CN103159829A - Extraction method for daptomycin - Google Patents
Extraction method for daptomycin Download PDFInfo
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- CN103159829A CN103159829A CN2011104074886A CN201110407488A CN103159829A CN 103159829 A CN103159829 A CN 103159829A CN 2011104074886 A CN2011104074886 A CN 2011104074886A CN 201110407488 A CN201110407488 A CN 201110407488A CN 103159829 A CN103159829 A CN 103159829A
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Abstract
The invention discloses an extraction method for daptomycin. The method comprises the following steps of: forming micelles from daptomycin in fermentation solution and filtering the micelles via a ceramic membrane system at first; then performing separation and purification by virtue of a multi-section macroporous adsorption resin separation system and a weak-base anion-exchange resin separation system; and finally concentrating and freeze-drying to obtain a daptomycin solid having a chromatographic purity of greater than 96%. The method disclosed by the invention is simple and practicable, low in cost, and suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation method of daptomycin, relate to specifically a kind of ceramic membrane filter, resin chromatographic technique of adopting and prepare the method for high purity daptomycin from broth extraction.
Background technology
Along with antibiotic development and antibiotic abuse, pathogenic bacteria is the severe challenge that society faces to Antibiotic resistance.Except controlling abuse of antibiotics, seek at present a kind of effective microbiotic to antimicrobial agent and become the optimal path that addresses this problem, vancomycin once was considered to the last line of defense to resisting gram-positive bacteria, had found increasing anti-this medicine bacterium but now the whole world is clinical.
Daptomycin (Daptomycin) is by Lilly (gift come) company's original research, a cyclic lipopeptide microbiotic of Cubist drugmaker exploitation.Answer patient to the antibiotic active demand of novel resistance, the end of the year 2003, FDA (FDA) is used for the treatment of through quick trial program approval injection daptomycin (Daptomycin) (trade(brand)name cubicin) the concurrency skin and the skin texture that are caused by some Gram-positive sensitive strains and infects, and infects and skin ulcer as abscess, operative incision.The mechanism of action of daptomycin is different from other microbiotic, and it passes through to upset cytolemma to amino acid whose transhipment, thereby hinders the biosynthesizing of bacteria cell wall peptidoglycan, changes the character of cytoplasmic membrane; In addition, it can also be by destroying the cytolemma of bacterium, its content leaked and reach the purpose of sterilization, so bacterium daptomycin is produced resistance may be more difficult.
Although daptomycin is realized suitability for industrialized production in the U.S., in China and unrealized scale production, its major cause is not have to realize industrialized extractive technique.
Existing daptomycin extracting method, the described daptomycin extracting method of Chinese patent application 200910058577.7 for example, only adopt macroporous resin separation and purification daptomycin, the daptomycin chromatographic purity of gained is only 80%-90%, not only the pharmacy demand can not be satisfied, and suitability for industrialized production can't be realized because it is with high costs.Although Chinese patent application 200910085837.X adopts the ion exchange resin method to obtain highly purified daptomycin, can't be realized the purpose of separation and purification daptomycin because there being daptomycin by the problem of havoc.
Summary of the invention
The purpose of this invention is to provide a kind of preparation method of Tobramycin easy and simple to handle, with low cost, make the high purity daptomycin from the daptomycin broth extraction.Technical scheme of the present invention is as follows:
A kind of extracting method of daptomycin comprises the steps:
1) with after daptomycin fermented liquid adjusting pH2.0-4.5, the ceramic membrane that is 0.01 μ m-0.1 μ m with membrane pore size filters, then use the acidic aqueous solution circulation cleaning ceramic membrane of pH2.0-4.0, abandon filtrate, use again the alkaline aqueous solution circulation cleaning ceramic membrane of pH8-10, collect daptomycin filtrate;
2) with step 1) gained daptomycin filtrate adjusting pH4.5-7.0, obtain the daptomycin elutriant after multistage absorption with macroporous adsorbent resin, wash-out;
3) with step 2) gained daptomycin elutriant after the weak base anion-exchange resin chromatography the daptomycin chromatographic solution;
4) with step 3) gained daptomycin chromatographic solution is that the nanofiltration membrane system of 50-500 is concentrated through molecular weight cut-off, obtains the daptomycin concentrated solution;
5) with step 4) obtain the solid daptomycin after gained daptomycin concentrated solution vacuum-freeze-dry drying.
Above-mentioned steps 1) in, at first fermented liquid pH is transferred to 2.0-4.5, because the daptomycin iso-electric point is PI3.5, under the condition of pH2.0-4.5, daptomycin forms the very large micella of molecular weight, can permeation ceramic membrane.Wash pH2.0-4.0 acidic aqueous solution used and can adopt phosphoric acid solution, its consumption normally fermentating liquid volume 1-2 doubly; Described alkaline aqueous solution can be sodium hydroxide or the potassium hydroxide solution of pH8-10, and its consumption doubly is advisable with the 4-5 of fermentating liquid volume.After having washed, the yield of daptomycin is more than 92%.
Above-mentioned steps 2) adopt macroporous adsorbent resin separation system separation and purification daptomycin, preferred D101 resin.The D101 resin price is cheap, and cost is low, and its particle is thicker, is equivalent to play the pre-column effect.The macroporous adsorbent resin separation system that this step is used is comprised of many segment posts and a large section post, wherein many macroporous adsorbent resin segment posts are connected successively for absorption, the segment post of many series connection during wash-out connect again large section post of a macroporous adsorbent resin for separating of, make daptomycin just can reach for the first time very high separation and purification effect during chromatography at this.Filling internal diameter and the aspect ratio of D101 resin segment post be generally 1: 7～and 1: 10, be preferably 1: 10, column length 20cm～35cm, its resin demand are 10%～15% of large section post of D101 resin.Filling internal diameter and the aspect ratio of large section resin column are 1: 5～1: 7, preferred 1: 6, and column length 35cm～52cm.Elutriant can adopt the solution that contains 0.06N sodium-acetate and 30%～40% ethanol of pH6.5.
Above-mentioned steps 3) adopt the further separation and purification daptomycin of weak base anion-exchange resin chromatographic system, preferred D301 resin, the D301 resin price is cheap, and cost is low, and it is stronger to the selectivity of daptomycin.Filling internal diameter and the aspect ratio of D301 resin be generally 1: 5～and 1: 7, be preferably 1: 6.Elutriant can adopt the NaCl solution of pH5.5-6.0.
Above-mentioned steps 4) molecular weight cut-off of nanofiltration membrane is preferably 100-200.
Above steps, general, adopt phosphoric acid, acetic acid and sodium hydroxide to come the pH of regulator solution.
In the methods of the invention, after the daptomycin fermented liquid was processed through ceramic membrane system, the separation and purification of macroporous resin separation system, weak base anion-exchange resin separation system, its chromatographic purity of the daptomycin that obtains was more than 98%.The method is simple, and is with low cost, is fit to carry out suitability for industrialized production.
Embodiment
Further describe by the following examples the present invention, but the scope that does not limit the present invention in any way.
Following embodiment experiment material used is the daptomycin fermented liquid, its be about pH7.0 than viscous feed liquid.
Embodiment 1
After the daptomycin fermented liquid is adjusted to pH3.0 with phosphoric acid, remove the macromolecular substance such as water-soluble protein in the daptomycin fermented liquid, pigment through the ceramic membrane filter of aperture 0.05 μ m, then use the phosphate aqueous solution circulation cleaning ceramic membrane (filtrate discards) of the pH3.0 of stock liquid 1-2 times volume, sodium hydroxide solution circulation cleaning ceramic membrane with the pH9.0 of stock liquid 4-5 times volume obtains ceramic membrane filtrate again, gained filtrate clear, and color is reddish yellow.
Filtrate is regulated pH6.0 with acetic acid,diluted, then cross successively the D101 resin column of the series connection of the 3 long 35cm of segment diameter 3.5cm, disconnect series connection, each segment post washes with water respectively to every section effluent liquid substantially colourless, then connect with 1 large section D101 resin of the long 50cm of diameter 5cm again after 3 segment D101 resin columns being connected successively, and with 0.06N sodium acetate, the 30% ethanolic soln wash-out of pH6.5.
The gained eluate is regulated the D301 resin column of the upper long 50cm of diameter 5cm of pH5.5 with acetic acid,diluted, wash the D301 resin, then uses the sodium chloride solution wash-out of the 300mM of pH5.5～6.0.
The nanofiltration membrane nanofiltration that D301 resin elution thing is 100-200 through molecular weight cut-off concentrates, and concentrated rear daptomycin concentration is at 20% (w/w).
The concentrated solution vacuum-freeze-dry, gained solid daptomycin adopts high performance liquid chromatography (testing conditions is identical with European patent " PROCESS FOR THE PURIFICATION OF DAPTOMYCIN " (EP 1 586 580 A2) disclosed method) to detect daptomycin purity, and its purity is more than 98%.
Embodiment 2
After the daptomycin fermented liquid is adjusted to pH3.5 with phosphoric acid, remove the macromolecular substance such as water-soluble protein in the daptomycin fermented liquid, pigment through the ceramic membrane filter of aperture 0.05 μ m, then use the phosphate aqueous solution circulation cleaning ceramic membrane (filtrate discards) of the pH3.0 of stock liquid 1-2 times volume, sodium hydroxide solution circulation cleaning ceramic membrane with the pH10 of stock liquid 4-5 times volume obtains ceramic membrane filtrate again, gained filtrate clear, and color is reddish yellow.
Filtrate is regulated pH6.0 with acetic acid,diluted, cross successively the D101 resin column that is cascaded of the 3 long 35cm of segment diameter 3.5cm, disconnect series connection, each segment post washes with water respectively to every section effluent liquid substantially colourless, then connect with 1 large section D101 resin of the long 50cm of diameter 5cm of large root again after 3 segment D101 resin columns being connected again, and with 0.06N sodium acetate, the 30% ethanolic soln wash-out of pH6.5.
The gained eluate is regulated the D301 resin column of the upper long 50cm of diameter 5cm of pH5.5 with acetic acid,diluted, wash the D301 resin, then uses the sodium chloride solution wash-out of the 300mM of pH5.5～6.0.
The nanofiltration membrane nanofiltration that D301 resin elution thing is 100-200 through molecular weight cut-off concentrates, and concentrated rear daptomycin concentration is at 20% (w/w).
The concentrated solution vacuum-freeze-dry, gained solid daptomycin adopts high performance liquid chromatography (testing conditions is identical with European patent " PROCESS FOR THE PURIFICATION OF DAPTOMYCIN " (EP 1 586 580 A2) disclosed method) to detect daptomycin purity, and its purity is 96%.
Embodiment 3
After the daptomycin fermented liquid is adjusted to pH3.0 with phosphoric acid, remove the macromolecular substance such as water-soluble protein in the daptomycin fermented liquid, pigment through the ceramic membrane filter of aperture 0.05 μ m, then use the phosphate aqueous solution circulation cleaning ceramic membrane (filtrate discards) of the pH3.0 of stock liquid 0.5-1 times volume, sodium hydroxide solution circulation cleaning ceramic membrane with the pH10.0 of stock liquid 2-3 times volume obtains ceramic membrane filtrate again, gained filtrate clear, and color is reddish yellow.
Filtrate is regulated pH6.0 with acetic acid,diluted, cross successively the D101 resin column of the 3 long 35cm series connection of segment diameter 3.5cm, disconnect series connection, it is substantially colourless that each segment post is washed to respectively every section effluent liquid, then connect with 1 large section D101 resin of the long 50cm of diameter 5cm of large root again after 3 segment D101 resin columns being connected again, and with 0.06N sodium acetate, the 30% ethanolic soln wash-out of pH6.5.
The gained eluate is regulated the D301 resin column of the upper long 50cm of diameter 5cm of pH5.5 with acetic acid,diluted, wash the D301 resin, then uses the sodium chloride solution wash-out of the 300mM of pH5.5～6.0.
The nanofiltration membrane nanofiltration that D301 resin elution thing is 100-200 through molecular weight cut-off concentrates, and concentrated rear daptomycin concentration is at 20% (w/w).
The concentrated solution vacuum-freeze-dry, gained solid daptomycin adopts high performance liquid chromatography (testing conditions is identical with European patent " PROCESS FOR THE PURIFICATION OF DAPTOMYCIN " (EP 1 586 580 A2) disclosed method) to detect daptomycin purity, and its purity is more than 97%.
The present invention's film used all will clean with cleaning agents of membrane after use, soaks with 0.5% sodium sulfite solution in case of necessity and preserves, to reach the recycling of film.
The present invention comprehensively adopts film, chromatographic technique that a kind of Technology of producing preparation high purity daptomycin feasible, with low cost is provided.Especially fermented liquid is crossed ceramic membrane and the desorb of D101 segmentation absorption string post designs the critical process reference mark of high purity daptomycin preparation especially in the micella situation.Although this paper has carried out detailed description to this invention; but be appreciated that; on the basis of the present invention's spirit and essence, those skilled in the art can make some modifications or change, and these modifications or change are all within the scope of protection of present invention.
Claims (10)
1. the extracting method of a daptomycin, comprise the steps:
1) with after daptomycin fermented liquid adjusting pH2.0-4.5, the ceramic membrane that is 0.01 μ m-0.1 μ m with membrane pore size filters, then use the acidic aqueous solution circulation cleaning ceramic membrane of pH2.0-4.0, abandon filtrate, use again the alkaline aqueous solution circulation cleaning ceramic membrane of pH8-10, collect daptomycin filtrate;
2) with step 1) gained daptomycin filtrate adjusting pH4.5-7.0, obtain the daptomycin elutriant after multistage absorption with macroporous adsorbent resin, wash-out;
3) with step 2) gained daptomycin stripping liquid after the weak base anion-exchange resin chromatography the daptomycin chromatographic solution;
4) with step 3) gained daptomycin chromatographic solution is that the nanofiltration membrane system of 50-500 is concentrated through molecular weight cut-off, obtains the daptomycin concentrated solution;
5) with step 4) obtain the solid daptomycin after gained daptomycin concentrated solution vacuum-freeze-dry drying.
2. the method for claim 1, is characterized in that step 1) in washing acidic aqueous solution used be phosphoric acid solution, its consumption be fermentating liquid volume 1-2 doubly.
3. the method for claim 1, is characterized in that step 1) described in alkaline aqueous solution be sodium hydroxide or potassium hydroxide solution, its consumption be fermentating liquid volume 4-5 doubly.
4. the method for claim 1, is characterized in that step 2) described macroporous adsorbent resin is the D101 resin.
5. method as claimed in claim 4, it is characterized in that, step 2) adopt many segment posts and large section post to form multistage D101 resin isolation system, wherein many segment posts are together in series for absorption, connect with large section post after will many segment posts during wash-out connecting again.
6. method as claimed in claim 5, is characterized in that, described large section column length 35cm～52cm, and filling internal diameter and aspect ratio are 1: 5～1: 7; Described segment column length 20cm～35cm, filling internal diameter and aspect ratio are 1: 7～1: 10, resin demand is 10%～15% of large section post.
7. method as claimed in claim 4, is characterized in that step 2) adopt the solution that contains 0.06N sodium-acetate and 30%～40% ethanol of pH6.5 that daptomycin is eluted from the D101 resin.
8. the method for claim 1, is characterized in that step 3) described weak base anion-exchange resin is the D301 resin, its filling internal diameter and aspect ratio are 1: 5～1: 7.
9. method as claimed in claim 8, is characterized in that step 3) adopt the NaCl solution of pH5.5-6.0 that daptomycin is eluted from the D301 resin.
10. the method for claim 1, is characterized in that step 4) molecular weight cut-off of nanofiltration membrane used is 100-200.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104387444A (en) * | 2014-11-13 | 2015-03-04 | 北大医药重庆大新药业股份有限公司 | Method for preparing high-purity sample of impurity RS-2 in daptomycin |
| CN105001305A (en) * | 2015-04-29 | 2015-10-28 | 利穗科技(苏州)有限公司 | Method for extracting high-purity daptomycin by utilizing chromatographic technique |
| CN105481950A (en) * | 2016-01-28 | 2016-04-13 | 丽珠集团福州福兴医药有限公司 | Daptomycin extraction method |
| CN106589065A (en) * | 2015-10-16 | 2017-04-26 | 江苏恒瑞医药股份有限公司 | Daptomycin purifying method |
| CN109666065A (en) * | 2018-11-22 | 2019-04-23 | 北大方正集团有限公司 | A kind of method of quick preparation high-purity daptomycin |
| CN111549015A (en) * | 2020-05-27 | 2020-08-18 | 南京工业大学 | Process for separating and removing citrinin in nuclease liquid by utilizing chromatographic technique |
| CN114344447A (en) * | 2021-12-16 | 2022-04-15 | 华北制药股份有限公司 | Daptomycin for injection and preparation method thereof |
Families Citing this family (2)
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| CN106866789A (en) * | 2015-12-11 | 2017-06-20 | 北大方正集团有限公司 | A kind of method for isolating and purifying Daptomycin RS-8 impurity |
| CN106866791A (en) * | 2015-12-11 | 2017-06-20 | 北大方正集团有限公司 | A kind of preparation method of high-purity daptomycin lactone hydrolysate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101240013A (en) * | 2000-01-20 | 2008-08-13 | 卡比斯特制药公司 | High purity lipopeptides, lipopeptide micelles, processes for preparing same |
| WO2009144739A1 (en) * | 2008-05-26 | 2009-12-03 | Biocon Limited | Amorphous daptomycin and a method of purification thereof |
| WO2010095953A1 (en) * | 2009-02-19 | 2010-08-26 | Axellia Pharmaceuticals Aps | Process for purifying lipopeptides |
| CN101899094A (en) * | 2009-06-01 | 2010-12-01 | 安徽丰原发酵技术工程研究有限公司 | Preparation method of high-purity Daptomycin |
-
2011
- 2011-12-08 CN CN201110407488.6A patent/CN103159829B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101240013A (en) * | 2000-01-20 | 2008-08-13 | 卡比斯特制药公司 | High purity lipopeptides, lipopeptide micelles, processes for preparing same |
| WO2009144739A1 (en) * | 2008-05-26 | 2009-12-03 | Biocon Limited | Amorphous daptomycin and a method of purification thereof |
| WO2010095953A1 (en) * | 2009-02-19 | 2010-08-26 | Axellia Pharmaceuticals Aps | Process for purifying lipopeptides |
| CN101899094A (en) * | 2009-06-01 | 2010-12-01 | 安徽丰原发酵技术工程研究有限公司 | Preparation method of high-purity Daptomycin |
Non-Patent Citations (1)
| Title |
|---|
| 石磊等: "达托霉素发酵液大孔树脂吸附分离的研究", 《中国抗生素杂志》 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104387444A (en) * | 2014-11-13 | 2015-03-04 | 北大医药重庆大新药业股份有限公司 | Method for preparing high-purity sample of impurity RS-2 in daptomycin |
| CN105001305A (en) * | 2015-04-29 | 2015-10-28 | 利穗科技(苏州)有限公司 | Method for extracting high-purity daptomycin by utilizing chromatographic technique |
| CN106589065A (en) * | 2015-10-16 | 2017-04-26 | 江苏恒瑞医药股份有限公司 | Daptomycin purifying method |
| CN106589065B (en) * | 2015-10-16 | 2020-10-20 | 江苏恒瑞医药股份有限公司 | Daptomycin purification method |
| CN105481950A (en) * | 2016-01-28 | 2016-04-13 | 丽珠集团福州福兴医药有限公司 | Daptomycin extraction method |
| CN105481950B (en) * | 2016-01-28 | 2019-01-04 | 丽珠集团福州福兴医药有限公司 | A kind of Daptomycin extracting method |
| CN109666065A (en) * | 2018-11-22 | 2019-04-23 | 北大方正集团有限公司 | A kind of method of quick preparation high-purity daptomycin |
| CN109666065B (en) * | 2018-11-22 | 2022-02-25 | 北大方正集团有限公司 | Method for rapidly preparing high-purity daptomycin |
| CN111549015A (en) * | 2020-05-27 | 2020-08-18 | 南京工业大学 | Process for separating and removing citrinin in nuclease liquid by utilizing chromatographic technique |
| CN114344447A (en) * | 2021-12-16 | 2022-04-15 | 华北制药股份有限公司 | Daptomycin for injection and preparation method thereof |
| CN114344447B (en) * | 2021-12-16 | 2023-08-25 | 华北制药股份有限公司 | Daptomycin for injection and preparation method thereof |
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Address after: 100871, Beijing, Haidian District Cheng Fu Road 298, founder building, 9 floor Patentee after: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee after: CHONGQING DAXIN PHARMACEUTICAL Co.,Ltd. Patentee after: PKU HEALTHCARE INDUSTRY Group Address before: 100871, Beijing, Haidian District Cheng Fu Road 298, founder building, 5 floor Patentee before: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee before: Peking University International Hospital Group Chongqing Daxin Pharmaceutical Co.,Ltd. Patentee before: Pku Healthcare Industry Group Co.,Ltd. |
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Effective date of registration: 20221020 Address after: 3007, Hengqin international financial center building, No. 58, Huajin street, Hengqin new area, Zhuhai, Guangdong 519031 Patentee after: New founder holdings development Co.,Ltd. Patentee after: CHONGQING DAXIN PHARMACEUTICAL Co.,Ltd. Patentee after: Peking University Medical Management Co.,Ltd. Address before: 100871, Beijing, Haidian District Cheng Fu Road 298, founder building, 9 floor Patentee before: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee before: CHONGQING DAXIN PHARMACEUTICAL Co.,Ltd. Patentee before: PKU HEALTHCARE INDUSTRY Group |