TW200536558A - 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

200536558 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a composition suitable for in vivo transmission of a radioactive nuclear species. More specifically, the present invention relates to a particulate composition containing ^ ^ 'radioactive nucleus or for production of α-radioactive nucleus, when produced. These compositions of the present invention are suitable for treating cancer and non-cancer diseases. [Prior art] In all fields of medical research and especially in cancer research, novel therapies… important areas of this research—the field relates to the use of radionuclides for therapeutic purposes. For many years, Fluoride I, GK9, and GK9 are used as public particle emitters in cancer treatment, and it has been suggested to use colloids labeled with stone particle emitters to treat intraluminal diseases, including metastatic ovarian cancer. In recent years, efforts have also been made to use α_emitters as antitumor agents. Some characteristics of the emitters are different from those of the emitters, including higher energy in tissues and lighter weights and shorter pregnancy duration. Target range. In the physiological environment, the "round range of the projectile is usually less than 1 million yuan, 1U0U, which is equivalent to direct control with only a few cells. Therefore, this text can be used for treatment. Micrometastasis tumors, because they rarely cross the target cells, can reduce damage to surrounding healthy tissues. On the contrary, P, ^ σ Hanzhiwan particles have a range of 1 mm or greater in water. Compared with ^ particle n-rays and χ-rays, 'the energy emitted by this particle is also high', in general, it is 5 to 8 MeV (one hundred electron volts), or 5 to 10 times the ρ particle, and r-ray energy 20 or more times. Therefore, when compared with r or Xingfu, such a large amount of energy is deposited in a short distance region 99711.doc 200536558, which can obtain very high linear energy transfer (LET) for alpha radiation. It can explain the abnormal cytotoxicity of these α _ radioactive nuclei, and the strict and rigorous requirements for the control and research level of the radionuclide distribution needed to avoid unacceptable side effects. It has been suggested that alpha-emitters can be used in combination with microparticles and colloids for internal radiation nucleation therapy (see Blomer and others, int.j. Radiat 〇nc〇1 Bi〇1

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 Verg. te et al., Prison "47 (3) · 366-372 (1992) and Gynecol Oncol 47 (3): 358_ 65 (1992)) 〇 One question about these previously used particulate and colloidal carriers is, The carrier materials used are not biocoexistent and biodegradable. Therefore, these carriers can accumulate especially when repeatedly administered to the body cavity. The accumulation of non-biological coexisting materials can thus cause diseases such as inflammation. Especially, for example Another problem of using the previous technique of _211 colloid and lead_212 colloid is the leakage of free radionuclides, because Shi'e 11 and bismuth-212 (from lead _212) have been proven to accumulate in normal conditions. Tissues, for example, accumulate in the sacral glands and stomach, and bismuth accumulates in the kidneys. A third problem with many of these radionuclides used is that they are difficult to prepare and are only available in small amounts, or their half-life So short that it is not suitable for therapeutic preparations. «High energy of particles , And its significant mass' will cause the emitted particle to have significant momentum once the nuclear decays. Therefore, equal but reversed momentum 99711.doc 200536558 is provided to the remaining " in the form of "nuclear recoll" (Dw) "nucleus. The momentum of this recoil is enough to cut off most of the chemical bonds and force the newly formed daughter nuclei to decouple and cooperate. If the daughter nucleus itself is radioactive, since the daughter nucleus is no longer restricted by the particle or integrative complex in which the mother nucleus has been injected, the impact of the above nuclear recoil is very significant. Because of the dagger, a major problem of the past method of administering radiochemicals i is how to control the biodistribution of α_ radionuclide species. It can limit the choice of α-emitters to those who do not need radioactive nuclei, or limit the dose to reduce the exposure of healthy tissues. You can maintain control over the distribution of daughter nucleus organisms, which has important advantages in forming radiopharmaceuticals with alpha emitters. By this method, the dose received through the healthy tissue during the administration period can be reduced, and several alpha decays can ideally occur in the range of the disease. However, if the final intensity of the daughter nucleus cannot be controlled, then if it is an alpha emitter, these emitters will become a problem. Therefore, it will then accumulate in healthy tissue and lead to: unwanted side effects. WOO 1/60417 proposes a method for maintaining control of alpha radionuclide. This method uses a liposome-containing chelating agent to control the alpha-emitter, and prevents the nuclei from kicking back the daughter nuclei into the solution. However, for all methods of administration, liposomes are not ideal, and in some cases, they can show undesired clearances and pathways. ι Therefore, there is a great demand for improved radiotherapy and mouthpieces that can display a stable radionuclide of α_ radioactive nucleus, and improve the radiotherapy treatment that hardly leaks the radionuclide to other tissues. In addition, there is a need for a radiotherapeutic composition having biocoexistence 99711.doc 200536558 and a biodegradable component. Moreover, there is a need for a radiotherapeutic composition that is suitable for use in pharmaceutical formulations, in which the nuclear species are easily prepared and available in sufficient quantities. [Summary of the Invention]

The inventors of the present case have now surprisingly determined that hydroxyapatite (HA) particles can be radiolabeled with alpha radioactive species, and that they can be stably maintained for a long time. In addition, the inventors of this case have determined that, on an unexpectedly comparable level of work, the 11 persons radiolabeled with an alpha emitter can still maintain daughter species after the mother species has decayed. This is a highly unexpected discovery because the recoil produced by the alpha decay usually breaks the chemical bond and results in the release of the daughter product. Therefore, the first aspect of the present invention is to provide hydroxyapatite (ΗΑ) which can incorporate α-radioactive species or radionuclides, which are in-vivo generators of α-radioactive species. In the present invention, the repertoire of the present invention is that the nucleus is stably captured in ΗΑ and does not significantly filter out under physiological conditions and enters a solution or other tissue. The HAs are more stable, that is, the daughter nucleus is also captured by the HA carrier, and does not substantially filter out under physiological conditions and enters the solution or other tissues. In addition, it is preferable to use the desired α-emitter that can produce a series of other emission lines, because the hydroxyapatite of the present invention can control these sub-cores of the aragonite of the present invention and the composition made from it. The advantage is that the α-radioactive nuclear species, which is more effective in treatment, can be used to replace the 10,000-radioactive nuclear species of the prior art, and the controllability of the daughter nuclei can be maintained. 99711.doc 200536558 Dare, W Zhenmai. As described by Unni et al. (Nucl Med Bio 129, 199-209 (2002)) and Brodack et al. (WO97 / (^ 304)), the only other use of hydroxyapatite particles is as a radioactive lubricant. Membraneectomy (i.e., used to treat the pain of inflammation), a carrier of radioactive species. All previously used / 5-emitters can decay into a nuclear species that has no association with the dose distribution ( That is, once decayed, there is basically no recoil, and the daughter nuclear product is not radioactive, so its distribution does not make any sense.) The hydroxyapatite and the composition made from it are very suitable for this application. Treatment of cancer and non-cancer diseases. Especially because of the therapeutically active α-emission system, the two hydroxyapatite administration or in vivo production, it can obtain high cytotoxicity compared with cold_emitters. And the damage to the deeper and surrounding areas of normal tissues is very low. Especially when the HAs of the present invention are used for local 1 * biopsy or target sexual medication (for example, intraluminal, target systemic / tumor methods) When the above effect is more applicable, and can be made shorter Cheng Zhixing is caused by Xingchang. Therefore, the second aspect of the present invention is to provide a base for the combined alpha radioactive nucleus or radioactive nucleus (which is a "_ in vivo generator of radioactive nucleus") by administration Wollastonite (ΗΑ), or a method of treating a human or animal patient (especially a mammal, especially a mammal in need of such a therapy) by administering a composition made from such ΗΑ. The present invention additionally— One aspect is to provide a pharmaceutical composition comprising the base wollastonite of the present invention and at least one physiologically acceptable carrier. The present invention also provides a combined alpha-radioactive nucleus or radionuclide (which is alpha-radioactive) The in vivo generator of radionuclide species), the beauty of 99711.doc 10 200536558 apatite (HA), which can be used for treatment. Yet another aspect of the present invention is to provide human and radiation radionuclides or radiation nuclei (which are ^ Hydroxyapatite (HA) of radioactive nuclear species in vivo generator) for the preparation of medicines (especially injectable, Human or a drug that can be applied in high doses). Another aspect of the present invention relates to a hydroxyapatite ( The pharmaceutical composition and device of η⑸, for example, a syringe filled with a medicinal preparation in advance. The present invention further relates to the preparation of hydroxyapatite (ηα) incorporating in vivo generators of α _ radioactive nuclear species or "_ radioactive nuclear species. A method comprising the steps of: (a) contacting a solution of an α-radioactive species or an α-radioactive species in vivo generator with hydroxyapatite particles; and (b) crystallizing in step (a) as required The prepared hydroxyapatite coating on the labeled particles is used to wrap the radionuclide or the in vivo generator in the particles. The method preferably includes: (a) absorption of the α-emitter radionuclide or α-emitter radionuclide in vivo generator solution, preferably at a pH ranging from about 3 to 12, to the base apatite Stone particles; and (b) optionally crystallizing the base plate graystone coating on the labeled particles made in step (a), thereby encapsulating the radionuclide in the particles. [Embodiment] The term used in the art, "hydroxyapatite" refers to various related dishes 9971 l.doc 200536558 ^ Salt compounds' are particularly of the formula [Ca "(p〇4) 6 (〇H) 2] A few base scale gray stone approx. = Jilin Grey Stone _ S is a healthy bone matrix component of all vertebrates. It is used as a pseudo-shaped material #, especially a material of "no mud" bone insert. Trans-Apatite < Other uses are as selective cation exchangers in the column. 1-Based Apatite is a bio-coexisting and biodegradable material, which is particularly useful for in vivo applications. In this connection, another advantage is that it can be heat or autoclaved. Therefore, the present invention additionally provides products and compositions that are stable to autoclave under standard conditions. The term "hydroxyapatite (ΗΑ)" is used in the plain text and the scope of patent applications to refer to any nicotinic apatite and any derivatives or analogues that have bio-existence or biodegradability. These materials should preferably have no adverse effects on the intended use. For example, as used herein, the term " hydroxyapatite * ηα " includes calcium hydroxyapatite and any compounds in which the calcium ion (Ca2 + ) May be substituted by any other (preferably biologically tolerable) cation (eg, such as 2+, 3+ or Ac3 +), or a combination of one or more of these cations. In a specific embodiment, hydroxyapatite containing hydroxyapatite calcium is preferred. The Ha can be further co-deposited or crystallized by other low-solubility minerals, especially low-solubility calcium salts. Suitable for the present invention and referred to herein as hydroxyapatite or HA or the h A, may be further surface modified to carry other substituents or groups, such as gas, phosphonates (which include bisphosphonates and Tetraphosphonates), proteins, amino acids, peptides and magnetic substances. By surface modification, the particulate ΗA can be made different. 99711.doc 12 200536558 High resistance to degradation. Another application of surface modification is to include associative molecules. The receptor-binding molecule can be used as a target sex carcass for combating biological and structural (especially tumor-related receptors). ★ The use of 'hydroxyapatite or HA in this text may also include complexes, for example:' Any hydroxyapatite compound that is compounded or co-deposited with other substances, such as metals, oxides, proteins, Amino acids, carbohydrates, phosphonic acids (which include bisphosphonates), organic compounds

(E.g., polylactide, polyethylene glycol), glass ceramics, titanium oxide, oxidation =, emulsified rhenium, oxidized stone, polyethylene, epoxy compounds, polyethylene glycol, fluorenyl tau acid, Gelatin, tincture, deacetylated chitin, squamous iron, iron oxide and / or magnet. These combinations can be used to make the final HA micro = to serve additional desired properties, for example, magnetic (magnet) or gel effect (mingle collagen, chitosan). In addition, as is familiar to those skilled in the art. Some of the above groups can make the HA more lipophilic, and it is considered an advantageous property of any HA derivative or analogue to be used in the present invention. The hydroxyapatite suitable for the present invention may have any solid type, and in the scope of this description and the patent application, they are commonly referred to as "fine particles", so as to communicate with the radiation particles (for example, alpha particles (helium nuclei), Or ys particles (electrons)). 4 HA particles can be, for example, crystals, microspheres, or colloids. The shape, pore size and density of the particles can be selected to suit the intended use. The size of the HA particles can usually be in the range from about 10 nanometers to about 100 micrometers'. However, including microparticles, colloids as small as 1 nanometer and other small particles can be used. 99711.doc 200536558. In a specific embodiment, the size of the particles is preferably such that they are maintained in the suspension without sedimentation. In this context, sedimentation systems include flotation, where the "sediment" is formed on the top of the suspension, rather than on the bottom: in more detail, when the particles are suspended in a fluid (eg, In a tolerant (especially aqueous) solution) and stored for at least one hour (preferably at least 6 hours, and most preferably at least one month), the size of the particles is preferably such that they do not deposit. It is therefore easy to determine the appropriate particle size of any particulate HA by routine deposition experiments. • According to the present invention, one of the M particles has a more preferred universal size range from ㈣ to 20 microns, and most preferably from 1 to 5 microns. It is preferred to use particles having a substantially uniform size distribution. Different size ranges are better 'and can be selected according to the purpose. In areas with three-dimensional obstruction, the distribution of small-sized particles is better. Similarly, when administered intravenously (e.g., for systemic cancer treatment) or local delivery (e.g., 'delivered to cancer-infected organs, such as liver), this # 毛 月 忒, and 合 日 日 守, Small size particles can have advantages. Therefore, particularly for tiger vein medication, a preferred small size range is from about 1 nm to about 2 microns, and a more preferred range is from about 8 nm to 40 nm. In the specific embodiment, small particles are administered to preferentially target tumor cells :. In more detail, tumor capillaries are more likely to leak than capillaries in healthy tissue (for example, due to their window surgery). Thus, the small, nano-particulate particles of the present invention (for example, 1 to 50 nm, preferably ^ to 10 nm, more preferably 3 to 5 nm) can be selectively removed from tumors. The inner capillary leaks, so the combined radionuclide species can be effectively set at the tumor site at 99711.doc -14 · 200536558. These microparticles can also be linked to target molecular groups (eg, antibodies or receptor-binding molecules (see above)) to increase their target utility. On the other hand, the 'larger-sized particles' can be better retained in the body cavity of the administered site. The second advantage of these larger particles is that they are not easily phagocytosed or destroyed by macrophages, so they are expected to retain the radionucleus in the living body. a Therefore, particularly in terms of the method of administration to the body cavity, another preferred size range is from about 100 nm to 100 microns, and a more preferred range is from about 500 nm to 20 microns. '. As used herein, the "size" of the particles means the average (mode) size of the largest size of the particles. The particles may have any shape or mixture of shapes' which includes spheres, flakes, needles, rods, etc., but usually the maximum size does not exceed 2G times the shortest size, preferably it does not exceed 5 Times. If the particles are prepared for injection (intravenous or intra-arterial) injection or infusion ', it is often the fact that there are no descriptive examples of particles having any size greater than 8 particles (preferably 5 microns). For example, for local or partial sensation in the cavity, intratumoral, subcutaneous, or intramuscular administration may not require such restrictions. The porosity is the second property of these HA particles, which can be selected to suit the intended use or the radionuclide species to be marked on the particles. In more detail, 'the porosity is closely related to the density of the microparticles, and for some of these applications, t' the better choice of porosity can result in water-like microparticles with a density that is very slow, if any effect. Any radionuclide suitable for labeling HA to obtain the composition of the present invention can be used in the present invention. At least one radionuclide can have or produce 99711.doc 15 200536558

(Eg, by at least one tritium decay text). This term, f α-in vivo generator of radioactive radionuclides "means" mother "radionuclides that will themselves decay, and will receive radioactive daughter nucleus during decay. Therefore, a radioactive decay chain can be obtained. At least one nuclear species in the chain decays through radiation. Usually, the parent nuclear species decays through radiation. Moreover, the half-life of the nuclear species in the decay chain, " During the in vivo period, a therapeutically important amount of radiation is generated. "" The isotope adjusted in the composition of the present invention is an alpha emitter, and its + agricultural period is preferably between -hour and -year, and more preferably between 5 and Between hours and days. Preferred nuclear species groups include the following groups: 0 Radioactive species: ,, 212

Bi 223

Ra 224

Ra 2 2 5 a 2? 7 Ac, Th, and any combination thereof

Another group of radionuclide species is a stone_emitter with at least one α_ radionuclide in the i decay chain. These include, for example, 2llpb, which can be: I-radio 2 " Bi's origin H, which can decay to ^ radio ma, which can decay to get ~, and then by four alpha radiations and two /? Radiations It decays, and finally produces a very good example 1. It can be used for its: sex :: species :: two-line decay. In a preferred embodiment of the present invention, 212Pb / 212Bi suitable for use in the present invention can be prepared by the following method, which method includes: 0 Preparation of 224Ra (for example, by anion exchange chromatography, obtained freely Xie Yuan), ϋ) purification of the 224Ra by contacting an f-blocking specific binding agent (for example, actinide / gangline-specific resin, especially in a columnar form), 99711.doc 16 • 200536558 ill) to make 2I2Pb Growing inwardly (eg, by leaving 224Ra to stand for 6 to 24 hours), and IV) purifying the formed 212 pb by contacting a lead-specific binding agent (eg, a specific resin, especially in a columnar form). In the above method, the same or different specific binding agent samples can be used to repeat any one of the purification steps i), ii) and / or iv) at least once. Suitable f-blocking element-specific binding agents include methanebisphosphonic acid derivatives, for example, P, P, di-octylmethanebisphosphonic acid (such as DIPEX (RTM)). Pb-specific binding conjugates of 4 include crown ethers, especially 18-crown-6 derivatives, for example, di-third-butyl-cyclohexyl 18-crown-6 (such as mchr containing Pb-B25_S0 〇m flutter specific resin). If a radionuclide is used, a non-labile carrier (for example, silica) containing a specific binding agent is preferred, but for purification, if the contact time with the resin is short, an organic resin carrier may be used. This method can be combined to form the HA of the combined radionuclide referred to herein. Forming " 2pb < " > by combining these methods, and merging HA, may constitute other aspects of the present invention. The advantages of the above-mentioned 212Pb manufacturing method are that it can provide a simple and easy-to-perform procedure 'and that the purity of the radionuclide species that can be obtained is higher than 2pb of the previous method. 2. The compositions of the present invention are stable against the loss of the load radionuclides due to the HA particles. A composition can be considered as stable if the HA particles (but not in the solution) can be radiated from the load once they are incubated in the solution for at least 20 minutes at 37 ° C. At least 80% activity was detected. The ratio should preferably be at least 85%, more preferably to 99711.doc -17- 200536558 and 90% less, and most preferably 95% or more. The compositions of the present invention are also stable against the loss of one of the seed nucleus, or one of its decay products, due to the decay of the loaded radionuclides (e.g., alpha-coated wheat). In this regard, a composition can be regarded as having a stability condition of 'once it is cultivated for a suitable time, if the distribution of the activity obtained from the daughter radionucleus produced during that cultivation period can make at least 70% active Associated with these ΗΑ particles. This ratio is preferably at least, more preferably at least 80%, and most preferably at least 900 /. . The labeling of the hydroxyapatite by radionucleation can be performed by, for example, the following method steps, the steps include: (a) preferably in the pH range of about 3 to 12 (more preferably in the pH range of 5 to 10) To absorb the solution of α_radioactive nucleus or the in vivo generator of the ^ _radioactive nucleus with the hydroxyapatite particles; and (b) crystallize the epoch-marked particles produced in step (a) if necessary A coating of hydroxyl wollastonite to encapsulate the radionuclide within the HA particles. The method also preferably includes the following steps: (c) The 2HA particles obtained from step (a) or step (b) are heated to 70 to 150 ° C. Its temperature is preferably 80 to 130 ° C, more preferably 100 to 120. ° C. The HA particles labeled according to (a) or (b), and any necessary or desired excipients and / or additives may be added to a biologically coexistent or physiologically acceptable liquid carrier (preferably an aqueous carrier) To prepare injectable or infused suspensions or dispersions. Additives include inerts suitable for preparing and stabilizing physiologically acceptable preparations for the treatment of cancer, and for radioactive synovectomy. If present 'typically', add these two additional components 99711.doc -18-200536558 before step (c) is selected as needed. Pharmaceutically tolerable carriers and excipients are well known to those skilled in the art and may include, for example, salt-sugar and other tonicity adjusting agents, buffers, acids, bases, and other pH adjusting agents, Selling earthenware from pm viscosity modifiers, colorants, etc. Alternatively, the steps (b) and / or (c) to be selected according to () at first glance can be used to define the j * ja particles, and any biyun # as defined or desired excipients and / or additives Contained in a pharmaceutical gel composition. Additives to the mouth are familiar with the art

It is well known ' and may include the foregoing and well-known gelling agents, such as natural and / or synthetic polymer gels. Compositions in a gel form preferably have sustained release properties. All other suitable pharmaceutical formulations, including liquids for injection or perfusion, knees, creams, pastes, Drop d patches, wipes, sprays, soaking films and tablets. These pharmaceutical formulations may constitute other specific embodiments of the present invention. . The preferred pharmaceutical formulations of the compositions of the present invention are usually liquid, physiologically accessible X T / primary or infusible suspensions or dispersions. In order to prepare these pharmaceutical compositions, the compositions of the present invention are added to a physiologically acceptable liquid core load J. More particularly preferred are isotonic saline or phosphate buffering agents, but can be used with any other liquid carrier or vehicle mixture that is physiologically acceptable and can be present with the compounds of the invention. Many of these liquid carriers or carriers are known to those skilled in the art of preparing heat-resistant pharmaceutical preparations for injection and / or infusion in vivo. Another advantage of the compositions of the present invention is that they and / or the 99711.doc -19- • 200536558 pharmaceutical preparations made therefrom can be heat-treated, for example, sterilized. Typically, the boots; the composition for more than 70t (preferably higher than and more preferably at least i heat treatment and the same from the particles and t ^ ~ '. It is not easy to sterilize by filtration, the larger the heat Stability is particularly important. In order to prevent the ΗΑ particulates from falling into the float, the skilled pharmaceutical preparation 2b :: 2, dispersant) can be added to the liquid substance of the present invention. The conventional examples of ^ ~ ^ can be the effective dose of carbohydrate or proteoglycan human tr to patients in need of treatment, which can depend on several dependent variable chains ::: ΓΓΓ The half-life of the radionuclide contained in the compound and the range of decay, Λ Type, the condition of the heart person, their age and weight, and the heart to be treated in a single-dose form, once administered to the pharmaceutical group of the present invention (typically, daily, _ Ge_2 hunting at least from the mother's day) -One single dose one or two. Human), the treatment period is at least one other day for 1: at least one day 'and takes one or more weeks or months. This step can be repeated at least once if the skilled physician considers it necessary or appropriate. If a radionuclide with a short half-life is used, it can produce a higher active dose per single administration than a radionuclide with a longer half-life. The general amount of sword is usually within the range of self-sustaining money gaBq per individual single administration, and the more preferred range is 1 megaBq to 1 gigaBq per individual individual administration. In addition, the compositions of the present invention can be used in pharmaceutical compositions (especially preparations or devices in a liquid energy or gelled state) to treat cancer and non-cancer diseases. . As described above, the present invention, in various aspects, provides a method for the treatment of a disease or a non-cancer disease 9971 l.doc -20- .200536558 disease, a composition for such a method, and a composition for use in the preparation thereof. Use of a therapeutic method of medicine. Diseases particularly suitable for this method of the present invention include metastatic and non-metastatic cancer-jx small cell and non-small cell lung cancer, malignant melanoma, ovarian cancer, breast cancer, bone itching, large «... bladder cancer, cervical cancer , Sarcoma, lymphoma, blood white: Photo: Adenocarcinoma. Particularly applicable to these aspects of the present invention are g, Dan disease, including non-cancerous (especially proliferative) diseases and reduction of pain related to diseases (particularly atypical diseases, including arthritis). Therefore, a specific embodiment of these aspects is related to a method for the local treatment of tumors. The method of administration of such a treatment method is preferably through on-demand; = therapy patients (usually human patients), intratumoral effective amount of the composition of the present invention "ca irradiation. In this specific embodiment, alpha radioactivity Radionuclide reports have a bureau = its short perimeter 'so it can reduce damage to surrounding healthy tissue: Examples of diseases that are particularly beneficial for this specific embodiment of the invention: Second, it can cause solid tumors (for example, non-compartment lung cancer, malignant Melanoma, colorectal cancer, sarcoma), and prostate cancer. ΊP Another specific embodiment of the present invention is related to the treatment of spleen, which does not go away— \ η >.% monthly cancer ( Such as liver tumors), or lacrimal or guilty confinement disorders (a more preferred method of administration of this therapy. This & practice is a guide to the need for local radiotherapy or perfusion therapy for this type of treatment) The composition of the present invention is described in Article 4. The present invention is another specific method for treating local disseminated liver tumors. The steps are to pull the mouth and supply To infected areas or organs', especially those with W For example, in the case of hepatoma 99711.doc.200536558 tumors, for the a ,, ^ / night, which is supplied to the liver, it can promote the composition of the present invention into the tumor), administration ,, Λ, A therapeutically effective amount of a liquid preparation containing the radiolabeled ha of the present invention. Another aspect of the present invention is a method for treating systemic disseminated cancer. The steps are: for patients in need of treatment, intravenous injection or perfusion (or other systemic single prescription, Λ ^^) / σ therapeutically effective amount containing the present invention has been shown by radiation. Α Another specific embodiment of the present invention relates to a method for treating intratumoral tumors. For patients receiving gastric therapy, a therapeutically effective amount of a radiation nucleus presenting the combination of japonica japonica according to the present invention is injected or injected into the affected tumor. In the infected cavity, there are 1 μ 囟 石 石 在 那里 where to get the surface of the cavity. These cavities include the cranial cavity, the diaphragm, the abdominal cavity, the anus, and the anus, and the cavities produced by the pericardial exudate and mesothelioma ' And this method is applicable to the following cancers, for example, intracranial cancer Intraperitoneal cancer or cancer located in the cavity produced by pericardial exudate and mesothelioma. 1 < Another-specific embodiment of the present invention is a method for combined treatment, including those who need such treatment,于 早 ^ 摩 定 之 心 # For a therapeutically effective amount of the active HA of the radioactive year, and HA of Bo Tianyuekou Xuanqiao Ding Zhiyu, and use one or more selected from the group consisting of surgery, therapy and radiotherapy ( The method of grouping composed of external beam radiation therapy is particularly useful. The combined therapy of external therapy is a more specific embodiment of the present invention, and can be performed in a continuous, alternating or alternate manner, or any combination thereof. Perform. So "combination therapy can include 'therapies' and then-or a variety of other treatments, where-each therapy can be repeated one or more times. Simultaneous combination therapy-item example ^ 中 9971] .doc -22- .200536558 At the same time point, ^, .. and again (can use the same or different methods of Chinese) chemotherapy of the composition of the present invention ^ Using the table method) Concomitant therapy can be combined with continuous therapy to deal with Shun, Luo, and Ping n. According to the patient's condition, the repeated therapy can be repeated one or more times. An example of alternating combination therapy here can be θ 之 chemotherapy performed in one or evening treatment periods, which is on different days or ... the next week, the parent administers the pharmaceutical composition of the present invention, or 'for example, after surgery,- 4. 42 & ^ ,, and k for one or more periods of treatment with the radiotherapy indicated in the present invention. The best embodiment of the present invention # 广 吉 去,;> Oral therapy method, which is a procedure for removing cancerous substances from the heart. Application -... Effects * = Application to the tumor bed or its surrounding tissues. This application can be performed on two tumor beds (and if appropriate, the effect is poor or sterilized around eight. In case the tumor ruptures (for example, during the external, Tu Zhuang + hiccup sequence), the application bucket, 1. Useful. This therapy can further (or) produce a suspension of anti-dust tumor compounds on the location and / or any residual tumor cells around it (for example, if it is prepared for the seventh test, it should be used) ^ ^, He W or wipes) to achieve this specific example. Or 'when related to this treatment, the composition of the present invention can preferably be a paste, patch, immersion tablet (especially can be Absorption patch or tablet), cream or gel type, and particularly a form that can be held in place, releases the formulation (eg, gel) of the therapeutic radioactive agent. Another embodiment of the present invention Examples are methods of synovectomy, that is, treating patients suffering from joint and / or bone pain (for example, pain from arthritis). 99711.doc -23- .200536558 • As used in this text, the term π `` Patient '' generally refers to a human patient, It can also indicate non-human mammal patients, especially canine or feline mammal patients. In the following section, the present invention is illustrated by examples to show that the hydroxyapatite particles are subjected to 0: -radioactive nuclear species and yS-the steps of radioactive radionuclide labeling. These examples are not to be considered as limiting the present invention. The present invention can also be illustrated by the accompanying drawings. General materials and methods • The hydroxyfiller used is Hydroxyapatite buffered aqueous solution, Type 1 (Sigma, St. Louis, MO, USA) or Macro-Prep Ceramic Hydroxyapatite Type 1, 20 microns (Bio Rad Laboratories, Hercules, CA, USA). Counters and detectors: use EG & G Ortec GEM15-P Germanium Detector performed 7-spectrum measurement. General radioactivity counting was performed using a multiwell Nal detector (Packard Crystal II? Packard Instrument Co.? Downers, Grove, IL, USA). Particle labeling and purification: in a vortex mixer (MSI Minishaker, IKΑ) , Germany), the reaction mixture was vigorously mixed for one minute, then incubated on a shaker for 30 minutes, and then centrifuged three times (5 Clock, 9000 rpm 'MiniSpin centrifuge, Eppendorf, Germany), and the pellets were washed twice with 1 ml of a 0.1 M citrate solution. Example 1 Self-immobilized on DIPEX by the method of microparticles labeled with -2 2 3 227Ac / 227Th source on -2 column to prepare radium-223, 99711.doc -24-.200536558 and elute this 223Ra using 1 M HC1. 0.1 M Na citrate was added to the HC1 eluate until the pH was above 5. Add 250 microliters of apatite-based dispersion (which has 40 mg of hydroxyapatite per milliliter) and 50 microliters of the 223Ra / citrate solution into a 2 milliliter Eppendorfer tube. This labeling and purification step is performed as described in the Materials and Methods section. The binding activity of the pellets exceeded 96% of the activity of all three triplicate experiments performed simultaneously. Example 2 In vitro stability test of 223Ra-labeled HA microparticles 500 microliters of 0.1 M sodium citrate or bovine serum albumin were added to the 223Ra-HA microparticles described in Example i. The dispersion was incubated at 37 ° C overnight, and the solutions were centrifuged according to Example 1. After 20 minutes, the particle-binding activity was more than 96%. Counting rate showed no significant difference (which indicates that the distribution of these seed species is consistent with the distribution of the seed species of 223Ra), and then re-measured. In a further experiment using ceramic HA microparticles, 223Ra (i MBq) incorporated into 10 mg of ceramic HA was incubated in fetal bovine serum at room temperature, after which the binding activity of the pellets was 93.2%. Example 3 A lead-212 containing substantially 228Th and 224Ra was prepared by a method of preparing 212Pb and 2] 2Bi-labeled rhenium A fine particles. 228Th was evaporated to dryness as a starting material, 0.5 ml of 8 M HNO3 'was added, and the solution was transferred to a column containing a pre-equilibrated anion exchanger (AGb X8). Radium-224 and daughter seeds were extracted in 3 ml of 8 M HNO3. Next, the 224Ra extract was evaporated to dryness, dissolved in 0.5 ml of 997997.doc -25-.200536558 M HC1 'and purified on a DIPEX column (AO resin, Eichrom Inc, Darienized, 1 ^ 8). By analysing 2241 ^ in 700 μl of 1] ^ 110: 1 to obtain the product without stove-2 28. The next day (after 212Pb in-growth), the 224Ra eluate was evaporated to dryness, and then it was dissolved in 0.5 ml of 1 M HNO3 and transferred to a Pb_specific resin (PB_B25-S, Eichrom). Inside the pillar. Radium-224 was eluted with 2 ml of 1 μΗNO3 and 2 ml of distilled Η20. Lead-212 was extracted from the Pb-resin using 650 µl of a 0.5 M ammonium oxalate solution. This final 212Pb solution can be directly combined with hydroxyapatite and reacted as described in Example 1 for 223Ra. Example 4 Stability test of ΗA microparticles labeled with 212Pb and 212Bi. Lead-212 labeled HA was cultured in fetal bovine serum, which took overnight, and then centrifuged as described above. The radioactivity related to the pellet and the supernatant was measured. It was found that more than 93% of the mPb and Chuan Bi were related to the pellet. The small particle binding activity fraction appears to be slightly higher than the ceramic particles. Example 5 Biodistribution of 212Pb-labeled HA The 212Pb-labeled HA (20 microliters, ceramic) made as described above was washed and centrifuged three times, and then dissolved in 0.01% sodium citrate / lemon Acid isotonic saline solution (pH 7.4). By intraperitoneal injection, 7 female Balb C females weighing 21 to 25 grams were administered with 0.5 ml of a suspension containing 11 mg of 4 MBq inhibitory capacity. At 1 hour (n = 3) and 24 hours (n = 4), the animals were slaughtered and dissected. Results: The student's 99711.doc -26- .200536558 * Material distribution data (Table 1) shows that the activity can be found almost quantitatively in the ip cavity, and the organs and tissues in the cavity show infiltration from the cavity Leakage is minimal. This distribution pattern is consistent with the free 212Bi, that is, a large amount of high kidney accumulation is not detected. Table 1. Tissue distribution at 1 hour and 24 hours after intraperitoneal injection of 212Pb-labeled ceramic hydroxyapatite particles. Tissue 1 hour 24 hours blood (0.46 ± 0.40) /0.39 ± 0.34 (0.32 ± 0.19) /0.30 ± 0.24 liver (3.04 ± 2.83) /3.09 ± 2.93 (2.10 ± 1.56) /2.06 ± 1.45 spleen (3.03 Judges 1.11) /3.25 Judges 1.21 (5.47 to 5.21) /5.58 Judges to 5.27 Kidneys (4.05 to 3.08) /3.32 Judges 2.84 (4.21 to 3.29) /4.12 Judges 3.39 Small Intestine (0.78 to 0.86 ) /0.72±0.80 (0.62 ± 0.25) /0.60±0.26 Large intestine (0.45 ± 0.41) /0.43±0·38 (0.52 ± 0.39) /0.52±0.40 Stomach (3.20 ± 2 · 09) / 3 · 29 ± 2 · 18 (5.11 soil 2.79) /5.10 soil 2.79 Diaphragm (6.23 ± 2.39) / 6 · 25 ± 2.33 (4.84 ± 1.95) / 4.49 ± 2.47 Heart (0.10 ± 0.11) /0.12 ± 0.13 (0.06 ± 0.06 ) /0.04±0.03 Lung (0.36 ± 0.29) /0.33±0.27 (0.18 ± 0.12) / 0 · 13 ± 0.09 Muscle (1.18 ± 1.89) /1.32±2.1 (0.35 ± 0.58) /0.37± 0 · 67 bone (0.44 ± 0.46) /0.44 ± 0.47 (0.44 ± 0.20) / 4.49 ± 2.47 Figures in parentheses: Tissues measured approximately 1 hour after killing these animals. Figures in bold print: Tissues measured one day after the animals were slaughtered (even if the daughter seed can be balanced with the 212Pb parent seed). If the number in parentheses is lower than the corresponding bold number, it means the consumption of 212Bi sub-nucleus vs 212Pb in the organization at the time of death (or vice versa, it means that at the time of death, it is rich in 212Bi vs 212Pb). [Schematic description] Figure 1 shows the retention of 212Bi in each tissue at 1 and 24 hours after 212Pb administration. It also indicates the degree of equilibrium, and proves that the 212Bi content is close to equilibrium. 99711.doc -27-

Claims (1)

.200536558 The scope of patent application: 1. A kind of hydroxyapatite (ha), which is an in-vivo generator incorporating alpha radiation species or alpha radiation species. 2. The hydroxyapatite as claimed in claim 1, comprising an a-radioactive nuclear species selected from the group consisting of Chuan ^, Huang Ze, 223 -q 224 j a Ra, 25ac, 227Th. 3. The hydroxyapatite as described above, which contains 10,000-radioactive nuclear species, which will decay by the alpha-radion nuclear species. 4. The hydroxyapatite according to claim 3, wherein the radioactive nuclear species is 212Pb, 2 " Pb, 2nB ^ 225Ra. The tritium gray stone according to any one of items 1 to 4, wherein ha comprises a divalent or trivalent cation or a mixture of these cations. 6 ·: The hydroxyapatite of claim 5, wherein the cation is selected from the group consisting of calcium, barium bismuth, yttrium, lanthanum, lead, or a mixture thereof. 7. The base plate gray stone according to any one of the items 1 to 4, wherein the HA is microparticles, and the size is in the range of 1 nm to 100 microns. & M seeking item 7 of the base-lin graystone ', wherein the negotiated size ranges from micron to 20 microns. Any of the moon-shell shells 1 to 4-the base of the base lin limestone 'wherein the dark is via amine ... peptides, proteins, antibodies, carbohydrates, phosphonic acid, fluorine, biodiversity, folic acid group or a combination thereof Surface Modification. 10.2 The base-stone flint limestone of any one of items 1 to 4, wherein the ΗΑ is combined or co-deposited by a substance from the group: -2, metal, oxide, melamine, amino acid, Carbohydrates, phosphonic acid vinegars, which include bilinate or organic compounds. 99711.doc 200536558 11. The hydroxyapatite according to any one of claims 1 to 4, wherein the HA is combined or co-deposited by a substance described in the following: polylactone, polyethylene glycol, glass- Ceramics, titanium oxide, aluminum oxide, silicon oxide, silicon oxide, polyethylene, epoxy, polyethylene glycol, polyhydroxybutyrate, gelatin, collagen, deacetylated shell poly-St, phosphorus nitrogen compounds, iron , Iron oxide, magnets or mixtures thereof. 12. · A method for preparing radionuclear-labeled hydroxyapatite microparticles, the method comprising: (a) contacting a q_radioactive nucleus or j_radioactive nucleus in vivo generator via a base apatite microparticle; Solution; and (b) optionally crystallizing the labeled microparticles prepared in step (i): a hydroxyapatite coating to encapsulate the radionuclide or the in vivo generator in the microparticles. 13. A method as in π seeking item 12, wherein step ⑷ is performed in the range of 3 to η. • 14. If the method of claim 12 or 13 is used, the bean # t α, the medium α-radioactive nuclear species in vivo will cry, 2 丨 2 pl, ”, and before performing steps a) and b), The method additionally includes: i) preparing 224Ra, purifying it by contacting an f-blocking specific binding agent, Hi) causing 212Pb to grow inward, and 15. 接触 purifying the heterosexual binding agent by contacting it) 212pb. A pharmaceutical composition 1 comprises the apatite according to any one of the claims ... and a physiologically acceptable carrier. 99711.doc 200536558 16. The pharmaceutical composition according to the claim 15, which is presented Liquid, injectable. 17. The pharmaceutical composition according to claim 15, which is in the form of a gel. 1δ. A hydroxyapatite (ΗΑ) and α_ radioactive nucleus or radioactive nucleus (which is α_radioactive Radionuclide in vivo generator) for use in the preparation of a medicament for the treatment of cancer or non-cancer diseases. 19. Use according to claim 18, wherein the medicament is an injectable, infusible or topically administrable drug. 2 〇. If the purpose of claim 18 or 19 'where Therapy includes radioactive synovectomy. 21. The use as claimed in item 18 or 19, wherein the treatment includes intratumoral treatment. 22. The use as requested in item 18 or 19, wherein the treatment is reintroduced into the patient In the blood supply of cancer organs. 23 · —A device comprising hydroxyapatite incorporating in vivo generators of α · radioactive nuclei < α · radioactive nuclear species. 99711.doc