Sodium Chloride Reconstitution Solution for Lyophilized Drugs
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Solution Overview
Problem
Current pharmaceutical solutions for intravenous injection often cause erythrocyte aggregation due to low ionic strength, and reconstitution with high ionic strength solutions can lead to hypertonicity, causing dehydration and thrombophlebitis.
Innovation Solution
A method involving the addition of a 36 mM to 44 mM sodium chloride solution to lyophilized pharmaceutical formulations to achieve isotonicity and sufficient ionic strength, preventing erythrocyte agglutination while maintaining appropriate osmolarity for intravenous injection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If lyophilized products are reconstituted with low ionic strength solutions (such as sterile water for injection or 5% dextrose), then the resultant preparation can be isotonic with respect to plasma, but the preparation does not have sufficient ionic strength to prevent erythrocyte aggregation
Solution Approach 1:
The patent changes the ionic strength parameter of the reconstitution solution by adding sodium chloride at concentrations of 36-44 mM to solutions that would otherwise have low ionic strength. This modification provides sufficient ionic strength to prevent erythrocyte aggregation while maintaining osmolarity within the isotonic range (270-330 mOsm/L), thereby resolving the contradiction between preventing aggregation and maintaining isotonicity.
2Reliability
If lyophilized products are reconstituted with high ionic strength solutions (such as 0.9% NaCl), then the resultant preparation has sufficient ionic strength to prevent agglutination, but the preparation becomes hypertonic with respect to blood, causing dehydration of red blood cells and venous inflammation
Solution Approach 1:
The patent optimizes the sodium chloride concentration to a specific range (36-44 mM) that provides sufficient ionic strength to prevent erythrocyte aggregation while keeping the osmolarity within or near the isotonic range (270-330 mOsm/L). This precise parameter control avoids the hypertonicity problems associated with 0.9% NaCl (154 mM) while still preventing agglutination, thereby resolving the contradiction between preventing aggregation and avoiding hypertonicity.
3Reliability
If pharmaceutical formulations are prepared with low ionic strength solutions, then the formulations can be isotonic with respect to plasma, but they cause erythrocyte aggregation upon intravenous injection
Solution Approach 1:
The patent modifies the ionic strength parameter of isotonic solutions by adding sodium chloride at concentrations of 36-44 mM. This change provides sufficient ionic strength to prevent erythrocyte aggregation while maintaining osmolarity within the isotonic range, thereby resolving the contradiction between maintaining isotonicity and preventing aggregation.
Data Source
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AI summary
The invention provides methods for preparing pharmaceutical formulations for injection such that upon injection the formulation does not cause erythrocyte agglutination, hemolysis, and/or cell shrinkage. To prevent agglutination, a pharmaceutical formulation ready for injection needs to have a sufficient ionic strength. To prevent hemolysis or cell shrinkage, a pharmaceutical formulation ready for injection needs to be about isotonic with respect to plasma. The invention provides methods that prepare pharmaceutical formulations for injection that have both the sufficient ionic strength to prevent agglutination and the requisite tonicity to prevent significant hemolysis or cell dehydration or shrinkage. The present methods involve the use of sodium chloride solutions that are about 25 mM to about 150 mM for reconstituting lyophilized cakes (or other non-liquid pharmaceutical formulations) into solution or for diluting pharmaceutical formulation solutions.