AC220 Tablet with HPBCD Composite for AML
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Solution Overview
Problem
Current tablet formulations of AC220 for treating acute myeloid leukemia (AML) lack bioavailability and exhibit poor dispersibility and dissolution, despite efforts to replicate the bioavailability of a liquid dosage form comprising AC220 and HPBCD at a 1:10 ratio by weight.
Innovation Solution
A tablet composition comprising AC220 or its pharmaceutically acceptable salt combined with hydroxypropyl-β-cyclodextrin in a ratio ranging from 1:8 to 1:20 by weight, along with specific amounts of lubricants, disintegrators, and diluents, to enhance dispersibility, dissolution, and bioavailability, while minimizing intermolecular interactions that hinder these properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If AC220 is formulated as a tablet using conventional carriers, then the dosage form is convenient for administration, but the dispersibility and dissolution are insufficient
Solution Approach 1:
The patent uses a composite material consisting of AC220 and hydroxypropyl-β-cyclodextrin (HPBCD) in a specific weight ratio range of 1:8 to 1:20. This composite formulation resolves the contradiction by combining AC220 with HPBCD, which enhances both dispersibility and dissolution while maintaining tablet form convenience for administration.
2Reliability
If AC220 forms a composite with HPBCD at a 1:10 ratio as in liquid dosage form, then bioavailability is achieved, but tablet formulation lacks equivalent performance
Solution Approach 1:
The patent applies parameter changes by optimizing the weight ratio of AC220 to HPBCD within the range of 1:8 to 1:20 for tablet formulation. This parameter optimization enables the tablet to achieve bioavailability equivalent to the liquid dosage form while maintaining manufacturability and stability of the tablet formulation.
3Stability of the object's composition
If AC220 is used in tablet form, then the dosage form is stable for storage, but intermolecular interactions hinder dispersibility
Solution Approach 1:
The patent introduces hydroxypropyl-β-cyclodextrin (HPBCD) as an intermediary substance that complexes with AC220. This intermediary action prevents harmful intermolecular interactions of AC220 that hinder dispersibility, while maintaining storage stability of the tablet formulation. The HPBCD acts as a mediator that improves wetting and dispersibility characteristics.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The tablet composition achieves rapid disintegration and dissolution rates of 85% or more within 30 minutes, matching the bioavailability of the liquid dosage form, and maintains stability during storage, with a bioavailability equivalent to the spray-dried material of AC220·2HCl and HPBCD at a 1:10 ratio.
Implementation Method 1
AC220 forms a composite with HPBCD in a ratio ranging from 1:8 to 1:20 by weight, which suppresses intermolecular interactions and enhances dispersibility and dissolution
Implementation Method 2
The tablet composition achieves rapid disintegration and dissolution rates of 85% or more within 30 minutes
Data Source
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AI summary
Provided herein is a tablet comprising, as a drug, N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea or a pharmaceutically acceptable salt thereof, which is a medicament for treating acute myeloid leukemia (AML), the tablet characterized by comprising a composite of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea or a pharmaceutically acceptable salt thereof and hydroxypropyl-β-cyclodextrin in a ratio ranging from 1:8 to 1:20.