Process for the manufacture of 117Sn...

Details Process for the manufacture of 117Sn... Process for the manufacture of 117Sn...

2001-05-02

2003-04-01

Nazario-Gonzalez, Porfirio (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heavy metal containing doai

C424S001650, C534S010000, C556S105000, C600S001000, C600S003000

Reexamination Certificate

active

06541514

ABSTRACT:

BACKGROUND OF THE INVENTION
Bone metastases are the most common cause of cancer pain, and primary bone cancers may also cause severe chronic pain. Approximately 75-80% of patients with prostate, breast, and lung cancer develop osseous metastases which cause bone pain during the late stages of their illness. Clinical management of cancer-related bone pain through palliation is necessary to improve the quality of life of terminal cancer patients.
A number of options are currently available for clinical management of bone pain. Nonsteroidal anti-inflammatory agents, opioids, hormones, and cytotoxic chemotherapy are used in the initial stages of bone metastasis, and external beam radiation can be applied locally when bone pain occurs at a single site. As the patient's skeletal tumor burden increases, pain can increase and become multifocal, tending to move from one site to another. Hemibody external beam radiation can afford rapid pain relief for disseminated skeletal tumors. However, such extensive exposure to radiation may affect noncancerous rapidly dividing tissues in the gastrointestinal tract or bone marrow, and morbidity may result from hemibody radiotherapy for bone pain palliation.
Radiation emitted by intravenously administered radionuclides may also be used to treat bone pain palliation. A number of bone-seeking radioisotopes have been studied for their ability to palliate bone pain. For example,
32
P, which emits a 1.7 MeV &bgr; particle and has a half-life of 14.3 days, exhibits a 3- to 5-fold increase in uptake in bone around osseous metastases as compared to normal bone. The uptake of
32
P into bone lesions can be increased by pretreatment with androgen, and patients thus treated frequently experienced pain relief within five to fourteen days of
32
P orthophosphate administration, with response duration of two to four months. However, bone marrow receives a disproportionately high dose of
32
P from the surrounding inorganic bone matrix and from the cellular component of the bone marrow space, resulting in myelosuppression as a side effect. Pancytopenia resulting from myelosuppression by
32
P, though reversible, may necessitate transfusions.
32
P orthophosphate is not currently used for palliation of metastatic bone pain.
153
Sm emits an 0.81 MeV &bgr; particle, with a half-life of 46.3 hours. The stable
153
Sm ethylenediaminetetramethylenephosphonate (EDTMP) complex has received FDA approval. Patients report clinical benefit within two weeks of
153
Sm-EDTMP treatment, frequently within 48 hours of treatment, and pain relief may last from four to forty weeks. Reversible myelosuppression also results from bone pain palliation treatment with
153
Sm-EDTMP. In addition, at the applied therapeutic doses (35 to 210 mCi) large amounts of radioactivity can be excreted in the patient's urine, creating contamination risks and potentially causing radiation cystitis.
186
Re emits a 1.07 MeV &bgr; particle and a 137 keV, 9% abundance &ggr; photon, having a half-life of 89.3 hours.
186
Re forms a stable complex with hydroxyethylidine diphosphonate (HEDP) which rapidly accumulates in osteoblastic metastases. Symptom relief occurs for 40-65% of patients within two weeks, and frequently within 24-48 hours.
186
Re-HEDP causes reversible myelosuppression, and therapeutic doses of
186
Re-HEDP (30 to 70 mCi) also create contamination and radiation cystitis risks. Phase III clinical trials of
186
Re-HEDP have been completed.
89
Sr emits a 1.46 MeV &bgr; particle and has a half-life of 50.5 days. The biological half-life of
89
Sr exceeds 50 days in osteoblastic metastases, as compared to 14 days in normal bone. Bone pain relief occurs in 60 to 80% of patients, with onset two to four weeks after injection, though some patients may not experience relief for as much as ten weeks after treatment. The average duration of relief from
89
Sr treatment is from three to six months. Treatment with
89
Sr delays development of new bone pain in pre-existing, but clinically silent metastases. Four weeks after therapy,
89
Sr treatment typically causes a 30% decrease in platelet count, which recovers slowly over 12 weeks. Toxicity from
89
Sr treatment is cumulative, resulting from the total absorbed dose of radiation delivered to the bone marrow and from replacement of marrow by tumor as disease advances. In 1993, the FDA approved an adult dosage of 4 mCi of
89
SrCl
2
for bone pain palliation.
Although pain relief is believed to occur independently from radiation-induced tumor cell killing, administration of bone pain-palliating doses of
153
Sm and
186
Re results in transient changes in levels of certain biochemical markers related to cancer progression. When administered with low doses of cisplatin,
89
Sr also demonstrates reductions in tumor markers. This observation has led to the suggestion that administration of higher doses of these nuclides might result in a tumoricidal effect. However, no anti-tumor effect or improvement in survival has been demonstrated to result from administration of
153
Sm,
186
Re, or
89
Sr, and the ability to increase dosages of these nuclides is limited by their myelosuppressive effects.
117m
Sn emits low energy conversion electrons (0.13 and 0.16 MeV) and a 159 keV photon, having a half-life of 14.0 days.
117m
Sn (Sn
4+
) diethylenetriaminepentaacetic acid (DTPA) exhibits higher bone uptake and retention than
32
P orthophosphate,
153
Sm-EDTMP,
186
Re-HEDP, and
89
SrCl
2
. Because of this, therapeutic doses of
117m
Sn (Sn
4+
) DTPA are lower than those of
153
Sm-EDTMP and
186
Re-HEDP, resulting in less risk of contamination and radiation cystitis. The lower energies of the conversion electrons emitted by
117m
Sn result in less radiation exposure to the bone marrow and fewer hematologic side effects than are observed with
153
Sm-EDTMP,
186
Re-HEDP, and
89
SrCl
2
. The photon emitted by
117m
Sn allows imaging and quantification of the isotope in normal and metastatic bone.
117m
Sn(Sn
4+
) is particularly suitable for the dose escalation necessary to effect cell killing in osseous tumors, since the myelosuppression which limits the benefits of the anti-tumor effects of
153
Sm,
186
Re, and
89
Sr is not a limiting factor for
117m
Sn(Sn
4+
).
Atkins, et al., Radiology (1993) 186, 279-283, discloses biodistribution of low doses of
117m
Sn (Sn
4
+) DTPA administered to humans. Atkins, et al. (1995) J. Nucl. Med. 36, 725-729 reports a Phase II pilot study which demonstrates palliation of bone pain resulting from
117m
Sn (Sn
4+
) DTPA treatment. A Phase II study of
117m
Sn (Sn
4+
) DTPA as a bone pain palliation agent is reported in Krishnamurthy, et al. (1997) J Nucl. Med. 38, 230-237. A dose escalation study of 47 patients treated with
117m
Sn (Sn4+) DTPA for bone pain palliation is reported in Srivastava, et al. (1998) Clin. Cancer Res. 4, 61-68. All of the
117m
Sn (Sn
4+
) DTPA formulations used in these studies contained a 20-fold molar excess of DTPA over
117m
Sn (Sn
4+
) and an amount of CaCl
2
corresponding to 80% of the molar amount of DTPA. The CaCl
2
was administered with the
117m
sn (Sn
4+
) DTPA to counteract any potential effect of uncomplexed DTPA on bone or blood calcium levels.
U.S. Pat. No. 4,533,541 discloses preparation of
117m
Sn (Sn
4+
) chelates capable of localizing to bone after intravenous injection, which were used for diagnostic purposes. The chelating agents disclosed in U.S. Pat. No. 4,553,541 include DTPA, which was formulated in significant molar excess (8-40-fold) over the concentration of
117m
Sn (Sn
4+
) (i.e., the concentration of total tin) in the radiopharmaceutical composition.
WO 95/29706 discloses
117m
Sn (Sn
4+
) DTPA compositions for bone pain palliation and bone cancer therapy, which employ a molar excess of DTPA over
117m
Sn (Sn
4+
). WO 95/29706 demonstrates dose-dependent relief of bone pain in humans after administration of
117m
Sn (Sn
4+
) DTPA, with particular efficacy at doses of about 9 t

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