CN103211825A - Novel celecoxib composition and preparation process thereof - Google Patents
Novel celecoxib composition and preparation process thereof Download PDFInfo
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- CN103211825A CN103211825A CN2013101375166A CN201310137516A CN103211825A CN 103211825 A CN103211825 A CN 103211825A CN 2013101375166 A CN2013101375166 A CN 2013101375166A CN 201310137516 A CN201310137516 A CN 201310137516A CN 103211825 A CN103211825 A CN 103211825A
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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 156
- 229960000590 celecoxib Drugs 0.000 title claims abstract description 156
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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 the preparation technology and its medical usage of a kind of new celecoxib composition, and said composition.
Background technology
Arthritis is a kind of disabling condition, and its Clinical symptoms is pain, dysarthrasis and limitation of activity.Osteoarthritis is restricted driving joint disease, causes handicap due to progressive destruction of joint；Rheumatoid arthritis is the chronic inflammation disease being involved by multisystem caused by autoimmune disorder.
NSAIDs is widely used in the treatment of the pain and inflammation of Osteoarthritis and rheumatoid arthritis.It is by suppressing Cycloxygenase（COX）Activity and suppress the formation of prostaglandin and thromboxane.COX has two isoenzymes：Key element enzyme COX-1 and induced enzyme COX-2.The product of COX-1 enzymatics participates in protection gastrointestinal mucosa, platelet function, the regulation physiological function such as renal hemodynamic and electrolyte balance.On the contrary, COX-2 promotes the formation of the prostaglandin of mediated pain and inflammatory process.Traditional NSAIDs has different degrees of suppression to two isoenzymes, in treatment concentration, and they produce analgesic and antiinflammatory action by suppressing COX-2.
Celecoxib is a kind of NSAIDs of new generation, and COX-2 is specifically suppressed with unique mechanism of action.Inflammatory stimulus can induce COX-2 generations, thus cause the synthesis and accumulation of inflammatory PG class materials, especially prostaglandin E2, cause inflammation, oedema and pain.Celecoxib can prevent the generation of PG class materials by suppressing COX-2, reach anti-inflammatory, analgesia and antipyretic effect.External and in vivo studies shows that celecoxib and the COX-1 of basal expression affinity are extremely weak, the celecoxib of therapeutic dose does not influence synthesizing for the PG class materials activated by COX-1, therefore do not disturb during normal physiological processes related to COX-1 in tissue, especially stomach, intestines, blood platelet and kidney etc. organize.
But celecoxib is a kind of low dissolving, Thief zone types of drug, its solubility in water is only 2 μ g/ml.Single oral dose celecoxib（200mg）Reach highest blood concentration within about 3 hours afterwards, its highest blood concentration is only 705ng/ml.Celecoxib, with taking, can postpone to reach highest blood concentration in 1 to 2 hour with high lipid food, while overall absorption can increase by 10% to 20%.From this, in the presence of effective drug excipient, improve the solubility of celecoxib, and then develop celecoxib new oral, injecting drug use prescription turns into the task of top priority.
Celecoxib bulk drug is crushed to D by patent CN99802185.7 reports90Less than 200 μm, preferably 1~10 μm, most preferably 5~7 μm, preparation is made according to a conventional method, effective treatment concentration can be reached in the short period of time.Point out celecoxib as other bulk drugs, granularity is smaller, and absorption strength is higher.But celecoxib heap density is low, light weight is easy-adhesion on wall or cohesive agglomerating during crushing, it is difficult to micro mist.Yuan Yan Pfizers are also only crushed to D9024 μm, and former lapping compound type is capsule, is, because working as celecoxib, when preparing tablet, easily to form sticky long acicular crystal crystalline state, be easily melted into lump.Even when being mixed with auxiliary material, also easily coalesce blocking, share with auxiliary material, tablet uniformity of dosage units is not reached requirement, and influence absorbs.
In order to improve the absorption of celecoxib, celecoxib is dissolved in liquid macrogol composition pharmaceutical composition by patent WO0178724, and the formulation of the pharmaceutical composition is soft capsule.It is subsequently found that celecoxib is in the system and unstable, the antioxidant of free radical can be removed by adding again（CN1292746C）.Soft capsule dosage form has two：1st, content is liquid, and bulk drug is dissolved in liquid, easily decomposes the generation of increase catabolite, unstable.2nd, it is restricted to solution total amount, such as more than 1.0ml, swallow and have any problem.Therefore, soft capsule is required to the solubility of bulk drug, and celecoxib is material with low solubility, and such a formulation limits it and heavy dose of pill is made.
Patent CN102000018B is mentioned is scattered in solid polyethylene glycol by celecoxib, then capsule and tablet are prepared by crushing, celecoxib is a kind of weak acidic drug, the release in vitro feature of such medicine can be significantly improved if preparing solid dispersion and should add appropriate basifier, and obvious non-PH dependences are presented.Celecoxib dispersion is prepared with polyethylene glycol is, need to melt to celecoxib in polyethylene glycol, temperature reaches 80 degree or so, and high temperature can make the increase of celecoxib degradation impurity, and the excellent cooling system of the scattered needs of solid, this brings difficulty to a large amount of manufactures of industry again.
Swati Rawat et al. are in " Solubility enhancement of celecoxib using b-cyclodextrin inclusion complexes "【European Journal of Pharmaceutics and Biopharmaceutics 57, (2004), 263-267】By celecoxib and beta-schardinger dextrin with 1 in one text：1 inclusion forms inclusion composition, the solubility of celecoxib is improved, but it does not study influence of the pH value to celecoxib solubility, and Benexate Hydrochloride can only prepare solid pharmaceutical preparation, such as tablet, capsule, it is impossible to prepare the celecoxib preparation of the intravenously administrables such as ejection preparation.
Celecoxib is slightly solubility weak acid compound, and almost insoluble in water, solubility increases with pH increase, and pH reaches that more than 12 can be only achieved clinical demand, but now easily dissociates, and shows stronger pH dependences.Intravenous injection is 3~10 to pH general requirement, is suitable for the celecoxib preparation of intravenous injection so can prepare and is difficult.
Celecoxib can be used for a variety of solid tumors such as treatment relaxing tumor pain, colitis and lung cancer, 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 practically insoluble in water, its water-insoluble limits the exploitation of its liquid preparation such as parenteral solution, above-mentioned solid dispersion, Benexate Hydrochloride, micronization technology can not solve celecoxib injecting medicine-feeding form, and also have in terms of solid pharmaceutical preparation preparation respective shortcoming.
The content of the invention
Present inventors have surprisingly discovered that, composition using glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin with celecoxib formation under pH value neutrality to alkalescence condition can greatly improve the solubility of celecoxib, bioavilability is improved, while there is no haemolysis adverse reaction when freeze drying powder injection is prepared into said composition.
The present inventor is had found by different pH value research, when the phosphate buffer using pH9.0 is as the solvent for preparing composition, is to be adapted to the maximum dicyandiamide solution of celecoxib solubility in intravenous injection administration pH value system.
The present invention now provides a kind of pharmaceutical composition, and said composition includes one or more absorbable dosage units, celecoxib of each dosage unit comprising about 10mg to 1000mg and glucityl-cyclodextrin or the composition of Sulfobutyl ether β _ cyclodextrin.Said composition can be used for compressed tablets, prepare capsule, the present invention is using dissolving medium of the phosphate buffer solution of pH value 9.0 as inclusion agents, while celecoxib solubility is increased, it is ensured that the pH requirements of intravenous injection, therefore it can be used for preparing celecoxib composition powder injection.
It is an object of the invention to by preparing celecoxib and glucose group-beta-cyclodextrin or the composition of Sulfobutyl ether β _ cyclodextrin, improve the water solubility of celecoxib, intravenous formulations can be developed to, so as to adapt to different needs clinically.It can also improve the body absorption of celecoxib solid pharmaceutical preparation simultaneously, improve its bioavilability.
Glucityl-cyclodextrin（G-CYD）Including：Glucityl-alpha-cyclodextrin, glucose group-beta-cyclodextrin and didextrose group-beta-cyclodextrin.Solubility of the glucityl-cyclodextrin in water is more much bigger than its corresponding parent, and particularly glucose group-beta-cyclodextrin is significantly more improved than the water solubility of beta-schardinger dextrin.The glucose group-beta-cyclodextrin and didextrose group-beta-cyclodextrin inclusion compound of high-dissolvability make injection possibly also with its inclusion compound, and the cyclodextrin of high concentration finds to cause the haemolysis of human erythrocyte, the haemocylolysis of didextrose group-beta-cyclodextrin and glucityl-alpha-cyclodextrin is less than their parent.
Sulfobutyl ether β _ cyclodextrin（SBE-β-CDs）It is 2,3 by Isosorbide-5-Nitrae-butane sultone and beta-schardinger dextrin glucose unit, hydroxyl occurs obtained by substitution reaction on 6 carbon, water-soluble high, can include to form noncovalent compositions with drug molecule well, so as to improve the stability, water solubility, security of medicine, reduction renal toxicity, volatility.Its substitution value maximum can be 21, and selected substitution value is 4~7 in the present invention.
Glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin can form the aqueous solution of inclusion compound or in solid-state with insoluble drug, can be through solubility method, UV-VIS spectrophotometry and differential scanning calorimetry（DSC）Etc. analyzing and identifying whether its inclusion succeeds.
Celecoxib is 4- [5- (4- aminomethyl phenyls) -3- (trifluoromethyl) pyrazol-1-yl] benzsulfamide, and molecular weight is 381.37.Due to not having volume too big group, molecular weight in celecoxib molecule nor very big, Sulfobutyl ether β _ cyclodextrin, glucityl-alpha-cyclodextrin, glucose group-beta-cyclodextrin and didextrose group-beta-cyclodextrin formation mol ratio that can be larger with molecule cavity be 1：1~10 composition.Celecoxib molecule is in hydrophobicity, after glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin inclusion, its solubility is significantly improved, such as after being included through didextrose group-beta-cyclodextrin, solubility of the celecoxib in water increases to 2300 μ g/ml by 2 μ g/ml, substantially increases solubility.Tested by hemolytic, the celecoxib after glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin inclusion finds no haemocylolysis in dose therapeutically effective, and the powder-injection security through being prepared is good.
In celecoxib composition of the present invention, containing active ingredient celecoxib and glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin, wherein glucityl-cyclodextrin includes glucityl-alpha-cyclodextrin, glucose group-beta-cyclodextrin and didextrose group-beta-cyclodextrin.Wherein Sulfobutyl ether β _ cyclodextrin substitution value is 4~7.
Celecoxib and the mol ratio of glucose cyclodextrin or Sulfobutyl ether β _ cyclodextrin are 1 in the present invention：1~10.
The preparation of celecoxib composition can use following distinct methods in the present invention：
Saturated aqueous solution is made in glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin by saturated water solution method, is added enclosed molecule medicine, for medicine insoluble in those water, can be added a small amount of appropriate solvent（Such as ethanol）After dissolving, stirring mixing more than 30 minutes is included enclosed molecule medicine, but some inclusion compound of the big enclosed molecule of solubility is remained dissolved in solution in water, can be added a kind of organic solvent, be precipitated precipitation.The solid clathrates of precipitation are filtered, it is clean, dry according to the property of enclosed molecule, then with appropriate solvent, produce stable composition.
Glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin saturated aqueous solution are added enclosed molecule medicine and dissolved by supercritical ultrasonics technology, are used sonicator or supersonic wave cleaning machine after mixing immediately, are selected suitable intensity, ultrasonic appropriate time, instead of mixing power, produces composition.
Polishing takes glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin to add 2~5 times of amount water and ground well, and adds enclosed molecule medicine（Enclosed molecule medicine is dissolved in a small amount of appropriate solvent if necessary）To put be sufficiently mixed in grinder and grind to form pasty state, cleaned again with appropriate solvent after low temperature drying, re-dry produces composition.
Freeze-drying is as soluble in water such as obtained inclusion compound, is difficult to separate out crystalline deposit, or easy-to-use decomposition, discoloration in heat drying, can be dried with freeze-drying, make inclusion compound profile loose, solubility property is good.Celecoxib can prepare composite freeze-dried powder agent with glucityl-cyclodextrin through this method.
Spray drying process is as soluble in water such as obtained inclusion compound, and heat property is relatively stablized again, and inclusion compound can be prepared with spray drying process, and drying temperature is high, and heated time is short, and yield is high.
Solution-paddling process glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin solubility in water are larger, it can then add enclosed molecule medicine in unsaturated glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin solution, crystallite formed in whipping process, filtering, is drying to obtain.
The water referred in above-mentioned composition preparation method can be the buffer salt solution of different pH value, and pH value mainly chooses pH7~10 in the present invention.
The composition of celecoxib and glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin can be as a kind of initiation material or a kind of composition, for preparing intestinal canal administration or non-intestinal drug delivery agent.Intestinal canal administration preparation preferably such as tablet, enteric coated tablet, capsule, granule, oral liquid, the preferred freeze-dried powder formulation of non-intestinal drug delivery agent.
Embodiment
In the composition of celecoxib and glucityl-cyclodextrin, preferred celecoxib didextrose group-beta-cyclodextrin composition, the preferred saturated water solution method of its preparation method and solution stirring method.
In the composition of celecoxib and Sulfobutyl ether β _ cyclodextrin, preferably substitution value is 7 Sulfobutyl ether β _ cyclodextrin（SBE7-β-CDs）, the preferred saturated water solution method of its preparation method and solution stirring method.
Celecoxib and glucityl-cyclodextrin or the composition of Sulfobutyl ether β _ cyclodextrin are prepared using saturated water solution method, Sai Laisaibu is added into certain ethanol saturated solution A is made；Take glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin that saturated solution B is made under 40 degree with pH9.0 phosphate buffer, in the lower slow B by A instillations of constant temperature stirring, drop ratio, white suspension must be clarified by continuing stirring 2h, stop heating, room temperature is cooled under stirring, place 2-4 hours at room temperature, suction filtration, filter cake is washed with ethanol in proper amount, is dried in vacuo to obtain white powder celecoxib glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin composition.
Celecoxib and glucityl-cyclodextrin or the composition of Sulfobutyl ether β _ cyclodextrin are prepared using solution stirring method, weigh glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin, with pH9.0 phosphate buffer stirring and dissolving, separately weigh celecoxib, add in above-mentioned cyclodextrin solution, mixed liquor is stirred 30~60 minutes with magnetic force or electric stirring method, and solution is gradually clarified, and produces celecoxib glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin composition solution.It is freeze-dried to solution made from the method for top, you can obtain celecoxib glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin composite freeze-dried powder agent.
Solubility is determined in terms of celecoxib with UV-VIS spectrophotometry in embodiment.
The saturated water solution method of embodiment 1 prepares celecoxib glucose group-beta-cyclodextrin composition
Weigh glucose group-beta-cyclodextrin 307g（0.237mol）, be placed in the 500ml three-necked bottles with electric mixing device, plus pH9.0 phosphate buffer 230ml, putting 40 DEG C of water-baths dissolves it；Weigh celecoxib 30g（0.079mol）, dissolved with 30ml ethanol, and instilled in glucose group-beta-cyclodextrin saturated solution, constant temperature is stirred 4 hours, and reaction solution is staticly settled, suction filtration, and sediment is washed with appropriate ethanol, in 50 DEG C of vacuum drying, is produced.
Take celecoxib glucose group-beta-cyclodextrin composition 0.337g (containing celecoxib 30mg) and celecoxib 30mg that this method is obtained, add water 10ml respectively, filtered after shake well dissolving, composition bottle takes subsequent filtrate 1ml to put in 100ml measuring bottles, uses water constant volume.Its trap is determined at 256nm with ultraviolet-visible spectrophotometer respectively, and it is respectively 2.0389mg/ml and 0.002mg/ml to calculate its solubility, that is, the solubility of celecoxib is obviously improved after including.
Take the celecoxib glucose group-beta-cyclodextrin composition 0.112g (containing celecoxib 10mg) that this method is obtained, it is dissolved in water and is settled in 100ml measuring bottles, precision measures 1ml into 10ml measuring bottles, with water dissolves and constant volume, trap is determined at 256nm with ultraviolet-visible spectrophotometer, it is 93.6% to calculate its inclusion rate, illustrates that celecoxib glucose group-beta-cyclodextrin composition inclusion rate is good.
The solution stirring method of embodiment 2 prepares celecoxib glucose group-beta-cyclodextrin composition
Weigh glucose group-beta-cyclodextrin 6.83g（5.23mol）, be placed in beaker, plus pH9.0 phosphate buffer 800ml, stirring and dissolving separately weighs celecoxib 1g（2.62mmol）, add in above-mentioned glucose group-beta-cyclodextrin solution.Mixed liquor is stirred 20 minutes in magnetic agitation mode, and solution is gradually clarified, filtering, and filtrate is celecoxib glucose group-beta-cyclodextrin composition solution.Solution made from above method is freezed, you can obtain solid-like celecoxib glucose group-beta-cyclodextrin composition.
Determined through spectrophotometry instrument, celecoxib glucose group-beta-cyclodextrin composition solubility is 2.0556mg/ml.
The saturated water solution method of embodiment 3 prepares celecoxib didextrose group-beta-cyclodextrin composition
Weigh didextrose group-beta-cyclodextrin 532g（0.395mol）, be placed in the 500ml three-necked bottles with electric mixing device, plus pH9.0 phosphate buffer 380ml, putting 40 DEG C of water-baths dissolves it；Weigh celecoxib 30g（0.079mol）, dissolved with 30ml ethanol, and instilled in didextrose group-beta-cyclodextrin saturated solution, constant temperature is stirred 4 hours, and reaction solution is staticly settled, suction filtration, and sediment is washed with appropriate ethanol, in 50 DEG C of vacuum drying, is produced.
The solution stirring method of embodiment 4 prepares celecoxib didextrose group-beta-cyclodextrin composition
Weigh didextrose group-beta-cyclodextrin 31.8g（23.6mmol）, be placed in beaker, plus pH9.0 phosphate buffer 1500ml, stirring and dissolving separately weighs celecoxib 3g（7.87mmol）, add in above-mentioned didextrose group-beta-cyclodextrin solution.Mixed liquor is stirred 20 minutes in magnetic agitation mode, and solution is gradually clarified, filtering, and filtrate is celecoxib didextrose group-beta-cyclodextrin composition solution.Solution made from above method is freezed, you can obtain solid-like celecoxib didextrose group-beta-cyclodextrin composition.
Determined through spectrophotometry instrument, celecoxib didextrose group-beta-cyclodextrin composition solubility is 2.3022mg/ml.
We obtain celecoxib beta-schardinger dextrin composition according to celecoxib beta-schardinger dextrin preparation method in document：
Take beta-schardinger dextrin 11.56g (10mmol) to put in beaker, add 35mlpH9.0 phosphate buffer, 3.8g (10mmol) celecoxib is added under agitation, stir to clarify, 45 degree of dryings, dry product crosses 100 eye mesh screens after crushed, produces.
Determined through ultraviolet-visible spectrophotometer, celecoxib beta-schardinger dextrin composition solubility is 0.0386mg/ml.Although the composition of document report improves nearly 20 times than celecoxib protype compound solubility, but the solubility of the celecoxib glucose group-beta-cyclodextrin composition in the present invention improves nearly 1100 times than protype compound, it improves the effect of solubility still obviously, the preparation significantly beneficial to effective administration concentration celecoxib injection.
The saturated solution method of embodiment 5 prepares celecoxib glucityl-alpha-cyclodextrin composition
Weigh glucityl-alpha-cyclodextrin 102g（0.079mol）, be placed in the 500ml three-necked bottles with electric mixing device, plus pH9.0 phosphate buffer 100ml, weigh celecoxib 3g（0.0079mol）, dissolved with 10ml ethanol, and instilled in glucityl-alpha-cyclodextrin saturated solution, constant temperature is stirred 4 hours, and reaction solution is staticly settled, suction filtration, and sediment is washed with appropriate ethanol, in 50 DEG C of vacuum drying, is produced.
Determined through spectrophotometry instrument, celecoxib glucityl-alpha-cyclodextrin composition solubility is 1.9833mg/ml.
The saturated solution method of embodiment 6 prepares celecoxib Sulfobutyl ether β _ cyclodextrin composition
Weigh Sulfobutyl ether β _ cyclodextrin（Substitution value is 4）134.6g（0.079mol）, be placed in the 500ml three-necked bottles with electric mixing device, plus pH9.0 phosphate buffer 300ml, weigh celecoxib 3g（0.0079mol）, dissolved with 10ml ethanol, and instilled Sulfobutyl ether β _ cyclodextrin（Substitution value is 4）In saturated solution, constant temperature is stirred 4 hours, and reaction solution is staticly settled, suction filtration, and sediment is washed with appropriate ethanol, in 50 DEG C of vacuum drying, is produced.
Determined through spectrophotometry instrument, celecoxib Sulfobutyl ether β _ cyclodextrin（Substitution value is 4）Composition solubility is 1.5667mg/ml.
The solution stirring method of embodiment 7 prepares celecoxib Sulfobutyl ether β _ cyclodextrin composition
Weigh Sulfobutyl ether β _ cyclodextrin（Substitution value is 7）52.9g（23.6mmol）, be placed in beaker, plus pH9.0 phosphate buffer 1200ml, stirring and dissolving separately weighs celecoxib 3g（7.87mmol）, add above-mentioned Sulfobutyl ether β _ cyclodextrin（Substitution value is 7）In solution.Mixed liquor is stirred 20 minutes in magnetic agitation mode, and solution is gradually clarified, filtering, and filtrate is celecoxib Sulfobutyl ether β _ cyclodextrin（Substitution value is 7）Composition solution.Solution made from above method is freezed, you can obtain solid-like celecoxib Sulfobutyl ether β _ cyclodextrin composition.
Determined through spectrophotometry instrument, celecoxib Sulfobutyl ether β _ cyclodextrin composition solubility is 2.4378mg/ml.
The preparation of the celecoxib didextrose base beta-schardinger dextrin composition tablet of embodiment 8
（1）The preparation be the same as Example 4 of celecoxib didextrose base beta-schardinger dextrin composition.
（2）Above-mentioned celecoxib didextrose base beta-schardinger dextrin composition is prepared into piece agent（Every 50mg containing celecoxib）, it is formulated as follows：
Celecoxib didextrose group-beta-cyclodextrin composition 227mg（50mg containing celecoxib）
Lactose 51mg
Low-substituted hydroxypropyl cellulose 15mg
Hydroxypropyl cellulose 6mg
Magnesium stearate 1mg
Gross weight 300mg
(3) celecoxib glucose group-beta-cyclodextrin composition, lactose, low-substituted hydroxypropyl cellulose are well mixed, add the ethanol solution softwood of 2% hydroxypropyl cellulose 50%, and the particle of about 24 mesh sizes is made, magnesium stearate compressing tablet is mixed into after drying.
(4) sheet above 6 is taken, by two annex dissolution methods of Chinese Pharmacopoeia 2010 piece, using paddle method, 50 revs/min, with the cushioning liquid of pH value 6.8 as dissolution medium, operate in accordance with the law, solution 5ml filterings are extracted at 30 minutes, the μ l of subsequent filtrate 20 are taken to inject liquid chromatograph detection, its solubility is 98.9%.
Embodiment 9 prepares the freeze drying powder injection of celecoxib didextrose group-beta-cyclodextrin composition
Weigh didextrose group-beta-cyclodextrin 31.8g（23.6mmol）, be placed in beaker, plus pH9.0 phosphate buffer 1500ml, stirring and dissolving separately weighs celecoxib 3g（7.87mmol）, add in above-mentioned didextrose group-beta-cyclodextrin solution.Mixed liquor is stirred 20 minutes in magnetic agitation mode, and solution is gradually clarified, filtering, and filtrate is celecoxib didextrose group-beta-cyclodextrin composition solution.By solution depyrogenation made from above method, sterile filtration is dispensed by every bottle of 5ml and freezed into cillin bottle, you can obtain celecoxib didextrose group-beta-cyclodextrin freeze-dried powder.
Embodiment 10 prepares the freeze drying powder injection of celecoxib Sulfobutyl ether β _ cyclodextrin composition
Weigh Sulfobutyl ether β _ cyclodextrin（Substitution value is 7）52.9g（23.6mmol）, be placed in beaker, plus pH9.0 phosphate buffer 1200ml, stirring and dissolving separately weighs celecoxib 3g（7.87mmol）, add above-mentioned Sulfobutyl ether β _ cyclodextrin（Substitution value is 7）In solution.Mixed liquor is stirred 20 minutes in magnetic agitation mode, and solution is gradually clarified, filtering, and filtrate is celecoxib Sulfobutyl ether β _ cyclodextrin（Substitution value is 7）Composition solution.By solution depyrogenation made from above method, sterile filtration is dispensed by every bottle of 4ml and freezed into cillin bottle, you can obtain celecoxib didextrose group-beta-cyclodextrin freeze-dried powder.
The security inspection of the celecoxib didextrose group-beta-cyclodextrin of embodiment 11 and celecoxib Sulfobutyl ether β _ cyclodextrin freeze-dried powder
New Zealand large ear rabbit ear vein blood 10ml is taken, is stirred to remove fibrin with glass rod.Plus appropriate physiological saline shakes up, 2000rpm centrifugation 10min remove supernatant.Operate 3 times repeatedly.Take whole blood 2ml, plus red cell suspension of the physiological saline to 100ml into 2%.Celecoxib Sulfobutyl ether β _ cyclodextrin freeze-dried powder prepared by the celecoxib didextrose group-beta-cyclodextrin freeze-dried powder and embodiment 10 prepared to embodiment 9 carries out hemolytic experiment, and test solution proportional quantity see the table below.Test tube is taken to number, according to the form below sequentially adds 2% red cell suspension, physiological saline, after mixing, with placing 30min in 37 DEG C of thermostat water baths, then add different amounts of decoction and shake up, then be placed in 37 DEG C of thermostat water baths, whether visually observed with 15,30,45min and 1,2,3,4h in the color of test tube, record test tube has haemolysis.As a result show, celecoxib didextrose group-beta-cyclodextrin freeze-dried powder and celecoxib Sulfobutyl ether β _ cyclodextrin freeze-dried powder are without hemolytic.
The Internal pharmacokinetics experimental study of embodiment 9：
Take rabbit 18, it is divided into two groups, every group 6, tablet prepared by the tablet of celecoxib didextrose group-beta-cyclodextrin composition preparation prepared by common celecoxib tablet, embodiment 8 and the celecoxib beta-schardinger dextrin composition of application literature method preparation is gavaged respectively, blood 2ml is taken respectively at 5,10,15,30,45,60,90min auricular veins, methanol ultrasonic extraction 10min. is centrifuged, and takes the μ l sample introduction HPLC detection levels of supernatant 20.The celecoxib plasma drug concentration data measured is calculated into relative bioavailability by control formulation of conventional tablet with 3p87 software processings " TG-AUC is calculated using trapezoidal method ".As a result it see the table below, show that tablet bioavilability prepared by celecoxib didextrose group-beta-cyclodextrin composition is more than tablet and common celecoxib tablet prepared by celecoxib beta-schardinger dextrin composition.
| Preparation | AUC0-4（ng·ml-1·min） | Cmax（ng·ml-1） | Tmax（min） | F/% |
| Celecoxib didextrose group-beta-cyclodextrin piece | 4089.55 | 304.89 | 30 | 1041.1 |
| Celecoxib beta-schardinger dextrin piece | 960.37 | 89.21 | 30 | 244.5 |
| Celecoxib ordinary tablet | 392.82 | 50.3 | 30 |
Claims (10)
1. a kind of celecoxib composition, it is characterised in that：Containing active component celecoxib and glucityl-cyclodextrin encapsulated dose or Sulfobutyl ether β _ cyclodextrin inclusion agents, the mol ratio of celecoxib and glucityl-cyclodextrin encapsulated dose is 1：1~10, wherein glucityl-cyclodextrin encapsulated dose is selected from glucityl-alpha-cyclodextrin, glucose group-beta-cyclodextrin or didextrose group-beta-cyclodextrin.
2. a kind of method of the celecoxib composition prepared described in claim 1, it is characterized in that saturated water solution method：Glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin are made to saturation pH9.0 phosphate buffer solution, according to the mol ratio 1 of celecoxib and glucityl-cyclodextrin：1~10 consumption, is added to after celecoxib is dissolved with ethanol in above-mentioned saturated solution, then constant temperature stirring 4h, and reaction solution is staticly settled, suction filtration, and sediment is washed with ethanol in proper amount, vacuum drying, is produced.
3. a kind of method of the celecoxib composition prepared described in claim 1, it is characterized in that solution-paddling process：Glucityl-cyclodextrin or Sulfobutyl ether β _ cyclodextrin are made to unsaturation pH9.0 phosphate buffer solution, according to the mol ratio 1 of celecoxib and glucityl-cyclodextrin：1~10 consumption, celecoxib is added in above-mentioned unsaturation solution, freeze-dried to produce then through magnetic force or electric stirring method formation composition.
4. the celecoxib composition according to claims 1 to 3, it is characterised in that the preferred didextrose group-beta-cyclodextrin of glucityl-cyclodextrin encapsulated dose.
5. the celecoxib composition according to claims 1 to 3, it is characterised in that the substitution value of Sulfobutyl ether β _ cyclodextrin inclusion agents is 4~7.
6. the celecoxib composition according to claims 1 to 3, it is characterised in that the mol ratio preferably 1 of celecoxib and glucityl-cyclodextrin encapsulated dose：1~3.
7. the celecoxib composition according to claims 1 to 3, it is characterised in that the mol ratio of celecoxib and Sulfobutyl ether β _ cyclodextrin inclusion agents preferably 1：1~3.
8. a kind of pharmaceutical composition, it is characterised in that：Contain the celecoxib composition and pharmaceutically acceptable excipients described in claims 1 to 3.
9. application of the celecoxib composition in antineoplastic is prepared described in claim 1.
10. application of the celecoxib composition in treatment medicine for treating rheumatoid arthritis is prepared described in claim 1.
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| 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 |
| CN113336874A (en) * | 2021-08-05 | 2021-09-03 | 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 |
| CN113521308A (en) * | 2021-09-16 | 2021-10-22 | 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104689304A (en) * | 2015-03-23 | 2015-06-10 | 合肥天麦生物科技发展有限公司 | Recombined insulin glargine injection liquid 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 |
| CN113336874A (en) * | 2021-08-05 | 2021-09-03 | 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 |
| 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 |
| CN113521308A (en) * | 2021-09-16 | 2021-10-22 | 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 |
| 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 |
| CN116421569A (en) * | 2023-06-15 | 2023-07-14 | 四川尚锐生物医药有限公司 | Parafaxib sodium pharmaceutical composition for injection and preparation method 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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