Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant...
Reexamination Certificate
2000-01-03
2003-10-21
Travers, Russell (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
C424S001610, C424S001690, C424S001130, C424S001210, C424S001250, C424S001290, C424S001330, C424S001730, C424S001570, C424S001530, C424S001490, C424S001450, C424S001410, C424S001370
Reexamination Certificate
active
06635234
ABSTRACT:
The present invention relates to the preparation and use of the “calcium analogue” alkaline-earth radionuclide 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 &bgr;-emitters and conversion electron emitters.
A substantial percentage of cancer patients is affected by skeletal metastases. As many as 85% of patients with advanced lung, prostate and breast carcinoma develop bony metastases (Garret, 1993; Nielsen et al., 1991). 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, Foss{dot over (a)} et al., 1992, Lee et al., 1996, Silberstein, 1996). These radiopharmaceuticals have been based on &bgr;-particle emitters (Atkins, 1998) and lately also a conversion electron ermitter (Atkins et al., 1995).Among these compounds which have so far been approved by US Food and Drug Administration, Le. are strontium-89 (Metastron™) and
153
Sm EDTMP (Lexidronam™). 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).
Recently, one of the inventors authored a publication (Larsen et al., 1999) showing by dosimetry that &agr;-emitters can be more advantageous than &bgr;-emitters as bone seekers. I.e. the shorter range of the &agr;-emitters effecting less bone marrow exposure when the source is located at bone surfaces. In this study two &bgr;-emitting bisphosphonate bone seekers were compared with two &bgr;-emitting compounds with similar chemical structures and bone affinity. Dosimetric calculations indicated that, in mice, the bone surface to bone marrow dose ratios were approximately 3 times higher with the &agr;-emitter compared to the &bgr;-emitter. This indicates that &bgr;-emitting bone seekers may have advantages over &bgr;- and/or electron emitting compounds because the radiation dose can be more strongly concentrated to the bone surfaces. Because of the short half life (t
½
=7.2 h) and since its production is limited to only a few sites worldwide, astatine-211 is at present not yet available for large scale marketing. Besides astatine-211 only a few &agr;-particle emitting radioisotopes are at present considered useful for biomedical applications (Feinendegen et al., 1997). The lead-212/bismuth-212 system has previously been used for preparation of bone seeking agents. Bismuth-212 complexed with ethylene-diamine-tetra(methylene-phosphonic acid) (EDTMP), or 1,4,7,10-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 (t
½
=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 &agr;-emitting bismuth isotope considered for biomedical use, the bismuth-213 (t½=46 min). Attempts have been made to use the &bgr;-emitter lead-212 (t
½
=10.6 h) as an in vivo generator for
212
Bi. However, a significant translocation affecting a high kidney accumulation of the &agr;-emitter was observed (Hassfjell et al., 1997). Other &agr;-emitting radioisotopes potentially useful for biomedical applications are the radium isotopes 224 and 226. As with other group II alkaline-earth metals, radium in its cationic state is a natural boneseeker.
Previously the radium isotopes 224 and 226 has been studied, partly because of their bone affinity (Loyd et al., 1982, 1991; Muggenburg et al., 1996, Müller, 1971; Raabe et al., 1993; Rundo, 1978). Radium-226 is, because of its long half-life (1600 years) and its noble gas radon-222 daughter (t
½
=3.8 days), not considered useful for targeted radionuclide therapy. Because of its chemical nature, radon is inert to chemical bonding under in vivo conditions. It can therefore readily translocate in vivo when generated from the decay of the mother nuclide (Rundo, 1978). Inhaled radon mainly dissolves in body fluid and fat and is mainly eliminated from the body by exhalation (Rundo, 1978). In an experiment using bone samples, Lloyd and Bruenger (1991) reported that 89.5-94.25% of the radon-222 escaped from the bone after radium-226 had been administered to dogs. In contrast to radium-226, radium-224 has a half life (t
½
=3.64 days) which seems very suitable for biomedical applications.
224
Ra was used medically for many years to treat ankylosing spondylitis (Delikan, 1978). Unfortunately, also a significant fraction of the daughter isotopes of radium-224 escaped from bone, probably mainly because of the radon-220 (t
½
of 55.6 s) daughter (Lloyd et al., 1982; Müller et al., 1971; Rundo, 1978).
It is thus known from previous studies that when the radium isotopes
224
Ra and
226
Ra were incorporated in bone, a significant translocalisation of their radon daughters occurred, which could, at least partly, explain the known carcinogenic effect of these two radium isotopes. This may be one of the reasons why (&agr;-emitters have not been evaluated clinically as bone seeking radiopharmaceutical against skeletal cancers.
It is the object of the present invention to provide a bone seeking radionuclide useful as a pharmaceutical agent, showing that radioactive decay products from its transformation do not translocalize significantly after its incorporation in bone (valid at least after 3 days from administration).
The present inventors made the significant and somewhat unexpected discovery that from
223
Ra localized in bone, very little translocation of the radon daughter (as well as other radionuclides from the decay chain) occurred. Hence, the
223
Ra series may be used to irradiate the bone surface without any significant translocation of radionuclides (including diffusion into bone marrow). Furthermore radium-223, should be more suitable as a boneseeking radiopharmaceutical since the half life (11.4 days) is about three times that of
224
Ra, allowing a deeper incorporation into the matrix of the bone surfaces before decay occurs. Also, perhaps even more important, 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. Three of the four &bgr;-particles emitted during decay of
223
Ra and daughter nuclides are emitted immediately following
223
Ra transformation (Seelman-Eggebert et al., 1981), i.e., of the first three transformations following
223
Ra, the 3.9 second
219
Rn alpha decay is the one with the longest half life (Table 1). The last &agr;-emitter in the
223
Ra chain,
211
Bi (t
½
=2.15 min) follows the decay of the &bgr;-emitter lead-211 (t
½
=36.1 min) and may therefore show some translocation. However, if the precursor, lead-211, is trapped inside of the bone matrix, also the last &agr;-particle in the
223
Ra series may be delivered to the bone surface area. In addition &agr;-particles are high linear energy transfer (high-LET) radiation that is extremely cytotoxic to mammalian cells (Hall, 1994; Ritter et al., 1977). An &agr;-particle emitting radiation source localized in target tissue can deliver radiation to a smaller target area, thus reducing normal tissue exposure compared to &bgr;-emitters.
The present invention relates to the preparation and the use of the “calcium analogue” alkaline-ea
Bruland Øyvind S.
Henriksen Gjermund
Larsen Roy H.
Anticancer Therapeutic Inventions AS
Clark & Elbing LLP
Sharareh S
Travers Russell
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