Coating processes – Medical or dental purpose product; parts; subcombinations;... – Implantable permanent prosthesis
Reexamination Certificate
2000-07-27
2004-03-23
Beck, Shrive P. (Department: 1762)
Coating processes
Medical or dental purpose product; parts; subcombinations;...
Implantable permanent prosthesis
C427S002280, C427S002300, C427S407100, C427S409000, C427S414000, C427S417000, C427S418000, C427S435000
Reexamination Certificate
active
06709693
ABSTRACT:
The invention relates to stents with a radioactive surface coating, processes for their production and their use for restenosis prophylaxis.
PRIOR ART
Radioactive stents are prior art (EP 0433011, WO 94/26205, U.S. Pat. No. 5,176,617). Stents are endoprostheses that make it possible to keep open duct-like structures in the bodies of humans or animals (e.g., vascular, esophageal, tracheal and bile duct stents). They are used as palliative measures in the case of stenoses by obstruction (e.g., arteriosclerosis) or external pressure (e.g., in the case of tumors). Radioactive stents are used, for example, after vascular-surgery interventions or radiological interventions (e.g., balloon angioplasty) for restenosis prophylaxis. Such radioactive stents can be produced, for example, by activation of a non-radioactive stent using irradiation with protons or deuterons from a cyclotron (WO 94/26205). This process for the production of radioactive stents is named ion implantation.
There is now the problem that, on the one hand, generally no cyclotron is available at the site of the use of the stent to undertake an activation of the stent, and, on the other hand, the activated stent cannot be stored indefinitely or transported in any arbitrary way due to the sometimes short half-life of the activated isotope and for reasons of protection against radiation.
The object of this invention is therefore to make available stents and new processes for their production, and said stents can be activated independently by a cyclotron. In particular, the object of the invention is to make available stents that can be coated independently by a cyclotron with a preselected radioactive isotope.
This object is achieved by the stents that are described below and the processes for their production, as they are characterized in the claims.
DESCRIPTION OF THE INVENTION
The above-described object is achieved by the production processes for radioactive stents that are described below. In contrast to ion implantation, the processes according to the invention for the production of radioactive stents are based on chemical or electrochemical methods.
Within the framework of this application, the notations
nn
X and X-nn (X: element symbol, nn: mass number) are to be regarded as synonymous for radioactive isotopes (Example:
110
Ag corresponds to Ag-110).
The above-described object is achieved in a first variant by a process for the production of a radioactive stent, in which a chemical deposition of the radioactive isotope is carried out on the stent.
To this end, the selected stent is immersed in a solution that contains the radioactive isotope. The radioactive isotope is then chemically deposited on the stent. Depending on the selected material of the stent, on the one hand, and the radioactive isotope that is to be deposited, on the other hand, two possible types of deposition are considered:
1) Chemical Reduction
During chemical reduction, a reducing agent (e.g., SnCl
2
, KBH
4
, dimethylborane, formaldehyde, sodium hypophosphite) is added to the solution that contains the radioactive isotope in dissolved form as well as the stent.
Survey:
M
2+
+2
e
−
(from the reducing agent)→catalytic surface→M
0
Reducing agent hypophospbite (with Ni)
H
2
PO
2
−
H
2
O→catalytic surface→HPO
3
2−
+2H
+
+H
−
2H
−
+Ni
2+
→Ni H
2
Addition of citrate, acetate, fluoride, succinate, lactate, propionate
pH=4−11
Reducing agent NaBH
4
(with Au, Ni)
BH
4
−
+H
2
O→BH
3
OH
−
+H
2
BH
3
OH
−
+3Au(CN)
2
−
+3OH
−
→catalytic surface→BO
2
−
+1.5H
2
+3Au
0
+6CN
−
+2H
2
O
2Ni
2+
+NaBH
4
+2H
2
O→catalytic surface→2Ni
0
+2H
2
+4H
+
+NaBO
2
Additions of dimethylammonium borane, boric acid, citric acid, malonic acid, glycine, pyrophosphate, malic acid,
pH=4-10
Reducing agent formaldehyde: (with Cu)
Cu
2+
+2HCOH+4OH
−
→catalytic surface→Cu
0
+H
2
+2H
2
O+2HCOO
−
with the addition of NaKtartrate, NaOH
Reducing agent hydrazine: (with Pd, Pt)
Pd, Pt with the addition of NH
4
OH, EDTA,
Reducing agent dimethylaminoborane (CH
3
)
2
NH—BH
3
(with Au, Ag)
(CH
3
)
2
NH—BH
3
+OH-→catalytic surface→BH
3
OH
−+(CH
3
)
2
NH
Au and Ag from cyanidic baths
After 1 minute to 10 hours, the stent is removed from the respective solution and washed. The stent is coated on the surface with the radioactive isotope.
In this way, for example, radioisotopes of elements Ag, Au, Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, P, Pb, Pd, Pm, Pt, Re, Rh, Ru, Sc, Sm, Tb, Tc or Y can be deposited on metal stents (e.g., steel, nitinol).
2) Chemical Precipitation
During chemical precipitation, a precipitating agent (e.g., oxalic acid, phosphoric acid or salts thereof or Na
2
CO
3
) is added to the solution that contains the radioactive isotope in dissolved form as well as the stent.
In this way, for example, radioisotopes of elements Ag, Au, Bi, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, Pb, Pd, Pm, Pt, Re, Rh, Ru, Sc, Sm, Tb, Tc or Y can be deposited on metal stents (e.g., steel, nitinol).
The above-described object is achieved in a second variant, in that the radioactive isotope is secured by means of an adhesive to the surface of the stent.
The device according to the invention thus consists of the metal parent substance of the stent, an adhesive on the surface of the stent and an adhesive radioactive isotope.
As a parent substance, the commercially available vascular implants can be used, e.g., a Wiktor stent, a Strecker stent or a Palmaz-Schatz stent.
As adhesives, peptides, fats or gold in combination with a thiol-group-containing complexing agent are used.
It is thus possible, for example, to use modified polyurethanes that in turn contain complexing agents.
As adhesives, however, peptides can also be used that on the one hand carry a complexing agent and on the other hand bind specifically to the metal of the stent. Examples of these compounds ar labeled endothelin derivatives, as they are described in, e.g., EP 606683, DE 4425778, DE 43 37 600, DE 4337599 and DE 19652374 (e.g., Tc-99m-Asp-Gly-Gly-Cys-Gly-Cys-Phe-(Dr-Trp)-Leu-Asp-Ile-Ile-Trp).
As adhesives, fats that carry a complexing agent can also b used. Examples of this are the complexing agents that carry lipophilic radicals and that are mentioned in DE 43 40 809, EP 450742, EP 438206, EP 413405 or WO 96/26182.
Moreover, gold in combination with a thiol-group-containing complexing agent can also be used as an adhesive. It is known that thiol-group-containing compounds show an increased affinity to gold-coated surfaces (H. Schönherr et al. J. Am. Chem. Soc. 118 (1996), 13051-13057). Surprisingly enough, elementary gold that is on the surface of the stent is also able to secure specific complexing agents, if they have thiol groups. The complexing agents in turn secure the radioactive isotopes.
For the purposes of this document, complexing agents are, e.g., DTPA, DOTA, DO3A, EDTA, TTHA, MAG
2
-amides, MAG
3
-amides and derivatives thereof.
As radioactive isotopes, the radioactive isotopes of elements Ag, Au, Ba, Bi, C, Co, Cr, Cu, Fe, Gd, Hg, Ho, In, Ir, Lu, Mn, Ni, P, Pb, Pd, Pm, Pt, Re, Rh, Ru, S, Sb, Sc, Sm, Tb, Tc or Y can be used.
The invention therefore relates to radioactive stents, characterized in that the radioactive isotope is secured to the surface of the stent by means of an adhesive.
The stents according to the invention can be produced as follows by way of example:
A. Peptide as an adhesive
A.1 First, a peptide is selected that for its part is able to complex heavy metal ions. The latter is activated by reaction with the radioactive isotope (e.g.,
186
Re or
188
Re) optionally together with a reducing agent. The radiolabled peptide is dissolved in a solvent (e.g., water, phosphate buffer), and the stent is immersed in the peptide solution. After the stent is removed fr
Blume Friedhelm
Dinkelborg Ludger
Duda Stephan
Goerner Heidemarie
Heldmann Dieter
Beck Shrive P.
Kolb Michener Jennifer
Schering Aktiengesellschaft
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