Amorphous Solid Dispersion of Compound (I) for Oral Bioavailability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing formulations of the FXIa inhibitor Compound (I) face challenges due to low aqueous solubility and difficulty in achieving therapeutically effective blood levels for oral administration, necessitating stable and bioavailable formulations.
Innovation Solution
Formulating Compound (I) as an amorphous solid dispersion in pharmaceutically relevant polymers like HPMCAS through spray drying, and solubilizing it in solutions with co-solvents and surfactants to enhance stability and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If Compound (I) is formulated as conventional solid dosage forms, then manufacturing is simple, but aqueous solubility is low and bioavailability is poor
Solution Approach 1:
The patent changes the physical state parameter of Compound (I) from crystalline to amorphous form, which fundamentally alters its solubility characteristics. The amorphous form exhibits significantly enhanced aqueous solubility compared to the crystalline form, directly resolving the solubility issue while maintaining manufacturability through established amorphous formulation techniques
Solution Approach 2:
The patent creates composite formulations by combining Compound (I) with pharmaceutically acceptable carriers, polymers, and excipients in solid dispersion matrices. These composite structures enhance the solubility and bioavailability of Compound (I) while providing a complete pharmaceutical formulation that can be manufactured using conventional equipment and processes
2Reliability
If Compound (I) is administered orally, then convenience is improved, but achieving therapeutically effective blood levels is difficult
Solution Approach 1:
The patent modifies key parameters of Compound (I) including transitioning to amorphous form, adjusting particle size, and modifying physical-chemical properties to enhance oral bioavailability. These parameter changes enable the compound to achieve therapeutically effective blood levels when administered orally, maintaining the convenience of oral administration while improving reliability
Solution Approach 2:
The patent introduces pharmaceutically acceptable carriers, polymers, and excipients as intermediary substances that facilitate the absorption and bioavailability of Compound (I) in the gastrointestinal tract. These intermediaries enhance the reliability of achieving therapeutic blood levels while preserving the ease of oral administration
3Reliability
If amorphous solid dispersion is formulated with polymers, then bioavailability is enhanced, but formulation stability may be compromised
Solution Approach 1:
The patent optimizes parameters including polymer selection, polymer-to-drug ratio, molecular weight of polymers, and processing conditions to achieve the right balance between bioavailability enhancement and formulation stability. By carefully controlling these parameters, the patent maintains stability while improving bioavailability
Solution Approach 2:
The patent develops composite amorphous solid dispersion formulations using specifically selected polymers and excipients that are compatible with Compound (I). These composite structures are designed to maintain both enhanced bioavailability and formulation stability through careful selection of compatible materials and optimized compositions
4Productivity
If high drug load is achieved, then dosage efficiency is improved, but physical and chemical stability may be reduced
Solution Approach 1:
The patent optimizes parameters including particle size distribution, amorphous form maintenance, polymer concentration, and processing conditions to achieve high drug load while preserving physical and chemical stability. By carefully controlling these parameters, the patent maintains stability even at high dosage concentrations
Solution Approach 2:
The patent creates composite formulations with optimized ratios of drug to excipients and polymers that maintain physical and chemical stability even at high drug loads. The composite structure is designed to preserve stability while achieving high dosage efficiency through careful formulation design
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 amorphous solid dispersion and solubilized formulations exhibit exceptional physical and chemical stability, maintaining therapeutic effectiveness with high drug load and improved bioavailability, reducing degradation, and requiring no special packaging controls.
Implementation Method 1
Compound (I) in an amorphous form... amorphous solid dispersion... exhibits exceptional physical and chemical stability
Implementation Method 2
amorphous solid dispersion comprising Compound (I) and a pharmaceutically relevant polymer
Implementation Method 3
preparing a liquid solution comprising Compound (I), at least one polymer and a solvent; and spray drying said liquid solution
Implementation Method 4
spray drying... thereby producing said amorphous solid dispersion
Data Source
AI summary
This invention relates to solid amorphous Compound (I) having the formula (I) and to solid amorphous dispersions comprising Compound (I) and one or more polymers or to solution formulations comprising Compound (I) and one or more co-solvents and surfactants. The formulations exhibit enhanced stability and bioavailability. This invention relates to solid amorphous dispersions comprising Compound (I) having the formula (I) and one or more polymers or to solution formulations comprising Compound (I) and one or more co-solvents and surfactants. The formulations exhibit enhanced stability and bioavailability.