A radiodiagnostic agent comprising a solid, insoluble nontoxic synthetic resin, such as polystyrene, bearing a detectable amount of technetium 99m thereon. This agent is useful for analyzing the gastrointestinal tract, for example, for gastric emptying time, by means of a gamma camera

Digenis, George A.

Shambhu, Manvendra B.

Theodorakis, Michael C.

English

University of Kentucky

University of KentuckyUKnowledgePharmaceutical Sciences Faculty Patents Pharmaceutical Sciences9-19-1978Radiodiagnostic AgentGeorge A. DigenisUniversity of Kentucky, digenis@uky.eduManvendra B. ShambhuUniversity of KentuckyMichael C. TheodorakisRight click to open a feedback form in a new tab to let us know how this document benefits you.Follow this and additional works at: https://uknowledge.uky.edu/ps_patentsPart of the Pharmacy and Pharmaceutical Sciences CommonsThis Patent is brought to you for free and open access by the Pharmaceutical Sciences at UKnowledge. It has been accepted for inclusion inPharmaceutical Sciences Faculty Patents by an authorized administrator of UKnowledge. For more information, please contactUKnowledge@lsv.uky.edu.Recommended CitationDigenis, George A.; Shambhu, Manvendra B.; and Theodorakis, Michael C., "Radiodiagnostic Agent" (1978). Pharmaceutical SciencesFaculty Patents. 139.https://uknowledge.uky.edu/ps_patents/139O United States Patent [19] ' [11] 4,115,540 Digenis et a1. [45] Sep. 19, 1978 [54] RADIODIAGNOSTIC AGENT [56] References Cited ' U.S. PATENT DOCUMENTS [75] Inventors: George A. Digenis; Manvendra B. shambhu’ both of Lexington, Ky; 4,010,250 3/1977 Parikh et al. .......................... .. 424/1 Michael C‘ Theodorakis’ Gumee’ 111' Primary Examiner—-Benjamin R. Padgett _ _ . Assistant Examiner-Christine M. Nucker [73] Asslgne?i The UmVel’sItY of Kentucky Research Attorney, Agent, or Firm-Birch, Stewart, Kolasch and Foundation, Lexington, Ky. Bil-ch [21] Appl. No.: 696,802 [57] ABSTRACT . _ A radiodiagnostic agent comprising a solid, insoluble [22] Filed: Jun. 16, 1976 nontoxic synthetic resin, such as polystyrene, bearing a detectable amount of technetium 99m thereon. This [51] Int. Cl.2 .................... .. A61K 43/00; A61K 29/00 agent is useful for analyzing the gastrointestinal tract, [52] us. Cl. ..................................... .. 424/1; 23/2306; for example, for gastric emptying time, by means of a 252/30L1 R; 264/0.5; 423/2; 424/ 1.5; 424/9 gamma camera. [58] Field of Search .................. .. 424/1, 1.5, 9, 78-80, 424/ 83; 423/2; 252/ 301. l R; 23/ 230.6; 264/ 0.5 11 Claims, 4 Drawing Figures U.S. Patent Sept. 19, 1978 Sheet 3 of3 4,115,540 IO0,000_- v - DETERMINATION OF GASTRIC EMP'IYING TIME POLYSTYRENE —TETA—Tc 99"‘ 10,0005 - I 1,2 = 45 min. COUNTS /MIN. P76. 3 50 I60 I50 2'00 250 TIME (MIN) ‘®@—TE TA 99mTc++ COMPLEX E E 2,556,096 cps /g Q 00 pH L3 (rel. 4%) I O . pH 7.5 (ml. 1.6%) A pH 4.5 (rel. 0.4%) I I ‘I 3b 4'0 5'0 60 4 TIME (min) 1 RADIODIAGNOSTIC AGENT This invention relates to a radiodiagnostic agent use ful in the clinical analysis of the gastrointestinal tract. More particularly, it relates to a preparation comprising a solid insoluble resin bearing technetium 99m which is especially useful in the evaluation of gastric emptying time. I Various techniques for clinically testing the gastroin testinal tract for numerous ailments are known in the art. Some of these techniques involve the use of radioac tivity as a means of scanning the GI. tract. In this re gard, technetium 99m is the most commonly used radio nuclide in nuclear medicine because of its favorable imaging characteristics (gamma energy 140 KeV, half life 6.0 hours). . Chemically, technetium (Tc) belongs to Group VII B of the Periodic Table (along with manganese and rhe nium) and is known to exist in valence states ranging from +1 to +7. The stable forms of the metal in water are the pertechnetate (TcO4-, similar to Mn04") and TcO2. Technetium 99m is formed by the beta decay of molybdenum 99 and decays to To 99 according to the following equation: . ‘ Tc 99m is obtained in the pertechnetate form by elution with normal saline from a technetium generator (“Chemistry of Technetium 99m”, J. Steigman and P. Richards, “Seminars in Nuclear _Medicine”, 4, 269 (1974). One of the speci?c techniques for clinically evaluat ing gastric emptying time in patients having abnormali ties of gastric function comprises administering a per 4,115,540 5 20 25 35 technetate solution to the patient together with a meal ' and monitoring its passage through the gastrointestinal tract by means of a gamma camera. However, this tech nique using, an aqueous solution of Te 99m has two drawbacks. First, the radioisotope is absorbed from the GI. tract, thereby making the test ‘unreliable, and, se condly, the solution does not move at‘the same rate as the solid food particles. To overcome these difficulties, a sulfur colloid of technetium has been employed in the place of the per technetate solution (“The Gamma Camera in Clinical Evaluation of Gastric Emptying”, A. P. van Dam, Ra diology, 110, 155 (1974)). However, this colloidal prepa ration is generally unstable and is dif?cult to prepare. Therefore, there has been a great need in this ?eld for a simple preparation which can be used on the clinical level even by relatively inexperienced personnel and which gives reliable results quickly and effectively without any ancillary problems. ‘ , 7 Accordingly, one of the objects of the present inven tion is to provide a radiodiagnostic agent which can be readily and simply prepared for use in clinical‘ evalua tions and which overcomes the disadvantages and de? ciencies of the prior art as noted above. Another object of the invention is to providearadio diagnostic agent having a high‘ret‘ention of label and which is clinically stable for use in determining gastric emptying time reliably and effectively. 11‘ ' l ' ‘ These and other objects and advantagesof the inven tion will become apparent to those skilled in the art from a consideration of the following speci?cation and 40 45 60 2 claims, taken in conjunction with the accompanyin, drawings, which showvvarious properties of the diag nostic preparation of the invention. In accordance with the present invention, it has bee: found that a preparation comprising a solid, insolubl non-toxic synthetic resin bearing technetium 99m pro vides a new and useful radiodiagnostic agent which i particularly well suited for the clinical evaluation 0 gastric emptying time. The technetium 99m-containin1 resin has been found to be a preparation from whicl little if any radioisotope is lost upon suspending tht resin in aqueous buffers and gastric and intestinal ?uids Thus, this solid form of technetium 99m comprises 2 convenient preparation which can be readily image: externally by the use of a gamma camera. Accordingly in addition to use in the clinical evaluation of gastric emptying time, the Tc-99m bearing resin of the inven tion can be used, for example, in in vivo studies on the disintegration of various pharmaceutical dosage form: such as pills or capsules when incorporated therein in the solid dose form. The solid preparation of technetium 99m of the in vention is obtained by binding or chelating the isotope to an insoluble, non-toxic chemically inert synthetic resin. This solid preparation is stable and is very simple to prepare, for example, within thirty minutes or less. Very little radionuclide is absorbed into the blood stream upon administration because of its physical na ture. For example, less than 1%, which is almost negli gible, of the radionuclide was detected in an experimen tal animal (dog) when administered thereto orally. Moreover, the preparation of the invention, being in a granular form, can be easily handled and readily mixed with solid food. Thus, it meets all of the criteria of a safe and reliable diagnostic agent which can be used clini cally in the ?eld of nuclear medicine. The base resin employed is preferably a porous non toxic synthetic resin such as “popcom” polystyrene, which is a white, brittle, insoluble and highly porous resin of irregular shape. Other forms of polystyrene can be suitably employed. These include polystyrene pre pared by bulk, suspension, solution or emulsion poly merization. Copolymers of styrene with suitable co polymerizable monomers may also be employed. Other polymers that can be prepared in granular form and which can bear the polyamine functions discussed below can also be used advantageously in the diagnostic preparation of the invention. Chloromethyl (CHZCI) groups or similar chemical binding functions are introduced into the base polymer. These functions are then converted to aliphatic poly amines by reaction with various amines, such as those shown in Table 1 below. The resulting resin is then treated with a solution of sodium pertechnetate, favor ably at pH 1.5, resulting in the transfer of the techne tium from the solution to the resin. The resulting Tc bearing resin is then washed with water until the wash ings do not show any radioactivity. The reaction scheme employed to prepare a polysty rene resin bearing Tc 99m is thus as follows: , E polystyrene I 3 -continued 0 c1 ——%R_NH2 H2 polyamine II chloromethylated polystyrene ., Na T004” III polyamine resin TABLE 1 Properties of the resins (lH) obtained by reacting _ chloromethylated polystyrene (I_I, % Cl= 13.2) with vanous Ul P I Analysis of the product III Resin No. Pnlyamine % Cl % N Illa ethylenediamine 0.07 6.46 (“en" or EDA) lllb diethylenetriamine 0.1 1 8. 1 (“dien” or DTA) Illc lriethylenetetramine 0.08 9.02 (“tr-len” or TETA) lIId pentaethylenetetramine 0.66 8.45 (“tetren” or PETA) The general technique for the synthesis of polysty rene with various functions and immobilization with substances such as amino acids on the polymer is known in the art; for example, note Merri?eld, J. Amer. Chem. Soc, 85, 2149 (1963) and Letsinger, J. Amer. Chem. Soc., 85, 3046 (1963). However, the novel ?nding of the in vention is the binding of Tc 99m thereon and the use of the resulting preparation in clinical evaluations. The following Example is given merely as illustrative of the present invention and is not to be considered as limiting. ’ BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 represents the uptake of KMn 04 by Polysty rene-Polyamine resins. FIG. 2 represents the uptake of 99Tc O-4by Polysty rene-Polyamine resin. FIGS. 3 and 4 represent a determination of gastric emptying time. EXAMPLE Preparation of “popcorn” polystyrene (I) — The polymer is prepared by copolymerization of styrene with a small amount of divinylbenzene (0.2 per cent). The polymerization is carried out at 55° C. in the ab sence of air after the addition of a few seeds of the polymer and usually requires about 48 hours. After washing with organic solvents, the resin is dried and reduced to 40-100 mesh size. Preparation of chloromethylated polystyrene (II) — To a suspension of polystyrene (70.0 g) in 500 m1 chlo roform at 0° C., a solution of anhydrous stannic chloride (35 ml) in chloromethylmethyl ether (90 ml) is added I . 4,115,540 15 20 25 30 35 55 65 4 over 30 minutes. The mixture is stirred at room temper ature for 2 hours and ?ltered. The polymer is washed repeatedly with chloroform, dioxane-water, water and ?nally methanol. After drying at 60° C. under vacuo, the polymer (85 g) is found to contain 3.5 meq of chlo rine per gram. Preparation of the polyamine resins (III) — Four polyamines are immobilized on the resin (see Table l) by the following procedure: The chloromethylated resin beads (II, 10 g) are swelled in 40 ml pyridine and 20 ml of the polyamine is added. The mixture is heated over a boiling water bath for 12 hours or until the analy sis of the washed resin shows little unreacted chlorine (below 0.5 per cent). The resin is separated by ?ltration and washed repeatedly with hot pyridine, water and methanol. , To demonstrate the abilities of the polyamine resins (III) to reduce metals in a high oxidation state (+7) to a lower state before immobilization of the metal to the polymer matrix, the resins are treated with potassium permanganate solutions at various pH values. (Manga nese and technetium both belong to Group VII B in the Periodic Table. Pertechnetate and permanganate anions are known to be similar in many respects.) The resin is added to the permanganate solution which is decolor ized due to the reducing ability of the resin. Samples are taken periodically from the solution and analyzed for manganese. The results are shown in FIG. 1 in the accompanying drawings. The technetium bearing resins can be prepared as follows: The polyamine resin is suspended in an aqueous solution at pH 1.5 obtained by the addition of dilute hydrochloric acid. The required amount of the sodium pertechnetate solution is added and the mixture stirred for 30 minutes. Samples are taken from the solution periodically and analyzed for technetium by counting. The results are shown in FIG. 2 in the drawings for two resins (111a and I110). The resin is removed by ?ltration after 30 minutes and washed three times with water. The resin can then be mixed with food for gastric emp tying studies. For applications requiring dry resin, it can be washed with a low boiling organic solvent such as acetone and dried. In a typical experiment, 0.5 g of the resin is treated with 100 ml of a solution of sodium pertechnetate con taining the Tc-99rn as pertechnetate. The results of the gastric emptying studies on a human volunteer are shown in FIG. 3 in the drawings. The logarithm of the counts is plotted as a function of time (minutes). FIG. 4 illustrates a test conducted to show that very little activity is lost with the preparation of the inven tion even in strongly acidic conditions. For instance, only about 4% activity was released initially when the preparation was washed at pH 1.3, and even this loss in activity stopped after about 15 minutes in this strongly acidic solution. Lower release percentages are observed as the pH approaches neutrality. Thus, it is quite clear that the labeled polymer complex of the invention is highly stable under the conditions as are found with gastric contents. f The radiodiagnostic agent of the invention, has been tested both in dogs as well as humans for the evaluation of gastric emptying, as noted above. Generally, disap pearance half times (human) of 40 minutes to 150 min utes have been observed. Hence, the present invention provides an insoluble resin-polyamine-Tc 99m complex which is stable, easy 4,115,540 5 to prepare and gives reliable results when used clini cally as a diagnostic agent. The invention being thus described, it will be obvious that the same may be varied in many ways. Such varia tions are not to be regarded as a departure from the spirit and scope of the invention, and all such modi?ca tions are intended to be included within the scope of the following claims. We claim: 1. A method for analyzing the gastrointestinal tract of a human being or animal which comprises orally admin istering a diagnostic amount of a solid, insoluble non toxic synthetic resin bearing a detectable amount of Tc 99m thereon, and analyzing the number of radioactive counts given off by the decay of the To 99m as said resin passes through the gastrointestinal tract. 2. A non-biodegradable radiodiagnostic agent useful for analyzing the gastrointestinal tract which comprises a solid, insoluble, non-toxic synthetic resin bearing a detectable amount of Tc-99m therein, said agent having no appreciable loss of Tc-99m to the digestive system. 3. The non-biodegradable radiodiagnostic agent of claim 2, wherein the synthetic resin is polystyrene con taining an aliphatic polyamine to which the Tc-99m is chemically bound. 4. The non-biodegradable radiodiagnostic agent of claim 2, wherein said aliphatic polyamine is ethylenedi amine, diethylenetriamine, triethylenetetrarnine or pen taethylenetetramine. 25 30 5. The non-biodegradable radiodiagnostic agent of . claim 2, wherein the synthetic resin is a polyacrylate 35 45 50 55 65 6 containing COOH, OH, or NH; functions for chemi cally bonding the Tc-99m thereto. 6. The non-biodegradable radiodiagnostic agent of claim 5, wherein the polyacrylate is hydroxymethylme thacrylate polymer. 7. The non-biodegradable radiodiagnostic agent of claim 2, wherein the synthetic resin is chemically bound to Tc-99 m by a member selected from the group con sisting of diethylenetriaminepentacetic acid (DTPA), iminodiacetic acid, and B-diketones. 8. A process for the preparation of a radiodiagnostic agent which comprises adding phosgene to hydroxyme thylmethacrylate polymer followed by the addition of a polyamine and then adding an aqueous solution of so dium pertechnetate thereto, thereby forming a polya mine-Tc-99m complex-containing polyhydroxymethyb methacrylate resin. 9. A process for the preparation of a radiodiagnostic agent which comprises mixing chloromethylated poly styrene with an organic swelling agent and then further adding an aliphatic polyamine thereto, heating the mix ture until a polyamine-containing resin is obtained, sus pending said polyamine-containing resin in an aqueous acidic solution, and then adding an aqueous solution of sodium pertechnetate thereto, thereby forming a polya mine-Tc 99m complex-containing polystyrene resin. 10. The process of claim 9, wherein said aliphatic polyamine is ethylenediamine, diethylenetriamine, tri ethylenetetramine or pentaethylenetetran'iine. 11. The process of claim 10, wherein said organic swelling agent is pyridine. * i ‘I i t 

Radiodiagnostic Agent

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Radiodiagnostic Agent

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