Isoxazoline Derivative Injectable Formulation via Segmentation

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Solution Overview

Problem

The challenge is to develop a high-concentration pharmaceutical formulation for injection that incorporates the poorly water-soluble isoxazoline derivative, Compound of Formula 1, while ensuring stability and long-term storage.

Innovation Solution

A pharmaceutical formulation for injection is developed, comprising a first formulation in powder form containing Compound of Formula 1, a phosphate buffer, a solubilizing agent (beta-cyclodextrin), and a pH adjusting agent. This formulation is combined with a reconstitution solution having a pH of 5 to 12, which, when mixed, results in a stable solution suitable for injection.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of operation

If the compound of Formula 1 is used as an oral preparation, then it can be administered systemically, but it cannot achieve high local concentration in the joint cavity and systemic side effects cannot be minimized

Engineering Contradiction:

Improveadministration methodVSAvoidlocal drug concentration

Core Design Contradiction:

Ease of operationVSQuantity of substance

Solution Approach 1:

The invention segments the drug delivery system into two separate components: a freeze-dried powder containing the compound and a reconstitution solution. This segmentation allows the drug to be administered locally in the joint cavity after reconstitution, achieving high local concentration while minimizing systemic exposure compared to oral administration.

Inventive Principle:

Principle #1Segmentation

2Quantity of substance

If the compound of Formula 1 is formulated for injection, then high concentration can be administered locally, but the compound's poor water solubility prevents formulation development

Engineering Contradiction:

Improvedrug concentration in formulationVSAvoidformulation feasibility

Core Design Contradiction:

Quantity of substanceVSEase of manufacture

Solution Approach 1:

The invention changes the physical state parameter of the compound from dissolved state to freeze-dried powder state. By formulating the compound as a freeze-dried powder rather than an aqueous solution, the formulation overcomes the poor water solubility issue while enabling high concentration administration upon reconstitution with the buffered solution.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention utilizes phase transition by freeze-drying the compound-containing solution to produce a solid powder form that is stable and easy to handle. The powder is then reconstituted by adding the reconstitution solution, transitioning back to a dissolved state suitable for injection. This phase transition approach resolves the solubility problem while maintaining high drug concentration.

Inventive Principle:

Principle #36Phase transitions

3Ease of operation

If the compound is stored in aqueous solution, then it is ready for administration, but long-term storage stability cannot be ensured

Engineering Contradiction:

Improvereadiness for administrationVSAvoidcompound stability during storage

Core Design Contradiction:

Ease of operationVSStability of the object's composition

Solution Approach 1:

The invention segments the formulation into a freeze-dried powder component and a reconstitution solution component, which are stored separately. The powder form provides long-term storage stability by preventing degradation that occurs in aqueous solutions, while the reconstitution solution is added immediately before administration, ensuring the compound is ready for use only when needed.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The compound is prepared in advance as a freeze-dried powder with appropriate buffers and solubilizing agents incorporated during the freeze-drying process. This preliminary preparation ensures stability during storage, and the final reconstitution with the reconstitution solution occurs just before administration, combining stability with readiness.

Inventive Principle:

Principle #10Preliminary action

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 achieves a high concentration of Compound of Formula 1, enhancing its therapeutic efficacy while maintaining stability and allowing for long-term storage, thus overcoming the solubility and stability issues of the compound.

Implementation Method 1

the solubilizing agent is beta-cyclodextrin

Methodology Applied

Scientific EffectInclusion complex formation: Absorption (physical)

Implementation Method 2

a phosphate buffer, a solubilizing agent and a pH adjusting agent

Methodology Applied

Scientific EffectBuffering:

Implementation Method 3

a first formulation in the powder form including the following compound of Formula 1, a phosphate buffer, a solubilizing agent and a pH adjusting agent

Methodology Applied

Scientific EffectFreeze-drying: Freeze Drying

Data Source

PatentUS20250152576A1Injectable formulation comprising isoxazoline derivative and method for preparing same

Publication Date: 2025.05.15 LG CHEM LTD

AI summary

The present invention relates to a pharmaceutical formulation for injection comprising an isoxazoline derivative useful as a caspase inhibitor or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API). The pharmaceutical formulation for injection according to the present invention includes the first formulation composed of a high-dose API and the second formulation including a reconstitution solution, so that it can be prepared by mixing the first formulation and the second formulation immediately before administration to a patient, and contains the Active-API stably. Therefore, there is an advantage that effective drug efficacy can be expected when administered to a patient.