WO2001000179A1

WO2001000179A1 - Dry coated tablet and method for producing the same and production system

Info

Publication number: WO2001000179A1
Application number: PCT/JP2000/004242
Authority: WO
Inventors: Ikuo Koyama
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 1999-06-29
Filing date: 2000-06-28
Publication date: 2001-01-04
Also published as: AU5704200A

Abstract

A dry coated tablet having an internal core part comprising a base which contains, for example, a trace amount of a drug and can be molten by heat and a cover part covering the core part. The above dry coated tablet is prepared, for example, by a method comprising liquefying the base by heating, discharging the resultant liquid intermittently as droplets, and then covering the droplet with a covering material. A production system for the dry coated tablet is preferably provided with a discharging apparatus comprising a pump for sending the base by pressure, a solenoid operated valve for intercepting the flow of the base and a controlling device therefor. The above core-having tablet can be used for rendering all tablets produced to contain a same amount of a drug which has a high pharmacological activity and the like and thus has a small dosage, with reliability and ease, and with no use of a volatile solvent.

Description

TECHNICAL FIELD The present invention relates to a dry coated tablet, a method for producing the same, and a production system.

The present invention relates to a tablet capable of uniformly containing a drug having a relatively small dose due to high pharmacological activity and the like in any tablet, a method for producing the tablet, and a production system thereof. Background art

Normally, tablets are administered with a few tens of milligrams of the active ingredient added to the tablets.However, for drugs with strong pharmacological activity, the dose per tablet is suppressed to a relatively low dose. ing.

When producing such tablets containing a relatively small amount of drug, a method of uniformly distributing the drug to all tablets, for example, a method of uniformly mixing a solution of the drug with an excipient is known. It has been adopted so far.

In this method, a desired drug is first dissolved in an appropriate solvent, and then this is uniformly mixed and dispersed in a small amount of excipient. Next, the operation of uniformly mixing and dispersing this dispersion in a predetermined amount of a new excipient is repeated several times to increase the amount, and then drying is performed. Then, a binder, a disintegrant, and the like are mixed with the dried product, if necessary, to produce granules, and the granules are compressed into an appropriate shape using a tableting machine to produce tablets. However, in this method, it was very difficult to guarantee the uniformity of the content of the drug contained in each tablet due to the small amount of the drug to be administered.

Thus, a method has been proposed for producing tablets containing a small amount of a drug by utilizing an atomizing device (also called a droplet ejector) using a piezo oscillator, which is widely used in inkjet printing. (Japanese Patent Publication No. 2-48585). In this method, a solution or suspension of a drug in a volatile solvent is discharged as extremely small droplets from a nozzle onto a vehicle using a piezo electric oscillator, and the tablet is formed into tablets. In addition, if necessary, each of the droplets is charged and electrostatically deflected so that the excipient table can be obtained. A droplet is applied to the surface in a desired shape.

However, the atomization device described in Japanese Patent Publication No. 2-84852 dispenses a droplet or droplet of a drug solution because the vibration or vibration of the piezo element makes the drug solution or suspension fine and ejects. The force is extremely weak, and as a result, the ejection amount per droplet is limited to a very small amount of about 0.008 mg. Therefore, there is almost no case in which the required amount of drug can be covered by discharging only one drop of the drug solution per tablet, and it is necessary to discharge the drug solution multiple times per tablet.

By the way, around the tableting machine where the nozzle of the atomizing device using the piezo oscillator described in Japanese Patent Publication No. 2-48585 is to be installed, powder of excipients flutters, and A relatively small turbulence is generated with the operation of the apparatus. For this reason, it is extremely difficult to always discharge a very light microdroplet of a chemical solution at a predetermined position on the excipient surface multiple times with high accuracy.

In addition, the piezo oscillator is originally used for ink jet printing, and the solvents that can be used there are limited to those having low viscosity and being volatile. Furthermore, in order to utilize this in tablet production, it is necessary to use a solvent that is compatible with the drug as the active ingredient and that is guaranteed in safety. Therefore, the solvents satisfying all these conditions are extremely limited, and none of them can withstand practical use.

And, even if a solvent that satisfies the above conditions is used, the atomization method described in Japanese Patent Publication No. 2-84852 requires a large amount of solvent to produce fine droplets. Since the use is indispensable, a part of the solvent is sealed together with the drug in the excipient by tableting, and there is a problem that its volatilization becomes difficult. Therefore, it is necessary to take new measures to prevent residual volatile solvents. As described above, the production of tablets by an atomizing device using a piezo oscillator has many problems, and it is extremely difficult to produce tablets containing a small amount of drug using this method. Was. Disclosure of the invention

An object of the present invention is to solve the above-mentioned problems in the prior art. One type of dry-coated tablet of the present invention comprises: (a) a drug as an active ingredient; And at least one inner core portion made of a heat-meltable base material; and (b) a coating portion including the inner core portion. The average weight of the inner core is preferably 0.5 mg or more. The base preferably melts at a temperature around body temperature or does not melt at a temperature near body temperature, but preferably has a property of dissolving in body fluids such as gastric juice and intestinal juice.

The base can be composed of a hydrophilic substance, a hydrophobic substance, an amphipathic substance, or a mixture thereof. Here, the term “amphiphilic substance” means a substance having both hydrophilic and hydrophobic properties. Preferably, the hydrophilic substance is selected from saccharides such as polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, glycerose gelatin, candy and the like, or a mixture thereof, and the hydrophobic substance is synthetic or natural phenols. Or an oil or a mixture thereof, and the amphipathic substance is stearyl alcohol, polyoxysyl stearate, cetyl alcohol, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearyl ether, or polyoxyethylene stearyl ether. Polyoxypropylene glycol, polyoxyethylene lauryl ether, polyoxyethylene sorbitan monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolarate, lauryl sulfate It is preferably selected from sodium acid, lauroyl sarcosine sodium, polyoxyethylene lauryl ether or a mixture thereof.

On the other hand, another type of the dry-coated tablet of the present invention is characterized in that it comprises (a) at least one inner core made of a heat-meltable drug, and (b) a coating part containing the inner core. You. Also in this case, it is preferable that the average weight of the inner core is 0.5 mg or more. Further, the method for producing a dry-coated tablet of the present invention comprises: (a) a mixing step of mixing a drug as an active ingredient with a heat-melted liquid base; and (b) dividing the liquid base containing the drug. And (c) a coating step of coating at least one of the droplets with a coating agent. When the drug is melted by heating and exists as a liquid, it may be divided as it is to form a droplet. The average weight of the droplets is preferably 0.5 mg or more.In the dividing step, the droplets may be formed by discontinuously discharging the liquid drug or the liquid base containing the drug. preferable. Further, the dry-coated tablet manufacturing system of the present invention comprises: (a) a drug (hereinafter, referred to as a “liquid drug”) which is melted by heating and exists as a liquid itself, or (B) a coating material supply device for supplying a coating of the liquid drug or the liquid base; and (c) a coating material supply device for supplying a coating material of the liquid drug or the liquid base. And a coating device for coating the agent with the coating agent. The base supply device preferably includes a pump for pumping the liquid drug or the liquid base under pressure, an electromagnetic valve for separating the flow path of the liquid drug or the liquid base, and a control device therefor. It is preferable that the coating device is a tableting device including a plurality of sets of upper punches and lower punches that can enter and exit the die. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a cross-sectional view of a substantially spherical dry-coated tablet as an example of an embodiment of the present invention. FIG. 2 is a cross-sectional view of a substantially spherical dry-coated tablet as another example of the embodiment of the present invention. FIG. 3 is a top view showing an example of the embodiment of the dry-coated tablet manufacturing system according to the present invention.

FIG. 4 is a partially transparent side view of the manufacturing system of FIG. 3 as viewed from the Y direction.

FIG. 5 is a diagram showing an example of a manufacturing process when manufacturing a dry-coated tablet having one inner core using the manufacturing systems of FIGS. 3 and 4.

FIG. 6 is a diagram showing an example of a manufacturing process when manufacturing a dry-coated tablet having two inner cores using substantially the same manufacturing system as in FIGS. 3 and 4. Detailed description of the invention

The subject of the present invention is to form a liquid by heating the drug itself or by mixing it with a liquid base obtained by heating and melting the drug, and then dividing the liquid into droplets of a predetermined size. Further, the present invention relates to a technique for coating the droplets with a coating agent such as an excipient to obtain a dry coated tablet. Another subject of the invention is the use of a liquid base and / or a medicament for the production of a dry-coated tablet comprising at least one inner core and its covering. According to the present invention, it is possible to incorporate a small amount of a drug as a pharmaceutically active ingredient into each tablet without mixing it with an excipient or a volatile solvent. It has the technical features of significantly improving the uniformity of the contents of various drugs and eliminating various technical problems caused by the solvent.

Hereinafter, the dry-coated tablet according to the present invention, its manufacturing method and its manufacturing system will be described in detail.

FIG. 1 is a cross-sectional view of a substantially spherical dry-coated tablet 1 which is an example of an embodiment of the present invention. The dry-coated tablet 1 has one inner core 2 containing a relatively small amount of a drug as a pharmaceutically active ingredient. And a covering portion 3 including an inner core portion 2. The size of the dry coated tablet 1 is not particularly limited, but is preferably a size that can be orally administered.

In the embodiment shown in FIG. 1, the inner core portion 2 is made of a heat-meltable base containing a drug as an active ingredient, and the base is heated to a temperature equal to or higher than a predetermined melting point. Can be liquefied. Various drugs can be used, for example, antibiotics, cardiotonic, antihypertensive, hypoglycemic, anticoagulant, antipyretic, analgesic, anti-inflammatory, antihistamine, hypnotic, sedative, anti-inflammatory Examples include lipemic agents, diuretics, vasodilators, antiepileptics, tranquilizers, anesthetics, antitumor agents, chemotherapeutics, respiratory stimulants, antitussives, expectorants, muscle relaxants, antidote, etc. These drugs may be used alone or in combination of two or more. The amount of drug added per tablet of dry coated tablet 1 is preferably smaller than the amount of general drug added, for example, 0.001 to 20 per tablet. mg, preferably from 0.001 to 10 mg, more preferably from 0.001 to 1 mg.

As a main component of the base, a hydrophilic substance, a hydrophobic substance, an amphipathic substance, or a mixture thereof can be employed. The hydrophilic substance melts at a predetermined temperature of 40 ° C., preferably 50 ° C. or higher by heating, but even at a lower temperature, at least a part thereof in a body fluid such as gastric juice or intestinal fluid. Is preferably a substance having the property of dissolving or swelling, for example, pharmaceutically acceptable polyethylene glycol, polyethylene oxide, polyvinyl bilidone, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulol, Sodium carboxymethylcellulose, polyvinyl alcohol, polyacrylate, polyvinyl acetate, aminoalkyl methacrylate copolymer, polyvinyl acetate getyl amino acetate, cellulose acetate phthalate, methyl It is possible to use methacrylate-methacrylic acid copolymer, hydroxybutyral methyl methyl cellulose ore phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, saccharides, etc., or a mixture thereof. In view of the heat resistance and the release property of the drug, sugars such as polyethylene glycol, polyethylene oxide, polyvinyl bilidone, glycerin gelatin, and candy are preferred.

On the other hand, the hydrophobic substance preferably melts at 30 to 38 ° C. by heating, but preferably has a property of not dissolving in water, and includes, for example, waxes, fats and oils, and the like. Mixtures can be used, but pharmaceutically acceptable synthetic, semi-synthetic, or natural resins or fats are preferred in terms of drug release. , Caprylic acid, Capric acid, Pelagonic acid, Pendecylic acid, Tridecylic acid, Lauric acid, Myristic acid, Noremitic acid, Penic decyl acid, Hepyl decyl acid, Stearic acid, Oleic acid, Elaidic acid, Linoleic acid Examples thereof include unsaturated fatty acids such as luic acid and linoleic acid, and unsaturated fatty acid glycerin esters, witibsol, and natural cocoa butter.

Further, the amphipathic substance is preferably dissolved at 30 to 38 ° C. by heating, or at least in a body fluid such as gastric juice or intestinal fluid even at a temperature lower than the melting temperature. A highly stable substance having a property of partially dissolving or swelling is preferable. For example, stearyl alcohol, polyoxyl stearate, cetyl alcohol (ceanol), polyoxyethylene hydrogenated castor oil, polyoxyethylene stearyl ether, polyoxy Ethylene (105) polyoxypropylene

(5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene lauryl ether, polyoxyethylene sorbyl monostearate (polysorbate), glyceryl monostearate, Sorbitan monostearate, sorbitan monolaurate, sodium lauryl sulfate, sodium lauroyl sarcosine, polyoxyethylene lauryl ether

(Lauromacrogol), lecithin such as lecithin or hydrogenated lecithin, or a mixture thereof is preferred.

The base includes, in addition to the various drugs described above, a saccharide, a surfactant, a melting point modifier, Various additives such as a viscosity modifier, a sequestering agent, an antioxidant, and a disintegrant may be mixed. In addition, the solvent components such as water and ethanol contained in the base must be kept to a minimum necessary, specifically, 20% or less, preferably 10% or less, and more preferably 5% or less. Is preferred.

When a drug capable of melting itself by heating to become a liquid is used as a pharmaceutically active ingredient, the inner core portion 2 may be composed of the drug alone without using the various bases described above. . Examples of such drugs include ubitecarenone (ubiq uinone, coenzymeQIO) and the like.

As the material of the coating 3, commonly used excipients such as calcium citrate, calcium hydrogen phosphate, magnesium aluminate metasilicate, calcium sulfate, corn starch, potato starch, and cellulose can be used. it can. In addition, if necessary, the covering portion 3 may contain a foaming agent such as sodium hydrogen carbonate, a saccharide such as lactose, a sweetener such as aspartame, a fragrance such as heart oil, a polysaccharide such as sodium alginate, gelatin, etc. Natural polymers, cellulosics such as hydroxyethyl cellulose, synthetic polymers such as polyethylene glycol, lubricants such as talc, or other additives alone or in combination. Good. The coating 3 may contain a drug having a relatively low activity in an amount usually used, for example, 10 to 500 mg, preferably 20 to 50 Omg.

In the embodiment shown in FIG. 1, the weight of the inner core portion 2 included in the dry-coated tablet 1 is preferably 0.5 mg or more, more preferably 2 mg or more. If the weight of the inner core 2 is less than 0.5 mg, it is inconvenient to manufacture the dry coated tablet 1 as described later. The upper limit of the weight of the inner core 2 is not particularly limited, but is preferably 50 mg or less from the viewpoint of maintaining the strength of the tablet.

The number of inner core portions included in the coated portion of the dry coated tablet of the present invention is not limited to one, and may be plural. FIG. 2 is a cross-sectional view of a substantially spherical dry-coated tablet 1, which is another example of the embodiment of the present invention. Here, the same components as those in FIG. 1 are denoted by the same reference numerals, and description thereof will be omitted.

As is clear from the figure, the dry coated tablet 1 in FIG. 2 has grooves 4 formed on the upper and lower surfaces of the covering portion 3, and two inner core portions 2 a and 2 b inside the covering portion 3. Is included This is different from the embodiment of FIG. The illustrated dry coated tablet 1 ′ may be administered as it is, but if necessary, is divided into two along the line X-X using the groove 4. The groove 4 may be formed only on the upper surface or only on the lower surface of the covering portion 3, or may be a continuous groove surrounding the covering portion 3.

When a plurality of inner cores are included in the coating 3 constituting the dry-coated tablet, the position of the inner core in the coating 3 can be appropriately set as necessary, for example, as shown in FIG. Thus, if the dry coated tablet 1 'is of a type that can be used by being divided, each part 3a, 3b of the covering part 3 which becomes an independent fragment by division is at least one inner core part. It is preferable to set the positions of the inner cores 2a and 2b so that 2 exists. By arranging the inner cores 2a and 2b in this way, it is possible to guarantee the medicinal effect of each of the divided pieces when the cored tablet is divided and used.

Note that a plurality of grooves 4 may be formed on the surface of the covering portion 3, and in that case, the covering portion 3 can be divided into more divided pieces. In this case, the inner core portion 2 preferably includes at least the number of the divided pieces in the covering portion 3, and in particular, the position of the inner core portion 2 so that at least one inner core portion 2 exists at a position corresponding to each of the divided pieces. Is preferably set.

In the embodiment shown in FIG. 2, for the same reason as in the embodiment of FIG. 1, the average weight of the plurality of inner cores 2 a and 2 b contained in the dry-coated tablet 1 ′ is 0.5 mg or more. Preferably, it is more preferably 2 mg or more. Further, the upper limit of the average weight of the inner core portions 2a and 2b is also preferably 50 mg or less. It should be noted that the shape of the dry coated tablet 1 ′ having the groove 4 on the surface and being usable separately can be a so-called caplet type (corner) in view of the ease of arrangement of the inner cores 2 a and 2 b. The shape is preferably a substantially rectangular parallelepiped with roundness.

The surface of the dry coated tablet 1, 1 'of the present invention may be coated with various pharmaceutically acceptable materials, if necessary. The coating layer thus obtained can function as, for example, a sugar coating, a sustained-release film, an enteric film, or a gastric film. A water-soluble film may be coated for printing. As the coating method, for example, a known method using a tablet coating device or the like can be adopted. The dry-coated tablet of the embodiment shown in FIG. 1 (or FIG. 2) can be manufactured, for example, by the following method.

First, a base made of various materials as described above is heated and melted to make a liquid. When the base is composed of a plurality of components, the components may be mixed in advance and then heated to melt the mixture.On the other hand, the components obtained by individually heating and melting the components may be mixed later. Is also good.

Next, a small amount of a drug as an active ingredient is added to and mixed with the heated and melted liquid base, followed by stirring or the like to dissolve or suspend. As described above, in the present invention, the drug is mixed with the liquid base, so that the concentration in each part of the base can be more easily uniform than in the case of mixing with a powdery base (excipient, etc.). It can be. In addition, since the base contains only a minimum amount of a volatile solvent, there is little risk that the solvent will remain in the manufactured tablets and smell or deteriorate, and that the solvent will explode during the manufacturing. In addition, there is little risk that the internal volume will decrease due to the volatilization of the volatile solvent and the tablet will be deformed or the tablet strength will be reduced.

In the case where a drug which can be liquid by heating and melting itself is used as an active ingredient, for example, only the drug is heated to form a melt. In this case, since the drug and the base are not mixed, the concentration of the drug can be made extremely uniform in each part of the melt, and further, there is no need to consider the combination of the type of the drug and the type of the base. Therefore, workability is improved. In addition, a relatively large amount of drug can be used as compared with the case where a base is used.

Next, the liquid base obtained by dissolving or dispersing the drug, which is a pharmaceutically active ingredient, or the liquid drug consisting of a melt of the drug is divided into droplets. The method of the division is not particularly limited. However, in view of easiness of division and production efficiency, it is preferable that the liquid base or the liquid drug is discontinuously discharged to form droplets. As a device for performing the discharge, a known device capable of discharging a liquid substance discontinuously can be used. At least, a reciprocating pump, a rotary pump, a spiral pump, a propeller pump, and a jet pump can be used. A pump having a function of pumping the liquid base or the liquid drug, such as a pump, an air pump, a discharge pump using compressed gas as a pressurized source, the liquid base or the liquid drug A discharge device including an electromagnetic valve that interrupts and cuts off the flow path of an object and a control device for controlling the opening and closing of the electromagnetic valve is preferable. The discharge device has a heating means for preventing the liquid base from solidifying in the device.

In such a discharge device, the liquid base or the liquid drug is atomized and discharged by electrically opening and closing a valve provided on the flow path of the liquid base or the liquid drug pressurized by a gear pump or the like. Therefore, unlike the atomization method using the vibration of the electrostrictive (piezo) element, it is easy to control the particle size and weight of the obtained droplet, and the restriction on the ejection amount is greatly eased. In addition, the base or chemical solution can be easily brought to a high pressure state, and the opening and closing of the valve can be controlled in a very short time, so that relatively large droplets can be formed at high speed and accurately. Can be discharged. As such a discharge device, for example, a so-called hot melt gun (also called a hot melt application) which is widely used for discharging a hot melt type adhesive can be cited.

The average weight of droplets obtained by dividing the liquid base or liquid drug in this way is preferably 0.5 mg or more, more preferably 1 mg or more, and particularly preferably 2 mg or more. . In a tablet manufacturing environment, powder such as excipients flutters and turbulence is swirled by the operation of the equipment, but when the weight of the discharged droplet is large, these factors cause The course is less affected. Therefore, the discharge position of the droplet can always be accurately controlled.

In this way, at least one of the droplets obtained by dividing the liquid base or the liquid drug before or after solidification is coated with a coating material to obtain a dry coated tablet. As the coating agent, for example, a commonly used powdered excipient such as calcium citrate, calcium hydrogen phosphate, magnesium aluminate metasilicate, calcium sulfate, corn starch, potato starch, and cellulose can be used. it can. If necessary, the coating agent may contain a foaming agent such as sodium bicarbonate, a saccharide such as lactose, a sweetener such as aspartame, a fragrance such as heart oil, a polysaccharide such as sodium alginate, and a natural sugar such as gelatin. Molecules, celluloses such as hydroxyshethyl cellulose, synthetic polymers such as polyethylene glycol, lubricants such as talc, or other additives may be added alone or in combination. The coating agent May contain a drug having relatively low activity in a commonly used amount, for example, in the range of 10 to 500 mg. The form of the coating using the coating agent is not particularly limited, and for example, the coating can be performed by using a tableting device usually used for tablet production.

The above-described method for producing a dry-coated tablet can be implemented, for example, by the following production system. FIG. 3 is a top view showing an example of an embodiment of a dry-coated tablet production system according to the present invention, and FIG. 4 is a partially transparent side view of the production system of FIG.

As shown in the figure, in this manufacturing system, a plurality of hollow cylinder-shaped dies 5a penetrating vertically through the evening table 5 are provided on the periphery of the evening table 5 rotatable by a drive mechanism (not shown). They are arranged in an arc.

A lower punch 5b, which can be moved up and down by a drive mechanism (not shown), is always inserted from below into each mill 5a, and the lower end of 5a is always closed. In the embodiment shown in FIG. 4, the upper end surface of the lower punch 5b is concave, but the shape of the upper end surface can be changed as needed.

As shown in FIG. 3, above the 5a, a first coating material supply device 6, a liquid drug or a liquid base discharge device 7 containing a drug, and a second A cover material supply device 8 and a tableting section 9 where tableting is performed are arranged in this order along the rotation direction of the turntable 5. The first and second coating agent supply devices 6, 8 are for intermittently supplying a predetermined amount of coating agent within 5a, and use various general-purpose supply devices. be able to. As the coating agent, various forms such as a dry powder, a wet powder, and the like can be used. In particular, a dry powder coating is preferable from the viewpoint of easy handling. Preferably, it is used.

The discharge device 7 is a device for discontinuously discharging a fixed amount of a liquid drug or a heated and heated liquid base containing the drug into the nozzle 5a from the nozzle 7a, and the above-described hot melt gun is preferable. Can be used for In order to prevent the liquid drug or liquid base from solidifying in the device or the nozzle, a heating mechanism (not shown) is attached to the discharge device 7 and the nozzle 7a. Note that the discharge device 7 may have a plurality of nozzles 7a as necessary. In the tableting section 9, an upper punch 9a is disposed above the 5a by a drive mechanism (not shown) so that the upper punch 9a can freely enter and exit the die 5a. It is sufficient that at least one upper punch which can enter and exit within 5a is present in the tableting section 9, but the number of the punches is not particularly limited. If necessary, other upper punches may be appropriately disposed along the periphery of the turntable 5, for example, before and after the coating material supply devices 6 and 8.

In the tableting section 9, an upper punch 9a is inserted into the portion 5a from above by a driving device (not shown) such as a biston cylinder mechanism, and tableting is performed by a predetermined pressure. The stroke, pressing force, moving speed, and the like of the upper punch 9a are set in accordance with predetermined conditions and / or a predetermined sequence input through various interfaces. In addition, in the embodiment shown in FIG. 4, the lower end surface of the upper punch 9a is concave, but the shape of the lower end surface can be appropriately changed as necessary.

Next, a manufacturing mode of a dry coated tablet using the manufacturing system of FIGS. 3 and 4 will be described with reference to FIG. FIG. 5 is a diagram showing an example of a manufacturing process when manufacturing the dry-coated tablet of FIG. 1 using the manufacturing systems of FIGS. 3 and 4.

First, a predetermined amount of the coating material 3 is supplied from the first coating material supply device 6 into the empty space 5a located immediately below the first coating material supply device 6, and an excess amount is supplied by a cutting mechanism (not shown). The coating material is removed from the mortar 5a to obtain the state shown in FIG. 5 (a).

When the predetermined amount of the coating material 3 has been introduced, 5 a moves to a position corresponding to the nozzle 7 a of the discharge device 7 with the rotation of the evening table 5. If necessary, before the mortar 5a reaches the ejection device 7, the lower punch 5b may be moved slightly downward to increase the volume in the mortar 5a. The coating agent 3 in a may be pre-tableted using another optionally provided upper punch.

When the mortar 5a reaches the position corresponding to the discharging device 7, a predetermined amount of the heated and melted liquid drug or liquid base containing the drug is discharged from the nozzle 7a. In the embodiment shown in FIG. 4, the number of ejections of the liquid material from the nozzle 7a is set to one because the number of inner cores is one, but a dry coated tablet having a plurality of inner cores is manufactured. In the case or when producing a dry-coated tablet having a large core, the number of ejections is set to multiple times. The discharged liquid drug or liquid base immediately starts to solidify, but in order to increase the solidification speed, the inside of 5a may be cooled. In this way, as shown in FIG. An inner core portion 2 made of a drug or a liquid base containing the drug is formed on the covering material 3.

The mortar 5a into which the liquid drug or the liquid base containing the drug is charged from the discharge device 7 in this manner corresponds to the second coating material supply device 8 by the rotation of the evening table 5. While moving to the position, the lower punch 5b is lowered slightly by a little while the volume in the area 5a is enlarged. A predetermined amount of the coating material 3 is further supplied to the mortar 5a moved immediately below the second coating material supply device 8, similarly to the case of the first coating material supply device 6. As a result, the inner core portion 2 is completely covered with the coating material 3, and the state shown in FIG. 5 (c) is obtained. Finally, the mortar 5a moves to a position corresponding to the tableting section 9 by rotating the evening table 5. As shown in FIG. 5 (d), the upper punch 9a is fitted from above into the portion 5a with a predetermined pressing force. Therefore, the coating material 3 in 5a is compressed and compressed from above and below in combination with the pressing force from the upper punch 9a and the stress from the lower punch 5b, thus forming the inner core 2 and the coating. A dry-coated tablet 1 comprising a part 3 is manufactured. After tableting, the upper punch 9a is pulled upward from the inside of the 5a, and the lower punch 5a rises and the dry-coated tablet 1 is discharged from the 5a as shown in Fig. 5 (e). It is taken out of the manufacturing system by a take-out mechanism (not shown) and supplied to the next process. Thereafter, if necessary, a coating layer or the like may be formed on the surface of the dry-coated tablet.

FIG. 6 is a diagram showing an example of a manufacturing process when manufacturing the dry-coated tablet shown in FIG. 2 using almost the same manufacturing system as in FIGS. 3 and 4.

As in the case of FIG. 5, first, a predetermined amount of the coating material 3 is supplied from the first coating material supply device 6 into the empty space 5 a located immediately below the first coating material supply device 6. 6 The state shown in (a) is reached. In the manufacturing system shown in FIG. 6, a ridge is provided on a part of the upper end surface of the lower punch 5b that fits into 5a, and the ridge forms a groove 4 on the surface of the dry-coated tablet shown in FIG. I do. The shape of the ridge is not particularly limited, and various patterns such as a linear shape, a curved shape, or an intersection shape of these lines can be adopted as necessary. When the predetermined amount of the coating material 3 is charged, the position 5 a moves to a position corresponding to the nozzle of the discharge device 7 as the evening table 5 rotates. In the manufacturing system shown in FIG. 6, the discharge device Ί is provided with two nozzles, and from each nozzle, a liquid drug or a liquid base containing a drug corresponding to the inner core portions 2a and 2b of the dry-coated tablet of FIG. The agent is discharged. If necessary, move the lower punch 5b slightly downward before the mortar 5a reaches the discharge device 7, and 5A shows that the volume in 5a may be expanded, and that the coating material 3 in 5a may be pre-pressed with another upper punch optionally provided. Same as in the case. In this way, as shown in FIG. 6 (b), two inner core portions 2a and 2b made of the drug or the base containing the drug are formed on the coating material 3.

Subsequently, the liquid base 5a from which the liquid base is introduced from the discharge apparatus 7 moves to a position corresponding to the second coating agent supply apparatus 8 by the rotation of the turntable 5, while the lower base 5a moves downward. The punch 5b is lowered by a predetermined amount to enlarge the volume in the mortar 5a. Within 5a, which has just moved below the second coating material supply device 8, a predetermined amount of the coating material 3 is further supplied from the first coating material supply device 6 as in the case of FIG. As a result, the inner core 2 is completely covered with the covering agent 3, and the state shown in FIG. 6 (c) is obtained.

Then, 5a is moved to a position corresponding to the tableting portion 9 by rotation of the evening table 5, and as shown in FIG. Inserted by pressing force. Next, the coating material 3 in the mortar 5a is compressed from the upper and lower directions and compressed by a combination of the pressing force from the upper punch 9a and the stress from the lower punch 5b, and thus the inner core 2, the coating A dry-coated tablet 1 ′ having a groove 3 and a groove 4 is manufactured. In this manufacturing system, a ridge of a predetermined shape is also formed on the lower end surface of the upper punch 9a that fits into the mortar 5a, and the ridge forms the groove 4 of the dry-coated tablet 1 'in FIG. Is done. Note that, in order to facilitate the division of the dry-coated tablet 1 ', the shape of the ridge on the upper surface of the lower punch 5b and the shape of the ridge on the lower surface of the upper punch 9a are appropriately determined as necessary.

After tableting, the upper punch 9a is pulled upward from the mortar 5a, and the lower punch 5a rises and the dry-coated tablet 1 'is discharged from the 5a as shown in Fig. 6 (e). Then, it is taken out of the manufacturing system by a take-out mechanism (not shown) and supplied to the next process. The shape of the upper surface of the lower punch 5b and the lower surface of the upper punch 9a are arbitrary. However, the cored tablet 1 'to be manufactured should be a so-called cablet type (rounded rectangular parallelepiped). It is preferable that the shape of the surface is adjusted. Example

Core preparation test:

A base having the composition shown in Table 1 was heated and dissolved at 80 ° C, and this was used as a pharmaceutically active ingredient. Was added and dissolved.

In order to produce droplets containing 20 / g of drug per 4 mg of this mixture, a gear pump type hot melt gun (HM-300 series from Nordson Corporation, type 310) ), The mixed solution was formed into droplets, and the droplets were discharged onto release paper, and the weight and the amount of drug contained in each droplet were measured. Table 2 shows the operating conditions of the hot melt gun, and Table 3 shows the measurement results. Table 2 Items Detailed data Gun model Nodson type 3100

Discharge conditions:

• Nozzle orifice 0.35mm

• Pressure 3.0kg per 1cm square

• Valve open time 5 ¾ U seconds

• Valve cross time 95 ms

• Drops per second 10 drops / sec

• Base chemical temperature 80. C Table 3

As is evident from Table 3, the weight of each droplet discharged onto the release paper and the amount of drug contained were almost as intended, with little variation, confirming that high-precision discharge was performed. Production of dry coated tablets:

A dry coated tablet was manufactured using the manufacturing system shown in FIGS. First, a cylindrical die 5 a having an inner diameter of 9 mm was filled with 11 O mg of an excipient having the composition shown in Table 4 below. <Table 4 75 parts of lactose

125 parts of corn starch

Hydroxypropyl methyl cellulose suitable amount

Magnesium stearate

Colloidal Keiic acid Suitable Next, the lower punch 5b in 5a is lowered, and a liquid base having the composition shown in Table 1 is placed at the center of the surface of the excipient with the same hot melt gun (HM-N manufactured by Nordson Corporation) as described above. One drop was ejected using a 3000 series, type 3100). Then, the lower punch 5b was pulled down, and the excipient having the composition shown in Table 4 was further filled with 110 mg on the discharged droplet. After that, the upper punch 9a with an outer diameter of 9mm was inserted into the 5a and pressed to produce a dry coated tablet. The dry-coated tablet thus obtained had a diameter of 9 mm, a thickness of 3.7 mm and a weight of 224 m. Table 5 shows the test results of the content uniformity of beraprostonadium in one of the dry coated tablets. As is evident from Table 5, the average value of the drug content in each of the 10 tablets taken arbitrarily was 19.94 µg, and the coefficient of variation was 1.38%. Table 5

N Amount of drug in one tablet

1 20.ll zg

2 20.20

3 20.13

4 19.09

5 19.87

6 20.06

7 19.97

8 20.53

9 19.58

10 19.83 Average 19.94 / zg

Coefficient of variation 1.38% Industrial applicability

INDUSTRIAL APPLICABILITY The present invention can be applied to all kinds of tablets and their production. According to the present invention, the following effects are exerted irrespective of the type of drug as an active ingredient.

(1) When a drug as a pharmaceutically active ingredient is mixed with a liquid base and handled as a solution or suspension, the concentration of each part of the solution or suspension should be uniform even if the amount of drug is very small. It can be. In addition, when a drug that has been made liquid by heating and melting is used as it is, the concentration of the drug solution is kept constant in each part. Therefore, by dividing the liquid material and including it in each tablet, the amount of drug contained in each tablet can be made constant with high accuracy.

(2) According to the present invention, a droplet (0.01 mg per drop according to Japanese Patent Publication No. 2-48524) prepared by a piezo oscillator is much larger than a droplet (0.01 mg). (5 mg or more) can be prepared, so if a small amount of drug is to be incorporated into tablets, it is sufficient to discharge one drop of the liquid base containing the drug or the liquid drug per tablet. Therefore, the manufacturing process is simplified as compared with the case where a minute droplet is ejected a plurality of times. In addition, powder is swirling around the rotary tableting machine, etc. where tablets are manufactured, and turbulence is generated. It is discharged to the surface of excipients and the like. Therefore, it is possible to ensure that each tablet contains the drug, and to make the amount of drug contained in each tablet uniform. Furthermore, since the position of the inner core can be kept constant, the inner core can be surely covered with an excipient or the like.

(3) In the present invention, when the inner core is composed of a base containing a drug, the base itself becomes liquid by heating and functions as a solvent or dispersion medium for the drug, so that a large amount of volatile solvent is used. There are few troubles such as residual solvent, explosion and odor as in the case of use. In addition, tablet deformation and strength deterioration due to volume reduction due to solvent volatilization are small. In addition, even when the inner core is composed of only a drug, the above-mentioned inconvenience does not occur because it is not necessary to use a volatile solvent in the first place. Further, since no base is used, there is no need to consider the combination of the base and the type of drug, and a relatively large amount of drug can be included in the tablet. (4) In the present invention, the manufacturing process can be simplified and cost can be reduced.In other words, in the dry coated tablet of the present invention, the content of the drug per tablet includes the amount of the drug solution or the drug. Since the amount can be adjusted by the amount of the liquid base, the amount of the coating can be freely increased or decreased. Therefore, tablets of various diameters can be easily produced without requiring examination and operation of scale-up. Further, since the discharge amount and discharge frequency of the liquid medicine or the liquid base containing the substance can be accurately controlled, the amount, shape, distribution, and the like of the core can be easily changed. Furthermore, since the drug containing the bitter ingredient is localized in the center of the tablet and is coated with a coating material, the surface of the tablet for a bitter mask used for a conventional tablet in which the drug is uniformly dispersed is used. No one-ting is required.

Claims

The scope of the claims

1. (a) at least one core comprising a heat-meltable base material, which contains a drug as an active ingredient; and

(b) a coating portion including the inner core portion

A dry-coated tablet comprising:

2. The dry-coated tablet according to claim 1, wherein the inner core has an average weight of 0.5 mg or more.

3. The dry-coated tablet according to claim 1, wherein the base comprises a hydrophilic substance, a hydrophobic substance, an amphipathic substance, or a mixture thereof.

4. The dry-coated tablet according to claim 3, wherein the hydrophilic substance is made of polyethylene glycol, polyethylene oxide, polyvinylidene, glycerinated gelatin, saccharides or a mixture thereof.

5. The dry-coated tablet according to claim 3, wherein the hydrophobic substance is made of synthetic or natural waxes or fats or oils, or a mixture thereof.

6. The amphiphile is stearyl alcohol, polyoxyl stearate, cetyl alcohol, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearyl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene lauryl ether, polyoxyethylene. The sorbitan monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, sodium lauryl sulfate, sodium lauroyl sarcosine, polyoxyethylene lauryl ether, or a mixture thereof. 6. The dry-coated tablet according to any one of 5.

7. (a) at least one core comprising a heat-meltable drug; and

(b) a coating portion including the inner core portion

A dry-coated tablet comprising:

8. The dry-coated tablet according to claim 7, wherein the inner core has an average weight of 0.5 mg or more.

9. (a) a mixing step of mixing a drug with a heat-melted liquid base;

(b) a step of dividing the liquid base containing the drug into droplets; and

(c) a coating step of coating at least one of the droplets with a coating agent

A method for producing a dry-coated tablet, comprising:

10. (A) a step of dividing the heated and melted liquid drug into droplets; and

(b) A method for producing a dry-coated tablet, comprising a step of coating at least one of the droplets with a coating agent.

11. The method for producing a dry-coated tablet according to claim 9 or 10, wherein the average weight of the droplets is 0.5 mg or more.

12. The dry coated tablet according to any one of claims 9 to 11, wherein in the dividing step, a liquid drug or the liquid base containing the drug is discontinuously discharged to form a droplet. Manufacturing method.

13. (a) Discharge device for discontinuously supplying a heated and molten liquid drug or a heated and molten liquid base containing a drug;

(b) a coating material supply device for supplying a coating material for the liquid drug or liquid base; and (c) a coating device for coating the liquid drug or liquid base with the coating material.

A manufacturing system for a dry-coated tablet, comprising:

14. The discharge device includes a pump for pumping the liquid drug or the liquid base, a solenoid valve for cutting off a flow path of the liquid drug or the liquid base, and a control device therefor. A manufacturing system for a dry-coated tablet according to claim 13.

15. The nucleated core according to claim 13, wherein the coating device is a tableting device provided with a die and a plurality of sets of an upper punch and a lower punch which can enter and leave the die. Tablet manufacturing system.

16. (a) at least one inner core containing a drug as an active ingredient;

(b) a coating portion including the inner core portion

Use of a liquid base for said drug for the manufacture of a dry-coated tablet comprising:

17. (a) at least one inner core comprising a drug as an active ingredient; and

(b) a coating portion including the inner core portion

Use of a liquid drug as the drug for the manufacture of a dry-coated tablet comprising the drug.