WO2003077827A1

WO2003077827A1 - Process for producing drug solid dispersion

Info

Publication number: WO2003077827A1
Application number: PCT/JP2003/003226
Authority: WO
Inventors: Tomio Nakano; Shogo Izumi
Original assignee: Nippon Shinyaku Co., Ltd.; Imoto Machinery Co., Ltd.
Priority date: 2002-03-19
Filing date: 2003-03-18
Publication date: 2003-09-25
Also published as: JPWO2003077827A1

Abstract

A process for producing a drug solid dispersion. In particular, a process for producing a drug solid dispersion, comprising effecting compression and shearing of a material to be kneaded by rotation of disk (3) and further effecting spiral transfer of the material by rotation of spiral screw (6a) to thereby produce a kneaded material, wherein a drug solid dispersion composed of at least a pharmaceutically acceptable polymer carrier and a drug is produced by kneading extruder (1) that is so constructed that, in a valley portion between rotary disk (3) and a stationary disk, the material is extruded toward the periphery by a boundary portion of the two disks and fed outward through the interstice provided between the circumference of the rotary disk and an internal surface of cylinder.

Description

Specification

Manufacturing method of pharmaceutical solid dispersion

The present invention relates to a method for producing a solid pharmaceutical dispersion useful as a raw material for a pharmaceutical preparation.

Pharmaceutical solid dispersions can be analyzed by X-ray diffractometry, as can be seen from the disappearance of the crystal peak of the drug in the inert carrier, as the drug is dissolved or in the solid state in the solid inert carrier. It can be said that it is dispersed in a monomolecular form, and is distinguished from a simple mixture or a physical mixture in which an inert carrier and a drug are present independently (eg, G¾em. Pharm. Bull. , 30, 4479 (1982)). In a solid dispersion of a drug, if an inert carrier is sufficiently used for the drug, it can be considered that the drug is largely amorphous in the carrier. The usefulness of a solid pharmaceutical dispersion is that it can improve the solubility of a poorly water-soluble drug in a living body and enhance its bioavailability.

Background art

Traditionally, solid pharmaceutical dispersions are prepared by dissolving a solid inert carrier and a drug in an appropriate solvent, and then distilling off the solvent. Then, it can be produced by a melting method by cooling and a solvent-melting method which is an eclectic method. It can also be manufactured by a mixing and pulverization method in which a solid inert carrier and a drug are mixed and pulverized vigorously. Recently, a twin-screw compound extruder with a special screw element called a kneading paddle has been developed. Production methods such as a kneading extrusion method (eg, WO92 / 18106) are also known.

On the other hand, the material to be kneaded is compressed and sheared by the rotation of a disk and spirally transferred by the rotation of a spiral screw to produce a kneaded material. A rotating disk is fixed at the center to the rotating shaft with a screw around the outer periphery so that the screw is transferred, and peaks and valleys are alternately radially formed on at least one surface of this rotating disk. Formed and opposed to this surface A fixed disk is fixed to the cylinder coaxially and arranged so that a gap is formed between the fixed disk and the rotary shaft, and peaks and valleys are alternately radially formed on the surface of the fixed disk with respect to the rotary disk. The fluid formed and sent through between the fixed disk and the rotating shaft is pushed outward in the valley between the two disks by the boundary line between the two disks, and the fluid between the outer circumference of the rotating disk and the inner surface of the cylinder is The kneading extruder (hereinafter referred to as “the main kneading extruder”) configured to be fed out is a machine for producing kneaded materials of plastic (polymer) material and other various materials. It can be considered as an extension of the principle of grinding raw materials with a mill. Such a kneading extruder is also referred to as a continuous kneader, a kneading extruder, a continuous kneading extruder, and the like (for example, a kneading extruder described in JP-A-8-183027).

Disclosure of the invention

An object of the present invention is to provide a novel method for producing a solid pharmaceutical dispersion. Alternatively, it can be said that a new method of using the kneading extruder is provided. This effort can include, for example:

(1) A method for producing a solid pharmaceutical dispersion comprising at least a pharmaceutically acceptable polymer carrier and a pharmaceutical by the kneading extruder.

(2) A method using the kneading extruder for producing a solid pharmaceutical dispersion comprising at least a pharmaceutically acceptable polymer carrier and a pharmaceutical.

Specific examples of the kneading extruder include the following.

(1) The material supply unit for feeding the material to be kneaded and the material to be kneaded sent from the material supply unit are compressed and sheared by rotation of a disk having a shallow groove on the peripheral surface, and are spirally transferred by rotation of the spiral screw. The material kneading unit 4 is positioned laterally around the spiral screw 6a and the material kneading unit 4 is positioned on the material supply unit 2 side and fed from the material supply unit 2. The disk 3 having a diameter larger than the rotation shaft 6 fixed coaxially with the rotation shaft 6 for transferring the material to be kneaded to the rotation shaft 6 while compressing / shearing and kneading the mixture; A cylindrical horizontal hole opening 8 formed in a size that can be rotated with the plate 3 provided inside is provided at the rear end portion 10b, and a cylindrical shape large enough to rotate with the rotation shaft 6 provided inside. A kneading extruder 1 in which a lateral hole 9 is constituted by a cylinder portion 10 formed from a bottom surface 8a of a cylindrical lateral hole opening portion 8 to a tip end surface 10c, and the cylinder portion 10 includes the rotary shaft 6 Is fixed to a movable portion 19 that reciprocates in the same direction as the longitudinal direction of the disk 3. The movable portion 19 is reciprocated to move between the rotation shaft side surface of the disk 3 and the bottom surface 8a of the cylindrical lateral hole opening 8. The degree of compression and shearing according to the type of the material to be kneaded can be obtained by adjusting the gap formed in the kneaded material.

(2) The material supply section for feeding the material to be kneaded and the material to be kneaded fed from the material supply section are compressed and sheared by rotation of a disk having a shallow groove on the peripheral surface, and are spirally transferred by rotation of the spiral screw. The material kneading unit 4 is positioned laterally around the spiral screw 6a and the material kneading unit 4 is positioned on the material supply unit 2 side and fed from the material supply unit 2. The disk 3 having a diameter larger than the rotation shaft 6 fixed coaxially with the rotation shaft 6 for transferring the material to be kneaded to the rotation shaft 6 while compressing / shearing and kneading the mixture; A cylindrical lateral hole opening 8 formed in a width that allows the plate 3 to be installed and rotatable is provided at the rear end 10b, and a cylindrical lateral hole 9 that is large enough to be rotatable with the rotary shaft 6 installed is a circle. Kneading-side cylinder portion formed from bottom surface 8a of column-shaped lateral hole opening 8 to tip end surface 10c A supply-side cylinder portion 13 having a distal end portion 13a having a shape in which the material supply portion 2 is reciprocally fitted into the cylindrical lateral hole opening portion 8 and the distal end portion 13a is opened; A kneading extruder 1 comprising a piston part 14 for extruding the material to be kneaded introduced into the supply-side cylinder part 13 to a tip part 13a, wherein the kneading-side cylinder part 10 is in the longitudinal direction of the rotary shaft 6. And the supply-side cylinder portion 13 is fixed to a supply-side movable portion 20 that reciprocates in the same direction as the longitudinal direction of the rotary shaft 6 and is kneaded. The movable section 19 is reciprocated to adjust the kneading-side gap formed between the rotation shaft side surface of the disk 3 and the bottom surface 8a of the cylindrical lateral hole opening 8, and to reciprocate the supply side movable section 20. To move the disk 3 and the supply-side cylinder In regulating the supply-side gap formed between the tip portion 13a end face 13 Therefore, a material having a degree of compression and shearing according to the type of the material to be kneaded can be obtained. (3) The material supply section for feeding the material to be kneaded and the material to be kneaded fed from the material supply section are compressed and sheared by rotation of a disk having a shallow groove on the peripheral surface, and are spirally transferred by rotation of the spiral screw. The material kneading unit 4 is positioned side by side with the rotating shaft 6 around the spiral screw 6a and the material kneading unit 4 is fed from the material supply unit 2. The disk 3 is coaxially fixed to the rotating shaft 6 and has a diameter larger than that of the rotating shaft 6 for transferring the material to be kneaded to the rotating shaft 6 while compressing and shearing the kneaded material; A cylindrical lateral hole opening 8 formed in the rear end portion 10b is formed in a rear end portion 10b so as to be rotatable with the disk 3 installed therein. Is formed from the bottom surface 8a of the cylindrical lateral hole opening 8 to the tip end surface 10c. A supply-side cylinder portion 13 having a distal end portion 13a having a shape in which the material supply portion 2 is reciprocally fitted into the cylindrical lateral hole opening portion 8 and the distal end portion 13a is opened; It is rotatably provided in the supply-side cylinder portion .13 and is fixed to the disk 3 coaxially with the rotary shaft 6 and the material to be kneaded introduced into the supply-side cylinder portion 13 is rotated to the tip portion 13a. A kneading extruder 1 comprising a transfer screw shaft 36 to be extruded, wherein the kneading-side cylinder portion 10 is fixed to a kneading-side movable portion 19 that reciprocates in the same direction as the longitudinal direction of the rotary shaft 6 and kneaded. The kneading material is adjusted by reciprocating the side movable portion 19 to adjust the kneading-side gap formed between the rotation shaft side surface of the disk 3 and the bottom surface 8a of the cylindrical lateral hole opening 8. A type that can obtain the degree of compression and shearing according to the type of

Hereinafter, a specific form of the kneading extruder will be described with reference to the drawings.

(1) Specific form of the main kneading extruder 1

FIG. 1 is a side view showing a kneading extruder according to the present kneading extruder, and FIG. 2 is a plan view of the kneading extruder shown in FIG. 1. In FIG. 1, the supply-side movable plate and the kneading side shown in FIG. The movable plate is omitted, and the supply-side cylinder portion and the kneading-side cylinder portion are illustrated in cross sections in FIGS. 1 and 2. FIG. 3 is an explanatory view of the kneading-side cylinder portion shown in FIG. 1. FIG. FIG. 3 (b) is a left side view of the kneading side cylinder section, and FIG. 3 (c) is a right side view of the kneading side cylinder section. FIG. 4 is an explanatory view of the disk shown in FIG. 1. FIG. 4 (a) is a front view of the disk, FIG. 4 (b) is a right side view of the disk, and FIG. ) Is a left side view of the disk, and FIG. 4 (d) is a vertical sectional view taken along line AA of the disk shown in FIG. 4 (c). FIG. 5 is a longitudinal sectional view illustrating a movable mechanism for reciprocating the supply-side movable plate and the kneading-side movable plate illustrated in FIG. In these figures, reference numeral 1 denotes a spiral which compresses and shears the material to be kneaded, which is fed from the material supply unit 2, and the disk 3, which has a shallow groove on its peripheral surface, by rotating it. A material kneading unit 4 that spirally transfers by rotation of the screw is a patch-type kneading extruder that is horizontally arranged on a gantry 5 in series.

The material kneading unit 4 compresses and kneads the kneaded material, which is positioned on the side of the material supply unit 2 and is fed from the material supply unit 2, by shearing and kneading the rotating shaft 6 around which the spiral screw 6 a is provided. The disk 3 having a diameter larger than that of the rotary shaft 6 fixed coaxially to the rotary shaft 6 for transferring to the rotary shaft 6 side, and a discharge port 7 for discharging the kneaded material to be kneaded are provided at the tip end. At the rear end 10b, a cylindrical horizontal hole opening 8 is provided at the rear end 10b, and is provided on the 10a side, and is formed to have a size that allows the disk 3 to be installed and rotated. A kneading side cylinder portion 10 formed from a bottom surface 8a of the cylindrical side hole opening 8 to an end surface 10c of the tip end portion 10a. The cylindrical side hole opening 8 has a width. As shown in Fig. 3, the bottom surface 8a of the cylindrical lateral hole opening 8 As such, radial shallow bottom groove 8b running include openings of the tubular lateral hole 9 is formed.

As shown in FIG. 4, the disk 3 is provided with a hexagonal shaft hole 3a at the center thereof, into which the rear end 6b (see FIG. 1) of the rotary shaft 6 is fitted and axially attached. On both sides of the plate 3, a plurality of fan-shaped shallow grooves 3b are formed radially extending from the vicinity of the hexagonal shaft hole 3a of the disk 3, and the circumferential surface of the disk 3 is A plurality of gutter-shaped shallow-bottom grooves 3c are formed at intervals so as to cross the fan-shaped shallow-bottom grooves 3b obliquely. As shown in FIGS. 1 and 2, the rotating shaft 6 has a distal end connected to a motor (not shown) and a connecting shaft having a diameter that can be rotatably provided in the cylindrical hole 9. A screw-type screw that fits on the tip end 10a side of the kneading-side cylinder part 10 around which a screw-type spiral screw 6e that continues through a circular constriction 6d having a width that fits in the diameter of the discharge port 7 is provided. A rotary shaft portion 6f; a screw rotary shaft portion 6g provided with the spiral screw 6a surrounding the screw-type rotary shaft portion 6f; and a hexagonal head formed at the rear end of the screw rotary shaft portion 6g. The circumferential surface of the screw-type rotary shaft portion 6f has a narrow groove 6h having a length that does not reach both ends of the screw-type rotary shaft portion 6f in parallel with the longitudinal direction of the rotary shaft 6. 2) is formed, and the narrow groove eh running halfway from both ends and the narrow groove 6h formed in ^ on the circumferential surface are spaced apart. And is provided so as not to overlap with (a contact, in FIG. 2, the screw-type spiral disk. Liu 6e is omitted.). Then, the connecting rotary shaft 6c of the rotary shaft 6 is passed through a bearing 12 provided in the fixed angle portion 11 on the kneading section side erected on the gantry 5, and the distal end of the connecting rotary shaft 6c is connected to the motor via a coupling or the like. The orbiting portion 6d of the rotating shaft 6 is located at the discharge port 7, and the screw-type rotating shaft 6f around which the spiral screw of the rotating shaft 6 is provided and the screw rotating shaft 6g are cylindrical. The disk 3, which is provided in the lateral hole 9 and fitted to the rear end 6 b of the rotary shaft 6, is provided in the column-shaped lateral hole opening 8.

The material supply unit 2 has a tip 13a formed in a circular shape that reciprocally fits into the cylindrical lateral hole opening 8.From the tip 13a, the rotation shaft 6 is rotated around the rotation shaft 6. A supply-side cylinder portion 13 provided with a horizontal hole-shaped cavity portion 13b for sending out the material to be kneaded formed in the same direction as the longitudinal direction and opening at both ends, and the material to be kneaded charged into the supply-side cylinder portion 13 are provided. An opening 13c for charging the material to be kneaded is formed in the rear upper wall of the supply-side cylinder 13 and is formed in the opening 13c. Has a hopper 15 attached. The piston portion 14 is provided with a pushing handle shaft 16 having a thread groove formed on a circumferential surface of the piston portion 14, and the handle shaft 16 is fixed to a supply portion standing upright on the base .5. Angle The hand screw (not shown) is screwed into the slot 17a and fixed to the rear end thereof.

Further, as shown in FIG. 2, two column shafts 18, 18 sandwiching a kneading-side cylinder portion 10 and a supply-side cylinder portion 13, which are connected in series and are arranged side by side, are connected to the longitudinal axis of the rotating shaft 6. The kneading part side fixed angle 11 and the supply part side fixed angle 17 are installed in parallel with the direction, and the kneading side movable plates (kneading side movable part) 19, 19 and the supply side movable One end of each of the plates (supply-side movable parts) 20 and 20 is reciprocally mounted, and the other ends of the kneading-side movable plates 19 and 19 are provided on both sides of the kneading-side cylinder unit 10 via heat insulating plates 21 from both sides. The supply ¾lj movable plates 20, 20 are fixed to the rear end portion 10b of the supply side cylinder portion 13 on both sides of the supply side cylinder portion 13 via heat insulating plates 21 from both sides. Is fixed to the flange 13d with a port '(not shown) or the like. A kneading-side movable mechanism 22, which reciprocates the kneading-side cylinder portion 10 in the same direction as the longitudinal direction of the rotary shaft 6, is provided at a connecting point between the two movable plates 19, 20 and the two support shafts 18, 18. Supply-side movable mechanisms 23 and 23 for reciprocating the supply cylinder 22 and the supply-side cylinder 13 in the same direction as the longitudinal direction of the rotating shaft 6 are provided.

In FIGS. 1 and 2, reference numeral 24 denotes a bearing provided on the end face 10c of the kneading cylinder part 10, and reference numeral 25 denotes a leakage of the kneaded matter fitted between the end face 10c of the kneading cylinder part 10 and the bearing 24. The stop ring 26 is a ring for preventing the material to be kneaded from being sheared, which is fitted to the end face of the rear end portion 10b of the kneading side cylinder portion 10. A heater is attached to the kneading cylinder 10 and the supply cylinder 13 so that the temperature can be adjusted.

Since the kneading-side movable mechanisms 22, 22 and the supply-side movable mechanisms 23, 23 are symmetrically arranged and have the same configuration, the kneading-side movable mechanism 22 arranged on the upper side in FIG. 2 is taken as an example. The configuration of the movable mechanisms 22 and 23 will be described. As shown in FIG. 5, the kneading-side movable mechanism 22 includes a spacer ₂₇ that reciprocates from the left side of the kneading-side movable plate 19 to the column shaft 18 and contacts the kneading-side movable plate 19, Disk 3 is inserted into cylindrical side hole opening 8 of kneading cylinder 10 A hexagonal nut 28 screwed into a thread groove '18a on the peripheral surface of the support shaft 18 formed so as to be positioned on the left side of the kneading-side movable plate 19 in the accommodated state until it comes into contact with the spacer 27; And a gap adjusting screw portion 29 that reciprocates from the right side of the movable plate 19 to the column shaft 18 and abuts on the kneading-side movable plate 19 .The gap adjusting screw portion 29 has a hexagonal head 30 a Represents the width of the kneading-side gap formed between the bolt-shaped fixing portion 30 composed of the body portion 30c having a thread groove 30b on the circumferential surface thereof, and the bottom surface 8a of the column-shaped lateral hole opening 8 and the side surface of the disk 3. A knob 31 is screwed onto the body 30c of the fixed part 30 and has a scale engraved on the circumferential surface. The scale marked on the knob 31 of the supply-side movable mechanism 23 represents the width of the supply-side gap formed between the end face 13a of the supply-side cylinder 13 and the side surface of the disk 3. Reference numeral 32 denotes a female screw hole for a set screw formed in the hexagonal head 30a. The fixing part 30 is fixed to the support shaft 18 by screwing a set screw 33 into the female screw hole 32 until the support shaft 18 is reached. .

Next, the operation of the movable mechanisms 22 and 23 will be described.

As shown in FIG. 2, the hex nuts 28 and the set screws 33 of the kneading-side movable mechanisms 22, 22 are loosened so that the bottom 8a of the cylindrical side hole opening 8 contacts the side surface of the disk 3 on the kneading side. The kneading cylinder 10 is moved in the direction of arrow X by reciprocating the movable plates 19, 19, and the set screw 33 is tightened while the bottom surface 8a of the cylindrical side hole opening 8 is in contact with the side surface of the disk 3. Fix the fixing part 30 to the support shafts 18 and 18 with. Thereafter, the knob 31 is turned to move the kneading-side movable plates 19, 19 in the arrow Y direction (arrow: in the direction opposite to the X direction) in order to obtain a gap width on the kneading side corresponding to the kind of material to be kneaded. Then, the hexagonal nut 28 is tightened with the desired kneading-side gap width formed, and the spacer 27 is pressed against the kneading-side movable plates 19, 19. Fix it. Next, loosen the hexagon nut 28 and the set screw 33 of the supply-side movable mechanisms 23, 23, and reciprocate the supply-side movable plates 20, 20 until the end surface 13a of the supply-side cylinder portion 13 contacts the side surface of the disk 3. To move the supply cylinder 13 in the direction of the arrow Y, and tighten the stop screw 33 with the end 13a of the supply cylinder 13 in contact with the side surface of the disk 3. And fix the fixing portion 30 to the support shafts 18, 18. Thereafter, the knob 31 is turned to move the movable plate 20 on the supply side in the direction of the arrow X (the direction opposite to the direction of the arrow Y) so as to obtain the above-mentioned gap on the supply side according to the type of the material to be kneaded. Then, the hexagon nut 28 is tightened in a state where the desired supply-side gap width is formed, and the spacer 27 is pressed against the supply-side movable plates 20 and 20 to fix the supply-side movable plates 20 and 20.

Next, the operation of the kneading extruder 1 will be described.

After the material to be kneaded is injected from the hopper 15 into the hollow portion 13b of the supply-side cylinder portion 13, the handwheel is turned to transfer the material to be kneaded to the tip portion 13a of the supply-side cylinder portion 13 by turning the handwheel. The material to be kneaded transferred to the distal end 13a is pressed by the supply side side surface of the rotating disk 3 in the supply side gap, and compressed by the shallow groove 3b formed on the side surface while melting by heating. Sheared. When the compressed and sheared material to be kneaded passes through the shallow bottom groove 3c of the disk 3, it is further compressed and sheared between the side wall of the cylindrical lateral hole opening 8 and the kneading side surface of the disk 3 while being kneaded. Reaches the shallow groove 3b formed at the bottom, and is compressed, sheared and kneaded between the kneading side gap and the radial shallow groove 8b formed at the bottom surface 8a of the cylindrical lateral hole opening 8. After passing through the groove 8b, it is sent to the tip 10a of the kneading cylinder portion 10 by the helical screw 6a of the rotating shaft 6, is further kneaded by the rotating shaft portion 6f, and then is discharged through the orifice 6d. Is discharged from

In the specific embodiment 1, the kneading-side cylinder portion 10 is fixed to the kneading-side movable plates 19, 19 which reciprocate in the same direction as the longitudinal direction of the rotating shaft 6, and the cylindrical horizontal hole orifice of the kneading-side cylinder portion 10 is fixed. The supply-side movable plate 20, 20 which reciprocates the supply-side cylinder portion 13 in the same direction as the longitudinal direction of the rotary shaft 6 with the distal end portion 13a of the supply-side cylinder portion 13 inserted in the mouth portion 8 so as to be able to reciprocate. And the kneading-side movable plates 19, 19 are reciprocated by the kneading-side movable mechanisms 22, 22 to form the kneading formed between the rotation shaft side surface of the disk 3 and the bottom surface 8a of the cylindrical lateral hole opening 8. In addition to adjusting the side clearance, the supply side movable plates 20, 20 are reciprocated by the supply side movable mechanisms 23, 23 so that the side surface of the disk 3 on the material supply side and the supply side cylinder 13 Since the supply-side gap formed between the tip 13a and the end face is adjusted, the compression * shearing degree can be obtained according to the type of the material to be kneaded, eliminating the need to provide a plurality of rotating disks. The kneading degree can also be improved, so that the kneading-side cylinder portion 10 can be shortened.

Also, if the hex nuts 28 of the kneading-side movable mechanisms 22, 22 are loosened and the kneading-side movable plates 19, 19 are moved in the direction of the arrow Y, the screw-type rotating shaft portion 6f of the rotating shaft 6 and the screw rotating shaft are rotated. Since the portion 6g and the disk 3 are pulled out from the kneading-side cylinder portion 10 and are exposed, the disk 3 and the rotating shaft 6 can be easily cleaned.

The shallow grooves 3b and 3c formed on the peripheral surface of the disk 3 may have a valley shape formed by forming a projection on the peripheral surface. Further, the rotary shaft 6 may have a helical screw 6a provided around the orbital constriction 6d.

(2) Specific form 2 of the kneading extruder

FIG. 6 is a plan view showing a kneading extruder according to the present embodiment, in which a supply-side cylinder portion and a kneading-side cylinder portion are illustrated in cross sections. 7 is a longitudinal sectional view illustrating the bearing portion illustrated in FIG. 6, and FIG. 8 is a longitudinal sectional view illustrating a movable mechanism that reciprocates the kneading-side movable plate illustrated in FIG.

The kneading extruder shown in FIG. 6 is a continuous kneading extruder, and the same reference numerals as those in FIGS. 1 to 5 indicate the same or corresponding parts.A spiral screw 6a is provided around a rotating shaft 6 in a material kneading section 4. The tip of the small screw 34 has a smaller diameter than the outer diameter of the spiral screw 6a (see FIG. 7), and the small screw 34 is fixed to the end face 10c of the kneading cylinder part 10. Axle-mounted inside part 35. Further, in the material supply section 2, a transfer screw shaft 36, which is fixed to the disk 3 coaxially with the rotating shaft 6 and pushes the material to be kneaded introduced into the supply side cylinder section 13 to the tip 13a while rotating, is rotated. The transfer screw shaft 36 is screwed with a screw screw shaft 37 for feeding the material to be kneaded into the transfer screw shaft 36. What is screw screw shaft 37 It is connected to a gear box 38 via a supply-side fixed angle portion 17, and is connected to a motor shaft 40 via a gear system 39 in the gear box 38. The kneading-side cylinder unit 10 is fixed to kneading-side movable plates 19, 19 and is reciprocally attached to the support shafts 18, 18 via kneading-side movable mechanisms 22, 22. The distal end 13a of the supply-side cylinder portion 13 is reciprocally inserted into the cylindrical side hole opening 8 of the kneading-side cylinder portion 10 with the supply-side gap provided, and the material is kneaded with the material supply portion 2. Part 4 is laid horizontally.

As shown in FIG. 7, the bearing portion 36 has a guide groove 41a formed in the middle of the circumferential surface in parallel with the longitudinal direction of the rotating shaft 6 and a hole opening from the end of the guide groove 41a toward the end face. A groove 41b is formed, and a kneaded material forming ring 41 is fixed to the small shaft portion 34 of the rotating shaft 6 with a gap between the spiral screw 6a, and a guide ring 41 is fixed to the small shaft portion 34. A cylindrical shaft-mounting opening 42a having a size capable of rotating and reciprocating internally in the state, and a discharge port 7 having a bottom formed in a mortar shape and opening toward the tip are formed. It is composed of a provided screw thread receiving portion 42 and a lotus root type breaker plate 43 having a myriad of holes that closes a mortar-shaped bottom surface and is fitted into a cylindrical shaft mounting opening portion 42a.

As shown in FIG. 8, the kneading-side movable mechanisms 22 and 22 are located on the left side from the position including the kneading-side movable plate 19 in a state where the disk 3 is accommodated in the cylindrical lateral hole opening 8 of the kneading-side cylinder unit 10. A hexagon nut 28 screwed into a screw groove 18a formed to the end surface of the support shaft 18 and a fitting formed on the kneading-side movable plate 19 by reciprocatingly passing through the support shaft 18 from the right side with respect to the kneading-side movable plate 19. It comprises a cylindrical slider 45 having an outer peripheral surface 45a fitted in the mating hole 44 and a gap adjusting screw portion 29 abutting on the cylindrical slider 45.

Reference numeral 46 denotes a heater, 47 denotes a fixing ring for fixing the leak preventing ring 26, and 48 denotes a port to which the fixing angle section 17 on the supply section side is fixed to a stand 5J.

Next, the operation of the movable mechanism 22 will be described.

Loosen the hexagon nuts 28 and set screws 33 of the kneading-side movable mechanisms 22, 22 and, as shown in FIG. 6, the bottom surface 8a of the cylindrical side hole opening 8 comes into contact with the side surface of the disk 3. Move the kneading side movable plate 19, 19 back and forth to move the kneading side cylinder part 10 in the direction of the arrow X, and stop it with the bottom surface 8a of the cylindrical side hole opening 8 in contact with the side surface of the disk 3. Tighten the screw 33 to fix the fixing part 30 to the pillar shafts 18, 18. Thereafter, as shown in FIG. 8, the knob 31 is turned to move the kneading-side movable plates 19, 19 in the direction of the arrow Y (in the direction of the arrow X) in order to obtain the above-mentioned kneading-side gap width according to the type of the material to be kneaded. In the opposite direction) and tighten the hexagon nut 28 with the desired kneading-side gap width formed to fix the kneading-side movable plates 19, 19.

In the bearing portion 35, the guide ring 41 fixed to the small shaft portion 34 of the rotary shaft 6 is moved by reciprocating the kneading-side movable plates 19, 19 in the directions of arrows X and Y, so that the shaft of the screw receiving portion 42 is rotated. It reciprocates in the receiving opening 42a. .

Next, the operation of the kneading extruder 1 will be described.

If the material to be kneaded is fed from the hopper 15 to the position where the transfer screw shaft 36 and the mating screw shaft 37 are screwed together, the transfer screw shaft 36 and the mating screw shaft 37 that are rotating inward to each other. It is transferred to the tip 13a of the supply-side cylinder unit 13. The material to be kneaded transferred to the leading end 13a is pressed by the supply side side surface of the rotating disk 3 in the supply side gap, and melts by heating to form the shallow bottom groove 3b formed on the side surface. Compressed and sheared. When the compressed and sheared material to be kneaded passes through the shallow groove 3c of the disk 3 and is further compressed and sheared with the side wall of the cylindrical lateral hole opening 8, the kneading side of the disk 3 is kneaded. It reaches the shallow groove 3b formed on the side surface and compresses and kneads with the radial shallow groove 8b formed on the bottom surface 8a of the cylindrical lateral hole opening 8 at the kneading-side gap. After passing through the bottom groove 8b, it is sent to the tip 10a of the kneading cylinder part 10 by the spiral screw 6a of the rotating shaft 6, and passes through the guide groove 41a and the hole groove 41b of the small shaft part 34 to form a play card. After passing through hole 43, it is discharged from outlet 7.

In the specific embodiment 2, the supply-side gap cannot be adjusted, but the kneading-side gap can be adjusted. By loosening the hexagon nuts 28 of the kneading-side movable mechanisms 22, 22, the rotating shaft 6 is connected to the kneading-side cylinder. It's stripped out of 10 Thus, the same effect as in the first embodiment can be obtained.

Note that the transfer screw shaft 36 and the mating screw shaft 37 may rotate outward from each other, or the rotating shaft 6 may be formed of a two-axis screw. Further, the transfer screw shaft 36 may be transferred by a single screw without the joint screw shaft 37 being provided. The polymer carrier that can be used in the present invention is not particularly limited, such as water-soluble or water-insoluble, as long as it is a pharmaceutically acceptable polymer carrier, but a pharmaceutically acceptable water-soluble polymer carrier is preferred. Examples of the polymer carrier that can be used in the present invention include a cellulose derivative, a synthetic polymer compound, a natural polymer compound (polybranides) or a derivative thereof, and a starch derivative. Specific examples are shown below. The term “water-soluble” refers to a property of dissolving in at least one water or aqueous solution such as distilled water, purified water, tap water, intestinal juice, gastric juice and the like.

1. Cell mouth derivative

(1) Water-soluble

Methylcellulose (MC), hydroxymethylcellulose (HMC), hydroxyxethyl cellulose (HEC), hydroxyquinpropyl cellulose (HPC), hydroxyxethyl methylcellulose (HEMC), hydroxypropylmethylcellulose ( HPMC; For example, HPMC 2208 (Metroze (registered trademark, same hereafter) 90 SH, SB-4), 2906 (Metroize 65 SH), 2910 (Metroze 60 SH, TC-5 (registered trademark, same hereafter) )), Etc.), oleoxymethylcellulose (CMC), carboxymethylcellulose sodium (CMC-Na), hydroxypropylmethylcellulose acetate succinate (HPMCAS; eg, AQOAT® L, M, H) ), Hydroxypropyl methylcellulose phthalate (HPMCP; eg, HPM CP220824 (HP50), 220731 (HP55)), carboxymethylethylcellulose (CM EC), cellulose acetate phthalate (CAP) ₀

(2) water-insoluble

Echinoresenorelose (EC). 2. Synthetic polymer compound

(1) Water-soluble

Polyvinylpyrrolidone (PVP; eg, Kollidone (registered trademark, the same applies hereinafter) K30, K60, K90), N-vinylpyrrolidone.Acetate copolymer (eg, Kollidone VA64), Polybutyl alcohol (PVA), canolepoxy vinyl polymer (polyacrylic acid; eg, Carbopol (registered trademark), Hibisco® (registered trademark)), polyethylene glycol (macrogol; eg, PEG400, 6000), polyethylene oxide ( PEO), methacrylic acid copolymer (eg, Eudragit (registered trademark, the same applies hereinafter) L30D-55, L100-55, L100, S100), aminoalkyl methacrylate copolymer (eg, Eudragit) E 100), polyvinyl acetate tilamino acetate (AEA).

(2) water-insoluble

Aminoalkyl methacrylate copolymer (eg, Eudragit RS 30D, RS 100, RL 30D, RL 100).

3. Natural polymer compound (polysaccharide) or its derivative

(1) Water-soluble

Arabia gum, sodium alginate, propylene glycolonoester anoregate, agar, gelatin, tragacanth, xanthan gum.

(2) water-insoluble

Starch (eg, potato starch, corn starch).

4. Starch derivatives

(1) Water-soluble

Dextrin, a-starch (eg, Amicol (registered trademark), matsunoline (registered trademark)), o cyclodextrin, 'cyclodextrin, γ-cyclodextrin, sodium carboxymethylstarch (eg, Primodiel (registered trademark), Explotab (registered trademark)), Pullulan.

(2) water-insoluble

Partially pregelatinized starch, hydroxypropyl starch (HPS). The drug that can be used in the present invention is not particularly limited, but has a solubility of 500 μg / m1 or less in the first or second liquid of the 14th pharmacopeia at a temperature of 2.5 ° C. A sparingly soluble drug is suitable, and a sparingly soluble drug having a solubility of 100 μg / m 1 or less in a first solution or a second solution of the Japanese Pharmacopoeia No. 14 at a temperature of 25 ° C. is preferable. Specific examples include the following medicaments.

1. Antipyretic, analgesic, anti-inflammatory

Indomethacin, aspirin, diclofenac natrium, ketoprofen, ipprofen, mefenamic acid, dexamethasone, dexamethasone sodium sulfate, hydrocortisone, predezolone, azulene, phenacetin, isopropinoleantipyrine, fasetominophene hydrochloride, fasenetaminophen hydrochloride Butazone, funolefenamic acid, sodium salicylate, choline salicylate, sazapyrine, clofiasone, etodolac, phenolepinac.

2. Antiulcer agent

Sulpiride, setraxa hydrochloride, gefarnato, inolesogladine maleate, cimetidine, laetidine hydrochloride, famotidine, dizatidine, xantidine acetate hydrochloride, sodium azulene sulfonate.

3. Coronary vasodilator

Difudipine, isosorbite dinitrate, diltiazem hydrochloride, travidil, dipyridamole, dilazep hydrochloride, methyl 2,6—dimethyl-1-41 (.2—trofuryl) 15— (2-oxo1-1,3,2—di) Oxaphospholinan-1-yl) 1,1,4-dihydropyridine—3-carboxylate, verapamil, ecardipine, carbdipine hydrochloride, verapamil hydrochloride.

4. Peripheral vasodilator

Ifenprodil tartrate, cinepaside maleate, cyclandate, cinnarizine, pentoxifylline. ■ 5 Antibiotics

Ampicillin, amoxicillin, cephalexin, erythromycin ethyl succinate, pacampicin hydrochloride, minocycline hydrochloride, chloramphenicore, tetracycline, erythromycin, griseofnolevin, cefditorenpiboxinole, azirisromycin, clarithromycin, clarithromycin

6. Synthetic antibacterial agent

Naliditasic acid, pyromidic acid, pimidic acid trihydrate, enoxacin, sinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, snorefamethoxazole / trimethoprim, 6-fluor-1-methinole 7- [4-- (5- Methyl-2-oxo-1,3, dioxolen-4-yl) Methyl-1-piperazinole] —4-oxo-4H [1,3] thiazeto [3,2-a] quinolin-1-3—carbone Acid, itraconazole.

7. Antispasmodic

Peptide bromide, patin sulphate, oxopodium bromide, timevidium bromide, butylscopolamine bromo, trospium chloride, butium pium bromide, N-methylscopolamine methyl sulphate, methyl octatropine bromide. ,

8. Antitussive ◆ Anti-asthmatic

Theophylline, aminophylline, methyl efedrine hydrochloride, propoterol hydrochloride, trimethoxine hydrochloride, codin phosphate, sodium chromoglycrate, traester, dextromethorphan hydrobromide, dimemorphuan phosphate , Croptinol hydrochloride, Hominoben hydrochloride, Benproperin phosphate, Tipididine hibenzate, Eprazinone hydrochloride, Cupid phdanol hydrochloride, Ephedrine hydrochloride, Noscapine, Carbetapentene quinate, Oxerazine tannate, Soxamiel , Pranlukast, flutizone, propionate.

9. Bronchodilators '' Diprofylline, sulphamol sulfate, chlorprenalin hydrochloride, formoterol fumarate, orciprenaline sulfate, pirputerol hydrochloride, hexoprenaline sulfate, bitolterol mesylate, clenbuterol hydrochloride, terbutaline sulfate, mabuterol hydrochloride, phenometrol hydrobromide, phenometrol hydrochloride

1 0. Diuretics

Furosemide, acetazolamide, trichlormethiazide, methyclothiazide, hydrocloth thiazide, hydrofmethiazide, ethiazide, cyclopentiazide, spironolatataton, triamterene, florothiazide, piretanide, mefurside, mefurside, mefluside Mid, Crofenamide.

1 1. Muscle relaxants

Chlorphenesin carpamic acid, Tolperisone hydrochloride, Eperisone hydrochloride, Tiza-zine hydrochloride, Mefenecin, Chronorezoxazone, Fenprobamate, Metocarpamol, Chlormezanone, Prisinoform mesylate, Afloqualone, / kuclofen, Dantrolene sodium.

1 2. Brain metabolism improving agent

Meclofenoxate hydrochloride.

1 3. Minor Tranquilizer

Oxazolam, diazepam, clotiazepam, medazepam, temazepam, funoresazepam, meprobamate, nitrazepam, chronorezazepoxide, quazepam.

1 4. Major Tranquilizer

Sulpiride, clocapramine hydrochloride, sodepine, chlorpromadinone, noperodidonore, risperidone.

1 5.] 3—Procker

Pindolol, propranolol hydrochloride, carteolol hydrochloride, metoprolol tartrate, labetaronole hydrochloride, seriprolonole hydrochloride, salt Aceputol acid, puetrolol hydrochloride, alprenolol hydrochloride, 'arorotinolol hydrochloride, oxprenolol hydrochloride, nadolol, bucmorol hydrochloride, indenolol hydrochloride, timolol maleate, befnolol hydrochloride, ppranolol hydrochloride, carvedilolone.

1 6. Antiarrhythmic agent

Procainamide hydrochloride, disopyramide, azimaline, quinidine sulfate, apridine hydrochloride, propafenone hydrochloride, mexiletine hydrochloride. 1 7. Gout treatment

Aloprinol, probenecid, conorechtin, snorefinpyrazone, benzbromarone, pcolome.

1 8. Anticoagulant

Ticlovidine hydrochloride, dicoumarol, perfluoroaluminium.

1 9. Antiepileptic drugs

Huetoin, sodium pulp oxalate, metal bital, carpa mazepine.

20. Antihistamine

Clonorefeniramine maleate, clemastine fumarate, mequitazine, alimemazine tartrate, cycloheptadine hydrochloride.

2 1.

Diphenedole hydrochloride, metoclopramide, domperidone, betahistine mesylate, trimeptin maleate.

2 2. Antihypertensive

Dimethylaminoethyl reserpine hydrochloride, resinamine, methyldopa, prazosin hydrochloride, bunazosin hydrochloride, clodzine hydrochloride, pudralazine, perapidine.

2 3. Sympathetic stimulants

Dihydroergotamine mesylate, isoproterenol hydrochloride, etilephrine hydrochloride.

2 4. Bromhexine hydrochloride, carbocysteine, ethyl cysteine hydrochloride, methyl cysteine acid.

2 5. Oral diabetes treatment

Daribengramide, tonolebutamide, glymidine sodium, troglitazone, oral ciglitazone, pioglitazone hydrochloride, epalrestat.

2 6. Cardiovascular agents.

Ubidecarenone, AT P—2 Na.

2 7. Iron agent

Ferrous sulfate, dried iron sulfate.

2 8. Vitamin preparation

Vitamin B Interview, vitamin B _2, vitamin B _6, vitamin B Interview _2, vitamin C,槳酸.

2 9, Frequent urination

Flavoxate hydrochloride, oxyptinin hydrochloride, terolidine hydrochloride, 4-ethylenamine 1,1-dimethinole-2-butyninole (±)-~ cyclohexinole-α-pheninoleglycolate hydrochloride mono / dihydrate.

30. Angiotensin converting enzyme inhibitor

Enalapril maleate, alasepril, delapril hydrochloride, candesartan cilexetin.

3 1. Nephritis treatment

(3 β, 4 a) 1, 2 3-Dihydroxy N-(2-methoxyethyl)-18 jS-Orean 1 12-1-2 8-amide (Compound A) .

3 2. Immunosuppressants

Tacrolimus.

3 3. Antineoplastic agent

Paclitaxel, Docetaxenole, Vicanoretamide.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a side view showing a kneading extruder according to Embodiment 1 of the present invention.

FIG. 2 is a plan view of the kneading extruder shown in FIG.

FIG. 3 is an explanatory diagram of the kneading cylinder shown in FIG.

FIG. 4 is an explanatory diagram of the disk shown in FIG.

FIG. 5 is a longitudinal sectional view illustrating a movable mechanism that reciprocates the supply-side movable plate and the kneading-side movable plate illustrated in FIG.

FIG. 6 relates to Embodiment 2 of the present invention. FIG. 1 is a plan view showing a kneading extruder.

FIG. 7 is a longitudinal sectional view illustrating the bearing shown in FIG.

FIG. 8 is a longitudinal sectional view illustrating a movable mechanism for reciprocating the mixing-side movable plate shown in FIG.

FIG. 9 shows the results of the dissolution test for Example 1. The vertical axis represents the dissolution concentration of the drug (^ g Zml, the horizontal axis represents the test time (minutes). X—is the result of the drug substance powder, 100—is the result of the physical mixture, and The results of the solid pharmaceutical dispersion according to Example 1 (the method of the present invention) are shown, and the results of the solid pharmaceutical dispersion according to Comparative Example 1 (solvent method) are shown as “△”. The results of the dissolution test for Example 2 are shown, where the vertical axis represents the dissolved concentration of the drug (^ g Zml, and the horizontal axis represents the test time (minutes). The results of the physical mixture, one bite shows the result of the solid pharmaceutical dispersion according to Example 2 (the method of the present invention), and one plot shows the result of the solid pharmaceutical dispersion according to Comparative Example 2 (solvent method). Respectively.

FIG. 11 shows the results of the dissolution test for Example 3. The vertical axis represents the dissolved concentration of the drug (g / ml), and the horizontal axis represents the test time (minutes). X represents the results of the drug substance powder, —〇 represents the results of the physical mixture, 口 —the results of the solid pharmaceutical dispersion according to Example 3 (the method of the present invention), and △ —the results of Comparative Example 3. The results of the solid pharmaceutical dispersion according to (solvent method) are shown.

FIG. 12 shows the results of the dissolution test of Example 6. The vertical axis represents the dissolved concentration of the drug (g / ml), and the horizontal axis represents the test time (minutes). One X— The results are as follows: ロー represents the result of the solid pharmaceutical dispersion according to Example 6 (the method of the present invention).

FIG. 13 shows the results of the dissolution test for Example 7. The vertical axis indicates the dissolution concentration of the drug (tg / ml, the horizontal axis indicates the test time (minutes). —X— indicates the result of the drug substance bulk, and bite— indicates the drug according to Example 7 (the method of the present invention). The results for solid dispersions are 'represented respectively.

FIG. 14 shows the results of the dissolution test for Example 8. The vertical axis represents the dissolved concentration (μgZml) of the drug, and the horizontal axis represents the test time (minutes). X represents the result of the drug substance,-represents the result of the physical mixture, and the bite represents the result of the solid pharmaceutical dispersion according to Example 8 (the method of the present invention).

FIG. 15 shows the results of the dissolution test for Example 9. The vertical axis dissolve concentration of the pharmaceutical _(μ δ Ζπι 1), it represents a horizontal axis test time (min). X represents the result of the drug substance powder, X represents the result of the physical mixture, and X represents the result of the solid pharmaceutical dispersion according to Example 9 (the method of the present invention).

FIG. 16 shows the result of X-ray diffraction analysis for Example 1. The vertical axis represents the diffraction intensity (cps), and the horizontal axis represents the diffraction angle (°). The top chart shows the results for the drug substance powder, the second chart from the top shows the results for the physical mixture, and the second chart from the bottom shows the results for the pharmaceutical solid dispersion according to Comparative Example 1 (solvent method). The chart at the bottom shows the result of the solid pharmaceutical dispersion according to Example 1 (the method of the present invention).

FIG. 17 shows the result of X-ray diffraction analysis for Example 2. The vertical axis represents the diffraction intensity (cps), and the horizontal axis represents the diffraction angle (°). The top chart shows the results for the drug substance powder, the second chart from the top shows the results for the physical mixture, and the second chart from the bottom shows the results for the solid pharmaceutical dispersion of Comparative Example 2 (solvent method). The bottom chart shows the results of the pharmaceutical solid dispersion according to Example 2 (the method of the present invention).

FIG. 18 shows the result of X-ray diffraction analysis for Example 3. The vertical axis is the diffraction intensity

(cps) and the horizontal axis represents the diffraction angle (°). The top chart shows the results for the drug substance powder, the second chart from the top shows the results for the physical mixture, and the second chart from the bottom The chart shows the results of the solid pharmaceutical dispersion according to Comparative Example 3 (solvent method), and the bottom chart shows the results of the solid pharmaceutical dispersion according to Example 3 (method of the present invention).

FIG. 19 shows the result of the X-ray diffraction analysis for Example 4. The vertical axis represents the diffraction intensity (cps), and the horizontal axis represents the diffraction angle (°). The top chart shows the results for the drug substance bulk, the middle chart shows the results for the physical mixture, and the bottom chart shows the results for the solid pharmaceutical dispersion according to Example 4 (the method of the present invention).

FIG. 20 shows the result of X-ray diffraction analysis on Example 5. The vertical axis represents the diffraction intensity (cps), and the horizontal axis represents the diffraction angle (°). The top chart shows the results for the drug substance powder, the middle chart shows the results for the physical mixture, and the bottom chart shows the results for the pharmaceutical solid dispersion according to Example 5 (the method of the present invention).

FIG. 21 shows the results of X-ray diffraction analysis for Examples 6 and 7. The vertical axis represents the diffraction intensity (cps), and the horizontal axis represents the diffraction angle (°). The top chart shows the results for the drug substance, the middle chart shows the results for the solid pharmaceutical dispersion according to Example 6 (the method of the present invention), and the bottom chart shows the results for the drug according to Example 7 (the method of the present invention). The results of the solid dispersion are shown respectively. '

FIG. 22 shows the result of X-ray diffraction analysis for Example 8. The vertical axis is the diffraction intensity

(cps) and the horizontal axis represents the diffraction angle (°). The top chart shows the results for the bulk drug substance, the middle chart shows the results for the physical mixture, and the bottom chart shows the results for the solid pharmaceutical dispersion according to Example 8 (the method of the present invention). · Figure 23 shows the result of X-ray diffraction analysis for Example 9. The vertical axis represents the diffraction intensity (cps), and the horizontal axis represents the diffraction angle (°). The top chart shows the results for the bulk drug substance, the middle chart shows the results for the physical mixture, and the bottom chart shows the results for the solid pharmaceutical dispersion according to Example 9 (the method of the present invention).

(Explanation of code)

1 kneading extruder (batch kneading extruder, intermittent kneading extruder), 2 material supply section, 3 discs, 4 material kneading section, 6 rotating shaft, 7 discharge port, 8 cylindrical side hole opening, 1 0 Kneading cylinder, 1 3 Supply cylinder, 1

8 post shaft, 1 9 kneading side movable plate, 20 supply side movable plate, 22 kneading side Movable mechanism,

2 3 Supply side movable mechanism, 2 9 Gap adjusting screw part, 30 Fixed part, 31 Knob part, 36 Transfer screw shaft

BEST MODE FOR CARRYING OUT THE INVENTION The present invention generally relates to a method for preparing a kneaded material such as a predetermined amount of a pharmaceutically acceptable polymer carrier, a drug, and optionally other additives. The mixture (simple mixture or physical mixture of the materials to be kneaded) is charged into the main kneading extruder, or the individual materials to be kneaded are simultaneously and quantitatively subjected to main kneading and extruding without a premix. It can be carried out by charging, shearing, kneading, extruding, etc., based on the function of the main kneading extruder to be used.

The compounding ratio of the polymer carrier and the drug to be used varies depending on the type of the polymer carrier and the drug used, the desired solid dispersion of the drug, etc., but does not differ from the compounding ratio in other production methods such as the solvent method. . In order to obtain a medically useful pharmaceutical solid dispersion in which the crystal peak of the drug has sufficiently disappeared by analyzing with an X-ray diffractometer, it depends on the drug used, the polymer carrier, other additives, etc. Generally, at least 3 to L0 times the weight of the pharmaceutical agent is required for the drug in many cases. Other additives may include compounds that overlap with each other, but include, for example, bulking agents, softeners, flow agents, lubricants, disintegrants, colorants, stabilizers, fragrances, solubilizers, and sorbents. , Antioxidants, pH regulators, surfactants, buffering agents, flavoring agents, desiccants, sweeteners, foaming agents, disintegration aids, preservatives, and cooling agents. These can be blended in appropriate amounts. Examples of the bulking agent include milk bran, corn starch, crystalline cellulose, D-mannitol, sorbitol, xylitol, and calcium phosphate. The bulking agent is used in a solid dispersion. For example, it can be blended within a range of 50% by weight or less. Examples of the softener include water (tap water, distilled water, purified water, isotonic water such as physiological saline, neutral or acidic or basic buffer, 'or ammonia water, etc.), methanol, ethanol, isopro Solvents represented by alcohols such as panol and butanol, halogenated hydrocarbons such as chloroform, methylene chloride and trichloroethylene, hydrocarbons such as hexane, benzene and toluene, ethers and ketones; Bran alcohol such as erythritol, mannitol, xylitol, sorbitol, inositol, maltitol, arabitol, dulcitol; bran alcohol such as triethyl citrate, triacetin, propylene glycol, Spans and Tweens; In the dispersion, for example, it can be blended in a range of 20% by weight or less. Examples of the fluidizing agent include long-chain fatty acids such as stearic acid; monoglycerides, diglycerides, and triglycerides of long-chain (C10-22) fatty acids; higher fats such as carnauba wax, polyoxyethylene hydrogenated castor oil, and stearyl alcohol. Wax such as alcohol and cetanol; lecithin and sodium lauryl sulfate; and the fluidizing agent can be blended in a solid dispersion, for example, within a range of 20% by weight or less. Lubricants include, for example, light silicic anhydride, hydrous silicon dioxide, sodium stearyl fumarate, magnesium stearate, calcium stearate, synthetic aluminum chelate, magnesium metasilicate aluminate, dry aluminum hydroxide gel, talc The lubricant may be incorporated in the solid dispersion, for example, in a range of 3% by weight or less. Examples of the disintegrant include low-substituted hydroxypropylcellulose, hydroxypropyl starch, carmellose, canolemellose sodium, croscanolemellose sodium, carmecium monocalcium, carboxymethyl starch sodium (Primodiel), Partially pregelatinized starch may be mentioned, and the disintegrant may be blended in a solid dispersion, for example, in a range of 20% by weight or less. Examples of the colorant include iron sesquioxide, yellow iron sesquioxide, titanium oxide, and tar dyes. The colorant is blended in a solid dispersion, for example, in a range of 1% by weight or less. be able to. As a stabilizer, for example, ascorbic acid or benzoic acid can be used, and the stabilizer can be blended in a solid dispersion, for example, within a range of 20% by weight or less. Examples of fragrances include 1-menthol and orange extract. It can be blended within the range of weight ° / o or less.

The premix of the material to be kneaded can be prepared by a conventional method.For example, the material to be kneaded can be simplified by a machine such as an Ader mixer, a V-type mixer, a double cone mixer, a cubic mixer, or a ribbon mixer, or manually. Can be obtained by mixing them.

The premix of the material to be kneaded is charged into the main kneading extruder manually or by using a suitable material feeder, for example, a screw feeder, a staple feeder, a belt conveyor type constant feeder, or an electromagnetic feeder. Can be done. In addition, these material feeders can be used not only for feeding the premix to the kneading extruder but also for simultaneously and quantitatively feeding the individual materials to be kneaded.

The processing temperature of the material to be kneaded depends on the type and blending ratio of the polymer carrier, medicine, and other additives used, the type of the main kneading extruder used (especially the shape characteristics of the rotating disk and the 'fixed disk') Although it depends on the speed, etc., it is desirable that the temperature of the material to be kneaded be higher than the glass transition temperature or higher than the softening temperature. Even at a temperature lower than the glass transition temperature or the softening temperature, a solid pharmaceutical dispersion may be produced depending on the type and blending ratio of the high molecular carrier and the pharmaceutical used. It is preferable that the material to be kneaded has reached at least near the processing temperature before reaching the rotating disk portion. Further, it is preferable that the temperature near the softening temperature of the material to be kneaded is maintained even before the material to be kneaded is extruded after passing through the rotating disk portion. The processing speed (the number of rotations of the screw) depends on the type of the main kneading extruder used (especially the shape characteristics of the rotating disk and the fixed disk), the material to be kneaded, the processing temperature, etc. It can be set within the range. Specifically, 5 rpra or more is appropriate, and 10 to 30 Orpm is preferable.

The kneaded extrudate (pharmaceutical solid dispersion) extruded from the outlet can be cut to a desired length by an appropriate cutting machine, for example, a roller-type crusher, a cutter mill, a pin mill, or the like. This cut product can be used as it is or dried to obtain a granular pharmaceutical preparation. The shape of the outlet is There is no particular limitation, and examples thereof include a polygon such as a circle, a triangle, a quadrangle, and a hexagon, and a star. The appropriate diameter of the outlet is 0.5 to 5 thighs.

A capsule preparation can be made by packing the above-mentioned granules in a capsule or the like, and a tablet can be made by compression molding.

In addition, it is also possible to fill the capsules with the granules that have been subjected to a coating treatment or the like, or the granules or those that have been subjected to a coating process. Thereby, the strength of the pharmaceutical preparation can be further improved, and the stability of the pharmaceutical preparation can be enhanced.

Naturally, the above-mentioned preparation can be carried out by appropriately blending various pharmaceutically acceptable additives and polymer compounds.

Example

Next, the present invention will be described in more detail with reference to Examples and Test Examples. It goes without saying that the present invention is not limited to the following examples. The following examples were performed using a patch-type kneading extruder 1 shown in FIGS.

Example 1

Hydroxypropyl methylcellulose acetate succinate (HPMC A'S, trade name: AQ OAT, AS-LF grade, manufactured by Shin-Etsu Gigaku Kogyo Co., Ltd.) was added to 20 g of diphenedipine. This pre-mixture is made of a 50 mm diameter, 20 mm wide disk (material: SACM645 nitrided) 3, and a 20 mm diameter, spiral screw 6a and screw type rotary shaft 6f. (Material: SACM645 with nitriding treatment) 6 and a patch-type kneading extruder equipped with a discharge port 7 with a diameter of 2 mm (Material of the kneading cylinder part: SACM645 with nitriding treatment, Material of supply cylinder part: Nitriding treatment SACM645) 1, the conditions were 20 rpm, the temperature of the kneading cylinder section 10 was 130 ° C, and the temperature of the supply cylinder section 13 was 120 ° C. Kneading gap 2 imn, supply gap 2 mm To obtain a kneaded extrudate (solid pharmaceutical dispersion).

Example 2

Diphenpine 20 g and hydroxypropyl methylcellulose phthalate (H PMCP, trade name: HP-50F, manufactured by Shin-Etsu Chemical Co., Ltd.) A kneaded extrudate (pharmaceutical solid dispersion) was obtained in the same manner as in Example 1 except that a premix with 100 g was used.

Example 3

Using a pre-mixture of 20 g of diphedipine, 160 g of hydroxypropyl methylcellulose (HPMC, trade name: TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.) and 20 g of erythritol, the temperature of the supply cylinder 13 was set to 160 ° C. A kneaded extrudate (pharmaceutical solid dispersion) was obtained in the same manner as in Example 1, except that the temperature of the kneading-side cylinder section 10 was changed to 170.

Example 4

Using a premix of 20 g of dihydrochloric acid / resipin, 100 g of hydroxypropyl methinoreseno-relorose acetate tosuccinate (HPMCAS, trade name: AQOAT, AS-LF grade, Shin-Etsu Chemical Co., Ltd.) and 10 ml of water, The temperature of the supply-side cylinder 13 was 90 ° C, and the temperature of the kneading-side cylinder 10 was 100. A kneaded extrudate (pharmaceutical solid dispersion) was obtained in the same manner as in Example 1 except that C was used.

Example 5

A kneaded extrudate (pharmaceutical solid dispersion) was obtained by treating in the same manner as in Example 4 except that oxypeptinine hydrochloride was used as a drug and the motor speed was 30 rpm. Example 6

A kneaded extrudate (pharmaceutical solid dispersion) was obtained in the same manner as in Example 5, except that indomethacin was used as the drug.

Example 7

Using a pre-mixture of 20 g of indomethacin and 100 g of a methacrylic acid copolymer (trade name: Eudragit L100-55, manufactured by Reem GmbH), the temperature of the supply-side cylinder 13 was set to 140 ° C, and the temperature of the kneading-side cylinder 10 was set. The kneaded extrudate (pharmaceutical solid dispersion) was obtained in the same manner as in Example 1 except that the temperature was set to 150 ° C. and the number of rotations of the motor was set to 30 rpm.

Example 8

Griseofulvin 20g, Hydroxypropyl methylcellulose (HPM C, Trade name: TC-15R, Shin-Etsu Chemical Co., Ltd.) 160 g and erythritol 20 g were used as a pre-mixture, and the temperature of the supply cylinder 13 was 160 ° C and the temperature of the kneading cylinder 10 was A kneaded extrudate (pharmaceutical solid dispersion) was obtained in the same manner as in Example 1 except that the temperature was changed to 170 ° C.

Example 9

A kneaded extrudate (pharmaceutical solid dispersion) was obtained in the same manner as in Example 8, except that phytoin was used as a pharmaceutical.

Comparative Example 1 Solvent method

Weigh 5 g of diphedipin and 25 g of hydroxypropinolemethylcenorellose acetate succinate (HPMC AS, trade name: AQ OAT, AS-LF grade, Shin-Etsu Chemical Co., Ltd.) 500 mL of ethyl alcohol and 500 raL of methylene chloride were added and dissolved. Thereafter, the solvent was completely evaporated at 50 ° C. using a rotary evaporator to obtain a solidified product (medicine solid dispersion).

Comparative Example 2 Solvent method

5 g of diphendipine and 25 g of hydroxypropyl methylcellulose phthalate (HPMCP, trade name: HP-50F, manufactured by Shin-Etsu Chemical Co., Ltd.) are weighed, and 500 mL of ethyl alcohol and 500 mL of methylene chloride are added thereto. Dissolved. Thereafter, the solvent was completely evaporated at 50 ° C. using a rotary evaporator to obtain a solidified product (a solid pharmaceutical dispersion).

Comparative Example 3 Solvent method

2 g of ephedipine and 16 g of hydroxypropylmethylcellulose (HPMC, trade name: TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.) were weighed, and dissolved in 500 mL of ethyl alcohol and 500 mL of methylene chloride. Separately, 2 g of erythritol was weighed, added to the above solution and suspended. Thereafter, the solvent was completely evaporated at 50 ° C. using a rotary evaporator to obtain a solidified product (a solid drug dispersion).

Test example 1

The kneaded extrudate (pharmaceutical solid dispersion) obtained in each example was finely pulverized by a sample mill, and the pulverized product obtained in each of the comparative examples and the solidified product (pharmaceutical solid dispersion) The dissolution test was carried out on the pulverized material obtained by finely pulverizing the powdered product using a table-top small pulverizer. Examples:! The solubility of the drug substance according to Examples 1 to 3 and the solubility of the drug in the physical mixture of the drug substance and the polymer carrier according to Examples 1 to 3 in the same ratio are also the corresponding examples. The test was performed under the same dissolution test conditions as in the test examples. Tables 1 and 2 show the conditions of the dissolution test. The results of each dissolution test are shown in Figs.

table 1

As is clear from the results of FIGS. 9 to 15, the solubility in the solid pharmaceutical dispersion obtained by the method of the present invention is much higher than the solubility in the drug substance powder or physical mixture, and It showed a solubility equal to or higher than that of a pharmaceutical solid dispersion obtained by a solvent method, which is one method for producing a solid dispersion.

Test example 2

Kneaded extrudate of each example (pharmaceutical solid dispersion) finely pulverized by a sample mill, solidified product of each example (pharmaceutical solid dispersion) finely pulverized by a tabletop small pulverizer, drug substance powder, and the like A physical mixture of the drug substance powder and the polymer carrier according to the example in the same ratio was subjected to crystal analysis using an X-ray diffractometer. The results are shown in Figs. 16 to 23. You.

As is clear from FIGS. 16 to 23, the X-ray diffraction peak of the drug in the drug solid dispersion obtained by the method of the present invention was hardly recognizable as in the case of the solvent method.

Claims

The scope of the claims

1. The material to be kneaded is compressed and sheared by the rotation of a disk, and is spirally transferred by the rotation of a helical screw to produce a kneaded product. The kneaded material is rotated in a cylinder and turned in the axial direction. A rotating disk is fixed at the center to the rotating shaft with a screw formed on the outer periphery to transfer the fluid, and at least one ffi of this disk has radially alternating peaks and valleys A fixed disk is fixed to the cylinder coaxially so as to face this surface, and is arranged so that a gap is formed between the fixed disk and the rotary shaft. The ridges and valleys are alternately formed radially, and the fluid sent through the space between the fixed disk and the rotating shaft is pushed outward by the boundary between the two disks between the valleys of the two disks, It is configured to be fed between the outer circumference of the rotating disk and the inner surface of the cylinder A method for producing a solid pharmaceutical dispersion comprising at least a pharmaceutically acceptable polymer carrier and a medicine by a kneading extruder.

2. The kneading extruder compresses and shears the kneaded material fed from the material supply unit and the kneaded material fed from the material supply unit by rotation of a disk having a shallow groove on the peripheral surface to form a spiral screw. A material kneading section for helically transferring by rotation is horizontally provided in series, and a material kneading section 4 is positioned on the rotating shaft 6 around the spiral screw 6a and the material supply section 2 and is positioned at the material supply section 2 side. The material to be kneaded is compressed, sheared and kneaded to be transferred to the rotating shaft 6 while being kneaded. One of the discs 3 has a diameter larger than the rotating shaft 6 and is coaxially fixed to the rotating shaft 6. A cylindrical lateral hole opening 8 formed in the rear end portion 10b is formed in a rear end portion 10b so as to be rotatable with the disk 3 installed therein. 9 is a series of holes formed from the bottom surface 8a of the cylindrical lateral hole opening 8 to the tip end surface 10c. A kneading extruder 1 comprising a cylinder section 10, wherein the cylinder section 10 is fixed to a movable section 19 that reciprocates in the same direction as the longitudinal direction of the rotary shaft 6, and the movable section 19 is By reciprocating to adjust the gap formed between the rotating shaft side surface of the disk 3 and the bottom surface 8a of the cylindrical lateral hole opening 8, the shape of the material to be kneaded is adjusted. The method for producing a pharmaceutical solid dispersion according to claim 1, wherein a degree of compression and shear is obtained.

3. The kneading extruder compresses and shears the kneaded material fed from the material supply unit and the kneaded material sent from the material supply unit by rotation of a disk having a shallow groove on its peripheral surface. A material kneading section for helically transferring by rotation is horizontally arranged in series, and a material kneading section 4 ′ is positioned on the side of the rotating shaft 6 around the spiral screw 6 a and the material supply section 2. The kneaded material fed from 2 is compressed and sheared and kneaded and transferred to the rotating shaft 6 side while being kneaded. One of the disks having a diameter larger than the rotating shaft 6 fixed coaxially with the rotating shaft 6. A cylindrical lateral hole opening 8 formed at a rear end portion 10b and having a size such that the rotary shaft 6 can be installed and rotated at a rear end portion 10b. A horizontal hole 9 is formed from the bottom surface 8a of the cylindrical horizontal hole opening 8 to the tip end surface 10c. The material supply unit 2 has a front end 13a shaped to fit reciprocally into the cylindrical lateral hole opening 8 and has a front end 13a opened. A kneading extruder 1 comprising a biston portion 14 for extruding the material to be kneaded introduced into the supply side cylinder portion 13 # to a tip portion 13a, wherein the kneading side cylinder portion 10 is A supply-side movable section that is fixed to the kneading-side movable section 19 that reciprocates in the same direction as the longitudinal direction of the rotating shaft 6 and that reciprocates the supply-side cylinder section 13 in the same direction as the longitudinal direction of the rotating shaft 6. The kneading-side movable portion 19 is fixed to 20 and reciprocates to adjust and supply the kneading-side gap formed between the rotating shaft side surface of the disk 3 and the bottom surface 8a of the cylindrical lateral hole opening 8. The side movable part 20 is reciprocated so that the side surface of the disc 3 on the material supply side is The degree of compression and shearing according to the type of the material to be kneaded can be obtained by adjusting the supply-side gap formed between the supply-side cylinder portion 13 and the end portion 13a of the supply-side cylinder portion 13. A method for producing a pharmaceutical solid dispersion according to claim 1.

4. The kneading extruder rotates the material supply section for feeding the material to be kneaded and the material to be kneaded sent from the material supply section by rotating a disk having a shallow groove on the peripheral surface. A material kneading unit which is compressed and sheared and spirally transferred by the rotation of the spiral screw is horizontally provided in series, and a material kneading unit 4 has a rotating shaft 6 around the spiral screw 6a, and a material supply unit. The rotating shaft 6 is coaxially fixed to the rotating shaft 6 for compressing, shearing and kneading the material to be kneaded, which is positioned on the side 2 and fed from the material supply unit 2 and kneading the material. A large-diameter single disk 3 and a cylindrical horizontal hole opening 8 formed in a size that allows the disk 3 to be installed and rotated are provided at the rear end 10b, and the rotary shaft 6 is provided inside. And a kneading cylinder 10 formed from a bottom surface 8a of the cylindrical side hole opening 8 to a tip end surface 10c. Has a leading end 13a shaped to fit reciprocally into the cylindrical lateral hole opening 8. The supply-side cylinder portion 13 that is opened, and the kneading material that is rotatably provided in the supply-side cylinder portion 13 and is fixed to the disk 3 coaxially with the rotary shaft 6 and is charged into the supply-side cylinder portion 13. A kneading extruder 1 comprising a transfer screw shaft 36 for extruding a material to a tip portion 13a while rotating the material, wherein the kneading-side cylinder portion 10 reciprocates in the same direction as the longitudinal direction of the rotating shaft 6. The kneading side is fixed to the kneading-side movable portion 19 and the reciprocating motion of the kneading-side movable portion 19 is formed between the rotating shaft side surface of the disk 3 and the bottom surface 8a of the cylindrical lateral hole opening 8. The method for producing a solid pharmaceutical dispersion according to claim 1, wherein a degree of compression and shearing according to the kind of the material to be kneaded is obtained by adjusting the gap.

5. The pharmaceutically acceptable polymer carrier is a pharmaceutically acceptable water-soluble polymer carrier, and the medicament is added at a temperature of 25 to the first liquid or the second liquid of the Japanese Pharmacopoeia No. 14 at 14th. The method for producing a 'pharmaceutical solid dispersion according to any one of claims 1 to 4, which is a poorly water-soluble drug having a solubility of not more than 00 µg / mL.

6. The pharmaceutically acceptable water-soluble polymer carriers are alkynolecellulose represented by methylcellulose, hydroxymethylcellulose, hydroxyshethyl cellulose, and hydroxyalkyl represented by hydroxypropylcellulose. Noresenorelose, hydroxycetyl methinoresenolerose, hydroxyalkylalkylcellulose represented by hydroxypropyl pillmethylcellulose, carboxyalkylcellulose represented by carboxymethylcell ore, hydroxypropylmethylcellulose acetate Hydroxyalkylalkylcellulose succinate represented by tosuccinate; hydroxyalkynolealkylcellulose phthalate represented by hydroxypropylmethylcellulose phthalate; polybutylpyrrolidone; N-vinylpyrrolidone 6. The method for producing a pharmaceutical solid dispersion according to claim 5, which is a vinyl acetate copolymer, polybutyl alcohol, gum arabic, dextrin, gelatin, or macrogol.

7. A pharmaceutical preparation containing a pharmaceutical solid dispersion produced by the production method according to any one of claims 1 to 6.

8. The pharmaceutical preparation according to claim 7, wherein the dosage form is a tablet, a granule, a capsule, a fine granule, or a powder.

9. In order to manufacture a solid pharmaceutical dispersion composed of at least a pharmaceutically acceptable polymer carrier and a medicament, the material to be kneaded is compressed and sheared by rotating a disk and spirally rotated by a spiral screw. A kneaded product is manufactured by transferring the mixture. A rotating disk is formed at the center of the rotating shaft with a screw formed on the outer periphery to rotate in the cylinder and transfer the fluid in the axial direction. Crests and valleys are alternately radially formed on at least one surface of the disk, and a coaxial fixed disk is fixed to the cylinder in opposition to this surface, and between the rotation shaft and the shaft. The fixed disk is arranged so that a gap is formed, and peaks and valleys are alternately radially formed on the surface of the fixed disk with respect to the rotating disk, and are fed through between the fixed disk and the rotating shaft. Fluid flows between the valleys of the disks due to the boundary between the disks. Pushed toward the outer circumference, configured method of using a kneading extruder as fed between the outer circumference and the cylinder inner surface of the rotary disk.

10. A kneading extruder compresses and shears the material to be mixed, which is fed from the material supply unit, and the circular plate having a shallow groove on its peripheral surface, by rotating a circular screw having a shallow groove on its peripheral surface. Material kneading unit that spirally transfers by rotation of The material kneading section 4 is arranged side by side, and the material kneading section 4 is provided on the rotating shaft 6 around the spiral screw 6a, and the kneading target positioned from the material supply section 2 and fed from the material supply section 2. One of the discs 3 having a diameter larger than that of the rotating shaft 6 fixed coaxially with the rotating shaft 6 for transferring the material to the rotating shaft 6 while compressing / shearing and kneading the material; 3. A cylindrical horizontal hole opening 8 formed at a rear end portion 10b and formed in a rear end portion 10b so as to be rotatable with a cylindrical horizontal hole 9 having a width rotatable with the rotary shaft 6 provided therein is formed as a cylindrical horizontal hole. A kneading extruder 1 comprising a cylinder portion 10 formed from a bottom surface 8a of the opening 8 to a tip end surface 10c, wherein the cylinder portion 10 is the same as the longitudinal direction of the rotary shaft 6. The movable part 19 is reciprocated in one direction and is fixed to the movable part 19 so as to reciprocate. The degree of compression / shearing according to the type of the material to be kneaded can be obtained by adjusting the gap formed between the columnar lateral hole opening 8 and the bottom surface 8a of the columnar horizontal hole opening 8. 9. The method described in 9.

1 1. The kneading extruder compresses and shears the kneading material fed from the kneading extruder by rotating a disk having a shallow groove on the peripheral surface of the kneading material fed from the material feeding unit and a spiral screw. A material kneading section for helical transfer by rotation of the screw is horizontally arranged in a row, and a material kneading section 4 is positioned on the rotating shaft 6 around the spiral screw 6a and the material supply section 2 to supply the material. The material to be kneaded is compressed, sheared and kneaded while being kneaded and transferred to the rotating shaft 6 side. A disk 3 and a columnar lateral hole opening 8 formed in a size that can be rotated with the disk 3 installed therein are provided at the rear end 10b. A cylindrical lateral hole 9 is formed from the bottom surface 8a of the cylindrical lateral hole opening 8 to the tip end surface .10c. A material supply unit 2 having a tip end 13a shaped to fit reciprocally into the cylindrical lateral hole opening 8 and having an opening at the tip end 13a. 13. A kneading extruder 1 comprising a kneading extruder 1 and a piston part 14 for extruding a material to be kneaded introduced into the supply side cylinder part 13 to a tip part 13a. The side cylinder portion 10 is fixed to the kneading side movable portion 19 which reciprocates in the same direction as the longitudinal direction of the rotary shaft 6 and the supply side cylinder portion 13 reciprocates in the same direction as the longitudinal direction of the rotary shaft 6. The kneading side formed between the rotating shaft side surface of the disk 3 and the bottom surface 8a of the cylindrical side hole opening 8 by reciprocating the kneading side movable portion 19 fixed to the moving supply side movable portion 20 which moves. By adjusting the gap and moving the supply-side movable section 20 back and forth, the supply-side gap formed between the side face of the material supply section of the disk 3 and the end face 13a of the supply cylinder section 13 is formed. 10. The method according to claim 9, wherein the degree of compression and shear according to the type of the material to be kneaded is obtained by adjusting.

12. The kneading extruder spirally compresses and shears the material to be mixed, which is fed from the material supply unit, and the disk having a shallow groove on its peripheral surface by rotating the disk. A material kneading unit that helically transfers by rotation of the spiral screw is horizontally provided in a row, and a material kneading unit 4 is positioned on the rotating shaft 6 around the spiral screw 6a and the material supply unit 2 side. The material to be kneaded fed from the material supply unit 2 is compressed, sheared, kneaded, and conveyed to the rotating shaft 6 while being kneaded, and one of a larger diameter than the rotating shaft 6 fixed coaxially with the rotating shaft 6. A front side disk 3 and a cylindrical horizontal hole opening 8 formed in the rear end portion 10b and having a width enough to allow the disk 3 to rotate inside the disk 3 are provided. A cylindrical horizontal hole 9 with a rollable width is formed from the bottom surface 8a of the cylindrical horizontal hole opening 8 to the tip end surface 10c. The material supply unit 2 has a front end 13a shaped to fit reciprocally into the cylindrical lateral hole opening 8 and has the front end 13a opened. And a tip end while rotating the material to be kneaded, which is rotatably provided in the supply-side cylinder portion 13, is fixed to the disk 3 coaxially with the rotation shaft 6, and is charged into the supply-side cylinder portion 13. A kneading extruder 1 comprising a transfer screw shaft 36 for extruding the kneading cylinder 13 into a kneading side movable portion 19 which reciprocates in the same direction as the longitudinal direction of the rotary shaft 6. The kneading-side movable portion 19 is reciprocated to adjust the kneading-side gap formed between the rotating shaft side surface of the disk 3 and the bottom surface 8a of the cylindrical lateral hole opening 8. 10. The method according to claim 9, wherein a degree of compression / shearing according to a type of the kneaded material is obtained.

1 3. The pharmaceutically acceptable polymer carrier is a pharmaceutically acceptable water-soluble polymer carrier, and the drug is a liquid at a temperature of 25 ° C, a first liquid or a second liquid of the Japanese Pharmacopoeia No. 14 The method according to any one of claims 9 to 12, wherein the drug is a poorly water-soluble drug having a solubility of 500 µg / h or less.

14. Pharmaceutically acceptable water-soluble polymer carriers include methylcellulose, hydroxymethyl / resenorelose, hydroxyxetinoresenorelose, hydroxypropynolecellulose, hydroxyxethyl methylcellulose, and hydroxypropynolemethyl. Representatives of Lucenololose, Carpoxymethylcellulose, Sodium phenolic methylcellulose, Hydroxypropyl methylcellulose acetate succinate, Hydroxypropyl methinoylcellulose phthalate, Cellulose propyloxymethylcellulose cellulose, Cellulose acetate phthalate Water-soluble cellulose derivatives; polybutylpyrrolidone, N-bielpyrrolidone 'biel acetate copolymer, polybutyl alcohol, carboxybutyl polymer, polyethylene glycol, polyethylene Water-soluble synthetic polymer compounds represented by xide, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, polybutylacetal getyl aminoacetate; gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, water-soluble natural polymer compound or its derivative represented by xanthan gum; or dextrin, _alpha starch, - cyclodextrin, beta - sheet Kurodekisu Trinh, gamma - cyclodextrin, a force Lupo carboxymethyl star pristinamycin thorium, 14. The method according to claim 13, which is a water-soluble starch derivative represented by pullulan.