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Modified release of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-n-5-(4-methyl-1h-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide solubilized using organic acids

A technology of trifluoromethyl and benzamide, applied in the field of pharmaceutical compositions, can solve problems such as difficult preparation and delivery

Inactive Publication Date: 2014-02-26
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

One problem in providing such compositions comprising nilotinib is the physiochemical properties of nilotinib since nilotinib and its salts are poorly water soluble compounds and difficult to formulate and deliver (i.e. available in time)

Method used

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  • Modified release of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-n-5-(4-methyl-1h-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide solubilized using organic acids
  • Modified release of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-n-5-(4-methyl-1h-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide solubilized using organic acids
  • Modified release of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-n-5-(4-methyl-1h-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide solubilized using organic acids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Embodiment 1 Nilotinib lactic acid preparation

[0106] It has been surprisingly found that nilotinib has very high solubility in lactic acid (>600 mg / ml at 65°C) and can maintain its solubility at intestinal pH in the presence of surfactants and / or polymers. A solubilized modified release solid dosage form of nilotinib containing lactic acid has been developed. Compared with FMI, this preparation showed higher bioavailability under both fasting and fed conditions, and inhibited the food effect associated with nilotinib. Surfactants and / or polymers are used to prevent precipitation of the solubilized nilotinib after release from the formulation matrix. Due to the liquid nature of lactic acid, the formulation base is in liquid form. However, by incorporating other suitable excipients, the formulation can be cured at room temperature. This improves the physical and chemical stability of nilotinib in this formulation. In addition, the solid state also offers the opport...

Embodiment 2

[0121] Embodiment 2 Nilotinib citrate solid dosage form preparation

[0122] To overcome the stability issues of lactic acid-solubilized solid dosage forms of nilotinib, the use of solid organic acids was considered. It was surprisingly found that citric acid provided a remarkably high solubility of the drug in ethanol. This approach allowed the development of a dedicated spray-drying method as a method for producing nilotinib solubilized solid dosage forms. The resulting AMN107 solubilized drug intermediate was compressed with other external excipients into MR (rapid and slow release) tablets, which showed good chemical stability and also inhibited the food effect in dogs.

[0123] An example of the composition of the solubilized solid AMN107 spray-dried drug intermediate is described in Table 2.

[0124] Table 2 uses the composition of the nilotinib solubilization intermediate of citric acid

[0125]

[0126] Figures 4 to 7 It is shown that nilotinib intermediates A ...

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Abstract

Soluble pharmaceutical compositions of amorphous nilotinib or a pharmaceutically acceptable salt thereof were invented using one or more organic acids that function as a solubilizing agent, increasing the bioavailability of nilotinib and supressing the food effect associated with certain compositions of nilotinib. The pharmaceutical compositions are in th form of solid oral dosage forms, including capsules and tablets.

Description

technical field [0001] The present invention relates to a pharmaceutical composition comprising the therapeutic compound nilotinib (Formula I) in solubilized or amorphous form. The pharmaceutical composition also includes at least one organic acid as a co-solvent to increase the bioavailability of nilotinib and inhibit the food effect associated with certain compositions of nilotinib. Background of the invention [0002] Nilotinib is 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl) -3-(Trifluoromethyl)phenyl]benzamide. A particularly effective salt of nilotinib is nilotinib hydrochloride monohydrate. These therapeutic compounds are useful as inhibitors of the protein tyrosine kinase (TK) activity of Bcr-Abl. Examples of disorders treatable with such therapeutic compounds include, but are not limited to, chronic myelogenous leukemia and gastrointestinal stromal tumors. [0003] There is a need to formulate nilotinib and the other therapeuti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/506A61P35/00
CPCC07D401/14A61K31/506A61P35/00A61P35/02A61K9/1617A61K9/1635A61K9/4858A61K9/4866A61K9/2027A61K9/2054A61K9/2013A61K47/12A61K47/22
Inventor 李守峰S·库马尔N·J·卡维曼丹卢恩先
Owner NOVARTIS AG
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