Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Coated – impregnated – or colloidal particulate
Reexamination Certificate
1999-04-02
2002-09-24
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Coated, impregnated, or colloidal particulate
C424S001290, C424S001250, C600S003000
Reexamination Certificate
active
06455024
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to radiotherapy agents comprising particles of an inorganic material containing a suitable radionuclide and having an average particle diameter of about 0.05 to 5000 microns. The solid or porous inorganic particles of the present invention are administered parenterally or nonparenterally to treat a tissue or organ system. They may also be administered by direct implantation in the case of brachytherapy applications.
BACKGROUND OF THE INVENTION
The use of radionuclides for treatment of various types of cancer has been an effective alternative to other therapies, such as chemotherapy and external beam radiation. A variety of different radionuclides have been used which possess three general decay characteristics: alpha-particle emitters, beta-particle emitters, and Auger electron- and Coster-Kronig electron-emitters following electron capture. The type of radionuclide used depends on a number of factors, including the distribution of the radiation relative to the sites of tumor being targeted. The general principle is to use the radionuclidic decay to destroy cancerous cells and prevent the spread of additional cancer.
Therapeutic radionuclides have been delivered in a variety of forms. The radionuclide can be bound to a carrier molecule, such as a simple organic or inorganic ligand, a small peptide, or a monoclonal antibody and then injected intravenously for targeting to the area of desired therapy. While this approach has been effective in some cases, it relies upon the proper targeting of the ligand-radionuclide complex to the desired cancer cells, while minimizing localization in other areas of the body. Achieving this high target-to-background ratio of specificity is often difficult.
A second approach uses the principle of brachytherapy, where the radionuclide is physically applied in a more directed manner, often by direct implantation. The radionuclide is often implanted inside a container, such as a capsule or seed. Using this technique, the desired radioactivity can be spatially directed to provide the best dose to the cancerous cells, while minimizing dose to other heathly cells in the body.
Kubiatowicz, U.S. Pat. No. 4,323,055, describes the use of iodine-125 seeds incorporated in a rod-like member which is detectable by X-rays. The I-125 seeds can thus be placed in the body and located using X-ray photographs.
Russell and Coggins, U.S. Pat. No. 4,702,228, describes the use of palladium seeds containing a fraction of palladium-103 as the X-ray emitting source and methods of producing capsules containing the seeds. The use of these seeds for implantation into a tumor is also described. Russell and Coggins, U.S. Pat. No. 4,784,116, further decribes capsules and radiation-emitting materials for implantation within a living body including description of a container means for sealing the radiation-emitting material.
Day and Ehrhardt, U.S. Pat. No. 4,889,707, describes radioactive microspheres comprising a biodegradable glass material and a beta-emitting radioisotope chemically dissolved in and distributed sustantially uniformly throughout the glass material. The materials which are initially nonradioactive are subjected to neutron irradiation, thus producing a beta-emitting radioisotope. The glasses described include aluminosilicate, magnesium aluminosilicate, lithium silicate, lithium aluminosilicate, lithium aluminoborate, lithium germanate, lithium aluminogerminate, potassium silicate, potassium aluminosilicate, potassium aluminoborate, potassium germanate, and potassium aluminogermanate containing samarium-153, holmium-166, erbium-169, dysprosium-165, rhenium-186, rhenium-188, and yttrium-90. These materials are biodegradable and gradually dissolve after they are no longer radioactive.
Suthanthiran and Lakshman, U.S. Pat. No. 5,163,896, describes a pellet for a radioactive seed for use in radiation therapy where the pellet comprises a metallic substance coated with a radioactive-absorbing material of polyamino acids and radioactive material absorbed such as I-125, Pd-103, Cs-131, Cs-134, Cs-1378 (sic), Ag-111, U-235, Au-198, P-32 and C-14 and other isotopes.
Carden, U.S. Pat. No. 5,405,309, describes seeds of Pd-103 of high activity formed by bombarding an Rh target in a cyclotron with high energy particles. The seeds thus obtained are Rh containing carrier-free-Pd-103, which are then combined with a small amount of Pd and electroplated onto a pellet of electroconductive material and encapsulated within a biocompatible container or shell.
Volkert, et al., J. Nucl. Med 1991; 32:174-185, review the production and decay property considerations of therapeutic radionuclides. They summarize the characteristics needed for radiotherapeutic agents and the considerations used in choosing the appropriate materials and production schemes.
Nag, et al., Int. J. Radiation Oncology Biol. Phys., Vol. 31, No. 1, pp. 103-107, 1995 surveyed the use of brachytherapy in the United States and included a substantial list of the radioisotopes being used, the clinical applications, and their frequency of use.
SUMMARY OF THE INVENTION
This invention relates to radiotherapy agents comprising solid or porous particles of an inorganic material having an average particle diameter of about 0.05 to 5000 microns and containing a suitable radionuclide. The inorganic material includes monomeric and polymeric forms, and mixtures of monomeric and polymeric forms of one or more of the following: aluminas, carbonates, silicas, and phosphates and organic or inorganic cationic salts thereof. The inorganic material may be in a crystalline form, an amorphous form, or a mixture of crystalline and amorphous forms. The radoinuclide is coated, adsorbed, or incorporated into the matrix of the particle directly.
The inorganic particles can be prepared and fabricated using known techniques into a variety of shapes, sizes, and extents of porosity. The porous particles contain one or more pores or cavities, which may be entirely or partially enclosed by the inorganic material particle shell. For parenteral use, the particles are preferably about 0.2-10 microns in average diameter. For use in brachytherapy applications, the particles are preferably from 50 to 5000 microns in size and may be incorporated into other delivery systems, such as tubes or encapsulated seeds.
The solid or porous inorganic particles of the invention may be coated with a variety of metallic, organic or lipid materials to control the stability, pharmacokinetics, targeting, and biological effects of the particles in vivo.
The porous inorganic particles of the invention should have a density of from 30% to 100% of the density of the solid nonporous inorganic material. The pore diameter may vary depending on the size of the particles and the number of pores, to achieve the preferred density. Thus, the pore size may range from about 20 angstrom to 5000 microns. The porous nature of the particles allows for a substantial range of surface areas to be achieved, thus allowing different loadings of radioactive materials on or within the particle matrix.
The solid or porous inorganic particles of the invention can be administered parentally or nonparentally with an optional pharmaceutically acceptable carrier to a patient in need thereof, to thereby treat a tissue or organ system of that patient. They may also be administered by direct implantation in the case of brachytherapy applications.
DETAILED DESCRIPTION OF THE INVENTION
[1] In a first embodiment, the present invention provides a novel radiotherapy agent, comprising: solid or porous particles of an inorganic material having an average particle diameter of about 0.05 to 5000 microns and a suitable radionuclide.
[2] In a preferred embodiment, the present invention provides a novel radiotherapy agent, wherein:
the radionuclide is selected from:
89
Sr,
169
Yb,
32
P,
33
p,
90
y,
125
I,
103
Pd,
177
Lu,
149
Pm,
140
La,
153
Sm,
186
Re,
188
Re,
166
Ho,
166
Dy,
169
Er,
165
Dy,
97
Ru,
193m
Pt,
195m
Pt,
105
Rh,
67
Cu,
64
Cu,
Glajch Joseph L.
Singh Prahlad R.
Bristol-Myers Squibb Pharma Company
Dolan Peter L.
Hartley Michael G.
O'Brien Maureen P.
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