Pharmaceutical composition with enhanced properties, method for preparation, and use thereof

Abstract

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

Description

[0001] PHARMACEUTICAL COMPOSITION WITH ENHANCED PROPERTIES, METHOD FOR PREPARATION, AND USE THEREOF

[0002] CROSS REFERENCE TO RELATED APPLICATION

[0003] 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.

[0004] FIELD OF THE APPLICATION

[0005] The present application relates to compositions and methods in preparation of spray dried amorphous solid dispersion comprising 5-{3-[4-(3-methyl-benzyloxy) phenylthio]fur-2- yl}imidazolidine-2, 4-dione (referred to as compound IVO hereafter) and hydroxypropyl betacyclodextrin (HPBCD). In particular, the present application relates to an improved spray drying method for producing amorphous solid dispersions with enhanced properties by the use of a cosolvent system and / or an antioxidant.

[0006] BACKGROUND OF THE APPLICATION

[0007] A series of compounds of 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2, 4-dione and analogues were disclosed in U.S. Patent Application No. 2006 / 0041000. These compounds were designed to be used as inhibitors of macrophage elastase. All these compounds are hydantoin derivatives and have been tested in vitro for their use as matrix metalloproteinase (MMP) inhibitors.

[0008] According to the method disclosed in U.S. Patent Application Publication No. 2019 / 0054178, approximate 10.0 g of compound IVO was weighed out into a volumetric flask and then completely dissolved in 660 mb of methanol (MeOH) by using ultrasonication to get a clear solution (15.2 mg / mL) at 25 ± 5°C. The solubility of IVO in methanol is about 15.2 mg / mL. After filtering it with a 0.45 um filter membrane to remove potential leftover crystal solid, approximate 30.05 g of HPBCD were added into the solution at a ratio of 25:75 (w / w) of IVO / HPBCD. The sample was stirred for 60 min to form a clear solution before it was spray dried to obtain an amorphous solid dispersion. The maximum solid content of 1 :3 (w / w) complex of compound IVO / HPBCD (referred to as ASD-01 hereafter) prepared in MeOH solution was limited to only 60 mg / ml for spray drying process. The low solubility of IVO in methanol requires a large amount of methanol to dissolve IVO and HPBCD. The large quantity of methanol will make large scale manufacturing of IVO / HPBCD complex impractical.

[0009] Therefore, it would be desirable to find an appropriate approach to use less organic solvent and prepare higher solid content solution for spray drying process optimization. It is advantageous to use less organic solvent as it reduces the costs and waste of the process.

[0010] According to the method disclosed in U.S. Patent Application Publication No. 2019 / 0054178, the spray dried powder of 1 :3 (w / w) complex of compound IVO / HPBCD (ASD- 01) is amorphous, and the composition can induce a greater area under the plasma concentration vs. time curve (AUC) of the compound than what is achieved when the compound is administered in the absence of a cyclodextrin at the same amount and under the same conditions. However, the IVO / HPBCD powder prepared using the disclosed method is not very stable, and so it is very difficult to develop a pharmaceutical product using such IVO / HPBCD powder.

[0011] Therefore, there remains a need for developing methods for preparing IVO / HPBCD powder with better stability so that the methods can be suitable for scaling up and reducing the waste and cost.

[0012] SUMMARY OF THE APPLICATION

[0013] The present application provides a method to improve the manufacturing process of a pharmaceutical composition comprising a compound of 5-{3-[4-(3-methyl- benzyloxy)phenylthio]fur-2-yl}imidazolidine-2, 4-dione (IVO) and hydroxypropyl betacyclodextrin (HPBCD). Also provided is a co-solvent system comprising at least two different organic solvents and a method for producing spray dried amorphous solid dispersions (ASD) comprising IVO and HPBCD, wherein the ASD has better physical and chemical characteristics, comparing to that obtained by using a single solvent, e.g., methanol.

[0014] In one general aspect, the present application provides a method for preparing a solid dispersion, the method comprising spray drying a solution comprising (i) a compound of 5-{3-[4- (3-methyl-benzyloxy) phenylthio]fur-2-yl}imidazolidine-2, 4-dione (IVO), (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

[0015] In some embodiments, the solubility of the compound IVO in the solvent mixture is higher than 15 mg / mL at 25 ± 5°C. In some embodiments, the ratio of the compound IVO to HPBCD in the solution is from 1 :99 to 99: 1 (w / w), preferably from 10:90 to 90:10 (w / w), more preferably from 20:80 to 80:20 (w / w), most preferably from 25:75 to 75:25 (w / w).

[0016] In certain embodiments, the ratio of the compound IVO to HPBCD is about 25:75 (w / w).

[0017] In some embodiments, the organic solvent is selected from the group consisting of acetone, tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), dichloromethane (DCM), and ethyl acetate (EtOAc), and any combination of the above.

[0018] In some embodiments, the solvent mixture comprises a first organic solvent and a second organic solvent.

[0019] In certain embodiments, the first organic solvent in the solvent mixture is methanol and the second organic solvent is acetone.

[0020] In some embodiments, the ratio of methanol to acetone is from 80:20 to 20:80 (v / v).

[0021] In some embodiments, the ratio of methanol to acetone is from 70:30 to 50:50 (v / v).

[0022] In certain embodiments, the ratio of methanol to acetone is about 60:40 (v / v).

[0023] In some embodiments, the solid dispersion is an amorphous solid dispersion (ASD) of IVO / HPBCD complex.

[0024] In some embodiments, the solid dispersion has a particle size distribution as expressed by Dv50 ranging from 0.1 to 25 pm, preferably from 1 to 20 pm, more preferably from 2 to 15 pm, and most preferably from 2 to 10 pm.

[0025] In certain embodiments, the solid dispersion has a particle size distribution as expressed by Dv90 / Dvl0 that is less than 15.

[0026] In some embodiments, the solid dispersion has a relative weight loss of less than 90% as determined by thermogravimetric analysis at 100 °C.

[0027] In some embodiments, the solid dispersion further comprises an antioxidant selected from the group consisting of butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), a- tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, ubiquinol (coenzyme Q), carotenes, ascorbyl palmitate (AP), monothiol glycerol (MTG), DL-a-Tocopherol, methoxypolyethylene glycol succinate (TPGS) and edetate disodium salt dihydrate (Na-EDTA).

[0028] In certain embodiments, the antioxidant is butylated hydroxyanisole (BHA).

[0029] In some embodiments, the solubility of the IVO / HPBCD complex in the solvent mixture is about 2 to 5.4 folds higher than that in a methanol-only solvent system. Solubility comparisons can be assessed by methods known to one skilled in the art, such as any of the specific methods and conditions detailed herein.

[0030] In some embodiments, residual solvents in the solid dispersion equal to or less than 5000 ppm.

[0031] In some embodiments, the solid dispersion comprises one or more residual solvents, and each of the individual residual solvents is less than 5000 ppm.

[0032] In some embodiments, the residual solvent is acetone. In some embodiments, the residual solvent is methanol.

[0033] In some embodiments, the solid dispersion has an improved stability.

[0034] In some embodiments, the solid dispersion has an improved chemical stability in comparison to a reference solid dispersion that is prepared by spray drying a solution comprising (i) a compound of IVO, (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) methanol.

[0035] In another general aspect, the present application provides a solid dispersion prepared by a method comprising spray drying a solution comprising (i) a compound of 5-{3-[4-(3-methyl- benzyloxy) phenylthio]fur-2-yl}imidazolidine-2, 4-dione (IVO), (ii) a hydroxypropyl beta- cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

[0036] In some embodiments, the ratio of the compound IVO to HPBCD in the solution is from 1 :99 to 99: 1 (w / w), preferably from 10:90 to 90:10 (w / w), more preferably from 20:80 to 80:20 (w / w), most preferably from 25:75 to 75:25 (w / w).

[0037] In certain embodiments, the ratio of the compound IVO to HPBCD is about 25:75 (w / w).

[0038] In some embodiments, the organic solvent is selected from the group consisting of acetone, tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), dichloromethane (DCM), and ethyl acetate (EtOAc), and any combination of the above.

[0039] In some embodiments, the solvent mixture comprises a first organic solvent and a second organic solvent.

[0040] In certain embodiments, the first organic solvent in the solvent mixture is methanol and the second organic solvent is acetone.

[0041] In some embodiments, the solid dispersion is an amorphous solid dispersion (ASD) of IVO / HPBCD complex.

[0042] In some embodiments, the solid dispersion has a relative weight loss of less than 90% as determined by thermogravimetric analysis at 100°C. In some embodiments, the solid dispersion further comprises an antioxidant selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), a- tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, ubiquinol (coenzyme Q), carotenes, ascorbyl palmitate (AP), monothiol glycerol (MTG), DL-a-Tocopherol, methoxypolyethylene glycol succinate (TPGS) and edetate disodium salt dihydrate (Na-EDTA).

[0043] In certain embodiments, the antioxidant is butylated hydroxyanisole (BHA).

[0044] In some embodiments, the solubility of IVO / HPBCD complex in the solvent mixture is about 2 to 5.4 folds higher than that in a methanol-only solvent system. Solubility comparisons can be assessed by methods known to one skilled in the art, such as any of the specific methods and conditions detailed herein.

[0045] In some embodiments, residual solvents in the solid dispersion equal to or less than 5000 ppm.

[0046] In some embodiments, the solid dispersion comprises one or more residual solvents, and each of the individual residual solvents is less than 5000 ppm.

[0047] In certain embodiments, the residual solvent is acetone. In certain embodiments, the residual solvent is methanol.

[0048] In some embodiments, the solid dispersion has an improved stability.

[0049] In some embodiments, the solid dispersion has an improved chemical stability in comparison to a reference solid dispersion that is prepared by spray drying a solution comprising (i) a compound of IVO, (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) methanol.

[0050] In another general aspect, the present application provides a solid dispersion, wherein the solid dispersion comprises (i) a compound of 5-{3-[4-(3-methyl-benzyloxy) phenylthio]fur-2- yl}imidazolidine-2, 4-dione (IVO), (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) acetone.

[0051] In some embodiments, the acetone in the solid dispersion is less than 5,000 ppm.

[0052] In some embodiments, the acetone in the solid dispersion is in the range of 100 ppm to 5,000 ppm.

[0053] In some embodiments, the acetone in the solid dispersion is in the range of 200 ppm to 4,000 ppm.

[0054] In some embodiments, the acetone in the solid dispersion is in the range of 200 ppm to

[0055] 3,500 ppm. In some embodiments, the ratio of IVO to HPBCD in the solid dispersion is from 1 :99 to 99: 1 (w / w), preferably from 10:90 to 90: 10 (w / w), more preferably from 20:80 to 80:20 (w / w), most preferably from 25:75 to 75:25 (w / w).

[0056] In certain embodiments, the ratio of IVO to HPBCD is about 25:75 (w / w).

[0057] In some embodiments, the solid dispersion has a particle size as expressed by Dv50 ranging from 0.1 to 25 pm, preferably from 1 to 20 pm, more preferably from 2 to 15 pm, and most preferably from 2 to 10 pm.

[0058] In some embodiments, the solid dispersion has a particle size distribution as expressed by Dv90 / Dvl0 that is less than 15.

[0059] In some embodiments, the solid dispersion comprises one or more residual solvents, and each of the individual residual solvents is less than 5000 ppm.

[0060] In some embodiments, the solid dispersion has a relative weight loss of less than 90% as determined by thermogravimetric analysis at 100°C.

[0061] In some embodiments, the solid dispersion further comprises an antioxidant selected from the group consisting of butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), a- tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, ubiquinol (coenzyme Q), carotenes, ascorbyl palmitate (AP), monothiol glycerol (MTG), DL-ot-Tocopherol, methoxypolyethylene glycol succinate (TPGS) and edetate disodium salt dihydrate (Na-EDTA).

[0062] In certain embodiments, the antioxidant is butylated hydroxyanisole (BHA).

[0063] In some embodiments, the solid dispersion has an improved stability.

[0064] In some embodiments, the solid dispersion has an improved chemical stability in comparison to a reference solid dispersion that is prepared by spray drying a solution comprising (i) a compound of IVO, (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) methanol.

[0065] In certain embodiments, the total IVO related impurities generated from the solid dispersion stored at 60 °C over one month are less than 0.5% relative to the weight of the IVO.

[0066] In some embodiments, the solid dispersion is prepared by a method comprising spray drying a solution to afford a powder composition, wherein the solution comprise (i) a compound of 5-{3-[4-(3-methyl-benzyloxy) phenylthio]fur-2-yl}imidazolidine-2, 4-dione (IVO), (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents. In another general aspect, the present application provides pharmaceutical compositions comprising the solid dispersion described herein and uses thereof.

[0067] BRIEF DESCRIPTION OF THE DRAWINGS

[0068] The foregoing summary, as well as the following detailed description of preferred embodiments of the present application, will be better understood when read in conjunction with the appended drawings. It should be understood, however, that the application is not limited to the precise embodiments shown in the drawings.

[0069] FIG. 1 shows the X-ray powder diffraction (XRPD) of IVO / HPBCD in ADS-01.

[0070] FIG. 2 shows the X-ray powder diffraction (XRPD) of IVO / HPBCD in ADS-04.

[0071] FIG. 3 shows the FT-IR characterization of IVO, HPBCD, and ASD-01 to ASD-05.

[0072] FIG. 4 shows the initial dissolution profiles of ASD-01, ASD-02, ASD-04 and ASD-05 (200 mg powder / capsule).

[0073] FIG. 5 shows the dissolution profiles of ASD-01, ASD-02, ASD-04 and ASD-05 (200 mg powder / capsule) under stress condition (60°C, open).

[0074] DETAILED DESCRIPTION OF THE APPLICATION

[0075] Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the disclosure. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to the disclosure.

[0076] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth fully herein.

[0077] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0078] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. For example, the phrase “at least A, B, and C” means that each of A, B, and C is present. The term “at least one of’ preceding a series of elements is to 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 phrase “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 of’ preceding a series of elements can also encompass situations in which any one or more of the elements is present in greater than one instance, e.g., “at least one of A, B, and C” can also encompass situations in which A is present in duplicate alone or further in combination with any one or more of elements B and C.

[0079] As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0080] Unless otherwise stated, any numerical value, such as a concentration or a concentration range described herein, are to be understood as being modified in all instances by the term “about.” Thus, a numerical value typically includes ± 10% of the recited value. For example, the recitation of “10-fold” includes 9-fold and 11 -fold. As used herein, the use of a numerical range expressly includes all possible subranges, all individual numerical values within that range, including integers within such ranges and fractions of the values unless the context clearly indicates otherwise.

[0081] As used herein, “subject” means any animal, preferably a mammal, most preferably a human, to whom will be or has been treated by a method according to an embodiment of the application. The term “mammal” as used herein, encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, etc., more preferably a human. As used herein, “DvlO,” “Dv50” and “Dv90” refer to particle distribution. In particular, “DvlO” means the 10% of particles in the powders 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.

[0082] Methods For Preparing a Solid Dispersion

[0083] In one general aspect, provided herein is a method for preparing a solid dispersion comprising spray drying a solution to afford a powder composition, wherein the solution comprises (i) a compound of 5-{3-[4-(3-methyl-benzyloxy) phenylthio]fur-2-yl}imidazolidine-2, 4-dione (IVO), (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

[0084] In some embodiments, the method further comprises further drying the powder composition to afford the solid dispersion.

[0085] As used herein, the terms “solid dispersion” and “dry powder composition” are interchangeable, and refer to the final product after the steps of spray drying and further drying.

[0086] In certain embodiments, the spray dried powder composition is further dried under vacuum condition at a temperature of about 25-70 °C, such as 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 °C, or any temperature in between thereof.

[0087] In certain embodiments, the spray dried powder composition is further air dried.

[0088] According to embodiments of the present application, organic solvents are carbon-based substances capable of dissolving or dispersing IVO and / or HPBCD.

[0089] In some embodiments, the organic solvents are volatile. Preferably, the organic solvent is selected from the group consisting of acetone, tetrahydrofuran, methanol, ethanol (EtOH), di chloromethane (DCM), acetate (EtOAc), and any combination of the above.

[0090] In some embodiments, the solubility of the compound IVO in the solvent mixture is higher than that in a single solvent, such as methanol. In certain embodiments, the solubility of the compound IVO in the solvent mixture is higher than 15 mg / mL at 25 ± 5 °C.

[0091] In some embodiments, the ratio of the compound IVO to HPBCD in the solution is from 1 :99 to 99: 1 (w / w), preferably from 10:90 to 90:10 (w / w), more preferably from 20:80 to 80:20 (w / w), most preferably from 25:75 to 75:25 (w / w).

[0092] In certain embodiments, the ratio of the compound IVO to HPBCD is about 25:75 (w / w). In some embodiments, the solvent mixture comprises a first organic solvent and a second organic solvent.

[0093] In certain embodiments, the first organic solvent in the solvent mixture is methanol and the second organic solvent is acetone.

[0094] In some embodiments, the ratio of methanol to acetone ranges from 99:1 to 1 :99 (v / v).

[0095] In certain embodiments, the ratio of methanol to acetone is from 70:30 to 50:50 (v / v).

[0096] In certain embodiments, the ratio of methanol to acetone is about 60:40 (v / v).

[0097] In some embodiments, the solution has a solid content (IVO+HPBCD) of 100-400 mg / ml, such as 100, 150, 200, 250, 300 or 400 mg / ml, or any number in between thereof. As used herein, the solid content refers to the total content of IVO and HPBCD in the solution.

[0098] In some embodiments, the inlet temperature of the spray drying process is about 60-100 °C, preferably 70-90 °C, more preferably 80 °C.

[0099] In some embodiments, the outlet temperature of the spray drying process is about 40-80 °C, preferably 50-70 °C, more preferably 60 °C.

[0100] In some embodiments, the solid dispersion is an amorphous solid dispersion (ASD) of IVO / HPBCD complex.

[0101] In some embodiments, the solid dispersion has a particle size distribution as expressed by Dv50 ranging from 0.1 to 25 pm, preferably from 1 to 20 pm, more preferably from 2 to 15 pm, and most preferably from 2 to 10 pm.

[0102] In certain embodiments, the solid dispersion has a particle size distribution as expressed by Dv90 / Dvl0 that is less than 15.

[0103] In some embodiments, the solid dispersion has a relative weight loss of less than 90% as determined by thermogravimetric analysis at 100°C.

[0104] In some embodiments, the solid dispersion further comprises an antioxidant selected from the group consisting of butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), a- tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, ubiquinol (coenzyme Q), carotenes, ascorbyl palmitate (AP), monothiol glycerol (MTG), DL-a-Tocopherol, methoxypolyethylene glycol succinate (TPGS) and edetate disodium salt dihydrate (Na-EDTA).

[0105] In certain embodiments, the antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), oi-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, ubiquinol (coenzyme Q), carotene, and ascorbic palmitate. In certain embodiments, the antioxidant is butylated hydroxy anisole (BHA).

[0106] In some embodiments, the solubility of IVO / HPBCD complex in the solvent mixture is about 2 to 5.4 folds higher than that in the methanol -only solvent system. Solubility comparisons can be assessed by methods known to one skilled in the art, such as any of the specific methods and conditions detailed herein.

[0107] In some embodiments, the total residual solvents in the powder composition are less than 50000 ppm.

[0108] In certain embodiments, the residual solvent is methanol, or acetone, or the mixture thereof.

[0109] In some embodiments, residual solvents in the solid dispersion equal to or less than 5000 ppm.

[0110] In some embodiments, the solid dispersion comprises one or more residual solvents, and each of the individual residual solvents is less than 5000 ppm.

[0111] In certain embodiments, the residual solvent is acetone. In certain embodiments, the residual solvent is methanol.

[0112] In some embodiments, the solid dispersion has an improved stability.

[0113] In some embodiments, the solid dispersion has an improved chemical stability compared to a reference solid dispersion that is prepared by spray drying a solution comprising (i) a compound of IVO, (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) methanol.

[0114] In certain embodiments, the solid dispersion generates impurities less than 80% of those generated by a reference solid dispersion that is prepared by spray drying a solution comprising (i) a compound of IVO, (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) methanol, after stored at 60 °C for one month.

[0115] In certain embodiments, the total IVO related impurities generated from the solid dispersion stored at 60 °C over one month are less than 0.5% relative to the weight of the IVO.

[0116] Solid Dispersions

[0117] In another general aspect, provided herein is a solid dispersion prepared by a method comprising spray drying a solution to afford a powder composition, wherein the solution comprises (i) a compound of 5-{3-[4-(3-methyl-benzyloxy) phenylthio]fur-2-yl}imidazolidine-2, 4-dione (IVO), (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents. In some embodiments, the method further comprises drying the powder composition to afford the solid dispersion.

[0118] In certain embodiments, the powder composition is dried under vacuum condition at a temperature of about 25-70 °C, such as 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 °C, or any temperature in between thereof.

[0119] In certain embodiments, the powder composition is air dried.

[0120] In some embodiments, the organic solvents are volatile. Preferably, the organic solvent is selected from the group consisting of acetone, tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), dichloromethane (DCM), ethyl acetate (EtOAc), and any combination of the above.

[0121] In some embodiments, the solubility of the compound IVO in the solvent mixture is higher than that in a single solvent, such as methanol. In certain embodiments, the solubility of the compound IVO in the solvent mixture is higher than 15 mg / mL at 25 ± 5 °C.

[0122] In some embodiments, the ratio of the compound IVO to HPBCD in the solution is from 1 :99 to 99: 1 (w / w), preferably from 10:90 to 90:10 (w / w), more preferably from 20:80 to 80:20 (w / w), most preferably from 25:75 to 75:25 (w / w).

[0123] In certain embodiments, the ratio of the compound IVO to HPBCD is about 25:75 (w / w).

[0124] In some embodiments, the solvent mixture comprises a first organic solvent and a second organic solvent.

[0125] In certain embodiments, the first organic solvent in the solvent mixture is methanol and the second organic solvent is acetone.

[0126] In some embodiments, the ratio of methanol to acetone ranges from 99:1 to 1 :99 (v / v).

[0127] In certain embodiments, the ratio of methanol to acetone is from 70:30 to 50:50 (v / v).

[0128] In certain embodiments, the ratio of methanol to acetone is about 60:40 (v / v).

[0129] In some embodiments, the solution has a solid content of 100-400 mg / ml, such as 100, 150, 200, 250, 300 or 400 mg / ml, or any number in between thereof. As used herein, the solid content refers to the total content of IVO and HPBCD in the solution.

[0130] In some embodiments, the inlet temperature of the spray drying process is about 60-100 °C, preferably 70-90 °C, more preferably 80 °C.

[0131] In some embodiments, the outlet temperature of the spray drying process is about 40-80 °C, preferably 50-70 °C, more preferably 60 °C. In some embodiments, the solid dispersion is an amorphous solid dispersion (ASD) of IVO / HPBCD complex.

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

[0133] In certain embodiments, the solid dispersion has a particle size distribution as expressed by Dv90 / Dvl0 that is less than 15.

[0134] In some embodiments, the solid dispersion has a relative weight loss of less than 90% as determined by thermogravimetric analysis at 100 °C.

[0135] In some embodiments, the solid dispersion further comprises an antioxidant selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), a- tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, ubiquinol (coenzyme Q), carotenes, ascorbyl palmitate (AP), monothiol glycerol (MTG), DL-a-Tocopherol, methoxypolyethylene glycol succinate (TPGS) and edetate disodium salt dihydrate (Na-EDTA).

[0136] In certain embodiments, the antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), a-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, ubiquinol (coenzyme Q), carotene, and ascorbic palmitate.

[0137] In certain embodiments, the antioxidant is butylated hydroxyanisole (BHA).

[0138] In some embodiments, the solubility of IVO / HPBCD complex in the solvent mixture is about 2 to 5.4 folds higher than that in the methanol -only solvent system. Solubility comparisons can be assessed by methods known to one skilled in the art, such as any of the specific methods and conditions detailed herein.

[0139] In some embodiments, the total residual solvents in the powder composition are less than 50000 ppm.

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

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

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

[0143] In certain embodiments, the residual solvent is acetone. In certain embodiments, the residual solvent is methanol. In some embodiments, the solid dispersion has an improved stability.

[0144] In some embodiments, the solid dispersion has an improved chemical stability compared to a reference solid dispersion that is prepared by spray drying a solution comprising (i) a compound of IVO, (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) methanol.

[0145] In certain embodiments, the solid dispersion generates impurities less than 80% of those generated by a reference solid dispersion that is prepared by spray drying a solution comprising (i) a compound of IVO, (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) methanol, after stored at 60 °C for one month.

[0146] In certain embodiments, the total IVO related impurities generated from the solid dispersion stored at 60 °C over one month are less than 0.5% relative to the weight of the IVO.

[0147] In another general aspect, the present application provides a solid dispersion, wherein the solid dispersion comprises (i) a compound of 5-{3-[4-(3-methyl-benzyloxy) phenylthio]fur-2- yl}imidazolidine-2, 4-dione (IVO), (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) acetone.

[0148] In some embodiments, the acetone in the solid dispersion is less than 5,000 ppm.

[0149] In some embodiments, the acetone in the solid dispersion is in the range of 100 ppm to 5,000 ppm.

[0150] In some embodiments, the acetone in the solid dispersion is in the range of 200 ppm to 5,000 ppm.

[0151] In some embodiments, the acetone in the solid dispersion is in the range of 200 ppm to 4,000 ppm.

[0152] In some embodiments, the acetone in the solid dispersion is in the range of 200 ppm to 3,500 ppm.

[0153] In some embodiments, the ration of IVO to HPBCD in the solid dispersion is from 1:99 to 99:1 (w / w), preferably from 10:90 to 90: 10 (w / w), more preferably from 20:80 to 80:20 (w / w), most preferably from 25:75 to 75:25 (w / w).

[0154] In certain embodiments, the ratio of IVO to HPBCD is about 25:75 (w / w).

[0155] In some embodiments, the solid dispersion has a particle size as expressed by Dv50 ranging from 0.1 to 25 pm, preferably from 1 to 20 pm, more preferably from 2 to 15 pm, and most preferably from 2 to 10 pm. In some embodiments, the solid dispersion has a particle size distribution as expressed by Dv90 / Dvl0 that is less than 15.

[0156] In some embodiments, the solid dispersion comprises one or more residual solvents other than acetone, and each of the individual residual solvents equals to or less than 5000 ppm.

[0157] In certain embodiments, each of the individual residual solvents is less than 5000 ppm.

[0158] In certain embodiments, the residual solvent is methanol.

[0159] In some embodiments, the solid dispersion has a relative weight loss of less than 90% as determined by thermogravimetric analysis at 100°C.

[0160] In some embodiments, the solid dispersion further comprises an antioxidant selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), a- tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, ubiquinol (coenzyme Q), carotenes, ascorbyl palmitate (AP), monothiol glycerol (MTG), DL-a-Tocopherol, methoxypolyethylene glycol succinate (TPGS) and edetate disodium salt dihydrate (Na-EDTA).

[0161] In certain embodiments, the antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), a-tocopherol (vitamin E), lipoic acid, ascorbic acid (vitamin C), glutathione, ubiquinol (coenzyme Q), carotene, and ascorbic palmitate.

[0162] In certain embodiments, the antioxidant is butylated hydroxyanisole (BHA).

[0163] In some embodiments, the solid dispersion has an improved stability.

[0164] In some embodiments, the solid dispersion has an improved chemical stability compared to a reference solid dispersion that is prepared by spray drying a solution comprising (i) a compound of IVO, (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) methanol.

[0165] In certain embodiments, the solid dispersion generates impurities less than 80% of those generated by a reference solid dispersion that is prepared by spray drying a solution comprising (i) a compound of IVO, (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) methanol, after stored at 60 °C for one month.

[0166] In certain embodiments, the total IVO related impurities generated from the solid dispersion stored at 60 °C over one month are less than 0.5% relative to the weight of the IVO.

[0167] In some embodiments, the solid dispersion is prepared by a method comprising spray drying a solution to afford a powder composition, wherein the solution comprise (i) a compound of 5-{3-[4-(3-methyl-benzyloxy) phenylthio]fur-2-yl}imidazolidine-2, 4-dione (IVO), (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

[0168] In certain embodiments, the method further comprises drying the powder composition to afford the solid dispersion.

[0169] In certain embodiments, the method further comprises drying the powder composition under vacuum condition at a temperature of about 25-70 °C, such as 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 °C, or any temperature in between thereof.

[0170] In certain embodiments, the method further comprises air drying the powder composition.

[0171] In certain embodiments, total residual solvents in the powder composition are less than 50000 ppm.

[0172] In certain embodiments, the residual solvent is acetone, or methanol, or the mixture thereof. In certain embodiments, the residual solvent is methanol.

[0173] Pharmaceutical Compositions and Uses Thereof

[0174] In another general aspect, provided herein are pharmaceutical compositions comprising the solid dispersion as described herein.

[0175] Pharmaceutical compositions of the present application can also comprise a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier is non-toxic and should not interfere with the efficacy of the active ingredient. Pharmaceutically acceptable carriers can include one or more excipients such as binders, disintegrants, swelling agents, suspending agents, emulsifying agents, wetting agents, lubricants, flavorants, sweeteners, preservatives, dyes, solubilizers and coatings. The precise nature of the carrier or other material can depend on the route of administration, e.g., intramuscular, intradermal, subcutaneous, oral, intravenous, cutaneous, intramucosal (e.g., gut), intranasal or intraperitoneal routes. For liquid injectable preparations, for example, suspensions and solutions, suitable carriers and additives include water, glycols, oils, alcohols, preservatives, coloring agents and the like. For solid oral preparations, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. For nasal sprays / inhalant mixtures, the aqueous solution / suspension can comprise water, glycols, oils, emollients, stabilizers, wetting agents, preservatives, aromatics, flavors, and the like as suitable carriers and additives.

[0176] Pharmaceutical compositions of the present application can be formulated in any matter suitable for administration to a subject to facilitate administration and improve efficacy, including, but not limited to, oral (enteral) administration and parenteral injections. The parenteral injections include intravenous injection or infusion, subcutaneous injection, intradermal injection, and intramuscular injection. Compositions can also be formulated for other routes of administration including transmucosal, ocular, rectal, long-acting implantation, sublingual administration, under the tongue, from oral mucosa bypassing the portal circulation, inhalation, or intranasal.

[0177] In some embodiments, the pharmaceutical compositions are formulated for oral administration.

[0178] The form of the pharmaceutical compositions, the route of administration, the dosage and the regimen depend upon the condition to be treated, such as the severity of the illness, the age, weight, and sex of the patient. Pharmaceutical compositions can be formulated for different modes of administration such as for topical, oral, intranasal, parenteral, intraocular, intravenous, intramuscular, or subcutaneous administration.

[0179] In yet another aspect, provided is a method of preparing a pharmaceutical composition comprising combining the solid dispersion, as described herein, with at least one pharmaceutically acceptable carrier. Pharmaceutical compositions can be prepared by any method known in the art in view of the present disclosure, and one of ordinary skill in the art will be familiar with such techniques used to prepare pharmaceutical compositions. For example, a pharmaceutical composition according to the application can be prepared by mixing the solid dispersion with one or more pharmaceutically acceptable carriers according to conventional pharmaceutical compounding techniques, including but not limited to, conventional admixing, dissolving, granulating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0180] Methods of Use

[0181] The application also provides methods of inhibiting a matrix metalloproteinase (MMP), and treating diseases mediated by MMPs using the solid dispersions or pharmaceutical compositions of the application. Matrix metalloproteinases (MMPs), also known as matrixins, are a group of enzymes that in concert are responsible for the degradation of most extracellular matrix proteins during organogenesis, growth, and normal tissue turnover. MMPs are calcium-dependent zinc-containing endopeptidases, and belong to a larger family of proteases known as the metzincin superfamily. MMPs are capable of degrading extracellular matrix proteins, but can also process a number of bioactive molecules, and are known to be involved in, e.g., cleavage of cell surface receptors, release of apoptotic ligands, and chemokine / cytokine inactivation. MMPs are also thought to play a major role in cell behaviors such as cell proliferation, migration (adhesion / dispersion), differentiation, angiogenesis, apoptosis, and host defense. The MMPs are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise 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 (stromelysin 1), MMP-7 (matrilysin), MMP-8 (neutrophil collagenase), MMP-9 (gelatinase-B), MMP-10 (stromelysin 2), MMP-11 (stromelysin 3), MMP-12 (macrophage elastase), MMP-13 (collagenase 3), MMP-14 (MT1-MMP), etc.

[0182] In preferred embodiments, the solid dispersions or pharmaceutical compositions of the application are capable of inhibiting microphage 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.

[0183] In other embodiments, the solid dispersions or pharmaceutical compositions of the application are capable of selectively inhibiting MMP-12. The terms “selective,” “selectivity,” and “selectively” when used with reference to binding or inhibiting the activity of a particular MMP, mean that a compound binds or inhibits the activity of a particular MMP to a greater extent than said compound binds or inhibits the activity of other MMPs. For example, a compound that has selectivity for MMP-12 inhibits the activity of MMP-12 to a greater extent than other MMPs, e.g., MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-13, MMP-14, etc.

[0184] The application also provides methods of treating a disease mediated by MMP-12. According to embodiments of the invention, a method of treating a disease mediated by MMP-12 comprises administering to the subject a therapeutically effective amount of a solid dispersion or a pharmaceutical composition of the application. As used herein, the terms “treat,” “treating,” and “treatment” are all intended to refer to an amelioration or reversal of at least one measurable physical parameter related to a disease mediated by MMP-12, which is not necessarily discernible in the subject, but can be discernible in the subject. The terms “treat,” “treating,” and “treatment,” can also refer to causing regression, preventing the progression, or at least slowing down the progression of a disease mediated by MMP-12. In a particular embodiment, “treat,” “treating,” and “treatment” refer to an alleviation, prevention of the development or onset, or reduction in the duration of one or more symptoms associated with a disease mediated by MMP-12. In a particular embodiment, “treat,” “treating,” and “treatment” refer to prevention of the recurrence of a disease mediated by MMP-12. In a particular embodiment, “treat,” “treating,” and “treatment” refer to an increase in the survival of a subject having a disease mediated by MMP-12. In a particular embodiment, “treat,” “treating,” and “treatment” refer to elimination of a disease mediated by MMP-12 in the subject.

[0185] As used herein, “a therapeutically effective amount” means an amount of a solid dispersion or a pharmaceutical composition that elicits a biological or medicinal response in a tissue system or subject that is being sought by a researcher, veterinarian, medical doctor or other conditions, which can include alleviation of the symptoms of the disease or disorder being treated. A therapeutically effective amount can vary depending upon a variety of factors, such as the physical condition of the subject, age, weight, health, etc.; and the particular disease to be treated. A therapeutically effective amount can readily be determined by one of ordinary skill in the art in view of the present disclosure.

[0186] In particular embodiments of the application, a therapeutically effective amount refers to the amount of a solid dispersion or a pharmaceutical composition of the application which is sufficient to inhibit MMP-12 or treat a disease mediated by MMP-12. Diseases mediated by MMP- 12 that can be treated according to the methods of the 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), Alport syndrome, and nephritis.

[0187] EXAMPLES The following examples illustrate the compositions of the present application. The examples do not limit the application, but are provided to teach how to prepare the useful compositions.

[0188] Example 1: Synthesis of compound IVO

[0189] The synthesis of compound IVO, i.e., 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]- imidazolidin-2, 4-dione, was performed according to the method disclosed in U.S. Patent Application Publication No. 2006 / 0041000.

[0190] Example 2: Determination of concentration of IVO / HPBCD in co-solvents

[0191] Approximate 2 mg of compound IVO was weighed, put in a glass vial, added solvents as shown below stepwise to test its approximate solubility by visual observation. Table 1 lists the solubility of IVO in different solvents at 25 ± 5 °C. In addition, Table 2 lists the solubility of HPBCD in different solvents at 25 ± 5 °C.

[0192] Table 1. Solubility of IVO in different solvents

[0193] Table 2. Solubility of HPBCD in different solvents

[0194] IVO is not very soluble in MeOH, but it is more than 8-fold more soluble in acetone. HPBCD is much more soluble in MeOH than in acetone. When 100 mg IVO and 300 mg HPBCD were weighed, put in glass vials, and added co-solvents, it was surprisingly found that the solubility of IVO and HPBCD is much higher than that in single solvent. Table 3 lists the solubility of 100 mg IVO and 300 mg HPBCD in different co-solvent systems at 25 ± 5°C.

[0195] Table 3. Solubility of IVO and HPBCD in different co-solvents

[0196] Table 4 lists the compositions for preparing different IVO / HPBCD dry powders via different co-solvents. A total weight of 4 g materials with different IVO / HPBCD ratios were dissolved in different co-solvents. After solvent evaporation, 4 g dry powders were tested in 10 ml water to determine their solubility in water. Table 5 lists the aqueous solubility results of IVO of different dry powders in water at 25 ± 5 °C.

[0197] Table 4. The compositions for preparing IVO / HPBCD dry powders in different co-solvents

[0198] Table 5. Solubility of different IVO / HPBCD dry powders after solvent evaporation in water

[0199]

[0200] To determine the maximum solid content in MeOH and 60 / 40 MeOH / Acetone (v / v), the fixed ratio of 1 :3 IVO / HPBCD (w / w) were weighed, put in a glass vial, and then added solvents to test solubility. Table 6 lists the maximum solid content of 1 :3 IVO / HPBCD (w / w) in MeOH and 60 / 40 MeOH / Acetone (v / v). It was surprisingly found that the solubility of IVO / HPBCD in co-solvent (60 / 40 MeOH / Acetone) is >5-fold higher than that in MeOH alone.

[0201] Table 6. The solubility of 1:3 IVO / HPBCD (w / w) in MeOH and 60 / 40 MeOH / Acetone (v / v)

[0202] Example 3: Preparation of the complex of compound IVO with HPBCD by solvent evaporation method

[0203] According to Table 7, approximate 10.0 g of compound IVO was weighed out into a volumetric flask and completely dissolved in adequate volume of MeOH or MeOH / Acetone (v / v) by using ultrasonication to get a clear solution. After filtering it with a 0.45 um filter membrane to remove potential leftover crystal solid, approximate 30.0 g of HPBCD (Ashland) were added into the solution at a ratio of 25:75 (w / w) of IVO:HPBCD. The sample was stirred for 60 min to form a clear solution before it was spray dried to obtain an amorphous solid dispersion. The samples obtained by spray drying (Mini Spray Dryer B-290, BUCHI) was further dried under vacuum condition at 30 °C for 24 hrs.

[0204] Table 7. The details of the IVO / HPBCD ASD

[0205] Table 8 lists the preparation parameters and the names of the complex of compounds. Based on X-ray powder diffraction (XRPD) results for ASD-01 and ASD-04 (FIG. 1 and FIG. 2), the prepared complexes of compound IVO:HPBCD (1:3, w / w) by spray drying method were amorphous. The higher solid content resulted in higher production yield of spray dried samples. FIG. 3 represents molecular fingerprints of the samples via Fourier Transform Infrared (FT-IR) spectroscopic analysis (650cnr'~-4000crrr', Thermo Nicolet 5700 with Microscope Continupm). Compared to ASD-01, the spectrums of all the spray dried samples show no conformation change.

[0206] Table 8. The spray drying parameter setting and results Example 4: Particle size distribution (PSD) measurement

[0207] The particle size of the samples was measured using a Malvern Mastersizer 3000 laser diffraction particle analyzer. The measurement mode was set in dry dispersion system. Table 9 lists parameters and Table 10 lists measurement results. The higher solid content resulted in larger PSD of spray dried solids.

[0208] Table 9. The parameters of PSD measurement mode

[0209] Table 10. Results of PSD measurement

[0210] Example 5: Thermogravimetric analysis (TGA)

[0211] This study was to evaluate samples’ thermal stability. The assay was measured by TA instrument (TGA Q50). Samples were weighed and placed in an open platinum pan and heated from room temperature to -300 °C at a rate of 10 °C / min. Table 11 lists weight loss of the samples from 36 °C to 200 °C. Except IVO initiated weight loss from 150 °C, the other groups showed weight loss from 38 °C. Table 12 lists the samples’ relative weight loss before 150 °C. ASD-01 was heated to reveal 100% weight loss at 94 °C (data not shown) compared to 150 °C. ASD-02, ASD-03, ASD-04 and ASD-05 revealed 100% weight loss between 120 °C~140 °C. Most of these weight losses are related to the residual solvent MeOH in ASD-01 and MeOH / Acetone mixture in other ASDs. The residual methanol in ASD-01 is about 2.4% or less. The residual methanol and acetone in ASD-02, ASD-03, ASD-04 and ASD-05 are about 0.58% and about 2.3%, respectively.

[0212] Table 11. The results of weight loss by TGA analysis

[0213] Table 12. The results of relative weight loss before 150 °C

[0214] Example 6: Stability test under 60 °C stress condition (open)

[0215] This study was to evaluate samples’ stability. 200 mg spray dried powder of each sample was filled into capsules (size 0). The capsules were tested under stress condition (60 °C, open). After 2 weeks and 1 month, the total amount of IVO related impurities or degradation products generated in the samples were analyzed by HPLC method. As shown in Table 13, ASD-01 unexpectedly generated more total impurities in comparison to ASD-02, ASD-04 or ASD-05. The solid dispersions prepared using combination of solvents have an improved chemical stability compared to the reference solid dispersion that is prepared by spray drying a solution using methanol alone. The only difference between ASD-01 and other ASDs is that ASD-02, ASD-04 or ASD-05 contains a small amount of acetone. ASD-01 contains about 2.4% methanol or less, while ASD-02, ASD-04 or ASD-05 contains about 2.3% acetone in addition to methanol. It is unexpected that this small amount of residual acetone in IVO / HPBCD solid dispersion makes spray dried powder more stable.

[0216] Table 13. The result of total impurities under stress condition (60 °C, open)

[0217] Table 14 lists the dissolution method to evaluate the samples’ dissolution profdes under stress condition. FIG. 4 indicated that ASD-01 showed slower dissolution profiles under stress condition.

[0218] Table 14. Dissolution method parameters

[0219] Example 7: Comparison of ASD-04 to ASD-01 in Rats

[0220] PURPOSE

[0221] The objectives of this study were to evaluate the pharmacokinetic profiles of IVO formulations over a period of 8 hours following oral administration by gavage (PO) in male Sprague-Dawley rats, for the purpose of determining and comparing the oral bioavailability of the following formulations: ASD-01 and ASD-04. The plasma concentration of IVO was determined by LC-MS / MS.

[0222] REGULATORY REQUIREMENTS

[0223] This study was not conducted in compliance with GLP regulations. This study was conducted consistent with sound scientific practices and following all applicable standard operating procedures of the Testing Facility.

[0224] STUDY SCHEDULE

[0225] Table 15. Proposed Study Schedule

[0226] STUDY DAY NOTATION

[0227] The first day of acclimation is designated as Pretest Day 1 and subsequent days are consecutively numbered until the first dosing day. The dosing day is designated as Day 1 of the study phase (Day 1 or DI).

[0228] TEST ARTICLE RELATED INFORMATION

[0229] Table 16. Bulk test article 1

[0230] Table 17. Bulk test article 2

[0231] DOSE FORMULATION PREPARATION

[0232] Dose formulations were prepared on the day of dosing. 30 mL of each formulation was prepared in the following steps:

[0233] 1) Weigh out the bulk test articles in the following compositions with the tolerance of measurement set at target weight ± 5 %. The powder was directly weighed in an appropriate size of cylinder for each test article or transfer into a cylinder after weigh.

[0234] Table 18. Dose formulation preparation

[0235] 2) Drop a stir bar in the cylinder. Add sufficient quantity of water for injection (WFI) (up to 4 / 5 of the target volume) to the dry powder by allowing the liquid to flow down the vessel wall slowly. Start mixing with the stir bar for at least 1 hour. (The stir bar speed may reach 500 rpm; reduce speed if bubble forms).

[0236] 3) Visually confirm complete suspension or emulsion, and absence of unsuspended clumps on the wall or at the bottom of the cylinder. Remove the stir bar and add WFI to the final target volume (30 mL final). Return stir bar to the mix. 4) Keep the dose formulation at room temperature and record the completion time of preparation.

[0237] 5) Complete dosing within one (1) hour after completion of dose formulation preparation.

[0238] 6) During dosing, the prepared formulations were kept stirring to minimize sedimentation. Avoid bubble formation or foaming during dosing and sampling. If bubbles form in the dose formulation, reduce stir bar speed until no bubbles or foams in suspension are visible.

[0239] DISPOSITION OF THE REMAINING MATERIALS:

[0240] All of the un-used test articles and remaining dose formulations were stored in a refrigerator at 2 - 8 °C. Sponsor was inquired for disposal or transfer options of the remaining materials.

[0241] TEST SYSTEM

[0242] Description [SOPs: CTPS-TE00032 and CTPS-TE00458]:

[0243] Table 19. Test system

[0244] ANIMAL CARE STATEMENT

[0245] The Testing Facility, CTPS, QPS Taiwan, accredited by AAALAC International, has an Institutional Animal Care and Use Committee (IACUC) responsible for compliance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 201 1) and Animal Protection Act of Taiwan.

[0246] Study animal procedures have been approved by the IACUC (IACUC protocol no.: CTPS- 18-012-06). All procedures described in this protocol were conducted in a manner to avoid or minimize discomfort, distress, or pain to the animals.

[0247] Veterinary Care:

[0248] If unacceptable pain and / or suffering were noted by Testing Facility Veterinarian(s), medical treatments including humane sacrifice would be initiated in agreement with the Study Director, if available. The Study Director would attempt to contact the Sponsor as soon as possible when learning about such animal conditions. If the Study Director or the Sponsor was not available at the time of such animal conditions, the veterinarian could perform the treatments without approval, in which case the Study Director and the Sponsor would be notified of such treatments as soon as possible.

[0249] Animal Housing Conditions [SOPs: CTPS-AC00023, CTPS-AC00025, CTPS-AC00026, and CTPS-AC00029]:

[0250] Housing condition described under this section conforms to the recommendation in the Guide for the Care and Use of Laboratory Animals.

[0251] Table 20. Animal Care Statement

[0252] 1The actual range will be described in the in-life report. Continuous excursions from

[0253] COMPUTER SYSTEM

[0254] The online data collection system Pristima® (Version 7.2.0 or higher; Xybion Medical Systems Corporation) was used in the Testing Facility for the capture of study data when appropriate.

[0255] EXPERIMENTAL DESIGN

[0256] Animal Selection and Acclimation [SOP: CTPS-AC00032]:

[0257] Animals released from the Testing Facility’s quarantine were assigned to the study followed by acclimation until the dosing day.

[0258] Randomization and Group Assignment [SOP: CTPS-TE00510]:

[0259] At least 1 day before dosing, clinically acceptable animals based on acclimation data were allocated to study groups using a randomization procedure The mean body weight of each group was statistically different (p < 0.05) from each other following the randomization by using oneway analysis of variance (ANOVA) or Kruskal-Wallis one-way ANOVA on ranks. The weight variation of animals selected did not exceed ± 20% of the mean weight of all animals.

[0260] Unassigned animals were kept as spares at least until completion of dosing on Day 1. Assigned animals could be replaced with spare animals due to health and / or suspected dosing errors. Collection of spare animal data could not be performed after completion of the acclimation period.

[0261] Table 21. Study design

[0262] Administration of Dose Formulations [SOPs: CTPS-TE00447 and CTPS-TE00488]:

[0263] Table 22. Administration of dose formulations

[0264] OBSERVATION AND EXAMINATION

[0265] Viability Assessment [SOP: CTPS-TE00469]:

[0266] All animals were checked for mortality and moribundity at least twice daily from Day 1 to the End of in-life. Additional observation including cage-side or detailed clinical observation could be performed as necessary.

[0267] Body Weights:

[0268] All study animals were weighed once during pretest phase and once on Day 1 before dosing. Additional body weights could be measured as necessary.

[0269] Blood Specimen Collection, Processing and Transfer [SOPs: CTPS-TE00032 and CTPS- TE00458]:

[0270] Blood was sampled from each study animal. Plasma collection and storage were performed according to the table below. Blood sampling that did not occur within the grace periods was described in the in-life report.

[0271] Table 23. Blood collection

[0272] Specimen transfer:

[0273] Plasma specimens were packed in an insulated container with dry ice and transferred to the Test Site.

[0274] Bioanalysis:

[0275] At Test Site, concentration of IVO in plasma specimens was determined by a LC MS / MS method.

[0276] Terminal Procedures [SOPs: CTPS-TE00475 and CTPS-TE00487]

[0277] Scheduled termination:

[0278] After completion of the last blood specimen sampling, all surviving animals were returned to stock or euthanized by CO2 exposure followed by exsanguination.

[0279] Unscheduled termination:

[0280] If animals needed to be euthanized before the scheduled termination days due to conditions such as moribundity, the animals were weighed and euthanized by CO2 exposure, blood collection and exsanguination followed by necropsy. If an animal was found dead, the animal was weighed and necropsied or stored refrigerated until necropsy within 48 h.

[0281] At necropsy, the external surface of the body, all orifices, cranial, thoracic, and abdominal cavities, and visceral organs were examined, and gross lesions were recorded. Organs or tissues could be collected at the discretion of study director or attending pathologist. Histopathology examination of the collected tissues required explicit request by the Sponsor at additional cost.

[0282] DATA ANALYSES

[0283] PK Parameters:

[0284] PK parameters were determined using non-compartmental analysis on individual profile using Microsoft Excel. The observed maximum plasma concentration (Cmax) and the time of Cmax (Tmax) were determined directly from the data. The area under the plasma concentrati on- time curve from time-0 to 24-hour post-dose (AUC0-24h) and the area under the plasma concentration-time curve from time-0 extrapolated to infinity (AUCO-oo) were determined by the linear trapezoidal rule:

[0285] AUC0-24h = (t2 - tl ) x (C 1 + C2) / 2 with extrapolation to infinity using:

[0286] AUCO-co = AUClast + Clast X

[0287] Where possible, the apparent terminal elimination half-life (tl / 2) was calculated according to the following formula, where is the terminal elimination rate constant: tl / 2 = In (2) / X

[0288] The selection criteria for inclusion of data points in the calculation of X required that at least three data points representing the terminal phase were regressed and that r > 0.85 when rounded. Halflife was defined as not determined (ND) if these criteria were not met. Mean residence time extrapolated to infinity (MRTO-oo) were determined according to the following formulae:

[0289] MRTO-co = ALTMCO-oo / AUCO-co

[0290] Nominal sample collection times were used for AUC, CL, and tl / 2 calculations. Nominal doses were used for dose normalized AUCO-oo in all test article-treated groups.

[0291] RESULTS AND DISCUSSION

[0292] The dosing groups and the blood collection schedule for this study are summarized in above Table 24. There is no obvious difference of PK parameters for ASD-01 and ASD-04 as demonstrated in Table 24. Table 24. PK parameters for ASD-01 and ASD-04 in Rats

[0293] Example 8: Effect of antioxidants in stability improvement of the pre-tablet formulation of ASD-04 (physical mixture).

[0294] The samples were prepared as a physical mixture according to the compositions listed in Table 25, with different antioxidants added in the formulations. The samples were test under stress condition (60°C, open). After 4 months, only the sample (T5) with butylated hydroxyanisole (BHA) as the antioxidant showed obvious stability improvement than others (Table 26).

[0295] Table 25. The physical mixture of pre-tablet formulation of ASD-04 with different antioxidants

[0296] Table 26. Stability results of the physical mixture of pre-tablet formulation of ASD-04 with different antioxidants (60 °C, open)

[0297] Example 9: Explore the antioxidant effect of BHA with ASD-04 directly

[0298] The samples were prepared as a physical mixture according to the compositions listed in Table 27. The samples were tested under stress condition (60 °C, open). After 2 weeks, the groups (S2-S5) of ASD-04 with BHA started to show stability improvement compared the group (SI) of ASD-04 only (Table 28).

[0299] Table 27. The compositions of the ASD with different amount of BHA

[0300] Table 28. Stability results of different ratio of AP within the 1:3 IVO / HPBCD formulation (60 °C, open)

[0301] Example 10: ASD preparation by spray drying with different solid contents

[0302] The mixture of IVO / HPBCD (1 / 3 w / w) with target solid contents of 20% & 30% were dissolved in MeOH / Acetone (59.25 / 40.75, w / w) and used as spray drying solution for solid dispersion preparation, respectively. About 13 g of IVO, 39 g of HPBCD and corresponding solvent were charged into 500 ml bottles and dissolved under stirring to obtain clear solutions, followed by spray drying to form solid dispersions. Detail process parameters for solid dispersion preparation were listed in Table 29. About 15 g of each spray dried ASDs (ASD-03-01, ASD-06 and ASD-03-02) were dried under vacuum oven (secondary drying), and the characterization results of the dried ASDs are listed in Table 30. The residual methanol can be removed under vacuum while the residual acetone can be reduced to 3,000 - 4,000 ppm. The remaining spray dried ASDs were not dried under vacuum oven and used for holding time and secondary drying study in Example 11.

[0303] Table 29. Spray drying parameters of IVO / HPBCD (1 / 3 w / w) ASD preparation

[0304]

[0305] Table 30. Characterization results for IVO / HPBCD (1 / 3 w / w) ASDs

[0306]

[0307] Example 11: Secondary drying study for spray dried ASD powder

[0308] In order to evaluate the stability of spray dried ASD powder in the secondary drying process, the spray dried ASD powder in 40 mL glass vials was dried at 50 °C and 65 °C under vacuum for up to 14 days, respectively. About 3.5 g of each spray dried ASD powder was weighed into a container. Then the samples were placed at 50 °C and 65 °C under continuous high vacuum (close to 0 mbar as measured by an absolute pressure gauge, Model 500 33 155). At each sampling point, certain amount of samples was withdrawn and characterized, and detailed information are listed in Table 31 and 32. Residual methanol can be reduced to the level undetectable at 65 °C. However, residual acetone can be reduced to about 200 ppm but cannot be completely removed even after drying at 65 °C under vacuum for 14 days.

[0309] Table 31. Secondary drying study results of ASD-03-01

[0310] Table 32. Secondary drying study results of (ASD-06) It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the present description.

Claims

What is claimed:

1. A solid dispersion with an improved stability comprising (i) a compound of 5-{3-[4-(3- methyl-benzyloxy) phenylthio]fur-2-yl}imidazolidine-2, 4-dione (IVO), (ii) a hydroxypropyl beta-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 from 1 :99 to 99: 1 (w / w), preferably from 10:90 to 90: 10 (w / w), more preferably from 20:80 to 80:20 (w / w), and most preferably from 25:75 to 75:25 (w / w).

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

5. The solid dispersion of claim 1, wherein the solid dispersion has a particle size distribution as expressed by Dv90 / Dvl0 that is less than 15.

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

7. The solid dispersion of claim 1, wherein the solid dispersion has a relative weight loss less than 90% as determined by thermogravimetric analysis at 100 °C.

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

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

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

1. The solid dispersion of claim 1, wherein the solid dispersion is prepared by a method comprising spray drying a solution to afford a powder composition, wherein the solution comprise (i) a compound of 5-{3-[4-(3-methyl-benzyloxy) phenylthio]fur-2- yl}imidazolidine-2, 4-dione (IVO), (ii) a hydroxypropyl beta-cyclodextrin (HPBCD), and (iii) a solvent mixture comprising two or more organic solvents.

12. A method for preparing a solid dispersion with an improved stability comprising spray drying a solution to afford a powder composition, wherein the solution comprise (i) a compound of 5-{3-[4-(3-methyl-benzyloxy) phenylthio]fur-2-yl}imidazolidine-2, 4-dione (IVO), (ii) a hydroxypropyl beta-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 the group consisting of 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 from 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 higher than 15 mg / mL at 25 ± 5 °C.

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

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

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

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

22. The method of claim 12, wherein the solid dispersion has a particle size distribution as expressed by Dv90 / Dvl0 that is less than 15.

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

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

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

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

27. The method of claim 12, wherein the solid dispersion has an improved chemical stability in comparison to a reference solid dispersion that is prepared by spray drying a solution comprising (i) a compound of IVO, (ii) a hydroxypropyl beta-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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