Calcium potassium ferrocyanide, a prophylactic mixture comprising this compound and the use thereof for decorporation of radiocesium in subjects affected by nuclear radiation

[Technical field] [0001] The Present Invention Provides Radioactive Cesium (From The In Vivo Environment Of An Individual Affected By Nuclear Radiation Exposure). ^* Cs), Radioactive Strontium ( ^* Sr), And A Preventive Mixture That Simultaneously Decontaminates Radioactive Iodine. [Background Technology ] [0002] Fission in experimental, isotope-producing, or energy-supplying reactors, and nuclear weapons by-products involves the formation of significant amounts of radioactive by-products. The majority of these radioactive atoms are fission products and active elements containing extremely dangerous radioisotopes such as iodine-131, strontium-89-90, cesium-134 and cesium-137, and cerium-141 and cerium-144. Is. These can cause radioactive contamination when radiated to the outside world. [0003] For these isotopes to enter the human body, they come into contact with the respiratory tract (inhaled with air), the gastrointestinal tract (taken with food and drink), and the epidermal layer of the skin (scratched or intact skin). There are three routes. [0004] Numerous methods are well known to reduce or even prevent health hazards from such radiation exposure. However, from some isotopes, essentially radioactive strontium, suitable adsorbents ( ^* Inhibits Sr absorption, or ^* Protection can only be achieved by orally concerned an if medical practice is only initiated hours after contamination, the current state of the medical field is histic due to the accumulation of radioisotope absorption in the bloodstream and lymphatic. flow in the bone. There is no efficient way to inhibit the absorption of radioisotopes, which prevents binding) and promotes its decontamination. [0005] Many of the effects of such radiation in the event of any nuclear accident, in addition to the immediate radiation hazard to the inhabitants of the "neighborhood" area, are effectively to "remote" through the atmosphere. radioactive cesium ( ^* Cs) and radioactive iodine (Cs) ^* The cause is that I) was exposed to radiation. In addition to recirculation through the plant-animal-human food chain, widespread dispersal, 30-year half- life, beta / gamma dose potential, ubiquitous dispersal throughout tissues (because of potassium homologues) in order to, ^* Cs poses a major radiobiological threat. [0006] Radioactive strontium ( ^*Sr) is another radionuclide that needs attention. Because, in addition to having a specific localization to bone that can damage the bone marrow of the affected body when entering the in vivo environment, it has a half-life of 28.5 years (because it has) A Half-Life Of 28.5 Years ( ⁹⁰ This Is Because It Is Long As Sr). It Basically Stuck To The Soil And Did Not Show Any Significant Transfer To Humans After The Chernobyl Nuclear Accident. ²³⁹ With The Exception Of Pu [0007] Of the various radioisotopes of cesium (Cs) , in addition to radioactive iodine, which induces thyroid damage early after the nuclear accident ¹³⁷ Cs and ⁹⁰ Only Sr deposits on the ground and enters the biological cycle.¹³⁷ In addition to being the most important and common fission by-product substance, Cs is often used as an active ingredient in sealed sources used in industry / medicine. It is a radionuclide of particular importance in radiation oncology and is found in hospitals That Provide Gynecological Proximity Radiation Therapy Or Intestinal Therapy For Solid Tumors. All Of These For A Variety Of Experimental, Diagnostic, And Therapeutic Purposes. ^* The Result Is A Steady Increase In Opportunities To Use Cs. The Large Number Of Reactors Around The world further increases the chances of accidental release, carried by air as well as reactor workers and neighbors. ^*Exposure to Cs or contaminated food / water poses a greater radiological hazard to distant populations. This danger has been clearly demonstrated by the radiation accidents at the Chernobyl reactor and Goiania. [0008] Radioactive cesium ( ^* Cs), especially ¹³⁷ Cs has a great impact on human health for the following reasons. 1. Easily absorbed by the body by different routes (oral ingestion, inspiration, and / or skin penetration). 2. Humans have a relatively long biological half-life of about 100 -110 days. 3. The physical half-life is 30 years. 4. Emit high-energy beta rays and osmotic gamma rays. 5. Since it is similar to potassium and sodium elements, it is distributed almost uniformly throughout the body. [0009] The most common treatment for metal poisoning is "chelation therapy". In conventional chelation therapy, a chelating agent has been injected intravenously into a patient. Widely known conventional chelating agents such as EDTA (ethylenediaminetetraacetic acid) and DTPA (diethylenetriaminepentaacetic acid) are often used .Traditional chelation therapies are very painful to the patient and their effectiveness is limited. [0010] In addition, most chelating agents used in this type of therapy are generally hydrophilic, are rapidly excreted, and have a limited ability to penetrate cells to remove the metal of interest. Thus, for example, the use of EDTA in the treatment of lead toxins is effective in removing lead in the blood, but not in removing lead that has penetrated (deposited) into cells (living tissues / organs). Absent. [0011] Also, conventional chelation therapies cannot target specific organs. Some metals deposit more significantly in one organ than in others. For example, there are metals that deposit significantly on bone. Therefore, in order to provide an effective treatment, a substance that can penetrate the With conventional chelating agents, this ability is not immediately available. [0012] It is also important that the composition promotes decontamination of the metal rather than redispersion of the metal. Some studies of known chelators have suggested that the metal is simply expelled from one tissue and re-deposited in another. In contrast, the compositions of the present invention actually remove the metal from the mammalian body. [0013] US Pat. No. 5,494,935 and US Pat. No. 5,403,862 provide several novel chelating agents, such as partially lipophilic polyaminocarboxylic acid (PACA), that decontaminate heavy metal ions from the affected in vivo system. I'm teaching. Unlike the non- lipophilic chelators EDTA and DTPA, these chelators show significant absorption from the intestine and can be administered orally. However, the problem with such chelating agents is that they are primarily directed only at certain specific organs. In addition, chelating agents target some specific absorbed metals. , not specifically those radioactive metals. [0014] US Pat. No. 5,288,718 Feeling monocyclic cryptate ligands and derivatives thereof suitable for removing radioactive strontium, and sometimes other radioactive metal isotopes, from living organisms. 1,4,10,13-Tetraoxa-7,16-Diazacyclooctadecane-N, N' -Dimalonate tetrasodium salt active agent is used in various parts of the animal body (peritoneal cavity, subcutaneous interstitium, lungs). [0015] US Pat. No. 4,780,238 describes new naturally produced chelating preparations and methods and consequent chelating methods for desorbing biologically available forms of cultures, including Pseudomonas or other microorganisms. Regarding. Suitable microorganisms are Pseudomonas aeruginosa, which forms a large number of chelates with thorium having a molecular weight of 100 to 1,000 and forms chelates with uranium having a molecular weight of 100 to 1,000 and a molecular weight of 1,000 to 2,000. [0016] XP002349586 microorganisms potassium ferrocyanide and its preparation process, which the step of precipitating the compound by However, the use of the compound for decontaminating radionuclides is not disclosed or described. [0017] [0019] GB 297 482 Discloses A Ferrocyanide Calcium-Potassium Compound Used To Prevent Crystallization Of Sugars From Solutions Such As Molasses. The Disclosed Preparation Process For Potassium Ferrocyanide Comprises Reacting Calcium Ferrocyanide With Potassium Chloride Or Reacting Sodium Ferrocyanide With A Solution Containing Potassium And Calcium Chloride. [ 0018] DE 37 35 204 A1 Contains Ammonium Iron (III) And Hexacyanoferrate (II) (Ammonium Iron) Of A Defined Purity In The Form Of Capsules For Decontaminating Radioactive Cesium After Ingestion Of Food Contaminated With Radioactive Cesium. III) Hexacyanoferrate (II) ) is disclosed. In this disclosure, it is stated that slowly crystallizing cesium iron (III) hexacyanoferrate (II) is excreted as feces. WO / 00/50046 describes a stabilized oral pharmaceutical composition containing iodine and iodate as activators in the presence of other pharmaceutical individuallys. In addition, methods and compositions that combine iodide and iodate to form oral compositions of iodide and iodate with suitable iodide and iodate stability that meet regulatory requirements by pH control. It is disclosed. [0020] Traditionally, Prussian blue (Radiogardase-Cs, sold by Heyl, Chem.-Pharm, Fabrik) in Berlin) has been used from the in vivo environment. ^* It has been used to eliminate Cs. Chemically, Prussian blue is empirical Fe ₄ [Fe (CN) ₆]₃, Ferric hexa-cyanoferrate (II), in soluble ferric hexacyanoferrate (II) with a molecular weight of 859.3 daltons, provided as a blue powder in 0.5 g gelatin capsules. [0021] [0021] By feeding animals a previously reported mixture of three compounds. , Prussian Blue, Calcium Alginate (CaA), And Potassium Iodide (KI) For Three Days Prior To Exposure To The Radionuclide. It Has Been Proposed To Eliminate Radionuclides From The In Vivo Environment. [0022] The Conventionally Known Process Has Some Problems As Follows, And The Present Invention Attempts To Solve Them. ^* 1) Prussian Blue, Calcium Alginate, And KI Need To Be Mixed With The Diet Before Being Exposed To Radionuclides, But This Is Not Always Feasible. 2) Prussian blue from the in vivo system of laboratory animals The speed of removing Cs is slow. Calcium Potassium Ferrocyanide, one of the constituents of the mixture of the present invention [CaK ₂ Fe (CN) ₆ ] Is from The in vivo system of laboratory animals ^* Decontamination of Cs is much faster than Prussian blue. 3) Prussian blue induces gastrointestinal and cardiotoxicity in laboratory animals. The mixture of the present invention does not cause such histopathological changes in these organs. Prussian blue Also causes more significant liver and kidney damage compared to calcium potassium ferrocyanide when given orally in the diet for approximately 6 months at the same dose level as Prussian blue. 4) Prussian blue has been observed to induce constipation in individuals, probably due to gastrointestinal toxicity. 5) It has been found that hemoglobin levels in animals decrease moderately after treatment with a mixture of previously reported antidote. 6) Prussian blue is stable in an acidic medium (pH 2-3) normally present in the gastric region / complexed with reactive cesium / extracted, and is a component of the mixture of the present invention. Calcium ferrocyanide [CaK] ₂ Fe (CN) ₆ ] At the same dose level, only about 25-50% of it is effective. 7) Calcium alginate, which is a component of a communicating known mixture, is a compound having a very high titer and a bad taste as compared with one of the common calcium salts used in this mixture. The calcium salts used in the mixture of the present invention include ^*It is as effective as calcium alginate in reducing the systemic residue rate of Sr. 8) KI, which is used in efficiently known etch, is known as a highly hygroscopic chemical and reduces the shelf life of the mixture. Therefore, storage problems arise. 9) Remedies Are Specific To A Particular Radionuclide And Are Not Directed Elsewhere. Therefore, Exposure To One Or More Radionuclides Requires Individual Treatment For Each Radioisotope. [0023] Therefore, There Has Been A Long-Standing Need For An Appropriate Radioactive Decontamination Agent That Specific requirements have been established for such prophylactic agents, such as: (a) Complex formation is a large amount of coions (Ca) ²⁺, Na ⁺ , K ⁺Etc.) and must be done in the biological system, even in the presence of ligands. (b) Toxicity (widespread efficacy) must be at chemically acceptable levels. (c) Must be readily administrable. [0024] The similarly of the present invention (a) Potassium ferrocyanide [CaK ₂ Fe (CN) ₆ ] -New compound, (b) Calcium iodate, and (c) Calcium carbonate By oral administration of a mixture of the three most important fission radionuclides ^* Cs, ^* Sr, and ^* It was found that the residual rate of I was reduced at the same time, and decontamination was performed from individuals accidentally exposed to these radionuclides. [0025] The detailed formulation of this mixture will be described below. [Disclosure of Invention] An object of the present invention Is Three Radionuclides Simultaneously From An Affected In Vivo System. ^* Cs, ^* Sr, And ^* I It Is To Provide A Preventive Mixture That Eliminates The Need To Decontaminate Them Individually By Efficiently Removing Them All. [0026] Another object of the invention is from the in vivo environment of affected humans and animals. ^* Cs, ^*Sr, and ^*It is an object of the present invention to provide a more effective and convenient mixture for simultaneous decontamination of I than the conventionally reported mixture of Prussian blue, calcium alginate, and KI. [0027] Another object of the present invention is novel , Relatively Non-Toxic, More Stable And Tastier Than Prussian Blue, Calcium Alginate, And Potassium Iodide Currently In Use. ^* Cs, ^* Sr, And ^* The Purpose Is To Provide A Decontamination Agent That Eliminates I. [0028] Another object of the present invention is to allow the preventive mixture to be sweetened and to be very easily administered to affected populations (humans and animals) in the turmoil following a radiation or nuclear emergency. It is to be able to be prepared as a single chewable agent. [Means for solving problems] [0029] The present invention is a radionuclide due to fission from an individual exposed to a dangerous radioactive substance. ^* Cs, ^* Sr, and ^* For a preventive mixture that efficiently removes I, the mixture contains: 1) Potassium ferrocyanide-[CaK ₂ Fe (CN) ₆ ], 2) Calcium iodate [Ca (IO)₃)₂ ] 3) Calcium carbonate (CaCO) ₃ ) The formulations according to the invention take the form of tablets, capsules, kits, suspensions and the like. The ingredients can be adequately formulated for children in doses as low as 50 % of the adult dose. [Best mode for carrying out the invention] [0030] The present invention relates to the formulation of preventive matrix used to decontaminate known radionuclides when released to the outside world. The mixture dissolves slowly, has a long shelf life, and is unaffected by the hot and humid climate of tropical countries such as India. Although The mixture can be stored as an aqueous suspension, it is preferably stored in the form of tablets / capsules. The mixture according to the invention contains: (a) 1000-1500 mg, more preferably 1100-1400 mg, most preferably 1200-1300 mg of calcium carbonate (CaCO) corresponding to 480-520 mg of calcium element ₃ ) (b) 45-65 mg, more preferably 50-60 mg, most preferably 52-56 mg calcium iodate corresponding to about 33 mg of stable iodine [Ca (IO) ₃)₂ ] (c) 900 to 1100 mg, more preferably 950 to 1050 mg, most preferably 980 to 1020 mg of calcium ferrocyanide [CaK] ₂ Fe (CN) ₆ ] The above mixture (most preferably 2.2-2.4 g by weight) ) Should be suspended in 15 ml of drinking water, soda water, soft drinks, or fruit juice, sweetened as a chewable agent, or swallowed with water. Can be formulated as tablets / capsules. This dose corresponds to the amount an adult ingests 2 -3 times a day (approximately 30-45 ml of the total suspension of the preventive mixture), depending on the severity of the cationic contamination in the event of a radiation emergency., Or equivalent to 4-6 tablets / capsules). [ 0031] Calcium carbonate (CaCO) ₃) Is radioactive strontium () ^* Used for decontamination of Sr). Calcium iodate is radioactive iodine absorbed by the thyroid gland ( ^* KI / KIO to inhibit I) ₃ Is as effective as. [CaK ₂ Fe (CN) ₆ ] Is radioactive cesium from the in vivo system ( ^* Used to enhance the elimination of Cs). [0032] [CaK ₂ Fe (CN) ₆ ], It was found that This substance is an insoluble compound whose use and effect as shown in the present invention have not been known in the past. This compound contains two commonly used compounds, calcium ferrocyanide [K].₄Fe (CN) ₆ ] And Calcium Chloride CaCl ₂ Can be synthesized from. It is combined with two elements that are not present in Prussian blue: calcium and potassium. These two core additional elements (especially calcium) come from the in vivo system. ^* It is more effective than Prussian blue in eliminating Cs. Its structure is represented by the following structural formula I. [0033] [Chemical 1] <img file="JP4885877B2_D0001.tif" /> The other two components of this mixture, calcium carbonate and calcium iodate, are commercially available. [0034] further, the present invention relates to an easy and efficient process for preparing calcium ferrocyanide, which includes the following steps. (a) In a 2 liter flask, 250 ml aqueous solution of potassium ferrocyanide 0.5 mol K ₄ Fe (CN) ₆ . 6H ₂ Insert O. (b) In the solution of (a), 250 ml of calcium chloride dihydrate 1 mol aqueous solution CaCl ₂ 2H ₂ Add O by dropping with continuous vigorous stirring. (C) The formed precipitates are allowed to settle overnight. (D) The precipitate and the efficiently are separated by decantation and gentle inspiration by applying a gentle vacuum. (E) Wash the precipitate with warm water to remove traces of soluble impurities. (G) The yellow precipitate thus obtained is dried at 90 ° C for 8 hours. [0035] The yield of the final compound obtained by this product is about 80%. [0036] The above mixture can be formulated in smaller doses (about 50% of the adult dose) for administration to children as follows. (A) 500 to 750 mg, more preferably 550 to 700 mg, most preferably 600 to 650 mg of calcium carbonate (CaCO) corresponding to 240 to 260 mg of calcium element ₃ ) (b) 20-35 mg, more preferably 25-30 mg , most preferably 26-28 mg calcium iodate corresponding to about 16 mg of stable iodine [Ca (IO) ₃)₂ ] (c) 450-550 mg, more preferably 475-525 mg, most preferably 490-510 mg ferrocyanide calcium potassium [CaK ₂ Fe (CN) ₆ ] The above preventive mixture (most preferably 1.1-1.2 g by weight) can be suspended in 7.5 ml of drinking water, soda water, soft drinks, or fruit juice, formulated as a chewable agent, or in water. It can be formulated as two smaller tablets / capsules to swallow. This dose corresponds to the amount that children take 2-3 times a day (about 15-22.5 ml of the total suspension of the preventive mixture), depending on the severity of the radioactive contamination in the event of a radiation emergency. Or equivalent to 4-6 tablets / capsules). [0037] The mixture can be formulated in the form of suspensions, preferably tablets or capsules. Tablets or capsules can be easily administered to humans affected by an emergency in a nuclear reactor and can be easily administered / distributed to all affected humans. [0038] 1 Calcium in the gastrointestinal tract is very useful in complexing with significant amounts of unwanted / toxic substances to eliminate them from the in vivo environment. The approximate dose of the mixture depends not only on the severity of the contamination, but also on the age and weight of the affected body. In both adult and pediatric dosage forms, the suspension is via the gastric tube (gastric lavage) if the affected entity is not ready to be taken orally in the event of such an emergency. Can be administered. [0039] The prophylactic mixture has been found to release free / excess calcium into the gastrointestinal system, which provides the following benefits: 2. In addition , calcium inhibits the intestinal active transport mechanism by slowing / stopping the synthesis of vitamin D in the (active) hormonal form, which promotes the rapid absorption of calcium and some other elements. 3. Calcium opposes these elements in the absorption of elements such as strontium by passive diffusion. 4. In addition, calcium helps delay damage to cell membranes. 5. In addition, calcium stabilizes vitamin E, glutathione, and protein thiols, which are known This plays an important role in the regulation of antioxidant defense mechanisms. [0040] The calcium salt used in this mixture is quite toxic and is useful for decontaminating not only thallium and stable strontium, which are used in many industrial and biomedical applications, but also stable cesium. [0041] The tablets and capsules can be prepared by any of the methods known to those skilled in the art. [0042] See Table 1 here. Table 1 below shows ( ^* Cs + ^* Sr + ^* I) The effect ₃ , And in comparison with a mixture of calcium alginate. Three radionuclides of the mixture of the present invention, Prussian blue, KIO, when the mixture of the present invention is mixed with the diet and given orally after administration of the mixture. (3 radionuclides) in experimental animals ^* I, ^* Cs, and ^* Two hours after oral administration of the mixture of Sr), a prophylactic mixture of this novel decontamination After 24 hours to 14 days, the systemic residual rate of each radionuclide was measured. This is Prussian blue (PB) + KIO given only in the diet ₃ + Compared with a mixture of calcium alginate. [0043 ] [Table 1] <img file="JP4885877B2_D0002.tif" /> Table 2 below shows ^* Cs + ^* Sr + ^*The effects of the mixture of the present invention administered orally after administration of the I mixture, PB, KIO ₃, And in comparison with a mixture of calcium gluconate. Two hours after administration of the mixture of the above three radionuclides to the experimental animals, this novel mixture was orally administered. After 24 hours to 14 days, the systemic residual rate of each radionuclide was measured. This was orally administered Prussian blue + KIO ₃ + Compared with a mixture of calcium gluconate. [0044] [Table 2] <img file="JP4885877B2_D0003.tif" /> See Table 3 here. Table 3 below shows [CaK ₂ Fe (CN) ₆ ] When using ^* The systemic residual rate count of Cs is shown in comparison with Prussian blue. As shown in the table, CKF is from the affected in vivo system. ^*It was twice as effective as PB after the 4th to 5th days to increase the elimination of Cs. [0045] [Table 3] <img file="JP4885877B2_D0004.tif" /> Table 4 shows KIO ₃ And Ca (IO ₃)₂ Stable iodine in the form of ip (intraperitoneal). 24 hours after administration ¹³¹ Shows the percentage of I. [0046] [Table 4] <img file="JP4885877B2_D0005.tif" /> Table 5 shows KIO ₃ And Ca (IO ₃)₂ 24 hours after oral administration of stable iodine in the form of ¹³¹ [Table 5] Shows the percentage of I. Results are shown on average ± SD (5-6 rats / group) as a percentage of the dose administered. [0047] <img file="JP4885877B2_D0006.tif" /> Table 6 shows Ca (IO) for the systemic residual rate of radioactive iodine. . ₃)₂ And KIO ₃ The Comparison With Is Shown. KIO ₃ And Ca (IO ₃)₂ Stable Iodine In The Form Of (Equivalent To 100 Mg / 70 Kg / Day For Adults) Is Mixed With The Diet . [0048] [Table 6] <img file="JP4885877B2_D0007.tif" /> Table 7 Shows KIO ₃ And Ca (IO ₃)₂Ca (IO) for the systemic residual rate of radioactive iodine when stable iodine in the form of (100 mg / 70 kg / day for adults) is orally administered. ₃)₂ And KIO ₃ The comparison with is shown. [0049] ] [Table 7] <img file="JP4885877B2_D0008.tif" /> Table 8 shows the different pH ranges (2-7). ^* Shows the percentage of Cs binding ability. From this data, Prussian blue is used for stability in acidic media / complex formation with iodine cesium / extraction thereof, [CaK ₂ Fe (CN) ₆ ], It can be seen that only about 25 to 50% of the dose level is effective. [0050] [Table 8] <img file="JP4885877B2_D0009.tif" /> [0051] Figure 1 shows [CaK ₂ Fe (CN) ₆ ] When using ^* The systemic residual rate of Cs is shown graphically in comparison with Prussian blue. As you can see from the graph ^*For Cs decontamination purposes only, [CaK₂ Fe (CN) ₆ ] Was twice as effective as Prussian blue. Figure 2 shows Prussian blue and [CaK] for micronucleus formation in rat bone marrow erythrocytes. ₂ Fe (CN) ₆₂ ] Is a genetic toxicity data showing the effect. For the formation of micronuclei (ie, part of the parent nucleus left in the cytoplasm as daughter nuclei due to chromosomal damage during cell division), [CaK₆ Fe (CN) ₂ ] And Prussian blue were evaluated for genetic toxicity. From the figure, in the test compound at a dose of 5 mg / 100 gBW (corresponding to 3.5 g / day / 70 kg for adults) , [CaK ₆ Fe (CN) ] And Prussian blue do not induce toxicity and are found to be completely non-toxic. It was observed that 5-10 times this dose induced a slight increase in micronucleus formation. However, at all test doses, the mean ± SE was not significantly 3 shows the results of the alkaline comet assay. This result also demonstrates that neither PB nor CKF is significantly different from the control and does not induce obvious DNA damage. In addition, FIG. 4 shows the CKF of CKF compared to PB, which shows weaker binding even at neutral pH. ^* It clearly shows a strong bond with Cs. [0052] The term "emergency" herein should be construed to include: (a) Accidental release of radioisotopes to the outside world due to some nuclear accident (b) Some accidental release of dangerous nuclides to the outside world (c) Radioactive fallout, including those that occur during the normal course of experimental, diagnostic, or therapeutic purposes. (D) Accidental absorption and retention of some kind of radionuclide by an individual human or animal (e) Other types of exposure to volatile radionuclides (f) Some kind of radioactive accident The acronym CKF in the text and in the attached tables and figures means the compound ferrocyanide calcium potassium. [0053] The above examples and formulas are presented for iSeries purposes only and should not be construed as limiting the scope of the invention. Modifications and modifications obvious to those skilled in the art shall be included in the scope and nature of the invention as defined in the accompanying claims. [Simple explanation of drawings] [0054] [Fig. 1] Fig. 1 shows [CaK. ₂ Fe (CN) ₆^* ] When using ₂ The systemic residual rate of Cs is shown graphically in comparison with Prussian blue. FIG. 2 shows Prussian blue and [CaK] for micronucleus formation in rat bone marrow erythrocytes. ₆ Fe (CN) ] Is a genetic toxicity data showing the effect. FIG. 3 shows the results of the alkaline comet assay. In addition, FIG. 4 shows that even at neutral pH, CKF was compared to PB, which showed weaker binding. ^* It clearly shows a strong bond with Cs.