Isofagomine Salts Stabilize GCase Enzyme
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Solution Overview
Problem
There is a need for additional forms of isofagomine, including various salts and polymorphic forms, to facilitate the preparation of improved formulations for treating Gaucher disease, particularly to enhance stability, solubility, and bioavailability of glucocerebrosidase (GCase).
Innovation Solution
The development of isofagomine salts and crystalline, hydrate, and solvate forms, specifically prepared from organic acids such as quinate, malate, fumarate, oxalate, and tartrate, which provide improved production, handling, storage, stability, solubility, and therapeutic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If isofagomine is used to stabilize GCase during synthesis and processing, then enzyme activity is increased, but the compound requires additional salt and polymorphic forms to improve manufacturing and storage properties
Solution Approach 1:
The patent applies parameter changes by developing multiple salt forms (sulfate, hydrochloride, acetate, formate, nitrate, perchlorate) and polymorphic forms of isofagomine. Each salt form is created by reacting isofagomine with different acids, and each form exhibits different physical and chemical properties including solubility, stability, and crystallinity. This allows optimization of manufacturing processes, storage conditions, and formulation characteristics while maintaining the pharmacological activity of isofagomine as a GCase stabilizer
Solution Approach 2:
The patent creates composite material systems by combining isofagomine with various counterions to form distinct salt compounds. Each salt form represents a composite structure where the isofagomine cation is paired with a specific anion (e.g., SO4^2-, Cl^-, CH3COO^-). These composite forms provide tailored properties for different application requirements, enabling improved handling, storage, and formulation while preserving the core function of stabilizing GCase enzyme
2Quantity of substance
If liquid compositions with high GCase concentration are prepared, then therapeutic efficacy is improved, but protein aggregation and degradation increase
Solution Approach 1:
The patent uses isofagomine and its salt forms as intermediary molecules that mediate between high GCase concentration and protein stability. Isofagomine acts as a pharmacological chaperone that binds to GCase, preventing aggregation and degradation even at high concentrations. The multiple salt forms of isofagomine provide different solubility and stability characteristics, allowing optimization of the intermediary's performance to maintain GCase stability in concentrated liquid formulations
Solution Approach 2:
The patent applies parameter changes by utilizing different salt forms of isofagomine with varying solubility and stability parameters. By selecting appropriate salt forms (e.g., sulfate, hydrochloride, acetate), the formulation can be optimized to maintain isofagomine in solution at concentrations sufficient to stabilize GCase, thereby enabling high GCase concentration in liquid compositions without aggregation or degradation
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
These novel forms of isofagomine significantly improve the stability and bioavailability of GCase, reducing aggregation and degradation, and enabling more effective treatment of Gaucher disease.
Implementation Method 1
specific GCase enzyme inhibitors could bind with specificity to the enzyme during its synthesis, stabilizing protein folding in the ER, and would subsequently dissociate from the enzyme at its native location in the lysosome, thereby increasing enzyme activity by increasing the level of enzyme that is processed instead of degraded
Implementation Method 2
Isofagomine, (3R,4R,5R)-3,4-dihydroxy-5-hydroxymethylpiperidine, also known as IFG, is such a GCase enzyme inhibitor that binds in the active site of both wild-type and mutant GCase and stabilizes the enzyme during synthesis and processing
Implementation Method 3
The development of isofagomine salts and crystalline, hydrate, and solvate forms, specifically prepared from organic acids such as quinate, malate, fumarate, oxalate, and tartrate, which provide improved production, handling, storage, stability, solubility, and therapeutic properties
Data Source
AI summary
The present invention relates generally to the field of pharmaceuticals, and specifically relates to isofagomine (IFG), novel salts thereof and preparation methods and uses of these, for example, in formulating pharmaceutical compositions for the treatment of Gaucher disease. Also provided are novel crystalline forms of isofagomine salts, methods for preparing the crystalline forms, and their use in formulating pharmaceutical compositions.