Therapeutic agent for hypozincemia

Abstract

To provide a therapeutic agent for hypozincemia, especially a therapeutic agent for hypozincemia with a specific dosage and administration.SOLUTION: A therapeutic agent for hypozincemia comprises zinc histidine, or a pharmaceutically acceptable salt or solvate thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a therapeutic agent for hypozincemia containing histidine zinc or a pharmaceutically acceptable salt or solvate thereof. Specifically, the present invention relates to a therapeutic agent for hypozincemia containing histidine zinc or a pharmaceutically acceptable salt or solvate thereof, which can effectively treat hypozincemia according to specific usage and dosage. Furthermore, the present invention relates to a therapeutic agent for hypozincemia which is a tablet containing histidine zinc or a pharmaceutically acceptable salt or solvate thereof and has improved stability.

Background Art

[0002] Zinc plays various roles depending on various pathological conditions and states, and accordingly is easily consumed and easily falls into a deficient state. Pathological conditions caused by zinc deficiency include sexual immaturity and growth retardation, oligospermia, amenorrhea, anemia, reduced immune function, liver damage, night blindness, hair loss and dermatitis, anorexia, taste disorder / abnormality, olfactory disorder, chronic diarrhea, delayed wound healing, mental / behavioral abnormalities, and various other symptoms. For such zinc deficiency states, in foreign countries, various zinc preparations such as zinc sulfate and zinc gluconate have been approved and sold as "zinc deficiency", "treatment of zinc deficiency states that cannot be solved by diet", "acrodermatitis enteropathica", "zinc supplementation", etc., although there are differences depending on the country. As domestic zinc preparations, Novergin (registered trademark, Novartis Pharma Co., Ltd., hereinafter the same) tablets 25 mg, Novergin tablets 50 mg, and Novergin granules 5% have obtained the efficacy and effect for hypozincemia and are on sale. All of these are preparations containing zinc acetate.

[0003] ​​​​​​​​​​​​​​。Regarding the usage of the noveldine preparation, in consideration of gastrointestinal side effects such as nausea and vomiting, which are the main side effects, the dose per administration is reduced and it is administered twice or three times a day.

[0004] As a preparation containing histidine zinc as an active ingredient, Zinkamin - Falk 15mg hard capsules are known. This preparation is for the treatment of clinically confirmed zinc deficiency ( when improvement is not seen by dietary therapy), and adults take one capsule corresponding to 15 mg of zinc one tablet per day, one hour before a meal (Non - Patent Document 1). However, a therapeutic agent for hypozincemia containing histidine zinc as an active ingredient, and a therapeutic agent for hypozincemia with a specific usage and dosage that can effectively treat hypozincemia were not known.

Prior Art Documents

Non - Patent Documents

[0005]

Non - Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] The present invention aims to provide a therapeutic agent for hypozincemia containing histidine zinc, or a pharmaceutically acceptable salt or solvate thereof, for adults and children over 30 kg in body weight. Furthermore, the present invention aims to provide a therapeutic agent for hypozincemia containing histidine zinc, or a pharmaceutically acceptable salt or solvate thereof, which can effectively treat hypozincemia in adults and children over 30 kg in body weight according to specific usage and dosage. Also The present invention provides a therapeutic agent for hypozincemia that takes into account the effect on patient medication adherence. This is the object.

[0007] In order to solve such problems, the present inventors diligently studied the dose of histidine zinc that is effective in the treatment of hypozincemia. As a result, they first discovered that the conventional usage and dosage used for the treatment of zinc deficiency states are not sufficient to obtain a sufficient effect on hypozincemia. Furthermore, through clinical trials, they found the usage and dosage for having an effect on hypozincemia and completed the present invention. Moreover, the present invention aims to provide a therapeutic agent for hypozincemia that contains histidine zinc, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient and has sufficient stability. The present invention also aims to provide a therapeutic agent for hypozincemia that contains histidine zinc, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient and is a tablet in which the decrease in elution or / and discoloration of the preparation is suppressed. The present inventors found that the above problems can be solved by a tablet containing one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn cide starch, and potato starch, and crystalline cellulose and not containing lactose, fructose, and glucose, and completed the present invention.

[0008] That is, the present invention provides the following [1] to

[19] .

[0009]

[0010]

[0011]

Means for Solving the Problems

[0010] That is, the present invention provides the following [1] to

[19] .

[0011] [1] Containing histidine zinc, or a pharmaceutically acceptable salt or solvate thereof, and 1 per day ​A therapeutic agent for treating hypozincemia, which is orally administered after meals. [2] The therapeutic agent according to [1], wherein the starting dose is 50 to 100 mg of zinc per time. [3] Based on the serum zinc concentration and the patient's condition, the dose is appropriately increased or decreased within a range not exceeding 150 mg of zinc per day for the therapeutic agent according to [1]. [4] For adults and children weighing 30 kg or more, the starting dose is 50 to 100 mg of zinc per time for the therapeutic agent according to [1]. [5] The dose is set to maintain the serum zinc concentration at 80 μg / dL or more and less than 200 μg / dL for the therapeutic agent according to [1]. [6] The therapeutic agent according to any one of [1] to [5], wherein histidine zinc, or a pharmaceutically acceptable salt or solvate thereof is histidine zinc dihydrate (JAN: histidine zinc hydrate). [7] Further, it contains one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose, and is a tablet that does not contain lactose, fructose, and glucose for the therapeutic agent according to [1]. [8] The therapeutic agent according to [7], wherein histidine zinc, or a pharmaceutically acceptable salt or solvate thereof is 40% to 75% by mass of the total tablet. [9] The content of one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch is 5% to 15% by mass of the total tablet for the therapeutic agent according to [7].

[10] The content of crystalline cellulose is 10% to 30% by mass of the total tablet for the therapeutic agent according to [7].

[11] Histidine zinc, or a pharmaceutically acceptable salt or solvate thereof as zinc The therapeutic agent according to [7], which contains 25 mg or 50 mg thereof. The therapeutic agent according to any one of [7] to

[11] , wherein the solvate is a hydrate.

[13] The therapeutic agent according to any one of [7] to

[11] , wherein histidine zinc or a pharmaceutically acceptable salt or solvate thereof is histidine zinc hydrate. The therapeutic agent according to any one of [7] to

[11] , wherein the elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) is 80% or more.

[14] The therapeutic agent according to any one of [7] to

[11] , wherein the elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) is 80% or more at both the start of storage and after 3 months when stored under the conditions of 40 °C, 75% RH, and open system. The therapeutic agent according to

[14] , wherein the elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) has a degradation rate of less than 10% from the start of storage to 3 months later when stored under the conditions of 40 °C, 75% RH, and open system.

[15] The therapeutic agent according to

[15] , wherein histidine zinc or a pharmaceutically acceptable salt or solvate thereof, and one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose are granulated together with a binder, the obtained granules are dried, and the dried granules are tabletted. The therapeutic agent according to [7], which contains histidine zinc or a pharmaceutically acceptable salt or 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 revolutions per minute) (however, it does not contain lactose, fructose, and glucose). The therapeutic agent according to

[14] , wherein the elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) has a degradation rate of less than 10% from the start of storage to 3 months later when stored under the conditions of 40 °C, 75% RH, and open system.

[16] The therapeutic agent according to

[15] , wherein histidine zinc or a pharmaceutically acceptable salt or solvate thereof, and one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose are granulated together with a binder, the obtained granules are dried, and the dried granules are tabletted. The therapeutic agent according to

[15] , wherein the elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) has a degradation rate of less than 10% from the start of storage to 3 months later when stored under the conditions of 40 °C, 75% RH, and open system. The therapeutic agent according to

[15] , wherein the elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) has a degradation rate of less than 10% from the start of storage to 3 months later when stored under the conditions of 40 °C, 75% RH, and open system.

[17] The therapeutic agent according to

[15] , wherein histidine zinc or a pharmaceutically acceptable salt or solvate thereof, and one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose are granulated together with a binder, the obtained granules are dried, and the dried granules are tabletted. The therapeutic agent according to

[15] , wherein histidine zinc or a pharmaceutically acceptable salt or solvate thereof, and one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose are granulated together with a binder, the obtained granules are dried, and the dried granules are tabletted. The therapeutic agent according to

[15] , wherein histidine zinc or a pharmaceutically acceptable salt or solvate thereof, and one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose are granulated together with a binder, the obtained granules are dried, and the dried granules are tabletted. The therapeutic agent according to

[15] , wherein histidine zinc or a pharmaceutically acceptable salt or solvate thereof, and one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose are granulated together with a binder, the obtained granules are dried, and the dried granules are tabletted. The therapeutic agent according to

[15] , wherein histidine zinc or a pharmaceutically acceptable salt or solvate thereof, and one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose are granulated together with a binder, the obtained granules are dried, and the dried granules are tabletted. The therapeutic agent according to

[15] , which contains histidine zinc or a pharmaceutically acceptable salt or 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 revolutions per minute) (however, it does not contain lactose, fructose, and glucose). The therapeutic agent according to [7], which contains histidine zinc or a pharmaceutically acceptable salt or 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 revolutions per minute) (however, it does not contain lactose, fructose, and glucose). The therapeutic agent according to [7], which contains histidine zinc or a pharmaceutically acceptable salt or 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 revolutions per minute) (however, it does not contain lactose, fructose, and glucose). ).

[18] The elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 rotations per minute) is 40 When stored under the conditions of 75% RH and open system at 40 In both cases at the start of storage and after 3 months, it is 80% or more, the therapeutic agent described in

[17] .

[19] The elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 rotations per minute) of 40 When stored under the conditions of 75% RH and open system at 40 The decrease rate from the start of storage to 3 months later is less than 10%, the therapeutic agent described in

[18] .

MODE FOR CARRYING OUT THE INVENTION

[0012] The therapeutic agent for hypozincemia of the present invention contains histidine zinc, or a pharmaceutically acceptable salt or solvate thereof. Examples of histidine zinc, or a pharmaceutically acceptable salt or solvate thereof include, for example, histidine zinc dihydrate (JAN: histidine zinc hydrate). Histidine zinc, or a pharmaceutically acceptable salt or solvate thereof, is a compound in which histidine and zinc ions are complexed.

[0013] In the present specification, "treatment of hypozincemia" means maintaining the serum zinc concentration of a hypozincemia patient within the normal range (also referred to as the "target serum zinc concentration"). According to the "Diagnostic Guidelines for Zinc Deficiency 2018" edited by the Japanese Society for Clinical Nutrition, a person with a serum zinc concentration of less than 60 μg / dL is defined as having zinc deficiency, and a person with a concentration of 60 or more and less than 80 μg / dL is defined as having potential zinc deficiency. For example, the "target serum zinc concentration" in the present invention has a lower limit of 80 μg / dL, and the upper limit value can be less than 250 μg / dL, more preferably less than 200 μg / dL, which is considered to have a low possibility of causing adverse effects on the body. Also, the "diagnosis of zinc deficiency" edited by the Japanese Society for Clinical Nutrition. According to this, a person with a serum zinc concentration of less than 60 μg / dL is defined as having zinc deficiency, and a person with a concentration of 60 or more and less than 80 μg / dL is defined as having potential zinc deficiency. For example, the "target serum zinc concentration" in the present invention has a lower limit of 80 μg / dL, and the upper limit value can be less than 250 μg / dL, more preferably less than 200 μg / dL, which is considered to have a low possibility of causing adverse effects on the body. Also, the "diagnosis of zinc deficiency" It may be 80 - 130 μg / dL, which is recommended in the "Treatment Guidelines 2018". That is, the "target serum zinc concentration" in the present invention is, for example, (1) 80 μg / dL or more, (2 ) 80 μg / dL or more and less than 250 μg / dL, (3) 80 μg / dL or more and less than 200 μg / dL, or (4) 80 μg / dL or more and 130 μg / dL or less.

[0014] The therapeutic agent of the present invention can be administered orally once a day after a meal. Administering once a day makes it easier to maintain medication as prescribed and can improve medication adherence. In particular in the treatment of hypozincemia, since it is necessary to maintain the target serum zinc concentration, it is important that the patient can take the medicine as prescribed without forgetting to drink or making dosage errors.

[0015] The serum zinc concentration can be measured by a known method. For example, in addition to the method by atomic absorption spectrometry , for example, the absorbance of the serum of the subject colored with a reagent such as Accuriad (registered trademark) Zinc (manufacturer: Nobel Pharma Co., Ltd.) is measured using an analyzer such as Accuriad (registered trademark) (manufacturer: Nobel Pharma Co., Ltd.) to obtain the result.

[0016] The starting dose of the therapeutic agent of the present invention for adults and children weighing 30 kg or more can be set at 50 - 100 mg of zinc per dose. The starting dose can be adjusted according to the patient's serum zinc concentration. For example, when the serum zinc concentration is 50 μg / dL or more, it can be 50 mg / day of zinc. The administration period at the starting dose in this case can be, for example, 4 weeks . Also, when the serum zinc concentration is less than 50 μg / dL, 1 mg of zinc per dose... ​It can be 00 mg / day. The administration period at the starting dose in this case can be, for example, 4 weeks and can be done.

[0017] The therapeutic agent of the present invention can be appropriately increased or decreased within the range not exceeding 150 mg of zinc per day according to the serum zinc concentration and the patient's condition. Specifically, for example, in adults and children weighing 30 kg or more, as zinc, 50 - 100 mg can be used as the starting dose and administered orally once after each meal of the day. Alternatively, it can be administered orally at a dose that maintains the serum zinc concentration at the target serum zinc concentration (for example, 80 μg / dL or more and less than 200 μg / dL). More specifically, for example, while continuing the administration, the serum zinc concentration is measured every certain period (for example, 4 weeks), and if it is less than the target serum zinc concentration (for example, less than 80 μg / dL), the dose is increased by 50 mg / day of zinc, and administration can be continued for a further certain period (for example, 4 weeks). Also, if the serum zinc concentration is equal to or higher than the target serum zinc concentration (for example, 200 μg / dL or more ), the dose is decreased by 25 mg / day of zinc, and administration can be continued for a further certain period (for example, 4 weeks ). In addition, when the serum copper concentration is below a certain value (for example, 30 μg / dL), from the viewpoint of preventing copper deficiency, the dose is decreased by 25 mg / day of zinc, and conditions such as stopping the administration when the value is lower (for example, less than 10 μg / dL) can also be used. ) can be done. ) .

[0018] The maximum daily dose of the therapeutic agent of the present invention can be 150 mg of zinc.

[0019] The dosage form when the therapeutic agent of the present invention is administered orally is not particularly limited. For example, tablets such as plain tablets and film-coated tablets, orally disintegrating tablets, capsules, powders, granules, or dry syrups, etc.​​​​ It can be made into a syrup or a liquid preparation such as a syrup. By using such a dosage form, it becomes easier to take once a day while adjusting the dosage as needed. The preparations of these dosage forms can be produced by a conventionally known method. Once a day, and it becomes easier to take while adjusting the dosage as needed. The preparations of these dosage forms can be produced by a conventionally known method. They can be manufactured by a conventionally known method.

[0020] In addition to histidine zinc or a pharmaceutically acceptable salt or solvate thereof, the therapeutic agent of the present invention may appropriately contain additives and pharmaceutically active ingredients generally used in pharmaceuticals. These can be used alone or in combination of two or more. In addition to histidine zinc or a pharmaceutically acceptable salt or solvate thereof, the therapeutic agent of the present invention may appropriately contain additives and pharmaceutically active ingredients generally used in pharmaceuticals. These can be used alone or in combination of two or more. They can be used alone or in combination of two or more.

[0021] When tablets are adopted as the dosage form, as additives, for example, one or more selected from excipients, disintegrants, lubricants, binders, coating agents, polishing agents, coloring agents, flavoring agents, sweetening agents, and fragrances may be included. Examples of excipients include sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, and isomalt; amino acids such as glycine and alanine; silicic acids such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate, and calcium silicate; celluloses such as crystalline cellulose and powdered cellulose; talc; titanium oxide, etc. Preferred excipients include crystalline cellulose, mannitol, etc. These excipients can be used singly or in combination of two or more. When tablets are adopted as the dosage form, as additives, for example, one or more selected from excipients, disintegrants, lubricants, binders, coating agents, polishing agents, coloring agents, flavoring agents, sweetening agents, and fragrances may be included. Examples of excipients include sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, and isomalt; amino acids such as glycine and alanine; silicic acids such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate, and calcium silicate; celluloses such as crystalline cellulose and powdered cellulose; talc; titanium oxide, etc. Preferred excipients include crystalline cellulose, mannitol, etc. These excipients can be used singly or in combination of two or more. When tablets are adopted as the dosage form, as additives, for example, one or more selected from excipients, disintegrants, lubricants, binders, coating agents, polishing agents, coloring agents, flavoring agents, sweetening agents, and fragrances may be included. Examples of excipients include sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, and isomalt; amino acids such as glycine and alanine; silicic acids such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate, and calcium silicate; celluloses such as crystalline cellulose and powdered cellulose; talc; titanium oxide, etc. Preferred excipients include crystalline cellulose, mannitol, etc. These excipients can be used singly or in combination of two or more. When tablets are adopted as the dosage form, as additives, for example, one or more selected from excipients, disintegrants, lubricants, binders, coating agents, polishing agents, coloring agents, flavoring agents, sweetening agents, and fragrances may be included. Examples of excipients include sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, and isomalt; amino acids such as glycine and alanine; silicic acids such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate, and calcium silicate; celluloses such as crystalline cellulose and powdered cellulose; talc; titanium oxide, etc. Preferred excipients include crystalline cellulose, mannitol, etc. These excipients can be used singly or in combination of two or more. When tablets are adopted as the dosage form, as additives, for example, one or more selected from excipients, disintegrants, lubricants, binders, coating agents, polishing agents, coloring agents, flavoring agents, sweetening agents, and fragrances may be included. Examples of excipients include sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, and isomalt; amino acids such as glycine and alanine; silicic acids such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate, and calcium silicate; celluloses such as crystalline cellulose and powdered cellulose; talc; titanium oxide, etc. Preferred excipients include crystalline cellulose, mannitol, etc. These excipients can be used singly or in combination of two or more. When tablets are adopted as the dosage form, as additives, for example, one or more selected from excipients, disintegrants, lubricants, binders, coating agents, polishing agents, coloring agents, flavoring agents, sweetening agents, and fragrances may be included. Examples of excipients include sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, and isomalt; amino acids such as glycine and alanine; silicic acids such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate, and calcium silicate; celluloses such as crystalline cellulose and powdered cellulose; talc; titanium oxide, etc. Preferred excipients include crystalline cellulose, mannitol, etc. These excipients can be used singly or in combination of two or more. When tablets are adopted as the dosage form, as additives, for example, one or more selected from excipients, disintegrants, lubricants, binders, coating agents, polishing agents, coloring agents, flavoring agents, sweetening agents, and fragrances may be included. Examples of excipients include sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, and isomalt; amino acids such as glycine and alanine; silicic acids such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate, and calcium silicate; celluloses such as crystalline cellulose and powdered cellulose; talc; titanium oxide, etc. Preferred excipients include crystalline cellulose, mannitol, etc. These excipients can be used singly or in combination of two or more. When tablets are adopted as the dosage form, as additives, for example, one or more selected from excipients, disintegrants, lubricants, binders, coating agents, polishing agents, coloring agents, flavoring agents, sweetening agents, and fragrances may be included. Examples of excipients include sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, and isomalt; amino acids such as glycine and alanine; silicic acids such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate, and calcium silicate; celluloses such as crystalline cellulose and powdered cellulose; talc; titanium oxide, etc. Preferred excipients include crystalline cellulose, mannitol, etc. These excipients can be used singly or in combination of two or more. These excipients can be used singly or in combination of two or more.

[0022] When the therapeutic agent of the present invention is made into tablets (histidine zinc tablets), the content of the excipient is not particularly limited, but can be about 5 to 80% by mass, or about 10 to 50% by mass based on the total mass of the histidine zinc tablets. When the therapeutic agent of the present invention is made into tablets (histidine zinc tablets), the content of the excipient is not particularly limited, but can be about 5 to 80% by mass, or about 10 to 50% by mass based on the total mass of the histidine zinc tablets. When the therapeutic agent of the present invention is made into tablets (histidine zinc tablets), the content of the excipient is not particularly limited, but can be about 5 to 80% by mass, or about 10 to 50% by mass based on the total mass of the histidine zinc tablets.

[0023] The disintegrant is not particularly limited, and examples thereof include crospovidone, sodium carboxymethylcellulose, carboxymethylcellulose, croscarmellose, croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, etc. Preferred disintegrants include crospovidone, carboxymethylcellulose, croscarmellose, low-substituted hydroxypropylcellulose, etc. These disintegrants can be used alone or in combination of two or more. The content of the disintegrant in the histidine zinc tablets is not particularly limited, but can be about 1 to 50% by mass, or about 5 to 20% by mass, based on the total mass of the histidine zinc tablets. The lubricant is not particularly limited, and examples thereof include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, etc. Preferred lubricants include talc, magnesium stearate, etc. These lubricants can be used alone or in combination of two or more. The content of the lubricant in the histidine zinc tablets is not particularly limited, but can be about 0.1 to 20% by mass, or about 0.5 to 10% by mass, based on the total mass of the histidine zinc tablets. The binder is not particularly limited, and examples thereof include povidone, hydroxypropylcellulose, hypromellose phthalate, hydroxypropylmethylcellulose acetate succinate, magnesium aluminometasilicate, synthetic aluminum silicate, light anhydrous aluminum silicate, etc.

[0024] The content of the binder in the histidine zinc tablets is not particularly limited, but can be appropriately selected according to the type of the binder and the production process of the histidine zinc tablets.

[0025] For example, when povidone is used as the binder, the content in the histidine zinc tablets can be about 1 to 20% by mass, or about 5 to 15% by mass, based on the total mass of the histidine zinc tablets.

[0026]

[0027] Silicic acid, calcium silicate, sodium carboxymethylcellulose, ethyl cellulose, methyl cellulose, hypromellose, gum arabic, sodium alginate, dextrin, crystalline cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose, gelatin, pullulan, carboxyvinyl polymer, and the like. These binders can be used alone or in combination of two or more.

[0028] In one embodiment, the histidine zinc tablet contains 156.7 mg of histidine zinc hydrate (25 mg as zinc), or 313.4 mg of histidine zinc hydrate (50 mg as zinc).

[0029] In one embodiment, the histidine zinc tablet contains 156.7 mg of histidine zinc hydrate (25 mg as zinc), D-mannitol, crystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and magnesium stearate.

[0030] In one embodiment, the histidine zinc tablet contains 313.4 mg of histidine zinc hydrate (50 mg as zinc), D-mannitol, crystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and magnesium stearate.

[0031] In one embodiment, the histidine zinc tablet can be an uncoated tablet, a film-coated tablet, or a scored uncoated tablet or film-coated tablet.

[0032] In one embodiment, the histidine zinc tablet can be an approximately cylindrical uncoated tablet or film-coated tablet with a diameter of about 9.0 mm and a thickness of about 3.7 mm. Or the histidine zinc tablet can be ​​, in the form of a substantially elliptical shape with a major diameter of about 17.0 mm, a minor diameter of about 7.0 mm, and a thickness of about 5.7 mm, and can be a scored plain tablet or a film-coated tablet.

[0033] As one aspect, the weight of the histidine zinc tablet can be about 310 mg or about 620 mg.

[0034] When the therapeutic agent of the present invention is in the form of a capsule, 156.7 mg of histidine zinc hydrate (25 mg as zinc) or 313.4 mg of histidine zinc hydrate (50 mg as zinc), and a pharmaceutically acceptable excipient can be filled into a hard capsule.

[0035] As another aspect, the present invention is a tablet for oral administration once a day after a meal, which contains histidine zinc, or a pharmaceutically acceptable salt or solvate thereof, and further contains one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose, and does not contain lactose, fructose, and glucose.

[0036] Hereinafter, the other aspect will be described.

[0037] The tablet of the present invention contains histidine zinc, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. The solvate may be any pharmaceutically acceptable solvate and is not particularly limited. Such solvates include, for example, hydrates, organic solvates, and mixed solvates of water and organic solvents. Preferred solvates are hydrates. The number of water molecules in the hydrate is not particularly limited, and examples of hydrates include 1 to 7 hydrates. A preferred hydrate is a dihydrate. ​​​​​​

[0038] The active ingredient of the tablets of the present invention can be histidine zinc hydrate. Here, histi dine zinc hydrate (JAN) is histidine zinc dihydrate.

[0039] The amount of the active ingredient contained in the tablets can be appropriately selected so as to be an amount approved as a pharmaceutical product (for example, 2 5 mg or 50 mg as zinc). The content of the active ingredient can be, for example, 40% to 75% by mass of the whole tablet. Alternatively, the content of the active ingredient can be 40% by mass or more, 45% by mass or more, 47% by mass or more, or 50% by mass or more, and 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, 55% by mass or less, or 52% by mass or less.

[0040] In a preferred embodiment, the tablets of the present invention further contain one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose.

[0041] The content of one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch in the tablets is not particularly limited, but can be, for example, 5% to 15% by mass of the whole tablet. Alternatively, the content of one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch can be 5% by mass or more, 6% by mass or more, 7% by mass or more, 8% by mass, or 9% by mass or more, and 15% by mass or less, 14% by mass or less, 13% by mass or less, 12% by mass or less, or 11% by mass or less. ​​​​​​​​

[0042] The content of crystalline cellulose in the tablets is not particularly limited, but for example, it can be 10% by mass ~ 30% by mass of the whole tablet. Alternatively, the content of crystalline cellulose is 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 % by mass or less, 28% by mass or less, or 26% by mass or less.

[0043] The content of histidine zinc hydrate in the tablets of the present invention is 40% by mass to 60% by mass of the whole tablet , and the content of one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch , and potato starch is 5% by mass to 15% by mass of the whole tablet, and the content of crystalline cellulose can be 20% by mass to 30% by mass of the whole tablet . .

[0044] The content of histidine zinc hydrate in the tablets of the present invention is 45% by mass to 55% by mass of the whole tablet , and the content of one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch , and potato starch is 8% by mass to 12% by mass of the whole tablet, and the content of crystalline cellulose can be 22% by mass to 28% by mass of the whole tablet . .

[0045] The tablets of the present invention may be plain tablets or film-coated tablets. However, the content (mass%) of each component in the above-mentioned tablets indicates the ratio of the content assuming that the tablets are plain tablets.

[0046] The tablets of the present invention do not contain lactose, fructose, and glucose. In particular, the tablets of the present invention do not contain lactose, fructose, and glucose as excipients. In the tablets, especially as excipients When lactose, fructose, and glucose are used as excipients, a decrease in elution properties and color change occur during storage, making it impossible to maintain the required performance as a pharmaceutical product. This is because the required performance as a pharmaceutical product cannot be maintained.

[0047] In addition to the above-described components, the tablets of the present invention may further contain additives generally used in pharmaceuticals, active ingredients other than "histidine zinc, or a pharmaceutically acceptable salt or solvate thereof". These can be used singly or in combination of two or more. Examples of additives include, for example, excipients, disintegrants, lubricants, binders, coating agents, polishing agents, coloring agents, correcting agents, sweeteners, flavors, etc., and preferably excipients, disintegrants, binders, and lubricants.

[0048] The excipient is not particularly limited, and examples include sugar alcohols such as erythritol, maltitol, and isomalt; amino acids such as glycine and alanine; silicic acids such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, and calcium silicate; talc; titanium oxide, etc.

[0049] In the present invention, one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose can also be used as excipients, but the use of these components is not limited to excipients. That is, the present invention does not exclude the case where these components are used for purposes other than excipients.

[0050] The disintegrant is not particularly limited, and examples include crospovidone, sodium carboxymethylcellulose, carboxymethylcellulose, croscarmellose, croscarmellose sodium, low-substituted hydroxypropyl Examples include droxypropyl cellulose and the like. Preferred disintegrants include low-substitution hydroxy propyl cellulose.

[0051] The lubricant is not particularly limited. Examples include magnesium stearate, stearic calcium, talc, sodium stearyl fumarate, and the like. Preferred lubricants include magnesium stearate.

[0052] As the binder, conventionally known ones can be used and are not particularly limited. Examples include povidone, hydroxypropyl cellulose, hypromellose, hypromellose phthalate, hydroxypropyl methylcellulose acetate succinate, ethyl cellulose, methyl cellulose, sodium alginate, gelatin, carboxyvinyl polymer, and the like. Preferred binders include hydroxypropyl cellulose.

[0053] The coating agent is not particularly limited. Examples include water-soluble polymers, water-insoluble polymers, gastric-soluble polymers, enteric-soluble polymers, titanium oxide, polyethylene glycol, talc, and the like.

[0054] Examples of water-soluble polymers include natural polymers such as sodium alginate; cellulose derivatives such as carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, carboxymethyl cellulose; water-soluble vinyl derivatives such as polyvinyl pyrrolidone and polyvinyl alcohol.

[0055] Examples of water-insoluble polymers include ethyl cellulose, vinyl acetate polymer, aminoalkyl methacrylate copolymer, ethyl acrylate-methyl methacrylate copolymer dispersion, etc. Examples of aminoacetal compounds such as polyvinyl acetal diethylaminoacetate, etc. are included.

[0056] Examples of gastric-soluble polymers include aminoacetal compounds such as polyvinyl acetal diethylaminoacetate, etc. are included.

[0057] Examples of enteric polymers include enteric cellulose esters such as cellulose acetate propionate, hydroxypropylmethyl cellulose acetate succinate, hypromellose phthalate, hydroxymethylethyl cellulose phthalate, carboxymethylethyl cellulose, cellulose acetate phthalate, etc. are included. Examples of preferred coating agents include hydroxypropyl cellulose and hypromellose. are included.

[0058] Examples of brightening agents are not particularly limited, and include, for example, carnauba wax, hardened oil, vinyl acetate resin, beeswax, titanium oxide, stearic acid, calcium stearate, polyoxyl 40 stearate, magnesium stearate, purified shellac, purified paraffin-carnauba wax mixture wax, cetyl alcohol, talc, white shellac, paraffin, povidone (polyvinylpyrrolidone), polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, beeswax, glycerin monostearate, rosin, etc. are included.

[0059] Examples of brightening agents are not particularly limited, and include, for example, carnauba wax, hardened oil, vinyl acetate resin, beeswax, titanium oxide, stearic acid, calcium stearate, polyoxyl 40 stearate, magnesium stearate, purified shellac, purified paraffin-carnauba wax mixture wax, cetyl alcohol, talc, white shellac, paraffin, povidone (polyvinylpyrrolidone), polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, beeswax, glycerin monostearate, rosin, etc. are included. are included. are included. are included. are included. are included.

[0060] Examples of the coloring agent include food dyes, food lake dyes, iron sesquioxide, yellow iron sesquioxide, etc. and the like.

[0061] Examples of the flavoring agent include citric acid, tartaric acid, malic acid, ascorbic acid, etc. and the like.

[0062] Examples of the sweetening agent include aspartame, acesulfame potassium, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, etc. and the like.

[0063] Examples of the fragrance include star anise oil, orange oil, chamomile oil, spearmint oil, ginger oil, clove oil, perilla oil, bergamot oil, eucalyptus oil, lavender oil, lemon oil, rose oil, Roman chamomile oil, menthol, etc.

[0064] The tablets of the present invention preferably have an elution 15-minute value of 80% or more in the paddle method (test solution: water, rotation speed: 75 revolutions per minute). Further, it is more preferable that such an elution 15-minute value is 80% or more both at the start of storage and after 3 months when stored under storage conditions without packaging, for example, at 40°C, 75% RH, in an open system. Such characteristics indicate that the tablets of the present invention are tablets having stability in maintaining the content of the active ingredient even after storage for a predetermined period. and after 3 months.

[0065] The tablets of the present invention preferably have a smaller decrease rate (dissolution decrease rate) of the elution 15-minute value from the start of storage to 3 months later in the paddle method (test solution: water, rotation speed: 75 revolutions per minute). In particular, under storage conditions without packaging, for example, when stored at 40°C, 75% RH, in an open system, ​​​​The elution property at the start of storage and after 3 months in combination is 80% or more in both cases, and it is more preferable that the elution property reduction rate during this period is smaller.

[0066] The elution property reduction rate indicates the reduction rate of the 15 - minute elution value from the start of storage to 3 months later, and is a percentage value that can be calculated by the following formula as the reduction in elution property between the start of storage, that is, the 15 - minute elution value at the start of storage, and after 3 months. The elution property at the start of storage, that is, with respect to the 15 - minute elution value at the start of storage, It is a percentage value that can be calculated by the following formula as the reduction in elution property between the start of storage and after 3 months.

[0067] Elution property reduction rate (%) = [(Elution property at the start of storage) - (Elution property after 3 months)] / (Elution property at the start of storage) × 100

[0068] The lower the elution property reduction rate, the better the stability. The elution property reduction rate is preferably less than 15%, or more preferably less than 10%, still more preferably less than 8%, and even more preferably less than 6 %. % is more preferable.

[0069] The tablets of the present invention can be produced, for example, by the following method. Step 1: Granulating a mixture of an active ingredient (for example, histidine zinc hydrate), and one or more components selected from D - mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose to obtain a granulated product (granulation step), Step 2: Drying the obtained granulated product (drying step), and Step 3: Tableting the obtained granulated product to obtain a core tablet (tableting step). Step 2: Drying the obtained granulated product (drying step), and Step 3: Tableting the obtained granulated product to obtain a core tablet (tableting step).

[0070] Furthermore, when making coated tablets, it can be produced by a method including the following Step 4 following Step 3. Step 4: Film - coating the core tablet and then drying (coating). Step 4: Film - coating the core tablet and then drying (coating).

[0071] These steps are usually carried out in the order of Step 1 to Step 3, or Step 1 to Step 4, and may further include other steps. Examples of other steps include a sizing step, a mixing step, etc.

[0072] Step 1: Granulation step Step 1 can be carried out by, for example, a wet granulation method such as a stirring granulation method or a fluidized bed granulation method, or a dry granulation method. When using histidine zinc hydrate as the active ingredient, for example, a mixture of histidine zinc hydrate, and one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch and crystalline cellulose is put into a granulator and mixed, and then water or an aqueous binder solution is added to the mixture by spraying or the like, and the mixture is mixed to obtain granules. After that, the obtained granules can be put into a sizing machine for sizing. Further, the sized granules can be dried using a dryer such as a fluidized bed dryer. Subsequent to Step 1, the obtained granules can be put into a sizing machine for sizing. Further, the sized granules can be dried using a dryer such as a fluidized bed dryer.

[0073] Step 2: Drying step Step 2 is a step for producing granules suitable for tableting in Step 3 by removing the solvent (for example, water) added in the granulation step. Step 2 can be carried out using a dryer such as a fluidized bed dryer. Specifically, the granules obtained in Step 1 are put into a dryer, and drying is carried out until the desired exhaust temperature is reached while controlling the weight loss on drying by the inlet air temperature and the exhaust temperature. If the weight loss on drying exceeds the control range, drying is repeated until the control range is reached. Here, when the active ingredient is histidine zinc hydrate, by setting the inlet air temperature to, for example, 60 °C and drying until the exhaust temperature reaches 32 °C, the moisture content suitable for tableting and the histidine of the raw material ​​​​​​​​​​​It is possible to obtain a dry granule that retains the water of hydration of histidine zinc hydrate. Histidine zinc hydrate has the property of losing the water of hydration (crystal water) and becoming anhydrous at high temperatures and low humidities. Therefore, if it is dried excessively (for example, if the product temperature exceeds 40 °C and continues for a certain period of time or more), it becomes difficult to maintain the appropriate amount of moisture for tableting.

[0074] Step 3: Tableting step Step 3 is a step of tableting the granule obtained in the previous step to obtain a core tablet. Tableting is performed by a compression molding mold, and at this time, additives may be further mixed. The compression molding method is not particularly limited, and for example, methods and apparatuses generally used for molding tablets, such as rotary tablet presses and single-shot tablet presses, can be used. Also, the conditions for this compression molding are not particularly limited as long as a core tablet can be obtained. In this step, tablets having a desired mass can be obtained.

[0075] Step 4: Coating Step 4 is a step of film-coating the core tablet and then drying it. The method of film-coating is not particularly limited, and a method generally used in the production of film-coated tablets can be adopted. Film-coating can be performed, for example, by using a coating machine to wet-spray coat a suspension of a coating agent and a solvent onto the core tablet. As the solvent, for example, water or alcohols such as ethanol and isopropanol can be used.

[0076] The drying following the film-coating is a step for drying the solvent of the coating agent, and is not particularly limited as long as the loss of the water of hydration in the active ingredient is suppressed. Conventionally, The drying method of the coating agent in the production of known tablets can be adopted.

[0077] For the tablets obtained by coating, a brightening agent or the like may be further applied by a conventionally known method. It may be applied.

[0078] In one aspect, the present invention provides an active ingredient comprising histidine zinc, or a pharmaceutically acceptable salt or solvate thereof, D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose, granulating with a binder, drying the obtained granulated product, and tableting the dried granulated product. The tablet contains histidine zinc, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, and has an elution value at 15 minutes of 80% or more in the paddle method (test solution: water, rotation speed: 75 revolutions per minute). In such an aspect, the elution value at 15 minutes in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) is preferably 80% or more both at the start of measurement and after storage for 3 months when stored under the conditions of 40 ° C, 75% RH, open system. One or more components selected from, and crystalline cellulose, granulating step of granulating with a binder, drying step of drying the obtained granulated product, and a step of tableting the dried granulated product, obtained by, histidine zinc, or its pharmaceutical containing a pharmaceutically acceptable salt or solvate as an active ingredient, paddle method (test solution: water, rotation number: 75 revolutions per minute) tablets with an elution value of 80% or more at 15 minutes. In such an embodiment In, 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 the conditions of 40 ° C, 75% RH, open system, both at the start of measurement and after storage for 3 months It is preferably 80% or more.

Example

[0079] The present invention will be described below with specific embodiments, but the present invention is not limited to those embodiments, and various changes and modifications therein can be carried out by those skilled in the art without departing from the scope or spirit of the present invention defined in the appended patent claims. It is understood that it can be carried out. It is understood that it can be carried out without departing from the scope or spirit of the present invention defined in the appended patent claims. It is understood.

[0080] Example 1: Single-dose study in healthy adult males (fasting / postprandial, 25 mg) ​A histidine zinc (N PC-25) capsule containing 25 mg of histidine zinc hydrate as zinc (hereinafter referred to as NPC-25 capsule) was used to conduct a single-dose administration test on healthy adult men under fasting and after meal administration For fasting administration, after fasting for 10 hours or more, together with 200 mL of water, an NPC-25 capsule (1 capsule) was administered. For after-meal administration, a high-calorie and high-fat meal was consumed within 20 minutes, and 30 minutes after the start of the meal an NPC-25 capsule (1 capsule) was administered orally as a single dose together with 200 mL of water (n = 12). Blood samples were collected at a total of 12 time points before administration, and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 21.0, and 24.0 hours after administration to measure the exogenous serum zinc concentration and observe the changes up to 24 hours later. The results are shown in Figure 1 Note that the "exogenous serum zinc concentration" indicates the change in serum zinc concentration from before the histidine zinc administration test (Points where the value became negative were judged as the disappearance of exogenous serum zinc, and the exogenous serum zinc concentration was recorded as 0.)

[0081] As can be seen from Figure 1, the average value of the exogenous serum zinc concentration during fasting administration reached a maximum value of 133.50 ± 34.46 μg / dL at 2 hours after administration and then decreased, and almost returned to the baseline value before administration at 8 hours after administration. During after-meal administration, in 4 out of 12 cases, the AUC (area under the serum drug concentration-time curve from 0 to 24 hours after administration) and C (maximum blood concentration) of the exogenous serum zinc concentration showed 0, and the average value of the exogenous serum zinc concentration was 2 .17 ± 6.59 μg / dL, which was the highest value at 3 hours after administration. That is, 25 m of NPC-25 capsule 0-24 (area under the serum drug concentration-time curve from 0 to 24 hours after administration) and C max (maximum blood concentration) of the exogenous serum zinc concentration showed 0, and the average value of the exogenous serum zinc concentration was 2 .17 ± 6.59 μg / dL, which was the highest value at 3 hours after administration. That is, 25 m of NPC-25 capsule ​​In the postprandial administration of g, compared with the administration under fasting, the AUCs were respectively about 0-24 0.02-fold and the C was about 0.03-fold at max . In the case of a single administration of 25 mg, the exogenous serum zinc concentration increased in the administration under fasting, but hardly increased in the postprandial administration. It can be seen .

[0082] Example 2: Single-dose study in healthy adult males (postprandial, 50, 100, 150 mg) Using NPC-25 capsules, a single-dose study was conducted in healthy adult males with the administered doses being 50 mg, 100 mg, and 150 mg as zinc respectively in the postprandial administration. A high-calorie high-fat meal was consumed within 20 minutes, and 30 minutes after the start of the meal, together with 200 mL of water, NPC-25 capsules (2 capsules for the 50 mg administration group, 4 capsules for the 100 mg administration group, 6 capsules for the 150 mg administration group) were orally administered once (n = 12). Blood samples were collected at a total of 12 time points before administration and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 21.0, and 24.0 hours after administration to measure the exogenous serum zinc concentration, and the changes up to 24 hours were observed. The results are shown in Figure 2. The average value of the exogenous serum zinc concentration at the postprandial administration of 50 mg of NPC-25 capsules reached the highest value of 34.33 ± 21.58 μg / dL at 3 hours after administration and then decreased, and almost returned to the baseline value before administration at 8 hours after administration. The average value of the exogenous serum zinc concentration at the postprandial administration of 100 mg of NPC-25 capsules reached the highest value of 145.25 ± 37.18 μg / dL at 3 hours after administration and then decreased, and almost returned to the baseline value before administration at 8 hours after administration. The average value of the exogenous serum zinc concentration at the postprandial administration of 150 mg of NPC-25 capsules reached the highest value of 2 After reaching 39.92±42.75 μg / dL, it decreased and almost returned to the pre-dose baseline value 12 hours after administration. That is, in the case of postprandial administration, it can be seen that the exogenous serum zinc concentration significantly increases when at least 50 mg equivalent of the therapeutic agent according to the present invention as zinc is administered. Example 3: Repeated dose study 1 (50 mg) for healthy adult males Three types of repeated dose studies were conducted for healthy adult males (n = 8 for each dosing group). Venous blood of the subjects was collected at the specified times from before dosing to 15 days after the start of dosing on the 1st day of dosing, and the serum zinc concentration at each blood collection time point was determined. Based on the determined serum zinc concentration, exogenous pharmacokinetic evaluation parameters (AUC (area under the serum drug concentration-time curve from 0 to 24 hours after dosing), C (maximum blood concentration), C

[0083] (blood concentration immediately before dosing (C on the 1st day of dosing is the concentration immediately before dosing on the 2nd day of dosing, and C on the 14th day of dosing is the concentration on the 15th day of dosing (24 hours after dosing on the 14th day of dosing))), and t (time to reach the maximum blood concentration)) were determined. 0-24 (area under the serum drug concentration-time curve from 0 to 24 hours after dosing), C (maximum blood concentration), C max (blood concentration immediately before dosing (C trough on the 1st day of dosing is the concentration immediately before dosing on the 2nd day of dosing, and C on the 14th day of dosing is the concentration on the 15th day of dosing (24 hours after dosing on the 14th day of dosing))), and t trough (time to reach the maximum blood concentration)) were determined. The dosages and administration methods of each dosing group of NPC-25 and the Novergin dosing group were as follows. trough NPC-25 (50 mg / day) once-daily dosing group: Two NPC-25 capsules (50 mg as zinc) were repeatedly orally administered once a day for 14 days after meals. NPC-25 (50 mg / day) twice-daily dosing group: One NPC-25 capsule (25 mg as zinc) was repeatedly orally administered twice a day for 14 days after meals. max

[0084] NPC-25 Administration Group ​​​​​​Novergine Administration Group Novergin (50 mg / day) twice-daily administration group: Novergin tablets (25 mg each tablet, equivalent to 25 mg of zinc) were orally administered twice daily after meals for 14 days. For each administration group, the inter-group ratios of the exogenous pharmacokinetic evaluation parameters were calculated, and the differences in exogenous pharmacokinetics in each administration group were evaluated. The ratios of the mean values of the exogenous pharmacokinetic evaluation parameters (AUC

[0085] Evaluation Results “NPC-25 (50 mg / day) twice-daily administration group vs Novergin (50 mg / day) twice-daily administration group” and “NPC-25 (50 mg / day) once-daily administration group vs Novergin (50 mg / day) twice-daily administration group” on the 1st day and 14th day of administration were shown in Figure 3. The ratios of the mean values of the exogenous pharmacokinetic evaluation parameters (AUC 0-24 , C max , C trough , and t max ) on the 1st day and 14th day of administration were shown in Figure 3. are shown in Figure 3.

[0086] The ratios of the mean values of AUC 0-24 on the 1st day and 14th day of administration were 1.7352 and 1.1515 respectively in “NPC-25 (50 mg / day) twice-daily administration group vs Novergin (50 mg / day) twice-daily administration group”, and 4.1001 and 1 respectively in “NPC-25 (50 mg / day) once-daily administration group vs Novergin (50 mg / day) twice-daily administration group”. That is, the AUC on the 1st day of administration in the NPC-25 (50 mg / day) twice-daily administration group was higher than that in the Novergin (50 mg / day) twice-daily administration group, and the AUC on the 14th day of administration was comparable to that in the Novergin 50 mg / day twice-daily administration group. On the other hand, the AUC on the 1st day and 0-24 on the 14th day of administration in the NPC-25 (50 mg / day) once-daily administration group was higher than that in the Novergin (50 mg / day) twice-daily administration group, and the AUC 0-24 on the 14th day of administration was comparable to that in the Novergin 50 mg / day twice-daily administration group. On the other hand, the AUC on the 1st day and ​AUC on the 14th day of administration 0-24 All were higher than those in the Novergin (50 mg / day) twice-daily administration group.

[0087] C max The ratios of the mean values on the 1st day and the 14th day of administration were 1.1518 and 0.9640 respectively in the "NPC-25 (50 mg / day) twice-daily administration group vs Novergin (50 mg / day) twice-daily administration group", and 4.2840 and 2.12 81 respectively in the "NPC-25 (50 mg / day) once-daily administration group vs Novergin (50 mg / day) twice-daily administration group". That is, C on the 1st day and the 14th day of administration in the NPC-25 (50 mg / day) twice-daily administration group was comparable to that in the Novergin (50 mg / day) twice-daily max administration group, and C on the 1st day and the 14th day of administration in the NPC-25 (50 mg / day) once-daily administration group was higher than that in the Novergin (50 mg / day) twice-daily max administration group in both cases.

[0088] C trough The ratios of the mean values on the 1st day and the 14th day of administration were 1.6136 and 1.2557 respectively in the "NPC-25( 50 mg / day) twice-daily administration group vs Novergin (50 mg / day) twice-daily administration group", and 1.8977 and 1. 5916 respectively in the "NPC-25 (50 mg / day) once-daily administration group vs Novergin (50 mg / day) twice-daily administration group". That is, C on the 1st day of administration in the NPC-25 (50 mg / day) twice-daily administration group was higher than that in the Novergin (50 mg / day) twice-daily trough administration group, and C on the 14th day of administration trough was comparable to that in the Novergin (50 mg / day) twice-daily administration group​ were at the same level. On the other hand, on the first day of administration and on the 14th day of administration in the NPC-25 (50 mg / day) once-daily administration group, C trough was higher in all cases compared to the Novergin (50 mg / day) twice-daily administration group.

[0089] t max The ratios of the average values on the first day of administration and the 14th day of administration of were 1.1739 and 1.9600 respectively for the "NPC-25 (50 mg / day) twice-daily administration group vs Novergin (50 mg / day) twice-daily administration group", and 0.9348 and 0.9600 respectively for the "NPC-25 (50 mg / day) once-daily administration group vs Novergin (50 mg / day) twice-daily administration group". That is, t on the first day of administration in the NPC-25 (50 mg / day) twice-daily administration group was at the same level as the Novergin (50 mg / day) twice-daily administration group, and t on the 14th day of administration was slower compared to the Novergin (50 mg / day) twice-daily administration group. [[ID=2,3]]t max on the first day of administration in the NPC-25 (50 mg / day) once-daily administration group was at the same level as the Novergin (50 mg / day) twice-daily administration group, and t on the 14th day of administration max was slower compared to the Novergin (50 mg / day) twice-daily administration group. t max on the first day of administration and the 14th day of administration in the NPC-25 (50 mg / day) once-daily administration group were both at the same level as the Novergin (50 mg / day) twice-daily administration group.

[0090] From the above results, it can be seen that once-daily administration of 50 mg / day of zinc in NPC-25 (histidine zinc) has an effect equivalent to or greater than twice-daily administration of 50 mg / day of zinc in Novergin.

[0091] Example 4: Repeated-dose study 2 (100 mg) in healthy adult males Three repeated-dose studies were conducted on healthy adult males as follows (for each administration group, (n=8) Before administration and at specified times from the first day of administration to the 15th day of administration, Venous blood was collected from the subjects, and serum zinc concentrations were determined at each blood collection point. Based on the exogenous pharmacokinetic evaluation parameters (AUC 0-24 , C max , C trough , and t max ) was sought.

[0092] The doses and administration methods for each NPC-25 administration group and Nobelzin administration group were as follows. NPC-25 Administration Group NPC-25 (100 mg / day) once-daily administration group: 4 capsules of NPC-25 capsules ( The subjects were given 100 mg of zinc orally once daily after meals for 14 days. NPC-25 (100 mg / day) twice-daily administration group: 2 capsules of NPC-25 capsules ( The subjects were given 50 mg of zinc twice daily after meals for 14 days. Novergine Administration Group Nobelzin (100 mg / day) twice-daily administration group: Nobelzin tablets 25 mg x 2 tablets (as zinc) The subjects were given 50 mg of the drug twice daily after meals for 14 days. The intergroup ratios of each exogenous pharmacokinetic evaluation parameter obtained for each administration group were calculated, and Differences in exogenous pharmacokinetics between the treatment groups were evaluated.

[0093] Evaluation Results NPC-25 (100 mg / day) twice daily administration group vs. Nobelzin (100 mg / day) Twice-daily administration group" and "NPC-25 (100 mg / day) once-daily administration group vs. Nobelzin Exogenous drugs on days 1 and 14 of administration in the "(100 mg / day) twice-daily administration group" Dynamic evaluation parameters (AUC 0-24 , C max , C trough , and tmax )'s mean The ratio of the mean values is shown in Figure 4.

[0094] AUC 0-24 The ratios of the mean values on the first day of administration and the 14th day of administration of "NPC-25 ( 100 mg / day) twice a day administration group vs. Novergin (100 mg / day) twice a day administration group" were 1.7264 and 1.3504 respectively, and in the case of "NPC-25 (100 mg / day) once a day administration group vs. Novergin (100 mg / day) twice a day administration group", they were 2.5295 and 1.5328 respectively. That is, the AUC on the first day of administration of the NPC-25 (100 mg / day) twice a day administration group 0-24 was higher than that of the Novergin (100 mg / day) twice a day administration group, and the AUC on the 14th day of administration was comparable to that of the Novergin (100 mg / day) twice a day administration group. On the other hand, the AUC on the first day of administration and the 14th day of administration of the NPC-25 (100 mg / day) once a day administration group 0-24 were both higher than those of the Novergin (100 mg / day) twice a day administration group. The ratios of the mean values on the first day of administration and the 14th day of administration of 0-24 C were 1.3269 and 1.1977 respectively in the case of "NPC-25 (100 m

[0095] C max g / day) twice a day administration group vs. Novergin (100 mg / day) twice a day administration group", and were 2.7825 and 2. respectively in the case of "NPC-25 (100 mg / day) once a day administration group vs. Novergin (100 mg / day) twice a day administration group". That is, the C on the first day of administration and the 14th day of administration of the NPC-25 (100 mg / day) twice a day administration group were both higher than those of the Novergin (100 mg / day) once a day administration group. The C on the first day of administration and the 14th day of administration of max the NPC-25 (100 mg / day) twice a day administration group It was comparable to the twice-daily administration group. On the other hand, for the once-daily administration group of NPC-25 (100 mg / day), C on the first day of administration and on the 14th day of administration max was higher in both cases compared to the twice-daily administration group of Novergin (100 mg / day ).

[0096] C trough The ratios of the average values on the first day of administration and on the 14th day of administration were "NPC-25 ( 100 mg / day) twice-daily administration group vs Novergin (100 mg / day) twice-daily administration group" and were 1.6810 and 1.1780 respectively, and "NPC-25 (100 mg / day) once-daily administration group vs Novergin (100 mg / day) twice-daily administration group" and were 1.9138 and 1.3620 respectively. That is, C on the first day of administration of the NPC-25 (100 mg / day) twice-daily administration group was higher compared to the Novergin (100 mg / day) twice-daily administration group, and C on the 14th day of administration trough was comparable to the Novergin (100 mg / day) twice-daily administration group. C on the first day of administration of the NPC-25 (100 mg / day) once-daily administration group was higher compared to the Novergin (100 mg / day) twice-daily administration group, and C on the 14th day of administration trough was comparable to the Novergin (100 mg / day) twice-daily administration group. C on the first day of administration of the NPC-25 (100 mg / day) once-daily administration group trough was higher compared to the Novergin (100 mg / day) twice-daily administration group, and C on the 14th day of administration was comparable to the Novergin (100 mg / day) trough twice-daily administration group.

[0097] t max The ratios of the average values on the first day of administration and on the 14th day of administration were "NPC-25 (100 mg / day) twice-daily administration group vs Novergin (100 mg / day) twice-daily administration group" and were 0.9583 and 1.2727 respectively, and "NPC-25 (100 mg / day) once-daily administration group vs Novergin (100 mg / day) twice-daily administration group" and were 1.0417 and 1​ was 0.2273. That is, the administration of NPC-25 (100 mg / day) twice a day at the first day and the 14th day of administration max was all at the same level as that of the novergine (100 mg / day) administered twice a day group. The administration of NPC-25 (100 mg / day) once a day at the first day and the 14th day of administration max was all at the same level as that of the novergine (100 mg / day) administered twice a day group.

[0098] From the above results, it can be seen that 100 mg / day per zinc of NPC-25 (histidine zinc), once a day administration also has an effect equivalent to or higher than that of 100 mg / day per zinc of novergine, administered twice a day.

[0099] Example 5: Open-label, uncontrolled, active-controlled trial for adult and pediatric patients with hypozincemia weighing 30 kg or more For adult and pediatric patients with hypozincemia weighing 30 kg or more, the efficacy and safety of NPC-25 tablets were examined by an open-label comparative trial with novergine tablets (manufactured by Novartis Pharma Co., Ltd.) as a control. Also, the dosage adjustment method until the target serum zinc concentration (80 μg / dL or more and less than 200 μg / dL) was reached by the administration of NPC-25 tablets and the maintenance effect after reaching were examined and confirmed.

[0100] The dosages and administration methods of the NPC-25 administration group and the novergine administration group were as follows.

[0101] NPC-25 Administration Group NPC-25 tablets were taken once a day after meals at the following dosages and usage. NPC-25 tablets: Histidine zinc hydrate was mixed with mannitol and a binder using a known method ​​​​Obtained by granulating together and tableting by a known method, a white tablet (NPC-25 tablet 25mg) containing 156.7 mg as a histidine zinc hydrate per tablet (25 mg as zinc). Initial dose: It was determined as follows according to the serum zinc concentration. · When the serum zinc concentration is 50 μg / dL or more and less than 70 μg / dL: Administered 50 mg / day as zinc (2 tablets once a day) for 4 weeks. · When the serum zinc concentration is less than 50 μg / dL: Administered 100 mg / day as zinc (4 tablets once a day) for 4 weeks. Subsequent dose adjustment: Until the serum zinc concentration reaches the target serum zinc concentration (80 μg / dL or more and less than 200 μg / dL), dose adjustment was performed according to the following criteria. <Increment criteria> Measure the serum zinc concentration every 4 weeks. If it is less than 80 μg / dL, · Increase by 50 mg / day as zinc and administer for 4 weeks. The maximum daily dose was 150 mg as zinc (6 tablets once a day). <Decrement criteria> · Measure the serum zinc concentration every 4 weeks. If it is 200 μg / dL or more, decrease by 25 mg / day as zinc and administer for 4 weeks. · When the serum copper concentration is 30 μg / dL or less, decrease by 25 mg / day as zinc. When it is less than 10 μg / dL, discontinue the administration. · When it is difficult to continue the administration of the dose determined due to the occurrence of adverse events, etc., decrease by 25 mg / day as zinc and administer for 4 weeks. <Administration termination criteria> · When the serum zinc concentration is maintained at 80 μg / dL or more and less than 200 μg / dL without changing the dose for 8 weeks (the blood zinc concentration 4 weeks and 8 weeks after reaching the target value is within the target value range )。However, it was stated that it can be administered up to a maximum of 52 weeks to patients who require continuous administration. · In cases where the serum zinc concentration was 200 μg / dL or more 4 weeks after administration even at 25 mg / day of zinc administration, the administration was discontinued.

[0102] Novergine Administration Group Novelgin tablets 25 mg were taken 1 to 3 times a day after meals according to the following dosage. Novelgin tablets 25 mg: White film-coated tablets containing 83.92 mg of zinc acetate hydrate (25 mg of zinc) in 1 tablet Initial dosage: It was as follows according to the serum zinc concentration. · When the serum zinc concentration was 50 μg / dL or more and less than 70 μg / dL: Zinc was administered at 50 mg / day (1 tablet once, 2 times a day) for 4 weeks. · When the serum zinc concentration was less than 50 μg / dL: 100 mg / day (2 tablets once, 2 times a day) was administered for 4 weeks. Subsequent dosage adjustment: Dosage adjustment was performed according to the following criteria until the serum zinc concentration reached the target serum zinc concentration (80 μg / dL or more and less than 200 μg / dL). <Increment criteria> The serum zinc concentration was measured every 4 weeks. If it was less than 80 μg / dL · The dosage was increased by 50 mg / day of zinc and administered for 4 weeks. The maximum daily dosage was 150 mg of zinc (2 tablets once, 3 times a day). <Decrement criteria> Same as the NPC-25 administration group. <Administration termination criteria> Same as the NPC-25 administration group. However, continuous administration was not approved, and the administration was up to a maximum of 24 weeks.

[0103] In this example, the serum zinc concentrations measured at the time of registration and within 8 weeks before the start of administration were at any time point A total of 216 adults and children aged 30 kg or more with serum zinc levels below 70 μg / dL were registered and randomly assigned to the NPC-25 treatment group or the nobelgin treatment group at a ratio of 1:1 (107 cases in the NPC-25 treatment group and 109 cases in the nobelgin treatment group). The subjects included in the efficacy analysis were those who were registered, excluding ineligible cases, cases with less than 20 days of investigational drug administration, and cases for which no information on efficacy was obtained after the start of investigational drug administration. The maximum analysis population (Full Analysis Set: FAS) was defined as such (103 cases in the NPC-25 treatment group and 107 cases in the nobelgin treatment group). The subjects included in the safety analysis were all cases for which any information on safety was obtained among the subjects who received the investigational drug, and this was defined as the safety analysis population (Safety Population: SP) (107 cases in the NPC-25 treatment group and 109 cases in the nobelgin treatment group). The treatment effect of hypozincemia was evaluated by measuring the changes in serum zinc concentration (analysis population: FAS), the changes in the proportion of subjects who reached the target serum zinc concentration (above 80 μg / dL and less than 200 μg / dL), the changes in the proportion of subjects who maintained the target serum zinc concentration (above 80 μg / dL and less than 200 μg / dL) at the same dose for 8 weeks, the period and dose from the start of administration until the first time the target serum zinc concentration (above 80 μg / dL and less than 200 μg / dL) was reached (analysis population: FAS), and the period and dose from the start of administration until the target serum zinc concentration (above 80 μg / dL and less than 200 μg / dL) could be maintained at the same dose for 8 weeks (analysis population: FAS).

[0104] Evaluation of the Therapeutic Effect on Hypozincemia

[0105] Changes in Serum Zinc Concentration (Analysis Population: FAS) ​​​​​​​​​​​​​​​Serum zinc concentration was measured every 4 weeks after the start of administration. Serum zinc concentration increased over time in both the NPC-25 administration group and the nobelgin administration group from 4 to 12 weeks. After 16 weeks, the NPC-25 administration group remained at the same level as at 12 weeks, but in the nobelgin administration group, serum zinc concentration decreased at 20 and 24 weeks after administration. The amount of change in serum zinc concentration at each observation time point according to the repeated measurement mixed effect model showed no significant difference between the NPC-25 administration group and the nobelgin administration group.

[0106] Proportion of Subjects Who Reached the Target Serum Zinc Concentration (80 μg / dL or More and Less than 200 μg / dL) Changes (Analysis Population: FAS) The proportion of subjects who reached the target serum zinc concentration increased in both administration groups after the start of the investigational drug administration. In both groups, by adjusting the dose, the target serum zinc concentration was rapidly reached, and by 24 weeks, 99.0% (102 / 103 cases) in the NPC-25 administration group and 95.3% (102 / 107 cases) in the nobelgin administration group achieved it. The achievement rate at each observation time point showed no significant difference between the NPC- 25 administration group and the nobelgin administration group.

[0107] Proportion of Subjects Who Could Maintain the Target Serum Zinc Concentration (80 μg / dL or More and Less than 200 μg / dL) for 8 Weeks at the Same Dosage Changes (Analysis Population: FAS) Regarding the cumulative achievement rate at each observation time point where the target serum zinc concentration could be maintained at the same dose for 8 weeks, by 24 weeks, 86.4% (89 / 103 cases) in the NPC-25 administration group and 80.4% (86 / 107 cases) in the nobelgin administration group achieved it. The achievement rate at 12 weeks was 47.6% (49 / 103 cases) in the NPC-2 5 administration group and 36.4% (39 / 10 7 cases) in the nobelgin administration group. The achievement rate at 12 weeks in the NPC-25 administration group tended to be higher compared to the nobelgin administration group, and it was confirmed that the target serum zinc concentration could be maintained earlier in the NPC-25 administration group. A tendency was observed.

[0108] Period from the Start of Administration until the Subject First Reached the Target Serum Zinc Concentration (80 μg / dL or More and Less than 200 μg / dL) Changes (Analysis Population: FAS) After the start of administration, the administration was continued according to the increase / decrease criteria, and the serum zinc concentration was measured every 4 weeks. The results of examining the period (days) until the target serum zinc concentration (80 μg / dL or more and less than 200 μg / dL) was first reached for each administration group by the Kaplan-Meier method are shown in FIGS. 5 and 6. For the period (days) until the target serum zinc concentration (80 μg / dL or more and less than 200 μg / dL) was first reached from the start of administration until 24 weeks after the start of administration, the 25th percentile value, median value, and 75th percentile value in the NPC-25 administration group were 22.0, 28. After the start of administration, the administration was continued according to the increase / decrease criteria, and the serum zinc concentration was measured every 4 weeks. The results of examining the period (days) until the target serum zinc concentration (80 μg / dL or more and less than 200 μg / dL) was first reached for each administration group by the Kaplan-Meier method are shown in FIGS. 5 and 6. .0, and 51.0 days, respectively. The 25th percentile value, median value, and 75th percentile value in the Novergin administration group were 23.0, 34 .0, and 53.0 days, respectively. No significant difference was observed between the NPC-25 administration group and the Novergin administration group in the period (days) until the target serum zinc concentration was first reached from the start of administration (p = 0.190). That is, NPC-25 was found to have a hypoleademia treatment effect equivalent to that of Novergin.

[0109] For the period (days) until the target serum zinc concentration was first reached from the start of administration until 24 weeks after the start of administration, the 25th percentile value, median value, and 75th percentile value in the NPC-25 administration group were 22.0, 28.0, and 51.0 days, respectively. The 25th percentile value, median value, and 75th percentile value in the Novergin administration group were 23.0, 34.0, and 53.0 days, respectively. No significant difference was observed between the NPC-25 administration group and the Novergin administration group in the period (days) until the target serum zinc concentration was first reached from the start of administration (p = 0.190). That is, NPC-25 was found to have a hypoleademia treatment effect equivalent to that of Novergin. .0, and 51.0 days, respectively. The 25th percentile value, median value, and 75th percentile value in the Novergin administration group were 23.0, 34 .0, and 53.0 days, respectively. No significant difference was observed between the NPC-25 administration group and the Novergin administration group in the period (days) until the target serum zinc concentration was first reached from the start of administration (p = 0.190). That is, NPC-25 was found to have a hypoleademia treatment effect equivalent to that of Novergin. .0, and 53.0 days, respectively. No significant difference was observed between the NPC-25 administration group and the Novergin administration group in the period (days) until the target serum zinc concentration was first reached from the start of administration (p = 0.190). That is, NPC-25 was found to have a hypoleademia treatment effect equivalent to that of Novergin. .0, and 53.0 days, respectively. No significant difference was observed between the NPC-25 administration group and the Novergin administration group in the period (days) until the target serum zinc concentration was first reached from the start of administration (p = 0.190). That is, NPC-25 was found to have a hypoleademia treatment effect equivalent to that of Novergin. .0, and 53.0 days, respectively. No significant difference was observed between the NPC-25 administration group and the Novergin administration group in the period (days) until the target serum zinc concentration was first reached from the start of administration (p = 0.190). That is, NPC-25 was found to have a hypoleademia treatment effect equivalent to that of Novergin. .0, and 53.0 days, respectively. No significant difference was observed between the NPC-25 administration group and the Novergin administration group in the period (days) until the target serum zinc concentration was first reached from the start of administration (p = 0.190). That is, NPC-25 was found to have a hypoleademia treatment effect equivalent to that of Novergin. .0, and 53.0 days, respectively. No significant difference was observed between the NPC-25 administration group and the Novergin administration group in the period (days) until the target serum zinc concentration was first reached from the start of administration (p = 0.190). That is, NPC-25 was found to have a hypoleademia treatment effect equivalent to that of Novergin.

[0110] Period from the Start of Administration until the Subject Could First Maintain the Target Serum Zinc Concentration (80 μg / dL or More and Less than 200 μg / dL) for 8 Weeks at the Same Dosage Changes (Analysis Population: FAS) After the start of administration, the administration was continued according to the increase / decrease criteria, and the serum zinc concentration was measured every 4 weeks. The results of examining the period (days) until the target serum zinc concentration (80 μg / dL or more and less than 200 μg / dL ) could be maintained at the same dose for 8 weeks from the start of administration until 24 weeks after the start of administration are shown in FIGS. 7 and 8 for each administration group by the Kaplan-Meier method. ) could be maintained at the same dose for 8 weeks from the start of administration until 24 weeks after the start of administration are shown in FIGS. 7 and 8 for each administration group by the Kaplan-Meier method. ) could be maintained at the same dose for 8 weeks from the start of administration until 24 weeks after the start of administration are shown in FIGS. 7 and 8 for each administration group by the Kaplan-Meier method. The period from the start of administration until the target serum zinc concentration can be maintained at the same dosage for 8 weeks for the first time ( days), for the 25th percentile value, median value, and 75th percentile value in the NPC-25 administration group were 79.0, 106.0, and 134.0 days, respectively. For the 25th percentile value, median value, and 75th percentile value in the Novergin administration group were 81.0, 106.0, and 148.0 days, respectively. For the period (days) from the start of administration until the target serum zinc concentration can be maintained at the same dosage for 8 weeks for the first time, no significant difference was observed between the NPC-25 administration group and the Novergin administration group (p = 0.100). That is, NPC-2 5 was found to have a therapeutic effect on hypozincemia equivalent to that of Novergin.

[0111] Proportion of Subjects by Dosage at the Time When the Serum Zinc Concentration First Reached 80 μg / dL or More (Analysis Population: FAS) Changes (Analysis Population: FAS) Figure 9 shows the percentage of subjects by dosage at the time when the serum zinc concentration first reached 80 μg / dL or more up to 24 weeks for each administration group.

[0112] The percentage of subjects by dosage at the time when the serum zinc concentration first reached 80 μg / dL or more was highest at 50 mg / day in all administration groups, followed by 100 mg / day. The achievement rates at 50 mg / day in the NPC-25 administration group and the Novergin administration group were 60.2 % (62 / 103 cases) and 51.4% (55 / 107 cases), respectively, and the achievement rates at 100 mg / day in the NPC-25 administration group and the Novergin administration group were 29.1% (30 / 103 cases) and 34.6% (37 / 107 cases), respectively. There was no significant difference between the NPC -25 administration group and the Novergin administration group in the achievement rate of subjects by dosage.

[0113] Proportion of Subjects by Dosage Who Could First Maintain the Target Serum Zinc Concentration (80 μg / dL or More and Less than 200 μg / dL) for 8 Weeks ​​​​​ Changes (Analysis Population: FAS) For each administration group, the proportion of subjects by dose who were able to maintain the target serum zinc concentration (80 μg / dL or more and less than 200 μg / dL) for the first time up to 24 weeks is shown in Fig. 10. The proportion of subjects by dose who were able to maintain the target serum zinc concentration (80 μg / dL or more and less than 200 μg / dL) for the first time for 8 weeks is as follows: in the NPC-25 administration group, the highest was 50 mg / day, followed by 100 mg / day. In the Novergin administration group, the proportion achieved at 100 mg / day was the highest, followed by 50 mg / day. The proportions in the NPC-25 administration group and the Novergin administration group at 50 mg / day were 46.6% (48 / 103 cases) and 36.4% (39 / 107 cases), respectively, and the proportions in the NPC-25 administration group and the Novergin administration group at 100 mg / day were 34.0% (35 / 103 cases) and 37.4% (40 / 107 cases), respectively. The achievement rate at 50 mg / day in the NPC-25 administration group tended to be higher than that in the Novergin administration group, and a tendency to achieve at a lower dose was observed in the NPC-25 administration group.

[0114] For the first time, the proportion of subjects by dose who were able to maintain the target serum zinc concentration (80 μg / dL or more and less than 200 μg / dL) for 8 weeks was as follows: in the NPC-25 administration group, the highest was 50 mg / day, followed by 100 mg / day. In the Novergin administration group, the proportion achieved at 100 mg / day was the highest, followed by 50 mg / day. The proportions in the NPC-25 administration group and the Novergin administration group at 50 mg / day were 46.6% (48 / 103 cases) and 36.4% (39 / 107 cases), respectively, and the proportions in the NPC-25 administration group and the Novergin administration group at 100 mg / day were 34.0% (35 / 103 cases) and 37.4% (40 / 107 cases), respectively. The achievement rate at 50 mg / day in the NPC-25 administration group tended to be higher than that in the Novergin administration group, and a tendency to achieve at a lower dose was observed in the NPC-25 administration group. The safety profile of NPC-25 is not significantly different from that of zinc preparations reported so far, and no problems were confirmed in comparison with Novergin, whose safety has been established in previous clinical use. Specifically, it is as follows. (39 / 107 cases), respectively, and the proportions in the NPC-25 administration group and the Novergin administration group at 100 mg / day were 34.0% (35 / 103 cases) and 37.4% (40 / 107 cases), respectively. The achievement rate at 50 mg / day in the NPC-25 administration group tended to be higher than that in the Novergin administration group, and a tendency to achieve at a lower dose was observed in the NPC-25 administration group. The safety profile of NPC-25 is not significantly different from that of zinc preparations reported so far, and no problems were confirmed in comparison with Novergin, whose safety has been established in previous clinical use. Specifically, it is as follows. The safety profile of NPC-25 is not significantly different from that of zinc preparations reported so far, and no problems were confirmed in comparison with Novergin, whose safety has been established in previous clinical use. Specifically, it is as follows. The safety profile of NPC-25 is not significantly different from that of zinc preparations reported so far, and no problems were confirmed in comparison with Novergin, whose safety has been established in previous clinical use. Specifically, it is as follows.

[0115] Safety (Analysis Population: SP) The safety profile of NPC-25 is not significantly different from that of zinc preparations reported so far, and no problems were confirmed in comparison with Novergin, whose safety has been established in previous clinical use. Specifically, it is as follows. The safety profile of NPC-25 is not significantly different from that of zinc preparations reported so far, and no problems were confirmed in comparison with Novergin, whose safety has been established in previous clinical use. Specifically, it is as follows. The safety profile of NPC-25 is not significantly different from that of zinc preparations reported so far, and no problems were confirmed in comparison with Novergin, whose safety has been established in previous clinical use. Specifically, it is as follows. Typical side effects of zinc preparations include digestive-related symptoms, and nausea and vomiting are factors that reduce the patient's medication compliance. The incidence of the side effect of nausea was 2.8% (3 / 107 cases) in the NPC-25 administration group and 6.4% (7 / 109 cases) in the Novergin administration group. Also, the incidence of vomiting was 2.8% (3 / 107 cases) in the NPC-25 administration group and 6.4% (7 / 109 cases) in the Novergin administration group. Also, the incidence of vomiting was 2.8% (3 / 107 cases) in the NPC-25 administration group and 6.4% (7 / 109 cases) in the Novergin administration group. Also, the incidence of vomiting The incidence rate of vomiting side effects was 0.9% (1 / 107 cases) in the NPC-25 administration group and 2.8% (3 / 109 cases) in the Novergin administration group. Thus, the incidence rates of typical side effects such as nausea and vomiting in the zinc preparation were all lower than those in the Novergin administration group.

[0116] Examples 6 and 7: Production of Test Samples 1 and 2 Histidine zinc hydrate, D-mannitol, and crystalline cellulose were combined by a stirring granulator, hydroxypropyl cellulose and purified water were added and granulated by stirring, and wet screening was performed using a screening machine. Subsequently, drying was carried out using a fluidized bed dryer. Since histidine zinc hydrate may change to an anhydride due to over-drying and the evaporation of crystal water in the active ingredient, the drying end point was evaluated by the weight loss of the granules. All lots showed a constant value slightly higher than the theoretical moisture content in terms of weight loss, and the water activity value was also as low as 0.3 or less, indicating that they were sufficiently dried and no over-drying occurred. Subsequently, after screening the obtained granulated and dried product, it was placed in a container rotation type mixer, low-substituted hydroxypropyl cellulose and magnesium stearate were added and mixed to obtain a powder for tableting, which was then tabletted to obtain a plain tablet (Test Sample 1). The total weight per plain tablet was 310 mg, the histidine zinc hydrate content was 156.7 mg (25 mg as zinc), the D-mannitol content was 33 mg, and the crystalline cellulose

[0117] content was 80 mg. Similarly, Test Sample 2 was produced by changing the amount of raw materials. The total weight per 0 mg), the D-mannitol content was 66 mg, and the crystalline cellulose content was 160 mg .

[0118] Example 8: Production of Test Sample 3 Purified water was added to hypromellose and hydroxypropyl cellulose and dissolved, and titanium oxide was mixed with a dispersion liquid dispersed in purified water to produce a coating liquid. The plain tablets obtained in Example 6 (total weight per tablet was 310 mg, histidine zinc hydrate content was 157 mg (25 mg as zinc , the D-mannitol content was 32.7 mg, and the crystalline cellulose content was 80 m g) were sprayed with the coating liquid and dried to obtain film-coated tablets (Test Sample 3). .

[0119] Examples 9, 10, 11, and 12: Production of Test Samples 6, 7, 8, and 9 Plain tablets were obtained in the same manner as Test Sample 1, except that sucrose (Test Sample 6), sorbitol (Test Sample 7), xylitol (Test Sample 8), and potato starch (Test Sample 9) were used instead of D-mannitol. The total weight per tablet of the obtained test samples was 313.2 mg for Test Sample 6, 313.1 mg for Test Sample 7, 311.0 mg for Test Sample 8, and 310.5 mg for Test Sample 9. The histidine zinc hydrate content in each test sample was 157 mg (25 mg as zinc), and the crystalline cellulose content was 80 mg. Also, the content of sucrose (Test Sample 6), sorbitol (Test Sample 7), xylitol (Test Sample 8), and potato starch ( Test Sample 9) in each test sample was 33 mg for all.

[0120] Comparative Example 1: Production of Test Sample 4 ​Tablets were prepared in the same manner as Test Sample 1, except that lactose hydrate was used instead of D-mannitol. (Test Sample 4) were obtained. The total weight per tablet of Test Sample 4 was 310 mg, the histidine zinc hydrate content was 157 mg (25 mg as zinc), and the lactose hydrate content was 32.7 mg, and the crystalline cellulose content was 80 mg. Comparative Example 2: Preparation of Test Sample 5

[0121] Using the coating solution used in the preparation of Test Sample 3, tablets were prepared in the same manner as Test Sample 4. (Total weight per tablet: 314 mg, histidine zinc hydrate content: 157 m g (25 mg as zinc), lactose hydrate content: 35.2 mg, crystalline cellulose content: 81 mg) were used to obtain film-coated tablets (Test Sample 5). Comparative Examples 3 and 4: Preparation of Test Samples 10 and 11

[0122] Tablets were obtained in the same manner as Test Sample 1, except that fructose (Test Sample 10) or glucose (Test Sample 11) was used instead of D-mannitol. The total weight per tablet of the obtained test samples was 313.1 mg for Test Sample 10 and 311.6 mg for Test Sample 11. The histidine zinc hydrate content in each test sample was 157 mg (25 mg as zinc), and the crystalline cellulose content was 80 mg. Also, the content of fructose (Test Sample 10) and glucose (Test Sample 11) in each test sample was 33 mg. Test Example 1: Dissolution rate (50 rotations per minute): Test Samples 1 to 3 and 5 The test samples were stored in open glass bottles at 40 °C and 75% RH. At the start of storage and after 3 months,

[0123] ... ... the test samples were stored with the glass bottles open at 40 °C and 75% RH, and at the start of storage and after 3 The elution property after months was evaluated by the following method. By the paddle method (paddle method) (solvent: water, test solution volume: 900 mL, rotation speed: 50 rotations per minute) moreover, the 15-minute values (dissolution rate (%)) at the start of storage and after 3 months were measured, and the elution property decrease rate was determined by the following formula.

[0124] Active ingredient (zinc) elution property decrease rate (%) = [(dissolution rate at the start of storage) - (dissolution rate after 3 months )] / (dissolution rate at the start of storage) × 100

[0125] The dissolution rate of test sample 1 (Example 6) at the start of storage was 83.9%, and after 3 months it was 82.5 %, and the elution property decrease rate was 1.67%. The dissolution rate of test sample 2 (Example 7) at the start of storage was 86.9%, and after 3 months it was 81.8 %, and the elution property decrease rate was 5.87%. The dissolution rates of test sample 3 (Example 8) at the start of storage and after 3 months were both 80% or more and almost the same, and no decrease in elution property was confirmed. The dissolution rate of test sample 5 (Comparative Example 2) at the start of storage was 88.8%, and after 3 months it was 75.4 %, and the elution property decrease rate was 15.1%.

[0126] Test Example 2: Elution property (rotation speed: 75 rotations per minute): Test samples 1, 2 The elution property decrease rate was measured in the same manner as in Test Example 1, except that the rotation speed was 75 rotations per minute.

[0127] The dissolution rate of test sample 1 (Example 6) at the start of storage was 100%, and after 3 months it was 98.2% and the elution property decrease rate was 1.8%. The dissolution rates of test sample 2 (Example 7) at the start of storage and after 3 months were both 98.8% and the elution property decrease rate was 0%.

[0128] Test Example 2-1: Dissolution (Rotation speed: 75 rotations per minute): Test samples 6 to 11 Similar to Test Example 2, the dissolution reduction rate was measured.

[0129] The dissolution rates of Test Sample 6 (Example 9) at the start of storage and after 3 months were both 90% or more and were almost the same, and no decrease in dissolution was confirmed. The dissolution rate of Test Sample 7 (Example 10) at the start of storage was 94.1%, and after 3 months it was 91. 5%, and the dissolution reduction rate was 2.6%. The dissolution rate of Test Sample 8 (Example 11) at the start of storage was 96.0%, and after 3 months it was 91. 0%, and the dissolution reduction rate was 5.0%. The dissolution rates of Test Sample 9 (Example 12) at the start of storage and after 3 months were both 90% or more and were almost the same, and no decrease in dissolution was confirmed. The dissolution rate of Test Sample 10 (Comparative Example 3) at the start of storage was 94.3%, and after 3 months it was 37. 7%, and the dissolution reduction rate was 56.6%. The dissolution rate of Test Sample 11 (Comparative Example 4) at the start of storage was 91.1%, and after 3 months it was 18. 6%, and the dissolution reduction rate was 72.5%.

[0130] Test Example 3: Appearance: Test samples 1 to 5 The test samples were stored in an open glass bottle at 40°C and 75% RH, and the appearance at the start of storage and after 3 months was visually evaluated.

[0131] Test Samples 1 and 2 (Examples 6 and 7) were white plain tablets, and there was no change in appearance at the start of storage and after 3 months Test Sample 3 (Example 8) was a white film-coated tablet, and there was no change in appearance at the start of storage and after 3 months Test Sample 4 (Comparative Example 1) was a white plain tablet at the start of storage, but after 3 months it was slightly ​It changed to a yellowish-brown color. Test sample 5 (Comparative Example 2) was a white film-coated tablet at the start of storage but changed to a yellowish-brown color after 3 months.

[0132] Test Example 3-1: Appearance: Test Samples 6 to 11 Similar to Test Example 3, the appearance at the start of storage and after 3 months was visually evaluated. Test samples 6, 7, 8, and 9 (Examples 9, 10, 11, and 12) were white plain tablets, and there was no change in appearance at the start of storage and after 3 months. Test samples 10 and 11 (Comparative Examples 3 and 4) were white plain tablets at the start of storage, but changed to light brown and brown, respectively, after 3 months.

Industrial Applicability

[0133] According to the present invention, it becomes possible to provide a therapeutic agent for hypozincemia containing histidine zinc or a pharmaceutically acceptable salt or solvate thereof. Further, according to the present invention, it becomes possible to provide a therapeutic agent for hypozincemia containing histidine zinc or a pharmaceutically acceptable salt or solvate thereof, which can effectively treat hypozincemia according to specific usage and dosage. Moreover, according to the present invention, it becomes possible to provide a therapeutic agent for hypozincemia with excellent patient compliance.

Brief Description of Drawings

[0134]

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Claims

1. A therapeutic agent for treating hypozincemia, which contains histidine zinc, or a pharmaceutically acceptable salt or solvate thereof, and is orally administered once a day after a meal.

2. The therapeutic agent according to claim 1, wherein the initial dose is 50 to 100 mg of zinc per administration.

3. The therapeutic agent according to claim 1, wherein the dosage is appropriately increased or decreased within a range not exceeding 150 mg of zinc per day based on the serum zinc concentration and the patient's condition.

4. The therapeutic agent according to claim 1, wherein the initial dose is 50 to 100 mg of zinc per administration in adults and children weighing 30 kg or more.

5. The therapeutic agent according to claim 1, wherein the dosage is such that the serum zinc concentration is maintained at 80 μg / dL or more and less than 200 μg / dL.

6. The therapeutic agent according to any one of claims 1 to 5, wherein histidine zinc, or a pharmaceutically acceptable salt or solvate thereof, is histidine zinc dihydrate (JAN: histidine zinc hydrate).

7. Furthermore, it is a tablet containing one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose, and does not contain lactose, fructose, and glucose. The therapeutic agent according to claim 1 。

8. The therapeutic agent according to claim 7, wherein histidine zinc, or a pharmaceutically acceptable salt or solvate thereof, is 40% to 75% by mass of the total tablet.

9. The content of one or more components selected from D-mannitol, sucrose, sorbitol, xylitol, corn starch, and potato starch is 5% to 15% by mass of the total tablet. The therapeutic agent according to claim 7

10. The content of crystalline cellulose is 10% to 30% by mass of the total tablet. The therapeutic agent according to claim 7

11. The therapeutic agent according to claim 7, which contains 25 mg or 50 mg of zinc as histidine zinc, or a pharmaceutically acceptable salt or solvate thereof.

12. The therapeutic agent according to any one of claims 7 to 11, wherein the solvate is a hydrate.

13. The therapeutic agent according to any one of claims 7 to 11, wherein histidine zinc, or a pharmaceutically acceptable salt or solvate thereof, is histidine zinc hydrate.

14. The therapeutic agent according to any one of claims 7 to 11, wherein the elution value at 15 minutes in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) is 80% or more.

15. The elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) is 80% or more both at the start of storage and after 3 months when stored under the conditions of 40 °C, 75 % RH, open system, the therapeutic agent according to claim 14.

16. The decrease rate of the elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) from the start of storage to 3 months later when stored under the conditions of 40 °C, 75 % RH, open system is less than 10%, the therapeutic agent according to claim 15.

17. Histidine zinc, or a pharmaceutically acceptable salt or solvate thereof, and D-mannitol A granulation step of granulating one or more components selected from sucrose, sorbitol, xylitol, corn starch, and potato starch, and crystalline cellulose together with a binder, A drying step of drying the obtained granulated product, and a step of tableting the dried granulated product, The therapeutic agent according to claim 7, which contains histidine zinc, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, and the elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) is 80% or more (however, it does not contain lactose, fructose, and glucose).

18. The elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) is 80% or more both at the start of storage and after 3 months when stored under the conditions of 40 °C, 75 % RH, open system, the therapeutic agent according to claim 17.

19. The decrease rate of the elution 15-minute value in the paddle method (test solution: water, rotation speed: 75 revolutions per minute) from the start of storage to 3 months later when stored under the conditions of 40 °C, 75 % RH, open system is less than 10%, the therapeutic agent according to claim 18. ​ ​ ​ ​ ​ ​ ​ ​

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