Pharmaceutical compositions of echinocandin analogs and methods for preparing same

Abstract

The present disclosure provides pharmaceutical compositions of echinocandin analogs and methods for preparing the same. Specifically, the present disclosure provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solubilizing agent, and a buffering agent. The compositions have excellent stability. [Formula 1] TIFF2025535828000015.tif57168

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 2022113124878, filed October 25, 2022, and Chinese Patent Application No. 2023108308433, filed July 7, 2023. This application cites the above Chinese patent applications in their entirety.

[0002] (Technical field) FIELD OF THE DISCLOSURE The present disclosure is in the field of pharmaceutical formulations, and specifically relates to pharmaceutical compositions of echinocandin analogs and methods for their preparation. [Background technology]

[0003] Currently, drugs available for the treatment of fungal infections include amphotericin B, a macrolide polyene that interacts with fungal membrane sterols; flucytosine, a fluoropyrimidine that interacts with fungal protein and DNA biosynthesis; and various azole antifungal drugs (e.g., ketoconazole, itraconazole, and fluconazole), which inhibit fungal membrane sterol biosynthesis (Alexander et al., Drugs, 54:657, 1997). Amphotericin B has a broad spectrum of activity and is considered the "gold standard" of antifungal therapy; however, its use is limited by infusion-related reactions and nephrotoxicity (Warnock, J. Antimicrob. Chemother., 41:95, 1998). The use of flucytosine is also limited by the development of resistant organisms and its narrow spectrum of activity. Widespread use of azole antifungals has led to the emergence of clinically resistant strains of Candida spp.

[0004] Echinocandins are a novel class of antifungal drugs that generally contain a cyclic hexapeptide and a lipophilic tail, the latter of which is attached to the hexapeptide core via an amide bond. These drugs disrupt the synthesis of β-1,3-glucose in fungal cell walls by noncompetitively inhibiting β-1,3-glucose synthase, altering the permeability of the fungal cell wall and lysing and killing the cells. Because fungal cells do not have a cell wall, whereas human cells do, echinocandins can directly act on fungal cell wall components. This allows these drugs to have low toxicity to the human body and is the safest type of antifungal drug to date.

[0005] Anidulafungin is a type of echinocandin drug developed by Vicuron Pharmaceuticals, Inc. in the United States. It is marketed under the trade name Eraxis and was approved for sale in the United States in 2006. Anidulafungin has broad-spectrum antibacterial activity. Patent document CN100335122C discloses a pharmaceutical composition containing anidulafungin and a micelle-forming surfactant.

[0006] WO2021110125 discloses echinocandin drugs with novel structures, such as the compound represented by formula I, which have excellent antibacterial activity. [ka] [Prior art documents] [Patent documents]

[0007] [Patent Document 1] CN100335122C [Patent Document 2] WO2021110125 [Non-patent literature]

[0008] [Non-Patent Document 1] Warnock, J. Antimicrob. Chemother., 41:95, 1998 Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present disclosure is to provide a pharmaceutical composition comprising an active ingredient, a compound represented by Formula I or a pharmaceutically acceptable salt thereof, which has good formulation stability. [ka] [Means for solving the problem]

[0010] The present disclosure provides pharmaceutical compositions comprising an active ingredient, a compound of Formula I or a pharmaceutically acceptable salt thereof, a solubilizing agent, and a buffering agent, wherein the buffering agent is selected from one or more of glycine, alanine, valine, leucine, isoleucine, phenylalanine, serine, threonine, tyrosine, cysteine, methionine, proline, tryptophan, lysine, arginine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, phosphate, citrate, maleate, borate, carbonate, acetate, lactate, tartrate, malate, succinate, ascorbate, oxalate, and sulfate.

[0011] The buffering agent may be in free form, in salt form, or in a combination of free and salt form.

[0012] The present disclosure provides a pharmaceutical composition comprising an active ingredient, a compound of Formula I or a pharmaceutically acceptable salt thereof, a solubilizing agent, and a buffering agent, wherein the buffering agent comprises at least one amino acid.

[0013] In some embodiments, the solubilizing agent is selected from one or more of polysorbates, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, sorbitan trioleate, bile salts, and lecithin. In some embodiments, the solubilizing agent is a polysorbate, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. The solubilizing agent helps prevent precipitation of the active ingredient in the body during storage or after administration and reduces the potential for side effects (e.g., irritation).

[0014] In some embodiments, the buffering agent is histidine, including histidine and combinations of histidine and histidine hydrochloride.

[0015] In some embodiments, the pharmaceutical composition further comprises a stabilizer selected from one or more of mannitol, sucrose, trehalose, maltose, dextrose, and lactose. In some embodiments, the stabilizer is mannitol.

[0016] In some embodiments, the pharmaceutical composition further comprises a pH adjusting agent, which may be sodium hydroxide, hydrochloric acid, or the like.

[0017] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is an acetate salt.

[0018] In some embodiments, the weight ratio of the active ingredient, a compound of Formula I or a pharmaceutically acceptable salt thereof, to the buffering agent is 1:0.01 to 1:5, and in some embodiments, the weight ratio of the active ingredient, a compound of Formula I or a pharmaceutically acceptable salt thereof, to the buffering agent is 1:0.05 to 1:5, including, but not limited to, 1:0.01, 1:0.02, 1:0.05, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, or any value between any two of them. In some embodiments, the weight ratio of the active ingredient, the compound of Formula I or a pharmaceutically acceptable salt thereof, to the buffer is 1:0.02 to 1:3, for example, 1:0.05 to 1:1, which is appropriate and advantageous for stabilizing the pH of the composition.

[0019] In some embodiments, the weight ratio of the active ingredient, a compound of Formula I or a pharmaceutically acceptable salt thereof, to the solubilizing agent is 1:0.1-10. In some embodiments, the weight ratio of the active ingredient, a compound of Formula I or a pharmaceutically acceptable salt thereof, to the solubilizing agent is 1:0.5-5, including, but not limited to, 1:1, 1:1.2, 1:1.4, 1:1.5, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.4, 1:2.5, 1:2.6, 1:2.8, 1:3, 1:3.2, 1:3.4, 1:3.5, 1:3.6, 1:3.8, 1:4, 1:4.2, 1:4.4, 1:4.5, 1:4.6, 1:4.8, 1:5, or any value between any two of these.

[0020] In some embodiments, the weight ratio of the active ingredient, a compound of Formula I or a pharmaceutically acceptable salt thereof, to the stabilizer is 1:0.1-10, preferably 1:0.5-5, including, but not limited to, 1:0.5, 1:0.6, 1:0.8, 1:0.9, 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1:5, or any value between any two of these.

[0021] In some embodiments, the pH of the pharmaceutical composition is 4 to 8. In some embodiments, the pH of the pharmaceutical composition is 4.5 to 7. In some embodiments, the pH of the pharmaceutical composition is 5.5 to 6.5, including, but not limited to, 4.5, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, or any value between any two of these.

[0022] In some embodiments, the pharmaceutical composition contains an active ingredient or a pharmaceutically acceptable salt thereof in a concentration range of 5-300 mg / ml, for example, 10-250 mg / ml, including, but not limited to, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250 mg / ml, or any value between any two of these.

[0023] The present disclosure further provides: 5 to 300 mg / ml of a compound of formula I or a pharmaceutically acceptable salt thereof; Mannitol as a stabilizer in a weight ratio of 1:0.5 to 5:1 to the compound represented by formula I or a pharmaceutically acceptable salt thereof; histidine as a buffer in a weight ratio of 1:0.05 to 5:1 to the compound represented by formula I or a pharmaceutically acceptable salt thereof; a polysorbate as a solubilizer in a weight ratio of 1:0.5 to 5:1 to the compound represented by formula I or a pharmaceutically acceptable salt thereof; and optionally a pH adjusting agent; Here, the pH is 5.5 to 6.5.

[0024] The pharmaceutical compositions of the present disclosure may further comprise other pharmaceutical excipients such as solubility enhancers, tonicity adjusting agents, adsorbents, complexing agents, and the like.

[0025] The pharmaceutical compositions provided by the present disclosure may be solid or liquid, where solid pharmaceutical compositions are often obtained by lyophilizing a liquid composition or by redissolving or reconstituting a liquid composition. Liquid pharmaceutical compositions may be in solution or suspension form, preferably in solution form. In some embodiments, the liquid composition is obtained by redissolving or reconstituting a lyophilized composition or is a liquid composition prior to lyophilization. In some embodiments, the solid composition is redissolved or reconstituted to obtain the pharmaceutical composition.

[0026] The present disclosure provides the use of said pharmaceutical composition in the preparation of a medicament for treating and / or preventing a fungal infection.

[0027] The disclosure provides for the use of said pharmaceutical composition in the preparation of a medicament for preventing, stabilizing or inhibiting the growth of, or killing, a fungus.

[0028] The pharmaceutical compositions provided by the present disclosure can be used as medicaments, which can be used to prevent, stabilize, or inhibit the growth of, or kill, fungi.

[0029] The present disclosure provides a method of preventing, stabilizing or inhibiting the growth of, or killing, a fungus, comprising administering to a patient in need thereof a therapeutically effective amount of said pharmaceutical composition.

[0030] The present disclosure provides a method for preparing said pharmaceutical composition, comprising the step of combining a compound of Formula I, or a pharmaceutically acceptable salt thereof, with a solubilizing agent and a buffer.

[0031] In some embodiments, the method further comprises adjusting the pH and lyophilizing.

[0032] As used herein, the terms "about" and "approximately" mean that a numerical value falls within an acceptable error range of the particular numerical value as determined by one of ordinary skill in the art, and the numerical value will vary in part depending on the measurement or determination method (i.e., the limitations of the measurement system). For example, "about" may mean a standard deviation within or greater than 1 in each practice of the art. Alternatively, "about" or "essentially comprising" may mean a range of up to 20%. Furthermore, particularly with respect to biological systems or processes, the term may mean up to an order of magnitude or up to 5 times the numerical value. Unless otherwise specified, when a specific numerical value is described in this application and claims, the meaning of "about" or "essentially comprising" should be assumed to be within an acceptable error range of the particular numerical value.

[0033] The numerical values ​​in this disclosure are instrumentally measured values ​​or calculated values ​​after instrumental measurement, and have a certain degree of error, and generally, ±10% is within a reasonable error range. Of course, the context in which the numerical value is used must be taken into consideration. For example, in the case of total impurity content, this numerical value should not have a post-measurement error variation of more than ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, and preferably ±5%.

[0034] "Weight to volume ratio" as used in this disclosure refers to the weight (g) of a component contained per 100 mL of a liquid system, i.e., g / 100 mL. DETAILED DESCRIPTION OF THE INVENTION

[0035] The present disclosure is further illustrated by the following examples, which are for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0036] The acetate content of the compounds of formula I described in the examples is calculated based on the free form of the compounds of formula I.

[0037] Example 1 Buffer Screening Experiment

[0038] Experimental method: The excipient Tween 80 was weighed, added with water for injection and stirred to dissolve uniformly, and the active ingredient was added and stirred to dissolve. The buffer and water for injection were weighed, stirred to dissolve, and mixed uniformly with the active ingredient solution. Mannitol was added to adjust the pH to 5.5-6.5, filtered to sterilize, filled into syringes, and freeze-dried to prepare Compositions 2 and 3, respectively.

[0039] [Table 1]

[0040] Test conclusion: After freeze-drying, the pH of Composition 1 increased significantly, indicating poor stability. The pH buffer systems of Compositions 2 and 3 consist of histidine and histidine hydrochloride, which can maintain the pH of the solution at 5.5-6.5 after reconstitution.

[0041] [Table 2]

[0042] Example 2: Formulation Stability The excipient Tween 80 was weighed, added with water for injection and stirred to dissolve uniformly, and the active ingredient was added and stirred to dissolve. The buffer solution and water for injection were weighed, stirred to dissolve, and mixed uniformly with the active ingredient solution. Mannitol was added to adjust the pH to 5.5-6.5, filtered to sterilize, filled into syringes, and freeze-dried to prepare Compositions A and B.

[0043] [Table 3]

[0044] Experimental design and protocol: Experiments on influencing factors were carried out on Compositions A and B to investigate the effects of temperature (40°C ± 2°C / RH 75% ± 5%), freeze-thaw cycles (2 days at -20°C and 2 days at 25°C per cycle), and light irradiation on the products. The specific protocol is shown in Table 4, and the results are shown in Table 5.

[0045] [Table 4]

[0046] [Table 5-1]

[0047] [Table 5-2]

[0048] [Table 5-3]

[0049] [Table 5-4]

[0050] Experimental conclusion: Each composition shows good stability under the test conditions of various influencing factors.

[0051] Example 3 Following the method of Example 1, different buffer solutions were selected depending on the components in Table 6 to prepare comparative compositions, and the pH of the compositions before lyophilization and after reconstitution was measured.

[0052] [Table 6]

[0053] Experimental conclusion: When other types of pH buffering agents are used, none of them have as good a buffering effect on the pH of the composition as histidine.

[0054] Example 4 According to the method of Example 1, compositions were prepared by selecting different contents of excipients according to the components in Table 7, and the pH of the compositions before lyophilization and after reconstitution was measured.

[0055] [Table 7]

[0056] Experimental conclusion: The pH buffering effect of each composition is good.

Claims

1. 1. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, a solubilizing agent, and a buffering agent, wherein the buffering agent is selected from one or more of glycine, alanine, valine, leucine, isoleucine, phenylalanine, serine, threonine, tyrosine, cysteine, methionine, proline, tryptophan, lysine, arginine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, phosphate, citrate, maleate, borate, carbonate, acetate, lactate, tartrate, malate, succinate, ascorbate, oxalate, and sulfate, more preferably histidine. 【Chemistry 1】

2. 2. The pharmaceutical composition of claim 1, wherein the solubilizing agent is selected from one or more of polysorbates, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, sorbitan trioleates, bile salts, lecithins, preferably polysorbates.

3. 3. The pharmaceutical composition according to claim 1 or 2, further comprising a stabilizer, preferably one or more of mannitol, sucrose, trehalose, maltose, dextrose and lactose, more preferably mannitol.

4. The pharmaceutical composition according to any one of claims 1 to 3, further comprising a pH adjuster.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is an acetate salt.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the weight ratio of the compound represented by formula I or a pharmaceutically acceptable salt thereof to the buffering agent is 1:0.01-5, preferably 1:0.05-5.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the weight ratio of the compound represented by formula I or a pharmaceutically acceptable salt thereof to the solubilizing agent is 1:0.1-10, preferably 1:0.5-5.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the weight ratio of the compound represented by formula I or a pharmaceutically acceptable salt thereof to the stabilizer is 1:0.1-10, preferably 1:0.5-5.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pH of the composition is 4 to 8, preferably 4.5 to 7, more preferably 5.5 to 6.

5.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the content of the compound represented by formula I or a pharmaceutically acceptable salt thereof is 5 to 300 mg / ml, preferably 10 to 250 mg / ml.

11. 5-300 mg / ml of a compound of formula I or a pharmaceutically acceptable salt thereof, mannitol as a stabilizer, histidine as a buffer, polysorbate as a solubilizing agent, and optionally a pH adjusting agent; the weight ratio of the compound represented by formula I or a pharmaceutically acceptable salt thereof to the stabilizer is 1:0.5-5; the weight ratio of the compound represented by formula I or a pharmaceutically acceptable salt thereof to the buffer is 1:0.05-5; the weight ratio of the compound represented by formula I or a pharmaceutically acceptable salt thereof to the solubilizing agent is 1:0.5-5; wherein the pH is 5.5 to 6.

5.

12. The pharmaceutical composition according to any one of claims 1 to 11, which is a liquid composition.

13. A solid composition that can be redissolved or reconstituted to provide a pharmaceutical composition according to any one of claims 1 to 12.

14. A freeze-dried composition obtained by freeze-drying the pharmaceutical composition according to any one of claims 1 to 12.

15. A reconstituted solution prepared by reconstituting the solid composition of claim 13 or the freeze-dried composition of claim 14.

16. Use of the pharmaceutical composition according to any one of claims 1 to 12, the solid composition according to claim 13, the lyophilized composition according to claim 14, or the reconstituted solution according to claim 15 in the preparation of a medicament for treating and / or preventing a fungal infection.

17. Use of the pharmaceutical composition of any one of claims 1 to 12, the solid composition of claim 13, the lyophilized composition of claim 14, or the reconstituted solution of claim 15 in the preparation of a medicament for preventing, stabilizing or inhibiting the growth of, or killing, fungi.

18. A process for preparing the pharmaceutical composition of any one of claims 1 to 13, comprising the step of mixing a compound of formula I or a pharmaceutically acceptable salt thereof with a solubilizing agent and a buffering agent.

19. 20. The method of claim 18, further comprising a freeze-drying step.

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