Compositions and methods for treating or preventing multiple organ dysfunction syndrome

Abstract

The 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 lipid bilayers and / or other particle configurations, which are capable of taking up nitric oxide and releasing it with enhanced rapidity, shifting the nitric oxide balance from one that worsens organ damage and reduces survival to one that reverses and / or inhibits organ damage and increases survival.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 004,769, filed April 3, 2020. The entirety of the aforementioned application is incorporated herein by reference.

[0002] The technical field is medical treatment, particularly methods and compositions for treating multiple organ dysfunction syndrome (MODS). [Background technology]

[0003] Multiple organ dysfunction syndrome (MODS) is a failure of multiple organs in the body requiring intensive medical intervention. MODS is a major cause of morbidity and mortality in current ICU practice. MODS can be caused by a wide variety of factors, including major trauma, burns, eclampsia, sepsis, pancreatitis, aspiration syndrome, extracorporeal circulation (e.g., cardiac bypass), multiple blood transfusions, ischemia-reperfusion injury, autoimmune disease, heat-induced illness, or intoxication / toxicity. MODS is strongly associated with widespread inflammation. However, anti-inflammatory agents have failed to demonstrate efficacy in treating MODS. A clear, single cause of MODS has not been identified.

[0004] Management of MODS attempts to address the initiating cause and provide intensive support specific to each vital organ's failure. The lungs are supported by a ventilator, which increases oxygen delivery to the lungs. The kidneys are supported by dialysis. The heart is supported by pharmacological agents or devices that increase cardiac output. There is no routine support for liver failure at this time, other than perhaps existing experimental protocols.

[0005] Some attempts to reverse vascular dysfunction have focused on treating the hypotension (low blood pressure) and / or reducing the high levels of nitric oxide (NO) typically seen in patients with septic shock. Excessive production of NO causes vasodilation and a decrease in blood pressure. However, simply increasing blood pressure does not automatically lead to improvement in other organ systems. In fact, administration of Levophed, a vasoconstrictor drug, to treat life-threatening hypotension (low blood pressure) is known to actually worsen organ damage. Similarly, attempts to treat patients with septic shock with the nitric oxide synthase inhibitor 546C88 have been unsuccessful and have actually resulted in increased mortality and multiple organ failure.

[0006] In patients with MODS, the blood's responsiveness to vasopressor drugs, which constrict blood vessels and increase blood pressure, is significantly reduced. Furthermore, cardiac contractility is reduced. Other vasoactive drugs, such as dobutamine, which increase cardiac contractility, or other drugs that act through other mechanisms, also fail to reverse the adverse effects of MODS. When a patient dies, they lose responsiveness to vasopressor drugs, and their blood pressure falls to nonsurvivable levels. Summary of the Invention [Problem to be solved by the invention]

[0007] In view of the above, there is a need for treatments that improve organ function in patients with MODS. The inventors of the present application have unexpectedly discovered that administration of phospholipid nanoparticle (PN) compositions can prevent or alleviate multiple organ dysfunction syndrome. [Means for solving the problem]

[0008] One aspect of the present application is a method for reducing or preventing multiple organ dysfunction syndrome (MODS) in a subject in need thereof. The method includes administering to the subject in need thereof an effective amount of a phospholipid nanoparticle (PN) composition comprising a lipophilic or hydrophobic component in an amount of 0-35% (w / v), an amphiphilic emulsifier in an amount of 0.1%-60% (w / v), a polar liquid carrier, and one or more electrolytes, wherein the PN composition comprises liposomes and / or micelles having an average diameter of 1-500 nm. In some embodiments, the PN composition comprises a lipophilic or hydrophobic component and an amphiphilic emulsifier in a total amount of 10-50% (w / v).

[0009] Another aspect of the present application is a method of treating multiple organ dysfunction syndrome (MODS) in a subject, comprising administering to a subject in need thereof an effective amount of a phospholipid nanoparticle (PN) composition comprising a lipophilic or hydrophobic component in an amount of 0-35% (w / v), an amphiphilic emulsifier in an amount of 0.6%-60% (w / v), a polar liquid carrier, and one or more electrolytes, wherein the PN composition comprises liposomes and / or micelles having an average diameter of 1-500 nm. In some embodiments, the PN composition comprises a lipophilic or hydrophobic component and an amphiphilic emulsifier in a total amount of 10-50% (w / v).

[0010] In certain embodiments, the lipophilic or hydrophobic component is selected from the group consisting of soybean oil, chia bean oil, algae oil, and silicone oil.

[0011] In certain embodiments, the amphiphilic emulsifier is selected from the group consisting of phospholipids and α-phosphatidylcholine, hi certain embodiments, the amphiphilic emulsifier is selected from the group consisting of egg yolk lecithin, soybean lecithin, and amphiphilic peptides.

[0012] In certain embodiments, the polar liquid carrier is selected from the group consisting of water, aqueous solutions, and non-aqueous polar liquids.

[0013] In certain embodiments, the non-aqueous polar liquid is selected from the group consisting of dimethyl sulfoxide, polyethylene glycol, and polar silicone liquids.

[0014] In certain embodiments, the electrolyte is selected from the group consisting of one or more of sodium chloride, sodium bicarbonate, sodium citrate, sodium lactate, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium glycerophosphate, sodium carbonate, sodium amino acid salts, sodium propionate, sodium hydroxybutyrate, sodium gluconate, potassium chloride, potassium acetate, potassium gluconate, potassium bicarbonate, potassium glycerophosphate, potassium sulfate, potassium lactate, potassium iodide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium citrate, amino acid potassium salts, potassium propionate, potassium hydroxybutyrate, calcium chloride, calcium gluconate, calcium lactate, calcium glycerophosphate, calcium pantothenate, calcium acetate, magnesium chloride, magnesium sulfate, magnesium glycerophosphate, magnesium acetate, magnesium lactate, amino acid magnesium salts, ammonium chloride, zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, zinc acetate, ferrous sulfate, ferrous chloride, ferrous gluconate, copper sulfate, and manganese sulfate.

[0015] In certain embodiments, the PN composition has a concentration of potassium ions in the sub-physiological range of 2-3 mEq / l K+ (2-3 mM).

[0016] In certain embodiments, the PN composition has a concentration of magnesium ions in the sub-physiological range.

[0017] In certain embodiments, the PN composition comprises micelles and liposomes, wherein the micelles in the PN composition have an average diameter in the range of 30-450 nm as measured by electron microscopy, and the liposomes in the PN composition have an average diameter in the range of 1-25 nm as measured by electron microscopy. In certain embodiments, the PN composition comprises micelles and liposomes, wherein the micelles in the PN composition have an average diameter in the range of 15-800 nm as measured by electron microscopy, and the liposomes in the PN composition have an average diameter in the range of 1-300 nm as measured by electron microscopy.

[0018] In certain embodiments, the PN composition is administered either intravenously, intraarterially, intraosseously, or intracardially.

[0019] In certain embodiments, the PN composition is an oxygenated PN composition having an oxygen content of 1-50 ml O2 / 100 ml PN composition.

[0020] In certain embodiments, the PN composition has an emulsifier:lipophilic or hydrophobic component ratio (w / w) of about 1:200 to about 1:1. In certain embodiments, the PN composition has an emulsifier:lipophilic or hydrophobic component ratio (w / w) of about 1:200 to about 1:1.7.

[0021] In certain embodiments, the PN composition further comprises a crystalloid.

[0022] In certain embodiments, the PN composition further comprises a bulking agent.

[0023] In certain embodiments, the PN composition further comprises an anti-inflammatory or immunomodulatory agent.

[0024] In certain embodiments, the PN composition further comprises a lipophilic gas.

[0025] In certain embodiments, the subject has sepsis-induced MODS caused by influenza virus or coronavirus infection. In certain embodiments, the subject has sepsis-induced MODS caused by one or more of the group consisting of major trauma, burns, eclampsia, sepsis, pancreatitis, aspiration syndrome, extracorporeal circulation, cardiac bypass, multiple blood transfusions, ischemia-reperfusion injury, autoimmune disease, heat-induced disease, and intoxication / toxicity.

[0026] Another aspect of the present application is a method of treating multiple organ dysfunction syndrome (MODS) in a subject, comprising administering to a subject in need of treatment an effective amount of a phospholipid nanoparticle (PN) composition comprising soybean oil in an amount of 5% to 35% (w / v), lecithin in an amount of 0.5% to 15% (w / v), sodium chloride and sodium lactate as electrolytes, wherein the total electrolyte composition is 50 mM to 200 mM, histidine in an amount of 0.001 mM to 10 mM, and water, wherein the lecithin forms (1) lipid-loaded micelles having a lipophilic or hydrophobic core in aqueous solution, the resulting micelles having an average diameter in the range of 30 to 500 nm as determined by electron microscopy, and (2) liposomes having an average diameter in the range of 1 to 500 nm as determined by electron microscopy, the lipid-loaded micelles being stable at room temperature for at least 4 weeks. In certain embodiments, the PN composition further comprises oxygen. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 shows nitric oxide uptake by water (Panel A) and PN compositions (Panel B) measured by mass spectrometry. DETAILED DESCRIPTION OF THE INVENTION

[0028] Reference will now be made in detail to certain aspects and exemplary embodiments of the present application, examples of which are shown in the accompanying structures and figures. Aspects of the present application will be described in conjunction with exemplary embodiments, including methods, materials, and examples; such description is non-limiting, and the scope of the present application is intended to encompass all equivalents, alternatives, and modifications that are commonly known or incorporated herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Those skilled in the art will recognize many techniques and materials similar or equivalent to those described herein, which can be used in the practice of aspects and embodiments of the present application. The described aspects and embodiments of the present application are not limited to the methods and materials described.

[0029] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0030] Ranges may be expressed herein as from "about" one particular value, and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each range are significant in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are several values ​​disclosed herein, and that each value is also disclosed herein as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, "about 10" is also disclosed. As will be appreciated by those of ordinary skill in the art, when a value is disclosed, it is understood that "less than or equal to," "greater than or equal to," and possible ranges between values ​​are also disclosed. For example, if the value "10" is disclosed, "less than or equal to 10" and "greater than or equal to 10" are also disclosed.

[0031] The term "acute critical illness" is meant to include any condition that causes a patient to require immediate intensive care. This condition may be caused by an acute and widespread insult to the body, including, but not limited to, physical trauma, burn trauma, infection (herein sepsis, severe sepsis, septic shock), systemic inflammatory response syndrome (SIRS), acute myocardial infarction, or other thromboembolic event.

[0032] The term "intensive care", also referred to herein as "organ support therapy", may include, but is not limited to, ventilation therapy (e.g., mechanical ventilation), hemodialysis, vasopressor therapy, fluid therapy, transfusion therapy involving administration of red blood cell concentrates, fresh frozen plasma, platelet concentrates, whole blood or clotting factor concentrates, systemic antibiotic and / or antiviral and / or antifungal and / or antiprotozoal therapy, parenteral nutrition, granulocyte infusions, T cell infusions, stem cell infusions, anticoagulants and / or antithrombotic therapy including low molecular weight heparins, administration of corticosteroids, strict glycemic control, and the like.

[0033] The term "trauma" as used herein means any shock or bodily injury resulting from sudden physical insult such as blast trauma, blunt trauma, penetrating trauma, trauma caused by chemical injury (spills, war or poisoning), accident, injury or impact to living tissue caused by external causes such as radiation or burns.

[0034] The term "shock" is used in its traditional clinical sense: it is a medical emergency in which the body's organs and tissues do not receive sufficient blood flow. This deprives the organs and tissues of oxygen (carried in the blood) and allows waste products to accumulate. Shock is caused by five major categories of problems: cardiogenic (meaning problems related to the function of the heart), hypovolemic / hemorrhagic (meaning that the total volume of the intravascular space is low due to fluid loss from the intravascular space or vasodilation, resulting in a low fluid volume in the circulatory system in either an absolute or relative sense), neurogenic (caused by severe injury to the central nervous system), septic (caused by an overwhelming infection, usually bacterial), or anaphylactic / allergic (caused by systemic histamine release from immune cells and excessive vasodilation).

[0035] As used herein, the terms "treatment" and "treating" refer to the management and care of a patient who has or is at risk of developing multiple organ dysfunction syndrome (MODS). This term is intended to encompass the full range of treatments for this condition, such as administration of the phospholipid nanoparticle compositions of the present application for the purpose of reducing the risk of or preventing a condition, disease, or disorder, including ameliorating, alleviating, or alleviating symptoms or complications, slowing the progression of the condition, disease, or disorder, curing or eliminating the condition, disease, or disorder, and / or preventing the recurrence of the disease, where "preventing" or "prevention" should be understood to refer to the management and care of a patient for the purpose of preventing the onset of the condition, disease, or disorder, including administration of a PN composition to prevent the onset of symptoms or complications. The individual being treated is a human. Individuals treated according to the present application may be of various ages and / or genders.

[0036] The term "organ failure" refers to altered organ function in acutely ill patients requiring medical intervention to achieve body homeostasis and / or compensate for the loss of function from that failing organ, including, but not limited to, the heart and blood vessels (heart failure, vascular collapse, hypotension, organ failure), lungs (respiratory failure), liver (hepatic failure), kidneys (renal failure), and brain (encephalopathy).

[0037] The term "multiple organ dysfunction syndrome" (abbreviated as MODS) refers to pathologically altered function of multiple organs in acutely ill patients, requiring intervention to achieve homeostasis and / or compensate for the loss of function from dysfunctional organs. The primary cause is an uncontrolled inflammatory response. In both surgical and non-surgical patients, sepsis is the most common cause. Sepsis can lead to septic shock. In the absence of infection, a sepsis-like disorder is called systemic inflammatory response syndrome (SIRS). Both SIRS and sepsis can ultimately progress to MODS. However, in one-third of patients, no primary cause can be identified. MODS is well established as the final stage on a continuum ranging from SIRS to sepsis, severe sepsis, and MODS. It should be noted that MODS differs from reperfusion injury. During reperfusion, there is a period of no or reduced blood flow. Once blood flow is restored, reperfusion injury results from reactive oxygen species. Scavengers of reactive oxygen species can protect against reperfusion injury. However, such scavengers do not protect against MODS. MODS can occur even when blood flow is not interrupted. The present application provides methods for removing sepsis and other inducers of MODS. For example, the methods of the present application may be used to treat MODS induced by sepsis caused by influenza virus or coronavirus (e.g., SARS, MERS, and COVID19 viruses (including variants)) infection, as well as bacterial, parasitic, and fungal infections.

[0038] The term "sepsis" is used in its traditional clinical sense to refer to a systemic inflammatory state (called systemic inflammatory response syndrome (SIRS)) and the presence of a known or suspected infection. "Severe sepsis" is defined as sepsis-induced organ dysfunction or tissue hypoperfusion (e.g., manifested as decreased blood pressure, elevated lactate, decreased urine output, or altered mental status). "Septic shock" is severe sepsis plus persistent hypotension despite administration of intravenous fluids. Sepsis can lead to severe sepsis, septic shock, multiple organ dysfunction syndrome / multiple organ failure (MODS), and death.

[0039] The term "systemic inflammatory response syndrome" or "SIRS" is used in its traditional clinical sense to refer to systemic inflammation in response to injury without a confirmed infectious process. SIRS can be diagnosed when two or more of the following criteria are present: 1) body temperature less than 36°C (96.8°F) or more than 38°C (100.4°F), 2) a heart rate greater than 90 beats per minute, 3) tachypnea (high respiratory rate) greater than 20 breaths per minute or an arterial carbon dioxide partial pressure less than 4.3 kPa (32 mmHg), and 4) an arterial blood carbon dioxide partial pressure of 4000 cells / mm 3 (4×10 9 cells / L) or less than 12,000 cells / mm 3 (12×10 9 White blood cell count > 100 cells / L or presence of > 10% immature neutrophils (band morphology). If infection is suspected or proven (by culture, staining, or polymerase chain reaction (PCR)), along with SIRS, this is sepsis by definition.

[0040] The term "systemic inflammation" refers to altered organ function in acutely ill patients due to a non-specific, preserved response of the body (vasculature, immune system, tissues) to infection, non-infectious antigens, trauma, burns, organ / tissue destruction / degeneration / injury, ischemia, hemorrhage, poisoning, and / or malignancy.

[0041] The terms "micelle" and "lipid-loaded micelle (LM)" are used interchangeably herein to refer to aggregates of molecules dispersed in a liquid, including aggregates having hydrophilic "head" regions in contact with the surrounding solvent that isolate a central hydrophobic single tail region of the micelle that forms a hydrophobic core suitable for containing and delivering hydrophobic substances.

[0042] As used herein, the term "liposome" refers to a vesicular structure composed of lipids with hydrophilic head groups and tail groups containing long hydrophobic hydrocarbon chains, arranged to form a lipid bilayer with an internal aqueous core environment suitable for containing and delivering aqueous substances, and a lipid wall suitable for containing hydrophobic substances, particularly gases such as oxygen.

[0043] Treatment method One aspect of the present application relates to a method of treating or preventing multiple organ dysfunction syndrome (MODS) in a patient, the method comprising administering to a subject an effective amount of a phospholipid nanoparticle (PN) composition, the PN composition comprising the PN composition of the present application. The inventors of the present application have unexpectedly discovered that administration of the PN composition of the present application can prevent or alleviate multiple organ dysfunction syndrome (MODS).

[0044] The PN compositions of the present application may be used to treat or prevent MODS caused by several different disease states affected by tissue injury, including, but not limited to, sepsis, major trauma, burns, pancreatitis, aspiration syndrome, extracorporeal circulation (e.g., cardiac bypass), multiple blood transfusions, ischemia-reperfusion injury, autoimmune disease, heat-induced disease, eclampsia, and intoxication / toxicity. In some embodiments, the PN compositions of the present application are used to treat or prevent MODS resulting from sepsis caused by influenza virus or coronavirus (e.g., SARS, MERS, and COVID-19 viruses) infection.

[0045] In one embodiment, the method comprises administering a PN composition of the present application in an amount effective to provide reversible uptake and release of nitric oxide in the treatment or prevention of MODS. The present application seeks to address the negative consequences associated with nitric oxide (NO) overproduction by providing a PN composition that promotes more effective redistribution of NO. Excessive production of NO causes vasodilation and a decrease in blood pressure. Patients with MODS or at risk of developing MODS have a significantly reduced blood responsiveness to vasopressor medications such as Levophed, vasopressin, or epinephrine, which constrict blood vessels and increase blood pressure.

[0046] Nitric oxide synthase (NOS) is an enzyme that catalyzes the conversion of arginine to NO. Previously, an NOS inhibitor (546C88) was tested to alleviate the problems caused by NO overproduction. However, this study was terminated prematurely due to increased mortality (Lopez et al., Crit. Care Med. 2004, Vol. 32, No. 1, pp. 21-30). The main problem with inhibiting NOS is that NO is required to maintain vascular patency. Therefore, removing NO increases blood pressure but also reduces tissue perfusion, promoting organ failure. Another problem with inhibiting NOS is its role in facilitating mitochondrial electron transport and ATP production. However, it is known that NOS inhibition reduces mitochondrial oxygen consumption rate and ATP production, potentially leading to mitochondrial oxidative stress and irreversible damage.

[0047] Without wishing to be bound by theory, it is believed that the PN compositions of the present application contain a variable reservoir of nitric oxide that may take up or release nitric oxide in a manner that varies with the local concentration of nitric oxide to provide more effective management of NO, which is predicted based in part on the fact that both NO and the phospholipid nanoparticle (PN) compositions of the present application are hydrophobic.

[0048] In this case, NO preferentially localizes to the hydrophobic regions of PN compared to the aqueous environment of blood. Figure 1 shows the uptake and release of NO in water and the PN composition of the present application as measured by mass spectrometry. The experimental procedure is described in Example 8.

[0049] Unlike nitric oxide inhibitors or nitric oxide scavengers, which do not release nitric oxide, PN rapidly releases the nitric oxide it absorbs. This allows PN to act as a nitric oxide redistributor, reducing its bioavailability in areas of overproduction and releasing it to increase nitric oxide concentrations in areas of insufficient levels, thereby shifting the nitric oxide balance from one favorable to nonsurvival to one favorable to survival. PN and its analogs, in contrast to inhibitors and scavengers, can be considered a new class of therapeutic agents called nitric oxide redistributors.

[0050] Therefore, infusion of PN into the bloodstream is thought to allow for the uptake of overproduced NO, which would otherwise be readily released in areas where local concentrations are insufficient. In other words, the PN composition serves to reduce the bioavailability of NO without affecting its biosynthesis or paracrine / autocrine effects. Reducing overproduced nitric oxide can also reduce the production of peroxynitrite, a highly reactive free radical that is the product of the reaction between nitric oxide and superoxide. In some embodiments, the PN composition is infused into patients with MODS to achieve a mean blood pressure of 60-65 mHg or other appropriate blood pressure goal as required by the clinical situation.

[0051] In some embodiments, patients receiving the PN compositions of the present application have been or are being treated with a vasopressor (also called a vasoactive agent). Examples of vasopressors and vasoactive agents include, but are not limited to, Levophed, vasopressin and epinephrine, Giapreza, phenylephrine, dopamine, and dobutamine.

[0052] The PN compositions of the present application may be administered intravenously, intraarterially, intraosseously, or intracardially to a subject in need of such treatment. In certain embodiments, the PN compositions are administered in the range of 50-5000 ml, 50-4000 ml, 50-3000 ml, 50-2000 ml, 50-1000 ml, 50-500 ml, 100-5000 ml, 100-4000 ml, 100-3000 ml, 100-2000 ml, 100-1000 ml, 100-500 ml, 200-5000 ml, 200-4000 ml, 200-4000 ml, 200-5000 ml, 200-4000 ml, 200-5000 ml, 200-5000 ml, 200-6000 ml, 200-6000 ml, 200-7000 ml, 200-7000 ml, 200-8000 ml, 200-8000 ml, 200-9000 ml, 200-9000 ml, 200-1000 ml, 200-1000 ml, 200-1000 ml, 200-2000 ml, 200-3000 ml, 200-3000 ml, 200-4000 ml, 200-5 ...6000 ml, 200-7000 ml, 200-8000 ml, 200- In some embodiments, the PN composition is administered in an amount equal to about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the subject's normal blood volume over a period of 30 seconds to 24 hours.

[0053] In certain embodiments, the PN composition is administered at a rate of 0.1-5000 ml / min, 0.1-2000 ml / min, 0.1-1000 ml / min, 0.1-500 ml / min, 0.1-200 ml / min, 0.1-100 ml / min, 0.1-50 ml / min, 0.1-20 ml / min, 0.1-10 ml / min, 0.1-5 ml / min, 0.1-2 ml / min, 0.1~1ml / min, 1~5000ml / min, 1~2000ml / min, 1~1000ml / min, 1~500ml / min, 1~200ml / min, 1~100ml / min, 1~50ml / min, 1~20ml / min, 1~10ml / min, 1~5ml / min, 1~2ml / min, 2~5000ml / min, 2~2000ml / min, 2~1000ml / min, 2~500ml / min, 2~200ml / min, 2~100ml / min, 2~50ml / min, 2~20ml / min, 2~10ml / min, 2~5ml / min, 5~5000ml / min, 5~2000ml / min, 5~1000ml / min, 5~500ml / min, 5~200ml / min, 5~100ml / min, 5~50ml / min, 5~20ml / min, 5~10ml / min, 10~5000ml / min, 10~4000ml / min, 10~3000ml / min, 10~2000ml / min, 10~1000ml / min, 10~500 ml / min. 00ml / min. , 100~4000ml / min, 100~3000ml / min, 100~2000ml / min, 100~1000ml / min, 100~500ml / min, 100~200ml / min, 200~5000ml / min, 200~4000ml / min, 200~3000ml / min, 200~200 The rates are given as 0ml / min, 200-1000ml / min, 200-500ml / min, 500-5000ml / min, 500-4000ml / min, 500-3000ml / min, 500-2000ml / min, 500-1000ml / min, 1000-5000ml / min, 1000-4000ml / min, 1000-3000ml / min, 1000-2000ml / min, 2000-5000ml / min, 2000-4000ml / min, 2000-3000ml / min, 3000-5000ml / min, 3000-4000ml / min or 4000-5000ml / min.

[0054] In yet other embodiments, the PN composition is administered at a rate of about 500-700 ml / min, 400-800 ml / min, or 300-900 ml / min.

[0055] In some embodiments, the PN composition is administered without oxygenation. In other embodiments, the PN composition is an oxygenated PN composition. In some embodiments, the PN composition is an oxygenated PN composition having an oxygen content of 2-50, 2-40, 2-30, 2-20, 2-10, 2-5, 5-50, 5-40, 5-30, 5-20, 5-10, 10-50, 10-40, 10-30, 10-20, 15-50, 15-40, 15-30, 15-20, 20-50, 20-40, 20-30, 25-50, 25-40, 25-30, 30-50, 30-40, or 40-50 ml O2 / 100 ml PN composition.

[0056] Other hemodynamic parameters such as brain, kidney, heart, muscle, spleen or other tissue perfusion, cardiac output, systolic blood pressure, diastolic blood pressure, mean arterial pressure, stroke volume index, mitochondrial oxidative phosphorylation followed by near-infrared spectroscopy or other means, blood lactate or membrane polarization may be used to determine the "effective amount" of a PN composition required to increase blood pressure in a subject.

[0057] While the PN compositions of the present application are administered to a subject and circulating through the subject, various agents, such as cardioplegic or inotropic agents, may be administered directly to the subject's circulatory system, directly to the subject's myocardium, or added to the PN compositions of the present application to achieve a desired physiological effect, such as maintaining regular cardiac contractile activity, terminating cardiac fibrillation, or completely inhibiting myocardium or heart muscle contractile activity.

[0058] Cardioplegics are materials that stop myocardial contractions and include anesthetics such as lidocaine, procaine, and novocaine, and monovalent cations such as potassium ions at concentrations sufficient to achieve myocardial contraction inhibition, generally greater than 15 mM.

[0059] Phospholipid Nanoparticle (PN) Composition In one embodiment, a PN composition for treating or preventing MODS comprises a lipophilic or hydrophobic component, one or more amphiphilic emulsifiers, a polar liquid carrier, and one or more electrolytes. The amphiphilic emulsifiers form lipophilic or hydrophobic-loaded micelles (LMs) having a lipophilic core surrounded by a polar liquid carrier and / or liposomes containing a lipid bilayer and a hydrophilic interior (or core).

[0060] In some embodiments, the PN compositions of the present application comprise LMs and liposomes having diameters of 1 to 500 nm, 1 to 400 nm, 1 to 300 nm, or 1 to 200 nm, as determined by electron microscopy.

[0061] In some embodiments, the PN compositions of the present application have a particle size of (1) 30-500 nm, 30-400 nm, 30-300 nm, 30-200 nm, 30-150 nm, 30-120 nm, 30-100 nm, 30-80 nm, 30-500 nm, 30-400 nm, 30-300 nm, 30-200 nm, 30-300 nm, 30-400 nm, 30-500 nm, 30-600 nm, 30-600 nm, 30-700 nm, 30-800 nm, 30-900 nm, 30-1000 nm, 30-1200 nm, 30-1500 nm, 30-1200 nm, 30-1000 nm, 30-10 0~150nm, 30~120nm, 30~100nm, 30~80nm, 40~500nm, 40~400nm, 40~300nm, 40~200nm, 40~150 nm, 40~120nm, 40~100nm, 40~80nm, 50~500nm, 50~400nm, 50~300nm, 50~200nm, 50~150nm, 50 (2) LMs having a diameter of 1 to 120 nm, 50 to 100 nm, 50 to 80 nm, 100 to 500 nm, 100 to 400 nm, 10 to 300 nm, 100 to 200 nm, 100 to 150 nm, or 100 to 120 nm, and (3) liposomes having a diameter of 1 to 30 nm, 1 to 25 nm, 1 to 20 nm, 1 to 15 nm, 1 to 10 nm, 3 to 30 nm, 3 to 25 nm, 3 to 20 nm, 3 to 15 nm, 3 to 10 nm, 5 to 30 nm, 5 to 25 nm, 5 to 20 nm, 5 to 15 nm, 5 to 10 nm, 1 to 30 nm, 7 to 25 nm, 7 to 20 nm, 7 to 15 nm, 7 to 10 nm, 10 to 30 nm, 10 to 25 nm, 10 to 20 nm, or 10 to 15 nm, as determined by electron microscopy.

[0062] In some embodiments, the PN compositions of the present application have a particle size of 1-100 nm, 1-80 nm, 1-50 nm, 1-40 nm, 1-30 nm, 1-25 nm, 1-20 nm, 1-15 nm, 1-10 nm, 1-5 nm, 5-100 nm, 5-80 nm, 5-50 nm, 5-40 nm, 5-30 nm, 5-25 nm, 5-20 nm, 5-15 nm, 5-10 nm, 10-100 nm, 10-80 nm, 10-50 nm, 10-40 nm, 10-30 nm, 10-25 nm, 10-20 nm, 15-100 nm, 15-80 nm, In some embodiments, the PN compositions of the present application comprise nanoparticles (including both micelles and liposomes) having an average particle size of 15-50 nm, 15-40 nm, 15-30 nm, 15-25 nm, 15-20 nm, 20-100 nm, 20-80 nm, 20-50 nm, 20-40 nm, 20-30 nm, 20-25 nm, 25-100 nm, 25-80 nm, 25-50 nm, 25-40 nm, 25-30 nm, 30-100 nm, 30-80 nm, 30-50 nm, 30-40 nm, 40-100 nm, 40-80 nm, 40-50 nm, 50-100 nm, 50-80 nm, or 80-100 nm. In some embodiments, the PN compositions of the present application comprise nanoparticles having an average particle size of 16-18 nm, 15-19 nm, or 14-20 nm, as determined by electron microscopy.

[0063] In some embodiments, the PN compositions of the present application have a particle size distribution of 10-300 nm, 10-200 nm, 10-150 nm, 10-120 nm, 10-100 nm, 10-90 nm, 10-70 nm, 10-50 nm, 10-30 nm, 30-300 nm, 30-200 nm, 30-150 nm, 30-120 nm, 30-100 nm, 30-90 nm, 30-70 nm, 30-50 nm, 50-300 nm, 50-200 nm, 50-150 nm, 50-120 nm, 50-100 nm, 50-90 nm, 50-70 nm, 70-30 ... Nanoparticles (including both micelles and liposomes) having an average diameter of 00 nm, 70 to 200 nm, 70 to 150 nm, 70 to 120 nm, 70 to 100 nm, 70 to 90 nm, 80 to 300 nm, 80 to 200 nm, 80 to 150 nm, 80 to 120 nm, 80 to 100 nm, 80 to 90 nm, 90 to 300 nm, 90 to 200 nm, 90 to 150 nm, 90 to 120 nm, 90 to 100 nm, 100 to 300 nm, 100 to 200 nm, 100 to 150 nm, 100 to 120 nm, 120 to 300 nm, 120 to 200 nm, 120 to 150 nm, 150 to 300 nm, 150 to 200 nm, or 200 to 300 nm. In some embodiments, the PN compositions of the present application comprise nanoparticles having an average particle size of 92-96 nm, 90-98 nm, or 85-105 nm.

[0064] Lipophilic or hydrophobic components are dispersed in a polar liquid carrier to form nanoemulsions containing unilamellar micelles with polar exteriors and internal hydrophobic spaces filled with lipophilic or hydrophobic components and / or other hydrophobic molecules, and bilayer liposomes with polar exteriors and internal hydrophilic spaces. Because hydrophobic gases such as oxygen and nitric oxide (NO) preferentially dissolve in the lipid core of micelles compared to water or other aqueous environments, the PN compositions of the present application provide the ability to deliver oxygen and other hydrophobic gases to body tissues.

[0065] The solubility of hydrophobic gases in the lipophilic or hydrophobic core facilitates the uptake and transport of these gases into tissues. The endogenously produced gases carbon monoxide, nitric oxide, and hydrogen sulfide can also be carried in emulsions for the regulation of vascular tone and apoptotic processes.

[0066] In some embodiments, the PN composition is an oxygenated PN composition that promotes aerobic metabolism, ie, has an oxygen content of 1-50, 1-40, 1-30, 1-20, 1-10, 1-5, 1-2, 2-50, 2-40, 2-30, 2-20, 2-10, 2-5, 5-50, 5-40, 5-30, 5-20, 5-10, 10-50, 10-40, 10-30, 10-20, 15-50, 15-40, 15-30, 15-20, 20-50, 20-40, 20-30, 25-50, 25-40, 25-30, 30-50, 30-40, or 40-50 ml O2 / 100 ml PN composition.

[0067] In some embodiments, the PN composition comprises NO in an amount of 1-50, 1-40, 1-30, 1-20, 1-10, 1-5, 1-2, 2-50, 2-40, 2-30, 2-20, 2-10, 2-5, 5-50, 5-40, 5-30, 5-20, 5-10, 10-50, 10-40, 10-30, 10-20, 15-50, 15-40, 15-30, 15-20, 20-50, 20-40, 20-30, 25-50, 25-40, 25-30, 30-50, 30-40, or 40-50 ml of NO / 100 ml of PN composition.

[0068] Xenon and argon are hydrophobic gases that can protect the brain during pathological conditions such as stroke. In some embodiments, the PN composition includes Xe or Ar, or both, in an amount of 1-50, 1-40, 1-30, 1-20, 1-10, 1-5, 1-2, 2-50, 2-40, 2-30, 2-20, 2-10, 2-5, 5-50, 5-40, 5-30, 5-20, 5-10, 10-50, 10-40, 10-30, 10-20, 15-50, 15-40, 15-30, 15-20, 20-50, 20-40, 20-30, 25-50, 25-40, 25-30, 30-50, 30-40, or 40-50 ml O / 100 ml PN composition.

[0069] In some embodiments, the PN compositions of the present application further comprise an inhibitor of apoptosis (e.g., the apoptosis inhibitor peptide Z-VAD-FMY), a protector of mitochondrial integrity (e.g., cyclosporin A, an inhibitor of mitochondrial pore opening), a modulator of signal transduction such as diacylglycerol or cyclic GMP, or an antioxidant such as coenzyme Q10.

[0070] When PN containing liposomes with an average diameter of less than 30 nm is used, the liposomes can cross the endothelial cell layer and enter the interstitial space. Such liposomes may be used in situations where the permeability of the vascular space is not increased, or to promote cellular uptake of lipophilic or hydrophobic mediators, or to promote the entry of molecules or cellular components that can beneficially modulate intracellular mechanisms.

[0071] In certain cases, the PN compositions of the present application can exert osmotic power and absorb mediators of tissue injury, such as prostaglandins, nitric oxide, leukotrienes, and thromboxanes, as well as other lipophilic or hydrophobic mediators, such as platelet-activating factor. Therefore, in some cases, the PN of the present application can absorb toxic molecules produced by MODS patients. For example, lymphatic factors produced in the intestinal and thoracic duct lymph nodes can lead to acute lung injury and red blood cell deformability. Other toxic molecules include, but are not limited to, leukotrienes, prostaglandins, nitric oxide, endotoxin, and tumor necrosis factor (TNF). The PN in the PN composition allows for the effective absorption of lipophilic or hydrophobic chemical mediators. In other cases, the PN may be loaded with an antagonist against the toxic chemical mediator, such as an antibody against endotoxin.

[0072] In patients with MODS, for example, who have increased vascular wall permeability caused by capillary leakage, the small size of the phospholipid nanoparticles (PNs) described above facilitates their entry into the interstitial space, which would otherwise be restricted by larger structures. Capillary leakage is caused by endothelial cell death and the action of neutrophils, which are mediated by cytokines such as IL-1 and TNF, as well as nitric oxide. Neutrophils adhere to damaged endothelial cells and release reactive oxygen species and cell wall-damaging enzymes such as myeloperoxidase. PNs can enter the interstitium via capillary leakage and provide, for example, anti-inflammatory effects within the interstitial space.

[0073] Preferably, the PN composition is formulated to contain LMs and / or liposomes that are stable at room temperature (e.g., 25°C) or 5°C for at least 3 days, 7 days, 2 weeks, 4 weeks, 12 weeks, 20 weeks, 180 days, 30 weeks, 40 weeks, 1 year, or more. Stability may be determined by measuring the change in micelle diameter. Unstable emulsions will have micelles that coalesce to form micelles of larger diameter. In certain preferred embodiments, the PN composition is stable at room temperature for at least 4 weeks.

[0074] In some embodiments, the PN composition is formed from soybean oil in an amount of 5%-40% (w / v) and lecithin in an amount of 0.1%-18% (w / v). In some embodiments, the PN composition further comprises NaCl at a final concentration of 50-200 mM. In some embodiments, the PN composition further comprises glycerin in an amount of 1-5%. In one embodiment, the PN composition comprises 10% (w / v) soybean oil, 0.6% (w / v) egg lecithin, 1.13% (w / v) glycerin, and 77 mM NaCl. In another embodiment, the PV composition comprises 20% (w / v) soybean oil, 1.2% (w / v) egg lecithin, and 2.25% (w / v) egg lecithin. In another embodiment, the PV composition comprises 20% (w / v) soybean oil, 1.2% (w / v) egg lecithin and 2.25% (w / v) egg lecithin and 77 mM NaCl.

[0075] In some embodiments, the composition is comprised of soybean oil in an amount of 10% to 40% (w / v), preferably 15% to 35%, lecithin in an amount of 6% to 18% (w / v), preferably 10% to 15%, sodium chloride and sodium lactate as electrolytes, with a total electrolyte composition of 50 mM to 200 mM, histidine in an amount of 0.1 mM to 10 mM, and water, such that the lecithin forms (1) lipid-loaded micelles having a lipophilic or hydrophobic core in aqueous solution, the resulting micelles having an average diameter of 70 to 150 nm, preferably 90 nm to 120 nm, as determined by dynamic light scattering, and stable at room temperature for at least 4 weeks, and (2) liposomes having a diameter in the range of 1 to 25 nm, as determined by electron microscopy.

[0076] In another embodiment, the PN composition comprises 10-40% (w / v) soybean oil and 6-18% (w / v) egg lecithin or soybean lecithin. In some embodiments, the PN composition further comprises 0.6% (w / v) NaCl, 0.385% (w / v) sodium lactate, and 0.155% (w / v) histidine. In some embodiments, the PN composition comprises 20-30% (w / v) soybean oil, 12% (w / v) egg lecithin or soybean lecithin, 0.6% (w / v) NaCl, 0.385% (w / v) sodium lactate, and 0.155% (w / v) histidine.

[0077] In another embodiment, the PN composition comprises 20% (w / v) soybean oil, 12% (w / v) egg lecithin or soybean lecithin, 0.6% (w / v) NaCl, 0.385% (w / v) sodium lactate (L), and 0.155% (w / v) histidine, prepared under conditions to form nanoparticles (including liposomes and micelles) having an average diameter of 80-120 nm as measured by dynamic light scattering. In some embodiments, the nanoparticles include liposomes having a diameter in the range of 1-25 nm or 7-20 nm as measured by electron microscopy, and micelles having a diameter in the range of 30-130 nm or 40-100 nm as measured by electron microscopy.

[0078] In another embodiment, the PN composition comprises 30% (w / v) soybean oil, 12% (w / v) egg lecithin or soybean lecithin, 0.6% (w / v) NaCl, 0.385% (w / v) sodium lactate (L), and 0.155% (w / v) histidine, prepared under conditions to form nanoparticles (including liposomes and micelles) having an average diameter of 80-120 nm as measured by dynamic light scattering. In some embodiments, the nanoparticles comprise liposomes having a diameter in the range of 1-25 nm or 7-20 nm as measured by electron microscopy, and micelles having a diameter in the range of 30-130 nm or 40-100 nm as measured by electron microscopy.

[0079] Other oils, such as oils from chia beans, pumpkin seeds, or other sources, may also be used. In certain embodiments, the PN compositions described above may further comprise about 2-40% (w / v), about 2-20% (w / v), about 4-10% (w / v), or about 5% (w / v) of albumin or albumin polymers or albumin polymers conjugated to amino acids or peptides, which are added to the PN composition after micelle formation. In other embodiments, the hydrophobic or hydrophilic components are carried within the red blood cell ghosts.

[0080] In certain embodiments, the LM comprises 10-40% (w / w) of the PN composition and the liposomes comprise 5-30% (w / w) of the PN composition. In some embodiments, the LM is made using soybean oil and the liposomes are made using chia bean oil, which has an anti-inflammatory effect greater than that of soybean oil.

[0081] In certain embodiments, the PN composition of the present application comprises a lipophilic or hydrophobic component selected from the group consisting of soybean oil, chia bean oil, and algal oil, an emulsifier selected from the group consisting of phospholipids and α-phosphatidylcholine, and an amino acid or n-acetyl amino acid at a final concentration of 0.2-20 mM, 0.5-10 mM, 0.5-5 mM, or 0.5-2 mM.

[0082] In certain embodiments, the PN composition has a final amino acid concentration of 0.001-10 mM, 0.01-10 mM, 0.1-10 mM, 0.2-10 mM, 0.5-10 mM, 1-10 mM, 2.5-10 mM, 5-10 mM, or 7.5-10 mM. In certain embodiments, the PN composition has a final amino acid concentration of 0.001, 0.01, 0.1, 0.2, 0.5, 1, 2.5, 5, 7.5, or 10 mM. The emulsifier:lipophilic or hydrophobic component ratio (w / w) may range from about 1:400 to about 1:1, preferably from about 1:200 to about 1:50. In one embodiment, the emulsifier:lipophilic or hydrophobic component ratio (w / w) is about 1:100. In another embodiment, the emulsifier:lipophilic or hydrophobic component ratio (w / w) is about 1.2:100.

[0083] In some embodiments, the PN composition consists essentially of liposomes and does not include lipophilic or hydrophobic components, such as soybean oil.

[0084] In some embodiments, the PN composition comprises one or more active pharmaceutical ingredients or drugs (e.g., nucleic acids, proteins, small molecule drugs, etc.) in the LMs and / or liposomes. The active pharmaceutical ingredients or drugs can be incorporated into the lipophilic or hydrophobic core of the LMs or liposomes or the hydrophilic core of the liposomes.

[0085] In one embodiment, the PN composition comprises soybean oil, egg phospholipids, and an amino acid, beta-endorphin or other modulator acting at or above femtomolar concentrations at a final concentration of 0.1 femtomolar (fM) to 10 mM.

[0086] The PN compositions of the present application are free of hemoglobin, hemoglobin derivatives, perfluorocarbons, and perfluorocarbon derivatives. As used herein, a composition is "free of hemoglobin, hemoglobin derivatives, perfluorocarbons, and perfluorocarbon derivatives" if it does not contain any hemoglobin, hemoglobin derivatives, perfluorocarbons, and perfluorocarbon derivatives, or if it contains hemoglobin, hemoglobin derivatives, perfluorocarbons, and perfluorocarbon derivatives at a level of less than 0.1% w / v.

[0087] The PN compositions of the present application typically contain Ca ++ , K. + , Mg ++ and Al +++ In certain embodiments, the compound does not contain Ca. ++ and K. + is added to the PN composition immediately prior to use (e.g., within 24 hours prior to use). ++ is premixed with the PN composition. +++ All oils and other ingredients contain the lowest possible amount of Al because it is toxic to bone, brain, hematopoiesis, heme synthesis, globulin synthesis, iron absorption and metabolism, and fetal development.+++ In certain embodiments, the PN composition has an Al concentration of less than 25 mg / L, 20 mg / L, 10 mg / L, or 5 mg / L. +++ In another embodiment, the PN composition contains Al +++ does not contain, i.e., cannot be detected by conventional methods.

[0088] In certain embodiments, the micelles in the PN compositions of the present application are free-floating micelles that are not encapsulated in any kind of particle. Furthermore, the walls of the micelles are composed of either a monolayer or bilayer of amphiphilic emulsifier molecules, allowing the micelles to easily merge with the cell membranes of tissues that come into contact with the PN composition. Furthermore, the micelles in the PN compositions of the present application are free of hemoglobin, hemoglobin derivatives, perfluorocarbons, and perfluorocarbon derivatives.

[0089] Lipophilic or hydrophobic components As used herein, the term "lipophilic component" refers to naturally occurring or non-naturally occurring fat-soluble materials.Examples of lipophilic components include, but are not limited to, fatty acyl, glycerolipid, phospholipid, sphingolipid, sterol lipid, prenol lipid, saccharolipid, polyketide, non-natural lipid(s), cationic lipid(s), amphiphilic alkylamino acid derivative, azialkyldimethylammonium, polyglycerol alkyl ether, polyoxyethylene alkyl ether, tri-n-octylamine, boric acid, tris(3,5-dimethyl-4-heptyl) ester, triglyceride, diglyceride and other acylglycerols, such as tetraglycerol, pentaglycerol, hexaglycerol, heptaglycerol, octoglycerol, nonaglycerol and decaglycerol, hydrophobic peptide, hydrophobic polysaccharide, silicone, lipopeptide, cyclopeptide and mixtures thereof. In certain embodiments, the lipophilic or hydrophobic component comprises soybean oil, chia bean oil, or algae oil.

[0090] In one embodiment, the lipophilic component is soybean oil.The lipophilic component may also be derived from chia beans, which have a high concentration of anti-inflammatory omega-3 fatty acids.Soybean oil is thrombogenic and procoagulant, and therefore would be preferred when clotting is desired.After bleeding is no longer a problem, oils rich in omega-3 fatty acids would be preferred due to their antithrombogenic properties.Oils rich in omega-3 fatty acids include, but are not limited to, chia oil, algae oil, pumpkin oil, flaxseed oil or fish oil.

[0091] In certain embodiments, the lipophilic or hydrophobic component comprises an unsaturated fatty acid having one or more alkenyl functional groups in a cis or trans configuration. The cis configuration means that adjacent hydrogen atoms or other groups are on the same side of the double bond. In the trans configuration, these moieties are on different sides of the double bond. The rigidity of the double bond freezes the conformation, and in the case of the cis isomer, it bends the chain, limiting the conformational freedom of the fatty acid. Generally, the more double bonds a chain has, the less flexible it is. If a chain has many cis bonds, it will be highly curved in its most accessible conformation. For example, oleic acid, which has one double bond, has a "kink" in it, while linoleic acid, which has two double bonds, has a more pronounced bend. α-linolenic acid, which has three double bonds, prefers a hook shape. The effect of this is that in confined environments, such as when fatty acids are part of phospholipids in lipid bilayers or triglycerides in lipid droplets, the cis bonds may limit the ability of fatty acids to pack tightly, thus affecting the melting temperature of the membrane or fat. In some embodiments, the lipophilic or hydrophobic component comprises up to 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% (w / v) unsaturated fatty acid(s) with one or more alkenyl functional groups in the cis configuration.

[0092] Examples of cis-unsaturated fatty acids include cis-unsaturated fatty acids, such as cis-unsaturated fatty acids, ... acid); n-3 unsaturated fatty acids such as α-linolenic acid, stearidonic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid; n-6 unsaturated fatty acids such as linoleic acid, linoelaidic acid, γ-linolenic acid, bis-homo-γ-linolenic acid, and arachidonic acid; conjugated fatty acids such as conjugated linoleic acid and α-eleostearic acid; fatty acids having a double bond at the 5-position such as pinolenic acid, siadonic acid, juniperic acid, and columbic acid; polyunsaturated fatty acids other than those mentioned above, for example, hiragonic acid, moroctic acid, clupanodonic acid, and nishinic acid; branched fatty acids such as isobutyric acid, isovaleric acid, isoacids, and antiisoacids; hydroxy fatty acids such as α-hydroxy acids, β-hydroxy acids, mycolic acids, and polyhydroxy acids; epoxy fatty acids; keto fatty acids; and cyclic fatty acids. In certain embodiments, the lipophilic or hydrophobic component also includes an amphiphilic molecule.

[0093] The lipophilic or hydrophobic component may comprise approximately 1-80%, 1-70%, 1-60%, 1-50%, 1-40%, 1-30%, 1-20%, 5-80%, 5-70%, 5-60%, 5-50%, 5-40%, 5-30%, 5-20%, 10-80%, 10-70%, 10-60%, 10-50%, 10-40%, 10-30%, 10-20%, 15-80%, 15-70%, 15-60%, 15-50%, 15-40%, 15-30%, 15-40%, 15-50%, 15-60%, 15-70%, 15-80%, 15-80%, 15-70%, 15-60%, 15-50%, 15-40%, 15-30%, 15-2 ...40%, 15-30%, 15-20%, 15-40%, 15-30%, 15-40%, 15-40%, 1 The lipophilic or hydrophobic component may comprise 5-20%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30%, 30-80%, 30-70%, 30-60%, 30-50%, 30-40%, 40-80%, 40-70%, 40-60%, 40-50%, 40-80%, 40-70%, 40-60%, 40-30%, 50-80%, 50-70%, 50-60%, 60-80%, 60-70%, or 70-80% (w / v). In certain embodiments, the lipophilic or hydrophobic component comprises about 10%, about 15%, about 20%, about 25%, about 30%, and about 35% (w / v) of the PN composition. In some embodiments, the lipophilic or hydrophobic component comprises 0-35%, 5-35%, 10-35%, 15-35%, 20-35%, 25-35%, 30-35%, 0-30%, 5-30%, 10-30%, 15-30%, 20-30%, 25-30%, 0-25%, 5-25%, 10-25%, 15-25%, 20-25%, 0-15%, 5-15%, or 10-15% (w / v) of the PN composition, or any combination of percent ranges containing integer values ​​selected from the group consisting of 10%, 15%, 20%, 25%, 30%, or 35%. In still other embodiments, the upper and / or lower limits of the lipophilic or hydrophobic component are defined by any of the recited concentrations described herein.

[0094] Amphiphilic emulsifiers An amphiphilic emulsifier can be any amphiphilic substance or molecule whose hydrophobic tail is in the lipophilic or hydrophobic core of the micelle and whose hydrophilic end is in contact with the polar carrier. Examples of emulsifiers are egg phospholipids, pure phospholipids, or amphipathic peptides.

[0095] As used herein, the term "amphiphile" refers to a compound that has both hydrophilic and lipophilic or hydrophobic properties. Examples of amphiphiles include, but are not limited to, naturally occurring amphiphiles, such as phospholipids, cholesterol, glycolipids, fatty acids, bile acids, and saponins, and synthetic amphiphiles, such as peptides.

[0096] Examples of phospholipids include natural or synthetic phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol, isophosphatidylcholine, sphingomyelin, egg yolk lecithin, soybean lecithin, and hydrogenated phospholipids.

[0097] Examples of glycolipids include glyceroglycolipids and glycosphingolipids. Examples of glyceroglycolipids include digalactosyl diglycerides (e.g., digalactosyl dilauroyl glyceride, digalactosyl dimyristoyl glyceride, digalactosyl dipalmitoyl glyceride, digalactosyl distearoyl glyceride) and galactosyl diglycerides (e.g., galactosyl dilauroyl glyceride, galactosyl dimyristoyl glyceride, galactosyl dipalmitoyl glyceride, and galactosyl distearoyl glyceride). Examples of glycosphingolipids include galactosylcerebroside, lactosylcerebroside, and ganglioside.

[0098] Examples of sterols include cholesterol, cholesterol hemisuccinate, 3β-[N—(N′,N′-dimethylaminoethane)carbamoyl]cholesterol, ergosterol, and lanosterol.

[0099] In one embodiment, the emulsifier comprises egg phospholipids or egg yolk lecithin, hi another embodiment, the emulsifier is soy lecithin or alpha-phosphatidylcholine.

[0100] In other embodiments, the emulsifier is 0.1-60%, 0.1-50%, 0.1-40%, 0.1-30%, 0.1-20%, 0.1-15%, 0.1-10%, 0.1-5%, 0.1-2%, 0.3-60%, 0.3-50%, 0.3-40%, 0.3-30%, 0.3-20%, 0.3-15%, 0.3-10%, 0.3-5%, 0.3-2%, 0.6-60%, 0.6-50%, 0.6-40%, 0.6-30%, 0.6-20%, 0.6-15%, 0.6-10%, 0.6-5%, 0.6-2%, 2-60%, 2-50% of the PN composition. %, 2-40%, 2-30%, 2-20%, 2-15%, 2-10%, 2-5%, 6-60%, 6-50%, 6-40%, 6-30%, 6-20%, 6-15%, 6-10%, 10-60%, 10-50%, 10-40%, 10-30%, 10-20%, 10-15%, 15-60%, 15-50%, 15-40%, 15-30%, 15-20%, 20-60%, 20-50%, 20-40%, 20-30%, 30-60%, 30-50%, 30-40%, 40-60%, 40-50%, or 50-60% (w / v). In certain embodiments, the emulsifier is present at a level of about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 18%, about 20% (w / v) of the PN composition, or any other range between any two of these recited integers. In other embodiments, the emulsifier is present at a level of about 7-9%, 9-11%, 11-13%, 13-15%, 15-17%, 17-19%, 10-14%, 9-15%, or 8-16% (w / v) of the PN composition, or any other range between any two of these recited integers. In still other embodiments, the upper and / or lower emulsifier limits are defined by any of the recited concentrations described herein.

[0101] In certain preferred embodiments, the emulsifier is a lecithin such as egg yolk lecithin or soy lecithin in one of the amounts or ranges described above.

[0102] Polar Liquid Carrier The polar liquid carrier can be any pharmaceutically acceptable polar liquid capable of forming an emulsion with a lipid. The term "pharmaceutically acceptable" refers to molecular entities and compositions of sufficient purity and quality for use in formulating the compositions or medicaments of the present application and that do not cause adverse allergic or other untoward reactions when properly administered to animals or humans. Both human use (clinical and commercial) and veterinary use are equally encompassed within the scope of the present application, and thus a pharmaceutically acceptable formulation would include a composition or medicament for either human or veterinary use. In one embodiment, the polar liquid carrier is water or an aqueous solution. In another embodiment, the polar liquid carrier is a non-aqueous polar liquid such as dimethyl sulfoxide, polyethylene glycol, and polar silicone fluids.

[0103] Aqueous solutions generally contain a physiologically compatible electrolyte vehicle that is isotonic or nearly isotonic with whole blood. The carrier can be, for example, saline, saline-glucose mixtures, Ringer's solution, lactated Ringer's solution, Locke's Ringer's solution, Krebs-Ringer's solution, Hartmann's balanced salt solution, heparinized sodium citrate-citric acid-dextrose solution, and polymeric plasma substitutes such as polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, and ethylene oxide-propylene glycol condensates. PN compositions may further contain other components, such as pharmaceutically acceptable carriers, diluents, fillers, and salts, the selection of which will depend on the dosage form utilized, the condition being treated, the particular objectives to be achieved as determined by one skilled in the art, and the properties of such additives.

[0104] electrolyte In one embodiment, the PN composition of the present application includes one or more electrolytes. Electrolytes used in the present application typically include various electrolytes used for pharmaceutical purposes. Examples of electrolytes include sodium salts (e.g., sodium chloride, sodium bicarbonate, sodium citrate, sodium lactate, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium glycerophosphate, sodium carbonate, sodium salts of amino acids, sodium propionate, sodium hydroxybutyrate, and sodium gluconate), potassium salts (e.g., potassium chloride, potassium acetate, potassium gluconate, potassium bicarbonate, potassium glycerophosphate, potassium sulfate, potassium lactate, potassium iodide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium citrate, potassium salts of amino acids, propionate, and sodium gluconate). Examples of suitable salts include potassium hydroxybutyrate, potassium hydroxybutyrate, calcium salts (e.g., calcium chloride, calcium gluconate, calcium lactate, calcium glycerophosphate, calcium pantothenate, and calcium acetate), magnesium salts (e.g., magnesium chloride, magnesium sulfate, magnesium glycerophosphate, magnesium acetate, magnesium lactate, and magnesium amino acid salts), ammonium salts (e.g., ammonium chloride), zinc salts (e.g., zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, and zinc acetate), iron salts (e.g., iron sulfate, iron chloride, and iron gluconate), copper salts (e.g., copper sulfate), and manganese salts (e.g., manganese sulfate). Among these, sodium chloride, potassium chloride, magnesium chloride, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium lactate, sodium acetate, sodium citrate, potassium acetate, potassium glycerophosphate, calcium gluconate, calcium chloride, magnesium sulfate, and zinc sulfate are particularly preferred.

[0105] The concentrations of calcium, sodium, magnesium, or potassium ions are typically within the range of the normal physiological concentrations of such ions in plasma. Generally, the desired concentrations of these ions are obtained from dissolved chloride salts of calcium, sodium, and magnesium. Sodium ions may also come from dissolved organic salts of sodium that are also in solution.

[0106] In one embodiment, the electrolyte comprises sodium chloride, sodium lactate, or both.

[0107] In certain embodiments, the PN composition comprises sodium chloride at a percentage concentration of about 0.2-1%, 0.3-0.9%, 0.4-0.8%, 0.5-0.7%, or about 0.6% (w / v).

[0108] In another embodiment, the pharmaceutical concentration comprises sodium chloride at a concentration of 50-150 mM, 70-130 mM, 80-120 mM, 90-110 mM, 95-100 mM or about 97.4 mM.

[0109] In another embodiment, the PN composition comprises sodium L-lactate, sodium D-lactate, or a mixture thereof in a percent concentration of about 0.1-0.7%, 0.2-0.6%, 0.3-0.5%, 0.35-0.45%, 0.38-0.39%, or about 0.385% (w / v).

[0110] In another embodiment, the PN composition comprises sodium L-lactate, sodium D-lactate, or a mixture thereof at a concentration of 10-60 mM, 20-50 mM, 30-40 mM, or about 34 mM.

[0111] In one embodiment, the sodium ion concentration is in the range of about 70 to 180 mM, 90 to 170 mM, 70 to 160 mM, 100 to 160 mM, 110 to 150 mM, 120 to 140 mM, 125 to 135 mM, 131 to 133 mM, or about 131.4 mM.

[0112] In one embodiment, the concentration of calcium ions is in the range of about 0.5 to 4.0 mM, 0.5 to 1.0 mM, 0.5 to 2 mM, 0.5 to 3 mM, 1 to 2 mM, 1 to 3 mM, 1 to 4 mM, 2 to 2.5 mM, 2 to 3 mM, 2 to 4 mM, 2.5 to 3 mM, or 3 to 4 mM.

[0113] In one embodiment, the magnesium ion concentration is in the range of 0-10 mM. In another embodiment, the magnesium ion concentration is in the range of about 0.3-0.45 mM, 0.3-0.35 mM, 0.3-0.4 mM, 0.35-0.4 mM, 0.35-0.4 mM, 0.35-0.4 mM, or 0.4-0.45 mM. It is best not to include excessive amounts of magnesium ion in the PN compositions of the present invention, as high magnesium ion concentrations can adversely affect the strength of cardiac contractile activity. In a preferred embodiment of the present invention, the solution contains a sub-physiological amount of magnesium ion.

[0114] In one embodiment, the potassium ion concentration is within the sub-physiological range of 0-5 mEq / L K+ (0-5 mM), preferably 2-3 mEq / L K+ (2-3 mM). Therefore, the PN composition allows for dilution of the potassium ion concentration in stored transfused blood. As a result, high potassium ion concentrations and the potential cardiac arrhythmias and heart failure caused by them can be more easily controlled. PN compositions containing sub-physiological amounts of potassium are also useful for blood replacement and hypothermia maintenance in subjects.

[0115] In one embodiment, the chloride ion concentration is in the range of 50-200 mM, 50-150 mM, 70-180 mM, 70-130 mM, 80-170 mM, 80-120 mM, 90-160 mM, 90-110 mM, 95-150 mM, 95-100 mM, or about 97.4 mM. In another embodiment, the chloride ion concentration is in the range of 110 mM to 125 mM.

[0116] Other sources of ions include sodium salts (e.g., sodium bicarbonate, sodium citrate, sodium lactate, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium glycerophosphate, sodium carbonate, sodium salts of amino acids, sodium propionate, sodium 3-hydroxybutyrate, and sodium gluconate), potassium salts (e.g., potassium acetate, potassium gluconate, potassium bicarbonate, potassium glycerophosphate, potassium sulfate, potassium lactate, potassium iodide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium citrate, potassium amino acids, Examples of suitable salts include ammonium salts, potassium propionate, and potassium 3-hydroxybutyrate), calcium salts (e.g., calcium gluconate, calcium lactate, calcium glycerophosphate, calcium pantothenate, and calcium acetate), magnesium salts (e.g., magnesium sulfate, magnesium glycerophosphate, magnesium acetate, magnesium lactate, and magnesium amino acid salts), ammonium salts, zinc salts (e.g., zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, and zinc acetate), iron salts (e.g., ferrous sulfate, ferrous chloride, and ferrous gluconate), copper salts (e.g., copper sulfate), and manganese salts (e.g., manganese sulfate). Among these, sodium chloride, potassium chloride, magnesium chloride, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium lactate, sodium acetate, sodium citrate, potassium acetate, potassium glycerophosphate, calcium gluconate, calcium chloride, magnesium sulfate, choline chloride, and zinc sulfate are particularly preferred.

[0117] Gas carrying capacity of PN compositions The lipophilic or hydrophobic components in the PN composition, such as in the form of micelles and / or red blood cell ghosts, provide the PN composition with the ability to carry larger amounts of lipophilic gases than a pure aqueous solution. Specifically, the lipophilic gas is dissolved in the lipophilic portion of the PN composition to form a homogeneous solution with the lipophilic or hydrophobic components and any other hydrophobic liquid material that may be present in the lipophilic or hydrophobic portion of the PN composition.

[0118] In one embodiment, the lipophilic gas is oxygen. Oxygen is 4.41 times more soluble in lipids than in water (Battion et al., J. Amer. Oil Chem. Soc. 1968, 45:830-833). Therefore, PN compositions with higher lipid content will be able to carry more oxygen than PN compositions with lower lipid content. In one embodiment, the PN composition has a lipid content of about 1-80% (w / v). In other embodiments, the PN composition has a lipid content of about 10-80% (w / v), 20-60% (w / v), about 20-50% (w / v), about 20-40% (w / v), or about 20-25% (w / v). In yet another embodiment, the PN composition has a lipid content of about 21.8%. In certain embodiments, the PN composition is prepared by mixing a lipophilic or hydrophobic component with a polar liquid component in the presence of normal air. In other embodiments, the PN composition is further oxygenated by bubbling normal air or pure oxygen through the PN composition for a desired period of time. Because air bubbles are undesirable in the circulation due to the possibility of air embolism, it may be necessary to add a bubble trap to remove the bubbles, leaving only the gas in the core of the micelles, solubilized in polar carriers, or attached to proteins or other additives. To avoid bubble formation, gas may be loaded into the micelles by equilibrating them in a gas-enriched atmosphere, combined with gentle movement of the PN composition through a mixing chamber. Loading may also be performed under pressures above 1 atmosphere, followed by releasing the pressure to allow the excess gas to escape.

[0119] In another embodiment, the lipophilic gas is xenon (Xe) or argon (Ar). In another embodiment, the lipophilic gas is nitric oxide (NO). In another embodiment, the lipophilic gas is hydrogen sulfide (HS). In yet another embodiment, the lipophilic gas is carbon monoxide (CO).

[0120] In one embodiment, the PN composition contains micelles loaded with a gas mixture (e.g., a mixture of oxygen, hydrogen sulfide, carbon monoxide, and / or nitric oxide). In another embodiment, the PN composition contains a mixture of micelles loaded with different gases. For example, a mixture of micelles may contain 50% NO-loaded micelles and 50% O-loaded micelles.

[0121] Rigid non-planar molecules The PN composition may further comprise molecules with rigid, non-planar structures. Such molecules create greater disorder and more space for gas molecules within the hydrophobic core of the micelle structure, thereby modifying the gas-carrying capacity of the micelle. Examples of such molecules include, but are not limited to, (+) naloxone, (+) morphine, and (+) naltrexone.

[0122] In one embodiment, the molecule having a rigid, non-planar structure is (+) naloxone, which, unlike the opiate receptor antagonist (-) naloxone, does not bind to opiate receptors and does not increase pain like (-) naloxone. In another embodiment, (+) naloxone is -5 ~10 -4 In another embodiment, (+) naloxone is used at a concentration of 10 -4 It is used at concentrations of M or higher.

[0123] During resuscitation, inflammatory processes may be triggered in the tissues of patients experiencing conditions that can lead to MODS, including endothelial cell (EC) injury and capillary leakage (CL). In sepsis and other diseases, systemic inflammation may be triggered by the disease, leading to EC injury and CL in a similar sequence. Thus, in one embodiment, (+) naloxone is administered at a dose of 10 -5 ~10 -4It is used in a concentration range that produces anti-inflammatory effects in M ​​(Simpkins CO, Ives N, Tate E, Johnson M. Naloxone inhibits superoxide release from human neutrophils (Life Sci. 1985 Oct 14;37(15):1381-6)).

[0124] Molecules having a non-planar structure also include organic molecules having a branched structure. Examples of such molecules include, but are not limited to, tri-n-octylamine, tri-n-hexylamine, boric acid, tris(3,5-dimethyl-4-heptyl) ester, metal-complexed and non-metal-complexed deuteroporphyrin dimethyl ester and their derivatives, hexaphenylsilole, and silicone polymers.

[0125] plasma components The PN composition may further comprise a plasma component. In one embodiment, the plasma is animal plasma. In another embodiment, the plasma is human plasma. While not wishing to be bound by any particular scientific theory, it is believed that administration of blood substitutes may dilute the concentration of clotting factors to undesirable levels. Therefore, using plasma as a diluent for oxygen-carrying components avoids this problem. Plasma can be collected by any means known in the art, provided that red blood cells, white blood cells, and platelets are essentially removed. Preferably, it is obtained using an automated plasmaphoresis device. Plasmaphoresis devices are commercially available and include, for example, devices that separate plasma from blood by ultrafiltration or centrifugation. Ultrafiltration-based plasmaphoresis devices, such as the Auto C, A200 (Baxter International Inc., Deerfield, Illinois), are preferred because they effectively remove red blood cells, white blood cells, and platelets while preserving clotting factors.

[0126] Plasma may be collected using an anticoagulant, many of which are well known in the art. Preferred anticoagulants are those that chelate calcium, such as citrate. In one embodiment, sodium citrate is used as the anticoagulant at a final concentration of 0.2-0.5%, preferably 0.3-0.4%, and most preferably 0.38%. Plasma may be fresh, frozen, pooled, and / or sterile. While plasma from an exogenous source may be preferred, it is within the scope of this application to use autologous plasma collected from the subject prior to formulation and administration of the PN composition.

[0127] In addition to plasma from natural sources, synthetic plasma may also be used. As used herein, the term "synthetic plasma" refers to any aqueous solution containing at least one plasma protein. Proteins similar to plasma proteins may also be used.

[0128] leavening agent In one embodiment, the PN composition further contains a bulking agent in addition to the lipid micelles. The bulking agent is composed of molecules of sufficient size to cross fenestrations in capillary beds and enter the interstitial spaces of bodily tissues, thereby preventing loss from circulation. Examples of bulking agents include, but are not limited to, dextran (e.g., low molecular weight dextran), dextran derivatives (e.g., carboxymethyl dextran, carboxydextran, cationic dextran, and dextran sulfate), hydroxyethyl starch, hydroxypropyl starch, branched, unsubstituted, or substituted starch, gelatin (e.g., modified gelatin), albumin (e.g., human plasma, human serum albumin, heated human plasma protein, and recombinant human serum albumin), PEG, polyvinylpyrrolidone, carboxymethylcellulose, acacia gum, glucose, dextrose (e.g., glucose monohydrate), oligosaccharides (e.g., oligosaccharides), polysaccharide degradation products, amino acids, and protein degradation products. Among these, low molecular weight dextran, hydroxyethyl starch, modified gelatin, and recombinant albumin are particularly preferred.

[0129] Due to its antioxidant effect, albumin may also be used to minimize reactive oxygen species interactions with the components of the micelles and may stabilize the micellar structure. In one embodiment, the swelling agent is about 2%, 5%, 7%, or 10% (w / v) albumin. In another embodiment, the swelling agent is a polysaccharide, e.g., dextran, in the molecular weight range of 30,000 to 50,000 Daltons (D). In yet another embodiment, the swelling agent is a polysaccharide, e.g., dextran, in the molecular weight range of 50,000 to 70,000 D. High molecular weight dextran solutions are more effective in preventing tissue swelling due to their reduced capillary leakage rate.

[0130] In one embodiment, the concentration of polysaccharide is sufficient to achieve a colloid osmotic pressure (of the organic ions from the organic salts of sodium and the hexose sugars listed above, when combined with the chloride salts of sodium, calcium, and magnesium) approximating that of normal human serum, approximately 28 mmHg.

[0131] In another embodiment, the bulking agent is glycerol or mannitol in an amount of about 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 10%, 15%, 20%, 25%, or 30% (w / v) of the PN composition. In other embodiments, the PN composition contains glycerol or mannitol in an amount of 2-5% w / v.

[0132] Crystalloids The PN composition may also include a crystalloid. The crystalloid can be any crystalloid capable of achieving an osmolality of preferably greater than 800 mOsm / L in the PN composition, i.e., making the PN composition "hypertonic." Examples of suitable crystalloids and their concentrations in the PN composition include, but are not limited to, 3% w / v NaCl, 7% NaCl, 7.5% NaCl, and 7.5% NaCl in 6% w / v dextran. In one embodiment, the PN composition has an osmolality of 800-2400 mOsm / L.

[0133] Anti-inflammatory and immunomodulatory agents In one embodiment, the PN composition of the present application further comprises an anti-inflammatory or immunomodulatory agent. Examples of anti-inflammatory agents that have been shown to inhibit reactive oxygen species include, but are not limited to, histidine, albumin, (+) naloxone, prostaglandin D2, and molecules of the phenylalkylamine class. Other anti-inflammatory compounds and immunomodulatory agents include interferons; interferon derivatives including betaseron and beta-interferon; prostane derivatives including iloprost and cicaprost; glucocorticoids including cortisol, prednisolone, methyl-prednisolone, and dexamethasone; immunosuppressants including cyclosporin A, methoxsalen, sulfasalazine, azathioprine, and methotrexate; lipoxygenase inhibitors including zileuton, MK-886, WY-50295, SC-45662, SC-41661A, and BI-L-357; leukotriene antagonists; peptide derivatives including ACTH and its analogs; soluble TNF receptors; anti-TNF antibodies; soluble receptors for interleukins or other cytokines; antibodies against receptors for interleukins or other cytokines, T-cell proteins; and calcipotriol and its analogs, administered alone or in combination.

[0134] Carbohydrates and amino acids The PN composition may contain a carbohydrate or mixture of carbohydrates. Suitable carbohydrates include, but are not limited to, simple hexoses (e.g., glucose, fructose, and galactose), mannitol, sorbitol, or others known in the art. In one embodiment, the PN composition contains physiological levels of hexoses. "Physiological levels of hexoses" includes hexose concentrations between 2 mM and 50 mM. In one embodiment, the PN composition contains 5 mM glucose. At times, it is desirable to increase the concentration of hexoses to provide nutrients to cells. Therefore, the hexose range may be expanded to approximately 50 mM as needed to provide minimal calories for nutrition.

[0135] Other suitable carbohydrates include various sugars used for pharmaceutical purposes, such as xylitol, dextrin, glycerin, sucrose, trehalose, glycerol, maltose, lactose, and erythritol.

[0136] The PN composition may contain one or more amino acids and / or one or more oligopeptides. Suitable amino acids include, but are not limited to, alanine, arginine, aspartate, asparagine, cysteine, glutamate, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, threonine, tryptophan, valine, and 2-aminopentaenoic acid. In one embodiment, the amino acid is selected from the group consisting of histidine, tyrosine, phenylalanine, and cysteine. In another embodiment, the PN composition includes one or more amino acids known to prevent apoptosis. Examples of such amino acids include glutamine, glycine, proline, and 2-aminopentaenoic acid.

[0137] Amino acids may be used in concentrations ranging from 0.1 fM to 200 mM, 0.1 fM to 100 pM, 100 pM to 10 nM, 10 nM to 10 μM, 0.01 to 200 mM, 0.2 to 50 mM, or 0.5 to 2 mM. In one embodiment, the amino acids are used at a concentration of 1 mM.

[0138] buffer The PN compositions of the present application may further comprise a biological buffer to maintain the pH of the fluid in the physiological range of pH 7 to 8. Examples of biological buffers include, but are not limited to, N-2-hydroxyethylpiperazine-N'-2-hydroxypropanesulfonic acid (HEPES), 3-(N-morpholino)propanesulfonic acid (MOPS), 2-([2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino)glycietanesulfonic acid (TES), 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxyethyl]-1-piperazinepropanesulfonic acid (EPPS), tris[hydroxymethyl]aminoethane (THAM), and tris[hydroxylmethyl]methylaminomethane (TRIS).

[0139] In one embodiment, the buffering agent is histidine, imidazole, a substituted histidine or imidazole compound that retains the amphiphilic portion of the imidazole ring, a histidine- or glycine-containing oligopeptide (e.g., glycylglycine), or a mixture thereof. Histidine can also reduce reactive oxygen species and inhibit cell contraction. (See, e.g., Simpkins et al., J. Trauma. 2007, 63:565-572.) Histidine or imidazole may be used at a concentration of about 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, or 50 mM, or in a concentration range of about 0.1 mM to about 200 mM, 1 mM to about 100 mM, 5 mM to about 50 mM, or 5 mM to about 20 mM, or any other range between any of the histidine concentrations listed herein.

[0140] In another embodiment, the PN compositions of the present application use normal biological components to maintain in vivo biological pH. Briefly, some biological compounds, such as lactate, can be metabolized in vivo and interact with other biological components to maintain a biologically appropriate pH in animals. The biological components are effective in maintaining a biologically appropriate pH even under hypothermic and essentially bloodless conditions. Examples of normal biological components include, but are not limited to, carboxylic acids, their salts, and esters. Carboxylic acids have the general structural formula RCOOX, where R is an alkyl, alkenyl, or aryl, branched or straight chain, containing 1 to 30 carbon atoms, optionally substituted, and X is a hydrogen atom or other biologically compatible ionic substituent that can be attached at the sodium or oxygen position, or a short straight or branched alkyl containing 1 to 4 carbon atoms, e.g., -CH3, -CH2CH3. Examples of carboxylic acids and carboxylate salts include, but are not limited to, lactate and sodium lactate, citrate and sodium citrate, gluconate and sodium gluconate, pyruvate and sodium pyruvate, succinate and sodium succinate, and acetate and sodium acetate.

[0141] Coagulation promoters Aggressive volume resuscitation without controlling bleeding can exacerbate bleeding by disrupting the initially formed soft clot and diluting the clotting factors. In certain embodiments, the PN composition may further comprise one or more procoagulants. Examples of clotting factors include, but are not limited to, factor VII, thrombin, platelets, and tranexamic acid. These factors may be derived from natural or non-natural sources. In certain embodiments, factor VII is added to the PN composition at a concentration of 70-150 IU / kg, prothrombin complex is added to the PN composition at a concentration of 15-40 IU / kg, and fibrinogen is added to the PN composition at a concentration of 50-90 mg / kg. Naturally derived or synthetic platelets or platelet substitutes may also be added.

[0142] antioxidants In certain embodiments, the PN composition may further comprise one or more antioxidants. Examples of antioxidants include sodium bisulfite, sodium sulfite, sodium pyrosulfite (e.g., sodium metabisulfite), Rongalite (CH2OHSO2Na), ascorbic acid, sodium ascorbate, erythorbic acid, sodium erythorbate, cysteine, cysteine ​​hydrochloride, homocysteine, glutathione, thioglycerol, α-thioglycerin, sodium edetate, citric acid, isopropyl citrate, potassium dichloroisocyanurate, sodium thioglycolate, sodium pyrosulfite, 1,3-butylene glycol, calcium disodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate, amino acid sulfites (e.g., L-lysine sulfite), and the like. sulfate), butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), propyl gallate, ascorbyl palmitate, vitamin E and its derivatives (e.g., dl-α-tocopherol, tocopherol acetate, natural vitamin E, d-δ-tocopherol, mixed tocopherols, and Trolox), guaiac, nordihydroguaiaretic acid (NDGA), L-ascorbic acid stearate ester, soy lecithin, palmitic acid, ascorbic acid, benzotriazole, and pentaerythrityl-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate]2-mercaptobenzimidazole. Among these, sodium bisulfite, sodium sulfite, ascorbic acid, homocysteine, dl-α-tocopherol, tocopherol acetate, glutathione, and Trolox are preferred.

[0143] Other ingredients In addition to the above ingredients, the PN composition may contain antibiotics such as penicillin, cloxacillin, dicloxacillin, cephalosporins, erythromycin, amoxicillin-clavulanate, ampicillin, tetracycline, trimethoprim-sulfamethoxazole, chloramphenicol, ciprofloxacin, aminoglycosides (e.g., tobramycin and gentamicin), streptomycin, sulfa drugs, kanamycin, neomycin, and randomonobactam; antivirals such as amantadine hydrochloride, rimantadine, acyclovir, famciclovir, foscarnet, ganciclovir sodium, idoxuridine, ribavirin, sorivudine, trifluridine, valacyclovir, valganciclovir, pencyclovir; Other additives may further be included, including, but not limited to, benzodiazepine, vidarabine, didanosine, stavudine, zalcitabine, zidovudine, interferon alpha, and edoxudine; antifungal agents such as terbinafine hydrochloride, nystatin, amphotericin B, griseofulvin, ketoconazole, miconazole nitrate, flucytosine, fluconazole, itraconazole, clotrimazole, benzoic acid, salicylic acid, voriconazole, caspofungin, and selenium sulfide; vasodilators such as vitamins, amino acids, alcohols, and polyalcohols; surfactants, antibodies against harmful cytokines such as tumor necrosis factor (TNF) or interleukins, and mediators of vascular potency and immunomodulators such as prostaglandins, leukotrienes, proopiomelanocortin fragments, and platelet-activating factor.

[0144] In certain embodiments, the PN composition may further contain beneficial anions, such as lactate or glutamate. Hypertonic lactate-containing compositions have been shown to be effective in reducing cerebral edema in patients with acute hemodynamic compromise. In one embodiment, the PN composition contains 250-2400 mM lactate or lactate. In another embodiment, the PN composition contains 250-2400 mM lactate or lactate and 2-10 mM potassium.

[0145] In certain other embodiments, the PN composition may contain a replacement cation, for example, the PN composition may contain choline to replace sodium ions.

[0146] In some other embodiments, the PN composition further comprises a potassium channel blocker, which can inhibit programmed cell death by preventing potassium efflux.

[0147] In certain embodiments, the PN composition further comprises an anti-cancer drug and / or an intracellular signaling molecule such as Camp and diacylglycerol, hi other embodiments, the PN composition further comprises, in whole or in part, one or more organelles or organelle components such as the endoplasmic reticulum, ribosomes, and mitochondria.

[0148] In other embodiments, the PN composition may be combined with red blood cells, modified red blood cells, or other cellular components of blood.

[0149] In yet another embodiment, the PN composition further comprises β-endorphin and a proopiomelanocortin fragment, such as melanocyte-stimulating hormone, enkephalin, or an opiate, to modify the immune response and provide analgesia. β-endorphin may be used at a final concentration of 0.01 to 100 nM, preferably 0.1 to 10 nM, and more preferably about 1 nM, to modulate neutrophil function in septic conditions (e.g., Simpkins et al., J Natl Med Assoc. 1988, 80:199-203).

[0150] In yet other embodiments, the PN composition further comprises one or more neurotropic agents for the treatment of psychiatric disorders or the prevention of psychiatric disorders.

[0151] Preparation of PN composition The PN composition may be prepared by mixing a lipophilic or hydrophobic component, an emulsifier, an aqueous carrier, and any other ingredients to form an emulsion. Commonly used mixing methods include, but are not limited to, stirring, shaking, homogenizing, vibrating, microfluidizing, and sonication.

[0152] An exemplary homogenizer is the APV2000 homogenizer (SPX Corporation). Emulsions may be formed at pressure settings of about 15,000-20,000 psi for nanoemulsions less than 100 nm, or about 22,000-28,000 psi for larger micellar emulsions of about 300 nm. Multiple homogenization cycles may be required to produce micelles of the desired size. The number of homogenization cycles may vary depending on the formulation; for example, 6, 8, 10, 12, or 15 cycles may be required.

[0153] Suitable particle and / or zeta potential analyzers may be used to assess and monitor the size and stability of the micelle compositions. Exemplary analyzers include the Malvern Zetasizer Nano ZS, which can provide measurements of both size and zeta potential.

[0154] In one embodiment, the PN composition is formed by mixing a preformed lipid emulsion from the above ingredients with an aqueous carrier. Furthermore, the PN composition can be carried within red blood cell ghosts. Specifically, the emulsion should be prepared to allow lipophilic gases to dissolve in the lipophilic or hydrophobic portions of the emulsion but not form microbubbles, which could increase the risk of gas embolism.

[0155] In certain embodiments, albumin or albumin polymers, or albumin polymers conjugated to amino acids or peptides, are added to the PN composition in an amount of 2-40% (w / v), about 2-20% (w / v), about 4-10% (w / v), or about 5% (w / v). The albumin or albumin polymers, or albumin polymers conjugated to amino acids or peptides, are added to the PN composition after micelle formation. In one embodiment, a lipophilic or hydrophobic component, an emulsifier, an aqueous carrier, and any other non-albumin components are mixed to form an emulsion. The albumin, albumin polymer, or albumin polymers conjugated to amino acids or peptides are then dissolved in the emulsion at the desired concentration.

[0156] In some embodiments, Part A or a mixture of Parts A and B is charged with oxygen, nitric oxide, carbon monoxide, xenon, argon, hydrogen sulfide, other hydrophobic gases, or mixtures of these gases prior to use. These gases may be used to deliver oxygen for aerobic metabolism after the initial bolus, provide an initial carbon monoxide bolus to protect against MODS, open blood vessels in vascular diseases or conditions involving vascular narrowing or blockage, provide xenon or argon to protect against the effects of traumatic brain injury or stroke, or provide hydrogen sulfide to promote long-term tissue preservation. Nitric oxide-loaded micelles may also be used as an antihypertensive. Part A, Part B, or a mixture of Parts A and B can be sterilized by autoclaving.

[0157] In some embodiments, soybean oil, which promotes clotting, is replaced with chia bean oil, which is anti-inflammatory and reduces clotting. In one embodiment, a PN composition containing soybean oil is used during the early stages of infusion when bleeding is occurring. A PN composition containing chia bean oil is used during the later stages of infusion when bleeding is no longer an issue.

[0158] In some other embodiments, glycerol in Part A is replaced with mannitol. In other embodiments, egg phospholipids are replaced with α-phosphatidylcholine to eliminate potential sources of protein contamination and anaphylaxis (due to contamination of egg phospholipids with egg proteins). In yet other embodiments, the amino acids in Part B of Recipe 2 are replaced with N-acetyl amino acids. In one embodiment, the PN composition is a non-oxygenated PN composition. As used herein, the term "non-oxygenated PN composition" refers to a formulation prepared in ambient air and not charged with oxygen by any oxygenation device or method.

[0159] In some embodiments, the PN composition comprises a lipophilic or hydrophobic component in an amount of 15-35% (w / v), an amphiphilic emulsifier in an amount of 6%-18% (w / v), a polar liquid carrier, and one or more electrolytes, wherein the amphiphilic emulsifier forms lipid-loaded micelles (LMs) having a lipophilic or hydrophobic core comprising the lipophilic or hydrophobic component in the polar liquid carrier, and the LMs have a diameter in the range of 20-140 nm. In some further embodiments, the PN composition has a diameter of 30-140 nm, 30-130 nm, 30-120 nm, 30-100 nm, 30-90 nm, 30-80 nm, 30-70 nm, 40-140 nm, 40-130 nm, 40-120 nm, 40-100 nm, 40-90 nm, 40-80 nm, 50-140 nm, 50-130 nm, 50-120 nm, 50-100 nm, 50-90 nm, 50-80 nm, 50-140 nm, 50-130 nm, 50-120 nm, 50-100 nm, 50-90 nm, 50-90 nm, 50-140 nm, 50-130 nm, 50-120 nm, 50-100 nm, 50-90 nm, 50-100 nm, 50-140 nm, 50-130 nm, 50-120 nm, 50-10 ... and LMs having diameters in the ranges of 0-80 nm, 50-70 nm, 60-140 nm, 60-130 nm, 60-120 nm, 60-100 nm, 60-90 nm, 60-80 nm, 80-140 nm, 80-130 nm, 80-120 nm, 80-110 nm, 80-100 nm, 100-140 nm, 100-130 nm, 100-120 nm, 100-110 nm, 120-140 nm, 120-130 nm, or 130-140 nm.

[0160] In some further embodiments, the PN composition further comprises liposomes having a diameter in the range of 1 to 30 nm, 1 to 25 nm, 1 to 20 nm, 1 to 15 nm, 1 to 10 nm, 3 to 30 nm, 3 to 25 nm, 3 to 20 nm, 3 to 15 nm, 3 to 10 nm, 5 to 30 nm, 5 to 25 nm, 5 to 20 nm, 5 to 15 nm, 5 to 10 nm, 7 to 30 nm, 7 to 25 nm, 7 to 20 nm, 7 to 15 nm, 7 to 10 nm, 10 to 30 nm, 10 to 25 nm, 10 to 20 nm, 10 to 15 nm, 15 to 30 nm, 15 to 25 nm, 15 to 20 nm, 20 to 30 nm, 20 to 25 nm, or 25 to 30 nm, as measured by electron microscopy.

[0161] In some further embodiments, the PN composition comprises nanoparticles (including micelles and liposomes) having an average diameter in the range of about 70-160 nm, 70-150 nm, 70-140 nm, 70-130 nm, 70-120 nm, 70-100 nm, 70-90 nm, 80-160 nm, 80-150 nm, 80-140 nm, 80-130 nm, 80-120 nm, 80-100 nm, 80-90 nm, 90-160 nm, 90-150 nm, 90-140 nm, 90-130 nm, 90-120 nm, 90-100 nm, 90-98 nm, 92-96 nm, or 95-100 nm, as measured by dynamic light scattering.

[0162] In some embodiments, the PN composition comprises a mixture of LMs having diameters in the range of 30-500 nm and liposomes having diameters in the range of 1-30 nm, as measured by electron microscopy.

[0163] In some embodiments, the PN composition comprises a mixture of LMs and liposomes, and the mean diameter of all particles is in the range of 5-25 nm, 5-20 nm, 5-15 nm, 5-10 nm, 10-25 nm, 10-20 nm, 10-15 nm, 15-25 nm, 15-20 nm, or 20-25 nm, as determined by electron microscopy.

[0164] In some embodiments, the PN composition comprises about 12% egg lecithin and comprises LMs having diameters of about 30-500 nm and liposomes having diameters of about 1-25 nm as determined by electron microscopy. In some embodiments, the PN composition comprises about 12% egg lecithin and comprises LMs having diameters of about 40-100 nm and liposomes having diameters of about 7-20 nm as determined by electron microscopy.

[0165] In some embodiments, the PN composition comprises about 5-35% soybean oil and about 0.5-20% egg lecithin, and contains LMs having a diameter of about 15-800 nm and liposomes having a diameter of about 1-300 nm as determined by electron microscopy.

[0166] In some embodiments, the PN composition comprises about 5-25% soybean oil and about 0.5-1.5% egg lecithin, and contains LMs having a diameter of about 30-400 nm and liposomes having a diameter of about 1-150 nm as determined by electron microscopy.

[0167] In some embodiments, the PN composition comprises about 5-25% soybean oil and about 0.5-1.5% egg lecithin, and contains LMs having a diameter of about 30-400 nm and liposomes having a diameter of about 1-150 nm as determined by electron microscopy.

[0168] In some embodiments, the PN composition comprises about 12% egg lecithin and includes LMs having a diameter of about 40-100 nm and liposomes having a diameter of about 7-20 nm as determined by electron microscopy.

[0169] In some embodiments, the PN composition further comprises glycerin in an amount of 1-10%, 1-8%, 1-5%, 1-3%, 1-2%, 5-10%, 2-8%, 2-5%, 2-3%, 3-10%, 3-8%, 3-5%, 5-10%, 5-8%, or 8-10% (w / v).

[0170] In some embodiments, the PN composition further comprises NaCl at a final concentration of 50-200 mM, 50-150 mM, or 50-100 mM.

[0171] In some embodiments, the PN composition is prepared under atmospheric conditions without enrichment of oxygen, carbon monoxide, nitric oxide, or xenon.

[0172] In certain embodiments, the PN composition may be charged with a lipophilic gas prior to clinical application. Examples of such gases include, but are not limited to, oxygen, xenon, argon, nitric oxide, carbon monoxide, and hydrogen sulfide. The gas is present in an amount sufficient to regulate vascular function and cytoembolic events. As used herein, a "lipophilic gas-charged PN composition" refers to a PN composition that has been subjected to a process to increase the content of such lipophilic gas in the PN composition. The PN composition may be charged with a lipophilic gas by bubbling the lipophilic gas through the PN composition for a desired period of time or by stirring the PN composition in the presence of the lipophilic gas under pressure.

[0173] In one embodiment, the PN composition is oxygenated by bubbling pure oxygen or a gas having an oxygen content ranging from 21% to 100% (v / v), preferably 40% to 100% (v / v), more preferably 60% to 100% (v / v), and most preferably 80% to 100% (v / v), through the mixture for 30 seconds or more, preferably 1 to 15 minutes, more preferably 1 to 5 minutes. The oxygen may be added under pressure, and the pressure may then be reduced to 1 atmosphere. In one embodiment, the PN composition is oxygenated immediately prior to application. The PN composition may be oxygenated using a portable oxygen tank or portable oxygen concentrator, such as the Evergo Portable Pulse Dose Oxygen concentrator manufactured by Philips Healthcare of Andover, Massachusetts.

[0174] Another method is to equilibrate the emulsion in an atmosphere filled with added gas. In most cases, a bubble trap will be required to remove bubbles that could become gas embolisms. The equilibration time for a particular PN composition may be determined experimentally.

[0175] In some embodiments, the PN composition comprises an oxygenated lipid emulsion. As used herein, the term "oxygenated lipid emulsion" or "oxygenated PN composition" refers to a specific type of gasified lipid emulsion or gasified fluid that has been subjected to absorption of oxygen such that the total concentration of oxygen contained therein is greater than that present in the same liquid at atmospheric equilibrium conditions. [Example]

[0176] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to carry out the methods of the present application, and are not intended to limit the scope of the invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0177] Example 1: Preparation of Phospholipid Nanoparticle (PN) Composition Preparation of Part A Soybean oil 10%-20% = 10-20 grams Egg yolk phospholipids 0.6%~12% = 0.6~12 grams Add water to a final volume of 100 ml Add sodium hydroxide until pH=8.0 Sonication to produce phospholipid nanoparticles Preparation of Part B 0.6 grams of NaCl Sodium lactate (L) 0.385g Histidine 0.155g

[0178] Part A may be used alone, mixed with Part B within 24 hours of use, or premixed. Either or both parts may be lyophilized and water added at the time of use. In some embodiments, glycerin was added to the final product at a final concentration of 1.13% (w / v) or 2.25% (w / v).

[0179] Example 2: Treatment of MODS in Patient A with PN Composition

[0180] MODS developed in Patient A, a 39-year-old woman with a failed heart transplant. Even after the use of a ventricular assist device, the patient experienced cardiac arrest. Multiple organ failure was present. Pulmonary insufficiency was evident by the need for 100% oxygen via a ventilator to achieve a viable level of oxygenation. Cardiac failure was demonstrated by the onset of cardiac arrest and the need for direct cardiac injection of epinephrine to restore spontaneous contractions. To manage cardiac arrest, the patient's chest was opened. The patient had no urinary output due to renal failure. Despite receiving high doses of Levophed and fluid boluses, her mean arterial pressure (MAP) was only 43 mmHg. Pulmonary function was severely impaired, as indicated by a P / F ratio of only 132. The lower the P / F and the lower the blood pressure, the lower the survival rate.

[0181] The patient received 500 ml of the PN composition of the present application over 30 minutes. No other intervention was administered. This resulted in an improvement in pulmonary function, as indicated by an increase in MAP from 43 mmHg to 69 mmHg. The P / F ratio increased from 132 to 235.

[0182] Example 3: Treatment of MODS in Patient B with PN Composition

[0183] Patient B, a 69-year-old woman, had an infected leg and developed septic shock, which led to MODS. Her lungs required ventilator support. Renal function was supported by dialysis. The patient had heart failure after cardiac arrest. Despite receiving boluses of albumin and saline and very high doses of vasopressors—Levophed 100 micrograms / minute, vasopressin 0.1 units / minute, and epinephrine 30 micrograms / minute—her MAP was only 39 mmHg. Despite being on a ventilator, her P / F ratio was only 131.

[0184] The patient was given 500 ml of the PN composition of the present application over a 30 minute period. Without additional intervention, the patient's MAP increased from 39 mmHg to 59 mmHg, and the patient's P / F ratio increased from 131 to 240.

[0185] Example 4: Treatment of MODS in Patient C with PN Composition

[0186] Patient C, a 65-year-old woman, presented to the emergency department with cardiac tamponade due to blood accumulation in the pericardial cavity. This severely restricted cardiac expansion and prevented adequate blood flow from reaching the rest of the body. The cardiac tamponade resulted in two episodes of cardiac arrest, necessitating needle drainage of blood from the pericardial cavity. These events resulted in MODS. After failure of fluid boluses and mask oxygen to improve blood pressure and oxygenation, respectively, the patient was placed on a ventilator and administered vasopressors. Pulmonary dysfunction was confirmed by a low P / F ratio. Renal failure was reflected by an increase in creatinine. Liver damage was indicated by an increase in the ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT). Organ malperfusion was indicated by elevated lactate. The patient was administered vasopressors: Levophed at 32 micrograms / min and vasopressin at 0.04 units / min.

[0187] The patient received 765 ml of the PN composition of the present application over 120 minutes. After receiving the PN composition, the patient's MAP increased from 68 mmHg to 86 mmHg. The patient's P / F ratio increased from 63 to 116. The dose of Levophed was reduced from 32 micrograms / min to 10 micrograms / min. Table 1 shows the improvement in the patient's blood test parameters 24 hours after PN infusion. The decrease in creatinine indicated improved renal function. AST is aspartate transaminase, and ALT is alanine aminotransferase. Both are enzymes present in liver tissue. The higher the AST / ALT ratio, the worse the liver damage. A normal AST / ALT ratio is less than 1.0. A decrease in this ratio after the PN composition is an indication of improved liver function. Lactate is an indicator of overall perfusion of tissues in the body. The higher the lactate, the worse the prognosis. The decrease in lactate after infusion of the PN composition is an indication of improved overall tissue perfusion. Triglyceride levels indicate the amount of lipids in the blood. After infusion of the PN composition, triglyceride levels increased from 109 to 736 mg / dL the day after infusion. Triglyceride concentrations are an indication of changes in PN levels in the bloodstream over time. No adverse effects of this elevated triglyceride were observed. 24 hours after this increase, triglyceride levels decreased to 244 mg / dL.

[0188] [Table 1]

[0189] There were no other interventions during the period of these results besides the infusion of the PN composition. Measurements showed that after the infusion of the PN composition, improvements were observed in the cardiovascular, pulmonary, renal, and hepatic systems. Additionally, there was an improvement in overall blood flow through the tissues.

[0190] Example 5: Treatment of MODS in Patient D with PN Composition

[0191] Patient D was a 65-year-old man with a laboratory-confirmed diagnosis of COVID-19. The patient had a decrease in MAP, which was not reversed by fluid infusion. Vasopressors were required to increase the patient's blood pressure to a viable level. The patient met criteria for septic shock when MAP did not increase after fluid infusion. The patient's blood pressure was 68 mmHg despite receiving the vasopressor Levophed at 11 micrograms per minute. The patient's pulmonary status significantly deteriorated, and the patient was placed on a ventilator. Despite maximum ventilator support, the patient's pulmonary status continued to decline, resulting in a PF ratio of only 56. The patient was administered 200 ml of PN composition intravenously over 2.4 hours. This increased the MAP from 68 mmHg to 78 mmHg. The patient's P / F ratio increased from 56 to 199.

[0192] Seven days later, while still on a ventilator, the patient was given 5 micrograms / minute of Levophed and 0.04 units / minute of vasopressin, which reduced the patient's P / F ratio to 62. The patient was given 200 ml of PN composition for 2.5 hours, which increased his blood pressure from 67 mmHg to 70 mmHg and his P / F ratio from 62 to 191.

[0193] Six days later, the patient was still on a ventilator and was receiving Levophed 5 micrograms / minute with vasopressin at 0.04 units / minute. The P / F ratio had decreased to 81. The patient was given 400 ml of PN composition over 10 minutes, which increased the P / F ratio from 81 to 145. The blood pressure increased, allowing the patient to be completely weaned from vasopressors. The vasopressors were discontinued, and the MAP was 107 mmHg.

[0194] Example 6: Treatment of MODS in Patient E with PN Composition

[0195] Patient E was a 62-year-old man diagnosed with COVID-19 based on clinical criteria. He presented to the hospital before diagnostic testing for COVID-19 was available. He was in septic shock. He also had multifocal pneumonia and blood cultures that were positive for gram-positive cocci. Due to hypotension, the patient was administered high-dose vasopressors: Levophed, vasopressin, and phenylephrine. Despite these measures, the patient went into asystole. Advanced Cardiac Life Support protocols were followed. However, the patient was unresponsive. The patient was given 1000 ml of PN composition. After this, the patient's blood pressure rose to 67 mmHg, and the patient was able to be weaned off the vasopressors. The patient's oxygen requirement decreased from 100% inspired oxygen to 55% inspired oxygen.

[0196] Example 7: Treatment of MODS in patient F with PN composition

[0197] Patient F#5 was a 58-year-old woman diagnosed with COVID-19 and septic shock. The patient had severe pneumonia. The patient was on a ventilator. Despite receiving high-dose vasopressors, the patient went into asystole. The patient did not respond to Advanced Cardiac Life Support protocols. The patient's blood pressure was 0 until the patient received 1000 ml of PN composition. After this infusion, the patient's blood pressure increased to an average of 69 mmHg. Prior to the PN composition, the patient's oxygen saturation was 55%, despite receiving 100% inspired oxygen. After the PN composition infusion, the patient's oxygen requirement decreased to 55%.

[0198] Example 8: Nitric oxide content in water and PN compositions

[0199] Five hundred microliters of PN (containing 20% ​​soybean oil, 1.2% egg lecithin, and 2.25% glycerin; mean particle size measured by dynamic light scattering: 400 nm) was placed in a 15-mL vial, and 100 ppm nitric oxide in helium was bubbled through the PN for 2 minutes. The same method was used for spiking nitric oxide in deionized water. A continuous sampling quadrupole mass spectrometer was used to quantify the nitric oxide content in the sample fluid. The water in the purge reservoir was maintained at 37°C and contained an antifoam solution as needed. For measurements of nitric oxide content in PN and water, 100 microliters of sample fluid was injected into the instrument's purge reservoir. The sample gas rapidly escaped from the fluid and was transported as a bolus from the purge reservoir toward the mass spectrometer. The signal generated by sample gas contact with the detector was integrated using Peakfit (Systat Software Inc., Chicago, IL, USA) and compared to the saturated value obtained with deionized water. Ten measurements were performed for each group. The volume of nitric oxide taken up was determined as the area under the curve. The mean and standard error were 3.19 × 10 for PN and water, respectively. -3 ±0.19×10 -3 and 2.12 × 10 -3 ±0.17×10 -3 The solubility of NO in 20% PN was 1.5 times that of water, indicating that the solubility of NO in 20% PN was 1.5 times that of water. The offloading of nitric oxide from PN and water was rapid, taking approximately 2 seconds, respectively.

[0200] The data obtained is shown in Table 2 below.

[0201] [Table 2]

[0202] As shown in Figure 1, compared to water (Panel A), PNs took up more nitric oxide (Panel B). In the representative experiment shown in Figure 1, the area under the curve correlates with the amount of nitric oxide absorbed, and the rate of nitric oxide release is rapid, similar to the release from water. This rapid release allows PNs to shift the distribution of nitric oxide from non-viable to viable tissues.

[0203] The terms and descriptions used herein are set forth by way of illustration only and are not meant to be limiting. Those skilled in the art will recognize that many variations are possible within the spirit and scope of the invention as defined in the following claims, and that, unless otherwise expressly stated, all terms should be understood in the broadest possible sense, at their equivalents. (Additional note 1) 1. A method of treating multiple organ dysfunction syndrome (MODS) in a subject, comprising: For those in need of treatment, a lipophilic or hydrophobic component in an amount of 0-35% (w / v); an amphiphilic emulsifier in an amount of 0.1% to 60% (w / v); a polar liquid carrier, and One or more electrolytes administering an effective amount of a phospholipid nanoparticle (PN) composition comprising: The method, wherein the PN composition comprises liposomes and / or micelles having a diameter of 1 to 800 nm. (Additional note 2) 2. The method of claim 1, wherein the lipophilic or hydrophobic component is selected from the group consisting of soybean oil, chia bean oil, and algae oil. (Additional note 3) 3. The method of claim 1 or 2, wherein the amphiphilic emulsifier is selected from the group consisting of phospholipids and α-phosphatidylcholines. (Additional note 4) 4. The method according to any one of appendix 1 to 3, wherein the amphiphilic emulsifier is selected from the group consisting of egg yolk lecithin and soybean lecithin. (Additional note 5) 5. The method according to any one of appended items 1 to 4, wherein the polar liquid carrier is selected from the group consisting of water, an aqueous solution, and a non-aqueous polar liquid. (Additional note 6) 6. The method according to any one of appended items 1 to 5, wherein the non-aqueous polar liquid is selected from the group consisting of dimethyl sulfoxide, polyethylene glycol, and polar silicone liquid. (Additional note 7) 7. The method according to any one of appended items 1 to 6, wherein the electrolyte is selected from the group consisting of one or more of sodium chloride, sodium bicarbonate, sodium citrate, sodium lactate, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium glycerophosphate, sodium carbonate, amino acid sodium salt, sodium propionate, sodium hydroxybutyrate, sodium gluconate, potassium chloride, potassium acetate, potassium gluconate, potassium bicarbonate, potassium glycerophosphate, potassium sulfate, potassium lactate, potassium iodide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium citrate, amino acid potassium salt, potassium propionate, potassium hydroxybutyrate, calcium chloride, calcium gluconate, calcium lactate, calcium glycerophosphate, calcium pantothenate, calcium acetate, magnesium chloride, magnesium sulfate, magnesium glycerophosphate, magnesium acetate, magnesium lactate, amino acid magnesium salt, ammonium chloride, zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, zinc acetate, ferrous sulfate, ferrous chloride, ferrous gluconate, copper sulfate, and manganese sulfate. (Additional note 8) The method according to any one of appendix 1 to 7, wherein the PN composition is administered intravenously, intraarterially, intraosseously, or intracardially. (Additional note 9) The PN composition is 1 to 50,000 ml of O 2 9. The method according to any one of appendixes 1 to 8, wherein the oxygenated PN composition has an oxygen content of 1 / 100 ml of the PN composition. (Additional note 10) 10. The method according to any one of appended items 1 to 9, wherein the PN composition has an emulsifier:lipophilic or hydrophobic component ratio (w / w) of about 1:200 to about 1:1.7. (Additional note 11) The method according to any one of appended claims 1 to 10, wherein the PN composition comprises micelles and liposomes, and the micelles in the PN composition have a diameter in the range of 30 to 200 nm when measured by electron microscopy, and the liposomes in the PN composition have a diameter in the range of 1 to 25 nm when measured by electron microscopy. (Additional note 12) 12. The method according to any one of claims 1 to 11, wherein the PN composition has a magnesium ion concentration in the sub-physiological range. (Additional note 13) 13. The method of any one of appendix 1 to 12, wherein the PN composition further comprises one or more selected from the group consisting of a crystalloid agent, a bulking agent, an anti-inflammatory agent, an immunomodulatory agent, and a lipophilic gas. (Additional note 14) The method according to any one of appendixes 1 to 13, wherein the PN composition further comprises glycerin. (Additional note 15) 15. The method according to any one of appendixes 1 to 14, wherein the subject has MODS induced by sepsis caused by a viral infection. (Additional note 16) 16. The method of appendix 15, wherein the subject has MODS induced by sepsis caused by the COVID19 virus. (Additional note 17) 15. The method according to any one of appendixes 1 to 14, wherein the subject has MODS induced by sepsis caused by a bacterial infection. (Additional note 18) 15. The method according to any one of appendixes 1 to 14, wherein the subject has MODS induced by sepsis caused by a fungal infection. (Additional note 19) 15. The method of any one of appendixes 1 to 14, wherein the subject has MODS induced by sepsis caused by a parasitic infection. (Additional note 20) 20. The method of any one of appendix 1 to 19 for treating sepsis-induced multiple organ dysfunction syndrome (MODS) in a subject, comprising: For those in need of treatment, a lipophilic or hydrophobic component in an amount of 0-35% (w / v); an amphiphilic emulsifier in an amount of 0.6% to 60% (w / v); a polar liquid carrier, and One or more electrolytes increasing oxygen saturation by administering an effective amount of a phospholipid nanoparticle (PN) composition comprising: The method, wherein the micelles in the PN composition have diameters in the range of 30 to 200 nm as measured by electron microscopy, and the PN composition comprises liposomes having diameters of 1 to 25 nm. (Additional note 21) 21. The method of any one of appendix 1 to 20 for treating sepsis-induced multiple organ dysfunction syndrome (MODS) in a subject, For those in need of treatment, a lipophilic or hydrophobic component in an amount of 0-35% (w / v); an amphiphilic emulsifier in an amount of 0.6% to 60% (w / v); a polar liquid carrier, and One or more electrolytes alleviating hypoxia by administering an effective amount of a phospholipid nanoparticle (PN) composition comprising: The method, wherein the micelles in the PN composition have diameters in the range of 30 to 200 nm as measured by electron microscopy, and the PN composition comprises liposomes having diameters of 1 to 25 nm. (Additional note 22) 22. The method of any one of appendixes 1 to 21 for treating multiple organ dysfunction syndrome (MODS) in a subject, comprising: For those in need of treatment, a lipophilic or hydrophobic component in an amount of 0-35% (w / v); an amphiphilic emulsifier in an amount of 0.6% to 60% (w / v); a polar liquid carrier, and One or more electrolytes increasing oxygen saturation by administering an effective amount of a phospholipid nanoparticle (PN) composition comprising: The method, wherein the micelles in the PN composition have diameters in the range of 30 to 200 nm as measured by electron microscopy, and the PN composition comprises liposomes having diameters of 1 to 25 nm. (Additional note 23) 23. The method of any one of appendixes 1 to 22 for treating multiple organ dysfunction syndrome (MODS) in a subject, comprising: For those in need of treatment, a lipophilic or hydrophobic component in an amount of 0-35% (w / v); an amphiphilic emulsifier in an amount of 0.6% to 60% (w / v); a polar liquid carrier, and One or more electrolytes alleviating hypoxia by administering an effective amount of a phospholipid nanoparticle (PN) composition comprising: The method, wherein the micelles in the PN composition have diameters in the range of 30 to 200 nm as measured by electron microscopy, and the PN composition comprises liposomes having diameters of 1 to 25 nm. (Additional note 24) 1. A method of treating multiple organ dysfunction syndrome (MODS) in a subject, wherein the subject has MODS caused by a critical illness; The method comprises administering to a subject in need of treatment: a lipophilic or hydrophobic component in an amount of 0-35% (w / v); an amphiphilic emulsifier in an amount of 0.1% to 60% (w / v); Polar Liquid Carrier administering an effective amount of a phospholipid nanoparticle (PN) composition comprising: The method, wherein the PN composition comprises liposomes and / or micelles having a diameter of 1 to 800 nm.

Claims

1. A composition for treating multiple organ dysfunction syndrome (MODS), comprising a phospholipid nanoparticle (PN) composition, The PN composition comprises a lipophilic or hydrophobic component in an amount of 1-40% (w / v), an amphiphilic emulsifier in an amount of 0.1% to 60% (w / v); a polar liquid carrier, and containing one or more electrolytes, The PN composition comprises liposomes and / or micelles having a diameter of 1 to 800 nm. Composition for MODS treatment.

2. 2. The composition for treating MODS of claim 1, wherein the lipophilic or hydrophobic component is selected from the group consisting of soybean oil, chia bean oil, and algae oil.

3. 3. The composition for treating MODS according to claim 1, wherein the amphiphilic emulsifier is selected from the group consisting of phospholipids and α-phosphatidylcholine.

4. The composition for treating MODS according to any one of claims 1 to 3, wherein the amphiphilic emulsifier is selected from the group consisting of egg yolk lecithin and soybean lecithin.

5. The composition for MODS treatment according to any one of claims 1 to 4, wherein the polar liquid carrier is selected from the group consisting of water, an aqueous solution, and a non-aqueous polar liquid.

6. 6. The MODS therapeutic composition of claim 5, wherein the non-aqueous polar liquid is selected from the group consisting of dimethyl sulfoxide, polyethylene glycol, and polar silicone liquids.

7. 7. The composition for treating MODS according to any one of claims 1 to 6, wherein the electrolyte is selected from the group consisting of one or more of sodium chloride, sodium bicarbonate, sodium citrate, sodium lactate, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium glycerophosphate, sodium carbonate, sodium amino acid salts, sodium propionate, sodium hydroxybutyrate, sodium gluconate, potassium chloride, potassium acetate, potassium gluconate, potassium bicarbonate, potassium glycerophosphate, potassium sulfate, potassium lactate, potassium iodide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium citrate, amino acid potassium salts, potassium propionate, potassium hydroxybutyrate, calcium chloride, calcium gluconate, calcium lactate, calcium glycerophosphate, calcium pantothenate, calcium acetate, magnesium chloride, magnesium sulfate, magnesium glycerophosphate, magnesium acetate, magnesium lactate, amino acid magnesium salts, ammonium chloride, zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, zinc acetate, ferrous sulfate, ferrous chloride, ferrous gluconate, copper sulfate, and manganese sulfate.

8. The composition for treating MODS according to any one of claims 1 to 7, which is administered intravenously, intraarterially, intraosseously or intracardially.

9. The PN composition contains 1 to 50 ml of O in 100 ml of the PN composition. 2 The composition for treating MODS according to any one of claims 1 to 8, which is an oxygenated PN composition having an oxygen content of

10. 10. The composition for treating MODS according to any one of claims 1 to 9, wherein the PN composition has an emulsifier:lipophilic or hydrophobic component ratio (w / w) of 1:200 to 1:1.

7.

11. The composition for MODS treatment according to any one of claims 1 to 10, wherein the micelles in the PN composition have diameters in the range of 30 to 200 nm as measured by electron microscopy, and the liposomes in the PN composition have diameters in the range of 1 to 25 nm as measured by electron microscopy.

12. The composition for treating MODS according to any one of claims 1 to 11, wherein the PN composition further comprises one or more selected from the group consisting of a crystalloid agent, a swelling agent, an anti-inflammatory agent, an immunomodulatory agent, and a lipophilic gas.

13. The composition for treating MODS according to any one of claims 1 to 12, wherein the PN composition further comprises glycerin.

14. The composition for treating MODS according to any one of claims 1 to 13, wherein the MODS includes MODS induced by sepsis caused by a viral infection.

15. The composition for treating MODS according to claim 14, wherein the MODS comprises MODS induced by sepsis caused by the COVID-19 virus.

16. The composition for treating MODS according to any one of claims 1 to 13, wherein the MODS includes MODS induced by sepsis caused by bacterial infection.

17. The composition for treating MODS according to any one of claims 1 to 13, wherein the MODS includes MODS induced by sepsis caused by a fungal infection.

18. The composition for treating MODS according to any one of claims 1 to 13, wherein the MODS includes MODS induced by sepsis caused by a parasitic infection.

19. The MODS is caused by sepsis, and the PN composition comprises: a lipophilic or hydrophobic component in an amount of 1-40% (w / v), an amphiphilic emulsifier in an amount of 0.6% to 60% (w / v); a polar liquid carrier, and One or more electrolytes Contains 19. A composition for treating MODS according to any one of claims 1 to 18, for increasing oxygen saturation, wherein the micelles in the PN composition have diameters in the range of 30 to 200 nm as measured by electron microscopy, and the PN composition comprises liposomes having diameters of 1 to 25 nm.

20. The MODS is caused by sepsis, and the PN composition comprises: a lipophilic or hydrophobic component in an amount of 1-40% (w / v), an amphiphilic emulsifier in an amount of 0.6% to 60% (w / v); a polar liquid carrier, and One or more electrolytes Contains 20. A composition for treating MODS according to any one of claims 1 to 19, for alleviating hypoxia, wherein the micelles in the PN composition have diameters in the range of 30 to 200 nm as measured by electron microscopy, and the PN composition comprises liposomes having diameters of 1 to 25 nm.

21. The PN composition is a lipophilic or hydrophobic component in an amount of 1-40% (w / v), an amphiphilic emulsifier in an amount of 0.6% to 60% (w / v); a polar liquid carrier, and One or more electrolytes Contains 21. A composition for treating MODS according to any one of claims 1 to 20, for increasing oxygen saturation, wherein the micelles in the PN composition have diameters in the range of 30 to 200 nm as measured by electron microscopy, and the PN composition comprises liposomes having diameters of 1 to 25 nm.

22. The PN composition is a lipophilic or hydrophobic component in an amount of 1-40% (w / v), an amphiphilic emulsifier in an amount of 0.6% to 60% (w / v); a polar liquid carrier, and One or more electrolytes Contains 22. A composition for treating MODS according to any one of claims 1 to 21, for alleviating hypoxia, wherein the micelles in the PN composition have diameters in the range of 30 to 200 nm as measured by electron microscopy, and the PN composition comprises liposomes having diameters of 1 to 25 nm.

23. A composition for treating multiple organ dysfunction syndrome (MODS) caused by a critical illness, comprising a phospholipid nanoparticle (PN) composition, The PN composition comprises a lipophilic or hydrophobic component in an amount of 1-40% (w / v), an amphiphilic emulsifier in an amount of 0.1% to 60% (w / v), and Polar Liquid Carrier Contains The PN composition comprises liposomes and / or micelles having a diameter of 1 to 800 nm. Composition for MODS treatment.

24. A composition for treating multiple organ dysfunction syndrome (MODS), comprising a phospholipid nanoparticle (PN) composition, The PN composition comprises a lipophilic or hydrophobic component selected from the group consisting of soybean oil, chia bean oil, and algae oil in an amount of 1-40% (w / v); an amphiphilic emulsifier selected from the group consisting of egg yolk lecithin and soybean lecithin in an amount of at least 0.1% (w / v); a polar liquid carrier, and One or more electrolytes Contains The PN composition comprises liposomes and / or micelles having a diameter of 1 to 800 nm. Composition for MODS treatment.

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