Sialic Acid Crystalline Forms for Bioavailability
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Solution Overview
Problem
Current methods for administering compounds in the sialic acid biosynthetic pathway in vivo face challenges due to rapid clearance and excretion, and there is a need for stable crystalline forms of sialic acid for pharmaceutical use to treat sialic acid deficiencies effectively.
Innovation Solution
Development of various crystalline forms of sialic acid, including polymorphic Forms 1-5, and their pharmaceutical acceptable salts and solvates, which are characterized by specific X-ray powder diffraction patterns, Differential Scanning calorimetry thermograms, and purity levels, for use in pharmaceutical compositions to treat sialic acid deficiencies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If compounds in the sialic acid biosynthetic pathway are administered in vivo, then the treatment of sialic acid deficiency is achieved, but the compounds are rapidly cleared and excreted before metabolism can occur
Solution Approach 1:
The patent modifies the chemical structure of sialic acid compounds by creating esters with fatty acid chains of varying lengths and degrees of unsaturation. These structural parameter changes increase lipophilicity and delay renal excretion, allowing the compounds to remain in circulation long enough to be metabolized into active sialic acid forms that can treat deficiency conditions.
Solution Approach 2:
The patent introduces prodrug intermediaries - specifically fatty acid ester derivatives of sialic acid - that serve as transport vehicles. These intermediaries are administered orally, absorbed through the gastrointestinal tract, and then metabolized by esterases in the body to release the active sialic acid compound, thereby bridging the gap between administration and therapeutic action.
2Reliability
If crystalline forms of sialic acid are developed for pharmaceutical use, then stability and bioavailability are improved, but the complexity of characterizing and controlling polymorphic forms increases
Solution Approach 1:
The patent systematically varies crystallization parameters including solvent composition, temperature, pH, and additives to generate and characterize different polymorphic forms of sialic acid esters. By controlling these parameters, the invention identifies specific crystalline forms with optimal stability and solubility profiles for pharmaceutical formulation.
Solution Approach 2:
The patent develops a comprehensive analytical framework that uses multiple characterization techniques (XRPD, DSC, TGA, NMR, IR) to simultaneously assess multiple critical quality attributes of the crystalline forms including polymorphic identity, purity, moisture content, and thermal stability. This multi-functional approach efficiently manages the complexity of characterizing different crystal forms.
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 crystalline forms of sialic acid provide stable and effective pharmaceutical compositions that can alleviate symptoms of sialic acid deficiencies, such as Hereditary Inclusion Body Myopathy, by ensuring bioavailability and prolonged action, thereby improving muscle function and reducing muscle injury.
Implementation Method 1
Form 1 exhibits X-ray powder diffraction pattern comprising peaks at about 10.34±0.3; 17.91±0.3; and 22.06±0.3 degrees two-theta
Implementation Method 2
exhibits an X-ray powder diffraction pattern comprising peaks at about 5.95±0.3 and 11.93±0.3
Implementation Method 3
Form 1 exhibits a Differential Scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 188.6° C.
Implementation Method 4
crystalline forms of sialic acid, including polymorphic Forms 1-5, and their pharmaceutical acceptable salts and solvates
Data Source
AI summary
The present invention includes crystalline forms of N-acetylneuraminic acid (NeuAc) and crystalline forms of salts and/or solvates of N-acetylneuraminic acid (NeuAc). Furthermore, the present invention provides compositions comprising these crystalline forms and therapeutic use of the crystalline forms.