Composition for treating autodigestion

文档序号：557104 发布日期：2021-05-18 浏览：29次中文

阅读说明：本技术 用于治疗自身消化的组合物 (Composition for treating autodigestion ) 是由 T·哈拉姆 R·杰克曼 J·罗登里斯于 2015-03-24 设计创作，主要内容包括：提供用于治疗休克、自身消化、多器官衰竭、肠缺血或肠灌注不足的组合物。在一些实施方案中,本文公开的组合物包含氨甲环酸、PEG、葡萄糖及一种或多种电解质。在一些实施方案中,所述PEG是PEG 3350。在一些实施方案中,本文公开的组合物包含氨甲环酸、PEG、葡萄糖及一种或多种电解质。在一些实施方案中,所述PEG是PEG 3350。在某些实施方案中,本文公开的组合物包含非结肠清洗量的PEG 3350。(Compositions for treating shock, autodigestion, multiple organ failure, intestinal ischemia, or intestinal hypoperfusion are provided. In some embodiments, the compositions disclosed herein comprise tranexamic acid, PEG, glucose, and one or more electrolytes. In some embodiments, the PEG is PEG 3350. In some embodiments, the compositions disclosed herein comprise tranexamic acid, PEG, glucose, and one or more electrolytes. In some embodiments, the PEG is PEG 3350. In certain embodiments, the compositions disclosed herein comprise a non-colonic cleansing amount of PEG 3350.)

1. A composition comprising tranexamic acid, PEG, glucose, and one or more electrolytes.

2. The composition of claim 1, wherein the PEG is PEG 3350.

3. The composition of claim 2, wherein the composition comprises a non-colonic cleansing amount of PEG 3350.

4. A composition comprising about 7.8g tranexamic acid, about 50.3g PEG3350, about 40g glucose, about 5.7g sodium sulfate, about 1.7g sodium bicarbonate, about 1.5g sodium chloride, and about 0.7g potassium chloride.

5. A composition comprising about 7.5g tranexamic acid, about 32.5g PEG3350, about 28g glucose, about 4.0g sodium sulfate, about 1.2g sodium bicarbonate, about 1.0g sodium chloride, and about 0.5g potassium chloride.

6. A composition comprising about 7.8g tranexamic acid and about 40g glucose.

7. A composition comprising about 7.5g tranexamic acid and about 28g glucose.

8. The composition of any one of claims 1-3, wherein the composition is formulated as an aqueous solution.

9. The composition of claim 4 or 6, wherein the composition is formulated as a 1000mL aqueous solution.

10. The composition of claim 5 or 7, wherein the composition is formulated as a 700mL aqueous solution.

11. A method of treating shock, autodigestion, multiple organ failure, intestinal ischemia, or hypoperfusion, comprising administering to a patient in need thereof a composition according to any one of claims 1-10.

12. The method of claim 11, wherein the method is for treating shock, and wherein the shock is cardiogenic shock.

13. The method of claim 12, wherein the cardiogenic shock is associated with or caused by myocardial infarction, arrhythmia, or mechanical complication.

14. The method of claim 12, wherein the cardiogenic shock is associated with or caused by cardiovascular surgery.

15. The method of claim 11, wherein the method is for treating shock, and wherein the shock is hemorrhagic shock.

16. The method of claim 15, wherein the hemorrhagic shock is associated with or caused by trauma.

17. The method of claim 11, wherein the method is for treating shock, and wherein the shock is septic shock.

18. The method of claim 17, wherein the septic shock is associated with or caused by sepsis.

19. The method of claim 11, wherein the method is for treating shock, wherein the shock is associated with or caused by a hemorrhagic virus.

20. The method of claim 19, wherein the hemorrhagic virus is an ebola virus.

21. The method of any one of claims 11-20, wherein the composition is administered orally.

22. The method of any one of claims 11-21, wherein the composition is administered via nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy tube or catheter.

23. A kit, comprising: the components tranexamic acid, PEG, glucose and one or more electrolytes, wherein at least one of the components tranexamic acid, PEG, glucose and one or more electrolytes is in a separate container from at least one of the other components tranexamic acid, PEG, glucose and one or more electrolytes; and instructions for combining the components tranexamic acid, PEG, glucose, and one or more electrolytes in a single composition.

24. The kit of claim 23, wherein the tranexamic acid, PEG, and one or more electrolytes are in a first container and the glucose is in a second container.

25. The kit of claim 23 or 24, wherein the kit further comprises instructions for reconstituting the components in water.

26. The kit of claim 24, wherein the first container comprises about 7.8g of tranexamic acid, about 50.3g of PEG3350, about 5.7g of sodium sulfate, about 1.7g of sodium bicarbonate, about 1.5g of sodium chloride, and about 0.7g of potassium chloride, and wherein the second container comprises about 40g of glucose.

27. The kit of claim 24, wherein the first container comprises about 7.5g tranexamic acid, about 32.5g PEG3350, about 4.0g sodium sulfate, about 1.2g sodium bicarbonate, about 1.0g sodium chloride, and about 0.5g potassium chloride, and wherein the second container comprises about 28g glucose.

28. The kit of claim 27, wherein the kit further comprises instructions for reconstituting tranexamic acid, PEG, glucose, and one or more electrolytes with water to 1000 mL.

29. The kit of claim 28, wherein the kit further comprises instructions for reconstituting tranexamic acid, PEG, glucose, and one or more electrolytes with water to 700 mL.

30. The kit of any one of claims 23-29, wherein the kit comprises instructions for administering the combined components orally or via nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy tubes or catheters.

Background

Shock is a life-threatening condition that can result from trauma, severe blood loss, heart attack, cardiovascular dysfunction, ischemia, sepsis, and burns. The main categories of shock include, but are not limited to, cardiogenic shock, hypovolemic shock, hemorrhagic shock, anaphylactic shock, neurogenic shock, and septic (or endotoxic) shock, which can lead to multiple organ failure (also known as multiple organ dysfunction syndrome) if not treated with immediate medical treatment. Under conditions of shock, the intestinal barrier and walls are compromised and digestive enzymes normally contained within the intestine permeate through the intestinal wall and into the blood stream, resulting in a condition known as autodigestion, in which digestive enzymes in the body begin to digest their own tissues. Autodigestion is presumed to be the mechanism of inflammation and multiple organ failure resulting from shock.

Summary of The Invention

Little therapy is available regardless of the severity of shock, autodigestion, multiple organ failure, ischemia, and hypoperfusion. Most efforts have focused on modulating various inflammatory mediators of shock (such as cytokines, nitric oxide and endotoxins) to alleviate the effects of shock. However, therapies targeting specific inflammatory mediators have proven largely ineffective because of the multifaceted nature of the mediators. Thus, there is a need for therapeutic agents to treat shock, autodigestion, multiple organ failure, ischemia, and hypoperfusion, particularly to maintain or help reestablish the integrity of the intestinal wall.

Disclosed herein are compositions for treating shock, autodigestion, multiple organ failure, intestinal ischemia, and/or hypoperfusion. In some embodiments, the compositions disclosed herein comprise tranexamic acid, PEG, glucose, and one or more electrolytes. In some embodiments, the PEG is PEG 3350. In certain embodiments, the compositions disclosed herein comprise a non-colonic cleansing amount of PEG 3350. In some embodiments, the compositions disclosed herein comprise about 7.8g of tranexamic acid, about 50.3g of PEG3350, about 40g of glucose, about 5.7g of sodium sulfate, about 1.7g of sodium bicarbonate, about 1.5g of sodium chloride, and about 0.7g of potassium chloride. In some embodiments, the compositions disclosed herein comprise about 7.8g of tranexamic acid and about 40g of glucose. In some embodiments, the compositions disclosed herein are formulated as an aqueous solution. In certain particular embodiments, the volume of the aqueous solution is 1000 mL. In some embodiments, the compositions disclosed herein comprise about 7.5g tranexamic acid, about 32.5g PEG3350, about 28g glucose, about 4.0g sodium sulfate, about 1.2g sodium bicarbonate, about 1.0g sodium chloride, and about 0.5g potassium chloride. In some embodiments, the compositions disclosed herein comprise about 7.5g of tranexamic acid and about 28g of glucose. In some embodiments, the compositions disclosed herein are formulated as an aqueous solution. In certain particular embodiments, the volume of the aqueous solution is 700 mL.

In some embodiments, the compositions disclosed herein are administered for the treatment of shock, autodigestion, multiple organ failure, intestinal ischemia, or hypoperfusion. In certain particular embodiments, the compositions disclosed herein are administered for the treatment of cardiogenic shock, hemorrhagic shock, or septic shock. In some embodiments, the compositions disclosed herein are administered for the treatment of septic shock associated with and resulting from sepsis. In some embodiments, the compositions disclosed herein are administered for the treatment of cardiogenic shock associated with and resulting from cardiovascular surgery, myocardial infarction, arrhythmia, or mechanical complications. In some embodiments, the compositions disclosed herein are administered for the treatment of hemorrhagic shock associated with and resulting from trauma. In some embodiments, the compositions disclosed herein are administered for the treatment of shock associated with and caused by a hemorrhagic virus. In some embodiments, the hemorrhagic virus is an ebola virus. In some embodiments, the compositions disclosed herein are administered orally or via nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy tubes or catheters.

In some embodiments, disclosed herein are kits comprising: the components tranexamic acid, PEG, glucose and one or more electrolytes, wherein at least one of the components tranexamic acid, PEG, glucose and one or more electrolytes is in a separate container from at least one of the other components tranexamic acid, PEG, glucose and one or more electrolytes; and instructions for combining the components tranexamic acid, PEG, glucose, and one or more electrolytes in a single composition. In some embodiments, the kit comprises tranexamic acid, PEG, and one or more electrolytes in a first container, and glucose in a second container. In some embodiments, the kit comprises instructions for reconstituting the components with water to provide an aqueous formulation. In some embodiments, the kit comprises a first container comprising about 7.8g of tranexamic acid, about 50.3g of PEG3350, about 5.7g of sodium sulfate, about 1.7g of sodium bicarbonate, about 1.5g of sodium chloride, and about 0.7g of potassium chloride, and a second container comprising about 40g of glucose. In some embodiments, a kit comprises a first container comprising about 7.8g of tranexamic acid, about 50.3g of PEG3350, about 5.7g of sodium sulfate, about 1.7g of sodium bicarbonate, about 1.5g of sodium chloride, and about 0.7g of potassium chloride, a second container comprising about 40g of glucose, and instructions for reconstituting tranexamic acid, PEG, glucose, and one or more electrolytes with water to 1000 mL. In some embodiments, the kit comprises a first container comprising about 7.5g of tranexamic acid, about 32.5g of PEG3350, about 4.0g of sodium sulfate, about 1.2g of sodium bicarbonate, about 1.0g of sodium chloride, and about 0.5g of potassium chloride, and a second container comprising about 28g of glucose. In some embodiments, a kit comprises a first container comprising about 7.5g of tranexamic acid, about 32.5g of PEG3350, about 4.0g of sodium sulfate, about 1.2g of sodium bicarbonate, about 1.0g of sodium chloride, and about 0.5g of potassium chloride, a second container comprising about 28g of glucose, and instructions for reconstituting tranexamic acid, PEG, glucose, and one or more electrolytes with water to 700 mL. In some embodiments, the kit comprises instructions to administer the combined components orally or via nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy tube or catheter.

Brief Description of Drawings

The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained with reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

figure 1 shows a representative cross section of the small intestine of rats treated with an enteric preparation and Superior Mesenteric Artery Occlusion (SMAO). Healthy villi are labeled with n and damaged villi are labeled with d.

Fig. 2A and 2B show cross sections of the small intestine of rats after treatment with representative formulation 1 and comparative formulation 1, respectively. Figure 2A shows that rat intestinal villi appear healthy and structurally intact, and that the entire length of villi is visible and completely covered in goblet cells following administration of representative formulation 1 and shock induction according to example 2.

Figure 2B shows that after administration of comparative formulation 1 and shock induction according to example 2, rat intestinal villi are structurally compromised with loss of villous tips and irregular goblet cell staining.

Figure 3 illustrates the percentage of structurally intact villi with an intact epithelial lining in all rats treated in example 2. Representative formulation 1 retained on average 92.6% fluff, while comparative formulation 1 retained on average 52.8% fluff. Data are mean ± SEM; n-4 rats per group; (iv) p <0.01, ANOVA compared to the corresponding treatment group.

Fig. 4A and 4B show cross sections of small intestine of rats treated with representative formulation 2 and comparative formulation 2, respectively. Figure 4A shows that the villi appeared healthy and structurally intact, and that the entire length of villi was visible and completely covered in goblet cells after administration of representative formulation 2 and shock induction according to example 3. Figure 4B shows that after administration of comparative formulation 2 and shock induction according to example 3, rat villi were structurally damaged with missing villus tips and irregular goblet cell staining.

Figure 5 illustrates the percentage of structurally intact villi with an intact epithelial lining in all rats treated in example 3. Representative formulation 2 retained on average 83.4% fluff, while comparative formulation 2 retained on average 51.3% fluff. Data are mean ± SEM; n-4 rats per group; (iv) p <0.01, ANOVA compared to the corresponding treatment group.

Fig. 6A and 6B show cross sections of the small intestine of rats treated with representative formulation 3 and comparative formulation 3, respectively. Fig. 6A shows that the villi appeared healthy and structurally intact, and that the entire length of villi was visible and completely covered in goblet cells following administration of representative formulation 3 and hemorrhagic shock induction according to example 4. Fig. 6B shows that after administration of comparative formulation 3 and hemorrhagic shock according to example 4, the rat villi was structurally compromised.

Figure 7 illustrates the percentage of structurally intact villi with an intact epithelial lining in all rats treated in example 4. Representative formulation 3 retained on average 88.8% fluff, while comparative formulation 3 retained on average 64.1% fluff. Data are mean ± SEM; n-4 rats per group; (iv) p <0.01, ANOVA compared to the corresponding treatment group.

Detailed Description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. All publications, patents and patent applications in this specification are herein incorporated by reference to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference.

Definition of terms

When the term "about" is present before a numerical value herein, it means ± 10% of the numerical value. For example, as defined herein, the term "about 10 g" means an amount of 9g to 11 g.

As defined herein, the terms "comprising," including, "" such as, "and" e.g., (or "such as") are used in their open, non-limiting sense.

The term "treating" and grammatical variations thereof (e.g., "treating") refers to administering an active pharmaceutical ingredient to a patient for the purpose of alleviating or reducing the incidence of one or more symptoms of a condition or disease state in the patient. In some embodiments, such symptoms are chronic or acute, and such relief is partial or complete in some cases. In this context, treatment entails administering to a patient a pharmaceutical composition described herein via the administration route disclosed herein.

As defined herein, "PEG" refers to a polyethylene glycol polymer. When used in conjunction with a "PEG" value, the value defines the average molecular weight of the polyethylene glycol polymer. For example, PEG3350 refers to a polyethylene glycol polymer having an average molecular weight of 3,350 Da.

As defined herein, the term "non-colonic cleansing amount" refers to an amount of material that, when administered to the gastrointestinal tract, does not result in significant or substantially complete removal of stool and toxins from the colon and intestinal tract.

As defined herein, the term "electrolyte" is used to describe any substance that ionizes when dissolved in an ionizing solvent, such as water. Electrolytes include, but are not limited to, soluble salts, acids, or bases.

As defined herein, the term "wt%" refers to the weight percent of a given component in a composition. For example, as defined herein, an aqueous solution comprising 4 wt% glucose refers to an aqueous solution comprising 4g glucose per 100g of solution.

Composition comprising a metal oxide and a metal oxide

Disclosed herein are compositions for treating shock, autodigestion, multiple organ failure, intestinal ischemia, or hypoperfusion. In some embodiments, the compositions disclosed herein comprise tranexamic acid. In some embodiments, the composition comprises about 7.0g, about 7.1g, about 7.2g, about 7.3g, about 7.4g, about 7.5g, about 7.6g, about 7.7g, about 7.8g, about 7.9g, about 8.0g, about 8.1g, about 8.2g, about 8.3g, about 8.4g, about 8.5g, or about 8.6g of tranexamic acid. In a particular embodiment, the compositions disclosed herein comprise about 7.8g of tranexamic acid. In some embodiments, the compositions disclosed herein comprise from about 7.0g to about 8.6g of tranexamic acid.

In some embodiments, the compositions disclosed herein comprise about 6.8g, about 6.9g, about 7.0g, about 7.1g, about 7.2g, about 7.3g, about 7.4g, about 7.5g, about 7.6g, about 7.7g, about 7.8g, about 7.9g, about 8.0g, about 8.1g, about 8.2, or about 8.3g of tranexamic acid. In a particular embodiment, the compositions disclosed herein comprise about 7.5g of tranexamic acid. In some embodiments, the compositions disclosed herein comprise from about 6.8g to about 8.3g of tranexamic acid.

In some embodiments, the compositions disclosed herein comprise a non-colonic cleansing amount of PEG. In certain particular embodiments, the compositions disclosed herein comprise a non-colonic cleansing amount of PEG 2000, PEG 3000, PEG3350, or PEG 4000. In a particular embodiment, the compositions disclosed herein comprise a non-colonic cleansing amount of PEG 3350. In some embodiments, the non-colonic cleansing amount of PEG, such as PEG3350, is about 33.9g, about 34.0g, about 34.1g, about 34.2g, about 34.3g, about 34.4g, about 34.5g, about 34.6g, about 34.7g, about 34.8g, about 34.9g, about 35.0g, about 35.1g, about 35.2g, about 35.3g, about 35.4g, about 35.5g, about 35.6g, about 35.7g, about 35.8g, about 35.9g, about 36.0g, about 36.1g, about 36.2g, about 36.3g, about 36.4g, about 36.5g, about 36.6g, about 36.7g, about 36.8g, about 36.9g, about 37.0g, about 37.1g, about 2g, about 37.4g, about 38.1g, about 38.38 g, about 38.1g, about 38.38 g, about 38g, about 38.6g, about 38g, about 38.6.7 g, about 38g, about 38.1g, about 38g, about 38.2g, about 38g, about 38.2g, About 39.8g, about 39.9g, about 40.0g, about 40.1g, about 40.2g, about 40.3g, about 40.4g, about 40.5g, about 40.6g, about 40.7g, about 40.8g, about 40.9g, about 41.0g, about 41.1g, about 41.2 g, about 41.3g, about 41.4g, about 41.5g, about 41.6g, about 41.7g, about 41.8g, about 41.9g, about 42.0g, about 42.1g, about 42.2g, about 42.3g, about 42.4g, about 42.5g, about 42.6g, about 42.7g, about 42.8g, about 42.9g, about 43.0g, about 43.1g, about 43.2g, about 43.3g, about 43.6g, about 45.7g, about 45.45 g, about 45.6.6 g, about 45.1g, about 45.45 g, about 45.9g, about 45.1g, about 45g, about 45.45 g, about 45.2g, about 45g, about 45.2g, about 45.6.6 g, about 45g, about 45.6.6.6.6 g, about 45g, about 45.6.6.6.6.6.6 g, about 45g, about 45.6.9.6.6 g, about 45g, about 45.6.6.9 g, about 45.6.6.6.6.6 g, about 45, About 46.3g, about 46.4g, about 46.5g, about 46.6g, about 46.7g, about 46.8g, about 46.9g, about 47.0g, about 47.1g, about 47.2g, about 47.3g, about 47.4g, about 47.5g, about 47.6g, about 47.7g, about 47.8g, about 47.9g, about 48.0g, about 48.1g, about 48.2g, about 48.3g, about 48.4g, about 48.5g, about 48.6g, about 48.7g, about 48.8g, about 48.9g, about 49.0g, about 49.1g, about 49.2g, about 49.3g, about 49.4g, about 49.5g, about 49.6g, about 49.7g, about 49.8g, about 9.0g, about 49.1g, about 50.2g, about 50.51 g, about 5g, about 5.5g, about 5g, about 5.6g, about 49.7g, about 49.8.8 g, about 9.0g, about 5.1g, about 50.2g, about 50.51.2 g, about 51.51.2 g, about 5g, about 5.2g, about 51.2g, about 5g, about 51.2g, about 51.2.2 g, about 51.2g, about 51., About 52.8g, about 52.9g, about 53.0g, about 53.1g, about 53.2g, about 53.3g, about 53.4g, about 53.5g, about 53.6g, about 53.7g, about 53.8g, about 53.9g, about 54.0g, about 54.1g, about 54.2g, about 54.3g, about 54.4g, about 54.5g, about 54.6g, about 54.7g, about 54.8g, about 54.9g, about 55.0g, about 55.1g, about 55.2g, or about 55.3 g. In a particular embodiment, the non-colonic cleansing amount of PEG, such as PEG3350, is about 50.3 g. In some embodiments, the non-colonic cleansing amount of PEG, such as PEG3350, is from about 45.2g to about 55.3 g. In a particular embodiment, the non-colonic cleansing amount of PEG, such as PEG3350, is about 37.7 g. In some embodiments, the non-colonic cleansing amount of PEG, such as PEG3350, is about 33.9g to about 41.5 g. In a particular embodiment, the non-colonic cleansing amount of PEG, such as PEG3350, is about 40.2 g. In some embodiments, the non-colonic cleansing amount of PEG, such as PEG3350, is about 36.2g to about 44.2 g.

In some embodiments, the non-colonic cleansing amount of PEG, such as PEG3350, is about 29.3g, about 29.4g, about 29.5g, about 29.6g, about 29.7g, about 29.8g, about 29.9g, about 30.0g, about 30.1g, about 30.2g, about 30.3g, about 30.4g, about 30.5g, about 30.6g, about 30.7g, about 30.8g, about 30.9g, about 31.0g, about 31.1g, about 31.2g, about 31.3g, about 31.4g, about 31.5g, about 31.6g, about 31.7g, about 31.8g, about 31.9g, about 32.0g, about 32.1g, about 32.2g, about 32.3g, about 32.4g, about 32.5g, about 32.6g, about 32.8g, about 33.9g, about 33.34 g, about 34g, about 32.34 g, about 34g, about 34.34 g, about 33.3.3.3.3.3.3.3.3 g, about 32.3.3 g, about 32.3g, about 32.3.3 g, about 32.3g, about 32.3.3.3.3, About 35.2g, about 35.3g, about 35.4g, about 35.5g, about 35.6g, about 35.7g, or about 35.8 g. In a particular embodiment, the non-colonic cleansing amount of PEG, such as PEG3350, is about 32.5 g. In some embodiments, the non-colonic cleansing amount of PEG, such as PEG3350, is from about 29.3g to about 35.8 g.

In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, about 5.0 wt%, about 5.1 wt%, about 5.2 wt%, about 5.3 wt%, about 5.4 wt%, or about 5.5 wt% PEG. In certain embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, about 5.0 wt%, about 5.1 wt%, about 5.2 wt%, about 5.3 wt%, about 5.4 wt%, or about 5.5 wt% PEG 3350. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 5.0 wt% PEG. In certain embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 4.5 wt% to about 5.5 wt% PEG. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 5.0 wt% PEG 3350. In certain embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 4.5 wt% to about 5.5 wt% PEG 3350.

In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, about 5.0 wt%, or about 5.1 wt% PEG. In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, about 5.0 wt%, or about 5.1 wt% PEG 3350. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 4.6 wt% PEG. In certain embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 4.2 wt% to about 5.1 wt% PEG. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 4.6 wt% PEG 3350. In certain embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 4.2 wt% to about 5.1 wt% PEG 3350.

In some embodiments, the compositions disclosed herein comprise glucose. In some embodiments, the compositions disclosed herein comprise about 19g, about 20g, about 21g, about 22g, about 23g, about 24g, about 25g, about 26g, about 27g, about 28g, about 29g, about 30g, about 31g, about 32g, about 33g, about 34g, about 35g, about 36g, about 37g, about 38g, about 39g, about 40g, about 41g, about 42g, about 43g, about 44g, about 45g, about 46g, about 47g, about 48g, about 49g, about 50g, about 51g, about 52g, about 53g, about 54g, about 55g, about 56g, about 57g, about 58g, about 59g, or about 60g of glucose. In a particular embodiment, the compositions disclosed herein comprise about 40g of glucose. In certain embodiments, the compositions disclosed herein comprise from about 25g to about 60g glucose or from about 25g to about 50g glucose. In a particular embodiment, the compositions disclosed herein comprise about 30g of glucose. In certain embodiments, the compositions disclosed herein comprise from about 19g to about 45g glucose or from about 19g to about 38g glucose. In a particular embodiment, the compositions disclosed herein comprise about 32g of glucose. In certain embodiments, the compositions disclosed herein comprise from about 20g to about 48g glucose or from about 20g to about 40g glucose.

In some embodiments, the compositions disclosed herein comprise about 25g, about 26g, about 27g, about 28g, about 29g, about 30g, or about 31g glucose. In a particular embodiment, the compositions disclosed herein comprise about 28g of glucose. In certain embodiments, the compositions disclosed herein comprise from about 25g to about 31g glucose

In some embodiments, the compositions disclosed herein are formulated to comprise an aqueous solution of about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3.0 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4.0 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, about 5.0 wt%, about 5.1 wt%, about 5.2 wt%, about 5.3 wt%, about 5.4 wt%, about 5.5 wt%, about 5.6 wt%, about 5.7 wt%, about 5.8 wt%, about 5.9 wt%, about 6 wt%, or about 6 wt% glucose. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 4 wt% glucose. In certain embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising from about 2.5 wt% to about 6.0 wt% glucose or from about 2.5 wt% to about 5.0 wt% glucose.

In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4.0 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, or about 4.4 wt% glucose. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 4 wt% glucose. In certain embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising from about 3.6 wt% to about 4.4 wt% glucose.

In some embodiments, the compositions disclosed herein comprise one or more electrolytes. In certain embodiments, the one or more electrolytes comprise sodium chloride (NaC 1). In some embodiments, the compositions disclosed herein comprise about 1.0g, about 1.1g, about 1.2g, about 1.3g, about 1.4g, about 1.5g, about 1.6g, or about 1.7g sodium chloride. In a particular embodiment, the compositions disclosed herein comprise about 1.5g of sodium chloride. In some embodiments, the compositions disclosed herein comprise from about 1.3g to about 1.7g of sodium chloride. In a particular embodiment, the compositions disclosed herein comprise about 1.1g of sodium chloride. In some embodiments, the compositions disclosed herein comprise from about 1.0g to about 1.2g of sodium chloride. In a particular embodiment, the compositions disclosed herein comprise about 1.2g of sodium chloride. In some embodiments, the compositions disclosed herein comprise from about 1.1g to about 1.3g sodium chloride.

In some embodiments, the compositions disclosed herein comprise about 0.9g, about 1.0g, or about 1.1g sodium chloride. In a particular embodiment, the compositions disclosed herein comprise about 1.0g of sodium chloride. In some embodiments, the compositions disclosed herein comprise from about 0.9g to about 1.1g sodium chloride.

In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.13 wt%, about 0.14 wt%, about 0.15 wt%, about 0.16 wt%, about 0.17 wt% sodium chloride. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.15 wt% sodium chloride. In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising from about 0.13 wt% to about 0.17 wt% sodium chloride.

In some embodiments, the one or more electrolytes comprise sodium sulfate (Na)₂SO₄). In some embodiments, the compositions disclosed herein comprise about 3.9g, about 4.0g, about 4.1g, about 4.2g, about 4.3g, about 4.4g, about 4.5g, about 4.6g, about 4.7g, about 4.8g, about 4.9g, about 5.0g, about 5.1g, about 5.2g, about 5.3g, about 5.4g, about 5.5g, about 5.6g, about 5.7g, about 5.8g, about 5.9g, about 6.0g, about 6.1g, about 6.2, or about 6.3g sodium sulfate. In a particular embodiment, the compositions disclosed herein comprise about 5.7g of sodium sulfate. In some embodiments, the compositions disclosed herein comprise from about 5.1g to about 6.3g sodium sulfate. In a particular embodiment, the compositions disclosed herein comprise about 4.3g of sodium sulfate. In some embodiments, the compositions disclosed herein comprise from about 3.9g to about 4.7g sodium sulfate. In a particular embodiment, the compositions disclosed herein comprise about 4.6g of sodium sulfate. In some embodiments, the compositions disclosed herein comprise from about 4.1g to about 5.1g sodium sulfate.

In some embodiments, the compositions disclosed herein comprise about 3.6g, about 3.7g, about 3.8g, about 3.9g, about 4.0g, about 4.1g, about 4.2g, about 4.3g, or about 4.4g sodium sulfate. In a particular embodiment, the compositions disclosed herein comprise about 4.0g of sodium sulfate. In some embodiments, the compositions disclosed herein comprise from about 3.6g to about 4.4g sodium sulfate.

In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising sodium sulfate. In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.51 wt%, about 0.52 wt%, about 0.53 wt%, about 0.54 wt%, about 0.55 wt%, about 0.56 wt%, about 0.57 wt%, about 0.58 wt%, about 0.59 wt%, about 0.60 wt%, about 0.61 wt%, about 0.62 wt%, or about 0.63 wt% sodium sulfate. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.57 wt% sodium sulfate. In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.51 wt% to about 0.63 wt% sodium sulfate.

In some embodiments, the one or more electrolytes comprise sodium bicarbonate (NaHCO)₃). In some embodiments, the compositions disclosed herein comprise about 1.2g, about 1.3g, about 1.4g, about 1.5g, about 1.6g, about 1.7g, about 1.8g, or about 1.9g sodium bicarbonate. In a particular embodiment, the compositions disclosed herein comprise about 1.7g of sodium bicarbonate. In some embodiments, the compositions disclosed herein comprise from about 1.5g to about 1.9g sodium bicarbonate. In a particular embodiment, the compositions disclosed herein comprise about 1.3g of sodium bicarbonate. In some embodiments, the compositions disclosed herein comprise from about 1.2g to about 1.4g sodium bicarbonate. In a particular embodiment, the compositions disclosed herein comprise about 1.4g of sodium bicarbonate. In some embodiments, the compositions disclosed herein comprise from about 1.3g to about 1.5g sodium bicarbonate.

In some embodiments, the compositions disclosed herein comprise about 1.1g, about 1.2g, or about 1.3g sodium bicarbonate. In a particular embodiment, the compositions disclosed herein comprise about 1.2g of sodium bicarbonate. In some embodiments, the compositions disclosed herein comprise from about 1.1g to about 1.3g sodium bicarbonate.

In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.15 wt%, about 0.16 wt%, about 0.17 wt%, about 0.18 wt%, or about 0.19 wt% sodium bicarbonate. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.17 wt% sodium bicarbonate. In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising from about 0.15 wt% to about 0.19 wt% sodium bicarbonate.

In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.16 wt%, about 0.17 wt%, about 0.18 wt%, or about 0.19 wt% sodium bicarbonate. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.17 wt% sodium bicarbonate. In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising from about 0.16 wt% to about 0.19 wt% sodium bicarbonate.

In some embodiments, the one or more electrolytes comprise potassium chloride (KC 1). In some embodiments, the compositions disclosed herein comprise about 0.4g, about 0.5g, about 0.6g, about 0.7g, or about 0.8g potassium chloride. In a particular embodiment, the compositions disclosed herein comprise about 0.7g of potassium chloride. In some embodiments, the compositions disclosed herein comprise from about 0.6g to about 0.8g potassium chloride. In a particular embodiment, the compositions disclosed herein comprise about 0.5g of potassium chloride. In some embodiments, the compositions disclosed herein comprise from about 0.4g to about 0.6g potassium chloride. In a particular embodiment, the compositions disclosed herein comprise about 0.6g of potassium chloride. In some embodiments, the compositions disclosed herein comprise from about 0.5g to about 0.7g potassium chloride.

In some embodiments, the compositions disclosed herein comprise about 0.4g, about 0.5g, or about 0.6g potassium chloride. In a particular embodiment, the compositions disclosed herein comprise about 0.5g of potassium chloride. In some embodiments, the compositions disclosed herein comprise from about 0.4g to about 0.6g potassium chloride.

In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.06 wt%, about 0.07 wt%, or about 0.08 wt% potassium chloride. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.07 wt% potassium chloride. In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising from about 0.06 wt% to about 0.08 wt% potassium chloride.

In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, or about 0.09% wt potassium chloride. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 0.07 wt% potassium chloride. In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising from about 0.06 wt% to about 0.09 wt% potassium chloride.

In some embodiments, the compositions disclosed herein are formulated in any suitable dosage form, including but not limited to solutions, dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, liquids, gels, syrups, elixirs, lyophilized formulations, powders, or multiparticulate formulations. Such intermediates are optionally prepared in conventional manners, such as by mere way of example conventional mixing, dissolving, emulsifying, and the like. In some embodiments, the compositions disclosed herein are formulated as a powder for reconstitution. In some embodiments, the compositions disclosed herein are formulated as an aqueous solution.

In certain embodiments, the compositions disclosed herein are formulated as a solution, such as an aqueous solution. In some embodiments, the compositions disclosed herein are formulated as a solution, such as an aqueous solution, having a volume of about 500mL, about 510mL, about 520mL, about 530mL, about 540mL, about 550mL, about 560mL, about 570mL, about 580mL, about 590mL, about 600mL, about 610mL, about 620mL, about 630mL, about 640mL, about 650mL, about 660mL, about 670mL, about 680mL, about 690mL, about 700mL, about 710mL, about 720mL, about 730mL, about 740mL, about 750mL, about 760mL, about 770mL, about 780mL, about 790mL, about 800mL, about 810mL, about 820mL, about 830mL, about 840mL, about 850mL, about 860mL, about 870mL, about 880mL, about 890mL, about 900mL, about 910mL, about 920mL, about 930mL, about 940mL, about 950mL, about 960mL, about 970mL, about 980mL, about 990mL, or about 1000 mL. In some embodiments, the compositions disclosed herein are formulated as a solution, such as an aqueous solution, having a volume of about 500mL to about 1000 mL. In some embodiments, the compositions disclosed herein are formulated as a solution, such as an aqueous solution, having a volume of about 750mL to about 1000 mL.

In some embodiments, the compositions disclosed herein are formulated as a solution, such as an aqueous solution, having a volume of about 630mL, about 640mL, about 650mL, about 660mL, about 670mL, about 680mL, about 690mL, about 700mL, about 710mL, about 720mL, about 730mL, about 740mL, about 750mL, about 760mL, or about 770 mL. In a particular embodiment, the compositions disclosed herein are formulated as a solution, such as an aqueous solution, having a volume of about 700 mL. In some embodiments, the compositions disclosed herein are formulated as a solution, such as an aqueous solution, having a volume of about 630mL to about 770 mL.

In some embodiments, the compositions disclosed herein comprise from about 7.0g to about 8.6g of tranexamic acid and from about 25g to about 60g of glucose. In some embodiments, the compositions disclosed herein comprise from about 7.0g to about 8.6g of tranexamic acid and from about 25g to about 50g of glucose. In certain particular embodiments, the compositions disclosed herein comprise about 7.8g of tranexamic acid and about 19g, about 20g, about 21g, about 22g, about 23g, about 24g, about 25g, about 26g, about 27g, about 28g, about 29g, about 30g, about 31g, about 32g, about 33g, about 34g, about 35g, about 36g, about 37g, about 38g, about 39g, about 40g, about 41g, about 42g, about 43g, about 44g, about 45g, about 46g, about 47g, about 48g, about 49g, about 50g, about 51g, about 52g, about 53g, about 54g, about 55g, about 56g, about 57g, about 58g, about 59g, or about 60g of glucose. In a particular embodiment, the composition disclosed herein comprises about 7.8g of tranexamic acid and about 40g of glucose.

In some embodiments, the compositions disclosed herein comprise from about 6.8g to about 8.3g of tranexamic acid and from about 25g to about 31g of glucose. In certain particular embodiments, the compositions disclosed herein comprise about 7.5g of tranexamic acid and about 25g, about 26g, about 27g, about 28g, about 29g, about 30g, or about 31g of glucose. In a particular embodiment, the composition disclosed herein comprises about 7.5g of tranexamic acid and about 28g of glucose.

In some embodiments, the compositions disclosed herein comprise from about 7.0g to about 8.6g of tranexamic acid and from about 45.2g to about 55.3g of PEG 3350. In some embodiments, the compositions disclosed herein comprise about 7.0g to about 8.6g of tranexamic acid and about 33.9g to about 41.5g of PEG 3350. In some embodiments, the compositions disclosed herein comprise about 7.0g to about 8.6g of tranexamic acid and about 36.2g to about 44.2g of PEG 3350. In certain specific embodiments, the compositions disclosed herein comprise about 7.8g tranexamic acid and about 33.9g, about 34.0g, about 34.1g, about 34.2g, about 34.3g, about 34.4g, about 34.5g, about 34.6g, about 34.7g, about 34.8g, about 34.9g, about 35.0g, about 35.1g, about 35.2g, about 35.3g, about 35.4g, about 35.5g, about 35.6g, about 35.7g, about 35.8g, about 35.9g, about 36.0g, about 36.1g, about 36.2g, about 36.3g, about 36.4g, about 36.5g, about 36.6g, about 36.7g, about 36.8g, about 36.9g, about 37.0g, about 37.1g, about 37.3g, about 38.4g, about 38g, about 37.1g, about 38.38 g, about 38.1g, about 38.38 g, about 38g, about 38.1g, about 38g, about 38.38 g, about 38g, about 38.9g, about 38g, about 38.1g, about 38g, about 38.2g, about 38g, about 38.1g, about 38.2g, about 38g, about 38.6.6.6.6.6.6 g, about 38g, About 39.6g, about 39.7g, about 39.8g, about 39.9g, about 40.0g, about 40.1g, about 40.2g, about 40.3g, about 40.4g, about 40.5g, about 40.6g, about 40.7g, about 40.8g, about 40.9g, about 41.0g, about 41.1g, about 41.2, about 41.3g, about 41.4g, about 41.5g, about 41.6g, about 41.7g, about 41.8g, about 41.9g, about 42.0g, about 42.1g, about 42.2g, about 42.3g, about 42.4g, about 42.5g, about 42.6g, about 42.7g, about 42.8g, about 42.9g, about 43.0g, about 43.1g, about 43.2g, about 43.4g, about 45.45 g, about 45.6g, about 45.7g, about 44.8g, about 45.8g, about 45.9g, about 45.0g, about 43.0g, about 43.1g, about 43.2g, about 43.2.2 g, about 43.4.4 g, about 45.4g, about 45.4.4 g, about 45.6.6.6 g, about 45g, about 45.6g, about 45g, about 45.7g, about 45g, about 45.6g, about 45.7g, about 45.6.7 g, about 45.6g, about 45.6.7 g, about 45.7g, about 45.6g, about, About 46.1g, about 46.2g, about 46.3g, about 46.4g, about 46.5g, about 46.6g, about 46.7g, about 46.8g, about 46.9g, about 47.0g, about 47.1g, about 47.2g, about 47.3g, about 47.4g, about 47.5g, about 47.6g, about 47.7g, about 47.8g, about 47.9g, about 48.0g, about 48.1g, about 48.2g, about 48.3g, about 48.4g, about 48.5g, about 48.6g, about 48.7g, about 48.8g, about 48.9g, about 49.0g, about 49.1g, about 49.2g, about 49.3g, about 49.4g, about 49.5g, about 49.6g, about 7.9g, about 49.0g, about 49.1g, about 49.2g, about 49.3g, about 49.4g, about 49.5g, about 49.6g, about 5.2g, about 5g, about 5.5g, about 5g, about 5.5.5 g, about 5.5g, about 5.5.5.5 g, about 5g, about 5.5.5.5.0 g, about 5.51.51.51.2 g, about 5g, about 50.51.2 g, about 50.2g, about 50.51.2 g, about 5g, about 5.2g, about 5.51.2 g, about 50.2g, about 5.2g, about 5., About 52.6g, about 52.7g, about 52.8g, about 52.9g, about 53.0g, about 53.1g, about 53.2g, about 53.3g, about 53.4g, about 53.5g, about 53.6g, about 53.7g, about 53.8g, about 53.9g, about 54.0g, about 54.1g, about 54.2g, about 54.3g, about 54.4g, about 54.5g, about 54.6g, about 54.7g, about 54.8g, about 54.9g, about 55.0g, about 55.1g, about 55.2g, or about 55.3g of PEG 3350. In a particular embodiment, the compositions disclosed herein comprise about 7.8g of tranexamic acid and about 59.0g of PEG 3350. In a particular embodiment, the compositions disclosed herein comprise about 7.8g of tranexamic acid and about 40.2g of PEG 3350. In a particular embodiment, the compositions disclosed herein comprise about 7.8g of tranexamic acid and about 37.7g of PEG 3350.

In some embodiments, the compositions disclosed herein comprise from about 6.8g to about 8.3g of tranexamic acid and from about 29.3g to about 35.8g of PEG 3350. In certain particular embodiments, the compositions disclosed herein comprise about 7.5g tranexamic acid and about 29.3g, about 29.4g, about 29.5g, about 29.6g, about 29.7g, about 29.8g, about 29.9g, about 30.0g, about 30.1g, about 30.2g, about 30.3g, about 30.4g, about 30.5g, about 30.6g, about 30.7g, about 30.8g, about 30.9g, about 31.0g, about 31.1g, about 31.2g, about 31.3g, about 31.4g, about 31.5g, about 31.6g, about 31.7g, about 31.8g, about 31.9g, about 32.0g, about 32.1g, about 32.2g, about 32.3g, about 32.4g, about 32.32 g, about 32.7.7 g, about 32.8g, about 33.34 g, about 32.34 g, about 33.34 g, about 3.34 g, about 32.34 g, about 32., About 35.0g, about 35.1g, about 35.2g, about 35.3g, about 35.4g, about 35.5g, about 35.6g, about 35.7g, or about 35.8g PEG 3350. In a particular embodiment, the compositions disclosed herein comprise about 7.5g of tranexamic acid and about 32.5g of PEG 3350.

In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 7.0g to about 8.6g of tranexamic acid, about 4.5 wt% to about 5.5 wt% PEG3350, about 2.5 wt% to about 6 wt% glucose, about 0.51 wt% to about 0.63 wt% sodium sulfate, about 0.15 wt% to about 0.19 wt% sodium bicarbonate, about 0.13 wt% to about 0.17 wt% sodium chloride, and about 0.06 wt% to about 0.08 wt% potassium chloride. In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 7.0g to about 8.6g of tranexamic acid, about 4.5 wt% to about 5.5 wt% PEG3350, about 2.5 wt% to about 5 wt% glucose, about 0.51 wt% to about 0.63 wt% sodium sulfate, about 0.15 wt% to about 0.19 wt% sodium bicarbonate, about 0.13 wt% to about 0.17 wt% sodium chloride, and about 0.06 wt% to about 0.08 wt% potassium chloride. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 7.8g tranexamic acid, about 5.0 wt% PEG3350, about 4 wt% glucose, about 0.57 wt% sodium sulfate, about 0.17 wt% sodium bicarbonate, about 0.15 wt% sodium chloride, and about 0.07 wt% potassium chloride.

In some embodiments, the compositions disclosed herein are formulated as an aqueous solution comprising about 6.8g to about 8.3g of tranexamic acid, about 4.2 wt% to about 5.1 wt% PEG3350, about 3.6 wt% to about 4.4 wt% glucose, about 0.51 wt% to about 0.63 wt% sodium sulfate, about 0.16 wt% to about 0.19 wt% sodium bicarbonate, about 0.13 wt% to about 0.17 wt% sodium chloride, and about 0.06 wt% to about 0.09 wt% potassium chloride. In a particular embodiment, the compositions disclosed herein are formulated as an aqueous solution comprising about 7.5g tranexamic acid, about 4.6 wt% PEG3350, about 4 wt% glucose, about 0.57 wt% sodium sulfate, about 0.17 wt% sodium bicarbonate, about 0.15 wt% sodium chloride, and about 0.07 wt% potassium chloride.

In some embodiments, the compositions disclosed herein are formulated with one or more inactive ingredients or pharmaceutical excipients that provide suitable formulation properties. Such inactive ingredients include, but are not limited to, antioxidants, carriers, viscosity modifiers, diluents, flavoring agents, preservatives, solubilizers, stabilizers, suspending agents, and surfactants. Any suitable amount of such inactive ingredients will depend on the particular form desired.

Method of treatment

In some embodiments, the compositions disclosed herein are administered for the treatment of shock, autodigestion, multiple organ failure, ischemia, or hypoperfusion. In certain particular embodiments, the compositions disclosed herein are administered for the treatment of cardiogenic shock, hemorrhagic shock, or septic shock. In some embodiments, the ischemia is an intestinal ischemia. In some embodiments, the compositions disclosed herein are administered for the treatment of septic shock associated with or resulting from sepsis. In some embodiments, the compositions disclosed herein are administered for the treatment of cardiovascular shock associated with or caused by cardiovascular surgery, myocardial infarction, arrhythmia, or mechanical complications. In some embodiments, the mechanical complication is a cardiovascular mechanical complication. In some embodiments, the compositions disclosed herein are administered for the treatment of cardiovascular shock associated with or resulting from myocardial infarction or mechanical complications. In some embodiments, the compositions disclosed herein are administered for the treatment of hemorrhagic or hypovolemic shock associated with or resulting from trauma. In some embodiments, the compositions disclosed herein can be administered for the treatment of hemorrhagic or hypovolemic shock associated with or caused by ebola virus disease or other hemorrhagic viruses. In some embodiments, the compositions disclosed herein are administered for the treatment of intestinal ischemia or hypoperfusion resulting in shock. In some embodiments, the compositions disclosed herein can be administered for the treatment of inflammatory bowel Disease or Crohn's Disease, or complications arising from inflammatory bowel Disease or Crohn's Disease. In some embodiments, the compositions disclosed herein can be administered for the treatment of Clostridium difficile colitis (Clostridium difficile colitis) or complications arising from Clostridium difficile colitis.

In some embodiments, the compositions disclosed herein are administered to a subject (e.g., a human) separately or simultaneously by a variety of routes of administration, including, but not limited to, oral, nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy administration, or other enteral routes. In some embodiments, the compositions disclosed herein are administered directly to the gastrointestinal tract. In some embodiments, the compositions disclosed herein are administered to the stomach. In some embodiments, the compositions disclosed herein are administered to the small intestine. In certain embodiments, the compositions disclosed herein are administered via a nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy tube or catheter. In some embodiments, the compositions disclosed herein are delivered orally or by direct injection. In some embodiments of the methods disclosed herein, the composition is administered by a single route of administration. In some embodiments of the methods disclosed herein, the composition is administered by a plurality of routes of administration.

Reagent kit

In some embodiments, the components of the compositions disclosed herein are provided in a kit, wherein one or more of the components are contained in a separate package or container along with instructions for combining the components into a single composition. In some embodiments, the kit comprises instructions to reconstitute the components in a liquid carrier, such as water, to produce a liquid (e.g., aqueous) formulation comprising the components. In some cases, the components of the compositions disclosed herein are provided in separate packages or containers with instructions for reconstituting them in a liquid carrier (such as water) to produce a liquid (e.g., aqueous) formulation. In some embodiments, the components of the compositions disclosed herein are provided in a kit, wherein one or more of the components are contained in a separate package or container and wherein a liquid carrier (such as water) is also provided in a separate package or container in the kit, along with instructions for combining the components and liquid carrier in a single composition to produce a liquid (e.g., aqueous) formulation. In some embodiments, the kit comprises instructions for administering a composition or formulation disclosed herein to a subject (e.g., a human) orally or via nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy tube or catheter to treat shock, autodigestion, multiple organ failure, ischemia, or hypoperfusion.

In certain particular embodiments, the kit comprises tranexamic acid and glucose packaged in separate containers. In some embodiments, the kit comprises tranexamic acid, polyethylene glycol, and one or more electrolytes in a first container and glucose in a second container. In some embodiments, the kit comprises tranexamic acid and polyethylene glycol in a first container and glucose and one or more electrolytes in a second container. In some embodiments, the kit comprises tranexamic acid and an electrolyte in a first container and glucose and polyethylene glycol in a second container. In some embodiments, the kit comprises tranexamic acid in a first container and glucose, polyethylene glycol, and an electrolyte in a second container. In some cases, the container is made from any suitable packaging material and is in any form suitable for dispensing a pharmaceutical product.

In some embodiments, disclosed herein are kits comprising: the components tranexamic acid, PEG, glucose and one or more electrolytes, wherein at least one of the components tranexamic acid, PEG, glucose and one or more electrolytes is in a separate container from at least one of the other components tranexamic acid, PEG, glucose and one or more electrolytes; and instructions for combining the components tranexamic acid, PEG, glucose, and one or more electrolytes in a single composition. In some embodiments, the kit comprises tranexamic acid, PEG, and one or more electrolytes in a first container and glucose in a second container. In some embodiments, the kit comprises instructions to combine tranexamic acid, PEG, one or more electrolytes, and glucose and reconstitute them in water. In some embodiments, the kit comprises a first container comprising about 7.8g of tranexamic acid, about 50.3g of PEG3350, about 5.7g of sodium sulfate, about 1.7g of sodium bicarbonate, about 1.5g of sodium chloride, and about 0.7g of potassium chloride, and a second container comprising about 40g of glucose. In some embodiments, a kit comprises a first container comprising about 7.8g of tranexamic acid, about 50.3g of PEG3350, about 5.7g of sodium sulfate, about 1.7g of sodium bicarbonate, about 1.5g of sodium chloride, and about 0.7g of potassium chloride, a second container comprising about 40g of glucose, and instructions for reconstituting tranexamic acid, PEG, glucose, and one or more electrolytes with water to 1000 mL. In some embodiments, the kit comprises a first container comprising about 7.5g of tranexamic acid, about 32.5g of PEG3350, about 4.0g of sodium sulfate, about 1.2g of sodium bicarbonate, about 1.0g of sodium chloride, and about 0.5g of potassium chloride, and a second container comprising about 28g of glucose. In some embodiments, a kit comprises a first container comprising about 7.5g of tranexamic acid, about 32.5g of PEG3350, about 4.0g of sodium sulfate, about 1.2g of sodium bicarbonate, about 1.0g of sodium chloride, and about 0.5g of potassium chloride, a second container comprising about 28g of glucose, and instructions for reconstituting tranexamic acid, PEG, glucose, and one or more electrolytes with water to 700 mL. In some embodiments, the kit comprises instructions to administer the combined components orally or via nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy tube or catheter.

Testing

In some embodiments, the compositions disclosed herein are tested in animal models indicative of shock, autodigestion, multiple organ failure, trauma, sepsis, and efficacy of ischemic therapy. Such animal models include, but are not limited to, mini-pig hemorrhagic shock models, rat hemorrhagic shock, rat superior mesenteric arterial block shock, rodent peritonitis shock by replacement of caecal material into the peritoneum, rodent endotoxin shock models, and rodent models of bacterial sepsis established by pseudomonas infection.

Examples

Example 1: exemplary compositions

Exemplary compositions are described in tables 1 and 2. In some embodiments, the compositions according to the present disclosure are prepared as dry powder formulations and reconstituted as indicated. Table 1 shows the composition for reconstitution in water to 1000 mL. Table 2 shows the composition for reconstitution in water to 700 mL. In some cases, the composition is administered to a patient in need thereof, e.g., orally or directly to the gastrointestinal tract via a nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy tube or catheter, after reconstitution.

TABLE 1

TABLE 2

Example 2: superior Mesenteric Artery Occlusion (SMAO) shock studies with formulations administered via oral gavage

The SMAO model was used to assess the ability of a representative composition comprising PEG3350 (representative formulation 1) and a comparative composition without PEG3350 (comparative formulation 1) to maintain the structural integrity of the gastrointestinal tract under ischemic conditions when administered by oral gavage.

Preparation of the formulations

The materials used to prepare the formulations and their sources are shown in table 3. All materials used were USP grade. As shown in table 3, representative formulation 1 included tranexamic acid, electrolyte, PEG3350, and glucose, and comparative formulation 1 included tranexamic acid, electrolyte, and glucose.

TABLE 3

Rat and diet

Male WISTAR rats weighing 360-400g were purchased from Charles River Laboratories, Wilmington, MA. All rats were maintained throughout the study with a 2018Teklad Global 18% protein rat diet (Harlan, San Diego, CA, USA) and water.

Formulation administration

Food was removed from the cages overnight prior to surgery. Rats were allowed ad libitum access to water while in home cages one night before surgery. During administration of the formulation, rats were restricted and given 4mL of either representative formulation 1 or comparative formulation 1 by oral gavage. After administration of the test formulation, rats were returned to their home cages and allowed free access to water. After a period of 3 hours, the rats were prepared to undergo laboratory-induced shock.

Anesthesia and preoperative preparation

Animals were anesthetized with ketamine/xylazine (75/4mg/kg, I.M.). As indicated, supplemental anesthesia was administered following a response to tail/toe pinching pain (ketamine/xylazine 10% initial dose, I.M.). Anesthesia was maintained throughout the experimental shock period.

Rats were mounted in a supine position to a temperature-controlled (water-circulating heat pump) console. Animals were maintained at 37 ℃ throughout the procedure.

All surgical procedures were performed using septic techniques. Sterile drapes, heat sterilized instruments, and surgical gowns (gowns, masks, and gloves) were used. Surgical sites on the abdomen and left groin were shaved and washed with povidone iodine, then 70% alcohol.

SMAO program

After anesthesia, the superior mesenteric artery was located and ligated (blocked) to prevent blood flow to the intestine and a 30 minute shock/hypoperfusion period was initiated. The surgical site was covered with moistened sterile gauze throughout the SMAO shock period. After a period of 30 minutes, the SMAO was undone (block removal). Perfusion was continued for a period of 2 hours, and the animals were then sacrificed.

Autopsy and histological processing

The intestines were then collected by shortening both ends, injecting a 10% neutral buffered formalin solution with a 30 gauge needle, and storing the intestines in a jar filled with 10% neutral buffered formalin.

After at least 24 hours of incubation in formalin, sections of approximately 5cm x 5cm ileum (approximately 5/6 for small intestine length) were cut out for structural analysis. Tissue samples were adhered to cardboard pallets and fixed for sectioning. 15-20 micron thick intestinal cross sections were generated on a Vibratome Series 3000 sectioning system. The free floating sections were washed in water overnight to remove formalin. Sections were then free-floating stained with Alcian blue (pH 2.5) (Diagnostic BioSystems, catalog No. KT 003) and fixed on slides for analysis.

Tissue analysis

A Leitz Wetzlar Dialux 20 microscope (Wetzlar, West Germany) and a 20X objective were used to image tissue sections. Still tissue images were captured using the Spot instrument Gigabit Camera, model 35.2, Diagnostic Instruments, inc. (Sterling Heights, Michigan) and software included. The image is saved as a TIFF file without compression. The image was loaded into Photoshop Elements 13 and enhanced to sharpen the outline of the villus. To quantify the extent of fluff damage, fluff was classified as damaged when any of the following criteria were met:

1) the fluff tip breaks away or the structure is damaged to any part of the fluff; or

2) From the bottom to the tip of the hair, goblet cells (normally stained blue) were virtually absent (≦ 3 goblet cells without staining)

The Photoshop Text tool was used to place n (for no damage) or d (for damage) near each individual villus of each tissue cross-section. When the determination of the damage is uncertain, the fuzz is excluded from the analysis. These indeterminate fluff was less than 5% of the total fluff analyzed. Images showing the identification method in fig. 1, which shows a cross section of the small intestine of rats treated with the intestine preparation. Healthy villi are labeled with n and damaged villi are labeled with d.

Results

A total of eight rats were tested. Four received representative formulation 1 by oral gavage, while four rats received comparative formulation 1 by oral gavage. Representative micrographs of villi after administration of the formulation and shock induction are shown in figures 2A and 2B. Figure 2A shows a cross section of the small intestine of rats treated with representative formulation 1. The villi in fig. 2A appear healthy and structurally intact, as the entire length of the villi is visible and completely covered in goblet cells. Fig. 2B shows a cross section of the small intestine of rats treated with comparative formulation 1. The villi in fig. 2B appeared structurally damaged, with missing villi tips and irregular goblet cell staining.

Quantification of structurally intact villi after administration of the formulation and shock induction is shown in tables 4 and 5 and figure 3. Table 4 shows individual rat data for quantification of structurally intact villi. Table 5 summarizes the total intact and damaged villi observed after administration of the formulation and shock induction. Figure 3 shows the average percentage of intact villi per rat after administration of the formulation and shock induction. 92.6% of the villi were intact in all rats receiving representative formulation 1, while only 52.8% of the villi were intact in all rats receiving comparative formulation 1. These results are consistent with the average calculated from the total fuzz observed in table 5.

TABLE 4

TABLE 5

Example 3: SMAO shock study with formulations administered via direct enteral injection

The SMAO model was used to evaluate the ability of a representative composition comprising glucose (representative formulation 2) and a comparative composition without glucose (comparative formulation 2) to maintain structural integrity under ischemic conditions when administered by direct enteral injection.

Preparation of the formulations

The materials used to prepare the formulations and their sources are shown in table 6. All materials used were USP grade. As shown in table 6, representative formulation 2 included tranexamic acid, electrolyte, PEG3350 and glucose, and comparative formulation 2 included tranexamic acid, electrolyte and PEG 3350.

TABLE 6

Rat and diet

Formulation administration

Food was removed from the cages overnight prior to surgery. Rats were allowed ad libitum access to water while in home cages one night before surgery. After anesthesia, a midline incision is made in the abdomen for separation of the small intestine. Using a 30 gauge needle, 17mL of representative formulation 2 or comparative formulation 2 was administered to rats via direct injection into the intestine. Following formulation administration, rats were subjected to experimentally induced shock via the SMAO procedure.

Anesthesia and preoperative preparation

Rats were mounted in a supine position to a temperature-controlled (water-circulating heat pump) console. Animals were maintained at 37 ℃ throughout the procedure.

SMAO program

To start the model, after anesthesia, the superior mesenteric artery was positioned and ligated (blocked) to prevent blood flow to the intestine and a 30 minute shock/hypoperfusion period was initiated. The surgical site was covered with moistened sterile gauze throughout the SMAO shock period. After a period of 30 minutes, the SMAO was undone (block removal). Perfusion was continued for a period of 2 hours, and the animals were then sacrificed.

Autopsy and histological processing

Tissue analysis

1) the fluff tip breaks away or the structure is damaged to any part of the fluff; or

2) From the bottom to the tip of the hair, goblet cells (normally stained blue) were virtually absent (<3 goblet cells were not stained)

The Photoshop Text tool was used to place n (for no damage) or d (for damage) near each individual villus of each tissue cross-section. When the determination of the damage is uncertain, the fuzz is excluded from the analysis. These indeterminate fluff was less than 5% of the total fluff analyzed. Images showing the identification method in fig. 1, a cross section of the small intestine of a rat treated with an intestinal preparation is shown. Healthy villi are labeled with n and damaged villi are labeled with d.

Results

A total of eight rats were tested. Four received representative formulation 2 by direct enteral injection, while four rats received comparative formulation 2 by direct enteral injection. Representative micrographs of villi after administration of the formulation and shock induction are shown in figures 4A and 4B. Figure 4A shows a cross section of the small intestine of rats treated with representative formulation 2. The villi in fig. 4A appear healthy and structurally intact, as the entire length of the villi is visible and completely covered in goblet cells. Fig. 4B shows a cross section of the small intestine of a rat treated with comparative formulation 2. The villi in fig. 4B appeared structurally damaged, with missing villi tips and irregular goblet cell staining.

Quantification of structurally intact villi after administration of the formulation and shock induction is shown in tables 7 and 8 and figure 5. Table 7 shows individual rat data for quantification of structurally intact villi. Table 8 summarizes the total intact and damaged villi observed after administration of the formulation and shock induction. Figure 5 shows the average percentage of intact villi per rat after administration of the formulation and shock induction. 83.4% of the villi were intact in all rats receiving representative formulation 2, while only 51.3% of the villi were intact in all rats receiving comparative formulation 2. These results are consistent with the average calculated from the total fuzz observed in table 8.

TABLE 7

TABLE 8

Example 4: study of hemorrhagic shock with formulations administered via direct gastric injection

The hemorrhagic shock model was used to evaluate the ability of a representative composition comprising PEG3350 (representative formulation 3) and a comparative composition without PEG3350 (comparative formulation 3) to maintain the structural integrity of the gastrointestinal tract under hemorrhagic conditions when administered by direct gastric injection.

Preparation of the formulations

The materials used to prepare the formulations and their sources are shown in table 9. All materials used were USP grade. As shown in table 9, representative formulation 3 contained tranexamic acid, electrolyte, PEG3350 and glucose, and comparative formulation 3 contained tranexamic acid, electrolyte and glucose.

TABLE 9

Rat and diet

Male WISTAR rats weighing 320-400g were purchased from Charles River Laboratories, Wilmington, MA. All rats were maintained ad libitum throughout the study with water fed and supplied by Charles River Laboratories.

Formulation administration

Food was removed from the cages overnight prior to surgery. After placement of the catheter, a small skin incision is made in the abdomen to isolate the stomach. Following stabilization post-laboratory-induced shock via the hemorrhagic shock procedure, rats were administered 4mL of either representative formulation 3 or comparative formulation 3 via direct injection into the stomach.

Anesthesia and preoperative preparation

Animals were anesthetized with ketamine (75mg/kg, I.M.). Anesthesia was maintained throughout the experimental shock period.

Rats were mounted in a supine position to a temperature-controlled (water-circulating heat pump) console. Animals were maintained at 37 ℃ throughout the procedure. Vital signs (systemic blood pressure or respiration rate, body temperature) were monitored throughout the procedure.

Hemorrhagic shock procedure

To start the model, rats were anesthetized with ketamine (75mg/kg, I.M.). The abdominal and groin areas were shaved and disinfected with alcohol. Cannulate the right femoral artery. The surgical site was covered with moistened sterile gauze throughout the hemorrhagic shock period. Hemorrhagic shock was achieved by lowering blood pressure (about 40% of total blood volume based on 6% body weight) to obtain 35mmHg (47.58cm H) for a 2 hour period₂O) blood pressure. Briefly, each rat was heparinized with a minimum concentration of heparin sodium (0.5USP units/ml blood volume, estimated at 6% body weight) to prevent blood coagulation during the procedure. The right femoral artery was connected to a 10cc syringe. About 6ml of blood over about 5-10 minutesTime is withdrawn from the femoral artery. The syringe was then placed at 47.58cm above the body level of the rat. The syringe is used as a blood reservoir and can automatically regulate and control the blood pressure to 47.58cm H₂O (35mm Hg). If the blood pressure is above 47.58cm H2O, the blood flows into the blood reservoir. If the blood pressure is lower than 47.58cm H₂O, the blood from the blood reservoir is infused into the blood circulation. Once Mean Arterial Pressure (MAP) stabilized, representative formulation 3 or comparative formulation 3 was injected into the middle of the stomach.

Autopsy and histological processing

Tissue analysis

1) the fluff tip breaks away or the structure is damaged to any part of the fluff; or

2) From the bottom to the tip of the hair, goblet cells (normally stained blue) were virtually absent (≦ 3 goblet cells without staining)

The Photoshop Text tool was used to place n (for no damage) or d (for damage) near each individual villus of each tissue cross-section. When the determination of the damage is uncertain, the fuzz is excluded from the analysis. These indeterminate fluff was less than 5% of the total fluff analyzed. Images showing the identification method in fig. 1, a cross section of the small intestine of a rat treated with an intestinal preparation is shown. Healthy villi are labeled with n and damaged villi are labeled with d.

Results

A total of eight rats were tested. Four received the representative formulation 3 by direct gastric injection, while four rats received the comparative formulation 3 by direct gastric injection. Representative micrographs of villi after administration of the formulation and shock induction are shown in fig. 6A and 6B. Figure 6A shows a cross section of the small intestine of rats treated with representative formulation 3. The villi in fig. 6A appear healthy and structurally intact, as the entire length of the villi is visible and completely covered in goblet cells. Fig. 6B shows a cross section of the small intestine of rats treated with comparative formulation 3. The pile in fig. 6B appears to be structurally compromised.

Quantification of structurally intact villi after administration of the formulation and shock induction is shown in tables 10 and 11 and figure 7. Table 10 shows the individual rat data for quantification of structurally intact villi. Table 11 summarizes the total intact and damaged villi observed after administration of the formulation and shock induction. Figure 7 shows the average percentage of intact villi per rat after administration of the formulation and shock induction. 88.8% of the villi were intact in all rats receiving representative formulation 3, while only 64.1% of the villi were intact in all rats receiving comparative formulation 3. These results are consistent with the average calculated from the total fuzz observed in table 11.

Watch 10

TABLE 11

Example 5: clinical study for treatment of septic shock

Main object of

This is a multicenter double-blind, parallel placebo-controlled phase 2 clinical study of septic shock patients to determine whether enteral administration of a formulation comprising tranexamic acid, PEG, glucose and one or more electrolytes by day 28 increases the number of surviving days compared to placebo without cardiovascular, pulmonary or renal replacement therapy.

Secondary target

A secondary objective of this study was to assess the safety and tolerability of the experimental compositions in septic shock patients.

Qualification of

1. First recorded or suspected peritoneum/abdominal, soft tissue or community-acquired lung-derived sepsis.

2. It is necessary to have septic shock that requires vasopressors, despite adequate humoral resuscitation with 30mL/kg crystalloid or glial equivalents for SBP ≦ 90mmHg or MAP ≦ 65mmHg (i.e., it is necessary to not maintain adequate blood pressure despite adequate humoral resuscitation).

3. The age is 18-75 years

Design of research

The study consisted of four phases:

screening: this phase begins when a patient has recorded or suspected peritoneum/abdomen, soft tissue, blood or community acquired lung-derived sepsis and is unable to maintain sufficient blood pressure despite intravenous fluid resuscitation (BP, systolic BP [ SBP ] >90mmHg or mean arterial pressure [ MAP ] >65 without vascular pressor support). Bowel study drug administration must begin within 4 hours of randomization and no more than 24 hours after the onset of shock.

Intervention: this period begins with the first administration of the test formulation or placebo and continues throughout the duration of treatment, with up to 8 days of pending patient refusal to take study medication, escape from hospital or death. There is no food or fluid restriction. However, during the first 48 hours post-recruitment, physicians are encouraged to delay enteral nutrition. If the patient is removed from the ICU and is still in the hospital, study drug administration should continue until 8 doses have been administered.

After intervention: this period begins after study drug administration is complete and continues until study day 28 or until patient discharge (if before day 28). If the patient had been discharged before study day 28, the field crew would contact the patient or an agent, a guardian, a family member, a physician or a healthcare facility to obtain patient survival status, organ support and functional outcome assessments.

Follow-up: the field staff member will contact the patient, agent, guardian, family member or other health care provider of the patient to determine the day 90 survival status.

All randomized patients will be assigned to both treatment arms at a 1:1 ratio, both groups being grouped by the highest overall SOFA score during the screening period (known at the time of randomization); and then grouped by the percent change in serum lactate between the first and subsequent lactate measurements (spaced at least 4 hours for randomization quantification).

A total of 250 patients were recruited. The 700mL aqueous solution formulation shown in table 2 was administered orally or via nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy tubes or catheters to patients within the experimental arm group. Patients in the placebo arm of this study received 700mL of placebo solution containing no tranexamic acid either orally or via nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal or percutaneous endoscopic gastrostomy tubes or catheters. Daily treatment is administered continuously or intermittently over a period of 8 to 24 hours. 700mL of the experimental or placebo was administered every 24 hours. Treatment was administered daily on study days 1-8, unless deceased or discharged. Final administration was delayed to study day 9 according to study day 1 start time of initial administration (infusion).

End of efficacy

The primary efficacy endpoint was the number of surviving days without cardiovascular, renal, or pulmonary organ support by day 28. A patient is classified as having organ support if organ support is required by using:

mechanical ventilation;

vasopressors to maintain proper BP, or

Renal replacement therapy.

Secondary efficacy endpoints were mortality: mortality will be recorded for all patients who have died at or before study day 90. Mortality and survival rates will be evaluated for 7-day, 28-day, and 90-day.

Results

The aqueous solution formulations shown in table 2 are safe and well tolerated by patients in the experimental arm. Patients in the experimental arm showed an increase in days without cardiovascular, renal or pulmonary support by day 28 of the study compared to patients in the placebo arm. Patients in the experimental arm exhibited a reduction in mortality on day 90 of the study compared to that of patients in the placebo arm.

Example 6: clinical study of shock and treatment of multiple organ dysfunction after cardiovascular surgery

Main object of

This is a multicenter randomized double-blind parallel placebo-controlled phase 2 clinical study to determine whether enteral administration of a formulation comprising tranexamic acid, PEG, glucose and one or more electrolytes prior to high-risk cardiovascular surgery increases the number of surviving days without cardiovascular, renal or pulmonary dysfunction by day 14 compared to placebo.

Design of research

All high risk cardiovascular surgery randomized patients will be divided into 2 treatment groups at a 1:1 ratio, both groups being grouped by:

the age (less than or equal to 64 or more than or equal to 65 years);

STS cardiac scoring, and

program.

The study consisted of four phases:

screening and randomization (no more than 4 weeks): prior to cardiovascular surgery.

Intervention: start will be initiated by first enteral administration of study drug 6-12 hours prior to surgery (day 0). Treatment should last for a minimum of 7 days (the patient refused to take study medication, fleeed from hospital, or died). In some cases, patients with persistent organ dysfunction continue to hold the study drug for up to 10 days as long as organ dysfunction persists.

Outcome of hospitalization intervention: will begin after study drug administration is terminated (day 8) and will continue until day 14 or until patient discharge.

Follow-up: the patient will contact by telephone on day 28 to assess the functional outcome.

A total of 100 patients were recruited. The 700mL aqueous solution formulation shown in table 2 or placebo containing no tranexamic acid was administered to the patient orally or via nasogastric, orogastric, nasojejunal, orojejunal, nasoduodenal, or percutaneous endoscopic gastrostomy tubes or catheters on days 0-7. If the patient continues to exhibit organ dysfunction, the physician will continue treatment, in some cases for up to 10 days. Patients, researchers, the person performing the assessment, and the data analyst were unaware of the identity of the treatment from the time of randomization until the database was locked.

End of efficacy

The primary efficacy endpoint was the number of surviving days without cardiovascular, renal, or pulmonary organ support by day 14. A patient is classified as requiring organ support if organ support is provided by using:

mechanical ventilation;

vasopressors to maintain adequate BP; or

Renal replacement therapy (hemodialysis, peritoneal dialysis or continuous venous hemofiltration).

Secondary efficacy endpoints were mortality: mortality will be recorded for all patients who have died on and before study day 28 and day 90. Mortality and survival will be assessed for 28-day and 90-day.

Results

The aqueous solution formulations shown in table 2 are safe and well tolerated by patients in the experimental arm. Patients in the experimental arm showed an increase in the number of survival days without cardiovascular, renal or pulmonary dysfunction by day 14 compared to placebo. Patients in the experimental arm showed a reduction in mortality at study day 90 compared to patients in the placebo arm.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerical changes, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various modifications of the embodiments of the invention described herein are possible in the practice of the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

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