Injectable Lipid Pre-Formulations for Sustained Prostacyclin Analogue Release

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Solution Overview

Problem

Existing prostacyclin analogue formulations, such as treprostinil, require frequent administration due to short half-life and cause site pain and irritation, necessitating continuous infusion or injection, which is uncomfortable and risky, and existing polymer-based delivery systems have high viscosity and burst/lag release profiles, leading to undesirable concentration fluctuations.

Innovation Solution

A pre-formulation comprising mono-, di-, or tri-acyl lipids, tocopherol, phospholipids, and a biocompatible solvent forms a non-lamellar liquid crystalline phase upon contact with aqueous fluids, allowing for a controlled release of prostacyclin analogues with reduced viscosity, minimal irritation, and a low-burst release profile, suitable for self-administration through narrow needles.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If continuous infusion or frequent injection is used to maintain therapeutic concentration, then the biological effect is maintained, but patient comfort and compliance deteriorate due to inconvenience and site pain

Engineering Contradiction:

Improveduration of therapeutic effectVSAvoidpatient compliance

Core Design Contradiction:

Duration of action of moving objectVSEase of operation

Solution Approach 1:

The formulation is prepared in advance with the prostacyclin analogue pre-complexed to the lipid carrier system, allowing a single administration to provide sustained release over several days. The pre-formulation undergoes phase transition upon contact with aqueous fluids to form a controlled release composition, eliminating the need for continuous administration while maintaining therapeutic concentration.

Inventive Principle:

Principle #10Preliminary action

2Duration of action of moving object

If polymer-based delivery systems are used to extend half-life, then the duration of action is improved, but the viscosity increases and causes site pain and irritation

Engineering Contradiction:

Improveduration of actionVSAvoidsite pain and irritation

Core Design Contradiction:

Duration of action of moving objectVSObject-affected harmful factors

Solution Approach 1:

The formulation utilizes lipid-based carriers instead of polymer-based systems, changing the fundamental material parameter. The pre-formulation comprises mono-, di-, or tri-acyl lipids, phospholipids, and a biocompatible solvent, which form a non-lamellar liquid crystalline phase that transitions upon contact with aqueous fluids. This parameter change eliminates high viscosity and associated site pain while maintaining extended duration of action.

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If conventional formulations are used to administer prostacyclin analogues, then the active agent is delivered, but burst/lag release profiles cause undesirable concentration fluctuations

Engineering Contradiction:

Improvedelivery of active agentVSAvoidplasma concentration stability

Core Design Contradiction:

Quantity of substanceVSStability of the object's composition

Solution Approach 1:

The pre-formulation undergoes a phase transition upon contact with aqueous fluids, transforming from a pre-formulation state to a non-lamellar liquid crystalline phase. This phase transition mechanism provides controlled release of the prostacyclin analogue, eliminating burst and lag phases while maintaining stable plasma concentrations throughout the duration of action.

Inventive Principle:

Principle #36Phase transitions

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 formulation provides sustained release of prostacyclin analogues for several days with minimal site irritation, reduced needle size requirements, and stable plasma concentrations, improving patient compliance and comfort.

Implementation Method 1

the pre-formulation forms, or is capable of forming, a non-lamellar liquid crystalline phase upon contact with excess aqueous fluid

Methodology Applied

Scientific EffectPhase transition: Phase Change

Implementation Method 2

forms a non-lamellar liquid crystalline phase following administration

Methodology Applied

Scientific EffectLiquid crystalline phase formation: Liquid Crystals

Data Source

PatentUS20250319097A1Prostacyclin analogue formulations

Publication Date: 2025.10.16 CAMURUS AB

AI summary

The present invention relates to an injectable pre-formulation comprising:a) at least one of a mono-, di- or tri-acyl lipid and/or a tocopherol;b) optionally at least one phospholipid;c) at least one biocompatible, organic solvent; andd) at least one prostacyclin analogue or a salt thereof;wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with excess aqueous fluid. Such compositions may additionally comprise polar co-solvents. Methods of treatment, particularly for management of pulmonary artery hypertension (PAH), severe PAH, Raynaud's disease, ischemia and related conditions are provided, as well as corresponding uses of the compositions. Administration devices comprising the formulations and kits comprising the devices are also provided.