Modified release formulation for (-)-(3AR,4S,7AR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester

A stable, modified release single dosage form comprising:

• (a) from about 50 mg to about 200 mg of (−)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester in free base form as an active pharmaceutical ingredient,
• wherein the active pharmaceutical ingredient has a D10 particle size of less than or equal to 50 μm and a D50 particle size of less than or equal to 100 μm, and a D90 particle size of less than or equal to 200 μm;
• (b) from about 69 mg to about 135 mg of a modified release agent, the modified release agent being hydroxypropyl methylcellulose;
• (c) from about 20 mg to about 160 mg of lactose monohydrate;
• (d) from about 3 mg to about 38 mg of sodium starch glycolate;
• (e) from about 2 mg to about 4.5 mg of magnesium stearate;
• (f) from about 1 mg to about 2.2 mg of colloidal silicone dioxide;
• and
• (g) a dissolution profile of the active pharmaceutical ingredient when tested using United States Pharmacopeia (USP) Apparatus 2 (paddle) at 37° C. in 900 mL of an aqueous solution containing 0.5% lauryldimethylamine N-oxide (LDAO) and water at 100 revolutions per minute (rpm) characterized by release of:
• (i) from 14% to 20% of the active pharmaceutical ingredient at 60 minutes;
• (ii) from 51% to 61% at 180 minutes;
• (iii) from 67% to 77% at 240 minutes;
• (iv) from 90% to 95% at 360 minutes;
• and
• (v) from 95% to 99% at 420 minutes;
• and
• further characterized by releasing less than 80% of the active pharmaceutical ingredient at 420 minutes when tested under identical conditions except that the aqueous solution contains 0.5% LDAO, water, and from 20% to 40% ethanol.