JP2023038181A - zinc acetate tablets - Google Patents

Abstract

[Problem] To provide a zinc acetate dihydrate-containing tablet in which the loss of water of crystallization of zinc acetate dihydrate in the tablet is inhibited, and the tablet has excellent disintegration and dissolution properties, no delay in disintegration or dissolution occurs even after storage, and a suitable tablet hardness, and a method for producing the same. [Solution] A method for producing a zinc acetate dihydrate-containing tablet, comprising: (Step 1) a step of mixing zinc acetate dihydrate and a lubricant and dry granulating the mixture; and (Step 2) a step of mixing the granules obtained in Step 1 with a disintegrant, followed by compression molding. [Selected Drawing] None

Description

TECHNICAL FIELD The present invention relates to a method for producing tablets containing zinc acetate dihydrate and the tablets.

Zinc acetate dihydrate (C ₄ H ₆ O ₄ Zn.2H ₂ O) is used as a therapeutic agent for Wilson's disease (hepatic lenticular degeneration) by suppressing copper absorption through competitive inhibition with copper. It is marketed as a zinc preparation for hypozincemia in the form of capsules and tablets (Non-Patent Document 1).

As a technology related to tablets containing zinc acetate dihydrate, for example, Patent Document 1 discloses that after granulation by wet granulation, the granules are dried at a low temperature of less than 40°C to obtain the hydrate. It is disclosed that a zinc acetate hydrate tablet with a small dosage can be produced without the water of crystallization inside disappearing and transforming into an anhydride. However, this method requires temperature control, and low-temperature drying requires a long drying time.

Patent Document 2 discloses a tablet containing a medicinal ingredient containing zinc acetate dihydrate, crystalline cellulose, and 0.5% by mass or less of magnesium stearate, wherein the content of the medicinal ingredient is Disclosed is a drug-rich tablet that accounts for at least 60% or more of the mass, according to which even if the content of the active ingredient is high, it is difficult to mold, and the stability, disintegration and dissolution of the active ingredient during manufacturing are difficult. It is described that the problem that the balance with sexuality is impaired can be solved. However, there is still room for improvement in the stability of zinc acetate dihydrate, the dissolution properties of tablets, the uniformity of formulations, and the like.

In Patent Document 3, a zinc acetate dihydrate tablet obtained by directly compressing a mixture containing zinc acetate dihydrate having a particle size (d ₅₀ ) of 40 to 600 μm and an additive has a uniform content. It is disclosed that the reliability is ensured. Further, in Patent Document 4, zinc acetate dihydrate tablets obtained by mixing high-moisture content additives such as crystalline cellulose and corn starch, crospovidone and zinc acetate dihydrate and directly compressing them are It is disclosed that zinc acetate dihydrate has an effect of suppressing migration and suppressing discoloration. However, these do not disclose the hardness, disintegration and stability of zinc acetate dihydrate tablets.

WO2016/088816 Japanese Patent Application Laid-Open No. 2021-104941 JP 2022-86833 A JP 2022-86872 A

"Nobelzin (registered trademark) tablets 25 mg, Nobelzin (registered trademark) tablets 50 mg, Nobelzin (registered trademark) granules 5%" Pharmaceutical Interview Form, Revised June 2021 (revised 12th edition)

In view of this situation, the formation of impurities such as dehydration due to the disappearance of the water of crystallization of zinc acetate dihydrate in the tablet is suppressed, and the tablet has excellent disintegration and dissolution properties, and does not disintegrate or dissolve even after storage. A simple method for manufacturing tablets containing zinc acetate dihydrate that does not cause delay, has suitable tablet hardness, and does not require special temperature control is desired. Furthermore, a tablet masking the bitterness and acridness derived from zinc acetate dihydrate is desired at the same time.

As a result of intensive studies to solve the problem, the present inventors mixed zinc acetate dihydrate and a lubricant, dry granulated them, and mixed the resulting granules and disintegrant. After that, the tablet containing zinc acetate dihydrate obtained by the manufacturing method including the step of compression molding has excellent stability of zinc acetate dihydrate, excellent disintegration and dissolution, and appropriate tablet hardness. and that the tablet can be obtained by a simple manufacturing method. Furthermore, the inventors have found that by coating the tablets by a specific method, the taste can be masked and the production of impurities can be suppressed in the coating process, and the present invention has been completed.

That is, the present invention
[1] A method for producing a tablet containing zinc acetate dihydrate,
(Step 1) A step of mixing zinc acetate dihydrate and a lubricant, followed by dry granulation; A method comprising
[2] The present invention also relates to the method according to [1], wherein a binder is further mixed in (step 1) according to [1].
[3] The present invention also relates to the method according to [1] or [2], wherein in (Step 1) according to [1] or [2], a high water activity excipient is further mixed. .
[4] The present invention further comprises mixing a disintegrant in (step 1) described in [1] to [3] above, and further mixing a lubricant in (step 2), [1] to [3] It relates to the method described.
[5] The present invention also relates to the method according to [3] or [4] above, wherein the high water activity excipient is one or more of lactose, lactose hydrate, mannitol, trehalose and maltose. It is.
[6] The present invention also relates to the method according to the above [1] to [5], further comprising the step of film-coating the tablet at an air supply temperature of 50°C or less.
[7] The present invention also relates to a tablet containing zinc acetate dihydrate and a high water activity excipient.
[8] The present invention also relates to the tablet according to [7], wherein the high water activity excipient is one or more of lactose, lactose hydrate, mannitol, trehalose and maltose.
[9] The present invention also relates to granules containing zinc acetate dihydrate and a high water activity excipient.
[10] The present invention also relates to the granules according to the above [9], which further contain a binder and a lubricant.
[11] The present invention also relates to the granules according to the above [10], which further contain a disintegrant.
[12] The present invention also relates to the granules according to [9] to [11], which are obtained by a dry granulation method. .
[13] The present invention also relates to a tablet containing the granules described in [9] to [12] above.
[14] The present invention also relates to the tablet according to the above [7], [8] or [13], which is a film-coated tablet.
[15] The present invention also relates to a tablet containing zinc acetate dihydrate with an impurity content of 0.5% or less as an active ingredient.

According to the present invention, the formation of impurities such as dehydration due to the loss of water of crystallization of zinc acetate dihydrate in the tablet is suppressed, the tablet has excellent disintegration and dissolution properties, and disintegration and dissolution are delayed even after storage. To provide a simple method for producing a tablet containing zinc acetate dihydrate, which does not cause a crack, has suitable tablet hardness, and does not require special temperature control, and a tablet containing zinc acetate dihydrate. can be done. In addition, by coating the tablets by a specific method, the formation of impurities due to the coating process is suppressed, and the bitterness and acridity derived from zinc acetate dihydrate are masked, giving zinc acetate dihydrate an excellent feeling of ingestion. A tablet containing the substance can be provided.

4 is a SEM photograph of zinc acetate dihydrate of Reference Example 1. FIG. 4 is an XRD chart of zinc acetate dihydrate of Reference Example 1. FIG. Elution test of Example 1 and Comparative Example 1. XRD charts of Example 5 and Comparative Example 3. XRD charts (2θ: 3 to 9°) of Comparative Example 3 of Example 6 and Comparative Example 4. XRD charts of Example 6 and Comparative Example 4 (2θ: 3 to 15°).

The present invention will be described in detail below.
The zinc acetate dihydrate used in the present invention is commercially available such as for pharmaceuticals and foods, and is used. For example, it is obtained by reacting acetic acid and zinc oxide, or zinc oxide and acetic acid It can be obtained by dissolving it and adding a poor solvent such as acetone to this solution to precipitate a solid.
Although the particle shape and size of the zinc acetate dihydrate are not particularly limited, the particle shape may be granular, plate-like, or rectangular plate-like. Among them, the rectangular plate shape is preferable because of its good tabletability, and as the particle size, for example, those having an average particle size of 2 to 300 μm, preferably 5 to 200 μm, more preferably 20 to 180 μm can be used. . Also, the thickness thereof is 0.5 to 40 μm, preferably 1 to 30 μm, more preferably 1 to 20 μm.
Plate-like particles of zinc acetate dihydrate having an aspect ratio of 1.5 to 20, preferably 2 to 15 can be used.
Further, zinc acetate dihydrate having a specific volume of 0.5 to 5 cm ³ /g, preferably 1 to 3 cm ³ /g can be used.
The average particle size means the median size (D ₅₀ : particle size corresponding to 50% of the cumulative distribution curve), and is calculated based on the volume.
The average particle size can be measured using known methods and measuring instruments, such as laser light scattering particle size distribution measurement and dynamic light scattering particle size distribution measurement.

The content of zinc acetate dihydrate is 40-90% by mass, preferably 55-80% by mass, more preferably 60-75% by mass, relative to the total mass of the tablet.

In step 1, the granules are dry-processed by mixing zinc acetate dihydrate, lubricants, optionally binders, high water activity excipients, disintegrants and other pharmaceutical additives. obtained by granulation.
Dry granulation is a granulation method in which the cohesive force of raw materials is increased without using a liquid component during granulation. As a dry granulation method, a dry granulation method commonly used in the field of pharmaceuticals can be used, for example, a slug method, a roller compactor method, and the like. Roller compactor conditions: Roll pressure, roll rotation speed, powder feeding screw rotation speed, etc. vary depending on the device. For example, TFmini and TF-208 manufactured by Freund Corporation preferably have a roll pressure of 2 to 15 MPa, a roll rotation speed of 2 to 30 rpm, and a powder feeding screw rotation speed of 5 to 80 rpm, which are arbitrary depending on the size of the equipment used. can be set to
The flakes obtained by the roller compactor are pulverized and sized to a predetermined particle size by a pulverizer or crusher such as an oscillator, combill, quick mill, or power mill. The particle size of the granules is preferably 10 to 50 mesh for ease of tableting, and the smaller the fine powder, the smaller, for example, 200 mesh or less.

In step 2, the granulated product obtained in step 1 is mixed with a disintegrant, optionally a binder, a lubricant and other pharmaceutical additives, and then compression molded to produce a tablet. .
Mixing can be performed by a generally used mixing method such as mixing, kneading, granulation, and the like. For mixing, for example, high-speed stirring mixer, universal kneader, fluidized bed granulator, V-type mixer, tumbler mixer, double cone mixer, ribbon type mixer, orbiting screw type mixer, manual mixing with bag etc. can be used.
For compression molding, a rotary tableting machine or the like that is commonly used for pharmaceuticals can be used, and the molding pressure at the time of tableting varies depending on the size of the tablet, but is, for example, 2 to 20 kN for tablets of φ8.5 mm. It is preferably 5 to 15 kN, and 2 to 15 kN, preferably 4 to 12 kN for tablets of φ6.5 mm. At this time, the set tablet hardness is 20-100N, preferably 30-100N, more preferably 40-90N.
Moreover, the tablet of the present invention can be compression-molded by an external lubrication method. When the external lubrication method is used, the dry granules, disintegrant, binder and the like are mixed and then compression-molded to obtain uncoated tablets of zinc acetate dihydrate. Compression molding conditions such as a mixing method and compression molding are the same as those of the uncoated tablet manufacturing method.

The lubricant used in the present invention is not particularly limited, but examples thereof include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate and the like, preferably magnesium stearate.
The lubricant is blended to produce the granules in step 1, but it can also be blended in the mixture (end) during compression molding in step 2. The amount to be incorporated in the granules in step 1 is 0.1 to 5% by mass, preferably 0.1 to 3% by mass, more preferably 0.1 to 2% by mass, relative to the total mass of the tablet. be.
In addition, when blended in the latter powder, the blending amount is 0.01 to 5% by mass, preferably 0.05 to 3% by mass, more preferably 0.1 to 2% by mass, relative to the total mass of the tablet. is.
In addition, blending into the powder includes localization of the lubricant on the surface of the uncoated tablet by an external lubrication method.

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

In the high water activity excipient of the present invention, the water activity means the ratio of the water vapor pressure in the closed container and the vapor pressure of pure water at that temperature, and the high water activity means a water activity value of 0.96 or more. , less than 1.0. High water activity excipients increase or decrease water content and have low hygroscopicity to inhibit dehydration of zinc acetate dihydrate.
Specific examples of excipients with high water activity include lactose, lactose hydrate, mannitol, trehalose, maltose, erythritol, xylitol and the like, preferably lactose hydrate and mannitol, More preferably, lactose hydrate can be mentioned. As for the particle size of the high water activity excipient, any size can be used as long as it is the size sold as a pharmaceutical product. Those having a diameter of up to 300 μm can be used, more preferably 2 to 200 μm, further preferably 5 to 100 μm.
The amount of the excipient with high water activity is 1-30% by weight, preferably 2-20% by weight, based on the total weight of the tablet.

The disintegrant used in the present invention is not particularly limited, but for example carmellose calcium, carmellose, croscarmellose, croscarmellose sodium, cellulose-based disintegrants such as low-substituted hydroxypropyl cellulose, sodium starch glycolate, Corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, starch-based disintegrants such as carboxymethyl starch sodium, crospovidone, etc. can be used, and preferably croscarmellose sodium and starch. Examples include sodium glycolate and crospovidone, and more preferably crospovidone.
The disintegrant is blended in the mixture (pulverized powder) during compression molding in step 2, but can also be blended in step 1 for producing granules.
The amount to be incorporated in the latter powder is 0.5 to 20% by mass, preferably 0.5 to 15% by mass, more preferably 1 to 10% by mass, based on the total mass of the tablet.
When blended in the granules, the blending amount in the granules is 1 to 25% by mass, preferably 2 to 20% by mass, more preferably 3 to 15% by mass, relative to the total mass of the tablet. be.

Pharmaceutical additives other than the above lubricants, binders, disintegrants and high water activity excipients that can be used to produce the tablet of the present invention include, for example, excipients, coloring agents , sweeteners and flavoring agents, and specific examples are as follows.

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, magnesium aluminometasilicate and the like. are mentioned.

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, and Food Red No. 2. Examples include aluminum lake, iron sesquioxide (red), titanium oxide, yellow iron sesquioxide, caramel, and talc.

Sweeteners include, for example, one or more sweeteners selected from sugar, oligosaccharides, maltitol, erythritol, sorbitol, xylitol, aspartame, acesulfame potassium, sucralose, and stevia.

Flavors include, for example, apple, orange, grapefruit, strawberry, peach, lemon, yoghurt and other flavored flavors.

Since zinc acetate dihydrate has a peculiar bitterness and acridity, the tablet of the present invention is preferably a film-coated tablet from the viewpoint of feeling of ingestion. For film coating, film coating agents, plasticizers, fluidizing agents, pigments, and solvents for dissolving/suspending these, which are also used in ordinary pharmaceuticals, can be used.

Here, the film coating agent is not particularly limited, but for example, carmellose, carmellose sodium, carmellose calcium, hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, carboxymethyl cellulose and other cellulose-based film coating agents, Gum arabic powder, gelatin pullulan, dextrin, sodium carboxymethyl starch, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, etc., preferably cellulose-based film coating agents, more preferably hypromellose.

Examples of plasticizers include, but are not limited to, polyethylene glycol (e.g., polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, etc.), triethyl citrate, glycerin, castor oil, poloxyethylene hydrogenated castor oil, polysorbate 80, Macrogol, lauromacrogol, triacetin, etc., preferably triacetin.

Lubricants for film coating include, but are not limited to, talc, hydrated silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, Stearic acid, calcium stearate, magnesium stearate and the like, preferably talc.

As the colorant for film coating, those described as the above colorant can be mentioned, and titanium oxide is preferred.

Solvents for dissolving/suspending film coating agents include, for example, alcohols such as methanol, ethanol, and isopropyl alcohol, acetone, toluene, hexane, methyl ethyl ketone and water, or mixed solvents thereof. is preferred, and water is more preferred.

Film coating can be carried out with an apparatus generally used for aqueous or non-aqueous coating of tablets, such as a pan coating type coating apparatus.

In the film-coated tablet, the coating amount of the film-coated portion is not clearly limited. and more preferably 1 to 10 mg/tablet, more preferably 2 to 8 mg/tablet, on uncoated tablets weighing 125 mg/tablet.

Film-coated tablets can be produced, for example, according to the method disclosed in JP-A-2020-169132.・The dispersed suspension is sprayed into the coating pan containing the uncoated tablets while maintaining a constant supply air temperature of 50 ° C or less (to suppress the formation of zinc acetate anhydrate), and the tablet surface is The film coating layer can be formed by uniformly attaching the film coating portion to the surface of the uncoated tablet by blowing hot air to remove the solvent from the tablet surface and then drying as necessary.

The zinc acetate-derived impurity content in the zinc acetate dihydrate tablet and film-coated tablet of the present invention can be determined by measuring XRD (CuKα ray (λ = 1.5406 Å). Zinc acetate dihydrate The main peak of the product is around 2θ = 12.5°, impurities such as zinc acetate anhydride have peaks around 11.8°, and other impurities have peaks around 6°. In addition, quantification of zinc acetate impurities can be measured by quantitative analysis of the powder X-ray Amendment method of the Japanese Pharmacopoeia 18th Edition. The content can be confirmed by adding 0.10%, 0.5%, 0.2%, etc. and comparing the peak heights.The zinc acetate dihydrate tablet and film coating of the present invention. The content of individual impurities in the tablet is 0.50% or less, preferably 0.2% or less, more preferably 0.1% or less.

The tablets and film-coated tablets containing zinc acetate dihydrate of the present invention produced by the production method described above have different tablet sizes depending on the content of zinc acetate dihydrate to be blended. In the case of a 25 mg tablet and a 50 mg tablet, the tablet size is 5 to 12 mm in diameter and 1 to 6 mm in thickness.
The tablet has excellent disintegration properties, and the disintegration time is, for example, 600 seconds or less, preferably 300 seconds or less, more preferably 150 seconds or less. According to the dissolution test method of the Japanese Pharmacopoeia in which the dissolution solution is pH 5, 85% or more of zinc acetate dihydrate is eluted 15 minutes after the start of the test, and the tablet is stored at 40 ° C. for 2 weeks. There is no delay in disintegration and dissolution at the start of the test and after 2 weeks, and no tablet hardness or zinc acetate anhydrate, which is a related substance, is produced. In addition, by coating the tablet, it does not have a bitter taste or the like derived from zinc acetate dihydrate, and thus has an excellent feeling of ingestion.

EXAMPLES The present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples below, but the present invention is not limited to these.

(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. 1,500 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 wet powder of zinc acetate dihydrate. This wet powder was dried to obtain a white powder of zinc acetate dihydrate having an average particle size of 70 μm and a bulk density of 0.49 g/mL. A SEM photograph of the resulting zinc acetate dihydrate is shown in FIG. 1, and an XRD chart is shown in FIG. According to the SEM photograph, the shape was plate-like particles having a long side of 30 to 150 μm, a short side of 30 to 90 μm, and a thickness of 2 to 10 μm. Moreover, a peak of zinc acetate dihydrate was confirmed at around 12.5° from the XRD chart. On the other hand, no peak around 11.7° derived from zinc acetate anhydrate was observed.

(Example 1)
[Tablet production by dry granulation method]
167.8 parts by weight of zinc acetate dihydrate obtained in Reference Example 1, 16.2 parts by weight of lactose hydrate, 20.0 parts by weight of crospovidone, 5.0 parts by weight of hydroxyprocellulose and magnesium stearate2. The mixture was mixed at a ratio of 0 parts by mass, compacted with a roller compactor, and pulverized with an oscillator (20 mesh) to obtain granules. 213.0 parts by weight of the granulated granules, 27.0 parts by weight of crystalline cellulose, 6.0 parts by weight of crospovidone, 5.0 parts by weight of hydroxypropyl procellulose and 1.0 parts by weight of magnesium stearate were mixed at a ratio of 1.0 parts by weight and rotary Using a type tableting machine, the number of rotations was 40 rpm, and tableting was performed with a punch having a tablet diameter of 8.5 mm and an R of 13.4 x 1.3 mm so as to have a set hardness of 70 N to obtain uncoated tablets weighing 250 mg each.
A coating liquid containing 5.5% hypromellose, 0.9% triacetin, 2.7% titanium dioxide and 0.9% talc was applied to the uncoated tablet in a coating apparatus at an air supply temperature of 45°C and an exhaust temperature of 34 to 36°C. to give film-coated tablets weighing 260 mg each. The tablet hardness was 69N and the disintegration time was 50 seconds.

(Example 2) to (Example 4)
Film-coated tablets of zinc acetate hydrate were prepared in the same manner as in Example 1 using rectangular zinc acetate dihydrate having an average particle size shown in Table 1.

(Comparative example 1)
[Production by wet granulation]
A film-coated tablet of zinc acetate dihydrate was produced according to the method of Example 3 of WO 2016/088816 pamphlet, except that croscarmellose sodium was changed to crospodone.

[Elution test]
A dissolution test was carried out according to the dissolution test method of the Japanese Pharmacopoeia with the dissolution solution having a pH of 5. Table 2 shows the results.
The zinc acetate dihydrate film-coated tablet of Example 1 subjected to dry granulation was superior in dissolution property to the zinc acetate dihydrate film-coated tablet of Comparative Example 1 subjected to wet granulation.

(Comparative example 2)
[Tablet production by dry granulation method]
Tablets were manufactured as in Example 1, except that no crospovidone was added after dry granulation.

[Stability test]
The tablets of Example 1 and Comparative Example 2 were wrapped in PVC, pillow-wrapped, and stored at 40° C. and 75% relative humidity for 2 weeks. Table 3 shows the disintegration properties, and Fig. 3 shows the dissolution properties. The disintegration test was conducted according to the Japanese Pharmacopoeia, and the dissolution property was measured by the method described in Comparative Example 1.
The tablet of Example 1 exhibited good formulation characteristics, as no delay in disintegration time occurred and no delay in dissolution occurred. On the other hand, the tablets of Comparative Example 2 were confirmed to have delayed disintegration time and dissolution properties.

(Example 5 and Comparative Example 3)
The uncoated tablet of Example 1 without film coating was prepared and used as the uncoated tablet of Example 5. Uncoated tablets were prepared by mixing and tableting in the same ratio as in Example 1, except that corn starch was used instead of lactose and no film coating was used. These uncoated tablets were kept open at 50°C for one day and night. Its XRD chart is shown in FIG. In the lactose hydrate composition of Example 5, formation of anhydrous zinc acetate was not confirmed, indicating stable formulation properties. On the other hand, it was confirmed that the corn starch of Comparative Example 3 produced anhydrous zinc acetate.

(Example 6)
[Tablet production by dry granulation method]
167.8 parts by mass of zinc acetate dihydrate obtained in Reference Example 1, 14.4 parts by mass of lactose hydrate, 24.0 parts by mass of crospovidone, 4.8 parts by mass of hydroxyprocellulose and magnesium stearate2. The mixture was mixed at a ratio of 0 parts by mass, compacted with a roller compactor, and pulverized with an oscillator (20 mesh) to obtain granules. 213.0 parts by weight of the granulated granules, 27.0 parts by weight of crystalline cellulose, 5.0 parts by weight of hydroxypropyl procellulose, 4.0 parts by weight of crospovidone and 1.0 parts by weight of magnesium stearate were mixed at a ratio of Using a type tableting machine, the number of revolutions was 40 rpm, and tableting was performed with a punch having a tablet diameter of 8.5 mm and an R of 13.4 x 1.3 mm so as to have a set hardness of 60 N to obtain uncoated tablets weighing 250 mg each.
A coating liquid containing 5.5% hypromellose, 0.9% triacetin, 2.7% titanium dioxide and 0.9% talc was applied to the uncoated tablet in a coating apparatus at an air supply temperature of 45°C and an exhaust temperature of 34 to 36°C. to give film-coated tablets weighing 260 mg each. The tablet hardness was 73N and the disintegration time was 50 seconds.

(Comparative Example 4)
[Tablet production by dry granulation method / FC exhaust temperature 45 ° C.]
The uncoated tablets were sprayed under film-coating conditions of an air supply temperature of 64 to 75°C and an exhaust temperature of 45 to 48°C to obtain film-coated tablets weighing 260 mg each.

[Elution test]
A dissolution test was performed on the film-coated tablet of Example 6 in the same manner as described above.
As a result, the dissolution properties after 5 minutes and 10 minutes were 91.3 and 97.0, indicating excellent dissolution.

[Stability test]
A dissolution test was performed on the film-coated tablet 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, whereas the disintegration time after one month from the start of the test was 56 seconds. It has been shown.

[Impurity confirmation test]
The film-coated tablets of Example 6 and Comparative Example 4 were tested for confirmation of impurity formation. The tablets were pulverized and sieved to remove the film coating according to the powder X-ray diffraction measurement method of the 18th Japanese Pharmacopoeia, and the generation of impurities was confirmed by powder X-ray diffraction.
As a result, no impurity peak was observed in the film-coated tablet of Example 6, but an impurity peak was observed in the film-coated tablet of Comparative Example 4.

Claims (15)

A method for producing a tablet containing zinc acetate dihydrate, comprising:
(Step 1) A step of mixing zinc acetate dihydrate and a lubricant, followed by dry granulation; method including. 2. The method of claim 1, further comprising mixing a binder in (step 1) of claim 1. 3. The method according to claim 1 or 2, wherein in (step 1) according to claim 1 or 2, a high water activity excipient is further mixed. The method according to any one of claims 1 to 3, wherein a disintegrant is further mixed in (step 1) according to claims 1 to 3, and a lubricant is further mixed in (step 2). 5. The method according to claim 3 or 4, wherein the high water activity excipient is one or more of lactose, lactose hydrate, mannitol, trehalose and maltose. The method according to any one of claims 1 to 5, further comprising a step of film-coating the tablet at an air supply temperature of 50°C or less. A tablet containing zinc acetate dihydrate and a high water activity excipient. 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. A granulation comprising zinc acetate dihydrate and a high water activity excipient. The granule according to claim 9, further comprising a binder and a lubricant. Granules according to claim 10, further comprising a disintegrant. Granules according to any one of claims 9 to 11, which are obtained by a dry granulation method. A tablet containing the granules according to claims 9-12. 14. The tablet according to claim 7, 8 or 13, which is a film-coated tablet. A tablet containing zinc acetate dihydrate with an impurity content of 0.5% or less as an active ingredient.

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