Compositions and methods for treating or preventing multiple organ dysfunction syndrome

Abstract

This invention provides methods for treating or preventing multiple organ dysfunction syndrome. [Solution] A method for 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 0-35% (w / v) of a lipophilic or hydrophobic component, 0.1-60% (w / v) of an amphiphilic emulsifier, a polar liquid carrier, and one or more electrolytes, wherein the PN composition comprises liposomes and / or micelles having a diameter of 1-800 nm.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Application No. 63 / 004,769, filed on 3 April 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 failure syndrome (MODS) is a form of multiple organ failure in the body that requires intensive medical intervention. MODS is a leading cause of morbidity and mortality in current ICU care. MODS can be caused by a wide variety of factors, including major trauma, burns, eclampsia, sepsis, pancreatitis, aspiration syndrome, cardiopulmonary bypass (e.g., cardiac bypass), multiple transfusions, ischemia-reperfusion injury, autoimmune diseases, heat-induced diseases, or poisoning / toxicity. MODS is strongly associated with widespread inflammation. However, anti-inflammatory drugs have not shown efficacy in treating MODS. A single, clear cause of MODS remains unknown.

[0004] Management of MODS aims to address the underlying causes and provide targeted support specific to the dysfunction of each vital organ. The lungs are supported by mechanical ventilation to increase oxygen delivery to the lungs. The kidneys are supported by dialysis. The heart is supported by pharmacological drugs or devices that increase cardiac output. At this point, there is probably no routine support for liver failure other than existing experimental protocols.

[0005] Some attempts to reverse vascular failure have focused on treating the hypotension (low blood pressure) and / or reducing high levels of nitric oxide (NO), which are typically seen in patients with septic shock. Excessive production of NO causes vasodilation and a drop in blood pressure. However, simply raising blood pressure does not automatically lead to improvement in other organ systems. In fact, the administration of levofed, a vasoconstrictor used 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, actually resulting in increased mortality and multiple organ failure.

[0006] In patients with MODS, the blood's response to vasopressors that constrict blood vessels and raise blood pressure is significantly reduced. Furthermore, myocardial contractility decreases. Other vasoactive agents, such as dobutamine, which increase myocardial contractility, or other drugs that act through other mechanisms, also cannot reverse the adverse effects of MODS. When a patient dies, they lose their response to vasopressors, and their blood pressure drops to unsustainable levels. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] Considering the above, there is a need for treatment that improves organ function in patients with MODS. Unexpectedly, the inventors of this application have found that administration of a phospholipid nanoparticle (PN) composition can prevent or alleviate multi-organ dysfunction syndrome. [Means for solving the problem]

[0008] One aspect of this application relates to a method for reducing or preventing multiple organ dysfunction syndrome (MODS) in subjects requiring reduction or prevention of MODS. The method comprises administering to a subject requiring treatment an effective amount of a phospholipid nanoparticle (PN) composition comprising 0-35% (w / v) of a lipophilic or hydrophobic component, 0.1-60% (w / v) of an amphiphilic emulsifier, 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 10-50% (w / v) of the lipophilic or hydrophobic component and the amphiphilic emulsifier in total.

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

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

[0011] In certain embodiments, the amphiphilic emulsifier is selected from the group consisting of phospholipids and α-phosphatidylcholine. In certain embodiments, the amphiphilic emulsifier is selected from the group consisting of egg yolk lecithin, soy 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 the following: 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, potassium amino acid 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, magnesium amino acid salts, ammonium chloride, zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, zinc acetate, iron sulfate, iron chloride, iron gluconate, copper sulfate, and manganese sulfate.

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

[0016] In certain embodiments, the PN composition has a magnesium ion concentration in the quasi-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 when measured by an electron microscope, and the liposomes in the PN composition have an average diameter in the range of 1 - 25 nm when measured by an electron microscope. In certain embodiments, the PN composition comprises micelles and liposomes, wherein the micelles in the PN composition have a diameter in the range of 15 - 800 nm when measured by an electron microscope, and the liposomes in the PN composition have a diameter in the range of 1 - 300 nm when measured by an electron microscope.

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

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

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

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

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

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

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

[0027] [Figure 1] This figure shows the uptake of nitric oxide by water (Panel A) and PN composition (Panel B) as measured by mass spectrometry. [Modes for carrying out the invention]

[0028] This application provides detailed reference to specific aspects and exemplary embodiments of this application, illustrating examples of structures and figures. The aspects of this application are described in conjunction with exemplary embodiments, including methods, materials, and examples, and such descriptions are not limiting. The scope of this application is intended to encompass all equivalents, substitutes, and modifications that are generally known or incorporated herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this application belongs. Those skilled in the art will recognize many similar or equivalent technologies and materials described herein that can be used in carrying out the aspects and embodiments of this application. The aspects and embodiments described herein are not limited to the methods and materials described.

[0029] As used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless the content clearly indicates otherwise.

[0030] Ranges may be expressed herein as “approximately” from one particular value and / or “approximately” to another particular value. Where such ranges are expressed, another embodiment includes one particular value and / or another particular value. Similarly, where a value is expressed as an approximation using the antecedent “approximately,” it will be understood that a particular value forms another embodiment. It will be further understood that the endpoint of each range is significant with respect to the other endpoint, and independently of the other endpoint. It should also be understood that there are several values ​​disclosed herein, and each value is disclosed herein not only as the value itself but also as “approximately” that particular value. For example, if the value “10” is disclosed, “approximately 10” is also disclosed. As will be appropriately understood by those skilled in the art, where a value is disclosed, it will also be understood that “less than or equal to” that value, “greater than or equal to” that value and possible ranges between the 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 severe illness” means any condition that causes a patient to require immediate intensive care. This condition may be caused by acute and widespread injury to the body, including but not limited to physical trauma, burns, infection (as herein, sepsis, severe sepsis, septic shock), systemic inflammatory response syndrome (SIRS), acute myocardial infarction, or other thromboembolic events.

[0032] The term “intensive care,” also referred to herein as “organ supportive care,” may include, but are not limited to, ventilation (e.g., mechanical ventilation), hemodialysis, vasopressor therapy, fluid therapy, transfusion therapy involving the administration of red blood cell concentrates, fresh frozen plasma, platelet concentrates, whole blood, or coagulation factor concentrates, systemic antibiotic and / or antiviral and / or antifungal and / or antiparasitic therapy, parenteral nutrition, granulocyte infusion, T cell infusion, stem cell infusion, antithrombotic therapy including anticoagulants and / or low molecular weight heparin, administration of corticosteroids, and strict blood glucose control.

[0033] As used herein, the term “trauma” means any shock or bodily injury resulting from an accident caused by an external cause such as blast trauma, blunt trauma, penetrating trauma, chemical injury (spilling, war or poisoning), radiation or burns, injury, or sudden physical injury such as impact to living tissue.

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

[0035] As used herein, the terms “treatment” and “to treat” refer to the management and care of a patient who has or is at risk of developing Multi Organ Failure Syndrome (MODS). This term is intended to encompass the full range of treatments for this condition, including the administration of the phospholipid nanoparticle compositions of this application for the purpose of reducing the risk of or preventing the condition, disease, or disability, including improving, alleviating, or reducing symptoms or complications; slowing the progression of the condition, disease, or disability; curing or eliminating the condition, disease, or disability; and / or preventing recurrence of the disease. Here, “to prevent” or “prevention” should be understood to refer to the management and care of a patient for the purpose of preventing the development of the condition, disease, or disability, and includes the administration of PN compositions to prevent the development of symptoms or complications. The individuals being treated are human. Individuals being treated in accordance with this application may be of various ages and / or sexes.

[0036] The term "organ failure" refers to changes in organ function in patients with acute illness who require medical intervention to achieve homeostasis and / or to compensate for the loss of function from the dysfunctional organ. Organs include, but are 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" (MODS) refers to the pathologically altered function of multiple organs in patients with acute illness who require intervention to achieve homeostasis and / or compensate for the loss of function from dysfunctional organs. The primary cause is an uncontrolled inflammatory response. Sepsis is the most common cause in both surgical and non-surgical patients. 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 eventually progress to MODS. However, in one-third of patients, the primary cause cannot be identified. MODS is well established as the final stage of a continuum ranging from SIRS to sepsis, severe sepsis, and MODS. It should be noted that MODS is different from reperfusion injury. In reperfusion, there is a period of no or little blood flow. Once blood flow is restored, reperfusion injury arises from reactive oxygen species. Reactive oxygen species scavengers can protect against reperfusion injury. However, such scavengers do not protect against MODS. MODS can occur even without interruption of blood flow. This application provides a method for eliminating sepsis and other inducing factors of MODS. For example, the method of this application may be used to treat MODS induced by sepsis caused by influenza virus or coronavirus (e.g., SARS, MERS, and COVID-19 viruses (including variants)) infections, 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 failure or decreased tissue perfusion (e.g., manifesting as hypotension, elevated lactate, decreased urine output, or altered mental state). "Septic shock" is severe sepsis plus persistent hypotension despite intravenous fluid administration. Sepsis can lead to severe sepsis, septic shock, multiple organ failure 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 if two or more of the following criteria are present: 1) body temperature below 36°C (96.8°F) or above 38°C (100.4°F); 2) heart rate greater than 90 beats per minute; 3) tachypnea (high respiratory rate) greater than 20 breaths per minute or arterial carbon dioxide partial pressure less than 4.3 kPa (32 mmHg); 4) 4000 cells / mm³ 3 (4×10 9 less than 12,000 cells / mm³ (cells / L) 3 (12×10 9 A white blood cell count exceeding 10% (cells / L), or the presence of more than 10% immature neutrophils (band morphology). If infection is suspected or confirmed (by culture, staining, or polymerase chain reaction (PCR)), along with SIRS, this is sepsis by definition.

[0040] The term "systemic inflammation" refers to changes in organ function in patients with acute illness due to the nonspecifically conserved responses of the body (vascular system, immune system, tissues) to infection, non-infectious antigens, trauma, burns, organ / tissue destruction / degeneration / injury, ischemia, hemorrhage, poisoning, and / or malignant tumors.

[0041] The terms “micelle” and “lipid-supported micelle (LM)” are used interchangeably herein with reference to aggregates of molecules dispersed in a liquid, including aggregates having a hydrophilic “head” region in contact with the surrounding solvent, which isolates a hydrophobic single tail region of the micelle center 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 having a tail group containing a long hydrophobic hydrocarbon chain and a hydrophilic head group. The lipids are arranged to form a lipid bilayer having 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 this application relates to a method for treating or preventing multiple organ dysfunction syndrome (MODS) in a patient, comprising administering an effective amount of a phospholipid nanoparticle (PN) composition comprising the PN composition of this application to the subject. The inventors of this application have unexpectedly found that administration of the PN composition of this application can prevent or alleviate multiple organ dysfunction syndrome (MODS).

[0044] The PN compositions of this application may be used to treat or prevent MODS caused by several different disease conditions affecting tissue damage, including but not limited to sepsis, major trauma, burns, pancreatitis, aspiration syndrome, extracorporeal circulation (e.g., cardiac bypass), multiple transfusions, ischemia-reperfusion injury, autoimmune diseases, heat-induced diseases, eclampsia, and poisoning / toxicity. In some embodiments, the PN compositions of this 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 the PN composition of this application in an amount effective to provide reversible uptake and release of nitric oxide in the treatment or prevention of MODS. This 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. Overproduction of NO causes vasodilation and hypotension. In patients with MODS or at risk of developing MODS, the blood response to vasopressors such as levofed, vasopressin, or epinephrine, which constrict blood vessels and raise blood pressure, is significantly reduced.

[0046] Nitric oxide synthase (NOS) is an enzyme that catalyzes the conversion of arginine to NO. Previously, NOS inhibitors (546C88) were tested to mitigate 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 necessary to maintain vascular patency. Therefore, removing NO increases blood pressure but also decreases tissue perfusion, promoting organ failure. Another problem with inhibiting NOS is its role in promoting mitochondrial electron transport and ATP production. However, NOS inhibition is known to decrease mitochondrial oxygen consumption rate and ATP production, potentially leading to mitochondrial oxidative stress and irreversible damage.

[0047] While we do not wish to be bound by theory, the PN compositions of this application are thought to include a variable reservoir of nitric oxide that may take in or release nitric oxide in a manner that varies with the local concentration of nitric oxide, in order to provide more effective control of NO, which is predicted to be based in part on the fact that both NO and the phospholipid nanoparticle (PN) compositions of this application are hydrophobic.

[0048] In this case, NO preferentially localizes in the hydrophobic region 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 this application as measured by mass spectrometry. The experimental procedure is described in Example 8.

[0049] Unlike nitric oxide inhibitors or nitric oxide scavengers that do not release nitric oxide, PN rapidly releases absorbed nitric oxide. This allows PN to act as a nitric oxide redistributor, releasing it to reduce bioavailability in areas of overproduction and to increase nitric oxide concentration in areas of insufficient concentration, thereby shifting the nitric oxide balance from one favorable to non-survivability to one favorable to survival. PN and its analogues can be considered a new class of therapeutic agents called nitric oxide redistributors, in contrast to inhibitors and scavengers.

[0050] Therefore, it is thought that injecting PN into the bloodstream allows for the uptake of excess NO, which can be readily released in areas where local concentrations are deficient. In other words, PN compositions help reduce the bioavailability of NO without affecting its biosynthesis or paracrine-autocrine effects. Reducing excess nitric oxide can also reduce the production of peroxynitrite, a highly reactive free radical that is a product of the reaction between nitric oxide and superoxide. In some embodiments, PN compositions are injected into MODS patients to achieve mean blood pressure targets of 60–65 mHg or other preferred blood pressure targets required by the clinical situation.

[0051] In some embodiments, patients receiving the PN composition of this application are being treated with or are being treated with vasopressors (also known as vasoactive agents). Examples of vasopressors and vasoactive agents include, but are not limited to, levofed, vasopressin and epinephrine, diapreza, phenylephrine, dopamine and dobutamine.

[0052] The PN composition of this application may be administered intravenously, intra-arterially, intraosseously, or intracardiacly to subjects requiring such treatment. In certain embodiments, the PN composition may be administered in quantities 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, or 200-400 ml. The PN composition is administered in amounts of 0 ml, 200-3000 ml, 200-2000 ml, 200-1000 ml, 200-500 ml, 500-5000 ml, 500-4000 ml, 500-3000 ml, 500-2000 ml, 500-1000 ml, 1000-5000 ml, 1000-4000 ml, 1000-3000 ml, and 1000-2000 ml. In some embodiments, the PN composition is administered in amounts equivalent to approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the target's normal blood volume over a period of 30 seconds to 24 hours.

[0053] In a specific embodiment, the PN composition is used in the following flow rates: 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, and 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 flow rate is given at 0 ml / min, 200-1000 ml / min, 200-500 ml / min, 500-5000 ml / min, 500-4000 ml / min, 500-3000 ml / min, 500-2000 ml / min, 500-1000 ml / min, 1000-5000 ml / min, 1000-4000 ml / min, 1000-3000 ml / min, 1000-2000 ml / min, 2000-5000 ml / min, 2000-4000 ml / min, 2000-3000 ml / min, 3000-5000 ml / min, or 4000-5000 ml / min.

[0054] In yet another embodiment, the PN composition is supplied at a rate of approximately 500-700 ml / min, 400-800 ml / min, or 300-900 ml / min.

[0055] In some embodiments, the PN composition is given 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 of O2 / 100 ml of the PN composition.

[0056] The "effective amount" of the PN composition required to raise blood pressure in a subject may be determined using perfusion of the brain, kidneys, heart, muscles, spleen, or other tissues, cardiac output, systolic blood pressure, diastolic blood pressure, mean arterial pressure, stroke volume coefficient, mitochondrial oxidative phosphorylation and subsequent near-infrared spectroscopy or other means, blood lactate, or other hemodynamic parameters such as membrane polarization.

[0057] While the PN composition of this application is administered to a subject and circulating within the subject, various drugs such as cardiac arresters or inotropes may be directly administered to the subject's circulatory system, directly administered to the subject's myocardium, or added to the PN composition of this application. These components are added to achieve desired physiological effects, such as maintaining regular cardiac contractile activity, cessating cardiac fibrillation, or completely inhibiting the contractile activity of the myocardium or heart muscle.

[0058] Cardiac arresting agents are materials that stop myocardial contraction and contain anesthetics such as lidocaine, procaine, and novocaine, as well as monovalent cations such as potassium ions in a concentration sufficient to achieve myocardial contraction inhibition. The concentration of potassium ions sufficient to achieve this effect is 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 substance-supported 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 composition of this application comprises LMs and liposomes having diameters of 1-500 nm, 1-400 nm, 1-300 nm, or 1-200 nm, as determined by electron microscopy.

[0061] In some embodiments, the PN composition of this application is (1) determined by electron microscopy to be 30-500nm, 30-400nm, 30-300nm, 30-200nm, 30-150nm, 30-120nm, 30-100nm, 30-80nm, 30-500nm, 30-400nm, 30-300nm, 30-200nm, 3 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) comprising LM having a diameter of ~120 nm, 50~100 nm, 50~80 nm, 100~500 nm, 100~400 nm, 10~300 nm, 100~200 nm, 100~150 nm or 100~120 nm, and (2) liposomes having a diameter of 1~30 nm, 1~25 nm, 1~20 nm, 1~15 nm, 1~10 nm, 3~30 nm, 3~25 nm, 3~20 nm, 3~15 nm, 3~10 nm, 5~30 nm, 5~25 nm, 5~20 nm, 5~15 nm, 5~10 nm, 1~30 nm, 7~25 nm, 7~20 nm, 7~15 nm, 7~10 nm, 10~30 nm, 10~25 nm, 10~20 nm or 10~15 nm, as determined by electron microscope.

[0062] In some embodiments, the PN composition of this application, when determined by electron microscope, has wavelengths of 1-100nm, 1-80nm, 1-50nm, 1-40nm, 1-30nm, 1-25nm, 1-20nm, 1-15nm, 1-10nm, 1-5nm, 5-100nm, 5-80nm, 5-50nm, 5-40nm, 5-30nm, 5-25nm, 5-20nm, 5-15nm, 5-10nm, 10-100nm, 10-80nm, 10-50nm, 10-40nm, 10-30nm, 10-25nm, 10-20nm, 15-100nm, 15-80nm, The PN composition comprises 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 composition of this application comprises 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, when the PN composition of this application is determined by dynamic light scattering using, for example, the Malvern Zetasizer model or nanoZS, the wavelengths are 10-300nm, 10-200nm, 10-150nm, 10-120nm, 10-100nm, 10-90nm, 10-70nm, 10-50nm, 10-30nm, 30-300nm, 30-200nm, 30-150nm, 30-120nm, 30-100nm, 30-90nm, 30-70nm, 30-50nm, 50-300nm, 50-200nm, 50-150nm, 50-120nm, 50-100nm, 50-90nm, 50-70nm, 70-3 The product contains nanoparticles (including both micelles and liposomes) having an average diameter of 00nm, 70-200nm, 70-150nm, 70-120nm, 70-100nm, 70-90nm, 80-300nm, 80-200nm, 80-150nm, 80-120nm, 80-100nm, 80-90nm, 90-300nm, 90-200nm, 90-150nm, 90-120nm, 90-100nm, 100-300nm, 100-200nm, 100-150nm, 100-120nm, 120-300nm, 120-200nm, 120-150nm, 150-300nm, 150-200nm, or 200-300nm. In some embodiments, the PN compositions of this application include nanoparticles having an average particle size of 92-96 nm, 90-98 nm, or 85-105 nm.

[0064] The lipophilic or hydrophobic components are dispersed in a polar liquid carrier to form nanoemulsions containing monolayer micelles having a polar outer surface and an internal hydrophobic space filled with the lipophilic or hydrophobic components and / or other hydrophobic molecules, and bilayer liposomes having a polar outer surface and an internal hydrophilic space. Since hydrophobic gases such as oxygen and nitric oxide (NO) preferentially dissolve in the lipid core of the micelles compared to water or other aqueous environments, the PN composition of this application provides the ability to deliver oxygen and other hydrophobic gases to body tissues.

[0065] The solubility of hydrophobic gases in lipophilic or hydrophobic cores facilitates the uptake and transport of these gases into tissues. Endogenously produced gases such as carbon monoxide, nitric oxide, and hydrogen sulfide can also be transported into emulsions to regulate vascular tone and apoptotic processes.

[0066] In some embodiments, the PN composition is an oxygenated PN composition having 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 of O2 / 100 ml of the PN composition.

[0067] In some embodiments, the PN composition contains 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 per 100 ml of the PN composition.

[0068] Xenon and argon are hydrophobic gases that can protect the brain in pathological conditions such as seizures. In some embodiments, the PN composition contains Xe or Ar or both in an amount of O2 / 100ml of the PN composition 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.

[0069] In some embodiments, the PN composition of this application further comprises an apoptosis inhibitor (e.g., Z-VAD-FMY, an apoptosis inhibitory peptide), a mitochondrial integrity protector (e.g., cyclosporine A, an inhibitor of mitochondrial pore opening), a signaling modulator such as diacylglycerol or cyclic GMP, or an antioxidant such as coenzyme Q10.

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

[0071] In certain cases, the PN compositions of this application can exert penetrating 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 factors. Therefore, in some cases, the PNs of this application can absorb toxic molecules produced by MODS patients. For example, lymphoid factors produced in the intestinal and thoracic lymph nodes may lead to acute lung injury and red blood cell deformability. Other toxic molecules include, but are not limited to, leukotrienes, prostaglandins, nitric oxide, endotoxins, and tumor necrosis factor (TNF). The PN in the PN composition enables the effective absorption of lipophilic or hydrophobic chemical mediators. In other cases, the PNs may be filled with antagonists to toxic chemical mediators, such as antibodies against endotoxins.

[0072] For example, in MODS patients with 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 LM 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 longer. Stability may be determined by measuring the change in micelle diameter. Unstable emulsions will have micelles that coalesce to form larger diameter micelles. 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 5% to 40% (w / v) of soybean oil and 0.1% to 18% (w / v) of lecithin. In some embodiments, the PN composition further comprises 50 to 200 mM of NaCl. In some embodiments, the PN composition further comprises 1 to 5% of glycerin. 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, 2.25% (w / v) egg lecithin, and 77 mM NaCl.

[0075] In some embodiments, the composition is formed from 10% to 40% (w / v), preferably 15% to 35% of soybean oil, 6% to 18% (w / v), preferably 10% to 15% of lecithin, sodium chloride and sodium lactate as electrolytes, with a total electrolyte composition of 50 mM to 200 mM, 0.1 mM to 10 mM of histidine, and water, so that the lecithin forms (1) lipid-supported micelles having a lipophilic or hydrophobic core in an 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 (L), 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 (L), 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 soy lecithin, 0.6% (w / v) NaCl, 0.385% (w / v) sodium lactate (L), and 0.155% (w / v) histidine, and the PN composition is prepared under conditions that form nanoparticles (including liposomes and micelles) having an average diameter of 80–120 nm when 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 when measured by electron microscopy, and micelles having a diameter in the range of 30–130 nm or 40–100 nm when measured by electron microscopy.

[0078] In another embodiment, the PN composition comprises 30% (w / v) soybean oil, 12% (w / v) egg lecithin or soy lecithin, 0.6% (w / v) NaCl, 0.385% (w / v) sodium lactate (L), and 0.155% (w / v) histidine, and the PN composition is prepared under conditions that form nanoparticles (including liposomes and micelles) having an average diameter of 80–120 nm when 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 when measured by electron microscopy, and micelles having a diameter in the range of 30–130 nm or 40–100 nm when measured by electron microscopy.

[0079] Other oils, such as chia bean, pumpkin seed, or oils from other sources, may be used. In certain embodiments, the above PN composition may further contain about 2-40% (w / v), about 2-20% (w / v), about 4-10% (w / v), or about 5% (w / v) of albumin or albumin polymer or albumin polymer conjugated with amino acids or peptides, which are added to the PN composition after micelle formation. In other embodiments, hydrophobic or hydrophilic components are supported within the erythrocyte ghost.

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

[0081] In certain embodiments, the PN composition of this 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-acetylamino acid at a final concentration of 0.2 to 20 mM, 0.5 to 10 mM, 0.5 to 5 mM, or 0.5 to 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 be in the range of about 1:400 to about 1:1, preferably 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 approximately 1.2:100.

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

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

[0085] In one embodiment, the PN composition contains soybean oil, egg phospholipid, and an amino acid, beta-endorphin, or other regulator that acts at a femtomolar concentration or a concentration exceeding that, at a final concentration of 0.1 femtomolar (fM) to 10 mM.

[0086] The PN composition of the present application does not contain hemoglobin, derivatives of hemoglobin, perfluorocarbons, and derivatives of perfluorocarbons. As used herein, a composition is "free of hemoglobin, derivatives of hemoglobin, perfluorocarbons, and derivatives of perfluorocarbons" if it contains no hemoglobin, derivatives of hemoglobin, perfluorocarbons, and derivatives of perfluorocarbons, or if it contains hemoglobin, derivatives of hemoglobin, perfluorocarbons, and derivatives of perfluorocarbons at a level of less than 0.1% w / v.

[0087] The PN composition of the present application typically does not contain Ca ++ , K + , Mg ++ and Al +++ . In certain embodiments, Ca ++ and K + are added to the PN composition immediately before use (e.g., within 24 hours before use). In other embodiments, Ca ++ is premixed with the PN composition. Since Al +++ is toxic to bone, brain, hematopoiesis, heme synthesis, globulin synthesis, iron absorption and metabolism, and fetal development, all oils and other components contain the minimum amount of Al possible.+++ It must have Al at concentrations of 25 mg / l, 20 mg / l, 10 mg / l, or less than 5 mg / l. In certain embodiments, the PN composition contains Al at concentrations of 25 mg / l, 20 mg / l, 10 mg / l, or less than 5 mg / l. +++ It contains Al +++ It does not contain, meaning it cannot be detected by conventional methods.

[0088] In certain embodiments, the micelles in the PN composition of this application are free-moving micelles that are not encapsulated in any type of particle. Furthermore, the micelle walls are composed of either a single or double layer of amphiphilic emulsifier molecules so that the micelles can readily annex with the cell membranes of the tissue in which they come into contact with the PN composition. In addition, the micelles in the PN composition of this application do not contain hemoglobin, hemoglobin derivatives, perfluorocarbons, or perfluorocarbon derivatives.

[0089] Lipophilic or hydrophobic components As used herein, the term “lipophilic component” refers to a lipid-soluble material that is naturally occurring or not naturally occurring. Examples of lipophilic components include, but are not limited to, fatty acyls, glycerolipids, phospholipids, sphingolipids, sterollipids, prenolipids, saccharolipids, polyketides, unnatural lipids, cationic lipids, amphiphilic alkyl amino acid derivatives, azialkyldimethylammonium, polyglycerol alkyl ethers, polyoxyethylene alkyl ethers, tri-n-octylamine, boric acid, tris(3,5-dimethyl-4-heptyl) ester, triglycerides, diglycerides, and other acylglycerols, such as tetraglycerol, pentaglycerol, hexaglycerol, heptaglycerol, octoglycerol, nonaglycerol, and decaglycerol, hydrophobic peptides, hydrophobic polysaccharides, silicones, lipopeptides, cyclopeptides, and mixtures thereof. In certain embodiments, the lipophilic or hydrophobic component includes soybean oil, chia bean oil, or algal 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 thrombotic and procoagulant, and therefore may be preferred when coagulation is desired. After bleeding is no longer a concern, oils rich in omega-3 fatty acids may be preferred due to their anti-thrombotic properties. Oils rich in omega-3 fatty acids include, but are not limited to, chia oil, algal 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. A cis configuration means that adjacent hydrogen atoms or other groups are on the same side of the double bond. In a trans configuration, these parts are on opposite sides of the double bond. The rigidity of the double bond freezes its conformation, and in the case of cis isomers, 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. When a chain has many cis bonds, the chain bends considerably in its most accessible conformation. For example, oleic acid, with one double bond, has a "twist" within it, while linoleic acid, with two double bonds, has a more pronounced bend. Alpha-linolenic acid, with three double bonds, prefers a hook shape. The effect of this is that, in restricted environments such as when fatty acids are part of phospholipids in a lipid bilayer or triglycerides in lipid droplets, cis bonds can limit the ability of fatty acids to densely pack, and thus can affect 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) of unsaturated fatty acids (or more) having one or more alkenyl functional groups in a cis configuration.

[0092] Examples of cis-unsaturated fatty acids include citric acid, lindelic acid, tuzic acid, palmitoleic acid, oleic acid, elaidic acid, vaccenic acid, petroseric acid, gadoleic acid, eicosenoic acid, erucic acid, cetoleic acid, nervonic acid, xymenic acid, and lumepuenoic acid. Examples of polyunsaturated fatty acids include, but are not limited to, alpha-linolenic acid, stearidonic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid; n-6 unsaturated fatty acids such as linoleic acid, linoleidic acid, gamma-linolenic acid, bis-homo-gamma-linolenic acid, and arachidonic acid; conjugated fatty acids such as conjugated linoleic acid and alpha-eleostearic acid; fatty acids with a double bond at the 5th position such as pinolenic acid, siadonic acid, juniperic acid, and columbic acid; polyunsaturated fatty acids other than those listed above, such as hiragonic acid, molocinic acid, clupanodonic acid, and nishinic acid; branched fatty acids such as isobutyric acid, isovaleric acid, isoacid, and anti-isoacid; hydroxy fatty acids such as alpha-hydroxy acids, beta-hydroxy acids, mycolic acid, and polyhydroxy acids; epoxy fatty acids; keto fatty acids; and cyclic fatty acids. In certain embodiments, the lipophilic or hydrophobic components also include amphiphilic molecules.

[0093] Lipophilic or hydrophobic components make up 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%, 1 The components may constitute 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 components constitute 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 includes any combination of percentage ranges including integer values ​​selected from the group consisting of 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), or 10%, 15%, 20%, 25%, 30%, or 35% of the PN composition. In yet other embodiments, the upper and / or lower limits of the lipophilic or hydrophobic component are defined by any of the enumerated concentrations described herein.

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

[0095] As used herein, the term “amphiphilic substance” refers to a compound that possesses both hydrophilic and lipophilic or hydrophobic properties. Examples of amphiphilic substances include, but are not limited to, naturally occurring amphiphilic substances such as phospholipids, cholesterol, glycolipids, fatty acids, bile acids, and saponins, as well as synthetic amphiphilic substances 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, soy lecithin, and hydrogenated phospholipids.

[0097] Examples of glycolipids include glyceroglycolipids and sphingoglycolipids. 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 sphingoglycolipids include galactosyl cerebroside, lactosyl cerebroside, 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 includes egg phospholipid or egg yolk lecithin. In another embodiment, the emulsifier is soy lecithin or alpha-phosphatidylcholine.

[0100] In other embodiments, the emulsifier is present in the following concentrations of the PN composition: 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% The percentages may be %, 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 levels 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 enumerated integers. In other embodiments, the emulsifier is present at levels 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 enumerated integers. In yet another embodiment, the upper and / or lower limits of the emulsifier are defined by any of the enumerated concentrations described herein.

[0101] In certain preferred embodiments, the emulsifier is a lecithin such as egg yolk lecithin or soy lecithin in the above-mentioned amount or range.

[0102] polar liquid carrier The polar liquid carrier can be any pharmaceutically acceptable polar liquid capable of forming an emulsion with lipids. The term “pharmaceutically acceptable” means molecular entities and compositions that are of sufficient purity and quality for use in the formulations of the compositions or pharmaceuticals of this application and that do not cause adverse allergic reactions or other undesirable reactions when appropriately administered to animals or humans. Since both human use (clinical and commercial) and veterinary use are equally included within the scope of this application, pharmaceutically acceptable formulations will include compositions or pharmaceuticals 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 liquid.

[0103] Aqueous solutions generally contain a physiologically compatible electrolyte vehicle that is isopermeable or nearly isopermeable to whole blood. The carrier may be, for example, physiological saline, physiological saline-glucose mixture, Ringer's solution, lactated Ringer's solution, Locke-Ringer's solution, Krebs-Ringer's solution, Hartmann equilibrium salt solution, heparinized sodium citrate-citric acid-dextrose solution, and high molecular weight plasma substitutes such as polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, and ethylene oxide-propylene glycol condensates. The PN composition may further contain other components such as pharmaceutically acceptable carriers, diluents, fillers, and salts, the choice of which depends on the dosage form used, the condition to be treated, the specific purpose to be achieved according to the determination of those skilled in the art, and the properties of such additives.

[0104] electrolyte In one embodiment, the PN composition of this application comprises one or more electrolytes. The electrolytes used in this application typically include a variety of 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 amino acid salts, 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 amino acid salts, propionate Examples include potassium sulfate and 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 normal physiological concentrations of such ions in plasma. Generally, desired concentrations of these ions are obtained from dissolved chloride salts of calcium, sodium, and magnesium. Sodium ions may also originate from dissolved organic salts of sodium, similarly present in solution.

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

[0107] In certain embodiments, the PN composition contains sodium chloride in 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 includes sodium chloride at concentrations of 50–150 mM, 70–130 mM, 80–120 mM, 90–110 mM, 95–100 mM, or approximately 97.4 mM.

[0109] In another embodiment, the PN composition comprises sodium L-lactate, sodium D-lactate, or a mixture thereof in a percentage 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 L-sodium lactate, D-sodium lactate, or a mixture thereof at concentrations 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 approximately 70-180 mM, 90-170 mM, 70-160 mM, 100-160 mM, 110-150 mM, 120-140 mM, 125-135 mM, 131-133 mM, or approximately 131.4 mM.

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

[0113] In one embodiment, the magnesium ion concentration is in the range of 0 to 10 mM. In another embodiment, the magnesium ion concentration is in the range of about 0.3 to 0.45 mM, 0.3 to 0.35 mM, 0.3 to 0.4 mM, 0.35 to 0.4 mM, 0.35 to 0.4 mM, or 0.4 to 0.45 mM. It is best that the PN composition of the present invention does not contain an excess amount of magnesium ions, because a high magnesium ion concentration adversely affects the intensity of myocardial contractility. In a preferred embodiment of the present invention, the solution contains a quasi-physiological amount of magnesium ions.

[0114] In one embodiment, the potassium ion concentration is within the quasi-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 potassium ion concentration in stored transfused blood. As a result, high concentrations of potassium ions and the potential cardiac arrhythmias and heart failure they cause can be more easily controlled. PN compositions containing quasi-physiological amounts of potassium are also useful for the purposes of target blood replacement and maintaining low temperatures.

[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 approximately 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 amino acid salts, 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 acid These include sodium chloride, 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., 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, choline chloride, and zinc sulfate are particularly preferred.

[0117] Gas transport capacity of PN composition Lipophilic or hydrophobic components in a PN composition, such as micelles and / or red blood cell ghosts, provide the PN composition with the ability to carry a larger amount of lipophilic gas than a pure aqueous solution. Specifically, the lipophilic gas dissolves in the lipophilic portion of the PN composition to form a homogeneous solution of 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, a PN composition with a higher lipid content will be able to carry more oxygen than a PN composition with a 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 ordinary air or pure oxygen through the PN composition for a desired period of time. Since bubbles are undesirable in 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 solubilized in the micelle core, polar carrier, or attached to proteins or other additives. To avoid bubble formation, gas may be filled into the micelles by equilibrating the micelles in a gas-concentrated atmosphere, combined with the gentle movement of the PN composition in the mixing chamber. Filling may also be carried out under a pressure greater than 1 atmosphere, followed by the release of the pressure to allow for the release of excess gas.

[0119] In another embodiment, the lipophilic gas is xenon (Xe) or argon (Ar). In yet another embodiment, the lipophilic gas is nitric oxide (NO). In yet another embodiment, the lipophilic gas is hydrogen sulfide (H2S). In yet another embodiment, the lipophilic gas is carbon monoxide (CO).

[0120] In one embodiment, the PN composition contains micelles filled 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 filled with various gases. For example, the mixture of micelles may contain 50% NO-filled micelles and 50% O2-filled micelles.

[0121] Rigid non-planar molecules The PN composition may further contain molecules having a rigid, non-planar structure. 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 a (+) naloxone that, unlike the opioate receptor antagonist (-) naloxone, does not bind to opioate receptors and does not increase pain like (-) naloxone. In another embodiment, the (+) naloxone is 10 -5 ~10 -4 It is used at a concentration of M. In another embodiment, (+)naloxone is 10 -4 It is used at concentrations of M or higher.

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

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

[0125] plasma components The PN composition may further contain plasma components. In one embodiment, the plasma is animal plasma. In another embodiment, the plasma is human plasma. While we do not wish to be bound by any particular scientific theory, it is considered that the administration of blood substitutes may dilute the concentration of coagulation factors to undesirable levels. Therefore, this problem is avoided by using plasma as a diluent for oxygen-carrying components. 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 plasma electrophoresis apparatus. Plasma electrophoresis apparatuses are commercially available and include, for example, devices that separate plasma from blood by ultrafiltration or centrifugation. Ultrafiltration-based plasma electrophoresis apparatuses, 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 coagulation factors.

[0126] Plasma may be collected using anticoagulants, 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 an anticoagulant at a final concentration of 0.2-0.5%, preferably 0.3-0.4%, most preferably 0.38%. The plasma may be fresh, frozen, pooled, and / or sterile. While plasma from an exogenous source may be preferred, it is also within the scope of this application to use autologous plasma collected from the subject before formulation and administration of the PN composition.

[0127] In addition to plasma from natural sources, synthetic plasma may 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 be used.

[0128] leavening agent In one embodiment, the PN composition further contains a leavening agent in addition to lipid micelles. The leavening agent consists of molecules large enough to prevent loss from circulation by crossing the fenestrations of the capillary bed and entering the interstitial space of the body's tissues. Examples of leavening agents include, but are not limited to, dextran (e.g., low molecular weight dextran), dextran derivatives (e.g., carboxymethyl dextran, carboxydextran, cationic dextran, and sulfated dextran), hydroxyethyl starch, hydroxypropyl starch, branched, unsubstituted, or substituted starches, 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, denatured 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 micelle components and potentially stabilize the micelle structure. In one embodiment, the leavening agent is about 2%, 5%, 7%, or 10% (w / v) albumin. In another embodiment, the leavening agent is a polysaccharide in the molecular weight range of 30,000 to 50,000 daltons (D), such as dextran. In yet another embodiment, the leavening agent is a polysaccharide in the molecular weight range of 50,000 to 70,000 D, such as dextran. High molecular weight dextran solutions are more effective in preventing tissue swelling because they have a lower leakage rate from capillaries.

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

[0131] In another embodiment, the leavening agent is glycerol or mannitol in amounts 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 yet another embodiment, the PN composition contains glycerol or mannitol in amounts of 2-5% w / v.

[0132] Crystalloid The PN composition may also contain a crystalloid agent. The crystalloid agent can be any crystalloid that, in the form of the PN composition, can preferably achieve a volume molar osmotic pressure concentration of over 800 mOsm / l, i.e., make the PN composition "hypertonic". Examples of suitable crystalloids in the PN composition and their concentrations 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 a volume molar osmotic pressure concentration of 800 to 2400 mOsm / l.

[0133] Anti-inflammatory agents and immunomodulators In one embodiment, the PN composition of this application further comprises an anti-inflammatory agent or an immunomodulator. Examples of anti-inflammatory agents 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 immunomodulators include interferons; interferon derivatives including betacerone and β-interferon; prostane derivatives including iloprost and cicaprost; glucocorticoids including cortisol, prednisolone, methylprednisolone, and dexamethasone; immunosuppressants including cyclosporine A, methoxsalen, sulfasalazine, azathioprine, and methotrexate; lipoxygenase inhibitors including Ziloton, MK-886, WY-50295, SC-45662, SC-41661A, and BI-L-357; leukotriene antagonists; peptide derivatives including ACTH and its analogues; 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 analogues administered alone or in combination.

[0134] Carbohydrates and amino acids The PN composition may contain carbohydrates or mixtures 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 a physiological level of hexose. A "physiological level of hexose" includes a hexose concentration of 2 mM to 50 mM. In one embodiment, the PN composition contains 5 mM glucose. Sometimes it is desirable to increase the concentration of hexose to provide nutrients to cells. Therefore, the range of hexose may be extended as needed to about 50 mM to provide the minimum calories for nutrition.

[0135] Other suitable carbohydrates include various sugars used for medicinal purposes. Examples of sugars include 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 acids are selected from the group consisting of histidine, tyrosine, phenylalanine, and cysteine. In another embodiment, the PN composition contains one or more amino acids known to prevent apoptosis. Examples of such amino acids include glutamine, glycine, proline, and 2-aminopentaenoic acid.

[0137] The amino acid may be used in a concentration range of 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 acid is used at a concentration of 1 mM.

[0138] cushioning agent The PN composition of this application may further contain a biological buffer for maintaining the pH of the fluid within 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(hydroxy-methyl)methylamino]-2-hydroxyethyl]-1-piperazinepropanesulfonic acid (EPPS), tris[hydroxymethyl]-aminoethane (THAM), and tris[hydroxylmethyl]methylaminomethane (TRIS).

[0139] In one embodiment, the buffer is histidine, imidazole, a substituted histidine or imidazole compound that retains the amphoteric site of the imidazole ring, an oligopeptide containing histidine or glycine (such as glycylglycine), or a mixture thereof. Histidine can also reduce reactive oxygen species and inhibit cell contraction (see, for example, Simpkins et al., J Trauma. 2007, 63:565-572). Histidine or imidazole may be used at concentrations of about 1 mm, 5 mm, 10 mm, 20 mm, 30 mm, 40 mm, or 50 mm, or in the concentration ranges of about 0.1 mm to about 200 mm, 1 mm to about 100 mm, 5 mm to about 50 mm, 5 mm to about 20 mm, or in any other range between any of the histidine concentrations listed herein.

[0140] In another embodiment, the PN composition of this application uses common biological components to maintain in vivo biological pH. Briefly, several biological compounds, such as lactate, are metabolized in vivo and can act with other biological components to maintain a biologically appropriate pH in animals. Biological components are effective in maintaining a biologically appropriate pH even under hypothermia and essentially bloodless conditions. Examples of common 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 linear, containing 1 to 30 carbon atoms, which may be substituted with carbon atoms; X is another biologically compatible ionic substituent that can be bonded at the position of hydrogen, sodium or oxygen; or a short linear or branched alkyl, e.g., -CH3, -CH2CH3, containing 1 to 4 carbon atoms. Examples of carboxylic acids and carboxylate salts include, but are not limited to, lactates and sodium lactate, citrates and sodium citrate, glucons and sodium gluconate, pyruvates and sodium pyruvate, succinates and sodium succinate, and acetates and sodium acetate.

[0141] Coagulation accelerator Aggressive, uncontrolled mass resuscitation can worsen bleeding by disrupting early-formed soft thrombi and diluting coagulation factors. In certain embodiments, the PN composition may further contain one or more coagulation accelerators. Examples of coagulation factors include, but are not limited to, factor VII, thrombin, platelets, and tranexamic acid. These factors may be of natural or non-natural origin. 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. Natural or synthetic platelets or platelet substitutes may be added.

[0142] Antioxidants In certain embodiments, the PN composition may further contain one or more antioxidants. Examples of antioxidants include sodium bisulfite, sodium sulfite, sodium pyrosulfite (e.g., sodium metabisulfite), longalite (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, disodium ethylenediaminetetraacetate calcium, disodium ethylenediaminetetraacetate, amino acid sulfites (e.g., L-lysine sulfate). Examples of suitable substances include, but are not limited to, sodium bisulfite, butylated hydroxyanisole (BHA), butylated hydroxytoluene (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, nordihydroguaiaretinic 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 components, the PN composition contains antibiotics such as penicillin, cloxacillin, dicloxacillin, cephalosporins, erythromycin, amoxicillin-clavranate, ampicillin, tetracycline, trimethoprim-sulfamethoxazole, chloramphenicol, ciprofloxacin, aminoglycosides (e.g., tobramycin and gentamicin), streptomycin, sulfonamides, kanamycin, neomycin, and landomonobactam; antiviral agents such as amantadine hydrochloride, rimantadine, acyclovir, famciclovir, foscarnet, ganciclovir sodium, idoxuridine, ribavirin, sorivudine, trifluridine, valacyclovir, valganciclovir, and pencyclovir. The formulation may further include, but is not limited to, other additives such as vir, vidarabine, didanosine, stabudine, zalcitabine, zidovudine, interferon alfa, 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 vascular potency mediators and immunomodulators such as prostaglandins, leukotrienes, propiomelanocortin fragments, and platelet-activating factors.

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

[0145] In certain other embodiments, the PN composition may contain substituted cations. For example, the PN composition may contain choline to substitute for sodium ions.

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

[0147] In certain embodiments, the PN composition further contains an anticancer drug and / or intracellular signaling molecules such as Camp and diacylglycerol. In other embodiments, the PN composition further contains one or more organelles or organelle components, such as the endoplasmic reticulum, ribosomes, and mitochondria, either whole or in part.

[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 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, 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 another embodiment, the PN composition further comprises one or more neurotropic agents for the treatment or prevention of mental disorders.

[0151] Preparation of PN composition PN compositions may be prepared by mixing lipophilic or hydrophobic components, emulsifiers, aqueous carriers, and any other components to form an emulsion. Commonly used mixing methods include, but are not limited to, stirring, shaking, homogenization, vibration, microfluidization, and ultrasonic treatment.

[0152] An exemplary homogenizer is the APV2000 homogenizer (SPX Corporation). Emulsions may be formed at pressure settings of approximately 15,000–20,000 psi for nanoemulsions smaller than 100 nm, or approximately 22,000–28,000 psi for larger micelle emulsions of approximately 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] The size and stability of the micelle composition may be evaluated and monitored using a suitable particle analyzer and / or zeta potential analyzer. An example analyzer is 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 pre-formed lipid emulsion from the above components with an aqueous carrier. Furthermore, the PN composition can be supported 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 without forming microbubbles that could increase the risk of gas embolism.

[0155] In certain embodiments, albumin or albumin polymer, or albumin polymer conjugated with amino acids or peptides, is added to the PN composition in amounts of 2-40% (w / v), about 2-20% (w / v), about 4-10% (w / v), or about 5% (w / v). Albumin or albumin polymer, or albumin polymer conjugated with amino acids or peptides, is added to the PN composition after micelle formation. In one embodiment, an emulsion is formed by mixing a lipophilic or hydrophobic component, an emulsifier, an aqueous carrier, and any other non-albumin component. Then, albumin, albumin polymer, or albumin polymer conjugated with amino acids or peptides is dissolved in the emulsion at a desired concentration.

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

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

[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 protein contamination and anaphylaxis (due to egg protein contamination of egg phospholipids). In yet another embodiment, the amino acids in Part B of Recipe 2 are replaced with N-acetylamino acids. In one embodiment, the PN composition is a deoxygenated PN composition. As used herein, the term “deoxygenated PN composition” refers to a formulation prepared in air and not oxygenated by any oxygenation apparatus or method.

[0159] In some embodiments, the PN composition comprises 15-35% (w / v) of a lipophilic or hydrophobic component, 6-18% (w / v) of an amphiphilic emulsifier, a polar liquid carrier, and one or more electrolytes, wherein the amphiphilic emulsifier forms lipid-supported micelles (LMs) having a lipophilic or hydrophobic core containing 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, when measured by electron microscopy, has wavelengths of 30-140nm, 30-130nm, 30-120nm, 30-100nm, 30-90nm, 30-80nm, 30-70nm, 40-140nm, 40-130nm, 40-120nm, 40-100nm, 40-90nm, 40-80nm, 50-140nm, 50-130nm, 50-120nm, 50-100nm, 50-90nm, 5 Includes LMs having diameters in the range of 0-80nm, 50-70nm, 60-140nm, 60-130nm, 60-120nm, 60-100nm, 60-90nm, 60-80nm, 80-140nm, 80-130nm, 80-120nm, 80-110nm, 80-100nm, 100-140nm, 100-130nm, 100-120nm, 100-110nm, 120-140nm, 120-130nm, or 130-140nm.

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

[0161] In some further embodiments, the PN composition comprises nanoparticles (including micelles and liposomes) having an average diameter in the range of approximately 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 a diameter in the range of 30 to 500 nm and liposomes having a diameter in the range of 1 to 30 nm, as measured by an electron microscope.

[0163] In some embodiments, the PN composition comprises a mixture of LM and liposomes, where the average diameter of all particles, as determined by electron microscopy, 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.

[0164] In some embodiments, the PN composition comprises about 12% egg lecithin and includes LMs having a diameter of about 30–500 nm and liposomes having a diameter of about 1–25 nm, as determined by electron microscopy. 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.

[0165] In some embodiments, the PN composition comprises about 5-35% soybean oil and about 0.5-20% egg lecithin, and includes LM 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 includes LM 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 includes LM 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 above PN composition further comprises glycerin in amounts 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 above 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 in atmosphere without concentrating oxygen, carbon monoxide, nitric oxide, or xenon.

[0172] In certain embodiments, the PN composition may be filled with a lipophilic gas before 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 cellular embolism. As used herein, “lipophilic gas-filled PN composition” refers to a PN composition that has been subjected to a process that increases the content of such lipophilic gas in the PN composition. The PN composition may be filled with a lipophilic gas by bubbling the lipophilic gas into 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 the mixture with pure oxygen or a gas having an oxygen content in the range of 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) for 30 seconds or more, preferably 1 to 15 minutes, more preferably 1 to 5 minutes. Oxygen may be added under pressure, followed by a reduction in pressure to 1 atmosphere. In one embodiment, the PN composition is oxygenated immediately before application. The PN composition may also be oxygenated using a portable oxygen tank or portable oxygen concentrator, such as the Evergo Portable Pulse Dose Oxygen Concentrator manufactured by Philips Healthcare in Andover, Massachusetts.

[0174] Another method may involve equilibrating the emulsion in an atmosphere filled with the added gas. In most cases, a bubble trap will be necessary to remove any bubbles that could become gas embolisms. The equilibrium 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 terms “oxygenated lipid emulsion” or “oxygenated PN composition” refer to a particular type of gaseous lipid emulsion or gaseous fluid that has been oxygenated such that the total concentration of oxygen contained therein is higher than that present in the same liquid under atmospheric equilibrium conditions. [Examples]

[0176] The following examples are provided to give a complete disclosure and explanation of how to carry out the methods of this application to those skilled in the art and are not intended to limit the scope of the invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantity, temperature, etc.), but some experimental errors and deviations should be taken into account. Unless otherwise specified, parts are by weight, molecular weight is weight-average molecular weight, temperature is in Celsius, and pressure is atmospheric pressure or near atmospheric pressure.

[0177] Example 1: Preparation of phospholipid nanoparticle (PN) composition Preparation of Part A 10%-20% soybean oil = 10-20 grams Egg yolk phospholipids: 0.6% to 12% = 0.6 to 12 grams Add water until the final volume reaches 100ml. Add sodium hydroxide until the pH reaches 8.0. Sonication is used to generate phospholipid nanoparticles. Preparation of Part B 0.6 grams of NaCl Sodium lactate (L) 0.385 grams Histidine 0.155 grams

[0178] Part A may be used alone, mixed with Part B within 24 hours of use, or pre-mixed. Either or both parts may be freeze-dried, and water may be 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] Modified pulmonary stenosis (MODS) developed in Patient A, a 39-year-old woman who had undergone a heart transplant failure. Even after the use of a ventricular assist device, the patient experienced cardiac arrest. Multiple organs were dysfunctional. Pulmonary dysfunction was evident, requiring 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 injection of epinephrine into the heart to restore spontaneous contractions. The patient's chest was opened to address the cardiac arrest. The patient had no urine output due to renal failure. Despite receiving high doses of levofed and intravenous bolus fluids, the mean arterial pressure (MAP) was only 43 mmHg. Pulmonary function was severely impaired, as indicated by a P / F ratio of only 132. Lower P / F ratios and lower blood pressure are associated with lower survival rates.

[0181] The patient was given 500 ml of the PN composition of this application over a period of 30 minutes. No other interventions were performed. This resulted in an improvement in lung 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 foot and developed septic shock, which led to MODS. Her lungs required mechanical ventilation. Renal function was supported by dialysis. The patient had heart failure after cardiac arrest. Despite receiving bolus doses of albumin and saline, and being administered extremely high doses of vasopressors: 100 micrograms / min of levofed, 0.1 units / min of vasopressin, and 30 micrograms / min of epinephrine, the patient's MAP was only 39 mmHg. Despite being on a ventilator, the patient's P / F ratio was only 131.

[0184] The patient was given 500 ml of the PN composition of this application over a period of 30 minutes. Without any 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 was a 65-year-old woman who presented to the emergency department with cardiac tamponade due to blood accumulation in the pericardial cavity. This severely restricted cardiac dilation, preventing adequate blood flow to the rest of the body. The cardiac tamponade resulted in two episodes of cardiac arrest, requiring puncture and drainage of blood from the pericardial cavity. These events led to MODS. After failures with fluid boluses and mask oxygenation 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 in elevated creatinine. Hepatic impairment was indicated by an increased ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT). Poor organ perfusion was indicated by elevated lactat. The patient was administered vasopressors: 32 micrograms / min of Levophed and 0.04 units / min of vasopressin.

[0187] Patients were administered 765 ml of the PN composition of this application over a period of 120 minutes. After administration of the PN composition, the patients' MAP increased from 68 mmHg to 86 mmHg. The patients' 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 patients' blood test parameters 24 hours after PN infusion. The decrease in creatinine indicated an improvement in renal function. AST is aspartate transaminase and ALT is alanine aminotransferase. Both are enzymes present in liver tissue. A higher AST / ALT ratio indicates a worse degree of liver damage. A normal AST / ALT ratio is less than 1.0. A decrease in this ratio after the PN composition is an indicator of improved liver function. Lactate is an indicator of overall tissue perfusion in the body. A higher lactate indicates a worse prognosis. The decrease in lactate after infusion of the PN composition is an indicator 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 concentration is an indicator of the change 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] During the period of these results, no interventions other than the infusion of the PN composition were performed. The measurements showed improvements in the cardiovascular, pulmonary, renal, and hepatic systems after the infusion of the PN composition. Furthermore, an improvement in overall blood flow through the tissues was observed.

[0190] Example 5: Treatment of MODS in patient D with PN composition

[0191] Patient D was a 65-year-old male whose diagnosis of COVID-19 was confirmed by laboratory testing. The patient had decreased MAP, which was not reversed by fluid resuscitation. Vasopressors were needed to raise the patient's blood pressure to a viable level. The patient met the criteria for septic shock when MAP did not increase after fluid infusion. The patient's blood pressure was 68 mmHg despite administration of the vasopressor Levophed at 11 micrograms / min. The patient's lung condition deteriorated significantly, and the patient was placed on a ventilator. Despite maximum ventilator support, the patient's lung condition continued to deteriorate, resulting in a patient PF ratio of only 56. The patient was intravenously administered 200 ml of PN composition over 2.4 hours. This increased 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, administration of 5 micrograms / min of Levophed and 0.04 units / min of vasopressin reduced the patient's P / F ratio to 62. The patient was then given 200 ml of the PN composition over 2.5 hours. This increased blood pressure from 67 mmHg to 70 mmHg and raised the P / F ratio from 62 to 191.

[0193] Six days later, the patient was still on a ventilator and was administered levofed at 5 micrograms / min using vasopressin at 0.04 units / min. The P / F ratio decreased to 81. The patient was given 400 ml of the PN composition over 10 minutes. This increased the P / F ratio from 81 to 145. Blood pressure increased, and as a result, the patient was able to completely discontinue the vasopressor. With the vasopressor discontinued, 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 male diagnosed with COVID-19 by clinical criteria. The patient presented to the hospital before tests to diagnose COVID-19 became available. The patient was in septic shock. The patient also had multifocal pneumonia and blood cultures that were positive for Gram-positive cocci. Due to hypotension, the patient was administered high doses of vasopressors, Levophed, vasopressin, and phenylephrine. Despite these measures, the patient went into asystole. The Advanced Cardiac Life Support protocol was followed, but the patient did not respond. 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 vasopressors. The patient's oxygen demand 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. She had severe pneumonia and was on mechanical ventilation. Despite receiving high doses of vasopressors, she experienced asystole. She did not respond to the Advanced Cardiac Life Support protocol. Her blood pressure was 0 until she received 1000 ml of PN composition. After this infusion, her blood pressure rose to an average of 69 mmHg. Prior to the PN composition, her oxygen saturation was 55%, despite being given 100% inspired oxygen. After the PN composition infusion, her oxygen demand decreased to 55%.

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

[0199] 500 microliters of PN (containing 20% ​​soybean oil, 1.2% egg lecithin, and 2.25% glycerin, with an average particle size of 400 nm by dynamic light scattering) were placed in a 15 mL vial, and 100 ppm nitric oxide in helium was bubbling into the PN for 2 minutes. The same method was used to add nitric oxide to deionized water. A continuous sampling quadrupole mass spectrometer was used to quantify the nitric oxide packed into the sample fluid. The water in the purge container was maintained at 37°C and contained an antifoaming solution as needed. 100 microliters of sample fluid were injected into the instrument's purge container for the measurement of nitric oxide packed in PN and water. The sample gas was rapidly released from the fluid and transported as a bolus from the purge container to the mass spectrometer. The signal generated by the contact of the sample gas with the detector was integrated using Peakfit (Systat Software Inc., Chicago, Illinois, USA) and compared with the saturation value obtained with deionized water. Ten measurements were performed for each group. The volume of absorbed nitric oxide was determined as the area under the curve. The mean and standard error were 3.19 × 10⁻⁶ for PN and water, respectively. -3 ±0.19 × 10 -3 and 2.12 × 10 -3 ±0.17 × 10 -3 The values ​​are in moles / liter, indicating that the solubility of NO in 20% PN is 1.5 times that of water. Offloading of nitric oxide from PN and water was rapid, taking approximately 2 seconds each.

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

[0201] [Table 2]

[0202] As shown in Figure 1, PN absorbed more nitric oxide compared to water (Panel A) (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 as rapid as that from water. This rapid release allows PN to shift the nitric oxide distribution from non-viable to viable.

[0203] The terms and descriptions used herein are for illustrative purposes only and are not intended to limit the invention. Those skilled in the art will recognize that many modifications are possible within the spirit and scope of the invention as defined in the following claims, and in those equivalents, all terms should be understood in the broadest possible sense unless otherwise specified.

Claims

1. A method for treating multiple organ dysfunction syndrome (MODS) in the subject, For those who require treatment, 0-35% (w / v) of lipophilic or hydrophobic components, 0.1% to 60% (w / v) of amphiphilic emulsifier, polar liquid NT, and One or more electrolytes The method includes administering an effective amount of a phospholipid nanoparticle (PN) composition containing the following: The method comprising the PN composition having a diameter of 1 to 800 nm, comprising liposomes and / or micelles.

2. The method according to claim 1, wherein the lipophilic or hydrophobic component is selected from the group consisting of soybean oil, chia bean oil, and algal oil.

3. The method according to claim 1 or 2, wherein the amphiphilic emulsifier is selected from the group consisting of phospholipids and α-phosphatidylcholine.

4. The method according to any one of claims 1 to 3, wherein the amphiphilic emulsifier is selected from the group consisting of egg yolk lecithin and soy lecithin.

5. The method according to any one of claims 1 to 4, wherein the polar liquid carrier is selected from the group consisting of water, aqueous solutions, and non-aqueous polar liquids.

6. The method according to any one of claims 1 to 5, wherein the non-aqueous polar liquid is selected from the group consisting of dimethyl sulfoxide, polyethylene glycol, and polar silicone liquid.

7. The method according to any one of claims 1 to 6, wherein the electrolyte is selected from the group consisting of one or more of the following: 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, potassium amino acid 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, magnesium amino acid salts, ammonium chloride, zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, zinc acetate, iron sulfate, iron chloride, iron gluconate, copper sulfate, and manganese sulfate.

8. The method according to any one of claims 1 to 7, wherein the PN composition is administered intravenously, intraarterially, intraosseously, or intracardiacly.

9. The PN composition is in 1 to 50,000 ml of O ２ The method according to any one of claims 1 to 8, wherein the oxygenated PN composition has an oxygen content of 100 ml of the PN composition.

10. The method according to any one of claims 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.

11. The method according to any one of claims 1 to 10, wherein the PN composition comprises micelles and liposomes, the micelles in the PN composition having a diameter in the range of 30 to 200 nm when measured by an electron microscope, and the liposomes in the PN composition having a diameter in the range of 1 to 25 nm when measured by an electron microscope.

12. The method according to any one of claims 1 to 11, wherein the PN composition has a magnesium ion concentration in the quasi-physiological range.

13. The method according to any one of claims 1 to 12, wherein the PN composition further comprises one or more selected from the group consisting of a crystalloid agent, a leavening agent, an anti-inflammatory agent, an immunomodulator, and a lipophilic gas.

14. The method according to any one of claims 1 to 13, wherein the PN composition further comprises glycerin.

15. The method according to any one of claims 1 to 14, wherein the subject has mods induced by sepsis caused by a viral infection.

16. The method according to claim 15, wherein the subject has mods induced by sepsis caused by the COVID-19 virus.

17. The method according to any one of claims 1 to 14, wherein the subject has mods induced by sepsis caused by bacterial infection.

18. The method according to any one of claims 1 to 14, wherein the subject has mods induced by sepsis caused by fungal infection.

19. The method according to any one of claims 1 to 14, wherein the subject has mods induced by sepsis caused by a parasitic infection.

20. A method according to any one of claims 1 to 19 for treating multiple organ failure syndrome (MODS) due to sepsis in a subject, For those who require treatment, 0-35% (w / v) of lipophilic or hydrophobic components, 0.6% to 60% (w / v) of amphiphilic emulsifier, polar liquid NT, and One or more electrolytes The process includes increasing oxygen saturation by administering an effective amount of a phospholipid nanoparticle (PN) composition containing the following: A method wherein the micelles in the PN composition have a diameter in the range of 30 to 200 nm when measured by an electron microscope, and the PN composition comprises liposomes having a diameter of 1 to 25 nm.

21. A method according to any one of claims 1 to 20 for treating multiple organ failure syndrome (MODS) due to sepsis in a subject, For those who require treatment, 0-35% (w / v) of lipophilic or hydrophobic components, 0.6% to 60% (w / v) of amphiphilic emulsifier, polar liquid NT, and One or more electrolytes The process includes reducing hypoxia by administering an effective amount of a phospholipid nanoparticle (PN) composition containing the following: A method wherein the micelles in the PN composition have a diameter in the range of 30 to 200 nm when measured by an electron microscope, and the PN composition comprises liposomes having a diameter of 1 to 25 nm.

22. A method according to any one of claims 1 to 21 for treating multiple organ dysfunction syndrome (MODS) in a subject, For those who require treatment, 0-35% (w / v) of lipophilic or hydrophobic components, 0.6% to 60% (w / v) of amphiphilic emulsifier, polar liquid NT, and One or more electrolytes The process includes increasing oxygen saturation by administering an effective amount of a phospholipid nanoparticle (PN) composition containing the following: A method wherein the micelles in the PN composition have a diameter in the range of 30 to 200 nm when measured by an electron microscope, and the PN composition comprises liposomes having a diameter of 1 to 25 nm.

23. A method according to any one of claims 1 to 22 for treating multiple organ dysfunction syndrome (MODS) in a subject, For those who require treatment, 0-35% (w / v) of lipophilic or hydrophobic components, 0.6% to 60% (w / v) of amphiphilic emulsifier, polar liquid NT, and One or more electrolytes The process includes reducing hypoxia by administering an effective amount of a phospholipid nanoparticle (PN) composition containing the following: A method wherein the micelles in the PN composition have a diameter in the range of 30 to 200 nm when measured by an electron microscope, and the PN composition comprises liposomes having a diameter of 1 to 25 nm.

24. A method for treating multiple organ dysfunction syndrome (MODS) in a subject, wherein the subject has MODS caused by a severe disease. The above method applies to subjects requiring treatment. 0-35% (w / v) of lipophilic or hydrophobic components, 0.1% to 60% (w / v) of amphiphilic emulsifier, polar liquid carrier The method includes administering an effective amount of a phospholipid nanoparticle (PN) composition containing the following: The method comprising the PN composition having a diameter of 1 to 800 nm, comprising liposomes and / or micelles.

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