Extended release formulation of a direct thrombin inhibitor
Extended release formulations of 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide (DPOC-4088) that provide for better control of blood plasma levels. The extended release formulations maintain substantially constant plasma levels of the active ingredient for at least about 16 hours and provide for once-daily dosing.
1. A method for providing a therapeutic blood plasma concentration of 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide (DPOC-4088) over a twenty four hour period which comprises administering orally to a patient in need thereof an extended release formulation comprising an effective amount of DPOC-4088 that provides a blood plasma concentration of DPOC-4088 of greater than 200 nM/100 mg of DPOC-4088 administered over a period of at least about 16 hours following a single oral dose, wherein the extended release formulation comprises a tablet core comprising the DPOC-4088 and a matrix forming polymer configured to modulate a release of the DPOC-4088 from the tablet core comprises:
100.00 mg DPOC-4088;
27.375 mg manitol;
15.00 mg povidone;
25.00 mg poloxamers;
60.00 mg hypromellose;
2.50 mg colloidal anhydrous silica;
0.25 mg ferric oxide; and
2.375 mg magnesium stearate.
2. The method of claim 1 wherein the period is at least about 18 hours.
3. The method of claim 1 , wherein the extended release formulation further comprises a surfactant and other conventional pharmaceutical excipients.
4. A method for providing a therapeutic blood plasma concentration of 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide (DPOC-4088) over a twenty four hour period which comprises administering orally to a patient in need thereof an extended release formulation comprising an effective amount of DPOC-4088 that provides a blood plasma concentration of DPOC-4088 of greater than 200 nM/100 mg of DPOC-4088 administered over a period of at least about 16 hours following a single oral dose, wherein the extended release formulation comprises a tablet core comprising the DPOC-4088 and a matrix forming polymer configured to modulate a release of the DPOC-4088 from the tablet core, wherein the extended release formulation provides a blood plasma concentration of DPOC-4088 of greater than 200 nM/100 mg of DPOC-4088 administered over a period of 18 hours following a single oral dose, and wherein the tablet core comprises:
200.00 mg DPOC-4088;
69.75 mg manitol;
30.00 mg povidone;
50.00 mg poloxamers;
75.00 mg hypromellose;
5.00 mg colloidal anhydrous silica;
0.50 mg ferric oxide; and
4.75 mg magnesium stearate.
5. A method for providing a therapeutic blood plasma concentration of 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide (DPOC-4088) over a twenty four hour period which comprises administering orally to a patient in need thereof an extended release formulation comprising an effective amount of DPOC-4088 that provides a blood plasma concentration of DPOC-4088 of greater than 200 nM/100 mg of DPOC-4088 administered over a period of at least about 16 hours following a single oral dose, wherein the extended release formulation comprises a tablet core comprising the DPOC-4088 and a matrix forming polymer configured to modulate a release of the DPOC-4088 from the tablet core, wherein the extended release formulation provides a blood plasma concentration of DPOC-4088 of greater than 200 nM/100 mg of DPOC-4088 administered over a period of 20 hours following a single oral dose, and wherein the tablet core comprises:
100.00 mg DPOC-4088;
17.5 mg manitol;
15.00 mg povidone;
25.00 mg poloxamers;
90.00 mg hypromellose;
2.50 mg colloidal anhydrous silica;
0.50 mg ferric oxide; and
2.50 mg magnesium stearate.
6. A method for providing a therapeutic blood plasma concentration of 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide (DPOC-4088) over a twenty four hour period which comprises administering orally to a patient in need thereof an extended release formulation comprising an effective amount of DPOC-4088 that provides a blood plasma concentration of DPOC-4088 of greater than 200 nM/100 mg of DPOC-4088 administered over a period of at least about 16 hours following a single oral dose, wherein the extended release formulation comprises a tablet core comprising the DPOC-4088 and a matrix forming polymer configured to modulate a release of the DPOC-4088 from the tablet core, wherein the extended release formulation provides a blood plasma concentration of DPOC-4088 of greater than 200 nM/100 mg of DPOC-4088 administered over a period of 20 hours following a single oral dose, and wherein the tablet core comprises:
200.00 mg DPOC-4088;
54.75 mg manitol;
30.00 mg povidone;
50.00 mg poloxamers;
120.00 mg hypromellose;
5.00 mg colloidal anhydrous silica;
0.50 mg ferric oxide; and
4.75 mg magnesium stearate.
7. The method of claim 1 , wherein the therapeutic blood plasma concentration of DPOC-4088 is provided to treat a thromboembolism in the patient in need thereof.
8. The method of claim 1 , wherein the matrix forming polymer comprises from about 10% to about 50% by weight of the extended release formulation.