CN113679669B - Pharmaceutical composition containing erexib - Google Patents
Pharmaceutical composition containing erexib Download PDFInfo
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Abstract
The present invention relates to a pharmaceutical composition comprising ereoxib. Specifically, the invention relates to a pharmaceutical composition containing ereoxib, wherein the particle size D90 of the ereoxib is less than 20 μm. The active metabolism of the erexib in the pharmaceutical composition in vivo is greatly enhanced, so that the erexib exists in the form of more active metabolites in vivo, and the therapeutic effect of the drug is enhanced.
Description
The application is a divisional application of Chinese patent application with the application number of 201810919234.4, the application date of 2018, 08 and 14 months, and the invention name of 'a pharmaceutical composition containing ereoxib'.
Technical Field
The invention relates to a pharmaceutical composition containing ereoxib and a preparation method thereof.
Background
Osteoarthritis (OA) is a common refractory degenerative disease, with an increasing incidence of age, with no apparent ethnic or geographic differences. Osteoarthritis ranks second only to cardiovascular disease in diseases that lead to long-term disability in people over the age of 50. The osteoarthritis disabling proportion is about 2% to 6% in the population. The data of the world health organization shows that the number of patients with global arthritis is up to 3.55 hundred million, and the number of patients with Chinese arthritis is up to 1 hundred million. The arthritic diseases are composed of two different diseases, rheumatoid arthritis and rheumatoid arthritis. According to statistics, about 62% of people over 60 years old in China have osteoarthritis, and the prevalence rate of people over 75 years old is as high as 80%. Osteoarthritis is more likely to affect the ability of elderly patients to walk, ascend and descend stairs, and other lower limb functions than other diseases. Therefore, osteoarthritis is a major disease that causes functional disability, economic loss, and affects social development in people over 50 years of age. The knee joint, which is the joint primarily responsible, is one of the most vulnerable joints in osteoarthritis.
The chemical name of the imrechoxib (Imrechoxib) is 1-n-propyl-3- (4-methylphenyl) -4- (4-methylsulfonylphenyl) -2, 5-dihydro-1H-2-pyrrolidone, which belongs to the family of non-steroidal anti-inflammatory drugs, and the imrechoxib reduces inflammation and relieves pain by inhibiting the generation of prostaglandin and derivatives thereof through selectively inhibiting cyclooxygenase-2 (COX-2). While avoiding gastrointestinal toxicity associated with inhibition of COX-1 by NSAIDs.
After entering the human body, the ereoxib is converted into various metabolites. The metabolic mechanism of ereoxib in humans has been reported by Zhijiang Feng et al (Bioorganic & Medicinal Chemistry Letters,19(2009), 2270-. Wherein, the ereoxib is mainly converted into 7 metabolites in human body, and only a small part of the ereoxib exists in the form of proto-type drug. Wherein the metabolite M4 and prototype drug have high COX-2 inhibitory activity, and the metabolite M2 has substantially no COX-2 inhibitory activity.
The erexib is approved to be marketed in 2011 in China, and the marketed dosage form is a common tablet with the specification of 0.1 g. According to researches, in the common tablets on the market at present, after the ereoxib enters a human body, a large amount of the ereoxib is converted into an inactive metabolite M2 (about 75%), and only a small amount of the ereoxib is converted into an active metabolite M4, so that the COX-2 inhibition capacity of the ereoxib is poor, and the treatment effect is not ideal. Therefore, there is a need for improvement of the preparation of dapoxib, increase of the content of the active metabolite M4 in vivo, decrease of the conversion of the inactive metabolite M2, and improvement of the therapeutic effect of the drug.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a pharmaceutical composition containing ereoxib, and the pharmaceutical composition can improve the treatment effect of the ereoxib.
In one aspect of the invention there is provided a pharmaceutical composition comprising ereoxib, wherein the particle size D90 of ereoxib is less than 20 μm, such as less than 15 μm, or less than 12 μm, or less than 10 μm, or less than 9 μm, or less than 8 μm, or less than 7 μm, or less than 6 μm, or less than 5 μm, or less than 4 μm, or less than 3 μm, such as from 50nm to 3um, preferably from 1100 to 2500nm, more preferably from 200 to 2000nm, most preferably from 200 to 600 nm. D50 is less than 5 μm, preferably less than 4 μm, or less than 3 μm, or less than 2 μm, or less than 1 μm, more preferably 10 to 600nm, most preferably 50 to 500 nm. D10 is less than 2 μm, preferably less than 1 μm, or less than 500nm, more preferably 5 to 300nm, most preferably 10 to 200 nm.
In certain embodiments, the particle size D50 of the ereoxib is less than 5 μm, D10 is less than 2 μm; preferably D50 is less than 2 μm, D10 is less than 500 nm; more preferably, D50 is 10-800 nm, D10 is 5-300 nm; most preferably, D50 is 50 to 600nm, and D10 is 10 to 200 nm.
In certain embodiments, the pharmaceutical composition further comprises a surface stabilizer, which may be various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface stabilizers may be nonionic, anionic, cationic and zwitterionic compounds or surfactants. Such as polyvinylpyrrolidone (PVP), polyvinyl alcohol, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyethylene glycol 1000 Vitamin E succinate (Vitamin E TPGS), tween 80, poloxamer, polyethylene glycol 15-hydroxystearate, lecithin, sodium deoxycholate, sodium cholate, sodium docusate, sodium lauryl sulfate, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated castor oil 40, hydroxypropyl cellulose, tyloxapol, polyglycerol-10 laurate, carbomer, copovidone, with one or more of copovidone, hydroxypropylmethyl cellulose, polyethylene glycol 1000 Vitamin E succinate, polyvinylpyrrolidone, sodium lauryl sulfate, tween 80, poloxamer, and sodium docusate being preferred.
Useful nonionic surface stabilizers include, but are not limited to, hydroxypropylmethyl cellulose (HPMC), polyvinylpyrrolidone, poloxamer, tween-80, polyhydroxystearate 15, polyoxyethylated castor oil 35, polyoxyethylated hydrogenated castor oil 40, hydroxypropyl cellulose, polyethylene glycol 1000 Vitamin E succinate (Vitamin E TPGS), polyvinyl alcohol, tyloxapol, polyglycerol-10 laurate, carbomer, copovidone.
Useful anionic surface stabilizers include, but are not limited to, sodium dioctyl succinate (DOSS), Sodium Lauryl Sulfate (SLS), Sodium Dodecyl Sulfate (SDS), sodium docusate, sodium cholate and sodium deoxycholate, potassium oleate.
Useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, poly-N-methylpyridinium, pyridinium sulfate chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polystyrene, polymethyl methacrylate trimethylammonium bromide (PMMTMABr), hexyl methyl trimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl dimethyl methacrylate sulfate.
Useful zwitterionic surface stabilizers include, but are not limited to, proteins, phospholipids, zwitterionic polymers, and zwitterionic surfactant molecules, which can be, for example, phosphatidylcholine, lecithin, gelatin, and the like.
The weight ratio of the ereoxib to the surface stabilizer can be 1: 0.01-1: 100, preferably 1: 0.01-1: 50, more preferably 1: 0.05-1: 5, and most preferably 1: 0.1-1: 1.
In certain preferred embodiments, the surface stabilizer comprises a first surface stabilizer selected from HPMC, copovidone, PVPK30, and a second surface stabilizer selected from tween 80, sodium docusate, Vitamin E TPGS, poloxamer, or sodium lauryl sulfate.
Wherein the weight ratio of the ereoxib to the first surface stabilizer can be 1: 0.01-1: 100, preferably 1: 0.01-1: 50, more preferably 1: 0.05-1: 5, and most preferably 1: 0.1-1: 1.
Wherein the weight ratio of the ereoxib to the second surface stabilizer can be 1: 0.01-1: 100, preferably 1: 0.01-1: 50, more preferably 1: 0.01-1: 5, and most preferably 1: 0.01-1: 1.
In the pharmaceutical composition, the content of the ereoxib can be 0.1-1000 mg, preferably 10-800 mg, and more preferably 50-500 mg.
In certain embodiments, the pharmaceutical composition further comprises a filler, which may be one or more of microcrystalline cellulose, dibasic calcium phosphate, mannitol, pregelatinized starch, lactose, and the like. The filler is present in an amount of about 5% to about 80% based on the total weight of the composition.
In certain embodiments, the pharmaceutical composition further comprises a disintegrant, which may be one or more of croscarmellose sodium, starch, sodium carboxymethyl starch, and crospovidone. The disintegrant may be present in an amount of 1% to 20%, based on the total weight of the composition.
In certain embodiments, the pharmaceutical composition further comprises a lubricant, which may be one or more of magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, aerosil, talc, colloidal silicon dioxide, preferably one or more of magnesium stearate and colloidal silicon dioxide. The lubricant may be present in an amount of 0.5% to 5% based on the total weight of the composition.
In another aspect of the invention there is provided a particle dispersion comprising ereoxib, wherein the particle size D90 of the ereoxib is less than 20 μm, such as less than 15 μm, or less than 12 μm, or less than 10 μm, or less than 9 μm, or less than 8 μm, or less than 7 μm, or less than 6 μm, or less than 5 μm, or less than 4 μm, or less than 3 μm, such as from 50nm to 3um, preferably from 1100 to 2500nm, more preferably from 200 to 2000nm, most preferably from 200 to 600 nm. D50 is less than 5 μm, preferably less than 4 μm, or less than 3 μm, or less than 2 μm, or less than 1 μm, more preferably 10 to 800nm, most preferably 50 to 600 nm. D10 is less than 2 μm, preferably less than 1 μm, or less than 500nm, more preferably 5 to 300nm, most preferably 10 to 200 nm.
In certain embodiments, the particle size D50 of the ereoxib is less than 5 μm, D10 is less than 2 μm; preferably D50 is less than 2 μm, D10 is less than 500 nm; more preferably, D50 is 10-800 nm, D10 is 5-300 nm; most preferably, D50 is 50 to 600nm, and D10 is 10 to 200 nm.
The particle dispersion further comprises a surface stabilizer, as described above, preferably a surface stabilizer selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyethylene glycol 1000 Vitamin E succinate (Vitamin E TPGS), polyethylene glycol 15-hydroxystearate, Tween 80, poloxamer, polyethylene glycol 15-hydroxystearate, lecithin, sodium deoxycholate, sodium cholate, sodium docusate, sodium lauryl sulfate, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated castor oil 40, hydroxypropyl cellulose, tyloxapol, polyglycerol-10 laurate, carbomer, and copovidone, wherein copovidone, hydroxypropylmethyl cellulose, polyethylene glycol 1000 Vitamin E succinate, polyvinylpyrrolidone, sodium lauryl sulfate, polyvinylpyrrolidone, polyethylene glycol 1000 Vitamin E succinate, and mixtures thereof, One or more of tween 80, poloxamer, and docusate sodium.
The weight ratio of the ereoxib to the surface stabilizer can be 1: 0.01-1: 100, preferably 1: 0.01-1: 50, more preferably 1: 0.05-1: 5, and most preferably 1: 0.1-1: 1.
In certain preferred embodiments, the surface stabilizer comprises a first surface stabilizer selected from HPMC, copovidone, PVPK30, and a second surface stabilizer selected from tween 80, sodium docusate, Vitamin E TPGS, poloxamer, or sodium lauryl sulfate.
Wherein the weight ratio of the ereoxib to the first surface stabilizer can be 1: 0.01-1: 100, preferably 1: 0.01-1: 50, more preferably 1: 0.05-1: 5, and most preferably 1: 0.1-1: 1.
Wherein the weight ratio of the ereoxib to the second surface stabilizer is 1: 0.01-1: 100, preferably 1: 0.01-1: 50, more preferably 1: 0.01-1: 5, and most preferably 1: 0.01-1: 1.
The content of the ereoxib in the particle dispersion may be 10% to 95%, preferably 30% to 90%, more preferably 50% to 85%, based on the total weight of the particles.
The particle dispersion may comprise a liquid medium selected from water, saline solution, vegetable oils (e.g. safflower seed oil) and organic solvents (e.g. ethanol, t-butanol, hexane and ethylene glycol) and the like, preferably water.
In some embodiments, the particle dispersion can be further used for preparing an ericoxib pharmaceutical composition, such as an oral preparation, an injection, an inhalation preparation or an external preparation, and can be tablets, capsules, injection, freeze-dried powder injection and the like.
In another aspect of the invention there is provided a method of preparing a dispersion of particles according to the invention comprising: and mixing and grinding the ereoxib and the surface stabilizer. Wherein the step can be carried out in a liquid medium selected from water, saline solution, vegetable oil (e.g., safflower seed oil), organic solvents (e.g., ethanol, t-butanol, hexane, and ethylene glycol), and the like, preferably water. Wherein the solubility of ereoxib in the liquid medium is poor.
In another aspect, the present invention provides a method for preparing the pharmaceutical composition of etoricoxib, which comprises: a step of mixing the particle dispersion of the present invention with an optional filler, disintegrant or lubricant.
In certain embodiments, the particle dispersion may be mixed directly with an optional filler, disintegrant, or lubricant. In certain embodiments, the particle dispersion may be subjected to a solidification process, which may be, but is not limited to, freeze-drying, spray-drying, a granulation process, or a coating process, and mixed with other excipients.
In another aspect of the present invention there is provided the use of the pharmaceutical composition of ereoxib or the dispersion of particles of ereoxib according to the present invention for increasing the conversion rate of ereoxib into an active metabolite, preferably metabolite M4, in vivo.
The present invention unexpectedly provides a substantial enhancement of the active metabolism of ereoxib in vivo by reducing the particle size of the ereoxib in the pharmaceutical composition to a sub-micron level. In the pharmaceutical composition of the ereoxib, the ereoxib exists in the form of an active metabolite M4 after entering the body, so that the COX-2 inhibition effect is more obvious. In addition, the composition has positive significance for reducing the dosage of the medicament, reducing the adverse reaction of the medicament and the like due to the improvement of the treatment effect.
As used herein, "D10" refers to the particle size corresponding to a cumulative percent particle size distribution of 10% for a sample. "D50" refers to the particle size at which the cumulative percent particle size distribution for a sample reaches 50%. "D90" refers to the particle size corresponding to 90% of the cumulative percent particle size distribution for a sample.
Drawings
FIG. 1 is a graph of mean plasma concentration of active metabolite M4 in formulation A, formulation B and a commercial formulation versus time.
Fig. 2 is a graph of mean plasma concentration of inactive metabolite M2 versus time for formulation a, formulation B, and a commercial formulation.
Detailed Description
Example 1:
prescription of pharmaceutical composition of imreoxib (formulation a):
about 62.5ml of 0.5mm zirconia balls were poured into a 125ml jar of the ball mill. 55ml of HPMC solution containing Tween-80 was added followed by 5.5g of drug. Weighing the ball milling tank, fixing after determining the balance weight, grinding for 80min by the ball mill, and then filtering and removing zirconia grinding balls by a 60-mesh sieve to obtain the dapoxib suspension. Samples were taken and the particle size distribution was measured by the Malvern Mastersizer3000 Hydro MV method (see Table 2).
Spray-drying the erexib suspension to obtain a drug-containing intermediate, placing the drug-containing intermediate and Ludipress (lactose, PVP and PVPP) with a prescription dose in a Turbula T2F Mixer, mixing for 15min, adding magnesium stearate and colloidal silicon dioxide, mixing uniformly, and directly tabletting according to a standard of 100mg of the erexib in each granule.
Example 2:
prescription of pharmaceutical composition of imreoxib (formulation B):
an ereoxib suspension was prepared by ball milling for 25min as in example 1. Samples were taken and the particle size distribution was measured (see table 2).
Spray drying the ereoxib suspension to obtain a drug-containing intermediate, placing the drug-containing intermediate and a prescribed amount of Ludipress in a Turbula T2F Mixer, mixing for 15min, adding magnesium stearate and colloidal silicon dioxide, mixing uniformly, and directly tabletting according to the standard of 100mg of the ereoxib in each granule.
Example 3
The formulation A of example 1, the formulation B of example 2 and
in contrast, subjects were fed a light diet overnight before the study, fasted the next morning after dinner, and administered the study orally with 200ml of warm water on an empty stomach in the morning of the study day. 9 subjects aged 22-27 (23.5 +/-1.9), had height of 1.68-1.78 (1.75 +/-0.04) m, had body mass index of 19.88-23.99 (23.05 +/-1.57), had no abnormality in health examination, blood routine, hepatitis B, electrocardiogram examination, liver and kidney function. After the testee takes the medicine for two cycles, venous blood is collected according to the experimental design time point, the LC-MS/MS is adopted to measure the elapsed blood concentration of TCS in the whole blood, the average blood concentration-time curve is shown in a graph of 1-2, and the average AUC and Cmax data are shown in a table 1. The particle size of the ereoxib in each formulation is shown in table 2.
TABLE 1 AUC (h. ng/mL) and Cmax (ng/mL) of the major metabolites M2, M4
Table 2 particle size of ereoxib in each formulation
As can be seen from tables 1 and 2, both formulation a and formulation B significantly improved the AUC of active metabolite M4 compared to the commercial formulation, which greatly improved the therapeutic effect of ereoxib. In the nano preparation A, the AUC of the inactive metabolite M2 was improved little (about 6%) compared with the micro preparation B, while the AUC of the active metabolite M4 was unexpectedly improved by more than 15%. This means that when the particle size of the ereoxib is reduced to the nanometer level, the amount of the ereoxib converted into the inactive metabolite M2 in vivo is not increased basically, but the amount of the active metabolite M4 is increased greatly, so that the ereoxib is converted into the active metabolite M4 in vivo more, the treatment effect of the ereoxib is more facilitated, and the method has positive significance for reducing the drug dosage, reducing the adverse drug reactions and the like.
Claims (35)
1. A pharmaceutical composition containing erexib is characterized in that the particle size D90 of the erexib is 100-2500 nm, the particle size D50 of the erexib is 50-600 nm, and the particle size D10 of the erexib is 10-200 nm.
2. The pharmaceutical composition according to claim 1, wherein the ereoxib has a particle size D90 of 200-2000 nm.
3. The pharmaceutical composition according to claim 1, wherein the particle size D90 of the ereoxib is 200-600 nm.
4. The pharmaceutical composition of claim 1, further comprising a surface stabilizer.
5. The pharmaceutical composition of claim 4, wherein the surface stabilizer is selected from one or more of polyvinylpyrrolidone (PVP), polyvinyl alcohol, hydroxypropylmethyl cellulose, polyethylene glycol 1000 Vitamin E succinate (Vitamin E TPGS), Tween 80, poloxamer, polyethylene glycol 15-hydroxystearate, lecithin, sodium deoxycholate, sodium cholate, docusate sodium, sodium lauryl sulfate, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated castor oil 40, hydroxypropyl cellulose, tyloxapol, polyglycerol-10 laurate, carbomer, and copovidone.
6. The pharmaceutical composition of claim 4, wherein the surface stabilizer is selected from one or more of copovidone, hydroxypropyl methylcellulose, polyethylene glycol 1000 vitamin E succinate, polyvinylpyrrolidone, sodium lauryl sulfate, Tween 80, poloxamer, and docusate sodium.
7. The pharmaceutical composition according to claim 4, wherein the weight ratio of the ereoxib to the surface stabilizer is 1: 0.01-1: 100.
8. The pharmaceutical composition according to claim 4, wherein the weight ratio of the ereoxib to the surface stabilizer is 1: 0.01-1: 50.
9. The pharmaceutical composition according to claim 4, wherein the weight ratio of the ereoxib to the surface stabilizer is 1: 0.05-1: 5.
10. The pharmaceutical composition according to claim 4, wherein the weight ratio of the ereoxib to the surface stabilizer is 1: 0.1-1: 1.
11. The pharmaceutical composition according to claim 1, wherein the amount of the ereoxib is 0.1-1000 mg.
12. The pharmaceutical composition according to claim 1, wherein the amount of the ereoxib is 10 to 800 mg.
13. The pharmaceutical composition according to claim 1, wherein the amount of the ereoxib is 50 to 500 mg.
14. The pharmaceutical composition of claim 1, further comprising a filler selected from one or more of microcrystalline cellulose, dibasic calcium phosphate, mannitol, pregelatinized starch, lactose.
15. The pharmaceutical composition of claim 14, wherein the filler comprises 5% to 80% based on the total weight of the composition.
16. The pharmaceutical composition of claim 1, further comprising a lubricant selected from one or more of magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, aerosil, talc, and colloidal silica.
17. The pharmaceutical composition of claim 16, wherein the lubricant is selected from one or more of magnesium stearate and colloidal silicon dioxide.
18. The pharmaceutical composition of claim 16, wherein the lubricant is present in an amount of 0.5% to 5% based on the total weight of the composition.
19. A particle dispersion containing ereoxib, wherein the particle size D90 of the ereoxib is 100-2500 nm, D50 is 50-600 nm, and D10 is 10-200 nm.
20. A particle dispersion according to claim 19, wherein the particle size D90 of ereoxib is 200 to 2000 nm.
21. A particle dispersion according to claim 19, wherein the ereoxib has a particle size D90 of 200 to 600 nm.
22. A particle dispersion according to claim 19, further comprising a surface stabilizer.
23. A particle dispersion according to claim 22, wherein the surface stabilizer is selected from one or more of polyvinylpyrrolidone (PVP), polyvinyl alcohol, hydroxypropylmethylcellulose, polyethylene glycol 1000 Vitamin E succinate (Vitamin E TPGS), tween 80, poloxamer, polyethylene glycol 15-hydroxystearate, lecithin, sodium deoxycholate, sodium cholate, docusate sodium, sodium dodecylsulfate, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated castor oil 40, hydroxypropylcellulose, tyloxapol, polyglycerol-10 laurate, carbomer, copovidone.
24. A particle dispersion according to claim 22, wherein the surface stabilising agent is selected from one or more of copovidone, hydroxypropylmethylcellulose, macrogol 1000 vitamin E succinate, polyvinylpyrrolidone, sodium lauryl sulphate, tween 80, poloxamer and docusate sodium.
25. A particle dispersion according to claim 22, wherein the weight ratio of ereoxib to surface stabilizer is selected from 1:0.01 to 1: 50.
26. A particle dispersion according to claim 22, wherein the weight ratio of ereoxib to surface stabilizer is selected from 1:0.05 to 1: 5.
27. A particle dispersion according to claim 22, wherein the weight ratio of ericoxib to surface stabilizer is selected from 1:0.1 to 1: 1.
28. A particle dispersion according to claim 19, further comprising a liquid medium selected from water, saline solution, vegetable oil and organic solvents.
29. A particle dispersion according to claim 19, further comprising water.
30. A process for preparing a particle dispersion according to any one of claims 19 to 29, comprising the steps of mixing and milling ereoxib with a surface stabilizer.
31. The method of claim 30, wherein said steps are performed in a liquid medium selected from the group consisting of water, saline solution, vegetable oil, and organic solvents.
32. The method of claim 30, wherein said steps are performed in a liquid medium, said liquid medium being water.
33. A process for preparing a pharmaceutical composition according to any one of claims 1 to 18, comprising: a step of preparing a particle dispersion according to claim 30 or 31, and a step of mixing the particle dispersion with an optional filler, disintegrant or lubricant.
34. Use of the pharmaceutical composition of ereoxib according to any of claims 1 to 18 or the dispersion of ereoxib particles according to any of claims 19 to 29 for the preparation of a medicament for increasing the conversion of ereoxib into active metabolites in vivo.
35. The use of claim 34, said active metabolite being metabolite M4.
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| CN201810919234.4A CN109394709B (en) | 2017-08-15 | 2018-08-14 | Pharmaceutical composition containing ereoxib |
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| IL165383A0 (en) * | 2002-06-21 | 2006-01-15 | Transform Pharmaceuticals Inc | Pharmaceutical compositions with improved dissolution |
| CN105147607A (en) * | 2015-10-14 | 2015-12-16 | 中国药科大学 | Celecoxib nanosuspension and preparation method thereof |
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