Selexipag Controlled-Release Composition for Lower Peak Exposure
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Solution Overview
Problem
Conventional immediate release formulations of Selexipag result in high peak-trough fluctuations of plasma concentration, leading to severe adverse events such as headache, nausea, and vomiting, particularly at higher doses, due to rapid absorption and high Cmax, which limits tolerability and may lead to therapy discontinuation.
Innovation Solution
A controlled release pharmaceutical composition of Selexipag or its active metabolite is developed to reduce side effects by controlling the release rate, achieving a mean or median Tmax of at least greater than 2.5 hours for Selexipag and at least greater than 4 hours for the active metabolite, using release rate controlling ingredients like matrixing agents or coatings to slow down the absorption.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If conventional immediate release formulation of Selexipag is used, then rapid absorption and high Cmax are achieved, but severe adverse events such as headache, nausea, and vomiting occur frequently
Solution Approach 1:
The patent applies dynamics by transitioning from a static immediate-release formulation to a dynamic controlled-release formulation. The composition uses pH-dependent coating materials that dynamically adjust drug release based on gastrointestinal pH conditions, enabling the system to adapt release rate to physiological environments while minimizing peak plasma concentrations and associated adverse events
Solution Approach 2:
The patent changes the release rate parameter of Selexipag from rapid (immediate release) to controlled/slowed (controlled release). By incorporating pH-dependent coating materials and specific excipients, the formulation modifies the release kinetics to achieve lower Cmax values and reduced incidence of headache, nausea, and vomiting without compromising therapeutic efficacy
2Reliability
If higher doses of Selexipag are administered to improve therapeutic effect, then better treatment outcome is achieved, but incidence of side effects increases
Solution Approach 1:
The patent segments the drug release process into multiple phases using pH-dependent coatings that activate at different pH levels along the gastrointestinal tract. This segmentation allows the drug to be released progressively rather than all at once, enabling higher total doses to be administered while maintaining lower peak concentrations that reduce side effect incidence
Solution Approach 2:
The patent introduces pH-dependent coating materials and excipients as intermediaries between the Selexipag drug substance and the gastrointestinal environment. These intermediaries control the interaction between the drug and biological systems, allowing higher doses to be delivered while the coating system mediates the release to prevent excessive peak concentrations that cause adverse events
3Speed
If Selexipag is administered in fasting condition, then rapid absorption occurs, but tolerability deteriorates with more severe adverse events
Solution Approach 1:
The patent applies beforehand cushioning by incorporating pH-dependent coating materials and excipients that pre-buffer the drug release process. These components are designed to modulate the release kinetics before the drug reaches systemic circulation, cushioning against the rapid absorption that causes severe adverse events in fasting conditions while maintaining adequate therapeutic effect
Data Source
AI summary
A controlled release pharmaceutical dosage form that improve tolerability by reducing incidence of side effect associated with a Selexipag or its active metabolite contained in the dosage form comprising a release rate controlling ingredient in addition to the Selexipag or its active metabolite that govern a release of the Selexipag or its active metabolite from the dosage form, wherein the dosage form after administration to a mammal in fasting condition providinga. a mean or median Tmax of at least greater than 2 hours for the Selexipag and/or at least greater than 3.5 hours for the active metabolite of the Selexipag, and/orb. at least 20% lower Cmax for Selexipag and/or it's active metabolite compared to Cmax obtained after administration of the same amount of an immediate release dosage form of Selexipag or its active metabolite in fasting condition.