ST-246 (tecovirimat monohydrate) suspension formulations
The present invention is directed to a dry suspension for reconstitution containing Tecovirimat (ST-246) powder and simethicone. The dry suspension is dispersed in water to provide an aqueous pharmaceutical suspension formulation for oral administration for treating orthopoxvirus infections and/or eczema vaccinatum. The suspension formulation exhibits excellent stability and good dissolution and has an improved taste and texture.
1. A dry suspension comprising polymorph Form I of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2-(1H)-yl)-benzamide (Tecovirimat (ST-246)) and simethicone.
2. A dry suspension according to claim 1 further comprising at least one suspending agent.
3. A dry suspension according to claim 2 wherein the suspending agent is methylcellulose or hydroxypropyl cellulose.
4. A dry suspension according to claim 3 wherein the methylcellulose is methylcellulose 400 Cps; or wherein the methylcellulose is 15 Cps.
5. A dry suspension according to claim 2 comprising methylcellulose and hydroxypropyl cellulose.
6. A dry suspension according to claim 1 further comprising one or more of a lubricant, an excipient, an antifoaming agent, a sweetener, and/or a flavoring.
7. A dry suspension according to claim 6 wherein the lubricant is magnesium stearate and/or wherein the excipient is lactose monohydrate.
8. A dry suspension according to claim 1 wherein the ST-246 is micronized; or wherein the ST-246 is granulated.
9. A dry suspension according to claim 1 wherein the simethicone is granular form; or wherein the simethicone is in liquid form and adsorbed on lactose monohydrate.
10. A dry suspension according to claim 1 comprising one or more of 10 to 70 wt % of ST-246; 0.2 to 6.0 wt % simethicone; 1 to 5 wt % methylcellulose; 1.0 to 30 wt % hydroxypropylcellulose; 0.1 to 1.0 wt % of lubricant; 10 to 20 wt % of excipient; 1.0 to 3.0 wt % of sweetener; and/or 0.1 to 1.0 wt % of flavoring.
11. A dry suspension according to claim 1 wherein the particle size of ST-246 is 0.5 to 10 μm.
12. An aqueous pharmaceutical suspension formulation comprising a dry suspension according to claim 1 and water; wherein the aqueous pharmaceutical suspension formulation optionally further comprises a pharmaceutically acceptable ingredient.
13. A formulation according to claim 12 wherein the pharmaceutically acceptable ingredient is selected from the group consisting of carrier, excipient, diluent, additive, filler, lubricant and binder.
14. A formulation according to claim 12 having a pH between 4 and 7.
15. A method of treating orthopoxvirus infections and/or eczema vaccinatum comprising oral administration to a subject in need thereof a formulation according to claim 12 .
16. The method of claim 15 , wherein the subject is administered 400 mg to 2000 mg daily of ST-246.
17. A process of making the dry suspension according to claim 1 comprising mixing ST-246 with simethicone and optionally at least one suspending agent, at least one lubricant, at least one excipient, at least one further anti-foaming agent, at least one sweetener and/or at least one flavoring.
18. A process according to claim 17 wherein the mixing is carried out using geometric mixing.
19. A method of making the formulation according to claim 12 comprising dispersing the dry suspension in water; wherein the water optionally contains a suspending agent.