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Pegylated leuprorelin

A technology of leuprolide and chemical method, applied in the directions of non-active ingredients medical preparations, peptide/protein ingredients, medical preparations containing active ingredients, etc. , irritation such as induration or redness

Active Publication Date: 2016-01-13
SHENZHEN XINGYIN PHARML
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the sustained and controlled release microsphere injection of leuprolide is clinically applied. Its polymer carrier material is PLGA, which belongs to suspension. The most commonly used preparation method is double emulsion method (w / o / w method). There are some disadvantages in its application: the particle size range of microspheres is generally 1-500 μm, the small one can be a few nanometers, and the large one can reach 800 μm. The injection needle required is relatively thick, and the injection site will be stimulated by pain, induration or redness; The particle size of the microspheres is not uniform, and the release of the drug is affected; if the material is not degradable, it may easily cause an inflammatory reaction, and the patient's compliance is poor; it is only used for subcutaneous administration, and intravenous injection may cause thrombosis
PEG conjugates of leuprolide have not yet been studied

Method used

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  • Pegylated leuprorelin
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Embodiment 1 prepares PEG-Mal-leuprolide

[0022] 1.1 Preparation of PEG-MAL sample (2)

[0023] Dissolve monomethoxypolyethylene glycol PEG with different molecular weights in appropriate amount of dichloromethane, add 2 equivalents of pyridine as an acid-binding agent, add 5 equivalents of maleic anhydride, control the temperature at 60°C, react for 8 hours, and concentrate , crystallization of isopropyl ether to obtain monomethoxypolyethylene glycol with a carboxyl group at one end of different molecular weights.

[0024] 1.2 Preparation of PEG-MAL-OSu sample (3)

[0025] Dissolve monomethoxypolyethylene glycol PEG-MAL with carboxyl group at one end of different molecular weights in appropriate amount of THF, add HOSu, DCC, stir, a large amount of white solid precipitates, filter, crystallize with isopropyl ether, filter, use Wash with appropriate amount of water and isopropyl ether, and dry in vacuum to obtain PEG-MAL-OSu with different molecular weights.

[0026...

Embodiment 2

[0030] The modification condition of embodiment 2PEG-Mal-leuprolide

[0031] 1. The influence of reaction pH value on the modified product

[0032] Take the protected leuprolide and prepare 2mg / mL with 100mmol / LPB buffer solution (pH4.0, pH5.0, pH5.5 and pH6.0) respectively. Weigh PEG-MAL-OSu-20KD at a molar ratio of 1:3 (ProLeuprorelin:PEG-MAL-OSu-20KD) and add it to the leuprolide reaction solution, stir and react at 100 rpm at 4°C for 24 hours, then add 1M glycine to terminate the reaction , purified by Sephadex Superdex200 column chromatography, concentrated, added to TFA:Tis:H 2 O (95:2.5:2.5) solution, stirred at room temperature for 3 to 5 hours, settled with isopropyl ether, filtered, purified by Sephadex Superdex200 column chromatography, concentrated, and freeze-dried. Samples were taken by enzyme-linked immunosorbent assay to determine the modification rate of PEG-Mal-leuprolide.

[0033] The experimental results showed that the proportion of PEG-Mal-leuprolide w...

Embodiment 3

[0043] Example 3HO-(CH 2 CH 2 O) 1000 - Preparation of Mal-Leuprorelin

[0044] HO-(CH 2 CH 2 O) 1000 -H is dissolved in an appropriate amount of dichloromethane, 2 equivalents of pyridine is added as an acid-binding agent, 5 equivalents of maleic anhydride is added, the temperature is controlled at 60°C, the reaction is for 8 hours, concentrated, crystallized from isopropyl ether, and one end is a carboxyl group. Monomethoxypolyethylene glycol, dissolve it in an appropriate amount of THF, add HOSu, DCC, stir, a large amount of white solid precipitates, filter, crystallize with isopropyl ether, filter, wash with appropriate amount of water and isopropyl ether, vacuum Dry to get HO-(CH 2 CH 2 O) 1000 -MAL-OSu; NaH with 100 mM pH 5.5 2 PO 4 -H 3 PO 4 The buffer solution dissolves the protected leuprolide to configure a 3mg / mL solution, and HO-(CH 2 CH 2 O) 1000 -MAL-OSu was reacted at a molar ratio of 1:5. After reacting at 4°C for 24h, 1M glycine was added to ter...

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Abstract

The invention provides a PEG-leuprorelin conjugate and a preparation method thereof. The preparation method is characterized in that: firstly PEG is connected with maleic anhydride for forming an active ester, the PEG modification agent is connected to leuprorelin with protection by Mal, and then a de-protection is carried out to obtain a PEG-leuprorelin conjugate with a single site modification. The compound has the original activity of leuprorelin, and simultaneously has a longer half life and a longer average peak time.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a PEG-modified leuprolide drug conjugate and a preparation method thereof. Background technique [0002] Leuprolide is a synthetic highly active derivative of luteinizing hormone-releasing hormone (LHRH, also known as gonadotropin-releasing hormone, GnRH), a GnRH antagonist, and a polypeptide drug. It stimulates the pituitary gland to secrete gonadotropins and induces steroid production in the reproductive organs. Long-term large-scale use will inhibit the secretion of gonadotropins from the pituitary gland and the production of testicular or ovarian steroids, and can treat or alleviate a variety of sex hormone-dependent diseases such as prostate cancer, endometriosis, uterine fibroids, and precocious puberty. [0003] At present, the sustained and controlled release microsphere injection of leuprolide is clinically applied. Its polymer carrier material is PLGA, which belongs ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/333C08G65/332A61K47/48A61K38/08
Inventor 李新宇支钦姚志勇刘自成吴丽芬
Owner SHENZHEN XINGYIN PHARML
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