Selexipag IV Formulation Prevents Adsorption and Hydrolysis
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Solution Overview
Problem
The development of a stable and reproducible intravenous (i.v.) formulation of selexipag is challenging due to the need for precise dosage control in the microgram to single digit milligram range, with issues of adsorption on syringes or tubing and the hydrolysable nature of the prodrug, requiring a formulation that prevents premature hydrolysis and maintains chemical and physical stability.
Innovation Solution
Aqueous pharmaceutical compositions comprising selexipag with glycine as a bulking agent, polysorbate 20 as a detergent, and an aqueous phosphate buffer, which are lyophilized to a stable cake and reconstituted for controlled i.v. administration, preventing adsorption and ensuring chemical and physical stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If selexipag is formulated for intravenous administration, then precise dosage control in the microgram to single digit milligram range is achieved, but adsorption on syringes or tubing occurs
Solution Approach 1:
The patent introduces a surfactant (polysorbate 20) as an intermediary substance that adsorbs to the syringe and tubing surfaces, creating a protective barrier that prevents selexipag from adhering to the plastic surfaces. This mediator allows precise dosage delivery by eliminating the adsorption loss that would otherwise occur in intravenous formulations.
Solution Approach 2:
The patent modifies the chemical environment by adjusting pH (using phosphate buffer) and adding specific excipients (glycine, polysorbate 20) to change the surface properties of the administration system. These parameter changes reduce the affinity between selexipag and the syringe/tubing surfaces, thereby minimizing adsorption while maintaining dosing precision.
2Stability of the object's composition
If selexipag is formulated as an aqueous solution, then chemical stability is improved, but premature hydrolysis of the prodrug occurs
Solution Approach 1:
The patent carefully controls pH parameters using a phosphate buffer system to maintain an optimal pH range that minimizes hydrolysis of the prodrug while still allowing aqueous formulation. By adjusting and maintaining specific pH conditions, the formulation achieves chemical stability without triggering premature hydrolysis of selexipag.
Solution Approach 2:
The patent uses buffer components (phosphate buffer and glycine) as intermediaries that create a protective chemical environment. These substances act as pH buffers and potential stabilizing agents that prevent the aqueous solution from promoting hydrolysis, thereby maintaining drug integrity throughout storage and administration.
3Duration of action of stationary object
If selexipag is formulated for extended storage, then availability is improved, but physical stability deteriorates
Solution Approach 1:
The patent utilizes freeze-drying (lyophilization) which involves phase transitions from liquid to solid and back. The formulation is frozen, then the water is sublimed directly from solid to vapor, creating a stable lyophilized cake that can be stored for extended periods. Upon reconstitution, the solid transitions back to a liquid solution ready for administration, thereby achieving both extended storage availability and physical stability.
Solution Approach 2:
The patent performs preliminary stabilization by formulating the solution with stabilizing excipients (glycine, polysorbate 20, phosphate buffer) before storage. These components are added in advance to prevent physical degradation during storage, and the formulation is then freeze-dried to lock in this stable state, ensuring physical stability is maintained throughout the storage period.
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 a stable and reproducible i.v. form of selexipag, preventing premature hydrolysis and adsorption, ensuring effective and controlled delivery of the drug, maintaining chemical and physical stability for extended periods.
Implementation Method 1
polysorbate 20 as a detergent
Implementation Method 2
aqueous phosphate buffer
Implementation Method 3
glycine as a bulking agent
Data Source
AI summary
The invention relates to aqueous pharmaceutical compositions comprising the compound 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl) acetamide; glycine; polysorbate 20; and an aqueous phosphate buffer, wherein the relative amounts are as described in the description, wherein the pH of said pharmaceutical composition is between about 7 and 8; to lyophilized pharmaceutical compositions prepared from said aqueous compositions, and to reconstituted aqueous compositions thereof which are suitable for i.v. administration. The invention further relates to processes for the preparation of said compositions, and to their use for the treatment of diseases and disorders which are related to IP receptor.