Title: Low density radionuclide-containing particulate material
Abstract: The invention relates to a particulate material consisting of a low density radiation-tolerant glass and a radionuclide incorporated into the low density glass or coated on the low density glass, the glass having a density of less than 2.5 g/cm3, processes for its production and a method of radiation therapy utilising the patentable material.
Patent Number: 6,998,105 Issued on 02/14/2006 to Ruys, et al.
| Inventors:
|
Ruys; Andrew John (Pymble, AU);
Gray; Bruce Nathaniel (Claremont, AU)
|
| Assignee:
|
Sirtex Medical Limited (New South Wales, AU)
|
| Appl. No.:
|
173497 |
| Filed:
|
June 17, 2002 |
Foreign Application Priority Data
| Current U.S. Class: |
424/1.37; 424/1.11; 424/1.29; 424/1.33; 424/1.65 |
| Current Intern'l Class: |
A61K 51/00 (20060101) |
| Field of Search: |
424/111,129,133,137,165,93,94,95,400,450
128/662.02,660.01,653.1
|
References Cited [Referenced By]
U.S. Patent Documents
| 4889707 | Dec., 1989 | Day et al.
| |
| 5362473 | Nov., 1994 | Panek.
| |
| 5885547 | Mar., 1999 | Gray.
| |
| 6149889 | Nov., 2000 | Chin et al.
| |
| 6258338 | Jul., 2001 | Gray.
| |
| 6537518 | Mar., 2003 | Gray.
| |
| 2002/0197207 | Dec., 2002 | Ruys et al.
| |
| 2003/0203205 | Oct., 2003 | Bi et al.
| |
| Foreign Patent Documents |
| 8603124 | Jun., 1986 | WO.
| |
| 9519841 | Jul., 1995 | WO.
| |
| 0045826 | Aug., 2000 | WO.
| |
Other References
Shepherd, F. et al., Cancer, vol. 70, No. 9, pp. 2250-2254 (Nov. 1, 1992).
Burton, M.A. et al., Europ. J. Cancer Clin. Oncol., 25:1487-1491 (1989).
Burton, M.A. et al., Europ. J. Cancer Clin. Oncol., 24(8):1373-1376 (1988).
Meade, V. et al., Europ. J. Cancer Clin. Oncol., 23:37-41 (1987).
|
Primary Examiner: Jones; Dameron L.
Attorney, Agent or Firm: Merchant & Gould PC
Parent Case Text
This application is a continuation of PCT/AU01/01369, filed Oct. 25, 2001.
Claims
The invention claimed is:
1. A particulate material comprising a low density radiation-tolerant glass and
one or two radionuclides incorporated into the low density glass, the glass having
a density of less than 2.5 g/cm
3, wherein the radionuclide is an isotope
selected from the group consisting of holmium, samarium, iodine, iridium, rhenium,
and yttrium, and wherein the low density glass comprises SiO
2 and B
2O
3,
and the weight percentage of [SiO
2+B
2O
3] in the
glass is at least 70%.
2. The particulate material according to claim 1, wherein the density of the
glass is less than 2.4 g/cm
3.
3. The particulate material according to claim 1, wherein low density glass comprises
from 95% to 100% SiO
2.
4. The particulate material according to claim 1, wherein the weight percentage
of [SiO
2+B
2O
3] in the glass is at least 80%.
5. The particulate material according to claim 1, wherein the SiO
2
content of the glass is at least 60% by weight, and the B
2O
3 content
is at least 10% by weight.
6. The particulate material according to claim 1, wherein the composition of
the glass is 72% SiO
2, 25% B
2O
3, 1% Al
2O
3,
0.5% Li
2O 0.5% Na
2O and 1% K
2O.
7. The particulate material according to claim 1, which is a microsphere having
a diameter in the range of from 5 to 200 microns.
8. The particulate material according to claim 7, wherein the diameter is in
the range of from 15 to 100 microns.
9. The particulate material according to claim 1, wherein the radionuclide is yttrium-90.
10. A process for the production of a particulate material according to claim
1 comprising melting together a low density radiation-tolerant glass and a radionuclide
or radionuclide precursor and solidifying the melt to produce a particulate material,
and then if necessary activating the precursor to form the radionuclide.
11. The process according to claim 10, wherein the radionuclide is yttrium-90.
12. A method of radiation therapy of a patient, which comprises administration
to the patient of a particulate material according to claim 1.
13. The method according to claim 12, wherein the radionuclide is yttrium-90.
14. The method according to claim 12, wherein the radiation therapy comprises
treatment of a primary or secondary liver cancer.
15. The particulate material according to claim 1, wherein the density of the
glass is less than 2.3 g/cm
3.
16. The particulate material according to claim 1, wherein the density of the
glass is less than 2.2 g/cm
3.
17. The particulate material according to claim 1, wherein the weight percentage
of [SiO
2+B2O
3] in the glass is at least 85%.
18. The particulate material according to claim 1, wherein the weight percentage
of [SiO
2+B2O
3] in the glass is at least 90%.
19. The particulate material according to claim 7, wherein the diameter is in
the range of from 20 to 50 microns.
20. The particulate material according to claim 7, wherein the diameter is in
the range of from 30 to 35 microns.
Description
FIELD OF THE INVENTION
This invention relates to a particulate material comprising a low density inorganic
glass material containing a radionuclide either within the matrix of the material
or coated onto the surface, to a method for the production thereof, and to methods
for the use of this particulate material.
In one particular aspect, this invention relates to a low-density inorganic glass
microspheres that are loaded with or coated with a radionuclide such as radioactive
yttrium, and to the use of these low-density radionuclide-containing microspheres
in the treatment of cancer in humans and other mammals. In this aspect, the low-density
inorganic microspheres of the invention are designed to be administered into the
arterial blood supply an organ to be treated, whereby they become entrapped in
the small blood vessels of the target organ and irradiate it. The low density is
necessary in order for the microspheres to be able to be transported into the target
organ by blood flow.
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 particles which are suitable for use in
the treatment methods described herein.
BACKGROUND OF THE INVENTION.
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.
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).
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 result 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).
If the microspheres or small particles do not contain sufficient ionising radiation,
then an excessive number will be required to deliver the required radiation dose
to the target organ. It has been shown that if large numbers of microspheres are
administered into the arterial supply of the liver, then they accumulate in and
block the small arteries leading to the tumour, rather than distribute evenly in
the capillaries and precapillary arterioles of the tumour.
Therefore, it is desirable to use the minimum number of microspheres that
will provide an even distribution in the vascular network of the tumour circulation.
If the microspheres or small particles are too dense or heavy, then they will
not distribute evenly in the target organ and will accumulate in excessive concentrations
in parts of the liver that do not contain the cancer. Heavy microspheres, particularly
microspheres with a density greater than about 2.3, can be difficult to deliver
through infusion tubing as they settle within the tubing unless the injection force
is great and the flow rate of the suspending fluid is high. High pressures and
fast delivery flow rates are absolutely contra-indicated when infusing radioactive
microspheres into the hepatic artery of patients as the microspheres will reflux
back into inappropriate blood vessels such as the gastro-duodenal artery, splenic
artery and left gastric artery. This will result in severe and even fatal consequences.
In addition, high density microspheres do not distribute evenly within the target
organ and settle heterogeneously within the tissues. 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 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).
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.
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 homogeneously throughout the
glass as one of the glass component oxides, has been developed (International Patent
Publication No. WO 86/03124). These microspheres are solid high density glass and
contain the element yttrium-89 as a component of the glass, which 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 density
than is desirable, i.e., more than 2.5 g/cm
3, and containing significant
amounts of other elements such as glass modifier oxides and fluxing oxides which
are activated to undesirable radionuclides when placed in a neutron beam. This
is as result of the glass composition used to produce the microspheres. It has
also been shown in clinical studies of patients that pre-treatment imaging with
technetium-99 labelled microspheres cannot be used to predict the behaviour of
these solid glass microspheres. As pre-treatment imaging and dosimetry is very
commonly used when treating patients with SIRT, this is a distinct disadvantage
of the solid glass microspheres described in International Patent Publication No.
WO 86/03124. These glass microspheres have also been shown to lodge in inappropriate tissues.
There have been several reports of clinical studies on the use of solid glass
radioactive microspheres. In one report, ten patients with primary hepatocellular
carcinoma were treated, however no patient had a complete or partial response (Shepherd,
F. et al.,
Cancer, Nov. 1, 1992, Vol.70, No.9, pp 2250-2254).
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 (see International Patent Application No. PCT/AU95/00027;
WO 95/19841). These microspheres were developed to overcome the high density problem
associated with the solid glass microspheres.
For radioactive microspheres to be used successfully for the treatment of cancer,
the radiation emitted from the microspheres should be of high energy and short
range. This ensures that the energy emitted from the microspheres will be deposited
into the tissues immediately around the microspheres and not into tissues which
are not the target of the radiation treatment. 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 isotopes of yttrium
(Yttrium-90). Yttrium-90 is the unstable isotope of yttrium-89 that can be manufactured
by placing the stable yttrium-89 in a neutron beam. The yttrium-90 that is generated
decays with a half life of 64 hours, while emitting a high energy pure beta radiation.
Other candidate radionuclides for this invention include but are not restricted
to holmium, iodine, phosphorous, iridium, rhenium, and samarium.
If the microspheres contain other radioactive substances that are not required
for the radiation treatment of the target tissue, then unwanted and deleterious
radiation effects may occur. It is therefore desirable to have microspheres of
such a composition that they only emit radiation of the desired type to achieve
the therapeutic effect. In this treatment mode, it is desirable to have microspheres
that emit high energy but short penetration beta-radiation that will confine the
radiation effects to the immediate vicinity of the microspheres.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a particulate material comprising
a low density radiation-tolerant glass and a radionuclide incorporated into the
low density glass or coated on the low density glass, the glass having a density
of less than 2.5 g/cm
3.
Preferably, the low density glass comprises SiO
2 and B
2O
3
and the weight percentage of [SiO
2+B
2O
3]
in the glass is at least 70%, more preferably at least 80%, 85% or even 90%. Preferably,
the SiO
2 content of the glass is at least 60% by weight, and the B
2O
3
content is at least 10% by weight.
The present invention also provides a method of radiation therapy of a patient
which comprises administration to the patient of a particulate material as discussed above.
The present invention also provides for the use of a particulate material as
discussed above in radiation therapy of a patient.
In another aspect, the present invention provides a process for the production
of a particulate material as described above comprising melting together a low
density radiation-tolerant glass and a radionuclide and solidifying the melt to
produce a particulate material. Alternatively, the melt may include a radionuclide
precursor which is subsequently activated to form the radionuclide.
Alternatively, the present invention provides a process comprising
the steps of forming a low density radiation-tolerant glass core and coating the
core with a radionuclide. Alternatively, the core may be coated with a radionuclide
precursor which is subsequently activated to form the radionuclide.
DETAILED DESCRIPTION OF THE INVENTION
The particulate material of this invention is a low density material having a
density of less than 2.5 g/cm
3. Preferably the material has a density
of less than 2.4, more preferably less than 2.3 or even 2.2 g/cm
3. Such
low density material contains little or none of the fluxing oxides and modifier
oxides that may be activated to undesirable radionuclides when placed in a neutron beam.
Preferably, the particulate material comprises microspheres having a
diameter in the range of from 5 to 200 microns, more particularly 15 to 100 microns.
Particularly preferred are microspheres in the range of 20 to 50 microns, especially
from 30 to 35 microns.
As previously described, the low density glass preferably comprises SiO
2
and B
2O
3, with the weight percentage of [SiO
2+B
2O
3]
in the glass being at least 70%, preferably at least 80% or even at least 90%.
Suitable low density glasses are set out by way of example in the following Table:
| position |
Density |
SiO2 |
Al2O3 |
B2O3 |
Li2O |
Na2O |
K2O |
Y2O3 |
|
| 1 |
2.27 |
75 |
2 |
15 |
|
4 |
2 |
2 |
| 2 |
2.24 |
66 |
3 |
22 |
|
4 |
3 |
2 |
| 3 |
2.24 |
67 |
2 |
23 |
|
6 |
|
2 |
| 4 |
2.29 |
66 |
3 |
18 |
1 |
1 |
9 |
2 |
| 5 |
2.13 |
71 |
1 |
24 |
.5 |
.5 |
1 |
2 |
| 6 |
2.26 |
80 |
2 |
12 |
|
4 |
|
2 |
| 7 |
2.23 |
79 |
2 |
13 |
|
4 |
|
2 |
| 8 |
2.24 |
77 |
2 |
15 |
|
3 |
1 |
2 |
| 9 |
2.24 |
64 |
5 |
22 |
|
7 |
|
2 |
| 10 |
2.16 |
64 |
5 |
26 |
1 |
2 |
|
2 |
| 11 |
2.23 |
79 |
2 |
13 |
|
4 |
|
2 |
|
In each case, the formulation is in weight percent oxide.
One particularly preferred low density glass composition is a composition containing
72% SiO
2, 25% B
2O
3, 1% Al
2O
3,
0.5% Li
2O, 0.5% Na
2O and 1% K
2O, which has a true
density of 2.13 g/cm
3.
Yttria is a dense ceramic (5.0 g/cm
3), however yttria can be successfully
incorporated into the glass composition in small amounts, either into the matrix
of the glass or as a surface coating, while maintaining the density of the particulate
material less than 2.5 g/cm
3.
In a further embodiment of this invention, the low density glass may comprise
from 95% to 100% SiO
2. In this instance, the radionuclide is incorporated
onto the microsphere as a surface coating, rather than being incorporated into
the matrix of the glass.
The radionuclide which is incorporated into particulate material in accordance
with the present invention is preferably yttrium-90.
If the particulate material contains other radioactive substances that are not
required for the radiation treatment of the target tissue, then unwanted and deleterious
radiation effects may occur. It is therefore preferably to have the particulate
material of such a composition that it contains a single desired radionuclide.
In a treatment mode, it is preferably emit high energy but short penetration beta-radiation
which will confine the radiation effects to the immediate vicinity. For this purpose,
yttrium-90 is a preferred radionuclide. Yttrium-90 has a half life of 64 hours
and emits β 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.
In some situations, it may be desirable to incorporate a second radionuclide,
for example one that will have a specific gamma emission so that the gamma emission
can be used for either dosimetry or imaging using a gamma camera. Such a gamma
emission will be in addition to the emission of the primary therapeutic radionuclide
in the particulate material of this invention.
Preferably, the particulate material of this invention is in the form
of low density glass microspheres. The radionuclide (or radionuclide precursor
such as yttrium-89) can be incorporated into the low density glass by mixing powdered
yttria to the powdered base materials of the glass and melting all the components
together to form a liquid composite material that is cooled to form a solid. The
solid composite material is then crushed to the desired size and the frit suitably
heated to spheroidise the particles. The particles are then sized to collect the
microspheres with the desired size range. By limiting the amount of yttria or other
radionuclide that is added to the base material or is applied as a coating, the
final microsphere density can be limited to less than 2.5, 2.4, 2.3 or 2.2.
As an alternative to incorporating the yttria or other radionuclide into the
matrix
of the microspheres, the radionuclide (or radionuclide precursor) can be coated
onto the surface of the microsphere matrix by a number of means including:
- (i) the radionuclide may be deposited onto the microsphere cores using
finely-divided solid radionuclide material, such as a yttria colloidal sol. Adhesion
in this case will be via electrostatic forces such as heterocoagulation, followed
by permanent fixation by solid state diffusion via heat-treatment methods; or
- (ii) the radionuclide may be deposited onto the microsphere cores using
a gas-entrained radionuclide precursor, for example an aerosol utilising an electrostatic
attachment mechanism, or a radionuclide precursor vapour such as a sputter-coating
process, chemical vapour deposition process, or physical vapour deposition process; or
- (iii) the radionuclide may be deposited onto the glass microspheres
using a radionuclide precursor solution, for example a solution of radionuclide
salt, or a solution of radionuclide alkoxide or other radionuclide organometallic.
Adhesion in this case would be via precipitation of an insoluble film that may
or may not be subjected to a post-coating heat-treatment procedure for the purposes
of enhancing fixation.
Preferably, the radionuclide is stably incorporated onto non-porous low-density
glass microspheres by precipitating it from a chemical solution of radionuclide
precursor, however the present invention also extends to coating from a vapour
or solid radionuclide source.
As used herein, references to the radionuclide being stably incorporated into
the glass microspheres are to be understood as referring to incorporation of the
radionuclide so that it does not leach out of, or spall from, the microspheres
under physiological conditions, such as in the patient or in storage.
Where a radionuclide precursor such as yttrium-89 is either incorporated into
low density glass or is coated on the surface of glass microspheres, it is then
made radioactive by neutron-irradiation or other technique.
Since the radionuclide is stably incorporated into or onto the microspheres,
the present invention provides microspheres with improved characteristics arising
from the fact that they can be formulated to be of such a size, shape and density
that they have improved distribution characteristics when administered into the
arterial supply of target organs to be treated. Preferably, the microspheres are
formulated in substantially spherical form and have a preferred diameter in the
range of from 15 to 100 microns, preferably from 20-50 micron and more preferably
from 30 to 35 microns. The size of the microspheres should be as uniform as possible
to achieve best results in subsequent use. The microspheres are also formulated
to have a specific gravity of less than 2.5 so as to assist in even distribution
of the microspheres within the target organ, particularly within the liver.
The present invention also provides a method of radiation therapy of a human
or other mammalian patient, which comprises administration to the patient of a
particulate material as described above.
In yet another aspect, this invention also extends to the use of a particulate
material as described above in radiation therapy of a human or other mammalian patient.
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.
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
High-purity oxide components are batched in accordance with the following
glass composition given in percentages by weight: 72% SiO
2, 25% B
2O
3,
1% Al
2O
3, 0.5% Li
2O, 0.5% Na
2O, 1%
K
2O, a glass composition which has a specific gravity of 2.13. To this
is added the required amount of yttria or other required radionuclides and the
mixture of parent oxides is smelted in a contamination-free crucible, homogenised,
and then quenched in demineralised water to produce the frit. The frit is then
ground and sieved to yield a 20 to 50 micron size range fraction. This sieved frit
is then flame spheroidised by passing the powder from a feed hopper through a flame
torch. The resultant product is sieved into the 30 to 35 micron size range fraction.
If the microspheres are to be surface coated with a radionuclide such as yttria
instead of incorporating it into the matrix of the microsphere, then the exact
same steps are taken with the exception that the radionuclide is not added to the
components that form the matrix. In this case a one wt % suspension of the microspheres
in alcohol is prepared and placed in a beaker on a magnetic stirrer inside a glove
box. Yttrium alkoxide or other material that will produce the required radionuclide
is added at an amount necessary to produce a surface coating, eg., an amount such
that the yttria yield from the yttrium alkoxide is 2.4 wt % of the weight of microspheres.
After a period of mixing, the yttrium alkoxide is hydrolysed. The microspheres
are then rinsed with three repeats, and then dried.
The coated microspheres are then irradiated in a neutron beam, sterilised, and
packed in a sterile tube.
EXAMPLE 2
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. This is followed
by embolisation of yttrium-90 coated 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.
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.
*
