U.S. patent application number 10/452398 was filed with the patent office on 2003-11-13 for products and methods.
Invention is credited to Bacon, Edward, Gustow, Evan, Mclntire, Gregory, Snow, Robert.
Application Number | 20030209291 10/452398 |
Document ID | / |
Family ID | 10856671 |
Filed Date | 2003-11-13 |
United States Patent
Application |
20030209291 |
Kind Code |
A1 |
Snow, Robert ; et
al. |
November 13, 2003 |
Products and methods
Abstract
A method for the immobilisation of a radioactive anion on the
surface of a metal substrate, said method comprising treating the
substrate with an oxidising agent in the presence of a solution of
a radioactive anion which forms an insoluble salt with ions of said
metal. Preferably, a binding agent will also be present.
Preferably, the metal is silver, the radioactive anion is
.sup.125I.sup.- and the binding agent comprises bromide ions.
Inventors: |
Snow, Robert; (West Chester,
PA) ; Mclntire, Gregory; (West Chester, PA) ;
Bacon, Edward; (Audubon, PA) ; Gustow, Evan;
(Villanova, PA) |
Correspondence
Address: |
Amersham Health, Inc.
101 Carnegie Center
Princeton
NJ
08540
US
|
Family ID: |
10856671 |
Appl. No.: |
10/452398 |
Filed: |
June 2, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10452398 |
Jun 2, 2003 |
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09577441 |
May 24, 2000 |
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6596097 |
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60138931 |
Jun 11, 1999 |
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Current U.S.
Class: |
148/245 |
Current CPC
Class: |
A61N 2005/1019 20130101;
C23C 22/68 20130101; G21G 4/06 20130101; G21G 4/08 20130101; A61N
5/1001 20130101 |
Class at
Publication: |
148/245 |
International
Class: |
C23C 022/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 5, 1999 |
GB |
9915714.1 |
Claims
What is claimed is:
1. A method for the immobilisation of a radioisotope on the metal
surface of a substrate, said method comprising treating the
substrate with an oxidising agent in the presence of a source of a
radioactive anion wherein the oxidising agent is capable of
oxidising the metal to the corresponding metal ion, and the
radioactive anion is capable of forming an insoluble salt with said
metal cation.
2. The method of claim 1, wherein the metal is selected from the
group consisting of silver, gold, copper and lead.
3. The method of claim 2, wherein the metal is silver.
4. The method of claim 1, wherein the radioactive anion comprises
.sup.125I, .sup.35S or .sup.32P.
5. The method of claim 1, wherein the radioactive anion is selected
from the group consisting of .sup.125I.sup.-, .sup.131I.sup.-,
.sup.123I.sup.-, .sup.35S.sup.2-, .sup.35SO.sub.4.sup.2-,
.sup.35SO.sub.3.sup.2-, .sup.125IO.sub.3.sup.-,
.sup.131IO.sub.3.sup.-, .sup.123IO.sub.3.sup.-,
.sup.51CrO.sub.4.sup.2-, .sup.32PO.sub.4.sup.3-,
H.sup.32PO.sub.4.sup.2-, H.sub.2.sup.32PO.sub.4.sup.- and
H.sub.3.sup.32P.sub.2O.sub.7.sup.-.
6. The method of claim 5, wherein the radioactive anion is
.sup.125I.sup.-.
7. The method of claim 1 which further comprises adding a binding
agent.
8. The method of claim 7, wherein the metal is silver and the
radioactive anion is .sup.125I.sup.-.
9. The method of claim 8, wherein the binding agent comprises
bromide or chloride ions.
10. The method of claim 1, wherein the oxidising agent is selected
from the group consisting of sodium chlorite (NaClO.sub.2), sodium
chlorate (NaClO.sub.3), sodium chromate (Na.sub.2CrO.sub.4),
hydrogen peroxide (H.sub.2O.sub.2), potassium dichromate
(K.sub.2Cr.sub.2O.sub.7), potassium permanganate (KMnO.sub.4), and
potassium ferricyanide (K.sub.3Fe(CN).sub.6).
11. The method of claim 10, wherein the oxidising agent is
potassium ferricyanide.
12. The method of claim 11 which further comprises adding potassium
ferrocyanide, to a molar ratio of
Fe(CN).sub.6.sup.3-:[Fe(CN).sub.6.sup.4- - of about 10:1 at the
start of the oxidising reaction.
13. The method of claim 1, wherein the source of the radioactive
anion comprises a solution or dispersion.
14. The method of claim 1, wherein the immobilisation takes place
in a solution comprising an elevated concentration of a salt
additive.
15. The method of claim 14, wherein the salt additive is NaCl, KCl,
CsCl, LiCl, CaCl.sub.2, NaNO.sub.3 or MgCl.sub.2.
16. The method of claim 14, wherein the concentration of the salt
additive is in the range of about 0.01 molar to the saturation
level of the added salt.
17. A radioactive metal substrate prepared by the method as of
claim 7.
18. A radioactive source for use in brachytherapy comprising a
radioactive metal substrate prepared by the method of claim 1.
19. A radioactive source for use in brachytherapy comprising the
radioactive metal substrate of claim 17.
20. The method of claim 1 wherein the source of the radioactive
anion comprises two or more radioisotopes.
Description
BACKGROUND OF INVENTION
[0001] Brachytherapy is a general term covering medical treatment
which involves placement of a radioactive source near a diseased
tissue and may involve the temporary or permanent implantation or
insertion of a radioactive source into the body of a patient. The
radioactive source is thereby located in proximity to the area of
the body which is being treated. This has the advantage that a high
dose of radiation may be delivered to the treatment site with
relatively low dosages of radiation to surrounding or intervening
healthy tissue.
[0002] Brachytherapy has been proposed for use in the treatment of
a variety of conditions, including arthritis and cancer, for
example breast, brain, liver and ovarian cancer and especially
prostate cancer in men (see for example J. C. Blasko et al., The
Urological Clinics of North America, 23, 633-650 (1996), and H.
Ragde et al., Cancer, 80, 442-453 (1997)). Prostate cancer is the
most common form of malignancy in men in the USA, with more than
44,000 deaths in 1995 alone. Treatment may involve the temporary
implantation of a radioactive source for a calculated period,
followed by its removal. Alternatively, the radioactive source may
be permanently implanted in the patient and left to decay to an
inert state over a predictable time. The use of temporary or
permanent implantation depends on the isotope selected and the
duration and intensity of treatment required.
[0003] Permanent implants for prostate treatment comprise
radioisotopes with relatively short half-lives and lower energies
relative to temporary sources. Examples of permanently implantable
sources include iodine-125 or palladium-103 as the radioisotope.
The radioisotope is generally encapsulated in a titanium casing to
form a "seed" which is then implanted. Temporary implants for the
treatment of prostate cancer may involve iridium-192 as the
radioisotope.
[0004] Recently, brachytherapy has also been proposed for the
treatment of restenosis (for reviews see R. Waksman, Vascular
Radiotherapy Monitor, 1998, 1, 10-18, and MedPro Month, January
1998, pages 26-32). Restenosis is a re-narrowing of the blood
vessels after initial treatment of coronary artery disease.
[0005] Coronary artery disease is a condition resulting from the
narrowing or blockage of the coronary arteries, known as stenosis,
which can be due to many factors including the formation of
atherosclerotic plaques within the arteries. Such blockages or
narrowing may be treated by mechanical removal of the plaque or by
insertion of stents to hold the artery open. One of the most common
forms of treatment is percutaneous transluminal coronary
angioplasty (PTCA)--also known as balloon angioplasty. At present,
over half a million PTCA procedures are performed annually in the
USA alone. In PTCA, a catheter having an inflatable balloon at its
distal end is inserted into the coronary artery and positioned at
the site of the blockage or narrowing. The balloon is then inflated
which leads to flattening of the plaque against the artery wall and
stretching of the artery wall, resulting in enlargement of the
intraluminal passage way and hence increased blood flow.
[0006] PTCA has a high initial success rate but 30-50% of patients
present themselves with stenotic recurrence of the disease, i.e.
restenosis, within 6 months. One treatment for restenosis which has
been proposed is the use of intraluminal radiation therapy. Various
isotopes including iridium-192, strontium-90, yttrium-90,
phosphorus-32, rhenium-186 and rhenium-188 have been proposed for
use in treating restenosis.
[0007] Conventional radioactive sources for use in brachytherapy
include so-called seeds, which are sealed containers, for example
of titanium or stainless steel, containing a radioisotope within a
sealed chamber but permitting radiation to exit through the
container/chamber walls (U.S. Pat. Nos. 4,323,055, and 3,351,049).
Such seeds are only suitable for use with radioisotopes which emit
radiation which can penetrate the chamber/container walls.
Therefore, such seeds are generally used with radioisotopes which
emit .gamma.-radiation or low-energy X-rays, rather than with
.beta.-emitting radioisotopes.
[0008] Brachytherapy seeds comprising a coating of radioactive
silver iodide on a silver wire encapsulated inside a titanium
container are known in the art (U.S. Pat. No. 4,323,055). Such
seeds are formed by first chloriding or bromiding the silver to
form a layer of silver chloride or bromide, and then replacing the
chloride or bromide ions with radioactive iodide ions (I-125) by
ion exchange. Such seeds are available commercially from
Medi-Physics, Inc., under the Trade Name I-125 Seed.RTM. Model No.
6711 or OncoSeed.TM. Iodine-125 seeds (Nycomed Amersham).
[0009] Other conventional brachytherapy seeds comprise titanium
containers encapsulating ion exchange resin beads onto which a
radioactive ion, for example I-125, has been absorbed (U.S. Pat.
No. 3,351,049). The immobilisation of a radioactive powder within a
polymeric matrix has also been proposed (WO97/19706).
[0010] The processes disclosed in U.S. Pat. No. 4,323,055 for the
production of I-125 containing seeds involve a number of separate
steps. We believe a more efficient and rapid method for the
production of radioactive sources comprising insoluble salts,
especially silver salts, is desirable from a manufacturing
viewpoint.
SUMMARY OF INVENTION
[0011] According to one aspect of the invention there is therefore
provided a method for the immobilisation of one or more
radioisotopes on the surface of a metal substrate, said method
comprising treating the substrate with an oxidising agent to
produce metal cations, in the presence of a source of a radioactive
anion containing one or more radioisotopes, which anion forms an
insoluble salt with said metal cations. Preferably, the radioactive
anion will be present in solution or in a dispersion. Preferably, a
binding agent will also be present. The products of the method of
the invention are radioactive substrates.
[0012] Any metal which can form an insoluble salt with a
radioactive anion on oxidation may be used as the metal substrate
in the method of the invention. Suitable metals include silver,
copper, lead, zinc, palladium, thallium, cadmium, lanthanum and
gold. Preferably, the metal substrate is silver. The substrate may
be made of solid metal or a suitable material plated with a layer
of metal, for example silver, zinc, palladium or thallium. Suitable
materials for plating include other metals, for example gold,
copper or iron, and plastics, for example polypropylene,
polystyrene, polyurethane, polyvinyl alcohol, polycarbonate,
Teflon.TM., nylon, delrin, Kevlar.TM., and any other plastic or
composite which can form a solid rod for plating with the metal of
interest. Suitable plating methods are known in the art and include
chemical deposition, sputtering and ion plating techniques.
[0013] The substrate should be of a suitable size and dimensions
for incorporation into a source, for example a seed, for use in
brachytherapy. Conventional seeds for use in the treatment of
prostate cancer, for example, are typically substantially
cylindrical in shape and approximately 4.5 mm long with a diameter
of approximately 0.8 mm, such that they may be delivered to the
treatment site using a hypodermic needle. For use in the treatment
of restenosis, a source should be of suitable dimensions to be
inserted inside a coronary artery, for example with a length of
about 10 mm and a diameter of about 1 mm, preferably a length of
about 5 mm and a diameter of about 0.8 mm, and most preferably with
a length of about 3 mm and a diameter of about 0.6 mm. Sources for
use in the treatment of restenosis are typically delivered to the
treatment site using conventional catheter methodology.
[0014] Preferably, the substrate is of a suitable size and
dimensions to fit inside a conventional seed container, such as
those disclosed in U.S. Pat. No. 4,323,055 which is hereby
incorporated by reference. Preferred seed containers are those made
of titanium, titanium alloy or stainless steel. Preferably, the
substrate will be substantially cylindrical in shape, for example
in the form of a rod or wire. Suitable dimensions are about 3 mm
long and about 0.10 mm to 0.70 mm in diameter, preferably about 0.5
mm in diameter.
[0015] Alternatively, the radioactive substrates may be
incorporated into a polymer or ceramic matrix. Suitable polymer
matrices include those disclosed in WO97/19706 which is hereby
incorporated by reference. If the radioactive anion comprises a
.beta.-emitter, the radioactive substrate should not be
encapsulated in a metal container as such containers would absorb
the .beta.-particles emitted and prevent them from reaching the
treatment site.
[0016] If the metal substrate comprises silver or another X-ray
opaque metal such as gold, copper or iron, there is the added
advantage that sources comprising the radioactive substrate will be
detectable by X-ray when inserted or implanted into a patient.
Preferably, the substrate is shaped such that its orientation can
also be determined by X-ray imaging. If the substrate comprises an
X-ray transparent material plated with a metal such as silver, the
radiopaque metal thickness is preferably greater than about 0.050
mm to ensure X-ray visualisation.
DETAILED DESCRIPTION OF INVENTION
[0017] The radioactive anions for use in the method of the
invention may be simple anions such as .sup.125I.sup.- or
.sup.35S.sup.2-, or complex anions such as .sup.32PO.sub.4.sup.3-,
.sup.35SO.sub.4.sup.2- or, .sup.51 CrO.sub.4.sup.2-. If the anion
is a complex anion, it may comprise one or more radioisotopes,
preferably one, two or three radioisotopes. More than one type of
radioactive anion may be used together in the method of the
invention, for example .sup.125I.sup.- together with
.sup.35SO.sub.4.sup.2-. The choice of anion(s) and radioisotopes
will depend in part on the intended use of the resulting
brachytherapy source and the type of radiation which the sources
should emit. For example, the radioactive anion may emit
.gamma.-radiation or low-energy X-rays, or it may be a
.beta.-emitter.
[0018] A radioactive anion which forms an insoluble salt with the
metal of the metal surface of the substrate should be used.
Preferred radioactive anions include those comprising .sup.125I,
.sup.35S, .sup.32P or .sup.33P. Possible anions include
.sup.125I.sup.-, .sup.131I.sup.-, .sup.123I.sup.-, .sup.35
S.sup.2-, .sup.35SO.sub.4.sup.2-, .sup.35SO.sub.3.sup.2-,
.sup.125IO.sub.3.sup.-, .sup.131IO.sub.3.sup.-,
.sup.123IO.sub.3.sup.-, .sup.51CrO.sub.4.sup.2-,
.sup.32PO.sub.4.sup.3-, H.sup.32PO.sub.4.sup.2-, and
H.sub.2.sup.32PO.sub.4.sup.-. For the purposes of the invention, a
salt is considered to be insoluble if its solubility product
constant is lower than about 1.times.10.sup.-5, preferably less
than about 1.times.10.sup.-12 and most preferably less than
1.times.10.sup.-16. For a sparingly soluble salt M.sub.xA.sub.y in
contact with its saturated solution, the solubility product is
given by K.sub.sp=[M.sup.y+].sup.x[A.sup.x-].sup.y.
[0019] Concentrations are normally given in moles/litre at
298.degree. K. For example, if the metal is silver, suitable anions
include those shown in the Table 1 below. Values are taken from the
Handbook of Chemistry and Physics, 74.sup.th Edition, 1993-4,
Section 8, page 49.
1 TABLE 1 Compound Ksp Possible Radioisotopes Silver(I) iodide 8.51
.times. 10.sup.-17 .sup.125I, .sup.131I, .sup.123I Silver(I)
chromate 1.12 .times. 10.sup.-12 .sup.51Cr Silver(I) iodate 3.0
.times. 10.sup.-8 .sup.125I, .sup.131I, .sup.123I Silver(I)
phosphate 1.4 .times. 10.sup.-16 .sup.32P Silver(I) sulfate 1.4
.times. 10.sup.-5 .sup.35S Silver(I) sulfide 6.3 .times. 10.sup.-50
.sup.35S Silver(I) sulfite 1.5 .times. 10.sup.-14 .sup.35S
[0020] Other possible anions include complex anions derived from
pyrophosphoric acid, such as H.sub.3P.sub.2O.sub.7.sup.-, wherein
one or more of H, P or O comprise a radioisotope. Suitable anions
derived from pyrophosphoric acid are disclosed in WO97/49335 which
is hereby incorporated by reference. When the metal surface is
silver, a preferred anion is .sup.125I-iodide.
[0021] One advantage of the method of the invention is that it is a
"one-step" chemical reaction. The prior art chemical processes
comprise two or more steps, which lead to longer preparation times,
greater variability of iodide distribution and greater costs. The
method of the invention is also readily applicable to substrates of
a variety of different geometric shapes, for example spheres or
rods. The method can be applied to a single substrate or to a
plurality of substrates wherein the number of substrates can range
from 2 to about 100,000 or more, for example in a batchwise
process. Treatment of a metal substrate with an oxidizing agent in
the presence of a radioactive anion in a one-pot reaction leads to
immobilization of the anion on the substrate in situ. Preferably,
both the oxidizing agent and the radioactive anion are used as
solutions in the same solvent, for example in aqueous solution.
Alternatively, a solid oxidising agent may be added to a reaction
mixture comprising the metal substrate and a solution or dispersion
of a radioactive anion.
[0022] The source of the radioactive anion may be present in
solution in a suitable solvent. Alternatively, it may be present in
the form of a dispersion or precipitate in a suitable liquid phase.
For example, if the radioactive anion is iodide, it may be present
as a dispersion of silver iodide, or a dispersion of any insoluble
metal iodide salt which displays greater solubility than that of
the insoluble radioactive salt to be formed using the method. For
example, if the substrate is silver and the radioactive anion is
iodide, the iodide source may be a dispersion of an iodide salt of
copper, lead, palladium or thallium. Table 2 below shows the
solubility of some iodide salts. Copper, lead, palladium and
thallium iodide are all more soluble than silver iodide, and so
could be used as an iodide source in the immobilisation of iodide
ions on a silver substrate using the method of the invention. Gold
iodide is less soluble than silver iodide and hence would not be a
suitable iodide source in such a method using a silver
substrate.
2 TABLE 2 Salt Ksp equilibrium solubility (M) AgI 8.3 .times.
10.sup.-17 9.11 .times. 10.sup.-9 CuI 1.1 .times. 10.sup.-12 1.05
.times. 10.sup.-6 PbI.sub.2 7.1 .times. 10.sup.-9 .about.1.3
.times. 10.sup.-3 PdI.sub.2 1.0 .times. 10.sup.-23 .about.1.4
.times. 10.sup.-8 TlI 6.5 .times. 10.sup.-8 3.0 .times. 10.sup.-4
AuI.sub.3 1.0 .times. 10.sup.-46 1.4 .times. 10.sup.-12
[0023] On oxidation of a silver substrate, the iodide should
transfer from the dispersion to the surface of the substrate.
[0024] Alternatively, the source of radioactive iodide ions may be
present in the form of an organic iodide-containing compound, for
example an alkyl iodide such as 2-iodoethanol, ethyl iodide,
iodobutylacetate, iodobutyric acid, 3-iodopropanol, epiiodohydrin,
glyceryl iodide, an activated iodomethylcarbonyl compound such as
iodoacetamide or iodoacetic acid, an iodinated lachrymator such as
iodinated acetone or 1-iodo-2-(trimethylsilyl)acetylene, or an
iodosilicon compound such as iodotrimethyl silane, each of which
may degrade over the course of the immobilisation reaction to
generate iodide ions in the solution phase.
[0025] Radioactive iodide ions may also be present in the form of a
complex with a suitable complexing agent, for example starch,
amylose, amylopectin, or another complex carbohydrate, which will
gradually release iodine, and thence iodide ions, in the presence
of hydroxide ions, into the solution phase over the course of the
immobilisation reaction. Complexes of other radioactive anions may
also be used in the method of the invention.
[0026] Alternatively, the radioactive anion source may be a
suitable ion exchange resin bead with radioactive anions adsorbed
thereon. Any ion exchange resin which can act as a reservoir for
the radioactive anions may be used (for example,
Pb-2e.sup.-.fwdarw.Pb.sup.2+,
Resin-SO.sub.4.sup.2-.fwdarw.Resin+SO.sub.4.sup.2-,
Pb.sup.2++SO.sub.4.sup.2-.fwdarw.PbSO.sub.4).
[0027] Suitable oxidizing agents are known in the art, including
those disclosed in U.S. Pat. No. 4,323,055 which is herein
incorporated by reference. They include sodium chlorite
(NaClO.sub.2), sodium chlorate (NaClO.sub.3), sodium chromate
(Na.sub.2CrO.sub.4), hydrogen peroxide (H.sub.2O.sub.2), potassium
dichromate (K.sub.2Cr.sub.2O.sub.7), potassium permanganate
(KMnO.sub.4), and potassium ferricyanide (K.sub.3Fe(CN).sub.6). For
the immobilization of iodide ions on silver metal, a preferred
oxidizing agent is potassium ferricyanide.
[0028] The oxidizing agent and the metal should be chosen such that
the oxidizing agent can oxidize the metal surface of the substrate
under the reaction conditions. The metal cations thus formed at the
surface of the substrate should combine with the radioactive anions
in solution to form a layer of an insoluble salt on the surface of
the substrate, thus immobilizing the anions on the surface of the
substrate. Immobilization of a radioactive anion on the metal
surface of a substrate provides a radioactive metal substrate.
[0029] Whether or not a particular oxidising agent is suitable for
use in the method of the invention with a particular metal and a
particular radioactive anion can be predicted by reference to the
standard electrode potentials of the relevant half-reactions. If
the sum of the standard electrode potentials for the oxidation
half-reaction and the reduction half-reaction is positive, then in
the absence of inhibiting kinetic effects, reaction should occur
spontaneously. Tables of standard electrode potentials are readily
available, for example in D. A. Skoog and D. M. West, Principles of
Instrumental Analysis, Holt, Rinehart, and Winston, Inc., New York,
1971, pp 678-680, and W. M. Latimer, The Oxidation States of the
Elements and Their Potentials in Aqueous Solution, Prentice Hall,
Englewood Cliffs, N.J., 1952. A selection of standard electrode
potentials (E.sup..theta.) is shown in Table 2 below. Values are
taken from Skoog and West.
3TABLE 3 Half reaction E.sup..theta./volts Possible radloisotopes
AgI + e.sup.- .fwdarw. Ag + I.sup.- -0.152 .sup.125I, .sup.123I,
.sup.131I 1/2Ag.sub.2S + e.sup.- .fwdarw. Ag + 1/2S.sup.2- -0.710
.sup.35S .alpha.Ag.sub.3PO.sub.4 + e.sup.- .fwdarw. Ag +
.alpha.PO.sub.4.sup.3- +0.4878 .sup.32P, .sup.33P CuI + e.sup.-
.fwdarw. Cu + I.sup.- -0.185 .sup.125I, .sup.123I, .sup.131I
PbSO.sub.4 + 2e.sup.- .fwdarw. Pb + SO.sub.4.sup.2- -0.356 .sup.35S
PbI.sub.2 + 2e .fwdarw. Pb + 2I.sup.- -0.365 .sup.125I, .sup.123I,
.sup.131I PbHPO.sub.4 + 2e.sup.- .fwdarw. Pb + HPO.sub.4.sup.2-
-0.465 .sup.32P, .sup.33P MnO.sub.4 + 8H.sup.+ + 5e.sup.- .fwdarw.
Mn.sup.2+ + +1.51 4H.sub.2O Fe(CN).sub.6.sup.3- + e.sup.- .fwdarw.
Fe(CN).sub.6.sup.4- +0.36 1/2I.sub.2 + e.sup.- .fwdarw. I.sup.-
+0.54
[0030] If the radioactive anion to be immobilised is iodide, then
preferably an oxidising agent is chosen which will not oxidise
iodide ions to molecular iodine under the reaction conditions.
Molecular iodine is volatile and generation of a volatile
radionuclide such as .sup.125I.sub.2 involves increased risk of
exposure to radiation for the manufacturing personnel or, at least,
rapid saturation of the carbon filters. However, if an oxidising
agent is used which is strong enough to oxidise silver and to
oxidise iodide to molecular iodine, the oxidation of the silver
should occur preferentially as this is the more favourable
reaction.
[0031] In one embodiment of the invention, ferricyanide is used as
the oxidising agent. Under standard conditions, it is postulated
that the reaction between ferricyanide and silver/silver iodide is
very energetically favourable, i.e.,
E.sub.cell=E.sub.cathode-E.sub.anode
E.sub.cell=0.36-(-0.152)
E.sub.cell=0.512
[0032] while the possible reaction between ferricyanide and iodide
would not be a spontaneous reaction under standard conditions,
i.e.,
E.sub.cell=0.36-(0.54)
E.sub.cell=0.18
[0033] Standard conditions are given as reagent activities of 1.
For example, the concentration of both ferricyanide and the reduced
form, ferrocyanide, would be equal to 1 molar.
[0034] However, the impact of concentration is predicted by the
Nernst equation:
E{fraction (1/2)}'=E{fraction (1/2)}.degree.-(0.059/n)log(reduced
form/oxidised form) (i)
[0035] For the oxidising half cell, this becomes:
E1/2'=E1/2.degree.-(0.059)log([Ag.degree.]/[Ag.sup.+]) (ii)
[0036] while the reduction half cell becomes:
E1/2'=E1/2.degree.-(0.059)log([Fe(CN).sub.6.sup.4-]/[Fe(CN).sub.6.sup.3-])
(iii)
[0037] However, in the presence of iodide, the silver oxidation is
coupled to the follow-up reaction as shown here:
[0038] Oxidation:
Ag.degree..fwdarw.Ag.sup.++e.sup.-
.sup.125I.sup.-+Ag.sup.+.fwdarw.Ag.sup.125I (iv)
[0039] The thermodynamics of equation (iv) are governed by the
equilibrium constant, which for insoluble species is also known as
the solubility product or K.sub.sp as shown here:
K.sub.sp=[Ag.sup.+][.sup.125I.sup.-] (v)
[0040] Substituting equation (v) into equation (ii), the operative
Nernst equation for the net reaction can be written as:
E{fraction (1/2)}'=E{fraction
(1/2)}.degree.-(0.059)log([Ag.degree.]/(K.su-
b.sp/[.sup.125I.sup.-])
[0041] By rearranging the log term and grouping all the constants
including the K.sub.sp term into a new E1/2.degree.', the impact of
[.sup.125I.sup.-] on the overall reaction can be seen:
E1/2'={E1/2.degree.+(0.059)log(K.sub.sp)}-0.059
log[.sup.125I.sup.-] (vi)
[0042] where {E1/2.degree.+(0.059)log(K.sub.sp)}=E1/2.degree.' for
reaction (iv) above.
[0043] Accordingly, it is postulated that in the oxidation of
silver by ferricyanide, the initial conditions and those throughout
the process are as follows:
4 Molar Ratio of [Fe(CN).sub.6.sup.4-]/ Condition
[Fe(CN).sub.6.sup.3-] [.sup.125I.sup.-] E.sub.cathode E.sub.anode
E.sub.cell Initial 1/1000 0.94 0.540 -0.15 0.690 10% 1/100 0.85
0.480 -0.147 0.627 50% 1 0.45 0.360 -0.131 0.491 90% 100/1 0.09
0.240 -0.089 0.329 100% 1000/1 0.01 0.180 -0.033 0.213
[0044] This suggests that this reaction remains energetically
favourable throughout the deposition of silver iodide.
[0045] The same type of process can be carried out for the possible
side reaction of the oxidation of iodide to iodine. The operative
Nernst equation for this half-cell is given by:
E{fraction (1/2)}'=E1/2-(0.059/2)log([I.sup.-].sup.2/[I.sub.2])
[0046]
5 Molar Ratio of [Fe(CN).sub.6.sup.4-]/ Ratio of Condition
[Fe(CN).sub.6.sup.3-] [I.sup.-].sup.2/[I.sub.2] E.sub.cathode
E.sub.anode E.sub.cell Initial 1/1000 1000/1 0.540 0.447 0.093 10%
1/100 100/1 0.480 0.476 0.004 50% 1 1 0.360 0.535 -0.175 90% 100/1
1/100 0.240 0.594 -0.354 100% 1000/1 1/1000 0.180 0.623 -0.443
[0047] These calculations suggest that in the earliest part of the
reaction, there is the chance to produce .sup.125I.sub.2 via
oxidation by ferricyanide.
[0048] In a preferred embodiment of the invention, both
ferricyanide and ferrocyanide are added to start the reaction to
minimize the production of .sup.125I.sub.2. Preferably,
ferricyanide and ferrocyanide are added at an initial molar ratio
of 10=[Fe(CN).sub.6.sup.3-]/[Fe(CN).sub.6.sup.4- -]. In particular,
an aqueous solution prepared from potassium ferricyanide and
potassium ferrocyanide trihydrate can be made and added to the
reaction vial. It is postulated that the presence of the
ferrocyanide reduces the propensity for the side reaction to occur
while the energetics behind the oxidation of silver to silver
iodide remain very good. Those skilled in the art will recognize
that similar reactions can occur in the presence of other redox
couples.
[0049] The more resistant the metal is to oxidation, the stronger
the oxidising agent should be. For example if the metal substrate
is gold, a more powerful oxidizing agent such as permanganate may
be used in the method of the invention.
[0050] The amount of oxidising agent required may be readily
calculated by a skilled person depending on the amount of
radioactive anion it is desired to immobilize on the metal
substrate.
[0051] The amount of the radioactive anion, for example the
concentration of a solution of the radioactive anion, can be chosen
depending on the activity level desired in the resultant
brachytherapy source. For example, substantially all of the anions
present may be radioactive (i.e. "hot") or the radioactive anions
may be diluted with non-radioactive (i.e. "cold" or carrier)
anions. For example, radioactive .sup.125I-iodide may be diluted
with non-radioactive .sup.127I-iodide. Conventional brachytherapy
sources for use in the treatment of prostate cancer normally have
activities in the region of 0.2 to 1.5 mCi. Using the method of the
invention, coated substrates with an activity of up to as high as
about a Curie may be prepared. Such substrates, and radioactive
sources comprising such substrates, form further features of the
invention.
[0052] In order for the insoluble salt to form a stable layer which
is strongly bound to the metal substrate and which does not flake
or fail to adhere to the substrate, it may be necessary to also use
a binding agent in the method of the invention. The binding agent
preferably comprises a non-radioactive anion which also forms an
insoluble salt with cations of the metal and which is different to
the radioactive anion. Preferably, the salt formed by cations of
the metal with the binding agent will be less insoluble, i.e. more
soluble than that formed by the radioactive anion with cations of
the metal or with the binding agent counter-ion. For example, if
the radioactive anion is .sup.125I-iodide, suitable binding agents
include chloride or bromide ions, preferably bromide ions.
[0053] Whether or not a binding agent is required in any particular
case will depend, at least in part, on the nature of the metal of
the substrate and the radioactive anion to be immobilized. Whether
or not a binding agent improves the stability of the coated
substrate in a particular case may be determined by routine trial
and error experiments.
[0054] The applicants do not wish to be bound by any particular
theory regarding the role played by the binding agent in the method
of the invention, but it is postulated that the binding anion is
preferably physically smaller than the radioactive anion such that
it can fit into gaps or cracks in the coating layer to help hold
the layer together. It is also possible that the binding ions take
part in establishing a template on the metal surface that affords a
more adhesive layer of the insoluble salt of interest.
[0055] A layer comprising both the binding agent and the
radioactive anion will form on the metal surface of the substrate.
Provided the reaction is carried out with sufficient mixing e.g.
stirring or agitation, the radioactive anion can be homogeneously
distributed throughout this layer. Silver substrates coated using
the prior art two-step process of U.S. Pat. No. 4,323,055 comprise
the radioactive anion in a layer of silver iodide on the surface of
a silver bromide-coated silver substrate.
[0056] If the metal is silver and the radioactive ion is
.sup.125I-iodide, carrying out the method of the invention in the
presence of an excess of bromide ions leads to formation of a more
physically stable layer than if the bromide ions are not present.
The binding agent thus enhances adherence of the Ag.sup.125I salt
to the surface of the substrate. In addition, the use of bromide
ions as a binding agent leads to formation of AgBr on the surface
of the substrate in addition to Ag.sup.125I. The AgBr may form a
coating over some or all of the Ag.sup.125I, which may help to
minimize loss of radioactivity from the source due to physical
handling of the coated substrate. It is postulated that the small
amount of bromide ion present may serve to help establish the
crystal form of the resulting AgI such that it is a more cohesive
layer, and adhesive to the metal substrate. In one embodiment, the
molar ratio of bromide to iodide present in the surface layer of
the substrate is preferably in the range of 2.25 to 2.75 and, more
preferably 2.5.
[0057] In one embodiment of the invention, I-125 may be immobilised
on a silver substrate by treating the substrate with a solution or
dispersion comprising I-125 ions and bromide ions and a solution of
an oxidising agent, for example an aqueous solution of potassium
ferricyanide. The I-125 and bromide ions may, for example, be
present as an aqueous solution of Na.sup.125I and NaBr.
Alternatively, the source of I-125 ions may be a dispersion of
Ag.sup.125I in a suitable solution phase, for example an aqueous
solution.
[0058] It is postulated that in this embodiment the following
reactions occur:
Ag+Fe(CN).sub.6.sup.3-.fwdarw.Ag.sup.++Fe(CN).sub.6.sup.4-
Ag.sup.++Br.sup.-.fwdarw.AgBr
Ag.sup.++.sup.125I.sup.-.fwdarw.Ag.sup.125I
AgBr+.sup.125I.sup.-.fwdarw.Ag.sup.125I+Br.sup.-
[0059] If the I-125 ions are present as a dispersion of
Ag.sup.125I, some of the Ag.sup.125I will gradually dissolve as the
immobilisation reaction progresses thus generating I-125 iodide
ions in solution. I-125 ions in solution may react directly with
the oxidised silver (i.e. the Ag.sup.+cation) to form Ag.sup.125I.
Alternatively, the oxidised silver may react first with bromide
ions to form AgBr, followed by ion-exchange of I-125 iodide for
bromide to give Ag.sup.125I. Thus both oxidation of the silver and
formation of AgBr will result in removal of I-125 from the solution
phase. Substantially all of the I-125 from the solution phase is
therefore immobilised on the substrate using the method of the
invention. The radioactivity of the product is therefore highly
dependent on the effective concentration of .sup.125I or on the
amount of .sup.125I effectively available in the initial solution
phase.
[0060] When a plurality of substrates, for example metal wires or
metal coated substrates such as metal coated organic compositions
including metal coated plastics or polymers, or metal coated
inorganic compositions such as metal coated ceramics or glasses are
treated together, the nominal amount of radioactive ion that is
immobilized on the metal surface of each substrate can vary from
substrate to substrate giving rise to a statistically normal
distribution of an average amount of radioactivity per substrate.
In a kinetically rapid reaction, the width of the statistical
distribution may be controlled to some extent by increasing the
volume of the reacting solution without increasing the amount of
reagents, thereby effectively diluting the reagents and slowing the
reaction. In addition, applicants have unexpectedly observed that
the presence of a salt additive to the reaction mixture at elevated
concentrations can narrow the statistical distribution of the
amount of radioactivity per substrate. One possible explanation is
that the increased concentration of ions in the solution decreases
the solution activity coefficient of the ions of interest (i.e. the
radioactive anions and/or the binding agent) and hence slows the
reaction.
[0061] The concentration of salt additive can range from about 0.01
molar up to saturation levels of the salt in solution, the latter
varying as a function of the salt and temperature of the solution.
For example, useful salts include NaCl which has a saturation level
of about 357 grams per liter in water at 0.degree. C. and about
391.2 grams per liter in water at 100.degree. C.; KCl which has a
saturation level of about 347 grams per liter in water at
30.degree. C. and about 567 grams per liter in water at 100.degree.
C.; CsCl which has a saturation level of about 745 grams per liter
in water at 20.degree. C. and about 1590 grams per liter in water
at 100.degree. C.; LiCl which has a saturation level of about 637
grams per liter in water at 0.degree. C. and about 1300 grams per
liter in water at 95.degree. C.; and MgCl.sub.2 which has a
saturation level of about 542.5 grams per liter in water at
20.degree. C. and about 727 grams per liter in water at 100.degree.
C.; and NaNO.sub.3 which has a saturation level of about 921 grams
per litre in water at 20.degree. C. and about 1800 grams per litre
in water at 100.degree. C. A number of these chloride and nitrate
salts have been evaluated and shown to be effective at narrowing
the statistical distribution of the amount of radioactive anion,
for example iodide, present from substrate to substrate.
[0062] The saturation levels of other useful highly soluble salts
can be found in the Handbook of Chemistry and Physics, CRC Press,
55.sup.th Edition. Saturated solutions of added salts can be
achieved when an excess of undissolved salt is present in the
reaction mixture in equilibrium with dissolved salt. The optimum
level of ionic strength per added salt or mixtures of added salts
which promotes the narrowest distribution of radioactivity uptake
per substrate can be readily found by one skilled in the art using
routine experimentation. At the end of the immobilisation reaction
leading to uptake of radioisotope onto the metal substrate to form
a radioactive substrate, excess salts can be removed by washing the
substrate with aliquots of water.
[0063] Without the added volume or the added salt, the statistical
distribution of radioactivity on the individual substrates is
critically dependant upon the rate of mixing. Distributions ranging
from 5 to 15% (relative standard deviation) are often observed.
With the addition of increased volumes, these values drop to <6%
(relative standard deviation). Addition of 2 M NaCl unexpectedly
results in distributions <3% (relative standard deviation). The
additional chloride ions may not take part in the reaction, but may
simply decrease the activity coefficient of the reacting ions
(e.g., bromide and iodide) thereby decreasing the critical
dependence oh the rates of mixing of the reagents themselves. It
is, however, known that silver chloride is appreciably soluble in
concentrated alkali chlorides where chloro complexes are formed
(see Cotton, F. A. and Wilkinson, G. in Advanced Inorganic
Chemistry, Interscience Publishers, John Wiley and Sons, page 863,
1962).
[0064] If the radioactive anion is present as a dispersion or in
the form of a complex or a degradable compound, there may be the
advantage that thorough mixing of the substrate(s), the oxidizing
agent and the source of the radioactive anion occurs before the
immobilisation reaction begins, leading to a more even distribution
of the radioactive anions over the substrate(s).
[0065] The use of organic salts of the radioactive anions might
also be useful at slowing the reaction of iodide with the silver
wires, for example pyridinium iodides may be useful as an iodide
source using this approach. Adding the radioactive anion to the
reaction mixture as a solid salt may also be useful as the kinetics
of dissolution may slow down the exposure of the wires to solution
phase anion until mixing is completed. While the solid salt is not
insoluble, the change from the solid phase to the solution phase
could accomplish the desired alterations in the speed of the
reaction.
[0066] In the specific case of the immobilisation of radioactive
iodide ions on a plurality of silver substrates using potassium
ferricyanide as the oxidising agent and bromide ions as a binding
agent, the addition of >1 M NaCl to the reaction mixture gives
rise to a yellow green precipitate shortly after the addition of
the potassium ferricyanide. This green precipitate clears as the
substrates coat with a mixed silver bromide/silver iodide salt.
Chemical analysis of the precipitate shows high levels of silver
and trace levels of iron suggesting the nature of the precipitate
to comprise silver halide. This precipitation may allow mixing to
occur before the bulk of the oxidation takes place, thereby
ensuring a better distribution of iodide amongst the individual
substrates.
[0067] Some metal halides, for example silver halides, are
light-sensitive. Among the silver halides, silver bromide is most
light-sensitive, followed by silver chloride and silver iodide
respectively. One disadvantage of the prior art process of U.S.
Pat. No. 4,323,055 for forming silver iodide-coated silver wires
was that the light-sensitivity of the silver iodide meant that the
process could not be carried out under natural light, but had to be
carried out under red light.
[0068] A further significant advantage of the method of the present
invention is that it need not be carried out under safe lights but
can be carried out under normal room (fluorescent) lights. While a
colour change is observed during the washing and drying steps from
lime green of the initial coated wires to a darker, olive green for
dried coated wires, analyses for iodide content either by
radiochemical analysis or by the spectrophotometric method
described in Example 1 below do not reveal any change in amount or
loss of iodide from the coated wires. Better than 99% uptake is
consistently achieved under normal, fluorescent lighting. It is
possible that since the iodide is distributed throughout the
deposited layer using the method of the invention, the light
sensitivity is not critical, whereas the previous process resulted
in iodide deposited onto the surface of an existing AgBr coating,
thereby exposing the AgI directly to any light incident upon the
wires. This significantly improves the ease of manufacture and
handling and avoids the need for expensive dark room facilities. It
also significantly improves working conditions for those personnel
involved in the manufacturing process and improves the morale of
the manufacturing team.
EXAMPLES
[0069] The method of the invention will be further illustrated with
reference to the following non-limiting Examples.
[0070] In the Examples, those skilled in the art will recognize
that cold (i.e. non-radioactive) iodide can easily be replaced with
radioactive iodide to render any Example germane for radioactive
uses. For example, radioactive iodide solutions are specified with
respect to levels of activity known as the specific activity.
Generally, these activities are as high as 17 Curies/mg of iodide
and may drop to very low levels. Thus, if an Example deposits 10
.mu.g of cold iodide per wire, it is an easy calculation to confirm
that those wires would contain 170 mCi each if the reaction was
carried out using radioactive iodide with a specific activity of 17
Curies/mg iodide.
[0071] In all the Examples, the silver wires used were 2.8 mm long
by 0.5 mm in diameter. Reaction vials were precoated with a
silicone polymer.
Example 1
One Step Preparation of Silver Iodide/Silver Bromide Coated Silver
Wires
[0072] 500 Silver wires, having been cleaned by rinsing with
heptane followed by acetone and dried, were loaded into a squared
(four-sided) glass vial (15 ml) together with 51.5 mg of NaBr (as
0.515 ml of a 100 mg/ml NaBr aqueous stock solution) and 0.126
.mu.L of a 0.1M NaI/0.01 M NaOH solution. The final volume was then
adjusted to 3.5 ml with water for injection. The vial was then
placed into a rotator at a fixed angle of 30 degrees from
horizontal. The rotator was then turned on at 30 rpm and 1 ml of a
41.2 mg/ml aqueous solution of potassium ferricyanide
(K.sub.3Fe(CN).sub.6) was added to the contents of the vial to
initiate the reaction. The resulting pale green solution was
rotated for an hour to complete the reaction.
[0073] Twenty of the resulting wires were individually extracted
with concentrated ammonium hydroxide,overnight to dissolve the
silver halide coating for analysis by ultraviolet
spectrophotometry. While other analytical methods can be
envisioned, this approach afforded rapid, easy analysis with
sufficient sensitivity for assay of each wire. The results show
that the wires were coated with a mixture of silver bromide and
silver iodide with approximate concentrations of 18 .mu.g of
Br.sup.- and 3.2 .mu.g of I.sup.- on each wire. This is more than
sufficient to make wires with activities as high as 100 mCi each
for use in brachytherapy devices, when sufficient amounts of
.sup.125I are used in the reaction.
Example 2
Repetitive Preparation of Silver Iodide/Silver Bromide Coated
Silver Wires
[0074] Five batches of 500 wires were prepared as described in
Example 1. The data for each batch are shown below and demonstrate
excellent reproducibility as well as a narrow standard deviation
for each batch.
6 Average [I-]/wire Relative standard Batch (.mu.g) deviation (%)
1. 4.76 3.1 2. 4.60 4.1 3. 4.72 5.0 4. 4.77 5.0 5. 4.82 4.8 Overall
4.74 4.7
Example 3
One Step Preparation of Silver Iodide/Silver Bromide Coated Silver
Wires Labelled With Ag.sup.125I
[0075] 500 Wires were prepared as described in Example 1 except
that an additional 8 micro Curies of Na.sup.125I were added to the
non-radioactive NaI used in the reaction. Upon completion of the
reaction, the variation in counts between wires (measured as
dpm=disintegrations per minute) was found to be comparable to the
data shown in Example 2. In addition, less than 1% of the total
activity remained in the supernatant liquid suggesting >99%
uptake of iodide ions by the wires in this one step preparation and
no volatilization of the iodide into the atmosphere.
Example 4
One Step Preparation of Silver Iodide Coated Silver Wires
[0076] 500 Wires were prepared as described in Example 1 except
that no NaBr was added to the mixture. While the reaction took
place to form a coating on the silver wires, that coating was not
cohesively stable and began to flake off during the remainder of
the coating process (i.e., the rest of the hour). This indicates
that a binding agent may be necessary to form a cohesively stable
layer containing AgI on a silver substrate.
Example 5
One Step Preparation of Silver Iodide Coated Silver Wires With
Increased Amounts of Iodide on the Wire
[0077] 500 Wires were prepared as described in Example 1 except
that the amount of NaI used was increased to 30 .mu.g/wire (approx
1.18 ml of 0.1 M NaI/0.001M NaOH). The reaction was successful in
depositing both. AgBr and AgI onto the wires. Each wire had an
average amount of 30 .mu.g I/wire.
Example 6
Kinetics of the Uptake of .sup.125I from the Solution Phase in the
Single Step Preparation of Silver Iodide/Silver Bromide Coated
Silver Wires
[0078] 500 Wires were prepared as described in Example 3 using an
additional 8 micro Curies of Na.sup.125I. Samples were taken from
the supernatant liquid at various times to follow the loss of
.sup.125I from the solution phase. These data are expected to
mirror the deposition of .sup.125I onto the wire.
7 Time (min.) Counts (dpm) 1 min 122,242 2 min 27,643 4 min 6,111 8
min 3,179 16 min 3,381 32 min 4,749 64 min 4,595
[0079] (dpm=disintegration per minute)
[0080] These data indicate that >90% of the AgI layer was formed
after the first 2 minutes. The slight increase in counts after 16
min probably resulted from prolonged rotation and tumbling which
can cause physical removal of AgI from the wires.
Example 7
One Step Preparation of Silver Iodide Coated Silver Wires: 1500
Wire Batch Size
[0081] 1500 Wires were prepared as described in Example 1 except
that the amounts of NaI, NaBr, and K.sub.3Fe(CN).sub.6, and the
total reaction volume were increased three fold to account for the
increased number of wires. In addition, a squared (four-sided) 25
ml vial was used to rotate the wires to accommodate the higher
reaction volume (i.e. 13.5 ml). These conditions resulted in wires
with an average amount of iodide per wire of 4.693 .mu.g/wire and a
standard deviation of 0.427 (9.1%, relative standard deviation).
These values compare well with earlier, smaller batches (see
Example 2) and afford advantages of scale.
Example 8
Kinetics of the One Step Preparation of Silver Iodide Coated Silver
Wires: 1500 Wire Batch Size
[0082] 1500 Wires were prepared as described in Example 1 except
that the amounts of NaI, NaBr and K.sub.3Fe(CN).sub.6, and the
total reaction volume were increased three fold to account for the
increased number of wires. In addition, a squared (four-sided) 25
ml vial was used to rotate the wires to accommodate the higher
reaction volume. A small amount of radioactive Na.sup.125I was also
added to afford quantitative assessment of the kinetics. 100
Microlitre aliquots of the supernatant liquid were removed and
counted at various time points to ascertain the kinetics of AgI
formation on the silver wire.
8 Time (min.) Counts (dpm/100 .mu.l) 2 min 13,431 4 min 5,229 8 min
5,186 16 min 5,163
[0083] (dpm=disintegration per minute)
[0084] Again, these data indicate that >90% of the iodide uptake
is over in 2 minutes.
Example 9
One Step Preparation of Silver Iodide Coated Silver Wires: 1500
Wire Batch Size and the Impact of Increased Volume
[0085] 1500 Wires were prepared as described in Example 1 except
that the amounts of NaI, NaBr and K.sub.3Fe(CN).sub.6 were
increased three fold to account for the increased number of wires.
In addition, a squared (four-sided) 25 ml vial was used to rotate
and tumble wires in the higher reaction volume. Experiments were
carried out at total reaction volumes of 6.75 ml and 24 ml. The
data below suggest that increased volumes can result in narrower
distributions of iodide from wire to wire.
9 Volume = 6.75 ml 24.0 ml % relative 11.4 5.0 standard 12.9 3.8
deviation 15.4
Example 10
One Step Preparation of Silver Iodide Coated Silver Wires: 1500
Wire Batch Size and the Impact of Elevated Concentrations of an
Added Salt: NaCl
[0086] 1500 Wires were prepared as described in Example 1 except
that the amount of NaI, NaBr, and K.sub.3Fe(CN).sub.6 were
increased three fold to account for the increased number of wires.
In addition, a square 25 ml vial was used to rotate the wires due
to the added reaction volume. Finally, the solution was made 2 M in
NaCl. The results of replicate preparations at 1500 wires and then
a repeat of a 500 wire batch as per Example 1 suggest that this
level of NaCl has a beneficial effect on the standard
deviation.
10 Relative Standard Deviation With NaCl Without NaCl Number off
Wires/batch = 1500 500 1500 Volume (ml) 4.5 2.7% 6.75 2.7% 11.4%
24.0 2.9% 5.0% 24.0 2.8% 3.8%
[0087] Even at the highest volume studied, the addition of NaCl
leads to the distribution of iodide amongst the wires being very
narrow.
Example 11
Iodination Reaction Using Solid AgI
[0088] Wires were prepared as in Example 1, using 500 wires, 51.5
mg NaBr and 2 M NaCl. However, approximately 35 mg of solid AgI was
substituted for NaI. When approximately 41 mg of ferricyanide was
added (as 1 ml of a 41.2 mg/ml aqueous solution of potassium
ferricyanide), AgBr was formed on the wires and the iodide ions
from the supernatant suspension of AgI exchanged onto the
wires.
[0089] Average: 20.2 .mu.g I/wire
[0090] Standard Deviation: 0.71
[0091] Deviation %: 2.8%
[0092] Thus, the iodide tied up as solid AgI was able to exchange
to the surface of the silver wires as they were oxidized by the
ferricyanide. The variation in the amount of iodide per wire was
very low, suggesting that the slow kinetics of release of iodide
from the AgI suspension is beneficial to the preparation of the
coated wires.
Example 12
One Step Preparation of Silver Iodide Coated Silver Wires: 1500
Wire Batch Size and the Impact of Elevated Concentrations of
NaNO.sub.3
[0093] 1500 wires were prepared as described in Example 1 except
that the amount of NaI was increased to 1.0 ml of 0.1 M NaI/0.1 M
NaOH, the NaBr was increased to 138 mg, and K.sub.3Fe(CN).sub.6 was
increased to 142.2 mg (i.e., 1 ml of a 142.2 mg/ml solution) to
account for the increased number of wires. A square 25 ml vial was
used to rotate the wires. In addition, the solution was made 3.0 M
in NaNO.sub.3. The results suggest that this salt is also effective
in narrowing the distribution of iodide per wire.
[0094] Mean: 12.3 .mu.g I/wire
[0095] Standard Deviation: 0.28
[0096] Deviation %: 2.3%
Example 13
Preparation of Radioactive Seeds
[0097] The method of Example 11 was used to prepare radioactive
seeds in a pilot production run. Four runs were carried out with
the following results:
11 Target* Actual* Computed* Standard Activity Activity Activity
Deviation % Uptake Run # mCi mCi mCi mCi % 1 0.34 0.34 0.31 0.01
92.78 2 0.41 0.45 0.41 0.02 99.02 3 0.34 0.38 0.34 0.01 99.18 4
0.40 0.45 0.40 0.01 98.91
[0098] These data demonstrate the utility of the method of the
invention, with very good uptake and the achievement of target
levels of activity with narrow distributions of activity from wire
to wire.
Example 14
Preparation of Radioactive Seeds 2
[0099] 1334 silver wires, cleaned with heptane and acetone, were
loaded into a square 30 ml glass vial together with 13 ml of an
aqueous solution of sodium chloride (3.43M) and sodium bromide
(0.13M). To this mixture was added 1.08 ml of an aqueous solution
of sodium iodide (0.1M) and sodium hydroxide (0.01M) and 1.25 ml of
an aqueous solution containing 1.278 Ci sodium [.sup.125I]-iodide.
The glass vial was then rotated at an angle of 30.degree. to the
horizontal for not less than 1 minute in order to mix the reagents.
The rotation was then stopped and 1.27 ml of an aqueous solution
prepared from potassium ferricyanide (100 mg/ml) and potassium
ferrocyanide trihydrate (12 mg/ml) was added to the reaction vial.
Rotation was then restarted and continued for 45 minutes (after
which time the solution was clear). The supernatant was removed
with a pipette and the wires were washed three times with deionised
water. They were then allowed to dry before being loaded into
titanium cans, which were subsequently sealed using standard
welding techniques.
[0100] The completed seeds were assayed and found to have a mean
apparent activity of 0.433 mCi with a relative standard deviation
of 1.92%.
Example 15
Preparation of High Activity Radioactive Seeds
[0101] The method of example 14 was used to prepare radioactive
seeds. Four runs were carried out using the following reaction
conditions (volumes of reagents were varied according to batch
size):
12 Volume Volume Number Vial Volume Volume ferro/ .sup.125I- of
volume NaCl/NaBr NaI/NaOH ferri iodide Run wires (ml) (ml) (ml)
(ml) (ml) #245 233 7.5 2.4 0.19 0.23 2.11 #246 178 7.5 2.4 0.15
0.18 2.77 #129 226 7.5 2.4 0.17 0.22 2.48 #130 335 15 3.0 0.25 0.32
3.71
[0102] The results obtained are shown as follows:
13 Mean Standard Activity Deviation Run (mCi) (mCi) % CV #245 4.025
0.0445 1.11 #246 6.352 0.0774 1.22 #129 5.469 0.0550 1.01 #130
5.589 0.0800 1.43
[0103] These data demonstrate the utility of the method of the
invention, in particular, the achievement of narrow distribution of
seed activity in the high activity range.
[0104] It is apparent that many modifications and variations of the
invention as hereinabove set forth may be made without departing
from the spirit and scope thereof. The specific embodiments
described are given by way of example only, and the invention is
limited only by the terms of the appended claims.
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