Methods for treatment of bleeding with topical tranexamic acid compositions

Abstract

The present disclosure relates to methods of treating external bleeding by topically administering a pharmaceutical composition of tranexamic acid to a patient in need thereof.

Description

METHODS FOR TREATMENT OF BLEEDING WITH TOPICAL TRANEXAMIC ACID COMPOSITIONSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 626,976, filed January 30, 2024, which is hereby incorporated by reference in its entirety for all purposes.BACKGROUND

[0002] Tranexamic acid (TXA) is a synthetic lysine derivative with anti-fibrinolytic activity. LYSTEDA® is an FDA-approved, orally administered TXA tablet approved for the treatment of heavy menstrual bleeding in females of reproductive potential. CYKLOKAPRON® Injection is an FDA-approved Intravenous (IV) formulation indicated in patients with hemophilia for short-term use to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction.

[0003] Orally and intravenously administered TXA provides systemic TXA exposure and, as such, associated systemic side effects (such as blood clots, seizures, and blurred vision). Additionally, systemic TXA does not concentrate its effect at the site of a wound or lesion. Thus, there is a need for TXA formulations that provide reduced bleeding while minimizing systemic exposure compared to orally or intravenously administered formulations.

[0004] The present disclosure provides methods of using TXA-containing compositions to topically treat external bleeding.SUMMARY OF THE DISCLOSURE

[0005] The present disclosure provides methods of using tranexamic acid (TXA) compositions for treatment of external bleeding.

[0006] In one aspect, the present disclosure provides a method of treating external bleeding in a patient in need thereof comprising topically administering a therapeutically effective amount of a pharmaceutical composition comprising about 0.1 pg / mL to about 50 mg / mL TXA.

[0007] In embodiments, the composition comprises about 0.1 pg / mL to about 20 mg / mL of TXA. In embodiments, the composition comprises about 1 pg / mL to about 10 mg / mL of TXA. In embodiments, the composition comprises about 10 pg / mL to about 10 mg / mL of TXA. Inembodiments, the composition comprises about 100 pg / mL to about 5 mg / mL of TXA. In embodiments, the composition comprises about 1 mg / mL to about 5 mg / mL of TXA.

[0008] In embodiments, the method comprises topically administering about 0.5 mL to about 20 mL of the composition to a patient in need thereof. In embodiments, the method comprises topically administering about 3 mL to about 8 mL to a patient in need thereof. In embodiments, the method comprises topically administering about 6 mL to a patient in need thereof.

[0009] In embodiments, the methods of the present disclosure provide about 0.1 pg / mL to about 5 mg / mL of TXA concentration to a target area (such as an external bleed to which the topical composition is applied). In embodiments, the method provides about 0.1 pg / mL to about 3 mg / mL to the target area. In embodiments, the method provides less than about 5 mg / mL of TXA to the target area.

[0010] In embodiments, the external bleeding comprises epistaxis, hemoptysis hematemesis, hematochezia, or hematuria. In embodiments, the external bleeding is from a minor wound.

[0011] In embodiments, the patient has a bleeding disorder. In embodiments, the patient is on an anticoagulant or antiplatelet therapy.

[0012] In embodiments, the present disclosure provides a method of treating epistaxis, hemoptysis, hematemesis, hematochezia, or hematuria in a patient in need thereof, comprising topically administering a pharmaceutical composition comprising about 0.1 pg / mL to about 50 mg / mL of tranexamic acid in a pharmaceutically acceptable vehicle.BREIF DESCRIPTION OF THE DRAWINGS

[0013] FIGS. 1A-C show the changes in in vitro thrombin generation (FIG. 1A), clot formation (FIG. IB), and t-PA-induced fibrinolysis (FIG. 1C) following the addition of tranexamic acid (TXA) formulation to human platelet-poor plasma or whole blood at concentrations 2.8 pg / mL, 5.6 pg / mL, 11.1 pg / mL, 22.2 pg / mL, 33.3 pg / mL, 50 pg / mL, and 75 pg / mL, as described in Example 1.

[0014] FIGS. 2A-C show the changes in in vitro thrombin generation (FIG. 2A), clot formation (FIG. 2B), and fibrinolysis (FIG. 2C) following the addition of tranexamic acid (TXA) formulation to human platelet-poor plasma or whole blood at different concentrations(HBS = HEPES-buffered saline; TXA = 66.7 mg / mL; BXP154 = 166.7 mg / mL), as described in Example 1. Placebo solution result uninterpretable due to precipitate formulation.

[0015] FIGS. 3A-B show the thromboelastograms following the addition of TXA formulation at low (4.7 mg / mL and 11.7 mg / mL, FIG. 3A) and high (62.5 mg / mL and 156.3 mg / mL, FIG. 3B) concentrations in the presence or absence of tissue plasminogen activator (tPA), as described in Example 1. BXP154 = tranexamic acid sterile topical formulation; HBS = HEPES- buffered saline; TXA = tranexamic acid injection solution

[0016] FIGS. 4A-B show the concentration response curves of TXA in clot formation (FIG. 4A), and change in turbidity (FIG. 4B), as described in Example 1.

[0017] FIGS. 5A-D show the time (in minutes) to achieve hemostasis in placebo and TXA formulation treated cohorts (12.7 min and 12.1 min, respectively, FIG. 5A); a scatter plot of time to achieve hemostasis in placebo and TXA formulation treated cohorts (FIG. 5B); and the time (in minutes) to achieve hemostasis excluding non-responders in placebo and TXA formulation treated cohorts (10.6 min and 7.7 min, respectively, FIG 5C), as described in Example 2. FIG. 5D shows the time (in minutes) to achieve hemostasis without rebleeding that require intervention within 72 hours in placebo and TXA formulation treated cohorts (17.2 min and 14.2 min, respectively), as described in Example 2.DETAILED DESCRIPTIONDefinitions

[0018] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0019] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0020] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10 % of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.

[0021] The phrase “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0022] The term “carrier” as used herein encompasses carriers, excipients, and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical agent (such as TXA) from one organ, or portion of the body, to another organ or portion of the body.

[0023] The terms “effective amount” and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound that, when administered to a patient, is capable of performing the intended result. For example, an effective amount of TXA in a composition is that amount that is required to reduce at least one symptom of bleeding in a patient. The actual amount that comprises the “effective amount” or “therapeutically effective amount” will vary depending on a number of conditions including, but not limited to, the severity of the disorder and the size and health of the patient, or the size of bleeding to be treated. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical field.

[0024] The term "treating" as used herein with regard to a patient, refers to improving at least one symptom of the patient’s condition or disease. For example, a patient’s external bleedingis treated when, after administering a TXA composition of the present disclosure, the rate of bleeding is reduced compared to prior to the administration. A patient’s epistaxis (nosebleed) is treated when, after administering the TXA composition of the present disclosure, the rate of bleeding is reduced compared to prior to the administration.Methods of the present disclosure

[0025] In embodiments, the present disclosure provides methods for treating external bleeding by topically administering a low concentration of tranexamic acid (TXA) composition to a patient in need thereof.

[0026] In embodiments, the present disclosure provides a method of treating external bleeding comprising topically administering a therapeutically effective amount of TXA composition. In embodiments, the external bleeding includes both an external bleeding or an internal bleeding that sources from a lumen or space and exposes an external site for a topical administration.

[0027] In embodiments, the present disclosure provides a method of treating epistaxis, hemoptysis, hematemesis, hematochezia, or hematuria in a patient in need thereof, in which the method comprises topically administering a pharmaceutical composition comprising tranexamic acid.

[0028] In one aspect, the present disclosure provides a method of treating external bleeding in a patient in need thereof comprising topically administering a therapeutically effective amount of a pharmaceutical composition comprising TXA at a concentration of about 0.05 pg / mL to about 100 mg / mL, e.g., about 0.05 pg / mL to about 50 mg / mL, about 0.1 pg / mL to about 50 mg / mL, about 0.2 pg / mL to about 50 mg / mL, about 0.5 pg / mL to about 50 mg / mL, about 1 pg / mL to about 50 mg / mL, about 2 pg / mL to about 50 mg / mL, about 5 pg / mL to about 50 mg / mL, about 10 pg / mL to about 50 mg / mL, about 50 pg / mL to about 50 mg / mL, about 100 pg / mL to about 50 mg / mL, about 500 pg / mL to about 50 mg / mL, about 1 mg / mL to about 50 mg / mL, about 2 mg / mL to about 50 mg / mL, about 5 mg / mL to about 50 mg / mL, about 10 mg / mL to about 50 mg / mL, about 0.1 pg / mL to about 20 mg / mL, 0.2 pg / mL to about 20 mg / mL, about 0.5 pg / mL to about 20 mg / mL, about 1 pg / mL to about 20 mg / mL, about 2 pg / mL to about 20 mg / mL, about 5 pg / mL to about 20 mg / mL, about 10 pg / mL to about 20 mg / mL, about 50 pg / mL to about 20 mg / mL, about 100 pg / mL to about 20 mg / mL, about 500 pg / mL to about 20 mg / mL, about 1 mg / mL to about 20 mg / mL, about 2 mg / mL to about 20 mg / mL, about 5 mg / mL to about 20 mg / mL, about 10 mg / mL to about 20 mg / mL, about 0.05gg / mL to about 10 mg / mL, about 0.1 gg / mL to about 10 mg / mL, about 0.2 gg / mL to about 10 mg / mL, about 0.5 gg / mL to about 10 mg / mL, about 1 gg / mL to about 10 mg / mL, about 2 gg / mL to about 10 mg / mL, about 5 gg / mL to about 10 mg / mL, about 10 gg / mL to about 10 mg / mL, about 20 gg / mL to about 10 mg / mL, about 40 gg / mL to about 10 mg / mL, about 50 gg / mL to about 10 mg / mL, about 100 gg / mL to about 10 mg / mL, about 500 gg / mL to about 10 mg / mL, about 1 mg / mL to about 10 mg / mL, about 2 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 100 gg / mL to about 5 mg / mL, about 200 gg / mL to about 5 mg / mL, about 500 gg / mL to about 5 mg / mL, about 1 mg / mL to about 5 mg / mL, or about 2 mg / mL to about 5 mg / mL, including all values and ranges therebetween.

[0029] In one aspect, the present disclosure provides a method of treating epistaxis, hemoptysis, hematemesis, hematochezia, or hematuria in a patient in need thereof comprising topically administering a therapeutically effective amount of a pharmaceutical composition comprising TXA at a concentration of about 0.05 gg / mL to about 100 mg / mL, e.g., about 0.05 gg / mL to about 50 mg / mL, about 0.1 gg / mL to about 50 mg / mL, about 0.2 gg / mL to about 50 mg / mL, about 0.5 gg / mL to about 50 mg / mL, about 1 gg / mL to about 50 mg / mL, about 2 gg / mL to about 50 mg / mL, about 5 gg / mL to about 50 mg / mL, about 10 gg / mL to about 50 mg / mL, about 50 gg / mL to about 50 mg / mL, about 100 gg / mL to about 50 mg / mL, about 500 gg / mL to about 50 mg / mL, about 1 mg / mL to about 50 mg / mL, about 2 mg / mL to about 50 mg / mL, about 5 mg / mL to about 50 mg / mL, about 10 mg / mL to about 50 mg / mL, about 0.1 gg / mL to about 20 mg / mL, 0.2 gg / mL to about 20 mg / mL, about 0.5 gg / mL to about 20 mg / mL, about 1 gg / mL to about 20 mg / mL, about 2 gg / mL to about 20 mg / mL, about 5 gg / mL to about 20 mg / mL, about 10 gg / mL to about 20 mg / mL, about 50 gg / mL to about 20 mg / mL, about 100 gg / mL to about 20 mg / mL, about 500 gg / mL to about 20 mg / mL, about 1 mg / mL to about 20 mg / mL, about 2 mg / mL to about 20 mg / mL, about 5 mg / mL to about 20 mg / mL, about 10 mg / mL to about 20 mg / mL, about 0.05 gg / mL to about 10 mg / mL, about 0.1 gg / mL to about 10 mg / mL, about 0.2 gg / mL to about 10 mg / mL, about 0.5 gg / mL to about 10 mg / mL, about 1 gg / mL to about 10 mg / mL, about 2 gg / mL to about 10 mg / mL, about 5 gg / mL to about 10 mg / mL, about 10 gg / mL to about 10 mg / mL, about 20 gg / mL to about 10 mg / mL, about 40 gg / mL to about 10 mg / mL, about 50 gg / mL to about 10 mg / mL, about 100 gg / mL to about 10 mg / mL, about 500 gg / mL to about 10 mg / mL, about 1 mg / mL to about 10 mg / mL, about 2 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 100 gg / mL to about 5 mg / mL, about 200 gg / mL to about 5 mg / mL, about 500 gg / mL to about 5 mg / mL, about 1mg / mL to about 5 mg / mL, or about 2 mg / mL to about 5 mg / mL, including all values and ranges therebetween.

[0030] In embodiments, the TXA concentration of the administered composition is about 0.1 pg / mL to about 50 mg / mL, for example, about 0.1 pg / mL, about 0.2 pg / mL, about 0.4 pg / mL, about 0.6 pg / mL, about 0.8 pg / mL, about 1 pg / mL, about 1.2 pg / mL, about 1.4 pg / mL, about1.6 pg / mL, about 1.8, about 2 pg / mL, about 4 pg / mL, about 6 pg / mL, about 8 pg / mL, about 10 pg / mL, about 20 pg / mL, about 30 pg / mL, about 40 pg / mL, about 50 pg / mL, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL, about 90 pg / mL, about 100 pg / mL, about 200 pg / mL, about 300 pg / mL, about 400 pg / mL, about 500 pg / mL, about 600 pg / mL, about 700 pg / mL, about 800 pg / mL, about 900 pg / mL, about 1 mg / mL, about 1.2 mg / mL, about 1.4 mg / mL, about 1.6 mg / mL, about 1.8 mg / mL, about 2 mg / mL, about 2.2 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.8 mg / mL, about 3 mg / mL, about 3.2 mg / mL, about 3.4 mg / mL, about 3.5 mg / mL, about 3.6 mg / mL, about 3.8 mg / mL, about 4 mg / mL, about 4.2 mg / mL, about 4.4 mg / mL, about 4.5 mg / mL, about 4.6 mg / mL, about 4.8 mg / mL, about 5 mg / mL, about 5.2 mg / mL, about 5.4 mg / mL, about 5.5 mg / mL, about 5.6 mg / mL, about 5.8 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, about10.5 mg / mL, about 11 mg / mL, about 11.5 mg / mL, about 12 mg / mL, about 12.5 mg / mL, about 13 mg / mL, about 13.5 mg / mL, about 14 mg / mL, about 14.5 mg / mL, about 15 mg / mL, about15.5 mg / mL, about 16 mg / mL, about 16.5 mg / mL, about 17 mg / mL, about 17.5 mg / mL, about 18 mg / mL, about 18.5 mg / mL, about 19 mg / mL, about 19.5 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 31 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, or about 50 mg / mL, including all values and ranges therebetween.

[0031] In embodiments, the methods of the present disclosure comprise administering about 0.1 pg / mL to about 20 mg / mL of TXA to the patient. In embodiments, about 1 pg / mL to about 10 mg / mL of TXA is administered to the patient. In embodiments, about 10 pg / mL to about 10 mg / mL of TXA is administered to the patient. In embodiments, about 100 pg / mL to about5 mg / mL of TXA wis as administered to the patient. In embodiments, about 1 mg / mL to about 5 mg / mL of TXA is administered to the patient. In embodiments, less than 10 mg / mL of TXA is administered to the patient. In embodiments, less than 8 mg / mL of TXA is administered to the patient. In embodiments, less than 5 mg / mL of TXA is administered to the patient. In embodiments, about 2.5 mg / mL of TXA is administered to the patient.

[0032] In embodiments, about 0.5 mL to about 30 mL (e.g., about 0.5 mL, about 1.0 mL, aboutI.5 mL, about 2.0 mL, about 2.5 mL, about 3.0 mL, about 3.5 mL, about 4.0 mL, about 4.5 mL, about 5.0 mL, about 5.5 mL, about 6.0 mL, about 6.5 mL, about 7.0 mL, about 7.5 mL, about 8.0 mL, about 8.5 mL, about 9.0 mL, about 9.5 mL, about 10.0 mL, about 10.5 mL, aboutI I.0 mL, about 11.5 mL, about 12.0 mL, about 12.5 mL, about 13.0 mL, about 13.5 mL, about14.0 mL, about 14.5 mL, about 15.0 mL, about 15.5 mL, about 16.0 mL, about 16.5 mL, about17.0 mL, about 17.5 mL, about 18.0 mL, about 18.5 mL, about 19.0 mL, about 19.5 mL, about20.0 mL, about 21.0 mL, about 22.0 mL, about 23.0 mL, about 24.0 mL, about 25.0 mL, about26.0 mL, about 27.0 mL, about 28.0 mL, about 29.0 mL, or about 30.0 mL, including all values and ranges there between) of the TXA composition is topically administered to the patient. In embodiments, about 0.5 mL to about 20 mL of the TXA composition is topically administered. In embodiments, about 3 mL to about 8 mL of the TXA composition is topically administered. In embodiments, about 6 mL of the TXA composition is topically administered.

[0033] In embodiments, the external bleeding is from a minor wound. In embodiments, the external bleeding is from a severe wound. In embodiments, the external bleeding comprises epistaxis, hemoptysis hematemesis, hematochezia, or hematuria.

[0034] In embodiments, the present disclosure provides a method of treating a patient by administering the TXA composition, wherein the patient has a propensity for increased bleeding. In embodiments, the patient is undergoing post-cardiac bypass, extracorporeal membrane oxygenation (ECMO), or hemodialysis. In embodiments, the patient is suffering from a bleeding disorder. In embodiments, the patient has hemophilia, kidney disease, liver disease, low platelets from medications, or cancer. In embodiments, the patient is undergoing a hemorrhagic drug treatment regimen, such as anticoagulants and / or antiplatelets. In embodiments, the pharmaceutical composition is topically administered after shaving.

[0035] In embodiments, the method of the present disclosure comprises topically administering the TXA composition to the patient as needed, e.g., once per day, twice per day,or three times per day. In embodiments, the compositions of the present disclosure are topically administered to a subject suffering from bleeding once per day, twice per day, three times per day, once per week, twice per week, three times per week, three times per week, five times per week, once every two weeks, one every three weeks, once per month, once every two months, once every three months, or once every six months. In embodiments, the method of the present disclosure comprises topically administering the TXA composition to a subject having epistaxis, hemoptysis, hematemesis, hematochezia, or hematuria once per day, twice per day, three times per day, once per week, twice per week, three times per week, five times per week, once every two weeks, one every three weeks, once per month, once every two months, once every three months, or once every six months.

[0036] In embodiments, the composition of the present disclosure comprises TXA at an effective concentration in a pharmaceutically acceptable aqueous vehicle and further comprises a pharmaceutically acceptable excipient, such as, for example, emulsifiers, wetting agents or fillers, such as, for example, the polyethylene glycols designated 200, 300, 400 and 600, or Carbowax designated 1000, 1500, 4000, 6000 and 10000. The amount and type of excipient added is in accordance with the particular requirements and is generally in the range of from approximately 0.0001 to approximately 90 % by weight.

[0037] In embodiments, the TXA compositions of the present disclosure further comprise a viscosity modifying agent. In embodiments, the viscosity agent is acacia, agar, alginic acid, aluminum monostearate, ammonium sulfate, attapulgite, bentonite, betadex sulfobutyl ether sodium, calcium alginate, calcium lactate, carbomers, carboxymethylcellulose calcium, carboxymethylcellulose sodium with microcrystalline cellulose, carrageenan, cellulose microcrystalline, carboxymethylcellulose sodium, ceratonia, ceresin, cetostearyl alcohol, cetyl palmitate, chitosan, colloidal silicon dioxide, corn syrup solids, cyclomethicone, dextrin, ethylcellulose, gelatin, gellan gum, glycerin, glyceryl behenate, glyceryl laurate, guar gum, hectorite, hydrogenated palm oil, hydrogenated vegetable oil type I, hydrophobic colloidal silica, bydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methylcellulose, microcrystalline cellulose, and carboxymethylcellulose sodium, modified starch, myristyl alcohol, octyldodecanol, pectin, polycarbophil, polydextrose, polyethylene glycol, polyethylene oxide, poly(methylvinyl ether / maleic anhydride), polyoxyethylene alkyl ethers, polyvinyl alcohol, potassium alginate, povidone, propylene glycol alginate, propylene glycol dilaurate, pullulan,saponite, sodium alginate, sodium chloride, starch, stearic acid, stearyl alcohol, sucrose, tragacanth, trehalose, or xanthan gum, or a mixture thereof.

[0038] In embodiments, the viscosity modifying agent is a polyol (such as, glycerol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, propylene glycol, and ethylene glycol), polyvinylpyrrolidone; a cellulose derivative (such hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose, and methyl cellulose); a dextran (such as dextran 70); a water soluble protein (such as gelatin); a carbomer (such as carbomer 934P, carbomer 941, carbomer 940 and carbomer 974P); or a gum (such as HP-guar), or a mixture thereof.

[0039] In embodiments, the viscosity modifying agent is methylcellulose, carboxymethyl cellulose sodium (MV), carbomers, xanthan gum, poloxamer 407, carboxymethyl cellulose, methylcellulose 400 cp, pemulen TR-1, pemulen TR-2, hydroxy ethyl cellulose, or a combination thereof.

[0040] In embodiments, the viscosity modifying agent is a hydrophobic oil. In embodiments, the viscosity modifying agent is a fatty alcohol, fatty acid, or a wax. In embodiments, the viscosity modifying agent is lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, tetracosanol, hexacosanol, octacosanol, triacontanol, tetratri acontanol; and wherein the fatty acid is selected from the group consisting of dodecanoic acid, tetradecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, eicosanoic acid, docosanoic acid, tetracosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, triacontanoic acid, dotriacontanoic acid, tritriacontanoic acid, tetratriacontanoic acid, pentatriacontanoic acid, plant wax, an animal wax, a petroleum derived wax, and a vegetable wax; or wherein the wax is selected from the group consisting of an albacer wax, an atlasene wax, a cardis wax, a ceramide, an alkyl-substituted aromatic compound, a naphthenesubstituted aromatic compound, a beeswax, a carnauba wax, a Chinese wax, a cotton wax, a bayberry wax, a carnauba wax, a castor wax, a Cuban palm wax, a duroxon wax, an esparto wax, a fat wax, a flax wax, a fischer-tropsch wax, a fir wax, a flexo wax a flower wax, glyco waxes, a japan wax, a jojoba oil, a lanolin wax, a palm wax, a rice bran wax, a rice-oil wax, a shellac wax, a soy wax, an ucuhuba wax, a hydrogenated oil, a hydrogenated castor oil, a hydrogenated cottonseed oil, a hydrogenated jojoba oil, a mink wax, a mixture of saturated n- and isoalkanes, a montan wax, a naphthene, an ouricury wax, an oxazoline wax, an ozokerite, a paraffin wax, a paraffin 58-62° C. wax, paraffin 51-53° C. wax, paraffin 42-44° C. wax, apolyethylene wax, a PEG-6 beeswax, a polymekon wax, a retamo wax, a rezo wax, a sandy wax, a spent grain wax, a stearyl dimethicone, a sugarcane wax, or a synthetic mineral wax, or a mixture thereof.

[0041] In embodiments, the viscosity modifying agent is hydroxyethyl cellulose. In embodiments, the hydroxyethyl cellulose has a viscosity of about 400 cps to about 2000 cps (2% aqueous solution at 20°C). In embodiments, the hydroxyethyl cellulose has a viscosity of about 800 cps to about 1500 cps (2% aqueous solution at 20°C). In embodiments, the hydroxyethyl cellulose has a viscosity of about 4000 cps to about 7000 cps (2% aqueous solution at 20°C). In embodiments, the hydroxyethyl cellulose has a viscosity of about 4500 cps to about 6500 cps (2% aqueous solution at 20°C).

[0042] In embodiments, the TXA composition comprises about 1 mg / mL to about 50 mg / mL of a viscosity modifying agent, e.g., about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 31 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, or about 50 mg / mL, including all values and ranges in between.

[0043] In embodiments, the TXA composition comprises about 15 mg / mL of a viscosity modifying agent. In embodiments, the composition comprises about 10 mg / mL of a viscosity modifying agent. In embodiments, the composition comprises about 5 mg / mL of a viscosity modifying agent. In embodiments, the composition comprises about 2 mg / mL of a viscosity modifying agent. In embodiments, the composition comprises about 1 mg / mL of a viscosity modifying agent.

[0044] In embodiments, the TXA composition comprises about 0.1 % by weight to about 0.5 % by weight of a viscosity modifying agent, e.g., about 0.1 % by weight, about 0.2 % by weight, about 0.3 % by weight, about 0.4 % by weight, or about 0.5 % by weight, including all valuesand ranges in between. In embodiments, the composition comprises about 0.15 % by weight of a viscosity modifying agent. In embodiments, the composition comprises about 0.10 % by weight of a viscosity modifying agent. In embodiments, the composition comprises about 0.20 % by weight of a viscosity modifying agent. In embodiments, the composition comprises about 0.5 % by weight of a viscosity modifying agent.

[0045] In embodiments, the viscosity of the TXA composition is about 1 to 2000 cps (or mPa- s), measured at 21 °C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 1 to 1000 cps, e.g., about 25 cps, about 50 cps, about 75 cps, about 100 cps, about 125 cps, about 150 cps, about 175 cps, about 200 cps, about 300 cps, about 400 cps, about 500 cps, about 600 cps, about 700 cps, about 800 cps, about 900 cps, or about 1000 cps, including all values and ranges there between. In embodiments, the viscosity of the composition is about 1 to 100 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 1 to 50 cps. In embodiments, the viscosity of the composition is from about 1 to 2000 cps, wherein the viscosity is measured at 21 °C using a rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is from about 1 to 50 cps, wherein the viscosity is measured at 21°C using a rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is from about 1 to 100 cps, wherein the viscosity is measured at 21°C using a rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>.

[0046] In embodiments, the viscosity of the composition is about 2000 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 1800 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 1600 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 1500 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 1400 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP<912>. In embodiments, the viscosity of the composition is about 1200 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 1000 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 800 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 600 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 400 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 300 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 200 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 100 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 100 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 90 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 80 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 70 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 60 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 50 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 40 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 20 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>. In embodiments, the viscosity of the composition is about 10 cps, measured at 21°Cusing the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>.

[0047] In embodiments, the viscosity of the composition is about 200 cps or less, 150 cps or less, 100 cps or less, 80 cps or less, 50 cps or less, or 25 cps or less. In embodiments, the viscosity of the composition is about 100 cps or less. In embodiments, the viscosity of the composition is about 50 cps or less.

[0048] The viscosity of the TXA composition is measured using methods known in the art, such as use of a viscometer or rheometer. In embodiments, the viscosity of the TXA composition is measured using a rotational viscosity method. One of ordinary skill in the art will recognize that factors such as temperature and shear rate may affect viscosity measurement. In embodiments, the viscosity of the composition of the present disclosure is measured at 20 °C + / - 1° C using a Brookfield LV / RV DV-II Viscometer, Brookfield Cone and Plate Viscometer Model VDV-III Ultra with a CP40, or equivalent Spindle with a shear rate of approximately 22.50 + / - approximately 10 (1 / sec), or a Brookfield Viscometer Model LVDV-E with a SC4-18 or equivalent Spindle with a shear rate of approximately 26 + / - approximately 10 (1 / sec)). In embodiments, the viscosity of the composition of the present disclosure is measured according to a protocol described in USP <912>. In embodiments, the viscosity of the TXA composition of the disclosure is measured at 20 °C + / - 5° C. In embodiments, the viscosity of the TXA composition is measured at 21 °C. In other embodiments, the viscosity of the TXA composition is measured when the viscosity modifying agent is slowly added to achieve about 1 to 1000 cps at 20 °C + / - 1 °C using a rotational viscosity method.

[0049] In embodiments, compositions of the present disclosure further comprise a stabilizing agent. In embodiments, the stabilizing agents is sodium citrate (all forms, 0.01 to 20 % by weight), sodium pyrophosphate (0.1 to 10 % by weight), EDTA (all forms, 0.01 to 20 %), pentetate (all forms, 0.01 to 20 %), or sodium glyconate (0.1 to 10 % weight / volume) or a mixture thereof. The stabilizing agent should be used in an amount sufficient to increase the stability of the composition. In embodiments, the amount of stabilizing agent used provides a stable composition showing no evidence of precipitation or sedimentation for at least about 24 hours after the composition formation.

[0050] In embodiments, the compositions of the present disclosure are stable following subjecting the composition to temperatures of about 10 to 40 °C for at least about 1-4 hours. In embodiments, the composition is stable following subjecting the composition to temperatures of about 30°C for at least about 2 hours. In embodiments, the composition is stable following subjecting the composition to temperatures of about 121 °C for at least about 30 minutes. In embodiments, the composition has a shelf-life of about 1 year at about 25 °C. In embodiments, the composition has a shelf-life of about 2 years at about 25 °C. In embodiments, the composition has a shelf-life of about 6 months at about 40 °C.

[0051] In embodiments, the compositions of the present disclosure are stable following subjecting the composition to ICH accelerated stability storage conditions. In embodiments, the compositions of the present disclosure are stable for at least one month at 40°C (± 2°) and 75% relative humidity (± 5%). In embodiments, the compositions of the present disclosure are stable for at least three months at 40°C (± 2°) and 75% relative humidity (± 5%). In embodiments, the compositions of the present disclosure are stable for at least six months at 40°C (± 2°) and 75% relative humidity (± 5%).

[0052] In embodiments, the composition has a residence time of about 5 to 120 minutes following application to a bleeding wound. In embodiments, the composition has a residence time of about 10 to 60 minutes following application to a bleeding wound. In embodiments, the composition has a residence time of about 1 hour or more, about 2 hours or more, about 4 hours or more, about 8 hours or more, about 16 hours or more, about 20 hours or more, or about 24 hours or more following application to a bleeding wound.

[0053] In embodiments, the compositions of the present disclosure are preservative free. Alternatively, in embodiments, the compositions of the present disclosure comprise a preservative. In embodiments, the preservative is quaternary ammonium compound (such as benzalkonium chloride, benzoxonium chloride). In embodiments, the preservative is alkylmercury salts of thiosalicylic acid (such as thiomersal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate, sodium perborate), sodium chlorite, parabens (such as methylparaben or propylparaben), alcohols (such as chlorobutanol, benzyl alcohol or phenyl ethanol), guanidine derivatives (such as, chlorohexidine or polyhexamethylene biguanide), sodium perborate, sorbic acid. Where appropriate, a sufficient amount of preservative is added to the TXA composition to ensure protection against secondary contaminations during use caused by bacteria and fungi.

[0054] In embodiments, the topical aqueous composition of TXA is sterile. The composition is sterilized by aseptic filtration, autoclaving or gamma irradiation.

[0055] In embodiments, the TXA compositions comprise an isotonicity agent. In embodiments, the isotonicity agent is betadex sulfobutyl ether sodium, calcium chloride, dextrose, dimethyl-P-cyclodextrin, glycerin, hydroxyethyl-P-cyclodextrin, hydroxypropyl betadex, magnesium chloride, magnesium oxide, maltodextrin, mannitol, potassium chloride, sodium chloride or trimethyl-P-cyclodextrin, or a mixture thereof. In embodiments, the isotonicity agent is sodium chloride, potassium chloride, calcium chloride or magnesium chloride, or a mixture thereof.

[0056] In embodiments, the TXA compositions comprise a wetting agent. In embodiments, the wetting agent is an alcohol (such as ethanol), glyceryl monooleate, benzethonium chloride, docusate sodium, emulsifying wax BP, hypromellose, phospholipids, polyethylene alkyl ethers, sodium lauryl sulfate, tricaprylin, benzalkonium chloride, cetrimide, cetrimonium bromide, cetylpyridinium chloride, xanthan gum, alpha tocopherol, butylparaben, ethylparaben, methylparaben, potassium sorbate, propylparaben, sorbic acid, emulsifying wax USP, glyceryl laurate, myristyl alcohol, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty-acid esters, polyoxyethylene stearates, polyoxyl 15 hydroxystearate, polyoxylglycerides, polysorbate 80, propylene glycol dilaurate, propylene glycol monolaurate, sorbitan esters, sucrose palmitate, sucrose stearate, tyloxapol, or vitamin E polyethylene glycol succinate, or a mixture thereof.

[0057] In embodiments, the TXA compositions comprise a pH buffer agent. In embodiments, the pH buffer agent is acetic acid, adipic acid, ammonia solution, ammonium phosphate, ammonium sulfate, arginine, asparagine, boric acid, calcium carbonate, calcium lactate, tribasic calcium phosphate, citric acid, dibasic potassium phosphate, dibasic sodium phosphate, diethanolamine, glycine, histidine, hydroxy ethylpiperazine ethanesulfonic acid, lysine acetate, lysine hydrochloride, maleic acid, malic acid, meglumine, methionine, monobasic sodium phosphate, monoethanolamine, monosodium glutamate, phosphoric acid, potassium citrate, potassium metaphosphate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium lactate, triethanolamine, or tromethamine, or a mixture thereof.

[0058] In embodiments, the pH buffer agent is sodium citrate. In embodiments, the pH buffer agent is citric acid. In embodiments, the pH buffer agent is sodium citrate and citric acid. In embodiments, the citric acid is anhydrous. In embodiments, the sodium citrate is the dihydrate.

[0059] In embodiments, the composition comprises about 0.1 mg / mL to about 20 mg / mL sodium citrate, e.g., about 0.1 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, or about 20.0 mg / mL, including all values and ranges in between. In embodiments, the composition comprises about 10 mg / mL sodium citrate. In embodiments, the composition comprises about 12 mg / mL sodium citrate. In embodiments, the composition comprises about 12.6 mg / mL sodium citrate. In embodiments, the sodium citrate is the dihydrate.

[0060] In embodiments, the composition comprises about 1 mg / mL to about 20 mg / mL citric acid, e.g., about 1.0 mg / mL, about 2.0 mg / mL, about 3.0 mg / mL, about 4.0 mg / mL, about 5.0 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, or about 20.0 mg / mL, including all values and ranges in between. In embodiments, the composition comprises about 10 mg / mL citric acid. In embodiments, the composition comprises about 10.15 mg / mL citric acid.

[0061] In embodiments, the TXA compositions comprise a pH adjusting agent. In embodiments, the pH adjusting agent is sodium hydroxide, hydrochloric acid, aqueous ammonia, diethanolamine, meglumine, sodium citrate, acetic acid, adipic acid, ammonium chloride, ascorbic acid, citric acid, fumaric acid, gluconolactone, lactic acid, maleic acid, malic acid, monobasic sodium phosphate, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, calcium hydroxide, monoethanolamine, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, triethanolamine, or tromethamine, or a mixture thereof. In embodiments, the pH adjusting agent is hydrochloric acid. In embodiments, the pH adjusting agent is sodium hydroxide.

[0062] In embodiments, the compositions of the present disclosure have a pH of about 4.0 to about 8.0. In embodiments, the compositions of the present disclosure have a pH of about 4.0to about 7.5, e.g., about 4.0 to about 7.0, about 4.0 to about 6.5, about 4.0 to about 6.0, about 4.0 to about 5.5, about 4.0 to about 5.0, about 4.0 to about 4.5, including any values or ranges therebetween. In embodiments, the compositions of the present disclosure have a pH of about 3.0 to about 5.0. In embodiments, the compositions of the present disclosure have a pH of about 4.0.

[0063] The compositions of the present disclosure are generally aqueous solutions. However, in embodiments, the compositions of the present disclosure are suspensions, viscous or semi- viscous gels, or other types of solid or semi-solid compositions, or those appropriate for sustained release. In embodiments, the pharmaceutical compositions of the present disclosure are formulated as solutions, ointments, sustained release formulation, and other dosage forms for topical administration or for sustained release delivery. Nonlimiting examples of the pharmaceutically acceptable vehicle or excipient or carrier are ointments, creams, liniments, pastes, patches, lotions, gels, shampoos, hydrogels, liposomes, sprays, aerosols, solutions, sponges, films, plasters, surgical dressings, bandages, or emulsions. In embodiments, the present disclosure employs TXA composition as described in International Application No. PCT / US2023 / 063500, which is hereby incorporated by reference for all purposes.

[0064] In embodiments, the present disclosure provides a method of using the composition of TXA for treating hemoptysis in a patient in need thereof, the method comprising administering an effective amount of a composition of the present disclosure to lungs of a patient in need thereof. In embodiments, the composition is aerosolized. In embodiments, the composition is administered by nebulization. In embodiments, the TXA composition is administered using a topical applicator, wherein the applicator is saturated with the TXA composition.

[0065] In embodiments, the TXA pharmaceutical composition is topically administered into a nasal, lung, oral, rectal, vaginal, colon, esophageal, or bronchial tissue by using a nebulizer. In embodiments, the TXA pharmaceutical composition is topically administered into a mucosal tissue during endoscopy or colonoscopy.

[0066] In embodiments, the compositions of the present disclosure further comprise an additional drug that would be desirable to deliver to the patient experiencing bleeding, particularly an epistaxis (nosebleed), preparatory to or as part of treatment of the epistaxis. In embodiments, the additional drug is a vasoconstrictor (e.g., epinephrine), antibiotic, antiseptic(e.g., chi orhexi dine), anti-fungal, antiviral, analgesic, local anesthetic (lidocaine, xylocaine, etc.), non-steroidal anti-inflammatory drug, opioid, or anti -neoplastic.

[0067] In embodiments, the methods of the present disclosure further comprise administering a vasoconstrictor. In embodiments, the vasoconstrictor is selected from the group consisting of epinephrine, phenylephrine, norepinephrine, and oxymetazoline. In embodiments, the TXA composition is sequentially administered with the vasoconstrictor. In embodiments, the TXA composition is concomitantly administered with the vasoconstrictor.

[0068] A vasoconstrictor is useful to help bleeding vessels constrict prior to administration of a hemostatic medication such as an antifibrinolytic, and may desirably be delivered to the nasal tissue at or around the site of the bleeding before, during, and / or after application to the nasal tissue. In embodiments, the vasoconstrictor is phenylephrine, oxymetazoline (Afrin), or epinephrine. In embodiments, the vasoconstrictor is epinephrine.

[0069] In embodiments, the methods of the present disclosure comprises topically administering TXA so that the concentration of TXA on a target tissue is about 0.1 pg / mL to about 5 mg / mL, for example, about 0.1 pg / mL, about 0.2 pg / mL, about 0.4 pg / mL, about 0.6 pg / mL, about 0.8 pg / mL, about 1 pg / mL, about 2 pg / mL, about 3 pg / mL, about 4 pg / mL, or about 5 pg / mL, including any values or ranges therebetween. In embodiments, the concentration of TXA on a target tissue is about 0.1 pg / mL to about 3 mg / mL. In embodiments, the concentration of TXA on a target tissue is less than about 5 mg / mL. In embodiments, the concentration of TXA on a target tissue is less than about 3 mg / mL. In embodiments, the concentration of TXA on a target tissue is less than about 2.5 mg / mL. In embodiments, the concentration of TXA on a target tissue is about 2.5 mg / mL.

[0070] In embodiments, the topical administration of a therapeutically effective amount of TXA reduces the patient’s time to achieve hemostasis at least about 5% to at least about 90% compared to a placebo, for example, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100%, including all values and ranges therebetween. In embodiments, the topical administration of a therapeutically effective amount of TXA reduces the patient’s time to re-bleeding compared a patient administered a topical placebo. In embodiments, the topical administration of a therapeutically effective amount of TXA reduces the severity of bleeding.

[0071] In embodiments, the topical administration of a therapeutically effective amount of TXA reduces epistaxis. In embodiments, the topical administration of a therapeutically effective amount of TXA reduces hemoptysis hematemesis. In embodiments, the topical administration of a therapeutically effective amount of TXA reduces hematochezia. In embodiments, the topical administration of a therapeutically effective amount of TXA reduces hematuria.EXAMPLES

[0072] The present invention is further illustrated by reference to the following Examples. However, it is noted that these Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the invention in any way.Example 1. In vitro study of Tranexamic Acid (TXA) in thrombin generation and clot formation.

[0073] Thrombin generation and clot formulation were assessed in vitro to evaluate the dosedependent effect of TXA on hemostasis. The TXA formulation was mixed to human plateletpoor plasma or whole blood in vitro at a concentration selected to achieve a final concentration that falls between 1.9 pg / mL to 48 mg / mL in the presence or absence of tissue plasminogen activator (tPA, 1.25 pg / mL). Thrombin generation and clot formulation / fibrinolysis were measured by calibrated automated thrombography and turbidity / thromboelastography (TEG), respectively. The clot formulation was triggered by recalcification (16.7 mM for platelet-poor plasma or 10 mM for whole blood) and addition of tissue factor (1 pM).

[0074] As shown in FIGS. 1A-C, no impact on thrombin generation (FIG. 1A), clot formulation profile (FIG. IB), or comparable inhibition of tPA-induced fibrinolysis (FIG. 1C) was observed when the TXA formulation was diluted to a final concentration within the range of 2.8 pg / mL to 75 pg / mL. As shown in FIG. 3A, TXA (i.e., 4.7 mg / mL and 11.7 mg / mL) at low concentrations demonstrated the expected clot formation and antifibrinolytic activity.

[0075] At high TXA concentrations with minimal dilution (i.e., 166.7 mg / mL and 66.7 mg / mL), inhibition of thrombin generation (FIG. 2A) and fibrin clot formulation assessed by turbidity (FIGS. 2B-C) was observed. As shown in FIG. 3B, 62.5 mg / mL and 156.3 mg / mL of TXA inhibited fibrin clot formulation.

[0076] To further elucidate the full concentration-response curve of TXA on inhibition of clot formation, the clot formation turbidity assays were repeated with commercially available TXA injection solution (TXAIS) concentrations in the range of 0 mg / mL to 48 mg / mL using 6 separate plasmas. As shown in FIGS. 4A-B, TXAIS concentrations up to 5 mg / mL did not alter clot formation, while a concentration-dependent decrease in clot formation was observed with higher TXAIS concentrations (i.e., > 5 mg / mL).Example 2. A Phase 2, randomized, double-blind, placebo-controlled, 2-way cross-over study evaluating Tranexamic Acid (TXA) topical formulation for efficacy and safety in treating external bleeding.

[0077] The primary objective of this study was to evaluate the efficacy and safety of selfadministered 2.5 mg / mL Tranexamic Acid (TXA) topically administered formulation in the reduction of time to hemostasis in anti coagulated subjects with minor wounds. The primary efficacy endpoint was time to achieve hemostasis (in minutes) following the start of treatment.

[0078] The secondary efficacy endpoints included to evaluate proportion of subjects who achieved hemostasis by timepoint; to evaluate proportion of subjects who required rescue treatment intervention to achieve initial hemostasis, and to evaluate proportion of subjects who experienced rebleeding following initial hemostasis that required self-managed or medical intervention to re-achieve hemostasis.

[0079] Subjects were randomized to receive a single topical administration of TXA (6 mL) or volume matched placebo (water for administration) for the treatment of bleeding following a punch biopsy procedure on their right or left inner thigh in Treatment Period 1 followed in a crossover manner 3 days later by a second punch biopsy and the alternating treatment and thigh in Treatment Period 2. All subjects were taking therapeutic doses of oral anti coagulated apixaban throughout the study period.

[0080] After local administration of lidocaine without epinephrine, a disposable instrument was used to perform a standardized punch biopsy of 5 mm in diameter and approximately 4-5 mm in depth on the subject’s right or left thigh in accordance with their randomized treatment sequence. The subject was provided with sterile gauze soaked in TXA formulation or placebo solution and began self-admini strati on of the treatment by applying the soaked gauze onto their wound while simultaneously applying pressure with their hand. Bleeding status was then be assessed after an initial period of 3 minutes, then every 1 minute through 20 minutes after thestart of treatment, every 2 minutes through 40 minutes, and every 5 minutes thereafter through 60 minutes until hemostasis was achieved or rescue therapy was required. Hemostasis was defined as cessation of bleeding with no blood flowing or oozing from the wound once the gauze had been lifted away and observed for 5 seconds. Subjects who required rescue or did not achieve hemostasis within 60 minutes after the start of treatment were assigned a value of 60 minutes in the analysis.

[0081] Results: The TXA formulation treatment was safe and well-tolerated in all subjects. No serious adverse events (SAEs) or serious treatment emergent adverse events (TESAEs) occurred. As shown in FIG. 5A, there was a clear trend toward improved external bleeding with the TXA formulation treatment compared to the placebo (12.7 min to reach hemostasis in placebo group and 12.1 min in the TXA treated group). Despite the visible trend, this difference was not statistically significant (p = 0.888) due to three outlier subjects who were unresponsive to the TXA formulation treatment (FIG. 5B). The effects of the TXA formulation in shortening the time to achieve hemostasis became more apparent when those non-responders were excluded from the analysis (10.6 min in placebo group and 7.7 min in the TXA treated group, p value 0.163), as shown in FIG. 5C. The TXA formulation treated group also exhibited a shorter time to achieve hemostasis and did not require additional intervention or rescue for rebleeding within 72 hours after treatment (17.2 min to reach hemostasis for placebo and 14.2 min for TXA formulation treated cohort, FIG. 5D).

[0082] It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described. Rather, the scope of the present invention is defined by the claims which follow. It should further be understood that the above description is only representative of illustrative examples of embodiments. The description has not attempted to exhaustively enumerate all possible variations. The alternate embodiments may not have been presented for a specific portion of the invention, and may result from a different combination of described portions, or that other un-described alternate embodiments may be available for a portion, is not to be considered a disclaimer of those alternate embodiments. It will be appreciated that many of those un-described embodiments are within the literal scope of the following claims, and others are equivalent.

Claims

CLAIMS1. A method of treating external bleeding in a patient in need thereof, comprising topically administering a therapeutically effective amount of a pharmaceutical composition comprising tranexamic acid at a concentration of about 0.1 pg / mL to about 50 mg / mL.

2. The method of claim 1, wherein the tranexamic acid concentration is about 0.1 pg / mL to about 20 mg / mL.

3. The method of claim 1 or 2, wherein the tranexamic acid concentration is about 1 pg / mL to about 10 mg / mL.

4. The method of any one of claims 1-3, wherein the tranexamic acid concentration is about 10 pg / mL to about 10 mg / mL.

5. The method of any one of claims 1-4, wherein the tranexamic acid concentration is about 100 pg / mL to about 5 mg / mL.

6. The method of any one of claims 1-5, wherein the tranexamic acid concentration is about 1 mg / mL to about 5 mg / mL.

7. The method of any one of claims 1-6, wherein the tranexamic acid concentration is about 2.5 mg / mL.

8. The method of any one of claims 1-7, wherein the viscosity of the pharmaceutical composition is about 1 to 2000 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>.

9. The method of any one of claims 1-8, wherein the viscosity of the pharmaceutical composition is about 1 to 100 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>.

10. The method of any one of claims 1-9, wherein the viscosity of the pharmaceutical composition is about 1 to 50 cps, measured at 21°C using the rotational viscosity Method III (Cone-and-Plate Rheometers) described in USP <912>.

11. The method of any one of claims 1-10, wherein pharmaceutical composition further comprises a viscosity modifying agent.

12. The method of claim 11, wherein the viscosity modifying agent is methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, acacia gum, guar gum, tragacanth gum, xanthan gum, polyvinylpyrrolidone, colloidal silicone dioxide, silicate, or a mixture thereof.

13. The method of any one of claims 1-12, wherein pharmaceutical composition further comprises a pH buffer agent.

14. The method of any one of claims 1-13, wherein the pharmaceutical composition is sterile.

15. The method of claim 14, wherein the pharmaceutical composition is sterilized by aseptic filtration or autoclaving.

16. The method of any one of claims 1-15, wherein the external bleeding is from a minor wound.

17. The method of any one of claims 1-15, wherein the external bleeding comprises epistaxis, hemoptysis hematemesis, hematochezia, or hematuria.

18. The method of any one of claims 1-17, wherein the topical administration reduces the patient’s time to hemostasis by at least 20% compared to a placebo.

19. The method of any one of claims 1-18, wherein the topical administration reduces the patient’s time to re-bleeding compared a patient administered a topical placebo.

20. The method of any one of claims 1-19, wherein the topical administration reduces the severity of bleeding.

21. The method of any one of claims 1-20, wherein the patient has a bleeding disorder.

22. The method of any one of claims 1-21, wherein the patient is on an anticoagulant or antiplatelet therapy.

23. The method of claim 21 or 22, wherein the pharmaceutical composition is topically administered after shaving.

24. The method of any one of claims 1-23, wherein the patient has hemophilia, kidney disease, liver disease, low platelets, or cancer.

25. The method of any one of claims 1-24, wherein the patient is undergoing post-cardiac bypass, extracorporeal membrane oxygenation (ECMO), or hemodialysis.

26. The method of any one of claims 1-25, further comprising administering an additional drug.

27. The method of claim 26, wherein the drug is a vasoconstrictor, antibiotic, anti-fungal, antiviral, analgesic, local anesthetic, non-steroidal anti-inflammatory drug, opioid, or anti -neoplastic.

28. The method of claim 27, wherein the drug is a vasoconstrictor.

29. The method of claim 28, wherein the vasoconstrictor is selected from the group consisting of epinephrine, phenylephrine, norepinephrine, and oxymetazoline.

30. The method of claim 28 or 29, wherein the pharmaceutical composition is sequentially administered with the vasoconstrictor.

31. The method of claim 28 or 29, wherein the pharmaceutical composition is concomitantly administered with the vasoconstrictor.

32. The method of claim 1, wherein the pharmaceutical composition is aerosolized.

33. The method of claim 32, wherein pharmaceutical composition is topically administered into a nasal, lung, oral, rectal, vaginal, colon, esophageal, or bronchial tissue by using a nebulizer.

34. The method of any one of claims 1-33, wherein the pharmaceutical composition is topically administered into a mucosal tissue during endoscopy or colonoscopy.

35. The method of any one of claims 1-34, wherein about 0.5 mL to about 20 mL of the pharmaceutical composition is topically administered.

36. The method of any one of claims 1-35, wherein about 3 mL to about 8 mL of the pharmaceutical composition is topically administered.

37. The method of any one of claims 1-36, wherein about 6 mL of the pharmaceutical composition is topically administered.

38. The method of any one of claims 1-37, wherein the concentration of tranexamic acid on a target tissue is about 0.1 pg / mL to about 5 mg / mL.

39. The method of any one of claims 1-38, wherein the concentration of tranexamic acid on a target tissue is about 0.1 pg / mL to about 3 mg / mL.

40. The method of any one of claims 1-39, wherein the concentration of tranexamic acid on a target tissue is less than about 5 mg / mL.

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