Radiopaque glass materials

Abstract

To provide a radiopaque glass material in the form of microspheres that may be used for vascular embolization and / or radiologic imaging.SOLUTION: A glass material includes: about 0.55 to about 0.85 mole fraction of SiO2; about 0.01 to about 0.23 mole fraction of Na2O, K2O, or a combination of Na2O and K2O; about 0.05 to about 0.28 mole fraction of Y2O3, BaO, or a combination of Y2O3 and BaO; and optionally Ta2O5. In the glass material, the sum of the Y2O3, the BaO, and the optional Ta2O5 is about 0.01 to about 0.31 mole fraction.SELECTED DRAWING: Figure 2D

Description

[Technical Field]

[0001] Cross-reference of related applications This application is based on U.S. Provisional Patent Application No. 62 / 855,285, filed on May 31, 2019. The author asserts the rights of the author, and the entire content is incorporated herein by reference.

[0002] This disclosure relates to radiopaque glass materials suitable for forming microparticles that can be administered to patients. . [Background technology]

[0003] The following paragraphs all discuss prior art or the knowledge of a person skilled in the art. This does not acknowledge that it is part of it.

[0004] Therapeutic vascular occlusion (embolization) is used to treat specific pathological conditions in situ. It is a technique that involves using a catheter to treat various processes (tumors, This procedure is performed to place embolic agents in the circulatory system, such as in vascular malformations and bleeding vessels. [Overview of the project] [Problems that the invention aims to solve]

[0005] The following preface is intended to introduce this specification to the reader and to define the invention. It does not mean that one or more inventions are described below or in other parts of this document as device elements. Alternatively, it may belong to a combination or subcombination of steps of the method. They do not claim that the claim is valid simply because it does not describe one or more other inventions. We do not waive or withdraw our rights to any invention disclosed herein. .

[0006] The particulate embolization agent used in vascular embolization may not be radio-opaque, and therefore, it is difficult to observe by radiation imaging unless the particulate embolization agent is treated with a contrast agent before being injected. The microparticles of TheraSphere (trademark) yttrium-90 are commercially available radioactive microparticles and are used for the treatment of primary liver cancer and metastatic liver cancer, and have a radio-opacity of about 6,000 Hounsfield units (HU) at 120 kVp.

[0007] Radio-opaque particulate embolization agents are desirable because they can be observed by radiation imaging during or after embolization treatment. One or more examples described in this disclosure attempt to provide a radio-opaque glass material that has a greater radio-opacity than the particulate embolization agent.

Means for Solving the Problem

[0008] The glass material ultimately intended for use in vascular embolization may have a density of about 2.7 g / cm 3 , 3 , 3 , 3 , ~ to about 4.3 g / cm 3 . In certain examples, the glass material may have a density of about 2.9 g / cm 3 to about 3.7 g / cm 3 , or about 3.3 g / cm 3 to about 3.6 g / cm 3 . Particles having a density within this range are considered to be appropriately distributed within the patient's vasculature.

[0009] In the glass materials of the present disclosure, all of Y2O3, BaO, and Ta2O5 contribute to the radio-opacity of the glass. However, an increase in the amount of these components results in the resulting glass material The density of the material is also increased. The authors of the present disclosure have identified glass compositions that provide radiopacity at a density suitable for vascular embolization. Some glass materials of the present disclosure may have a radiopacity greater than 9,000 HU at 120 kVp. Some glass materials of the present disclosure may have a density of from about 2.7 g / cm to about 4.3 g / cm , for example, from about 2.9 g / cm to about 3.7 g / cm 3 , or from about 3.3 g / cm 3 to about 3.6 g / cm 3 . 3 3 3

[0010] In one aspect, the present disclosure provides a glass material comprising from about 0.55 to about 0.85 mole fraction of SiO2; from about 0.01 to about 0.23 mole fraction of Na2O, K2O, or a combination of Na2O and K2O; from about 0.05 to about 0.28 mole fraction of Y2O3, BaO, or a combination of Y2O3 and BaO; and optionally Ta2O5. In the glass material, the total of Y2O3, BaO, and optional Ta2O5 is from about 0.10 to about 0.31 mole fraction.

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[0014] In one specific example, the glass material contains approximately 0.74 mole fractions of SiO2; approximately 0.09 Mole fraction of Na2O; approximately 0.085 mole fraction of BaO; approximately 0.085 mole fraction of Ta2O 5; and contains B2O3 at a mole fraction of approximately 0.006. This particular glass material is 120kV It exhibits radiopaqueness of approximately 16,000 HU at p.

[0015] In another specific example, the glass material contains approximately 0.79 mole fractions of SiO2; approximately 0.06 moles Mole fraction of Na2O; approximately 0.08 mole fraction of BaO; approximately 0.07 mole fraction of Ta2O5; and It contains approximately 0.003 mole fractions of B2O3.

[0016] In yet another specific example, the glass material contains approximately 0.77 mole fractions of SiO2; approximately 0.03 1 mole fraction of Na2O; approximately 0.10 mole fraction of BaO; approximately 0.096 mole fraction of Ta2O 5; and approximately 0.002 mole fraction of B2O3.

[0017] In yet another specific example, the glass material contains approximately 0.80 mole fractions of SiO2; approximately 0.03 3 mole fractions of Na2O; approximately 0.82 mole fractions of BaO; approximately 0.085 mole fractions of Ta2O 5; and approximately 0.001 mole fraction of B2O3.

[0018] In some examples of this disclosure, the glass material of this disclosure is bulk glass. "Kuglass" is a glass material suitable for vascular embolization, and no additional processing is required. This refers to glass materials obtained by forming glass from starting reagents that have not been used. For example, to produce irregularly shaped glass particles, no processing steps are performed. Glass materials manufactured on an industrial scale can be considered bulk glass.

[0019] In other examples, the glass material of this disclosure is an irregular fine-particle glass material. The "fine particle glass material" is sized for vascular embolization, but is not properly molded. It means fine particle material. Irregular fine particle glass material is obtained by crushing bulk glass. The resulting particles can be prepared by sieving them and recovering fine particles of the desired size.

[0020] In yet another example, the glass material of this disclosure is a substantially spherical microparticle glass material. The term "substantially spherical microparticle glass material" is sized and molded for vascular embolization. This refers to finely divided microparticle material. A substantially spherical glass microparticle material is an irregular glass microparticle material. It can be prepared by remelting the surface of the material and forming substantially spherical particles. .

[0021] In another embodiment, a method for producing the glass material of the present disclosure is provided.

[0022] In yet another aspect of this disclosure, substantially spherical particulate matter as described herein. Glass materials are used in radiation imaging, computed tomography (CT) imaging, and cone-type imaging. X-ray-based radiographic imaging such as CT imaging or fluorescence fluoroscopy imaging. It can be used in smearing technology. This disclosure further relates to substantially spherical particulate smearing as described herein. This paper provides a method for imaging mammals using lath material.

[0023] In vascular embolization therapy using radioactive microparticles, increasing the number of microparticles allows for a more effective approach. Administering fewer particles with higher specific activity results in better tumor coverage. Therefore, it is desirable to administer more particles with lower specific activity, as this will result in a lower specific activity. It is thought that, although we do not wish to be bound by theory, the authors of this disclosure believe that microparticles are We believe they will remain at the first effective localization spot within the blood vessels they encounter. If there are enough localization spots to interact with the majority of the administered particles, Administering small amounts of microparticles can concentrate some of the particles in a portion of the tumor. In contrast, low Administering more specific-activity particles increases the saturation of effective localization spots, and tumors The effective area becomes more uniform.

[0024] For at least some tumor sizes and / or degrees of angiogenesis, (i) radiation (ii) administering a mixture of radioactive particles and (ii) radiopaque, non-radioactive particles according to the present disclosure to a patient. By doing so, even if individual radioactive particles have a higher specific activity, the specific emission will be lower. At least some of the advantages associated with administering more microparticles by injection may be offered. .

[0025] In one aspect, the Disclosure relates to (i) radioactive glass particles and (ii) non-radioactive materials as a result of the Disclosure. We provide a mixture of radiopaque glass microparticles, and the radioactive glass microparticles are used in the liver. Suitable for treating tumors, containing radioactive glass particles and non-radioactive radiopaque particles. The glass material is substantially the same size. In certain examples, the fine particle glass material of this disclosure and The radioactive glass particles have virtually the same density.

[0026] In some cases, the mixture was obtained by exposing glass particles to neutron radiation before radioactive induction. The radioactive glass microparticles are formed, and the radioactive glass microparticles are radiopaque microparticles of the present disclosure. It can be prepared by mixing it with lath material.

[0027] In a specific example, the mixture consists of (i) about 40% by mass of SiO2 and about 20% by mass of Al2O3. , and substantially spherical radioactive yttrium aluminum oxide containing approximately 40 mass% Y2O3 Silicate glass microparticles (approximately 0.170 mole fraction of Y2O3, approximately 0.189 mole fraction of Al) (ii) 2O3, and SiO2 at a mole fraction of approximately 0.641 moles, and (ii) approximately 0.73 to approximately SiO2 at a mole fraction of 0.80, Na2O at a mole fraction of approximately 0.03 to 0.11, and approximately 0.07 BaO at approximately 0.10 mole fractions, Ta2O5 at approximately 0.07 to 0.10 mole fractions, and approximately A substantially spherical glassy material containing B2O3 at a mole fraction of 0.001 to approximately 0.006. Includes.

[0028] In yet another aspect of this disclosure, if the mixture contains radioactive glass microspheres, the mixture is radioactive. By administering it to dairy animals, radiation is delivered to mammals. Such methods are additional Using X-ray-based radiation imaging techniques, particularly static imaging techniques... This may include imaging mammals. Imaging techniques include fluorescence fluoroscopy, etc. Computer tomography / positron emission tomography (CT / PET), or cone-beam tomography This may include Pewter tomography (CBCT).

[0029] The glass material relating to this disclosure may be included in a composition or a delivery device, or in a diagnostic device. It may be used as a method of discontinuation or treatment.

[0030] In some embodiments, the disclosure includes a mixture of radioactive and non-radioactive particles. A therapeutic or diagnostic set comprising at least some non-radioactive particles, including the glass material of this disclosure. To provide finished products.

[0031] In other embodiments, the Disclosure describes a method that includes administering a therapeutic or diagnostic composition to a patient. The present invention provides a method of administration by intravascular delivery, intraperitoneal delivery, or transdermal delivery.

[0032] In one embodiment, the present disclosure relates to the intravascular delivery of a mixture of radioactive and non-radioactive particles to a patient. The present invention provides a delivery device for intraperitoneal delivery or transdermal delivery. The delivery device is a mixed The delivery device can be fluidly coupled to the transport medium. A fluid inlet, a fluid outlet, and a fluid mixer fluidically coupled to the fluid inlet and fluid outlet, A source of radioactive particles fluidly coupled to a fluid mixer, and a non- Includes a source of radioactive particulate matter. At least some of the non-radioactive particulate matter are glass according to this disclosure. It is composed of materials. Radioactive particulate matter sources are distinct from non-radioactive particulate matter sources. The fluid mixer mixes radioactive particles with non-radioactive particles, and the radioactive and non-radioactive particles The mixture is delivered to the outside of the fluid outlet using a mixed transport medium.

[0033] In another aspect, the disclosure describes the intravascular administration of a mixture of radioactive and non-radioactive particles to a patient. The present invention provides a delivery device for delivery, intraperitoneal delivery, or transdermal delivery. The delivery device is a delivery device for delivery A fluid inlet capable of fluidically coupling to the transport medium, and at least one fluid inlet A fluid-coupled source of radioactive particles and radiation fluid-coupled to at least one fluid inlet. A source of radioactive particulate matter, a first fluid outlet fluidly coupled to the source of radioactive particulate matter, and a source of non-radioactive particulate matter It includes a second fluid outlet that is fluidly coupled. At least some of the non-radioactive particles are this It is composed of glass materials as disclosed. Radioactive particulate matter sources are distinguished from non-radioactive particulate matter sources. It is something that is done.

[0034] In the context of this disclosure, one aggregate of fine particles is defined as the case when two aggregates are not mixed. It should be understood that it is distinct from other aggregates of microparticles. For example, two s The syringe was able to expel fine particles in order to form a mixture by fluidizing. However, radioactive particles in the barrel of one syringe will not react with non-radioactive particles in the barrel of the second syringe. It should be understood as something distinct from the other.

[0035] In yet another aspect, the Disclosure relates to (i) a first aggregate of radioactive particles and (ii) non-radioactive particles. Mixing with a second aggregate of projectile particles, and mixing in an appropriate amount for therapeutic or diagnostic use. The present invention provides a method that involves administering a substance to a patient. At least some of the non-radioactive particles are , composed of the glass material as disclosed herein.

[0036] In yet another aspect, the disclosure provides for administering to a patient an appropriate amount of microparticles for therapeutic or diagnostic purposes. The present invention provides a method for administering non-radioactive particles to a patient, and the non-radioactive particles This includes administering radioactive particles to a patient without first detecting them. Non-radioactive particles At least some of these are composed of glass materials according to this disclosure. Administration is by intravascular delivery. The delivery route for non-radioactive particles is via intraperitoneal delivery or percutaneous delivery. It is the same as the administration route for particles.

[0037] In yet another aspect, the Disclosure provides a patient with an appropriate amount of microparticles for therapeutic or diagnostic purposes. The present invention provides a method for administering radioactive particles to a patient and for the radioactive particles to This includes administering non-radioactive particles to a patient without first detecting them. At least some of these are composed of glass materials according to this disclosure. Administration is by intravascular delivery. The delivery route for non-radioactive particles is via intraperitoneal delivery or percutaneous delivery. It is the same as the administration route for particles.

[0038] In yet another aspect, the disclosure relates to administering an appropriate amount of microparticles for therapeutic or diagnostic purposes. The method provides (i) a first aggregate of radioactive particles and (ii) non-radioactive particles This includes co-administration to the patient with the second aggregate of this substance. At least some of the non-radioactive particles are , composed of the glass material as disclosed herein.

[0039] In yet another aspect, the disclosure relates to administering an appropriate amount of microparticles for therapeutic or diagnostic purposes. The method provides a single therapeutic session for patients with non-radioactive particles and radioactive particles. This includes continuous administration in a test. At least some of the non-radioactive particles are gassed according to this disclosure. It is made from lath material.

[0040] In yet another aspect, the Disclosure relates to (i) radioactive particles for therapeutic use, and then (ii) non-emitting The present invention provides a method for the continuous administration of radioactive particles to a patient. The handle is composed of the glass material according to this disclosure.

[0041] In any of the above embodiments, the non-radioactive particles are the following “glass composition” This may be any of the non-radioactive glass compositions discussed in the section, and / or any of the characteristics of glass materials discussed in the following section titled "Glass Materials" They may be present individually or in combination. In any of the above embodiments, radioactive micro The particles are radioactive glass compositions relating to radiotherapy mixtures as described in the following sections. It's okay if it's slightly off. [Brief explanation of the drawing]

[0042] Hereinafter, embodiments of the present disclosure will be described with reference to the accompanying drawings, which are for illustrative purposes only.

[0043] [Figure 1] Figure 1 is a graph showing the cumulative ion emission curves obtained for exemplary glass compositions (spherical and after spheroidization) of the present disclosure, extracted in calcium and magnesium-free phosphate-buffered saline (CMF-PBS).

[0044] [Figure 2A] Figure 2A is a set of SEM images of irregular BIC2 glass powder at 250x and 1000x magnification.

[0045] [Figure 2B] Figure 2B is a set of SEM images of the spheroidized BIC2 nanoparticles at 250x and 1000x magnification.

[0046] [Figure 2C] Figure 2C is a set of SEM images at 250x and 1000x of BIC2 particles after spheroidization and sieving 24 hours after processing.

[0047] [Figure 2D] Figure 2D is a set of SEM images at 250x and 1000x magnification of BIC2 particles after spheroidization and sieving (72 hours) after processing.

[0048] [Figure 3]Figure 3 is a graph showing the CT radiopaqueness of various glass nanoparticles as a function of their volume fraction.

[0049] [Figure 4] Figure 4 is a graph showing the degree of R1 relaxation as a function of the volume fraction of various glass microspheres.

[0050] [Figure 5] Figure 5 shows representative images of T1-weighted, T2-weighted, and T2*-weighted BIC2 and COMP1 in various fractional volumes.

[0051] [Figure 6] Figure 6 is a graph showing the degree of R2 relaxation as a function of the volume fraction of various glass microspheres.

[0052] [Figure 7] Figure 7 is a graph showing the degree of R²* relaxation as a function of the volume fraction of various glass microspheres.

[0053] [Figure 8] Figure 8 is a graph showing the local magnetic dose (LMD) relaxation degree obtained by MRI susceptometry measurements as a function of the volume fraction of various glass microspheres. [Modes for carrying out the invention]

[0054] In the context of this disclosure, “glass material” generally refers to materials such as bulk or particulate materials. It should be understood as a qualitative material, and is understood to include glass of the specified composition. It should be. The terms “glass” or “glass composition” define the specific components of the composition. Therefore, reference to the physical properties of the material (e.g., particle size) is relevant to glass materials, on the other hand. References to compositional properties (e.g., mole fraction) relate to glass or glass composition. In some parts, the terms “glass,” “glass composition,” and “glass material” are used, for example. For example, if the glass material consists only of the described glass composition, They are used interchangeably, as if they were referring to the same component.

[0055] In the context of this disclosure, the range of disclosed values ​​is explicitly enumerated as the limits of the range. Not only are the numbers listed, but it's as if each number and its subrange are explicitly enumerated. This can be resolved in a flexible way that includes all individual numerical values ​​or subranges contained within that range. It should be explained. For example, the range "approximately 1 to approximately 10" simply includes approximately 1 to approximately 10. Rather, individual values ​​within the range of disclosed values ​​(for example, 1, 1.5, 2, 4, etc.) This should be interpreted as including sub-ranges (e.g., 1-3, 2-7, 5-6, etc.).

[0056] glass composition Generally speaking, this disclosure provides glass materials, which are approximately 0.55 to approximately 0.85 moles A fraction of SiO2, and approximately 0.01 to 0.23 mole fractions of Na2O, K2O, or Na2O It also contains a K2O compound. The amounts of Y2O3, BaO, and Ta2O5 in the glass are all Additionally, other elements for forming the glass affect the radiopaqueness and density of the glass. Because it can affect performance, the permissible amounts of Y2O3, BaO and / or Ta2O5 have been conventionally... It is unpredictable. Based on experimental results, the authors of this disclosure believe that the glass material of this disclosure is approximately Y2O3, BaO, or a mixture of Y2O3 and BaO in a mole fraction of 0.05 to approximately 0.28 moles. and any Ta2O5, and the sum of Y2O3, BaO, and any Ta2O5 is It was determined that the mole fraction should be approximately 0.10 to 0.31. In some examples, Y2 The total amount of O3, BaO, and selective Ta2O5 is approximately 0.10 to 0.25 mole fractions. It is also acceptable to use a fraction of approximately 0.10 to 0.15 moles.

[0057] In the context of mole fractions, "approximately X mole fractions" is related to the given value and the oxide being measured. It should be understood that this means any value within the range of estimation uncertainty. For example, In the context of inductively coupled plasma mass spectrometry (ICP-MS), the estimated uncertainty of SiO2 is the reported value. The estimated uncertainty for Na2O is 1% of the reported value, the estimated uncertainty for BaO is 2% of the reported value. The estimated uncertainty for Ta2O5 may be 1% of the reported value.

[0058] The glass of this disclosure contains Y2O3, BaO, or Y2O in a mole fraction of about 0.05 to about 0.08 moles. It may also contain a compound of 3 and BaO. Some exemplary glasses of this disclosure are any It does not contain Y2O3. Such exemplary glass will be discussed in detail below. This may be useful in mixtures of fine particles.

[0059] The glass of this disclosure contains up to about 0.12 mole fractions of Ta2O5, for example, about 0.10 moles Ta2O5 up to a mole fraction, for example, approximately 0.05 to approximately 0.12 mole fractions, for example, approximately 0.0 It may contain Ta2O5 in a mole fraction of 5 to approximately 0.10 moles.

[0060] The glass of this disclosure may also contain B2O3 in an amount up to 0.20 mole fraction. The total of B2O3 and SiO2 is approximately 0.60 to approximately 0.85, for example, approximately 0.60 to approximately The concentration may be 0.80 mole fraction. B2O3 is known in the art as a glass-forming agent. When B2O3 is incorporated into sodium silicate glass, sodium borosilicate glass Glass is obtained. Some examples of sodium borosilicate glass of this disclosure are resistant to decomposition. It may be more resistant. Some examples of sodium borosilicate glass of this disclosure are improved. It may have the ability to form glass.

[0061] Although this disclosure focuses on sodium silicate glass, both Na2O and K2O are also It acts as a modifier for the glass network, exerting many similar effects on the properties of the glass. It is known that... In some of the intended glasses of this disclosure, the glass composition is N It may contain only a2O (without K2O), or only K2O (without Na2O). In intended glass, the glass composition consists of Na2O and K in a ratio of 100:1 to 1:100. It may contain 2O. This disclosure further includes 50:1, 25:1, 10:1, 5:1, 1 This refers to ratios such as 1:1, 1:5, and 1:10, and any range of ratios in between. In some examples of this disclosure, the Na:K ratio is approximately 75:25, approximately 50:50, and approximately 25 It could be :75, or approximately 10:90.

[0062] In addition to its effect on the radiopaqueness of glass, BaO acts as a modifier of the glass network and It is known in this technology that the network in sodium silicate glass acts in this way. If the total amount of glass modifier is too high, glass may not form, or there may be concerns about the glass network. For qualitative reasons, glass may not be suitable as a durable embolizer. (BaO-containing) In the glass material shown, the total amount of BaO, Na2O, and K2O is approximately 0.10 to 0.33. The mole fraction may be, for example, about 0.15 to about 0.33 mole fractions. For example, BaO, The total amount of Na2O and K2O is approximately 0.10 to 0.25, for example, approximately 0.15 to 0. A 25 mole fraction is also acceptable.

[0063] The glass of this disclosure is preferably mainly sodium silicate glass. The total amount of SiO2 and Na2O in the lath may be approximately 0.65 to 0.90 mole fractions. stomach.

[0064] In some examples of glass materials disclosed herein, the sum of SiO2 and Na2O is The mole fraction is approximately 0.69 to 0.90 for , and for glass it is approximately 0.05 to 0.09 for It contains Ta2O5, and the total amount of Y2O3, BaO, and Ta2O5 is approximately 0.10 to 0. This is a mole fraction of 17. An exemplary glass material of such composition exhibits a high level of radiopaqueness and 3.3~3.6 g / cm³ 3 It shows a beneficial balance with particle density.

[0065] In other examples of glass materials disclosed herein, the sum of SiO2 and Na2O is approximately 0 The molar fraction is 0.65 to approximately 0.80, while glass has a Ta content of approximately 0.05 to approximately 0.10. Including 2O5, the total of Y2O3, BaO, and Ta2O5 is approximately 0.18 to 0.31 mg. This is a fraction. An example of a glass material with such a composition is dense, but has a high level of radiation. It may exhibit linear opacity.

[0066] In yet another example of glass materials disclosed herein, the glass is approximately 0.55 to approximately 0. 80, for example, SiO2 with a mole fraction of approximately 0.55 to approximately 0.75 and approximately 0.03 to approximately 0.23 For example, Na2O in a mole fraction of approximately 0.05 to approximately 0.22, and approximately 0.05 to approximately 0.12, for example For example, a mole fraction of approximately 0.05 to 0.08 of Y2O3, BaO, or Y2O3 and BaO The mixture contains approximately 0.05 to 0.12 mole fractions of Ta2, for example, approximately 0.05 to 0.09 mole fractions. Contains O5

[0067] For example, glass contains SiO2 in a mole fraction of approximately 0.70 to 0.73 and approximately 0.16 to 0 Na2O at a mole fraction of 0.18, Y2O3 at a mole fraction of approximately 0.05 to approximately 0.7, and approximately 0.05 It may contain approximately 0.7 mole fractions of Ta2O5. In one particular example, approximately 0.7 SiO2 at 1 mole fraction, Na2O at approximately 0.17 mole fractions, and Y2 at approximately 0.06 mole fractions. This is a glass containing O3 and approximately 0.06 mole fractions of Ta2O5. Another specific example is approximately 0. 72 mole fractions of SiO2, approximately 0.17 mole fractions of Na2O, and approximately 0.05 mole fractions of Y This glass contains 2O3 and approximately 0.06 mole fractions of Ta2O5.

[0068] In some examples of glass materials disclosed herein, the glass is approximately 0.55 to approximately 0.82, for example, SiO2 with a mole fraction of approximately 0.55 to 0.75 and approximately 0.03 to 0. 23. For example, Na2O in a mole fraction of approximately 0.05 to approximately 0.22, and approximately 0.05 to approximately 0.12 For example, Y2O3, BaO, or Y2O3 and Ba in a mole fraction of approximately 0.05 to 0.08 moles. A mixture of O and T in a mole fraction of approximately 0.05 to 0.12, for example, approximately 0.05 to 0.09. It contains a2O5 and B2O3 up to 0.1 mole fraction.

[0069] In some examples, the glass is approximately 0.65 to 0.82, for example, approximately 0.73 to 0. SiO2 at 80 mole fractions, and approximately 0.03 to 0.23, for example, approximately 0.03 to 0.11 The mole fraction of Na2O is approximately 0.06 to 0.12, for example, approximately 0.07 to 0.10 moles. The fractional amount of BaO and the mole fractions of approximately 0.06 to 0.12, for example, approximately 0.07 to 0.10. Ta2O5 and approximately 0.001 to 0.015 moles, for example, approximately 0.001 to 0.006 moles. Includes fractional B2O3.

[0070] One specific example is SiO2 at a mole fraction of approximately 0.69 and Na2O at a mole fraction of approximately 0.16. And, BaO at a mole fraction of approximately 0.07 moles, Ta2O5 at a mole fraction of approximately 0.07 moles, and approximately 0.01 moles This is a glass containing B2O3 in a specific fraction.

[0071] Another specific example is a mixture of approximately 0.66 mole fractions of SiO2 and approximately 0.20 mole fractions of Na2O. , approximately 0.065 mole fraction of BaO, approximately 0.06 mole fraction of Ta2O5, and approximately 0.011 This is a glass containing B2O3 in mole fraction.

[0072] Another specific example is a mixture of approximately 0.73 mole fractions of SiO2 and approximately 0.10 mole fractions of Na2O. Approximately 0.08 mole fraction of BaO, approximately 0.08 mole fraction of Ta2O5, and approximately 0.01 mole This is a glass containing fractional amounts of B2O3.

[0073] Another specific example is SiO2 at approximately 0.74 mole fractions and Na at approximately 0.09 mole fractions. 2O, approximately 0.085 mole fraction of BaO, approximately 0.085 mole fraction of Ta2O5, and approximately 0 This is a glass containing B2O3 at a mole fraction of 0.006.

[0074] Another specific example is SiO2 at approximately 0.79 mole fractions and Na at approximately 0.06 mole fractions. 2O, BaO in a mole fraction of approximately 0.08, Ta2O5 in a mole fraction of approximately 0.07, and approximately 0.0 This is a glass containing B2O3 at a mole fraction of 0.3.

[0075] A further specific example is SiO2 at approximately 0.77 mole fractions and Na at approximately 0.031 mole fractions. 2O, approximately 0.10 mole fraction of BaO, approximately 0.096 mole fraction of Ta2O5, and approximately 0. This is a glass containing B2O3 at a mole fraction of 0.02.

[0076] Another specific example is SiO2 at approximately 0.80 mole fractions and N at approximately 0.033 mole fractions. a2O, approximately 0.082 mole fractions of BaO, approximately 0.085 mole fractions of Ta2O5, and approximately This is a glass containing B2O3 at a mole fraction of 0.001.

[0077] A further example is a mixture of approximately 0.58 mole fractions of SiO2 and approximately 0.20 mole fractions of Na2O, A mixture of Y2O3 and BaO at approximately 0.06 mole fractions, and Ta2O5 at approximately 0.07 mole fractions. The glass contains approximately 0.09 mole fractions of B2O3. It may contain a fraction of Y2O3 and approximately 0.035 mole fraction of BaO.

[0078] The glass composition disclosed herein preferably comprises Li2O, Rb2O, V2O5, ZnO, and Fe Substantially free of O2 and one or more fluorides. Lithium oxide, rubidium oxide , and vanadium oxide, these oxides are present in sufficiently high concentrations, and these oxides When these oxides leach from glass materials, they can form cytotoxic glass. 0.01, for example, 0.001 or 0.0001 mole fractions, preferably 0 mole fractions. This is desirable. Fluorides in glass degrade the physiological state. Preferably, fluoride The compound is added in a mole fraction of 0.005 mole fraction or less, for example, 0.0001 mole fraction, preferably 0 mole fraction. This is expressed as a rate. Zinc oxide can leach from glass materials when present at sufficiently high concentrations. This may impair liver function. Preferably, zinc oxide should be present at a concentration of 0.01 mole fraction or less, for example. For example, a mole fraction of 0.001 or 0.0001, preferably 0 mole fraction. Iron oxide is added at a mole fraction of 0.01 mole fraction or less, for example, 0.001 or 0.0001 mole fraction, preferably. Alternatively, use 0 mole fraction.

[0079] The authors of this disclosure have identified glass compositions with properties particularly desirable for vascular embolization applications. The glass composition is shown in Table 1.

[0080] The compositions of formulations "TRCR#" and "BIC#" are reported based on the relative amounts of the starting materials. However, the actual composition of manufactured glass may differ slightly from the theoretical composition.

[0081] The composition of formulation “BIC#-IGP” is sieved to recover particles smaller than 45 μm. These compositions are reported based on measurements of the corresponding irregular glass powders. This is thought to more accurately reflect the actual composition of the manufactured glass.

[0082] The composition of formulation “BIC#-MPS” is manufactured from the corresponding BIC#-IGP composition. This is reported based on measurements of substantially spherical glass microparticles. These were sieved and obtained as microspheres with an average size range of 20 μm to 30 μm. The glass particle composition is prepared by flame-treating the particles to remelt the surface of the irregular particles, and then, The change occurs when essentially spherical particles are formed.

[0083] The composition of the formula “BIC#-MPC” is determined by the measurement of post-processing materials manufactured from the corresponding BIC#. The values ​​are reported. The substantially spherical microparticle glass material is composed of calcium and magnesium. Using 0.2 g / mL phosphate-buffered saline (CMF-PBS) that does not contain nesium, Post-treatment is performed at 50°C for 72 to 366 hours. The composition of the flame-treated particles is as follows: The particles change when they are treated to reduce the resulting surface reaction precipitates.

[0084] The composition of formulation “BIC2-MPC#” is manufactured from irregular BIC2 glass powder. This is reported based on measurements of the fine-particle glass material after it has been processed to be substantially spherical. The different compositions in the formulations are a result of different flame treatment parameters. Irregular BIC2 The glass powder is sieved to collect particles smaller than 45 μm, and the surface of the irregular particles is cleaned. It is remelted and flame-treated to form substantially spherical particles with an average size range of 20 μm. The material is sieved to obtain microspheres of approximately 30 μm in size, and is free of calcium and magnesium. After 72 hours of treatment at 80°C using 0.2 g / mL phosphate-buffered saline (CMF-PBS), the sample was treated. It was determined.

[0085] The composition of the glass is (a) a portion of the starting reagents and (b) the measured composition of the manufactured glass. When compared to (c) microparticles that have been processed to be substantially spherical and are useful for embolic angiogenesis, there were differences. They may be, however, in this disclosure, all of these are the same blood at various stages of production. It should be understood to refer to tubal embolization products. Therefore, for example, based on theoretical molar percentage. A BIC2 composition containing "SiO2 at approximately 0.69 mole fractions" is (i) a BIC2 composition containing "SiO2 at approximately 0.66 mole fractions (ii) Irregular glass powder containing SiO2'' and (ii) SiO2'' at a concentration of approximately 0.73 mole fractions A processed glass material having (iii) "SiO2 at a mole fraction of about 0.74 moles", "about 0 "SiO2 with a mole fraction of 0.77", "SiO2 with a mole fraction of approximately 0.79", or "SiO2 with a mole fraction of approximately 0.80". This refers to a treated glass material having a fraction of SiO2. Unless otherwise specified, this The mole percentages discussed in the specification refer to theoretical percentages based on the amount of starting reagents. [Table 1]

[0086] Irregularly spaced glass particles, sieved to collect particles smaller than 45 μm. Degree, density of substantially spherical fine-particle glass material, and radiation of substantially spherical glass composition The opacity is shown in Table 2. [Table 2]

[0087] In various tests, as disclosed in more detail below, TheraSpher® Ittriu The glass used in the Mu-90 microspheres is used as a control, and these microspheres are , 40% by mass Y2O3, 20% by mass Al2O3, and 40% by mass SiO2 (this specification Includes (referred to as "YAS4" or "COMP1" in the document). Irregular glass powder of YAS4 The mixture is then sieved to collect particles smaller than 45 μm, and contains 65.795 mol% SiO2. 2 (36.56% by mass), 19.111mol% of Al2O3 (20.90% by mass), and The measured composition was 15.095 mol% Y2O3 (42.40 mass%). The spherical microparticles of YAS4 glass contain 64.448 mol% SiO2 (38.12 mass). %, 19.492 mol% Al2O3 (20.89 mass%), and 16.060 mo The measured composition was 1% Y2O3 (40.70 mass%).

[0088] In contrast to the exemplary glass compositions described above, YAS4 glass contains particles smaller than 45 μm. The irregular glass powder sieved for recovery contained 3.3466±0.0060 g / c m 3 The material has a density of 3.3078±0.0077 g / cm³, and is substantially spherical. 3 density It has the property of being substantially spherical, and when measured using the CT radiopaqueness measurement method, it is found to be 70k The CT radiopaqueness at Vp is 10,387 ± 245 HU, which is for a substantially spherical material. The radiopaqueness of CT at 120 kVp is 5,955 ± 202 HU.

[0089] Glass formulations TRCR3, TRCR9, TRCR12, TRCR13, TRCR16, TRCR23, BIC1-MPS, BIC2-MPS, and BIC3-MPS are all, At 120kVp, it showed CT radiopaqueness exceeding 13,000 HU, which indicates control The radiopaqueness of the YAS4 glass composition is more than twice that of the other formulations. , TRCR3, TRCR9, TRCR13, BIC1-MPS, BIC2-MPS, and BIC3-MPS is a substantially spherical microparticle glass material, controlled by YAS4 glass. It has a density of no more than 10% of the density of the composition.

[0090] Glass materials The substantially spherical microparticles provided in this disclosure may be useful for embolic angiogenesis, firstly, bulk gas It is manufactured by forming lath. The bulk glass is then irregular according to the disclosure. It is processed to provide a fine particle glass material. The irregular particles are substantially spherical. Flame treatment is used to form particles. Irregular to form substantially spherical fine particles. The flame treatment of glass microparticles is well known in this art. An example of flame treatment is a flame ball. This includes shaping, ultrasonic atomization, droplet generation, and vertical flame. Various glass of the Disclosure The composition can melt at various temperatures. It is used to remelt the surface of irregular fine particles. The flame treatment process provides the surface of the target irregular glass microparticles with a temperature at which they can be remelted. To do this, various gases or gas mixtures such as propane-oxygen or acetylene-oxygen are used. It is possible. The fine particles that are sphericalized by flame treatment are produced as a result of flame treatment. The surface can be treated to reduce or remove reaction deposits.

[0091] In the context of this disclosure, the terms “particulate matter” and “fine particles” are interchangeable. This means particles having a diameter of less than 1200 μm. In a mixture of particles, the mixture is It has an average diameter of 1200 μm.

[0092] This disclosure may refer to “microspheres,” “glass microspheres,” or “spherical particles.” However, it should be understood that the particles in this disclosure do not need to be perfectly spherical. So, "substantially spherical" means a particle with an average sphericity (%SPHT) of at least 90%. It means a mixture of. Sphericity (%SPHT) is defined in ISO9276-6 and ISO1333. According to 22-2, the CamSizer P4 (ATS Scien) operates based on the principles of dynamic image analysis. Measurements can be taken using the (Tific, Burlington, ON) system.

[0093] %SPHT can be determined using the following formula:

number

[0094] The terms “microsphere” and “substantially spherical particles” can be used interchangeably, 12 This refers to substantially spherical particles with an average diameter of less than 00 μm. A mixture of fine particles is 1 It has an average diameter of less than 200 μm.

[0095] The bulk glass according to this disclosure may have the glass composition described above, which This can reflect the mol% of the constituent elements as theoretically shown. One specific example of such bulk glass is An example is BIC2 glass, with 0.687 mole fraction SiO2 and 0.163 mole fraction Na2O, BaO at 0.068 mole fraction, Ta2O5 at approximately 0.070 mole fraction, and approximately 0 It has a theoretical composition of B2O3 with a mole fraction of 0.012.

[0096] The irregular particles include any technology well known in the art, such as a ZrO2 grinding medium. Bulk glass is crushed using a planetary ball mill, and the resulting particles are sieved to obtain the desired result. It can be produced by recovering particles of a certain size. The use of ZrO2 as a grinding medium is Due to the toughness of the grinding medium over bulk glass, it helps reduce contaminants during the process. It is possible. One specific example of irregular fine particles according to this disclosure is BIC2-IGP glass. It consists of 0.659 mole fractions of SiO2, 0.146 mole fractions of Na2O, and 0.065 mole fractions of SiO2. BaO in a mole fraction of 1, Ta2O5 in approximately 0.062 mole fractions, and B2 in approximately 0.011 mole fractions. It contains O3. Other specific examples are BIC1-IGP and BIC3-IGP glass. ru.

[0097] Irregular particles can have an average diameter of approximately 15 μm to 1200 μm. The microparticles can be used in various vascular embolization protocols. The microparticles of this disclosure are used in tumor vascular systems. The size of the particles may be selected to preferentially distribute them over normal tissue. The distribution is affected. The microparticles according to this disclosure are, for example, microparticles used to visualize or treat liver tumors. It is useful for producing small spheres and can have an average diameter of approximately 15 μm to approximately 45 μm. In the example, the particles may have an average diameter of approximately 20 μm to approximately 35 μm. In other examples, see the disclosure. These irregular particles range from approximately 40 μm to 500 μm, approximately 40 μm to 300 μm, and approximately 300 μm. μm ~ approx. 500 μm, approx. 500 μm ~ approx. 700 μm, or approx. 700 μm ~ approx. 1200 μm To provide particles, they may be sieved. The microbulbs can be selected according to the inner diameter of the blood vessel to be occluded. For example, a substantive tumor (so Although they are far from the lid of the tumor, the blood vessels that supply blood to support tumor growth are located in the tumor. The microspheres can be larger in diameter than the blood vessels found within the tumor. Even if it is not useful for blocking larger blood vessels, larger particles are used to block larger blood vessels. It may be desirable to use it.

[0098] In the context of particle size and particle diameter, "approximately X μm" refers to the size measured using a test sieve of the indicated size. It should be understood that this is determined based on the tolerance range according to ASTM E-11. For example, the tolerance for a 50 μm test sieve is 3 μm. Therefore, "approximately 50 μm" means This refers to particles with a size of 47 μm to 53 μm. Another example is the tolerance of a 35 μm test sieve. The error is 2.6 μm. Therefore, "approximately 35 μm" means a range of 32.4 μm to 38.6 μm. This refers to particle size. The ASTM tolerance for a 25 μm sieve is 2.2 μm. (Reference) For test sieves without a specified diameter (for example, test sieves less than 20 μm), the label should read "approximately X μm". This means ±15% for 5-15 μm and ±50% for less than 5 μm. For example, "approximately 1 μm" This refers to particles with a size of 0.5 to 1.5 μm.

[0099] The irregular particles are flame-treated, causing their surface to remelt and form substantially spherical particles. The flame-treated irregular particles are irregular particles of appropriate size, and the propane / oxygen This can be achieved by introducing the system into the flame and directing the flame towards the collection system to create a spherical flame.

[0100] One specific example of substantially spherical microparticles as described herein is BIC2-MPS glass. 0.733 mole fraction SiO2, 0.109 mole fraction Na2O, 0.073 mole fraction The gases of BaO (0.074 mole fraction), Ta2O5 (0.011 mole fraction), and B2O3 (0.011 mole fraction) It has a lath composition. Other specific examples are BIC1-MPS and BIC3-MPS glass. That is the case.

[0101] Treating glass microspheres to reduce surface reactivity is a technique used in the field of the circumstances of the art. This is a known process, for example, stirring flame-treated fine particles at preferably 120 rpm. While doing so, the CMF-PBS solution is brought into contact with the material at a temperature of 80°C for at least 72 hours to achieve ultra-high purity. This can be achieved by washing with water. The number of particles is 0.2 per 1 mL of CMF-PBS. The concentration may be g. One specific example of the fine particles treated according to this disclosure is BIC2 -MPC glass with 0.739 mole fraction SiO2 and 0.086 mole fraction Na2 O, BaO at 0.085 mole fraction, Ta2O5 at 0.085 mole fraction, and 0.006 mole fraction It has a glass composition with a B2O3 fraction.

[0102] Spherical, irregularly shaped microparticles are not expected to have a substantially changing particle diameter. However, the spherical particles are sieved either before or after processing to obtain the desired result. It can provide particles of a certain size.

[0103] Imaging The radiopaque glass microspheres described herein are used in radiography imaging and computer Tomography (CT) imaging, cone-beam CT imaging, or fluorescence fluoroscopy imaging It can be used for X-ray-based imaging such as the following.

[0104] The desired radiopaqueness of glass microspheres depends on the type of imaging used, the target, and This may depend on the treatment area and / or clinical scenarios such as the estimated packing density of microspheres. When a small number of particles are delivered, the particles are distributed over a relatively wide area. When this is expected, when relatively low-power imaging techniques are used, or when these conditions In the case of the combination of materials, a glass with a higher degree of radiopaqueness is desirable. On the other hand, radiation If the line opacity is too high, imaging artifacts may occur, and the image Because the coating quality deteriorates, glass with low radiopaqueness allows a relatively large number of particles to be delivered. If the fine particles are expected to be distributed over a relatively small area, When relatively high-power imaging techniques are used, or any combination thereof This is desirable.

[0105] Less than 45 μm and 2.7 g / cm³ 3 ~Approx. 4.3g / cm 3 For example, approximately 2.9g / cm 3 ~Approx. 3.7g / cm 3 , or approximately 3.3 g / cm³ 3 ~Approx. 3.6g / cm 3 The density The glass microspheres according to this disclosure are administered by intra-arterial or intravenous delivery. It may be useful in its intended application. Approximately 3.3 g / cm³ 3 Glass microfibers having the density of the present disclosure The spheres have substantially the same density as currently commercially available radioactive particles.

[0106] Some of the glass microspheres described herein are used in positron emission tomography (PET) imaging. ), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (M It can be used with PET, SPECT, and / or MRI because it does not affect radioisotopes (RI).

[0107] To image the patient's liver, glass microspheres are delivered via intra-arterial or intravenous delivery. For imaging applications administered to patients, at least approximately 750 microscopic cells per gram of liver are required. The spheres may be administered to the patient. In some cases, approximately 1000 to 5 gram of liver. 000 microspheres may be administered. In a typical adult patient, approximately 1 million to 7 million microspheres are administered. A sphere may be administered.

[0108] Mixtures, compositions, delivery devices, and methods for radiotherapy Radioactive particles are being manufactured in only a few locations and are being prepared to be delivered to hospitals around the world. The specific activity of the particles provides the desired activity at the planned time of administration. It is calibrated in such a way. For example, TheraSphere yttrium-90 glass nanoparticles are calibrated in such a way. To produce fine particles with a nominal specific activity of approximately 110 GBq / g at noon, yttrium Prepared by neutron activation of -89-containing glass nanoparticles. Typically, each vial contains approximately 1.2 million particles (approximately 3 GBq in approximately 27 mg). It is supplied in quantities of 8 million microparticles (approximately 20 GBq in approximately 180 mg). Calibration and administration. Depending on the delay, the amount of effective radioactivity delivered is 0.17 GBq per vial. (1.2 million microparticles injected 9 days after calibration) to 18 GBq (1 day after calibration) This could range from up to 8 million microparticles being injected.

[0109] As mentioned above, increasing the number of particles allows for the deployment of fewer particles with higher specific activity. Because a better tumor-effective range is obtained than with a given amount of radioactivity delivery, It is considered desirable to administer a larger number of particles with specific radioactivity. For example, To administer 3 GBq of radioactivity to a patient, the total specific activity of the particles must be 22 GBq / g. If 6 million particles are administered, then 1.5 million microparticles are administered at 88 GBq / g. Furthermore, it is expected that favorable results can be obtained within the effective range of the tumor.

[0110] While it is not desirable to be bound by theory, the authors of this disclosure have found that at least some tumors In terms of size and / or degree of angiogenesis, (i) radioactive particles and (ii) by the present disclosure By administering a mixture of non-radioactive particles to the patient, the individual radioactive particles become more concentrated. Even with radioactivity, administering more particles with a lower specific activity results in at least... We believe it can also offer several advantages.

[0111] This disclosure includes (i) radioactive glass particles and (ii) non-radioactive radiation as a result of this disclosure. A mixture of permeable glass microparticles is provided. Radioactive glass microparticles are used to treat liver tumors. Suitable for: Radioactive glass microparticles and non-radioactive, radiopaque glass microparticles. The materials have substantially the same size. Particles of substantially the same size will be injected into the patient after They are expected to behave in virtually the same way. Therefore, they are a mixture of particles of virtually the same size. Administering this substance is thought to result in a uniform distribution of radioactive and non-radioactive particles.

[0112] In the context of this disclosure, particles having substantially the same size are (a) radioactive particles, and (b) The average size of radiopaque, non-radioactive particles is the average of these two average sizes. This means it is within 40% of the average. For example, radioactive particles have an average diameter of 20 μm. On the other hand, radiopaque, non-radioactive particles may have an average diameter of 30 μm. A 10 μm difference between the two types of microparticles is 40% of the average of the two values. (Size difference) The smaller the difference, the more similar the particle behavior is expected to be. Therefore, the difference in average size is 2 It is preferable that the size is within 10% of the average size of each individual.

[0113] The density of the microparticles can further influence the behavior of the microparticles after injection into the patient. In the example, the radiopaque particles and radioactive glass particles of this disclosure have substantially the same density. To possess.

[0114] 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 large number of particles in a given area. Particle density is, Bulk density is an inherent property of the material, and it changes depending on the material's properties in its total volume. Particle density can be discussed in terms of specific gravity, which is the ratio of the density of a substance to the density of a standard substance. In the context of this disclosure, specific gravity refers to water. In the context of this disclosure, substantially the same density Particles having this characteristic mean particles that make up about 30% of the average, preferably about 15%.

[0115] (a) The particle density of radioactive particles and (b) radiopaque, non-radioactive particles is, on average It may be within approximately 30%, preferably within approximately 15%. For example, radioactive particles are 3. 3g / cm 3 It may have a particle density of the above, while radiopaque, non-radioactive fine particles are 3.9 g / cm³ 3 It may have a particle density of 0.6 g / cm³ between the two types of fine particles. 3 The difference is 16.7% of the average of these two values.

[0116] The mixtures according to this disclosure use any radiopaque glass composition disclosed herein. It can be manufactured by [doing something].

[0117] The mixture is obtained by exposing glass particles to neutron radiation before radioactive impregnation. Forming particles and mixing radioactive glass microparticles with the radiopaque glass microparticles of this disclosure. It can be prepared by [method].

[0118] In one particular example, the mixture consists of (i) about 40% by mass of SiO2 and about 20% by mass of Al 2O3, and about 40% by mass of Y2O3 (equivalent to about 0.170 mole fraction of Y2O3, about 0.189 mole fraction of Al2O3, and about 0.641 mole fraction of SiO2), substantially spherical shaped radioactive yttrium-aluminosilicate glass microparticles, and (ii) about 0.7 41 mole fraction of SiO2, about 0.086 mole fraction of Na2O, about 0.085 mole fraction of B aO, about 0.085 mole fraction of Ta2O5, and about 0.006 mole fraction of B2O3, containing substantially spherical radiation-impermeable microparticle glass material.

[0119] Yttrium-89 can be converted to yttrium-90 by exposing the yttrium-89 contained in the microparticles to a thermal neutron flux. The specific activity of the resulting microparticles depends on the level of the flux and the exposure time. For example, yttrium-89 can reach a specific activity exceeding 150 GBq / g by being exposed to a flux of nominally 10 thermal neutrons / cm 14 per second for several days. / s and allowing the neutron radiation to act for several days. 2 An improvement in the tumor effective range, such as a more uniform distribution of microparticles, can be achieved using a mixture having a quantity of radioactive microparticles in the range of about 80% to about 10% (w / w) of the total mass of the microparticles in the composition. In the context of the present disclosure, any mention of an improvement should be understood as a comparison with the same number of radioactive microparticles in the absence of additional non-radioactive microparticles.

[0120] For radioactive microparticles having a high specific activity such as 140 GBq / g, the mixture may have fewer radioactive microparticles (such as about 10% by mass). In contrast, for radioactive microparticles having a low specific activity such as 4 GBq / g, the mixture may have more radioactive microparticles (such as about 80 %). In the context of the present disclosure, any mention of an improvement should be understood as a comparison with the same number of radioactive microparticles in the absence of additional non-radioactive microparticles. <00.....913>It should be understood that the comparison is made with the same number of radioactive microparticles in the absence of additional non-radioactive microparticles.

[0121] For radioactive microparticles having a high specific activity such as 140 GBq / g, the mixture may have fewer radioactive microparticles (such as about 10% by mass). In contrast, for radioactive microparticles having a low specific activity such as 4 GBq / g, the mixture may have more radioactive microparticles (such as about 80 % by mass). % by mass). It may have a specific activity (such as mass%). In certain examples, for example, a specific activity of about 88 GBq / g In the case of radioactive particles, the mixture may contain approximately 25% by mass of radioactive particles.

[0122] "Specific activity" refers to the radioactivity per unit mass of radioactive particles, while "overall activity" refers to the radioactivity per unit mass of radioactive particles. "Radioactivity" refers to the radioactivity per unit mass of a mixture of radioactive and non-radioactive particles. This should be understood as follows: For example, radioactive particles with a specific activity of 10 GBq / g When you take the rum and mix these particles with 1 gram of non-radioactive particles, the total is 5G A mixture of fine particles having an overall specific radioactivity of Bq / g is obtained.

[0123] A mixture of radioactive and non-radioactive particles is formulated with a desired radioactivity and varying numbers of total particles. It can be prepared by the following: The total number of microparticles is based on the tumor size and / or the degree of angiogenesis. A sample can be selected based on the following criteria. For example, a sample containing 10 GBq of radioactivity in 0.5 grams of fine particles. One method is desirable for treating tumors with a certain degree of angiogenesis, while the other method uses 10G per gram. Prescriptions containing Bq radioactivity may be preferable for treating more angiogenic tumors. ru.

[0124] In yet another aspect of this disclosure, if the mixture contains radioactive glass microspheres, the therapeutic amount By administering a mixture to mammals, radiation is delivered to them. In addition, it involves imaging mammals using X-ray-based radiation imaging techniques. This may include administering such a mixture of particulate matter to a patient in therapeutic amounts, within the tissues. Based on the measured distribution of non-radioactive, radiopaque particles, imaging is impossible. It can enable the calculation of the radiation dose delivered to tissues by radioactive microparticles.

[0125] Although not desired to be bound by theory, the authors of the present disclosure further believe that at least some of the advantages of administering a mixture of radioactive and non-radioactive microparticles can be obtained upon separate administration of radioactive and non-radioactive microparticles.

[0126] In some embodiments, the present disclosure provides a therapeutic or diagnostic composition comprising a mixture of radioactive and non-radioactive microparticles, wherein at least some of the non-radioactive microparticles are the glass materials disclosed in this specification.

[0127] The radioactive microparticles and the non-radioactive microparticles have a difference in particle density, and the difference is within 30% of the average of the two particle densities, preferably within 15%.

[0128] The radioactive microparticles may have an average diameter of about 10 to about 1200 microns, for example, an average diameter of about 20 to about 40 microns. The non-radioactive microparticles may have an average size of about 10 to about 1200 microns, for example, an average diameter of about 20 to about 40 microns. The radioactive microparticles and the non-radioactive microparticles may have a difference in average size, and the difference is within 40% of the average of the two average sizes.

[0129] In some examples, the radioactive microparticles and the non-radioactive microparticles have substantially the same resistance when flowed in a liquid through a conduit.

[0130] Those skilled in the art will understand that the resistance of an object flowing in a liquid through a conduit is reflected by the drag coefficient, and the drag coefficient is a function of surface friction and form drag. Therefore, when flowing through a conduit The resistance of fine particles flowing in a liquid depends, for example, on the size, surface area, shape, density, and / or it may be affected by the surface condition of the fine particles. Those skilled in the art will further know how to increase the drag Changing characteristics in order to reduce drag is done by changing other characteristics. Since they can cancel each other out, it is easy to understand that two different particles can have virtually the same resistance. For example, if the surface state of the first particle is sufficiently smoother than the surface state of the second particle If so, even if the first particle is larger than the second particle, the two particles are still substantially the same. They may have the same drag coefficient.

[0131] In the context of this disclosure, the requirements for a bolus of particulate matter passing through a liquid to fall a set distance are The time it takes can represent the resistance of particles flowing through the liquid in the conduit. This time is equivalent to distilled water. This can be measured by filling a transparent column with a known number of microparticles. The number of microparticles should be selected so that the height of the particle bolus is 2 to 5 times the inner diameter of the column. The process involves first allowing the fine particles to settle at the bottom of the column, then inverting the column to counteract gravity. The drag force causes the fine particles to fall into the distilled water. The fine particles then drop to a transition point. The total time required for the particles to descend and pass through is measured. The transition point is measured from the apex of the particle bolus. It is determined to be at least 100 times the inner diameter of the column. For example, a column with an inner diameter of 0.5 cm. So, the settled particles may be 1.5 cm high, and the bolus of particles falls... The total time is when all the particles fall to a point 50 cm away from the peak of the settled particles. This is the time required to pass through.

[0132] This total fall time was measured under the same conditions (i.e., the same liquid, the same column, the same transition point). The total fall time is compared to that of a substantially equal number of different groups of particles tested. Relative drag ratio This is calculated by dividing the fall time of the first group of particles by the fall time of the second group of particles. In the context of this disclosure, the first and second fine particles have a relative drag ratio of approximately 0.95:1. When the ratio is approximately 1:0.95, the resistance is substantially the same when flowing through the liquid in the conduit. That's what I think.

[0133] In some cases, the radioactive particles are approximately 10 times the total mass of particles in the composition. It is composed of approximately 80%, for example, about 25%.

[0134] In some cases, radioactive particles are diagnostic radioactive particles. In some cases, These are radioactive particles used for therapeutic purposes.

[0135] Diagnostic radioactive particles include copper-67, holmium-166, indium-111, and iodine. -131, Lutetium-177, Molybdenum-99, Phosphorus-32, Rubidium-82, Te One of the radioactive isotopes selected from the group consisting of knetium-99m and thallium-201. The above may be included.

[0136] The therapeutic radioactive particles are actinium-225, bismuth-213, copper-67, indi Iodine-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 Contains one or more radioactive isotopes selected from the group consisting of -89 and tungsten-188. You can stay like that.

[0137] Radioactive glass particles can be substantially spherical. Non-radioactive particles are substantially spherical. could be.

[0138] In another aspect, the Disclosure relates to a mixture of radioactive and non-radioactive particles as described above. The present invention provides a method for administering to a patient, wherein the administration is by intravascular delivery, intraperitoneal delivery, or This is done via transdermal delivery.

[0139] In yet another aspect, the disclosure describes the use of a mixture of radioactive and non-radioactive particles to a patient. The present invention provides a delivery device for intravascular, intraperitoneal, or transdermal delivery. It is a fluid that can be fluidically coupled to a mixed transport medium, and a fluid input that can be fluidly coupled to a mixed transport medium. A fluid mixer with a port, fluid outlet, fluid inlet and fluid outlet, and a fluid mixer with a fluid outlet. A fluid-coupled source of radioactive particles, and a fluid mixer with a fluid-coupled non-radioactive particle supply. Includes particle sources. Radioactive particulate matter sources are distinct from non-radioactive particulate matter sources. Fluid micro The Xer mixes radioactive and non-radioactive particles and uses a mixed transport medium to deliver the fluid. A mixture of radioactive and non-radioactive particles is delivered orally. At least the non-radioactive particles Some of these are composed of the glass material described herein.

[0140] In yet another aspect, the disclosure describes the use of a mixture of radioactive and non-radioactive particles to a patient. The present invention provides a delivery device for intravascular, intraperitoneal, or transdermal delivery. It includes at least one fluid inlet that can be fluidly coupled to the transport medium, and at least one fluid inlet A source of radioactive particulate matter fluidly coupled to the mouth, and a non-fluidally coupled non-fluidally coupled to at least one fluid inlet. A source of radioactive particulate matter, a first fluid outlet fluidically coupled to the source of radioactive particulate matter, and non-radioactive fine particles It includes a second fluid outlet that is fluidically coupled to the source. The radioactive particulate source is connected to the non-radioactive particulate source. These are distinguishable. At least some of the non-radioactive particles are glass according to this disclosure. It is composed of materials. In some examples, the delivery device is used in a single treatment session. This delivers radioactive and non-radioactive particles. In some examples, the first fluid outlet and The second fluid outlets are in close proximity to each other. In the context of this disclosure, for example, a single therapeutic session In the process, when it is possible to administer radioactive and non-radioactive particles to the patient substantially simultaneously. The fluid outlets should be understood to be in close proximity to each other.

[0141] The radioactive particles in the delivery device may be any of the radioactive particles disclosed herein. Non-radioactive particles within the delivery device are any non-radioactive particles disclosed herein. It can be a child. In some cases, radioactive particles contribute to the total mass of particles in the delivery device. In contrast, it is composed of approximately 10% to 80%, for example, about 25%.

[0142] In yet another aspect, the disclosure relates to (i) a first aggregate of radioactive particles and (ii) non-radioactive particles. Mix the mixture with a second aggregate of fine particles and administer an appropriate amount of the mixture to the patient for therapeutic or diagnostic purposes. The present invention provides a method that includes doing so. At least some non-radioactive particles are provided by the present disclosure. It is composed of a glass material. The radioactive particles used in the method are disclosed herein. The non-radioactive particles used in the above method may be any radioactive particles. Any non-radioactive particles disclosed in this document may be used. In some examples, radioactive particles This is approximately 10% to 80% of the total mass of the fine particles used in this method, for example, approximately 25% It is composed of %. Administration can be by intravascular delivery, intraperitoneal delivery, or transdermal delivery.

[0143] In other embodiments, the Disclosure relates to a method for administering to a patient an appropriate amount of microparticles for therapeutic or diagnostic purposes. The method provides the administration of non-radioactive particles to a patient, and first the non-radioactive particles Administering radioactive particles to a patient without detecting the particles, or administering radioactive particles to a patient Administering the drug, and first administering non-radioactive particles to the patient without detecting radioactive particles. This includes any of the following: At least some of the non-radioactive particles are gas as a result of this disclosure. It is composed of lath material. Administration is by intravascular, intraperitoneal, or transdermal delivery. Non-aerosolized. The administration route for radioactive particles is the same as that for radioactive particles.

[0144] In some examples, the method includes the simultaneous administration of non-radioactive particles and radioactive particles. In other examples, the method involves the continuous administration of non-radioactive particles and radioactive particles, or radioactive fine particles. This includes continuous administration of radioactive and non-radioactive particles.

[0145] In yet another aspect, the disclosure relates to a method for administering an appropriate amount of microparticles for therapeutic or diagnostic purposes. The method provides (i) a first aggregate of radioactive particles, and (ii) non-radioactive particles This includes simultaneous administration of the second aggregate of this drug to the patient. At least some of the non-radioactive particles are It is composed of glass materials as disclosed herein.

[0146] In some cases, a first aggregate of radioactive particles and a second aggregate of non-radioactive particles These are distinct entities: a first aggregate of radioactive particles and a second aggregate of non-radioactive particles. The body can be administered as a mixture.

[0147] In yet another aspect, the disclosure relates to a method for administering an appropriate amount of microparticles for therapeutic or diagnostic purposes. The method provides a treatment for non-radioactive and radioactive particles in a single treatment session. This includes continuous administration to the person. At least some of the non-radioactive particles are glass materials according to this disclosure. It is composed of ingredients.

[0148] In yet another aspect, the Disclosure relates to (i) radioactive particles for therapeutic use, and then (ii) non-radioactive The present invention provides a method for the continuous administration of microparticles to a patient, comprising at least several non-radioactive microparticles. It is composed of the glass material according to this disclosure.

[0149] In some cases, continuous administration includes intermittent administration of non-radioactive and radioactive particles. Intermittent administration may include alternating administration of radioactive particles.

[0150] In some cases, continuous administration requires administering one type of microparticle before administering the next type of microparticle. This includes all administrations. For example, in a series of doses, non-reactive material is used before administering any of the radioactive particles. Before administering all of the radioactive particles, or before administering any of the non-radioactive particles, This may include administering all of the radioactive particles.

[0151] The method described herein allows for the delivery of an appropriate amount of radiation to a patient for treatment, and This allows for the delivery of a sufficient amount of non-radioactive particles to the patient for diagnostic purposes.

[0152] In the method described herein, administration may be by intravascular delivery, intraperitoneal delivery, or transdermal delivery. The radioactive particles and / or non-radioactive particles may be those described above, and Approximately 10% to 80% of the total mass of particles reached, for example, about 25%, are radioactive particles. They may be children, or any combination thereof.

[0153] The above description relates to a method for administering radioactive and non-radioactive particles, but this disclosure is , the corresponding “use” of the fine particles, including fine particles useful in the disclosed method, and the disclosed The use of microparticles in the manufacture of useful, administerable formulations is similarly intended in the methods described above. ru.

[0154] In the context of this disclosure, non-radioactive particles discussed in this section of this disclosure are "ga Any of the characteristics of the glass materials discussed in the above section titled "Lath Materials" or It should be understood that combinations are possible. For example, non-radioactive particles are as described above. Any or all of the characteristics related to fine particles, microspheres, glass microspheres, or spherical particles It is possible to have.

[0155] In the context of this disclosure, the radioactive particles discussed in this section of this disclosure are the same as those described in this disclosure. It may have one or a combination of any of the characteristics of the radioactive glass materials discussed. It should be understood.

[0156] Examples

[0157] Synthesis of irregular glass powder and microspheres Various glasses were synthesized in accordance with this disclosure. Theoretical sets of TRCR# and BIC# glasses. The composition is shown in Table 1 above. In addition, glass COMP# was synthesized for comparison. Comparison of these The theoretical composition of the example is shown in Table 3. [Table 3]

[0158] The density of irregularly sized glass particles sieved to collect particles smaller than 45 μm, The density of glass material with substantially spherical fine particles, and the radiation-resistant properties of a substantially spherical glass composition. The transparency is shown in Table 4. [Table 4]

[0159] Comparative example “COMP1” corresponds to YAS4 disclosed in U.S. Patent No. 4,789,501. For the clinical utility of this glass and the known composition-structure-properties relationship, the authors of this disclosure Using this comparative example, they found substantially equivalent microsphere density (±10%) and enhanced radiation immunity. Permeability, acceptable in vitro cytotoxicity, acceptable blood compatibility, and / or acceptable genetics. A glass composition possessing transmissible toxicity was identified. While not bound by theory, the authors of this disclosure believe that... Glass compositions that meet many or all of these requirements are suitable for transarterial radioembolization. I expect it to be useful for [purpose].

[0160] For glass synthesis, analytical grade reagents were used according to the theoretical compositions outlined in Tables 1 and 3. The reagents were weighed. After blending uniformly for more than an hour, the reagents were placed in a platinum-rhodium crucible (50cc~ Place in a 200cc container and fire in an electric furnace (Carbolite Furnaces, Sheffield, UK). (1500℃~1600℃, 3 hours~5 hours), then sterile water for injection (USP, Ph. Eur. Grade, Shock quenching was performed on Rocky Mountain Biologics (MT, US). The resulting irregular glass samples were... The powder was dried in an oven (120°C) overnight.

[0161] All of the exemplary glass in this disclosure, as well as COMP1 and COMP3, are shock-resistant. Before the inch, it provided an easily melting, non-viscous fluid. The glass of COMP2 did not melt. Phase separation or a viscous fluid was provided.

[0162] Irregular glass powders from various molten materials are mixed together, and a planetary bore containing a ZrO2 grinding medium is used. The glass was ground in batches using a glass mill. The resulting crushed, irregular glass powder was then sieved. Then, particles smaller than 45 μm were collected.

[0163] Next, the appropriately sorted irregular glass powder is subjected to a process that appropriately controls the flow of oxygen and propane. The material was introduced into a propane / oxygen flame. The material was remelted and processed in a manner also known as spheroidization. In the process, spherical particles were formed by surface tension. The flame of the burner was directed at the glass microspheres. It was intended for a stainless steel recovery system that would collect the glass microspheres as they were released. Afterward, the glass microspheres were sieved to obtain microspheres with an average size range of 20 μm to 30 μm.

[0164] X-ray diffraction X-ray diffraction (XRD) measurement of irregular glass powder and / or fine particles is performed using an X-ray generator (3 Bruker D2 Phaser diffractometer coupled to a Cu target X-ray tube (0kV; 10mA). The experiment was conducted using (Bruker AXS Inc., Madison, WI). Irregular glass powder or fine particles were used. Each experimental material sample is pressed into a hollow zero-background holder. The powder diffraction was prepared using a scanning angle range of 10° < 2θ < 100° and a step size of 0.02. The data was acquired in °. The XRD spectrum acquisition time was 4930 seconds.

[0165] Helium pycnometry The density of irregular glass powder and / or fine particles is determined by helium pycnometry (AccuPyc II). Measurements were taken using 1340 (Micromeritics), and in the form of irregular glass powder, the material after quenching was measured. The average value (± standard deviation SD) of 10 to 60 measurements recorded using the same method was used to determine the final shape of the fine particles. For the state, the average value of 10 measurements (±SD) was used.

[0166] Differential scanning calorimetry Regarding the thermal properties of irregular glass powder, a Netzsch Pegasus F404 differential scanning calorimeter (DSC) was used. Characterized by Burlington, MA. From ambient temperature to 1000°C, heating rate 10°C. DSC measurements were performed at a rate of / min, and the initial (Tg, start) was recorded using Proteus 6.0 software. The glass transition temperature at the midpoint (Tg, midpoint) was also determined graphically. D used in this study The tolerance for SC is 2%.

[0167] Treatment of microspheres A substantially smooth surface with virtually no surface reaction deposits resulting from spheroidization. To obtain the surface, flame-treated microspheres are subjected to a calcium and magnesium-free phosphate solution. 0.2 in CMF-PBS (Product Code: MT21040CV, Corning (Trademark), NY, US) The spheroidized samples were processed by extraction at a concentration of g / mL.

[0168] The initial experiment involved placing microspheres in a sealed container in a shaking water bath at 50°C for 72±2 hours, and then 120± Continuous stirring at 120 rpm for 2 hours, 240±2 hours, 288±2 hours, and 360±2 hours. Extracted using [method]. Further analysis revealed that [features] that facilitate the processing steps designed for manufacturing. To investigate the possibility, microspheres were subjected to acceleration conditions (80°C) in a shaking water bath in a sealed container. Extraction was completed by continuous stirring at 120 rpm for 4 ± 2 hours and 72 ± 2 hours.

[0169] After extraction, the fine particles were separated from CMF-PBS and then treated with sterile water for injection (USP, Ph. Eur. Grey). After washing (10 times) with Rocky Mountain Biologics (MT, US), constant weight (mass difference ≤ 0. It was dried at 120±2℃ until it reached 1%.

[0170] The glass microspheres were then stored for analysis or re-grinding. The final average size was 20 To ensure fine particles of μm to 30μm, washed glass storage vials for bulk storage are used. Before packing them, I sorted them by size.

[0171] The cleanliness of the microspheres (i.e., the presence of surface reaction deposits and / or contaminants as determined by visual inspection) The qualitative absence was confirmed by scanning electron microscopy (SEM) analysis. (As mentioned above, 72±2 hours) Research on processing for 120±2 hours, 240±2 hours, 288±2 hours, and 360±2 hours. The extracts of microparticles obtained during the investigation were tested at an ISO 17025 accredited laboratory (NSL Analytical). The test program was verified at 4450 Cranwood Pkwy, Warrensville Heights, OH, US. Using Tocol, the concentrations of Si, Na, Ta, B, and Ba elements were determined by ICP-OES. It was analyzed.

[0172] Composition analysis For compositional analysis, irregular glass powder and / or microspheres are subjected to fusion / microwave acid decomposition. Sample preparation was performed by an ISO 17025 accredited laboratory (NSL Analytical, 450 Cran, USA). Using a validated test protocol at Wood Pkwy, Warrensville Heights, OH) The analysis was performed using ICP-OES.

[0173] Scanning electron microscope Regarding the form of irregular glass powder and / or microspheres coated with carbon, 1. Acceleration voltage of 5KV to 10.0KV, light emission current of approximately 15μA to 22μA, and approximately 12mm Using a Hitachi S-4700 field emission SEM (FE-SEM) operating with a working distance of 14 mm We investigated this and obtained SEM images at magnifications of 250x and 1000x.

[0174] Safety evaluation of axial computed tomography (CT) scans and MRI. The radiopaqueness of bulk microspheres was evaluated by quantitative radiopaqueness measurement, and here In this measurement, 1.2 mL of glass containing 500 mg of fine particles was used in 6 μL of sterile physiological saline. Using Sigma Aldrich v-vial (product code: Z115061, Canada), each Axial CT scan (1mm slice thickness, pitch = 0.5, 70kVp and 120kV) Hans Fee obtained from five important iterative regions (ROL, n=5) recorded from p) The values ​​are shown as HU units. All measurements were taken with an average diameter (±SD) of 20 μm. The experiment was conducted on experimental materials within a 30 μm range using a Siemens Somatom Definition AS+ scanner. - (Siemens Healthcare, Erlangen, Germany) and the extended HU rangefinder used for the scan I used the option.

[0175] This study investigates the effects of microsphere concentration on the quantitative radiopaqueness of CT and the safety of MRI. To achieve this, microspheres from BIC1-BIC3 and COMP1 control were measured at five different concentrations. Prepared with (the following volume fractions: 1.25%, 2.5%, 5%, 7.5%, and 10%) (3 times). Gel-specific tubes (0%) were also used as a baseline control. All The volume fraction was calculated using the densities of microspheres in Tables 2 and 4, and in 1.5 mL of 8% gelatin. Prepare the mixture, then add microspheres to the gelatin which has been vigorously shaken in a 5 mm NMR tube. After optimizing the uniformity of the particle distribution, it was quickly set on the ice. The tube was excessively uneven. In some cases, the gel was melted, the microspheres were redispersed, and then reset using ice. Depending on the density, some aggregation of microspheres formed around and at the bottom of the tube.

[0176] CT data was obtained using a Trifoil Preclinical PET / CT scanner, with a 100 μm size. Acquired at 80kVp with sample resolution, all CT images were converted to H for subsequent analysis. The data was converted to U format. MRI data was obtained using a 3T Varian MRI system with an INOVA console. Acquired. Bulk T1, T2, and T2 * For quantitative measurement, a birdcage-type RF transceiver carp Using a coil, bulk measurements are not limited to a single slice of tube within the coil. The tube was positioned so that the bulk of microspheres would fall within the imaging region of the coil. Sexual MRI measurements use a standard tilt echo sequence (T2 * (Emphasis) Spin echo sequence Even using T2-weighted and short TR anatomical localizer scans (T1-weighted), Obtained. To improve scientific comparison, all quantitative parameters are R1, R2, or R2 *Please note that this is written as follows: Here, the degree of relaxation (R) is the time decay constant (T). It is inversely proportional to R1, R2 is 1 / T1, R2 is 1 / T2, R2 * is 1 / T2 * That is the case.

[0177] Next, CT radiopaqueness, R1 relaxation, R2 relaxation, R2 * The degree of relaxation and the magnetic susceptibility are 5 We evaluated several image characteristics. For each characteristic, for example, R1 (or R2, etc.) of each tube. The values ​​were measured and compared with the control gel tubes, and Delta(D)R1 was calculated. Next, each For the tube set, DR1 was graphed against the volume fraction, and a linear regression line was plotted. did.

[0178] In vitro cytotoxicity Biological reactivity of mammalian cell monolayers and L929 mouse fibroblasts in response to experimental materials. , ISO 10993-5:2009, Biological evaluation of medical devices - Part 5: Verified biological In vitro cytotoxicity testing using a suitability testing laboratory (Toxikon Corporation, Bedford, MA, an d Nelson Labs, Salt Lake City, UT, Nelson Labs, Salt Lake City, UT, US) It's decided.

[0179] ISO 10993-12:2012, Biological evaluation of medical devices - Part 12: Sample preparation The experimental materials were prepared according to the manufacturing method and standard substance, using an extraction ratio of 0.2 g / mL per mass / volume. To verify the functionality of the test system, positive (natural rubber) and negative (plastic) samples were taken. A control substance was prepared.

[0180] The experimental and control material extracts were used in place of the maintenance culture medium for cell culture. The extracts of the experimental materials were tested with and without 5% bovine serum (1XMEM5), and serum addition (complete). In the minimum essential medium (MEM), 100% (NEAT), 50%, 25%, and 12.5% The tests were conducted with a series of dilutions.

[0181] All culture media were incubated at 37±1℃ in a humidified atmosphere containing 5±1%CO2 for 24±2 hours. (For untreated microspheres during the initial screening) or 72 ± 2 hours (for microsphere optimization) In the case of microspheres after accelerated treatment, they were cultured by repeating the process at least six times.

[0182] The viability of cells after exposure to the extract is determined by their ability to take up vital staining dyes and MTT reagents. This was measured. This dye was added to the cells, and the surviving cells were encouraged to take it up actively. Number of surviving cells This correlates with the color intensity determined by photometric measurement at 570 nm after extraction.

[0183] Genotoxicity in vitro This study conforms to ISO 10993-3:2014 "Biological evaluation of medical devices - Part 3: "Tests for transmissibility, carcinogenicity, and reproductive toxicity," and the Organisation for Economic Co-operation and Development (OECD) 471 , and the chemical substance testing guidelines "Accredited Biocompatibility Testing Laboratories (NAMSA Corporation, N The requirements for the "bacterial reverse mutation test using orthwood, OH, US)" will be partially met. did.

[0184] The test substance, control, and experimental blank (extraction solvent without the test substance) are I SO10993-12:2012 "Biological evaluation of medical devices - Part 12: DMSO and Sample preparation and standard substance preparation in physiological saline under continuous stirring at 50°C for 72 hours, according to the instructions. The solution was prepared using a mass / volume extraction ratio of 0.2 g / mL. After extraction, the color of all extracts was determined. Turbidity and particle size were visually inspected, and the samples were kept at room temperature for less than 3 hours before use. The extract was centrifuged. It was not separated, filtered, or subjected to any other alternative method. Prior to administration and testing, Test strain culture solution (test strains of Salmonella typhimurium TA98, TA100, TA1535, and TA 1537, and the E. coli test strain WP2uvrA, were checked for genetic markers. I did it.

[0185] Next, the melted top agar is mixed with the test strains of Salmonella typhimurium or E. coli. Then, a histidine-biotin solution or a tryptophan solution was added. This addition resulted in The bacteria on the plate are measured using a darkfield colony counter. It can be tested and undergoes several divisions to form a background bacterial flora that can be seen with the naked eye. Five test strains were placed in separate test tubes, each containing 2.0 mL of molten top agar. Each 0.1 mL culture medium and 0.1 mL of DMSO or physiological saline extract of the test substance are inoculated. . 0.5 mL of sterile water for injection or S9 homogenate, which provides a metabolic activation system. To was added as needed. This mixture was then identified by test number, appropriate test strain, and S9 metabolic activity. The samples were poured onto three sheets of minimum E medium labeled with the chemical system (if applicable). Each negative control and Six positive controls were also tested in parallel. Histidine-free culture medium Barrel plates (for Salmonella typhimurium) and culture plates without tryptophan (for E. coli) The following was prepared three times: Test substance extracts of DMSO and physiological saline with and without I.S9 activity II. Negative control in the presence or absence of S9 activity III. Benzo[a]pyrene and S9 activity present in the TA98 strain in the presence of S9 2-nitrofluorene IV. 2-aminoanthracene with S9 and S9 activity absent in strain TA100 sodium azide in 2-aminoanthracene in the presence of V.S9 and S9 activity absent in the TA1535 strain sodium azide in VI.S9 present in 2-aminoanthracene and S9 activity-free strain with TA1537 ICR-191 in VII. S9 activity absent in the presence of 2-aminoanthracene and WP2uwA in the presence of S9. MMS in

[0186] The plates were cultured at 37°C for 2 days. After the culture period, the average number of reverse mutants and the calculations were performed. The revert mutant colonies on each plate were recorded by the calculated standard deviation. Next, the experiment For each strain used, the average number of reverse mutants on the test plate was compared with the negative control plate. We compared the average number of reverse mutants with those mentioned above, and also recorded the characteristics of the background bacterial flora.

[0187] In vitro blood compatibility This procedure adopts the principles outlined in ASTM F756:2017. The M method conforms to ISO 10993-4:2017, "Biological evaluation of medical devices - Part 3: Blood In accordance with the "Selection of Interaction Tests," an accredited biocompatibility testing laboratory (Nelson Labs, S) Using Salt Lake City, UT and Nelson Labs LLC (Salt Lake City, UT), and approved by the U.S. FDA. In accordance with GMP Rules 21 CFR Parts 210, 211, and 820, there will be no deviations from procedures. It is not, and has been verified. The tests are based on the principles outlined in ASTM F756:2017. Accordingly, PBS that does not contain calcium and magnesium was used as the extraction solvent. ISO 10993-4:2017 (Use human blood whenever possible, due to differences in blood activity) The ASTM method was validated using citrate-supplemented human blood in accordance with the guidelines (which state that it should be done). did.

[0188] In blood collection, equal amounts of blood from three donors are mixed with 0.1M sodium citrate in a 9:1 ratio. Blood was collected in a vacuum containing a 3.2% anticoagulant. The collected blood was... The samples were refrigerated and pooled until the test was performed, and used for testing within 4 hours of collection. Dilute the hemoglobin standard with Drabkin's reagent to 0.80, 0.60, 0.40, 0 Solutions with concentrations of 0.30, 0.20, 0.10, 0.02, and 0.01 mg / mL were obtained. These solutions were allowed to stand at room temperature for at least 15 minutes, and their absorbance was measured using a spectrometer at 540 nanometers (nm). The readings were taken using a thermometer. Subsequently, linear regression was performed using hemoglobin absorbance values ​​and standard concentrations. The standard curve was determined. To measure plasma hemoglobin, blood was collected at 700-800 × g Then, centrifuge for 15 minutes. Next, add a 1 mL aliquot of plasma to 1 mL of Drabkin's reagent. After adding the substance and allowing it to stand at room temperature for at least 15 minutes, the absorbance was read using a 540 nm spectrophotometer. The hemoglobin concentration is determined from the standard curve and multiplied by a coefficient of 2 to obtain plasma free hemoglobin. The globin concentration was determined (confirmed to be less than 2 mg / mL). The total amount of hemoglobin present in the blood was... Add a 20 μL aliquot of the solution to 5 mL of Drabkin's reagent and measure the absorbance using a spectrophotometer at 540 nm. Before reading the temperature, repeat the measurement twice by letting the solution stand at room temperature for at least 15 minutes. Determined. Next, the hemoglobin concentration was determined from the standard curve, and a coefficient of 2 was used to account for dilution. Multiplied by 51. Based on the total hemoglobin present, the blood was diluted 10±1 in CMF-PBS. Diluted to mg / mL. To verify the dilution of the blood, 300 aliquots of the diluted blood were used. Add μL to 4.5 mL of Drabkin's reagent, repeat this three times, and analyze the results at a wavelength of 540 nm. Before reading the absorbance with a hygrometer, the sample was allowed to stand at room temperature for at least 15 minutes. Afterward, the hemoglobin concentration was measured. The coefficient was determined from the standard curve and multiplied by a factor of 16 to account for dilution.

[0189] Positive control (hemolytic), negative control (non-hemolytic), and brand of experimental materials. The amount is 0.2 g / mL in mass / volume ratio or 6 cm 2 Use the surface area / extraction volume in mL. This was prepared and is in accordance with ISO 10993-12:2012 "Biological evaluation of medical devices - Part It conforms to "12: Sample Preparation and Standard Materials," and is prepared at 50±2℃ (stirred) for 72±2 hours. This conforms to the indirect contact (extract) analysis sample prepared in MF-PBS. For both the extract method and the direct contact method, an appropriate concentration of extract or material is applied to a labeled gas. The solution was added to a glass tube, prepared three times, and 1 mL of diluted blood was added to each. Then, the glass tube was used. Incubate the tubes at 37±2°C for a minimum of 3 hours, and gently invert them twice at 30-minute intervals throughout the incubation period. The culture was performed. After incubation, the test substance and control substance were centrifuged at 700-800 × g for 15 minutes. Remove the mixture, mix 1 mL of the supernatant with 1 mL of Drabkin's reagent, and let it stand at room temperature for at least 15 minutes. After centrifugation, the color, turbidity, and particulate matter of the supernatants of the test substance, blank, and control were measured. The substances were visually inspected. Afterward, all test substances and control substances were measured using a spectrophotometer at 54°C. It was read at 0nm.

[0190] The hemolysis index (% hemolysis rate) was expressed using the following formula. Hemolysis index = Hemoglobin released (mg / mL) / Hemoglobin present (mg / mL) ×100 Released hemoglobin (mg / mL) = (optical concentration × coefficient X + constant) × 16 Present hemoglobin (mg / mL) = Diluted blood 10 ± 1 mg / mL

[0191] The hemolysis index of the CMF-PBS blank solution was determined from the hemolysis indices of the test substance and the control substance. The corrected hemolysis index is calculated by subtracting the negative control from the hemolysis index of the test substance. The test substance and the negative control were compared by subtracting the hemolytic index of the control.

[0192] statistical analysis CT and MRI measurements expressed as the average of three replicates (± mean standard error, SEM) Linear regression analysis was performed on each microsphere formulation prepared with various volume fractions, and if the result was not zero... To confirm this, we performed a statistical evaluation and further used Prism 8.0 software (Grap The study compared this with other prescriptions using hPad Software Inc. (San Diego, CA, US). The significance level was set to p. It was set to <0.05.

[0193] Amorphous form, density, and glass transition temperature The glass of the embodiments and the glass of the comparative examples of this disclosure are formed from irregular glass powder and microspheres. In this state, the amorphous morphology, density, and glass transition temperature were evaluated. Irregular glass Regardless of the heat treatment (spherification) performed after powder preparation, all samples remain amorphous. No identifiable crystalline peaks were detected in any of the formulations evaluated. Table 5 shows: Comparative example glass and microspheres formed after spheroidization in both irregular glass powder and microspheres The glass of the embodiments of this disclosure is shown to have density and Tg (midpoint TgM and inflection point TgI). . [Table 5]

[0194] Regarding density, the commercially available control "COMP1" has a density of approximately 3.3 g / cm³. 3 The density of This provided only slight variations between the irregular glass powder and the morphology of microspheres. The TRCR glass series has a low content of approximately 3.05 g / cm³. 3 (TRCR20) The highest is 4.2674 g / cm³. 3 It provides a wide range of densities up to (TRCR23), and similarly, No significant differences were observed between the formulations in the form of irregular glass powder and fine particles. There was none. In examining the TRCR formulation itself, the increase in Ta2O5 in the glass network A tendency for the density of flits and microspheres to increase with time was observed. Formulation C showed a similar trend in density between irregular glass powder and microsphere morphology. (Each of these values ​​is 3.459 g / cm³) 3 ~3.542 g / cm³ 3 and 3.4326 g / cm³ 3 ~3.5739g / cm 3 ).

[0195] In the analysis of the glass transition temperature, the commercially available controls were 909°C (TgM) and 915°C ( It consisted of data points from TgM and TgI between TgI. In contrast, TRC The R and BIC glass series are suitable for temperatures between 512°C and 794°C and between 513°C and 799°C. The data showed a wide range of TgM and TgI levels across the target points.

[0196] Consideration of processing Figure 1 shows BIC2 microspheres (after spheroidization) in CMF-PBS at 0.2 g / mL. Extraction was performed over 360 hours (under continuous stirring (120 rpm) and maintained at 50°C). The resulting cumulative ion release curve is shown. In summary, Ba released IC after a 72-hour extraction period. It was the only element recorded below the P-OES detection limit (10 ppm), along with B, Ta, and Na. Si is present at 20 ppm, 30 ppm, 500 ppm, and 430 ppm to 440 ppm, respectively. It was detected in ppm. Then, over a 120-hour extraction time frame, all remaining elements were thoroughly analyzed. Although a low level of extraction was confirmed (reported as being below the ICP-OES detection limit (10 ppm)), Si (530 ppm to 540 ppm) is an exception, and thereafter, between 240 and 360 hours It was shown that thorough extraction could be achieved.

[0197] Chemical analysis and surface morphology Table 6 shows the COMP product and the supply material (irregular glass powder) used for spheroidization. We compared the BIC formulation with the recovered microspheres after spheroidization (processed from the same lot for each formulation). This shows variations in chemical composition.

[0198] In summary, all three BIC formulations involve significant volatilization of alkali elements after spheroidization. This was observed, with the supply material decreasing by up to half of its starting composition (from 10.05 mass% to 7.84 mass%). BIC1), from 14.60 mass% to 7.03 mass% (BIC2), and 10.95 mass Significant decrease in Na2O concentration from % to 5.36 mass% (BIC3) (external laboratory) The concentration of other elements (i.e., Ta) was observed (in terms of mass %). Collectively, the concentrations of other elements (i.e., Ta) were observed. The concentrations of these elements (2O5 and / or SiO2) clearly increase after spheroidization. Therefore, it was observed to compensate for the relative loss. In addition, BIC3 is B2O3 concentration As a result of the significant decrease (from 3.62 mass% to 1.12 mass%), B2O is spheroidized. It showed clear volatility of 3. In contrast, when used as a supply material, COMP1 item (Table) The composition remained unchanged (i.e., within ±3 mass% of each elemental component). (An acceptable (acceptable) range).

[0199] The surface morphology of the supplied material is shown in Figure 2A and compared with the surface morphology of the microspheres after spheroidization (Figure 2B). The SEM images collected in the same way as the spherical material show that (I) glass reaction in a gaseous environment (II) Accumulation of surface deposits, and / or (II) residues from the glass manufacturing process or airborne particles Alternatively, it indicates the accumulation of surface reaction deposits on microspheres resulting from contamination by particles on the product contact surface. vinegar.

[0200] Table 7 shows the chemical composition obtained by processing the BIC2 microsphere lot separated after 360 hours. This shows fluctuations, and as shown in Figure 1 above, as a result of the aqueous environment, Na from the glass network Thorough extraction of 2O has been achieved. Na2 as a result of this processing step compared to spheroidization. The decrease in O was not widespread (from 7.03 mass% to 5.36 mass% vs. 14.6, respectively). From 0% by mass to 7.03% by mass, before the time frame (72 hours) in which the initial extraction was evaluated, binding This is likely mainly due to the treatment process for removing surface reaction deposits that have not been removed, and here, This involves minimal elution of Na2O from the glass network.

[0201] Utilizing the findings of this study, we will accelerate the extraction temperature and shorten the time frame to 24 hours (extraction ratio, (Without changing temperature and all other variables such as stirring speed), (for process optimization) Further extraction analysis was performed, and microspheres without surface reaction deposits could be observed by SEM. We checked whether it was spherical or not. Figure 2C shows microspheres treated at 80°C for 24 hours, and they are spherical. It provides nearly complete removal of surface reaction deposits and / or contaminants observed immediately after fertilization (Figure 2B). In contrast, microspheres treated at 80°C for 72 hours and then re-sieved after spheroidization had a surface This clearly shows the complete removal of reaction deposits (Figure 2D) after 24 hours and 72 hours. The BIC2 microspheres treated with the appropriate agent were then stored for biocompatibility evaluation. [Table 6] [Table 7]

[0202] CT radiopaque In the glass composition of the examples in Table 1, the control item (COMP1: 5,952±18) Compared to 0HU, at a clinically appropriate tube potential (120kVp), radiation-ineffective Transparency has been enhanced. The radiopaqueness of the benchtop CT is 9,978 ± 579. Observed in the range from HU(TRCR8) to 21,858±1037HU(TRCR23). The densities of TRCR3, 8, and 13 were 10% of the density of the comparative example item COMP1. Their radiopaqueness ranges from 9,978±579HU(TRCR8) to 16,374± It was observed in the range of 465HU (TRCR13).

[0203] BIC1, BIC2, and BIC3 are desirable to be comparable to control item COMP1. It has a density within the target range, in the range of 13,676±642HU to 16,952±205HU. The surrounding area showed radiopaqueness.

[0204] CT scans show variations in the concentration of microspheres BIC1-BIC3 compared to the control sample. Regarding the evaluation of radiopaqueness, Figure 3 shows prepared samples with various volume fractions at 80 kVp. The radiopaqueness of the sample increases with increasing concentration (volume fraction) of microspheres. Furthermore, a good correlation exists between the obtained HU value and the volume fraction of microspheres, The slope and R of each calibration curve created by this method 2 The values ​​were as follows (low CT radiation) Radiation opacity to high radiopaqueness): COMP1(R 2 = 0.9739 = 287.2 ), BIC3(R 2 =0.9465 (357.9), BIC1(R 2 = 0.9994 = 3 94.5), and BIC2(R 2 =0.9742 (407.7). The data is In terms of the concentration of microspheres expected to be administered for therapeutic purposes, compared to COMP1 product As a promising candidate material that provides enhanced radiopaqueness, BIC1 to BIC3 Port it.

[0205] MRI evaluation The formulations for microspheres BIC1-BIC3 and COMP1 products were created for the R1 relaxation degree. As supported by the calibration curve shown in Figure 4, a large T1 contrast effect is observed. This is not expected to result. The calibration curve shows a significant correlation between R1 relaxation and microsphere concentration. This shows that the slope in the range of 0.007 (COMP1) to 0.034 (BIC3) is statistically zero. Although not a perfect fit (p<0.002), the slope is very small, so the formulation of these microspheres is not a good option. It is not expected that any possible T1 difference will occur. This is also supported by Figure 5. Furthermore, the change in T1 contrast is not evident in the tube image.

[0206] Similarly, prescriptions for microspheres of BIC1-BIC3 or COMP1 products are due to the R2 relaxation degree. As supported by the calibration curve shown in Figure 6, which was created, a large T2 contrast It is not expected to produce a positive effect. The calibration curve shows a relationship between the R2 relaxation level and the concentration of microspheres. It shows a significant correlation. The slope in the range from 0.068 (COMP1) to 0.688 (BIC3) is Although not statistically zero (p<0.003), the slope is very small, so these prescriptions Compared to physiological differences, it does not produce a significant difference in signal contrast. This means that As shown in Figure 5, here, the image of the highest BIC2 microsphere concentration is There is a very slight change in T2 contrast.

[0207] R2 * A calibration curve is shown in Figure 7 for measuring the degree of relaxation. The microsphere formulation is (as shown in Figure 5) Uni) T2 * It induces some change in contrast. However, in the vascular system Target location of microspheres (significant T2 due to blood) * Considering the effect, the contrast The change is clinically T2 * It may be sufficient to induce a significant change in the enhanced scan. The possibility is low. Similar to the T1 and T2 calibration curves created, R2 * The slope of relaxation is statistically zero. Instead (p<0.04), the slope is 3.5s. -1 ~6.3s -1 This is the range. (As shown in Figure 5) As shown above, at the highest microsphere concentration in the control item, visible T2 * Perception of contrast There are possible differences, with relatively few bubbles visible in the microspheres of BIC2.

[0208] The local magnetic dose (L) obtained from the MRI susceptibility (susceptometry) results (shown in Figure 8) MD) shows that the formulation of microspheres from BIC1 to BIC3 has a small negative slope (-0.0074~- This is similar to 0.0190, indicating that these materials are slightly diamagnetic. This is in contrast to the COMP1 item, which has a small positive slope (0.0 It generates 264) and is classified as having slight paramagnetism. BIC1 is 0 (i.e., magnetization While no statistical significance was observed (the rates were neutral), BIC2 and BI showed statistical significance. All of the C3 and YAS4 values ​​showed statistical significance from non-zero (p<0.04). ).

[0209] To support the safety of MRI prescriptions for BIC1, BIC2, and BIC3 microspheres. Therefore, the following problems were considered: (I) magnetically induced displacement torque, (II) magnetically induced displacement force, and (III) RF-induced tissue heating of tissues around the device.

[0210] Magnetically induced displacement torque Medical devices interact with the magnetic moment of the device and the main static magnetic field of the MRI system. This may indicate displacement force and / or rotational torque resulting from use. Rotational torque is a predetermined value. This is a tendency in asymmetrically shaped devices that are magnetized in a particular direction, and the direction of the magnetic moment. The direction aligns with the direction of the main magnetic field. Magnetized, such as the formulation of the microspheres of BIC and COMP1. The microspheres have a symmetrical shape and do not have the ability to generate torque. Torque is generated by the device's magnetic field. It is calculated from the vector product of the moment (μ) and the main static MRI magnetic field (B0). BIC and metal oxides composed of transition metals such as the formulation of microspheres of COMP1, and magnetic materials Materials classified as such may exhibit either paramagnetic or diamagnetic properties. It does not have a magnetic moment until it is placed in an external magnetic field, and the induced magnetic moment is primarily They either align with the direction of the static magnetic field (paramagnetic) or are completely opposed to it (diamagnetic). MRI magnetic susceptibility ( (See Figure 8) Measurements obtained for the suspension of BIC1 to BIC3 and COMP1 The baseline value is a mere 0.0264 ppm (SI units) relative to the control microsphere itself. It was shown to have a paramagnetic volume susceptibility (corrected for the effect of the suspension medium). In contrast, The microspheres of BIC1, BIC2, and BIC3 are each -0.0 relative to the microsphere itself. Slight diamagnetic volume magnetic fields of 0.74 ppm, -0.0119 ppm, and -0.019 ppm It was shown that it has a conversion ratio (corrected for the effect of the suspension medium).

[0211] The magnetic moment of a diamagnetic material is (by definition) opposite to the principal magnetic field, and the torque (magnetic moment) Since the vector product T = μ × B between the ment and the main magnetic field is zero, BIC1, BI There is no risk of particle rotation torque in C2 or BIC3 microspheres. Nevertheless, The magnetic moment was approximately the same for all samples tested, including the control microspheres. Since it is 0, none of the microsphere formulations indicate a risk of particle rotation torque.

[0212] Magnetically induced displacement force Displacement forces increase the risk of device impact on the MRI system (or the patient's body). This is caused by the magnetic moment of the device and the space between the main static magnetic field of the MRI system. It is calculated from the interaction with the rate of change. This spatial gradient of the principal magnetic field is typically used in MRI systems. The maximum size is near the stem entrance (the entrance hole), and in typical 3T clinical MRI systems... It is approximately 15 Tesla / M or less (e.g., in the case of the GE Healthcare MR750 3T MRI, the operating time is less than 15 Tesla / M). (As specified in the safety section of the manual, it is 14.7 T / m).

[0213] Specifically, the displacement force is the dot between the magnetic moment (μ) and the static magnetic field gradient (gradient (B)). It is calculated from the product by the formula [F = μ·Gradient (B)]. Paramagnetic particles such as BIC2 particles. Materials generate magnetic moments only as a result of being exposed to a strong magnetic field, and the applied magnetic field They align in the same direction. In contrast, BIC1, BIC2, and BIC3 fine particles, etc. Diamagnetic materials generate a magnetic moment only as a result of being exposed to a strong magnetic field and applied to it. They align in the opposite direction to the magnetic field. Nevertheless, the force generated in the formulation of all the particles is , on the order of ppm (μ=V*ΔX, V is the radiopaque MS volume), and Brownian motion ( It is small compared to the force of particle dispersion, and therefore does not pose a risk to magnetically induced displacement forces. stomach.

[0214] Heating tissue using radio frequency (RF) Parmar et al. "Size-dependent heating efficiency of iron oxide single-domain nanoparticles" Procedia Engineer As discussed in ng (2015) Volume 102, pages 527-533, magnetized particles RF heating is primarily a magnetic heating mechanism, rather than an inductive mechanism (electrical conduction). This is caused by the following: Magnetic heating from an RF magnetic field is due to Neel's mechanism (internal magnetic moment of a particle). (The particles rotate due to the applied RF magnetic field without rotating themselves) or Brow The mechanism of n (where particles physically rotate under the influence of an RF rotating magnetic field that generates resistive heating) These can be caused by a mismatch. These mechanisms involve magnetically mediated hyperthermia (MMH) and therapeutic responses. This relates to iron oxide nanoparticles for applications such as targeted cancer ablation. The child can only operate under conditions including an RF magnetic field of the order of 10 kA / M, and under low-temperature conditions (stations at 2°C to 4°C). It can create a localized temperature increase.

[0215] Conversely, an MRI system uses a peak RF magnetic field of approximately 0.1 kA / M (1 Gauss), or It generates a peak RF magnetic field that is two orders of magnitude weaker than that used in MMH applications. In addition, it generates a superparamagnetic iron oxide (SPIO). )The particles are in a microsphere formulation (0.0264 ppm (COMP1) vs. 0.0074 ppm (B) IC1), -0.0119 ppm (BIC2), and -0.019 ppm (BIC3) It has a magnetic moment that is approximately five orders of magnitude larger than BIC1, BIC2, and BIC Because the microspheres in 3 are made of a material with weak paramagnetic / diamagnetic properties, their magnetic heating ability is compared to that of SPIO materials. It can be ignored.

[0216] In addition, SPIO nanoparticles are FDA-approved contrast agents (e.g., Ferridex), Despite being metal oxide particles, as in the formulations of BIC1 to BIC3, they are also magnetic. Despite the much larger moment, no problems associated with RF heating occur. BI The RF heating capability of C microparticles is several orders of magnitude weaker than these SPIO materials, due to their magnetic moment. Furthermore, due to its weak magnetic moment, BIC particles pose a risk of tissue heating in an MRI environment. This should not cause that.

[0217] In vitro cytotoxicity In vitro cytotoxicity screening involves experimental negative controls and positive controls. The viability of cells exposed to extracts of the material was >70% and <70%, respectively, and analysis was performed. The validity of the law was confirmed. Prescriptions that meet the requirements of the trial account for more than 70% of the untreated controls. The cell viability was shown. Table 8 shows the formulations of each microsphere before treatment in various series of dilutions. The results of the obtained cell viability are shown. [Table 8]

[0218] COMP1 showed no cytotoxicity and demonstrated a cell viability rate of 98-94%. In contrast, Most of the formulations of TRCR microparticles are based on the TRCR13 stock solution test (48% cell viability). Except for the others, it was considered to have no potential for cytotoxicity. All other TRCR formulations were 75%~ It showed a cell viability of 112% (undiluted, undiluted). Regarding the formulation of microspheres in BIC, 3 Two of the three, namely BIC2 (100%~105%) and BIC3 (72%~10%). %) did not show cytotoxicity. The cell viability of BIC1 was 22% (undiluted and undiluted) and The concentration was 44% (50% dilution), and it showed dose-dependent cytotoxicity.

[0219] Genotoxicity in vitro For both COMP1 samples and BIC2 microspheres before processing, DMSO and physiological salt The background flora of the water test extract appeared normal. The average number of revertant mutants in the test strains TA98, TA100, and WP2uvrA was 2 There were no cases of more than double the increase, and the reverting mutants of the test strains TA1535 and TA1537 were not found. There were no cases where the average number increased by more than three times. According to past data collected by the testing company, it shows a characteristic number of naturally reverting mutants. The average value for each positive control was calculated for each of the five test strains, compared to the negative control. This showed an increase of at least three times the average value of the control item. The results are summarized in Table 9, along with the control item. The DMSO and saline extracts in the microparticle formulation of BIC are both derived from Salmonella typhimurium. Test strains TA98, TA100, TA1535, and TA1537, and Escherichia coli test strains It was considered that WP2uvrA did not exhibit mutagenicity. [Table 9]

[0220] In vitro cytotoxicity and hemolysis of treated microspheres Table 10 shows the repeated cytotoxicity and / or lysis of BIC2 microspheres treated for 24 to 72 hours. Blood evaluation is shown. In vitro cytotoxicity, when observed under magnification, normal cells after the exposure step are observed. The validity of the test method was confirmed using culture medium control cells that exhibited proliferation characteristics. Rolle extract (undiluted) reduced the viability of the culture medium control to less than 70%, compared to Furthermore, the negative control extract did not reduce the viability of the culture medium control to less than 70%. In summary, microspheres of BIC2 treated for 24 hours and 27 hours were found to be in a series of dilutions. In tests using concentrations of 2.5% to 50% compared to the undiluted solution, no cytotoxicity was observed (i.e., fine-grained Cellular viability (CV) > 70%, and cell viability was 82%-84% and 88%-92%, respectively. It was within that range. Subsequently, the processing step was extended to 72 ± 2 hours for extraction before MTT analysis. Therefore, the microspheres of BIC2 before processing (0 hours) (cell viability after extraction at 24±2 hours) Compared to the range of 100% to 105%, in vitro cytotoxicity We confirmed that there were no adverse effects.

[0221] In vitro hemolysis (direct and indirect contact hemolysis) involves treating microspheres of BIC2 and experimentally... The difference in hemolysis index from the typical negative control was less than 2% under all test conditions. The validity of the test method was confirmed. According to ASTM F756:2017, hemolytic materials For a reaction level > 5, a hemolysis rate of 0-2 indicates a non-hemolytic reaction, while 2-5 indicates a mild hemolytic reaction. This indicates a bloody reaction. According to this hemolytic rating system (Table 10): • Processed BIC2 microparticles prepared using a mass / volume extraction ratio (0.2 g / mL) If considered non-hemolytic and treated for 24 to 72 hours, each (direct contact method) 1 While the percentages range from 0.29% to 0.29%, when processing is done for 24 to 360 hours, each The percentage (indirect contact method) is 0.00% to 0.00%. • Processed BIC2 prepared using surface area (SA) / volume extraction ratio (0.2 g / mL) These microparticles are also considered non-hemolytic, and when treated for 24 to 72 hours, they are (directly) (Contact method) 0.00% to 0.00%. [Table 10]

[0222] The data shown in Table 10 is for BIC subjected to accelerated processing parameters (80°C for 24 hours). Despite the fact that two microspheres showed a clear lack of surface cleanliness as observed by SEM in Figure 2, Furthermore, it does not cause cytotoxicity (82%-92% after treatment, 100%-106% after globulation) or hemolysis. This is to confirm that there is no impact. Nevertheless, the 72-hour time frame for treatment is It was observed that the hemolysis rate using the direct contact method was significantly reduced to 0.29.

[0223] The previous explanation included numerous details to provide a complete understanding of the examples for explanatory purposes. However, it is obvious to those skilled in the art that these specific details are not necessary. It is likely. Therefore, the matters described are merely illustrative examples of the application of the described examples. In light of the above instructions, many modifications and variations are possible.

[0224] The above explanation is for illustrative purposes only; modifications and variations may be made by those skilled in the art to a specific example. It will be understood that this can be implemented. Accordingly, the claims are as specified herein. The specification as a whole should not be limited by the specific embodiments described herein, but should be consistent with the overall specification. It should be interpreted in this way.

Claims

1. A glass material, wherein the glass in the glass material is (A) SiO₂ at a mole fraction of 0.55–0.80 ２ and, Na at a mole fraction of 0.05 to 0.22 ２ O, K ２ O, or Na ２ O and K ２ The O compound and Y with a molar fraction of 0.05 to 0.28 ２ O ３ , BaO, or Y ２ O ３ and a composition of BaO, and Ta at a mole fraction of 0.05 to 0.09 ２ O ５ and The aforementioned Y ２ O ３ , the BaO, and the Ta ２ O ５ The sum of these is between 0.10 and 0.17 mole fractions. The SiO ２ , and the Na ２ The total amount of O is between 0.69 and 0.90 mole fractions; (B) SiO₂ at a mole fraction of 0.55–0.80 ２ and, Na at a mole fraction of 0.05 to 0.22 ２ O, K ２ O, or Na ２ O and K ２ The O compound and Y in a mole fraction of 0.05 to 0.08 ２ O ３ , BaO, or Y ２ O ３ and a mixture of BaO, Ta at a mole fraction of 0.05 to 0.10 ２ O ５ and The aforementioned Y ２ O ３ , the BaO, and the Ta ２ O ５ The total is between 0.18 and 0.31 mole fractions. The SiO ２ , and the Na ２ The total amount of O is between 0.65 and 0.80 mole fractions; or (C) SiO₂ at a mole fraction of 0.55–0.82 ２ and, Na at a mole fraction of 0.03 to 0.23 ２ O and, Y in a mole fraction of 0.05 to 0.08 ２ O ３ , BaO, or Y ２ O ３ and a mixture of BaO, Ta in a mole fraction of 0.05 to 0.12 ２ O ５ Glass material, including

2. The aforementioned glass is made of BaO and Na ２ It contains O, and the BaO and the Na ２ The glass material according to claim 1, wherein the total amount of O is 0.10 to 0.33 mole fractions.

3. The aforementioned BaO and the aforementioned Na ２ The glass material according to claim 2, wherein the total amount of O is 0.10 to 0.25 mole fractions.

4. The glass is (C) when, The SiO ２ and the Na ２ The glass material according to claim 1, wherein the total amount of O is 0.65 to 0.90 mole fractions.

5. SiO₂ at a mole fraction of 0.70–0.73 ２ ; Na at a mole fraction of 0.16–0.18 ２ O; Y in a mole fraction of 0.05 to 0.07 ２ O ３ ; and, Ta at a mole fraction of 0.05 to 0.07 ２ O ５ including, The glass material according to claim 1.

6. Approximately 0.71 mole fraction of SiO ２ ; Na at a mole fraction of approximately 0.17 ２ O; Y at approximately 0.06 mole fraction ２ O ３ ; and, Ta at approximately 0.06 mole fraction ２ O ５ including, The glass material according to claim 5.

7. Approximately 0.72 mole fractions of SiO ２ ; Na at a mole fraction of approximately 0.17 ２ O; Y at approximately 0.05 mole fraction ２ O ３ ; and, Ta at approximately 0.06 mole fraction ２ O ５ including, The glass material according to claim 5.

8. The glass material according to any one of claims 1 to 7, wherein the glass material is bulk glass or an irregular fine particle glass material.

9. A fine-particle glass material, A substantially spherical fine particle glass material obtained from spheroidizing the irregular fine particle glass material described in claim 8.

10. A mixture of the fine-particle glass material described in claim 9 and radioactive glass fine particles, A mixture in which the fine-particle glass material and the radioactive glass particles are substantially the same size.

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