Hypozincemia therapeutic agent

Abstract

To provide a hypozincemia therapeutic agent for children with an administration condition for exerting effect while reducing adverse effect.SOLUTION: A hypozincemia therapeutic agent contains zinc acetate, and is administered to children with a body weight of less than 30 kg by oral administration or administration through tube with a starting dosage of zinc at 1.0 mg / kg / day or 1.5 mg / kg / day.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a therapeutic agent for hypozincemia. More specifically, the present invention relates to a therapeutic agent for hypozincemia containing zinc acetate as an active ingredient. With specific dosage regimens, it is possible to safely and effectively treat hypozincemia in children. This invention relates to a therapeutic agent for hypozincemia. [Background technology]

[0002] Zinc acetate preparations are the first and only zinc preparations in Japan that are indicated for hypozincemia. It is sold under the name Nobelzin® Tablets (Nobelpharma Co., Ltd.) and is marketed by Wilson. This preparation contains 200mg of zinc per tablet. There are two types on the market: one containing 5 mg and one containing 50 mg. For the treatment of hypozincemia in children weighing 30 kg or more, 25 to 50 mg of zinc should be taken at a time. It is administered orally twice a day with a starting dose of 0 mg. For the treatment of hypozincemia in children weighing less than 30 kg, zinc at 25 mg / day has been recommended. The initial dose is administered orally once a day. Depending on the severity and condition of the patient, adults and children weighing 30 kg or more may receive 150 mg daily (50 mg at a time). mg three times a day), and for children weighing less than 30 kg, 75 mg (25 mg three times a day). The maximum dose is used, and the dose can be increased or decreased as appropriate.

[0003] Patent Document 1 also describes zinc acetate and other compounds containing L-carnosine as therapeutic agents for zinc deficiency. Patent Document 2 describes a powder containing zinc (Example 1) for the purpose of improving the tolerability of oral zinc therapy. A gastroretentive formulation containing potassium carbonate and zinc acetate is described (claim 8, etc.). However, none of the literature describes the specific method or dosage for administering zinc preparations to children. do not have. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO01 / 091762 publication [Patent Document 2] Special Publication No. 2013-509443 Summary of the Invention [Problem to be solved by the invention]

[0005] In order to maximize the effectiveness of hypozincemia treatment in children while minimizing side effects, It is necessary to use dosages and conditions suitable for children, but no such dosages and conditions have been established so far. There is no disclosure of a pediatric hypozincemia treatment agent that is associated with this condition. For children who rely on tube feeding, it is difficult to take the tablets as they are, and it is difficult to maintain sufficient efficacy. In addition, the dosage and administration method that took safety into consideration were not disclosed, and the drug was given flexible treatment depending on the symptoms. It was also not possible to perform flexible dose adjustments.

[0006] The present invention has been made in view of the above circumstances, and aims to provide a method for reducing side effects while still achieving beneficial effects. The objective of the present invention is to provide a therapeutic agent for hypozincemia for children, which is administered under the conditions necessary for the treatment of hypozincemia.

[0007] In order to solve this problem, the inventors have developed a drug for infants and children who are dependent on tube feeding. The granules are easy to administer and the dosage can be easily adjusted, and the starting dose is determined based on the child's symptoms and weight. In addition to setting the dosage, serum zinc levels should be checked periodically and the dosage adjusted accordingly. We proposed a hypozincemia treatment agent with the following dosage regimen and confirmed its effectiveness through clinical trials. Based on these findings, the present invention has been completed. [Means for solving the problem]

[0008] That is, the present invention contains zinc acetate and provides 100mg of zinc for children weighing less than 30kg. Oral administration was performed with a starting dose of 0.0 mg / kg / day or 1.5 mg / kg / day. is a drug for treating hypozincemia that is administered by tube administration.

[0009] The present invention also provides a method for treating zinc deficiency by administering to a subject a zinc-containing compound having a serum zinc concentration value classified as being indicative of potential zinc deficiency. For children weighing less than 30 kg, 1.0 mg / kg / day of zinc is recommended. For children weighing less than 30 kg who have a serum zinc concentration classified as The starting dose is 100 mg / kg / day, and the drugs are administered orally or by tube. It is a drug for treating hypozincemia.

[0010] The present invention also provides a method for treating zinc deficiency, comprising administering to a subject a zinc acetate-containing diet containing zinc acetate, and showing a serum zinc concentration value classified as potential zinc deficiency, For children weighing less than 30 kg who do not show typical clinical symptoms of zinc deficiency, The serum zinc concentration classified as zinc deficiency is 1.0 mg / kg / day. For children weighing less than 30 kg who have symptoms typical of zinc deficiency, The starting dose was 1.5 mg / kg / day of lead, and the animals were administered orally or by tube. It is a hypozincemia treatment agent administered by

[0011] Furthermore, the present invention provides a method for treating a patient having a serum zinc concentration of 50 μg / dL or more but less than 80 μg / dL, which method comprises the step of administering zinc acetate to a patient having a serum zinc concentration of 50 μg / dL or more but less than 80 μg / dL. For children weighing less than 30 kg, 1.0 mg / kg / day of zinc is recommended. For children weighing less than 30 kg with a serum zinc concentration less than 50 μg / dL, The starting dose was 1.5 mg / kg / day, and the drugs were administered orally or by tube. It is a therapeutic agent for hypozincemia.

[0012] Furthermore, the present invention provides a method for treating a patient having a serum zinc concentration of 50 μg / dL or more and 80 μg / dL or more, which comprises using zinc acetate. Children weighing less than 30 kg with a zinc deficiency level of less than 1000 mg / kg and who do not exhibit symptoms characteristic of zinc deficiency For those with a serum zinc concentration of less than 50 μg / dL, the recommended dose is 1.0 mg / kg / day of zinc. For children weighing less than 30 kg who have symptoms characteristic of zinc deficiency, zinc and The starting dose was 1.5 mg / kg / day, and the dose was administered orally or by tube. It is a hypozincemia treatment agent administered. [Effects of the Invention]

[0013] This invention makes it possible to safely and effectively treat hypozincemia in children with specific dosage regimens. It is possible to provide a therapeutic agent for hypozincemia that can be effectively used. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention will be described in detail below.

[0015] A therapeutic agent for hypozincemia according to one embodiment of the present invention contains zinc acetate and is effective in treating children weighing less than 30 kg. The starting dose of zinc is 1.0 mg / kg / day or 1.5 mg / kg / day. It is a therapeutic agent for hypozincemia that is administered orally or via an enteral tube.

[0016] In this specification, the term "children" refers to children under the age of 15, and includes newborns, infants, and young children.

[0017] The starting dose is selected based on the serum zinc concentration and clinical symptoms of the subject. For example, if a subject is diagnosed with potential zinc deficiency based on serum zinc concentration or clinical symptoms, In cases where the doctor in charge has determined that a small dose is sufficient to be effective, such as when If the subject has zinc deficiency, the dose should be 1.0 mg / kg / day. If the subject has zinc deficiency, the dose should be higher. If your doctor determines that a dose of 1.5 mg / kg / day is necessary, select a starting dose of 1.5 mg / kg / day. The present invention allows the starting dose to be selected from two dose levels. In addition, the dosage was determined based on the subject's weight, so children weighing less than 30 kg were This makes it possible to safely and effectively treat hypozincemia.

[0018] A therapeutic agent for hypozincemia according to another embodiment of the present invention contains zinc acetate and is effective in treating potential zinc deficiency. For children weighing less than 30 kg who have similar serum zinc concentrations, 1.0 mg of zinc / kg / day for children weighing less than 30 kg who have a serum zinc concentration classified as zinc deficiency For the patients with rheumatoid arthritis, the starting dose was 1.5 mg / kg / day of zinc orally. Alternatively, it is a therapeutic agent for hypozincemia administered by enteral administration.

[0019] A therapeutic agent for hypozincemia according to yet another aspect of the present invention contains zinc acetate, and is effective in treating potential zinc deficiency. A patient with a body weight of 3 or less who has a serum zinc concentration classified as deficient and does not show typical clinical symptoms of zinc deficiency For children under 0 kg, 1.0 mg / kg / day of zinc is recommended. Those with a body weight of 3 or above who have serum zinc concentrations exceeding the range indicated by the standard or who exhibit symptoms typical of zinc deficiency For children under 0 kg, the starting dose is 1.5 mg / kg / day of zinc. It is a therapeutic agent for hypozincemia that is administered orally or via an enteral tube.

[0020] In this specification, the serum zinc concentration classified as potential zinc deficiency is a healthy serum zinc concentration. Serum zinc levels that are lower than the lower limit of the normal range and are above the reference value for zinc deficiency Zinc concentration is shown. "2018 Guidelines for the Treatment of Zinc Deficiency" (edited by the Japanese Society of Clinical Nutrition) According to the National Institute of Health (NIH), the serum zinc concentration level that is considered to be a potential zinc deficiency is 60 μg / dL or higher and 80 μg / dL or lower. However, the actual dosage should be determined based on the daily serum zinc concentration. To allow for variability, another cut-off value may be established around this value. For example, starting dose The lower limit of serum zinc concentration determined as 1.0 mg / kg / day as zinc is 50 μg / d. The serum concentration may be set between 60 μg / dL and 60 μg / dL. The upper limit of the zinc concentration may be set to a value between less than 70 μg / dL and less than 90 μg / dL.

[0021] The serum zinc concentration can be measured by known methods. For example, the serum zinc concentration can be measured by atomic absorption spectrometry. Measurement equipment such as the ZA3300 (manufactured by Hitachi High-Tech Science Corporation), and Aqurasu Auto Measurement can be performed using a measurement kit such as Zn (manufactured by Shino Test Co., Ltd.).

[0022] The cut-off value is also called a pathological condition identification value, and in this specification, it is used to determine the dosage of a preparation. It is used as a value to determine whether to increase or decrease the dose, or to discontinue administration.

[0023] On the other hand, the serum zinc concentration required to determine zinc deficiency is based on the "2018 Guidelines for the Treatment of Zinc Deficiency" ( The Japanese Society of Clinical Nutrition (ed.) defines it as less than 60 μg / dL. However, when determining the actual dosage, the diurnal variation of serum zinc concentration should be taken into consideration, and different doses should be administered around this value. For example, a cut-off value of 1.5 mg / kg / day for zinc may be set. The upper limit of serum zinc concentration for determining daily intake is less than 50μg / dL to less than 60μg / dL. It may be set between.

[0024] As used herein, typical clinical symptoms of zinc deficiency are those observed in patients with zinc deficiency. These symptoms include dermatitis, hair loss, taste abnormalities, anemia, susceptibility to infection, and poor wound healing. If these symptoms are confirmed, the serum zinc concentration is judged to be zinc deficiency. Even if the value is higher than the recommended value, the patient should be treated as having zinc deficiency and the starting dose should be adjusted to a submaximal level. Set at 1.5 mg / kg / day as lead.

[0025] Another embodiment of the present invention provides a therapeutic agent for hypozincemia, which contains zinc acetate and can reduce serum zinc levels to 50μg / mL. Weight 3: ≥ 80 μg / dL and < 80 μg / dL, and not showing symptoms characteristic of zinc deficiency For children under 100 kg, 1.0 mg / kg / day of zinc is administered. For children weighing less than 30 kg who have symptoms characteristic of zinc deficiency or whose blood sugar is less than μg / dL The starting dose for each group was 1.5 mg / kg / day of zinc, administered orally or orally. It is a hypozincemia treatment agent administered via the tube.

[0026] In a preferred embodiment, the therapeutic agent for hypozincemia according to the present invention is administered based on certain conditions. In a preferred embodiment, the amount of the drug is increased or decreased for a certain period of time. If administration is continued at the same dose, serum zinc concentration is judged to be below the normal range. If this occurs, increase the dose by 0.5 mg / kg / day until serum zinc levels exceed the safety limit. If it is determined that the patient has a high level of copper, or if the serum copper concentration is determined to be below the safe range, In particular, if the serum copper concentration is less than 10 μg / dL, the dosage should be reduced by 0.5 mg / kg / day. If it is less than this, discontinue administration.

[0027] Generally, the healthy range of serum zinc concentration is considered to be 80-130 μg / dL. Based on this standard, the cutoff value for determining whether to increase the dose should be set at less than 80 μg / dL. However, when setting the actual cutoff value, it is necessary to consider the diurnal variation of serum zinc concentration. Taking this into consideration, another value may be set around this value. In other words, if the current dosage is not effective enough, If it is judged that the serum zinc concentration is not sufficient, the dose can be increased. If the serum zinc concentration is less than 90 μg / dL, or if the serum zinc concentration is less than 8 μg / dL, the If the zinc level is less than 5 μg / dL, the dose should be increased by 0.5 mg / kg / day. However, the serum zinc concentration should be set as the cutoff value for increasing the dosage. Even if the dose is lower than the maximum daily dose, safety is assured if the current dose reaches the maximum daily dose. Taking this into consideration, administration will continue at the same dosage as currently.

[0028] In a preferred embodiment, the cutoff value when the serum zinc concentration exceeds the safety range is: The cut-off value for serum copper concentrations below the safety limit can be set at 160 μg / dL or higher. For example, a serum copper concentration of 10 μg / dL can be 30 μg / dL or less. If the dose is more than 30 μg / dL, reduce the dose by 0.5 mg / kg / day based on zinc. If the serum copper concentration is less than 10 μg / dL, administration should be discontinued. It is possible.

[0029] The decision to increase or decrease the dosage is made after administering the same dosage for a certain period of time. The period of administration of the drug should be determined taking into account the diurnal variation of serum zinc concentration. It is set as the period required for the blood pressure to stabilize. It is usually set between 1 and 4 weeks. The period can be set to 4 weeks.

[0030] In a preferred embodiment, the therapeutic agent for hypozincemia according to the present invention is administered in a daily dose divided into two doses: Administer orally or via a gastric tube after breakfast and dinner or approximately 30 to 60 minutes after the end of tube feeding in the morning and evening. It can be used by

[0031] The therapeutic agent for hypozincemia according to the present invention is in a form that can be administered orally or through an enteral tube, with the dosage flexibly adjusted. It may be in any form, preferably in the form of granules, dry syrup, tablets, etc. Granules or dry syrups can be particularly preferably used.

[0032] The therapeutic agent for hypozincemia according to the present invention can be formulated into granules, dry syrup, tablets, etc. by known methods. For example, in the case of tablets, the formulation can be prepared as described in International Publication WO2016 / 088816. Alternatively, in the case of granules, the preparation can be carried out by, for example, the process (1): Approximately spherical particles mainly composed of sugar and / or crystalline cellulose, zinc acetate, and spraying a solution or suspension containing the agent, followed by spraying a solution or suspension of the disintegrant. Step (2): spraying a water-dispersed ethyl cellulose suspension containing a plasticizer; and Step (3): Add a fluidizing agent and heat in a sealed state at 70 to 100°C for 15 to 180 minutes. It can be produced by sequentially carrying out a heating step. [Example]

[0033] The present invention will be described below with reference to specific embodiments, but the present invention is not limited to these embodiments. It is understood that various changes and modifications therein will occur to those skilled in the art without departing from the spirit and scope of the appended claims. It is understood that such practice can be practiced without departing from the scope or spirit of the invention as defined in the appended claims. It is understood.

[0034] Preparation of granules containing zinc acetate as an active ingredient Spherical particles with a particle size of 355 to 500 μm (product name: No) made of refined white sugar and corn starch 1300 g of PAREL (registered trademark -101, manufactured by Freund Corporation) was placed in a rolling fluidization device. The drug substance solution and disintegrant suspension with the following composition were sprayed in this order under the condition of an inlet air temperature of 65°C. As a result, the drug substance-coated particles were obtained. Drug substance dissolving solution: 1207 g of 6% hydroxypropyl cellulose solution, zinc acetate hydrate (C A solution containing 351.1 g of 4H6O4Zn·2H2O. Disintegrant suspension: 352 g of 6% hydroxypropyl cellulose solution, 4 g of partially pregelatinized starch 1.1g was added and suspended in the liquid.

[0035] 1500g of the obtained coated particles was mixed with 20% ethyl acetate containing approximately 2% triethyl citrate. 450 g of ethyl cellulose suspension was sprayed onto the surface of the substrate, and the mixture was sieved through an 18-mesh sieve to remove ethyl cellulose. The resulting ethyl cellulose-coated particles were mixed with 0.7% of a light inorganic powder. Add hydrated silica and mix, then place in a sealed container and heat at 80°C for 2 hours. Granules containing the active ingredient were obtained.

[0036] Evaluation method Eleven subjects weighing less than 30 kg (starting age 5.0 ± 2.6 years (0-7 years), weight 14.1±4.6kg (6.0-20.8kg), serum zinc concentration at the start 61.8±6.0 μg / dL, the granules obtained above (1g contains 167.8mg (substances) of zinc acetate hydrate) The test substance was administered twice a day, in the morning and evening, after meals or Approximately 30 to 60 minutes after the end of tube feeding, the drug was administered orally or through a gastric tube (oral administration: 7 cases, Tube administration: 4 cases)

[0037] Dosage and administration method The starting dose is (A) For subjects with serum zinc concentrations of 50 μg / dL or greater but less than 70 μg / dL, zinc and 1.0 mg / kg / day, (B) For subjects with a serum zinc concentration of less than 50 μg / dL, 1.5 mg / kg of zinc g / day, It was decided.

[0038] Serum zinc levels were measured every four weeks, and the dosage was increased according to the following criteria: Maximum dosage The dose was 3.0 mg / kg / day. (C) If serum zinc concentration is less than 90 μg / dL: 0.5 mg / kg based on most recent body weight g / day increase (D) If the serum zinc concentration is less than 80 μg / dL after 8 weeks of administration at the same dose: Increase dose by 0.5 mg / kg / day based on body weight

[0039] In addition, if the serum zinc concentration is 160 μg / dL or higher or the serum copper concentration is 1 If the level is between 0 μg / dL and 30 μg / dL, reduce the dose by 0.5 mg / kg / day. If the serum copper concentration was less than 10 μg / dL, administration was discontinued.

[0040] Until serum zinc concentration reaches 80 μg / dL or higher after 8 weeks of administration at the same dose The administration of the test substance was continued while increasing or decreasing the dose according to the above conditions. Subjects who achieved a serum zinc concentration of 80 μg / dL or higher after 1 week of administration were considered to be therapeutically effective. The proportion of patients who received the treatment was calculated to evaluate the effectiveness of the treatment.

[0041] Evaluation results The administration period of the test substance ranged from 8 to 28 weeks, and therapeutic efficacy was observed in 10 of 11 subjects. The dose at which the therapeutic effect was observed was 1.0 mg / kg / day in 4 cases and 1.0 mg / kg / day in 1 case. 0.5mg / kg / day in 1 case, 2.0mg / kg / day in 3 cases, and 2.5mg / kg / One case was at 3.0 mg / kg / day, and one case was at 3.0 mg / kg / day.

[0042] Furthermore, no significant adverse events suspected to be causally related to the test substance were observed. As a result, by using the therapeutic agent for hypozincemia according to the present invention, it is possible to safely and effectively It has been shown that hypozincemia can be treated in children weighing less than 100 kg. [Industrial Applicability]

[0043] The present invention provides a therapeutic agent for hypozincemia that can safely and effectively treat hypozincemia in children. It will be possible to provide.

Claims

1. Contains zinc acetate, and for children weighing less than 30 kg, the dose is 1.0 mg / kg / d as zinc. The starting dose was 1.5 mg / kg / day, and the drug was administered orally or by tube. A drug for treating hypozincemia.

2. Contains zinc acetate, For children weighing less than 30 kg who have serum zinc concentrations that are classified as potentially zinc deficient, 1.0 mg / kg / day as zinc, For children weighing less than 30 kg who have serum zinc levels classified as zinc deficiency, zinc and 1.5 mg / kg / day, A hypozincemia treatment agent administered orally or via tube administration at the starting dose.

3. Contains zinc acetate, Serum zinc concentration values ​​classified as potential zinc deficiency and clinical symptoms typical of zinc deficiency For children weighing less than 30 kg who do not exhibit rheumatoid arthritis, 1.0 mg / kg / day of zinc is recommended. 、 Those with serum zinc levels that are classified as zinc deficiency or who have symptoms typical of zinc deficiency For children weighing less than 30 kg, 1.5 mg / kg / day of zinc is recommended. 、 A hypozincemia treatment agent administered orally or via tube administration at the starting dose.

4. Contains zinc acetate, For children weighing less than 30 kg with serum zinc concentrations between 50 μg / dL and 80 μg / dL For example, 1.0 mg / kg / day of zinc For children weighing less than 30 kg with a serum zinc concentration of less than 50 μg / dL, 1.5 mg / kg / day, A hypozincemia treatment agent administered orally or via tube administration at the starting dose.

5. Contains zinc acetate, Serum zinc concentration is 50 μg / dL or more but less than 80 μg / dL, and is characteristic of zinc deficiency For asymptomatic children weighing less than 30 kg, 1.0 mg / kg / day of zinc day, Those with a serum zinc concentration of less than 50 μg / dL or those with symptoms characteristic of zinc deficiency who weigh 30 For children under 1 kg, 1.5 mg / kg / day of zinc A hypozincemia treatment agent administered orally or via tube administration at the starting dose.

6. The method according to any one of claims 1 to 5, wherein the dosage is increased according to the following criteria: Treatment for hypozincemia. (i) When the measured serum zinc concentration at a certain period is less than the lower limit of the healthy range: 0.5 m g / kg / day increase

7. Any one of claims 1 to 5, wherein the dosage is reduced or administration is discontinued according to the following conditions: The therapeutic agent for hypozincemia described in (ii) If the measured serum zinc concentration is 160 μg / dL or more: 0.5 mg / kg / da y weight loss (iii) When the measured serum copper concentration is 10 μg / dL or more and less than 30 μg / dL: 0.5 mg / kg / day weight loss (iv) If the measured serum copper concentration is less than 10 μg / dL: Discontinue administration.

8. The daily dose is divided into two doses, morning and evening, and administered orally or through a tube after meals or tube feeding. The therapeutic agent for hypozincemia according to any one of claims 1 to 7, characterized in that it is administered.

9. The therapeutic agent for hypozincemia according to any one of claims 1 to 8, which is in the form of granules.