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Oral dosage forms of cyclopropanecarboxylic acid {2-[(1s)-1-(3-ethoxy-4-methoxy-phenyl]-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-amide

一种羟丙基甲基纤维素、口服剂的技术，应用在环丙烷羧酸{2-[(1S)-1-(3-乙氧基-4-甲氧基-苯基)-2-甲烷磺酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺的口服剂型领域，能够解决水溶性差、不适合等问题

Inactive Publication Date: 2013-11-13
CELGENE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Compound A exhibits poor water solubility (2 μg / mL) and is generally not suitable for oral administration with standard formulations

Method used

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  • Oral dosage forms of cyclopropanecarboxylic acid {2-[(1s)-1-(3-ethoxy-4-methoxy-phenyl]-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-amide
  • Oral dosage forms of cyclopropanecarboxylic acid {2-[(1s)-1-(3-ethoxy-4-methoxy-phenyl]-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-amide
  • Oral dosage forms of cyclopropanecarboxylic acid {2-[(1s)-1-(3-ethoxy-4-methoxy-phenyl]-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-amide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] 5.1. Example 1: Cyclopropanecarboxylic acid {2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methane-sulfonyl-ethyl]-3- Synthesis of oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

[0117] Preparation of methyl 2-methyl-6-nitrobenzoate

[0118] 2-Methyl-6-nitrobenzoic acid (300.0 g, 1.66 mol, from Acros Organics, Morris Plains, NJ) and trimethyl orthoacetate (298.3 g, 2.48 mol, from Aldrich Chemicals, Milwauke, WI) were The mixture was charged to a 3-liter three-necked flask at about 20-25°C under nitrogen. The reaction mixture is gradually heated to distill off the low-boiling components produced in the reaction to an internal temperature of 95-100°C. After 2 hours, the reaction mixture was allowed to cool to 20-25°C over 1-2 hours. After heptane (1.50 L, from Aldrich Chemicals) was charged to the reaction mixture over 1.0-1.5 hours, methyl 2-methyl-6-nitrobenzoate (0.5 g) was inoculated when the reaction mixture became cloudy. The suspension was cooled to 0-5°C within 0.5-1 hour...

Embodiment 2

[0131] 5.2. Example 2: Hot melt extrusion formulation 1

[0132] Formulation 1, a solid powder dispersion of Compound A was prepared as follows:

[0133] 1. use Mixer blends Compound A with HPMC for 460 turns;

[0134] 2. Process the blended compound A at 190°C by hot melt extrusion;

[0135] 3. Use a 18-mesh sieve to grind the extruded product;

[0136] 4. Blend the ground extrudate with pre-screened (35 mesh) croscarmellose sodium and mannitol M200 for 460 rpm;

[0137] 5. Blend the resulting product with pre-screened calcium stearate for 75 revolutions; and

[0138] 6. Capsule the blended product using a semi-automatic encapsulator.

[0139] The above procedure resulted in a physically stable solid dispersion of Compound A with a water solubility of approximately 2 μg / mL.

[0140] Preparation 1

[0141] In other formulations, alternative HPMC products can be used in place of HPMC E3. Schematic diagram for the preparation of hot-melt extruded capsules in f...

Embodiment 3

[0142] 5.3. Example 3: Hot melt extrusion formulation 2

[0143] Preparation 2 is prepared according to the method of Example 2:

[0144] Preparation 2

[0145] Mannitol M200

[0146] In other formulations, alternative HPMC products can be used in place of HPMC E3.

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Abstract

Provided herein are controlled release oral dosage forms of poorly soluble drugs, methods of making the dosage forms, and methods of their use for the treatment of various diseases and / or disorders.

Description

[0001] This application claims priority to US Provisional Patent Application No. 61 / 431,355, filed January 10, 2011, which is hereby incorporated by reference in its entirety. 1. Field of invention [0002] Provided herein is cyclopropanecarboxylic acid {2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo- Oral dosage forms of 2,3-dihydro-1H-isoindol-4-yl}-amides, methods of making said dosage forms and methods of their use in the treatment of various diseases and / or disorders. 2. Background of the invention [0003] One aim in the development of drugs is to provide dosage forms which make it possible to maintain a certain amount or concentration of drug in the body of a subject and remain constant for several hours. Typically, this is not possible with traditional fast-disintegrating tablets, which immediately release the active ingredient contained within them. To this end, alternative dosage forms have been developed that improve the bioavailability of d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/16A61K9/48A61K31/4035
CPCA61K9/1652A61K9/4866A61K9/4858A61K31/4035A61K9/1617A61K9/1641A61K9/1623A61K9/1635A61P9/00A61P11/00A61P31/04A61P31/12A61P35/00A61P35/02A61P37/06A61P43/00A61K9/4825A61K9/4833
Inventor 陈明璋许浩华托马斯·李保罗·库里图里克谢卡尔·苏拉潘尼
Owner CELGENE CORP
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