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Water soluble paclitaxel product

A kind of paclitaxel, water-soluble technology, applied in the field of water-soluble paclitaxel products

Inactive Publication Date: 2007-09-05
PG TXL COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Another drawback is that paclitaxel is not effective in all tumors, which may be due to the inability of paclitaxel to enter the tumor

Method used

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  • Water soluble paclitaxel product
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  • Water soluble paclitaxel product

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118] DTPA-paclitaxel

[0119] Synthesis of DTPA-paclitaxel:

[0120] To a solution of paclitaxel (100 mg, 0.117 mmol) in anhydrous DMF (2.2 ml) was added diethylenetriaminepentaacetic anhydride (DTPA A) (210 mg, 0.585 mmol) at 0°C. The reaction mixture was stirred overnight at 4°C. The suspension was filtered (0.2um Millipore filter) to remove unreacted DTPA. The filtrate was poured into distilled water, stirred at 4°C for 20 minutes, and the precipitate was collected. C by preparative thin layer chromatography (TLC) 18 The crude product was purified on a silica gel plate and developed in acetonitrile / water (1:1). Paclitaxel R f The value is 0.34. Scrape off the R on top of paclitaxel f The band with a value of 0.65-0.75 was eluted with a mixture of acetonitrile / water (1:1), and the solvent was removed to obtain 15 mg of DTPA-paclitaxel (yield 10.4%): mp: >226°C decomposition. The ultraviolet spectrum (sodium salt solution) has the maximum absorpt...

Embodiment 2

[0137] polyglutamate-paclitaxel

[0138] This example demonstrates the conjugation of paclitaxel to a water-soluble polymer, poly(L-glutamic acid) (PG). Water-soluble polymers used as drug carriers are well known (kopecek, 1990; Maeda and Matsumura, 1989). In addition to their ability to solubilize otherwise insoluble drugs, drug-polymer conjugates can also be used as slow release sites for controlled drug release.

[0139] Synthesis of PG-paclitaxel

[0140] PG was chosen as the carrier of paclitaxel because it is easily degraded by lysosomal enzymes, stable in plasma and contains sufficient functional groups for drug adsorption. Several antineoplastic drugs have been conjugated to PG, including doxorubicin (Van Heeswijk et al., 1985; Hoes et al., 1985), cyclophosphamide (Hirano et al., 1979) and cytarabine.

[0141] PG sodium salt (MW34k, Sigma, 0.35g) was dissolved in water. The pH of the aqueous solution was adjusted to 2 with 0.2M HCl. The precip...

Embodiment 3

[0168] PEG-paclitaxel

[0169]Synthesis of polyethylene glycol-paclitaxel (PEG-paclitaxel)

[0170] This synthesis is done in two steps. 2'-Succinyl-paclitaxel was first prepared according to known methods (Deutsch et al., 1989). Paclitaxel (200mg, 0.23mmol) and succinic anhydride (228mg, 2.22mmol) were reacted in anhydrous pyridine (6ml) at room temperature for 3 hours. Pyridine was then evaporated and the residue was treated with water, stirred for 20 minutes and filtered. The precipitate was dissolved in acetone, water was slowly added, and the last crystals were collected to obtain 180 mg of 2'-succinyl-paclitaxel. PEG-paclitaxel was synthesized by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-mediated coupling reaction. Methoxypolyoxyethyleneamine (PEG-NH 2 , MW 5000, 900 mg, 0.18 mmol) was added EEDQ (180 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 4 hours. The crude product was chromatographed on silica ge...

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Abstract

Disclosed are water soluble compositions of paclitaxel and docetaxel formed by conjugating the paclitaxel or docetaxel to a water soluble chelator, polyethylene glycol or polymer such as poly (1-glutamic acid) or poly (1-aspartic acid). Also disclosed are methods of using the compositions for treatment of tumors, autoimmune disorders such as rheumatoid arthritis and for prediction of paclitaxel uptake by tumors and radiolabeled DTPA-paclitaxel tumor imaging. Other embodiments include the coating of implantable stents for prevention of restenosis.

Description

[0001] This application is a divisional application of the application dated March 11, 1997, application number 97194360.5, and invention name "water-soluble paclitaxel product". technical field [0002] The present invention relates to pharmaceutical compositions for the treatment of cancer, autoimmune diseases and restenosis. It also relates to pharmaceutical anticancer agents such as paclitaxel (paclitaxel) and taxotere, and in particular to the preparation of water-soluble paclitaxel by conjugating the drug with a water-soluble moiety. Background technique [0003] Paclitaxel, an anti-microtubule agent extracted from the needles and bark of Taxus brevifolia-Taxus brevifolia, has shown significant antitumor activity against human cancers in phase I clinical studies and early phase II and III clinical trials role (Horwitzet et al., 1993). This effect was initially found in advanced ovarian and breast tumors. It has also been do...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/337A61K47/48A61K51/04A61P35/00A61L31/10A61L31/16A61K31/335A61K31/47A61K31/4738A61K31/4745A61K31/70A61K31/7042A61K31/7048A61K33/24A61K51/00A61P9/00A61P37/02A61P43/00
CPCA61K2123/00A61K47/48315A61K51/0497A61L2300/416A61K47/48215A61K31/337A61L31/16A61L31/10A61K2121/00A61K47/48076A61L2300/606A61K47/60A61K47/547A61K47/645A61P25/00A61P35/00A61P37/02A61P43/00A61P9/00A61P9/08A61P9/10A61K31/365
Inventor C·李S·华莱士D-F·于D·J·杨
Owner PG TXL COMPANY
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