Compositions and methods for treating or preventing multiple organ dysfunction syndrome
Inventors
Assignees
Publication Number
US-12036321-B2
Publication Date
2024-07-16
Expiration Date
2041-04-02
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Abstract
A PN composition for treating multiple organ dysfunction syndrome (MODS) comprises a lipophilic or hydrophobic component, an amphiphilic emulsifier, a polar liquid carrier, and one or more electrolytes, where the amphiphilic emulsifier forms micelles having a lipophilic or hydrophobic core comprising the lipophilic or hydrophobic component in the polar liquid carrier, and/or liposomes organized as a lipid bilayer and/or other particle configurations. This is a PN composition that takes up nitric oxide and releases it with enhanced rapidity enabling it to shift the balance of nitric oxide from one that exacerbates organ damage and decreased survivability to one that reverses and/or inhibits organ damage and increases survivability.
Core Innovation
The invention relates to compositions and methods for preventing or treating multiple organ dysfunction syndrome (MODS) by administering a phospholipid nanoparticle (PN) composition. This PN composition comprises a lipophilic or hydrophobic component, an amphiphilic emulsifier, a polar liquid carrier, and one or more electrolytes. The amphiphilic emulsifier forms micelles with a lipophilic or hydrophobic core in the polar liquid carrier, and/or liposomes organized as a lipid bilayer and/or other particle configurations. In various embodiments, these particles have mean diameters in ranges such as 1–500 nm or 1–800 nm.
The core problem being addressed is the lack of effective treatments for MODS, a critical condition with high morbidity and mortality in intensive care units. MODS is triggered by various causes, including trauma, sepsis, and other insults, and current interventions focus mainly on symptomatic support for each failing organ. Anti-inflammatory agents and traditional attempts targeting blood pressure or nitric oxide overproduction have failed to improve survival or reverse MODS, sometimes even worsening outcomes.
The invention provides a solution by introducing a PN composition that can reversibly take up and release nitric oxide (NO), enabling redistribution rather than inhibition or scavenging of NO. This mechanism shifts the balance of NO in the body from levels that exacerbate organ damage toward levels that prevent or reverse organ injury, thereby increasing survivability. The compositions can also be engineered with additional agents or features such as oxygenation, crystalloid agents, oncotic agents, or anti-inflammatory components, and can be administered via various routes including intravenous, intra-arterial, intraosseous, or intracardial injection.
Claims Coverage
The independent claims define thirteen inventive features focused on methods of treating MODS using specifically formulated phospholipid nanoparticle (PN) compositions with various properties and component selections.
Phospholipid nanoparticle composition with specific lipid sources for treating MODS
A method comprising administering to a subject an effective amount of a PN composition containing: - a lipophilic or hydrophobic component (0–35% w/v) selected from soybean oil, chia bean oil, or algae oil; - an amphiphilic emulsifier (at least 0.1% w/v); - a polar liquid carrier; - one or more electrolytes; where the composition comprises liposomes and/or micelles having a diameter of 1–800 nm.
PN composition with specified emulsifier sources for treating MODS
A method in which the amphiphilic emulsifier is specifically selected from egg yolk lecithin and soybean lecithin, combined with a lipophilic or hydrophobic component, a polar liquid carrier, and electrolytes, forming liposomes and/or micelles of 1–800 nm diameter.
PN composition employing specific non-aqueous polar liquid carriers
A method wherein the polar liquid carrier is chosen from dimethyl sulfoxide, polyethylene glycol, and polar silicone liquids, and the composition otherwise includes the PN components and forms liposomes and/or micelles with defined particle size.
Oxygenated PN composition for treating MODS
A method involving an oxygenated PN composition characterized by an oxygen content of 1–50,000 ml O2 per 100 ml PN composition, alongside the defined lipid, emulsifier, polar carrier, and electrolytes.
Defined emulsifier to lipophilic component ratio in PN composition
A method where the PN composition has an emulsifier-to-lipophilic or hydrophobic component ratio (w/w) between about 1:200 to about 1:1.7, in combination with the other specified PN composition requirements.
PN composition with defined micelle and liposome sizes
A method utilizing a PN composition in which micelles have diameters of 30–500 nm and liposomes have diameters of 1–30 nm as measured by electron microscopy.
PN composition with subphysiological concentration of magnesium ion
A method with the PN composition formulated to include a concentration of magnesium ion in a subphysiological range, alongside the other standard PN ingredients and nanostructure dimensions.
PN composition further comprising additional therapeutic agents
A method where the PN composition additionally includes one or more of the following: a crystalloid agent, an oncotic agent, an anti-inflammatory agent, an immunomodulatory agent, or a lipophilic gas, with the required base PN components and nanostructure.
PN composition further comprising glycerin
A method where the PN composition further includes glycerin, in addition to the standard PN composition components and size specifications.
Treatment of MODS induced by sepsis caused by COVID 19 virus
A method explicitly addressing MODS in subjects where MODS is induced by sepsis caused by the COVID 19 virus, using the described PN composition.
Increasing oxygen saturation in MODS due to sepsis using defined PN composition
A method for treating MODS due to sepsis by increasing oxygen saturation, administering a PN composition with micelles of 30–500 nm and liposomes of 1–30 nm in diameter.
Reducing hypoxia in MODS due to sepsis with defined PN composition
A method for treating MODS due to sepsis by reducing hypoxia, using a PN composition with particle sizes as specified (micelles 30–500 nm; liposomes 1–30 nm).
Increasing oxygen saturation in MODS with defined PN composition
A method for treating MODS by increasing oxygen saturation, through administration of a PN composition containing micelles of 30–500 nm and liposomes of 1–30 nm diameter, with defined minimum content of amphiphilic emulsifier (at least 0.6% w/v).
These inventive features collectively define methods of treating MODS using phospholipid nanoparticle compositions with specific sources and ratios of lipid and emulsifiers, tailored nanostructure size, selection of polar carrier, oxygenation status, ionic composition, and optional inclusion of other therapeutic agents or excipients.
Stated Advantages
The PN composition rapidly absorbs and releases nitric oxide, enabling redistribution of NO without inhibiting its synthesis and improving the balance of NO to favor reversal or inhibition of organ damage.
Administration of the PN composition can improve organ function in MODS patients, as demonstrated by observed increases in blood pressure and oxygenation and reductions in markers of organ failure after infusion.
The composition allows for effective uptake and transport of hydrophobic gases such as oxygen and nitric oxide, surpassing the solubility capabilities of water-based solutions.
The PN compositions can be engineered for stability, enabling storage at room temperature for extended periods without significant particle coalescence.
PN compositions can be customized to include anti-inflammatory, immunomodulatory, oncotic, or crystalloid agents, providing versatility in addressing various clinical needs in MODS.
Documented Applications
Treating or preventing multiple organ dysfunction syndrome (MODS) in patients, including MODS caused by sepsis, trauma, burns, pancreatitis, aspiration syndromes, extracorporeal circulation, multiple blood transfusion, ischemia-reperfusion injury, autoimmune disease, heat-induced illness, eclampsia, or poisoning/toxicity.
Treating MODS induced by sepsis caused by flu virus or coronavirus infections, including COVID-19, SARS, and MERS.
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