Recombinant Enzyme Formulation for ASMD Treatment Stability
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Solution Overview
Problem
Acid sphingomyelinase deficiency (ASMD) is a rare and life-threatening genetic disorder with severe neurovisceral and visceral manifestations, leading to early childhood mortality due to sphingomyelin accumulation in organs, necessitating an effective treatment.
Innovation Solution
The development of recombinant human acid sphingomyelinase (rhASM) compositions, specifically olipudase alfa, combined with sodium phosphate, methionine, and sucrose, which are formulated into lyophilized or aqueous liquid forms to enhance stability and shelf life, providing a pharmaceutical composition for treating ASMD.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recombinant human ASM compositions are formulated for treatment, then therapeutic effectiveness is improved, but stability and shelf life deteriorate
Solution Approach 1:
The patent applies parameter changes by optimizing the formulation composition, including specific concentrations of stabilizing excipients (sucrose, trehalose, mannitol), buffering agents (phosphate, citrate), and surfactants (polysorbate 80). The formulation specifies precise pH ranges (5.5-7.0) and component ratios to maintain enzyme stability while preserving therapeutic activity.
Solution Approach 2:
The patent uses intermediary substances (excipients) as mediators between the recombinant human ASM enzyme and the storage environment. These intermediaries include stabilizing sugars (sucrose, trehalose), buffering agents, and surfactants that protect the enzyme from degradation, aggregation, and denaturation during storage and administration.
2Reliability
If recombinant human ASM compositions are formulated for treatment, then therapeutic effectiveness is improved, but aggregation increases
Solution Approach 1:
The patent employs surfactants (polysorbate 80 at 0.001-0.01%) and stabilizing excipients as intermediary substances that prevent aggregation of the recombinant human ASM enzyme. These intermediaries create a protective interface between enzyme molecules and the formulation matrix, reducing intermolecular aggregation while preserving monomeric enzyme activity.
Solution Approach 2:
The patent optimizes formulation parameters including pH (5.5-7.0), ionic strength, and excipient concentrations to control enzyme aggregation. The specific composition ratios and environmental conditions are tuned to maintain enzyme solubility and prevent aggregation throughout the shelf life and storage conditions.
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 compositions demonstrate improved stability and biological activity, effectively reducing sphingomyelin accumulation and providing a potential treatment for severe ASMD phenotypes, including Niemann-Pick Disease type A and B, with enhanced storage stability and reduced aggregation.
Implementation Method 1
The compositions demonstrate improved stability and biological activity, effectively reducing sphingomyelin accumulation and providing a potential treatment for severe ASMD phenotypes, including Niemann-Pick Disease type A and B, with enhanced storage stability and reduced aggregation.
Implementation Method 2
The development of recombinant human acid sphingomyelinase (rhASM) compositions, specifically olipudase alfa, combined with sodium phosphate, methionine, and sucrose, which are formulated into lyophilized or aqueous liquid forms to enhance stability and shelf life
Data Source
AI summary
The present invention provides compositions such as aqueous liquid compositions and lyophilized compositions comprising a recombinant human acid sphingomyelinase. Provided also are methods for using the compositions to treat patients who are deficient in acid sphingomyelinase.