WO2023172958A1

WO2023172958A1 - Stable formulations of talabostat

Info

Publication number: WO2023172958A1
Application number: PCT/US2023/063939
Authority: WO
Inventors: Vasukumar Kakumanu; Vobalaboina Venkateswarlu; Vijaykumar NAGABANDI
Original assignee: Onkosxcel Therapeutics, Llc
Priority date: 2022-03-08
Filing date: 2023-03-08
Publication date: 2023-09-14
Also published as: TW202345857A

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 TALABOSTAT

CROSS REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63/317,726, which was filed on March 8, 2022, the disclosure of which is incorporated herein by reference in its entirety.

FIELD

[002] The disclosure relates to formulations (e.g., a tablets or capsules) of talabostat or a pharmaceutically acceptable salt thereof that are suitable for oral administration. The disclosure encompasses formulations comprising talabostat or a pharmaceutically acceptable salt thereof, silicified microcrystalline cellulose, sodium phosphate monobasic monohydrate, phosphoric acid, and magnesium stearate. The formulation is stable on storage in a container at room temperature at about 60% relative humidity for a period of at least 6 months. The disclosure further relates to process of preparation of the formulations and methods of treatment using the same.

BACKGROUND

[003] Talabostat also known as PT- 100 (Vai -boro-Pro; L-valinyl-L-boroproline) is an orally available synthetic selective inhibitor of dipeptidyl peptidases like FAP, DPP8 and DPP9. It plays an important role in immune evasion and regulates both innate and/or acquired immunity. The stereoisomer of talabostat is disclosed in U.S. Patent No. 6,825,169 while oral formulations such as tablets, capsules, and lozenges are disclosed in U.S. Patent No. 7,265,118.

[004] The prior manufactured tablet formulations of talabostat issues require storage at refrigerated conditions (e.g., 2-8°C) due to issues with stability. However, such storage condition is not conventional for a tablet dosage form as it impacts the distribution chain of the medicine in terms of costs and also in terms of logistics for the patient. The formation of impurities may influence safety and efficacy and thus are detrimental to the drug product. [005] The stability of a pharmaceutical formulation is one of the most important criteria for ensuring safety and consistent and effective administration. The choice of excipients in the design of the formulation is made based on their function as well as chemical compatibility with the drug substance. The drug product stability may also be influenced by formulation processes, environmental conditions (e.g., microenvironmental pH, temperature, water content, water activity, and/or oxygen), and any changes in the drug/excipient ratio or API particle size.

[006] There exists a need to develop a stable formulation that can be stored under a range of temperature conditions such that there are no longer any storage implications. Such formulations would remove any concern of patients to keep the medication within a particular storage condition.

[007] The disclosure addresses the problems in the art by developing a formulation of talabostat or a pharmaceutically acceptable salt thereof that maintains stability for at least 6 months with minimal potency loss and minimal levels of impurities when stored at room temperature and about 60% relative humidity as long-term conditions and at 40°C and 75% relative humidity under accelerated conditions.

SUMMARY

[008] The present disclosure is based on the discovery that the root cause of initial potency loss and impurities during the manufacturing of talabostat formulation is due to oxidative and hydrolytic degradation caused by interaction with one or more components of the formulation. After conducting several trials and binary mixture studies of talabostat with excipients at different ratios, the inventors surprisingly found that a significant drop in initial assay and impurity formation at RRT 1.16 was due to interaction of talabostat with an oxidative compound in the formulation. One such compound is the disintegrant, crospovidone. Removing crospovidone, however, provided formulations with unacceptably long disintegration times, therefore the presence of an alternate disintegrant is necessary to achieve quick disintegration within 5 minutes. [009] Accordingly, the formulations of talabostat or a pharmaceutically acceptable salt thereof 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 even at accelerated storage condition of 40°C and 75% RH with minimal impurities and potency loss. The formulations are acceptable with respect to all physicochemical parameters (including, for example, hardness, thickness, disintegration time, dissolution, content uniformity ) and are also beneficial from a patient compliance perspective making it easier to take the required medication.

Formulations Including Talabostat

[010] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

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

[012] In embodiments, the disclosure provides a stable tablet formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

[013] In embodiments, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is less than 1% and with no detectable impurities at relative retention times (RRT) of 1.06 and 1.16.

[014] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

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

[016] In embodiments, the formulation retains about 96%, about 97%, about 98%, or about 99% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof. In embodiments, the total amount of impurities is less than 0.5% after six months storage in a container at room temperature and about 60% relative humidity. In embodiments, the formulation retains about 99.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 0.2% after six months storage in a container at room temperature and about 60% relative humidity.

[017] In embodiments, the formulation retains about 98% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof after twelve months in a container at room temperature and about 60% relative humidity.

[018] In embodiments, the present disclosure provides a formulation suitable for oral administration comprising:

(i) an intragranular portion and

(ii) an extragranular portion; wherein the intragranular portion comprises:

(a) sodium phosphate monobasic 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) silicified microcrystalline cellulose in an amount of about 85% to about 99% w/w; and wherein the extragranular portion comprises:

(a) talabostat or a pharmaceutically acceptable salt thereof 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.

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

[020] In embodiments, after six months storage in a container at about 2 °C to about 8 °C for over 6 months and about 60% RH, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than about 1 %. In embodiments, the formulation is stored in a multiblock HDPE bottle. In embodiments, the formulation is stored in a normal HDPE bottle.

[021] In embodiments, the formulation retains about 96%, about 97%, about 98%, or about 99% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 0.5 % after six months storage in a container at about 2 °C to about 8 °C.

[022] In embodiments, the formulation retains about 98.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 0.2% after six months storage in a container at about 2° C to about 8 °C.

[023] In embodiments, the disclosure provides a stable, tablet formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate. [024] In embodiments, after one month storage in a container under accelerated conditions at temperature of 40 °C and about 75% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[025] In an embodiment, the formulation is stored in a multiblock HDPE bottle. In an embodiment, the formulation is stored in a normal HDPE bottle.

[026] In embodiments, the disclosure provides a formulation suitable for oral administration comprising: (i) an intragranular portion and (ii) an extragranular portion, wherein the intragranular portion comprises: (a) sodium phosphate monobasic 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) silicified microcrystalline cellulose in an amount of about 85% to about 99% w/w and the extragranular portion comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w, and (e) magnesium stearate in an amount of about 0.01% to about 5% w/w.

[027] In embodiments, after six months of storage in a container under accelerated conditions at temperature of 40 °C and about 75% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[028] In embodiments, the total amount of impurities is less than 0.2 % after one month storage in a container at temperature of 40°C and about 75% relative humidity.

[029] In embodiments, talabostat or the pharmaceutically acceptable salt thereof is present in an amount of about 0.05% to about 0.2% w/w of the total weight of formulation.

[030] In embodiments, talabostat or the pharmaceutically acceptable salt thereof is present in an amount of about 50 micrograms to about 800 micrograms. In embodiments, talabostat or the pharmaceutically acceptable salt thereof is present in an amount of about 50 micrograms to about 600 micrograms. In embodiments, talabostat or the pharmaceutically acceptable salt thereof is present in an amount of about 50 micrograms to about 400 micrograms. [031] In embodiments, the amount of talabostat or the pharmaceutically acceptable salt thereof in a unit dose, for example, 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.

[032] In embodiments, a formulation (e.g., a tablet) of talabostat or the pharmaceutically acceptable salt thereof comprises:

(i) talabostat or the pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w;

(ii) silicified microcrystalline cellulose in an amount of about 85% to about 99% w/w;

(iii) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w; and

(iv) phosphoric acid in an amount of about 0.005% to about 0.1% w/w.

[033] In embodiments, the formulation of talabostat or the pharmaceutically acceptable salt thereof comprises:

(iii) sodium phosphate monobasic 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.

[034] In embodiment, the formulation further comprises microcrystalline cellulose; stearic acid; lactose monohydrate, and/or pregelatinized starch.

[035] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate; (iii) microcrystalline cellulose;

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate; and

(viii) phosphoric acid.

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

[037] In embodiments, the disclosure provides a stable tablet formulation of talabostat or a pharmaceutically acceptable salt thereof comprising or consisting of

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate; and

(viii) phosphoric acid.

[038] In embodiments, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%. In embodiments, the formulation retains about 96% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.8% after six months storage in a container at room temperature at about 60% relative humidity.

[039] In embodiments, the present disclosure provides a formulation suitable for oral administration comprising:

(i) an intragranular portion; and

(ii) an extragranular portion; wherein the intragranular portion comprises:

(a) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w;

(b) sodium phosphate monobasic 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 wherein the extragranular portion comprises:

(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 95% w/w;

(c) silicified microcrystalline cellulose in an amount of 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.

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

[041] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose,

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate; and

(viii) phosphoric acid.

[042] In embodiments, the formulation after six months of storage in a container at temperature of about 2 °C to about 8 °C retains at least about 98% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[043] In embodiments, the formulation retains about 99% or about 100% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.8% after six months storage in a container at temperature of about 2 °C to about 8 °C.

[044] In embodiments, the disclosure provides a stable tablet formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate; and

(viii) phosphoric acid.

[045] In embodiments, after six months of storage in a container under accelerated conditions at a temperature of 40 °C and about 75% relative humidity, the formulation retains at least about 90% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[046] In embodiments, the formulation retains about 91%, about 92%, about 93%, or about 93.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.8% after six months storage in a container at temperature of 40°C and about 75% relative humidity.

[047] In embodiments, the present disclosure provides a formulation suitable for oral administration, comprising: (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises:

(a) talabostat or a pharmaceutically acceptable salt thereof at about 0.1% to about

0.2% w/w; (b) sodium phosphate monobasic monohydrate at about 0.01% to about 2% w/w; and

(c) phosphoric acid at about 0.005% to about 1% w/w; wherein the extragranular portion comprises:

(a) lactose monohydrate at about 25% to about 95% w/w;

(b) microcrystalline cellulose at about 5% to about 95% w/w;

(c) silicified microcrystalline cellulose at about 2% to about 95% w/w;

(d) pregelatinized starch at about 0.05% to about 10% w/w;

(e) stearic acid at about 0.05% to about 2% w/w; and

(f) magnesium stearate at about 0.01% to about 5% w/w.

[048] In embodiments, after six months of storage in a container under accelerated conditions at a temperature of 40°C and about 75% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and total amount of impurities is less than 1%.

[049] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises:

(i) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w;

(ii) silicified microcrystalline cellulose in an amount of about 2% to about 95% w/w;

(iv) lactose monohydrate in an amount of about 50% to about 95% w/w;

(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. [050] In embodiments, the amount of talabostat or a pharmaceutically acceptable salt thereof in a tablet is about 300 micrograms. In embodiments, the amount of talabostat or a pharmaceutically acceptable salt thereof in a tablet is about 200 micrograms. In embodiments, the amount of talabostat or a pharmaceutically acceptable salt thereof in a tablet is about 50 micrograms

[051] In embodiments, the formulation optionally comprises a moisture barrier coating. In embodiments, the coating is present in an amount of about 2% to about 8% w/w of the total weight of the formulation. In embodiments, the coating comprises about 4% /w/w of the total weight of the formulation.

[052] In embodiments, the moisture barrier coating polymers include, but are not limited to, cellulose and its derivatives such as ethyl cellulose, hydroxypropylmethyl cellulose, e.g., hypromellose 5cP and hypromellose 15cP, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxy ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes; polyvinyl derivatives such as PVA (polyvinyl alcohol) such as those available under the trademark Opadry AMB, Opadry II, Opadry QX (Kollicoat) or PVP- PVAc copolymer (polyvinylpyrrolidone-polyvinylacetate copolymer) and methacrylic acid polymers (e.g., Eudragit) and the like.

[053] In embodiments, the coating comprises Opadry AMB-II Blue Light.

[054] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate;

(viii) phosphoric acid; and

(ix) a moisture barrier film coat. [055] In embodiments, after six months of storage in a container at room temperature and about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1% .

[056] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate;

(viii) phosphoric acid; and

(ix) a moisture barrier film coat.

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

[058] In embodiments, the formulation retains about 98.5% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and the total amount of impurities is about 0.7% on storage in a container at room temperature and about 60% relative humidity.

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

[060] In embodiments, the formulation further comprises a moisture barrier coating at about 2% w/w to about 4% w/w, and after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[061] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate;

(viii) phosphoric acid; and

(ix) a moisture barrier film coat.

[062] In embodiments, after six months of storage in a container at temperature of about 2 to about 8°C, the formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and total amount of impurities is less than 1%.

[063] In embodiments, the formulation retains about 96%, about 97%, about 98%, or about 99% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1% storage in a container at about 2 to about 8°C.

[064] In embodiments, the formulation retains about 99.5% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.6% on storage in a container at about 2 to about 8°C. [065] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate;

(viii) phosphoric acid; and

(ix) a moisture barrier film coat.

[066] In embodiments, after six months storage in a container under accelerated conditions at temperature of 40 °C and about 75% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and 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 talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.7% on storage in a container at temperature of 40° C and about 75% relative humidity.

[067] In embodiments, the disclosure provides a formulation suitable for oral administration comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w (b) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w and (c) phosphoric acid in an amount of about 0.5% to about 1% w/w; and the extragranular portion comprises (d) lactose monohydrate in an amount of about 25% to about 95% w/w, (e) microcrystalline cellulose in an amount of about 5% to about 95% w/w, (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. [068] In embodiments, the formulation further comprises moisture barrier coating at about 2% w/w to about 4% w/w and after six months of storage in a container at temperature of 40°C and about 75% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[069] In embodiments, the formulation contains nondetectable impurities at RRT 1.06 after six months storage in a container at temperature of 40°C and about 75% relative humidity.

[070] In embodiments, the formulation contains nondetectable impurities at RRT 1.16 after six months storage in a container at temperature of 40°C and about 75% relative humidity.

[071] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises:

(i) talabostat or a pharmaceutically acceptable salt thereof at about 0.1% to about 2% w/w;

(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 of about 2% to about 95% w/w;

(vii) sodium phosphate monobasic 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

(ix) a moisture barrier film coat in an amount of about 2% w/w to about 4% w/w. [072] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; (v) magnesium stearate; and

(vi) a moisture barrier film coat.

[073] In embodiments, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, 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 talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.8% on storage in a container at room temperature at about 60% relative humidity.

[074] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises:

(c) phosphoric acid in an amount of about 0.005% to about 2% w/w; and wherein the extragranular portion comprises:

(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 of 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 comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w.

[075] In embodiments, the formulation is a stable tablet and comprises (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) talabostat or a pharmaceutically acceptable salt thereof 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 wherein the extragranular portion comprises:

(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;

(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 comprises a moisture barrier coating in an amount of about 2% w/w to about 4% w/w.

[076] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises:

(b) citric acid in an amount of about 0.01% to about 2% w/w; and wherein the extragranular portion comprises:

(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;

(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 comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w. [077] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises:

(a) talabostat or a pharmaceutically acceptable salt thereof at about 0.1% to about 0.2% w/w;

(b) malic acid at about 0.01% to about 2% w/w; and wherein the extragranular portion comprises:

(a) lactose monohydrate at about 25% to about 95% w/w;

(b) microcrystalline cellulose at about 5% to about 40% w/w;

(c) silicified microcrystalline cellulose at about 2% to about 95%;

(d) pregelatinized starch at about 0.05% to about 5% w/w;

(e) stearic acid at about 0.02% to about 2% w/w; and

(f) magnesium stearate at about 0.01% to about 5% w/w, wherein the formulation further comprises moisture barrier coating at about 2% w/w to about 4% w/w.

[078] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises:

(ii) silicified microcrystalline cellulose at about 2% to about 95% w/w;

(iii) sodium phosphate monobasic monohydrate at about 0.01% to about 2% w/w;

(iv) lactose monohydrate at about 50% to about 95% w/w;

(v) microcrystalline cellulose at about 5% to about 40% w/w;

(vi) pregelatinized starch at about 0.05% to about 5% w/w;

(vii) phosphoric acid at about 0.05% to about 0.1% w/w; and

(viii) magnesium stearate at about 0.01% to about 5% w/w, preferably about 0.05% to about 2% w/w, wherein the formulation further comprises moisture barrier coating at about 2% w/w to about 4% w/w.

[079] In embodiments, the present disclosure provides a formulation suitable for oral administration, for example, a tablet comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w (b) phosphoric 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 comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w and (e) magnesium stearate in an amount of about 0.01% to about 5% w/w.

[080] In embodiments, the formulation further comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w and after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and total amount of impurities is less than 1%.

[081] In embodiments, the formulation of talabostat or the pharmaceutically acceptable salt thereof, comprises (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w; (b) phosphoric acid in an amount of about 0.5% to about 1% w/w; and (c) microcrystalline cellulose in an amount of about 85% to about 99% w/w and the extragranular portion comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w; and (e) magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the formulation further comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w.

[082] In embodiments, the present disclosure provides a formulation of talabostat or the pharmaceutically acceptable salt thereof comprises (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic monohydrate at about 0.01% to about 2% w/w; (b) phosphoric acid at about 0.5% to about 1% w/w; and (c) silicified microcrystalline cellulose at about 25% to about 75% w/w; (d) microcrystalline cellulose at about 25% to about 75% w/w; and the extragranular portion comprises: (e) talabostat or a pharmaceutically acceptable salt thereof at about 0.1% to about 0.2% w/w and (f) magnesium stearate at about 0.01% to about 5% w/w, wherein the formulation further comprises moisture barrier coating at about 2% w/w to about 4% w/w. [083] In embodiments, the microcrystalline cellulose is MCC-101. In embodiments, microcrystalline cellulose is present at about 25% w/w and silicified microcrystalline cellulose at about 75% w/w. In embodiments, microcrystalline cellulose is present at about 50% w/w and silicified microcrystalline cellulose at about 50% w/w. In embodiments, microcrystalline cellulose is present at about 75% w/w and silicified microcrystalline cellulose at about 25% w/w.

[084] In embodiments, the disclosure provides a formulation suitable for oral administration comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic monohydrate at about 0.01% to about 2% w/w; (b) phosphoric acid at about 0.025% to about 1% w/w and (c) microcrystalline cellulose at about 85% to about 99% w/w; and the extragranular portion comprises: (d) talabostat or a pharmaceutically acceptable salt thereof at about 0.1% to about 0.2% w/w; (e) magnesium stearate at about 0.01% to about 5% w/w; and (f) optionally pregelatinized starch at about 0.5% to about 5% w/w, wherein the formulation further comprises moisture barrier coating at about 2% w/w to about 4% w/w.

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

[086] In embodiments, the disclosure provides a formulation suitable for oral administration, comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) malic acid at about 0.5% to about 2% w/w and (b) silicified microcrystalline cellulose at about 85% to about 99% w/w and the extragranular portion comprises: (c) talabostat or a pharmaceutically acceptable salt thereof at about 0.1% to about 0.2% w/w, and (d) magnesium stearate at about 0.01% to about 5% w/w. [087] In embodiments, the disclosure provides a formulation suitable for oral administration, comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) citric acid at about 0.1% to about 2% w/w and (b) silicified microcrystalline cellulose at about 85% to about 99% w/w, and the extragranular portion comprises: (c) talabostat or a pharmaceutically acceptable salt thereof at about 0.1% to about 0.2% w/w and (d) magnesium stearate at about 0.01% to about 5% w/w. In embodiments, the formulation contains no detectable impurities at RRT 1.06 after six months storage in a container at room temperature at about 60% relative humidity.

[088] In embodiments, the formulation contains no detectable impurities at RRT 1.16 after six months storage in a container at room temperature at about 60% relative humidity.

[089] In embodiments, the disclosure provides a formulation, for example, a stable tablet of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid;

(v) magnesium stearate; and

(vi) a moisture barrier film coat.

[090] In embodiments, after six months of storage in a container at temperature of about 2 to about 8° C, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%. In embodiments, the stable tablet formulation retains about 96%, about 96.5%, about 97%, or about 97.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.8% on storage in a container at about 2 °C to about 8 °C.

[091] In embodiments, the stable tablet formulation contains no detectable impurities at RRT 1.06 after six months storage in a container at 2-8°C. In embodiments, the stable tablet formulation contains no detectable impurities at RRT 1.16 after six months storage in a container at room temperature at about 2 °C to about 8 °C. [092] In embodiments, the present disclosure provides a stable tablet formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid;

(v) magnesium stearate; and

(vi) a moisture barrier film coat.

[093] In embodiments, after six months of storage in a container at temperature of 40°C at about 75% relative humidity, the stable tablet formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1.5%. In embodiments, the stable tablet formulation retains about 96%, about 96.5%, or about 97% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 1% on storage in a container at temperature of 40 °C at about 75% relative humidity.

[094] In embodiments, the present disclosure provides a stable tablet formulation suitable for oral administration comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w (b) phosphoric 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 comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w; and (e) magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the tablet further comprises moisture barrier coating in an amount of about 2% to about 4% w/w.

[095] In embodiments, after six months of storage in a container at temperature of 40°C at about 75% relative humidity, the stable tablet formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%. [096] In embodiments, the stable tablet formulation contains nondetectable impurities at RRT 1.06 after six months storage in a container at temperature of 40 °C at about 75% relative humidity. In embodiments, the stable tablet formulation contains nondetectable impurities at RRT 1.16 after six months storage in a container at room temperature at temperature of 40 °C at about 75% relative humidity.

[097] In embodiments, the coating comprises cellulose and its derivatives such as ethyl cellulose, hydroxypropylmethyl cellulose, (e.g., hypromellose 5cP and hypromellose 15cP), hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes; polyvinyl derivatives, such as PVA (polyvinyl alcohol) such as those available under the trademark Opadry AMB, Opadry II, Opadry QX (Kollicoat) or PVP-PVAc copolymer (poly vinylpyrrolidone-poly vinylacetate copolymer) and methacrylic acid polymers, (e.g., Eudragit., and the like), preferably Opadry AMB blue light.

[098] In embodiments, the stable tablet formulation of talabostat or a salt thereof comprises:

(ii) silicified microcrystalline cellulose at about 2% to about 95% w/w;

(iii) sodium phosphate monobasic monohydrate at about 0.01% to about 2% w/w;

(iv) phosphoric acid at about 0.005% to about 0.1% w/w;

(v) magnesium stearate at about 0.01% to about 5% w/w, preferably about 0.05% to about 2% w/w, and

(vi) a moisture barrier film coat at about 2% w/w to about 4% w/w.

[099] In embodiments, the coating comprises Opadry AMB blue light.

[100] In embodiments, the stable tablet formulation is free of crospovidone.

[101] In embodiments, the formulation is stored in multiblock HDPE bottles.

[102] In embodiments, the formulation is stored in normal HDPE bottles. Methods of Manufacturing the Formulations

[103] In embodiments, the present disclosure provides a process of preparing a stable tablet formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(i) preparing a clear buffer solution by dissolving O-phosphoric acid and sodium phosphate in purified water;

(ii) adding silicified microcrystalline cellulose to above buffer solution;

(iii) granulating the solution followed by drying the granules;

(iv) blending with talabostat or a pharmaceutically acceptable salt thereof extra- granularly;

(v) optionally lubricating the blend with magnesium stearate and compressing into tablets; and

(vi) optionally coating the tablets with a film-coat.

[104] In embodiments, the disclosure provides a process of preparing a stable tablet formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(ii) adding talabostat or a pharmaceutically acceptable salt thereof into above solution and granulating the solution;

(iii) drying the granules and blending with pre-gelatinized starch and silicified microcrystalline cellulose;

(iv) lubricating the blend and compressing into tablets; and

(v) optionally coating the tablets with a film coat.

[105] In embodiments, the disclosure provides a process of preparing a stable tablet formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(i) sifting and dividing silicified microcrystalline cellulose into multiple portions,

(ii) geometrically mixing talabostat or a pharmaceutically acceptable salt thereof, a first portion of silicified microcrystalline cellulose, and O-phosphoric acid and sodium phosphate buffer in a polybag for 10 minutes;

(iii) manually mixing step (ii) blending a second portion of silicified microcrystalline cellulose in the polybag for 15 minutes followed by sifting; (iv) manually mixing step (iii) blending a third portion of silicified microcrystalline cellulose in the polybag for 15 minutes followed by sifting;

(v) manually mixing step (iv) blending a fourth portion of silicified microcrystalline cellulose in the polybag for 15 minutes followed by sifting;

(vi) lubricating the blend and compressing into tablets; and vii) optionally coating the tablets with a film coat.

[106] In embodiments, the disclosure provides a process of preparing a stable tablet formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(i) sifting and dividing silicified microcrystalline cellulose into 4 portions,

(ii) geometrically mixing talabostat or a pharmaceutically acceptable salt thereof, portion- 1 of silicified microcrystalline cellulose and O-phosphoric acid and sodium phosphate buffer in a polybag for 10 minutes;

(iii) manually mixing step (ii) blend and second portion of silicified microcrystalline cellulose in the polybag for 15 minutes followed by sifting;

(iv) manually mixing step (iii) blend and third portion of silicified microcrystalline cellulose in the polybag for 15 minutes followed by sifting;

(v) manually mixing step (iv) blend and fourth portion of silicified microcrystalline cellulose in the polybag for 15 minutes followed by sifting;

(vi) pre-lubricating the step (v) blend and forming slugs or compacts;

(vii) milling the slugs or compacts by passing through a screen;

(viii) lubricating the blend; and

(ix) optionally coating with a film coat.

[107] In embodiments, the tablet formulation of talabostat or a pharmaceutically acceptable salt thereof is prepared by any of the known processes including direct compression, dry granulation, or wet granulation. In embodiments, silicified microcrystalline cellulose, acidic buffer and magnesium stearate are dry blended in in rapid mixer granulator and compressed. In embodiments, the buffer is coated onto microcrystalline cellulose and buffer coated microcrystalline cellulose is used for direct compression.

[108] In embodiments, the talabostat or a pharmaceutically acceptable salt thereof is added extra-granularly in wet granulation process. In embodiments, silicified microcrystalline cellulose is granulated with acidic buffer and then acidified silicified microcrystalline cellulose is blended with talabostat or a pharmaceutically acceptable salt thereof.

[109] In embodiments, talabostat or a pharmaceutically acceptable salt thereof is dissolved in acidic buffer solution to form a granulation fluid. In embodiments, a blend of lactose monohydrate and microcrystalline cellulose is formed into granules using said granulation fluid.

[HO] In embodiments, the disclosure provides a dry formulation process for preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof, which includes the step of mixing talabostat or a pharmaceutically acceptable salt thereof with one or more excipients selected from silicified microcrystalline cellulose, sodium phosphate, phosphoric acid, magnesium stearate, in the absence of added water.

[Hl] In embodiments, the relative humidity is maintained at or below 60% during the process of preparation of formulation of talabostat or a pharmaceutically acceptable salt thereof to prevent moisture absorption and degradation. In embodiments, the process is conducted under subdued light (i.e., sodium vapor lamp) to prevent photolytic degradation of talabostat or a pharmaceutically acceptable salt thereof. In embodiments, talabostat or a pharmaceutically acceptable salt thereof is not in direct contact with aqueous vehicle during the process.

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

Methods of Treatment

[113] In embodiments, the disclosure provides a method of treating cancer in a subject comprising orally administering the formulation of talabostat or the pharmaceutically acceptable salt thereof. In embodiments, the formulation (e.g., a tablet or capsule) comprising talabostat or the pharmaceutically acceptable salt thereof is orally administered at a dose of about 300 micrograms twice daily in divided doses. In embodiments, the formulation comprising talabostat or a pharmaceutically acceptable salt thereof is orally administered at a dose of about 200 micrograms twice daily. In embodiments, the formulation comprising talabostat or a pharmaceutically acceptable salt thereof is orally administered at a dose of about 200 micrograms thrice daily in divided doses. In embodiments, the formulation comprising talabostat or a pharmaceutically acceptable salt thereof is administered orally twice daily, such as at a dose of about 400 micrograms in the morning and about 200 micrograms in the evening in a day.

[114] In embodiments, the disclosure provides a method of treating cancer in a subject in need thereof by orally administering the formulation comprising an effective amount of talabostat or a pharmaceutically acceptable salt thereof and an additional active agent in a suitable unit dosage form to be administered simultaneously or sequentially separated by an appropriate period of time. In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises another active agent. In embodiments, another active agent is present in a different dosage form, that may be tablets, capsules, granules, minitablets and the like for oral administration.

Kits

[115] In embodiments, the disclosure relates to an individual unit dosage form provided as a kit comprising the formulation of talabostat or a pharmaceutically acceptable salt thereof as described herein in a container with or without instructions for administration to a subject in need thereof.

[116] In embodiments, the kit comprises a package insert comprising instructions for using the formulation of talabostat or pharmaceutically acceptable salt thereof described herein for treatment of cancer in a subject.

[117] Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

[118] Fig. 1 illustrates an exemplary flow-chart describing the manufacturing process of Formulation 1, Example 1.

[119] Fig. 2 illustrates an exemplary flow-chart describing the manufacturing process of Formulation 1 (without silicified microcrystalline cellulose), Example 1.

[120] Fig. 3 illustrates an exemplary flow-chart describing the manufacturing process of Formulation 2, Example 1.

[121] Fig. 4 illustrates an exemplary flow-chart describing the manufacturing process of Formulation 2 (without buffer), Example 1.

[122] Fig. 5 illustrates an exemplary flow-chart describing the manufacturing process of Formulation 3, Example 1.

[123] Fig. 6 illustrates an exemplary flow-chart describing the manufacturing process of Formulation 4, Example 1.

DETAILED DESCRIPTION

[124] In the following passages, different aspects of the disclosure are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. Abbreviations

[125] API: Active Pharmaceutical Ingredient

[126] Avg: Average

[127] %: Percentage

[128] CQA: critical quality attributes

[129] CCS: Croscarmellose sodium

[130] DPP: Dipeptidyl peptidase

[131] DT : Disintegration time

[132] FAP: Fibroblast activation protein

[133] FBD: Fluid Bed Drier

[134] HDPE: High Density Polyethylene

[135] HPLC: High-performance liquid chromatography

[136] MCC: Microcrystalline cellulose

[137] mg: milligrams

[138] min: minutes

[139] ml: milliliter

[140] NA: Not Applicable

[141] ND: Not detected

[142] RH: relative humidity

[143] RMG: rapid mixer granulator

[144] RRT: relative retention time

[145] RSD: Relative Standard Deviation

[146] SMCC: silicified microcrystalline cellulose

[147] SSG: sodium starch glycolate

[148] °C: Degree Centigrade

[149] pg: micrograms

[150] UOD: Uniformity of Dosage Units

[151] USP: United States Pharmacopoeia Definitions

[152] It will be understood that the terminology used herein is for the purpose of describing 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.

[153] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).

[154] As used herein, the term “about” refers to ±10% of the indicated numerical value. For example, about 50% includes a range of from 45% to 55%, while about 20 molar equivalents includes a range of from 18 to 22 molar equivalents. Accordingly, when referring to a range, “about” refers to each of the stated values +/- 10% of the stated value of each end of the range. For instance, a ratio of from about 1 to about 3 (weight/weight) includes a range of from 0.9 to 3.3.

[155] As used herein, the term “administering” refers to administration of the composition of the disclosure to a subject.

[156] As used herein, the term “cancer” as used herein include malignant tumors can spread into, or invade, nearby tissues. They can also spread to other parts of the body through the blood and lymph systems.

[157] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “having,” means “including, but not limited to.”

[158] As used herein, the term “composition” as used herein is intended to encompass a product that includes the specified active product ingredient (API) and pharmaceutically acceptable excipients, carriers or diluents as described herein, such as in specified amounts defined throughout the originally filed disclosure, which results from combination of specific components, such as specified ingredients in the specified amounts as described herein. The terms “formulation”, “composition” and “drug dosage form”, are used interchangeably, except where otherwise clearly intended to have different meanings.

[159] As used herein, the term “disintegrant” refers to a pharmaceutical excipient that is incorporated into a composition to promote their disintegration when they come into contact with a liquid. For example, a disintegrant is a pharmaceutically acceptable agent, used in preparation of tablets, which causes tablets to disintegrate and release medicinal substances on contact with moisture. Examples of disintegrants include, without limitation, crosslinked polymers, including crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), and modified starch sodium starch glycolate and the like. In embodiments of the disclosure, the disintegrant does not include crosslinked polyvinylpyrrolidone (i.e., crospovidone).

[160] As used herein, the term “disintegration” refers to that state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test PROCEDURE apparatus or adhering to the lower surface of the disk, if used, is a soft mass having no palpably firm core.

[161] As used herein, the term “dissolution” means process in which a substance forms a solution. Dissolution testing measures the extent and rate of solution formation from a dosage form, such as tablet, capsule, ointment, etc. The dissolution of a drug is important for its bioavailability and therapeutic effectiveness.

[162] As used herein, the term “drying” is intended to have its usual meaning, as disclosed in e.g. Remington: The Science and Practice of Pharmacy, 19th Edition (1995) or in Handbook of pharmaceutical granulation technology, chapter 7, “Drugs and the pharmaceutical sciences”, vol. 81, 1997; and comprises drying the granulation mixture in a conventional manner either inside or outside the high shear mixing means, such as, but is not limited to, by placing the moist granulation mixture in drying cabinets with circulating air current and thermostatic heat control.

[163] As used herein, the term “effective amount” can be used interchangeably with “therapeutically effective dose,” or “therapeutically effective amount,” and it refers to an amount sufficient to produce the desired effect. [164] As used herein, the term “excipient” means a pharmacologically inactive component useful in preparing a pharmaceutical composition and are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one excipient and more than one excipient.

[165] As used herein, the term “glidanf ’ refers to a substance that is added to a powder to improve its flowability and/or lubricity. Examples of glidants, may include, but is not limited to, magnesium stearate, fumed silica, starch and talc and the like.

[166] As used herein, the terms “patient” or “subject” refers to a living organism suffering from or prone to a condition that can be treated by administration of a pharmaceutical formulation as provided herein. Non-limiting examples include humans, other mammals and other non-mammalian animals.

[167] As used herein, the term “granulation” is intended to have its usual meaning, as disclosed in e.g., Remington: The Science and Practice of Pharmacy, 19th Edition (1995) or in Handbook of pharmaceutical granulation technology, chapter 7, “Drugs and the pharmaceutical sciences”, vol. 81, 1997; and include one or more of dry blending, wet massing, and after granulation.

[168] As used herein, the term “hydrophilic silica” refers to a pharmaceutical excipient that can be employed as flow agent (anti -caking), adsorbent and desiccant in solid product forms. It can also be used to increase the mechanical stability and the disintegration rate of the compositions. The hydrophilic silica can be fumed, i.e., referring to its production through a pyrogenic process to generate fine particles of silica. Particles of fumed silica can vary in size such as from 5 nm to 100 nm, or from 5 to 50 nm. The particles can be non-porous and have a surface area from 50-1,000 m²/g or from 50-600 m²/g. Examples of hydrophilic silicas include Aerosil 200, having a specific surface area of about 200 m²/g.

[169] As used herein, the term “intragranular” refers to a component that is added prior to granulation such that the component is incorporated within the granules. As used herein, the tern “extragranular” refers to a component that is combined with the granules prior to compression, such as in a tablet press. [170] As used herein, the term “lubricant” refers to a substance added to a formulation to reduce friction. Compounds that serve as lubricants can also have properties as glidants. Examples of lubricants may include, but is not limited to, talc, silica, and fats such as vegetable stearin, magnesium stearate or stearic acid and the like.

[171] As used herein, the term “microcrystalline cellulose” refers to chemicals of the formula (C6H10O5)n including a white, free-flowing powder. Microcrystalline cellulose is a commonly used excipient that has excellent compressibility properties and is used in solid dose forms, such as tablets. Tablets can be formed that are hard, but dissolve quickly. Microcrystalline cellulose is the same as cellulose, except that it meets USP standards. Silicified microcrystalline cellulose (SMCC) is a tableting excipient which can improve binding capability as a material and in tablet formulations. The material also shows improved resistance to the degrading effects of magnesium stearate compared with regular microcrystalline cellulose. The MCC can be unmodified or chemically modified, such as silicified microcrystalline cellulose (SMCC). MCC can serve the function of a bulking agent and aid in tablet formation due to its favorable compressibility characteristics.

[172] As used herein, the terms “pharmaceutically or pharmacologically acceptable” refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.

[173] As used herein, the term “pharmaceutically acceptable salt” represents salt forms of an active ingredient that are physiologically suitable for pharmaceutical use. The pharmaceutically acceptable salts can exist in conjunction with talabostat as acid addition primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts. The term also encompasses either salts with inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, mesylic acid, tartaric acid, benzoic acid, methanesulfonic acid, p- toluenesulfonic acid, and the like.

[174] As used herein, the term “related substance” as used herein, is to denote certain process and/or degradation related impurities, which could be formed during manufacture and/or storage of the drug, and during manufacture and/or storage of a pharmaceutical formulation containing the drug.

[175] As used herein, the term “relative retention time” is the ratio of the retention time of analyte peak relative to that of another used as a reference obtained under identical conditions.

[176] As used herein, the term “room temperature stable” means that after three months of storage of the drug dosage form at 25°C and 60% RH, there is no more than 1% of any impurity detected by HPLC.

[177] As used herein, the term “sequential administration” means that two compositions being administered to a subject are administered separated by a time interval sufficient to permit the resultant beneficial effect obtained when each composition exerts its effect. In embodiments, “sequential administration” may mean that compositions are administered with a time separation of more than about 60 minutes; for example, 2 hours apart, 3 hours apart, 4 hours apart, 5 hours apart, 6 hours apart, 7 hours apart, 8 hours apart, 9 hours apart, 10 hours apart, 11 hours apart, or 12 hours apart. In embodiments, the compositions may be administered from about 1 hour to about 24 hours apart.

[178] As used herein, the term “shelf life” means the storage period during which an active agent in a pharmaceutical formulation has minimal degradation (e.g., not more than about 5% degradation) when the pharmaceutical formulation is stored under specified storage conditions, for example, room temperature at normal humidity.

[179] As used herein, the term “silicified microcrystalline cellulose,” or “SMCC,” refers to a particulate agglomerate of co-processed microcrystalline cellulose and silicon dioxide. Suitable for use in the disclosure, SMCC may include amounts from about 0.1% to about 20% silicon dioxide, by weight of the microcrystalline cellulose, where the silicon dioxide can have a particle size from about 1 nanometer (nm) to about 100 microns (pm), based on average primary particle size. For example, the silicon dioxide can contain from about 0.5% to about 10% of the silicified microcrystalline cellulose, or from about 1.25% to about 5% by weight relative to the microcrystalline cellulose. Moreover, the silicon dioxide can have a particle size from about 5 nm to about 40 pm, or from about 5 nm to about 50 pm. The silicon dioxide can have a surface area from about 10 m2/g to about 500 m2/g, or from about 50 m2/g to about 500 m2/g, or from about 175 m2/g to about 350 m2/g. Silicified microcrystalline cellulose is commercially available from a number of suppliers known to one of skill in the art, including Penwest Pharmaceuticals, Inc., under the trademark PROSOLV®. PROSOLV® is available in a number of grades, including, for example, PROSOL V® SMCC 50, PROSOLV® SMCC 90, and PROSOLV® HD. Other products include, without limitation, SMCC 50LD, SMCC HD90 and SMCC 90LM and the like.

[180] As used herein, the term “simultaneous administration” means at the same time or within a short period of time, for example, less than 1 hour, less than 30 minutes, less than 15 minutes, or less than 5 minutes.

[181] 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 comply with the standard stability criteria given in USP compendia.

[182] As used herein, the term “sorbitol” refers to the sugar alcohol D-glucitol and which may serve as a binder promoting adhesion of ingredients in tablet compositions.

[183] As used herein, the term “therapeutically effective amount” refers to an amount of a compound or of a pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. "Therapeutically effective amount" further includes within its meaning a non-toxic but sufficient amount of the particular drug to which it is referring to provide the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as the patient's general health, the patient's age, etc. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 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 Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[184] As used herein, the terms “treat”, “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.

[185] As used herein, the term “tumor” as used herein include an abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should. Tumors may be benign (not cancer) or malignant (cancer). Benign tumors may grow large but do not spread into, or invade, nearby tissues or other parts of the body.

[186] As used herein, the term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals (e.g., dogs), each unit containing a predetermined quantity of active material calculated to produce the desired onset, tolerability, and/or therapeutic effects, in association with a suitable pharmaceutical excipient.

[187] As used herein, the term “wet granulation method” represents a conventional way of making granules and is disclosed in, for example, Remington: The Science and Practice of Pharmacy, 19th Edition (1995) and/or in Handbook of pharmaceutical granulation technology, chapter 7, “Drugs and the pharmaceutical sciences”, vol. 81, 1997. The wet method usually comprises the steps of weighing, mixing, granulation, screening the damp mass, drying, and optionally dry screening, lubrication and compression.

[188] The abbreviation, “(w/w)” refers to the phrase “weight for weight”, i.e., the proportion of a particular substance within a mixture, as measured by weight or mass or a weight amount of a component of the composition disclosed herein relative to the total weight amount of the composition. Accordingly, the quantity is unit less and represents a weight percentage amount of a component relative to the total weight of the composition. For example, a 2% (w/w) solution means 2 grams of solute is dissolved in 100 grams of solution. Active Agent: Talabostat or a Pharmaceutically Acceptable Salt Thereof

[189] Talabostat is referred to interchangeably as PT-100, talabostat (USAN), and [(2R)-I- I [(2S)-2-amino-3-methyl-l-oxobutyl]-2-pyrrolidinyl] boronic acid. Talabostat has a CAS registration number of 149682- 77-9. Talabostat, also known as Val-boro-pro (L-valinyl-L- boroproline), is disclosed in PCT Appl. Publication No. 1989/003223. The IUPAC name of talabostat is [(2R)-1- [(2 S)-2-amino-3 -methylbutanoyl] pyrrolidin-2-yl] boronic acid. Talabostat (PubChem ID: 6918572), or a pharmaceutically acceptable salt thereof, such as, for example, talabostat mesylate (PubChem CID: 1152248). In embodiments, the free base may be used. In embodiments, the talabostat or a pharmaceutically acceptable salt thereof may be a solvate. In most clinical formulations, talabostat is provided as a salt form, (e.g., talabostat mesylate). The pharmaceutically acceptable salts can exist in conjunction with talabostat as acid addition primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts. It also encompasses either salts with inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, mesylic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like. Talabostat has two chiral centers with a R, S configuration. Talabostat or a pharmaceutically acceptable salt thereof can exist as both linear and cyclic forms (RJ Snow et al., J. Am. Chem. Soc., 1994, 116 (24), pp 10860-10869).

[190] Talabostat or a pharmaceutically acceptable salt thereof is effective for the treatment of cancer by modulating multiple intracellular and extracellular dipeptidyl peptidases. More specifically, intracellular and extracellular dipeptidyl peptidases comprise Fibroblast Activation Protein, DPP 8/9, CD26/DPP4 and DPP2. Talabostat or a pharmaceutically acceptable salt thereof has a dual mechanism of action which includes stromal targeted activity via FAP inhibition and targeted immunostimulatory activity via DPP 8/9 inhibition. Talabostat inhibits FAP enzymatic activity thereby suppressing tumor growth. Talabostat or a pharmaceutically acceptable salt thereof also inhibits DPP8/9 thereby inducing an IL ip response (via caspase-1) in the stroma of tumor and lymph nodes. Talabostat’s dual mechanism of action introduces a novel approach to the treatment of cancer because it combines both tumor-targeted and immune-stimulatory activity in a single agent.

Dosage

[191] The amount of talabostat or a pharmaceutically acceptable salt thereof included in the formulation should in general be in the range of about 0.01% to about 10% w/w and preferably in an amount of about 0.1% to about 2% w/w of the total composition weight.

[192] In embodiments, the amount of talabostat or a pharmaceutically acceptable salt thereof present in the formulation, for example a tablet, is about 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, 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) of the composition.

[193] In embodiments, the dosage of talabostat or a pharmaceutically acceptable salt thereof is in the range of between about 0.05 micrograms to about 600 micrograms. Examples of suitable dosages included for example in a tablet include about 0.05 micrograms to about 580 micrograms, about 0.1 micrograms to about 570 micrograms, about 0.5 microgram to about 560 micrograms, about 1 micrograms to about 550 micrograms, about 1 micrograms to about 500 micrograms, 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.

[194] The dose may be administered one or more times a day including twice, three times, four times, five times or six times per day.

[195] In embodiments, talabostat or a pharmaceutically acceptable salt thereof (e.g., talabostat mesylate) is administered in a tablet or capsule in an amount of about 50 micrograms.

[196] In embodiments, talabostat or a pharmaceutically acceptable salt thereof (e.g., talabostat mesylate) is administered in a tablet or capsule in an amount of about 100 micrograms.

[197] In embodiments, talabostat or a pharmaceutically acceptable salt thereof (e.g., talabostat mesylate) is administered in a tablet or capsule in an amount of about 150 micrograms.

[198] In embodiments, talabostat or a pharmaceutically acceptable salt thereof (e.g., talabostat mesylate) is administered in a tablet or capsule in an amount of about 200 micrograms.

[199] In embodiments, talabostat or a pharmaceutically acceptable salt thereof (e.g., talabostat mesylate) is administered in a tablet or capsule in an amount of about 250 micrograms. [200] In embodiments, talabostat or a pharmaceutically acceptable salt thereof (e.g., talabostat mesylate) is administered in a tablet or capsule in an amount of about 300 micrograms.

[201] In embodiments, talabostat or a pharmaceutically acceptable salt thereof (e.g., talabostat mesylate) is administered in a tablet or capsule in an amount of about 350 micrograms.

[202] In embodiments, talabostat or a pharmaceutically acceptable salt thereof (e.g., talabostat mesylate) is administered in a tablet or capsule in an amount of about 400 micrograms.

[203] In embodiments, talabostat or a pharmaceutically acceptable salt thereof (e.g., talabostat mesylate) is administered in a tablet or capsule in an amount of about 450 micrograms.

[204] In embodiments, talabostat or a pharmaceutically acceptable salt thereof (e.g., talabostat mesylate) is administered in a tablet or capsule in an amount of about 500 micrograms.

[205] In embodiments, talabostat or a pharmaceutically acceptable salt thereof (e.g., talabostat mesylate) is administered in a tablet or capsule in an amount of about 550 micrograms.

[206] In embodiments, talabostat or a pharmaceutically acceptable salt thereof (e.g., talabostat mesylate) is administered in a tablet or capsule in an amount of about 600 micrograms.

[207] In embodiments, the formulation comprising talabostat, or a pharmaceutically acceptable salt thereof may be administered orally at a dose of about 200 micrograms twice daily in divided doses. In embodiments, the formulation comprising talabostat, or a pharmaceutically acceptable salt thereof may be administered orally at a dose of about 300 micrograms twice daily in divided doses. In embodiments, the formulation comprising talabostat or a pharmaceutically acceptable salt thereof is orally administered at a dose of about 200 micrograms three times daily in divided doses. In embodiments, the formulation comprising talabostat or a pharmaceutically acceptable salt thereof is administered orally twice daily, such as at a dose of about 400 micrograms in the morning and about 200 micrograms mg in the evening in a 24 hour period.

[208] The dosage of talabostat or a pharmaceutically acceptable salt thereof (e.g., mesylate salt) to be administered to a particular patient may depend on a variety of factors such as the type and extent of the condition, the overall health status of the particular patient, the particular form of talabostat being administered, and the particular formulation used to treat the patient.

Pharmaceutical Formulation

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

Pharmaceutically Acceptable Carriers

[210] Diluents: In accordance with the present disclosure, the formulations as described herein may include at least one filler or diluent. Examples of fillers or diluents of the disclosure include, but not limited to, sugars such as lactose, dextrose, glucose, sucrose, cellulose, starches, modified starches (starches whose hydroxyl groups have been esterified, hydroxypropyl di-starch phosphate, an enzymatically modified starch, hydroxyethyl starch, hydroxypropyl starch) and carbohydrate derivatives, polysaccharides (including dextrates and maltodextrin), pullulan, maltodextrin, isomalt, gums such as acacia, guar, agar, and xanthan, polyols (including mannitol, xylitol, lactitol, and sorbitol), cyclodextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, combinations thereof, and the like. Several types of microcrystalline cellulose may be suitable for use in compositions described herein, for example, microcrystalline cellulose may be selected from, but is not limited to A partially depolymerized cellulose (e.g., MICROCEL®) or purified, partially depolymerized alphacellulose made by acid hydrolysis of specialty wood pulp (e.g., AVICEL®) including types: PH101, PH102, PH103, PH105, PH 112, PHI 13, PH200, PH301, and the like and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. In embodiments, the diluent is microcrystalline cellulose (AVICEL PHI 02). In embodiments, the diluent is microcrystalline cellulose (AVICEL PH101). In embodiments, the diluent is silicified microcrystalline cellulose (SMCC HD90)

[211] In embodiments, the diluents/fillers can be present in an amount of 2 to 99% (w/w) of the formulation. For example, the amount of diluents/fillers present in the formulation may range from about 2% w/w to about 98% w/w, 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, about 20% w/w to about 70% w/w, about 30% w/w to about 90% w/w, about 30% w/w to about 85% w/w and including all the values ranging in between (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). [212] Disintegrants: In embodiments, the disintegrants as used in the present disclosure include, but are not limited to, low- substituted hydroxypropyl cellulose, carboxymethyl starch, natural starch, carboxymethyl starch, sodium starch glycolate, dextrins, and other modified starches (starches whose hydroxyl groups have been esterified, hydroxypropyl distarch phosphate, an enzymatically modified starch, a pregelatinized starch, hydroxyethyl starch, hydroxypropyl starch, a pregelatinized acetylated di-starch phosphate and a pregelatinized purified starch); carboxymethylcellulose calcium, carboxymethylcellulose sodium (or croscarmellose sodium), silicified microcrystalline cellulose, microcrystalline cellulose, cellulose gum and mixtures thereof. In embodiments, the disintegrant is pregelatinized starch. In embodiments, the amount of disintegrant is present in the formulation in the range of 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, 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.

[213] Lubricants: In embodiments, the lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, sodium fumarate stearate, sucrose fatty acid esters, aluminum stearate, potassium sodium tartrate, light silicic anhydride, carnauba wax, carmellose calcium, carmellose sodium, hydrated silicon dioxide, hydrogenated oil, hydrogenated rapeseed oil, and mixtures thereof. In embodiments, the lubricant is magnesium stearate.

[214] 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 amount of lubricant present in the formulation is 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).

[215] Buffers (or pH modifying agents): In embodiments, the buffers include, but are not limited to, inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid), an inorganic base (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide), an organic acid (e.g., 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 an organic base (e.g., ethanolamine, triethanolamine) or mixtures thereof. In embodiments, the buffer may be present in a range from about 0.05% to about 2% w/w of the formulation. For example, the amount of buffer may 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, buffer is present in an amount of 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, 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.

[216] Coating polymers : In embodiments, the formulation includes coating and examples of the moisture barrier coating polymers include cellulose and its derivatives such as ethyl cellulose, hydroxypropylmethyl cellulose, e.g., hypromellose 5cP and hypromellose 15cP, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, waxes; polyvinyl derivatives, such as PVA (polyvinyl alcohol) such as those available under the trademark Opadry AMB, Opadry II, Opadry QX (Kollicoat) or PVP-PVAc copolymer (polyvinylpyrrolidone-polyvinylacetate copolymer) and methacrylic acid polymers, e.g., Eudragit., and the like. In embodiments, the moisture barrier coating is present in an amount of about 2% to about 8% by total weight of the formulation. In embodiments, the coating is present in an amount of about 4% by total weight of the formulation. In embodiments, the amount of moisture barrier coating polymers present in the formulation is 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).

[217] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate, wherein, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[218] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

[219] In embodiments, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and contains nondetectable impurities at RRT 1.06 and 1.16

[220] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, consisting of: (i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

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

[222] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising or consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

[223] In embodiments, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation contains nondetectable impurities at RRT 1.06 and 1.16.

[224] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

[225] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising or consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof; (ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

[226] In embodiments after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains about 96%, about 97%, about 98% or about 99% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and the total amount of impurities is less than 0.5%.

[227] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising or consisting of

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

[228] In embodiments after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains about 96%, about 97%, about 98% or about 99% of the initial amount of talabostat and contains nondetectable impurities at RRT of 1.06 and 1.16.

[229] In embodiments, the formulation retains about 99.5% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and the total amount of impurities is less than 0.2% on storage in a container at room temperature at about 60% relative humidity.

[230] 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 the initial amount of talabostat a pharmaceutically acceptable salt thereof, and the total amount of impurities is less than about 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% on storage in a container at room temperature at about 60% relative humidity. [231] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising/consi sting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate

[232] In embodiments, after six months of storage in a container at temperature of about 2°C to about 8°C, the formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[233] In embodiments, the formulation retains about 96%, about 97%, about 98% or about 99% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 0.5 % after six months storage in a container at about 2°C to about 8°C.

[234] In embodiments, the formulation retains about 98.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is less than 0.2 % after six months storage in a container at about 2 °C to about 8°C.

[235] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising or consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

[236] In embodiments, after one month of storage in a container under accelerated conditions at temperature of 40 °C at about 75% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[237] In embodiments, the present disclosure provides a formulation of talabostat or the pharmaceutically acceptable salt thereof suitable for oral administration, comprising or consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) sodium phosphate monobasic monohydrate;

(v) phosphoric acid,

(vi) pregelatinized starch,

(vii) stearic acid; and

(viii) silicified microcrystalline cellulose.

[238] In embodiments, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and contains nondetectable impurities at RRT of 1.06 and 1.16.

[239] In embodiments, the formulation retains about 96% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is about 0.8%.

[240] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising or consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) sodium phosphate monobasic monohydrate;

(v) phosphoric acid,

(vi) pregelatinized starch;

(vii) stearic acid; and

(viii) silicified microcrystalline cellulose. [241] In embodiments, after six months of storage in a container at a temperature of about 2 to about 8°C, the formulation retains 98% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is less than about 1%.

[242] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising or consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) sodium phosphate monobasic monohydrate;

(v) phosphoric acid,

(vi) pregelatinized starch;

(vii) stearic acid; and

(viii) silicified microcrystalline cellulose.

[243] In embodiments, after six months of storage in a container at a temperature of 2-8°C, the formulation retains 98% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and contains no detectable impurities at RRT of 1.06 and 1.16.

[244] In embodiments, the formulation retains about 99%, about 100%, of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.8% after six months storage in a container at temperature of about 2-8 °C.

[245] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) sodium phosphate monobasic monohydrate;

(v) phosphoric acid;

(vi) pregelatinized starch;

(vii) stearic acid; and (viii) silicified microcrystalline cellulose.

[246] In embodiments, after six months of storage in a container under accelerated conditions at a temperature of 40 °C and at 75% relative humidity, the formulation retains about 90% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is less than about 1%.

[247] In embodiments, the formulation retains about 91%, about 92%, about 93% or about 93.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is about 0.8% after six months storage in a container at temperature of 40°C and about 75% relative humidity.

[248] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises:

(i) talabostat or a pharmaceutically acceptable salt thereof at about 0.1% to about 0.2% w/w;

(ii) silicified microcrystalline cellulose in an amount of about 2% to about 95% wlw,

(iii) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w,

(iv) lactose monohydrate in an amount of 50% to about 95% w/w,

(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.

[249] The formulation of the disclosure may be further coated with one or more functional or non-functional coating layers. Preferably, the formulation is coated with one or more nonfunctional coating layers. The coating layers may comprise one or more film-forming polymers and coating additives. In embodiments, the coating is a moisture barrier film coating. In embodiments, the coating provides a barrier to oxidation.

[250] Examples of film-forming polymers include cellulose and its derivatives such as ethyl cellulose, hydroxypropylmethyl cellulose, e.g., hypromellose 5cP and hypromellose 15cP, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes; and methacrylic acid polymers, e.g., Eudragit., and the like. Alternatively, commercially available coating compositions comprising film-forming polymers including, for example, coating systems which combine a polymer, plasticizer and pigment in a dry concentrate or formulated PVA- based immediate release systems without polyethylene glycol (PEG), which are marketed 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, coloring agents, lubricants, opacifiers, or mixtures thereof.

[251] In embodiments, the plasticizer may be selected from, but are not limited to, triacetin, diethyl phthalate, tributyl sebacate, polyethylene glycol (PEG), glycerin, triacetin, and triethyl citrate. In embodiments, the coating can optionally include an anti-adherent or glidant such as talc, fumed silica, or magnesium stearate.

[252] In embodiments, the coating can optionally include an opacifying agent, such as titanium dioxide.

[253] Coating of the formulation, where appropriate, may be performed using conventional methods and standard equipment.

[254] Coating may be performed by applying the coating composition as a solution/suspension/blend using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor, dip coating, or compression coating.

[255] In embodiments, the moisture barrier coating polymers include cellulose and its derivatives such as ethyl cellulose, hydroxypropylmethyl cellulose, e.g., hypromellose 5cP and hypromellose 15cP, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose 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 copolymer (polyvinylpyrrolidone- polyvinylacetate copolymer) and methacrylic acid polymers, e.g., Eudragit., and the like, preferably Opadry AMB.

[256] In embodiments, the coating comprises Opadry AMB-II Light Blue.

[257] In embodiments, the coating is present in an amount of about 2% to about 8% w/w of the total weight of composition. In embodiments, the coating comprises about 4% /w/w of the total weight of composition. In embodiments, the formulation is coated using an automated coating pan.

[258] In embodiments, solid content during the coating process is about 20%.

[259] In embodiments, the gun to bed distance may range from about 10-15 cm.

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

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

[262] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) sodium phosphate monobasic monohydrate;

(v) phosphoric acid;

(vi) pregelatinized starch;

(vii) stearic acid; and

(viii) silicified microcrystalline cellulose and (ix) a moisture barrier film coat.

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

[264] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate; (iii) microcrystalline cellulose;

(iv) sodium phosphate monobasic monohydrate;

(v) phosphoric acid;

(vi) pregelatinized starch;

(vii) stearic acid;

(viii) silicified microcrystalline cellulose; and

(ix) a moisture barrier film coat.

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

[266] In embodiments, the disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, consisting of

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) sodium phosphate monobasic monohydrate;

(v) phosphoric acid;

(vi) pregelatinized starch;

(vii) stearic acid;

(viii) silicified microcrystalline cellulose; and

(ix) a moisture barrier film coat.

[267] In embodiments, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and contains no detectable impurities at RRT of 1.06 and 1.16

[268] In embodiments, the formulation retains about 96%, about 97%, about 98%, or about 99% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1% on storage in a container at room temperature and about 60% relative humidity. [269] In embodiments, the formulation retains about 98.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.7% on storage in a container at room temperature and about 60% relative humidity.

[270] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) sodium phosphate monobasic monohydrate;

(v) phosphoric acid;

(vi) pregelatinized starch;

(vii) stearic acid;

(viii) silicified microcrystalline cellulose; and

(ix) a moisture barrier film coat.

[271] In embodiments, after six months of storage in a container at a temperature of about 2 to about 8°C, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than about 1%.

[272] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) sodium phosphate monobasic monohydrate;

(v) phosphoric acid;

(vi) pregelatinized starch;

(vii) stearic acid;

(viii) silicified microcrystalline cellulose; and

(ix) a moisture barrier film coat.

[273] In embodiments, after six months of storage in a container at a temperature of about

2 to about 8°C, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and contains no detectable impurities at RRT 1.06 and 1.16.

[274] In embodiments, the formulation retains about 96%, about 97%, about 98% or about 99% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1% on storage in a container at about 2 to about 8°C.

[275] In embodiments, the formulation retains about 99.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.6% on storage in a container at about 2 to about 8°C.

[276] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) sodium phosphate monobasic monohydrate;

(v) phosphoric acid;

(vi) pregelatinized starch;

(vii) stearic acid;

(viii) silicified microcrystalline cellulose; and

(ix) a moisture barrier film coat.

[277] In embodiments, after six months of storage in a container at temperature of 40°C at about 75% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than about 1%.

[278] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) sodium phosphate monobasic monohydrate;

(v) phosphoric acid; (vi) pregelatinized starch;

(vii) stearic acid;

(viii) silicified microcrystalline cellulose; and

(ix) a moisture barrier film coat.

[279] In embodiments, after six months of storage in a container at temperature of 40°C at about 75% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and contains no detectable impurities at RRT 1.06 and 1.16.

[280] In embodiments, the formulation retains about 96%, about 97%, about 98% or about 99% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.7% on storage in a container at temperature of 40° C and about 75% relative humidity.

[281] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises:

(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;

(vii) sodium phosphate monobasic 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) a moisture barrier film coat in an amount of about 2%w/w to about 4%w/w.

[282] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises:

(a) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w; (b) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w; and

(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;

(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 comprises moisture barrier coating at about 2% w/w to about 4% w/w.

[283] In embodiments, the formulation comprises (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises:

(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;

(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 comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w. [284] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises:

(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;

(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 comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w.

[285] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises:

(b) malic acid in an amount of about 0.01% to about 2% w/w; and wherein the extragranular portion comprises:

(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 of 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 comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w. [286] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises:

(iv) lactose monohydrate in an amount of about 50% to about 95% w/w;

(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, wherein the formulation further comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w.

[287] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration comprising (i) talabostat or a pharmaceutically acceptable salt thereof; (ii) silicified microcrystalline cellulose; (iii) sodium phosphate monobasic monohydrate; (iv) phosphoric acid; (v) magnesium stearate, and (vi) moisture barrier film coat.

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

[289] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising (i) talabostat or a pharmaceutically acceptable salt thereof; (ii) silicified microcrystalline cellulose; (iii) sodium phosphate monobasic monohydrate; (iv) phosphoric acid; (v) magnesium stearate, and (vi) moisture barrier film coat.

[290] In embodiments, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and contains no detectable impurities at RRT 1.06 and 1.16.

[291] In embodiments, the formulation retains about 96%, about 96.5%, or about 97% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.8% on storage in a container at room temperature at about 60% relative humidity.

[292] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid;

(v) magnesium stearate; and

(vi) moisture barrier film coat.

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

[294] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid;

(v) magnesium stearate; and

(vi) moisture barrier film coat. [295] In embodiments, after six months of storage in a container at temperature of about 2- 8°C, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and contains no detectable impurities at RRT 1.06 and 1.16.

[296] In embodiments, the formulation retains about 96%, about 96.5%, about 97% or about 97.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is about 0.8% on storage in a container at about 2-8°C.

[297] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid;

(v) magnesium stearate; and

(vi) moisture barrier film coat.

[298] In embodiments, after six months of storage in a container at temperature of 40°C at about 75% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1.5%.

[299] In embodiments, the present disclosure provides a formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid;

(v) magnesium stearate; and

(vi) moisture barrier film coat.

[300] In embodiments, after six months of storage in a container at temperature of 40°C at about 75% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and contains no detectable impurities at RRT 1.06 and 1.16.

[301] In embodiments, the formulation retains about 96%, about 96.5%, or about 97% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is about 1% on storage in a container at temperature of 40°C at about 75% relative humidity.

[302] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises:

(i) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% 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) a moisture barrier film coat in an amount of about 2% w/w to about 4% w/w.

[303] In embodiments, the formulation of talabostat or the pharmaceutically acceptable salt thereof, comprises (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w (b) phosphoric acid in an amount of about 0.5% to about 1% w/w and (c) microcrystalline cellulose in an amount of about 85% to about 99% w/w and the extragranular portion comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w, and (e) magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the formulation further comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w.

[304] In embodiments, the disclosure provides a formulation of talabostat or the pharmaceutically acceptable salt thereof comprises (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w (b) phosphoric acid in an amount of about 0.5% to about 1% w/w and (c) silicified microcrystalline cellulose in an amount of about 25% to about 75% w/w (d) microcrystalline cellulose in an amount of about 25% to about 75% w/w and the extragranular portion comprises: (e) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w and (f) magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the formulation further comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w.

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

[306] In embodiments, the disclosure provides a formulation suitable for oral administration comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w (b) phosphoric acid in an amount of about 0.025% to about 1% w/w and (c) microcrystalline cellulose in an amount of about 85% to about 99% w/w and the extragranular portion comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w (e) magnesium stearate in an amount of about 0.01% to about 5% w/w and (f) optionally pre-gelatinized starch in an amount of about 0.5% to about 5% w/w , wherein the formulation further comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w.

[307] In embodiments, the disclosure provides a formulation suitable for oral administration, comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) potassium dihydrogen phosphate in an amount of about 0.01% to about 2% w/w, (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 comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w and (e) magnesium stearate in an amount of about 0.01% to about 5% w/w.

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

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

[310] It will be appreciated that any given excipient may serve more than one function, for example, as filler/diluent, disintegrant, and lubricant.

[311] Silicified microcrystalline cellulose or SMCC or silicified MCC as available from supplier Dupont/Signet is used in the present disclosure, preferably SMCC HD90. It is a combination of microcrystalline cellulose (MCC) and colloidal silicon dioxide (CSD). The process of silicification leads to the deposition of silicon, presumably in the form of silicon dioxide, both on the outer envelope surface of the particle and on exposed surfaces within the particle. In the present disclosure, SMCC is selected to be added mainly in extra-granular portion during preparation of formulation and provides a disintegration time of about 1-3 minutes. In embodiments, silicified MCC is added in the intragranular portion.

[312] 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, carboxymethyl cellulose calcium, sodium alginate, starches such as corn starch, potato starch, pre-gelatinized and modified starches, microcrystalline cellulose and the like, and combinations thereof.

[313] In embodiments, microcrystalline cellulose (MCC) is used as a filler and binder for wet granulation, direct compression tableting and as a filler for hard gelatin capsules. It has low chemical reactivity combined with excellent compatibility at low pressures. Its limitations include low bulk density, high lubricant sensitivity, poor flow characteristics and the influence of moisture on the compression characteristics. Although 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 a reduced surface area for bonding during compression. In addition, the reduced surface area of large particle size grades makes them more susceptible to the effects of lubricants and they can form poor ordered blends with low particle size drugs. Although no bulk chemical change in the MCC is observed at the resolutions and polymorphic form when microcrystalline cellulose is silicified in the preparation of SMCC 90, SMCC shows improved bulk physical properties and mechanical characteristics.

[314] In embodiments, the amount of microcrystalline cellulose used in the present 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.

[315] In embodiments, the container is a normal HDPE bottle. In embodiments, the container is a multiblock HDPE bottle.

[316] In embodiments, talabostat or a pharmaceutically acceptable salt thereof is talabostat mesylate.

[317] In embodiments, the formulation retains about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof after six months in a container at room temperature and at about 60% relative humidity.

[318] In embodiments, the formulation retains about 98% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof after twelve months in a container at room temperature and about 60% relative humidity.

[319] In embodiments, the formulation retains at least about 95% of the initial amount of talabostat at room temperature at about 60% relative humidity after 3 months, 6 months or 9 months, or preferably 12 months or longer, e.g., 15 months, 18 months, 21 months, 2 years, 2.5 years, 3 years or longer. Preferably the tablet retains at least about 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof after storage at room temperature for such time periods.

[320] 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 embodiments, talabostat mesylate cyclic form is analyzed by a reversed-phase high-pressure liquid chromatography (HPLC) method.

[321] In embodiments, the formulation of talabostat or the pharmaceutically salt thereof has a shelf-life of about 24 months at room temperature.

[322] Stability data prepared at 25±2°C/60±5%RH better reflect the accurate, long-term storage condition of the formulations rather than accelerated storage conditions at 40±2°C/75±5%RH.

[323] Talabostat stability was determined using a reversed-phase high-pressure liquid chromatography (HPLC) method to measure the amount of drug and related substances for peaks later than retention time 2.5 minutes.

[324] In embodiments, the initial amount of talabostat or the 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 micrograms, 100 micrograms, 110 micrograms, 120 micrograms, 130 micrograms, 140 micrograms, 150 micrograms, 160 micrograms, 170 micrograms, 180 micrograms, 190 micrograms, or 200 micrograms. [325] In embodiments, talabostat or the pharmaceutically acceptable salt is present in an amount of about 0.05% to about 1.0% w/w of the total weight of formulation.

[326] In embodiments, talabostat or the pharmaceutically acceptable salt thereof is present in an amount of about 0.05% of the total weight of formulation.

[327] In embodiments, talabostat or the pharmaceutically acceptable salt thereof is present in an amount of about 0.5%w/w of the total weight of formulation.

[328] In embodiments, talabostat or the pharmaceutically acceptable salt thereof is present in an amount of about 0.2% w/w of the total weight of formulation.

[329] In embodiments, talabostat or the 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 talabostat or the pharmaceutically acceptable salt thereof in a unit dose is about 10 micrograms, about 20 micrograms, about 30 micrograms, about 40 micrograms, about 50 micrograms, about 60 micrograms, about 70 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, about 800 micrograms.

[330] In an embodiment, the amount of talabostat or a pharmaceutically acceptable salt thereof in a unit dose is about 600 micrograms. In an embodiment, the amount of talabostat or a pharmaceutically acceptable salt thereof in a unit dose is about 500 micrograms.

[331] In an embodiment, the amount of talabostat or a pharmaceutically acceptable salt thereof in a unit dose is about 400 micrograms. In an embodiment, the amount of talabostat or a pharmaceutically acceptable salt thereof in a unit dose is about 300 micrograms. In another embodiment, the amount of talabostat or the pharmaceutically acceptable salt thereof in a unit dose is about 200 micrograms. In another embodiment, the amount of talabostat or a pharmaceutically acceptable salt thereof in a unit dose is about 50 micrograms. In various embodiments, the talabostat or pharmaceutically acceptable salt there is comprised in a unit dosage form including, but not limited to, a tablet, capsule, or caplet.

[332] In embodiments, the formulation further comprises microcrystalline cellulose; stearic acid; lactose monohydrate, and pregelatinized starch.

[333] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof comprises

(ii) silicified microcrystalline cellulose in an amount of about 85% to about 99% l i,

(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.

[334] In embodiments, the formulation is free of crospovidone.

[335] In embodiments, the formulation is stored in a container that provides moisture barrier. In embodiments, the formulation is stored in a container that provides barrier to oxygen. In embodiments, the formulation is stored in multiblock HDPE bottle containers. In embodiments, the formulation is stored in normal HDPE bottle containers.

[336] In embodiments, the storage container contains desiccant. In embodiments, the desiccant is silica gel. In embodiments, the package contains an additional aluminum pouch. In embodiments, the aluminum pouch provides additional protective barrier and long-term stability at controlled room temperature.

[337] In embodiments, the storage container does not contain desiccant or additional aluminum pouch.

[338] In embodiments, the container is closed with aluminum induction seal and polypropylene cap. [339] In embodiments, the formulation contains not more than 5.0% (w/w) water. In embodiments, the formulation contains not 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 embodiments, the water content of the tablet is determined by Karl Fischer titration, such as Karl Fischer Coulometric Titration Method.

[340] In embodiments, the formulation exhibits loss on drying of 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 0.4% or less.

[341] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof disintegrates in presence of water in less than 5 minutes, for example, 3 minutes or less, 2 minutes or less, 1.5 minutes or less, 1 minute or less to improve ease of administration. In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof disintegrates in about 40 to 60 seconds. In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof disintegrates in about 50 seconds. In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof disintegrates in about 15 to 30 seconds. In embodiments, the disintegration testing is performed by the USP method 701.

[342] Dissolution testing is routinely carried out in the pharmaceutical industry to determine the rate of dissolution of solid dosage forms. In addition to being routinely used by pharmaceutical companies to demonstrate adequate drug release in vivo, in vitro dissolution testing is used to assist with formulation design, process development, and especially the demonstration of batch-to-batch reproducibility in production. Dissolution testing is one of several tests that pharmaceutical companies typically conduct on oral dosage formulations (e.g., tablets, capsules, etc.) to determine compliance and to release products for distribution and sales.

[343] Talabostat converts from linear to cyclic form in neutral and alkaline environment, in order to avoid this conversion, acidic buffer is preferred to include in the formulation.

[344] In embodiment, the pH of the formulation of talabostat or the pharmaceutically acceptable salt is about 2 to about 5. In embodiment, the pH of the formulation of talabostat or the pharmaceutically acceptable salt is about 2, about 2.5, about 3, about 3.5, about 4, about 4.5 or about 5.

[345] The desired pH is adjusted by with O-phosphoric acid although the disclosure contemplates other acids such as citric acid, malic acid, hydrochloric acid, tartaric acid, aspartic acid, glutamic acid, succinic acid or combinations thereof.

[346] In embodiments, the formulation of the disclosure may be a tablet or capsule and vary in shape and be, for example, round, oval, oblong, cylindrical, clover-shaped or any other suitable shape. In embodiments, the tablets are round. The edges of the tablets may be beveled or rounded. In embodiments, the tablets are clover shaped with beveled edges. The tablets may be scored or engraved.

[347] In embodiments, the formulation may have a diameter ranging between 5 and 10 mm (for example a diameter of 5 to 8 mm such as a diameter of 7 mm), and in particular a diameter ranging between 7 and 9 mm. Its thickness is ranging from about 3 to 5 mm, preferably between 3.5 and 4.5 mm. In embodiments, the formulations may have a hardness ranging from about 8 to about 15kP.

[348] In embodiments, the maximum weight loss during friability testing of the formulation is no greater than 1%. As used herein, friability testing refers to the technique described in “Tablet Friability”, Chapter 1216, USP 28, page 2745, incorporated by reference herein.

[349] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt is prepared by any of the processes known to the person having ordinary skill the art of pharmaceutical technology such as direct compression, dry granulation, wet granulation or melt granulation. One process includes dissolving talabostat or a pharmaceutically acceptable salt in a suitable solvent (with or without binder) and this solution is distributed uniformly over filler particles (which may contain lactose monohydrate, microcrystalline cellulose or both) to form agglomerated particles/granules. Granules may be appropriately sized or may be further processed by a dry granulation/slugging/roller compaction method followed by a milling step to achieve suitable granules of specific particle size distribution. The sized granules may be further blended with other components and/or and then lubricated in a suitable blender.. Wet granulation, coating or spraying processes can also be used. [350] In embodiments, silicified microcrystalline cellulose, acidic buffer and magnesium stearate are dry blended in in rapid mixer granulator and compressed. In embodiments, the buffer is coated onto microcrystalline cellulose and buffer coated microcrystalline cellulose is used for direct compression. In embodiments, talabostat or a pharmaceutically acceptable salt and silicified microcrystalline cellulose are co-sifted and directly blended in RMG. In embodiments, the resulting blend is lubricated and directly compressed in the same RMG.

[351] In accordance with the present disclosure, the compositions as described herein may include at least one filler in any amount adapted for use in the present disclosure. In embodiments, the composition of the present disclosure may comprise, but is not limited to one or more of alpha cellulose, beta cellulose, gamma cellulose, starch, modified-starch, sorbitol, mannitol, lactose, dextrose, sucrose, dibasic calcium phosphate, tribasic calcium phosphate, or calcium carbonate and the like.

[352] In embodiments, [0001] representative fillers for use in the compositions of the disclosure may include, but are not limited to, starch, lactitol, lactose, an inorganic calcium salt (e.g. calcium phosphate), microcrystalline cellulose, sucrose, combinations thereof and the like. Additional fillers or diluents for use in the compositions of the disclosure, may include, but are not limited to fillers or diluents conventionally known in the art, i.e., which are typically used in 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, starches and carbohydrate derivatives, polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, combinations thereof, and the like. In embodiments, such fillers or diluents suitable for use in the disclosure may include, but are not limited to, lactose, microcrystalline cellulose, combinations thereof and the like. Several types of microcrystalline cellulose may be suitable for use in compositions described herein, for example, microcrystalline cellulose includes, but is not limited to, MICROCEL® or AVICEL® types: PH101, PH102, PH103, PH105, PH 112, PHI 13, 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 disclosure may include microcrystalline cellulose (AVICEL PHI 02). In another aspect, a filler suitable for use in the disclosure may include microcrystalline cellulose (AVICEL PH101).

[353] In embodiments, the composition further can include microcrystalline cellulose. In embodiments, the composition further can include a silicified microcrystalline cellulose. In embodiments, the composition further can include one or more of alpha cellulose, beta cellulose, gamma cellulose, starch, modified-starch, sorbitol, mannitol, lactose, dextrose, sucrose, dibasic calcium phosphate, tribasic calcium phosphate, or calcium carbonate. In embodiments, the composition further can include mannitol. In embodiments, the composition further can include sorbitol.

[354] In embodiments, the microcrystalline cellulose can be present in the internal phase of the composition in an amount of 2 to 95% (w/w) of the composition. In embodiments, the disintegrants as used in the present disclosure include, but are not limited to, low-substituted hydroxypropyl cellulose, carboxymethyl starch, natural starch, carboxymethyl starch, sodium starch glycolate, dextrins, and other modified starches (starches whose hydroxyl groups have been esterified, hydroxypropyl di-starch phosphate, an enzymatically modified starch, a pregelatinized di-starch phosphate, hydroxyethyl starch, hydroxypropyl starch, a pregelatinized acetylated di-starch phosphate and a pregelatinized purified starch); carboxymethylcellulose calcium, carboxymethylcellulose sodium (or croscarmellose sodium), silicified microcrystalline cellulose, microcrystalline cellulose, cellulose gum and mixtures thereof. In embodiments, the amount of disintegrant is present in the formulation in the range of about 2% to about 95% w/w.

[355] In embodiments, the amount of disintegrant present in the formulation is 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 about 95 % (w/w).

[356] In embodiments, the diluents/fillers include, but are not limited to, gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; and polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes, 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 silicates; and amino acids having from 2 to 12 carbon atoms such as a 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).

[357] In embodiments, the binders include, but are not limited to, starch, pregelatinized starch, polyethylene oxide, polyethylene glycol, acacia, alginic acid, tragacanth, sucrose, guar gum, bentonite, cellulose derivatives, such as hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts; and mixtures thereof.

[358] In embodiments, the lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, sodium fumarate stearate, sucrose fatty acid esters, aluminum stearate, potassium sodium tartrate, light silicic anhydride, carnauba wax, carmellose calcium, carmellose sodium, hydrated silicon dioxide, 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 amount of lubricant present in the formulation is 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).

[359] In embodiments, the moisture barrier coating polymers include cellulose and its derivatives such as ethyl cellulose, hydroxypropylmethyl cellulose, e.g., hypromellose 5cP and hypromellose 15cP, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, waxes; polyvinyl derivatives, such as PVA (polyvinyl alcohol) such as those available under the trademark Opadry AMB, Opadry II, Opadry QX (Kollicoat) or PVP-PVAc copolymer (polyvinylpyrrolidone-polyvinylacetate copolymer) and methacrylic acid polymers, e.g., Eudragit., and the like. In embodiments, the moisture barrier coating is present in an amount of about 2% to about 8% by total weight of the formulation. In embodiments, the coating is present in an amount of about 4% by total weight of the formulation. In embodiments, the amount of moisture barrier coating polymers present in the formulation is 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).

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

[361] In embodiments, the granulating liquid is water, ethanol, isopropanol, methylene chloride alone or in combination. In embodiments, the granulating liquid is an acidic solution of sodium phosphate in water. In embodiments, the acidic solution is prepared by dissolving sodium phosphate in water and adjusting pH to 2-2.5 with O-phosphoric acid. In embodiments, the volume of granulating fluid used for wet granulation is about 30 mL. In embodiments, the volume of granulating fluid used for wet granulation is about 70 mL. In embodiments, the volume of granulating fluid used for wet granulation is about 10, 20, 30, 40, 50, 60, 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.

[362] Exemplary non-limiting formulations of the invention are illustrated below in exemplary Formulation A and exemplary Formulation B:

Exemplary Formulation A

Exemplary Formulation B

Process of The Preparation of Talabostat Formulations

[363] In embodiments, the present disclosure provides a process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(i) sifting the required quantity of all excipients selected from one or more of diluents, binders, and disintegrants;

(ii) preparing a uniform mixture of a diluent (such as lactose) and a disintegrant (such as microcrystalline cellulose);

(iii) dissolving sodium phosphate in sufficient quantity of water and adjusting to required acidic pH using phosphoric acid to form a buffer solution,

(iv) adding talabostat or a pharmaceutically acceptable salt thereof into above buffer solution; (v) granulating the mixture of step (ii) with solution of step (iv) to obtain a wet mass;

(vi) drying and screening the wet mass to obtain granules;

(vii) optionally blending the granules of step (vi) with remaining excipient(s) selected from pregelatinized starch and stearic acid,

(viii) lubricating the blend and (ix) optionally coating with a moisture barrier film coat.

[364] In embodiments, the disclosure provides a process of preparing a formulation comprising talabostat or a pharmaceutically acceptable salt thereof, comprising:

(ii) preparing an acidic buffer solution;

(iii) adding silicified microcrystalline cellulose in step (ii) and granulating the solution;

(iv) drying the granules and co-sifting with talabostat or a pharmaceutically acceptable salt thereof extragranularly,

(v) optionally blending with one or more extra-granular excipients,

(vi) lubricating the blend and

(vii) optionally coating with a film-coat.

[365] In embodiments, the present disclosure provides a process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(ii) adding silicified microcrystalline cellulose to above buffer solution;

(iii) granulating the solution followed by drying the granules;

(iv) blending with talabostat or a pharmaceutically acceptable salt thereof extragranularly;

(v) optionally lubricating the blend with magnesium stearate; and (vi) optionally coating with a film-coat.

[366] In embodiments, the disclosure provides a process of preparing formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(ii) adding drug talabostat or a pharmaceutically acceptable salt thereof into above solution and granulating the solution;

(iii) drying the granules and blending with pregelatinized starch and silicified microcrystalline cellulose;

(iv) lubricating the blend; and

(v) optionally coating with a film coat.

[367] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof is prepared by any of the known processes including direct compression, dry granulation or wet granulation. In embodiments, silicified microcrystalline cellulose, acidic buffer and magnesium stearate are dry blended in in rapid mixer granulator and compressed. In embodiments, the buffer is coated onto microcrystalline cellulose and buffer coated microcrystalline cellulose is used for direct compression.

[368] In embodiments, talabostat or a pharmaceutically acceptable salt thereof is added extra-granularly in wet granulation process. In embodiments, silicified microcrystalline cellulose is granulated with acidic buffer and then acidified silicified microcrystalline cellulose is blended with talabostat or a pharmaceutically acceptable salt thereof.

[369] In embodiments, talabostat or a pharmaceutically acceptable salt thereof is dissolved in acidic buffer solution to form a granulation fluid. In embodiments, a blend of lactose monohydrate and microcrystalline cellulose is formed into granules using said granulation fluid.

[370] In embodiments, the disclosure provides a dry formulation process for preparing the formulation of talabostat or a pharmaceutically acceptable salt thereof, which includes mixing talabostat or a pharmaceutically acceptable salt thereof with one or more excipients selected from silicified microcrystalline cellulose, sodium phosphate, phosphoric acid, magnesium stearate, in the absence of added water.

[371] In embodiments, the drying temperature of granules in fluidized bed drier (FBD) is in the range of about 35°C to about 60°C. In embodiments, the manufacturing process does not involve milling step. In embodiments, the manufacturing process involves milling/screening step.

[372] In embodiments, the talabostat or a pharmaceutically acceptable salt is added extra granularly in wet granulation process. In embodiments, silicified microcrystalline cellulose is granulated with acidic buffer and then acidified silicified microcrystalline cellulose is blended with talabostat or a pharmaceutically acceptable salt thereof.

[373] In embodiments, talabostat or a pharmaceutically acceptable salt is dissolved in acidic buffer solution to form a granulation fluid. In embodiments, a blend of lactose monohydrate and microcrystalline cellulose is granulated with said granulation fluid.

[374] In embodiments, the disclosure provides a process of preparing the formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(ii) adding talabostat or a pharmaceutically acceptable salt into above solution and granulating the solution;

(iv) lubricating the blend and

(v) optionally coating with a moisture barrier film coat.

[375] In embodiments, the disclosure provides a process of preparing formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(ii) adding silicified microcrystalline cellulose to above buffer solution;

(iii) granulating the solution followed by drying the granules; (iv) blending with talabostat or a pharmaceutically acceptable salt thereof extragranularly;

(v) optionally lubricating the blend with magnesium stearate; and

(vi) optionally coating with a moisture barrier film-coat.

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

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

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

[379] In embodiments, magnesium stearate is added at about 0.01% to about 5% w/w during the process.

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

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

[382] In embodiment, the disclosure provides a process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof as shown in Fig. 1.

[383] In embodiments, the disclosure provides a process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof as shown in Fig. 2.

[384] In embodiments, the disclosure provides a process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof as shown in Fig. 3.

[385] In embodiments, the disclosure provides a process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof as shown in Fig. 4.

[386] In embodiments, the disclosure provides a process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof as shown in Fig. 5.

[387] In embodiments, the disclosure provides a process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof as shown in Fig. 6. [388] The stability of the pharmaceutical composition may be tested in conventional manner, e.g., by measurement of talabostat and its degradation products, dissolution, cyclic content, disintegration time, water content, appearance and/or microscopy, e.g., after storage at 25° C. and 60% relative humidity, storage at 2-8°C and/or storage at 40° C. and 75% relative humidity for defined periods of time.

[389] The formulation to be tested may be divided into one or more different batches and stored under typical storage conditions, for example, 4° C. (refrigerator) or 25° C. (room temperature). Degradation of the drug in a pharmaceutical formulation can also be detected using accelerated testing under exaggerated storage conditions designed to increase the degradation rate of the drug substance. For example, a batch can be “stressed” (placed in chamber which maintains a temperature of 45° C. and 75% humidity). Samples of each batch of formulation are then analyzed at different time points (e.g., time zero, 1 month, 3 months, 6 months, for amount of drug still present in the formulation. Analysis of the drug in the formulation may be carried out by a variety of detection methods including high performance liquid chromatography, crystal or powder X-ray diffraction, infrared or Raman spectra studies, microscopy, differential scanning calorimetry, thermal gravimetric analysis, hot- stage microscopy, and solid state nuclear magnetic resonance.

[390] In various embodiments, the disclosure further contemplates all stable solid formulations for oral administration, e.g., tablets, capsules, pills or troches, with similar stability properties.

Methods of Treatment

[391] In embodiments, the present disclosure provides a method of treating cancer in a subject, comprising orally administering the formulation of talabostat or a pharmaceutically acceptable salt thereof.

[392] In embodiments, the formulation comprising talabostat, or a pharmaceutically acceptable salt thereof is orally administered at a dose of about 300 micrograms twice daily. In embodiments, the formulation comprising talabostat or a pharmaceutically acceptable salt thereof is orally administered at a dose of about 200 micrograms twice daily. In embodiments, the formulation comprising talabostat or a pharmaceutically acceptable salt thereof is orally administered at a dose of about 200 micrograms thrice daily in divided doses. In embodiments, the formulation comprising talabostat or a pharmaceutically acceptable salt thereof is administered orally twice daily, such as at a dose of about 400 micrograms in the morning and about 200 micrograms in the evening in a day.

[393] In embodiments, the formulation comprising talabostat, or a pharmaceutically acceptable salt thereof is orally administered at a dose of about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, or about 600 micrograms once daily. In embodiments, the formulation comprising talabostat, or a pharmaceutically acceptable salt thereof is orally administered at a dose of about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, or about 600 micrograms twice daily.

[394] In embodiments, the formulation comprising talabostat, or a pharmaceutically acceptable salt thereof is orally administered at a dose of about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, or about 600 micrograms three times daily.

[395] In embodiments, the formulation comprising talabostat, or a pharmaceutically acceptable salt thereof is orally administered at a dose of about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, or about 600 micrograms four times daily.

[396] The formulations of the disclosure may be used alone or in conjunction with other therapies suitable for the cancer to be treated and other clinical symptoms.

[397] In embodiments, the present disclosure provides a method of treating cancer in a subject by orally administering the formulation comprising effective amount of talabostat or a pharmaceutically acceptable salt thereof and additional active agent in a suitable unit dosage form to be administered simultaneously or sequentially separated by an appropriate period of time.

[398] In embodiments, the formulation of talabostat or a pharmaceutically acceptable salt thereof additionally comprises another active agent in same dosage form. In embodiments, the additional active agent is present in a different dosage form, that may be tablet, capsule, granules, minitablets and the like for oral administration. [399] In embodiments, “simultaneous administration” means at the same time or within a short period of time, usually less than 1 hour.

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

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

[402] Preferred cancers whose growth may be inhibited using the stable tablet formulation of present disclosure include cancers typically responsive 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, urogenital cancer, acute myeloid leukemia, breast cancer, chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma; myelodysplastic syndromes; ovarian cancer; uveal melanoma, colorectal cancer, hematological malignancies, non-Hodgkin’s lymphoma, chronic myeloid leukemia and glioma.

[403] 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 (e.g., non-small cell lung cancer, small cell lung cancer), gastric cancer, myelodysplastic syndromes; esophageal cancer; ovarian cancer; urogenital cancer; uveal melanoma, adrenal cancer; liver cancer.

[404] In embodiments, the cancer is a solid tumor. In some embodiments, the cancer is urogenital cancers (such as prostate cancer, renal cell cancer, bladder cancer), thyroid cancer, testicular cancer, vulvar cancer, Wilms’ tumor, hormone sensitive or hormone refractory prostate cancer, gynecological cancers (such as ovarian cancer, cervical cancer, endometrial cancer, uterine cancer), lung cancer, non-small cell lung cancer, small cell lung cancer, gastrointestinal stromal cancers, gastrointestinal cancers (such as non-metastatic or metastatic colorectal cancers, pancreatic cancer, gastric cancer, esophageal cancer, hepatocellular cancer, cholangiocellular cancer), 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 sarcomas, oral squamous cell carcinoma, glioblastoma, brain cancer, osteosarcoma, neuroblastoma, advanced metastatic, an inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, cystadenocarcionoma, ameloblastoma, chondrosarcoma, dermatofibrosarcoma, ganglioglioma, leiomyosarcoma, medulloblastomma, osteoblastoma and inoperable noninflammatory locally advanced disease and the like. The most preferred cancer is solid tumor (such as pancreatic cancer, colorectal cancer, ovarian cancer, lung cancer, breast cancer, glioblastoma, gastric cancer, astroglial, neuroectodermal tumors, head and neck cancer, triple negative breast cancer, gastroesophageal cancer, non-small cell lung cancer and the like) or hematopoietic cancer (leukemia, lymphoma, a lymphocytic leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, an anaplastic large-cell lymphoma, myeloid leukemia, multiple myeloma, acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia).

[405] In embodiments, the cancers whose growth may be inhibited include virally associated cancers include, but are not limited to, cancers associated with Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma viruses (HPV), human T lymphotropic virus type 1 (HTLV-1), human T lymphotropic type 2 (HTLV-2) and human herpesvirus, such as human herpesvirus 8 (HHV-8). The cancers associated with particular viruses are known to those of ordinary skill in the art. For example, EBV- associated cancers include, but are not limited to, lymphomas, nasopharyngeal cancer, gastric carcinoma, parotid carcinoma, breast carcinoma, and leiomyosarcoma. Examples of cancers associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) include but are not limited to cancers of the liver. Examples of cancers associated with human papilloma viruses (HPV) include, but are not limited to, oropharyngeal head and neck cancer, nasopharyngeal head and neck cancer, and cancers of the cervix, vulva, vagina, penis and anus. Examples of cancers associated with human T lymphotropic virus type 1 (HTLV-1) and 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 virally associated cancer is a cancer associated with HPV. In embodiments, the virally associated cancer is a cancer associated with HCV.

Kits

[406] In embodiments, the kit comprises a formulation of talabostat or a pharmaceutically acceptable salt thereof and a package insert comprising instructions for using the formulation to treat or delay progression of cancer in a subject or to enhance immune function of a subject having cancer.

[407] In embodiments, the kit comprises a container containing talabostat or a pharmaceutically acceptable salt thereof. The container may include bottles that are formed from a variety of materials such as glass or plastic. The bottle may be normal HDPE or multiblock HDPE. In some embodiments, the kit may comprise a label (e.g., on or associated with the container) or a package insert. The label or the package insert may indicate that the compound contained therein may be useful or intended for treating or delaying progression of cancer in a subject or for enhancing immune function of a subject having cancer

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

[409] As used herein, a desiccant is a material that absorbs moisture by physical and/or chemical means. Activated desiccants are desiccants that have been treated by heating and ventilating, or by other means, to develop an internal surface on which moisture and certain vapors or gases may be collected. Examples of the desiccant to be used in the present disclosure include activated carbon, calcium chloride, metallic oxide, such as an alkaline earth metallic oxide (e.g. calcium oxide (CaO) etc.), an alkaline earth metallic hydroxide (e.g. calcium hydroxide etc.), sulfate of an alkaline earth metal (e.g. magnesium sulfate, calcium sulfate etc.), silicon dioxide (silica gel), a bonded product of alumina oxide and silicon dioxide (silica alumina), alumina oxide (active alumina), natural or synthetic zeolite (molecular sieves 3 A, 4A, SA, 13X), allophane, clay, a mixture of clay and activated carbon, a mixture of silica gel and activated carbon, a mixture of silica gel and clay, a mixture of silica alumina and activated carbon, a mixture of synthetic zeolite and activated carbon, a mixture of allophane and activated carbon (e.g., allophane added with activated carbon, or allophane kneaded with activated carbon etc.), pulp containing silica gel (e.g., ultrafine silica gel mixed between paper fibers, silica gel packaged in paper tube etc.), pulp containing calcium chloride (e.g., paper material impregnated with liquid calcium chloride, dried and coated with film etc.), pulp containing allophane (e.g., pulp impregnated with allophane liquid, dried and film coated, allophane packaged in paper tube etc.) and the like. The quantity of desiccant in an ideal case should be at least sufficient to absorb this moisture and maintain a desiccated environment within the package for the products shelf life.

[410] In embodiments, the present disclosure is directed to kits which comprise a formulation comprising talabostat or a pharmaceutically acceptable salt thereof and an additional active agent. In embodiments, the additional active agent is contained in a second composition. In embodiments, the talabostat formulation and second compositions, may be administered either simultaneously or sequentially (i.e., spaced out over a period of time) so as to obtain the maximum efficacy.

Exemplary Embodiments

[411] Embodiment 1. A formulation of talabostat suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

[412] Embodiment 2. The formulation of embodiment 1, wherein after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is less than 1%.

[413] Embodiment 3. A formulation of talabostat suitable for oral administration, consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate;

[414] Embodiment 4. The formulation of embodiment 3, wherein, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is less than 1%.

[415] Embodiments. The formulation of any of embodiments 1 to 4, wherein the formulation retains about 96%, about 97%, about 98% or about 99% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and the total amount of impurities is less than 0.5%.

[416] Embodiment 6. The formulation of any of embodiments Ito 4, wherein the formulation retains about 99.5% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and the total amount of impurities is less than 0.2%.

[417] Embodiment 7. The formulation of any of embodiments 1 to 4, wherein the formulation retains about 98% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof after twelve months in a container at room temperature and about 60% relative humidity.

[418] Embodiment 8. The formulation of any of embodiments 1 to 7, wherein the formulation contains nondetectable impurities at relative retention time (RRT) of 1.06 and 1.16.

[419] Embodiment 9. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising/consisting of:

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

[420] Embodiment 10. The formulation of embodiment 9, wherein after six months of storage in a container under long term conditions at about 2 to about 8°C, the formulation retains about 98% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof; and total amount of impurities is less than 0.5%.

[421] Embodiment 11. The formulation of embodiment 9, wherein the formulation contains nondetectable impurities at relative retention time (RRT) of 1.06 and 1.16.

[422] Embodiment 12. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising/consisting of

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid; and

(v) magnesium stearate.

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

[424] Embodiment 14. The formulation of embodiment 12, wherein the formulation contains nondetectable impurities at relative retention time (RRT) of 1.06 and 1.16.

[425] Embodiment 15. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration comprises:

(i) silicified microcrystalline cellulose in an amount of about 85% to about 99% l i,

(ii) sodium phosphate monobasic monohydrate in an amount of 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.

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

[427] Embodiment 17. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose,

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate; and

(viii) phosphoric acid.

[428] Embodiment 18. The formulation of embodiment 17, wherein, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is less than 1%.

[429] Embodiment 19. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose,

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate; and

(viii) phosphoric acid.

[430] Embodiment 20. The formulation of embodiment 19, wherein, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is less than 1%.

[431] Embodiment 21. The formulation of any of embodiments 17 to 19, wherein the formulation contains nondetectable impurities at relative retention time (RRT) of 1.06 and 1.16

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

[433] Embodiment 23. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising or consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose,

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate; and

(viii) phosphoric acid.

[434] Embodiment 24. The formulation of embodiment 23, wherein, after six months of storage in a container at 2-8°C, the formulation retains at least about 98% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and total amount of impurities is less than 1%.

[435] Embodiment 25. The formulation of embodiment 23, wherein the formulation retains about 100.9% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is 0.8%.

[436] Embodiment 26. The formulation of any of embodiments 23 to 25, wherein the formulation contains nondetectable impurities at relative retention time (RRT) of 1.06 and 1.16.

[437] Embodiment 27. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising/ consisting of: (i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose,

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate; and

(viii) phosphoric acid,

[438] Embodiment 28. The formulation of embodiment 27, wherein, after six months of storage in a container at a temperature of 40°C and about 75% relative humidity, retains at least about 90% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is less than 1%.

[439] Embodiment 29. The formulation of embodiment 23 or 24, wherein the formulation retains about 93% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is 0.8%.

[440] Embodiment 30. The formulation of any of embodiment 27 to 29, wherein the formulation contains nondetectable impurities at relative retention time (RRT) of 1.06 and 1.16.

[441] Embodiment 31. The formulation of any of embodiments 17 to 30, wherein the formulation comprises:

(i) silicified microcrystalline cellulose in an amount of about 2% to about 95% w/w;

(ii) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w;

(iii) lactose monohydrate in an amount of about 50% to about 95% w/w;

(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. [442] Embodiment 32. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose;

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate;

(viii) phosphoric acid; and

(ix) a moisture barrier film coat.

[443] Embodiment 33. The formulation of embodiment 32, wherein after six months storage in a container at room temperature and about 60% relative humidity, the formulation retains at least about 95% of the initial amount of Talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[444] Embodiment 34. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose,

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate;

(viii) phosphoric acid; and

(ix) a moisture barrier film coat.

[445] Embodiment 35. The formulation of embodiment 34, wherein after six months storage in a container at room temperature and about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and total amount of impurities is less than 1 %. [446] Embodiment 36. The formulation of any of embodiment 32 to 35, wherein the formulation retains about 98.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is 0.7%.

[447] Embodiment 37. The formulation of any of embodiments 32 to 36, wherein the formulation contains nondetectable impurities at relative retention time (RRT) of 1.06 and 1.16

[448] Embodiment 38. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate;

(iii) microcrystalline cellulose,

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate;

(viii) phosphoric acid; and

(ix) a moisture barrier film coat.

[449] Embodiment 39. The formulation of embodiment 38, wherein after six months storage in a container at 2-8°C, the formulation retains about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and total amount of impurities is less than 1%.

[450] Embodiment 40. The formulation of embodiment 38 or 39, wherein the formulation retains about 99.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is 0.6%.

[451] Embodiment 41. The formulation of embodiment 38 to 40, wherein the formulation contains nondetectable impurities at relative retention time (RRT) of 1.06 and 1.16

[452] Embodiment 42. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) lactose monohydrate; (iii) microcrystalline cellulose,

(iv) pregelatinized starch;

(v) stearic acid;

(vi) silicified microcrystalline cellulose;

(vii) sodium phosphate monobasic monohydrate;

(viii) phosphoric acid; and

(ix) a moisture barrier film coat.

[453] Embodiment 43. The formulation of embodiment 42, wherein after six months storage in a container at temperature of 40°C and about 75% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and total amount of impurities is less than 1%.

[454] Embodiment 44 The formulation of embodiment 42 or 43, wherein the formulation retains about 98% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and the total amount of impurities is 0.7%

[455] Embodiment 45. The formulation according to any of embodiment 42 to 44, wherein the formulation contains nondetectable impurities at relative retention time (RRT) of 1.06 and 1.16.

[456] Embodiment 46. The formulation according to any of embodiments 32 to 45, comprises:

(ii) lactose monohydrate at about 50% to about 95% w/w;

(iii) microcrystalline cellulose at about 5% to about 95% w/w;

(iv) pregelatinized starch at about 0.05% to about 10% w/w,

(v) stearic acid at about 0.05% to about 2% w/w;

(vi) silicified microcrystalline cellulose at about 2% to about 95% w/w;

(vii) sodium phosphate monobasic monohydrate at about 0.01% to about 2% w/w;

(viii) phosphoric acid at about 0.005% to about 0.1% w/w; and

(ix) a moisture barrier film coat at about 2%w/w to about 4% w/w.

[457] Embodiment 47. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising: (i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid;

(v) magnesium stearate; and

(vi) a moisture barrier film coat.

[458] Embodiment 48. The formulation of embodiment 47, wherein, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[459] Embodiment 49. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, consisting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid;

(v) magnesium stearate; and

(vi) a moisture barrier film coat.

[460] Embodiment 50. The formulation of embodiment 49, wherein, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and the total amount of impurities is less than 1%

[461] Embodiment 51. The formulation of any of embodiment 47 to 50, wherein the formulation retains at about 97% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and the total amount of impurities is 0.8%

[462] Embodiment 52. The formulation of any of embodiments 47 to 51, wherein the formulation contains nondetectable impurities at relative retention time (RRT) of 1.06 and 1.16.

[463] Embodiment 53. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising/consi sting of: (i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid;

(v) magnesium stearate; and

(vi) a moisture barrier film coat.

[464] Embodiment 54. The formulation of embodiment 53, wherein, after six months of storage in a container at temperature of 2-8°C, the formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

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

[466] Embodiment 56. The formulation of any of embodiments 53 to 55, wherein the formulation contains nondetectable impurities at relative retention time (RRT) of 1.06 and 1.16.

[467] Embodiment 57. A formulation of talabostat or a pharmaceutically acceptable salt thereof suitable for oral administration, comprising/consi sting of:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid;

(v) magnesium stearate; and

(vi) a moisture barrier film coat.

[468] Embodiment 58. The formulation of embodiment 57, wherein, after six months of storage in a container at temperature of 40°C at about 75% relative humidity, the formulation retains at least about 96% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1.5%. [469] Embodiment 59. The formulation of embodiment 57 or 58, wherein the formulation retains about 97% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is 1%.

[470] Embodiment 60. The formulation of any of embodiments 57 to 59, wherein the formulation contains nondetectable impurities at relative retention time (RRT) of 1.06 and 1.16.

[471] Embodiment 61. The formulation of any of embodiments 47 to 60, comprises:

(ii) silicified microcrystalline cellulose at about 2% to about 95% w/w;

(iii) sodium phosphate monobasic monohydrate at about 0.01% to about 2% w/w;

(iv) phosphoric acid at about 0.005% to about 0.1% w/w;

(v) magnesium stearate at about 0.01% to about 5% w/w, preferably about 0.05% to about 2% w/w; and

(vi) a moisture barrier film coat at about 2% w/w to about 4% w/w.

[472] Embodiment 62. The formulation of any of embodiments 32 to 61, wherein the moisture barrier coating comprises cellulose and its derivatives such as ethyl cellulose, hydroxypropylmethyl cellulose, e.g., hypromellose 5cP and hypromellose 15cP, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes; polyvinyl derivatives, such as PVA (polyvinyl alcohol) such as those available under the trademark Opadry AMB, Opadry II, Opadry QX (Kollicoat) or PVP-PVAc copolymer (polyvinylpyrrolidone-polyvinylacetate copolymer) and methacrylic acid polymers, e.g., Eudragit., and the like.

[473] Embodiment 63. The formulation of embodiment 62, wherein the moisture barrier coating comprises PVA based polymer, preferably Opadry AMB blue light.

[474] Embodiment 64. The formulation of any of embodiments 1 to 63, wherein the formulation is free of crospovidone. [475] Embodiment 65. A formulation suitable for oral administration comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic monohydrate at about 0.01% to about 2% w/w (b) phosphoric acid at about 0.005% to about 0.1% w/w and (c) silicified microcrystalline cellulose at about 85% to about 99% w/w and the extragranular portion comprises: (d) talabostat or a pharmaceutically acceptable salt thereof at about 0.1% to about 0.2% w/w and (e) magnesium stearate at about 0.01% to about 5% w/w.

[476] Embodiment 66. The formulation of embodiment 65, wherein, after six months of storage in a container at room temperature at about 60% relative humidity, the stable tablet formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[477] Embodiment 67. A formulation suitable for oral administration comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic 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) silicified microcrystalline cellulose at about 85% to about 99% w/w and the extragranular portion comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w and (e) magnesium stearate in an amount of about 0.01% to about 5% w/w.

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

[479] Embodiment 69. The formulation of any of embodiments 65 to 68, wherein the formulation contains nondetectable impurities at RRT 1.06 and 1.16.

[480] Embodiment 70. A formulation of talabostat or the pharmaceutically acceptable salt thereof, comprises (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w (b) phosphoric acid in an amount of about 0.5% to about 1% w/w and (c) microcrystalline cellulose in an amount of about 85% to about 99% w/w and the extragranular portion comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w and (e) magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the formulation further comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w.

[481] Embodiment 71. A formulation of talabostat or the pharmaceutically acceptable salt thereof comprises (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w (b) phosphoric acid in an amount of about 0.5% to about 1% w/w and (c) silicified microcrystalline cellulose in an amount of about 25% to about 75% w/w (d) microcrystalline cellulose in an amount of about 25% to about 75% w/w and the extragranular portion comprises: (e) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w and (f) magnesium stearate in an amount of about 0.01% to about 5% w/w, wherein the formulation further comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w.

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

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

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

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

[486] Embodiment 76. A formulation suitable for oral administration, comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic monohydrate in an amount of about 0.01% to about 2% w/w (b) phosphoric acid in an amount of about 0.025% to about 1% w/w and (c) microcrystalline cellulose in an amount of about 85% to about 99% w/w and the extragranular portion comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w (e) magnesium stearate in an amount of about 0.01% to about 5% w/w and (f) optionally pre-gelatinized starch in an amount of about 0.5% to about 5% w/w, wherein the formulation further comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w.

[487] Embodiment 77. A formulation suitable for oral administration, comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) potassium dihydrogen phosphate in an amount of about 0.01% to about 2% w/w, (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 comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w and (e) magnesium stearate in an amount of about 0.01% to about 5% w/w.

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

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

[490] Embodiment 80. A formulation suitable for oral administration comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w (b) sodium phosphate monobasic 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 portion comprises (d) lactose monohydrate in an amount of about 25% to about 95% w/w, (e) microcrystalline cellulose in an amount of about 5% to about 95% w/w (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) stearic acid in an amount of about 0.02% to about 2% w/w (i) magnesium stearate in an amount of about 0.01% to about 5% w/w.

[491] Embodiment 81. The formulation of embodiment 80, wherein, after six months of storage in a container at room temperature at about 60% relative humidity, the stable tablet formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and the total amount of impurities is less than 1%.

[492] Embodiment 82. A formulation suitable for oral administration comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w (b) sodium phosphate monobasic 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 portion comprises (d) lactose monohydrate in an amount of about 25% to about 95% w/w, (e) microcrystalline cellulose in an amount of about 5% to about 95% w/w (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) stearic acid in an amount of about 0.02% to about 2% w/w (i) magnesium stearate in an amount of about 0.01% to about 5% w/w. [493] Embodiment 83. The formulation of 82, wherein, after six months of storage in a container under accelerated conditions at a temperature of 40°C and about 75% relative humidity, the stable tablet formulation retains at least about 95% of the initial amount of Talabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[494] Embodiment 84. The formulation of embodiments 82 and 83, wherein the formulation contains nondetectable impurities at RRT 1.06 and 1.16.

[495] Embodiment 85. A formulation suitable for oral administration comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic 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) silicified microcrystalline cellulose in an amount of about 85% to about 99% w/w and the extragranular portion comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w and (e) magnesium stearate in an amount of about 0.01% to about 5% w/w.

[496] Embodiment 86. The formulation of embodiment 85, wherein the formulation further comprises moisture barrier coating at about 2% to about 4% w/w.

[497] Embodiment 87. The formulation of embodiment 84 and 85, wherein after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

[498] Embodiment 88. A formulation suitable for oral administration comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) sodium phosphate monobasic 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) silicified microcrystalline cellulose in an amount of about 85% to about 99% w/w and the extragranular portion comprises: (d) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w and (e) magnesium stearate in an amount of about 0.01% to about 5% w/w. [499] Embodiment 89. The formulation of embodiment 88, wherein the tablet further comprises moisture barrier coating at about 2% w/w to about 4% w/w and wherein after six months of storage in a container at temperature of 40°C at about 75% relative humidity, the stable tablet formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and the total amount of impurities is less than 1%.

[500] Embodiment 90. A formulation suitable for oral administration comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w; (b) sodium phosphate monobasic 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 portion comprises (d) lactose monohydrate in an amount of about 25% to about 95% w/w, (e) microcrystalline cellulose in an amount of about 5% to about 95% w/w (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) stearic acid in an amount of about 0.02% to about 2% w/w (i) magnesium stearate in an amount of about 0.01% to about 5% w/w; wherein the formulation further comprises moisture barrier coating in an amount of about 2% to about 4% w/w.

[501] Embodiment 91. The formulation of embodiment 90, wherein, after six months of storage in a container at room temperature at about 60% relative humidity, the stable tablet formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof and the total amount of impurities is less than 1%.

[502] Embodiment 92 A formulation suitable for oral administration comprising (i) an intragranular portion and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w (b) sodium phosphate monobasic 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 portion comprises (d) lactose monohydrate in an amount of about 25% to about 95% w/w, (e) microcrystalline cellulose in an amount of about 5% to about 95% w/w (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) stearic acid in an amount of about 0.02% to about 2% w/w (i) magnesium stearate in an amount of about 0.01% to about 5% w/w; wherein the formulation further comprises moisture barrier coating in an amount of about 2% to about 4% w/w.

[503] Embodiment 93. The formulation of embodiment 92, wherein, after six months of storage in a container at temperature of 40° C and about 75% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or a pharmaceutically acceptable salt thereof, and the total amount of impurities is less than 1%.

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

[505] Embodiment 95. A formulation of talabostat or a pharmaceutically acceptable salt thereof comprises (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises:

(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;

(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

[506] Embodiment 96. A formulation comprises (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises: (a) talabostat or a pharmaceutically acceptable salt thereof in an amount of about 0.1% to about 0.2% w/w;

(b) potassium dihydrogen phosphate at about 0.01% to about 2% w/w; and

(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;

(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

[507] Embodiment 97. A formulation of talabostat or a pharmaceutically acceptable salt thereof comprising (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises:

(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;

(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 comprises moisture barrier coating in an amount of about 2% w/w to about 4% w/w. [508] Embodiment 98. A formulation of talabostat or a pharmaceutically acceptable salt thereof comprising (i) an intragranular portion; and (ii) an extragranular portion; wherein the intragranular portion comprises:

(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;

(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

[509] Embodiment 99. A formulation of talabostat or a pharmaceutically acceptable salt thereof comprises:

(i) talabostat 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;

(iii) lactose monohydrate in an amount of about 50% to about 95% w/w;

(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 moisture barrier coating in an amount of about 2% w/w to about 4% w/w.

[510] Embodiment 100. The formulation of any of embodiments 1 to 99, wherein the formulation is stored in a normal HDPE bottle. [511] EmbodimentlOl. The formulation of any of embodiments 1 to 99, wherein the formulation is stored in a multiblock HDPE bottle.

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

[513] Embodiment 103. The formulation of embodiments 32 to 63, wherein the coating comprises about 4% w/w of the total weight of the formulation.

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

[515] Embodiment 105. The formulation of embodiments 32 to 63, wherein the coating provides a barrier to oxygen.

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

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

[518] Embodiment 108. The formulation of embodiment 100 or 101, wherein the packaging optionally contains an aluminum pouch.

[519] Embodiment 109. The formulation of any of embodiments 1 to 108, wherein the formulation disintegrates in presence of water in less than 5 minutes e.g. 3 minutes or less, 2 minutes or less, 1.5 minutes or less, 1 minute or less.

[520] Embodiment 110. The formulation of any of embodiments 1 to 109, wherein the formulation disintegrates in presence of water in about 40 to about 60 seconds.

[521] Embodiment 111. The formulation of any of preceding embodiments, wherein the talabostat or a pharmaceutically acceptable salt thereof is talabostat mesylate.

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

[523] Embodimentl 13. The formulation of embodiment 112, wherein the talabostat or a pharmaceutically acceptable salt thereof is present in an amount of about 50 micrograms. [524] Embodiment 114. The formulation of embodiment 112, wherein the talabostat or a pharmaceutically acceptable salt thereof is present in an amount of about 200 micrograms.

[525] Embodimentl 15. The formulation of embodiment 112, wherein the talabostat or a pharmaceutically acceptable salt thereof is present in an amount of about 400 micrograms.

[526] Embodiment 116. The formulation of any of preceding embodiments, wherein talabostat or a pharmaceutically acceptable salt is present in an amount of about 0.05% to about 0.2% w/w of the total weight of formulation.

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

[528] Embodiment 118. The formulation of any of 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.

[529] Embodiment 119. The formulation of any of preceding embodiments, is formed by a wet granulation process wherein talabostat is added extra granularly.

[530] Embodiment 120. The formulation of any of preceding embodiments, is formed by dry granulation process.

[531] Embodiment 121. The formulation of any of preceding embodiments, is formed by direct compression.

[532] Embodiment 122. The formulation of any of embodiments! 19 to 121, wherein the relative humidity is maintained at or below 35% during the process of preparation.

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

[534] Embodiment 124. The formulation of any of preceding embodiments, wherein the formulation shows complete release within 15 minutes.

[535] Embodiment 125. The formulation of any of preceding embodiments, wherein the formulation meets the acceptable criteria of content uniformity, hardness and friability.

[536] Embodiment 126. The formulation of any of preceding embodiments, wherein the cyclic form (%) is within the acceptable range of about 10% to about 60%. [537] Embodiment 127. The formulation of any of preceding embodiments, wherein the formulation exhibits a loss on drying of 1%.

[538] Embodiment 128. A process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(ii) adding silicified microcrystalline cellulose to above buffer solution;

(iii) granulating the solution followed by drying the granules;

(v) optionally lubricating the blend with magnesium stearate and

(vi) optionally coating with a moisture barrier film-coat.

[539] Embodimentl29. A dry formulation process for preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising mixing talabostat or a pharmaceutically acceptable salt thereof with one or more excipients selected from silicified microcrystalline cellulose, sodium phosphate, phosphoric acid, magnesium stearate, in the absence of added water.

[540] Embodiment 130. A process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(ii) adding talabostat or a pharmaceutically acceptable salt thereof into above buffer solution and granulating the solution;

(iii) drying the granules and blending with starch and silicified microcrystalline cellulose;

(iv) lubricating the blend; and

(v) optionally coating with a moisture barrier film coat.

[541] Embodiment 131. The process of embodiments 128 or 130, wherein blending/mixing is done in rapid mixer granulator.

I l l [542] Embodiment 132. The process of any of embodiments 128 to 131, wherein silicified microcrystalline cellulose is in an amount of about 2% to about 95% w/w.

[543] Embodiment 133. The process of any of embodiments 128 to 131, wherein phosphoric acid is in an amount of about 0.005% to about 1% w/w.

[544] Embodimentl34. The process of any of embodiments 128 to 131, wherein sodium phosphate monobasic monohydrate is at about 0.01% to about 2% w/w.

[545] Embodiment 135. The process of any of embodiments 128 to 131, wherein magnesium stearate is in an amount of about 0.01% to about 5% w/w.

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

[547] Embodiment 137. The process of any of embodiments 128 to 131, wherein talabostat or a pharmaceutically acceptable salt thereof is not in direct contact with aqueous vehicle.

[548] Embodiment 138. The process of any of embodiments 128 to 131, wherein the process is performed at relative humidity below 60%.

[549] Embodiment 139. A process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(i) sifting and dividing silicified microcrystalline cellulose into 4 portions,

(ii) geometrically mixing of talabostat or a pharmaceutically acceptable salt thereof, portion-1 of silicified microcrystalline cellulose and O-phosphoric acid and sodium phosphate buffer in a polybag for 10 minutes;

(vi) pre-lubricating the step (v) blend and forming slugs or compacts;

(vii) milling the slugs or compacts by passing through a screen;

(viii) lubricating the blend; and

(ix) optionally coating with a moisture barrier coat. [550] Embodiment 140. A method of treating cancer or tumor in a subject, comprising orally administering the formulation of talabostat or a pharmaceutically acceptable salt thereof of any of the preceding embodiments to the subject.

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

[552] Embodiment 142. The method of embodiment 141, wherein second composition is administered orally, buccally, intravenously, subcutaneously, intra-arterially, intramuscularly, transdermally, inhalation, and any combination thereof, preferably orally.

[553] Embodiment 143. The method of embodiment 140, wherein the formulation comprises talabostat or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 200 micrograms twice daily.

[554] Embodiment 144. The method of embodiment 140, wherein the formulation comprises talabostat or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 200 micrograms thrice a day.

[555] Embodiment 145. The method of embodiment 140 or 141, wherein the formulation of talabostat or a pharmaceutically acceptable salt thereof and second composition may be administered either simultaneously or sequentially separated by a specific period of time.

[556] Embodiment 146. The method of embodiment 140 or 141, wherein the formulation talabostat or a pharmaceutically acceptable salt thereof and second composition may be administered by the same route of administration or a different route of administration.

[557] Embodiment 147. An individual unit dosage form provided as a kit comprising the formulation of talabostat or a pharmaceutically acceptable salt thereof of any of the preceding embodiments in a container with or without instructions for administration to a subject in need thereof.

[558] Embodiment 148. The kit of embodiment 147, comprises a package insert comprising instructions for using the formulation of talabostat or pharmaceutically acceptable salt thereof described herein for treatment of cancer in a subject.

[559] Embodiment 149. The formulation, method, process or kit of any of the preceding embodiments, wherein the subject is human. EXAMPLES

[560] The following examples are included to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[561] Example 1: Stable Talabostat Formulations as per the present disclosure

[562] Formulation 1

Table 1

Note: Volume of water used for wet granulation was 70mL

[563] Brief Manufacturing Process (See also Figures 1 and 2)

[564] All the raw materials were dispensed as per the batch manufacturing formula.

[565] Microcrystalline cellulose and lactose monohydrate were sifted through #40mesh, transferred to RMG and dry mixing was performed for 5 minutes at 200rpm. [566] Preparation of granulating fluid: Dispensed quantity of sodium phosphate was dissolved in required quantity of water; pH was adjusted to 2.0-2.5 with o-phosphoric acid. Into this dispensed quantity of talabostat was added and allowed to dissolve by stirring. Contents of RMG were granulated using above prepared granulating solution. The above granulated material was collected in transferred to fluid bed drier (FBD) and dried at 60°C until the % LOD was reached to less than 1.0% (Drying time was 5 minutes and % LOD was 0.40%)

[567] Dried granules were sifted through #40 mesh and retains were milled through multimill using 1.00mm screen at medium speed.

% Retains on #40 mesh : 56.62

% total yield after drying and milling: 93.55%

Dried and milled material was transferred to same RMG.

[568] Extra granular material was dispensed as per the % yield. SMCC and starch were sifted through #40 stearic acid and added to and prelubrication was done at 200 RPM for 5 minutes.

[569] Stearic acid was sifted through #60 mesh and transferred to RMG.

[570] Lubrication was done at 200 rpm for 5 minutes.

[571] Lubricated blend was compressed on rotary compression machine using 7.00mm round standard punches

[572] Formulation 2

Table 2

[573] Brief Manufacturing Process (See also Figures 3 and 4) [574] Sodium phosphate and o-phosphoric acid were dissolved in purified water to form a clear solution. Silicified microcrystalline cellulose was granulated in RMG with above buffer solution followed by drying in FBD. Talabostat was co-sifted with 2X-3X quantity buffered Silicified microcrystalline cellulose through #40 mesh. Remaining silicified microcrystalline cellulose was sifted through the same sieve and magnesium stearate was sifted through #60 mesh. Silicified microcrystalline cellulose and talabostat were mixed in RMG for about 10 minutes and followed by lubrication in RMG for another 10 minutes at 100 rpm. The lubricated blend was compressed into tablets.

[575] Formulation 3

Table 3

[576] Brief Manufacturing Process (See also Figure 5)

[577] All the raw materials were dispensed as per the batch manufacturing formula.

[578] Microcrystalline cellulose and lactose monohydrate were sifted through #40mesh, transferred to RMG and dry mixing was performed for 5 minutes at 200rpm.

[579] Preparation of granulating fluid: dispensed quantity of sodium phosphate was dissolved in required quantity of water; pH was adjusted to 2.0-2.5 with O-phosphoric acid. Into this dispensed quantity of API was added and allowed to dissolve by stirring.

[580] Contents of RMG were granulated using above prepared granulating solution and granulation parameters are mentioned below in Table 4

Table 4

[581] The above granulated material was collected in transferred to fluid bed drier (FBD) and dried at 60°C until the % LOD was reached to less than 1.0% (drying time was 16 minutes and % LOD was 0.79%). Dried granules were sifted through #40 mesh and no retains were present on mesh % total yield after drying and milling: 98.63%. Dried and milled material was transferred to same RMG. Extra granular material was dispensed as per the % yield. SMCC and starch were sifted through #40 stearic acid and added to and prelubrication was done at 200 RPM for 5 minutes. Stearic acid was sifted through #60 mesh and transferred to RMG. Lubrication was done at 200 rpm for 5 minutes. Lubricated blend was compressed on rotary compression machine using 7.00mm round standard punches.

[582] Compressed tablets (equivalent to 6000 tablets) were coated with moisture barrier film coating (Opadry AMB-II) using automated coating pan.

Table 5. Comparison of results of core and coated Talabostat tablets (200 mcg) of Formulation 3

[583] Results: Uniform thin film coating was achieved on core tablets and all film coating properties were satisfactory. All the CQA’s of core tablets and coated tablets were found to be satisfactory. There was no impact of film coating on dissolution as complete drug release was observed within 15 minutes from both core tablets and coated tablets. Initial assay of core tablets and even after coating was 100.0% and no impurities at 1.06 RRT and 1.16 RRT were observed (see Table 5).

[584] Formulation 4

Table 6

[585] Manufacturing process (See also Figure 6)

[586] Sodium phosphate and o-phosphoric acid were dissolved in purified water to form a clear solution. Silicified microcrystalline cellulose was granulated in RMG with above buffer solution followed by drying in FBD. Talabostat was co-sifted with 2X-3X quantity buffered silicified microcrystalline cellulose through #40 mesh. Remaining silicified microcrystalline cellulose was sifted through the same sieve and magnesium stearate was sifted through #60 mesh. Silicified microcrystalline cellulose and talabostat were mixed in RMG for about 10 minutes and followed by lubrication in RMG for another 10 minutes at 100 rpm. The lubricated blend was compressed into tablets and coated with a moisture barrier film coating with below composition.

[587] Coating Solution preparation (20% solid content): 24 grams of Opadry AMB-II was weighed accurately and dissolved in 96 grams of purified water with continuous stirring for 45 minutes with slow RPM of 80-100 with mechanical stirrer. Table 7: Physical Parameters of Talabostat Core Tablets 200mcg and 50mcg of

Formulation 4

Table 8: Chemical Parameters of Talabostat Core Tablets 200mcg and 50 mcg of

Formulation 4

Table 9. Physical Parameters of Talabostat Film Coated Tablets 200mcg and 50mcg of

Formulation 4

Table 10: Chemical Parameters of Talabostat Film Coated Tablets 200mcg and 50mcg of Formulation 4

[588] Results: Uniform thin film coating was achieved on core tablets and all film coating properties were satisfactory. All the CQA’s of core tablets and coated tablets were found to be satisfactory. No impact of film coating on dissolution was observed as complete drug release was observed within 15 minutes from both core tablets and coated tablets. Initial assay or core tablets and even after coating was 100.0% and no impurities at 1.06 RRT and 1.16 RRT were observed.

[589] Table 11: Comparative effect on stability of Talabostat mesylate tablets in Formulation 3 by using various other ratios of diluent (Lactose monohydrate: microcrystalline cellulose)

[590] Procedure: Four batches of 0.1 mg talabostat mesylate tablets (See Formulation 3) were prepared in the same manner as the manufacturing process given under Table 3 but with different concentrations of diluent i.e. lactose monohydrate: microcrystalline cellulose in ratios of 80:20, 60:40, 40:60 and 10:90 (referred herein as Batch 1, 2, 3 and 4 respectively). The stability was assessed by exposing these tablet batches in open condition at 40°C/75%RH for 7 days.

Results and Discussion: The results of the studied batches (batch 1-4) of various ratios of diluents are provided in table 12 as below:

Table 12

[591] It was observed that disintegration time for all the studied batches with different lactose: MCC ratios ranged from 25sec to 2.40 min and hardness ranged from 4.5 to 7.2 KP, both these parameters were found similar to those of optimum batch tablets. Assay values dropped to 73.77- 80.18% after open exposure for 7days. Overall percent of drop of assay values was observed from 19.82 to 26.23 % while optimum batch tablets had shown about 16.77% drop in assay. Comparatively higher drop was observed in 60:40, 40:60 and 10:90 ratios of lactose: MCC. Total impurities at initial were 0.11% in all the batches. The total impurities range in all batches after open exposure stage was 1.35- 2.30%. The total impurity observed with optimum batch tablets was 1.63%.

[592] Table 13: Comparative effect on stability of Talabostat tablets in Formulation 3 using alternative disintegrants (crospovidone, sodium starch glycolate (SSG) and croscarmellose sodium (CCS)) at varying concentrations.

[593] Procedure: Nine batches of 0.1 mg talabostat mesylate tablets (See Formulation 3) were prepared in the same manner as manufacturing process given under Table 3 but with different concentrations of disintegrants. Pregelatinized starch was studied at concentrations of 0 mg, 2.5mg, and 5.0mg whereas other disintegrants like crospovidone, sodium starch glycolate (SSG) and croscarmellose sodium were studied at two levels of l.Omg and 5.0mg per tablet (herein referred as Batch 5 -13 respectively). The tablets stability was assessed by exposing these batches in open condition at 40o/75%RH for 7 days. Table 13

[594] Results and Discussion: The results of the studied batches (batch no. 5-13) of alternate disintegrants on tablet stability are provided in table 14 as below:

Table 14

[595] Disintegration time ranged from 25 sec to 45 sec. for the tablets manufactured with various disintegrants at different levels and was similar to the DT of optimum tablets. The hardness range observed for all tablets of talabostat produced with different disintegrants at various concentration levels was from 3.4 to 5.5 KP. Hence, no significant effect was observed with selected disintegrants and levels on the hardness of tablets. The assay values of all the tablets manufactured with different variables ranged from 74.3 to 84.7% after open exposure for 7 days. Highest drop in assay was observed when CCS was used and least drop in assay is observed with PGS. Total impurities at initial stage for all batches were from 0.42 -0.95 %. The total impurities levels increased when stored at 40°C/75% for 7 days in open condition and the values were in the range of 0.94 to 3.51 %. The optimum batch showed total impurities value of 1.63%.

[596] Table 15: To study the comparative effect on stability of Talabostat tablets in Formulation 3 by using different concentrations of stearic acid (0.5 mg and 3 mg).

[597] Procedure: Two batches of 0.1 mg Talabostat mesylate tablets (See Formulation 3) were prepared in the same manner as process given under Table 3 but with different concentrations of lubricant stearic acid at 0.5 mg and 5.0mg per tablet (herein referred as Batch 14 and 15 respectively). The tablets stability was assessed by exposing these tablets in open condition at 40o/75%RH for 7 days.

[598] Results and Discussion: The results of the studied batches (batch no. 14 and 15) on tablet stability are provided in table 16 as below:

Table 16

[599] Disintegration time ranged from 45 sec to 01 min with stearic acid (5mg per unit) and was similar to the disintegration time range of optimum tablets of talabostat. The hardness range is similar to optimum tablets (4.5 to 5.1 KP). The drop in assay was 24.84% when subjected for open exposure at 40oC/75%RH for 7 days. The total impurities increased to 2.08% after open exposure from initial 0.65% in the tablets containing 5mg stearic acid per tablet. [600] Table 17: To study the comparative effect of different buffering agents (potassium hydrogen phosphate and HCl/citric acid/malic acid/tartaric acid) used at different levels on stability of Talabostat mesylate in Formulation 3.

[601] Procedure: In order assess the suitability of other buffer systems for the stabilization of Talabostat in tablets, buffer systems that provided pH about 2.5 were identified and initial titration was made to find out the minimum quantities required. Eight batches of 0.1 mg Talabostat mesylate tablets (See Formulation 3) were prepared in the same manner as given under Table 3 process but with different buffers at different levels (herein referred as Batch 16-23 respectively). Buffers Potassium dihydrogen phosphate & hydrochloric acid and citric acid anhydrous were studied at 0.09mg and 0.18mg 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. The tablets stability was assessed by exposing these tablets in open condition at 40o/75%RH for 7 days.

Attorney Docket No. BXTI-041/01WO 349191-2011

[602] Results and discussion: The results of the studied batches (batch no. 16-23) on tablet stability are provided in table 18 as below:

Table 18

128

282706941 v1

[603] Disintegration time range observed with studied buffer variables (Potassium dihydrogen phosphate &Hydrochloric acid, Citric acid, Malic acid and Tartaric acid) was from 30 to 55 seconds is similar to that of optimum tablets. There was no significant effect of buffer components on the hardness of tablets. Higher assay drop was observed with tartaric acid as stabilizer (21.7-3.42%) at 40°C/75%-7days open exposure condition. Citric acid at 0.09mg per tablet and maleic acid at both the studied levels showed stability comparable with optimum tablets. There was no significant increase in total impurities level compared with optimum tablets.

[604] Table 19: To study the comparative effect of different types of coatings (Opadry QX (Kollicoat IR), HEC Coating and PVA based Opadry II coatings at two different levels of percent build up) on stability of Talabostat mesylate tablets as used in Formulation 3.

[605] Procedure: Six batches of 0.1 mg Talabostat mesylate tablets (See Formulation 3) were prepared in the same manner as process given under Table 3 but coated with different coating materials at two levels of percent build up (herein referred as Batch 24-29 respectively). The tablets stability was assessed by exposing these tablets in open condition at 40o/75%RH for 7 days.

[606] Results and discussion: The results of the studied batches (batch no. 24-29) on tablet stability are provided in table 20 as below:

Table 20

[607] Disintegration time ranged from 1.10 min to 5.10 sec. for the tablets coated with various coating materials at different coating percentage weight buildup levels and HEC, Opadry-II and Opadry blue coated tablets DT was similar to DT of optimum tablets (Opadry AMB-II coated tablets). Higher DT was observed in Opadry QX coated tablets i.e. 5.10 min. The hardness range observed for all the optimum composition tablets of Talabostat coated with different coating materials at different levels was from 4.9 to 6.2 KP. Hence, no significant effect was observed with selected coating materials and levels on hardness of tablets. In all batches assay drop was similar as optimum batch tablets (Opadry-AMB-II, 4% coating weight buildup) at 40°C/75%-7days open exposure condition. There was no significant increase in total impurities level compared with optimum tablets.

[608] Table 21. To study the comparative effect of different diluents (MCC101, MCC200) and different diluents ratios (SMCCHD90: MCC 101, SMCC HD90: Calcium phosphate and SMCCHD90: Lactose monohydrate) on the stability of Talabostat tablets used in core tablet formulation 4.

[609] Procedure: Twelve batches of 0.1 mg Talabostat mesylate tablets (See Formulation 4) were prepared in the same manner as process given under Table 6 but with different diluents and different diluent ratios (herein referred as Batch 30-41 respectively). The tablets stability was assessed by exposing these tablets in open condition at 40o/75% RH for 7 days.

[610] Results and Discussion: The results of the studied batches (batch no. 30-41) on tablet stability are provided in table 22 as below:

Table 22

[611] Disintegration time observed for selected diluents ratios ranged from 20sec to 4.30 min. The hardness of tablets in these batches was similar to the hardness of tablets manufactured with optimum conditions. Assay values dropped to 61.1 - 97.4% after open exposure for 7days. Overall percent of drop of assay values was observed from 2.50 to 38.89% while optimum batch tablets showed about 11.40% drop in assay. Comparatively higher drop was observed in 50:50 and 25:75 ratios of SMCC: lactose monohydrate, i.e., 23.91 - 38.89%. Tablets manufactured with SMCC: Calcium phosphate (90: 10) yielded total impurity value of 1.82%. The total impurities range in other batches was 0.02 -0.79%. The total impurity observed with optimum tablets was 0.40% at initial stage. During the stability, total impurities observed in tablets produced with different ratios of diluents were in the range of 0.21 - 3.64%.

[612] Table 23: To study the comparative effect of different disintegrants (pregelatinized starch, crospovidone, sodium starch glycolate, croscarmellose sodium) at varying levels on the stability of Talabostat tablets used in core tablet formulation 4.

[613] Procedure: Eight batches of 0.1 mg talabostat mesylate tablets (See Formulation 4) were prepared in the same manner as process given under Table 6 but with different disintegrants at two levels 1 mg and 5 mg (herein referred as Batch 42-49) respectively). The tablets stability was assessed by exposing these tablets in open condition at 40o/75%RH for 7 days.

[614] Results and Discussion: The results of the studied batches (batch no. 42-49) on tablet stability are provided in table 24 as below:

Table 24

[615] Disintegration time ranged from 15 sec to 40 sec. for the tablets manufactured with various disintegrants at different levels and was similar to the DT of optimum tablets containing no disintegrant (SMCC itself functioned as disintegrant). The hardness range observed for all tablets of Talabostat produced with different disintegrants at various concentration levels was from 3.1 to 5.2 KP. Hence, no significant effect was observed with selected disintegrants and levels on hardness of tablets. Highest drop in assay was observed when crospovidone was used and least drop in assay was observed with remaining disintegrants. Total impurities at initial stage for all batches were from 0.03 -0.43 %. The

total impurities levels increased when stored at 40°C/75% for 7days in open condition and the values were in the range of 0.42 to 2.12 %. The optimum batch showed total impurities value of 1.54%. Highest maximum total impurities were observed in crospovidone used tablets.

[616] Table 25: To study the comparative effect of different concentrations of magnesium stearate as lubricant on the stability of Talabostat tablets used in core tablet formulation 4.

[617] Procedure: 2 batches of 0.1 mg talabostat mesylate tablets (See Formulation 4) were prepared in the same manner as process given under Table 6 but with different levels (0.5 mg and 3 mg) of magnesium stearate as lubricant (herein referred as Batch 50 and 51 respectively). The tablets stability was assessed by exposing these tablets in open condition at 40°C/75%RH for 7 days.

[618] Results and Discussion: The results of the studied batches (batch no. 50 and 51) on tablet stability are provided in table 26 as below:

Table 26

[619] Disintegration time ranged from 30 sec to 45 sec with magnesium stearate (0.5 - 3.0 mg per tablet) and was similar to the disintegration time range of optimum tablets of talabostat. The hardness range was also found similar to optimum tablets. The drop in assay was 14.88 -21.28% when subjected for open exposure at 40°C/75%RH for 7 days. The total impurities levels increased when stored at 40°C/75% for 7days in open condition and the values were in the range of 0.00 to 1.42 %. Total impurities were similar as optimum batch in stability condition i.e. 1.54%.

[620] Table 27: To study the comparative effect of different buffering agents (potassium hydrogen phosphate and HCl/citric acid/malic acid/tartaric acid) used at different levels and different concentrations of sodium phosphate monohydrate /HC1 on stability of Talabostat mesylate as used in core tablet Formulation 4.

[621] Procedure: In order to assess the suitability of other buffer systems for the stabilization of Talabostat in tablets, buffer system that provided pH about 2.5 were identified and initial titration was made to find out the minimum quantities required. Ten batches of 0.1 mg talabostat mesylate tablets (See Formulation 4) were prepared in the same manner as process given under Table 6 but with different buffers at different levels (herein referred as Batches 52-61 respectively). Buffers, potassium dihydrogen phosphate & hydrochloric acid and Citric acid anhydrous were studied at 0.09mg and 0.18mg per tablet. Tartaric acid was studied at 0.10 mg and 0.2 mg and buffer malic acid was studied at 0.12 mg and 0.24 mg. The tablets stability was assessed by exposing these tablets in open condition at 40o/75%RH for 7 days.

Table 27

[622] Results and Discussion: The results of the studied batches (batch no. 52-61)on tablet stability are provided in table 28 as below:

Table 28

[623] Disintegration time range observed with studied buffer variables sodium dihydrogen phosphate/hydrochloric acid, potassium dihydrogen phosphate/hydrochloric acid, citric acid, malic acid and tartaric acid) was from 15 to 42 sec and was similar to that of optimum tablets. There was no significant effect of buffer components on the hardness of tablets. Higher assay drop (31.85% and 24.48%) was observed with sodium dihydrogen phosphate & hydrochloric acid (0.18mg per tablet) and citric acid (0.18 mg per tablet) respectively at 40°C/75% - 7days open exposure condition. With remaining buffers at both the levels and sodium dihydrogen phosphate & hydrochloric acid (0.12mg per tablet) and citric acid (0.09 mg per tablet) showed stability comparable with optimum tablets. Total impurities at initial stage for all batches were from 0.09 -0.68 %. The total impurities levels increased when stored at 40°C/75% for 7days in open condition and the values were in the range of 0.29 to 4.61 %. The optimum batch has shown total impurities value of 1.54%. Highest maximum total impurities were observed in sodium dihydrogen phosphate & hydrochloric acid (0.18 per units) used tablets i.e. 4.61%.

[624] Table 29: To study the comparative effect of different coating materials used at two levels of percent build up on stability of talabostat mesylate as used in core tablet Formulation 4.

[625] Procedure: Eight batches of 0.1 mg talabostat mesylate tablets (See Formulation 4) were prepared in the same manner as process given under Table 6 but with different levels (2% and 4% build up) of coating materials (herein referred as Batch 62-67) respectively). The tablets stability was assessed by exposing these tablets in open condition at 40o/75%RH for 7 days.

Table 29

[626] Results and Discussion: The results of the studied batches (batch no. 62-67) on tablet stability are provided in table 30 as below:

Table 30

[627] Disintegration time ranged from 50 sec to 5.10 min. for the tablets coated with various coating materials at different coating percentage weight buildup levels and Opadry QX, Opadry-II and Opadry blue coated tablets. DT observed for various coated tablets is similar to DT of optimum tablets (Opadry AMB-II coated tablets). Higher DT was observed in HEC coated tablets i.e. 5.10 min. The hardness range observed for all the optimum composition tablets of talabostat coated with different coating materials at different levels is from 4.9 to 8.4 KP. Hence, no significant effect was observed with selected coating materials and levels on hardness of tablets. Assay drop in all batches was similar to that of optimum batch tablets (Opadry-AMB-II, 4% coating weight buildup) at 40°C/75%-7days open exposure condition. Total impurities at initial stage for all batches are from 0.03 -0.22 %. The total impurities levels increased when stored at 40°C/75% for 7days in open condition and the values were in the range of 0.96 to 1.52 %. The optimum batch showed total impurities value of 1.54%. Initial and stability data was similar as optimum batch data.

[628] Table 31: To study the comparative effect of different diluent’s ratios (Lactose monohydrate: microcrystalline cellulose) on the stability of Talabostat tablets used in tablet formulation 2.

[629] Procedure: 4 batches of 0.1 mg talabostat mesylate tablets (See Formulation 2) were prepared by dry granulation process with different ratios of diluents lactose: microcrystalline cellulose at 20:80, 40:60, 60:40 and 80:20 (herein referred as Batch 68-71respectively). The tablets stability was assessed by exposing these tablets in open condition at 40o/75%RH for

7 days.

[630] Results and Discussion: The results of the studied batches (batch no.68-71) on tablet stability are provided in table 32 as below:

Table 32

[631] Disintegration time was observed for Lactose: MCC ratios in the range of 15sec to lmin.10 sec. and was similar as optimum batch. All studied variables tablets were compressed at 2.0 to 5.3 KP similar as optimum batch. Assay values dropped to 69.17 - 72.04% after open exposure for 7days. Overall percent of drop of assay values was observed from 27.96 to 30.83% while optimum batch tablets had about 9.96% drop in assay. Comparatively higher drop was observed in Lactose: MCC ratios batches than the optimum batch.

[632] Total impurities at initial stage were from 0.17 to 0.22 % in all the batches. At 40°C/75%RH-7days open exposure condition total impurities were in the range of 1.47 to 2.25 % whereas optimum batch total impurities value after open exposure at 40oC/75%RH was 0.74%. Increased impurity trend was observed in Lactose: MCC combination compared with optimum batch having only SMCC. [633] Table 33: To study the comparative effect of different disintegrants (pregelatinized starch, crospovidone, sodium starch glycolate, croscarmellose sodium) at varying levels on the stability of Talabostat tablets used in formulation 2.

[634] Procedure: 8 batches of 0.1 mg talabostat mesylate tablets (See Formulation 2) were prepared by dry granulation process with different disintegrants each in amounts of Img and 5mg per tablet (herein referred as Batch 72-79) respectively). The tablets stability was assessed by exposing these tablets in open condition at 40o/75%RH for 7 days.

[635] Results and Discussion: The results of the studied batches (batch no. 72-79) on tablet stability are provided in table 34 as below:

Table 34

[636] Disintegration time ranged from 10 sec to 40 sec for the tablets manufactured with various disintegrants at different levels and was similar to the DT of optimum tablets containing no disintegrant (as SMCC itself functioned as disintegrant). All blends were compressed to yield tablets having hardness range of 3.8 to 6.5 KP. The assay drop values of all the tablets manufactured with different ratios of diluents in range from 74.87 to 83.92%. The percent drop in the assay ranged from 16.08 to 25.13% for the studied tablets, whereas percent drop in optimum tablets was 9.9%. Total impurities at initial stage ranged from 0.22 -1.43 % and at 40°C/75% RH for 7days open exposure condition the range was from 0.78 to 1.43%, whereas optimum batch total impurities values was 0.74% after exposure to open conditions for 7 days at 40°C/75%RH. During the analysis of batch with 5mg SSG per unit batch, peak split was observed due to drug talabostat and SSG interaction.

[637] Table 35: To study the comparative effect on stability of Talabostat mesylate tablets by using different concentrations of magnesium stearate lubricant (0.5 mg and 1.5 mg) used in tablet Formulation 2.

[638] Procedure: 2 batches of 0.1 mg talabostat mesylate tablets (See Formulation 2) were prepared by dry granulation process with different amounts of magnesium stearate 0.5 mg and 1.5 mg per tablet (herein referred as Batch 80-81) respectively). The tablets stability was assessed by exposing these tablets in open condition at 40o/75%RH for 7 days.

[639] Results and Discussion: The results of the studied batches (batch no. 80 and 81) on tablet stability are provided in table 36 as below:

Table 36

[640] Disintegration time ranged from 30 sec to 50 sec with magnesium stearate (0.5 - 1.5 mg per tablet) and was similar to the disintegration time range of optimum tablets of Talabostat. The hardness range was similar to optimum tablets (4.5 to 6.5 KP). The drop in assay was observed from 15.0 to 26.5% when subjected for open exposure at 40°C/75%RH for 7 days. The total impurities levels increased when stored at 40°C/75%RH for 7days in open condition and the values were in the range of 0.73 to 2.89%.

[641] Table 37. To study the comparative effect of different buffering agents (potassium hydrogen phosphate and HC1/ Sodium Phosphate monohydrate /HCl/citric acid/malic acid/tartaric acid) used at different levels on stability of talabostat mesylate as used in tablet Formulation 2.

[642] Procedure: Five batches of 0.1 mg talabostat mesylate tablets (See Formulation 2) were prepared by dry granulation process with different buffering agents (herein referred as Batch 82-86 respectively). The tablets stability was assessed by exposing these tablets in open condition at 40o/75%RH for 7 days.

Table 37

[643] Results and Discussion: The results of the studied batches (batch no. 82-86) on tablet stability are provided in table 38 as below:

Table 38

[644] Disintegration time was observed with studied buffer variables (Sodium dihydrogen phosphate and Hydrochloric acid, Potassium dihydrogen phosphate &Hydrochloride, Citric acid, Malic acid and Tartaric acid) was from 15 to 30seconds was similar to that of optimum tablets. There was no significant effect of buffer components on the hardness of tablets. Higher assay drop was observed with Sodium dihydrogen phosphate & hydrochloric acid at 40°C/75%RH-7days open exposure condition. Other buffers showed stability comparable with tablets manufactured with optimum composition. Total impurities at initial stage for all batches were from 0.09 -0.49%. The total impurities levels increased when stored at 40°C/75%RH for 7days in open condition and the values were in the range of 0.94 to 2.29 %. The optimum batch showed total impurities value of 0.74% after open exposure. Highest maximum total impurities were observed in Potassium dihydrogen phosphate & hydrochloric acid used tablets i.e.2.29%.

[645] Table 39: To assess the stability of Talabostat mesylate per se after open exposure at 40°C /75%RH for 7 days and 15 days.

[646] Procedure: Talabostat mesylate (lOOmg) was taken into 20mL vial. Vials were covered with aluminium foil and small holes were made with fine needle. Then vials were loaded onto stability for evaluation of physical and chemical characters at initial stage and after direct open exposure at 40o/75%RH condition for 7 days and 15days.

[647] Results: Talabostat mesylate molecular weight is 310.18 g/mole and Talabostat molecular weight is 214.07 g/mole. Each lOOmg of Talabostat mesylate contains 69.01 mg of Talabostat and the results were as below:

ND: Not detected.

[648] There was no significant change observed in assay and impurities level within 07 days and 15 days in open condition at 40°C /75%RH.

[649] Example 2:

[650] Below is the prior art formulation (termed herein as Formulation A) in Table 40 that was prepared per excipients disclosed in W02008066729 (Point Therapeutics) and W02017011831 (Table 3 ofBioXcel).

Table 40

[651] Process: Sodium phosphate and o-phosphoric acid were dissolved in purified water to form a clear buffer solution. Talabostat was added to dissolve in the buffer solution. Microcrystalline cellulose and lactose monohydrate were mixed and granulated using this drug solution. The granules were dried and milled/screened through a suitable sieve. The dried granules were blended with starch and crospovidone. The obtained blend was lubricated with stearic acid and lubricated blend was compressed to obtain suitable size tablets.

[652] Further the formulations of the present disclosure are compared with Formulation A w.r.t assay values and impurity profile and tabulated in table 41.

[653] Table 41: Initial Assay values and impurities data for Talabostat tablet formulation for different batches manufactured at different time points.

[654] The data in above Table 41 shows that tablet formulations (formulation A) had low assay values after manufacturing (t=0) and formed two impurities at RRT 1.06 & 1.16 at high concentration (>1%). On the other hand, formulations 3 and 4 prepared according to the present disclosure have appropriate assay value and no detectable impurities formed at RRT 1.06 & 1.16.

[655] Example 3 : Degradation study of formulation 2 with/without buffer.

[656] To understand the degradation nature of API (Talabostat mesylate) in the formulation, product exposure studies at condition such as one week exposure at 60±2°C in open and closed condition in HDPE bottle and 15 days exposure at 40±2°C/75±5%RH in open condition were carried out.

Table 42: Stability study of Formulation 2 (with or without buffer):

[657] Results: It was observed that both the formulations were found to show similar stability at 60±2°C in open and closed condition, indicating that the presence of buffer has no additional advantage in the formulation with respect to thermolytic stability of drug product. However, it was observed that the formulation containing no buffer has degraded more (47.0% of initial talabostat) when it was exposed for 15 days at 40±2°C/75±5%RH in open condition, compared to the formulation containing additional acidic buffer (72.5% of initial Talabostat), indicating that the presence of buffer in the formulation provides additional stability in presence of combination of high temperature and high humidity.

[658] Example 4. Comparative stability data of Formulations 1 to 4 with prior art Formulation A under different storage conditions as shown in below Tables 43 and 44. [659] The stability studies of formulations 1 to 4 and formulation A was conducted in a conventional manner and studied for change in appearance by visual inspection, content of Talabostat by chemical assay and measuring its degradation products and related substance data, cyclic content, e.g. after storage at room temperature 25°C. and 60% relative humidity and storage at 40° C and 75% relative humidity for defined periods of time. The results of the stability tests are summarized in the below tables.

[660] Results: All the physico-chemical parameters of prepared tablets (formulations 1 to 4) were found to be acceptable. Cyclic form was found to be within the acceptable range. Product was found to be stable for 6 months at 25°C/60%RH and 40°C/75%RH. All the estimated CQA’s were within acceptable ranges in both Packs (Normal HDPE and Multiblock HDPE Bottle).

[661] Table 43: Comparison of stability study of formulations 1 to 4 with Formulation

A (prior art formulation) at storage condition-25°C/60%RH

[662] Table 44: Comparison of stability study of formulations 1 to 4 with Formulation

A (prior art formulation) at storage condition - 40°C/75%RH

[663] While the disclosure has been specifically described with respect to separation and recovery of carbon dioxide, it will be appreciated that the disclosure may be readily used to separate other gases.

[664] It is to be understood that, although prior art use and publications may be referred to herein, such reference does not constitute an admission that any of these form a part of the common general knowledge in the art in any country.

[665] Numerous variations and modifications will suggest themselves to persons skilled in the relevant art, in addition to those already described, without departing from the basic inventive concepts. All such variations and modifications are to be considered within the scope of the disclosure, the nature of which is to be determined from the foregoing description.

Claims

CLAIMS What is claimed is:

1. A formulation suitable for oral administration comprising:

(i) talabostat or a pharmaceutically acceptable salt thereof;

(ii) silicified microcrystalline cellulose;

(iii) sodium phosphate monobasic monohydrate;

(iv) phosphoric acid, and

(v) magnesium stearate.

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

3. A formulation suitable for oral administration comprising:

(i) an intragranular portion and

(ii) an extragranular portion; wherein the intragranular portion comprises:

(a) sodium phosphate monobasic 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

(b) magnesium stearate in an amount of about 0.01% to about 5% w/w.

4. The formulation of claim 3, wherein after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and a total amount of impurities is less than 1%.

5. The formulation of claim 1 , wherein the formulation retains about 99.5% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and a total amount of impurities is less than 0.5%.

6. The formulation according to any of claims 1 to 5, wherein the formulation contains non-detectable amount of impurities at relative retention time (RRT) of 1.06 and 1.16.

7. The formulation according to claim 1, further comprising

(i) microcrystalline cellulose;

(ii) stearic acid;

(iii) lactose monohydrate, and

(iv) pregelatinized starch.

8. The formulation according to any of claims 1 to 7 comprising:

(iii) lactose monohydrate in an amount of about 25% to about 95% w/w;

(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.

9. The formulation according to any of claims 1 to 7 comprising

(i) silicified microcrystalline cellulose in an amount of about 2% to about 95% wlw,

(iii) stearic acid in an amount of about 0.05% to about 2% w/w,

(iv) phosphoric acid in an amount of about 0.005% to about 2.0% w/w and

(v) magnesium stearate in an amount of about 0.01% to about 5% w/w.

10. A formulation suitable for oral administration comprising:

(i) an intragranular portion; and

(ii) an extragranular portion, wherein the intragranular portion comprises:

(c) phosphoric acid in an amount of about 0.005% to about 2.0% w/w; and wherein the extragranular portion comprises:

(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 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.

11. The formulation according to claim 10, wherein, after six months of storage in a container at room temperature at about 60% relative humidity, the formulation retains at least about 95% of the initial amount of talabostat or the pharmaceutically acceptable salt thereof and a total amount of impurities is less than 1%.

12 . A process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(i) sifting and dividing silicified microcrystalline cellulose into 4 portions,

(ii) geometrically mixing talabostat or a pharmaceutically acceptable salt thereof, portion- 1 of silicified microcrystalline cellulose, O-phosphoric acid and sodium phosphate buffer in a polybag for 10 minutes;

(iv) manually mixing step (iii) blend and third portion of silicified microcrystalline cellulose in the polybag for 15 minutes followed by sifting; (v) manually mixing step (iv) blend and fourth portion of silicified microcrystalline cellulose in the polybag for 15 minutes followed by sifting;

(vi) pre-lubricating the step (v) blend;

(vii) milling; and

(viii) lubricating the blend.

13. The formulation according to any of claims 1 to 11 or the process according to claim 12, wherein the talabostat or a pharmaceutically acceptable saltthereof is talabostat mesylate.

14. The formulation according to any of claims 1 to 11, wherein the formulation retains at least about 98% of the initial amount of talabostat or the pharmaceutically acceptable salt after twelve months in a container at room temperature and about 60% relative humidity.

15. The formulation according to any of claims 1 to 11, 13 and 14 or the process according to claim 12, wherein the talabostat or the pharmaceutically acceptable salt thereof is present in an amount of about 50 micrograms to about 400 micrograms.

16. The formulation according to any of claims 1 to 11, 13 and 14 or the process according to claim 12, wherein the talabostat or the pharmaceutically acceptable salt thereof is present in a tablet in an amount of about 100 micrograms, about 200 micrograms, or about 300 micrograms.

17. The formulation according to any of claims 1 to 11, 13 and 14 or the process according to claim 12, wherein the talabostat or the pharmaceutically acceptable salt thereof is present in a tablet in an amount of about 100 micrograms.

18. The formulation according to any of claims 1 to 11, 13 and 14 or the process according to claim 12, wherein the talabostat or the pharmaceutically acceptable salt thereof is present in a tablet in an amount of about 200 micrograms.

19. The formulation according to any of claims 1 to 11, 13 and 14 or the process according to claim 12, wherein the talabostat or the pharmaceutically acceptable salt thereof is present in a tablet in an amount of about 300 micrograms.

20. The formulation according to any of claims 1 to 11, 13 and 14, wherein the formulation is free of crospovidone.

21. The formulation according to any of claims 1 to 11, 13 and 14, further comprising a moisture barrier coating in an amount of about 2% to about 8% w/w of the total weight of composition.

22. The formulation according to claims 1 to 11, 13 and 14, wherein the formulation disintegrates in less than 5 minutes in the presence of water.

23. The formulation according to claims 1 to 11, 13 and 14, wherein the pH of the formulation is about 1 to 5.

24. The formulation according to claims 1 to 11, 13 and 14, wherein the formulation is formed by a wet granulation process and wherein talabostat is added extra granularly.

25. The formulation according to claims 1 to 11, 13 and 14, wherein the formulation is formed by a dry granulation process.

26. The formulation according to any of claims 1 to 25 further comprising one or more additional active agents.

27. A method of treating cancer in a subject, comprising orally administering the formulation of talabostat or a pharmaceutically acceptable salt thereof according to any of claims 1 to 26 to the subject.

28. The method of claim 27, further comprising administering a formulation comprising a second active agent to the subject.

29. A process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof comprising:

(ii) adding silicified microcrystalline cellulose to the buffer solution; (iii) granulating the solution to provide granules and then drying the granules;

(iv) blending with talabostat or a pharmaceutically acceptable salt thereof; and

(v) optionally lubricating the blend with magnesium stearate.

30. A process of preparing a formulation of talabostat or a pharmaceutically acceptable salt thereof, comprising:

(i) sifting and dividing silicified microcrystalline cellulose into one or more portions;

(ii) mixing talabostat or a pharmaceutically acceptable salt thereof with a first portion of silicified microcrystalline cellulose and O-phosphoric acid and sodium phosphate buffer in a polybag for about 10 minutes;

(iii) mixing the step (ii) blend and a second portion of silicified microcrystalline cellulose in the polybag for about 15 minutes followed by sifting;

(iv) mixing the step (iii) blend and a third portion of silicified microcrystalline cellulose in the polybag for 15 minutes followed by sifting;

(v) mixing the step (iv) blend and a fourth portion of silicified microcrystalline cellulose in the polybag for 15 minutes followed by sifting;

(vi) pre-lubricating the step (v) blend;

(vii) milling the blend by passing through screen; and lubricating the blend.

31. The process according to claim 29 or 30, is performed at relative humidity below about 60%.

32. The process according to claim 29 or 30, wherein talabostat or a pharmaceutically acceptable salt thereof is not in direct contact with an aqueous vehicle.

33. The process according to claim 29 or 30, wherein silicified microcrystalline cellulose is present in an amount of about 2% to about 95% w/w.

34. The process according to claim 29 or 30, wherein phosphoric acid is present in an amount of about 0.005% to about 0.1% w/w.

35. The process according to claim 29 or 30, wherein sodium phosphate monobasic monohydrate is present in an amount of about 0.01% to about 2% w/w.

36. The process according to claim 29 or 30, wherein magnesium stearate is present in an amount of about 0.01% to about 5% w/w.

37. The process according to claim 30, wherein the buffer solution of step (i) has a pH of about 2 to 3.

38. The formulation of claims 1-11, wherein the formulation is a tablet.