Amorphous Solid Dispersion for Hydrophobic Drug Bioavailability

Solution Overview

Problem

Current pharmaceutical compositions face challenges in achieving high bioavailability and stability of Raf kinase inhibitors, such as Compound I and Compound II, due to their crystalline form, which affects their absorption and release in the gastrointestinal tract, and require high polymer usage that can impair tablet disintegration.

Innovation Solution

A solid dispersion composition is developed where the drugs are molecularly dispersed in polyvinylpyrrolidone (PVP) or copovidone, with optional surfactants and HPMC-AS, using a hot melt extrusion process, maintaining the drugs in an amorphous form and immobilizing them within a polymer matrix for improved bioavailability and stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If the drugs are used in crystalline form, then stability is maintained, but bioavailability and absorption are reduced

Engineering Contradiction:

ImprovestabilityVSAvoidbioavailability

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent changes the physical state of the drug from crystalline to amorphous form, and incorporates it into a solid dispersion matrix with hydrophilic polymers (PVP, copovidone, HPMC-AS). This parameter change increases bioavailability while the polymer matrix maintains stability during storage and throughout the GI tract.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite material system consisting of the Raf kinase inhibitor drug molecularly dispersed in a polymer matrix (PVP, copovidone, and/or HPMC-AS). This composite structure combines the stability properties of the polymer with the enhanced solubility and bioavailability characteristics of the amorphous drug state.

Inventive Principle:

Principle #40Composite materials

2Productivity

If high polymer usage is employed to achieve solid dispersion, then bioavailability improves, but tablet disintegration is impaired

Engineering Contradiction:

ImprovebioavailabilityVSAvoidtablet disintegration

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The patent optimizes the polymer-to-drug ratio and selects specific hydrophilic polymers (PVP, copovidone, HPMC-AS) that provide adequate bioavailability enhancement without excessive polymer content. The use of HPMC-AS specifically helps maintain tablet disintegration properties while still achieving the desired solid dispersion effect.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite material system consisting of the Raf kinase inhibitor drug molecularly dispersed in a polymer matrix (PVP, copovidone, and/or HPMC-AS). This composite structure combines the stability properties of the polymer with the enhanced solubility and bioavailability characteristics of the amorphous drug state.

Inventive Principle:

Principle #40Composite materials

3Productivity

If drugs are molecularly dispersed in polymer matrix, then bioavailability increases, but drug stability during processing may be compromised

Engineering Contradiction:

ImprovebioavailabilityVSAvoiddrug stability

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent changes the physical state of the drug from crystalline to amorphous form, and incorporates it into a solid dispersion matrix with hydrophilic polymers (PVP, copovidone, HPMC-AS). This parameter change increases bioavailability while the polymer matrix maintains stability during storage and throughout the GI tract.

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 composition enhances bioavailability, stability, and absorption of the drugs, allowing for lower doses, faster disintegration, and improved physico-chemical properties, including increased AUC and C max, while reducing polymer usage and maintaining stability throughout the GI tract.

Implementation Method 1

the molecules of the drug are held in the aforementioned matrix and prevented from crystal nucleation due to lack of mobility

Methodology Applied

Scientific EffectPhysical entrapment: Physical Containment

Implementation Method 2

the molecules of the drug interact with the molecules of the polymer in such a way that the molecules of the drug are held in the aforementioned matrix

Methodology Applied

Scientific EffectIntermolecular interactions: Van der Waals Force

Implementation Method 3

using a hot melt extrusion process

Methodology Applied

Scientific EffectMelting: Melting

Implementation Method 4

the drug is in substantially amorphous form

Methodology Applied

Scientific EffectAmorphous state:

Implementation Method 5

the drug is molecularly dispersed in said polymer

Methodology Applied

Scientific EffectMolecular dispersion: Dispersion (of waves)

Data Source

PatentEP2790699B2Pharmaceutical composition with improved bioavailability for high melting hydrophobic compound

Publication Date: 2020.01.01 F HOFFMANN LA ROCHE & CO AG

Figure 1
Figure 2

AI summary

The present invention relates to a pharmaceutical composition comprising a solid dispersion of a drug, represented by the compounds of the formulae (I) or (II) as disclosed herein. In the composition, the drug is in substantially amorphous form.