CN103690968A - Voriconazole composition and preparation method thereof - Google Patents
Voriconazole composition and preparation method thereof Download PDFInfo
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- CN103690968A CN103690968A CN201310586867.5A CN201310586867A CN103690968A CN 103690968 A CN103690968 A CN 103690968A CN 201310586867 A CN201310586867 A CN 201310586867A CN 103690968 A CN103690968 A CN 103690968A
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- Prior art keywords
- voriconazole
- pharmaceutical composition
- phosphate buffer
- beta
- cyclodextrin
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- 229960004740 voriconazole Drugs 0.000 title claims abstract description 54
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 title claims abstract description 48
- 239000000203 mixture Substances 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 239000008363 phosphate buffer Substances 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 238000004108 freeze drying Methods 0.000 claims abstract description 6
- 239000007788 liquid Substances 0.000 claims abstract description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000012982 microporous membrane Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000012417 linear regression Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000007928 solubilization Effects 0.000 description 3
- 238000005063 solubilization Methods 0.000 description 3
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 3
- 206010017533 Fungal infection Diseases 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 206010025482 malaise Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- NZAQRZWBQUIBSF-UHFFFAOYSA-N 4-(4-sulfobutoxy)butane-1-sulfonic acid Chemical group OS(=O)(=O)CCCCOCCCCS(O)(=O)=O NZAQRZWBQUIBSF-UHFFFAOYSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a voriconazole composition and a preparation method thereof. The invention provides a pharmaceutical composition containing voriconazole and sulfobutyl ether-beta-cyclodextrin, and a mole ratio of voriconazole to sulfobutyl ether-beta-cyclodextrin is in a range of 1: 1 to 1: 10 and preferably, the mole ratio is 1: 1. The pharmaceutical composition exists in a liquid form and a solvent is a phosphate buffer having a pH value of 5.0-8.0. The invention also provides a pharmaceutical composition obtained by freeze drying of the pharmaceutical composition containing voriconazole and sulfobutyl ether-beta-cyclodextrin and a preparation method thereof.
Description
Technical field
The present invention relates to a kind of voriconazole composition and method of making the same, belong to technical field of medicine.
Background technology
According to the World Health Organization's statistical estimate of 2004, the annual deep fungal infection number in the whole world is 33.5 ten thousand.Increasing along with clinical practice broad ectrum antibiotic, glucocorticoid, cell toxicity medicament, the increase year by year of tumor, organ transplantation and row Invasive procedures patient quantity, the sickness rate of deep fungal infection is remarkable ascendant trend.Be characterized in " two height ", " two is low ", " one is fast ", sickness rate and case fatality rate are high, and recall rate and cure rate are low, and disease progression is fast.
Voriconazole (Voriconazole) is a kind of triazole antifungal agent of wide spectrum, and treatment Aspergillosis is mainly used in progressive in immunodeficiency patient, the life-threatening infection of possibility.
Intravenous injection can quick control be infected, but the dissolubility of voriconazole in water is only 0.2mg/ml(pH=3) and unstable, can not meet the demand of clinical injection.Be made into the stability that clathrate not only can increase dissolubility and can improve medicine.Sulfobutyl ether-beta-cyclodextrin is water solublity than the pharmaceutic adjuvant that HP-β-CD is stronger, Toxicity of Kidney is less, very important for the exploitation of novel formulation.
The injection voriconazole of Pfizer's listing at present has just adopted sulfobutyl ether-beta-cyclodextrin (SBE-β-CD) as major auxiliary burden, improves the dissolubility of voriconazole.The Chinese patent 98806446.4 of Pfizer's application, discloses the pharmaceutical preparation of voriconazole and sulfo group butyl ether beta-schardinger dextrin-.While being made into the aqueous compositions of vein or intramuscular injection, the concentration of voriconazole is 5mg/ml-50 mg/ml, the mol ratio of voriconazole and sulfo group butyl ether beta-schardinger dextrin-is 1:1-1:10, and the average sulfobutyl ether substitution value of sulfo group butyl ether beta-schardinger dextrin-molecule is 6.5.
Summary of the invention
The present inventor has investigated under different pH value sulfobutyl ether-beta-cyclodextrin to the solubilising of voriconazole and clathration, and has investigated the increase situation of the relevant thing of voriconazole, for exploitation injection voriconazole provides more detailed reference.
The invention provides a kind of pharmaceutical composition that contains voriconazole and sulfobutyl ether-beta-cyclodextrin, wherein said compositions exists with liquid form, the phosphate buffer that solvent is pH5.0-8.0.
The phosphate buffer that preferred described solvent is pH5.0-7.0.
The phosphate buffer that further preferred described solvent is pH5.0 or pH6.0.
In the above-mentioned pharmaceutical composition that contains voriconazole and sulfobutyl ether-beta-cyclodextrin, the mol ratio of the two is 1:1-1:10, preferably 1:1.
The present invention also provides a kind of pharmaceutical composition, it is characterized in that described compositions is above-mentioned pharmaceutical composition to be carried out to lyophilization obtain.
The present invention further provides a kind of method of preparing aforementioned pharmaceutical compositions, containing having the following steps:
1. prepare the phosphate buffer that pH is 5.0-8.0;
2. sulfobutyl ether-beta-cyclodextrin is joined account for final volume 80% 1. in resulting phosphate buffer;
3. add voriconazole stirring and dissolving;
4. in adding 1., resulting phosphate buffer reaches volume required;
5. filtering with microporous membrane degerming is in sterile chamber;
6. subpackage, lyophilization.
The specific embodiment
By following object lesson, more specifically bright the present invention, but the present invention is not limited to following example.Wherein content (%) refers to percentage by weight.
Embodiment 1
Voriconazole compositions
Preparation method
1. prepare pH and be 5.0 phosphate buffer;
2. sulfobutyl ether-beta-cyclodextrin is joined account for final volume 80% 1. in resulting phosphate buffer;
3. add voriconazole stirring and dissolving;
4. in adding 1., resulting phosphate buffer reaches volume required;
5. filtering with microporous membrane degerming is in sterile chamber;
6. subpackage, lyophilization.
Embodiment 2
Voriconazole compositions
Preparation method
1. prepare pH and be 6.0 phosphate buffer;
All the other steps are with embodiment 1.
Embodiment 3
Voriconazole compositions
Preparation method
1. prepare pH and be 7.0 phosphate buffer;
All the other steps are with embodiment 1.
Embodiment 4 voriconazole content and relevant thing are measured chromatographic condition
Instrument: Waters e2695-2998;
Chromatographic column: Agilent(4.6*150mm, 5-Miron);
Column temperature: 35 ℃;
Mobile phase: 0.03mol/L ammonium formate buffer (adjusting pH to 4.0 with formic acid)-methanol-acetonitrile (28:31:41);
Flow velocity: 1ml/min; Detect wavelength 254nm.
The solubilization of SBE-β-CD to voriconazole under different pH value
Preparation pH is 5.0,6.0,7.0,8.0 phosphate buffer.Water and above-mentioned phosphate buffer compound concentration are serial SBE-β-CD solution of 0%, 4%, 8%, 16%, 24%, 32% and 40%, excessive voriconazole is joined in above SBE-β-CD solution, room temperature concussion is dissolved 24 hours, standing 30min, get supernatant and filter with 0.45 μ m microporous filter membrane, be diluted to the content (S that suitable concentration detects voriconazole
0) and relevant thing.Wherein S represents the intrinsic solubility of voriconazole in the water that does not add SBE-β-CD.S/S
0represent solubilising multiple.The results are shown in Table 1.
The relevant thing measured value of table 1 phase solubility research measured value and voriconazole
Measurement result shows that the dissolubility with SBE-β-CD concentration increase voriconazole in solution enlarges markedly; PH value of solution increases the relevant thing of voriconazole and increases, particularly remarkable when pH is 8.0.
Embodiment 5 SBE-beta-CD inclusion conditional formation constants calculate
Take SBE-β-CD concentration (x, mol/L) as abscissa, and voriconazole dissolubility (y, mol/L), for vertical coordinate mapping, carries out linear regression and obtains 5 regression equations.Equation of linear regression slope k ' be all less than 1, the clathrate that forms 1:1 according to SBE-β-CD and voriconazole calculates conditional formation constant Kc, and computing formula is: Kc=k '/S
0(1-k '), k ' is equation of linear regression slope, S
0for the intrinsic solubility of voriconazole in different pH solution.The results are shown in Table 2.
Conditional formation constant under table 2 equation of linear regression and different pH
The dissolubility of voriconazole is linear to be increased along with the increase of SBE-β-CD concentration.According to classification such as Higuchi, system phase solubility data show typical AL type feature, show SBE-β-CD with voriconazole with amount of substance than 1:1 enclose.Okimoto etc. think SBE-β-CD with medicine conventionally with amount of substance than 1:1 enclose.This is that to be found be the earliest also modal a kind of enclose mode.
The present inventor has mainly investigated the solubilization of sulfobutyl ether-beta-cyclodextrin to voriconazole under different pH, and the Kc value that result is presented at SBE-β-CD-voriconazole clathrate within the scope of pH5.0-8.0 changes little.But for weakly alkaline compound voriconazole, should there is impact to its enclose constant in pH.Because SBE-β-CD has negative charge side chain; the nitrogenous medicine that makes its commute form positive charge has special affinity and enclose; therefore can increase better dissolubility and the stability of medicine, regulate pH until conventionally can cause the variation of clathrate Kc value while changing the charged situation of medicine.The pKa of voriconazole is 1.76, if reduce below the pH to 1.76 of solution, makes voriconazole bear electricity, likely can cause voriconazole and SBE-β-CD to have repulsion, thereby change the Kc value of clathrate.The present inventor has only investigated pH5.0-8.0, because higher and lower pH does not meet the requirement of injection.
Have researcher to investigate the solubilization of HP-β-CD to voriconazole, and the Kc value of trying to achieve HP-β-CD-voriconazole clathrate is 311.1, the Kc value that the present inventor tries to achieve SBE-β-CD-voriconazole clathrate is 474-514 before.Kc is the important parameter of weighing clathrate stability, and Kc is larger, and clathrate is more stable.The Kc of SBE-β-CD-voriconazole clathrate is greater than the Kc of HP-β-CD-voriconazole clathrate, shows that SBE-β-CD-voriconazole clathrate is more stable.
Claims (8)
1. a pharmaceutical composition that contains voriconazole and sulfobutyl ether-beta-cyclodextrin, is characterized in that described compositions exists with liquid form, the phosphate buffer that solvent is pH5.0-8.0.
2. pharmaceutical composition as claimed in claim 1, is characterized in that described solvent is the phosphate buffer of pH5.0-7.0.
3. pharmaceutical composition as claimed in claim 2, is characterized in that described solvent is the phosphate buffer of pH5.0.
4. pharmaceutical composition as claimed in claim 2, is characterized in that described solvent is the phosphate buffer of pH6.0.
5. the pharmaceutical composition as described in any one in claim 1-4, the mol ratio that it is characterized in that voriconazole and sulfobutyl ether-beta-cyclodextrin is 1:1-1:10.
6. pharmaceutical composition as claimed in claim 5, the mol ratio that it is characterized in that voriconazole and sulfobutyl ether-beta-cyclodextrin is 1:1.
7. a pharmaceutical composition, is characterized in that described compositions is the pharmaceutical composition as described in any one in claim 1-4 to be carried out to lyophilization obtain.
8. a method of preparing pharmaceutical composition as claimed in claim 7, containing having the following steps:
1. prepare the phosphate buffer that pH is 5.0-8.0;
2. sulfobutyl ether-beta-cyclodextrin is joined account for final volume 80% 1. in resulting phosphate buffer;
3. add voriconazole stirring and dissolving;
4. in adding 1., resulting phosphate buffer reaches volume required;
5. filtering with microporous membrane degerming is in sterile chamber;
6. subpackage, lyophilization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310586867.5A CN103690968A (en) | 2013-11-21 | 2013-11-21 | Voriconazole composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310586867.5A CN103690968A (en) | 2013-11-21 | 2013-11-21 | Voriconazole composition and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103690968A true CN103690968A (en) | 2014-04-02 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310586867.5A Pending CN103690968A (en) | 2013-11-21 | 2013-11-21 | Voriconazole composition and preparation method thereof |
Country Status (1)
| Country | Link |
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| CN (1) | CN103690968A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107281099A (en) * | 2017-07-26 | 2017-10-24 | 西南大学 | A kind of voriconazole pharmaceutical composition |
| CN108778338A (en) * | 2016-01-28 | 2018-11-09 | 好利安科技有限公司 | The continuous complexing of active pharmaceutical ingredient |
| CN108938576A (en) * | 2017-05-25 | 2018-12-07 | 万特制药(海南)有限公司 | A kind of Voriconazole Dispersible Tablets and preparation method thereof |
| CN110090200A (en) * | 2019-04-16 | 2019-08-06 | 周锡明 | A kind of voriconazole injection type composition |
| CN113509436A (en) * | 2021-06-18 | 2021-10-19 | 陕西省眼科研究所 | Preparation method of eye drops |
| CN116570558A (en) * | 2023-06-21 | 2023-08-11 | 广州仁恒医药科技股份有限公司 | Voriconazole ophthalmic nanometer slow-release composition and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1261287A (en) * | 1997-06-21 | 2000-07-26 | 辉瑞大药厂 | Pharmaceutical formulations containing voriconazole |
| CN1813751A (en) * | 2005-11-24 | 2006-08-09 | 南京都药医药科技有限公司 | Voriconazole injection and its preparing method |
-
2013
- 2013-11-21 CN CN201310586867.5A patent/CN103690968A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1261287A (en) * | 1997-06-21 | 2000-07-26 | 辉瑞大药厂 | Pharmaceutical formulations containing voriconazole |
| CN1813751A (en) * | 2005-11-24 | 2006-08-09 | 南京都药医药科技有限公司 | Voriconazole injection and its preparing method |
Non-Patent Citations (1)
| Title |
|---|
| 奚念朱: "《药剂学》", 30 June 1985 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108778338A (en) * | 2016-01-28 | 2018-11-09 | 好利安科技有限公司 | The continuous complexing of active pharmaceutical ingredient |
| CN108778338B (en) * | 2016-01-28 | 2022-04-01 | 好利安科技有限公司 | Continuous complexation of active pharmaceutical ingredients |
| CN108938576A (en) * | 2017-05-25 | 2018-12-07 | 万特制药(海南)有限公司 | A kind of Voriconazole Dispersible Tablets and preparation method thereof |
| CN107281099A (en) * | 2017-07-26 | 2017-10-24 | 西南大学 | A kind of voriconazole pharmaceutical composition |
| CN107281099B (en) * | 2017-07-26 | 2020-04-07 | 西南大学 | Voriconazole pharmaceutical composition |
| CN110090200A (en) * | 2019-04-16 | 2019-08-06 | 周锡明 | A kind of voriconazole injection type composition |
| CN113509436A (en) * | 2021-06-18 | 2021-10-19 | 陕西省眼科研究所 | Preparation method of eye drops |
| CN116570558A (en) * | 2023-06-21 | 2023-08-11 | 广州仁恒医药科技股份有限公司 | Voriconazole ophthalmic nanometer slow-release composition and preparation method and application thereof |
| CN116570558B (en) * | 2023-06-21 | 2023-12-26 | 广州仁恒医药科技股份有限公司 | Voriconazole ophthalmic nanometer slow-release composition and preparation method and application thereof |
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Application publication date: 20140402 |