Radiopharmaceutical combination

Abstract

To provide a radiopharmaceutical combination agent capable of reducing the dose of a radiopharmaceutical and reducing the exposure dose of a patient by delaying the discharge rate of radioactive atoms from blood to urine.SOLUTION: A radiopharmaceutical combination comprising a hydroxypropylated cyclodextrin, wherein the radiopharmaceutical combination is for intravenous administration.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a radiopharmaceutical combination agent that is used in combination with a radiopharmaceutical that utilizes a radioactive atom. [Background technology]

[0002] Radiopharmaceuticals containing radioactive atoms are used, for example: 123 I, 125 I, 131 Radioactive iodine such as I is used in nuclear medicine as a diagnostic and therapeutic agent for thyroid cancer and thyroid diseases such as hyperthyroidism and hypothyroidism. Radioactive iodine is also used as a diagnostic agent for detecting abnormalities in myocardial fatty acid metabolism and sympathetic nerve distribution, and as a therapeutic agent for neuroendocrine tumors. Once administered, radioactive iodine is transferred to the blood and excreted from the body in urine within a short time. For example, 131 In the oral administration of radioactive iodine ( 131 80-90% of I) is excreted in urine within a few days (ICRP publ.78, 2001, etc.). Therefore, in order to deliver the amount of radioactive iodine required for treatment to the target organ or lesion, it is necessary to administer a certain amount of radioactive iodine or more, with the expectation that it will be excreted and reduced in a short period of time, which raises concerns about excessive exposure.

[0003] The standard for the concentration of radioactive iodine discharged into general sewage is set at 1 / 10 to 1 / 100 of that of other radioisotopes. 131 In order to reduce the concentration of radioactive iodine-containing urine generated during internal thyroid cancer therapy using I to below the standard for discharge as general wastewater, the urine must be stored for more than six months to allow the radioactivity to decay, or diluted approximately 40 million times. The treatment of radioactive liquid waste containing radioisotopes requires large-scale drainage facilities equipped with storage tanks, dilution tanks, etc. Furthermore, because radioactive iodine and radioactive astatine are highly volatile, specialized measures are required not only for the drainage facilities but also for the buildings surrounding them to prevent leakage to the outside in the event of a breakdown in the drainage facilities. Therefore, the installation and maintenance of drainage facilities for treating radioactive liquid waste is extremely costly. Furthermore, when treatment of radioactive liquid waste cannot keep up with demand or when storage space is full, the number of patients treated must be limited, which can result in delays in the start of treatment.

[0004] The present inventors have proposed an invention of an oral composition for preventing thyroid radiation exposure, which contains cyclodextrin and prevents or reduces internal exposure of the thyroid to radioactive iodine. This invention utilizes the property of cyclodextrin to encapsulate radioactive iodine, and by encapsulating radioactive iodine in the digestive tract, the cyclodextrin prevents the radioactive iodine from being absorbed from the small intestine. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2024-011102 Summary of the Invention [Problem to be solved by the invention]

[0006] If the rate at which radioactive atoms are excreted from the blood into the urine can be slowed, there will be no need to administer them in anticipation of their rapid excretion and reduction, which will reduce the amount of radioactive drugs required for treatment and testing. An object of the present invention is to provide a radiopharmaceutical combination drug that can reduce the dose of a radiopharmaceutical administered and thereby reduce the amount of radiation exposure of a patient by slowing the rate at which radioactive atoms are excreted from the blood into the urine. [Means for solving the problem]

[0007] The present inventors have succeeded in slowing the rate of excretion of radioactive atoms from the blood into the urine by utilizing the property of cyclodextrin to encapsulate various atoms such as radioactive iodine, as shown in Cited Document 1, and have thus completed the present invention. That is, the means for solving the problems of the present invention are as follows. 1. A radiopharmaceutical combination drug containing hydroxypropylated cyclodextrin and intended for intravenous administration. 2. The radiopharmaceutical combination preparation according to 1, wherein the cyclodextrin contains α-cyclodextrin in an amount of 50% by mass or more. [Effects of the Invention]

[0008] The radiopharmaceutical combination drug of the present invention can slow the rate of excretion of radioactive atoms from the blood into the urine. By using the radiopharmaceutical combination drug of the present invention, the concentration of radioactive atoms in the blood can be maintained higher than when the radiopharmaceutical combination drug is not used in combination, and therefore the dose of the radiopharmaceutical can be reduced, thereby reducing the patient's exposure to radiation. The radioactive drug combination drug of the present invention can reduce the dose of the radioactive drug, thereby reducing the amount of radioactive atoms in the generated radioactive waste liquid (urine). By using the radioactive drug combination drug of the present invention, there is more room for treatment and storage of the radioactive waste liquid, so the number of patients who can be treated can be increased without additional capital investment, and the risk of aggravation can be reduced by starting treatment early, and the burden on patients can be reduced. [Brief explanation of the drawings]

[0009] [Figure 1] 1 is a graph showing the measurement results of 125I radioactivity in blood collected from the thyroid gland and the heart in Example 1 and Comparative Example 1. [Figure 2] 1 is a graph showing the measurement results of 125I radioactivity in blood collected from the thyroid gland and the heart in Example 2 and Comparative Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0010] The radiopharmaceutical combination drug of the present invention contains hydroxypropylated cyclodextrin (hereinafter also referred to as HP-CD) and is for intravenous administration. Cyclodextrins (hereinafter referred to as CDs) are compounds with a truncated cone structure in which α-glucopyranose groups are linked together in a ring via α-1,4-glycosidic bonds, and are also called cyclic oligosaccharides. There are three main types of cyclodextrins, depending on the number of pyranose groups that make up the ring: αCD (6 groups), βCD (7 groups), and γCD (8 groups). While αCD and γCD have excellent water solubility, βCD has low water solubility. The HP-CD used in the present invention has improved water solubility due to hydroxypropylation, and hydroxypropylated βCD also has excellent water solubility. The radiopharmaceutical combination drug of the present invention is for intravenous administration, but the use of HP-CD allows it to remain dissolved in the blood. HP-CD has been approved as an additive to oral and injectable drugs, and its safety has been confirmed.

[0011] CDs have a hydrophobic interior and a hydrophilic exterior, and can incorporate and encapsulate hydrophobic substances, i.e., radioactive substances, into their interior. The CD used in the present invention can be selected depending on the size of the radioactive atom contained in the radiopharmaceutical used, and one or more of αCD, βCD, and γCD can be used. For example, in the case of radioactive iodine (I) and radioactive astatine (At), αCD and βCD are preferred, and αCD is more preferred.

[0012] When radioactive iodine (I) or radioactive astatine (At) is targeted, it is preferable that αCD is contained in an amount of 50 mass% or more of the total CD. αCD and βCD have inner diameters close to the sizes of iodine atoms and astatine atoms, allowing them to be encapsulated more efficiently. Furthermore, αCD is less likely to release encapsulated radioactive atoms from CD than βCD, so it is possible to suppress the excretion of radioactive atoms in urine more effectively than βCD, allowing them to remain in the body for a longer period of time.

[0013] The radiopharmaceutical combination drug of the present invention may contain, in addition to HP-CD, pH adjusters, buffers, stabilizers, preservatives, antiseptics, surfactants, physiological saline, and the like, which are used in intravenous drugs, as needed. The radiopharmaceutical combination drug of the present invention is intravenously administered simultaneously with the radiopharmaceutical, or before or after the administration of the radiopharmaceutical. Since the radiopharmaceutical combination drug is preferably present in the blood simultaneously with the radiopharmaceutical, when the radiopharmaceutical is administered intravenously, it is preferably administered simultaneously with or before the administration of the radiopharmaceutical. Furthermore, when the radiopharmaceutical is administered orally and the radioactive atoms are absorbed in the digestive tract and then transferred into the blood, the radiopharmaceutical combination drug is intravenously administered depending on the timing of the transfer.

[0014] In the radiopharmaceutical combination preparation of the present invention, HP-CD encapsulates the radioactive atom by associating with the radioactive atom in the blood. The greater the amount of HP-CD, the higher the probability of encapsulating the radioactive atom. Therefore, the number of moles of HP-CD administered intravenously is preferably at least one time the number of moles of the administered radioactive atom, more preferably at least two times, even more preferably at least three times, and even more preferably at least four times.

[0015] The radioactive atoms encapsulated in the HP-CD are released from the HP-CD stochastically according to thermodynamic equilibrium. The released radioactive atoms are in ionic form and are efficiently excreted in urine. On the other hand, since there is no enzyme in the blood that can break down CD, CD is excreted in the urine as a molecule. Because HP-CD exists as a molecule, it is larger in size and is excreted in urine more slowly than ionic radioactive atoms. Therefore, radioactive atoms encapsulated in HP-CD are less likely to be excreted in urine, increasing their retention time in the blood.

[0016] By using the radioactive drug combination drug of the present invention in combination with radioactive iodine, the accumulation of radioactive iodine in the thyroid gland can be increased; specifically, the accumulation amount after 24 hours can be increased by about 1.5 times compared to when the drug is not used in combination. This increase in accumulation is thought to be due to the fact that the radioactive iodine concentration in the blood is maintained at a high level for a longer period of time by the radioactive drug combination drug of the present invention, thereby increasing the amount of radioactive iodine transferred to the thyroid gland. For example, in cases where 24 hours are required between the administration of a radioactive drug containing radioactive iodine and the time of thyroid examination for radioactive iodine to accumulate in the thyroid gland to a certain extent, the use of the radioactive drug combination drug of the present invention can increase the amount of radioactive iodine in the thyroid gland after 24 hours by about 1.5 times, thereby reducing the amount of radioactive iodine required to accumulate the same amount of radioactive iodine to about 0.67 times (= 1 / 1.5), thereby reducing the patient's radiation exposure. [Example]

[0017] HP-αCD (Wacker, CAVASOL (registered trademark) W6 HP) was used as the radiopharmaceutical combination agent. "Example 1" 125 The radiopharmaceutical combination drug was dissolved in 0.1 ml (185 kBq) of saline solution containing I to a concentration of 5% HP-αCD, and this solution was injected into the tail vein of mice (n = 3). "Comparative Example 1" The same procedure as in Example 1 was carried out except that no radiopharmaceutical was used concomitantly. 125 0.1 ml (185 kBq) of I dissolved in saline was injected into the tail vein of mice.

[0018] "Example 2" The radiopharmaceutical combination drug was dissolved in physiological saline to prepare a 5% HP-αCD aqueous solution, and 0.1 ml of this solution was intravenously injected into mice. 125 0.1 ml (185 kBq) of an aqueous solution of I dissolved in physiological saline was orally administered. "Comparative Example 2" The same procedure as in Example 2 was carried out except that no radiopharmaceutical was used. 125Mice were orally administered 0.1 ml (185 kBq) of I dissolved in physiological saline.

[0019] 24 hours after injection, the levels of thyroid and heart blood samples were 125 The radioactivity was measured using a gamma counter (Hitachi Aloka, ARC-7000). The results are shown in Figures 1 and 2.

[0020] Radioactive iodine ( 125 In Example 1 and Comparative Example 1, in which Calcium I) was administered into the blood, the radioactivity in the thyroid gland was about 1.6 times higher and the radioactivity in the blood was about 1.1 times higher in Example 1, in which a radioactive drug combination drug of the present invention was also administered, compared to Comparative Example 1, in which a radioactive drug combination drug was not administered. Radioactive iodine ( 125 In Example 2 and Comparative Example 2, in which 1) was orally administered, the radioactivity in the thyroid gland was about 1.5 times higher and the radioactivity in the blood was about 2.8 times higher in Example 2, in which a radioactive drug combination drug of the present invention was used in combination, compared to Comparative Example 2, in which a radioactive drug combination drug was not used in combination. From this, it was confirmed that by using the radioactive drug combination drug of the present invention in combination with a radioactive drug, it is possible to suppress the excretion of radioactive atoms from the blood into the urine and maintain a high concentration of radioactive atoms in the blood.

Claims

1. A radiopharmaceutical combination drug containing hydroxypropylated cyclodextrin, for intravenous administration.

2. 2. The radiopharmaceutical combination preparation according to claim 1, wherein the cyclodextrin contains α-cyclodextrin in an amount of 50% by mass or more.

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