Pharmaceutical compositions of mifepristone
Pharmaceutical compositions and stable nano-suspensions comprising mifepristone and at least one pharmaceutically acceptable excipient, which exhibit enhanced bioavailability compared to the currently marketed or commercially available formulations. Manufacturing process and methods of use are also provided. The pharmaceutical compositions are used for prevention, treatment or prophylaxis of disorders in human patients in need thereof. Oral pharmaceutical compositions of mifepristone, methods for their administration, processes for their production, and use of these compositions are described for the treatment of diseases for which mifepristone is indicated.
1. An oral pharmaceutical composition comprising:
(a) a therapeutically effective dose of mifepristone having an average D90 particle size less than 1000 nm;
(b) a surface stabilizer; and
(c) optionally, at least one pharmaceutically acceptable excipient;
wherein the oral pharmaceutical composition is an immediate-release pharmaceutical composition;
wherein the oral pharmaceutical composition is a tablet or a capsule;
wherein the oral pharmaceutical composition provides an in-vitro release of not less than about 70 wt % of the mifepristone, within 45 minutes of dissolution in a 900 mL pH 1.8 potassium chloride dissolution medium, measured using USP Apparatus II, at 50 RPM and 37° C.; and
wherein the therapeutically effective dose of mifepristone in the oral pharmaceutical composition is reduced by at least 10% compared to therapeutically effective dose of mifepristone in a reference composition, when administered to a human subject.
2. The oral pharmaceutical composition according to claim 1 , wherein a therapeutically effective dose of mifepristone administered in the pharmaceutical composition is 250 mg.
3. The oral pharmaceutical composition according to claim 1 , wherein a therapeutically effective dose of mifepristone administered in the reference composition is 300 mg.
4. The oral pharmaceutical composition according to claim 1 , wherein the surface stabilizer is a non-ionic surfactant, a cationic surfactant, an anionic surfactant, or a zwitterionic surfactant.
5. An oral pharmaceutical composition of claim 1 , prepared by:
(a) mixing mifepristone and a surface stabilizer with purified water, and milling to obtain a nano-suspension containing mifepristone with an average D90 particle size less than 1000 nm;
(b) spraying the nano-suspension from (a) onto an intra-granular material and drying to obtain granules;
(c) mixing the granules from (b) with an extra-granular material to obtain a blend; and
(d) compressing the blend from (c) into a tablet or filling it into a capsule;
(e) optionally, coating the tablet,
wherein the oral pharmaceutical composition is an immediate-release pharmaceutical composition;
wherein the oral pharmaceutical composition provides an in-vitro release of not less than about 70 wt % of the mifepristone, within 45 minutes of dissolution in a 900 mL pH 1.8 potassium chloride dissolution medium, measured using USP Apparatus II, at 50 RPM and 37° C.
6. The pharmaceutical composition according to claim 5 , wherein the intra-granular material comprises at least one pharmaceutically acceptable excipient.
7. The pharmaceutical composition according to claim 5 , wherein the extra-granular material comprises at least one pharmaceutically acceptable excipient.
8. The pharmaceutical composition according to claim 6 , wherein the pharmaceutically acceptable excipient is selected from diluents, binders, disintegrants, lubricants, glidants, surfactants, plasticizers, solubilizers, antioxidants, or mixtures thereof.
9. The pharmaceutical composition according to claim 7 , wherein the pharmaceutically acceptable excipient is selected from diluents, binders, disintegrants, lubricants, glidants, surfactants, plasticizers, solubilizers, antioxidants, or mixtures thereof.
10. The pharmaceutical composition according to claim 5 , wherein the intra-granular material is selected from silicified microcrystalline cellulose, sodium starch glycolate, or mixtures thereof.
11. The pharmaceutical composition according to claim 5 , wherein the extra-granular material is selected from microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, or mixtures thereof.
12. An oral pharmaceutical composition according to claim 5 , wherein the surface stabilizer is a non-ionic surfactant, a cationic surfactant, an anionic surfactant, or a zwitterionic surfactant.