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high titer polymyxin e 2 Sodium methanesulfonate

A technology of polymyxin and sodium methanesulfonate, applied in the field of medicine, can solve problems such as difficulty in guaranteeing the quality stability between batches of products

Active Publication Date: 2021-11-02
CHIA TAI TIANQING PHARMA GRP CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Both of these drugs are multicomponent drugs, and in polymyxin E sulfate, there is E 1 ,E 2 ,E 3 At least 5 components (see European Pharmacopoeia 7.0), also contain at least the corresponding polymyxin E in polymyxin E sodium methanesulfonate 1 Sodium methanesulfonate, polymyxin E 2 5 components such as sodium methanesulfonate, however, different components may bring differences in pharmacodynamics, pharmacokinetics and toxicology, in order to ensure the quality stability between batches of polymyxin E products, it is necessary to Preparation of single-component polymyxin E compositions
[0003] Chinese patent application CN102190710A discloses a kind of polymyxin E 2 Compositions wherein polymyxin E 2 The structure of is shown in formula I, and embodiment 4 discloses polymyxin E 2 The preparation of the sodium methanesulfonate composition, the potency of the composition is 560 μg / mg, although its potency is higher than that of commercially available products, it is determined that there are many types of modified products in the composition, and it is difficult to guarantee the product batch-to-batch quality stability

Method used

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  • high titer polymyxin e <sub>2</sub> Sodium methanesulfonate
  • high titer polymyxin e <sub>2</sub> Sodium methanesulfonate
  • high titer polymyxin e <sub>2</sub> Sodium methanesulfonate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1 Polymyxin E 2 Preparation of sodium methanesulfonate

[0047] (1) Purified Polymyxin Sulfate 2

[0048] Weigh an appropriate amount of industrial-grade polymyxin E sulfate (purchased from Lvkang Biochemical Co., Ltd.), dissolve it in water to make a solution containing 120 mg per 1 ml, and separate it on a chromatographic column. The chromatographic conditions are as follows:

[0049] Chromatography filler: reversed-phase microspheres with polystyrene / divinylbenzene as the skeleton, the model is XT-30, produced by Dow (DOW) Chemical Co., Ltd., USA

[0050] Column specification: 50×250mm,

[0051] Column volume (CV): 491ml

[0052] Flow rate: 20.0ml / min

[0053] Sample volume: 300ml

[0054] Elution conditions: first elute 5CV with dilute sulfuric acid solution containing 3% ethanol (use 0.05mol / L sulfuric acid to adjust the pH value of the solution to 2.4), and then use dilute sulfuric acid solution containing 8% ethanol (use 0.05mol / L sulfuric acid to ...

Embodiment 2

[0059] Example 2 Polymyxin E 2 Analysis of modification degree of sodium methanesulfonate

[0060] The polymyxin E that embodiment 1 prepares by LC-MS 2 Sodium methanesulfonate was used for modification analysis.

[0061] (1) LC-MS detection method

[0062] HPLC conditions are as follows:

[0063] Instrument: Shimadzu UFLC XR (LC-20AD XR pump; SIL-20AC XR autosampler; CTO-20AC column thermostat; SPD-M20A detector)

[0064] Chromatographic column: Waters Atlantis T3 (150mm×4.6mm, 3μm) 620#

[0065] Mobile phase: Phase A: 10mM ammonium formate-acetonitrile (95:5)

[0066] Phase B: 10mM ammonium formate-acetonitrile (50:50)

[0067] Linear gradient elution, the elution program is as follows:

[0068]

[0069] Flow rate: 1.0ml / min

[0070] Column temperature: 30°C

[0071] Detection wavelength: 210nm

[0072] The mass spectrometry conditions are as follows:

[0073] Instrument: AB SCIEX Triple TOF 4600

[0074] Ion source: DuoSpray TM Ion Source (ESI)

[0075] pa...

Embodiment 3

[0094] Example 3 Polymyxin E 2 Preparation of sodium methanesulfonate

[0095] With reference to the method purification polymyxin sulfate of embodiment 1 step (1) 2 , to obtain 140ml of concentrated solution, which contains 5.6g of polymyxin E sulfate 2 .

[0096] With the 140ml polymyxin E sulfate that step (1) obtains 2 Put the concentrated solution in a water bath at 25°C for 10 minutes, add 4.4ml of formaldehyde solution, adjust the pH with 2.5mol / L NaOH to keep it between 6.5-7.5, stir for 2 hours, then add 40% NaHSO 3 The solution was 16ml, and the pH was adjusted to 7.0 with 2.5mol / L NaOH, and the temperature was controlled by a water bath at 25°C for 18h. The ultrafiltration membrane (MILLIPORE company) that is 3000Da molecular weight cut-off is carried out desalting treatment by reaction solution, when the total volume remaining about 50ml of ultrafiltration intercepted liquid, add deionized water to 220ml, control feed liquid temperature in ultrafiltration proce...

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Abstract

Provides a high potency polymyxin E 2 Sodium methanesulfonate, its preparation method and its use in the preparation of medicines for treating Gram-negative bacterial infections.

Description

technical field [0001] The invention belongs to the field of medicine and relates to polymyxin E with a potency not lower than 600 μg / mg 2 Sodium methanesulfonate, its preparation method and its use in the preparation of medicines for treating Gram-negative bacterial infections. Background technique [0002] Polymyxin E (colistin) is a polypeptide antibiotic composed of multiple components, mainly composed of E 1 and E 2 Composition (or called A or B). In the 1950s, polymyxin E was used clinically, mainly for infections caused by Gram-negative bacteria, especially those caused by multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, etc. Treatment of infections caused by bacteria, etc. There are two types of polymyxin E products in clinical use, one is polymyxin E sulfate (also known as colistin sulfate) for oral or topical use, and the other is polymyxin E for injection Sodium methanesulfonate (Colistimethate Sodium). Both of thes...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/62C07K1/34C07K1/36C07K1/16A61K38/12A61P31/04
CPCA61K38/12A61P31/04C07K1/16C07K1/34C07K1/36C07K7/62Y02A50/30
Inventor 冯军张喜全吴勇郭猛薛春佳胡明通朱裕辉周杰王猛力
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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