JP2018052884A - Agent for oral administration containing radionuclide chelating agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an agent for oral administration containing radionuclide chelating agent by which Ca-DTPA or Zn-DTPA can be easily administered to a patient even under a confused state, and which allows blood to efficiently intake Ca-DTPA or Zn-DTPA.SOLUTION: An agent for oral administration containing radionuclide chelating agent according to the present invention is constituted of a medicinally effective component containing at least one of diethylenetriamine pentaacetic acid calcium trisodium and diethylenetriamine pentaacetic acid zinc trisodium, and an enteric capsule into which the medicinally effective component is encapsulated. It is more preferable that absorption promoter promoting absorption of the medicinally effective component in a small intestine or a large intestine be encapsulated into the enteric capsule in addition to the medicinally effective component.SELECTED DRAWING: None

Description

  The present invention relates to an orally administered agent containing a radionuclide chelating agent which is a drug for promoting the excretion of radionuclides taken into the body.

  Radionuclides of transuranium elements such as plutonium (Pt), americium (Am) and curium (Cm), which are abundant in spent fuel of nuclear power plants, damage surrounding cells by α rays when they are taken into the body ( Internal exposure). In particular, when these radionuclides are inhaled, many of them are deposited in the nasopharynx, trachea, bronchi, and alveolar regions, and the radionuclides that have reached the alveoli are blood directly from the alveolar wall or via lymph nodes. Migrate in. Transuranium elements that have migrated into the blood are taken into organs such as bones and liver, and cause various diseases such as cancer. For this reason, countermeasures in the event of a contamination accident due to radionuclides at nuclear facilities in Japan are being considered.

In order to reduce internal exposure due to radionuclides, it is necessary to rapidly excrete radionuclides that have migrated into the blood. One of the drugs that promotes the excretion of radionuclides in the blood is one of trisodium diethylenetriamine pentaacetate (CaNa ₃ -DTPA (hereinafter referred to as “Ca-DTPA”)) and trisodium diethylenetriamine zinc pentaacetate ( ZnNa ₃ -DTPA (hereinafter referred to as “Zn-DTPA”)) (Non-Patent Document 1). Currently, intravenous administration is the most effective administration method for the removal of radionuclides in vitro. Therefore, Ca-DTPA and / or Zn-DTPA are stocked as injections in countries with nuclear weapons or countries with nuclear facilities.

  Ca-DTPA and Zn-DTPA are chelating agents that form a more chemically stable complex by substituting the radionuclide with calcium or zinc contained therein. It is believed that Ca-DTPA and / or Zn-DTPA can promote extracorporeal excretion of radionuclides in blood, particularly by intravenous administration.

Junko Iwamoto, Jun Fujita, JAERI, 4048 (1969) Shun Fukuda, "Toxicity Evaluation of Chelating Agent DTPA", Health Physics, 24, pp. 201-210, 1989

  Intravenous administration allows Ca-DTPA or Zn-DTPA to be rapidly and efficiently taken into the blood. However, intravenous administration must be performed by doctors, nurses, etc., and there are problems as a method for many people in the event of an emergency such as an accident. Development is desired.

  On the other hand, it has been studied that Ca-DTPA or Zn-DTPA is taken into blood by inhalation or oral administration, which is a dosage form that can be performed by the patient himself. For inhalation administration, Ca-DTPA or Zn-DTPA is taken into blood from the alveoli via the nasopharynx, trachea, bronchi, and for oral administration, Ca-DTPA or Zn-DTPA is taken into blood from the intestine It is. The former has poor efficiency in reaching the alveoli, and the effect is about 1/10 of the effect of intravenous administration. The use of Ca-DTPA or Zn-DTPA by inhalation is acceptable in the United States, but not in Germany and France. Further, in the United States, a spraying method in which a drug is taken into the alveoli using a nebulizer (nebulizer) has been adopted, but phytotoxicity due to the spraying method has also been reported. Furthermore, in view of the physiological differences between Japanese and Americans, demonstration experiments are necessary, and the administration methods used in the United States cannot be immediately applied to Japan. On the other hand, as the latter oral administration method, Ca-DTPA or Zn-DTPA has been reported to be administered orally after dissolving in water (Non-patent Document 2), but according to this, the absorption efficiency from the intestine is said to be poor. No use in any country. For this reason, it has been pointed out that when a chelating agent of powder is taken, it becomes hard to drink because it hardens in the throat and causes stomach burning / vomiting / chest burning.

  The problem to be solved by the present invention is that a patient can easily take Ca-DTPA or Zn-DTPA even in a confused situation, and can efficiently carry Ca-DTPA or Zn-DTPA to the small intestine and large intestine. The idea is to be absorbed.

  The oral administration agent containing the radionuclide chelating agent according to the present invention, which is made to solve the above-mentioned problems, includes diethylenetriamine calcium pentaacetate trisodium (Ca-DTPA) and diethylenetriamine zinc pentaacetate trisodium (Zn-DTPA). It is comprised from the medicinal component containing at least one of these, and the enteric capsule which encloses this medicinal component.

  Although the present invention has been developed in the past, the oral administration of Ca-DTPA or Zn-DTPA has not been put to practical use. This has been conceived as a result of repeated studies by the inventors of the present invention on dynamics. That is, the absorption rate from the intestinal tract when Ca-DTPA or Zn-DTPA is orally administered is as low as 3 to 8%, and vomiting, chest burning, inflammation of the small intestinal mucosa, etc. are observed (Non-patent Document 2). These symptoms are most likely caused by diethylenetriaminepentaacetic acid (DTPA), with some of Ca-DTPA and Zn-DTPA reaching the intestine. Therefore, the present inventor considered the possibility of DTPA reaching the small intestine and large intestine instead of Ca-DTPA or Zn-DTPA in the conventional oral administration agent. For example, in the data reported so far, a chelating agent (Ca-DTPA / Zn-DTPA) dissolved in water and orally administered (see Non-Patent Document 2), Ca-DTPA or Zn-DTPA is converted to DTPA in the stomach. There is a possibility that the evaluation in the intestine is a pharmacological evaluation with DTPA. In addition, even if Ca-DTPA or Zn-DTPA is encapsulated in the capsule, the capsule collapses in the stomach with a pH of about 1-2, and Ca-DTPA or Zn-DTPA in the capsule is exposed to gastric acid, resulting in , Ca-DTPA or Zn-DTPA may react with gastric acid and change to DTPA. To verify this, an experiment was conducted to investigate the reaction of hydrochloric acid (pH 1) corresponding to gastric acid with Ca-DTPA and Zn-DTPA. Ca-DTPA and Zn-DTPA easily changed to DTPA. It was confirmed.

  Therefore, in the present invention, an enteric capsule is employed as a capsule for encapsulating a drug component. An enteric capsule refers to a capsule that does not dissolve or disintegrate in the stomach but dissolves or disintegrates in the small or large intestine. For this reason, the orally administered agent according to the present invention can reach the small intestine or large intestine in a state where the drug is encapsulated, and can be taken into the blood from there. In this case, a single dose (about 1 g) of Ca-DTPA or Zn-DTPA is encapsulated in one capsule, or an amount obtained by dividing the single dose is encapsulated.

  The oral administration agent according to the present invention preferably contains an absorption enhancer that promotes absorption of the medicinal component from the small intestine or large intestine in addition to the medicinal component. Absorption enhancers include components that transiently increase the mucosal permeability of Ca-DTPA and Zn-DTPA in the small and large intestines, such as surfactants, bile acids, chelating agents, fatty acids, and nitric oxide. It is done. In particular, as compared with surfactants, bile acids, chelating agents, and fatty acids, nitric oxide has low mucosal damage and is effective.

  According to the present invention, after oral administration, the capsule does not dissolve or disintegrate in the stomach, but dissolves or disintegrates after reaching the small intestine or large intestine to release the internal medicinal component, and the blood is discharged from the small intestine or large intestine. Therefore, the radionuclide taken in the body can be chelated and rapidly excreted outside the body.

  An orally administered agent containing the radionuclide chelating agent according to the present invention includes a medicinal component containing at least one of diethylenetriaminepentaacetic acid calcium triacetate (Ca-DTPA) and diethylenetriaminepentaacetic acid zinc trisodium salt (Zn-DTPA); It consists of an enteric capsule that encapsulates the medicinal component.

  An enteric capsule can be realized by coating an ordinary enteric film with an enteric film. Examples of the material for the enteric film include hydroxypropylcellulose phthalate, hydroxypropylmethylcellulose acetate, and cellulose acetate phthalate.

  Moreover, what formed the whole capsule from the enteric component is good also as an enteric capsule. Examples of such enteric capsules include hard capsules (QUALI-V-S) manufactured by Qualicaps Co., Ltd. Of course, it is also possible to use as an enteric capsule for an oral administration agent according to the present invention a capsule composed of a gastric component and having a surface coated with an enteric film.

  In addition, there are two types of enteric capsules, hard capsules and soft capsules, which can be used, but when filling medicinal ingredients in solid form, hard capsules are filled with medicinal ingredients in liquid form. When doing so, soft capsules are desirable. Since Ca-DTPA and Zn-DTPA are in powder form, hard capsules are preferable, but it is possible to fill soft capsules by suspending the powder in a base oil to form a liquid.

Enteric capsules are sold by various manufacturers, examples of which are as follows.
(1) Qualicaps hard capsule (QUALI-VS)
Dissolution characteristics
pH 1.2 (similar to stomach acid): disintegrates in 42 minutes
pH 6.8 (same as intestinal fluid): disintegration in 5 minutes

(2) Enteric soft capsule manufactured by Fuji Capsule Co., Ltd. Dissolution characteristics
1 liquid (artificial gastric fluid): not disintegrated after 120 minutes 2 liquid (artificial intestinal fluid): disintegrated after 8 minutes

(3) Enteric Capsule (IS-Capsule) manufactured by Central Japan Capsule Co., Ltd.
Artificial gastric juice (pH 1.2, temperature 37 ± 1 ° C): Retains shape after 120 minutes (content is not eluted)
Artificial intestinal fluid (pH approx. 7, temperature 37 ± 1 ° C): Elution starts after 10 minutes, almost releases after 30 minutes, completely disintegrates after 40 minutes

(4) Enteric capsules manufactured by Sansei Pharmaceutical Co., Ltd. (E-capsules (soft capsules and hard capsules)
Dissolution characteristics (acid resistance, enteric)
Artificial gastric juice: Not disintegrated after 2 hours Artificial intestinal fluid: Disintegrated within 1 hour Heat resistance and humidity resistance Capsules did not adhere to each other even when stored at a temperature of 50 ° C and humidity of 75% for 24 hours.

  In addition to the above, enteric capsules developed by Aicero Chemical Co., Ltd. (enteric capsules coated with a chitosan coating and an enteric coating on the surface of the capsule) and enteric capsules manufactured and sold by Tokai Capsule Co., Ltd. are used. It is also possible.

  In addition, the oral administration agent containing the radionuclide chelating agent according to the present invention may be one in which Ca-DTPA or Zn-DTPA and an absorption promoter are enclosed in an enteric capsule.

Next, in order to investigate the dynamics of Ca-DTPA and Zn-DTPA in the stomach, the following experiment was performed.
<Experiment: neutralization experiment of hydrochloric acid with Ca-DTPA and Zn-DTPA>
The following two experiments were conducted to investigate the behavior of trisodium diethylenetriaminepentaacetate (Ca-DTPA) and diethylenetriaminezinc pentaacetate (Zn-DTPA) in the stomach using hydrochloric acid, the main component of stomach acid. went.

<Experiment 1>
At room temperature, 200.07 g of distilled water was added to 20.00 g (40.2 mmol) of Ca-DTPA and stirred to dissolve. The pH of the solution at this time was 7.37.
To this solution, 205.10 g (201.1 mmol) of 1 mol / L hydrochloric acid was added dropwise. The pH of the solution after dropping was 1.43. After completion of the dropwise addition, cooling was performed at 5 ° C. overnight, and white crystals were precipitated. This was filtered, rinsed with 10 ml of distilled water, and dried at O.2 kPa / 80 ° C. for 6 hours to obtain 13.44 g (34.2 mmo1) of white crystals (crude yield 85.0%). This was recrystallized from distilled water to obtain 12.84 g of white crystals (yield 81.2% from Ca-DTPA).

<Experiment 2>
Under room temperature, 200.03 g of distilled water was added to 20.OOg (38.3 mmol) of Zn-DTPA, and the mixture was stirred and dissolved. The pH of the solution at this time was 7.32. Here, 191.15 g (191.3 mmol) of 1 mol / L hydrochloric acid was added dropwise. The pH after the dropwise addition was 1.40. After completion of the dropwise addition, cooling was performed at 5 ° C. overnight, and white crystals were precipitated. This was filtered, rinsed with 10 ml of distilled water, and dried at O.2 kPa / 80 ° C. for 6 hours to obtain 12.88 g (32.8 mmol) of white crystals (crude yield 85.6%). This was recrystallized with distilled water to obtain 12.34 g of white crystals (yield 82.0% from Zn-DTPA).

The white crystalline material obtained in Experiment 1 and Experiment 2 and the commercially available DTPA (manufactured by Tokyo Chemical Industry Co., Ltd. (TCI)), and the melting points of Ca-DTPA and Zn-DTPA used as raw materials in Experiment 1 and Experiment 2, The pH was measured.
Table 1 shows the measurement results of the melting point. Here, the melting point is a melting point measuring device (model: MP-21) manufactured by Yamato Scientific Co., Ltd.
Was used as an average value of the results of three measurements.

As is clear from Table 1, the melting points of the white crystals obtained in Experiment 1 and Experiment 2 were both 211 ° C. and the same. Moreover, it was almost the same as 210 ° C., which is the melting point of commercially available DTPA. On the other hand, the raw materials Ca-DTPA and Zn-DTPA did not melt up to 300 ° C, and the melting point was 300 ° C or higher.
From the above results, it was speculated that the white crystalline material obtained in Experiment 1 and Experiment 2 was not DTPA and Zn-DTPA as raw materials but DTPA.

The measurement results of pH are shown in Table 2 below. The pH was measured by dissolving 1 g of crystals of each sample with 10 ml of distilled water, and using a portable pH meter (model: D-71) manufactured by Horiba, Ltd. As can be seen from Table 2, the pH of the solution of white crystals obtained in Experiment 1 and Experiment 2 was 2.29 and 2.30, respectively, which were almost in agreement. The pH of the commercially available DTPA solution was 2.34, which was almost the same as the pH of the white crystal solution obtained in Experiments 1 and 2.
On the other hand, the pH of the solution of the raw material Ca-DTPA and Zn-DTPA was 7.36 and 7.34, respectively, which was clearly different from the white crystal.
From the results shown in Tables 1 and 2 above, it was confirmed that the white crystalline material obtained in Experiments 1 and 2 was DTPA.

  From the above results, the inventor's assumption that Ca-DTPA and Zn-DTPA are changed to DTPA by gastric acid was proved.

Claims (2)

a) a medicinal component comprising at least one of triethylenesodium diethylenetriaminepentaacetate and trisodium zinc diethylenetriaminepentaacetate;
b) An orally administered drug containing a radionuclide chelating agent characterized by comprising an enteric capsule encapsulating the medicinal component. In the oral administration agent according to claim 1,
Furthermore, the oral administration agent which encloses the radionuclide chelating agent characterized by the absorption promoter being enclosed with the said enteric capsule.