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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
  • A61K51/1282—Devices used in vivo and carrying the radioactive therapeutic or diagnostic agent, therapeutic or in vivo diagnostic kits, stents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators

Definitions

• the present invention relates to the preparation and use of the "calcium analogue" alkaline-earth radionuchde radium-223 for the targeting of calcified tissues, e.g., bone and a physiological acceptable solution comprising 223 Ra.
• Biomedical use of radionuclides for pain palliation and/or cancer treatment, including prophylactic treatment of bone surfaces to slow down/inactivate undetectable metastases has previously been based upon ⁇ -emitters and conversion electron emitters.
• a substantial percentage of cancer patients is affected by skeletal metastases.
• Established treatments such as hormone therapy, chemotherapy and external radiotherapy often causes temporary responses, but ultimately most bone cancer patients experience relapses (Kanis, 1995). There is thus a strong need for new therapies to relieve pain and slow down tumor progression.
• Bone targeting radioisotopes has been included in clinical trials for the treatment of cancer to the skeleton (De Klerk et al, 1992, Fossa et al, 1992, Lee et al., 1996, Silberstein, 1996). These radiopharmaceuticals have been based on ⁇ -particle emitters (Atkins, 1998) and lately also a conversion electron ermitter (Atkins et al., 1995).
• these compounds which have so far been approved by US Food and Drug Administration Le., are strontium-89 (MetastronTM) and 153 Sm EDTMP (LexidronamTM).
• the strontium-89 compound can only be administered in amounts sufficient for pain palliation, not for tumor therapy, because a significant myelotoxicity occurs before significant antitumour therapeutic dose levels can be reached (Silberman, 1996).
• Bismuth-212 complexed with ethylene-diamine-tetra(methylene- phosphonic acid) (EDTMP), or 1,4,1, 10-tetraazacyclododecane 1,4,7, 10- tetra(methylene-phosphonic acid) (DOTMP), showed a significant bone affinity. But because of the short half life of bismuth-212 60.6 min), normal tissue exposure during the uptake phase of the radiopharmaceutical would be considerable (Hassfjell et al., 1994, 1997). This would be ever more pronounced with the other ⁇ -emitting bismuth isotope considered for biomedical use, the bismuth-213 (t 1/2 46 min).
• a significant translocation affecting a high kidney accumulation of the ⁇ -emitter was observed (Hassfjell et al., 1997).
• Other ⁇ -emitting radioisotopes potentially useful for biomedical applications are the radium isotopes 224 and 226. As with other group 1 1 alkaline-earth metals, radium in its cationic state is a natural boneseeker.
• Inhaled radon mainly dissolves in body fluid and fat and is mainly eliminated from the body by exhalation (Rundo, 1978).
• Lloyd and Bruenger (1991) reported that 89.5-94J5 % of the radon-222 escaped from the bone after radium-226 had been administered to dogs.
• 224 Ra was used medically for many years to treat ankylosing spondylitis (Delikan, 1978).
• the present inventors made the significant and somewhat unexpected discovery that from Ra localized in bone, very little translocation of the radon daughter (as well as other radionuclides from the decay chain) occurred.
• the 223 Ra series may be used to irradiate the bone surface without any significant translocation of radionuclides (including diffusion into bone marrow).
• radium-223 should be more suitable as a boneseeking radiopharmaceutical since the half life (1 1.4 days) is about three times that of 224 Ra, allowing a deeper incorporation into the matrix of the bone surfaces before decay occurs.
• the radon daughter radon-219 has a short half-life (3.9 seconds), which should diminish translocation in, or as a result from the radon step.
• ⁇ -particles are high linear energy transfer (high-LET) radiation that is extremely cytotoxic to mammalian cells (Hall, 1994; Ritter et al., 1977).
• An ⁇ -particle emitting radiation source localized in target tissue can deliver radiation to a smaller target area, thus reducing normal tissue exposure compared to ⁇ -emitters.
• the present invention relates to the preparation and the use of the "calcium analogue" alkaline-earth radionuchde radium-223 for the targeting of calcified tissues, e.g., bone and a physiological acceptable solution comprising 223 Ra.
• radium-223 can be suitable as a bone seeking radiopharmaceutical.
• the invention may be used for prophylactic cancer treatment by delivering a focused dose to bone surfaces in patients with a high probability of having undetected micrometastases at bone surfaces.
• Another example of its potential use would be in the treatment of painful osseous sites in a similar fashion as the previously described ⁇ - and electron emitting radiopharmaceuticals for bone pain palliation.
• Radium-223 localized onto the bone surfaces and/or in calcified tumors can, together with its daughter nuclides, deliver an intense and highly local dose of ⁇ -particles with less bone marrow dose compared to currently used ⁇ -emitting and/or electron emitting radiopharmaceuticals.
• Skeletal diseases, e.g., primary or metastatic cancer to the bone may be treated with the 223 Ra radiopharmaceutical.
• the present invention includes the use of the nuclide as a cationic species and/or associated to a chelator or another form of a carrier molecule with affinity for calcified tissues.
• This also includes, but are not limited to the combination of radium-223 with a chelator that can be subsequently conjugated to a molecule with affinity for calcified tissues.
• the intent is to use the radioisotope to generate a cascade of ⁇ -particles on bone surfaces and/or in calcified tumors for the palliation of pain caused by various diseases and/or for the prophylactic use against possible minimal disease to the skeleton, and/or also for the therapeutic treatment of established cancer to the bone.
• the diseases where the radioisotopes could be used includes, but are not limited to skeletal metastases of prostate-, breast-, kidney- and lung cancer as well as primary bone cancer and also multiple myeloma.
• Radium-223 solutions are prepared for use in the targeting of calcified tissues or for bone surface irradiation.
• the following examples are showing a high and selective uptake of the 223 Ra in bone with very little relocalization of daughter nuclides. This shows that bone surfaces can be sterilized to inactivate microscopical deposits of cancer cells and also that calcified cancerous lesions can be irradiated either for palliation or therapy with this isotope.
• the compound differs from other commonly used radiopharmaceuticals with bone affinity because the main dose component comes from ⁇ - particles which has a much shorter range compared to the frequently used beta and electron emitters. Therefore the dose delivered to red bone marrow can be significantly reduced with this new compound, i.e., myelotoxicity is likely to be reduced.
• Radium-223 differs from the previously used medical radionuchde radium-224 in the following: (1) 223 Ra has a significantly longer half-life affecting better bone to soft tissue ratios because a significantly larger fraction of this isotope would be eliminated from the soft tissues before decay occurs.
• the 223 Ra salt or derivative thereof will be administered to a mammal, such as a human, in need thereof by all available administration routes, such as oral, subcutaneous, intravenous, intraarterial or transcutane.
• administration routes such as oral, subcutaneous, intravenous, intraarterial or transcutane.
• the active compound is administered by injection or infusion.
• Oral administration is performed by use of tablets, capsules, powders or in liquid form, such as suspension, solution, syrup or emulsion.
• tablets When formed into tablets conventional expicients, lubricating agents and binding agents are used.
• liquids When administered as liquids conventional liquid carriers are used.
• the carrier When administered as injection or infusion • solutions the carrier is preferably isotonic saline, with or without agent(s) to stabilize the radium cation to prevent precipitation of radium salts or insoluble complexes.
• the active principle according to the invention could be used both in prophylactic, palliative and therapeutic treatment of non-malignant and malignant diseases affecting bones and soft tissues.
• the malignant diseases are selected from the group consisting of prostate cancer, breast cancer, kidney and urinary cancer, primary bone cancer, lung cancer and multiple myeloma
• the non-malignant disease are selected from the group consisting of autoimmune diseases affecting joints and skeleton, e.g. rheumatoid arthritis, schleroderma and spondyloartropathies.
• the physiologically acceptable preparation for in vivo administration comprises dissolved radium-223 salt, with or without a single or a combination of several cations, as stabilizing alkaline earth metal cation analogue carrier, with or without an agent to prevent precipitation and/or generation of colloids, in addition to pharmacologically acceptable carriers and adjuvans.
• the cation acting as stabilizing alkaline earth metal cation can be selected from the group consisting of magnesium, calcium and strontium.
• the agent to prevent precipitation and/or generation of colloids is a carboxylic acid or a combination of carboxylic acids, such as oxalic acid, oxaloacetic acid, tartaric acid, succinic acid, malic acid and malonic acid.
• the concentrations of the compounds in the preparation will generally be less than the individual LD 50 dose, for example less than 20% of the LD 50 dose, and thus vary for the different components.
• the activity of 223 Ra will be dependent upon the type and route of administration and the underlying condition or disease and will vary between approximately 50 kBq to approximately 10 MBq, administered in single or multiple doses for mammals, such as for example humans.
• radium-223 is furthermore used to produce a pharmaceutically active preparation to treat non-malignant and malignant diseases affecting bone, bone surfaces and soft tissues, both palliative and therapeutically.
• the preparation is administered to the mammal, such as humans or animals ,i.e. dogs, in need thereof, in a palliative or therapeutically effective amount.
• radium-223 can be used in a combination therapy, wherein the 223 Ra preparation is combined with the following classes of treatment; chemotherapy including bisphosphonates, surgery, external beam irradiation, low-
• the invention is furthermore directed to a kit including 223 Ra produced according to the inventive method, cations as stabilizing alkaline earth metal cation analogue carrier according and an agent to prevent precipitation and/or generation of colloids in addition to pharmaceutically acceptable carriers and suitable administration equipment.
• Table 1 presents the physical properties of radium-223 and its daughter nuclides (Ekstr ⁇ m et al., 1989).
• the decay of the 223 Ra and its daughters causes the emissions of four ⁇ -particles.
• Such a cascade of ⁇ -particles can deliver a large radiation dose to a limited volume.
• Radium-223 therefore possesses extreme cytotoxicity, also compared to most ⁇ -emitters (Howell et al, 1997).
• Table 1 Emittance from 223 Ra and daughters*.
• gamma radiation ( ⁇ 0,3 MeV total) is also emitted during decay and can be used to determine the quality and quantity of isotopes in samples using gamma spectroscopy.
• radium-223 has a characteristic gamma peak at 154.19 keV (5.59% abundance)
• radon-219 has a peak at 401.78 keV (6,6%)
• bismuth-21 1 has a 351.0 keV peak (12.8%) (Ekstrom et al., 1989).
• 223 Ra has a 269.41 keV peak with 13.6%) abundance, but this may be difficult to distinguish from a 271.23 keV peak, with 9.9% abundance of 219 Rn.
• Atcher et al. (1989) used a cation exchange system (Bio-rad AG 50) to produce 223 Ra from 227 Ac. Howell et al.
• the novel method according to the invention for producing 223 Ra for biomedical uses comprises both columns of inorganic matrix and liquid/liquid systems.
• a generator column containing a methane bis-phosphonic acid derivative on an inorganic matrix or the method can as well comprise a step of liquid/liquid extraction procedure in which one or more P,P' di- esterified methylene bis-phosphonic acid derivates are used as phase transfer agents.
• the generator column containing P,P' di-octyl methane bis-phosphonic acid on a silica matrix and the liquid/liquid extraction procedure is performed using P,P' di-octyl methylene bis-phosphonic acid or P,P' di(2-ethylhexyl) methane bis- phosphonic acid or combinations thereof as phase transfer agents.
• the prosedure with respect to the generator column is performed by using mineral acids which after neutralization is capable of giving physiologically compatible solutions of their salts, preferably nitric acid or hydrochlorid acid.
• the concentration of said mineral acids being in the range of 0.01 to 8M, more preferably between 0.1 and 2M, most preferably between 0.5 and 1M.
• the liquid/liquid extraction step is performed using a water phase consisting of a mineral acid, preferably nitric acid or hydrochloric acid, the concentration of which being in the range of 0.01 to 8M, more preferably between 0.1 and 2M most preferably between 0.8 and 1.5M.
• a mineral acid preferably nitric acid or hydrochloric acid
• the purified Ac and Th were subsequently adsorbed onto another f-element selective extraction chromatographic resin and used as a cow for 223 Ra.
• the latter material has been used by Wu et al. (1997) for construction of a generator for 21j Bi based on 225 Ac.
• Silica Actinide Resin (EiChroM, Darien, IL, USA) consisting of P,P' di-octyl methane bis-phosphonic acid (DIPEX, EiChroM Industries, Darien, IL, USA) on silica particles with a diameter in the range of 20 - 50 ⁇ m was prepared and preconditioned with 1M HC1. Approximately one half of the resin was then removed from the column and mixed with the eluate from the TRU-resin column.
• DIPEX Di-octyl methane bis-phosphonic acid
• the eluate containing Ac, Th and Ra was thereafter loaded onto 3 mm i.d. and 50 mm long column containing Actinide-resin (Ac-resin) on 30-50 ⁇ m silica (EiCroM Industries, Darien IL, USA). Briefly, the column had been prepared according to the method of Wu et al. (1997). After preconditioning the column with 1 M HCI, half of the material was removed and mixed with the eluate from the preceding step.
• the slurry containing the radionuclides was loaded onto the column. Finally, the column was washed with 5 ml of 1 M HCI. The column was retaining 227 Ac and 227 Th while 223 Ra could be eluted with a few ml of either HCI or HNO 3 , without any significant breakthrough of its parent and grandparent radionuclides. If desired, a subsequent purification step could be added by simply eluting the Ra eluate through a second AC-resin column to remove any traces of mother and grandmother nuclides. The HCI solution containing the Ra could be diluted in a buffer, sterile filtered and used as such.
• the purified 2 3 Ra could be concentrated before use by loading the HCI solution onto a 2 mm i.d. and 25 mm long column containing a resin, e.g., AG 50W-X4-16 (Bio-Rad, Richmond, CA, USA). Thereafter the 223 Ra could be eluted nearly quantitatively by a small volume of 6 M HNO 3 . The HNO 3 could thereafter be evaporated of and the residue could be resolved in a solution that could subsequently be sterile filtered.
• a resin e.g., AG 50W-X4-16 (Bio-Rad, Richmond, CA, USA.
• Radioactivity quality and quantity measurements were performed either using Ge-detector (Canberra, Meriden, CT, USA) combined with an amplifier and bias supply from EG&G Ortec (Oak Ridge, TN, USA) for gamma spectroscopy and/or a Canberra (model 7404-0 1 A) combined with an EG&G Ortec for alpha spectroscopy.
• the biodistribution data is presented in Table 2. The data shows that 223 Ra was selectively concentrated in bone compared to soft tissues. While all the soft tissue values were reduced between 6 h and 3 days after injection, the bone values increased with time. Femur to blood ratios increased from 129 to 691 from 6 h to 3 days. Spleen had the highest retention measured among the soft tissues, but the femur to spleen ratio also increased with time from 6.4 to 23.7 between 6 h and 3 days after injection.
• EXAMPLE 4 To study potential release of daughter isotopes after 223 Ra was incorporated in bone, due to either nuclear recoil or diffusion processes, femurs from five animals killed 6 h, and 5 animals killed 3 days after injection were examined
• EXAMPLE 5 It has been developed animal models with experimental metastasis pattern resembling those frequently observed in human patients (Engebraaten and Fodstad, 1999).
• One of these models consists of MT-1 cells injected intracardially into nude rats and is characterized by the consistent development of hind leg paralysis in the animals.
• Treatment (seven days after tumour cell inoculation) with the chemotherapeutics cisplatin or doxorubicin did not improve survival.
• Dissection and microscopic examination of the spine from animals affected by tumours revealed large masses of tumour cells replacing normal bone marrow and eroding the bony part of the spine.
• radium-223 The therapeutic potential of radium-223 was studied in the MT-1/nude rat model where animals were inoculated with 1 x 10 6 MT-1 human breast cancer cells by injection into the left ventricle of the heart as described (Engebraaten and Fodstad, 1999). These animals usually develop paralysis caused by growth of tumours in the spine. Groups of 4 and 5 animals each were then treated seven days later by receiving an intravenous injection of 200 ⁇ l of a vehicle solution without or with 10 kBq of radium-223 according to the invention.
• Results The group of four animals treated with vehicle solution alone experienced paralysis affected by tumour growth in the spine and was sacrificed between 20-25 days (means 22,25 days) after tumour cell inoculation. In the group of five animals receiving vehicle solution containing 223 Ra one animal had paralysis after 26 days, one after 40 days and one after 64 days while the two remaining animals lived throughout the experimental follow-up period of 90 days after tumour cell inoculation, without showing signs of paralysis. Conclusion: 223 Ra demonstrated a significant anti-tumour effect in animals with skeletal metastases.
• Atcher RW Friedman AM, Huizenga JR, Spencer RP. A radionuchde generator for the production of 211 Pb and its daughter. J. Radioanal. Nucl. Chem. Letters 135, 215-221 (1989). Atkins HL, Mausner LF, Srivastava SC, Meinken GE, Cabahug GE, D'Alessandro T. Tin-1 17m(4+)DTPA for palliation of pain from osseous metastases: A pilot study. J NucIMed 36, 725 (1995).
• Raabe OG Parks NJ. Skeletal uptake and lifetime retention of Sr-90 and Ra-226 in beagles. Radial Res 133, 204-218 (1993).
• Ritter MA Cleaver JE, Tobias CA. High-LET radiations induce a large proportion of nonrejoining DNA breaks. Nature, 266, 653-655 (1977).

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