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Preparation of octreotide acetate and octreotide acetate injection pharmaceutical composition

A technology of octreotide acetate and octreotide, which is applied in the field of medicine and can solve problems such as long half-life

Active Publication Date: 2017-06-20
CHENGDU TIANTAISHAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] (2) Long half-life: the half-life of subcutaneous injection is 2 hours

Method used

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  • Preparation of octreotide acetate and octreotide acetate injection pharmaceutical composition
  • Preparation of octreotide acetate and octreotide acetate injection pharmaceutical composition
  • Preparation of octreotide acetate and octreotide acetate injection pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Embodiment 1: the preparation of octreotide acetate

[0084] 1. Synthetic peptide chain

[0085] (1) Preparation of Boc-Thr(tBu)-OCs

[0086] Take 30.3 g of Boc-Thr(tBu)-OH (FW: 275.3, 110 mmol), dissolve it in 250 ml of methanol and 250 ml of water, pH 2.5. Take another 24g of cesium carbonate (147mmol) and add 100ml of water to dissolve until clear, and slowly add the above-mentioned Boc-Thr(tBu)-OH solution under stirring, and carbon dioxide gas will be generated. The pH of the solution was 7.5. It was dissolved in water at 40-50°C and concentrated to dryness under reduced pressure to obtain 54.2 g of Boc-Thr(tBu)-OCs as a syrupy residue.

[0087] (2) Preparation of Boc-Thr(tBu)-O-resin

[0088] Get 100 grams of chloromethyl resin (100-200 mesh, 1.0mmol / g, 100mmol), soak in DMF for 30 minutes, make the resin fully swell, add step (1) gained syrupy residue 107g and DMF of 700ml, 50- React at 55°C for 48 hours.

[0089] After filtering, the resin was washed twice...

Embodiment 2

[0120] Embodiment 2: the preparation of octreotide acetate

[0121] 1. Synthetic peptide chain

[0122] With embodiment 1.

[0123] Two, disulfide bond ring formation

[0124] Dissolve 90g of the reduced octreotide crude product in 90L of water, slowly add 2M ammonia water dropwise to pH7.8 under stirring, and feed air into the solution at room temperature (the used air passes through saturated calcium hydroxide solution and 2M sulfuric acid solution in advance successively) ), so that the disulfide bonds undergo ring-forming reaction for about 24-36 hours, add glacial acetic acid to adjust the pH to 5.5, add activated carbon to stir for 30 minutes, and filter.

[0125] 3. Separation and purification

[0126] Gained whole filtrate is purified in batches through C18 column when disulfide bonds are formed into rings, mobile phase: 0.25mol / L potassium acetate: acetonitrile (7.2:2.8); Flow rate is: 800ml / min; Effluent, the detection wavelength is: 280nm; After the sample pea...

Embodiment 3

[0127] Embodiment 3: the preparation of octreotide acetate

[0128] 1. Synthetic peptide chain

[0129] With embodiment 1.

[0130] Two, disulfide bond ring formation

[0131] Dissolve 90g of the reduced octreotide crude product in 90L of water, slowly add 2M ammonia water dropwise to pH7.8 under stirring, and feed air into the solution at room temperature (the used air passes through 2M sulfuric acid solution and saturated calcium hydroxide solution successively in advance) ), so that the disulfide bonds undergo ring-forming reaction for about 24-36 hours, add glacial acetic acid to adjust the pH to 5.5, add activated carbon to stir for 30 minutes, and filter.

[0132] 3. Separation and purification

[0133] Gained whole filtrate is purified in batches through C18 column when disulfide bonds are formed into rings, mobile phase: 0.25mol / L potassium acetate: acetonitrile (7.2:2.8); Flow rate is: 800ml / min; Effluent, the detection wavelength is: 280nm; After the sample pea...

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Abstract

The invention relates to preparation of octreotide acetate and an octreotide acetate injection pharmaceutical composition. Specifically, the invention relates to a method for preparing the octreotide acetate; the method comprises the following steps: taking merrifield resin as a starting raw material and preparing Boc-Thr(tBu)-OH into cesium salt; sequentially connecting amino acid with protecting groups according to a solid-phase synthesis method to obtain protected octapeptide resin; removing Boc-protecting groups in sequence by utilizing HCl / isopropyl alcohol and carrying out peptide linking reaction by utilizing a condensing agent; reducing with palladium-carbon / hydrogen; meanwhile, chopping off a peptide chain to obtain reduced octreotide; ventilating air under the condition that the pH (Potential of Hydrogen) is 8 to 9 to form a ring by a disulfide bond, so as to obtain an octreotide crude product; separating and purifying the octreotide crude product through a C18 column to prepare refined octreotide. The invention further relates to the octreotide acetate injection pharmaceutical composition. The method for preparing the octreotide acetate and the octreotide acetate injection pharmaceutical composition, provided by the invention, have the excellent technical effects shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically, the invention discloses a preparation of octreotide acetate and a pharmaceutical composition of octreotide acetate injection. The octreotide acetate preparation and the octreotide acetate injection pharmaceutical composition prepared by the invention have excellent properties. Background technique [0002] Octreotide Acetate (Octreotide Acetate) is a synthetic polypeptide composed of eight amino acids, its chemical name is: D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophanyl-L- Lysyl-L-threonyl-N-[(1R,2R)-2-hydroxy-1-(hydroxymethyl)propyl]-L-cysteineamide ring (2→7)-disulfide bond Acetate, its English chemical name is: L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl) Propyl]-, cyclic(2→7)-disulfide; [R-(R*, R*)] acetate salt, CAS: 83150-76-9, its chemical structural formula, molecular formula an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/16C07K1/06C07K1/04A61K38/08A61K9/08A61K47/26A61K47/12A61P35/00A61P1/00A61P1/18
CPCA61K9/0019A61K9/08A61K38/00A61K47/12A61K47/26C07K7/06Y02P20/55
Inventor 王敬江威谢晓飞胥宁曹海峰姚波方专赵东明
Owner CHENGDU TIANTAISHAN PHARMA
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