Divalent Ursolic Acid Salts for Enhanced Solubility
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Solution Overview
Problem
Ursolic acid has poor water solubility and low bioavailability, limiting its effectiveness as a pharmaceutical agent due to its monovalent salts providing only limited improvement in solubility and dissolution rates.
Innovation Solution
Development of divalent ursolic acid salt preparations such as dipotassium ursolate and dicholine ursolate, combined with a self-nanoemulsifying drug delivery system (SNEDDS) to enhance solubility and bioavailability, including methods for synthesizing water-based dicholine ursolate and incorporating sulfation and glucuronidation inhibitors to reduce pre-systemic metabolism.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If monovalent salts of ursolic acid are used to improve solubility, then solubility increases slightly, but the improvement is limited and insufficient for effective drug delivery
Solution Approach 1:
The patent changes the valency parameter of ursolic acid salts from monovalent to divalent, creating salts with two ionizable groups that provide significantly enhanced solubility and bioavailability compared to traditional monovalent salts
Solution Approach 2:
The patent creates composite salt structures by combining ursolic acid with divalent bases (such as choline hydroxide or potassium hydroxide) to form divalent salts that incorporate multiple cationic components, achieving superior solubility properties
2Reliability
If ursolic acid is administered orally to achieve systemic effects, then pharmacological activity is desired, but poor water solubility and low bioavailability prevent effective delivery
Solution Approach 1:
The patent modifies the chemical parameter of ursolic acid by converting it to divalent salt forms with improved hydrophilicity, enabling effective oral administration and systemic delivery while maintaining pharmacological activity
Solution Approach 2:
The patent uses divalent cations (such as choline or potassium) as intermediary structures that bridge the hydrophobic ursolic acid core and the aqueous biological environment, facilitating solubility and cellular uptake
3Speed
If salt formation is used to increase dissolution rates, then dissolution improves, but monovalent salts provide only limited improvement
Solution Approach 1:
The patent changes the stoichiometric parameter of salt formation from 1:1 monovalent ratios to 1:2 divalent ratios, creating salts with enhanced dissolution rates and significantly greater solubility improvement
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 divalent ursolic acid salt preparations significantly increase solubility and bioavailability, enabling effective oral administration and improved pharmacological activity, with the SNEDDS formulation enhancing permeability and stability, thus overcoming the limitations of monovalent salts.
Implementation Method 1
Salt formation is one method used to increase solubility and dissolution rates of acidic and basic drugs. However, previously prepared monovalent salts of ursolic acid have provided limited improvement.
Implementation Method 2
One aspect of the disclosure provides compositions, such as a self-nanoemulsifying drug delivery system (SNEDDS) composition, comprising at least one UA preparation, wherein the at least one UA preparation is selected from the group consisting of monopotassium ursolate (UAK), dipotassium ursolate (UAK2), monocholine ursolate (UAmC), ursolic acid dicholine complex (UAdC-O), ursolic acid dicholine hydroxide hydrated complex (UAdC-W)... and at least two emulsifying agents.
Implementation Method 3
One aspect of the disclosure provides a method of synthesizing water-based dicholine ursolate (UAdC-W), comprising mixing ursolic acid and aqueous choline hydroxide in water to form a solution, heating the solution, cooling and incubating the solution at 20-25° C. until UAdC-W forms, and isolating UAdC-W.
Data Source
AI summary
Ursolic acid (UA) preparations and a self-nanoemulsifying drug delivery system (SNEDDS) composition containing at least one UA preparation selected from monopotassium ursolate (UAK), dipotassium ursolate (UAK2), monocholine ursolate (UAmC), dicholine ursolate (UAdC), pharmacological salts thereof, and mixtures thereof are provided. Methods for synthesizing UA preparations and delivering UA preparations to subjects in need thereof are also provided.