Tablets with improved stability

Abstract

To provide a tablet containing histidine zinc or its solvate as an active ingredient and possessing sufficient stability. [Solution] A tablet containing histidine zinc or its solvate as an active ingredient, further containing one or more components selected from sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose, but not containing D-mannitol (limited to those included as excipients), lactose, fructose, and glucose.

Description

Technical Field

[0001] The present invention relates to tablets containing histidine zinc or its solvate as an active ingredient and having improved stability. Specifically, the present invention relates to tablets containing histidine zinc or its solvate as an active ingredient, further containing one or more components selected from sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose, and not containing D-mannitol (limited to those contained as an excipient), lactose, fructose, and glucose. The present invention relates to tablets containing histidine zinc or its solvate as an active ingredient, further containing one or more components selected from sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose, and not containing D-mannitol (limited to those contained as an excipient), lactose, fructose, and glucose. The present invention relates to tablets containing histidine zinc or its solvate as an active ingredient, further containing one or more components selected from sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose, and not containing D-mannitol (limited to those contained as an excipient), lactose, fructose, and glucose. The present invention relates to tablets containing histidine zinc or its solvate as an active ingredient, further containing one or more components selected from sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose, and not containing D-mannitol (limited to those contained as an excipient), lactose, fructose, and glucose. The present invention relates to tablets containing histidine zinc or its solvate as an active ingredient, further containing one or more components selected from sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose, and not containing D-mannitol (limited to those contained as an excipient), lactose, fructose, and glucose. The present invention relates to tablets containing histidine zinc or its solvate as an active ingredient, further containing one or more components selected from sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose, and not containing D-mannitol (limited to those contained as an excipient), lactose, fructose, and glucose.

Background Art

[0002] Zinc plays various roles depending on various pathological conditions and states, and accordingly, it is easily consumed and easily falls into a deficiency state or hypozincemia. As a therapeutic agent for zinc deficiency, preparations containing histidine zinc are known, and in Germany and Korea, hard capsule preparations containing histidine zinc are commercially available. Further, for example, Non-Patent Document 1 discloses tablets of histidine zinc prepared using lactose as an excipient. Zinc plays various roles depending on various pathological conditions and states, and accordingly, it is easily consumed and easily falls into a deficiency state or hypozincemia. As a therapeutic agent for zinc deficiency, preparations containing histidine zinc are known, and in Germany and Korea, hard capsule preparations containing histidine zinc are commercially available. Further, for example, Non-Patent Document 1 discloses tablets of histidine zinc prepared using lactose as an excipient. Zinc plays various roles depending on various pathological conditions and states, and accordingly, it is easily consumed and easily falls into a deficiency state or hypozincemia. As a therapeutic agent for zinc deficiency, preparations containing histidine zinc are known, and in Germany and Korea, hard capsule preparations containing histidine zinc are commercially available. Further, for example, Non-Patent Document 1 discloses tablets of histidine zinc prepared using lactose as an excipient. Zinc plays various roles depending on various pathological conditions and states, and accordingly, it is easily consumed and easily falls into a deficiency state or hypozincemia. As a therapeutic agent for zinc deficiency, preparations containing histidine zinc are known, and in Germany and Korea, hard capsule preparations containing histidine zinc are commercially available. Further, for example, Non-Patent Document 1 discloses tablets of histidine zinc prepared using lactose as an excipient. Zinc plays various roles depending on various pathological conditions and states, and accordingly, it is easily consumed and easily falls into a deficiency state or hypozincemia. As a therapeutic agent for zinc deficiency, preparations containing histidine zinc are known, and in Germany and Korea, hard capsule preparations containing histidine zinc are commercially available. Further, for example, Non-Patent Document 1 discloses tablets of histidine zinc prepared using lactose as an excipient.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] The capsule preparations of histidine zinc that have been commercially available in Germany and the like so far are large size No. 0 capsules. We are currently using capsules. However, considering ease of administration, we would like to create a more compact tablet. It is preferable.

[0005] Non-patent document 1 describes a formulation containing histidine zinc as a tablet, which includes lactose as an excipient. It has been disclosed. However, when lactose is used as an excipient, a decrease in elution and discoloration occur during storage. This has been shown to occur by the present inventors.

[0006] The present invention contains histidine zinc or its solvate as an active ingredient and has sufficient stability The present invention aims to provide a tablet having histidine zinc, or the Tablets containing a solvate as the active ingredient, which suppresses reduced dissolution and / or discoloration of the formulation. The purpose is to provide.

[0007] The inventors of this invention have identified sucrose, sorbitol, xylitol, corn starch, and It contains one or more components selected from potato starch, and crystalline cellulose, and D-man Nitol (only as an excipient), lactose, fructose, and glucose We discovered that the above problems can be solved by using tablets that do not contain the substance, and thus completed the present invention. [Means for solving the problem]

[0008] In other words, the present invention provides the following [1] to

[13] .

[0009] [1] Contains histidine zinc or its solvate as an active ingredient, and further contains sucrose Selected from sorbitol, xylitol, corn starch, and potato starch. It contains one or more components, and crystalline cellulose, and D-mannitol (contained as an excipient). Tablets that do not contain lactose, fructose, or glucose (limited to those that are naturally produced). [2] The tablet described in [1] contains an active ingredient that is 40% to 75% by mass of the whole tablet. Agent. [3] Sucrose, sorbitol, xylitol, corn starch, and potato The content of one or more components selected from starch is 5% to 15% by mass of the entire tablet. [1] The tablets described above. [4] The crystalline cellulose content is 10% to 30% by mass of the whole tablet, [1] A tablet as described in any of [3]. [5] The active ingredient is either 25 mg or 50 mg of zinc, one of [1] to [3] The tablets described in the image. [6] A tablet according to any of [1] to [3], wherein the solvate is a hydrate. [7] Contains histidine zinc hydrate as an active ingredient, as described in any of [1] to [3]. Tablets. [8] The elution value at 15 minutes in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) was 80%. The tablets described in any of [1] to [3] above. [9] The elution value at 15 minutes in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) was 40 When stored under conditions of °C, 75% RH, and an open system, at the start of storage and after 3 months: All tablets are 80% or more, as described in [8].

[10] The elution value at 15 minutes in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) was 4 When stored at 0°C, 75% RH, and in an open system, the results are for up to 3 months from the start of storage. The tablets described in [9], wherein the reduction rate is less than 10%.

[11] Zinc histidine or its solvate, sucrose, sorbitol, xylitol One or more components selected from corn starch and potato starch, and crystalline sediment A granulation step of granulating rulose together with a binder, a drying step of drying the obtained granulated product, and a tablet obtained by a step of tabletting the dried granulated product, which contains histidine zinc or a solvate thereof as an active ingredient and has an elution 15-minute value of 80% or more in the paddle method (test solution: water, rotation speed: 75 rotations per minute) (however, limited to those containing D-mannitol as an excipient), and does not contain lactose, fructose, and glucose.

[12] The tablet according to

[11] , wherein the elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 rotations per minute) is 80% or more both at the start of storage and after 3 months when stored under the conditions of 4 0°C, 75% RH, open system.

[13] The tablet according to

[12] , wherein the decrease rate of the elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 rotations per minute) from the start of storage to 3 months later when stored under the conditions of 4 0°C, 75% RH, open system is less than 10%.

MODE FOR CARRYING OUT THE INVENTION

[0010] The tablet of the present invention contains histidine zinc or a solvate thereof as an active ingredient and does not contain D-m annitol (limited to those contained as an excipient), lactose, fructose, and glucose. The solvate may be any pharmaceutically acceptable solvate and is not particularly limited. Examples of such solvates include hydrates, organic solvent solvates, and mixed solvent solvates of water and organic solvents. A preferred solvate is a hydrate. The number of water molecules in the hydrate is not particularly limited, and examples of the hydrate include 1 to 7 hydrates. A preferred hydrate is a dihydrate. In the present specification, the "active ingredient" is a substance that exhibits pharmacological activity as "zinc" in the body. Histidine zinc, or its solvate. In this specification, "eluting properties" and "solubility" are used. "Dissolution Value" and "Dissolution Rate" indicate the dissolution of zinc from the tablet, the dissolution value, and the dissolution rate, respectively. vinegar.

[0011] In one embodiment, the tablets of the present invention contain histidine zinc hydrate as an active ingredient. Histidine zinc hydrate (JAN) is histidine zinc dihydrate.

[0012] The amount of active ingredient contained in the tablet is the amount approved for use as a medicine (for example, 2 units of zinc). The amount can be appropriately selected to be 5 mg or 50 mg. The content of the active ingredient is, for example, For example, it can be 40% to 75% by mass of the entire tablet. Alternatively, the content of the active ingredient The amount is 40% by mass or more, 45% by mass or more, 47% by mass or more, or 50% by mass or more, 75% by mass or less, 70% by mass or less, 65% by mass or less, 60% by mass or less, 57% by mass or less, It can be 55% by mass or less, or 52% by mass or less.

[0013] In a preferred embodiment, the tablets of the present invention further contain sucrose, sorbitol, and xylitol. One or more components selected from tol, corn starch, and potato starch, and knot Contains crystalline cellulose.

[0014] Sucrose, sorbitol, xylitol, corn starch, and in the tablets The content of one or more components selected from potato starch is not particularly limited, but for example, tablets It can be 5% to 15% by mass of the total. Alternatively, sucrose or sorbitol can be used. One or more components selected from xylitol, corn starch, and potato starch. The content is 5% by mass or more, 6% by mass or more, 7% by mass or more, 8% by mass or more, or 9% by mass The above, and 15% by mass or less, 14% by mass or less, 13% by mass or less, 12% by mass or less, or It can be 11% by mass or less.

[0015] The crystalline cellulose content in the tablet is not particularly limited, but for example, 10% by mass of the total tablet. It can be ~30% by mass. Alternatively, the crystalline cellulose content can be 10% by mass or more. , 15% by mass or more, 20% by mass or more, 22% by mass or more, or 24% by mass or more, and 30 It can be less than or equal to mass%, less than or equal to 28% by mass, or less than or equal to 26% by mass.

[0016] In one embodiment, the content of histidine zinc hydrate in the tablets of the present invention is 40% by mass of the total tablet. It is %~60% by mass, and contains sucrose, sorbitol, xylitol, and corn starch. The content of one or more ingredients selected from corn and potato starch is 5% to 15% by mass of the entire tablet. The amount is expressed as a percentage, and the crystalline cellulose content is 20% to 30% by mass of the entire tablet.

[0017] In one embodiment, the content of histidine zinc hydrate in the tablets of the present invention is 45% by mass of the total tablet. It is %~55% by mass, and consists of sucrose, sorbitol, xylitol, and corn starch. The content of one or more ingredients selected from corn and potato starch is 8% to 12% by mass of the entire tablet. The amount is in percent, and the crystalline cellulose content is 22% to 28% by mass of the entire tablet.

[0018] The tablets of the present invention may be uncoated tablets or film-coated tablets. However, in the tablets described above... The content (mass %) of each component indicates the percentage of content assuming the tablet is uncoated.

[0019] The tablets of the present invention do not contain lactose, fructose, and glucose. In particular, the tablets of the present invention The preparation does not contain lactose, fructose, and glucose as excipients. The tablets contain, in particular, excipients. When lactose, fructose, and glucose are used as binders, a decrease in elution or change in properties occurs during storage. This is because the resulting discoloration would prevent the product from retaining the necessary properties for a pharmaceutical product.

[0020] In addition to the above-mentioned components, the tablets of the present invention further contain additives commonly used in pharmaceuticals. The agent may contain active ingredients other than "histidine zinc or its solvate." One or more types may be used. Examples of additives include excipients and disintegrants. Examples include lubricants, binders, coating agents, glossing agents, colorants, flavoring agents, sweeteners, and fragrances. Preferably, these are excipients, disintegrants, binders, and lubricants.

[0021] Excipients are not particularly limited, but examples include erythritol, maltitol, iso Sugar alcohols such as malt; amino acids such as glycine and alanine; light anhydrous silicic acid, synthetic Silicates such as aluminum silicate, magnesium aluminometasilicate, and calcium silicate Examples include talc and titanium dioxide.

[0022] In this invention, sucrose, sorbitol, xylitol, and corn starch are used. One or more components selected from corn starch and potato starch, and crystalline cellulose are used as excipients. These components can also be used as excipients, but their uses are not limited to excipients. This does not exclude cases where these components are used for purposes other than as excipients.

[0023] The disintegrant is not particularly limited, but examples include crospovidone, carmellose calci. Um, carmellose, croscarmellose, croscarmellose sodium, low-substitution hyaluronic acid Examples include hydroxypropylcellulose. Preferred disintegrants include low-substituted hydroxypropylcellulose. One example is cypropylcellulose.

[0024] Lubricants are not particularly limited, but examples include magnesium stearate, stearyl Examples include calcium phosphate, talc, and sodium stearyl fumarate. Preferred lubrication Magnesium stearate is one example of an agent.

[0025] The binder can be any conventionally known one and is not particularly limited, for example, povidone Hydroxypropylcellulose, hypromellose, hypromellose phthalate Hydroxypropyl methylcellulose acetate succinate, ethylcellulose, Examples include cellulose, sodium alginate, gelatin, and carboxyvinyl polymer. A preferred binder is hydroxypropylcellulose.

[0026] The coating agent is not particularly limited, but examples include water-soluble polymers and water-insoluble polymers. Examples include gastric-soluble polymers, enteric-coated polymers, titanium dioxide, polyethylene glycol, and talc. It can be done.

[0027] Examples of water-soluble polymers include natural polymers such as sodium alginate; and carboxymethylcellulose. Carmellose sodium, carmellose calcium, hydroxypropylcellulose , hypromellose, hydroxyethylcellulose, hydroxymethylcellulose, methyl Cellulose, carboxymethylcellulose and other cellulose derivatives; polyvinylpyrrolidone Examples include water-soluble vinyl derivatives such as polyvinyl alcohol.

[0028] Examples of water-insoluble polymers include ethylcellulose, vinyl acetate polymer, and amino acids. Calcium methacrylate copolymer, ethyl acrylate / methyl methacrylate copolymer Examples include spraying liquids.

[0029] Examples of gastric-soluble polymers include polyvinyl acetal diethylaminoacetate. Examples include aminoacetal compounds.

[0030] Examples of enteric-coated polymers include cellulose acetate propionate and hydroxypropyl polymers. Hypromellose methylcellulose acetate succinate, hypromellose phthalate, Droxymethylethylcellulose phthalate, carboxymethylethylcellulose, cell Examples include enteric-coated cellulose esters such as rose acetate phthalate.

[0031] Preferred coating agents include hydroxypropylcellulose and hypromellose. It can be done.

[0032] The glossing agent is not particularly limited, but examples include carnauba wax, hardened oil, and vinyl acetate. Resin, bleached beeswax, titanium dioxide, stearic acid, calcium stearate, stear Polyoxyl 40 phosphate, magnesium stearate, purified shellac, purified paraffin. Carnauba wax mixture, cetanol, talc, white shellac, paraffin, povidone Polyvinylpyrrolidone, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, beeswax, glyceryl monostearate Rosin and the like are examples.

[0033] Examples of coloring agents include food coloring, food lake coloring, ferric oxide, yellow ferric oxide, etc. These are some examples.

[0034] Examples of flavoring agents include citric acid, tartaric acid, malic acid, and ascorbic acid. ru.

[0035] Examples of sweeteners include aspartame, acesulfame potassium, saccharin, and Examples include sodium charin, dipotassium glycyrrhizinate, stevia, and thaumatin. ru.

[0036] Examples of fragrances include fennel oil, orange oil, chamomile oil, spearmint oil, and ke Ich oil, clove oil, peppermint oil, bergamot oil, eucalyptus oil, lavender oil, lemon oil Examples include rose oil, Roman chamomile oil, and menthol.

[0037] The tablets of the present invention dissolve in 15 minutes using the paddle method (test solution: water, rotation speed: 75 revolutions per minute). A value of 80% or higher is preferable. Furthermore, such a elution value at 15 minutes is suitable for storage without packaging. Conditions, for example, when stored under conditions of 40°C, 75%RH, and an open system, at the start of storage and It is more preferable that all values ​​exceed 80% after 3 months. Such characteristics are... The tablets of the invention are stable tablets that maintain the content of the active ingredient even after being stored for a predetermined period. This indicates that.

[0038] The tablets of the present invention dissolve in 15 minutes using the paddle method (test solution: water, rotation speed: 75 revolutions per minute). It is preferable that the rate of decrease in the value from the start of storage to 3 months later (dissolution decrease rate) is smaller. In particular, when stored under unpackaged conditions, such as 40°C, 75% RH, and in an open system... The elution rate at the start of storage and after 3 months in the combination is 80% or higher, and during this period A smaller decrease in dissolution rate is more preferable.

[0039] The dissolution rate refers to the rate of decrease in the 15-minute dissolution value from the start of storage to 3 months later. Dissolution at the start of storage, i.e., the dissolution value at 15 minutes at the start of storage, compared to the dissolution value at the start of storage and at 3 months. The decrease in elution is a percentage value that can be calculated using the following formula.

[0040] Dissolution reduction rate (%) = [(Dissolution at the start of storage) - (Dissolution after 3 months)] / (Start of storage) (Dissolution rate over time) × 100

[0041] A lower dissolution rate indicates superior stability. A dissolution rate of 15% or less indicates superior stability. It is preferable that it is full or less than 10%, and more preferably less than 8%, and 6 It is more preferable if the percentage is less than %.

[0042] The tablets of the present invention can be manufactured, for example, by the following method. Step 1: Active ingredient (e.g., histidine zinc hydrate), and sucrose, sorbitol, One or more components selected from xylitol, corn starch, and potato starch , a process of granulating a mixture of crystalline cellulose to obtain granules (granulation process), Step 2: A step to dry the obtained granules (drying step), and Step 3: The process of compressing the obtained granules into tablets to obtain uncoated tablets (tableting process).

[0043] Furthermore, if a coated tablet is to be manufactured, it is produced by a method including the following step 4 following step 3. It can be made. Step 4: The process of coating the tablets with a film and then drying them (coating).

[0044] These processes are usually carried out in the order of process 1 to process 3, or process 1 to process 4, and further Other processes may be included. Examples of other processes include granulation processes and mixing processes. It can be done.

[0045] Process 1: Granulation process Step 1 is carried out by a wet granulation method such as agitation granulation or fluid bed granulation, or by a dry granulation method. This can be done. When histidine zinc hydrate is used as the active ingredient, for example, his Zinc thidine hydrate, and sucrose, sorbitol, xylitol, corn starch A mixture of crystalline cellulose and one or more components selected from corn and potato starch is granulated in a granulator. After adding and mixing, water or a binder solution is added to the mixture by spraying or other means, and then mixed. Granules can be obtained. Following step 1, the obtained granules can be placed in a sizing machine to sizing them. The granulated material can then be dried using a dryer such as a fluidized bed dryer.

[0046] Process 2: Drying process Step 2 involves removing the solvent (e.g., water) added in the granulation step to create a material suitable for tableting in Step 3. This is a process for producing granular material. Step 2 uses a dryer, such as a fluidized bed dryer. This can be done. Specifically, the granules obtained in step 1 are put into a dryer, and the supply air temperature and Drying is carried out while controlling the drying loss by adjusting the exhaust temperature until the desired exhaust temperature is reached. If weight loss exceeds the control range, repeat the drying process until it falls within the control range. Here, if the active ingredient is histidine zinc hydrate, the supply air temperature is set to, for example, 60°C. By drying until the exhaust temperature reaches 32°C, the moisture content suitable for tableting and the raw materials are properly processed. A dried granule containing the water of hydration of histidine zinc hydrate can be obtained. Japanese liquor has the property of becoming dehydrated and dehydrated at high temperatures and low humidity, so excessive drying Drying (for example, when the product temperature exceeds 40°C for a certain period of time) reduces the moisture content suitable for tableting. It becomes difficult to maintain the quantity.

[0047] Process 3: Tableting process Step 3 is the process of compressing the granules obtained in the previous step into tablets to obtain uncoated tablets. Tableting is a compression process. This is done by mold, and additional additives may be mixed in at this time. The compression molding method is not particularly limited. For example, methods commonly used for forming tablets, such as rotary tablet presses and single-shot tablet presses. or equipment can be used. Also, the conditions during this compression molding are as long as a plain tablet can be obtained. In this process, tablets having a desired mass can be obtained. .

[0048] Step 4: Coating Step 4 is the process of coating the uncoated tablets with film and then drying them. The coating method is not particularly limited and is commonly used in the manufacture of film-coated tablets. A method can be adopted for film coating, for example, using a coating machine. The suspension of the coating agent and solvent is then wet-spray coated onto the uncoated tablets. This can be done by [method]. As a solvent, for example, water or ethanol, isopropan Alcohols such as ol can be used.

[0049] The drying process following film coating is a step to dry the solvent of the coating agent. Furthermore, it is not particularly limited as long as the loss of water of hydration in the active ingredient is suppressed, conventional A known method for drying coating agents in the manufacture of tablets can be employed.

[0050] The tablets obtained by coating are further treated with a glossing agent, etc., by a conventionally known method. It may be applied.

[0051] In one embodiment, the present invention relates to an active ingredient comprising histidine zinc or a solvate thereof , sucrose, sorbitol, xylitol, corn starch, and potato starch A granulation process in which one or more components selected from and crystalline cellulose are granulated together with a binder, The resulting granules are obtained through a drying process, and a tableting process of the dried granules. It contains histidine zinc or its solvate as an active ingredient, and is tested using the paddle method (test solution: water These are tablets in which the dissolution rate at 15 minutes (rotation speed: 75 revolutions per minute) is 80% or higher. In this embodiment, the elution value at 15 minutes in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) is For example, when stored under conditions of 40°C, 75%RH, and an open system, the measurement start time and storage time. It is preferable that all levels be 80% or higher after 3 months of storage. [Examples]

[0052] The present invention will be described below with reference to specific embodiments, but the present invention is not limited to these embodiments. These are not intended to be modified, and various changes and modifications therein may be made by those skilled in the art, as per the attached patent application. It may be carried out without departing from the scope or spirit of the present invention as defined in the scope of the request. It will be understood.

[0053] (Example 1) Preparation of test sample 1 Histidine zinc hydrate, sucrose, and crystalline cellulose are mixed using a stirring granulator. Hydroxypropyl cellulose and purified water are added and granulated by stirring, and then wet sizing is performed using a sizing machine. Then, drying was carried out using a fluidized bed dryer. Histidine zinc hydrate was over-dried. Because the water of crystals in the active ingredient may evaporate and change into an anhydrous substance, the drying endpoint is set to the drying of the granules. Weight loss was evaluated. In all lots, the dry weight loss value was a consistent value slightly higher than the theoretical moisture content. Furthermore, the water activity value is low, below 0.3, indicating that it has been thoroughly dried, We confirmed that no over-drying had occurred. Next, after sizing the obtained granulated and dried product, Place in a rotary mixer and add low-substituted hydroxypropyl cellulose and magnesium stearate. Um was added and mixed to form a powder for tableting, which was then compressed into tablets to obtain uncoated tablets (test sample 1). Each tablet contains 313.2 mg of total weight and 156.7 mg of histidine zinc hydrate. (25 mg as zinc), sucrose content is 33 mg, and crystalline cellulose content is 80 mg. there were.

[0054] (Examples 2-4) Manufacturing of test samples 2-4 Sorbitol instead of sucrose (test sample 2), xylitol (test sample 3) Except for using potato starch (test sample 4), the uncoated tablets were prepared in the same manner as in test sample 1. The total weight per tablet of the obtained test sample was 313.1 for test sample 2. Each test sample contained 311.0 mg, 310.5 mg, and The histidine zinc hydrate content in the test sample was 157 mg (25 mg as zinc), crystalline The lurose content was 80 mg. In addition, the sorbitol content in each test sample was 80 mg. Sample 2), xylitol (test sample 3), potato starch (test sample 4) The content was 33 mg in both cases.

[0055] (Comparative Example 1) Manufacturing of Test Sample 5 Except for using lactose monohydrate instead of sucrose, the test sample was the same as test sample 1 (uncoated tablets). Sample 5) was obtained. Test sample 4 had a total weight of 310 mg per uncoated tablet, containing histidine. The zinc hydrate content is 157 mg (25 mg as zinc), and the lactose hydrate content is 32.7 mg. The crystalline cellulose content was 80 mg.

[0056] (Comparative Example 2) Manufacturing of Test Sample 6 Dissolve hypromellose and hydroxypropyl cellulose in purified water, then add titanium dioxide. A coating solution was prepared by mixing the mixture with a dispersion obtained by dispersing the substance in purified water. (Same as Test Sample 5) Tablets manufactured in the manner described above (total weight per tablet is 314 mg, histidine zinc hydrate content is 157mg (25mg as zinc), lactose monohydrate content 35.2mg, crystalline cellulose content A film-coated tablet (test sample 6) was obtained using 81 mg of the substance.

[0057] (Comparative Examples 3 and 4) Manufacturing of Test Samples 7 and 8 Instead of sucrose, use fructose (test sample 7) or glucose (test sample 8). A plain tablet was obtained in the same manner as test sample 1, except that the following was used. The total weight per tablet is 313.1 mg for test sample 7 and per uncoated tablet for test sample 8. The total weight was 311.6 mg, and the histidine zinc hydrate content in each test sample was 15 The content was 7 mg (25 mg as zinc), and the crystalline cellulose content was 80 mg. Furthermore, each test... In the samples, fructose (test sample 7) and glucose (test sample 8) The content was 33 mg in both cases.

[0058] (Test Example 1) Dissolution (50 revolutions per minute): Test Sample 6 The test samples were stored in open glass bottles at 40°C and 75% RH, and the results were measured from the start of storage and 3 months later. The dissolution rate after one month was evaluated using the following method. Paddle method (solvent: water, test solution volume: 900 mL, rotation speed: 50 revolutions per minute) Therefore, the 15-minute value (elution rate (%)) at the start of storage and 3 months later was measured, and the elution rate was calculated using the following formula. The rate of decline was calculated.

[0059] Decreased percentage of active ingredient (zinc) dissolution = [(Dissolution rate at the start of storage) - (Dissolution rate after 3 months)] )] / (elution rate at the start of storage) × 100

[0060] The elution rate of test sample 6 (Comparative Example 2) at the start of storage was 88.8%, and after 3 months it was 75.4%. The percentage was 15.1%, and the dissolution reduction rate was 15.1%.

[0061] (Test Example 2) Dissolution (Rotation speed: 75 revolutions per minute): Test samples 1-4, 7, 8 The dissolution reduction rate was measured in the same manner as in Test Example 1, except that the rotation speed was set to 75 revolutions per minute.

[0062] The elution rate of test sample 1 (Example 1) at the start of storage and after 3 months was both over 90%. They were identical, and no decrease in elution was observed. The elution rate of test sample 2 (Example 2) at the start of storage was 94.1%, and after 3 months it was 91.5%. The percentage was 2.6%, and the dissolution reduction rate was 2.6%. The elution rate of test sample 3 (Example 3) at the start of storage was 96.0%, and after 3 months it was 91.0%. The percentage was 5.0%, and the dissolution reduction rate was 5.0%. The elution rate of test sample 4 (Example 4) at the start of storage and after 3 months was both over 90%. They were identical, and no decrease in elution was observed. The elution rate of test sample 7 (comparative example 3) at the start of storage was 94.3%, and after 3 months it was 37.7%. The percentage was 56.6%, and the dissolution reduction rate was 56.6%. The elution rate of test sample 8 (Comparative Example 4) at the start of storage was 91.1%, and after 3 months it was 18.6%. The percentage was 72.5%, and the dissolution reduction rate was 72.5%.

[0063] (Test example 3) Appearance: Test samples 5 and 6 The test samples were stored in open glass bottles at 40°C and 75% RH, and the results were measured from the start of storage and 3 months later. The appearance was visually evaluated one month later.

[0064] Test sample 5 (Comparative Example 1) was a white, uncoated tablet at the start of storage, but after 3 months it had thinned. It changed to a yellowish-brown color. Test sample 6 (Comparative Example 2) was a white film-coated tablet at the start of storage. However, after three months, it changed to a yellowish-brown color.

[0065] (Test example 4) Appearance: Test samples 1-4, 7, 8 Similar to Test Example 3, the appearance was visually evaluated at the start of storage and after 3 months. Test samples 1, 2, 3, and 4 (Examples 1, 2, 3, and 4) were white, uncoated tablets, and storage commenced. There was no change in appearance after 24 hours and 3 months. Test samples 7 and 8 (comparative examples 3 and 4) were white, uncoated tablets at the start of storage, but after 3 months... Later, they changed to light brown and brown, respectively. [Industrial applicability]

[0066] The present invention provides a product containing histidine zinc or its solvate as an active ingredient, and is sufficiently safe It is possible to provide tablets with qualitative properties. Furthermore, the present invention makes it possible to provide histidine zinc, The solvate contains the active ingredient, and the decrease in dissolution and / or discoloration of the formulation is suppressed. This makes it possible to provide tablets that have been processed.

Claims

1. It contains histidine zinc or its solvate as an active ingredient, and further contains sucrose, so Selected from rubitol, xylitol, corn starch, and potato starch. The above ingredients, and crystalline cellulose, and D-mannitol (included as an excipient) Tablets that do not contain lactose, fructose, or glucose (limited to those containing the specified ingredients).

2. The tablet according to claim 1, wherein the content of the active ingredient is 40% to 75% by mass of the entire tablet.

3. Sucrose, sorbitol, xylitol, corn starch, and potato starch Claim that the content of one or more components selected from the above is 5% to 15% by mass of the total tablet. The tablets described in item 1.

4. Claims 1 to 3, wherein the crystalline cellulose content is 10% to 30% by mass of the entire tablet. The tablets listed in either of the above.

5. The active ingredient comprises 25 mg or 50 mg of zinc, as described in any one of claims 1 to 3. Tablets.

6. A tablet according to any one of claims 1 to 3, wherein the solvate is a hydrate.

7. A tablet according to any one of claims 1 to 3, comprising histidine zinc hydrate as an active ingredient.

8. In the paddle method (test solution: water, rotation speed: 75 revolutions per minute), the elution value at 15 minutes is 80% or higher. A tablet according to any one of claims 1 to 3.

9. In the paddle method (test solution: water, rotation speed: 75 revolutions per minute), the elution value at 15 minutes was 40°C, 7 When stored under 5% RH and open system conditions, both at the start of storage and after 3 months, The tablet according to claim 8, wherein the content is 80% or more.

10. Elution value at 15 minutes in the paddle method (test solution: water, rotation speed: 75 revolutions per minute), 40°C, 7 The rate of decrease from the start of storage to 3 months after storage when stored under 5% RH and open system conditions. The tablet according to claim 9, wherein the content is less than 10%.

11. Histidine zinc or its solvate, sucrose, sorbitol, xylitol, and One or more components selected from sorghum starch and potato starch, and crystalline cellulose. A granulation process in which the material is granulated together with a binder, a drying process in which the obtained granules are dried, and drying The histidine zinc or its solvate obtained by the process of compressing the granulated material into tablets is effectively processed. It contains as a fraction, and the elution value at 15 minutes in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) Tablets containing 80% or more of the active ingredient (however, this is limited to those containing D-mannitol as an excipient) (It does not contain lactose, fructose, or glucose.)

12. In the paddle method (test solution: water, rotation speed: 75 revolutions per minute), the elution value at 15 minutes was 40°C, 7 When stored under 5% RH and open system conditions, both at the start of storage and after 3 months, The tablet according to claim 11, wherein the content is 80% or more.

13. Elution value at 15 minutes in the paddle method (test solution: water, rotation speed: 75 revolutions per minute), 40°C, 7 The rate of decrease from the start of storage to 3 months after storage when stored under 5% RH and open system conditions. The tablet according to claim 12, wherein the content is less than 10%.