MXPA99000100A - Novelty radiopharmaceutical compositions and matrices and uses of mis - Google Patents

Abstract

Novel radiopharmaceutical compositions comprising, in combination with a pharmaceutically acceptable carrier, a radioactive salt of pyrophosphoric acid, also novel radiopharmaceutical compositions comprising, in combination with one or more polymeric resins, a radioactive salt of pyrophosphoric acid, the compositions and matrices are suitable , among other things, to be used in treatment methods that include brachyrap

Description

NOVELTY RADIOPHARMACEUTICAL COMPOSITIONS AND MATRICES AND USES THEREOF CROSS REFERENCE TO RELATED REQUEST This application is a continuation in part of the co-pending application of the United States Serial No. 08 / 779,169, filed on June 24, 1996, the descriptions of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION The present invention relates to novel radiopharmaceutical compositions and matrices and the use thereof. More particularly, the present invention relates to novel radiopharmaceutical compositions and matrices for use in radiotherapy.

BACKGROUND OF THE INVENTION It has been predicted that a third of all individuals in the United States of America may develop cancer. Cancer remains the second leading cause of death in the United States of America after cardiovascular disease. More than 20% of the population of the States United of America die of cancer, and this figure has increased continuously as the population ages and deaths from heart disease are reduced. In the United States of America, malignancy accounted for 526,000 deaths in 1992. Breast cancer is the most common form of cancer in women (and is considered nonpreventable), while prostate cancer is the most common form of cancer in men in the United States of America. In 1995, there were approximately 230,000 newly diagnosed prostate cases and more than 44,000 prostate cancer deaths in the United States alone. The disease is rare before age 50, and its incidence increases with age. The frequency of prostate cancer varies in different parts of the world. For example, the United States of America has 14 deaths per 100,000 men per year compared to 22 in Sweden and 2 in Japan. However, Japanese immigrants to the United States of America develop prostate cancer at a rate similar to that of other men in this country. This suggests that a factor of environment may be the main cause of differences in population. Despite these statistics, the appropriate treatment for prostate cancer remains controversial. Treatment methods have included radiation therapy, such as external beam radiation therapy and prostatectomy. Of these, radiotherapies were developed in an effort to avoid undesirable side effects, including impotence and occasional incontinence, which are often associated with prostatectomy. However, radiotherapies and especially external beam therapies also produce undesirable secondary effects. Specifically, chronic complications often occur after courses - full of external radiation with rays, including impotence, chronic proctitis and rectal stricture, fistula or bleeding. In addition, it is not clear and external radiation with rays eradicates ^ 0 really prostate cancer, since many patients in whom the tumor progresses slow or stops, have a persistent tumor after rebiopsy. The biological potential of these persistent tumors is unclear. Also, once external radiation has been initiated with lightning, other methods of treatment such as those involving surgery, are generally prohibited afterwards. An alternative to external radiation treatment ^ Rays is brachytherapy. Brachytherapy, usually • refers to radiation therapy in which the source of radiation is located near the area of the body being treated. Brachytherapy typically involves the implantation of a radiation source, commonly referred to as "seed," directly into a tumor. These seeds may consist of radioisotopes or radiolabeled compounds. Brachytherapy offers the concept attractant to release a high dose of radiation to a confined area with relative saving of adjacent normal tissue. The Brachytherapy is one of the oldest radiotherapy techniques for prostate cancer. In 1911 the first report on brachytherapy treatment for prostate cancer was published, which included the insertion of radio into the prostatic urethra by means of a catheter. 0. Pasteau and others, Rev. Maldad. Nutr. , pp. 363-367 (1911). In the last 10 years, improvements in brachytherapy methods have been stimulated by advances in technology, including innovative posterior loading techniques, treatment planning by means of dosing analysis ^ 0 based on computer, and modern imaging modalities, as well as an improved understanding of the radiobiology associated with different radiation dosing regimens. As a result, brachytherapy has been used successfully in the treatment of many cancers other than cancer. prostate, including carcinomas of the cervix, breast, endometrium, head and neck. The prostate is located adjacent to the ^ P critical structures of the bladder, urethra and rectum, and therefore is very suitable for confined radiation doses created by the implantation of radioactive seeds. Brachytherapy can release more radiation to the prostate with fewer dosages to surrounding normal tissue than conventional external beam radiation therapy. This higher intraprostatic dose should theoretically originate treatment plus tumor tumor with fewer complications. However, the use of brachytherapy for carcinoma of the prostate is controversial, due to the combined results that have been reported and due to the availability of other treatment methods. Brachytherapy implantation methods may include temporary implantation, where the source of radiation is left in the patient for a defined period and then removed, or permanent implantation, where the radiation source is permanently implanted in the patient and allowed decay during a period in an inert state. Included among the radioisotopes that have been used in brachytherapy include iodine 125 (I), gold 198 (Au) palladium 103 (103Pd), ytterbium 169 (169Yb) and iridium 192 (192Ir). Radiation sources such as radioisotopes are characterized by the type and energy of particles and / or photons they emit, as well as their half-life. Radioisotopes -i qn i not such as Ir and Au, which are typically encapsulated for example in titanium, usually only release photons to the patient which can subsequently penetrate into the tissue. The position of these sources is usually less critical to achieve a homogenous dose. However, this depth of radiation penetration may result in a greater exposure of the normal tissue surrounding the radiation. Radiation from low to moderate energy sources such as 1 5I, 103Pd and 169Yb, can release a dose more confined radiation, but must be stained in vivo with great precision to avoid areas of underdosing (cold spots) in cancer due to the limited penetration of low energy radiation, as well as exposure to radiation from nearby healthy tissue such as the urethra and rectum. Thus, the release of an effective radiation dosage with radiation sources that are currently available can be difficult. Phosphorus 32 (3 P) has also been used in brachytherapy. For example, radiation therapy of cystic brain tumors with P is reported in V. Tassan et al., J. Nucí. Med., Vol. 26 (11), pp. 1335-1338 (1985). 32P can be a • isotope suitable for brachytherapy since it is a pure ß emitter. The radiation emitted from P has a maximum penetration in water of 7 to 8 mm and an average penetration in water of 1 to 4 mm. D. Van Nostrand et al., Nuclear Medicine Annual, Raven 3 or 15 Press, New York (1985). P is generally incorporated in radiopharmaceuticals such as the phosphate salt, particularly as chromic phosphate (Cr32P? 4). See vgr. J.T.

^ P Sprengelmeyer et al., The Journal of Medicine, Vol. 31 (12), pp. 2034-2036 (1990). However, said phosphate salts can be soluble in blood plasma and consequently can be distributed throughout the body through the circulatory system. As a result, the phosphate salts can circulate from the implantation site to other non-cancerous regions of the body, including bone marrow and liver. L.J.

Anghileri, International Journal of Applied Radiation and Isotopes, Vol. 16, pp. 623,630 (1965). This is highly inconvenient since it can result in exposure of normal tissues to potentially dangerous radiation. In addition, this solubility in blood plasma can result in a reduction in the concentration of phosphate salt at the site of implantation and therefore a reduction in the amount of radioactivity at which the tumor is exposed. This can result in inefficient or incomplete treatment and continued growth of the tumor. Therefore, new and / or better ILO radiopharmaceuticals are required, as well as methods for the treatment of disease. The present invention is directed towards these important purposes, as well as others.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed, in part, to radiopharmaceutical agents. Specifically, in one embodiment, a radiopharmaceutical composition comprising a radioactive salt of the formula I 0 M2 + HxP207 (I) is provided. wherein: 5 M is a metal ion; x is an integer from 0 to 3; and z is an integer from 1 to 4; with the proviso that the sum of x and z equals 4, and at least one of M. H. P. and 0 comprises a radioisotope; and a pharmaceutically acceptable vehicle. Another embodiment of the invention relates to a radiopharmaceutical composition comprising a radioactive salt of pyrophosphoric acid and a pharmaceutically acceptable carrier. Another embodiment of the invention relates to a radioactive salt of pyrophosphoric acid. Another embodiment of the invention relates to a solid radiopharmaceutical matrix comprising a biocompatible sleeve substantially surrounding a radiopharmaceutical composition comprising a radioactive salt of pyrophosphoric acid and one or more polymeric resins. Another embodiment of the invention relates to a process for the preparation of a radiopharmaceutical composition. The process comprises providing a radioactive salt of pyrophosphoric acid, and combining the salt with a pharmaceutically acceptable carrier. Another embodiment of the invention relates to a process for the preparation of a solid radiopharmaceutical matrix. The method comprises providing a biocompatible sleeve substantially surrounding a mixture of a radioactive salt of pyrophosphoric acid and a curable polymer resin, and curing said resin. Another embodiment of the invention relates to a radiopharmaceutical equipment comprising a radioactive salt of pyrophosphoric acid. Highly desirable and unexpected benefits are achieved with the embodiments of the present invention. Specifically, the novel radioactive salts described herein, and the compositions and matrices which contain them, are very useful in methods for the treatment of diseases such as cancer, especially methods of treatment including brachytherapy. The radioactive salts and the radiopharmaceutical compositions and matrices of the present invention are generally substantially insoluble in aqueous media, including blood and other body fluids. Therefore, these radioactive materials generally do not solubilize or circulate in the blood at a location in the body that is different from the implant site. Thus, the present invention can avoid highly undesirable exposure of normal tissues in the body to potentially dangerous radiation that could occur, for example, with prior art radiopharmaceuticals. In addition, since the implanted radiopharmaceutical compositions and / or matrices remain substantially at the implantation site, cancer can be treated with desirable and controllable dosages of radiation.

These and other aspects of the invention will become more apparent from the present specification and claims.

BRIEF DESCRIPTION OF THE DRAWINGS 5 FIG. 1 is a graphic representation of studies of the biological elimination of radiopharmaceutical agents according to an embodiment of the present invention. Figures 2A, 2B, 2C, 2D, 2E, 3A, 3B, 3C, 4A, 4B, 4C, 4D and 4E are graphical representations of studies of the biological elimination of radioactive materials according to the prior art. Figure 5A is a graphical representation of pharmacological test studies of radiopharmaceutical agents 15 in accordance with one embodiment of the present invention. Figures 5B, 5C and 5D are graphic representations of pharmacological test studies of radioactive materials < V in accordance with the prior art. Figure 6 is a graphical representation of pharmacological test studies of radiopharmaceutical agents according to one embodiment of the present invention. Figures 7A, 7B and 7C are graphic representations of studies of the biological elimination of radiopharmaceutical matrices according to an embodiment of the present invention. Figures 8A, 8B and 8C are graphic representations of pharmacological test studies of radiopharmaceutical matrices in accordance with one embodiment of the present invention. • DETAILED DESCRIPTION OF THE INVENTION The present invention is directed, in part, to radiopharmaceutical compositions. Broadly speaking, the radiopharmaceutical compositions present comprise a salt radioactive and a pharmaceutically acceptable vehicle. As is known to those skilled in the art, salts are compounds that can be produced from the reaction between acids and bases, and generally comprise a positive ion (cation) and a negative ion (anion). Positive and negative ions comprise each of them a single element, or a combination of two or more elements. Thus, in the context of the present invention, at least one of the elements in the positive ions or ^ P negative of radioactive salts, is a radioisotope. As indicated above, the radioactive salts that are Known and which can be used in brachytherapy include phosphoric acid salts such as for example chromium (III) phosphate (Cr3 PÜ). However, the salts of phosphoric acid that are known up to now, as in the case of Cr 33PO4, generally also have very good properties. undesirable substances that include, for example, undesired blood solubility. It has been unexpectedly and surprisingly discovered that radioactive compounds that can be derived from pyrophosphoric acid (H4P2O7), may lack the undesirable solubility in blood which is a general characteristic of the phosphoric acid salts. Thus, in accordance with the present invention, the radioactive salts preferably comprise salts of pyrophosphoric acid. Preferably, the radioactive salts are represented by the formula I.

MZ + HXP207 W (I) in which: M is a metal ion; x is an integer from 0 to 3; and z is an integer from 1 to 4; 15 with the condition that the sum of x and z equals 4, and at least one of M, H, P and 0 comprises a radioisotope (that is, the compound of formula (I) comprises at least one radioisotope). Preferably, M is selected from the group consisting of indium (In), calcium (Ca), strontium (Sr) and transition metals. Preferably, M is a transition metal. Preferred among the transition metals are those selected from the group consisting of chromium (Cr), yttrium (Y), holmium (Ho), samarium (Sm), iron (Fe), gold (Au), silver (Ag), 25 cerium (Ce) and mixtures thereof, with chromium being the most preferred. It is contemplated that several of the oxidation states of the metal ions mentioned above are included within the definition of M. Thus, when M is for example ^ fc chromium, the chromium ion may be present as Cr, Cr or Cr. In particularly preferred embodiments, M is chromium, x is 0 or 5 I and z is 3 or 4. Thus, for example, when M is chromium, x is 0 and z is 3, the compound of formula (I) can be represented for example as Cr4 (P2? 7) 3- The radioactivity of the salts described herein, including the preferred salts of formula (I) arises ^ o of the presence of at least one radioisotope. Thus, in embodiments including radioactive salts of the compound of formula I, at least one of M, H, P or O comprises a radioisotope. Preferably, at least one of M, P or O * comprises a radioisotope. Preferably, at least one of M or P comprises a radioisotope. As is known to the person skilled in the art, different radioisotopes can differ markedly in their ß properties including, for example, the particular type or types of energy emitted therefrom, the average energies and Maximum of the particles emitted, the average and maximum penetration depths of the particles emitted in water or in another medium including, for example, soft biological tissue, and the like. In this way, the particular radioisotope incorporated in the salts described herein may affect the radioactive properties of the resulting radioactive salt. A wide variety of radioisotopes may be included in the present radioactive salts and can be selected as necessary, based on the properties sought to be present in the radioactive salt. • In accordance with a preferred embodiment of the invention, the radioactive salts comprise a radioisotope that * is a β-particle emitter, with radioactive salts comprising radioisotopes that emit substantially β particles being preferred. "Substantially", as used herein, refers to radioisotopes in which the particles emitted are at least about 50%, preferably at least about 75%, and preferably at least about 90% of β particles. Particularly preferred are radioisotopes in which more J of approximately 90% of the particles emitted are particles ß. Also preferred are radioactive salts comprising radioisotopes having an average energy of less than about 2 MeV, such as radioisotopes having ^ P an average energy that varies from about 0.2 to about 1.8 MeV, and all combinations and subcombinations of scales within it. Preferably, the radioactive salts comprise radioisotopes having an average energy of about 0.3 to about 1.6 MeV, with radioisotopes having average energies of about 0.4 to about 1.4 MeV being most preferred. Very Preferably, the radioactive salts comprise radioisotopes having an average energy of about 0.5 to about 1.2 MeV, radioisotopes having average energies of about 0.6 to about 1 MeV being most preferred. Particularly preferred are radioactive salts comprising a radioisotope having an average energy of about 0.7 to about 0.8 MeV. Also, in the preferred embodiments of the invention, the radioactive salts comprise a radioisotope having a maximum energy of less than about 5 MeV, such as radioisotopes having a maximum energy ranging from about 0.2 to about 4.5 MeV, and all the combinations and subcombinations of scales in it. Preferably, the radioactive salts comprise radioisotopes having a maximum energy of about 0.4 to about 4 MeV, with radioisotopes having maximum energies of about 0.6 to about 3.5 MeV being most preferred. Most preferably, the radioactive salts comprise radioisotopes having a maximum energy of about 0.8 to about 3 MeV, with radioisotopes having maximum energies of about 1 to about 2.5 MeV being preferred. Even more preferred are radioactive salts comprising radioisotopes having a maximum energy of about 1.2 a. about 2 MeV, with radioisotopes having maximum energies of about 1.4 to less than about 2 MeV being highly preferred. Particularly preferred radioactive salts are those which comprise a radioisotope which have a maximum energy of about 1.6 to about 1.8 MeV. As indicated above, certain phosphorus radioisotopes may possess properties that make them especially useful in treatments involving brachytherapy. For example, the radioisotope P is a pure β-emitter and the particles emitted therefrom have a maximum penetration in water of 7 to 8 mm and an average penetration in water of 1 to 4 mm. Thus, radioactive materials which comprise phosphorus radioisotopes, and especially 3 P, can be advantageously used to irradiate cancerous tissue in vivo while minimizing exposure and potential damage to normal tissues near the cancerous tissue. However, as indicated above, the radioactive materials known hitherto comprising phosphorus radioisotopes, also possess high properties • undesirable including, for example, undesirable solubility in blood. It is believed, that due to this solubility, these radioactive materials of the prior art can have a The tendency to distribute itself in the bloodstream and thus to result in the exposure of non-cancerous regions in the body to potentially dangerous radiation. Also, due to this solubilization in the blood, the concentration of the radioactive materials of the technique above at the implantation site may be reduced. This can result in a reduction in the amount of radioactivity to which the cancerous tissue is exposed. To avoid exposure of normal tissue to radioactivity and / or a reduction in the concentration of radioactive materials at the site of implantation, it has generally been necessary to refrain from using radioactive materials having blood solubility, including the radioactive materials of the art. above that contain phosphorus radioisotopes. This is undesirable since as indicated above, phosphorus radioisotopes, and ^ especially P may possess highly desirable properties that make them well suited for brachytherapy. It has now been surprisingly and unexpectedly found that the radioactive salts of pyrophosphoric acid, which represent a preferred embodiment of the invention, may possess properties Especially advantageous when they comprise a phosphorus radioisotope. Not only such salts are conveniently ^^ Substantially insoluble in aqueous medium, including blood, but may also possess desirable medium and maximum penetration depths in water and biological tissue, as well as desirable half lives. Thus, the distribution in the blood of salts containing phosphorus radioisotopes can be substantially prevented. This can prevent the exposure of non-cancerous regions in the body to potentially dangerous radiation, as well as the reduction in the amount of radiation to which the cancerous tissue is exposed. Therefore, a preferred embodiment of the invention is represented by the compounds of formula I above in which phosphorus (P) comprises a radioisotope. As is known to the person skilled in the art, phosphorus can exist as a stable isotope (31 P) or as a non-Qt r \ variety of isotopes including for example P, P, P, 32 P, 33P and 34P. It is contemplated that the phosphorus atom of the pyrophosphate portion may comprise any one, or combinations of two or more of these phosphorus radioisotopes.

Preferably, the phosphorus atom of the pi • rophosphate portion comprises 32P. As is known to the person skilled in the art, the other elements in the compounds of formula I, including hydrogen (H) and oxygen (O), and those represented by M, including for example indium (In), chromium (Cr) and Yttrium (Y) may exist as a variety of isotopes and radioisotopes. Thus, in the embodiments in which M, H or 0 comprises an isotope or a radioisotope, M can be for example a radioactive or stable isotope of indium, including In, 107ln, 108ln, 109In, 110In, m, 112In, 113In, 114 In, 115 In, 115 In, 116 In, 117 In, 118 In, 119 In, 120 In, 121 In, 122 In, 123 In Or 124 In; chromium, including 48Cr, 49Cr, 50Cr, 51Cr, 53Cr, 54Cr, 55Cr or 56Cr; or yttrium, including 92Y, 93Y, 94Y, 95Y or 96Y; the hydrogen can be 150, 170, 180, 190 or 20O. The radioactive salts of pyrophosphoric acid can be prepared using methods that are readily apparent to the expert in the field, once supported by the present description. Generally speaking, the radioactive salts of pyrophosphoric acid can be obtained by dehydration of radiolabelled orthophosphoric acid (H3PO4) or a salt thereof, such as sodium orthophosphate radiolabelled with 32P. Orthophosphoric acid and radiolabelled salts thereof are commercially available from NEN (Boston, MA) and JCN Biomedicals, Inc. (Irvine, CA). The dehydration of the orthophosphate to the corresponding pyrophosphate can be achieved using methods that are well known to those skilled in the art, including for example heating at elevated temperatures as described by Bell. Ind. Eng. Chem., Vol. 40, p. 1464 (1948). The radioactive salts of the present invention may be especially useful in the treatment of cancer in a patient using brachytherapy, although other patient treatments are also within the scope of the present invention. "Patient", as used herein, refers to animals, including mammals, and preferably humans. In embodiments including salts of pyrophosphoric acid containing radiolabelled phosphorus, and especially P, implantation of radioactive salts in a tumor in vivo can provide desirable exposure of the tumor to radiation, while radiation exposure of the neighboring tissue is minimized. normal, it is contemplated that a wide variety of cancers, especially solid tumor cancers, may be treated using the salts radioactive agents of the present invention. Examples of such solid tumor cancers include for example head cancers, such as brain cancer, and cancers of the neck, endometrium, liver, breast, ovaries, cervix and prostate. The embodiments of the invention which include radioactive salts of pyrophosphoric acid, which include the compounds of formula I, may be particularly suitable for use in the treatment of prostate cancer. The radioactive salts of the present invention can be administered to the patient in a variety of ways, depending on the particular route of administration, the particular salt and / or isotope involved, the particular cancer being treated, and the like. In the case of brachytherapy, the radioactive salts can be administered using techniques that are well understood by the person skilled in the art, including for example surgical implantation. In the case of the administration of radioactive salts in the form of for example an aqueous composition or suspension (discussed more fully below), the aqueous composition or suspension can be administered by injection at the desired site. In addition, the radioactive salts of the present invention can be administered in the form of a radiopharmaceutical matrix (discussed more fully below), also by injection or surgical implantation at the desired site. The particular technique used to administer the matrix may depend, for example, on the form and dimensions of the matrix involved.

In general terms, the introduction of the radioactive salts of the present invention for the treatment of prostate cancer may involve retropubic or transperineal techniques. See A.T. Porter et al., CA Cancer J. Clin., Vol. 45 (3), p. 165-578 (1995). Preferably, the radioactive salt is introduced substantially homogeneously into a tumor to minimize the occurrence in the tumor of cold (untreated) areas. In certain preferred embodiments, the radioactive salt ILO is administered in combination with a pharmaceutically acceptable vehicle. A wide variety of pharmaceutically acceptable carriers are available and may be combined with the radioactive salts of the present invention. Said vehicles will be apparent to the person skilled in the art, in based on the present description. Of course, any material used as a vehicle is preferably biocompatible. "Biocompatible", as used herein, refers to • Geological materials are usually not harmful to biological functions and do not result in any degree of unacceptable toxicity, including allergic responses and pathological states. Suitable vehicles include, but are not limited to, water, buffer or saline. Other vehicles are described, for example, in Remington's, Pharmaceutical Sciences, Gennaro, A.R., ed. , Mack Publishing Co., Easton, PA (1985), and The United States Pharmacopeia - The National Formulary, 22nd. Review, Mack Printing Company, Easton, Pennsylvania E.U. (1990), the descriptions of each of which are incorporated herein by reference in their entirety. The concentration of radioactive salt used in the pharmaceutical compositions and / or the amount of radioactive salt administered to the patient can vary and depends on a variety of factors including, for example, the particular radioactive salt and / or pharmaceutically employed vehicle, the disease particular to deal with, the magnitude of ^ D disease, the size and weight of the patient, and the like.

Typically, the radioactive salt can be employed in the pharmaceutical compositions, and the compositions can be administered to a patient to initially provide lower levels of radiation dosages that can be increased until achieving the desired therapeutic effect. Generally speaking, the radioactive salt can be employed in pharmaceutical compositions comprising an aqueous carrier ^ r to provide a concentration of absolute radioactivity that can vary from about 4 MBq per milliliter (ml) to approximately 0.1 mCi / ml) or less at approximately 370 MBq / ml 10 mCi / ml), and all combinations and sub-combinations of scales within it. Preferably, the concentration of the radioactive salt in the pharmaceutical compositions can be from about 37 MBq / ml to about 1 mCi / ml) to approximately 370 MBq / ml at approximately 10 mCi / ml). In addition, the compositions can be administered to a patient to provide a radiation dose that can vary from about 1 KSv (about 1 x 105 Rem) to about 74 KSv (at about 7.4 MRem), and all combinations and sub-combinations of scales therein. Preferably, the compositions can be administered to a patient to provide a radiation dose of about 7.4 KSv (at about 7.4 x 10 Rem) to about 74 KSv (at about 7.4 MRem). Said amounts are referred to herein as effective amounts or therapeutically effective amounts. In certain preferred embodiments, the pharmaceutically acceptable carrier may further comprise a thickening agent. "Thickening agent" as used herein, refers to any of a variety of generally hydrophilic materials that when incorporated into the present compositions, can act as viscosity modifying agents, emulsifying and / or solubilizing agents, suspending agents, and / or tonicity enhancing agents. Thickening agents which may be suitable for use in the present radiopharmaceutical compositions include for example gelatins, starches, gums, pectin, cacein and phycocolloids including carrageenan, algin and agar; semi-synthetic cellulose derivatives; polyvinyl alcohol and carboxyvinylates; and bentonite, silicates and colloidal silica. Examples of the above materials are carbohydrates such as for example mannitol, glucose and dextrose, and the derivatives phosphorylated and sulphonated thereof; rough polyesters including polyethers including polyethers having a 4fe molecular weight of for example about 400 to about 100,000; and di- and tri-hydroxyalkanes and their polymers having a molecular weight for example from about 200 to about 50,000; acacia; dietolamin; glyceryl monostearate; lanolin alcohols; lecithin; mono- and di-glycerides; monoethanolamine; oleic acid, oleyl alcohol; polyoxyethylene stearate 50; oil of ^ D Polyoxyl resins 35; polyoxyl polyoxyl ether 10 polyoxyl etherstearyl ether 20; polyoxyl stearate 40 propylene glycol diacetate; sodium propylene glycol stearate monostearate; stearic acid; trolamine; emulsifying wax; agar; alginic acid; aluminum monostearate; bentonite; magma; carbomer 934p; hydroxyethylated starch; carboxymethylcellulose; calcium and sodium and sodium 12; carrageenan; cellulose; dextran; jelly; guar gum; carob gum; ^ P vegun; hydroxyethylcellulose; hydroxypropylmethylcellulose; magnesium aluminum silicate; methylcellulose; pectin; oxide polyethylene; povidone; propylene glycol alginate; silicon dioxide; sodium alginate; tragacanth; xanthan gum; alpha-d-glucolactone; glycerol; mannitol, polyethylene glycol (PEG) polyvinylpyrrolidone (PVP), polyvinyl alcohol PVA) polypropylene glycol; polysorbate; sorbitol; propylene glycol glycerol; and polyoxyethylene-polyoxythylene-polyoxypropylene glycol block copolymers. Preferred among the Polyoxyethylene-polyoxypropylene glycol block copolymers are the block copolymers of alpha-hydroxy-omega-hydroxypoly (oxyethylene) poly (oxypropylene) -poly (oxyethylene). These latter block copolymers are generally referred to as poloxamer copolymers. Examples of poloxamer copolymers which may be particularly suitable for use in the present compositions include for example poloxamer F68, poloxamer L61 and poloxamer L64. These poloxamer copolymers are commercially available from Spectrum 1100 (Houston, Texas E.U.). • Preferred thickeners indicated above are gelatins, polyvinylpyrrolidone and polyoxyethylene-polyoxypropylene glycol block copolymers. Other thickening agents, in addition to the illustrated ones , Above, will be apparent to the person skilled in the art based on the present disclosure. The concentration of thickening agent, when it is ^^ present in the compositions of the present invention, may vary and depends on several factors including, for example, the thickened particular agent, radioactive salt, pharmaceutically acceptable carrier, and the like which are employed. Preferably, the concentration of the thickening agent is at least sufficient to impart desirable properties to the compositions, including for example a change in the viscosity of the compositions. Generally speaking, the concentration of thickening agent can vary from about 0.1 to about 500 milligrams (mg) per ml of pharmaceutical composition, and all combinations and subcombinations of scales therein. Preferably, the concentration of thickening agent may be from about 5 1 to about 400 mg / ml, with concentrations from about 5 to about 300 mg / ml being preferred. Preferably, the concentration of thickening agent can be from 10 to 200 mg / ml, with concentrations from about 20 to about 100 being very preferred. ^^ mg / ml. Thickening agent concentrations of 25 to 50 mg / ml are especially preferred. Compositions that can be prepared from the radiative salts, pharmaceutically acceptable carriers and optional thickening agents include for example , 15 suspensions, emulsions and dispersions. Preferably, the radiative salts can be formulated and administered to a patient as a suspension. "Suspension", as used here, refers to A mixture, dispersion or emulsion of finely divided colloidal particles in a liquid. "Colloidal", as used herein, refers to a state of subdivision of matter comprising individual large molecule particles or aggregates of smaller molecules. The particles can be dimensioned microscopically and together comprise the dispersed phase. This dispersed phase is generally surrounded by different matter, generally referred to as the dispersion medium or external phase.

The suspensions can be obtained for example by combining the radioactive salt with an inert support material. "Inert", as used herein, refers to substances that are generally resistant to chemical or physical action. Preferably, the inert substances are also biocompatible. In the preferred form, the inert support material is a solid absorber and / or absorbent upon which the radioactive salt can be absorbed and / or absorbed, in certain preferred embodiments, the inert solid can comprise particles, and preferably finely divided particles. . Said support materials are referred to herein as "particulate support materials". Particulate support materials which may be suitable for use as an inert solid support in the compositions of the present invention include, for example, carbon-derived materials, including those carbon forms typically referred to as carbon black and / or activated carbon, as well as finely pulverized oxides, diatomite and diatomaceous earth. Preferably, the support material comprises carbon black or activated carbon. The particle size of the particulate support material can vary and depends for example on the particular support material, radioactive salt, thickening agent and the like which are employed. Generally, the particulate support material may comprise particles ranging in size from, for example, from about 0.1 miera (μm) to approximately 50 μm, and all combinations and sub-combinations of scales in it. Preferably, the B particle size can be from about 0.5 to about 25 μm, with particle sizes from about 1 to about 10 μm being preferred. Preferably, the particle size of the particulate support material may be from about 2 to about 5 μm. The radioactive salt may be adsorbed and / or absorbed onto the solid adsorbent and / or absorbent material by a • variety of techniques known to the person skilled in the art. Suitable techniques include for example dissolution of a radioactive salt in an appropriate solvent, including aqueous solvents. This mixture of salts can then be combined with the # 15 support material which is then isolated, for example by means of filtration, and dried to provide the radiolabelled support material. In modalities involving radioactive salts of In the case of pyrophosphoric acid, the support material can be combined, for example, with an aqueous acid solution of a radioactive salt of pyrophosphoric acid. In alternative embodiments, the support material may be combined with an aqueous solution of a radioactive salt of phosphoric acid. In these latter embodiments, the radioactive salt of phosphoric acid which is adsorbed and / or absorbed onto the support material may be converted to the corresponding radioactive salt of pyrophosphoric acid. Said conversion may include, for example Dehydration of the phosphoric acid salt. Generally speaking, this dehydration may include heating the inert radiolabelled material to a • temperature and for a time to substantially convert the phosphoric acid salt to the corresponding pyrophosphoric acid salt. Suitable temperatures at which the radiolabelled material can be heated to achieve this conversion include, for example, temperatures of about 500 to about 1110 ° C. This heating can be done ^ Or under a variety of atmospheres, such as air atmosphere or inert atmosphere, for example argon or nitrogen. The dehydration reaction is completed generally in less than about 5 hours. Other methods to formulate salts ? radioactive with the support materials, in addition to the methods described herein, will be readily apparent based on the present disclosure. It should be obvious to the expert in the field, a Once supported with the present description, that in relation to the methods for the preparation of the radioactive salts and / or radiopharmaceutical agents of the present invention, the particular material obtained by heating a phosphoric acid salt can vary and depends for example on the particular temperature and the time involved in the conversion process. For example, heating an acid salt phosphoric at higher temperatures, for example about 1100 ° C, and / or heating a phosphoric acid salt during Prolonged periods may result in a degree of dehydration that may be greater than that required to provide a salt of pyrophosphoric acid. Therefore, the increased dehydration can provide for other salts other than the pyrophosphate salts described above, including for example polyphosphoric acid salts such as, for example, linear salts of polyphosphoric acid which can have the formula Cpn ° 3n + 1] n + 2 '~, branched salts of polyphosphoric acid, or cyclic salts of polyphosphoric acid which may have the formula [Pr * 3nJ n ~ • As with the salts of pyrophosphoric acid, the salts which may be provided by increased dehydration are generally substantially insoluble in aqueous medium, including blood. Therefore, these salts can also be used in the methods and _15 compositions of the present invention and therefore are contemplated within the scope of the present invention. The amount of particulate support material that is ^ P can be used in the compositions can vary and depends for example on the particular support material, the radioactive salt, Thickening agent and the like employed. Generally speaking, the support material may be employed in the compositions to provide concentrations, after absorption and / or adsorption thereon of the radioactive salt, which may vary from about 0.1 to about 100. mg / ml of the composition, and * all the combinations and sub-combinations of scale in it. Preferably, after of absorption / adsorption thereon of the radioactive salt, the support material can be employed in an amount of about 0.5 to about 90 mg / ml, with amounts of about 1 to about 80 mlg / ml, to about 2 to about 70 mg / ml, at about 3 to about 60 mg / ml to about 5 to about 50 mg / ml. In a preferred alternative embodiment of the present invention, the radioactive salts described herein are They can be administered in the form of a solid radiopharmaceutical matrix. "Matrix" as used herein, refers to a solid article of manufacture comprising an external substance substantially surrounding an internal substance. Preferably, the radioactive salts of the present invention are , 15 included within the internal substance. A wide variety of materials are available for use as internal and external substances. Preferably, the substances ^ P internal and external are composed of materials that are inert and preferably bio-compatible. In preferred form, The matrices comprise a biocompatible sleeve substantially surrounding a radiopharmaceutical composition. Preferably, the sleeve is formulated from a biocompatible polymer such as for example aliphatic polymers including polyethylene polymers, polymers formed by condensation reactions such as for example polyester polymers, including polymers sold under the Dacron brand? (DuPont Corp., ilmington, DE), fluorocarbon polymers such as for example polytetrafluoroethylene polymers, including polymers sold under the trademark Teflon (DuPont Corp., Wilmington, Delaware EU) and organosilicon polymers such as for example polymers sold under the Silastic® brand (Dow Corning, Corp., Midland, Michigan EU). Preferred among the polymers indicated above are polyester polymers, especially p polymers sold under the trademark Dacron (DuPont Corp., Wilmington, Del. E.U.). Other polymers, in addition to those exemplified above, will be apparent to the person skilled in the art based on the present disclosure. In the present matrices, the bio-compatible sleeve preferably surrounds substantially a composition _15 radiopharmaceutical. The radiopharmaceutical composition preferably comprises a radioactive salt of pyrophosphoric acid and one or more polymeric resins. Suitable radioactive salts of acid P-pyrophosphoric acid include those described in detail above such as, for example, the salts of formula I.

Preferred, the polymeric resins included in the radiopharmaceutical compositions can be for example thermoplastic resins such as polymer resins of acrylic acid and derivatives thereof, including polymers of metalacrylate resins and resin and of cyanomethacrylate, polymers formed by condensation reactions such as for example polyester polymers and thermosetting resins such as for example epoxy resins. Preferred among the resins indicated above 4fe are the epoxy resins, with the modified epoxy resins sold under the trademark Araldite 5 GY 507 (Ciba Geigy Corp., Brawater, NY) being particularly preferred. Other resins, in addition to those exemplified above, will be apparent to the person skilled in the art based on the present description. A wide variety of methods are available to prepare the matrices of the present invention. By For example, a radioactive salt of pyrophosphoric acid can be combined with a suitable curable polymeric resin such as an epoxy resin. To promote the curing of the polymeric resin, including the epoxy resins described above, additional components can be incorporated JL5 such as for example curing agents, hardening agents, and the like. Preferably, the resin further comprises a hardening agent. A hardening agent ^ P Particularly preferred is the Hy 951 hardener, commercially available from Ciba Geigy Corp. (Brawater, New York, E.U.). The concentration of the radioactive salt can vary and depends on a variety of factors including, for example, the particular radioactive salt and / or the polymeric resins employed, the use of additional agents in the resin mixture, such as curing agents and / or hardening agents, the The particular disease to be treated, the magnitude of the disease, the size and weight of the patient, and the like. Typically, the radioactive salt can be used in the resin or polymeric resins and, consequently, the matrices, and the matrices are M ^ can be administered to a patient to initially provide lower levels of radiation dosages that can be increase until achieving the desired therapeutic effect.

Generally speaking, the radioactive salt can be used in a concentration of, or greater than, 0 to approximately 50%, and all combinations and sub-combinations of scales in it, based on the total weight of the resin or resins and optional curing or hardening agents employed. Preferably, the concentration of the radioactive salt is from about 0.5 to about 40% with concentrations of about 1 to about 30% being preferred. Preferably, the radioactive salt is It is used in a concentration of about 1-5 to about 20%, with a concentration of about 2 to about 10% being very preferred. It is more preferred that ^ P the concentration of radioactive salt is from about 3 to about 5%, with particularly preferred concentration of approximately 4%. The mixture of radioactive salt, polymeric resin and optional additional ingredients can be combined until homogeneous, and the resulting mixture can be introduced into the biocompatible p sleeve, preferably a Dacron sleeve, such that the sleeve substantially surrounds the radioactive resin mixture. The introduction of the resin mixture in A sleeve can be made for example by pumping the mixture in the sleeve using an appropriate mechanical and / or vacuum pump. Pumps suitable for this purpose are readily available and will be apparent to the person skilled in the art, based on the present disclosure. The particular pump employed may depend for example on a variety of. factors that include the viscosity of the resinous mixture as well as the dimensions of the sleeve used, particularly its length and internal and external diameters. In turn, the ^^ dimensions of the sleeve used, and depend on a variety of factors including, for example, the particular radioactive salt and / or the polymeric resin employed, the particular disease to be treated, the extent of the disease, the size and weight of the patient, and Similar. Generally speaking, _15 the length of the sleeve used can vary from approximately 0.1 cm to approximately 5 cm, and combinations and sub-combinations of scales therein. Preferably, the The length of the sleeve may vary from 0.3 cm to 3 cm, with a length from about 0.8 cm to 20 about 2 cm being preferred. Even more preferred, the length of the sleeve can be about 1 cm. The outer diameter of the sleeve can vary from approximately 0.2 mm to approximately 2 mm, and all combinations of scales in it. Preferably, the external diameter can vary from 0.525mm to about 1.5mm, with an outer diameter of about 1mm being preferred. The internal diameter of Cuff can vary from 0.1 to about 1.8 mm, and all combinations of scales in it. Preferably, the internal diameter can vary from about 0.3 to about 1.3 mm, with an inner diameter of about 5 mm being about 0.8 mm. Preferably, after insertion into the sleeve, the resin mixture containing the radioactive salt is preferably cured to provide the solid matrices present. The method of curing employed can vary and depends for example on the particular polymer resin and the optional curing and / or curing agents employed. Generally speaking, the resin mixture can be cured, for example, by the application of heat or ultraviolet (UV) light, with heat curing being preferred. The The resulting matrix can then be administered to a patient as described herein. The present invention also provides equipment ^ P convenient pharmacists. These equipment may comprise a radioactive salt of pyrophosphoric acid and, typically, a pharmaceutically acceptable vehicle. The equipment may also comprise conventional equipment components such as needles for use in the injection of the compositions, one or more bottles for mixing the components of the composition and the like, as will be apparent to the person skilled in the art.

In addition, instructions may be included on the equipment, either as inserts or as labels, indicating the quantities of the components, guides for mixing the components and administration protocols. The radioactive salts, pharmaceutical compositions and radiopharmaceutical matrices of the present invention provide surprising and unexpected results in the treatment of disease, such as carcinomas, since they resist mobilization and / or distribution in the bloodstream. In addition, the radioactive salts and radiopharmaceutical compositions and matrices herein can be highly effective for the treatment of cancers, especially prostate cancer. In relation to prostate cancer, it has been observed that patients suffering from it can exhibit a marked reduction in the levels of prostate specific antigen (PCA) after the administration of the salts, compositions and / or radioactive matrices present. As is known to the person skilled in the art, the observation of PCA levels may be a preferred method for evaluating the response of a particular treatment. The invention is further described in the following examples. All the examples are real examples. These examples are for illustrative purposes only, and are not intended to be limiting of the appended claims.

EXAMPLE 1 This example describes the preparation of a radiopharmaceutical composition within the scope of the present invention.

• A. Inert support 5 Carbon black (2 g) was suspended, having an active adsorption surface p of approximately 450 m per g, in analytical / pharmaceutical grade petroleum ether (40 ml). The suspension was centrifuged, and the supernatant was decanted. This procedure was repeated, and the carbon black was washed ^^ Subsequently with acetone (1 x 40 ml) and ethanol (2 x 40 ml).

The carbon black was dried by heating in an oven (200 ° C) for 24 hours. To the dried carbon black, a 1% solution (25 ml) of potassium dichromate (^ C ^ Oy) was added, with stirring, over a period of about 5 minutes.

The resulting mixture was centrifuged, the supernatant was decanted and the carbon black was washed twice with bidistilled water. After the second wash, the carbon black was resuspended ^ P in a minimum volume of bidistilled water, and transferred to a flask suitable for oven drying. The carbon black suspension was then dried in an oven (50 ° C) for two days, cooled and stored in a glass jar.

B. Radiolabelling of the inert support The carbon black material of step A (50 mg) is introduced into a flexible polyethylene tube. A vehicle-free solution of sodium orthophosphate labeled with P, having an activity of approximately 2mCi, and HCl was added at 0.02 N. Approximately 1 ml of this orthophosphate solution was added to the polyethylene tube. The mixture was dried in an oven (50 to 60 ° C) for a period of about 24 hours. The dried material was transferred to a neutral glass jar, the opening of which was covered, with a small porcelain or platinum capsule. The flask was heated in a sterile environment to a temperature of about 550 ° C to about 600 ° C for a period of about 15 minutes, during which time the contents of the flask • were kept free of any foreign matter. During this heating phase, the carbon black developed a red hue. The mixture was cooled, and sterile stainless steel supports or cylinders were introduced into the flask. .15 diameter from about 1 mm to about 2 mm. The flask was covered with a sterile rubber stopper, sealed and placed behind a protection of lucite. The dried mixture was stirred ^^ vigorously for approximately 30 minutes, after which approximately 5 ml of a solution was added physiological sterile (pharmaceutical grade NaCl, 9 g) in injectable grade H2O (1000 ml). The resulting mixture was homogenized by vigorous stirring for a period of about 5 minutes. The absolute activity of the mixture was measured in an ionization chamber calibrated for 32P. He The flask was centrifuged at 500 to 600 rpm for a period of about 10 minutes. Using a sterile syringe, the The supernatant was substantially removed, and its activity was measured in an ionization chamber. The activity of the supernatant was negligible.

C. Addition of a pharmaceutically acceptable carrier A solution of 3% bovine gelatin was sterilized by heating in an autoclave (121 ° C) for a period of about 30 minutes. The solution was allowed to cool until warmed, and an aliquot (2 ml) of the radiolabeled carbon gelatin solution from step B was added. The resulting mixture was stirred vigorously for a period of about 5 minutes to provide a composition. radiopharmaceutical of chromium pyrophosphate labeled with 3PP, carbon black and gelatin.

EXAMPLE ÍA Example 1 was repeated, except that the 3% bovine gelatin solution of step C was replaced with a 15% polyvinylpyrrolidone solution.

EXAMPLE 2 This example includes a description of chemical and physical analyzes that were carried out on the radiopharmaceutical composition prepared in Example 1.

A. Radiochemical purity analysis A sample of the radiopharmaceutical composition prepared in example 1 was analyzed for radiochemical purity. This analysis was carried out using paper chromatography (Whatman No 1 paper) and 0.1 N HCl as the mobile phase. Chromatography was developed from about 35 to about 40 minutes. The radiolabeled carbon had an Rf of 0, while the P-labeled orthophosphate had an Rf of about 0.8 to about 0.9. The paper for chromatography was analyzed using radioautography, and the areas of • interest were measured using a Geiger-Muller (GM) tube. The radiochemical purity of the composition was determined to be n p greater than 95% as pyrophosphate labeled with P. It was determined that the concentration of the P-labeled orthophosphate is about 1%.

B. Physico-Critical Analysis • A sample of the radiopharmaceutical composition prepared in Example 1 was analyzed for its physicochemical properties using optical microscopy and flow cytometry, the last of which included light scattering with an argon laser of 500 mW. These analyzes revealed that 90% of the particles in the radiopharmaceutical composition had an average diameter of around 2.5. to about 4 μm.

C. Stability Analysis The stability of the radiopharmaceutical composition prepared in Example 1 was studied as a function of time, using the paper chromatography technique described in paragraph A above. This study indicated that the p amounts of P-labeled pyrophosphate and 32 P-labeled orthophosphate remained constant for a period of at least about 1 month.

EXAMPLE 3 • This example includes a description of preliminary studies of toxicity and pyrogenicity that were carried out using the corresponding non-radiolabeled form (P) 15 of the radiopharmaceutical compositions of the present invention.

A. Preparation of a pyrrophosphate composition - = 1 P Example 1 was repeated, except that the radiolabeled form of the orthophosphate salt was used in step B.

B. Toxicity studies and pyro-activity The non-radioactive composition (1 ml) prepared in step A was injected intraperitoneally in 10 Sprague-25 Dawley rats. No toxicity was observed. Following the procedure outlined in the Pharmacopoeia Argentina, VI edition, a warm solution of gelatin (3%) or polyvinylpyrrolidone (15%) was injected into the marginal vein of the ear of 3 rabbits. No pyrogenicity was observed.

EXAMPLE 4 This example describes radiopharmaceutical compositions of the prior art. The compositions of the prior art are as follows: (A) a chromic p-orthophosphate composition labeled with P and gelatin comprising particles having an average particle size of about 10 to about 30 nanometers (nm); (B) a chromic orthophosphate composition labeled with P and gelatin comprising particles having an average particle size of about 30 to about 70 nm; and (C), Phosphocol (Mallinckrodt Medical), which is a 32P labeled dephosphorus (30%) chromophobic orthophosphate composition comprising particles having an average particle size of about 0.5 to about 4 μm, having 90% the particles an average particle size of about 0.6 to about 2 μm. The following examples include descriptions of in vivo pharmacological test procedures in animals that are thought to correlate with therapeutic activity in humans and other animals, and pharmacological test procedures in humans. The testing procedures included a comparison of the amounts of radioactivity removed (referred to herein as "biological elimination") in the urine and feces of rats to which the compositions of the present invention and compositions of the prior art were administered. The test procedures also included a comparison of the distribution of radioactivity in various tissues in the rats. The test procedures further included a comparison of the effectiveness for the treatment of cancer using radioactive compositions within the scope of the present invention, with the efficacy for the treatment of cancers using radioactive materials of the prior art.

EXAMPLE 5 This example describes experimental protocols included in certain in vivo pharmacological test procedures.

A. Induction of Cancers Multiple mammary adenocarcinones were induced in female Sprague-Dawley rats by administering, thereto, N-nitroso-N-methylurea (NMU) according to the methods described in Gullino et al., Nati. Cancer Inst. Vol. 54, pp. 401-404 (1975), and modified in Rivera et al., Cancer Lett., Vol. 86, pp. 223-228 (1994). The NMU was administered to rats of 50, 80 and 110 days. The average latency period was 82 days, and the mean incidence of tumors was 96%. Most tumors also developed metastases.

B. Administration of radioactive materials H Induced tumors were identified in the rats, and the size of said tumors was measured with a calibrator along two axes to locate substantially the geometric center of the tumor. The area around the tumor was depilated ^^ Substantially. The tumor was injected from about 0.6 to about 1 ml of radioactive material to provide an injected radioactivity of about 0.6 to about 1 mCi. To minimize tissue destruction, the radioactive material was injected slowly through a needle _15 fine. In addition, the needle was slowly removed after the injection was completed to allow the tissues to collapse, thus preventing the reflux of the radioactive materials. The ^ tumors that were treated with radioactive compositions are referred to later as "treated tumors". The tumors that were not treated with the radioactive compositions, are referred to below as "control tumors". At the end of the experiments, the rats died due to the growth of control tumors, or were sacrificed. Organs, bones and tumors treated, were removed, fragmented and mineralized with sulfochromic mixture. Radioactivity was measured in the urine, feces, treated organs, bones and tumors, and the standard 32P was measured on a single-channel gamma spectrometer with an ordinary well crystal of Nal (TI) measuring 5.08 cm x 5.08 cm, and using the Bremsstrahlung photons of P. The counter was calibrated 5 previously, and the geometry of all measurements remained constant. The efficiency of the measurements was approximately 0.1%. Unless otherwise indicated, the rats were kept in stainless steel metabolic cages that ^ & they allowed the collection and separation of feces and urine during in vivo experiments. The rats were provided with water and food at all times. In the following examples, the radioactivity of urine and faeces collected was analyzed and expressed as the "radioactivity removed". The term "eliminated radioactivity" is expressed as a percentage of the amount of radioactivity in the urine and faeces, with respect to the total amount of ^ P radioactivity injected into the experimental animal.

EXAMPLE 6 This example includes a description of biological elimination test procedures that include the radiopharmaceutical compositions of the present invention.

Biological elimination tests were carried out, and included the administration of the composition of Example 1 to a total of 28 rats, referred to below as "test 6". The results of test 6 are given in table 1 below, and are shown graphically in figure 1.

TABLE 1 The analysis of Table 1 and Figure 1 reveals that a substantially small amount of the radioactivity administered using the compositions of the present invention was removed from the body. In test 6, the radioactivity in the collected urine was substantially greater than the radioactivity in the collected faeces.

EXAMPLE 7 This example includes a description of biological elimination test procedures that include prior art radioactive compositions.

A. Biological elimination test procedures including the composition of Example 4 (A) Biological clearance tests were carried out, and included administration of the composition of Example 4 (A) to 14 rats, hereinafter referred to as "Test 7 (A) ". The results of test 7 (A) are given in Table 2 below, and are shown graphically in Figures 2A through 2E.

TABLE 2 Test sample 7 (A) (i) and figure 2A show the radioactivity removed for 10 of the treated animals as mean + standard deviation. Each of the test samples 7 (A) (ii) to 7 (A) (v) and the corresponding figures (Figures 2B to 2E, respectively), show the radioactivity removed for each of the animals.

The analysis of Table 2 above and Figures 2A to 2E reveals that the radioactivity removed using a prior art radioactive composition (example 4 (A)) is significantly greater than the radioactivity removed for the radioactive compositions of the present invention. HE * thinks that the increased elimination is due, at least in part, to the increased solubility, in the bloodstream, of the radioactive compositions of Example 4 (A). This increased solubility results in mobilization ^? Increased composition in the bloodstream, which in turn results in phagocytosis by the liver and ultimate hydrolysis and excretion of the body. The analysis of Table 2 and Figures 2A through 2E also reveals that the radioactivity eliminated was not reproducible, and that it varied significantly between the test samples. Table 2 and the related figures also show generally an increase in radioactivity eliminated along the course of ^ the test procedures.

B. Biological elimination test procedures which include the composition of example 4 (B) Biological elimination tests were carried out, and included the administration of the composition of the example 4 (B) to 14 rats, referred to below as "Test 7 (B)". The results of test 7 (B) are given in table 3 below, and are shown graphically in figures 3A, 3B and 3C.

TABLE 3 Test sample 7 (B) (i) and figure 3A show the radioactivity removed for 12 of the treated animals as mean ± standard deviation. Each of the test samples 7 (B) (ii) and 7 (B) (iii) and the corresponding figures (Figures 3B and 3C, respectively), show the radioactivity removed for each of the animals. The analysis of Table 3 and Figures 3A, 3B and 3C reveals that more than 35% of the injected radioactivity was removed using the composition of Example 4B. This is an inconveniently high amount of radioactivity removed, and indicates that the composition of Example 4 (B) of the prior art has a high degree of solubility in blood. Table 3 and the related figures also generally show an increase in radioactivity removed throughout the course of the test procedures.

C. Biological elimination test procedures which include the composition of Example 4 (C) Biological elimination tests were carried out, and included administration of the composition of Example 4 (C) to 28 rats, referred to below as "Test 7 (C) ". The results of test 7 (C) are given in table 4 below, and are shown graphically in figures 4A to 4E.

TABLE 4 Test sample 7 (C) (i) and figure 4A show the radioactivity removed for 24 of the treated animals as the mean ± standard deviation. Each of the test samples 7 (C) (ii) to 7 (C) (v) and the corresponding figures (Figures 4B to 4E, respectively), show the radioactivity removed for each of the animals. The analysis of Table 4 and Figures 4A through 4E reveals that the radioactivity removed varied from about 30% to a value as high as approximately 98%. Thus, the radioactivity removed was substantially non-reproducible, and varied dramatically among the test samples. Table 4 and the related figures also generally show an increase in radioactivity removed throughout the course of the test procedures.

EXAMPLE 8 This example includes a capacity comparison • of the radiopharmaceutical compositions of the present invention and that of the compositions of the prior art to remain in the treated tumors. This comparison included an analysis of the biological distribution of the radioactivity in the injected tumors, as well as in other tissues in the experimental animal, particularly the bone, liver, spleen, kidney and lung. The procedures of • Biological distribution test described in this example are discussed later in Table 5. Biological test identified in Table 5 below as "test 8 (A)", included the administration of the composition of Example 1. The biological tests identified in Table 5 as "tests 8 (B), 8 (C) and 8 (D) ) ", included the compositions of examples 4 (A), 4 (B) and 4 (C) of the prior art, respectively. The numerical values in table 5 represent percentages of radioactivity in the tissue involved, based on the total amount of radioactivity injected into the animal's tumor. The percentage balance of the total radioactivity measured generally corresponded to the radioactivity eliminated.

TABLE 5 -fifteen The analysis of Table 5 reveals that the radioactivity 20 administered to a tumor using the compositions of the present invention remains substantially in the tumor, with negligible transport to other tissues. See test 8 (A) in Table 5. In contrast, substantial amounts of radioactivity administered to a tumor using compositions of the prior art do not remain in the tumor, and rather are transported to other body tissues. See tests 8 (B), 8 (C) and 8 (D). Other distribution tests were carried out (biological to compare the capacity of the radiopharmaceutical compositions of the present invention with that of the compositions of the prior art to remain in the > treated tumors. These additional biological distribution test procedures are discussed later in Table 6. The biological test identified in Table 6 below as "Test 8 (E)" involved the administration of the J? composition of Example 1. The biological test identified in Table 6 as "Test 8 (F)", included the composition of Example 4 (B) of the prior art, and the biological tests identified in Table 6 as "Tests 8 ( G) and 8 (H) ", included the composition of example 4 (C) of the technique previous.

TABLE 6 • ? The analysis of table 6 reveals that the compositions of the present invention provide reproducible biological distributions. See tests 8 (E) and 8 (A). However, the distributed radioactivity was substantially non-reproducible, and it varied dramatically in the test samples including the prior art compositions. See tests 8 (F) and 8 (C); and tests 8 (G), 8 (H) and 8 (D).

EXAMPLE 9 Test procedures were carried out to evaluate the biological effectiveness of the compositions of the present invention and the biological efficacy of the compositions of the prior art. These tests usually included injecting tumors with a radioactive composition, and measuring the size of the tumors at regular intervals. The results of the tests are shown graphically in Figures 5A, 5B, 5C and 5D.

A. Biological Efficacy of the Compositions of the Present Invention The biological efficacy testing procedures for the composition of Example 1 are shown graphically in Figure 5A. This graph demonstrates dramatically that the growth of a tumor (Tumor 1) was counteracted after injection of the composition of Example 1, and that the size of the treated tumor decreased until it had substantially disappeared. In comparison, five control tumors (tumors 2 to 6), which received no treatment, grew rapidly throughout the tests.

B. Biological Efficacy of the Prior Art Compositions The biological efficacy test procedures for the compositions of Examples 4 (A), 4 (B) and 4 (C) were carried out and shown graphically in Figures 5B , 5C and 5D, respectively. Tests that include the composition of Example 4 (C) also included a control tumor.

The analysis of Figure 5B reveals that the composition of Example 4 (A) had no effect on tumor growth. The analysis of Figure 5C reveals that the composition of Example 4 (B) caused a brief stabilization in tumor growth after injection. Nevertheless, the tumor resumed its growth and continued to increase in size after several days. The analysis of Figure 5D reveals that the composition of Example 4 (C) stopped tumor growth. However, unlike the tumors treated with the compositions of the present invention, the size of the tumor treated with the composition of Example 4 (C) remained almost the same. As can be seen in Figure 5D, the size of the control tumor increased rapidly.

EXAMPLE 10 This example includes a description of pharmacological test procedures in humans using radiopharmaceutical compositions within the scope of the present invention. Radiopharmaceutical compositions of the type prepared in example 1 were implanted in the prostates of 10 patients (patients A to J) with prostate adenocarcinoma. This involved transperineal implantation with a needle guide for transrectal ultrasound. In one patient, implantation was carried out directly on the remaining prostatic tissue whole after transurethral resection of a prostatic adenoma, which showed histological evidence of prostatic adenocarcinoma (grade 2 Gleason). In the latter case, the radiopharmaceutical composition was also radiolabelled with In to allow external visualization with a gamma camera. Complete absence of diffusion of the radiopharmaceutical composition was observed. In all the patients included in this study, no immediate or late onset of adverse side effects was observed. None of the patients experienced impaired sexual function or bladder voiding, and none of the patients exhibited cystitis or rectal inflammation. In addition, none of the patients exhibited any symptoms associated with radiation sickness. Patients were monitored after the implantation of the radiopharmaceutical composition using ultrasound and evaluation of PSA levels. The majority of patients received a single implant of the radioactive composition. Patients who exhibited neoplastic cell activity, in the first control after implantation, received additional doses of the radiopharmaceutical composition with little or no side effect. The results of these pharmacological test results are given in Table 7 below, and are shown graphically in Figure 6. a < : The analysis of the previous chart and of Figure 6 reveals that all patients exhibited a substantial reduction in PSA levels, indicating a reduction in the size of prostatic tumors. 5 EXAMPLE 11 This example describes the preparation of a radiopharmaceutical matrix within the scope of the present invention.

# A. Radio-labeled epoxy resin Steps A and B of Example 1 were repeated to provide the radiolabeled carbon. This radiolabelled carbon (70 mg) was combined with epoxy resin Araldita GY 507 (1 g) and L5 hardener HY 951 (1 g), and the resulting mixture was mixed until homogeneous.

B. Inclusion in plastic sleeve The mixture prepared in step A was pumped into a Dacron sleeve having an external diameter of 1 mm, an internal diameter of 0.8 mm and a length of 1 ctn. The filled Dacron sleeve was heated to about 50 ° C for about 2 to 3 hours to cure the radiolabeled epoxy resin. 25 EXAMPLE 12 This example includes a description of the chemical and physical analyzes that were carried out on the radiopharmaceutical matrix prepared in Example 11.

A. Stability analysis The matrix prepared in example 11 was analyzed for possible failure of radioactivity. This analysis was carried out by storing the matrix in a glass flask containing 2 ml of distilled water. The bottle was sealed, narrowed and autoclaved at 1 atmosphere for 30 minutes. Two samples of the supernatant of distilled water (1 ml each) were analyzed for radioactivity using a detector thereof. The radioactivity measured in the samples was 0.04% and 0.06%, respectively, indicating that the matrix possessed high stability.

EXAMPLE 13 This example describes the experimental protocols implicit in some of the in vivo radiopharmacological test procedures.

A. Induction of cancers Cancers were induced using the methods described in example 5A above.

B. Administration of the matrix The matrix prepared in Example 11 (1 cm in length with a radioactivity of approximately 300 μCi) was injected into mammary adenocarcinomas., the liver and muscle of the right hind leg of rats. At the end of the experiments, the rats with tumors, as well as the healthy rats, were sacrificed. The organs, bones and treated tumors, as well as the injected livers and the injected hind legs, in any case, were removed, fragmented and mineralized with sulfochromic mixture. Radioactivity was measured in the urine, feces, organs, bones and injected organs, and the standard P was measured in a single-channel gamma spectrometer with an ordinary well crystal of Nal (TI) measuring 5.08 cm x 5.08 cm, and using the P Bremsstrahlung photons. The counter was previously calibrated, and the geometry of all measurements remained constant. The efficiency of the measurements was approximately 0.1%. Unless otherwise indicated, the rats were kept in stainless steel metabolic cages that allowed the collection and separation of faeces and urine during in vivo experiments. The rats were provided with water and food at all times. In the following examples, the radioactivity of urine and faeces collected was analyzed and expressed as the "radioactivity eliminated". The term "eliminated radioactivity" is expressed as a percentage of the amount of flp radioactivity in urine and faeces, relative to the total amount of radioactivity injected into the experimental animal. 5 EXAMPLE 14 This example includes a description of biological elimination test procedures that include a radiopharmaceutical matrix of the present invention. HE • carried out biological tests, and included intratumoral administration of the matrix of example 11 to 4 rats, referred to below as "Test 14A", intrahepatic administration of the matrix to 3 rats ("Test J.5 14B"), and intramuscular administration of the matrix to 10 rats ("14C Test"). The results of these tests are given in Table 8 below, and are shown graphically in Figures 7A, 7B and 7C.

TABLE 8 The test samples 14 (A), 14 (B) and 14 (C), and the corresponding figures (Figures 7A, 7B and 7C, respectively), show the radioactivity removed for 4, 3 and 10 of the treated animals, respectively , as mean ± standard deviation. The analysis of Table 8 above and Figures 7A to 7C reveals that a substantially small amount of the radioactivity administered using the matrices of the present invention was removed from the body. In each of the tests 14 (A), 14 (B) and 14 (C), the radioactivity in the collected urine was higher than in the faeces collected.

EXAMPLE 15 This example includes a study of the biological distribution of radioactivity after intratumoral (15A), intrahepatic (15B) and intramuscular (15C) administration of the matrix of the present invention. The study included an analysis of the biological distribution of radioactivity in the organs, tissues and / or tumors injected, as well as in other tissues or organs in the experimental animal, particularly the bone, liver, spleen, kidneys and lungs. The • Biological distribution test procedures described in this example are given later in Table 9, and are shown graphically in Figures 8A, 8B and 8C, respectively. The numerical values in table 9 represent percentage of radioactivity in the tissue involved, based on the total amount of radioactivity administered. The percentage balance of the radioactivity measured corresponded to ^ Generally to radioactivity removed.

TABLE 9 The analysis of Table 9 indicates that the radioactivity administered using the matrices of the present invention remains substantially in the tumor, injected organ or tissue, with negligible transport to other tissues. The descriptions of each patent, patent application and publication cited or described in this document are hereby incorporated herein by reference in their entirety. Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. It is also intended that said modifications be within the scope of the appended claims.

Claims (21)

NOVELTY OF THE INVENTION CLAIMS

1. - A radiopharmaceutical composition, characterized in that it comprises a radioactive salt of the formula Mz + HxP207 wherein: M is a metal ion; x is an integer from 0 to 3; and z is an integer from 1 to 4; with the conditions that the sum of x and z equals 4, and at least one of M, H, P or 0 comprises a * radioisotope; and a pharmaceutically acceptable vehicle.

2. A radiopharmaceutical composition according to claim 1, characterized in that M is selected from the group consisting of indium, calcium, strontium and transition metals.

3. - A radiopharmaceutical composition according to claim 2, further characterized in that ^ comprises a transition metal.

4. A radiopharmaceutical composition in accordance 20 with claim 3, further characterized in that said transition metal is selected from the group consisting of chromium, yttrium, holmium, samarium, iron, gold, silver, cerium, and mixtures thereof.

5.- A radiopharmaceutical composition in accordance 25 with claim 4, further characterized in that said transition metal is selected from the group consisting of chrome and yttrium.

6. A radiopharmaceutical composition according to claim 5, further characterized in that M comprises chromium.

7. A radiopharmaceutical composition according to claim 6, further characterized in that x is 0 or 1, and z is 3 or 4.

8. A radiopharmaceutical composition according to claim 1, further characterized in that at least one of M , P or O comprises a radioisotope.

9. A radiopharmaceutical composition according to claim 8, further characterized in that at least one of M or P comprises a radioisotope. J

10. A radiopharmaceutical composition according to claim 9, further characterized in that P comprises a radioisotope.

11. A radiopharmaceutical composition according to claim 8, further characterized in that said radioisotope comprises

12. A radiopharmaceutical composition according to claim 1, further characterized in that it is in the form of a suspension.

13. - A radiopharmaceutical composition according to claim 1, further characterized in that said radioactive salt comprises a radioisotope that emits β particles.

14. A radiopharmaceutical composition in accordance with claim 13, further characterized in that said radioisotope emits substantially only β-particles.

15. A radiopharmaceutical composition according to claim 1, further characterized in that it further comprises an inert support material.

16. A radiopharmaceutical composition according to claim 15, further characterized in that said inert support material is selected from the group consisting of a solid adsorbent material and a solid absorbent material.

17. A radiopharmaceutical composition according to claim 16, further characterized in that said inert solid material comprises a support material in * particles.

18. A radiopharmaceutical composition according to claim 17, further characterized in that said particulate support material comprises finely divided particles of carbon.

19. A radiopharmaceutical composition according to claim 1, further characterized in that said pharmaceutically acceptable carrier is selected from the group consisting of water, pH regulator and saline.

20. A radiopharmaceutical composition according to claim 19, further characterized in that said pharmaceutically acceptable carrier further comprises a thickener.

21. A radiopharmaceutical composition according to claim 20, further characterized in that said thickener is selected from the group consisting of gelatins, polyvinylpyrrolidone and polyoxyethylene-polyoxypropylene glycol block copolymers. .22.- A radiopharmaceutical composition, characterized in that it comprises a radioactive salt of the formula Mz + HxP207 where: M is a metal ion; x is an integer from 0 to 3; and z is an integer from 1 to 4; with the conditions that the sum of x and z equals 4, and at least one of M, H, P or O comprises a radioisotope; and one or more polymeric resins. 23. - A radiopharmaceutical composition according to claim 22, further characterized in that said polymeric resins are selected from the group consisting of acrylic, polyester and epoxy resins. 24. A radiopharmaceutical composition according to claim 23, further characterized in that said polymeric resin is an epoxy resin. 25. A radiopharmaceutical composition according to claim 22, further characterized in that said composition is incorporated in a biocompatible sleeve. 26. A radiopharmaceutical composition according to claim 25, further characterized in that said sleeve is formulated from a polymer. 27.- A radiopharmaceutical composition in accordance with claim 26, further characterized in that said polymer of said sleeve is selected from the group consisting of polymers of polyester, polytetrafluoroethylene, polyethylene and polyorganosilicon. 28. A radiopharmaceutical composition according to claim 27, further characterized in that said polymer of said sleeve is a polyester polymer. 29. A radiopharmaceutical composition according to claim 28, further characterized in that said polyester is polyethylene terephthalate. 30. A radiopharmaceutical composition, characterized in that it comprises a radioactive salt of pyrophosphoric acid and a pharmaceutically acceptable vehicle. 31. A radiopharmaceutical composition, further characterized in that it comprises a radioactive salt of pyrophosphoric acid and one or more polymeric resins. 32.- A radioactive salt, characterized in that it has ^ ^ the formula Mz + HxP207 20 where: M is a metal ion; x is an integer from 0 to 3; and z is an integer from 1 to 4; with the conditions that the sum of x and z is equal to 4, and at least one of M, H, P or O comprises a radioisotope. 33.- A radioactive salt in accordance with the 25 claim 32, further characterized in that M is selected from the group consisting of indium, calcium, strontium and metals of transition. 34. A radioactive salt according to claim 33, further characterized in that M comprises a transition metal. 35. A radioactive salt according to claim 34, further characterized in that said transition metal is selected from the group consisting of chromium, yttrium, holmium, samarium, iron, gold, silver, cerium, and mixtures thereof. 36.- A radioactive salt in accordance with the # claim 35, further characterized in that said transition metal is selected from the group consisting of chromium and yttrium. "37.- A radioactive salt in accordance with the 15 claim 36, further characterized in that said transition metal comprises chromium. 38.- A radioactive salt according to claim 37, further characterized because x is 0 or 1, and z is 3 or 4. 20 39.- A radioactive salt according to claim 32, further characterized because at least one of M, P or O comprises a radioisotope. 40.- A radioactive salt according to claim 39, further characterized in that at least one of M or P comprises a radioisotope. 41.- A radioactive salt in accordance with the claim 40, further characterized in that P comprises a radioisotope. 42. A radioactive salt according to claim 41, further characterized in that said radioisotope is 32P. 43. - A radioactive salt according to claim 32, further characterized in that it is adsorbed or absorbed on an inert support material. 44.- A radioactive salt of pyrophosphoric acid. 45. A solid radiopharmaceutical matrix comprising a biocompatible sleeve substantially surrounding a radiopharmaceutical composition comprising a radioactive salt of pyrophosphoric acid and one or more polymeric resins. 46.- A radiopharmaceutical matrix according to claim 45, further characterized in that said sleeve is formulated from a polymer. 47. A radiopharmaceutical matrix according to claim 46, further characterized in that said polymer of said sleeve is selected from the group consisting of polymers of polyester, polytetrafluoroethylene, polyethylene and polyorganosilicon. 48. A radiopharmaceutical matrix according to claim 47, further characterized in that said polymer of said sleeve is a polyester polymer. 49.- A radiopharmaceutical matrix in accordance with Claim 48, further characterized in that said polyester is polyethylene terephthalate. 50.- A radiopharmaceutical matrix according to claim 44, further characterized in that said polymeric resins are selected from the group consisting of acrylic resins, polyester and epoxy. 51.- A radiopharmaceutical matrix according to claim 50, further characterized in that said polymeric resin is an epoxy resin. 52. The use of a composition according to claim 30, for the manufacture of a medicament for the treatment of cancer in a patient. 53. The use according to claim 52, wherein said cancer is selected from the group consisting of cancers of the head, neck, endometrium, liver, breast, ovaries, cervix and prostate. 54. The use according to claim 53, wherein said cancer comprises prostate cancer. 55.- The use according to claim 52, which includes brachytherapy. 56.- The use of a radiopharmaceutical matrix according to claim 45, for the manufacture of a medicament for the treatment of cancer in a patient. 57.- A process for the preparation of a radiopharmaceutical composition, characterized in that it comprises: (a) provide a radioactive salt of pyrophosphoric acid; and (b) combining said salt with a pharmaceutically acceptable carrier. 58.- A method according to claim 57, characterized in that it further comprises, before step (b), combining said radioactive salt with an inert support material. 59. A method of conformity - with claim 58, further characterized in that said combination of said radioactive salt with said inert support material comprises adsorbing or absorbing said salt on said support material. • 60.- A method according to claim 59, further characterized in that said adsorption or absorption step comprises (i) combining with said material - "inert support" a radioactive salt of phosphoric acid, and (ii) t 1 V5 dehydrate said phosphoric acid salt 61.- A method according to claim 57, further characterized in that said pharmaceutically acceptable carrier further comprises a thickener 20 62. A process according to claim 61, further characterized in that said thickener is selected from the group consisting of gelatins, polyvinylpyrrolidone and polyoxyethylene-polyoxypropylene glycol block copolymers. of a radiopharmaceutical composition, characterized in that it comprises: (a) provide a radioactive salt of phosphoric acid and an inert support material; and (b) dehydrating said salt. 64. - A process for the preparation of a solid radiopharmaceutical matrix, characterized in that 5 comprises: (a) providing a biocompatible sleeve that surrounds ^ Substantially a mixture of a radioactive acid salt * pyrophosphoric and a curable polymer resin; and (b) curing said resin. 65.- A radiopharmaceutical equipment, characterized in that it comprises a radioactive salt of pyrophosphoric acid. 66 - A device according to claim 65, further characterized in that it comprises a pharmaceutically acceptable carrier. 67.- A device according to claim ^ 5 66, further characterized in that said pharmaceutically acceptable carrier further comprises a thickening agent. 68.- A device according to claim 65, further characterized in that it comprises components of conventional radiopharmaceutical equipment.