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Preparation method for octreotide

A technology of octreotide and chromatography, applied in the field of biopharmaceuticals, can solve the problems of dilute sample concentration, low yield, and large volume, and achieve the effect of optimizing the production process

Active Publication Date: 2017-05-31
SPH NO 1 BIOCHEM & PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is to provide a preparation method of octreotide in order to overcome the defects of complex preparation process, low yield, dilute sample concentration and bulky volume in the prior art

Method used

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  • Preparation method for octreotide
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  • Preparation method for octreotide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1 (HPLC method detects octreotide precursor crude product and product solution purity after purification)

[0027] Instrument: Waters 2695 / 2489 high performance liquid chromatography

[0028] Separation column: Kromasil 100-3.5C18column 4.6×100mm

[0029] Mobile phase: A is 10% tetramethylammonium hydroxide: water: acetonitrile volume percentage is 2:88:10 aqueous solution, B is 10% tetramethylammonium hydroxide: water: acetonitrile volume percentage is 2:38:60 of aqueous solution.

[0030] Flow rate is 0.8mL / min, detection wavelength is 210nm, room temperature detection,

[0031] The elution gradient is shown in the table below, and the percentages are volume percentages.

[0032] mobile phase elution gradient

[0033] Elution step Elution time eluent 1 0~30min 73%A+27%B 2 30~31min 73%A+27%B→55%A+45%B 3 31~37min 73%A+27%B

Embodiment 2

[0034] Embodiment 2 (75mm inner diameter L&L4003 preparative column packing)

[0035] Using Load&Lock dynamic axial compression and static locking technology, the filler is styrene-divinylbenzene copolymer (reversed phase packing Agilent PLRP-S), the pore size is 10nm, the particle size is 10μm, and the column packing density is 0.33g / mL. Bed pressure 650psi, using Varian chromatography packing system, 370g dry powder filler, 2L methanol after stirring and homogenizing, poured into the L&L4003 preparative column with an inner diameter of 75mm, the compression ratio is 3:1, and the carrier gas is N 2 , adjust the carrier gas pressure so that the pressure of the oil pressure gauge is 2000psi, and the dynamic axial compression to the height of the column bed is 26cm, which is used as the preparative column for the reverse-phase cyclization, reverse-phase purification and reverse-phase desalination schemes.

Embodiment 3

[0036] Example 3 Reverse-phase cyclization, reverse-phase purification and reverse-phase desalting of octreotide precursor crude product raw material

[0037] Instrument: Varian SD-1 high pressure liquid phase preparation system

[0038] Chromatographic column: self-packed preparative column Load&Lock4003 75×260mm in Example 2, PLRP-S 10μm 10nm

[0039] The crude product of octreotide precursor is the crude product of octreotide precursor obtained by cleavage and drying by solid phase synthesis, and its structural formula is D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophanyl- Trifluoroacetate salt of L-lysyl-L-threonyl-L-cysteinyl-L-threoninol.

[0040] The crude octreotide precursor solution is a 5 g / L solution formed by dissolving the crude octreotide precursor in 5% acetonitrile aqueous solution.

[0041] Mobile phase A1 is pure water, A2 is 0.02% H by volume 2 o 2 pH is the NaOH aqueous solution of 7.5, and mobile phase B is acetonitrile, and mobile phase C1 is d...

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Abstract

The invention discloses a preparation method for octreotide. The preparation method comprises the following step: successively subjecting a solution of a crude octreotide precursor product to reversed-phase cyclization, reversed-phase purification and reversed-phase desalination by adopting a highly-efficient liquid-phase reversed-phase chromatography process, wherein a filling material for the highly-efficient liquid-phase reversed-phase chromatography process is a styrene-divinyl benzene copolymer; and the crude octreotide precursor product contains two free sulfhydryl groups. The preparation method provided by the invention prepares a pure polypeptide product by adopting reversed-phase adsorption for cyclization, purification and desalination through a one-step method, optimizes production process, and is applicable to continuous industrial production.

Description

technical field [0001] The invention relates to the field of biopharmaceuticals. More specifically, the present invention relates to a preparation method of octreotide. Background technique [0002] Octreotide acetate is a synthetic polypeptide composed of seven amino acid residues and a threonine alcohol, with a chemical structure of D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D- Tryptophanyl-L-lysyl-L-threonyl-L-cysteinyl-L-threoninyl (2→7)-disulfide acetate, the theoretical molecular weight of octreotide is 1019.26, its raw material The content of acetic acid in the freeze-dried powder of the medicine is 5% to 12%. Octreotide acetate can inhibit growth hormone, inhibit gastrointestinal and pancreatic secretion of polypeptides, etc., and its preparations are clinically used for active acromegaly that requires long-term octreotide treatment, such as increased serum growth hormone levels caused by postoperative growth hormone residues, pituitary external irradiation radiatio...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/20C07K1/04
CPCC07K7/06
Inventor 江锡铭丁金国黄臻辉
Owner SPH NO 1 BIOCHEM & PHARMA CO LTD
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