Controlled-Release PGI2 Agonist Composition for Once-Daily PAH Dosing

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Solution Overview

Problem

Current treatments for pulmonary arterial hypertension (PAH) using prostacyclin analogs are invasive, costly, and associated with significant side effects, while orally available non-prostanoid PGI2-receptor agonists like Compound 1 offer a promising but require optimization for once-daily dosing and improved pharmacokinetics to balance efficacy and side effects.

Innovation Solution

Development of pharmaceutical compositions of Compound 1 with controlled release rates in an aqueous medium, allowing for once-daily dosing and optimized blood plasma levels, using specific release rates and excipients to manage side effects and improve treatment efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If intravenous prostacyclin is used to treat PAH, then therapeutic efficacy is improved, but treatment complexity and risk of complications increase due to continuous infusion requirement

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtreatment complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent changes the pharmacokinetic parameters of prostacyclin by developing oral formulations with extended half-life, transforming it from a short-acting intravenous drug requiring continuous infusion to a long-acting oral medication suitable for once-daily dosing

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent replaces the mechanical delivery system (intravenous infusion pump and catheter) with an oral administration route, eliminating the need for continuous infusion equipment and reducing treatment complexity

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Reliability

If intravenous prostacyclin is used to treat PAH, then therapeutic efficacy is improved, but risk of harmful effects increases due to catheter-related complications

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidcatheter-related complications

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts the harmful catheter-related component from the treatment system by switching from intravenous to oral administration, eliminating catheter insertion and associated complications while maintaining therapeutic efficacy

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent introduces an oral formulation as an intermediary delivery system that avoids direct intravenous access, using gastrointestinal absorption as a mediator to deliver the drug systemically without catheter-related risks

Inventive Principle:

Principle #24Intermediary (Mediator)

3Ease of operation

If orally available non-prostanoid PGI2-receptor agonist is used, then ease of administration is improved, but pharmacokinetic optimization is needed to balance efficacy and side effects

Engineering Contradiction:

Improveease of administrationVSAvoidpharmacokinetic optimization

Core Design Contradiction:

Ease of operationVSManufacturing precision

Solution Approach 1:

The patent optimizes pharmacokinetic parameters including half-life, bioavailability, and plasma concentration profiles through formulation development, enabling once-daily dosing while maintaining therapeutic efficacy and reducing side effects

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs pharmacokinetic feedback mechanisms by designing formulations that maintain drug concentrations within the therapeutic window, adjusting release rates to balance efficacy and side effect profile

Inventive Principle:

Principle #23Feedback

4Loss of time

If controlled release formulation is used, then dosing frequency is reduced to once daily, but formulation complexity increases

Engineering Contradiction:

Improvedosing frequencyVSAvoidformulation complexity

Core Design Contradiction:

Loss of timeVSDevice complexity

Solution Approach 1:

The patent changes the release rate parameter of the drug formulation to achieve extended half-life and once-daily dosing, using controlled-release mechanisms to maintain therapeutic concentrations over 24 hours

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite formulation systems combining multiple excipients and delivery mechanisms to achieve controlled release, using material composition to regulate drug release kinetics and enable once-daily administration

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS20250375408A1Compositions comprising PGI2-receptor agonists and processes for the preparation thereof

Publication Date: 2025.12.11 ARENA PHARMACEUTICALS INC

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.