Pharmaceutical formulation of odevixibat
The invention relates to a pharmaceutical formulation, e.g. a paediatric formulation, of odevixibat, which comprises a plurality of small particles. The formulation may be used in the treatment of liver diseases such as bile acid-dependent liver diseases, and particularly cholestatic liver diseases such as biliary atresia, progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome (ALGS) and paediatric cholestatic pruritus. The invention also relates to a process for the preparation of the pharmaceutical formulation.
1. A pharmaceutical formulation of odevixibat, comprising a plurality of particles, wherein each particle is between about 0.1 and about 1.5 mm in size and comprises:
a) a core, and
b) a coating layer surrounding the core, wherein the coating layer comprises odevixibat or a pharmaceutically acceptable salt thereof, in an amount of from about 0.1% w/w to about 5.0% w/w based on the total weight of the particle, and a film-forming polymer;
wherein each particle of the formulation substantially contains the same amount of odevixibat; and
wherein the coating layer comprises odevixibat agglomerates having a d 90 particle size distribution of less than 15 μm.
2. The formulation according to claim 1 , wherein each particle contains odevixibat, or a pharmaceutically acceptable salt thereof, in an amount of from about 0.5% w/w to about 2.0% w/w based on the total weight of the particle.
3. The formulation according to claim 1 , wherein each particle contains odevixibat, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5% w/w based on the total weight of the particle.
4. The formulation according to claim 1 , wherein each particle contains odevixibat, or a pharmaceutically acceptable salt thereof, in an amount of about 1.5% w/w based on the total weight of the particle.
5. The formulation according to claim 1 , wherein the core does not contain odevixibat.
6. The formulation according to claim 1 , wherein the core comprises microcrystalline cellulose.
7. The formulation according to claim 1 , wherein the coating layer is prepared by spraying onto the cores a homogeneous suspension of odevixibat in water.
8. The formulation according to claim 7 , wherein the homogenous suspension is prepared by dispersing odevixibat in water by wet milling.
9. The formulation according to claim 7 , wherein the homogenous suspension does not contain agglomerates of odevixibat that are larger than 200 μm.
10. The formulation according to claim 1 , wherein the coating layer does not contain a surfactant.
11. The formulation according to claim 1 , wherein the particles are between about 0.1 and about 1.0 mm in size.
12. The formulation according to claim 1 , wherein odevixibat is present as a crystalline hydrate of odevixibat.
13. The formulation according to claim 1 , wherein odevixibat is present as crystal modification 1 of odevixibat.
14. The formulation according to claim 13 , wherein crystal modification 1 of odevixibat has an X-ray powder diffraction (XRPD) pattern, obtained with CuKα1-radiation, with at least specific peaks at °2θ positions 5.6±0.2, 6.7±0.2 and/or 12.1±0.2.
15. The formulation according to claim 1 , which is a paediatric formulation.
16. The pharmaceutical formulation of claim 1 , wherein the coating layer comprises odevixibat agglomerates having a d 90 particle size distribution of less than 12 μm.