Aprepitant Nanoliposome Formulation for IV Stability
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Solution Overview
Problem
Current formulations of aprepitant for intravenous administration face challenges due to poor aqueous solubility, stability issues, and toxicity concerns, including allergic reactions and injection-related toxicities from surfactants and cosolvents.
Innovation Solution
A nanoliposome formulation of aprepitant is developed, comprising aprepitant, phospholipid, bilayer stabilizer, antioxidant, osmotic adjusting agent, and pH buffering agent, which enhances bioavailability and stability, and is free from polysorbate, oil, and solvent, maintaining prolonged circulation and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nanoparticulate formulations are used to improve aqueous solubility, then bioavailability is improved, but particle size may cause capillary blockage
Solution Approach 1:
The patent uses liposomes with phospholipid bilayer membranes to encapsulate aprepitant. These flexible thin film structures provide a safe size range (50-200 nm) that improves aqueous solubility and bioavailability while being small enough to avoid capillary blockage. The liposomal membrane allows controlled drug release and maintains stability in physiological conditions.
Solution Approach 2:
The patent optimizes critical parameters including particle size (50-200 nm), pH (6.5-7.5), and composition ratios to achieve the desired balance between solubility enhancement and safety. By controlling these parameters, the formulation maintains nanoscale dimensions for improved solubility while ensuring particles remain below the threshold for capillary obstruction.
2Reliability
If polysorbate 80 surfactant is used to improve solubility, then aqueous solubility is improved, but allergic reactions and anaphylaxis risk increase
Solution Approach 1:
The patent removes polysorbate 80 and other harmful surfactants from the formulation entirely. Instead, it uses phospholipids as the primary surfactant component, which are naturally biocompatible and do not trigger allergic reactions. This extraction of harmful substances while retaining solubility-enhancing functionality through safe alternatives directly addresses the contradiction.
Solution Approach 2:
The patent introduces phospholipids as an intermediary substance that performs the surfactant function without causing allergic reactions. Phospholipids serve as a safe mediator between the hydrophobic aprepitant and aqueous environment, providing solubility enhancement without the immunogenicity of polysorbate 80.
3Reliability
If cosolvents are used to improve solubility, then aqueous solubility is improved, but injection-related toxicities increase
Solution Approach 1:
The patent eliminates cosolvents such as dimethylacetamide, ethanol, and PEG400 from the formulation. By removing these toxic substances, the patent avoids injection-related adverse events while maintaining aprepitant solubility through alternative mechanisms including liposomal encapsulation and pH optimization.
Solution Approach 2:
The patent uses phospholipid bilayers and optimized pH conditions as intermediaries to achieve solubility without toxic cosolvents. These safe mediators enable drug dissolution and stability in aqueous environments without causing phlebitis or other injection-related toxicities.
4Duration of action of stationary object
If soybean oil is used in emulsion formulations, then prolonged stability is achieved, but fat overload and high blood triglycerides occur
Solution Approach 1:
The patent removes soybean oil and other lipid emulsifiers from the formulation. By eliminating these triglyceride-rich components, the patent prevents fat overload and hypertriglyceridemia while maintaining formulation stability through phospholipid-based liposomes and other non-lipid stabilizing agents.
Solution Approach 2:
The patent uses phospholipids and other biocompatible excipients as intermediaries to provide prolonged stability without relying on soybean oil. These alternative stabilizing agents maintain formulation integrity and drug release characteristics without causing metabolic complications.
5Stability of the object's composition
If high concentration of egg lecithin is used to improve stability, then formulation stability is improved, but allergic reactions increase
Solution Approach 1:
The patent removes egg lecithin from the formulation to eliminate the source of allergic reactions. By extracting this allergenic component, the patent maintains formulation stability through alternative phospholipid sources and stabilizing agents that do not trigger immune responses.
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 nanoliposome formulation provides enhanced stability, reduced toxicity, and improved bioavailability, with prolonged circulation half-life and neutral pH, making it suitable for intravenous administration without causing capillary blockage or embolization.
Implementation Method 1
a phospholipid; a bilayer stabilizer
Implementation Method 2
an antioxidant
Implementation Method 3
an osmotic adjusting agent and/or a lyoprotectant
Implementation Method 4
pH buffering agent; and water
Data Source
AI summary
Disclosed herein are pharmaceutical formulations of aprepitant suitable for parenteral administration including intravenous administration. The pharmaceutical formulations are stable and ready-to-use liposomes for the treatment of emesis and are particularly useful for treatment of chemotherapy or surgery-induced nausea and vomiting. Methods of preparation of the aprepitant formulations are also provided.