Tranexamic acid composition for topical use and method of use thereof

Abstract

The present disclosure relates to pharmaceutical compositions of tranexamic acid and methods of using the compositions. The pharmaceutical compositions of the present disclosure are stable and suitable for topical application.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 315,113, filed March 1, 2022, and U.S. Application No. 17 / 970,933, filed October 21, 2022, the contents of which are incorporated by reference in their entirety into this specification. [Background technology]

[0002] background

[0002] Tranexamic acid (TXA) is a synthetic lysine derivative with antifibrinolytic activity. LYSTEDA® is an FDA-approved, orally administered TXA tablet approved for the treatment of heavy menstrual bleeding in women of childbearing potential. CYKLOKAPRON® injection is an FDA-approved intravenous (IV) preparation for short-term use in patients with hemophilia, indicated to reduce or prevent bleeding during and after tooth extraction and to reduce the need for replacement therapy.

[0003]

[0003] Orally and intravenously administered TXA provides systemic TXA exposure and therefore associated systemic side effects (such as blood clots, seizures, and blurred vision). Furthermore, systemic TXA does not concentrate its effects at the site of the wound or lesion. Therefore, there is a need for a TXA formulation that minimizes systemic exposure and at the same time reduces bleeding compared to formulations administered orally or intravenously.

[0004]

[0004] The present disclosure provides a TXA-containing composition having an effective amount of TXA for topical use. Summary of the Invention [Means for solving the problem]

[0005] Disclosure Summary

[0005] The present disclosure provides tranexamic acid (TXA) compositions for use in pharmaceutical and cosmetic applications.

[0006]

[0006] In one aspect, the present disclosure provides an aqueous composition for topical use for reducing bleeding. In an embodiment, the composition of the present disclosure comprises TXA in a pharma- ceutically acceptable aqueous vehicle and is suitable for topical administration.

[0007]

[0007] In an embodiment, the present disclosure provides a stable composition comprising a therapeutically effective amount of TXA and a viscosity modifier in a pharma- ceutically acceptable aqueous vehicle. In an embodiment, the viscosity modifier is hydroxyethyl cellulose.

[0008]

[0008] In an embodiment, the composition of the present disclosure contains about 200-300 mg / mL of TXA. In an embodiment, the composition of the present disclosure contains about 200 mg / mL of TXA. In an embodiment, the composition of the present disclosure contains about 300 mg / mL of TXA. In an embodiment, the composition of the present disclosure contains about 250 mg / mL of TXA.

[0009]

[0009] In an embodiment, the viscosity of the composition is about 1-2000 cps, the viscosity being measured at 21° C. using a rotational viscosimetry. In an embodiment, the viscosity of the composition is about 1-50 cps, the viscosity being measured at 21° C. using a rotational viscosimetry. In an embodiment, the viscosity of the composition is about 1-100 cps, the viscosity being measured at 21° C. using a rotational viscosimetry.

[0010]

[0010] In an embodiment, the composition includes a viscosity modifier. In an embodiment, the composition includes about 0.05% to about 2% by weight of a viscosity modifier. In an embodiment, the viscosity modifier is hydroxyethyl cellulose. In an embodiment, the hydroxyethyl cellulose has a viscosity of about 800 cps to about 1500 cps, determined in a 2% aqueous solution of hydroxyethyl cellulose at 20°C. In an embodiment, the hydroxyethyl cellulose has a viscosity of about 4500 cps to about 6500, determined in a 2% aqueous solution of hydroxyethyl cellulose at 20°C. In an embodiment, the hydroxyethyl cellulose has a viscosity of about 2000 cps, determined in a 2% aqueous solution of hydroxyethyl cellulose at 20°C.

[0011]

[0011] In an embodiment, the composition further comprises a pH buffering agent. In an embodiment, the pH buffering agent is sodium citrate and citric acid.

[0012] In an embodiment, the composition has a pH value of about 3 to about 5. In an embodiment, the pH of the composition is about 4.

[0013]

[0013] In an embodiment, the topical aqueous composition of TXA is sterile. [Brief description of the drawings]

[0014] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 shows a flow diagram illustrating a method for making the compositions of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Detailed Description definition

[0015] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications are incorporated by reference in their entirety into this disclosure for all purposes in order to more fully describe the state of the art known to those skilled in the art as of the date of this disclosure. In the event of a conflict between the cited patents, patent applications and publications and this disclosure, this disclosure shall govern.

[0016]

[0016] For convenience, certain terms employed in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0017]

[0017] The term "about" immediately preceding a numerical value denotes a range (e.g., plus or minus 10% of the value). Unless the context of this disclosure indicates otherwise or is inconsistent with such an understanding, for example, "about 50" may mean 45 to 55, "about 25,000" may mean 22,500 to 27,500, etc. For example, in a list of numerical values ​​such as "about 49, about 50, about 55, ...", "about 50" means a range extending less than half the interval between the preceding value and the following value, for example, from more than 49.5 to less than 52.5. Furthermore, the phrases "less than about" or "more than about" should be understood in light 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 to 30") refers to the endpoints of all values ​​or ranges in the series, respectively.

[0018]

[0018] As used herein, the term "aqueous" refers to a composition that contains greater than 50% water by weight. In embodiments, the aqueous compositions of the present disclosure contain greater than 75% water by weight. In embodiments, the aqueous compositions of the present disclosure contain greater than 90% water by weight.

[0019]

[0019] As used herein, the term "carrier" encompasses carriers, excipients, and diluents and means a material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material that is involved in carrying or transporting a pharmaceutical agent (such as TXA) from one organ or part of the body to another organ or part of the body.

[0020]

[0020] The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound that is capable of performing an intended result when administered to a patient. For example, an effective amount of TXA in a composition is the amount required to reduce at least one symptom or bleeding of a skin disorder in a patient. The actual amount, including "effective amount" or "therapeutically effective amount", will vary depending on several conditions, including, but not limited to, the severity of the disorder and the size and health of the patient, or the size of the wound to be treated. A skilled physician can easily determine the appropriate amount using methods known in the medical field.

[0021]

[0021] As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0022]

[0022] The term "salts" as used herein includes pharma- ceutically acceptable salts that are commonly used to form alkali metal salts of free acids and addition salts of free bases. The nature of the salt is not critical, so long as the salt is pharma- ceutically acceptable. The term "salts" also includes solvates of addition salts, such as hydrates, and polymorphs of addition salts. Suitable pharma- ceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid and sulfuric acid. Examples of organic acids include ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, straight-chain monocarboxylic acids (e.g., acetic acid and formic acid), polycarboxylic acids (e.g., citric acid and oxalic acid), and lactic acid. Suitable pharma- ceutically acceptable alkali metal salts of free acids can be prepared from inorganic or organic bases. Examples of inorganic bases include hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, and the like. Examples of organic bases include mono-, di-, and trialkylamines such as methylamine, dimethylamine, and triethylamine; mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine; amino acids such as arginine and lysine; guanidine; N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; (trihydroxymethyl)aminoethane; tromethamine, and the like. See, for example, J.Pharm.Sci., 66:1-19 (1977).

[0023]

[0023] The term "preventing" as used herein with respect to a condition (such as scarring) refers to the administration of a composition to a subject not receiving the composition, which reduces the frequency or delays the onset of signs and / or symptoms of the condition in the subject. For example, the TXA composition of the present disclosure can be used to prevent scarring in a patient in need thereof.

[0024]

[0024] The term "treating" as used herein with respect to a patient refers to improving at least one symptom of the patient's condition or disease. For example, a patient's epistaxis (nosebleeds) is treated if, after administration of a composition of the present disclosure, the rate of bleeding is reduced compared to before administration. A patient's wound or external bleeding is treated if, after administration of a composition of the present disclosure, the rate of bleeding is reduced compared to before administration.

[0025] Tranexamic Acid Composition

[0025] In an embodiment, the present disclosure provides a high concentration tranexamic acid (TXA) composition suitable for topical administration. In an embodiment, the viscosity of the composition of the present disclosure is such that the TXA composition remains on the wound or abnormal skin site for an extended period of time (e.g., at least about 10 minutes). In an embodiment, the present disclosure provides a TXA composition that is stable (e.g., physically and chemically stable) during storage (such as under ICH accelerated stability test conditions).

[0026]

[0026] In one aspect, the present disclosure provides an aqueous composition for topical use for reducing bleeding. In an embodiment, the composition comprises about 50 mg / mL to about 500 mg / mL of TXA, for example, about 50 mg / mL, about 100 mg / mL, about 150 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 225 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 275 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 325 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 400 mg / mL, about 450 mg / mL, or about 500 mg / mL, including all values ​​and ranges therebetween. In an embodiment, the composition comprises about 200 mg / mL TXA. In an embodiment, the composition comprises about 250 mg / mL TXA. In an embodiment, the composition comprises about 275 mg / mL TXA. In an embodiment, the composition comprises about 300 mg / mL TXA. In an embodiment, the composition comprises about 350 mg / mL TXA.

[0027]

[0027] In an embodiment, the composition comprises about 50 mg / mL to about 500 mg / mL of TXA in a pharma- ceutically acceptable aqueous vehicle, e.g., about 50 mg / mL to about 480 mg / mL, about 50 mg / mL to about 450 mg / mL, about 50 mg / mL to about 430 mg / mL, about 50 mg / mL to about 400 mg / mL, about 50 mg / mL to about 380 mg / mL, about 50 mg / mL to about 350 mg / mL, about 50 mg / mL to about 330 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 280 mg / mL, about 50 mg / mL to about 250 mg / mL. mL, about 50 mg / mL to about 230 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 180 mg / mL, about 50 mg / mL to about 150 mg / mL, about 50 mg / mL to about 130 mg / mL, about 50 mg / mL to about 100 mg / mL, about 100 mg / mL~about 500mg / mL, about 100mg / mL~about 480mg / mL, about 100mg / mL~about 450mg / mL, about 100mg / mL~about 430mg / mL, about 100mg / mL~about 400mg / mL, about 100mg / mL~about 380mg / mL, about 100mg / mL ~350mg / mL, 100mg / mL~330mg / mL, 100mg / mL~300mg / mL, 100mg / mL~280mg / mL, 100mg / mL~250mg / mL, 100mg / mL~230mg / mL, 100mg / mL~280mg / mL 200mg / mL, about 100mg / mL to about 180mg / mL, about 100mg / mL to about 150mg / mL, about 100mg / mL to about 130mg / mL, about 150mg / mL to about 500mg / mL, about 150mg / mL to about 480mg / mL, about 150mg / mL to about 450 mg / mL, about 150 mg / mL to about 430 mg / mL, about 150 mg / mL to about 400 mg / mL, about 150 mg / mL to about 380 mg / mL, about 150 mg / mL to about 350 mg / mL, about 150 mg / mL to about 330 mg / mL, about 150 mg / mL to about 300 mg / mL mL, about 150 mg / mL to about 280 mg / mL, about 150 mg / mL to about 250 mg / mL, about 150 mg / mL to about 230 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 180 mg / mL, about 200 mg / mL to about 500 mg / mL,The composition may comprise from about 200 mg / mL to about 480 mg / mL, from about 200 mg / mL to about 450 mg / mL, from about 200 mg / mL to about 430 mg / mL, from about 200 mg / mL to about 400 mg / mL, from about 200 mg / mL to about 380 mg / mL, from about 200 mg / mL to about 350 mg / mL, from about 200 mg / mL to about 330 mg / mL, from about 200 mg / mL to about 300 mg / mL, from about 200 mg / mL to about 280 mg / mL, from about 200 mg / mL to about 250 mg / mL, or from about 200 mg / mL to about 230 mg / mL. In an embodiment, the composition comprises from about 200 mg / mL to about 300 mg / mL of TXA.

[0028]

[0028] In an embodiment, the composition comprises about 50-350 mg / mL of TXA in a pharma- ceutically acceptable aqueous vehicle. In an embodiment, the composition comprises about 100-250 mg / mL of TXA in a pharma- ceutically acceptable aqueous vehicle. In an embodiment, the composition comprises about 50-350 mg / mL of TXA. In an embodiment, the composition comprises about 100-300 mg / mL of TXA. In an embodiment, the composition comprises about 120-250 mg / mL of TXA. In an embodiment, the composition comprises about 150-200 mg / mL of TXA. In an embodiment, the composition comprises about 200-500 mg / mL of TXA. In an embodiment, the composition comprises about 200-400 mg / mL of TXA. In an embodiment, the composition comprises about 200-300 mg / mL of TXA.

[0029]

[0029] In an embodiment, the composition comprises about 500 mg / mL TXA. In an embodiment, the composition comprises about 400 mg / mL TXA. In an embodiment, the composition comprises about 350 mg / mL TXA. In an embodiment, the composition comprises about 300 mg / mL TXA. In an embodiment, the composition comprises about 250 mg / mL TXA. In an embodiment, the composition comprises about 200 mg / mL TXA. In an embodiment, the composition comprises about 100 mg / mL TXA. In an embodiment, the composition comprises about 50 mg / mL TXA.

[0030] In an embodiment, the concentration of TXA is selected based on the type and severity of the patient's bleeding.

[0031]

[0031] In an embodiment, the composition comprises about 5% to about 45% by weight TXA, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45% by weight, including all values ​​and ranges therebetween. In an embodiment, the composition comprises about 10-25% by weight TXA in a pharma- ceutically acceptable aqueous vehicle. In an embodiment, the composition comprises about 5-35% by weight TXA. In an embodiment, the composition comprises about 10-30% by weight TXA. In an embodiment, the composition comprises about 12-25% by weight TXA. In an embodiment, the composition comprises about 12-40% by weight TXA. In an embodiment, the composition comprises about 15-20% by weight TXA. In an embodiment, the composition comprises about 15-40% by weight TXA. In an embodiment, the composition comprises about 20-50% by weight TXA. In an embodiment, the composition comprises about 50% TXA by weight. In an embodiment, the composition comprises about 40% TXA by weight. In an embodiment, the composition comprises about 35% TXA by weight. In an embodiment, the composition comprises about 30% TXA by weight. In an embodiment, the composition comprises about 20% TXA by weight. In an embodiment, the composition comprises about 10% TXA by weight. In an embodiment, the composition comprises about 50% TXA by weight. In an embodiment, the composition comprises about 18% TXA by weight. In an embodiment, the composition comprises about 27% TXA by weight.

[0032]

[0032] In an embodiment, the composition is packaged in a suitable container. In an embodiment, the volume of the composition is about 0.5mL to about 30mL, for example, about 0.5mL, about 1.0mL, about 1.5mL, about 2.0mL, about 2.5mL, about 3.0mL, about 3.5mL, about 4.0mL, about 4.5mL, about 5.0mL, about 5.5mL, about 6.0mL, about 6.5mL, about 7.0mL, about 7.5mL, about 8.0mL, about 8.5mL, about 9.0mL, about 9.5mL, about 10.0mL, about 10.5mL, about 11.0mL, about 11.5mL, about 12.0mL, about 13.0mL, about 14.0mL, about 15.0mL, about 16.0mL, about 17.0mL, about 18.0mL, about 19.0mL, about 20.0mL, about 21.0mL, about 22.0mL, about 23.0mL, about 24.0mL, about 25.0mL, about 26.0mL, about 27.0mL, about 28.0mL, about 29.0mL, about 30.0mL, about 31.0mL, about 32.0mL, about 33.0mL, about 34.0mL, about 35.0mL, about 36.0mL, about 37.0mL, about 38.0mL, about 39 ... 2.0 mL, about 12.5 mL, about 13.0 mL, about 13.5 mL, about 14.0 mL, about 14.5 mL, about 15.0 mL, about 15.5 mL, about 16.0 mL, about 16.5 mL, about 17.0 mL, about 17.5 mL, about 18.0 mL, about 18.5 mL, about 19.0 mL, about 19.5 mL, about 20.0 mL, about 21.0 mL, about 22.0 mL, about 23.0 mL, about 24.0 mL, about 25.0 mL, about 26.0 mL, about 27.0 mL, about 28.0 mL, about 29.0 mL, or about 30.0 mL.

[0033]

[0033] In an embodiment, the volume of the composition is about 2 mL to about 10 mL, for example, 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, or about 10 mL, including all values ​​and ranges therebetween. In an embodiment, the volume of the composition is about 10 mL. In an embodiment, the volume of the composition is about 9 mL. In an embodiment, the volume of the composition is about 8 mL. In an embodiment, the volume of the composition is about 7 mL. In an embodiment, the volume of the composition is about 6 mL. In an embodiment, the volume of the composition is about 5 mL. In an embodiment, the volume of the composition is about 4 mL. In an embodiment, the volume of the composition is about 3 mL. In an embodiment, the volume of the composition is about 2 mL.

[0034] In an embodiment, the packaged composition contains from about 100 mg to about 5,000 mg of TXA, for example, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, and the like, including all values ​​and ranges therebetween. The TXA content may be about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, or about 5000 mg. In an embodiment, the packaged composition contains about 200 mg to about 2000 mg of TXA. In an embodiment, the packaged composition contains about 200 mg to about 300 mg of TXA. In an embodiment, the packaged composition contains about 250 mg of TXA.

[0035] In an embodiment, the packaged composition contains from about 250 mg to about 2,000 mg of TXA, for example, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, including all values ​​and ranges therebetween. About 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg about 1900 mg, about 1950 mg, or about 2000 mg.

[0036]

[0036] In an embodiment, the packaged composition contains about 1000 mg to about 2,000 mg of TXA, for example, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg, including all values ​​and ranges therebetween.

[0037] In an embodiment, the composition of the present disclosure comprises an effective concentration of tranexamic acid (TXA) in a pharma- ceutically acceptable aqueous vehicle, and further comprises a pharma- ceutically acceptable excipient, such as an emulsifier, wetting agent, or filler, such as polyethylene glycol designated 200, 300, 400, and 600, or Carbowax designated 1000, 1500, 4000, 6000, and 10000. The amount and type of excipient added will depend on the specific requirements, and generally range from about 0.0001 to about 90% by weight.

[0038] In an embodiment, the composition of the present disclosure further comprises a viscosity modifier. In an embodiment, the viscosity agent is selected from the group consisting of gum arabic, agar, alginic acid, aluminum monostearate, ammonium sulfate, attapulgite, bentonite, betadex sulfobutylether sodium, calcium alginate, calcium lactate, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose and microcrystalline cellulose, carrageenan, microcrystalline cellulose, sodium carboxymethylcellulose, 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, hydroxyethylcellulose ... Examples of suitable cellulose acetate preparations include cellulose acetate, hydroxypropylcellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose, modified starch, myristyl alcohol, octyldodecanol, pectin, polycarbophil, polydextrose, polyethylene glycol, polyethylene oxide, poly(methyl vinyl 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 mixtures thereof.

[0039]

[0039] In embodiments, the viscosity modifier is a polyol (such as glycerol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, propylene glycol, and ethylene glycol), polyvinylpyrrolidone; cellulose derivatives (such as hydroxypropyl methylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and methylcellulose); dextran (such as dextran 70); water-soluble proteins (such as gelatin); carbomers (such as carbomer 934P, carbomer 941, carbomer 940, and carbomer 974P); or gums (such as HP-guar), or mixtures thereof.

[0040]

[0040] In an embodiment, the viscosity modifier is methylcellulose, sodium carboxymethylcellulose (MV), carbomer, xanthan gum, Poloxamer 407, carboxymethylcellulose, methylcellulose 400cp, Pemulen TR-1, Pemulen TR-2, hydroxyethylcellulose, or a combination thereof.

[0041]

[0041] In an embodiment, the viscosity modifier is a hydrophobic oil. In an embodiment, the viscosity modifier is an aliphatic alcohol, a fatty acid, or a wax. In an embodiment, the viscosity modifier is lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, tetracosanol, hexacosanol, octacosanol, triacontanol, tetratriacontanol; 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, animal wax, petroleum-derived wax, and vegetable wax;Or the wax may be albacer wax, atlasene wax, cardis wax, ceramide, alkyl substituted aromatic compounds, naphthene substituted aromatic compounds, beeswax, carnauba wax, privet wax, cotton wax, white bayberry fruit wax, carnauba wax, hydrogenated castor oil, cuban palm wax, duroxon wax, esparto wax, fat wax, linseed wax, Fischer-Tropsch wax, fir wax, flexo wax, flower wax, glyco wax, wax), Japan wax, jojoba oil, lanolin wax, coconut wax, rice bran wax, rice oil wax, shellac wax, soy wax, ukhuba wax, hydrogenated oil, hydrogenated castor oil, hydrogenated cottonseed oil, hydrogenated jojoba oil, mink wax, mixture of saturated n-alkanes and isoalkanes, montan wax, naphthene, ouric wax, oxazoline wax, ozokerite, paraffin wax, paraffin 58-62°C wax, paraffin 51-53°C wax, paraffin 42-44°C wax, polyethylene wax, PEG-6 beeswax, polymekon wax, retamo wax, rezo wax, sandy wax, malt husk wax, stearyl dimethicone, sugarcane wax, or synthetic mineral wax, or mixtures thereof;

[0042]

[0042] In an embodiment, the viscosity modifier is hydroxyethyl cellulose. In an embodiment, the hydroxyethyl cellulose has a viscosity of about 400 cps to about 2000 cps (2% aqueous solution at 20°C). In an embodiment, the hydroxyethyl cellulose has a viscosity of about 800 cps to about 1500 cps (2% aqueous solution at 20°C). In an embodiment, the hydroxyethyl cellulose has a viscosity of about 4000 cps to about 7000 cps (2% aqueous solution at 20°C). In an embodiment, the hydroxyethyl cellulose has a viscosity of about 4500 cps to about 6500 cps (2% aqueous solution at 20°C). In an embodiment, the hydroxyethyl cellulose has a viscosity of about 2000 cps (2% aqueous solution at 20°C).

[0043]

[0043] In an embodiment, the composition contains from about 1 mg / mL to about 50 mg / mL of a viscosity modifier, for example, 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, about 15 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, including all values ​​and ranges therebetween. 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.

[0044]

[0044] In an embodiment, the composition comprises about 15 mg / mL of the viscosity modifier. In an embodiment, the composition comprises about 10 mg / mL of the viscosity modifier. In an embodiment, the composition comprises about 5 mg / mL of the viscosity modifier. In an embodiment, the composition comprises about 2 mg / mL of the viscosity modifier. In an embodiment, the composition comprises about 1 mg / mL of the viscosity modifier.

[0045] In an embodiment, the composition includes about 0.1% to about 0.5% by weight of a viscosity modifier. In an embodiment, the composition includes about 0.05% to about 2% by weight of a viscosity modifier, such as about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 75%, about 75%, about 76%, about 77 %, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, or about 2% by weight. In an embodiment, the composition comprises about 0.05% by weight of the viscosity modifier. In an embodiment, the composition comprises about 0.10% by weight of the viscosity modifier. In an embodiment, the composition comprises about 0.15% by weight of the viscosity modifier. In an embodiment, the composition comprises about 0.20% by weight of the viscosity modifier. In an embodiment, the composition comprises about 0.25% by weight of a viscosity modifier. In an embodiment, the composition comprises about 0.5% by weight of a viscosity modifier. In an embodiment, the composition comprises about 1.75% by weight of a viscosity modifier.

[0046]

[0046] In an embodiment, the viscosity of the composition is about 1-2000 cps (or mPa-s). In an embodiment, the viscosity of the composition is about 1-1000 cps, for example, 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 therebetween. In an embodiment, the viscosity of the composition is about 1-100 cps. In an embodiment, the viscosity of the composition is about 1-50 cps. In an embodiment, the viscosity of the composition is about 1-2000 cps, and the viscosity is determined according to the United States Pharmacopeia <912> The viscosity is measured at 21° C. using the rotational viscosity method III (cone and plate rheometer) described in U.S. Pharmacopoeia 1997. In an embodiment, the viscosity of the composition is about 1-50 cps, and the viscosity is measured according to the U.S. Pharmacopoeia 1997. <912> The viscosity is measured at 21° C. using the rotational viscosity method III (cone and plate rheometer) described in U.S. Pharmacopoeia 1997. In an embodiment, the viscosity of the composition is about 1-100 cps, and the viscosity is measured according to the U.S. Pharmacopoeia 1997. <912> The viscosity is measured at 21° C. using the rotational viscosity method III (cone and plate rheometer) described in U.S. Pharmacopoeia 1997. In an embodiment, the viscosity of the composition is about 5-50 cps, and the viscosity is measured according to the U.S. Pharmacopoeia 1997. <912> The viscosity is measured at 21° C. using the rotational viscosity method III (cone-plate rheometer) described in .

[0047]

[0047] In an embodiment, the viscosity of the composition is about 2000 cps. In an embodiment, the viscosity of the composition is about 1800 cps. In an embodiment, the viscosity of the composition is about 1600 cps. In an embodiment, the viscosity of the composition is about 1500 cps. In an embodiment, the viscosity of the composition is about 1400 cps. In an embodiment, the viscosity of the composition is about 1200 cps. In an embodiment, the viscosity of the composition is about 1000 cps. In an embodiment, the viscosity of the composition is about 800 cps. In an embodiment, the viscosity of the composition is about 600 cps. In an embodiment, the viscosity of the composition is about 400 cps. In an embodiment, the viscosity of the composition is about 300 cps. In an embodiment, the viscosity of the composition is about 200 cps. In an embodiment, the viscosity of the composition is about 100 cps. In an embodiment, the viscosity of the composition is about 100 cps. In an embodiment, the viscosity of the composition is about 90 cps. In an embodiment, the viscosity of the composition is about 80 cps. In embodiments, the viscosity of the composition is about 70 cps. In embodiments, the viscosity of the composition is about 60 cps. In embodiments, the viscosity of the composition is about 50 cps. In embodiments, the viscosity of the composition is about 40 cps. In embodiments, the viscosity of the composition is about 20 cps. In embodiments, the viscosity of the composition is about 10 cps.

[0048] 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.

[0049]

[0049] The viscosity of the TXA composition is measured using methods known in the art, such as using a viscometer or rheometer. In an embodiment, the viscosity of the TXA composition is measured using a rotational viscosimetry. One of ordinary skill in the art will recognize that factors such as temperature and shear rate can affect viscosity measurements. In an embodiment, the viscosity of the compositions of the present disclosure is measured at 20°C ± 1°C using a Brookfield LV / RV DV-II Viscometer, 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 compositions of the present disclosure is measured according to the United States Pharmacopoeia <912> In an embodiment, the viscosity of the TXA composition of the present disclosure is measured at 20° C.±5° C. In an embodiment, the viscosity of the TXA composition is measured at 21° C. In another embodiment, the viscosity of the TXA composition is measured using a rotational viscometer at 20° C.±1° C. when the viscosity modifier is slowly added to achieve about 1-1000 cps.

[0050]

[0050] In an embodiment, the composition of the present disclosure further comprises a stabilizer. In an embodiment, the stabilizer is sodium citrate (all forms, 0.01-20% by weight), sodium pyrophosphate (0.1-10% by weight), EDTA (all forms, 0.01-20%), pentetate (all forms, 0.01-20%), or sodium glyconate (0.1-10% weight / volume) or mixtures thereof. The stabilizer should be used in an amount sufficient to increase the stability of the composition. In an embodiment, the amount of stabilizer used provides a stable composition that shows no evidence of precipitation or settling for at least about 24 hours after the composition is formed.

[0051]

[0051] In an embodiment, the composition of the present disclosure is stable after exposing the composition to a temperature of about 10-40°C for at least about 1-4 hours. In an embodiment, the composition is stable after exposing the composition to a temperature of about 30°C for at least about 2 hours. In an embodiment, the composition is stable after exposing the composition to a temperature of about 121°C for at least about 30 minutes. In an embodiment, the composition has a shelf life of about 1 year at about 25°C. In an embodiment, the composition has a shelf life of about 2 years at about 25°C. In an embodiment, the composition has a shelf life of about 6 months at about 40°C.

[0052]

[0052] In an embodiment, the composition of the present disclosure is stable after the composition is exposed to ICH accelerated stability storage conditions. In an embodiment, the composition of the present disclosure is stable at 40°C (±2°) and 75% relative humidity (±5%) for at least 1 month. In an embodiment, the composition of the present disclosure is stable at 40°C (±2°) and 75% relative humidity (±5%) for at least 3 months. In an embodiment, the composition of the present disclosure is stable at 40°C (±2°) and 75% relative humidity (±5%) for at least 6 months.

[0053] In an embodiment, the composition has a residence time of about 5 to 120 minutes after application to a bleeding wound. In an embodiment, the composition has a residence time of about 10 to 60 minutes after application to a bleeding wound. In an embodiment, 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 after application to a bleeding wound.

[0054]

[0054] In an embodiment, the composition of the present disclosure does not include a preservative. Alternatively, in an embodiment, the composition of the present disclosure includes a preservative. In an embodiment, the preservative is a quaternary ammonium compound (such as benzalkonium chloride, benzoxonium chloride, etc.). In an embodiment, the preservative is an alkyl-mercury salt of thiosalicylic acid (such as thiomersal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate, sodium perborate, etc.), sodium chlorite, parabens (such as methylparaben or propylparaben), alcohols (such as chlorobutanol, benzyl alcohol or phenylethanol), 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 cross-contamination during use caused by bacteria and fungi.

[0055]

[0055] In an embodiment, the aqueous composition for topical use of TXA is sterile. The composition is sterilized by sterile filtration, autoclaving, or gamma irradiation.

[0056]

[0056] In an embodiment, the TXA composition comprises an isotonicity agent. In an embodiment, the isotonicity agent is betadex sulfobutyl ether sodium, calcium chloride, dextrose, dimethyl-β-cyclodextrin, glycerin, hydroxyethyl-β-cyclodextrin, hydroxypropyl betadex, magnesium chloride, magnesium oxide, maltodextrin, mannitol, potassium chloride, sodium chloride or trimethyl-β-cyclodextrin, or a mixture thereof. In an embodiment, the isotonicity agent is sodium chloride, potassium chloride, calcium chloride or magnesium chloride, or a mixture thereof.

[0057] In an embodiment, the TXA composition includes a wetting agent. In an embodiment, the wetting agent is 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, myris tyl alcohol, poloxamer, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polyoxyl 15 hydroxystearate, polyoxylglyceride, polysorbate 80, propylene glycol dilaurate, propylene glycol monolaurate, sorbitan ester, sucrose palmitate, sucrose stearate, tyloxapol, or vitamin E polyethylene glycol succinate, or mixtures thereof.

[0058]

[0058] In an embodiment, the TXA composition comprises a pH buffer.In an embodiment, the pH buffer 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, hydroxyethylpiperazineethanesulfonic acid, lysine acetate, lysine hydrochloride, maleic acid, malic acid, meglumine, methionine, sodium dihydrogen 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.

[0059]

[0059] In an embodiment, the composition comprises a citrate buffer. In an embodiment, the composition comprises about 10 mM to about 250 mM citrate buffer, for example, about 10 mM, about 20 mM, about 30 mM, about 40 mM, about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, and about 250 mM, including any value or range therebetween. In an embodiment, the composition comprises about 100 mM to about 250 mM citrate buffer. In an embodiment, the composition comprises about 100 mM to about 200 mM citrate buffer. In an embodiment, the composition comprises about 200 mM citrate buffer. In an embodiment, the composition comprises about 100 mM citrate buffer.

[0060]

[0060] In an embodiment, the pH buffer is sodium citrate. In an embodiment, the pH buffer is citric acid. In an embodiment, the pH buffer is sodium citrate and citric acid. In an embodiment, the citric acid is anhydrous. In an embodiment, the sodium citrate is a dihydrate.

[0061] In an embodiment, the composition comprises about 0.1 mg / mL to about 20 mg / mL sodium citrate, for example, 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, about 15 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 therebetween. In an embodiment, the composition comprises about 10 mg / mL sodium citrate. In an embodiment, the composition comprises about 12 mg / mL sodium citrate. In an embodiment, the composition comprises about 12.6 mg / mL sodium citrate. In an embodiment, the composition comprises about 9.9 mg / mL sodium citrate. In an embodiment, the sodium citrate is a dihydrate. In an embodiment, the composition comprises about 20 mg / mL sodium citrate. In an embodiment, the composition comprises about 10 mg / mL or about 20 mg / mL sodium citrate.

[0062]

[0062] In an embodiment, the composition comprises an acetate buffer. In an embodiment, the composition comprises an acetate buffer of about 10 mM to about 250 mM, for example, about 10 mM, about 20 mM, about 30 mM, about 40 mM, about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, and about 250 mM, including any value or range therebetween. In an embodiment, the composition comprises an acetate buffer of about 100 mM to about 250 mM. In an embodiment, the composition comprises about 100 mM to about 200 mM acetate buffer. In an embodiment, the composition comprises about 200 mM acetate buffer. In an embodiment, the composition comprises about 100 mM acetate buffer.

[0063] In an embodiment, the composition comprises about 0.1 mg / mL to about 20 mg / mL sodium acetate, for example, 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, about 15 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 therebetween. In an embodiment, the composition comprises about 10 mg / mL sodium acetate. In an embodiment, the composition comprises about 12 mg / mL sodium acetate. In an embodiment, the composition comprises about 12.6 mg / mL sodium acetate. In an embodiment, the composition comprises about 9.9 mg / mL sodium acetate. In an embodiment, the composition comprises about 20 mg / mL sodium acetate. In an embodiment, the composition comprises about 10 mg / mL or about 20 mg / mL sodium acetate.

[0064] In an embodiment, the composition comprises about 1 mg / mL to about 20 mg / mL citric acid, for example, 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, 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 therebetween. In an embodiment, the composition comprises about 10 mg / mL citric acid. In an embodiment, the composition comprises about 10.15 mg / mL citric acid. In an embodiment, the composition comprises about 12.7 mg / mL citric acid.

[0065]

[0065] In an embodiment, the TXA composition comprises a pH adjuster. In an embodiment, the pH adjuster 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, sodium dihydrogen 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 an embodiment, the pH adjuster is hydrochloric acid. In an embodiment, the pH adjuster is sodium hydroxide.

[0066]

[0066] In an embodiment, the composition of the present disclosure has a pH of about 4.0 to about 8.0. In an embodiment, the composition of the present disclosure has a pH of about 3.5 to about 4.5, for example, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, or about 4.5, including any value or range therebetween. In an embodiment, the composition of the present disclosure has a pH of about 4.0 to about 7.5, for example, 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 value or range therebetween. In an embodiment, the composition of the present disclosure has a pH of about 3.0 to about 5.0. In an embodiment, the composition of the present disclosure has a pH of about 3.5 to about 4.5. In an embodiment, the composition of the present disclosure has a pH of about 3.9 to about 4.1. In an embodiment, the composition of the present disclosure has a pH of about 4.0.

[0067]

[0067] 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 suitable for sustained release. In embodiments, the pharmaceutical compositions of the present disclosure are formulated as solutions, ointments, sustained release formulations, and other dosage forms for topical administration or sustained release delivery. Non-limiting examples of pharma-ceutically acceptable vehicles or excipients or carriers are ointments, creams, rennets, pastes, patches, lotions, gels, shampoos, hydrogels, liposomes, sprays, aerosols, solutions, sponges, films, plasters, surgical dressings, bandages, or emulsions.

[0068] In embodiments, the compositions of the present disclosure further comprise an additional drug that may be desirable to deliver to a patient experiencing bleeding, particularly epistaxis (nosebleeds), prior to or as part of treatment for the epistaxis. In embodiments, the additional drug is a vasoconstrictor (e.g., epinephrine), an antibiotic, an antiseptic (e.g., chlorhexidine), an antifungal agent, an antiviral agent, an analgesic, a local anesthetic (such as lidocaine, xylocaine), a nonsteroidal anti-inflammatory drug, an opioid, or an antineoplastic agent.

[0069]

[0069] A vasoconstrictor is useful to help shrink bleeding blood vessels prior to administration of a hemostatic agent such as an antifibrinolytic agent, and may desirably be delivered to the intranasal tissue at or around the site of bleeding before, during, and / or after application to the intranasal tissue. In an embodiment, the vasoconstrictor is phenylephrine, oxymetazoline (Afrin), or epinephrine. In an embodiment, the vasoconstrictor is epinephrine.

[0070]

[0070] In an embodiment, the composition comprises TXA and hydroxyethylcellulose at a concentration of about 200 mg / mL to about 300 mg / mL. In an embodiment, the composition comprises TXA at ​​a concentration of about 200 mg / mL to about 300 mg / mL and hydroxyethylcellulose at 0.5 mg / mL to about 2.5 mg / mL. In an embodiment, the composition comprises TXA at ​​a concentration of about 200 mg / mL to about 300 mg / mL, sodium citrate dihydrate, citric acid, and hydroxymethylcellulose. In an embodiment, the composition is formulation A, formulation B, formulation C, formulation D, and formulation E shown in Tables 3A and 3B.

[0071] External applicator for TXA composition

[0071] In one aspect, the present disclosure provides an external applicator filled with an external aqueous composition of the present disclosure (e.g., Formulation A, Formulation B, Formulation C, Formulation D, and Formulation E shown in Tables 3A and 3B). In embodiments, the use of any external applicator known in the art, with or without some type of reservoir for the composition, may be contemplated. In embodiments, the external applicator is an applicator described in International Application PCT / US2021 / 046745, the contents of which are incorporated herein by reference in their entirety.

[0072]

[0072] In an embodiment, the external applicator is a pad. In an embodiment, the external applicator pad is filled with the TXA composition of the present disclosure at about 5% to about 100% of the pad volume. In an embodiment, the external applicator pad is filled with about 10% to about 90% of the pad volume. In an embodiment, the external applicator pad is filled with about 20% to about 80% of the pad volume. In an embodiment, the external applicator pad is filled with about 30% to about 70% of the pad volume. In an embodiment, the external applicator pad is filled with about 40% to about 60% of the pad volume. In an embodiment, the external applicator pad is filled with about 50% to about 55% of the pad volume. In an embodiment, the external applicator pad is filled with about 30% to about 70% of the pad volume.

[0073] How to use In one aspect, the disclosure provides methods of using a TXA composition (e.g., Formulation A, Formulation B, Formulation C, Formulation D, and Formulation E shown in Tables 3A and 3B) to reduce bleeding. The disclosure also provides methods of using a TXA composition to treat or prevent various skin abnormalities, including wounds, scars, blemishes, dark spots, or other skin discolorations such as melasma.

[0074] In one aspect, the present disclosure provides a method of treating a wound, comprising: filling a topical applicator pad with a composition of the present disclosure; and applying an effective amount of the composition to the wound. In an embodiment, bleeding includes both external bleeding and internal bleeding arising from an internal cavity or space, exposing an external site for topical administration.

[0075]

[0075] In an embodiment, the present disclosure provides a method of treating epistaxis (nose bleeding), comprising filling an external applicator pad with a composition of the present disclosure; and applying an effective amount of the composition to a patient's nose. In an embodiment, the method of treating epistaxis (nose bleeding) comprises administering about 1,000 mg to about 2,000 mg of tranexamic acid to the patient's nose, in one or both nostrils in need thereof.

[0076] In one aspect, the disclosure provides a method of using a composition of TXA to treat a patient with a tendency for increased bleeding. In an embodiment, the patient is undergoing extracorporeal membrane oxygenation (ECMO) after post-cardiac bypass, or hemodialysis. In an embodiment, the patient is suffering from a bleeding disorder. In an embodiment, the patient has hemophilia, kidney disease, liver disease, drug-induced low platelets, or cancer. In an embodiment, the patient is undergoing a bleeding drug treatment regimen, such as an anticoagulant and / or an antiplatelet agent.

[0077] In an embodiment, the present disclosure provides a method of using a composition of TXA to treat hemoptysis in a patient in need thereof, comprising administering an effective amount of the composition of the present disclosure to the lungs of the patient in need thereof. In an embodiment, the composition is administered by nebulization.

[0078]

[0078] In an embodiment, the present disclosure provides a method of using a TXA composition to treat hemoptysis, hematemesis (vomiting blood), bloody stools (rectal bleeding), or hematuria, comprising administering an effective amount of a composition of the present disclosure to a patient in need thereof.

[0079]

[0079] In an embodiment, the present disclosure provides a method for treating a skin abnormality by administering an effective amount of a composition of the present disclosure. In an embodiment, the method includes filling an external applicator pad with an external TXA composition; and applying an effective amount of the composition to the melasma.

[0080]

[0080] In an embodiment, the present disclosure provides a method for preventing scar or wound pigmentation. In an embodiment, the method includes filling an external applicator pad with a TXA composition; and providing an effective amount of the composition to the scarred or pigmented area.

[0081]

[0081] In an embodiment, the compositions of the present disclosure are administered topically to a subject suffering from bleeding once per day, twice per day, three times per day, or four times per day as needed.

[0082] In an embodiment, the composition of the present disclosure is administered topically to a subject suffering from a wound, for example, once per day, twice per day, or three times per day, as needed.In an embodiment, the composition of the present disclosure is administered topically to a subject suffering from a skin disorder, 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, once every three weeks, once per month, once every two months, once every three months, or once every six months. In embodiments, the compositions of the present disclosure are administered topically to a subject of cosmetic concern 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, once every three weeks, once per month, once every two months, once every three months, or once every six months.

[0083] Numbered embodiments

[0083] In addition to the above disclosure, the following examples, and the appended claims, the present disclosure describes the following numbered embodiments. 1. An aqueous composition for topical application for reducing bleeding comprising tranexamic acid in a concentration of about 50-500 mg / mL in a pharma-ceutically acceptable aqueous vehicle. 2. The composition of embodiment 1, wherein the concentration of tranexamic acid is from about 200 mg / mL to about 300 mg / mL. 3. The topical composition of embodiment 1 or 2, wherein the concentration of tranexamic acid is about 200 mg / mL. 4. The topical composition of embodiment 1 or 2, wherein the concentration of tranexamic acid is about 250 mg / mL. 5. The topical composition of embodiment 1 or 2, wherein the concentration of tranexamic acid is about 300 mg / mL. 6. The topical composition of embodiment 1, wherein the concentration of tranexamic acid is about 350 mg / mL. 7. The topical composition of any one of embodiments 1 to 6, packaged in a suitable container. 8. The composition for topical application of embodiment 7, wherein the packaged composition contains about 200 mg to about 2,000 mg of tranexamic acid. 9. The composition for topical application of embodiment 7 or 8, wherein the packaged composition contains about 200 mg to about 300 mg of tranexamic acid. 10. The topical composition of any one of embodiments 7 to 9, wherein the packaged composition comprises about 200 mg of tranexamic acid. 11. The topical composition of any one of embodiments 7 to 9, wherein the packaged composition comprises about 250 mg of tranexamic acid. 12. The topical composition of any one of embodiments 7 to 9, wherein the packaged composition comprises about 300 mg of tranexamic acid. 13. The topical composition of any one of embodiments 7 to 12, wherein the volume of the composition in a suitable container is about 2 to 10 mL. 14. The topical composition of any one of embodiments 7 to 12, wherein the volume of the composition in a suitable container is about 5 mL. 15. The topical composition of any one of embodiments 7 to 12, wherein the volume of the composition in a suitable container is about 1 mL. 16. The viscosity of the composition is in accordance with the United States Pharmacopoeia <912> The topical composition of any one of embodiments 1 to 15, wherein the viscosity is about 1 to 2000 cps when measured at 21°C using the rotational viscosity method III (cone and plate rheometer) described in. 17. The viscosity of the composition is in accordance with the United States Pharmacopoeia <912> The topical composition of any one of embodiments 1 to 16, wherein the viscosity is about 50 cps or less or about 100 cps or less when measured at 21 ° C. using a rotational viscosity method III (cone and plate type rheometer) described in. 18. The viscosity of the composition is in accordance with the United States Pharmacopoeia <912> The topical composition of any one of embodiments 1 to 16, wherein the viscosity is about 1 cps to about 50 cps when measured at 21 ° C. using the rotational viscosity method III (cone and plate rheometer) described in. 19. The viscosity of the composition is in accordance with the United States Pharmacopoeia <912> The topical composition of any one of embodiments 1 to 16, wherein the viscosity is about 30 cps when measured at 21 ° C. using the rotational viscosity method III (cone and plate rheometer) described in. 20. The topical composition of any one of embodiments 1 to 19, further comprising a viscosity modifier. 21. The topical composition of embodiment 20, wherein the viscosity modifier is a cellulose derivative (e.g., methylcellulose, microcrystalline cellulose, and hydroxypropylmethylcellulose), a gum (e.g., gum arabic, guar gum, tragacanth, and xanthan gum), a polymer (e.g., polymer, polyvinylpyrrolidone), colloidal silicone dioxide or a silicate, or a mixture thereof. 22. The topical composition of embodiment 21, wherein the viscosity modifier is hydroxyethyl cellulose. 23. The topical composition of embodiment 22, wherein the concentration of hydroxyethylcellulose is from about 1 mg / mL to about 2 mg / mL. 24. The topical composition of embodiment 22 or 23, wherein the concentration of hydroxyethylcellulose is from about 0.05% w / w to about 2% w / w. 25. The topical composition of any one of embodiments 22-23, wherein the concentration of hydroxyethylcellulose is from about 0.05% w / w to about 0.2% w / w. 26. The topical composition of any one of embodiments 22 to 25, wherein the hydroxyethyl cellulose has a viscosity of about 800 cps to about 6500 cps, as determined in a 2% aqueous solution of hydroxyethyl cellulose at 20°C. 27. The topical composition of any one of embodiments 22 to 26, wherein the hydroxyethyl cellulose has a viscosity of about 800 cps to about 1500 cps, determined in a 2% aqueous solution of hydroxyethyl cellulose at 20°C. 28. The topical composition of any one of embodiments 22 to 25, wherein the hydroxyethyl cellulose has a viscosity of about 4500 cps to about 6500 cps, determined in a 2% aqueous solution of hydroxyethyl cellulose at 20°C. 29. The topical composition of any one of embodiments 22-25, wherein the hydroxyethyl cellulose has a viscosity of about 2000 cps, determined in a 2% aqueous solution of hydroxyethyl cellulose at 20°C. 30. The topical composition of any one of embodiments 1 to 29, further comprising a pH buffer. 31. The topical composition of embodiment 30, wherein the pH buffer is sodium citrate and citric acid. 32. The topical composition of any one of embodiments 1 to 29, comprising a citrate buffer or an acetate buffer. 33. The topical composition of any one of embodiments 1 to 29, comprising a citrate buffer. 34. The topical composition of embodiment 33, wherein the concentration of the citrate buffer is from about 10 mM to about 250 mM. 35. The topical composition of embodiment 33, wherein the concentration of the citrate buffer is about 50 mM to about 100 mM. 36. The topical composition of embodiment 33, wherein the concentration of the citrate buffer is about 50 mM to about 150 mM. 37. The topical composition of embodiment 33, wherein the concentration of the citrate buffer is about 10 mM to about 100 mM. 38. The topical composition of embodiment 33, wherein the concentration of the citrate buffer is about 100 mM. 39. The topical composition of embodiment 33, wherein the concentration of the citrate buffer is about 20 mM. 40. The topical composition of embodiment 32, wherein the pH buffer is an acetate buffer. 41. The topical composition of embodiment 40, wherein the concentration of the acetate buffer is about 10 mM to about 100 mM. 42. The topical composition of embodiment 40, wherein the concentration of the acetate buffer is about 20 mM. 43. The topical composition of embodiment 30, wherein the pH buffer is sodium acetate. 44. The topical composition of any one of embodiments 1 to 43, wherein the pH of the composition is about 3 to 5. 45. The topical composition of any one of embodiments 1 to 44, wherein the pH of the composition is about 3.9 to 4.1. 46. ​​The topical composition of any one of embodiments 1 to 45, wherein the pH of the composition is about 4. 47. The topical composition of embodiment 1, wherein the composition comprises tranexamic acid in a concentration of about 200 mg / mL to about 300 mg / mL, hydroxyethylcellulose, and a pH buffer, and the pH of the composition is about 4. 48. The topical composition of embodiment 1, wherein the composition comprises tranexamic acid in a concentration of about 200 mg / mL, hydroxyethylcellulose, and a pH buffer, and the pH of the composition is about 4. 49. The topical composition of embodiment 1, wherein the composition comprises tranexamic acid in a concentration of about 250 mg / mL, hydroxyethylcellulose, and a pH buffer, and the pH of the composition is about 4. 50. The topical composition of embodiment 1, wherein the composition comprises tranexamic acid in a concentration of about 300 mg / mL, hydroxyethylcellulose, and a pH buffer, and the pH of the composition is about 4. 51. The composition has a pH of about 4 and a viscosity according to the United States Pharmacopoeia <912> The topical composition of any one of embodiments 1 to 50, wherein the viscosity is about 1 cps to 50 cps when measured at 21°C using the rotational viscosity method III (cone and plate rheometer) described in. 52. The composition has a pH of about 4 and a viscosity according to the United States Pharmacopoeia <912> The topical composition of any one of embodiments 1 to 50, wherein the viscosity is about 30 cps when measured at 21 ° C. using the rotational viscosity method III (cone and plate rheometer) described in. 53. The topical composition of any one of embodiments 1-52, wherein the composition is stable after exposing the composition to a temperature of about 30° C. for at least about 2 hours. 54. The topical composition of any one of embodiments 1 to 53, which is sterilized. 55. The topical composition of any one of embodiments 1 to 54, which is sterilized by sterile filtration or autoclaving. 56. The topical composition of any one of embodiments 1 to 55, further comprising a vasoconstrictor (e.g., epinephrine, phenylephrine), a local anesthetic (lidocaine, xylocaine, etc.), an antibiotic, an antiseptic (e.g., chlorhexidine), an antifungal agent, an antiviral agent, an analgesic, a nonsteroidal anti-inflammatory drug, an opioid, a chemotherapeutic agent, a biologic, a monoclonal antibody, or another anti-neoplastic agent. 57. An external applicator pad filled with the external composition of any one of embodiments 1-56. 58. The external applicator pad of embodiment 57, wherein about 30% to about 70% of the pad volume is filled with the composition. 59. A method for reducing bleeding in a wound, comprising: Filling an external applicator pad with the external composition of any one of embodiments 1 to 56; and administering an effective amount of the composition to the wound; The method includes: 60. A method for treating nosebleeds, comprising: Filling an external applicator pad with the external composition of any one of embodiments 1 to 56; and administering an effective amount of the composition to the nose of a patient in need thereof; The method includes: 61. A method for treating melasma, comprising: Filling an external applicator pad with the external composition of any one of embodiments 1 to 56; and administering an effective amount of the composition to the subject The method includes: 62. A method for preventing scar or wound pigmentation, comprising: Filling an external applicator pad with the external composition of any one of embodiments 1 to 56; and administering an effective amount of the composition to the wound area; The method includes: 63. A method for treating hemoptysis, comprising: Administering an effective amount of the composition of any one of embodiments 1-56 to the lungs of a patient in need thereof. The method includes: 64. The method of embodiment 63, wherein the administration is by nebulization. 65. A kit comprising the topical composition of any one of embodiments 1 to 56, packaged in a suitable container. 66. The kit of embodiment 65, wherein the packaged composition comprises about 250 mg to about 2,000 mg of tranexamic acid. 67. The kit of embodiment 66, wherein the volume of the composition in a suitable container is from about 0.5 mL to about 20 mL. EXAMPLES

[0084] Working Example

[0084] The present invention will be further described with reference to the following examples. However, it is noted that these examples, like the above-mentioned embodiments, are illustrative and should not be construed as limiting the scope of the present invention in any way.

[0085] Example 1. Preparation of TXA formulations

[0085] Exemplary viscosity-modified formulations of tranexamic acid (TXA) were prepared having concentrations of TXA and viscosity modifiers ranging from 200 mg / mL to 350 mg / mL.

[0086] A flow chart illustrating a method for making the compositions of the present disclosure is shown in FIG.

[0087]

[0087] Under the conditions tested, the following viscosity modifiers provided compositions that were not suitable for further pharmaceutical development: Carbomer (Carbopol 981 and 5984), Xanthan gum, Poloxamer 407, Carboxymethylcellulose (low, medium and high viscosity), Methylcellulose 400 cP, Pemulen TR-1 and Pemulen TR2. For example, the compositions were physically unstable (phase separated) at elevated temperatures (such as 40°C, or autoclave conditions (121°C for about 25 minutes)) or provided inadequate composition viscosity.

[0088] For example, Table 1 shows the results of certain viscosity modifiers with compositions containing 350 mg / mL TXA.

[0089] [Table 1]

[0090] In contrast, and unexpectedly, the use of hydroxyethylcellulose (HEC) as a viscosity modifier provided compositions suitable for further pharmaceutical development (e.g., suitable physical stability and viscosity). Table 2 shows the results for HEC compositions containing different TXA and buffer concentrations. Outside of exceptionally high buffering capacity (i.e., 200 mM citrate) and certain cryoprotectant-containing compositions, the HEC compositions provided acceptable viscosities and were physically stable (i.e., no precipitation or phase separation) from 18 to 225°C.

[0091] [Table 2]

[0092]

[0090] Therefore, formulations A to D (containing 200 mg / mL or 300 mg / mL TXA and 800 to 1500 cps hydroxyethylcellulose) listed in Table 3A and formulation E (containing 250 mg / mL TXA and 2000 cps hydroxyethylcellulose) in Table 3B were prepared.

[0093] [Table 3]

[0094] [Table 4]

[0095] Example 2: Extended single-dose dermal toxicity and toxicokinetic study with 2 and 14 day observation periods in Göttingen minipigs

[0091] The Gottingen minipig model was used to study the dermal toxicity and toxicokinetic profile of TXA compositions (200 mg / mL and 300 mg / mL) following single-dose topical transdermal administration with 2 and 14 day observation periods.

[0096]

[0092] Göttingen minipigs were administered a single topical dermal dose of 0 mg / kg (vehicle control, 0.2% w / w hydroxyethylcellulose 2000 cp in citrate buffer, pH 4.0), 400 mg / kg TXA (Formulation C, 200 mg / mL TXA, 2 mL / kg dose), or 600 mg / kg TXA (Formulation D, 300 mg / mL TXA, 2 mL / kg dose) applied to 10% of the body surface area, covered with an occlusive dressing for 24 hours, and observed for 2 or 14 days.

[0097]

[0093] The TXA compositions were well tolerated, with no TXA-related findings observed at terminal or recovery necropsies, no effects on organ weights or clinical pathology, no edema or erythema, and no microscopic findings indicating local irritation or skin toxicity observed at the administration site.

Claims

1. An aqueous topical composition for reducing bleeding comprising tranexamic acid in a concentration of about 200 mg / mL to about 300 mg / mL and hydroxyethylcellulose.

2. The topical composition according to claim 1, wherein the concentration of tranexamic acid is about 200 mg / mL.

3. The topical composition according to claim 1, wherein the concentration of tranexamic acid is about 250 mg / mL.

4. The topical composition according to claim 1, wherein the concentration of tranexamic acid is about 300 mg / mL.

5. The composition for external use according to claim 1, wherein the viscosity of the composition is about 1 to 2000 cps, as measured at 21° C. using a rotational viscometer III (cone and plate rheometer) as described in the United States Pharmacopeia <912>.

6. The composition for external use according to claim 1, wherein the viscosity of the composition is about 1 to 50 cps, as measured at 21° C. using a rotational viscometer III (cone and plate rheometer) as described in the United States Pharmacopeia <912>.

7. The composition for external use according to claim 1, wherein the viscosity of the composition is about 1 to 100 cps, as measured at 21° C. using a rotational viscometer III (cone and plate rheometer) as described in the United States Pharmacopeia <912>.

8. The composition for external use according to claim 1, wherein the concentration of hydroxyethyl cellulose is from about 1 mg / mL to about 2 mg / mL.

9. The topical composition of claim 1, wherein the concentration of hydroxyethylcellulose is from about 0.05% w / w to about 2% w / w.

10. The topical composition of claim 9, wherein the concentration of hydroxyethylcellulose is from about 0.05% w / w to about 0.2% w / w.

11. 2. The topical composition of claim 1, wherein the hydroxyethyl cellulose has a viscosity of about 800 cps to about 6500 cps, determined in a 2% aqueous solution of the hydroxyethyl cellulose at 20°C.

12. 2. The topical composition of claim 1, wherein the hydroxyethyl cellulose has a viscosity of about 800 cps to about 1500 cps, determined in a 2% aqueous solution of the hydroxyethyl cellulose at 20°C.

13. 2. The topical composition of claim 1, wherein the hydroxyethyl cellulose has a viscosity of about 4500 cps to about 6500 cps, determined in a 2% aqueous solution of the hydroxyethyl cellulose at 20°C.

14. 2. The topical composition of claim 1, wherein the hydroxyethyl cellulose has a viscosity of about 2000 cps, determined in a 2% aqueous solution of the hydroxyethyl cellulose at 20°C.

15. The topical composition of claim 1 , further comprising a pH buffer.

16. The topical composition of claim 1 , wherein the composition comprises a citrate buffer.

17. The composition for external use according to claim 16, wherein the concentration of the citrate buffer is from about 10 mM to about 250 mM.

18. The composition for external use according to claim 16, wherein the concentration of the citrate buffer is from about 10 mM to about 150 mM.

19. The composition for external use according to claim 16, wherein the concentration of the citrate buffer is from about 50 mM to about 150 mM.

20. The topical composition according to claim 16, wherein the concentration of the citrate buffer is about 100 mM.

21. The topical composition of claim 16, wherein the concentration of the citrate buffer is about 20 mM.

22. The composition for topical use according to claim 1, wherein the pH of the composition is from about 3 to about 5.

23. The topical composition of claim 22, wherein the pH of the composition is from about 3.9 to about 4.

1.

24. 24. The topical composition of claim 23, wherein the pH of the composition is about 4.

25. 2. The topical composition of claim 1, wherein the composition comprises tranexamic acid in a concentration of about 200 mg / mL to about 300 mg / mL, hydroxyethylcellulose, and a pH buffer, and the pH of the composition is about 4.

26. 2. The topical composition of claim 1, wherein the composition comprises tranexamic acid at a concentration of about 200 mg / mL, hydroxyethylcellulose, and a pH buffer, and the pH of the composition is about 4.

27. 2. The topical composition of claim 1, wherein the composition comprises tranexamic acid at a concentration of about 250 mg / mL, hydroxyethylcellulose, and a pH buffer, and the pH of the composition is about 4.

28. 2. The topical composition of claim 1, wherein the composition comprises tranexamic acid at a concentration of about 300 mg / mL, hydroxyethylcellulose, and a pH buffer, and the pH of the composition is about 4.

29. 2. The composition for external use according to claim 1, wherein the pH of the composition is about 4, and the viscosity of the composition is about 1 to 50 cps, as measured at 21° C. using a rotational viscometer III (cone and plate rheometer) as described in the United States Pharmacopeia <912>.

30. 2. The composition for external use according to claim 1, wherein the pH of the composition is about 4, and the viscosity of the composition is about 1 to 100 cps, as measured at 21° C. using a rotational viscometer III (cone and plate rheometer) as described in the United States Pharmacopeia <912>.

31. 2. The composition for external use according to claim 1, wherein the concentration of tranexamic acid is about 200 mg / mL, the pH of the composition is about 4, and the viscosity of the composition is about 1 to 50 cps, as measured at 21° C. using a rotational viscometer III (cone and plate rheometer) as described in the United States Pharmacopeia <912>.

32. 2. The composition for external use according to claim 1, wherein the concentration of tranexamic acid is about 200 mg / mL, the pH of the composition is about 4, and the viscosity of the composition is about 1 to 100 cps, as measured at 21° C. using a rotational viscometer III (cone and plate rheometer) as described in the United States Pharmacopeia <912>.

33. 2. The composition for external use according to claim 1, wherein the concentration of tranexamic acid is about 250 mg / mL, the pH of the composition is about 4, and the viscosity of the composition is about 1 to 50 cps, as measured at 21° C. using a rotational viscometer III (cone and plate rheometer) as described in the United States Pharmacopeia <912>.

34. 2. The composition for external use according to claim 1, wherein the concentration of tranexamic acid is about 250 mg / mL, the pH of the composition is about 4, and the viscosity of the composition is about 1 to 100 cps, as measured at 21° C. using a rotational viscometer III (cone and plate rheometer) as described in the United States Pharmacopeia <912>.

35. 2. The composition for external use according to claim 1, wherein the concentration of tranexamic acid is about 300 mg / mL, the pH of the composition is about 4, and the viscosity of the composition is about 1 to 50 cps, as measured at 21° C. using a rotational viscometer III (cone and plate rheometer) as described in the United States Pharmacopeia <912>.

36. 2. The composition for external use according to claim 1, wherein the concentration of tranexamic acid is about 300 mg / mL, the pH of the composition is about 4, and the viscosity of the composition is about 1 to 100 cps, as measured at 21° C. using a rotational viscometer III (cone and plate rheometer) as described in the United States Pharmacopeia <912>.

37. The topical composition of claim 1 , wherein the composition is sterile.

38. The topical composition of claim 37, wherein the composition is sterilized by sterile filtration or autoclaving.

39. A kit comprising the topical composition of claim 1 packaged in a suitable container.

40. 40. The kit of claim 39, wherein the volume of the composition in the suitable container is from about 0.5 mL to about 20 mL.

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