MXPA06009375A - Alpha-emitting hydroxyapatite particles - Google Patents

Abstract

The present invention provides Hydroxyapatite (HA) incorporating an alpha-emitting radionuclide or an in vivo generator for an alpha-emitting radionuclide. The invention further provides methods for the formation of such HA, pharmaceutical compositions comprising the HA and methods of medical treatment of cancerous or non-cancerous disease including administering the HA or compositions thereof.

Description

HYDROXIAPATITA PARTICLES ALPHA ARTICLES EMITTERS Description of the Invention The present invention relates to compositions suitable for the delivery of a radionuclide in vivo. In particular, the invention relates to particulate compositions comprising alpha particle emitting radionuclides or generators for alpha particle-emitting radionuclides. The compositions of the invention are suitable for use in the treatment of both cancerous and non-cancerous diseases. The introduction of novel therapies is important in pharmaceutical research in all fields and particularly in cancer research. One field of this search refers to the use of radionuclides for therapeutic purposes. For many years, beta particle emitters have been investigated for use in the treatment of cancers and colloids labeled with beta particle emitters have been proposed to treat intracavitary diseases including metastatic cancer of the ovaries. In recent years, efforts have also been made to use alpha particle emitters in anti-tumor agents. Alpha particle emitters have several characteristics that distinguish them from beta particle emitters including higher energies and shorter Ref..174870 intervals in tissues. The radiation range of typical alpha particle emitters in physiological environments is generally less than 100 microns, the equivalent of only a small number of cell diameters. This makes these sources very suitable for the treatment of tumors including micrcmethastasis because a small amount of radiated energy will pass beyond the target cells, and therefore damage to surrounding healthy tissue can be minimized. In contrast, a beta particle has an interval of 1"mm or greater in water.The radiation energy of alpha particles is also compared to beta particles, gamma rays and X-rays which is typically 5-8. MeV, or 5 to 10 times that of a beta particle and 20 or more times the energy of a gamma ray.Therefore, this deposition of a large amount of energy over a very short distance gives alpha radiation an energy transfer linearly exceptionally high (LET), when compared to gamma or beta radiation, this explains the exceptional cytotoxicity of alpha-emitting radionuclides • and also imposes strict demands on the level of control and study of the distribution of radionuclides necessary to avoid unacceptable side effects It has been suggested that alpha particle emitters be used bound to particulate and colloidal odes for internal radionuclide therapy (see Bloomer et al., Int. J. Radiat. Oncol. Biol. Phys. 10 (3) 341-348 (1984); Rotmensch et al., Int. J. Radiat. Oncol. Biol. Phys. 34, 609-616 (1996); US 970062, US 5030441, US 5085848; and Vergote et al., Gynecol. Oncol. 47 (3): 366-372 (1992) and Gynecol. Oncol. 47 (3): 358-65 (1992)). . A problem with these colloidal and particulate carriers previously used is that the carrier materials used are not biocompatible and biodegradable. As a result, carriers can accumulate, particularly when administered repeatedly to a body cavity. This accumulation of non-biocompatible material can therefore cause inflammation, etc. Another problem, particularly for example with the astatin colloids 211 and the lead colloids 212 of the prior art, is the leakage of the free radionuclides, since astatine-211 and bismuth-212 (generated from lead 212) are has shown that they accumulate in normal tissues similar to the thyroid and stomach for astatin and in the kidneys with bismuth. A third problem with many of the radionuclides used, is that they are difficult to prepare and are available only in small quantities or because they have a short half life that makes them unsuitable for use in therapeutic preparations. The very high energy of an alpha particle, combined with its significant mass, leads to a significant moment that is imparted to the particle emitted during nuclear decomposition. As a result, an equal but opposite moment is imparted to the remaining "offspring" nuclei in the form of a "nuclear recoil." This recoil * is powerful enough to break most chemical bonds and force newly formed children nuclides out of chelation. - This is highly significant where the child nucleus is itself radioactive with alpha particles because of this son will not be confined by the particle or chelated complex in which the original nucleus was administered. As a result, a significant problem with the methods of the past for the administration of alpha radiochemicals has been the control of the distribution of the child nuclides emitting alpha particles. This may limit the choice of emitters of alpha particles to those without children emitting alpha particles or cause the dose to be limited to reduce the exposure of healthy tissues. Where control over the biodistribution of daughter nuclei can be maintained, then there is a considerable advantage in the formation of radiopharmaceutical substances with emitters of alpha particles that have a chain of children emitting additional alpha particles. By this method, the dose received by the healthy tissue during administration can be minimized and ideally several decompositions of alpha particles can be carried out in the diseased area. However, if control over the fate of the child nuclei can not be established, then this becomes a problem if the children are emitters of alpha particles. This is because they can then accumulate in the healthy tissue and cause undesirable side effects. A method for maintaining control of the daughter nuclei emitting alpha particles was proposed in WO 01/60417. This method employs liposomes that contain the chelating agent to contain alpha particle emitters and prevent nuclear back-off from driving the daughter nuclei out of solution. However, liposomes are not ideal for all administration methods and may show undesirable speeds and clearance routes in some cases. There is thus a considerable need for improved radiotherapeutic compositions which show a stable labeling of the radionuclides emitting alpha particles and which have a very small leak, if any, of radioactive offspring to other tissues. There is an additional need for radiotherapeutic compositions that have biocompatible and biodegradable components. There is also a need for radiotherapeutic compositions in which the radionuclides are sufficiently easy to prepare and are available in amounts large enough for use in pharmaceutical preparations. The present inventors have now surprisingly established that the hydroxyapatite (HA) particles can be radiolabelled with alpha particle emitting radionuclides and will stably retain the radionuclides for a considerable period. In addition, the present inventors have established that HA radiolabelled with alpha emitters will retain, to an unexpectedly high degree, the daughter nuclides after the decomposition of the original nuclide. This was a highly unexpected discovery since the recoil produced by alpha decomposition usually alters the chemical bonds and effects the release of the child product. In a first aspect, the present invention therefore provides a hydroxyapatite (HA) that incorporates a radionuclide emitting alpha particles or a radionuclide that is an in vivo generator for a radionuclide emitting alpha particles. The hydroxyapatites of the present invention are preferably stable in the sense that the radionuclide is stably trapped within the HA and does not leach significantly towards the solution or to other tissues under physiological conditions. The HAs are also preferably stable in the sense that the daughter nuclides are also trapped by the HA carrier and substantially do not leach into the solution or into other tissues under physiological conditions. The hydroxyapatites of the invention and the compositions prepared therefrom have the advantage of using the therapeutically stronger alpha particle emitting radionuclides in place of the beta particle-emitting nuclides of the prior art while maintaining control over the daughter nuclides. . further, the emitters of desirable alpha particles that are broken down to provide a chain of additional alpha emissions may be preferably used because the hydroxyapatites of the present invention provide control over the fate of such children. The only known previous use of hydroxyapatite particulate materials as carriers has been for radionuclides emitting beta particles in radiosynovectomy (ie in the treatment of arthritis pain) by Unni et al. (Nucí, Med. Biol. 29, 199-209 (2002)) and Brodack et al. (WO 97/01304). The previously used beta particle emitters were all decomposed into stable nuclides that have no relevance for dose distribution (ie, there is essentially no regression during decomposition and the child product was not radioactive and therefore its distribution was not some meaning). The hydroxyapatites of the present invention and the compositions prepared therefrom are highly suitable for use in the treatment of cancerous and non-cancerous diseases. This is especially because the therapeutically active alpha particle emitters, administered directly with the hydroxyapatites of the invention or generated in vivo, provide high cytotoxicity and cause less damage to the surrounding and deeper regions of normal tissues when compared with the emitters of beta particles. This applies particularly when the HAs of the invention are used in a method of local, regional or objective administration, such as intracavitary, systemic and intra-tumoral systemic methods and results from the shorter interval of alpha radiation. In a second aspect, the present invention therefore provides a method of treating a human subject or an animal, especially a mammal (especially one in need thereof) by the administration of an effective amount of a hydroxyapatite (HA) incorporating a radionuclide emitting alpha particles or a radionuclide that is an in vivo generator for a radionuclide emitting alpha particles or by administration of a composition prepared from such HA. In a further aspect, the present invention provides a pharmaceutical composition comprising a hydroxyapatite of the present invention and at least one physiologically acceptable carrier. In a still further aspect, the present invention provides a hydroxyapatite (HA) incorporating a radionuclide emitting alpha particles or a radionuclide that is an in vivo generator for a radionuclide emitter of alpha particles, for use in therapy. In a still further aspect, the invention provides the use of hydroxyapatite (HA) that incorporates a radionuclide emitting alpha particles or a radionuclide that is an in vivo generator for a radionuclide emitting alpha particles in the manufacture of a medicament (especially a medicament injectable, infusible or locally applicable) for the treatment of a cancerous or non-cancerous disease (such as any of those diseases indicated hereinafter). In still a further aspect, the invention relates to pharmaceutical compositions and devices comprising a hydroxyapatite (HA) incorporating an alpha particle emitting radionuclide or an in vivo generator of a radionuclide emitter of alpha particles such as syringes prefilled with pharmaceutical preparations. . The invention further relates to a process for preparing a hydroxyapatite (HA) incorporating an alpha particle emitting radionuclide or an in vivo generator of an alpha particle emitting radionuclide, comprising the steps of: (a) contacting a solution of a radionuclide emitting alpha particles or an in vivo generator of a radionuclide emitting alpha particles with hydroxyapatite particulates; and (b) optionally crystallizing a coating of hydroxyapatite on the labeled particulate materials prepared in step (a) whereby the radionuclide or the in vivo generator is encapsulated in the particulate material. Preferably the process comprises: (a) absorbing a solution of the alpha particle-emitting radionuclide or the in vivo generator of the alpha-emitting radionuclide to the hydroxyapatite particulates, preferably at a pH in the range of about 3-12; and (b) optionally crystallizing a coating of hydroxyapatite on the labeled particulate materials prepared in step (a) whereby the radionuclide is encapsulated in the particulate material. The term "hydroxyapatite" is used in the art to indicate a variety of related phosphate compounds, especially hydroxyapatite calcium having the formula [Caio (P04) 6 (OH) 2]. Hydroxyapatite calcium is a constituent of the healthy bone matrix in all vertebrates. It is currently used as a material in artificial limbs, particularly in bone grafts "without cement." An additional use of hydroxyapatite is as selective cation exchangers in the columns.Hydroxyapatite is a biocompatible and biodegradable material and is therefore Especially useful for in vivo application In this regard, an additional advantage is that it can be heat treated or in an autoclave The present invention further provides products and compositions which are stable for autoclaving under standard conditions. When used herein in the description and claims, the term hydroxyapatite (HA) is used to indicate any hydroxyapatite and any derivative or analogue thereof that is biocompatible or biodegradable, these preferably should not exhibit adverse effects for the intended use., the term hydroxyapatite or HA, as used herein, encompasses hydroxyapatite calcium as well as any compound wherein the calcium ion, Ca2 +, is replaced by any other cation (preferably biotolerable) such as Sr2 +, Ba2 +, Bi3 + or Ac3 +, or a combination of one or more of these cations. In one embodiment, hydroxyapatite comprising hydroxyapatite calcium is preferred. The HA can be co-sedimented or further crystallized with other minerals having a low solubility, especially Ca salts of low solubility. The HA that can be used in the present invention and referred to as hydroxyapatite or HA here can also be surface modified to carry other substituents or groups, such as fluorine, phosphonates including bisphosphonates and tetraphosphonates, proteins, amino acids, peptides and magnetic substances. By means of the surface modification, different properties, such as for example a higher resistance to degradation, can be imparted to the particulate HA. Another use of surface modification is to include receptor agglutination molecules that can act as a target ligand to target biological target structures, especially receptors associated with the tumor. Hydroxyapatite or HA as used herein, also encompasses composite materials such as any hydroxyapatite compound combined or co-sedimented with other materials such as metals, oxides, proteins, amino acids, carbohydrates, phosphonates including bisphosphonates, organic compounds, eg, polylactide , polyethylene ketones, glass-ceramic materials, titania, alumina, zirconia, silica, polyethylene, epoxy, polyethylene glycol, polyhydroxybutyrate, gelatin, collagen, chitosan, phosphazene, iron, iron oxide and / or magnetic iron. Such combinations are useful to provide additional desirable properties to the final HA particulate materials, such as for example magnetism (magnetic iron) or the ability to gel (gelatin, collagen, chitosan). In addition, some of the groups mentioned above will make HA more lipophilic, as is well known to a person skilled in the art, and this is considered an advantageous property for any HA derivative or analogue to be used in the present invention. . Hydroxyapatites which are suitable for use in the present invention can have any solid form, and will generally be called "particulate materials" in the present description and claims to distinguish them from radioparticles such as alpha particles (helium nuclei) or particles. beta (electrons). The particulate materials of HA can be, for example, crystals, microspheres or colloids. The shape, size, porosity and density of the particulate materials can be chosen to adapt to the proposed use. The size of the HA particulates can generally be in the range of from about 10 n to about 100 μm, but colloids and other small particulate materials can be used including small t-an particulate materials such as 1 nm. In one embodiment, it is preferable that the particulate materials be of a size such that they can remain in suspension without sedimentation. Sedimentation in this context is understood to include flotation, where the "sediment" is formed in the upper part, rather than in the bottom of the suspension. In particular, it is preferable that the particulate materials are of a size such that they will not settle when stored for a period of at least 1 hour, preferably at least 6 hours and more preferably at least 1 month when suspended in a fluid such as a pharmaceutically tolerable solution (especially aqueous). The sizes of the suitable particulate materials will thus easily be determinable for any particular HA type by routine sedimentation experiments. A generally preferred size range especially for the HA particulate materials according to this invention will be from 1 μm to 20 μm, particularly from 1 μ to 5 μm. It is preferred to use particulate materials having a substantially uniform size distribution. Different size ranges will be preferred and are chosen depending on the proposed use. Particulate materials of small size can be better distributed in areas where there is a spherical impediment. Similarly, they may have advantages when the composition of the invention is administered intravenously (for example for the treatment of cancer systemically) or for delivery locally (for example, to an organ infected with cancer such as for example the liver) . Thus, a small, preferred size range, particularly for intravenous administration, is from about 1 nm to about 2 μm and a more preferred range is from about 8 nm to 40 nm. In a preferred embodiment, the very small particulate materials are administered to the tumor cells which are preferably the target. In particular, tumor capillaries may be more prone to leakage than capillaries of healthy tissue (for example due to their fenestration). The very small "nanoparticulate" HA particulates of the present invention (such as from 1 to 50 nm, preferably 2 to 10 nm, more preferably 3 to 5 n), can thus selectively elute from the capillaries within the tumors and to locate its radionuclides incorporated in the tumor site as effectively. Such particulate materials can also be attached to "target" portions (such as antibodies or receptor agglutination molecules - see above) to increase this objective effect.On the other hand, the larger-sized particulate materials can be better retained. within the administered site, for example in a body cavity. A second advantage of such larger particulate materials is that they are not easily surrounded or fragmented by the macrophages and it is expected that they will better retain the radionuclide in vivo. Accordingly, a further preferred size range, particularly for administration to a body cavity, is from about 100 nm to 100 μm and a more preferred range is from about 500 nm to 20 μm. When used here, the "size" of a particulate material refers to the average size (mode) of the largest dimension of the particulate materials. The particulate materials can have any shape or mixture of shapes uding spheres, plates, needles, bars, etc., but in general the longest dimension will not be greater than 20 times, preferably not more than five times the shortest dimension. Where the particulate materials are formulated for injection or infusion (especially intravenous or intra-arterial), it will generally be the case that no detectable proportion of the particulate materials has any dimension larger than 8 μm, preferably 5 μm. Local or regional infection, for example to a cavity, intra-tumorally, subcutaneously or intramuscularly, may not require this restriction. Porosity is a second property of the particulate materials of HA that can be chosen to correspond to the proposed use or to the radionuclide to be labeled on the particulate material. In particular, the porosity can be closely related to the density of the particulate material and for some of the applications it will be favorable to choose the particulate materials of HA that have a porosity that provides a density similar to that of water to achieve a very slow sedimentation, if is that there is some. Any suitable radionuclide for the labeling of HA to provide a composition according to the invention can be used in the present invention. This will be an isotope that has or generates (for example by at least one beta decomposition) at least one alpha radioactive nucleus. By the term an in vivo generator for a radionuclide emitting alpha particles, is meant an "original" radionuclide that by itself decomposes and in doing so provides a radioactive child nuclide, so as to provide a chain of radioactive decay, where at least one of the nuclei in the chain is decomposed by emission of alpha particles. Generally, the original nuclide will be broken down by emission of beta particles. Also, the nuclei in the decay chain will typically have half-lives such that a therapeutically significant amount of alpha radiation will be generated during the residence of the various nuclei within the body. Where an isotope formulated in a composition of the invention is an alpha emitter, it will preferably have a half-life of between 1 hour and 1 year, more preferably between 5 hours and 90 days. A group of preferred cores udes the alpha particle emitting cores of the following group: iaAt / 212Bi, 23Ra, 22Ra, 225Ac, 227Th, and any combination thereof. Another group of radionuclides are the emitters of beta particles that have at least one child emitting alpha particles in their decay chain. These ude, for example, 2: aPb, which acts as a source for the 211Bi alpha particle emitter, 213Bi, which decomposes to 213Po alpha particle emitter; and 225Ra, which decomposes through beta particles to provide 225Ac, and subsequently decomposes by means of four alpha emissions and two beta emissions to finally give the stable 209Bi. An especially preferred example is: 212Pb, which is broken down by its 12Bi child, emitter of alpha particles. In a preferred embodiment of the invention, 212Pb / 212Bi which is suitable for use in the HA of the present invention, can be prepared by a method comprising: (i) preparing 224Ra (e.g., from a source of by anion exchange chromatography), (ii) purify 224Ra by contact with a specific binder for block f (eg, a resin specific for an actinide / lanthanide, especially in the form of a column), (iii) allow internal growth of 212Pb (per example allowing the 224Ra to remain for 6-24 hours), and _ (iv) purifying the resulting 212Pb by contact with a specific binder for the lead (for example a specific resin for Pb, especially in the form of a column). In the above method, any of the purification steps (i), (ii) and / or (iv) can be repeated at least once with the same or with different examples of the specific binder. Suitable binders specific for the f-block element include methane derivatives bis-phosphonic acid such as P ~, P 'di-octyl methane bis-phosphonic acid (eg DIPEX (RTM)). Suitable binders specific for Pb include crown-ether, particularly 18-crown-6 derivatives such as di-t-butyl-cyclohexane-18 ~ crown-6 (e.g., the specific resin for Pich from Eichrom containing the Pb B25 cartridge) -S) Where radionuclides are used, it is preferable to use specific binders on a non-labile support such as silica but for purification where contact with the resin is short, supports - of organic resin may be used. This method can be combined with any method for the formation of the radionuclides incorporating HA referred to herein. The a2Pb and the HA that incorporates the 212Pb formed and that can be formed by these methods, form additional aspects of the invention. The preparation method for 212Pb indicated above has the advantage of offering a simple and easily carried out processing and also to provide 212Pb with a higher purity of the radionuclide than previously obtained. The compositions of the present invention are stable with respect to the loss of the radionuclide charged from the HA particulates. A composition can be considered stable if, during incubation in a solution at 37 ° C for at least 20 minutes, at least 80% of the activity of the charged radionuclide is detectable in the HA particulate materials rather than in the solution. This ratio should preferably be at least 85%, more preferably at least 90% and still more preferably at 95% or higher. The compositions are also stable with respect to the loss of daughter nuclides generated from the decomposition (eg, alpha decomposition) of the charged radionuclide or one of its decomposition products. A composition can be considered stable in this respect if, during the incubation for a suitable period, the activity that can be attributed to the child radionuclide generated during that period is distributed in such a way that at least 70% remains associated with the HA particulate materials. . This ratio is preferably at least 75%, more preferably at least 80% and even more preferably at least 90%. The labeling of hydroxyapatite with a radionuclide can be effected, for example, by means of the following process steps of: (a) absorbing a solution of the alpha-emitting radionuclide or the in vivo generator of the alpha-emitting radionuclide with respect to the hydroxyapatite particulate materials, preferably at a pH in the range of about 3-12, more preferably at a pH of 5 to 10; and (b) optionally crystallizing a coating of hydroxyapatite on the labeled particulate materials, prepared in step (a) to encapsulate the radionuclide in the particulate material of HA. The method also preferably comprises the step of: (c) heating the HA particles of step (a) or step (b) to a temperature of 70 to 150 ° C, preferably 80 to 130 ° C, more preferably 100 at 120 ° C. The HA particulate materials labeled according to (a) or (b) can be added to a biocompatible or physiologically acceptable liquid carrier (preferably an aqueous carrier) to prepare an injectable or infusible suspension or dispersion., together with any necessary or desirable excipient and / or additive. The additives include suitable adjuvants for preparing and stabilizing a physiologically acceptable preparation for use in the treatment of cancer and radiosynovectomy. Typically, these additional components, where they are present, will be added before the optional step (c). Pharmaceutically tolerable carriers and excipients are well known to a person skilled in the art and may include, for example, salts, sugars and other tonicity adjusters, buffers, acids, bases and other pH adjusters, viscosity modifiers, dyes , etc. Alternatively, the HA particulate materials labeled according to (a), followed by the optional steps (b) and / or (c) can be included in a pharmaceutical gel composition, together with any necessary or desirable excipient and / or additive. . Suitable additives will be well known to those skilled in the art and may include those indicated above and well-known gelling agents such as natural and / or synthetic polymer gels. The compositions in the gel form preferably have sustained release properties. All other suitable pharmaceutical formulations which can be prepared starting from the HA particulate materials labeled with an alpha particle emitting radionuclide or an in vivo generator for an alpha particle emitting radionuclide, including liquids for injection or infusion, gels, creams, pastes, drops, patches, rinsing solutions, spraying solutions, membranes and impregnated sheets, etc., form additional embodiments of the invention. The most preferred pharmaceutical preparations of the compositions according to the invention are generally injectable or immiscible, physiologically acceptable, liquid dispersions or suspensions. To prepare such pharmaceutical compositions, the compositions of the invention are added to the physiologically acceptable liquid carriers. Especially preferred are phosphate buffers or an isotonic saline solution, but any other carrier or liquid carrier mixture that is physiologically acceptable and compatible with the compound of the invention can be used. Many such carriers or liquid carrier systems are already known to those skilled in the art of preparing pharmaceutical preparations for injection and / or infusion in vivo. The compositions of the present invention offer a further advantage in that the same and / or the pharmaceutical preparations made therefrom can be heat treated, for example, for sterilization purposes. The compositions of the invention will typically be stable for heat treatment up to above 70 ° C, preferably above 80 ° C and more preferably up to at least 100 ° C. This is particularly significant for larger particulate materials that will not be easily sterilized by filtration. To prevent aggregation of HA particulates when in suspension, suitable modifiers or adjuvants as are well known in the art, such as dispersing agents, can be added to the liquid pharmaceutical preparation according to the invention. Examples of such modifiers can be carbohydrates or proteins. The effective dosage to be administered to a patient in need of treatment will depend on several factors such as the half-life and the chain of decomposition of the radionuclide included in the composition according to the invention.; the administration route; the patient's medical condition and his / her weight and age; as well as the disease that is going to be treated. Such effective dosage can be achieved by the administration of a pharmaceutical composition according to the invention as a one-time dosage; or by means of at least one single dosage per day (typically one, two or three times per day) for a treatment period of at least one individual day or at least one day per week for one or more weeks or months. The treatment can be repeated at least once when it is considered necessary or appropriate by the expert medical specialist. If a radionuclide having a short half-life is used, it generally provides a higher activity dosage per single administration when compared to a radionuclide having a longer half-life. Typical dosages will generally lie in the range from 10 kiloBq to 10 gigaBq for each single administration, with a more preferred range being 1 megaBq to 1 gigaBq for each single administration. The compositions according to the present invention are useful in pharmaceutical compositions, especially preparations or devices in a liquid or gelled state and for the treatment of cancer and non-cancerous diseases. As indicated below, the present invention provides, in several aspects, a method for the treatment of cancer or non-cancerous diseases, compositions for use in such methods and the use of a composition for the manufacture of a medicament for its Use in such treatment method. Diseases applicable particularly to these aspects of the invention include metastatic and non-metastatic cancer diseases such as small cell and non-small cell lung cancer, malignant melanoma, ovarian cancer, breast cancer, bone cancer, cancer of the colon, cancer of the bladder, cervical cancer, sarcomas, lymphomas, leukemias and tumors of the prostate. Other diseases particularly applicable to the application of these aspects of the invention include non-cancerous diseases, especially hyperplastic diseases and for the reduction of pain in diseases (especially in bone diseases) including arthritis. Accordingly, one embodiment of these aspects relates to a method for the treatment of a tumor locally. Such treatment can be preferably applied by means of an intratumoral injection or infusion to a subject (generally a human patient) in need of such treatment, of a therapeutically effective amount of a composition according to the invention. Such a method provides local irradiation of the tumor tissue. Alpha-emitting radionuclides are highly effective in this modality because their range is short and damage to surrounding healthy tissue is minimized. Examples of diseases that can particularly benefit from this embodiment of the invention are those that cause solid tumors, such as non-small cell lung cancer, malignant melanoma, cancer of the ovaries, colon cancer, sarcomas and tumors of the prostate.

A further embodiment of the invention relates to methods for the treatment of locally disseminated cancers, such as, for example, liver tumors, or diseases confined peritoneally or intracranially. This treatment can be applied preferably in a special way through in loco-regional injections or infusions, to a subject in need of such treatment, of a therapeutically effective amount of a composition according to the invention. Yet another embodiment of the invention is a method for the treatment of locally disseminated cancers such as liver tumors, by administering a therapeutically effective amount of a liquid preparation comprising a radiolabelled HA according to the invention to a subject. in need of such treatment, especially for the supply to the patient's blood related to the affected area or organ, for example for the delivery of blood to the liver in the case of a liver tumor. This can promote the transport of the composition towards the tumor. A further embodiment of the invention relates to a method for the treatment of cancer disseminated systemically by intravenous injection or infusion, or other systemic administration, to a subject in need of such treatment, of a therapeutically effective amount of a pharmaceutical preparation that - comprises a radiolabelled HA according to the invention. A further embodiment of the invention relates to a method for the treatment of intracavitary tumors, wherein a therapeutically effective amount of a radionuclide in the form of a composition of the present invention is administered to a subject in need of such treatment by injection or infusion into the cavity affected by the tumor and retained there to obtain irradiation of the surfaces of the cavity. Such cavities include the cranial cavity, the peritoneal cavity and the cavities generated by the effusion of the pericardium and mesothelioma and the administration is suitable for cancers such as intracranial cancers, intraperitoneal cancers or cancers located in the cavities created by pericardiac effusion and mesothelioma. . A further embodiment of the invention relates to a method for combination therapy, comprising administering to a subject in need of such treatment a therapeutically effective amount of active radiolabelled HA according to the present invention and one or more treatments chosen from the group consisting of: surgery, chemotherapy and radiotherapy (especially external beam radiotherapy). The combination therapy is a particularly preferred embodiment of the present invention and may be performed in a simultaneous, consecutive or alternative manner, or any combination thereof. Accordingly, a combination treatment may comprise a type of treatment followed by one or more other types of treatments, wherein each type of treatment may be repeated one or more times. An example of simultaneous combination therapy is chemotherapy combined with the administration of a composition according to the present invention at the same point in time (either by the same method or by a different method of administration). Such combination treatment can be combined with sequential therapy by the initiation of a simultaneous treatment, for example, after a tumor has been surgically removed. The combination therapy can be repeated one or more times when necessary, based on the patient's condition. An example of alternative combination therapy could be chemotherapy in one or more treatment periods, alternating in different days or weeks with the administration of the pharmaceutical composition of the invention; or for example the surgery followed by one or more periods of treatment with the radiolabelled HA according to the invention. A highly preferred embodiment of the invention relates to a method for treatment through the application of a composition or device according to the invention in a therapeutically effective amount during surgery, after a procedure has been performed to remove the cancerous material in a subject. The composition of the present invention can be applied to the tumor bed or surrounding tissue. Such an application can be executed to achieve a sterilizing effect on the location of, or in a surrounding part of the tumor bed and if applicable, on the cavity. This may be particularly useful in the event of tumor rupture (for example during the surgical procedure). Such treatment may also additionally or alternatively, achieve an anti-tumor effect on any of the remaining tumor cells in this location and / or in their proximity. This embodiment could be effected using a suspension of the active compound (eg, formulated as a spray solution or a rinse solution). Alternatively, when related to this method of treatment, it may be preferred that the composition of the invention be in the form of a paste, patch, impregnated sheet (especially an absorbable sheet or sheet), a cream or gel and especially a formulation ( for example a gel) that provides a sustained release of the therapeutic radioactive agent. Yet another embodiment of the present invention relates to a method for synovectomy, that is, to treat a subject suffering from pain in the joints and / or bones, such as for example pain arising from arthritis. When used herein, the term "subject" will generally indicate a human patient but may also indicate a mammalian, non-human subject, especially a mammalian canine or feline subject. In the following section, the invention is exemplified to show how the hydroxyapatite particulate materials can be labeled with a radionuclide emitting alpha particles and a radionuclide emitting beta particles, respectively. The examples are not going to be considered limiting on the invention. The invention is also illustrated by the accompanying figure in which: Figure 1 shows the retention of 212Bi in various tissues after 1 and 24 hours after administration of 212Pb. The equilibrium level is also shown and shows that 212Bi levels are close to equilibrium. Materials and general methods The hydroxyapatite particulate materials used were hydroxyapatite, the aqueous suspension buffered, type 1 (Sigma, St. Louis, MO, USA) or type 1 ceramic hydroxyapatite Macro-Prep, 20 μm (Bio Rad Laboratories, Hercules, CA, USA). Counters and detectors: gamma-ray spectroscopy was performed with a germanium detector EG &; G Ortec GEM15-P. The general radioactivity count was performed with a multi-cavity Nal detector (Packard Crystal II, Packard Instrument Co., Downers Grove, IL, USA). Labeling and purification of particulate material: the reaction mixture was "mixed strongly on a whirlpool mixer (MSI Minishaker, IKA, Germany) for 1 minute and then incubated on a shaker for 30 minutes before centrifugation three times (5 minutes) , 9000 rpm, MiniSpin centrifuge, Eppendorf, Germany) and twice washing the pellet with 1 ml of the 0.1 M citrate solution. Example 1 Preparation of etched particulate materials with radium 223. The radius 223 was prepared from a 27Ac / 227Th source immobilized on a DIPEX-2 column by the elution of 223Ra with 1 M HCl. To the eluate of HCl, 0.1M Na citrate is added until the pH was above 5. To a 2 ml Eppendorfer tube is added. add 250 μl of the 40 mg / ml hydroxyapatite dispersion and 50 μl of the citrate / 223Ra solution, and the labeling and purification was carried out as described in the materials and methods section. with the pellet it was in excess of 96% for the totality of the three triplicate experiments carried out in parallel. Example 2 In vitro stability test of the HA particulate materials labeled with 223Ra x The 223Ra-HA particulate materials described in Example 1 were added with 500 μl of either 0.1 M sodium citrate or bovine serum albumin. The dispersion was incubated overnight at 37 ° C and the solutions were centrifuged according to example 1. The activity related to the pellet was in excess of 96% as measured after 20 minutes. A re-measurement two hours later did not show significant differences in the counting rates that indicate that the distribution of the nuclides children was very in agreement with those of 223Ra. In a further experiment, using the ceramic HA particulates, the 223Ra (1 MBq) incorporated in 10 mg of ceramic HA was incubated in fetal bovine serum for two weeks at room temperature, after which 93.2% was bound to the pellet Example 3 Preparation of HA particulate materials labeled with 212 Pb and 212Bi. Lead 212 was prepared substantially free of 228Th and 224Ra. With 228Th evaporated to dryness as the raw material, 0.5 ml of 8 M HN03 was added and the solution was transferred to a column containing the pre-equilibrated anion exchanger (AG1-X8). Radium 224 and the offspring were extracted in 3 ml of HN03 8 M. Subsequently, the 224Ra extract was evaporated to dryness, dissolved in 0.5 ml of 5 M HCl and purified on a DIPEX column (AC-resin, Eichrom Inc. , Darien, IL, USA), by elution of 224Ra in 700 microliters of 1 M HCl to obtain a thorium-free product 228. The following day (after internal growth of 212Pb), the material eluted from 224Ra was evaporated to dryness and after that dissolved in 0.5 ml of 1 M HN03 and transferred to a column containing a specific resin for Pb (PB-B25-S, Eichrom). Radio 224 was eluted with 2 ml of 1 M HN03 and 2 ml of distilled H20. Lead 212 was extracted from the Pb resin using 650 microliters of the 0.1 M ammonium oxalate solution. The final 212Pb solution can be directly combined with the hydroxyapatite and reacted as described for 223Ra in Example 1. Example 4 Stability test of HA particulate materials labeled with 212Pb and 212Bi. HA labeled 212 with lead was incubated in fetal bovine serum overnight and centrifuged afterwards as described above. The radioactivity associated with the pellets and the supernatant was measured. It was found that an excess of 93% of both 212Pb and 212Bi was associated with the pellet. The fraction of activity bound to the pellet appeared to be slightly higher with the ceramic particulate materials. Example 5 Biodistribution of HA labeled 212Pb. HA labeled with 212Pb (20μ, ceramic) was prepared as described above, washed and centrifuged three times and dissolved in 0.01 M citric acid / sodium citrate in an isotonic saline solution at pH 7.4. To 7 female Balb C mice with body weights of 21-25 g were administered intra-peritoneally 0.5 ml of a suspension containing 0.4 MBq of 212Pb bound to 1.0 mg of HA. The animals were sacrificed at 1 h (n = 3) and 24 h (n = 4) and dissected. Results: the biodistribution data (table 1) showed that the activity was found almost quantitatively in the cavity i.p. and in the organs and tissues within this cavity indicating a very small leakage out of the cavity. The distribution configuration associated with the free 212Bi, that is, a high accumulation in the kidney, was not detected to a significant degree.

Table 1. Tissue distribution at 1 hour and 24 hours after intra-peritoneal injection of hydroxyapatite particulate materials labeled with 212Pb to ceramics Numbers in brackets: Tissues measured approximately 1 hour after slaughter of the animals. Bold numbers: tissues measured one day after the slaughter of the animals, that is, allow time for the child nuclides to be in balance with the mother nuclide 212Pb. If the number in the bracket is lower than the corresponding bold number, it indicates a depletion of the child nuclide of 2a2Bi against 212Pb -in the tissue at the time of death (the opposite could mean the enrichment of 212Bi against 212Pb at the time of death). It is noted that in relation to this date the best method known to the applicant to implement the aforementioned invention, is that which is clear from the present description of the invention.

Claims (19)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property. A hydroxyapatite (HA) characterized in that it incorporates an alpha particle emitting radionuclide selected from the group 11At, 212Bi, 223Ra, 224Ra, 225Ac, 227Th or a beta-emitting radionuclide chosen from the group of 212Pb, 211Pb, 213Bi or 225Ra.
2. 2. The hydroxyapatite according to claim 1, characterized in that the HA comprises a cation that is bivalent or trivalent or a mixture of such cations.
3. 3. The hydroxyapatite according to claim 2, characterized in that the cation is selected from the group consisting of calcium, strontium, barium, bismuth, yttrium, lanthanum, lead or mixtures thereof.
4. 4. The hydroxyapatite according to any of claims 1 to 3, characterized in that the HA is particulate and has a size in the range of 1 nm to 100 μm.
5. 5. The hydroxyapatite according to claim 4, characterized in that the HA has a size in the range of 1 μm to 20 μm.
6. 6. The hydroxyapatite according to any of claims 1 to 5, characterized in that the HA is combined or co-sedimented with a substance selected from polylactide, polyethylene kenes, glass-ceramics, titania, alumina, zirconia, silica, polyethylene, epoxy, polyethylene glycol, polyhydroxybutyrate, gelatin, collagen, chitosan, phosphazene, or mixtures thereof.
7. 7. A process for preparing a hydroxyapatite particulate material labeled with a radionuclide, characterized in that it comprises: "(a) contacting a solution of an alpha-emitting radionuclide chosen from the group of 211At, 212Bi, 223Ra, 224Ra, 225Ac , 227Th or a beta particle emitting radionuclide chosen from the group of 212Pb, 211Pb, 213Bi or 225Ra with hydroxyapatite particulate materials that do not contain 15 magnetic iron; and (b) optionally crystallizing a coating of hydroxyapatite on the labeled particulate materials prepared in step (a) whereby the radionuclide or the generator is encapsulated in vivo in the material 20 particulate.
8. 8. A process according to claim 7, characterized in that step (a) is carried out at a pH in the range of 3-12.
9. 9. A process according to claim 25 or claim 8, characterized in that the in vivo generator of an alpha particle emitting radionuclide is 212Pb and, prior to steps a) and b), the method further comprises; i) Prepare 22Ra, ii) Purify 224Ra by contact with a specific binder of block f, iii) Allow internal growth of 212Pb, and iv). Purify the resulting 212Pb by contact with the specific binder for lead. ""
10. 10. A pharmaceutical composition, characterized in that it comprises a hydroxyapatite according to any of claims 1 to 6 and a physiologically acceptable carrier.
11. 11. A pharmaceutical composition according to claim 10, characterized in that it is in an injectable, liquid form.
12. 12. A pharmaceutical composition according to claim 10, characterized in that it is in the form of a gel.
13. 13. The use of hydroxyapatite (HA) not containing magnetic iron and an alpha particle-emitting radionuclide selected from the group of 2alAt, 212Bi, 223Ra, 224Ra, 225Ac, 227Th or a beta-emitting radionuclide chosen from the group of 212Pb, 211Pb, 213Bi or 225Ra in the manufacture of a drug for use in the treatment of a cancerous disease.
14. 14. Use in accordance with the claim 13, wherein the medicament is an injectable, infusible or locally applicable medicament.
15. 15. Use in accordance with the claim 14, wherein the treatment comprises an intratumor therapy.
16. 16. The use according to claim 14, wherein the treatment comprises administering the blood of a cancerous organ.
17. 17. A device, characterized by comprising hydroxyapatite incorporating a radionuclide emitting alpha particles or an in vivo generator for a radionuclide emitting alpha particles.
18. 18. Use according to claim 13 wherein the cancer disease is a primary intracavitary or metastatic tumor.
19. 19. Use according to claim 13 wherein the treatment is for treatment and sterilization of the tumor bed wherein the administration is effected after the surgical removal of at least a part of the tumor.