Modified release 1- [ (3-hydroxy-adamant-1-ylamino)-acetyl] -pyrrolidine-2 (s) -carbonitrile formulation

A pharmaceutical tablet formulation, comprising per 400 mg tablet the following ingredients:

• (a) vildagliptin or a pharmaceutically acceptable salt thereof.
• (b) a hydroxypropyl methylcellulose in an amount of about 160 mg, wherein the hydroxypropyl methylcellulose has an apparent viscosity of 80,000 cP to 120,000 cP (nominal value 100,000 cP) when present in a 1% solution;
• (c) a microcrystalline cellulose in an amount of 120 mg;
• (d) a lactose in an amount of about 16 mg;
• and
• (e) a magnesium stearate in an amount of 4 mg.

A pharmaceutical tablet formulation comprising per unit dosage form e.g. per tablet the following ingredients:

• (a) a compound as an active ingredient, wherein the compound has a formula:
• wherein R is substituted adamantyl and n is an integer from 0 to 3;
• or a pharmaceutically acceptable salt thereof;
• and
• (b) a hydroxypropyl methylcellulose with an apparent viscosity of 80,000 cP to 120,000 cP (nominal value 100,000 cP) when present in a 1% solution.

A pharmaceutical tablet formulation, comprising per 600 mg tablet the following ingredients:

• (a) 1-[(3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(S)-carbonitrile or a pharmaceutically acceptable salt thereof in an amount of about 150 mg;
• (b) a hydroxypropyl methylcellulose in an amount of about 240 mg, wherein the hydroxypropyl methylcellulose has an apparent viscosity of 80,000 cP to 120,000 cP (nominal value 100,000 cP) when present in a 1% solution;
• (c) a microcrystalline cellulose in an amount of 180 mg;
• (d) a lactose in an amount of about 24 mg;
• and
• (e) a magnesium stearate in an amount of 6 mg.

A pharmaceutical tablet formulation, comprising per 400 mg tablet the following ingredients:

• (a) 1-[(3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(S)-carbonitrile or a pharmaceutically acceptable salt thereof in an amount of about 100 mg;
• (b) a hydroxypropyl methylcellulose in an amount of about 160 mg, wherein the hydroxypropyl methylcellulose has an apparent viscosity of 80,000 cP to 120,000 cP (nominal value 100,000 cP) when present in a 1% solution;
• (c) a microcrystalline cellulose in an amount of 120 mg;
• (d) a lactose in an amount of about 16 mg;
• and
• (e) a magnesium stearate in an amount of 4 mg.

A pharmaceutical tablet formulation comprising 100 mg of vildagliptin or a salt thereof, preferably compressed in the form of a sustained release tablet, wherein;

• between 10% and 16% preferably between 11% and 15% of vildagliptin is released after 0.5 hour,
• between 18% and 24% preferably between 19% and 23% of vildagliptin is released after 1 hour,
• between 30% and 36% preferably between 31% and 35% of vildagliptin is released after 2 hours,
• between 46% and 52% preferably between 47% and 51% of vildagliptin is released after 4 hour,
• between 58% and 64% preferably between 59% and 63% of vildagliptin is released after 6 hours,
• between 67% and 73% preferably between 68% and 72% of vildagliptin is released after 8 hours,
• between 74% and 80% preferably between 75% and 79% of vildagliptin is released after 10 hours,
• between 80% and 86% preferably between 81% and 85% of vildagliptin is released after 12 hours,
• between 91% and 97% preferably between 92% and 96% of vildagliptin is released after 18 hours,
• between 95% and 100% preferably between 96% and 100% of vildagliptin is released after 24 hours.

A pharmaceutical tablet formulation comprising 150 mg of vildagliptin or a salt thereof, preferably compressed in the form of a sustained release tablet, wherein;

• between 3.8% and 9.8% preferably between 4.8% and 8.8% of vildagliptin is released after 0.25 hour,
• between 8.1% and 14.1% preferably between 9.1% and 13.1% of vildagliptin is released after 0.5 hour,
• between 14.7% and 20.7% preferably between 15.7% and 19.7% of vildagliptin is released after 1 hours,
• between 25.3% and 31.3% preferably between 26.3% and 30.3% of vildagliptin is released after 2 hour,
• between 40.9% and 46.9% preferably between 41.9% and 45.9% of vildagliptin is released after 6 hours,
• between 62.1% and 68.1% preferably between 63.1% and 67.1% of vildagliptin is released after 8 hours,
• between 76.5% and 82.5% preferably between 77.5% and 81.5% of vildagliptin is released after 10 hours,
• between 83.5% and 89.5% preferably between 84.5% and 88.5% of vildagliptin is released after 12 hours,
• between 88.5% and 94.5% preferably between 89.5% and 93.5% of vildagliptin is released after 18 hours.

A sustained release solid oral pharmaceutical dosage form which is;

• i-1) a solid oral pharmaceutical dosage form comprising about 100 mg of vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean maximum plasma concentration of vildagliptin ranging from about 15.8 ng/mL+/−6.85 ng/mL to about 173 ng/mL+/−52 ng/mL between about 0.5 and about 16 hours following oral administration of said dosage form in a patient not treated with vildagliptin before said administration and wherein patient is under fasted conditions, and/or
• i-2) a solid oral pharmaceutical dosage form comprising about 100 mg of vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean maximum plasma concentration of vildagliptin ranging from about 26.3 ng/mL+/−13.1 ng/mL to about 175 ng/mL+/−62.5 ng/mL between about 0.5 and about 16 hours following administration of said dosage form on day 9 in a patient treated with said dosage form once a day since day 1 and wherein said patient has been served an ADA breakfast within 30 minutes of the morning administration of said dosage form, and/or
• i-3) a solid oral pharmaceutical dosage form comprising about 100 mg of vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean maximum plasma concentration of vildagliptin ranging from about 26.9 ng/mL+/−14.1 ng/mL to about 186 ng/mL+/−80.6 ng/mL between about 0.5 and about 16 hours following administration of said dosage form on day 10 in a patient treated with said dosage form once a day since day 1 and wherein said patient is under fasted conditions, and/or
• ii-1) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean AUC(0-inf) of vildagliptin ranging from about 1073 to about 1825 ng·h/mL i.e. 1449 ng·h/mL+/−376 ng·h/mL following oral administration of said dosage form, in a patient not treated with vildagliptin before said administration and wherein said patient is under fasted conditions, and/or
• ii-2) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean AUC(0-24) of vildagliptin ranging from about 1001 to about 1977 ng·h/mL i.e. 1489 ng·h/mL+/−488 ng·h/mL following oral administration of said dosage form, on day 9 in a patient treated with said dosage form once a day since day 1 and wherein said patient has been served an ADA breakfast within 30 minutes of the morning administration of said dosage form, and/or
• ii-3) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean AUC(0-24) of vildagliptin ranging from about 1103 to about 2173 ng·h/mL i.e. 1638 ng·h/mL+/−535 ng·h/mL following oral administration of said dosage form, on day 10 in a patient treated with said dosage form once a day since day 1 and wherein said patient is under fasted conditions, and/or
• iii-1) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean tmax of vildagliptin of 3.61 hr+/−1.44 hr following oral administration of said dosage form, in a patient not treated with vildagliptin before said administration and wherein said patient is under fasted conditions, and/or
• iii-2) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean tmax of vildagliptin of 2.59 hr+/−1.4 hr following oral administration of said dosage form, on day 9 in a patient treated with said dosage form once a day since day 1 and wherein said patient has been served an ADA breakfast within 30 minutes of the morning administration of said dosage form, and/or
• iii-3) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean tmax of vildagliptin of 3.74 hr+/−1.44 hr following oral administration of said dosage form, on day 10 in a patient treated with said dosage form once a day since day 1 and wherein said patient is under fasted conditions, and/or
• iv-1) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean Cmax of vildagliptin of 205 ng/ml+/−47 ng/ml following oral administration of said dosage form, in a patient not treated with vildagliptin before said administration and wherein said patient is under fasted conditions, and/or
• iv-2) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean Cmax of vildagliptin of 200 ng/ml+/−64 ng/ml following oral administration of said dosage form, on day 9 in a patient treated with said dosage form once a day since day 1 and wherein said patient has been served an ADA breakfast within 30 minutes of the morning administration of said dosage form, and/or
• iv-3) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean Cmax of vildagliptin of 245 ng/ml+/−68 ng/ml following oral administration of said dosage form, on day 10 in a patient treated with said dosage form once a day since day 1 and wherein said patient is under fasted conditions, and/or
• v-1) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean % inhibition of DPP-IV activity over 24 hours of 85.64%+/−12.76% following oral administration of said dosage form, in a patient not treated with vildagliptin before said administration and wherein said patient is under fasted conditions, and/or
• v-2) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean % inhibition of DPP-IV activity over 24 hours of 87.78%+/−16.37% following oral administration of said dosage form, on day 9 in a patient treated with said dosage form once a day since day 1 and wherein said patient has been served an ADA breakfast within 30 minutes of the morning administration of said dosage form, and/or
• v-3) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean % inhibition of DPP-IV activity over 24 hours of 90.20%+/−7.35% following oral administration of said dosage form, on day 10 in a patient treated with said dosage form once a day since day 1 and wherein said patient is under fasted conditions, and/or
• vi-1) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing a pharmacokinetic profile as substantially depicted in FIG. 24, following oral administration of said dosage form, in a patient not treated with vildagliptin before said administration and wherein said patient is under fasted conditions, and/or
• vi-2) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing a pharmacokinetic profile as substantially depicted in FIG. 25, following oral administration of said dosage form, on day 9 in a patient treated with said dosage form once a day since day 1 and wherein said patient has been served an ADA breakfast within 30 minutes of the morning administration of said dosage form, and/or
• vi-3) a solid oral dosage form comprising about 100 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing a pharmacokinetic profile as substantially depicted in FIG. 26, following oral administration of said dosage form, on day 10 in a patient treated with said dosage form once a day since day 1 and wherein said patient is under fasted conditions.

A sustained release solid oral pharmaceutical dosage form which is;

• i-a) a solid oral pharmaceutical dosage form comprising about 150 mg of vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean maximum plasma concentration of vildagliptin ranging from about 30.7 ng/mL+/−21.9 ng/mL to about 223 ng/mL+/−77.3 ng/mL between about 0.5 and about 16 hours following oral administration of said dosage form in a patient not treated with vildagliptin before said administration and wherein patient is under fasted conditions, and/or
• i-b) a solid oral pharmaceutical dosage form comprising about 150 mg of vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean maximum plasma concentration of vildagliptin ranging from about 48.7 ng/mL+/−25.8 ng/mL to about 223 ng/mL+/−99.7 ng/mL between about 0.5 and about 16 hours following administration of said dosage form on day 9 in a patient treated with said dosage form once a day since day 1 and wherein said patient has been served an ADA breakfast within 30 minutes of the morning administration of said dosage form, and/or
• i-c) a solid oral pharmaceutical dosage form comprising about 150 mg of vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean maximum plasma concentration of vildagliptin ranging from about 44.6 ng/mL+/−28.5 ng/mL to about 263 ng/mL+/−84.4 ng/mL between about 0.5 and about 16 hours following administration of said dosage form on day 10 in a patient treated with said dosage form once a day since day 1 and wherein said patient is under fasted conditions, and/or
• ii-a) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean AUC(0-inf) of vildagliptin ranging from about 1346 to about 3196 ng·h/mL i.e. 2271 ng·h/mL+/−925 ng·h/mL following oral administration of said dosage form, in a patient not treated with vildagliptin before said administration and wherein said patient is under fasted conditions, and/or
• ii-b) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean AUC(0-24) of vildagliptin ranging from about 1277 to about 3207 ng·h/mL i.e. 2242 ng·h/mL+/−965 ng·h/mL following oral administration of said dosage form, on day 9 in a patient treated with said dosage form once a day since day 1 and wherein said patient has been served an ADA breakfast within 30 minutes of the morning administration of said dosage form, and/or
• ii-c) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean AUC(0-24) of vildagliptin ranging from about 1643 to about 3273 ng·h/mL i.e. 2458 ng·h/mL+/−815 ng·h/mL following oral administration of said dosage form, on day 10 in a patient treated with said dosage form once a day since day 1 and wherein said patient is under fasted conditions, and/or
• iii-a) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean tmax of vildagliptin of 3.57 hr+/−1.17 hr following oral administration of said dosage form, in a patient not treated with vildagliptin before said administration and wherein said patient is under fasted conditions, and/or
• iii-b) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean tmax of vildagliptin of 2.87 hr+/−1.59 hr following oral administration of said dosage form, on day 9 in a patient treated with said dosage form once a day since day 1 and wherein said patient has been served an ADA breakfast within 30 minutes of the morning administration of said dosage form, and/or
• iii-c) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean tmax of vildagliptin of 4.13 hr+/−1.24 hr following oral administration of said dosage form, on day 10 in a patient treated with said dosage form once a day since day 1 and wherein said patient is under fasted conditions, and/or
• iv-a) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean Cmax of vildagliptin of 257 ng/ml+/−59 ng/ml following oral administration of said dosage form, in a patient not treated with vildagliptin before said administration and wherein said patient is under fasted conditions, and/or
• iv-b) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean Cmax of vildagliptin of 272 ng/ml+/−111 ng/ml following oral administration of said dosage form, on day 9 in a patient treated with said dosage form once a day since day 1 and wherein said patient has been served an ADA breakfast within 30 minutes of the morning administration of said dosage form, and/or
• iv-c) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean Cmax of vildagliptin of 308 ng/ml+/−91 ng/ml following oral administration of said dosage form, on day 10 in a patient treated with said dosage form once a day since day 1 and wherein said patient is under fasted conditions, and/or
• v-a) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean % inhibition of DPP-IV activity over 24 hours of 90.04%+/−11.91% following oral administration of said dosage form, in a patient not treated with vildagliptin before said administration and wherein said patient is under fasted conditions, and/or
• v-b) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean % inhibition of DPP-IV activity over 24 hours of 90.4%+/−17.50% following oral administration of said dosage form, on day 9 in a patient treated with said dosage form once a day since day 1 and wherein said patient has been served an ADA breakfast within 30 minutes of the morning administration of said dosage form, and/or
• v-c) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing an arithmetic mean % inhibition of DPP-IV activity over 24 hours of 91.64%+/−8.47% following oral administration of said dosage form, on day 10 in a patient treated with said dosage form once a day since day 1 and wherein said patient is under fasted conditions, and/or
• vi-a) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing a pharmacokinetic profile as substantially depicted in FIG. 24, following oral administration of said dosage form, in a patient not treated with vildagliptin before said administration and wherein said patient is under fasted conditions, and/or
• vi-b) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing a pharmacokinetic profile as substantially depicted in FIG. 25, following oral administration of said dosage form, on day 9 in a patient treated with said dosage form once a day since day 1 and wherein said patient has been served an ADA breakfast within 30 minutes of the morning administration of said dosage form, and/or
• vi-c) a solid oral dosage form comprising about 150 mg vildagliptin free base, or a respective amount of a pharmaceutically acceptable salt thereof, and a carrier medium, said dosage form providing a pharmacokinetic profile as substantially depicted in FIG. 26, following oral administration of said dosage form, on day 10 in a patient treated with said dosage form once a day since day 1 and wherein said patient is under fasted conditions.