Zinc acetate tablets

Abstract

To provide tablets having a suitable hardness containing zinc acetate dihydrate in which dehydration due to loss of water of crystallization of zinc acetate dihydrate in tablets is suppressed, tablet disintegration and elution properties are excellent, and delay of disintegration or elution after storage does not occur, and to provide a manufacturing method therefor.SOLUTION: A method for producing a tablet containing zinc acetate dihydrate comprises (step 1) a step for mixing zinc acetate dihydrate and a lubricant, followed by dry granulation, and (step 2) a step for compression molding after mixing granules obtained in step 1 and a disintegrant.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for manufacturing tablets containing zinc acetate dihydrate and the tablets thereof.

Background Art

[0002] Zinc acetate dihydrate (C4H6O4Zn·2H2O) is sold in the form of capsules and tablets as a therapeutic agent for Wilson's disease (hepatolenticular degeneration) by suppressing copper absorption due to competitive inhibition with copper, and also as a zinc preparation for hypozincemia (Non-Patent Document 1).

[0003] As a technology related to tablets containing zinc acetate dihydrate, for example, Patent Document 1 discloses that after granulating by wet granulation and then drying the granulated product at a low temperature of less than 40°C, zinc acetate hydrate tablets with a small tablet diameter can be produced without the loss of crystal water in the hydrate and the transition to an anhydride. However, this method requires temperature control and has points to be improved in the production of tablets, such as a long drying time due to low-temperature drying.

[0004] Also, Patent Document 2 discloses a tablet containing a medicinal ingredient containing zinc acetate dihydrate, crystalline cellulose, and magnesium stearate of 0.5% by mass or less, and having a high drug content in which the content of the medicinal ingredient occupies at least 60% or more of the tablet mass. According to this, even when the content of the medicinal ingredient is high, the problem of difficult formability and the impairment of the balance between the stability, disintegration property, and elution property of the medicinal ingredient during production can be solved. However, there is still room for improvement in the stability of zinc acetate dihydrate, the elution property of the tablets, and the formulation uniformity.

[0005] Patent Document 3 discloses that the particle size (d 50It has been disclosed that zinc acetate dihydrate tablets obtained by directly compressing a mixture containing zinc acetate dihydrate with a particle size of 40-600 μm and an additive have uniform content. Furthermore, Patent Document 4 discloses that zinc acetate dihydrate tablets obtained by directly compressing a mixture of crystalline cellulose, a high-moisture-content additive such as corn starch, crospovidone, and zinc acetate dihydrate have an effect of suppressing the transfer and discoloration of zinc acetate dihydrate. However, these documents do not disclose the hardness, disintegration, or stability of zinc acetate dihydrate tablets. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2016 / 088816 [Patent Document 2] Japanese Patent Publication No. 2021-104941 [Patent Document 3] Japanese Patent Publication No. 2022-86833 [Patent Document 4] Japanese Patent Publication No. 2022-86872 [Non-patent literature]

[0007] [Non-Patent Document 1] "Novelzin® Tablets 25mg, Novelzin® Tablets 50mg, Novelzin® Granules 5%" Pharmaceutical Interview Form, Revised June 2021 (12th Revised Edition) [Overview of the project] [Problems that the invention aims to solve]

[0008] In light of these circumstances, there is a need for a simple method for manufacturing zinc acetate dihydrate tablets that suppresses the generation of impurities such as dehydration due to the loss of crystal water of zinc acetate dihydrate in the tablet, exhibits excellent disintegration and dissolution properties, does not experience delays in disintegration or dissolution after storage, has a suitable tablet hardness, and does not require special temperature control. Furthermore, there is a need for tablets in which the bitterness and astringency derived from zinc acetate dihydrate are masked. [Means for solving the problem]

[0009] The inventors conducted diligent research to solve the problem and found that tablets containing zinc acetate dihydrate, obtained by a manufacturing method including the steps of mixing zinc acetate dihydrate and a lubricant and dry granulation, and mixing the obtained granules and a disintegrant, followed by compression molding, exhibit excellent stability of zinc acetate dihydrate, excellent disintegration and dissolution properties, and appropriate tablet hardness, and that these tablets can be obtained by a simple manufacturing method. Furthermore, they found that by coating these tablets by a specific method, the taste can be masked and the generation of impurities in the coating process can be suppressed, thus completing the present invention.

[0010] In other words, the present invention is [1] A method for producing tablets containing zinc acetate dihydrate, (Step 1) A step of mixing zinc acetate dihydrate and a lubricant and dry granulating, and (Step 2) This method includes a step of mixing the granules obtained in Step 1 with a disintegrant and then compressing and molding them. [2] The present invention also relates to the method described in [1] above, wherein a binder is further mixed in step 1 described in [1] above. [3] The present invention also relates to the method described in [1] or [2] above, wherein a highly water-active excipient is further mixed in (step 1) described in [1] or [2] above. [4] The present invention also relates to the method described in [1] to [3] above, wherein a disintegrant is further mixed in (step 1) and a lubricant is further mixed in (step 2). [5] The present invention also relates to the method described in [3] or [4] above, wherein the highly water-active excipient is one or more of the following: lactose, lactose monohydrate, mannitol, trehalose, and maltose. [6] The present invention also relates to the method described in [1] to [5] above, further comprising the step of film coating the tablets at an air supply temperature of 50°C or lower. [7] The present invention also relates to tablets comprising zinc acetate dihydrate and a highly water-active excipient. [8] The present invention also relates to the tablets described in [7] above, wherein the highly water-active excipient is one or more of the following: lactose, lactose monohydrate, mannitol, trehalose, and maltose. [9] The present invention also relates to granules containing zinc acetate dihydrate and a highly water-active excipient.

[10] The present invention also relates to the granules described in [9] further comprising a binder and a lubricant.

[11] The present invention also relates to the granules described in

[10] above, further comprising a disintegrant.

[12] The present invention also relates to the granules described in [9] to

[11] above, wherein the granules described in [9] to

[11] above are obtained by a dry granulation method.

[13] The present invention also relates to tablets containing the granules described in [9] to

[12] above.

[14] The present invention also relates to the tablets described in [7], [8] or

[13] above, which are film-coated tablets.

[15] The present invention also relates to tablets containing zinc acetate dihydrate with an impurity content of 0.5% or less as an active ingredient. [Effects of the Invention]

[0011] According to the present invention, generation of impurities such as anhydration due to disappearance of crystal water of zinc acetate dihydrate in tablets is suppressed, the tablets are excellent in disintegration and dissolution properties, no delay in disintegration or dissolution occurs even after storage, they have a suitable tablet hardness, and a simple method for producing tablets containing zinc acetate dihydrate that does not require special temperature control and tablets containing zinc acetate dihydrate can be provided. Further, by coating the tablets by a specific method, generation of impurities in the coating process is suppressed and bitterness and astringency derived from zinc acetate dihydrate are masked, and tablets containing zinc acetate dihydrate excellent in taste can be provided.

Brief Description of Drawings

[0012] [Figure 1] SEM photograph of zinc acetate dihydrate of Reference Example 1. [Figure 2] XRD chart of zinc acetate dihydrate of Reference Example 1. [Figure 3] Dissolution test of Example 1 and Comparative Example 1. [Figure 4] XRD chart of Example 5 and Comparative Example 3. [Figure 5] XRD chart (at 2θ: 3 to 9°) of Example 6, Comparative Example 4, and Comparative Example 3. [Figure 6] XRD chart (at 2θ: 3 to 15°) of Example 6 and Comparative Example 4.

Modes for Carrying Out the Invention

[0013] Hereinafter, the present invention will be described in detail. The zinc acetate dihydrate used in the present invention can be purchased and used as commercially available products for pharmaceuticals, foods, etc., or can be obtained, for example, by reacting acetic acid and zinc oxide, or by dissolving zinc oxide and acetic acid in water and adding a poor solvent such as acetone to this solution to precipitate a solid. The particle shape and size of zinc acetate dihydrate are not particularly limited, but granular, plate-shaped, or rectangular plate-shaped particles can be used. Of these, rectangular plate-shaped particles are preferred because they have good tableting properties, and as for particle size, for example, particles with an average particle diameter of 2 to 300 μm, preferably 5 to 200 μm, and more preferably 20 to 180 μm can be used. Furthermore, particles with a thickness of 0.5 to 40 μm, preferably 1 to 30 μm, and more preferably 1 to 20 μm can be used. Furthermore, the aspect ratio of the plate-like particles of zinc acetate dihydrate can be 1.5 to 20, preferably 2 to 15. Furthermore, the specific volume of zinc acetate dihydrate is 0.5 to 5 cm³. 3 / g, preferably 1-3cm 3 You can use products that are / g. Note that the average particle diameter is the median diameter (D 50 This refers to the particle size corresponding to 50% of the cumulative distribution curve, and is calculated based on volume. The average particle size can be determined using known methods and measuring instruments, such as laser light scattering particle size distribution measurement or dynamic light scattering particle size distribution measurement.

[0014] The amount of zinc acetate dihydrate added is 40 to 90% by mass, preferably 55 to 80% by mass, and more preferably 60 to 75% by mass, based on the total mass of the tablet.

[0015] In step 1, the granules are obtained by dry granulation, which involves mixing zinc acetate dihydrate with a lubricant, optionally a binder, a highly water-active excipient, a disintegrant, and other pharmaceutical additives as appropriate. Dry granulation is a granulation method that enhances the cohesive force of raw materials without using liquid components during granulation. Dry granulation methods commonly used in the pharmaceutical field can be employed, such as the slug method and the roller compactor method. Conditions for roller compactors, such as roll pressure, roll rotation speed, and powder supply screw rotation speed, vary depending on the equipment. For example, for Freund Industrial's TFmini and TF-208, the roll pressure is preferably 2-15 MPa, the roll rotation speed is preferably 2-30 rpm, and the powder supply screw rotation speed is preferably 5-80 rpm, and these can be arbitrarily set depending on the size of the equipment used. The flakes obtained by the roller compactor are crushed and granulated to a predetermined particle size using a crusher or pulverizer such as an oscillator, co-mill, quick mill, or power mill. For ease of tableting, the particle size of the granulated material should be between 10 and 50 mesh, and it is preferable to have fewer fine particles, for example, fewer particles below 200 mesh.

[0016] In step 2, tablets are manufactured by mixing the granules obtained in step 1 with a disintegrant, optionally a binder, a lubricant, and other pharmaceutical additives as appropriate, and then compressing and molding them. Mixing can be carried out by commonly used mixing methods, such as mixing, kneading, and granulation. Mixing can be performed using, for example, a high-speed agitator, a universal kneader, a fluidized bed granulator, a V-type mixer, a tumbler mixer, a double-cone mixer, a ribbon mixer, a swirling screw mixer, or manual mixing in bags. Compression molding can be performed using rotary tablet presses or the like commonly used in pharmaceuticals. The molding pressure during tableting varies depending on the size of the tablet, but for example, for a φ8.5 mm tablet, it is 2 to 20 kN, preferably 5 to 15 kN, and for a φ6.5 mm tablet, it is 2 to 15 kN, preferably 4 to 12 kN. At this time, the set tablet hardness is 20 to 100 N, preferably 30 to 100 N, and more preferably 40 to 90 N. Furthermore, the tablets of the present invention can be compressed by an external sliding method. When using the external sliding method, the dry granules, disintegrant, and binder are mixed, and then compressed to obtain zinc acetate dihydrate tablets. The mixing method and compression molding conditions are the same as those for the method of producing the tablets described above.

[0017] The lubricant used in the present invention is not particularly limited, but examples include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, and is preferably magnesium stearate. The lubricant is added to produce the granules in step 1, but it can also be added to the mixture (final stage) during compression molding in step 2. The amount added to the granules in step 1 is 0.1 to 5% by mass, preferably 0.1 to 3% by mass, and more preferably 0.1 to 2% by mass, based on the total mass of the tablets. Furthermore, when added to the final powder, the amount added is 0.01 to 5% by mass, preferably 0.05 to 3% by mass, and more preferably 0.1 to 2% by mass, relative to the total mass of the tablet. Furthermore, the formulation of the final ingredient includes localizing the lubricant on the surface of the tablet by an external lubrication method.

[0018] The binders used in the present invention are not particularly limited, but examples include cellulose-based binders such as hydroxypropylcellulose, hypromellose phthalate, hydroxypropyl methylcellulose acetate succinate, crystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, carmellose sodium, ethylcellulose, methylcellulose, and hypromellose; starch-based binders such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, and pregelatinized starch; silicic acid-based binders such as magnesium aluminometasilicate, synthetic aluminum silicate, light anhydrous silicic acid, and calcium silicate; gum arabic, sodium alginate, dextrin, gelatin, pullulan, povidone, and carboxyvinyl polymer. Cellulose-based binders are preferred, and hydroxypropylcellulose is particularly preferred. Hydroxypropyl cellulose with a molecular weight of 20,000 to 200,000 can be used, but preferably 30,000 to 100,000, and more preferably 40,000. Hydroxypropylcellulose with an average particle size of 10 to 200 μm can be used, but preferably 10 to 120 μm, and more preferably 10 to 30 μm. The amount of binder added is 1 to 15% by mass, preferably 1 to 10% by mass, and more preferably 1.5 to 7% by mass, relative to the total mass of the tablet.

[0019] In the highly water-active excipient of the present invention, water activity refers to the ratio of the water vapor pressure in a sealed container to the vapor pressure of pure water at that temperature, and high water activity refers to a water activity value of 0.96 or higher and less than 1.0. The highly water-active excipient has low moisture content fluctuation and hygroscopicity, and suppresses the dehydration of zinc acetate dihydrate. Specific examples of highly water-active excipients include, for example, lactose, lactose monohydrate, mannitol, trehalose, maltose, erythritol, xylitol, etc., with lactose monohydrate and mannitol being preferred, and lactose monohydrate being more preferred. The particle size of the highly water-active excipient can be any size that is available for sale as a pharmaceutical product. For example, an average particle diameter of 1 to 300 μm is preferred, more preferably 2 to 200 μm, and even more preferably 5 to 100 μm. The amount of the highly water-active excipient added is 1 to 30% by mass, preferably 2 to 20% by mass, relative to the total mass of the tablet.

[0020] The disintegrants used in the present invention are not particularly limited, but for example, cellulosic disintegrants such as carmellose calcium, carmellose, croscarmellose, croscarmellose sodium, and low-substituted hydroxypropyl cellulose, starch-based disintegrants such as sodium starch glycolate, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and carboxymethyl starch sodium, and crospovidone can be used. Preferably, croscarmellose sodium, sodium starch glycolate, and crospovidone are used, and more preferably, crospovidone is used. The disintegrant is added to the mixture (final stage) during compression molding in step 2, but it can also be added during granulation production in step 1. The amount added to the final powder is 0.5 to 20% by mass, preferably 0.5 to 15% by mass, and more preferably 1 to 10% by mass, relative to the total mass of the tablet. When incorporated into granules, the amount incorporated into the granules is 1 to 25% by mass, preferably 2 to 20% by mass, and more preferably 3 to 15% by mass, relative to the total mass of the tablets.

[0021] Other pharmaceutical additives, besides the above-mentioned lubricants, binders, disintegrants, and highly water-active excipients, that can be used to manufacture the tablets of the present invention include, for example, excipients, colorants, sweeteners, and flavorings, which are specifically as follows.

[0022] Examples of excipients include sugars such as sucrose, lactose, and glucose; sugar alcohols such as erythritol, isomalt, lactitol, maltitol, sorbitol, and xylitol; crystalline cellulose; anhydrous calcium hydrogen phosphate; and magnesium aluminometasilicate.

[0023] Examples of coloring agents include Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Red No. 2, Food Red No. 3, Food Blue No. 1 aluminum lake, Food Blue No. 2 aluminum lake, Food Red No. 2 aluminum lake, iron(III) oxide (red), titanium dioxide, yellow iron(III) oxide, caramel, talc, etc.

[0024] Examples of sweeteners include one or more sweeteners selected from sugar, oligosaccharides, maltitol, erythritol, sorbitol, xylitol, aspartame, acesulfame potassium, sucralose, and stevia.

[0025] Examples of flavorings include those for apple, orange, grapefruit, strawberry, peach, lemon, and yogurt.

[0026] Because zinc acetate dihydrate has a distinctive bitter and astringent taste, the tablets of the present invention are preferably film-coated tablets from the viewpoint of ease of administration. The film coating can be made using film coating agents, plasticizers, fluidizers, dyes, and solvents for dissolving / suspending them, which are also used in conventional pharmaceuticals.

[0027] Here, the film coating agent is not particularly limited, but examples include cellulosic film coating agents such as carmellose, carmellose sodium, carmellose calcium, hydroxypropylcellulose, hypromellose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, and carboxymethylcellulose, as well as acacia powder, gelatin pullulan, dextrin, carboxymethyl starch sodium, sodium alginate, polyvinylpyrrolidone, and polyvinyl alcohol. Cellulosic film coating agents are preferred, and hypromellose is more preferred.

[0028] The plasticizer is not particularly limited, but examples include polyethylene glycol (e.g., polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, etc.), triethyl citrate, glycerin, castor oil, propylene glycol hydrogenated castor oil, polysorbate 80, macrogol, lauromacrogol, triacetin, etc., with triacetin being preferred.

[0029] The lubricant for film coating is not particularly limited, but examples include talc, hydrated silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, and magnesium stearate, with talc being preferred.

[0030] Examples of dyes for film coating include those listed above as colorants, with titanium dioxide being preferred.

[0031] Examples of solvents for dissolving / suspending film coating agents include alcohols such as methanol, ethanol, and isopropyl alcohol, acetone, toluene, hexane, methyl ethyl ketone, and water, or mixtures thereof. Ethanol and water are preferred, and water is more preferred.

[0032] Film coating can be performed using equipment typically used for aqueous or non-aqueous coatings of tablets, such as a pan-coating system.

[0033] In the film-coated tablets, there are no clear limitations on the amount of film coating, but for example, a 250 mg / tablet uncoated tablet is preferably coated with 2 to 20 mg / tablet, more preferably with 4 to 12 mg / tablet, and a 125 mg / tablet uncoated tablet is preferably coated with 1 to 10 mg / tablet, more preferably with 2 to 8 mg / tablet.

[0034] Film-coated tablets can be manufactured, for example, according to the method disclosed in Japanese Patent Application Publication No. 2020-169132. This method involves dissolving and dispersing a suspension of film coating agents, plasticizers, lubricants, light-shielding agents, colorants, etc., in a solvent such as water or ethanol, spraying the suspension into a coating pan containing uncoated tablets while maintaining a constant air supply temperature of 50°C or lower (to suppress the formation of anhydrous zinc acetate), and then blowing warm air onto the tablet surface to remove the solvent and dry it, thereby uniformly adhering the film coating portion to the surface of the uncoated tablet. After drying as necessary, a film coating layer can be formed.

[0035] The zinc acetate-derived impurity content in the zinc acetate dihydrate tablets and film-coated tablets of the present invention can be determined by measuring XRD (CuKα radiation, λ=1.5406 Å). The main peak of zinc acetate dihydrate is around 2θ=12.5°, while impurities, such as anhydrous zinc acetate, have peaks around 11.8°, and other impurities have peaks around 6°. These peaks can be detected to confirm the presence of zinc acetate impurities. The quantitative determination of zinc acetate impurities can also be performed by quantitative analysis using the powder X-ray diffraction method of the 18th edition of the Japanese Pharmacopoeia. Alternatively, a simpler method is to add a certain amount of standard material, such as 0.10%, 0.5%, or 0.2%, and compare the peak heights to determine the content. The individual impurity content in the zinc acetate dihydrate tablets and film-coated tablets of the present invention is 0.50% or less, preferably 0.2% or less, and more preferably 0.1% or less.

[0036] The tablets and film-coated tablets containing zinc acetate dihydrate of the present invention, manufactured by the above manufacturing method, will have different tablet sizes depending on the content of zinc acetate dihydrate they contain. For example, 25 mg and 50 mg tablets of zinc acetate dihydrate will have a diameter of 5 to 12 mm and a thickness of 1 to 6 mm. The tablets exhibit excellent disintegration properties, with a disintegration time of, for example, 600 seconds or less, preferably 300 seconds or less, and more preferably 150 seconds or less. In the Japanese Pharmacopoeia dissolution test method using a pH 5 eluate solution, 85% or more of zinc acetate dihydrate dissolves 15 minutes after the start of the test. Furthermore, when the tablets are stored at 40°C for two weeks, there is no delay in disintegration or dissolution at the start of the test or after two weeks. The tablets exhibit stable formulation characteristics, such as tablet hardness and the absence of the formation of related substances like anhydrous zinc acetate. In addition, by being coated tablets, they have excellent palatability, as they do not produce the bitter taste derived from zinc acetate dihydrate. [Examples]

[0037] The present invention will be described in more detail below with reference to examples, comparative examples, and test examples, but the present invention is not limited thereto.

[0038] (Reference example 1) [Production of zinc acetate dihydrate] A zinc acetate solution was prepared by adding 97.7 g of zinc oxide and 158.5 g of glacial acetic acid to 811.9 g of water. 1500 g of acetone was added to this zinc acetate solution to obtain a suspension of zinc acetate dihydrate, which was then filtered and washed to obtain a wet powder of zinc acetate dihydrate. This wet powder was dried to obtain a white powder of zinc acetate dihydrate with an average particle size of 70 μm and a bulk density of 0.49 g / mL. Figure 1 shows an SEM image of the obtained zinc acetate dihydrate, and Figure 2 shows the XRD chart. From the SEM image, the particle shape was plate-like, with a long side of 30-150 μm, a short side of 30-90 μm, and a thickness of 2-10 μm. Furthermore, a peak of zinc acetate dihydrate was confirmed around 12.5° in the XRD chart. On the other hand, the peak around 11.7° derived from anhydrous zinc acetate was not confirmed.

[0039] (Example 1) [Tablet manufacturing using dry granulation method] 167.8 parts by mass of zinc acetate dihydrate, 16.2 parts by mass of lactose hydrate, 20.0 parts by mass of crospovidone, 5.0 parts by mass of hydroxyprocellulose, and 2.0 parts by mass of magnesium stearate were mixed in the proportions obtained in Reference Example 1, compacted with a roller compactor, and crushed with an oscillator (20 Mesh) to obtain granulated granules. 213.0 parts by mass of these granulated granules were mixed with 27.0 parts by mass of crystalline cellulose, 6.0 parts by mass of crospovidone, 5.0 parts by weight of hydroxypropylprocellulose, and 1.0 part by mass of magnesium stearate. Using a rotary tablet press at a rotation speed of 40 rpm, tablets with a diameter of 8.5 mm and a radius of R13.4 × 1.3 mm were compressed to a set hardness of 70 N, obtaining 250 mg tablets. A coating solution containing 5.5% hypromellose, 0.9% triacetin, 2.7% titanium dioxide, and 0.9% talc was sprayed onto the uncoated tablets in a coating apparatus at an intake air temperature of 45°C and an exhaust air temperature of 34-36°C to obtain 260 mg film-coated tablets. The tablet hardness was 69 N and the disintegration time was 50 seconds.

[0040] (Examples 2) to (Examples 4) Using rectangular plate-shaped zinc acetate dihydrate with the average particle size shown in Table 1, film-coated zinc acetate hydrate tablets were prepared in the same manner as in Example 1.

[0041] [Table 1]

[0042] (Comparative Example 1) [Manufactured by wet granulation] Film-coated tablets of zinc acetate dihydrate were manufactured according to the method of Example 3 in International Publication No. 2016 / 088816, with the exception that croscarmellose sodium was replaced with crospodone.

[0043] [Dissolution test] The eluate was set to pH 5, and a dissolution test was performed according to the dissolution test method of the Japanese Pharmacopoeia. The results are shown in Table 2. The zinc acetate dihydrate film-coated tablets of Example 1, which were produced using dry granulation, exhibited superior dissolution properties compared to the zinc acetate dihydrate film-coated tablets of Comparative Example 1, which were produced using wet granulation.

[0044] [Table 2]

[0045] (Comparative Example 2) [Tablet manufacturing using dry granulation method] Tablets were manufactured in the same manner as in Example 1, except that crospovidone was not added after dry granulation.

[0046] [Stability Testing] Tablets from Example 1 and Comparative Example 2 were packaged in PVC and then in pillow packaging, and stored at 40°C and 75% relative humidity for two weeks. Disintegration is shown in Table 3, and dissolution is shown in Figure 3. Disintegration tests were performed according to the Japanese Pharmacopoeia, and dissolution was tested using the method described for Comparative Example 1. The tablets of Example 1 showed good formulation characteristics, as there was no delay in disintegration time or dissolution. On the other hand, the tablets of Comparative Example 2 showed delays in both disintegration time and dissolution.

[0047] [Table 3]

[0048] (Example 5 and Comparative Example 3) Uncoated tablets of Example 1, without film coating, were prepared and designated as the uncoated tablets of Example 5. Uncoated tablets were prepared by mixing and compressing in the same proportions as in Example 1, except that lactose was replaced with corn starch and film coating was omitted, and designated as the uncoated tablets of Comparative Example 3. These uncoated tablets were kept at 50°C in an open environment for 24 hours. The XRD charts are shown in Figure 4. No formation of anhydrous zinc acetate was observed in the lactose hydrate composition of Example 5, indicating stable formulation characteristics. On the other hand, the formation of anhydrous zinc acetate was observed in the corn starch composition of Comparative Example 3.

[0049] [Table 4]

[0050] (Example 6) [Tablet manufacturing using dry granulation method] 167.8 parts by mass of zinc acetate dihydrate, 14.4 parts by mass of lactose hydrate, 24.0 parts by mass of crospovidone, 4.8 parts by mass of hydroxyprocellulose, and 2.0 parts by mass of magnesium stearate were mixed in the proportions obtained in Reference Example 1, compacted with a roller compactor, and crushed with an oscillator (20 Mesh) to obtain granulated granules. 213.0 parts by mass of these granulated granules were mixed with 27.0 parts by mass of crystalline cellulose, 5.0 parts by weight of hydroxypropylprocellulose, 4.0 parts by mass of crospovidone, and 1.0 part by mass of magnesium stearate. Using a rotary tablet press at a rotation speed of 40 rpm, tablets with a diameter of 8.5 mm and a radius of R13.4 × 1.3 mm were compressed to a set hardness of 60 N, obtaining 250 mg tablets. A coating solution containing 5.5% hypromellose, 0.9% triacetin, 2.7% titanium dioxide, and 0.9% talc was sprayed onto the uncoated tablets in a coating apparatus at an air supply temperature of 45°C and an exhaust temperature of 34-36°C to obtain 260 mg film-coated tablets. The tablet hardness was 73N and the disintegration time was 50 seconds.

[0051] (Comparative Example 4) [Dry granulation method / Tablet manufacturing using FC exhaust temperature of 45°C] The film coating was applied to the uncoated tablets by spraying under the conditions of an intake air temperature of 64-75°C and an exhaust air temperature of 45-48°C to obtain 260 mg film-coated tablets.

[0052] [Dissolution test] Dissolution tests were performed on the film-coated tablets of Example 6 in the same manner as described above. As a result, the dissolution values ​​after 5 minutes and 10 minutes were 91.3 and 97.0, respectively, demonstrating excellent dissolution properties.

[0053] [Stability Testing] Dissolution tests were performed on the film-coated tablets of Example 6 in the same manner as described above. As a result, the disintegration time at the start of the test was 66 seconds, while the disintegration time one month after the start of the test was 56 seconds. No delay in disintegration time or dissolution occurred, indicating that it is a good formulation.

[0054] [Impurity Confirmation Test] A test to confirm the generation of impurities was conducted on the film-coated tablets of Example 6 and Comparative Example 4. The tablets were crushed and sieved to remove the film coating according to the powder X-ray diffraction method of the 18th Japanese Pharmacopoeia, and the generation of impurities was confirmed by powder X-ray diffraction. As a result, no impurity peaks were observed in the film-coated tablets of Example 6, but impurity peaks were observed in the film-coated tablets of Comparative Example 4.

Claims

1. 1. A method for producing a tablet containing zinc acetate dihydrate, comprising: (Step 1) mixing zinc acetate dihydrate and a lubricant and dry granulating the mixture; and (Step 2) A method comprising a step of mixing the granules obtained in step 1 with a disintegrant, and then compressing and molding the mixture.

2. A method as described in claim 1, further comprising mixing a binder in (step 1).

3. The method described in claim 1, wherein a high water activity excipient is further mixed in (step 1).

4. The method according to claim 1, wherein in (step 1), a disintegrant is further mixed, and in (step 2), a lubricant is further mixed.

5. 4. The method according to claim 3, wherein the high water activity excipient is one or more of lactose, lactose hydrate, mannitol, trehalose and maltose.

6. The method according to any one of claims 1 to 5, further comprising a step of film-coating the tablets at an inlet air temperature of 50°C or less.

7. A tablet comprising zinc acetate dihydrate and a high water activity excipient.

8. 8. The tablet according to claim 7, wherein the high water activity excipient is one or more of lactose, lactose hydrate, mannitol, trehalose and maltose.

9. A granulation comprising zinc acetate dihydrate and a high water activity excipient.

10. The granules according to claim 9, further comprising a binder and a lubricant.

11. The granule according to claim 10, further comprising a disintegrant.

12. The granulated product according to claim 9, which is obtained by a dry granulation method.

13. A tablet containing the granules according to any one of claims 9 to 12.

14. 9. The tablet according to claim 7 or 8, which is a film-coated tablet.

15. A tablet containing zinc acetate dihydrate as the active ingredient with an impurity content of 0.5% or less.

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