IL-17A Antibody Formulation With Methionine and Nitrogen Filling
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Solution Overview
Problem
Existing pharmaceutical formulations of IL-17A antibodies, such as secukinumab, face challenges in maintaining stability and preventing oxidation due to inadequate methionine content and lack of effective anti-oxidation processes, which affect the formulation's efficacy in treating immune diseases like psoriasis and ankylosing spondylitis.
Innovation Solution
A stable pharmaceutical formulation containing 150 mg/ml secukinumab, 30 to 50 mM methionine, 0.02% surfactant, 170 to 200 mM stabilizer, and 20 mM histidine buffer, prepared through a nitrogen filling process and venting and nitrogen filling during stopper insertion, effectively inhibits oxidation, ensuring stability under various storage conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If methionine content is maintained at about 20 mM or less as in prior art, then the formulation can be simple, but oxidation of light-chain Cys97 occurs and stability is compromised
Solution Approach 1:
The patent optimizes the methionine concentration parameter to a specific range of 20-50 mM, which is higher than the prior art's 20 mM or less. This parameter change enables sufficient inhibition of light-chain Cys97 oxidation while maintaining formulation simplicity, resolving the contradiction between stability and complexity
Solution Approach 2:
The patent implements nitrogen filling during the manufacturing process to create an inert atmosphere that prevents oxidation. This environmental control measures protects the antibody formulation from oxidative degradation without requiring complex formulation compositions
2Reliability
If nitrogen filling process is implemented to prevent oxidation, then oxidation rate decreases to ≤ 0.7%, but manufacturing process complexity increases
Solution Approach 1:
The nitrogen filling is performed preliminarily during the manufacturing process before the product is completed and stored. This preliminary action prevents oxidation from the outset, ensuring long-term stability without requiring complex ongoing manufacturing interventions
Solution Approach 2:
By establishing an inert nitrogen atmosphere during manufacturing and storage, the patent creates a protective environment that simplifies the overall approach to oxidation prevention, despite the initial process step
3Object-affected harmful factors
If methionine content is increased to 30-50 mM to inhibit oxidation, then oxidation rate is suppressed, but formulation cost and complexity increase
Solution Approach 1:
The patent establishes an optimized methionine concentration range of 20-50 mM, balancing oxidation inhibition effectiveness with formulation simplicity. This parameter optimization achieves sufficient protection against oxidation without excessive complexity or cost
Solution Approach 2:
Methionine acts as an intermediary substance that sacrificially oxidizes instead of the critical light-chain Cys97 residues. By providing this intermediate protection mechanism, the formulation maintains simplicity while achieving oxidation suppression
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 maintains an oxidation rate of ≤ 0.7% for light-chain Cys97 after 4 weeks at 40°C and 75% humidity, ≤ 0.5% under 1,000 lux light illumination, and ≤ 0.7% under agitation, ensuring long-term stability and therapeutic efficacy.
Implementation Method 1
the content of methionine used in the prior art does not sufficiently inhibit the oxidation of pharmaceutical ingredients
Implementation Method 2
a process of filling a container with nitrogen gas during the manufacturing of a drug product
Data Source
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AI summary
A stable pharmaceutical formulation according to the present invention comprises: (A) an antibody or antigen-binding fragment thereof that binds to interleukin-17A (IL-17A); (B) a surfactant; (C) a stabilizer; (D) a buffer; and (E) an antioxidant. The present invention also comprises a pharmaceutical formulation prepared by a step of filling a container with nitrogen and a venting and nitrogen filling step when a rubber stopper is inserted into a pre-filled syringe, in manufacturing a drug product. The stable pharmaceutical formulation according to the present invention has low viscosity even when the formulation comprises an antibody, particularly an antibody in a large amount, has excellent long-term storage stability on the basis of excellent stability under accelerated and harsh conditions, and can be administered intravenously or subcutaneously.