Manufacturing method of tablets having printing

Abstract

To provide a tablet having printing on the surface of an uncoated tablet that resists discoloration and fading of dye ink caused by light.SOLUTION: According to an embodiment of the present invention, a tablet has an uncoated tablet containing D-mannitol and an additive with a water absorption of 14 wt.% or more and 44 wt.% or less, and printing disposed on the surface of the uncoated tablet and containing a colorant component of dye ink. The uncoated tablet contains 1 wt.% or more and 50 wt.% or less of the additive. The uncoated tablet has a water infiltration time of 35 seconds or longer. The uncoated tablet may contain 30 wt.% or more and 98 wt.% or less of D-mannitol.SELECTED DRAWING: None

Description

[Technical field]

[0001] One embodiment of the present invention relates to a tablet having printing. In particular, one embodiment of the present invention relates to a tablet having printing on the surface of the plain tablet. [Background technology]

[0002] Generally, tablets are printed or engraved on their surfaces to provide identification. Engraving has been widely used to identify plain tablets without a film. However, since tablet engraving is formed by applying unevenness to the tablet surface during tableting, the engraved part and the other surface parts are the same color, and it cannot be said that the visibility is sufficiently high. In addition, since the amount of information that can be applied to the tablet surface is small, it cannot be denied that it may lead to the mix-up of medicines. On the other hand, since printing on tablets is formed by directly printing on the tablet surface, it has higher visibility and identification than engraving. In addition, since more information can be applied to the tablet surface, such as the drug name and dosage indication, it is required by the medical field as it is useful for preventing medical malpractice. In particular, with the increasing need for printing on tablets, there is a demand for printing not only on conventional film-coated tablets, but also on plain tablets without a film.

[0003] Among the printing methods for tablets, inkjet printing, which is a non-contact method, can print not only on film-coated tablets but also on plain tablets without a film. Inks used in inkjet printing are broadly classified into dye ink and pigment ink, and dye ink generally has the advantages of being inexpensive, having good color development, and having a wide variety of colors. However, dye ink has low light resistance, and there is a problem that characters printed on the surface of tablets may discolor or fade due to the effects of light.

[0004] In printing on tablets printed with dye ink, the above problems have been solved by devising tablet formulations or dye inks themselves. Among these, as an effort to devise tablet formulations, a method has been reported in which the film of a film-coated tablet has a specific composition to improve the fixability of the dye ink. For example, Patent Document 1 describes printing with dye ink on the film coating of a solid formulation in which the content of polyethylene glycol as an additive in the film coating is less than 22.3% by mass when the total amount of the film coating is 100% by mass.

[0005] Furthermore, Patent Document 2 describes a film-coated tablet that coats a plain tablet and contains an ink attached onto a coating layer that contains a polymer having a vinyl alcohol unit in the main chain or side chain.

[0006] In addition to the above, as an effort to improve the dye ink itself, a method of improving discoloration or fading of the dye ink by examining the ink composition has been reported. For example, Patent Document 3 describes an inkjet ink composition that contains a copolymer of polyvinyl alcohol, acrylic acid, and methyl methacrylate, and a dye, and the copolymer is contained in an amount of 0.5 to 10 mass % of the entire composition.

[0007] Furthermore, Patent Documents 4 and 5 also describe studies on the composition of dye inks. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Patent Publication No. 2021-038210 [Patent Document 2] JP 2020-132600 A [Patent Document 3] Patent No. 6345504 [Patent Document 4] Patent No. 6223119 [Patent Document 5] International Publication No. 2020 / 171183 Summary of the Invention [Problem to be solved by the invention]

[0009] In solving the above problems, the previously reported methods for investigating film compositions cannot be applied to plain tablets without a film, and the method for investigating dye ink compositions limits the available ink compositions, which in turn limits the available inks and colors.

[0010] One object of one embodiment of the present invention is to provide a tablet having printing on the surface of the plain tablet that suppresses discoloration and fading of dye ink due to light. [Means for solving the problem]

[0011] According to one embodiment of the present invention, there is provided a tablet comprising: an uncoated tablet containing D-mannitol and an additive having a water absorption rate of 14% by weight or more and 44% by weight or less; and a print containing a pigment component of a dye ink arranged on the surface of the uncoated tablet, wherein the uncoated tablet contains 1% by weight or more and 50% by weight or less of the additive; and the uncoated tablet has a water conductivity time of 35 seconds or more.

[0012] The uncoated tablet may contain 30% by weight or more and 98% by weight or less of D-mannitol.

[0013] The excipient may be selected from disintegrants.

[0014] The additive may be one or more selected from the group consisting of carmellose, corn starch, low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, carmellose calcium, croscarmellose sodium, microcrystalline cellulose, partially pregelatinized starch, hypromellose, hydrous silicon dioxide, light anhydrous silicic acid, and hydroxypropyl cellulose. Effect of the Invention

[0015] According to one embodiment of the present invention, there is provided a tablet having, on the surface of the plain tablet, printing that suppresses discoloration and fading of dye ink due to light. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The tablet having the print according to the present invention will be described below. The tablet having the print according to the present invention is not limited to the description of the embodiment and the examples shown below. In the present embodiment and the examples described below, the same parts or parts having similar functions will not be described repeatedly.

[0017] In the tablet according to one embodiment of the present invention, a print using a dye ink is placed directly on the surface of the plain tablet. That is, the tablet according to one embodiment of the present invention is different from a film-coated tablet in which a print is placed on the film surface. In this specification, the term "plain tablet" refers to a tablet produced by compressing a pharmaceutical composition containing an active pharmaceutical ingredient, and does not have a film or sugar coating on its surface. In this specification, the term "plain tablet" refers to a generic term for tablets that do not have a film or sugar coating, including bare tablets, orally disintegrating tablets, chewable tablets, sublingual tablets, and buccal tablets.

[0018] As a result of the study by the present inventor, it was found that when D-mannitol was selected as an excipient constituting the plain tablet, the discoloration and fading of the dye ink due to light was remarkable. The effect of D-mannitol on the discoloration and fading of the dye ink due to light has not been reported so far, and this was the first finding by the present inventor. From this finding, it is possible to select an excipient other than D-mannitol as the excipient to be used for the plain tablet, but depending on the drug substance, a substance related to the drug substance may be generated due to the influence of a specific excipient. Since D-mannitol is one of the commonly used excipients, the present inventor studied a combination of additives that can suppress the discoloration and fading of the dye ink due to light in a tablet in which printing using dye ink is arranged on the surface of the plain tablet containing D-mannitol.

[0019] The tablet according to one embodiment of the present invention comprises an uncoated tablet containing D-mannitol and an additive having a water absorption rate of 14% by weight or more and 44% by weight or less, and a print containing a dye ink color component arranged on the surface of the uncoated tablet. In this embodiment, the content of the additive having a water absorption rate of 14% by weight or more and 44% by weight or less is adjusted to adjust the water conduction time of the uncoated tablet containing D-mannitol to 35 seconds or more, thereby suppressing discoloration and fading of the dye ink due to light. In one embodiment, the uncoated tablet contains 1% by weight or more and 50% by weight or less of an additive having a water absorption rate of 14% by weight or more and 44% by weight or less.

[0020] In one embodiment, the tablet may contain 30% by weight or more and 98% by weight or less of D-mannitol. As a result of the investigation by the present inventor, discoloration and fading of dye ink due to light was observed in uncoated tablets containing 30% by weight or more of D-mannitol. Therefore, the present invention is suitable for uncoated tablets containing 30% by weight or more of D-mannitol.

[0021] In one embodiment of the present invention, the additive having a water absorption rate of 14% by weight or more and 44% by weight or less may be selected from disintegrants having a water absorption rate of 14% by weight or more and 44% by weight or less. Examples of disintegrants having such a water absorption rate include one or more disintegrants selected from the group consisting of carmellose, corn starch, low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, carmellose calcium, croscarmellose sodium, crystalline cellulose, and partially pregelatinized starch.

[0022] In one embodiment, the additive having a water absorption rate of 14% by weight or more and 44% by weight or less can be exemplified by one or more additives selected from the group consisting of hypromellose, hydrated silicon dioxide, light anhydrous silicic acid, and hydroxypropyl cellulose.

[0023] In one embodiment, the additive having a water absorption rate of 14% by weight or more and 44% by weight or less can be one or more selected from one or more disintegrants selected from the above group and one or more additives selected from the above group, or two or more of them can be combined and contained in the core tablet of the tablet of the present invention.

[0024] In this embodiment, the type and content of the drug substance contained in the uncoated tablet are not particularly limited. In the case of a tablet containing D-mannitol in the uncoated tablet according to this embodiment, even if the drug substance is contained, the effect of suppressing discoloration and fading of the dye ink due to light can be obtained by adding an additive having a water absorption rate of 14% by weight or more and 44% by weight or less to adjust the water conduction time of the uncoated tablet to 35 seconds or more, so that the type and content of the drug substance do not affect it. Therefore, the tablet according to one embodiment of the present invention can contain a wide range of drug substances. In one embodiment, the present invention is also applied to a placebo tablet that does not contain a drug substance.

[0025] In one embodiment, the tablet may contain a lubricant. In this embodiment, the lubricant is not particularly limited. In the tablet containing D-mannitol in the uncoated tablet according to this embodiment, an additive having a water absorption rate of 14% by weight or more and 44% by weight or less is added to adjust the water conduction time of the uncoated tablet to 35 seconds or more, thereby obtaining the effect of suppressing discoloration and fading of the dye ink due to light, so the type and content of the lubricant do not affect it. Therefore, the tablet according to one embodiment of the present invention can be selected from commonly used lubricants and contain them. For example, as the lubricant, one or more lubricants can be selected from talc, starch, magnesium stearate, calcium stearate, sodium stearyl fumarate, boric acid, paraffin, cocoa butter, polyethylene glycol, leucine, sodium benzoate, etc. In one embodiment, the uncoated tablet can contain a lubricant in an amount of 1% by weight or more and 30% by weight or less.

[0026] In one embodiment, the plain tablet may contain additives other than D-mannitol, additives having a water absorption rate of 14% by weight or more and 44% by weight or less, and lubricants, within the scope of the effects of the present application. For example, the excipient may contain one or more selected from the group consisting of sugars such as lactose hydrate, sucrose, maltose, fructose, glucose, maltose, trehalose, dextrin, and pullulan, sugar alcohols such as maltitol, sorbitol, xylitol, erythritol, and lactitol, starches such as starch and pregelatinized starch, celluloses such as ethyl cellulose, synthetic aluminum silicate, calcium silicate, magnesium aluminometasilicate, anhydrous calcium hydrogen phosphate, calcium carbonate, and calcium sulfate. In addition, the colorant may contain one or more selected from the group consisting of iron oxides such as ferric oxide and yellow ferric oxide, titanium oxide, and tar dyes.

[0027] In one embodiment, the print placed on the surface of the plain tablet contains a dye component of the dye ink. In this embodiment, the dye ink is not particularly limited as long as it is a dye ink that can be used for printing on pharmaceuticals, and may be either a natural dye or a synthetic dye. The color of the dye ink is also not particularly limited. In addition to the dye component of the dye ink, the print placed on the surface of the plain tablet may contain non-volatile components such as a binder that constitutes the dye ink. In addition, it is preferable that the print placed on the surface of the plain tablet does not contain volatile components that constitute the dye ink, but it may be contained in the print placed on the surface of the plain tablet or on the surface of the plain tablet within a range acceptable for pharmaceuticals.

[0028] [Manufacturing method of uncoated tablets] In one embodiment of the present invention, the plain tablet can be produced by a dry method or a wet method. As the dry method, for example, a direct tableting method can be suitably used. Specifically, the raw drug, D-mannitol, the additive having the above-mentioned water absorption rate of 14% by weight or more and 44% by weight or less, a lubricant, and other additives as necessary are mixed homogeneously, and the resulting mixture is tableted to produce the plain tablet. Alternatively, a placebo tablet can be produced by preparing a mixture without adding the raw drug and tableting it. The plain tablet can be produced by compression molding using a commonly used tablet press. Regarding molding, any shape can be adopted, and for example, it can be molded into a tablet-shaped, elliptical, spherical, or rod-shaped shape.

[0029] [Tablet manufacturing method] Using a medicamentously acceptable dye ink, a print is placed on the surface of the obtained plain tablet by inkjet printing. Since inkjet printing is a well-known printing technique, a detailed description thereof will be omitted.

[0030] [Method for evaluating water absorption rate of additives] In this specification, the water absorption rate of the additive is evaluated by the following method. First, the weight of the bottle in which the additive is stored is measured, and 3 g of the additive is placed in the bottle. The bottle containing the additive is stored under conditions of 60°C and 10% RH for 4 days, and then the weight of the bottle and the additive is measured. After that, the bottle and the additive are stored under conditions of 25°C and 90% RH for 4 days, and then the weight of the bottle and the additive are measured, and the water absorption rate of the additive is calculated by the following formula. Water absorption rate of additive (wt%) = (Wc-Wb) x 100 / (Wb-Wa) Wa: Weight of the bottle Wb: Weight of the bottle and additives after storage for 4 days under conditions of 60°C and 10% RH Wc: Weight of the bottle and additives after storage for 4 days under conditions of 25°C and 90% RH

[0031] [Method for evaluating water conductivity time of uncoated tablets] In this specification, the water conduction time of an uncoated tablet is evaluated by the following method. First, a Kimwipe (registered trademark) is folded in half and placed in a petri dish with a diameter of 4 cm, 3 ml of purified water is dropped onto the Kimwipe (registered trademark), and one uncoated tablet is placed on the Kimwipe (registered trademark). Purified water is allowed to permeate the uncoated tablet from one end that is in contact with the Kimwipe (registered trademark) to the other end (the upper surface of the uncoated tablet), and the time it takes for the entire upper surface of the uncoated tablet to become wet is measured. The average value of the values ​​measured by this method for three tablets is regarded as the water conduction time of the uncoated tablet.

[0032] [Photostability evaluation method] In this specification, the light stability of the print placed on the surface of the plain tablet of the tablet is evaluated based on the color difference between the print before and after light exposure. First, a print is placed on the surface of the plain tablet by inkjet printing using dye ink (Black No. 1) from Qualicaps Co., Ltd. The tablet with the print placed on the surface of the plain tablet is stored for 8 days under conditions of 25°C, 60% RH, and 1000 lx·hr. Using a spectrophotometer (Model SE-6000, manufactured by Nippon Denshoku Industries Co., Ltd.), the color tone change ΔE of the print of the tablet stored under the above conditions is measured based on the color tone of the print before light exposure. * The value is measured for three tablets. The average value is calculated and the color difference (ΔE* ) EXAMPLES

[0033] [Reference example 1] As a reference example, the influence of excipients on discoloration and fading of ink was examined. As reference example 1, 147.0 g of D-mannitol (Granutol (registered trademark) F, Freund Corporation) and 3.0 g of magnesium stearate (plant, Taihei Chemical Industry Co., Ltd.) were mixed in a plastic bag and compressed using a rotary tablet press to produce plain tablets. Using dye ink (Black No. 1) from Qualicaps Co., Ltd., printing was placed on the surface of the obtained plain tablets by inkjet printing to obtain tablets.

[0034] [Reference examples 2~3] The uncoated tablets and tablets of Reference Example 2 were produced in the same manner as in Reference Example 1, except that D-mannitol was changed to anhydrous calcium hydrogen phosphate (GS, anhydrous calcium hydrogen phosphate). In addition, the uncoated tablets and tablets of Reference Example 3 were produced in the same manner as in Reference Example 1, except that D-mannitol was changed to lactose hydrate (Dilactose (registered trademark) S, Freund Corporation).

[0035] The water conductivity time of the uncoated tablets of Reference Examples 1 to 3 was measured by the above method, and the light stability of the printing on the tablets was evaluated. The results are shown in Table 1.

[0036] In this specification, the color difference (ΔE * If the color difference (ΔE *) exceeds 5.0, it is judged that discoloration or fading of the dye ink due to light has occurred, resulting in a significant change in the appearance of the print. As shown in Table 1, the color difference of Reference Example 1 exceeded 5.0, while the color difference of Reference Example 2 and Reference Example 3 was 5.0 or less, making it clear that D-mannitol contained as an excipient has a strong effect on discoloration or fading of the dye ink due to light. On the other hand, it was made clear that anhydrous calcium hydrogen phosphate and lactose hydrate have only a small effect on discoloration or fading of the dye ink due to light. [Table 1]

[0037] [Reference examples 4~7] The results of Reference Example 1 revealed that D-mannitol has a strong effect on discoloration and fading of dye ink due to light, so the effect of the D-mannitol content in the plain tablets on discoloration and fading of dye ink due to light was examined. Plain tablets and tablets of Reference Examples 4 to 7 were manufactured by reducing the D-mannitol content compared to Reference Example 1 and adding lactose hydrate, which was shown to have little effect on discoloration and fading of dye ink due to light in Reference Example 3.

[0038] [Reference example 4] Specifically, 30.0 g of D-mannitol (Granutol (registered trademark) F, Freund Corporation), 117.0 g of lactose hydrate (Dilactose (registered trademark) S, Freund Corporation), and 3.0 g of magnesium stearate (plant, Taihei Chemical Industry Co., Ltd.) were mixed in a plastic bag and compressed using a rotary tablet press to produce the plain tablets of Reference Example 4. Using dye ink (Black No. 1) from Qualicaps Corporation, printing was arranged on the surface of the obtained plain tablets by inkjet printing to obtain the tablets of Reference Example 4.

[0039] [Reference example 5] The plain tablet and the tablet of Reference Example 5 were produced in the same manner as in Reference Example 4, except that the amount of D-mannitol was changed to 45.0 g and the amount of lactose hydrate was changed to 102.0 g.

[0040] [Reference example 6] The plain tablet and the tablet of Reference Example 6 were produced in the same manner as in Reference Example 4, except that the amount of D-mannitol was changed to 75.0 g and the amount of lactose hydrate was changed to 72.0 g.

[0041] [Reference example 7] The plain tablet and the tablet of Reference Example 7 were produced in the same manner as in Reference Example 4, except that the amount of D-mannitol was changed to 105.0 g and the amount of lactose hydrate was changed to 42.0 g.

[0042] Using the above method, the water conduction time and color difference of the printing on the tablets of the uncoated tablets of Reference Examples 4 to 7 were measured. The measurement results are shown in Table 2, which reproduces the results of Reference Example 1. In Table 2, (20% by weight) etc. indicate the percentage of D-mannitol content relative to the uncoated tablet. From the results in Table 2, it was revealed that in tablets containing 30% by weight or more of D-mannitol, discoloration and fading of the dye ink occurs due to light, and it was found that this effect depends on the content of D-mannitol. [Table 2]

[0043] [Measurement of water absorption rate of additives] In order to investigate the combination of additives that can suppress discoloration and fading of dye ink due to light in tablets containing D-mannitol, we first measured the water absorption rate of the additives added to the plain tablets using the method described above.

[0044] Additives include carmellose (NS-300 (registered trademark), Nichirin Chemical Industry Co., Ltd.), corn starch (xx16, Nihon Shokuhin Kako Co., Ltd.), low-substituted hydroxypropyl cellulose (L-HPC (registered trademark) LH-21, Shin-Etsu Chemical Co., Ltd.), crospovidone (kollidon (registered trademark) CL-F, BASF), sodium starch glycolate (Primogel (registered trademark), DMV), carmellose calcium (ECG-505 (registered trademark), Gotoku Pharmaceutical Co., Ltd.), croscarmellose sodium (Acdisol (registered trademark), FMC The water absorption rates of cellulose acetate (Ceola International), crystalline cellulose (Ceolas® PH102, Asahi Kasei Corporation), partially pregelatinized starch (PCS® PC10, Asahi Kasei Corporation), hypromellose (TC-5® E, Shin-Etsu Chemical Co., Ltd.), hydrous silicon dioxide (SYLOPURE®, Fuji Silysia Chemical Ltd.), light anhydrous silicic acid (Adsolider® 101, Freund Corporation), and hydroxypropyl cellulose (L, Nippon Soda Co., Ltd.) were measured. For reference, the water absorption rates of lactose hydrate (Dilactose (registered trademark) S, Freund Corporation), anhydrous calcium hydrogen phosphate (GS, anhydrous calcium hydrogen phosphate), D-mannitol (Granutol (registered trademark) F, Freund Corporation), magnesium stearate (plant, Taihei Chemical Industry Co., Ltd.), dibutylhydroxytoluene (Butylhydroxytoluene, Merck Ltd.), ammonioalkyl methacrylate copolymer (Eudragit (registered trademark) RSPO, Evonik), titanium oxide (NA61, Toho Titanium Co., Ltd.), and sucralose (P, San-Ei Gen F.F.I. Co., Ltd.) were also measured. The water absorption rates of each additive are shown in Table 3. [Table 3]

[0045] [Example 1] The additives whose water absorption rate was measured were used to study the effect of suppressing discoloration and fading of dye ink due to light. In Example 1, 139.5 g of D-mannitol (Granutol (registered trademark) F, Freund Corporation), 7.5 g of crystalline cellulose (Ceolas (registered trademark) PH102, Asahi Kasei Corporation), and 3.0 g of magnesium stearate (plant, Taihei Chemical Industry Co., Ltd.) were mixed in a plastic bag and compressed using a rotary tablet press to produce plain tablets. Using dye ink (Black No1) from Qualicaps Co., Ltd., printing was arranged on the surface of the obtained plain tablets by inkjet printing to obtain the tablets of Example 1.

[0046] [Example 2] The plain tablet and the tablets of Example 2 were produced in the same manner as in Example 1, except that the crystalline cellulose was changed to carmellose calcium (ECG-505 (registered trademark), Gotoku Pharmaceutical Co., Ltd.).

[0047] [Example 3] The plain tablet and tablets of Example 3 were produced in the same manner as in Example 1, except that the microcrystalline cellulose was changed to croscarmellose sodium (Acdisol (registered trademark), FMC International).

[0048] Using the above method, the water conduction time and color difference of the print on the tablets of the uncoated tablets of Examples 1 to 3 were measured. The measurement results are shown in Table 4. In Table 4, (14 wt%) etc. indicate the water absorption rate of each additive. The results in Table 4 reveal that in tablets containing 5 wt% of an additive with a water absorption rate of 14 wt% to 44 wt% and having a print made using dye ink, discoloration and fading of the dye ink due to light can be suppressed. [Table 4]

[0049] Using croscarmellose sodium, which has a high water absorption rate, we investigated the effect of the additive content in uncoated tablets on the suppression of discoloration and fading of dye ink due to light.

[0050] [Comparative Example 1] 146.8 g of D-mannitol (Granutol (registered trademark) F, Freund Corporation), 0.2 g of croscarmellose sodium (Acdisol (registered trademark), FMC International), and 3.0 g of magnesium stearate (plant, Taihei Chemical Industry Co., Ltd.) were mixed in a plastic bag and compressed using a rotary tablet press to produce the plain tablets of Comparative Example 1. Using dye ink (Black No. 1) from Qualicaps Co., Ltd., printing was placed on the surface of the obtained plain tablets by inkjet printing to obtain the tablets of Comparative Example 1.

[0051] [Example 4] The plain tablet and the tablet of Example 4 were produced in the same manner as in Comparative Example 1, except that the amount of D-mannitol was changed to 145.5 g and the amount of croscarmellose sodium was changed to 1.5 g.

[0052] [Comparative Example 2] The plain tablets and tablets of Comparative Example 2 were produced in the same manner as in Comparative Example 1, except that the amount of D-mannitol was changed to 142.5 g and the amount of croscarmellose sodium was changed to 4.5 g.

[0053] [Example 5] The plain tablet and the tablet of Example 5 were produced in the same manner as in Comparative Example 1, except that the amount of D-mannitol was changed to 72.0 g and the amount of croscarmellose sodium was changed to 75.0 g.

[0054] The water conduction time and the color difference of the printing of the tablets of Examples 4-5 and Comparative Examples 1-2 were measured by the above method. The measurement results are shown in Table 5, and the measurement results of Example 3 are recited. In Table 5, (0.1% by weight) etc. indicate the content ratio of croscarmellose sodium to the uncoated tablet. From the results of Table 5, it became clear that the effect of suppressing discoloration and fading of dye ink due to light does not necessarily depend on the content of croscarmellose sodium. In the uncoated tablet of Comparative Example 2 containing 3% by weight of croscarmellose sodium, the water conduction time was significantly short at 22 seconds, and it became clear that the effect of suppressing discoloration and fading of dye ink due to light was reduced. From this result, it was suggested that the water conduction time of the uncoated tablet has a significant effect on the effect of suppressing discoloration and fading of dye ink due to light. [Table 5]

[0055] The effect of the water-transmitting time of the uncoated tablet on the suppression of discoloration and fading of dye ink due to light was investigated.

[0056] [Example 6] 145.5 g of D-mannitol (Granutol (registered trademark) F, Freund Corporation), 1.5 g of crystalline cellulose (Ceolas (registered trademark) PH102, Asahi Kasei Corporation), and 3.0 g of magnesium stearate (plant, Taihei Chemical Industry Co., Ltd.) were mixed in a plastic bag and compressed using a rotary tablet press to produce the plain tablets of Example 6. Using dye ink (Black No. 1) from Qualicaps Co., Ltd., printing was placed on the surface of the obtained plain tablets by inkjet printing to obtain the tablets of Example 6.

[0057] [Example 7] The plain tablet and the tablet of Example 7 were produced in the same manner as in Example 6, except that the amount of D-mannitol was changed to 142.5 g and the amount of crystalline cellulose was changed to 4.5 g.

[0058] [Comparative Example 3] The plain tablets and tablets of Comparative Example 3 were produced in the same manner as in Example 6, except that the amount of D-mannitol was changed to 72.0 g and the amount of crystalline cellulose was changed to 75.0 g.

[0059] [Comparative Example 4] The plain tablets and tablets of Comparative Example 4 were produced in the same manner as in Example 6, except that the amount of D-mannitol was changed to 139.5 g and the amount of crystalline cellulose was changed to carmellose (NS-300 (registered trademark), Nichirin Chemical Industry Co., Ltd.) 7.5 g.

[0060] [Comparative Example 5] The plain tablet and the tablet of Comparative Example 5 were produced in the same manner as in Example 6, except that the amount of D-mannitol was changed to 139.5 g and the amount of crystalline cellulose was changed to 7.5 g of low-substituted hydroxypropyl cellulose (L-HPC (registered trademark) LH-21, Shin-Etsu Chemical Co., Ltd.).

[0061] [Comparative Example 6] The plain tablets and tablets of Comparative Example 6 were produced in the same manner as in Example 6, except that the amount of D-mannitol was changed to 139.5 g and the crystalline cellulose was changed to 7.5 g of corn starch (xx16, Nippon Shokuhin Kako Co., Ltd.).

[0062] [Example 8] The plain tablet and the tablet of Example 8 were produced in the same manner as in Example 6, except that the amount of D-mannitol was changed to 139.5 g and the amount of crystalline cellulose was changed to 7.5 g of crospovidone (kollidon (registered trademark) CL-F, BASF).

[0063] [Example 9] The plain tablets and tablets of Example 9 were produced in the same manner as in Example 6, except that the amount of D-mannitol was changed to 139.5 g and the crystalline cellulose was changed to 7.5 g of sodium starch glycolate (Primogel (registered trademark), DMV).

[0064] Using the above method, the water conductivity time and color difference of the printing on the tablets of the uncoated tablets of Examples 6 to 9 and Comparative Examples 3 to 6 were measured. The measurement results are shown in Table 6. As shown in Table 6, the color difference was 5.0 or less for tablets with a water conductivity time of 35 seconds or more, and discoloration and fading of the dye ink due to light was suppressed. [Table 6]

[0065] From the above results, it was revealed that in tablets with dye ink printing on the surface of uncoated tablets containing D-mannitol, discoloration and fading of the dye ink due to light can be suppressed by including an additive with a water absorption rate of 14% by weight or more and 44% by weight or less and adjusting the water conduction time of the uncoated tablet to 35 seconds or more.

[0066] Next, we investigated the effect of the active pharmaceutical ingredients contained in the tablets on the inhibition of discoloration and fading of dye ink due to light.

[0067] [Example 10] 7.5g of drug substance A, 3.75g of hydroxypropylcellulose (L, Nippon Soda Co., Ltd.), 53.42g of D-mannitol, 11.73g of corn starch, 5.0g of crystalline cellulose, 5.0g of low-substituted hydroxypropylcellulose, 0.9g of sucralose (San-Ei Gen F.F.I. Co., Ltd.), 0.9g of light anhydrous silicic acid (Adsolider 101 (registered trademark), Fuji Silysia Chemical Co., Ltd.), and 1.8g of magnesium stearate were mixed in a plastic bag and compressed using a rotary tablet press to produce the uncoated tablets of Example 10. Using dye ink (Black No1) from Qualicaps Co., Ltd., printing was arranged on the surface of the obtained uncoated tablets by inkjet printing to obtain the tablets of Example 10. The content of D-mannitol contained in the uncoated tablets was 59.4% by weight, and the content of additives having a water absorption rate of 14% by weight or more and 44% by weight or less was 29.3% by weight.

[0068] [Example 11] The uncoated tablets and tablets of Example 11 were produced in the same manner as in Example 10, except that the drug substance A was not added. The content of D-mannitol contained in the uncoated tablets was 64.8% by weight, and the content of additives having a water absorption rate of 14% by weight or more and 44% by weight or less was 32.0% by weight.

[0069] Using the above method, the water permeability time and color difference of the print on the tablets of the uncoated tablets of Examples 10 and 11 were measured. The measurement results are shown in Table 7. The results in Table 7 show that in the uncoated tablets containing D-mannitol, in which an additive with a water absorption rate of 14% by weight or more and 44% by weight or less was added to adjust the water permeability time to 35 seconds or more, discoloration and fading of the dye ink due to light could be suppressed, regardless of the presence or absence of the drug substance. [Table 7]

[0070] [Comparative Example 7] 2.5 g of drug substance B, 1.75 g of hypromellose (TC-5E (registered trademark), Shin-Etsu Chemical Co., Ltd.), 10.0 g of hydrous silicon dioxide (SYLOPURE P100 (registered trademark), Fuji Silysia Chemical Co., Ltd.), 0.14 g of dibutyl hydroxytoluene (Merck Ltd.), 4.25 g of ammonioalkyl methacrylate copolymer (Eudragit RSPO (registered trademark), Evonik Roehm), 2.2 g of light anhydrous silicic acid, 77.44 g of D-mannitol, 1.5 g of titanium oxide (NA61 (registered trademark), Toho Titanium Co., Ltd.), 19.3 g of crystalline cellulose, 4.4 g of low-substituted hydroxypropylcellulose, 3.52 g of crospovidone, 1.1 g of sucralose, and 1.9 g of magnesium stearate were mixed in a plastic bag and compressed using a rotary tablet press to produce the plain tablets of Comparative Example 7. Using dye ink (Black No. 1) manufactured by Qualicaps Co., Ltd., printing was arranged on the surface of the obtained uncoated tablet by inkjet printing to obtain a tablet of Comparative Example 7. The content of D-mannitol contained in the uncoated tablet was 59.6% by weight, and the content of additives having a water absorption rate of 14% by weight or more and 44% by weight or less was 31.7% by weight.

[0071] [Comparative Example 8] The uncoated tablets and tablets of Comparative Example 8 were produced in the same manner as in Comparative Example 7, except that no drug substance B was added. The content of D-mannitol contained in the uncoated tablets was 60.7% by weight, and the content of additives having a water absorption rate of 14% by weight or more and 44% by weight or less was 32.3% by weight.

[0072] Using the above method, the water conduction time of the uncoated tablets of Comparative Example 7 and Comparative Example 8 and the color difference of the printing on the tablets were measured. The measurement results are shown in Table 8. From the results in Table 8, it can be seen that for uncoated tablets containing D-mannitol, in those tablets with a water conduction time of less than 35 seconds, discoloration and fading of the dye ink due to light could not be suppressed, regardless of the presence or absence of the drug substance. [Table 8]

[0073] From the results in Tables 7 and 8, it was revealed that, regardless of whether the tablet contains an active pharmaceutical ingredient, in tablets having dye ink printing on the surface of a plain tablet containing D-mannitol, discoloration and fading of the dye ink due to light is suppressed by including an additive with a water absorption rate of 14% by weight or more and 44% by weight or less and adjusting the water conduction time of the plain tablet to 35 seconds or more.

Claims

1. D-mannitol, an additive having a water absorption rate of 14% by weight or more and 44% by weight or less, and a lubricant are mixed homogeneously, and the mixture is compressed into tablets to produce plain tablets. A method for producing a tablet, comprising the steps of: arranging a print containing a dye component on the surface of the plain tablet using a pharma- ceutical acceptable dye ink; The uncoated tablet contains 1% by weight or more and 50% by weight or less of the additive, The water conductivity time of the uncoated tablet is 35 seconds or more, The water absorption rate of the additive was measured by measuring the weight of a bottle in which the additive was stored, putting 3 g of the additive into the bottle, storing the bottle containing the additive under conditions of 60° C. and 10% RH for 4 days, measuring the weight of the bottle and the additive, and then storing the bottle containing the additive under conditions of 25° C. and 90% RH for 4 days, measuring the weight of the bottle and the additive, and calculating the water absorption rate of the additive according to the following formula: The water conductivity time of the uncoated tablets is measured by placing a Kimwipe (registered trademark) folded in half in a petri dish having a diameter of 4 cm, dropping 3 ml of purified water onto the Kimwipe (registered trademark), placing one uncoated tablet on the Kimwipe (registered trademark), allowing the purified water to permeate from one end of the uncoated tablet in contact with the Kimwipe (registered trademark) to the other end, measuring the time until the entire upper surface of the uncoated tablet is wet, and the average of the values ​​measured by this method for three uncoated tablets is regarded as the water conductivity time of the uncoated tablets. Water absorption rate of additive (wt%)=(Wc-Wb)×100 / (Wb-Wa) Wa: Weight of the bottle Wb: Weight of the bottle and additives after storage for 4 days under conditions of 60° C. and 10% RH Wc: Weight of the bottle and the additive after storage for 4 days under conditions of 25° C. and 90% RH

2. The method for producing a tablet according to claim 1, wherein the uncoated tablet contains 30% by weight or more and 98% by weight or less of D-mannitol.

3. The method for producing a tablet according to claim 1 , wherein the additive is selected from a disintegrant.

4. 2. The method for producing tablets according to claim 1, wherein the additive is one or more selected from the group consisting of carmellose, corn starch, low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, carmellose calcium, croscarmellose sodium, microcrystalline cellulose, partially pregelatinized starch, hypromellose, hydrous silicon dioxide, light anhydrous silicic acid, and hydroxypropyl cellulose.

5. A method for producing a tablet as described in any one of claims 1 to 4, comprising homogeneously mixing the drug substance together with the D-mannitol, the additive having a water absorption rate of 14% by weight or more and 44% by weight or less, and the lubricant, and compressing the resulting mixture to produce the plain tablet.

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