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Antiproliferative drug

A technology of hyaluronic acid and conjugates, which is applied in the field of esterified conjugates of hyaluronic acid, and can solve problems such as limitations in therapeutic use

Inactive Publication Date: 2008-07-23
EURAND PHAMACEUTICALS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, their therapeutic use is strongly limited by their high systemic toxicity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Example 1: Determination of chlorine content in HA-Cl and HA conjugates

[0095] pass 13 CNMR (Spectrometer Varian Mercury 200), using 13 Standard sequence for C-spectrum capture (std 13 C sequence) to determine the chlorine content of the conjugate Dissolve 20 mg of the conjugate sample in 650 μL in a 5 mm tube at room temperature D 2 O middle. Gentle heating (50°C) was used to remove air bubbles in the solution. Spectra were collected after 24 hr at 30 °C and analyzed by integrating the CH of HA-Cl 2 OH signal (61ppm) and C h 2 Cl signal (44ppm) was analyzed. For the HA-MTX-Cl derivatives, in addition to these two signals, the C h 2 The OMTX signal (64ppm) is integrated. The chlorine content was determined as the ratio of the number of HA repeat units containing 6-chloro groups to the total number of HA repeat units. This ratio is then converted to weight percent chlorine.

Embodiment 2

[0096] Embodiment 2: determine methotrexate content by HPLC

[0097] The methotrexate content of the HA conjugates was determined by HPLC, analyzing samples before and after alkaline hydrolysis according to the accepted monograph on methotrexate (USP 23-p 984). The analysis conditions are, chromatograph: DionexDX-600. Column: Column Phenomenex Synergi 4μHydro-RP80, column size: 150×460mm, column particle size: 4μ, temperature: 40°C, eluent: 90% 0.2M disodium hydrogen phosphate / 0.1M citric acid (630:270), 10% CH 3 CN, isocratic conditions: 0.5 mL / min. Detector: diode array (range 200-780 nm), selected wavelength for quantification: 302 nm, injection volume: 25 μl, run time 30 minutes. The solution used for the determination of free methotrexate was prepared by directly dissolving HA-MTX in MilliQ water at an appropriate concentration. The total methotrexate content was measured after alkaline hydrolysis in NaOH 0.1M at room temperature for 2 hours. After neutralization wi...

Embodiment 3

[0099] Embodiment 3: measure weight-average molecular weight (Mw)

[0100] The molecular weight of the hyaluronic acid conjugate was measured by HP-SEC (High Performance Size Exclusion Chromatography). The analysis conditions are, chromatograph: HPLC pump980-PU (Jasco serial number B3901325), equipped with a Rheodyne 9125 syringe. Column: TSK PWxI (TosoBioscience) G6000+G5000+G3000 6, 10, 13μm particle size; temperature: 40°C Mobile phase: NaCl0.15M+0.01%NaN 3 Flow rate: 0.8mL / min. Detector: MALLS (WYATT DAWNEOS-WYATT, USA), λ=690nm, (dn / dc=0.167mL / g), UV spectrophotometer detector 875-UV (Jasco, serial number D3693916), λ=305nm, the refractive index of the interferometer refers to OPTILABREX (WYATT, USA); λ=690nm, sensitivity: 128x; temperature: 35°C; injection volume: 100 μl, run time 60 minutes HA-Cl and HA to be analyzed - A sample of MTX was prepared at a concentration of about 1.0 mg / ml in 0.9% NaCl and kept under stirring for 12 hours. Then, the solution was filter...

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Abstract

Object of the present invention are esterified conjugates of hyaluronic acid having anti-proliferative activity.

Description

field of invention [0001] The present invention relates to esterified conjugates of hyaluronic acid with antiproliferative activity. Background technique [0002] Several organic molecules, known to be useful as antiproliferative agents, have been tested, but many of them have limited clinical use due to their high toxicity, low solubility and / or unsuitable pharmacokinetic parameters. [0003] Where these compounds are N-derivatives of glutamic acid having inhibitory activity against dihydrofolate reductase (DHFR), these compounds constitute a family of antiproliferative agents having methotrexate as a parent compound. [0004] These drugs are effective in several diseases such as tumors, psoriasis and rheumatoid arthritis. However, their therapeutic use is strongly limited by their high systemic toxicity. [0005] It was found in WO01 / 68105 that the toxicity problem of the above DHFR inhibitors can be solved by conjugating them to polysaccharides. Indeed, the conjugates ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/48A61K31/728A61P35/00
CPCA61K31/728A61K47/61A61P17/00A61P17/06A61P19/02A61P29/00A61P35/00A61P37/00A61P43/00
Inventor 埃尔米尼奥·穆拉诺安东内拉·弗拉伊巴尼马西莫·贝尔加明斯特凡诺·诺尔贝多克洛迪娅·索尔比里亚·艾哈迈德·卡恩
Owner EURAND PHAMACEUTICALS LTD
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