Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1995-05-15
2002-08-06
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C534S010000, C534S014000
Reexamination Certificate
active
06428768
ABSTRACT:
BACKGROUND
The present invention relates to the stabilization of radiopharmaceutical preparations and to the stabilization of components of radiopharmaceutical kits. In particular, the present invention relates to stabilization of lyophilized components of radiopharmaceutical kits by the addition of a cyclic oligosaccharide, such as a modified or unmodified cyclodextrin, to the kit.
Modified cyclodextrins are known to be useful in stabilizing drugs. For example, U.S. Pat. No. 4,727,064 to Pitha describes pharmaceutical preparations consisting generally of a drug with a substantially low water-solubility and an amorphous, water-soluble complex of cyclodextrin. In particular, the Pitha patent describes (1) a method of converting drug compositions which are crystalline and of low water-solubility into intrinsically amorphous complexes which have improved pharmaceutical properties; and (2) the method comprising inclusion of multi-component mixtures of cyclodextrin derivatives in the drug compositions. Pitha points out that in order for the cyclodextrin derivatives to be effective in assisting dissolution of the drugs, that a substantial part of the drug molecule should fit into the hydrophobic cavity of the cyclodextrin molecule and the same part of the drug molecule should be hydrophobic. The method of Pitha is most directly concerned with stabilization of hormone compositions, such as testosterone, progesterone, and estrogenic drugs.
European Patent 149,197 to Brauns et al, also relates to ways of increasing the solubility of drug compositions which are sparingly water-soluble by themselves. Brauns et al particularly relates to pharmaceutical preparations containing such drug compositions and a partially etherified beta-cyclodextrin. Brauns et al also indicates that medicinal substances which exhibit the greatest increased water-solubility when converted to inclusion complexes with the beta-cyclodextrin are those having a corresponding fitting shape, i.e. they have to fit into the cavity of the beta-cyclodextrin cyclic system. Examples of such medicinal substances mentioned in Brauns et al, include non-steroidal antirheumatic agents, steroids, cardiac glycosides and derivatives of benzodiazepin, benzimidazole, piperidine, piperizine, imidazole, and triazole.
However, the prior art does not relate to stabilization of radiopharmaceutical preparations or to kits for forming radiopharmaceuticals. Further, the prior art relates only to formation of inclusion complexes wherein the drug fits within the framework of the modified cyclodextrin. Finally, the prior art does not relate to the stabilization of volatile components of a radiopharmaceutical kit.
Therefore, there remains a need to develop stabilization techniques for radiopharmaceutical kits.
OBJECT OF THE INVENTION
It is one object of the present invention to provide means of stabilizing volatile and/or oxidizable components of radiopharmaceutical preparations.
It is another object of the present invention to provide means of stabilizing the components of radiopharmaceutical kits.
SUMMARY OF THE INVENTION
These objects and others as will be apparent from the following discussion are accomplished according to the present invention by the addition of stabilizing amounts of a cyclic oligosaccharide, such as a modified or unmodified cyclodextrin, to the radiopharmaceutical kit.
DETAILED DESCRIPTION OF THE INVENTION
Kits of the type used to make radiopharmaceuticals containing radioactive metals (e.g. Tc-99m, Re-186, and Re-188) normally include at least one ligand capable of bonding to the radioactive metal, a reducing agent, an inert, pharmaceutically acceptable carrier and auxiliary substances such as anti-oxidants, stabilizers and bulking agents, all combined and stored in a lyophilized condition. To form the radiopharmaceutical composition, the ingredients of the kit are combined with a radioactive ingredient such as technetium or rhenium in the form of a radioactive solution.
Components of the radiopharmaceutical kit are sometimes volatile or oxidizable thereby requiring storage under refrigerated and air-tight conditions. Volatilization can occur during the lyophilization process, or during storage, with subsequent deleterious leakage from the storage container, oxidation or adsorption to the storage vial or vial stopper. Oxidation may occur by interaction with molecular oxygen, sterilizing radiation, or other components of the kit.
In particular, radiopharmaceutical kits normally include at least one lyophilized ligand which is capable of bonding to a radioisotope during formulation to produce a radiopharmaceutical solution. These ligands are sometimes very susceptible to volatilization and/or oxidation.
Ligands that may be used in radiopharmaceutical kits include phosphines, arsines, thiols, thioethers, isonitriles, amines and ligands including combinations of these groups. Such ligands are susceptible to volatilization and/or oxidation because they comprise organic compounds that are generally oxygen sensitive or which, under normal circumstances, are unable to be lyophilized because they are liquids or sublimable solids. Particular ligands which have shown a relatively high risk of volatilization and/or oxidation are those ligands which include 1 to 4 phosphine groups per molecule.
Particular examples of ligands which may be components of a radiopharmaceutical kit are phosphine ligands such as:
tris(3-ethoxypropyl)phosphine (TEPP);
trimethylphosphine (PMe
3
);
triethylphosphine (PEt
3
);
tris(3-methoxy-3-methylbutyl)phosphine;
tris(3-methoxypropyl)phosphine (TMPP);
tris[2-[2-(1,3-dioxanyl)]]ethylphosphine;
tris[2-[2-(1,3-dioxolanyl)]]ethylphosphine;
methylbis(3-methoxypropyl)phosphine;
tris(4-methoxybutyl)phosphine (TMBP);
dimethyl(3-methoxypropyl)phosphine;
methylbis[2-[2-(1,3-dioxanyl)]]ethylphosphine;
bis(1,2-dimethylphosphino)ethane (DMPE);
1,3-bis(dimethylphosphino)-2,2-di(methoxymethyl)propane; or
1,2-bis(di((2-ethoxy)ethyl)phosphino)ethane.
It has been discovered that cyclic oligosaccharides act as effective stabilizers for radiopharmaceutical kits. In particular, modified or unmodified cyclodextrins have been found to provide superior stabilization qualities. From preliminary studies, it is believed that the addition of cyclic oligosaccharides, such as modified or unmodified cyclodextrin, to the radiopharmaceutical kits helps to inhibit oxidation of the kit components and to inhibit the volatilization of generally non-lyophilizable components. However, other mechanisms of stabilization can not be entirely ruled out at this time.
Because modified or unmodified cyclodextrins have a hydrophobic interior, their use is especially attractive for stabilization of the organic ligands included in a radiopharmaceutical kit. The addition of modified or unmodified cyclodextrins to a kit formulation which includes such organic compounds acts to inhibit the disadvantageous oxidation and/or volatilization.
The modified or unmodified cyclodextrin must be pharmaceutically acceptable and may be selected from &agr;-cyclodextrins, &bgr;-cyclodextrins, &ggr;-cyclodextrins, and combinations thereof. Particular &agr;-cyclodextrins which may be used in the kits according to the present invention are hydroxypropyl-&agr;-cyclodextrin, and hydroxyethyl-&agr;-cyclodextrin.
Particular &bgr;-cyclodextrins which may be used in the kits according to the present invention are hydroxypropyl-&bgr;-cyclodextrin, carboxymethyl-&bgr;-cyclodextrin, dihydroxypropyl-&bgr;-cyclodextrin, hydroxyethyl-&bgr;-cyclodextrin, 2,6-di-O-methyl-&bgr;-cyclodextrin, and sulfated-&bgr;-cyclodextrin. Preferably, hydroxypropyl-&bgr;-cyclodextrin is added to the kits according to the present invention.
Particular &ggr;-cyclodextrins which may be used in the kits according to the present invention are hydroxypropyl-&ggr;-cyclodextrin, dihydroxypropyl-&ggr;-cyclodextrin, hydroxyethyl-&ggr;-cyclodextrin, and sulfated-&ggr;-cyclodextrin.
The cyclic oligosaccharide should be included in an amount suitable to inhibit
DeRosch Mark A.
Deutsch Edward A.
Dyszlewski Mary Marmion
Nosco Dennis L.
Hartley Michael G.
MallincKrodt Medical, Inc.
LandOfFree
Stabilized radiopharmaceutical kits does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Stabilized radiopharmaceutical kits, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Stabilized radiopharmaceutical kits will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2973320