CN114605484A - Purification method for obtaining new crystal form of amphotericin B - Google Patents
Purification method for obtaining new crystal form of amphotericin B Download PDFInfo
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- CN114605484A CN114605484A CN202011431086.5A CN202011431086A CN114605484A CN 114605484 A CN114605484 A CN 114605484A CN 202011431086 A CN202011431086 A CN 202011431086A CN 114605484 A CN114605484 A CN 114605484A
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- amphotericin
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- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 title claims abstract description 50
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 title claims abstract description 44
- 229960003942 amphotericin b Drugs 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000000746 purification Methods 0.000 title claims abstract description 23
- 239000013078 crystal Substances 0.000 title claims abstract description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000000047 product Substances 0.000 claims abstract description 19
- 238000001914 filtration Methods 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 11
- 238000013375 chromatographic separation Methods 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000007853 buffer solution Substances 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 4
- 239000011259 mixed solution Substances 0.000 claims abstract description 3
- 238000005406 washing Methods 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 13
- 238000012856 packing Methods 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000001514 detection method Methods 0.000 claims description 7
- -1 hydrogen halides Chemical class 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 150000007519 polyprotic acids Polymers 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000002441 X-ray diffraction Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 229930183010 Amphotericin Natural products 0.000 description 6
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 description 6
- 229940009444 amphotericin Drugs 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 239000000872 buffer Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- 238000004237 preparative chromatography Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 238000005374 membrane filtration Methods 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- JAYUDPKFDQGKFQ-UHFFFAOYSA-N n,n-diethylethanamine;ethanol Chemical compound CCO.CCN(CC)CC JAYUDPKFDQGKFQ-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention provides a purification method for obtaining a new crystal form of amphotericin B, which is characterized by comprising the following steps: step 1, adding dimethylformamide and acid into a crude product of amphotericin B; step 2, stirring and dissolving the mixed solution obtained in the step 1 at the temperature of 10-40 ℃, and filtering to remove insoluble substances for later use; step 3, performing chromatographic separation on the sample to be used obtained in the step 2, and collecting the target fraction into a weak alkaline buffer solution; and 4, standing for 7-20 hours, filtering, washing and drying to obtain the target product. The invention provides a brand new crystal form which has the characteristic of good stability.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a purification method for obtaining a new amphotericin B crystal form.
Background
Amphotericin B is a polyene antifungal antibiotic, the first choice for deep infection. The product is yellow or orange yellow powder, and has hygroscopicity. Is soluble in dimethyl sulfoxide, slightly soluble in dimethyl formamide, slightly soluble in methanol, and insoluble in water, anhydrous ethanol, chloroform or diethyl ether.
Is easily damaged and lost in sunlight and is easily damaged by heat and acid. Salts may form in neutral or acidic media, which have increased aqueous solubility but decreased antimicrobial activity. Gradually decompose at 170 deg.C or higher, and is unstable at 37 deg.C.
At present, the purification method of amphotericin B mainly comprises a solvent crystallization method, resin adsorption, membrane filtration and the like. The solvent crystallization method needs a plurality of refinements to obtain a qualified product. The resin adsorption and membrane filtration need to refine the amphotericin crude product with 70% purity to more than 95% purity, and then carry out resin adsorption or membrane filtration treatment to improve the product quality.
Disclosure of Invention
The invention aims to overcome the defects and obtains a brand-new amphotericin B crystal form through a new process method and new conditions, wherein the amphotericin B crystal form has the advantages of low product impurity, good stability and high purity, and the average purity can reach more than 98%. The product of the invention can reach the standard after one-time crystallization, namely, the product quality meets the pharmacopoeia standard.
The invention provides a purification method for obtaining a new crystal form of amphotericin B, which is characterized by comprising the following steps:
the crude product is obtained by conventional processes, such as: is obtained by extracting amphotericin fermentation liquor. Can be used directly without refining.
and 4, standing for 7-20 hours, filtering, washing and drying to obtain the target product.
Further, the purification method for obtaining the new crystal form of amphotericin B provided by the invention is characterized in that: the acid is selected from one or more of organic acid or inorganic acid;
the organic acid is selected from polybasic acid and halogenated alkyl acid;
the inorganic acid is selected from hydrogen halides.
Further, the purification method for obtaining the new crystal form of amphotericin B provided by the invention is characterized in that: the dosage of the dimethyl formamide or the dimethyl sulfoxide is 10-50ml per gram of crude amphotericin B.
Further, the purification method for obtaining the new crystal form of amphotericin B provided by the invention is characterized in that: the mass ratio of the citric acid to the amphotericin B crude product is 1: 0.8-1.2.
Further, the purification method for obtaining the new crystal form of amphotericin B provided by the invention is characterized in that: the above chromatographic separation was a 50mm by 500mm commercial preparative chromatographic system preloaded with C18 packing.
Further, the purification method for obtaining the new crystal form of amphotericin B provided by the invention is characterized in that: the chromatographic separation process is carried out under the conditions that the detection wavelength is 383nm and the temperature is higher than 20 ℃.
Further, the purification method for obtaining the new crystal form of amphotericin B provided by the invention is characterized in that: the chromatographic conditions of the chromatographic separation process are as follows: acetonitrile/water solution is used as a mobile phase, and the flow rate is 30-100 ml/min.
Further, the purification method for obtaining the new crystal form of amphotericin B provided by the invention is characterized in that: the weak alkaline buffer solution is a buffer solution of alkaline earth metal salt with the mass concentration of 1-10%.
Further, the purification method for obtaining the new crystal form of amphotericin B provided by the invention is characterized in that: the above drying is carried out at a temperature of not higher than 80 ℃.
Drawings
FIG. 1, X-ray diffraction pattern of the product of the example;
FIG. 2 is a liquid phase spectrum of the product of the example;
FIG. 3, x-ray diffraction pattern of amphotericin B prepared by conventional method;
FIG. 4 shows a liquid chromatogram of amphotericin B prepared by conventional method.
Detailed Description
The preparation process of the amphotericin B crude product comprises the following steps:
amphotericin mycelia were prepared as follows: 1, soaking the mixture in purified water for 18-24 hours, pumping the mixture into a 70-75% ethanol tank by a pump, wherein the ethanol content is 1: 12-18, stirring at 35-45 ℃, adding alkali liquor, and adjusting the pH value to 10.1-10.8. Filtering, adjusting pH of the filtrate to 5.1-7.0 with 6mol/L hydrochloric acid, stirring at 30-42 deg.C for 1 hr, cooling to 0-15 deg.C, and standing for 16-24 hr. And (5) carrying out suction filtration to obtain a crude product of the amphotericin.
The amphotericin B refining process comprises the following steps:
dissolving 2g of crude amphotericin in 20ml of DMF, stirring at room temperature, and dropwise adding 6mol/LHCl for dissolving, wherein the pH is controlled to be 4.3-5.5. Filtering to remove insoluble substances, and adding 70-75% ethanol 60ml into the filtrate. Heating to 35-45 deg.C, adjusting pH to 5.3-6.7 with triethylamine ethanol solution under stirring, crystallizing, maintaining for 1 hr, cooling to 0-15 deg.C, and maintaining for 16 hr. And (5) carrying out suction filtration to obtain an amphotericin refined product. Drying at 50 ℃ to obtain 0.93g of the product, the purity of the product is 92.9 percent, and the maximum single impurity content is 2.54 percent. I.e. conventional crystallization. The liquid phase spectrum is shown in figure 4.
Example 1
Preparing a sample: 2g of the crude amphotericin B was put into a 100ml reaction flask, and 40ml of dimethylformamide and 2g of trifluoroacetic acid were added thereto. After stirring and dissolving for 30 minutes at room temperature, the insoluble matter was removed by filtration, and the reaction solution was used.
Loading: the sample was injected into a 50mm by 500mm commercial preparative chromatography system preloaded with C18 packing at a packing height of 220mm, a detection wavelength of 383nm and a temperature > 20 ℃ for separation. The chromatographic conditions were 30% acetonitrile/water as the mobile phase at a flow rate of 60 ml/min.
And (3) collecting fractions: the target fraction was collected in 5% sodium bicarbonate buffer and a solid precipitated. The reaction solution was left to stand overnight and then filtered under suction, and the filter cake was washed with purified water. Drying at 50 deg.C to obtain 0.79g product. The liquid phase spectrum is shown in figure 2.
The crystal form is shown as a new crystal form through x-ray diffraction (as shown in figure 1, and specific lattice data are shown in the following table 1). Good stability, purity of 98.6 percent and maximum single impurity of 0.82 percent.
TABLE 1
The x-ray diffraction pattern of amphotericin B prepared by the conventional method is shown in fig. 3. The lattice data are shown in table 2 below.
TABLE 2
From the comparison of the data in tables 1 and 2 above, it can be seen that the two amphotericin B lines have completely different crystal structures.
Stability data:
example 2
Preparing a sample: 2g of the crude amphotericin B was put into a 100ml reaction flask, and 40ml of dimethylformamide and 2g of 6N hydrochloric acid were added thereto. After stirring and dissolving for 30 minutes at room temperature, the insoluble matter was removed by filtration, and the reaction solution was used.
Loading: the sample was injected into a 50mm by 500mm commercial preparative chromatography system preloaded with C18 packing at a packing height of 220mm, a detection wavelength of 383nm and a temperature > 20 ℃ for separation. The chromatographic conditions were 30% acetonitrile/water as mobile phase at a flow rate of 60 ml/min.
And (3) collecting fractions: the target fraction was collected in 5% sodium bicarbonate buffer and a solid precipitated. The reaction solution was left to stand overnight and then filtered under suction, and the filter cake was washed with purified water. Drying at 50 deg.C to obtain 0.74g product. It was shown to be a new crystalline form by x-ray diffraction (same as example 1). Good stability, 96.3 percent of purity and 0.91 percent of maximum single impurity.
Example 3
Preparing a sample: 2g of the crude amphotericin B was put into a 100ml reaction flask, and then 40ml of dimethylformamide and 2g of citric acid were added thereto. After stirring and dissolving for 30 minutes at room temperature, the insoluble matter was removed by filtration, and the reaction solution was used.
Loading: the sample was injected into a 50mm by 500mm commercial preparative chromatography system preloaded with C18 packing at a packing height of 220mm, a detection wavelength of 383nm and a temperature > 20 ℃ for separation. The chromatographic conditions were 30% acetonitrile/water as mobile phase at a flow rate of 60 ml/min.
And (3) collecting fractions: the target fraction was collected in 1% sodium bicarbonate buffer and a solid precipitated. The reaction solution was left to stand overnight and then filtered under suction, and the filter cake was washed with purified water. Drying at 50 deg.C to obtain 0.76g product. It was shown to be a new crystalline form by x-ray diffraction (same as example 1). Good stability, purity of 97.2 percent and maximum single impurity of 0.87 percent.
Example 4
Preparing a sample: 2g of the crude amphotericin B was put into a 100ml reaction flask, and 60ml of dimethylformamide and 2.5g of citric acid were added thereto. After stirring and dissolving for 20 minutes at room temperature, the insoluble matter was removed by filtration, and the reaction solution was used.
Loading: the sample was injected into a 50mm by 500mm commercial preparative chromatography system preloaded with C18 packing at a packing height of 220mm, a detection wavelength of 383nm and a temperature > 20 ℃ for separation. The chromatographic conditions were 30% acetonitrile/water as mobile phase at a flow rate of 60 ml/min.
And (3) collecting fractions: the target fraction was collected in 5% sodium bicarbonate buffer and a solid precipitated. The reaction solution was left to stand overnight and then filtered under suction, and the filter cake was washed with purified water. Drying at 50 deg.C to obtain 0.69g product. It was shown to be a new crystalline form by x-ray diffraction (same as example 1). Good stability, purity of 97.9 percent and maximum single impurity of 0.84 percent.
Example 5
Preparing a sample: 2g of the crude amphotericin B was put into a 100ml reaction flask, and 70ml of dimethylformamide and 1.5g of citric acid were added thereto. After stirring and dissolving for 60 minutes at room temperature, the insoluble matter was removed by filtration, and the reaction solution was used.
Loading: the sample was injected into a 50mm by 500mm commercial preparative chromatography system preloaded with C18 packing at a packing height of 220mm, a detection wavelength of 383nm and a temperature > 20 ℃ for separation. The chromatographic conditions were 30% acetonitrile/water as mobile phase at a flow rate of 60 ml/min.
And (3) collecting fractions: the target fraction was collected in 3% sodium bicarbonate buffer and a solid precipitated. The reaction solution was left to stand overnight and then filtered under suction, and the filter cake was washed with purified water. Drying at 50 deg.C to obtain 0.72g product. It was shown to be a new crystalline form by x-ray diffraction (same as example 1). Good stability, purity of 98.1 percent and maximum single impurity of 0.83 percent.
Claims (9)
1. A purification method for obtaining a new crystal form of amphotericin B is characterized by comprising the following steps:
step 1, adding dimethylformamide or dimethyl sulfoxide and acid into a crude product of amphotericin B;
step 2, stirring and dissolving the mixed solution obtained in the step 1 at the temperature of 10-40 ℃, and filtering to remove insoluble substances for later use;
step 3, performing chromatographic separation on the sample to be used obtained in the step 2, and collecting the target fraction into a weak alkaline buffer solution;
and 4, standing for 7-20 hours, filtering, washing and drying to obtain a target product.
2. The purification process according to claim 1, for obtaining a new crystalline form of amphotericin B, characterized by: the acid is selected from one or more of organic acid or inorganic acid;
the organic acid is selected from polybasic acid and halogenated alkyl acid;
the inorganic acid is selected from hydrogen halides.
3. The purification process according to claim 1, for obtaining a new crystalline form of amphotericin B, characterized by: the dosage of the dimethyl formamide or the dimethyl sulfoxide is 10-50ml per gram of crude amphotericin B.
4. The purification process according to claim 1, for obtaining a new crystalline form of amphotericin B, characterized by: the mass ratio of the citric acid to the amphotericin B crude product is 1: 0.8-1.2.
5. The purification process according to claim 1, for obtaining a new crystalline form of amphotericin B, characterized by: the chromatographic separation was a 50mm x 500mm commercial preparative chromatographic system preloaded with C18 packing.
6. The purification process according to claim 1, for obtaining a new crystalline form of amphotericin B, characterized by: the chromatographic separation process is carried out under the conditions that the detection wavelength is 383nm and the temperature is higher than 20 ℃.
7. The purification process according to claim 1 for obtaining a new form of amphotericin B, characterized in that: the chromatographic conditions of the chromatographic separation process are as follows: acetonitrile/water solution is used as a mobile phase, and the flow rate is 30-100 ml/min.
8. The purification process according to claim 1, for obtaining a new crystalline form of amphotericin B, characterized by: the weak alkaline buffer solution is a buffer solution of alkaline earth metal salt with the mass concentration of 1-10%.
9. The purification process according to claim 1, for obtaining a new crystalline form of amphotericin B, characterized by: the drying is carried out at a temperature not higher than 80 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1053794A (en) * | 1987-10-27 | 1991-08-14 | E.R.斯奎布父子公司 | The purification process of amphotericin B and composition |
| US20060105968A1 (en) * | 2002-10-03 | 2006-05-18 | Cleary John D | Compositions comprising highly purified amphotericin b |
| CN102746352A (en) * | 2011-04-20 | 2012-10-24 | 上海新先锋药业有限公司 | Technology for purifying medicines for treating deep fungal infection |
| CN110467645A (en) * | 2019-07-03 | 2019-11-19 | 浙江工业大学 | A kind of method of separation and Extraction high-purity amphotericin B |
-
2020
- 2020-12-09 CN CN202011431086.5A patent/CN114605484A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1053794A (en) * | 1987-10-27 | 1991-08-14 | E.R.斯奎布父子公司 | The purification process of amphotericin B and composition |
| US20060105968A1 (en) * | 2002-10-03 | 2006-05-18 | Cleary John D | Compositions comprising highly purified amphotericin b |
| CN102746352A (en) * | 2011-04-20 | 2012-10-24 | 上海新先锋药业有限公司 | Technology for purifying medicines for treating deep fungal infection |
| CN110467645A (en) * | 2019-07-03 | 2019-11-19 | 浙江工业大学 | A kind of method of separation and Extraction high-purity amphotericin B |
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