Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant...
Reexamination Certificate
1998-07-30
2001-01-16
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
C424S130100, C424S178100, C424S179100, C424S181100, C424S001490, C424S001690, C514S002600, C514S975000, C530S387100, C530S389100, C530S391300, C436S804000
Reexamination Certificate
active
06174513
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to a novel use of surfactants alone or in combination with salts to stabilize radiolabeled peptides and proteins contained in diagnostic or therapeutic radiopharmaceutical compositions and, more particularly, to the use of one or more surfactants alone or in combination with one or more salts to stabilize radiolabeled peptides, polypeptides or proteins contained in diagnostic or therapeutic radiopharmaceutical compositions for diagnostic tissue imaging or therapeutic use.
BACKGROUND OF THE INVENTION
Scintigraphic imaging and similar radiographic techniques for visualizing tissues in vivo are finding ever-increasing applications in diagnostic procedures. Generally, scintigraphic procedures involve the preparation of radioactive agents which, upon introduction to a biological subject, become localized in the specific organ, tissue, or skeletal structure of choice. When so localized, traces, plots, or scintigraphic images depicting the in vivo distribution of radioactive agents can be generated from data collected by various radiation detectors, such as scintillation cameras. The distribution and corresponding relative intensity of the detected radioactive agent indicate the space occupied by the targeted tissue and may also indicate a presence of receptors, antigens, aberrations, pathological conditions, and the like.
Radioactive agents are also finding increasing applications in therapeutic procedures. As with scintigraphic procedures, the radioactive agents, upon introduction to a biological subject, become localized in the specific organ, tissue, or skeletal structure of choice. Emissions from the radionuclide deliver a therapeutic dose to the targeted tissue.
In general, depending on the type of radionuclide and the target organ or tissue of interest, the compositions of the radioactive agents comprise a radionuclide, a carrier agent designed to target the specific organ or tissue site, possibly various auxiliary agents, e.g. chelating agents, which affix the radionuclide to the carrier, and water or other delivery vehicles suitable for injection into, or aspiration by, the patient, such as physiological buffers, salts, and the like.
Over the years, there has been growing interest in preparing radiolabeled proteins such as macroaggregated albumin (“MAA”), human serum albumin (“HSA”), monoclonal antibodies, or monoclonal antibody fragments for the purpose of diagnosing and treating diseases, such as inflammation, deep vein thrombosis, or cancer.
Recently, the use of radiolabeled peptides for diagnostic and therapeutic applications has attracted much attention. One such radiolabeled peptide is derived from an octapeptide somatostatin analog known as octreotide and is described in U.S. Pat. No. 4,395,403. Octreotide has a very high binding affinity to somatostatin receptors in a variety of human tumors. By linking octreotide to a suitable chelating agent capable of forming a complex with radionuclides, it has been possible to create radiolabeled octreotide which effectively images tumors having somatostatin receptors. Somatostatin analogs containing chelating groups are described in greater detail in UK Patent Publication No. 2,225,579.
Despite the potential usefulness of radiolabeled peptides and proteins, it has been found that such radiolabeled compounds are extremely susceptible to radiolysis, caused by the radionuclide attached thereto for a label.
As used herein, the term radiolysis includes chemical decomposition of the peptide, polypeptide, or protein by the action of radiation emitting from the radionuclide attached for a label. This chemical decomposition can occur in the radiopharmaceutical compositions incubated at room temperature. Often, in the preparation of radiopharmaceutical compositions, these preparations require heating to form the desired product or autoclaving for sterilization. Either of these two processes may accelerate the decomposition of the radiolabeled compounds by the action of radiolysis.
To inhibit or prevent radiolysis, experts have suggested adding a stabilizer such as HSA to the composition (e.g., R. A. J. Kishore, et al., “Autoradiolysis of Iodinated Monoclonal Antibody Preparations,”
Int. J. Radiat. Apnl. Instrum., Part B
, Vol. 13, No. 4, pp. 457-459 (1986) and European Patent Application having International Publication Number WO91/04057), keeping the radiopharmaceutical composition frozen between preparation and administration (e.g., R. L. Wahl, et al., “Inhibition of Autoradiolysis of Radiolabeled Monoclonal Antibodies by Cryopreservation,”
J. Nuc. Med., Vol.
31, No. 1, pp. 84-89 (1990)), or storing a radiolabeled biological molecule in contact with an ion exchange resin (European Patent Application 0 513 510 A1). These techniques for preventing radiolysis are often not effective or practical when used with many radiolabeled peptides and proteins.
Surfactants have been shown to alter the reactivity of radiolytically generated radicals (e.g. e
−1
(aq), .OH, .H) towards substrates such as benzene (J. H. Fendler, et al., “Radiation Chemistry of Aqueous Miceller Systems”, Report, RRL-3238-364, 12 pp., Avail, Dep. NTIS), pyrimidines (J. H. Fendler, et al., “Radiolysis of Pyrimidines in Aqueous Solutions”,
J. Chem. Soc., Faraday Trans.
1, Vol. 70, No. 7, pp. 1171-9, 1974) and dimethyl viologen cations (M. A. J. Rodgers, D. C. Foyt, and Z. A. Zimek, “The Effect of Surfactant Micelles on the Reaction Between Hydrated Electrons and Dimethyl Viologen”,
Radiat. Res
., Vol. 75, No. 2, p. 296-304, 1978). Cationic, nonionic, and anionic surfactants have been used, at concentrations both below and above the critical micelle concentration. Reaction rates have been observed to decrease, increase, or remain unchanged, depending on the type of surfactant, the substrate used, and the free radical produced by gamma radiolysis.
Surfactants and in particular polyoxyethylene (20) sorbitan monooleate have likewise been said to stabilize dilute protein solutions (e.g., Dr. W. R. Ashford and Dr. S. Landi: “Stabilizing Properties of Tween® 80 in Dilute Protein Solutions”
Bull. Parent. Drug Assoc
., Vol. 20, pp. 74-81, 1966). Ashford, et al. suggests that such solution stabilization could be applicable to radiolabeled proteins as directed to the prevention of adsorption to glass since adsorption results in a loss of potency of the particular protein solution. Surfactants have also been taught as stabilizers of proteins against denaturing, thus maintaining, for example, their enzymatic activity or their solubility at an air/liquid interface (Y. J. Wang and M. A. Hanson, “Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers”,
J. Parent. Sci. Tech
., Vol. 42, pp. S4-S26, 1988, and references therein). The use of surfactants as stabilizers of large molecules such as radiolabeled protein, polypeptides, or peptides to avoid radiolytic decomposition has not been previously taught.
From the foregoing, it will be appreciated that what is needed in this particular art field are stabilizers for radiolabeled peptides and proteins in a pharmaceutically effective concentration. Thus, it would be a significant advancement in this art field to provide stabilizing agents which substantially inhibit radiolysis of such radiolabeled peptides, polypeptides, and proteins.
Such stabilizers for substantially inhibiting peptide, polypeptide, or protein radiolysis are thereby disclosed and claimed herein.
SUMMARY OF THE INVENTION
The present invention overcomes and prevents the problem of radiolytic decomposition of radiolabeled peptides, polypeptides or proteins that are contained in diagnostic or therapeutic radiopharmaceutical compositions. The present invention discloses the use of surfactants, used alone or in combination with one or more salts, to stabilize radiolabeled peptides, polypeptides or proteins and thereby avoid radiolytic decomposition thereof. These stabilized compounds may be used for the diagnostic imaging of targeted tissues or for therapeutic treatment.
In diagnostic imaging
de La Fourniere Laurence
Miller Kathleen M.
DeCloux Amy
Mallinckrodt Inc.
Saunders David
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