US 2832722 A
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RADKBPAQUE FDRMULATEON COMPRISING PVP AS BODYENG AGENT No Drawing. Appiication July 15, 1953 erial No. 368,230
6 Claims. (Cl. 167-95) This invention relates to a radiopaque formulation, for introduction into hollow body organs and body' tissues containing sinuses and more particularly relates to such a formulation which is especially suitable for use in salpingography, the radiographic visualization of the Fallopian tubes.
Some of the earliest radiographic examinations of the Fallopian tubes were made by means of injection of sodium bromide solution; however, it was found that this means produced peritoneal irritation and also remained inspissated in the tubal lumen and produced an obstruc tion in previously patent tubes. In place of a solution of sodium bromide alone, a solution of sodium bromide, thorium nitrate and sodium iodide was subsequently used and although this eliminated inspissation to some extent, irritation and spasm were disagreeable symptoms arising from the use of the later solution.
In salpingography, the radiopaque formulation is injected by means of a cannula into the cervix from which it passes through the uterus and into the Fallopian tubes. Since the tubes open into the abdominal cavity, there is a possibility that some of the formula ion may be introduced into the abdomen and in this event, it is desirable that the formulation be readily absorbed, nonirritating, and nontoxic.
Radiopaque materials, such as iodinated oils, iodinated fatty oils and iodinated poppy-seed oil containing 40% of iodine in particular, as well as aqueous solutions of iodinated aliphatic aromatic and heterocyclic compounds, and polyvinyl alcohol or acacia, were used in salpingography and generally in the visualization of hollow body organs and body tissues containing sinuses. Iodinated oils give very high X-ray contrast because each molecule contains at least one atom of iodine; however, they are reported to be highly irritating to sensitive membranes and surface tissues of body organs and to be only slowly absorbed from body cavities which often results in undesirable tissue reactions because of their protracted contact with the tissues of body cavities.
Iodinated oils act as a foreign body, particularly in the narrowed lumen and have a tendency to remain in the body indefinitely which leads to occlusion Histological examination of tubes in which an iodinated oil has been present has shown nodular tissue filled with foreign body granulation cells. In cases where iodinated oil has been present in the free peritoneal cavity following salpingography the rate of absorption has been slow and it was found that iodinated oil had produced a foreign body reaction in the pelvis with the formation of giant cells and cysts.
Aqueous solutions of radiopaque substances such as iodinated derivatives of aliphatic, aromatic and heterocyclic organic compounds have received some acceptance for use in the visualization of hollow body organs but they have the inherent disadvantage of being irritating to tissues, slowly absorbed or of providing a roentenogram of low contrast, or a combination of these disadvantages.
As a result of some untoward sequelae encountered after injection of iodinated oils and the use of other radiopaque media in salpingography, the desiderata of an ideal radiopaque substance were expressed to be: (1) The ideal radiographic medium must be totally innocuous to the organism as well as 'to the reproductive organs. (2) It must possess that degree of resorbability which shall enable it to disappear from the system rapidly and com pletely after it has accomplished its diagnostic puropse, leaving no residue. (3) It must have the proper viscosity that will adequately permit of radiographic demonstration of adherent and partially strictured tubes. Page 363, l. C. Rubin Uterotubal Insufilation, published in 1947 by the C. V. Mosby Company, St. Louis, Missouri.
It was later found that a viscous radiopaque formulation, which has the property of adhesion to tissues, provides the most satisfactory roentenogram, particularly in salpingography. A solution of an organic radiopaque material in polyvinyl alcohol has been used as a radiopaque formulation in the visualization of hollow body organs and particularly in salpingography; however, the solubility of most organic radiopaque compounds in polyvinyl alcohol is, in general, not sufiicient for a roentenogram of satisfactory contrast to be obtained. The rate of absorption of polyvinyl alcohol from hollow body organs is slow and because of this there is. frequently some undesirable tissue reaction when this material is used as a solvent for radiopaque substances. Polyvinyl alcohol is particularly irritating in the peritoneal cavity and its use is accompanied in a great number of instances with pelvic cramps and pain in cases of patent tubes.
It is an object of this invention to provide a nonanti genie, nonirritating, rapidly absorbed and excreted radiopaque formulation having the property of adhesion to tissues and which when introduced into hollow body organs furnishes high contrast roentenograms with clear out lines.
Other objects of this invention will be apparent from the following description and appended claims.
It has now been discovered that an aqueous solution of polyvinyl pyrrolidone and a water-soluble salt of an iodinated, aliphatic, aromatic or heterocyclic organic compound may be introduced into hollow body cavities and provide roentenograms of high contrast and clear outline and that polyvinylpyrrolidone and most radiopaque substances are readily absorbed from the hollow body cavities and excreted, without irritation, fissue reaction or pain. It has also been discovered that the radiopaque formulations of this invention are particularly suitable for use in uterosalpingography for with their use roentenograms are obtained which show in the uterus the extent of uterine lumen, the presence of benign tumors, fundal cancer, myomata, and papillomata; and show in the Fallopian tubes any tubal obstruction and its location without injury to the tubal mucosa.
Water-soluble salts of an iodinated, aliphatic, aromatic or heterocyclic organic compound, including salts of alkali metals, trimethyl ammonium and mono-, di-, and tri-ethanolamine salts as well as salts of organic cations in general, are suitable for use as a radiopaque material in the formulation of this invention. Specific examples of such salts are: diethanolamine salt of 2,4-dioxo-3-iodo-6- methyl-tetrahydropyridine-N-acetic acid; diethanolarnine and diethylamine salts of 3,S-diiodo-4-pyridone-N-acetic acid; sodium ortho-iodohippurate; disodium N-methyl-3,5- diodo-4-pyridoxyl-2,6-dicarboxylate; and sodium monoiodo-methanesulfonate. Water-soluble salts of Z-acetylamino-2,4,6-triiodobenzoic acid, and especially the sodium salt which is manufactured and sold by Mallinkrodt Chemical Works, St. Louis, Missouri, under the registered trademark Urckon; including alkali metal salts as well as ammonium and trimethylammonium salts, are
and is obtained by polymerization of monomeric-n-vinylpyrrolidone at 30-60 percent concentration in aqueous solution in the presence of hydrogen peroxide and ammonia or amines.
Aqueous solutions of polyvinylpyrrolidone are more or less viscous depending upon the concentration and molecular weight distribution of the polyvinylpyrrolidone used and any other substituents present and have sufficient adhesion to tissues so that a roentenogram of good contrast and clear outline may be obtained when an aqueous solution of a radiopaque material and polyvinylpyrrolidone is present in a hollow body cavity.
A polyvinylpyrrolidone having a viscosity coefficient K, of about to 33, is particularly suitable for use in the radiopaque formulation of this invention. Viscosity coefficient K is defined in the following equation where c is the concentration in g./ 100 cc. of solution and a is the ratio of the viscosity of the solution to that of the pure solvent. The K values are given throughout as 1000 times the calculated viscosity coefficient in order to avoid the use of decimals.
A polyvinylpyrrolidone having a viscosity coefiicient K of 20 to 33 has been reported to have a molecular weight range of 15,000 to 80,000 and an average melee, ular weight of about 40,000 or less depending on the V specific K value. An average molecular weight of about 40,000 corresponds to a chain of 192-720 monomeric members. If the viscosity coeflicient K is less than about 20, and the average molecular weight is significantly less than 20,000, the viscosity of the formulation is too low, especially for use in salpingography, principally because it will readily flow through partially closed Fallopian tubes and result in a roentenogram which does not reveal a partial obliteration of the tube. It the viscosity coefficient K is substantially greater than 33, and the average molecular weight is substantially greater than 40,000, the viscosity of the formulation is markedly increased and the formulation can no longer be administered with a reasonable degree of facility, and it is accumulated and retained for undesirably long periods of time in the body and particularly in the reticulo-endothelial system.
In general, any radiopaque material of the class defined above which is sulliciently soluble in an aqueous solution of polyvinylpyrrolidone, having a viscosity coeflicient of about 20 to 33, to give a solution containing 150 to 325 milligrams of iodine per gram and a viscosity of 50 to 300 centipoises at 37 C., after sterilization, is a satisfactory radiopaque formulating but it is preferred that the formulation contain 225 toj 275 milligrams of '4 iodine per gram and have a viscosity of 175 to 200 centipoises at 37 C., after sterilization.
The radiopaque formulation of this invention is particularly suitable for use in salpingography and in general, is valuable for use in the visualization of any hollow body organ and body tissues containing sinuses into which it may be introduced, including the uterus, Fallopian tubes, alimentary canal, spinal column, and frontal, ethnoid and cranial sinuses. The radiopaque formulation may be introduced by intraorgan administration, or by intramuscular and subcantaneous injection. By the appropriate means of introduction, the radiopaque formulation may be used for the visualization of soft tissues, sinuses, the urinary tract and salpingography, as well as the lumena of hollow body organs.
The following examples are given to illustrate specific embodiments of the invention, but it is not intended that the scope of the invention be delineated thereby but only by the breadth of the appended claims.
The radiopaque formulation used in the following examples was made by adding grams of polyvinylpyrrolidone, having a viscosity coeflicient of about 30 to a 65% by Weight aqueous solution of the sodium salt of 2-acetylamino-2,4,6-triiodobenzoic acid. Sufiicient water was then added so that the solution Weighed 731 grams. The solution was heat sterilized and then had a viscosity of 182 centipoises at 37 C. and contained 249 milli grams of iodine per gram.
Example I Four cc. of the radiopaque formulation were administered to each of 52 women by intrauterine injection and roentenograms were made of'the uterus and Fallopian tubes within 15 minutes after injection. The shadows of the area where the formulation was present were very dense and afforded excellent visualization of the uterine cavity and the tubal lumena. Roentenograms taken onehalf to one hour after injection showed the formulation was rapidly absorbed and that the iodinated compound was not present in the genital tract one hour after injection. There was no pelvic irritation or pain following injection.
Example II The radiopaque formulation was administered by gavage on an empty stomach to two rats, one cc. to the first and two cc. to the second rat. Roentenograms were made within 15 minutes and after one-half hour. Visualization of the stomach and the large and small intestines was excellent. There was no histological evidence of irritation due to the administration of the radiopaque formulation. One monkey was given 15 cc. of the radiopaque formulation by gavage on an empty stomach and a roentenogram taken within 15 minutes after administration gave excellent visualization of the esophagus, stomach and intestines, large and small.
Example III tenogram taken 15 minutes. after administration.
Example IV A dog was injected in the subscapular region on the dorsal surface with two and one-half cc. and on the ventral surface with two and one-half cc. of theradiopaque formulation. Roentenograms of the kidney and bladder taken 15 minutes after injection showed allparts of the kidney and bladder clearly outlined. A roentenogram taken 30 minutes after injection showed all parts of the kidney and bladder outlined by shadows substantially less dense than the shadows of the roentenogram taken 15 minutes after administration, indicating the formulation was already being removed. I
This application is a continuation-impart of my U. S. patent application Serial No. 327,915, filed December 24, 1952, now abandoned.
What is claimed is:
1. A radiopaque formulation for introduction into hollow body organs and body tissues containing sinuses comprising: an aqueous solution of polyvinylpyrrolidone and a salt of an iodinated organic compound, the solution having a viscosity after sterilization of 50-300 centipoises at 37 C. and an iodine content of 150-325 milligrams of iodine per gram; the polyvinylpyrrolidone having a viscosity coefficient of about 20-33, a molecular weight range of 15,000-80,000 and an average molecular weight of about 20,000-40,000; and the salt of an iodinated organic compound being selected from the class consisting of salts of iodinated aliphatic, aromatic and heterocyclic compounds.
2. A formulation according to claim 1 in which the iodinated organic compound is 2-acetylamino-2,4,6-t1'iiodobenzoic acid.
3. A formulation according to claim 1 in which the salt of an iodinated organic compound is the sodium salt of Z-acetylamino-Z,4,6-triiodobenzoic acid.
4. A radiopaque formulation for introduction into hollow body organs and body tissues containing sinuses comprising: an aqueous solution of polyvinylpyrrolidone and a salt of an iodinated organic compound, the solution having a viscosity after sterilization of 175-200 centipoises at 37 C. and an iodine content of 225-275 milligrams of iodine per gram; the polyvinylpyrrolidone having a viscosity coeflicient of about 20-33, a molecular weight range 5 of 15,000-80,000 and an average molecular weight of about 20,00040,000; and the salt of an iodinated organic compound being selected from the class consisting of salts of iodinated aliphatic aromatic and heterocyclic compounds.
5. A formulation according to claim 4 in which the salt of an iodinated organic compound is the sodium salt of 2-acetylamino-2,4,G-triiodobenzoic acid.
6. A formulation according to claim 4 in which the iodinated organic compound is 2-acetylamino-2,4,6-triiodobenzoic acid.
References Cited in the file of this patent UNITED STATES PATENTS 2,474,729 Durel June 28, 1949 2,603,586 Singher July 15, 1952 2,739,922 Shelanski Mar. 27,- 1956 OTHER REFERENCES