Compositions and methods for reducing reperfusion injury
Inventors
Assignees
Publication Number
US-10716756-B2
Publication Date
2020-07-21
Expiration Date
2037-06-15
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Abstract
A pharmaceutical composition comprising a lipid component, an amphiphilic emulsifier, a polar liquid carrier, and one or more electrolytes, where the amphiphilic emulsifier forms lipid carrying micelles having a lipophilic core comprising the lipid component in the polar liquid carrier, and/or liposomes organized as a lipid bilayer and/or other particle configurations. The pharmaceutical composition is free of hemoglobin and fluorocarbon and can be used for treating ischemic conditions with reduced reperfusion injury.
Core Innovation
The invention provides a pharmaceutical composition comprising a lipid component, an amphiphilic emulsifier, a polar liquid carrier, and one or more electrolytes, where the emulsifier forms lipid-carrying micelles with a lipophilic core and can also form liposomes organized as a lipid bilayer. The composition is designed to be free of hemoglobin and fluorocarbon. In some embodiments, histidine is included in the formulation. The micelles have diameters in the range of 30 nm to 160 nm, and liposomes (if present) are generally in the range of 1–30 nm.
The pharmaceutical composition addresses the problem that current resuscitation fluids for treating shock and ischemic conditions are of limited efficacy, either diffusing rapidly from the blood or causing complications such as enhanced bleeding or impaired tissue perfusion. Existing approaches fail to sufficiently deliver oxygen and nutrients to tissues or adequately modulate inflammatory responses and mediators arising from reperfusion injury.
In use, this composition is administered to a subject needing treatment for ischemia to reduce reperfusion injury, particularly in the lung, and may also be used for other tissues. The emulsifier enables formation of micelles and/or liposomes of defined, stable sizes capable of carrying and delivering lipophilic gases such as oxygen and nitric oxide, as well as absorbing and modulating inflammatory mediators. This targeted delivery system is intended to better restore tissue perfusion, minimize inflammatory injury, and improve survival and hemodynamics following ischemic events compared to conventional resuscitation fluids.
Claims Coverage
There are two independent claims, each defining a distinct inventive feature covering a method of reducing reperfusion injury and a pharmaceutical composition for this purpose.
Method for reducing reperfusion injury in lung tissue using specific micelle-based compositions
A method comprising administering to a subject an effective amount of a pharmaceutical composition that includes: - A lipid component (0-35% w/v) - An amphiphilic emulsifier (6%-60% w/v) - A polar liquid carrier - One or more electrolytes The amphiphilic emulsifier forms lipid-carrying micelles with a lipophilic core in the polar liquid carrier, wherein micelle diameters are between 30 nm and 160 nm. The administration of this composition reduces reperfusion injury in lung tissue.
Pharmaceutical composition for reducing reperfusion injury in lung tissue incorporating histidine and defined nanoparticles
A pharmaceutical composition comprising: - A lipid component (0-35% w/v) - An amphiphilic emulsifier (6%-60% w/v) - A polar liquid carrier - One or more electrolytes - Histidine (0.001 μM–100 mM) The amphiphilic emulsifier forms liposomes (diameter 1–30 nm) with a hydrophilic core and micelles (diameter 30–160 nm) with a lipophilic core. The composition effectively reduces reperfusion injury in lung tissue.
The first independent claim covers a method of reducing reperfusion injury in the lung by administering a lipid-micelle based formulation of specified size and composition, while the second claim covers a pharmaceutical composition for this purpose, defining its constituents, particle sizes, and inclusion of histidine.
Stated Advantages
The pharmaceutical composition provides improved ability to deliver oxygen and nutrients to tissue and to reduce inflammatory responses compared to existing resuscitation fluids.
The composition is free from complications associated with hemoglobin, derivatives of hemoglobin, perfluorocarbon and their derivatives.
The composition absorbs and releases lipophilic gases such as oxygen and nitric oxide and can act as a reservoir to modulate their tissue concentrations.
The defined nanoparticle size enhances retention in the intravascular space or allows penetration into the interstitial space to inhibit inflammatory processes and reduce tissue injury.
The composition demonstrates stability at room temperature and after autoclaving (under specified conditions).
In animal models, the formulations raised and maintained blood pressure more effectively than standard fluids and show significant reduction in tissue injury during reperfusion, particularly with smaller nanoparticles.
Documented Applications
Method for reducing reperfusion injury in lung tissue in subjects treated for ischemia.
Treatment of conditions related to lack of blood supply, including hypovolemia, shock, trauma, septic shock, anemia, and organ perfusion.
Method for increasing blood pressure in subjects experiencing hemorrhagic shock.
Oxygenation in patients with severe lung injury as a potential alternative to extracorporeal membrane oxygenation (ECMO).
Preservation of biological integrity of organs for transplantation via perfusion with the pharmaceutical composition.
Treatment of neuronal injury and seizures using xenon- or argon-carrying versions of the composition.
Use in exchange transfusion and whole circulation perfusion to remove harmful materials from blood.
Absorption of endogenous nitric oxide in the treatment of septic shock to stabilize blood pressure.
Treatment of diseases such as Raynaud's disease, Prinzmetal's angina, cerebral vasospasm, or atherosclerosis via nitric oxide-loaded compositions for vasodilation.
Use as a diagnostic tool to absorb and subsequently analyze lipophilic disease biomarkers.
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