Sustained release oral dosage forms of an R-baclofen prodrug
View Patent ↗Sustained release oral dosage forms of an R-baclofen prodrug are disclosed.
1. A sustained release oral tablet dosage form comprising:
dibasic calcium phosphate dihydrate or dibasic calcium phosphate anhydrous coated with about 5 to about 50 mg (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid or a pharmaceutically acceptable salt thereof;
about 15 wt-% to about 40 wt-% microcrystalline cellulose;
about 15 wt-% to about 40 wt-% hydroxypropylmethyl cellulose; and
about 3 wt-% to about 30 wt-% of a release rate-controlling polymer
based on the total weight of the dosage form;
wherein the dosage form provides for sustained release of (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid or a pharmaceutically acceptable salt thereof during passage of the dosage form through the gastrointestinal tract.
2. The sustained release oral tablet dosage form of claim 1 , wherein the release rate-controlling polymer is a copolymer comprising poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2.
3. The sustained release oral tablet dosage form of claim 1 , comprising about 0.5 wt-% to about 1.5 wt-% magnesium stearate, colloidal silicon dioxide, and dibasic calcium phosphate, anhydrous.
4. The sustained release oral tablet dosage form of claim 1 , wherein the total weight of the dosage form is about 100 mg to about 600 mg.
5. The sustained release oral tablet dosage form of claim 1 , wherein release of the (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid of pharmaceutically acceptable salt thereof from the oral dosage form exhibits an in vitro dissolution profile in 50 mM, pH 6.8 sodium phosphate buffer at 37° C. stirred at 75 rpm (USP, Type II) as follows:
about 10% to about 30% of the (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid or pharmaceutically acceptable salt thereof is released within about 4 hours;
about 15% to about 35% of the (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid or pharmaceutically acceptable salt thereof is released within about 8 hours;
about 20% to about 50% of the (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid or pharmaceutically acceptable salt thereof is released within about 12 hours; and
about 30% to about 80% of the (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid or pharmaceutically acceptable salt thereof is released within about 18 hours.
6. The sustained release oral tablet dosage form of claim 1 , wherein release of the (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid or pharmaceutically acceptable salt thereof from the oral dosage form exhibits an in vitro dissolution profile in 50 mM, pH 6.8, sodium phosphate buffer at 37° C. stirred at 75 rpm (USP Type II) as follows:
about 10% to about 20% of the (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid or pharmaceutically acceptable salt thereof is released with about 4 hours;
about 20% to about 30% of the (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid or pharmaceutically acceptable salt thereof is released within about 8 hours;
about 25% to about 45% of the (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid or pharmaceutically acceptable salt thereof is released within about 12 hours; and
about 35% to about 55% of the (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid or pharmaceutically acceptable salt thereof is released within about 18 hours.
7. The sustained oral tablet dosage form of claim 1 , which following oral administration to sixteen healthy adult human patients at a dose of about 60 mg (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid provides a mean steady state pharmacokinetic profile characterized by: a C ss,max of about 202±56 ng/mL; a T ss,max of about 3.9±1.0 hours; a C ss,12 of about 19 ng/mL; a T ss,1/2 of about 10.9±3.8 hours; and an AUC ss,24 of about 1803±420 ng·hr/mL.
8. The sustained release oral tablet dosage form of claim 1 , which following oral administration to sixteen healthy adult human patients at a dose of about 60 mg (3R)-4{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid provides a mean steady state pharmacokinetic profile of R-3-amino-3-(4-cholorophenyl)butanoic acid in the blood of the patient characterized by a C ss,max /C ss,12 of about 8 to about 15.
9. The sustained release oral tablet dosage form of claim 1 , having a friability less than about 0.5 wt-% determined according to USP 1216.
10. The sustained release oral tablet dosage form of claim 1 , comprising
0.1 wt-% to 2 wt-% colloidal silicon dioxide; and
0.1 wt-% to 2 wt-% magnesium stearate.
11. The sustained release oral tablet dosage form of claim 1 , comprising
0.1 wt-% to 2 wt-% colloidal silicon dioxide; and
0.1 wt-% to 2 wt-% magnesium stearate.
12. The sustained release oral tablet dosage form of claim 1 , wherein the hydroxypropylmethyl cellulose comprises a hydroxypropoxy content of approximately 8 wt-%, a methoxy content of approximately 22 wt-%, a nominal viscosity in water at 2% concentration of approximately 4,000 centipoise, and a particle size such that at least 75 wt-% is less than 250 microns.