Isoquinolinyl Triazolone Cyclodextrin Complexes for Solubility

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Solution Overview

Problem

Existing isoquinolinyl triazolone complexes with low aqueous solubility limit their absorption and bioavailability when administered orally, hindering their effectiveness as BTK inhibitors for treating diseases associated with Bruton's tyrosine kinase.

Innovation Solution

Formation of solid complexes with cyclodextrin, resulting in amorphous solids that exhibit improved aqueous solubility and bioavailability, which are prepared through methods involving atomization and solvent removal to create pharmaceutical compositions for treating various conditions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If crystalline form of isoquinolinyl triazolone is used, then the compound has good stability and defined structure, but it exhibits low aqueous solubility and poor bioavailability

Engineering Contradiction:

Improvestructural stabilityVSAvoidaqueous solubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent changes the physical state parameter of the compound from crystalline to amorphous form. This parameter change fundamentally alters the solubility characteristics while maintaining the chemical identity and stability of the active compound, resolving the contradiction between structural stability and aqueous solubility.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite material system consisting of the isoquinolinyl triazolone compound combined with excipients in an amorphous matrix. This composite approach allows the compound to achieve improved solubility and bioavailability while maintaining stability through the protective amorphous structure and formulation components.

Inventive Principle:

Principle #40Composite materials

2Ease of manufacture

If crystalline form is used, then manufacturing and handling is straightforward, but oral absorption and bioavailability are limited

Engineering Contradiction:

Improveprocessing simplicityVSAvoidbioavailability

Core Design Contradiction:

Ease of manufactureVSQuantity of substance

Solution Approach 1:

The patent transforms the physical state parameter from crystalline to amorphous, which fundamentally changes both the manufacturing characteristics and bioavailability profile. The amorphous form requires different processing methods but delivers superior oral absorption, resolving the contradiction between ease of manufacture and bioavailability.

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If high dose is administered to overcome low solubility, then sufficient drug reaches target, but side effects increase and therapeutic index decreases

Engineering Contradiction:

Improvedrug delivery to targetVSAvoidside effects

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

By changing the physical state from crystalline to amorphous, the patent dramatically increases aqueous solubility and bioavailability. This allows achieving the same therapeutic effect at lower doses, thereby reducing side effects and improving the therapeutic index while maintaining sufficient drug delivery to the target.

Inventive Principle:

Principle #35Parameter changes

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 cyclodextrin complexes enhance the solubility and bioavailability of isoquinolinyl triazolones, enabling more effective oral administration and treatment of conditions related to BTK, such as autoimmune diseases and cancers.

Implementation Method 1

solid complexes of isoquinolinyl triazolones and cyclodextrin. The complexes are amorphous solids which exhibit improved aqueous solubility

Methodology Applied

Scientific EffectInclusion complex formation: Absorption (physical)

Implementation Method 2

The complexes are amorphous solids which exhibit improved aqueous solubility and bioavailability over the corresponding crystalline forms

Methodology Applied

Scientific EffectAmorphization: Phase Change

Implementation Method 3

atomizing a liquid solution into droplets, the liquid solution comprising a compound, stereoisomer or tautomer as defined above, a cyclodextrin derivative, and water

Methodology Applied

Scientific EffectAtomization: Aerosol

Implementation Method 4

removing at least a portion of the water from the droplets to form the complex

Methodology Applied

Scientific EffectEvaporation: Evaporation

Data Source

PatentUS11786608B2Isoquinolinyl triazolone complexes

Publication Date: 2023.10.17 TAKEDA PHARMA CO LTD

AI summary

Disclosed is a complex of a compound of Formula 1,a stereoisomer thereof, or a tautomer of the compound of Formula 1 or stereoisomer thereof, and a cyclodextrin, in which the complex is an amorphous solid. This disclosure also relates to materials and methods for preparing the complex, to pharmaceutical compositions which contain the complex, and to the use of the complex to treat Type I hypersensitivity reactions, autoimmune diseases, inflammatory disorders, cancer, non-malignant proliferative disorders, and other conditions associated with BTK.