Subcutaneous Anti-HER2 Formulation With Hyaluronidase for High Concentration
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Solution Overview
Problem
There is a need for highly concentrated, stable pharmaceutical formulations of anti-HER2 antibodies suitable for subcutaneous injection, as existing formulations are limited by solubility, stability, and viscosity issues, which can lead to protein aggregation and immunogenicity, particularly when administered repeatedly.
Innovation Solution
The formulation includes anti-HER2 antibodies, a buffering agent, stabilizers, a nonionic surfactant, and an effective amount of hyaluronidase enzyme, with specific concentrations and pH levels to maintain stability and reduce viscosity, allowing for high concentrations suitable for subcutaneous use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If high concentration of anti-HER2 antibody is formulated for subcutaneous injection, then therapeutic dose and volume are increased, but solubility and stability are compromised leading to protein aggregation
Solution Approach 1:
The patent introduces hyaluronidase enzyme as an intermediary substance that degrades hyaluronan in the subcutaneous tissue, creating a pathway for high-concentration antibody formulations to be administered safely. This mediator resolves the contradiction by enabling high doses without compromising stability or causing aggregation.
Solution Approach 2:
The formulation optimizes multiple parameters including pH (6.0-7.5), ionic strength, and excipient concentrations to maintain antibody stability at high concentrations. By carefully adjusting these parameters, the patent achieves both high antibody concentration and formulation stability simultaneously.
2Quantity of substance
If high concentration of anti-HER2 antibody is formulated, then therapeutic efficacy is improved, but viscosity increases making injection difficult
Solution Approach 1:
Hyaluronidase acts as a mediator that temporarily reduces subcutaneous tissue viscosity by degrading hyaluronan, allowing high-viscosity antibody formulations to be injected easily. The enzyme creates a transient low-viscosity pathway during injection without affecting the formulation's therapeutic concentration.
Solution Approach 2:
The hyaluronidase enzyme is included in the formulation to pre-degrade hyaluronan before the antibody injection, creating favorable injection conditions in advance. This preliminary action reduces tissue resistance and facilitates easy injection of high-concentration formulations.
3Duration of action of moving object
If repeated subcutaneous injections are administered, then maintenance dosing is achieved, but immunogenicity and aggregation increase
Solution Approach 1:
Hyaluronidase serves as a protective intermediary that enables repeated injections by preventing antibody aggregation in the subcutaneous space. By continuously degrading hyaluronan, it maintains a favorable environment for multiple administrations without increasing immunogenicity.
Solution Approach 2:
The hyaluronidase enzyme acts as a transient, short-lived agent that performs its function locally at the injection site and is rapidly cleared. This disposable-like action allows repeated dosing without cumulative immunogenic effects, as the enzyme does not persist in the system.
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 achieves stable, high-concentration anti-HER2 antibody solutions that can be safely administered subcutaneously, reducing aggregation and immunogenicity, and facilitating larger volume injections with improved bioavailability.
Implementation Method 1
The hyaluronidase enzyme increases the delivery of the therapeutic anti-HER2 antibody into the systemic circulation via the subcutaneous application route by the reversible hydrolyzation of hyaluronan, an extracellular component of the SC interstitial tissue.
Data Source
AI summary
The present invention relates to a highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody, such as e.g. Trastuzumab (HERCEPTIN™), Pertuzumab or T-DM1, or a mixture of such antibody molecules for subcutaneous injection. In particular, the present invention relates to formulations comprising, in addition to a suitable amount of the anti-HER2 antibody, an effective amount of at least one hyaluronidase enzyme as a combined formulation or for use in form of a co-formulation. The formulations comprise additionally at least one buffering agent, such as e.g. a histidine buffer, a stabilizer or a mixture of two or more stabilizers (e.g. a saccharide, such as e.g. α,α-trehalose dihydrate or sucrose, and optionally methionine as a second stabilizer), a nonionic surfactant and an effective amount of at least one hyaluronidase enzyme. Methods for preparing such formulations and their uses thereof are also provided.