Netupitant Liquid Formulations for Solubility and Parenteral Stability
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Solution Overview
Problem
The development of stable liquid formulations of netupitant, alone or in combination with palonosetron, suitable for parenteral administration is challenging due to netupitant's poor solubility in aqueous environments, necessitating the creation of formulations that are safe, therapeutically effective, and exhibit prolonged physical and chemical stability without significant loss of potency.
Innovation Solution
The formulation of stable liquid compositions comprising netupitant, optionally with palonosetron, includes pharmaceutically acceptable stabilizers, solubilizers, and vehicles, with a pH range of 2 to 6, which are suitable for subcutaneous, intravenous, or intramuscular administration, and may include additional excipients such as nucleation inhibiting agents, tonicity contributing agents, surfactants, buffers, chelating agents, anti-oxidants, anti-foaming agents, and preservatives.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If netupitant is formulated in aqueous environments for parenteral administration, then ease of administration and patient compliance are improved, but solubility and stability are worsened due to netupitant's poor aqueous solubility
Solution Approach 1:
The patent employs solubilizing agents such as cyclodextrins, surfactants, and co-solvents as intermediaries to facilitate the dissolution of netupitant in aqueous environments. These agents act as mediators between the hydrophobic netupitant and the hydrophilic aqueous formulation, enabling parenteral administration while maintaining adequate solubility levels
Solution Approach 2:
The patent modifies formulation parameters including pH adjustment to acidic ranges (pH 2-6), temperature control during storage, and selection of specific solubilizing agents to optimize netupitant solubility. By changing these physical and chemical parameters, the formulation achieves both solubility and stability requirements for parenteral administration
2Ease of operation
If netupitant is formulated in aqueous environments, then ease of administration is improved, but chemical stability and physical stability are worsened
Solution Approach 1:
Stabilizing agents including antioxidants (e.g., ascorbic acid, sodium metabisulfite), chelating agents (e.g., EDTA), and buffering agents are used as intermediaries to protect netupitant from chemical degradation. These agents mitigate oxidative stress, prevent precipitation, and maintain pH stability throughout the shelf life of the formulation
Solution Approach 2:
The patent employs inert atmosphere techniques by excluding oxygen from the formulation headspace and using oxygen-scavenging systems to create a protective environment that prevents oxidative degradation of netupitant, thereby enhancing chemical stability while maintaining aqueous solubility
3Ease of operation
If netupitant is formulated in aqueous environments, then ease of administration is improved, but manufacturing complexity increases
Solution Approach 1:
The patent employs pre-gelatinized starch and pre-formed cyclodextrin inclusion complexes as ready-to-use solubilizing systems that simplify the manufacturing process. These pre-prepared components eliminate the need for complex in-process solubilization steps, reducing manufacturing complexity while ensuring adequate netupitant solubility in the final aqueous formulation
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 compositions achieve increased solubility and stability of netupitant, allowing for safe and effective parenteral administration, maintaining potency and stability for at least 2 months under various storage conditions, with impurity levels below 0.5% w/w and bioequivalence to reference drug products.
Implementation Method 1
The composition comprises netupitant, at least one pharmaceutically acceptable stabilizer, at least one pharmaceutically acceptable solubilizer, and at least one pharmaceutically acceptable vehicle
Implementation Method 2
The composition comprises netupitant, at least one pharmaceutically acceptable stabilizer, at least one pharmaceutically acceptable solubilizer, and at least one pharmaceutically acceptable vehicle
Data Source
AI summary
The present invention relates to stable liquid composition suitable for parenteral administration in the form of a solution comprising:(a) netupitant at a concentration of about 0.5 mg/mL to about 20 mg/ml;(b) at least one pharmaceutically acceptable stabilizer at a concentration of 1 mg/mL to 22 mg/mL selected from the group consisting of tromethamine, phosphoric acid, aspartic acid, tartaric acid, citric acid, maleic acid, ascorbic acid and mixtures thereof; and(c) at least one pharmaceutically acceptable vehicle,wherein the composition is in the form of a solution and has a pH of 2 to 6. The compositions are suitable for subcutaneous, intravenous, or intramuscular administration. The invention further relates to methods for manufacturing the compositions and methods of using such compositions for prevention, treatment or management of nausea and vomiting.