TW202345857A - Stable formulations of talabostat - Google Patents

Abstract

The disclosure relates to a stable formulations of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising talabostat or a pharmaceutically acceptable salt thereof; silicified microcrystalline cellulose, sodium phosphate monobasic monohydrate; phosphoric acid, and magnesium stearate. The formulations show particularly good stability for longer periods of storage and at higher relative humidity. The disclosure further relates to process of preparing said formulations and treatment methods using the same.

Description

Stable formulations of tapostatin

The present disclosure relates to formulations ( eg, tablets or capsules) suitable for oral administration of talabostat or a pharmaceutically acceptable salt thereof. This disclosure covers formulations including taboxostat or a pharmaceutically acceptable salt thereof, silicified microcrystalline cellulose, sodium phosphate dihydrogen phosphate monohydrate, phosphoric acid, and magnesium stearate. The formulation is stable when stored in a container at room temperature at about 60% relative humidity for a period of at least 6 months. The present disclosure further relates to processes for preparing the formulations and methods of treatment using the formulations.

Tabostat is also known as PT-100 (Val-boro-Pro; L-valinyl-L-boroproline), which is an oral antidote for dipeptidyl peptidases (such as FAP, DPP8 and DPP9). Synthetic selective inhibitors are available. It plays an important role in immune evasion and modulates innate immunity and/or acquired immunity. U.S. Patent No. 6,825,169 discloses stereoisomers of taboxostat, while U.S. Patent No. 7,265,118 discloses oral formulations such as tablets, capsules and lozenges.

Due to stability issues, previously manufactured tablet formulations of Tabostat required storage under refrigerated conditions ( eg, 2°C-8°C). However, this storage condition is not customary for tablet dosage forms since it affects the distribution chain of the drug in terms of cost but also in terms of patient logic. The formation of impurities may affect safety and efficacy and may therefore be harmful to pharmaceutical products.

Stability of pharmaceutical formulations is one of the most important criteria to ensure safety and consistent and effective administration. The selection of excipients in formulation design is based on their functionality and chemical compatibility with the drug substance. Any changes in the formulation process, environmental conditions ( such as microenvironmental pH, temperature, water content, water activity and/or oxygen) and drug/excipient ratio or API particle size can also affect drug product stability.

There is a need to develop stable formulations that can be stored under a range of temperature conditions so that there are no longer any storage problems. These formulations will remove any concerns from patients about keeping medications within specific storage conditions.

The present disclosure solves problems in this technology by developing formulations of tabostat, or a pharmaceutically acceptable salt thereof, that perform under long-term conditions at room temperature and about 60% relative humidity and at 40 Maintain stability for at least 6 months when stored under accelerated conditions at ℃ and 75% relative humidity, with minimal loss of performance and minimal levels of impurities.

This disclosure is based on the discovery that the root cause of initial potency loss and impurities during the manufacture of tapoxostat formulations is due to oxidative and hydrolytic degradation caused by interaction with one or more components of the formulation. After performing several experiments and binary mixture studies of different ratios of tapoxostat to excipients, the inventors surprisingly found that at RRT 1.16, a significant decrease in initial analysis and impurity formation was attributed to taboxostat Interacts with oxidizing compounds in formulations. One such compound is the disintegrant crospovidone. However, removal of crospovidone provided the formulation with an unacceptably long disintegration time, so the presence of an alternative disintegrant was required to achieve rapid disintegration within 5 minutes.

Therefore, formulations of Tabostat or its pharmaceutically acceptable salts are based on the selection of suitable disintegrants that are stable at room temperature and 60% relative humidity (RH) for at least 6 months, And it is stable even under accelerated storage conditions of 40°C and 75% RH, with minimal impurities and performance loss. All physicochemical parameters of the formulation (including, for example, hardness, thickness, disintegration time, dissolution, content uniformity) are acceptable and beneficial from a patient compliance perspective, making it easier to take the required Drugs. Formulations including taposostat

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And the total amount of impurities is less than 1%.

In embodiments, the present disclosure provides a stable tablet formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the stable tablet formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, The total amount of impurities is less than 1%, and there are no detectable impurities at the relative retention times (RRT) of 1.06 and 1.16.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And the total amount of impurities is less than 1%.

In embodiments, the formulation retains about 96%, about 97%, about 98%, or about 99% of the original amount of taboxostat or a pharmaceutically acceptable salt thereof. In embodiments, the total amount of impurities is less than 0.5% after 6 months of storage in a container at room temperature and about 60% relative humidity. In an embodiment, after 6 months of storage in a container at room temperature and about 60% relative humidity, the formulation retains about 99.5% of the initial amount of tabosostat or a pharmaceutically acceptable salt thereof and impurities The total amount is less than 0.2%.

In an example, the formulation retains about 98% of the initial amount of Taboxostat or a pharmaceutically acceptable salt thereof after 12 months in the container at room temperature and about 60% relative humidity.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising: (i) Intra-particle fraction and (ii) Extra-granular part; The intra-particle part includes: (a) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; (b) Phosphoric acid in an amount of about 0.005% to about 0.1% w/w; and (c) about 85% to about 99% w/w silicified microcrystalline cellulose; and The extragranular part includes: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; and (b) Magnesium stearate in an amount of about 0.01% to about 5% w/w.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And the total amount of impurities is less than 1%.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable thereof after storage in the container for 6 months at about 2°C to about 8°C and about 60% RH. of salt, and the total amount of impurities is less than about 1%. In the examples, the formulations were stored in Multiblock HDPE bottles. In the examples, the formulations were stored in normal HDPE bottles.

In embodiments, the formulation retains about 96%, about 97%, about 98%, or about 99% of the initial amount of tabostat or Its pharmaceutically acceptable salt, and the total amount of impurities is less than 0.5%.

In an embodiment, after 6 months of storage in a container at about 2°C to about 8°C, the formulation retains about 98.5% of the initial amount of tabosostat or a pharmaceutically acceptable salt thereof and 1% of the impurities. The total amount is less than 0.2%.

In embodiments, the present disclosure provides a stable tablet formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the stable tablet formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or its pharmaceutically acceptable form after storage in a container under accelerated conditions for 1 month at a temperature of 40°C and a relative humidity of about 75%. Salt is acceptable and the total impurity content is less than 1%.

In the examples, the formulations were stored in Multiblock HDPE bottles. In the examples, the formulations were stored in normal HDPE bottles.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising: (i) an intragranular portion, and (ii) an extragranular portion, wherein the intragranular portion comprises: (a) from about 0.01% to about 2% w/w sodium dihydrogen phosphate monohydrate, (b) about 0.005% to about 0.1% w/w phosphoric acid, and (c) about 85% to about 99% w/w silica micron Crystalline cellulose, and the extragranular portion contains: (d) about 0.1% to about 0.2% w/w amount of Taboxostat or a pharmaceutically acceptable salt thereof, and (e) about 0.01% to about 5% w/w amount of magnesium stearate.

In an embodiment, the formulation retains at least about 95% of the initial amount of tabosostat or its pharmaceutically acceptable form after storage in a container under accelerated conditions for 6 months at a temperature of 40°C and a relative humidity of about 75%. Salt is acceptable and the total impurity content is less than 1%.

In an embodiment, the total amount of impurities is less than 0.2% after 1 month of storage in a container at a temperature of 40°C and a relative humidity of about 75%.

In embodiments, taboxostat or a pharmaceutically acceptable salt thereof is present in an amount from about 0.05% to about 0.2% w/w based on the total weight of the formulation.

In embodiments, taboxostat or a pharmaceutically acceptable salt thereof is present in an amount of about 50 micrograms to about 800 micrograms. In embodiments, taboxostat or a pharmaceutically acceptable salt thereof is present in an amount of about 50 micrograms to about 600 micrograms. In embodiments, taboxostat or a pharmaceutically acceptable salt thereof is present in an amount of about 50 micrograms to about 400 micrograms.

In embodiments, the amount of tabostat or a pharmaceutically acceptable salt thereof in a unit dose (e.g., a tablet) is about 10 micrograms, about 20 micrograms, about 30 micrograms, about 40 micrograms, about 50 micrograms, about 75 micrograms, about 100 micrograms, about 150 micrograms, about 180 micrograms, about 190 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 600 micrograms, about 700 micrograms, or about 800 micrograms.

In embodiments, a formulation ( eg, a tablet) of tabinostat or a pharmaceutically acceptable salt thereof includes: (i) an amount of about 0.1% to about 0.2% w/w of taboxostat or a pharmaceutical thereof Scientifically acceptable salts; (ii) about 85% to about 99% w/w of silicified microcrystalline cellulose; (iii) about 0.01% to about 2% w/w of sodium dihydrogen phosphate monohydrate ; and (iv) phosphoric acid in an amount of about 0.005% to about 0.1% w/w.

In an embodiment, a formulation of tabostat or a pharmaceutically acceptable salt thereof includes: (i) Tabostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (ii) about 85% to about 99% w/w silicified microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; (iv) Phosphoric acid in an amount of about 0.005% to about 0.1% w/w; and (v) Magnesium stearate in an amount of about 0.05% to about 5% w/w.

In embodiments, the formulation further comprises microcrystalline cellulose; stearic acid; lactose monohydrate, and/or pregelatinized starch.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; and (viii) Phosphoric acid.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And the total amount of impurities is less than 1%.

In embodiments, the present disclosure provides a stable tablet formulation of taboxostat or a pharmaceutically acceptable salt thereof, the stable tablet formulation comprising or consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; and (viii) Phosphoric acid.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And the total amount of impurities is less than 1%. In an embodiment, after 6 months of storage in a container at room temperature at about 60% relative humidity, the formulation retains about 96% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof, and The total amount of impurities is approximately 0.8%.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising: (i) Intra-granular portion; and (ii) Extra-granular part; The intra-particle part includes: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; and (c) phosphoric acid in an amount of about 0.005% to about 0.1% w/w; and The extragranular part includes: (a) About 25% to about 95% w/w lactose monohydrate; (b) Microcrystalline cellulose in an amount of about 5% to about 95% w/w; (c) Silicated microcrystalline cellulose in an amount from about 2% to about 95% w/w; (d) Pregelatinized starch in an amount of about 0.05% to about 10% w/w; (e) Stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And the total amount of impurities is less than 1%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose, (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; and (viii) Phosphoric acid.

In embodiments, the formulation retains at least about 98% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container for 6 months at a temperature of about 2°C to about 8°C, And the total amount of impurities is less than 1%.

In embodiments, the formulation retains about 99% or about 100% of the initial amount of taboxostat or its pharmaceutically acceptable form after storage in the container for 6 months at a temperature of about 2°C to about 8°C. of salt, and the total amount of impurities is approximately 0.8%.

In embodiments, the present disclosure provides a stable tablet formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the stable tablet formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; and (viii) Phosphoric acid.

In an embodiment, the formulation retains at least about 90% of the initial amount of tabosostat or its pharmaceutically acceptable form after storage in a container under accelerated conditions for 6 months at a temperature of 40°C and a relative humidity of about 75%. Salt is acceptable and the total impurity content is less than 1%.

In embodiments, the formulation retains about 91%, about 92%, about 93%, or about 93.5% of the initial amount of other components after storage in a container for 6 months at a temperature of 40° C. and a relative humidity of about 75%. Sistat or its pharmaceutically acceptable salt, and the total amount of impurities is about 0.8%.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising: (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) About 0.1% to about 0.2% w/w of Tabostat or its pharmaceutically acceptable salt; (b) About 0.01% to about 2% w/w sodium dihydrogen phosphate monohydrate; and (c) About 0.005% to about 1% w/w phosphoric acid; The extragranular part includes: (a) About 25% to about 95% w/w lactose monohydrate; (b) About 5% to about 95% w/w microcrystalline cellulose; (c) About 2% to about 95% w/w silicified microcrystalline cellulose; (d) About 0.05% to about 10% w/w pregelatinized starch; (e) About 0.05% to about 2% w/w stearic acid; and (f) About 0.01% to about 5% w/w magnesium stearate.

In an embodiment, the formulation retains at least about 95% of the initial amount of tabosostat or its pharmaceutically acceptable form after storage in a container under accelerated conditions for 6 months at a temperature of 40°C and a relative humidity of about 75%. Salt is acceptable and the total impurity content is less than 1%.

In an embodiment, a formulation of tabostat or a pharmaceutically acceptable salt thereof includes: (i) Tabostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (ii) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (iii) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; (iv) About 50% to about 95% w/w lactose monohydrate; (v) Microcrystalline cellulose in an amount of about 5% to about 95% w/w; (vi) Pregelatinized starch in an amount of about 0.05% to about 10% w/w; (vii) Stearic acid in an amount of about 0.05% to about 2% w/w; (viii) Phosphoric acid in an amount of about 0.05% to about 1% w/w; and (ix) Magnesium stearate in an amount of about 0.01% to about 5% w/w, preferably about 0.05% to about 2% w/w.

In an embodiment, the amount of tabinostat or a pharmaceutically acceptable salt thereof in the tablet is about 300 micrograms. In an embodiment, the amount of tabinostat or a pharmaceutically acceptable salt thereof in the tablet is about 200 micrograms. In an embodiment, the amount of tabinostat or a pharmaceutically acceptable salt thereof in the tablet is about 50 micrograms.

In embodiments, the formulation optionally includes a moisture barrier coating. In embodiments, the coating is present in an amount from about 2% to about 8% w/w based on the total weight of the formulation. In an example, the coating represents about 4%/w/w of the total weight of the formulation.

In embodiments, moisture-proof coating polymers include (but are not limited to) cellulose and its derivatives, such as ethyl cellulose, hydroxypropyl methylcellulose (such as hypromellose 5cP and hypromellose 15cP), hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropylmethylcellulose phthalate, phthalate Cellulose acetate dicarboxylate, cellulose acetate trimellitate; waxes; polyvinyl derivatives, such as PVA (polyvinyl alcohol), such as those available under the trademarks Opadry AMB, Opadry II, Opadry QX (Kollicoat), Or PVP-PVAc copolymers (polyvinylpyrrolidone-polyvinyl acetate copolymer) and methacrylic polymers ( such as Eudragit) and the like.

In an embodiment, the coating includes Opadry AMB-II Blue Light.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; (viii) Phosphoric acid; and (ix) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after 6 months of storage in the container at room temperature and about 60% relative humidity, and The total amount of impurities is less than 1%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; (viii) Phosphoric acid; and (ix) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after 6 months of storage in the container at room temperature and about 60% relative humidity, and The total amount of impurities is less than 1%. In embodiments, the formulation retains about 96%, about 97%, about 98%, or about 99% of the initial amount of tabostat or its pharmaceutical when stored in the container at room temperature and about 60% relative humidity. Scientifically acceptable salt with a total impurity content of less than 1%.

In embodiments, when stored in a container at room temperature and about 60% relative humidity, the formulation retains about 98.5% of the initial amount of tabosostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities It is about 0.7%.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising: (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.1% to about 0.2% w/w tabosostat or a pharmaceutically acceptable salt thereof, (b) about 0.01% to about 2% w/w sodium dihydrogen phosphate monohydrate, and (c) about 0.5% to About 1% w/w phosphoric acid; and the extragranular portion contains (d) about 25% to about 95% w/w lactose monohydrate; (e) about 5% to about 95% w/w microcrystalline fibers (f) about 2% to about 95% w/w silicified microcrystalline cellulose; (g) about 0.05% to about 10% w/w pregelatinized starch; (h) about 0.05% to about 2 % w/w stearic acid; and (i) about 0.01% to about 5% w/w magnesium stearate.

In an embodiment, the formulation further comprises from about 2% w/w to about 4% w/w a moisture barrier coating, and after storage in the container at room temperature at about 60% relative humidity for 6 months, the formulation At least about 95% of the initial amount of tabosat or its pharmaceutically acceptable salt is retained, and the total amount of impurities is less than 1%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; (viii) Phosphoric acid; and (ix) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container for 6 months at a temperature of about 2°C to about 8°C, And the total amount of impurities is less than 1%.

In embodiments, the formulation retains about 96%, about 97%, about 98%, or about 99% of the initial amount of tabostat or its pharmaceutical composition when stored in the container at about 2°C to about 8°C. acceptable salt, and the total amount of impurities is less than 1%.

In embodiments, when stored in the container at about 2°C to about 8°C, the formulation retains about 99.5% of the original amount of tabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is About 0.6%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; (viii) Phosphoric acid; and (ix) Moisture-proof film coating.

In an embodiment, the formulation retains at least about 95% of the initial amount of tabosostat or its pharmaceutically acceptable form after storage in a container under accelerated conditions for 6 months at a temperature of 40°C and a relative humidity of about 75%. Salt is acceptable and the total impurity content is less than 1%. In embodiments, the formulation retains about 96%, about 97%, about 98% or about 99% of the initial amount of tabostat or Its pharmaceutically acceptable salt, and the total amount of impurities is about 0.7%.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.1% to about 0.2 % w/w of Tabostat or a pharmaceutically acceptable salt thereof, (b) about 0.01% to about 2% w/w of sodium dihydrogen phosphate monohydrate, and (c) about 0.5% to about 1% w/w phosphoric acid; and the extragranular portion contains (d) about 25% to about 95% w/w lactose monohydrate, (e) about 5% to about 95% w/w Microcrystalline cellulose, (f) silicified microcrystalline cellulose in an amount of about 2% to about 95% w/w, (g) pregelatinized starch in an amount of about 0.05% to about 10% w/w, (h) stearic acid in an amount of about 0.05% to about 2% w/w, and (i) magnesium stearate in an amount of about 0.01% to about 5% w/w.

In an embodiment, the formulation further comprises a moisture-proof coating of about 2% w/w to about 4% w/w, and is formulated after storage in a container at a temperature of 40° C. and a relative humidity of about 75% for 6 months. The substance retains at least about 95% of the original amount of tabosat or its pharmaceutically acceptable salt, and the total amount of impurities is less than 1%.

In the Examples, the formulation contained undetectable impurities at an RRT of 1.06 after 6 months of storage in the container at a temperature of 40°C and a relative humidity of about 75%.

In the Examples, the formulations contained undetectable impurities at RRT 1.16 after 6 months of storage in containers at a temperature of 40°C and a relative humidity of about 75%.

In an embodiment, a formulation of tabostat or a pharmaceutically acceptable salt thereof includes: (i) About 0.1% to about 2% w/w of Tabostat or its pharmaceutically acceptable salt; (ii) About 50% to about 95% w/w lactose monohydrate; (iii) Microcrystalline cellulose in an amount of about 5% to about 95% w/w; (iv) Pregelatinized starch in an amount of about 0.05% to about 10% w/w; (v) Stearic acid in an amount of about 0.05% to about 2% w/w; (vi) Silicated microcrystalline cellulose in an amount from about 2% to about 95% w/w; (vii) Sodium dihydrogen phosphate monohydrate in an amount from about 0.01% to about 2% w/w, (viii) Phosphoric acid in an amount of about 0.005% to about 0.1% w/w; and (ix) Moisture-proof film coating in an amount of about 2% w/w to about 4% w/w.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; (v) Magnesium stearate; and (vi) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And the total amount of impurities is less than 1%. In embodiments, the formulation retains about 96%, about 96.5%, or about 97% of the initial amount of tabosostat or its pharmaceutically acceptable form when stored in the container at room temperature at about 60% relative humidity. Salt is accepted, and the total amount of impurities is approximately 0.8%.

In embodiments, a formulation of taboxostat or a pharmaceutically acceptable salt thereof includes (i) an intragranular portion; and (ii) an extragranular portion; The intra-particle part includes: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; and (c) Phosphoric acid in an amount from about 0.005% to about 2% w/w; and The extragranular part includes: (a) Lactose monohydrate in an amount from about 25% to about 95% w/w; (b) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (c) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (d) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (e) Stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w, The formulation further includes a moisture-proof coating in an amount of about 2% w/w to about 4% w/w.

In embodiments, the formulation is a stable tablet and includes (i) an intragranular portion; and (ii) an extragranular portion; The intra-particle part includes: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) Potassium dihydrogen phosphate in an amount of about 0.01% to about 2% w/w; and (c) Hydrochloric acid in an amount of about 0.005% to about 0.1% w/w; and The extragranular part includes: (a) About 25% to about 95% w/w lactose monohydrate; (b) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (c) Silicated microcrystalline cellulose in an amount from about 2% to about 95% w/w; (d) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (e) Stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w, The formulation further includes a moisture-proof coating in an amount of about 2% w/w to about 4% w/w.

In embodiments, a formulation of taboxostat or a pharmaceutically acceptable salt thereof includes (i) an intragranular portion; and (ii) an extragranular portion; The intra-particle part includes: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) Citric acid in an amount from about 0.01% to about 2% w/w; and The extragranular part includes: (a) About 25% to about 95% w/w lactose monohydrate; (b) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (c) Silicated microcrystalline cellulose in an amount from about 2% to about 95% w/w; (d) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (e) Stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w, The formulation further includes a moisture-proof coating in an amount of about 2% w/w to about 4% w/w.

In embodiments, a formulation of taboxostat or a pharmaceutically acceptable salt thereof includes (i) an intragranular portion; and (ii) an extragranular portion; The intra-particle part includes: (a) About 0.1% to about 0.2% w/w of Tabostat or its pharmaceutically acceptable salt; (b) About 0.01% to about 2% w/w malic acid; and The extragranular part includes: (a) About 25% to about 95% w/w lactose monohydrate; (b) About 5% to about 40% w/w microcrystalline cellulose; (c) About 2% to about 95% silicified microcrystalline cellulose; (d) About 0.05% to about 5% w/w pregelatinized starch; (e) About 0.02% to about 2% w/w stearic acid; and (f) About 0.01% to about 5% w/w magnesium stearate, The formulation further includes a moisture-proof coating of about 2% w/w to about 4% w/w.

In an embodiment, a formulation of tabostat or a pharmaceutically acceptable salt thereof includes: (i) Tabostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (ii) about 2% to about 95% w/w silicified microcrystalline cellulose; (iii) About 0.01% to about 2% w/w sodium dihydrogen phosphate monohydrate; (iv) About 50% to about 95% w/w lactose monohydrate; (v) About 5% to about 40% w/w microcrystalline cellulose; (vi) About 0.05% to about 5% w/w pregelatinized starch; (vii) About 0.05% to about 0.1% w/w phosphoric acid; and (viii) about 0.01% to about 5% w/w, preferably about 0.05% to about 2% w/w magnesium stearate, The formulation further includes a moisture-proof coating of about 2% w/w to about 4% w/w.

In embodiments, the present disclosure provides formulations suitable for oral administration, such as lozenges, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) about 0.01 % to about 2% w/w sodium dihydrogen phosphate monohydrate, (b) about 0.5% to about 1% w/w phosphoric acid, and (c) about 85% to about 99% w/w Silicated microcrystalline cellulose, and the extragranular portion contains: (d) about 0.1% to about 0.2% w/w of Tabostat or a pharmaceutically acceptable salt thereof, and (e) about 0.01% to about 0.2% w/w Approximately 5% w/w magnesium stearate.

In an embodiment, the formulation further comprises a moisture barrier coating in an amount from about 2% w/w to about 4% w/w, and is formulated after storage in a container at room temperature at about 60% relative humidity for 6 months. The substance retains at least about 95% of the original amount of tabosat or its pharmaceutically acceptable salt, and the total amount of impurities is less than 1%.

In embodiments, a formulation of taboxostat or a pharmaceutically acceptable salt thereof includes (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion includes: (a) about 0.01% to Sodium dihydrogen phosphate monohydrate in an amount of about 2% w/w; (b) phosphoric acid in an amount of about 0.5% to about 1% w/w; and (c) trace amounts in an amount of about 85% to about 99% w/w Crystalline cellulose, and the extragranular portion contains: (d) from about 0.1% to about 0.2% w/w of Taboxostat or a pharmaceutically acceptable salt thereof; and (e) from about 0.01% to about 5% Magnesium stearate in an amount w/w, wherein the formulation further includes a moisture-proof coating in an amount from about 2% w/w to about 4% w/w.

In embodiments, the present disclosure provides a formulation of tabostat or a pharmaceutically acceptable salt thereof comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) About 0.01% to about 2% w/w sodium dihydrogen phosphate monohydrate; (b) about 0.5% to about 1% w/w phosphoric acid; and (c) about 25% to about 75% w/w silicified microcrystalline cellulose; (d) about 25% to about 75% w/w microcrystalline cellulose; and the extragranular portion contains: (e) about 0.1% to about 0.2% w/w tabostat or Its pharmaceutically acceptable salt, and (f) about 0.01% to about 5% w/w magnesium stearate, wherein the formulation further includes about 2% w/w to about 4% w/w moisture-proof package Clothes.

In the examples, the microcrystalline cellulose is MCC-101. In embodiments, microcrystalline cellulose is present at about 25% w/w and silicified microcrystalline cellulose is present at about 75% w/w. In embodiments, microcrystalline cellulose is present at about 50% w/w and silicified microcrystalline cellulose is present at about 50% w/w. In embodiments, microcrystalline cellulose is present at about 75% w/w and silicified microcrystalline cellulose is present at about 25% w/w.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.01% to about 2 % w/w sodium dihydrogen phosphate monohydrate; (b) about 0.025% to about 1% w/w phosphoric acid, and (c) about 85% to about 99% w/w microcrystalline cellulose; and The extragranular portion contains: (d) from about 0.1% to about 0.2% w/w of tabostat or a pharmaceutically acceptable salt thereof; (e) from about 0.01% to about 5% w/w of stearic acid magnesium; and (f) optionally from about 0.5% to about 5% w/w of pregelatinized starch, wherein the formulation further includes from about 2% w/w to about 4% w/w of a moisture-resistant coating.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.01% to about 2 % w/w potassium dihydrogen phosphate, (b) about 0.5% to about 1% w/w hydrochloric acid, and (c) about 85% to about 99% w/w silicified microcrystalline cellulose, and extragranular Comprising in part: (d) from about 0.1% to about 0.2% w/w of taboxostat or a pharmaceutically acceptable salt thereof, and (e) from about 0.01% to about 5% w/w of magnesium stearate .

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.5% to about 2 % w/w malic acid, and (b) about 85% to about 99% w/w silicified microcrystalline cellulose, and the extragranular portion contains: (c) about 0.1% to about 0.2% w/w others Bosistat or a pharmaceutically acceptable salt thereof, and (d) about 0.01% to about 5% w/w magnesium stearate.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.1% to about 2 % w/w citric acid, and (b) about 85% to about 99% w/w silicified microcrystalline cellulose, and the extragranular portion contains: (c) about 0.1% to about 0.2% w/w others Bosistat or a pharmaceutically acceptable salt thereof, and (d) about 0.01% to about 5% w/w magnesium stearate. In the Examples, the formulations contained no detectable impurities at an RRT of 1.06 after 6 months of storage in containers at room temperature at about 60% relative humidity.

In the Examples, the formulations contained no detectable impurities at an RRT of 1.16 after 6 months of storage in containers at room temperature at about 60% relative humidity.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, such as a stable lozenge, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; (v) Magnesium stearate; and (vi) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container for 6 months at a temperature of about 2°C to about 8°C, And the total amount of impurities is less than 1%. In embodiments, the stable lozenge formulation retains about 96%, about 96.5%, about 97%, or about 97.5% of the initial amount of tabostat or Its pharmaceutically acceptable salt, and the total amount of impurities is about 0.8%.

In the Examples, the stable tablet formulations contained no detectable impurities at an RRT of 1.06 after 6 months of storage in containers at 2°C-8°C. In the Examples, the stable tablet formulations contained no detectable impurities at an RRT of 1.16 after 6 months of storage in the container at room temperature at about 2°C to about 8°C.

In embodiments, the present disclosure provides a stable tablet formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the stable tablet formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; (v) Magnesium stearate; and (vi) Moisture-proof film coating.

In embodiments, the stable tablet formulation retains at least about 95% of the initial amount of tabosostat or its pharmaceutically acceptable form after storage in a container for 6 months at a temperature of 40°C and a relative humidity of about 75%. Salt is acceptable and the total impurity content is less than 1.5%. In embodiments, the stable lozenge formulation retains about 96%, about 96.5%, or about 97% of the initial amount of tapoxostat or Its pharmaceutically acceptable salt, and the total amount of impurities is about 1%.

In embodiments, the present disclosure provides stable tablet formulations suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) about 0.01% to about 2% w/w sodium dihydrogen phosphate monohydrate, (b) about 0.5% to about 1% w/w phosphoric acid, and (c) about 85% to about 99% w/w Silicated microcrystalline cellulose, and the extragranular portion contains: (d) about 0.1% to about 0.2% w/w of Tabostat or a pharmaceutically acceptable salt thereof; and (e) about 0.01% to about Magnesium stearate in an amount of 5% w/w, wherein the tablet further contains a moisture-proof coating in an amount of about 2% to about 4% w/w.

In embodiments, the stable tablet formulation retains at least about 95% of the initial amount of tabosostat or its pharmaceutically acceptable form after storage in a container for 6 months at a temperature of 40°C and a relative humidity of about 75%. Salt is acceptable and the total impurity content is less than 1%.

In the Examples, stable tablet formulations contained undetectable impurities at an RRT of 1.06 after 6 months of storage in containers at a temperature of 40°C and a relative humidity of about 75%. In the Examples, stable tablet formulations contained undetectable impurities at RRT 1.16 after storage in containers for 6 months at room temperature at a temperature of 40°C and a relative humidity of about 75%.

In embodiments, the coating includes cellulose and its derivatives, such as ethylcellulose, hydroxypropylmethylcellulose (such as hypromellose 5cP and hypromellose 15cP), hydroxypropylmethylcellulose , methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, metaphenylene Cellulose triacid acetate; waxes; polyvinyl derivatives such as PVA (polyvinyl alcohol), such as those available under the trademarks Opadry AMB, Opadry II, Opadry QX (Kollicoat), or PVP-PVAc copolymers (polyvinyl alcohol). Vinylpyrrolidone-polyvinyl acetate copolymer) and methacrylic polymers (e.g. Eudragit and the like), preferably Opadry AMB Blu-ray.

In an embodiment, a stable tablet formulation of tabostat or a salt thereof includes: (i) About 0.1% to about 2% w/w of Tabostat or its pharmaceutically acceptable salt; (ii) about 2% to about 95% w/w silicified microcrystalline cellulose; (iii) About 0.01% to about 2% w/w sodium dihydrogen phosphate monohydrate; (iv) About 0.005% to about 0.1% w/w phosphoric acid; (v) about 0.01% to about 5% w/w, preferably about 0.05% to about 2% w/w magnesium stearate, and (vi) About 2% w/w to about 4% w/w moisture-proof film coating.

In an embodiment, the coating includes Opadry AMB Blue Light.

In an embodiment, the stable tablet formulation does not contain crospovidone.

In the examples, the formulations were stored in Multiblock HDPE bottles.

In the examples, the formulations were stored in normal HDPE bottles. Methods of making preparations

In embodiments, the present disclosure provides a process for preparing a stable tablet formulation of taboxostat or a pharmaceutically acceptable salt thereof, which process includes: (i) Prepare a clear buffer solution by dissolving orthophosphoric acid and sodium phosphate in purified water; (ii) Add silica microcrystalline cellulose to the above buffer solution; (iii) Granulate the solution and then dry the granules; (iv) Extragranularly blended with Tabostat or its pharmaceutically acceptable salt; (v) Where appropriate, the blend is lubricated with magnesium stearate and compressed into tablets; and (vi) Coat tablets with film coating as appropriate.

In embodiments, the present disclosure provides a process for preparing a stable tablet formulation of taboxostat or a pharmaceutically acceptable salt thereof, which process includes: (i) Prepare a clear buffer solution by dissolving orthophosphoric acid and sodium phosphate in purified water; (ii) Add Tabostat or its pharmaceutically acceptable salt to the above solution and granulate the solution; (iii) Dry the granules and blend them with pregelatinized starch and silicified microcrystalline cellulose; (iv) Lubricate the blend and compress it into tablets; and (v) If appropriate, coat the tablets with a film coating.

In embodiments, the present disclosure provides a process for preparing a stable tablet formulation of taboxostat or a pharmaceutically acceptable salt thereof, which process includes: (i) Sieve the silica microcrystalline cellulose and divide it into multiple parts, (ii) Mix Tabostat or its pharmaceutically acceptable salt, the first part of siliconized microcrystalline cellulose, orthophosphoric acid and sodium phosphate buffer in a plastic bag for 10 minutes; (iii) Manually mix the blend of step (ii) and the second portion of silica microcrystalline cellulose in a plastic bag for 15 minutes, and then sieve; (iv) Manually mix the blend of step (iii) and the third portion of silica microcrystalline cellulose in a plastic bag for 15 minutes, and then sieve; (v) Manually mix the blend of step (iv) and the fourth portion of silica microcrystalline cellulose in a plastic bag for 15 minutes, and then sieve; (vi) Lubricate the blend and compress it into tablets; and vii) If appropriate, coat the tablets with a film coating.

In embodiments, the present disclosure provides a process for preparing a stable tablet formulation of taboxostat or a pharmaceutically acceptable salt thereof, which process includes: (i) Sieve the silicified microcrystalline cellulose and divide it into 4 parts, (ii) Mix Tabostat or its pharmaceutically acceptable salt, the first part of siliconized microcrystalline cellulose, orthophosphoric acid and sodium phosphate buffer in a plastic bag for 10 minutes; (iii) Manually mix the blend of step (ii) and the second portion of silica microcrystalline cellulose in a plastic bag for 15 minutes, and then sieve; (iv) Manually mix the blend of step (iii) and the third portion of silica microcrystalline cellulose in a plastic bag for 15 minutes, and then sieve; (v) Manually mix the blend of step (iv) and the fourth part of silica microcrystalline cellulose in a plastic bag for 15 minutes, and then sieve; (vi) Pre-lubrication step (v) blends and forms small pieces or compacts; (vii) By grinding small pieces or briquettes through a screen; (viii) Lubricating blends; and (ix) Coat with film coating as appropriate.

In embodiments, tablet formulations of taboxostat or a pharmaceutically acceptable salt thereof are prepared by any known process including direct compression, dry granulation, or wet granulation. In the examples, siliconized microcrystalline cellulose, acid buffer, and magnesium stearate were dry blended and compressed in a rapid mixer granulator. In the examples, buffer was coated onto microcrystalline cellulose and the buffer-coated microcrystalline cellulose was used for direct compression.

In embodiments, Tabostat or its pharmaceutically acceptable salt is added extragranularly during the wet granulation process. In an embodiment, the silicified microcrystalline cellulose is granulated with an acidic buffer, and the acidified silicated microcrystalline cellulose is then admixed with Taboxostat or a pharmaceutically acceptable salt thereof.

In embodiments, Tabostat or a pharmaceutically acceptable salt thereof is dissolved in an acidic buffer solution to form a granulation fluid. In an embodiment, the granulation fluid is used to form particles of a blend of lactose monohydrate and microcrystalline cellulose.

In an embodiment, the present disclosure provides a dry formulation process for preparing a formulation of taboxostat or a pharmaceutically acceptable salt thereof, which process includes the following steps: mixing taboxostat in the presence of added water. Sistat or its pharmaceutically acceptable salt and one or more excipients selected from the group consisting of siliconized microcrystalline cellulose, sodium phosphate, phosphoric acid, and magnesium stearate.

In embodiments, during the process of preparing formulations of taboxostat or a pharmaceutically acceptable salt thereof, the relative humidity is maintained at or below 60% to prevent water absorption and degradation. In embodiments, the process is performed under dark light (i.e., sodium vapor lamp) to prevent photolytic degradation of Tabostat or its pharmaceutically acceptable salt. In embodiments, tabostat or a pharmaceutically acceptable salt thereof is not in direct contact with the aqueous vehicle during the manufacturing process.

In embodiments, silicified microcrystalline cellulose is added during the process of preparing the formulation at about 2% to about 95% w/w. In embodiments, silicified microcrystalline cellulose is added during the process of preparing the formulation at about 85% to about 99% w/w. In embodiments, phosphoric acid is added during the process at about 0.005% to about 0.1% w/w. In embodiments, phosphoric acid is added during the process at about 0.005% to about 2% w/w. In embodiments, sodium dihydrogen phosphate monohydrate is added during the process at about 0.01% to about 2% w/w. In embodiments, magnesium stearate is added during processing at about 0.01% to about 5% w/w. In embodiments, the buffer solution prepared during tablet manufacture has a pH of about 2 to 3. Treatment

In embodiments, the present disclosure provides methods of treating cancer in a subject, comprising orally administering a formulation of tapoxostat or a pharmaceutically acceptable salt thereof. In embodiments, formulations (eg, tablets or capsules) containing Tabostat or a pharmaceutically acceptable salt thereof are administered orally in divided doses at a dose of about 300 micrograms twice daily. In an embodiment, a formulation comprising tabinostat or a pharmaceutically acceptable salt thereof is administered orally twice daily at a dose of about 200 micrograms. In an embodiment, a formulation comprising tabinostat or a pharmaceutically acceptable salt thereof is administered orally in divided doses at a dose of about 200 micrograms three times daily. In embodiments, a formulation comprising tabostat or a pharmaceutically acceptable salt thereof is administered orally twice daily, for example, during the day, with a morning dose of about 400 micrograms and an evening dose of about 200 micrograms. microgram.

In embodiments, the present disclosure provides methods of treating cancer in a subject in need thereof by orally administering a formulation comprising an effective amount of taboxostat or a pharmaceutically acceptable salt thereof and another An active agent, administered simultaneously or sequentially at appropriate intervals of time, in appropriate unit dosage forms. In embodiments, a formulation of tabinostat or a pharmaceutically acceptable salt thereof includes another active agent. In embodiments, the other active agent is presented in a different dosage form for oral administration, which dosage form may be a tablet, a capsule, a granule, a lozenge, and the like. set

In embodiments, the present disclosure is directed to individual unit dosage forms provided as sets containing tabostat as described herein or otherwise in a container with or without instructions for administration to an individual in need thereof. A preparation of pharmaceutically acceptable salts.

In an embodiment, the kit includes a package insert containing instructions for treating cancer in an individual using a formulation of tabostat or a pharmaceutically acceptable salt thereof as described herein.

Other features, objects, and advantages of the present disclosure will be apparent from the description and drawings, as well as the scope of the patent application.

Cross-references to related applications

This application claims priority rights under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 63/317,726 filed on March 8, 2022. The entire disclosure content of this U.S. Provisional Patent Application is incorporated by reference. method is incorporated into this article.

In the following paragraphs, different aspects of the present disclosure are defined in more detail. Unless expressly indicated to the contrary, each aspect so defined may be combined with any other aspect. In particular, any feature indicated as being better or advantageous may be combined with any other feature indicated as being better or advantageous. Abbreviation

API: Active Pharmaceutical Ingredient Avg: Average %: Percent CQA: Critical Quality Attribute CCS: Croscarmellose Sodium DPP: Dipeptidyl Peptidase DT: Disintegration Time FAP: Fibroblast Activated Protein FBD: Fluid Bed Drying HDPE: high density polyethylene HPLC: high performance liquid chromatography MCC: microcrystalline cellulose mg: mg min: minutes ml: milliliter NA: not applicable ND: not detected RH: relative humidity RMG: rapid mixer granulator RRT: relative retention time RSD: relative standard deviation SMCC: silica microcrystalline cellulose SSG: sodium starch glycolate °C: degrees Celsius µg: microgram UOD: Uniformity of dosage unit USP: United States Pharmacopeia definition

It is to be understood that the terminology used herein is for the purpose of describing the embodiments only and is not intended to be limiting. As used in this specification, the singular forms "a, an" and "the" include plural referents unless the context clearly dictates otherwise.

Throughout this specification, numerical ranges are provided for certain quantities. It is understood that such ranges include all subranges therein. Thus, the range "50 to 80" includes all possible ranges therein (eg, 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Additionally, all values within a given range may be the endpoints of the range encompassed therein (eg, a range of 50-80 includes ranges with endpoints such as 55-80, 50-75, etc.).

The term "approximately" as used herein means ±10% of the indicated value. For example, about 50% includes the range of 45% to 55%, and about 20 molar equivalents includes the range of 18 to 22 molar equivalents. Thus, when referring to a range, "about" means each of the stated value +/- 10% of the stated value at each end of the range. For example, a ratio (weight/weight) of about 1 to about 3 includes a range of 0.9 to 3.3.

The term "administering" as used herein refers to administering a composition of the present disclosure to an individual.

As used herein, the term "cancer" as used herein includes malignant tumors that can spread to or invade nearby tissue. It can also spread to other parts of the body through the blood and lymphatic systems.

As used herein, the terms "comprises", "comprising", "includes", "including" and "having" mean "including (but not limited to)".

As used herein, the term "composition" as used herein is intended to encompass a specified active product ingredient (API) as described herein and a pharmaceutically acceptable product including, for example, a specified amount as defined throughout the disclosure in which the application originally filed. A product of an excipient, carrier, or diluent resulting from a combination of specific ingredients (e.g., specified amounts of specified ingredients as described herein). The terms "formulation", "composition" and "pharmaceutical dosage form" are used interchangeably unless otherwise expressly intended to have a different meaning.

The term "disintegrant" as used herein refers to a pharmaceutical excipient incorporated into a composition to promote its disintegration upon contact with a liquid. For example, a disintegrant is a pharmaceutically acceptable agent used in the preparation of tablets that causes the tablet to disintegrate and release the drug substance upon contact with moisture. Examples of disintegrants include, but are not limited to, cross-linked polymers, including croscarmellose sodium (croscarmellose sodium), and modified starch sodium starch glycolate, and the like. In embodiments of the present disclosure, the disintegrant does not include cross-linked polyvinylpyrrolidone (i.e., crospovidone).

The term "disintegration" as used herein refers to the state in which any unit, other than fragments of the insoluble coating or capsule shell, remain on the screen of the test procedure device or adhere to the lower surface of the disc (if used) Residues are soft lumps without a palpable hard core.

The term "dissolution" as used herein means the process by which a substance forms a solution. Dissolution testing measures the extent and rate of solution formation from a dosage form (e.g., tablet, capsule, ointment, etc.). Dissolution of drugs is critical to their bioavailability and therapeutic effectiveness.

The term "drying" as used herein is intended to have its ordinary meaning as, for example, Remington: The Science and Practice of Pharmacy, 19th Edition (1995) or Handbook of pharmaceutical granulation technology, Chapter 7, "Drugs and the pharmaceutical sciences", Volume 81, 1997; and includes drying the granulated mixture within or outside the high shear mixing element in a conventional manner, such as (but not limited to) by placing the moist granulated mixture in a chamber with circulating air flow and constant temperature heat. Controlled drying cabinet.

The term "effective amount" as used herein is used interchangeably with "therapeutically effective dose" or "therapeutically effective amount" and refers to an amount sufficient to produce the desired effect.

The term "excipient" as used herein means a pharmacologically inactive component that can be used in the preparation of pharmaceutical compositions and that is generally safe, non-toxic and acceptable for veterinary and human pharmaceutical use. Reference to an excipient includes one excipient and more than one excipient.

The term "glidant" as used herein refers to a substance added to a powder to improve its flow and/or lubricity. Examples of glidants may include, but are not limited to, magnesium stearate, fumed silica, starch and talc, and the like.

The term "patient" or "individual" as used herein refers to a living organism suffering from or susceptible to a disorder treatable by administration of a pharmaceutical formulation as provided herein. Non-limiting examples include humans, other mammals, and other non-mammals.

The term "granulation" as used herein is intended to have its ordinary meaning as, for example, Remington: The Science and Practice of Pharmacy, 19th Edition (1995) or Handbook of pharmaceutical granulation technology, Chapter 7, "Drugs and the pharmaceutical sciences" , Volume 81, 1997; and includes one or more of dry blending, wet agglomeration and post-granulation.

The term "hydrophilic silica" as used herein refers to pharmaceutical excipients that can be used as flow agents (anti-caking), adsorbents and desiccants in solid product forms. It can also be used to increase the mechanical stability and disintegration rate of the composition. Hydrophilic silica can be fuming, meaning that it is produced through a pyrolysis process to produce fine particles of silica. The size of the fumed silica particles may vary, for example, from 5 nm to 100 nm, or from 5 nm to 50 nm. The particles may be non-porous and have a surface area of 50-1,000 ^m2 /g or 50-600 ^m2 /g. Examples of hydrophilic silica include Aerosil 200, which has a specific surface area of approximately 200 m ² /g.

The term "intragranular" as used herein refers to a component added prior to granulation such that the component is incorporated within the granules. The term "extragranular" as used herein refers to components that are combined with the granules prior to compression (eg, in a tablet press).

The term "lubricant" as used herein refers to a substance added to a formulation to reduce friction. Compounds that act as lubricants may also have properties that act as glidants. Examples of lubricants may include, but are not limited to, talc, silica, and fats such as vegetable fats, magnesium stearate or stearic acid, and the like.

The term "microcrystalline cellulose" as used herein refers to the chemical of formula (C6H10O5)n, including a free-flowing white powder. Microcrystalline cellulose is a commonly used excipient for use in solid dosage forms such as tablets, having excellent compression properties. Forms into hard, but quickly dissolving tablets. Microcrystalline cellulose is the same as cellulose except it meets USP standards. Silicified microcrystalline cellulose (SMCC) is a tableting excipient that improves binding capabilities as a material and in tablet formulations. This material also shows improved resistance to the degradative effects of magnesium stearate compared to regular microcrystalline cellulose. MCC can be unmodified or chemically modified, such as silicified microcrystalline cellulose (SMCC). MCC can function as a extender and aid in tablet formation due to its favorable compression characteristics.

The term "pharmaceutically or pharmacologically acceptable" as used herein refers to molecular entities and compositions that do not produce adverse, allergic or other adverse reactions when administered to animals or humans.

The term "pharmaceutically acceptable salts" as used herein means salt forms of the active ingredient that are physiologically suitable for pharmaceutical use. Pharmaceutically acceptable salts may be present in combination with Tabostat as acid addition primary, secondary, tertiary or quaternary ammonium salts, alkali metal salts or alkaline earth metal salts. The term also covers inorganic or organic acids such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, methanesulfonic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid and Any salt like this.

As used herein, the term "related substances" as used herein means certain process and/or degradation related impurities that may occur during the manufacture and/or storage of pharmaceuticals and in the manufacture and/or storage of pharmaceutical formulations containing the pharmaceuticals. formed during.

The term "relative retention time" as used herein is the ratio of the retention time of an analyte peak relative to the retention time of another analyte peak obtained under the same conditions and used as a reference.

The term "room temperature stable" as used herein means that the pharmaceutical dosage form does not contain more than 1% of any impurities detected by HPLC after storage for 3 months at 25°C and 60% RH.

The term "sequential administration" as used herein means that the two compositions are administered to an individual at a time interval sufficient to allow the resulting beneficial effects to be obtained as each composition exerts its effect. In embodiments, "sequentially administered" may mean administering the composition at intervals of more than about 60 minutes; for example, 2 hours apart, 3 hours apart, 4 hours apart, 5 hours apart, 6 hours apart, etc. 7 hours, interval 8 hours, interval 9 hours, interval 10 hours, interval 11 hours or interval 12 hours. In embodiments, the compositions may be administered about 1 hour to about 24 hours apart.

The term "shelf life" as used herein means that the active agent in the pharmaceutical formulation has minimal degradation (e.g., no more than about 5 % degradation) storage period.

The term "silicified microcrystalline cellulose" or "SMCC" as used herein refers to co-processed particle agglomerates of microcrystalline cellulose and silica. SMCC suitable for use in the present disclosure may include silica in an amount of about 0.1% to about 20% by weight of microcrystalline cellulose, wherein the silica may have a particle size of about 1 nanometer (nm) to about 20% based on the average primary particle size. Particle size of approximately 100 microns (μm). For example, the silica may contain about 0.5% to about 10% by weight, or about 1.25% to about 5% by weight of silicified microcrystalline cellulose relative to microcrystalline cellulose. Additionally, the silicon dioxide may have a particle size of about 5 nm to about 40 μm, or about 5 nm to about 50 μm. Silica may have a surface area of about 10 m2/g to about 500 m2/g, or about 50 m2/g to about 500 m2/g, or about 175 m2/g to about 350 m2/g. Silicified microcrystalline cellulose is commercially available from a number of suppliers known to those skilled in the art, including Penwest Pharmaceuticals, Inc., under the trademark PROSOLV®. PROSOLV® is available in multiple grades, including, for example, PROSOLV® SMCC 50, PROSOLV® SMCC 90 and PROSOLV® HD. Other products include (but are not limited to) SMCC 50LD, SMCC HD90 and SMCC 90LM and the like.

The term "administered simultaneously" as used herein means at the same time or within a short period of time, such as less than 1 hour, less than 30 minutes, less than 15 minutes, or less than 5 minutes.

As used herein, the term "stable" or "stability" as used herein refers to a pharmaceutical formulation that retains its physical stability, polymorphic stability and/or chemical stability and meets the standard stability criteria given in the USP Pharmacopoeia things.

The term "sorbitol" as used herein refers to the sugar alcohol D-glucitol and may act as a binder to promote adhesion of ingredients in tablet compositions.

The term "therapeutically effective amount" as used herein refers to an amount of a compound or pharmaceutical composition that is useful in treating or ameliorating an identified disease or disorder, or that is useful in exhibiting a detectable therapeutic or inhibitory effect. "Therapeutically effective amount" further includes within its meaning an amount of a particular drug that is non-toxic but sufficient to provide the desired therapeutic effect. The exact amount required will vary from individual to individual depending on factors such as the general health of the patient, the age of the patient, and other factors. The exact amount will depend on the therapeutic purpose and will be determined by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volume 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, edited by Gennaro, Lippincott, Williams & Wilkins).

As used herein, the terms "treat", "treating" and "treatment" refer to any sign of success in treating or ameliorating an injury, pathology or disorder, including any objective or subjective parameter, such as reduction of ; Alleviate; reduce symptoms or make the patient more tolerant of an injury, pathology, or disease; slow the rate of degeneration or decline; make the endpoint of degeneration less debilitating; improve the physical or mental health of the patient. Treatment or improvement of symptoms may be based on objective or subjective parameters; including results of physical examination, neuropsychiatric examination, and/or psychiatric evaluation.

As used herein, the term "tumor" as used herein includes an abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should. Tumors can be benign (non-cancerous) or malignant (cancer). Benign tumors may grow but do not spread or invade nearby tissue or other parts of the body.

The term "unit dosage form" as used herein refers to physically discrete units suitable as unit dosages for human subjects and other mammals (e.g., dogs), each unit containing a protein calculated to produce the desired onset effects, tolerability and/or A predetermined amount of active material for therapeutic effect, and suitable pharmaceutical excipients.

The term "wet granulation process" as used herein represents a customary way of making granules and is disclosed, for example, in Remington: The Science and Practice of Pharmacy, 19th Edition (1995) and/or Handbook of pharmaceutical granulation technology, Chapter 7, "Drugs and the pharmaceutical sciences", Volume 81, 1997. Wet methods typically include the steps of weighing, mixing, granulating, screening the wet mass, drying and optionally dry screening, lubrication and compression.

The abbreviation "(w/w)" refers to the phrase "weight for weight", that is, the specific substance in the mixture relative to the composition as measured by the weight or mass or gravimetric amount of the components of the composition disclosed herein. Proportion of total weight. Thus, amounts are unitless and represent weight percent amounts of components relative to the total weight of the composition. For example, a 2% (w/w) solution means 2 grams of solute dissolved in 100 grams of solution. Active agent: Taboxostat or its pharmaceutically acceptable salt

Taboxostat is interchangeably referred to as PT-100, taboxostat (USAN), and [(2R)-I-I [(2S)-2-amino-3-methyl-1-side-oxybutyl] -2-pyrrolidinyl]boronic acid. The CAS registration number of Tabostat is 149682-77-9. Tabostat is also known as Val-boro-pro (L-valinyl-L-boroproline), which is disclosed in PCT Application Publication No. 1989/003223. The IUPAC name of Tabostat is [(2R)-1-[(2S)-2-amino-3-methylbutyl]pyrrolidin-2-yl]boronic acid. Taboxostat (PubChem ID: 6918572) or a pharmaceutically acceptable salt thereof, such as taboxostat mesylate (PubChem CID: 1152248). In embodiments, a free base may be used. In embodiments, taboxostat or a pharmaceutically acceptable salt thereof may be a solvate. In most clinical formulations, tapoxostat is provided as a salt form (eg, tapoxostat mesylate). Pharmaceutically acceptable salts may be present in combination with Tabostat as acid addition primary, secondary, tertiary or quaternary ammonium salts, alkali metal salts or alkaline earth metal salts. It also covers compounds with inorganic or organic acids such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, methanesulfonic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid and the like. any salt. Tabostat has two chiral centers in R and S configurations. Tabostat or its pharmaceutically acceptable salt can exist in linear and cyclic forms (RJ Snow et al., J. Am. Chem. Soc., 1994, 116 (24), pp. 10860-10869).

Taboxostat or its pharmaceutically acceptable salts effectively treat cancer by regulating a variety of intracellular and extracellular dipeptidyl peptidases. More specifically, intracellular and extracellular dipeptidyl peptidases include fibroblast-activating proteins DPP 8/9, CD26/DPP4 and DPP2. Taboxostat or its pharmaceutically acceptable salt has a dual mechanism of action, which includes the interstitial targeting activity through inhibition of FAP and the targeted immunostimulatory activity through inhibition of DPP 8/9. Taboxostat inhibits FAP enzyme activity, thereby inhibiting tumor growth. Tabostat or its pharmaceutically acceptable salt also inhibits DPP8/9, thereby inducing an IL 1β response (via caspase-1) in the stroma between tumors and lymph nodes. Taboxostat's dual mechanism of action introduces a novel therapeutic approach to treating cancer by combining tumor-targeting activity and immunostimulatory activity in a single agent. dose

Taboxostat or a pharmaceutically acceptable salt thereof will generally be included in the formulation in an amount ranging from about 0.01% to about 10% w/w, and preferably in an amount based on the total weight of the composition. of about 0.1% to about 2% w/w.

In embodiments, Tabostat or a pharmaceutically acceptable salt thereof is present in the formulation (e.g., a tablet) in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05% of the composition. ,0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22 %, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55% ,0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72 %, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 090%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.00%, 1.01%, 1.02%, 1.03%, 1.04%, 1.05% , 1.06%, 1.07%, 1.08%, 1.09%, 1.10%, 1.11%, 1.12%, 1.13%, 1.14%, 1.15%, 1.16%, 1.17%, 1.18%, 1.19%, 1.20%, 1.21%, 1.22 %, 1.23%, 1.24%, 1.25%, 1.26%, 1.27%, 1.28%, 1.29%, 1.30%, 1.31%, 1.32%, 1.33%, 1.34%, 1.35%, 1.36%, 1.37%, 1.38%, 1.39%, 1.40%, 1.41%, 1.42%, 1.43%, 1.44%, 1.45%, 1.46%, 1.47%, 1.48%, 1.49%, 1.50%, 1.51%, 1.52%, 1.53%, 1.54%, 1.55% ,1.56%, 1.57%, 1.58%, 1.59%, 1.60%, 1.61%, 1.62%, 1.63%, 1.64%, 1.65%, 1.66%, 1.67%, 1.68%, 1.69%, 1.70%, 1.71%, 1.72 %, 1.73%, 1.74%, 1.75%, 1.76%, 1.77%, 1.78%, 1.79%, 1.80%, 1.81%, 1.82%, 1.83%, 1.84%, 1.85%, 1.86%, 1.87%, 1.88%, 1.89%, 190%, 1.91%, 1.92%, 1.93%, 1.94%, 1.95%, 1.96%, 1.97%, 1.98%, 1.99%, 2.00%, 2.50%, 3.00%, 3.50%, 4.00%, 4.50% , 5.00%, 6.00%, 7.00%, 8.00%, 9.00% or 10.00% (w/w).

In embodiments, the dosage of tabostat or a pharmaceutically acceptable salt thereof ranges from about 0.05 micrograms to about 600 micrograms. Examples of suitable dosages included in a lozenge include about 0.05 microgram to about 580 microgram, about 0.1 microgram to about 570 microgram, about 0.5 microgram to about 560 microgram, about 1 microgram to about 550 microgram, about 1 microgram to about 500 microgram. , about 2 micrograms to about 480 micrograms, about 5 micrograms to about 450 micrograms, about 10 micrograms to about 400 micrograms, about 15 micrograms to about 350 micrograms, about 20 micrograms to about 300 micrograms, about 30 micrograms to about 280 micrograms, about 35 micrograms to about 270 micrograms, about 40 micrograms to about 250 micrograms, about 45 micrograms to about 200 micrograms, about 50 micrograms to about 150 micrograms, about 60 micrograms to about 120 micrograms, about 65 micrograms to about 110 micrograms, about 70 micrograms To about 100 micrograms, about 75 micrograms, about 80 micrograms, about 85 micrograms, about 90 micrograms, about 95 micrograms, about 100 micrograms, about 120 micrograms, about 130 micrograms, about 140 micrograms, about 150 micrograms, about 160 micrograms, about 170 micrograms, about 180 micrograms, about 190 micrograms, about 200 micrograms, or about 300 micrograms.

Doses may be administered one or more times per day, including two, three, four, five, or six times per day.

In embodiments, tabinostat or a pharmaceutically acceptable salt thereof (eg, tabinostat mesylate) is administered in an amount of about 50 micrograms in a tablet or capsule.

In embodiments, tabinostat or a pharmaceutically acceptable salt thereof (eg, tabinostat mesylate) is administered in a lozenge or capsule in an amount of about 100 micrograms.

In embodiments, tabinostat or a pharmaceutically acceptable salt thereof (eg, tabinostat mesylate) is administered in a lozenge or capsule in an amount of about 150 micrograms.

In embodiments, tabinostat or a pharmaceutically acceptable salt thereof (eg, tabinostat mesylate) is administered in a lozenge or capsule in an amount of about 200 micrograms.

In embodiments, tabinostat or a pharmaceutically acceptable salt thereof (eg, tabinostat mesylate) is administered in a lozenge or capsule in an amount of about 250 micrograms.

In embodiments, tabinostat or a pharmaceutically acceptable salt thereof (eg, tabinostat mesylate) is administered in a lozenge or capsule in an amount of about 300 micrograms.

In embodiments, tabinostat or a pharmaceutically acceptable salt thereof (eg, tabinostat mesylate) is administered in a lozenge or capsule in an amount of about 350 micrograms.

In embodiments, tabinostat or a pharmaceutically acceptable salt thereof (eg, tabinostat mesylate) is administered in a lozenge or capsule in an amount of about 400 micrograms.

In embodiments, tabinostat or a pharmaceutically acceptable salt thereof (eg, tabinostat mesylate) is administered in a lozenge or capsule in an amount of about 450 micrograms.

In embodiments, tabinostat or a pharmaceutically acceptable salt thereof (eg, tabinostat mesylate) is administered in a lozenge or capsule in an amount of about 500 micrograms.

In embodiments, tabinostat or a pharmaceutically acceptable salt thereof (eg, tabinostat mesylate) is administered in a lozenge or capsule in an amount of about 550 micrograms.

In embodiments, taboxostat or a pharmaceutically acceptable salt thereof (eg, taboxostat mesylate) is administered in a lozenge or capsule in an amount of about 600 micrograms.

In embodiments, a formulation comprising tabinostat or a pharmaceutically acceptable salt thereof may be administered orally in divided doses at a dose of about 200 micrograms twice daily. In embodiments, a formulation comprising tabinostat or a pharmaceutically acceptable salt thereof may be administered orally in divided doses at a dose of about 300 micrograms twice daily. In an embodiment, a formulation comprising tabinostat or a pharmaceutically acceptable salt thereof is administered orally in divided doses at a dose of about 200 micrograms three times daily. In embodiments, a formulation comprising tabinostat or a pharmaceutically acceptable salt thereof is administered orally twice daily, for example, a morning dose of about 400 micrograms and an evening dose of about 400 micrograms over a 24-hour period. About 200 micrograms.

The dosage of taboxostat or a pharmaceutically acceptable salt thereof (e.g., mesylate) to be administered to a particular patient will depend on factors such as the type and extent of the disorder and the overall health of the particular patient. The condition, the specific form of tabostat administered, and the specific formulation used to treat the patient. pharmaceutical preparations

In embodiments, the present disclosure provides formulations comprising Taboxostat or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients or carriers. In embodiments, excipients or carriers for inclusion in the formulations include, but are not limited to, fillers/diluents, disintegrants, lubricants, buffers or pH modifiers, and combinations thereof. In other embodiments, excipients or carriers for inclusion in the formulation are selected from the group consisting of fillers/diluents, disintegrants, lubricants, buffers or pH modifiers, and combinations thereof. Pharmaceutically acceptable carriers are generally nontoxic to the recipient at the doses and concentrations employed. In embodiments, one or more additional excipients are in the tablet core. Pharmaceutically acceptable carriers

Diluents: In accordance with the present disclosure, formulations as described herein may include at least one filler or diluent. Examples of fillers or diluents of the present disclosure include (but are not limited to) sugars (such as lactose, dextrose, glucose, sucrose, cellulose, starch, modified starch (hydroxyl-esterified starch, hydroxypropyl Distarch phosphate, enzyme modified starch, hydroxyethyl starch, hydroxypropyl starch) and carbohydrate derivatives), polysaccharides (including dextran and maltodextrin), polytriglucose, maltodextrin, isomalt, gum (such as gum arabic, guar gum, agar and xanthan gum), polyols (including mannitol, xylitol, lactitol and sorbitol), cyclodextrin, calcium carbonate, magnesium carbonate, microcrystalline cellulose, phosphoric acid Calcium hydrogen, calcium phosphate, calcium carbonate, combinations thereof and the like. Several types of microcrystalline cellulose may be suitable for use in the compositions described herein. For example, microcrystalline cellulose may be selected from (but not limited to) partially depolymerized cellulose (e.g., MICROCEL®) or by the acidification of specialized wood pulps. Purified partially depolymerized α-cellulose (such as AVICEL®) produced by hydrolysis, including the following types: PH101, PH102, PH103, PH105, PH 112, PH113, PH200, PH301 and the like, and other types of microcrystalline fibers Elements such as silicified microcrystalline cellulose. In the examples, the diluent is microcrystalline cellulose (AVICEL PH102). In the examples, the diluent is microcrystalline cellulose (AVICEL PH101). In the examples, the diluent is silicified microcrystalline cellulose (SMCC HD90).

In embodiments, the diluent/filler may be present in an amount from 2% to 99% (w/w) of the formulation. For example, the amount of diluent/filler present in the formulation may range from about 2% w/w to about 98% w/w, from about 2% w/w to about 95% w/ w, about 2% w/w to about 90% w/w, about 2% w/w to about 80% w/w, about 2% w/w to about 70% w/w, about 2% w/w to about 60% w/w, about 2% w/w to about 50% w/w, about 5% w/w to about 90% w/w, about 10% w/w to about 80% w/w, From about 20% w/w to about 70% w/w, from about 30% w/w to about 90% w/w, from about 30% w/w to about 85% w/w, and including all values therebetween (For example, about 97%, about 96% w/w, about 95% w/w, about 94% w/w, about 90% w/w, about 85% w/w, about 80% w/w, about 75 % w/w, about 70% w/w, about 65% w/w, about 60% w/w, about 55% w/w, about 50% w/w, about 45% w/w, about 40% w/w, about 35% w/w, about 30% w/w, about 25% w/w, about 20% w/w, about 15% w/w, about 10% w/w, about 5% w /w, about 4% w/w, about 3% w/w, about 2% w/w). In embodiments, the amount of diluent is present in the formulation in the range of about 50% to about 90% w/w. In embodiments, the amount of diluent is present in the formulation in the range of about 85% w/w. In embodiments, the amount of diluent/filler present in the formulation is about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76% , 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or about 95% (w/w).

Disintegrants: In embodiments, disintegrants as used in the present disclosure include (but are not limited to) low-substituted hydroxypropyl cellulose, carboxymethyl starch, native starch, carboxymethyl starch, starch glycolate Sodium, dextrin and other modified starches (hydroxyl-esterified starch, hydroxypropyl distarch phosphate, enzyme modified starch, pregelatinized starch, hydroxyethyl starch, hydroxypropyl starch, pregelatinized starch Celated distarch phosphate and pregelatinized purified starch); calcium carboxymethylcellulose, sodium carboxymethylcellulose (or croscarmellose sodium), silicified microcrystalline cellulose, microcrystalline cellulose, Cellulose gums and mixtures thereof. In embodiments, the disintegrant is pregelatinized starch. In embodiments, the disintegrant is present in the formulation in an amount ranging from about 1% to about 5% w/w. For example, the amount of disintegrant present in the dosage form may range from about 1% w/w to about 5% w/w, from about 1% w/w to about 4% w/w, About 1% w/w to about 3% w/w, about 1% w/w to about 2% w/w, about 2% w/w to about 5% w/w, about 2% w/w to about 4% w/w, about 2% w/w to about 3% w/w, about 3% w/w to about 5% w/w, about 3% w/w to about 4% w/w, or about 4% w/w to about 5% w/w. In embodiments, the disintegrant is present in an amount of about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, or about 5% w/w.

Lubricant: In embodiments, lubricants include (but are not limited to) magnesium stearate, calcium stearate, stearic acid, talc, sodium stearate fumarate, sucrose fatty acid ester, aluminum stearate, Potassium sodium tartrate, light silicic anhydride, palm wax, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydrated silica, hydrogenated oil, hydrogenated rapeseed oil, and mixtures thereof. In embodiments, the lubricant is magnesium stearate.

In embodiments, the amount of lubricant in the formulation is present in the range of about 0.05% to about 5% w/w. In embodiments, the lubricant is present in the formulation in an amount of about 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32% ,0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49 %, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82% ,0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 090%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99 %, 1.00%, 1.01%, 1.02%, 1.03%, 1.04%, 1.05%, 1.06%, 1.07%, 1.08%, 1.09%, 1.10%, 1.11%, 1.12%, 1.13%, 1.14%, 1.15%, 1.16%, 1.17%, 1.18%, 1.19%, 1.20%, 1.21%, 1.22%, 1.23%, 1.24%, 1.25%, 1.26%, 1.27%, 1.28%, 1.29%, 1.30%, 1.31%, 1.32% ,1.33%, 1.34%, 1.35%, 1.36%, 1.37%, 1.38%, 1.39%, 1.40%, 1.41%, 1.42%, 1.43%, 1.44%, 1.45%, 1.46%, 1.47%, 1.48%, 1.49 %, 1.50%, 1.51%, 1.52%, 1.53%, 1.54%, 1.55%, 1.56%, 1.57%, 1.58%, 1.59%, 1.60%, 1.61%, 1.62%, 1.63%, 1.64%, 1.65%, 1.66%, 1.67%, 1.68%, 1.69%, 1.70%, 1.71%, 1.72%, 1.73%, 1.74%, 1.75%, 1.76%, 1.77%, 1.78%, 1.79%, 1.80%, 1.81%, 1.82% ,1.83%, 1.84%, 1.85%, 1.86%, 1.87%, 1.88%, 1.89%, 190%, 1.91%, 1.92%, 1.93%, 1.94%, 1.95%, 1.96%, 1.97%, 1.98%, 1.99 % or about 2.00% (w/w).

Buffer (or pH modifier): In embodiments, buffers include (but are not limited to) inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid), inorganic bases (such as sodium hydroxide, potassium hydroxide, calcium hydroxide) , organic acids (such as citric acid, acetic acid, tartaric acid, succinic acid, boric acid, edetic acid, glucuronic acid, glutaric acid, malic acid, formic acid, gluconic acid, ascorbic acid or fatty acids), and/or organic bases (such as ethanolamine, triethanolamine) or mixtures thereof. In embodiments, buffering agents may be present in the range of about 0.05% to about 2% w/w of the formulation. For example, the amount of buffer can range from about 0.005% w/w to about 1% w/w, about 0.1% w/w to about 2% w/w, about 0.1% w/w to About 1% w/w, about 0.5% w/w to about 2% w/w, about 0.5% w/w to about 1% w/w, or about 1% w/w to about 2% w/w. In embodiments, the buffer is present at about 0% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w , present in an amount of about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w or about 2% w/w.

Coating Polymers: In embodiments, the formulations include coatings and examples of moisture barrier coating polymers include cellulose and its derivatives, such as ethylcellulose, hydroxypropylmethylcellulose (e.g., hypromellose Vegetarian 5cP and hypromellose 15cP), hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl phthalate Methylcellulose, cellulose acetate phthalate, cellulose acetate trimellitate, waxes; polyvinyl derivatives such as PVA (polyvinyl alcohol), for example trademarks Opadry AMB, Opadry II, Opadry QX ( Kollicoat), or PVP-PVAc copolymers (polyvinylpyrrolidone-polyvinyl acetate copolymer) and methacrylic polymers (such as Eudragit) and the like. In embodiments, the moisture barrier coating is present in an amount from about 2% to about 8% based on the total weight of the formulation. In an embodiment, the coating is present in an amount of about 4%, based on the total weight of the formulation. In embodiments, the moisture barrier coating polymer is present in the formulation in an amount of about 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4. 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0% (w/w).

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate, wherein the formulation retains at least about 95% of the initial amount of tabostat or a pharmaceutically acceptable salt thereof after storage in a container at room temperature and about 60% relative humidity for 6 months, and the impurities are The total amount is less than 1%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And contains undetectable impurities at RRT 1.06 and 1.16.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And the total amount of impurities is less than 1%.

In embodiments, the present disclosure provides formulations suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulations comprising or consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

In the Examples, the formulations contained undetectable impurities at RRT 1.06 and 1.16 after storage in containers for 6 months at room temperature at about 60% relative humidity.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

In embodiments, the present disclosure provides formulations suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulations comprising or consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

In the examples, the formulations retained about 96%, about 97%, about 98%, or about 99% of the initial amount of tabostat after storage in the container at room temperature and about 60% relative humidity for 6 months. or its pharmaceutically acceptable salt, and the total amount of impurities is less than 0.5%.

In embodiments, the present disclosure provides formulations suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulations comprising or consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

In the examples, the formulations retained about 96%, about 97%, about 98%, or about 99% of the initial amount of tabostat after storage in the container at room temperature and about 60% relative humidity for 6 months. , and contains undetectable impurities at RRTs of 1.06 and 1.16.

In an embodiment, when stored in a container at room temperature at about 60% relative humidity, the formulation retains about 99.5% of the original amount of tabosostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities The amount is less than 0.2%.

In embodiments, the formulation retains about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.1%, 99.2% 99.3%, 99.3%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% of tabostatin pharmaceutically acceptable salts , and the total amount of impurities is less than approximately 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19% or at least about 0.2%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising/consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container for 6 months at a temperature of about 2°C to about 8°C, And the total amount of impurities is less than 1%.

In embodiments, the formulation retains about 96%, about 97%, about 98%, or about 99% of the initial amount of tabostat or Its pharmaceutically acceptable salt, and the total amount of impurities is less than 0.5%.

In an embodiment, after 6 months of storage in a container at about 2°C to about 8°C, the formulation retains about 98.5% of the initial amount of tabosostat or a pharmaceutically acceptable salt thereof and 1% of the impurities. The total amount is less than 0.2%.

In embodiments, the present disclosure provides formulations suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulations comprising or consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

In embodiments, the formulation retains at least about 95% of the initial amount of tabosostat or its pharmaceutical counterpart after storage in a container under accelerated conditions for 1 month at a temperature of 40°C and a relative humidity of about 75%. acceptable salt, and the total amount of impurities is less than 1%.

In embodiments, the present disclosure provides formulations suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulations comprising or consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Sodium dihydrogen phosphate monohydrate; (v) Phosphoric acid, (vi) Pregelatinized starch, (vii) Stearic acid; and (viii) Silicated microcrystalline cellulose.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And it contains undetectable impurities at the RRT of 1.06 and 1.16.

In an embodiment, the formulation retains about 96% of the original amount of taboxostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.8%.

In embodiments, the present disclosure provides formulations suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulations comprising or consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Sodium dihydrogen phosphate monohydrate; (v) Phosphoric acid, (vi) Pregelatinized starch; (vii) Stearic acid; and (viii) Silicated microcrystalline cellulose.

In an embodiment, after 6 months of storage in a container at a temperature of about 2°C to about 8°C, the formulation retains 98% of the initial amount of tabostat or a pharmaceutically acceptable salt thereof and impurities The total amount is less than approximately 1%.

In embodiments, the present disclosure provides formulations suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulations comprising or consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) microcrystalline cellulose; (iv) Sodium dihydrogen phosphate monohydrate; (v) Phosphoric acid, (vi) pregelatinized starch; (vii) Stearic acid; and (viii) Silicated microcrystalline cellulose.

In the Examples, after 6 months of storage in the container at a temperature of 2°C to 8°C, the formulation retained 98% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof, and the formulation retained No detectable impurities at RRT 1.16.

In embodiments, the formulation retains about 99%, about 100% of the initial amount of tabostat or its pharmaceutically acceptable counterpart after storage in the container at a temperature of about 2°C-8°C for 6 months. salt, and the total amount of impurities is approximately 0.8%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Sodium dihydrogen phosphate monohydrate; (v) Phosphoric acid; (vi) Pregelatinized starch; (vii) Stearic acid; and (viii) Silicated microcrystalline cellulose.

In the Examples, after 6 months of storage in a container under accelerated conditions at a temperature of 40°C and a relative humidity of 75%, the formulation retained approximately 90% of the initial amount of tabosstat or its pharmaceutical Salt is acceptable and the total impurity content is less than about 1%.

In embodiments, the formulation retains about 91%, about 92%, about 93%, or about 93.5% of the initial amount of other components after storage in a container for 6 months at a temperature of 40° C. and a relative humidity of about 75%. Sistat or its pharmaceutically acceptable salt, and the total amount of impurities is about 0.8%.

In an embodiment, a formulation of tabostat or a pharmaceutically acceptable salt thereof includes: (i) About 0.1% to about 0.2% w/w tabosostat or its pharmaceutically acceptable salt; (ii) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w, (iii) Sodium dihydrogen phosphate monohydrate in an amount from about 0.01% to about 2% w/w, (iv) 50% to about 95% w/w lactose monohydrate, (v) Microcrystalline cellulose in an amount of about 5% to about 30% w/w, (vi) Pregelatinized starch in an amount of about 0.05% to about 10% w/w, (vii) stearic acid in an amount of about 0.05% to about 2% w/w, (viii) phosphoric acid in an amount of about 0.005% to about 0.1% w/w, and (ix) Magnesium stearate in an amount of about 0.01% to about 5% w/w, preferably about 0.05% to about 2% w/w.

The formulations of the present disclosure may be further coated with one or more functional or non-functional coating layers. Preferably, the formulation is coated with one or more non-functional coating layers. The coating layer may include one or more film-forming polymers and coating additives. In embodiments, the coating is a moisture-proof film coating. In embodiments, the coating provides an oxidative barrier.

Examples of film-forming polymers include cellulose and its derivatives, such as ethylcellulose, hydroxypropylmethylcellulose (such as hypromellose 5cP and hypromellose 15cP), hydroxypropylcellulose, Methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, trimellitamine Acid cellulose acetate; waxes; and methacrylic acid polymers (such as Eudragit) and the like. Alternatively, commercially available coating compositions comprise film-forming polymers, including, for example, coating systems that combine polymers, plasticizers, and pigments in an anhydrous concentrate or formulated without polyethylene glycol (PEG). PVA-based immediate release systems are sold under various trade names such as Opadry AMB, Opadry II or Opadry QX (Kollicoat). Coating additives may be selected from the group consisting of: binders, plasticizers, chelating agents, colorants, lubricants, opacifiers or mixtures thereof.

In embodiments, the plasticizer may be selected from (but not limited to) triacetin, diethyl phthalate, tributyl sebacate, polyethylene glycol (PEG), glycerin, triacetin ester and triethyl citrate. In embodiments, the coating optionally includes an anti-sticking agent or glidant, such as talc, fumed silica, or magnesium stearate.

In embodiments, the coating optionally includes an opacifier, such as titanium dioxide.

Where appropriate, coating of the formulation may be carried out using conventional methods and standard equipment.

Coatings may be applied by applying the coating composition as a solution/suspension using any conventional coating technique known in the art, such as spray coating, dip coating or compression coating in a conventional coater or fluidized bed processor. liquid/blend.

In embodiments, the moisture-proof coating polymer includes cellulose and its derivatives, such as ethyl cellulose, hydroxypropyl methylcellulose (such as hypromellose 5cP and hypromellose 15cP), hydroxypropyl methylcellulose Cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate , cellulose acetate trimellitate; waxes; polyvinyl derivatives such as PVA (polyvinyl alcohol) such as those available under the trademark Opadry AMB, or PVP-PVAc copolymers (polyvinylpyrrolidone-polyvinyl alcohol). Vinyl acetate copolymers) and methacrylic polymers (e.g. Eudragit) and the like, preferably Opadry AMB.

In an embodiment, the coating includes Opadry AMB-II Blue Light.

In embodiments, the coating is present in an amount from about 2% to about 8% w/w based on the total weight of the composition. In embodiments, the coating accounts for about 4%/w/w of the total weight of the composition. In examples, the formulations are coated using an automated coating machine.

In embodiments, the solids content during the coating process is about 20%.

In embodiments, the gun to bed distance may be in the range of approximately 10-15 cm.

In embodiments, the spray rate during coating is about 2-5 g/min.

In embodiments, the inlet temperature, exhaust temperature and product temperature during coating may range from about 40°C to about 60°C.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Sodium dihydrogen phosphate monohydrate; (v) Phosphoric acid; (vi) Pregelatinized starch; (vii) Stearic acid; and (viii) Silicified microcrystalline cellulose, and (ix) moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And the total amount of impurities is less than about 1%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Sodium dihydrogen phosphate monohydrate; (v) Phosphoric acid; (vi) Pregelatinized starch; (vii) Stearic acid; (viii) Silicated microcrystalline cellulose; and (ix) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And the total amount of impurities is less than about 1%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Sodium dihydrogen phosphate monohydrate; (v) Phosphoric acid; (vi) Pregelatinized starch; (vii) Stearic acid; (viii) Silicated microcrystalline cellulose; and (ix) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And it contains no detectable impurities at the RRT of 1.06 and 1.16.

In embodiments, the formulation retains about 96%, about 97%, about 98%, or about 99% of the initial amount of tabostat or its pharmaceutical when stored in the container at room temperature and about 60% relative humidity. Scientifically acceptable salt with a total impurity content of less than 1%.

In embodiments, when stored in a container at room temperature and about 60% relative humidity, the formulation retains about 98.5% of the initial amount of tabosostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities It is about 0.7%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Sodium dihydrogen phosphate monohydrate; (v) Phosphoric acid; (vi) Pregelatinized starch; (vii) Stearic acid; (viii) Silicated microcrystalline cellulose; and (ix) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container for 6 months at a temperature of about 2°C to about 8°C, And the total amount of impurities is less than about 1%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Sodium dihydrogen phosphate monohydrate; (v) Phosphoric acid; (vi) Pregelatinized starch; (vii) Stearic acid; (viii) Silicated microcrystalline cellulose; and (ix) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container for 6 months at a temperature of about 2°C to about 8°C, And it contains no detectable impurities at RRT 1.06 and 1.16.

In embodiments, the formulation retains about 96%, about 97%, about 98%, or about 99% of the initial amount of tabostat or its pharmaceutical composition when stored in the container at about 2°C to about 8°C. acceptable salt, and the total amount of impurities is less than 1%.

In embodiments, when stored in the container at about 2°C to about 8°C, the formulation retains about 99.5% of the original amount of tabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is About 0.6%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Sodium dihydrogen phosphate monohydrate; (v) Phosphoric acid; (vi) Pregelatinized starch; (vii) Stearic acid; (viii) Silicated microcrystalline cellulose; and (ix) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or its pharmaceutically acceptable counterpart after storage in a container for 6 months at a temperature of 40°C and a relative humidity of about 75%. salt, and the total amount of impurities is less than about 1%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Sodium dihydrogen phosphate monohydrate; (v) Phosphoric acid; (vi) Pregelatinized starch; (vii) Stearic acid; (viii) Silicated microcrystalline cellulose; and (ix) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or its pharmaceutically acceptable counterpart after storage in a container for 6 months at a temperature of 40°C and a relative humidity of about 75%. salt and contains no detectable impurities at RRT 1.06 and 1.16.

In embodiments, the formulation retains about 96%, about 97%, about 98% or about 99% of the initial amount of tabostat or Its pharmaceutically acceptable salt, and the total amount of impurities is about 0.7%.

In an embodiment, a formulation of tabostat or a pharmaceutically acceptable salt thereof includes: (i) About 0.1% to about 2% w/w tabosostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate in an amount of about 50% to about 95% w/w; (iii) Microcrystalline cellulose in an amount of about 5% to about 95% w/w; (iv) Pregelatinized starch in an amount of about 0.05% to about 10% w/w; (v) stearic acid in an amount of about 0.05% to about 2% w/w; (vi) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (vii) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; (viii) Phosphoric acid in an amount of about 0.005% to about 0.1% w/w; and (xi) Moisture-proof film coating in an amount of about 2% w/w to about 4% w/w.

In embodiments, a formulation of taboxostat or a pharmaceutically acceptable salt thereof includes (i) an intragranular portion; and (ii) an extragranular portion; The intra-particle part includes: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; and (c) phosphoric acid in an amount of about 0.005% to about 0.1% w/w; and The extragranular part includes: (a) Lactose monohydrate in an amount of about 25% to about 95% w/w; (b) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (c) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (d) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (e) stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the formulation further includes a moisture-proof coating of about 2% w/w to about 4% w/w.

In embodiments, the formulation comprises (i) an intragranular portion; and (ii) an extragranular portion; The intra-particle part includes: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) Potassium dihydrogen phosphate in an amount of about 0.01% to about 2% w/w; and (c) Hydrochloric acid in an amount of about 0.005% to about 0.1% w/w; and The extragranular part includes: (a) Lactose monohydrate in an amount of about 25% to about 95% w/w; (b) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (c) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (d) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (e) stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the formulation further includes a moisture-proof coating in an amount of about 2% w/w to about 4% w/w.

In embodiments, a formulation of taboxostat or a pharmaceutically acceptable salt thereof includes (i) an intragranular portion; and (ii) an extragranular portion; The intra-particle part includes: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) Citric acid in an amount of about 0.01% to about 2% w/w; and The extragranular part includes: (a) Lactose monohydrate in an amount of about 25% to about 95% w/w; (b) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (c) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (d) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (e) stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w. The formulation further includes a moisture-proof coating in an amount of about 2% w/w to about 4% w/w.

In embodiments, a formulation of taboxostat or a pharmaceutically acceptable salt thereof includes (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion includes: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) Malic acid in an amount from about 0.01% to about 2% w/w; and The extragranular part includes: (a) Lactose monohydrate in an amount of about 25% to about 95% w/w; (b) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (c) silicified microcrystalline cellulose in an amount from about 2% to about 95%; (d) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (e) stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w, The formulation further includes a moisture-proof coating in an amount of about 2% w/w to about 4% w/w.

In an embodiment, a formulation of tabostat or a pharmaceutically acceptable salt thereof includes: (i) Tabostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (ii) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (iii) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; (iv) About 50% to about 95% w/w lactose monohydrate; (v) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (vi) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (vii) Phosphoric acid in an amount of about 0.05% to about 0.1% w/w; and (viii) magnesium stearate in an amount of about 0.01% to about 5% w/w, preferably about 0.05% to about 2% w/w, The formulation further includes a moisture-proof coating in an amount of about 2% w/w to about 4% w/w.

In embodiments, the present disclosure provides formulations suitable for oral administration of taboxostat or a pharmaceutically acceptable salt thereof, the formulations comprising (i) taboxostat or a pharmaceutically acceptable salt thereof salt; (ii) silicified microcrystalline cellulose; (iii) sodium dihydrogen phosphate monohydrate; (iv) phosphoric acid; (v) magnesium stearate, and (vi) moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And the total amount of impurities is less than 1%.

In embodiments, the present disclosure provides formulations suitable for oral administration of taboxostat or a pharmaceutically acceptable salt thereof, the formulations comprising (i) taboxostat or a pharmaceutically acceptable salt thereof salt; (ii) silicified microcrystalline cellulose; (iii) sodium dihydrogen phosphate monohydrate; (iv) phosphoric acid; (v) magnesium stearate, and (vi) moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container at room temperature at about 60% relative humidity for 6 months, And it contains no detectable impurities at RRT 1.06 and 1.16.

In embodiments, the formulation retains about 96%, about 96.5%, or about 97% of the initial amount of tabosostat or its pharmaceutically acceptable form when stored in the container at room temperature at about 60% relative humidity. Salt is accepted, and the total amount of impurities is approximately 0.8%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; (v) Magnesium stearate; and (vi) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container for 6 months at a temperature of about 2°C-8°C, and The total amount of impurities is less than 1%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; (v) Magnesium stearate; and (vi) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof after storage in the container for 6 months at a temperature of about 2°C-8°C, and Contains no detectable impurities at RRT 1.06 and 1.16.

In embodiments, the formulation retains about 96%, about 96.5%, about 97%, or about 97.5% of the initial amount of tabosostat or its pharmaceutically active ingredient when stored in the container at about 2°C-8°C. Salt is acceptable and the total impurity content is approximately 0.8%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; (v) Magnesium stearate; and (vi) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or its pharmaceutically acceptable counterpart after storage in a container for 6 months at a temperature of 40°C and a relative humidity of about 75%. Salt, and the total amount of impurities is less than 1.5%.

In embodiments, the present disclosure provides a formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; (v) Magnesium stearate; and (vi) Moisture-proof film coating.

In embodiments, the formulation retains at least about 95% of the initial amount of taboxostat or its pharmaceutically acceptable counterpart after storage in a container for 6 months at a temperature of 40°C and a relative humidity of about 75%. salt and contains no detectable impurities at RRT 1.06 and 1.16.

In embodiments, the formulation retains about 96%, about 96.5%, or about 97% of the initial amount of tabosostat or its pharmaceutical composition when stored in a container at a temperature of 40° C. and a relative humidity of about 75%. acceptable salt, and the total impurity content is approximately 1%.

In an embodiment, a formulation of tabostat or a pharmaceutically acceptable salt thereof includes: (i) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 2% w/w; (ii) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (iii) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; (iv) Phosphoric acid in an amount of about 0.005% to about 0.1% w/w; (v) Magnesium stearate in an amount of about 0.01% to about 5% w/w, preferably about 0.05% to about 2% w/w; and (vi) Moisture-proof film coating in an amount of about 2% w/w to about 4% w/w.

In embodiments, a formulation of taboxostat or a pharmaceutically acceptable salt thereof includes (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion includes: (a) about 0.01% to Sodium dihydrogen phosphate monohydrate in an amount of about 2% w/w, (b) phosphoric acid in an amount of about 0.5% to about 1% w/w, and (c) trace amounts in an amount of about 85% to about 99% w/w. Crystalline cellulose, and the extragranular portion contains: (d) about 0.1% to about 0.2% w/w amount of Taboxostat or a pharmaceutically acceptable salt thereof, and (e) about 0.01% to about 5% Magnesium stearate in an amount w/w, wherein the formulation further includes a moisture-proof coating in an amount from about 2% w/w to about 4% w/w.

In embodiments, the present disclosure provides a formulation of tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises (a) sodium dihydrogen phosphate monohydrate in an amount from about 0.01% to about 2% w/w, (b) phosphoric acid in an amount from about 0.5% to about 1% w/w, and (c) from about 25% to about 75% w/w silicified microcrystalline cellulose, (d) about 25% to about 75% w/w microcrystalline cellulose, and the extragranular portion contains: (e) about 0.1% to about 0.2% w /w amount of taboxostat or a pharmaceutically acceptable salt thereof, and (f) about 0.01% to about 5% w/w magnesium stearate, wherein the formulation further comprises about 2% w/w Moisture-proof coating to about 4% w/w amount.

In the examples, the microcrystalline cellulose is MCC-101. In embodiments, microcrystalline cellulose is present in an amount of about 25% w/w and silicified microcrystalline cellulose is present in an amount of about 75% w/w. In embodiments, microcrystalline cellulose is present in an amount of about 50% w/w and silicified microcrystalline cellulose is present in an amount of about 50% w/w. In embodiments, microcrystalline cellulose is present in an amount of about 75% w/w and silicified microcrystalline cellulose is present in an amount of about 25% w/w.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.01% to about 2 % w/w sodium dihydrogen phosphate monohydrate, (b) about 0.025% to about 1% w/w phosphoric acid, and (c) about 85% to about 99% w/w microcrystalline fiber element, and the extragranular portion contains: (d) Taboxostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w, (e) about 0.01% to about 5% w/w an amount of magnesium stearate, and (f) optionally an amount of pregelatinized starch of about 0.5% to about 5% w/w, wherein the formulation further comprises an amount of about 2% w/w to about 4% w/w Moisture-proof coating.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.01% to about 2 % w/w potassium dihydrogen phosphate, (b) about 0.5% to about 1% w/w hydrochloric acid, and (c) about 85% to about 99% w/w silicified microcrystalline cellulose, And the extragranular part contains: (d) about 0.1% to about 0.2% w/w amount of taboxostat or a pharmaceutically acceptable salt thereof, and (e) about 0.01% to about 5% w/w amount of magnesium stearate.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.5% to about 2 % w/w malic acid, and (b) about 85% to about 99% w/w silicified microcrystalline cellulose, and the extragranular portion contains: (c) about 0.1% to about 0.2% w/w an amount of Taboxostat or a pharmaceutically acceptable salt thereof, and (d) magnesium stearate in an amount of about 0.01% to about 5% w/w.

In embodiments, the present disclosure provides formulations suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.1% to about 2 % w/w citric acid, and (b) about 85% to about 99% w/w silicified microcrystalline cellulose, and the extragranular portion contains: (c) about 0.1% to about 0.2% w/w an amount of Taboxostat or a pharmaceutically acceptable salt thereof, and (d) magnesium stearate in an amount of about 0.01% to about 5% w/w.

It will be appreciated that any given excipient may serve more than one function, such as as a filler/diluent, a disintegrant, and a lubricant.

Siliconized microcrystalline cellulose or SMCC or siliconized MCC available from the supplier Dupont/Signet is used in this disclosure, preferably SMCC HD90. It is a combination of microcrystalline cellulose (MCC) and colloidal silica (CSD). The silicification process results in silicon deposition, possibly in the form of silicon dioxide, both on the outer coating surface of the particles and on exposed surfaces within the particles. In the present disclosure, SMCC is selected to be added primarily in the extragranular portion during preparation of the formulation and to provide a disintegration time of about 1-3 minutes. In the examples, siliconized MCC was added in the intragranular fraction.

The amount of silicified microcrystalline cellulose in the present disclosure may range from about 2% to about 99% w/w. In embodiments, other alternatives include croscarmellose sodium, polacrilin potassium, sodium starch glycolate, calcium carboxymethylcellulose, sodium alginate, starch (e.g., corn starch, potato starch , pregelatinized starch and modified starch), microcrystalline cellulose and the like and combinations thereof.

In embodiments, microcrystalline cellulose (MCC) is used as a filler and binder for wet granulation, direct compression tableting, and a filler for hard gelatin capsules. It has low chemical reactivity and excellent compatibility at low pressures. Limitations include low overall density, high lubricant sensitivity, poor flow characteristics and the effect of moisture on compression characteristics. Although the high density and large particle size grades of MCC have some advantages in terms of greater plasticity, they form weaker compacts than the base material, which may reflect reduced surface area for bonding during compression. Additionally, the reduced surface area of larger particle size grades makes them more sensitive to the effects of lubricants and they can form less ordered blends with lower particle size drugs. Although no overall chemical changes in the resolution and polymorphic form of MCC were observed when microcrystalline cellulose was silicified in the preparation of SMCC 90, SMCC showed improved overall physical properties and mechanical characteristics.

In embodiments, the amount of microcrystalline cellulose used in the disclosure may range from about 5% to about 95% w/w. In embodiments, the amount of microcrystalline cellulose used in the present disclosure may range from about 15% to about 75% w/w. In embodiments, the amount of microcrystalline cellulose used in the present disclosure may range from about 25% to about 60% w/w. In embodiments, the amount of microcrystalline cellulose used in the present disclosure may range from about 30% to about 50% w/w.

In the example, the container is a normal HDPE bottle. In an example, the container is a Multiblock HDPE bottle.

In embodiments, taboxostat or a pharmaceutically acceptable salt thereof is taboxostat mesylate.

In embodiments, the formulations retain about 95%, about 96%, about 97%, about 98%, about 99% of the initial amount after 6 months in the container at room temperature and about 60% relative humidity. Or about 99.5% of Tabostat or its pharmaceutically acceptable salt.

In an example, the formulation retains about 98% of the initial amount of Taboxostat or a pharmaceutically acceptable salt thereof after 12 months in the container at room temperature and about 60% relative humidity.

In embodiments, at room temperature at about 60% relative humidity after 3 months, 6 months or 9 months, or preferably after 12 months or more, such as after 15 months, The formulation retains at least about 95% of the initial amount of tabostat after 18 months, 21 months, 2 years, 2.5 years, 3 years or more. Preferably, the tablet retains at least about 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% of the original amount of tabosil after storage at room temperature for such periods of time. or other pharmaceutically acceptable salts.

In embodiments, the cyclic form (%) is within the acceptable range and is about 10% to about 60%. In embodiments, the cyclic form (%) is about 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55%. In the Examples, the cyclic form of tapoxostat mesylate was analyzed by reversed phase high pressure liquid chromatography (HPLC) method.

In embodiments, formulations of tabostat or pharmaceutical salts thereof have a shelf life of about 24 months at room temperature.

Stability data prepared at 25±2°C/60%±5% RH better reflects the precise long-term storage conditions of the formulation rather than the accelerated storage conditions at 40°C±2°C/75%±5% RH.

Reverse-phase high-pressure liquid chromatography (HPLC) method was used to measure the amount of drug and related substances in peaks with retention times exceeding 2.5 minutes to determine the stability of tapoxostat.

In embodiments, the initial amount of tabostat or a pharmaceutically acceptable salt thereof in the formulation is about 10 micrograms, 20 micrograms, 30 micrograms, 40 micrograms, 50 micrograms, 60 micrograms, 70 micrograms, 80 micrograms, 90 mcg, 100 mcg, 110 mcg, 120 mcg, 130 mcg, 140 mcg, 150 mcg, 160 mcg, 170 mcg, 180 mcg, 190 mcg or 200 mcg.

In embodiments, taboxostat or a pharmaceutically acceptable salt is present in an amount from about 0.05% to about 1.0% w/w based on the total weight of the formulation.

In embodiments, tabostat or a pharmaceutically acceptable salt thereof is present in an amount of about 0.05% based on the total weight of the formulation.

In embodiments, Tabostat or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% w/w based on the total weight of the formulation.

In embodiments, Tabostat or a pharmaceutically acceptable salt thereof is present in an amount of about 0.2% w/w based on the total weight of the formulation.

In embodiments, tabostat or a pharmaceutically acceptable salt thereof is present in an amount of about 50 micrograms to about 800 micrograms, preferably about 50 micrograms to about 600 micrograms, or about 50 micrograms to about 400 micrograms. . In embodiments, the amount of taboxostat or a pharmaceutically acceptable salt thereof in the unit dose is about 10 micrograms, about 20 micrograms, about 30 micrograms, about 40 micrograms, about 50 micrograms, about 60 micrograms, about 70 micrograms. Micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, about 130 micrograms, about 140 micrograms, about 150 micrograms, about 160 micrograms, about 170 micrograms, about 180 micrograms, about 190 micrograms, About 200 micrograms, about 210 micrograms, about 220 micrograms, about 230 micrograms, about 240 micrograms, about 250 micrograms, about 260 micrograms, about 270 micrograms, about 280 micrograms, about 290 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 600 micrograms, about 700 micrograms, or about 800 micrograms.

In embodiments, the amount of taboxostat or a pharmaceutically acceptable salt thereof in a unit dose is about 600 micrograms. In embodiments, the amount of taboxostat or a pharmaceutically acceptable salt thereof in a unit dose is about 500 micrograms.

In embodiments, the amount of taboxostat or a pharmaceutically acceptable salt thereof in a unit dose is about 400 micrograms. In embodiments, the amount of taboxostat or a pharmaceutically acceptable salt thereof in a unit dose is about 300 micrograms. In another embodiment, the amount of taboxostat or a pharmaceutically acceptable salt thereof in the unit dose is about 200 micrograms. In another embodiment, the amount of taboxostat or a pharmaceutically acceptable salt thereof in the unit dose is about 50 micrograms. In various embodiments, taboxostat or a pharmaceutically acceptable salt thereof is included in a unit dosage form, including, but not limited to, a lozenge, a capsule, or a capsule-type lozenge.

In an embodiment, the formulation further includes microcrystalline cellulose; stearic acid; lactose monohydrate, and pregelatinized starch.

In an embodiment, a formulation of tabostat or a pharmaceutically acceptable salt thereof comprises (i) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 2% w/w; (ii) about 85% to about 99% w/w silicified microcrystalline cellulose, (iii) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; (iv) Phosphoric acid in an amount of about 0.005% to about 0.1% w/w; and (v) Magnesium stearate in an amount of about 0.05% to about 5% w/w.

In an embodiment, the formulation does not contain crospovidone.

In embodiments, the formulations are stored in containers that provide a moisture barrier. In embodiments, the formulation is stored in a container that provides an oxygen barrier. In examples, formulations are stored in Multiblock HDPE bottle containers. In the examples, the formulations were stored in normal HDPE bottle containers.

In embodiments, the storage container contains a desiccant. In embodiments, the desiccant is silica gel. In an embodiment, the package contains another aluminum bag. In embodiments, aluminum bags provide an additional protective barrier and long-term stability at controlled room temperatures.

In embodiments, the storage container does not contain desiccant or additional aluminum bags.

In an example, the container was closed with an aluminum induction seal and a polypropylene lid.

In embodiments, the formulation contains no more than 5.0% (w/w) water. In embodiments, the formulation contains no more than 1.0%, 1.2%, 1.5%, 1.6%, 1.7%, 1.8%, 1.85%, 1.9%, 1.95%, 2%, 2.5%, 3%, 3.5%, 4 %, 4.5%, 5.5%, 6.0% (w/w) water. In the examples, the water content of the tablets is determined by Karl Fischer titration (eg, Karl Fischer Coulometric Titration method).

In embodiments, the formulation exhibits 1% or less, or 0.9% or less, or 0.8% or less, or 0.7% or less, or 0.6% or less, or 0.5% or less, or Drying loss of 0.4% or less.

In embodiments, a formulation of tabostat, or a pharmaceutically acceptable salt thereof, reacts in the presence of water in less than 5 minutes (e.g., 3 minutes or less, 2 minutes or less, 1.5 minutes or less, Disintegrates within 1 minute or less) to improve ease of administration. In embodiments, a formulation of tabinostat or a pharmaceutically acceptable salt thereof disintegrates in about 40 to 60 seconds. In embodiments, a formulation of tabinostat or a pharmaceutically acceptable salt thereof disintegrates in about 50 seconds. In embodiments, formulations of tabostat or a pharmaceutically acceptable salt thereof disintegrate in about 15 to 30 seconds. In the Examples, disintegration testing was performed by USP Method 701.

Dissolution testing is commonly performed in the pharmaceutical industry to determine the dissolution rate of solid dosage forms. In addition to being commonly used by pharmaceutical companies to demonstrate adequate drug release in vivo, in vitro dissolution testing is used to assist in formulation design, process development, and especially to demonstrate batch-to-batch reproducibility in production. Dissolution testing is one of several tests commonly performed by pharmaceutical companies on oral dosage formulations (e.g., tablets, capsules, etc.) to determine compliance and release the product for distribution and sale.

Taboxostat converts from the linear to the cyclic form in neutral and alkaline environments. To avoid this conversion, an acidic buffer is preferably included in the formulation.

In embodiments, the pH of the formulation of tabostat or a pharmaceutically acceptable salt is from about 2 to about 5. In embodiments, the pH of a formulation of tabostat or a pharmaceutically acceptable salt is about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5.

Orthophosphoric acid is used to adjust the desired pH, but the present disclosure contemplates other acids such as citric acid, malic acid, hydrochloric acid, tartaric acid, aspartic acid, glutamic acid, succinic acid, or combinations thereof.

In embodiments, the formulations of the present disclosure may be in the form of tablets or capsules, and the shapes may vary and be, for example, round, oval, rectangular, cylindrical, clover-shaped, or any other suitable shape. In embodiments, the lozenges are round. The edges of the tablet may be beveled or rounded. In an embodiment, the lozenge is clover-shaped with sloping edges. Lozenges may be scored or engraved.

In embodiments, the formulation may have a diameter of between 5 mm and 10 mm (eg a diameter of 5 mm to 8 mm, for example a diameter of 7 mm), and specifically between 7 mm and 9 mm diameter. Its thickness ranges from approximately 3 mm to 5 mm, preferably between 3.5 mm and 4.5 mm. In embodiments, the formulation may have a hardness ranging from about 8 kP to about 15 kP.

In embodiments, the maximum weight loss of the formulation during the crispness test is no greater than 1%. Friability testing, as used herein, refers to the technique described in "Tablet Friability," Chapter 1216, USP 28, page 2745, which document is incorporated herein by reference.

In embodiments, the formulation of tabostat or a pharmaceutically acceptable salt is prepared by any process known to those skilled in the medical art (such as direct compression, dry granulation, wet granulation, or melt granulation) Preparation. One process involves dissolving tabostat or a pharmaceutically acceptable salt in a suitable solvent (with or without a binder), and evenly distributing this solution among filler particles (which may contain lactose monohydrate, micron crystalline cellulose or both) to form cohesive particles/granules. The particles may be of appropriate size, or may be further processed by dry granulation/agglomeration/rolling methods followed by grinding steps to achieve appropriate particles of a specific particle size distribution. The sized particles can be further blended with other ingredients and then lubricated in a suitable blender. Wet granulation, coating or spray processes can also be used.

In the examples, siliconized microcrystalline cellulose, acid buffer, and magnesium stearate were dry blended and compressed in a rapid mixer granulator. In the examples, buffer was coated onto microcrystalline cellulose and the buffer-coated microcrystalline cellulose was used for direct compression. In the embodiment, Taboxostat or a pharmaceutically acceptable salt and silicified microcrystalline cellulose are co-sieved and directly blended in RMG. In the examples, the resulting blends were lubricated and directly compressed in the same RMG.

In accordance with the present disclosure, compositions as described herein may include at least one filler in any amount suitable for use in the present disclosure. In embodiments, the compositions of the present disclosure may include (but are not limited to) one or more of the following: alpha cellulose, beta cellulose, gamma cellulose, starch, modified starch, sorbitol, mannitol , lactose, dextrose, sucrose, dicalcium phosphate, calcium phosphate or calcium carbonate and the like.

In embodiments, representative fillers for use in compositions of the present disclosure may include, but are not limited to, starch, lactitol, lactose, inorganic calcium salts (such as calcium phosphate), microcrystalline cellulose, sucrose, and combinations thereof and so on. Other fillers or diluents used in the compositions of the present disclosure may include, but are not limited to, fillers or diluents commonly known in the art that are commonly used in the formulation of pharmaceutical compounds. Examples of such fillers or diluents for use in accordance with the present disclosure may include, but are not limited to, sugars (such as lactose, dextrose, glucose, sucrose, cellulose, starch, and carbohydrate derivatives), polysaccharides (including dextran and maltodextrin), polyols (including mannitol, xylitol and sorbitol), cyclodextrins, calcium carbonate, magnesium carbonate, microcrystalline cellulose, combinations thereof and the like. In embodiments, such fillers or diluents suitable for use in the present disclosure may include, but are not limited to, lactose, microcrystalline cellulose, combinations thereof, and the like. Several types of microcrystalline cellulose are suitable for use in the compositions described herein, for example microcrystalline cellulose, including (but not limited to) MICROCEL® or AVICEL® types: PH101, PH102, PH103, PH105, PH 112, PH113, PH200, PH301 and the like, and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. In one aspect, a filler suitable for use in the present disclosure may include microcrystalline cellulose (AVICEL PH102). In another aspect, a filler suitable for use in the present disclosure may include microcrystalline cellulose (AVICEL PH101).

In embodiments, the composition may further comprise microcrystalline cellulose. In embodiments, the composition may further comprise silicified microcrystalline cellulose. In embodiments, the composition may further comprise one or more of the following: alpha cellulose, beta cellulose, gamma cellulose, starch, modified starch, sorbitol, mannitol, lactose, dextrose, sucrose , calcium hydrogen phosphate, calcium phosphate or calcium carbonate. In embodiments, the composition may further include mannitol. In embodiments, the composition may further include sorbitol.

In embodiments, microcrystalline cellulose may be present in the internal phase of the composition in an amount ranging from 2% to 95% (w/w) of the composition. In embodiments, disintegrants used in the present disclosure include (but are not limited to) low-substituted hydroxypropylcellulose, carboxymethyl starch, native starch, carboxymethyl starch, sodium starch glycolate, dextrin and other modified starches (starches with esterified hydroxyl groups, hydroxypropyl distarch phosphate, enzyme modified starch, pregelatinized distarch phosphate, hydroxyethyl starch, hydroxypropyl starch, pregelatinized acetate distarch phosphate and pregelatinized purified starch); calcium carboxymethylcellulose, sodium carboxymethylcellulose (or croscarmellose sodium), silicified microcrystalline cellulose, microcrystalline cellulose, fiber Glue and mixtures thereof. In embodiments, the disintegrant is present in the formulation in an amount ranging from about 2% to about 95% w/w.

In embodiments, the disintegrant is present in the formulation in an amount of about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12% , 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29 %, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62% , 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79 %, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or approximately 95% (w/w).

In embodiments, diluents/fillers include (but are not limited to) gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethyl cellulose; carrageenan; paste-like Essence; pectin; and polypeptide/protein or polysaccharide complexes, such as gelatin-gum arabic complex, starch, mannitol, dicalcium phosphate, potassium sulfate, microcrystalline cellulose, dextrose, lactose, galactose and trehalose ; Cyclic sugars, such as cyclodextrin; inorganic salts, such as sodium phosphate, sodium chloride and aluminum silicate; and amino acids with 2 to 12 carbon atoms, such as glycine, L-alanine, L- Aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine and mixtures thereof. In embodiments, the amount of diluent is present in the formulation in the range of about 50% to about 90% w/w. In embodiments, the amount of diluent is present in the formulation in the range of about 85% w/w. In embodiments, the amount of diluent/filler present in the formulation is about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76% , 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or about 95% (w/w).

In embodiments, binders include, but are not limited to, starch, pregelatinized starch, polyoxyethylene, polyethylene glycol, gum arabic, alginic acid, tragacanth, sucrose, guar gum, bentonite, cellulose derived Materials (such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) and carboxymethylcellulose (CMC) and their salts); and mixtures thereof.

In embodiments, lubricants include (but are not limited to) magnesium stearate, calcium stearate, stearic acid, talc, sodium fumarate stearate, sucrose fatty acid ester, aluminum stearate, potassium sodium tartrate , light silicic anhydride, palm wax, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydrated silica, hydrogenated oil, hydrogenated rapeseed oil, and mixtures thereof. In embodiments, the amount of lubricant in the formulation is present in the range of about 0.05% to about 5% w/w. In embodiments, the lubricant is present in the formulation in an amount of about 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32% ,0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49 %, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82% ,0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 090%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99 %, 1.00%, 1.01%, 1.02%, 1.03%, 1.04%, 1.05%, 1.06%, 1.07%, 1.08%, 1.09%, 1.10%, 1.11%, 1.12%, 1.13%, 1.14%, 1.15%, 1.16%, 1.17%, 1.18%, 1.19%, 1.20%, 1.21%, 1.22%, 1.23%, 1.24%, 1.25%, 1.26%, 1.27%, 1.28%, 1.29%, 1.30%, 1.31%, 1.32% ,1.33%, 1.34%, 1.35%, 1.36%, 1.37%, 1.38%, 1.39%, 1.40%, 1.41%, 1.42%, 1.43%, 1.44%, 1.45%, 1.46%, 1.47%, 1.48%, 1.49 %, 1.50%, 1.51%, 1.52%, 1.53%, 1.54%, 1.55%, 1.56%, 1.57%, 1.58%, 1.59%, 1.60%, 1.61%, 1.62%, 1.63%, 1.64%, 1.65%, 1.66%, 1.67%, 1.68%, 1.69%, 1.70%, 1.71%, 1.72%, 1.73%, 1.74%, 1.75%, 1.76%, 1.77%, 1.78%, 1.79%, 1.80%, 1.81%, 1.82% ,1.83%, 1.84%, 1.85%, 1.86%, 1.87%, 1.88%, 1.89%, 190%, 1.91%, 1.92%, 1.93%, 1.94%, 1.95%, 1.96%, 1.97%, 1.98%, 1.99 % or about 2.00% (w/w).

In embodiments, the moisture-proof coating polymer includes cellulose and its derivatives, such as ethyl cellulose, hydroxypropyl methylcellulose (such as hypromellose 5cP and hypromellose 15cP), hydroxypropyl methylcellulose Cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate , cellulose acetate trimellitate, waxes; polyvinyl derivatives such as PVA (polyvinyl alcohol), such as those available under the trademarks Opadry AMB, Opadry II, Opadry QX (Kollicoat), or PVP-PVAc copolymers (polyvinylpyrrolidone-polyvinyl acetate copolymer) and methacrylic polymers (such as Eudragit) and the like. In embodiments, the moisture barrier coating is present in an amount from about 2% to about 8% based on the total weight of the formulation. In an embodiment, the coating is present in an amount of about 4%, based on the total weight of the formulation. In embodiments, the moisture barrier coating polymer is present in the formulation in an amount of about 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0% (w/w).

The granulation liquid (fluid) contains a solvent or carrier material, which must be volatile so that it can be removed by drying, and non-toxic depending on the intended application.

In the embodiment, the granulation liquid system is water, ethanol, isopropyl alcohol, or methylene chloride alone or in combination. In the embodiment, the granulation liquid system is an acidic solution of sodium phosphate in water. In embodiments, an acidic solution is prepared by dissolving sodium phosphate in water and adjusting the pH to 2-2.5 with orthophosphoric acid. In an embodiment, the volume of granulation fluid used for wet granulation is about 30 mL. In an embodiment, the volume of granulation fluid used for wet granulation is about 70 mL. In embodiments, the volume of granulation fluid used for wet granulation is about 10 mL, 20 mL, 30 mL, 40 mL, 50 mL, 60 mL, or about 70 mL. In embodiments, the pH of the final formulation ranges from about 1 to about 5. In embodiments, the pH of the final formulation is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5.

Exemplary non-limiting formulations of the present invention are illustrated in Exemplary Formulation A and Exemplary Formulation B below. Exemplary Formulation A Sample number Ingredients ( trade name) For 50 mcg Qty/ unit (mg) For 200 mcg Qty/ unit (mg) For 100 mcg Qty/ unit (mg) ( referred to as optimal tablet batch in Table 22 , Table 24 , Table 26 , Table 28 and Table 30 ) intragranular part 1 Silicated microcrystalline cellulose (SMCC HD90) 49.38 197.54 98.768 2 Sodium Phosphate Monohydrate (USP Granules) 0.03 0.12 0.06 3 Orthophosphate 0.01 0.05 0.025 4 purified water Sufficient Sufficient Sufficient extragranular part 5 Tabostat mesylate 0.07 0.29 0.147 6 Magnesium stearate 0.5 2.00 1.00 Total weight of core tablets (mg) 50.00 200.00 100.00 coating 7 Opadry AMB-II Blu-ray (88A205031) 2.00 8.00 4.00 8 purified water Sufficient Sufficient Sufficient Total weight of coated tablets (mg) 52.00 208.00 104.00 Exemplary Formulation B Sample number Ingredients ( trade name) For 50 mcg Qty/ unit (mg) For 200 mcg Qty/ unit (mg) For 100 mcg Qty/ unit (mg) intragranular part 1 Tabostat mesylate 0.05 0.200 0.100 2 Silicated Microcrystalline Cellulose (SMCC HD90) 49.41 197.63 98.815 3 Sodium phosphate monohydrate (USP granules) 0.03 0.12 0.06 4 Orthophosphate 0.01 0.05 0.025 5 purified water Sufficient Sufficient Sufficient extragranular part 6 Magnesium stearate 0.5 2.00 1.00 Total weight of core tablets (mg) 50.00 200.00 100.00 coating 7 Opadry AMB-II Blu-ray (88A205031) 2.00 8.00 4.00 8 purified water Sufficient Sufficient Sufficient Total weight of coated tablets (mg) 52.00 208.00 104.00 Process for Preparing Tabostat Formulations

In embodiments, the present disclosure provides a process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, which process includes: (i) Sieve the required amount of all excipients selected from one or more of diluents, binders and disintegrants; (ii) Prepare a homogeneous mixture of diluent (e.g. lactose) and disintegrant (e.g. microcrystalline cellulose); (iii) Dissolve sodium phosphate in sufficient water and adjust to the required acidic pH using phosphoric acid to form a buffer solution, (iv) Add Tabostat or its pharmaceutically acceptable salt to the above buffer solution; (v) Use the solution of step (iv) to granulate the mixture of step (ii) to obtain wet pellets; (vi) Drying and screening the wet agglomerates to obtain granules; (vii) Optionally blend the granules of step (vi) with remaining excipients selected from pregelatinized starch and stearic acid, (viii) Lubricate the blend, and (ix) coat with a moisture-resistant film coating, as appropriate.

In embodiments, the present disclosure provides a process for preparing a formulation comprising tabostat or a pharmaceutically acceptable salt thereof, the process comprising: (i) Sieve the required amount of all excipients selected from one or more of diluents, binders and disintegrants; (ii) Preparation of acidic buffer solution; (iii) Add the siliconized microcrystalline cellulose in step (ii) and granulate the solution; (iv) The granules are dried and co-sieved extragranularly with Tabostat or its pharmaceutically acceptable salt, (v) optionally blended with one or more extragranular excipients, (vi) Lubricating blends, and (vii) Coat with film coating as appropriate.

In embodiments, the present disclosure provides a process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, which process includes: (i) Prepare a clear buffer solution by dissolving orthophosphoric acid and sodium phosphate in purified water; (ii) Add silica microcrystalline cellulose to the above buffer solution; (iii) Granulate the solution and then dry the granules; (iv) Extragranularly blended with Tabostat or its pharmaceutically acceptable salt; (v) Lubricate the blend with magnesium stearate, as appropriate; and (vi) Coat with film coating as appropriate.

In embodiments, the present disclosure provides a process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, which process includes: (i) Prepare a clear buffer solution by dissolving orthophosphoric acid and sodium phosphate in purified water; (ii) Add the drug taboxostat or its pharmaceutically acceptable salt to the above solution and granulate the solution; (iii) dry the granules and blend them with pregelatinized starch and silicified microcrystalline cellulose; (iv) Lubricating blends; and (v) Coat with film coating as appropriate.

In embodiments, formulations of taboxostat or a pharmaceutically acceptable salt thereof are prepared by any known process including direct compression, dry granulation, or wet granulation. In the examples, siliconized microcrystalline cellulose, acid buffer, and magnesium stearate were dry blended and compressed in a rapid mixer granulator. In the examples, buffer was coated onto microcrystalline cellulose and the buffer-coated microcrystalline cellulose was used for direct compression.

In embodiments, Tabostat or its pharmaceutically acceptable salt is added extragranularly during the wet granulation process. In an embodiment, the silicified microcrystalline cellulose is granulated with an acidic buffer, and the acidified silicated microcrystalline cellulose is then admixed with Taboxostat or a pharmaceutically acceptable salt thereof.

In embodiments, Tabostat or a pharmaceutically acceptable salt thereof is dissolved in an acidic buffer solution to form a granulation fluid. In an embodiment, the granulation fluid is used to form particles of a blend of lactose monohydrate and microcrystalline cellulose.

In embodiments, the present disclosure provides a dry formulation process for preparing a formulation of taboxostat or a pharmaceutically acceptable salt thereof, the dry formulation process comprising mixing taboxostat in the presence of added water. or a pharmaceutically acceptable salt thereof and one or more excipients selected from silicified microcrystalline cellulose, sodium phosphate, phosphoric acid, and magnesium stearate.

In embodiments, the drying temperature of the particles in the fluidized bed dryer (FBD) ranges from about 35°C to about 60°C. In embodiments, the manufacturing process does not involve a grinding step. In embodiments, the manufacturing process involves grinding/screening steps.

In embodiments, Tabostat or a pharmaceutically acceptable salt is added extragranularly during the wet granulation process. In an embodiment, the silicified microcrystalline cellulose is granulated with an acidic buffer, and the acidified silicated microcrystalline cellulose is then admixed with Taboxostat or a pharmaceutically acceptable salt thereof.

In embodiments, Tabostat or a pharmaceutically acceptable salt is dissolved in an acidic buffer solution to form a granulation fluid. In an example, the granulation fluid was used to granulate a blend of lactose monohydrate and microcrystalline cellulose.

In embodiments, the present disclosure provides a process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, which process includes: (i) Prepare a clear buffer solution by dissolving orthophosphoric acid and sodium phosphate in purified water; (ii) Add Tabostat or a pharmaceutically acceptable salt to the above solution and granulate the solution; (iii) dry the granules and blend them with pregelatinized starch and silicified microcrystalline cellulose; (iv) lubricating blends, and (v) Coat with moisture-proof film coating as appropriate.

In embodiments, the present disclosure provides a process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, which process includes: (i) Prepare a clear buffer solution by dissolving orthophosphoric acid and sodium phosphate in purified water; (ii) Add silica microcrystalline cellulose to the above buffer solution; (iii) Granulate the solution and then dry the granules; (iv) Extragranularly blended with Tabostat or its pharmaceutically acceptable salt; (v) Lubricate the blend with magnesium stearate, as appropriate; and (vi) Coat with moisture-proof film coating as appropriate.

In embodiments, silicified microcrystalline cellulose is added during the process of preparing the formulation at about 2% to about 95% w/w.

In embodiments, phosphoric acid is added during the process at about 0.005% to about 0.1% w/w. In embodiments, phosphoric acid is added at about 0.005% to about 2% w/w.

In embodiments, sodium dihydrogen phosphate monohydrate is added during the process at about 0.01% to about 1% w/w.

In embodiments, magnesium stearate is added during processing at about 0.01% to about 5% w/w.

In embodiments, the buffer solution prepared has a pH of about 2 to 5.

In embodiments, the present disclosure provides a dry formulation process for preparing a formulation of taboxostat or a pharmaceutically acceptable salt thereof, the dry formulation process comprising mixing taboxostat in the presence of added water. or a pharmaceutically acceptable salt thereof and one or more excipients selected from the group consisting of silicified microcrystalline cellulose, sodium phosphate, phosphoric acid and magnesium stearate.

In an embodiment, the present disclosure provides a process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, as shown in Figure 1 .

In an embodiment, the present disclosure provides a process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, as shown in Figure 2.

In an embodiment, the present disclosure provides a process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, as shown in Figure 3.

In an embodiment, the present disclosure provides a process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, as shown in Figure 4.

In an embodiment, the present disclosure provides a process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, as shown in Figure 5.

In an embodiment, the present disclosure provides a process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, as shown in Figure 6.

The stability of the pharmaceutical composition can be tested in a conventional manner, for example by measuring Tabostat and its degradation products, dissolution, ring content, disintegration time, water content, appearance and/or microscopy, for example at 25°C. and 60% relative humidity, storage at 2°C-8°C, and/or storage at 40°C and 75% relative humidity after a defined period of time.

The formulations to be tested can be divided into one or more different batches and stored under typical storage conditions (eg, 4°C (refrigerator) or 25°C (room temperature)). Accelerated testing can also be used to detect the degradation of drugs in pharmaceutical formulations under excessive storage conditions designed to increase the rate of degradation of the drug substance. For example, a batch can be "stressed" (placed in a chamber maintained at a temperature of 45°C and a humidity of 75%). Samples of each batch of formulations are then analyzed at different time points (eg, time 0, 1 month, 3 months, 6 months) for the amount of drug still present in the formulation. Analysis of drugs in formulations can be performed by a variety of detection methods, including high performance liquid chromatography, crystal or powder X-ray diffraction, infrared or Raman spectral studies, microscopy , differential scanning calorimetry, thermogravimetric analysis, high-temperature stage microscopy and solid-state nuclear magnetic resonance.

In various embodiments, the present disclosure further contemplates all stable solid formulations having similar stability properties for oral administration, such as tablets, capsules, pills, or lozenges. Treatment

In an embodiment, the present disclosure provides a method of treating cancer in a subject, comprising orally administering a formulation of taboxostat or a pharmaceutically acceptable salt thereof.

In an embodiment, a formulation comprising tabinostat or a pharmaceutically acceptable salt thereof is administered orally twice daily at a dose of about 300 micrograms. In an embodiment, a formulation comprising tabinostat or a pharmaceutically acceptable salt thereof is administered orally twice daily at a dose of about 200 micrograms. In an embodiment, a formulation comprising tabinostat or a pharmaceutically acceptable salt thereof is administered orally in divided doses at a dose of about 200 micrograms three times daily. In embodiments, a formulation comprising tabostat or a pharmaceutically acceptable salt thereof is administered orally twice daily, for example, during the day, with a morning dose of about 400 micrograms and an evening dose of about 200 micrograms. microgram.

In embodiments, formulations comprising tabostat or a pharmaceutically acceptable salt thereof are administered at about 50 micrograms, 100 micrograms, 150 micrograms, 200 micrograms, 250 micrograms, 300 micrograms, 350 micrograms, 400 micrograms, 450 micrograms Doses of micrograms, 500 micrograms, 550 micrograms, or about 600 micrograms are administered orally once daily. In embodiments, formulations comprising tabostat or a pharmaceutically acceptable salt thereof are administered at about 50 micrograms, 100 micrograms, 150 micrograms, 200 micrograms, 250 micrograms, 300 micrograms, 350 micrograms, 400 micrograms, 450 micrograms Doses of micrograms, 500 micrograms, 550 micrograms, or about 600 micrograms are administered orally twice daily.

In embodiments, formulations comprising tabostat or a pharmaceutically acceptable salt thereof are administered at about 50 micrograms, 100 micrograms, 150 micrograms, 200 micrograms, 250 micrograms, 300 micrograms, 350 micrograms, 400 micrograms, 450 micrograms Doses of micrograms, 500 micrograms, 550 micrograms, or about 600 micrograms are administered orally three times daily.

In embodiments, formulations comprising tabostat or a pharmaceutically acceptable salt thereof are administered at about 50 micrograms, 100 micrograms, 150 micrograms, 200 micrograms, 250 micrograms, 300 micrograms, 350 micrograms, 400 micrograms, 450 micrograms Doses of micrograms, 500 micrograms, 550 micrograms, or about 600 micrograms are administered orally four times daily.

The formulations of the present disclosure may be used alone or in combination with other therapies suitable for treating cancer and other clinical conditions.

In embodiments, the present disclosure provides methods of treating cancer in a subject by orally administering a formulation comprising an effective amount of Taboxostat or a pharmaceutically acceptable salt thereof and an additional active agent to Suitable unit dosage forms are administered simultaneously or sequentially at appropriate intervals.

In embodiments, a formulation of tabinostat or a pharmaceutically acceptable salt thereof additionally includes another active agent in the same dosage form. In embodiments, the other active agent is present in a different dosage form, which may be tablets, capsules, granules, troches, and the like for oral administration.

In the embodiments, "administered simultaneously" means at the same time or within a short period of time, typically less than 1 hour.

In embodiments, "appropriate time period" means anywhere from 1 hour to 30 days. For example, one agent may be administered about 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days from administration of another active agent. days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day, or 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 Administer within hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour, and in one embodiment, the specific time period is 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day, or 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours , 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours or 1 hour.

In embodiments, the subject is a mammal, preferably a human patient in need of therapeutic intervention.

Preferred cancers whose growth may be inhibited using the stable lozenge formulations of the present disclosure include cancers that typically respond to immunotherapy. Non-limiting examples of preferred cancers for treatment include malignant melanoma, non-small cell lung cancer, renal cancer, Hodgkin's disease, gastric cancer, glioblastoma; head and neck cancer, hepatocellular carcinoma, Multiple myeloma, esophageal cancer, small cell lung cancer, genitourinary cancer, acute myeloid leukemia, breast cancer, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma; myelodysplastic syndrome; ovarian cancer ; Uveal melanoma, colorectal cancer, hematological malignancies, non-Hodgkin's lymphoma, chronic myelogenous leukemia and glioma.

Non-limiting examples of cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), breast cancer, glioblastoma , colon cancer and lung cancer (such as non-small cell lung cancer, small cell lung cancer), gastric cancer, myelodysplastic syndrome; esophageal cancer; ovarian cancer; genitourinary cancer; uveal melanoma, adrenal cancer; liver cancer.

In embodiments, the cancer is a solid tumor. In some embodiments, the cancer is genitourinary cancer (eg, prostate cancer, renal cell carcinoma, bladder cancer), thyroid cancer, testicular cancer, vulvar cancer, Wilms' tumor, hormone-sensitive or hormone-refractory Sexual prostate cancer, gynecological cancer (such as ovarian cancer, cervical cancer, endometrial cancer, uterine cancer), lung cancer, non-small cell lung cancer, small cell lung cancer, gastrointestinal stromal cancer, gastrointestinal cancer (such as non-metastatic or metastatic Colorectal cancer, pancreatic cancer, gastric cancer, esophageal cancer, hepatocellular carcinoma, cholangiocarcinoma), malignant glioblastoma, malignant mesothelioma, non-metastatic or metastatic breast cancer (such as hormone-refractory metastatic breast cancer, Triple negative breast cancer), malignant melanoma, melanoma, metastatic melanoma, Merkel cell carcinoma or bone and soft tissue sarcoma, oral squamous cell carcinoma, glioblastoma, brain cancer, osteosarcoma, Neuroblastoma, advanced metastatic cancer, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, cystadenocarcinoma, amelloblastoma, chondrosarcoma, dermatofibrosarcoma, ganglioglioma, leiomyosarcoma, neural tube Blastoma, osteoblastoma and inoperable non-inflammatory locally advanced disease and the like. The best cancers are solid tumors (such as pancreatic cancer, colorectal cancer, ovarian cancer, lung cancer, breast cancer, glioblastoma, gastric cancer, astrocytoma, neuroectodermal tumors, head and neck cancer, triple negative breast cancer, gastric cancer Esophageal cancer, non-small cell lung cancer and the like) or hematopoietic system cancer (leukemia, lymphoma, lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, degenerative large cell lymphoma, myeloid leukemia , multiple myeloma, acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia).

In embodiments, cancers whose growth may be inhibited include virus-associated cancers, including but not limited to cancers associated with the following viruses: Epstein-Barr virus (EBV), hepatitis B virus (EBV), HBV), hepatitis C virus (HCV), human papillomavirus (HPV), human T-lymphotropic virus type 1 (HTLV-1), human T-lymphotropic virus type 2 (HTLV-2) and human herpesvirus , such as human herpesvirus 8 (HHV-8). Cancers associated with specific viruses are known to those skilled in the art. For example, EBV-related cancers include, but are not limited to, lymphoma, nasopharyngeal cancer, gastric cancer, parotid gland cancer, breast cancer, and leiomyosarcoma. Examples of cancers associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) include, but are not limited to, liver cancer. Examples of human papillomavirus (HPV)-related cancers include, but are not limited to, oropharyngeal head and neck cancer, nasopharyngeal head and neck cancer, and cancer of the cervix, vulva, vagina, penis, and anus. Examples of cancers associated with human T-lymphotropic virus type 1 (HTLV-1) and human T-lymphotropic virus type 2 (HTLV-2) include, but are not limited to, adult T-cell leukemia and hairy cell leukemia, respectively. Examples of cancers associated with human herpesvirus 8 (HHV-8) include, but are not limited to, Kaposi sarcoma. In embodiments, the virus-associated cancer is an HPV-associated cancer. In embodiments, the virus-associated cancer is an HCV-associated cancer. set

In an embodiment, a kit includes a formulation of tabostat or a pharmaceutically acceptable salt thereof and a package insert comprising use of the formulation to treat or delay the progression or enhancement of cancer in an individual suffering from cancer. Instructions for immune function in individuals with cancer.

In an embodiment, the kit includes a container containing tabostat or a pharmaceutically acceptable salt thereof. Containers may include bottles formed from a variety of materials, such as glass or plastic. Bottles can be normal HDPE or Multiblock HDPE. In some embodiments, the kit may include a label (eg, on or associated with the container) or package insert. The label or package insert may indicate that the compound contained therein is useful or intended for use in treating or delaying the progression of cancer in an individual suffering from cancer or for enhancing immune function in an individual suffering from cancer.

In embodiments, the kit also contains a predetermined amount of desiccant.

Desiccant, as used herein, is a material that absorbs moisture through physical and/or chemical means. Activated desiccant is a desiccant that has been treated by heating and ventilation or other methods, and its inner surface can collect moisture and certain vapors or gases. Examples of desiccants to be used in the present disclosure include activated carbon, calcium chloride, metal oxides (such as alkaline earth metal oxides (such as calcium oxide (CaO), etc.), alkaline earth metal hydroxides (such as calcium hydroxide, etc.) ), sulfates of alkaline earth metals (such as magnesium sulfate, calcium sulfate, etc.)), silica (silica gel), combination products of alumina and silica (silica alumina), alumina (activated alumina), Natural or synthetic zeolites (molecular sieves 3A, 4A, SA, 13X), aluminite, clay, mixtures of clay and activated carbon, mixtures of silica gel and activated carbon, mixtures of silica gel and clay, silica, alumina and activated carbon Mixtures, mixtures of synthetic zeolite and activated carbon, mixtures of almite and activated carbon (such as almite added together with activated carbon or almite kneaded together with activated carbon, etc.), pulp containing silica gel (such as in Ultrafine silicone mixed between paper fibers, silicone packaged in paper tubes, etc.), paper pulp containing calcium chloride (such as paper materials impregnated with liquid calcium chloride, dried and coated with film, etc.), containing aluminite Pulp (such as pulp impregnated with aluminumite liquid, dried and coated with film, aluminumite packaged in paper tubes, etc.) and the like. Ideally, the amount of desiccant should be at least sufficient to absorb this moisture and maintain a dry environment within the package for the shelf life of the product.

In embodiments, the present disclosure is directed to kits comprising a formulation of taboxostat, or a pharmaceutically acceptable salt thereof, and another active agent. In embodiments, another active agent is included in the second composition. In embodiments, the tabostat formulation and the second composition may be administered simultaneously or sequentially (i.e., separated by a period of time) to achieve maximum efficacy. Illustrative embodiments

Example 1. A formulation suitable for oral administration of tabostat, comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

Embodiment 2. The formulation of Embodiment 1, wherein the formulation retains at least about 95% of the initial amount of tabostat or other after storage in a container at room temperature at about 60% relative humidity for 6 months. Pharmaceutically acceptable salts with a total impurity content of less than 1%.

Example 3. A formulation suitable for oral administration of tabostat, consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

Embodiment 4. The formulation of Embodiment 3, wherein the formulation retains at least about 95% of the initial amount of tabosostat or other after storage in a container at room temperature at about 60% relative humidity for 6 months. Pharmaceutically acceptable salts with a total impurity content of less than 1%.

Embodiment 5. The formulation of any one of embodiments 1 to 4, wherein the formulation retains about 96%, about 97%, about 98%, or about 99% of the initial amount of tabostat or its pharmaceutically acceptable Salt is acceptable and the total impurity content is less than 0.5%.

Embodiment 6. The formulation of any one of embodiments 1 to 4, wherein the formulation retains about 99.5% of the initial amount of Taboxostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 0.2 %.

Embodiment 7. The formulation of any one of embodiments 1 to 4, wherein the formulation retains about 98% of the initial amount of Tabos after 12 months in the container at room temperature and about 60% relative humidity. or other pharmaceutically acceptable salts.

Embodiment 8. The formulation of any one of embodiments 1 to 7, wherein the formulation contains undetectable impurities at relative retention times (RRT) of 1.06 and 1.16.

Example 9. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising/consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

Embodiment 10. The formulation of Embodiment 9, wherein the formulation retains about 98% of the initial amount of taboxostat or Its pharmaceutically acceptable salt; and the total amount of impurities is less than 0.5%.

Embodiment 11. The formulation of Embodiment 9, wherein the formulation contains undetectable impurities at relative retention times (RRT) of 1.06 and 1.16.

Example 12. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising/consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; and (v) Magnesium stearate.

Embodiment 13. The formulation of Embodiment 12, wherein the formulation retains about 95% of the initial amount of hemoglobin after storage in a container under accelerated conditions for 1 month at a temperature of 40°C and a relative humidity of about 75%. Bosistat or its pharmaceutically acceptable salt; and the total amount of impurities is less than 0.2%.

Embodiment 14. The formulation of Embodiment 12, wherein the formulation contains undetectable impurities at relative retention times (RRT) of 1.06 and 1.16.

Example 15. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) about 85% to about 99% w/w silicified microcrystalline cellulose, (ii) Sodium dihydrogen phosphate monohydrate in an amount from about 0.01% to about 2% w/w, (iii) Phosphoric acid in an amount of about 0.005% to about 0.1% w/w; and (iv) Magnesium stearate in an amount of about 0.05% to about 2% w/w.

Embodiment 16. The formulation of any one of embodiments 1 to 15, wherein the formulation further comprises microcrystalline cellulose; stearic acid; lactose monohydrate, and pregelatinized starch.

Example 17. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose, (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; and (viii) Phosphoric acid.

Embodiment 18. The formulation of Embodiment 17, wherein after storage in a container at room temperature at about 60% relative humidity for 6 months, the formulation retains at least about 95% of the initial amount of tabostat or other Pharmaceutically acceptable salts with a total impurity content of less than 1%.

Example 19. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose, (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; and (viii) Phosphoric acid.

Embodiment 20. The formulation of Embodiment 19, wherein after storage in a container at room temperature at about 60% relative humidity for 6 months, the formulation retains at least about 95% of the initial amount of tabostat or other Pharmaceutically acceptable salts with a total impurity content of less than 1%.

Embodiment 21. The formulation of any one of embodiments 17 to 19, wherein the formulation contains undetectable impurities at relative retention times (RRT) of 1.06 and 1.16.

Embodiment 22. The formulation of any one of embodiments 17 to 19, wherein the formulation retains about 96% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is 0.8 %.

Example 23. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising or consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose, (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; and (viii) Phosphoric acid.

Embodiment 24. The formulation of Embodiment 23, wherein the formulation retains at least about 98% of the initial amount of tabosostat or its pharmaceutically acceptable Salt is acceptable and the total impurity content is less than 1%.

Embodiment 25. The formulation of Embodiment 23, wherein the formulation retains about 100.9% of the initial amount of tabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is 0.8%.

Embodiment 26. The formulation of any one of embodiments 23 to 25, wherein the formulation contains undetectable impurities at relative retention times (RRT) of 1.06 and 1.16.

Example 27. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising/consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose, (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; and (viii) Phosphoric acid.

Embodiment 28. The formulation of Embodiment 27, wherein at least about 90% of the initial amount of tabosostat or other is retained after storage in a container for 6 months at a temperature of 40°C and a relative humidity of about 75%. Pharmaceutically acceptable salts with a total impurity content of less than 1%.

Embodiment 29. The formulation of Embodiment 23 or 24, wherein the formulation retains about 93% of the initial amount of Taboxostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is 0.8%.

Embodiment 30. The formulation of any one of embodiments 27 to 29, wherein the formulation contains undetectable impurities at relative retention times (RRT) of 1.06 and 1.16.

Embodiment 31. The formulation of any one of embodiments 17 to 30, wherein the formulation comprises: (i) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (ii) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; (iii) About 50% to about 95% w/w lactose monohydrate; (iv) Microcrystalline cellulose in an amount of about 5% to about 95% w/w; (v) Pregelatinized starch in an amount of about 0.05% to about 10% w/w; (vi) Stearic acid in an amount of about 0.05% to about 2% w/w; (vii) Phosphoric acid in an amount of about 0.005% to about 0.1% w/w; and (viii) Magnesium stearate in an amount of about 0.01% to about 2% w/w, preferably about 0.05% to about 2% w/w.

Example 32. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose; (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; (viii) Phosphoric acid; and (ix) Moisture-proof film coating.

Embodiment 33. The formulation of Embodiment 32, wherein the formulation retains at least about 95% of the initial amount of taboxostat or a pharmaceutical thereof after storage in a container for 6 months at room temperature and about 60% relative humidity. Scientifically acceptable salt with a total impurity content of less than 1%.

Example 34. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose, (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; (viii) Phosphoric acid; and (ix) Moisture-proof film coating.

Embodiment 35. The formulation of Embodiment 34, wherein the formulation retains at least about 95% of the initial amount of tabostat or its pharmaceutical agent after storage in a container for 6 months at room temperature and about 60% relative humidity. Scientifically acceptable salt with a total impurity content of less than 1%.

Embodiment 36. The formulation of any one of embodiments 32 to 35, wherein the formulation retains about 98.5% of the initial amount of tabosat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is 0.7 %.

Embodiment 37. The formulation of any one of embodiments 32 to 36, wherein the formulation contains undetectable impurities at relative retention times (RRT) of 1.06 and 1.16.

Example 38. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose, (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; (viii) Phosphoric acid; and (ix) Moisture-proof film coating.

Embodiment 39. The formulation of Embodiment 38, wherein after storage in the container for 6 months at about 2°C to about 8°C, the formulation retains about 95% of the initial amount of tabostat or its pharmaceutically acceptable Salt is acceptable and the total impurity content is less than 1%.

Embodiment 40. The formulation of Embodiment 38 or 39, wherein the formulation retains about 99.5% of the initial amount of Taboxostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is 0.6%.

Embodiment 41. The formulation of embodiments 38 to 40, wherein the formulation contains undetectable impurities at relative retention times (RRT) of 1.06 and 1.16.

Example 42. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Lactose monohydrate; (iii) Microcrystalline cellulose, (iv) Pregelatinized starch; (v) Stearic acid; (vi) Silicated microcrystalline cellulose; (vii) Sodium dihydrogen phosphate monohydrate; (viii) Phosphoric acid; and (ix) Moisture-proof film coating.

Embodiment 43. The formulation of Embodiment 42, wherein the formulation retains at least about 95% of the initial amount of tabostat or Its pharmaceutically acceptable salt, and the total amount of impurities is less than 1%.

Embodiment 44 The formulation of Embodiment 42 or 43, wherein the formulation retains about 98% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is 0.7%.

Embodiment 45. The formulation of any one of embodiments 42 to 44, wherein the formulation contains undetectable impurities at relative retention times (RRT) of 1.06 and 1.16.

Embodiment 46. The formulation of any one of embodiments 32 to 45, comprising: (i) About 0.1% to about 2% w/w of Tabostat or its pharmaceutically acceptable salt; (ii) About 50% to about 95% w/w lactose monohydrate; (iii) About 5% to about 95% w/w microcrystalline cellulose; (iv) about 0.05% to about 10% w/w pregelatinized starch, (v) About 0.05% to about 2% w/w stearic acid; (vi) About 2% to about 95% w/w silicified microcrystalline cellulose; (vii) About 0.01% to about 2% w/w sodium dihydrogen phosphate monohydrate; (viii) About 0.005% to about 0.1% w/w phosphoric acid; and (ix) Moisture-proof film coating from about 2% w/w to about 4% w/w.

Example 47. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; (v) Magnesium stearate; and (vi) Moisture-proof film coating.

Embodiment 48. The formulation of Embodiment 47, wherein after storage in a container at room temperature at about 60% relative humidity for 6 months, the formulation retains at least about 95% of the initial amount of tabostat or Its pharmaceutically acceptable salt, and the total amount of impurities is less than 1%.

Example 49. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; (v) Magnesium stearate; and (vi) Moisture-proof film coating.

Embodiment 50. The formulation of Embodiment 49, wherein after storage in a container at room temperature at about 60% relative humidity for 6 months, the formulation retains at least about 95% of the initial amount of tabostat or Its pharmaceutically acceptable salt, and the total amount of impurities is less than 1%

Embodiment 51. The formulation of any one of embodiments 47 to 50, wherein the formulation retains about 97% of the initial amount of taboxostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is 0.8 %.

Embodiment 52. The formulation of any one of Embodiments 47 to 51, wherein the formulation contains undetectable impurities at relative retention times (RRT) of 1.06 and 1.16.

Example 53. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising/consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; (v) Magnesium stearate; and (vi) Moisture-proof film coating.

Embodiment 54. The formulation of Embodiment 53, wherein the formulation retains at least about 95% of the initial amount of tabostat or its pharmaceutical agent after storage in the container for 6 months at a temperature of 2°C to 8°C. Scientifically acceptable salt with a total impurity content of less than 1%.

Embodiment 55. The formulation of Embodiment 53 or 54, wherein the formulation retains about 97.5% of the initial amount of Taboxostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is 0.8%.

Embodiment 56. The formulation of any one of embodiments 53 to 55, wherein the formulation contains undetectable impurities at relative retention times (RRT) of 1.06 and 1.16.

Example 57. A formulation suitable for oral administration of Tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising/consisting of: (i) Tabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid; (v) Magnesium stearate; and (vi) Moisture-proof film coating.

Embodiment 58. The formulation of Embodiment 57, wherein the formulation retains at least about 96% of the initial amount of Tabos after storage in a container for 6 months at a temperature of 40° C. and a relative humidity of about 75%. It or its pharmaceutically acceptable salt, and the total amount of impurities is less than 1.5%.

Embodiment 59. The formulation of Embodiment 57 or 58, wherein the formulation retains about 97% of the initial amount of Tabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is 1%.

Embodiment 60. The formulation of any one of embodiments 57 to 59, wherein the formulation contains undetectable impurities at relative retention times (RRT) of 1.06 and 1.16.

Embodiment 61. The formulation of any one of embodiments 47 to 60, comprising: (i) About 0.1% to about 2% w/w of Tabostat or its pharmaceutically acceptable salt; (ii) About 2% to about 95% w/w silicified microcrystalline cellulose; (iii) About 0.01% to about 2% w/w sodium dihydrogen phosphate monohydrate; (iv) About 0.005% to about 0.1% w/w phosphoric acid; (v) About 0.01% to about 5% w/w, preferably about 0.05% to about 2% w/w magnesium stearate; and (vi) Moisture-proof film coating from about 2% w/w to about 4% w/w.

Embodiment 62. The formulation of any one of embodiments 32 to 61, wherein the moisture barrier coating comprises cellulose and its derivatives, such as ethylcellulose, hydroxypropylmethylcellulose (e.g., hypromellose 5cP and hypromellose 15cP), hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropyl phthalate Methylcellulose, cellulose acetate phthalate, cellulose acetate trimellitate; waxes; polyvinyl derivatives, such as PVA (polyvinyl alcohol), for example under the trademarks Opadry AMB, Opadry II, Opadry QX (Kollicoat ), or PVP-PVAc copolymers (polyvinylpyrrolidone-polyvinyl acetate copolymer) and methacrylic polymers (such as Eudragit) and the like.

Embodiment 63. The formulation of embodiment 62, wherein the moisture barrier coating comprises a PVA-based polymer, preferably Opadry AMB Blue Light.

Embodiment 64. The formulation of any one of embodiments 1 to 63, wherein the formulation does not contain crospovidone.

Example 65. A formulation suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.01% to about 2% w/w Sodium dihydrogen phosphate monohydrate, (b) about 0.005% to about 0.1% w/w phosphoric acid, and (c) about 85% to about 99% w/w silicified microcrystalline cellulose, and the extragranular portion Comprised of: (d) about 0.1% to about 0.2% w/w Tabostat or a pharmaceutically acceptable salt thereof, and (e) about 0.01% to about 5% w/w magnesium stearate.

Embodiment 66. The formulation of Embodiment 65, wherein the stable tablet formulation retains at least about 95% of the initial amount of tablets after storage in a container at room temperature at about 60% relative humidity for 6 months. Sistat or its pharmaceutically acceptable salt, and the total amount of impurities is less than 1%.

Embodiment 67. A formulation suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.01% to about 2% w/w an amount of sodium dihydrogen phosphate monohydrate, (b) an amount of about 0.005% to about 0.1% w/w phosphoric acid, and (c) about 85% to about 99% w/w silicified microcrystalline cellulose, and the particles The outer portion contains: (d) about 0.1% to about 0.2% w/w of tabosostat or a pharmaceutically acceptable salt thereof, and (e) about 0.01% to about 5% w/w of hard Magnesium fatty acid.

Embodiment 68. The formulation of Embodiment 67, wherein the formulation retains at least about 95% of the initial amount after storage in a container under accelerated conditions for 6 months at a temperature of 40°C and a relative humidity of about 75%. Tabostat or its pharmaceutically acceptable salt, and the total amount of impurities is less than 1%.

Embodiment 69. The formulation of any one of Embodiments 65 to 68, wherein the formulation contains undetectable impurities at RRT 1.06 and 1.16.

Embodiment 70. A formulation of taboxostat or a pharmaceutically acceptable salt thereof, the formulation comprising (i) an intragranular part, and (ii) an extragranular part; wherein the intragranular part comprises: (a) Sodium dihydrogen phosphate monohydrate in an amount from about 0.01% to about 2% w/w, (b) phosphoric acid in an amount from about 0.5% to about 1% w/w, and (c) from about 85% to about 99% w/ w/w of microcrystalline cellulose, and the extragranular portion contains: (d) about 0.1% to about 0.2% w/w of tabosostat or a pharmaceutically acceptable salt thereof, and (e) about 0.01% to about 5% w/w magnesium stearate, wherein the formulation further includes a moisture-proof coating in an amount of about 2% w/w to about 4% w/w.

Embodiment 71. A formulation of tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising (i) an intragranular part, and (ii) an extragranular part; wherein the intragranular part comprises: (a) Sodium dihydrogen phosphate monohydrate in an amount from about 0.01% to about 2% w/w, (b) phosphoric acid in an amount from about 0.5% to about 1% w/w, and (c) from about 25% to about 75% w/ w amount of silicified microcrystalline cellulose, (d) about 25% to about 75% w/w amount of microcrystalline cellulose, and the extragranular portion contains: (e) about 0.1% to about 0.2% w/w amount of Tabostat or a pharmaceutically acceptable salt thereof, and (f) magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the formulation further includes about 2% w/w to about 4% w/w amount of moisture-proof coating.

Embodiment 72. The formulation of embodiment 70 or 71, wherein the microcrystalline cellulose is MCC-101.

Embodiment 73. The formulation of embodiment 70 or 71, wherein microcrystalline cellulose is present at about 25% w/w and the siliconized microcrystalline cellulose is present at about 75% w/w.

Embodiment 74. The formulation of embodiment 70 or 71, wherein microcrystalline cellulose is present at about 50% w/w and the silicified microcrystalline cellulose is present at about 50% w/w.

Embodiment 75. The formulation of embodiment 70 or 71, wherein microcrystalline cellulose is present at about 75% w/w and the silicified microcrystalline cellulose is present at about 25% w/w.

Embodiment 76. A formulation suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.01% to about 2% w/w An amount of sodium dihydrogen phosphate monohydrate, (b) an amount of about 0.025% to about 1% w/w of phosphoric acid, and (c) an amount of about 85% to about 99% w/w of microcrystalline cellulose, and the particles The outer part contains: (d) about 0.1% to about 0.2% w/w of tabostat or a pharmaceutically acceptable salt thereof, (e) about 0.01% to about 5% w/w of stearin magnesium phosphate, and (f) optionally pregelatinized starch in an amount from about 0.5% to about 5% w/w, wherein the formulation further includes a moisture-proof coating in an amount from about 2% w/w to about 4% w/w .

Embodiment 77. A formulation suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.01% to about 2% w/w An amount of potassium dihydrogen phosphate, (b) hydrochloric acid in an amount of about 0.5% to about 1% w/w, and (c) silicified microcrystalline cellulose in an amount of about 85% to about 99% w/w, and the extragranular portion Containing: (d) Taboxostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w, and (e) stearic acid in an amount of about 0.01% to about 5% w/w magnesium.

Embodiment 78. A formulation suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.5% to about 2% w/w an amount of malic acid, and (b) silicified microcrystalline cellulose in an amount of about 85% to about 99% w/w, and the extragranular portion contains: (c) about 0.1% to about 0.2% w/w tabos or its pharmaceutically acceptable salt, and (d) magnesium stearate in an amount of about 0.01% to about 5% w/w.

Embodiment 79. A formulation suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.1% to about 2% w/w an amount of citric acid, and (b) an amount of about 85% to about 99% w/w of silicified microcrystalline cellulose, and the extragranular portion contains: (c) an amount of about 0.1% to about 0.2% w/w of hexabol stearate or a pharmaceutically acceptable salt thereof, and (d) magnesium stearate in an amount of about 0.01% to about 5% w/w.

Embodiment 80. A formulation suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.1% to about 0.2% w/w An amount of Taboxostat or a pharmaceutically acceptable salt thereof, (b) an amount of about 0.01% to about 2% w/w sodium dihydrogen phosphate monohydrate, and (c) an amount of about 0.005% to about 0.1% w/w phosphoric acid; and the extragranular portion contains (d) about 25% to about 95% w/w lactose monohydrate, (e) about 5% to about 95% w/w microcrystalline fibers Vegetables, (f) silicified microcrystalline cellulose in an amount of about 2% to about 95%, (g) pregelatinized starch in an amount of about 0.05% to about 10% w/w, (h) about 0.02% to about 2% Stearic acid in an amount w/w, (i) about 0.01% to about 5% magnesium stearate in an amount w/w.

Embodiment 81. The formulation of Embodiment 80, wherein the stable tablet formulation retains at least about 95% of the initial amount of tablets after storage in a container at room temperature at about 60% relative humidity for 6 months. Sistat or its pharmaceutically acceptable salt, and the total amount of impurities is less than 1%.

Embodiment 82. A formulation suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.1% to about 0.2% w/w An amount of Taboxostat or a pharmaceutically acceptable salt thereof, (b) an amount of about 0.01% to about 2% w/w sodium dihydrogen phosphate monohydrate, and (c) an amount of about 0.005% to about 0.1% w/w phosphoric acid; and the extragranular portion contains (d) about 25% to about 95% w/w lactose monohydrate, (e) about 5% to about 95% w/w microcrystalline fibers Vegetables, (f) silicified microcrystalline cellulose in an amount of about 2% to about 95%, (g) pregelatinized starch in an amount of about 0.05% to about 10% w/w, (h) about 0.02% to about 2% Stearic acid in an amount w/w, (i) about 0.01% to about 5% magnesium stearate in an amount w/w.

Embodiment 83. The formulation of 82, wherein the stable tablet formulation retains at least about 95% of the initial amount after storage in a container under accelerated conditions for 6 months at a temperature of 40°C and a relative humidity of about 75%. Tabostat or its pharmaceutically acceptable salt, and the total amount of impurities is less than 1%.

Embodiment 84. The formulation of embodiments 82 and 83, wherein the formulation contains undetectable impurities at RRT 1.06 and 1.16.

Embodiment 85. A formulation suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.01% to about 2% w/w an amount of sodium dihydrogen phosphate monohydrate, (b) phosphoric acid in an amount of about 0.005% to about 0.1% w/w, and (c) silicified microcrystalline cellulose in an amount of about 85% to about 99% w/w, and The extragranular portion contains: (d) an amount of about 0.1% to about 0.2% w/w of tabosostat or a pharmaceutically acceptable salt thereof, and (e) an amount of about 0.01% to about 5% w/w of Magnesium stearate.

Embodiment 86. The formulation of embodiment 85, wherein the formulation further comprises from about 2% to about 4% w/w a moisture barrier coating.

Embodiment 87. The formulation of embodiments 84 and 85, wherein the formulation retains at least about 95% of the initial amount of tabostat after storage in a container at room temperature and about 60% relative humidity for 6 months. or its pharmaceutically acceptable salt, and the total amount of impurities is less than 1%.

Embodiment 88. A formulation suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.01% to about 2% w/w an amount of sodium dihydrogen phosphate monohydrate, (b) phosphoric acid in an amount of about 0.005% to about 0.1% w/w, and (c) silicified microcrystalline cellulose in an amount of about 85% to about 99% w/w, and The extragranular portion contains: (d) tabosostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w, and (e) about 0.01% to about 5% w/w Magnesium stearate.

Embodiment 89. The formulation of Embodiment 88, wherein the tablet further comprises a moisture barrier coating of about 2% w/w to about 4% w/w, and wherein the formulation is at a temperature of 40°C and a relative humidity of about 75% After storage in the container for 6 months, the stable tablet formulation retains at least about 95% of the original amount of taboxostat or a pharmaceutically acceptable salt thereof and the total amount of impurities is less than 1%.

Embodiment 90. A formulation suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.1% to about 0.2% w/w An amount of Taboxostat or a pharmaceutically acceptable salt thereof; (b) an amount of about 0.01% to about 2% w/w sodium dihydrogen phosphate monohydrate; and (c) an amount of about 0.005% to about 0.1% w/w phosphoric acid; and the extragranular portion contains (d) about 25% to about 95% w/w lactose monohydrate, (e) about 5% to about 95% w/w microcrystalline fibers Vegetables, (f) silicified microcrystalline cellulose in an amount of about 2% to about 95%, (g) pregelatinized starch in an amount of about 0.05% to about 10% w/w, (h) about 0.02% to about 2% w/w stearic acid, (i) magnesium stearate in an amount of about 0.01% to about 5% w/w; wherein the formulation further includes a moisture-proof coating in an amount of about 2% to about 4% w/w.

Embodiment 91. The formulation of Embodiment 90, wherein the stable tablet formulation retains at least about 95% of the initial amount of tablets after storage in a container at room temperature at about 60% relative humidity for 6 months. Sistat or its pharmaceutically acceptable salt, and the total amount of impurities is less than 1%.

Example 92 A formulation suitable for oral administration, comprising (i) an intragranular portion, and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) from about 0.1% to about 0.2% w/w Taboxostat or its pharmaceutically acceptable salt, (b) sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w, and (c) about 0.005% to about 0.1% w/w /w amount of phosphoric acid; and the extragranular portion contains (d) about 25% to about 95% w/w amount of lactose monohydrate, (e) about 5% to about 95% w/w amount of microcrystalline cellulose , (f) silicified microcrystalline cellulose in an amount of about 2% to about 95%, (g) pregelatinized starch in an amount of about 0.05% to about 10% w/w, (h) about 0.02% to about 2% w /w stearic acid, (i) magnesium stearate in an amount of about 0.01% to about 5% w/w; wherein the formulation further includes a moisture-proof coating in an amount of about 2% to about 4% w/w.

Embodiment 93. The formulation of Embodiment 92, wherein the formulation retains at least about 95% of the initial amount of tabostat after storage in a container for 6 months at a temperature of 40° C. and a relative humidity of about 75%. or its pharmaceutically acceptable salt, and the total amount of impurities is less than 1%.

Embodiment 94. The formulation of embodiments 85 to 93, wherein the formulation contains undetectable impurities at RRT 1.06 and 1.16.

Embodiment 95. A formulation of tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion includes: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; and (c) phosphoric acid in an amount of about 0.005% to about 0.1% w/w; and The extragranular part includes: (a) Lactose monohydrate in an amount of about 25% to about 95% w/w; (b) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (c) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (d) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (e) stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the formulation further includes a moisture-proof coating in an amount of about 2% w/w to about 4% w/w.

Example 96. A formulation comprising (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) About 0.01% to about 2% w/w potassium dihydrogen phosphate; and (c) Hydrochloric acid in an amount of about 0.005% to about 0.1% w/w; and The extragranular part includes: (a) Lactose monohydrate in an amount of about 25% to about 95% w/w; (b) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (c) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (d) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (e) stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the formulation further includes a moisture-proof coating in an amount of about 2% w/w to about 4% w/w.

Embodiment 97. A formulation of tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion includes: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) Citric acid in an amount of about 0.01% to about 2% w/w; and The extragranular part includes: (a) Lactose monohydrate in an amount of about 25% to about 95% w/w; (b) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (c) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (d) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (e) stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the formulation further includes a moisture-proof coating in an amount of about 2% w/w to about 4% w/w.

Embodiment 98. A formulation of tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion includes: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) Malic acid in an amount from about 0.01% to about 2% w/w; and The extragranular part includes: (a) Lactose monohydrate in an amount of about 25% to about 95% w/w; (b) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (c) silicified microcrystalline cellulose in an amount from about 2% to about 95%; (d) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (e) stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the formulation further includes a moisture-proof coating in an amount of about 2% w/w to about 4% w/w.

Embodiment 99. A formulation of tabostat or a pharmaceutically acceptable salt thereof, the formulation comprising: (i) Taboxostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w; silicified microcrystalline cellulose in an amount of about 2% to about 95% w/w; (ii) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; (iii) About 50% to about 95% w/w lactose monohydrate; (iv) Microcrystalline cellulose in an amount of about 5% to about 40% w/w; (v) Pregelatinized starch in an amount of about 0.05% to about 5% w/w; (vi) Phosphoric acid in an amount of about 0.05% to about 0.1% w/w; and (vii) Magnesium stearate in an amount of about 0.01% to about 5% w/w, preferably about 0.05% to about 2% w/w, wherein the formulation further comprises about 2% w/w to about 4% w /w amount of moisture-proof coating.

Embodiment 100. The formulation of any one of embodiments 1 to 99, wherein the formulation is stored in a normal HDPE bottle.

Embodiment 101. The formulation of any one of embodiments 1 to 99, wherein the formulation is stored in a Multiblock HDPE bottle.

Embodiment 102. The formulation of embodiments 32 to 63, wherein the coating is present in an amount from about 2% to about 8% w/w of the total weight of the formulation.

Embodiment 103. The formulation of embodiments 32 to 63, wherein the coating accounts for about 4% w/w of the total weight of the formulation.

Embodiment 104. The formulation of embodiments 32 to 63, wherein the coating provides a moisture barrier.

Embodiment 105. The formulation of embodiments 32 to 63, wherein the coating provides an oxygen barrier.

Embodiment 106. The formulation of embodiment 100 or 101, wherein the storage container optionally contains a desiccant.

Embodiment 107. The formulation of embodiment 106, wherein the desiccant is silica gel.

Embodiment 108. The formulation of embodiment 100 or 101, wherein the packaging optionally contains an aluminum bag.

Embodiment 109. The formulation of any one of embodiments 1 to 108, wherein the formulation reacts in the presence of water in less than 5 minutes (e.g., 3 minutes or less, 2 minutes or less, 1.5 minutes or less, 1 minutes or less).

Embodiment 110. The formulation of any one of Embodiments 1 to 109, wherein the formulation disintegrates in the presence of water in about 40 to about 60 seconds.

Embodiment 111. The formulation of any one of the preceding embodiments, wherein taboxostat or a pharmaceutically acceptable salt thereof is taboxostat mesylate.

Embodiment 112. The formulation of any one of the preceding embodiments, wherein tabostat or a pharmaceutically acceptable salt thereof is present in an amount from about 50 micrograms to about 400 micrograms.

Embodiment 113. The formulation of Embodiment 112, wherein tabostat or a pharmaceutically acceptable salt thereof is present in an amount of about 50 micrograms.

Embodiment 114. The formulation of Embodiment 112, wherein tabostat or a pharmaceutically acceptable salt thereof is present in an amount of about 200 micrograms.

Embodiment 115. The formulation of Embodiment 112, wherein tabostat or a pharmaceutically acceptable salt thereof is present in an amount of about 400 micrograms.

Embodiment 116. The formulation of any one of the preceding embodiments, wherein taboxostat or a pharmaceutically acceptable salt is present in an amount from about 0.05% to about 0.2% w/w based on the total weight of the formulation.

Embodiment 117. The formulation of any of the preceding embodiments, wherein the pH of the composition is less than about 5.

Embodiment 118. The formulation of any of the preceding embodiments, wherein the pH of the composition is about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5.

Embodiment 119. The formulation of any of the preceding embodiments, formed by a wet granulation process, wherein Taboxostat is added extragranularly.

Embodiment 120. The formulation of any of the preceding embodiments, formed by a dry granulation process.

Embodiment 121. The formulation of any of the preceding embodiments, formed by direct compression.

Embodiment 122. The formulation of any one of embodiments 119 to 121, wherein the relative humidity is maintained at or below 35% during the preparation process.

Embodiment 123. The formulation of any one of embodiments 119 to 121, wherein taboxostat or a pharmaceutically acceptable salt thereof is not in direct contact with the aqueous vehicle during the process.

Embodiment 124. The formulation of any of the preceding embodiments, wherein the formulation exhibits complete release within 15 minutes.

Embodiment 125. The formulation of any of the preceding embodiments, wherein the formulation meets acceptance criteria for content uniformity, hardness, and brittleness.

Embodiment 126. The formulation of any of the preceding embodiments, wherein the cyclic form (%) is within an acceptable range of about 10% to about 60%.

Embodiment 127. The formulation of any of the preceding embodiments, wherein the formulation exhibits a drying loss of 1%.

Embodiment 128. A process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, the process includes: (i) Prepare a clear buffer solution by dissolving orthophosphoric acid and sodium phosphate in purified water; (ii) Add silica microcrystalline cellulose to the above buffer solution; (iii) Granulate the solution and then dry the granules; (iv) Extragranularly blended with Tabostat or its pharmaceutically acceptable salt; (v) Where appropriate, lubricate the blend with magnesium stearate, and (vi) Coat with moisture-proof film coating as appropriate.

Embodiment 129. A dry compounding process for preparing a formulation of taboxostat or a pharmaceutically acceptable salt thereof. The dry compounding process includes mixing taboxostat or a pharmaceutically acceptable salt thereof in the presence of added water. The above acceptable salts and one or more excipients selected from the group consisting of silicified microcrystalline cellulose, sodium phosphate, phosphoric acid, and magnesium stearate.

Embodiment 130. A process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, the process includes: (i) Prepare a clear buffer solution by dissolving orthophosphoric acid and sodium phosphate in purified water; (ii) Add Tabostat or its pharmaceutically acceptable salt to the above buffer solution and granulate the solution; (iii) Dry the granules and blend them with starch and silicified microcrystalline cellulose; (iv) Lubricating blends; and (v) Coat with moisture-proof film coating as appropriate.

Embodiment 131. The process of Embodiment 128 or 130, wherein blending/mixing is performed in a rapid mixing granulator.

Embodiment 132. The process of any one of embodiments 128 to 131, wherein the amount of silicified microcrystalline cellulose is from about 2% to about 95% w/w.

Embodiment 133. The process of any one of embodiments 128 to 131, wherein the amount of phosphoric acid is from about 0.005% to about 1% w/w.

Embodiment 134. The process of any one of embodiments 128 to 131, wherein sodium dihydrogen phosphate monohydrate is about 0.01% to about 2% w/w.

Embodiment 135. The process of any one of embodiments 128 to 131, wherein the amount of magnesium stearate is from about 0.01% to about 5% w/w.

Embodiment 136. The process of any one of embodiments 128 to 131, wherein the buffer solution prepared in step (i) has a pH of about 2 to 3.

Embodiment 137. The process of any one of Embodiments 128 to 131, wherein Tabostat or its pharmaceutically acceptable salt is not in direct contact with the aqueous vehicle.

Embodiment 138. The process of any one of Embodiments 128 to 131, wherein the process is performed at a relative humidity of less than 60%.

Embodiment 139. A process for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, the process includes: (i) Sieve the silica microcrystalline cellulose and divide it into 4 parts, (ii) Mix Tabostat or its pharmaceutically acceptable salt, the first part of siliconized microcrystalline cellulose, orthophosphoric acid and sodium phosphate buffer in a plastic bag for 10 minutes; (iii) Manually mix the blend of step (ii) and the second portion of silica microcrystalline cellulose in a plastic bag for 15 minutes, and then sieve; (iv) Manually mix the blend of step (iii) and the third portion of silica microcrystalline cellulose in a plastic bag for 15 minutes, and then sieve; (v) Manually mix the blend of step (iv) and the fourth portion of silica microcrystalline cellulose in a plastic bag for 15 minutes, and then sieve; (vi) Pre-lubrication step (v) blends and forms small pieces or compacts; (vii) By grinding small pieces or briquettes through a screen; (viii) Lubricating blends; and (ix) Coat with moisture-proof coating as appropriate.

Embodiment 140. A method of treating cancer or tumors in a subject, comprising orally administering to the subject a formulation of taboxostat or a pharmaceutically acceptable salt thereof as in any of the preceding embodiments.

Embodiment 141. The method of Embodiment 140, further administering to the subject a composition comprising a second active agent.

Embodiment 142. The method of Embodiment 141, wherein the second composition is administered orally, bucally, intravenously, subcutaneously, intraarterially, intramuscularly, transdermally, inhalation, and any combination thereof, preferably orally. and.

Embodiment 143. The method of Embodiment 140, wherein the formulation comprising taboxostat or a pharmaceutically acceptable salt thereof is administered orally twice daily at a dose of about 200 micrograms.

Embodiment 144. The method of Embodiment 140, wherein the formulation comprising taboxostat or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 200 micrograms three times per day.

Embodiment 145. The method of Embodiment 140 or 141, wherein the formulation of taboxostat or a pharmaceutically acceptable salt thereof and the second composition may be administered simultaneously, or administered sequentially with a specific period of time apart.

Embodiment 146. The method of embodiment 140 or 141, wherein the formulation of taboxostat or a pharmaceutically acceptable salt thereof and the second composition can be administered by the same route of administration or by different routes of administration.

Embodiment 147. An individual unit dosage form provided as a kit, comprising Taboxostat or a medicament thereof according to any one of the preceding embodiments in a container with or without instructions for administration to an individual in need thereof. A scientifically acceptable salt preparation.

Embodiment 148. The kit of embodiment 147, comprising a package insert including instructions for treating cancer in an individual using a formulation of tabostat or a pharmaceutically acceptable salt thereof as described herein.

Embodiment 149. The formulation, method, process or kit of any one of the preceding embodiments, wherein the individual system is human. Example

The following examples are included to illustrate preferred embodiments of the present disclosure. Those skilled in the art should understand that the techniques disclosed in the following examples represent techniques discovered by the inventor to function well in the practice of this disclosure, and therefore may be considered to constitute preferred modes for its practice. However, those skilled in the art should appreciate from the present disclosure that many changes can be made in the specific embodiments disclosed and still obtain a similar or similar result without departing from the spirit and scope of the disclosure. Example 1 : Stable Tabostat Formulation According to the Present Disclosure Formulation 1 Table 1 Element Composition (mg/ unit ) Tabostat (Taposstat mesylate) 0.2 (0.29) Microcrystalline cellulose, NF (Avicel PH 101) 18.68 Lactose monohydrate, NF (Pharmatose 100M) 171 Sodium Phosphate Monohydrate, USP 0.12 Orthophosphoric acid, 85%, NF QS Silicated Microcrystalline Cellulose, NF (SMCC HD90) 4 Pregelatinized starch, NF (Starch 1500) 3 Stearic acid, NF (Kolliwax S Fine) 3 total 200 Note: The volume of water used for wet granulation is 70 mL for the simple manufacturing process ( see also Figure 1 and Figure 2)

All raw materials are allocated according to batch manufacturing recipes.

Microcrystalline cellulose and lactose monohydrate were sieved through a #40 mesh, transferred to RMG, and dry mixed at 200 rpm for 5 minutes.

Prepare the granulation fluid: Dissolve the dispensed amount of sodium phosphate in the required amount of water; adjust the pH to 2.0-2.5 with orthophosphoric acid. To this is added the dispensed amount of Tabostat and dissolved by stirring. The contents of the RMG were granulated using the granulation solution prepared above. The above granulated material was collected, transferred to a fluid bed dryer (FBD) and dried at 60°C until the LOD% reached less than 1.0% (drying time was 5 minutes and LOD% was 0.40%).

The dry granules were sieved through a #40 mesh and the residue was ground through a multi-mill using a 1.00 mm sieve at medium speed. % of residue on #40 mesh: 56.62 Total yield % after drying and grinding: 93.55%

Transfer the dried and ground material to the same RMG.

Distribute extragranular material based on yield %. SMCC and starch were sieved through #40 stearic acid and added to and pre-lubricated at 200 RPM for 5 minutes.

The stearic acid was sieved through a #60 mesh and transferred to RMG.

Lubricate for 5 minutes at 200 rpm.

Compress the lubricated blend on the rotary compressor using 7.00 mm round standard punch holes. Formulation 2 Table 2 Element Composition (mg/ unit ) 0.1 mg ( referred to as optimal tablet batch in Table 32 , Table 34 , Table 36 and Table 38 )) Composition (mg/ unit ) 0.2 mg Tabostat (Taposstat mesylate) 0.10 0.2 (0.29) Orthophosphate 0.025 0.05 Sodium dihydrogen phosphate monohydrate 0.6 0.12 Siliconized MCC 98.82 197.54 Magnesium stearate 1 2 total 100 mg 200 mg Simple manufacturing process (see also Figure 3 and Figure 4)

Dissolve sodium phosphate and orthophosphoric acid in purified water to form a clear solution. Silicated microcrystalline cellulose was granulated in RMG with the above buffer solution and then dried in FBD. Co-sieve Tabostat with 2X-3X amounts of buffered siliconized microcrystalline cellulose through a #40 mesh. The remaining silicified microcrystalline cellulose was sieved through the same sieve and the magnesium stearate was sieved through a #60 mesh. The silicified microcrystalline cellulose and tapoxostat were mixed in the RMG for approximately 10 minutes and then lubricated in the RMG for an additional 10 minutes at 100 rpm. The lubricating blend is compressed into lozenges. Formulation 3 Table 3 Element Composition (mg/ unit ) Composition (mg/ unit ) ( referred to as optimal tablet batch in Table 12 , Table 14 , Table 16 , Table 18 and Table 20 ) Core Tablet Composition Tabostat (Taposstat mesylate) 0.2 (0.29) 0.1 Microcrystalline Cellulose, NF (Avicel PH 101) 18 9.48 Lactose monohydrate, NF (Pharmatose 100M) 171.68 85.36 Sodium Phosphate Monohydrate, USP 0.12 0.06 Phosphoric acid, 85%, NF QS QS Silicated Microcrystalline Cellulose, NF (SMCC HD90) 5 2.5 Pregelatinized starch, NF (Starch 1500) 2 1 Stearic acid, NF (Kolliwax S Fine) 3 1.5 Total weight of core tablets (mg) 200 100 Moisture-proof film coating Opadry AMB-II Blu-ray (88A205031) 8.00 4.00 purified water QS QS Total weight of film-coated tablets (mg) 208 104 Simple manufacturing process (see also Figure 5)

All raw materials are allocated according to batch manufacturing recipes.

Microcrystalline cellulose and lactose monohydrate were sieved through a #40 mesh, transferred to RMG, and dry mixed at 200 rpm for 5 minutes.

Prepare the granulation fluid: Dissolve the dispensed amount of sodium phosphate in the required amount of water; adjust the pH to 2.0-2.5 with orthophosphoric acid. Add the dispensed amount of API to this and dissolve by stirring.

The contents of RMG were granulated using the granulation solution prepared above and the granulation parameters are mentioned in Table 4 below. Table 4 parameters Impeller shredder Time (Min) speed Amperage speed Amperage dry mix 200 1.11-1.12 NA NA 5 minutes Add drug solution 200 1.12-1.14 NA NA 3 minutes Mix 1 200 1.12-1.15 NA NA 5 minutes

The above granulated material was collected, transferred to a fluid bed dryer (FBD) and dried at 60°C until the LOD% reached less than 1.0% (drying time was 16 minutes and LOD% was 0.79%). The dried granules are sieved through a #40 mesh with no residue present on the mesh. Total yield % after drying and grinding: 98.63%. Transfer the dried and ground material to the same RMG. Distribute extragranular material based on yield %. SMCC and starch were sieved through #40 stearic acid and added to and pre-lubricated at 200 RPM for 5 minutes. The stearic acid was sieved through a #60 mesh and transferred to RMG. Lubricate for 5 minutes at 200 rpm. Compress the lubricated blend on the rotary compressor using 7.00 mm round standard punch holes.

Compressed tablets (equivalent to 6000 tablets) were coated with a moisture-resistant film coating (Opadry AMB-II) using an automated coater. Table 5. Comparison of Results for Formulation 3 Core and Coated Tabostat Tablets (200 mcg) parameters Formulation 3 Core Tablets Formulation 3 Coated Tablets analyze(%) 101.3 100.6 Water content(%) 4.4 4.2 total impurities 0.08 0.08 Dissolve time Drug release percentage (%) (mean ± % RSD, N=3) At 15 minutes 100.6±1.0 101.0±0.4 at 30 minutes 103.1±0.4 103.9±0.3 At 45 minutes 106.0±0.7 100.4±0.7 at 60 minutes 104.7±0.7 105.8 ± 0.9 cyclic form (%) 22.7 22.0 Uniformity Average: 97.8; Min: 95.9 Max: 99.7; %RSD: 1.4; AV: 3.90

Results: A uniform film coating was achieved on the core tablets and all film coating properties were satisfactory. All CQA core tablets and coated tablets were found to be satisfactory. Film coating had no effect on dissolution as complete drug release was observed from the core tablets and coated tablets within 15 minutes. Initial analysis of the core tablets and even after coating was 100.0% and no impurities were observed at 1.06 RRT and 1.16 RRT (see Table 5). Formulation 4 Table 6 Sample number Ingredients ( trade name ) For 50 mcg Qty/ unit (mg) For 200 mcg Qty/ unit (mg) For 100 mcg Qty/ unit (mg) ( referred to as optimal tablet batch in Table 22 , Table 24 , Table 26 , Table 28 and Table 30 ) intragranular part 1 Silicated Microcrystalline Cellulose (SMCC HD90) 49.38 197.54 98.768 2 Sodium phosphate monohydrate (USP granules) 0.03 0.12 0.06 3 Orthophosphate 0.01 0.05 0.025 4 purified water Sufficient Sufficient Sufficient extragranular part 5 Tabostat mesylate 0.07 0.29 0.147 6 Magnesium stearate 0.5 2.00 1.00 Total weight of core tablets (mg) 50.00 200.00 100.00 coating 7 Opadry AMB-II Blu-ray (88A205031) 2.00 8.00 4.00 8 purified water Sufficient Sufficient Sufficient Total weight of coated tablets (mg) 52.00 208.00 104.00 Manufacturing Process ( see also Figure 6)

Dissolve sodium phosphate and orthophosphoric acid in purified water to form a clear solution. Silicated microcrystalline cellulose was granulated in RMG with the above buffer solution and then dried in FBD. Co-sieve Tabostat with 2X-3X amounts of buffered siliconized microcrystalline cellulose through a #40 mesh. The remaining silicified microcrystalline cellulose was sieved through the same sieve and the magnesium stearate was sieved through a #60 mesh. The silicified microcrystalline cellulose and tapoxostat were mixed in the RMG for approximately 10 minutes and then lubricated in the RMG for an additional 10 minutes at 100 rpm. The lubricated blend is compressed into tablets and coated with a moisture barrier film coating having the following composition.

Prepare coating solution (20% solids): Accurately weigh 24 grams of Opadry AMB-II and dissolve it in 96 grams of purified water and stir continuously with a mechanical stirrer at a slow RPM of 80-100 for 45 minutes. Table 7 : Physical parameters of 200 mcg and 50 mcg Taboxostat core tablets of Formulation 4 intensity 200 mg 50 mg Process time Compression starts Compression middle Compression nearing end Compression starts Compression middle Compression nearing end Weight change (mg) 200-205 199-205 199-204 48-52 48-52 49-53 Tablet hardness (kp) 9.9-12.0 9.8-11.9 9.7-11.9 8.2-10.5 8.9-12.9 8.0-11.0 Thickness (mm) 4.24-4.28 4.23-4.27 4.22-4.29 2.98-3.05 2.99-3.04 2.99-3.03 Disintegration time (sec) 15-30 15-35 15-40 50-60 50-60 40-55 Crispness (% w/w) 0.00 0.00 0.00 0.00 0.00 0.00 Table 8 : Chemical parameters of 200 mcg and 50 mcg Taboxostat core tablets of Formulation 4 intensity 200 mg 50 mg analyze (%) 102.5 101.1 Water content (%) 5.9 5.5 Dissolve time % drug release (mean±%RSD; N=3) NA 05 minutes 77.7 ± 4.4 10 minutes 93.0±1.0 20 minutes 96.5±0.8 30 minutes 98.3±0.4 45 minutes 98.8±0.3 60 minutes 100.7±0.6 Recycle 101.5±0.8 Related substances Method A (after 2.5 minutes) Peak -1 NMT 3% 0.030 at 1.19 RRT NMT 3% At 2.17 RRT, 0.049 Peak -2 NMT 3% At 2.16 RRT, 0.037 NMT 3% ND Method C ( before 2.5 minutes ) Peak -1 NMT 3% At 0.83 RRT, 0.01 NMT 3% ND Total impurities (%) (A+C) NMT 10.0% 0.08 NMT 10.0% 0.05 cyclic form (%) 12.2 17.6 Table 9. Physical parameters of Formulation 4 , 200 mcg and 50 mcg Taboxostat film-coated tablets Batch number 200 mg 50 mg Average weight of tablets (mg) 209.76 53.20 Tablet hardness(kp) 11.9-16.0 9.9-14.8 Thickness(mm) 4.28-4.35 3.00-3.03 Disintegration time 50 sec-01 min 15 sec 01 min to 01 min 20 sec Table 10 : Chemical parameters of 200 mcg and 50 mcg Taboxostat film-coated tablets of Formulation 4 Batch number 200 mg 50 mg Uniformity of drug distribution Average: 99.9 Min: 96.4 Max: 103.4 %RSD: 2.6 AV: 6.10 Average: 98.1 Min: 94.5 Max: 102.1 %RSD: 2.8 AV: 6.90 analyze(%) 101.1 100.9 water content 5.1 5.1 Dissolve time % drug release (mean±%RSD; N=3) Not carried out 05 minutes 91.4 ± 0.6 10 minutes 95.0±0.7 20 minutes 97.1±0.7 30 minutes 99.5±0.9 45 minutes 101.0±0.8 60 minutes 101.7±0.2 Recycle 102.3 ± 0.3 Related substances Method A (after 2.5 minutes) Peak-1 NMT 3% At 1.16 RRT, 0.005 At 1.18 RRT, 0.042 Peak-2 NMT 3% At 2.18 RRT, 0.217 At 2.16 RRT, 0.112 Method C (before 2.5 minutes) Peak -1 NMT 3% At 0.67 RRT, 0.01 ND Total impurities (%) (A+C) NMT 10% 0.23 0.15 cyclic form (%) 13.5 16.8

Results: A uniform film coating was achieved on the core tablets and all film coating properties were satisfactory. All CQA core tablets and coated tablets were found to be satisfactory. Film coating was observed to have no effect on dissolution as complete drug release was observed from the core tablets and coated tablets within 15 minutes. Initial analysis of the core tablets and even after coating was 100.0% and no impurities were observed at 1.06 RRT and 1.16 RRT. Table 11: Comparative effect on the stability of tapoxostat mesylate tablets in Formulation 3 by using different ratios of diluents (lactose monohydrate:microcrystalline cellulose)

Procedure: Four batches of 0.1 mg Tabostat Mesylate Lozenges (see Formulation 3) were prepared in the same manner as the manufacturing procedure given below, but using different concentrations of the diluent, lactose monohydrate: The ratios of microcrystalline cellulose were 80:20, 60:40, 40:60 and 10:90 (referred to herein as Batch 1, Batch 2, Batch 3 and Batch 4 respectively). Stability was evaluated by exposing the tablet batches to 40°C/75% RH under open conditions for 7 days. intragranular part Batch 1 (80:20) Batch 2 (60:40) Batch 3 (40:60) Lot 4 (10:90) Element Technical level Q/unit Q/unit Q/unit Q/unit 1 Lactose monohydrate Pharmatose 100M 75.87 56.90 37..94 9.48 2 microcrystalline cellulose Avicel PH 101 18.97 37.9 56.90 85.36 Granulating fluid / drug solution 3 Sodium phosphate monohydrate USP granules 0.06 0.06 0.06 0.06 4 Orthophosphate Emparta 0.025 0.025 0.025 0.025 5 purified water N/A Sufficient Sufficient Sufficient Sufficient 6 Tabostat mesylate N/A 0.1 0.1 0.1 0.1 extragranular part 7 pregelatinized starch Starch 1500 1 1 1 1 8 SMCC SMCC HD90 2.5 2.5 2.5 2.5 9 Stearic acid (Kolliwax S fine) Kolliwax’s fine 1.5 1.5 1.5 1.5 Total core weight (mg) 100 100 100 100 Results and Discussion: The results of the study batches (Batches 1-4) of different ratios of diluents are provided in Table 12 below: Table 12 parameters Hardness (KP) Disintegration time (DT) Regularization Analysis - Initial (%) Regularized Analysis -OE (%) Analysis of Diff ( Initial -OE) RS initial (%) RS-OE (%) Diff RS (OE- Initial ) Best batch for lactose:MCC ratio (90:10) 3.9-4.8 38-45 seconds 100 83.23 16.77 0.14 1.63 1.49 Batch-1 (80:20) 6.5-7.0 25-30 seconds 100 80.18 19.82 0.11 1.6 1.46 Batch-2 (60:40) 5.8-7.2 2.30-2.40 minutes 100 73.77 26.23 0.11 2.0 1.89 Batch-3 (40:60) 4.5-5.5 45 seconds-1.10 minutes 100 74.01 25.99 0.11 2.3 2.16 Lot-4 (10:90) 4.5-5.2 1.10 min to 1.20 min 100 74.02 25.98 0.11 1.35 1.24

It was observed that the disintegration time of all studied batches with different lactose:MCC ratios ranged from 25 sec to 2.40 min and the hardness ranged from 4.5 KP to 7.2 KP, and these two parameters were found to be associated with the optimal batch of tablets The parameters are similar. After 7 days of open exposure, the analytical value decreased to 73.77%-80.18%. A total % reduction in analytical values from 19.82% to 26.23% was observed, with the best batch of tablets already showing an analytical reduction of approximately 16.77%. Considerable reductions were observed in lactose:MCC ratios of 60:40, 40:60 and 10:90. Across all batches, initial total impurities were 0.11%. The total impurities ranged from 1.35% to 2.30% in all batches after the open exposure period. The total impurities observed with the best batch of tablets were 1.63%.

Table 13: Stabilization of Tabostat tablets in Formulation 3 using alternative disintegrants (crospovidone, sodium starch glycolate (SSG) and croscarmellose sodium (CCS)) at different concentrations. The comparative effect of sex.

Procedure: Nine batches of 0.1 mg Tabostat Mesylate Lozenges (see Formulation 3) were prepared in the same manner as the manufacturing procedure given below Table 3, but using different concentrations of disintegrant. Pregelatinized starch was studied at concentrations of 0 mg, 2.5 mg and 5.0 mg, while other disintegrants such as crospovidone, sodium starch glycolate (SSG) and croscarmellose sodium were studied at concentrations of 0 mg, 2.5 mg and 5.0 mg. Studies were conducted at two levels, 1.0 mg and 5.0 mg (referred to herein as batches 5-13, respectively). Tablet stability was evaluated by exposing the batches to 40°C/75% RH under open conditions for 7 days. Batch 5 (PGS : 0 mg) Batch 6 (PGS : 2.5 mg) Batch 7 (PGS : 5 mg) Lot 8 ( crospovidone 1 mg) Lot 9 ( crospovidone 5 mg) Lot 10 (SSG 1 mg) Batch 11 (SSG 5 mg) Lot 12 (CCS 1 mg) Lot 13 (CCS 5 mg) Element Technical level Q/ unit Q/ unit Q/ unit Q/ unit Q/ unit Q/ unit Q/ unit Q/ unit Q/ unit 1 Lactose monohydrate Pharmatose 100M 85.36 85.36 85.36 85.36 85.36 85.36 85.36 85.36 85.36 2 microcrystalline cellulose Avicel PH 101 9.48 9.48 9.48 9.48 9.48 9.48 9.48 9.48 9.48 3 Sodium phosphate monohydrate USP granules 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 4 Orthophosphate Emparta Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient 5 purified water N/A Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient 6 Tabostat mesylate N/A 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 7 pregelatinized starch Starch 1500 0 2.5 5 0 0 0 0 0 0 crospovidone Kollidon CL 0 0 0 1 5 0 0 0 0 sodium starch glycolate Type A SSG 0 0 0 0 0 1 5 0 0 Croscarmellose sodium Ac-di-sol SD 711 0 0 0 0 0 0 0 1 5 8 SMCC SMCC HD90 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 9 stearic acid Kolliwax’s fine 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Total core weight (mg) 100 100 100 100 100 100 100 100 100 Results and Discussion: Tablet stability results for study batches of alternative disintegrants (batch numbers 5-13) are provided in Table 14 below: Table 14 : parameters Hardness(KP) Disintegration time (DT) Regularization Analysis - Initial (%) Normalized analysis - at OE ( %) Diff.Analysis ( Initial-OE) RS initial(%) RS at OE (%) Diff RS (OE- Initial) Best Batch (PGS 1 mg) 3.9-4.8 38-45 seconds 100 83.23 16.77 0.14 1.63 1.49 Lot 5 (PGS 0.0 mg) 4.5-5.1 35-45 seconds 100 83.38 16.62 0.65 2.138 1.488 Lot 6 (PGS 2.5 mg) 3.4-4.5 40-45 seconds 100 84.79 15.21 0.84 2.112 1.272 Lot 7 (PGS 5.0 mg) 3.5-4.35 29-35 seconds 100 79.27 20.73 0.62 2.390 1.77 Lot 8 (crospovidone 1 mg) 3.5-4.5 25-35 seconds 100 78.38 21.62 0.73 2.21 1.48 Lot 9 (crospovidone 5 mg) 4.5-5.5 25 seconds 100 75.31 24.69 0.95 3.51 2.56 Lot 10 (SSG 1 mg) 3.8-5.0 40 seconds 100 74.32 25.68 0.46 1.38 0.92 Batch 11 (SSG 5 mg) 4.5-5.2 35 seconds 100 64.2 35.8 0.49 0.94 0.45 Lot 12 (CCS 1 mg) 3.9-4.9 40 seconds 100 70.27 29.73 0.46 1.48 1.02 Lot 13 (CCS 5 mg) 3.9-5.1 30 seconds 100 69.46 30.54 0.42 1.44 1.02

The disintegration times of tablets made with different levels of disintegrants ranged from 25 sec to 45 sec and were similar to the DT of the best tablets. The hardness range observed for all Tabostat tablets produced with different disintegrants at different concentration levels ranged from 3.4 KP to 5.5 KP. Therefore, no significant effect on tablet hardness was observed using the selected disintegrant and level. After 7 days of open exposure, the analytical values for all tablets manufactured with different variables ranged from 74.3% to 84.7%. The highest reduction in analysis was observed using CCS and the smallest reduction in analysis was observed with PGS. The initial total impurities for all batches ranged from 0.42% to 0.95%. When stored under open conditions at 40°C/75% for 7 days, total impurity levels increased and values ranged from 0.94% to 3.51%. The best batch showed a total impurity value of 1.63%.

surface 15 : By using different concentrations of stearic acid (0.5 mg and 3 mg) Research on formulations 3 Comparative Effects on the Stability of Tabostat Tablets.

Procedure: Prepare two batches of 0.1 mg tabostat mesylate tablets (see Formulation 3) in the same manner as the procedure given below in Table 3, but using different concentrations of the lubricant stearic acid, i.e., per tablet 0.5 mg and 5.0 mg (referred to herein as batch 14 and batch 15, respectively). Tablet stability was evaluated by exposing the tablets to 40°C/75% RH under open conditions for 7 days. intragranular part Batch 14 ( stearic acid: 0.5 mg) Batch 15 ( stearic acid: 3 mg) Element Technical level Q/ unit Q/ unit 1 Lactose monohydrate Pharmatose 100M 85.36 85.36 2 microcrystalline cellulose Avicel PH 101 9.48 9.48 Granulating fluid/ drug solution 3 Sodium phosphate monohydrate USP granules 0.06 0.06 4 Orthophosphate Emparta Sufficient Sufficient 5 purified water N/A Sufficient Sufficient 6 Tabostat mesylate N/A 0.1 0.1 extragranular part 7 pregelatinized starch Starch 1500 1.0 1.0 8 SMCC SMCC HD90 2.5 2.5 9 stearic acid Kolliwax’s fine 0.5 5.0 Total core weight (mg) 100 100 Results and Discussion: The results of the tablet stability of study batches (Batch Nos. 14 and 15) are provided in Table 16 below: Table 16. parameters Hardness(KP) Disintegration time (DT) Regularization Analysis - Initial (%) Normalized analysis - at OE ( %) Analysis of Diff ( Initial-OE) RS initial(%) RS at OE (%) Diff RS (OE- Initial) Best Batch (Stearic Acid 1 mg) 3.9-4.8 38-45 seconds 100 83.23 16.77 0.14 1.63 1.49 Batch 14 (stearic acid 0.5 mg) Severe adhesion problems were observed during compression with 0.5 mg stearic acid per tablet. Therefore mass production was stopped. Lot 15 (stearic acid 5.0 mg) 4.5-5.1 45 seconds to 1 minute 100 75.16 24.84 0.65 2.08 1.43

The disintegration time using stearic acid (5 mg per unit) ranged from 45 sec to 01 min and was similar to the disintegration time range of the optimal tablet form of tapoxostat. The hardness range is similar to the optimal lozenges (4.5 KP to 5.1 KP). When exposed to open air for 7 days at 40°C/75% RH, the analysis showed a reduction of 24.84%. In tablets containing 5 mg of stearic acid per tablet, total impurities increased from an initial 0.65% to 2.08% after open exposure.

surface 17 : Study of different buffers used at different levels ( Potassium hydrogen phosphate and HCl/ citric acid / malic acid / tartaric acid ) to the formulation 3 Comparative Effect on the Stability of Tabostat Mesylate.

Procedure: To evaluate the suitability of other buffer systems for stabilizing Taboxostat in tablets, a buffer system providing a pH of approximately 2.5 was identified and an initial titration was performed to find the minimum amount required. Eight batches of 0.1 mg Tabostat mesylate lozenges (see Formulation 3) were prepared in the same manner as the process given below in Table 3, but using different levels of different buffers (referred to herein as batches). 16-23). The buffers potassium dihydrogen phosphate and hydrochloric acid and anhydrous citric acid were studied at 0.09 mg and 0.18 mg per tablet. Malic acid was studied at 0.10 mg and 0.2 mg and tartaric acid was studied at 0.08 mg and 0.16 mg. Tablet stability was evaluated by exposing the tablets to 40°C/75% RH under open conditions for 7 days. intragranular part Lot 16 Lot 17 Lot 18 Lot 19 Batch 20 Batch 21 Lot 22 Lot 23 Element Technical level Q/ unit Q/ unit Q/ unit Q/ unit Q/ unit Q/ unit Q/ unit Q/ unit 1 Lactose monohydrate Pharmatose 100M 85.36 85.36 85.36 85.36 85.36 85.36 85.36 85.36 2 microcrystalline cellulose Avicel PH 101 9.48 9.48 9.48 9.48 9.48 9.48 9.48 9.48 Granulating fluid / drug solution 3 Potassium dihydrogen phosphate and HCl NA 0.09 0.18 0 0 0 0 0 0 citric acid NA 0 0 0.09 0.18 0 0 0 0 malic acid NA 0 0 0 0 0.10 0.20 0 0 tartaric acid NA 0 0 0 0 0 0 0.08 0.16 4 purified water N/A Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient 5 Tabostat mesylate N/A 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 extragranular part 6 pregelatinized starch Starch 1500 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 7 SMCC SMCC HD90 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 8 stearic acid Kolliwax’s fine 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Total core weight (mg) 100 100 100 100 100 100 100 100 Results and Discussion: The results of the tablet stability of study batches (Batch Nos. 16-23) are provided in Table 18 below: Table 18 : parameters Hardness (KP) DT Regularization Analysis - Initial (%) Regularized Analysis-OE (%) Diff.Analysis ( Initial-OE) RS initial screening (%) RS OE (%) Diff. RS (OE- Initial) Best Batch ( Sodium Phosphate Monohydrate/Phosphoric Acid 0.06 mg) 3.9-4.8 38-45 seconds 100 83.23 16.77 0.14 1.63 1.49 KH2PO4 and HCl Batch 16 0.09 mg 4.0-5.0 35 sec to 50 sec 100 85.53 14.47 0.48 1.33 0.85 Batch 17 0.18 mg 4.5-5.5 40 sec to 50 sec 100 83.09 16.91 0.42 1.97 1.55 citric acid Batch 18 0.09 mg 4.5-5.2 30-45 seconds 100 84.85 15.15 0.28 0.55 0.27 Batch 19 0.18 mg 4.6-5.2 38-50 seconds 100 78.63 21.37 0.23 0.43 0.2 Maleic acid Lot 20 0.1 mg 4.1-5.1 40-50 seconds 100 86.35 13.65 0.74 0.66 -0.08 Batch 21 0.20 mg 4.7-5.20 40-55 seconds 100 84.51 15.49 0.39 0.68 0.29 tartaric acid Batch 22 0.08 mg 4.5-5.6 30-40 seconds 100 78.26 21.74 0.39 0.71 0.32 Batch 23 0.16 mg 4.0-5.5 40-52 seconds 100 67.51 32.49 0.217 0.36 0.143

The observed disintegration time range for the studied buffer variables (potassium dihydrogen phosphate and hydrochloric acid, citric acid, malic acid and tartaric acid) ranged from 30 seconds to 55 seconds, which is similar to the disintegration time range of the optimal tablets. The buffer component has no significant effect on tablet hardness. Higher analytical decreases were observed using tartaric acid as stabilizer (21.7%-3.42%) under 40°C/75%-7 days open exposure conditions. Citric acid at 0.09 mg per tablet and maleic acid at both study levels showed comparable stability to the best tablets. There was no significant increase in total impurity levels compared to the best tablets.

surface 19 : Research on different types of coatings ( Two different levels of growth % Of Opadry QX (Kollicoat IR) , HEC Coated and based on PVA Of Opadry II coating ) as a mixture 3 Comparative effects on the stability of tabostat mesylate tablets used in .

Procedure: Six batches of 0.1 mg Tabostat mesylate tablets (see Formulation 3) were prepared in the same manner as the process given below in Table 3, but using two different coating materials with two levels of % growth. clothing (referred to herein as batches 24-29 respectively). Tablet stability was evaluated by exposing the tablets to 40°C/75% RH under open conditions for 7 days. intragranular part Lot 24 Lot 25 Lot 26 Lot 27 Lot 28 Lot 29 Element Technical level Q/ unit Q/ unit Q/ unit Q/ unit Q/ unit Q/ unit 1 Lactose monohydrate Pharmatose 100M 85.36 85.36 85.36 85.36 85.36 85.36 2 microcrystalline cellulose Avicel PH 101 9.48 9.48 9.48 9.48 9.48 9.48 Granulating fluid / drug solution 3 Sodium phosphate monohydrate USP granules 0.06 0.06 0.06 0.06 0.06 0.06 Orthophosphate Emparta Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient 4 purified water N/A Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient 5 Tabostat mesylate N/A 0.1 0.1 0.1 0.1 0.1 0.1 extragranular part 6 pregelatinized starch Starch 1500 1.0 1.0 1.0 1.0 1.0 1.0 7 SMCC SMCC HD90 2.5 2.5 2.5 2.5 2.5 2.5 8 stearic acid Kolliwax’s fine 1.5 1.5 1.5 1.5 1.5 1.5 Total core weight (mg) 100 100 100 100 100 100 coating 9 Opadry-II based on PVA 85F18422 WHITE 2 4 0 0 0 0 10 Opadry QX (Kollicoat) 321A180025 WHITE 0 0 2 4 0 0 11 HEC NATROSOL 250L PHARM 0 0 0 0 2 4 Total weight of coated tablets (mg) 102 104 102 104 102 104 Results and Discussion: The results of the tablet stability of study batches (Batch Nos. 24-29) are provided in Table 20 below: Table 20 parameters Hardness(KP) DT Regularization Analysis - Initial (%) Regularized Analysis-OE (%) Analysis of Diff. ( Initial-OE) RS initial(%) RS OE (%) Diff. RS (OE- Initial) Opadry AMB-II ( Best) 4% 4.9-6.2 1 minute 10 seconds 100 80.95 19.05 0.49 3.158 2.668 PVC based Opadry-II Lot 24 (2%) 5.5 7.0 1 min 20 sec 100 82.04 17.96 0.47 3.812 3.342 Lot 25 (4%) 5.5-7.0 1 min 30 sec 100 80.34 19.66 0.46 2.69 2.23 Opadry QX (Kollicoat) Lot 26 (2%) 5.5-6.0 5 minutes 10 seconds 100 79.76 20.24 0.94 0.62 -0.32 Lot 27 (4%) 5.9-7.0 5 minutes 10 seconds 100 79.72 20.28 2.81 2.66 -0.15 HEC Lot 28 (2%) 4.8-5.6 50 seconds 100 80.18 19.82 0.81 3.1 2.29 Lot 29 (4%) 5.5-6.5 1 minute 10 seconds 100 79.29 20.71 0.44 4.29 3.85

The disintegration time of tablets coated with different coating materials with different coating weight gain percentage levels ranged from 1.10 min to 5.10 sec, and HEC, Opadry-II and Opadry blue coated tablets DT were the same as the best tablets (Opadry AMB-II coated tablets) is similar to the DT. A higher DT of 5.10 min was observed in Opadry QX coated tablets. The observed hardness range of 4.9 KP to 6.2 KP was observed for all optimal composition tablets of Tabostat coated with different levels of different coating materials. Therefore, no significant effect on tablet hardness was observed at the selected coating material and level. Analytical reductions were similar to the best batch tablet (Opadry-AMB-II, 4% coated weight gain) at 40°C/75%-7 days open exposure in all batches. There was no significant increase in total impurity levels compared to the best tablets.

surface twenty one. Research different diluents (MCC101 , MCC200) and different diluent ratios (SMCCHD90: MCC 101 , SMCC HD90: Calcium phosphate and SMCCHD90: Lactose monohydrate ) For core tablet formulations 4 Comparative effects on the stability of tabostat tablets used in .

Procedure: Twelve batches of 0.1 mg Tabostat mesylate lozenges (see Formulation 4) were prepared in the same manner as the procedure given below Table 6, but using different diluents and different diluent ratios (respectively in this article Called batches 30-41). Tablet stability was evaluated by exposing the tablets to 40°C/75% RH under open conditions for 7 days. Table 21 intragranular part Lot 30 (MCC 101 replaces SMCC) Lot 31 (MCC 200 replaces SMCC) Batch 32 (SMCC:MCC 75:25) Batch 33 SMCC:MCC 50:50 Batch 34 SMCC:MCC 25:75 Batch 35 (Calcium Phosphate: SMCC 5:95) Batch 36 (Calcium Phosphate: SMCC 10:90) Batch 37 (Calcium Phosphate:SMCC 20:80) Batch 38 (SMCC: Lactose 90:10) Batch 39 (SMCC: Lactose 75:25) Batch 40 (SMCC: Lactose 50:50) Batch 41 (SMCC: Lactose 25:75) Element Technical level Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) 1 Silicated microcrystalline cellulose SMCC HD90 0 0 74.08 49.378 24.69 93.83 88.888 79.014 88.89 74.08 49.39 24.69 MCC-101 Avicel PH-101 98.77 0 24.69 49.39 74.028 0 0 0 0 0 0 0 MCC-200 Avicel PH-200 0 98.77 0 0 0 0 0 0 0 0 0 0 calcium phosphate N/A 0 0 0 0 0 4.94 9.88 19.7536 0 0 0 0 lactose Pharmatose 100M 0 0 0 0 0 0 0 0 9.88 24.69 49.39 74.08 2 Sodium phosphate monohydrate (USP granules) USP granules 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 3 Orthophosphate Emparta 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 4 purified water N/A Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient extragranular part 5 Tabostat mesylate 0.147 0.147 0.147 0.147 0.147 0.147 0.147 0.147 0.147 0.147 0.147 0.147 6 Magnesium stearate Ligamed MF-2V 1 1 1 1 1 1 1 1 1 1 1 1 Total weight of core tablets (mg) 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Results and Discussion: The results of the tablet stability of study batches (Batch Nos. 30-41) are provided in Table 22 below: Table 22 : parameters Hardness(KP) DT Regularization Analysis - Initial (%) Regularized Analysis-OE (%) Diff.Analysis ( Initial-OE) RS initial(%) RS OE (%) Diff. RS (OE- Initial) Best Batch (SMCC-98.7 mg) 3.9-4.5 35-40 seconds 100 88.60 11.40 0.40 1.54 1.14 Lot 30 (MCC 101) 5.5-6.8 4 minutes 30 seconds 100 91.40 8.60 0.02 0.21 0.19 Lot 31 (MCC 200) 2.6-3.5 25 seconds 100 84.68 15.32 0.03 1.37 1.34 SMCC:MCC ratio Lot 32 (75:25) 3.5-4.5 1 minute 10 seconds 100 97.48 2.52 0.03 0.71 0.68 Batch 33 (50:50) 4.0-4.6 1 min 20 sec 100 91.81 8.19 0.02 0.54 0.52 Lot 34 (25:75) 4.2-4.8 1 minute 10 seconds 100 92.78 7.22 0.01 0.5 0.49 Calcium phosphate:SMCC ratio Lot 35 (95:05) 3.9-5.1 40 seconds 100 86.25 13.75 0.59 3.28 2.69 Lot 36 (90:10) 4.5-5.5 38-45 seconds 100 88.09 11.91 1.82 3.64 1.82 Lot 37 (80:20) 4.5-5.5 38-50 seconds 100 88.84 11.16 0.79 2.42 1.63 SMCC: lactose ratio Batch 38 (90:10) 2.5-3.5 20-25 seconds 100 80.87 19.13 0.09 2.46 2.37 Lot 39 (75:25) 1.5-2.5 20 seconds 100 84.11 15.89 0.07 1.29 1.22 Batch 40 (50:50) 1.2-2.2 30-40 100 76.09 23.91 0.08 2.06 1.98 Lot 41 (25:75) 1.5-2.5 40.00 100 61.11 38.89 0.13 3.55 3.42

The observed disintegration times for the selected diluent ratios ranged from 20 sec to 4.30 min. The hardness of the tablets in these batches was similar to tablets manufactured using optimal conditions. After 7 days of open exposure, the analytical values decreased to 61.1%-97.4%. A total % reduction in analytical values from 2.50% to 38.89% was observed, with the best batch of tablets showing an analytical reduction of approximately 11.40%. Significantly higher reductions were observed in the 50:50 and 25:75 ratios of SMCC:lactose monohydrate, i.e. 23.91%-38.89%. Tablets made using SMCC:calcium phosphate (90:10) produced a total impurity value of 1.82%. The total impurities in other batches ranged from 0.02% to 0.79%. At the initial stage, the total impurities observed with the optimal tablets were 0.40%. During the stability period, total impurities observed in tablets produced with different ratios of diluent ranged from 0.21% to 3.64%.

surface twenty three. Study different disintegrants at different levels ( Pregelatinized starch, crospovidone, sodium starch glycolate, croscarmellose sodium ) For core tablet formulations 4 Comparative effects on the stability of tabostat tablets used in .

Procedure: Eight batches of 0.1 mg tabostat mesylate lozenges (see Formulation 4) were prepared in the same manner as the procedure given below Table 6, but using two different disintegrant levels, 1 mg and 5 mg. (referred to herein as batches 42-49, respectively). Tablet stability was evaluated by exposing the tablets to 40°C/75% RH under open conditions for 7 days. parameters Hardness (KP) DT Regularization Analysis - Initial (%) Regularized Analysis-OE (%) Diff.Analysis ( Initial-OE) RS initial(%) RS OE (%) Diff. RS (OE- Initial) Best Batch (SMCC-98.7 mg) 3.9-4.5 35-40 seconds 100 88.60 11.40 0.40 1.54 1.14 Lot 30 (MCC 101) 5.5-6.8 4 minutes 30 seconds 100 91.40 8.60 0.02 0.21 0.19 Lot 31 (MCC 200) 2.6-3.5 25 seconds 100 84.68 15.32 0.03 1.37 1.34 SMCC:MCC ratio Lot 32 (75:25) 3.5-4.5 1 minute 10 seconds 100 97.48 2.52 0.03 0.71 0.68 Batch 33 (50:50) 4.0-4.6 1 min 20 sec 100 91.81 8.19 0.02 0.54 0.52 Lot 34 (25:75) 4.2-4.8 1 minute 10 seconds 100 92.78 7.22 0.01 0.5 0.49 Calcium phosphate:SMCC ratio Lot 35 (95:05) 3.9-5.1 40 seconds 100 86.25 13.75 0.59 3.28 2.69 Lot 36 (90:10) 4.5-5.5 38-45 seconds 100 88.09 11.91 1.82 3.64 1.82 Lot 37 (80:20) 4.5-5.5 38-50 seconds 100 88.84 11.16 0.79 2.42 1.63 SMCC: lactose ratio Batch 38 (90:10) 2.5-3.5 20-25 seconds 100 80.87 19.13 0.09 2.46 2.37 Lot 39 (75:25) 1.5-2.5 20 seconds 100 84.11 15.89 0.07 1.29 1.22 Batch 40 (50:50) 1.2-2.2 30-40 100 76.09 23.91 0.08 2.06 1.98 Lot 41 (25:75) 1.5-2.5 40.00 100 61.11 38.89 0.13 3.55 3.42 Results and Discussion: The results of the tablet stability of study batches (Batch Nos. 42-49) are provided in Table 24 below: Table 24 : parameters Hardness (KP) DT Regularization Analysis - Initial (%) Regularized Analysis-OE (%) Diff.Analysis ( Initial-OE) RS initial(%) RS OE (%) Diff. RS (OE- Initial) Best batch (without disintegrant) 3.9-4.5 35-40 seconds 100 88.60 11.40 0.40 1.54 1.14 Batch 42-PGS 1.0 mg 3.8-4.4 30 seconds 100 88.89 11.11 0.08 0.50 0.42 Lot 43-PGS 5.0 mg 3.8-4.5 20-25 seconds 100 87.62 12.38 0.07 0.54 0.47 Lot 44 - Crospovidone 1.0 mg 3.5-4.2 20-30 seconds 100 83.30 16.70 0.08 1.69 1.61 Lot 45 - Crospovidone 5.0 mg 3.1-4.0 15-25 seconds 100 81.05 18.95 0.43 2.12 1.69 Batch 46-SSG 1.0 mg 3.9-4.6 30-40 seconds 100 91.34 8.66 0.09 0.49 0.40 Batch 47-SSG 5.0 mg 4.0-5.2 25-30 seconds 100 95.40 4.60 0.03 0.42 0.39 Batch 48-CCS 1.0 mg 3.6-4.4 28-38sec 100 89.34 10.66 0.13 0.52 0.39 Lot 49-CCS 5.0 mg 3.5-4.5 20 seconds 100 86.80 13.20 0.11 0.79 0.68

The disintegration times of tablets made with different levels of different disintegrants ranged from 15 sec to 40 sec and were similar to the DT of the best tablets without disintegrant (SMCC itself was used as the disintegrant). The hardness range observed for all Tabostat tablets produced with different disintegrants at different concentration levels ranged from 3.1 KP to 5.2 KP. Therefore, no significant effect on tablet hardness was observed using the selected disintegrant and level. The highest reduction in the assay was observed with crospovidone and the smallest reduction in the assay was seen with the remaining disintegrant. The initial total impurities for all batches ranged from 0.03% to 0.43%. When stored under open conditions at 40°C/75% for 7 days, total impurity levels increased and values ranged from 0.42% to 2.12%. The best batch showed a total impurity value of 1.54%. The highest maximum total impurities were observed with crospovidone tablets.

Table 25. Study of the comparative effect of different concentrations of magnesium stearate as lubricant on the stability of Tabostat tablets used in Core Tablet Formulation 4 .

Procedure: Prepare 2 batches of 0.1 mg tabostat mesylate lozenges (see Formulation 4) in the same manner as the procedure given below Table 6, but using different levels (0.5 mg and 3 mg) of stearic acid Magnesium as lubricant (referred to herein as batch 50 and batch 51 respectively). Tablet stability was evaluated by exposing the tablets to 40°C/75% RH under open conditions for 7 days. intragranular part Lot 50 (MgS: 0.5 mg) Batch 51 (MgS: 3 mg) Element Technical level Q/ unit (mg) Q/ unit(mg) 1 Silicated microcrystalline cellulose SMCC HD90 98.85 98.77 2 Sodium phosphate monohydrate (USP granules) USP granules 0.06 0.06 3 Orthophosphate Emparta 0.025 0.025 4 purified water N/A Sufficient Sufficient 5 Tabostat mesylate 0.147 0.147 6 Magnesium stearate Ligamed MF-2V 0.5 3 Total weight of core tablets (mg) 100.0 102.0 Results and Discussion: The results of the tablet stability of study batches (Batch Nos. 50 and 51) are provided in Table 26 below: Table 26. parameters Hardness(KP) DT Regularization Analysis - Initial (%) Regularized Analysis-OE (%) Diff.Analysis ( Initial-OE) RS initial (%) RS OE (%) Diff. RS (OE- Initial) Best Batch (MgS 1.5 mg) 3.9-4.5 35-40 seconds 100 88.60 11.40 0.40 1.54 1.14 Batch 50-MgS 0.5 mg 2.8-3.5 30 seconds 100 78.72 21.28 0.00 0.00 0.00 Batch 51-MgS 3.0 mg 4.5-5.2 40-45 seconds 100 85.12 14.88 0.08 1.42 1.34

The disintegration time using magnesium stearate (0.5-3.0 mg per tablet) ranged from 30 sec to 45 sec and was similar to the optimal tablet disintegration time range for taboxostat. The hardness range was also found to be similar to the optimal tablets. When exposed to open air for 7 days at 40°C/75% RH, the analysis showed a reduction of 14.88%-21.28%. When stored under open conditions at 40°C/75% for 7 days, total impurity levels increased and values ranged from 0.00% to 1.42%. Under stability conditions, total impurities were similar to the best batch, i.e. 1.54%.

surface 27 : Study of different buffers used at different levels ( Potassium hydrogen phosphate and HCl/ citric acid / malic acid / tartaric acid ) and different concentrations of sodium phosphate monohydrate /HCl For core tablet formulations 4 Comparative Effect on the Stability of Tabostat Mesylate Used in.

Procedure: To evaluate the suitability of other buffer systems for stabilizing Taboxostat in tablets, a buffer system providing a pH of approximately 2.5 was identified and an initial titration was performed to find the minimum amount required. Ten batches of 0.1 mg Tabostat mesylate lozenges (see Formulation 4) were prepared in the same manner as the procedure given below Table 6, but using different levels of different buffers (referred to herein as batches). 52-61). The buffers potassium dihydrogen phosphate and hydrochloric acid and anhydrous citric acid were studied at 0.09 mg and 0.18 mg per tablet. Tartaric acid was studied at 0.10 mg and 0.2 mg and the buffer malic acid was studied at 0.12 mg and 0.24 mg. Tablet stability was evaluated by exposing the tablets to 40°C/75% RH under open conditions for 7 days. Table 27. intragranular part Lot 52 Lot 53 Lot 54 Lot 55 Lot 56 Lot 57 Lot 58 Lot 59 Lot 60 Lot 61 Element Technical level Q/ unit(mg) Q/ unit(mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) 1 Silicated microcrystalline cellulose SMCC HD90 98.85 98.77 98.77 98.77 98.77 98.77 98.77 98.77 98.77 98.77 2 Sodium Phosphate Monohydrate (USP Granules) USP granules 0.12 0.18 0 0 0 0 0 0 0 0 3 Orthophosphate Emparta 0.05 0.075 0 0 0 0 0 0 0 0 Potassium dihydrogen phosphate USP granules 0 0 0.09 0.18 0 0 0 0 0 0 hydrochloric acid Emparta 0 0 qs qs 0 0 0 0 0 0 citric acid N/A 0 0 0 0 0.09 0.18 0 0 0 0 malic acid N/A 0 0 0 0 0 0 0.10 0.20 0 0 tartaric acid N/A 0 0 0 0 0 0 0 0 0.08 0.16 4 purified water N/A Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient 5 Tabostat mesylate 0.147 0.147 0.147 0.147 0.147 0.147 0.147 0.147 0.147 0.147 6 Magnesium stearate Ligamed MF-2V 1 1 1 1 1 1 1 1 1 1 Total weight of core tablets (mg) 100.0 102.0 100.0 100.0 100.0 100.5 100.0 100.0 100.0 100.0 Results and Discussion: The results of the tablet stability of study batches (Batch Nos. 52-61) are provided in Table 28 below: Table 28 parameters Hardness(KP) DT Regularization Analysis - Initial (%) Regularized Analysis-OE (%) Diff.Analysis ( Initial-OE) RS initial(%) RS OE (%) Diff. RS (OE- Initial) Best Batch (Sodium Phosphate/Phosphoric Acid 0.06 mg) 3.9-4.5 35-40 seconds 100 88.60 11.40 0.40 1.54 1.14 NaH2PO4 and HCl Batch 52 (0.12 mg) 3.6-4.5 30-35 seconds 100 89.44 10.56 0.68 1.84 1.16 Batch 53 (0.18 mg) 3.9-4.8 35-42 seconds 100 68.15 31.85 0.14 4.61 4.47 KH2PO4 and HCl Batch 54 (0.09 mg) 3.2-4.2 15-25 seconds 100 91.26 8.74 0.09 0.63 0.54 Batch 55 (0.18 mg) 3.5-4.5 30 seconds 100 94.08 5.92 0.08 0.53 0.45 citric acid Batch 56 (0.09 mg) 2.5-3.5 20 seconds 100 93.28 6.72 0.22 1.80 1.58 Batch 57 (0.18 mg) 2.8-4.2 20-25 seconds 100 75.52 24.48 0.21 1.69 1.48 malic acid Batch 58 (0.12 mg) 2.8-3.6 15-25 seconds 100 94.68 5.32 0.02 0.29 0.27 Batch 59 (0.24 mg) 3.6-4.2 20-30 seconds 100 97.00 3.00 0.22 0.42 0.20 tartaric acid Lot 60 (0.10 mg) 3.9-4.5 20 seconds 100 91.33 8.67 0.04 0.53 0.49 Batch 61 (0.20 mg) 3.6-4.2 25-30 seconds 100 88.96 11.04 0.02 0.47 0.45

The disintegration times observed with the buffer variables studied (sodium phosphate monobasic/HCl, potassium phosphate monobasic/HCl, citric acid, malic acid, and tartaric acid) ranged from 15 sec to 42 sec and were consistent with those of the optimal tablets. The solution timeframes are similar. The buffer component has no significant effect on tablet hardness. High analytical reductions (31.85% and 24.48) were observed with sodium phosphate dibasic and hydrochloric acid (0.18 mg per tablet) and citric acid (0.18 mg per tablet), respectively, under 40°C/75%-7 days open exposure conditions. %). The use of two levels of residual buffer along with sodium phosphate dihydrogen and hydrochloric acid (0.12 mg per tablet) and citric acid (0.09 mg per tablet) showed comparable stability to the best tablets. The initial total impurities for all batches ranged from 0.09% to 0.68%. When stored under open conditions at 40°C/75% for 7 days, total impurity levels increased and values ranged from 0.29% to 4.61%. The best batch has shown a total impurity value of 1.54%. The highest maximum total impurities, 4.61%, were observed in tablets using sodium dihydrogen phosphate and hydrochloric acid (0.18 per unit).

Table 29: Study of the comparative effect of different coating materials used at two levels of % growth on the stability of tapoxostat mesylate as used in core tablet formulation 4.

Procedure: Eight batches of 0.1 mg tabostat mesylate tablets (see Formulation 4) were prepared in the same manner as the process given below in Table 6, but using different levels of coating (2% and 4% growth) Materials (referred to herein as batches 62-67, respectively). Tablet stability was evaluated by exposing the tablets to 40°C/75% RH under open conditions for 7 days. Table 29 intragranular part Lot 62 Lot 63 Lot 64 Lot 65 Lot 66 Lot 67 Element Technical level Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) Q/ unit (mg) 1 Silicated microcrystalline cellulose SMCC HD90 98.85 98.85 98.85 98.77 98.85 98.85 2 Sodium Phosphate Monohydrate (USP Granules) USP granules 0.06 0.06 0.06 0.06 0.06 0.06 3 Orthophosphate Emparta 0.025 0.025 0.025 0.025 0.025 0.025 4 purified water N/A Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient 5 Tabostat mesylate 0.147 0.147 0.147 0.147 0.147 0.147 6 Magnesium stearate Ligamed MF-2V 1 1 1 1 1 1 Total weight of core tablets (mg) 100.0 100.0 100.0 100.0 100.0 100.0 7 Opadry QX (Kollicoat IR) 321A180025 WHITE 2 4 0 0 0 0 Hydroxyethylcellulose NATROSOL 250L PHARM 0 0 2 4 0 0 Based on PVA (Opadry II) 85F18422 WHITE 0 0 0 0 2 0 purified water Sufficient Sufficient Sufficient Sufficient Sufficient Sufficient Total weight of coated tablets (mg) 102.0 104.0 102.0 104.0 102.0 104.0 Results and Discussion: The results of the tablet stability of study batches (Batch Nos. 62-67) are provided in Table 30 below: Table 30 parameters Hardness(KP) DT Regularization Analysis - Initial (%) Regularized Analysis-OE (%) Diff.Analysis ( Initial-OE ) RS initial (%) RS OE (%) Diff. RS (OE- Initial) Opadry AMB-II ( Best) 4% 5.2-6.2 1 minute 10 seconds 100 84.80 15.20 0.03 1.37 1.34 Opadry QX Lot 62 (2%) 4.9-5.5 50 seconds 100 83.33 16.67 0.22 1.30 1.08 Lot 63 (4%) 5.2-6.2 1 min to 1 min 20 seconds 100 82.24 17.76 0.17 1.39 1.22 HEC Lot 64 (2%) 6.2-7.0 1 min 10 sec to 1 min 30 sec 100 83.28 16.72 0.10 1.52 1.42 Lot 65 (4%) 7.5-8.4 4 min 10 sec to 5 min 10 sec 100 81.31 18.69 0.22 1.27 1.05 Opadry-II Lot 66 (2%) 4.9-5.6 50 seconds to 1 minute 100 82.62 17.38 0.08 1.23 1.15 Lot 67 (4%) 5.5-6.5 1 min 10 sec to 1 min 30 sec 100 86.46 13.54 0.03 0.96 0.93

The disintegration times of tablets coated with different coating materials at different coating weight gain percentage levels and Opadry QX, Opadry-II and Opadry Blue coated tablets ranged from 50 sec to 5.10 min. The DT observed for the different coated tablets was similar to that of the best tablet (Opadry AMB-II coated tablets). A higher DT was observed in HEC-coated tablets, i.e. 5.10 min. The observed hardness range of 4.9 KP to 8.4 KP was observed for all optimal composition tablets of Tabostat coated with different levels of different coating materials. Therefore, no significant effect on tablet hardness was observed using the selected coating material and level. Under 40°C/75%-7 day open exposure conditions, the analytical reduction for all batches was similar to that for the best batch of tablets (Opadry-AMB-II, 4% coated weight gain). The initial total impurities for all batches ranged from 0.03% to 0.22%. When stored under open conditions at 40°C/75% for 7 days, total impurity levels increased and values ranged from 0.96% to 1.52%. The best batch showed a total impurity value of 1.54%. Initial and stability data are similar to best batch data.

surface 31. Study different diluent ratios ( Lactose monohydrate : microcrystalline cellulose ) For tablet formulations 2 Comparative effects on the stability of tabostat tablets used in .

Procedure: Prepare 4 batches of 0.1 mg Tabostat mesylate tablets through dry granulation process using diluent lactose:microcrystalline cellulose in different ratios of 20:80, 40:60, 60:40 and 80:20. (See Formulation 2) (referred to herein as batches 68-71 respectively). Tablet stability was evaluated by exposing the tablets to 40°C/75% RH under open conditions for 7 days. Element Batch 68 Lactose :MCC (80:20) Qty/ unit (mg) Batch 69 Lactose :MCC (60:40) Qty/ unit (mg) Batch 70 Lactose :MCC (40:60) Qty/ unit (mg) Batch 71 Lactose :MCC (10:90) Qty/ unit (mg) Tabostat (Taposstat mesylate) 0.147 0.147 0.147 0.147 Orthophosphate 0.025 0.025 0 0 Sodium dihydrogen phosphate monohydrate 0.06 0.1 0.1 0.1 MCC 79.06 59.29 39.53 19.76 lactose 19.76 39.53 59.29 79.06 Magnesium stearate 1 1 1 1 total 100.1 mg 100.1 mg 100.1 mg 100.1 mg Results and Discussion: The results of the tablet stability of study batches (Batch Nos. 68-71) are provided in Table 32 below: Table 32 parameters Hardness (KP) DT Regularization Analysis - Initial (%) Regularized Analysis -OE (%) Diff.Analysis ( Initial -OE ) RS initial (%) RS OE (%) Diff. RS (OE- Initial ) Best Batch (SMCC 98.2 mg) 3.5-4.5 30-40 seconds 100 90.04 9.96 0.53 0.74 0.21 Lot 68 2.0-3.0 15-20 seconds 100 71.34 28.66 0.20 1.53 1.33 Lot 69 2.0-3.2 30-40 seconds 100 69.17 30.83 0.21 2.25 2.04 Lot 70 3.6-4.2 1 min-1 min 10 sec 100 72.04 27.96 0.22 1.47 1.25 Lot 71 4.5-5.3 35 sec-45 sec 100 72.24 27.96 0.17 1.92 1.75

Disintegration times were observed for lactose:MCC ratios ranging from 15 sec to 1 min.10 sec and were similar to the best batches. All study variable tablets were compressed from 2.0 KP to 5.3 KP, similar to the best batches. After 7 days of open exposure, the analytical value decreased to 69.17%-72.04%. A total % reduction in analytical values of 27.96% to 30.83% was observed, with the best batch of tablets having an analytical reduction of approximately 9.96%. A rather high reduction was observed in the lactose:MCC ratio batch compared to the optimal batch.

Across all batches, initial total impurities ranged from 0.17% to 0.22%. Total impurities ranged from 1.47% to 2.25% under open exposure at 40°C/75% RH for 7 days, while after open exposure at 40°C/75% RH, the optimal batch total impurity value was 0.74% . An increasing impurity trend was observed in the lactose:MCC combination compared to the best batch with SMCC only.

Table 33. Study of the stability of Tabostat tablets used in Formulation 2 with different levels of different disintegrants (pregelatinized starch, crospovidone, sodium starch glycolate, croscarmellose sodium) The comparative effect of sex. Table 33 Element Batch 72 (PGS-1 mg) Qty/ unit (mg) Batch 73 (PGS-5 mg) Qty/ unit (mg) Batch 74 ( Crospovidone 1 mg) Qty/ unit (mg) Batch 75 ( Crospovidone 5 mg) Qty/ unit (mg) Batch 76 (SSG-1 mg) Qty/ unit (mg) Batch 77 (SSG-5 mg) Qty/ unit (mg) Batch 78 (CCS 1 mg) Qty/ unit (mg) Batch 79 (CCS 5 mg) Qty/ unit (mg) Tabostat (Taposstat mesylate) 0.147 0.147 0.147 0.147 0.147 0.147 0.147 0.147 Orthophosphate 0 0 0 0.1 0 0.1 0 0.1 Sodium dihydrogen phosphate monohydrate 0.1 0.2 0.1 0.2 0.1 0.2 0.1 0.2 Silicated microcrystalline cellulose 98.82 98.6 98.82 98.6 98.82 98.6 98.82 98.6 pregelatinized starch 1 5 0 0 0 0 0 0 crospovidone 0 0 1 5 0 0 0 0 sodium starch glycolate 0 0 0 0 1 5 0 0 Croscarmellose sodium 0 0 0 0 0 0 1 5 Magnesium stearate 1 1 1 1 1 1 1 1 Total(mg) 101.1 105.0 101.1 105.0 101.1 105.0 101.1 105.0

Procedure: Eight batches of 0.1 mg tabostat mesylate tablets (see Formulation 2) were prepared by a dry granulation process using different disintegration doses of 1 mg and 5 mg per tablet respectively (see Formulation 2) are called batches 72-79) respectively. Tablet stability was evaluated by exposing the tablets to 40°C/75% RH under open conditions for 7 days. Results and Discussion: The results of the tablet stability of study batches (Batch Nos. 72-79) are provided in Table 34 below: Table 34 parameters Hardness (KP) DT Regularization Analysis - Initial (%) Regularized Analysis -OE (%) Diff.Analysis ( Initial -OE ) RS initial (%) RS OE (%) Diff. RS (OE- Initial ) Best batch (without disintegrant) 3.5-4.5 30-40 seconds 100 90.04 9.96 0.53 0.74 0.21 Lot 72 3.8-4.6 20-35 seconds 100 81.47 18.53 0.27 1.26 0.99 Lot 73 4.0-5.2 15-20 seconds 100 82.20 17.80 0.26 1.0 0.74 Lot 74 4.8-5.2 40 seconds 100 83.61 16.39 0.31 1.13 0.82 Lot 75 5.5-6.5 15-20 seconds 100 81.13 18.87 0.78 1.43 0.65 Lot 76 4.5-5.3 20-35 seconds 100 81.48 18.52 0.33 0.88 0.55 Lot 77 4.0-4.5 10-15 seconds 100 74.87 25.13 0.51 0.78 0.27 Lot 78 4.5-5.3 20-30 seconds 100 83.92 16.08 0.22 0.86 0.64 Lot 79 4.0-4.5 10-15 seconds 100 79.37 20.63 0.22 0.94 0.72

The disintegration times of tablets made with different levels of disintegrants ranged from 10 sec to 40 sec and were similar to the DT of the best tablets without disintegrant (SMCC itself was used as the disintegrant). All blends were compressed to produce tablets with hardness ranging from 3.8 KP to 6.5 KP. The analytical reduction values for all tablets made with different ratios of diluent ranged from 74.87% to 83.92%. The analyzed % reduction for the study tablets ranged from 16.08% to 25.13%, and the % reduction for the optimal tablet was 9.9%. The total impurities in the initial stage ranged from 0.22% to 1.43%, and under 7 days of open exposure at 40°C/75% RH, the range was 0.78% to 1.43%, while at 40°C/75% RH After 7 days of exposure to open conditions, the optimal batch total impurity value was 0.74%. During the analysis of batches containing 5 mg of SSG per unit batch, peak separation was observed due to the interaction of the drugs tabinostat and SSG.

surface 35. By using lozenge formulations 2 Different concentrations of magnesium stearate lubricants used in (0.5 mg and 1.5 mg) To study the comparative effects on the stability of tabostat mesylate tablets.

Procedure: Two batches of 0.1 mg Tabostat mesylate tablets (see Formulation 2) were prepared by a dry granulation process using varying amounts of magnesium stearate 0.5 mg and 1.5 mg per tablet (respectively in this article Called batch 80-81). Tablet stability was evaluated by exposing the tablets to 40°C/75% RH under open conditions for 7 days. Element Batch 80 (MgS-0.5 mg) Qty/ unit (mg) Batch 81 (MgS-1.5 mg) Qty/ unit (mg) Tabostat (Taposstat mesylate) 0.147 0.147 Orthophosphate 0.03 0 Sodium dihydrogen phosphate monohydrate 0.06 0.1 Silicated microcrystalline cellulose 98.82 98.8 Magnesium stearate 0.50 1.5 total 99.5 mg 100.5 mg Results and Discussion: The results of the tablet stability of study batches (Batch Nos. 80 and 81) are provided in Table 36 below: Table 36 parameters Hardness(KP) DT Regularization Analysis - Initial (%) Regularized Analysis-OE (%) Diff.Analysis ( Initial-OE) RS initial(%) RS OE (%) Diff. RS (OE- Initial) Best Batch (MgS 1 mg) 3.5-4.5 30-40 seconds 100 90.04 9.96 0.53 0.74 0.21 Lot 80 4.5-5.5 30 seconds 100 73.49 26.51 0.24 2.89 2.65 Lot 81 5.2-6.5 38-50 seconds 100 84.91 15.09 0.49 0.73 0.24

The disintegration time using magnesium stearate (0.5-1.5 mg per tablet) ranged from 30 sec to 50 sec and was similar to the optimal tablet disintegration time range for taboxostat. The hardness range is similar to the optimal lozenges (4.5 KP to 6.5 KP). When exposed to open exposure at 40°C/75% RH for 7 days, an analytical decrease of 15.0% to 26.5% was observed. When stored under open conditions at 40°C/75% RH for 7 days, total impurity levels increased and values ranged from 0.73% to 2.89%.

Table 37. Study of the effects of different buffers (potassium hydrogen phosphate and HCl/sodium phosphate monohydrate/HCl/citric acid/malic acid/tartaric acid) used at different levels on tabolat mesylate as used in Tablet Formulation 2 Comparative effect on the stability of Si.

Procedure: Five batches of 0.1 mg Tabostat mesylate lozenges (see Formulation 2) were prepared by dry granulation using different buffers (referred to herein as batches 82-86). Tablet stability was evaluated by exposing the tablets to 40°C/75% RH under open conditions for 7 days. Table 37 Element Batch 82 ( Sodium phosphate monohydrate /HCl : 0.12 mg/0.05 mg) Qty/ unit (mg) Batch 83 (KH2PO4 and HCl-0.09 mg) Qty/ unit (mg) Batch 84 ( Citric Acid - 0.1 mg) Qty/ unit (mg) Batch 85 ( Malic acid - 0.1 mg) Qty/ unit (mg) Batch 86 ( Tartaric Acid - 0.1 mg) Qty/ unit (mg) Tabostat (Taposstat mesylate) 0.147 0.147 0.147 0.147 0.147 Orthophosphate 0.05 0 0 0 0 Sodium dihydrogen phosphate monohydrate 0.12 0 0 0 0 Potassium dihydrogen phosphate and HCl 0 0.09 0 0 0 citric acid 0 0 0.1 0 0 malic acid 0 0 0 0.1 0 tartaric acid 0 0 0 0 0.1 Silicated microcrystalline cellulose 98.82 98.82 98.82 98.82 98.82 Magnesium stearate 1 1 1 1 1 total 100.1 mg 100.1 mg 100.1 mg 100.1 mg 100.1 mg Results and Discussion: Results for tablet stability of study batches (Batch Nos. 82-86) are provided in Table 38 below. Table 38 parameters Hardness (KP) DT Regularization Analysis - Initial (%) Regularized Analysis -OE (%) Diff.Analysis ( Initial -OE ) RS initial (%) RS OE (%) Diff. RS (OE- Initial ) Best Batch (Sodium Phosphate/Phosphoric Acid 0.06 mg/0.025 mg 3.5-4.5 30-40 seconds 100 90.04 9.96 0.53 0.74 0.21 Lot 82 3.5-4.3 15-25 100 76.77 23.23 0.49 1.93 1.44 Lot 83 4.1-5.0 30 seconds 100 82.20 17.80 0.42 2.29 1.87 Lot 84 4.0-5.0 25-30 seconds 100 84.12 15.88 0.11 0.94 0.83 Lot 85 4.2-5.2 20-25 seconds 100 83.52 16.48 0.09 1.12 1.03 Lot 86 4.5-5.5 20-30 seconds 100 80.56 19.44 0.10 1.07 0.97

The disintegration times observed with the buffer variables studied (sodium phosphate dibasic and hydrochloric acid, potassium dihydrogen phosphate and hydrochloric acid, citric acid, malic acid and tartaric acid) ranged from 15 seconds to 30 seconds, which is comparable to that of the best tablets. Disintegration times are similar. The buffer component has no significant effect on tablet hardness. Higher analytical reduction was observed with sodium phosphate dibasic and hydrochloric acid at 40°C/75% RH - 7 days open exposure. Other buffers showed comparable stability to tablets made with the optimal composition. The initial total impurities for all batches ranged from 0.09% to 0.49%. When stored under open conditions at 40°C/75% RH for 7 days, total impurity levels increased and values ranged from 0.94% to 2.29%. After open exposure, the best batch showed a total impurity value of 0.74%. The highest maximum total impurities, 2.29%, were observed in tablets using potassium dihydrogen phosphate and hydrochloric acid.

surface 39. Rated at 40℃/75%RH open exposure 7 Tianji 15 The stability of Tabostat mesylate itself.

Procedure: Absorb tapoxostat mesylate (100 mg) into a 20 mL bottle. Cover the bottle with aluminum foil and poke a small hole with a fine needle. The bottles were then loaded onto a stability rack to evaluate physical and chemical characteristics during the initial phase and after 7 and 15 days of direct open exposure at 40°C/75% RH.

Results: The molecular weight of tapoxostat mesylate is 310.18 g/mol and the molecular weight of tapoxostat is 214.07 g/mol. Each 100 mg of taboxostat mesylate contains 69.01 mg of tabinostat and the results are as follows: Description ( initial ) Description (40℃/75% RH-7 days ) Description (40°C/75% RH-15 days ) Initial analysis Analysis at 40℃/75% RH-7 days Analysis at 40℃/75% RH-15 days RS method -A ( maximum unknown ) RS method -C ( maximum unknown ) initial Stability at 40℃/75% RH-7 days Stability at 40°C/75% RH-15 days initial Stability at 40°C/75% RH - 7 days Stability at 40°C/75% RH-15 days White to off-white solid White to off-white solid White to off-white solid 99.4 99.6 100.0 0.07 0.07 0.08 ND ND ND ND: Not detected.

No significant changes in analytical and impurity levels were observed over 07 days and 15 days under open conditions at 40°C/75% RH. Example 2 :

Below is a prior art formulation in Table 40 (referred to herein as Formulation A) prepared according to the excipients disclosed in WO2008066729 (Point Therapeutics) and WO2017011831 (Table 3 of BioXcel). Table 40 Element Composition (% w/w) Tabostat (Taposstat mesylate) 0.145 Lactose monohydrate 85.315 microcrystalline cellulose 9.480 Phosphoric acid Sufficient sodium phosphate 0.060 crospovidone 2.500 pregelatinized starch 1.000 stearic acid 1.500

Process: Dissolve sodium phosphate and orthophosphoric acid in purified water to form a clear buffer solution. Add Tabostat to dissolve in buffer solution. Microcrystalline cellulose and lactose monohydrate are mixed and the drug solution is used for granulation. The granules are dried and ground/sieved through a suitable sieve. The dried granules are blended with starch and crospovidone. The resulting blend is lubricated with stearic acid and the lubricated blend is compressed to obtain tablets of suitable size.

Additionally, the analytical values and impurity profiles of the formulations of the present disclosure and Formulation A were compared and tabulated in Table 41. Table 41 : Initial analytical values and impurity data for different batches of tabostat tablet formulation manufactured at different time points. Preparations Batch number Manufacturing date Tablet strength Analysis % when T=0 RRT 1.RRT 1.06 when T=0 RRT 1.RRT 1.16 when T=0 Formulation A (Engg batch) April 2018 0.2 mg 94.6 0.51 2.50 Batch numberCBPHG July 2018 0.2 mg 92.2 0.46 2.77 Batch number CCTWN March 2019 0.05 mg 96.2 ND 1.28 Batch numberCGSMC January 2021 0.1 mg 95.6 0.13 1.81 Formulation 3 (200 mcg) NEU070-A-019B1 Oct2020 0.2 mg 101.3 ND 0.056 Formulation 4 (200 mcg) NEU070-A-020B1 December 2020 0.2 mg 102.5 ND 0.03 Formulation 4 (50 mcg) NEU070-B-020B1 December 2020 0.05 mg 101.1 ND ND

The data in Table 41 above show that the tablet formulation (Formulation A) had low analytical values after manufacture (t=0) and formed high concentrations (>1%) of both impurities at RRT 1.06 and 1.16. On the other hand, Formulation 3 and Formulation 4 prepared according to the present disclosure had appropriate analytical values and formed no detectable impurities at RRT 1.06 and 1.16.

Example 3: Degradation study of Formulation 2 with/without buffer.

To understand the degradation properties of the API (tapoxostat mesylate) in the formulation, product exposure studies were conducted under conditions such as: Exposure in HDPE bottles at 60°C ± 2°C under open and closed conditions 1 weeks, and exposed to open conditions for 15 days at 40℃±2℃/75%±5% RH. Table 42 : Stability studies of Formulation 2 ( with or without buffer ) : Preparations analyze(%) initial 60℃±2℃ , under open conditions 60℃±2℃ , under closed conditions 40℃±2℃/75%±5% RH , under open conditions Example 2 (contains buffer) 98.5 94.4 93.2 72.5 Example 2 (without buffer) 98.1 95.0 91.0 47.0

Results: It was observed that both formulations were found to show similar stability in open and closed conditions at 60°C ± 2°C, indicating that the presence of buffer does not have an additional advantage for the pyrolytic stability of the drug product in the formulation. However, it was observed that the formulation without buffer when exposed to open conditions for 15 days at 40°C ± 2°C/75% ± 5% RH was significantly different from the formulation containing additional acidic buffer (initial taboxostat (72.5% of the initial Tabostat) degraded more (47.0% of the initial Taboxostat), indicating that the presence of a buffer in the formulation provides additional stability in the presence of the combination of high temperature and high humidity.

Example 4. Under different storage conditions, formulations 1 to 4 Formulations with prior art A The comparative stability data is as shown in the table below 43 and table 44 shown in .

Stability studies of Formulations 1 to 4 and Formulation A were carried out in a conventional manner, and changes in appearance (by visual inspection), changes in Tabostat content (by chemical analysis) were studied, and their degradation was measured. Product and related substance data, cyclic content, for example after storage at room temperature of 25°C and 60% relative humidity and storage at 40°C and 75% relative humidity for a defined period of time. The results of the stability tests are summarized in the table below.

Results: All physico-chemical parameters of the prepared tablets (Formulations 1 to 4) were found to be acceptable. The cyclic form was found to be within acceptable limits. The product was found to be stable for 6 months at 25°C/60% RH and 40°C/75% RH. In both packages (normal HDPE and Multiblock HDPE bottles), all estimated CQAs were within the acceptable range. Table 43 : Comparison of stability studies of Formulations 1 to 4 and Formulation A ( prior art formulation ) under storage conditions of 25°C/60% RH Attribute analysis(%) Preparations initial 3M 6M Formulation A 92.2 90.2 88.5 Concoction 1 101.3 98.8 98.8 Concoction 2 102.5 99.4 99.1 Concoction 3 HDPE 100.6 99.0 98.5 Multiblock 100.6 99.3 98.7 Concoction 4 HDPE 101.1 99.4 99.0 Multiblock 101.1 99.3 99.1 Related substances/total impurities (%) Formulation A total 4.74 4.48 6.2 RRT 1.06 0.46 0.43 0.95 RRT 1.16 2.77 2.47 2.88 Concoction 1 HDPE 0.08 0.89 0.63 Multiblock 0.08 0.80 0.63 Concoction 2 HDPE 0.08 0.72 0.51 Multiblock 0.08 0.77 0.46 Concoction 3 HDPE 0.08 0.66 0.68 Multiblock 0.07 0.66 0.58 Concoction 4 HDPE 0.15 0.39 0.17 Multiblock 0.15 0.42 0.40 Cyclic form content (%) Formulation A 23.8 29.3 30.3 Concoction 1 HDPE 22.7 NA 20.2 Multiblock 22.7 13.6 20.2 Concoction 2 HDPE 12.2 19.8 19 Multiblock NA 14.3 17.4 Concoction 3 HDPE twenty two 11.8 24.6 Multiblock twenty two 12.5 25.3 Concoction 4 HDPE 15.1 12.1 13.9 Multiblock 15.1 11.6 15.0 Table 44 : Comparison of stability studies of Formulations 1 to 4 and Formulation A ( prior art formulation ) under storage conditions of 40°C/75% RH Attribute analysis(%) Preparations initial 3M 6M Formulation A 95.6 Not obtained Not obtained Concoction 1 HDPE 101.3 NA 98.4 MultiblockHDPE 101.3 NA 98.2 Concoction 2 HDPE 102.5 98.7 97.7 MultiblockHDPE 102.5 98.6 98.6 Concoction 3 HDPE 100.6 98.3 98.3 MultiblockHDPE 100.6 98.2 98.1 Concoction 4 HDPE 101.1 99.2 97.5 MultiblockHDPE 101.1 99.1 98.4 Related Substances/Impurities Data Formulation A total 2.49 Not reported Not reported RRT 1.06 0.13 RRT 1.16 1.81 Concoction 1 HDPE 0.08 0.83 0.65 MultiblockHDPE 0.08 0.89 0.67 Concoction 2 HDPE 0.08 0.68 0.47 MultiblockHDPE 0.08 0.77 0.42 Concoction 3 HDPE 0.08 0.90 0.69 MultiblockHDPE 0.08 0.82 0.70 Concoction 4 HDPE 0.15 0.43 0.22 MultiblockHDPE 0.15 0.55 0.41 Cyclic form content (%) Formulation A 23.0 Not reported Not reported Concoction 1 HDPE 22.7 20.5 21.2 MultiblockHDPE 22.7 14.8 22.1 Concoction 2 HDPE 12.2 13.7 20.0 MultiblockHDPE 12.2 14.8 18.0 Concoction 3 HDPE 22.0 12.1 25.4 MultiblockHDPE 22.0 12.7 26.0 Concoction 4 HDPE 15.1 12.7 14.2 MultiblockHDPE 17.6 12.0 15.8

Although the present disclosure has specifically addressed the separation and recovery of carbon dioxide, it should be understood that the present disclosure can readily be used to separate other gases.

It will be understood that although reference may be made herein to prior art uses and publications, such references do not constitute an admission that any of these references form part of the common general knowledge in the art in any country.

Without departing from the basic inventive concept, various changes and modifications in addition to those already described will be apparent to those skilled in the relevant art. All such changes and modifications shall be deemed to be within the scope of this disclosure, and the nature of this disclosure shall be determined from the foregoing description.

Figure 1 illustrates an exemplary flow chart illustrating the manufacturing process of Formulation 1 of Example 1. Figure 2 illustrates an exemplary flow chart illustrating the manufacturing process of Formulation 1 of Example 1 (without silicified microcrystalline cellulose). Figure 3 illustrates an exemplary flow chart illustrating the manufacturing process of Formulation 2 of Example 1. Figure 4 illustrates an exemplary flow chart illustrating the manufacturing process of Formulation 2 (without buffer) of Example 1. Figure 5 illustrates an exemplary flow chart illustrating the manufacturing process of Formulation 3 of Example 1. Figure 6 illustrates an exemplary flow chart illustrating the manufacturing process of Formulation 4 of Example 1.

Claims (38)

A formulation suitable for oral administration, comprising: (i) talabostat or its pharmaceutically acceptable salt; (ii) Silicated microcrystalline cellulose; (iii) Sodium dihydrogen phosphate monohydrate; (iv) Phosphoric acid, and (v) Magnesium stearate. The formulation of claim 1, wherein the formulation retains at least about 95% of the initial amount of tabosostat or its pharmaceutical agent after storage in a container at room temperature and about 60% relative humidity for about 6 months. Scientifically acceptable salt with a total impurity content of less than 1%. A formulation for oral administration, comprising: (i) Intra-particle fraction and (ii) The extragranular part; The part inside the particle contains: (a) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; (b) Phosphoric acid in an amount of about 0.005% to about 2.0% w/w; and (c) about 85% to about 99% w/w silicified microcrystalline cellulose; and The extragranular part contains: (a) Taboxostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; and (b) Magnesium stearate in an amount of about 0.01% to about 5% w/w. The formulation of claim 1, wherein the formulation retains at least about 95% of the initial amount of tabosostat or its pharmaceutically acceptable substance after storage in a container at room temperature and about 60% relative humidity for 6 months. Salt is acceptable and the total impurity content is less than 1%. For example, the preparation of claim 1, wherein when stored for about 6 months, the preparation retains about 99.5% of the initial amount of tabostat or its pharmaceutically acceptable salt, and the total amount of impurities is less than 0.5 %. The formulation of claim 1, wherein the formulation contains an undetectable amount of impurities at a relative retention time (RRT) of about 1.06 and about 1.16. The preparation of claim 1, further comprising (i) Microcrystalline cellulose; (ii) Stearic acid; (iii) Lactose monohydrate, and (iv) Pregelatinized starch. For example, the preparation of claim 7 contains: (i) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w; (ii) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; (iii) About 25% to about 95% w/w lactose monohydrate; (iv) Microcrystalline cellulose in an amount of about 25% to about 95% w/w; (v) Pregelatinized starch in an amount of about 0.05% to about 10% w/w; (vi) Stearic acid in an amount of about 0.05% to about 2% w/w; (vii) Phosphoric acid in an amount of about 0.005% to about 2.0% w/w; and (viii) Magnesium stearate in an amount of about 0.01% to about 5% w/w. The preparation of claim 1, further comprising (i) silicified microcrystalline cellulose in an amount from about 2% to about 95% w/w, (ii) Sodium dihydrogen phosphate monohydrate in an amount from about 0.01% to about 2% w/w, (iii) stearic acid in an amount of about 0.05% to about 2% w/w, (iv) About 0.005% to about 2.0% w/w phosphoric acid and (v) Magnesium stearate in an amount of about 0.01% to about 5% w/w. A formulation suitable for oral administration, comprising: (i) Intra-granular portion; and (ii) The extragranular part, The part inside the particle contains: (a) Tabostat or its pharmaceutically acceptable salt in an amount of about 0.1% to about 0.2% w/w; (b) Sodium dihydrogen phosphate monohydrate in an amount of about 0.01% to about 2% w/w; and (c) Phosphoric acid in an amount of about 0.005% to about 2.0% w/w; and The extragranular part contains: (a) Lactose monohydrate in an amount from about 25% to about 95% w/w, (b) Microcrystalline cellulose in an amount of about 5% to about 95% w/w; (c) silicified microcrystalline cellulose in an amount from about 2% to about 95%; (d) Pregelatinized starch in an amount of about 0.05% to about 10% w/w; (e) Stearic acid in an amount of about 0.02% to about 2% w/w; and (f) Magnesium stearate in an amount of about 0.01% to about 5% w/w. The formulation of claim 10, wherein the formulation retains at least about 95% of the initial amount of tabosostat or its pharmaceutical composition after storage in a container at room temperature and about 60% relative humidity for 6 months. acceptable salt, and the total amount of impurities is less than 1%. A method for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, the method comprising: (i) Sieve the silica microcrystalline cellulose and divide it into 4 parts, (ii) Mix Tabostat or its pharmaceutically acceptable salt, the first part of siliconized microcrystalline cellulose, orthophosphoric acid and sodium phosphate buffer in a plastic bag for 10 minutes; (iii) Manually mix the blend of step (ii) and the second portion of silica microcrystalline cellulose in the plastic bag for 15 minutes, and then sieve; (iv) Manually mix the blend of step (iii) and the third portion of silica microcrystalline cellulose in the plastic bag for 15 minutes, and then sieve; (v) Manually mix the blend of step (iv) and the fourth part of silica microcrystalline cellulose in the plastic bag for 15 minutes, and then sieve; (vi) Pre-lubricate the blend of step (v); (vii) Grinding; and (viii) Lubricate the blend. For example, the formulation of claim 10, wherein the taboxostat or its pharmaceutically acceptable salt is taboxostat mesylate. The formulation of claim 10, wherein the formulation retains at least about 98% of the initial amount of tabostat or a pharmaceutically acceptable substance after 12 months in a container at room temperature and about 60% relative humidity. salt. The formulation of claim 10, wherein the tabostat or a pharmaceutically acceptable salt thereof is present in an amount of about 50 micrograms to about 400 micrograms. The formulation of claim 10, wherein the tabostat or a pharmaceutically acceptable salt thereof is present in the tablet in an amount of about 100 micrograms, about 200 micrograms, or about 300 micrograms. The formulation of claim 10, wherein the tabostat or a pharmaceutically acceptable salt thereof is present in the tablet in an amount of about 100 micrograms. The formulation of claim 10, wherein the tabostat or a pharmaceutically acceptable salt thereof is present in the tablet in an amount of about 200 micrograms. The formulation of claim 10, wherein the tabostat or a pharmaceutically acceptable salt thereof is present in the tablet in an amount of about 300 micrograms. The formulation of claim 10, wherein the formulation does not contain crospovidone. The formulation of claim 10, further comprising a moisture-proof coating in an amount from about 2% to about 8% w/w of the total weight of the composition. The formulation of claim 10, wherein the formulation disintegrates in less than 5 minutes in the presence of water. The formulation of claim 10, wherein the pH of the formulation is about 1 to 5. The formulation of claim 1, wherein the formulation is formed by a wet granulation method and wherein Taboxostat is added extragranularly. The formulation of claim 1, wherein the formulation is formed by a dry granulation method. The formulation of claim 1, further comprising one or more additional active agents. A method of treating cancer in an individual in need thereof, the method comprising orally administering to the individual a formulation of taboxostat or a pharmaceutically acceptable salt thereof as claimed in claim 10. The method of claim 27, further comprising administering to the individual a formulation comprising a second active agent. A method for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, the method comprising: (i) Prepare a clear buffer solution by dissolving orthophosphoric acid and sodium phosphate in purified water; (ii) Add silica microcrystalline cellulose to the buffer solution; (iii) granulate the solution to provide granules, and then dry the granules; (iv) admixed with tabostat or its pharmaceutically acceptable salt; and (v) Optionally lubricate the blend with magnesium stearate. A method for preparing a formulation of tabostat or a pharmaceutically acceptable salt thereof, the method comprising: (i) Sieve the silica microcrystalline cellulose and divide it into one or more portions; (ii) Mix Tabostat or its pharmaceutically acceptable salt with the first part of siliconized microcrystalline cellulose, orthophosphoric acid and sodium phosphate buffer in a plastic bag for about 10 minutes; (iii) Mix the blend of step (ii) and the second portion of silica microcrystalline cellulose in the plastic bag for about 15 minutes, and then sieve; (iv) Mix the blend of step (iii) and the third portion of silica microcrystalline cellulose in the plastic bag for 15 minutes, and then sieve; (v) Mix the mixture of step (iv) and the fourth part of silica microcrystalline cellulose in the plastic bag for 15 minutes, and then sieve; (vi) Pre-lubricate the blend of step (v); (vii) By grinding the blend through a screen; and lubricating the blend. The method of claim 29 is performed at a relative humidity of less than about 60%. The method of claim 29, wherein tabostat or its pharmaceutically acceptable salt is not in direct contact with the aqueous vehicle. The method of claim 29, wherein the silicified microcrystalline cellulose is present in an amount from about 2% to about 95% w/w. The method of claim 29, wherein the phosphoric acid is present in an amount of about 0.005% to about 0.1% w/w. The method of claim 29, wherein sodium dihydrogen phosphate monohydrate is present in an amount of about 0.01% to about 2% w/w. The method of claim 29, wherein magnesium stearate is present in an amount of about 0.01% to about 5% w/w. The method of claim 29, wherein the buffer solution of step (i) has a pH of about 2 to 3. The formulation of claim 1, wherein the formulation is a tablet.