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Polyethylene glycol modified octreotide and preparation method thereof

A technology of polyethylene glycol and octreotide, applied in the preparation methods of peptides, chemical instruments and methods, medical preparations containing active ingredients, etc., can solve the problems of thick injection needles, induration or redness, pain, etc. The effect of market prospects

Inactive Publication Date: 2019-12-13
应连心
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the sustained and controlled release microsphere injection of octreotide acetate is clinically applied. Its polymer carrier material is PLGA, which belongs to suspension. There are some shortcomings: the particle size range of microspheres is generally 1~500um, the small ones can be several nanometers, and the large ones can reach 800um. The injection needles required are relatively thick, and the injection site will have pain, induration or redness and other irritations.
[0007] The molecular size and structure of polyethylene glycol have an impact on the spatial structure, stability and biological activity of proteins or peptides, and there is no related research on the modification of octreotide by polyethylene glycol

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Coupling of Fmoc-threoninol p-carboxybenzacetal (8th amino acid)

[0035] Weigh Rink Amide AM Resin (100.00g, loading: 0.6mmol / g) and wash it once with 1000mL dry DMF, drain it, swell in 1000mL DMF for 2 h, and drain it.

[0036] Add 20% piperidine / DMF solution (DBLK solution) for deprotection twice, 1000mL / time, 5min+15min. After the deprotection is completed, wash with DMF 6 times, 1000 mL / time / min, drain, and detect ninhydrin, K+.

[0037]Weigh 55.14 g Fmoc-Cys(Trt)-OH, dissolve 17.84 g HOBt in 1000 mL DMF, add 16.67 g DIC under ice cooling to activate the solution for about 5 min, pour it into the reaction column, stir the reaction at room temperature for 2 h, and take a sample , ninhydrin detection, K-; wash the resin 3 times with DMF, 1000 mL / time / min, and drain.

Embodiment 2

[0038] Example 2: Coupling of Fmoc-Cys(Trt)-OH (7th amino acid)

[0039] Add 20% piperidine / DMF solution (DBLK solution) for deprotection twice, 1000mL / time, 5min+15min. After the deprotection is completed, wash with DMF 6 times, 1000 mL / time / min, drain, and detect ninhydrin, K+.

[0040] Weigh 70.29 g Fmoc-Cys(Trt)-OH, dissolve 17.84 g HOBt in 1000 mL DMF, add 16.67 g DIC under ice cooling to activate the solution for about 5 min, pour it into the reaction column, stir the reaction at room temperature for 2 h, and take a sample , ninhydrin detection, K-; wash the resin 3 times with DMF, 1000 mL / time / min, and drain.

Embodiment 3

[0041] Example 3: Coupling of Fmoc-Thr(tBu)-OH (the 6th amino acid)

[0042] Add 20% piperidine / DMF solution (DBLK solution) for deprotection twice, 1000mL / time, 5min+15min. After the deprotection is completed, wash with DMF 6 times, 1000 mL / time / min, drain, and detect ninhydrin, K+.

[0043] Weigh 47.70 g Fmoc-Thr(tBu)-OH, dissolve 17.84 g HOBt in 1000 mL DMF, add 16.67 g DIC under ice cooling to activate the solution for about 5 min, pour it into the reaction column, stir the reaction at room temperature for 2 h, and take a sample , ninhydrin detection, K-; wash the resin 3 times with DMF, 1000 mL / time / min, and drain.

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PUM

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Abstract

The invention relates to the technical field of polypeptide drug preparation, and provides polyethylene glycol modified octreotide and a preparation method thereof. The method is characterized in thatthe method adopts a solid-phase synthesis method to couple octreotide main chains onto resin from a C end to an N end in sequence, an N end protecting group Fmoc is removed and then coupled with oneend of adipic acid through an amido bond, the other end of the adipic acid is coupled with polyethylene glycol, and finally, trifluoroacetic acid is used for deprotection and then liquid-phase cyclization is carried out. The compound can keep the original activity of the octreotide, overcomes the problem of short half-life period of the octreotide, greatly improves the clinical application compliance and has better application value.

Description

technical field [0001] The invention relates to the technical field of preparation of polypeptide drugs, in particular to a polyethylene glycol-modified octreotide and a preparation method thereof. Background technique [0002] Octretide acetate is a synthetic polypeptide composed of seven amino acid residues and one threonine alcohol, which can inhibit growth hormone, inhibit gastrointestinal pancreas secretion of polypeptides, etc., and is clinically used to treat active acromegaly, digestion Endocrine tumors of the tract, non-secretory tumors of the digestive tract, upper gastrointestinal bleeding, acute pancreatitis, systemic sclerosis, irritable bowel syndrome, cancer cachexia, dumping syndrome, orthostatic hypotension, hypotension during surgery, etc. Treatment. [0003] There are two FDA-approved octreotide acetate preparations, one is Sandostatin injection, which is injected subcutaneously three times a day; the other is Sandostatin LAR Depot microspheres for depot ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/107C07K1/06C07K1/04A61K38/08A61P35/00A61P1/00A61P1/18A61P37/02A61P19/00A61P9/00
CPCC07K7/06A61P35/00A61P1/00A61P1/18A61P37/02A61P19/00A61P9/00A61K38/00Y02P20/55
Inventor 应连心
Owner 应连心
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