DEVICE FOR THE CONTINUOUS PRODUCTION OF SOLID DOSAGE FORMS, AND USE OF SAID DEVICE FOR MEDICINAL DRUGS AND/OR USE THEREOF FOR FOOD SUPPLEMENTS

Abstract

A device for the continuous production of a solid form, including: an extruder for mixing and hot-melting at least one component with at least one polymer for an amorphous solution; and a cutting device mounted downstream of the extruder, for cutting the semi-solid bead that results from the melting of the mixture of the component with the polymer for an amorphous solid solution, the cutting device being combined with a forming system for forming the solid form supplied by the cutting device.

Claims

1. A device for preparing continuously solid forms, the device comprising: an extruder configured to mix and hot melt at least one component with at least one polymer for amorphous solution; a chopper mounted downstream of the extruder, wherein the chopper is configured to chop a semisolid rod resulting from melting the mixture of the component with the polymer for amorphous solid solution; said chopper being configured with a forming system configured to shape the solid form delivered by the chopper, wherein the chopper comprises an actuating system of a knife, said actuating system being associated with a motor with an alternating piston actuating a to and fro movement of the knife between two extreme positions, an initial position before chopping and a final position after chopping.

2. The device as claimed in claim 1, wherein the chopper is mounted on a die of the extruder.

3. The device as claimed in claim 1, wherein the chopper is also arranged with a cooling system oriented toward the surface of the semisolid rod, wherein the device is capable of producing solid forms at a controlled temperature.

4. The device as claimed in claim 3, wherein the cooling system comprises a blower arranged downstream of a die of the extruder.

5. The device as claimed in claim 3, wherein the cooling system comprises an annular air jet provided with openings focused on an orifice of the die.

6. The device as claimed in claim 1, wherein the knife of the actuating system is mounted on a sliding arm with a compression spring that is arranged for pushing the knife back along the sliding arm.

7. The device as claimed in claim 6, further comprising a fixed spindle, about which the sliding arm swivels.

8. The device as claimed in claim 1, wherein the actuating system also comprises a pawl provided with a shoulder allowing the knife to avoid the rod in its return movement to the initial position before chopping.

9. The device as claimed in claim 8, wherein the pawl is arranged to swivel about a spindle as far as a stop.

10. The device as claimed in claim 1, wherein the knife further comprises a cam arranged for sliding on a shoulder of a pawl during return of the knife to its position before chopping.

11. The device as claimed in claim 1, wherein the to and fro movement of the knife takes place at a frequency of between 0.1 and 1 m/s.

12. The device as claimed in claim 1, wherein the forming system comprises two corotating Archimedean screws with an angular displacement between 0 and 20.

13. The device as claimed in claim 1, wherein the forming system is a hot forming system.

14. The device as claimed in claim 1, wherein the mixture comprises a thermoplastic polymer.

15. The device as claimed in claim 1, wherein the mixture comprises a component and a water-soluble polymer whose glass transition temperature (Tg) is below 200 C. and at least 50 C. below the degradation temperature of the polymer and melting of said mixture at a temperature below 250 C.

16. A method of producing an oral solid form comprising an active substance with low water solubility, the method comprising using the device according to claim 1.

17. The method of claim 16, wherein the oral solid form comprises itraconazole.

18. The method of claim 16, wherein the oral solid form comprises a food supplement.

19. The method of claim 18, wherein the food supplement is curcumin.

Description

[0043] The device and its use according to the invention will now be illustrated with figures and nonlimiting examples in a particular embodiment of the invention.

[0044] FIGS. 1 and 2 show a general view of the device according to the invention.

[0045] FIG. 1 shows a general view of the device according to the invention with an extruder downstream (not shown).

[0046] FIG. 2 illustrates a device according to the invention with an exploded view of the cover, revealing a chopping device (1) associated with an orifice (8) of the die of an extruder (3) and a forming system (2) consisting of two corotating Archimedean screws. A detachable heating system is mounted on the two Archimedean screws of the forming system.

[0047] FIG. 3 shows a side view of the chopping device

[0048] FIG. 4 shows a general front view of the chopping device

[0049] FIG. 5 illustrates the actuating mechanism. FIG. 5a shows the initial position of the chopping means or knife. FIG. 5b shows the position of the knife before chopping the rod.

[0050] FIG. 5c shows the knife after chopping. FIG. 5d is a general view showing the shoulder of the pawl responsible for the chopping means or knife going round the rod. FIG. 5e illustrates the movement of the knife in its sliding arm during the downward and upward movement of the knife going round the rod.

[0051] FIG. 6 illustrates the system for cooling the surface of the rod by means of an annular air jet.

[0052] FIG. 7a illustrates the system for forming the extrudates by means of 2 Archimedean screws and FIG. 7b illustrates the axis of rotation induced on the solid forms by slight axial offset of the screws and the gap angle.

[0053] FIG. 8 shows a section in the hot forming system illustrating the heating and cooling zones covering each forming screw.

[0054] FIG. 3 shows the chopped part of the molten mass starting from the die (4) by means of the actuating mechanism (6) actuated by a linear motor (7). The die is a cylindrical part connected to the extruder (3), having a circular orifice (8) between 0.5 and 15 mm in diameter depending on the appropriate solid forms to be obtained and preferably of 6 mm for the solid forms comprising an active substance. The die discharge surface is made up of two stepped planes (9 and 10). The first plane (9) is located above the die orifice (8). This plane is in sliding contact with a knife (5), which also allows a clean cut of the rod on actuation of the knife. Underneath the die orifice, a second plane (10), parallel to the first but set back relative to the die orifice, allows the knife to release the chopped rod. This arrangement prevents the chopped rod adhering to the die and thus facilitates its detachment and falling toward the gap of the Archimedean screw. FIG. 3 shows the position of the knife (5) at the end of travel (C) at the moment of ejection of the solid form toward the gap of the Archimedean screw.

[0055] The actuating system (6) of the knife (5) has been specially designed so that its return movement to the initial position (A) located above the orifice (8) of the die (4), i.e. ready to chop off the next solid form, does not come into contact with the continuously extruded rod. For this purpose, the knife (5) is mounted on a sliding arm (11FIG. 4) with a compression spring (12) that pushes the knife (5) to the maximum of its forward position. When the sliding arm (11) swivels upward about its spindle (13) to return the knife to the initial position before chopping (A), a cam (14) that is integral with the knife (5) will come up against a pawl (15) that swivels about a spindle (16).

[0056] FIG. 5 illustrates the actuating mechanism and the movement of the chopping device

[0057] In fact, during the upward movement of the knife (5), the pawl (15) cannot swivel owing to the stop (17). The pawl (15) therefore forces the knife (5) to move in its slide (11), compressing its spring (12). This backward movement of the knife to position (B) allows it to avoid coming into contact with the extruded rod, as illustrated in FIG. 5e. After a sufficient upward travel, the cam (14) is no longer in contact with the pawl (15) owing to a shoulder in the pawl (18FIG. 5c and d). The spring (12) of the knife pushes the latter forward in the slide (11) to return it to its position before chopping (A).

[0058] During the downward movement of the knife (5) to initiate a new chopping operation, the cam (14) comes up against the upper face (19) of the pawl (15). The latter may then swivel counterclockwise, which is not constrained by the stop (17). The pawl (15) is retracted and thus allows the knife (5) to descend freely for the next chopping operation of the rod, to its position after chopping (C).

[0059] The linear motor (7FIG. 3) may be adjusted for acceleration and for frequency of actuation. These two settings allow adaptation to the cutting force required, which may vary with the rod discharge temperature, and to the rate of extrusion in order to achieve a length of cut and therefore a weight corresponding to the specified objective. The latter is generally of the order of 500 mg with possible variations of some hundreds of mg.

[0060] When the rod leaves the die (4) and is readied for chopping by the knife (5), it requires slight surface cooling to limit the risks of adhesion on the knife on the one hand and on the two Archimedean screws on the other hand. The surface cooling of the rod is performed by an annular blowing system (21) positioned opposite the die (4) and concentric with the latter. This system is shown in FIG. 6. It comprises a series of 8 small openings (20) communicating via a common manifold (21). The 8 openings are focused on the outlet of die (8).

[0061] The oral form is formed by two corotating Archimedean screws preferably made of stainless steel (FIG. 7a).

[0062] The two screws are identical. The length of the screws is between 400 and 1000 mm, preferably 550 mm, the diameter is between 30 and 100 mm and is preferably 50 mm, the pitch may be between 2 and 20 mm and depends on the size of the pellets, but is preferably 14 mm. The depth of the flights varies between 1 and 10 mm, and is preferably 3.6 mm. The shape of the flights makes it possible to produce almost spherical solid forms. The relative angular position of the two screws, and consequently the axial offset of the flights relative to one another, may be adjusted so as to produce axes of rotation on the solid forms additional to the main rotation axis parallel to the axis of the screws. These secondary rotations that are induced generate a movement on the solid forms that is favorable to the generation of spherical shapes (FIG. 7b). They help to remove the mark from chopping of the rod and thus eliminate any surface roughness, which is proscribed for ingestion of the oral form. Typically, the relative angular position of the two screws varies between 0 and 20.

[0063] However, it is difficult to remove this roughness completely, and FIG. 8 illustrates a system (22) for heating to a temperature between 70 and 150 C., obtained for example with infrared heaters (24), which are mounted above the first part of the forming system in order to limit rapid cooling of the solid form coming into contact with the screw. Owing to this heating system, increased malleability of the solid form is ensured in its initial forming phase. A cooling zone (25) obtained by inlet of air at room temperature is provided downstream of this heating zone, in order to achieve a sufficient solid consistency of the solid forms at the end of the travel of the screws and at the moment when they are ejected from the system.

[0064] The heating zone (22) is isolated by side walls by means of an upper outer cover and a cover under the screws (23). Inside the heating zone, two IR heaters (24) are placed above the Archimedean screw. The air cooling zone (25) is isolated from the heating zone by a wall (26) that is movable and adjustable. The cooling in the cooling zone is provided by a fan (27) aspirating air via the gap between the screws and discharging it to the surroundings.

EXAMPLE 1

Use of the Device for Preparing an Oral Solid Form Comprising Itraconazole

[0065] A 150-g premix comprising 25 wt % of itraconazole, 72.5 wt % of pharmaceutical-grade water-soluble polymer soluplus (poly(ethylene glycol grafted with a copolymer of polyvinyl caprolactam and polyvinyl acetate) and with a molecular weight of 110 000 g/mol and 2.5% of AcDisol superdisintegrant (sodium bicarbonate and poloxamer) for easier dissolution of the active substance starting from the solid form, is fed into the extruder using a feed system at a speed of 6 rpm. The mixture of itraconazole with the water-soluble polymer is heated to a temperature of 155 C. in the extruder provided with 2 rotating screws with a length of 550 mm and rotating at a speed of 150 rpm. A temperature gradient is applied to the mixture all the way along the bar of the extruder by the heating system divided into 5 heating zones at the following temperatures: 0-0-140-150-160 C. The temperature of the amorphous mass leaving the extruder is 90C and is controlled by means of the air-stream cooling system at a pressure of 2 atm.

[0066] The extrudate is then delivered in semisolid oral form by means of the chopping device described above at a rate of 0.3 m/s and a frequency of 1 oral solid form per second by means of a linear motor.

[0067] The solid form obtained after thermoforming has a mass of 392 g with a relative standard deviation of 3%, which complies with the norms of less than 5% stipulated by the European Pharmacopeia. The average content of active substance is 98 mg with a standard deviation of 1.5%, which also complies with the norms of less than 15% of the pharmacopeia. The spheres obtained no longer have a pronounced mark associated with cutting by the knife.

EXAMPLE 2

Use of fhe Device for Preparing an Oral Solid Form Comprising a Food Supplement, Curcumin

[0068] A 150-g premix comprising 15, 25 or 35 wt % of curcumin (from Bioextract) and 85, 75 or 65 wt % of Eudraguard EPO (poly(butylnnethacrylate-co-(2-dinnethylanninoethyl)nnethacrylate-co-methyl methacrylate polymer soluble at pH<5 of food grade and with a molecular weight of 47 000 g/mol) for increasing the solubility of curcumin by amorphization starting from the crystalline form of the latter, is fed into the extruder using a feed system at a speed of 4 rpm. Mixing of the curcumin with the Eudragard EPO thermoplastic polymer is carried at a temperature of 155 C. in the extruder provided with 2 corotating screws with a length of 550 mm and rotating at a speed of 100 rpm.

[0069] A temperature gradient is applied to the mixture all the way along the extruder barrel by the heating system divided into 5 heating zones at the following temperatures: 0-0-140-150-160 C. The temperature of the amorphous mass leaving the extruder is 90 C. and is controlled by means of the air-stream cooling system at a pressure of 2 atm.

[0070] The extrudate is then delivered in semisolid oral form by means of the chopping device described above at a rate of 0.3 m/s and a frequency of 1 oral solid form per second by means of a linear motor provided with a reciprocating piston.

[0071] The solid form obtained after thermoforming has a mass of 500 mg with a relative standard deviation of less than 5%. The average curcumin content is 75 mg (if 15% of curcumin), 125 mg (if 25% of curcumin) or 175 mg with a standard deviation of less than 5%. The spheres obtained no longer have a pronounced mark associated with cutting by the knife.