U.S. patent application number 17/167494 was filed with the patent office on 2021-05-27 for radioactive microspheres made of nanoporous glass for radiation therapy.
This patent application is currently assigned to SphereRx LLC. The applicant listed for this patent is SphereRx LLC. Invention is credited to Eberhard FRITZ.
Application Number | 20210154339 17/167494 |
Document ID | / |
Family ID | 1000005381462 |
Filed Date | 2021-05-27 |
United States Patent
Application |
20210154339 |
Kind Code |
A1 |
FRITZ; Eberhard |
May 27, 2021 |
RADIOACTIVE MICROSPHERES MADE OF NANOPOROUS GLASS FOR RADIATION
THERAPY
Abstract
A radiation therapy product of spherical nanoporous glass beads
that are loaded with a radionuclide. Each microsphere has a
diameter in the range of about 25 to 60 microns. The pore structure
of each microsphere occupies between about 30 and 90 percent of the
microsphere's volume, and the inner surface area measures between
about 30 and 500 m.sup.2/g. One or more radionuclides is embedded
in the nanopores of each microsphere. In a preferred embodiment the
product has at least two radionuclides, a first radionuclide
achieves a therapeutic effect and a second radionuclide has nuclear
medical diagnostic properties. Preferably the therapeutic
radionuclide is Y-90 and the diagnostic radionuclide is In-111,
Ga-68, or Ga-67. In a preferred embodiment the radionuclides are
made less soluble or insoluble in blood components to avoid
leaching or washing the radionuclide away.
Inventors: |
FRITZ; Eberhard; (Berlin,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SphereRx LLC |
Seattle |
WA |
US |
|
|
Assignee: |
SphereRx LLC
Seattle
WA
|
Family ID: |
1000005381462 |
Appl. No.: |
17/167494 |
Filed: |
February 4, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16506174 |
Jul 9, 2019 |
10940219 |
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17167494 |
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15033298 |
Aug 1, 2016 |
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PCT/DE2014/000561 |
Oct 30, 2014 |
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16506174 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 51/1255 20130101;
A61K 51/02 20130101 |
International
Class: |
A61K 51/12 20060101
A61K051/12; A61K 51/02 20060101 A61K051/02 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 1, 2013 |
DE |
10 2013 018 685.4 |
Claims
1. A radiotherapy product comprising: a. microspheres made of glass
having nanopores; and b. one or more radionuclides chemically bound
to the surface of the nanopores.
2. The radiotherapy product of claim 1 wherein one or more of the
radionuclides is insoluble in blood.
3. The radiotherapy product of claim 1 wherein the product
comprises two radionuclides: a. a first radionuclide has a
therapeutic effect; and b. a second radionuclide has nuclear
medical diagnostic properties.
4. The radiotherapy product of claim 1 wherein the product
comprises two radionuclides: a. a first radionuclide is Y-90; and
b. a second radionuclide is selected from In-111, Ga-68, or
Ga-67.
5. A method for treating a liver tumor comprising: a. injecting a
plurality of microspheres into the vascular supply of the tumor,
wherein the microspheres comprise glass having nanopores and one or
more radionuclides chemically bound to the surface of the
nanopores.
6. The method of claim 5 wherein one or more of the radionuclides
is insoluble in blood.
7. The method of claim 5 wherein the product comprises two
radionuclides: a. a first radionuclide has a therapeutic effect;
and b. a second radionuclide has nuclear medical diagnostic
properties.
8. The method of claim 5 wherein the product comprises two
radionuclides: a. a first radionuclide is Y-90; and b. a second
radionuclide is selected from In-111, Ga-68, or Ga-67.
9. A process for making radioactive glass microspheres for
radiation therapy, wherein each glass microsphere has a plurality
of nanopores and each nanopore has a surface, the process
comprising: a. loading the nanopores of the glass microspheres with
a loading solution comprising a radionuclide in a first acid
wherein the radionuclide is selected from Ga-68 or Ga-67; b.
evaporating the loading solution until the radionuclide
precipitates onto the surface of the nanopores in the microspheres;
and c. thermally treating the microspheres so that precipitated
radionuclide salt is converted into a low-solubility or insoluble
form and is affixed to the surface of the nanopores.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of and claims benefit of
co-pending U.S. application Ser. No. 16/506,174 filed Jul. 9, 2019
which was a continuation of and claims the benefit of Ser. No.
15/033,298 filed Aug. 1, 2016 which was a national stage entry of
and claims the benefit of PCT/DE2014/000561 filed Oct. 30, 2014
which claimed the benefit of German application 10 2013 018 685.4
filed Nov. 1, 2013.
BACKGROUND
[0002] Radioactive microspheres for tumor therapy have a spherical
geometry and contain a therapeutic radionuclide, usually yttrium-90
(Y-90). They are used in the treatment of non-operable liver
tumors. The method is known as Selective Internal Radiation Therapy
(SIRT) or radioembolization. More than a million patients fall ill
from liver tumors across the world each year, with predominantly
poor prognosis. Radiation therapy with radioactive microspheres
improves the quality of life of affected patients and extends
survival.
[0003] To date, two types of microspheres have been used. They
differ in their physical parameters and their manufacturing
process. Salem 2006 gives an overview of the use of microspheres by
the NORDION (Canada), now BTG, and SIRTEX Medical (Australia)
companies. In an earlier review, Hafeli 2001 summarised the
therapeutic value of the microspheres. In both variants,
Radionuclide Y-90 beta radiation is used therapeutically.
[0004] NORDION (TheraSphere.RTM.) generates the Y-90 by neutron
activation in a nuclear reactor from non-radioactive Y-89, added in
the glass manufacturing process. NORDION uses the technology
disclosed in the patents U.S. Pat. Nos. 4,789,501 and 5,011,677
(University of Missouri, USA). Neutron activation however not only
generates the Y-90 radionuclide in the glass microspheres but also
other unwanted radionuclides that are sometimes harmful in
treatment. This effect can be mitigated but not completely avoided
by extending the interval between neutron activation and therapy.
The current state of knowledge on therapy using TheraSphere.RTM. is
summarised in a bibliography (NORDION 2013).
[0005] The Sirtex company's microspheres use the ability of resin
spheres to bind a certain amount of Y-90 to the surface ionically.
Sirtex has disclosed the technology for production and use of
radioactive resin spheres (WO 02/34300 AI; US 2007/0253898 A1, US
2010/0215571 AI). Sirtex 2013 contains a bibliography of
publications on the use of SirSpheres.RTM..
[0006] SIRTEX has also made a patent disclosure on the production
of radioactive glass microspheres (U.S. Pat. No. 6,998,105)
describing how the weight of the solid spheres can be reduced by
modifying the molten glass mix, thus eliminating the disadvantage
of high glass density. An achievable density of less than 2.5
g/cm.sup.3 is specified, as compared to a density of greater than 3
g/cm.sup.3 in NORDION microspheres. The minimum density achievable
by SIRTEX is less than 2.2 g/cm.sup.3, with an absolute minimum of
2.13 g/cm.sup.3. The radionuclide Y-90 to be loaded, achieved as in
the NORDION process by neutron activation of Y-89, is fixed to the
surface of non-porous glass. However, the invention does not in
principle reduce the formation of unwanted radionuclides in neutron
activation.
[0007] There are no known radioactive microspheres by other
manufacturers, apart from the NORDION full glass microspheres
(TheraSphere.RTM.) and Sirtex resin microspheres
(SIR-Spheres.RTM.).
[0008] EP 0210875 (Theragenics Corporation, USA) disclosed a system
for delivering the microspheres to a vascular tumor. This system is
currently used worldwide by the NORDION company. Another system is
disclosed in U.S. Pat. No. 4,745,907 (Nuclear Medicine Inc., USA)
for delivering small radioactive particles, such as microspheres,
to liver tumors.
SUMMARY
[0009] One object of the invention is to produce radioactive
microspheres for the treatment and diagnosis of tumors with
vascular supply, especially liver tumors. The radionuclide is bound
to the microsphere in such a way that it is not leached or released
into the tumor, instead only emitting the ionizing radiation for
the treatment of the tumorous tissue.
[0010] A further object is to produce glass microspheres without
radiochemical impurities, with a similar or lower weight to resin
microspheres of the same size.
[0011] A further object is the loading of the microspheres with
radionuclides by conventional physical and chemical methods and
devices in radionuclide laboratories without the use of nuclear
reactors for neutron activation. One option of this object allows
the simple loading technology to be kept very simple indeed,
facilitating use in specialized radio-pharmaceutical or chemical
laboratories of hospitals, thus enabling these institutions to
provide rapid patient care.
[0012] A further object is an option involving loading of
microspheres for diagnostics in nuclear medicine using
radionuclides, which act primarily as photon emitters and ensure
accurate diagnostic preparation of therapy and follow-up
controls.
[0013] A further object of the invention is multiple loading of
microspheres with therapeutic and diagnostic radionuclides.
[0014] The invention is a radiation therapy product of spherical
nanoporous glass beads that are loaded with a radionuclide. Each
microsphere has a diameter in the range of about 25 to 60 microns.
The pore structure of each microsphere can occupy between about 30
and 90 percent of the microsphere's volume, and the inner surface
area measures between about 30 and 500 m.sup.2/g. One or more
radionuclides is embedded in the nanopores of each microsphere. In
a preferred embodiment the product has at least two radionuclides,
a first radionuclide achieves a therapeutic effect and a second
radionuclide has nuclear medical diagnostic properties. Preferably
the therapeutic radionuclide is Y-90 and the diagnostic
radionuclide is In-111, Ga-68, or Ga-67. In a preferred embodiment
the radionuclides are made less soluble or insoluble in blood
components to avoid washing the radionuclide away.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The objects of the invention are achieved by the use of
microscopically small nanoporous glass beads with a spherical
geometry, which are loaded with a radionuclide of the highest
radiochemical purity.
[0016] The microspheres have a physical size within the range of 25
to 60 .mu.m. The microsphere pores have a size within the range of
5 to 400 nm. The pore structure can occupy between 30 and 90
percent of a microsphere's volume. The inner surface of the
nanoporous glass thus provided for loading is much greater than the
outer surface, measuring between 30 and 500 m.sup.2/g.
[0017] The effective (apparent) density of the nanoporous glass
depends on the void content of the glass. In aqueous solutions, a
high void content means that the effective density of the
microspheres will be closer to but slightly greater than the
density of the aqueous solution. This property of the nanoporous
glass allows an effective microsphere density of less than 2.2
g/cm.sup.3 to be achieved, which corresponds to the minimum density
of pure nonporous silica. Ideally, an effective microsphere density
of less than 1.5 g/cm.sup.3 is achieved during radiotherapy.
[0018] The nanoporous microspheres take the radionuclide up during
loading and retain it in the pores during therapy following a
fixing procedure. The loading and fixing of one or more
radionuclides can be achieved using normal laboratory chemical and
physical procedures and devices available in the prior art. No
neutron activation is used for the manufacture of microspheres
given the commercial availability of high purity radionuclides for
loading, such as Y-90 and In-111.
[0019] Y-90 is preferred for use as a therapeutic radionuclide.
Diagnostic radionuclides are chosen from the group Indium 111
(In-111), Gallium-68 (Ga-68). High-purity Y-90 and In-111 can be
purchased commercially, for instance from by the Perkin-Elmer
company (Canada). Ga-68 is obtained from radionuclide
generators.
[0020] Both nanoporous glass and the way it is produced are
well-known and form part of the prior art. The product and its
manufacture is described for example in DD 250 471 AI; DD 143 898
AI; DE 196 33 257 C1 and DE 410 26 35 AI (VitraBio GmbH, Steinach,
Germany). The loading of the radionuclide contained in a chemical
solution onto the microspheres is achieved by means of incubation
in the exposed surface pore system. The pore system inside the
spheres is a surface-connected channel system in which each pore
has an opening hole to the surface. All pores can be loaded from
the surface through these holes.
[0021] Subsequently, the solution is dried into the pore system and
the chemical compound is calcined. Thermal treatments of the
incubated microspheres should preferably be used, with the required
decomposition temperature for the chemical compound of the
radionuclide. Other alternative methods like the use of microwaves
or light, for example, may be used with suitable chemical
compounds. In the process, the radionuclide is preferably converted
into its oxide inside the void volume, which is then deposited in
the void volume of the inner surfaces. Gaseous decomposition
products escape and non-gaseous products can be washed away with
suitable solvents. Some radionuclide oxides are dissolvable by
blood components, causing unwanted leaching or washing away of the
radionuclide. Such oxides, for example yttrium oxide, may be
converted in a further step to another compound that is far less
soluble or insoluble in the blood. Conversion may be achieved, for
example, by addition of acids such as hydrofluoric acid, oxalic
acid, sulphuric acid, sulphurous acid or phosphoric acid at very
low concentrations. In a further step, the isolated radionuclide,
the oxide or the optionally obtained low solubility compounds of
the radionuclide may be thermally baked onto the glass, thus
lowering its propensity to being leached or washed away. This is
done at temperatures below the decomposition temperature of the
compounds. In one embodiment, yttrium oxide (yttria) can chemically
bind with the glass surface once embedded in the pore structure
during high temperature treatment of the microspheres.
[0022] Additional optional steps may also be taken for the surface
finishing of the microspheres. For example, the suspensibility and
mechanical flow of the microspheres in vascular application can be
improved by hydrophobization.
[0023] Another option is the simultaneous loading of two different
radionuclides, wherein a first radionuclide achieves a therapeutic
effect and a second radionuclide has nuclear medical diagnostic
properties. For this purpose radionuclides are used with similar
chemical and physical properties to those in the manufacturing
steps, such as Y-90 and In-111 or Ga-67 and Ga-68.
[0024] Compounds of the radionuclide that can only be dissolved in
organic solvents are also suitable for the loading process. Fixing
is carried out by evaporation of the solvent and baking of the
compound into the nanoporous structure. Another embodiment of the
loading process is loading by the clinical users themselves (e.g.
in the clinical radiopharmaceutical centre). The latter receive the
raw materials and implement the prescribed loading steps in their
own laboratory (kit solution).
[0025] SIRT tumor treatment involves injection of a very high
number of loaded microspheres into the vascular supply of the
tumor. The microspheres are blocked in the arteries of the tumor
due to their large diameter. The tumor is then treated by
radioembolization. Radioactive loading of the total number of
microspheres for the tumor site is set sufficiently high to deliver
a radiation dose of between 80 and 150 Gray to the tumor. Given the
very high load variability of nanoporous microspheres, the number
of microspheres in a single tumor dose can be set within a range of
less than 1 million to several millions, something that could not
be achieved to date with existing microspheres. This allows new
therapeutic approaches. The number of microspheres per tumor in the
case of tumors with a diameter of a few centimetres can be set at
between one and four million.
[0026] Simple loading and fixing procedures mean that the
above-mentioned kit solution can be used for production in the
clinical environment.
[0027] The possibility of double loading of therapeutic and
diagnostic radionuclides meets the need in radiation medicine for
follow-up controls during and after the therapy, again something
that could not be achieved with existing microspheres.
Embodiment 1
[0028] The therapeutic treatment plan based on the radiologically
assessed size of the liver tumor provides for catheter application
of 20 GBq of Y-90 activity and four million microspheres.
[0029] The 20 GBq of activity selected for loading is intended to
compensate for radioactive decay during manufacture and logistical
delivery. Y-90 is used as a nitrate in a nitric acid solution. The
porosity of the microspheres is 75%. The effective density in
aqueous solutions is therefore 1.4 g/mm.sup.3. The average diameter
of the microspheres is 30 .mu.m.
[0030] Production is patient-specific based on the requirements of
the oncologists, in other words the patient dose in this example is
prepared for one given particular patient only.
[0031] The following steps are to be implemented in order:
[0032] Weigh out 38 mg (approximately 76 .mu.l) of microspheres,
equivalent to the required number of 4 million.
[0033] Triple-wash the microspheres in distilled water and then dry
them at 105.degree. C.
[0034] Prepare the radioactive loading solution of 20 GBq
Y-90-nitrate in 60 .mu.l 0.05 M HNO.sub.3 (approximately equivalent
to the void volume of the microspheres).
[0035] Place the microspheres in an Eppendorf tube and drip on the
60 .mu.l of Y-90 loading solution.
[0036] Place the unsealed Eppendorf tube in a desiccator and
evacuate to 10 mbar for about one hour.
[0037] Dry the unsealed Eppendorf tube in a drying cabinet, slowly
raising the temperature from 60 to 105.degree. C.
[0038] Transfer the microspheres to a porcelain combustion boat and
slowly heat in a furnace to 600.degree. C. and maintain temperature
for one hour.
[0039] After they have cooled, transfer the microspheres to a new
Eppendorf tube and triple wash in 1 ml of distilled water,
centrifuge, then dry in heating cabinet at 80.degree. C. for one
hour.
[0040] Drip on 60 .mu.l of 0.005 M HF and incubate in a desiccator
at 10 mbar for 10 minutes, followed by 30 minutes reaction time in
a heating cabinet at 30.degree. C. in the Eppendorf tube.
[0041] Dry in the heating cabinet at 105.degree. C. for the
complete removal of the non-converted HF.
[0042] Transfer the microspheres to porcelain combustion boats and
bake in the yttrium fluoride at 750.degree. C.
[0043] Transfer the microspheres to an Eppendorf tube.
[0044] Triple wash with 1 ml distilled water, with subsequent
removal of water by centrifuging.
[0045] Measure the load activity in an ionization chamber.
[0046] Transfer the microspheres by absorption with 1.5 ml
physiological saline solution to a sterilisable V-Vial (3 ml) and
seal with a sterilisable crimp seal
[0047] Autoclave.
[0048] After autoclaving, the microspheres can be used after about
six days, after they have reached the required activities by
radioactive decay. Prior to application to the patient's tumor, a
further metrological activity control should be performed by a
medical physicist.
Embodiment 2
[0049] Shunt determination is necessary during preparation for
tumor treatment to clarify whether the patient is suitable for
liver tumor treatment using microspheres. The shunt measures the
loss of microspheres that would not be retained in the liver tumor
but would rather be deposited as unwanted in other parts of the
body.
[0050] Diagnostic imaging using nuclear medicine techniques can be
performed with the In-111 radionuclide. A load activity of 200 MBq
is selected and the number of microspheres is weighed at
400,000.
[0051] Subsequent steps are to be performed as described in
Embodiment 1. The amount of microspheres used is correspondingly
reduced to 3.8 mg and the amounts of HNO.sub.3 and HF adjusted to 6
.mu.l. Indium fluoride is formed and baked in as the insoluble
compound.
* * * * *