Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Water soluble paclitaxel derivatives

a technology of paclitaxel and derivatives, applied in the field of pharmaceutical compositions, can solve the problems of prolonged drug exposure to tumor cells and tumor accumulation, and achieve the effects of novel drug activity, improved efficacy and controlled release, and surprising anti-tumor activity

Inactive Publication Date: 2006-05-25
PG TXL COMPANY
View PDF19 Cites 8 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides new compositions and methods for treating tumors using water soluble taxoids, such as paclitaxel and docetaxel, that are conjugated to a water soluble polymer. These compositions have improved efficacy and controlled release, and can be used in combination with other anti-tumor drugs or therapies. The water soluble polymer-drug conjugates can selectively leak from blood vessels into tumors, resulting in tumor accumulation of active therapeutic drug. The compositions can also act as drug depots for sustained release and stabilize drugs that are insoluble in their native form. The invention provides a novel approach to reduce systemic toxicity and improve the therapeutic index of chemotherapy drugs."

Problems solved by technology

Thus, a polymer-drug conjugate that would normally remain in the vasculature may selectively leak from blood vessels into tumors, resulting in tumor accumulation of active therapeutic drug.
Additionally, polymer-drug conjugates may act as drug depots for sustained release, producing prolonged drug exposure to tumor cells.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Water soluble paclitaxel derivatives
  • Water soluble paclitaxel derivatives
  • Water soluble paclitaxel derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

Poly-glutamic Acid-Paclitaxel (PG-TXL)

[0092] The present example concerns a first study involving the conjugation of paclitaxel to a water-soluble polymer, poly (1-glutamic acid) (PG) and the efficacy of the preparation against a variety of tumors in mice and rats. The potential of water-soluble polymers used as drug carriers is well established (Kopecek, 1990; Maeda and Matsumura, 1989).

Synthesis of Poly-Glutamic Acid-Paclitaxel (PG-TXL)

[0093] PG was selected as a carrier for paclitaxel because it can be readily degraded by lysosomal enzymes, is stable in plasma and contains sufficient functional groups for drug attachment. Several antitumor drugs, including Adriamycin (Van Heeswijk et al., 1985; Hoes et al., 1985), cyclophosphamide (Hirano et al., 1979), Ara-C (Kato et al., 1984) and melphalan (Morimoto et al., 1984) have been conjugated to PG. However, poly-aspartic acid may be conjugated to anti-tumor drugs using the reaction scheme described herein for PG-TXL.

[0094] The re...

example 2

DTPA-Paclitaxel

Synthesis of DTPA-Paclitaxel:

[0117] To a solution of pacitaxel (100 mg, 0.117 mmol) in dry DMF (2.2 ml) was added diethylenetriaminepentaacetic acid anhydride (DTPA A) (210 mg, 0.585 mmol) at 0° C. The reaction mixture was stirred at 4° C. overnight. The suspension was filtered (0.2 μm Millipore filter) to remove unreacted DTPA anhydride. The filtrate was poured into distilled water, stirred at 4° C. for 20 min, and the precipitate collected. The crude product was purified by preparative TLC over C18 silica gel plates and developed in acetonitrile / water (1:1). Paclitaxel had an Rf value of 0.34. The band above the paclitaxel with an Rf. value of 0.65 to 0.75 was removed by scraping and eluted with an acetonitrile / water (1:1) mixture, and the solvent was removed to give 15 mg of DTPA-paclitaxel as product (yield 10.4%): mp: >226° C. dec. The UV spectrum (sodium salt in water) showed maximal absorption at 228 nm which is also characteristic for paclitaxel. Mass spect...

example 3

Polyethylene glycol-Paclitaxel

Synthesis of Polyethylene Glycol-Paclitaxel (PEG-Paclitaxel)

[0128] The synthesis was accomplished in two steps. First 2′-succinyl-paclitaxel was prepared according to a reported procedure (Deutsch et al., 1989). Paclitaxel (200 mg, 0.23 mmol) and succinic anhydride (288 mg, 2.22 mmol) were allowed to react in anhydrous pyridine (6 ml) at room temperature for 3 h. The pyridine was then evaporated, and the residue was treated with water, stirred for 20 mm, and filtered. The precipitate was dissolved in acetone, water was slowly added, and the fine crystals were collected to yield 1 80 mg 2′-succinyl-paclitaxel. PEG-paciitaxel was synthesized by an N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) mediated coupling reaction. To a solution of 2′-succinyl-paclitaxel (160 mg, 0.18 mmol) and methoxypolyoxyethylene amine (PEG-NH2, MW 5000, 900 mg, 0.18 mmol) in methylene chloride was added EEDQ (180 mg, 0.72 mmol). The reaction mixture was stirred at roo...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
molecular weightaaaaaaaaaa
molecular massaaaaaaaaaa
diameteraaaaaaaaaa
Login to View More

Abstract

Disclosed are water soluble compositions of paclitaxel and docetaxel formed by conjugating the paclitaxel or docetaxel to a water soluble polymer such as polyglutamic acid, poly-aspartic acid or poly-lysine. Also disclosed are methods of using the compositions for treatment of tumors, auto-immune disorders such as rheumatoid arthritis. Other embodiments include the coating of implantable stents for prevention of restenosis.

Description

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS [0001] This application claims priority of U.S. Ser. No. 09 / 050,662 filed Mar. 30, 1998.FIELD OF THE INVENTION [0002] The present invention relates generally to the fields of pharmaceutical compositions to be used in the treatment of cancer, autoimmune diseases and restenosis. The present invention also relates to the field of pharmaceutical preparations of anticancer agents such as paclitaxel (Taxol™) and docetaxel (Taxotere), in particular making paclitaxel water soluble by conjugating the drug to water soluble moieties. BACKGROUND OF THE INVENTION [0003] Paclitaxel, an anti-microtubule agent extracted from the needles and bark of the Pacific yew tree, Taxus brevifolia, has shown a remarkable anti-neoplastic effect in human cancer in Phase I studies and early Phase II and III trials (Horwitz et at, 1993). This has been reported primarily in advanced ovarian and breast cancer. Significant activity has been documented in small-cell and ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/16A61K31/337A61K41/00A61K47/48A61K51/04A61K51/08A61L31/10A61L31/16C08G73/10
CPCA61K31/337A61K31/4375A61K38/13A61K41/0038A61K47/48076A61K47/48192A61K47/48215A61K47/48315A61K51/0497A61K51/065A61K2121/00A61K2123/00A61L31/10A61L31/16A61L2300/416A61L2300/606C08G73/1092A61K47/60A61K47/547A61K47/59A61K47/645A61P35/00A61P35/02A61P35/04
Inventor LI, CHUNWALLACE, SIDNEYYU, DONG-FANGYANG, DAVID
Owner PG TXL COMPANY
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com