CN103655478A - Celecoxib solid dispersion and preparation method and application thereof - Google Patents
Celecoxib solid dispersion and preparation method and application thereof Download PDFInfo
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- CN103655478A CN103655478A CN201210362698.2A CN201210362698A CN103655478A CN 103655478 A CN103655478 A CN 103655478A CN 201210362698 A CN201210362698 A CN 201210362698A CN 103655478 A CN103655478 A CN 103655478A
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Abstract
The invention specifically relates to a celecoxib solid dispersion and a preparation method and application thereof. The celecoxib solid dispersion is prepared from celecoxib and poloxamer 188 at a mass ratio of 1:(1-20) by a melting process and a solvent process. The dispersion provided by the invention has good dispersity and high stability; the solubility and dissolution rate of the medicine are increased; the solubility of the medicine in water is 5-200 times higher than that of the raw medicines; with good dissolution rate in water, the in-vivo absorption of the medicine can be enhanced so as to improve the bioavailability. The solid dispersion also can be made into multiple clinically acceptable dosage forms which are used as new dosage forms of celecoxib.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of celecoxib solid dispersion and its preparation method and application.
Technical background
Celecoxib is the medicine that is used for the treatment of rheumatic arthritis, osteoarthritis and ankylosing spondylitis of Pfizer's development and sale, it also can be used for management of acute pain, dysmenorrhea, colorectal polyp and Postoperative analgesia etc., is one of medicine of current best-selling treatment of arthritis.Celecoxib structure is as follows:
The celecoxib mechanism of action be selectively acting in cyclooxygenase 2 (COX-2), belong to selective COX-2-inhibitor 2.Owing to not acting on COX-1, do not affect PGI2 synthetic that gastrointestinal tract and kidney is had to protective effect, gastrointestinal side effect and nephrotoxicity are all little than general NSAID (non-steroidal anti-inflammatory drug), and it does not have cardiovascular side effects.
Chinese patent 99802185.7 and divide an application in 200410037522.5 and recorded the preparation method of tablet and the capsule of celecoxib, and carried out pharmaceutics experiment, but it only adopts the method for pulverizing celecoxib that its bioavailability is increased.In Chinese patent 00805635.8, recorded and utilized unbodied celecoxib improve dissolution velocity and/or reduce and treat onset time.In Chinese patent 201010301422.4, record a kind of preparation method of celecoxib solid dispersion, under heating condition, celecoxib has been distributed in Polyethylene Glycol, through quick cooling formation solid dispersion, then made oral formulations.The application of carrier Polyethylene Glycol has improved the dispersion rate of celecoxib, contributes to celecoxib absorption in vivo and evenly discharges.
Celecoxib dissolubility in water-bearing media is very poor, when oral administration, absorbs poorly, be difficult for to form uniform mixture when other material mixes with celecoxib, is easy to form crystalline state.
Summary of the invention
In order to overcome above-mentioned shortcoming, the inventor is the dispersible carrier as celecoxib through the selected PLURONICS F87 of overtesting, makes solid dispersion, has overcome the shortcoming on the oral Preparation of existing celecoxib.
Solid dispersion preparation method has: fusion method, solvent method, melting-solvent method, polishing etc.
Fusion method: medicine and carrier are mixed, be cooled to rapidly solid after heating and melting.The key of this law is should be cooling rapidly by high temperature, and a plurality of colloidal state nucleus are formed rapidly, obtains the medicine of high degree of dispersion, rather than separates out thick.This method is applicable to heat stable medicine and carrier.
Solvent method: medicine and carrier are dissolved in organic solvent jointly, obtains the co-precipitation solid dispersion that medicine mixes in carrier after boiling off solvent, drying and get final product.While there is the solvent not eliminating on a small quantity in solid dispersion, easily cause the recrystallization of medicine and reduce the dispersion of principal agent.Conventional organic solvent has chloroform, dehydrated alcohol, ethanol, acetone etc.This method is suitable for thermally labile or volatile medicine, can select can be water-soluble, organic solvent and fusing point is high, to heat-labile carrier material.
Solvent-fusion method: every carrier material for fusion method all can adopt.Medicine is first dissolved in a small amount of organic solvent, more evenly mixes with the carrier having melted, boil off organic solvent, after cooling curing and get final product.The organic solvent that toxicity is very little can not boil off yet, but generally must not surpass 10%, otherwise is difficult to form crisp and frangible solid dispersion.This law can be used for the solid drugs that liquid drug or dosage are less than 50mg.
PLURONICS F87 is easy to dissolve in water or organic solvent, as surface activity class water-solubility carrier material, can make celecoxib in solid dispersion, keep the state of high degree of dispersion on the one hand, the surface activity that PLURONICS F87 itself has on the other hand can promote the rapid stripping of medicine, and making intestinal peristalsis promoting slack-off, medicine increased in the time of gastric retention, simultaneously, surfactant also likely increases the permeability of small intestine epithelium and promotes drug absorption, improves bioavailability.The result of extraction that it increases medicine is greater than polyethylene glycol carrier.
It is active component that the present invention adopts celecoxib, add PLURONICS F87 to make solid dispersion as carrier material, described medicine and the mass ratio of PLURONICS F87 are 1: 1~1: 20, and wherein celecoxib can be crude drug, or through further micronized crude drug.
Because solvent method is in preparation dispersion process, solvent load is larger, is not suitable for industrial large-scale production, and the present invention adopts fusion method, solvent-fusion method to prepare celecoxib solid dispersion.
1. fusion method
Fusion method: celecoxib and PLURONICS F87, by physical method mix homogeneously, are cooled to rapidly solid after heating and melting.Preferred: within 1: 1 in mass ratio~1: 20, to take celecoxib and PLURONICS F87,55~90.At ℃ first by PLURONICS F87 melting, again celecoxib is joined in PLURONICS F87, be stirred to homogeneous (uniform) fluid shape, by fused mass impouring, in container, stand straticulation shape, makes it fully curing, dry, pulverize, then be placed in abundant being dried in vacuum drying oven, obtain celecoxib solid dispersion.
PLURONICS F87 is heated to 55~90 ℃, preferably 60~70 ℃.
Celecoxib joins in the PLURONICS F87 of melting, fully stirs, and mixing time is greater than 0.5 hour, preferably 0.5~3 hour.Wherein stir and can adopt mechanical agitation, magnetic agitation, hand operated mixing etc., preferred mechanical stirs.
The container of fused mass impouring is the steel plate of surface smoothing or other container that surface area is conducive to more greatly quick heat radiating, such as: surface plate, ganoid iron plate, metal tray etc.
Solidify and can under room temperature or low temperature, carry out, preferred low temperature, low temperature described here is-25~25 ℃, further preferred-10~10 ℃, more preferably-5~5 ℃.
The dispersion vacuum drying time after pulverizing is greater than 0.5 day, preferably 0.5~2 day.
2. solvent method-fusion method
Solvent-fusion method: celecoxib, PLURONICS F87 and solvent, by physical method mix homogeneously, are made dispersion after removal solvent.
Preferred: within 1: 1 in mass ratio~1: 20, to take celecoxib and PLURONICS F87, celecoxib, PLURONICS F87, organic solvent three are mixed in any order, room temperature or heating, make mixture become homogeneous phase, steaming desolventizes and solidifies dry, after grinding, then be placed in abundant being dried in vacuum drying oven, obtain celecoxib solid dispersion.
More preferably: within 1: 1 in mass ratio~1: 20, take celecoxib and PLURONICS F87, celecoxib is dissolved in to organic solvent and forms mixed solution, and then mix with the PLURONICS F87 of heating and melting, fully stir, remove organic solvent and solidify dry, after grinding, then be placed in abundant being dried in vacuum drying oven, obtain celecoxib solid dispersion.
Organic solvent is selected from: one or more in methanol, ethanol, ethyl acetate, acetone, dichloromethane, particular methanol.
Organic solvent addition so that celecoxib completely dissolve and be as the criterion, preferably: 1/6~1/50 (g/mL).
The solution of the organic solvent of celecoxib mixes with the PLURONICS F87 of heating and melting, fully stirs, and wherein stirs and can adopt mechanical agitation, magnetic agitation, hand operated mixing etc., and preferred mechanical stirs.
Be heated to 55~90 ℃ and make PLURONICS F87 melting.
Mixing time is greater than 0.5 hour, preferably 0.5~3 hour.
Remove organic solvent and solidify dry can employing:
Decompression rotary evaporation, solidifies vacuum drying;
Or vacuum freezing, vacuum drying.
Rotary evaporation is that decompression room temperature or decompression heating steaming desolventize, and vacuum lyophilization is that decompression cryogenic conditions goes down to desolventize.
The dispersion that boils off solvent is shifted out from rotary evaporation bottle, for example: scrape.And spread out straticulation shape, its large as far as possible area is contacted with air.
The solid dispersion migrating out can be cured under room temperature or low temperature, preferred low temperature, and low temperature described here is-25~25 ℃, further preferred-10~10 ℃, more preferably-5~5 ℃.
The dispersion vacuum drying time after pulverizing is greater than 0.5 day, preferably 0.5~2 day.
The PLURONICS F87 solid dispersion of celecoxib prepared by the present invention is pulverized through conventional breaking method, makes granularity below 200 μ m.
Solid dispersion will be controlled the granularity of pulverizing when pulverizing, and controls the temperature of whole process, can add the equipment of cooling, to ensure the quality of products.
The dispersion of celecoxib can be mixed formulation method routinely and be made oral solid formulation, preferred tablet, capsule, granule with pharmaceutic adjuvant.
Pharmaceutic adjuvant is selected from one or more in diluent, disintegrating agent, binding agent, lubricant, antioxidant, adsorbent, correctives or does not select, and can also need to add other to be conducive to improve the adjuvant of medicine quality according to the difference of oral solid formulation.The Optimization of Adjuvant diluent, disintegrating agent, binding agent, lubricant, the antioxidant that add.
Diluent is selected from: one or more in starch, dextrin, Icing Sugar, mannitol, lactose, calcium sulfate, calcium hydrogen phosphate, magnesium oxide, magnesium carbonate, calcium carbonate, gel aluminum hydroxide powder, microcrystalline Cellulose, pregelatinized Starch, sorbitol, preferably lactose and microcrystalline Cellulose;
Disintegrating agent is selected from: one or more in sodium carboxymethylstarch, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, crosslinked Carboxymethyl cellulose sodium, dried starch, preferably crosslinked Carboxymethyl cellulose sodium;
Binding agent is selected from: one or more in PVP K30, starch slurry, Carboxymethyl cellulose sodium, syrup, polyvinylpyrrolidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, preferably polyethylene ketopyrrolidine;
Lubricant is selected from: one or more in stearic acid, calcium stearate, magnesium stearate, hydrogenated vegetable oil, Pulvis Talci, colloidality silicon dioxide, PEG6000, sodium lauryl sulphate, preferably magnesium stearate;
Antioxidant is selected from: one or more in vitamin C, sodium sulfite, sodium thiosulfate, preferred vitamin C.
In the capsule of being made by celecoxib solid dispersion, optimum ratio is that the consumption of fluidizer and lubricant is recipe quantity 1%~3%; The consumption of filler is 60%~95% of recipe quantity.
In the tablet of being made by celecoxib solid dispersion, the consumption that optimum ratio is diluent accounts for 20%~80% of recipe quantity: the consumption of binding agent accounts for 1%~8% of recipe quantity; The consumption of disintegrating agent accounts for 0.1%~10% of recipe quantity; The consumption of lubricant accounts for 0.2%~5% of recipe quantity.
In the granule of being made by celecoxib solid dispersion, the consumption that optimum ratio is diluent accounts for 20%~80% of recipe quantity; The consumption of disintegrating agent accounts for 0.2%~10% of recipe quantity; The consumption of binding agent accounts for 0.5%~8% of recipe quantity.
The PLURONICS F87 solid dispersion that the invention has the advantages that celecoxib shows good stripping property and disintegrative, increases it and absorbs at gastrointestinal, improves bioavailability.Preparation method of the present invention is simple, is easy to apply in commercial production.
The specific embodiment
Embodiment 1
The preparation of solid dispersion A:
By 300g PLURONICS F87, heating in water bath to 55 ℃ thawing, adds celecoxib 15g while stirring.Make mixture keep molten condition, after fully stirring, be poured on the steel plate of crossing in-25 ℃ of precoolings, in-25 ℃ of below curing 3min, within dry 1 day, pulverize, then be placed in afterwards abundant being dried in vacuum drying oven, obtain celecoxib solid dispersion A.
Embodiment 2
The preparation of solid dispersion B:
By 300g PLURONICS F87, heating in water bath to 90 ℃ thawing, adds celecoxib 20g while stirring.Make mixture keep molten condition, after fully stirring, be poured on the steel plate of crossing in 0 ℃ of precooling, in 0 ℃ of below curing 8min, within dry 2 days, pulverize, then be placed in afterwards abundant being dried in vacuum drying oven, obtain celecoxib solid dispersion B.
Embodiment 3
The preparation of solid dispersion C:
By 300g PLURONICS F87, join in the 900mL acetone soln of 30g celecoxib, be heated to 55 ℃ it is melted, fully stir.Continue heating mixed liquor acetone is fully volatilized, be poured on the steel plate of crossing in-15 ℃ of precoolings, in-15 ℃ of below curing 3min, within dry 2 days, pulverize, then be placed in afterwards abundant being dried in vacuum drying oven, obtain celecoxib solid dispersion C.
Embodiment 4
The preparation of solid dispersion D:
By 300g PLURONICS F87, join in the 500mL methanol solution that has dissolved 60g celecoxib, be heated to 60 ℃ it is melted, fully stir.Heating mixed liquor fully volatilizees dichloromethane, is poured on the steel plate of crossing in-20 ℃ of precoolings, in-20 ℃ of below curing 3min, within dry 1 day, pulverizes, then be placed in afterwards abundant being dried in vacuum drying oven, obtains celecoxib solid dispersion D.
Embodiment 5
The preparation of solid dispersion E:
By 300g PLURONICS F87, heating in water bath to 70 ℃ thawing, adds the medicine 15g with 240mL dissolve with ethanol while stirring, and it is dissolved completely.In 50 ℃ of water-baths, with Rotary Evaporators, evaporate 30min~60min, by solvent evaporate to dryness.Collect solids, be placed in vacuum drying oven inner drying 1 day, after grinding, then be placed in abundant being dried in vacuum drying oven, obtain celecoxib solid dispersion E.
Embodiment 6
The preparation of solid dispersion F:
By 300g PLURONICS F87, heating in water bath to 70 ℃ thawing, adds the medicine 20g with 800mL acetic acid ethyl dissolution while stirring, and it is dissolved completely.In 50 ℃ of water-baths, with Rotary Evaporators, evaporate 30min~60min, by solvent evaporate to dryness.Collect solids, be placed in vacuum drying oven inner drying 2 days, after grinding, then be placed in abundant being dried in vacuum drying oven, obtain celecoxib solid dispersion F.
Embodiment 7
The preparation of solid dispersion G:
By 300g PLURONICS F87, heating in water bath to 90 ℃ thawing, adds the medicine 30g with 700mL dissolve with ethanol while stirring, fully stirs, and it is dissolved completely.Vacuum lyophilization 2 days, after grinding, obtains celecoxib solid dispersion G.
Embodiment 8
The preparation of solid dispersion H:
By 300g PLURONICS F87, heating in water bath to 60 ℃ thawing, adds the medicine 60g with 500mL dissolve with methanol while stirring, fully stirs, and it is dissolved completely.Vacuum lyophilization 2 days, after grinding, obtains celecoxib solid dispersion H.
Embodiment 9
Capsule containing celecoxib 100mg
Solid dispersion A is pulverized, cross 80 mesh sieves and mix with lactose, cross-linking sodium carboxymethyl cellulose, with polyvinylpyrrolidone, starch, granulate, dry, add magnesium stearate to mix, be distributed into 100 capsules, obtain the capsule containing celecoxib 100mg.
Embodiment 10
Capsule containing celecoxib 100mg
Solid dispersion B is pulverized, cross 80 mesh sieves, mix with micro-product cellulose, lactose, cross-linking sodium carboxymethyl cellulose, with polyvinylpyrrolidone, starch, granulate, dry, add magnesium stearate, be distributed into 100 capsules, obtain the capsule containing celecoxib 100mg.
Implement 11
Capsule containing celecoxib 100mg
Solid dispersion C is pulverized, cross 80 mesh sieves, mix with micro-product cellulose, lactose, cross-linking sodium carboxymethyl cellulose, with polyvinylpyrrolidone, starch, granulate, dry, add magnesium stearate, be distributed into 100 capsules, obtain the capsule containing celecoxib 100mg.
Embodiment 12
Capsule containing celecoxib 100mg
Solid dispersion C is pulverized, cross 80 mesh sieves, mix with micro-product cellulose, lactose, cross-linking sodium carboxymethyl cellulose, with polyvinylpyrrolidone, starch, granulate, dry, add magnesium stearate, be distributed into 100 capsules, obtain the capsule containing celecoxib 100mg.
Embodiment 13
Sheet containing celecoxib 100mg
Solid dispersion B is pulverized, cross 80 mesh sieves, with microcrystalline Cellulose, partly measure cross-linking sodium carboxymethyl cellulose and mix, with polyvinylpyrrolidone, starch, granulate, dry, add magnesium stearate and separately partly measure cross-linking sodium carboxymethyl cellulose and mix, compacting is heavily the plain sheet of 450mg in flakes, obtains the plain sheet containing celecoxib 100mg.
Embodiment 14
Granule containing celecoxib 200mg
Solid dispersion B is pulverized, cross 80 mesh sieves, mix with micro-product cellulose, lactose, polyvinylpolypyrrolidone, with starch, starch, granulate, dry, be distributed into 1100mg mono-bag, must be containing the granule of celecoxib 200mg.
The detection of dissolution
Dissolution medium: contain 1.0% sodium lauryl sulphate/0.04M sodium phosphate (pH=12).
Dissolving-out method: oar method, 50r/min, in 5,10,20,30,45,60,90min sampling
The oral formulations of getting embodiment 8,9,10,11,12,13,14 preparation, carries out respectively dissolution detection, and result is as table one:
Table one Dissolution Rate Testing data
Sample time (min) | 5 | 10 | 20 | 30 | 45 | 60 | 90 |
Embodiment 8 | 49.2% | 72.9% | 80.3% | 85.7% | 89.3% | 96.1% | 98.9% |
Embodiment 9 | 32.6% | 59.1% | 70.6% | 78.2% | 84.0% | 91.1% | 92.4% |
Embodiment 10 | 36.5% | 55.8% | 68.1% | 79.2% | 88.5% | 89.2% | 94.7% |
Embodiment 11 | 19.2% | 28.5% | 36.1% | 43.7% | 48.6% | 53.8% | 56.5% |
Embodiment 12 | 38.8% | 44.3% | 49.1% | 57.0% | 72.8% | 85.6% | 91.4% |
Embodiment 13 | 40.3% | 48.2% | 55.7% | 60.9% | 75.1% | 82.3% | 89.6% |
Embodiment 14 | 35.6% | 43.9% | 50.6% | 57.8% | 70.9% | 78.1% | 85.9% |
Stability test
Accelerated test: by after the product aluminum bag of embodiment 9 and embodiment 10, place 6 months under the condition of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%.In 0th month, 1 month, 2 months, 3 months, 6 samplings at the end of month of duration of test, by stability high spot reviews project, detect, the results are shown in Table two.
Table two accelerated test data
Long term test: by after the product aluminum bag of embodiment 9 and embodiment 10, under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10%, place 12 months, sampling in every 3 months once, respectively at 0 month, 3 months, 6 months, 9 months, 12 months, by stability high spot reviews project, detect, the results are shown in Table three.
Table three long term test data
As can be seen from the above data, gained celecoxib solid dispersion of the present invention has good stability and dissolution in vitro, can be used as the dosage form that celecoxib is new and is applied to clinical.
Above-described embodiment is only the preferred embodiments of the present invention; be not limited to the present invention; for a person skilled in the art; in the situation that not paying creative work; all any changes of doing within the spirit and principles in the present invention, within being all included in protection scope of the present invention.
Claims (9)
1. containing a solid dispersion for celecoxib, it is characterized in that this medicine solid dispersion comprises celecoxib and PLURONICS F87, in this solid dispersion, the weight ratio of celecoxib and PLURONICS F87 is 1: 1~1: 20, preferably 1: 5~1: 15.
2. the preparation method of solid dispersion claimed in claim 1, is characterized in that this preparation method is:
Fusion method or solvent-fusion method.
3. preparation method according to claim 2, is characterized in that fusion method comprises the steps:
Within 1: 1 in mass ratio~1: 20, take celecoxib and PLURONICS F87, at 55~90 ℃ first by PLURONICS F87 melting, again celecoxib is joined in PLURONICS F87, be stirred to homogeneous (uniform) fluid, fused mass impouring, in the container of-25~25 ℃, is spread out to straticulation shape, solidify, crushed after being dried, then be placed in vacuum drying oven inner drying, obtain celecoxib solid dispersion.
4. preparation method according to claim 2, is characterized in that solvent-fusion method comprises the steps:
Within 1: 1 in mass ratio~1: 20, take celecoxib and PLURONICS F87, celecoxib is dissolved in to organic solvent and forms mixed solution, and then mix with the PLURONICS F87 of heating and melting, stir 0.5~3 hour, remove organic solvent and solidify dry, grind, then be placed in vacuum drying oven inner drying, obtain celecoxib solid dispersion.
5. preparation method according to claim 4, is characterized in that described organic solvent is selected from one or more in methanol, ethanol, ethyl acetate, acetone, dichloromethane, particular methanol.
6. preparation method according to claim 4, is characterized in that removing organic solvent and solidifies drying steps and can adopt following method:
Decompression rotary evaporation solvent, solidifies vacuum drying;
Or vacuum freezing, vacuum drying.
7. a preparation for solid dispersion claimed in claim 1, is characterized in that the PLURONICS F87 solid dispersion of the celecoxib through pulverizing mixes with acceptable adjuvant in pharmaceutical preparation, and formulation method is made oral solid formulation routinely.
8. the preparation of solid dispersion according to claim 7, is characterized in that described adjuvant is selected from one or more in diluent, disintegrating agent, binding agent, lubricant, antioxidant, adsorbent, correctives.
9. the preparation of solid dispersion according to claim 7, the preparation that it is characterized in that solid dispersion is oral solid formulation, preferred tablet, capsule, granule.
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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 |
CN105287384A (en) * | 2014-06-23 | 2016-02-03 | 天津金耀集团有限公司 | Lactose celecoxib solid dispersoid combination prepared through fusion method |
WO2017103677A1 (en) * | 2015-12-16 | 2017-06-22 | Druggability Technologies Ip Holdco Limited | Complexes of celecoxib and its salts and derivatives process for the preparation thereof and pharmaceutical compositions containing them |
US10507214B2 (en) | 2016-12-14 | 2019-12-17 | Druggability Technologies Ip Holdco Limited | Pharmaceutical composition containing celecoxib |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105287384A (en) * | 2014-06-23 | 2016-02-03 | 天津金耀集团有限公司 | Lactose celecoxib solid dispersoid combination prepared through fusion method |
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 |
WO2017103677A1 (en) * | 2015-12-16 | 2017-06-22 | Druggability Technologies Ip Holdco Limited | Complexes of celecoxib and its salts and derivatives process for the preparation thereof and pharmaceutical compositions containing them |
US10307429B2 (en) | 2015-12-16 | 2019-06-04 | Druggability Technologies Ip Holdco Limited | Complexes of celecoxib and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
US10688110B2 (en) | 2015-12-16 | 2020-06-23 | Nangenex Nanotechnology Incorporated | Complexes of Celecoxib and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
US10507214B2 (en) | 2016-12-14 | 2019-12-17 | Druggability Technologies Ip Holdco Limited | Pharmaceutical composition containing celecoxib |
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Application publication date: 20140326 |