Pharmaceutical compositions with enhanced properties, methods of making and uses thereof

Abstract

The present application relates to compositions and methods for the preparation of a spray dried amorphous solid dispersion comprising 5-{3-[4-(3-methyl-benzyloxy) thiophenyl] furan-2-yl} imidazolidine-2, 4-dione and hydroxypropyl beta-cyclodextrin. In particular, the present application relates to an improved spray drying process for producing amorphous solid dispersions with enhanced performance by using a co-solvent system and / or an antioxidant.

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 580,742, filed on 09 / 06 / 2023, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0002] This application relates to compositions and methods for preparing spray-dried amorphous solid dispersions comprising 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (hereinafter referred to as compound IVO) and hydroxypropyl β-cyclodextrin (HPBCD). In particular, this application relates to an improved spray-drying method for producing amorphous solid dispersions with enhanced properties using a co-solvent system and / or antioxidants. Background Technology

[0003] A series of compounds, including 5-[3-(4-benzyloxyphenylthio)furan-2-yl]imidazolidine-2,4-dione and analogues, are disclosed in U.S. Patent Application 2006 / 0041000. These compounds are designed to act as inhibitors of macrophage elastase. All of these compounds are hydantoin derivatives and their use as matrix metalloproteinase (MMP) inhibitors has been tested in vitro.

[0004] According to the method disclosed in U.S. Patent Application Publication No. 2019 / 0054178, approximately 10.0 g of compound IVO was weighed into a volumetric flask and then completely dissolved in 660 mL of methanol (MeOH) by sonication to obtain a clear solution (15.2 mg / mL) at 25 ± 5 °C. The solubility of IVO in methanol is approximately 15.2 mg / mL. After filtration through a 0.45 μm filter to remove potentially residual crystalline solids, approximately 30.05 g of HPBCD was added to the solution at a 25:75 (w / w) IVO / HPBCD ratio. The sample was stirred for 60 minutes to form a clear solution, which was then spray-dried to obtain an amorphous solid dispersion. The maximum solids content of the 1:3 (w / w) compound IVO / HPBCD complex prepared in MeOH solution (hereinafter referred to as ASD-01) was limited to only 60 mg / mL for use in the spray-drying process. The low solubility of IVO in methanol necessitates the use of a large amount of methanol to dissolve both IVO and HPBCD. Large quantities of methanol would make large-scale production of IVO / HPBCD complexes impractical.

[0005] Therefore, in order to optimize the spray drying process, it is desirable to find a suitable method to prepare a solution with a higher solids content using less organic solvent. Using less organic solvent is advantageous because it reduces process costs and minimizes process waste.

[0006] According to the method disclosed in U.S. Patent Application Publication No. 2019 / 0054178, the spray-dried powder of a 1:3 (w / w) complex of IVO / HPBCD (ASD-01) is amorphous, and the composition induces a larger area under the plasma concentration versus time (AUC) curve compared to applying the compound in the absence of cyclodextrin under the same amount and conditions. However, the IVO / HPBCD powder prepared using the disclosed method is not very stable, making it very difficult to develop pharmaceutical products using such IVO / HPBCD powder.

[0007] Therefore, there is still a need to develop methods for preparing IVO / HPBCD powders with better stability, so that the method can be scaled up and waste reduced and costs lowered. Summary of the Invention

[0008] This application provides an improved method for preparing a pharmaceutical composition comprising the compound 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (IVO) and hydroxypropyl β-cyclodextrin (HPBCD). This application also provides a co-solvent system comprising at least two different organic solvents and a method for producing a spray-dried amorphous solid dispersion (ASD) comprising IVO and HPBCD, wherein the ASD exhibits better physical and chemical properties compared to ASD obtained using a single solvent, such as methanol.

[0009] In one general aspect, this application provides a method for preparing a solid dispersion, the method comprising spray-drying a solution comprising (i) a compound 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (IVO), (ii) hydroxypropyl β-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

[0010] In some embodiments, the solubility of compound IVO in the solvent mixture is greater than 15 mg / mL at 25 ± 5 °C.

[0011] In some embodiments, the ratio of compound IVO to HPBCD in the solution is 1:99 to 99:1 (w / w), preferably 10:90 to 90:10 (w / w), more preferably 20:80 to 80:20 (w / w), and most preferably 25:75 to 75:25 (w / w).

[0012] In some embodiments, the ratio of compound IVO to HPBCD is approximately 25:75 (w / w).

[0013] In some embodiments, the organic solvent is selected from acetone, tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), dichloromethane (DCM), and ethyl acetate (EtOAc), as well as any combination thereof.

[0014] In some embodiments, the solvent mixture comprises a first organic solvent and a second organic solvent.

[0015] In some embodiments, the first organic solvent in the solvent mixture is methanol and the second organic solvent is acetone.

[0016] In some implementations, the ratio of methanol to acetone is 80:20 to 20:80 (v / v).

[0017] In some implementations, the ratio of methanol to acetone is 70:30 to 50:50 (v / v).

[0018] In some implementations, the ratio of methanol to acetone is approximately 60:40 (v / v).

[0019] In some embodiments, the solid dispersion is an amorphous solid dispersion (ASD) of the IVO / HPBCD complex.

[0020] In some embodiments, the solid dispersion has a particle size distribution of 0.1 to 25 μm, preferably 1 to 20 μm, more preferably 2 to 15 μm, and most preferably 2 to 10 μm, as expressed by Dv50.

[0021] In some embodiments, the solid dispersion has a particle size distribution of less than 15, represented by Dv90 / Dv10.

[0022] In some implementations, by 100 o Thermogravimetric analysis at C showed that the solid dispersion had a relative weight loss of less than 90%.

[0023] In some embodiments, the solid dispersion further comprises an antioxidant selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, panthenol (coenzyme Q), carotene, ascorbyl palmitate (AP), monothiol glycerol (MTG), DL-α-tocopherol, methoxy polyethylene glycol succinate (TPGS), and disodium edetate dihydrate (Na-EDTA).

[0024] In some implementations, the antioxidant is butylated hydroxyanisole (BHA).

[0025] In some embodiments, the solubility of the IVO / HPBCD complex in a solvent mixture is approximately 2 to 5.4 times that in a solvent system containing only methanol. Solubility comparisons can be assessed using methods known to those skilled in the art, such as any specific methods and conditions detailed herein.

[0026] In some implementations, the residual solvent in the solid dispersion is equal to or less than 5000 ppm.

[0027] In some embodiments, the solid dispersion contains one or more residual solvents, and each individual residual solvent is less than 5000 ppm.

[0028] In some embodiments, the residual solvent is acetone. In some embodiments, the residual solvent is methanol.

[0029] In some implementations, the solid dispersion has improved stability.

[0030] In some embodiments, the solid dispersion has improved chemical stability compared to a reference solid dispersion prepared by spray drying a solution containing (i) an IVO compound, (ii) hydroxypropyl β-cyclodextrin (HPBCD) and (iii) methanol.

[0031] In another general aspect, this application provides a method for preparing a solid dispersion, the method comprising spray-drying a solution comprising (i) a compound 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (IVO), (ii) hydroxypropyl β-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

[0032] In some embodiments, the ratio of compound IVO to HPBCD in the solution is 1:99 to 99:1 (w / w), preferably 10:90 to 90:10 (w / w), more preferably 20:80 to 80:20 (w / w), and most preferably 25:75 to 75:25 (w / w).

[0033] In some embodiments, the ratio of compound IVO to HPBCD is approximately 25:75 (w / w).

[0034] In some embodiments, the organic solvent is selected from acetone, tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), dichloromethane (DCM), and ethyl acetate (EtOAc), as well as any combination thereof.

[0035] In some embodiments, the solvent mixture comprises a first organic solvent and a second organic solvent.

[0036] In some embodiments, the first organic solvent in the solvent mixture is methanol and the second organic solvent is acetone.

[0037] In some embodiments, the solid dispersion is an amorphous solid dispersion (ASD) of the IVO / HPBCD complex.

[0038] In some implementations, by 100 o Thermogravimetric analysis at C showed that the solid dispersion had a relative weight loss of less than 90%.

[0039] In some embodiments, the solid dispersion further comprises an antioxidant selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, panthenol (coenzyme Q), carotene, ascorbyl palmitate (AP), monothiol glycerol (MTG), DL-α-tocopherol, methoxy polyethylene glycol succinate (TPGS), and disodium edetate dihydrate (Na-EDTA).

[0040] In some implementations, the antioxidant is butylated hydroxyanisole (BHA).

[0041] In some embodiments, the solubility of the IVO / HPBCD complex in a solvent mixture is approximately 2 to 5.4 times that in a solvent system containing only methanol. Solubility comparisons can be assessed using methods known to those skilled in the art, such as any specific methods and conditions detailed herein.

[0042] In some implementations, the residual solvent in the solid dispersion is equal to or less than 5000 ppm.

[0043] In some embodiments, the solid dispersion contains one or more residual solvents, and each individual residual solvent is less than 5000 ppm.

[0044] In some embodiments, the residual solvent is acetone. In some embodiments, the residual solvent is methanol.

[0045] In some implementations, the solid dispersion has improved stability.

[0046] In some embodiments, the solid dispersion exhibits improved chemical stability compared to a reference solid dispersion prepared by spray drying a solution containing (i) an IVO compound, (ii) hydroxypropyl β-cyclodextrin (HPBCD) and (iii) methanol.

[0047] In another general aspect, this application provides a solid dispersion comprising (i) the compound 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (IVO), (ii) hydroxypropyl β-cyclodextrin (HPBCD) and (iii) acetone.

[0048] In some implementations, the acetone content in the solid dispersion is less than 5,000 ppm.

[0049] In some embodiments, the acetone in the solid dispersion is in the range of 100 ppm to 5,000 ppm.

[0050] In some embodiments, the acetone in the solid dispersion is in the range of 200 ppm to 4,000 ppm.

[0051] In some embodiments, the acetone in the solid dispersion is in the range of 200 ppm to 3,500 ppm.

[0052] In some embodiments, the ratio of IVO to HPBCD in the solid dispersion is 1:99 to 99:1 (w / w), preferably 10:90 to 90:10 (w / w), more preferably 20:80 to 80:20 (w / w), and most preferably 25:75 to 75:25 (w / w).

[0053] In some implementations, the ratio of IVO to HPBCD is approximately 25:75 (w / w).

[0054] In some embodiments, the solid dispersion has a particle size distribution of 0.1 to 25 μm, preferably 1 to 20 μm, more preferably 2 to 15 μm, and most preferably 2 to 10 μm, as expressed by Dv50.

[0055] In some embodiments, the solid dispersion has a particle size distribution of less than 15, represented by Dv90 / Dv10.

[0056] In some embodiments, the solid dispersion contains one or more residual solvents, and each individual residual solvent is less than 5000 ppm.

[0057] In some implementations, by 100 o Thermogravimetric analysis at C showed that the solid dispersion had a relative weight loss of less than 90%.

[0058] In some embodiments, the solid dispersion further comprises an antioxidant selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, panthenol (coenzyme Q), carotene, ascorbyl palmitate (AP), monothiol glycerol (MTG), DL-α-tocopherol, methoxy polyethylene glycol succinate (TPGS), and disodium edetate dihydrate (Na-EDTA).

[0059] In some implementations, the antioxidant is butylated hydroxyanisole (BHA).

[0060] In some implementations, the solid dispersion has improved stability.

[0061] In some embodiments, the solid dispersion has improved chemical stability compared to a reference solid dispersion prepared by spray drying a solution containing (i) an IVO compound, (ii) hydroxypropyl β-cyclodextrin (HPBCD) and (iii) methanol.

[0062] In some implementations, the total IVO-related impurities generated by a solid dispersion stored at 60 °C for one month are less than 0.5% relative to the weight of IVO.

[0063] In some embodiments, the solid dispersion is prepared by a method comprising a spray-dried solution to provide a powder composition, wherein the solution comprises (i) a compound 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (IVO), (ii) hydroxypropyl β-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

[0064] In another general aspect, this application provides pharmaceutical compositions comprising the solid dispersions described herein and their uses. Attached Figure Description

[0065] The foregoing summary of the invention and the following detailed description of preferred embodiments of the present application will be better understood when read in conjunction with the accompanying drawings. However, it should be understood that the present application is not limited to the specific embodiments shown in the drawings.

[0066] Figure 1 X-ray powder diffraction (XRPD) of IVO / HPBCD in ADS-01 is shown.

[0067] Figure 2 X-ray powder diffraction (XRPD) of IVO / HPBCD in ADS-04 is shown.

[0068] Figure 3FT-IR characterizations of IVO, HPBCD, and ASD-01 to ASD-05 are shown.

[0069] Figure 4 Initial dissolution profiles for ASD-01, ASD-02, ASD-04, and ASD-05 (200 mg powder / capsule) are shown.

[0070] Figure 5 The dissolution profiles of ASD-01, ASD-02, ASD-04 and ASD-05 (200 mg powder / capsule) under pressure conditions (60°C, open) are shown. Detailed Implementation

[0071] Various publications, articles, and patents are cited or described in the background art and throughout the specification; each of these references is incorporated herein by reference in its entirety. Discussions of documents, actions, materials, devices, articles, etc., already included in this specification are intended to provide context for this disclosure. Such discussions are not an admission that any or all of these matters constitute part of the prior art with respect to this disclosure.

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Additionally, certain terms used herein have the meanings set forth in the specification. All patents, published patent applications, and publications cited herein are incorporated herein by reference as if fully set forth herein.

[0073] It must be noted that, unless the context clearly specifies otherwise, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural references.

[0074] Unless otherwise stated, the term "at least" preceding a series of elements should be understood to refer to each element in the series. For example, the statement "at least A, B, and C" means that each of A, B, and C is present. The term "at least one" preceding a series of elements should be understood to refer to a single element in the series or any combination of two or more elements in the series. For example, the statement "at least one of A, B, and C" means that only A is present, only B is present, only C is present, both A and B are present, both A and C are present, both B and C are present, or each of A, B, and C is present. Depending on the context, "at least one" preceding a series of elements may also cover the case where any one or more elements are present in more than one instance; for example, "at least one of A, B, and C" may also cover the case where A is present alone or in combination with any one or more of elements B and C.

[0075] As used herein, the connecting term “and / or” between multiple elements is understood to include both individual and combined options. For example, in the case of two elements combined by “and / or”, the first option refers to the applicability of the first element in the absence of the second element. The second option refers to the applicability of the second element in the absence of the first element. The third option refers to the applicability of the first and second elements coexisting. Any of these options is understood to fall within this meaning and thus satisfy the requirement of the term “and / or” as used herein. The applicability of more than one option coexisting is also understood to fall within this meaning and thus satisfy the requirement of the term “and / or”. Unless otherwise stated, any numerical value, such as concentrations or concentration ranges as described herein, should be understood to be modified by the term "about" in all cases. Therefore, numerical values ​​generally include ±10% of the stated value. For example, the statement "10 times" includes both 9 times and 11 times. Unless the context clearly indicates otherwise, as used herein, the use of numerical ranges explicitly includes all possible subranges, all individual numerical values ​​within that range, including integers and fractions of that value within the range.

[0076] As used herein, “subject” means any animal that will be treated, or has been treated, by the method according to the embodiments of this application, preferably a mammal, and most preferably a human. As used herein, the term “mammal” covers any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, etc., more preferably humans.

[0077] As used herein, “Dv10”, “Dv50” and “Dv90” refer to particle size distribution. Specifically, “Dv10” means that 10% of the particles in the powder are smaller than this size, “Dv50” means that 90% of the total particles are smaller than this size, and “Dv90” means that 50% of the total particles are smaller than this size.

[0078] Methods for preparing solid dispersions

[0079] In one general aspect, this document provides a method for preparing a solid dispersion, the method comprising spray drying a solution to provide a powder composition, wherein the solution comprises (i) a compound 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (IVO), (ii) hydroxypropyl β-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

[0080] In some embodiments, the method further includes drying the powder composition to provide a solid dispersion.

[0081] As used herein, the terms “solid dispersion” and “dry powder composition” are interchangeable and refer to the final product after the spray drying step and further drying steps.

[0082] In some embodiments, the spray-dried powder composition is dried under vacuum conditions at approximately 25-70°C. o C, for example, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70. o Further drying at C or any temperature in between.

[0083] In some embodiments, the spray-dried powder composition is further air-dried.

[0084] According to the embodiments of this application, the organic solvent is a carbon-based substance capable of dissolving or dispersing IVO and / or HPBCD.

[0085] In some embodiments, the organic solvent is volatile. Preferably, the organic solvent is selected from acetone, tetrahydrofuran, methanol (MeOH), ethanol (EtOH), dichloromethane (DCM), ethyl acetate (EtOAc), and any combination thereof.

[0086] In some embodiments, the IVO compound has a higher solubility in the solvent mixture than in a single solvent, such as methanol. In some embodiments, the IVO compound has a solubility greater than 15 mg / mL in the solvent mixture at 25 ± 5 °C.

[0087] In some embodiments, the ratio of compound IVO to HPBCD in the solution is 1:99 to 99:1 (w / w), preferably 10:90 to 90:10 (w / w), more preferably 20:80 to 80:20 (w / w), and most preferably 25:75 to 75:25 (w / w).

[0088] In some embodiments, the ratio of compound IVO to HPBCD is approximately 25:75 (w / w).

[0089] In some embodiments, the solvent mixture comprises a first organic solvent and a second organic solvent.

[0090] In some embodiments, the first organic solvent in the solvent mixture is methanol and the second organic solvent is acetone.

[0091] In some implementations, the ratio of methanol to acetone is 99:1 to 1:99 (v / v).

[0092] In some implementations, the ratio of methanol to acetone is 70:30 to 50:50 (v / v).

[0093] In some implementations, the ratio of methanol to acetone is approximately 60:40 (v / v).

[0094] In some embodiments, the solids content (IVO + HPBCD) of the solution is 100-400 mg / ml, such as 100, 150, 200, 250, 300 or 400 mg / ml, or any value in between. As used herein, solids content refers to the total amount of IVO and HPBCD in the solution.

[0095] In some implementations, the inlet temperature of the spray drying process is approximately 60-100°C. o C, preferably 70-90 o C, more preferably 80 o C.

[0096] In some implementations, the outlet temperature of the spray drying process is approximately 40-80°C. o C, preferably 50-70 o C, more preferably 60 o C.

[0097] In some embodiments, the solid dispersion is an amorphous solid dispersion (ASD) of the IVO / HPBCD complex.

[0098] In some embodiments, the solid dispersion has a particle size distribution of 0.1 to 25 μm, preferably 1 to 20 μm, more preferably 2 to 15 μm, and most preferably 2 to 10 μm, as expressed by Dv50.

[0099] In some embodiments, the solid dispersion has a particle size distribution of less than 15, represented by Dv90 / Dv10.

[0100] In some implementations, by 100 o Thermogravimetric analysis at C showed that the solid dispersion had a relative weight loss of less than 90%.

[0101] In some embodiments, the solid dispersion further comprises an antioxidant selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, panthenol (coenzyme Q), carotene, ascorbyl palmitate (AP), monothiol glycerol (MTG), DL-α-tocopherol, methoxy polyethylene glycol succinate (TPGS), and disodium edetate dihydrate (Na-EDTA).

[0102] In some embodiments, the antioxidant is selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, panthenol (coenzyme Q), carotene, and ascorbyl palmitate.

[0103] In some implementations, the antioxidant is butylated hydroxyanisole (BHA).

[0104] In some embodiments, the solubility of the IVO / HPBCD complex in a solvent mixture is approximately 2 to 5.4 times that in a solvent system containing only methanol. Solubility comparisons can be assessed using methods known to those skilled in the art, such as any specific methods and conditions detailed herein.

[0105] In some embodiments, the total residual solvent in the powder composition is less than 50,000 ppm.

[0106] In some embodiments, the residual solvent is methanol or acetone or a mixture thereof.

[0107] In some implementations, the residual solvent in the solid dispersion is equal to or less than 5000 ppm.

[0108] In some embodiments, the solid dispersion contains one or more residual solvents, and each individual residual solvent is less than 5000 ppm.

[0109] In some embodiments, the residual solvent is acetone. In some embodiments, the residual solvent is methanol.

[0110] In some implementations, the solid dispersion has improved stability.

[0111] In some embodiments, the solid dispersion has improved chemical stability compared to a reference solid dispersion prepared by spray drying a solution containing (i) an IVO compound, (ii) hydroxypropyl β-cyclodextrin (HPBCD) and (iii) methanol.

[0112] In some implementations, in 60 o After being stored at C for one month, the solid dispersion produced fewer than 80% of the impurities produced by the reference solid dispersion, which was prepared by spray drying a solution containing (i) compound IVO, (ii) hydroxypropyl β-cyclodextrin (HPBCD) and (iii) methanol.

[0113] In some implementations, the total IVO-related impurities generated by a solid dispersion stored at 60 °C for one month are less than 0.5% relative to the weight of IVO.

[0114] solid dispersions

[0115] In another general aspect, this document provides a method for preparing a solid dispersion comprising spray drying a solution to provide a powder composition, wherein the solution comprises (i) a compound 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (IVO), (ii) hydroxypropyl β-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

[0116] In some embodiments, the method further includes drying the powder composition to provide a solid dispersion.

[0117] In some embodiments, the spray-dried powder composition is dried under vacuum conditions at approximately 25-70°C. o C, for example, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70. o Dry at C or any temperature in between.

[0118] In some embodiments, the powder composition is air-dried.

[0119] In some embodiments, the organic solvent is volatile. Preferably, the organic solvent is selected from acetone, tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), dichloromethane (DCM), and ethyl acetate (EtOAc), as well as any combination thereof.

[0120] In some embodiments, the IVO compound has a higher solubility in the solvent mixture than in a single solvent, such as methanol. In some embodiments, the IVO compound has a solubility greater than 15 mg / mL in the solvent mixture at 25 ± 5 °C.

[0121] In some embodiments, the ratio of compound IVO to HPBCD in the solution is 1:99 to 99:1 (w / w), preferably 10:90 to 90:10 (w / w), more preferably 20:80 to 80:20 (w / w), and most preferably 25:75 to 75:25 (w / w).

[0122] In some embodiments, the ratio of compound IVO to HPBCD is approximately 25:75 (w / w).

[0123] In some embodiments, the solvent mixture comprises a first organic solvent and a second organic solvent.

[0124] In some embodiments, the first organic solvent in the solvent mixture is methanol and the second organic solvent is acetone.

[0125] In some implementations, the ratio of methanol to acetone is 99:1 to 1:99 (v / v).

[0126] In some implementations, the ratio of methanol to acetone is 70:30 to 50:50 (v / v).

[0127] In some implementations, the ratio of methanol to acetone is approximately 60:40 (v / v).

[0128] In some embodiments, the solids content of the solution is 100-400 mg / ml, such as 100, 150, 200, 250, 300, or 400 mg / ml, or any value in between. As used herein, solids content refers to the total amount of IVO and HPBCD in the solution.

[0129] In some implementations, the inlet temperature of the spray drying process is approximately 60-100°C. o C, preferably 70-90 o C, more preferably 80 o C.

[0130] In some implementations, the outlet temperature of the spray drying process is approximately 40-80°C. o C, preferably 50-70 o C, more preferably 60 o C.

[0131] In some embodiments, the solid dispersion is an amorphous solid dispersion (ASD) of the IVO / HPBCD complex.

[0132] In some embodiments, the solid dispersion has a particle size distribution of 0.1 to 25 μm, preferably 1 to 20 μm, more preferably 2 to 15 μm, and most preferably 2 to 10 μm, as expressed by Dv50.

[0133] In some embodiments, the solid dispersion has a particle size distribution of less than 15, represented by Dv90 / Dv10.

[0134] In some implementations, by 100 o Thermogravimetric analysis at C showed that the solid dispersion had a relative weight loss of less than 90%.

[0135] In some embodiments, the solid dispersion further comprises an antioxidant selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, panthenol (coenzyme Q), carotene, ascorbyl palmitate (AP), monothiol glycerol (MTG), DL-α-tocopherol, methoxy polyethylene glycol succinate (TPGS), and disodium edetate dihydrate (Na-EDTA).

[0136] In some embodiments, the antioxidant is selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, panthenol (coenzyme Q), carotene, and ascorbyl palmitate.

[0137] In some implementations, the antioxidant is butylated hydroxyanisole (BHA).

[0138] In some embodiments, the solubility of the IVO / HPBCD complex in a solvent mixture is approximately 2 to 5.4 times that in a solvent system containing only methanol. Solubility comparisons can be assessed using methods known to those skilled in the art, such as any specific methods and conditions detailed herein.

[0139] In some embodiments, the total residual solvent in the powder composition is less than 50,000 ppm.

[0140] In some embodiments, the residual solvent is methanol or acetone or a mixture thereof.

[0141] In some embodiments, the residual solvent in the solid dispersion is equal to or less than 5000 ppm.

[0142] In some embodiments, the solid dispersion contains one or more residual solvents, and each individual residual solvent is less than 5000 ppm.

[0143] In some embodiments, the residual solvent is acetone. In some embodiments, the residual solvent is methanol.

[0144] In some implementations, the solid dispersion has improved stability.

[0145] In some embodiments, the solid dispersion has improved chemical stability compared to a reference solid dispersion prepared by spray drying a solution containing (i) an IVO compound, (ii) hydroxypropyl β-cyclodextrin (HPBCD) and (iii) methanol.

[0146] In some implementations, in 60 oAfter being stored at C for one month, the solid dispersion produced fewer than 80% of the impurities produced by a reference solid dispersion, which was prepared by spray drying a solution containing (i) compound IVO, (ii) hydroxypropyl β-cyclodextrin (HPBCD) and (iii) methanol.

[0147] In some implementations, the total IVO-related impurities generated by a solid dispersion stored at 60 °C for one month are less than 0.5% relative to the weight of IVO.

[0148] In another general aspect, this application provides a solid dispersion comprising (i) the compound 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (IVO), (ii) hydroxypropyl β-cyclodextrin (HPBCD), and (iii) acetone.

[0149] In some implementations, the acetone content in the solid dispersion is less than 5,000 ppm.

[0150] In some embodiments, the acetone in the solid dispersion is in the range of 100 ppm to 5,000 ppm.

[0151] In some embodiments, the acetone in the solid dispersion is in the range of 200 ppm to 5,000 ppm.

[0152] In some embodiments, the acetone in the solid dispersion is in the range of 200 ppm to 4,000 ppm.

[0153] In some embodiments, the acetone in the solid dispersion is in the range of 200 ppm to 3,500 ppm.

[0154] In some embodiments, the ratio of IVO to HPBCD in the solution is 1:99 to 99:1 (w / w), preferably 10:90 to 90:10 (w / w), more preferably 20:80 to 80:20 (w / w), and most preferably 25:75 to 75:25 (w / w).

[0155] In some implementations, the ratio of IVO to HPBCD is approximately 25:75 (w / w).

[0156] In some embodiments, the solid dispersion has a particle size distribution of 0.1 to 25 μm, preferably 1 to 20 μm, more preferably 2 to 15 μm, and most preferably 2 to 10 μm, as expressed by Dv50.

[0157] In some embodiments, the solid dispersion has a particle size distribution of less than 15, represented by Dv90 / Dv10.

[0158] In some embodiments, the solid dispersion contains one or more residual solvents other than acetone, and each individual residual solvent is equal to or less than 5000 ppm.

[0159] In some implementations, each individual residual solvent is less than 5000 ppm.

[0160] In some implementations, the residual solvent is methanol.

[0161] In some implementations, by 100 o Thermogravimetric analysis at C showed that the solid dispersion had a relative weight loss of less than 90%.

[0162] In some embodiments, the solid dispersion further comprises an antioxidant selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, panthenol (coenzyme Q), carotene, ascorbyl palmitate (AP), monothiol glycerol (MTG), DL-α-tocopherol, methoxy polyethylene glycol succinate (TPGS), and disodium edetate dihydrate (Na-EDTA).

[0163] In some embodiments, the antioxidant is selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, panthenol (coenzyme Q), carotene, and ascorbyl palmitate.

[0164] In some implementations, the antioxidant is butylated hydroxyanisole (BHA).

[0165] In some implementations, the solid dispersion has improved stability.

[0166] In some embodiments, the solid dispersion has improved chemical stability compared to a reference solid dispersion prepared by spray drying a solution containing (i) an IVO compound, (ii) hydroxypropyl β-cyclodextrin (HPBCD) and (iii) methanol.

[0167] In some implementations, in 60 o After being stored at C for one month, the solid dispersion produced fewer than 80% of the impurities produced by the reference solid dispersion, which was prepared by spray drying a solution containing (i) compound IVO, (ii) hydroxypropyl β-cyclodextrin (HPBCD) and (iii) methanol.

[0168] In some implementations, the total IVO-related impurities generated by a solid dispersion stored at 60°C for one month are less than 0.5% relative to the weight of IVO.

[0169] In some embodiments, the solid dispersion is prepared by a method comprising a spray-dried solution to provide a powder composition, wherein the solution comprises (i) a compound 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (IVO), (ii) hydroxypropyl β-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

[0170] In some embodiments, the method further includes drying the powder composition to provide a solid dispersion.

[0171] In some embodiments, the method further includes operating under vacuum conditions at approximately 25-70°C. o C, for example, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70. o Dry powder composition at C or any temperature between C and C.

[0172] In some embodiments, the method further includes air-drying the powder composition.

[0173] In some embodiments, the total residual solvent in the powder composition is less than 50,000 ppm.

[0174] In some embodiments, the residual solvent is acetone or methanol or a mixture thereof. In some embodiments, the residual solvent is methanol.

[0175] Pharmaceutical compositions and their uses

[0176] In another general aspect, this document provides pharmaceutical compositions comprising solid dispersions as described herein.

[0177] The pharmaceutical compositions of this application may also contain a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier is non-toxic and should not interfere with the efficacy of the active ingredient. A pharmaceutically acceptable carrier may include one or more excipients, such as binders, disintegrants, swelling agents, suspending agents, emulsifiers, wetting agents, lubricants, flavoring agents, sweeteners, preservatives, dyes, solubilizers, and coatings. The precise properties of the carrier or other materials may depend on the route of administration, such as intramuscular, intradermal, subcutaneous, oral, intravenous, skin, mucosal (e.g., intestinal), intranasal, or intraperitoneal routes. For liquid injectable formulations, such as suspensions and solutions, suitable carriers and additives include water, glycols, oils, alcohols, preservatives, colorants, etc. For solid oral formulations, such as powders, capsules, tablets, soft capsules, and tablets, suitable carriers and additives include starch, sugars, diluents, granulators, lubricants, binders, disintegrants, etc. For nasal spray / inhaler mixtures, aqueous solutions / suspensions may contain water, glycols, oils, emollients, stabilizers, humectants, preservatives, fragrances, and other suitable carriers and additives.

[0178] The pharmaceutical compositions of this application can be formulated in any manner suitable for administration to a subject to facilitate administration and improve efficacy, including but not limited to oral (enteral) administration and parenteral injection. Parenteral injection includes intravenous injection or infusion, subcutaneous injection, intradermal injection, and intramuscular injection. The compositions can also be formulated for other routes of administration, including via mucosa, eye, rectum, long-acting implantation, sublingual administration, under the tongue, through the oral mucosa bypassing the portal vein circulation, inhalation, or nasal administration.

[0179] In some implementations, the pharmaceutical composition is formulated for oral administration.

[0180] The form, route of administration, dosage, and regimen of a pharmaceutical composition depend on the condition being treated, such as the severity of the disease, the patient's age, weight, and sex. Pharmaceutical compositions can be formulated for different modes of administration, such as topical, oral, intranasal, parenteral, intraocular, intravenous, intramuscular, or subcutaneous.

[0181] In another aspect, a method for preparing a pharmaceutical composition is provided, comprising combining a solid dispersion as described herein with at least one pharmaceutically acceptable carrier. In view of this disclosure, pharmaceutical compositions can be prepared by any method known in the art, and those skilled in the art will be familiar with such techniques for preparing pharmaceutical compositions. For example, a pharmaceutical composition according to this application can be prepared by mixing a solid dispersion with one or more pharmaceutically acceptable carriers according to conventional pharmaceutical compounding techniques, including but not limited to conventional mixing, dissolving, granulation, emulsification, encapsulation, embedding, or lyophilization processes.

[0182] How to use

[0183] This application also provides methods for inhibiting matrix metalloproteinases (MMPs) and treating MMP-mediated diseases using the solid dispersions or pharmaceutical compositions of this application.

[0184] Matrix metalloproteinases (MMPs), also known as matrices, are a group of enzymes that collectively are responsible for the degradation of most extracellular matrix proteins during organogenesis, growth, and normal tissue transition. MMPs are calcium-dependent zinc-containing endopeptidases and belong to a larger family of proteases known as the zinc superfamily. While capable of degrading extracellular matrix proteins, MMPs can also process many bioactive molecules and are known to be involved in, for example, the cleavage of cell surface receptors, the release of apoptotic ligands, and the inactivation of chemokines / cytokines. MMPs are also believed to play a major role in cellular behaviors such as cell proliferation, migration (adhesion / dispersion), differentiation, angiogenesis, apoptosis, and host defense. MMPs are inhibited by specific endogenous tissue inhibitors (TIMPs), a family of four protease inhibitors: TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Examples of MMPs include, but are not limited to, MMP-1 (interstitial collagenase), MMP-2 (gelatinase-A), MMP-3 (matrilylic acid 1), MMP-7 (matrilylysin), MMP-8 (neutrophil collagenase), MMP-9 (gelatinase-B), MMP-10 (matrilylic acid 2), MMP-11 (matrilylic acid 3), MMP-12 (macrophage elastase), MMP-13 (collagenase 3), and MMP-14 (MT1-MMP).

[0185] In a preferred embodiment, the solid dispersion or pharmaceutical composition of this application is capable of inhibiting macrophage elastase (MMP-12) and / or treating diseases mediated by MMP-12. MMP-12, also known as macrophage metalloelastase (MME) or macrophage elastase (ME), is encoded by the MMP12 gene in humans.

[0186] In other embodiments, the solid dispersion or pharmaceutical composition of this application is capable of selectively inhibiting MMP-12. When the terms "selective," "selectivity," and "selectively" are used in the context of binding to or inhibiting the activity of a particular MMP, they mean that the compound binds to or inhibits the activity of that particular MMP to a greater extent than the compound binds to or inhibits the activity of other MMPs. For example, compounds that are selective for MMP-12 inhibit the activity of MMP-12 to a greater extent than other MMPs, such as MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-13, MMP-14, etc.

[0187] This application also provides a method for treating MMP-12-mediated diseases. According to embodiments of the invention, the method for treating MMP-12-mediated diseases includes administering a therapeutically effective amount of the solid dispersion or pharmaceutical composition of this application to a subject.

[0188] As used herein, the terms “treat,” “treating,” and “treatment” are intended to refer to improving or reversing at least one measurable physical parameter associated with MMP-12-mediated disease, which may or may not be identifiable in the subject. The terms “treat,” “treating,” and “treatment” may also refer to inducing remission of MMP-12-mediated disease, preventing the progression of MMP-12-mediated disease, or at least slowing its progression. In specific implementations, “treat,” “treating,” and “treatment” refer to reducing, preventing, or shortening the duration of one or more symptoms associated with MMP-12-mediated disease. In specific implementations, the terms “treat,” “treating,” and “treatment” refer to preventing recurrence of MMP-12-mediated disease. In specific implementations, “treat,” “treating,” and “treatment” refer to an increase in the survival rate of subjects with MMP-12-mediated disease. In specific implementations, “treat,” “treating,” and “treatment” refer to the elimination of MMP-12-mediated disease in subjects.

[0189] As used herein, a "therapeutic effective amount" refers to the amount of a solid dispersion or pharmaceutical composition that elicits a biological or pharmaceutical response sought by researchers, veterinarians, physicians, or otherwise in an tissue system or subject, which may include relief of symptoms of a disease or condition being treated. Therapeutic effective amounts can vary depending on various factors, such as the subject's physical condition, age, weight, health, etc., and the specific disease to be treated. In view of this disclosure, those skilled in the art can readily determine the therapeutic effective amount.

[0190] In specific embodiments of this application, a therapeutically effective amount refers to an amount of the solid dispersion or pharmaceutical composition of this application sufficient to inhibit MMP-12 or treat MMP-12-mediated diseases. MMP-12-mediated diseases that can be treated according to the methods of this application include, but are not limited to, asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, nonalcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Allport syndrome, and nephritis.

[0191] Example

[0192] The following examples illustrate the compositions of this application. These examples are not intended to limit application, but rather to teach how to prepare usable compositions.

[0193] Example 1: Synthesis of compound IVO

[0194] The synthesis of compound IVO, namely 5-[3-(4-benzyloxyphenylthio)furan-2-yl]imidazolidine-2,4-dione, was carried out according to the method disclosed in U.S. Patent Application Publication No. 2006 / 0041000.

[0195] Example 2: Determination of IVO / HPBCD concentration in co-solvent

[0196] Weigh approximately 2 mg of compound IVO and place it in a glass vial. Gradually add the solvents shown below and visually observe the approximate solubility. Table 1 lists the solubility of IVO at 25±5 μL. o Solubility of HPBCD in different solvents at C. Furthermore, Table 2 lists the solubility of HPBCD at 25±5 ppm in different solvents. o Solubility of C in different solvents.

[0197] Table 1. Solubility of IVO in different solvents

[0198] Table 2. Solubility of HPBCD in different solvents

[0199] IVO is not very soluble in MeOH, but its solubility in acetone is more than eight times that in MeOH. HPBCD is more soluble in MeOH than in acetone. Surprisingly, when 100 mg of IVO and 300 mg of HPBCD were weighed, placed in glass vials, and a co-solvent was added, the solubility of IVO and HPBCD was found to be much higher than their solubility in individual solvents. Table 3 lists the solubility of 100 mg of IVO and 300 mg of HPBCD in 25±5 mL of MeOH. o Solubility of C in different co-solvent systems.

[0200] Table 3. Solubility of IVO and HPBCD in different cosolvents

[0201] Table 4 lists the compositions of different IVO / HPBCD dry powders prepared using different co-solvents. A total weight of 4 g of materials with different IVO / HPBCD ratios was dissolved in different co-solvents. After solvent evaporation, 4 g of dry powder was tested in 10 ml of water to determine their solubility in water. Table 5 lists the water solubility results of IVO in different dry powders at 25±5 °C.

[0202] Table 4: Compositions for preparing IVO / HPBCD dry powder in different co-solvents

[0203] Table 5: Solubility of different IVO / HPBCD dry powders in water after solvent evaporation

[0204] To determine the maximum solids content in MeOH and 60 / 40 MeOH / acetone (v / v), IVO and HPBCD were weighed in a fixed ratio of 1:3 IVO / HPBCD (w / w) and placed in glass vials. Solvent was then added to test solubility. Table 6 lists the maximum solids content of 1:3 IVO / HPBCD (w / w) in MeOH and 60 / 40 MeOH / acetone (v / v). Surprisingly, the solubility of IVO / HPBCD in the co-solvent (60 / 40 MeOH / acetone) was >5 times that in MeOH alone.

[0205] Table 6. Solubility of 1:3 IVO / HPBCD (w / w) in MeOH and 60 / 40 MeOH / acetone (v / v)

[0206] Example 3: Preparation of a complex of compound IVO and HPBCD by solvent evaporation

[0207] According to Table 7, approximately 10.0 g of compound IVO was weighed and placed in a volumetric flask, and completely dissolved in a sufficient volume of MeOH or MeOH / acetone (v / v) by sonication to obtain a clear solution. After filtration through a 0.45 μm filter membrane to remove any potential residual crystalline solids, approximately 30.0 g of HPBCD (Ashland) was added to the solution at a ratio of 25:75 (w / w) IVO / HPBCD. The sample was stirred for 60 minutes to form a clear solution, and then spray-dried to obtain an amorphous solid dispersion. The sample obtained by spray drying (micro-spray dryer B-290, BUCHI) was further dried under vacuum at 30 °C for 24 hours.

[0208] Table 7. Details of IVO / HPBCD ASD

[0209] Table 8 lists the preparation parameters and names of the compound complexes. X-ray powder diffraction (XRPD) results based on ASD-01 and ASD-04 ( Figure 1 and Figure 2 The IVO:HPBCD (1:3, w / w) complex prepared by spray drying is amorphous. Higher solids content results in higher yields of spray-dried samples. Figure 3 This shows the molecular fingerprint (650 cm⁻¹) of the sample analyzed by Fourier transform infrared (FT-IR) spectroscopy. -1 -4000cm -1 (ThermoNicolet 5700 equipped with a Continuμm microscope). Compared to ASD-01, none of the spray-dried samples showed conformational changes in their spectra.

[0210] Table 8. Spray Drying Parameter Settings and Results

[0211] Example 4: Particle Size Distribution (PSD) Measurement

[0212] The particle size of the samples was measured using a Malvern Mastersizer 3000 laser diffractometer. The measurement mode was set to dry dispersion system. Table 9 lists the parameters, and Table 10 lists the measurement results. The higher the solids content, the greater the PSD of the spray-dried solids.

[0213] Table 9. Parameters of PSD Measurement Mode

[0214] Table 10. Results of PSD Measurements

[0215] Example 5: Thermogravimetric Analysis (TGA)

[0216] This study aimed to assess the thermal stability of the samples. The tests were performed using a TA instrument (TGA Q50). Samples were weighed and placed in an open platinum pan, then heated from room temperature to ~300 °C at a rate of 10 °C / min. Table 11 lists the weight loss of the samples from 36 °C to 200 °C. Except for IVO, which showed weight loss starting at 150 °C, the other groups showed weight loss starting at 38 °C. Table 12 lists the relative weight loss of the samples up to 150 °C. ASD-01 was heated to reveal its 100% weight loss at 94 °C compared to 150 °C (data not shown). ASD-02, ASD-03, ASD-04, and ASD-05 showed 100% weight loss between 120 °C and 140 °C. Most of these weight losses are related to the residual solvent MeOH in ASD-01 and the MeOH / acetone mixture in other ASDs. The residual methanol in ASD-01 was approximately 2.4% or less. The residual methanol and acetone in ASD-02, ASD-03, ASD-04 and ASD-05 were approximately 0.58% and 2.3%, respectively.

[0217] Table 11. Weight loss results from TGA analysis

[0218] Table 12. Results of relative weight loss before 150℃

[0219] Example 6: Stability test under 60°C pressure (open) conditions

[0220] This study aimed to evaluate the stability of the samples. 200 mg of spray-dried powder from each sample was filled into capsules (size 0). The capsules were tested under pressure conditions (60°C, open). After 2 weeks and 1 month, the total amount of IVO-related impurities or degradation products generated in the samples was analyzed by HPLC. As shown in Table 13, ASD-01 unexpectedly generated more total impurities compared to ASD-02, ASD-04, or ASD-05. The solid dispersions prepared using a solvent combination showed improved chemical stability compared to the reference solid dispersions prepared by spray drying a solution using methanol alone. The only difference between ASD-01 and the other ASDs is that ASD-02, ASD-04, or ASD-05 contain a small amount of acetone. ASD-01 contains approximately 2.4% or less methanol, while ASD-02, ASD-04, or ASD-05 contain approximately 2.3% acetone in addition to methanol. Surprisingly, these trace amounts of residual acetone in the IVO / HPBCD solid dispersion made the spray-dried powder more stable.

[0221] Table 13. Results of total impurities under pressure conditions (60°C, open).

[0222] Table 14 lists the dissolution methods used to evaluate the dissolution curves of the samples under pressure conditions. Figure 4 This indicates that ASD-01 exhibits a slower dissolution curve under pressure conditions.

[0223] Table 14. Dissolution Method Parameters

[0224] Example 7: Comparison of ASD-04 and ASD-01 in rats

[0225] Purpose

[0226] The objective of this study was to evaluate the pharmacokinetic profiles of IVO formulations in male Sprague-Dawley rats within 8 hours of administration via forced feeding (PO), with the aim of determining and comparing the oral bioavailability of the following formulations: ASD-01 and ASD-04. Plasma concentrations of the IVOs were determined by LC-MS / MS.

[0227] Regulatory requirements

[0228] This study was not conducted in accordance with GLP guidelines. It was conducted in accordance with sound scientific practice and followed all applicable standard operating procedures of the testing organization.

[0229] Research Plan

[0230] Table 15. Draft Research Plan

[0231] Study on date marking method

[0232] The first day of adaptation was designated as Day 1 prior to testing, and subsequent days were numbered consecutively until the first dosing day. The dosing day was designated as Day 1 of the study phase (Day 1 or D1).

[0233] Test substance related information

[0234] Table 16. Raw materials of the test substance 1

[0235] Table 17. Test Substance Raw Material 2

[0236] Dosage Formulation Preparation

[0237] Prepare the dosage form on the day of administration. Prepare 30 mL of each formulation in the following steps: 1) Weigh the test material in the following composition, with the allowable measurement error set at ±5% of the target weight. For each test material, weigh the powder directly in a cylinder of appropriate size, or weigh it and then transfer it to a cylinder.

[0238] Table 18. Dosage Formulation Preparation

[0239] 2) Place the stir bar into the cylinder. Add sufficient water for injection (WFI) (up to 4 / 5 of the target volume) to the dry powder by allowing the liquid to flow slowly down the container wall. Begin mixing with the stir bar for at least 1 hour. (The stir bar speed can reach 500 rpm; reduce the speed if bubbles form).

[0240] 3) Visually confirm that the mixture is completely suspended or completely emulsion-like, and that there are no unsuspended clumps on the walls or bottom of the cylinder. Remove the stir bar and add WFI to the final target volume (final 30 mL). Add the stir bar back into the mixture.

[0241] 4) Keep the dosage form at room temperature and record the time it takes to complete preparation.

[0242] 5) Administer the medication within one (1) hour after the preparation of the dosage form is completed.

[0243] 6) During administration, keep the prepared formulation stirred to minimize sedimentation. Avoid bubble formation or foaming during administration and sampling. If bubbles form in the dosage form, reduce the stirring speed until no visible bubbles or foam are present in the suspension.

[0244] Disposal of remaining materials:

[0245] Store all unused test articles and remaining dosage forms in a refrigerator at 2–8 °C. Inquire with the sponsor about options for the disposal or transfer of remaining materials.

[0246] Test System

[0247] Description of [SOP: CTPS-TE00032 and CTPS-TE00458]:

[0248] Table 19. Test System

[0249] Animal care statement

[0250] The procedures for handling laboratory animals have been approved by the IACUC (IACUC Protocol No.: CTPS-18-012-06). All procedures described in this protocol shall be performed in a manner that avoids or minimizes discomfort, pain, or suffering in the animals.

[0251] Veterinary care:

[0252] If the testing facility's veterinarian notices unacceptable pain and / or suffering, medical treatment, including humane euthanasia, will begin with the research principal's consent, if feasible. Upon becoming aware of the animal's condition, the research principal will attempt to contact the sponsor as quickly as possible. If the research principal or sponsor cannot be contacted when the animal exhibits the aforementioned condition, the veterinarian may perform treatment without approval; in such cases, the research principal and sponsor will be notified of the treatment as soon as possible.

[0253] Animal living conditions [SOP: CTPS-AC00023, CTPS-AC00025, CTPS-AC00026 and CTPS-AC00029]:

[0254] The living conditions described in this section are in accordance with the recommendations in the guidelines for the care and use of laboratory animals.

[0255] Table 20. Animal Care Statement

[0256] Computer System

[0257] The online data collection system Pristima® (version 7.2.0 or later; Xybion Medical Systems Corporation) is used in testing facilities to capture research data when appropriate.

[0258] Experimental Design

[0259] Animal selection and adaptation [SOP: CTPS-AC00032]:

[0260] Animals released from quarantine at the testing facility were assigned to this study and then underwent an acclimatization period until the day of administration.

[0261] Randomization and group assignment [SOP: CTPS-TE00510]:

[0262] At least one day prior to administration, clinically acceptable animals were assigned to the study group using a randomization procedure based on adaptation data. Following randomization, one-way ANOVA or rank-based Kruskal-Wallis one-way ANOVA showed that the mean body weights of each group were statistically different from each other (p < 0.05). The weight variation of the selected animals did not exceed ±20% of the mean weight of all animals.

[0263] Unassigned animals should be kept in reserve until administration is completed on Day 1. Assigned animals may be substituted with reserve animals due to health issues and / or suspected administration errors. Data collection from reserve animals cannot be conducted after the adaptation phase is complete.

[0264] Table 21. Research Design

[0265] Dosage formulations [SOP: CTPS-TE00447 and CTPS-TE00488]:

[0266] Table 22. Administration of Dosage Forms

[0267] Observation and inspection

[0268] Vitality assessment [SOP: CTPS-TE00469]:

[0269] From day 1 until the end of the live experiment, check all animals for mortality and near-death status at least twice daily. Additional observations may be performed as needed, including cage-side or detailed clinical observation.

[0270] weight:

[0271] All study animals were weighed once before the testing phase and once before administration on day 1. Additional weight measurements may be taken as needed.

[0272] Blood sample collection, processing and transfer [SOP: CTPS-TE00032 and CTPS-TE00458]:

[0273] Blood samples were taken from each study animal. Plasma collection and storage were performed according to the table below. Blood samples not taken within the grace period were described in the in vivo experiment report.

[0274] Table 23. Blood Collection

[0275] Sample transfer:

[0276] Plasma samples were packaged in insulated containers with dry ice and transferred to the testing site.

[0277] Bioanalysis:

[0278] At the testing site, the concentration of IVO in plasma samples was determined by LC MS / MS.

[0279] Terminal Operation Procedures [SOP: CTPS-TE00475 and CTPS-TE00487]

[0280] Planned endpoint:

[0281] After the final blood samples were taken, all surviving animals were either restored to reserve or euthanized by exposing them to CO2, and then bled.

[0282] Unplanned endpoint:

[0283] If an animal needs to be euthanized before the planned termination date due to a near-death state or other conditions, the animal will be weighed, euthanized by exposing it to CO2, its blood will be collected, it will be bled, and then an autopsy will be performed. If the animal is found to be dead, it will be weighed and an autopsy will be performed, or it will be refrigerated and an autopsy will be performed within 48 hours.

[0284] During an autopsy, the external surface of the body, all orifices, cranial cavity, thoracic cavity, abdominal cavity, and internal organs are examined, and serious lesions are recorded.

[0285] Organs or tissues may be collected based on the judgment of the study principal investigator or the pathologist on duty. Histopathological examination of the collected tissues must be explicitly requested by the sponsor and will incur additional costs.

[0286] Data Analysis

[0287] PK parameters:

[0288] PK parameters were determined using non-compartmental analysis of individual profiles in Microsoft Excel. The observed maximum plasma concentration (Cmax) and the time to Cmax (Tmax) were determined directly from the data. The area under the plasma concentration-time curve from 0 to 24 hours post-dose (AUC0–24h) and the area under the plasma concentration-time curve extrapolated from time 0 to infinity (AUC0–∞) were determined using the linear trapezoidal rule. AUC0-24h=(t2-t1)×(C1+C2) / 2

[0289] The extrapolation to infinity is used as follows: AUC0-∞=AUClast+Clast / λ

[0290] Where feasible, the apparent terminal elimination half-life (t1 / 2) is calculated according to the following formula, where λ is the terminal elimination rate constant: t1 / 2=ln(2) / λ

[0291] The selection criteria for data points included in the calculation of λ require that at least three data points representing the terminal phase must be used for regression analysis, and the rounded r values ​​must be accurate. 2 ≥ 0.85. If these criteria are not met, the half-life is defined as undetermined (ND). The mean residence time extrapolated to infinity (MRT0-∞) is determined according to the following formula: MRT0-∞=AUMC0-∞ / AUC0-∞

[0292] The nominal sampling time was used for the calculation of AUC, CL, and t1 / 2. The nominal dose was used for dose-normalized AUC0-∞ in all test article treatment groups.

[0293] Results and discussion

[0294] The dosing groups and blood collection schedules for this study are summarized in Table 24 above. As shown in Table 24, there were no significant differences in the PK parameters between ASD-01 and ASD-04.

[0295] Table 24. PK parameters of ASD-01 and ASD-04 in rats

[0296] Example 8: Effect of antioxidants on the stability improvement of pre-tablet formulations of ASD-04 (physical mixture).

[0297] The samples were prepared as physical mixtures according to the compositions listed in Table 25, with different antioxidants added to the formulation. The samples were tested under pressure conditions (60 °C, open). After 4 months, only the sample containing butylated hydroxyanisole (BHA) as an antioxidant (T5) showed a significant improvement in stability compared to the other samples (Table 26).

[0298] Table 25. Physical mixtures of ASD-04 with pre-tablet formulations of different antioxidants

[0299] Table 26. Stability results of ASD-04 pre-tablet formulations with physical mixtures of different antioxidants (60 °C, open).

[0300] Example 9: Direct study of the antioxidant effect of BHA on ASD-04

[0301] The samples were prepared as physical mixtures according to the compositions listed in Table 27. The samples were tested under pressure conditions (60 °C, open). After 2 weeks, the groups with BHA and ASD-04 (S2-S5) began to show improved stability compared to the group with only ASD-04 (S1) (Table 28).

[0302] Table 27. Composition of ASD with different amounts of BHA

[0303] Table 28. Stability results of different AP ratios in 1:3 IVO / HPBCD formulations (60 °C, open).

[0304] Example 10: Preparation of ASD by spray drying with different solid contents

[0305] A mixture of IVO / HPBCD (1 / 3 w / w) with a target solids content of 20% & 30% was dissolved in MeOH / acetone (59.25 / 40.75, w / w) and used as spray-drying solutions for preparing solid dispersions. Approximately 13 g of IVO, 39 g of HPBCD, and the corresponding solvent were placed in 500 ml bottles and dissolved with stirring to obtain a clear solution, which was then spray-dried to form a solid dispersion. Detailed process parameters for the preparation of the solid dispersion are listed in Table 29. Approximately 15 g of each spray-dried ASD (ASD-03-01, ASD-06, and ASD-03-02) were dried in a vacuum oven (secondary drying), and the characterization results of the dried ASD are listed in Table 30. Residual methanol could be removed under vacuum, while residual acetone was reduced to 3,000-4,000 ppm. The remaining spray-dried ASD was not dried in a vacuum oven and was used for the storage time and secondary drying studies in Example 11.

[0306] Table 29. Spray drying parameters for IVO / HPBCD (1 / 3 w / w) ASD formulation

[0307] Table 30. Characterization results of IVO / HPBCD (1 / 3 w / w) ASD

[0308] Example 11: Study on secondary drying of spray-dried ASD powder

[0309] To evaluate the stability of spray-dried ASD powder during the secondary drying process, spray-dried ASD powder in 40 mL glass vials was dried under vacuum at 50 °C and 65 °C for up to 14 days. Approximately 3.5 g of each type of spray-dried ASD powder was weighed and placed in a container. The samples were then subjected to continuous high vacuum (near 0 mbar, measured by an absolute pressure gauge, model 500 33 155) at 50 °C and 65 °C. At each sampling point, a certain amount of sample was removed and characterized; details are listed in Tables 31 and 32. Residual methanol could be reduced to 65 °C. o Levels undetectable below C. However, even at 65 o After drying under vacuum for 14 days, the residual acetone can be reduced to about 200 ppm, but it cannot be completely removed.

[0310] Table 31. Results of the secondary drying study of ASD-03-01

[0311] Table 32. Results of the secondary drying study of ASD-06

[0312] Those skilled in the art will understand that changes can be made to the above embodiments without departing from its broad inventive concept. Therefore, it should be understood that the present invention is not limited to the specific embodiments disclosed, but is intended to cover modifications within the spirit and scope of the invention as defined in this specification.

Claims

1. A solid dispersion with improved stability comprising (i) the compound 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (IVO), (ii) hydroxypropyl β-cyclodextrin (HPBCD) and (iii) acetone.

2. The solid dispersion of claim 1, wherein the acetone is in the range of 100 ppm to 5,000 ppm.

3. The solid dispersion of claim 1, wherein the ratio of IVO to HPBCD in the solid dispersion is 1:99 to 99:1 (w / w), preferably 10:90 to 90:10 (w / w), more preferably 20:80 to 80:20 (w / w), and most preferably 25:75 to 75:25 (w / w).

4. The solid dispersion of claim 1, wherein the solid dispersion has a particle size in the range of 0.1 to 25 μm, preferably 1 to 20 μm, more preferably 2 to 15 μm, and most preferably 2 to 10 μm, as expressed by Dv50.

5. The solid dispersion of claim 1, wherein the solid dispersion has a particle size distribution represented by Dv90 / Dv10 of less than 15.

6. The solid dispersion of claim 1, wherein the solid dispersion comprises one or more residual solvents, and each individual residual solvent is less than 5000 ppm.

7. The solid dispersion according to claim 1, wherein the solid dispersion has a content of 100 o C represents a relative weight loss of less than 90%, as determined by thermogravimetric analysis.

8. The solid dispersion of claim 1, wherein the solid dispersion further comprises an antioxidant selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, panthenol (coenzyme Q), carotene, and ascorbyl palmitate.

9. The solid dispersion of claim 8, wherein the antioxidant is butylated hydroxyanisole (BHA).

10. The solid dispersion of claim 1, wherein the total IVO-related impurities generated by the solid dispersion stored at 60 °C for one month relative to the weight of IVO are less than 0.5%.

11. The solid dispersion of claim 1, wherein the solid dispersion is prepared by a method comprising a spray-dried solution to provide a powder composition, wherein the solution comprises (i) compound 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (IVO), (ii) hydroxypropyl β-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

12. A method for preparing a solid dispersion having improved stability, the method comprising spray drying a solution to provide a powder composition, wherein the solution comprises (i) a compound 5-{3-[4-(3-methylbenzyloxy)phenylthio]furan-2-yl}imidazolidine-2,4-dione (IVO), (ii) hydroxypropyl β-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

13. The method of claim 12, wherein the organic solvent is selected from acetone, tetrahydrofuran, methanol, ethanol, dichloromethane, and ethyl acetate.

14. The method of claim 12, wherein the solvent mixture comprises methanol and acetone.

15. The method of claim 14, wherein the ratio of methanol to acetone is 70:30 to 50:50 (v / v).

16. The method of claim 15, wherein the ratio of methanol to acetone is 60:40 (v / v).

17. The method of claim 12, wherein the solubility of IVO in the solvent mixture is 25 ± 5. o The concentration of C is higher than 15 mg / mL.

18. The method of claim 12, wherein the solubility of the IVO / HPBCD complex in the solvent mixture is about 2 to 5.4 times that in a solvent system containing only methanol.

19. The method of claim 12, wherein the ratio of IVO to HPBCD in the solution is 1:99 to 99:1 (w / w), preferably 10:90 to 90:10 (w / w), more preferably 20:80 to 80:20 (w / w), and most preferably 25:75 to 75:25 (w / w).

20. The method of claim 12, wherein the solid dispersion is an amorphous solid dispersion (ASD) of the IVO / HPBCD complex.

21. The method of claim 12, wherein the solid dispersion has a particle size in the range of 0.1 to 25 μm, preferably 1 to 20 μm, more preferably 2 to 15 μm, and most preferably 2 to 10 μm, as expressed by Dv50.

22. The method of claim 12, wherein the solid dispersion has a particle size distribution represented by Dv90 / Dv10 of less than 15.

23. The method of claim 12, wherein the solid dispersion comprises one or more residual solvents, and each individual residual solvent is less than 5000 ppm.

24. The method of claim 12, wherein the solid dispersion has a content of 100 o C represents a relative weight loss of less than 90%, as determined by thermogravimetric analysis.

25. The method of claim 12, wherein the solid dispersion further comprises an antioxidant selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, panthenol (coenzyme Q), carotene, and ascorbyl palmitate.

26. The method of claim 25, wherein the antioxidant is butylated hydroxyanisole (BHA).

27. The method of claim 12, wherein, The solid dispersion exhibits improved chemical stability compared to a reference solid dispersion prepared by spray drying a solution containing (i) an IVO compound, (ii) hydroxypropyl β-cyclodextrin (HPBCD) and (iii) methanol.

28. A pharmaceutical composition comprising the solid dispersion of any one of claims 1-11 and at least one pharmaceutically acceptable carrier.

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