CN103211825B - Novel celecoxib composition and preparation process thereof - Google Patents
Novel celecoxib composition and preparation process thereof Download PDFInfo
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- CN103211825B CN103211825B CN201310137516.6A CN201310137516A CN103211825B CN 103211825 B CN103211825 B CN 103211825B CN 201310137516 A CN201310137516 A CN 201310137516A CN 103211825 B CN103211825 B CN 103211825B
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Abstract
The invention relates to a novel composition of celecoxib and glucosyl-cyclodextrin or sulfobutyl-beta-cyclodextrin as well as a preparation method of the composition and application in medicine preparations. According to the invention, the prepared composition of celecoxib and glucosyl-cyclodextrin or sulfobutyl-beta-cyclodextrin has the advantages of improving the water solubility and the stability and has no adverse effect of hemolysis, so that the composition can serve as a starting material or a constituent for preparing intestinal-administration preparations or non-intestinal-administration preparations for treating tumors or rheumatoid arthritis; and the solid preparations have high bioavailability and the freeze-dried powder injections meet the requirements on the aspect of pH value and have no adverse effect of hemolysis.
Description
Technical field
The present invention relates to a kind of new celecoxib compositions, and the preparation technology of said composition and medical usage thereof.
Background technology
Arthritis is a kind of disabling condition, and its Clinical symptoms is pain, joint deformity and limitation of activity.Osteoarthritis is restricted driving joint disease, because carrying out property destruction of joint causes handicap; Rheumatoid arthritis is the chronic inflammation disease that the multisystem that caused by autoimmune disorder is got involved.
NSAID (non-steroidal anti-inflammatory drug) is widely used in the treatment of pain and the inflammation of osteoarthritis and rheumatoid arthritis.The formation that suppresses prostaglandin and thromboxane by the activity of inhibition Cycloxygenase (COX).COX has two isozymes: key element enzyme COX-1 and inducible enzyme COX-2.The product of COX-1 enzymatic participates in physiological functions such as protection gastrointestinal mucosa, platelet function, adjusting kidney blood flow and electrolyte balance.On the contrary, COX-2 promotes the formation of the prostaglandin of mediated pain and inflammatory process.Traditional NSAID (non-steroidal anti-inflammatory drug) has inhibition in various degree to two isozymes, and in the time for the treatment of concentration, they produce pain relieving and antiinflammatory action by suppressing COX-2.
Celecoxib is a kind of NSAID (non-steroidal anti-inflammatory drug) of a new generation, has unique mechanism of action and suppresses specifically COX-2.Inflammatory stimulus can induce COX-2 to generate, thereby causes the synthetic of inflammatory PG class material and build up especially prostaglandin E
2, cause inflammation, edema and pain.Celecoxib can stop by suppressing COX-2 the generation of PG class material, reaches antiinflammatory, analgesia and antipyretic effect.External and in vivo test show celecoxib and basal expression COX-1 affinity extremely a little less than, the celecoxib of therapeutic dose does not affect the synthetic of the PG class material that activated by COX-1, therefore do not disturb in the tissues such as normal physiological processes relevant to COX-1 in tissue, especially stomach, intestinal, platelet and kidney.
But celecoxib is a kind of low dissolving, high infiltration types of drug, and its dissolubility in water is only 2 μ g/ml.After single oral dose celecoxib (200mg), within approximately 3 hours, reach the highest blood drug level, its highest blood drug level is only 705ng/ml.Celecoxib and high lipid food, with clothes, can postpone to reach for 1 to 2 hour the highest blood drug level, and overall absorption can increase by 10% to 20% simultaneously.In view of this, under effectively drug excipient participates in, improve the dissolubility of celecoxib, and then novel oral, the injecting drug use prescription of exploitation celecoxib become the task of top priority.
Celecoxib crude drug is crushed to D by patent CN99802185.7 report
90below 200 μ m, preferably 1～10 μ m, most preferably 5～7 μ m, make preparation according to a conventional method, can reach in the short period of time effective treatment concentration.Prompting celecoxib is the same with other crude drug, and granularity is less, and absorption strength is higher.But celecoxib bulk density is low, and quality is light, when pulverizing, easily stick on wall or bond agglomeratingly, be difficult to micropowder.Yuan Yan Pfizer is also only crushed to D
9024 μ m, and former lapping compound type is capsule, are because when celecoxib, while preparing tablet, easily form the long acicular crystal crystalline state of viscosity, are easily melted into lump.Even, in the time mixing with adjuvant, also easy coalescent in bulk, shares with adjuvant, not only makes tablet uniformity of dosage units not reach requirement, and impact absorbs.
In order to improve the absorption of celecoxib, celecoxib is dissolved in liquid macrogol composition pharmaceutical composition by patent WO0178724, and the dosage form of this pharmaceutical composition is soft capsule.Find that subsequently celecoxib is also unstable in this system, added again the antioxidant (CN1292746C) that can remove free radical.There are two problems in soft capsule dosage form: 1, content is liquid, and crude drug is dissolved in liquid, easily decomposes the generation that increases catabolite, unstable.2, restricted to solution total amount, as exceed 1.0ml, swallow and have any problem.Therefore, soft capsule has requirement to the dissolubility of crude drug, and celecoxib is material with low solubility, and this kind of dosage form limited it and made heavy dose of pill.
Patent CN102000018B mentions celecoxib is scattered in to solid polyethylene glycol, then prepare capsule and tablet through pulverizing, celecoxib is a kind of weak acidic drug, should add appropriate bases agent can significantly improve the release in vitro feature of such medicine if prepare solid dispersion, and present obvious non-PH dependency.Preparing celecoxib dispersion with Polyethylene Glycol is, celecoxib need to be melted in Polyethylene Glycol, temperature reaches 80 degree left and right, and high temperature can make celecoxib degradation impurity increase, and solid disperses to need good cooling system, this has brought difficulty to again a large amount of manufacture of industry.
The people such as Swati Rawat are at " Solubility enhancement of celecoxib using b-cyclodextrin inclusion complexes " [European Journal of Pharmaceutics and Biopharmaceutics 57, (2004), 263 – 267] celecoxib and beta-schardinger dextrin-are formed to enclose compositions with 1:1 enclose in a literary composition, improve the dissolubility of celecoxib, but it does not study the impact of pH value on celecoxib dissolubility, and Benexate Hydrochloride can only be prepared solid preparation, as tablet, capsule etc., can not prepare the celecoxib preparation of the intravenously administrables such as ejection preparation.
Celecoxib is slightly solubility weak acid compound, and almost insoluble in water, dissolubility increases with the increase of pH, and pH reaches more than 12 just can reach clinical demand, but now easily occurs dissociating, and shows stronger pH dependency.Intravenous injection is 3～10 to the General Requirements of pH, is suitable for intravenous celecoxib preparation and is difficult to so can prepare.
Celecoxib can also be used for the treatment of the multiple solid tumors such as relaxing tumor pain, colitis and pulmonary carcinoma, and patient with rheumatoid arthritis and cancer patient are badly in need of a kind of celecoxib preparation that can be used in drug administration by injection, but celecoxib is water-soluble hardly, its water-insoluble has limited its liquid preparation as the exploitation of injection, above-mentioned solid dispersion, Benexate Hydrochloride, micronization technology all can not solve celecoxib injecting medicine-feeding form, and also have shortcoming separately at solid preparation aspect preparing.
Summary of the invention
The inventor have been surprisingly found that, adopt glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin can greatly improve the dissolubility of celecoxib to the compositions forming with celecoxib under alkali condition in pH value neutrality, improve bioavailability, while being prepared into lyophilized injectable powder by said composition, there is no haemolysis untoward reaction simultaneously.
The inventor finds by the research of different pH value, when the phosphate buffer that uses pH9.0 is during as the solvent of preparation compositions, is the dicyandiamide solution that is applicable to celecoxib dissolubility maximum in intravenous administration pH value system.
The present invention now provides a kind of pharmaceutical composition, and said composition comprises one or more absorbable dosage units, the compositions of the celecoxib that each dosage unit comprises about 10mg to 1000mg and glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin.Said composition can be used for compressed tablets, prepares capsule, the present invention adopts the dissolve medium of pH value 9.0 phosphate buffered solution as inclusion agents, in increasing celecoxib dissolubility, ensure intravenous pH requirement, therefore can be used for preparing celecoxib composition powder injection.
The object of the invention is to the compositions by preparing celecoxib and glucose group-beta-cyclodextrin or sulphur fourth group-beta-cyclodextrin, improve the water solublity of celecoxib, can be developed to intravenous formulations, thereby adapt to difference needs clinically.Also can improve interior absorption of body of celecoxib solid preparation, improve its bioavailability simultaneously.
Glucityl-cyclodextrin (G-CYD) comprising: glucityl-alpha-cyclodextrin, glucose group-beta-cyclodextrin and didextrose group-beta-cyclodextrin.The dissolubility of glucityl-cyclodextrin in water is more much bigger than its corresponding parent, and particularly glucose group-beta-cyclodextrin improves more significantly than the water solublity of beta-schardinger dextrin-.The glucose group-beta-cyclodextrin of high-dissolvability and didextrose group-beta-cyclodextrin clathrate may utilize its clathrate to make injection, and the cyclodextrin of high concentration finds to cause the haemolysis of human erythrocyte, the haemolysis of didextrose group-beta-cyclodextrin and glucityl-alpha-cyclodextrin is lower than their parent.
Sulphur fourth group-beta-cyclodextrin (SBE-β-CDs) is by 1,2 of 4-butane sultone and beta-schardinger dextrin-glucose unit, 3, hydroxyl generation substitution reaction gained on 6 carbon, water solublity is high, can well form non-covalent compositions with drug molecule enclose, thereby improve stability, water solublity, the safety of medicine, reduction nephrotoxicity, volatility.Its substitution value maximum can be 21, and in the present invention, selected substitution value is 4～7.
Whether glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin and insoluble drug can form the aqueous solution of clathrate or be solid-state, can be successful through its enclose of Analysis and Identification such as solubility method, ultraviolet visible spectrophotometry and differential scanning calorimetries (DSC).
Celecoxib is 4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl) pyrazol-1-yl] benzsulfamide, molecular weight is 381.37.Owing to there is no the group that volume is too large in celecoxib molecule, molecular weight neither be very large, and sulphur fourth group-beta-cyclodextrin, glucityl-alpha-cyclodextrin, glucose group-beta-cyclodextrin and didextrose group-beta-cyclodextrin that can be larger with molecule cavity form the compositions that mol ratio is 1:1～10.Celecoxib molecule is hydrophobicity, after glucityl-cyclodextrin or sulphur butyl-beta-cyclodextrin inclusion compound, its dissolubility is significantly improved, for example, after didextrose group-beta-cyclodextrin enclose, the dissolubility of celecoxib in water is increased to 2300 μ g/ml by 2 μ g/ml, greatly improved dissolubility.Test by hemolytic, the celecoxib after glucityl-cyclodextrin or sulphur butyl-beta-cyclodextrin inclusion compound finds no haemolysis in dose therapeutically effective, through preparation and injectable powder safety good.
In celecoxib compositions of the present invention, contain active ingredient celecoxib and glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin, wherein glucityl-cyclodextrin comprises glucityl-alpha-cyclodextrin, glucose group-beta-cyclodextrin and didextrose group-beta-cyclodextrin.Wherein sulphur fourth group-beta-cyclodextrin substitution value is 4～7.
In the present invention, the mol ratio of celecoxib and glucityl cyclodextrin or sulphur fourth group-beta-cyclodextrin is 1:1～10.
In the present invention, the preparation of celecoxib compositions can adopt following distinct methods:
Saturated aqueous solution made by glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin by saturated water solution method, add enclosed molecule medicine, for medicine insoluble in those water, after can adding a small amount of appropriate solvent (as ethanol etc.) and dissolving, be uniformly mixed more than 30 minutes, make enclosed molecule medicine by enclose, but some clathrate of the enclosed molecule that in water, dissolubility is large is still dissolved in solution, can add a kind of organic solvent, make to separate out precipitation.The solid clathrates of separating out is filtered, according to the character of enclosed molecule, then clean, be dried with suitable solvent, obtain stable compositions.
Glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin saturated aqueous solution are added enclosed molecule medicine dissolution by supercritical ultrasonics technology, after mixing, use immediately ultrasonic disruption instrument or ultrasonic washing unit, select suitable intensity, ultrasonic appropriate time, replace mixing power, obtain compositions.
Polishing gets glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin adds 2～5 times of water gagings to grind well, add enclosed molecule medicine (if desired enclosed molecule medicine being dissolved in a small amount of appropriate solvent) to put abundant mixed grinding in grinder and become pasty state, after cold drying, clean with appropriate solvent again, dry again, obtain compositions.
Freeze-drying is as soluble in water in the clathrate making, and is difficult for crystallization precipitation, or easy-to-use decomposition, variable color in the time of heat drying, and available freeze-drying is dry, makes clathrate profile loose, and solubility property is good.Celecoxib and glucityl-cyclodextrin can be through this legal system for composite freeze-dried powder agent.
Spray drying method is as soluble in water in the clathrate making, and heat character is more stable again, and available spray drying method is prepared clathrate, and baking temperature is high, and heated time is short, and productive rate is high.
Solution-paddling process glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin dissolubility in water are larger, can, in unsaturated glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin solution, add enclosed molecule medicine, in whipping process, form crystallite, filter, be drying to obtain.
The water of mentioning in above-mentioned composition preparation method can be the buffer salt solution of different pH value, and in the present invention, pH value is mainly chosen pH7～10.
The compositions of celecoxib and glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin can be used as a kind of initiation material or a kind of composition, for the preparation of intestinal canal administration or non-intestinal drug delivery agent.Intestinal canal administration preparation is preferably as tablet, enteric coated tablet, capsule, granule, oral liquid etc., the preferred freeze-dried powder dosage form of non-intestinal drug delivery agent.
Detailed description of the invention
In the compositions of celecoxib and glucityl-cyclodextrin, preferably celecoxib didextrose group-beta-cyclodextrin compositions, the preferred saturated water solution method of its preparation method and solution stirring method.
In the compositions of celecoxib and sulphur fourth group-beta-cyclodextrin, the sulphur fourth group-beta-cyclodextrin (SBE that preferably substitution value is 7
7-β-CDs), the preferred saturated water solution method of its preparation method and solution stirring method.
Adopt saturated water solution method to prepare the compositions of celecoxib and glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin, add certain ethanol to make saturated solution A Sai Laisaibu; Get the phosphate buffer of glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin pH9.0 and under 40 degree, make saturated solution B, constant temperature slowly splashes into A in B under stirring, drip ratio, continue to stir 2h and must clarify white suspension, stop heating, under stirring, be cooled to room temperature, under room temperature, place 2-4 hour, sucking filtration, the appropriate washing with alcohol of filter cake, vacuum drying obtains white powder celecoxib glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin compositions.
Adopt solution stirring method to prepare the compositions of celecoxib and glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin, take glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin, by the phosphate buffer stirring and dissolving of pH9.0, separately take celecoxib, add in above-mentioned cyclodextrin solution, mixed liquor stirs 30～60 minutes with magnetic force or electric stirring method, and solution is clarified gradually, obtains celecoxib glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin composition solution.The solution making in order to top method carries out lyophilization, can obtain celecoxib glucityl-cyclodextrin or the agent of sulphur fourth group-beta-cyclodextrin composite freeze-dried powder.
In embodiment, measure dissolubility all in celecoxib with ultraviolet visible spectrophotometry.
Embodiment 1 saturated water solution method is prepared celecoxib glucose group-beta-cyclodextrin compositions
Take glucose group-beta-cyclodextrin 307g(0.237mol), be placed in the 500ml three-necked bottle with electric mixing device, add the phosphate buffer 230ml of pH9.0, put 40 DEG C of water-baths and make its dissolving; Take celecoxib 30g(0.079mol), with 30ml dissolve with ethanol, and splashed in glucose group-beta-cyclodextrin saturated solution, constant temperature stirs 4 hours, and reactant liquor staticly settles, sucking filtration, and precipitate, with appropriate washing with alcohol, in 50 DEG C of vacuum dryings, to obtain final product.
Get celecoxib glucose group-beta-cyclodextrin compositions 0.337g (containing celecoxib 30mg) and celecoxib 30mg that this method obtains, 10ml adds water respectively, shake well filters after dissolving, and compositions bottle is got subsequent filtrate 1ml and put in 100ml measuring bottle, water standardize solution.Respectively with ultraviolet-visible spectrophotometer in its trap of 256nm place mensuration, and calculate its dissolubility and be respectively 2.0389mg/ml and 0.002mg/ml, after enclose, the dissolubility of celecoxib has had and has significantly improved.
Get the celecoxib glucose group-beta-cyclodextrin compositions 0.112g (containing celecoxib 10mg) that this method obtains, be dissolved in water and be settled in 100ml measuring bottle, precision measures in 1ml to 10ml measuring bottle, with water dissolution standardize solution, measure trap at 256nm place with ultraviolet-visible spectrophotometer, calculating its inclusion rate is 93.6%, illustrates that celecoxib glucose group-beta-cyclodextrin compositions inclusion rate is good.
Embodiment 2 solution stirring methods are prepared celecoxib glucose group-beta-cyclodextrin compositions
Take glucose group-beta-cyclodextrin 6.83g(5.23mol), be placed in beaker, add the phosphate buffer 800ml of pH9.0, stirring and dissolving, separately takes celecoxib 1g(2.62mmol), add in above-mentioned glucose group-beta-cyclodextrin solution.Mixed liquor stirs 20 minutes in magnetic agitation mode, and solution is clarified gradually, filters, and filtrate is celecoxib glucose group-beta-cyclodextrin composition solution.The solution that above method is made carries out lyophilizing, can obtain solid, shaped celecoxib glucose group-beta-cyclodextrin compositions.
Measure through spectrophotometry instrument, celecoxib glucose group-beta-cyclodextrin composition dissolves degree is 2.0556mg/ml.
Embodiment 3 saturated water solution methods are prepared celecoxib didextrose group-beta-cyclodextrin compositions
Take didextrose group-beta-cyclodextrin 532g(0.395mol), be placed in the 500ml three-necked bottle with electric mixing device, add the phosphate buffer 380ml of pH9.0, put 40 DEG C of water-baths and make its dissolving; Take celecoxib 30g(0.079mol), with 30ml dissolve with ethanol, and splashed in didextrose group-beta-cyclodextrin saturated solution, constant temperature stirs 4 hours, and reactant liquor staticly settles, sucking filtration, and precipitate is with appropriate washing with alcohol, in 50 DEG C of vacuum dryings, to obtain final product.
Embodiment 4 solution stirring methods are prepared celecoxib didextrose group-beta-cyclodextrin compositions
Take didextrose group-beta-cyclodextrin 31.8g(23.6mmol), be placed in beaker, add the phosphate buffer 1500ml of pH9.0, stirring and dissolving, separately takes celecoxib 3g(7.87mmol), add in above-mentioned didextrose group-beta-cyclodextrin solution.Mixed liquor stirs 20 minutes in magnetic agitation mode, and solution is clarified gradually, filters, and filtrate is celecoxib didextrose group-beta-cyclodextrin composition solution.The solution that above method is made carries out lyophilizing, can obtain solid, shaped celecoxib didextrose group-beta-cyclodextrin compositions.
Measure through spectrophotometry instrument, celecoxib didextrose group-beta-cyclodextrin composition dissolves degree is 2.3022mg/ml.
We obtain celecoxib beta-schardinger dextrin-compositions according to celecoxib beta-schardinger dextrin-preparation method in document:
Get beta-schardinger dextrin-11.56g (10mmol) and put in beaker, add the phosphate buffer of 35mlpH9.0, under agitation add 3.8g (10mmol) celecoxib, stir to clarify, 45 degree are dry, and dry product is crossed 100 eye mesh screens after crushed, to obtain final product.
Measure through ultraviolet-visible spectrophotometer, celecoxib beta-schardinger dextrin-composition dissolves degree is 0.0386mg/ml.Although the compositions of bibliographical information improves nearly 20 times than celecoxib protype compound dissolubility, but the dissolubility of the celecoxib glucose group-beta-cyclodextrin compositions in the present invention improves nearly 1100 times than protype compound, its effect that improves dissolubility is still very obvious, is greatly beneficial to the preparation of effective administration concentration celecoxib injection.
Embodiment 5 saturated solution methods are prepared celecoxib glucityl-alpha-cyclodextrin compositions
Take glucityl-alpha-cyclodextrin 102g(0.079mol), be placed in the 500ml three-necked bottle with electric mixing device, the phosphate buffer 100ml that adds pH9.0, takes celecoxib 3g(0.0079mol), with 10ml dissolve with ethanol, and splashed in glucityl-alpha-cyclodextrin saturated solution, constant temperature stirs 4 hours, and reactant liquor staticly settles, sucking filtration, and precipitate is with appropriate washing with alcohol, in 50 DEG C of vacuum dryings, to obtain final product.
Measure through spectrophotometry instrument, celecoxib glucityl-alpha-cyclodextrin composition dissolves degree is 1.9833mg/ml.
Embodiment 6 saturated solution methods are prepared celecoxib sulphur fourth group-beta-cyclodextrin compositions
Take sulphur fourth group-beta-cyclodextrin (substitution value is 4) 134.6g(0.079mol), be placed in the 500ml three-necked bottle with electric mixing device, the phosphate buffer 300ml that adds pH9.0, takes celecoxib 3g(0.0079mol), with 10ml dissolve with ethanol, and splashed in sulphur fourth group-beta-cyclodextrin (substitution value is 4) saturated solution, constant temperature stirs 4 hours, and reactant liquor staticly settles, sucking filtration, and precipitate is with appropriate washing with alcohol, in 50 DEG C of vacuum dryings, to obtain final product.
Measure through spectrophotometry instrument, celecoxib sulphur fourth group-beta-cyclodextrin (substitution value is 4) composition dissolves degree is 1.5667mg/ml.
Embodiment 7 solution stirring methods are prepared celecoxib sulphur fourth group-beta-cyclodextrin compositions
Take sulphur fourth group-beta-cyclodextrin (substitution value is 7) 52.9g(23.6mmol), be placed in beaker, add the phosphate buffer 1200ml of pH9.0, stirring and dissolving, separately take celecoxib 3g(7.87mmol), add in above-mentioned sulphur fourth group-beta-cyclodextrin (substitution value is 7) solution.Mixed liquor stirs 20 minutes in magnetic agitation mode, and solution is clarified gradually, filters, and filtrate is celecoxib sulphur fourth group-beta-cyclodextrin (substitution value is 7) composition solution.The solution that above method is made carries out lyophilizing, can obtain solid, shaped celecoxib sulphur fourth group-beta-cyclodextrin compositions.
Measure through spectrophotometry instrument, celecoxib sulphur fourth group-beta-cyclodextrin composition dissolves degree is 2.4378mg/ml.
The preparation of embodiment 8 celecoxib didextrose base beta-schardinger dextrin-composition tablets
(1) preparation of celecoxib didextrose base beta-schardinger dextrin-compositions is with embodiment 4.
(2) above-mentioned celecoxib didextrose base beta-schardinger dextrin-compositions is prepared into tablet (every containing celecoxib 50mg), fills a prescription as follows:
Celecoxib didextrose group-beta-cyclodextrin compositions 227mg(is containing celecoxib 50mg)
Lactose 51mg
Low-substituted hydroxypropyl cellulose 15mg
Hydroxypropyl cellulose 6mg
Magnesium stearate 1mg
Gross weight 300mg
(3) by celecoxib glucose group-beta-cyclodextrin compositions, lactose, low-substituted hydroxypropyl cellulose mix homogeneously, add 2% hydroxypropyl cellulose 50% alcoholic solution soft material processed, and make the granule of approximately 24 order sizes, after being dried, sneak into magnesium stearate tabletting.
(4) get above-mentioned 6, press 2,010 two annex dissolution methods of Chinese Pharmacopoeia, adopt oar method, 50 revs/min, with the buffer solution of pH value 6.8, as dissolution medium, operation in accordance with the law, extracts solution 5ml and filters 30 minutes time, get subsequent filtrate 20 μ l injection liquid chromatographies and detect, its dissolubility is 98.9%.
Embodiment 9 prepares the lyophilized injectable powder of celecoxib didextrose group-beta-cyclodextrin compositions
Take didextrose group-beta-cyclodextrin 31.8g(23.6mmol), be placed in beaker, add the phosphate buffer 1500ml of pH9.0, stirring and dissolving, separately takes celecoxib 3g(7.87mmol), add in above-mentioned didextrose group-beta-cyclodextrin solution.Mixed liquor stirs 20 minutes in magnetic agitation mode, and solution is clarified gradually, filters, and filtrate is celecoxib didextrose group-beta-cyclodextrin composition solution.The solution depyrogenation that above method is made, aseptic filtration, divides to be filled in cillin bottle by every bottle of 5ml and carries out lyophilizing, can obtain celecoxib didextrose group-beta-cyclodextrin lyophilized powder.
Embodiment 10 prepares the lyophilized injectable powder of celecoxib sulphur fourth group-beta-cyclodextrin compositions
Take sulphur fourth group-beta-cyclodextrin (substitution value is 7) 52.9g(23.6mmol), be placed in beaker, add the phosphate buffer 1200ml of pH9.0, stirring and dissolving, separately take celecoxib 3g(7.87mmol), add in above-mentioned sulphur fourth group-beta-cyclodextrin (substitution value is 7) solution.Mixed liquor stirs 20 minutes in magnetic agitation mode, and solution is clarified gradually, filters, and filtrate is celecoxib sulphur fourth group-beta-cyclodextrin (substitution value is 7) composition solution.The solution depyrogenation that above method is made, aseptic filtration, divides to be filled in cillin bottle by every bottle of 4ml and carries out lyophilizing, can obtain celecoxib didextrose group-beta-cyclodextrin lyophilized powder.
The security inspection of embodiment 11 celecoxib didextrose group-beta-cyclodextrins and celecoxib sulphur fourth group-beta-cyclodextrin lyophilized powder
Get New Zealand large ear rabbit ear vein blood 10ml, stir to remove fibrin with glass rod.Add appropriate normal saline and shake up, the centrifugal 10min of 2000rpm, removes supernatant.Repeatable operation 3 times.Get whole blood 2ml, add normal saline and become 2% red cell suspension to 100ml.Celecoxib sulphur fourth group-beta-cyclodextrin lyophilized powder prepared by celecoxib didextrose group-beta-cyclodextrin lyophilized powder prepared by embodiment 9 and embodiment 10 carries out hemolytic test, and test solution proportional quantity sees the following form.Get test tube numbering, according to the form below adds 2% red cell suspension successively, normal saline, after mixing, with in 37 DEG C of thermostat water baths, place 30min, then add not commensurability medicinal liquid to shake up, then be placed in 37 DEG C of thermostat water baths, with 15,30, the color of 45min and 1,2,3,4h perusal test tube, whether record in vitro has haemolysis.Result shows, celecoxib didextrose group-beta-cyclodextrin lyophilized powder and celecoxib sulphur fourth group-beta-cyclodextrin lyophilized powder are without hemolytic.
Pharmacokinetics experimentation in embodiment 9 bodies:
Get 18 of rabbit, be divided into two groups, every group 6, gavage respectively tablet prepared by celecoxib beta-schardinger dextrin-compositions prepared by tablet prepared by celecoxib didextrose group-beta-cyclodextrin compositions prepared by common celecoxib tablet, embodiment 8 and application literature method, respectively at 5,10,15,30,45,60,90min auricular vein gets blood 2ml, 10min. is centrifugal for methanol supersound extraction, gets supernatant 20 μ l sample introduction HPLC detection level.The celecoxib blood drug level data 3p87 software processes " area under curve is calculated with trapezoidal method " that record are calculated to relative bioavailability taking conventional tablet as control formulation.The results are shown in following table, show that tablet bioavailability prepared by celecoxib didextrose group-beta-cyclodextrin compositions is greater than tablet and common celecoxib tablet prepared by celecoxib beta-schardinger dextrin-compositions.
| Preparation | AUC 0-4（ng·ml -1·min） | C max（ng·ml -1） | T max（min） | F/% |
| Celecoxib didextrose group-beta-cyclodextrin sheet | 4089.55 | 304.89 | 30 | 1041.1 |
| Celecoxib beta-schardinger dextrin-sheet | 960.37 | 89.21 | 30 | 244.5 |
| Celecoxib ordinary tablet | 392.82 | 50.3 | 30 |
Claims (7)
1. a celecoxib compositions, it is characterized in that: contain active component celecoxib and the agent of glucityl-cyclodextrin inclusion compound or the agent of sulphur butyl-beta-cyclodextrin inclusion compound, the mol ratio of celecoxib and glucityl-cyclodextrin or the agent of sulphur butyl-beta-cyclodextrin inclusion compound is 1:1～10, and wherein the agent of glucityl-cyclodextrin inclusion compound is selected from glucityl-alpha-cyclodextrin, glucose group-beta-cyclodextrin or didextrose group-beta-cyclodextrin.
2. prepare the method for celecoxib compositions claimed in claim 1 for one kind, it is characterized by saturated water solution method: the phosphate buffer solution of glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin being made to saturated pH9.0, according to the consumption of mol ratio 1:1～10 of celecoxib and glucityl-cyclodextrin, by celecoxib with joining after dissolve with ethanol in above-mentioned saturated solution, then constant temperature stirs 4h, and reactant liquor staticly settles, sucking filtration, and precipitate is with appropriate washing with alcohol, vacuum drying, to obtain final product.
3. prepare the method for celecoxib compositions claimed in claim 1 for one kind, it is characterized by solution-paddling process: the phosphate buffer solution of glucityl-cyclodextrin or sulphur fourth group-beta-cyclodextrin being made to unsaturation pH9.0, according to the consumption of mol ratio 1:1～10 of celecoxib and glucityl-cyclodextrin, celecoxib is added in above-mentioned unsaturation solution, then form compositions through magnetic force or electric stirring method, through lyophilization and get final product.
4. according to the celecoxib compositions described in claim 1, it is characterized in that the preferred didextrose group-beta-cyclodextrin of glucityl-cyclodextrin inclusion compound agent.
5. according to the celecoxib compositions described in claim 1, it is characterized in that the substitution value of sulphur butyl-beta-cyclodextrin inclusion compound agent is 4～7.
6. according to the celecoxib compositions described in claim 1, it is characterized in that preferred 1:1～3 of mol ratio of celecoxib and the agent of glucityl-cyclodextrin inclusion compound.
7. according to the celecoxib compositions described in claim 1, it is characterized in that preferred 1:1～3 of mol ratio of celecoxib and the agent of sulphur butyl-beta-cyclodextrin inclusion compound.
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| CN104689304B (en) * | 2015-03-23 | 2017-12-19 | 合肥天麦生物科技发展有限公司 | One kind restructuring insulin glargine injecta 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 |
| CN113336874B (en) * | 2021-08-05 | 2021-10-29 | 奥信阳光(北京)药业科技有限公司 | Inclusion compound of celecoxib and lactone modified sulfobutyl betacyclodextrin sodium and preparation method thereof |
| CN113521308B (en) * | 2021-09-16 | 2021-12-07 | 奥信阳光(北京)药业科技有限公司 | Inclusion compound of celecoxib and gallic acid modified sulfobutyl betacyclodextrin sodium and preparation method thereof |
| CN114028581A (en) * | 2021-10-15 | 2022-02-11 | 南方科技大学 | PH response composite material and preparation method and application thereof |
| CN116421569B (en) * | 2023-06-15 | 2023-09-05 | 四川尚锐生物医药有限公司 | Parafaxib sodium pharmaceutical composition for injection and preparation method thereof |
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| CN1535680A (en) * | 2003-04-08 | 2004-10-13 | 中奇制药技术（石家庄）有限公司 | Abidor inclusion compound |
| CN102764264A (en) * | 2012-07-25 | 2012-11-07 | 杭州和泽医药科技有限公司 | Celecoxib solid composition with high dissolution, preparation method and application |
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| CN1535680A (en) * | 2003-04-08 | 2004-10-13 | 中奇制药技术（石家庄）有限公司 | Abidor inclusion compound |
| CN102764264A (en) * | 2012-07-25 | 2012-11-07 | 杭州和泽医药科技有限公司 | Celecoxib solid composition with high dissolution, preparation method and application |
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