Composition of radioactive and non-radioactive particles

Abstract

The present disclosure provides a composition comprising a mixture of (i) radioactive microparticles and (ii) non-radioactive microparticles. The radioactive microparticles may be suitable for treating vascularized tumors, such as liver tumors or metastatic liver tumors. The radioactive composition and the non-radioactive composition may have substantially the same resistance to flow in a liquid through a conduit. The present disclosure further provides methods of making and using the mixture of microparticles.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Patent Application No. 62 / 901,159, filed on 16 September 2019, and U.S. Provisional Patent Application No. 63 / 031,109, filed on 28 May 2020. The entire contents of these applications are incorporated herein by reference.

[0002] This disclosure relates to mixtures of radioactive and non-radioactive particles, and the use of said mixtures. [Background technology]

[0003] The following paragraphs do not constitute prior art or part of the knowledge of a person skilled in the art.

[0004] Selective internal radiotherapy (SIRT) is sometimes used to treat primary or metastatic liver malignancies. In SIRT, yttrium-90( 90 Y) Radiolabeled microparticles are injected into the patient's hepatic artery and preferentially localized to liver tumors accompanied by increased angiogenesis. The radiolabeled yttrium-90 microparticles decay and deliver radiation to the surrounding tissue. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] The following preface is intended to introduce this specification to the reader and does not define the inventions. One or more inventions may consist of combinations or subcombinations of apparatus elements or steps of a method described below or in other parts of this document. The inventors do not waive or withdraw any rights to any invention disclosed herein simply because the claims do not describe one or more other inventions.

[0006] Radioactive microparticles are manufactured in only a few locations and prepared for delivery to hospitals worldwide. The specific activity of the microparticles is calibrated to provide the desired activity at a planned time in administration. For example, TheraSphere yttrium-90 glass microparticles are prepared by neutron activation of yttrium-89-containing glass microparticles to produce microparticles with a nominal specific activity of approximately 110 GBq / g at calibration, typically supplied in quantities ranging from approximately 1.2 million microparticles (approximately 3 GBq in approximately 27 mg) to 8 million microparticles (approximately 20 GBq in approximately 180 mg) per vial. Depending on the delay between calibration and administration, the amount of effective radioactivity delivered may range from 0.17 GBq per vial (1.2 million microparticles injected 9 days after calibration) to 18 GBq per vial (8 million microparticles injected 1 day after calibration).

[0007] For the delivery of a given amount of radioactivity, it is considered desirable to administer more microparticles with lower specific activity. This is because increasing the number of microparticles results in better tumor coverage compared to administering fewer microparticles with higher specific activity. For example, to deliver 3 GBq of radioactivity to a patient, administering 6 million microparticles with an overall specific activity of 22 GBq / g is considered to yield better tumor coverage than administering 1.5 million microparticles with an overall specific activity of 88 GBq / g. While it is not desirable to be bound by theory, the authors of this disclosure assume that microparticles will remain at the first effective localization spot in the blood vessels they encounter. If there are enough localization spots to interact with the majority of the administered particles, administering a small number of microparticles may concentrate some of the particles in a portion of the tumor. In contrast, administering more particles with lower specific activity increases the saturation of effective localization spots, resulting in more uniform tumor coverage. [Means for solving the problem]

[0008] For at least some tumor sizes and / or degrees of angiogenesis, administering a mixture of (i) radioactive particles and (ii) radiopaque, non-radioactive particles according to the present disclosure to a patient may provide at least some of the benefits associated with administering more particles at lower specific activity, even if the individual radioactive particles have higher specific activity.

[0009] In one embodiment, the present disclosure provides a therapeutic or diagnostic composition comprising (i) radioactive particles and (ii) a mixture of non-radioactive particles.

[0010] In one embodiment, the present disclosure provides a composition comprising (i) radioactive particles and (ii) a mixture of non-radioactive particles. The radioactive particles are suitable for the treatment of tumors in which new blood vessels are formed, such as liver tumors or metastatic liver tumors. The radioactive particles and non-radioactive particles have substantially the same resistance when flowing through a liquid via a conduit such as a blood vessel.

[0011] While it is not desirable to be bound by theory, the authors of this disclosure believe that radioactive and non-radioactive particles, having substantially the same resistance when flowing through a liquid via a conduit, will be distributed substantially the same way across the tumor's blood vessels. Therefore, for at least some tumor sizes and / or degrees of angiogenesis, the particle mixtures according to this disclosure can provide an improved tumor coverage, which may exceed that of the same number of radioactive particles administered in the absence of non-radioactive particles. For example, administration of a mixture of (i) 1.5 million particles at 88 GBq / g and (ii) 4.5 million non-radioactive particles (i.e., a total of 6 million particles) is expected to provide a better coverage than administration of 1.5 million particles at 88 GBq / g alone, and may provide a tumor coverage similar to that of administration of 6 million particles at 22 GBq / g.

[0012] Radioactive particles can be formulated to have a specific activity of 140 GBq / g to 4 GBq / g at the time of administration. In mixtures containing non-radioactive particles, the overall specific activity of the mixture can range from approximately 110 GBq / g (in a mixture containing 80% radioactive particles relative to the mass at the radioactive peak) to approximately 0.4 GBq / g (in a mixture containing 10% radioactive particles relative to the mass at the lowest practical level after decay).

[0013] Radioactive particles can be produced from the same non-radioactive particles that make up the mixture. For example, the non-radioactive particles in the mixture may consist of about 40% by mass of Y2O3, about 20% by mass of Al2O3, and about 40% by mass of SiO2, where at least some of the yttrium is yttrium-89 and none of the yttrium is yttrium-90. Radioactive particles in the mixture can be produced by neutron activation of the same non-radioactive particles. The resulting radioactive particles consist of about 40% by mass of Y2O3, about 20% by mass of Al2O3, and about 40% by mass of SiO2, where at least some of the yttrium is yttrium-90. In such a mixture, the radioactive and non-radioactive particles may have substantially equal resistance when flowing through a conduit in a liquid. Such radioactive and non-radioactive particles have substantially identical densities and substantially identical size distributions. These radioactive and non-radioactive particles are expected to be equally distributed within the tumor.

[0014] Radioactive particles are typically not visible by X-ray imaging. In some examples of this disclosure, at least a portion of the non-radioactive particles in a mixture may be sufficiently radiopaque to be detected by X-ray imaging such as radiography, computed tomography, cone-beam tomography, and / or fluoroscopy. Administration of a therapeutic amount of such a mixture of particles allows (i) to perform X-ray imaging in real time after administration, and / or (ii) to calculate the amount of radiation delivered to the tissue by the unimagingable radioactive particles based on the measured distribution of the non-radioactive, imagingable particles in the tissue.

[0015] In another embodiment, the disclosure includes exposing a first plurality of non-radioactive particles to neutron activation to form a plurality of radioactive particles, and mixing at least a portion of the plurality of radioactive particles with a second plurality of non-radioactive particles to obtain a desired overall specific activity. In a particular example, the method includes mixing the radioactive particles and non-radioactive particles before the radioactivity level of the radioactive particles decays to 35%.

[0016] In another embodiment, the Disclosure provides a method for delivering radiation to a neovascular tumor, such as a liver tumor or metastatic liver tumor, in a patient. The method comprises injecting a composition according to the Disclosure into the patient's hepatic artery. Where the non-radioactive particles are sufficiently radiopaque to be detectable by X-ray imaging, the method may further include imaging the administered particles and, if necessary, calculating the amount of radiation delivered to the tissue by the non-imaging radioactive particles based on the measured distribution of the non-radioactive, imageable particles in the tissue.

[0017] While we do not wish to be bound by theory, the authors of this disclosure believe that administering radioactive and non-radioactive particles separately may yield at least some of the benefits associated with administering a mixture of radioactive and non-radioactive particles.

[0018] In one aspect, the present disclosure provides a delivery device for intravascular delivery, intraperitoneal delivery, or percutaneous delivery to a patient of a mixture of radioactive microparticles and non-radioactive microparticles. The delivery device is fluidly coupled to a mixed transport medium. The delivery device includes a fluid inlet fluidly coupled to the mixed transport medium, a fluid outlet, a fluid mixer fluidly coupled to the fluid inlet and the fluid outlet, a source of radioactive microparticles fluidly coupled to the fluid mixer, and a source of non-radioactive microparticles fluidly coupled to the fluid mixer. The source of radioactive microparticles is distinct from the source of non-radioactive microparticles. The fluid mixer mixes the radioactive microparticles and the non-radioactive microparticles and delivers, using the mixed transport medium, a mixture of radioactive microparticles and non-radioactive microparticles out of the fluid outlet.

[0019] In another aspect, the present disclosure provides a delivery device for intravascular delivery, intraperitoneal delivery, or percutaneous delivery to a patient of a mixture of radioactive microparticles and non-radioactive microparticles. The delivery device includes at least one fluid inlet fluidly coupled to a transport medium, a source of radioactive microparticles fluidly coupled to the at least one fluid inlet, a source of non-radioactive microparticles fluidly coupled to the at least one fluid inlet, a first fluid outlet fluidly coupled to the source of radioactive microparticles, and a second fluid outlet fluidly coupled to the source of non-radioactive microparticles. The source of radioactive microparticles is distinct from the source of non-radioactive microparticles.

[0020] In the context of the present disclosure, one aggregate of microparticles should be understood to be distinct from another aggregate of microparticles if the two aggregates are not mixed. For example, even if two syringes are fluidly coupled and can discharge microparticles together to form a mixture, the radioactive microparticles within the barrel of one syringe should be understood to be distinct from the non-radioactive microparticles within the barrel of the second syringe.

[0021] In yet another aspect, the present disclosure provides a method comprising (i) mixing a first aggregate of radioactive microparticles and (ii) a second aggregate of non-radioactive microparticles and administering an appropriate amount of the mixture to a patient for therapeutic or diagnostic use.

[0022] In yet another aspect, the present disclosure provides a method of administering to a patient an appropriate amount of microparticles for therapeutic or diagnostic use. The method includes administering non-radioactive microparticles to the patient and administering radioactive microparticles to the patient without first detecting the non-radioactive microparticles. The administration is by intravascular delivery, intraperitoneal delivery, or percutaneous delivery, and the route of administration of the non-radioactive microparticles is the same as the route of administration of the radioactive microparticles.

[0023] In yet another aspect, the present disclosure provides a method of administering to a patient an appropriate amount of microparticles for therapeutic or diagnostic use. The method includes administering radioactive microparticles to the patient and administering non-radioactive microparticles to the patient without first detecting the radioactive microparticles. The administration is by intravascular delivery, intraperitoneal delivery, or percutaneous delivery, and the route of administration of the non-radioactive microparticles is the same as the route of administration of the radioactive microparticles.

[0024] In yet another aspect, the present disclosure provides a method of administering an appropriate amount of microparticles for therapeutic or diagnostic use. The method includes co-administering to the patient (i) a first aggregate of radioactive microparticles and (ii) a second aggregate of non-radioactive microparticles.

[0025] In yet another aspect, the present disclosure provides a method of administering an appropriate amount of microparticles for therapeutic or diagnostic use. The method includes sequential administration of non-radioactive and radioactive microparticles to the patient in a single treatment session.

[0026] In yet another aspect, the present disclosure provides a method that includes sequential administration to a patient of (i) therapeutic radioactive microparticles and then (ii) non-radioactive microparticles.

[0027] In yet another aspect, the Disclosure provides a delivery device for intravascular, intraperitoneal, or transdermal delivery of a mixture of radioactive and non-radioactive particles to a patient. The delivery device may be a delivery device disclosed in WO2020 / 082168, which is incorporated herein by reference. The delivery device disclosed in WO2020 / 082168 may be used to administer a mixture of radioactive and non-radioactive particles. [Modes for carrying out the invention]

[0028] In one embodiment, the present disclosure provides a mixture of (i) radioactive particles and (ii) non-radioactive particles, wherein the radioactive particles are suitable for treating neovascular tumors such as liver tumors or metastatic liver tumors, and the radioactive and non-radioactive particles have substantially the same resistance when flowing through a liquid via a conduit. In the context of the present disclosure, the conduit may be a blood vessel or a tumor vascular system.

[0029] In connection with this disclosure, it should be understood that radioactive and non-radioactive particles in a given mixture have sufficiently similar resistance when flowing through a conduit into a liquid and behave substantially the same after injection into a patient.

[0030] Those skilled in the art will understand that the resistance of an object flowing through a liquid in a conduit is reflected in the drag coefficient, which is a function of surface friction and shape drag. Thus, the resistance of particulate matter flowing through a liquid in a conduit may be influenced, for example, by the size, surface area, shape, density, and / or surface condition of the particulate matter. Those skilled in the art will also readily understand that two different particles flowing through a liquid in a conduit may have substantially the same resistance, since changing a characteristic to increase drag can be offset by changing another characteristic to decrease drag. For example, if the surface condition of the first particle is sufficiently smoother than that of the second particle, the two particles may still have substantially the same drag coefficient, even if the first particle is larger than the second particle.

[0031] In the context of this disclosure, the time required for a bolus of microparticles to fall a set distance through a liquid may represent the resistance of the microparticles flowing through the liquid in a conduit. This time can be measured by filling a transparent column filled with distilled water with a known number of microparticles. The number of microparticles should be selected so that the height of the microparticle bolus is 2 to 5 times the inner diameter of the column. The microparticles are then allowed to settle to the bottom of the column, the column is inverted, and the microparticles are allowed to fall into the distilled water by the resistance force against gravity. The total time required for the microparticles to fall and pass through a transition point is measured. The transition point is measured from the top of the microparticle bolus and is set to at least 100 times the inner diameter of the column. For example, in a column with an inner diameter of 0.5 cm, the settled microparticles may be 1.5 cm high, and the total time for the microparticle bolus to fall is the time required for all microparticles to fall and pass through a point 50 cm away from the top of the settled microparticles.

[0032] This total fall time is compared to the total fall time of substantially equal numbers of different particle groups tested under the same conditions (i.e., the same liquid, the same column, the same transition point). The relative drag ratio is calculated by dividing the fall time of the first particle group by the fall time of the second particle group. In the context of this disclosure, the first and second particles are considered to have substantially the same resistance when flowing through the liquid in the conduit, given that the relative drag ratio is approximately 0.95:1 to approximately 1:0.95.

[0033] In a given mixture, radioactive and non-radioactive particles have substantially the same density. The term “particle density” refers to the mass of individual particles per unit volume. This is in contrast to the term “bulk density,” which refers to the mass of a number of particles per total volume. Particle density is an inherent property of the material, while bulk density varies depending on the material properties in the overall volume.

[0034] The term "non-radioactive particles" should be understood to refer to particles with radioactivity levels that do not substantially contribute to the therapeutic or diagnostic effects of a mixture. In some examples, non-radioactive particles are less than 0.15 GBq / g, for example, non-radioactive particles that may contain Y-90 as a radioactive isotope and have a radioactivity level of less than 0.15 GBq / g. In some preferred examples, non-radioactive particles are 0 GBq / g.

[0035] The particle density of radioactive and non-radioactive particles may be within approximately 30% of the average, preferably within approximately 15%. For example, the particle density of radioactive fine particles is 3.3 g / cm³. 3 The particle density of non-radioactive particles is 3.9 g / cm³. 3 The difference between the two types of fine particles is 0.6 g / cm³. 3 The difference is 16.7% of the average of the two values. Particle density is discussed in terms of specific gravity, which is the ratio of the density of a substance to the density of a control substance. In the context of this disclosure, specific gravity is relative to water.

[0036] The radioactive and non-radioactive particles used in the compositions of this disclosure are selected to preferentially distribute in the blood vessels of tumors rather than in normal tissue. The size of the particles may affect this distribution. Compositions according to this disclosure, for example, compositions useful for treating neovascular tumors such as liver tumors or metastatic liver tumors, may have an average diameter of about 15 to about 45 microns. In certain examples, the particles may have an average diameter of about 20 to about 35 microns.

[0037] The radioactive and non-radioactive particles in a given mixture may be substantially the same size. The average size of the radioactive and non-radioactive particles may be within 40% of the average of the two average sizes. For example, the radioactive particles may have an average diameter of 20 microns, and the non-radioactive particles may have an average diameter of 30 microns. A difference of 10 microns between the two types of particles is 40% of the average of the two values.

[0038] Improvements in the effective range to tumors, such as a more uniform distribution of microparticles, can be achieved using a mixture containing radioactive microparticles in an amount of approximately 80% to approximately 10% (w / w) of the total mass of microparticles in the composition. In the context of this disclosure, any reference to improvements should be understood as a comparison with the same number of radioactive microparticles in the absence of additional non-radioactive microparticles.

[0039] For radioactive particles with a high specific activity, such as 140 GBq / g, the mixture may contain fewer radioactive particles (e.g., about 10% by mass). In contrast, for radioactive particles with a low specific activity, such as 4 GBq / g, the mixture may contain more radioactive particles (e.g., about 80% by mass). In a specific example, for radioactive particles with a specific activity of about 88 GBq / g, the mixture may contain about 25% by mass of radioactive particles.

[0040] "Specific activity" refers to the radioactivity per unit mass of radioactive particles, while "total specific activity" should be understood as the radioactivity per unit mass of a mixture of radioactive and non-radioactive particles. For example, if 1 g of radioactive particles with a specific activity of 10 GBq / g is taken and mixed with 1 g of non-radioactive particles, a mixture of particles with a total specific activity of 5 GBq / g is obtained.

[0041] A mixture of radioactive and non-radioactive particles can be prepared by formulating various numbers of total particles with a desired radioactivity. The total number of particles can be selected based on tumor size and / or the degree of angiogenesis. For example, a formulation with 10 GBq of radioactivity in 0.5 grams of particles may be desirable for treating tumors with a certain degree of angiogenesis, while a formulation with 10 GBq of radioactivity in 1 g may be more desirable for treating tumors with angiogenesis. Thus, different formulations can be prepared by taking the same amount of radioactive particles and adding different amounts of non-radioactive particles.

[0042] The microparticles according to this disclosure may be inorganic polymer microparticles. In this specification, inorganic polymer microparticles may be referred to as “glass microparticles.” Radioactive glass microparticles may be formed from the neutron activation of the same microparticles as the non-radioactive glass microparticles constituting the mixture. For example, a first portion of non-radioactive glass microparticles may be converted into radioactive glass microparticles via neutron activation. The resulting radioactive glass microparticles are mixed with a second portion of non-radioactive glass microparticles to form the composition according to this disclosure. The first and second portions of the non-radioactive glass microparticles may be identical, resulting in substantially identical resistance, substantially identical density, and substantially identical size distribution when the radioactive and non-radioactive microparticles flow through a conduit in a liquid.

[0043] The radioactive glass nanoparticles according to this disclosure may contain yttrium-90 as a radioactive element. The non-radioactive glass nanoparticles according to this disclosure may contain yttrium-89 or zirconium-90. Other radionuclides, such as radioisotopes like holmium, samarium, iodine, iridium, phosphorus, or rhenium, may be used instead of or in addition to yttrium-90.

[0044] Yttrium-89 can be converted to yttrium-90 by exposing yttrium-89 contained in particulate matter to a neutron beam. The specific activity of the resulting particulate matter depends on the level of the beam and the exposure time. For example, yttrium-89 is nominally 10 14 neutrons / cm 2 As a result of exposure to a beam of radioactivity per second for several days, a specific activity greater than 150 GBq / g can be achieved.

[0045] Zirconium-90 can be converted to yttrium-90 by irradiating particles with neutron beams at energy levels of about 4.7 MeV to about 12.1 MeV, as described in WO / 2017 / 004088 (incorporated herein by reference).

[0046] In certain cases, the radioactive particles are glass particles, which contain about 40% by mass of Y2O3, about 20% by mass of Al2O3, and about 40% by mass of SiO2, with at least a portion of the yttrium being yttrium-90. The radioactive particles can be formed by mixing yttrium-89 oxide with ultrapure aluminum oxide and silicon dioxide, melting the mixture in a furnace at a temperature of about 1,600°C, cooling the mixture to produce glass embedded with yttrium-89, crushing the glass, and passing the crushed glass through a flame injector. The resulting spheres are filtered through a sieve, and those with an average diameter of 20–40 microns may be selected. The non-radioactive particles are then exposed to a neutron beam, which can convert at least a portion of the embedded yttrium-89 into yttrium-90.

[0047] In some examples provided herein, the radioactive particles are glass particles having about 40% by mass of Y2O3, about 20% by mass of AlO3, and about 40% by mass of SiO2, with at least a portion of the yttrium being yttrium-90, and the non-radioactive particles are glass particles having about 40% by mass of Y2O3, about 20% by mass of AlO3, and about 40% by mass of SiO2, with none of the yttrium being yttrium-90. The radioactive glass particles are formed from a first portion of the non-radioactive particles and can be mixed with a second portion of the non-radioactive glass particles. The first and second portions of the non-radioactive glass particles may be identical, resulting in substantially identical resistance, substantially identical density, and substantially identical size distribution when the radioactive and non-radioactive particles flow through a conduit in a liquid.

[0048] The radioactive and non-radioactive glass particles used in the compositions of this disclosure have a specific gravity of approximately 3.3 to 3.9 relative to water and an average diameter of approximately 20 to 40 microns.

[0049] Alternatively, the microparticles according to this disclosure may be resin-based microparticles. Resin-based radioactive microparticles can be formed by the ionic bonding of radioactive elements to particles of the same resin-based non-radioactive microparticles. For example, resin-based radioactive microparticles can be formed by ion exchange of non-radioactive cations bonded to resin-based microparticles with radioactive cations in a solution during an ion exchange process. The radioactive cations bonded to the resin-based microparticles can further be immobilized on the resin by precipitation of the radioactive cations by anions, forming a low-solubility salt.

[0050] The resin-based radioactive microparticles according to this disclosure may contain yttrium-90 as a radioactive element. Yttrium-90 can be incorporated into non-radioactive biocompatible microparticles coated with a partially crosslinked cation-exchange polystyrene resin by ion exchange between yttrium-90 dissolved in an ion-exchange solution and sodium bound to the non-radioactive microparticles. The exchanged yttrium-90 can be precipitated and immobilized on the resin-based microparticles by precipitation of the corresponding phosphate, as described in WO / 2002 / 034300 (incorporated herein by reference).

[0051] In some examples provided herein, the radioactive particles are resin-based particles containing yttrium-90 phosphate precipitated on a partially crosslinked cation-exchange polystyrene resin, and the non-radioactive particles are resin-based particles coated with a partially crosslinked cation-exchange polystyrene resin. The non-radioactive particles may contain yttrium-89 phosphate precipitated thereon.

[0052] Yttrium-90 can be obtained as a daughter product of the decay process of Sr-90. Yttrium-90 can be recovered from strontium-90 generators using chemical separation. This can be achieved by separating yttrium-890 from a solution containing radioactive strontium-90 using the method disclosed in U.S. Patent No. 7,101,484 (incorporated herein by reference).

[0053] The resin-based radioactive and resin-based non-radioactive particles used in the compositions according to this disclosure may have a specific gravity of about 1.0 to about 1.2 when wet and an average diameter of about 30 to about 35 microns.

[0054] The compositions according to this disclosure may include, for example, resin-based or glass-based fine particles along with sufficiently radiopaque, non-radioactive fine particles detectable by X-ray imaging such as radiography, computed tomography, cone-beam tomography, and / or fluoroscopy. The radiopaque fine particles may have radiopaqueness of 6,000 Hunsfield units (HU) or more at 120 kVp, for example, 9,000 HU or more at 120 kVp.

[0055] Administering a therapeutic dose of such a mixture of microparticles to a patient may allow for the calculation of the amount of radiation delivered to the tissue by the non-imaging radioactive microparticles, based on the measured distribution of non-radioactive, imageable particles within the tissue.

[0056] In compositions according to this disclosure, which include glass microparticles, the non-radioactive microparticles may include glass microparticles containing Ga2O3, SiO2, SrO, and selective Y2O3. Such microparticles are sufficiently radiopaque and detectable by X-ray imaging. Examples of such microparticles are disclosed in WO / 2016 / 082045 (incorporated herein by reference).

[0057] One specific example of such non-radioactive particulate matter is glass microparticles containing approximately 0.17 mole fractions of Y2O3, approximately 0.05 mole fractions of SrO, approximately 0.167 mole fractions of Ga2O3, and approximately 0.613 mole fractions of SiO2. Such exemplary microparticles have a particle density of approximately 3.93 g / cm³. 3 The radioactive glass nanoparticles, having approximately 40% by mass of Y2O3, approximately 20% by mass of Al2O3, and approximately 40% by mass of SiO2 (corresponding to approximately 0.17, 0.19, and 0.64 mole fractions, respectively), contain at least a portion of yttrium that is yttrium-90, and have a particle density of approximately 3.3 g / cm³. 3The difference between the two densities is approximately 17% of the average of the two densities.

[0058] In another aspect, the Disclosure provides a method comprising: exposing a first plurality of non-radioactive particles to a neutron beam to form a plurality of radioactive particles; and mixing at least a portion of the plurality of radioactive particles with a second plurality of non-radioactive particles to achieve a desired overall specific activity. Specific examples of radioactive particles can be formed using the method described above. Specific examples of non-radioactive particles are those described above.

[0059] In the mixing process, radioactive particles and non-radioactive particles may be mixed in a mass ratio of approximately 4:1 to approximately 1:9 to obtain a mixture containing approximately 80% to approximately 10% by mass of radioactive particles.

[0060] This method may further include formulating a mixture of radioactive and non-radioactive particles, or a portion thereof, in a composition suitable for arterial injection, such as a composition containing sterile water, dextrose in sterile water, or physiological saline.

[0061] Another aspect of this disclosure provides a method for delivering radiation to a neovascular tumor, such as a liver tumor or a metastatic liver tumor, in a patient. This method includes injecting a mixture of radioactive and non-radioactive particles according to this disclosure into the patient's hepatic artery.

[0062] When injecting a mixture of glass microparticles, this method may involve injecting 20 mL of saline / microparticle mixture at a rate of approximately 20 mL per minute under a pressure not exceeding 30 psi.

[0063] If the mixture of particulate matter contains sufficiently radiopaque, non-radioactive particulate matter detectable by X-ray imaging, the method may further include calculating the amount of radiation delivered to the tissue by the non-imaging radioactive particulate matter based on the measured distribution of the non-radioactive, imageable particles within the tissue. Specific examples of such additional calculation steps are described above.

[0064] In another aspect, the present disclosure provides a therapeutic or diagnostic composition comprising a mixture of (i) radioactive microparticles and (ii) non-radioactive microparticles.

[0065] The radioactive microparticles have an average density of about 1.0 g / cm 3 to about 4.5 g / cm 3 and, for example, may be 3.3 g / cm 3 to about 3.9 g / cm 3 The non-radioactive microparticles have an average density of about 1.0 g / cm 3 to about 4.5 g / cm 3 and, for example, may be 3.3 g / cm 3 to about 3.9 g / cm 3 The radioactive microparticles and the non-radioactive microparticles may have a difference in particle density within 30%, preferably within 15%, of the average of the two particle densities.

[0066] The radioactive microparticles have an average diameter of about 10 to about 1200 microns, for example about 20 to about 40 microns. The non-radioactive microparticles have an average diameter of about 10 to about 1200 microns, for example about 20 to about 40 microns. The radioactive microparticles and the non-radioactive microparticles may have a difference in average size within 40% of the average of the two average sizes.

[0067] In some examples, the radioactive microparticles and the non-radioactive microparticles have substantially the same resistance when flowing in a liquid through a conduit.

[0068] In some examples, the radioactive microparticles constitute about 10% to about 80%, for example about 25%, of the total mass of the microparticles in the composition.

[0069] The radioactive microparticles may be bioabsorbable microparticles. The non-radioactive microparticles may be bioabsorbable microparticles.

[0070] The radioactive microparticles may be polymer microparticles, glass microparticles, or resin microparticles. The non-radioactive microparticles may be polymer microparticles, glass microparticles, or resin microparticles.

[0071] In some cases, radioactive particles are diagnostic radioactive particles. In some cases, non-radioactive particles are therapeutic radioactive particles.

[0072] Diagnostic radioactive particles may contain one or more radioactive isotopes selected from the group consisting of copper-67, holmium-166, indium-111, iodine-131, lutetium-177, molybdenum-99, phosphorus-32, rubidium-82, technetium-99m, and thallium-201.

[0073] Therapeutic radioactive particles may contain one or more radioactive isotopes selected from the group consisting of actinium-225, bismuth-213, copper-67, indium-111, iodine-131, iodine-125, gadolinium-157, holmium-166, lead-212, lutetium-177, palladium-103, phosphorus-32, radium-223, rhenium-186, rhenium-188, samarium-153, strontium-89, and tungsten-188.

[0074] In some cases, non-radioactive particles are sufficiently radiopaque to be detectable by X-ray imaging such as radiography, computed tomography, cone-beam tomography, and / or fluoroscopy, for example, having radiopaqueness greater than 6,000 Hunsfield units (HU) at 120 kVp, and for example, having radiopaqueness greater than 9,000 HU at 120 kVp.

[0075] In some cases, non-radioactive microparticles contain therapeutic compounds that elute from the microparticles under physiologically relevant conditions.

[0076] In some examples, radioactive and non-radioactive particles are inorganic polymer particles. The radioactive particles may also be particles formed from the neutron activation of the same non-radioactive particles.

[0077] Radioactive and non-radioactive particles have a specific gravity of approximately 3.3 to 3.9 relative to water, and an average diameter of approximately 20 to 40 microns.

[0078] The radioactive particles may contain yttrium-90. The non-radioactive particles may contain yttrium-89. The non-radioactive particles may contain zirconium-90. The non-radioactive particles are sufficiently radiopaque to be detectable by X-ray imaging such as radiography, computed tomography, cone-beam tomography, and / or fluoroscopy, and may be radiopaque to a degree greater than 6,000 Hunsfield units (HU) at 120 kVp, for example, and may be radiopaque to a degree greater than 9,000 HU at 120 kVp.

[0079] Non-radioactive particles may contain Ga2O3, SiO2, SrO, and selectively Y2O3.

[0080] The radioactive particles may contain approximately 40% by mass of Y2O3, approximately 20% by mass of Al2O3, and approximately 40% by mass of SiO2, with at least a portion of the yttrium being yttrium-90.

[0081] In one example, the radioactive particles contain approximately 40% by mass of Y2O3, approximately 20% by mass of Al2O3, and approximately 40% by mass of SiO2, with at least a portion of the yttrium being yttrium-90, while the non-radioactive particles contain approximately 40% by mass of Y2O3, approximately 20% by mass of Al2O3, and approximately 40% by mass of SiO2, with none of the yttrium being yttrium-90.

[0082] In some examples, the radioactive and non-radioactive compositions are resin-based microparticles. The radioactive microparticles may be microparticles formed by ionic bonding between a radioactive element and the same particles as those in the non-radioactive microparticles. The radioactive element may be yttrium-90.

[0083] Non-radioactive particles may be sufficiently radiopaque to be detectable by X-ray imaging such as radiography, computed tomography, cone-beam tomography, and / or fluoroscopy, for example, having radiopaqueness greater than 6,000 Hunsfield units (HU) at 120 kVp, and for example, having radiopaqueness greater than 9,000 HU at 120 kVp.

[0084] Radioactive and non-radioactive particles, when wet, have a specific gravity of approximately 1.0 to 1.2 relative to water, and an average diameter of approximately 30 to 35 microns.

[0085] In another aspect, the Disclosure provides a method comprising administering a mixture of radioactive and non-radioactive particles, as described above, wherein the administration is by intravascular, intraperitoneal, or transdermal delivery.

[0086] In a further embodiment, the present disclosure provides a delivery device for intravascular, intraperitoneal, or transdermal delivery of a mixture of radioactive and non-radioactive particles to a patient. The delivery device includes a fluid inlet that is fluidically connectable to a mixed transport medium, a fluid outlet, a fluid mixer fluidly connected to the fluid inlet and the fluid outlet, a source of radioactive particles fluidly connected to the fluid mixer, and a source of non-radioactive particles fluidly connected to the fluid mixer. The source of radioactive particles is distinct from the source of non-radioactive particles. The fluid mixer mixes the radioactive and non-radioactive particles and delivers the mixture of radioactive and non-radioactive particles out of the fluid outlet using the mixed transport medium.

[0087] In yet another embodiment, the Disclosure provides a delivery device for intravascular, intraperitoneal, or transdermal delivery of a mixture of radioactive and non-radioactive particles to a patient. The delivery device comprises at least one fluid inlet that can be fluidly coupled to a transport medium, a source of radioactive particles fluidly coupled to the at least one fluid inlet, a source of non-radioactive particles fluidly coupled to the at least one fluid inlet, a first fluid outlet fluidly coupled to the source of radioactive particles, and a second fluid outlet fluidly coupled to the source of non-radioactive particles. The source of radioactive particles is distinct from the source of non-radioactive particles. In some examples, the delivery device delivers the radioactive and non-radioactive particles in a single treatment session. In some examples, the first and second fluid outlets are in close proximity to each other. In the context of the Disclosure, the fluid outlets being in close proximity to each other should be understood as being able to administer the radioactive and non-radioactive particles to a patient substantially simultaneously, for example, in the course of a single treatment session.

[0088] The radioactive and / or non-radioactive particles in the delivery device may be those described above. In some examples, the radioactive particles constitute about 10% to about 80%, for example, about 25%, of the total mass of particles in the delivery device. In some examples, the radioactive and non-radioactive particles have substantially the same resistance when flowing through the fluid in the conduit.

[0089] In yet another aspect, the Disclosure provides a method comprising (i) mixing a first aggregate of radioactive particles and (ii) a second aggregate of non-radioactive particles, and administering to a patient an appropriate amount of the mixture for therapeutic or diagnostic purposes. The radioactive particles and / or non-radioactive particles in the method may be those described above. In some examples, the radioactive particles constitute about 10% to about 80%, for example, about 25%, of the total mass of particles in the method. The administration may be by intra-arterial, intraperitoneal, or transdermal delivery.

[0090] In other embodiments, the Disclosure provides a method for administering to a patient an appropriate amount of particles for therapeutic or diagnostic purposes. The method comprises either administering non-radioactive particles to the patient and administering radioactive particles to the patient without first detecting the non-radioactive particles, or administering radioactive particles to the patient and administering non-radioactive particles to the patient without first detecting the radioactive particles. The administration is by intra-arterial, intraperitoneal, or transdermal delivery. The route of administration of the non-radioactive particles is the same as the route of administration of the radioactive particles.

[0091] In some examples, the method includes the simultaneous administration of non-radioactive particles and radioactive particles. In other examples, the method includes the sequential administration of non-radioactive particles and radioactive particles, or the sequential administration of radioactive particles and non-radioactive particles.

[0092] In yet another aspect, the Disclosure provides a method for administering an appropriate amount of microparticles for therapeutic or diagnostic purposes. The method includes the simultaneous administration to a patient of (i) a first aggregate of radioactive microparticles and (ii) a second aggregate of non-radioactive microparticles.

[0093] In some examples, the first aggregate of radioactive particles is distinct from the second aggregate of non-radioactive particles. The first aggregate of radioactive particles and the second aggregate of non-radioactive particles may be administered as a mixture.

[0094] In yet another aspect, the disclosure provides a method for administering an appropriate amount of microparticles for therapeutic or diagnostic purposes. The method includes the sequential administration of non-radioactive and radioactive microparticles to a patient in a single treatment session.

[0095] In yet another aspect, the disclosure provides a method comprising the sequential administration to a patient of (i) radioactive particles for therapeutic use, and then (ii) non-radioactive particles.

[0096] In some cases, continuous administration includes intermittent administration of non-radioactive particles and radioactive particles. Such intermittent administration may include alternating administration of non-radioactive particles and radioactive particles.

[0097] In some examples, a sequence of doses includes all doses of one type of microparticles prior to the dose of the next type of microparticles. For example, a sequence of doses may include all doses of non-radioactive microparticles prior to the dose of any radioactive microparticles, or it may include all doses of radioactive microparticles prior to the dose of any non-radioactive microparticles.

[0098] The method of this disclosure may deliver an appropriate amount of radiation to a patient for therapeutic purposes, or an appropriate amount of non-radioactive particles to a patient for diagnostic purposes.

[0099] In some examples of the methods described above, the radioactive particles contain a diagnostically detectable radioisotope, and the non-radioactive particles contain a therapeutically active compound, the therapeutically active compound elutes from the particles under physiologically relevant conditions, and the method delivers a suitable amount of radioactive particles to the patient for therapeutic purposes and a suitable amount of non-radioactive particles to the patient for diagnostic purposes.

[0100] In the method of this disclosure, the administration may be by intra-arterial delivery, intraperitoneal delivery, or transdermal delivery, and the radioactive particles and / or non-radioactive particles may be those described above, and about 10% to about 80%, for example about 25%, of the total mass of particles delivered may be radioactive particles, or any combination thereof.

[0101] In various examples of compositions, delivery devices, and methods, radioactive and non-radioactive particles have substantially the same resistance when flowing through a conduit in a liquid, and / or the radioactive and non-radioactive particles can be used to treat neovascular tumors such as liver tumors or metastatic liver tumors.

[0102] While the above discussion concerns methods for administering radioactive and non-radioactive particles, this disclosure also intends to "use" corresponding particles, including particles useful in the disclosed methods, and to use particles in the manufacture of administerable formulations useful in the disclosed methods.

[0103] The radiopaqueness of bulk microsphere CT can be evaluated by quantitative radiopaqueness measurement, where the measurement is expressed as Hunsfield units (HU) obtained from five key repeating regions (ROL, n=5) recorded from each axial CT scan (1 mm slice thickness, pitch=0.5, 70 kVp and 120 kVp) using a 1.2 mL glass v-vial (product code: Z115061, Sigma Aldrich, Canada) containing 500 mg of microparticles in 6 μL of sterile saline. All measurements were performed on experimental materials with an average diameter (±SD) in the range of 20 μm to 30 μm, using a Siemens Somatom Definition AS+ scanner (Siemens Healthcare, Erlangen, Germany) and the extended HU range option used for scanning.

[0104] experiment

[0105] As will be described in more detail below, the exemplary mixture according to this disclosure was filled into a delivery device and then transferred from a microcatheter to simulate administration to a patient. Aliquots of the mixture dispensed from the microcatheter were taken over time, and the specific activity of each aliquot was measured. The measured specific activity remained substantially constant for aliquots containing particles. This suggests that hot and cold particles of the exemplary mixture did not separate from the delivery device during administration.

[0106] Raw materials and methods

[0107] Non-radioactive glass microparticles and radioactive glass microparticles were dispensed into 3 mL glass vials containing water using gravity measurement, and the mass ratio of non-radioactive microparticles to radioactive microparticles was set to 3:1.

[0108] Non-radioactive particles had a diameter distribution of 20-32 μm, with D5 < 22.2 μm, D50 < 28.1 μm, and D90 < 32.8 μm (measured with a HORIBA Instruments Camsiger X2 Particle size Analyzer with X-flow module), and a density of 3.36 g / cm³. 3 The average sphericity was 0.985 (measured with an AccuPyc II 1340 Pycnometer) (measured with a HORIBA Instruments Camsiger X2 Particle size Analyzer with an X-Flow module). The radioactive particles contained Y-90, had a size distribution of 20-32 μm in diameter, with D5 < 20.3, D50 < 26.6, D90 < 31.4, and a density of 3.39 g / cm³. 3 The average sphericity was 0.914.

[0109] The vials were secured with septums held in place by crimp seals. To ensure homogenization of the mixture, the vials were vortexed for approximately 30 seconds, after which the radioactivity of the blended vials was measured. The specific activity per "unit dose" was calculated using the measured radioactivity and mass.

[0110] A mixture of particulate matter was filled into a delivery device according to Figure 9 (incorporated herein by reference) disclosed in WO2020 / 082168. First, water was injected into the delivery device to remove all air from the system. The mixed vial was connected to the device and drawn into an elongated housing (910), which was then fixed at the administration site. The elongated housing (910) used in this experiment had a length of 21.6 cm, an inner diameter of 0.078” (approximately 1.98 mm), and an outer diameter of 0.125” (approximately 3.18 mm). This fixation provided the first opportunity for the particulate matter to form layers.

[0111] The settled microspheres were dispensed from a delivery device disclosed in WO2020 / 082168. Briefly, water was used as both the transport medium (904) and the replacement medium (906). Using a syringe filled with water, the microspheres were pushed from an elongated housing into a channel that transported the microspheres out of the fluid outlet (908). The length of the tube constituting the channel between the mixer (902), which mixed the microspheres and the transport medium (904), and the fluid outlet (908) was 150 cm. The inner diameter of the tube constituting the channel was 0.021” (approximately 0.53 mm). The downward movement of the channel provided another opportunity for the radioactive microspheres to separate from the non-radioactive microspheres.

[0112] Aliquotes were collected from the fluid outlet. After collection, the radioactivity of different aliquots was measured using an ionization chamber (Capintec Model CRC-15R). After measuring the radioactivity, water was evaporated using a hot plate, and the dry mass of the particles was measured. The specific activity (radioactivity per unit mass) from each aliquot was measured and compared to the theoretical specific activity (i.e., unit dose) of the initially blended mixture.

[0113] The above procedure was performed with unit doses of 100 mg and 800 mg. The results are shown in Tables 1-5 below. These results indicate that radioactive and non-radioactive particles in the exemplary mixture do not separate to a recognizable extent during filling of the delivery device and during subsequent administration from the delivery device. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0114] The preceding description includes numerous details for explanatory purposes to provide a complete understanding of the examples. However, it will be apparent to those skilled in the art that these specific details are unnecessary. Therefore, the matters described are merely illustrative of the application of the described examples, and many modifications and variations are possible in light of the above teachings.

[0115] Since the above description is for illustrative purposes only, modifications and variations may be carried out by those skilled in the art for specific examples. Accordingly, the claims should not be limited by the specific examples described herein, but should be interpreted in a manner consistent with the specification as a whole.

Claims

1. A therapeutic composition comprising (i) radioactive particles and (ii) non-radioactive particles, The non-radioactive particles have a radioactivity level of less than 0.15 GBq / g. The aforementioned radioactive particles contain 40% by mass of Y ２ O ３ , 20% by mass of Al ２ O ３ , and 40% by mass of SiO ２ It includes, and at least some of the yttrium is yttrium-90, The radioactive particles constitute 10% to 80% of the total mass of the particles in the composition. The mixture of the radioactive particles and the non-radioactive particles has an overall specific activity of 0.4 GBq / g or more. A composition in which the radioactive particles and non-radioactive particles have a size, surface area, shape, particle density, and surface state such that the relative drag ratio is 0.95:1 to 1:0.95, and the relative drag ratio is calculated by dividing the fall time of the radioactive particles by the fall time of the non-radioactive particles.

2. The falling time of the bolus of fine particles is A transparent column filled with distilled water is packed with a known number of microparticles, and the number of microparticles is selected such that the bolus of the microparticles is 2 to 5 times the height of the inner diameter of the column. The process involves first allowing the fine particles to settle at the bottom of the column and then inverting the column, The method involves measuring the total time required for a particle to fall and pass through a transition point, wherein the transition point is measured from the apex of the bolus of the particle and is at least 100 times the inner diameter of the column. Measured by, The composition according to claim 1.

3. The composition according to claim 1 or 2, wherein the radioactive fine particles and the non-radioactive fine particles have a size, surface area, shape, particle density, and surface state such that the relative drag ratio is 1.

0.

4. The composition according to any one of claims 1 to 3, wherein the difference in particle density between the radioactive fine particles and the non-radioactive fine particles is within 30% of the average of the two particle densities.

5. The composition according to any one of claims 1 to 3, wherein the difference in the average size of the radioactive particles and the non-radioactive particles is within 40% of the average of the two average sizes.

6. The composition according to claim 1, wherein the non-radioactive fine particles are inorganic polymer fine particles.

7. The composition according to any one of claims 1 to 6, wherein the radioactive particles and the non-radioactive particles have a specific gravity of 3.3 to 3.9 with respect to water and an average diameter of 20 to 40 microns.

8. The composition according to any one of claims 1 to 7, wherein the non-radioactive fine particles contain yttrium-89.

9. The non-radioactive fine particles are Ga ２ O ３ , SiO ２ , SrO, and optional Y ２ O ３ The composition according to any one of claims 1 to 8, which contains these.

10. The non-radioactive particles consist of 0.167 moles of Ga ２ O ３ fraction of 0.613 moles of SiO ２ The fractions of , 0.05 moles of SrO, and 0.17 moles of Y ２ O ３ The composition according to claim 9, comprising the fraction of the above.

11. The composition according to any one of claims 1 to 9, wherein the non-radioactive fine particles have radiopaqueness of 6,000 or more Hunsfield units (HU) at 120 kVp.

12. The aforementioned non-radioactive particles consist of 40% by mass of Y ２ O ３ , 20% by mass of Al ２ O ３ , and 40% by mass of SiO ２ A composition according to any one of claims 1 to 10, comprising the above.

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