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RAF kinase inhibitor preparation and preparation method thereof

A technology of kinase inhibitors and oral preparations, which is applied in the direction of pharmaceutical formulations, medical preparations containing no active ingredients, and medical preparations containing active ingredients. Good stability, good fluidity, good stability effect

Active Publication Date: 2020-05-22
百济神州(苏州)生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, Lifirafenib itself has poor fluidity, easy agglomeration, electrostatic interaction, and low solubility, which poses some challenges for Lifirafenib formulation development
The inventors have tried to prepare capsule fillings by directly mixing them with dry powders of conventional fillers such as lactose. Especially for preparations with high content specifications, the problem of poor fluidity caused by electrostatic interaction still cannot be solved, and the powder obtained by direct mixing of dry powders cannot Automated or semi-automated capsule filling greatly limits the development of Lifirafenib formulations

Method used

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  • RAF kinase inhibitor preparation and preparation method thereof
  • RAF kinase inhibitor preparation and preparation method thereof
  • RAF kinase inhibitor preparation and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1: the capsule of Lifirafenib, specification is 100mg, and every 100g prescription is:

[0058]

[0059] The prescription amount of Lifirafenib is based on 5-(((1R,1aS,6bR)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro crystalline sesquimaleic acid of -1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthalene-2(1H)-one Salt meter.

[0060] Strength 100mg as 5-(((1R,1aS,6bR)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H- Cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthalene-2(1H)-one.

[0061] Preparation Process:

[0062] (1) Mixing: mix the Lifirafenib crude drug of the prescribed amount, the silicified microcrystalline cellulose of the prescribed amount, the croscarmellose sodium of the prescribed amount and 85% to 90% of the prescribed amount of sodium stearyl fumarate.

[0063] (2) Dry granulation: put the mixture into a Freund Vector granulator (TFC-LAB Micro), feed the material at a speed of 20-...

Embodiment 2

[0068] Embodiment 2: the capsule of Lifirafenib, specification is 5mg, and every 100g prescription is:

[0069]

[0070] The prescription amount of Lifirafenib is based on 5-(((1R,1aS,6bR)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro crystalline sesquimaleic acid of -1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthalene-2(1H)-one Salt meter.

[0071] Strength 5mg as 5-(((1R,1aS,6bR)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H- Cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthalene-2(1H)-one.

[0072] Preparation Process:

[0073] (1) Mixing: Lifirafenib bulk drug in the prescribed amount, silicified microcrystalline cellulose accounting for 30% to 40% of the prescribed amount, croscarmellose sodium in the prescribed amount and stearin in 85% to 90% of the prescribed amount Sodium fumarate mixed.

[0074] (2) Dry granulation: put the mixture into a Freund Vector granulator (TFC-LAB Micro), feed the material at a ...

Embodiment 3

[0079] Embodiment 3: the capsule of Lifirafenib, specification is 5mg, and every 100g prescription is:

[0080]

[0081] The prescription amount of Lifirafenib is based on 5-(((1R,1aS,6bR)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro crystalline sesquimaleic acid of -1H-cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthalene-2(1H)-one Salt meter.

[0082] Strength 5mg as 5-(((1R,1aS,6bR)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H- Cyclopropa[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthalene-2(1H)-one.

[0083] Preparation Process:

[0084] (1) Mixing: mix the Lifirafenib crude drug of the prescribed amount, the silicified microcrystalline cellulose of the prescribed amount, the croscarmellose sodium of the prescribed amount and 85% to 90% of the prescribed amount of sodium stearyl fumarate.

[0085] (2) Dry granulation: put the mixture into the granulator, feed the material at a speed of 20-40 RPM, carry out rolling and co...

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Abstract

The invention belongs to the field of pharmaceutic preparations, and relates to an RAF kinase inhibitor particle composition. The composition comprises the following components: (1) 5-(((1R,1aS,6bR)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropal[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one or a pharmaceutically acceptable salt as an active component,(2) silicified microcrystalline cellulose and (3) an optionally selected other pharmaceutically acceptable excipient. The particle composition is prepared by using a rolling granulation technology. The method adopts the rolling granulation technology to solve the problems of easy agglomeration and poor fluidity of materials, obtains the particle composition with better fluidity, stability and dissolution for preparing a corresponding formulation dosage form, and is suitable for commercial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, in particular to a RAF kinase inhibitor containing 5-(((1R, 1aS, 6bR)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazole-2 -yl)-1a,6b-dihydro-1H-cyclopropane[b]benzofuran-5-yl)oxy)-3,4-dihydro-1,8-naphthyridine-2(1H )-ketone or a pharmaceutically acceptable salt thereof and a preparation method thereof. Background technique [0002] RAS / RAF / MEK / ERK is an important pathway to regulate the growth of tumor cells, and participates in the regulation of various biological processes in cells, such as cell growth, differentiation and apoptosis. RAF is a family of serine / threonine-specific kinases, including A-RAF, B-RAF, and C-RAF, among which, the B-RAF gene is found to be mutated in many malignant tumors, such as melanoma (40-50%) , thyroid cancer (27%), ovarian cancer (15%), colorectal cancer (5-14%), non-small cell lung cancer (2-4%). Two first-generation B-RAF inhibitors have been approved by ...

Claims

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Application Information

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IPC IPC(8): A61K9/16A61K47/38A61K31/4375A61P35/00
CPCA61K9/1652A61K9/1682A61K31/4375A61P35/00
Inventor 张国良周昌友范文源杜争鸣
Owner 百济神州(苏州)生物科技有限公司
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