U.S. patent application number 10/173496 was filed with the patent office on 2003-01-09 for polymer based radionuclide containing particulate material.
Invention is credited to Gray, Bruce Nathaniel.
Application Number | 20030007928 10/173496 |
Document ID | / |
Family ID | 3825030 |
Filed Date | 2003-01-09 |
United States Patent
Application |
20030007928 |
Kind Code |
A1 |
Gray, Bruce Nathaniel |
January 9, 2003 |
Polymer based radionuclide containing particulate material
Abstract
The invention relates to a particulate material having a
diameter in the range of from 5 to 200 microns comprising polymeric
matrix and stably incorporated radionuclide, processes for its
production and a method of radiation therapy utilising the
particulate material.
Inventors: |
Gray, Bruce Nathaniel;
(Claremont, AU) |
Correspondence
Address: |
BAKER & BOTTS
30 ROCKEFELLER PLAZA
NEW YORK
NY
10112
|
Family ID: |
3825030 |
Appl. No.: |
10/173496 |
Filed: |
June 17, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10173496 |
Jun 17, 2002 |
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PCT/AU01/01370 |
Oct 25, 2001 |
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Current U.S.
Class: |
424/9.3 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 51/1251 20130101; A61P 1/16 20180101; A61K 51/06 20130101;
A61K 51/1255 20130101 |
Class at
Publication: |
424/9.3 |
International
Class: |
A61B 005/055 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 25, 2000 |
AU |
PR0983 |
Claims
1. A particulate material having a diameter in the range of from 5
to 200 microns comprising a polymeric matrix and stably
incorporated radionuclide.
2. The particulate material according to claim 1 wherein the
radionuclide is incorporated by precipitation.
3. The particulate material according to claim 1 wherein the
polymeric matrix is partially cross linked.
4. The particulate material according to claim 3 wherein the
polymeric matrix comprises from about 1% to about 20% cross
linking.
5. The particulate material according to claim 4 wherein the
polymeric matrix comprises about 4% cross linking.
6. The particulate material according to claim 1 wherein the
polymeric matrix is an ion exchange resin.
7. The particulate material according to claim 6 wherein the
polymeric matrix is a cation exchange resin.
8. The particulate material according to claim 6 wherein the ion
exchange resin comprises a partially cross linked aliphatic
polymer.
9. The particulate material according to claim 6 wherein the ion
exchange resin comprises a partially cross linked polystyrene.
10. The particulate material according to claim 9 wherein the ion
exchange resin comprises polystyrene partially cross linked with
divinyl benzene.
11. The particulate material according to claim 1, wherein the
radionuclide is an isotope of yttrium, holmium, samarium, iodine,
phosphorus, iridium or rhenium.
12. The particulate material according to claim 1, wherein the
radionuclide is yttrium-90.
13. The particulate material according to claim 1 being a
microsphere.
14. A particulate material having a diameter in the range of from
30 to 35 microns comprising a copolymer comprised of styrene and
divinyl benzene and precipitated yttrium-90.
15. A process for the production of a particulate material
according to claim 1 comprising the step of combining a polymeric
matrix and a radionuclide in solution for a time and under
conditions sufficient to stably incorporate the radionuclide in the
matrix to produce a particulate material having a diameter in the
range of from 5 to 200 microns.
16. A process according to claim 15 wherein the radionuclide is
stably incorporated by precipitation into the polymeric matrix.
17. A process according to claim 15 wherein the radionuclide is
yttrium-90.
18. A method of radiation therapy of a patient, which comprises
administration to the patient of a particulate material having a
diameter in the range of from 5 to 200 microns comprising a
polymeric matrix and a stably incorporated radionuclide.
19. A method according to claim 18 wherein the radionuclide is
yttrium-90.
20. A method according to claim 18 wherein the radiation therapy
comprises treatment of a primary or secondary liver cancer.
21. Use of particulate material having a diameter in the range of
from 5 to 200 microns comprising a polymeric matrix and a stably
incorporated radionuclide in radiation therapy of a patient.
22. Use according to claim 21 wherein the radionuclide is
yttrium-90.
23. Use according to claim 21 wherein the radiation therapy
comprises treatment of a primary or secondary liver cancer.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a particulate material that
comprises a polymer, particularly a polymer and a radionuclide, to
a method for the production thereof, and to methods for the use of
this particulate material.
[0002] In one particular aspect, this invention relates to
microspheres which comprise a polymer and a radionuclide such as
radioactive yttrium, and to the use of these microspheres in the
treatment of cancer in humans and other mammals.
[0003] The particulate material of this invention is designed to be
administered into the arterial blood supply of an organ to be
treated, whereby it becomes entrapped in the small blood vessels of
the target organ and irradiates it. An alternate form of
administration is to inject the polymer based particulate material
directly into the target organ or a solid tumour to be treated.
[0004] The particulate material of the present invention therefore
has utility in the treatment of various forms of cancer and
tumours, but particularly in the treatment of primary and secondary
cancer of the liver and the brain. It is to be understood that the
particulate material of the invention is not limited to radioactive
microspheres, but may be extended to other radioactive polymeric
particles which are suitable for use in the treatment methods
described herein.
BACKGROUND OF THE INVENTION
[0005] Many previous attempts have been made to locally administer
radioactive materials to patients with cancer as a form of therapy.
In some of these, the radioactive materials have been incorporated
into small particles, seeds, wires and similar related
configurations that can be directly implanted into the cancer. When
radioactive particles are administered into the blood supply of the
target organ, the technique has become known as Selective Internal
Radiation Therapy (SIRT). Generally, the main form of application
of SIRT has been its use to treat cancers in the liver.
[0006] There are many potential advantages of SIRT over
conventional, external beam radiotherapy. Firstly, the radiation is
delivered preferentially to the cancer within the target organ.
Secondly, the radiation is slowly and continually delivered as the
radionuclide decays. Thirdly, by manipulating the arterial blood
supply with vasoactive substances (such as Angiotensin-2), it is
possible to enhance the percentage of radioactive particles that go
to the cancerous part of the organ, as opposed to the healthy
normal tissues. This has the effect of preferentially increasing
the radiation dose to the cancer while maintaining the radiation
dose to the normal tissues at a lower level (Burton, M. A. et al.;
Effect of Angiotensin-2 on blood flow in the transplanted sheep
squamous cell carcinoma. Europ. J. Cancer Clin. Oncol. 1988,
24(8):1373-1376).
[0007] When microspheres or other small particles are administered
into the arterial blood supply of a target organ, it is desirable
to have them of a size, shape and density that results in the
optimal homogeneous distribution within the target organ. If the
microspheres or small particles do not distribute evenly, and as a
function of the absolute arterial blood flow, then they may
accumulate in excessive numbers in some areas and cause focal areas
of excessive radiation. It has been shown that microspheres of
approximately 25-50 micron in diameter have the best distribution
characteristics when administered into the arterial circulation of
the liver (Meade, V. et al.; Distribution of different sized
microspheres in experimental hepatic tumours. Europ. J. Cancer
& Clin. Oncol. 1987, 23:23-41).
[0008] If the particles are too dense or heavy, then they will not
distribute evenly in the target organ and will accumulate in
excessive concentrations in areas that do not contain the cancer.
It has been shown that solid, heavy microspheres distribute poorly
within the parenchyma of the liver when injected into the arterial
supply of the liver. This, in turn, decreases the effective
radiation reaching the cancer in the target organ, which decreases
the ability of the radioactive microspheres to kill the tumour
cells. In contrast, lighter microspheres with a specific gravity of
the order of 2.0 distribute well within the liver (Burton, M. A. et
al.; Selective International Radiation Therapy; Distribution of
radiation in the liver. Europ. J. Cancer Clin. Oncol. 1989,
25:1487-1491).
[0009] For radioactive particulate material to be used successfully
for the treatment of cancer, the radiation emitted should be of
high energy and short range. This ensures that the energy emitted
will be deposited into the tissues immediately around the
particulate material and not into tissues which are not the target
of the radiation treatment. In this treatment mode, it is desirable
to have high energy but short penetration beta-radiation which will
confine the radiation effects to the immediate vicinity of the
particulate material. There are many radionuclides that can be
incorporated into microspheres that can be used for SIRT. Of
particular suitability for use in this form of treatment is the
unstable isotope of yttrium (Y-90). Yttrium-90 decays with a half
life of 64 hours, while emitting a high energy pure beta radiation.
However, other radionuclides may also be used in place of
yttrium-90 of which the isotopes of holmium, samarium, iodine,
iridium, phosphorus, rhenium are some examples.
[0010] Ceramic particles have been produced that are either coated
with or contain radionuclides. However, the presence of other
radioactive substances that are not required for the radiation
treatment of the target tissue, has then unwanted and deleterious
radiation effects may occur. It is therefore desirable to have
particulate material of such a composition that it only contains
the single desired radionuclide.
[0011] In the earliest clinical use of yttrium-90 containing
microspheres, the yttrium was incorporated into a polymeric matrix
that was formulated into microspheres. While these microspheres
were of an appropriate density to ensure good distribution
characteristics in the liver, there were several instances in which
the yttrium-90 leached from the microspheres and caused
inappropriate radiation of other tissues. Attempts to incorporate
other radionuclides such as holmium into resin or polymer based
materials have resulted in leaching of the radionuclide and this
has resulted in severe consequences for the patients that have been
treated with the product.
[0012] In one attempt to overcome the problem of leaching, a
radioactive microsphere comprising a biologically compatible glass
material containing a beta- or gamma-radiation emitting
radioisotope such as yttrium-90 distributed throughout the glass,
has been developed (International Patent Publication No. WO
86/03124). These microspheres are solid glass and contain the
element yttrium-89 that can be activated to the radionuclide
yttrium-90 by placing the microspheres in a neutron beam. These
glass microspheres have several disadvantages including being of a
higher specific gravity than is desirable and containing other
elements such as alumina and silica which are activated to
undesirable radionuclides when placed in a neutron beam.
[0013] Another approach has been focussed on the use of small
hollow or cup-shaped ceramic particles or microspheres, wherein the
ceramic base material consists or comprises yttria or the like
(International Patent Publication No. WO 95/19841). These
microspheres were developed to overcome the problem of high density
associated with the solid glass microspheres described in
International Patent Publication No. WO86/03124.
SUMMARY OF THE INVENTION
[0014] In one aspect the present invention provides a particulate
material having a diameter in the range of from 5 to 200 microns
comprising a polymeric matrix and a stably incorporated
radionuclide.
[0015] In another aspect, the invention provides a process for the
production of a particulate material having a diameter in the range
of from 5 to 200 microns comprising the step of combining a
polymeric matrix and a radionuclide for a time and under conditions
sufficient to stably incorporate the radionuclide in the matrix to
produce a particulate material having a diameter in the range of
from 5 to 200 microns.
[0016] In another aspect, the present invention provides a method
of radiation therapy of a patient, which comprises administration
to the patient of a particulate material having a diameter in the
range of from 5 to 200 microns comprising a polymeric matrix and a
stably incorporated radionuclide.
[0017] The present invention also provides for the use of
particulate material having a diameter in the range of from 5 to
200 microns comprising a polymeric matrix and a stably incorporated
radionuclide in the radiation therapy of a patient.
DETAILED DESCRIPTION OF THE INVENTION
[0018] As used herein, references to the radionuclide being stably
incorporated into particulate material or polymeric matrix are to
be understood as referring to incorporation of the radionuclide so
that it does not substantially leach out of the particulate
material under physiological conditions such as in the patient or
in storage. In a preferred embodiment the radionuclide is
incorporated by precipitation into a polymeric matrix.
[0019] The leaching of radionuclides from the polymeric matrix can
cause non-specific radiation of the patient and damage surrounding
tissue. Preferably the amount of leaching is less than 5%, more
preferably less than 4%, 3%, 2%, 1% or 0.4%. One method of
assessing leaching is by adjusting a sample to pH 7.0 and agitating
in a water bath at 37.degree. C. for 20 minutes. A 100 .mu.L sample
is counted for beta emission in a Geiger-Muller counter. Another
representative 100 .mu.L sample is filtered through a 0.22 .mu.m
filter and the filtrate counted for beta emission in the
Geiger-Muller counter. The percent unbound radionuclide is
calculated by: 1 FiltrateCount SampleCount .times. 100 = %
UnboundRadionuclide
[0020] The radionuclide can be stably incorporated into the
polymeric matrix by precipitating it as an insoluble salt. Where
the radionuclide used is yttrium-90 the yttrium is preferably
precipitated as a phosphate salt. However the present invention
also extends to precipitation of the radionuclide as other
insoluble salts including, for example, carbonate and bicarbonate
salts. The radionuclide which is incorporated into the polymeric
matrix in accordance with the present invention is preferably
yttrium-90, but may also be any other suitable radionuclide which
can be precipitated in solution, of which the isotopes of holmium,
samarium, iodine, phosphorous, iridium and rhenium are some
examples.
[0021] In a preferred embodiment the particulate material is a
microsphere. The term microsphere is used in this specification as
an example of a particulate material, it is not intended to limit
the invention to microspheres, as the person skilled in the art
will appreciate that the shape of the particulate material while
preferably without sharp edges or points that could damage the
patients arteries or catch in unintended locations, is not limited
to spheres. Nor should the term microsphere be limited to spheres.
Preferably the particulate material is substantially spherical, but
need not be regular or symmetrical in shape.
[0022] In a preferred embodiment the polymeric matrix is partially
cross linked. Preferably there is about 1% to about 20% cross
linking, preferably about 2% to 10% cross linking and more
preferably about 4% cross linking.
[0023] In particular, the present invention provides a particulate
material as described above in which the polymeric matrix is an ion
exchange resin, particularly a cation exchange resin. Preferably
the ion exchange resin comprises a partially cross linked aliphatic
polymer, including polystyrene. One particularly preferred cation
exchange resin is the styrene/divinylbenzene copolymer resin
commercially available under the trade name Aminex 50W-X4 (Biorad,
Hercules, Calif.). However, there are many other commercially
available cation exchange resins which are suitable.
[0024] When small particles are administered into the arterial
blood supply of a target organ, it is desirable to have them of a
size, shape and density that results in the optimal homogeneous
distribution within the target organ. If the small particles do not
distribute evenly then they may accumulate in excessive numbers in
some areas and cause focal areas of excessive radiation. The
particulate material is preferably low density, more particularly a
density below 3.0 g/cc, even more preferably below 2.8 g/cc, 2.5
g/cc, 2.3 g/cc, 2.2 g/cc or 2.0 g/cc. The ideal particle for
injection into the blood stream would have a very narrow size range
with a SD of less than 5%, so as to assist in even distribution of
the microspheres within the target organ, particularly within the
liver and would be sized in the range 5-200 micron preferably
15-100 micron and preferably 20-50 micron, and most preferably
30-35 micron.
[0025] It is also desirable to have the particulate material
manufactured so that the suspending solution has a pH less than 9.
If the pH is greater than 9 then this may result in irritation of
the blood vessels when the suspension is injected into the artery
or target organ. Preferably the pH is less than 8.5 or 8.0 and more
preferably less than 7.5.
[0026] The present invention particularly provides a method for the
production of a radioactive particulate material comprising a
polymeric matrix as described above, characterised by the steps
of:
[0027] (i) absorbing a radionuclide onto an ion-exchange resin
particulate material having a diameter in the range of 20 to 50
microns and a specific gravity of less than 2.5; and
[0028] (ii) precipitating the radionuclide as an insoluble salt to
stably incorporate the radionuclide into the particulate
material.
[0029] In a preferred embodiment, the method of the present
invention is carried out by firstly irradiating yttria (yttrium
oxide) in a neutron beam to activate yttria to the isotope
yttrium-90. The yttrium-90 oxide is then solubilised, for example
as yttrium-90 sulphate solution. The ion exchange resin is
preferably provided in the form of an aqueous slurry of
microspheres of ion exchange resin having a particle size 30 to 35
microns, and the yttrium-90 sulphate solution is added to the
slurry to absorb the yttrium-90 into the ion exchange resin
microspheres. Subsequently, the yttrium-90 is precipitated as a
phosphate salt, for example by addition of tri-sodium phosphate
solution, to stably incorporate the yttrium-90 into the
microspheres. The particulate material may be combined with a
solution of the radionuclide or the salt of the radionuclide may be
combined with the particulate matter, in a solution suitable for
solubilising the radionuclide.
[0030] Alternate sources of yttrium-90 may be used in the
production of these microspheres. For example, a highly pure source
of yttrium-90 may be obtained by extracting yttrium-90 from a
parent nuclide and using this extracted yttrium-90 as the source of
the soluble yttrium salt that is then incorporated into the
polymeric matrix of the microspheres.
[0031] In order to decrease the pH of the suspension containing the
microspheres for injection into patients the microspheres may be
washed to remove any un-precipitated or loosely adherent
radionuclide. The present invention provides a suspension of the
required pH by precipitating the yttrium with a tri-sodium
phosphate solution at a concentration containing at least a
three-fold excess of phosphate ion, but not exceeding a 30-fold
excess of phosphate ion, and then washing the microspheres with
de-ionised water. Another approach which ensures that the pH of the
microsphere suspension is in the desired range is to wash the resin
with a phosphate buffer solution of the desired pH.
[0032] The present invention also provides a method of radiation
therapy of a human or other mammalian patient that comprises
administration to the patient of particulate material as described
above. The person skilled in the art will appreciate the
administration may be by any suitable means and preferably by
delivery to the relevant artery. For example in treating liver
cancer, administration is preferably by laparotomy to expose the
hepatic artery or by insertion of a catheter into the hepatic
artery via the femoral, or brachial artery. Pre or
co-administration of another agent may prepare the tumour for
receipt of the particulate material, for example a vasioactive
substance, such as angiotension-2 to redirect arterial blood flow
into the tumour. Delivery of the particulate matter may be by
single or multiple doses, until the desired level of radiation is
reached.
[0033] Throughout this specification, unless the context requires
otherwise, the word "comprise", and or variations such as
"comprises" or "comprising", will be understood to imply the
inclusion of a stated integer or step or group of integers or steps
but not the exclusion of any other integer or step or group of
integers or steps.
[0034] Further features of the present invention are more fully
described in the following Examples. It is to be understood,
however, that this detailed description is included solely for the
purposes of exemplifying the present invention, and should not be
understood in any way as a restriction on the broad description of
the invention as set out above.
EXAMPLE 1
[0035] Yttrium (90Y) labelled microspheres are made in the form of
a sterile, pyrogen free suspension of resin beads labelled with
yttrium (90Y) phosphate. The resin beads consist of sulphuric acid
groups attached to a styrene divinylbenzene copolymer lattice.
[0036] Yttrium oxide is irradiated to produce yttrium-90 from the
nuclear reaction Y-89 (n, .gamma.) Y-90. Yttrium-90 has a half life
of 64 hours. The yttrium (90Y) oxide is then dissolved in 0.1M
sulphuric acid with gentle heating and stirring to form a clear,
colourless solution of yttrium (90Y) sulphate.
[0037] Symmetrical microspheres of ion exchange resin (Aminex
50W-X4 cation exchange resin; supplied by `Bio-Rad Cat # 1474313`)
with a diameter of approximately 30 to 35 microns are added to
water (Water for injections BP) to form a slurry that is then
transferred into a reaction vessel. Yttrium (90Y) sulphate solution
is added to the reaction vessel and the mixture stirred at a speed
sufficient to ensure homogeneity to absorb the yttrium (90Y)
solution into the resin-based microspheres. Tri-sodium phosphate
solution (1.25% w/v) is then added to the reaction vessel with
further stirring to precipitate the radionuclide as yttrium (90Y)
phosphate.
[0038] The microspheres are then washed with a phosphate buffer
solution until the pH of the wash solution is less than 9 and
preferable less than 8.5. Following washing of the microspheres
with water (Water for Injection BP), the microspheres are
resuspended and diluted (if necessary) with water (Water for
Injections BP) to give a light brown suspension having an activity
of 3000 MBq .quadrature.10%.
[0039] The resin-based yttrium microspheres produced by the above
method have 0.01-0.4% unbound or unprecipitated 90Y when tested in
the following leaching test:
[0040] A 5 .mu./L sample is diluted with water to 5 mL, adjusted to
pH 7.0 and agitated in a water bath at 37.degree. C. for 20
minutes. A 100 .mu.L sample is counted for beta emission in a
Geiger-Muller counter. Another representative 100 .mu.L sample is
filtered through a 0.22 .mu.m filter and the filtrate counted for
beta emission in the Geiger-Muller counter. The percent unbound 90Y
is calculated by:
FiltrateCount/SampleCount.times.100=% Unbound.sup.90Y
EXAMPLE 2
[0041] The effect of phosphate concentration in the precipitation
solution, and the effects of washing with phosphate buffer on the
pH of a microsphere suspension are shown in the attached FIG. 1
which sets out the results of a number of experiments.
EXAMPLE 3
[0042] The technique of Selective Internal Radiation Therapy (SIRT)
has been described above. It involves either a laparotomy to expose
the hepatic arterial circulation or the insertion of a catheter
into the hepatic artery via the femoral, brachial or other suitable
artery. This may be followed by the infusion of Angiotensin-2 into
the hepatic artery to redirect arterial blood to flow into the
metastatic tumour component of the liver and away from the normal
parenchyma.
[0043] This is followed by embolisation of resin based yttrium-90
containing microspheres (produced in accordance with Example 1)
into the arterial circulation so that they become lodged in the
microcirculation of the tumour. Repeated injections of microspheres
are made until the desired radiation level in the normal liver
parenchyma is reached. By way of example, an amount of yttrium-90
activity that will result in an inferred radiation dose to the
normal liver of approximately 80 Gy may be delivered. Because the
radiation from SIRT is delivered as a series of discrete point
sources, the dose of 80 Gy is an average dose with many normal
liver parenchymal cells receiving much less than that dose.
[0044] The measurement of tumour response by objective parameters
including reduction in tumour volume and serial estimations of
serum carcino-embryonic antigen (CEA) levels, is an acceptable
index of the ability of the treatment to alter the biological
behaviour of the tumour.
* * * * *