| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | January 14, 2003 |
| PATENT TITLE |
Radioiodinated sulfonated phenols for the study of renal function |
| PATENT ABSTRACT | The present invention concerns the use of a radioiodinated phenolic compound of the formula ##STR1## wherein: m and n are independently 0, 1, 2 or 3, X is a group that is negatively or positively charged at physiological pH, R, R.sup.1, R.sup.2 and R.sup.3 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, or a carboxyl group, and I* is .sup.123 I, .sup.131 I or .sup.125 I, and its pharmaceutically-acceptable salts. The compound is formulated and used in vivo in an animal in brachytherapy in an implantable catheter. In addition, due to the rapid renal clearance of these compounds, they may be used to study renal function. A process to prepare these compounds is also disclosed |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | September 28, 2000 |
| PATENT REFERENCES CITED |
Wahl, R.; Bohner, J.; Kallee, E. Nucl. Med. Suppl. (1973), No. 11, p. 179-83 (German plus translation). Wahl, R.; Bohner, Jurgen; et al. Arzneim.-Forsch (1973), 23(8), p. 1009-14 (German plus translation). De Wit, Peter; Woldhuis, Alex F.; Cerfontain, Hans; Lab. Org. Chem. U of Amsterdam; Recl. Trav. Chim. Pays-Bas 107, 668-675 (1988). Philip, Manfred; Fresenius J. Anal. Chem (1998), 360(2), p. 184-191. Krummeich C. et al. "Convenient Direct NCA Electrophilic Radioiodination of Arenes using lodo-gen<.TM." Applied Radiation and Isotopes, vol. 47, No. 5, May 6, 1996, pp. 489-495. Krummeich C. et al. Kit preparation of n.c.a.3-[.sup.123 !]lodo-L-.alpha.-methyltyrosine [.sup.123 !]IMT, 3-[.sup.123 !]lodo-O-methyl-L-tyrosine [.sup.123 !]OMIT and 3-[.sup.123 !]lodo-O-methyl-L-60 -methyltryrosine [.sup.123 !]OMIMT Using Sep-Pak.TM. C-18 Cartridges, appl. Radiat. Isol. vol. 46, No. 9, pp. 917-921, 1995. Krummeich C. et al., "Synthesis and Biodistribution of Radioiodinated Amino acids: A Comparative Evaluation" Journal of Nucl. Med. vol. 3, No. 5 Suppl., pp. 94, 1994. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method for the study of renal function in an animal which comprises: administering to an animal an effective amount of a pharmaceutical formulation comprising as an active ingredient a radioiodinated compound of the formula ##STR12## wherein: m and n are independently 0, 1, 2 or 3, X is a sulfonate or a salt thereof, R, R.sup.1, R.sup.2 and R.sup.3 are independently hydrogen, C.sub.1 -C.sub.4 alkyl or a carboxyl group, and I* is .sup.123 I, .sup.131 I or .sup.125 I, and its pharmaceutically-acceptable salts, with a pharmaceutically-acceptable carrier, having less than about 15% of unbound iodine present; collecting urine from the animal; and, determining radioactivity in the urine. 2. The method of claim 1 wherein the formula groups m and n are 0, R, R.sup.1, R.sup.2, and R.sup.3 are hydrogen, and X is a sulfonate, as its pharmaceutically-acceptable salt. 3. The method of claim 2 which has as its active ingredient a compound that is sodium 3-iodo-4-hydroxybenzenesulfonate. 4. The method of claim 1 where the formula term I* is .sup.125 I. 5. The method of claim 1 wherein the formulation has as its pharmaceutically-acceptable carrier water that is buffered to physiological pH. 6. The method of claim 5 wherein the buffer is HEPES and the pH is from 6 to 8. 7. The method of claim 5 or 6 wherein a radiolytic protectant is present in said formulation. 8. The method of claim 7 wherein the radiolytic protectant is one or more of benzyl alcohol, ascorbic acid, gentisic acid, cysteine, butylated hydroxytoluene (BHT), citric acid, human serum albumin (HSA), glycerol, cysteamine, sulfarem, glutathione, tryptophan, and iodoacetamide. 9. The method of claim 8 wherein the radiolytic protectant is the sodium salt of ascorbic acid. 10. The method of claim 3 wherein the iodo atom is .sup.125 I, and having as pharmaceutically-acceptable carriers HEPES and acetate buffers, with a radiolytic protectant of ascorbic acid. 11. The method of claim 1 wherein less than 10% of unbound iodine is present in the formulation. 12. The method of claim 1 wherein the formulation is injected intravenously. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The present invention relates to a radioactive fluid used to treat tumors in vivo in an animal body. The fluid is to be used in combination with an implantable catheter attached to an inflatable balloon that is placed in proximity of a tumor or in the cavity left by the surgical removal of a tumor from an animal body. The radioactive fluid of this invention is used to inflate the balloon and provide a radiation dose to tumor tissue or to tissue surrounding the resection cavity. This solution is a "brachytherapy fluid" that consists of an aqueous solution of a water-soluble radioactive molecule with other appropriate physiologically-acceptable ingredients. BACKGROUND OF THE INVENTION In many cases, surgical procedures for the removal of a tumor leaves cancer cells in the area adjacent to the tumor. This occurs for various reasons, for examples, the cancer cells are not visible to the surgeon's view or no dye or stain is available to enable the cancer cells to be seen by the surgeon. These remaining cells can cause recurrence of the cancer. Additional therapies are thus needed to treat this surgical area. One form of treatment is to give a local radiation dose to this area. This can be accomplished by brachytherapy, which involves the implantation of a radioactive source (as solid pellets) in an area near or surrounding a tumor. Traditional brachytherapy involves placing one or more solid radioactive pellets or needles in the area to be treated. Determining proper placement of the radioactive pellets is not simple and the implantation itself is difficult, expensive, time consuming and offers a potential for the introduction of infection. Additionally, dosimetry for these sources is often difficult to calculate because of complex geometry issues. U.S. Pat. No. 5,429,582 teaches the use of an implantable apparatus, such as a catheter, for the treatment of tissue surrounding a cavity left by surgical removal of a brain tumor. This technique has the advantage over traditional brachytherapy in that the apparatus is inserted during the same surgical procedure used to remove the tumor; thus no additional surgery is required and the possibility of infection is greatly reduced. Additionally, the balloon fills the volume left by the tumor mass and the determination of where to place the radioactivity is less complicated. Dosimetry calculations are also simplified with a single, spherical radioactive source. In addition, U.S. Pat. No. 5,611,767 teaches the method and apparatus for radiation treatment of a tumor using an inflatable treatment device placed in an incision adjacent to the tumor wherein the inflatable device is filled with a radioactive treatment fluid. However, a description of the radioactive solution to be used with the device is not included in these above patents. Several radioactive isotopes of iodine have been used for medical applications. Some of these isotopes include iodine-123 (.sup.123 I), iodine-125 (.sup.1251 I ), and iodine-131(.sup.131 I). Iodine-123 has a 13.1 hour half life and emits gamma photons that are useful for nuclear medicine imaging. Iodine-125 has a 60.14 day half life and emits several relatively low energy photons that are used as labels on antibodies to guide surgical procedures in cancer patients and as a tracer to evaluate kidney function. Iodine-131 has a 8.04 day half life and emits gamma photons that are useful for nuclear medicine imaging plus beta particles useful for therapeutic applications. Much work has been done on radioiodination methods. Molecules of interest have generally been proteins such as antibodies, smaller peptides, and other biologically active molecules. For example, the dye--tetraiodotetrachlorofluorescein (rose bengal)--has been labeled with .sup.131 I to study liver function [Taplin, G. V., et al., J. Lab. Clin. Med., 45, 665 (1955)]. Alpha-methyltyrosine iodinated with .sup.123 I can be used to assess amino acid transport rate in gliomas [Kuwert, T., et al., J. Nuclear Medicine 38(10), 1551 (1997)]. Also, .sup.125 I labeled monoclonal antibodies have been used to help identify cancer tissue during surgical procedures [Nieroda, C. A., et al., Cancer Res., 55(13), 2858-65 (1995)]. A process for radioiodination of molecules is usually accomplished by either an exchange reaction or an electrophilic substitution. For example, sodium iothalamate is labeled with .sup.125 I in an exchange reaction by heating radioactive sodium iodide (e.g., Na .sup.125 I) with iothalamate [Hung, Joseph C., et al., Nucl. Med. Biol., 21(7), 1011-12 (1994)]. The electrophilic process is facilitated by the oxidation of iodide to an electrophile in the presence of the molecule to be labeled. Electrophilic attack can then occur, typically at the ortho position of phenolic groups, such as tyro sine. Several common oxidizing agents are commercially available, for example from Pierce Chemical Company, PO Box 117, Rockford, Ill. 61705, US. Chloramine-T (N-chloro-4-methylbenzenesulfonamide sodium salt, Pierce Chemical Company) is a water soluble oxidizing agent. It requires the addition of an another reagent to stop the reaction and must then be separated from the solution. IODO-GEN.RTM. (Pierce Chemical Company) is a water-insoluble oxidizing agent for iodination. It is typically coated as a film on the inside of the reaction vessel. This is accomplished by dissolving it in chloroform, applying the solution to a reaction tube, then evaporating the solvent. Iodination is accomplished by addition of an aqueous solution containing the radioactive iodide and the material to be labeled to the IODO-GEN.RTM.-coated test tube. Removing the solution from the tube terminates the reaction and effects separation of the substrate from the reagent. Another popular method involves the use of IODO-BEADS.RTM. (Pierce Chemical Company) which are polystyrene beads with the oxidizing agent (Chloramine-T) chemically bonded to the bead. Removing the plastic beads from solution terminates the reaction. The structures of these oxidizing agents are shown below: ##STR2## Most commonly, the above reagents are used to radiolabel proteins. The amino acid most reactive towards electrophilic iodination is tyrosine because of the phenolic group. Scheme 1 below illustrates the radioiodination of tyrosine using IODO-GEN.RTM. as the oxidizing agent. Iodide is oxidized to an electrophilic species, postulated to be I--Cl. Electrophilic attack then occurs at the ortho position of the phenol. ##STR3## Although iodine-125 has ideal nuclear properties for use in the above described devices, in the iodide form I.sup.125 I has less than ideal properties. For example, it is readily oxidized to form volatile iodine, I.sub.2. In addition, if leakage from the device occurs, activity will concentrate in body tissues, such as thyroid and stomach, giving an undesirable radiation dose to those tissues for the patient. Thus, although technology exists for the iodination of many molecules, no one has described the properties and compounds to be used with said implantable devices described above. There is thus a need for a compound that has the appropriate properties for use with these devices. SUMMARY OF THE INVENTION This invention provides a radioactive solution to be used in conjunction with the implantable apparatus described in U.S. Pat. Nos. 5,429,582 and 5,611,767 and still have the solution clear from the body if leakage should occur without undesirable concentration of radioactivity in any tissue. Surprisingly, it has been found that radioiodinated compounds meet these desired properties are compounds of the formula ##STR4## m and n are independently 0, 1, 2 or 3, X is a group that is negatively or positively charged at physiological pH, R, R.sup.1, R.sup.2 and R.sup.3 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, or a carboxyl group, and I* is .sup.123 I, .sup.131 I or .sup.125 I, and its pharmaceutically-acceptable salts. A method for using these radioiodinated compounds of Formula (II) in a catheter for treating the tissue around a tumor cavity after removal of the tumor, especially in vivo in the brain, is described. A formulation for using these compounds of Formula (II) as a physiological solution is described. These compounds are formulated to be physiologically-acceptable, and may have a radiolytic protectant present. The compound is formulated and used in vivo in an animal in brachytherapy in an implantable catheter. In addition, due to the rapid renal clearance of the compounds of Formula (II), they may be used to study kidney function. A process for preparing a compound of Formula (II) comprises radioiodinating a compound of Formula (I) ##STR5## wherein: m, n, X, R, R.sup.1, R.sup.2 and R.sup.3 are as defined above, with an radioiodinating agent, under these conditions a small amount of the radioactivity may be as the bisiodinated compound of the formula ##STR6## wherein: m, n, X, R, R.sup.1, R.sup.2, R.sup.3 and I* are as defined as above. The process to prepare the compounds of Formula (II) is also provided so that minimum exposure to the radiation is provided during preparation while providing high yield and purity; less than 15%, preferably less than 10%, of unbound iodine is present at the end of the iodination reaction. Upon completion of the radioiodination reaction any unbound iodide is further reduced to less than 5%, preferably less than 3%, in the final solution. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is the graphic representation of the NaI data from Table 1. FIG. 2 is the graphic representation of the .sup.131 I-HBS data from Table 1. FIG. 3 is a schematic diagram of the apparatus that may be used to prepare the radioiodinated compounds of Formula (II). DETAILED DESCRIPTION OF THE INVENTION This invention provides a radioactive solution to be used in conjunction with the implantable apparatus described in U.S. Pat. Nos. 5,429,582 and 5,611,767. When the balloon apparatus is filled with the radioactive solution of this invention, it provides a radiation dose to the area surrounding the balloon without giving significant dose to other areas of the body or to those personnel handling the radioactive solution. In case of leakage of the radioactive solution, it is desirable for the radioactivity to be rapidly excreted from the body without significant uptake in any tissue. In addition, it is an object of this invention for the radioactive solution to be easily prepared in high yields. It is a further object of this invention to provide a means to remove the radioactive components from the solution after the solution is removed from the device. This latter aspect of the invention helps with waste disposal of the radioactive component after it is used in an animal, including a human patient. It is another advantage of this invention to provide compounds for the study of renal function. Several radiopharmaceuticals have been used to study the kidneys, particularly compounds that have some retention in the kidneys were used for imaging studies. For example, in 1960 radioactive mercury compounds were used to image the kidneys [McAfee, J. G., et al., "Comparison of renal extraction efficiencies for radioactive agents in the normal dog", J. Nucl. Med,. 22, 333 (1981)]. Later a series of .sup.99m Tc agents were used for the same purpose [Chervu, L. R., et al., "Renal radiopharmaceuticals--An update," Semin. Nucl. Med. 12, 224 (1982)]. A second class of compounds was used to study renal function. These compounds are cleared by the kidneys with little to no retention. Examples include iothalamate labeled with .sup.125 I, .sup.99m Tc-DTPA [Barbour, G. L., et al., "Comparison of inulin, iothalamate, and .sup.99m Tc-DTPA for measurement of glomerular filtration rate," J. Nucl. Med. 17, 317 (1976)], ortho-.sup.131 I-iodohippurate [Tubis, M., et al., "Preparation and use of .sup.131 I-hippurate in kidney function tests," Proc. Soc. Exp. Biol. Med. 103, 497 (1960)], and .sup.99m Tc-DADS [Fritzberg, A. R., et al., "Chemical and biological studies of Tc-99m N,N'-bis(mercaptoacetamido)ethylenediamine: a potential replacement for I-131-iodohippurate," J. Nucl. Med. 22, 28 (1981)]. The radioactive solution of this invention consists of an aqueous solution of a water soluble phenolic compound that is labeled with iodine, especially .sup.125 I. The compound to be labeled with radioactive iodine has the general formula below: ##STR7## wherein: m and n are independently 0, 1, 2 or 3, X is a group that is negatively or positively charged at physiological pH, and R, R.sup.1, R.sup.2 and R.sup.3 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, or a carboxyl group. Examples of X groups are primary amines, substituted amines which may be secondary, tertiary, or quaternary, or sulfonates. The sulfonates are particularly preferred. At physiological pH (.about.7.4) sulphonic acid groups will be deprotonated to give a negative charge, while the amines would be protonated giving a positive charge. Some preferred examples of compounds of Formula (I) are shown below: ##STR8## wherein: Q and Z includes any suitable pharmaceutically-acceptable salt, for example, when Q is present then the salt is alkali metal ions such as sodium or potassium, or ammonium ion, and r is 0, 1 or 2; when Z is present then the salt is chloride or bromide. The preferred compound of Formula (IA) is when r is 0, Q is sodium, and named as sodium 4-hydroxybenzenesulfonate ("HBS"). At physiological pH (.about.7.4) sulphonic acid groups will be deprotonated to give a negative charge. Formula (IB) is tyrosine and Formula (IC) is tyramine, both having the amine protonated at physiological pH with a suitable pharmaceutically-acceptable salt as an anion, such as chloride or bromide. The compounds of Formula (I) are easily radioiodinated in high yields using previously described techniques to provide a compound of the formula below: ##STR9## wherein: m, n, R, R.sup.1, R.sup.2, R.sup.3 and X are defined as for Formula (I) above, and I* is .sup.123 I, .sup.131 I, or .sup.125 I. The Formulas (IA), (IB) and (IC) are also iodinated in the same manner to provide the corresponding compounds of Formulas (IIA), (IIB) and (IIC). ##STR10## The formulations of the above compounds of Formula (II) with suitable pharmaceutically-acceptable carriers is a part of this invention. The formulation must be in a liquid form to be used in the balloon catheter and be physiologically acceptable in the event that the liquid may come in contact with tissue in the animal during use. The liquid may be a solution, emulsion, or suspension in a physiologically-acceptable form. Examples of preferred carriers arc aqueous solutions e.g., buffers such as phosphate or HEPES adjusted to physiological pH. It is important that the compound be in solution with no solids present. The amount of radioactive compound present in the formulation depends upon which iodine isotope is used, the desired dose, the balloon volume, and the contact time. For example, for .sup.125 I with about a one week contact time in a device of U.S. Pat. No. 5,429,582, the desired activity is from about 20 to about 1000 mCi, preferably 50 to about 500 mCi. Although Chemical Abstracts lists registry number 121208-93-3 as 4-hydroxy-3-iodobenzenesulfonic acid, this compound is not radioactive and has no given utility. Also a kinetic study was done by P. De Witt et al., Neth. Recl. Trav. Chim. Pays-Bas, 107(12), 668-75 (1988) but no radioactive molecule or utility was given. Thus the literature does not discuss the compounds of Formula (II) or their use. The effect of the diiodophenolsulphonic acid (or 3,5-diiodo-4-hydroxybenzenesulphonic acid or sozoiodolic acid) on thyroid hormones was discussed by R. Wahl et al., Nucl.-Med., Suppl. 11, 179-83 (1973). They found that diiodophenolsulphonic acid at concentrations up to 0.2 mM did not displace triiodothyronine from its thyroxine-binding globulin and albumin, but did selectively display thyroxine from prealbumin-binding sites. Thus the effect of diiodophenolsulphonic acid on thyroid hormones was minimal. The use of 3,5-diiodo-4-hydroxybenzenesulphonic acid as an X-ray contrast agent and as a disinfectant is discussed by R. Wahl et al., Arzneim.-Forsch. 23(8), 1009-14 (1973). The article focus is on the diiodo compound and its effect on thyroid hormones. The process for preparing the diiodo compound also produced the mono-iodo compound (.sup.125 I-iodophenolsulphonate) which was separated but not tested nor any utility given. No toxic effects were found with the diiodo compound. To purify the final radioactive solution, after the iodination reaction is completed by any of the known methods described above, residual unbound iodine is converted to iodide (I.sup.-) by use of a reducing agent such as metabisulfite or thiosulfate. Iodide in the solution is then removed by precipitation with silver ions. Addition of silver can be accomplished by using a water-soluble silver salt, such as silver nitrate, or by passing the solution through a cation exchange resin in the silver form. The solution can then be passed through a cation exchange resin in the sodium form to remove residual silver. After the silver precipitation the solids can then be removed from the solution by filtration. To prevent radiolysis of the radioactive solution prior to use, it can be frozen and/or radioprotectants are used, such as benzyl alcohol, ascorbic acid, gentisic acid, cysteine, butylated hydroxytoluene ("BHT"), citric acid, human serum albumin ("HSA"), glycerol, cysteamine, sulfarem, glutathione, tryptophan, and iodoacetamide. In addition to the compounds of Formula (II) above, it is believed that small amounts of the bis-iodinated compounds could be formed. The structure of these compounds is shown below: ##STR11## Wherein: m, n, R, R.sup.1, R.sup.2, R.sup.3 and X are defined as in Formula (I) above, and I* is defined as in Formula (II) above. If desired, the amount of bis-iodinated compound can be minimized by using a large excess of starting material over iodide. Additionally, the mono-iodinated compound could be separated from excess starting material and bis-iodinated compound by using standard chromatographic techniques. It has now been found that the best mode for making the present radioactive solutions of Formula (II) occurs when an apparatus is used as described in our copending application U.S. Ser. No. 09/323,673, filed on even date herewith, and entitled "Apparatus for the Preparation of Radioactive Solutions" having Attorney docket no 44191A, and inventors of R. Keith Frank and Jaime Simon, particularly FIG. 5 thereof with its discussion, the disclosure of which is hereby incorporated by reference An apparatus has been used to prepare the radioactive compounds of Formula (II) where a plastic housing that has a reagent support adapted to receive a plurality of radiation-shielded vials, which vials are pivotally mounted to allow agitation or inverting of the vials. The apparatus also includes a series of valve manifolds secured within the housing and connected by plastic tubing with the vials to ensure proper routing of the reagent within the housing. A computer controlled syringe pump is used to transfer the solution between reagent vials and to dispense the reagents. The computer controls both the syringe pump and prompts an operator, where necessary, for any manual operations to conduct the process. A schematic diagram is provided of this apparatus as FIG. 3. Optionally, computer controlled valves may be used. When iodinated with radioactive iodine, the compounds of Formula (II) are water soluble. When introduced into the bloodstream of an animal, the iodinated compounds of Formula (II) are readily cleared from the body via the renal system and are expected to have low toxicity. Compounds of Formula (II) may also be lyophilized for storage or transport. To maintain physiological pH (.about.7.4) suitable buffers are used such as bicarbonate, phosphate, HEPES, or other known suitable buffers. A radiolytic protectant can be used as mentioned above. The pH of the solution can range from about 5 to about 9, preferably from about 6.5 to about 8.5, but physiological pH is most preferred from about 7 to about 8. The amount of radioactive solution used for therapeutic applications depends upon several factors, such as which iodine isotope, the size of the resected area to be treated, the contact time, and dose of radioactivity desired. An effective amount of the .sup.125 I-labeled solution for therapeutic uses in devices taught in U.S. Pat. No. 5,429,582 is in the range from about 50 to about 500 mCi, preferably from about 100 to about 200 mCi, and more preferably about 150 mCi per dose. The formulation is injected into the implanted catheter and the solution left in the device for the desired treatment period. The solution is then removed by syringe and the deflated catheter removed. The following definitions are used in the specification and examples below. cm=centimeter mCi=milliCurie; the conversion factor to IUPAC units is 1 mCi=37 MBq .mu.L=microliter mm=millimeter mL=milliliter mg=milligram g=gram HBS=sodium 4-hydroxybenzenesulfonate dihydrate HEPES=N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid The invention will be further clarified by a consideration of the following examples, which are intended to be purely exemplary of the present invention |
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