Radiopaque glass material

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 TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 855,285, filed May 31, 2019. No. 6,399,433, filed on Oct. 23, 2003, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to radiopaque glass materials suitable for forming microparticles that can be administered to a patient. . [Background technology]

[0003] The following paragraphs are provided to clarify that anything discussed therein is prior art or is beyond the knowledge of one of ordinary skill in the art. does not acknowledge that it is part of

[0004] Therapeutic vascular occlusion (embolization) is used to treat certain pathological conditions in situ. Therapeutic embolization is a technique that generally uses catheters to treat various processes (tumors, It is performed to place embolic agents in circulatory systems, such as blood vessels (vascular malformations, and bleeding processes). Summary of the Invention [Problem to be solved by the invention]

[0005] The following preface is intended to introduce the specification to the reader and defines the invention. One or more of the inventions may include device elements, as described below or elsewhere in this document. Or it may belong to a combination or subcombination of method steps. They are not merely based on the absence of a recitation of another invention or inventions in the claims. No waiver or withdrawal of claims to any inventions disclosed herein. .

[0006] Particulate embolic agents used in vascular embolization may not be radiopaque and therefore Therefore, unless the particulate embolic agent is treated with a contrast agent before injection, it cannot be seen by radiological imaging. TheraSphere™ Yttrium-90 microparticles are commercially available It is a radioactive particle that is used to treat primary and metastatic liver cancer, and has a voltage of 120kVp. It has a radiopacity of approximately 6,000 Hounsfield Units (HU).

[0007] Radiopaque particulate embolic agents are useful for imaging during and after embolization therapy. One or more of the examples described in this disclosure may be used to detect particulate matter by other means. An attempt was made to provide a radiopaque glass material having greater radiopacity than the plugging agent. See. [Means for solving the problem]

[0008] The glass material ultimately intended for use in vascular embolization has a viscosity of about 2.7 g / cm 3 ~ Approximately 4.3g / cm 3 In a particular example, the glass material may have a density of about 2.9 g / cm 3 ~Approx. 3.7g / cm 3 , or about 3.3 g / cm 3 ~Approx. 3.6g / cm 3 The density of Particles having a density in this range are believed to distribute adequately within the vasculature of a patient. It is assumed.

[0009] In the glass material of the present disclosure, Y2O3, BaO, and Ta2O5 all contribute to the formation of the glass. However, increasing the amount of these components can lead to poorer radiopacity in the resulting glass material. The authors of this disclosure have demonstrated that the desired radiation density can be achieved at a density suitable for vascular embolization. Glass compositions that provide radiopacity have been identified. Several glass materials of the present disclosure have Some of the gauging devices disclosed herein may have a radiopacity of over 9,000 HU at 20 kVp. The lath material is approximately 2.7 g / cm 3 ~Approx. 4.3g / cm 3 , for example, about 2.9 g / cm 3 ~ Approximately 3.7g / cm 3 , or about 3.3 g / cm 3 ~Approx. 3.6g / cm 3 The density of the sintered body may be 0.01 to 0.01.

[0010] In one embodiment, the present disclosure provides a SiO2 having a mole fraction of about 0.55 to about 0.85; 0.23 mole fraction of Na2O, K2O, or a blend of Na2O and K2O; about 0.28 mole fraction of Y2O3, BaO, or a combination of Y2O3 and BaO; and optionally The present invention provides a glass material containing Ta2O5 in the glass material. and optionally Ta2O5, the sum of which is about 0.10 to about 0.31 mole fraction.

[0011] In some examples, the glass material has a viscosity of about 0.03 to about 0.23, for example, about 0.05 to about Contains 0.23 mole fraction of Na2O, K2O, or a blend of Na2O and K2O.

[0012] In some examples, the glass material has a viscosity of about 0.55 to about 0.82, for example, about 0.55 ~About 0.80 mole fraction of SiO2.

[0013] In a particular example, the glass material comprises about 0.55 to about 0.80 mole fraction of SiO2, about 0. Contains from about 0.05 to about 0.22 mole fraction of Na2O, K2O, or a combination of Na2O and K2O. nothing.

[0014] In one particular example, the glass material has a mole fraction of about 0.74 SiO2; about 0.085 mole fraction of BaO; about 0.085 mole fraction of TaO 5; and about 0.006 mole fraction of B2O3. This particular glass material is p, showing radiopacity of approximately 16,000 HU.

[0015] In another particular example, the glass material has about 0.79 mole fraction SiO2; about 0.08 mole fraction of BaO; about 0.07 mole fraction of Ta2O5; and and about 0.003 mole fraction B2O3.

[0016] In yet another particular example, the glass material has a mole fraction of about 0.77 SiO; 1 mole fraction Na2O; about 0.10 mole fraction BaO; about 0.096 mole fraction Ta2O 5; and about 0.002 mole fraction of B2O3.

[0017] In yet another particular example, the glass material has a mole fraction of about 0.80 SiO; 3 mole fraction Na2O; about 0.82 mole fraction BaO; about 0.085 mole fraction Ta2O 5; and about 0.001 mole fraction of B2O3.

[0018] In some examples of the present disclosure, the glass material of the present disclosure is a bulk glass. The "glass" is a glass material suitable for vascular embolization that does not require any additional processing. means a glass material obtained by forming glass from unmixed starting reagents. For example, the irregular particulate glass material may be commercially produced without any processing steps. Glass materials produced on an industrial scale may be considered bulk glasses.

[0019] In other examples, the glass materials of the present disclosure are irregular particulate glass materials. The "particulate glass material" is sized for vascular embolization but is appropriately shaped. Irregular particulate glass material is obtained by crushing bulk glass and then grinding it into fine particles. The desired size of the fine particles may be recovered by sieving the mixed particles.

[0020] In yet another example, the glass material of the present disclosure is a substantially spherical particulate glass material. The term "substantially spherical particulate glass material" refers to a material that is sized and shaped for vascular embolization. Substantially spherical particulate glass material means irregular particulate glass material. It can be prepared by remelting the surface of the material and forming substantially spherical grains. .

[0021] In another aspect, a method of making the glass material of the present disclosure is provided.

[0022] In yet another aspect of the present disclosure, a substantially spherical microparticle as described herein is Glass materials are used in radiological imaging, computed tomography (CT) imaging, and cone-based imaging. X-ray based radiological imaging, such as multi-view CT imaging or fluoroscopic imaging The present disclosure further relates to a method for producing a substantially spherical microparticle gas as described herein. A method of imaging a mammal using the glass material is provided.

[0023] In vascular embolization therapy using radioactive particles, the number of particles can be increased to make the treatment more effective. Better tumor coverage than administering fewer particles at higher specific activities ), it is desirable to administer more microparticles with lower specific activity. Without wishing to be bound by theory, the authors of this disclosure believe that the microparticles , we believe, will remain at the first valid localization spot within the blood vessel they encounter. If there are enough localized spots to interact with the majority of the administered particles, Administration of small amounts of microparticles may result in some particles concentrating in a portion of the tumor. The administration of particles with a higher specific activity leads to a higher saturation of the effective localization spot and a higher tumor The coverage is more uniform.

[0024] For at least some tumor size and / or degree of vascularization, (i) radiation and (ii) a mixture of radiopaque, non-radioactive microparticles according to the present disclosure. By exposing the particles to radiation, the individual radioactive particles will have a lower specific radioactivity even though they have a higher specific activity. At least some of the benefits associated with administering more microparticles at a given dose may be provided. .

[0025] In one aspect, the present disclosure provides a method for preparing a glass microparticle comprising the steps of: (i) a radioactive glass microparticle; and (ii) a non-radioactive glass microparticle according to the present disclosure. and a mixture of radiopaque particulate glass material of the formula: It is suitable for the treatment of tumors in the vascular system and contains radioactive glass particles and non-radioactive radiopaque particles. The glass materials are substantially the same size. In certain instances, the particulate glass materials and The radioactive glass particles and the radioactive glass particles have substantially the same density.

[0026] In some instances, the mixture is prepared by exposing pre-irradiated glass particles to neutron radiation. and forming radioactive glass microparticles, which are then immersed in a radiopaque microparticle gas according to the present disclosure. It can be prepared by mixing with the glass material.

[0027] In a particular example, the mixture is: (i) about 40% by weight SiO2, about 20% by weight Al2O3 and about 40% by weight of Y2O3. Silicate glass particles (approximately 0.170 mole fraction Y2O3, approximately 0.189 mole fraction Al 2O3, and about 0.641 mole fraction of SiO2), and (ii) about 0.73 to about 0.80 mole fraction of SiO2, about 0.03 to about 0.11 mole fraction of Na2O, about 0.07 about 0.07 to about 0.10 mole fraction of BaO, about 0.07 to about 0.10 mole fraction of Ta2O5, and about A substantially spherical particulate glass material containing 0.001 to about 0.006 mole fraction of B2O3. Includes.

[0028] In yet another aspect of the present disclosure, when the mixture includes radioactive glass microspheres, the mixture is By administering to the mammal, radiation is delivered to the mammal. , using radiographic imaging techniques based on X-rays, especially still imaging techniques Imaging techniques may include imaging the mammal. Computed tomography / positron emission tomography (CT / PET) or cone beam computed tomography (CBE) This may include computer-based computed tomography (CBCT).

[0029] The glass materials according to the present disclosure may be included in a composition or delivery device, or may be used in diagnostic The present invention may be used in diagnostic or therapeutic methods.

[0030] In some aspects, the present disclosure includes a mixture of radioactive and non-radioactive microparticles, At least some of the non-radioactive microparticles comprise the glass material of the present disclosure. The composition is provided.

[0031] In another aspect, the disclosure provides a method comprising administering a therapeutic or diagnostic composition to a patient. wherein the administration is by intravascular, intraperitoneal, or transdermal delivery.

[0032] In one aspect, the present disclosure provides a method for the intravascular delivery of a mixture of radioactive and non-radioactive microparticles to a patient. The delivery device is adapted for intraperitoneal or transdermal delivery of the mixture. The delivery device is fluidly connectable to the transport medium. a fluid inlet, a fluid outlet, and a fluid mixer fluidly coupled to the fluid inlet and the fluid outlet; A radioactive particulate source fluidly coupled to the fluid mixer and a non-radioactive particulate source fluidly coupled to the fluid mixer. At least some of the non-radioactive particles are made of glass according to the present disclosure. Radioactive particulate sources are distinct from non-radioactive particulate sources. The fluid mixer mixes the radioactive particles with the non-radioactive particles to form a mixture of the radioactive and non-radioactive particles. The mixture is delivered out a fluid outlet utilizing a mixed transport medium.

[0033] In another aspect, the present disclosure provides a method for administering a mixture of radioactive and non-radioactive microparticles intravascularly to a patient. The delivery device is adapted for intravenous, intraperitoneal, or transdermal delivery. At least one fluid inlet fluidly connectable to a transport medium; a radioactive particulate source fluidly coupled to the at least one fluid inlet; a first fluid outlet fluidly coupled to the radioactive particulate source; and a second fluid outlet fluidly coupled thereto. At least some of the non-radioactive particulates are The present invention relates to a method for manufacturing a radioactive particulate source, the method comprising: It is something that can be done.

[0034] In the context of this disclosure, one collection of particulates is considered to be a single collection of particulates when the two collections are not mixed. It should be understood that the particle is distinct from other aggregates of particles. For example, The syringes were fluidly coupled to each other to allow for the ejection of particulates to form a mixture. However, radioactive particles in one syringe barrel may be mixed with non-radioactive particles in the second syringe barrel. It should be understood to be distinct from.

[0035] In yet another aspect, the present disclosure provides a method for producing a radioactive nanoparticle comprising: (i) a first population of radioactive nanoparticles; and (ii) a non-radioactive nanoparticle. and mixing the mixture in an amount suitable for therapeutic or diagnostic use with a second population of radioactive particles. The method includes administering to a patient at least some of the non-radioactive particles. , composed of glass material according to the present disclosure.

[0036] In yet another aspect, the present disclosure provides a method for administering a suitable amount of microparticles to a patient for therapeutic or diagnostic purposes. The method includes administering non-radioactive particles to a patient and and administering the radioactive particles to the patient without first detecting the non-radioactive particles. At least some of the glass material according to the present disclosure may be used for administration by intravascular delivery. The routes of administration for non-radioactive microparticles are intraperitoneal, intraperitoneal, or transdermal. The route of administration is the same as that of the particles.

[0037] In yet another aspect, the present disclosure provides a method for administering a therapeutically or diagnostically appropriate amount of microparticles to a patient. The method includes administering radioactive particles to a patient and and administering the non-radioactive particles to the patient without first detecting the non-radioactive particles. At least some of the glass material according to the present disclosure may be used for administration by intravascular delivery. The routes of administration for non-radioactive microparticles are intraperitoneal, intraperitoneal, or transdermal. The route of administration is the same as that of the particles.

[0038] In yet another aspect, the present disclosure provides a method for administering an appropriate amount of microparticles for therapeutic or diagnostic purposes. The method includes: (i) a first population of radioactive particles; and (ii) a first population of non-radioactive particles. At least some of the non-radioactive particles are co-administered to the patient with a second collection of non-radioactive particles. , composed of glass material according to the present disclosure.

[0039] In yet another aspect, the present disclosure provides a method for administering an appropriate amount of microparticles for therapeutic or diagnostic purposes. The method provides a method for administering non-radioactive and radioactive microparticles to a patient in a single treatment session. At least some of the non-radioactive microparticles may be administered in a continuous manner in accordance with the present disclosure. It is made of lath material.

[0040] In yet another aspect, the present disclosure provides a method for the preparation of (i) therapeutic radioactive microparticles and then (ii) non-radioactive microparticles. The method includes administering to a patient at least some of the non-radioactive particles. The glass material is constructed according to the present disclosure.

[0041] In any of the above embodiments, the non-radioactive particulates are described below in the section entitled "Glass Composition." and / or any of the non-radioactive glass compositions discussed in Section any of the characteristics of the glass materials discussed in the section entitled "Glass Materials" below. In any of the above embodiments, the radioactive microorganism may be included. The particles may be any of the radioactive glass compositions described in the following section regarding radiotherapeutic mixtures. Either one may be used. [Brief description of the drawings]

[0042] Embodiments of the present disclosure will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0043] [Figure 1] FIG. 1 is a graph showing cumulative ion release curves obtained for an exemplary glass composition of the present disclosure (spheres, post-spheronization) extracted in calcium- and magnesium-free phosphate buffered saline (CMF-PBS).

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

[0045] [Figure 2B] FIG. 2B is a set of SEM images at 250x and 1000x of BIC2 microparticles after spheronization.

[0046] [Figure 2C] FIG. 2C is a set of SEM images at 250x and 1000x of BIC2 microparticles after spheronization and sieved after treatment (24 hours).

[0047] [Figure 2D] FIG. 2D is a set of SEM images at 250x and 1000x of BIC2 microparticles after spheronization and sieved after treatment (72 hours).

[0048] [Diagram 3]FIG. 3 is a graph showing CT radiopacity as a function of volume fraction of various glass particulates.

[0049] [Figure 4] FIG. 4 is a graph showing R1 relaxivity as a function of volume fraction of various glass microspheres.

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

[0051] [Figure 6] FIG. 6 is a graph showing R2 relaxivity as a function of volume fraction of various glass microspheres.

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

[0053] [Figure 8] FIG. 8 is a graph showing local magnetic dose (LMD) relaxivity obtained from MRI susceptometry measurements as a function of the volume fraction of various glass microspheres. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] In the context of this disclosure, a "glass material" generally refers to any object, such as a bulk or particulate material. The term "glass" should be understood to mean any qualitative material and should be understood to include glasses of the specified composition. The term "glass" or "glass composition" defines the specific components of the composition. Thus, references to the physical properties of the material (e.g., particle size) relate to glass materials, while References to compositional properties (e.g., mole fractions) relate to glasses or glass compositions. In some parts of the present application, the terms "glass," "glass composition," and "glass material" are used interchangeably. For example, all glass materials are made of the glass compositions described. are used interchangeably as if they were referring to the same component.

[0055] In the context of this disclosure, the disclosed ranges of values ​​are expressly recited as limits of the ranges. Not only numerical values, but also ranges are included as if each numerical value and subrange were explicitly recited. The ranges are resolved in a flexible manner to include any individual values ​​or subranges contained within the ranges. For example, the range "about 1 to about 10" should be interpreted as simply including about 1 to about 10. rather, each individual value within the disclosed range of values ​​(e.g., 1, 1.5, 2, 4, etc.) ) and subranges (e.g., 1 to 3, 2 to 7, 5 to 6, etc.).

[0056] Glass composition Generally, the present disclosure provides a glass material, the glass having a molecular weight of about 0.55 to about 0.85 mole percent. SiO2, and from about 0.01 to about 0.23 mole fraction of Na2O, K2O, or Na2O The amounts of Y2O3, BaO, and Ta2O5 in the glass are all , radiopacity and density of the glass, and additionally, other components for forming the glass. The allowable amounts of Y2O3, BaO and / or Ta2O5 have traditionally been Based on experimental results, the authors of the present disclosure believe that the glass material of the present disclosure has a melting point of about 0.05 to about 0.28 mole fraction of Y2O3, BaO, or a combination of Y2O3 and BaO; and any Ta2O5, and the sum of Y2O3, BaO, and any Ta2O5 is It has been determined that the molar fraction of Y2 should be about 0.10 to about 0.31. The sum of O3, BaO, and optionally Ta2O5 is about 0.10 to about 0.25 mole fraction. For example, the molar fraction may be about 0.10 to about 0.15.

[0057] In the context of mole fraction, "about X mole fraction" refers to the oxide being measured relative to the value indicated. should be understood to mean any value within the range of estimated uncertainty. In the context of inductively coupled plasma mass spectrometry (ICP-MS), the estimated uncertainty of SiO2 is The estimated uncertainty for Na2O is 10% of the reported value, and the estimated uncertainty for BaO is 2. %, and the estimated uncertainty for Ta2O5 can be 1% of the reported value.

[0058] The glasses of the present disclosure contain from about 0.05 to about 0.08 mole fraction of Y2O3, BaO, or Y2O Some exemplary glasses of the present disclosure may include a blend of 3 and BaO. Such exemplary glasses are also free of Y2O3, as discussed in detail below. In particular, it may be useful in mixtures of particulates.

[0059] The glasses of the present disclosure may contain Ta2O5 in an amount up to about 0.12 mole fraction, e.g., about 0.10 mole fraction. up to about 0.05 to about 0.12 mole fraction, for example, about 0.0 It may contain from about 0.5 to about 0.10 mole fraction of Ta2O5.

[0060] The glasses of the present disclosure may additionally contain B2O3 in an amount up to 0.20 mole fraction. The sum of B2O3 and SiO2 is about 0.60 to about 0.85, for example, about 0.60 to about 0.80 mole fraction. B2O3 is known in the art as a glass former. When B2O3 is added to sodium silicate glass, the sodium borosilicate glass Some examples of sodium borosilicate glasses of the present disclosure are resistant to decomposition. Some examples of sodium borosilicate glasses of the present disclosure may be improved. The glass forming ability may be improved.

[0061] Although this disclosure focuses on sodium silicate glasses, both Na2O and K2O are They act as modifiers of the glass network and exert many similar effects on glass properties. In some contemplated glasses of the present disclosure, the glass composition is It may contain only A2O (no K2O) or only K2O (no Na2O). In the intended glass, the glass composition is Na2O and K in a ratio of 100:1 to 1:100. 2O. The present disclosure further includes 50:1, 25:1, 10:1, 5:1, 1 Ratios such as 1:1, 1:5, and 1:10, and any range of ratios therebetween are contemplated. In some examples of the present disclosure, the Na:K ratio is about 75:25, about 50:50, about 25 :75, or about 10:90.

[0062] In addition to its effect on the radiopacity of the glass, BaO acts as a modifier of the glass network. It is known in the art that networks in sodium silicate glasses act as If the total amount of the lattice modifier is too high, glass may not be formed or the glass network may be unstable. Due to its qualitative nature, glass may not be suitable as a durable embolization agent. In the glass material shown, the total of BaO, Na2O, and K2O is about 0.10 to about 0.33. The molar fraction may be, for example, about 0.15 to about 0.33. For example, BaO, The total of Na2O and K2O is about 0.10 to about 0.25, for example, about 0.15 to about 0. It may be 25 mole fraction.

[0063] The glasses of the present disclosure are preferably predominantly sodium silicate glasses. The sum of SiO2 and Na2O in the glass may be about 0.65 to about 0.90 mole fraction. stomach.

[0064] In some examples of the glass materials disclosed herein, the sum of SiO2 and Na2O is , about 0.69 to about 0.90 mole fraction, and the glass is about 0.05 to about 0.09 mole fraction. The total of Y2O3, BaO, and Ta2O5 is about 0.10 to about 0. 17 mole fraction. An exemplary glass material of such composition has a high level of radiopacity and 3.3~3.6g / cm 3 This represents a beneficial balance between the amount of heat and the particle density.

[0065] In other examples of the glass materials disclosed herein, the sum of SiO2 and Na2O is about 0. 0.65 to about 0.80 mole fraction, and the glass has about 0.05 to about 0.10 mole fraction of Ta 2O5, and the total of Y2O3, BaO, and Ta2O5 is about 0.18 to about 0.31 molar. An exemplary glass material of such composition has a high density but high levels of radiation. It may exhibit radiopacity.

[0066] In yet another example of the glass material disclosed herein, the glass has a viscosity of about 0.55 to about 0. 80, for example, about 0.55 to about 0.75 mole fraction of SiO2 and about 0.03 to about 0.23 , for example, about 0.05 to about 0.22 mole fraction of Na2O and about 0.05 to about 0.12, e.g. For example, about 0.05 to about 0.08 mole fraction of Y2O3, BaO, or Y2O3 and BaO. and about 0.05 to about 0.12, e.g., about 0.05 to about 0.09 mole fraction of Ta2 Including O5.

[0067] For example, the glass may have a mole fraction of about 0.70 to about 0.73 SiO2 and about 0.16 to about 0. 0.18 mole fraction of Na2O, about 0.05 to about 0.7 mole fraction of Y2O3, and about 0.05 In one particular example, the composition may include about 0.7 mole fraction of Ta2O5. 1 mole fraction of SiO2, about 0.17 mole fraction of Na2O, and about 0.06 mole fraction of Y2 O3 and about 0.06 mole fraction Ta2O5. Another specific example is a glass containing about 0. 72 mole fraction of SiO2, about 0.17 mole fraction of Na2O, and about 0.05 mole fraction of Y 2O3 and about 0.06 mole fraction Ta2O5.

[0068] In some examples of the glass materials disclosed herein, the glass has a viscosity of about 0.55 to about 0.82, for example, about 0.55 to about 0.75 mole fraction of SiO2 and about 0.03 to about 0. 23, for example, about 0.05 to about 0.22 mole fraction of Na2O and about 0.05 to about 0.12 For example, about 0.05 to about 0.08 mole fraction of Y2O3, BaO, or Y2O3 and Ba and about 0.05 to about 0.12, e.g., about 0.05 to about 0.09 mole fraction of T a2O5 and up to 0.1 mole fraction of B2O3.

[0069] In some examples, the glass has a viscosity of about 0.65 to about 0.82, for example, about 0.73 to about 0. 80 mole fraction of SiO2 and about 0.03 to about 0.23, for example, about 0.03 to about 0.11 molar fraction of Na2O and about 0.06 to about 0.12, for example, about 0.07 to about 0.10 molar fraction of Na2O. and about 0.06 to about 0.12, e.g., about 0.07 to about 0.10, mole fraction of BaO. Ta2O5 and about 0.001 to about 0.015, for example, about 0.001 to about 0.006 mol Contains a fraction of B2O3.

[0070] One particular example is a SiO2 alloy having about 0.69 mole fraction and Na2O3 having about 0.16 mole fraction. , about 0.07 mole fraction of BaO, about 0.07 mole fraction of Ta2O5, and about 0.01 mole fraction of It is a glass containing a B2O3 fraction.

[0071] Another specific example is a SiO2 having about 0.66 mole fraction and Na2O having about 0.20 mole fraction. , about 0.065 mole fraction BaO, about 0.06 mole fraction Ta2O5, and about 0.011 mole fraction It is a glass containing a mole fraction of B2O3.

[0072] Another specific example is a SiO2 having about 0.73 mole fraction and Na2O having about 0.10 mole fraction. , about 0.08 mole fraction of BaO, about 0.08 mole fraction of Ta2O5, and about 0.01 mole fraction of It is a glass containing a fraction of B2O3.

[0073] Yet another specific example is a SiO2 having about 0.74 mole fraction and a Na2O3 having about 0.09 mole fraction. 2O, about 0.085 mole fraction BaO, about 0.085 mole fraction Ta2O5, and about 0. It is a glass containing .006 mole fraction B2O3.

[0074] Yet another specific example is a SiO2 having about 0.79 mole fraction and a Na2O3 having about 0.06 mole fraction. 2O, about 0.08 mole fraction BaO, about 0.07 mole fraction Ta2O5, and about 0.0 03 mole fraction of B2O3.

[0075] A further specific example is a SiO2 alloy having about 0.77 mole fraction and a Na2O3 mole fraction of about 0.031 mole fraction. 2O, about 0.10 mole fraction BaO, about 0.096 mole fraction Ta2O5, and about 0. 002 mole fraction of B2O3.

[0076] Yet another specific example is a SiO2 having about 0.80 mole fraction and a N aO, about 0.082 mole fraction BaO, about 0.085 mole fraction TaO, and about It is a glass containing 0.001 mole fraction of B2O3.

[0077] A further example is about 0.58 mole fraction SiO2, about 0.20 mole fraction Na2O, A blend of Y2O3 and BaO at about 0.06 mole fraction and Ta2O5 at about 0.07 mole fraction and about 0.09 mole fraction B2O3. The glass has about 0.024 mole fraction B2O3. The composition may comprise about 0.035 mole fraction of Y2O3 and about 0.035 mole fraction of BaO.

[0078] The glass composition of the present disclosure preferably contains Li2O, Rb2O, V2O5, ZnO, Fe Substantially free of one or more of O2 and fluoride. Lithium oxide, rubidium oxide , and vanadium oxides, when these oxides are present in sufficiently high concentrations, If these oxides leach out of the glass material, they can result in a cytotoxic glass. 0.01, for example 0.001 or 0.0001 mole fraction, preferably 0 mole fraction Fluoride in glass deteriorates physiological conditions. The compound is added in an amount of 0.005 mole fraction or less, for example, 0.0001 mole fraction, preferably 0 mole fraction. Zinc oxide may be dissolved from glass materials if present in a sufficiently high concentration. It is desirable to use zinc oxide at a mole fraction of 0.01 or less, e.g. For example, it is 0.001 or 0.0001 mole fraction, preferably 0 mole fraction. The iron oxide is preferably present in an amount of 0.01 mole fraction or less, for example, 0.001 or 0.0001 mole fraction. Or, the mole fraction is set to 0.

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

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

[0081] The composition of the formulation "BIC#-IGP" is sieved to collect particles smaller than 45 μm. The reported values ​​are based on measurements of the corresponding irregular glass powders. is believed to more accurately reflect the actual composition of the glass produced.

[0082] The compositions of the formula "BIC#-MPS" are prepared from the corresponding compositions of BIC#-IGP. The measurements are based on measurements of substantially spherical particulate glass material. The particles were sieved and obtained as microspheres with an average size range of 20 μm to 30 μm. The composition of glass particles is prepared by flame treating the particles to remelt the surfaces of the irregular particles, followed by This changes when substantially spherical particles are formed.

[0083] The composition of the formula "BIC#-MPC" is the measurement of the post-processing material produced from the corresponding BIC#. The substantially spherical particulate glass material is Using 0.2 g / mL CaCl-free phosphate buffered saline (CMF-PBS), The flame-treated particles are post-treated at 50°C for 72 to 366 hours. This changes when the particles are treated to reduce the resulting surface reaction deposits.

[0084] The composition of formula "BIC2-MPC#" is made from irregular BIC2 glass powder, The measurements are based on measurements of particulate glass material after processing into a substantially spherical shape. The different compositions in the formulations are the result of different flame treatment parameters. The glass powder is sieved to collect particles smaller than 45 μm, and the surface of irregular particles is and flame treated to remelt and form substantially spherical grains having an average size range of 20 μm Sieved to obtain ~30μm microspheres, calcium and magnesium free Post-treatment at 80°C for 72 hours using 0.2g / mL phosphate-buffered saline (CMF-PBS) It has been understood that

[0085] The composition of the glass is determined by (a) a portion of the starting reagents and (b) the measured composition of the produced glass. and (c) substantially spherically processed microparticles useful in embolization. However, in this disclosure, all of these are based on the same blood at various stages of production. It should be understood that the term refers to a vessel plugging product. Thus, for example, based on theoretical mole percent The BIC2 composition of "about 0.69 mole fraction of SiO2" is (i) "about 0.66 mole fraction of (ii) an irregular glass powder having “about 0.73 mole fraction of SiO2” (iii) a processed glass material having “about 0.74 mole fraction of SiO2”, “about 0 "about 0.77 mole fraction SiO2," "about 0.79 mole fraction SiO2," or "about 0.80 mole fraction SiO2." Unless otherwise specified, this refers to a processed glass material having a SiO2 fraction of 0.1% or less. The mole % / fractions discussed in the specification refer to theoretical % / fractions based on the amounts of starting reagents. [Table 1]

[0086] A dense sample of irregular particulate glass material sieved to collect particles smaller than 45 μm. The degree of radiation, the density of the substantially spherical particulate glass material, and the radiation of the substantially spherical glass composition The impermeability is shown in Table 2. [Table 2]

[0087] In various tests, as disclosed in more detail below, TheraSpher™ Yttrium The glass used in the Mu-90 microspheres was used as a control, and the microspheres 40% by mass Y2O3, 20% by mass Al2O3, and 40% by mass SiO2 (see the specification) The YAS4 irregular glass powder is referred to as "YAS4" or "COMP1" in the literature. was sieved to collect particles smaller than 45 μm and was found to be 65.795 mol% SiO 2 (36.56% by mass), 19.111mol% of Al2O3 (20.90% by mass), and The measured composition was 15.095 mol% Y2O3 (42.40 wt%). The YAS4 glass is a spherical glass with 64.448 mol% SiO2 (38.12 mass %). %), 19.492 mol% Al2O3 (20.89 mass%), and 16.060 mol It had a measured composition of 1% Y2O3 (40.70 wt%).

[0088] In contrast to the exemplary glass compositions above, YAS4 glass contains particles smaller than 45 μm. Irregular glass powder sieved for recovery: 3.3466±0.0060g / c m 3 3.3078±0.0077g / cm for a substantially spherical material 3 Density of and a 70k of substantially spherical material as measured using CT radiopacity measurements. CT radiopacity at Vp was 10,387 ± 245 HU for the essentially spherical material. CT radiopacity at 120 kVp was 5,955 ± 202 HU.

[0089] Glass formula TRCR3, TRCR9, TRCR12, TRCR13, TRCR16, TRCR23, BIC1-MPS, BIC2-MPS, and BIC3-MPS are all At 120 kVp, the CT radiopacity was greater than 13,000 HU, which is consistent with the control These formulations have more than double the radiopacity of the YAS4 glass composition of the original. , TRCR3, TRCR9, TRCR13, BIC1-MPS, BIC2-MPS, and BIC3-MPS is a substantially spherical particulate glass material, and the control YAS4 glass It has a density within 10% of the density of the composition.

[0090] Glass Material The substantially spherical microparticles according to the present disclosure may be useful in embolization, primarily in bulk gas. The bulk glass is then fabricated by forming a lath. The irregular particles are processed to provide a substantially spherical particulate glass material. Flame treated to form particles. Irregular particles to form substantially spherical microparticles. Flame treatment of glass particulates is well known in the art. Examples of flame treatment include flame balls. These include shaping, ultrasonic spray pyrolysis, droplet generators, and vertical thermal flames. The composition can be melted at various temperatures. It can be used to remelt the surface of irregular particulates. The flame treatment process provides a temperature that can remelt the surface of the targeted irregular glass particles. To achieve this, various gases or gas mixtures such as propane-oxygen or acetylene-oxygen are used. The particles that are spheronized by flame treatment are the result of the flame treatment. The surface may be treated to reduce or eliminate reaction deposits.

[0091] In the context of this disclosure, the terms "microparticle" and "microparticle" may be used interchangeably. It means particles having a diameter of less than 1200 μm. In the case of a mixture of particles, the mixture , having an average diameter of 1200 μm.

[0092] This disclosure may refer to "microspheres" or "glass microspheres" or "spherical particles." However, it should be understood that the particles of the present disclosure need not be perfectly spherical. In the present specification, "substantially spherical" refers to particles having a mean sphericity (%SPHT) of at least 90%. The sphericity (%SPHT) is based on ISO9276-6 and ISO1333 22-2, respectively, and CamSizer P4 (ATS Science), which operates based on the dynamic image analysis principle. The measurement can be performed using a tific (Burlington, ON) system.

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

number

[0094] The terms "microsphere" and "substantially spherical microparticle" may be used interchangeably. The term "particles" refers to substantially spherical particles having an average diameter of less than 100 μm. It has an average diameter of less than 200 μm.

[0095] The bulk glass according to the present disclosure can have a glass composition as described above, which , may reflect the theoretically indicated mol% of the components. An example is a BIC2 glass, with 0.687 mole fraction SiO2 and 0.163 mole fraction Na2O, 0.068 mole fraction BaO, about 0.070 mole fraction Ta2O5, and about 0 It has a theoretical composition of .012 mole fraction B2O3.

[0096] The irregular particulates can be milled using any technique known in the art, including ZrO2 grinding media. The bulk glass is milled using a planetary ball mill and the resulting particles are sieved to obtain the desired The use of ZrO2 as a grinding medium is The toughness of the grinding media relative to the bulk glass may help reduce contaminants in the process. One specific example of an irregular microparticle according to the present disclosure is a glass microparticle of BIC2-IGP. 0.659 mole fraction of SiO2, 0.146 mole fraction of Na2O, 0.065 mole fraction of about 0.062 mole fraction of Ta2O5, and about 0.011 mole fraction of B2 Other specific examples are BIC1-IGP and BIC3-IGP glasses. do.

[0097] The irregular microparticles may have an average diameter of about 15 μm to about 1200 μm. The microparticles of the present disclosure can be used in a variety of vascular embolization protocols. The size of the microparticles can be selected to distribute preferentially in the tissue compared to normal tissue. The microparticles according to the present disclosure can be used, for example, in microtubules for visualizing or treating liver tumors. It is useful for producing small globules, which may have an average diameter of about 15 μm to about 45 μm. In an example, the microparticles can have an average diameter of about 20 μm to about 35 μm. The irregular particles are about 40 μm to about 500 μm, about 40 μm to about 300 μm, and about 300 μm ~ approx. 500 μm, approx. 500 μm ~ approx. 700 μm, or approx. 700 μm ~ approx. 1200 μm The microparticles obtained from the various sizes of the microparticles may be sieved to provide particles of The size of the globules can be selected depending on the diameter of the blood vessel to be occluded. The blood vessels that supply the blood that supports the growth of the tumor are located in the tumor lid tumour. The diameter of the microspheres may be larger than the blood vessels found within the tumor. Even if larger particles are not as useful in blocking larger blood vessels, It may be desirable to use

[0098] "About X μm" in the context of particle size and particle diameter refers to the particle size measured using a test sieve of the indicated size. It should be understood that the tolerances are determined based on ASTM E-11. For example, the tolerance of a 50 μm test sieve is 3 μm. Therefore, "about 50 μm" means This means particles with a size between 47 μm and 53 μm. In another example, the tolerance of the 35 μm test sieve The error is 2.6μm. Therefore, "approximately 35μm" means 32.4μm to 38.6μm. The ASTM tolerance for a 25 μm sieve is 2.2 μm. For test sieves without a size (e.g. test sieves smaller than 20 μm), the indication "approximately X μm" shall be used. means ±15% for 5 to 15 μm, and ±50% for less than 5 μm. For example, "about 1 μm" means particles with a size between 0.5 and 1.5 μm.

[0099] The irregular particles are flame treated to remelt the surface and form substantially spherical particles. Flame treated irregular particles are produced by mixing the appropriate size irregular particles with propane / oxygen. This can be accomplished by flame spherical injection into a flame and directing the flame into a collection system.

[0100] One specific example of a substantially spherical microparticle according to the present disclosure is BIC2-MPS glass. 0.733 mole fraction of SiO2, 0.109 mole fraction of Na2O, 0.073 mole fraction of The gallium arsenide is composed of 0.011 mole fraction of B2O3, 0.074 mole fraction of BaO, and 0.074 mole fraction of Ta2O5. Other specific examples include glasses BIC1-MPS and BIC3-MPS. It is.

[0101] Treating glass microspheres to reduce their surface reactivity has been widely reported in the art. The treatment may be carried out, for example, by stirring the flame-treated particles at a rate of preferably 120 rpm. The ultrapure cellulose was then exposed to the CMF-PBS solution at 80°C for at least 72 hours. This can be achieved by washing with water. The microparticles are 0.2 mL per mL of CMF-PBS. One specific example of a treated microparticle according to the present disclosure may have a BIC2 -MPC glass with 0.739 mole fraction of SiO2 and 0.086 mole fraction of Na2 O, 0.085 mole fraction BaO, 0.085 mole fraction Ta2O5, and 0.006 mole fraction The glass composition is B2O3 with a B2O3 fraction of 0.1%.

[0102] Irregular particles that are spheroidized are not expected to change substantially in particle diameter. However, the spheronized particles may be sieved either before or after processing to obtain the desired spheronization results. The size of the particles may be provided.

[0103] Imaging The radiopaque glass microspheres of the present disclosure are useful in radiographic imaging, computer Computed tomography (CT) imaging, cone-beam CT imaging, or fluoroscopic imaging Such X-ray based imaging may be used.

[0104] The desired radiopacity of the glass microspheres depends on the type of imaging used, the target and The results may depend on the clinical scenario, such as the area of ​​treatment to be performed, the estimated packing density of the microspheres, etc. When a relatively small number of particles are being delivered, the particles may be distributed over a relatively large area. where relatively low-power imaging techniques are used, or where these In any combination, the more radiopaque glass is preferred. Too much radiopacity can result in imaging artifacts, and the image Glasses with low radiopacity deliver a relatively large number of particles due to the poor grafting quality. In the case of a slab, where the particles are expected to be distributed over a relatively small area, When relatively high power imaging techniques are used, or any combination thereof is desirable.

[0105] Less than 45 μm and 2.7 g / cm 3 ~Approx. 4.3g / cm 3 , for example, about 2.9 g / cm 3 ~Approx. 3.7g / cm 3 , or about 3.3 g / cm 3 ~Approx. 3.6g / cm 3 The density of The glass microspheres according to the present disclosure may be administered by intra-arterial or intravenous delivery. It may be useful in applications. 3 The glass microparticles according to the present disclosure have a density of The pellets have substantially the same density as currently commercially available radioactive microparticles.

[0106] Some glass microspheres according to the present disclosure are characterized in that the glass microspheres are PET ), single photon emission computed tomography (SPECT), or magnetic resonance imaging (M It may be compatible with PET, SPECT, and / or MRI in that it does not affect radioisotope (RI).

[0107] To image the patient's liver, glass microspheres are delivered intra-arterially or intravenously. For imaging applications administered to patients, there are at least about 750 microtubules per gram of liver. In some instances, about 1000 to about 500 globules per gram of liver may be administered to the patient. 000 microspheres may be administered. In a typical adult patient, about 1 million to about 7 million microspheres may be administered. Spheres may be administered.

[0108] Radiotherapeutic mixtures, compositions, delivery devices, and methods The radioactive particles are manufactured in only a few locations and prepared for delivery to hospitals around the world. The specific activity of the microparticles provides the desired activity at the planned time of administration. For example, the TheraSphere yttrium-90 glass particles are calibrated Yttrium to produce fine particles with a nominal specific activity of approximately 110 GBq / g on the hour. It was prepared by neutron activation of -89-containing glass particles. Typically, about 1.2 million microparticles per vial (about 3 GBq in about 27 mg) Provided in a dose of 8 million microparticles (~20 GBq in ~180 mg). Calibration and Administration Depending on the delay between doses, the amount of effective radioactivity delivered is 0.17 GBq per vial. (1.2 million particles injected 9 days after calibration) to 18 GBq (1 day after calibration) The dose can range from 100 to 8 million microparticles injected.

[0109] As mentioned above, increasing the number of particles allows for the injection of fewer particles at a higher specific activity. This results in better tumor coverage than administering a lower dose of radioactivity for a given amount of delivery. It may be desirable to administer more particles with a lower specific activity. For example, To administer 3 GBq of radioactivity to a patient, a total specific activity of 22 GBq / g of particulate matter is required. 6 million particles per child is equivalent to 1.5 million particles per child at 88 GBq / g. It is believed that this will result in better tumor coverage than the conventional method.

[0110] Without wishing to be bound by theory, the authors of this disclosure believe that at least some tumors In terms of size and / or degree of vascularization, (i) radioactive microparticles and (ii) the present disclosure By administering a mixture of non-radioactive particles to the patient, the individual radioactive particles are released at a higher ratio. Even with radioactivity, there is at least a slight increase in the dose associated with administering more particles at a lower specific activity. I think it can offer some advantages too.

[0111] The present disclosure provides (i) radioactive glass microparticles, and (ii) non-radioactive, radiation-resistant glass microparticles according to the present disclosure. A mixture of transparent particulate glass materials is provided. Radioactive glass particulates are used to treat tumors in the liver. Radioactive glass particles and non-radioactive radiopaque glass particles are suitable for The material has substantially the same size. The substantially same sized particles are It is expected that they will behave in substantially the same way. Thus, a mixture of particles of substantially the same size It is believed that administering the same results in a uniform distribution of radioactive and non-radioactive particles.

[0112] In the context of this disclosure, particles having substantially the same size include (a) radioactive particles, and and (b) the mean size of the radiopaque non-radioactive particles is the average of these two mean sizes. This means that the particle size is within 40% of the average. For example, radioactive particles have an average diameter of 20 μm. whereas the radiopaque non-radioactive microparticles may have an average diameter of 30 μm. A 10 μm difference between the two types of particles is 40% of the average of the two values. The smaller the particle size, 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 the two.

[0113] The density of the microparticles may also affect the behavior of the microparticles after injection into a patient. In an example, the radiopaque microparticles and radioactive glass microparticles of the present disclosure have substantially the same density. Yes.

[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 means the mass of many particles per unit area. Being an inherent property of a material, bulk density varies depending on the properties of the material in the 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 is relative to water. In the context of this disclosure, substantially the same density By particles having an average is meant particles that are within about 30%, preferably within about 15%, of the average.

[0115] The particle densities of (a) radioactive particles and (b) radiopaque non-radioactive particles are averaged For example, the radioactive particles may be within about 30%, preferably within about 15% of the total. 3g / cm 3 while the radiopaque non-radioactive particulates may have a particle density of 3.9g / cm 3 The particle density between the two types of particulates may be 0.6 g / cm. 3 The difference between the mean of these two values ​​is 16.7%.

[0116] The mixtures according to the present disclosure can be prepared using any of the radiopaque glass compositions disclosed herein. It can be made by

[0117] The mixture is made by exposing pre-irradiated glass particles to neutron radiation to produce radioactive glass particles. Forming particles and mixing radioactive glass particulates with the radiopaque glass particulates of the present disclosure It can be prepared by

[0118] In one particular example, the mixture is: (i) about 40 wt. % SiO2, about 20 wt. % Al 2O3, and about 40% by mass Y2O3 (about 0.170 mole fraction Y2O3, about 0.189 mole fraction A substantially spherical sphere containing approximately 0.51 mole fraction of Al2O3 and approximately 0.641 mole fraction of SiO2. 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 Ta2O5, and about 0.006 mole fraction B2O3. The device includes a substantially spherical, radiopaque particulate glass material.

[0119] Yttrium-89 is produced by exposing yttrium-89 contained in fine particles to a medium flux of ions. The specific activity of the resulting particles is: It depends on the level of flux and the duration of exposure. For example, yttrium-89 has a nominal 14 Medium sex / cm 2 / sec flux, neutron radiation for days, 150GB Specific activities of more than q / g can be reached.

[0120] Improved tumor coverage, e.g., more uniform distribution of microparticles, may be achieved by increasing the total mass of microparticles in the composition. This can be achieved using a mixture having radioactive particles in an amount of about 80% to about 10% (w / w). In the context of this disclosure, any reference to an improvement is to the absence of additional non-radioactive particles. It should be understood that this is in comparison with the same number of radioactive particles in the presence of

[0121] For radioactive particles with a high specific activity, such as 140 GBq / g, the mixture In contrast, the radioactive particles may contain no radioactive particles (such as about 10% by mass). For radioactive particles with a low specific activity, the mixture contains more radioactive particles (about 80 In a particular example, the specific activity may be, for example, about 88 GBq / g. For radioactive microparticles, the mixture may have about 25% by weight of radioactive microparticles.

[0122] "Specific activity" means the radioactivity per unit mass of a radioactive particle, while "total activity" means the radioactivity per unit mass of a radioactive particle. "Radioactivity" means the radioactivity per unit mass of a mixture of radioactive and non-radioactive particles For example, one gram of radioactive particles with a specific activity of 10 GBq / g is If you take a gram of rum and mix these particles with 1 gram of non-radioactive particles, the total will be 5G. A mixture of particles is obtained with an overall specific activity of Bq / g.

[0123] Mixtures of radioactive and non-radioactive particles are formulated to yield various numbers of total particles at the desired radioactivity. The total number of microparticles can be determined based on tumor size and / or the degree of vascularization. For example, a treatment with 10 GBq of radioactivity in 0.5 grams of particles may be used. One is desirable for treating tumors with a certain degree of vascularization, whereas the other is desirable for treating tumors with 10 Formulations with radioactivity of 1000Bq may be desirable for treating more vascularized tumors. do.

[0124] In yet another aspect of the present disclosure, when the mixture includes radioactive glass microspheres, a therapeutic amount of By administering the mixture to the mammal, radiation is delivered to the mammal. Additionally, the present invention relates to imaging mammals using X-ray based radioimaging techniques. Administering a therapeutic amount of such a mixture of microparticles to a patient may include administering a therapeutically effective amount of the mixture to the patient. Non-imageable radioactive particles based on the measured distribution of This may allow calculation of the delivered dose of radiation to tissue by a radioactive particle.

[0125] Without wishing to be bound by theory, the authors of this disclosure further describe radioactive and non-radioactive At least some of the advantages of administering a mixture of microparticles include the use of radioactive and non-radioactive microparticles. It is believed that this can be achieved by administering the same dose to each child separately.

[0126] In some aspects, the present disclosure provides a treatment comprising a mixture of radioactive and non-radioactive microparticles. The present invention provides a therapeutic or diagnostic composition, wherein at least some of the non-radioactive microparticles are The glass material disclosed in the document.

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

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

[0129] In some instances, radioactive and non-radioactive particles may be released into a liquid passing through a conduit. When the voltage Vcc is 1, the resistance Vcc is 1 and the voltage Vcc is 2. The voltage Vcc is

[0130] Those skilled in the art will appreciate that the resistance of an object to flow through a liquid through a conduit is reflected by the drag coefficient, It will be appreciated that the coefficient is a function of skin friction and form drag. The resistance of a particle to flow through a liquid depends on, for example, the particle's size, surface area, shape, density, and The drag can be further increased by the surface condition of the microparticles. Changing a feature to reduce drag is done by changing another feature to reduce drag. It is easy to see that two different particles can have substantially the same resistance since the resistances can be cancelled out by the For example, if the surface condition of the first particle is sufficiently smoother than that of the second particle, In this case, even if the first particle is larger than the second particle, the two particles are still substantially may have the same drag coefficient as

[0131] In the context of this disclosure, the time it takes for a bolus of particles passing through a liquid to fall a set distance. The time it takes to dissolve the distilled water may represent the resistance of particulates to flow through the liquid passing through the conduit. It can be measured by loading a known number of particles into a packed transparent column. The number of particles should be chosen so that the height of the particle bolus is 2-5 times the inner diameter of the column. Once the particles have settled to the bottom of the column, the column is inverted and the particles are moved against gravity. The particles are dropped into distilled water by drag. The particles fall through the transition point. The total time it takes for the particle to pass through the bolus is measured. The transition point is measured from the apex of the particle bolus. The column diameter is set at 0.5 cm and should be at least 100 times the inner diameter of the column. In this case, the settled particles may be 1.5 cm high, and the bolus of particles falls The total time it takes for all particles to fall to a point 50 cm away from the apex of the settling particles is It is the time it takes to pass through.

[0132] This total fall time was measured under the same conditions (i.e., same liquid, same column, same transition point). The drag ratio is compared to the total fall time of a substantially equal number of different particle populations tested. is calculated by dividing the fall time of the first particle group by the fall time of the second particle group. In the context of the present disclosure, the first and second microparticles have a relative drag ratio of about 0.95:1 to about 0.95:1. have substantially the same resistance to flow through a liquid in a conduit when the ratio is about 1:0.95 I think so.

[0133] In some instances, the radioactive microparticles are present in an amount of about 10% by weight relative to the total weight of the microparticles in the composition. % to about 80%, for example, about 25%.

[0134] In some instances, the radioactive microparticle is a diagnostic radioactive microparticle. The radioactive microparticles are therapeutic radioactive microparticles.

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

[0136] Therapeutic radioactive particles include actinium-225, bismuth-213, copper-67, and indium. Umium-111, Iodine-131, Iodine-125, Gadolinium-157, Holmium- 166, Lead-212, Lutetium-177, Palladium-103, Phosphorus-32, Radium -223, Rhenium-186, Rhenium-188, Samarium-153, Strontium -89, and tungsten-188. It's okay to do that.

[0137] The radioactive glass particles can be substantially spherical. The non-radioactive particles are substantially spherical. could be.

[0138] In another aspect, the present disclosure provides a method for preparing a mixture of radioactive and non-radioactive microparticles, as described above. and administering to a patient, wherein the administration can be by intravascular delivery, intraperitoneal delivery, or is by transdermal delivery.

[0139] In yet another aspect, the present disclosure provides a method for administering a mixture of radioactive and non-radioactive microparticles to a patient. A delivery device for intravascular, intraperitoneal, or transdermal delivery is provided. is fluidly coupleable to the mixed transport medium, and a fluid inlet is fluidly coupleable to the mixed transport medium. a fluid inlet, a fluid outlet, a fluid mixer fluidly coupled to the fluid inlet and the fluid outlet, A source of radioactive particles fluidly coupled to the fluid mixer and a source of non-radioactive particles fluidly coupled to the fluid mixer. Radioactive particulate sources are to be distinguished from non-radioactive particulate sources. The mixer 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 by mouth. Some are constructed from glass materials according to the present disclosure.

[0140] In yet another aspect, the present disclosure provides a method for administering a mixture of radioactive and non-radioactive microparticles to a patient. A delivery device for intravascular, intraperitoneal, or transdermal delivery is provided. At least one fluid inlet fluidly connectable to a transport medium, a radioactive particulate source fluidly coupled to the mouth; a radioactive particle source, a first fluid outlet fluidly coupled to the radioactive particle source, and a second fluid outlet fluidly coupled to the radioactive particle source; At least some of the non-radioactive particles are glass particles according to the present disclosure. In some instances, the delivery device comprises a single treatment session. In some examples, the first fluid outlet and the second fluid outlet deliver radioactive and non-radioactive microparticles. The second fluid outlets are adjacent to each other. In the context of this disclosure, for example, during a single treatment session In the course of treatment, radioactive and non-radioactive particles can be administered to the patient substantially simultaneously. It should be understood that the fluid outlets are adjacent to one another.

[0141] The radioactive microparticles in the delivery device can be any of the radioactive microparticles disclosed herein. The non-radioactive microparticles in the delivery device may be any of the non-radioactive microparticles disclosed herein. In some instances, the radioactive microparticles may be present in a total mass of microparticles in the delivery device. It is composed of about 10% to about 80%, for example, about 25%.

[0142] In yet another aspect, the present disclosure provides a method for producing a radioactive nanoparticle comprising the steps of: (i) a first population of radioactive nanoparticles; and (ii) a non-radioactive nanoparticle. and administering to the patient an appropriate amount of the mixture for therapeutic or diagnostic purposes. At least some of the non-radioactive microparticles are The radioactive particles used in the method are made of glass material. The non-radioactive microparticles used in the method may be any radioactive microparticles. The microparticles may be any of the non-radioactive microparticles disclosed in the literature. In some examples, the microparticles may be radioactive. is about 10% to about 80%, for example, about 25%, based on the total mass of the microparticles used in the present method. %. Administration can be by intravascular, intraperitoneal, or transdermal delivery.

[0143] In another aspect, the present disclosure provides a method for administering a therapeutically or diagnostically appropriate amount of microparticles to a patient. The method includes administering non-radioactive microparticles to a patient and first administering radioactive particles to a patient without detecting the particles or administering radioactive particles to a patient and administering non-radioactive particles to a patient without first detecting the radioactive particles. At least some of the non-radioactive particles are The drug is administered intravascularly, intraperitoneally, or transdermally. The route of administration of the radioactive particles is the same as the route of administration of the radioactive particles.

[0144] In some instances, the methods include co-administration of non-radioactive and radioactive microparticles. In another embodiment, the method includes sequential administration of non-radioactive and radioactive microparticles, or radioactive microparticles. This involves the sequential administration of radioactive particles and non-radioactive particles.

[0145] In yet another aspect, the present disclosure provides a method for administering a suitable amount of microparticles for therapeutic or diagnostic purposes. The method includes: (i) a first population of radioactive microparticles; and (ii) a first population of non-radioactive microparticles. At least some of the non-radioactive particles include a second collection of non-radioactive particles. Consisting of a glass material according to the present disclosure.

[0146] In some instances, a first population of radioactive particles is mixed with a second population of non-radioactive particles. A distinction is made between a first collection of radioactive particles and a second collection of non-radioactive particles. The bodies can be administered as a mixture.

[0147] In yet another aspect, the present disclosure provides a method for administering a suitable amount of microparticles for therapeutic or diagnostic purposes. The method provides for the administration of non-radioactive and radioactive microparticles to a patient in a single treatment session. At least some of the non-radioactive particles are made of a glass material according to the present disclosure. It consists of the fee.

[0148] In yet another aspect, the present disclosure provides a method for the preparation of a therapeutic radioactive microparticle comprising the steps of: (i) administering a therapeutic radioactive microparticle to a patient; and (ii) administering a therapeutic radioactive microparticle to a patient. The method includes administering to a patient at least some of the non-radioactive microparticles. is constructed from a glass material according to the present disclosure.

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

[0150] In some instances, sequential administration may involve administration of one type of microparticle prior to administration of the next type of microparticle. For example, sequential administration includes administration of non-radioactive particles prior to administration of any of the radioactive particles. Before administering all of the radioactive particles or any of the non-radioactive particles, This may include administering all of the radioactive particles.

[0151] The methods of the present disclosure allow for the delivery of therapeutically appropriate amounts of radiation to a patient, and can deliver diagnostically relevant amounts of non-radioactive microparticles to a patient.

[0152] In the methods according to the present disclosure, administration may be by intravascular, intraperitoneal, or transdermal delivery. The radioactive and / or non-radioactive particles may be as described above. About 10% to about 80%, for example about 25%, of the total mass of the delivered particles is radioactive particles. It may be a child, a second child, or any combination thereof.

[0153] While the above description relates to methods of administering radioactive and non-radioactive microparticles, the present disclosure , corresponding "uses" of the microparticles, including the microparticles useful in the disclosed methods, and Also contemplated is the use of the microparticles in the manufacture of administrable formulations useful in the disclosed methods. do.

[0154] In the context of this disclosure, the non-radioactive particulates discussed in this section of the disclosure are referred to as “gas or any one of the characteristics of the glass materials discussed in the section above entitled "Glass Materials" It should be understood that combinations may be used. For example, the non-radioactive particles may be Any or all of the characteristics associated with microparticles, microspheres, glass microspheres, or spherical particles It is possible.

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

[0156] Working Example

[0157] Synthesis of irregular glass powders and microspheres. In accordance with the present disclosure, various glasses were synthesized. Theoretical compositions of TRCR# and BIC# glasses The compositions are shown in Table 1 above. In addition, a comparative glass COMP# was also synthesized. The theoretical compositions of the examples are shown in Table 3. [Table 3]

[0158] The density of the irregular particulate glass material, sieved to collect particles of 45 μm or less; The density of the glass material of the substantially spherical particulate and the radiation immunity of the substantially spherical glass composition The permeability is shown in Table 4. [Table 4]

[0159] Comparative Example "COMP1" corresponds to YAS4 disclosed in US Pat. No. 4,789,501. Due to the clinical usefulness of this glass and the known composition-structure-property relationships, the authors of this disclosure Using this comparative example, they demonstrated that the microspheres had substantially the same density (±10%), enhanced radiation resistance, and permeability, acceptable in vitro cytotoxicity, acceptable hemocompatibility, and / or acceptable genetic Without being bound by theory, the authors of this disclosure believe that Glass compositions that meet many or all of these requirements are believed to be suitable for use in transarterial radioembolization. I hope it will be useful for

[0160] For glass synthesis, analytical grade reagents were prepared according to the theoretical compositions outlined in Tables 1 and 3. After uniformly blending for more than 1 hour, the reagents were placed in a platinum-rhodium crucible (50 cc or 200cc) and fired in an electric furnace (Carbolite Furnaces, Sheffield, UK). 1500℃~1600℃, 3 hours~5 hours), followed by water for injection (USP, Ph. Eur. Grade, The resulting irregular glass was shock quenched in a 1000-milliliter flask (Rocky Mountain Biologics, MT, US). The powder was dried in an oven (120°C) overnight.

[0161] All of the exemplary glasses of the present disclosure, as well as COMP1 and COMP3, are shock quenched. The glass melted easily and provided a non-viscous fluid prior to punching. The glass in COMP2 did not melt and Phase separation occurred or provided a viscous fluid.

[0162] Irregular glass powders from different melts were mixed and milled with planetary balls containing ZrO2 grinding media. The glass was ground as one batch using a mill. The resulting crushed irregular glass powder was sieved. Particles smaller than 45 μm were collected.

[0163] The properly classified irregular glass powder is then mixed with oxygen and propane in a controlled manner. The material was then introduced into a propane / oxygen flame, which remelted the material and caused a process known as spheronization. In the process, spherical particles were formed by surface tension. The flame of the burner was ignited by glass microspheres. The study was directed to a stainless steel recovery system that captures glass microspheres as they are released from a water tank. After that, 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) measurements of irregular glass powders and / or particles were performed using an X-ray generator (3 A Bruker D2 Phaser diffractometer equipped with a Cu target X-ray tube coupled to a 1000 V AC (100 Hz, 100 kV, 10 mA) was used. The procedure was carried out using a 300-millimeter column (Bruker AXS Inc., Madison, WI). Irregular glass powder or particles were Samples of each experimental material were prepared by pressing them into hollow zero background holders. The powder diffraction powder was prepared with a scan angle range of 10° < 2θ < 100° and a step size of 0.02. The acquisition time for the XRD spectrum was 4930 seconds.

[0165] Helium pycnometry The density of irregular glass powders and / or particles was measured using helium pycnometry (AccuPyc II 1340, Micromeritics) and the irregular glass powder morphology was The final particle shape was determined using the average (± standard deviation SD) of 10 to 60 measurements recorded for each sample. In each case, the mean value of 10 measurements (±SD) was used.

[0166] Differential scanning calorimetry Thermal properties of irregular glass powders were investigated using a Netzsch Pegasus F404 Differential Scanning Calorimeter (DSC The material was characterized by a 1000°C heating rate from ambient to 1000°C. DSC measurements were performed at 1000 nm / min and the onset (Tg, onset) was recorded using Proteus 6.0 software. The glass transition temperatures at and midpoints (Tg, midpoints) were determined graphically. The SC has a tolerance of 2%.

[0167] Microsphere Processing A substantially smooth surface that is substantially free of any surface reaction deposits resulting from spheronization. To obtain a smooth surface, the flame-treated microspheres were buffered with calcium- and magnesium-free phosphate buffer. 0.2 in buffer (CMF-PBS, product code: MT21040CV, Corning (trademark), NY, US) Post-spheronization processing was performed by extracting at a ratio of g / mL.

[0168] In the first experiment, the microspheres were incubated in a closed container in a shaking water bath at 50°C for 72±2 hours and 120± 2 hours, 240±2 hours, 288±2 hours, 360±2 hours, under continuous stirring at 120 rpm Further analysis then revealed that the enzyme could be used to facilitate processing steps designed for manufacturing. To investigate the possibility of this, the microspheres were incubated in a closed container under accelerated conditions (80°C) in a shaking water bath for 2 h. Extraction was completed for 4±2 hours and 72±2 hours under continuous stirring at 120 rpm.

[0169] After extraction, the microparticles were separated from the CMF-PBS and resuspended in sterile water for injection (USP, Ph. Eur. Gray). After washing 10 times with PBS (Rocky Mountain Biologics, MT, US), the mixture was weighed to constant weight (mass difference ≦0. The mixture was dried at 120±2°C until the concentration reached 1%).

[0170] The glass microspheres were then stored for analysis or regrind. Pre-cleaned glass storage vials for bulk storage to ensure particulates between 100 and 300 μm The sizes were sorted before being packed into boxes.

[0171] Microsphere cleanliness (i.e., visual inspection reveals no reaction deposits and / or contaminants on the surface) The above-mentioned 72±2 h was confirmed by scanning electron microscopy (SEM). Treatments for 120±2 hours, 240±2 hours, 288±2 hours, and 360±2 hours were studied. The extracts of particles obtained during the study were analyzed by an ISO 17025 accredited laboratory (NSL Analytical , 4450 Cranwood Pkwy, Warrensville Heights, OH, US) The concentrations of Si, Na, Ta, B, and Ba elements were analyzed by ICP-OES using a fluororesin. Analyzed.

[0172] Composition analysis Irregular glass powders and / or microspheres are fused / microwave acid digested for compositional analysis The samples were prepared by ISO17025 accredited laboratory (NSL Analytical, 450 Cran, USA). Wood Pkwy, Warrensville Heights, Ohio, using a validated testing protocol. , and analyzed by ICP-OES.

[0173] Scanning electron microscope For irregular glass powder and / or microspheres coated with carbon, 1. Acceleration voltage of 5KV to 10.0KV, light emission current of about 15μA to 22μA, and A Hitachi S-4700 field emission SEM (FE-SEM) operating at a working distance of 14 mm was used. SEM images were then taken at magnifications of 250x and 1000x.

[0174] Safety evaluation of axial computed tomography (CT) scans and MRI The CT radiopacity of bulk microspheres was evaluated by quantitative radiopacity measurements, here In this measurement, 1.2 mL of glass containing 500 mg of particles in 6 μL of sterile saline was used. Using a v-vial manufactured by Sigma Aldrich (product code: Z115061, Sigma Aldrich, Canada), Axial CT scans (1 mm slice thickness, pitch = 0.5, 70 kVp and 120 kV Hansfeldt-J. p. All measurements were performed with a mean diameter (± SD) of 20 μm–30 μm. The experimental material was analyzed using a Siemens Somatom Definition AS+ scanner with a 30 μm range. (Siemens Healthcare, Erlangen, Germany) and the extended HU range used for scanning. option was used.

[0175] We investigated the effect of microsphere concentration on quantitative CT radiopacity and MRI safety. To achieve this, microspheres containing BIC1–BIC3 and the COMP1 control were incubated at five different concentrations. (at the following volume fractions: 1.25%, 2.5%, 5%, 7.5%, and 10%) ( 3 times). Gel-only tubes (0%) were also used as baseline controls. The volume fraction of the microspheres was calculated using the densities of the microspheres in Tables 2 and 4, and was then added to 1.5 mL of 8% gelatin. The microspheres were added to the gelatin prepared in the above procedure and vigorously shaken in a 5 mm NMR tube. After optimizing the uniformity of particle distribution, place on ice immediately. In some cases, the gel was melted and the microspheres were redispersed, followed by resetting with ice. Depending on the density of the microspheres, some clumps of microspheres formed around the periphery and bottom of the tube.

[0176] CT data was collected using a Trifoil Preclinical PET / CT scanner at a resolution of 100 μm. Acquire at 80 kVp with sample resolution and store all CT images in H for subsequent analysis. MRI data were acquired on a 3T Varian MRI system using an INOVA console. Bulk T1, T2, and T2 were obtained. * For quantitative measurement of Using the FTIR, bulk measurements are not limited to a single slice within the coil, but rather to a section of the tube. The tube was positioned so that the bulk of the microspheres was in the imaging region of the coil. Sexual MRI measurements were performed using standard gradient echo sequences (T2 * Emphasis), spin echo sequence (T2-weighted), and short TR anatomical localizer scans (T1-weighted). To improve scientific comparison, all quantitative parameters were calculated using the R1, R2, Or R2 *Note that the relaxation rate is written as: where R is the time decay constant (T) R1 is inversely proportional to 1 / T1, R2 is 1 / T2, and R2 * is 1 / T2 * It is.

[0177] Next, CT radiopacity, R1 relaxivity, R2 relaxivity, R2 * Relaxivity and magnetic susceptibility 5 Three image characteristics were evaluated. For each characteristic, e.g., R1 (or R2, etc.) for each tube The R1 was measured and compared with the control gel tube, and the delta (D)R1 was calculated. Graph DR1 against volume fraction for the tube set and plot the linear regression line. did.

[0178] In vitro cytotoxicity Biological reactivity of mammalian cell monolayers, L929 mouse fibroblast cells, in response to experimental materials , ISO10993-5:2009, Biological evaluation of medical devices - Part 5: Validated biological In vitro cytotoxicity testing using a compatible laboratory (Toxikon Corporation, Bedford, MA, USA) d Nelson Labs, Salt Lake City, UT, Nelson Labs, Salt Lake City, UT, US) It has been decided.

[0179] ISO10993-12: 2012, Biological evaluation of medical devices - Part 12: Sample preparation Prepare the experimental materials according to the manufacturer and standard substance, adopting an extraction ratio of 0.2 g / mL mass / volume. To verify the functionality of the test system, positive (natural rubber) and negative (plastic) controls were A control substance was prepared.

[0180] Extracts of experimental and control materials were used to replace the maintenance medium of cell cultures. Extracts of experimental materials were cultured in the presence or absence of 5% bovine serum (1XMEM5) and serum supplemented (complete). In minimal essential medium (MEM), 100% (NEAT), 50%, 25%, and 12.5% A series of dilutions were tested.

[0181] All cultures were incubated at 37 ± 1 °C in a humidified atmosphere containing 5 ± 1% CO2 for 24 ± 2 h ( for untreated microspheres during initial screening) or 72 ± 2 hours (for microsphere optimization) In the case of accelerated treated microspheres), the cultures were replicated at least six times.

[0182] The viability of cells after exposure to the extract was assessed by their ability to take up a vital dye, MTT reagent. The dye was added to cells and actively taken up by viable cells. is correlated to color intensity as determined by photometric measurement at 570 nm after extraction.

[0183] In vitro genotoxicity This study is based on ISO10993-3:2014 "Biological evaluation of medical devices - Part 3: Genotoxicity, Carcinogenicity, and Reproductive Toxicity Testing" and the Organization for Economic Cooperation and Development (OECD) 471 , and Chemical Substance Testing Guidelines "Accredited Biocompatibility Testing Agency (NAMSA Corporation, N The test was conducted to partially satisfy the requirements of the "Bacterial Reverse Mutation Test Using Orthodontic Treatment Plants (Oregon, Ohio, US)." did.

[0184] The test substances, controls, and experimental blanks (extraction solvent without test substance) were SO10993-12:2012 "Biological Evaluation of Medical Devices - Part 12: DMSO and According to "Sample preparation and standard materials in physiological saline at 50°C for 72 hours under continuous stirring," A mass / volume extraction ratio of 0.2 g / mL was used. After extraction, the color of all extracts was The extracts were visually inspected for turbidity and particulates and kept at room temperature for less than 3 hours before use. The samples were not isolated, filtered, or subjected to any other alternative methods prior to dosing and testing. Test strain culture fluid (Salmonella typhimurium test strains TA98, TA100, TA1535, and TA 1537, and the E. coli test strain WP2uvrA) were checked for genetic markers. I did.

[0185] This was followed by addition of either Salmonella typhimurium or Escherichia coli test strains to the molten top agar. A histidine-biotin solution or a tryptophan solution was added to each of the samples. The bacteria on the plates were counted using a darkfield colony counter. ) and undergo several divisions that form the background flora visible to the naked eye. In separate test tubes containing 2.0 mL of molten top agar, each of the five test strains was Inoculate each culture with 0.1 mL of broth and 0.1 mL of DMSO or saline extract of the test substance. A 0.5 mL aliquot of sterile water for injection or S9 homogenate was used to provide metabolic activation. The mixture was labeled with the test number, the appropriate test strain, and the S9 metabolic activity. Each plate was poured onto three plates of minimal E medium labeled with the chemical system (if applicable). Six positive controls were also tested in parallel. Base plate (for Salmonella typhimurium) and tryptophan-free medium plate (for Escherichia coli) ) was prepared in triplicate as follows: DMSO and saline test article extracts with and without I.S9 activity II. Negative controls with and without S9 activity III. Benzo[a]pyrene in the Presence of S9 and S9 Activity with TA98 Strain 2-Nitrofluorene IV. 2-Aminoanthracene in the Presence of S9 and No S9 Activity with TA100 Strain Sodium azide in V. 2-aminoanthracene in the presence of S9 and no S9 activity with TA1535 strain Sodium azide in VI. 2-Aminoanthracene in the Presence of S9 and Absence of S9 Activity with TA1537 Strain ICR-191 in VII. No S9 activity with 2-aminoanthracene and WP2uwA in the presence of S9 MMS in

[0186] The plates were incubated at 37° C. for 2 days. After the incubation period, the average number of revertants and the calculation The revertant colonies on each plate were scored with the standard deviation calculated. For each strain used, the average number of revertants on the test plates was compared with the average number on the negative control plates. The average number of revertants was compared with the above and the characteristics of the background flora were also recorded.

[0187] In vitro hemocompatibility This procedure employs the principles outlined in ASTM F756:2017. AST The M method complies with ISO 10993-4:2017, "Biological evaluation of medical devices - Part 3: Blood In accordance with the "Selection of Biocompatibility Testing for Interactions with (U.S. FDA) Comply with GMP regulations 21 CFR parts 210, 211 and 820 and deviate from procedures The test follows the principles outlined in ASTM F756:2017. In accordance with this, calcium- and magnesium-free PBS was used as the extraction solvent. ISO10993-4:2017 (Due to differences in blood activity, human blood should be used if possible. Validation of ASTM methods using citrated human blood in accordance with the FDA's FDA guidelines (which state that ASTM methods should be used with citrated human blood). did.

[0188] For blood collection, the same amount of blood from three donors was diluted in a 9:1 ratio with 0.1 M sodium citrate ( The blood was collected in a vacutainer containing 3.2% anticoagulant. The samples were refrigerated and pooled until testing using the method, and were used for testing within 4 hours of collection. Hemoglobin standards were diluted with Drabkin's reagent to give 0.80, 0.60, 0.40, and 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 the absorbance was measured spectrophotometrically at 540 nanometers (nm). The hemoglobin absorbance was then measured using a linear regression of the hemoglobin absorbance and standard concentration. To measure plasma hemoglobin, blood was collected at 700–800 × g The plasma was centrifuged at 4°C for 15 min. A 1 mL aliquot of plasma was then added to 1 mL of Drabkin's reagent. After addition and leaving at room temperature for a minimum of 15 minutes, the absorbance was read in a spectrophotometer at 540 nm. The hemoglobin concentration was determined from the standard curve and multiplied by a factor of 2 to obtain the plasma free hemoglobin concentration. The globin concentration was determined (confirmed to be less than 2 mg / mL). The total amount of hemoglobin present was Add a 20 μL aliquot of this to 5 mL of Drabkin's reagent and measure the absorbance in a spectrophotometer at 540 nm. Duplicate measurements were performed by allowing the solution to stand at room temperature for a minimum of 15 minutes before reading the concentration. The hemoglobin concentration was then determined from the standard curve and increased by a factor of 2 to account for the dilution. Based on the total hemoglobin present, blood was diluted to 10 ± 1 in CMF-PBS. To verify the dilution of blood, aliquots of diluted blood were Add 4.5 μL of Drabkin's reagent in triplicate and measure spectrophotometrically at 540 nm. The samples were allowed to stand at room temperature for a minimum of 15 minutes before the absorbance was read using a spectrophotometer. was determined from the standard curve and multiplied by a factor of 16 to account for the dilution.

[0189] Positive control (hemolytic), negative control (non-hemolytic), and blank control of experimental materials The mass / volume ratio of the solution was 0.2 g / mL or 6 cm 2 Surface area / extraction volume per mL This was prepared in accordance with ISO10993-12:2012 "Biological evaluation of medical devices - Part 12: Sample preparation and standard materials" and 50±2℃ (stirring), 72±2 hours C It complies with the indirect contact (extract) analysis sample prepared in MF-PBS. For both the bleeding and direct contact methods, extracts or materials at appropriate concentrations were The blood was then added to a glass tube, and 1 mL of the diluted blood was added to each tube. Incubate the tubes at 37 ± 2 °C for a minimum of 3 h, gently inverting twice at 30 min intervals throughout the incubation period. After incubation, the test substance and the control substance were centrifuged at 700 to 800 × g for 15 minutes. The supernatant was mixed with 1 mL of Drabkin's reagent and allowed to stand at room temperature for at least 15 minutes. After centrifugation, the color, turbidity, and particulate matter of the test substance, blank, and control supernatants were measured. All test and control substances were then spectrophotometrically inspected for 54 The reading was taken at 0 nm.

[0190] The hemolysis index (% hemolysis) was expressed using the following formula: Hemolysis index = released hemoglobin (mg / mL) / present hemoglobin (mg / mL) ×100 Hemoglobin released (mg / mL) = (optical density x coefficient X + constant) x 16 Hemoglobin present (mg / mL) = diluted blood 10 ± 1 mg / mL

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

[0192] statistical analysis CT and MRI measurements expressed as the mean (±standard error of the mean, SEM) of three replicates. Each microsphere formulation prepared at various volume fractions was subjected to linear regression analysis, and if the linear regression analysis was not zero, The results were statistically evaluated to confirm that the data were consistent with those of the original data. Comparisons were made with other treatments using the hPad. Software Inc., San Diego, CA, US. Significance was p It was set to <0.05.

[0193] Amorphous morphology, density, and glass transition temperature The glasses of the examples of the present disclosure and the comparative examples are prepared in the form of irregular glass powder and microspheres. The amorphous morphology, density, and glass transition temperature were evaluated in the disordered glass state. Regardless of the heat treatment (spheroidization) after powder preparation, all samples remained amorphous. No identifiable crystalline peaks were detected in any of the formulations evaluated. The comparative glass and microspheres formed after spheronization, both in the irregular glass powder, The density, Tg (midpoint TgM and inflection point TgI) of the glass of the embodiment of the present disclosure are shown. . [Table 5]

[0194] The density of the commercially available control "COMP1" is approximately 3.3 g / cm 3 The density of The results showed that the morphology of the glass particles was uniform and that there was only a small variation between the irregular glass powder and the microsphere morphology. The TRCR glass series has a low viscosity of about 3.05 g / cm 3 (TRCR20) Highest is 4.2674g / cm 3 It offers a wide range of densities up to (TRCR23) as well as No significant differences were observed between the irregular glass powder and particulate morphology formulations. In the examination of the TRCR formulation itself, the increase in Ta2O5 in the glass network A trend of increasing flit and microsphere density with time was observed. C formulation showed a similar trend in density between the irregular glass powder and microsphere morphology. (3.459 g / cm 3 ~3.542g / cm 3 and 3.4326 g / cm 3 ~3.5739g / cm 3 ).

[0195] Analysis of the glass transition temperature showed that the commercial control had a TgM of 909°C and a TgM of 915°C. The data points consisted of TgM and TgI between TgI and TgM. The R and BIC glass series are designed for temperatures between 512℃~794℃ and 513℃~799℃. A wide range of TgM and TgI data points were observed.

[0196] Consideration of processing Figure 1 shows the results of the spheronization of BIC2 microspheres at 0.2 g / mL in CMF-PBS. Extraction was performed over a period of 360 hours (maintained at 50°C under continuous stirring (120 rpm)). The cumulative ion release curves obtained are shown. In summary, Ba was released at IC It was the only element recorded below the P-OES detection limit (10 ppm), and was not affected by B, Ta, or Na. , Si is 20 ppm, 30 ppm, 500 ppm, and 430 ppm to 440 ppm, respectively. ppm. A 120 hour extraction window was then used to thoroughly characterize all remaining elements. Although substantial extraction (reported to be below the ICP-OES detection limit (10 ppm)) was confirmed, Si (530ppm~540ppm) is the exception, and then between 240 hours and 360 hours It has been shown that exhaustive extraction can be achieved.

[0197] Chemical analysis and surface morphology Table 6 shows the COMP1 item and the feed material (irregular glass powder) used for spheronization. The BIC formulation was compared with the microspheres recovered after spheronization (the same lot was processed for each formulation). The chemical composition of the samples varies.

[0198] In summary, all three BIC formulations showed significant volatilization of alkali elements after spheronization. was observed, with up to half of the starting composition of the feedstock (from 10.05 wt.% to 7.84 wt.% ( BIC1), 14.60% by mass to 7.03% by mass (BIC2), and 10.95% by mass % to 5.36% by mass (BIC3)) (external testing laboratory) (in terms of mass % reported by ). Concomitantly, the concentrations of other elements (i.e., Ta 2O5 and / or SiO2) were observed after spheroidization, as the concentrations of these elements increased significantly. Thus, it was observed that the relative loss was compensated for. In addition, BIC3 increased with increasing B2O3 concentration. As a result of the significant decrease in B2O3 (from 3.62% by mass to 1.12% by mass), In contrast, when used as a feedstock, COMP1 item showed significant volatilization. (Table) remained compositionally unchanged (i.e., within ±3% by mass of each elemental component) (the acceptable range between

[0199] The surface morphology of the feed material is shown in FIG. 2A and is compared with that of the microspheres after spheronization (FIG. 2B). SEM images collected as well as the spheroidized material show that (I) the spheroidized material is formed due to a glass reaction in a gas environment. (II) accumulation of surface deposits from the glass manufacturing process or airborne particles or particulate contamination on product contact surfaces, resulting in the accumulation of surface reaction deposits on microspheres. vinegar.

[0200] Table 7 shows the chemical composition obtained by processing the BIC2 microsphere lot separated after 360 hours. As shown in Figure 1, the aqueous environment results in the loss of Na from the glass network. As a result of this processing step compared to spheronization, the extraction of Na2O is achieved. The decrease in O was not widespread (7.03% to 5.36% vs. 14.6%, respectively). 0% to 7.03% by weight, prior to the time frame in which the first extraction was evaluated (72 hours), This can be mainly attributed to the treatment step of removing unreacted surface reaction deposits, where With minimal dissolution of Na2O from the glass network.

[0201] Utilizing the findings of this study, we accelerated the extraction temperature and shortened the time frame to 24 hours (extraction ratio, All other variables such as temperature and agitation speed were kept constant (for process optimization). ) Further extraction analysis was performed and microspheres without surface reaction deposits could be observed by SEM. Figure 2C shows the microspheres treated at 80°C for 24 hours, showing their spherical shape. Provides nearly complete removal of surface reaction deposits and / or contaminants observed immediately after oxidation (Figure 2B ), whereas the microspheres treated at 80°C for 72 hours and resieved after spheronization had a surface roughness of 1.0 mm. The complete removal of the reaction deposits is clearly shown (Figure 2D). After 24 and 72 hours The treated BIC2 microspheres were then stored for biocompatibility evaluation. [Table 6] [Table 7]

[0202] CT radiopaque In the glass composition of the example in Table 1, the control item (COMP1: 5,952±18 At clinically relevant tube potentials (120 kVp) compared with 0 HU, The radiopacity of the benchtop CT is 9,978 ± 579. The observed range was from HU (TRCR8) to 21,858 ± 1037 HU (TRCR23). The densities of TRCR3, 8 and 13 are 10% of the density of the comparative example COMP1. Their radiopacity ranged from 9,978±579HU (TRCR8) to 16,374± was observed in the range of 465 HU (TRCR13).

[0203] BIC1, BIC2, and BIC3 are comparable in desirability to control item COMP1. The densities were within the target range of 13,676±642HU to 16,952±205HU. The periphery showed radiopacity.

[0204] CT with variation in concentration of microspheres of BIC1 to BIC3 compared to the control item Regarding the evaluation of radiopacity, FIG. 3 shows the results of the measurement of the prepared PET with various volume fractions at 80 kVp. The radiopacity increases with increasing concentration (volume fraction) of microspheres in the samples. Furthermore, there is a good correlation between the obtained HU values ​​and the volume fraction of the microspheres, which The slope and R of each calibration curve created by 2 The values ​​were as follows (low CT radiation Radiopacity to high radiopacity: 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, which was 407.7). At the concentration of microspheres expected to be administered for therapeutic purposes, compared with the COMP1 product BIC1 to BIC3 were selected as promising candidates for providing enhanced radiopacity. Port.

[0205] MRI evaluation The BIC1 to BIC3 microsphere formulations and COMP1 items are created for R1 relaxation. As supported by the calibration curve shown in Figure 4, the large T1 contrast effect was observed. The calibration curves show a significant correlation between R1 relaxivity and microsphere concentration. The slopes range from 0.007 (COMP1) to 0.034 (BIC3), and are statistically non-zero. Although the slope was not significant (p<0.002), these microsphere formulations were acceptable because the slope was very small. This is supported by Fig. 5. and the T1 contrast change is not evident in the tube images.

[0206] Similarly, for BIC1 to BIC3 microsphere prescriptions or COMP1 items, the R2 relaxation is As supported by the calibration curves shown in Figure 6, The calibration curves show a significant relationship between R2 relaxivity and microsphere concentration. The slopes range from 0.068 (COMP1) to 0.688 (BIC3). Although not statistically zero (p<0.003), the slope is very small, so these prescriptions Compared to physiological differences, this does not result in a significant difference in signal contrast. This is also shown in Figure 5, where the highest BIC2 microsphere concentration image shows There is very mild T2 contrast change in the sigma-positive and sigma-negative areas.

[0207] R2 * For the relaxivity measurements, a calibration curve is shown in Figure 7. The microsphere formulation was Sea urchin) T2 * Induces some changes in contrast. However, Target location of microspheres (prominent T2 due to blood * (effective) of the contrast The changes are clinically * may be sufficient to induce significant changes in the weighted scan. The possibility is low. As with the T1 and T2 calibration curves, the R2 * The slope of relaxation is statistically zero (p<0.04), and the slope was 3.5s -1 ~6.3s -1 As shown in Figure 5, As can be seen, at the highest microsphere concentration in the control article, the visible T2 * Contrast Perception There are possible differences, with relatively few air bubbles visible in the BIC2 microspheres.

[0208] The local magnetic dose (L MD) showed a small negative slope (-0.0074 to - 0.0190), indicating that these materials are slightly diamagnetic. This is in contrast to the COMP1 items, which have a small positive slope (0.0 264) and is classified as slightly paramagnetic. No statistical significance was observed for BIC2, BI All of the non-zero to statistically significant results were observed for C3 and YAS4 (p<0.04). ).

[0209] To support the MRI safety of BIC1, BIC2, and BIC3 microsphere formulations, To this end, the following issues are considered: (I) magnetically induced displacement torque, (II) magnetically induced displacement force, and (III) RF-induced tissue heating of tissue around the device.

[0210] Magnetically Induced Displacement Torque Medical devices are sensitive to the interaction of the device's magnetic moment with the primary static magnetic field of the MRI system. The torque may refer to the displacement force and / or torque resulting from the application of a certain The tendency in asymmetrically shaped devices to be magnetized in the The magnetized particles, such as the BIC and COMP1 microsphere formulations, are aligned with the direction of the main magnetic field. The microspheres are symmetrical in shape and have no ability to generate torque. It is calculated from the vector product of the magnetic moment (μ) and the main static MRI magnetic field (B0). and a metal oxide composed of transition metals such as the microsphere formulation of COMP1, which is a magnetic material Materials classified as such may exhibit either paramagnetic or diamagnetic properties. It has no magnetic moment until it is placed in an external magnetic field, and the induced magnetic moment is mainly They either align with the direction of the static magnetic field (paramagnetic) or completely oppose it (diamagnetic). MRI magnetic susceptibility ( 8) for suspensions of BIC1 to BIC3 and COMP1. The set point is just 0.0264 ppm (SI units) relative to the control microspheres themselves. It has been shown that it has a paramagnetic volume susceptibility (corrected for the effects of the suspending medium). The BIC1, BIC2, and BIC3 microspheres are each −0.0 relative to the microsphere itself. Slightly diamagnetic volume magnetic field of 0.074 ppm, -0.0119 ppm, and -0.019 ppm It was shown that the solubility of the suspending medium was significantly increased by 100%.

[0211] The magnetic moment of a diamagnetic material is (by definition) opposite to the main magnetic field, and so a torque (magnetic moment Since the vector product T = μ × B between the symmetry and the main magnetic field is zero, BIC1, BI There is no risk of particle torque for C2 or BIC3 microspheres. Nevertheless, The magnetic moment was approximately 1.0 nm for all samples tested, including the control microspheres. 0, so none of the microsphere formulations presents a risk of particle rotational torque.

[0212] Magnetically Induced Displacement Force Displacement forces pose a risk of inducing shock to the device into the MRI system (or inside the patient's body). This is caused by the magnetic moment of the device and the main static magnetic field of the MRI system passing through the space. This spatial gradient of the main magnetic field is typically calculated from the interaction with the rate of change of the magnetic field. The maximum value is near the entrance of the stem (entrance hole), and in a typical 3T clinical MRI system, Approximately 15 Tesla / M or less (e.g., GE Healthcare MR750 3T MRI, operation manual (14.7T / m as specified in the safety section of the manual).

[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)]. The material develops a magnetic moment only as a result of exposure to a strong magnetic field, and the applied magnetic field In contrast, the particles of BIC1, BIC2, and BIC3 are aligned in the same direction. Diamagnetic materials develop a magnetic moment only as a result of exposure to a strong magnetic field. Nevertheless, the forces induced in all microparticle formulations were , ppm order (μ=V*ΔX, V is the radiopaque MS volume), and Brownian motion ( small compared to the forces of particle dispersion and therefore do not present a risk to magnetically induced displacement forces stomach.

[0214] Radiofrequency (RF) heating of tissue Parmar et al., "Size-Dependent Heating Efficiency of Iron Oxide Single-Domain Nanoparticles," Procedia Engineeri 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) Magnetic heating from an RF magnetic field occurs due to the Neel mechanism (internal magnetic moment of the particle) (The ball is rotated by the applied RF magnetic field without rotating the particle) or Brow n mechanism (particles physically rotate under the influence of a rotating RF magnetic field that produces resistive heating) These mechanisms include magnetic mediated hyperthermia (MMH) and therapeutic responses. These particles are related to iron oxide nanoparticles for applications such as targeted cancer ablation. The device was tested under low temperature conditions (2°C to 4°C) only under conditions including RF magnetic fields of the order of 10 kA / M. It is possible to create a localized temperature rise.

[0215] In contrast, MRI systems have a peak RF 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 for MMH applications. In addition, superparamagnetic iron oxide (SPIO ) particles in the microsphere formulation (0.0264 ppm (COMP1) vs. 0.0074 ppm (B IC1), -0.0119ppm (BIC2), and -0.019ppm (BIC3) The magnetic moment of BIC1, BIC2, and BIC The microspheres in 3 are weakly paramagnetic / diamagnetic materials, so their magnetic heating ability is lower than that of SPIO agents. and can be ignored.

[0216] In addition, SPIO nanoparticles are FDA approved contrast agents (e.g., Ferridex); Although the formulations BIC1 to BIC3 are made of metal oxide particles, they also have magnetic properties. Even though the moment is much larger, the problems associated with RF heating do not occur. The RF heating capability of C particles is several orders of magnitude weaker than that of these SPIO agents. Due to its low magnetic moment, BIC particles pose no risk of tissue heating in an MRI environment. should not cause

[0217] In vitro cytotoxicity For in vitro cytotoxicity screening, experimental negative and positive controls were used. The viability of cells exposed to extracts of the analytical material was >70% and <70%, respectively. The validity of the method was confirmed. Formulations that met the test requirements had a mean variability of 70% or more compared to untreated controls. Table 8 shows the cell viability of each microsphere formulation before treatment at various dilution series. The cell viability results obtained are shown. [Table 8]

[0218] COMP1 showed no cytotoxicity and cell viability of 98-94%. Most of the TRCR microparticle formulations have been tested in stock with TRCR13 (48% cell viability). All other TRCR formulations were considered to have no cytotoxic potential, except for 1. The cell viability was 112% (undiluted). Regarding the formulation of BIC microspheres, Two of the three, namely BIC2 (100%-105%) and BIC3 (72%-103%), %) showed no cytotoxicity. The cell viability of BIC1 was 22% (undiluted) and 44% (50% dilution), indicating dose-dependent cytotoxicity.

[0219] In vitro genotoxicity For both COMP1 and untreated BIC2 microspheres, DMSO and saline were used. The background flora of the water test extract appeared normal. In the presence of the DMSO and saline test extracts The average number of revertants for the test strains TA98, TA100, and WP2uvrA was 2 There were no cases in which the number of mutants increased by more than 2-fold, and the number of revertants of the test strains TA1535 and TA1537 In no cases did the mean number of bacteria increase by more than three-fold. Historical data collected by the testing company shows a characteristic number of spontaneous revertants. The mean value of each positive control was 100% of the mean value of the negative control for each of the five test strains. The results were summarized in Table 9. Both DMSO and saline extracts of the microparticle formulations of BIC and S. typhimurium were Test strains TA98, TA100, TA1535, and TA1537, and E. coli test strain It was not considered to show mutagenicity against WP2uvrA. [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. The blood test shows that the in vitro cytotoxicity was normal after the cell exposure step when observed under magnification. The validity of the test method was confirmed by culture control cells that exhibited growth characteristics. The roll extract (undiluted) reduced the viability of the medium control to less than 70%. The negative control extract did not reduce the viability of the medium control to less than 70%. In summary, BIC2 microspheres treated for 24 and 27 hours were When tested at 2.5% to 50% versus undiluted solution (undiluted), it showed no cytotoxicity (i.e., cytotoxicity to cells) Cell viability (CV>70%), cell viability was 82%-84% and 88%-92%, respectively. The processing step was then extended to extraction for 72 ± 2 hours prior to MTT analysis. Therefore, the cell viability of BIC2 microspheres before treatment (0 hours) was 24±2 hours after extraction. in vitro cytotoxicity compared to It was confirmed that there was no adverse effect on

[0221] In vitro hemolysis (direct and indirect contact hemolysis) was performed with treated BIC2 microspheres and The hemolysis index was determined to be less than 2% different from the typical negative control under all test conditions. According to ASTM F756:2017, the hemolytic material A hemolysis rate of 0-2 indicates a nonhemolytic reaction, whereas a rate of 2-5 indicates mild lysis, whereas a rate of >5 indicates a reaction. It represents a hemolytic reaction. According to this hemolytic scoring system (Table 10): The processed BIC2 microparticles prepared using a mass / volume extraction ratio of 0.2 g / mL , which are considered non-hemolytic and treated for 24 to 72 hours, respectively (direct contact method) 0.29% to 0.29% when treated for 24 hours to 360 hours, respectively. The content (indirect contact method) is 0.00% to 0.00%. Processed BIC2 prepared with a surface area (SA) / volume extraction ratio of 0.2 g / mL The microparticles were also considered non-hemolytic and showed a 95% hemolytic activity when treated for 24 to 72 hours, respectively (direct Contact method) 0.00% to 0.00%. [Table 10]

[0222] The data presented in Table 10 are the BIC values ​​subjected to accelerated processing parameters (80°C for 24 hours). Although the microspheres in Fig. 2 show a clear lack of surface cleanliness as observed by SEM, No adverse effects on cytotoxicity (82%-92% after treatment vs. 100%-106% after spheronization) or hemolysis. Nonetheless, the 72-hour treatment window It was observed that the hemolysis rate measured by the direct contact method was significantly reduced to 0.29.

[0223] In the preceding description, for purposes of explanation, numerous details are set forth in order to provide a thorough understanding of the embodiments. However, it will be apparent to one skilled in the art that these specific details are not required. Therefore, what has been described is merely illustrative of the application of the described embodiments. Many modifications and variations are possible in light of the above teaching.

[0224] The above description provides examples, and modifications and variations may occur to particular examples by those of ordinary skill in the art. It is understood that the claims may be implemented in any manner whatsoever in accordance with the present specification. and should not be limited by the specific examples described in, and should be taken in accordance with the specification as a whole. should be interpreted in such a way that

Claims

1. A glass material, the glass comprising: About 0.55 to about 0.85 mole fraction of SiO ２ and, About 0.01 to about 0.23 mole fraction of Na ２ O.K. ２ O or Na ２ O and K ２ Mixture of O Things and about 0.05 to about 0.28 mole fraction of Y ２ O ３ , BaO, or Y ２ O ３ and BaO Things and Selectively, Ta ２ O ５ and The Y ２ O ３ , the BaO, and optionally the Ta ２ O ５ The sum of is about 0.10 to about 0 .31 mole fraction of a glass material.

2. The glass has about 0.03 to about 0.23 mole fraction of Na ２ O.K. ２ O or Na ２ O and BiK ２ 2. The glass material of claim 1 comprising a blend of O.

3. The glass has about 0.05 to about 0.23 mole fraction of Na ２ O.K. ２ O or Na ２ O and BiK ２ The glass material of claim 2 comprising a blend of O.

4. The glass has about 0.55 to about 0.82 mole fraction of SiO ２ The method according to any one of claims 1 to 3, 13. The glass material according to claim 1 .

5. The glass has about 0.55 to about 0.80 mole fraction of SiO ２ The composition of claim 4 comprising Glass material.

6. The glass is About 0.55 to about 0.80 mole fraction of SiO ２ and, About 0.05 to 0.22 mole fraction of Na ２ O.K. ２ O or Na ２ O and K ２ O. Formulation The glass material of claim 1 , comprising:

7. The Y ２ O ３ , the BaO, and optionally the Ta ２ O ５ The sum of about 0.10 to about 0 0.25 mole fraction, for example, about 0.10 to about 0.15 mole fraction.

1. The glass material according to claim 1.

8. The glass may have a mole fraction of about 0.05 to about 0.12, for example about 0.05 to about 0.

08. Y ２ O ３ , BaO, or Y ２ O ３ and BaO. Item 1. The glass material according to item 1.

9. The glass may contain Ta in an amount up to about 0.12 mole fraction, e.g., up to about 0.10 mole fraction. ２ O ５ The glass material according to any one of claims 1 to 8, comprising:

10. The glass may have a mole fraction of about 0.05 to about 0.12, for example about 0.05 to about 0.

10. Ta fraction ２ O ５ The glass material of claim 9 , comprising:

11. The glass further comprises up to 0.20 mole fraction of B. ２ O ３ Claims 1 to 10 13. The glass material according to claim 12 .

12. B ２ O ３ and the SiO ２ The sum of about 0.60 to about 0.85, for example, about 0.6 The glass material of claim 11 having a mole fraction of 0 to about 0.

80.

13. The glass contains BaO and Na ２ O, and the BaO and the Na ２ The total of O is about 0.10 to about 0.33 mole fraction, for example, about 0.15 to about 0.33 mole fraction. Item 13. The glass material according to any one of items 1 to 12.

14. The BaO and the Na ２ The total of O is about 0.10 to about 0.25 mole fraction, for example about The glass material of claim 13 having a mole fraction of 0.15 to about 0.

25.

15. The SiO ２ and the Na ２ The sum of O is about 0.65 to about 0.90 mole fraction. The glass material according to any one of claims 1 to 14.

16. The SiO ２ and the Na ２ the sum of O is from about 0.69 to about 0.90 mole fraction; The glass has about 0.05 to about 0.09 mole fraction of Ta. ２ O ５ and The Y ２ O ３ , the BaO, and the Ta ２ O ５ The total is about 0.10 to about 0.17 mo The glass material of claim 6, wherein the solubility is 1.0% by mass.

17. The SiO ２ and the Na ２ the sum of O is from about 0.65 to about 0.80 mole fraction; The glass has about 0.05 to about 0.10 mole fraction of Ta. ２ O ５ and The Y ２ O ３ and the BaO and the Ta ２ O ５ The sum of about 0.18 to about 0.31 The glass material of claim 6, wherein the molar fraction is

18. About 0.55 to about 0.82 mole fraction, for example, about 0.55 to 0.75 mole fraction of SiO ２ ； About 0.03 to about 0.23 mole fraction, for example, about 0.05 to about 0.22 mole fraction of Na ２ O; about 0.05 to about 0.12 mole fraction, for example, about 0.05 to about 0.08 mole fraction of Y ２ O ３ , BaO, or Y ２ O ３ and BaO; and About 0.05 to about 0.12 mole fraction, for example, about 0.05 to about 0.09 mole fraction of Ta ２ O ５ Including, The glass material according to claim 1 .

19. About 0.70 to about 0.73 mole fraction of SiO ２ ; About 0.16 to about 0.18 mole fraction of Na ２ O; about 0.05 to about 0.7 mole fraction of Y ２ O ３ and About 0.05 to about 0.7 mole fraction of Ta ２ O ５ Including, 19. The glass material of claim 18.

20. About 0.71 mole fraction of SiO ２ ; About 0.17 mole fraction of Na ２ O; About 0.06 mole fraction of Y ２ O ３ and About 0.06 mole fraction of Ta ２ O ５ Including, 20. The glass material of claim 19.

21. About 0.72 mole fraction of SiO ２ ; About 0.17 mole fraction of Na ２ O; About 0.05 mole fraction of Y ２ O ３ and About 0.06 mole fraction of Ta ２ O ５ Including, 20. The glass material of claim 19.

22. In addition, up to 0.1 mole fraction of B ２ O ３ 20. The glass material of claim 18, comprising:

23. About 0.65 to about 0.82 mole fraction, for example, about 0.73 to about 0.80 mole fraction of SiO ２ ； About 0.03 to about 0.23 mole fraction, for example, about 0.03 to about 0.11 mole fraction of Na ２ O; About 0.06 to about 0.12 mole fraction, for example, about 0.07 to about 0.10 mole fraction of BaO ； About 0.06 to about 0.12 mole fraction, for example, about 0.07 to about 0.10 mole fraction of Ta ２ O ５ and From about 0.001 to about 0.015 mole fraction, for example, from about 0.001 to about 0.006 mole fraction B ２ O ３ Including, 23. The glass material of claim 22.

24. About 0.69 mole fraction of SiO ２ ; About 0.16 mole fraction of Na ２ O; About 0.07 mole fraction of BaO; About 0.07 mole fraction of Ta ２ O ５ and About 0.012 mole fraction of B ２ O ３ Including, 24. The glass material of claim 23.

25. About 0.66 mole fraction of SiO ２ ; About 0.20 mole fraction of Na ２ O; About 0.065 mole fraction of BaO; About 0.06 mole fraction of Ta ２ O ５ and About 0.011 mole fraction of B ２ O ３ Including, 24. The glass material of claim 23.

26. About 0.73 mole fraction of SiO ２ ; About 0.11 mole fraction of Na ２ O; About 0.07 mole fraction of BaO; About 0.07 mole fraction of Ta ２ O ５ ; And, About 0.011 mole fraction of B ２ O ３ Including, 24. The glass material of claim 23.

27. About 0.74 mole fraction of SiO ２ ; About 0.09 mole fraction of Na ２ O; About 0.085 mole fraction of BaO; About 0.085 mole fraction of Ta ２ O ５ and About 0.006 mole fraction of B ２ O ３ Including, 24. The glass material of claim 23.

28. About 0.79 mole fraction of SiO ２ ; About 0.06 mole fraction of Na ２ O; About 0.08 mole fraction of BaO; About 0.07 mole fraction of Ta ２ O ５ and About 0.003 mole fraction of B ２ O ３ Including, 24. The glass material of claim 23.

29. About 0.77 mole fraction of SiO ２ ; About 0.031 mole fraction of Na ２ O; About 0.10 mole fraction of BaO; About 0.096 mole fraction of Ta ２ O ５ and About 0.002 mole fraction of B ２ O ３ Including, 24. The glass material of claim 23.

30. About 0.80 mole fraction of SiO ２ ; About 0.033 mole fraction of Na ２ O; About 0.082 mole fraction of BaO; About 0.085 mole fraction of Ta ２ O ５ and About 0.001 mole fraction of B ２ O ３ Including, 24. The glass material of claim 23.

31. About 0.58 mole fraction of SiO ２ ; About 0.20 mole fraction of Na ２ O; About 0.06 mole fraction of Y ２ O ３ and BaO blends; About 0.07 mole fraction of Ta ２ O ５ and About 0.09 mole fraction of B ２ O ３ Including, 23. The glass material of claim 22.

32. About 0.024 mole fraction of Y ２ O ３ and about 0.035 mole fraction BaO.

2. The glass material according to claim 1.

33. Li ２ O, Rb ２ O.V. ２ O ５ , ZnO, Fe ２ O, and one or more of fluoride are substantially The glass material according to any one of claims 1 to 32, which does not contain

34. The glass material according to any one of claims 1 to 33, wherein the glass material is bulk glass. Material.

35. 34. The glass material according to claim 1, wherein the glass material is an irregular particulate glass material. The glass material according to claim 1.

36. 3. The particulate glass material has an average diameter of about 15 μm to about 1200 μm.

6. The glass material according to claim 5.

37. The glass material has a CT radiation of 9,000 Hounsfield units or more at 120 kVp. A glass material according to any one of claims 1 to 36, which exhibits radiopacity.

38. The density of the glass material is about 2.7 g / cm ３ ~Approx. 4.3g / cm ３ , for example, about 2. 9 g / cm ３ ~Approx. 3.7g / cm ３ , or about 3.3 g / cm ３ ~Approx. 3.5g / cm ３ Yes The glass material according to any one of claims 1 to 37.

39. 1. A particulate glass material, comprising:

37. A substantially uniform glass spheronization resultant from the irregular particulate glass material according to claim 35 or 36. A particulate glass material that is spherical in shape.

40. The irregular particulate glass material is spheroidized by heating the surface of the irregular particulate glass material.

40. The method of claim 39, further comprising remelting in a flame to form substantially spherical particles. Las material.

41. The substantially spherical particulate glass material is obtained by processing the substantially spherical particles. The calcium and magnesium-free phosphate buffered saline solution is used for example. A solution of CMF in saline (CMF-PBS) was used. The CMF-PBS solution had a concentration of 0.2 g / mL. The flame-treated particulate glass material is treated in a solution containing 41. The particulate glass material of claim 40,

42. 42. The particulate gas according to claim 41, wherein the treatment is at 80° C. for at least 12 hours. Las material.

43. The particulate glass material is substantially spherical, as compared to the flame-treated particulate glass material.

43. The method of claim 41 or 42, wherein the amount of spheronization reaction products is reduced. Material.

44. Any of claims 1 to 33, wherein the glass material is a substantially spherical particulate glass material.

1. The glass material according to claim 1.

45. 3. The particulate glass material has an average diameter of about 15 μm to about 1200 μm.

9. The particulate glass material according to any one of claims 9 to 44.

46. The particulate glass material may be from about 15 μm to about 1200 μm, for example, from about 15 μm to about 35 μm, about 40 μm to about 500 μm, about 40 μm to about 300 μm, about 300 μm to about 500 500 μm to about 700 μm, or about 700 μm to about 1200 μm.

46. ​​The particulate glass material of claim 45.

47. The glass material has a CT radiation of 9,000 Hounsfield units or more at 120 kVp.

47. The particulate glass material according to any one of claims 39 to 46, which exhibits radiopacity.

48. Radiation imaging, computed tomography (CT) imaging, cone beam CT imaging The present invention relates to a method for detecting a tumor, comprising: The particulate glass material described herein.

49. The glass material is suitable for use in positron emission tomography (PET), single photon emission computed tomography (SPE), and CT), magnetic resonance imaging (MRI), or any combination thereof. Item 49. The particulate glass material according to item 48.

50. The particulate glass material according to any one of claims 39 to 47 is delivered intra-arterially or intravenously. and administering to the mammal by Radiation imaging, computed tomography (CT) imaging, cone beam CT imaging and detecting the presence or absence of a tumor in the mammal, e.g., by imaging, fluoroscopy, or fluoroscopic imaging. A method comprising imaging the liver.

51. 51. The method of claim 50, wherein the mammal is a human.

52. The method comprises providing at least about 750 particles of the particulate glass material per gram of liver, e.g. administering about 1,000 to about 5,000 particles of said particulate glass material per gram of liver.

52. The method of claim 50 or 51, comprising:

53. The method comprises administering to a human about 1,000,000 to about 7,000,000 particles of the microparticles.

53. The method of claim 52, comprising dispensing a glass material.

54. 5. The method of claim 50, further comprising intra-arterial delivery of the particulate glass material to the hepatic artery.

3. The method according to any one of claims 2 to 3.

55. Radiation imaging, computed tomography (CT) of a mammal, e.g., the liver of said mammal. T) Imaging, cone beam CT imaging, or fluoroscopic imaging Use of the particulate glass material according to any one of claims 39 to 47 for imaging. 。

56. The particulate glass material is at least 750 particles per gram of liver. For example, about 1,000 to 5,000 particles of the particulate glass material per gram of liver.

56. The method according to claim 55 for imaging the liver of a mammal, Use of the above.

57. A particulate glass material according to any one of claims 39 to 47, and radioactive glass particulates. A mixture of The particulate glass material and the radioactive glass particulates are substantially the same size. Compound.

58. The difference in average size between the particulate glass material and the radioactive glass particulates is 58. The mixture of claim 57, wherein the average size is within 40% of the average.

59. The difference in average size between the particulate glass material and the radioactive glass particulates is 58. The mixture of claim 57, wherein the average size is within 10% of the average.

60. The particulate glass material and the radioactive glass particulate have substantially the same density.

60. The mixture according to any one of claims 57 to 59.

61. The difference in average size between the particulate glass material and the radioactive glass particulates is 61. The method of claim 60, which is within 30% of the average of the average size, preferably within 15%. A mixture of.

62. The particulate glass material is About 0.65 to about 0.82 mole fraction, for example, about 0.73 to about 0.80 mole fraction of SiO ２ 、 About 0.03 to about 0.23 mole fraction, for example, about 0.03 to about 0.11 mole fraction of Na ２ O. About 0.06 to about 0.12 mole fraction, for example, about 0.07 to about 0.10 mole fraction of BaO 、 About 0.06 to about 0.12 mole fraction, for example, about 0.07 to about 0.10 mole fraction of Ta ２ O ５ , and From about 0.001 to about 0.015 mole fraction, for example, from about 0.001 to about 0.006 mole fraction B ２ O ３ , The mixture according to any one of claims 57 to 61, comprising a glass having the formula:

63. The radioactive glass particles are preferably yttrium oxide aluminosilicate glass. About 40% by weight of SiO ２ , about 20% by weight of Al ２ O ３ and about 40% by weight of Y ２ O ３ The mixture according to any one of claims 57 to 62, comprising:

64. 64. The radioactive glass microparticle according to any one of claims 57 to 63, wherein the radioactive glass microparticle is substantially spherical. The mixture described.

65. The particulate glass material is About 0.73 to about 0.80 mole fraction of SiO ２ , About 0.03 to about 0.11 mole fraction of Na ２ O. From about 0.07 to about 0.10 mole fraction of BaO; About 0.07 to about 0.10 mole fraction of Ta ２ O ５ , and About 0.001 to about 0.006 mole fraction of B ２ O ３ The glass includes a glass having The radioactive glass particles are substantially spherical yttrium oxide aluminosilicate glass particles. The particles are about 40% by mass of SiO ２ , about 20% by weight of Al ２ O ３ and about 40% by weight Y ２ O ３ The mixture according to any one of claims 57 to 64, comprising:

66. 1. A method of delivering radiation to a mammal, comprising: The method comprises intra-arterially or intravenously delivering a mixture according to any one of claims 57 to 65. administering to the mammal by

67. Radiography, computed tomography (CT), cone-beam CT, or fluoroscopy imaging the mammal, e.g., the liver of the mammal. Item 67. The method according to item 66.

68. 68. The method of claim 67, further comprising calculating an absorbed dose of radiation to the cells.

69. A mixture according to any one of claims 57 to 65 for the delivery of radiation to a mammal. Use, The mixture is formulated for intravenous or intraarterial infusion into the mammal. For.

70. (i) radioactive particles, and (ii) the glass material according to any one of claims 1 to 33.

1. A therapeutic or diagnostic composition comprising a mixture of non-radioactive microparticles containing a radioactive material.

71. The radioactive particles and the non-radioactive particles have a difference in particle density, and the difference is 71. The combination of claim 70, wherein the density of the particles is within 30%, preferably within 15%, of the average of the density of the particles. Composition.

72. The radioactive microparticles have an average diameter of about 10 to about 1200 microns, for example, about 20 to about 4 0 microns average diameter, The non-radioactive microparticles have an average size of about 10 to about 1200 microns, for example about 20 to about 1000 microns.

72. The composition of claim 70 or 71, having an average diameter of about 40 microns.

73. The radioactive and non-radioactive particles have a difference in average size, A composition according to any one of claims 70 to 72, which is within 40% of two average sizes. 。

74. The radioactive particles and the non-radioactive particles flow through a conduit in a liquid, and are substantially The composition of any one of claims 70 to 73, having substantially the same resistance.

75. The radioactive microparticles comprise from about 10% to about 80% of the total mass of the microparticles in the composition, e.g. The composition according to any one of claims 70 to 74, comprising, for example, about 25%.

76. The radioactive microparticles according to any one of claims 70 to 75, wherein the radioactive microparticles are diagnostic radioactive microparticles. The composition described.

77. The radioactive microparticles according to any one of claims 70 to 75, wherein the radioactive microparticles are therapeutic radioactive microparticles. The composition described.

78. The radioactive particles are copper-67, holmium-166, indium-111, iodine- 131, lutetium-177, molybdenum-99, phosphorus-32, rubidium-82, tech One or more radioisotopes selected from the group consisting of netium-99m and thallium-201 77. The composition of claim 76, comprising a body.

79. The radioactive particles include actinium-225, bismuth-213, copper-67, indium Mu-111, Iodine-131, Iodine-125, Gadolinium-157, Holmium-16 6. Lead-212, Lutetium-177, Palladium-103, Phosphorus-32, Radium-2 23. Rhenium-186, Rhenium-188, Samarium-153, Strontium-8 9, and one or more radioisotopes selected from the group consisting of tungsten-188; 78. The composition of claim 77.

80. The radioactive particles are about 40% by mass of Y ２ O ３ , about 20% by weight of Al ２ O ３ , and about 4 0% by weight of SiO ２ At least a portion of the yttrium is yttrium-90. The composition according to any one of claims 70 to 75.

81. The non-radioactive microparticles include a glass material according to any one of claims 18 to 33. The composition according to any one of claims 70 to 80.

82. One or both of the radioactive and non-radioactive microparticles are substantially spherical. The composition according to any one of claims 70 to 81.

83. Administering to a patient a composition according to any one of claims 70 to 82, The method, wherein the administration is by intra-arterial, intraperitoneal, or transdermal delivery.

84. Intravascular, intraperitoneal, or intraperitoneal delivery of a mixture of radioactive and non-radioactive microparticles to a patient.

1. A delivery device for dermal delivery, comprising: the delivery device is fluidly connectable to a mixed transport medium; The delivery device comprises: a fluid inlet for fluidly coupling to the mixed transport medium; A fluid outlet; a fluid mixer fluidly coupled to the fluid inlet and the fluid outlet; a radioactive particle source fluidly coupled to the fluid mixer; a non-radioactive particulate source fluidly coupled to the fluid mixer; The non-radioactive microparticles include a glass material according to any one of claims 1 to 33, said radioactive particulate source being distinct from said non-radioactive particulate source; The fluid mixer mixes the radioactive particles with the non-radioactive particles to produce radioactive and non-radioactive particles. and delivering said mixture of projectile particles out of said fluid outlet using said mixed transport medium. Reach device.

85. The mixture of radioactive and non-radioactive microparticles is delivered intravascularly, intraperitoneally, or intraperitoneally to the patient.

1. A delivery device for dermal delivery, comprising: The delivery device comprises: at least one fluid inlet fluidly connectable to a transport medium; a radioactive particulate source fluidly coupled to the at least one fluid inlet; a non-radioactive particulate source fluidly coupled to the at least one fluid inlet, The non-radioactive microparticles include the glass material according to any one of claims 1 to 33. A particulate source; a first fluid outlet fluidly coupled to the source of radioactive particles; a second fluid outlet fluidly coupled to the non-radioactive particulate source; The radioactive particulate source is distinct from the non-radioactive particulate source. vinegar.

86. The delivery device delivers the radioactive microparticles and the non-radioactive microparticles in a single treatment session.

86. The delivery device of claim 85, which delivers a polymeric microparticle.

87. 87. The method of claim 85 or 86, wherein the first fluid outlet and the second fluid outlet are adjacent to each other. The delivery device according to claim 1 .

88. (i) a first collection of radioactive particles; and (ii) a second collection of non-radioactive particles. a second population of non-radioactive particles comprising the glass material according to any one of claims 1 to 33; and mixing the body with administering to a patient an appropriate amount of said mixture for therapeutic or diagnostic purposes.

89. The radioactive particles comprise from about 10% to about 80% of the total mass of particles in the mixture, e.g.

89. The method of claim 88, wherein the amount of the stimulant comprises, for example, about 25%.

90. 88. The method of claim 87, wherein the administration is by intravascular, intraperitoneal, or transdermal delivery. The method according to claim 89.

91. 1. A method for administering to a patient a suitable amount of microparticles for therapeutic or diagnostic purposes, the method comprising: Non-radioactive particles containing the glass material according to any one of claims 1 to 33 are administered to the patient. Administering administering radioactive particles to the patient without first detecting the non-radioactive particles; Prepared with the means, the administration is by intravascular, intraperitoneal, or transdermal delivery; The method, wherein the route of administration of said non-radioactive microparticles is the same as the route of administration of said radioactive microparticles.

92. 92. The method of claim 91, comprising administering the non-radioactive microparticles and the radioactive microparticles simultaneously. The method described above.

93. 91. The method of claim 91, comprising sequential administration of the non-radioactive microparticles and the radioactive microparticles. The method described above.

94. 1. A method for administering to a patient a suitable amount of microparticles for therapeutic or diagnostic purposes, the method comprising: administering radioactive particles to the patient; The method according to any one of claims 1 to 33, without first detecting the radioactive particles. administering to the patient non-radioactive particles comprising a glass material; the administration is by intravascular, intraperitoneal, or transdermal delivery; The method, wherein the route of administration of said non-radioactive microparticles is the same as the route of administration of said radioactive microparticles.

95. 95. The method of claim 94, wherein the method comprises co-administration of the radioactive and non-radioactive microparticles. The method according to

96. 95. The method of claim 94, wherein the method comprises sequential administration of the radioactive and non-radioactive microparticles. The method according to

97. 1. A method for administering a suitable amount of microparticles for therapeutic or diagnostic purposes, the method comprising: (i) a first collection of radioactive particles and (ii) a second collection of non-radioactive particles. With continuous administration to The second aggregate of non-radioactive particles is a glass according to any one of claims 1 to 33. Methods, including materials.

98. The first population of radioactive particles is distinguished from the second population of non-radioactive particles.

98. The method of claim 97,

99. The first collection of radioactive particles and the second collection of non-radioactive particles are mixed together to form a mixture.

99. The method of claim 98, wherein the administration is

100. 1. A method for administering a suitable amount of microparticles for therapeutic or diagnostic purposes, the method comprising: Non-radioactive particles and radioactive particles comprising the glass material according to any one of claims 1 to 33. The method comprises sequential administration of particles to a patient in a single treatment session.

101. (i) therapeutic radioactive particles, then (ii) non-radioactive microparticles comprising the glass material according to any one of claims 1 to 33, The method comprises continuous administration to the patient.

102. The continuous administration comprises intermittent administration of the non-radioactive microparticles and the radioactive microparticles. 93, 96, 100, or 101.

103. The intermittent administration comprises alternating administration of the non-radioactive and the radioactive microparticles.

102. The method according to claim 102.

104. The sequential administration may be administration of all of the non-radioactive microparticles prior to administration of any of the radioactive microparticles.

101. The method of claim 93 or 100, comprising administration of:

105. The sequential administration may include administration of all of the radioactive microparticles prior to administration of any of the non-radioactive microparticles.

102. The method of claim 96 or 101, comprising administration of:

106. The method of any one of claims 88 to 104, further comprising delivering a therapeutically appropriate amount of radiation to the patient.

13. The method according to any one of claims 1 to 12.

107. 9. The method of claim 8, wherein the non-radioactive microparticles are delivered to the patient in a diagnostically suitable amount.

8. The method according to any one of claims 8 to 105.

108. The administration is by intravascular, intraperitoneal, or transdermal delivery.

107. The method according to any one of claims 107.

109. About 10% to about 80%, e.g., about 25%, of the total mass of the delivered microparticles is radioactive microparticles. The method according to any one of claims 88 to 108, wherein

110. The radioactive particles and the non-radioactive particles flow through a conduit in a liquid, and are substantially and / or The radioactive microparticles and the non-radioactive microparticles are compatible with vascular embolization. A mixture according to any one of claims 57 to 65, a mixture according to any one of claims 70 to 82 The composition according to claim 84, the delivery device according to claim 8 or the delivery device according to claim 8 3 and the method according to any one of claims 88 to 109.

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