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Nanoparticulate compositions of tubulin inhibitor compounds

A technology of tubulin inhibition and nanoparticle, which can be used in drug combination, drug delivery, medical preparations containing active ingredients, etc., and can solve problems such as microtubule instability

Inactive Publication Date: 2007-12-19
BAXTER INT INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It destabilizes tumor cells as well as microtubules in cell-free systems

Method used

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  • Nanoparticulate compositions of tubulin inhibitor compounds
  • Nanoparticulate compositions of tubulin inhibitor compounds
  • Nanoparticulate compositions of tubulin inhibitor compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0192] Example 1: Small scale preparation (300 g) of a suspension of D-24851 (composition 1)

[0193] An aqueous surfactant solution containing 0.1% sodium deoxycholate, 2.2% glycerol (tension agent), and 0.142% disodium phosphate (buffer) was cooled to low temperature (<10°C). The lactic acid solution of D-24851 and Poloxamer 188 was added to the above surfactant solution. The two solutions are mixed to form a suspension. The total suspension weight is 300 g, and the drug concentration is about 1% (w / w). Immediately after the precipitation, carry out high-pressure homogenization, the pressure is about 10,000 psi, and the temperature is <70°C. Lactic acid was removed by centrifugation, and the suspension was homogenized again at about 10,000 psi at a temperature <70°C. After homogenization, the particle size of the suspension was measured using light scattering. The average particle size is about 190nm.

Embodiment 2

[0194] Example 2: Preparation of 2,000 g of a suspension of D-24851 (Composition 2)

[0195] An aqueous surfactant solution containing 0.1% sodium deoxycholate, 2.2% glycerol (tension agent), and 0.142% disodium phosphate (buffer) was cooled to low temperature (<10°C). The lactic acid solution of D-24851 and Poloxamer 188 was added to the above surfactant solution. The two solutions are mixed to form a suspension. The total suspension weight was 2,000 g, and the drug concentration was about 1% (w / w). Immediately after the precipitation, carry out high-pressure homogenization, the pressure is about 10,000 psi, and the temperature is <70°C. Lactic acid was removed by centrifugation, and the suspension was homogenized again at about 10,000 psi at a temperature <70°C. After homogenization, the particle size of the suspension was measured using light scattering. The average particle size is about 325nm.

Embodiment 3

[0196] Example 3: Large scale preparation (6,000 g) of a suspension of D-24851 (Composition 3)

[0197] An aqueous surfactant solution containing 0.1% sodium deoxycholate, 2.2% glycerol (tension agent), and 0.142% disodium phosphate (buffer) was cooled to low temperature (<10°C). The lactic acid solution of D-24851 and Poloxamer 188 was added to the above surfactant solution. The two solutions are mixed to form a suspension. The total suspension weight was 6,000 g, and the drug concentration was about 1% (w / w). Immediately after the precipitation, carry out high-pressure homogenization, the pressure is about 10,000 psi, and the temperature is <70°C. Lactic acid was removed by centrifugation, and the suspension was homogenized again at about 10,000 psi at a temperature <70°C. After homogenization, the particle size of the suspension was measured using light scattering. The average particle size is about 370nm.

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Abstract

The present invention is directed to novel pharmaceutical compositions comprinsing nano- and micro-particulate formulations of poorly water soluble tubulin inhibitors of the indole chemical class, preferably N-substituted indol-3-glyoxyamides, and more preferably N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]glyoxylic acid amide (D-24851), also known as ''Indibulin'', and methods of making and using such compositions for the treatment of anti-tumor agent resistant cancers and other diseases.

Description

[0001] The present invention relates to nano- and microparticle formulations, methods of manufacture and methods of use of indole tubulin inhibitors. Preferred indole tubulin inhibitors include N-substituted indole-3-glyoxylamides, more preferably N-(pyridin-4-yl)-[1-(4-chlorobenzyl)-indole -3-yl]glyoxylamide (D-24851), also known as "Indibulin". Although particulate compositions of indole tubulin inhibitors can be prepared by various methods, a preferred method involves precipitating the tubulin inhibitor compound in an aqueous medium in the presence of a surfactant, forming a presuspension, and then applying energy to The desired size distribution of nanoparticles is obtained in the suspension. Such compositions are useful in various treatments, preferably in the treatment of cancer and other diseases resistant to anticancer agents. Background of the invention [0002] A. Background on nanoparticles for poorly soluble drugs [0003] The number of formulations of poorly so...

Claims

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Application Information

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IPC IPC(8): A61K31/404A61P35/00A61K9/00
Inventor 帕夫洛斯・帕帕佐普洛斯格哈德・拉伯马克・J・多蒂詹姆斯・E・基普贝托尔德・勒斯勒尔
Owner BAXTER INT INC
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