Maralixibat Tablet Composition for pH-Dependent Dissolution Stability
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Solution Overview
Problem
Current formulations of maralixibat lack favorable dissolution and pharmacokinetic profiles, and there is a need for improved storage stability and effective treatment of cholestatic pruritus and cholestatic liver diseases.
Innovation Solution
A pharmaceutical composition comprising maralixibat with specific excipients such as diluents, glidants, lubricants, and disintegrants, formulated to ensure rapid dissolution in acidic pH and sustained dissolution in physiological pH, with oral dosage forms designed for once-daily or twice-daily administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If maralixibat is formulated as an oral solution, then it is available for administration, but it lacks favorable dissolution and pharmacokinetic profiles
Solution Approach 1:
The patent applies parameter changes by modifying the physical and chemical parameters of maralixibat through salt selection (chloride, mesylate, tosylate), hydration state control (anhydrous vs. hydrate forms), and particle size reduction via milling. These parameter changes transform the drug substance to achieve favorable dissolution profiles and pharmacokinetic characteristics while maintaining formulation feasibility
Solution Approach 2:
The patent employs composite materials by creating tablets that combine maralixibat with specific excipients including hydrophilic materials (lactose monohydrate, microcrystalline cellulose), glidants (colloidal silicon dioxide), and lubricants (magnesium stearate). This composite formulation approach resolves the contradiction by achieving reliable dissolution through material composition while maintaining manageable formulation complexity
2Reliability
If maralixibat is formulated with excipients for rapid dissolution, then dissolution in acidic pH is improved, but storage stability may be compromised
Solution Approach 1:
The patent applies local quality by creating pH-dependent dissolution behavior where the tablet formulation exhibits rapid dissolution specifically in acidic gastric environment (pH 1.2) while maintaining stability during storage. The hydrophilic excipients and milled drug substance are strategically positioned to dissolve rapidly only under acidic conditions, leaving storage stability unaffected
Solution Approach 2:
The patent applies preliminary action by pre-milling the maralixibat to reduce particle size before formulation, and by selecting excipients that will activate dissolution mechanisms only under acidic conditions. This preliminary preparation ensures rapid dissolution when needed while preventing premature dissolution or degradation during storage
3Reliability
If maralixibat is administered multiple times daily, then therapeutic effectiveness is improved, but patient compliance decreases
Solution Approach 1:
The patent applies continuity of useful action by designing a tablet formulation that provides sustained therapeutic effect through controlled dissolution and absorption. The combination of milled drug substance, hydrophilic excipients, and specific formulation architecture creates continuous drug release and maintenance of therapeutic levels, enabling once-daily or twice-daily dosing while maintaining effectiveness
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 achieves rapid dissolution in acidic pH and sustained dissolution in physiological pH, providing effective treatment of cholestatic pruritus and cholestatic liver diseases with improved stability and patient compliance.
Implementation Method 1
about 100% of maralixibat, or a pharmaceutically acceptable salt thereof, dissolves in an acidic pH environment of a pH less than about 5.0; and upon pH increase from the acidic pH environment to a pH of about 6.0 to about 7.4, at least about 65% of maralixibat, or a pharmaceutically acceptable salt thereof, remains dissolved for at least about 1 hour
Data Source
AI summary
The invention relates to a pharmaceutical composition comprising maralixibat, or a pharmaceutically acceptable salt thereof, as the active ingredient. The invention further relates to the use of the pharmaceutical composition as a solid dosage drug product. The invention also relates to the use of the pharmaceutical composition and the solid dosage drug product described herein for treating cholestatic pruritus and cholestatic liver disease.