Polymyxin B Liposomal Formulation Pulmonary Delivery

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Solution Overview

Problem

Current treatments for multidrug-resistant Gram-negative bacterial infections, particularly pulmonary infections, face challenges due to limited penetration of polymyxin B into the site of infection and associated nephrotoxicity, which hinders effective treatment and dose escalation.

Innovation Solution

An intravenous liposomal formulation of polymyxin B is developed, using unilamellar vesicles composed of dipalmitoylphosphatidylcholine, cholesterol, or α-tocopherol, with a vesicle size of 714 nm to 1372 nm, encapsulating a low dose of polymyxin B at a weight ratio of 1:20 to 1:2, to enhance delivery to the infection site while reducing renal exposure and delaying nephrotoxicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If standard polymyxin B formulations are used to treat multidrug-resistant Gram-negative bacterial infections, then the drug can reach the bloodstream, but penetration into the epithelial lining fluid at the infection site is limited

Engineering Contradiction:

Improvepolymyxin B concentration in epithelial lining fluidVSAvoidtreatment efficacy

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

Liposomes serve as intermediary carriers that facilitate the transport of polymyxin B from the bloodstream to the epithelial lining fluid. The liposomal encapsulation protects the drug during circulation and enables targeted delivery to the infection site, significantly enhancing penetration into the epithelial lining fluid where standard formulations fail to achieve adequate concentrations

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the physical and chemical parameters of polymyxin B delivery by encapsulating it in liposomes with specific size ranges (50-200 nm diameter). This parameter change in the delivery system's physical state enables the drug to overcome biological barriers and achieve superior penetration into the epithelial lining fluid compared to conventional formulations

Inventive Principle:

Principle #35Parameter changes

2Quantity of substance

If high doses of polymyxin B are administered to overcome poor concentration achievement in the epithelial lining fluid, then drug concentration at the infection site may improve, but nephrotoxicity increases

Engineering Contradiction:

Improvepolymyxin B concentration in epithelial lining fluidVSAvoidnephrotoxicity

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The liposomal formulation creates local quality differences in drug distribution by concentrating polymyxin B delivery at the infection site (epithelial lining fluid) while minimizing exposure of healthy tissues, particularly the kidneys. This localized delivery approach achieves therapeutic concentrations where needed without proportionally increasing systemic toxicity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

Liposomes act as mediators that decouple the relationship between systemic drug dose and renal exposure. The liposomal carrier protects polymyxin B from direct interaction with renal tissues during circulation and facilitates selective release at the infection site, thereby reducing nephrotoxicity even at effective dosing levels

Inventive Principle:

Principle #24Intermediary (Mediator)

3Quantity of substance

If polymyxin B is administered to treat pulmonary infections, then the drug reaches the bloodstream, but uptake by activated tissue macrophages is insufficient to achieve higher antimicrobial concentrations in pulmonary tissues

Engineering Contradiction:

Improveantimicrobial concentration in pulmonary tissuesVSAvoidtreatment efficacy

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The invention changes the pharmacokinetic parameters of polymyxin B by encapsulating it in liposomes with optimized size and composition. This parameter change in the delivery system enables the drug to be efficiently taken up by activated tissue macrophages through liposome-macrophage interactions, thereby achieving higher intracellular concentrations in pulmonary tissues

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

Liposomes serve as intermediaries that facilitate macrophage uptake and intracellular delivery of polymyxin B. The liposomal structure is recognized and internalized by activated macrophages, acting as a delivery vehicle that transports the antibiotic into the macrophage cytoplasm where it can effectively concentrate and exert antimicrobial activity

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS10092515B2Liposomal formulations of polymyxin B and uses thereof

Publication Date: 2018.10.09 UNIV HOUSTON SYST

AI summary

The present invention provides an intravenous liposomal formulation of a low dose polymyxin B or a pharmaceutical composition thereof. The present invention also provides methods utilizing the intravenous liposomal formulation or its pharmaceutical composition for increasing the therapeutic efficacy during treatment of a bacterial infection in a subject, for decreasing exposure of renal tissue to the polymyxin B during a course of polymyxin B treatment and for lowering exposure to polymyxin B in renal tissues in a subject receiving polymyxin B treatment.