Pharmaceutical Compositions Comprising Ledipasvir And Sofosbuvir

Abstract

The present invention relates to novel pharmaceutical compositions comprising Ledipasvir and Sofosbuvir as well as to methods for their preparation.

Claims

1. A pharmaceutical composition comprising a compound of formula (I) ##STR00005## or a pharmaceutically acceptable salt or solvate thereof and a compound of formula (II) ##STR00006## or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula (I) and the compound of formula (II) are in amorphous form.

2. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is a solid dispersion.

3. The pharmaceutical composition of claim 1, wherein the compound of formula (II) is a solid dispersion.

4. The pharmaceutical composition of claim 1, wherein the compound of formula (I) and the compound of formula (II) are a homogeneous solid dispersion.

5. The pharmaceutical composition of claim 1 further comprising at least one pharmaceutically acceptable excipient.

6. The pharmaceutical composition of claim 5, wherein the at least one pharmaceutically acceptable excipient is a pharmaceutically acceptable polymer.

7. The pharmaceutical composition of claim 6, wherein the at least one pharmaceutically acceptable polymer is selected from the group consisting of hypromellose, copovidone and povidone.

8. The pharmaceutical composition of claim 1 in the form of a tablet.

9. A tablet composition comprising the pharmaceutical composition of claim 1.

10. The tablet composition of claim 9, further comprising at least one pharmaceutically acceptable excipient.

11. The pharmaceutical composition of claim 5, wherein the at least one pharmaceutically acceptable excipient further comprises at least one diluent, or at least one disintegrant, or at least one glidant, or at least one lubricant, or a combination of two or more thereof.

12. A process for the preparation of a pharmaceutical composition comprising a compound of formula (I) ##STR00007## or a pharmaceutically acceptable salt or solvate thereof and a compound of formula (II) ##STR00008## or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula (I) and the compound of formula (II) are in amorphous form, the process comprising the steps of: (i) providing a compound of formula (I) or a pharmaceutically acceptable solvate or salt thereof, (ii) providing a compound of formula (II) or a pharmaceutically acceptable salt thereof, (iii) mixing the compound of formula (I) or a pharmaceutically acceptable solvate or salt thereof and the compound of formula (II) or a pharmaceutically acceptable salt thereof, (iv) optionally blending the mixture provided in (iii) with at least one pharmaceutically acceptable excipient, and (v) optionally preparing a tablet based on the blend obtained in (iv).

13. The process of claim 12, wherein (iii) comprises (iii.1) adding a suitable amount of a pharmaceutically acceptable matrix to the compound of formula (I) and to the compound of formula (II) provided in (i) and (ii), (iii.2) adding a suitable amount of at least one suitable solvent, (iii.3) removing the at least one solvent, and (iii.4) optionally milling and drying the solid resulting from (iii.3)

14. The process of claim 13, wherein the pharmaceutically acceptable matrix is a pharmaceutically acceptable polymer.

15. The process of any of claim 13, wherein the at least one suitable solvent is ethanol.

Description

EXPERIMENTAL

[0416] The present invention is further illustrated by the following examples.

Reference Example 1: Determination of Physical Parameters

[0417] 1.1 X-Ray Powder Diffraction (XRPD) Patterns

[0418] XRPD patterns were obtained with an X'Pert PRO diffractometer (PANalytical, Alme-lo, The Netherlands) equipped with a theta/theta coupled goniometer in transmission geometry, programmable XYZ stage with well plate holder, Cu-Kalpha1,2 radiation source (wavelength 0.15419 nm) with a focusing mirror, a 0.5° divergence slit, a 0.02° soller slit collimator and a 0.5° anti-scattering slit on the incident beam side, a 2 mm anti-scattering slit, a 0.02° soller slit collimator, a Ni-filter and a solid state PIXcel de-tector on the diffracted beam side. The diffractogram was recorded at room temperature at a tube voltage of 40 kV, tube current of 40 mA, applying a step size of 0.013° 2-theta with 40 sec per step in the angular range of 2° to 40° 2-theta. A typical precision of the 2-theta values is in the range of +0.2° 2-theta. Thus, a diffraction peak that appears for example at 8.1° 2-theta can appear between 7.9 and 8.3° 2-theta on most X-ray diffractometers under standard conditions.

Comparative Example 1—Preparation of an Amorphous Solid Dispersion of the Compound of Formula (I) (Ledipasvir)

[0419] 1.1 g Ledipasvir acetone solvate (crystalline Form II) prepared according to WO2013/184702 and 1.0 g Copovidone (Kollidon V64, BASF) were dissolved in 10 g ethanol and the resulting solution was evaporated to dryness in a rotary evaporator at 40° C. and 900-20 mbar. The resulting solid was grinded and dried at 60° C. for 15 hours. XRPD analysis of the solid confirmed the presence of the compound of formula (I) in amorphous form. The XRPD pattern is shown in FIG. 1.

Comparative Example 2—Preparation of a Crystalline Solid Dispersion of the Compound of Formula (I) (Ledipasvir)

[0420] 1.1 g Ledipasvir acetone solvate (crystalline Form II) prepared according to WO2013/184702 was suspended in a solution of 1.0 g Copovidone (Kollidon V64, BASF) in 3.0 g water and the solvent was evaporated to dryness in a rotary evaporator at 40° C. and 900-20 mbar. The resulting solid was grinded and dried at 60° C. for 16 hours. XRPD analysis of the solid confirmed the presence of the compound of formula (I) in crystalline Form II. The XRPD pattern is shown in FIG. 2.

Comparative Example 3—Preparation of Compositions in the Form of a Tablet Comprising an Amorphous or a Crystalline Solid Dispersion of the Compound of Formula (I) (Ledipasvir) and the Compound of Formula (II) (Sofosbuvir) in Crystalline Form VII

[0421] Sofosbuvir of polymorphic Form VII was prepared by the process described above for example in 1.4. 2.0 g of polymorphic Form VII of the compound of formula (II) were blended with 900 mg of the solid dispersion of the compound of formula (I) prepared according to example 1 or to example 2, 0.825 g lactose, 0.4 g MCC 101, 125 mg crosscarmellose, 50 mg silicium dioxide and 37.5 mg magnesium stearate. For blending the compounds, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 10-25 kN to obtain flat tablets having a diameter of 10-25 mm. These tablets were crushed over a sieve having a mesh size of 0.5-1.5 mm. The obtained granulate was admixed with 500 mg MCC 101, 125 mg crosscarmellose and 37.5 mg magnesium stearate. For admixing the granulate with the excipients, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 10-25 kN to obtain 1000 mg oblong tablets of dimensions 18×8 mm. In particular, the tablets had the following compositions shown in Table 1, divided in intragranular and extragranular portions:

TABLE-US-00002 content content Component [mg] [mg] Intragranular Sofsobuvir polymorphic form VII 400 400 Ledipasvir solid dispersion 180 according to example 1 Ledipasvir solid dispersion 180 according to example 2 Lactose 165 165 MCC 101 80 80 Crosscarmellose 25 25 Silicium dioxide 10 10 Magnesium stearate 7.5 7.5 Extragranular MCC 101 100 100 Crosscarmellose 25 25 Magnesium stearate 7.5 7.5 Total 1000 1000

Comparative Example 4—Preparation of Compositions in the Form of a Tablet Comprising an Amorphous or a Crystalline Solid Dispersion of the Compound of Formula (I) (Ledipasvir) and the Compound of Formula (II) (Sofosbuvir) in Amorphous Form

[0422] Sofosbuvir of polymorphic Form I was prepared according to WO 2011/123645 A, Example 10. 2.0 g of polymorphic Form I of the compound of formula (II) were blended with 900 mg of the solid dispersion of the compound of formula (I) prepared according to example 1 or to example 2 and the mixture was molten. The solidified molten product was crushed over a sieve having a mesh size of 0.5-1.5 mm. The obtained granulate was admixed with 825 mg lactose, 900 mg MCC 101, 250 mg crosscarmellose, 50 mg silicon dioxide and 70 mg magnesium stearate. For admixing the granulate with the excipients, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 10-25 kN to obtain 1000 mg oblong tablets of dimensions 18×8 mm. In particular, the tablets had the following compositions shown in Table 2:

TABLE-US-00003 content content Component [mg] [mg] Intragranular Sofsobuvir I 400 400 Ledipasvir solid dispersion 180 according to example 1 Ledipasvir solid dispersion 180 according to example 2 Lactose 165 165 MCC 101 180 180 Crosscarmellose 50 50 Silicondioxid 10 10 Magnesium stearate 15 15 Total 1000 1000

Comparative Example 5—Preparation of an Amorphous Solid Dispersion Comprising the Compound of Formula (I) (Ledipasvir) and the Compound of Formula (II) (Sofosbuvir)

[0423] Form I of sofosbuvir was prepared according to WO 2011/123645 A1, Example 10. 1.1 g Ledipasvir acetone solvate (crystalline Form II) prepared according to WO2013/184702, 4.4 g Sofosbuvir (Form I) and 1.0 g Copovidone (Kollidon V64, BASF) were dissolved in 16 g ethanol and the resulting solution was evaporated to dryness in a rotary evaporator at 40° C. and 900-20 mbar. The resulting solid was grinded and dried at 60° C. for 18 hours. XRPD analysis of the solid confirmed the presence of the compound of formula (I) and compound of formula (II) in amorphous form. The XRPD pattern is shown in FIG. 3.

Comparative Example 6—Preparation of a Composition in the Form of a Tablet Comprising an Amorphous Solid Dispersion Comprising the Compound of Formula (I) (Ledipasvir) and the Compound of Formula (II) (Sofosbuvir)

[0424] 2900 g of the amorphous solid dispersion of Ledipasvir and Sofosbuvir prepared according to example 5 were blended with 825 mg lactose, 400 mg MCC 101, 125 mg crosscarmellose, 50 mg silicon dioxide and 37.5 mg magnesium stearate. For blending the compounds, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 5-15 kN to obtain flat tablets having a diameter of 10-25 mm. These tablets were crushed over a sieve having a mesh size of 0.5-1.5 m. The obtained granulate was admixed with 500 mg MCC 101, 125 mg crosscarmellose and 37.5 mg magnesium stearate. For admixing the granulate with the excipients, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 10-25 kN to obtain 1000 mg oblong tablets of dimensions 18×8 mm. In particular, the tablets had the following compositions shown in Table 3, divided in intragranular and extragranular portions:

TABLE-US-00004 content Component [mg] Intragranular Ledipasvir and Sofosbuvir solid dispersion 580 according to Example 5 Lactose 165 MCC 101 80 Crosscarmellose 25 Silicondioxid 10 Magnesium stearate 7.5 Extragranular MCC 101 100 Crosscarmellose 25 Magnesium stearate 7.5 Total 1000

Comparative Example 7—Preparation of a Composition in the Form of a Tablet Comprising an Amorphous Solid Dispersion Comprising the Compound of Formula (I) (Ledipasvir) and the Compound of Formula (II) (Sofosbuvir)

[0425] 2900 mg of the amorphous solid dispersion of Ledipasvir and Sofosbuvir prepared according to example 5 were blended with 825 mg lactose, 900 MCC 101, 250 mg crosscarmellose, 50 mg silicon dioxide and 70 mg magnesium stearate. For admixing the granulate with the excipients, an overhead reax mixture was used. The obtained mixture was compressed under a pressure of 10-25 kN to obtain 1000 mg oblong tablets of dimensions 18×8 mm. In particular, the tablets had the following compositions shown in Table 4:

TABLE-US-00005 content Component [mg] Intragranular Ledipasvir and Sofosbuvir solid dispersion 580 according to Example 5 Lactose 165 MCC 101 180 Crosscarmellose 50 Silicondioxid 10 Magnesium stearate 15 Total 1000

Comparative Example 8—Composition Comprising the Crystalline Compound of Formula I (Ledipasvir) for Dissolution Studies

[0426]

TABLE-US-00006 content Component [mg] Crystalline Ledipasvir acetone solvate 200 Polysorbat 80 100

[0427] 200 mg crystalline Ledipasvir acetone solvate (crystalline Form II) prepared according to WO2013/184702 and 100 mg Polysorbat 80 were blended in a mortar with a pistil until a homogenous mixture was achieved.

Comparative Example 9—Dissolution Experiments

[0428] The dissolution profiles for Sofosbuvir and Ledipasvir in the compositions according to Comparative Examples 3a, 3b, 4b and 7 above were determined using a USP Type 2 dissolution apparatus in 900 ml 1,5% polysorbate 80 in 10 mM Sodium phosphate Puffer pH 6.0 as the medium with 75 rpm at 37° C. (i.e. using the same conditions described in WO2014/120981). In addition, the dissolution profile for a composition comprising only Ledipasvir (see Comparative Example 8) was also determined using the same conditions as described above.

[0429] As can be seen from FIGS. 4 and 5 below, under the tested experimental conditions the solubility of Ledipasvir alone is very low, resulting in less than 20% dissolution after 70 minutes. In contrast, using the compositions of the invention, the dissolution of both Sofosbuvir and Ledipasvir, and in particular of Ledipasvir, was very fast under the tested experimental conditions, resulting in an increased dissolution rate.

[0430] In particular, the tablet composition according to Comparative Example 7 wherein Sofosbuvir is in amorphous form and Ledipasvir is in amorphous form results in complete dissolution for both compounds after 70 minutes. This is comparable to the data reported in WO2014/120981, which reports dissolution data for compositions comprising crystalline Sofosbuvir and amorphous Ledipasvir. According to WO2014/120981 ([173]), the tablet formulations described therein display greater than 85% dissolution for both compounds after 30 minutes. The tablet composition according to Comparative Example 7 of the present invention shows >99% dissolution for Sofosbuvir after 30 minutes. For Ledipasvir, 74% dissolution is achieved after 30 minutes and 87% dissolution is reached after 40 minutes, which is comparable to the compositions of WO2014/120981. However, unlike the compositions of WO2014/120981, the tablet composition according to Comparative Example 7 of the present invention comprises both active compounds Sofosbuvir and Ledipasvir in an amorphous form. In addition to the advantageous dissolution rate, this composition is much easier to prepare, since both active compounds (i.e. the compounds of formula (I) Ledipasvir and of formula (II) Sofosbuvir) as well as suitable excipients (such as for example copovidone) can be dissolved in a single solvent system and then dried, leading to a composition comprising both compounds of formula (I) and of formula (II) which can be easily prepared in a single process step. Advantageously, only one solvent system is needed, which eliminates the use of further solvents or solvent mixtures, and the mixture can be dried employing a variety of methods such as described in Comparative Example 5 (such as for example solvent evaporation, spray-drying, lyophilization, melt extrusion and other similar methods known in the art).

[0431] Another preparation having the advantages described above (i.e.such as increased solubility and ease of preparation) is the use of a melt-extrusion process. Advantageously, the compound of formula (I) Ledipasvir either in amorphous or in crystalline form can be dissolved in a suitable solvent (such as for example ethanol) and admixed with the compound of formula (II) Sofosbuvir either in crystalline or amorphous form and with suitable excipients (such as for example copovidone). Subjecting the mixture to melt extrusion leads to a composition in which both active compounds are in amorphous form and in the form of a solid dispersion. Advantageously, only one solvent system is needed, which eliminates the use of further solvents or solvent mixtures.

[0432] Even more advantageously, the compound of formula (I) Ledipasvir in amorphous form can be admixed with the compound of formula (II) Sofosbuvir either in crystalline or amorphous form and with suitable excipients (such as for example copovidone) and the resulting mixture can be subjected to a melt extrusion process thus leading to a composition in which both active compounds are in amorphous form and in the form of a solid dispersion. In this case, no solvent is needed at all, resulting in a simple, unwasteful and efficient process.

[0433] The thus advantageously obtained compositions described above can then be easily formulated into a tablet, such as the tablet composition of Comparative Example 7.

SHORT DESCRIPTION OF THE FIGURES

[0434] FIG. 1 shows a representative X-ray powder diffraction (XRPD) pattern of a solid dispersion comprising the compound of formula (I) in amorphous form according to Comparative Example 1 of the present invention, as determined according to Reference Example 1.1. The x-axis shows the 2-theta angle/°, with tick marks, from left to right, at 10, 20, 30° 2-theta. The y-axis shows the intensity/counts, with tick marks, from bottom to top, at 200, 400, 600, 800, 1000, 1200, 1400.

[0435] FIG. 2 shows a representative X-ray powder diffraction (XRPD) pattern of a solid dispersion comprising the compound of formula (I) in crystalline Form II according to Comparative Example 2 of the present invention, as determined according to Reference Example 1.1. The x-axis shows the 2-theta angle/°, with tick marks, from left to right, at 10, 20, 30° 2-theta. The y-axis shows the intensity/counts, with tick marks, from bottom to top, at 200, 400, 600, 800, 1000, 1200, 1400.

[0436] FIG. 3 shows a representative X-ray powder diffraction (XRPD) pattern of a solid dispersion comprising the compound of formula (I) and the compound of formula (II) in amorphous form according to Comparative Example 5 of the present invention, as determined according to Reference Example 1.1. The x-axis shows the 2-theta angle/°, with tick marks, from left to right, at 10, 20, 30° 2-theta. The y-axis shows the intensity/counts, with tick marks, from bottom to top, at 200, 400, 600, 800, 1000, 1200, 1400.

[0437] FIG. 4 shows the dissolution profile of the compound of formula I Ledipasvir for the compositions according to Comparative Examples 3a, 3b, 4b, 7 and 8. The x-axis shows the time in minutes and the y-axis shows the % of dissolved compound of formula I.

[0438] FIG. 5 shows the dissolution profile of the compound of formula II Sofosbuvir for the compositions according to Comparative Examples 3a, 3b, 4b and 7. The x-axis shows the time in minutes and the y-axis shows the % of dissolved compound of formula II.