CN113413371B - Celecoxib capsule and preparation method thereof - Google Patents
Celecoxib capsule and preparation method thereof Download PDFInfo
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- CN113413371B CN113413371B CN202110757801.2A CN202110757801A CN113413371B CN 113413371 B CN113413371 B CN 113413371B CN 202110757801 A CN202110757801 A CN 202110757801A CN 113413371 B CN113413371 B CN 113413371B
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- celecoxib
- maleic anhydride
- hydroxyethyl starch
- parts
- wetting agent
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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 98
- 229960000590 celecoxib Drugs 0.000 title claims abstract description 98
- 239000002775 capsule Substances 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000010521 absorption reaction Methods 0.000 claims abstract description 52
- 239000000080 wetting agent Substances 0.000 claims abstract description 48
- 239000003623 enhancer Substances 0.000 claims abstract description 46
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 25
- 229930195725 Mannitol Natural products 0.000 claims abstract description 25
- 239000000594 mannitol Substances 0.000 claims abstract description 25
- 235000010355 mannitol Nutrition 0.000 claims abstract description 25
- 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 abstract description 22
- 239000000600 sorbitol Substances 0.000 claims abstract description 22
- 239000006187 pill Substances 0.000 claims abstract description 19
- RWZXIUKKMTXBQY-UHFFFAOYSA-M sodium dodecanoylazanide Chemical compound C(CCCCCCCCCCC)(=O)[NH-].[Na+] RWZXIUKKMTXBQY-UHFFFAOYSA-M 0.000 claims abstract description 18
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 15
- GWTCIAGIKURVBJ-UHFFFAOYSA-L dipotassium;dodecyl phosphate Chemical compound [K+].[K+].CCCCCCCCCCCCOP([O-])([O-])=O GWTCIAGIKURVBJ-UHFFFAOYSA-L 0.000 claims abstract description 14
- 229940033623 potassium lauryl phosphate Drugs 0.000 claims abstract description 14
- 229920001612 Hydroxyethyl starch Polymers 0.000 claims description 53
- 229940050526 hydroxyethylstarch Drugs 0.000 claims description 53
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical group O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 53
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 34
- 230000001070 adhesive effect Effects 0.000 claims description 27
- 239000000853 adhesive Substances 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 24
- 239000007864 aqueous solution Substances 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 18
- 239000008188 pellet Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000002202 Polyethylene glycol Substances 0.000 claims description 17
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 17
- 229920001223 polyethylene glycol Polymers 0.000 claims description 17
- 238000011049 filling Methods 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- 239000007921 spray Substances 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 10
- 230000002572 peristaltic effect Effects 0.000 claims description 10
- 238000005507 spraying Methods 0.000 claims description 10
- 238000000889 atomisation Methods 0.000 claims description 9
- 239000008213 purified water Substances 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 7
- 229940124532 absorption promoter Drugs 0.000 abstract description 3
- 239000004094 surface-active agent Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 13
- 238000002156 mixing Methods 0.000 description 10
- 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 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000000843 powder Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000007664 blowing Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000003945 anionic surfactant Substances 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940042880 natural phospholipid Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- 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
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- 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]
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
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Abstract
The invention discloses a celecoxib capsule and a preparation method thereof, wherein the celecoxib capsule comprises the following materials in parts by weight: 25-80 parts of celecoxib, 19-72 parts of blank pill cores, 0.5-2 parts of wetting agents and 0.2-1 part of absorption promoters; the wetting agent is one or two of sodium dodecyl sulfate, sodium lauroyl amide or potassium lauryl phosphate; the absorption enhancer is mannitol or/and sorbitol; the celecoxib capsule provided by the invention takes the novel surfactant as the wetting agent and takes mannitol or/and sorbitol as the absorption enhancer, so that the celecoxib has the advantages of good dissolution effect, easiness in absorption, high bioavailability and good clinical utilization value.
Description
Technical Field
The invention relates to the technical field of pharmaceutical engineering, in particular to a celecoxib capsule and a preparation method thereof.
Background
Celecoxib is the first specific cyclooxygenase-2 (COX-2) inhibitor developed by Searle, usa for the treatment of osteoarthritis and rheumatoid arthritis, and is currently the most widely prescribed non-steroidal anti-inflammatory analgesic worldwide.
The celecoxib is almost insoluble in water due to the crystal structure, belongs to an insoluble drug, and has extremely poor physical and chemical properties in preparation performance of the preparation; firstly, it is almost insoluble in water, has a solubility of only 0.007mg/ml in water at 25 ℃, is slowly dissolved in a common dissolution medium, and if an uncrushed drug is directly filled into a capsule, the uncrushed celecoxib is not easily dissolved and dispersed, and thus cannot be rapidly absorbed in the gastrointestinal tract; secondly, the weight is light, the bulk density is low, the powder is easy to agglomerate and is not easy to be uniformly mixed with auxiliary materials, so that the uniformity of the medicine content of the preparation is unqualified, and the absorption is influenced.
The celecoxib capsules sold in the market in China at present mostly adopt the traditional wet granulation, the prepared granules have poor liquidity and are difficult to fill, the phenomenon of low content uniformity caused by uneven mixing of celecoxib and auxiliary materials is easy to generate, and the dissolution rate is not ideal. Because the dissolution of the medicine is a precondition for playing a therapeutic role, how to promote the celecoxib to be rapidly and completely dissolved and improve the bioavailability is a problem which needs to be solved by technical personnel in the field.
On the other hand, the pellet capsule does not need a glidant, has small weight difference compared with a method of filling powder into the capsule, has good fluidity, releases stably and dissolves better, has large specific surface area and high bioavailability, and is a more scientific and reasonable method compared with wet granulation.
Disclosure of Invention
In order to solve the above problems, the present invention provides a celecoxib capsule and a preparation method thereof.
In order to achieve the purpose, the invention is realized by the following technical scheme:
the celecoxib capsule comprises the following raw materials in parts by weight: 25-80 parts of celecoxib, 19-72 parts of blank pill cores, 0.5-2 parts of wetting agents and 0.2-1 part of absorption promoters;
the wetting agent is one or two of sodium dodecyl sulfate, sodium lauroyl amide or potassium lauryl phosphate;
the absorption enhancer is mannitol or/and sorbitol.
Preferably, the adhesive also comprises 0.1-0.5 part of adhesive;
the adhesive is maleic anhydride crosslinked hydroxyethyl starch;
the maleic anhydride crosslinked hydroxyethyl starch is prepared according to the following steps:
adding hydroxyethyl starch, maleic anhydride and polyethylene glycol into a reaction bottle, adding toluene and sulfamic acid, starting stirring, heating the reaction solution to 80-90 ℃, stirring for reaction for 2-6 hours, filtering, washing a filter cake with acetone, and drying in vacuum to obtain maleic anhydride crosslinked hydroxyethyl starch;
wherein the mass ratio of hydroxyethyl starch, maleic anhydride, polyethylene glycol, toluene, sulfamic acid and acetone is 100: 3-4: 8-20: 200-300 parts by weight: 0.5-2: 50-70.
Preferably, the blank pellet core is a microcrystalline cellulose pellet core.
Preferably, the particle size D90 of the celecoxib is less than 100 mu m.
Preferably, the particle size D90 of the celecoxib is less than 20 microns.
The invention also comprises a preparation method of the celecoxib capsule, which comprises the following steps:
the absorption enhancer is mannitol or/and sorbitol;
starting a peristaltic pump, controlling the pump speed at 14-18 r/min, controlling the diameter of a spray gun nozzle at 0.8mm and the atomization pressure at 0.04-0.06 MPa, spraying the aqueous solution into a centrifugal fluidized bed, granulating, drying and filling to obtain celecoxib capsules;
the wetting agent is one or two of sodium dodecyl sulfate, sodium lauroyl amide and potassium lauryl phosphate.
The invention also comprises a preparation method of the celecoxib capsule, which comprises the following steps:
adding 25-80 parts by weight of celecoxib, 19-72 parts by weight of blank pellet core and 0.2-1 part by weight of absorption enhancer into a centrifugal fluidized bed, starting a blower, setting air flow of 2.0-2.5 m3/min, setting the air inlet temperature of 45-55 ℃ and the rotating speed of a turntable of 180-220 r/min;
the absorption enhancer is mannitol or/and sorbitol;
adding 0.5-2 parts of wetting agent into purified water to prepare an aqueous solution with the mass concentration of 12-18%; adding 0.1-0.5 part of adhesive, and uniformly stirring for later use;
starting a peristaltic pump, controlling the pump speed at 14-18 r/min, controlling the diameter of a spray gun nozzle at 0.8mm and the atomization pressure at 0.04-0.06 MPa, spraying the aqueous solution into a centrifugal fluidized bed, granulating, drying and filling to obtain celecoxib capsules;
the wetting agent is one or two of sodium dodecyl sulfate, sodium lauroyl amide and potassium lauryl phosphate;
the adhesive is maleic anhydride crosslinked hydroxyethyl starch;
the maleic anhydride crosslinked hydroxyethyl starch is prepared according to the following steps:
adding hydroxyethyl starch, maleic anhydride and polyethylene glycol into a reaction bottle, adding toluene and sulfamic acid, starting stirring, heating the reaction solution to 80-90 ℃, stirring for reaction for 2-6 hours, filtering, washing a filter cake with acetone, and drying in vacuum to obtain maleic anhydride crosslinked hydroxyethyl starch;
wherein the mass ratio of hydroxyethyl starch, maleic anhydride, polyethylene glycol, toluene, sulfamic acid and acetone is 100: 3-4: 8-20: 200-300: 0.5-2: 50-70.
Compared with the prior art, the invention has the following advantages:
the celecoxib capsule is obtained by attaching celecoxib, a wetting agent (sodium dodecyl sulfate, sodium lauroyl amide, potassium lauryl phosphate) and an absorption enhancer (mannitol and sorbitol) on a blank pill core, and has the advantages of good dissolution effect, easy absorption and high bioavailability; the celecoxib capsule does not need glidants, has small weight difference compared with a method of filling powder into the capsule, has stable drug release of the pellet and better dissolution, and has large specific surface area and high bioavailability because the drug is adhered to the surface of the pellet.
According to the preparation method of the celecoxib capsule, the blank pill core is directly sprayed by the centrifugal fluidized bed, so that the problem that celecoxib raw material medicines are insoluble in water and easy to agglomerate is solved, the problems that the celecoxib raw material medicines are poor in flowability and difficult to fill after being prepared into particles are solved, water is used for replacing an organic solvent, the safety is high, the obtained pellet capsule is stable in medicine release and good in dissolution, the celecoxib is adhered to the surface of the pellet, the specific surface area is large, the bioavailability is high, and the clinical curative effect is good.
Detailed Description
The invention aims to provide a celecoxib capsule and a preparation method thereof, and the celecoxib capsule is prepared by the following technical scheme:
the celecoxib capsule comprises the following materials in parts by weight: 25-80 parts of celecoxib, 19-72 parts of blank pill cores, 0.5-2 parts of wetting agents and 0.2-1 part of absorption promoters;
the wetting agent is one or two of sodium dodecyl sulfate, sodium lauroyl amide or potassium lauryl phosphate; the wetting agent adopted by the invention can promote the dissolution of the medicine.
Sodium lauroyl amide is white to light yellow liquid, is easily soluble in water, is a novel amino acid anionic surfactant, has good wetting and emulsifying effects, can be added as wetting agent to promote absorption of medicine in human body, and improves bioavailability.
The potassium lauryl phosphate is colorless to light yellow transparent viscous liquid, is easily soluble in water, is a novel anionic surfactant, has mild performance, is non-toxic and low-irritation, is similar to natural phospholipid, is easily compatible with alcohol ether sulfate, lauryl sulfate and other various types of surfactants, has excellent wetting and emulsifying effects, and can be independently used.
The absorption enhancer is mannitol or/and sorbitol, and the absorption enhancer adopted by the invention can change osmotic pressure, promote absorption and improve bioavailability.
Mannitol is usually used as a filling agent, however, in the technology, mannitol is added into a prescription as an absorption enhancer, the mannitol has a good dissolution assisting effect and a good dissolution effect, and mannitol can change the osmotic pressure of a human body to play a role in promoting absorption, so that the bioavailability is improved. Meanwhile, sorbitol is used for comparison experiments, and the dissolution effect is similar.
Preferably, the adhesive also comprises 0.1-0.5 part of adhesive;
the adhesive is maleic anhydride crosslinked hydroxyethyl starch;
the maleic anhydride crosslinked hydroxyethyl starch is prepared according to the following steps:
adding hydroxyethyl starch, maleic anhydride and polyethylene glycol into a reaction bottle, adding toluene and sulfamic acid, starting stirring, heating the reaction solution to 80-90 ℃, stirring for reacting for 2-6 hours, filtering, washing a filter cake with acetone, and drying in vacuum to obtain maleic anhydride crosslinked hydroxyethyl starch;
wherein the mass ratio of hydroxyethyl starch, maleic anhydride, polyethylene glycol, toluene, sulfamic acid and acetone is 100: 3-4: 8-20: 200-300 parts by weight: 0.5-2: 50-70.
The preferable adhesive component can promote the adhesion between the celecoxib and each auxiliary material, improve the dissolution speed of the celecoxib capsule and improve the bioavailability of the celecoxib capsule.
The preferred maleic anhydride cross-linked hydroxyethyl starch binder of the present invention,
preferably, the blank pellet core is a microcrystalline cellulose pellet core.
Preferably, the particle size D90 of the celecoxib is less than 100 μm.
Preferably, the particle size D90 of the celecoxib is less than 20 microns.
The invention also comprises a preparation method of the celecoxib capsule, which comprises the following steps:
the absorption enhancer is mannitol or/and sorbitol;
starting a peristaltic pump, controlling the pump speed at 14-18 r/min, controlling the diameter of a spray gun nozzle at 0.8mm and the atomization pressure at 0.04-0.06 MPa, spraying the aqueous solution into a centrifugal fluidized bed, granulating, drying, and filling into a capsule shell to obtain celecoxib capsules;
the wetting agent is one or two of sodium dodecyl sulfate, sodium lauroyl amide and potassium lauryl phosphate.
The preparation method of the preferred celecoxib capsule comprises the following steps:
the absorption enhancer is mannitol or/and sorbitol;
starting a peristaltic pump, controlling the pump speed to be 14-18 r/min, controlling the diameter of a spray gun nozzle to be 0.8mm and the atomizing pressure to be 0.04-0.06 MPa, spraying the aqueous solution into a centrifugal fluidized bed, granulating, drying, and filling into a capsule shell to obtain a celecoxib capsule;
the wetting agent is one or two of sodium dodecyl sulfate, sodium lauroyl amide and potassium lauryl phosphate;
the adhesive is maleic anhydride crosslinked hydroxyethyl starch;
the maleic anhydride crosslinked hydroxyethyl starch is prepared according to the following steps:
adding hydroxyethyl starch, maleic anhydride and polyethylene glycol into a reaction bottle, adding toluene and sulfamic acid, starting stirring, heating the reaction solution to 80-90 ℃, stirring for reaction for 2-6 hours, filtering, washing a filter cake with acetone, and drying in vacuum to obtain maleic anhydride crosslinked hydroxyethyl starch;
wherein the mass ratio of hydroxyethyl starch, maleic anhydride, polyethylene glycol, toluene, sulfamic acid and acetone is 100: 3-4: 8-20: 200-300: 0.5-2: 50 to 70
The preparation method of the celecoxib capsule comprises the steps of putting celecoxib, an absorption enhancer and a blank pill core into a centrifugal fluidized bed, blowing air, forming a particle flow in a vortex rotation motion on curved surfaces of a stator and a rotor under the action of centrifugal force and friction force, enabling particles to roll and be uniformly stirred, simultaneously injecting a proper amount of atomized slurry through a spray gun, condensing the powder into particles, continuously injecting the atomized slurry to increase parent nucleus into pills, drying, and refilling the capsules into capsule shells to obtain the celecoxib capsule.
The invention is further described with reference to specific examples.
The weight of the celecoxib capsule prepared by the invention is 0.45-0.55 g/capsule.
Example 1
A celecoxib capsule, comprising the following materials: 250g of celecoxib, 190g of blank pill core, 5g of wetting agent and 2g of absorption enhancer;
the wetting agent is sodium dodecyl sulfate;
the absorption enhancer is mannitol.
Example 2
A celecoxib capsule, comprising the following materials: 800g of celecoxib, 720g of blank pill core, 20g of wetting agent and 10g of absorption enhancer;
the wetting agent is sodium lauroyl amide;
the absorption enhancer is sorbitol.
Example 3
A celecoxib capsule comprises the following materials: 500g of celecoxib, 400g of blank pill core, 12g of wetting agent and 8g of absorption enhancer;
the wetting agent is potassium lauryl phosphate;
the absorption enhancer is prepared from mannitol and sorbitol according to a mass ratio of 1: 1 are mixed to obtain the product.
Example 4
A celecoxib capsule, comprising the following materials: 600g of celecoxib, 450g of blank pill core, 15g of wetting agent and 5g of absorption enhancer;
the wetting agent is obtained by mixing sodium dodecyl sulfate and sodium lauroyl amide according to the mass ratio of 2: 3;
the absorption enhancer is prepared from mannitol and sorbitol according to a mass ratio of 1: 4, mixing to obtain the product.
Example 5
A celecoxib capsule, comprising the following materials: 250g of celecoxib, 190g of blank pill core, 5g of wetting agent, 2g of absorption enhancer and 1g of adhesive;
the adhesive is maleic anhydride crosslinked hydroxyethyl starch;
the maleic anhydride crosslinked hydroxyethyl starch is prepared according to the following steps:
adding 10g of hydroxyethyl starch, 0.3g of maleic anhydride and 0.8g of polyethylene glycol into a reaction bottle, adding 20g of toluene and 0.05g of sulfamic acid, starting stirring, heating the reaction solution to 80 ℃, stirring for reacting for 6 hours, filtering, washing a filter cake with 5g of acetone, and performing vacuum drying to obtain maleic anhydride crosslinked hydroxyethyl starch;
the wetting agent is sodium dodecyl sulfate;
the absorption enhancer is mannitol.
Example 6
A celecoxib capsule, comprising the following materials: 800g of celecoxib, 720g of blank pill core, 20g of wetting agent, 10g of absorption enhancer and 5g of adhesive;
the adhesive is maleic anhydride crosslinked hydroxyethyl starch;
the maleic anhydride crosslinked hydroxyethyl starch is prepared according to the following steps:
adding 10g of hydroxyethyl starch, 0.4g of maleic anhydride and 2g of polyethylene glycol into a reaction bottle, adding 30g of toluene and 0.2g of sulfamic acid, starting stirring, heating the reaction solution to 90 ℃, stirring for reacting for 2 hours, filtering, washing a filter cake with 7g of acetone, and performing vacuum drying to obtain maleic anhydride crosslinked hydroxyethyl starch;
the wetting agent is sodium lauroyl amide;
the absorption enhancer is sorbitol.
Example 7
A celecoxib capsule comprises the following materials: 500g of celecoxib, 400g of blank pill core, 12g of wetting agent, 8g of absorption enhancer and 3g of adhesive;
the adhesive is maleic anhydride crosslinked hydroxyethyl starch;
the maleic anhydride crosslinked hydroxyethyl starch is prepared according to the following steps:
adding 10g of hydroxyethyl starch, 0.35g of maleic anhydride and 1g of polyethylene glycol into a reaction bottle, adding 25g of toluene and 0.1g of sulfamic acid, starting stirring, heating the reaction solution to 84 ℃, stirring for reacting for 3 hours, filtering, washing a filter cake with 6g of acetone, and performing vacuum drying to obtain maleic anhydride crosslinked hydroxyethyl starch;
the wetting agent is potassium lauryl phosphate;
the absorption enhancer is prepared from mannitol and sorbitol according to a mass ratio of 1: 1 are mixed to obtain the product.
Example 8
A celecoxib capsule, comprising the following materials: 600g of celecoxib, 450g of blank pill core, 15g of wetting agent, 5g of absorption enhancer and 4g of adhesive;
the adhesive is maleic anhydride crosslinked hydroxyethyl starch;
the maleic anhydride crosslinked hydroxyethyl starch is prepared according to the following steps:
adding 10g of hydroxyethyl starch, 0.32g of maleic anhydride and 1.2g of polyethylene glycol into a reaction bottle, adding 25g of toluene and 0.12g of sulfamic acid, starting stirring, heating the reaction solution to 85 ℃, stirring for reacting for 5 hours, filtering, washing a filter cake with 6.5g of acetone, and performing vacuum drying to obtain maleic anhydride crosslinked hydroxyethyl starch;
the wetting agent is obtained by mixing sodium dodecyl sulfate and sodium lauroyl amide according to the mass ratio of 2: 3;
the absorption enhancer is prepared from mannitol and sorbitol according to a mass ratio of 1: 4, mixing to obtain the product.
Example 9
The method of preparing the celecoxib capsule of embodiment 1 comprising the steps of:
the absorption enhancer is mannitol;
starting a peristaltic pump, controlling the pump speed at 14-18 r/min, controlling the diameter of a spray gun nozzle at 0.8mm and the atomization pressure at 0.04-0.06 MPa, spraying the aqueous solution into a centrifugal fluidized bed, granulating, drying and filling to obtain celecoxib capsules;
the wetting agent is sodium dodecyl sulfate.
Example 10
The method of preparing the celecoxib capsule of embodiment 2 comprising the steps of:
the absorption enhancer is sorbitol;
starting a peristaltic pump, controlling the pump speed at 14-16 r/min, controlling the diameter of a spray gun nozzle at 0.8mm and the atomization pressure at 0.04-0.05 MPa, spraying the aqueous solution into a centrifugal fluidized bed, granulating, drying, and filling to obtain celecoxib capsules;
the wetting agent is sodium lauroyl amide.
Example 11
The method of preparing the celecoxib capsule of embodiment 3 comprising the steps of:
the absorption enhancer is prepared from mannitol and sorbitol according to a mass ratio of 1: 1, mixing to obtain;
starting a peristaltic pump, controlling the pump speed at 15-17 r/min, controlling the diameter of a spray gun nozzle at 0.8mm and the atomization pressure at 0.05-0.06 MPa, spraying the aqueous solution into a centrifugal fluidized bed, granulating, drying and filling to obtain celecoxib capsules;
the wetting agent is potassium lauryl phosphate.
Example 12
The method of preparing the celecoxib capsule of embodiment 4 comprising the steps of:
the absorption enhancer is prepared from mannitol and sorbitol according to a mass ratio of 1: 4, mixing to obtain;
starting a peristaltic pump, controlling the pump speed at 14-16 r/min, controlling the diameter of a spray gun nozzle at 0.8mm and the atomization pressure at 0.04-0.05 MPa, spraying the aqueous solution into a centrifugal fluidized bed, granulating, drying, and filling to obtain celecoxib capsules;
the wetting agent is obtained by mixing sodium dodecyl sulfate and sodium lauroyl amide according to the mass ratio of 2: 3.
The celecoxib capsules of examples 5-8 were prepared according to examples 9-12 except that maleic anhydride crosslinked hydroxyethyl starch, such as
Example 13
The method of preparing the celecoxib capsule of embodiment 8 comprising the steps of:
the absorption enhancer is prepared from mannitol and sorbitol according to a mass ratio of 1: 4, mixing to obtain;
starting a peristaltic pump, controlling the pump speed to be 14-16 r/min, controlling the diameter of a spray gun nozzle to be 0.8mm and the atomization pressure to be 0.04-0.05 MPa, spraying the aqueous solution into a centrifugal fluidized bed, granulating, drying and filling to obtain celecoxib capsules;
the wetting agent is obtained by mixing sodium dodecyl sulfate and sodium lauroyl amide according to the mass ratio of 2: 3;
the adhesive is maleic anhydride crosslinked hydroxyethyl starch;
the maleic anhydride crosslinked hydroxyethyl starch is prepared according to the following steps:
adding 10g of hydroxyethyl starch, 0.32g of maleic anhydride and 1.2g of polyethylene glycol into a reaction bottle, adding 25g of toluene and 0.12g of sulfamic acid, starting stirring, heating the reaction solution to 80-90 ℃, stirring for reacting for 2-6 hours, filtering, washing a filter cake with 6.5g of acetone, and drying in vacuum to obtain the maleic anhydride crosslinked hydroxyethyl starch.
The samples of examples 1-8 were examined for dissolution curves at pH12.0, pH6.8, pH1.0 and aqueous medium conditions, and the original preparation (Celepor) batch W60990, and the results were as follows:
TABLE 1
TABLE 2
TABLE 3
TABLE 4
The data in tables 1 to 4 show that the cumulative dissolution rates of the celecoxib capsules in 5 minutes, 15 minutes, 30 minutes, 60 minutes and 120 minutes are all superior to those of the original preparation (celecoxib) W60990, and the water solubility of the capsule components is superior to that of the original preparation (celecoxib) W60990.
The effect of the embodiments 5 to 8 of the invention is obviously better than that of the embodiments 1 to 4, and the added maleic anhydride crosslinked hydroxyethyl starch adhesive can not only increase the adhesive property of the celecoxib raw drug, but also promote the dissolution rate of the celecoxib raw drug.
Claims (5)
1. A celecoxib capsule characterized by: the material comprises the following materials in parts by weight: 25-80 parts of celecoxib, 19-72 parts of blank pill core, 0.5-2 parts of wetting agent, 0.2-1 part of absorption enhancer and 0.1-0.5 part of adhesive;
the wetting agent is one or two of sodium dodecyl sulfate, sodium lauroyl amide or potassium lauryl phosphate;
the absorption enhancer is mannitol or/and sorbitol;
the adhesive is maleic anhydride crosslinked hydroxyethyl starch;
the maleic anhydride crosslinked hydroxyethyl starch is prepared according to the following steps:
adding hydroxyethyl starch, maleic anhydride and polyethylene glycol into a reaction bottle, adding toluene and sulfamic acid, starting stirring, heating the reaction solution to 80-90 ℃, stirring for reaction for 2-6 hours, filtering, washing a filter cake with acetone, and drying in vacuum to obtain maleic anhydride crosslinked hydroxyethyl starch;
wherein the mass ratio of hydroxyethyl starch, maleic anhydride, polyethylene glycol, toluene, sulfamic acid and acetone is 100: 3-4: 8-20: 200-300: 0.5-2: 50-70.
2. A celecoxib capsule according to claim 1 wherein: the blank pellet core is a microcrystalline cellulose pellet core.
3. A celecoxib capsule according to claim 1 wherein: the particle size D90 of the celecoxib is less than 100 mu m.
4. A celecoxib capsule according to claim 1, wherein: the particle size D90 of the celecoxib is less than 20 μm.
5. A process for the preparation of celecoxib capsules according to claim 1 wherein: the method comprises the following steps:
adding 25-80 parts by weight of celecoxib, 19-72 parts by weight of blank pellet core and 0.2-1 part by weight of absorption enhancer into a centrifugal fluidized bed, starting a blower, and setting a blowing-in airflow of 2.0-2.5 m 3 The air inlet temperature is 45-55 ℃, and the rotating speed of the rotary table is 180-220 r/min;
the absorption enhancer is mannitol or/and sorbitol;
adding 0.5-2 parts of wetting agent into purified water to prepare an aqueous solution with the mass concentration of 12-18%, and adding 0.1-0.5 part of adhesive into the aqueous solution;
starting a peristaltic pump, controlling the pump speed at 14-18 r/min, controlling the diameter of a spray gun nozzle at 0.8mm and the atomization pressure at 0.04-0.06 MPa, spraying the aqueous solution into a centrifugal fluidized bed, granulating, drying and filling to obtain celecoxib capsules;
the wetting agent is one or two of sodium dodecyl sulfate, sodium lauroyl amide or potassium lauryl phosphate;
the adhesive is maleic anhydride crosslinked hydroxyethyl starch;
the maleic anhydride crosslinked hydroxyethyl starch is prepared according to the following steps:
adding hydroxyethyl starch, maleic anhydride and polyethylene glycol into a reaction bottle, adding toluene and sulfamic acid, starting stirring, heating the reaction solution to 80-90 ℃, stirring for reacting for 2-6 hours, filtering, washing a filter cake with acetone, and drying in vacuum to obtain maleic anhydride crosslinked hydroxyethyl starch;
wherein the mass ratio of hydroxyethyl starch, maleic anhydride, polyethylene glycol, toluene, sulfamic acid and acetone is 100: 3-4: 8-20: 200-300: 0.5-2: 50-70.
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| CN103191065A (en) * | 2013-04-17 | 2013-07-10 | 贵州联盛药业有限公司 | Celecoxib new formulation and preparation method thereof |
| CN104721146A (en) * | 2015-04-03 | 2015-06-24 | 海南海力制药有限公司 | Celecoxib solvent dispersoid, pellet capsule and preparation methods of celecoxib solvent dispersoid and pellet capsule |
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| CN114340638A (en) * | 2019-06-26 | 2022-04-12 | 杭州艾瑞莎生物医药科技有限公司 | Low dose celecoxib formulations |
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Denomination of invention: A celecoxib capsule and its preparation method Effective date of registration: 20231027 Granted publication date: 20220913 Pledgee: Bank of Communications Ltd. Jining branch Pledgor: AMICOGEN (CHINA) BIOPHARM CO.,LTD. Registration number: Y2023980063066 |
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