Method for improving the solubility of tranexamic acid

Abstract

1. A method for increasing the solubility of tranexamic acid, comprising the steps of: a) first dissolving tranexamic acid in water; b) measuring the pH value of the solution obtained in step (a); c) adding a strong acid (which completely dissociates in water) to the solution obtained in step (a) and simultaneously monitoring the decrease in the pH value of the solution to increase the solubility of tranexamic acid until the pH value of the solution is about pH 4.5 or less; d) adding tranexamic acid to the solution obtained in step (c) so that the pH value of the solution is 2.0 or higher; and e) Repeating steps (c) and (d) until the desired amount of tranexamic acid has been added to the solution of step (a), i.e., until the desired concentration of tranexamic acid in the final solution is reached.

Description

[Technical Field]

[0001] This application relates generally to therapeutic formulations and methods for their preparation. In particular, this application relates to methods for increasing the solubility of tranexamic acid and methods for preparing liquid formulations thereof. Summary of the Invention [Problem to be solved by the invention]

[0002] Tranexamic acid is a bleeding control medication used to treat or prevent excessive bleeding caused by major trauma, postpartum hemorrhage, surgery, or tooth extraction. It also aids in blood clotting, so it's used to treat nosebleeds and menorrhagia. For example, using a tranexamic acid mouthwash can help stop bleeding after a tooth extraction. Tranexamic acid is also effective in treating conditions such as hereditary angioedema, which causes swelling under the skin. Tranexamic acid may be prescribed several days before surgery or dental procedures if you experience more bleeding than usual.

[0003] Tranexamic acid is usually prescribed as a tablet, or as a liquid for children and those who cannot swallow tablets, while mouthwash and injections are usually only available in hospitals.

[0004] Tranexamic acid is sold as tablets in the United States and Australia as Lysteda, as an intravenous injection and tablets in Australia and Sweden as Cyclokapron, and as Cyclo-F in the United Kingdom and Sweden. It is also sold as Femstrual in the United Kingdom, Transcam in Asia, Pause in India, Espercil in South America, Nicolda in Japan, and Exacyl in France, Poland, Belgium, and Romania. It is sold as capsules in the Philippines as Hemostan and in Israel as Hexakapron.

[0005] Tranexamic acid tablets are available in 500 mg tablets. The usual adult dose is two or three tablets three times daily. Patients with renal problems typically receive a lower dose. Liquid formulations are available in various concentrations. For example, Cyklokapron is administered as a 100 mg / mL injectable solution. However, higher concentrations of tranexamic acid are often urgently needed due to bleeding or complications related to surgery or other aforementioned conditions. Unfortunately, such dosages are not currently available due to tranexamic acid's relatively low aqueous solubility (approximately 167 mg / mL under standard conditions). Therefore, there has been a long-felt need to develop a liquid formulation with a higher concentration than the solubility of tranexamic acid. [Means for solving the problem]

[0006] The present invention describes an embodiment of a method for increasing the solubility of tranexamic acid, the method comprising the steps of: a) first dissolving tranexamic acid in water; b) measuring the pH value of the solution obtained in step (a); c) adding a strong acid (which completely dissociates in water) to the solution obtained in step (a) and simultaneously monitoring the decrease in the pH value of the solution to increase the solubility of tranexamic acid until the pH value of the solution is about pH 4.5 or less; d) adding tranexamic acid to the solution obtained in step (c) so that the pH value of the solution is 2.0 or higher; and e) Repeating steps (c) and (d) until the desired amount of tranexamic acid has been added to the solution of step (a), i.e., until the desired concentration of tranexamic acid in the final solution is reached.

[0007] In some embodiments, the initial concentration of tranexamic acid dissolved in water in step (a) of the method of the present invention is about 120-200 mg / mL. In certain embodiments, the initial concentration of tranexamic acid is about 130-180 mg / mL, 130-170 mg / mL, or 130-160 mg / mL. In certain embodiments, the initial concentration of tranexamic acid is about 130 mg / mL.

[0008] In other embodiments, in step (c), the pH value of the solution of step (a) is reduced to about pH 4.5 or less than pH 4.5. In certain embodiments, in step (c), the pH value of the solution of step (a) is reduced to less than pH 4.0, less than pH 3.5, less than pH 3.0, less than pH 2.5, less than pH 2.0, less than pH 1.5, less than pH 1.0, or less than pH 0.5.

[0009] In a further embodiment, the strong acid used in the present invention to decrease the pH value of the solution in step (c) and thereby increase the solubility of tranexamic acid is selected from hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid, and phosphoric acid, and the concentration of the strong acid is about 0.01 to 10.00 eq / L.

[0010] In yet another embodiment, in step (d) of adding tranexamic acid, the pH value of the solution of step (c) is increased to above pH 2.5, above pH 3.0, above pH 3.5, above pH 4.0, above pH 4.5, above pH 5.0, or above pH 5.5. In a specific embodiment, the pH is increased to about pH 3.5 in step (d).

[0011] In yet other embodiments, the desired tranexamic acid concentration in the final solution is greater than 160 mg / mL, greater than 250 mg / mL, greater than 350 mg / mL, greater than 400 mg / mL, in the range of about 200 to 600 mg / mL, or in the range of about 300 to 500 mg / mL. In certain embodiments, the desired tranexamic acid concentration in the final solution is about 400 mg / mL, specifically 440 mg / mL.

[0012] Another aspect of the present invention relates to liquid formulations having a tranexamic acid concentration greater than 160 mg / mL, greater than 250 mg / mL, greater than 350 mg / mL, greater than 400 mg / mL, in the range of about 200-600 mg / mL, or in the range of about 300-500 mg / mL. In certain embodiments, the liquid formulations of the present invention contain tranexamic acid at a concentration of about 400 mg / mL, or specifically at a concentration of 440 mg / mL.

[0013] Various embodiments provide different advantages and can be used in different applications. Details of one or more embodiments are set forth in the following specification. Other features, objects, and advantages of the described technology will become apparent from the specification and claims. DETAILED DESCRIPTION OF THE INVENTION

[0014] In the following description, various aspects of the present application are described. For purposes of explanation, specific configurations and details are presented in order to provide a thorough understanding of the present application. However, it will be apparent to those skilled in the art that the present application may be practiced without the specific details presented herein. Furthermore, well-known features may be omitted or simplified so as not to obscure the present application.

[0015] The term "comprising" as used in the claims is "open-ended" and means the recited elements or elements equivalent in structure or function, as well as other elements not recited. It should not be interpreted as being limited to the means thereafter recited, nor as excluding other elements or steps. It should be interpreted as specifying the presence of recited features, integers, steps, or referenced components, but not as excluding the presence or addition of one or more other features, integers, steps, or components, or groups thereof. Thus, the scope of the expression "a method comprising steps x and z" should not be limited to a method consisting solely of these steps.

[0016] Unless otherwise specified, the terms "about" and "approximately" as used herein are understood to mean within normal tolerances in the art, e.g., within two standard deviations of the mean. In one embodiment, the terms "about" and "approximately" mean within 10%, preferably within 5%, of the reported value of the numerical value with which it is used. For example, the term "about" can be immediately understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the specified value. In other embodiments, the term "about" can mean a greater tolerance for variation, depending, for example, on the research methodology used. Such variation in specific values is understood by those of skill in the art and is within the context of the present invention. By way of illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly stated values of about 1 to about 5, but also individual values and subranges within the stated range. Thus, this numerical range includes individual values such as 2, 3, and 4, as well as subranges such as 1 to 3, 2 to 4, and 3 to 5, and even individual values such as 1, 2, 3, 4, 5, and 6. This principle also applies to ranges that recite only one numerical value as the minimum or maximum value. Unless otherwise clear from the context, all numerical values described herein are modified by the term "about." Terms such as "substantially," "generally," and "up to" and similar terms are to be construed as modifying a non-absolute term or numerical value. Such terms are defined to the extent understood by one of ordinary skill in the art, depending on the context and the term they modify. This includes, at a minimum, the degree of expected experimental, technical, and instrumental error associated with the particular experiment, technique, or device used to measure the value.

[0017] As used herein, the term "and / or" includes any and all combinations of one or more of the items in the associated list. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which this invention belongs. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of this specification and the related art, and should not be interpreted in an idealized or overly formal sense unless expressly defined herein. Well-known functions or structures may not be described in detail for the sake of brevity and / or clarity.

[0018] The present invention relates to a method for increasing the solubility of tranexamic acid, comprising the steps of: a) first dissolving tranexamic acid in water; b) measuring the pH value of the solution obtained in step (a); c) adding a strong acid (which completely dissociates in water) to the solution obtained in step (a) and simultaneously monitoring the decrease in the pH value of the solution to increase the solubility of tranexamic acid until the pH value of the solution is about pH 4.5 or less; d) adding tranexamic acid to the solution obtained in step (c) so that the pH value of the solution is 2.0 or higher; and e) Repeating steps (c) and (d) until the desired amount of tranexamic acid has been added to the solution of step (a), i.e., until the desired concentration of tranexamic acid in the final solution is reached.

[0019] Tranexamic acid is an organic acid having the following formula: [ka] IUPAC name: trans-4-(aminomethyl)cyclohexanecarboxylic acid, CAS No. 1197-18-8

[0020] Tranexamic acid is a synthetic analog of lysine. It acts as an antifibrinolytic agent by reversibly binding to four or five lysine receptor sites on plasminogen. This reduces the conversion of plasminogen to plasmin, preventing fibrin degradation and maintaining the structural framework of the fibrin matrix. Therefore, it is used as a blood coagulant to control bleeding and to treat or prevent excessive bleeding following trauma, postpartum hemorrhage, surgery, and tooth extraction.

[0021] It should be noted that the solubility of tranexamic acid is a limiting factor in all currently commercially available dosage forms. Therefore, no liquid formulations of tranexamic acid with a concentration higher than 180 mg / mL are known. The inventors unexpectedly discovered that the above-described method of the present invention significantly improves the solubility of tranexamic acid in liquid formulations, which are surprisingly very stable and have a long shelf life.

[0022] In some embodiments, the initial concentration of tranexamic acid dissolved in water in step (a) of the method of the present invention is about 120 to 200 mg / mL. In certain embodiments, the initial concentration of tranexamic acid is about 130 to 180 mg / mL, 130 to 170 mg / mL, or 130 to 160 mg / mL. In certain embodiments, the initial concentration of tranexamic acid is about 130 mg / mL.

[0023] In other embodiments, in step (c), the pH value of the solution in step (a) is reduced to about pH 4.5 or less. In certain embodiments, in step (c), the pH value of the solution in step (a) is reduced to less than pH 4.0, less than pH 3.5, less than pH 3.0, less than pH 2.5, less than pH 2.0, less than pH 1.5, less than pH 1.0, or less than pH 0.5. In certain embodiments, in step (c), the pH value of the solution in step (a) is reduced to about pH 0.2.

[0024] In a further embodiment, the strong acid used in step (c) to decrease the pH of the solution and thereby increase the solubility of tranexamic acid is selected from hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid, and phosphoric acid, and has a concentration of about 0.01 to 10.00 eq / L.

[0025] In yet another embodiment, in step (d) of adding tranexamic acid, the pH value of the solution in step (c) is increased to above pH 2.5, above pH 3.0, above pH 3.5, above pH 4.0, above pH 4.5, above pH 5.0, or above pH 5.5. In certain embodiments, the pH is increased to about pH 3.5 in step (d). In certain embodiments, the pH is increased to about pH 4.5 in step (d).

[0026] In still other embodiments, the desired concentration of tranexamic acid in the final solution is greater than 160 mg / mL, greater than 250 mg / mL, greater than 350 mg / mL, greater than 400 mg / mL, within the range of about 200-600 mg / mL, or within the range of about 300-500 mg / mL. In certain embodiments, the desired concentration of tranexamic acid in the final solution is about 400 mg / mL, specifically 440 mg / mL.

[0027] Another aspect of the present invention relates to liquid formulations containing tranexamic acid at a concentration of greater than 160 mg / mL, greater than 250 mg / mL, greater than 350 mg / mL, greater than 400 mg / mL, in the range of about 200-600 mg / mL, or in the range of about 300-500 mg / mL. In certain embodiments, the liquid formulations of the present invention contain tranexamic acid at a concentration of about 400 mg / mL, or specifically at a concentration of 440 mg / mL.

[0028] In yet another aspect, the invention relates to a liquid formulation produced by the method of the invention, comprising a tranexamic acid concentration greater than 160 mg / mL, greater than 250 mg / mL, greater than 350 mg / mL, greater than 400 mg / mL, in the range of about 200-600 mg / mL, or in the range of about 300-500 mg / mL. In certain embodiments, the liquid formulation of the invention comprises tranexamic acid at a concentration of about 400 mg / mL, or specifically at a concentration of 440 mg / mL.

[0029] In a further embodiment of the invention, the method of the invention comprises the steps of: a) dissolving tranexamic acid in water to a concentration of about 120 to 200 mg / mL; b) measuring the pH value of the solution obtained in step (a); c) dropwise adding a strong acid selected from hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid, and phosphoric acid to the solution obtained in step (a) to increase the solubility of tranexamic acid, while monitoring the decrease in the pH value of the solution until it reaches about pH 3.0 to about pH 4.0; d) adding tranexamic acid to raise the pH value of the solution obtained in step (c) to about pH 3.5 to 4.5; and e) Repeating steps (c) and (d) until the tranexamic acid concentration in the final solution reaches about 250-450 mg / mL. [Example]

[0030] The method of the present invention is not only characterized by the ability to prepare an aqueous solution containing tranexamic acid at a concentration higher than its solubility in water, but also by the fact that the highly concentrated TXA solution is very stable at 40°C for 3 months, as shown in the following experimental example.

[0031] [Test Example 1: Stability Data - Tranexamic Acid (TXA) 400 mg / ml, 2.5 ml Syringe] Batch number: D-2363 Dose: 400mg / ml, 2.5ml Conditions: 40℃ / 75% RH The drug product stability study was evaluated by comparing the stability data with the current TXA Injection BP monograph to ensure that the results were within acceptable standards throughout the product's shelf life. The clarity of the product indicates that the solution is pure and all materials are completely dissolved.

[0032] The stability data is shown in Table 1 below.

[0033] [Table 1] 1 For TXA injection, specification limits were set according to the BP monograph wherever possible. Impurity b - set at 0.2% instead of 0.5% in accordance with ICH Q3b(R2) to take into account the MDD (maximum daily dose). Impurity E - not included in the BP monograph, set at 0.15% in accordance with ICH Q3b(R2).

[0034] (1. Appearance - Colorless to slightly yellow transparent solution) There is no change in the appearance of the product.

[0035] (2. Assay - 95.0% to 105.0% of the declared concentration of TXA) All analytical results were within the specified limits. For such products, it is common approach to define limits for analysis.

[0036] (3. pH) The pH was stable and did not fluctuate significantly after 6 months of stability. The pH limit will be evaluated during development studies.

[0037] 4. Impurities and Decomposition Products 4.1 Impurity B cis-tranexamic acid - not to exceed 0.1% Impurity B is an isomer of TXA. Results after 6 months are within specifications. 4.2 Impurity C - not exceeding 0.1% The results are within specifications. 4.3 Impurity D Aminomethylbenzoin - Not to exceed 0.1% The results are within specifications. 4.4 Total impurities - not exceeding 2.0% The results are within specifications.

[0038] Conclusion: TXA 400 mg / ml in a 2.5 ml syringe was stable for 6 months under accelerated conditions (40°C / 75% RH) without significant increase in degradation products or significant decrease in assay levels.

[0039] [Test Example 2: Release Data - TXA 400mg / ml, 2.5ml] Batch number: D-2363 Dose: 400mg / ml, 2.5ml Test external use: The pH value throughout the entire process was approximately pH 4. The purpose of the test was to confirm that the dissolving ability of TXA was possible even at pH 4.

[0040] The release data is shown in Table 2 below.

[0041] [Table 2]

[0042] A 400 mg / ml TXA product in a 2.5 ml syringe can be prepared at an acidic pH of approximately 4. In addition to a clear solution showing complete solubility of TXA, analytical results met the acceptance criteria.

[0043] Test Example 3: Preparation of a formulation of tranexamic acid according to the present invention 1. Dissolve 135mg / ml in water 2. Lower the pH value of the solution to about 3.0 with strong acid (HCl 5N). 3. Add tranexamic acid until the pH is approximately 4.0. 4. Add strong acid (HCl 5N) to lower the pH to about 3. 5. Continue steps 3 and 4 until the concentration of tranexamic acid is 400 mg / ml.

[0044] [Test Example 4: Main process stability data - TXA 400 mg / ml, 2.5 ml] Batch number: D-2556 Dose: 400mg / ml, 2.5ml Conditions: 2 weeks / 65℃ Manufacturer's intended recipe and process for Batch No. D-2556: 1. Weighing WFI 2. Add TXA and mix until dissolved. 3. Add HCl to bring the pH to approximately 3. 4. Add TXA and mix until dissolved. 5. Repeat steps 3 + 4 until the desired amount of TXA is reached. 6. Adjust the weight with WFI

[0045] The drug product stability study was evaluated by comparing the stability data with the current TXA Injection BP monograph to ensure that the results were within acceptable standards throughout the product's shelf life. The clarity of the product indicates that the solution is pure and all materials are completely dissolved.

[0046] The above batches were stored under accelerated conditions at 65°C and 40°C.

[0047] Stability data for 2 weeks at 65°C is shown in Table 3 below.

[0048] [Table 3] 1 For TXA injection, the specification limits were set according to the BP monograph wherever possible. Impurity B - set at 0.2% instead of 0.5% to account for the maximum daily dose (MDD) according to ICH Q3B(R2). Impurity E - not included in the BP monograph, set at 0.15% according to ICH Q3b(R2).

[0049] (1. Appearance - Colorless to slightly yellow transparent solution) There is no change in the appearance of the product.

[0050] (2. Assay - 95.0% to 105.0% of the declared concentration of TXA) After two weeks of storage at 65°C, all analytical results remained within the specified limits.

[0051] (3. pH) The pH remained stable and did not fluctuate significantly during the two-week stabilization period at 65°C.

[0052] 4. Impurities and Decomposition Products 4.1 Impurity B cis-tranexamic acid - not to exceed 0.1% The results are within the acceptance criteria and are below the QL (0.05%) after 2 weeks at 65°C. 4.2 Impurity C - not exceeding 0.1% The results are within the acceptance criteria and are below the QL (0.05%) after 2 weeks at 65°C. 4.3 Impurity D Aminomethylbenzoin - Not to exceed 0.1% The results are within the acceptance criteria and are below the QL (0.05%) after 2 weeks at 65°C. 4.4 Impurity E - not exceeding 0.15% The results are within the acceptable standards after two weeks at 65°C. 4.5 Impurities (type unknown) - not exceeding 0.1% The results are within the acceptance criteria and are below the QL (0.05%) after 2 weeks at 65°C. 4.6 Total impurities - not exceeding 2.0% The results are within the acceptable standards after two weeks at 65°C.

[0053] Conclusion: TXA 400 mg / ml, 2.5 ml, is a stable product, even under accelerated conditions (65°C for 2 weeks), without a significant increase in degradation products or a significant decrease in assay levels.

Claims

1. 1. A method for increasing the solubility of tranexamic acid, comprising the steps of: a) first dissolving tranexamic acid in water; b) measuring the pH value of the solution obtained in step (a); c) adding a strong acid (which completely dissociates in water) to the solution obtained in step (a) and simultaneously monitoring the decrease in the pH value of the solution to increase the solubility of tranexamic acid until the pH value of the solution is about pH 4.5 or less, or until the pH value is equal to or less than pH 4.5; d) adding tranexamic acid to the solution obtained in step (c) so that the pH value of the solution becomes pH 2.0 or higher; and e) Repeating steps (c) and (d) until the desired amount of tranexamic acid has been added to the solution of step (a), i.e., until the desired concentration of tranexamic acid in the final solution is reached.

2. 2. The method according to claim 1, wherein in step (a), the initial concentration of tranexamic acid dissolved in water is about 120 to 200 mg / mL.

3. 3. The method of claim 2, wherein the initial concentration of tranexamic acid is about 130 to 180 mg / mL.

4. 4. The method of claim 3, wherein the initial concentration of tranexamic acid is about 150-170 mg / mL.

5. 5. The method of claim 4, wherein the initial concentration of tranexamic acid is about 165 mg / mL.

6. 2. The method of claim 1, wherein in step (c), the pH value of the solution of step (a) is lowered to about pH 4.

0.

7. 2. The method of claim 1, wherein in step (c), the pH value of the solution of step (a) is reduced to less than pH 4.

0.

8. 8. The method of claim 7, wherein in step (c), the pH value of the solution of step (a) is reduced to less than pH 3.5, less than pH 3.0, less than pH 2.5, less than pH 2.0, less than pH 1.5, less than pH 1.0, or less than pH 0.

5.

9. 8. The method of claim 7, wherein in step (c), the pH value of the solution of step (a) is lowered to about pH 0.

2.

10. 2. The method of claim 1, wherein the strong acid is selected from hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid, and phosphoric acid.

11. 2. The method of claim 1, wherein the concentration of the strong acid is about 0.01 to 10.00 eq / L.

12. 2. The method of claim 1, wherein in step (d) of adding tranexamic acid, the pH value of the solution of step (c) is increased to above pH 2.5, above pH 3.0, above pH 3.5, above pH 4.0, above pH 4.5, above pH 5.0, or above pH 5.

5.

13. 13. The method of claim 12, wherein in step (d), the pH value of the solution of step (c) is increased to about pH 3.

5.

14. 13. The method of claim 12, wherein in step (d), the pH value of the solution of step (c) is increased to above pH 4.

5.

15. 10. The method of claim 1, wherein the desired tranexamic acid concentration in the final solution is greater than 160 mg / mL, greater than 250 mg / mL, or greater than 350 mg / mL.

16. 16. The method of claim 15, wherein the desired tranexamic acid concentration in the final solution is greater than 400 mg / mL.

17. 10. The method of claim 1, wherein the desired tranexamic acid concentration in the final solution is about 200 to 600 mg / mL, or 300 to 500 mg / mL.

18. 18. The method of claim 17, wherein the desired tranexamic acid concentration in the final solution is about 400 mg / mL.

19. 19. The method of claim 18, wherein the desired tranexamic acid concentration in the final solution is about 450 mg / mL.

20. 10. The method of claim 1, comprising the steps of: a) dissolving tranexamic acid in water to a concentration of about 120-200 mg / mL; b) measuring the pH value of the solution obtained in step (a); c) dropwise adding a strong acid selected from hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid, and phosphoric acid to the solution obtained in step (a) to increase the solubility of tranexamic acid, while monitoring the decrease in the pH value of the solution until it reaches about pH 3.0 to about pH 4.0; d) adding tranexamic acid to raise the pH value of the solution obtained in step (c) to about pH 3.5 to 4.5; and e) Repeating steps (c) and (d) until a tranexamic acid concentration of about 250-450 mg / mL is reached in the final solution.

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