Mannitol-Sucrose Lyophilized Biologics for Rapid Reconstitution

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Solution Overview

Problem

Existing formulations for activatable CTLA-4 antibodies, such as Activatable Ipilimumab, face challenges with stability and storage, particularly due to the lability of protease cleavable linkers, which can lead to unwanted cleavage and degradation, making it difficult to deliver high doses effectively.

Innovation Solution

Formulations comprising mannitol and sucrose, or glycine and sucrose, along with additional components like histidine, polysorbate 80, and diethylenetriaminepentaacetic acid, are developed to stabilize Activatable Ipilimumab, allowing for lyophilized formulations that reconstitute quickly and maintain stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If high concentration lyophilized formulations are used to enable high-dose delivery, then dose delivery capability is improved, but reconstitution time increases and stability decreases

Engineering Contradiction:

Improvedose delivery capabilityVSAvoidreconstitution time

Core Design Contradiction:

Quantity of substanceVSLoss of time

Solution Approach 1:

The patent changes the chemical composition parameters of the formulation by incorporating specific excipients (mannitol, glycine, sucrose, histidine, polysorbate 80, and diethylenetriaminepentaacetic acid) in optimized concentrations. This allows the formulation to achieve high concentration (high dose delivery capability) while maintaining rapid reconstitution and stability through the synergistic effects of these excipients on dissolution kinetics and protein protection.

Inventive Principle:

Principle #35Parameter changes

2Quantity of substance

If high concentration lyophilized formulations are used to enable high-dose delivery, then dose delivery capability is improved, but formulation stability worsens due to linker cleavage and degradation

Engineering Contradiction:

Improvedose delivery capabilityVSAvoidformulation stability

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent introduces multiple excipients as intermediary substances that mediate between the protease cleavable linkers and the environmental factors causing degradation. Specifically, mannitol and glycine act as stabilizing agents that protect the linkers from unwanted cleavage, while histidine and diethylenetriaminepentaacetic acid provide additional protection against degradation, allowing high concentration formulations to maintain stability during storage.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Adaptability or versatility

If protease cleavable linkers are used in activatable antibodies, then therapeutic functionality is improved, but susceptibility to cleavage and degradation increases

Engineering Contradiction:

Improvetherapeutic functionalityVSAvoidsusceptibility to cleavage and degradation

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent applies beforehand cushioning by incorporating stabilizing excipients (mannitol, glycine, histidine, polysorbate 80, and diethylenetriaminepentaacetic acid) into the formulation before storage and administration. These excipients create a protective environment that cushions the protease cleavable linkers against unwanted cleavage and degradation during storage, while preserving the linkers' functionality for therapeutic activation when needed.

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

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 formulations enable rapid reconstitution of Activatable Ipilimumab to a clear solution within minutes, ensuring stability and convenience for high-dose delivery, reducing the risk of cleavage and degradation during storage.

Implementation Method 1

addition of mannitol or glycine to protein formulations comprising sucrose significantly lowers the time needed to reconstitute a lyophilized cake at high concentration

Methodology Applied

Scientific EffectDissolution:

Implementation Method 2

lyophilized formulations that reconstitute quickly and maintain stability

Methodology Applied

Scientific EffectLyophilization: Freeze Drying

Data Source

PatentUS20250332251A1Use of sucrose, mannitol and glycine to reduce reconstitution time of high concentration lyophilized biologics drug products

Publication Date: 2025.10.30 BRISTOL MYERS SQUIBB CO

AI summary

The present invention provides methods of lyophilizing proteins, including activatable antibodies such as an activatable ipilimumab, as well as related solution and lyophilized antibody formulations. Exemplary lyophilized formulations comprise a combination of mannitol and sucrose, in a weight ratio of two or three, or a combination of glycine and sucrose, in a weight ratio or two or three. Such lyophilized formulations exhibit stability and reduced reconstitution time.