Modified-Release PGI2 Agonist for Pulmonary Arterial Hypertension
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Solution Overview
Problem
Current treatments for pulmonary arterial hypertension (PAH) rely on intravenous prostacyclin analogs with short half-lives, requiring continuous infusion and posing risks of rebound pulmonary hypertension and catheter-related complications, while oral options are limited and associated with side effects like nausea and headaches.
Innovation Solution
Development of a novel, non-prostanoid PGI2 receptor agonist, 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), with a long plasma half-life, formulated for once-daily oral administration using modified-release pharmaceutical compositions to optimize pharmacokinetics and minimize side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If intravenous prostacyclin analogs are used to treat PAH, then therapeutic efficacy is improved, but treatment complexity and risk of complications increase due to requiring continuous infusion and catheter-related issues
Solution Approach 1:
The patent replaces the mechanical intravenous infusion system with an oral pharmaceutical composition system. Compound 1 is administered orally as a modified-release tablet or capsule, eliminating the need for continuous intravenous infusion pumps, catheters, and associated monitoring equipment while maintaining therapeutic efficacy through sustained plasma concentrations.
Solution Approach 2:
The patent introduces modified-release formulation technology as an intermediary between the drug substance and the patient. The formulation includes matrix-forming excipients and controlled-release mechanisms that mediate the delivery of Compound 1, providing sustained release over 24 hours and eliminating the need for continuous infusion while maintaining stable plasma levels.
2Reliability
If intravenous prostacyclin is administered to achieve therapeutic effect, then PAH symptoms are improved, but safety deteriorates due to rebound pulmonary hypertension and catheter-related complications
Solution Approach 1:
The patent employs modified-release formulation technology that preliminarily structures the drug delivery system to release Compound 1 at controlled rates over 24 hours. This preliminary action prevents abrupt discontinuation of therapy and eliminates rebound pulmonary hypertension by maintaining steady plasma concentrations without the need for continuous infusion.
Solution Approach 2:
The patent extracts and eliminates the harmful catheter-related complications by removing the intravenous administration route entirely. The oral modified-release formulation delivers the same therapeutic agent without requiring catheter insertion, thereby taking out the source of catheter-related infections, thrombosis, and other complications.
3Ease of operation
If oral PGI2 receptor agonists are used to simplify administration, then ease of operation is improved, but side effects increase causing nausea and headaches
Solution Approach 1:
The patent implements periodic action through modified-release formulation that releases Compound 1 at controlled intervals over 24 hours. This periodic release pattern maintains steady plasma concentrations and avoids peak-trough fluctuations that cause side effects, while still providing once-daily oral administration for ease of use.
4Reliability
If short-acting prostacyclin analogs are administered frequently, then therapeutic coverage is improved, but loss of time and patient burden increase due to multiple dosing requirements
Solution Approach 1:
The patent achieves continuity of useful action through modified-release formulation technology that maintains sustained plasma concentrations of Compound 1 over 24 hours. The formulation uses matrix-forming excipients and controlled-release mechanisms to provide continuous therapeutic coverage, eliminating the need for multiple dosing while maintaining reliable PAH treatment.
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 modified-release formulation of Compound 1 provides a stable and effective once-daily dosing regimen, reducing peak-trough fluctuation and improving tolerability, thereby enhancing treatment efficacy and patient compliance for PAH patients.
Implementation Method 1
the composition having a release rate by weight of the compound in an aqueous medium
Implementation Method 2
modified-release pharmaceutical compositions to optimize pharmacokinetics
Data Source
AI summary
Provided herein in some embodiments are pharmaceutical compositions comprising a prostacyclin (PGI2) receptor agonist selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1) and pharmaceutically acceptable salts, solvates, and hydrates thereof, as disclosed herein. In some embodiments the pharmaceutical compositions comprise a compound selected from 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), and pharmaceutically acceptable salts, solvates, and hydrates thereof, in an amount equivalent to a therapeutically effective amount of Compound 1, the composition having a release rate by weight of the compound in an aqueous medium that is one or more of release rates (a), (b) and (c) as disclosed herein. The compositions of the present invention are useful in the treatment of PGI2 related disorders, such as those disclosed herein.