Method of using SAHA and Erlotinib for treating cancer

A technology of suberoylanilide hydroxamic acid and agent erlotinib, applied in the field of erlotinib, can solve the problem that DNA is difficult to enter transcriptional regulatory elements and structures

Inactive Publication Date: 2008-11-05
MERCK & CO INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This affinity results in tight binding of DNA to histones, making it difficult for DNA to access transcriptional regulatory elements and structures

Method used

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  • Method of using SAHA and Erlotinib for treating cancer
  • Method of using SAHA and Erlotinib for treating cancer
  • Method of using SAHA and Erlotinib for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0325] Embodiment 1: the synthesis of SAHA

[0326] SAHA can be synthesized as described below, or as described in US Patent No. 5,369,108 (which is incorporated herein by reference in its entirety), or by any other method.

[0327] Synthesis of SAHA

[0328] Step 1 - Synthesis of N-suberanilic acid

[0329]

[0330] In a 22L flask, add 3500g (20.09mol) of suberic acid, and heat and melt the acid. The temperature was raised to 175° C., and then 2040 g (21.92 mol) of aniline were added. The temperature was raised to 190° C. and maintained at this temperature for 20 minutes. The melt was poured into a Nalgene tank containing 4017 g of potassium hydroxide in 50 L of aqueous solution. The mixture was stirred for 20 minutes, then the melt was added. The reaction was repeated on the same scale and a second batch of the melt was poured into the same potassium hydroxide solution. After the mixture was stirred well, the stirrer was turned off and the mixture was allowed to...

Embodiment 2

[0347] Example 2: Production of Wet Milled Small Particles in 1:1 Ethanol / Water

[0348] SAHA polymorph I crystals were suspended in a 1:1 (by volume) EtOH / aqueous solution mixture at a slurry concentration of 50 mg / g to 150 mg / g (crystal / solvent mixture). Use IKA-WorksRotor-Stator high-shear homogenizer T50 type, wet-grind the slurry with a superfine powder blade at 20-30m / s, until the average particle size of SAHA is less than 50μm, and 95% is less than 100μm, while keeping the temperature at room temperature . The wet milled slurry was filtered and washed with a 1:1 EtOH / aq mixture at room temperature. The wet cake was then dried at 40°C. The final average particle size of the wet ground material was less than 50 μm as determined by the following Microtrac method.

[0349] The particle size was analyzed using a SRA-150 laser scattering particle size analyzer (manufactured by Microtrac Inc.). The analyzer is equipped with an ASVR (Automatic Small Volume Recirculator). ...

Embodiment 2A

[0350] Example 2A: Large scale production of wet milled small particles in 1:1 ethanol / water

[0351] Add 56.4kg of SAHA polymorph I crystals to 610kg (10.8kg solvent / kg SAHA) of 50% vol / vol 200 strength standard ethanol and water (50 / 50 EtOH / water) at 20-25°C in solution. The slurry (~700 L) was repeatedly cycled through the IKA Works wet milling unit with a micropowder generator until a steady state particle size distribution was reached. Conditions were: DR3-6, 23 m / s rotor tip speed, 30-35 Lpm, 3 gens, ~96 cycles (one cycle is a batch of volume through one gen), ~12 hours.

[0352]

[0353] The wet cake was filtered, washed 2X with water (6 kg / kg total, ~340 kg), dried under vacuum at 40-45°C. The dry cake was then sieved (595 μm sieve) and packaged as Refined API.

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Abstract

The present invention relates to a method of treating cancer in a subject in need thereof, by administering to a subject in need thereof a first amount of a histone deacetylase (HDAC) inhibitor such as suberoylanilide hydroxamic acid (SAHA), or a pharmaceutically acceptable salt or hydrate thereof, and a second amount of one or more anti-cancer agents, including Erlotinib. The HDAC inhibitor and the anti-cancer agent may be administered to comprise therapeutically effective amounts. In various aspects, the effect of the HDAC inhibitor and the anti-cancer agent may be additive or synergistic.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application Serial No. 60 / 733,666, filed November 4, 2005. [0003] Each of the applications and patents cited herein, and documents or references cited in such applications and patents (including each issued patent during the prosecution; Each of the US and foreign patent applications from which priority is claimed, and each document cited or referenced in an application cited in each document, are hereby expressly incorporated herein by reference. More generally, documents or references are incorporated herein, either in the list of references preceding the claims or within the text itself; and each of those documents or references (“herein cited references”), and The documents or references cited in each of the herein cited references, including any manufacturer's specifications, technical notes, etc., are hereby expressly incorporated herein by reference. Documents ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/70
CPCA61K31/19A61K31/167A61K31/517A61P35/00A61P43/00A61K2300/00
Inventor P·班S·维塔V·M·里雄S·弗兰克尔P·多伊特施S·兰多尔夫
Owner MERCK & CO INC
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