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 239000008213 purified water Substances 0.000 claims description 8
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 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
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 229940069328 povidone Drugs 0.000 claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
- 235000013539 calcium stearate Nutrition 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims 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 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 229940083542 sodium Drugs 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 239000011230 binding agent Substances 0.000 claims 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims 1
- 235000019700 dicalcium phosphate Nutrition 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 20
- 238000005054 agglomeration Methods 0.000 abstract description 11
- 230000002776 aggregation Effects 0.000 abstract description 11
- 230000007547 defect Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229920001503 Glucan Polymers 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000032023 Signs and Symptoms Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 208000005298 acute pain Diseases 0.000 description 2
- 229960005069 calcium Drugs 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- -1 4-toluene-yl Chemical group 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001744 Sodium fumarate Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- MSJMDZAOKORVFC-SEPHDYHBSA-L disodium fumarate Chemical compound [Na+].[Na+].[O-]C(=O)\C=C\C([O-])=O MSJMDZAOKORVFC-SEPHDYHBSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229940005573 sodium fumarate Drugs 0.000 description 1
- 235000019294 sodium fumarate Nutrition 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K9/4858—Organic 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
- 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]
Abstract
The invention provides a celecoxib capsule and a preparation method thereof, and belongs to the technical field of medicinal preparations. The celecoxib capsule can overcome the defects of low solubility, low bulk density and easy formation of long viscous needle-like crystals and agglomeration by matching calcium gluconate with a crystal inhibitor, thereby solving the technical problems of slow dissolution, poor content uniformity and difficult preparation process of the celecoxib capsule.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to a celecoxib capsule and a preparation method of the capsule.
Background
Celecoxib (Celecoxib) is a nonsteroidal anti-inflammatory drug (Nonsteroidal Antiinflammatory Drugs, NSAIDs) and acts by inhibiting prostaglandin production through inhibition of COX-2. It is observed in animal models that it has anti-inflammatory, analgesic and antipyretic effects, mainly for: 1. for alleviating Osteoarthritis (OA) symptoms and signs; 2. for alleviating the symptoms and signs of adult Rheumatoid Arthritis (RA); 3. for the treatment of Acute Pain (AP) in adults; 4. can be used for relieving symptoms and signs of ankylosing spondylitis. Celecoxib has no inhibitory effect on the isozyme-cyclooxygenase-1 (COX-1) in the human therapeutic state. Celecoxib slows the occurrence and progression of tumors in animal colon tumor models.
Celecoxib chemical name is 4- [5- (4-toluene-yl) -3- (trifluoromethyl) -1 hydrogen-1-pyrazol-1-yl ] benzenesulfonamide, and the structural formula is as follows:
。
celecoxib is a white to off-white crystalline powder having unique physical and chemical properties, particularly its low solubility and related to its crystalline structure including cohesiveness and low bulk density. Celecoxib is almost insoluble in water, and the solubility in water is about 5 mug/ml (5-40 ℃), so that celecoxib is a poorly soluble drug, and belongs to BCS II, namely a low-solubility high-permeability drug, and dissolution of the celecoxib is often the speed-limiting process of absorption. Meanwhile, celecoxib is prone to forming long needle-like crystals with viscosity, which are prone to melting into a monolithic mass, and which are prone to agglomerating into a mass when mixed with other excipients, resulting in poor uniformity. The low bulk density of celecoxib also presents difficulties in the preparation process of the formulation.
Patent application number 201110243045.8 discloses a celecoxib composition, a preparation method and application, and dissolution of celecoxib is improved by micronizing the celecoxib. Micronization of drugs is a common technical measure for improving dissolution, but for celecoxib, micronized celecoxib has poor fluidity, is easy to generate static electricity, is easy to generate the phenomenon of agglomeration and agglomeration in the preparation process, does not meet the quality standard, and is not easy to carry out large-scale production.
Patent application number 201310382316.7 discloses an inclusion compound containing celecoxib and a preparation method thereof, wherein inclusion materials and celecoxib are respectively dissolved in water and an organic solvent for inclusion, and the celecoxib inclusion compound is obtained by adopting a decompression drying or freeze drying mode. In the inclusion process, the raw materials are not crushed, but are limited by inclusion materials, a large amount of inclusion materials are required to be added, and the raw materials are difficult to be filled into capsules.
Patent application number 201310551574.3 discloses a celecoxib solid composition with increased dissolution, a preparation method and application thereof, which consists of celecoxib, a dispersion promoter and an alkaline compound, wherein the alkaline compound is one or more of sodium carbonate, sodium acetate, sodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate or sodium hydroxide, and celecoxib, the dispersion promoter and the alkaline compound are ground into micro powder under the protection of nitrogen. In the scheme, the celecoxib is ground under alkaline conditions, so that the stability of celecoxib is inevitably influenced, and therefore, nitrogen is required to be filled, the temperature is controlled to be 15-30 ℃, and inconvenience is brought to production.
Therefore, the invention focuses on selecting proper excipient, overcoming the property defects of low solubility, low bulk density, easy crystallization and agglomeration of celecoxib, and ensuring the stable quality of celecoxib capsule.
Disclosure of Invention
The invention aims to solve the technical problems of low solubility, low bulk density and easy formation of viscous long needle-like crystals and agglomeration of celecoxib, thereby solving the technical problems of slow dissolution, poor content uniformity and difficult preparation process of celecoxib capsules. The celecoxib capsule prepared by the invention has good dissolution rate, ensures that celecoxib is not easy to be transformed into crystal, obviously improves the fluidity of medicine-containing materials, is not easy to agglomerate into blocks, and has good content uniformity. Meanwhile, the preparation process of the capsule is simple, the process in the preparation process is smooth, and the quality of the obtained product meets the standard requirement, so that the capsule is suitable for industrial mass production.
The invention provides a celecoxib capsule, which comprises celecoxib, calcium gluconate, a diluent, a crystal inhibitor, an adhesive and a lubricant.
Through experimental research, the inventor discovers that the calcium gluconate is added into the celecoxib capsule, so that the defects of low bulk density, easy agglomeration and low solubility of celecoxib can be overcome, and the process smoothness of the celecoxib capsule in the preparation process is ensured. Furthermore, the material fluidity of celecoxib can be obviously improved, and in the preparation process of celecoxib capsules, when celecoxib is mixed with other auxiliary materials, the celecoxib is easy to uniformly mix and difficult to agglomerate, so that the celecoxib has good content uniformity. Meanwhile, the dissolution effect of the celecoxib capsule can be improved by adding the calcium gluconate, so that the celecoxib capsule has good dissolution and better curative effect.
In the celecoxib capsule, the crystal inhibitor is glucan. Celecoxib is easy to form viscous long needle-shaped crystals, cellulose substances such as povidone, hydroxypropyl methyl cellulose and the like are added to inhibit celecoxib crystallization in the prior art, but the substances generally play a role of an adhesive in a preparation, the crystallization inhibition effect is not obvious, and the problems of low solubility, low bulk density and easy agglomeration of celecoxib cannot be solved. Through a large number of experiments, the selected glucan not only has a good crystal inhibiting effect, but also can well solve the problems of low solubility, easy agglomeration and low bulk density of celecoxib through being matched with calcium gluconate.
In the celecoxib capsule, the diluent comprises one or more of sorbitol, calcium hydrophosphate, microcrystalline cellulose, lactose, mannitol and pregelatinized starch.
In the celecoxib capsule, the lubricant comprises one or more of magnesium stearate, stearic acid, calcium stearate, talcum powder and hard sodium fumarate.
In the celecoxib capsule, the adhesive comprises one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone and sodium carboxymethyl cellulose.
In the celecoxib capsule, the dosage of each component is as follows in parts by mass: 100-200 parts of celecoxib, 5-18 parts of calcium gluconate, 45-100 parts of diluent, 1-5 parts of crystallization inhibitor, 3-10 parts of adhesive and 1-4 parts of lubricant.
In the celecoxib capsule, the capsule further contains a disintegrating agent, wherein the disintegrating agent comprises one or more of low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch and croscarmellose sodium. The above-mentioned amounts of disintegrants can be obtained according to the level of general knowledge of the person skilled in the art.
The invention also provides a preparation method of the celecoxib capsule, which comprises the following steps:
a. mixing celecoxib, calcium gluconate, a diluent, a crystal inhibitor and an adhesive uniformly to prepare mixed powder;
b. adding purified water into the mixed powder prepared in the step a, and granulating by a wet method to obtain medicine particles;
c. and d, uniformly mixing the drug particles prepared in the step b with a lubricant, and encapsulating.
In the preparation method of the celecoxib capsule, the step a further comprises the step of adding a disintegrating agent.
According to the celecoxib capsule provided by the invention, calcium gluconate is added, so that the physicochemical properties of low bulk density, easy agglomeration and low solubility of celecoxib can be overcome, the prepared capsule has good dissolution effect and content uniformity, and the smoothness of a preparation process is ensured. The calcium gluconate and the glucan serving as the crystal inhibitor are matched for use, so that the celecoxib can be better inhibited from forming viscous long needle-shaped crystals, and the problems of low solubility, easy agglomeration, and low bulk density of the celecoxib are solved. The invention can be prepared by adopting the conventional preparation process such as dry granulation, wet granulation and the like, and is more suitable for industrial production.
Detailed Description
Example 1
The preparation method comprises the following steps:
a. uniformly mixing celecoxib, calcium gluconate, pregelatinized starch, mannitol, glucan and hydroxypropyl cellulose to prepare mixed powder;
b. adding purified water into the mixed powder prepared in the step a, and granulating by a wet method to obtain medicine particles;
c. and d, uniformly mixing the drug particles prepared in the step b with magnesium stearate, and encapsulating.
Example 2
The preparation method comprises the following steps:
a. uniformly mixing celecoxib, calcium gluconate, microcrystalline cellulose, lactose, glucan and hydroxypropyl methylcellulose to prepare mixed powder;
b. adding purified water into the mixed powder prepared in the step a, and granulating by a wet method to obtain medicine particles;
c. and d, uniformly mixing the drug particles prepared in the step b with talcum powder, and filling into capsules.
Example 3
The preparation method comprises the following steps:
a. uniformly mixing celecoxib, calcium gluconate, calcium hydrophosphate, lactose, glucan and povidone to prepare mixed powder;
b. adding purified water into the mixed powder prepared in the step a, and granulating by a wet method to obtain medicine particles;
c. and d, uniformly mixing the drug particles prepared in the step b with sodium stearyl fumarate, and encapsulating.
Example 4
The preparation method comprises the following steps:
a. uniformly mixing celecoxib, calcium gluconate, lactose, glucan and sodium carboxymethyl cellulose to prepare mixed powder;
b. adding purified water into the mixed powder prepared in the step a, and granulating by a wet method to obtain medicine particles;
c. and d, uniformly mixing the drug particles prepared in the step b with calcium stearate and sodium stearyl fumarate, and encapsulating.
Example 5
The preparation method comprises the following steps:
a. uniformly mixing celecoxib, calcium gluconate, pregelatinized starch, sorbitol, glucan, povidone and hydroxypropyl methylcellulose to prepare mixed powder;
b. adding purified water into the mixed powder prepared in the step a, and granulating by a wet method to obtain medicine particles;
c. and d, uniformly mixing the drug particles prepared in the step b with magnesium stearate, and encapsulating.
Example 6
The preparation method comprises the following steps:
a. uniformly mixing celecoxib, calcium gluconate, mannitol, glucan, hydroxypropyl cellulose and crospovidone to obtain mixed powder;
b. adding purified water into the mixed powder prepared in the step a, and granulating by a wet method to obtain medicine particles;
c. and d, uniformly mixing the medicine particles prepared in the step b with stearic acid, and encapsulating.
Comparative example
The preparation method is the same as in example 1.
Repose angle test
The repose angles of the powders prepared in examples 1 to 6 and comparative examples 1 to 5 were measured by a powder particle flowability analyzer (model FT-104 BA) and the results were as follows:
from the above data, examples 1 to 6 have a small angle of repose, and are excellent in powder flowability, and suitable for industrial mass production. In comparative examples 1 to 5, calcium gluconate and dextran were not added at the same time, and the mixed powder had a large repose angle and poor powder flowability, and was not suitable for industrial production.
Dissolution measurement
Samples prepared in examples 1 to 6 and comparative examples 1 to 5 were taken, and a dissolution rate measurement method (four parts 0931 dissolution rate and dissolution rate measurement method (second method) of the chinese pharmacopoeia 2020 edition) was performed by using a 0.04mol/L trisodium phosphate buffer (pH adjusted to 12.0 with phosphoric acid or sodium hydroxide solution) containing 1% sodium dodecyl sulfate as a dissolution medium at a rotation speed of 50 revolutions per minute, and dissolution solutions were taken at 5, 10, 15, 20, 30, 45 minutes, and the experimental results were as follows:
from the above data, it is clear that celecoxib capsules prepared in examples 1 to 6 of the present invention have an initial dissolution rate of 37% or more in 5 minutes, an integrated dissolution rate of 75% or more in 15 minutes, and complete dissolution in 45 minutes. In comparative examples 1 to 5, calcium gluconate and dextran were not added at the same time, but the dissolution data of the obtained celecoxib capsule was less than 32% at the beginning of 5 minutes, and there was a problem of slow dissolution.
Content uniformity determination
The preparation of examples 1 to 6 and comparative examples 1 to 5 was observed for the agglomeration and the celecoxib capsules prepared in examples 1 to 6 and comparative examples 1 to 5 were sampled at 6 points to determine the average content (%) and the RSD (%) of the 6 points was calculated and the content was determined by HPLC, as follows:
from the data, the celecoxib capsules of examples 1-6 have good content uniformity, and the medication safety of patients is ensured.
Claims (7)
1. A celecoxib capsule, which is characterized by comprising celecoxib, calcium gluconate, a diluent, a crystal inhibitor, a binder and a lubricant; the crystal inhibitor is dextran, the adhesive is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone and sodium carboxymethylcellulose, and the dosages of the components are as follows in parts by mass: 100-200 parts of celecoxib, 5-18 parts of calcium gluconate, 45-100 parts of diluent, 1-5 parts of crystallization inhibitor, 3-10 parts of adhesive and 1-4 parts of lubricant.
2. Celecoxib capsule according to claim 1, wherein the diluent is one or more of sorbitol, calcium hydrogen phosphate, microcrystalline cellulose, lactose, mannitol and pregelatinized starch.
3. The celecoxib capsule according to claim 1, wherein the lubricant is one or more of magnesium stearate, stearic acid, calcium stearate, talcum powder and sodium hard fumarate.
4. Celecoxib capsule according to claim 1, characterized in that the capsule further comprises a disintegrant.
5. The celecoxib capsule according to claim 4, wherein the disintegrating agent is one or more of low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch and croscarmellose sodium.
6. A method of preparing the celecoxib capsule of claim 1, comprising the steps of:
a. mixing celecoxib, calcium gluconate, a diluent, a crystal inhibitor and an adhesive uniformly to prepare mixed powder;
b. adding purified water into the mixed powder prepared in the step a, and granulating by a wet method to obtain medicine particles;
c. and d, uniformly mixing the drug particles prepared in the step b with a lubricant, and encapsulating.
7. The method of preparing celecoxib capsule according to claim 6, wherein step a further comprises the step of adding a disintegrant.
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| CN111803464A (en) * | 2020-06-30 | 2020-10-23 | 北京福元医药股份有限公司 | Celecoxib capsule preparation |
| JP2021075686A (en) * | 2020-07-29 | 2021-05-20 | 旭化成株式会社 | Cellulose composition, tablet, and orally disintegrating tablet |
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| CN111803464A (en) * | 2020-06-30 | 2020-10-23 | 北京福元医药股份有限公司 | Celecoxib capsule preparation |
| JP2021075686A (en) * | 2020-07-29 | 2021-05-20 | 旭化成株式会社 | Cellulose composition, tablet, and orally disintegrating tablet |
Non-Patent Citations (2)
| Title |
|---|
| Evaluation of drug-excipient interaction in the formulation of celecoxib tablets;Sibel Bozdağ-Pehlivan 等;《Acta Pol Pharm.》;第68卷(第3期);第423-433页 * |
| 难溶性药物塞来昔布胶囊的制备及质量研究;张小幸;《中国优秀硕士学位论文全文数据库医药卫生科技辑》;第E079-64页 * |
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