CN105147607A - Celecoxib nanosuspension and preparation method thereof - Google Patents
Celecoxib nanosuspension and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical preparations and provides a Celecoxib nanosuspension and a preparation method thereof. Celecoxib is a novel non-steroidal anti-inflammatory drug, inhibits cyclooxygenase -2(COX-2) is through specificity, has anti-inflammatory and pain-easing effects and is clinically used for treating osteoarthritis and rheumatoid arthritis. However, the Celecoxib has very low solubility and in-vivo bioavailability. In order to increase the dissolution and the bioavailability of the drug, a high-speed shearing combined high-pressure homogenizing method is adopted to prepare the Celecoxib nanosuspension, the particle size and the polydispersion index PI are used as indicators for formulation technology optimization, a laser particle analyzer and a transmission electron microscope are adopted to study the particle size and form of the drug, the dissolution of the drug is evaluated through in-vitro dissolution experiments, and rat in-vivo pharmacokinetic study is conducted. Measurement results prove that the drug particle size of the nanosuspension is 50-500 nm, and the dissolution and the in-vivo bioavailability of the drug are increased obviously.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly relate to a kind of celecoxib nano suspension and preparation method thereof.
Background technology
Celecoxib (celecoxib) is a kind of NSAID (non-steroidal anti-inflammatory drug) (NSAID
s), Transitional cell carcinomas (COX-2) can be suppressed by specificity, stop the generation of inflammatory prostaglandins, and then play antiinflammatory, analgesia and refrigeration function.Be mainly used in treatment osteoarthritis, rheumatoid arthritis and periphery and central analgesia clinically.
Celecoxib is dissolved in methanol, ethanol, dimethyl sulfoxine, acetone and other organic solvent and be insoluble in water, and in water, dissolubility is only 3 ~ 7 μ g/mL (pH7,40 DEG C), belongs to Biopharmaceutics Classification system BCSII class medicine.The gastrointestinal absorption that dissolubility extremely low in celecoxib water directly causes this medicine poor and lower oral administration biaavailability, strongly limit its clinical practice.The existing different dosage forms such as solid dispersion, Benexate Hydrochloride, microsphere, gel of being made by celecoxib are to improve the correlational study report of its undesirable feature both at home and abroad.Disclose in Chinese patent CN102988296A and a kind of Celecoxib solid dispersion and preparation method thereof; A kind of Benexate Hydrochloride containing celecoxib and preparation method thereof is disclosed in Chinese patent CN103405782A; A kind of celecoxib microsphere and preparation method thereof is disclosed in Chinese patent CN103610649A.But the preparation process of above-mentioned preparation all needs to use organic solvent, and there are dissolvent residual, preparation process complexity, preparation cost higher, are all unfavorable for large-scale industrial production.
A kind of sub-micrometer colloidal dispersion that nano suspension system adopts the pure drug particle of a small amount of surfactants stabilize to be formed.Research finds, nano suspension can increase drug dissolution, improves the bioavailability of medicine, increases medicine stability and improve drug effect, and this makes the narrow medicine of poorly soluble antibiotics, antitumor drug and some treatment windows play better effect.The advantage of nano suspension is that (1) drug particle is little, specific surface area increases, and increases the adhesion of skin surface and cell membrane; (2) dosage of surfactant is few, and toxic and side effects is little; (3) method such as lyophilization, spraying dry can be used, nanosuspension is solidified, increase the stability of preparation.(4) preparation technology is comparatively simple, is easy to suitability for industrialized production.The method preparing nano suspension at present mainly comprises media milling process, high pressure homogenization method, the anti-solvent sedimentation method, emulsion process and supercritical fluid technology.In recent years, derive multiple combination preparation method based on the above method, particularly high speed shear associating high pressure homogenization method, simple and easy, the preparation process of this method operation is without the need to organic solvent and the wearing and tearing that there is not abrasive media material cause the problem of contamination of products, is thus specially adapted to industrialized great production.
At present, the listing kind of celecoxib is the Celebret (celecoxib) researched and developed by Pfizer, due to capsule formulation, not improve celecoxib bioavailability low, the defects such as drug use dosage is large, therefore still need to develop a kind of celecoxib preparation, on the basis overcoming crude drug character deficiency, significantly improve drug bioavailability, and reduce kind and the consumption of adjuvant as far as possible, and celecoxib nano suspension a kind of like this new formulation with significant application value and broad mass market prospect just.
Summary of the invention
The object of this invention is to provide a kind of celecoxib nano suspension and preparation method thereof, to improve the slightly water-soluble of celecoxib and to improve its bioavailability.
The technical solution used in the present invention is as follows: a kind of celecoxib nano suspension, and containing celecoxib and stabilizing agent, the mass ratio of celecoxib and stabilizing agent is 1: 0.1 ~ 1: 2.
As preferably, described stabilizing agent comprise in following compounds one or more: Tween 80, sodium lauryl sulphate, polyvinyl alcohol, polyvinylpyrrolidone, poloxamer, Polyethylene Glycol, hypromellose, sodium carboxymethyl cellulose, D-alpha-tocopherol cetomacrogol 1000 succinate (TPGS).
As preferably, in described nano suspension, the mean diameter of celecoxib is 50 ~ 500nm.
The preparation method of celecoxib nano suspension of the present invention adopts high speed shear in conjunction with high pressure homogenization method, and its preparation process is as follows:
(1) by formation aqueous dispersion medium soluble in water for stabilizing agent;
(2) celecoxib powder is slowly poured in disperse medium, is placed in the ultrasonic 5min of ultrasonic washing unit, celecoxib is scattered in stabilizing agent aqueous solution, and under 8000 ~ 16000rpm high speed shear process 1 ~ 10min, obtain thick suspension;
(3) the thick suspension that above-mentioned high speed shear obtains is placed in high pressure homogenizer, after certain condition homogenizing, obtains described nano suspension.
As preferably, in described step (1) disperse medium, the mass body volume concentrations of stabilizing agent is 0.02 ~ 2%; The mass body volume concentrations of described step (2) disperse medium Chinese medicine is 0.1 ~ 5%; Described step (3) high pressure homogenize condition is circulate 2 ~ 5 times under 200 ~ 300bar, circulates 8 ~ 15 times under 500 ~ 1000bar.
The present invention also provides a kind of application of celecoxib nano suspension, and described celecoxib nano suspension is obtained celecoxib nanosuspension frozen powder end through lyophilization.
As preferably, described freeze drying protectant is selected from: one or more combination in mannitol, lactose, glucose, trehalose, sorbitol, sucrose.
The present invention finds through screening, celecoxib is prepared into nano suspension, has good particle size distribution and dissolution rate, can be used for the treatment of disease for oral, injection and Transdermal delivery systems.
The invention has the advantages that:
(1) celecoxib nano suspension of the present invention, simply, stabilizing agent dosage is few for prescription and technique, and preparation process is without the need to an organic solvent, and gained preparation safety is effective, and cost is lower, is easy to industrialization.
(2) this nano suspension particle diameter is little, narrowly distributing, good stability, and effectively can increase dissolubility and the dissolution rate of medicine, in body, bioavailability also significantly improves.
(3) celecoxib nano suspension of the present invention solidifies further by Freeze Drying Technique, effectively improves the stability in storage and transportation.Freeze drying process better can keep chemical composition and the physical property of material self; can prevent the adding of freeze drying protectant growing up and assembling of particle in freeze-drying process, the nanosuspension frozen powder thus redissolved still can keep the original good nature of nanosuspension.
Accompanying drawing explanation
The grain size distribution of Fig. 1 celecoxib nano suspension
The transmission electron microscope picture of Fig. 2 celecoxib nano suspension
The stripping curve of Fig. 3 celecoxib nano suspension, physical mixture and celecoxib crude drug
Fig. 4 celecoxib and nano suspension thereof be mean blood plasma concentration-time graph (n=5) in rat body
Detailed description of the invention
Below will the present invention will be further described by specific embodiment, but it is pointed out that following examples can not form any limitation of the invention.
Embodiment 1
Take 0.25g hypromellose, adding 100mL pure water makes it dissolve completely, take the celecoxib crude drug of 0.5g, under agitation slowly pour in the aqueous solution containing hypromellose, be placed in the ultrasonic 5min of ultrasonic washing unit, make celecoxib be scattered in stabilizing agent aqueous solution, high-speed shearing machine 10000rpm shears 5min, obtains just suspension.By gained just suspension impouring high pressure homogenize machine inlet capable, 200bar circulates 5 times, and 800bar circulates 15 times, obtains celecoxib nano suspension.The mean diameter of the celecoxib nano suspension that this legal system is standby is 382.2nm, PI is 0.15, and the settling ratio placed after 48h is 95.7%.
Embodiment 2
Take 0.25g PLURONICS F87, adding 100mL pure water makes it dissolve completely, take the celecoxib crude drug of 0.5g, under agitation slowly pour in the aqueous solution containing PLURONICS F87, be placed in the ultrasonic 5min of ultrasonic washing unit, make celecoxib be scattered in stabilizing agent aqueous solution, high-speed shearing machine 10000rpm shears 5min, obtains just suspension.By gained just suspension impouring high pressure homogenize machine inlet capable, 200bar circulates 5 times, and 800bar circulates 15 times, obtains celecoxib nano suspension.The mean diameter of the celecoxib nano suspension that this legal system is standby is 251.3nm, PI is 0.30, and the settling ratio placed after 48h is 92.5%.
Embodiment 3
Take 0.25g PVP K30, adding 100mL pure water makes it dissolve completely, take the celecoxib crude drug of 0.5g, under agitation slowly pour in the aqueous solution containing PVP K30, be placed in the ultrasonic 5min of ultrasonic washing unit, make celecoxib be scattered in stabilizing agent aqueous solution, high-speed shearing machine 10000rpm shears 5min, obtains just suspension.By gained just suspension impouring high pressure homogenize machine inlet capable, 200bar circulates 5 times, and 800bar circulates 15 times, obtains celecoxib nano suspension.The mean diameter of the celecoxib nano suspension that this legal system is standby is 265.3nm, PI is 0.29, and the settling ratio placed after 48h is 96.2%.
Embodiment 4
Take 0.25gD-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), adding 100mL pure water makes it dissolve completely, take the celecoxib crude drug of 0.5g, under agitation slowly pour in the aqueous solution containing D-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), be placed in the ultrasonic 5min of ultrasonic washing unit, make celecoxib be scattered in stabilizing agent aqueous solution, high-speed shearing machine 10000rpm shears 5min, obtains just suspension.By gained just suspension impouring high pressure homogenize machine inlet capable, 200bar circulates 5 times, and 800bar circulates 15 times, obtains celecoxib nano suspension.The mean diameter of the celecoxib nano suspension that this legal system is standby is 215nm, PI is 0.25, and the settling ratio placed after 48h is 98.1%.
Embodiment 5
Take 0.05gD-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), adding 100mL pure water makes it dissolve completely, take the celecoxib crude drug of 0.5g, under agitation slowly pour in the aqueous solution containing D-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), be placed in the ultrasonic 5min of ultrasonic washing unit, make celecoxib be scattered in stabilizing agent aqueous solution, high-speed shearing machine 10000rpm shears 5min, obtains just suspension.By gained just suspension impouring high pressure homogenize machine inlet capable, 200bar circulates 5 times, and 800bar circulates 15 times, obtains celecoxib nano suspension.The mean diameter of the celecoxib nano suspension that this legal system is standby is 50.3nm, PI is 0.26, and the settling ratio placed after 48h is 92.2%.
Embodiment 6
Take 0.125gD-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), adding 100mL pure water makes it dissolve completely, take the celecoxib crude drug of 0.5g, under agitation slowly pour in the aqueous solution containing D-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), be placed in the ultrasonic 5min of ultrasonic washing unit, make celecoxib be scattered in stabilizing agent aqueous solution, high-speed shearing machine 10000rpm shears 5min, obtains just suspension.By gained just suspension impouring high pressure homogenize machine inlet capable, 200bar circulates 5 times, and 800bar circulates 15 times, obtains celecoxib nano suspension.The mean diameter of the celecoxib nano suspension that this legal system is standby is 192.9nm (Fig. 1), PI is 0.2, and the settling ratio placed after 48h is 97.4%.
Embodiment 7
Take 0.125gD-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), adding 100mL pure water makes it dissolve completely, take the celecoxib crude drug of 0.5g, under agitation slowly pour in the aqueous solution containing D-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), be placed in the ultrasonic 5min of ultrasonic washing unit, make celecoxib be scattered in stabilizing agent aqueous solution, high-speed shearing machine 10000rpm shears 5min, obtains just suspension.By gained just suspension impouring high pressure homogenize machine inlet capable, 200bar circulates 5 times, and 650bar circulates 15 times, obtains celecoxib nano suspension.The mean diameter of the celecoxib nano suspension that this legal system is standby is 311.7nm, PI is 0.353, and the settling ratio placed after 48h is 95.3%.
Embodiment 8
Take 0.125gD-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), adding 100mL pure water makes it dissolve completely, take the celecoxib crude drug of 0.5g, under agitation slowly pour in the aqueous solution containing D-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), be placed in the ultrasonic 5min of ultrasonic washing unit, make celecoxib be scattered in stabilizing agent aqueous solution, high-speed shearing machine 10000rpm shears 5min, obtains just suspension.By gained just suspension impouring high pressure homogenize machine inlet capable, 200bar circulates 5 times, and 800bar circulates 15 times, obtains celecoxib nano suspension.Mannitol is added in obtained celecoxib nanosuspension, stir and make it fully dissolve, after being placed in the refrigerator pre-freeze 12h of-60 DEG C, proceed to lyophilization 48h in freezer dryer immediately, obtain the full loose celecoxib nanosuspension frozen powder of outward appearance.Obtained freeze-drying powder adds water and easily redissolves, and particle diameter is 414.2nm, PI is 0.35.
Embodiment 9
Take 0.125gD-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), adding 100mL pure water makes it dissolve completely, take the celecoxib crude drug of 0.5g, under agitation slowly pour in the aqueous solution containing D-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), be placed in the ultrasonic 5min of ultrasonic washing unit, make celecoxib be scattered in stabilizing agent aqueous solution, high-speed shearing machine 10000rpm shears 5min, obtains just suspension.By gained just suspension impouring high pressure homogenize machine inlet capable, 200bar circulates 5 times, and 800bar circulates 15 times, obtains celecoxib nano suspension.Lactose is added in obtained celecoxib nanosuspension, stir and make it fully dissolve, after being placed in the refrigerator pre-freeze 12h of-60 DEG C, proceed to lyophilization 48h in freezer dryer immediately, obtain the full loose celecoxib nanosuspension frozen powder of outward appearance.Obtained freeze-drying powder adds water and easily redissolves, and particle diameter is 388.1nm, PI is 0.21.Utilize transmission electron microscope observing, result display drug particle is corynebacterium (Fig. 2).
Embodiment 10
Take 0.125gD-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), adding 100mL pure water makes it dissolve completely, take the celecoxib crude drug of 0.5g, under agitation slowly pour in the aqueous solution containing D-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), be placed in the ultrasonic 5min of ultrasonic washing unit, make celecoxib be scattered in stabilizing agent aqueous solution, high-speed shearing machine 10000rpm shears 5min, obtains just suspension.By gained just suspension impouring high pressure homogenize machine inlet capable, 200bar circulates 5 times, and 800bar circulates 15 times, obtains celecoxib nano suspension.Glucose is added in obtained celecoxib nanosuspension, stir and make it fully dissolve, after being placed in the refrigerator pre-freeze 12h of-60 DEG C, proceeding to immediately in freezer dryer and carry out lyophilization 48h, obtain the celecoxib nanosuspension frozen powder of white loose.Obtained freeze-drying powder adds water and can redissolve, and particle diameter is 473.5nm, PI is 0.42.
Embodiment 11
Celecoxib nano suspension study in vitro dissolution
The celecoxib nano suspension of celecoxib crude drug, physical mixture and the embodiment of the present invention 9 is carried out dissolution contrast experiment, and the sample of different time points is through assay and calculate accumulation stripping percent.Result shows celecoxib nano suspension dissolution rate prepared by the present invention apparently higher than celecoxib crude drug and physical mixture, sees Fig. 3.
1. Dissolution experiments method
Get celecoxib micronization crude drug, physical mixture, each 6 parts of nanosuspension frozen powder end, every part is equivalent to celecoxib 50mg, be placed in stripping rotor, by " Chinese Pharmacopoeia " version in 2010 second annex XC dissolution determination second method (paddle method), with 0.3%SDS aqueous solution for dissolution medium, temperature (37 ± 0.5) DEG C, rotating speed is 50rpm/min, in 5,10,15,20,30,45,60min samples 5mL, supplements equivalent isothermal dissolution medium simultaneously.Sample, in the centrifugal 5min of 10000rpm, is got supernatant and is injected HPLC detection.
2.HPLC chromatographic condition
Chromatographic column: Chinese nation HederaODS-2 post (250mm × 4.6mm, 5 μm); Mobile phase: methanol-water (78: 22); Determined wavelength: 252nm; Flow velocity: 1.0mL/min; Column temperature: 30 DEG C; Sampling volume: 20 μ L
3. linear relationship is investigated
It is appropriate that precision takes celecoxib standard substance, put in 50mL volumetric flask, is diluted to scale, obtains the celecoxib reference substance storing solution that mass concentration is 1mg/mL with dissolve with methanol.Precision measures storing solution in right amount in 10mL volumetric flask respectively, with methanol dilution to scale, obtain the series standard solution that concentration is respectively 1,10,25,50,100,150,200 μ g/mL, measure as stated above, with peak area (A), linear regression is carried out to mass concentration (C), obtain regression equation A=67058C-26876 (R
2=0.9999), show that celecoxib peak area and drug level in 1 ~ 200 μ g/mL are good linear relationship.
Embodiment 12
The oral administration biaavailability research of celecoxib nano suspension
Adopt male SD rat (200g ~ 220g) 10, be divided at random two groups (n=5), before administration, fasting 12h, freely drinks water.Two groups of rats respectively gavage give embodiment 9 and prepare gained celecoxib nano suspension and celecoxib micronization crude drug (mean diameter 3.7 μm), dosage 40mg/kg.
1. blood specimen collection
Respectively at after administration 0.25,0.5,1,1.5,2,3,4,6,8,12,24,36h gets blood 0.3mL in rat eye socket, be placed in the centrifuge tube of heparinization, the centrifugal 10min of 10000rpm, get upper plasma-20 DEG C and save backup.
2. chromatographic condition
Chromatographic column: inertsilODS-SP (4.6 × 150mm, 5 μm); Mobile phase: methanol-water (70: 30); Determined wavelength: 252nm; Flow velocity: 1mL/min; Column temperature: 30 DEG C; Interior mark: diazepam; Sampling volume: 20 μ L.
3. data analysis
Adopt pharmacokinetics software DAS2.1 to calculate pharmacokinetic parameters, result shows, the AUC of celecoxib micronization crude drug is 63.40mg/Lh, and the AUC of nano suspension is 155.86mg/Lh, and the blood concentration-time curve of celecoxib in rat body as shown in Figure 4.Using celecoxib micronization crude drug as reference, the relative bioavailability of celecoxib nano suspension is 245.84%, illustrates that this nano suspension can improve the oral administration biaavailability of celecoxib.
Claims (9)
1. a celecoxib nano suspension, is characterized in that, containing celecoxib and stabilizing agent, the mass ratio of celecoxib and stabilizing agent is 1: 0.1 ~ 1: 2.
2. celecoxib nano suspension according to claim 1, it is characterized in that, described stabilizing agent is selected from: one or more in Tween 80, sodium lauryl sulphate, polyvinyl alcohol, polyvinylpyrrolidone, poloxamer, Polyethylene Glycol, hypromellose, sodium carboxymethyl cellulose, D-alpha-tocopherol cetomacrogol 1000 succinate (TPGS).
3. celecoxib nano suspension according to claim 1 and 2, is characterized in that, in described nano suspension, the particle diameter of celecoxib is 50 ~ 500nm.
4. a preparation method for celecoxib nano suspension, is characterized in that: adopt high speed shear in conjunction with high pressure homogenization method.
5. the preparation method of celecoxib nano suspension according to claim 4, is characterized in that, comprise the steps:
(1) by formation aqueous dispersion medium soluble in water for stabilizing agent;
(2) celecoxib powder is slowly poured in disperse medium, is placed in the ultrasonic 5min of ultrasonic washing unit, celecoxib is scattered in stabilizing agent aqueous solution, and under 8000 ~ 16000rpm high speed shear process 1 ~ 10min, obtain thick suspension;
(3) the thick suspension that above-mentioned high speed shear obtains is placed in high pressure homogenizer, after certain condition homogenizing, obtains described nano suspension.
6. preparation method according to claim 5, is characterized in that, in described step (1) disperse medium, the mass body volume concentrations of stabilizing agent is 0.02 ~ 2%; In described step (2) disperse medium, the mass body volume concentrations of celecoxib is 0.1 ~ 5%; Described step (3) high pressure homogenize condition is circulate 2 ~ 5 times under 200 ~ 300bar, circulates 8 ~ 15 times under 500 ~ 1000bar.
7. the application of celecoxib nano suspension described in any one of Claims 1 to 5, is characterized in that, described celecoxib nano suspension obtains celecoxib nanosuspension frozen powder end through lyophilization.
8. the application of celecoxib nano suspension according to claim 7; it is characterized in that; add freeze drying protectant in lyophilization step, described freeze drying protectant is selected from: one or more combination in mannitol, lactose, glucose, trehalose, sorbitol, sucrose.
9. the application of celecoxib nano suspension according to claims 1 to 8, is characterized in that, can be used for the treatment of disease for oral, injection and Transdermal delivery systems.
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| CN105534947A (en) * | 2016-02-16 | 2016-05-04 | 山东省药学科学院 | Preparation method of celecoxib nanosuspension capsules |
| CN106166141A (en) * | 2016-09-11 | 2016-11-30 | 复旦大学 | A kind of Multifunctional composite nanometer medicine for tumor imaging and treatment and preparation method thereof |
| CN107281100A (en) * | 2016-03-30 | 2017-10-24 | 上海现代药物制剂工程研究中心有限公司 | A kind of preparation method of insoluble drug nanosuspension |
| CN109528737A (en) * | 2018-12-05 | 2019-03-29 | 天津医科大学 | Sodium alginate anti-tumor nano preparation and preparation method |
| CN110840850A (en) * | 2018-07-24 | 2020-02-28 | 烟台药物研究所 | Celecoxib freeze-dried orally disintegrating tablet with high bioavailability and preparation method thereof |
| CN111135761A (en) * | 2019-12-30 | 2020-05-12 | 上海亮仓能源科技有限公司 | Preparation method of anti-settling fuel cell catalyst slurry |
| CN111297876A (en) * | 2020-01-16 | 2020-06-19 | 武汉理工大学 | Celecoxib micelle and honokiol micelle drug combination controlled release system and preparation method thereof |
| CN111557914A (en) * | 2019-02-14 | 2020-08-21 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition containing ereoxib |
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| CN105534947A (en) * | 2016-02-16 | 2016-05-04 | 山东省药学科学院 | Preparation method of celecoxib nanosuspension capsules |
| CN107281100B (en) * | 2016-03-30 | 2021-05-07 | 上海现代药物制剂工程研究中心有限公司 | Preparation method of insoluble drug nanosuspension |
| CN107281100A (en) * | 2016-03-30 | 2017-10-24 | 上海现代药物制剂工程研究中心有限公司 | A kind of preparation method of insoluble drug nanosuspension |
| CN106166141A (en) * | 2016-09-11 | 2016-11-30 | 复旦大学 | A kind of Multifunctional composite nanometer medicine for tumor imaging and treatment and preparation method thereof |
| CN113679669A (en) * | 2017-08-15 | 2021-11-23 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition containing ereoxib |
| CN110840850A (en) * | 2018-07-24 | 2020-02-28 | 烟台药物研究所 | Celecoxib freeze-dried orally disintegrating tablet with high bioavailability and preparation method thereof |
| CN110840850B (en) * | 2018-07-24 | 2023-03-17 | 烟台药物研究所 | Celecoxib freeze-dried orally disintegrating tablet with high bioavailability and preparation method thereof |
| CN109528737B (en) * | 2018-12-05 | 2021-08-13 | 天津医科大学 | Polysaccharide sulfate anti-tumor nano preparation and preparation method thereof |
| CN109528737A (en) * | 2018-12-05 | 2019-03-29 | 天津医科大学 | Sodium alginate anti-tumor nano preparation and preparation method |
| CN111557914A (en) * | 2019-02-14 | 2020-08-21 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition containing ereoxib |
| WO2020258081A1 (en) * | 2019-06-26 | 2020-12-30 | 杭州艾瑞莎生物医药科技有限公司 | Low-dose celecoxib preparation |
| CN114340638A (en) * | 2019-06-26 | 2022-04-12 | 杭州艾瑞莎生物医药科技有限公司 | Low dose celecoxib formulations |
| CN111135761A (en) * | 2019-12-30 | 2020-05-12 | 上海亮仓能源科技有限公司 | Preparation method of anti-settling fuel cell catalyst slurry |
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