Pharmaceutical composition of echinocandin analogue and preparation method thereof

Abstract

The invention provides a pharmaceutical composition of an echinocandin analogue and a preparation method of the pharmaceutical composition. Specifically, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a solubilizer and a buffer agent. The composition has excellent stability. # imgabs0 #

Description

Pharmaceutical composition of echinocandin analogs and preparation method thereof

[0001] This application claims priority to Chinese Patent Application No. 2022113124878 filed on October 25, 2022, and Chinese Patent Application No. 2023108308433 filed on July 7, 2023. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present disclosure belongs to the field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition of an echinocandin analog and a preparation method thereof. Background Art

[0003] Currently available drugs for treating 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) that inhibit fungal membrane-sterol biosynthesis (Alexander et al., Drugs, 54:657, 1997). Although amphotericin B has a broad spectrum of activity and is considered the "gold standard" of antifungal therapy, 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 microorganisms and its narrow spectrum of activity. The widespread use of azole antifungals is leading to the emergence of clinically resistant strains of Candida spp.

[0004] Echinocandins are a new class of antifungal drugs, typically consisting of a cyclic hexapeptide and a lipophilic tail, the latter of which is linked to the hexapeptide core via an amide bond. These drugs interfere with the synthesis of β-1,3-glucose in the fungal cell wall by non-competitively inhibiting β-1,3-glucose synthase, leading to changes in the permeability of the fungal cell wall and cell lysis and death. Because human cells lack cell walls, while fungal cells do, echinocandins can act directly on components of the fungal cell wall. Therefore, they exhibit low toxicity to humans and are the safest class of antifungal drugs to date.

[0005] Anidulafungin is an echinocandin drug developed by Vicuron Pharmaceuticals in the United States under the trade name Eraxis. It was approved for marketing in the United States in 2006. Anidulafungin has broad-spectrum antibacterial activity. CN100335122C discloses a pharmaceutical composition comprising anidulafungin and a micellar-forming surfactant.

[0006] WO2021110125 discloses a novel structure of an echinocandin drug, such as a compound shown in Formula I, which has excellent antibacterial activity.

[0007] Summary of the Invention

[0008] The present disclosure aims to provide a pharmaceutical composition comprising an active ingredient of a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein the composition has good formulation stability.

[0009] The present disclosure provides a pharmaceutical composition, which comprises an active ingredient, a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, a solubilizer, and a buffer, wherein the buffer 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.

[0010] The buffer may be in the form of a free form or a salt, or a combination of a free form and a salt.

[0011] The present disclosure provides a pharmaceutical composition comprising an active ingredient, a compound represented by Formula I or a pharmaceutically acceptable salt thereof, a solubilizer, and a buffer, wherein the buffer comprises at least one amino acid.

[0012] In certain 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 certain embodiments, the solubilizing agent is a polysorbate, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. The solubilizing agent is beneficial in preventing the active ingredient from precipitating during storage or in vivo after administration, thereby reducing possible side effects (e.g., irritation).

[0013] In certain embodiments, the buffer is histidine, including histidine, and a combination of histidine and histidine hydrochloride.

[0014] In certain embodiments, the pharmaceutical composition may further comprise a stabilizer selected from one or more of mannitol, sucrose, trehalose, maltose, dextrose, and lactose. In certain embodiments, the stabilizer is mannitol.

[0015] In certain embodiments, the pharmaceutical composition may further comprise a pH adjuster, which may be sodium hydroxide, hydrochloric acid, or the like.

[0016] In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is acetate.

[0017] In certain embodiments, the weight ratio of the active ingredient, the compound of Formula I, or a pharmaceutically acceptable salt thereof, to the buffer is 1:0.01-1:5. In certain embodiments, the weight ratio of the active ingredient, the compound of Formula I, or a pharmaceutically acceptable salt thereof, to the buffer is 1:0.05-1:5, and non-limiting examples include: 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 in between. In certain embodiments, the weight ratio of the active ingredient, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, to the buffer is 1:0.02-1:3, for example, 1:0.05-1:1. The appropriate ratio of the active ingredient, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, to the buffer is beneficial to the stability of the pH of the composition.

[0018] In certain embodiments, the weight ratio of the active ingredient, the compound of Formula I, or a pharmaceutically acceptable salt thereof, to the solubilizer is 1:0.1-10; in certain embodiments, the weight ratio of the active ingredient, the compound of Formula I, or a pharmaceutically acceptable salt thereof, to the solubilizer is 1:0.5-5, and non-limiting examples include: 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 ratio between two of them.

[0019] In certain embodiments, the weight ratio of the active ingredient, the compound of Formula I or a pharmaceutically acceptable salt thereof, to the stabilizer is 1:0.1-10, preferably 1:0.5-5, and non-limiting examples include: 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 in between.

[0020] In certain embodiments, the pH of the pharmaceutical composition is 4 to 8. In certain embodiments, the pH of the pharmaceutical composition is 4.5 to 7. In certain embodiments, the pH of the pharmaceutical composition is 5.5 to 6.5, non-limiting examples of which include 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 in between.

[0021] In certain embodiments, the active ingredient or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at 5-300 mg / ml, for example, 10-250 mg / ml. Non-limiting examples include: 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 therebetween.

[0022] The present disclosure also provides a pharmaceutical composition comprising:

[0023] 5-300 mg / ml of the compound represented by formula I or a pharmaceutically acceptable salt thereof;

[0024] The stabilizer is mannitol, wherein the weight ratio of the compound represented by Formula I or a pharmaceutically acceptable salt thereof to the stabilizer buffer is 1:0.5-5;

[0025] The buffer is histidine, wherein the weight ratio of the compound represented by Formula I or a pharmaceutically acceptable salt thereof to the buffer is 1:0.05-5;

[0026] The solubilizer is polysorbate, wherein the weight ratio of the compound represented by Formula I or its pharmaceutically acceptable salt to the solubilizer is 1:0.5-5;

[0027] and optionally a pH adjuster,

[0028] The pH of the composition is 5.5-6.5.

[0029] The pharmaceutical composition of the present disclosure may further comprise other pharmaceutical excipients, such as cosolvents, isotonicity regulators, adsorbents, complexing agents, and the like.

[0030] The pharmaceutical compositions provided herein may be solid or liquid, wherein the solid form of the pharmaceutical composition is often obtained by freeze-drying a liquid form composition or by reconstitution or reconstitution to obtain a liquid form composition. The liquid form of the pharmaceutical composition may be in the form of a solution or a suspension, preferably a solution. In certain embodiments, the liquid composition is obtained by reconstitution or reconstitution of a freeze-dried composition or is a liquid composition before freeze-drying. In certain embodiments, the solid composition is reconstituted or reconstituted to obtain the aforementioned pharmaceutical composition.

[0031] The present disclosure provides use of the aforementioned pharmaceutical composition in preparing a medicament for treating and / or preventing fungal infection.

[0032] The present disclosure provides use of the aforementioned pharmaceutical composition in the preparation of a medicament for preventing, stabilizing or inhibiting fungal growth or killing fungi.

[0033] The pharmaceutical compositions provided by the present disclosure are used as medicaments. The medicaments can be used to prevent, stabilize or inhibit the growth of fungi or kill fungi.

[0034] The present disclosure provides a method for preventing, stabilizing or inhibiting fungal growth or killing fungi, which comprises administering a therapeutically effective amount of the pharmaceutical composition to a patient in need thereof.

[0035] The present disclosure provides a method for preparing the aforementioned pharmaceutical composition, comprising the step of mixing the compound represented by Formula I or a pharmaceutically acceptable salt thereof with a solubilizer and a buffer.

[0036] In certain embodiments, the method further comprises the steps of adjusting pH and lyophilizing.

[0037] As used herein, the terms "about" and "approximately" refer to values ​​that are within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, in each practice in the art, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially comprising" can mean a range of up to 20%. In addition, particularly for biological systems or processes, the term can mean up to an order of magnitude or up to 5 times the value. Unless otherwise indicated, when a specific value appears in the application and claims, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for that specific value.

[0038] The numerical values ​​in this disclosure are instrumental measurements or calculated values ​​after instrumental measurement, and are subject to a certain degree of error. Generally speaking, a value within a reasonable error range of plus or minus 10% is within the reasonable error range. Of course, the context in which the numerical value is used must be considered. For example, the total impurity content, which is a value with an error variation of no more than plus or minus 10% after measurement, can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

[0039] The “weight to volume ratio” described in the present disclosure refers to the weight (in g) of the component contained in every 100 mL of liquid system, that is, g / 100 mL. DETAILED DESCRIPTION

[0040] The present disclosure is further described in detail by the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0041] The content of acetate in the compound of formula I described in the examples is based on the free form of the compound of formula I.

[0042] Example 1 Buffer screening experiment

[0043] Experimental method: Weigh the excipient Tween 80 and stir it evenly with water for injection until dissolved, then add the active ingredient and stir to dissolve; weigh the buffer and stir it with water for injection, dissolve it, mix it evenly with the active ingredient solution, then add mannitol, adjust the pH to 5.5-6.5, filter and sterilize, fill the vials, and freeze-dry to prepare compositions 2 and 3, respectively.

[0044] Table 1 Components of each composition

[0045] Test conclusion: After freeze-drying, the pH of composition 1 increased significantly, indicating poor stability. The pH buffer system of compositions 2 and 3, consisting of histidine and histidine hydrochloride, can maintain the pH of the solution at 5.5-6.5 after reconstitution.

[0046] Table 2 Buffer screening results

[0047] Example 2: Formulation Stability

[0048] The excipient Tween 80 was weighed and mixed with water for injection until dissolved, and the active ingredient was added and stirred to dissolve; the buffer was weighed and mixed with water for injection, stirred to dissolve, and mixed evenly with the active ingredient solution, and then mannitol was added, and the pH was adjusted to 5.5-6.5. The mixture was filtered and sterilized, filled into vials, and freeze-dried to prepare compositions A and B.

[0049] Table 3 Components of each composition

[0050] Experimental Design and Plan: Compositions A and B were tested for their effects on temperature (40°C ± 2°C / RH 75% ± 5%), freeze-thaw cycles (-20°C for 2 days, 25°C for 2 days as one cycle), and light. See Table 4 for the detailed plan and Table 5 for the results.

[0051] Table 4. Experimental plan of influencing factors

[0052] Table 5.1 Test results of influencing factors - high temperature results

[0053] Note: “ / ” means the item is not tested at that point.

[0054] Table 5.2 Test results of influencing factors - freeze-thaw cycle results

[0055] Note: “ / ” means the item is not tested at that point.

[0056] Table 5.3 Test results of influencing factors - Lighting results (composition A)

[0057] Note: “ / ” means the item is not tested at that point.

[0058] Table 5.4 Test results of influencing factors - Light results (composition B)

[0059] Note: “ / ” means the item is not tested at that point.

[0060] Experimental conclusion: Each composition has good stability under the test conditions of various influencing factors.

[0061] Example 3

[0062] According to the method of Example 1, different buffers were selected according to the composition in Table 6 to prepare comparative compositions, and the pH of the compositions before lyophilization and after reconstitution were measured.

[0063] Table 6 Composition

[0064] Experimental conclusion: The buffering effect of other types of pH buffers on the pH of the composition is not as good as that of histidine.

[0065] Example 4

[0066] According to the method of Example 1, according to the composition of Table 7, different amounts of excipients were selected to prepare compositions, and the pH of the compositions before lyophilization and after reconstitution were measured.

[0067] Table 7 Composition

[0068] Experimental conclusion: The pH buffering effect of each composition is good.

Claims

1. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, a solubilizer, and a buffer, wherein the buffer 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, and more preferably histidine.

2. The pharmaceutical composition according to claim 1, wherein the solubilizing agent is selected from one or more of polysorbate, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, sorbitan trioleate, bile salts, and lecithin, preferably polysorbate.

3. The pharmaceutical composition according to claim 1 or 2, further comprising a stabilizer, wherein the stabilizer is preferably selected from 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 regulator.

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

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the buffer 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 of formula I or a pharmaceutically acceptable salt thereof to the solubilizer 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 of 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 4-8, preferably 4.5-7, more preferably 5.5-6.

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 5-300 mg / ml, preferably 10-250 mg / ml.

11. A pharmaceutical composition comprising: 5-300 mg / ml of the compound represented by formula I or a pharmaceutically acceptable salt thereof; The stabilizer is mannitol, wherein 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 buffer is histidine, wherein 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 solubilizer is polysorbate, wherein the weight ratio of the compound represented by Formula I or its pharmaceutically acceptable salt to the solubilizer is 1:0.5-5; and optionally a pH adjuster, The pH of the composition is 5.5-6.

5.

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

13. A solid composition, which can be reconstituted or reconstituted to obtain the pharmaceutical composition according to claims 1-12. 14 . A freeze-dried composition, wherein the freeze-dried composition is obtained by freeze-drying the pharmaceutical composition according to claim 1 . 15 . A reconstituted solution, wherein the reconstituted solution is prepared by reconstituted the solid composition according to claim 13 or the freeze-dried composition according to 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 fungal infection.

17. 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 preventing, stabilizing, or inhibiting fungal growth or killing fungi.

18. A method for preparing the pharmaceutical composition according to claims 1-13, comprising: The step of mixing the compound represented by formula I or a pharmaceutically acceptable salt thereof with a solubilizer and a buffer.

19. The method according to claim 18, further comprising the step of freeze-drying.

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