TW201014608A - Radioactive mixture and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a radioactive mixture and a manufacturing method thereof, which uses MN series medication of organic quadridentate ligand that belong to amine-amide-thiamine disulfide and TcO4- or ReO4- to carry out chelation reaction and dissolved in lipiodol to form a radioactive mixture (188Re-Mn/Lipiodol mixture). Furthermore, the present invention uses 99mTc or 188Re of TcO4- or ReO4- to protect bone marrow from severe damage caused by free 90Y. The radioactive mixture applies the characteristics of lipiodol that may stay long in hepatoma and can be applied through injection to achieve the purpose of treating liver cancer, so that the human body damage caused by surgery operation can be avoided.

Description

201014608 IX. Description of the invention: 'Technical field to which the invention pertains>> The present invention relates to a mixture of a mixture and a method for producing the same, a radioactive mixture of the same, and a method for producing the same. [Prior Art] The liver is the largest organ in the abdominal cavity. The cancer can be divided into two types depending on the source. It is derived from the liver and is called the primary job. 'Other- paste is the other part of the ridge that spreads to the liver. It is called continuous hepatocellular carcinoma. Among them, hepatocellular carcinoma (hepatoma) is also the most common malignant primary liver tumor. Hepatocellular carcinoma is not common among the majority of the population in the United States and Europe, but in many Asian and African countries it is one of the three most deadly cancers. According to the statistics of the Department of Health of China's Executive Yuan, the main cause of death in Taiwan in the year of 1996, cancer is the top ten cause of death, while liver cancer is the leading cause of cancer death in men and second in women. Liver cancer has no early signs of symptoms. Liver recording methods include 1 dirty ultrasound, _ tomography, liver angiography, etc. Since 60.80% of patients have an increase in the value of alPha-fetoprotein in the blood, it is helpful to measure this value. Diagnosis of liver cancer. Although liver cancer can be assessed by liver ultrasound and traditional computer-scanning, the two methods are usually not enough. ββ-sensitive, so that small liver cancers with multiple focal points cannot be detected, especially 2% of tumors smaller than two millimeters. It can't be detected by ultrasound, especially when it is hardened by the liver. Although the treatment of liver cancer is considered to be the preferred method of treatment, it will cause harm to the human body and is not optimistic after the hand. Iodized oil (Li_ol) is a moth-like fatty acid extracted from poppy seed oil. The glycerin in its structure is brewed with ethanol. It is commonly used in lymphatic and hepatobiliary tracts. Contrast agent. Lipiodol can be retained in hepatic tumors for a long period of time. Because of its structure containing a large amount of iodine, radioactive iodine]31 can be used for radiotherapy of liver tumors by replacing the formulation of caffeine. Already listed in Europe, Case 5 201014608 is a treatment of fine tears, but mi half-degraded mail (four) 峨 for 13 days, and placed in the gamma ray (3641 ^ 〇, and its beehive ray energy is not high, not The best therapeutic core: = outside, the National Cancer Center in Tokyo, Professor Takayasu recommended Y-Lip1〇dd of radioactive beta cells to treat liver cancer, but the half-life of the isotope 9〇γ is (4) hours, although = Nuclear species of pure beta cells (β = 2.2 MeV). In the past, many literatures reported that the financial characteristics were far superior to I, but the free 9GY caused serious damage to the bone marrow. Therefore, the present invention provides a radioactive mixture for treating liver cancer and The manufacturing method is to avoid serious injury caused by the free 9GY, and can be used for treating liver cancer. [Invention] The main object of the present invention is to provide a radioactive mixture and a method for producing the same, the radioactive The invention relates to a radioactive mixture and a manufacturing method thereof, which can avoid serious damage of bone marrow caused by free 90Y, as A further object of the present invention is to provide a radioactive mixture and a method for producing the same, which can be retained in a liver tumor for a long time by using liipodol. Another object of the present invention is to provide A radioactive mixture and a method for producing the same can achieve the effect of treating liver cancer by / main injection, thereby avoiding the use of human body damage caused by surgery. The present invention provides a radioactive mixture and a method for producing the same, the radioactive mixture include:

Sj 0 Sj-R 5 to 10% by weight of [, | ; and 50 to 55% by weight of lipiodol; wherein R is (CH2)14COOC2H5 or (CH2)13CH3 or (CH2)15CH3. The method for producing the radioactive mixture includes the steps of: dissolving the related compound in acetic acid, adding stannous chloride, glucoheptonate, 丨88Re 201014608 〗 88Re perrhenate solution and After iodized oil, set 90-10 (TC, rotation speed 500-750 rpm and mix for 90 minutes with temperature control oscillator; remove the oil layer after centrifugation to obtain radioactive mixture. For the purpose of this review, Further understanding and understanding of the technical features and the achievable effects will be described with reference to the preferred embodiment and the detailed description. [Embodiment] The present invention provides a radioactive mixture and a method for producing the same, the radioactive The mixture includes ··

The chemical structure of 5 to 10% by weight (lipiodol); ^ t R T^(CH2)14COOC2H5 ^(CH2)13CH3 ^(CH2)15CH3 is as follows:

® M=TcorRe MO-MN MN-14:R=(CH2)13CH3 MN-16:R=(CH2)15CH3 MN-16ET : R= (CH2)14C00C2H5 Since the MN series of drugs belong to the amine-melamine-dithiamine The four chelate organic ligands, which can be used with

Tc03+ and Re〇3+ undergo a chelation reaction, which will release three protons to form an electrically neutral a substance. ΜΝ 'There is no simple release (4) proton, and no sister can be transformed by the outer/child method. Anion or Yang Xuan and Wei Wei, ❹ 长 filament increases (b) the solubility, so soluble in hardened oil (lipiodol). 201014608 The method for producing a radioactive mixture of the present invention comprises the steps (as shown in the first figure): Step S11, dissolving the MN series compound in acetic acid; Step S12, adding stannous chloride, glucoheptane After the glycolate (gluc〇heptonate), 188Re perrhenate solution and deuterated oil, set 1 以 with a temperature-controlled oscillator (arc rotation at 75 rpm and mix well for 90 minutes; and step S13, take after centrifugation) The lower oily liquid gives a radioactive mixture. In the step S11, the MN series compound includes MN-14 (15-(2-thioethyl)_17-|χ2-thioethyl]amino)-15-aza-17-oxohepata decane hydrochloride ) 'MN-16 (17-(2- thioethyl)-19-[(2-thioethylamino)- 17-aza- 19-oxonano-decane hydrochloride) or MN-16ET (ethyl 17-(2-thioethyl)-19- [(2-thioethyl) amino]_17-aza-19-oxo_nonadecanoate hydrochloride), using the long-burning dinitrodithiotetrazole organic ligand MN series ligand to form a stable and easily soluble More than the complex, suitable for in vivo radiation treatment of liver cancer.

M=TcorRe MO-MIST MN-14 : R = (CH2)i3C Hj MN-16 : R= (CH,)15CH3 MIV-16ET . R = (CH2>i4COOC2H5 188Re perrhenate solution is produced using 188W/188Re Prepared by adding 0.9% sodium chloride solution. Example Preparation of radioactive mixture for treatment of liver cancer (188Re-MN/L ipi odo 1) 8 201014608 188Re-MN is synthesized by 5 mg MN-16ET The 188Re perrhenic acid is further added to the mixture. 5% Resin 188Re perrhenic acid is added to the sulphate sulphate sulphate sulphate sulphate sulphate sulphate sulphate Salt (188Re-perrhenate) solution and 3~4ml of iodized oil (Lipiodol) solution, shake it at 100°C and 750rpm with temperature-controlled oscillator and mix well for 90 minutes, mix it thoroughly by shaking, and finally mix the reaction bottle. After centrifugation, the lower layer of oil was taken to obtain a radioactive mixture for treatment of liver cancer 188Re-MN/Lipiodol. 放射 Radiochemical analysis

The radio-chemical purity of Re MN/Lipiodol products is determined by thin layer chromatography (TLC), and Silica-gel is used as the stationary phase. The mobile phase is ethyl acetate and Normal saline, Normal Saline. In order to expand the phase, '188Re-MN-16ET/Lipiodol stays at the Rf=〇 position, when

When Ethylacetate is the unfolded phase, 188Re-MN-16ET/Lipi〇dol appears between Rf=〇. 4-0. © The experimental results show that the final chemical product 188Re-MN-16ET/Lipiod〇l after extraction and purification can reach 95% or more by radioactive thin layer analysis and can be stored for 24 hours. Tumor cell culture and implantation Select N1-S1 liver cancer cells (ATCC, Maryland, U.S. A.) to Dulbecco’s

Modified Eagle Medium (GIBCO, Paisley, UK) is further mixed with 5% fetal bovine serum (FBS), 1% L-glutamine, and 20% horse serum. After about 1 week, it can reach about 4 cells per liter. Further, using Trypan_biue exciusi〇n, it was found that the cell survival rate exceeded 90%, and the test in the body of the mouse was performed. k used a 200-250 g white rat (SpragUe-j) awley rats) for the experimental animal, using 201014608 under the xiphoid laparotomy to draw a 1.5-2 cm length of wound, the left and right liver leaves were exposed. Using a 27-gauge needle, a suspension of about 4 X 1〇6 tumor cells in 1 ml was slowly injected into the liver capsule until a pale papule was formed. The injection site was gently pressed to stop bleeding, and the wound was layered. Stitching. Two weeks after the implantation, the size of the liver tumor in the rat was confirmed by ultrasonic wave. After the tumor was as long as 15×15 mm, the experimental animal was subjected to the subsequent biodistribution test. Biodistribution of 188Re-MN-16ET/Upiodol The tissue distribution of 188Re-MN-16ET/Lipi〇d〇l was obtained from 15 male mice that developed liver cancer. The rats were injected in the hepatic artery. I ml 7. 4 MBq of 1MRe_MN_16ET/Upi〇d〇i was killed in batches 24 and 48 hours, 5 in each batch. Carefully remove approximately gram of tumor, normal liver, lung, kidney, spleen, sputum, muscle, tilt, and full milliliters and weigh. The paste plus horse counter measures the radioactivity to calculate the tissue concentration, which is expressed as a percentage of the injected dose per gram of organ (% dose/g, % ID/g). Injection of Lui Iip〇d〇1) via the hepatic artery, and found that one hour after administration _ Π.55±, 44, ID/g, , 24 13 16±146 % 1〇'67±〇'95" Φ m ' The distribution after injection-hours was 6. _ G. Μ % _, but the amount of drug distribution decreased with time. In addition, until the ===" From the second circle A to the younger-graph C, respectively, after the injection of the hepatic artery, the 24th and 24th, respectively, from the second graph A to the second w (^ the tree shows the radioactive tumor site. /, the main radiation Activity stays in the liver and swelling 201014608

Table 1 Distribution of 188Re-MN-16ET/Lipiodol in the tissues and body fluids of rats after hepatic artery injection (%ID/g) ^Time organ tissue and 1 Hr 24 Hr 48 Hr blood 0.27 ±0.16 0.13 ±0.07 0.08 ±0.05 瞌11.55 ±1.44 13.16 ±1.46 10.67 ±0.95 Liver 6.96 ±0.19 5.11 ±0.28 3.26 ±0.27 Lung 0.60 ±0.56 2.11 ±0.67 1.12 ±0.36 Spleen 0.31 ±0.23 1.38 ±0.71 0.81 ±0.92 Muscle 0.05 ±0.02 0.14 ±0.20匕0.04 ±0.05 bone 0.06 ±0.01 0.18 soil 0.30 0.02 ±0.02 睪 pill 0.04 ±〇.〇1 0.06 ±0.06 0.01 ±0.00 Intestine 0.38 ±0.41 0.35 ±0.18 0.10 ±0.08 ¥dirty 0.31 ±0.16 0.42 soil 0.16 0.10 ±0.03 ^_______ 0.00 ± 0.00 0.41 ± 0.34 0.68 ± 0.61 In summary, the present invention has the following features: 1. The radioactive mixture of the present invention is a completely new mixture. 2. The present invention can avoid serious bone marrow damage caused by free 9〇γ. 3. The present invention utilizes iodized oil (Lipi〇d〇1) to retain the liver tumor for a long time and can be used for treating liver cancer. 4. The invention can achieve the effect of treating liver cancer by injection, so that the human body damage caused by surgical removal of the liver tumor can be avoided. Therefore, the present invention is practical - a novelty, progressive and available for industrial use, should meet the requirements of the special patent law of China's patent law, practice the invention patents, please pray for the early patents, to the prayer . However, the above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention. The structures, features, and spirits described in the scope of the patent application of the present invention are It is included in the scope of the patent application of the present invention. 201014608 [Simple Description of the Drawings] The first figure is a flow chart of the steps of the method for producing a radioactive mixture for treating liver cancer of the present invention. The second panel A is a radioactive distribution image showing the first hour after the injection of the hepatic artery. = Figure B shows the radioactive bifurcation presented at the first hour after the injection of the hepatic artery. The first figure c _ the 48th axis distribution image after the incumbent flight ^ [main component symbol description]

Claims (1)

201014608 X. Patent application scope: • 1. A radioactive mixture 'includes: K ^ isi-R 5~10% by weight of 1: and 8, s, 50~55% by weight of iodized oil (iipi〇d〇) i); wherein R is (CH2)14COOC2H5 or (CH2)15CH3 or (CH2)13CH3. φ 2. The radioactive mixture described in the scope of claim 1 wherein the radioactive mixture is used to treat liver cancer. A method for producing a radioactive mixture, the method comprising the steps of: Vn NH NrR () dissolving hs in acetic acid, and R is (ch2) 丨4COOC2H5 or (ch2) 丨5ch3 or (ch2) 13ch3; ❹ adding an emulsification sub After stannous chloride, glucoheptonate, 188Re perrhenate solution and eucalyptus oil, mix well; and centrifuge to remove the lower layer of oil to obtain a radioactive mixture. 4. The method for producing a radioactive mixture according to claim 3, wherein a stannous chloride, a glucoheptonate, a 188Re perrhenate solution, and After the iodized oil, in the step of thoroughly mixing, the step of fully mixing comprises a step of: shaking with a temperature-controlled oscillator at 100 ° C, rotating at 750 rpm and thoroughly mixing for 90 minutes, and thoroughly mixing by shaking at 13 201014608. The method for producing a radioactive mixture according to claim 3, wherein the method The SH HS is 5 mg. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. The method for producing a radioactive mixture according to claim 3, wherein the stannous chloride is 7.5 mg. The method for producing a radioactive mixture according to claim 3, wherein the iodized oil is 3 to 4 ml. The method for producing a radioactive mixture according to claim 3, wherein the 188Re perrhenate solution is 1 ml. The method for producing a radioactive mixture according to claim 3, wherein the glucoheptonate is 40 mg. The method for producing a radioactive mixture according to claim 3, wherein the 188Re perrhenate solution is prepared by the following steps: adding a 0.9% sodium carbonate solution using a 188 W/188 Re generator. 14