PROCESS AND DEVICE FOR PREPARING A SOLID DISPERSION

Abstract

The present invention relates to a melt extrusion process for preparing a solid dispersion comprising a pharmaceutically active ingredient, a polymeric binder, and, optionally, one or more auxiliary agents, comprising a) in a batch-wise operation, placing a pre-determined amount of the polymeric binder, a pre-determined amount of the active ingredient, and, optionally, a pre-determined amount of the auxiliary agent(s) in a melting vessel; melting the polymeric binder with agitation to disperse the active ingredient in the polymeric binder to obtain a molten pre-dispersion; b) feeding the pre-dispersion into an extruder to homogenize the pre-dispersion and release a melt through a die; and c) allowing the melt to solidify.

Claims

1. A melt extrusion process for preparing a solid dispersion comprising a pharmaceutically active ingredient, a polymeric binder, and, optionally, one or more auxiliary agents, comprising a) in a batch-wise operation, placing a pre-determined amount of the polymeric binder, a pre-determined amount of the active ingredient, and, optionally, a pre-determined amount of the auxiliary agent(s) in a melting vessel; melting the polymeric binder in the melting vessel with agitation to disperse the active ingredient in the polymeric binder to obtain a molten pre-dispersion; b) feeding the pre-dispersion into an extruder to homogenize the pre-dispersion and release a melt through a die; and c) allowing the melt to solidify, wherein at least one of the active ingredient, the polymeric binder, and the auxiliary agent comprise a component that is semi-solid, tacky or viscous at ambient temperature.

2. The process of claim 1, wherein the polymeric binder and the pharmaceutically active ingredient together amount for at least 80 wt-% of the total weight of the pre-dispersion.

3. The process according to claim 1, wherein the polymeric binder comprises a semi-solid polymeric binder component with a glass transition temperature below 40 C. and a solid polymeric binder component.

4. The process according to claim 3, wherein the solid polymeric binder component has a glass transition temperature of 10 C. or higher.

5. The process according to claim 3, wherein the semi-solid polymeric binder component is a poly(lactide-co-glycolide) having a molecular weight distribution centered around a number average molecular weight Mn2 and the solid polymeric binder component is a poly(lactide-co-glycolide) having a molecular weight distribution centered around a number average molecular weight Mn1, wherein Mn1 is in the range of from 2000 to 3000 g/mol and the ratio of Mn1/Mn2 is from 1.8 to 3.5.

6. The process according to claim 3, wherein the weight ratio of semi-solid polymeric binder component to solid polymeric binder component is from 1:10 to 1.5:1.

7. The process according to claim 1, wherein the active ingredient is selected from nicardipine, a pharmaceutically acceptable salt, hydrate or solvate thereof.

8. The process according to claim 1, wherein at least part of the polymeric binder is placed in the melting vessel and is at least partially molten before the active ingredient, and, optionally, the auxiliary agent(s) is (are) placed in the melting vessel.

9. The process according to claim 1, wherein an ultrasonic treatment is carried out while dispersing the active ingredient in the polymeric binder and/or after dispersing the active ingredient in the polymeric binder.

10. The process according to claim 1, wherein the temperature of the pre-dispersion while being fed into the extruder is above its solidification temperature.

11. The process according to claim 1, wherein feeding the pre-dispersion into the extruder involves a displacement of the pre-dispersion from the melting vessel through an opening of the melting vessel, the displacement of the pre-dispersion being enforced by reducing a volume of the melting vessel being accessible for the pre-dispersion.

12. The process according to claim 11, wherein the volume of the melting vessel being accessible for the pre-dispersion is reduced by a translational movement of a displacement element, e.g., a punch, into the melting vessel.

13. The process according to claim 1, wherein the pharmaceutically active ingredient and/or at least part of the polymeric binder is comminuted before it is placed in the melting vessel.

Description

EXAMPLE 1

[0082] PLGA Resomer Mn 2300 (98.42 g) and PLGA Resomer Mn 800 (37.49 g) were directly weighed into a mixing and melting beaker at a temperature of 90 C. After approximately ten minutes, the polymers were sufficiently liquid so that the portion of nicardipine base (15.28 g) could be incorporated into the melt. After the nicardipine base had been melted and incorporated by agitation, the pre-dispersion was treated in the beaker with an ultrasonic device at a temperature of 100 C. After 5 minutes of ultrasonic treatment with 20 kHz, the lid was closed and the molten pre-dispersion was transferred with a punch into a twin screw extruder (type: Mini CTW). Extrusion was performed at 68 C., while the temperature of the lid was reduced to 70 C.

[0083] After extrusion, the strand was applied on a conveyor belt to adjust the diameter by setting of belt velocity. When the extrudate had reached ambient temperature, segments (length=10 cm) were cut and stored in appropriate vials with desiccant. During extrusion the conveyor belt velocity was adjusted to 70 mm/min (+/10 mm/min), while the extruder torque was balanced to 15 Ncm (+/3 Ncm) at a screw speed of 3 rpm. The yield of extrusion was measured to be 78% (118.5 g output of 151.2 g input), mainly due to material losses at the beginning and end of extrusion as well as losses by material transfer of melting container to extruder.

[0084] Homogeniety of the contents of the beaker was monitored by routine analysis of samples taken from the beaker before and after agitation and at defined timepoints after start of extrusion. The results are summarized in Table 1

TABLE-US-00001 TABLE 1 Analysis of contents of the beaker Sample taken Expected Measured from position in amount of amount of Timepoint beaker nicardpine [mg] nicardipine [mg] after melting, middle 40 43.7 before start of agitation after melting, edge 1 40 40.5 before start of agitation after melting, edge 2 40 44.5 before start of agitation after agitation middle 40 41.7 after agitation edge 1 40 43.1 after agitation edge 2 40 42.5 start of random 120 122.0 extrusion after 30 min of random 120 122.4 extrusion after 60 min of random 120 126.0 extrusion after 120 min random 120 126.3 of extrusion after 180 min random 120 122.1 of extrusion

[0085] Table 1 demonstrates high uniformity of the contents of the beaker throughout the process of the invention.

EXAMPLE 2

[0086] One portion of PLGA Resomer Mn 2300 (37.61 g) was mixed with nicardipine base (15.19 g). A second portion of PLGA Resomer Mn 2300 was weighed (58.54 g). The mixture of PLGA Resomer Mn 2300 with nicardipine base and the second portion of PLGA Resomer Mn 2300 were cryogenically milled as shown in Table 2, i.e. one portion of PLGA Resomer Mn 2300 was milled separately and the second portion of PLGA Resomer Mn 2300 was milled with nicardipine base.

TABLE-US-00002 TABLE 2 Cryogenic milling Precool [min] 10 Milling cycle [min] 2 Intermediate cooling time [min] 2 Number of cycles 2 Frequency [Hz] 15

[0087] The PLGA Resomer Mn 800 (37.69 g) was directly poured into the melting and mixing beaker until sufficiently liquid by applying 80 C. for 5 minutes. The milled mixture and the milled second portion of PLGA Resomer Mn 2300 were added to the already molten PLGA Resomer Mn 800. This mixture was melted at 90 C. for 10 minutes and subsequently homogenized by applying ultrasound for 5 minutes at 20 Hz and 100 C.

[0088] Transfer into the extruder and extrusion were carried out as described for example 1.

[0089] After extrusion, the strand was applied on a conveyor belt to adjust the diameter by setting of belt velocity. When the extrudate had reached ambient temperature, segments (length=10 cm) were cut and stored in appropriate vials with desiccant. Conveyor belt velocity was 95 mm/min (+/5 mm/min). Extruder torque was 10 Ncm (+/3 Ncm). A yield of 86% was reached.

[0090] Homogeniety of the contents of the beaker was monitored by routine analysis of samples taken from the beaker before and after agitation and at defined timepoints after start of extrusion. The results are summarized in Table 3

TABLE-US-00003 TABLE 3 Analysis of contents of the beaker Sample taken Expected Measured form position in amount of amount of Timepoint beaker nicardpine [mg] nicardipine [mg] after melting, middle 40 41.1 before start of agitation after melting, edge 1 40 40.6 before start of agitation after melting, edge 2 40 39.8 before start of agitation after agitation middle 40 41.1 after agitation edge 1 40 40.0 after agitation edge 2 40 40.5 start of random 120 120.3 extrusion after 30 min of random 120 120.1 extrusion after 60 min of random 120 119.8 extrusion after 120 min random 120 119.8 of extrusion after 155 min random 120 119.7 of extrusion

[0091] Table 3 demonstrates high uniformity of the contents of the beaker throughout the process of the invention.

[0092] It is important to note that uniformity of the contents of the beaker in table 1, i.e. without cryo-milling, was fully sufficient for feeding it into an extruder. This demonstrates that it is not necessary to comminute any of the constituents before placing them into the beaker.