Boronic Acid Esters for Stable Liposomal Formulations
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Solution Overview
Problem
Current liposomal formulations of boronic acid compounds, such as bortezomib, face challenges with low encapsulation efficacy, complex preparation methods, and poor stability, leading to high toxicity and short therapeutic use due to rapid clearance and limited shelf life.
Innovation Solution
Development of boronic acid esters that form stable liposomal formulations with improved encapsulation and release properties, using specific compounds defined by Formula I and II, which include a polyol moiety and a lipid component, enhancing stability and therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If passive entrapment methods are used to prepare liposomal formulations of boronic acid compounds, then the preparation process is simple, but the encapsulation efficacy is very low (lower than 15%)
Solution Approach 1:
The patent applies preliminary action by modifying the boronic acid compound with a lipophilic moiety before liposome formation. This pre-modification enables the compound to be incorporated into the liposomal structure during the formation process itself, achieving high encapsulation efficacy without requiring complex post-formation loading steps. The lipophilic modification allows the compound to partition into the lipid bilayer during liposome assembly, resolving the contradiction between simple preparation and high encapsulation.
2Manufacturing precision
If remote loading methods are used to increase encapsulation efficacy, then the encapsulation can be driven by pH and chemical gradient, but the process becomes complex and requires overnight incubation
Solution Approach 1:
The invention performs the encapsulation action during the liposome formation process itself rather than requiring a separate loading step. By designing the boronic acid compound with a lipophilic moiety, the compound is incorporated into liposomes as they form, eliminating the need for complex remote loading procedures with overnight incubation. This preliminary incorporation during formation resolves the contradiction between high encapsulation efficacy and process simplicity.
3Duration of action of moving object
If liposomal formulations of boronic acid compounds are prepared using conventional methods, then they can provide prolonged systemic circulation time, but the stability during lyophilization is poor leading to leakage
Solution Approach 1:
The patent creates a composite structure by conjugating the boronic acid compound with a lipophilic moiety that integrates it into the liposomal lipid bilayer. This composite approach ensures the compound is structurally incorporated into the liposome rather than merely trapped in the aqueous core, providing stability during lyophilization while maintaining the prolonged circulation benefits of liposomal formulation. The lipophilic integration prevents leakage during dehydration and rehydration processes.
4Reliability
If free boronic acid compounds are administered clinically, then they can achieve therapeutic effects, but they exhibit high toxicity, non-specific tissue uptake, side effects, and rapid clearance
Solution Approach 1:
The patent applies the nesting principle by placing the boronic acid compound inside a liposomal carrier structure. The liposome acts as a protective container that delivers the therapeutic agent to the target site while shielding it from non-specific tissue uptake and rapid clearance. This nested structure maintains therapeutic effectiveness while reducing toxicity and side effects associated with free compound administration.
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 boronic acid ester formulations demonstrate enhanced stability during lyophilization and prolonged systemic circulation, reducing toxicity and increasing the shelf life of boronic acid therapeutic agents, while maintaining therapeutic effectiveness.
Implementation Method 1
Liposomes are spherical vesicles made of a lipid bilayer (e.g., a phospholipid bilayer) that are capable of encapsulating hydrophilic drugs in their aqueous core or hydrophobic drugs within their lipid bilayer.
Implementation Method 2
In order to further increase the shelf-life of liposomes, lyophilization has been utilized.
Data Source
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AI summary
Provided herein are boronic acid esters of boronic acid therapeutic agents, such as bortezomib. The boronic acid esters can be used to prepare liposomal formulations of boronic acid therapeutic agents with improved properties, such as enhanced stability. This disclosure, in one aspect, relates to compositions and methods of making and using the compositions.