JP7072431B2 - Tablets and their manufacturing methods - Google Patents

Description

The present invention relates to a tablet containing duloxetine as an active ingredient and a method for producing the same.

Duloxetine has a serotonin-noradrenaline reuptake inhibitor (SNRI) action and is marketed as a therapeutic agent for depression (see, for example, Patent Document 1).
Since duloxetine is unstable under strong acid such as gastric acid, it is commercially available in the form of an enteric solution such as a capsule. In addition, duloxetine produces a decomposing substance in the presence of an acidic substance, so that the pharmaceutical additives that can be used are limited.

As described above, although duloxetine capsules are commercially available, they are required to be formulated in the form of tablets from the viewpoint of ease of swallowing.
In the case of a tablet containing duloxetine, it is necessary to make a tablet that is released into the intestine due to the above-mentioned properties of duloxetine. For enteric release tablets, it is generally considered to coat the surface of the drug nucleus containing the drug with an enteric layer containing an enteric polymer.

Therefore, it is considered that an enteric-releasing tablet having acid resistance to gastric acid or the like can be produced by using a conventional production method.

However, in the case of a normal tablet having a diameter of more than 2 mm, it is known that the time it takes to be discharged from the stomach after taking the tablet varies greatly, and as a result, the medicinal efficacy generally varies.
For the acid resistance of enteric release tablets, it is generally necessary to use one solution in the dissolution test method of the Japanese Pharmacopoeia and reduce the dissolution rate to 10% or less in 2 hours.

Therefore, even during mass production of tablets, it is possible to promptly provide a tablet capable of producing a tablet having excellent acid resistance, which can suppress the acid resistance of the obtained tablet to about 10% at the maximum, and a method for producing the tablet. The current situation is that there is a strong demand.

Japanese Unexamined Patent Publication No. 63-185946

An object of the present invention is to solve the above-mentioned problems in the prior art and to achieve the following objects. That is, an object of the present invention is to provide a tablet having the required acid resistance and a method for producing a tablet capable of mass-producing the tablet.

As a result of diligent studies to achieve the above object, the present inventors have made a particulate composition having an enteric layer containing at least an enteric polymer in an outer layer covering a drug nucleus containing the active ingredient duroxetine. In the tableting step of tableting the mixture containing It was found that tablets with excellent acid resistance can be mass-produced by performing the temperature control process.

The present invention is based on the above-mentioned findings of the present inventors, and the means for solving the above-mentioned problems are as follows. That is,
<1> A method for producing a tablet, which comprises a tableting step of tableting a mixture containing a particulate composition.
The particulate composition has an enteric layer containing at least an enteric polymer in an outer layer covering a drug nucleus containing the active ingredient duloxetine.
In the tableting step, at least one of a temperature control process for raising the temperature of the tableting machine to 25 ° C. or higher and a temperature control process for raising the temperature of the mixture containing the particulate composition to 25 ° C. or higher is performed. It is a method for producing a tablet, which comprises performing.
"Having an enteric layer in the outer layer covering the drug nucleus" means (i) when the enteric layer is formed directly on the surface of the drug nucleus, (ii) intestine directly on the surface of the drug nucleus. When a molten layer is formed and another layer is formed on the surface of the enteric layer, (iii) when an enteric layer is indirectly formed on the surface of the drug nucleus. When another layer is interposed between the surface of the drug nucleus and the enteric layer, it means to include any aspect, and the "other layer" of (ii) and (iii) may be a single layer. It may have multiple layers.
<2> The method for producing a tablet according to <1>, wherein the tableting pressure is 5 kN / pestle to 18 kN / pestle.
<3> The particulate composition contains a drug-containing layer containing the active ingredient duroxetine, an enteric-coated layer containing an enteric polymer, and the drug-containing layer and the enteric-coated layer in the outer layer of the nuclear particles. The tablet according to any one of <1> to <2>, which has a separation layer for separating the drug, and is formed by laminating the drug-containing layer, the separation layer, and the enteric layer in this order. It is a manufacturing method.
<4> The method for producing a tablet according to <3>, wherein the separation layer has at least one layer of an intermediate layer containing a binder and a light-shielding layer containing a colorant.
<5> The method for producing a tablet according to any one of <1> to <4>, wherein the enteric polymer in the enteric layer is hydroxypropylmethylcellulose acetic acid ester succinic acid ester.
<6> A duloxetine-containing tablet characterized by containing a particulate composition in which at least a separation layer and an enteric layer containing an enteric polymer are laminated in this order on a drug-containing layer containing duloxetine as an active ingredient. be.

INDUSTRIAL APPLICABILITY According to the present invention, it is intended to provide a tablet having the required acid resistance and a method for producing a tablet capable of mass-producing the tablet, which can solve the conventional problems and achieve the object. Can be done.

FIG. 1 is a schematic view of an example of a rotary lock locker.

(Tablet manufacturing method)
The method for producing a tablet of the present invention includes at least a tableting step, and further includes other steps as necessary.

<Locking process>
The tableting step is a step of locking a mixture containing a particulate composition.

<< Mixture containing particulate composition >>
The mixture containing the particulate composition (hereinafter, may be referred to as “powder for tableting” or “mixed powder”) contains at least the particulate composition, and further contains other components as necessary.

-Particulate composition-
The particulate composition has at least an enteric layer in the outer layer covering the drug nucleus, and if necessary, further has another layer such as a separation layer (intermediate layer, light-shielding layer).
The embodiment of the particulate composition is not particularly limited and may be appropriately selected depending on the intended purpose.

－－Drug nucleus －－
The drug nucleus contains at least the active ingredient duloxetine and, if necessary, other components.

The mode of the drug nucleus is not particularly limited and may be appropriately selected depending on the intended purpose. For example, duloxetine, a granulated product having a drug-containing layer containing the active ingredient duloxetine in the outer layer of the nuclear particles, and the like. Granulations formed from available pharmaceutical additives can be mentioned. Among these, granulated products having a drug-containing layer containing duloxetine, which is an active ingredient, in the outer layer of the nuclear particles are preferable.

The duloxetine may be in the form of a salt.
The salt is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include hydrochloride.
The content of the duloxetine in the tablet is not particularly limited and may be appropriately selected depending on the intended purpose.

The nuclear particles are not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include inert carriers such as nonpareil (manufactured by Freund Sangyo Co., Ltd.) and selfia (manufactured by Asahi Kasei).
The content of the nuclear particles in the tablet is not particularly limited and may be appropriately selected depending on the intended purpose.

The method for producing a granulated product having a drug-containing layer containing the active ingredient duloxetine in the outer layer of the nuclear particles is not particularly limited and may be appropriately selected depending on the intended purpose. For example, the nuclear particles. Examples thereof include a method of appropriately blending and coating duloxetine and an excipient usually used for formulation on the surface of the above.
The coating method is not particularly limited, and a known method can be appropriately selected. For example, a wet granulation method using a centrifugal rolling granulator, a rolling granulator, etc., duloxetine and a binder, etc. Examples thereof include a method of spraying a solution containing the above-mentioned nuclear particles onto the surface of the nuclear particles.
The device used for the method of coating by spraying is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a fluidized bed granulator, a centrifugal rolling granulator, a rolling granulator and the like can be used. Can be mentioned. These may be used alone or in combination of two or more.
The coating may be carried out in one step or in two or more steps.

The method for producing a granule formed from the above-mentioned duloxetine and a usable pharmaceutical additive is not particularly limited and may be appropriately selected depending on the intended purpose. For example, an excipient and duloxetine , A method of granulating by adding a binder and the like can be mentioned.
The excipient is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include lactose, sucrose, mannitol, cornstarch and crystalline cellulose. These may be used alone or in combination of two or more.
The binder is not particularly limited and may be appropriately selected depending on the intended purpose. For example, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, macrogol, purlonic F68, gum arabic, gelatin, starch and the like can be selected. Can be mentioned. These may be used alone or in combination of two or more.
The apparatus used for the granulation is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a stirring granulator, a wet extrusion granulator, a fluidized layer granulator, and a centrifugal rolling granulator , Rolling granulators, spray dryers and the like.
Particles of a desired size can be obtained from the granulated product by a sieving operation. Further, the granulated product may be prepared by dry granulation using a roller compactor or the like.

The average particle size of the drug nucleus is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include 100 μm to 1,000 μm.
In the present invention, the average particle size is a value measured by using a laser diffraction / scattering type particle size distribution measuring device (LA-920 manufactured by HORIBA, Ltd.).

－－Separation layer (intermediate layer) －－
When the embodiment of the drug nucleus is a granulated product having a drug-containing layer containing the active ingredient duloxetine in the outer layer of the nuclear particles, the separation layer separates the drug-containing layer and the enteric layer. Formed as a layer for.
The separation layer is a layer having at least one of an intermediate layer containing a binder and a light-shielding layer containing a colorant, preferably having at least an intermediate layer, and both the intermediate layer and the light-shielding layer. It is preferable to have a layer.
The intermediate layer is a layer containing other components such as binders, plasticizers, lubricants, fluidizers, colorants and usable pharmaceutical additives.
In general, the function of the middle layer is to prolong the resistance of duloxetine to acidic conditions and to improve the stability of duloxetine by interfering with the interaction between duloxetine and the enteric polymer of the enteric layer. To provide a smooth base for application of the enteric layer, to improve stability by protecting duloxetine from exposure to light.

The binder used in the intermediate layer is not particularly limited and may be appropriately selected depending on the intended purpose. For example, hypromellose (hydroxypropylmethylcellulose), hydroxypropylcellulose, pregelatinized starch, arabic rubber, carboxyvinyl polymer, etc. Examples include dextrin and povidone. These may be used alone or in combination of two or more. Among these, hypromellose, hydroxypropyl cellulose and povidone are preferable, and hypromellose is more preferable.

The method for forming the intermediate layer is not particularly limited, and a known method can be appropriately selected. Examples thereof include an aqueous coating method usually performed in a pharmaceutical step. Specifically, the intermediate layer can be formed by coating the drug nucleus with a solution containing the components of the intermediate layer by spraying or the like.
The apparatus used for the formation is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a fluidized bed granulator, a rolling fluidized bed granulator, and a centrifugal fluidized bed machine. ..

－－Separation layer (light-shielding layer) －－
The light-shielding layer is a layer containing at least a colorant and, if necessary, other components such as a binder and usable pharmaceutical additives.
By providing the light-shielding layer, the stability of the drug unstable to light can be improved.

The colorant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include titanium oxide and iron oxide. These may be used alone or in combination of two or more.
Among these, titanium oxide is preferable.

The blending amount of the colorant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, 0.1% by mass to 10% by mass with respect to the total amount of the particulate composition can be mentioned. Be done.

The binder used in the light-shielding layer is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include the same binders used in the intermediate layer described above.

The method for forming the light-shielding layer is not particularly limited, and a known method can be appropriately selected. Examples thereof include the same method as the method for forming the intermediate layer described above.

－－Enteric layer －－
The enteric layer is a layer containing at least an enteric polymer and, if necessary, other components such as a plasticizer, a lubricant, a fluidizing agent, a colorant, and usable pharmaceutical additives.
The enteric layer allows the drug to pass through the stomach of an individual without change and to rapidly dissolve and release the drug as it passes through the stomach and enters the small intestine.

The enteric polymer is not particularly limited and may be appropriately selected depending on the intended purpose, but a layer capable of forming a layer without using an organic solvent is preferable, and an enteric polymer having high acidity is more preferable. ..
The enteric polymer capable of forming a layer without using the organic solvent is not particularly limited and may be appropriately selected depending on the intended purpose. For example, hydroxypropylmethylcellulose acetic acid ester succinate (“hydroxypropylmethylcellulose”). (Sometimes referred to as "acetate succinate"), carboxymethyl ethyl cellulose, methyl cellulose, polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S and the like. These may be used alone or in combination of two or more.
Among these, methacrylic acid copolymer LD and hydroxypropylmethylcellulose acetate succinate are preferable, and hydroxypropylmethylcellulose acetate succinate is more preferable.
The same enteric polymer used in the enteric layer and the poorly water-soluble polymer used in the intermediate layer are not used at the same time.

The blending amount of the enteric polymer is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include 5 parts by mass to 100 parts by mass with respect to 100 parts by mass of the drug nucleus. ..

The method for forming the enteric layer is not particularly limited, and a known method can be appropriately selected. Examples thereof include the same method as the method for forming the intermediate layer described above.

－－Other layers －－
The other layers are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected depending on the intended purpose. Examples thereof include a finishing layer.
As the finishing layer, essentially, the enteric-soluble preparation can be smoothed, sealed and colored in the pharmaceutical product, and the same components as the finishing layer used in the usual preparation can be used, and the finished product is applied by a usual method. It can be formulated.

The lubricant that can be blended as needed in each of the above layers is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include talc, glycerin monostearate, and macrogol. Be done. These may be used alone or in combination of two or more.
Among these, talc and glycerin monostearate are preferable, and talc is more preferable.
The blending amount of the lubricant in each layer is not particularly limited and may be appropriately selected depending on the intended purpose.

A surfactant may be added to the above-mentioned drug nucleus and each layer for a pharmaceutical additive that is difficult to be compatible with water.
The surfactant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include polysorbate 20, polysorbate 80, polyoxyethylene / polyoxypropylene copolymer, sodium lauryl sulfate and the like. These may be used alone or in combination of two or more.
The amount of the surfactant to be blended in the drug nucleus or each layer is not particularly limited and may be appropriately selected depending on the intended purpose.

The average particle size of the particulate composition is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include 100 μm to 2,000 μm.

-Other ingredients-
The other components in the mixture containing the particulate composition are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected depending on the intended purpose. Examples thereof include general pharmaceutical additives. Be done.
Specific examples of the pharmaceutical additives include excipients, binders, disintegrants, lubricants, acidulants, sweeteners, flavoring agents, fragrances, colorants, stabilizers and the like. These may be used alone or in combination of two or more.
The blending amount of the other components in the mixture containing the particulate composition is not particularly limited and may be appropriately selected depending on the intended purpose. For example, 0.01% by mass or more with respect to the entire mixture. 80% by mass and the like can be mentioned.

The excipient is not particularly limited and may be appropriately selected depending on the intended purpose. For example, saccharides such as sucrose, lactose and glucose; mannitol, erythritol, isomalt, lactitol, martitol, sorbitol, xylitol and the like. Examples include sugar alcohols; crystalline celluloses; anhydrous calcium hydrogen phosphate; magnesium aluminometasilicate. These may be used alone or in combination of two or more.

The binder is not particularly limited and may be appropriately selected depending on the intended purpose. For example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymer, carmellose sodium, pregelatinized starch, polyvinylpyrrolidone, gum arabic powder. , Gelatin, pullulan, polyvinyl alcohol and the like. These may be used alone or in combination of two or more.

The disintegrant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, starches such as corn starch and potato starch; partially pregelatinized starch; sodium carboxymethyl starch; carmellose; carmellose calcium; cloth. Carmellose sodium; crospovidone; low-substituted hydroxypropyropill cellulose; crystalline cellulose; hydroxypropyl starch and the like. These may be used alone or in combination of two or more.

The lubricant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include stearyl sodium fumarate, magnesium stearate, calcium stearate, and sucrose fatty acid ester. These may be used alone or in combination of two or more.

The embodiment of the mixture containing the particulate composition is not particularly limited and may be appropriately selected depending on the intended purpose. For example, an embodiment comprising the particulate composition, the particulate composition and the other. Aspect of a granulated product composed of a component selected from the components, a mode of a mixture of the granulated product composed of the particulate composition and the components selected from the other components, and the lubricant. And so on.

The method for preparing the mixture containing the particulate composition is not particularly limited, and a known method can be appropriately selected depending on the intended purpose. For example, a commonly used mixture such as mixing, kneading, and granulation can be selected. The method etc. can be mentioned.
The mixing means is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a high-speed stirring mixer, a universal kneader, a fluidized layer granulator, a V-type mixer, a tumbler mixer, and the like. Examples include a double cone mixer, a ribbon type mixer, a swivel screw type mixer, and manual mixing with a bag.

<< Locking >>
The apparatus used in the tableting step is not particularly limited, and an apparatus usually used in the manufacture of pharmaceutical products can be appropriately selected depending on the intended purpose, and examples thereof include a rotary locking machine.

FIG. 1 shows a schematic diagram of an example of a rotary type lock lock machine, which is an example of the lock lock machine.
In the rotary type locking machine, a vertical rotation shaft 1 is arranged so as to be driven and connected to a motor (not shown). The vertical rotating shaft 1 supports a disk-shaped turntable 2, and the vertical rotating shaft 1 and the turntable 2 rotate in a predetermined direction at a constant speed based on the drive of a motor.
The turntable 2 has a plurality of locking cells (mills) that penetrate the turntable 2 and extend in parallel with the vertical rotation axis 1 at regular intervals on a circumference having a predetermined radius centered on the vertical rotation axis 1. ) 3 is formed.
Below each locking cell 3, a lower locking rod (pestle) 4 having an upper end portion having an outer diameter substantially the same as the inner diameter of the locking cell 3 is arranged. Each lower locking rod (pestle) 4 rotates with the rotation of the vertical rotation shaft 1 and moves upward along the lower pressure roller 5.
Above each locking cell 3, an upper locking rod (pestle) 6 having a lower end portion having an outer diameter substantially the same as the inner diameter of the locking cell 3 is arranged. Each upper locking rod (pestle) 6 rotates with the rotation of the vertical rotation shaft 1 and moves downward along the upper pressure roller 7.
As a result, in the tableting cell 3, the upper end portion of the lower tableting rod (pestle) 4 and the lower end portion of the upper tableting rod (pestle) 6 cooperate with each other to contain the particulate composition (a mixture containing the particulate composition. Hereinafter, "tablet powder" and "mixed powder") may be pressed from above and below to form a tablet.

The rotary type tableting machine is provided with a powder supply device for supplying and filling each tableting cell 3 with powder for tableting. This powder supply device guides, for example, a hopper 8 that drops and supplies a locking powder onto the turntable 2 and a locking powder 9 supplied from the hopper 8 to the turntable 2 to each locking cell 3. It is equipped with a feeder (not shown).

According to the rotary locking machine having the above configuration, the locking powder is dropped and supplied from the hopper 8 onto the turntable 2. The locking powder on the turntable 2 is guided to each locking cell 3 by a feeder (not shown) based on the rotation of the turntable 2. While the lock cell 3 is filled with the lock powder, each lock rod is located away from the lock cell, whereby a predetermined amount of the lock powder is filled in each lock cell 3. .. Next, the upper and lower tableting rods 4 and 6 approach each other along the pressure rollers 5 and 7 with respect to the tableting cell 3 filled with a predetermined amount of tableting powder, and as a result, the tableting cell The tableting powder in 3 is compressed between the upper and lower tableting rods 4 and 6 to form a tablet.

-Temperature control processing-
In the tableting step, at least one of a temperature control process for raising the temperature of the tableting machine to 25 ° C. or higher and a temperature control process for raising the temperature of the mixture containing the particulate composition to 25 ° C. or higher is performed. conduct. Either one of these temperature control treatments may be performed, or both may be performed, but it is preferable to perform both in terms of producing tablets having better acid resistance.

--Temperature control processing of the locker ---
The temperature of the tableting machine in the temperature control process of the tableting machine means the temperature of the tableting machine at a position in contact with the mixture containing the particulate composition, and more specifically, with the mixture containing the particulate composition. The temperature measured by a temperature detector installed at the contacting position.
The temperature of the locker in the temperature control process is not particularly limited as long as it is 25 ° C. or higher, and can be appropriately selected depending on the intended purpose, but is preferably 30 ° C. to 45 ° C., preferably 35 ° C. to 45 ° C. Is more preferable.

--Temperature control treatment of the mixture containing the particulate composition ---
The temperature of the mixture containing the particulate composition in the temperature control treatment is not particularly limited as long as it is a temperature exceeding room temperature, that is, 25 ° C. or higher, and can be appropriately selected depending on the intended purpose. 50 ° C is preferable, and 40 ° C to 50 ° C is more preferable. The room temperature means the temperature in the room where the lock is performed in the normal locking step, and usually means 20 ° C to 24 ° C.

--season--
The timing of performing the temperature control treatment is not particularly limited as long as the effects of the present invention can be obtained, and can be appropriately selected depending on the intended purpose. For example, a mixture containing a particulate composition is supplied to a tableting machine. When the mixture containing the particulate composition is supplied to the tableting machine from the time of feeding to the tableting, after the mixture containing the particulate composition is supplied to the tableting machine, and on the turntable. This includes the period from before being supplied to the time when the mixture is tableted, from the time when the mixture containing the particulate composition is supplied onto the turntable of the tableting machine to the time when the mixture is tableted.

－－Heating means －－
The heating means in the temperature control process is not particularly limited, and a known heating means can be appropriately selected according to the purpose, and is a non-contact type such as an infrared heater, a hot air heater, and a radiant heater. Examples thereof include a contact type heating means such as a heating means, a resistance heater, and a radiant heater. These may be used alone or in combination of two or more.
If the temperature of the locker rises due to the idle operation or continuous operation of the locker, the locker may be heated by these.

－－Heating place －－
The heating place in the temperature control process is not particularly limited and may be appropriately selected depending on the intended purpose. The entire tableting machine and the portion of the tableting machine to which the mixture containing the particulate composition comes into contact (for example). , Turntable, mortar for tableting), a portion on the turntable that supplies the mixture containing the particulate composition (for example, a hopper), a feeder portion that guides the mixture containing the particulate composition to the tableting cell, and the like. , The space itself where the locker is installed, etc. Further, the mixture itself containing the particulate composition may be heated.
The heating of the portion of the locking machine in which the mixture containing the particulate composition is in direct contact may be a non-contact type or a contact type, but a method of heating by a non-contact type. Is preferable.
The heating of the portion of the locking machine where the mixture containing the particulate composition does not come into direct contact may be a non-contact type or a contact type. Examples of the portion that does not come into direct contact include the back surface of the turntable, the upper pestle holder, the lower pestle holder, and the like.

The place where the heating means is installed is not particularly limited, and can be appropriately selected depending on the above-mentioned heating place.

--control--
The method for controlling the heating by the heating means is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a temperature detector is arranged in the locker and based on the detected temperature. Then, a method of determining the necessity of heating by the heating means and setting the temperature to the target can be mentioned.
The place where the temperature detector is arranged is not particularly limited, and can be appropriately selected depending on the heating place, the place where the heating means is installed, and the like.
The timing for detecting the temperature by the temperature detector is not particularly limited, and can be appropriately selected depending on the timing for performing the temperature control process.

-Molding-
In the tableting, the mixture containing the particulate composition is an embodiment of a mixture of a granule composed of a component selected from the particulate composition and the other components, and the lubricant. After that, compression molding may be performed, or the lubricant may be applied in advance to the surface of the punch of the compression molding machine and the wall surface of the mortar without mixing with other components, and the mixture containing the particulate composition is compression molded. (External sliding method) may be used.
According to the external sliding method, desired hardness and disintegration property can be imparted. The method of applying the lubricant to the mortar is not particularly limited, and a conventionally known method or machine can be appropriately selected and performed.

The lower limit of the tableting pressure in the tableting may vary depending on the type of the compound constituting the particulate composition, but the tableting pressure must be at least 3 kN / pestle, preferably 5 kN / pestle. Is necessary, more preferably 5 kN / pestle to 18 kN / pestle.

The hardness of the obtained tablet is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 20N to 200N, more preferably 30N to 140N.
The tableting pressure varies depending on the size of the tablet. For example, when a 450 mg tablet is tableted using a pestle with a diameter of 10 mm, the hardness is 20N to 150N when the tableting pressure is 3 kN / pestle to 19 kN / pestle. It is preferable to have a hardness of 30N to 100N when the tableting pressure is 5 kN / pestle to 17 kN / pestle.

The shape, structure, and size of the tablet are not particularly limited and may be appropriately selected depending on the intended purpose.

The type of the tablet is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include ordinary tablets, orally rapidly disintegrating tablets, chewable tablets and the like.
The orally rapidly disintegrating tablet is a tablet that can rapidly disintegrate in the oral cavity. The disintegration time in the oral cavity varies depending on the size and shape of the tablet, but is not particularly limited and may be appropriately selected depending on the intended purpose. For example, 60 seconds or less is preferable, 45 seconds or less is more preferable, and 30 seconds or less. Within seconds is particularly preferred.

<Other processes>
The other steps are not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected depending on the intended purpose. For example, the particulate composition preparation step for preparing the above-mentioned particulate composition. Examples thereof include a step of preparing a powder for tableting, in which the particulate composition is mixed with other components as needed to prepare a powder for tableting.

According to the tablet manufacturing method of the present invention, tablets having the required acid resistance can be mass-produced.
The acid resistance can be determined by conducting a duloxetine dissolution test with one solution according to the dissolution test method of the Japanese Pharmacopoeia.
The acid resistance is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably less than 9%, more preferably 6% or less, and particularly preferably 5% or less.

A preferred embodiment of the tablet includes, for example, a particulate composition in which at least the separation layer and the enteric layer containing the enteric polymer are laminated in this order on the drug-containing layer containing the active ingredient duloxetine. Examples include tablets to be used.

Hereinafter, the present invention will be described with reference to test examples, but the present invention is not limited to these test examples.

(Test Example 1)
<Preparation of particulate composition>
-Formation of drug nuclei-
500 g of Nonpareil 101 (Freund Sangyo Co., Ltd., sucrose / starch spherical granules, particle size 355 to 500 μm) is placed in a rolling fluid coating machine (Paurek Co., Ltd. MP-01 type), and the exhaust temperature in the steady state is about 45 ° C. The blast temperature was controlled so as to be. 400 g of duroxetine hydrochloride was dispersed in a solution in which 200 g of hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd., degree of substitution type 2910, display viscosity 3 mPa · s) was dissolved in 3400 g of purified water. The obtained dispersion was sprayed at a liquid speed of 6 g / min to form a drug-containing layer on the nuclear particles, and a drug nucleus was obtained.

-Formation of a separation layer (intermediate layer)-
A solution prepared by dissolving 148 g of hypromellose in 2812 g of purified water was sprayed onto the obtained drug nuclei under the same conditions as when the drug-containing layer was formed to form an intermediate layer.

-Formation of a separation layer (light-shielding layer)-
For the obtained granules after forming the intermediate layer, a solution in which 101 g of titanium oxide (titanium oxide A-HR manufactured by Freund Sangyo Co., Ltd.) was dispersed in a solution of 101 g of hypromellose in 1818 g of purified water was added to the drug-containing layer. A light-shielding layer was formed by spraying under the same conditions as when the film was formed.

-Formation of enteric layer-
After adding 59 g of triethyl citrate (manufactured by Morimura Brothers) to 990 g of Eudragit L30D55 (manufactured by Ebonic, methacrylic acid copolymer LD), 148 g of talc (manufactured by Nippon Tarku) and polysorbate 80 (manufactured by Nikko Chemicals) in 1336 g of purified water. 2.4 g of the above was dispersed using a disperser, and this dispersion was added to Eudragit L30D55 solution with stirring to prepare an enteric coating solution.
The particles after forming the light-shielding layer were placed in a rolling flow type coating machine (MP-01 type manufactured by Paulek Co., Ltd.), and the blowing temperature was controlled so that the exhaust temperature in the steady state was about 30 ° C. The prepared enteric coating solution was sprayed at a liquid rate of 5 g / min to form an enteric layer.

<Preparation of mixture containing particulate composition>
-Preparation of granulated products-
A fluid layer containing 321.0 g of lactose hydrate (Phartose 200M manufactured by DMV), 164.0 g of corn starch (Cornstarch manufactured by Nihon Shokuhin Kako Co., Ltd.), and 60.0 g of crystalline cellulose (Theoras PH-101 manufactured by Asahi Kasei Chemicals Co., Ltd.). It was placed in a coating machine (MP-01 type manufactured by Paulec), and the blast temperature was controlled so that the exhaust temperature in the steady state was about 40 ° C. 16.4 g of hypromellose (NISSO HPC-L, manufactured by Nippon Soda Corporation) was dissolved in 311.6 g of purified water. The obtained solution was sprayed at a liquid speed of 10 g / min, and after the spraying was completed, the mixture was dried until the exhaust temperature reached 48 ° C. This operation was performed a total of 4 times to obtain a granulated product (granulated powder).

-Preparation of powder for tableting-
Place 1318.4 g of granules after forming an enteric layer and 2245.6 g of granulated product in a V-type mixer (V-10 type manufactured by Tokuju Kosakusho Co., Ltd.), mix at a rotation speed of 36 rpm for 5 minutes, and magnesium stearate (NOF Corporation). (Magnesium stearate S) 36 g was added and further mixed at a rotation speed of 36 rpm for 1 minute to obtain a powder for tableting (mixed powder).

<Locking process>
Using a rotary tableting machine (manufactured by Kikusui Seisakusho, Correct 19K type), 3600 g of a mixture containing the particulate composition (the powder for tableting, which may be hereinafter referred to as "mixed powder") is described below. Perform one of the temperature control processes, set the rotation speed to 10 rpm, and tablet with a tablet diameter of 10 mm and a flat-sumi angle (planar corner) so that the tableting pressure is 15.0 kN / tablet, and one tablet is 450 mg. I got a tablet of. The prescription per tablet is shown in Table 1-1.

-Temperature control processing-
[Test Example 1-1]
Rotary locker ・ ・ ・ No temperature control processing (room temperature (about 24 ℃))
Mixing powder: No temperature control processing (room temperature (about 24 ° C))
[Test Example 1-2]
Rotary locker ・ ・ ・ With temperature control processing (38 ℃ ～ 40 ℃)
Mixing powder: No temperature control processing (room temperature (about 24 ° C))
[Test Example 1-3]
Rotary locker ・ ・ ・ With temperature control processing (35 ℃ ～ 37 ℃)
Mixing powder: With temperature control processing (45 ° C to 46 ° C)
[Test Example 1-4]
Rotary locker ・ ・ ・ No temperature control processing (room temperature (about 24 ℃))
Mixing powder: With temperature control processing (40 ° C to 43 ° C)

FIG. 1 shows a schematic diagram of the rotary type locker used in this test example.
The temperature control process of the rotary type locking machine was performed by heating the turntable 2 with warm air before locking. The temperature in parentheses in the above temperature control processing item indicates the temperature of the turntable 2 at the start of locking.
The temperature control process of the mixed powder was performed by heating the mixed powder before being charged into the hopper 8 with a thermostat. The temperature in parentheses in the above-mentioned temperature control processing item indicates the temperature at the end of mixing when the mixture is charged into the hopper 8.

<Evaluation>
-Acid resistant-
The tablets obtained in each test example were subjected to a duloxetine dissolution test in one solution according to the dissolution test method of the Japanese Pharmacopoeia. The dissolution time in the dissolution test was 2 hours. The elution rate (acid resistance) of duloxetine was calculated from the concentration of duloxetine measured at a wavelength of 289 nm using a spectrophotometer (UV-2600, manufactured by Shimadzu Corporation). The results are shown in Table 1-2.

-hardness-
The measurement was performed using a load cell type tablet hardness tester (portable checker PC-30 manufactured by Okada Seiko Co., Ltd.). The test was performed 10 times and the value was calculated. The results are shown in Table 1-2.

From the results in Table 1-2, in Test Examples 1-2 to 1-4 in which at least one of the locker and the mixed powder was heated, the acid resistance performance was significantly improved as compared with Test Example 1-1. rice field. Therefore, it was confirmed that according to the production method of the present invention, tablets having an acid resistance of 10% or less, which is a guideline for pharmaceutical products, can be efficiently produced (mass-produced).
Further, in Test Example 1-3 in which both the tableting machine and the mixed powder were heated, it was confirmed that tablets having further excellent acid resistance could be produced.

(Test Example 2)
Tablets were produced in the same manner as in Test Example 1-3, except that the tableting pressure in the tableting step of Test Example 1-3 was one of the following.
-Locking pressure-
[Test Example 2-1]
13.0kN / Pestle [Test Example 2-2]
15.0kN / Pestle [Test Example 2-3]
18.0kN / Pestle

<Evaluation>
The tablets obtained in each test example were evaluated for acid resistance and hardness in the same manner as in test example 1. The results are shown in Table 2.

From the results in Table 2, it was confirmed that even when tablets are produced by changing the tableting pressure, tablets with guaranteed acid resistance can be mass-produced by performing the temperature control treatment of the present invention.

(Test Example 3)
The enteric coating agent "Eudragit L30D55" in the tablet formulation of Test Example 1 (Table 1-1) was replaced with AQOAT AS-LF (Shinetsu Chemical Co., Ltd., hydroxypropylmethylcellulose acetate succinate), and porsorbate 80 was replaced with sodium lauryl sulfate. , Tablets (tablets of Test Examples 3-1 to 3-4, 300 mg per tablet) were produced in the same manner as in Test Example 1 with the formulations shown in Table 3-1 below (formulations per tablet). The temperature control process for the rotary tableting machine and the mixed powder was set to the conditions shown in Table 3-2 below, and the tableting pressure was 10 kN / pestle.

<Evaluation>
The tablets obtained in Test Example 3 were tested for the effect of heating on hardness and acid resistance in the same manner as in the test in Test Example 1. The results are shown in Table 3-2.

From the results in Table 3-2, it was confirmed that the acid resistance of Test Example 3 was also improved in the pharmaceutical product in which at least one of the tableting machine and the mixed powder was heated.

(Test Example 4)
Based on the formulation of Test Example 3, the tablets of Test Examples 4-1 to 4-3 were produced and tested by the rotary tableting machine shown in Table 4 below, the temperature control treatment of the mixed powder, and the tableting pressure. The test was performed in the same manner as in Example 1. The results are shown in Table 4.

From the results in Table 4, as in Test Example 2, even when tablets are manufactured by changing the tableting pressure, the tablets with guaranteed acid resistance can be mass-produced by performing the temperature control treatment of the present invention. Was confirmed.

1 ・ ・ ・ Vertical rotation axis 2 ・ ・ ・ Turntable 3 ・ ・ ・ Locking cell (mortar)
4 ・ ・ ・ Lower locking rod (pestle only)
5 ・ ・ ・ Lower pressure roller 6 ・ ・ ・ Upper locking rod (pestle only)
7 ・ ・ ・ Upper pressure roller 8 ・ ・ ・ Hopper 9 ・ ・ ・ Powder for locking

Claims (3)

A method for producing a normal tablet , which comprises a tableting step of tableting a mixture containing a particulate composition.
The particulate composition covers a drug -containing layer containing duloxetine, which is an active ingredient, with an intermediate layer containing at least a binder and a light-shielding layer containing a colorant as a separation layer, and further contains an enteric polymer. It is made by stacking
The tableting step is usually characterized in that both a temperature control process for raising the temperature of the locker to 25 ° C. or higher and a temperature control process for raising the temperature of the mixture containing the particulate composition to 25 ° C. or higher are performed. How to make a lock . The method for producing an ordinary tablet according to claim 1, wherein the enteric polymer in the enteric layer is a hydroxypropylmethylcellulose acetic acid ester succinic acid ester. A drug-containing layer containing duloxetine, which is an active ingredient, is coated with an intermediate layer containing at least a binder and a light-shielding layer containing a colorant as a separation layer, and an enteric layer containing an enteric polymer is laminated in the form of particles. A duloxetine-containing ordinary tablet characterized by containing a composition.

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