High-Concentration FcRn Inhibitor Formulation for Subcutaneous Dosing
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Solution Overview
Problem
There is a need for improved formulations and methods of administration of FcRn inhibitors for the treatment of autoimmune diseases, as existing treatments like IVIg and blocking antibodies require repeated administrations and have limitations.
Innovation Solution
Development of aqueous formulations comprising 100-300 mg/mL of an isolated neonatal Fc receptor (FcRn) antagonist, specifically a variant Fc region homodimer, in specific pH and salt concentrations, suitable for subcutaneous administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If FcRn inhibitors are administered via intravenous infusion, then the treatment effectiveness is maintained, but the administration frequency and complexity increase
Solution Approach 1:
The patent changes the physical and chemical parameters of the FcRn inhibitor formulation, specifically developing concentrated aqueous formulations (100-300 mg/mL) with optimized pH (6.0-6.5) and excipient compositions. These parameter changes enable the formulation to be suitable for subcutaneous administration, which is less invasive and more convenient than intravenous infusion, while maintaining treatment effectiveness.
Solution Approach 2:
The patent introduces specific excipients as intermediaries to stabilize the FcRn inhibitor for subcutaneous administration. These include histidine or histidine HCl buffer systems, sucrose, arginine HCl, polysorbate 20 or 80, and L-methionine. These intermediary substances enable the formulation to maintain stability and efficacy in the subcutaneous route, bridging the gap between the biologic agent and the new administration route.
2Quantity of substance
If FcRn inhibitors are formulated at high concentrations, then the dosing volume is reduced, but the formulation stability becomes more challenging
Solution Approach 1:
The patent creates a composite formulation system combining the FcRn inhibitor with multiple stabilizing excipients including histidine buffer, sucrose, arginine HCl, polysorbate, and L-methionine. This composite material approach allows the formulation to achieve high concentrations (100-300 mg/mL) while maintaining stability, as each component contributes specific stabilizing properties that collectively prevent aggregation and degradation at high concentrations.
Solution Approach 2:
The patent optimizes specific formulation parameters including pH (6.0-6.5), ionic strength, and excipient concentrations to enable high protein concentration formulations. By carefully controlling these parameters, the formulation achieves both high concentration and stability, resolving the contradiction between concentration and stability.
3Ease of operation
If FcRn inhibitors are administered subcutaneously, then the patient comfort is improved, but the maximum dosable volume is limited
Solution Approach 1:
The patent changes the concentration parameter of the formulation to 100-300 mg/mL, which is significantly higher than conventional formulations. This parameter change allows the required therapeutic dose to be delivered in a smaller volume, making subcutaneous administration feasible and comfortable for patients while still achieving the necessary dosing volume.
Data Source
AI summary
Provided are various aqueous formulations of the neonatal Fc receptor (FcRn) antagonist ARGX-113, including formulations useful as pharmaceutical compositions, methods for their preparation, devices comprising the various formulations, and uses thereof. In certain embodiments the formulations are suitable and useful for administration of ARGX-113 to a human subject. In certain embodiments the formulations are suitable and useful for subcutaneous administration of ARGX-113 to a human subject. The formulations can be used in the treatment of any condition that would benefit from inhibition of FcRn-mediated antibody recycling. Such conditions can include any one or more of various antibody-mediated autoimmune diseases, including, for example and without limitation, myasthenia gravis (MG) and immune thrombocytopenia (ITP).